EP1976533A2 - Derives de triterpenequinone et de triterpenephenol et leur application pour le traitement de tumeurs et de maladies parasitaires - Google Patents

Derives de triterpenequinone et de triterpenephenol et leur application pour le traitement de tumeurs et de maladies parasitaires

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Publication number
EP1976533A2
EP1976533A2 EP06830856A EP06830856A EP1976533A2 EP 1976533 A2 EP1976533 A2 EP 1976533A2 EP 06830856 A EP06830856 A EP 06830856A EP 06830856 A EP06830856 A EP 06830856A EP 1976533 A2 EP1976533 A2 EP 1976533A2
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EP
European Patent Office
Prior art keywords
substituted
alkyl
group
independently hydrogen
hydroxyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06830856A
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German (de)
English (en)
Inventor
Juan Carlos LACAL SANJUÁN
Ana RAMÍREZ DE MOLINA
Mónica BÁÑEZ CORONEL
Ángel GUTIÉRREZ RAVELO
Ana ESTÉVEZ BRAUN
Dulce YAZMÍN MESA SIVERIO
Elisa PÉREZ SACAU
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Consejo Superior de Investigaciones Cientificas CSIC
Universidad de La Laguna
Original Assignee
Consejo Superior de Investigaciones Cientificas CSIC
Universidad de La Laguna
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Application filed by Consejo Superior de Investigaciones Cientificas CSIC, Universidad de La Laguna filed Critical Consejo Superior de Investigaciones Cientificas CSIC
Publication of EP1976533A2 publication Critical patent/EP1976533A2/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/723—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic
    • C07C49/727—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups polycyclic a keto group being part of a condensed ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C69/753—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring of polycyclic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention generally relates to triterpenequinone and triterpenephenol derivatives blocking the biosynthesis of phosphorylcholine by means of the selective blocking of the choline kinase enzyme in tumor cells or in cells affected by parasitic infection, and which are consequently applicable in the treatment of tumors and parasitic diseases or diseases caused by viruses, bacteria and fungi in animals, including human beings, as well as to a method for preparing the compounds of the invention.
  • Choline kinase is the first enzyme of the Kennedy pathway or the phospatidylcholine (PC) synthesis pathway, and it phosphorylates choline to phosphorylcholine (PCho) using adenosine 5' -triphosphate (ATP) as a phosphate group donor.
  • Ras genes form a family of the so-called oncogenes which have been widely studied since they are activated in 25-30% of all human tumors and in several of them in 90%. Ras proteins have an important role in the transmission of intracellular signals due to their involvement in the regulation of cell proliferation, terminal differentiation and senescence.
  • Hemicholinium-3 (HC-3) as a relatively potent and selective blocking agent [Cuadrado A., Carnero A., Dolfi F., Jimenez B. and Lacal J. C. Oncogene 8, 2959-2968 (1993); Jimenez B., del Peso L., Montaner S., Esteve P. and Lacal J. C. J. Cell Biochem. 57, 141-149 (1995); Hernandez-Alcoceba, R., Saniger, L., Campos, J., Nunez, M. C., Khaless, F., Gallo, M. A., Espinosa, A., Lacal, J. C.
  • Bisquaternized symmetric compounds derived from pyridinium have also been used and their ability to inhibit PCho production in entire cells has been evaluated (WO98/05644) . However, these derivatives have high toxicity levels limiting their extended therapeutic application.
  • celastrol and pristimerin formed by a pentacyclic triterpene structure, induce apoptosis, said activity having been proved in human models with leukemia [Nagase, M., Oto, J., Sugiyama, S., Yube, K., Takaishi, and Sakato, N., Biosci. Biotechnol. Biochem 67, 1883 (2003)]. Nevertheless, these compounds show a serious toxicity at cell level which makes their development as useful drugs in the treatment of tumor conditions impossible. In this sense, application US 2004/0220267 describes celastrol and pristimerin derivatives which allow improving the toxicity problem.
  • the present invention relates to the use of a compound of formula (I) :
  • the present invention refers to the use of a compound of formula (II) :
  • Rl I R-2 ⁇ R-3 ⁇ R-4 I R-5 ⁇ R ⁇ ⁇ R ⁇ ⁇ RlO ⁇ Rll ⁇ Rl2 ⁇ Rl3 ⁇ Rl4 ⁇ Rl5 ⁇ Rl6 ⁇ Rl7 I Rl ⁇ ⁇
  • R 7 and R 8 are independently hydrogen; substituted or non- substituted Ci-Ci 2 alkyl; C 6 -Ci 0 aryl; a COR XVI1 group (where R XVI1 is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; 0-Ci-Ci 2 alkyl; or N(R XVI11 ) (R XIX ) amino, where R XVI11 and R XIX are independently hydrogen or a C x -Ci 2 alkyl group); a (CH 2 ) n -0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group,
  • R 2 i and R 24 are independently substituted or non-substituted C 1 - C 12 alkyl; a COR XX group (where R xx is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non- substituted C 6 -Ci 0 aryl; or N(R XXI ) (R XXI1 ) amino, where R XXI and R XXI1 are independently hydrogen or a C x -Ci 2 alkyl group) ; a [ (C 1 - C 12 ) alkyl-O- (C x -C 12 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; R 22 and R 23 are: - hydrogen; substituted or non-substituted C x -C 12 alkyl; a COR XXIII group (where R XXI11 ⁇ S hydrogen;
  • OR 22 ' and OR 23 ' respectively, where R 22 ' and R 23 ' are independently hydrogen; substituted or non-substituted C 1 - C 12 alkyl; a COR XXVI group (where R XXVI is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; or N (R XXVI1 ) (R XXVI11 ) amino, where R XXVI1 and R XXVI11 are independently hydrogen or a Ci-Ci 2 alkyl group); a [ (Ci-Ci 2 ) alkyl-O- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R 24 is in the meta position with respect to R 20 .
  • the disease or condition is cancer.
  • the disease is a parasitic disease.
  • the disease is a bacterial disease.
  • the disease is a fungal disease.
