WO2004016622A1

WO2004016622A1 - Derivatives of 4-4'-bipyridyl-2-2'-bisoxazoles and 4-4'-bipyridyl-2-2'-bistiazoles as antineoplasic agents

Info

Publication number: WO2004016622A1
Application number: PCT/ES2003/000424
Authority: WO
Inventors: Yolanda MARTÍN SÁNCHEZ-CANTALEJO; María Jesús VILLA HORMAECHE; Beatríz SAEZ PIZARRO; Javier Soto Romero; Miguel FERNÁNDEZ BRAÑA; Juan Carlos Lacal Sanjuan
Original assignee: Consejo Superior De Investigaciones Científicas; Universidad Europea De Madrid
Priority date: 2002-08-16
Filing date: 2003-08-14
Publication date: 2004-02-26
Also published as: AU2003260515A1; AU2003260515A8; ES2200706B1; ES2200706A1

Abstract

The invention relates to novel derivatives of 4-4'-bipyridyl-2-2'-bisoxazoles and 4-4'-bipyridyl-2-2'-bistiazoles, having general formula I with antiproliferative activity and, more specifically, malignant cells such as HT-29. The invention also relates to the industrial production method for same and to the use thereof in the development of pharmaceutical compounds for the treatment of human tumours.

Description

TITLE

DERIVATIVES OF 4-4'-BIPIRIDIL-2-2'-BISOXAZOLES AND 4-4'-BIPIRIDIL-2-2'- BISTIAZOLES AS ANTINEOPLASTIC AGENTS

SECTOR OF THE TECHNIQUE

Chemical anti-tumor compounds Chemical synthesis Bisoxazoles and bistiazoles.

STATE OF THE ART Recently the synthesis of bis- and tris-oxazoles has attracted a lot of attention due to the presence of this heterocycle in several natural products, such as hennoxazoles as described in T. Ichiba et al. J. Am. Chem. Soc. ( 1991), 113, p 3173, ulapualides in JA Rosener et al. J. Am. Chem. Soc. (1986), 108, p 846, and micalolides in Panek et al. Am. Chem. Soc. (2000), 122, p 1235, all of them with antifungal activity. The structure of bistiazoles is also found in natural products such as micrococcines according to the work of T. R. Kelly et al Tetrahedron Lett. (1995), 36, p 5319. In general, all these compounds are characterized by the binding of the corresponding heterocycles in 2.4 'position, and their synthesis is addressed by sequential construction of the oxazole or thiazole rings as shown in CJ Moody et al Tetrahedron Lett. (1992), 33, p 7769, or by cross-coupling the previously formed heterocycles as described by D. R. Williams et al Tetrahedron Lett (1998), 39, p 8023.

Examples of bisoxazoles or symmetrical bistiazoles are very scarce in the literature, and less frequent is the simultaneous formation of both rings with 2,2 'junction. R. Schróeder et al Liebigs. Ann. Chem. (1975), p 533, describe the synthesis of 5,5'-biphenyl-2,2'-bisoxazole by coupling of 5-phenyloxazol-2-illitium with 2-tosyloxazole in 25% yield. Later, K. Burguess et al Synthesis (1988), 36, p 199, synthesized 4,4'-trifluoromethyl-5,5'-fluor-2,2'-bisoxazole, and the corresponding bistiazole, with p-spacer phenyl among the heterocyclic rings, by treatment of 4,4-bis (trifluoromethyl) -hetero-1, 3- dienes with tin (II) chloride; also, K. Burguess et al Synthesis (1988), 36, p 194, describe the synthesis of other ^5,5' symmetrical -bisoxazoles by coupling the 5--fluoroxazol preformed through a spacer. In later work, B. et Helmreich to the United States Patent No. 5300625 ^s (1994) using the methodology developed by Burgess to obtain polymers with 2,2'-bisoxazole structure. Notwithstanding the foregoing, no background has been found on the use of bisoxazoles or bistiazoles in anticancer therapy.

