EP1976533A2 - Triterpenequinone and triterpenephenol derivatives and their application for the treatment of tumors and parasitic diseases - Google Patents

Triterpenequinone and triterpenephenol derivatives and their application for the treatment of tumors and parasitic diseases

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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Withdrawn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)
French (fr)
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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Publication of EP1976533A2 publication Critical patent/EP1976533A2/en
Withdrawn legal-status Critical Current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.

Abstract

The invention relates to triterpenequinone and triterpenephenol derivatives, their pharmaceutically acceptable 5 salts, prodrugs, solvates or stereoisomers as selective blocking agents of the choline kinase enzyme, pharmaceutical compositions containing them and their use in the treatment of tumors and parasitic diseases or diseases caused by viruses, bacteria or fungi.

Description

TRITERPENEQUINONE AND TRITERPENEPHENOL DERIVATIVES AND THEIR APPLICATION FOR THE TREATMENT OF TUMORS AND PARASITIC DISEASES
FIELD OF THE INVENTION 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.
BACKGROUND 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. The transformation mediated by different oncogenes, among which the ras oncogenes stand out, induces high choline kinase activity levels, resulting in an abnormal increase in the intracellular levels of its product, PCho. Complementary facts support the role of ChoK in the generation of human tumors, as studies using nuclear magnetic resonance (NMR) techniques have shown high PCho levels in human tumor tissues with respect to normal tissues including breast, colon, lung and prostate tumors, among others. It is common knowledge that ras is one of the most deeply studied oncogenes in human carcinogenesis and that ChoK inhibition has been shown to be a new and effective antitumor strategy in cells transformed by oncogenes. These first observations were later extrapolated in vivo in nude mice.
In view of this data, the design of compounds directly affecting choline kinase activity or the enzyme activated by phosphorylcholine in an individual or combined manner would allow the development of effective antitumor therapies.
In this sense, the research on ChoK inhibitors has identified 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. Oncogene, 15, 2289-2301 (1997)]. This choline homologue with a biphenyl structure has been used for designing new antitumor drugs, nevertheless, due to the fact that HC-3 is a potent respiratory paralyzing agent, it is not a good candidate for its use in clinical practice. The synthesis of some derivatives has been based on structural modifications of HC-3 improving the inhibitory activity of the ChoK enzyme and partly eliminating its toxic effects.
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.
On the other hand, it is known that the compounds called 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. Nevertheless, there is a great need to develop compounds that provide a high inhibitory activity of the ChoK enzyme for the purpose of allowing their use for the treatment of tumors, while at the same time they considerably reduce their toxicity against compounds of the state of the art. BRIEF DESCRIPTION OF THE INVENTION
After laborious research, the authors of the present invention have found that certain modifications in the structure of the previously described compounds celastrol and pristimerin allow providing compounds acting as blocking agents of the biosynthesis of phosphorylcholine by means of the selective blocking of the choline kinase (ChoK) enzyme and which have shown to be a new and effective antitumor strategy in human tumor cells. Thus, in one aspect the present invention relates to the use of a compound of formula (I) :
α: where :
Ri, R2, R3, R4, R5, R6, R7, Re? Rn and Ri2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; an OCOR group, where R is (CH2J2COOH or (CH2) 2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Ri0 are independently hydrogen; substituted or non- substituted Cx-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Ci-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group; the bond means a double bond or a single bond; and where the tricyclic structure
is selected from the following structures:
(a) (b) (c;
(d) (e) (f)
where :
Ri3, Ri4, Ri5, Ri6, R21, R22 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group; an OCORVI11 group, where RVI11 is (CH2) 2COOH or (CH2J2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached or each pair can form a (C=O) group together with the carbon to which they are attached; Ri7 is hydrogen or methyl; Ri8 and Ri8- are independently hydrogen; hydroxyl; halogen; Cx-Ci2 alkyl; C6-Ci0 aryl; CORIX (where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N(RX) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-Ci2 alcoxyl); or trifluoromethyl ; Ri9, Ri9', R2o and R20- are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-C12 alkyl; substituted or non-substituted C6-C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 and R25 are independently hydrogen, hydroxyl or halogen;
or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof, in the manufacture of a medicament for the treatment and/or prevention of a ChoK mediated disease or condition.
