JPS58206592A - Trifluoromethylspiro(imidazolydine-4,3'- indolin)-2,2',5-trione, manufacture and antidiabetic or antigalactosemic pharmaceutical composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention discloses novel spiro[imidazolidine-4,3'-yne P, which is a potent inhibitor of the enzyme aldose reductase.
The present invention relates to fluoroalkyl derivatives of [phosphorus]-2,2',5-trione, and more particularly to novel trifluoromethyl derivatives. The present invention also relates to a method of farming the new compound and to pharmaceutical compositions containing the compound.

The enzyme alr-threductase is responsible in humans and other warm-blooded animals for the catalytic conversion of alP-ses, such as glucose-7s and galactose, to the corresponding alnotols, sorbitol and galactitol, respectively. Arunode-'''' cell membranes are insufficiently Kt, J-permeable, and once formed, they wait for the property of being removed only by subsequent metabolism. As a result, alditol tends to accumulate in the formed cells, e.g. lens, peripheral nervous tissue and kidneys, leading to an increase in internal osmotic pressure, which destroys or impairs the function of the cells themselves. Sometimes it's enough.

Furthermore, elevated alditol concentrations lead to abnormal concentrations of its intermediate metabolites, which can impair or damage cellular functions. However, the enzyme aldose reductase has a relatively low substrate affinity, ie the enzyme is only effective in the presence of relatively high concentrations of aldose. Such high concentrations of aldose are present in the clinical conditions of pityriasis (ilj glucose) and galactosemia (excess galactose). As a result, inhibitors of aldose reductase are useful in reducing or preventing the development of complications of prolonged diabetes or galactose disk disease, due in part to accumulation of sorbitol or glactitol, respectively. Such complications include spotting, cataracts,
If you have retinopathy, kidney disease or damaged nerve conduction.

having a series of substituents on the benzene ring of the indoline moiety,
Certain 1'-substituted spiro[imidazolidine-4,37
It is known from previous studies that 2,7,5-trione has useful aldose reductase inhibitory properties (European Patent Application Publication No. 28906AI). By the way, strictly defined
It has now been discovered that such compounds containing a new class of S/, 6/- or 7'-trifluoromethyl substituents have unexpectedly strong aldose reductase inhibitory properties.
This is the basis of the present invention.

According to the invention, formula I: b [wherein the trifluoromethyl substituent of benzene iA is 5'
position, 6' or 7'position; and benzene fiB
is nohalogenophenyl, where R is fluoro or chloro, up to Rbk is hydrogen, and R is chloro, bromo or rayoido, or Ra is hydrogen; are independently chloro or bromo;
Non-,4,3'-indoline)-2,2',5-1-
Lyone or its salts with bases giving pharmaceutically acceptable cations or non-toxic, biodegradable precursors are obtained. The compound of formula I is a derivative of spiro[imidazolidine-4,3'-indoline]-2,2',5-)ion represented by formula (1):

In this specification, Ra, Rb, etc. are used to represent generic groups, and other fi: tasteless.

All compounds of formula (1) have an asymmetric carbon atom, ie, a spiro carbon atom, at the 4-position of the imidazolidine ring. Compounds of formula I therefore exist and can be isolated in racemic and optically active forms. The present invention encompasses compounds of formula I in racemic form or in any optically active form having aldose reductase inhibitory properties, and by resolution of the racemic form,
' or by synthesis from optically active starting materials and methods for determining aldose reductase inhibitory properties by the standard tests described below are well known in the art.

An excellent benzene ring B is 3,4-dichloro-13,
4-dibromo-13-bromo-4-chloro-14-bromo3-chloro-14-chloro-2-fluoro,4-
Bromo-2-fluoro- or 2-fluoro-4-iodo-phenyl.

An excellent group of compounds according to the invention is of the formula [[:[wherein Hensen II B Ka4-zolomo2-ri'o.

-14-bromo-2-fluoro- and 2-fluoro-
selected from 4-iodo-phenyl; and Rd and R
, one of which is trifluoromethyl and the other is hydrogen], pharmaceutically acceptable salts thereof and non-toxic, biodegradable.

It is a sexual precursor.

