CS204995B2 - Process for preparing derivatives of indane - Google Patents

Description

The invention relates to a process for the preparation of indane derivatives of the formula I

in which

X represents a hydrogen atom or a halogen atom,

R 1 and R 2, which may be identical or different, represent an alkyl group having 1 to 5 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, wherein at least one of the substituents may also be a hydrogen atom,

R 5 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms and

Y is -CH 2 OH or -COOR 4 wherein R 4 is hydrogen or a metal equivalent selected from the group consisting of sodium, potassium, calcium and aluminum, or a group wherein n is an integer from 1 to 5 and each of R 5 and R 5 which may be identical or odbšné is hydrogen, ^alkyl: alkoxycarbonyl having 1 to 5 carbon atoms: se'- cycloalkyl groups from 3 to 7 carbon atoms, α-phenethyl, / 3-fehethylůvou or benzyl substituent, or may R 5 and R 6 together with the nitrogen atom to which they are attached form an N-heterocyclic group of 5 to 7 members selected from the group consisting of pyrrolidine, morpholine, thiomorpholine, 3,5-dimethylmorpholine, piperidine, 4'- methylpiperidine, piperazine, 4- (3-hydroxyethyl) piperazine, 4-p-chlorophenylpiperazine and azepine.

The above-mentioned novel compounds of formula I have significant pharmacological properties and can be used as medicaments, in particular as analgesics and anti-inflammatory agents. In particular, the compounds of the formula I can be used as medicaments against rheumatoid inflammations.

The present invention relates to a process for the preparation of indane derivatives of the formula I

- (CH 2) n - NR 5 R e,

ω in which

R 1, R 2, R 3, X and Y are as defined above, wherein the indane of formula (II)

(II) in which

R1, R2 and X are as defined above, reacted with an acid halide or anhydride of formulas III and V

R3 - CO - Y - (III) or

R 3 —CO — OCORs (V), wherein R 3 is as defined above and Y ‘is a halogen atom, in the presence of a Lewis acid

in which

R1, R2, R3 and X are as defined above, reduced with a reducing agent to provide an alcohol of formula XIII

in which

R1, R2, R3 and X are as defined above, then the alcohol of formula XIII is converted by treatment with a halogenating agent to a halogenated derivative, which is then converted by treatment with an alkali metal cyanide into a nitrile of formula IV

(IV) wherein

R 1, R 2, R 3 and X are as defined above, after which said nitrile is subjected to acidic or basic hydrolysis to give an acid of formula I wherein Y is -CO 4 R 4 where R 4 is hydrogen and optionally said acid of formula I , obtained by acidic or basic hydrolysis, or a C 1 -C 4 alkyl ester thereof, obtained by esterification of said acid, is reduced with a reducing agent in an organic solvent to obtain an alcohol of formula I wherein Y is -CH 2 OH or optionally an acid of formula I is converted to the acid halide which is reacted with an amino alcohol of formula VI

Rs

OF

H0- (CH 2) n -N

R 5 (VI), wherein n, R 5 and R 6 are as defined above, to provide a compound of formula I wherein Y is -COOR 4, wherein R 4 is

R 5 (CH 2) n -N

Re or the acid of formula I is converted to a salt which is reacted with a halide of formula VII,

Rs

Z (CH ₂ ) n -N

Re (VII), wherein n, R 5 and R 6 are as defined above and

Z is a halogen atom to obtain a compound of formula I wherein Y is -COOR 1 wherein R 4 is

Rs /

- (CH 2) n -N

Rs

In the reaction of an indane of formula II with a halide of formula R3-CO-Y- or an acid anhydride of formula R3-CO-OCOR3, it is preferred to use aluminum chloride as Lewis acid.

In the reduction of the ketone of formula X, sodium borohydride, potassium borohydride or sodium aluminum hydride is preferably used as the reducing agent.

When the alcohol of the formula (XIII) is converted to the corresponding halogenated derivative, phosphorus tribromide or thionyl chloride is preferably used as the halogenating agent.

In reducing the acid of formula (I) or its alkyl ester, sodium or potassium hydride is used as reducing agent and ether or tetrahydrofuran are used as organic solvent.

