HU187360B - Komplex-forming cyclodextrine-crown-ether derivatives and process for producing them - Google Patents

Abstract

SUMMARY OF THE INVENTION The present invention relates to a complexing feature of the process of formula I wherein n = 1-7, m = 0, 1, or 2, p = 0, or 1, q = 0, or 1, t = 0, or 1, r = 1, or 2, A = - CH2 - S - CH2 -, --CH2 - O - CH2 - or --CH2 - CH2 - CH2 - is a derivative of CD = cyclodextrin by removal of a number of OH radicals - for the preparation of cyclodextrin crown ether derivatives by: a) a cyclodextrin amino derivative of the formula (II): 4-20 wt% solution CD "NH-CH2-Am-CH2 · prepared with dipolar aprotic solvents. At a temperature of from about 1 ° C to about 1 to 2 moles of the compound of formula III wherein Y = -H, -halogen, -Nitro, X = -N = C = O, -COC 1 - is reacted with a crown ester derivative, or b) a crown ether amino derivative of formula V prepared with dipolar aprotic solvents for 5-10 sec ly as% solution at 25 to 100 ° C and 0.5 to 1 mole per mole of (IV) - wherein R = methyl, phenyl, tolyl group is reacted with the cyclodextrin derivative, optionally in the presence of an acid binding agent. When a crown ether moiety is attached to a cyclodextrin molecule via a side chain containing amino or carbonyl groups, the giant molecule thus formed can complex the cation of the salt-like organic compounds and the apo-lar group of the anion-like organic anion with it. we can change the pharmacokinetic properties of ionic organic molecules. CD NH-CH2-Ani-CH2-NH2 II NW2-CH2-Arn'CH- (NN ^ V. -1-

Description

The present invention relates to a new numerical formula I wherein n = 1-2, m = 0-2, p = 0-1, q = 0-1, t = 0-1, r = 1,

Process for the preparation of cyclodextrin crown ether derivatives having complexing properties, = -CH ₂ -O-CH ₂ -, a group derived from the removal of n OH radicals from the CD = cyclodextrin molecule. These cyclodextrin crown ether derivatives provide perfect molecular packaging of salt-like molecules, such that they contain a moiety capable of complexing cations and anions at the same time.

Many organic molecules of physiological importance, such as certain pharmacones, have little or no solubility in water, or lack sufficient stability in aqueous solution to exert their effects. By using complexing agents to increase water solubility or stability, it has been found that complexing agents generally form complex bonds with only a portion of the molecules. There has been a need to use complexing agents that are capable of complexing both ions of ionic compounds.

It is known that apolar molecules can be implanted into the cavity formed inside cyclodextrin molecules, forming an inclusion complex. It has now been discovered that by attaching a cation-complexing moiety to a cyclodextrin molecule, the resulting giant molecule can complex both the cation of the salt-like organic compound and the apolar moiety of its organic anion.

Surprisingly, it has now been found that compounds of this kind are obtained by attaching crown ether moieties to a cyclodextrin molecule via a side chain containing amino or carbonyl groups. The crown ether unit is capable of complexing metal ions, particularly alkali metal, alkaline earth metal, and ammonium ions, and the apolar portion of the organic anion may enter the cyclodextrin cavity. Thus, perfect molecular packaging of salt-like organic compounds can also be achieved in aqueous solution. This complexation may advantageously alter the pharmacokinetic properties of salt-like molecules.

The above applies not only to salts but also to organic acids, including amino acids, because the cyclodextrin-attached moiety can form salts with the acids by its basic group, while the organic anion is enclosed in the cavity by cyclodextrin.

Cyclodextrin crown ether derivatives are also capable of resolving racemic mixtures of acids and salts.

Hitherto known substances capable of complexing the cation or only the anion of the salt-like molecules have no or only a few of these properties.