In another aspect, the present invention refers to the use of a compound of formula (II) :
:II: where :
Rl I R-2 Λ R-3 Λ R-4 I R-5 Λ Rδ Λ Rθ Λ RlO Λ Rll Λ Rl2 Λ Rl3 Λ Rl4 Λ Rl5 Λ Rl6 Λ Rl7 I Rlβ Λ
Ri9 and R2o are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N(RXV) (RXVI) amino group, where Rxv and RXVI are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a carboxyl (C=O) group together with the carbon to which they are attached;
R7 and R8 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a CORXVI1 group (where RXVI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RXVI11) (RXIX) amino, where RXVI11 and RXIX are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group,
R2i and R24 are independently substituted or non-substituted C1- C12 alkyl; a CORXX group (where Rxx is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; or N(RXXI) (RXXI1) amino, where RXXI and RXXI1 are independently hydrogen or a Cx-Ci2 alkyl group) ; a [ (C1- C12) alkyl-O- (Cx-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; R22 and R23 are: - hydrogen; substituted or non-substituted Cx-C12 alkyl; a COR XXIII group (where RXXI11 ±S hydrogen; hydroxyl; substituted or non-substituted Cx-C12 alkyl; substituted or non-substituted C6-C10 aryl; or N (RXXIV) (Rxxv) amino, where RXXIV and Rxxv are independently hydrogen or a Cx-C12 alkyl group); a [ (C1-C12) alkyl-O- (Cx-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R24 is in the para position with respect to R20; or
OR22' and OR23' respectively, where R22' and R23' are independently hydrogen; substituted or non-substituted C1- C12 alkyl; a CORXXVI group (where RXXVI is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-Ci0 aryl; or N (RXXVI1) (RXXVI11) amino, where RXXVI1 and RXXVI11 are independently hydrogen or a Ci-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R24 is in the meta position with respect to R20. or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof, in the manufacture of a medicament for the treatment and/or prevention of a ChoK mediated disease or condition. In a particular embodiment, the disease or condition is cancer. In another particular embodiment the disease is a parasitic disease. In another particular embodiment the disease is a bacterial disease. Finally, in another particular embodiment the disease is a fungal disease.
I n another aspect the pre sent inve ion relates to compounds o f general formula ( I ) :
(D where:
Ri, R2, R3, R4, R5, R6, R7, Re, Rn and Ri2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci- Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; an OCOR group, where R is (CH2J2COOH or (CH2J2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Ri0 are independently hydrogen; substituted or non- substituted Cx-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Ci-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group; the bond means a double bond or a single bond; and where the tricyclic structure
is selected from the following structures:
(a) (b ) ( c ;
( d) ( e ) ( f )
where : Ri3, Ri4, Ris, Ri6, R2x, R22 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) ammo group, where RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group; an OCORVI11 group, where RVI11 is (CH2) 2COOH or (CH2J2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached or each pair can form a (C=O) group together with the carbon to which they are attached; Ri7 is hydrogen or methyl;
Ri8 and Ri8- are independently hydrogen; hydroxyl; halogen; Cx-Ci2 alkyl; C6-Ci0 aryl; CORIX (where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N(RX) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-Ci2 alcoxyl); or trifluoromethyl ;
Rig, Rig-, R20 and R20- are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-C12 alkyl; substituted or non-substituted C6-C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 and R25 are independently hydrogen, hydroxyl or halogen;
or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof, with the following provisos:
- when the tricyclic structure is (a) then the compound of formula (I) is not:
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;
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; 3-Hydroxy-4 , 6b, 8a, 11, 12b, 14a-hexamethyl- 7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H- picene-2, 10-dione;
3, 9-Dihydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl- 7,8,8a,ll,12,12a,12b,13,14,14a-decahydro-6bH,9H- picene-2, 10-dione;
- 3,7, 9-Trihydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl- 7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H- picene-2, 10-dione; - 14-Bromo-3, 7, 9-trihydroxy-4 , 6b, 8a, 11, 12b, 14a- hexamethyl-7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a- decahydro-6bH, 9H-picene-2 , 10-dione;
Succinic acid mono- (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;
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;
- Acetic 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; - Dodecanoic 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;
Dimethyl-carbamic 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;
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; 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;
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 .
- when the tricyclic structure is (b) and Ri9 and R20 are independently hydrogen or an acyl group, then:
R5 is hydroxyl; or
R2i and R22 form a C=O group together with the carbon to which they are attached and Ri0 is not
COOH.
