HU223807B1 - Condensed indole derivatives of protein kinase c inhibitor activity, process for preparing them and pharmaceutical compositions containing them - Google Patents

Abstract

The compounds of formula (II) according to the invention are intermediates for the preparation of compounds which act as protein kinase Cinhibitors. In formula (II), V is oxygen or -N (CH3), and W is oxygen or sulfur, -SO-, SO2- , -CO- or phenylenoxy, C 2-6 alkylene, -NR 3, (a) or (tt), a divalent heterocyclic group, a divalent, fused bicyclic group; X and Y are independently C 1-4 alkylene; R 1 is independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, nitro or hydroxy, or -NR 4 R 5; R3 is hydrogen or C1-C4 alkyl; or Z is - (CH2) p -, R6 is hydroxy, -COO- (CH2) m-phenyl, C1-4alkoxy, (C1-C4) alkoxycarbonyl, -NR4R5 is -NH (CH 2) m-pyridyl, NH (CH 2) m -phenyl, C 1-4 alkylsulfonyl, -NHSO 2 - (CH 2) m -phenyl or cyano; R4 and R5 are independently selected from the group consisting of hydrogen, C1-C4 alkyl, benzyl, and, together with the nitrogen to which they are attached, morpholino, pyrrolidino, imidazolo or 4- (C1-C4 alkyl) piperazino, m is 0, 1, 2 , or 3, and p is 0, 1 or 2. ŕ

Description

(54) Condensed indole derivatives having a protein kinase C inhibitory action, process for their preparation and pharmaceutical compositions containing them

HU 223 807 Β1 (57) Extracts

The compounds of formula (II) of the present invention are intermediates in the preparation of compounds that act as protein kinase C inhibitors.

In the general formula (II)

V is oxygen or -N (CH ₃ ), and W is oxygen or sulfur, -SO-, SO ₂ -,

-CO- or phenyleneoxy, C 2 -C 6 alkylene, -NR ₃ , a or tt, a divalent heterocyclic group, a divalent fused bicyclic group;

X and Y are each independently C 1-4 alkylene;

R _{3, at each} occurrence, is hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, nitro, or hydroxy, or -NR 4 R ₅ ;

R ₃ is hydrogen or C 1-4 alkyl; obsession

Z is - (CH ₂ ) _p -,

R ₆ is hydroxy, -COO- (CH ₂ ) _m -phenyl, C 1-4 alkoxy, (C 1-4 alkoxy) carbonyl, -NR 4 R ₅ , -NH (CH ₂ ) _m -

m (H2 ₂ ) ^ ( _{CH2) in} % (a)

The scope of the description is 44 pages (including 16 pages).

Pyridyl, NH (CH ₂ ) _m -phenyl, C 1-4 alkylsulfonyl, -NHSO ₂ - (CH ₂ ) _m -phenyl or cyano;

R ₄ and R ₅ are each independently hydrogen, C 1-4 alkyl, benzyl, or, together with the nitrogen to which they are attached, morpholino, pyrrolidino, imidazolo or 4- (C 1-4 alkyl) piperazino, m is 0 , 1,2, or 3, and p is 0,1 or 2.

The present invention relates to compounds of formula II and processes for their preparation. Compounds of formula (II) are intermediates in processes for the preparation of compounds of formula (I) which act as inhibitors of protein kinase C. Compounds of formula (I) are disclosed and protected in U.S. Patent Publication No. 71130, Publication No. 219709.

In the compounds of formula I according to the said patent

W is oxygen or sulfur, -SO-, SO ₂ -, -CO- or (uu), C 2 -C 6 alkylene, -NR ₃ , (a) or (tt), (aa), (bb) or a divalent heterocyclic group of formula (dd), a divalent fused bicyclic group of formula (cc), (ee) or (ff);

X and Y are each independently C 1-4 alkylene;

R 1), independently at each occurrence, is hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, nitro, hydroxy, or -NR ₄ R ₅ ;

R ₂ is hydrogen;

R ₃ is hydrogen or C 1-4 alkyl; obsession

Z is - (CH ₂ ) _p -,

R ₆ is hydroxy, -COO- (CH ₂ ) _m -phenyl, C 1-4 alkoxy, (C 1-4 alkoxy) carbonyl, -NR ₄ R ₅ , -NH ( CH ₂ ) _{m is} pyridyl, NH (CH ₂ ) _m -phenyl, C 1 -C 4 alkylsulfonyl, -NHSO ₂ - (CH ₂ ) _m -phenyl or cyano;

R ₄ and R ₅ are each independently hydrogen, C 1-4 alkyl, benzyl, or, together with the nitrogen to which they are attached, morpholino, pyrrolidino, imidazolo or 4- (C 1-4 alkyl) piperazino, m is 0 , 1,2, or 3, and p is 0,1 or 2;

or pharmaceutically acceptable salts and solvates thereof.

This patent relates to these compounds, to their preparation and to pharmaceutical compositions containing them, which contain a pharmaceutically acceptable excipient or carrier and / or diluent in an effective amount of the active ingredient.

Novel intermediates useful in the preparation of the above compounds are compounds of formula II wherein:

V is O or -N (CH ₃ ); and

W, X, Y, R-ι and m are as defined above for formula (I).

Compounds of formula (II) are prepared by formulating compounds of formula (Va) in a concentration of 0.001 mol / l to 1.5 mol / l, wherein

V, R ₃ and m are as defined above for a compound of formula (VII) at a concentration of 0.001 mol / l to 1.5 mol / l, wherein

L is a leaving group; and

W, X, and Y are a mixture of the above alkylating agent in a polar aprotic solvent at a rate of from 0.1 to 2.0 ml / hour in an amount of 0.5 to 10 equivalents of cesium carbonate (Cs ₂ CO ₃ ). .

Another embodiment of the process for the preparation of compounds of formula (II) comprises the preparation of a compound of formula (IX) at a concentration of from 0.001 mol / liter to 3 mol / liter, wherein

L-2 represents a group independently of the meaning of the other groups,

V, W, X, Y, R- | and m is a mixture of the above compound in a polar aprotic solvent, at a rate of from 0.1 ml / hr to 2.0 ml / hr, with 0.5 equivalents to 10 equivalents of cesium carbonate (Cs ₂ CO ₃ ).

The term "cleavage group" as used herein is known to those skilled in the art. The leaving group may generally be any atom or group which increases the electrophilic nature of the atom to which it is attached for substitution. Preferred leaving groups are triflate, mesylate, tosylate, imidate, chloride, bromide and iodide.

As used herein, the term "carboxy protecting group" refers to an ester derivative of a carboxyl group commonly used to protect or reduce the reactivity of carboxyl groups while reacting on other functional groups of the compound. The nature of the carboxy protecting group is not critical if the carboxylic acid derivative obtained by its use is stable under the conditions of the following reaction (s) and the protecting group may be cleaved at a suitable point in the reaction sequence without damaging the rest of the molecule. TW Greene and P. Wuts provide a list of commonly used protecting groups in Chapter 5 of "Protective Groups in Organic Synthesis" (John Wiley and Sons, New York, NY, 1991). See also E. Hasiam, Protective Groups in Organic Chemistry, edited by JGW McOmie, Plenum Press, New York, ,Y.Y.1973. Related to this is the term "protected carboxyl group" which refers to a carboxy protecting group.

HU 223 807 Β1

As used herein, the term "hydroxy protecting group" refers to an ether or ester derivative of a hydroxyl group that is commonly used to protect hydroxyl groups or to diminish their reactivity while undergoing reactions on other functional groups of the compound. The nature of the hydroxy protecting group is not critical if the resulting compound containing the hydroxy group as a derivative thereof is stable under the conditions of their subsequent reactions and can be cleaved at a suitable point in the reaction sequence without causing damage to the remainder of the molecule. TW Greene and P. Wuts in "Protective Groups in Organic Synthesis" (John Wiley and Sons, New York, NY, 1991) provide a list of commonly used protecting groups. Preferred hydroxy protecting groups are tert-butyl diphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBDMS), triphenylmethyl (trityl), methoxytrityl, and alkyl and aryl esters. -groups. Related to this is the term "protected hydroxyl group, which refers to a hydroxy protecting group.

As used herein, the term "amine protecting group" refers to any substituent on the amino group that is conventionally used to protect the amino groups or to reduce their reactivity while reactions are performed on other functional groups of the compound. The nature of the amine protecting group is not critical if the resulting compound containing the amino group as a derivative is stable under the conditions of the following reaction (s) and the protecting group may be cleaved at a suitable point in the reaction sequence without compromising the remainder of the molecule. suffer damage. TW Greene and P. Wuts provide a list of commonly used protecting groups in Chapter 7 of "Protective Groups in Organic Synthesis". See also JW Barton, Chapter 2, "Protective Groups in Organic Chemistry". Preferred amine protecting groups are tert-butoxycarbonyl, phthaloyl, cyclic alkyl and benzyloxycarbonyl. Related to this is the term "protected amino group" which refers to an amino group substituted with an amine protecting group as defined above.

As used herein, the term "NH protecting group" refers to a subgroup of amine protecting groups, the members of which are customarily used to protect or reduce the reactivity of NH groups while reactions are performed on other functional groups of the compound. The nature of the protecting group is not critical if the compound containing the amino group as obtained by its use is stable under the conditions of the following reaction (s) and the protecting group may be cleaved at a suitable point in the reaction sequence without damaging the rest of the molecule. . TW Greene and P. Wuts, Chapter 7, Protective Groups in Organic Synthesis, pp. 362-385. page gives a list of commonly used protecting groups. Preferred NH protecting groups are carbarates, amides, and alkyl and arylsulfonamides. Related to this is the term "protected NH group", which refers to a group substituted with an NH protecting group as defined above.

The preparation of certain bisindolyl N-maleimide derivatives is described in Davis et al., U.S. Patent 5,057,614, which is incorporated herein by reference. The compounds of the present invention may generally be prepared as illustrated in Scheme A, wherein R 1, m and "halo" are as defined above, and particularly "halo" is preferably chlorine, bromine or iodine. Preferably, the compound of formula (III) is 2,3-dichloro-N-methyl-maleimide. The reaction between the compound of Formula III and the indole derivative of Formula IV is generally known as a Grignard reaction. This reaction is carried out in an inert organic solvent such as toluene at a temperature between room temperature and the reflux temperature of the reaction mixture. It is very important that the outcome of the reaction shown in Scheme A depends on the solvent conditions. If this reaction is carried out in a mixture of toluene, tetrahydrofuran and diethyl ether, the compound of formula (V) is obtained in greater than 80% and more than 95% pure form. The product was precipitated from the reaction mixture with ammonium chloride. The resulting intermediate compound of formula (V) may be isolated by conventional methods known per se.

The resulting compound of formula (V), bis [3,4- (3'-indolyl)] - 1 N -methylpyrroline-2,5-dione, is known in the art from Brenner et al., Tetrahedron 44, 2887-7. 2892nd (1988)] can be converted to the anhydride of formula VI by hydrolysis under alkaline conditions. For this purpose, the compound of formula (V) is preferably reacted with 5N potassium hydroxide in ethanol at a temperature between 25 ° C and reflux temperature.

Compounds of formula (V) are generally more stable than compounds of formula (VI). Therefore, it is more preferred that the compounds of formula (V) are subjected to the reaction shown in Scheme B rather than the preparation of compounds of formula (II). However, it will be apparent to those skilled in the art that the compounds of formula (VI) may also be reacted as shown in the Scheme. In the general formulas of Scheme B, X, Y and W are as defined above and L is an easily leaving group, preferably chlorine, bromine, iodine, mesyl, tosyl. L can also be a hydroxyl group or other suitable group which can be easily, in a manner known per se, converted into a readily cleavable group. For example, a hydroxyl group can simply be converted to a sulfonic acid ester group, such as a mesyl group, by reacting the hydroxyl group compound with methanesulfonyl chloride.

EN 223,807 Β1 to form the mesylate group as a leaving group.

The reaction shown in Scheme B can be carried out by any of the methods used to prepare the N-substituted indole derivatives. Usually the molar amounts of the two reagents are used in the reaction, but other ratios may be used, for example, in particular an excess of the alkylating agent. Most preferably, the solvent is a polar aprotic solvent (not containing a proton) and an alkali metal salt or other alkylation conditions known in the art. If the leaving group is chlorine or bromine, a catalytic amount of iodide such as potassium iodide may be added to accelerate the reaction. The reaction conditions may be, for example, potassium hexamethyldisilazide in dimethylformamide or tetrahydrofuran or sodium hydride in dimethylformamide.

Preferably, the reaction is carried out with cesium carbonate, slow addition, in acetonitrile, dimethylformamide or tetrahydrofuran. The reaction temperature is preferably between room temperature and the reflux temperature of the reaction mixture.

It will be apparent to those skilled in the art that in the reaction illustrated in the Breakdown Scheme, compounds of formula (VIIa) may also be used, wherein

X 'and Y' represent a protected hydroxy group, a protected carboxyl group or a protected amino group.

Following the alkylation illustrated in Scheme B, the groups X 'and Y' can be converted into groups which can be subjected to the coupling reaction required to form W. This is a preferred method for the preparation of compounds of formula I wherein:

W is S, O or NR ₃ .

Conversion of groups X 'and Y' to various ether derivatives, thioether derivatives or amino ether derivatives is known in the art and is described, for example, in lto et al., Chem. Pharm. Bull. 41 (6), 1066-1073. (1993); Kató et al., J. Chem. Pharm. Bull. 34, 486 (1986); Goodrow et al., Synthesis 1981, 457; Harpp et al., J. Am. Chem. Soc. 93, 2437 (1971); and Evans et al., J. Org. Chem. 50, 1830 (1985).

It will be apparent to those skilled in the art that the compounds of formula (V) may be converted to the compounds of formula (II) by a two-step synthesis shown in Scheme C, wherein the compounds of Scheme C

R ₄ , X, W, Υ, V, and L are as defined above, and

L ² is a protected hydroxyl group or other group which can be converted into a good cleavage group by simple means known in the art.

The coupling of a compound of formula (V) or (VI) with a compound of formula (VIII) is the alkylation step discussed above. The singly alkylated intermediate product of formula (IX) is deprotected, and ^L2 is converted to a leaving group. For example, when the hydroxyl group is protected with a tert-butyldimethylsilyl group, it is selectively cleaved with acidic methanol. The resulting free hydroxyl group is then converted into a leaving group, for example, an alkyl halide, preferably an alkyl iodide or (using carbon tetrabromide and triphenylphosphine) alkyl bromide or (using methanesulfonyl chloride and triethylamine) a sulfonate. Subsequently, the macrolide ring is formed by slow reversal addition to a solution of a base such as potassium hexamethyldisilazide or sodium hydride, or preferably cesium carbonate, in a polar aprotic solvent such as acetonitrile, dimethyl -formamide or tetrahydrofuran at room temperature to the reflux temperature of the reaction mixture.

The process for the preparation of compounds of formula II is illustrated by the following Schemes B and C. Surprisingly, it has been found that the compounds of formula II can be prepared in substantially higher yields by alkylation by slow addition to cesium carbonate in a polar aprotic solvent. Slow, reverse addition means that the compound to be alkylated and the alkylating agent (Scheme B) or the monoalkylated compound (Scheme B) are added to the base at a rate of from 0.1 ml / hr to 2.0 ml / hr. The concentration of all reagents in the mixture is between 0.001 mol and 1.5 mol. When working with the monoalkylated compound (Scheme C), the concentration of this reagent is between 0.001 mol and 3 mol. By slow addition, the concentration of the reactants in the reaction mixture is between 0.01 pmol and 1.5 mol. It will be apparent to those skilled in the art that the reaction may be carried out at a lower concentration of reagents at a faster rate. Similarly, if dosing is slower, the reagents could be used in higher concentrations. Preferably, the compound to be alkylated is added at a rate of 0.14 mL / hour and the concentration of this compound and the alkylating agent is 0.37 mol. It is preferred that the cesium carbonate be used in excess, most preferably the ratio of cesium carbonate to alkylating agent is 4: 1. Preferred polar aprotic solvents include acetonitrile, dimethylformamide, acetone, dimethyl sulfoxide, dioxane, diethylene glycol dimethyl ether (diglyme), tetrahydrofuran, and other polar aprotic solvents in which the reagents are soluble. The reaction is carried out at a temperature between 0 ° C and the boiling point of the reaction mixture. It will be appreciated by those skilled in the art that the amount of compound to be alkylated to the amount of alkylating agent is not critical. However, the ratio of reagents to each other is preferably between 0.5 and 3 equivalents. Most preferably, the ratio of reagents is 1: 1.

In that case if

V is methyl substituted nitrogen then

The compound of formula (II) is converted to the corresponding anhydride by alkaline hydrolysis, wherein

V is oxygen.

Alkaline hydrolysis consists of treating the compound with a base in a C 1 -C 4 alcohol (preferably ethanol) or in a mixture of dimethylsulfoxide and water, dioxane and water or acetonitrile and water at a temperature between 25 ° C and preferably reflux temperature. such as sodium hydroxide or potassium hydroxide. The concentration of reagents is not critical.

The anhydride containing AV is converted to the maleimide of formula (I) by ammonolysis. Ammonolysis involves the anhydride in a C 1 -C 4 alcohol (preferably methanol) or in a polar aprotic solvent such as dimethylformamide at room temperature in hexamethyldisilazane or an ammonium salt (preferably ammonium acetate, ammonium bromide or ammonium chloride). excess. The hexamethyldisilazane or ammonium salt is preferably used in an amount of more than 5 equivalents relative to the anhydride.

For all of the above reaction schemes, the reactions are preferably carried out with compounds having appropriate protecting groups. It is particularly advantageous to protect the R ₃ group before alkylation and / or acylation, and to remove the protecting group after these operations. Similarly, when R ₆ is -NR ₄ R ₅ , the reaction is conveniently carried out in the presence of an amine protecting group. However, it will be apparent to those skilled in the art that many of these reactions can be carried out without protecting groups, provided that suitable reaction conditions, reactivity reducing groups, and the like are employed. In the case where W contains a hydroxy group, it is preferred to protect it in the form of a tert-butyldiphenylsilyloxy group or a triphenylmethyl (trityl) group before alkylation or acylation of the indole ring. The resulting compounds of formula (I) may be isolated and purified by conventional methods known per se.

The compounds of formulas (III), (IV), (V), (VII), (Vlla), (Vili) and all other reagents required for the above reactions are either commercially available and are known or can be prepared by methods known in the art. . For example, compounds of formula (III) may be prepared by the methods described by Edge et al., Chem. and Ind. 130 (1991)]. Preferably, a compound of formula (IV) is prepared in situ (directly in the reaction mixture) by reacting an appropriately substituted indole with an alkyl magnesium halide such as ethyl magnesium bromide in a manner known per se.

The compounds of the present invention and the process for their preparation will now be described by way of example without limiting the scope of the invention. The high performance liquid chromatography operations mentioned in the examples were carried out on silica gel columns. For purposes of information to those skilled in the art, Formula (Ic) illustrates one representative type of compound of the present invention and indicates the numbering of the ring system.

