US 20030087900A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0087900 A1 Telerman et al. (43) Pub. Date: May 8, 2003 (54) DRUGS WHICH CAN BE USED IN THE Related U.S. Application Data TREATMENT OF CANCER (63) Continuation of application No. 09/885,031, filed on Jun. 20, 2001, now abandoned. (75) Inventors: Adam Telerman, Paris (FR); Robert Amson, Paris (FR); Marius Tuijnder, (30) Foreign Application Priority Data Mechelen (BE) Jun. 1, 2001 (FR)............................................ 01/07285 Correspondence Address: Publication Classification PENNIE & EDMONDS LLP 7 1667 K Street, N.W. (51) Int. Cl. ...................... A61K 3.1/542; A61K 31/495 Washington, DC 20006 (US) (52) U.S. Cl. ................................... 514/225.2; 514/255.04 (57) ABSTRACT (73) Assignee: Molecular Engines Laboratories The present invention relates to the use of a compound (21)21) AppAppl. No.: 10,304,964/304, Inhibitinginhibiting ththe eXpreSSLOnpressi Off the TPT1 g ene, or off theth products which it controls, for producing a drug which is (22) Filed: Nov. 27, 2002 intended for treating cancer. Patent Application Publication May 8, 2003 Sheet 1 of 10 US 2003/0087900 A1 20 100 68 OO 4. O 2 O 1.9 0.0 3.4 O O Control A 100 A B 1OO B C 100 C D 100 D 1000 1 OOO 1000 1000 FG. A 120 113.5 100 80 60 40 20 E-- Control A 100 A B 100 B C 100 C D 1 OO D 1000 1000 1000 1000 FIG.1B Patent Application Publication May 8, 2003 Sheet 2 of 10 US 2003/0087900 A1 20 1 OO 100 69.7 100.0 8 O 6 O w 4. O 2 O 11.6 - 0.0 % O M Control A 100 A B 100 B C 100 C D 100 D 1000 1 OOO 1000 1000 FIG.2A 120 100 8 O 2 O O Control A 100 A B 100 B C 100 C 000 1000 1000 FIG.2B Patent Application Publication May 8, 2003 Sheet 3 of 10 US 2003/0087900 A1 Patent Application Publication May 8, 2003 Sheet 4 of 10 US 2003/0087900 A1 1200 100.0 80.0 60.0 40.0 8 20.0 : X : : 0.0 Control A 100 A 1000 B OO B 000 C 100 C 1000 D 100 D 1000 FIG.4A Patent Application Publication May 8, 2003 Sheet 5 of 10 US 2003/0087900 A1 120.0 100.0 80.0 60.0 40.0 20.0 s - -- 0.0 Control A 100 A 1000 B 100 B 1000 C 100 C 1000 D 100 D 1000 FG.5A 100.0 Patent Application Publication May 8, 2003 Sheet 6 of 10 US 2003/0087900 A1 Control A 100 A 1000 B 100 B 1000 C 100 C 1000 D 100 D 1000 FIG.6A Patent Application Publication May 8, 2003 Sheet 7 of 10 US 2003/0087900 A1 1 OOO 100.0 90.0 80.0 700 60.0 50.0 43.3 40.0 Ž 30.0 1 O.O O O.O 1 Control A 100 A 1000 B 100 B 1OOO C 100 ( 1000 D iOOD 1 000 FG./A 100.0 Patent Application Publication May 8, 2003 Sheet 8 of 10 US 2003/0087900 A1 2 322 2 Control A 1000 A 2000 A 5000 C 1000 C 2000 C 5000 FG.8A 100.0 97.1 a W. Contro A OOO. A 2000. A 5000 C 1000 C 2000 C 5000 FIG.8B Patent Application Publication May 8, 2003 Sheet 9 of 10 US 2003/0087900 A1 120.0 100 u? 100.0 84.5 85.0 77.5 s , 80.0 71.7 % 60.0 is 40.0 30.5 20.0 O.O -- - 2 control A 1000 A 2000 A 5000 C 1000 C 2000 C 5000 FG.9 Patent Application Publication May 8, 2003 Sheet 10 of 10 US 2003/0087900 A1 120.0 2 100.0 80.0 60.0 40.0 20.0 0.0 Control A 1000 A 2000 A 5000 C 1000 C 2000 C 5000 F.G. 1 OA 120.0 100.0 80.0 60.0 40.0 20.0 O.0 Control A 1000 A 2000 A 5000 C 1000 C 2000 C 5000 FIG.10B US 2003/0O87900 A1 May 8, 2003 DRUGS WHICH CAN BE USED IN THE 0013 Those phenothiazine derivatives which may be TREATMENT OF CANCER mentioned are dimethothiazine, hydroxyethylpromethazine, isothipendyl, mecquitazine, methdilazine, oxomemazine, 0001. The present invention relates to the use of novel promethazine, propiomazine, thiazinamium and trimepra classes of compounds which are designed for producing a drug which is intended for treating cancer. ZC. 0014 Those piperazine derivatives which may in particu 0002 Research carried out by the applicant, in particular lar be mentioned are buclizine, cetirizine, chlorcyclizine, in the context of the phenomenon of tumor reversion, has led cinnarizine, clocinizine, cyclizine, flumarizine, homochlor to the demonstration that certain genes are overexpressed cycline, hydroxy Zine, meclozine, niaprazine and Oxatomide. during the tumor phase as compared with the reversion phase. 