- when the tricyclic structure is (c) and Ri9 and R20 are both CH3, then R15 and Ri6 do not form a C=O group together with the carbon to which they are attached.
In another aspect, the invention relates to a compound of formula (II) :
where : Ri, R2, R3, R4 , R5, R6, R9, Rio, Rn, Ri2, Ri3? RI4Λ RISΛ RI6Λ RI7Λ Riβ? RI9 and R20 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1-C12 alkyl; substituted or non- substituted C6-Ci0 aryl; a N(RXV) (RXVI) amino group, where Rxv and
Rx are independently hydrogen or a C1-C12 alkyl group; or each pair can form a carboxyl (C=O) group together with the carbon to which they are attached;
R7 and R8 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a CORXVI1 group (where RXVI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RXVI11) (RXIX) amino, where RXVI11 and RXIX are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group,
R2i and R24 are independently substituted or non-substituted C1- Ci2 alkyl; a CORXX group (where Rxx is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; or N(RXXI) (RXXI1) amino, where RXXI and RXXI1 are independently hydrogen or a Cx-Ci2 alkyl group) ; a [ (C1- Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; R22 and R23 are: hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXXI11 group (where RXXI11 ±S hydrogen; hydroxyl; substituted or non-substituted Cx-C12 alkyl; substituted or non-substituted C6-C10 aryl; or N (RXXIV) (Rxxv) amino, where
RXXIV and Rxxv are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R24 is in the para position with respect to R20; or
OR22' and OR23' respectively, where R22' and R23' are independently hydrogen; substituted or non-substituted C1-
C12 alkyl; a CORXXVI group (where RXXVI is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-C10 aryl; or N (RXXVI1) (RXXVI11) amino, where
RXXVI1 and RXXVI11 are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R24 is in the meta position with respect to R20. or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof.
In another aspect, the invention is directed to 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.
DETAILED DESCRIPTION OF THE INVENTION
One object of the present invention is the use of a compound of formula (I)
α: where :
R1, R2, R3, R4, R5, R6, R7, Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-C10 aryl; a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a C1-C12 alkyl group; an OCOR group, where R is (CH2) 2COOH or (CH2) 2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and R10 are independently hydrogen; substituted or non- substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-C10 aryl; 0-C1-C12 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a C1-C12 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group; the bond means a double bond or a single bond; and where the tricyclic structure
is selected from the following structures:
(a) (b) (c;
(d) (e) (f)
where :
Ri3, Ri4, R15, Ri6, R2I, R22 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) ammo group, where RVI and RVI1 are independently hydrogen or a C1-C12 alkyl group; an OCORVI11 group, where RVI11 is (CH2) 2COOH or (CH2J2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached or each pair can form a
(C=O) group together with the carbon to which they are attached;
Ri7 is hydrogen or methyl;
Ri8 and Ri8- are independently hydrogen; hydroxyl; halogen; Ci-Ci2 alkyl; C6-Ci0 aryl; CORIX (where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N(RX) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-Ci2 alcoxyl); or trifluoromethyl ;
Ri9, Ri9', R2o and R20. are independently hydrogen; substituted or non-substituted Ci-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Ci-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3) ; trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to which they are attached;
R24 and R25 are independently hydrogen, hydroxyl or halogen;
or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof, in the manufacture of a medicament for the treatment and/or prevention of a ChoK mediated disease or condition.
In a particular embodiment of the invention, 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) :
(Ia) where R1, R2, R3, R^ R5Λ Re? R7Λ Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-C10 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a C1-C12 alkyl group; an OCOR group, where R is (CH2) 2COOH or (CH2) 2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and R10 are independently hydrogen; substituted or non- substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-C10 aryl; 0-C1-C12 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a C1-C12 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group,
R13, R14, R15 and R16 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-C10 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a C1-C12 alkyl group; an OCORVI11 group, where RVI11 is (CH2) 2COOH or (CH2) 2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached; R17 is hydrogen or methyl; R18 is hydrogen; hydroxyl; halogen; C1-C12 alkyl; C6-C10 aryl; CORIX (where RIX is hydrogen; hydroxyl; C1-C12 alkyl; N (Rx) (RXI) amino, where Rx and RXI are independently hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl) ; or trifluoromethyl;
R19 is hydrogen; substituted or non-substituted C1-C12 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6- C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl- 0- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond. In a preferred embodiment, the compounds of formula (Ia) used in the invention comprise a substructure having the following formula (Ia') :
(Ia') where
R5 is hydroxyl or a OCOR group where R is (CH2J2COOH or (CH2) 2CO2CH2CH3;
R7 and R8 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R' ' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
Ri2 is independently hydrogen or a halogen; and
Ri9 is hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6- Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Cx-C12) alkyl- 0- (Cx-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond.