In the examples, unless otherwise indicated, "%" is by weight, the ratio being by volume.

Example 1

1,4-bis- (3'-indolyl) -furan-2,5-dione

To a solution of 5.56 g (33.3 mmol) of 2,3-dichloro-maleic anhydride and 3.50 g (55.0 mmol) of methylamine hydrochloride in 40 ml of acetic acid is added 3.56 g (50 mmol) of sodium ethylate. . The reaction mixture was stirred for 16 hours at 25 ° C, protected from air humidity with a calcium chloride tube and then heated to reflux for 4 hours. After cooling, it was poured into 350 ml of water and extracted three times with 75 ml of ethyl acetate each time. The combined organic extracts were washed with saturated aqueous sodium bicarbonate (100-100 mL), water and brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol as a white crystalline solid (3.82 g, 64%).

2,3-dichloro-N-methyl maleimide is obtained. Evaporation of the mother liquor and purification of the residue by radial preparative thin layer chromatography on a Chromatotron (Hamison Research) gave an additional 0.81 g of 2,3-dichloro-N-methyl maleimide, yielding 77% yield.

To a solution of indole (10.5 g, 90 mmol) in anhydrous toluene (175 mL) was added dropwise a solution of ethyl magnesium bromide (1.0 mL, tetrahydrofuran) (90 mL, 90 mmol) under nitrogen atmosphere over 1 h. After the addition was complete, the light green solution was heated at 40 ° C for 30 minutes and then cooled to 25 ° C. A solution of 3.8 g (21 mmol) of 2,3-dichloro-N-methyl maleimide in 50 mL of toluene is then added over 30 minutes. The resulting reaction mixture was heated at 100 ° C for 3 hours, cooled to 25 ° C, and quenched by the addition of 20% aqueous citric acid (100 mL). The aqueous layer was separated and partitioned between ethyl acetate (50 mL). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in 30 ml of acetone and allowed to stand for 40 hours at 5 ° C. The precipitated solid was filtered off and washed with ice-cold diethyl ether. This gave 5.25 g (73%) of 3,4-bis (3'-indolyl) -1-methylpyrroline-2,5-dione as a red solid, m.p. 276-278 ° C. .

To a solution of 3,4-bis (3'-indolyl) -1-methylpyrroline-2,5-dione in 150 ml of ethanol was added 50 ml of 5 N potassium hydroxide solution and the mixture was heated at 25 ° C for 4 hours. stirred. The reaction mixture was diluted with water (150 mL), most of the ethanol was distilled off under reduced pressure and the residue was acidified to pH = 1. The precipitated product is filtered off and washed with water. The crude product obtained is dissolved in the minimum amount of dichloromethane required, and the solution is slowly passed through a column of silica gel, about 5 cm in diameter,

Then elute the column with 50:50 ethyl acetate / hexane. This gave 3.10 g (79%) of the title compound as a red solid, mp 225-228 ° C.

Example 2

2,6-Bis (bromomethyl) pyridine

A mixture of 2,6-bis (hydroxymethyl) pyridine (735 mg, 5.28 mmol) and triphenylphosphine (3.20 g, 12.2 mmol) in anhydrous dichloromethane (35 mL) was heated at 0 ° C under nitrogen for 10 min. 2.16 g (12.2 mmol) of N-bromosuccinimide are added in small portions, and the mixture is stirred at 0 ° C for 1 hour and then allowed to stand at room temperature for 16 hours. Most of the solvent was then distilled off under reduced pressure and diethyl ether (100 mL) was added to the residue. The diethyl ether solution was discarded from the insolubles, concentrated to a volume of about 20 mL, and diluted with hexane / ethyl acetate (3: 1, 50 mL). The resulting cloudy solution was kept in a refrigerator overnight and then the solvents were distilled off under reduced pressure. The crude product was recrystallized from hexane to give 766 mg (55%) of 2,6-bis (bromomethyl) pyridine as a white crystalline solid.

The mass spectrum of the product is consistent with the expected chemical structure.

Example 3 (±) -3-Benzyloxymethyl-1,6-dibromohexane

A solution of (±) -3-cyclohexene-1-methanol (853 mg, 7.60 mmol) in tetrahydrofuran (35 mL) was added dropwise under nitrogen (25 ° C), 8.27 mL (8.27 mmol) of 1.0 M potassium tertiary tetrahydrofuran. butylate solution and the resulting mixture was stirred at 25 ° C for 30 minutes. Benzyl bromide (1.0 mL, 8.37 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hours. Saturated aqueous ammonium chloride solution (5 ml) was added and the solvent was distilled off. The residue was dissolved in diethyl ether (50 mL), washed with water (20 mL), brine (20 mL), dried (MgSO4) and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on silica gel using a 5:95 mixture of ethyl acetate and hexane as eluent. 1.42 g (92%) of (±) -3- (benzyloxymethyl) -1-cyclohexene are obtained in the form of a colorless oil. The NMR spectrum of the product is consistent with the expected chemical structure.

A solution of (±) -3- (benzyloxymethyl) -1-cyclohexene (1.35 g, 6.70 mmol) in dichloromethane (65 mL) was charged with ozone at -78 ° C until the blue color of the unreacted ozone was will not stay. The mixture was then allowed to warm to room temperature under nitrogen. A solution of borane / dimethylsulfide complex (2.7 ml, 27.8 mmol) in borane / dimethylsulfide complex (10.0 mol) was added over a few minutes and the reaction mixture was allowed to stand for 24 hours. Subsequently, 1 ml of 5% hydrochloric acid was added and stirred vigorously for 1 hour. Solid sodium hydrogencarbonate is then added until the pH is alkaline according to litmus paper. The solution is dried over anhydrous magnesium sulfate, the desiccant is filtered off and the solvent is distilled off. 1.49 g (ca. 100%) of crude (±) 3-benzyloxymethyl-1,6-hexanediol are obtained in the form of an oil. This material, which in the thin layer chromatography (rf = 0.25, eluent: ethyl acetate / hexane 25:75) yields essentially one spot, is used directly in the next step without further purification.

A mixture of (+) - 3- (benzyloxymethyl) -1,6-hexanediol (1.45 g, 6.10 mmol) and triphenylphosphine (3.67 g, 14.0 mmol) in dichloromethane (50 mL) At 9 ° C, 2.4 g (14.0 mmol) of N-bromosuccinimide were added under a nitrogen atmosphere. After 12 hours, the solvent was distilled off and 100 ml of diethyl ether were added to the residue. After stirring for 15 minutes, the diethyl ether portion was discarded from the insoluble solids. This operation was then repeated using 50 ml of diethyl ether. The combined diethyl ether portions were concentrated to about 50 mL and then diluted with 100 mL of hexane. The mixture was kept overnight at 5 ° C, the precipitate was discarded and the solvent was evaporated. This gave 1.09 g (49%) of dibromide, (±) -3- (benzyloxymethyl) 1,6-dibromohexane, as a light yellow oil, which was determined by TLC (rf = 0). , 75, Running solvent: ethyl acetate / hexane (10:90)) is substantially uniform. The NMR spectrum of the product is consistent with the expected chemical structure.

Example 4

1- (tert-Butyldimethylsilyloxy) -4- (tert-butyldiphenylsilyloxy) butane-3-ol (0.21 mol) 3-buten-1-ol in 110 ml of anhydrous 28.6 g (0.42 mol, 2 equivalents) of imidazole are added to a solution of methane, followed by 32 g (0.22 mol) of tert-butyldimethylsilyl chloride. After 90 minutes, thin layer chromatography (eluent: ethyl acetate / hexane = 10:90) indicated the reaction was complete. The dichloromethane solution was poured into a separatory funnel and diluted with 110 mL dichloromethane. The solution was washed with water (200 mL) followed by brine (200 mL). The organic layer was separated, dried over magnesium sulfate, filtered and the solvent was evaporated. The 1- (tert-butyldimethylsilyloxy) -3-butene obtained as an oil is used directly in the next step. The mass spectrum of the product is consistent with the expected chemical structure.

The oil obtained as described in the previous paragraph was dissolved in a mixture of 400 ml of acetone and 50 ml of water, 85.2 g (0.63 mol, 3 equivalents) of N-methylmorpholine N-oxide were added and the resulting suspension was cooled to 0 ° C. After 10 minutes, a catalytic amount of osmium tetroxide (0.3 g) was added and the mixture was stirred overnight while gradually warming to room temperature. The ez6

Thin layer chromatography (eluent: ethyl acetate / hexane 25:75) showed that the reaction was complete. At this time, the reaction was quenched with sodium bisulfite and diluted with diethyl ether (1 L). The resulting solution was washed with water (400 mL) followed by brine (400 mL) and the organic layer was separated. The aqueous portion was shaken with diethyl ether (2 x 500 mL), the combined organic portions were dried, the desiccant was filtered off and the solvent was distilled off. This gives 4- (tert-butyldimethylsilyloxy) -1,2-butanediol as an oil, which is used directly in the next step.

The oil obtained as described in the previous paragraph was dissolved in 250 ml of anhydrous dichloromethane, and 30 g (0.44 mol, 2.5 equivalents) of solid imidazole were added with stirring, and the resulting solution was cooled to 0 ° C. After cooling for 15 minutes, 50 g (0.18 mol, 1 equivalent) of tert-butyl diphenylsilyl chloride are added dropwise over 45 minutes. After the addition was complete, the mixture was stirred for an additional 2.5 hours at 0 ° C. The reaction mixture was then transferred to a separatory funnel and diluted with dichloromethane (250 mL). The solution was washed with water followed by brine, dried over magnesium sulfate, filtered and the solvent was evaporated. The crude oil was purified by silica gel short column chromatography (eluent: ethyl acetate / hexane = 10:90). The solvent used for the elution was evaporated under reduced pressure to give the title intermediate as a viscous oil (78.1 g, 93%). The mass spectrum of the product is consistent with the expected chemical structure.

Example 5

1- (tert-butyldimethyl-butyldimethylsilyl) -3- (3-iodo-propoxy) 4- (tert-butyldimethyl-butyldiphenylsilyloxy) -butane

In a nitrogen-charged balloon flask was added allyl trichloroacetimidate (17.82 g, 88 mmol, 2.2 eq.) In a solution of the alcohol of Example 4 (20 mL) in cyclohexane (100 mL) followed by trifluoromethanesulfonic acid (0.92 mL). (corresponding to 50 μΙ / g starting material). After 20 hours, the insolubles were filtered off and the solution was washed with a saturated aqueous sodium bicarbonate solution, followed by water and finally with a saturated sodium chloride solution. The organic layer was separated, dried over magnesium sulfate and the solvent was distilled off. The resulting oil was purified by flash chromatography on silica gel. For this purpose, a gradient elution is performed, starting with hexane (mixture of isomers) and gradually adding more ethyl acetate to the eluent as the elution solvent is used up to a final concentration of 5% ethyl acetate. Thus, 19.27 g (97% yield) of allyl ether, i.e. 1- (tert-butyldimethylsilyloxy) -3- (allyloxy) -4- (tert-butyldiphenylsilyl), as a light brown oil, are obtained. oxy) butane is obtained. The mass spectrum of the product is consistent with the expected chemical structure.

To a solution of allyl ether (14.16 g, 28.38 mmol, 1 equivalent) in tetrahydrofuran (60 mL) was added dropwise under nitrogen (60 mL, 30 mmol, 1.1 equiv.) 9-borabicyclo-tetrahydrofuran (0.5 mol). [3.3.1] nonánoldatot. After 3 hours, thin layer chromatography (eluent: ethyl acetate / hexane = 10:90) showed the starting material was consumed. To the resulting solution was added 10.41 mL (31.22 mmol, 1.1 eq.) Of 3M aqueous sodium hydroxide solution and 10.3 mL (90.82 mmol, 3.2 eq.) Of 30% solution was added slowly dropwise. hydrogen peroxide. The temperature of the reaction mixture was maintained below 50 ° C during peroxide freezing in an ice-cooling bath.

After a minute, sodium chloride was added to the solution until saturation. The organic portion was separated and the aqueous portion was partitioned between diethyl ether. The combined organic phases are dried, the desiccant is filtered off and the solvent is distilled off. The crude oily product thus obtained was purified by flash chromatography on silica gel eluting with ethyl acetate / hexane (isomer mixture) (10:90) and ca.

After 1.5 liters of eluent, the polarity of the mixture was increased by changing the ratio of ethyl acetate to hexane (isomer mixture) to 20:80. This gave 9.53 g (65%) of product as a light yellow oil having a mass spectrum consistent with the expected chemical structure.

To a solution of the alcohol prepared in the preceding paragraph in 150 ml of anhydrous diethyl ether, cooled to 0 ° C, was added 2.93 g (28.91 mmol, 1.5 eq.) Of triethylamine and added dropwise with vigorous stirring. 31 g (28.91 mmol)

1.5 equivalents) of methanesulfonyl chloride. The mixture was stirred for 3 hours at 0 ° C, and the subsequent thin layer chromatography (eluent: ethyl acetate / hexane = 10:90) showed the starting material was consumed. The reaction mixture was diluted with diethyl ether, washed with water, brine, dried over magnesium sulfate, and the solvent was distilled off. The resulting oil was filtered through a pad of silica gel eluting with a 25:75 mixture of ethyl acetate and hexane (isomer mixture). The solvent was distilled off, and 0.17 g (1.93 mmol, 0.1 eq) of sodium bicarbonate and 28.88 g (192.7 mmol, 10 eq) were added to a solution of the resulting oil in 200 mL of acetone. sodium iodide. The reaction mixture was stirred under nitrogen for 30 minutes and then heated in a water bath to 50 ° C and

Stir at the same temperature for 2.5 hours. Subsequent thin layer chromatography (eluent: ethyl acetate / hexane = 10:90) showed that the mesylate was consumed. The reaction mixture was diluted with diethyl ether (500 mL), washed with cooled saturated aqueous sodium sulfite solution, water, and finally saturated sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off. The resulting oil was filtered through a pad of silica gel

Using a 5:95 mixture of ethyl acetate and hexane (isomer mixture) as eluent. This gave 10.3 g (85%) of the title compound as a colorless oil.

Example 6 (±) -3,4 - [[N, N'-1,1 '- (3' - (3-tert-butyldiphenylsilyloxy) methyl] hexane] bis (3,3) indolyl)] - 1-methyl-dione pirrolin2,5

3.41 g (10.0 mmol) of bis (3,3'-indolyl) -1-methylpyrroline-2,5-dione was prepared in 50 ml of dimethylformamide and the dibromide, 5.64 g (11 mmol), A solution of 3- (tert-butyldiphenylsilyloxymethylene) -1,6-dibromohexane, prepared analogously to the bromo derivative described in Example 2, is treated with 11.2 g (34.3 mmol) of cesium in a dosing pump over 15 hours. carbonate in 350 ml of dimethylformamide at 60 ° C. After 4 hours, the reaction mixture was cooled to room temperature, poured into water (1.5 L) and extracted with dichloromethane (3 x 300 mL). The organic layer was washed with water, dried, the desiccant was filtered off and the solvent was distilled off. The residue was purified by flash chromatography eluting with 10% to 25% ethyl acetate in hexane. In this way, 2.95 g (43% yield) of a macrocycle, i.e. 3,4 - [[N, N'-1,1 '- (3' -3-tert-butyldiphenylsilyloxy)] as a red oil were obtained. methylene) hexane] bis (3,3'-indolyl) -1-methylpyrroline-2,5-dione. The mass spectrum of the product is consistent with the expected chemical structure.

Example 7 Methyl (S) -4- (tert-butyldiphenylsilyloxy) -3-allyloxy-butyric acid

To a solution of (S) -4- (tert-butyldiphenylsilyloxy) -3-hydroxybutyric acid methyl ester (20.0 g, 53.7 mmol) in cyclohexane (400 mL) was added with stirring under nitrogen (21.74 g). (107.4 mmol) of allyl trichloroacetimidate followed by 5 ml of trifluoromethanesulfonic acid (equivalent to 50 μΙ / g alcohol) in five portions over 30 minutes. After 70 hours, the precipitated solids were filtered off and washed with cyclohexane. The filtrate was stripped of the volatiles under reduced pressure. The resulting oil was applied to a silica gel filter pad and eluted with a mixture of ethyl acetate and hexane (10:90). Although the NMR spectrum of the product obtained shows that it contains about 10% of unreacted imidate, this material was used in the next step without further purification. The weight of said residue is 24.76 g, of which about 22.2 g is the desired product (yield: 100%). The mass spectrum of the product is consistent with the expected chemical structure.

Example 8 (S) -4- (Tert-Butyl-diphenylsilyloxy) -3- (2-iodoethoxy) 1-iodobutane

To a solution of 23.8 g (57 mmol) of (S) -4- (tert-butyldiphenylsilyloxy) -3-allyloxy-butyric acid in 1.0 L of dry tetrahydrofuran at -75 ° C under nitrogen, 231 mL (231 mmol) of a 1.0 M solution of diisobutylaluminum hydride in toluene was added dropwise over 40 minutes and the mixture was stirred for 1.5 hours. The reaction mixture was allowed to warm to -10 ° C and the reaction was quenched by addition of a 5:95 mixture of water and methanol and a large amount of celite. After the reaction was quenched, the mixture was filtered through a pad of celite, the solvent was distilled off from the filtrate, and the residue was partitioned between diethyl ether and 20% citric acid. The diethyl ether portion was dried and the solvent was distilled off under reduced pressure. The residual oil was passed through a pad of silica gel eluted with chloroform. 20.6 g (93%) of (S) -4- (tert-butyldiphenylsilyloxy) -3- (allyloxy) butan-1-ol are obtained.

A solution of (S) -4- (tert-butyldiphenylsilyloxy) -3- (allyloxy) butan-1-ol (20.6 g, 53.6 mmol) in methanol (500 mL) at -78 ° C for about 12 minutes we pass through ozone, during which time the mixture becomes pale blue. 12.2 g (321 mmol, 6 equivalents) of sodium tetrahydroborate are then added and the mixture is allowed to warm to room temperature. The volatiles were distilled off under reduced pressure and the residue was passed through a pad of silica gel eluted with ethyl acetate. 16.4 g (79%) of (S) -4- (tert-butyldiphenylsilyloxy) -3- (2-hydroxyethoxy) butan-1-ol are obtained in the form of a colorless oil.

