IE950700L - Novel derivatives of þ-cyclodextrin - Google Patents

Description

80908 DERIVATIVES OF y-CYCLODEXTRIN• Background of the invention The present invention is concerned with new ethers of 15 y-cyclodextrin, their preparation and their use as coraplexants for chemicals and pharmaceuticals. -y-CD is prepared by the enzymatic cleavage and religation of starch and a subsequent separation from the thus obtained cyclodextrin mixture containing i.a. cs-cyclodextrin (containing 5 glucose units), 30 3-cvclodexcrin (J3-CD) (7 glucose units) and y-cyclodextrin (y-CD).

Cyc!©dej:trins are known in the art to possess the ability to form inclusion complexes and to have concomitant solubilizing properties. Mi exhaustive review which describes such complexes and their properties can be found in w. Sanger. &ngewandte Cherale. 92, 343-361 (1981). ■y-cyclodextrin (y~CD) is a cyclic oligosaccharide consisting of 8 glucose units which are joined together by q(1-4) linkages.

CH»OH H OH 80908 Derivatives of cyclodextrins are also known to possess the above-mentioned properties. Said derivatives have been reviewed in an article by A.P. Croft and R.A.. Bartsch in Tetrahedron. 39, 1417-1474 (1983).

More particularly, the German Offenlegungsschrift DE 3118218 discloses the 2,6-dimethyl derivatives of B-CD, while in U.S. Patent No. 3,459,731 there are described hydroxyethyl, hydroxypropyl and hydroxypropy1/hydroxy-ethyl ethers of 0-CD. Furthermore, in U.S. Patent Appl. Ser. Wo. 5-603 839 there is described the use of specific derivatives of cvclodextrines to improve the systemic administration of sex hormones. Most of the cyclodextrin derivatives presently known in the art are derived from 0-CD, while the derivatives of &-CD and particularly of y-CD remain relatively unknown.

The use of derivatives of B-CD has the following advantages. B-CD is only poorly water soluble and therefore it is disadvantageous to use it as a coraplexant and solufailizer. Derivatives of B-CD on the other hand, due to their increased solubility, are more suitable coraplexants and solubilizers. In contrast herewith, a-CD and y-CD having an excellent water solubility do not need such substitutions. Hence, it is obvious to use unsubstituted y-CD (and c-CD) as complexant and solubilizer. Particularly for y-CD, a number of such complexes with various useful compounds can be found in e.g. Int. J. Pharm. 10. 1-15 (1982) with steroid hormones, in Picta Pharm. Suec. 20, 11-20 (1983) with flurtripofen, in Cheru. Pharm. Bull. 3U 286-291 (1983) with spirolacton and in Acta Pharm. Suec. 20, 287-294 (1983) with proscillaridin. y-CD does not form such inclusion complexes with any given compound. Often, such complexation is only established in the lower concentration range. At higher concentrations of y~CD, the formed complex is precipitated.

It has now been found that an appropriately alkylated, hydroxy-alkylated, carboxyalkylated or (alkyloxycarbonyl)alkylated form of y-CD or a mixed ether thereof prevents the crystallisation of such complexes. The advantages of y-CD over its lower horaologues. i.e. its larger cavity resulting in e superior propensity to form inclusion complexes, its favourable toxicological properties and the fact that it can be cleaved enzymafcically by e-axaylase (in contrast with B-CD), can therefore fully be exploited. y-CD contains three free hydroxy functions par glucose unit which can completely or partially be derivatized. In view of this, the average degree of substitution (D.S.) is introduced, which is the average number of substituted hydroxy functions per glucose unit. Said D.S. can vary 5 from its minimal value 0.125 up to its maximal value 3. In the latter case all 24 hydroxy groups are substituted, while in the former case only one is substituted. A minimal D.S. is especially preferred when y-CO is used as solubilizer of pharmaceuticals for use in parenteral applications, while a higher D.S. is preferred when used In technical 10 applications, such as, for example, for pesticides or enzymes. In the latter instance, the higher D.S. causes that also chose hydroxy groups are functionalised which are located in the cavity of the y-CD molecule. Consequently, the diameter of the cavity is decreased. By selecting the appropriate D.S. the size of the cavity can be adapted In 15 order to obtain the optimum space required for a certain molecule to appropriately fit into the cavity of the cyclodextrin. when introducing hydroxvalkyl substitutions on y-CD, the hydroxy function of the thus obtained hydroxyalkyl ether group can further be hydroxyalkylated, generating multiple substitutions on one particular 20 OH-group. In such cases the term average molar substitution (M.S.) is introduced. Said M.S. is defined as the average number of moles of the substituting agent per glucose unity. In view of this, it is evident that the M.S. can be greater than 3 and has. theoretically, no upper limit.