Particular examples of this substructure (Ia') are:
3, 9-Dihydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-
2,10-dione; - Acetic 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;
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- picene-3-yl propionic acid ester (Cl);
Dodecanoic 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; - Dimethyl-carbamic 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;
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;
4-bromo- ( 9-hydroxy-6b, 8a, 11, 12b, 14a-hexamethyl-2, 10-dioxo-
2, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a-tetradecahydro- picene-3-yl) benzoic acid ester (C2); - 14-Bromo-3, 7, 9-trihydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-
2,10-dione;
12-bromo-9-hydroxy-6b, 8a, 11 , 12b, 14a-hexamethyl-2 , 10-dioxo-
2, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a-tetradecahydro- picene-3-yl dimethyl-carbamic acid ester (C4);
4-bromo- (12-bromo-9-hydroxy-6b, 8a, 11, 12b, 14a-hexamethyl-
2,10-dioxo-2, 6b, 7, 8, 8a, 9, 10 , 11, 12 , 12a, 12b, 13, 14 , 14a- tetradecahydro-picene-3-yl) benzoic acid ester (C5) ;
12-bromo-3, 9-dihydroxy- 6b, 8a, 11 , 12b, 14a-hexamethyl- 7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-
2,10-dione (C3) ;
- 3, 9, 10-trihydroxy-6b, 8a, 11, 12b, 14a-hexamethyl- 7,8,8a, 9,10,ll,12,12a,12b,13,14,14a-dodecahydro-6bH- picene-2-one (C6) ; - Succinic acid mono- (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;
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.
In another preferred embodiment, the compounds of formula (Ia) used in the present invention comprise a substructure having the following formula (Ia'') :
(Ia") where :
R7 and R8 are independently hydrogen, hydroxyl, halogen, substituted or non-substituted Ci-Ci2 alkyl, substituted or non- substituted C6-Ci0 aryl, a N (R') (R'') amino group, where R' and
R' ' are independently hydrogen or a Cx-Ci2 alkyl group, or each pair can form a (C=O) group together with the carbon to which they are attached;
Ri5 is hydrogen or halogen; R19 is hydrogen, substituted or non-substituted C1-C12 alkyl; a
CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6- Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a C1-C12 alkyl group); a [ (Ci-Ci2) alkyl- 0- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond.
Particular examples of 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);
- 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- picene-3-yl acetic acid ester (C8);
- 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- picene-3-yl nicotinic acid ester (C9) ;
- 3, 10-dihydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14 , 14a-dodecahydro-6bH- picene-2-one (ClO);
- 3-hydroxy-4 , 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 12a, 12b, 13, 14, 14a-octahydro-6bff, 9ff-picene-2, 10- dione (CIl) .
In another preferred embodiment, the compounds of formula (Ia) used in the present invention comprise a substructure having the following formula (Ia' ' ' ) :
(Ia'") where :
R7 is hydrogen, hydroxyl, halogen, substituted or non- substituted Cx-Ci2 alkyl, substituted or non-substituted C6-Ci0 aryl, or a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; and
Ri9 is substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Ci-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl .
Particular examples of 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) ; - lO-dimethylcarbamoyloxy-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 (C14) .
In another particular embodiment of the invention, 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) :
(Ib) where :
Ri, R2, R3, R4, R5, Rε, R7, Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1-
Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a Ci-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Ri0 are independently hydrogen; substituted or non- substituted Cx-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Ci-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group,
Ri3, Ri4, Ri5, Ri6, R2i, R22 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; Ri7 is hydrogen or methyl; Ri8 is hydrogen; hydroxyl; halogen; Cx-Ci2 alkyl; C6-C10 aryl; CORIX (where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N (Rx) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-C12 alcoxyl) ; or trifluoromethyl;
R19 and R20 are independently hydrogen, substituted or non- substituted Cx-C12 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond.
In a preferred embodiment, the compounds of formula (Ib) used in the present invention comprise a substructure having the following formula (Ib') :
(Ib') where :
Ri9 and R20 are independently substituted or non-substituted C1- C12 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Ci-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; or N(Rxlil) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group) ; a [ (Ci- Ci2) alkyl-0- (Ci-Ci2) 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).