A solution of 15.7 g (40.4 mmol) of (S) -4- (tert-butyldiphenylsilyloxy) -3- (2-hydroxyethoxy) butane-1-ol in 600 ml of diethyl ether at 0 ° C under nitrogen, 16.8 mL (121 mmol) of triethylamine and then 9.38 mL (121 mmol) of methanesulfonyl chloride are added. After 3 hours, the solution was filtered. The filtrate was washed twice with water and twice with saturated sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was bis-mesylate (21.9 g,> 99%) as a yellow oil which was directly reacted. This bis-mesylate is dissolved in 1.4 liters of acetone distilled from potassium carbonate. Sodium iodide (90.4 g, 603 mmol) and sodium bicarbonate (0.05 equivalent, 170 mg, 2 mmol) were added and the mixture was heated at 56 ° C for 24 hours. The insolubles were then filtered off and the filtrate was evaporated under reduced pressure. The residue was partitioned between diethyl ether and 10% sodium sulfite solution. The diethyl ether portion was washed with saturated sodium chloride solution, dried over sodium sulfate, and the solvent was distilled off. This gave 17.9 g (73.2%) of (S) -4- (tert-butyldiphenylsilyloxy) -3- (2-iodoethoxy) -1-iodobutane as a colorless oil. Total yield: 54%.

Mass Spectrum (knee desorption method, chloroform): Molecular Weight: Calculated: 608.39, Found: 559 (M - tertiary-butyl).

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Example 9 (S) -3,4 - [(N, N'-1,1 ') - [(2 "-Ethoxy) -3' - (O) -4" (methanesulfonyloxy) butane] - bis (3-indolyl)] - 1H-pyrroline-2,5-dione [Compound (Id)]

10.04 g (29.4 mmol) of 3,4-bis (3-indolyl) -1H-pyrroline-2,5-dione and 17.9 g (29.4 mmol) of (S) -4-tert-butyl diphenylsilyloxy) -3- (2-iodoethoxy) -1-iodobutane was mixed and dissolved in 80 ml of anhydrous dimethylformamide. 38.3 g (118 mmol) of cesium carbonate are added over 72 hours under nitrogen, with the aid of a metering pump.

For a suspension of 1.7 liters of anhydrous dimethylformamide at 50 ° C. The solvent was distilled off under reduced pressure and the residue was partitioned between chloroform and 1N hydrochloric acid. The acidic aqueous portion was shaken with chloroform and ethyl acetate. The combined organic extracts were washed once with 1 N hydrochloric acid, twice with water and twice with brine, dried over sodium sulfate and the solvent was distilled off. This gives a purple solid. This crude intermediate was used in the next step without further purification.

The above crude intermediate is suspended in 700 ml of ethanol and 800 ml of 5 N potassium hydroxide solution are added. The mixture was heated to 80 ° C and maintained at the same temperature for 72 hours. The ethanol is then distilled off under reduced pressure, the resulting aqueous slurry is cooled to 0 ° C and acidified with 5N hydrochloric acid. The resulting violet precipitate was filtered off and filtered through a pad of silica gel using ethyl acetate as eluent. From the eluate, the solvent was distilled off. This gave 8.7 g of partially silylated maleimide as a purple solid which was used in the next step without further purification.

To a solution of anhydride (8.7 g, 19.7 mmol) in dimethylformamide (1 L) in a nitrogen atmosphere at room temperature was added 41.6 mL (197 mmol).

1,1,1,3,3,3-hexamethyldisilazane and 4 ml (98.5 mmol) of methanol. After 40 hours, the solvent was distilled off under reduced pressure and a mixture of acetonitrile and 1 N hydrochloric acid (2: 1, 100 mL) was added to the residue. After stirring for 1 hour, the organic solvent was distilled off and the resulting aqueous suspension was partitioned between ethyl acetate. The solvents were evaporated to give 8.9 g of maleimide, which was used without further purification.

To a suspension of maleimide (8.9 g, 20 mmol) in dichloromethane (800 mL), prepared as described in the previous paragraph, was added pyridine (4.85 mL, 60 mmol) and methanesulfonic anhydride (4.21 g, 24 mmol) in small excess at room temperature. . After 16 hours, the reaction mixture was washed with 0.1N hydrochloric acid and then with saturated sodium chloride solution, and the organic solvent was evaporated. The residue was passed through a pad of silica gel, eluting with a gradient of pure dichloromethane followed by the slow addition of acetonitrile from 0% to 10%. From the eluted fractions containing the desired mesylate, the solvent was distilled off to give 2.8 g of the title compound as a purple solid. Its overall yield, calculated as the diiodide, is 18%.

Mass Spectrum (knee desorption method, chloroform): Molecular Weight: Calculated: 520, Found: 520.

Example 10

3- (tert-butyl-diphenyl-silyloxy) -1-cyclohexene

13.0 ml (Aldrich, 0.11 mol) of 3-cyclohexene-1-methanol, 43 ml (0.244 mol) of Ν, Ν'-diisopropylethylamine and 2.70 g (0.022 mol) of 4- (dimethyl- To a mixture of amino) pyridine in 375 ml of anhydrous dichloromethane is added 32 ml (0.123 mol) of tert-butyl diphenylchlorosilane under nitrogen at 25 ° C and the mixture is stirred for 48 hours at 25 ° C. The reaction mixture was washed with 150 ml of 1N hydrochloric acid, 150 ml of water and 150 ml of a saturated sodium chloride solution, dried over magnesium sulfate and the solvent was distilled off. The residue was applied to a 10.16 cm x 10.16 cm silica gel column and the column was slowly eluted with hexane (isomer mixture). This gave 33.6 g (86%) of 3- (tert-butyldiphenylsilyloxymethylene) -1-cyclohexene as a colorless oil, TLC [rf = 0.4, running solvent: hexane (isomeric mixture)]. Calcd for C ₂₃ H ₃₀ OSi.O, 3H ₂ 0 calculated: C, 77.6; H, 8.67;

Found: C, 77.38; H, 8.72.

Example 11

3- (tert-butyl-diphenyl-silyloxy methyl) -1,6-hexanediol

To a solution of 18.0 g (51.3 mmol) of 3- (tert-butyldiphenylsilyloxymethylene) -1-cyclohexene in 550 mL of dichloromethane was added -O, at -78 ° C with vigorous stirring until the unreacted the blue color of ozone will not remain. The mixture was then allowed to warm to 25 ° C and nitrogen was passed through for 30 minutes. Subsequently, 10 ml of a borane / dimethylsulfide complex solution (23 ml, 0.23 mol) was added dropwise over 10 minutes, and the reaction mixture was stirred slowly under nitrogen at 25 ° C for 24 hours. Then 15 ml of 5% hydrochloric acid are added and the mixture is stirred for 1 hour. Solid sodium bicarbonate is then added until the pH paper, previously moistened, shows no alkalinity. The insolubles were filtered off, and the filtrate was washed with 5% sodium bicarbonate solution (200 mL), water (200 mL), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The crude product was filtered through a 10.16 cm x 10.16 cm silica gel filter bed and eluted with ethyl acetate. In this way, 17.8 g (90%) of 3- (tert-butyl) as a colorless viscous oil are obtained.

This gives a diphenylsilyloxymethylene) -1,6-hexanediol which is uniform according to TLC (rf = 0.5, solvent: diethyl ether).

Calcd C23H34O3Si.0,2H ₂ O: Calc'd: C, 70.80; H, 8.88;

Found: C, 70.72; H, 8.86.

Example 12

3- (tert-butyl-diphenyl-silyloxy methyl) -1,6-dibromohexane

To a solution of 17.5 g (45.2 mmol) of 3- (tert-butyldiphenylsilyloxymethyl) -1,6-hexanediol and 28.6 g (109 mmol) of triphenylphosphine in 550 ml of anhydrous dichloromethane at 0 ° C At room temperature, under nitrogen, with stirring, 19.3 g (109 mmol) of N-bromosuccinimide are added portionwise over 5 minutes. The mixture was stirred for 5 hours at 0 ° C and allowed to stand in a refrigerator at 5 ° C for 16 hours. Most of the solvent was then distilled off and 300 ml of anhydrous diethyl ether was slowly added to the residue. The diethyl ether solution was decanted from the precipitated solid and the solid was washed with another 200 ml of diethyl ether. The combined diethyl ether portions were concentrated to a volume of 100 ml, the residue was triturated with 300 ml of hexane (isomeric mixture) and the solution was discarded from the solids. The solid was washed with diethyl ether / hexane (25:75), the combined organic solutions were dried over anhydrous magnesium sulfate and the solvent was distilled off. The crude product was applied to a 10.16 cm * 10.16 cm silica gel column and eluted with 25:75 diethyl ether / hexane (isomer mixture). This gave 3- (tert-butyldiphenylsilyloxymethyl) -1,6-dibromohexane (20.1 g, 86%) as a colorless oil, m.p. Running solvent: diethyl ether / hexane (isomer mixture) 10:90].

¹ H NMR (300 MHz, CDCl ₃ , δ): 1.06 (s, 9H),

1.35-2.10 (m, 7H), 3.55 (m, 4H), 3.56 (apparent d, 2H, J = 4Hz), 7.40 and 7.64 (m, 10H).

¹³ C NMR (75 MHz, CDCl ₃ , δ): 19.2, 26.9,

29.3, 30.0, 31.9, 33.8, 34.7, 38.5, 65.0, 127.7,

129,7,133,4, 135,5.

Example 13 (S) - (-) - 3-Cyclohexene-1-methanol

8.20 g (34.5 mmol) of known ester are (S) - (-) - 3-cyclohexene-1-methyleneoxy- (S) -N-methyl-2-hydroxysuccinimide (see Ireland, et al., J. Org. Chem. 57 (19), 5071-5073. (1992) and references cited therein, dropwise a solution of 75.8 ml (75.8 mmol) of lithium tetrahydrofuran in aluminum (75.8 ml, 75.8 mmol) in tetrahydrofuran (90 ml). The mixture was allowed to warm to room temperature, stirred at 25 ° C for 1 hour, and quenched with water and 1 N sodium hydroxide solution. The insolubles were filtered off with celite and washed with 100 mL of tetrahydrofuran. The filtrate was evaporated under reduced pressure and the residue was dissolved in 150 ml of diethyl ether. The solution was washed with water (2 x 50 mL), brine (50 mL), dried over anhydrous magnesium sulfate, and the solvent was distilled off. 3.24 g (83%) of (S) - (-) - 3-cyclohexene-1-methanol are obtained as a clear oil, [α] _D = -90.3 ° (c = 1, methanol). This product and the TLC properties and H NMR spectrum of the same ^one in all respects with the racemic material (Aldrich).

¹ H NMR (300 MHz, CDCl ₃ , δ): 1.21-1.42 (m, 2H), 1.68-1.88 (m, 3H), 2.04-2.21 ( m, 3H),

3.54 (br s, 2H), 5.69 (s, 2H).

Example 14 (S) - (-) - 3- (tert-Butyldiphenylsilyloxymethyl) -1-cyclohexene

(S) - (-) - 3-cyclohexene-1-methanol (3.17 g, 28.3 mmol) in N, N'-diisopropylethylamine (10.9 mL, 62.3 mmol) and 1.03 g (8.5 g). mmol). In the presence of 4- (dimethylamino) pyridine, 8.15 ml (31.1 mmol) of tert-butyldiphenylchlorosilane in 100 ml of dichloromethane were treated. After working up the reaction mixture and purifying by chromatography, 8.73 g (88%) of the silyl ether, i.e. (S) - (-) - 3- (tert-butyldiphenylsilyloxymethyl) -1-cyclohexene, is obtained as a clear oil. we get. The TLC behavior and the ¹ H-NMR spectrum of this product are identical in all respects to the corresponding data for racemic 3- (tert-butyldiphenylsilyl-oxyethyl) -1-cyclohexene.

¹ H NMR (300 MHz, CDCl ₃ , δ): 1.05 (s, 9H),

1.29 (m, 1H), 1.71-2.18 (m, 4H), 3.54 (d, 2H,

J = 6Hz), 5.66 (br s, 2H), 7.38 and 7.66 (m, 10H).

Example 15 (S) - (-) - 3- (tert-Butyldiphenylsilyloxymethyl) -1,6-hexanediol

8.35 g (23.9 mmol) of silyl ether, namely (S) - (-) 3- (tert-butyldiphenylsilyloxymethyl) -1-cyclohexene, was added to the racemic diol, 3- (tertiary) (butyldiphenylsilyloxymethylene) ozonization with 1,6-hexanediol, followed by reductive treatment (using borane / dimethylsulfide complex). This gives 5.01 g (55%) of (S) (-) - 3- (tert-butyldiphenylsilyloxymethyl) -1,6-hexanediol as a colorless viscous oil, which is a thin layer. chromatographic assay (rf = 0.4, running solvent: ethyl acetate). ¹ H NMR (300 MHz, CDCl ₃ , δ): 1.05 (s, 9H),

1.21-1.81 (m, 7H), 2.32 (br s, 2H), 3.50-3.75 (m,

6H), 7.32 and 7.70 (m, 10H).

Example 16 (S) - (-) - 3- (tert-Butyldiphenylsilyloxymethyl) -1,6-dibromohexane

4.85 g (12.53 mmol) of (S) - (-) - 3- (tert-butyldiphenylsilyloxymethylene) -1,6-hexanediol are racemic dibromide, 3- (tert-butyldiphenyl) -Silyloxymethyl) -1,6-dibromohexane as described for 150 ml of dichloromethane at 0 ° C, 5.35 g (30.1 mmol)

HU 223 807 Β1

Reaction with N-bromosuccinimide and triphenylphosphine (7.87 g, 30.1 mmol). This gives 4.81 g (75%) of (S) - (-) - 3- (tert-butyldiphenylsilyloxymethyl) -1,6-dibromohexane as a clear colorless oil, m.p. TLC [rf = 0.8 (eluent: ethyl acetate / hexane = 10:90]). The TLC behavior and ¹ H NMR spectrum of this product were identical in all respects to those of the racemic compound. The mass spectrum of the product is consistent with the expected chemical structure.

¹ H NMR (300 MHz, CDCl ₃ , δ): 1.06 (s, 9H),

1.35-2.10 (m, 7H), 3.55 (m, 4H), 3.56 (apparent d, 2H, J = 4Hz), 7.40 and 7.64 (m, 10H).

Example 17 (R) -3- (Tert-Butyl-diphenylsilyloxymethyl) -1,6-dibromohexane

5.05 g (13.04 mmol) of (R) -3- (tert-butyldiphenylsilyloxymethylene) -1,6-hexanediol are obtained from (S) - (-) - 3- (tert-butyldiphenylsilyl). as described for the preparation of oxymethyl) -1,6-dibromohexane in 160 ml of dichloromethane at 0 ° C with 5.57 g (31.32 mmol) of N-bromosuccinimide and 8.21 g (31.32). millimoles) of triphenylphosphine. This gave 5.85 g (87% yield) of chiral dibromide as a clear colorless oil, (R) -3- (tert-butyldiphenylsilyloxymethyl) -1,6-dibromohexane. TLC [rf = 0.8 (eluent: ethyl acetate / hexane = 10:90]). The mass spectrum of the product is consistent with the expected chemical structure.

¹ H NMR (300 MHz, CDCl ₃ , δ): 1.06 (s, 9H),

1.35-2.10 (m, 7H), 3.55 (m, 4H), 3.56 (apparent d, 2H, J = 4Hz), 7.40 and 7.64 (m, 10H).

Example 18

2-allyl-4-pentenoic acid

To a suspension of sodium methylate (59.4 g, 1.1 mol) in anhydrous methanol (1 L) was added dimethyl malonic acid (57 ml, 0.5 mol) at 0 ° C under nitrogen. After 30 minutes, 95 ml (1.1 mol) of allyl bromide was added all at once and the reaction mixture was kept at room temperature for 14 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in 0.5 L of methanol and 500 mL of 5N sodium hydroxide solution was added. The resulting mixture was stirred for 24 hours, then methanol was distilled off under reduced pressure and the basic aqueous phase was washed twice with ethyl acetate. The aqueous portion was acidified with 0.5 L of 5N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed twice with water and then with brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting white solid was triturated with pentane and air dried to give 51.4 g (57% yield) of dicarboxylic acid. A portion of this dicarboxylic acid (50 g, 274 mmol) was heated at 150 ° C until the evolution of carbon dioxide ceased (about 2 hours). The resulting brown oil was filtered through a small pad of silica gel with ethyl acetate as eluent. This gave 32.8 g (85%) of the title compound as a golden yellow oil. Total yield of the three steps: 48%.

¹ H NMR (CD ₃ CN, δ): 2.4 (m, 4H), 2.5 (m,

1H), 5.05 (dd, 2H), 5.15 (dd, 2H), 5.9 (m, 2H), 12.8 (br, 1H).

The mass spectrum of the product is consistent with the expected chemical structure.

Example 19

3- (tert-butyl-diphenyl-silyloxy methyl) -1,5-pentanediol

To a suspension of lithium tetrahydroaluminate (4.33 g, 114 mmol) in anhydrous diethyl ether (125 mL) was added dropwise 2-allyl-4-pentenoic acid (16.0 g, 114 mmol) at 0 ° C with stirring under nitrogen. warm the mixture to room temperature. After 16 hours, the reaction was quenched with ethanol (25 mL) followed by 4N hydrochloric acid (40 mL). The mixture is extracted twice with diethyl ether, the organic phase is dried and the solvent is distilled off under reduced pressure. This gave 11.7 g (82%) of the alcohol as a colorless oil, 2-allyl-4-penten-1-ol, which was used without further purification.

A solution of 11.7 g (93 mmol) of 2-allyl-4-penten-1-ol in 0.5 L of anhydrous dichloromethane was added.

12.6 g (185 mmol) of imidazole followed by 25.48 g (93 mmol) of tert-butyldiphenylchlorosilane are added and the mixture is stirred for 16 hours. The insolubles were then filtered off, the filtrate was washed with water and brine, dried and the solvent was distilled off under reduced pressure. This gave 32.5 g (96%) of the silyl ether as an oil, 3- (tert-butyldiphenylsilyloxymethylene) -penta-1,4-diene, which was used without further purification.

Ozone was added to a solution of 3- (tert-butyldiphenylsilyloxymethyl) -1,5-pentanediol (47 mmol) in anhydrous methanol (500 mL) at -78 ° C until blue (30 minutes). Nitrogen was bubbled through the mixture for 20 minutes and sodium tetrahydroborate (17.6 g, 47 mmol) was added, the cooling bath removed, and the mixture allowed to warm to room temperature. The solvent was distilled off under reduced pressure and the residue was partitioned between diethyl ether and saturated sodium chloride solution. The solvent was distilled off from the diethyl ether solution and the residue was filtered through a pad of silica gel with 0% to 50% ethyl acetate in hexane (isomer mixture) as eluent. The fractions containing the minor component were combined and the solvent was distilled off. This gave 3.8 g (22%) of the desired diol, 3- (tert-butyldiphenylsilyloxymethyl) -1,5-pentanediol as a colorless oil. The overall yield of the three steps is 17%. The mass spectrum of the product is consistent with the expected chemical structure.

¹ H NMR Spectrum (δ): 1.17 (s, 9H), 1.6 (dt, 4H), 1.83 (m, 1H), 2.14 (s, 2H), 3.6 (m, 6H), 7.41 (t, 2H), 7.45 (t, 2H), 7.66 (d, 4H).