The term non-toxic, biodegradable precursor means that one or two of the imino hydrogen atoms in the imidazolidine ring are not inherently toxic and can be removed in vivo (e.g. by enzymatic hydrolysis), resulting in aldose The compound of formula I is isolated in an amount sufficient to inhibit retalitase and without producing pharmacologically acceptable by-products (.substituted with biodegradable protecting groups known in the art). examples of suitable groups included in the biodegradable precursors of compounds of formula
Alkanoyloxy)alkyl groups such as ethoxycarbonyl, t-butyloxybenzenyl, benzyloxycarbonyl, ethoxyoxalyl, methoxyoxalyl and piparoyloquinemethyl groups are included. In general, the biodegradable precursor itself is either an inhibitor of aldose remectase or is active in vivo because the biodegradable protecting group is not removed. Thus, by appropriate selection of the biodegradable protecting group (e.g., based on the rate of enzymatic degradation known to its yield), its bioabsorption and distribution may differ from that of compounds of formula I. It will be clear that biodegradable precursors of compounds of Formula I may be prepared.

An example of a highly toxic, biodegradable protecting group is pipacoyloxymenal.

Particular salts of compounds of formula I with bases which provide pharmaceutically acceptable cations include, for example, alkali metal or alkaline earth metal salts (such as sodium, potassium, calicylum or magnesium salts), aluminum or ammonium salts, or organic bases. (for example, triethanolamine).

Particularly excellent compounds of the present invention are ni)-1'-(4-zolomo-2-fluorobenzyl)-5'-), lJfluoromethyl-spiro[imitasoIJ)-4°3-indoline)-2,2' , 5-trione 2 and -- or (d
)-1'-(4-bromo-2-fluorobenol) -
7'-17 Fluoromethyl-spiro[imidazolidine-4,3'-indoline]-2,z',5-)I
J-on or a pharmaceutically acceptable salt thereof or non-toxic;
Includes biodegradable precursors.

The novel compounds of formula I can be obtained by any method known in the art for the preparation of structurally related compounds.

According to another feature of the invention, such a method is provided,
and the method is illustrated by the following current method, where Ra-Re represents any of the foregoing.

(al Indoline-2,3-dione of formula ■: b is reacted with an alkali metal cyanide and ammonium carbonate or ammonium carbamate.

Suitable alkali metal cyanides are, for example, sodium cyanide or potassium cyanide.

This method is well known in the art and is described in "Puchalber Chemical Reviews".
, Vol. 46, pp. 422-425 (1950)].

Therefore, this method uses the formula V: R Clean up hydroxycunitrile and/or formula ■: b Proceeding via an amino-nitrile.

These intermediates are generally not stable enough to be isolated. However, these are methods (a), for example by reacting a compound of formula (1) with hydrogen cyanide to obtain a compound of formula V;
It is produced by subsequent reaction with ammonium carbonate or ammonium carbamate. Similarly, a compound of formula (1) may be reacted with ammonia and hydrogen cyanide to give a compound of formula (1), followed by reaction with carbon dioxide (preferably obtained from ammonium carbonate or ammonium cal-cuminate).

This method is generally carried out using a suitable solvent or diluent, such as (1)
~4C) an alkanol, such as methanol or ethanol, or ethylene glycol, preferably containing water, or c) ethylene glycol and at a temperature of, for example, 20 to 10
Performed at 0'C.

If desired, ammonium carbonate or ammonium carbamate may be formed in situ in a conventional manner.

The starting material of formula (1) can be obtained by conventional methods of indole chemistry. For example, Koshira is a suitable indoline-2,3-
The dione is prepared in the presence of a base, e.g. sodium or -potassium hydroxide or sodium or potassium carbonate.
- by reaction with pen, nor or benzyl bromide in dimethylformamide or dimethyl sulfoxide at 20-40°C.

(bl Rf is acyl or tri[(1-4C)alkyl]silyl, the compound of formula 2: is reacted with ammonium carbonate or ammonium carbamate.

The details of R( when it is acyl are examples, E is (1 to
6C) Alkanoyl, such as acetyl or propionyl, phenylsulfonyl, toluene p-sulfonyl, benzoyl or benzyloxycarbonyl.