Examples of cycloalkyl groups falling under the general substituents R 1 and R 2 in formula I (-cycloalkyl groups of 3 to 7 carbon atoms) include cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl and cyclohexyl, with a preferred group is cyclohexyl.

The metal equivalent of the general substituent R 4 is preferably an equivalent of metal I, II. or III. groups of the Periodic Table of Elements, in particular sodium, potassium, calcium or aluminum equivalent.

Among the N-heterocyclic groups belonging to the general substituents R 5 and R 6, mention may be made of pyrrolidine, morpholino, thiomorpholino,

3,5-dimethylmorpholine, piperidine, 4‘-methylpiperidine, piperazine,

A 4- (β-hydroxyethyl) piperazine group, a 4-p-chlorophenylpiperazine group, and an azepine group.

Among the aralkyl groups under the general substituents R 5 and R 6, mention may be made of N-phenethyl, (3-phenethyl and benzyl).

The invention also encompasses the preparation of addition salts of compounds of formula I in a manner known per se, in the case where Y represents a group - COOR 4; when R4 is hydrogen, it is an amine addition salt, and when R4 is - (CH2) _n —N — R5Re, it is an acid addition salt or a quaternary ammonium salt.

When R 4 is - (CH 2) _{n -} N - R 5 R 6, acid addition salts are obtained in a manner known per se by reacting a compound of formula I with a mineral or organic acid.

Examples of acids which may be used in the production of the above acid addition salts include hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, succinic acid, methanesulfonic 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 and p-toluenesulfonic acid.

The compounds of formula (I) prepared by the process of the invention can be used for the preparation of medicaments useful in particular for the treatment of inflammation and rheumatic pain and pain syndromes. The pharmaceutical compositions comprise, in addition to an effective amount of at least one compound of formula I, or at least one non-toxic salt of a compound of formula I, a suitable physiologically acceptable excipient.

The compounds of the formula I can be administered in the form of pills containing 50 to 250 mg of active ingredient in a total daily dose of 2 to 6 pills; said compounds may also be administered in the form of suppositories containing 100 to 500 mg of active ingredient in a total daily dose of 2 to 5 suppositories, in the form of drinking suspensions containing 25 mg of active ingredient in 5 ml, in a total daily dose of 10 to 40 ml of suspension or as injectable solutions containing 50 mg of active ingredient in 2 ml solution for injection in a total daily dose of 2-4 injections.

The compounds of Formula I have a lethal dose of DL 50 of about 250 mg / kg for oral administration; these compounds have only a negligible ulcerogenic effect and also have a higher pharmaceutical efficacy / toxicity ratio than previously known compounds having analogous pharmacological properties.

The preparation of the compounds of formula (I) according to the invention will be illustrated by the following examples.

Example 1 [(2-isopropyl) -5-indanyl] methylketone

A solution of 2-isopropylindane (100 g) and acetic anhydride (65 ml) in methylene chloride (400 ml) was added with stirring to a suspension of aluminum chloride (190 g) in methylene chloride (400 ml) over 1 hour while cooling the reaction mixture to not exceed 10 ° C. The mixture was then stirred for 5 hours at room temperature, then poured onto 2 kg of ice and acidified to pH 3 with hydrochloric acid. The methylene chloride phases were separated and the mother liquor was extracted with methylene chloride. The methylene chloride phases are combined, washed with water and dried over sodium sulfate.

After evaporation of the solvent, the residue (137 g) was distilled under reduced pressure to give 105.5 g of [(2-isopropyl) -5-indanyl] methylketone as white crystals of very low melting point (below 40 ° C).

The boiling point of the product obtained is 121 to 125 ° C / 66.7 Pa.

EXAMPLE 2 2 [(2-Isopropyl) -5-indanyl] -α-ethanol

To a solution of 105.5 g of [(2-isopropyl) -5-indanyl] methylketone in 600 ml of methanol was added in small portions 25.6 g of potassium borohydride. After stirring for 3 hours at room temperature with a magnetic stirrer, the reaction mixture is concentrated under reduced pressure, ice is added and the organics are extracted with ether.

After washing with water and drying over sodium sulfate, the ether was evaporated to give 106 grams of [(2-isopropyl) -5-indanyl] -N-ethanol which was used as such in the next step.

