CS250654B2 - Method of indoline-2-on's substituted derivatives production - Google Patents

Description

In addition, elevated alditol levels may result in abnormal levels of their metabolites, which themselves may impair or completely inhibit cell function. However, the aldose reductase enzyme has a relatively low affinity for the substrate, i. It is effective only in the presence of a ratio of high aldose concentrations. Such high aldose concentrations occur in the clinical conditions of diabetes (excessive glucose level) and galactosemia (excessive galactose level). Accordingly, aldose reductase enzyme inhibitors are useful in reducing or preventing the onset and development of those complications associated with protracted diabetes or galactosemia, which may be due in part to the accumulation of sorbitol or galactitol. Such complications are, for example, macular edema, cataract, retinopathy or impaired conduction of nerve impulses.

Certain spiro-linked hydantoins (spiro-linked imidazolidine-2,5-dionic derivatives derived from various bicyclic ketones) are known to be inhibitors of the enzyme aldose reductase, such as compounds of the formula

H O in which

Z is oxygen, sulfur, sulfinyl group 250504, sulfonyl, methylene or a direct bond; and

Y represents various optional substituents described by Sarges in U.S. Patent 4,117,230.

In accordance with the invention, it has now been found that certain novel spiro-linked hydantoins of formula I below, derived from 1-subst. indoline-2,3-diones are potent aldose reductase inhibitors. This finding is surprising in view of the different differences in the chemical structure of these compounds, for example the presence of the amide carbonyl function at the α-position relative to the spirane carbon, which is the position of the prior art spiro-hydantoin derivatives which inhibit aldose reductase. always occupied by a methylene group.

Certain related spiro-hydantoins derived from 1-substitutedindoline-2,3-dione are known. Specifically, 1‘-methyl-, 1‘-allyl- and 1‘-benzylspiro [imidazolidine-4,3‘-indoline] -2,2 ‘, 5-trione have been described by Otomasu et al. in Chem. Pharm. Bull., 1975, 23, 1 431-1 435, but they did not confer any pharmacological properties on these substances.

The present invention provides a process for the preparation of 1‘-substituted spiro [imidazolidine-4,3‘-indoline] -2,2,5,5-triones of formula (I)

in which

R ¹ represents an alkyl group having 1 to 12 carbon atoms, a phenyl group, a naphthylmethyl group or a cinnamyl group, the aromatic rings of which optionally bear one or two halogen atoms, or a benzyl group optionally substituted by one, two or three substituents independently selected from halogen groups, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro, cyano and hydroxyl, and benzene ring A is optionally substituted with one substituent selected from the group consisting of halogen atoms, alkyl groups C 1 -C 4 alkoxy, C 1 -C 4 alkoxy, nitro and hydroxyl, or optionally substituted with two substituents independently selected from the group consisting of halogen atoms, C 1 -C 4 alkyl and nitro, and pharmaceutically acceptable salts thereof upotřeb salts with the exception of those compounds in which R ¹ represents a methyl, ethyl, n-propyl or unsubstituted benzyl group and the benzene ring A is not substituted.

The compounds of formula I are spiro [imidazolidine-4,3‘-indoline] derivatives in which the individual positions are numbered as shown in the following formula II

This numbering system is used throughout the invention.

The compounds of formula I contain at least one asymmetric carbon atom, in particular a spiro-linked carbon atom. Thus, the compounds may exist, and may be isolated in racemic form and in optically active forms. The invention encompasses both the racemic form of the compounds of formula (I) and any optically active form which acts to inhibit aldose reductase, and it is well known how optically active forms can be prepared by resolution of the racemic form or by synthesis from optically active starting materials and determine the inhibitory activity on aldose reductase using standard assays described below.

Suitable alkyl groups having 1 to 12 carbon atoms represented by R ¹ is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, nonyl or decyl.

Suitable substituents which may be present on the benzene ring A or on the aryl part of the radicals R @ ¹ include, but are not limited to, halogen atoms, fluorine atoms, chlorine atoms, bromine atoms or iodine atoms for alkyl groups of 1; C 1-4 alkyl, methyl or ethyl, for C 1-4 alkoxy, methoxy or ethoxy.