Example 20

3- (tert-butyl-diphenyl-silyloxy methyl) -1,5-dijódpentán

To a solution of 3- (tert-butyldiphenylsilyloxymethylene) -1,5-pentanediol (6.9 g, 19 mmol) in diethyl ether (300 mL) was added methanesulfonyl chloride (4.3 mL, 56 mmol) at 0 ° C. followed by 7.7 ml (56 mmol) of triethylamine and then allowed to gradually warm to room temperature. After 3-16 hours, the reaction mixture was washed with water and brine, dried over magnesium sulfate, and the solvent was distilled off. This gave 8.5 g (90%) of 1,5-bis (methanesulfonyloxy) -3-tert-butyldiphenylsilyloxymethylpentane as a colorless oil which was used without further purification. .

To a solution of 8.5 g (16 mmol) of bis-mesylate, i.e. 1,5-bis (methanesulfonyloxy) -3-tert-butyldiphenylsilyloxymethyl) pentane, in 500 ml of freshly distilled acetone, Sodium iodide (1 g, 241 mmol) and sodium bicarbonate (67 mg, 0.8 mmol) were added and the mixture was refluxed at 57 ° C for 72 h. After cooling to room temperature, the insolubles were filtered off and the solvent was distilled off under reduced pressure. The residue was diluted with diethyl ether, the solution was washed with 10% sodium sulfite solution, dried and the solvent was distilled off. This gave 7.4 g (78%) of the title compound as a colorless oil. The overall yield of the two reaction steps is 70%. The mass spectrum of the product is consistent with the expected chemical structure.

¹ H NMR (DMSO-d ₆ , δ): 1.06 (s, 9H), 1.78 (m, 1H), 1.8-2.06 (m, 4H), 3.13 ( m, 4H), 3.57 (d,

2H), 7.38-7.46 (m, 3H), 7.64 (d, 2H).

Example 21

2- (2'-Bromo-ethoxy) benzyl bromide

7.0 g (43 mmol) of 2-allyloxy-benzyl alcohol [LaChapelle et al., Tetrahedron 44 (16), 5033-5044. (1988)] in anhydrous methanol at -78 [deg.] C. for 13 minutes under ozone, while checking the disappearance of the starting olefin (rf = 0.8, eluent: ethyl acetate / hexane 75:25) by TLC. ratio). Nitrogen was added to the mixture and 9.7 g (0.25 mole) of sodium tetrahydroborate was added and the temperature was raised to 0 ° C. After 30 minutes, the mixture was warmed to room temperature, the solvent was evaporated and the residue was diluted with diethyl ether. The solution was washed with water and brine, dried and the solvent was distilled off. The residue was filtered through a pad of silica gel using a gradient of 25% to 75% ethyl acetate in hexane as the eluent. The eluent was evaporated to give 4.8 g (67%) of the diol, 2- (2'-hydroxyethoxy) -benzyl alcohol, as an oil.

Mass spectrum (knee desorption method, chloroform): molecular weight: calculated: 168, found: 168.

To a solution of 4.38 g (26 mmol) of diol, i.e. 2- (2'-hydroxyethoxy) benzyl alcohol, in 250 ml of anhydrous dichloromethane, is added 15.8 g (60 mmol) of triphenylphosphine and 10 ml of ethyl acetate. 7 g (60 mmol) of N-bromosuccinimide and kept at 0 ° C for 2 hours. TLC (ethyl acetate: dichloromethane = 20:80, eluting) then showed complete reaction. At this time, the solvent was distilled off under reduced pressure and the residue was filtered through a pad of silica gel, eluting with a gradient of pure hexane followed by the addition of increasing amounts of ethyl acetate to complete a 15:85 mixture of ethyl acetate and hexane. The fractions were evaporated to give 6.91 g (90%) of dibromide, 2- (2'-bromoethoxy) benzyl bromide, as a colorless solid. The mass spectrum of the product is consistent with the expected chemical structure. ¹³ C NMR (CDCl ₃ , 75.4 MHz, δ): 28.7, 29.1,

68.2, 112.3, 121.6, 126.8, 130.2, 131.1, 156.0.

¹ H NMR (CDCl ₃ , 200 MHz, δ): 3.72 (2H, t,

J = 5Hz, 4.34 (2H, t, J = 5Hz), 4.59 (2H, s), 6.84 (H, d, J = 7Hz), 6.95 (H, t , J = 7Hz), 7.25-7.38 (2H).

Example 22

1- (tert-butyl-dimethyl- $ zilil) -3- (2-iodoethoxy) -4- (tert -butyl-diphenyl-silyl) butane

21.6 g (43.4 mmol) of allyl ether, namely 1- (tert-butyldimethylsilyloxy) -3- (allyloxy) -4- (tert-butyldiphenylsilyloxy) butane, are dissolved in 500 ml of methanol and the solution was cooled to -78 ° C under a nitrogen atmosphere. Ozone was introduced and after 11 minutes, the reaction was judged complete by TLC (hexane: ethyl acetate = 90:10). Then we add

Sodium tetrahydroborate (9.9 g, 6 equiv.) Was added and after 5 minutes the mixture was allowed to warm to room temperature. Methanol was distilled off under reduced pressure and the residue was suspended in diethyl ether. The diethyl ether portion was washed with water and the aqueous portion was shaken with diethyl ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was distilled off under reduced pressure. The resulting oil was filtered through a pad of silica gel which was eluted first with ethyl acetate / hexane (5:95) and then with ethyl acetate / hexane (25:75). There was thus obtained 11.0 g (50% yield) of alcohol as a light yellow oil, i.e. 1- (tert-butyldimethylsilyloxy) -3- (2-hydroxyethoxy) -4- (tert-butyldiphenyl). yields silyloxy) butane. Its mass spectrum and ^1H-NMR spectra were consistent with the expected structure.

11.0 g (21.9 mmol) of alcohol, i.e. 1- (tert-butyldimethylsilyloxy) -3- (2-hydroxyethoxy) -4- (tert-butyldiphenylsilyloxy) butane 200 ml anhydrous di12

To a solution of ethyl ether in ethyl ether at 80 DEG C., add 4.6 ml (1.5 eq.) Of triethylamine followed by 2.5 ml (1.5 eq.) Of methanesulfonyl chloride. After 1.5 hours, TLC (eluent: ethyl acetate / dichloromethane 5:95) showed complete reaction. The reaction mixture was diluted with diethyl ether (250 mL), washed twice with water, twice with brine, dried over sodium sulfate, filtered and the solvent was distilled off under reduced pressure. The resulting oil was filtered through a pad of silica gel which was eluted first with ethyl acetate / hexane (5:95) and then with ethyl acetate / hexane (25:75). 11.6 g (91%) of mesylate, i.e. 1- (tert-butyldimethylsilyloxy) -3- [2- (methanesulfonyloxy) ethoxy)] - 4- (tert-butyldiphenyl) are obtained as an oil. (silyloxy) butane is obtained. Its mass spectrum and ^1H-NMR spectra were consistent with the expected structure.

11.6 g (20 mmol) of mesylate, i.e. 1- (tert-butyldimethylsilyloxy) -3- [2- (methanesulfonyloxy) ethoxy)] - 4- (tert-butyldiphenylsilyloxy) and then a solution of 44 g (15 eq.) of sodium iodide and 170 ml (0.1 eq.) of sodium bicarbonate in 300 ml of acetone are added under a nitrogen atmosphere. The mixture was refluxed for 18 hours, then acetone was distilled off under reduced pressure and the residue was suspended in diethyl ether. The diethyl ether portion was washed twice with water and the aqueous portion shaken with diethyl ether. The combined diethyl ether portions were washed twice with 10% sodium sulfite solution and then with saturated sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. This gave 10.7 g (87%) of the title iodide as an oil which was used without further purification. Its mass spectrum and ^1H-NMR spectra were consistent with the expected structure.

Example 23

1- [2- (Methanesulfonyloxy-ethoxy)] - 2- [2- (methanesulfonyloxy-ethyl)] - 3- (tert-butyl-diphenylsilyloxy) -propane g (0.2 mole) allyl To a solution of dimethylmalonic acid dimethyl ester in 0.5 L of tert-butyl alcohol is added 19 g (0.5 mol) of sodium tetrahydroborate. The mixture was heated to 70 ° C, 162 mL of methanol was added dropwise over 1 hour and the reaction mixture was stirred overnight at room temperature. Water (20 ml) was then added to decompose the excess tetrahydroborate and the mixture was filtered through a pad of celite. The filtrate was concentrated to 100 mL and extracted with ethyl acetate (4 x 20 mL). The combined organic layers were dried over magnesium sulfate and the solvent was distilled off under reduced pressure. This affords 19 g (83%) of the diol, 2-allyl-1,3-propanediol, in relatively pure form, which is used in the next step without further purification.

To a solution of 23.2 g (0.19 mol) of diol, i.e. 2- (2-propen-1-yl) -1,3-propanediol in 1 liter of toluene, 27.3 g (0.20 mol) of anisaldehyde and 4 g of 10 mol% p-toluenesulfonic acid. The flask was fitted with a Dean-Stark trap and the mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature and diluted with 1 L of diethyl ether. The diethyl ether solution was washed three times with 50 ml of saturated sodium bicarbonate solution, three times with 50 ml of water, and finally with 50 ml of saturated sodium chloride solution. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was passed through a short column of silica gel eluting with a mixture of ethyl acetate and hexane (10:90). The eluent was evaporated to give 40 g (89%) of the anisilidene compound, m.p.

1.3-O-Anisilidene-2- (2-propen-1-yl) -propane is obtained. TLC Rf = 0.62 (eluent: ethyl acetate / hexane 25:75).

20.0 g (85.3 mmol) of anisilidene derivative, m.p.

To a mixture of 1.3-O-anisilidene-2- (2-propen-1-yl) -propane in 500 mL of dichloromethane and 25 mL of pH 7 buffer solution was added 38.7 g (170 g, 170 mL) with stirring at 0 ° C. Dichlorodicyanobenzoquinone (7 mmol), the mixture was stirred vigorously and allowed to warm to room temperature. After 12 hours, the reaction mixture was diluted with diethyl ether (1 L), washed with saturated aqueous sodium bicarbonate (2 x 200 mL), and with 10% aqueous sodium sulfite (3 x 200 mL), dried and evaporated under reduced pressure. The residue was chromatographed on a silica gel column, eluting with a gradient of 10% to 25% ethyl acetate in hexane. Evaporation of the eluent gave 12.7 g (61%) of the anisoate alcohol, 3- (4-methoxybenzoyloxy) -2- (2-propen-1-yl) -1-propanol. TLC Rf = 0.14 (eluent: ethyl acetate / hexane 25:75). The ¹ H-NMR spectrum of the product is consistent with the expected chemical structure.

To a solution of 16.58 g (66.32 mmol) of alcohol, i.e. 3- (4-methoxybenzoyloxy) -2- (2-propen-1-yl) -1-propanol, in 250 ml of dichloromethane, is added 24.80 g of (132.64 mmol) of trichloroallyl imidate in 500 ml of cyclohexane. To the resulting mixture was added 1 mL of trifluoroacetic acid under a nitrogen atmosphere. Within 12 hours a white precipitate formed. The precipitate was filtered off and the filtrate was diluted with 500 ml of diethyl ether. The diethyl ether layer was washed with water (3 x 100 mL) and brine (100 mL), dried and the solvent was distilled off under reduced pressure. The residue was chromatographed on a silica gel column, eluting with a gradient of 0% to 25% ethyl acetate in hexanes. 24 g of diene, 1- (2-propen-1-yloxy) -2- (2-propen-1-yl) -3- (4-methoxybenzoyloxy) -propane, containing a small amount of acetamide, were obtained. is carried on to the next step without further purification. TLC Rf 0.38 (eluent: ethyl acetate / hexane 25:75).

807 Β g of the ester, i.e. 1- (2-propen-1-yloxy) -2- (2-propen-1-yl) -3- (4-methoxybenzoyloxy) -propane, is dissolved in 60 ml of tetrahydrofuran. In 100 ml of methanol, 40 ml of 1 N aqueous sodium hydroxide solution are added and the resulting mixture is stirred overnight. The methanol and tetrahydrofuran are then distilled off under reduced pressure. The residue was diluted with diethyl ether (250 mL), washed with water (3 x 100 mL), dried and evaporated under reduced pressure. The residue was chromatographed on a silica gel column eluting with ethyl acetate / hexane (10:90). Evaporation of the eluent gave 4.10 g (30% in two steps) of the alcohol, i.e. 1- (2-propen-1-yloxy) -2- (2-propen-1-yl) -3-propanol. The ¹ H-NMR spectrum of the product is consistent with the expected chemical structure. TLC Rf = 0.23 (eluent: ethyl acetate / hexane 25:75).

To a solution of 4.10 g (26.2 mmol) of alcohol, i.e. 1- (2-propen-1-yloxy) -2- (2-propen-1-yl) -3-propanol, in 150 mL of dichloromethane, is added under nitrogen atmosphere. Imidazole (2.70 g, 39.7 mmol) was added and a solution of tert-butyldiphenylchlorosilane (8.24 g, 29.97 mmol) in dichloromethane (50 mL) was added over 10 minutes. After stirring for 12 hours, the mixture was diluted with diethyl ether (100 mL) and quenched with water (100 mL). The resulting mixture was extracted three times with 100 ml of diethyl ether, the combined organic phases were washed with 100 ml of saturated sodium chloride solution, dried and the solvent was distilled off under reduced pressure. The residue was chromatographed on a short column of silica gel eluting with hexane containing increasing amounts of ethyl acetate from 0% to 25%. The eluent was distilled off to give 7.41 g (72%) of silyl ether, 1- (2-propen-1-yloxy) -2- (2-propen-1-yl) -3- (tert-butyldiphenyl). yields silyloxy) propane. TLC Rf = 0.76 (eluent: ethyl acetate / hexane 25:75).

7.41 g (18.80 mmol) of diene, i.e. 1- (2-propen-1-yloxy) -2- (2-propen-1-yl) -3- (tert-butyl-diphenylsilyloxy) Ozone is added to a solution of propane in 500 ml of methanol at -78 ° C. As soon as the starting material disappeared by thin layer chromatography (eluent: ethyl acetate / hexane 25:75), nitrogen was added to the mixture, 2.13 g (56.30 mmol) of sodium tetrahydroborate was added and warm to room temperature. After 12 hours, the solvent was distilled off and the white residue was treated with water to decompose the excess reagent. The aqueous mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried, and the solvent was distilled off under reduced pressure. The residue was chromatographed on a short column of silica gel, eluting with 10% to 50% ethyl acetate in hexane. The eluent was distilled off to give 5.48 g (72%) of 1,7-diol, i.e. 1- (2-hydroxyethoxy) -2- (2-hydroxyethyl) -3- (tert-butyldiphenylsilyl). oxy) propane is obtained. TLC Rf 0.21 (50:50 ethyl acetate: hexane).

The ¹ H-NMR spectrum of the product is consistent with the expected chemical structure.

To a solution of 5.48 g (13.6 mmol) of 1- (2-hydroxyethoxy) -2- (2-hydroxyethyl) -3- (tert-butyldiphenylsilyloxy) propane in 400 ml of dichloromethane under stirring, under nitrogen, triethylamine (11.2 mL, 78 mmol) was added dropwise over 30 minutes, and a solution of methanesulfonyl chloride (3 mL, 39.00 mmol) in dichloromethane (100 mL) was added dropwise. After 12 hours, the mixture was diluted with diethyl ether (500 mL), washed with water (3 x 100 mL), brine (100 mL), dried and the solvent was distilled off under reduced pressure. The residue was chromatographed on a short column of silica gel eluting with 10% to 50% ethyl acetate in hexanes. The elution solvent was distilled off to obtain 7.40 g (97% yield) of bis-mesylate, i.e. 1- [2- (methanesulfonyloxy) ethoxy] -2- [2- (methanesulfonyloxy) ethyl] -3- (tertiary). butyldiphenylsilyloxy) propane is obtained. TLC Rf = 0.55 (50:50 ethyl acetate: hexane). The ¹ H-NMR spectrum of the product is consistent with the expected chemical structure.

Example 24

3,4 - [(N, N'-1,1'-Ethoxyethyl) bis (3,3'-indolyl)] - 1 H -pyrroline-2,5-dione [Compound (le)

To a solution of 337 mg (1.02 mmol) of 3,4-bis (3'-indolyl) -2,5-dihydrofuran-2,5-dione in 5 ml of anhydrous dimethylformamide was added 113 mg (2.82 mmol) of sodium in portions over a quarter hour. hydride (60% dispersion in mineral oil). After stirring for 1.5 hours, the mixture was diluted with 5 ml of dimethylformamide and 0.14 ml (1.13 mmol) of bis (2,2'-dibromoethyl) ether was added dropwise to the green solution. The reaction mixture was stirred at 25 ° C for 30 minutes and then heated at 50 ° C overnight. The next day, it was cooled, poured into dilute aqueous citric acid (75 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic extracts were washed with water (3 x 20 mL), brine (20 mL), dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on a short column of silica gel, eluting with a 50:50 mixture of ethyl acetate and hexane (isomer mixture). The resulting material was further purified by radial preparative layer chromatography on a Chromatotron using 50:50 ethyl acetate: hexane (isomer mixture) as eluent. This gave 82 mg (20%) of 2,3-[(N, N'-1,1'-ethoxyethyl) bis (3,3'-indolyl)] as 1H-2 as a wine-red solid. 5-dihydrofuran-2,5-dione is obtained, m.p.> 320 ° C.

mg (0.15 mmol) 2,3 - [(N, N'-1,1'-ethoxyethyl) bis (3,3'-indolyl)] - 1H-furan-2,5-dione 1,5 ml dimethyl14

A solution of 0.33 mL (1.45 mmol) of 1,1,1,3,3,3,3-hexamethyldisilazane and 23 mg (0.73 mmol) of methanol was added 10 min earlier to a solution of formamide in formamide under nitrogen. After stirring for 16 hours at room temperature, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic extracts were washed several times with water, dried over magnesium sulfate and the solvent was distilled off. The residue was purified by radial chromatography (eluent: methanol: chloroform = 3:97). In this way, 3,4 - [(N, N'-1,1'-ethoxyethyl) bis (3,3'-indolyl)] - 41.5 mg (yield: 72%) as a purple solid was obtained. 1H-pyrrole-2,5-dione is obtained, m.p.> 320 ° C. Mass spectrum, molecular weight based on C24H-19N3O3:

Calculated: 397.1426;

found: 397.1438.