DESCRIPTION Brief Description

The present invention presents new derivatives of 4-4'-bipyridyl-2-2'-bisoxazoles and 4-4'-bipyridyl-2-2'-bistiazoles of general formula I:

I where X can be oxygen or sulfur; Z may not exist or be 1,2-ethylidene, isopropylidene, p, p-biphenyl, p-phenyl, m-phenyl, 2,6-pyridylene, p, p-oxidiphenyl, p, p'-hexafluoroisopropylidendiphenyl; R may be hydrogen or substituents of those usual in organic chemistry, such as alkyls, alkylidenes, alkynes, aryls, or functional groups such as halogens, alcohols, thiols, ethers, thioethers, sulfoxides, sulfones, amines with or without substituents, nitro, aldehydes , ketones, nitrile, carboxylic acids and any of their derivatives, such as esters, amides, hydrazides, hydroxamic acids, with or without substituents, sulfonic acids and any of their derivatives equivalent to those mentioned for carboxylic acids, etc., as well as a salt , organic or inorganic, pharmacologically acceptable or prodrugs thereof, such as sulfate, methanesulfonate, hydrochloride, phosphate, nitrate, acetate, propionate, butyrate, palmitate, oxalate, malonate, maleate, malate, fumarate, citrate, benzoate, etc .; R 'may not exist or be alkyl groups; And it can, in turn, not exist, or be sulfate, methanesulfonate, hydrochloride, phosphate, nitrate, acetate, propionate, butyrate, palmitate, oxalate, malonate, maleate, malate, fumarate, citrate, benzoate, etc. On the other hand, the mechanism of its industrial production is indicated in the present patent and forms part of the present invention. Finally, the present patent describes the ability of these compounds to inhibit cell proliferation and, specifically, that of malignant cells such as HT-29, so they have application in anticancer therapy, and such use is part of the present invention. .

Detailed description

On the other hand, the chemical synthesis of the bisoxazoles object of this patent can be described in this patent can be carried out as indicated in Figure 1.

Through an acylation reaction of 4-aminomethylpyridine with different acylating agents, in the form of dicarboxylic acids (HO ₂ CZ-CO ₂ H) in the presence of a condensation reagent or activated derivatives thereof, NA diamides with different spacers are obtained ( Z). HA compounds are directly transformed into VAT bisoxazoles by treatment with some fluorinated anhydrides, such as trifluoroacetic, pentafluoropropionic and heptafluorbutanoic anhydrides at different temperatures and in toluene as a solvent and using a base, such as pyridine.

For the introduction of other R groups, a complementary method is used via the anhydrobase IIIA, obtained by treatment of the corresponding HA diamide with ethyl chloroformate, using a base like triethylamine. NIA compounds are generally obtained as insoluble solids within the reaction solvent (acetone) and are purified by conventional methods. However, the subsequent oxazole formation reaction can be carried out successfully by working with the insoluble solid, which contains the triethylamine anhydrobase and hydrochloride in a 1: 5 ratio, as can be estimated based on its NMR- ¹ spectra. H. Thus, NIA anhydrobases are subsequently treated with different anhydrides or acid derivatives at different temperatures to obtain the bisoxazoles IVA, which give rise to the general structure IA by quaternization of the pyridine nitrogen with the corresponding alkyl derivative. Both the IA and VAT products thus obtained are purified by conventional methods, and can be identified and characterized by the usual analytical procedures.

On the other hand, for the synthesis of bistiazoles, bistioamide is initially prepared and the previous sequence is continued as indicated in the scheme. The corresponding thioamides IIB with different spacers (Z) are obtained by reacting the NA diamides with the Lawensson reagent at the reflux temperature of THF. These HB compounds are directly transformed into IVB bistiazoles by treatment with some fluorinated anhydrides, for example, trifluoroacetic anhydride, under the conditions identical to those described for the transformation of HA amides into VAT bisoxazoles. For the introduction of other R groups, a methodology similar to that already described for the synthesis of bisoxazoles is followed.