  • Ri 8 and Ri 8 - are independently hydrogen; hydroxyl; halogen; C x -Ci 2 alkyl; C 6 -Ci 0 aryl; COR IX (where R IX is hydrogen; hydroxyl; C x -Ci 2 alkyl; N(R X ) (R XI ) amino, where R x and R XI are independently hydrogen or a C x -Ci 2 alkyl group; or C x -Ci 2 alcoxyl); or trifluoromethyl ;
  • 10-Hydroxy-2 4a, 6a, 9, 12b, 14a-hexamethyl-ll-oxo- 1,2, 3, 4, 4a, 5, 6, 6a, 11, 12b, 13, 14, 14a, 14b- tetradecahydro-picene-2-carboxylic acid; 10-Hydroxy-2 , 4a, 6a, 9, 12b, 14a-hexamethyl-ll-oxo- 1,2, 3, 4, 4a, 5, 6, 6a, 11, 12b, 13, 14, 14a, 14b- tetradecahydro-picene-2-carboxylic acid methyl ester;
  • Succinic acid ethyl ester 10-hydroxy- 2, 4a, 6a, 9, 12b, 14a-hexamethyl-3, 11-dioxo- 1,2, 3, 4, 4a, 5, 6, 6a, 11, 12b, 13, 14, 14a, 14b- tetradecahydro-picen-4-yl ester;
  • R 5 is hydroxyl
  • the invention relates to a compound of formula (II) :
  • R I9 and R 20 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1 -C 12 alkyl; substituted or non- substituted C 6 -Ci 0 aryl; a N(R XV ) (R XVI ) amino group, where R xv and
  • R 7 and R 8 are independently hydrogen; substituted or non- substituted Ci-Ci 2 alkyl; C 6 -Ci 0 aryl; a COR XVI1 group (where R XVI1 is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; 0-Ci-Ci 2 alkyl; or N(R XVI11 ) (R XIX ) amino, where R XVI11 and R XIX are independently hydrogen or a C x -Ci 2 alkyl group); a (CH 2 ) n -0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group,
  • R 2 i and R 24 are independently substituted or non-substituted C 1 - Ci 2 alkyl; a COR XX group (where R xx is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non- substituted C 6 -Ci 0 aryl; or N(R XXI ) (R XXI1 ) amino, where R XXI and R XXI1 are independently hydrogen or a C x -Ci 2 alkyl group) ; a [ (C 1 - Ci 2 ) alkyl-O- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; R 22 and R 23 are: hydrogen; substituted or non-substituted C x -Ci 2 alkyl; a COR XXI11 group (where R XXI11 ⁇ S hydrogen;
  • R XXIV and R xxv are independently hydrogen or a C 1 -C 12 alkyl group); a [ (C 1 -C 12 ) alkyl-O- (C 1 -C 12 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R 24 is in the para position with respect to R 20 ; or
  • OR 22 ' and OR 23 ' respectively, where R 22 ' and R 23 ' are independently hydrogen; substituted or non-substituted C 1 -
  • R XXVI1 and R XXVI11 are independently hydrogen or a C 1 -C 12 alkyl group); a [ (C 1 -C 12 ) alkyl-O- (C 1 -C 12 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R 24 is in the meta position with respect to R 20 . or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof.
  • the invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a compound of formula (II), or mixtures thereof, or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof together with a pharmaceutically acceptable carrier, adjuvant or vehicle, for the administration to a patient.
  • One object of the present invention is the use of a compound of formula (I)
  • Ri 7 is hydrogen or methyl
  • Ri 8 and Ri 8 - are independently hydrogen; hydroxyl; halogen; Ci-Ci 2 alkyl; C 6 -Ci 0 aryl; COR IX (where R IX is hydrogen; hydroxyl; C x -Ci 2 alkyl; N(R X ) (R XI ) amino, where R x and R XI are independently hydrogen or a C x -Ci 2 alkyl group; or C x -Ci 2 alcoxyl); or trifluoromethyl ;
  • Ri 9 , Ri 9' , R 2 o and R 20 are independently hydrogen; substituted or non-substituted Ci-Ci 2 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; or N(R XI11 ) (R XIV ) amino, where R XI11 and R XIV are independently hydrogen or a Ci-Ci 2 alkyl group); a [ (Ci-Ci 2 ) alkyl-O- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3) ; trifluoromethyl; or each 19-19' or
  • R 24 and R 25 are independently hydrogen, hydroxyl or halogen
  • the compound of formula (I) used in the prevention and/or treatment of a ChoK mediated disease or condition is a compound of formula (Ia) :
  • R 19 is hydrogen; substituted or non-substituted C 1 -C 12 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 - C 10 aryl; or N(R XI11 ) (R XIV ) amino, where R XI11 and R XIV are independently hydrogen or a C 1 -C 12 alkyl group); a [ (C 1 -C 12 ) alkyl- 0- (C 1 -C 12 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond.
  • the compounds of formula (Ia) used in the invention comprise a substructure having the following formula (Ia') :
  • R 5 is hydroxyl or a OCOR group where R is (CH 2 J 2 COOH or (CH 2 ) 2 CO 2 CH 2 CH 3 ;
  • Ri 2 is independently hydrogen or a halogen
  • Ri 9 is hydrogen; substituted or non-substituted C x -Ci 2 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 - Ci 0 aryl; or N(R XI11 ) (R XIV ) amino, where R XI11 and R XIV are independently hydrogen or a C x -Ci 2 alkyl group); a [ (C x -C 12 ) alkyl- 0- (C x -C 12 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond.
  • Nicotinic acid 9-hydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl- 2,10-dioxo-2, 6b, 7, 8, 8a, 9, 10 , 11, 12 , 12a, 12b, 13, 14 , 14a- tetradecahydro-picen-3-yl ester;
  • the compounds of formula (Ia) used in the present invention comprise a substructure having the following formula (Ia'') :
  • R 7 and R 8 are independently hydrogen, hydroxyl, halogen, substituted or non-substituted Ci-Ci 2 alkyl, substituted or non- substituted C 6 -Ci 0 aryl, a N (R') (R'') amino group, where R' and
  • Ri 5 is hydrogen or halogen
  • R 19 is hydrogen, substituted or non-substituted C 1 -C 12 alkyl
  • R XI1 is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 - Ci 0 aryl; or N(R XI11 ) (R XIV ) amino, where R XI11 and R XIV are independently hydrogen or a C 1 -C 12 alkyl group); a [ (Ci-Ci 2 ) alkyl- 0- (C 1 -C 12 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond.
  • this substructure (Ia'') are: - 14-bromo-3-hydroxy-4 , 6b, 8a, 11, 12b, 14a-hexamethyl- 7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bff, 9ff-picene- 2,10-dione (C7);
  • the compounds of formula (Ia) used in the present invention comprise a substructure having the following formula (Ia' ' ' ) :
  • R 7 is hydrogen, hydroxyl, halogen, substituted or non- substituted C x -Ci 2 alkyl, substituted or non-substituted C 6 -Ci 0 aryl, or a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a C x -Ci 2 alkyl group; and
  • Ri 9 is substituted or non-substituted C x -Ci 2 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; or N(R XI11 ) (R XIV ) amino, where R XI11 and R XIV are independently hydrogen or a Ci-Ci 2 alkyl group); a [ (Ci-Ci 2 ) alkyl-O- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl .
  • this substructure (Ia'') are: 10-hydroxy-2, 4a, 6a, 9, 12b, 14a-hexamethyl-ll-oxo- 1,2, 3, 4, 4a, 5, 6, 6a, 11, 12b, 13, 14, 14a, 14b-tetradecahydro- picene-2-carboxylic acid methyl ester; 3, 10-dihydroxy-2 , 4a, 6a, 9, 12b, 14a-hexamethyl-ll-oxo- 1,2, 3, 4, 4a, 5, 6, 6a, 11, 12b, 13, 14, 14a, 14b-tetradecahydro- picene-2-carboxylic acid methyl ester (C12); 2, 4a, 6a, 9, 12b, 14a-hexamethyl-ll-oxo-10-propionyloxy- 1,2, 3, 4, 4a, 5, 6, 6a, 11, 12b, 13, 14, 14a, 14b-tetradecahydro- picene-2-carboxylic acid methyl ester (C13) ; -
  • the compound of formula (I) used in the prevention and/or treatment of a ChoK mediated disease or condition is a compound of formula (Ib) :
  • Ri, R 2 , R3, R4, R5, R ⁇ , R7, Re? Rn and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1 -
  • Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a Ci-Ci 2 alkyl group; or each pair can form a (C O) group together with the carbon to which they are attached;
  • R 9 and Ri 0 are independently hydrogen; substituted or non- substituted C x -Ci 2 alkyl; C 6 -Ci 0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; 0-Ci-Ci 2 alkyl; or N(R IV ) (R v ) amino, where R IV and R v are independently hydrogen or a Ci-Ci 2 alkyl group); a (CH 2 )
  • R 19 and R 20 are independently hydrogen, substituted or non- substituted C x -C 12 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -C 10 aryl; or N(R XI11 ) (R XIV ) amino, where R XI11 and R XIV are independently hydrogen or a C 1 -C 12 alkyl group); a [ (C 1 -C 12 ) alkyl-O- (C 1 -C 12 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond.
