NO750175L - - Google Patents

Description

Procedure© for the preparation of indane derivatives.

The present invention relates to a method for the production of new indan derivatives, with particular application as medicines.

The invention relates more particularly to a method for the production of indan derivatives with the formula:

where in

X denotes a hydrogen atom or a halogen atom,

R^ and Hg, which may be the same or different, denote a lower alkyl group (C^-C,,) or a cycloalkyl group (C^-C^), at least one of the groups and Rg may be a hydrogen atom,

denotes a hydrogen atom or a lower alkyl group (C^-C^),

Y denotes a radical -CHgOH or the radical -COOR^ where R^ denotes a hydrogen atom, the group M l/v where M denotes a metal and v is the valence of the metal, or the group

where n denotes an integer from 1 to 5" and R^ and R^, the same or different, denote a hydrogen atom, a lower alkyl group (C^-C^), a cycloalkyl group (C^-C^), an aryl group or a aralkyl group, and where R[- and R^ together and together with the nitrogen atom to which they are bound can form an N-heterocyclic group with 5 or 7 ring members which may optionally contain a second heteroatom and optionally be substituted,

and where the method for producing these compounds consists in man0

a) converts an indan with formula:

where R^, Rg and X have the same meaning as above,

with an ethyloxalyl halide of formula CgHj. Z CO C00 where Z denotes a halogen atom, preferably chlorine, after which, by alkaline or acid hydrolysis, the produced keto ester is converted into a keto acid with the formula:

which compound of formula VI:

b) undergoes a ttolff-Kishner reduction to produce a product of formula (i) where Y = COOR^and R^and R. is

hydrogen atoms, or

c) reacting the product of formula (Vi) with an organomagnesium compound of formula R^MgZ, where Z represents a halogen atom, followed by a dehydration and a hydrogenation to produce a product of formula (i) where Y = -COOR^and R ss alkyl (C 1 -C 1 )

and Rj^ denotes a hydrogen atom,

d) then, if necessary, reduces the product produced under b) or c) with a reducing agent in an organic solvent,

or reduces the alkyl ester of this acid prepared in a known manner

by esterification and where the alkyl radical has 1 to 4 c atoms, to produce an alcohol of formula (i) where Y = CHgOH.

Step b) can be carried out by treating the ketone of formula (Vi) with hydrazine in a solution of sodium or potassium hydroxide.

In step d), aluminum hydride or lithium hydride can be used as a reducing agent and as an organic solvent

ether or tetrahydrofuran.

According to the invention, the term lower alkyl group means a hydrocarbon chain comprising 1 to 5 carbon atoms, linear or branched. Cycloalkyl groups comprise 3 to 7 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, wherein cyclohexyl is the preferred cycloalkyl group.

The preferred M group is a metal from group I, II or III of the periodic table, in particular sodium, potassium, calcium or aluminium.

Among N-heterocyclic groups that are relevant, mention is made in particular: - pyrrolidino, morpholino, thiomorpholino, 3f5-dimethyl-morpholino, piperidino, k • -methylpiperidino, piperazino, 4-(|3-hydroxyethyl)-piperazino, 4-p- chlorophenylpiperazino, azeplno,

- eryl,

- aralkyl, G-phenethyl, {3-phenethyl, benzyl.

The invention also relates to the preparation of addition salts of compounds of formula (i), in otherwise known manner, when Y = COOR^, i.e. addition salts with amines when R^= H and acid addition salts or quaternary ammonium salts when R^ is equal to -(CHg^ - NR^L^.

The acid addition salts when R^= (CH,,)n - W R^R^ are prepared by reaction with a mineral or organic acid in an otherwise known manner.

Among the acids that can be used for this purpose, mention is made in particular of hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, succinic acid, methanesulfonic acid, cyclohexylsulfamic acid, formic acid, aspartic acid, glutamic acid, N-acetylaspartic acid, N-acetylglutamic acid, ascorbic acid, maleic acid, malic acid, fumaric acid , lactic acid, benzoic acid, cinnamic acid, p-1 oleinsulfonic acid.

The general method above for the preparation of derivatives of formula (i) is the method provided according to the invention.

However, compounds of formula (i) can also be prepared in various other analogous ways using known principles which give products of the same class, mainly using as starting material an indan of formula

where R^tRg and X have the above meanings.

The invention further relates to a method e) for the production of products with formula (i) where Y is equal to -CGOR^ and R^

denotes

characterized by converting an acid of formula (i), produced by a method according to the invention, and its halide, and where the halide is reacted with an amino alcohol of formula:

where n, Rj. and R^ have the previously indicated meanings.

According to a variant f), the invention also proposes a method for producing compounds

with formula (i) where Y is COOR^and R. denotes

which is characterized by forming a salt of an acid with formula (i) prepared according to the invention and that the prepared salt is reacted with a halide of formula: where Z denotes a halogen atom and n, R,, and R^ have the same meaning as previously indicated . Steps a), b), c) in the method according to the invention are illustrated by the form below, steps e) and f) in the following form II.

Step a) is advantageously carried out by the action of ethyl oxalyl chloride on a starting material of formula (II), in a solvent such as ethylene chloride and preferably with a Lerøis acid which

Step c) is carried out in a known manner with a Grignard reagent 1 ether, for the production of product (VII), which is then dehydrated with a strong acid such as sulfuric acid to produce a product of formula (VII) which is hydrogenated with the aid of e.g. a Ranye-nickel catalyst.

The new compounds which can be prepared according to the method of the invention have pharmacologically interesting effects and can be used as therapeutic agents, in particular as analgesics and anti-inflammatory drugs. In particular, compounds according to the invention can e.g. are used as rheumatism-suppressing anti-inflammatory agents.

One can thus prepare therapeutic compounds which are particularly useful for the treatment of rheumatic inflammations and pains by mixing an effective amount of at least one compound of formula (i) or one of the non-toxic addition salts with a physiological mixing medium.

Products of formula (i) can be administered to humans as capsules containing 50 to 250 mg of active substance in a dose of 2 to 6 capsules per day. day, as suppositories containing 100 to 500 mg of active substance in daily doses of 2 to 5 suppositories per day, as drinkable suspensions containing 25 mg of active substance per 5 cm in a daily dose of 10 to ho cm, and as injectable solutions containing 50 mg of active substance per 2 ml of solution, in daily doses of two to four injections.

