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United States Patent (19) 11) Patent Number: 4,870,060 Miller (45) Date of Patent: Sep

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United States Patent (19) 11) Patent Number: 4,870,060 Miller (45) Date of Patent: Sep United States Patent (19) 11) Patent Number: 4,870,060 Miller (45) Date of Patent: Sep. 26, 1989 (54) DERIVATIVES OFy-CYCLODEXTRIN 4,727,064 2/1988 Pitha ................................... 514/965 (75) Inventor: Bernd W. W. Miller, Flintbek, Fed. FOREIGN PATENT DOCUMENTS Rep. of Germany 1548917 10/1968 France. (73) Assignee: Janssen Pharmaceutica, Beerse, 57-200361 6/1981 Japan. Belgium 144376 2/1982 Japan . 138473 12/1985 Japan. (21) Appl. No.: 224,025 122701 11/1986 Japan. 22 Filed: Jul. 25, 1988 OTHER PUBLICATIONS Enhanced Water Solubility of Vitamins A,D,E, and K, Related U.S. Application Data by Substituted Cycloamyloses; Life Sciences, vol. 29, (62) Division of Ser. No. 833,622, Feb. 27, 1986, Pat. No. pp. 307-311 Printed in USA. 4,764,604. The Chemistry of Cyclodextrin Derivatives; I.Int. Symp. on Cyclodextrins Budapest, 1981. (51) Int, C. ...... as a w w w w a w a as a so C08B 37/16 (52) U.S. Cl. ....................................... 514/58; 536/103 Windholz et al, The Merck Index, an encyclopedia of Field of Search ........................... 536/103; 514/58 chemicals, drugs, and biologicals, Tenth Edition, Pub (58) lished by Merck & Co., Inc., Rahway, N.J., pp. 560, 56) References Cited 592,753 and 762 (1983). U.S. PATENT DOCUMENTS Primary Examiner-Ronald W. Griffin 3,453,259 7/1969 Parmerter ........................... 536/103 Attorney, Agent, or Firm-Robert L. Minier 3,459,731 10/1969 Gramera et al... ... 536/103 4,054,736 10/1977 Masaki et al. ... 536/103 57 ABSTRACT 4,371,673 2/1983 Pitha ............. ... 424/78 Novel derivatives of y-cyclodextrin, their preparation 4,535,152 8/1985 Szejtli et al. ...... ... 536/103 and their use as complexants and solubilizers. Composi 4,542,211 9/1985 Szejtli et al. ...... ... 53.6/03 4,596,795 6/1986 Pitha ............. ... 514/58 tions containing the novel y-cyclodextrin derivatives 4,609,640 9/1986 Renji et al. ............................ 514/12 and method of preparing such compositions. 4,659,696 4/1987 Hirai et al..... ... 514/5 4,670,419 6/1987 Hirai et al. ............................ 514/6 31 Claims, No Drawings 4,870,060 1. 2 y-CD does not form such inclusion complexes with DERIVATIVES OF y-CYCLODEXTRIN any given compound. Often, such complexation is onlyu established in the lower concentration range. At This is a division of application Ser, No. 833,622, filed higherr concentrations of y-CD, the formed complex is Feb. 27, 1986, now U.S. Pat. No. 4,764,604, issued Aug. 5 precipitated. 16, 1988. It has now been found that an appropriately alkyl ated, hydroxyalkylated, carboxyalkylated or (alkylox BACKGROUND OF THE INVENTION ycarbonyl)alkylated form of y-CD or a mixed ether The present invention is concerned with new ethers thereof prevents the crystallization of such complexes. of y-cyclodextrin, their preparation and their use as O The advantages of y-CD over its lower homologues, complexants for chemicals and pharmaceuticals. i.e. its larger cavity resulting in a superior propensity to ty-cyclodextrin (y-CD) is a cyclic oligosaccharide form inclusion complexes, its favourable toxicological consisting of 8 glucose units which are joined together properties and the fact that it can be cleaved enzymati by a(1-4) linkages. cally by a-amylase (in contrast with 6-CD), can there 15 fore fully be exploited. y-CD contains three free hydroxy functions per glu cose unit which can completely or partially be deriva tized. In view of this, the average degree of substitution (D.S.) is introduced, which is the average number of 20 substituted hydroxy functions per glucose unit. Said D.S. can vary 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 pre 25 ferred when y-CD is used as solubilizer of pharmaceuti ty-CD is prepared by the enzymatic cleavage and religa cals for use in parenteral applications, while a higher tion of starch and a subsequent separation from the thus D.S. is preferred when used in technical applications, obtained cyclodextrin mixture containing i.a. a such as, for example, for pesticides or enzymes. In the cyclodextrin (containing 6 glucose units), g-cyclodex latter instance, the higher D.S. causes that also those trin (3-CD) (7 glucose units) and y-cyclodextrin 30 hydroxy groups are functionalized which are located in (y-CD). the cavity of the y-CD molecule. Consequently, the Cyclodextrins are known in the art to possess the diameter of the cavity is decreased. By selecting the ability to form inclusion complexes and to have con appropriate D.S. the size of the cavity can be adapted in comitant solubilizing properties. An exhaustive review order to obtain the optimum space required for a certain which describes such complexes and their properties 35 molecule to appropriately fit into the cavity of the cy can be found in W. Sanger, Angewandte Chemie, 92, clodextrin. 