Suitable rings A include unsubstituted or 4'-chloro-, 5'-fluoro-, 5'-chloro-, 5'-bromo-, 5'-methyl-, 5'-methoxy-, 5'-hydroxy- 5'-nitro-, 6'-chloro-, 7'-fluoro-, 7'-chloro-, 7'-methyl-, 7'-ethyl-, 5 ', 6', - difluoro-, 5 ', 6'-dichloro-, 4 ', 5'-dichloro-, 5', 6'-dimethyl-, 5'-bromo-7'-nitro- or 5'-chloro-7'-methyl-substituted ring.

A suitable residue in the meaning of the symbol

R ¹ is methyl, n-propyl, n-hexyl, n-nonyl, n-decyl, phenyl, cinnamyl, 3,4-dichlorcinnamylo250654 naphthidinyl group, a 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 3,4-dichlorobenzyl, 2-fluoro-4-bromobenzyl, 4-methylbenzyl, 2-fluoro-4-iodobenzyl, 3-chloro-4-bromobenzyl, 4-chlorobenzyl, 4-bromobenzyl group,

3,4-dimethoxybenzyl, 3- (trifluoromethyl) benzyl, 2-cyanobenzyl, 4-cyanobenzyl, 2-fluoro-4-bromo-5-nitrobenzyl, 4-nitrobenzyl, 3,5-dichloro-4- bromobenzyl, 2,4-dichlorobenzyl, 4-hydroxybenzyl or 3,5-dichlorobenzyl.

A preferred ring A is an unsubstituted ring or a ring bearing halogen, for example chlorine, especially at the 5 ', 6' or 7 'position.

A preferred radical R @ ¹ is a benzyl group bearing one or two halogen atoms, for example 4-halo-, 2,4-dihalo-, 3,4-dihalo- or

3,5-dihalobenzyl, such as 4-bromo, 2-fluoro-4-bromo, 2-fluoro-4-iodo, 3,4-dichloro, 3-chloro-4-bromo or 3,5- dichlorobenzyl.

Suitable groups of compounds according to the invention are the following compounds of formula (I) in which (and R ¹ is C 1 -C 12 alkyl or unsubstituted benzyl and the benzene ring A carries at least one halogen as a substituent;

(b) R ¹ represents a phenyl group, a cinnamyl group or a naphthylmethyl group, the aromatic rings of which optionally bear one or two halogen atoms, and the benzene ring A is unsubstituted or bears at least one halogen substituent and (cj R ¹ represents a benzyl group bearing one) two or three substituents independently selected from the group consisting of halogen atoms, trifluoromethyl, cyano, hydroxy, nitro, methyl and methoxy, and the benzene ring A is unsubstituted or carries one or two substituents as defined above and pharmaceutically acceptable salts of the compounds of all these groups.

One preferred group of compounds produced by the process of the invention are those compounds of formula I wherein R ¹ and the benzene ring A have any of the preferred meanings defined above, and pharmaceutically acceptable salts thereof.

Another group of preferred compounds of the present invention are those compounds of formula (I) wherein R ¹ is 3,4-dichlorobenzyl, 2-fluoro-4-bromobenzyl, 3-chloro-4-bromobenzyl or 2-fluoro-4. the iodobenzyl group and the benzene ring A is unsubstituted or is 5'-fluoro-, 5'-chloro, 5'-bromo, 5 ', 6'-difluoro-, or 5', 6'-dichloro-substituted and their pharmaceutically acceptable useful salts.

The specific compounds produced by the process according to the invention are given in the Examples below, of which the following compounds are of interest:

1‘- (3,4-dichlorobenzyl) spiro [imidazolidine-4,3‘-indoline] -2,2,5,5-trione,

1‘- (2-fluoro-4-bromobenzyl) spiro [imidazolidine-4,3‘-indoline] -2,2,5,5-trione,

1‘- (3,4-dichlorobenzyl) -5‘-fluorospiro [imidazolidine-4,3‘-indoline] -2,2,5,5-trione,

Γ- (3-chloro-4-bromobenzyl) spiro [imidazolidine-4,3‘-indoline] -2,2,5,5-trione,

1‘- (3,4-dichlorobenzyl) -5‘-chlorspiro [imidazolidine-4,3‘-indoline] -2,2,5,5-trione,

1‘- (2-fluoro-4-bromobenzyl) -5‘-chlorospiro [imidazolidine-4,3‘-indoline] -2,2,5,5-trione,