Products of formula (i) have a DL^q in rats of approx. 250 mg/kg orally, has little tumor-forming effect and has a better ratio between activity and toxicity than known substances with similar pharmacological properties.

The invention is illustrated in the following by non-limiting synthesis examples.

Example 1.

3-Dimethyl-5-indanyl-7-ethylglyoxalate.

Formula V Ri = R 2 CH 3 X H

A solution of 78 g of 1,3-dim«tyli»clan and 83.5 g of ethyl oxalyl chloride in 300 ml of methylene chloride is added over the course of 1 hour to a stirred suspension of 125 g of aluminum chloride in 300 ml of methylene chloride while cooling so that the mixture temperature remains below 5°. The mixture is then stirred for 2 hours at room temperature and poured onto 2 kg of ice and acidified to pH 3 with hydrochloric acid. The methylene chloride phase is separated and the mother liquor is extracted with methylene chloride. The methylene chloride phases are combined, washed with saturated sodium chloride solution and dried over sodium sulfate. After evaporation of the solvent, one has 119 g/l,3-dimethyl-5-indanyl 7©ethylglyoxalate as an oil which is used crude for the next step.

Example 2.

/ Tl. 3- dimethyl& »5- indanyl27-glyoxyl8yre.

Formula VI ^ = R2m CH^X = H

A resolution of 119 g /X1! 3-<iin»ethyl)-5indanyl7-ethyl glyoxylate in 600 ml of ethanol is treated with a solution of 20.5 g of caustic soda in 600 ml of water and heated at reflux for 2 hours. The mixture is then cooled, diluted with 300 ral of water and acidified at 0°C with 10% hydrochloric acid. The mixture is extracted with chloroform and washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. After distillation in vacuum of the residue formed, 77 g of 3-methyl-5-indanyl-7-glyoxylic acid are isolated.

K.p.. _ mm TT_ ss 170^C.

1.5 mm Hg

Example 3.

£\ 1,3-diethyl)-5-indanyl-7-acetic acid.

Formula I R1~R2=CH3R3=RkX~H

A mixture of 12 g of 3-dimethyl)-5-indanyl-7-glyoxylic acid and 25 ml of hydrazine hydrate is heated at reflux for 30 minutes. The mixture is cooled to 70°C and 15 g of potassium hydroxide in pastille form is added in small portions. After the addition, the mixture is heated \\ hour by reflux, after which the excess of hydrazine hydrate is evaporated in vai-aura. The solution is cooled and acidified at 0°C with 10% hydrochloric acid. The precipitate is filtered off, washed with water and dried. After recrystallization from toluene, 7.7 g of (T1» 3-<iiia©tyl)-5-iiidanyl7-acetic acid is obtained as white crystals, m.p. 116-117°C.

t Example 4. ^T6-kl°r-1» 3-dimethyl)-5-indanyl7-ethylglyoxalate

Formula V BJ3H 2 = CH^X s Cl

In the same way as in example 1 but with 50 g of 1,3-dimethyl-6-chloro-indane and 3 g of ethyloxalyl chloride, 80 g of chloro-1,3-dimethyl)-5-indanyl-7-ethylglyoxalate is obtained as an oil, and this is used further without purification.

Example 5.

^X^-chloro-1,3-dimethyl)-5-indanyl-7-glyoxylic acid

Formula VI R±a R2 = CH^X = Cl

In the same way as in example 2, but from 80 g of ((6-chloro-1,3-dimethyl)-5-indanyl)-ethylglyoxylate, 6l g of ((X6-chloro-1,3-diethyl)-5-indanyl) are obtained -glyoxylic acid as pale yellow crystals.

Sm.p. 170 - 173°C.

Example 6.

(X^-Chloro-1,3-dimethyl)-5-indanyl-7-acetic acid

Formula I a Rg a CH^X Cl

R3Rkm H

In the same way as in example 3, but from 20 g of acid (((6-chloro-1,3-dimethyl)-5-indanyl-7-glyoxylic acid, 10.5 g of (6-chloro-1,3-dimethyl)-5-indanyl-7-glyoxylic acid is obtained after recrystallization from toluene) )-5-indanyl7-acetic acid as white crystals, m.p. 158-160°C.

Example 7.

X2isopropyl-2)indanyl-57-glyoxalate-ethyl.

In the same way as in example 1, but with 43 g of 2-iso-propyl-indane and 42.2 g of ethyl oxalyl chloride, 69 g of ((X2-isopropyl)-5-indanyl-7-ethylglyoxalate is obtained as an oil which is further used in raw state.

Example 8.

^X2-isopropyl)-5-indanyl7-2-glyoxylic acid

In the same way as in example 2, but from 69 g of ((T2-isopropyl)-5-indanyl7-ethylglyoxalate, 58 g of (X2-isopropyl)-5-indanyl7-2-glyoxylic acid are obtained as yellow crystals, recrystallized from a mixture of hexane - cyclohexane 50/50, m.p. 55-60°C.

Example 9.

((X2-isopropyl)-5-indanyl7-acetic acid

In the same way as in example 3, but from 20 g of isopropyl)-5-indanyl-7-glyoxylic acid, after recrystallization from hexane, 11 g of (t2-isopropyl)-5-indanyl-7-acetic acid are obtained as white crystals. Sm.p. 80-81°C.

Example 10.

/X1-cyclohexyl)-5-indanyl7-ethylglyoxalate

In the same way as in example 1, but from 70 g of 1-cyclohexyl-indane and 54.6 g of ethyloxalyl chloride, 110 g of ((X1-cyclohexyl)-5-indanyl-7-ethylglyoxalate is obtained as an oil which is further used in the crude state.

Example 11.

/X1-cyclohexyl)-5-indanyl7-glyoxylic acid

In the same way as in example 2, but from 110 g of /Xl-cyclohexyl)-5-indanyl7-ethylglyoxalate, 90 g of /Xi-cyclohexylJ-S-indanyl7-glyoxylic acid are obtained in the form of an oil which is further used in the crude state.

Example 12.

/Xl"*cyclohexyl)-5-indanyl-7-acetic acid.

As described in example 3, but from 30 g of ((X1-cyclohexyl)-5-indanyl)-glyoxylic acid, after recrystallization from pentane, 15.9 g of (((11-cyclohexyl)-5-indanyl)-acetic acid is obtained in the form of white crystals, m.p. 75-78°C.