Rf in the case of 1-4C)alkyl]silyl
For example, trimethylsilyl is a specific example.

Method (b) is a modification of method (a) above and therefore similar reaction conditions may be used. Similarly, ammonium carbonate or ammonium lupamate may be formed in situ if desired.

The starting material of formula (1) can be produced by a conventional method. That is, compounds of formula (2) in which Rf is acyl are preferably prepared by preparing, for example, the ittrin-2,3-dione of (2) in aqueous methylene chloride in the presence of sodium cyanide or potassium cyanide and sodium or potassium hydroxide.
It is obtained by reaction with a suitable acyl halide (eg benzoyl chloride or benzyl chloroformate) at 25°C. Similarly, Rf is tree [(1~4C)-
Compounds of formula (1) which are silyl (alkyl]silyl) can be prepared by, for example, preparing a suitable indoline-2,3-dione of formula (1) by IJ in a non-aqueous solvent such as 1,2-dimethoxyethane at 15-40"C.
-[('1-4C)alkyl]silyl cyanide (for example, trimethylsilyl cyanide).

It is clear that the process described above produces compounds of formula (II) in the form of base addition salts, which can be prepared in a conventional manner, for example by inorganic acids,
For example, a non-toxic, biodegradable precursor of a compound of formula I, which can be easily converted to the free acid by treatment with hydrochloric acid, can be used in the preparation of compounds already used in the introduction of the necessary biodegradable precursor. It can be obtained by the acylation or alkylation method. Examples of suitable affylating or alkylating agents for introducing a series of protecting groups include, for example, alkoxycarzenyl halides, aralkoxylzenyl halides, alkoxyoxalyl halides and 1-(alkanoyloxy)alkyl halides, For example, ethoxycarbonylchloride
, i-butyloxycarbonyl chloride, ethoxyoxalyl chloride, methoxyoxalyl chloride, and piparoyloxymethyl chloride.

The reaction is carried out using conventional N-acylation/alkylation conditions, e.g. the lithium, sodium or potassium salt of a compound of formula I in the presence of a base, e.g. potassium carbonate, and a suitable solvent or diluent, e.g. . It may be carried out in 2-dimethoxyethane, dibutyl ether or diethyl ether, for example at a temperature of 10 DEG to 80 DEG C.

Pharmaceutically acceptable salts of compounds of formula I are obtained in conventional manner, eg by reaction with a suitable base to provide a pharmaceutically acceptable cation.

If an optically active form of a compound of formula I is required, it may be prepared in racemic form by a suitable organic base, such as in particular N, , N, N, -) IJ acyl-(1-phenylethyl). ammonium hydroxide, such as N,
reaction with N,N-trimethyl-(l-phenylethyl)ammonium hydroxide and subsequent fractional crystallization of the diastereomeric mixture of the salts thus obtained in a conventional manner, for example from a suitable solvent, such as a (1-4C) alkanol. The optically active form of the compound can then be separated by treatment with an acid, for example using an aqueous mineral acid, such as dilute hydrochloric acid.

The properties of inhibiting aldose reductase can be demonstrated in the following standard laboratory tests. Rats are given streptocytosine to induce diabetes (as evidenced by the presence of significant glucosuria). Animals are then dosed with test compound daily for 5 days. After standard processing steps in which the animals are sacrificed and the eye lens and sciatic nerve are excised, the residual sorbitol concentration in each tissue is determined by conversion wave gas-liquid chromatography to poly-trimethylsilyl derivatives. Inhibition of aldose reductase in vivo is then evaluated by comparing the residual nrubitol concentration in the tissues of the diabetic rats in the test compound-administered group with those in the diabetic rats in the non-administered group and the normal rats in the non-administered group. .

A modified test may be used in which streptocytosine-induced diabetic rats are administered the test compound daily for two days. Animals are sacrificed 2-4 hours after the last dose. The sciatic nerve is then excised and the residual nrubitol concentration assessed as described above.