Γ- (3,4-dichlorobenzyl) -5‘-bromospiro (imidazolidine-4,3‘-indoline) -2,2,5,5-trione,

Γ- (2-fluoro-4-bromobenzyl) -5‘-fluorospiro [imidazolidine-4,3‘-indoline] -2,2,5,5-trione,

1'- (3,4-dichlorobenzyl) -5 ', 6'-dichlorspiro [imidazolidine-4,3'-indoline] -2,2', 5-trione, 1 '- (3,4-dichlorobenzyl) -5 6'-difluorspiro [imidazolidine-4,3'-indoline] -2,2 ', 5-trione and

1‘- (2-fluoro-4-iodobenzyl) spiro [imidazolidine-4,3‘-indoline] -2,2,5,5-trione and their pharmaceutically acceptable salts.

Suitable pharmaceutically acceptable salts of the compounds of formula I are, for example, alkali metal or alkaline earth metal salts such as sodium, potassium, calcium or magnesium salts, aluminum or ammonium salts, or salts with organic bases such as triethanolamine forming pharmaceutically useful cations .

The compounds of the formula I are prepared according to the invention by the preparation of an indoline-2,3-dione of the formula III

is reacted with alkaline cyanide co250654 vu and ammonium carbonate or carbamate.

A suitable alkali metal cyanide is, for example, sodium or potassium cyanide.

It is understood that the method of the invention is an example of the Bucherer-Bergs synthesis of imidazolidine-2,4-diones (hydantoins), which is well known in the art (see E. Ware, Chemical Reviews, 1950, 46, 422-425), and whereas this reaction can therefore be carried out via a hydroxynitrile corresponding to the general formula IV

OH (IV) and / or via an aminonitrile of formula V

L ^{CN V}

Accordingly, the invention includes an embodiment in which the intermediate of formula (IV) is prepared separately or in situ (for example by reacting a compound of formula (III) with hydrogen cyanide) and then reacted with ammonium carbonate or carbamate. Similarly, the invention includes an embodiment wherein the intermediate of formula (V) is prepared separately or in situ (for example by reacting a compound of formula (III) with ammonia and hydrogen cyanide) and then reacted with carbon dioxide which can be conveniently employed as carbonate or ammonium carbamate.

The process of the invention may conveniently be carried out in a solvent or diluent, for example in a C 1 -C 4 alkanol such as methanol or ethanol, or in ethylene glycol or diethyl glycol, preferably water, at a temperature in the range, for example, 20 to 100. Deň: 32 ° C.

The ammonium carbonate or carbamate can, if desired, be prepared in conventional manner in situ.

The starting materials of the formula (III) can be prepared by methods customary in indole chemistry. For example, those compounds of formula III in which R @ ¹ is other than a phenyl moiety may be obtained by reacting an indoline-2,3-dione of formula III in which the moiety is as defined below.

R ^{1 is} replaced by hydrogen, with an appropriate alkyl or aralkyl halide, for example -chloride, -bromide or-iodide, in the presence of a base such as sodium or potassium hydroxide, in dimethylsulfoxide at a temperature of 20 to 40 ° C.

Those starting materials of formula III in which R @ ¹ is phenyl may be prepared, for example, by condensation of the corresponding diphenylamine with oxalyl chloride and aluminum chloride, as described in U.S. Patent No. 3,509,149.

If a pharmaceutically acceptable salt is to be prepared, the compound of formula (I) is reacted with an appropriate base providing a pharmaceutically acceptable cation using a conventional procedure.

If an optically active form of a compound of formula (I) is to be prepared, the racemic form of the compound may be reacted with an optically active form of a suitable orgadic base such as brucine, horse, or 2-pipecoline and then separated in a conventional manner, e.g. crystallization from a suitable solvent, for example from a C 1 -C 4 alkanol. The desired optically active form of the above compound can be liberated by treatment with an acid in a conventional manner, for example using an aqueous mineral acid such as dilute hydrochloric acid.

Aldose reductase enzyme inhibitory activity can be demonstrated by the following standard laboratory test.

In rats, administration of streptozotocin is induced by diabetes (as evidenced by severe glucosuria). The animals are then treated with the test compound for 5 days per day. The test animals are sacrificed and their eye lenses and sciatic nerves are removed. After standard processing, residual sorbitol levels (after conversion to poly-trimethylsilyl derivatives) were determined by gas chromatography in each of these tissues.

