US 20070213382A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0213382 A1 Rudy et al. (43) Pub. Date: Sep. 13, 2007 (54) 2-METHYLTHIAZOLIDINE-2, Publication Classification 4-DICARBOXYLIC ACID-CONTAINING COMBINATION PREPARATIONS (51) Int. Cl. A6II 3/426 (2006.01) (76) Inventors: Susilo Rudy, Koln (DE); Eberhard A6II 38/19 (2006.01) Amtmann, Heidelberg (DE) A6II 38/09 (2006.01) A6II 38/16 (2006.01) Correspondence Address: A6II 38/18 (2006.01) J C PATENTS, INC. A6II 3 L/704 (2006.01) 4 VENTURE, SUITE 250 A61K 3 1/7048 (2006.01) IRVINE, CA 92.618 (US) A6II 3/522 (2006.01) A61K 31/7072 (2006.01) (21) Appl. No.: 11/568,506 A6II 3/53 (2006.01) A61K 31/4745 (2006.01) (22) PCT Fed: May 2, 2005 (52) U.S. Cl. .............................. 514/365: 514/34: 514/27; 514/492; 514/109; 514/8: 514/283; (86) PCT No.: PCT/DEOS/OO810 514/12: 514/171; 514/449; 424/85.1; 424/649: 424/155.1; S 371(c)(1), 424/94.63: 514/49; 514/263.34; (2), (4) Date: Oct. 30, 2006 514/251; 514/269; 514/410; Related U.S. Application Data 514/15 (57) ABSTRACT (60) Provisional application No. 60/569,570, filed on May The invention relates to a combination preparation of 2-me 10, 2004. thylthiazolidine-2,4-dicarboxylic acid and/or physiologi (30) Foreign Application Priority Data cally acceptable salts thereof and at least one cytotoxic and/or cytostatic compound as well as the use of these May 3, 2004 (DE).......................... 10-2004-021-658.4 combination preparations for the treatment of cancer. US 2007/0213382 A1 Sep. 13, 2007 2-METHYLTHIAZOLIDINE-2,4-DICARBOXYLIC 0010 Thus, the present invention relates to combination ACID-CONTAINING COMBINATION preparations which comprise 2-methylthiazolidine-2,4-di PREPARATIONS carboxylic acid and/or physiologically acceptable salts 0001) The invention relates to a combination preparation thereof and at least one antiangiogenically and/or cytotoxi of 2-methylthiazolidine-2,4-dicarboxylic acid and/or physi cally and/or cytostatically active compound. ologically acceptable salts thereof and of at least one anti 0011) 2-Methylthiazolidine-2,4-dicarboxylic acid is a angiogenic cytotoxic and/or cytostatic compound. The chemical compound with two stereogenic centers wherein invention relates further to the use of these combination the R-configuration at position 4 is especially preferred. The preparations for the treatment of cancer as well as to the Stereogenic centre at position 2 has no preferred configura increase of the efficacy of antiangiogenic and/or cytotoxic t1On. and/or cytostatic compounds by the additional administra tion of 2-methylthiazolidine-2,4-dicarboxylic acid. 0012. The term “2-methylthiazolidine-2,4-dicarboxylic acid is supposed to refer to the diastereomeric compounds 0002 The synthesis of 2-methylthiazolidine-2,4-dicar (2R-4R)-2-methylthiazolidine-2,4-dicarboxylic acid, (2S, boxylic acid is well known from DE-OS 21 16629. EPO 969 4R)-2-methylthiazolidine-2,4-dicarboxylic acid as well as 834 B1 discloses the use of 2-methylthiazolidine-2,4-dicar (2RS.4R)-2-methyl-thiazolidine-2,4-dicarboxylic acid. In boxylic acid as mucolytic agent, EP 98 916 809 describes a the case of (2RS.4R)-2-methylthiazolidine-2,4-dicarboxylic combination preparation of 2-methylthiazolidine-2,4-dicar acid, the molar ratio of (2R,4R)-2-methylthiazolidine-2,4- boxylic acid and paracetamol, and EP 01915 023 discusses dicarboxylic acid to (2S,4R)-2-methylthiazolidine-2,4-di the use of 2-methylthiazolidine-2,4-dicarboxylic acid for the carboxylic acid can range from 90:10 to 10:90, wherein the treatment of infective diseases, especially HIV. percentages of (2R.4R)-2-methylthiazolidine-2,4-dicar 0003 European patent EP 1255 538 B1 discloses the use boxylic acid preferably prevails. of 2-methylthiazolidine-2,4-dicarboxylic acid for the treat 0013 Furthermore, the term “2-methylthiazolidine-2,4- ment and prophylaxis of cancer. In this patent the use of dicarboxylic acid” is supposed to comprise not only the free 2-methylthiazolidine-2,4-dicarboxylic acid for the prepara acid but also physiologically acceptable salts. Accordingly, tion of a drug for prevention and/or reduction of undesired the compound 2-methylthiazolidine-2,4-dicarboxylic acid side effects of cytostatics is also described. and respectively an enantiomer, diastereomer or an enantio 0004 Cytostatics represent substances which prevent or meric and/or diastereomeric mixture thereof can be admin considerably delay the initiation and interrupt or respec istered as free acid and/or in form of the pharmacologically tively disturb the cycle of the nuclear and/or plasma division acceptable salt. Suitable examples of these salts comprise (karyokinesis or respectively cytokinesis). They interfere acid addition salts and alkaline metal salts. Thus, alkaline