In another preferred embodiment, the compounds of formula (Ib) comprise a substructure having the following formula (Ib") :
where : Ri8 is hydrogen; hydroxyl ; halogen; Ci-Ci2 alkyl ; C6-Ci0 aryl ; COR IX
(where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N (Rx) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-Ci2 alcoxyl) ; or trifluoromethyl; Ri9 is hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6- C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-C12 alkyl group); a [ (Cx-C12) alkyl- 0- (Cx-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl;
R23 is hydrogen; hydroxyl; halogen; substituted or non- substituted C1-C12 alkyl; substituted or non-substituted C6-C10 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a C1-C12alkyl group.
Particular examples of this substructure (Ib'') are:
7,10, ll-trihydroxy-2 , 4a, 6a, 9, 12b, 14a-hexamethyl-8-oxo- 1,2, 3, 4, 4a, 5, 6, 6a, 8, 12b, 13, 14 , 14a, 14b-tetradecahydro- picene-2-carboxylic acid methyl ester (F16);
9-formyl-10 , 11-dihydroxy-2 , 4a, 6a, 12b, 14a-pentamethyl-8- oxo-1, 2, 3, 4, 4a, 5, 6, 6a, 8 , 12b, 13, 14 , 14a, 14b-tetradecahydro- picene-2-carboxylic acid methyl ester (C17); ll-hydroxy-10- (2-methoxy-ethoxymethoxy) -2, 4a, 6a, 9, 12b, 14a- hexamethyl-8-oxo-l,2,3, 4, 4a, 5, 6, 6a, 8, 12b, 13, 14, 14a, 14b- tetradecahydro-picene-2-carboxylic acid methyl ester (C18) .
In another particular embodiment of the invention, 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) :
( Ic ) where : Ri, R2, R3, R4, R5, R6, R7, Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
R9 and Ri0 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group; Ri3, Ri4, Ri5, Ri6, R2i and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R18 is hydrogen; hydroxyl; halogen; Cx-C12 alkyl; C6-C10 aryl; CORIX (where RIX is hydrogen; hydroxyl; C1-C12 alkyl; N (Rx) (RXI) amino, where Rx and RXI are independently hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl) ; or trifluoromethyl; Ri9 and R20 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Ci-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond.
In an embodiment, the compounds of formula (Ic) used in the present invention comprise a substructure having the following formula (Ic' ) :
(IC) where :
Ri9 and R20 are independently hydrogen; substituted or non- substituted Cx-Ci2 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Ci-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3) or trifluoromethyl; and the bond means a double bond or a single bond.
Particular examples of 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-
4a, 5, 6, 6a, 13, 14 , 14a, 14b-octahydro-4H-picene-3-one (C20) .
In another preferred embodiment, the compounds of formula (Ic) used in the present invention comprise a substructure having the following formula (Ic'') :
(Ic") where : Ri9 and R2o are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RX (Rx amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-0- (Ci-Ci2) 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-
1,2, 3, 4, 4a, 5, 6, 6a, 13, 14,14a, 14b-dodecahydro-picene-2-carboxylic acid methyl ester.
In another particular embodiment of the invention, 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):
( Id) where : Ri, R2, R3, R4, R5, R6, R7, Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
R9 and Ri0 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Ci-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group, Ri3? Ri5? R21 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl ; a N (R VI \ ) / (TR1VI I i amino group, where
RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O ) group together with the carbon to which they are attached; R18 is hydrogen; hydroxyl ; halogen; Cx-C12 alkyl ; C6-C10 aryl ; CORIX (where RIX i s hydrogen; hydroxyl ; C1-C12 alkyl ; N (Rx) (RXI ) amino , where Rx and RXI are independently hydrogen or a C1-C12 alkyl group ; or C1-C12 alcoxyl ) ; or tri f luoromethyl ; Ri9, Rig', R20 and R20- are independently hydrogen; substituted or non-substituted Ci-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 and R25 are independently hydrogen, hydroxyl or halogen; and the bond means a double bond or a single bond.