By comparing the residual sorbitol levels in the tissues of the treated group of diabetic rats to that of the untreated group of diabetic rats and the untreated group of normal rats, the inhibition of aldose reductase in vivo was found.

Alternatively, a modified test can be used in which a test compound is administered to a group of rats induced by streptozotocin for two days daily. Two to four hours after the last dose, the animals are sacrificed, their sciatic nerves removed and the residual sorbitol level determined as described above.

Preferred compounds produced by the method of the invention in both of these assays reduce residual sorbitol levels to values similar to those found in normal rats not receiving the test compound. In general, 250504 compounds of formula I exhibit marked inhibition of the aldose reductase enzyme when administered orally at a dose. 100 mg / kg or at a much lower dose. ,.

By way of illustration, mention may be made, for example, of 1'- (3,4-dichlorobenzyl) -piro [imidazolidine-4,3'-indoline] -2,2 ', 5-trione and 1- (2-fluoro-4-bromobenzyl) spiro. [imidazolidine-4,3'-indoline] -2,2 ', 5'-trione, which compounds, after 5 days of oral administration at a dose of 10 mg / kg, produce a residual level of sorbitol in the sciatic nerve corresponding to approximately 20% of that observed in the control In the tests described above, no marked toxic or other adverse effects were observed when the compounds of general formula I were administered at doses of 100 mg / kg.

Preferred compounds of formula I as defined above generally reduce residual phladin. orbitol, in a sleep-inducing nerve to the value found in normal untreated rats at oral doses ranging from 5 to 20 mg / kg.

Aldose reductase enzyme inhibitory effects can also be demonstrated in vitro. In this case, purified aldose reductase is isolated from bovine eye lenses in a known manner, using a standard spectrophotometer to determine the percentage of inhibition of the ability of this enzyme in vitro to reduce alcohols to polyhydric alcohols, particularly to reduce glucose. to sorbitol caused by the test compound. In this test, compounds of general formula. In general, they also show significant inhibition of the aldose reductase enzyme at a concentration of about 10 ° M or even much lower.

When using a compound of this invention to induce effects on aldose epzym iktasu re ^ _{u: t} teplokre vnýc _(h animals, may, be administered primarily orally at a daily, dose. Transversely from 0.5 ... up to 20 µg / µg, which in humans corresponds to a total daily dose ranging from 10 to 750 mg per patient, which total dose may, if desired, be administered in several divided doses.

The compounds produced by the process of the invention may be administered in the form of pharmaceutical compositions, and the invention therefore also provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof, together with pharmaceutically acceptable diluents or carriers.

Particularly preferred pharmaceutical compositions are those suitable for oral administration, for example tablets, capsules, suspensions or solutions, which may be prepared by conventional methods and which may optionally contain conventional diluents, carriers or other excipients. Other preferred compositions are those in a form suitable for parenteral administration, for example. ; '. -. f. sterile injectable aqueous or non-aqueous solutions or suspensions, and for rectal administration such as suppositories. Dosage forms generally contain from about 10 mg to about 250 mg of a compound of Formula I, or an equivalent amount of a pharmaceutically acceptable salt thereof, per unit dose.

These compositions may also contain one or more agents which may have beneficial effects in the treatment of diabetes or galactosemia, such as hypoglycaemic agents such as tolbutamide, chlorpropamide or glyhenclamide.

The invention is illustrated by the following non-limiting examples. In these cases, unless otherwise stated, (ij all evaporations are carried out on a rotary evaporator under vacuum;

(11j) all operations are carried out at room temperature, i.e. at a temperature ranging from 18 to 28 ° C;

(iii) all compounds were complete; characterized by microanalysis and NMR and IR spectroscopy; and (iv) all yields, when given, are for illustrative purposes only and in no way represent the maximum attainable yields.