Thus, cyclodextrin crown ether derivatives have increased water solubility relative to cyclodextrins and crown ethers, thus solubilizing the water-insoluble or poorly soluble salts, acids or neutral molecules (e.g. . The stability of the complexes formed is much higher than that of either the crown ether or the cyclodextrin moiety.

According to the present invention, the compounds of formula I are prepared by:

a) N-cyclodextrin of formula (II) - where n = 1-2, m = 0 or 2, A = -CH ₂ -O-CH ₂ -, CD = n of OH = cyclodextrin acylating its amino derivative by removing a radical. The acylating reagent may be a crown isocyanate or a crown acid chloride of the formula (III) wherein r = 1, Y = -H, X = -N = C = O, -COC1. The reaction is carried out in dipolar aprotic solvents, preferably pyridine or dimethylsulfoxide or a 1: 1 mixture of the two in a 4-20% by weight solution of the starting materials at 10-40 ° C for 1-5 hours. After completion of the reaction, the solvent was distilled off in vacuo and the product obtained after digestion with ethanol, filtration and washing,

b) β - a sulfonic acid derivative of the formula (IV) wherein n = 1-2, R = a tolyl group, a group derived by removing n OH radicals from a CD = cyclodextrin and a compound of formula (V) wherein m = 0 or 2, q = Ö or 1, the numerical value is r = 1, A = -CH ₂ -O-CH ₂ - is reacted with a crownether amino derivative also in dipolar-aprotic solvents, preferably dimethylformamide dissolving the starting materials in a 5-10 wt% solution. The reaction temperature is 25-100 ° C, the reaction time is 3-30 hours and the reaction is carried out, if desired, in the presence of an acid acceptor, preferably triethylamine. After evaporation of the excess solvent in vacuo, the product was dissolved in water, the sulfonic acid was removed with an anion exchange resin, the aqueous solution was evaporated to dryness in vacuo, the residue was digested with ethanol and the product obtained after filtration and washing.

If, in the starting compound of formula (II), n = 2, i.e., 2 side chains are attached to the 6 carbon atoms of the glucopyranose units of the β-cyclodextrin at positions 1,3 and 1,4, then the compound of formula (I) = 2) a cyclodextrin derivative containing 2 crown ether units and thus having a particularly high tendency to complex is formed by the reaction of so-called sandwich complexes.

The starting materials of the process of the present invention are prepared partly by methods known in the literature and partly by the methods described in the Examples.

CLAIMS 1. A group of starting materials for process (a) is a cyclodextrin amino derivative of formula (II). Their preparation is described in the Examples.

187,360

2. Another starting material for process (a) is the crown ether derivative (III), the crown isocyanates and the crown acid chlorides.

Corona isocyanates can be prepared from the corresponding amino compounds in a 10-30 wt% solution of aromatic hydrocarbons or halogenated aromatic hydrocarbons with a constant phosgene introduction for 1-5 hours at 60-170 ° C.

After removal of excess phosgene and solvent, the product is recovered by crystallization or distillation. The preparation of crown acid chlorides is known in the art (J, A.C.S. 97, 3462).

3. Process b) is based on the cyclodextrin derivatives represented by the general formula (IV) and their preparation is described in the Examples.

4. Another starting material for process b) is the crown ether amino derivative of formula (V). They can be prepared from the corresponding amino compounds by reaction with halogenated binaamide derivatives followed by hydrolysis with halohydrocarbons. The preparation of the corresponding crown ether amines is known in the art (J. A. C. S. 98, 5199).

The following examples illustrate the invention without limiting the invention thereto.

Example 1

Mono-6-deoxy-6- {2- [3,4- (1,4,7,10,13-pentaoxa-tridecyl) -benzamido] -ethyl} -amino-β-cyclodextrin

2.35 g (2.0 mmol) of mono-6-deoxy-6 - [(2-aminoethyl) amino] -? - cyclodextrin (II, where n = 1, m = 0) 20 ml A solution of absolute pyridine in 0.66 g (2.0 mmol) of 3,4 (1,4,7,10,13-pentaoxatetridecyl) -benzoyl chloride (coronacarboxylic acid chloride III, where r = 1, Y = H, X = -COCl) for 1 hour at room temperature. The solvent was then distilled off in vacuo, the residue was digested with 2 x 20 mL of 96% ethanol, and the precipitated cream crystals were filtered off and washed with 96% ethanol. 2.0 g of the title compound are obtained. Yield: 68%. Analysis: Ms: 1471

Calculated N = 1.90%, Found N = 1.76%.