Example 13»

2-Hydroxy-2-methyl-(3-dimethyl)-5-indanyl-7-acetic acid.

A Grignard reagent is prepared from 34.2 g of magnesium in 75 ml of ether and 105 tal of methyl iodide in 200 ml of ether is added dropwise to a cooled solution in an ice bath containing 65*5 g of ^Tl»3-dimethyl)-5-indanyl7-glyoxylic acid in 900 ml of ether. The addition takes 1 hour. The reaction mixture is then stirred at room temperature for 2 hours and poured into 2 kg of ice and acidified with 10% hydrochloric acid. It is extracted with ethyl acetate, which is washed with water and dried. After evaporation of the solvent, 53 g of 2-hydroxy-2-methyl((1,3-dimethyl)-5-indanyl-7-acetic acid is obtained, which is used in the crude state for the following reactions.

Example 14.

2-methylene/X11 3-dimethyl)-5-indanyl-7-acetic acid.

A solution of 48 g of 2-hydroxy-2-methyl(X1»3-dimethyl)-5-indanyl-7-acetic acid in 2.1 l of dioxane and 105 ml of concentrated sulfuric acid is refluxed for 2 hours and cooled, after which the mixture is poured into 2 kg of ice and extracted with chloroform.

The extracts are washed with water and dried over sodium sulfate. After evaporation of the solvent, 42 g of 2-methylene-((X1-3-dimethyl)-5-indanyl-7-acetic acid is obtained in the form of light beige colored crystals).

Sm.p. 66-69°C after recrystallization from pentane. Example 15.

2-methyl-((X1,3-dimethyl)-5-indanyl-7-acetic acid sodium salt.

35.5 g of 2-methylene-[(X1,3-dlmethyl)-5-indanyl-7-acetic acid.

in 350 ml of methanol is hydrogenated in the presence of 10 g of Taney nickel at 80°C under 40 kg's pressure, for 7 hours. After cooling, filtering and evaporating the filtrate, a thick white oil is obtained which does not crystallize. 21.4 g of this oil is treated with a solution of 20 ml of sodium ethylate prepared from 2 g of sodium dissolved in 20 ml of ethanol.

After evaporation of the solvent, reieau©tav ether is taken up and

one obtains 16 g of 2-methyl-, (X1» 3-<iim©tyl)-5-indanyl7-©acetic acid sodium salt in the form of a white water-soluble powder.

Analysis: potentiometric dose (perchloric acid)

PM found 239.6 PM calculated: 240.

Example 16.

2-Hydroxy-2-methyl-((X2-isopropyl)-5-indanyl7-acetic acid

In the same way as in example 13, but from 44 g of (X2-isopropyl)-5-indanyl-7-glyoxylic acid, after crystallization from isopropanol, 39 g of 2-hydroxy-2-methyl-(X2-isopropyl)-5-inda- nyl7-acetic acid in the form of white crystals, m.p. 140-143°C. Example 17.

2-Methylene-((2-isopropyl)-5-indanyl-7-acetic acid).

As described in example 14, but from 21.8 g of 2-hydroxy-2-methyl-(X2-isopropyl)-5-indanyl7-acetic acid, 19 g of 2-methylene/X2-isopropyl)-5-indanyl7 is obtained -acetic acid in the form of light beige colored crystals, sm,p. 145-148°C,

Example 18,

2-methyl((2-isopropyl)-5-indanyl-7-acetic acid).

A solution of 19 g of 2-methylene-((X2-isopropyl)-5-indanyl-7-acetic acid in 250 ml of dioxane containing 1.5 g of Pd/C 5$ is hydrogenated under a pressure of 50 kg for 4 hours. The catalyst is filtered off and the filtrate is evaporated in a vacuum. After crystallization from pentane, 15 g of 2-methyl-(X2-isopropyl)-5-indanyl-7-acetic acid is obtained in the form of white crystals, m.p. 8l-83°C.

Example 19.

((X2-isopropyl)-5-indanyl7-acetic acid chloride.

A solution of 9 g of ((X2-isopropyl)-5-indanyl-7-acetic acid and 6 g of thionyl chloride in 50 ml of benzene is heated to 80°C for 2 hours. The softening agent and the thionyl chloride excess are evaporated in vacuo. The oil is used in its raw state for the following process steps. Example 20.

The ethyl morpholine ester hydrochloride of (X2-isopropyl)-5-indanyl7-©acetic acid.

6 g of morpholine-ethanol are added drop by drop at 0°C to a solution of ((x2-isopropyl)-5-indanyl-7-acetic acid chloride prepared from 9 g of acid in 100 ml of ether). The mixture is stirred for 1 hour at room temperature and stirred with 100 ml of water containing 5% hydrochloric acid. The water phase is separated, made alkaline at 0°C with a 5% caustic soda solution and the organic products are extracted with ether. The ether extract is washed with water and dried over sodium carbonate. After evaporation of the ether, 7 g of (2-isopropyl)-5-indanyl-7-acetic acid ethylmorpholine ester are obtained. By adding ethereal hydrochloric acid and recrystallization from acetone, 7 g of hydrochloride are obtained in the form of white crystals. Sm.p. 153-156°C.

Example 21.

2-Methyl-^X2-is°Pr°Py1)-5-indanyl7-©acetic acid chloride.

In the same way as in example 19, 2-methyl-(X2-is°Pr°Pyl)-5-indanyl-7-acetic acid chloride is prepared from 10 g of acid. Example 22.

Ethyl morpholine esters of 2-methyl-(X2-isopropyl)-5-indanyl7-acetic acid.

As described in example 20, but from the acid chloride of 2-methyl-(T2-isopropyl)-5-»indanyl7-acetic acid, prepared from 10 g of acid, 7 g of ethyl morpholine ester of 2-methyl-(T2-isopropyl) are obtained -5-indanyl7-acetic acid. After adding 2.55 g of oxalic acid in acetone and recrystallization in acetone, 7 >3 g of oxalate is obtained as white crystals. Sm.p. 135-140°C.

Example 23.

((X2-cyclohexyl)-5-indanyl7-ethylglyoxalate.