  • the compounds of formula (Ib) used in the present invention comprise a substructure having the following formula (Ib') :
  • Ri 9 and R 20 are independently substituted or non-substituted C 1 - C 12 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substituted or non-substituted Ci-Ci 2 alkyl; substituted or non- substituted C 6 -Ci 0 aryl; or N(R xlil ) amino, where R XI11 and R XIV are independently hydrogen or a C x -Ci 2 alkyl group) ; a [ (Ci- Ci 2 ) alkyl-0- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl .
  • a particular example of this substructure (Ib') is 4-nitro- (3-dimethylcarbamoyloxy-5, 9-dihydroxy-4 , 6b, 8a, 11, 12b, 14a- hexamethyl-10-oxo-5, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a- tetradecahydro-picene-2-yl) benzoic acid ester (C15).
  • the compounds of formula (Ib) comprise a substructure having the following formula (Ib") :
  • Ri 8 is hydrogen; hydroxyl ; halogen; Ci-Ci 2 alkyl ; C 6 -Ci 0 aryl ; COR IX
  • R IX is hydrogen; hydroxyl; C x -Ci 2 alkyl; N (R x ) (R XI ) amino, where R x and R XI are independently hydrogen or a C x -Ci 2 alkyl group; or C x -Ci 2 alcoxyl) ; or trifluoromethyl;
  • Ri 9 is hydrogen; substituted or non-substituted C x -Ci 2 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 - C 10 aryl; or N(R XI11 ) (R XIV ) amino, where R XI11 and R XIV are independently hydrogen or a C x -C 12 alkyl group); a [ (C x -C 12 ) alkyl- 0- (C x
  • R 23 is hydrogen; hydroxyl; halogen; substituted or non- substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -C 10 aryl; a N(R VI ) (R VI1 ) amino group, where R VI and R VI1 are independently hydrogen or a C 1 -C 12 alkyl group.
  • the compound of formula (I) used in the prevention and/or treatment of a ChoK mediated disease or condition is a compound of formula (Ic) :
  • R 9 and Ri 0 are independently hydrogen; substituted or non- substituted Ci-Ci 2 alkyl; C 6 -Ci 0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; 0-Ci-Ci 2 alkyl; or N(R IV ) (R v ) amino, where R IV and R v are independently hydrogen or a C x -Ci 2 alkyl group); a (CH 2 ) n -0H carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group; Ri 3 , Ri 4 , Ri 5 , Ri 6 , R 2 i and R 23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C x -Ci 2 alkyl
  • the compounds of formula (Ic) used in the present invention comprise a substructure having the following formula (Ic' ) :
  • Ri 9 and R 20 are independently hydrogen; substituted or non- substituted C x -Ci 2 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; or N(R XI11 ) (R XIV ) amino, where R XI11 and R XIV are independently hydrogen or a Ci-Ci 2 alkyl group); a [ (Ci-Ci 2 ) alkyl-O- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3) or trifluoromethyl; and the bond means a double bond or a single bond.
  • this substructure (Ic') are: 10, ll-dihydroxy-2 , 4a, 6a, 9, 14a-pentamethyl- 1,4, 4a, 5, 6, 6a, 13, 14,14a, 14b-decahydro-2fl-picene-3-one (C19) ; 10, ll-dihydroxy-2 , 4a, 6a, 9, 14a-pentamethyl-
  • the compounds of formula (Ic) used in the present invention comprise a substructure having the following formula (Ic'') :
  • Ri 9 and R 2 o are independently hydrogen; substituted or non- substituted Ci-Ci 2 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; or N(R X (R x amino, where R XI11 and R XIV are independently hydrogen or a C x -Ci 2 alkyl group); a [ (Ci-Ci 2 ) alkyl-0- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl .
  • a particular example of this substructure (Ic'') is 10, ll- dihydroxy-2 , 4a, 6a, 9, 14a-pentamethyl-
  • the compound of formula (I) used in the prevention and/or treatment of a ChoK mediated disease or condition is a compound of formula (Id):
  • R 9 and Ri 0 are independently hydrogen; substituted or non- substituted Ci-Ci 2 alkyl; C 6 -Ci 0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; 0-Ci-Ci 2 alkyl; or N(R IV ) (R v ) amino, where R IV and R v are independently hydrogen or a Ci-Ci 2 alkyl group); a (CH 2 ) n -0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group, Ri3 ?
  • R21 and R 23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C x -Ci 2 alkyl; substituted or non- substituted C 6 -Ci 0 aryl ; a N (R VI ⁇ ) / ( T R 1 VI I i amino group, where
  • R 18 is hydrogen; hydroxyl ; halogen; C x -C 12 alkyl ; C 6 -C 10 aryl ; COR IX (where R IX i s hydrogen; hydroxyl ; C 1 -C 12 alkyl ; N (R x ) (R XI ) amino , where R x and R XI are independently hydrogen or a C 1 -C 12 alkyl group ; or C 1 -C 12 alcoxyl ) ; or tri f luoromethyl ; Ri 9 , Rig ' , R 20 and R 20 - are independently hydrogen; substituted or non-substituted Ci-Ci 2 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substitute
  • the compounds of formula (Id) used in the present invention comprise a substructure having the following formula (Id') :
  • this substructure (Id') are: l-bromo-9-hydroxy-4 , 6b, 8a, 11, 12b, 14b-hexamethyl- 6b, 7, 8, 8a, 9,11, 12 , 12a, 12b, 14b-decahydro-lH-picene-2 , 3, 10- trione (C22); - l-bromo-4, 6b, 8a, 11, 12b, 14b-hexamethyl-
  • the compounds of formula (Id) used in the present invention comprise a substructure having the following formula (Id'') :
  • the compound of formula (I) used in the prevention and/or treatment of a ChoK mediated disease or condition is a compound of formula (Ie) :
  • Ri 8 and Ri 8 - are independently hydrogen; hydroxyl ; halogen ; C x -Ci 2 alkyl ; C 6 -Ci 0 aryl ; COR IX (where R IX i s hydrogen; hydroxyl ; C x -Ci 2 alkyl ; N (R X ) (R XI ) amino , where R x and R XI are independently hydrogen or a C x -Ci 2 alkyl group; or C x -Ci 2 alcoxyl ) ; or trifluoromethyl ;
  • R 19 , R 19 -, R 20 and R 20 - are independently hydrogen; substituted or non-substituted C x -Ci 2 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -C 10 aryl; or N(R ' XII I v / RXIV) ammo , where R XI11 and R XIV are independently hydrogen or a C X -C X2 alkyl group); a [ (C x -C 12 ) alkyl-O- (C x -C 12 ) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or
  • R 24 is hydrogen, hydroxyl or halogen; and the bond means a double bond or a single bond.