IR (KBr) 1640 cm ^- '(amide I band)

Example 2

Mono-6-deoxy-6- {2 ~ [3,4- (1,4,7,10,13-pentaoxa)

-tridecyl) -phenylcarbamoylamino-N-ethylamino-β-cyclodextrin

5.9 g (5 mmol) of mono-6-deoxy-6 - [(2-aminoethyl) amino] -? - cyclodextrin (II, where η = 1, m = 0) in 50 ml absolute dimethyl sulfoxide in 1.6 g (5.2 mmol) of 3,4 (1,4,7,10,13-pentaoxatetridecyl) phenyl isocyanate (Corona isocyanate III, where r = 1, Y = H, X = -N = C = 0) for 30 minutes at room temperature. The solvent was then distilled off in a vacuum bath at a maximum temperature of 60 ° C. The residue was digested with 3 x 50 mL of 96% ethanol, the crystalline material was filtered off and washed with 96% ethanol. Yield: 5.8 g (78%).

Analysis: Ms: 1489

N, 2.85. Found N, 2.82.

IR (KBr) 1650 ^cm-1 (urea-CO-bands)

Example 3

Mono-6-deoxy-6 - {[8- (3,4-11,4,7,10,13-pentaoxa-tridecyl-phenylcarbamoylamino) -3,6-dioxa-octyl] -amino] - ss-cyclodextrin

7.8 g (6.2 mmol) of mono-6-deoxy-6 - [(8-amino3,6-dioxaoctyl) amino] -? - cyclodextrin (II), where η = 1, m = 2, A = -CH ₂ -O-CH ₂ -) in 150 ml of an absolute pyridine solution of 2.0 g (6 4 mmol) of 3,4- (1,4,7,10,13-pentaoxa-4-pyridyl) phenyl isocyanate ( The corona isocyanate of formula III, where r = 1, Y = H, X = -N = C = O) is stirred for 1 hour at room temperature and then the pyridine is distilled off under vacuum

The residue was triturated with 4 x 40 mL of 96% ethanol, filtered, and washed with 96% ethanol.

Yield: 7.75 g (79.4%).

Analysis: Ms: 1574

N, 2.67. Found N, 2.46.

IR (KBr) 1660 ^cm-1 (urea-CO-bands)

Example 4

6,6-Dideoxy-6,6-bis {[2- (3,4- (1,4,7,10,13-pentaoxa-tridecyl) -phenylcarbamoylamino) -ethyl] -amino] -β cyclodextrin

1.22 g (1 mmol) of 6,6-dideoxy-6,6-bis [(2-aminoethyl) amino] -? - cyclodextrin (II, where n = 2, m = 0). ml of absolute pyridine + 20 ml of absolute dimethylsulfoxide in 0.65 g (2.1 mmol) of 3,4- (1,4,7,10,13-pentaoxatetridecyl) phenyl isocyanate (corona isocyanate III), where r = 1, Y = H, X = - NCO) is stirred for 1 hour at room temperature. The solvent is then distilled off in a vacuum at a maximum of 60 ° C. The residue was digested with 3 x 20 mL warm 96% ethanol, and the pale yellow crystalline product was filtered and washed with 96% ethanol.

Yield: 1.7 g (92.4%). Analysis: Ms: 1840

N, 4.57; N, 4.32.

