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(12) Patent Application Publication (10) Pub US 20050090659A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0090659 A1 Herrmann (43) Pub. Date: Apr. 28, 2005 (54) PHOSPHOLEPID DERIVATIVES OF NUCLEOSIDES AS ANTITUMAORL MEDICAMENTS (I) (76) Inventor: Dieter Herrmann, Heidelberg (DE) Correspondence Address: ROTHWELL, FIGG, ERNST & MANBECK, P.C. 1425 K STREET, N.W. SUTE 800 WASHINGTON, DC 20005 (US) (21) Appl. No.: 10/496,499 (22) PCT Filed: Nov. 18, 2002 (86) PCT No.: PCT/EPO2/12908 R represents an alkyl chain with 10-14 carbon atoms, (30) Foreign Application Priority Data R represents an alkyl chain with 8-12 carbon atoms, in represents an integer equal to 0 to 2, Nov. 21, 2001 (DE)..................................... 101-56-910.6 R represents a hydroxy group, Mar. 4, 2002 (DE)..................................... 102-09-564.7 R and Rs represent hydrogen, and Publication Classification B represents 5-fluorouracil, (51) Int. Cl." ........................ C07H 19/048; CO7H 19/10 for use as antitumoral or antiproliferative active ingredients (52) U.S. Cl. ............................................................ 536/26.8 for the prophylaxis and/or curative, palliative or Supportive treatment of tumor diseases or neoplasias, Such as for (57) ABSTRACT example carcinomas, Sarcomas, lymphomas or leukemias, The present invention relates to drugs containing phospho both as therapeutic or prophylactic agents for monotherapy lipid derivatives preferably of non-natural nucleosides cor and in free or fixed combination with other modalities of responding to general formula I: in which prophylaxis or therapy. US 2005/0090659 A1 Apr. 28, 2005 PHOSPHOLEPID DERIVATIVES OF can Suppress the proliferation of retroviruses by inhibiting NUCLEOSIDES AS ANTITUMAORL the enzyme, reverse transcriptase. Of Special therapeutic MEDICAMENTS interest in this context is the inhibiting effect of these compounds on HIV, the cause of immunodeficiency disease, 0001. The present invention relates to drugs containing AIDS. It is expressly pointed out in EP 545 966 that the phospholipid derivatives preferably of non-natural nucleo antiviral or antiretroviral efficacy of these Substances is not Sides corresponding to general formula I: asSociated with cytotoxic effects at pharmacologically rel evant dosages. (I) 0012 Lipid esters of nucleoside monophosphates with an (O) antitumoral effect have already been described in WO R-S 95/32984. The compounds according to the invention differ from the Structures claimed therein by a changed Substitu R-O O tion pattern at the C-2 carbon atom of the Sugar ring. B O-P-O R4 Rs 0013. It was now surprisingly found that some of the -On phospholipid derivatives of nucleosides known from EP545 OH 966 have additional valuable pharmacological properties. These Substances are particularly Suitable for the prophy laxis and/or treatment of malignant tumors, Such as for R. H example malignomas, neoplasias, carcinomas, Sarcomas or hematological tumor diseases, Such as for example leuke mias. Surprisingly, the compounds of the present invention 0002 in which act antitumoral or antiproliferative without exerting unspe 0003 R represents an alkyl chain with 10-14 car cific-toxic effects on other organ Systems, Such as for bon atoms, example bone marrow or gastrointestinal tract, at pharma cologically relevant dosages. 0004 R 2 representsp an alkyl chain with 8-12 carbon atOmS, 0014. The compounds according to the invention corre sponding to the following general formula, I: 0005) in represents an integer equal to 0, 1 or 2, 0006) R represents a hydroxy group, (I) 0007) R and Rs represent hydrogen, and (O)n O008) B represents 5-fluorouracil, R-S R-O O 0009 for use as antitumoral or antiproliferative active | B ingredients for the prophylaxis and/or curative, palliative or O-P-O R4 Rs Supportive treatment of tumor diseases or neoplasias, Such -O- as for example carcinomas, Sarcomas, lymphomas or leu OH kemias. The phospholipid derivatives corresponding togen eral formula I can also be provided in the form of their pharmacologically tolerable alkali or earth alkali Salts. R. H 0.010 Phospholipid derivatives of nucleosides are known from printed patent specification, EP 545 966 B1. The compounds are described to be Substances with antiviral 0.015 in which activity that are particularly Suitable for the therapy and 0016 R represents an alkyl chain with 10-14 car prophylaxis of infections caused by DNA viruses, Such as bon atoms, for example the Herpes Simplex virus, cytomegalovirus, Papovaviridae, Varicella Zoster virus or Epstein-Barr virus, 0017 R represents an alkyl chain with 8-12 carbon or RNA viruses, Such as for example Togaviridae or, in atOmS, particular retroviruses, such as for example HTLV-I and HTLV-II oncoviruses, as well as Lentiviridae, Visna and 0018 in represents an integer equal to 0, 1 or 2, human immunodeficiency virus, HIV-1 and HIV-2. More 0019 R, R and Rs represent, independent of each over, the printed patent Specification cited above emphasizes other, hydrogen or a hydroxy group, provided that R. that compounds corresponding to general formula I are and R are not both hydroxy groups, and particularly Suitable for the treatment of clinical manifesta tions of retroviral HIV infection in man, such as persistent 0020 B represents a possibly modified or substi generalized lymphadenopathy (PGL), advanced Stage of tuted nucleo-base as well as its physiologically tol AIDS-related complex (ARC), and the full clinical mani erable Salts of inorganic or organic acids including festation of AIDS. The compounds purportedly inhibit the the various possible enantiomers, diastereomers or proliferation of DNA or RNA viruses at the stage of virus tautomerS. specific DNA or RNA transcription. 