? See below

A mixture of 12.0 g of 1- (3,4-dichlorobenzyl) -indoline-2,3-dione, 36.0 g of ammonium carbonate and 5.2 g of potassium cyanide in 300 ml of methanol and 300 ml of water was refluxed for 3 hours. The resulting dark colored solution was cooled somewhat and 3.0 g of charcoal was added, the mixture was heated to 95-100 ° C and all methanol was distilled off. The filtrate is combined with the washings, cooled and acidified with concentrated hydrochloric acid to pH 2. The precipitated yellow-orange solid is separated and washed with water, dried to give a yellow solid. of air and recrystallized twice from ethyl acetate / petroleum ether (b.p. 60-80 ° C; 4: 1 v / v). 3.3 g of 1 '- (3,4-dichlorobenzyl) spiro [imidazolidin-4, 269 DEG-271 DEG C. 3 ' -indoline] -2,2 ', 5-trione.

The starting material was prepared as follows.

To a solution of 14.7 g of indoline-2,3-dione (isatin) in 200 ml of dimethyl sulfoxide was added 100 ml of 1M ethanolic potassium hydroxide solution with stirring, and after 10 minutes a solution of 21.5 g of 3,4-dichlorobenzyl chloride in 10 ml was added. dimethylsulfoxide. The mixture was stirred for 72 hours and then poured into 600 ml of water. The precipitated solid product is collected, washed with water, dried over air and recrystallized from a 3: 2 (v / v) mixture of ethyl acetate and petroleum ether (bp 60-80 degrees Celsius). 13.8 g of 1- (3,4-dichlorobenzyl) indoline-2,3-dione, m.p. 183 DEG-184 DEG C., are obtained.

Examples 2 to 5

Using the corresponding indoline-2 ', 3-dione of the general formula III] as starting material, the following compounds are obtained in an analogous manner to Example 1; of formula I:

example number R ¹ benzene- vém Circle A melting point (° C crystallization solvents (v / v) yield (%)

2 2-fluoro-4-bromobenzyl - 298- 3 1-naphthylmethyl · - 268- 4 n-propyl 6‘-chloro 261- 5 3,4-dichlorobenzyl 5‘-fluoro 240

300 methanol / ethyl acetate (1: 3) 19 Dec 270 isopropanol / PET * ’ (1 = 3) 25 263 Isopropanol / PET * ¹ (1: 3) 46 242 ethyl acetate / PET * ’ (13) 13

Legend:

* petroleum ether (boiling point 60 to 80 ° C)

The necessary starting materials of the formula III are obtained in an analogous manner to that described for the preparation of the starting material in Example 1, using in each case the corresponding isatin and the halides of the formula R'X.

Compounds with the following properties are obtained in the following yields:

merge-X to a number

R ¹ substi- crystallization melting temperature (° CJ solvent-boron- (v / v) new ring A yield (%)

1 Br 2-fluoro-4-bromobenzyl - 151- -153 isopropanol / PET * ’ 73 (13] 2 Cl 1-naphthylmethyl - 172- -174 ethyl acetate / PET * ’ 54 (13) 3 ' Br n-propyl 6-chloro 118- -120 petroleum ether (b. 80-100 ° C) 57 4 Cl 3,4-dichlorobenzyl 5-fluoro 190- -192 ethyl acetate / PET * ’ 40

(13}

Legend:

petroleum ether (bp 60 to 80 ° C) Examples 6 to 33

The following compounds of the formula I are obtained in an analogous manner to that of the corresponding indole-2,3-dione of the formula III in each case as starting material:

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>. (a) = the product is isolated as a waxy material which, according to thin-layer chromatography on silica gel, is used a mixture of equal volumes of ethyl acetate and toluene as the solvent system net

The procedure described in U.S. Pat. No. 3,509,149 affords 1-phenylindoline-2,3-dione (for Example 33) in a yield of 56% as a solid melting after recrystallization from 2-propanol at 138-139 ° C.

Examples 34 to 40

Using the corresponding 1-substituted indoline-2,3-dione of the formula III as starting material, the following compounds of the formula I are obtained in a manner analogous to Example 1:

example number R ¹ suhstituent on benzene ring melting point (° C crystallization solvents yield (° / o) 34 4-methylbenzyl 5‘-Cl 257— 259 ethyl acetate / PET * ’ 12 35 methyl 5‘-Cl 306—308 acetone / PET * ’ 25 36 n-hexyl 5‘-Cl 158—160 ethyl acetate / PET * ¹ 26 37 3,4-dichlorobenzyl 4 ', 5'-Cl ₂ 155—156 (decomposition) ethyl acetate / PET * ’ 10 38 3,4-dimethoxybenzyl 5‘-Cl 285—287 ethyl acetate / PET * ’ 14 39 3,4-dichlorobenzyl 5'-chloro-7'-methyl 273—275 ethyl acetate / 2-methyl- thoxyethanol 29 40 2-fluoro-4-bromobenzyl 5'-chloro-7'-methyl 247—249 ethyl acetate / PET * ’ 25