A solution of 110.3 g of 2-cyclonexylidane and 68 g of ethyl oxalyl chloride in 400 ml of methylene chloride is stirred for 1 hour together with a suspension of 128.g of aluminum chloride in 400 ml of methylene chloride under cooling, so that the temperature does not exceed 5°C in the reaction mixture. The mixture is then stirred for 2 hours at room temperature and poured into 2 kg of ice, after which it is acidified to pH 3 with hydrochloric acid. The methylene chloride phase is separated and the mother liquor is extracted with methylene chloride. The methylene chloride phases are combined, washed with sodium chloride-treated water and dried over sodium sulfate.

After evaporation of the solvent, 156.3 g of (T2-cyclohexyl)-5-indan7-ethylglyoxalate are obtained, which are used in the crude state for the following step.

Example 24.

((T2-cyclohexyl)-5-indanyl7-glyoxylic acid.

A solution of 156.3 g of (X2-cyclohexyl)-5-indanyl7-ethylglyoxalate in 700 ml of ethanol is treated with a solution of 30 g of sodium hydroxide in 700 ml of water and heated under reflux for 2 hours. The mixture is then cooled, diluted with 350 ml of water and acidified at 0°C with 10% hydrochloric acid. The mixture is extracted with ether which is washed with water, dried over sodium sulphate and evaporated. After washing with a mixture of péntane-petroleum ether, 136 g of /T2-cyclohexyl)-5-indanyl7-glyoxylic acid is obtained in the form of pale yellow crystals, m.p. 117-121°C.

Example 25.

^T2-cyclohexyl)-5-indanyl7-acetic acid.

A mixture of 40 g of (X2-cyclohexyl)-5-indanyl7-glyoxylic acid and 100 ml of hydrazine hydrate is refluxed for 45 minutes. The mixture is cooled to 70°C and 50 g of potassium hydroxide lozenges are added in small portions. After the addition is complete, the mixture is heated for 1 hour at reflux, after which the excess hydrazine hydrate is evaporated in vacuo, the solution is cooled, diluted with distilled water and then neutral products are extracted with chloroform.

The mother liquor is acidified at 0°C with 10% hydrochloric acid and the acid is extracted with ether which is washed with water, dried and evaporated. After crystallization from a mixture of cyclohexane-hexane 50/50, 29 g of β-cyclohexyl)-5-indanyl-7-acetic acid are obtained in the form of white crystals. Sm.p. 126-132°C.

Example 26.

((X2-methyl)-5-indanyl7-ethylglyoxalate.

In the same way as in example 23, but from 66 g of 2-methylindan and 78.5 g of ethyloxalyl chloride, 110 g of (X2-methyl!l=)-5-indanyl7-ethylglyoxalate is obtained in the form of an oil which is further used in raw state.

Example 27.

((2-methyl)-5-indanyl-7-glyoxylic acid.

In the same way as in example 24, but from 110g of (X2-methyl)-5-indanyl-7-ethylglyoxalate, 98g of (X2-methyl)-5-inda-nyl7-glyoxylic acid is obtained, which is used in the crude state for the further reactions . Example 28.

((X2-methyl)-5-indanyl7-acetic acid.

In the same way as described in example 25, but from 40 g of (X2-methyl)-5-indanyl7-glyoxylic acid, after recrystallization from pentane, 26 g of (X2-methyl)-5-indanyl7-acetic acid are obtained in the form of crystals, sm .p. 57-58°C.

Example 29.

^X2,2-dimethyl)-5-indanyl7-ethylglyoxalate.

k In the same way as described in example 23, but from 68 g of 2,2-dimethylindan and 73.5 g of ethyloxalyl chloride, 110 g of ((X2,2dimethyl)-5-indanyl-7-ethylglyoxalate is obtained in the form of an oil which is further used in raw state.

Example 30.

/\ Zt2-dimethyl)-5-indanyl7-glyoxylic acid.

As in example 24, but from 110 g of /X2,2-diethyl)-5-indanyl7-ethylglyoxalate, 92 g of /X2,2-dimethyl)-5-indanyl7-glyokelic acid is obtained, which is used in the crude state for the following preparations . Example 31.

£{2,2-Dimethyl)-5-indanyl-7-acetic acid.

In the same way as in example 25, but from 35 g of ((2(2-dimethyl)-5-indanyl7-glyoxylic acid, after recrystallization from pentane, 24.7 g of (2(2-dimethyl)-5-indanyl7- acetic acid in the form of white crystals, m.p.^40°C.

Example 32.

2-hydroxy-2-methyl (X2-cyclohexyl)-5-indanyl7-acetic acid.

A Grignard reagent is prepared from 42.3 g of magnesium and 135 ml of methyl iodide in 850 ml of anhydrous ether, and this is added dropwise to a cooled solution of 100 g of (X2-cyclohexyl)-5-indanyl7-glyoxylic acid in 850 ml of anhydrous © ter. The addition lasts 1 hour. The reaction mixture is then stirred at room temperature for 2 hours and poured into ice which is acidified with 10% hydrochloric acid. It is extracted with ethyl acetate, washed with water and dried. After evaporation of the solvent and washing of the produced crystals with petroleum ether, 80.2 g of 2-hydroxy-2-methyl-((X2-cyclohexyl)-5-indanyl7-acetic acid is obtained in the form of white crystals, m.p. 142-144°C. Example 33.

2-methylene- (X2-cyclohexyl)-5-indanyl7-acetic acid.

A solution of 80.2 g of 2-hydroxy-2-methyl-((X2-cyclohexyl)-5-indanyl-7-acetic acid in 1.950 l of dioxane and 106 ml of concentrated sulfuric acid is refluxed for 2 hours and cooled and poured into 2 kg ice* The precipitate is washed with water and dried. 72 g of 2-methylene-((((2»cyclohexyl)-5-indanyl-7-acetic acid) is obtained as light brown* clear crystals). Sm.p. 179-182°C.

Example 34.

2-methyl-[(2-cyclohexyl)-5-indanyl-7-acetic acid.

72 g of 2-methylene- (X2-cyclohexyl)-5-indanyl7-acetic acid dissolved in 600 ml of dioxane is hydrogenated in the presence of 10 g of Raney nickel at 80°C under 50"kg<*>s pressure for 7 hours. After cooling , filtering and evaporating the filtrate, the crystals are recrystallized in a mixture of toluene and petroleum ether 10/90, and 48 g of 2-methyl-((X2-cyclohexyl)-5-indanyl7-acetic acid is obtained in the form of white crystals, m.p. 119 -121°C.