0021 Preferably, the nucleo-base in general formula I 0011. It is known from Proc. Natl. Acad. Sci. USA 83, represents cytosine, adenine, thymine, guanine, 5-fluorou 1911, 1986 and Nature 325, 773, 1987 that said substances racil, 5-bromouracil, 5-ethinyluracil, 5-propenyluracil, 5-tri US 2005/0090659 A1 Apr. 28, 2005 fluoromethyluracil, 2-amino-6-chloropurine, 2-chloroad continuously for a longer period of time. Discontinuation or enine, 2-fluoroadenine, 2,6-diaminopurine, intermittent administration, as is often common or abso 2-bromoadenine, 6-mercaptopurine or 6-methylmercap lutely required with the cytostatic or chemotherapeutic topurine. Non-natural and, in particular, halogenated nucleo agents currently used in the drug therapy of tumors due to bases are preferred. It is preferable for the purine bases to be their Substantial undesired Side effects, can be dispensed connected to the Sugar by means of the No nitrogen, and for with in the application of drugs containing compounds the pyrimidine bases to be connected by means of the corresponding to general formula I as antitumoral active N-nitrogen. ingredients. Only due to the good tolerability of the com pounds corresponding to general formula I according to the 0022 Preferred Sugars comprise the following combina invention, the continuous enteral or parenteral application of tions of residues, R., R., and Rs: these Substances is possible. 0031. The compounds corresponding to general formula I contain asymmetrical carbon atoms, all optically active forms and racemic mixtures of the compounds are also an Rs R Rs object of the present invention. a) OH H OH b) OH H H 0032. In this context, the diastereomers corresponding to c) H OH H general formulas IIa and IIb are of a particular interest: d) H H OH 0023. In general formula I, R preferably represents a (IIa) C-C, alkyl group with a linear chain. In particular, R, represents a decyl, undecyl, dodecyl, tridecyl or tetradecyl group. It is particularly preferred for R to represent the B undecyl and the dodecyl residue. R4 R5 0024 R preferably represents a C-C alkyl group with -On a linear chain, in particular an octyl, nonyl, decyl, undecyl or dodecyl group. It is particularly preferred for R to represent the decyl and the undecyl residue. R3 H 0.025 Sulphur, being characterized by various oxidation (IIb) States equal to 0, 1 or 2, represents a thioether, a Sulfoxide (O) or a Sulfone. Thioethers and Sulfoxides are particularly preferred. R1-S H O. III O B 0026. The alkali and earth alkali salts are the preferred Salts of the compounds corresponding to general formula I. 14 O-P-O| R4 R5 Sodium, calcium, and magnesium Salts are particularly -Oa preferred. OH 0.027 Particularly preferred are compounds correspond ing to general formula I, in which Rs represents hydrogen. R3 H These compounds are not yet known by name. 0028 Particularly preferred is the compound, 5-fluoro 0033 in which R, R, n, R., R., Rs, and B represent the 2'-deoxyuridine-5'-phosphoric acid-(3-dodecylmercapto-2- Same groups as in general formula I above, and can possibly decyloxy)propyl ester as well as its Sulfoxide and Sulfone be provided in the form of their salts. derivative (R, represents dodecyl, R2 represents decyl, R/Rs represent hydrogen, R represents hydroxy, n equal to 0,1 or 0034) Moreover, the tautomers of the compounds accord 2, and B represents 5-fluorouracil). These compounds have ing to the invention and their physiologically tolerable Salts not been previously described in EP 545 966 or in WO of inorganic and organic acids or bases are also considered in the present invention. These also show Selective antitu 95/32984 and therefore are new. moral or antiproliferative properties. 0029. An analogous route for the production of the com pounds corresponding to general formula I is described in 0035) Another object of the present invention are new EPO 545 966 B1 and WO95/32984, the contents of which Substances corresponding to general formula I, in which are incorporated herein by reference. 0036 R. represents an alkyl chain with 10-14 C-at 0030 Compared to chemotherapeutic agents that have oms, and been used hitherto for the treatment of malignant neoplasiaS 0037 R represents an alkyl residue with 8-12 C-at or tumors, the compounds according to the invention poS SeSS higher pharmacological-medical potency, improved OmS, efficacy and/or significantly lower toxicity, and therefore 0038 in can equal 0, 1 or 2, have a broader therapeutic range under in-vivo conditions.
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