Compounds of formula I generally have 2
Oral administration of 0 to 100 mg or less at active doses or multiples thereof causes significant inhibition of aldose reductase (as measured by the effect on residual sorbitol concentrations) without any signs of overt toxicity or other adverse effects. ). Furthermore, formula I
The superior compounds of the present invention, when applied orally at doses below 10 m9/y, generally reduce the residual N-rubyl concentration in the sciatic nerve to that of normal untreated rats.

Aldose reductase inhibitory properties cannot be demonstrated in vitro. That is, purified aldose reductase is isolated from a bovine lens by a known method. The rate of inhibition of the in vitro action of the enzyme to reduce aldoses to polyhydric alcohols, in particular glucose to sorbitol, caused by the test compound is determined by standard spectrophotometric methods. In this test, the compound of formula I generally has a concentration of about 10
M shows significant inhibition of aldose reductase.

Formula I which has potent inhibitory properties in this in vitro test and is not particularly effective in the above mentioned in vivo test by oral administration.
The compounds may be applied in in vivo therapeutic or prophylactic situations, eg, by direct topical application to the tissue or organ in which inhibition of the enzyme is required, eg, by topical application to the eye. However, compounds of formula I are primarily administered systemically (generally orally) to warm-blooded animals to exert an inhibitory effect on aldose reductase, for example at doses of 0.5 to 25 cm/day. be done. For humans, it is planned that a total daily dose of 10 to 750 μl per person will be administered in divided doses as necessary.

Compounds of formula I are usually in the form of special pharmaceutical compositions.
Applies to warm-blooded animals. According to the present invention, a compound of formula I, or a pharmaceutically acceptable salt thereof, or one of its non-toxic biodegradable precursors, together with a pharmaceutically acceptable diluent or carrier. A pharmaceutical composition is obtained containing:

The composition may be in a form suitable for oral administration, such as tablets, capsules, granules, dispersible powders, syrups, elixirs, emulsions, or glues; for parenteral administration;
For example in the form of a sterile, injectable aqueous suspension or solution, an oily solution; for rectal administration, e.g. in the form of a herbal medicine; or for topical administration to the eye, e.g. at an ophthalmically acceptable pH. For example, it may be in the form of an ointment, a glue or a sterile solution buffered to a pH of 7.0 to 7.6.

The topical formulations may be applied to the eyes of animals, such as humans or dogs, in need of treatment for diabetic cataracts or NI4 membrane disease in the conventional manner using eye drops or eyewash topical formulations.

The composition may also contain one or more other drugs known to have a useful effect in the treatment of diabetes or galactosemia, such as hypoglycemic agents, such as tolbu
tam d), chlorpropamide (chlorprop
amjde) or glibenclamide (glybenc)
lamide).

Next, the present invention will be explained in detail with reference to Examples, but the invention is not limited thereto. Unless otherwise stated in the examples, (1) Evaporations were carried out by rotary evaporation in vacuum; (I) All operations were carried out at room temperature, i.e. 18, ~26 °C: (ii+) Formula The final product of I was subjected to thorough microanalysis and was isolated in the cerami form (di); (iVl petroleum ether (boiling point 60-80)
Yields (where indicated) expressed as 0-80 are for illustration only and are not necessarily the maximum values obtained.

Example l 150 g of methanol and 150 g of water 1-(4-promo-2-fluorobenzyl)-7-dolifluoromethylindoline-2,3-dione 335 g, potassium cyanide 1.06.9 and ammonium carbonate hydrate Thing 7
．． 8 g of the mixture was heated at 45-50°C for 16 hours. The reaction mixture was cooled and a slight precipitate was removed by filtration. The filtrate was acidified (2M hydrochloric acid, 8
0M). The solid formed was washed with water and crystallized from tetrahydrofuran (THF)/petroleum 60-80 to give 1'-(4-bromo-2-fluorobenzyl)-7'-(trifluoromethyl) with a melting point of 197-199°C. )-spiro[imidanolidine-4,3'-indoline], -2,
2', 5-trion concentration 1.98.9 was obtained.