IR (KBr) 1650 cm ^-1 (urea CO band)

Example 5

Mono-6-deoxy-6 ~ ([2- (3,4- (1,4,7,10,13-pentaoxa-tridecyl] -phenylamino) -ethyl] -amino} -? - cyclodextrin

2.66 g (6.66 mmol) of 2- [3,4- (1,4,7,10,13-pentaoxatridecyl) phenylamino] ethylamine dihydrochloride salt (crown ether amino compound V) derivative where m = 0, q = r = 1) 100 ml distilled aqueous solution of Varion AT 660 anion exchange resin

-3187 360, the chloride-free solution is evaporated to dryness in vacuo. The residue was dissolved in 150 mL of dimethylformamide, followed by 1.5 mL of triethylamine acid binder and 7.1 g (5.5 mmol) of 6-deoxy-6-tosyloxy -? - cyclodextrin (IV) where n = 1, R = tolyl). The reaction mixture was stirred for 3 hours at 80 ° C and evaporated in vacuo. The residue was dissolved in distilled water, treated with Varion AT 660 anion exchange resin and the aqueous solution evaporated to dryness in vacuo. The residue was digested with 96% ethanol, filtered, and washed with 96% ethanol.

Yield: 5.0 g (63%).

Analysis: Ms: 1443

Calculated N = 1.94%, Found N = 1.88%.

Preparation of Examples 1 and 2: Mono-6-deoxy-6 - [(2-aminoethyl) amino] -? - cyclodextrin (compound of formula [II], where η = 1, m = 0) Preparation:

2.26 g (2 mmol) of β-cyclodextrin are treated with 2.0 g of p-toluenesulfonic acid chloride (tosyl chloride) in 100 ml of pyridine medium at 20 ° C for 1 hour. After 1 h, quench the reaction with 5 mL of water. The pyridine was distilled off and the residue was triturated with 50 ml of 56% ethyl alcohol in crystalline powder. The product was filtered off, washed with 96% ethyl alcohol and dried in vacuo at 80-90 ° C.

This gives 2.52 g (1.94 mmol) of 6-deoxy-6-tosyloxy / cyclodextrin, which is stirred in an excess of 50 ml of ethylenediamine for 2 hours at 80 DEG C., and the excess ethylene diamine is distilled off in vacuo. The residue was dissolved in 50 ml of distilled water with 2 x 2 mmol of anion exchange resin (in this case 2x 10 ml of VARION AT 660) to remove the sulfonic acid. The aqueous solution was evaporated and the residue was triturated with 96% ethyl alcohol, the crystalline product was filtered off and washed with 96% ethyl alcohol.

2.13 g of the title compound are obtained.

Preparation of Example 3 Starting Material

Mono-6-deoxy-6 - [(8-amino-3,6-dioxaoctyl) -amino] -β-cyclodextrin (Compound [II], where η = 1, m = 2, A = -CH ₂ -O-CH ₂ -):

A solution of 6-deoxy-6-tosyloxy-β-cyclodextrin (38.8 mmol), prepared as described above, in dimethylformamide (186 mL) was stirred with triethylene glycol diamine (43 g, 290.5 mmol) for 2 hours. and evaporate the solvent in vacuo. The evaporation residue was dissolved in 600 ml of distilled water and desulfurized with 2 x 40 mmol anion exchange resin (in this case 2 x 100 ml VARION AT 660). The filtered aqueous solution was concentrated in vacuo and the residue was triturated with 2 x 200 mL of 96% ethanol or acetone to give a crystalline powder. The product is filtered off and dried in vacuo at 90-100 ° C. 40.3 g of the title compound are obtained.

Preparation of Example 4 Starting Material

Preparation of 6,6-dideoxy-6,6-bis (2-aminoethyl) amino] -β-cyclodextrin (compound of formula [II], where n = 2, m = 0):

A "bridged" cyclodextrin disulfonate (14.29 g, 10 mmol) (prepared from J.A.C.S. 98.7855) in 100 mL of dimethylformamide was stirred with 2.4 g (40 mmol) of ethylenediamine at 80 ° C for 2 hours. The solvent was then distilled off in vacuo, the residue was dissolved in 300 mL of distilled water and desulfurized with 2 x 20 mmol anion exchange resin (in this case 2 x 50 mL VARION AT 660). The residue obtained by evaporation of the aqueous solution was triturated with 96% ethyl alcohol in crystalline powder, filtered and washed with 96% ethyl alcohol.