Example 25

3,4 - [(N, N'-1,1 ') - [(3' -Propoxy) -3 '' - (O) -4 '' - hydroxybutane] -bis (3'-indolyl)] - 1H -pyrrole-2,5-dione (Compound 1f)

3,4-Bis (3,3'-indolyl) -1-methylpyrroline-2,5-dione (4.35 g, 12.8 mmol) and cesium carbonate (8.31 g, 25.5 mmol) in dimethylformamide (125 mL) A solution of 4.0 g (6.4 mmol) of 1- (tert-butyldimethylsilyloxy) -3- (3-iodopropyl) -4- (tert-butyldiphenyl) silyloxy) butane in 20 ml of dimethylformamide. Thin layer chromatography (3: ethyl acetate / hexane, 1: 1) indicates that the starting iodide is consumed. At this time, the reaction mixture was diluted with 200 mL of ethyl acetate and the solution was washed with water. The aqueous portion was partitioned between ethyl acetate (200 mL), the combined organic portions were dried and the solvent was distilled off. The residue was purified by flash chromatography eluting with 10% to 25% ethyl acetate in hexane. This gave 3.94 g (69%) of the desired monoalkylated product as a red oil, 3 - [(N-1- (3-propoxy-3 (O) -4-tert-butyl-diphenylsilyloxy)]. 1- (tert-butyldimethylsilyloxy) butane -4- (3'-indolyl) -1-methylpyrroline-2,5-dione is obtained and the mass spectrum of the product is consistent with the expected chemical structure.

To a solution of 3.14 g (3.74 mmol) of the alkylated product obtained in the preceding paragraph in 100 ml of methanol is added 60 mg (2%) of ptoluenesulfonic acid. After 2 hours, thin layer chromatography (eluent: ethyl acetate / hexane 50:50) showed the starting material was consumed. The mixture was concentrated to half its original volume and diluted with ethyl acetate (300 mL). The solution was washed with 1 N sodium hydroxide solution and brine, dried, and the solvent was distilled off. The residue was purified by filtration through a pad of silica gel, eluting with a 50:50 mixture of ethyl acetate and hexane. In this way, 1.76 g (65%) of 3 - [(N-1- (3-propoxy-3 (O) -4- (tert-butyldiphenylsilyloxy) butane)) as a red foamy material were obtained. 1-ol] -4- (3'-indolyl) -1-methylpyrroline-2,5-dione The mass spectrum of the product is consistent with the expected chemical structure.

The alcohol obtained as described in the preceding paragraph, i.e., 3 - [(N-1- (3-propoxy-3 (O) -4- (tert-butyldiphenylsilyloxy) butan-1-ol) -4- ( To a solution of 3'-indolyl) -1-methylpyrroline-2,5-dione in 200 ml of diethyl ether was added 0.5 ml (1.5 eq.) Of triethylamine at 0 ° C, followed by 0.28 ml (1.5 eq.) After allowing the mixture to warm to room temperature, the reaction was complete in 1 hour, diluted with diethyl ether (200 mL), washed with water, brine, dried, and evaporated to give a residue. It was filtered through a pad of silica gel eluting with 50:50 ethyl acetate: hexane to give the mesylate, which was used immediately.

To a solution of the mesylate obtained in the preceding paragraph in 250 ml of acetone was added 3.6 g (10 equivalents) of sodium iodide and 20 mg of sodium bicarbonate. After stirring for 4 hours, TLC (50:50 ethyl acetate: hexanes) gave starting material. At this time, an additional 10 equivalents of sodium iodide were added and the mixture heated at 60 ° C for 4 hours. Subsequent thin layer chromatography (50:50 ethyl acetate / hexane) showed the starting material was consumed. At this time, the solvent was distilled off and the residue was diluted with 250 mL of ethyl acetate. The solution was washed with water and then with 10% sodium sulfite solution, dried and the solvent was distilled off. The residue was purified by filtration through a pad of silica gel, eluting with a 50:50 mixture of ethyl acetate and hexane. Thus, 1.71 g (85%) of the desired iodide, 3 - [(N-1- (3-propoxy-3 (O) -4- (tert-butylphenyl) silyl)) After oxy-1-iodo-b] -4- (3'-indolyl) -1-methylpyrroline-2,5-dione, the mass spectrum of the product is consistent with the expected chemical structure.

2.0 g (2.4 mmol) of iodide obtained in the same manner as in the preceding paragraph, i.e. 3 - [(N-1- (3-propoxy-3 (O) -4-tert-butyl-diphenylsilyloxy) A solution of -1-iodobutane] -4- (3'-indolyl) 1-methylpyrroline-2,5-dione in 10 ml of dimethylformamide is added via a dosing pump over a period of 80 hours to 3.12 g (9.6 mmol) ) to a suspension of cesium carbonate in 400 ml of dimethylformamide, 3 hours after addition, thin layer chromatography (eluent: ethyl acetate / hexane 50:50) shows the starting material to be consumed, and then 1 liter of ethyl acetate. After dilution, the solution was washed with water, brine, extracted with ethyl acetate (500 mL), and the combined organic extracts were evaporated to give a residue which was purified by filtration through a pad of silica gel eluting with ethyl acetate and hexane. Uses a 50:50 mixture1 5

HU 223 807 Β1 after all. The eluent solvent was distilled off to give 1.65 g (97% yield) of the desired macrocycle, i.e., 3,4 - [(N, N'-1,1 ') - [(3' propoxy) -3 '''- (0) -4 '' - hydroxybutane] bis (3,3'-indolyl) -1-methylpyrroline-2,5-dione is obtained. The mass spectrum of the product is consistent with the expected chemical structure.

1.7 g (2.4 mmol) of N-methyl maleimide obtained as described in the previous paragraph, i.e. 3,4 - [(N, N'-1,1 ') [(3' -propoxy) -3 '] To a solution of '- (O) -4''- hydroxybutane] bis (3,3'indolyl)] - 1-methylpyrroline-2,5-dione in 100 ml ethanol is added 50 ml of 5 N potassium hydroxide solution, and after 12 hours, the mixture was heated at 50 ° C for 2 hours. After cooling to room temperature, the solvent was distilled off and diluted with ethyl acetate. The organic layer was washed with water, dried and the solvent was distilled off. Thus, 1.37 g (83% yield) of the desired anhydride as a red solid, i.e. 2,3 - [(N, N'-1,1 '- (3' -propoxy-3 '' - (O) 4-hydroxybutane) bis (3,3'-indolyl) -2,5-dihydrofuran-2,5-dione The mass spectrum of the product is consistent with the expected chemical structure.

37 g (3 mmol) of the anhydride obtained in the same manner as in the previous paragraph, i.e. 2,3 - [(N, N'-1,1 '- (3-propoxy-3''- (O) -4'-hydroxy) butane) bis (3,3'-indolyl)] 2,5-dihydrofuran-2,5-dione in 100 ml of dimethylformamide was added 12.6 ml (20 equivalents)

1,1,1,3,3,3-hexamethyldisilazane and 1.21 ml (10 equivalents) of methanol. Thin layer chromatography (eluent: ethyl acetate / hexane 50:50) after 24 hours showed the starting material to be consumed. At this time, the mixture was diluted with ethyl acetate, and the solution was washed with 1N hydrochloric acid, water, dried, and the solvent was evaporated. The residue was stirred with 1N hydrochloric acid or cesium fluoride to cleave the remaining trimethylsilyl groups, then diluted with ethyl acetate, washed with water, dried and the solvent was distilled off. In this way, 1.02 g (75%) of the desired maleimide, i.e. 3,4 - [(N, N'1,1 ') - [(3' -propoxy) -3 '' - as a red solid is obtained. (O) -4 '' - hydroxybutane] bis (3,3'indolyl) -1H-pyrroline-2,5-dione is obtained. The mass spectrum of the product is consistent with the expected chemical structure. ¹ H NMR (300 MHz, DMSO-d ₆ , δ): 2.1 (m,

4H), 2.4 (m, 2H), 3.28 (br, m), 3.4 (m, 1H), 4.25 (m, 4H), 4.5 (t, J = 6Hz, 1H), 7.0-7.9 (m, 10H),

II, 0 (s, 1H).

¹³ C NMR (75 MHz, _DMSO-d6, δ): 20,9,28,9,

30.3, 30.9, 34.3, 40.2, 41.6, 42.4, 62.4, 65.9, 78.1,

104.0, 104.1, 110.0, 110.1, 119.6, 119.7, 121.4,

121.8, 124.8, 126.5, 126.6, 127.9, 131.5, 131.6,

131.7.135.8, 135.9, 139.1, 151.4, 172.2.

Example 26

3,4 - [(N, N'-1,1 '- [(2-Ethoxy) -3' - (O) -4'-hydroxybutane] bis (3,3'-indolyl)) - 1H-pyrroline -2,5-dione [Compound (Ig)]

To a solution of 17.9 g (52.5 mmol, 3 equivalents) of bis (3,3'-indolyl) -1-methylpyrrole-2,5-dione in 250 ml of dimethylformamide was added 68.4 g (4 equivalents) of cesium carbonate followed by 10.7 g (17.5 mmol) of iodide, 1- (tert-butyldimethylsilyloxy) -3- (2-iodoethoxy) -4- (tert-butyldiphenyl) -Silyloxy) -butane is added. The reaction mixture was stirred at room temperature for 18 hours. Thin layer chromatography (eluent: ethyl acetate / hexane = 5:95) showed that the iodide was consumed. The mixture was poured into ethyl acetate (1200 mL), washed with 1N hydrochloric acid (400 mL), and the acidic aqueous phase was shaken twice with ethyl acetate. The combined ethyl acetate portions were washed twice with saturated sodium bicarbonate solution and then with saturated sodium chloride solution, dried over magnesium sulfate, filtered and the solvent was distilled off under reduced pressure. The dimethylformamide is removed by azeotropic distillation with xylene. The resulting red gum was triturated with dichloromethane and acetonitrile to give a suspension containing a solid. This was concentrated, additional dichloromethane was added, cooled and the red solid filtered off. Further part of the desired product is obtained by trituration of this solid with dichloromethane and then with ethyl acetate. From the filtrates, the solvent was distilled off under reduced pressure, the residue was bound to silica gel and applied to a large column filled with flash silica gel. First, the dialkylated by-product was eluted with 5: 1 hexane: ethyl acetate followed by 3: 1 hexane: ethyl acetate (57% yield). 1- [2-ethoxy- (3 '' (O) -4 "'- (tert-butyldimethyl-butyldiphenylsilyloxy) -1''- (tert-butyldimethylsilyl-oxy) butane)] - indol-3-yl] -4- (indol-3-yl) -1Nmetil-pyrroline-2,5-dione. the mass spectrum and ^1H-NMR spectra were consistent with the expected structure.

8.2 g (9.9 mmol) of tert-butyldimethylsilyl ether obtained in the same manner as in the preceding paragraph, i.e. 3 - [(N-1- [2-ethoxy- (3 '' - (O) - "'- (tert-butyldiphenylsilyloxy) -1''- (tert-butyldimethylsilyloxy) butane] -indol-3-yl] -4- (indol-3-yl) -1 N p-toluenesulfonic acid monohydrate (0.16 g, 0.085 eq) was added to a solution of methyl-pyrroline-2,5-dione (450 ml) in methanol (450 ml) at 2 ° C. acetate / hexane 50:50) indicates that the reaction is almost complete, then quenched by the addition of 0.14 g of solid sodium bicarbonate and distilled off under reduced pressure. The residue is dissolved in ethyl acetate, , Washed twice with 1N sodium hydroxide solution and then with saturated sodium chloride solution, dried over magnesium sulfate, k, and the solvent was distilled off under reduced pressure. The resulting red-colored foam was absorbed on silica and applied to a pad of silica gel. The filtrate bed was eluted with hexane / ethyl acetate 2: 1 to give the starting material and then eluted with hexane / ethyl acetate 1: 2 (6.4 g, 91%).

EN 223 807 Β1 i.e. 3 - [(N-1- [2-ethoxy- (3 '' - (O) -4 '' - (tert-butyl-diphenylsilyloxy) -] - hydroxybutane)) - Indol-3-yl] -4- (indol-3-yl) -1N-methylpyrroline-2,5-dione The product has a mass spectrum and ¹ H-NMR consistent with the expected chemical structure.

6.36 g (8.9 mmol) of the alcohol obtained as described in the preceding paragraph, i.e. 3 - [(N-1- [2-ethoxy- (3 '' (O) -4 '' - (tert-butyl) diphenylsilyloxy) -1 "'- hydroxybutane)] - indol-3-yl] -4- (indol-3-yl) -1N-methylpyrroline-2,5-dione in 500 ml of anhydrous diethyl ether under a nitrogen atmosphere 1.9 ml (1.5 eq.) Of triethylamine and 1.0 ml (1.5 eq.) Of methanesulfonyl chloride are added at 5 [deg.] C. After 3 hours, an additional 1.25 ml (1.0 eq.) Of triethylamine is added. amine and 0.7 mL (1.0 eq.) of methanesulfonyl chloride were added and the reaction was complete 1 hour later by TLC (ethyl acetate / hexane 50:50). the reaction mixture was diluted with 250 mL of diethyl ether, and the solution was washed twice with water, followed by 0.1 N hydrochloric acid, and finally with saturated sodium chloride solution, and the diethyl ether portion was dried over magnesium sulfate. The desiccant is filtered off and the solvent is distilled off under reduced pressure. Thus 7.0 g of mesylate, i.e. 3 - [(N 1 - [2-ethoxy- (3 '- (O) -4' - (tert-butyldiphenylsilyloxy) -1 '' - (methanesulfonyloxy)) (butane)] - indol-3-yl] -4 (indol-3-yl) -1N-methylpyrroline-2,5-dione The mass spectrum of the product is consistent with the expected chemical structure.

7.0 g (8.9 mmol) of the mesylate obtained as described in the previous paragraph, i.e. 3 - [(N-1- [2-ethoxy- (3 '' - (O) -4 '' - tert-butyl] diphenylsilyloxy) -1 '' - (methanesulfonyloxy) butane)] indol-3-yl] -4- (indol-3-yl) -1 N-methylpyrroline-2,5-dione in 200 ml acetone To the solution of the reaction mixture was added 13.3 g (10 equivalents) of sodium iodide and 75 mg (0.1 equivalents) of sodium bicarbonate under nitrogen, and the reaction mixture was stirred at 50 ° C for 13 hours, then the solvent was distilled off under reduced pressure. ether, and the solution was washed with 10% sodium sulfite solution, the diethyl ether layer was separated, washed again with 10% sodium sulfite solution, then washed twice with water and then with saturated sodium chloride solution, and dried. The solvent was evaporated under reduced pressure and the residue was filtered through a pad of silica gel eluting with hexane: ethyl acetate (1: 1). hexane and ethyl acetate

A mixture of 1.2 is used. In this way, 7.6 g (total yield in two steps: quantitative) of iodide, i.e., 3 - [(N-1- [2-ethoxy (3 '' - (O) -4 '' - (tertiary)) as a red solid (butyldiphenylsilyloxy) -1 '' - iodobutane)] indol-3-yl] -4- (indol-3-yl) -1 N-methylpyrroline-2,5-dione. and 1 H NMR consistent with the expected chemical structure.

To a slurry of cesium carbonate (4 equivalents) in dimethylformamide (1 L) under nitrogen is added, with the aid of a metering pump, over a period of 65 hours, 7.6 g (9.2 mmol) of iodide obtained as described in the preceding paragraph. ethoxy (3 '' - (O) -4 "'- (tert-butyldimethyl-butyldiphenylsilyloxy) -1''iodobutane)] - indole-3-yl] -4- (indole-3 -yl) -1-N-methylpyrroline-2,5-dione in 25 ml of dimethylformamide, 3 hours after completion of the addition, the solvent was distilled off under reduced pressure, and the residue was dissolved in 700 ml of ethyl acetate and washed twice with 300 ml of water. and the aqueous portions were shaken with ethyl acetate (2 x 200 mL), and the combined ethyl acetate portions were washed with brine (2 x 200 mL), dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. bound on silica gel, and applied onto a flash silica gel column eluting with 5.2 g (82%) of macrocycle, eluting with hexane: ethyl acetate (3: 1) and then hexane: ethyl acetate (1: 1). - [(N, N'1,1 '- [(2 "-ethoxy) -3"' - (O) -4 '' (t-butyldimethyl-silyl diphenylphosphino) butane] bis (3, 3'-indolyl) -1H-pyrroline-2,5-dione is obtained. Its mass spectrum and ^1H-NMR spectra were consistent with the expected structure.

The N-methylmaleimide obtained as described in the preceding paragraph, i.e. 3,4 - [(N, N'-1,1 '- [(2' -ethoxy) -3 '' (O) -4 '- (tert-butyl)] diphenylsilyloxy) -butane] -bis (3,3'-indolyl)] - 1H-pyrroline-2,5-dione in 150 ml of 5N potassium hydroxide solution and 300 ml of ethanol for 65 hours at room temperature and then 1 hour. After stirring for 1 hour at 60 DEG C., the mixture was concentrated under reduced pressure to 150 ml, the residue was suspended in water, cooled to 5 DEG C. and acidified to pH = 3 with concentrated hydrochloric acid. The organic layer was dried and the solvent was distilled off under reduced pressure to give crude anhydride alcohol (3.3 g) as a purple solid (2.3 - [(N, N'-1,1'-)). [(2 "-ethoxy) -3" - (O) -4 "'-hydroxybutane] -bis (3,3'-indolyl)] - 2,5-dihydrofuran-2,5-dione. sum is in tune with the expected chemical structure.

3.3 g (7.5 mmol) of the anhydride obtained as described in the previous paragraph, i.e. 2,3 - [(N, N'-1,1 '- [(2' -ethoxy) -3 '' - (O)). ) -4 "'- hydroxybutane] bis (3,3'-indolyl) -2,5-dihydrofuran-2,5-dione in 250 ml of dimethylformamide was added 32 ml (2 equivalents) of 1,1,1 3,3,3-hexamethyldisilazane and 3 ml (10 equivalents) of methanol are stirred for 16 hours at room temperature and then heated for 2 hours at 60 DEG C. The dimethylformamide is distilled off under reduced pressure and the residue is dissolved in 250 ml of acetonitrile. 50 ml of 1N hydrochloric acid were added and the resulting mixture was stirred for 15 minutes, then the solvent was distilled off and the residue was partitioned between ethyl acetate (1 liter) and water (250 ml) to give 0.92 g of a solid. g (28% yield) of alcohol maleimide, i.e. 3,4 - [(N, N'-1,1 '- [(2' -ethoxy) -3 "- (O) -4"'- hydroxybutane] -bis- (3,3'-indolyl)] - 1H-pyrrole In-2,5-dione is obtained. A small portion (50 mg) of this product is bound to silica gel and applied to a flash silica gel pad.

HU 223 807 Β1 column. The column was eluted with dichloromethane first, then acetonitrile / dichloromethane (5:95) and finally acetonitrile / dichloromethane (10:90) to give 38 mg of analytically pure product. The ethyl acetate portion was distilled off and the residue was chromatographed. This gives an additional 8% crude product. The mass spectrum of the product is consistent with the expected chemical structure.