Description of the preferred embodiments.

The present invention is concerned with a y-cyclodextrin ether or mixed ether wherein the ether sub-stituents are alkyl, hydroxy C2„,, a Iky 3, or carboxy C,_2 alkyl and wherein the degree of substitution is in the range of 0.125 to 2 or the average molar substitution is in the range of 0.125 to 3 , octakis™ (2 ? 6-di~0-methyl) -y-cyclodextrin and per~0~r«ethylated y-cyclodextrin being excluded.

Particularly preferred compounds are the methyl, ethyl, isopcopyl, hydroxyschyl, hydroxypropyl, hydroxybutyl, carboxymethyl and carboxyethyl substituted y~cyclodextrins and further the 10 (methyl)(hydroxyethyl). (methyl)(hydroxypropyl) and (methyl)(hydroxy-ethyl) (carboxyraethyl) substituted y-cyclodextrIns, having a D.S. of 0.3 to 2 and a M.S. of from 0„3 to 3.

The compounds of the present invention can generally be prepared by 15 reacting the starting y~CD with an appropriate O-alkylating agent or a mixture of such agents in a concentration being selected so that the desired D.S. is obtained. The said reaction is preferably conducted in a suitable solvent in the presence of an appropriate base. An appropriate O-alkylating agent is, for example, an alkyl, hydroxyalkyl, carboxy-20 alkyl or (alkvloxycarbonyl)alkyl halide or sulfonate, e.g. methyl chloride, ethyl bromide, propyl mefchvlsulfonate, ethyl chloroacetate, a-chloroacetic acid; or an oxirane, e.g. oxirane, methyloxirane.

Suitable solvents are, for example, water; an alcohol or polyalcohol. e.g. methanol, ethanol, 1-propanol, 2-propanol, l-but&nol, 25 1»2-ethanediol, 1.2-propanediol and the like; a ketone, e.g. 2-propanone, 2-butanone» 4-methv1-2-pentanone, and the like; an ether or polyether, e.g. ethoxyethane, 2-(2-propyloxy)propane, tetrahvdrofuran, 1,2-disaethoxyethane and the like; and C^-C^-alkyloxy-C^-C^-alkanol and mixtures of such solvents. An appropriate base is, for 30 example, an alkali or earth alkaline metal hydroxide, e.g. sodium hydroxide, potassium hydroxide; or an alkali or earth alkaline metal hydride or amide, e.g. sodium hydride, calcium hydride and sodium amide„ Preferably the said O-alkylation reaction is conducted with 0.1 to 3 parts by weight of water per part by weight y-CD in case there is no organic solvent used, and with 1 to 40 parts by weight organic solvent per part by weight y-CD in case no water is used.

In a particularly preferred way of preparing the compounds of the present invention, the reaction mixture containing the starting y-CD, the solvent, base and O-alkylating agent is heated in an autoclave at a teaperature comprised between 30" and 200°C. Depending on the reactivity at the O-alkylating agent, the reaction mixture is allowed to react at this temperature for 15 minutes up to 24 hours. Subsequently, the mixture is acidified and the reaction product is isolated and purified by standard separation and purification procedures such as. for example, column chromatography, ultra filtration, centrifugatlon, and dried.

The compounds of the present invention can also be converted into each other. For example, the (alkyloxycar&onyl)alley 1 substituted y-cyclodextrines may conveniently converted to the corresponding car&oxyalkyl substituted y-cyclodextrines following art-known saponification procedures, e.g. by treating the starting compounds with an aqueous acidic or basic solution.