  • the compounds of formula (Ie) used in the present invention comprise a substructure having the following formula (Ie') :
  • R 18 and R 18 - are independently hydrogen; hydroxyl; halogen; C 1 -C 12 alkyl; C 6 -C 10 aryl; COR IX (where R IX is hydrogen; hydroxyl; C 1 -C 12 alkyl; N(R X ) (R XI ) amino, where R x and R XI are independently hydrogen or a Ci-Ci 2 alkyl group; or C x -Ci 2 alcoxyl); or trifluoromethyl ;
  • a particular example of this substructure (Ie') is 9- hydroxy-2 , 4a, 6a, 9, 12b-hexamethyl-10 , 11-dioxo- 1,2, 3, 4, 4a, 5, 6, 6a, 9, 10, 11, 12b, 13, 14 , 14a, 14b-hexadecahydro- picene-2-carboxylic acid methyl ester (C25) .
  • the compound of formula (I) used in the prevention and/or treatment of a ChoK mediated disease or condition is a compound of formula (If) :
  • R 18 and R 18 - are independently hydrogen; hydroxyl; halogen; C 1 -C 12 alkyl; C 6 -C 10 aryl; COR IX (where R IX is hydrogen; hydroxyl; C 1 -C 12 alkyl; N(R X ) (R XI ) amino, where R x and R XI are independently hydrogen or a C 1 -C 12 alkyl group; or C 1 -C 12 alcoxyl); or trifluoromethyl ;
  • Ri 8 and Ri 8 are independently hydrogen; hydroxyl; halogen; Ci-Ci 2 alkyl; C 6 -Ci 0 aryl; C0R IX (where R IX is hydrogen; hydroxyl; C x -Ci 2 alkyl; N(R X ) (R XI ) amino, where R x and R XI are independently hydrogen or a C x -Ci 2 alkyl group; or C x -Ci 2 alcoxyl); or trifluoromethyl ;
  • R 24 is hydrogen, hydroxyl or halogen.
  • a particular example of this substructure (If) is the 9- hydroxy-2 , 4a, 6a, 6b, 9-hexamethyl-10, 11-dioxo- 1,2, 3, 4, 4a, 5, 6, 6a, 6b, 8a, 9, 10, 11, 14, 14a, 14b-hexadecahydro-picene- 2-carboxylic acid methyl ester (C26).
  • the compound of formula (II) used in the prevention and/or treatment of a ChoK mediated disease or condition is a compound of formula (Ha) :
  • R 7 and R 8 are independently hydrogen; substituted or non- substituted Ci-Ci 2 alkyl; C 6 -Ci 0 aryl; a COR XVI1 group (where R XVI1 is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; 0-Ci-Ci 2 alkyl; or N(R XVI11 ) (R XIX ) amino, where R XVI11 anc ⁇ R XIX are independently hydrogen or a C x -Ci 2 alkyl group); a (CH 2 ) n -0H carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group,
  • R 2 i and R 24 are independently substituted or non-substituted Ci- Ci 2 alkyl; a COR XX group (where R xx is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non- substituted C 6 -Ci 0 aryl; or N(R X X X I i ⁇ ) ( / T R 1 XXII i amino, where R XXI and R XXI1 are independently hydrogen or a C x -Ci 2 alkyl group) ; a [ (Ci- Ci 2 ) alkyl-O- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; R 22 and R 23 are: hydrogen; substituted or non-substituted C x -Ci 2 alkyl; a COR XX group (where R xx is hydrogen;
  • R XXIV and R xxv are independently hydrogen or a C x -Ci 2 alkyl group); a [ (Ci-Ci 2 ) alkyl-O- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R 24 is in the para position with respect to R 20 ; or
  • OR 22 ' and OR 23 ' respectively, where R 22 ' and R 23 ' are independently hydrogen; substituted or non-substituted C 1 -
  • Ci 2 alkyl a COR XXVI group (where R XXVI is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; or N (R XXVI1 ) (R XXVI11 ) amino, where R XXVI1 and R XXVI11 are independently hydrogen or a Ci-Ci 2 alkyl group); a [ (Ci-Ci 2 ) alkyl-O- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R 24 is in the meta position with respect to R 20 .
  • R XXVI is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; or N (R
  • the compounds of formula (Ha) used in the present invention comprise a substructure having the following formula (Ha') :
  • Ri 9 and R 20 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C x -Ci 2 alkyl; substituted or non- substituted C 6 -Ci 0 aryl; a N(R XV ) (R XVI ) amino group, where R xv and
  • this substructure (Ha') is: 8- [2- ( 6, 7-dihydroxy-l , 5-dimethyl-naphthalen-2-yl) -ethyl ] -2 , 4a- tetramethyl-1 ,2, 3, 4, 4a, 5, 6, 7-octahydro-naphthalen-2-carboxylic acid methyl ester (C27) .
  • the compounds of the invention act as blocking agents of the biosynthesis of phosphorylcholine by means of the selective blocking of the choline kinase (ChoK) enzyme and have shown a selective effect on signaling pathways necessary for the transformation by certain oncogenes which do not affect normal cells with the same intensity and therefore leave a sufficient margin for a greater efficacy in the tumor treatment.
  • ChoK choline kinase
  • the Chok mediated disease or condition to be prevented or treated is cancer, preferably selected from breast, lung, colorectal and pancreatic cancer.
  • the biological assays carried out allow extending the use of the compounds described in the present invention for the treatment of viral, parasitic, bacterial and fungal conditions because some parasites such as Plasmodium falciparum or Trypanosoma cruci, some viruses such as adenovirus, bacteria such as Streptococcus pneumoniae and fungi such as Candida albicans require the metabolic phosphatidylcholine synthesis pathway through choline kinase to complete its infective cycles in humans and animals.
  • parasites such as Plasmodium falciparum or Trypanosoma cruci
  • viruses such as adenovirus
  • bacteria such as Streptococcus pneumoniae
  • fungi such as Candida albicans
  • the bibliographic background supports the role of the ChoK enzyme in the intracellular metabolism of certain nucleosides in Hep-G2 cells, the use of said enzyme as an enzymatic marker in parasitic diseases and the participation thereof in the biosynthesis of important phospholipids in viruses, bacteria and fungi. Consequently, in another embodiment the ChoK mediated disease or condition to be prevented and/or treated is a viral disease, preferably that caused by Adenovirus .
  • the ChoK mediated disease or condition to be prevented and/or treated is a parasitic disease, preferably that caused by Plasmodium or Trypanosoma .
  • the ChoK mediated disease or condition to be prevented and/or treated is bacterial disease, preferably that caused by Streptococcus .
  • the ChoK mediated disease or condition to be prevented and/or treated is a fungal disease, preferably that caused by Candida.