0015 Those ethanolamine derivatives which may be mentioned, in particular, are the phenhydramine derivatives 0003. The overexpression of one of these genes, i.e. the Such as bromodiphenhydramine and diphenhydramine and gene TPT1, standing for “translationally controlled tumor their homologues. protein encoding histamine releasing factor', demonstrated that the expression of this gene was Strongly decreased 0016. The ethylendiamines which may be mentioned are, during tumor reversion. for example, the compounds of the mepyramine type. 0004 Thus, a tumor cell line designated U937 is capable 0017 Finally, examples of the various compounds which of reverting and thereby resulting in what is termed a US do not have a Sedative component and which may be cell, that is to Say a cell line which no longer exhibits Such mentioned are acrivastine, ebastine, taZifyline and terfena a pronounced malignant phenotype characteristic. dine. 0005. In the U937 cell line, out of 2 000 sequences, for 0018. These compounds only represent the basic mol example, the number of clones for the TPT1 gene was 248 ecules which can be used in accordance with the present whereas it was no more than 2 in the US cell line. invention; it is also possible to use derivatives, in particular Substitution derivatives, of the abovementioned compounds, 0006. This has led the applicant to focus on the impor as well as physiologically acceptable Salts. tance of the histamine activation pathway in the phenom 0019. According to the present invention, treatment of enon of tumor reversion and to demonstrate the activity of the cancer is essentially understood as being the ability of a products which interfere with this pathway as a way of compound to Selectively destroy the tumor cells without treating cancer. appreciably affecting healthy cells, it being understood that 0007 More specifically, the present invention relates to this Selectivity can vary depending on the compounds and the use of compounds which totally or partially inhibit the depending on the condition of the patient and the type of expression of the TPT1 gene, or of the products which it cancer being treated. controls, for the purpose of producing a drug which is 0020. As will be observed in the examples which follow, intended for treating cancer. the products according to the present invention exhibit 0008. The present invention naturally relates not only to remarkable Selectivity and, in particular, a very great ability the possibility of inhibiting the expression of the TPT1 gene to destroy tumor cells, in particular, the results have been in the cell but also to that of totally or partially inhibiting the found to be particularly impressive in relation to cells of the expression of the products whose metabolic chain it controls leukemic type and in relation to breast cancer, ductal carci directly or indirectly, up to and including the release of noma and carcinoma of the mammary glands. histamine, in particular. 0021. The compounds according to the present invention 0009 Among the compounds which can be used within can be used in the form of pharmaceutical compositions the context of the present invention, those which may more which may be employed by any route of administration; Specifically be mentioned are the antihistamines, that is to however, in a general manner, preference will be given to Say the antagonists of the histamine H1 receptors, in par using injectable routes, in particular, for treating tumors. It ticular. is, of course, possible to use other galenic forms, in particu lar the oral route. The daily doses have to take account of the 0010. It should be clearly understood that the antine compound, the condition of the patient and the nature and oplastic function of these compounds may be linked to Stage of the cancer being treated. Subsidiary elements of the cell, taking into account the fact that, for example, one of the antihistamine prototypes, i.e. 0022. The appended results demonstrate that there is a polaramine, is inactive within the context of the present dose above which the product loses most of its activity. invention. 0023. It is also possible to envisage using the compounds 0.011 Among these compounds which can be used within according to the present invention in combination with other the present invention, those which may very particularly be antineoplastic agents, whether these be antimetabolites, mentioned are the phenothiazine derivatives and the deriva alkylating agents, Spindle poisons, intercalating agents or tives of the piperazine type. other types of hormonal cytolytic agents or antineoplastic agents, as well as certain proteins Such as interferons in 0012.