The starting material was obtained as follows: 10.7.9 mL of anhydrous potassium carbonate and 7-dolifluoromethylindoline-2.3-phono 14,4 N in N,N-trimethylformamide (DMF) 100 WLl. The mixture was stirred for 30 minutes. 7 & 9 ml of a 25 w/v % solution of 4-bromo-2-fluorodibenzylbromide in chlorobenzene were added and the mixture was stirred at 75-78°C for 2 hours. The mixture was then cooled to ambient temperature and poured into 400μ of water. Petroleum 60-80 (20 parts) was added to the aqueous mixture and the whole was stirred for 30 minutes. The solid formed was separated by filtration to give 1-(
4-Bromo-2-fluorobennor)-7-)lifluoromethylimbilin-2,3-phono 1789 was obtained.

Using the in vitro test method described above, Compound A was tested at a concentration of 1. O
It was found that 5×10 M caused a 50-fold reduction in the conversion of glucose to sorbitol in aldose reductase preparations obtained from bovine M crystals.

Example 2 1'-(4-furomo-2-fluorobenzyl)y/
' Trifluoromethyl-spiro[imidazolidine-4
,3'-indoline]-2.2', s-trione51.
7 g to (1)-N, N, N-trimethyl (1
-722ethyl)ammoniumhydroquine)'c7)
O, 16M-sol 342 m1VcfFs added.

The resulting bath solution was evaporated. Room the residue with anhydrous ether.
and dissolved in a mixture of about 200 M acetonitrile and about 250 M anhydrous ether. The resulting bath solution was kept at ambient temperature for 2 hours.

The solid formed was collected by filtration, washed with the cooled filtrate, and then recrystallized twice from a mixture of acetonitrile and ether to give (1)-N,N,N-trimethyl(1-phenylethyl)ammonium hydroxide and l/ (a
-bromo-2-fluorobenol) -7' -) I
J Fluoromethylose [imidabrinone-4,3'
- indoline salt 2.2', 5-trione (dl-norstereomer salt) 1799, melting point 137~
140'c (decomposition), [α:]:2+ 26.3° (c
, l, 078; MeOH).

This salt was mixed with 1051 u of methanol and the suspension was filtered. The filtrate was acidified with 18μ of 2M hydrochloric acid,
And 120M of water was added. The precipitated solid was collected by filtration, washed with the filtrate, and recrystallized from aqueous methanol to yield (d) -1'-(4-bromo2-fluorobenzyl)-7'-trifluoromethyl-spiro[imidazolidine a, 3/-indoline]-2,2',5-
128 g of trion was obtained. Melting point 227-229℃,
[α]: 2+ 30.7 (c, 1,074; Me
OH).

◆The starting quaternary ammonium hydroxide solution is (1)-
N,N,N-)'Tmethyl(1-phenylethyl)ammonium iosito27.8! ! An aqueous solution of anion exchange resin [Amberlite]
■'', IRA 401, 200 fj] column to convert it into the hydroxide form again.

Examples 3-5 By repeating a similar procedure to Example 1, the following compounds of formula I were obtained in racemic form: Example 3: 11-(4-Bromo-2-fluorobenzyl)-s with melting point 231-232°C '-Trifluoromethylose [imidanolinone-4,3-indoline]-2,2'
, 5-1-ion (as solid); starting materials: 1-(
4-bromo2-fluorobennor)-5-trifluoromethylindoline-2,3-phono (which itself is Example 1
5-trifluoromethylindo-9-phosphorus-2,3-) with 4-bromo-2-fluorobenzyl bromide (obtained as a syrup, According to 臘, sufficient purity).

Example 4: 1'-(3,4-dichlorobenzyl)-2'-2', melting point 170-171'', linked with 5-tri; Starting material: 1-(3,4-dichlorobenzyl) -7-) Lifluoromethylindolin-2,3-/one, which itself was prepared in a manner similar to that described for the starting materials in Example 1 (3.4-dichlorobenzyltalolide and 7-trifluoromethyl By reacting indoline-2,3-phono, a syrup of sufficient purity according to NMR'IC is obtained.