The compounds of the present invention are useful due to their ability to form inclusion complexes having a stabilising effect on the cotoplexed compounds, and due to their concomitant solubilizing activity. Compounds exhibiting a significantly increased water solubility and improved stability after having been transferred to inclusion complexes with the above-mentioned y-CD derivatives, are those having the required shape and six a, i.e. which fit into the cavity. The sise of the cavity can be adapted by selecting the appropriate y-CD derivatives h&vlng a suitable D.S. Examples of such compounds are. for example, non-steroid enti-rheumatic agents, steroids, cardiac glycosides and derivatives of benzodiazepine, benzimidazole, piperidine. piperasins, imidazole, triazole, pyridazine, 1,2,4-triazinedione or 2.3.5,6-tetrahydro-imidazo[2,1-b]thiazoles, or amides, hydratropic acid derivatives or trialkylamines, whereby the derivatives of benzodiazepine, benz imidazole, piperidine, piperazine, imidazole, triazole, pyridazine, I,2,4-triazinedione or 2,3,5,5- tetrahydro-imidazo[2,1-b]thiazole, or amides, hydratropic acid derivatives or trialkylamines are preferred.

Useful benzimidazole derivatives are thiabendazole, tuberidszole, ciclobendazole, oxihendazole, parbendazole, caiabendasole, mebendazole, fenbendazole, flubendazole, albendazole, oxfendazole, nocodazole and asteraizole.

Suitable piperidine derivatives are diphenoxylate, phenoperid ins „ haloperidol. haloperidol decanoate. broraperidol decanoate, bromperldol„ moperone. trifluperidol, piparaperone. piritramide, fentanyl. benperidol„ droperidol, benzitramide, benzetimide, doraperidone, sufentanil, carfentanil, alfentanil, dexetimide. milenperone. difenoxin, fluspirilene, penfluridol, pimozide., lorcainide, loperamide, astemizole. ketanserine, levocabastine, cisapride, altanserin, ritanserin, 3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,7-dimethyl-4H-pyrido[l. 2-a]pvr iraldin-4-one, 3-[2-[4-[bis(4-fluorophenyl)methylane]-1-piperidinyl]-ethvl]-2-methyl-4H-pyrido[1,2~a]pyriraidin-^-one and 3-[2-[4-[ [3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridln-2-yl]amino]-1-piper idinyl] ethyl ]-2-methyl-4K-pvrido[ 1 „ 2-a]pyrimidin-4-one.

Suitable piperazine derivatives include azaperone. fluanisone, lidoflazine, flunarizine, raianserine, oxatomide, mioflazine«, clocinlzine and cirmarisine.

Examples of suitable imidazole derivatives are metronidazole, ornidazole, ipronidazole, tinidazole. isoconazole. nimorazole. ' miconazole, burimamide, metiaiaide. uietomidate, enilconazole or iiaasalll P etomidate, econazole, clotrimazole, carnidazole, cimetidine,. doconazole, sulconazole, parconazole, orconazole, butoconazole. triadimlnole, cioconazole. valconazole. fluotrimazole. ketocon&zole. oxtconazole. lombazole, bifonasole, oxraetidine, fenticonazole, tubulazole and (Z) -1- [ 2-ch loro-2- (2,4-d ichlorophenv 1) e thenv 1 ] - lK-imidazo le.

As suitable triazole derivatives there may be mentioned virazole. azaconazole, etacoriazole, propiconazole, penconazole, itraconazole and terconazole.

Useful pyridazine derivative are. tor example, 3-chloro-5-[3.6-5 dihydro-4-(3-raethylphenyl)~1(2H)-pyridinyl]pyridazine, 3-methoxy-3-[4- (3-raethylphenyl)-l-piperazinyl]pyridazine and the compounds of Publ. Eur. Pat. Appl. Mo. 0.156,433.

Useful 1,2.4-triazinediones are. Cor example, 2-chloro-a-(4-chloro-pheny 1 )-4- (4.5~dihydro-3, 5-dioxo-l»2,4~tr iazin-2 (3H) -y 1) benzeneaceto-10 nit rile, 2.6-dichloro-e.-( 4-chloropheny1 )-4- (4 c 5-dihydro-3,5-dioxo- l,2.4-tria3;in-2(3H)-yl)benzeneacetoRitrile and the compounds of Publ. Eur. Pat. &opl. Ho. 0,170,316.

Useful trialkylamines are, for example, diisoproraine, prosaplne.

Useful 2,3.5,5*-tetrahydrG-iraidazo[2,l-b]thi£ZOles comprise, tor 15 example, tetramisole or levamisole.

Useful amides are, for example, closantel, smbucetamide, isopropamide, bu%epide metiodide, dextromoramide.

A useful hydratropic acid derivative is, for example, suprofen.

Particularly valuable pharmaceutical compositions are obtained when converting etomidate, ketoconazole, tubulazole, itraconazole, levocabastine or flunarizine into a water-soluble fora using the complex forming agents of the invention. Such compositions are therefore a .25 special subject of the present invention.