¹ H NMR (DMSO-d ₆ , δ): 1.96 (1H, m), 2.09 (1H, m), 3.31 (1H, m), 3.40 (1H, m) , 3.51 (1H, m),

3.62 (1H, m), 3.89 (1H, m), 4.18 (3H, m), 4.35 (1H, m), 4.68 (1H, t, J = 2Hz), 7.11 (2H, m), 7.19 (2H, m), 7.44 (1H, s), 7.46 (1H, d, J = 9Hz), 7.51 (1H, s), 7.53 (1H, d, J = 9Hz), 7.79 (1H, d, J = 8Hz), 7.83 (1H, d, J = 8Hz), 10.91 (1H, s) .

Example 27

3,4 - [(N, N'-1,1 '- [(2 "-ethoxy) -3''- [(O) -methylene] -4''is a hydroxy butane] bis (3,3 ' -indolyl)] - 1H-pyrroline-2,5-dione (Compound (lk))

7.40 g (13.30 mmol) of bis-mesylate, i.e. 1- (2-methanesulfonyloxyethoxy) -2- (methanesulfonyloxyethyl) -3-tert-butyldiphenylsilyloxypropane and 4, A solution of 43 g (13.30 mmol) of bis (3,3'-indolyl) -1-methylpyrroline-2,5-dione in 100 ml of anhydrous dimethylformamide was added over 16 hours to 25.4 g (78 mmol) of cesium carbonate. It is made up into a suspension of 400 ml of dimethylformamide, stirred at 50 ° C. After a further 8 hours, the solvent was distilled off under reduced pressure at 80 ° C. The residue was dissolved in 200 mL of ethyl acetate and the solution was washed with 50 mL of water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried and the solvent was distilled off. The residue was chromatographed on a silica gel column eluting with ethyl acetate-hexane (25:75) and then methanol-dichloromethane (5:95). In this way, three main products are obtained: 2.35 g of a macrocycle bearing a silyl ether group, i.e., 2,3 - [(N, N'-1,1 '[4'') - ethoxy-1' -yl- (3 '). tert -butyldiphenylsilyloxymethyl) butan-1-yl] bis (3,3'-indolyl)] - 1-methylpyrroline-2,5-dione, [mass spectrum: based ^ 45 0 ₄ Si: Calc'd MW 707.31, found MW: 708;

TLC: 0.84 (50:50 ethyl acetate: hexane));

and 600 mg of a desilylated alcoholic macrocycle having a mass spectrum consistent with the expected chemical structure.

1.65 g (2.33 mmol) of N-methyl macrocycle, m.p.

2,3 - [(N, N'-1,1 '- [4''-ethoxy-1'-yl-(3''- tert-butyldiphenylsilyloxymethyl) butan-1-yl] -bis (3,3'-indolyl)] - 1-methylpyrroline-2,5-dione in 500 ml of ethanol is added 100 ml of 5N potassium hydroxide solution and the mixture is heated for 12 hours at 50 ° C. After cooling to room temperature, the solvent was distilled off under reduced pressure, the residue was acidified to pH 1 with concentrated hydrochloric acid, extracted with ethyl acetate (5 x 200 mL), the organic phase was dried, the solvent was distilled off under reduced pressure and a short pad of silica gel. Chromatography (5:95 methanol / dichloromethane as eluant) gave the anhydride, m.p.

2,3 - [(N, N'-1,1 '- [4''-ethoxy-1'-yl-(3''- tert-butyl-butyldiphenylsilyloxy-methyl) butan-1-yl] -bis (3,3'-indolyl)] - 2,5-dihydrofuran-2,5-dione is obtained which is used in the next step.

600 mg (1.3 mmol) of anhydride, i.e. 2,3 - [(N, N'1, T- [4 '') - ethoxy-T-yl- (3'-tert-butyl-diphenylsilyloxy) methyl) -butan-1-yl] -bis (3,3'-indolyl) -2,5-dihydrofuran-2,5-dione in 250 ml of anhydrous dimethylformamide was treated with 2.1 g (13 mmol) of hexamethyldisilazane followed by mg (6.5 mmol) of methanol was added. After 48 hours, the solvent was distilled off under reduced pressure and the residue was dissolved in 100 mL of ethyl acetate. The solution was washed with 1N aqueous hydrochloric acid (25 mL), water (25 mL), and brine (25 mL). The organic layer was dried and the solvent was distilled off. The residue was chromatographed on a silica gel column, eluting with a gradient of 0% to 5% methanol in dichloromethane. The eluent was evaporated to give 300 mg (50% yield) of the imide as a solid, i.e. 3,4 - [(N, N'-1, r - [(2 "-ethoxy) -3" - [(O) -methylene) ] -4 "'- hydroxybutane) bis (3,3'-indolyl) -1H-pyrrole-2,5-dione. The mass spectrum of the product is consistent with the expected chemical structure.

¹ H NMR (CDCl ₃ , δ): 9.65 (s, 1H), 7.79 (t,

J = 7.65 Hz), 7.61 (s, 1H), 7.54 (s, 1H), 7.46-7.40 (m, 2H), 7.24-7.08 (m, 2H). ), 7.07-7.02 (m, 2H),

4.43-4.33 (m, 2H), 4.30 ^ 4.21 (m, 1H), 4.14-4.06 (m, 1H), 3.64 (t, J = 4.64). Hz), 3.58-3.38 (m, 5H),

3.71 (t, J = 8.64 Hz, 1H), 1.89-1.85 (m, 1H).

Example 28

3,4- [N, N'-1,1 '- (2-Methyl-6-methylpyridine) bis (3,3'-indolyl)] -1H-pyrroline-2,5-dione [(lo )]

The procedure described in Example 24 is carried out in a solution of 2,3-bis (indolyl) maleic anhydride (287 mg, 0.88 mmol) in dimethylformamide (5 mL) with sodium hydride (88 mg, 2.19 mmol) for 1.5 hours. 60% mineral oil), diluted with dimethylformamide (11 mL) and 2,6-bis (bromomethyl) pyridine (245 mg, 0.93 mmol). After stirring overnight at 50 ° C, the crude product was filtered through a short column of silica gel eluting with ethyl acetate / hexane (50:50) to give the crude product. This gave 142 mg (37%) of N, N '- (bridged with 2,6-bismethylene-pyridyl) -bis (indolyl) -maleic anhydride as a dark red solid, which essentially gave a single spot in the TLC. , which is used in the next step without further purification.

HU 223 807 Β1

140 mg (0.32 mmol) of 3,4- [N, N'-1,1 '- (2-methyl-6-methylpyridine) bis (3,3'-indolyl)] - 1H-furan-2, To a mixture of 5-dione in 2 mL of dimethylformamide was added 0.72 mL (3.2 mmol) of 1,1,1,3,3,3-hexamethyldisilazane and 0.063 mL (1.6 mmol) of methanol. The reaction mixture was worked up and the crude product was purified by radial chromatography on silica gel to give 42 mg of the title N, N '- (2,6-bis-methylenepyridyl bridged) bis (indolyl) -maleimide as a wine-red solid. TLC (rf = 0.35, eluent: methanol: chloroform = 3:97).

Example 29

3,4 - [(N, N'-1,1 '- (2-Ethoxybenzyl) bis (3,3'indolyl)] - 1H-pyrroline-2,5-dione hydrochloride [Formula (Ip) compound]

To a suspension of 8.9 g (27 mmol) of cesium carbonate in 550 ml of anhydrous dimethylformamide is added 2.0 g (6.8 mmol) of dibromide in a nitrogen pump at 55 ° C under vigorous stirring over a period of 20 hours. 2- (2-Bromoethoxy) benzyl bromide and 2.3 g (6.8 mmol) of bis (3,3'-indolyl) -1-methylpyrrole-2,5-dione in 45 ml of anhydrous formamide solution. After a further 2 hours, the solvent was distilled off under reduced pressure and the residue was dissolved in dichloromethane. The solution was washed with 1N hydrochloric acid and brine, dried, and the solvent was distilled off under reduced pressure. The resulting purple oil was filtered through a pad of silica gel eluting with a 50:50 mixture of hexane (isomer mixture) and ethyl acetate. The eluting solvent was distilled off as a purple solid, 2.76 g (71%) of the macrocycle, m.p.

3.4 - [(N, N'-1,1 '- (2-ethoxybenzyl) bis (3,3'-indolyl)] - 1-methylpyrroline-2,5-dione This material isopropanol and dichloro recrystallized from methane to give an analytically pure product.

Mass Spectrum (knee desorption method, chloroform): Molecular Weight: Calculated: 473, Found: 473.

Analysis:

H, 4.90; N, 8.87 Found: C, 76.09;

Found: C, 75.86; H, 4.93; N, 8.79.

710 mg (15 mmol) of macrocycle, i.e. 3,4 [(N, N'-1,1 '- (2' -ethoxybenzyl) bis (3,3'-indolyl)] - 1-methylpyrrole-2, To a suspension of 5-dione in 100 ml of ethanol and 20 ml of tetrahydrofuran was added 80 ml of 5 N potassium hydroxide solution, and the reaction mixture was stirred for 70 hours at 55 ° C. It is acidified to pH 1 with 325 ml of 1N hydrochloric acid and extracted with ethyl acetate, washed twice with saturated sodium chloride solution, dried and evaporated to give 700 mg (quantitative conversion) of anhydride, i.e. 3,4- [(N, N'-1,1 '- (2' -ethoxybenzyl) bis (3,3'-indolyl)) - 2,5-dihydrofuran-2,5-dione is obtained.

760 mg (1.7 mmol) of anhydride, i.e. 3,4 - [(N, N'1,1 '- (2' -ethoxybenzyl) bis (3,3'-indolyl)] - 2,5-dihydrofuran] To a solution of 2,5-dione in 500 ml of anhydrous dimethylformamide was added 0.34 ml (8.3 mmol) of methanol and 3.5 ml (17 mmol)

1,1,1,3,3,3-hexamethyldisilazane. After heating at 55 ° C for 22 hours, the solvent was distilled off under reduced pressure and the residue was diluted with ethyl acetate. The solution was washed with 0.1 N hydrochloric acid, the combined organic portions were dried and the solvent was distilled off. The purple residue was applied to a short column packed with silica gel, eluting with a gradient of dichloromethane and hexane, from 0% to 100% dichloromethane. The eluent was distilled off to give 483 mg (70%) of the free NH group maleimide, i.e. 3,4 - [(N, N'-1,1 '- (2') -ethoxybenzyl) as a purple solid. bis (3,3'-indolyl)] - 1H-pyrroline-2,5-dione The product was recrystallized from a mixture of dichloromethane and hexane to give a mass spectrum consistent with the expected chemical structure.

¹ H NMR (DMSO-d ₆ , δ): 4.29 (2H, br s), 4.59 (2H, br s), 5.23 (2H, br s), 6.90-6 , 99 (2H),

7.01-7.18 (3H), 7.20-7.27 (2H), 7.59-7.68 (2H),

7.71-7.80 (5H), 10.92 (H, s).

Example 30

3.4 - [(N, N'-1,1 '- (Hexane) -bis (3,3'-indolyl)] - 1H-pyrrol-2,5-dione [Compound (Iq)]

To a solution of 499 mg (1.46 mmol) of 3,4-bis (indolyl) -1-methylpyrrol-2,5-dione in 10 mL of dimethylformamide was added 146 mg (3.65 mmol) of sodium in portions over 30 minutes under nitrogen. hydride (60% oil) and the resulting green solution was stirred for 1 hour. It was then diluted with 10 ml of dimethylformamide and 0.24 ml (1.57 mmol) of 1,6-dibromohexane was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes and then heated at 45 ° C for 16 hours. After cooling, it was poured into 125 ml of dilute aqueous ammonium chloride solution and extracted three times with 40 ml of ethyl acetate each time. The combined organic extracts were washed with water, dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a 1: 1 mixture of dichloromethane and hexane (isomer mixture) and ending with a 3: 1 mixture of the two solvents. This gave 137 mg (22%) of 3,4- [N, N'-1,1 '- (hexane) -bis (3,3'-indolyl)] - 1-methyl as a purple solid. pyrroline-2,5-dione, m.p.> 320 ° C.

137 mg (0.322 mmol) of 3,4- [N, N'-1,1 '- (hexane) bis (3,3'-indolyl)] - 1-methylpyrroline-2,5-dione in 15 ml of ethanol A mixture of 5 ml of 5 N potassium hydroxide solution and 2 ml of tetrahydrofuran was stirred for 4 hours at room temperature. Subsequent thin layer chromatography indicated that the starting material was consumed. The mixture was diluted with water (15 mL) and the solvent was spun

EN 223 807 Β1 distillate. The aqueous residue was cooled, acidified to pH 1 with 3N hydrochloric acid and extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed well with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The purple-red solid (116 mg) was a 1: 1 mixture of the desired anhydride and starting material according to ¹ H NMR. This material was used directly in the next step without further purification.

In the same manner as in Example 27, 108 mg (0.263 mmol) of 3,4- [N, N'-1,1 '- (hexane) -bis (3,3'-indolyl)] - 2,5-dihydrofuran-2 Of 5-dione in 1.5 ml of dimethylformamide overnight under a nitrogen atmosphere with a mixture of 0.59 ml (2.62 mmol) of 1,1,1,3,3,3,3hexamethyldisilazane and 0.05 ml (1.31 mmol) of methanol treated. After working up with ethyl acetate, the crude product was purified by flash chromatography on silica gel eluting with a 10: 1 mixture of dichloromethane and ethyl acetate and ending with a 5: 1 mixture of the two solvents. Two color fractions were obtained. The first eluted colored fraction was the impurity from the previous reactions, 3,4- [N, N'-1,1 '- (hexane) -bis (3,3'-indolyl)] - 1-methylpyrroline-2,5- contains dion. The second eluted colored fraction gave 56 mg of the desired product, m.p.

3.4- [N, N'-1,1 '- (hexane) -bis (3,3'-indolyl)] - 1H-pyrroline-2,5-dione, m.p.> 320 ° C. The mass spectrum of the product is consistent with the expected chemical structure.

Calcd for C ₂₆ H23N3O2.0,3H ₂ O Calcd: C: 76.26, H: 5.66, N: 10.26;

Found: C, 75.21; H, 5.65; N, 10.05.

Example 31 (+) - 3,4 - [(N, N'-1,1 '- [3' - (Benzyloxymethyl) hexane] bis (3,3'-indolyl)] - 1H- Pyrroline-2,5-dione [Compound (Is)]

In the same manner as in the previous examples, 117 mg (2.93 mmol) of a mixture of 400 mg (1.17 mmol) of 3,4-bis (indolyl) -1-methylpyrroline-2,5-dione in 8 mL of dimethylformamide was obtained. ), treated with sodium hydride (60% oily) and (±) -3-benzyloxymethylene-1,6-dibromohexane dissolved in 7 ml of dimethylformamide. The mixture was heated at 50 ° C overnight, and the crude product obtained after work-up of the reaction mixture was purified by silica gel flash chromatography, gradient elution, starting with a 1: 1 mixture of dichloromethane and hexane (isomer mixture). 1 mixture. 149 mg (23%) of (±) -3,4 - [(N, N'-1,1 '- [3' - (benzyloxymethylene) hexane)] as a purple solid are thus obtained. bis (3,3'-indolyl)] - 1-methylpyrroline-2,5-dione is obtained.

141 mg (0.359 mmol) of (+) - 3,4 - [(N, N'-1,1 '- [3' - (benzyloxymethyl) hexane] bis (3,3'-indolyl)) A mixture of -1-methylpyrroline-2,5-dione, 15 ml of ethanol and 5 ml of 5 N potassium hydroxide solution was stirred at room temperature for 3 hours. The TLC then showed that the starting material was consumed. Thin layer chromatography (eluent: dichloromethane) of the crude product (101 mg) indicated two spots, namely the starting compound, and the desired anhydride, i.e. (+) - 3,4 - [(N, N). '-1, Γ [3 "- (benzyloxy methylene) hexane] bis (3,3'-indolyl)] -. furan-2,5-dione The patch of ^1H-NMR analysis indicates that the product is a mixture of anhydride and starting material in a ratio of about 4: 1. This product is used directly in the next step without further purification.

mg (0.180 mmol) of (±) -3,4 - [(N, N'-1,1 '- [3' (benzyloxymethyl) hexane] bis (3,3'-indolyl)] - A mixture of 2,5-dihydrofuran-2,5-dione in 1 ml of dimethylformamide was treated with 0.41 ml (1.80 mmol) of 1,1,1,3,3,3-hexamethyldisilazane and 0.036 ml at 25 ° C overnight. After treatment of the reaction mixture with ethyl acetate, the crude product is purified by flash chromatography on silica gel, starting with pure dichloromethane and eluting with 10: 1 dichloromethane: ethyl acetate. 30 mg of purified (±) -3,4 - [(N, N'-1,1 '- [3' - (benzyloxymethyl) hexane] bis (3,3'-indolyl) are thus obtained. 1 H-pyrroline-2,5-dione, m.p. 171-173 DEG C. The product has a mass spectrum consistent with the expected chemical structure.

Example 32

3,4 - [(N, N'-1,1 '- [3- (Hydroxymethylene) hexane] bis (3,3'-indolyl)] -1H-pyrroline-2,5-dione [( lt)

To a solution of cesium carbonate (11.2 g, 34.3 mmol) in dimethylformamide (350 mL) was added 3.41 g (10.0 mmol) of bis (30 mL) over 30 hours at 55 ° C under nitrogen with vigorous stirring using a batch pump. 3,3'-indolyl) -1-methylpyrrole-2,5-dione and 5.64 g (11.0 mmol) of 3- (tert-butyldiphenylsilyloxymethyl) -1,6-dibromohexane. ml of dimethylformamide. After the addition was complete, the mixture was heated at the same temperature for an additional 16 hours. After cooling, it was poured into a mixture of 1.2 liters of water and 20 ml of 3N hydrochloric acid and extracted three times with 300 ml of dichloromethane each time. The combined organic extracts were washed with water followed by brine, dried over magnesium sulfate and the solvent was distilled off. The residue was passed through a 7.62 cm by 7.62 cm silica gel column, eluting with chloroform. The crude product thus obtained is purified by flash chromatography on silica gel using chloroform as eluent. In this way, 2.87 g (41% yield) of 3,4 - [(N, N'-1,1 '- [3' - (tert-butyldiphenylsilyloxymethylene)) as a purple solid are obtained. hexane] bis (3,3'-indolyl)] -1-methylpyrroline-2,5-dione, m.p. 220-224 ° C.

High Resolution Mass Spectrum: (M + 1) calculated for C ^ HH ^^O SiSiO: 692.3307, found: 692.3299.