Legend:

⁺⁾ yield of recrystallized product * PET = petroleum ether (boiling point 60-80 ° C)

The necessary starting materials of formula III were obtained in an analogous procedure to that described for the preparation of the starting material in Example 1, i.e. by reaction of the appropriate indoline-2,3-dione with a halide of general formula R ¹ .X. These compounds are summarized as follows:

compound no. X R ¹ benzene- vém Circle A melting point (° C) crystallization solvents yield (%) 1 Br 4-methylbenzyl 5-C1 156—158 isopropanol 52 2 AND methyl 5-C1 170—172 isopropanol 60 3 Br n-hexyl 5-C1 86—88 isopropanol 49 4 Cl 3,4-dichlorobenzyl 4,5-Cl ₂ 185-187 ethyl acetate / PET * ' 71 5 Cl 3,4-dimethoxybenzyl 5-C1 162—164 isopropanol / dimethylformamide 33 6 Cl 3,4-dichlorobenzyl 5-chloro- -7-methyl 191—194 acetonitrile / dlme- thoxyethanol 41 7 Cl 2-fluoro-4-bromobenzyl 5-chloro- -7-methyl 179—182 acetonitrile / dimime- thoxyethanol 43

Legend:

⁺ 'yield of recrystallized product ¹ PET = petroleum ether (boiling point 6 (1-80 ° C)

Example 1 a d 4 1 Example 1 a d 4 2

A filtered solution of 3.76 g '- (3,4-dichlorobenzyl) spiro [imidazolidine-4,3'-indoline] -2,2', 5-trione in 20 ml of water containing 0.40 g of sodium hydroxide was evaporated and the remaining traces of water were removed by azeotropic distillation with toluene. In quantitative yield, the corresponding monosodium salt is obtained in the form of an amorphous hygroscopic solid with a satisfactory microanalysis.

To 61.5 ml of a 0.19M solution of (1) -N, N, N-trimethyl-1-phenylethylammonium hydroxide was added 4.4 g of (dl) -1 '- (3,4-dichlorobenzyl) spiro (imidazolidine-4,3'). -indoline] -2,2 ', 5-trione.

To facilitate dissolution, the mixture is heated and then evaporated. The residue was dissolved in 11 mL of warm 2-propanol and cooled to 0 ° C for 48 hours. The precipitated crystalline material is filtered off, washed first with 5 ml of cold 2-propanol and then with 20 ml of petroleum ether (b.p. 40-60 ° C) and recrystallized twice from 2-propanol to give (dj-diastereomer of salt (1) - N, N, N-trimethyl-1-phenylethylammonium hydroxide and (d) -1 '- (3,4-dichlorobenzyl) spiro [imidazolidine-4,3'-indoline] -2,2'-5-triazine, yield 1.6. g, mp 148-150 ° C, optical rotation [rE | ^{n? 3} --- + 32.8 ° (c - 1.4 in methanol first

The 1.6 g salt obtained is dissolved in 10 ml of water and 3 ml of methanol and the solution is acidified with 1 ml of concentrated hydrochloric acid. The precipitated solid product is collected, washed with water and recrystallized from ethanol to give (d) -1 '- (3,4-dichlorobenzyl) spiro [imidazolidine-4,3'-indoline] -2,2' , 5-trione, mp 199-200 ^C C. [.alpha, and _D - ³ - + 41 ° (c 1.6, methanol).

The starting solution of the quaternary ammonium hydroxide is obtained by an aqueous solution of 27.8 grams of (1) -N, N, N-trimethyl-1-phenylethylammonium iodide (I. Angres and E. Zieger, J. Org. Chem. 1975, 40, 1,457-1,460) was passed through a column of anion exchange resin &quot; Amberlite &quot; JRA 401 (200 grams) freshly converted to the hydroxide form.