Example 35.

2-Hydroxy-2-methyl-((X2-methyl)-5-lndanyl-7-acetic acid.

As in example 32, but from 63 g of ((X2-methyl)-5-indanyl7-glyoxylic acid, 48 g of 2-hydroxy-2-methyl-(X2-methyl)-5-indanyl7-acetic acid is obtained in the form of white crystals . Sm.p. 97-100°C. Example 36.

2-Methylene-(X2-methyl)-5-indanyl-7-acetic acid.

In the same way as in example 33, but from 33 g of 2-hydroxy-2-(X2-methyl)-5-indanyl7-acetic acid, 29 g of 2-methylene/X2-methyl)-5-indanyl7-acetic acid is obtained in the form of light brown clear crystals. Sm.p. 119°C.

Example 37.

Sodium salt of 2-methyl-((X2-methyl)-5-indanyl7-acetic acid.

29 g of 2-methylene-((X2-methyl)-5-indanyl-7-acetic acid dissolved in 200 ml of methanol is hydrogenated in the presence of 10 g of Raney nickel at 80°C under 50 kg's pressure, for 7 hours. After cooling, filtering and evaporating the filtrate, you get an oil that does not crystallize. l4.6g of this oil is treated with a solution of 20 ml of sodium ethylate prepared from. 1.65 g of sodium dissolved in 20 ml of ethanol. After evaporation of the solvent, the evaporation residue is dissolved in ether and 13 g of the sodium salt of 2-methyl-(2-methyl)-5-indanyl-7-acetic acid is obtained in the form of a white powder which is soluble in water. Sm.p. 127-130°C.

Example 38.

2-Hydroxy-2-methyl-(2,2-diethyl)-5-indanyl 17 -acetic acid.

In the same way as in example 32, but from 62 g of /T2,2-dimethyl)-5-indanyl7-glyoxylic acid, 37»3g of 2-hydroxy«2-methyl/T2»2-dimethyl)-5-indanyl7- Acetic acid in the form of white crystals. Sm.p. 99-103°C.

Example 39.

2-Methylene-((2,2-dimethyl)-5-indanyl-7-acetic acid).

As in example 33, but from 37" 3 g of 2-hydroxy-2-methyl- (X2,2-dimethyl)-5-indanyl-7-acetic acid, 30.7 g of 2-methylene- (X2,2-dimethyl)- 5-indanyl-7-acetic acid in the form of light brown clear crystals, m.p. 115°C.

Example 40.

2-Methyl-((X2»2-Dimethyl)-5-indanyl-7-acetic acid.

As in example 3k, but from 30.7 g of 2-methylene-((X2,2-dimethyl)-5-indanyl-7-acetic acid, after recrystallization from pentane, 22.5 g of 2-methyl-(X2,2-dimethyl)-5 is obtained -indanyl7-acetic acid in the form of white crystals, m.p. 64-65°C.

Example 41. 2-Hydroxy-2-ethyl-((X2-isopropyl)-5-indanyl-7-acetic acid).

In the same way as in example 32, but from 64.5 g of /X2-isopropyl)-5-indanyl7-glyoxylic acid (described earlier) and 207 g of ethyl bromide, 70.9 g of 2-hydroxy-2-ethyl-/X2- isopropyl)-5-indanyl-7-acetic acid in the form of white crystals. Temp. 113-116°C.

Example 42.

2-Ethylene ((X2-isopropyl)-5-indanyl7-acetic acid).

In the same way as in example 33, but from 70.9 g of 2-hydroxy-2-(X2-isopropyl)-5-indanyl-7-acetic acid, 60.7 g of 2-ethylene-(X2-isopropyl)-5-± ndanyl7-acetic acid in the form of light brown clear crystals, m.p. 118-123°C.

Example 43.

2-ethyl-((2-isopropyl)-5-indanyl-7-acetic acid).

In the same way as in example 34, starting from 60.7 g of 2-ethylene-((X2.-isopropyl)-5-indanyl-7-acetic acid, after recrystallization from pentane, 40 g of 2-ethyl-[2-isopropyl) -5-indany 1-acetic acid in the form of white crystals, m.p. 78-80° C. Example 44.

^X2-ethyl)-5-indanyl7-ethylglyoxalate.

In the same way as in example 23, but from 77 g of 2-ethylindan and 83 g of ethyloxalyl chloride, 116.3 g of /X2-e*yi)<r->5-indanyl7-ethylglyoxalate is obtained in the form of an oil which is used further in raw state.

Example 45.

/X2~e*yl)-5-indan<yl>7-<g>lyoxylic acid.

In the same way as in example 24, but from 116.3 g of /X2-ethyl)-5-indanyl7-ethylglyoxalate, 93.6 g of /X2-ethyl)-5-indanyl7-glyoxylic acid is obtained, which is further used in the crude state .

Example 46.

2-bydroxy-2-methyl (X2-ethyl)-5-indanyl7-©acetic acid0

In the same way as in example 32, but from 93.6 g of ethyl)-5-indanyl-7-glyoxylic acid, 100 g of 2-hydroxy-2-methyl- (X2-yl)-5-indanyl-7-diacetic acid is obtained .e as used sufferers in their raw state.

Example 47.

2-methylene- (X2-ethyl)-5-indanyl7-acetic acid.

In the same way as in example 33, but from 100 g of 2-hydroxy-2-methyl- (T2-ethyl)-5-indanyl-7-acetic acid, 77.5 g of 2-caethylene- (T2-ethyl)-5- iridanyl7-acetic acid in the form of crystals. Sm.p. 88-91°C.

Example 48.

2-Methyl-(X2-ethyl)-5-indanyl-7-acetic acid.

In the same way as described in example 3, "aen from 77"5g of 2-methylene-((X2-ethyl)-5-indanyl-7-acetic acid, a residue of 79g of son" is distilled in vacuum. 53.6 g of 2-methyl-((2-ethyl)-5-indanyl-7-acetic acid is then isolated, which crystallizes from pentane in the form of white crystals. Sm.p. 44-46°C.

Example 49.

The dimethylaminoethanol salt of 2-ethyl-((2-isopropyl)-5-indanyl-7-acetic acid).