In a preferred embodiment, the compounds of formula (Id) used in the present invention comprise a substructure having the following formula (Id') :
(Id') where :
R5 and R6 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R' ' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
Rig, Rig-, R20 and R20- are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-C12 alkyl; substituted or non-substituted C6-C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a C1-C12 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 and R25 are independently hydrogen, hydroxyl or halogen. Particular examples of 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-
6b, 7, 8, 8a, 9,11, 12 , 12a, 12b, 14b-decahydro-lH-picene-2 , 3, 10- trione (C23) .
In another preferred embodiment, the compounds of formula (Id) used in the present invention comprise a substructure having the following formula (Id'') :
(Id' where :
Ri9, Ri9', R2o and R20. are independently hydrogen; substituted or non-substituted Ci-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Ci-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 and R25 are independently hydrogen, hydroxyl or halogen. A particular example of this substructure (Id' is 12- bromo-2 ,4a, 6a, 9, 12a, 14a-hexamethyl-10 , 11-dioxo-
1,2, 3, 4, 4a, 5, 6, 6a, 10, 11, 12, 12a, 14a, 14b-tetradecahydro-picene-2- carboxylic acid methyl ester (C24) .
In another particular embodiment of the invention, 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) :
(Ie) where : Ri, R2, R3, R4, R5, R6, Ri, Rs, Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Ri0 are independently hydrogen; substituted or non- substituted Cx-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or an alkyl group Ci-Ci2); a carbinol group (CH2) n-0H (where n is an integer comprised between 1 and 10); or together form a methylene group;
Ri3, Ri4, Ri5, Ri6, R2i and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R ) (R amino group , where RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group ; or each pair can form a (C=O ) group together with the carbon to which they are attached;
Ri8 and Ri8- are independently hydrogen; hydroxyl ; halogen ; Cx-Ci2 alkyl ; C6-Ci0 aryl ; CORIX (where RIX i s hydrogen; hydroxyl ; Cx-Ci2 alkyl ; N (RX) (RXI ) amino , where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-Ci2 alcoxyl ) ; or trifluoromethyl ;
R19, R19-, R20 and R20- are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-C10 aryl; or N(R' XII I v / RXIV) ammo , where RXI11 and RXIV are independently hydrogen or a CX-CX2 alkyl group); a [ (Cx-C12) alkyl-O- (Cx-C12) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to which they are attached;
R24 is hydrogen, hydroxyl or halogen; and the bond means a double bond or a single bond.
In a preferred embodiment, the compounds of formula (Ie) used in the present invention comprise a substructure having the following formula (Ie') :
(Ie') where :
R18 and R18- are independently hydrogen; hydroxyl; halogen; C1-C12 alkyl; C6-C10 aryl; CORIX (where RIX is hydrogen; hydroxyl; C1-C12 alkyl; N(RX) (RXI) amino, where Rx and RXI are independently hydrogen or a Ci-Ci2 alkyl group; or Cx-Ci2 alcoxyl); or trifluoromethyl ;
Rig, Rig-, R20 and R20- are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3) ; trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 is hydrogen, hydroxyl or halogen.
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) .
In another particular embodiment of the invention, 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) :
(If)
where : R1, R2, R3, R4, R5Λ Re? R7Λ Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-C10 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a C1-C12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and R10 are independently hydrogen; substituted or non- substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-C10 aryl; 0-C1-C12 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a C1-C12 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group, R13, R14, R15, R21 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-C10 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a C1-C12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
R18 and R18- are independently hydrogen; hydroxyl; halogen; C1-C12 alkyl; C6-C10 aryl; CORIX (where RIX is hydrogen; hydroxyl; C1-C12 alkyl; N(RX) (RXI) amino, where Rx and RXI are independently hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl); or trifluoromethyl ;
R19, R19-, R20 and R20. are independently hydrogen; substituted or non-substituted C1-C12 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3) ; trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 is hydrogen, hydroxyl or halogen; and the bond means a double bond or a single bond. In a preferred embodiment, the compounds of formula (If) used in the present invention comprise a substructure having the following formula (If) :
(If) where :
Ri8 and Ri8. are independently hydrogen; hydroxyl; halogen; Ci-Ci2 alkyl; C6-Ci0 aryl; C0RIX (where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N(RX) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-Ci2 alcoxyl); or trifluoromethyl ;
Rig, Rig-, R20 and R20- are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-0- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3) ; trifluoromethyl; or each 19-19' or 20-20' pair can form a group C=O group together with the carbon to which they are attached;
R24 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).