Example 3

To a solution of 106 g of [(2-isopropyl) -5-indanyl] -N-ethanol in 500 ml of benzene was added 70 ml of thionyl chloride over two hours with magnetic stirring. After

The reaction mixture was poured onto ice for 15 minutes at room temperature. The benzene phase is separated and the mother liquor is extracted with ether. The combined organic phases were washed with water, 5% sodium bicarbonate solution and again with water, and then dried over sodium sulfate.

The residue obtained after evaporation of the organic solvent under reduced pressure was distilled under reduced pressure to give 104.1 g of [(2-isopropyl) -5-indanyl] -α-chloroethane as an oil, b.p. 132-136 ° C / 199. , 5 Pa.

Example 4 [(2-Isopropyl) -5-indanyl] -2-methylacetone-tril

To a solution of 24.3 g of sodium cyanide in 210 ml of dimethyl sulfoxide was added dropwise a solution of 104.1 g of [(2-isopropyl) -5-indanyl] -N-chloroethane in 70 ml of dimethylsulfoxide. After the addition was complete, the reaction mixture was heated at 70-80 ° C for 4.5 hours, cooled, poured into ice-water and extracted with ether.

The ether extract was washed thoroughly with water and dried over sodium sulfate. After evaporation of the ether, the residue was distilled under reduced pressure to obtain 74.1 g of [(2-isopropyl) -5-indanyl] -2-methylacetonitrile as an oil, b.p. 135-150 ° C. .

Example 5

2-Methyl [(2-isopropyl) -5-indanyl] acetic acid

A solution of 74.1 g of 2-methyl- [(2-isopropyl) -5-indanyl] acetonitrile in 185 ml of ethanol containing 185 ml of water and 74 g of potassium hydroxide is heated at reflux for 12 hours.

Thereafter, a mixture of ice and water was added to the reaction mixture, and the neutral compounds were extracted with ether.

After acidifying the mother liquor, the acid is extracted with ether. The ether phase was washed with water and dried over sodium sulfate.

Evaporation of ether and recrystallization from petroleum ether gave 50.6 g of 2-methyl- [(2-isopropyl) -5-indanyl] acetic acid as white crystals, m.p. 81-83 ° C.

Example 1 a d 6

2-methyl- [(2-isopropyl) -5-indanyl] -β-ethanol;

general formula

Ri = H,

R 2 = isopropyl and R 3 = methyl.

A solution of 10 g of 2-methyl- [(2-isopropyl-5-indolyl) -5-indanyl] acetic acid in 50 ml of anhydrous ether was added dropwise to a suspension of 3.3 g of lithium aluminum hydride in 50 ml of anhydrous ether. After the addition was complete, the reaction mixture was heated to reflux for 3 hours.

After cooling, a saturated aqueous sodium sulfate solution was added dropwise at 0 ° C to decompose the excess lithium aluminum hydride. When the lithium aluminum hydride no longer reacted, sodium sulfate was added to the reaction mixture and filtered. The precipitate was carefully washed with ether, and the combined filtrates were distilled to distill off the ether. 9.5 g of 2-methyl [(2-isopropyl) -5-indanyl] -. Beta.-ethanol are obtained in the form of white crystals, m.p.

Example 7 [(2-isopropyl-5-indanyl) -ethanol;

Formula I:

R1 = H,

R2 = isopropyl,

R3 = H.

Using the procedure of previous Example 6 but using 25 g of [(2-isopropyl) -5-indanyl] acetic acid, 20.5 g of [(2-isopropyl) -5-indanyl] - [3-ethanol] are obtained as white solids after recrystallization from pentane. m.p. 41-42 ° C.

Example 8

2-Methyl- [(2-isopropyl-5-indanyl) -acetic acid chloride

A solution of 31.7 g of 2-methyl- [(2-isopropyl) -5-indanyl] -acetic acid, m.p. 81-83 ° C and 22 ml of thionyl chloride in 220 ml of benzene, was heated at 80 ° C for two hours. . Then, the solvent and excess thionyl chloride were evaporated under reduced pressure.

The residue is subjected to fractional distillation under reduced pressure to give 30.1 g of 2-methyl- ((2-isopropyl) -5-indanyl) -acetic acid chloride, b.p. 150 DEG C./0.1 mbar.