11.6 g of 2-methyl-((X2-isopropyl)-5,12-idanyl-7-diacetic acid, m.p. 8l-83°C (described earlier) dissolved in 50 ml of ether, 4.5 g of dimethylaminoethanol is added. The solution is concentrated in vacuo and the residue is diluted with 50 ml of pentane. In the cold, 9.8 g of the dimethylaminoethanol salt of 2-methyl-(X2-isopropyl)-5-indanyl-7-acetic acid is then precipitated in the form of white crystals, m.p. 59-60°C.

Example 50.

Dimethylaminoethanol salt of 2-ethyl-((X2-isopropyl)-5-indanyl7-acetic acid).

In the same way as described in example 49, but from 13.5 g of 2-ethyl-((X2-isopropyl)-5-indanyl-7-acetic acid and 4.9 g of dimethylaminoethanol, 11.2 g of the dimethylaminoethanol salt of 2-ethyl- ((X2-isopropyl)-5-indanyl7-acetic acid in the form of white crystals.

Sm.p. 69-71°C.

Example 51.

((X2-methyl)-5-indariyl7-acetic acid chloride.

A solution of 11 g of (X2-methyl)-5-indanyl7-acetic acid, 7.5 ml of thionyl chloride in 75 ml of benzene is kept at 80°C for 2 hours. The solvent and the excess of thionyl chloride are distilled off in vacuo. The evaporation residue is fractionally distilled in vacuum to give

8.6 g of acid chloride of (X2-methyl)-5-indanyl7-acetic acid in the form of a liquid, b.p. 12 mmHg = 148-151°C

Example 52.

Ethyl morpholine ester hydrochloride of (X2-methyl)-5-indanyl7-©acetic acid.

To a solution containing 5.4g of morpholmethanol

in 150 ml of anhydrous benzene and 7.7 ml of triethylamine, a solution of 8.6 g of (X2-methyl)-5-indanyl7-acetic acid chloride in 50 ml of benzene is added dropwise at 0°C. After the addition is complete, the mixture is stirred for 2 hours at room temperature and allowed to stand overnight. The benzene phase is separated and the mother liquor is extracted with ether. The organic phases are combined and washed carefully with water and dried over sodium sulfate. After evaporation in vacuo, the evaporation residue is taken up in a mixture of acetone and ether and hydrochloric acid is then added to ether, which gives 9.4 g of ethyl morpholine ester hydrochloride of (X2-methyl)-5-indanyl7-acetic acid as white crystals, m.p. 107-H0°C.

Example 53.

2- methyl-/ T2- methyl)- 5- indanyl7- acetic acid chloride.

A solution of 11.3 g of 2-ethyl-[(2-methyl)-5-indanyl-7-acetic acid and 7 g of thionyl chloride in 100 ml of benzene is heated at 80°C

for 2 hours. Solvent and excess thionyl chloride are evaporated in vacuo. The produced oil is used in its crude state for the following reactions.

Example 54.

Ethyl morphoOline ester oxalate of .2-methyl- (X2-methyl)-5-indanyl7-acetic acid.

In the same way as in example 52, but from 7 g of 2-methyl-(X2-methyl)-5-indanyl7-acetic acid, 6.8 g of ethyl morpholine ester of 2-methyl-(X2-methyl)-5-indanyl7- acetic acid in the form of an oil. By adding 2.7 g of oxalic acid dissolved in ethanol, you get after recrystallization from isopropanol 7"! g ethyl morpholine ester oxalate of 2-methyl-((X2-methyl)-5-indanyl7-acetic acid as white crystals, m.p. 140-145°C.

Example 55.

^X2» 2-Dimethyl)-5-indanyl-7-acetic acid chloride.

In the same way as described in example 51, but from 16 g of /X2,2-dimethyl)-5-indanyl7-acetic acid, after vacuum distillation of the evaporation residue, 14.7 g of /X2,2-diraethyl)-5-indanyl7- acetic acid chloride as a liquid. K»p*iOmmHg 38 l^°~1^5°c»

Example 56.

Ethyl morpholine ester hydrochloride of (\ 2,2-ditoethyl)-5-indanyl-7-acetic acid.

On the same food as in example 52, but from 14.7 g ((X2,2-dimethyl)-5-in.danyl7-acetic acid chloride, after evaporation of the organic solvents, an evaporation residue is obtained which is taken up in acetone/ether, hydrochloric acid ether is added and then gives l6g of ethyl morpholine ester hydrochloride of (X2*2-dimethyl)-5-indanyl7-acetic acid as white crystals, m.p. 145-150°C.

Example 57.

2-Methyl-(2,2-dimethyl)-5-indanyl-7-acetic acid chloride.

As described in example 51, starting from 10.2 g of 2-methyl-((2,2-dimethyl)-5-indanyl-7-acetic acid, 10.5 g of 2-methyl-(12,2-dimethyl)-5- indanyl-7-acetic acid chloride as an oil, and this is further used in the crude state.

Example 58.

Ethyl morpholine ester hydrochloride of 2-niethyl- (X2,2-dimethyl)-5-indanyl3/Z-acetic acid.

As described in example 52, but from 10.5 g of 2-methyl-((2,2-dimethyl)-5-indanyl-7-acetic acid chloride is obtained after dissolving the residue in a mixture of acetone and ether and adding hydrochloric acid ether, 12 g of ethyl morpholine ester hydrochloride of 2-methyl-((X2,2-dimethyl)-5-indanyl7-acetic acid as white crystals, m.p. l40-l42°C. Example 59.

2-methyl-((X2-cyclohexyl)-5-indanyl-7-acetic acid chloride.

In the same way as described in example 51, but from 10 g of 2-methyl-(X2-cyclohexyl)-5-indanyl7-acetic acid, 10.2 g of 2-methyl-(X2-cyclohexyl)-5-in.cLanyl7 are obtained -acetic acid chloride in the form of an oil which is further used in its raw state.

Example 60.

The ethyl morpholine ester hydrochloride of 2-methyl-((X2-cyclohexyl)-5-ind-nyl7-acetic acid chloride).