HU 223 807 Β1

1.55 g (2.22 mmol) of 3,4 - [(N, N'-1,1 '- [3' - (tert-butyldiphenylsilyloxymethyl) hexane] bis (3.3) (indolyl)] - 1-methylpyrroline-2,5-dione, 100 ml of 4 N potassium hydroxide solution, 10 ml of tetrahydrofuran and 200 ml of 95% ethanol are heated at 90 ° C for 16 hours. The reaction mixture was concentrated in a rotary evaporator, acidified to pH = 1 with 6N hydrochloric acid, and extracted with dichloromethane (3 x 75 mL). The combined organic extracts were washed with water, brine, dried over anhydrous sodium sulfate, The solvent was evaporated under reduced pressure, and the residue was dissolved in a minimum of 5:95 methanol: chloroform and applied to a 7.62 cm by 7.62 cm silica gel column. eluted with a mixture of methanol and chloroform (10:90) The two fractions were evaporated to give the second fraction as a purple solid, anhydride alcohol (676 mg, 69% yield) which was uniform (TLC: methanol / hexane). chloroform (10:90)). This material was used directly in the next step without further purification.

To a solution of anhydride (510 mg, 1.15 mmol) in the same manner as in the preceding paragraph, add 5.14 mL (23 mmol) of dimethylformamide.

Premixed mixture of 1,1,1,3,3,3-hexamethyldisilazane and 0.45 mL (11.5 mmol) of methanol. The resulting reaction mixture was heated at 50 ° C for 24 hours under nitrogen. The reaction mixture was cooled and poured into 100 ml of water. The precipitated product is filtered off, washed with water and dried overnight. In this way, 409 mg of 3,4 - [(N, N'-1, T [3 '- (hydroxymethylene) hexane] bis (3,3'-indolyl)) as a reddish-purple solid was obtained. 1H-pyrrole-2.5-dione This product was found to be 93% pure and was contaminated with an unidentified compound with similar retention time on high performance liquid chromatography on reverse phase silica gel High resolution mass spectra: Calculated for C27H25N3O3: 43 , 1896, found: 439.1911.

Example 33 (R) -3,4 - [(N, N'-1,1 '- [3- (Hydroxymethyl) hexane] bis (3,3'-indolyl)] - 1H-pyrroline-2 , 5-dione

In the same manner as in Example 62 above, starting from dibromide, i.e., (R) -3-tert-butyldimethylsilyloxymethyl) -1,6-dibromohexane, the bis (3,3 '), indolyl) -1-methylpyrrole-2,5-dione is dialkylated, the resulting intermediate is hydrolyzed, and the 1H-pyrrole-2,5-dione structure is formed to give (R) -3,4- [ (N, N'-1,1 '- [3' - (hydroxymethylene) hexane] bis (3,3'-indolyl) -1H-pyrroline-2,5-dione, m.p.> 300 ° C.

¹ H NMR (300 MHz, DMSO-d ₆ , δ): 1.05-2.25 (m, 7H), 4.04-4.45 (m, 6H) (m, 8H), δ , 08-7.88 (m,

10H).

Example 34 (S) -3,4 - [(N, N'-1,1 '- [3- (Hydroxymethyl) hexane] bis (3,3'-indolyl)] -1H-pyrroline 2,5-Dione In the same manner as in Example 62 above, starting from dibromide, i.e. (S) -3-tert-butyldimethylsilyloxymethyl) 1,6-dibromohexane, the bis (3,3 ', Indolyl) 1-methylpyrrole-2,5-dione is dialkylated, the resulting intermediate is hydrolyzed and the 1H-pyrrole-2,5-dione is obtained in a yield of 39%. ) -3,4 [(N, N'-1,1 '- [3' - (hydroxymethylene) hexane] bis (3,3'-indolyl)] -1H-pyrroline-2,5-dione The mass spectrum of the product is consistent with the expected chemical structure.

¹ H NMR (DMSO-d ₆ , δ): 1.05-1.15 (2H),

1.23-1.24 (1H), 1.50-1.52 (1H), 1.71 (1H), 1.94 (1H), 2.07-2.12 (1H), 4.05 -4.4 (m, 6H), 7.09-7.21 (m, 4H), 7.35 (d, J = 15 Hz, 2H), 7.49 (d, J = 9 Hz,

2H), 7.8 (d, J = 9Hz, 2H), 10.93 (s, 1H).

Example 35

3.4 - [(N, N'-1,1 '- [3' - (aminomethyl) hexane] bis (3,3'-indolyl)] -1H-pyrroline-2,5-dione (lu) trifluoroacetic acid salt and

Example 36

3.4 - [(N, N'-1,1 '- [3' - (aminomethyl) hexane] bis (3,3'-indolyl)] -1H-pyrroline-2,5-dione hydrochloride

0.18 g (0.41 mmol) of anhydride alcohol, i.e. 2,3 [(N, N'-1,1 '- [3' - (hydroxymethyl) hexane] bis (3,3'-indolyl) )] - To a solution of 2,5-dihydrofuran-2,5-dione in 10 ml of anhydrous dichloromethane is added 0.10 g (1.06 mmol) of triethylamine and 0.11 g (0.98 mmol) of nitrogen under stirring. After stirring for 30 minutes at room temperature, the solvent was distilled off under reduced pressure, the residue was dissolved in 10 ml of anhydrous dimethylformamide, and 0.26 g (4.1 mmol) of sodium azide were added and the reaction mixture was stirred for 1.5 hours. After heating under nitrogen atmosphere at 50 DEG C., the reaction mixture was cooled and partitioned between 0.2N hydrochloric acid and ethyl acetate, the combined organic extracts were dried over magnesium sulfate, filtered and the solvent was evaporated to give 185 mg of azide. used directly in the next reaction step n) The crude azide was dissolved in 3 ml of dimethylformamide under nitrogen and 1.25 g (7.75 mmol) was added to the solution.

1,1,1,3,3,3-hexamethyldisilazane and 0.12 g (3.87 mmol) of methanol. The mixture was heated at 50 ° C, then cooled after 12 hours and diluted with ethyl acetate. The solution was washed with water and 2N hydrochloric acid. The aqueous washings were shaken with ethyl acetate (3 x 50 mL). The combined organic extracts are dried over magnesium sulfate, the desiccant is filtered off and the solvent is distilled off. Thus, 175 mg of azidoimide, i.e. 3,4 - [(N, N'-1,1 '- [3' - (azidomethyl) hexane] bis (3,3'-indolyl)) as a purple solid, is obtained. -1H-pyrroline-2,5-dione This product was obtained by high performance liquid chromatography on a Rainin Dynamex®-60 C18 column (size 21.4 mm * 250 mm) for 60 minutes per minute.

HU 223,807 Β1 ml of eluate was purified by linear gradient elution. Elution was begun with a mixture of acetonitrile, water and trifluoroacetic acid 5: 94.9: 0.1 (solvent A) and pure acetonitrile (solvent B) 80:20, and completed with pure acetonitrile (solvent B). . Thus purified in a 57% yield is 3,4 - [(N, N'-1,1 '- [3' (azidomethyl) hexane] bis (3,3'-indolyl)] - 1H - The pyrroline-2,5-dione is obtained, and its mass spectrum and ¹ H-NMR are consistent with the expected chemical structure.

0.1 g (0.21 mmol) of azide, i.e. 3,4 - [(N, N'-1,1 '- [3' - (azidomethyl) hexane] bis (3,3 ', indolyl)) To a solution of 1 H -pyrroline-2,5-dione in 15 ml of ethyl acetate and 5 ml of ethanol is added 0.1 g of Lindlar catalyst and the mixture is stirred at room temperature under normal pressure of hydrogen for 12 hours. The solvent was evaporated under reduced pressure and the resulting material was purified by preparative reverse phase HPLC using a Rainin Dynamax®-60 C18 column (size 21.4 mm * 250 mm), collecting 15 ml of eluent per minute for 60 minutes and linear gradient elution. Elution was begun with a mixture of acetonitrile, water and trifluoroacetic acid 5: 94.9: 0.1 (solvent A) and pure acetonitrile (solvent B) 80:20, and completed with pure acetonitrile (solvent B). In this way, the trifluoroacetic acid salt of the primary amine (80 mg, yield 63%) was obtained as a solid, or s

3,4 - [(N, N'-1,1 '- [3' - (aminomethyl) hexane] bis (3,3'-indolyl)) - 1H-pyrroline-2,5-dione trifluoro- The product has a mass spectrum consistent with the expected chemical structure.

¹ H-Nuclear magnetic resonance spectrum (acetone-d ₆ , δ): 0.77-0.78 (m, 1H),

1.0-1.1 (m, 1H), 1.27-1.34 (m, 1H), 1.43 (m, 1H),

1.52-1.56 (m, 4H), 1.60-1.68 (m, 1H), 1.90-1.94 (m, 1H), 3.17-3.21 (m, 1H) ), 3.35-3.38 (m, 1H),

3.64-3.67 (m, 1H), 3.75-3.82 (m, 2H), 6.61-6.72 (m, 4H), 6.824 (d, J = 16 Hz, 2H). , 6.936 (t,

J = 8.31 Hz, 2H), 7.397 (t, J = 7.83 Hz, 2H), 9.3 (s,

1H).

¹³ C NMR (acetone-d ₆ , δ): 26.0, 28.0,

32.1,35.4, 40.8, 41.0, 41.1, 45.1, 45.8, 50.9, 105.1,

105.2, 110.8, 111.0, 121.24, 121.29, 122.7, 122.9,

123.0, 128.4, 128.6, 131.5, 132.0, 134.0, 134.1,

136.8, 137.1, 172.6, 172.7, 192.5.

Example 37

3,4 - [(N, N'-1,1 '- [3- (N-Benzylaminomethyl) hexane] bis (3,3'-indolyl)) - 1H-pyrroline-2,5- dione trifluoroacetic acid salt (compound of formula (IV)) mg (0.05 mmol) of primary amine, i.e. 3,4 [(N, N'-1,1 '- [3' - (aminomethyl) hexane] bis) (3,3'-indolyl)] - 1H-pyrroline-2,5-dione in 2 ml of anhydrous tetrahydrofuran was added with stirring under nitrogen, 9.39 mg (0.08 mmol) of benzaldehyde, and after half an hour 18.75 g of Sodium triacetoxyborohydride (0.08 mmol) was added and the reaction mixture was stirred for 1 hour, diluted with water and extracted with ethyl acetate (3 x 25 mL), dried over magnesium sulfate, filtered, and the solvent was evaporated. The residue was subjected to reversed-phase high performance liquid chromatography on a Rainin Dynamax®-60 C18 column (size:

21.4 mm x 250 mm), purified by linear gradient elution, collecting 15 ml of eluant every 60 minutes. Elution was begun with a mixture of acetonitrile, water and trifluoroacetic acid 5: 94.9: 0.1 (solvent A) and pure acetonitrile (solvent B) 80:20, and completed with pure acetonitrile (solvent B). . In this way, two different fractions are obtained, one of which is the monobenzyl compound, i.e. 3,4 - [(N, N'-1,1 '- [3' - (N-benzylaminomethyl) hexane] bis) , 3'-indolyl)] - 1 H -pyrroline-2,5-dione (yield: 16 mg, 66%) and the other is the dibenzylamino compound, i.e. 3,4 - [(N, N'-1, 1 '[3' - (N, N'-dibenzylaminomethyl) hexane] bis (3,3'-indolyl)] - 1H-pyrrole-2,5-dione (7 mg, 20%) The mass spectrum of the monobenzyl compound is consistent with the expected chemical structure.

¹ H-Nuclear magnetic resonance spectrum (acetone-d ₆ , δ): 1.1-1.3 (m, 1H),

1.5-1.6 (m, 1H), 1.71-1.77 (m, 1H), 1.93-2.10 (m,

3H), 2.5 (m, 1H), 3.1-3.2 (m, 1H), 3.37-3.41 (m,

1 H), 4.13 (t, J = 5.1 Hz, 2H), 4.28 (t, J = 5.1 Hz, 2H),

4.36 (d, J = 3.6 Hz, 2H), 7.13-7.24 (m, 4H), 7.33 (d,

J = 25 Hz, 2H), 7.39-7.51 (m, 7H), 7.89-7.96 (m,

2H), 9.76 (s, 1H).

¹³ C NMR (acetone-d ₆ , δ): 25.6, 27.3, 32.1,

32.9, 44.7, 45.4, 50.1, 52.2, 105.0, 105.2, 110.8,

111.1, 121.2, 121.3, 122.8 122.9, 123.1, 128.5,

129.8, 130.3, 131.2, 131.3, 132.0, 132.4, 133.7,

134.0, 136.8, 137.0, 172.5, 172.6.

Example 38

3,4 - [(N, N'-1, T- [3- (N, N-dibenzylamino-methyl) hexane] bis (3,3 'indolyl)] - 1H-2-pyrroline, 5-Dione trifluoroacetic acid salt (Compound 1x)

3,4 - [(N, N'1,1 '[3' - (N, N'-dibenzylaminomethyl) hexane] bis (3,3'-indolyl)] -1H-pyrroline-2 5-Dione was prepared as described in Example 67. The mass spectrum of the product was consistent with the expected chemical structure.

¹ H-Nuclear magnetic resonance spectrum (acetone-d ₆ , δ): 0.2-0.3 (m, 1H),

0.6-0.9 (m, 4H), 1.2-1.3 (m, 1H), 1.50 (d, J = 5.4 Hz,

2H), 2.27 (m, 1H), 3.3-3.8 (m, 8H), 6.6-6.9 (m,

18H), 7.35 (dd, J = 7.5 Hz, J = 24.9 Hz, 2H), 9.1 (s,

1H).

Example 39 (R) -3,4 - [(N, N'-1, T- [3 '' - (N-Pyrrolidinomethyl) hexane] bis (3,3'-indolyl)) - 1 H-pyrroline-2,5-dione hydrochloride (compound of formula (ly))

202 mg of mesylate, namely (R) -3,4 - [(N, N'-1,1 '- [3' (methanesulfonyloxymethyl) hexane] bis (3,3'-indolyl)] - A solution of 1 H -pyrroline-2,5-dione and 1.5 ml of pyrrolidine in 15 ml of tetrahydrofuran was heated at 50 ° C with stirring until TLC showed the starting material to disappear, after which 16 ml of ethyl acetate was added. the organic solution was added with 10-10 ml of 5% sodium bicarbonate solution, water and

After washing with sodium chloride solution, the solvent was distilled off. The dark red residue was purified by preparative high performance liquid chromatography (Waters reverse phase column gradient elution with acetonitrile: water: trifluoroacetic acid (5: 94.9: 0.1) to pure acetonitrile). Thus, in the form of its trifluoroacetic acid salt, pure (R) -3,4 - [(N, N'-1,1 '- [3' - (N-pyrrolidinomethylene) hexane] bis (3,3'-) indolyl)] 1H-pyrrole-2,5-dione This was converted in the same manner to the hydrochloride salt as a light red solid (42) (R) -3,4 - [(N, N'-1,1 '- [3 '' - (N-pyrrolidinomethyl) hexane] bis (3,3'-indolyl) -1H-pyrroline-2,5-dione hydrochloride, m.p. 220 ° C (dec.).

High resolution mass spectrum: (M + 1) calculated for C ₃₁ H ₃₃ N ₄ O ₂ : 493.2604, found: 493.2605.

Example 40

3,4 - [(N, N'-1,1 '- [3' - (Methoxymethyl) hexane] bis (3,3'-indolyl)] -1H-pyrroline-2,5-dione [( flavor compound)

1.25 g (1.81 mmol) of 3,4 - [(N, N'-1,1 '- [3- (tert-butyldiphenylsilyloxymethyl) hexane] bis (3,3') (indolyl)] - A solution of 1-methylpyrroline-2,5-dione in 20 ml of tetrahydrofuran is added 2.0 ml (2.0 mmol) of a 1 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran and the mixture is stirred for 1 hour After stirring at 25 DEG C., the reaction was quenched by the addition of 5 ml of 1N hydrochloric acid and 75 ml of ethyl acetate were added, the organic solution was washed with water and brine, dried over magnesium sulfate and the solvent was distilled off. The residue was subjected to flash chromatography on silica gel eluting with a 1: 1 mixture of tetrahydrofuran and hexane (isomer mixture) containing increasing amounts of methanol (3% to 5%) to give purple-red solid (509 mg). (yield: 62%) alcohol, i.e. 3,4 - [(N, N'-1,1 '- [3'] - (hydroxymethyl) hex) bis (3,3'-indolyl)] - 1-methylpyrroline-2,5-dione, which was used directly in the next step. To a solution of 285 mg (0.63 mmol) of the above alcohol and 170 mg (0.95 mmol) of 47% aqueous tetrafluoroboric acid in 6 mL of dichloromethane are added dropwise 0.47 mL (0, Trimethylsilyldiazomethane (Aldrich, 2.0 M, 2.0 mmol) in hexane and the resulting mixture was stirred for 2 hours at 0 ° C and then for 4 hours at 25 ° C. TLC analysis of the reaction mixture indicated the presence of large amounts of unchanged starting material. At this time, the mixture was cooled and an additional 1 equivalent of tetrafluoroboric acid and trimethylsilyldiazomethane was added. The reaction mixture was stirred for 2 hours at 0 ° C and then for 6 hours at 25 ° C. The reaction mixture was diluted with dichloromethane (20 ml), washed with 2N hydrochloric acid (10 ml), water (10 ml), dried over magnesium sulfate and the solvent was distilled off. The residue is applied to one

7.62 cm * 7.62 cm column filled with silica gel and eluted with dichloromethane. This gave 114 mg (39%) of methyl ether as a reddish-purple solid, m.p. 3,4 - [(N, N'-1,1 '- [3' - (methoxymethyl) hexane)]. bis (3,3'-indolyl)] - 1-methylpyrroline-2,5-dione, m.p. 234-236 DEG C. The ¹ H-NMR spectrum of the product is consistent with the expected chemical structure.

High Resolution Mass Spectrum: Calcd for C ₂₉ H ₂ gN ₃ O ₃ : 467.2208, found: 467.2210.

110 mg (0.243 mmol) of 3,4 - [(N, N'-1, T- [3 '- (methoxymethyl) hexane] bis (3,3'-indolyl)] - 1-methylpyrroline-2 A mixture of 5-dione and 8 ml of 5 N potassium hydroxide solution in 15 ml of ethanol and 1 ml of tetrahydrofuran was heated at 90 DEG C. for 24 hours, then most of the ethanol was distilled off under reduced pressure, with 6N hydrochloric acid. acidified and extracted three times with 15 ml of dichloromethane, the combined organic phases are washed with dilute aqueous sodium bicarbonate solution and then with water, dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure to give a crude product. A 5.08 cm silica gel column was eluted with dichloromethane to give the anhydride, which was used directly in the next step.