Example 5: 1'-(2-chloro-4-
bromopenol) -6'-toIJfluoromethyl-
Spiro [imidazolidine-4,3'-indoline)-2
,2',5-) ion as a solid; starting material: 1-
(2-chloro-4-bromobenzyl)-6-) I
J fluoromethylindoline-2°3-phono (which itself was prepared in a manner analogous to that described for the starting materials in Example 1, 2-dichoro-4-bromobenzyl, !=6-dolifluoromethylindoline-2,3- Obtained as a solid by reacting with phono, melting point 132-4°C).

Example 6 x'-(4-Solomo-2-fluorobenzyl)-t/
(trifluoromethyl)-spiro[imidanollysine-4,3'-indoline]-2,2'.

A mixture of 50 parts of 5-trione (all parts are 1 part by weight), 27 parts of lactose and 20 parts of corn starch is thoroughly stirred and a paste formed from 2 parts of corn starch and 40 parts of water is added. , ρ) were sufficiently mixed. The resulting material was passed through a 16 mesh screen, then dried at 60°C and passed through a 20 mesh screen. 10.2 Active ingredient suitable for oral therapeutic administration by adding 1 part of magnesium stearate to the granules obtained and compressing the whole in a conventional manner.
Tablets containing 0.50 or i'o o g.

The active ingredient may be replaced with any other compound of Formula I or a salt thereof or a non-toxic, biodegradable precursor.

Example 7 1L (4-noromo-2-fluorobenzyl)-7'
-) Lifluoromethylose [imidanolinone-4,
3'-indoline l:l g,2/,5-trione5
A homogeneous powder form was obtained by vigorously stirring a mixture of 0 part (1 part is 1 part by weight), 20 parts of calcium carbonate, and 30 parts of polyethylene glycol (average molecular weight 4000). . This material was loaded into gelatin cuff cells using conventional methods to form capsules each containing 1 t, 20.50 or 100 ml of active ingredient, suitable for therapeutic tap administration. .

Any other compound of formula I or a salt thereof or a non-toxic, biodegradable precursor may be substituted for the active ingredient in the methods described above.

Agent Patent Attorney Satoshi Yano Claimed priority ■November 1, 1982■UK (GB
)■8231129 0 Inventor David Brown Macclesfield Alderley Park, Cheshire, England (no street address) 0 Inventor Robin Wood Macclesfield Alderley Park, Cheshire, England (no street address)

Claims (1)