The following examples describe the synthesis of compounds derived from formula I, and finally the results of antiproliferative activity in HT29 cancer cells (see Example 8 and Table II) that indicate that these compounds have an antitumor activity and are therefore candidates for The development of new drugs for the treatment of human carcinogenic processes and such use is part of the present invention. On the other hand, in the following table (Table I) more examples of bisoxazoles and bistiazoles derived from the general formula I are indicated, and form part of the present invention. Table I. Chemical compounds of bisoxazoles and bistiazoles derived from the general formula I

The chemical compounds described in this patent can be used as anti-tumor active ingredients in human patients, and can be prepared and administered, according to the knowledge of the state of the art of galenic development, in different ways such as injectables, capsules, dragees or tablets, both as a free base as in the form of any of the salts mentioned, and all of them form part of the present invention. Similarly, solid forms are made in the presence of the necessary excipients, such as, among others, mannitol, polyvinylpyrrolidone, microcrystalline cellulose, silica gel, talcum, magnesium stearate, titanium oxide, USP grade dyes and antioxidants, and form part of the present invention.

Some non-limiting examples of the scope of the present invention are described below.

EXAMPLES

Example 1.- Preparation of 2,2-bis [(5-methyl-4- (4-pyridyl) -2-oxazolyl)] propane

(Z = (CH ₃ ) ₂ C; X = O; R = CH ₃ ).

On a suspension of / V, Λ / -bis (1-ethoxycarbonyl-1, 4-dihydropyridylmethylene) -2,2-dimethylmalonamide with triethylamine hydrochloride (218 mg, 0.48 mmol) in acetic anhydride (5 ml) kept under an atmosphere of Argon, tin tetrachloride (0.3 mL, 1M SnCI ₄ , 0.3 mmol) was added. The mixture was heated at reflux for 4 h, and then the solvent was removed under reduced pressure on the rotary evaporator. Water (3 ml) was added to the crude obtained and a time was allowed until the resulting solid could be crushed. This solid was filtered under vacuum, washed successively with a 5% sodium bicarbonate solution, with water, and finally, with acetone. The solid that was collected was found to be 2,2-bis [(5-methyl-4- (4-pyridyl) -2-oxazolyl)] propane (150 mg, 80%), as a beige solid, mp> 300 ⁹ C. ¹ H-NMR (δ, ppm) (DMSO-d ₆ ): 2.54 (s, 6H, CH ₃ ), 7.60 (d, 4H, J = 6.0, Py); 8.57 (d, 4H, J = 6.0, Py). ¹³ C-NMR (δ, ppm) (DMSO-de): 11.83, 25.01, 38.00, 120.27, 131.29, 138.79, 147.46, 149.98, 163.27. IR (crτϊ ¹ ) (KBr): 3432, 2987, 1621, 1596, 1543, 1458, 1415, 1291. Em (m / z) (%): 360 (M ⁺ , 68), 345 (47), 317 ( 6), 201 (100), 159 (7), 106 (5), 69 (81). Analysis calculated for C ₂ ιH oN ₂ ₄ 0 _2: 69.98% C, 5.59% H, 15.55% N; exp. 69.87% C, 5.54% H, 15.49% N.

Example 2.- Preparation of 2,2-bis [(5-trifluoromethyl-4- (4-pyridyl) -2-oxazolyl)] propane (Z = (CH ₃ ) ₂ C; X = O; R = CF ₃ ) .