It will be understood that other individual enantiomers of optically active quaternary ammonium hydroxides, such as k, Ν, trim-trimethyl- (1-methyl-2-hydroxy-2-phenylethyl) ammonium, may also be used to resolve racemic forms of the compounds of formula I .hydroxide.

Example 43 to 5 5

Using the corresponding indoline-2,3-dione of the formula III as starting material, the following compounds of the formula I can be obtained in analogy to Example 1 in yields of 15 to 70%:

example

C.

R ¹ substituent on benzene ring A crystallization melting point (° CJ solvent (v / v)

43 3,5-dichloro-4-bromobenzyl - 290-292 aqueous dimethyl- formamide 44 3,4-dichlorobuzyl 6 * -chlor 266—267 ethyl acetate / petroleum ether (m.p. 60-80 ° CJ.) 45 3,4-dlchlorobenzyl 5 ‘, 6‘-dimethyl 262-263 ethyl acetate / petroleum ether (60-80 ^C C TV) 46 3,4-dichlorobenzyl 7‘-ethyl 232—233 ethyl acetate / petroleum ether (m.p. 60-80 ° C) 47 3,4-dichlorobenzyl 5‘-nitro 249—251 ethyl acetate / petroleum ether (b.p. 60-80 ° C) 48 2-fluoro-4-bromo-5-nitrobenzyl 5‘-nitro 180-181 isopropanol / petroleum ether (b.p. 60-80 ° C) 49 4-nitrobenzyl 5'-bromo-7'-nitro 245—246 ethyl acetate / petroleum ether (b.p. 60-80 ° C) 50 3,4 dichlorcinnamyl 5‘-chloro 295—297 aqueous dimethylformamide 51 4-hydroxybenzyl - 285—286 methanol 52 3,4-dichlorobenzyl 5 ‘, 6‘-difluoro 244—245 ethyl acetate / petroleum ether (b.p. 80-100 ° C) 53 3,4-dichlorobenzyl 5 ‘, 6‘-dichloro 255—256 ethyl acetate / petroleum ether (b.p. 60-80 ° C) 54 3,5-dichlorobenzyl - 237—238 toluene 55 3,4-dichlorobenzyl 5‘-hydroxy 296—298 ethyl acetate / petroleum ether

(m.p. 60-80 ° C)

Default indoline-2,3-diones of formula III can be obtained in a generally analogous manner to the starting material in Example 1 but starting from the appropriate N (l) -unsubstituted indoline-2,3-dione and halide of the formula R ^L .X as starting materials. Representative starting materials of the formula III are:

Í9

5 06 5 5

X R ¹ substituents temperature crystallization on benzene melting (° Cj solvents Circle A 241—243 Cl 3,5-dichloro-4-bromobenzyl - 241—243 methanol Cl 3,4-dichlorobenzyl 6-chloro 180—182 isopropanol Cl 3,4-dichlorobenzyl 5,6-dimethyl 218—220 ethyl acetate Cl 3,4-dichlorobenzyl 7-ethyl 124—126 petroleum ether (m.p. 60-80 ° C) Cl 3,4-dichlorocinnamyl 5-chloro 194—196 ethyl acetate Cl 3,4-dichlorobenzyl 5,6-difluoro 170—171 toluene Cl 3,4-dichlorobenzyl 5,6-dichloro 197—200 ethyl acetate / petroleum ether (m.p. 60-80 ° C) WHOSE 3,5-dichlorobenzyl - 192—193 ethanol  (4-hydroxybenzyl) indoline-2,3-dione; This solid product together with the next

required as starting material in the process of Example 51, can be prepared as follows.

A solution of 16.6 g of potassium hydroxide in 400 ml of ethanol is added to a solution of 43.6 g of indoline-2,3-dione (isatin in 400 ml of dimethylsulfoxide) with stirring. After 10 minutes, a solution of 76.3 g of 4-acetoxybenzyl bromide in 40 ml is added. ml of dimethylsulfoxide, the mixture is stirred for 72 hours and then poured into about 1000 ml of ice-water, initially precipitating a gum which slowly crystallizes, and the resulting solid is recrystallized from 500 ml of methanol to give 1- (4-). acetoxybenzyl i indoline-2,3-dione as a solid melting at 159-161 degrees Celsius.

the product obtained from the mother liquors is chromatographed on 500 g of silica gel using toluene containing increasing amounts of ethyl acetate (up to 25% by volume) as eluent. Toluene eluted fractions containing 20-25% ethyl acetate by volume were combined and evaporated to give 1- (4-hydroxybenzylindindolin-2,3-dione as a low melting solid, having a melting point of 28-35 ° after recrystallization from toluene / ethyl acetate). 'C.