[Claims] 1. Formula ■: danb [In the formula, the trifluoromethyl substituting group to the benzene ring is located at the 5-, 6'-, or 7'-position; benzene ring B is a dihalogen phenyl, where R8 is fluoro or chloro, Rb is hydrogen, and R8 is chloro, bromo or iodo, or Ra is hydrogen, and Rb and R6 are independently chloro or bromo ] of trifluoromethyl spiro[imidazolidine-4
,3'-indoline]-2,2',5-) ion or its salts with bases that give pharmaceutically acceptable cations or non-toxic, biodegradable precursors. 2 Benzene ring B is 3,4-dichloro-13°4-nobromo, 3-bromo-4-chloro-14-bromo-3-
2. A compound according to claim 1, selected from chloro-14-chloro-2-fluoro-14-bromo-2-fluoro- and 2-fluoro-4-io14-phenyl. 3. Formula ■: [In the formula, benzene iB is 4-fcomo-2-chloro-54-
selected from 2-fluoro-2-fluoro-4-iodo-phenyl: and 1 of R, 1 and Re
are trifluoromethyl and the others are hydrogen]
The compound according to claim 1, which is a compound of 4.1'-(4-bromo-2-fluorobenzyl)-5
'-trifluoromethylspiro[imidazolidine-4
,3'-indoline]-2,2'. 5-trione, 1'-(4-bromo-2-fluorohene, nor)-7'-) +7 fluoromethyl-spiro[imidazolidine-4,3'-indoline)-2,z'
, s-trione. s, (d)-1'-(4-bromo-2-fluorobenzyl)-7'-trifluoromethylspiro[imidazolidine-4,37-indoline]-2°2',
5-) The compound according to claim 1, which is IJon. 6. Any one of claims 1 to 5, wherein the salt is an alkali metal salt, alkaline earth metal salt, aluminum salt, or ammonium salt, or a salt with an organic base that provides a pharmaceutically acceptable cation. The compound according to item 1. 7. Any one of claims 1 to 5, wherein the biodegradable precursor is an alkoxycarbonyl, aralkoxybenzenyl, alkoxyoxalyl or 1-(alkanoyloxy)alkyl derivative of the compound of formula I. compound. & Formula I: Rb [wherein benzene [trifluoromethyl substituent of A is 5'
position, 6' or 7'position; and benzene flA
B is dihalogenophenyl, where R8 is fluoro or chloro, Rb is hydrogen, and R6 is chloro, bromo or iodo, or Ra is hydrogen, and Rb2 and Ro are independently chloro. trifluoromethylspiro[imidazolidine-4,3'-indoly/]-2,2',5-to1
7 or a salt thereof with a base giving a pharmaceutically acceptable cation or a non-toxic, biodegradable precursor of the formula ■: Lb [wherein benzene ring A, benzene ring B, Ra, Rb and R6 represent the above-mentioned indoline-2,3
- reacting the dione with a metal cyanide and ammonium carbonate or ammonium carnomidate; if a non-toxic, biodegradable precursor is required then the compound of formula I is reacted with a suitable alkoxycarbonyllide; ,
Aralkoxycarbonyl halides 9, alkoxyoxalyl halides or 1-(alkanoyloxy)alkyl halides can be reacted with 1-(alkanoyloxy)alkyl halides to form the racemic compound of formula I in optically active form if the active form is desired. The diastereomeric mixture of the salts thus obtained is subsequently resolved and the optically active form 40 of formula I
The compound of formula I is separated by treatment with an acid and, if a salt is required, the free acid form of the compound of formula I is reacted with a suitable base to give a pharmaceutically acceptable cation. , trifluoromethylspiro[imidazolidine-4,
3'-indoline) -2,2'. 5-Production method of trion. 9, Formula ■: Rb [In the formula, benzene [trifluoromethylspiro of A is 5'
position, 6' or 7'position; benzene EiK
B is dihalogenophenyl, where Ra is fluoro or chloro, Rb is hydrogen, and R6 is chloro, bromo, or iodo, or Ra is hydrogen, and Rb and R6 are independently chloro trifluoromethylspiro[imidazoly, dine-4,3'-indoline]-2,2',5-
) A method for producing IJ-one or a salt or non-toxic, biodegradable precursor thereof with a base that gives a pharmaceutically acceptable cation, comprising the formula ■: Rb [wherein benzene iA, benzene ring B, Ra, Rb
and R6 represents the above-mentioned group, and R (is acyl or tri((1-4C) alkyl halide).
If a non-toxic, biodegradable precursor is required, the compound of formula I is then reacted with ammonium carbonate or ammonium carnomate;
Carzenylhalai F1 React with an aralkoxycarbonyl halide, alkoxyoxalyl halide or l-(alkanoyloxy)alkyl halide; if an optically active form is required, the racemic form of the compound of formula I is reacted with an optically active form of a suitable organic base. The diastereomeric mixture of the salts thus obtained is subsequently resolved and the optically active form of the compound of formula 11 is separated by treatment with an acid; if a salt is required, the free acid form is separated. Trifluoromethylspiro[imidazolidine-4,3'-indoline]-2,2',5-, characterized in that the compound of formula I is reacted with a suitable base to give a pharmaceutically acceptable cation. Trion manufacturing method. 10. Mixed or combined with a pharmaceutically acceptable diluent or carrier to form a compound of the formula ■: [where the trifluoromethyl substituent of benzene mA is 5'
and benzene iB is dihalogenophenyl, where Ra is fluoro or chloro, Rb is hydrogen, and R6 is chloro, bromo or iodo; or Ra is hydrogen and Rb and Ro are independently chloro or bromo] of trifluoromethylspiro[imidazolidine-4
,3'-indoline]-2.2',5-t! Used in the treatment or prevention of complications of diabetes or galactosemia, characterized in that it contains J-on or its salts with bases giving pharmaceutically acceptable cations or non-toxic, biodegradable precursors. Pharmaceutical composition for. 11. A pharmaceutical composition according to claim 10, which is in a form suitable for topical application to the eye.