On a suspension of Λ /, / V-bis (4-pyridylmethylene) -2,2-dimethylmalonamide (190 mg, 0.6 mmol) in 15 ml of dry toluene, kept under argon, pyridine (0.6 mi, 7 was added mmol). The mixture was cooled to 0 ^e C and then trifluoroacetic anhydride (0.6 ml, 4.25 mmol) was added dropwise. The set was allowed to reach room temperature and stirring was maintained for 12 h. After this time, the solvent was removed under reduced pressure and a 5% sodium carbonate solution (5 ml) was added. The reaction crude was extracted with ethyl acetate (3 x 15 mL) and the organic extracts were combined, washed with a saturated sodium chloride solution and dried with anhydrous sodium sulfate. After removing the solvent under reduced pressure, the crude obtained was purified by column chromatography (silica gel, ethyl acetate) and 2,2-bis [(5-trifluoromethyl-4- (4-pyridyl) -2] -oxazolyl)] propane (200 mg, 80%), as a yellow-beige solid, mp 126-128 ^S C (ethanol). ¹ H-NMR (δ, ppm) (CDCI ₃ ): 2.09 (s, 6H, CH ₃ ), 7.64 (d, 4H, J = 6.0, Py), 8.73 (d, 4H, J = 6.0, Py). ¹³ C-NMR (δ, ppm) (CDCI ₃ ): 25.32, 39.83, 118.97, 120.75, 136.29, 137.56, 150.08, 150.34, 165.54. IR (cm ^"1 ) (KBr): 3447, 2992, 1701, 1622, 1594, 1570, 1545, 1500, 1418, 1382. Em (m / z) (%): 468 (M ⁺ , 81), 453 ( 8), 255 (100), 189 (15), 158 (7), 63 (8) Analysis calculated for C2iHι ₄ F ₆ N ₄ O: 53.86% C, 3.01% H, 11.96% N; exp. 53.77% C, 2.97% H, 11.86% N.

Example 3.- Preparation of 4,4'-bis [(5-trifluoromethyl-4- (1-methyl-4-pyridinium) -2-oxazolyl)] biphenyl (Z = p-biphenyl; X = O; R = CF ₃ , R '= CH ₃ )

On a solution of 4,4'-bis [(5-trifluoromethyl-4- (4-pyridyl) -2-oxazolyl)] biphenyl (40 mg, 0.07 mmol) in dry isopropanol (2 ml), kept under argon , methyl iodide (2.5 ml, 40 mmol) was added. The mixture was heated at reflux for 5h and after this time, cooled, more methyl iodide (1 mL, 16 mmol) was added and heated at reflux for another 12h. After this time, the reaction was cooled and the solvent was evaporated in the rotary evaporator, obtaining a crude which was identified as the 4,4'-bis [(5-trifluoromethyl-4- (1-methyl-4-) diiodide pyridinium) -2-oxazolyl)] biphenyl (53 mg, 89%). The crude was not purified later. ¹ H-NMR (δ, ppm) (DMSO-d ₆ ): 4.21 (s, 6H, CH ₃ ), 8.09 (d, 4H, J = 7.9, Py), 8.27 (d, 4H, J = 8.5, Ph ), 8.42 (d, 4H, J = 8.5, Ph), 9.14 (d, 4H, J = 4.1, Py). ¹³ C-NMR (δ, ppm) (CDCI ₃ ): 48.06, 119.35, 123.50, 124.19, 124.27, 124.53, 126.09, 126.11, 127.82, 127.95, 128.00, 135.3, 137.18, 142.05, 142.33, 142.37, 143.20, 146.45, 147.92, 161.95. IR (cm ^'1 ) (KBr): 3436, 3042, 2360, 1643, 1613, 1585, 1514, 1486, 1463, 1381, 1293. Analysis calculated for C32H22F6I2N4O2: 44.57% C, 2.57% H, 6.50% N; exp. 44.60% C, 2.51% H, 6.46% N.