It should be noted that during the above-described silica gel chromatography, the acetoxy group is hydrolyzed to the desired hydroxy group.

Claims (6)

SUBJECT VYNALEZU A process for the preparation of substituted indolih-2-one derivatives of the general formula I Τ> ϊΓ ~ O R (i) halogen atoms, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy, nitro and hydroxyl groups, or carries two substituents independently selected from the group consisting of halogen atoms, (C 1 -C 4) alkyl groups carbon atoms and nitro groups, and pharmaceutically acceptable salts thereof, with the exception of those compounds wherein R ¹ is methyl, ethyl, n-propyl or unsubstituted benzyl and the benzene ring A is unsubstituted, characterized in that indoline-2,3 a dione of formula III wherein: R ¹ represents an alkyl group having 1 to 12 carbon atoms, a phenyl, riaphthylmethyl or cinnamyl group, the aromatic rings of which optionally bear one or two halogen atoms, or a benzyl group optionally bearing one, two or three substituents independently selected from the group including halogen atoms, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro, cyano and hydroxyl, and the benzene ring A optionally bears one substituent selected from the group consisting of (A) R ¹ (III) wherein R ¹ and benzene ring A have the above meanings, is reacted with an alkali metal cyanide and ammonium carbonate or carbamate, then, if desired, to produce optically active forms of the compound The racemic form of this compound is reacted with an optically active form of a suitable organic base, the mixture of diastereomeric salts thus formed is separated and the optically active form of said compound is liberated by treatment with acid, and the compound of formula I is optionally left reacting with an appropriate base providing a pharmaceutically acceptable cation to form a pharmaceutically acceptable salt. 2. The process of item 1, for the preparation of compounds of the above general formula I, wherein: R ¹ represents an alkyl group having 1 to 12 carbon atoms, a phenyl, naphthylmethyl or cinnamyl group, the aromatic rings of which optionally bear one or two halogen atoms, or the benzyl group optionally bearing one, two or three substituents independently selected from one another from the group consisting of halogen atoms, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro and cyano, and the benzene ring A optionally bears one substituent selected from the group consisting of halogen atoms, C 1 -C 4 alkyl Or carries two substituents independently selected from the group consisting of halogen atoms, C 1 -C 4 alkyl and nitro groups, and pharmaceutically acceptable salts thereof, with the exception of those compounds in which: R ¹ represents methyl, ethyl, n-propyl or unsubstitute The benzyl group and the benzene ring A are unsubstituted, characterized in that the indoline-2,3-dione of the above-mentioned general formula III, in which ^RJ and the benzene ring A is as defined above, is reacted with an alkali metal cyanide. and ammonium carbonate or carbamate, followed by optionally reacting the optically active form of a suitable organic base to produce the optically active form of a compound of formula (I), separating the resulting mixture of diastereomeric salts in a conventional manner and liberating the reaction by acid treatment. the active form of the aforementioned compound, and the compound of formula I obtained, optionally in a conventional manner, reacted with an appropriate base providing a pharmaceutically acceptable cation to form a pharmaceutically acceptable salt. 3. A process according to claim 1 or 2, wherein the alkali metal cyanide is sodium or potassium cyanide. 4. Process according to claim 1, 2 or 3, characterized in that the reaction is carried out in a solvent or diluent, such as a C1-C4 alkanol, ethylene glycol or diethylene glycol. 5. The method of any one of items 1 to 4, characterized in that the reaction is carried out at a temperature in the range of from 20 to 100 ° C. 6. The method according to any one of items 1 to 5, characterized in that the starting material used is a compound of formula (III) in which the benzene ring A is unsubstituted or is 5'-fluoro-, 5'-chloro-, 5'-bromo-, 5 ', 6 '-difluoro- or 5', 6'-dichloro-substituted a R ¹ represents 3,4-dichlorobenzyl, 2-fluoro-4-bromobenzyl, 3-chloro-4-bromobenzyl or 2-fluoro-4-iodobenzyl.