  • Another object of the present invention are the compounds of general formula (I) :
  • Ri 8 and Ri 8 are independently hydrogen; hydroxyl; halogen; C x -Ci 2 alkyl; C 6 -Ci 0 aryl; COR IX (where R IX is hydrogen; hydroxyl; C x -Ci 2 alkyl; N(R X ) (R XI ) amino, where R x and R XI are independently hydrogen or a C x -Ci 2 alkyl group; or C x -Ci 2 alcoxyl); or trifluoromethyl ;
  • R 5 is hydroxyl
  • the invention is directed to compounds of formula (Ia) :
  • R IX is hydrogen; hydroxyl; C x -Ci 2 alkyl; N (R x ) (R XI ) amino, where R x and R XI are independently hydrogen or a C x -C 12 alkyl group; or C x -C 12 alcoxyl) ; or trifluoromethyl;
  • R 19 is hydrogen; substituted or non-substituted C x -C 12 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 - C 10 aryl; or N(R XI11 ) (R XIV ) amino, where R XI11 and R XIV are independently hydrogen or a C 1 -C 12 alkyl group); a [ (C 1 -C 12 ) alkyl- 0- (C 1 -C 12 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond, with the proviso that the compound of formula (Ia) is not: - 10-Hydroxy-2 , 4a, 6a, 9, 12b, 14a-hexamethyl-ll-ox
  • the compounds of formula (Ia) comprise a substructure having the following formula (Ia' ) :
  • R 5 is hydroxyl or a OCOR group where R is (CH 2 J 2 COOH or (CH 2 ) 2 CO 2 CH 2 CH 3 ;
  • R i2 is independently hydrogen or a halogen
  • Ri 9 is hydrogen; substituted or non-substituted C x -Ci 2 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 - Ci 0 aryl; or N(R XI11 ) (R XIV ) amino, where R XI11 and R XIV are independently hydrogen or a C x -Ci 2 alkyl group); a [ (C x -C 12 ) alkyl- 0- (C x -C 12 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond, with the proviso that the compound of formula (Ia') is not: - 10-Hydroxy-2 , 4a, 6a, 9, 12b, 14a-
  • Nicotinic acid 9-hydroxy-4 , 6b, 8a, 11 , 12b, 14a-hexamethyl-2, 10- dioxo-2, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a- tetradecahydro-picen-3-yl ester;
  • this substructure (Ia') are: 9-hydroxy-4 , 6b, 8a, 11, 12b, 14a-hexamethyl-2 , 10-dioxo- 2,6b,7,8,8a,9,10,ll,12,12a,12b,13,14,14a-tetradecahydro- picene-3-yl propionic acid ester (Cl);
  • the compounds of formula (Ia) comprise a substructure having the following formula (Ia") :
  • Ri 9 is hydrogen, substituted or non-substituted C x -Ci 2 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 - Ci 0 aryl; or N(R XI11 ) (R XIV ) amino, where R XI11 and R XIV are independently hydrogen or a C x -Ci 2 alkyl group); a [ (Ci-Ci 2 ) alkyl- 0- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond, with the proviso that the compound of formula (Ia'') is not: - 3-Hydroxy-4, 6b, 8a, 11, 12b, 14a-hex
  • this substructure (Ia'') are: - 14-bromo-3-hydroxy-4 , 6b, 8a, 11, 12b, 14a-hexamethyl- 7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bff, 9ff-picene- 2,10-dione (C7);
  • the compounds of formula [Ia) comprise a substructure having the following formula :ia'") :
  • R 7 is hydrogen, hydroxyl, halogen, substituted or non- substituted C x -Ci 2 alkyl, substituted or non-substituted C 6 -Ci 0 aryl, or a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a C x -Ci 2 alkyl group; and
  • Ri 9 is substituted or non-substituted C x -Ci 2 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; or N(R XI11 ) (R XIV ) amino, where R XI11 and R XIV are independently hydrogen or a Ci-Ci 2 alkyl group); a [ (Ci-Ci 2 ) alkyl-O- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; with the proviso that the compound of formula (Ia''') is not: - 3 , 10-Dihydroxy-2 , 4a, 6a, 9, 12b, 14a-hexamethyl-ll-oxo-
  • this substructure (Ia''') are: 2, 4a, 6a, 9, 12b, 14a-hexamethyl-ll-oxo-10-propionyloxy- 1,2, 3, 4, 4a, 5, 6, 6a, 11, 12b, 13, 14, 14a, 14b-tetradecahydro- picene-2-carboxylic acid methyl ester (C13) ;
  • Ri 8 is hydrogen; hydroxyl; halogen; C x -Ci 2 alkyl; C 6 -C 10 aryl; COR IX (where R IX is hydrogen; hydroxyl; C x -Ci 2 alkyl; N (R x ) (R XI ) amino, where R x and R XI are independently hydrogen or a C x -Ci 2 alkyl group; or C x -C 12 alcoxyl) ; or trifluoromethyl;
  • R 19 and R 20 are independently hydrogen, substituted or non- substituted C x -C 12 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -C 10 aryl; or N(R XI11 ) (R XIV ) amino, where R XI11 and R XIV are independently hydrogen or a C 1 -C 12 alkyl group); a [ (C 1 -C 12 ) alkyl-O- (C 1 -C 12 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond, with the proviso that when R 19 and R 20 are independently hydrogen or an acyl group, then: R 5 is hydroxyl; or
  • the compounds of formula (Ib) comprise a substructure having the following formula (Ib') :
  • Ri 9 and R 20 are independently substituted or non-substituted C 1 - C 12 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substituted or non-substituted Ci-Ci 2 alkyl; substituted or non- substituted C 6 -Ci 0 aryl; or N(R xlil ) amino, where R XI11 and R XIV are independently hydrogen or a C x -Ci 2 alkyl group) ; a [ (Ci- Ci 2 ) alkyl-0- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl .
  • a particular example of this substructure (Ib') is 4-nitro- (3-dimethylcarbamoyloxy-5, 9-dihydroxy-4 , 6b, 8a, 11, 12b, 14a- hexamethyl-10-oxo-5, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a- tetradecahydro-picene-2-yl) benzoic acid ester (C15).
  • the compounds of formula (Ib) comprise a substructure having the following formula (Ib") :
  • Ri 8 is hydrogen; hydroxyl ; halogen; Ci-Ci 2 alkyl ; C 6 -Ci 0 aryl ; COR IX
  • R IX is hydrogen; hydroxyl; C x -Ci 2 alkyl; N (R x ) (R XI ) amino, where R x and R XI are independently hydrogen or a C x -Ci 2 alkyl group; or C x -Ci 2 alcoxyl) ; or trifluoromethyl;
  • Ri 9 is hydrogen; substituted or non-substituted C x -Ci 2 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 - C 10 aryl; or N(R XI11 ) (R XIV ) amino, where R XI11 and R XIV are independently hydrogen or a C x -C 12 alkyl group); a [ (C x -C 12 ) alkyl- 0- (C x
  • R 23 is hydrogen; hydroxyl; halogen; substituted or non- substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -C 10 aryl; a N(R VI ) (R VI1 ) amino group, where R VI and R VI1 are independently hydrogen or a C 1 -C 12 alkyl group.
  • the invention is directed to compounds of formula (Ic) :
  • R 9 and Ri 0 are independently hydrogen; substituted or non- substituted Ci-Ci 2 alkyl; C 6 -Ci 0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; 0-Ci-Ci 2 alkyl; or N(R IV ) (R v ) amino, where R IV and R v are independently hydrogen or a C x -Ci 2 alkyl group) ; a (CH 2 ) n -0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group; Ri 3 , Ri 4 , Ri 5 , Ri 6 , R 2 i and R 23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C x -Ci
  • the compounds of formula (Ic) comprise a substructure having the following formula (Ic') :
  • Ri 9 and R 20 are independently hydrogen; substituted or non- substituted C x -Ci 2 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; or N(R XI11 ) (R XIV ) amino, where R XI11 and R XIV are independently hydrogen or a C x -Ci 2 alkyl group); a [ (Ci-Ci 2 ) alkyl-O- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3) or trifluoromethyl; and the bond means a double bond or a single bond.