The invention is further directed to a method of preparing compositions of sparingly water-soluble or water-instable compounds which method is characterised by dissolving the y-cyclodeictrin ether in water 30 and adding thereto the selected compound as well as optionally drying the solution of the formed inclusion compound using methods known per se. Formation of the solution may preferably take place at temperatures between 15 and 35°C.

The drug is suitably added batchwise. The water may further comprise physiologically compatible corapounds such as sodium chloride, potassium nitrate, glucose, mannitol, sorbitol, xylitol or buffers such as phosphate, acetate or citrate buffer.

Using y-cyclodextrin ethers in accordance with the invention it is possible to prepare commonly known application forms of drugs tor oral„ parenteral, topical, rectal or vaginal application, e.g. infusion and injection solutions, drop solutions (e.g. eye drops or nasal drops), sprays, tablets, powders,1 capsules, aerosols, sirups, jellies, ointments, medical baths,, rectalia and vaginalis.

The aqueous solutions may further comprise suitable physiologically compatible preserving agents such as. for example, quaternary ammonium soaps, chlorbutanol, phenoxetol, bromopol, and the like, and also anti-oxidantia, such as, for example, ascorbic acid.

For the preparation of solid formulations the solutions of the inclusion compounds are dried using conventional methods; thus the water may be evaporated in a rotation evaporator or by Ivophilisation. The residue is pulverized and. optionally after addition of further inert ingredients, converted into uncoated or coated tablets, suppositories, capsules, creams or ointments. ~9» Examples The following examples are meant to illustrate and not to limit the present invention in all its aspects. Unless stated otherwise, all parts therein are by weight.

A. Preparation examples.

Example 1 1 Part of y~CD and a solution of 1.5 parts of sodium hydroxide in 10 1.5 parts of water were raised in an autoclave. Than there were added 3 parts of methyl chloride and 0.5 parts of methyloxirane. The mixture was heated tor 1 hour at 65°C and subsequently for 2 hours at 100°C. after cooling, the remaining methyloxirane was expelled and the reaction mixture was neutralized with hydrochloric acid. The volatile components 15 were evaporated and the remainder was filtered. The filtrate was liberated from sodium chloride over an ion exchanger and subsequently freeze-dried, yielding the (methyl)(hydroxypropyl) derivative of y-CD. Following the same procedures and using the appropriate starting materials the (ethyl) (hydroxvethy 1) derivative of y-CD was also 20 prepared.

Example 2 In an autoclave there were mixed 2.5 parts of 1,2-diraethoxyethane, I part of y-CD and a solution of 1 part of sodium hydroxide in 1.2 parts 25 of water. To this mixture, there were added 2 parts of oxirane and the whole was heated to 110°C for 5 hours. After cooling, the remaining oxirane was expelled and the .reaction mixture was neutralized with hydrochloric acid. The volatile components were evaporated and the remainder was filtered. The filtrate was subsequently liberated fraa 30 sodium chloride over an ion exchanger and subsequently freeze-dried, yielding the hydroxyethvi derivative of t~C0 with a M.S. of 0-77.

Following the sense procedures and using the appropriate starting materials there was also prepared the 2-hydroxypropyl derivative of y-CD with a M.S. of 0 = 66.

Exampl® 3 1 Part of 7-CD, 3 pares of 1,2-diraethoxyethane and 1.5 pares of sodium hydroxide in 1.5 pares of water ware mixed in an autoclave. Subsequently, there were added 4 parts of chloromethane and the whole was .5 heated at 120°C for 4 hours. After cooling the reaction mixture was neutralized with hydrochloric acid and the volatile components evaporated. The remainder was filtered and the filtrate was liberated com sodium chloride over an ion exhanger and subsequently freeze-dried. yielding the methyl derivative of y-CD with a D.S. of 1.49. 10 Following the same procedures and using the appropriate starting materials there were also prepared the methyl derivative of y-CD with a D.S. of 0.13? the carboxyraethyl derivative of y-CD with a D.S. of 0.86: and the (ethoxycarbonyl)methyl derivative of y-CD: the ethyl derivative of y-CD; the butyl derivative of y-CD: the isobutyl derivative of 15 y-CD; the isopropyl derivative of y-CD; the carboxyethyl derivative of y-CD; the 3-hydroxypropyl derivative of y-CD; and the 4-hydroxybuty1 derivative of y-CD.