either with the reduplication or the transcription of the DNA metal salts can be used, such as the sodium salt, the or with the formation and disjunction of its carrier structures potassium salt, the lithium salt, the magnesium salt, the and lead to division perturbing chromosome aberrations or calcium salt and/or alkyl ammonium salts. As acids which respectively suppress the formation and disturb the function form an acid addition salt the following ones can be men of the spindle apparatus (and are almost always mutage tioned: Sulphuric acid, Sulphonic acid, phosphoric acid, neous). In the broader sense, cytostatics also represent nitric acid, nitrous acid, perchloric acid, hydrobromic acid, Substances which respectively disturb and prevent the pro hydrochloric acid, formic acid, acetic acid, propionic acid, Vision of the necessary energy for the nucleoprotein synthe Succinic acid, oxalic acid, gluconic acid (glyconic acid, sis or the spindle function. Generally, they are classified into dextronic acid), lactic acid, malic acid, tartaric acid, tartronic antimetabolites, alkylating agents, cytostatically active anti acid (hydroxymalonic acid, hydroxypropionic diacid), biotics and mitosis inhibitors according to their mode of fumaric acid, citric acid, ascorbic acid, maleic acid, malonic action (Roche Lexikon Medizin, 4. Edition; (C) Urban & acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, Fischer Verlag, Munchen 1984/1987/1993/1999). (o, m, p)-toluic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, salicylic acid, p-aminosalicylic 0005) Paclitaxel (TaxolR) is probably one of the best acid, methanesulfonic acid, ethanesulfonic acid, hydroxy investigated cytostatics. ethanesulfonic acid, ethylenesulfonic acid, p-toluene 0006 EP 1255 538 B1 discloses the use of 2-methylthi Sulfonic acid, naphthylsulfonic acid, naphthylamine sulfonic azolidine-2,4-dicarboxylic acid for the reduction of undes acid, Sulfanilic acid, camphersulfonic acid, china acid ired side effects of cytostatics. Thus, EP 1255 538 B1 gives (canine acid), o-methylmandelic acid, hydrogen-benzene a solution for the problem of reducing undesired side effects Sulfonic acid, picric acid (2,4,6-trinitrophenol), adipic acid, of cytostatics. and D-o-tolyltartaric acid. Amino acids can also be used for the salt formation such as glycine, alanine, valine, leucine, 0007 The object of the present invention, however, is to isoleucine, serine, threonine, phenylalanine, tyrosine, tryp increase the effect, i.e. the efficacy and/or activity of cyto tophan, lysine, arginine, histidine, aspartic acid, glutamic statics. acid, asparagine, glutamine, cysteine, methionine and pro 0008. This object is solved by the technical teaching of line wherein the amino acids methionine, tryptophan, lysine the independent patent claims. Advantageous embodiments and arginine are preferred. of the invention are given in the dependent patent claims, the 0014) A combination preparation which contains 2-me description as well as in the examples. thylthiazolidine-2,4-dicarboxylic acid, i.e. at least one enan 0009 Surprisingly, it was shown that the above described tiomer or a diastereomer of 2-methylthiazolidine-2,4-dicar effect of cytostatics can be increased by administration of boxylic acid as free acid or as salt and at least one 2-methylthiazolidine-2,4-dicarboxylic acid. antiangiogenic and/or at least one cytotoxic compound and/ US 2007/0213382 A1 Sep. 13, 2007 or at least a cytostatic compound does not have to contain mycin, Cerubidine), doxorubicin (adriamycin) as well as obligatorily both active agents in one pharmaceutical for liposomaladriamycin, dactinomycin, mitomycin C, bleomy mulation. cin (Blenoxane), epirubicin (4-epi-adriamycin), idarubicin 0015. Obviously, pharmaceutical formulations can be (Idamycin), dactinomycin (Actinomycin D. Cosmegen), provided which contain 2-methylthiazolidine-2,4-dicar mitoxantrone (Novantrone), mitomycin C (Mitomycin), Pli boxylic acid together with the antiangiogenic and/or cyto camycin (Mithracin), amsacrine and actinomycin D. toxic and/or cytostatic compound. The preferred prepara 0021 Methotrexate (MTX, Mexate), 5-fluorouracil tions, however, are combination preparations which (Fluoracil, 5-FU), 6-thioguanine (Thioguanine, 6-TG), comprise two separate pharmaceutical formulations, namely 6-mercaptopurine, fludarabine (Fludara), floxuridine one for 2-methylthiazolidine-2,4-dicarboxylic acid and (FUDR), cladribine, pentostatin, gemcitabine (Gemzar), cyt another one for the at least one antiangiogenic and/ or arabine, azathioprine, raltitrexed, capecitabine (Xeloda), cytotoxic and/or cytostatic compound. This is advantageous cytosine arabinoside, deoxycoformycin (Pentostatin, since both active agents can