Example 4.- Preparation of 4,4'-bis [(5-pentafluoroethyl-4- (1- methyl-4-pyridinyl) -2-oxazolyl)] b -phenyl (Z = p-biphenyl; X = O; R = CF ₂ CF ₃ , R = CH ₃ )

On a solution of 4,4'-bis [(5-pentafluoroethyl-4- (4-pyridyl) -2-oxazolyl)] biphenyl (27 mg, 0.044 mmol) in dry isopropanol (2 ml), kept under argon , excess methyl iodide (2.5 ml, 40 mmol) was added. The whole was heated at reflux for 5h and, after this time, cooled, more methyl iodide (1ml, 16mmol) was added and heated at reflux for another 12h. After this time, the reaction was cooled and the solvent was evaporated on the rotary evaporator, obtaining 4,4'-bis [(5- pentafluoroethyl-4- (1-methyl-4-pyridinium) -2-oxazolyl diiodide) )] Biphenyl (27 mg, quantitative yield). The crude was not purified later. ¹ H-NMR (δ, ppm) (DMSO-de): 4.42 (s, 6H, CH ₃ ), 8.10 (d, 4H, J = 6.7, Py), 8.26 (d, 4H, J = 8.5, Ph) , 8.40 (d, 4H, J = 8.5, Ph), 9.14 (d, 4H, J = 6.7, Py). ¹³ C-NMR (δ, ppm) (DMSO-d ₆ ): 48.11, 109.3, 118.4, 124.22, 126.48, 126.52, 127.96, 128.12, 130.12, 137.35, 142.50, 143.41, 146.43, 162.97. IR (cm ^"1 ) (KBr): 3437, 2361, 2342, 1717, 1684, 1646, 1616, 1559, 1541, 1588, 1489, 1374, 1337, 1218, 1120. Analysis calculated for C34H22F10I2N-A .: 42.43% C, 2.30% H, 5.82% N; exp. 42.36% C, 2.27% H, 5.79% N.

Example 5.- Preparation of 4,4'-bis [(5-trifluoromethyl-4- (1-methyl-4-pyridinium) -2-oxazolyl)] hexafluoroisopropylidenediphenyl (Z = Ph- (CF ₃ ) ₂ C- Ph; X = O; R = CF ₃ , R ^' = CH ₃ ) On a solution of 4,4'-bis [(5-trifluoromethyl-4- (4-pyridyl) -2-oxazolyl)] hexafluoroisopropylidenediphenyl (3 mg , 0.04 mmol) in isopropanol (4 ml) maintained under an argon atmosphere, excess methyl iodide (0.1 ml, 1.6 mmol) was added and the mixture was heated at reflux for 4 h. After this time, it was cooled, more methyl iodide (0.1 ml, 1.6 mmol) was added and the mixture was stirred at room temperature overnight. The solid obtained which was found to be 4,4'-bis [(5-trifluoromethyl-4- (1-methyl-4-pyridium) -2-oxazolyl)] hexafluoroisopropididenediphenyl (24 mg, 60%) was filtered. The crude was not purified later. ¹ H-NMR (δ, ppm) (DMSO-d ₆ ): 9.13 (d, 4H, J = 7 Hz); 8.38 (d, 4H, J = 6.69 Hz Pyr); 8.29 (d, 4H, J = 8.55 Hz, Ph); 7.67 (d, 4H, J = 7.92, Ph); 4.41 (s, 6H, Me). ¹³ C-NMR (δ, ppm) (DMSO-d ₆ ): 48.12, 118.69, 124.04, 125.86, 126.14, 127.79, 130.95, 135.73, 136.47, 137.15, 143.09, 146.54, 161.29. IR (cm ^"1 ) (KBr): 3468, 1647, 1508, 1466, 1383, 1289, 1255, 1213, 1176, 1140. Analysis calculated for C35H22F12N4O2: 52% C, 2.19% H, 5.53% N; exp. 41.46 % C, 2.13% H, 5.48% N.