B. Examples illustrating the properties of the y-CD derivatives Example 4 Starting from a 5% stock solution of a particular y-CD derivative in a phosphate buffer of pH 7.4, a dilution series was obtained with concentrations varying of from 0% to 5% with 0.5% steps. 3 ml of these 25 solutions were pipetted into a closed container containing an appropriate amount of progesteron. After 5 days shaking at 25°C, the thus obtained mixture was filtered over a membrane filter (pore diameter: 0.22 uis) „ and the content of progesteron was determined with high pressure liquid chromatography (using a column of 25 cm length. 5 mm internal diameter; 30 packed with 5 ym ODS-hypersil (RP-18): eluent: acetonitrile/water; U.V. detection). The results of these concentration measureraents for a number of the y-CD derivatives of the present invention and for unsubstituted y-CD gathered in the following table. concentration of y-CD derivative in % (weight by volume) content of progesteron in vg/ml jnsubs t i- tuted f-CD raethvl substituted D.S.=0.13 methyl substituted D.S.=1.49 carboxyraethyl subst. M.S.=0.86 hydroxy ethyl subst. M.S.=0.77 hydroxy propyl subst. M.S.-0.66 0 .9 o .9 .9 .9 .9 0.5 425 438 379 102 234 302 1 343 972 748 209 452 582 1.5 275 1458 1144 313 673 872 2 203 1902 1470 417 860 1165 2.5 163 2149 1888 517 1055 1431 3 93 2258 2260 610 1291 1704 3.5 50 2392 2686 79 1472 1987 4 54 2592 3050 796 1722 2287 4.5 46 2627 3411 891 1817 2595 45 2602 3876 979 2065 2865 Table: Content of progesteron in solutions containing various concentrations of y-CD derivative and y-CD.

Example 5.

Following the procedures described in example 4 the content of 3-chloro-6-E3,6-dihydro-4-(3-Hiethylphenyl)-i(2H)-pyridinyL]pyridazine was determined in solutions containing various concentrations of y-CD derivatives. Said pyridazine compound is described in Published Europ. Pat. Rpp1. No. 0.156,433 as a useful anti-viral agent. concentration content of 3- chloro-6- [ 3 ,5-dihyd.ro-4- (3-rae thy Ipheny 1 )- oE y-CD l(2H)-pyrldinyl]pyridazine in yg/ml derivative in % (weight unsubscituted methyl- hydroxypropyl by volume) y-CD substituted substituted D.S.=1.49 M.S.=0.66 0 0.4 0.4 0.4 1 2.0 2.0 1.5 2.5 CO Q 8.0 4.5 3.5 - 12.6 7.0 o CO .0 o o

Claims (9)

1. A y-eye1odsxtrin ether or mixed ether wherein the ether sub- stituents are Ci_3 alkyl, hydroxy C2„A alkyl or carboxy Cj„2 \ alkyl and therein the degree of substitution is in the range of 0.125 to 2 or the average molar substitution is in the range of 0.125 to 3, octakis-(2,6~di-0-methyl) -y-cyclo» dextrin and per-O-onethylated y-cyclodextrin being excluded.

2. A Y~cYcloc^e3ttrin according to claiifl 1 wherein the sub-stituents are methyl, ethyl, isopropyl, hvdroxyethyl, hydroxypropyl , hvdroxybutyl, carboxymethyl or. carboxyethyl.

3. A y-cyclodextrin according to claim 1 wherein the substitu-ents are hydroxyethyl or hydroxypropyl.

4. A y-cyclodextrin according to any of the claims 1 to 3 wherein the degree of substitution is in the range of 0.3 to 2 and the average molar substitution is in the range of 0,3 to 3.

5. A process for preparing a Y~cycl°dextrin as claimed in any of claims 1-4, characterised by O-alkylating Y~cycl0c*e3c~ trin with an appropriate O-alkylating agent in a concentration being selected so that the desired D.S. is obtained.

6. A process according to claim 5, wherein the process is conducted in a reaction-inert solvent in the presence of a base and at a temperature in the range from 30° to 200°. -14-

7. A y-cyclodextrin according to claim 1, substantially as hereinbefore described and exemplified.

8. A process for preparing a y-cyclodeKtrin according to claim 1, substantially as hereinbefore described and 5 exemplified.

9. A y-cyclodextrin according to claim 1, whenever prepared by a process claimed in a preceding claim. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.