In the same way as described in example 52, but from 10.2 g of 2-methyl-((X2-cyclohexyl)-5-indanyl-7-acetic acid chloride, after dissolving the residue in acetone/ether and adding hydrochloric acid ether, 8.9 g of ethyl morpholine ester is obtained -hydrochloride of 2-methyl-((X2-cyclohexyl)-5-indanyl7-acetic acid in the form of white crystals, m.p. 154-156°C. Example 61. 2-Methyl-(2-ethyl)-5-isidanyl-7-acetic acid chloride.

In the same way as in example 51, but from 19.2 g of 2-methyl-(X2-ethyl)-5-indanyl7-acetic acid, after distillation of the residue in vacuum, 18.5 g of acid chloride of 2-methyl-/X2-ethyl is obtained )-5-

indanyl7-acetic acid. K»P« lomrnHg53 170-175°C.

Example 62.

Ethyl morpholine ester oxalate of 2-methyl-((X2-e*yl)-5-indanyl7-acetic acid).

On the same starting material as in example 52, but from 16.5 g of 2-methyl- (X2-e*y1)^5-indanyi7-acetic acid chloride, 15 g of ethyl chloro-folinic ester of 2-methyl- (X2-ethyl) -5-indanyl7-acetic acid as an oil. By adding 5.5 g of oxalic acid dissolved in ethanol, after recrystallization from ethanol, 15.5 g of ethyl morpholine ester oxalate of 2-methyl-((X2-ethyl)5-indanyl7-acetic acid is obtained as white crystals, m.p. 143-145°C.

Example 63.

2-methyl-((X2-isopropyl)-5-indanyl-7-acetic acid chloride.

As described in example 51, but starting from 31.7 g of 2-methyl-((2-isopropyl)-5-indanyl-7-acetic acid, m.p. 81-83°C described earlier, after vacuum distillation of the evaporation residue, 30.1 g of 2-methyl-((X2-isopropyl)-5-indanyl-7-acetic acid chloride is obtained.

B.p., „ a<1>50°C.

^ lmmHg

Example 64.

The dimethylaminoethyl ester hydrochloride of 2-methyl-^X2**isoP??0Pyl)-5-indanyl7-acetic acid.

In the same way as in example 52, but from 10 g of 2-methyl-((X2-isopropyl)-5-indanyl-7-acetic acid chloride and 3.6 g of dimethylaminoethanol, after evaporation of the organic solvents in vacuum, an evaporation residue is obtained which after solution in acetone/ether, hydrochloric acid is added to ether and after recrystallization from acetone gives crystals in the form of 11.4 g of ethyldimethylaminoester hydrochloride of 2-methyl-^X2-isoProPy1)-5-indanyl7-acetic acid in the form of white crystals, m.p. . 123-124°C. . Example 65. Diethylaminoethyl ester oxalate of 2~methyl-((X2-isopropyl)-5-indanyl7~ acetic acid).

As described in example 52, but from 10 g of 2-methyl-((X2-isopropyl)-5-indanyl-7-acetic acid chloride and 4.1 g of diethylaminoethanol, after evaporation of the solvents in vacuo, 10g of diethylaminoethyl ester of 2-methyl- ((X2-isopropyl)-5-indanyl7-acetic acid which, on addition of 3.8 g of oxalic acid dissolved in ethanol, gives, after recrystallization from isopropanol, llg diethylaminoethyl ester oxalate of 2-methyl-(X2-isopropyl)-5-indanyl7- acetic acid, as white crystals, m.p. 135-137°C.

Example 66.

Dimethylamino-α-dimethylethyl ester maleate of 2-methyl-((X2-isopropyl)-5-indanyl7-acetic acid).

In the same way as in example 52, but from 10g of 2-methyl-(X2-isoPr°Py1)-5-iiidanyl-7-acetic acid chloride and 4.1 g of a-dimethyl-dimethylaminoethanol, llg dimethylamino-a-ditaethylethyl ester is obtained of 2-methyl-(X2-ieopropyl)-5-indanyl7-acetic acid which, on addition of 3.8 g of maleic acid dissolved in acetone, gives 11.2 g of dimethylamino-α-dimethylethyl ester jaaleate of 2-methyl-(X2-isopropyl) -5-indanyl7-acetic acid as white crystals, m.p. 92-95°C.

Example 67.

Piperidine ethyl ester oxalate of 2-methyl-((X2-isopropyl)-5-indanyl7-acetic acid).

As described in example 52, but from 14 g of 2-methyl-((X2-isopropyl)-5-indanyl-7-acetic acid chloride and 7.2 g of piperidinoethanol, 15 g of ester are obtained which, by adding 5.5 g of oxalic acid dissolved in ethanol after recrystallization from ethanol gives 14g of the oxalate of the piperidinoethyl ester of 2-methyl-((X2-isopropyl)-5-indanyl7-acetic acid,

as white crystals. Temp. 139-141°C. Example 68.

The sodium salt of 2-methyl-((X2-isopropyl)-5-indanyl7-acetic acid).

25.5 g of 2-methyl-(2-isopropyl)-5-indanyl-7-acetic acid is treated with a sodium methylate solution prepared from 2.5 g of sodium dissolved in 40 ml of methanol. After evaporation of the solvent, the residue is dissolved in otter and 23 g of the sodium salt of 2-methyl-((X2-iso-propyl)-5-indanyl-7-acetic acid is obtained as a white water-soluble powder. Example 69.

Pyrrolidino-ethyl ester maleate of 2-methyl-((X2-isopropyl)-5-indanyl-7-acetic acid).

A solution of 1.1 g of 2-methyl-((2-isopropyl)-5-indanyl-7-acetic acid sodium salt and 6.9 g of 8-chloroethylpyrrolidine in 100 ml of xylene is refluxed for 7 hours. After cooling the reaction mixture, the organic phase is washed with water and dried over sodium carbonate. After evaporation of the solvent, a residue of 14.3 g is obtained, which is added to a solution of 5 g of maleic acid in acetone* This gives 17.4 g of pyrrolidino-ethyl ester maleate of 2-Eaethyl- (X2-isopropyl)-5-indanyl7- acetic acid in the form of white crystals, m.p. 114-116°C.

Example 70.

2-methyl-((T2-isopropyl)-5-indanyl7-B-ethanol.

A solution of 10 g of 2-methyl-((2-isopropyl)-5-indanyl-7-acetic acid in 50 ml of anhydrous ether is added dropwise to a suspension of 3-9-3 g of aluminium-lithium hydride in 50 ml of anhydrous ether). After the addition is complete, the mixture is heated for 3 hours at reflux temperature.