Example 6.- Preparation of 2,2-bis [(5-trifluoromethyl-4- (4-pyridyl) -2-thiazolyl)] propane (Z = (CH ₃ ) ₂ C; X = S; R = CF ₃ ) . On a suspension of / V, Λ / '- bis (4-pyridylmethylene) -2,2-dimethyl-1, 3- propanedithioamide (123 mg, 0.36 mmol) in 4 ml of dry toluene, kept under argon, added pyridine (0.35 ml, 4.32 mmol). The mixture was cooled to 0 ^Q C and then was added drop trifluoroacetic anhydride (0.31 mi, 2.16 mmol). The whole was allowed to reach room temperature and stirring was maintained for 12 h. After this time, the solvent was removed under reduced pressure and a 5% sodium carbonate solution (5 ml) was added. The reaction crude was extracted with ethyl acetate (3 x 15 mL) and the organic extracts were combined, washed with a saturated sodium chloride solution and dried with anhydrous sodium sulfate. After removing the solvent under reduced pressure, the crude obtained was purified by column chromatography (silica gel, ethyl acetate: hexane 9: 1) and 2,2-bis [(5-trifluoromethyl-4- (4 -pyridyl) -2-thiazolyl)] propane (Z = (CH ₃ ) ₂ C; X = S; R = CF ₃ ) (36 mg, 25%), as a yellow solid. 1 H-NMR (δ, ppm) (DMSO-de): 1.96 (s, 6H, CH ₃ ); 7.61 (d, 4H, J = 6.1 Hz, Py); 8.74 (d, 4H, J = 6.1 Hz, Py). ¹³ C-NMR (δ, ppm) (DMSO-d ₆ ): 117.23, 120.79, 122.38, 135.06, 135.69, 138.76, 138.79, 142.54, 150.44, 150.63, 165.78, 180.18. IR (cm ^"1 ) (KBr): 2928, 2360, 1829, 1733, 1717, 1653, 1647, 1623, 1594, 1570, 1546, 1506, 1457, 1419, 1383, 1373, 1337, 1250, 1208, 1182, 1147, 1103, 988. Analysis calculated for C ₂ .Hι ₄ F ₆ N ₄ S2: 50.40% C, 2.80% H, 11.20% N; exp. 50.27% C, 2.78% H, 11.15% N. Example 7. Preparation of 4,4'-diiodide bis [(5-trifluoromethyl-4- (1-methyl - 4-pyridinio) -2-thiazolyl)] - 1.1 ^{'-oxibisbenceno} (Z = Ph-O-Ph ; X = S; R = CF ₃ , R = CH ₃ )

To a solution of 4,4'-bis [(5-trifluoromethyl-4- (4-pyridyl) -2-thiazolyl)] - 1, 1 ^{'-oxibisbenceno} (40 mg, 0.06 mmol) in a mixture

Sopropanol: MeOH: EtOH 1: 1: 1 (4 mL) kept under argon, excess methyl iodide (0.1 mL, 1.3 mmol) was added and the mixture was heated at reflux for 7h. More methyl iodide (0.1 ml) was added and stirred at room temperature overnight. Methyl iodide (0.1 ml) was added again, refluxed for another 7 hours and kept stirring at room temperature overnight. The solid obtained was filtered in vacuo and was found to be 4,4'-bis [(5-trifluoromethyl-4- (1-methyl-4-pyridinium) -2-thiazolyl)] -1,1'-oxybisbenzene ( 51 mg, 93%). ¹ H-NMR (δ, ppm) (DMSO-d6): 4.41 (s, 6H, CH ₃ ), 7.38 (d, 4H, J = 9.1, Ph), 8.22 (d, 4H, J = 9.1, Ph) , 8.39 (d, 4H, J = 6.1, Py), 9.12 (d, 4H, J = 6.7, Py). ¹³ C-NMR (δ, ppm) (CDCI ₃ ): 48.07, 119.93, 120.40, 120.60, 126.13, 126.16, 126.17, 129.80, 135.92, 137.14, 137.17, 143.28, 146.33, 146.63, 159.17, 161.92. IR (cm ^"1 ) (KBr): 3882, 3839, 3739, 3676, 2360, 1772, 1749, 1717, 1654, 1636, 160.6, 1559, 1541, 1508, 1489, 1473, 1458, 1418, 1376, 1339, 1295. Analysis calculated for C32H22F6I2N4OS2: 42.19% C, 2.42% H, 5.15% N; exp. 42.21% C, 2.38% H, 5.13% N.