  • this substructure (Ic') are: 10, ll-dihydroxy-2 , 4a, 6a, 9, 14a-pentamethyl-
  • [Ic) comprise a substructure having the following formula lie”) :
  • Ri 9 and R 2 o are independently hydrogen; substituted or non- substituted Ci-Ci 2 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; or N(R XI11 ) (R XIV ) amino, where R XI11 and R XIV are independently hydrogen or a Ci-Ci 2 alkyl group); a [ (Ci-Ci 2 ) alkyl-0- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl .
  • a particular example of this substructure (Ic'') is 10, ll- dihydroxy-2 , 4a, 6a, 9, 14a-pentamethyl-
  • the invention is directed to compounds of formula (Id) :
  • R 9 and Ri 0 are independently hydrogen; substituted or non- substituted Ci-Ci 2 alkyl; C 6 -Ci 0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; 0-Ci-Ci 2 alkyl; or N(R IV ) (R v ) amino, where R IV and R v are independently hydrogen or a Ci-Ci 2 alkyl group); a (CH 2 ) n -0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group, Ri3 ?
  • R21 and R 23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C x -Ci 2 alkyl; substituted or non- substituted C 6 -Ci 0 aryl ; a N (R VI ⁇ ) / ( T R 1 VI I i amino group, where
  • R 18 is hydrogen; hydroxyl ; halogen; C x -C 12 alkyl ; C 6 -C 10 aryl ; COR IX (where R IX i s hydrogen; hydroxyl ; C 1 -C 12 alkyl ; N (R x ) (R XI ) amino , where R x and R XI are independently hydrogen or a C 1 -C 12 alkyl group ; or C 1 -C 12 alcoxyl ) ; or tri f luoromethyl ; Ri 9 , Rig ' , R 20 and R 20 - are independently hydrogen; substituted or non-substituted Ci-Ci 2 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substitute
  • the compounds of formula (Id) comprise a substructure having the following formula (Id') :
  • the compounds of formula (Id) comprise a substructure having the following formula (Id") :
  • the invention is directed to compounds of formula (Ie) :
  • Ri 8 and Ri 8 ' are independently hydrogen; hydroxyl; halogen; Ci-Ci 2 alkyl; C 6 -Ci 0 aryl; COR IX (where R IX is hydrogen; hydroxyl; C x -Ci 2 alkyl; N(R X ) (R XI ) amino, where R x and R XI are independently hydrogen or a C x -Ci 2 alkyl group; or C x -Ci 2 alcoxyl); or trifluoromethyl ;
  • Ri 9 , Ri 9' , R 2 o and R 20 are independently hydrogen; substituted or non-substituted C x -Ci 2 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -C 10 aryl; or N(R ' XII I v / RXIV) ammo , where R XI11 and R XIV are independently hydrogen or a C x -Ci 2 alkyl group); a [ (Ci-Ci 2 ) alkyl-O- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3) ; trifluoromethyl; or each 19-19' or
  • R 24 is hydrogen, hydroxyl or halogen; and the bond means a double bond or a single bond.
  • the compounds of formula lie) comprise a substructure having the following formula (Ie' ) :
  • Ri 8 and Ri 8 - are independently hydrogen; hydroxyl; halogen; C x -Ci 2 alkyl; C 6 -C 10 aryl; COR IX (where R IX is hydrogen; hydroxyl; C x -C 12 alkyl; N(R X ) (R XI ) amino, where R x and R XI are independently hydrogen or a C 1 -C 12 alkyl group; or C 1 -C 12 alcoxyl); or trifluoromethyl ; Ri 9 , Rig ' , R 20 and R 20 - are independently hydrogen; substituted or non-substituted Ci-Ci 2 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; or N(R XI11 ) (R XIV )
  • a particular example of this substructure (Ie') is 9- hydroxy-2 , 4a, 6a, 9 , 12b-hexamethyl-10 , 11-dioxo- 1,2, 3, 4, 4a, 5, 6, 6a, 9, 10, 11, 12b, 13, 14 , 14a, 14b-hexadecahydro- picene-2-carboxylic acid methyl ester (C25) .
  • the invention is directed to compounds of formula (If) :
  • the compounds of formula (If) comprise a substructure having the following formula (If ) :
  • Ri 8 and Ri 8 - are independently hydrogen ; hydroxyl ; halogen ; Ci-Ci 2 alkyl ; C 6 -Ci 0 aryl ; C0R IX (where R IX i s hydrogen ; hydroxyl ; C x -Ci 2 alkyl ; N ( R X ) ( R XI ) amino , where R x and R XI are independently hydrogen or a C x -Ci 2 alkyl group ; or C x -Ci 2 alcoxyl ) ; or trifluoromethyl ;
  • Rig, Rig-, R 20 and R 20 - are independently hydrogen; substituted or non-substituted C x -Ci 2 alkyl; a COR XI1 group (where R XI1 is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -C 10 aryl; or N(R XI11 ) (R XIV ) amino, where R XI11 and R XIV are independently hydrogen or a C x -Ci 2 alkyl group); a [ (Ci-Ci 2 ) alkyl-0- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3) ; trifluoromethyl; or each 19-19' or
  • R 24 is hydrogen, hydroxyl or halogen.
  • a particular example of this substructure (If) is the 9- hydroxy-2 , 4a, 6a, 6b, 9-hexamethyl-10, 11-dioxo-
  • Another aspect of the invention is formed by compounds of formula (II) :
  • R I9 and R 2 o are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-Ci 2 alkyl; substituted or non- substituted C 6 -Ci 0 aryl ; a N ( R X X V V N ) ( / ⁇ RXVI N amino group, where R xv and
  • R 7 and R 8 are independently hydrogen; substituted or non- substituted C x -Ci 2 alkyl; C 6 -Ci 0 aryl; a COR XVI1 group (where R XVI1 is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; 0-Ci-Ci 2 alkyl; or N(R XVI11 ) (R XIX ) amino, where R XVI11 anc ⁇ R XIX are independently hydrogen or a C x -Ci 2 alkyl group); a (CH 2 ) n -0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group,
  • R 2 i and R 24 are independently substituted or non-substituted Ci- Ci 2 alkyl; a COR XX group (where R xx is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non- substituted C 6 -Ci 0 aryl ; or N ( R X X X I 1 N ) ( / -RT 1 XXI I , amino , where R XXI and R XXII are independently hydrogen or a C x -Ci 2 alkyl group) ; a [ (C x - C 12 ) alkyl-O- (C x -C 12 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; R 22 and R 23 are: hydrogen; substituted or non-substituted C x -C 12 alkyl; a COR XX group (where R xx
  • R XXIV and R xxv are independently hydrogen or a C x -Ci 2 alkyl group); a [ (Ci-Ci 2 ) alkyl-O- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R 24 is in the para position with respect to R 20 ; or
  • OR 22 ' and OR 23 ' respectively, where R 22 ' and R 23 ' are independently hydrogen; substituted or non-substituted C 1 -
  • Ci 2 alkyl a COR XXVI group (where R XXVI is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; or N (R XXVI1 ) (R XXVI11 ) amino, where R XXVI1 and R XXVI11 are independently hydrogen or a Ci-Ci 2 alkyl group); a [ (Ci-Ci 2 ) alkyl-O- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R 24 is in the meta position with respect to R 20 . or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof.