In another particular embodiment of the invention, 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) :
( H a ) where :
Rl 1 R-2 Λ R-3 Λ R4 1 R5 Λ Rδ Λ Rθ Λ RlO 1 RlI Λ R 12 Λ R 13 Λ Rl4 Λ Rl5 Λ Rl6 Λ Rl7 Λ R 18 Λ
Ri9 and R20 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N(R XXVV N) (/πRXVIv amino group, where R and RXVI are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a carboxyl (C=O) group together with the carbon to which they are attached;
R7 and R8 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a CORXVI1 group (where RXVI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RXVI11) (RXIX) amino, where RXVI11 anc} RXIX are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group,
R2i and R24 are independently substituted or non-substituted Ci- Ci2 alkyl; a CORXX group (where Rxx is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; or N(R XXXXIi \) ( / TR1XXII i amino, where RXXI and RXXI1 are independently hydrogen or a Cx-Ci2 alkyl group) ; a [ (Ci- Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; R22 and R23 are: hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a
CORXXI11 group (where Rπiπ is hydrogen; hydroxyl; substituted or non-substituted Ci-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N (RXXIV) (Rxxv) amino, where
RXXIV and Rxxv are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R24 is in the para position with respect to R20; or
OR22' and OR23' respectively, where R22' and R23' are independently hydrogen; substituted or non-substituted C1-
Ci2 alkyl; a CORXXVI group (where RXXVI is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N (RXXVI1) (RXXVI11) amino, where RXXVI1 and RXXVI11 are independently hydrogen or a Ci-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R24 is in the meta position with respect to R20.
In a preferred embodiment, the compounds of formula (Ha) used in the present invention comprise a substructure having the following formula (Ha') :
(Ha') where :
Ri9 and R20 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N(RXV) (RXVI) amino group, where Rxv and
Rx are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) carboxyl group together with the carbon to which they are attached;
R2i and R24 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-C10 aryl ; a N (RXX1 ) (/-RT1XXII, amino group , where RXXI and pxxn are independently hydrogen or a Ci-Ci2 alkyl group; or each pair can form a (C=O) carboxyl group together with the carbon to which they are attached;
R22 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N(RXXIV) (Rxxv) amino group, where RXXIV and Rxxv are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) carboxyl group together with the carbon to which they are attached.
A particular example of 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.
Accordingly, in a particular embodiment, the Chok mediated disease or condition to be prevented or treated is cancer, preferably selected from breast, lung, colorectal and pancreatic cancer.
On the other hand, 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. In this sense, 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 .
In another embodiment the ChoK mediated disease or condition to be prevented and/or treated is a parasitic disease, preferably that caused by Plasmodium or Trypanosoma .
In another embodiment the ChoK mediated disease or condition to be prevented and/or treated is bacterial disease, preferably that caused by Streptococcus .
In another embodiment 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) :
(D where :
Ri, R2, R3, R4, R5, Rβr R7, Re? Rn and Ri2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; an OCOR group, where R is (CH2) 2COOH or (CH2) 2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Ri0 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) ammo, where RIV and Rv are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbmol group (where n is an integer comprised between 1 and 10); or together form a methylene group; the bond means a double bond or a single bond; and where the tricyclic structure
is selected from the following structures:
(a) (b ) ( c ;
( d) ( e ) ( f )
where :
Ri3, Ri4, Ri5, Ri6, R2i, R22 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group; an OCORVI11 group, where RVI11 is (CH2) 2COOH or (CH2J2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached or each pair can form a (C=O) group together with the carbon to which they are attached; Ri7 is hydrogen or methyl;
Ri8 and Ri8. are independently hydrogen; hydroxyl; halogen; Cx-Ci2 alkyl; C6-Ci0 aryl; CORIX (where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N(RX) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-Ci2 alcoxyl); or trifluoromethyl ;
R19, R19-, R20 and R20- are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-C12 alkyl group); a [ (Cx-C12) alkyl-O- (Cx-C12) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 and R25 are independently hydrogen, hydroxyl or halogen;
or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof, with the following provisos:
- when the tricyclic structure is (a) then the compound of formula (I) is not:
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; - 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;
3-Hydroxy-4 , 6b, 8a, 11, 12b, 14a-hexamethyl- 7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H- picene-2, 10-dione;
3, 9-Dihydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H- picene-2, 10-dione;
- 3,7, 9-Trihydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl- 7,8,8a,ll,12,12a,12b,13,14,14a-decahydro-6bH,9H- picene-2, 10-dione;
- 14-Bromo-3, 7, 9-trihydroxy-4 , 6b, 8a, 11, 12b, 14a- hexamethyl-7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a- decahydro-6bH, 9H-picene-2 , 10-dione; - Succinic acid mono- (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;
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;
- Acetic 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;
Dodecanoic 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;
Dimethyl-carbamic 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; - 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;
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;
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 .