10.6 g of the title compound are obtained. (The preparation of the title compound is also described in J.A.C.S. 707, 1614.)

Example 5 Preparation of starting material.

Preparation of 2- [3,4- (1,4,7,10,13-pentaoxa-tridecyl) -phenylamino] -ethylamine (Compound V where m = 0, q = r = 1) :

1.5 g (5.3 mmol of [3,4-] 1,4,7,10,13-pentaoxatetridecyl) phenylamine (known from the literature: JACS 98, 5199) and 1.4 g ( 6 mmol) of a mixture of 2-chloroethylbenzamide (known from the literature: Chemische Berichte 28, 2933) was heated at 90 ° C for 1 hour. After cooling, the melt was dissolved in 20 mL of water and basified with 6 mL of 5% potassium hydroxide solution and extracted with 3 x 15 mL of chloroform. The organic phase is concentrated in vacuo and the residue is taken up in 10 ml of 5% hydrochloric acid ethanol. The precipitated crystalline product is filtered off, washed, dried.

1.8 g (yield: 72.8%) of intermediate [2- [3,4- (1,4,7,10,13-pentaoxa-tridecyl) -phenylamino] -N-benzoyl-ethyl are obtained. amine hydrochloride m.p. 207-209 ° C (crystallized from ethanol). The material obtained is refluxed for 2 hours with 5% hydrochloric acid in ethanol, the solution is filtered while still hot and evaporated. The residue was washed with ether. 1.07 g (85%) of the title compound are obtained. MS: 326, mp: 206-207 ° C.

Analysis: Calculated N = 5.99%, Found N = 5.76%.

Example 6

Influence of salt absorption through complexation

In order to verify the complexation, an optical observable change, the absorption of sodium 2,4-dinitrophenolate (Na ⁺ DNP ~) was investigated through the gastric wall modeling membrane using a Sartorius device. The employee

187360 conditions: t = 36.5 ± 0.5 ° C, membrane area: 40 cm ^2, concentration: 10 ^-3 mol / l in distilled water, 4etektálás UV spectroscopy.

Under the conditions described above, the diffusion rate of Na ⁺ DNP ~ was 2.2 mmol / h. The cyclodextrin crown ether derivative prepared according to Example 3 (a compound of formula I wherein n = 1, m = 2, A = -CH ₂ -O-CH ₂ -, t = p = q = r = 1) as a ligand. diffusion rate under the same conditions gave 0.4 mmol / h. An equimolar amount of Na ⁺ DNP and the aforementioned cyclodextrin crown ether derivative were reacted and the salt formed had a diffusion rate of 0.4 mmol / h, i.e. a Na ⁺ DNP diffusion rate corresponding to the passage of the cyclodextrin crown ether ligand. decreased, representing a 5.5-fold deceleration.

The decrease in diffusion rate was due to the fact that the coronaether portion of the cyclodextrin crown ether derivative complexed the Na ⁺ ion and the cyclodextrin moiety complexed the DNP anion, thereby achieving perfect molecular packaging of the Na ⁺ DNP salt. .