  • the invention is directed to compounds of formula (Ha) :
  • R 2 i and R 24 are independently substituted or non-substituted C 1 - Ci 2 alkyl; a COR XX group (where R xx is hydrogen; hydroxyl; substituted or non-substituted C x -Ci 2 alkyl; substituted or non- substituted C 6 -Ci 0 aryl; or N(R XXI ) (R XXI1 ) amino, where R XXI and R XXI1 are independently hydrogen or a C x -Ci 2 alkyl group) ; a [ (C 1 - Ci 2 ) alkyl-O- (Ci-Ci 2 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; R 22 and R 23 are: hydrogen; substituted or non-substituted C x -Ci 2 alkyl; a COR XXIII group (where R XXI11 -j_ s hydrogen
  • the compounds of formula (Ha) comprise a substructure having the following formula (Ha') :
  • Ri 9 and R 20 are independently hydrogen ; hydroxyl ; halogen ; substituted or non- substituted Ci-Ci 2 alkyl ; substituted or non- substituted C 6 -Ci 0 aryl; a N(R X X V V N ) (/ ⁇ RXVIv amino group, where R and
  • R 2 i and R 24 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C x -Ci 2 alkyl; substituted or non- substituted C 6 -Ci 0 aryl; a N(R XXI ) (R XXI1 ) amino group, where R XXI and
  • this substructure (Ha') is: 8- [2- ( 6, 7-dihydroxy-l , 5-dimethyl-naphthalen-2-yl) -ethyl ] -2 , 4a- tetramethyl-1 ,2, 3, 4, 4a, 5, 6, 7-octahydro-naphthalen-2-carboxylic acid methyl ester (C27) .
  • the present invention relates to a process for preparing compounds of formula (I) comprising the following features: a) The usual methodology for the chemoselective introduction in the hydroxyl in C-3 of the natural Friedelane derivative of the chemical family of pristimerin-related methylene triterpenequinones requires an analysis of the basicity conditions for abstracting the phenolic proton and subsequent reaction with the indicated acylation agents or agents of another type. It is relevant that if the pH control is not appropriate, reactions on C-6 that complicate the synthetic process occur. b) The method for the chemoselective introduction in C-23 of the indicated groups will be carried out by controlled oxidation with specific reagents for allyl aromatic systems and subsequent transformations of the functionality thus obtained.
  • pharmaceutically acceptable salts, solvates, prodrugs refers to any pharmaceutically salt, ester, solvate or any other compound which when administered to a receptor is able to provide (directly or indirectly) a compound as described in the present document.
  • pharmaceutically unacceptable salts are also within the scope of the invention because the latter can be useful in the preparation of pharmaceutically acceptable salts.
  • the preparation of salts, prodrugs and derivatives can be carried out by means of methods known in the art.
  • salts of compounds provided in the present document are synthesized by means of conventional chemical methods from an original compound containing a basic or acid residue.
  • Such salts are generally prepared, for example, by reacting the free acid or base forms of the compounds with a stoichiometric amount of the suitable base or acid in water or an organic solvent or a mixture of both.
  • Non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are generally preferred.
  • acid addition salts include mineral acid addition salts such as for example, hydrochloride, bromohydrate, iodohydrate, sulfate, nitrate, phosphate and organic acid addition salts such as for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p- toluenesulfonate .
  • base addition salts include inorganic salts such as for example sodium, potassium, calcium, ammonium, magnesium, aluminium and lithium salts and organic base salts such as for example ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glucamine and basic amino acid salts.
  • the particularly preferred derivatives or prodrugs are those increasing the bioavailability of the compounds of this invention when such compounds are administered to a patient (for example, by making a compound administered orally be absorbed more easily by blood) , or enhancing the release of the original compound in a biological compartment (for example, the brain or the lymphatic system) in relation to the original species.
  • prodrug is used in its widest sense and includes those derivatives which are converted in vivo into the compounds of the invention. Such derivatives are evident for the persons skilled in the art and depending on the functional groups present in the molecule and without limitation, include the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salt sulfonate esters, carbamates and amides. Examples of methods for producing a prodrug of a given active compound are known by the person skilled in the art and can be found for example in Krogsgaard- Larsen et al .
  • the compounds of the invention can be in crystalline form as free compounds or as solvates and it is intended that both of them are within the scope of the present invention.
  • the solvation methods are generally known in the art.
  • the suitable solvates are pharmaceutically acceptable solvates.
  • the solvate is a hydrate.
  • the compounds of the present invention represented by the formula (I) described previously can include enantiomers, depending on the presence of chiral centers on a C, or isomers, depending on the presence of multiple bonds (for example, Z, E) .
  • the individual isomers, enantiomers or diastereoisomers and the mixtures thereof are included within the scope of the present invention .
  • hydroxyl groups act as hydrogen bond donors and intra or intermolecular links can be established even in the case of phenols.
  • the presence of carbonyl or carboxyl groups generates proton acceptor groups in the molecule.
  • the presence of halogens generates very deficient carbons and considerably modifies the biological properties.
  • the amino groups generate good nucleophiles on the molecule and in most cases significantly modify its polarity and polarizability and the presence of additional alkyl and/or aryl groups increases the lypophilicity of the molecules.
  • the present invention additionally provides pharmaceutical compositions comprising a compound of formula (I), (Ia), (Ia') ,
  • compositions can be administered by any suitable administration route, for example an oral, topical, rectal or parenteral route (including subcutaneous, intraperitoneal, intradermal, intramuscular and intravenous route) .
  • Suitable pharmaceutical forms for oral administration include any solid composition (tablets, pastilles, capsules, granules, etc.) or liquid composition (solutions, suspensions, emulsions, syrups, etc.) and can contain conventional excipients known in the art, such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, cornstarch, calcium fosfate, sorbitol or glycine; lubricants for the preparation of tablets, for example magnesium stearate, disintegrants, for example starch, polyvinylpirrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium laurylsulfate .
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose
  • Solid oral compositions can be prepared by means of conventional methods for mixing, filling or preparing tablets.
  • the repeated mixing operations can be used to distribute the active ingredient through the entire compositions by using large amounts of filler agents. Such operations are conventional in the art.
  • the tablets can be prepared, for example by means of wet or dry granulation and can be optionally coated according to methods well known in normal pharmaceutical practice, particularly with an enteric coating.
  • compositions can also be adapted for parenteral administration such as sterile solutions, suspensions or lyophilized products in a suitable unitary pharmaceutical form.
  • Suitable excipients such as bulk agents, buffering agents or surfactants can be used.
  • the mentioned formulations will be prepared using usual methods such as those described or referred to in Spanish Pharmacopoeia and the Pharmacopoeia of the United States and in similar reference texts.
  • the administration of the compounds or compositions used in the present invention can be by any suitable method, such as intravenous infusion, oral preparations and intraperitoneal and intravenous administration. Nevertheless, the preferred administration route will depend on the patient's condition. Oral administration is preferred due to the comfort for the patient and the chronic character of the diseases which are to be treated.