Example 8.- Antitumor activity assays of the chemical compounds of the present patent.

The products described in the previous examples have shown an important antiproliferative activity in HT29 cancer cells valued as described previously [Hernández-Alcoceba R., Saniger L., Campos J., Núñez MC, Khaless F., Gallo MA, Espinosa A ., and Lacal JC (1997). Choline kinase inhibitors as a novel approach for antiproliferative drug design. Oncogene 15, 2289-2301; Hernández-Alcoceba R., Fernández F. and Lacal JC (1999). A novel mechanism for anticancer drug discovery: ln vivo antitumor activity by inhibition of phsphorylcholine production. Cancer Research 59: 3112-3118]. The following table (Table II) shows the activities of some of the examples: Table II.- IC50 level of the chemical compounds of the previous examples.

Claims

1.- Chemical compounds derived from 4-4'-bipyridyl-2-2'-bisoxazoles and 4-4'- bipyrid¡l-2-2'-bistiazoles of general formula I:

I where X can be oxygen or sulfur; Z may not exist or be 1,2-ethylidene, isopropylidene, p, p-biphenyl, p-phenyl, m-phenyl, 2,6-pyridylene, p, p'-oxidiphenyl, p, p'-hexafluoroisopropylidendiphen the; R may be hydrogen or substituents of those usual in organic chemistry, such as alkyls, alkylidenes, alkynes, aryls, or functional groups such as halogens, alcohols, thiols, ethers, thioethers, sulfoxides, sulfones, amines with or without substituents, nitro, aldehydes , ketones, nitrile, carboxylic acids and any of its derivatives, such as esters, amides, hydrazides, hydroxamic acids, with or without substituents, sulfonic acids and any of their derivatives equivalent to those mentioned, among others, for carboxylic acids, as well as a salt, organic or inorganic, pharmacologically acceptable or prodrugs thereof, such as sulfate, methanesulfonate, hydrochloride, phosphate, nitrate, acetate, propionate, butyrate, palmitate, oxalate, malonate, maleate, malate, fumarate, citrate, benzoate, etc .; R 'may not exist or be alkyl groups; And it can, in turn, not exist, or be, among others, sulfate, methanesulfonate, hydrochloride, phosphate, nitrate, acetate, propionate, butyrate, palmitate, oxalate, malonate, maleate, malate, fumarate, citrate, benzoate.

2. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which X is O.

3. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which X is S.

4. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which Z is a single bond.

5. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which Z is ethane-1,2-diyl.

6. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which Z is propane-2,2-diyl.

7. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which Z is m-phenyl.

8. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which Z is p-phenyl.

9. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which Z is p-biphenyl.

10. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which Z is 4,4'-oxidiphenyl.

11. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which Z is 4,4'- (hexafluoesopropylidene) diphenyl.

12. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which Z is pyridin-2,6-diyl.

13. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which R is methyl.

14. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which R is trifluoromethyl.

15. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which R is pentafluoroethyl.

16. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which R is heptafluoropropyl.

17. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which R 'is methyl.

18. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which R 'is ethyl.

19. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which R 'is / -propyl.

20. Chemical compounds according to claim 1 characterized in that the compounds of formula I are those in which R 'is n-butyl.

Preferred 21. Compounds according to claim chemicals 1, in which the compounds of formula I are those wherein R 'is benzyl.

22. Salts of chemical compounds according to any one of claims 1 to 21, pharmacologically acceptable or prodrugs thereof such as, among others, sulfate, methanesulfonate, hydrochloride, phosphate, nitrate, acetate, propionate, butyrate, palmitate, oxalate, malonate, maleate, malate, fumarate, citrate and benzoate.

23. A medicament characterized in that some of its active ingredients is a chemical compound according to any one of claims 1 to 22.

24. The use of the medicament according to claim 23 in the treatment of tumor processes.

25. A method for the industrial production of the chemical compounds according to any one of claims 1 to 21 according to any method used in organic synthesis.