343-361 (1981). When introducing hydroxyalkyl substitutions on Derivatives of cyclodextrins are also known to pos y-CD, the hydroxy function of the thus obtained hy sess the above-mentioned properties. Said derivatives droxyalkyl ether group can further be hydroxyalk have been reviewed in an article by A. P. Croft and R. ylated, generating multiple substitutions on one particu A. Bartsch in Tetrahedron, 39, 1417–1474 (1983). More lar OH-group. In such cases the term average molar particularly, the German Offenlegungsschrift DE No. substitution (M.S.) is introduced. Said M.S. is defined as 31 18218 discloses the 2,6-dimethyl derivatives of 6-CD, the average number of moles of the substituting agent while in U.S. Pat. No. 3,459,731 there are described per glucose unity. In view of this, it is evident that the hydroxyethyl, hydroxypropyl and hydroxypropyl/hy 45 M.S. can be greater than 3 and has, theoretically, no droxyethyl ethers of (3-CD. Furthermore, in U.S. patent upper limit. application Ser. No. 6-603, 839 there is described the use of specific derivatives of cyclodextrines to improve the DESCRIPTION OF THE PREFERRED systemic administration of sex hormones. Most of the EMBODIMENTS cyclodextrin derivatives presently known in the art are 50 The present invention is concerned with novely-CD derived from 3-CD, while the derivatives of a-CD and derivatives, said novel y-CD derivatives being y-CD particularly of y-CD remain relatively unknown. substituted with C1-C6 alkyl, hydroxy C1-C6 alkyl, The use of derivatives of 6-CD has the following carboxy C1-C6 alkyl or C1-C6 alkyloxycarbonylc1-C6 advantages. (3-CD is only poorly water soluble and alkyl or mixed ethers thereof. therefore it is disadvantageous to use it as a complexant 55 In the foregoing definitions the term “C1-C6-alkyi' is and solubilizer. Derivatives of 3-CD on the other hand, meant to include straight and branched saturated hy due to their increased solubility, are more suitable com drocarbon radicals, having from 1 to 6 carbon atoms, plexants and solubilizers. In contrast herewith, a-CD such as, methyl, ethyl, 1-methylethyl, 1,1-dime and y-CD having an excellent water solubility do not thylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl need such substitutions. Hence, it is obvious to use un and the like. substituted y-CD (and a-CD) as complexant and solubi Preferred compounds are those y-CD derivatives lizer. Particularly for y-CD, a number of such com being y-CD substituted with C1-C3 alkyl, hydroxy plexes with various useful compounds can be found in C2-C4 alkyl, carboxy C1-C2 alkyl or (C1-C2 alkylox e.g. Int. J. Pharm. 10, 1-15 (1982) with steroid hor ycarbonyl)C1-C2 alkyl or mixed ethers thereof. mones, in Acta Pharm. Suec. 20, 11-20 (1983) with 65 Particularly preferred new compounds are the furtripofen, in Chem. Pharm. Bull. 31, 286-291 (1983) methyl, ethyl, isopropyl, hydroxyethyl, hydroxypropyl, with spirolacton and in Acta Pharm. Suec. 20, 287-294 hydroxybutyl, carboxymethyl and carboxyethyl substi (1983) with proscillaridin. tuted y-cyclodextrins and further the (methyl)(hydrox 4,870,060 3 4. yethyl), (methyl)(hydroxpropyl) and (methyl)(hydrox zinedione or 2,3,5,6-tetrahydro-imidazo2, 1-bithiazoles, yethyl)(carboxymethyl) substituted y-cyclodextrins or amides, hydratropic acid derivatives or trialkyla having a D.S or M.S. of from 0.125 to 3, more prefera mines, whereby the derivatives of benzodiazepine, bly of from 0.3 to 2. benzimidazole, piperidine, piperizine, imidazole, tri The compounds of the present invention can gener- 5 azole, pyridazine, 1,2,4-triazinedione or 2,3,5,6-tetrahy ally be prepared by reacting the starting y-CD with an dro-imidazo2, 1-bithiazole, or amides, hydratropic acid appropriate O-alkylating agent or a mixture of such derivatives or trialkylamines are preferred. agents in a concentration being selected so that the Useful benzimidazole derivatives are thiabendazole, desired D.S. is obtained. The said reaction is preferably fuberidazole, ciclobendazole, oxibendazole, parben conducted in a suitable solvent in the presence of an 10 dazole, cambendazole, mebendazole, fenbendazole, flu appropriate base. An appropriate O-alkylating agent is, bendazole, albendazole, oxfendazole, nocodazole and for example, an alkyl, hydroxyalkyl, carboxyalkyl or astemizole. (alkyloxycarbonyl)alkyl halide or sulfonate, e.g. methyl Suitable piperidine derivatives are diphenoxylate, chloride, ethyl bromide, propyl methylsulfonate, ethyl phenoperidine, haloperidol, haloperidol decanoate, chloroacetate, a-chloroacetic acid; or an oxirane, e.g. 15 bromperidol decanoate, bromperidol, moperone, tri oxirane, methyloxirane. Suitable solvents are, for exam fluperidol, pipamperone, piritramide, fentanyl, ben ple, water; an alcohol or polyalcohol, e.g.
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