Example 9

2-Methyl- [(2-isopropyl) -5-indanyl] -acetic acid dimethylaminoethyl ester hydrochloride;

Formula I:

R1 = H,

R 2 - isopropyl,

R3 = methyl,

CH3

OF

R4 = -CH2-CH2-N1

CH3

X = H.

To a solution of 3.6 g of dimethylaminoethanol in 1 ml of anhydrous benzene containing 9 ml of triethylamine is added dropwise a solution of 10 g of 2-methyl- [(2-isopropyl) -5-indanyl] acetic acid chloride in 50 ml of anhydrous benzene, the reaction mixture is maintained at 0 ° C. After the addition was complete, the reaction mixture was stirred for two hours at room temperature and allowed to stand overnight.

The benzene phase is separated and the mother liquor is extracted with ether. The combined organic phases are washed thoroughly with water and then dried over sodium carbonate. The residue obtained by concentration under reduced pressure is taken up in a mixture of acetone and ether and treated with ethereal hydrogen chloride until neutral.

The separated crystals are filtered off with suction, washed with ether and recrystallized from acetone. 11.4 g of 2-methyl- [(2-isopropyl) -5-indanyl] acetic acid dimethylaminoethyl ester hydrochloride are obtained in the form of white crystals, m.p. 123 DEG-124 DEG.

Example 10

2-Methyl- [(2-isopropyl) -5-indanyl] acetic acid, sodium salt;

Formula I:

R 1 == isopropyl,

Rz = H,

R3 = CH3,

R4 = Na and X = H.

25.5 g of 2-methyl - [(2-isopropyl) -5-indanyl] acetic acid is treated with a solution of sodium methylate prepared by dissolving 2.5 g of sodium in 40 ml of ethanol. 23 g sodium acid salt

2-methyl- [(2-isopropyl) -5-indanyl] acetic acid as a white water-soluble powder.

Example 11

Pyrrolidinoethyl ester of maleate

2-methyl- [(2-isopropyl-5-indanyl) acetic acid;

Formula I:

R1 = isopropyl,

Rz = H,

R3-CH3, v- ^CH and ^CH dCl

X = H.

A solution of 11 g of 2-methyl- [(2-isopropyl) -5-indanyl] acetic acid sodium salt and 6.9 g of β-chloroethylpyrrolidine in 100 ml of xylene was heated at reflux for 7 hours. After cooling the reaction mixture, the organic phase was washed with water and dried over sodium carbonate. A solution of 5 g of maleic acid in acetone is added to the residue of 14.3 g obtained by evaporation of the solvent. There was thus obtained 2-methyl - [(2-isopropyl) -5-indanyl] acetic acid pyrrolidinoethyl ester maleate (17.4 g) as white crystals.

Melting point 114-116 ° C.

The pharmacological properties of the compounds prepared by the process of the invention are illustrated by the following tests.

A) Anti-inflammatory activity

Groups of 12 male rats of SPF strain OFA weighing 120-130 g were administered orally for 2.5 hours (half-dose each) prior to subcutaneous injection of 0.05 ml of a 1% carrageenan solution into the paw. The volume of the hind paw into which the carrageenan solution was injected was measured at regular intervals.

The results of these experiments are shown in Table I below, which shows the percent reduction in inflammation.

Table I

mg / kg orally Example 8 Example 11 Example 12 Example 14 Example 16 4 - - - 29 19 Dec 8 29 0 - - - 16 43 13 0 54 21 32 61 34 1 - - 64 73 52 21 61 59 128 75 58 41 64 55 256 80 30 76 - - DEso 22nd 85 higher than 256 22nd 65 (mg / kg, orally) B) Analgesic efficacy phenylbenzoquinone and starting from the fifth to the de- sucked minute after injection of this solution Groups 6 of male mice (SPFi strains the number of painful reactions (abdomi- OFi) weighing 19 to 20 g is orally administered torsion). test substances. The results are shown in next ta- One hour later, each mouse was intra- bull II, where percent inhibition is shown inject 0.3 ml peritoneally 0.02% solution of these reactions. Table II mg / kg Example 8 Example 11 Example 12 Example 14 Example 16 orally 2 8 _ __ 4 - 25 - - - 8 17 42 - 7 6 16 61 68 0 42 47 32 96 90 40 69 79 64 - - 55 94 99 128 - - 62 99 - 256 - - 81 - - DEso 14 9 60 23 18