Claims (13)

A process for the preparation of a compound of formula I having a complexing property of the formula: wherein n = 1-2, m = 0-2, p = 0-1, q = 0-1, t = 0-1, r = 1, A = -CH ₂ -O-CH ₂ -, CD = denotes a group deriving from the removal of n OH radicals from a cyclodextrin molecule for the preparation of cyclodextrin crown ether derivatives, characterized in that (a) a cyclodextrin amino derivative of the formula (II) wherein n, m, A, CD are as defined herein, in the form of a 4-20 wt.% solution in dipolar aprotic solvents at 10-40 ° C, -2 moles of a crown ether derivative of formula (III) wherein r is as defined above, Y = -H, X = -N = C = O or -COC1; or b) a crownether amino derivative of the Formula V, wherein m, q, r, A are as defined herein, in the form of a 5-10 wt% solution of dipolar aprotic solvents at 25-100 ° C, 0.5- 1 mole IV. with a cyclodextrin derivative of the formula wherein n is as defined herein, R = tolyl, optionally in the presence of an acid acceptor. A process for the preparation of compounds of formula I according to claim 1, wherein n = 1, m = 0, and t, p, q, r, CD are as defined in the scope of claim 1, characterized by: that the starting material was II. using a cyclodextrin slag product of the formula wherein n = 1, m = 0, CD = represents a group derived from the removal of a hydroxyl radical from a cyclodextrin molecule. Process a) according to claim 1, mono-6-deoxy-6 - {[8- (3,4- / 1,4,7,10,13-pentaoxa-tridecyl / phenylcarbamoylamino) -3,6] -dioxaoctyl] -amino} -? cyclodextrin, characterized in that the starting material is a compound of formula II. using a cyclodextrin derivative of the general formula wherein n = 1, m = 2, A = -CH ₂ -O-CH ₂ - CD = represents a group derived from the removal of a hydroxyl radical from a cyclodextrin molecule. 4. Process a) according to claim 1 for the preparation of 6,6-dideoxy-6,6-bis {[2- (3,4- / 1,4,7,10,13-pentaoxa-tridecyl / phenylcarbamoylamino) ethyl] amino] -N-cyclodextrin characterized in that the starting material used is a cyclodextrin derivative of formula II wherein n = 2, m == 0, CD = denotes a group derived by removing two hydroxyl radicals from a cyclodextrin molecule. The process for the preparation of compounds of formula I according to claim 1, wherein n = 1 or 2, m = 0, 1 or 2, A = -CH ₂ -O-CH ₂ -, CD = a group derived by the removal of one or two hydroxyl radicals from a cyclodextrin molecule; using a crown ether derivative of general formula wherein r = 1, Y = —H X = -N = C = O. Process a) according to claim 1, mono-6-deoxy-6 - {[2- (3,4- / 1,4,7,10,13-pentoxa-tridecyl-benzamido) -ethyl] - amino} -? - cyclodextrin, characterized in that an acylating reagent is a compound of formula III. using a crown ether derivative of general formula wherein r = 1, Y = H X = -COC1. Process b) according to claim 1, mono-6-deoxy-6 - {[2- (3,4- / 1,4,7,10,13-pentoxa-tridecyl-1-phenylamino) -ethyl] -amino} -? - cyclodextrin, characterized in that the starting material is IV. using a cyclodextrin derivative of the general formula wherein η = 1, CD = can be derived by removing a hydroxyl radical from a cyclodextrin molecule, R = tolyl. Process b) according to claim 1, mono-6-deoxy-6 - {[2- (3,4- / 1,4,7,10,13-pentoxa-tridecyl-phenylamino) -ethyl] - amino} -? - cyclodextrin, characterized in that the starting material is a crown ether amino derivative of formula V wherein m = 0, q = r = 1. _ 187,360 Process according to any one of the preceding claims, characterized in that the reaction is carried out in a solution of 5 to 20% by weight of pyridine. Process according to any one of the preceding claims, characterized in that the reaction is carried out in a medium containing from 10 to 15% by weight of dimethylsulfoxide. Process according to any one of the preceding claims, characterized in that the reaction is carried out in a solution of 4-5% by weight in a 1: 1 by volume mixture of pyridine and dimethylsulfoxide. Process according to any one of the preceding claims, characterized in that the reaction is carried out in a solution containing 5 to 10% by weight of dimethylformamide. Process according to any one of the preceding claims, characterized in that the reaction is carried out in the presence of 10 to 12% by weight of triethylamine acid binder, based on the starting materials.