After cooling, a saturated solution of sodium sulfate is added drop by drop at 0°C to destroy excess hydride. When the hydride no longer reacts, sodium sulfate is added to the reaction mixture and filtered. The precipitate is washed thoroughly with ether, the filtrates are combined and the ether is evaporated. 9.5 g of 2-ethyl-((2-iso-propyl)-5-indanyl7-8-ethanol is obtained in the form of white crystals. Sm.p. 45°C. Example 71.

2-methyl-((X2-ethyl)-5-indanyl7-8-ethanol.

As described in example 70, but with the help of 12.8 g of 2-methyl-(X2-ethyl)-5-indanyl-7-acetic acid, after distillation in vacuum of the formed evaporation residue, 10 g of 2-methyl-(X2-ethyl)-5 -indanyl7-B-ethanol as a clear oil. ^P*!^Hgæ 130-132°C. Example 72.

/X 2-03 ethyl)-5-indany l7-3-ethanol.

As described in example 70, but from 3.5 g of /X2-methyl)-5-indanyl7-acetic acid, after distillation of the evaporation residue, 2.6 g of /X2-methyl)-5-indanyl7-S-ethanol are obtained as a colorless oil , k.p.^„ TT<=>- - 0.5mmHg 115 C.

Example 7 3.

((X2-isopropyl)-5-indanyl7-p-ethanol.

As in example 70, but from 25 g of /T2-isopropyl)-5-indanyl-7-acetic acid, after recrystallization from pentane, 20.5 g of /T2-isopropyl)-5-indanyl7-8-othananol is obtained as white crystals, m.p. . 4l-42°C.

The pharmacological properties of products according to the invention are illustrated by means of the experiments below. Anti-inflammatory effect.

Groups of 12 male SPF rats, strain OFA, weighing 120-130g per animals receive orally the relevant test compounds 2 hours and 30 minutes before injection (2 x 1/2 dose) subcutaneously in the paw, 0.05 n»l carrageenin solution 1$. The rear paw volume is measured after administration of an inflammatory reagent at regular intervals. DE^jq is calculated from the maximum inflammation in the control animals.

The results are listed in Tables I to IV, where the percentage reduction in inflammation is found.

Analgesic effect.

Groups of 6 male mice (SPF^ strain OF^) with a body weight of 19-20 g receive the test compounds orally. 1 hour later, another 093ml is injected intraperitoneally. each mouse of a solution containing 0.02$ of phenylbenzoquinone and from the 5th to the 10th minute after each treatment the number of pain reactions (stomach twitches) is counted•

The following tables V to VIII indicate the inhibition percentage for these reactions.

Claims (1)

1. Procedure© for the production of indane derivatives with formula: where: X denotes a hydrogen atom or a halogen atom, and Rg, which may be the same or different, denotes a lower alkyl group (C^ -C^ ) or a cycloalkyl group (CyC^ ), and where at least one of the groups R^<p> g R 2 may be a hydrogen atom, R^ denotes a hydrogen atom or a lower alkyl group (C^ -C^ ), Y denotes a group -CHgOH <;.'....ar -COOR^ , where R^ denotes a hydrogen atom, further the group M l/ v iivor M is a metal and v is the valence of the metal, or the group: where n denotes an integer from 1 to 5»© g where R^ and R^ , which may be the same or different, denote a hydrogen atom, a lower alkyl group (C^-C,.), a cycloalkyl group (C^-C ^ ), an aryl group, or an aralkyl group, where and together with the nitrogen atom to which they are attached can form an N-heterocyclic group with 5 to 7 ring members which can also contain another heteroatom and be substituted, characterized by carrying out the following reactions: a) converting an indan with formula: where R^ , Rg and X have the same meaning as above, with an ethoxalyl halide of formula ZCOCOOCgH^ where Z denotes a halogen atom, and by alkaline or acid hydrolysis converts the produced keto-ester into a keto-acid of the formula after which the product with formula (Vi) is allowed to undergo: b) a Wolff-Kishner reduction to produce products of formula (i) where Y = COOR^ and and R^ are hydrogen atoms, or c) a reaction with an organomagnesium compound of formula R^ MgZ where Z denotes a halogen atom, followed by © n dehydration and a hydrogenation to produce a product of formula (i) where Y = -COOR^ and R^ = alkyl ( Cj -C^K and R^ denotes a hydrogen atom, and d) optionally carries out a reduction of the acid produced according to b) or c) by means of a reducing agent in an organic solvent, or a reduction of the alkyl ester of said acid produced in a known manner by esterification and where the alkyl radical has 1 to k c- atoms, for the preparation of an alcohol of formula (i) where Y = -CHgOH. 2. Method as stated in claim 1, characterized in that the reducing agent is aluminum lithium hydride and the organic solvent is ether or tetrahydrofuran. 3« Method as stated in one or more of the above claims, characterized in that step a) comprises the effect of an oxalyl chloride on a starting substance of formula (II) in the presence of AlCl^ in a solvent. ho Process as stated in one or more of the above claims, characterized in that step b) comprises treating a ketone of formula (IV) with hydrazine in a solution of sodium or potassium hydroxide. 5» Method as stated in claim 3, characterized in that the solvent is ethylene chloride. 6. Method as stated in one or more of the above claims, characterized in that step c) comprises the effect of a Grignard reagent in ether on a product of formula (Vi), for the production of a substance of formula; that one dehydrates the product with formula (Vil) using a strong acid for the production of the following compounds which compound is finally hydrogenated in the presence of Raney cycle to produce a product of formula (i) where Y -. COOH. 7. Process for the production of products of formula (i) where Y m -COOR^ and R^ are equal to -(CH2^n"W\ 5, characterized by converting an acid *6 of formula (i) prepared according to to one or more of claims 1-6 above for its halide, and that the halide is reacted with an auinoalcohol of formula; ;where n, R,, and R^ have the same meaning as before.;8.Procedure for the production of products of formula (in) where Y equals -COOR^ and R^ equals ;characteri characterized by forming a salt of an acid of formula (i), prepared as stated in one or more of claims 1 to 6, and reacting the prepared salt with a halide of formula ;where Z is a halogen atom and n, R^ and R^ has the same meaning as before.*