To a solution of the above anhydride (1.5 mg, 0.17 mmol) in dimethylformamide (1.5 mL) was added 0.75 mL (3.34 mmol) of 1,1,1,3,3,3-hexamethyldisilazane and 0.07 mL (1, 67 mmol) of methanol mixed 5 minutes earlier. The reaction mixture was stirred for 1 hour at 25 ° C and then heated at 50 ° C for 20 hours. Subsequent thin layer chromatography indicated that the reaction was complete. At this time, the mixture was cooled and worked up using ethyl acetate as described above. The crude product was purified by flash chromatography on silica gel eluting with a gradient of pure dichloromethane and finishing with ethyl acetate / dichloromethane (4:96). Thus, 42 mg (yield 55%) of 3,4 - [(N, N'-1,1 '- [3' (methoxymethyl) hexane] bis (3,3 ') as a dark red solid was obtained. (indolyl)] - 1H-pyrrole-2,5-dione This material was recrystallized from acetone / water to give 28 mg of an analytically pure 3,4 - [(N, N'-1,1 ') as a reddish-purple solid. [3 '(methoxymethyl) hexane] bis (3,3'-indolyl)] - 1H-pyrroline-2,5-dione, m.p. 272-274 ° C.

Analysis calculated for C 8 H ₂₇ N ₂ O _{3 3} .0,1H ₂ O: Calc'd: C, 73.86; H, 6.02; N, 9.23;

Found: C, 73.51; H, 5.92; N, 8.99.

Example 41

3,4 - [(N, N'-1,1 '- [3' - (1-imidazolylmethyl) hexane] bis (3,3'-indolyl)] -1H-pyrroline-2,5- dion [Compound (Idd)]

100 mg (0.23 mmol) of 3,4 - [(N, N'-1,1 '- [3' - (hydroxymethyl) hexane] bis (3,3'-indolyl)] - 1H-pyrrole -2.5-dione and

HU 223 807 Β1

Methanesulfonyl chloride (0.025 mL, 0.32 mmol) was added dropwise to a solution of triethylamine (0.05 mL, 0.36 mmol) in anhydrous chloroform at 25 ° C under nitrogen. After stirring for 20 minutes, the mixture was diluted with chloroform (15 ml), washed with water and brine, dried, filtered and the solvent was distilled off. The red residue was purified by chromatography on a short column of silica gel eluting with chloroform followed by ethyl acetate / chloroform (10:90). There was thus obtained 53 mg of 3,4 [(N, N'-1,1 '- [3' - (methanesulfonyloxymethyl) hexane] bis (3,3'-indolyl)] as a red solid. 1H-pyrroline-2,5-dione is obtained which is uniform by TLC (ethyl acetate / dichloromethane 5:95).

mg (0.095 mmol) of 3,4 - [(N, N'-1,1 '- [3' (methanesulfonyloxymethyl) hexane] bis (3,3'-indolyl)] -1H-pyrroline-2, To a solution of 5-dione in 0.75 mL of dimethylformamide was added dropwise a solution of imidazole sodium salt in dimethylformamide under nitrogen atmosphere (prepared by adding 16 mg (0.24 mmol) of imidazole in 0.5 mL of dimethylformamide). 7 mg (0.22 mmol) of 60% sodium hydride). The reaction mixture was stirred at 25 ° C for a quarter hour and then heated at 50 ° C for half an hour. It is then diluted with 25 ml of 3% methanol in dichloromethane. The mixture was washed several times with water (10 ml) and then with saturated sodium chloride solution (10 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The crude product obtained is applied to a 7.62 cm x 7.62 cm silica gel column and eluted with dichloromethane and then 5:95 methanol / dichloromethane containing 1% triethylamine. There was thus obtained 21.5 mg (46% yield) of 3,4 - [(N, N'-1,1 '- [3' - (1-imidazolylmethyl) hexane] bis (3.3) as a red solid). 1-indolyl)] - 1H-pyrroline-2,5-dione This material was purified by reverse phase silica gel high performance liquid chromatography (gradient elution with acetonitrile: water: trifluoroacetic acid = 5: 94.9: 0.1). (12.4 mg of analytically pure 3,4 - [(N, N'-1,1 '[3' - (1-imidazolylmethyl)) as a red solid). -hexane] -bis- (3,3'-indolyl)] - 1Hpirrolin-2,5-dione, mp 261-166 ° C. the ¹ H NMR spectrum was consistent with the expected structure..

High resolution mass spectrum: (M + 1) calculated for C30H27N5O2: 490.2244, found: 490.2242.

The following compounds of formula (lee), wherein η, η _υ Q and R are prepared by methods analogous to those described in the Examples above, are provided by way of further examples of the present invention. The structure of the compounds shown in the table below is confirmed by their ¹ H-NMR spectrum, mass spectrum and / or elemental analysis.

Example number n Q R 42nd 3 3 CH H 43rd 2 2 CH H 44th 3 4 CH H 45th 3 3 CH nh ₂ 46th 3 3 CH NHCOCH 3 47th 3 3 CH NHCH ₂ C ₆ H ₅ 48th 3 3 C (-OCH ₂ CH ₂ O-) 49th 3 3 C = 0

Example 50

3,4 - [(N, N'-1,1 '- (Propylthiopropyl) bis (3,3'indolyl)) -1H-pyrrole-2,5-dione [Compound (Iff) ]

To a solution of 102 g (0.47 mole) of N- (3-acetoxypropyl) indole in 1.0 liter of anhydrous dichloromethane was added dropwise with stirring at 0 ° C 43.04 ml (0.494 mole, 1.05 equivalents). oxalyl chloride. After a quarter, the cooling bath was removed, allowed to warm to room temperature, and stirred for 3 hours. The volatiles were distilled off under reduced pressure and the resulting purple solid was redissolved in 1.0 L dichloromethane under nitrogen. 129.25 g (0.47 mol) of N-tert-butoxycarbonylindole-3-acetic acid are added to the solution with vigorous stirring followed by rapid addition of 130.6 ml (0.94 mol, 2 equivalents) of triethylamine. After 16 hours, the solvent was distilled off and the residue was purified by flash silica gel column chromatography (hexane: ethyl acetate = 3: 1). From the fractions containing the colored main product, the solvent was distilled off. This gave 101 g (40%) of the anhydride as a red solid, i.e. 2- [1- (3-acetoxypropyl) -3-indolyl] -3- [1-tert-butoxycarbonyl-3-indolyl]. ] -furan. The mass spectrum of the product is consistent with the expected chemical structure.

Tefluoroacetic acid (27 mL, 350 mmol) containing ethanethiol (1 mL, 14 mmol) was added with stirring to 7.4 g (14 mmol) of anhydride protected with tert-butoxycarbonyl. After 1 hour, the reaction mixture was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate, filtered, and the filtrate was evaporated. The crude anhydride is obtained in the form of a red semi-solid. The residue is applied to a thin bed of silica gel and the bed is eluted with hexane followed by dichloromethane. The colored material is washed with ethyl acetate and the resulting 5.7 g (95% yield) of the purified free anhydride, i.e. 4- [1- (3-acetoxypropyl) -3-indolyl] -3- 3-Indolyl) -2,5-dihydrofuran-2,5-dione is obtained, and the mass spectrum of the product is consistent with the expected chemical structure.

HU 223 807 Β1

To a solution of 3.0 g (7 mmol) of free anhydride in 125 ml of anhydrous dimethylformamide was added 420 mg (10.5 mmol) of sodium hydride (60% mineral oil) with stirring at room temperature, causing the mixture to stir. its bright orange color changes to purple immediately. After half an hour, 3 equivalents of 3-bromopropyl acetate were added rapidly. The reaction mixture was then heated to 75 ° C where the orange color gradually returned. After 6 hours, dimethylformamide was distilled off under reduced pressure. The residue was applied to a flash silica gel column eluted with hexane: ethyl acetate (3: 2). The fractions containing the red main product were combined and the solvent was distilled off. Thus, 1.32 g (36%) of an alkylated anhydride, i.e. 3,4-bis [1- (3- (3-acetoxypropyl) -3-indolyl) -2,5-dihydrofuran, as a red solid The mass spectrum of the product is consistent with the expected chemical structure.

1.32 g (2.52 mmol) of 3,4-bis [1- (3- (3-acetoxypropyl) -3-indolyl-2,5-dihydrofuran-2,5-dione) are suspended in 125 ml of anhydrous ethanol with stirring, 125 ml of 5N potassium hydroxide solution are added and the mixture is stirred for 16 hours, then concentrated to a volume of 126 ml and acidified slowly with 5N hydrochloric acid until a red solid precipitates. dried in a pressure oven at 60 ° C to give 1.1 g (99%) of the alcoholic anhydride as a red powder.

1.1 g (2.47 mmol) of alcoholic anhydride are dissolved in 30 ml of anhydrous dimethylformamide under stirring under nitrogen. A premix solution of 5.22 mL (24.7 mmol, 10 equivalents) of 1,1,1,3,3,3-hexamethyldisilazane and 0.50 mL (12.4 mmol, 5 equivalents) of methanol is added and the whole was stirred for 16 hours at room temperature. The dimethylformamide is then distilled off under reduced pressure, 100 ml of acetone and excess (about 500 mg) of cesium fluoride are added and the mixture is stirred for 4 hours. The solvent was distilled off and the residue was partitioned between ethyl acetate and water. The organic layer was washed five times with 1N hydrochloric acid and twice with saturated sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. In this way, 1.0 g (91%) of bisindolyl maleimide, i.e. 3,4-bis [1- (3-hydroxypropyl) -3-indolyl] -1H-pyrroline-2,5 as a red powder are obtained. we get a dion. The total yield of the two steps is more than 90%. The mass spectrum of the product is consistent with the expected chemical structure.

Dissolve 1.0 g (2.25 mmol) of 3,4-bis [1- (3-hydroxypropyl) 3-indolyl] -1H-pyrroline-2,5-dione in 250 ml of anhydrous dichloromethane at room temperature. . 2.09 g (6.3 mmol, 2.8 eq) of carbon tetrabromide and 2.83 g (10.8 mmol, 4.8 eq) of triphenylphosphine are added to the solution and the mixture is stirred for 16 hours. The solvent was evaporated and the residue was purified by flash silica gel column chromatography (hexane: ethyl acetate = 7: 3). The desired product is eluted as the main red band. From this fraction, 876 mg (68%) of the dibromo compound, 3,4-bis [1- (3-bromopropyl) 3-indolyl] -1H-pyrroline, were redistilled to remove the solvents. 2,5-dione is obtained.

47.8 mg (0.084 mmol) of dibromo compound are dissolved in acetone at room temperature with stirring. An excess of sodium sulfide nonahydrate (229 mg, 0.95 mmol, 11.3 eq) was added and the heterogeneous mixture was stirred overnight. The next day, acetone was distilled off under reduced pressure and the residue was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was distilled off. This gave 35.5 mg (94%) of the title compound as a red-orange solid.

The mass spectrum of the product is consistent with the expected chemical structure.

Example 51

3,4 - [(N, N'-1,1 '- [3''- (hydroxymethylene) pentan-1'', 5-yl] bis (3,3'-indolyl)] - 1H- pyrroline-2,5-dione (compound of formula Igg)

To a suspension of 16.06 g (49.3 mmol) of cesium carbonate in 1 liter of anhydrous dimethylformamide was added 7.3 g (12 mmol) of 1.5 diiodide in a nitrogen pump under nitrogen with vigorous stirring over 48 hours. -3-tert-butyldiphenylsilyloxymethylpentane and 4.21 g (12 mmol) of bis (3,3'-indolyl) -1H-pyrroline-2,5-dione in 35 ml of anhydrous dimethylformamide. After a further 2 hours, the solvent was distilled off under reduced pressure and the residue was dissolved in dichloromethane. The solution was washed with 1N hydrochloric acid and brine, dried, and the solvent was distilled off under reduced pressure. The resulting purple oil was filtered through a pad of silica gel eluting with a 4: 1 mixture of hexane (isomer mixture) and ethyl acetate. The eluent was distilled off as a purple solid macrocycle, 4.5 g (55% yield), i.e. 3,4 - [(N, N'-1, r- [3 '- (tert-butyldiphenylsilyloxy)). methyl) pentan-1 ', 5-yl] bis (3,3'-indolyl) -1-methylpyrroline-2,5-dione.

4.2 g (6.2 mmol) of 3,4 - [(N, N'-1,1 '- [3' - (tert-butyldiphenylsilyloxymethyl) pentane-1 ', 5') il] -bis (3,3'-indolyl)] - 1-methylpyrroline-2,5-dione in 300 ml of ethanol was added 300 ml of 5N potassium hydroxide solution and the mixture was refluxed for 48 hours (86 ° C). After stirring, the mixture was cooled to room temperature and the ethanol was distilled off under reduced pressure, the residue was acidified to pH 1 with 5N hydrochloric acid (325 ml) and extracted with ethyl acetate, washed twice with saturated sodium chloride solution and dried. and the solvent was evaporated to give 2.6 g (100%) of the anhydride, m.p.

3,4 - [(N, N'-1,1 '- [3' - (hydroxymethyl) pentan-1 ', 5' -yl] bis (3,3'-indolyl)] - 2.5 -dihydrofuran-2,5-dione is obtained.

HU 223 807 Β1

2.6 g (6.2 mmol) of anhydride, i.e., 3,4 - [(N, N'-1,1 '- [3' - (hydroxymethyl) pentan-1 ", 5" -yl] bis) To a solution of (3,3'-indolyl)] 2,5-dihydrofuran-2,5-dione in 500 ml of anhydrous dimethylformamide was added 1.25 ml (31 mmol) of methanol and 13.1 ml (62 mmol) of 1.1 3,3,3-hexamethyldisilazane and the mixture was heated at 55 ° C for 36 hours, then the solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate and the solution was washed with 1N hydrochloric acid. The combined organic extracts were dried and the solvent was distilled off and the purple residue was applied to a silica gel filter pad which was eluted with 2% to 10% methanol in dichloromethane. fractions containing the solvent were distilled off under reduced pressure to give a purple solid 650 mg (25%) of the title alcohol as a colorless solid, i.e. 3,4] (N, N'-1,1 '- [3' - (hydroxymethyl) pentan-1,5-yl) ] bis (3,3'-indolyl)] - 1H-pyrroline-2,5-dione. The mass spectrum of the product is consistent with the expected chemical structure. ¹ H NMR (DMSO-d ₆ , δ): 0.7 (m, 1H), 1.48 (m, 2H), 1.82 (m, 2H), 3.19 (dd, 2H). , 4.16 (m, 2H),

4.4 (t, 1H), 7.05 (t, 2H), 7.16 (t, 2H), 7.17 (s, 2H),

7.46 (d, 2H), 7.65 (d, 2H), 10.96 (s, 1H).

Example 52

3.4- [N, N'-1,1 '[3- (N, N'-Dimethylaminomethyl) pentan-1,5-yl] bis (3,3'-indolyl)] - 1H-pyrroline -2,5-dione hydrochloride (compound of formula Ijj)

The title compound was prepared as the hydrochloride salt by 110 mg (0.2 mmol) of mesylate, i.e. 3,4 - [(N, N'-1,1 '- [3' - (methanesulfonyloxymethylene)). pentan-1 ”, 5” -yl] -bis (3,3'-indolyl) -1H-pyrroline-2,5-dione and 5 ml of 40% aqueous dimethylamine solution, The resulting material was converted to the hydrochloride to give the title compound (28 mg, 26%), consistent with the expected chemical structure.

¹ H NMR (DMSO-d ₆ , δ): 1.17 (m, 1H),

1.5-1.63 (m, 2H), 1.8-1.95 (m, 2H), 2.73 (m, 2H),

4.18 (m, 4H), 7.12 (t, 2H), 7.15 (s, 2H), 7.23 (t, 2H),

7.56 (d, 2H), 7.75 (d, 2H), 7.8 (br, 3H), 11.01 (s, 1H).

The following compounds are prepared by methods analogous to those described above, and further illustrate the scope of the present invention.

Compounds of formula (Ikk) wherein n, n _t , W and

R has the meaning given in the table below.

Example number n 1 W R 53rd 3 2 SHE = CHCH ₂ NHCH ₂ C ₆ H ₅ 54th 3 2 SHE = chch ₂ nhso ₂ c ₆ h ₅ 55th 3 2 SHE = chch ₂ ch ₂ oh 56th 3 2 SHE = chch ₂ ch ₂ nh ₂ 57th 2 2 SHE = chch ₂ ch ₂ oh 58th 2 2 SHE = chch ₂ ch ₂ nh ₂

Example number n Π1 W R 59th 2 2 OCH₂- CH-CH₂nh₂ 60th 2 2 OCH₂- CH-CH₂NHCH₃ 61st 2 2 OCH₂- CH-CH₂NHCH₂c₆h₅ 62nd 2 2 OCH₂- CH-CH₂NHSO₂c₆h₅ 63rd 2 2 OCH₂- CH-CH₂ch₂oh 64th 2 2 OCH₂- CH-CH₂ch₂nh₂ 65th 2 3 aa

Claims (3)

Compounds of formula (II) wherein V is O or -N (CH ₃ ) W is O or S, -SO-, SO ₂ -, -CO- or (uu), C 2 -C 6 alkylene, -NR ₃ , a or tt, a divalent heterocyclic group of formula (aa), (bb) or (dd), (cc) , a divalent fused bicyclic group of formula (ee) or (ff); X and Y are each independently C 1-4 alkylene; R-ι, independently at each occurrence, is hydrogen, halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, nitro or hydroxy, or -NR4R5; R ₃ is hydrogen or C 1-4 alkyl; obsession R ₆ is hydroxy, -COO- (CH ₂ ) _m -phenyl, C 1-4 alkoxy, (C 1-4 alkoxy) carbonyl, -NR ₄ R g, -NH (CH). ₂ ) _{m is} pyridyl, -NH (CH ₂ ) _m -phenyl, C 1 -C 4 alkylsulfonyl, -NHSO ₂ - (CH ₂ ) _m -phenyl or cyano; R ₄ and R ₅ are independently hydrogen, C 1-4 alkyl, benzyl, or, together with the nitrogen to which they are attached, morpholino, pyrrolidino, imidazolo or 4- (C 1-4 alkyl) piperazino; Z is - (CH ₂ ) _p -, m is 0, 1, 2 or 3 and p is 0, 1 or 2. 2. A process for the preparation of a compound according to claim 1, characterized in that it is 0.001 mol / liter and At a concentration of 1.5 mol / liter of formula Va V, R ₃ and m are as defined in claim 1 for a compound of formula (VII) at a concentration of 0.001 mol / liter to 1.5 mol / liter, wherein L is a leaving group; and W, X and Y are a mixture of the alkylating agent as defined in claim 1 in a polar aprotic solvent at a rate of from 0.1 ml / hr to 2.0 ml / hr with 0.5 equivalents to 10 equivalents of cesium carbonate (Cs _2). CO ₃ ). 3. A process for the preparation of a compound according to claim 1, wherein the compound of formula (IX) is present in a concentration of 0.001 mol / liter to 3 mol / liter, wherein L ₂ is a group independently of the meaning of the other groups, V, W, X, Y, R ₃ and m are a mixture of the compound of claim 1 in a polar aprotic solvent at a rate of between 0.1 ml / hr and 2.0 ml / hr, between 0.5 eq and 10 eq. with cesium carbonate (Cs ₂ CO ₃ ).