(mg / kg, oral)

Claims (5)

SUBJECT A process for the preparation of indane derivatives of the general formula I in which X represents a hydrogen atom or a halogen atom, R 1 and R 2, which may be the same or different, represent an alkyl group having 1 to 5 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, wherein at least one of the substituents may also be a hydrogen atom, R 3 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms and Y is -CH 2 OH or -COOR 4 wherein R 4 is hydrogen or a metal equivalent selected from the group consisting of sodium, potassium, calcium and aluminum, or - (CH 2) _n -NR 5 R 5 wherein n is an integer from 1 to 5 and each of R 5 and R 6, which may be the same or different, represents a hydrogen atom, a C 1 -C 5 alkyl group, a C 3 -C 7 cycloalkyl group, an α-phenethyl group, a β-phenethyl group or a benzyl group or R 5 and R 6 together with the nitrogen atom to which they are attached may form an N-heterocyclic group of 5-7 members selected from the group consisting of pyrrolidine, morpholino, thiomorpholino, 3,5-dimethylmorpholino, piperidine, 1-methylpiperidine, piperazine, 4 - ((3-hydroxyethyl) piperazine, 4-p-chlorophenylpiperazine and azepine, characterized in that the indane is in general it Formula II In which R1, Ra and X are as defined above, reacted with an acid halide or anhydride of formulas III and V R3 - CO - Y - (III) or R3-CO-OCOR3, (V) in which it has R 3 is as defined above and Y ‘represents a halogen atom, in the presence of a Lewis acid lysator, whereupon the obtained ketone is obtained of formula X fo R, y, r in which R ^ AAy ÍX) R 1, R 2, R 3 and X are as defined above, reduced with a reducing agent to obtain an alcohol of Formula XIII R1, R2, R3 and X are as defined above, then the alcohol of formula XIII is converted by treatment with a halogenating agent to a halogenated derivative, which is then converted by treatment with an alkali metal cyanide into a nitrile of formula IV 1β in which R 1, R 2, R 3 and X are as defined above, after which said nitrile is subjected to acidic or basic hydrolysis to give an acid of formula I wherein Y is -COOR 6 wherein R 4 is hydrogen and optionally said acid of formula I , obtained by acidic or basic hydrolysis, or a C 1 -C 4 alkyl ester thereof, obtained by esterification of said acid, reduced with a reducing agent in an organic solvent to obtain an alcohol of formula I wherein Y is -CH 2 OH or optionally an acid of formula I is converted to the acid halide which is reacted with an amino alcohol of formula VI Rs OF HO— (CHžjn — N Re (VI), wherein n, R 5 and R 6 are as defined above, to provide a compound of formula I wherein Y is -COOR 4, wherein R 1 is Rs OF - (CH 2) _{n -} N \ Re or the acid of formula I is converted to a salt which is then reacted with a halide of formula VII Rs OF Z (CH 2) n -N Re (VII), wherein n, R 5 and R 6 are as defined above and Z is a halogen atom to obtain a compound of formula I wherein Y is -COOR 6 wherein R 4 is R5 Z - (CH2-N \ Re 2. A process according to claim 1, wherein the reaction of an indane of formula II with a halide of formula III, R3-CO-Y, or an acid anhydride of formula V, R3-CO-OCOR3, is used as the Lewis acid of the aluminum chloride. 3. A process according to claim 1, wherein sodium borohydride, potassium borohydride or sodium aluminum hydride is used as the reducing agent in the reduction of the ketone of formula X. 4. A process according to claim 1, wherein phosphorus tribromide or thionyl chloride is used as the halogenating agent when the alcohol of formula (XIII) is converted to the corresponding halogenated derivative. 5. A process according to claim 1, wherein sodium or potassium hydride is used as the reducing agent in the reduction of the acid of the formula I or its alkyl ester, and preferably ether or tetrahydrofuran is used as the organic solvent.