  • the compounds of formula (I) and formula (II) will preferably be found in pharmaceutically acceptable or substantially pure form, i.e. the compounds of formula (I) and formula (II) have a pharmaceutically acceptable purity level excluding the pharmaceutically acceptable excipients and not including material considered to be toxic at the normal dosage levels.
  • the purity levels for a compound of formula (I) or for a compound of formula (II) preferably exceed 50%, more preferably exceed 70%, more preferable exceed 90%. In a preferred embodiment, they exceed 95%.
  • the therapeutically effective amount of the compound of formula (I) or of the compound of formula (II) to be administered will generally depend, among other factors, on the individual who is to be treated, on the severity of the disease said individual suffers from, on the administration form chosen etc. For this reason, the doses mentioned in this invention must be considered as guides for the person skilled in the art and the latter must adjust the doses according to the variables mentioned previously. Nevertheless, a compound of formula (I) can be administered once or more times a day, for example, 1, 2, 3 or 4 times a day in a typical daily total amount comprised between 1 and 200 mg/kg body mass/day, preferably 1-10 mg/kg body mass/day.
  • a compound of formula (II) can be administered once or more times a day, for example, 1, 2, 3 or 4 times a day in a typical daily total amount comprised between 1 and 200 mg/kg body mass/day, preferably 1-10 mg/kg body mass/day.
  • the compounds described in this invention, their pharmaceutically acceptable salts, prodrugs and/or solvates, as well as the pharmaceutical compositions containing them can be used together with other additional drugs to provide a combination therapy.
  • Said additional drugs can form part of the same pharmaceutical composition or can alternatively be provided in the form of a separate composition for its simultaneous or non-simultaneous administration with the pharmaceutical composition comprising a compound of formula (I) or of formula (II), or a pharmaceutically acceptable prodrug, solvate or salt thereof .
  • the other drugs can form part of the same composition or be provided as a separate composition for its administration at the same time or at different times.
  • a last object of the invention is formed by a compound of formula (I), (Ia), (Ia'), (Ia”), (Ia'"), (Ib), (Ib'), (Ib"),
  • a total of 41 fractions were obtained which were gathered in seven groups (A, B, C, D, E, F and G) according to thin layer chromatography. These groups were in turn fractioned in sephadex LH-20 columns, in medium pressure silica gel columns and in preparation plates, from which the starting compound 22 ⁇ -hydroxy-tingenone or [3, 9-dihydroxy- 6b, 8a, 11, 12b, 14a-hexamethyl-7 , 8 , 8a, 11, 12, 12a, 12b, 13, 14, 14a- decahydro-6bH, 9H-picen-2, 10-dione] was obtained.
  • Recombinant human alpha-1 choline kinase expressed in E. coli in the assay of the buffer 100 inM Tris-HCl pH 8.0, 100 inM MgCl 2 , 10 mM ATP and 200 ⁇ M of choline in the presence of methyl [ 14 C] -choline chloride (50-60 ⁇ Ci/mmol) were used for the ex vivo assays.
  • the reactions were carried out at 37° C for 30 min and were stopped with trichloroacetic acid cooled with ice at a final 16% concentration.
  • the samples were washed with diethyl ether saturated with water and were lyophilized.
  • hydrophilic choline derivatives were resolved in thin layer chromatography plates according to a described process [Ramirez, A., Penalva, V., Lucas, L., Lacal, J. C. Oncogene 21, 937-946 (2002) ] .
  • HT-29 cells were seeded in 24-well plates (35 H 10 3 cells/well) and were incubated for 24 h. Then, the cells were treated with different concentrations of ChoK inhibitors in the usual culture medium. Three days later, the wells were aspirated and both fresh medium and more drug was added, and the cells were kept for 3 more days. The quantification of the cells remaining in each well was carried out by means of the Crystal Violet method [Gillies, R. J., Didier, N., Denton, M. Anal. Biochem. 159, 109-113 (1986)], with some modifications [Hernandez-Alcoceba, R., Saniger, L., Campos, J., Nunez, M.
  • This value is determined by the iterative adjustment of the curve. Two values were determined for each point of the curve, the experiment was repeated two or three times and the average values were estimated. In the few cases in which the two values differed by more than 50%, a third experiment was carried out to determine the real value.
  • the IC 50 value as a measurement of the potency is used to relate the biological activity of the compounds with their chemical structure. These assays are carried out with the compounds of the invention C3, Cl 1 C8, C9, ClO, C12 and C14 as well as with another eight compounds known in the state of the art (ES 2 117 950) . The results are summarized in table I.

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Abstract

La présente invention concerne des dérivés de triterpènequinone et de triterpènephénol, leurs sels promédicaments, solvates ou stéréo-isomères pharmaceutiquement acceptables, en tant qu'agents bloquants sélectifs de l'enzyme choline kinase, des compositions pharmaceutiques les contenant et leur utilisation pour le traitement de tumeurs et de maladies parasitaires ou de maladies causées par des virus, des bactéries ou des champignons.
EP06830856A 2005-12-30 2006-12-29 Derives de triterpenequinone et de triterpenephenol et leur application pour le traitement de tumeurs et de maladies parasitaires Withdrawn EP1976533A2 (fr)

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ES200503263A ES2277568B1 (es) 2005-12-30 2005-12-30 Derivados de triterpenoquinona y triterpenofenoles y su aplicacion para el tratamiento de tumores y enfermedades parasitarias.
PCT/EP2006/070276 WO2007077203A2 (fr) 2005-12-30 2006-12-29 Derives de triterpenequinone et de triterpenephenol et leur application pour le traitement de tumeurs et de maladies parasitaires

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WO2009026163A1 (fr) * 2007-08-17 2009-02-26 Burnham Institute For Medical Research Compositions et procédés pour inhiber la croissance et la métastase d'un mélanome
CN101434635B (zh) 2007-11-16 2012-05-16 上海华拓医药科技发展股份有限公司 一类具抗肿瘤活性的水溶性酚性三萜化合物及其制备方法
US20100068302A1 (en) * 2008-09-17 2010-03-18 Traslational Cancer Drugs Pharma, S.L. Methods and compositions for the treatment of cancer
WO2010049173A1 (fr) * 2008-10-31 2010-05-06 Cenix Bioscience Gmbh Utilisation d’inhibiteurs de kinases hôtes pour traiter les maladies infectieuses
US8691977B2 (en) * 2010-08-23 2014-04-08 Neupharma, Inc. Certain chemical entities, compositions, and methods
AU2016342375B2 (en) 2015-10-23 2022-03-17 Erx Pharmaceuticals Inc Analogs of celastrol
US10808005B2 (en) 2016-07-04 2020-10-20 Ixmedicine (Xiamen) Biological Technology Company Limited Ligand for orphan nuclear receptor Nur77 and uses thereof
CN109790164B (zh) 2016-07-25 2022-01-25 内尔维亚诺医疗科学公司 作为胆碱激酶抑制剂的嘌呤和3-去氮杂嘌呤类似物
JP7178401B2 (ja) 2017-07-11 2022-11-25 ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ コリンキナーゼ阻害剤としてのピラゾロキナゾリン誘導体
WO2020257658A1 (fr) 2019-06-20 2020-12-24 University Of Iowa Research Foundation Nanoparticules comprenant des quinone-méthides et compositions à utiliser
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