- when the tricyclic structure is (b) and Ri9 and R2o are independently hydrogen or an acyl group, then:
R5 is hydroxyl; or
R2i and R22 form a C=O group together with the carbon to which they are attached and Ri0 is not
COOH.
- when the tricyclic structure is (c) and Ri9 and R20 are both CH3, then R15 and Ri6 do not form a C=O group together with the carbon to which they are attached.
In one particular aspect, the invention is directed to compounds of formula (Ia) :
(Ia) where
R1, R2, R3, R4, R5, R6, R7, R8, Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a Ci-Ci2 alkyl group; an OCOR group, where R is (CH2) 2COOH or (CHz)2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Ri0 are independently hydrogen; substituted or non- substituted Cx-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group,
Ri3, Ri4, Ri5 and R16 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group; an OCORVI11 group, where RVI11 is (CH2J2COOH or (CH2J2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached; R17 is hydrogen or methyl; R18 is hydrogen; hydroxyl; halogen; Cx-Ci2 alkyl; C6-Ci0 aryl; CORIX
(where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N (Rx) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-C12 alkyl group; or Cx-C12 alcoxyl) ; or trifluoromethyl;
R19 is hydrogen; substituted or non-substituted Cx-C12 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6- C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl- 0- (C1-C12) 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-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;
- 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;
- 3-Hydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-2, 10- dione; - 3, 9-Dihydroxy-4, 6b, 8a,ll, 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-2, 10- dione;
- 3,7, 9-Trihydroxy-4, 6b, 8a, 11 , 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-2, 10- dione;
- 14-Bromo-3, 7, 9-trihydroxy-4 , 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-2, 10- dione;
- Succinic acid mono- (10-hydroxy-2, 4a, 6a, 9, 12b, 14a-hexamethyl- 3,ll-dioxo-l,2,3,4,4a,5,6,6a,ll,12b,13,14,14a,14b- tetradecahydro-picen-4-yl) 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;
- Acetic 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;
- Dodecanoic 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;
- Dimethyl-carbamic 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; - 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.
In a preferred embodiment, the compounds of formula (Ia) comprise a substructure having the following formula (Ia' ) :
(Ia') where
R5 is hydroxyl or a OCOR group where R is (CH2J2COOH or (CH2) 2CO2CH2CH3;
R7 and R8 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R' ' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
Ri2 is independently hydrogen or a halogen; and
Ri9 is hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6- Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Cx-C12) alkyl- 0- (Cx-C12) 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-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;
- 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; - 3-Hydroxy-4, 6b, 8a,ll, 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-2, 10- dione;
- 3, 9-Dihydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-2, 10- dione;
- 3,7, 9-Trihydroxy-4, 6b, 8a, 11 , 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-2, 10- dione;
- 14-Bromo-3, 7, 9-trihydroxy-4 , 6b, 8a, 11, 12b, 14a-hexamethyl- 7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-2, 10- dione;
- Succinic acid mono- (10-hydroxy-2, 4a, 6a, 9, 12b, 14a-hexamethyl- 3,ll-dioxo-l,2,3,4,4a,5,6,6a,ll,12b,13,14,14a,14b- tetradecahydro-picen-4-yl) 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;
- Acetic 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;
- Dodecanoic 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; - Dimethyl-carbamic 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;
- 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;
- 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;
- 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.
Particular examples of 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);
4-bromo- ( 9-hydroxy-6b, 8a, 11, 12b, 14a-hexamethyl-2, 10-dioxo- 2, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a-tetradecahydro- picene-3-yl) benzoic acid ester (C2); - 12-bromo-3, 9-dihydroxy-4, 6b, 8a, 11 , 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene- 2,10-dione (C3) ;
12-bromo-9-hydroxy-6b, 8a, 11, 12b, 14a-hexamethyl-2, 10-dioxo- 2, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a-tetradecahydro- picene-3-yl dimethyl-carbamic acid ester (C4);
4-bromo- (12-bromo-9-hydroxy-6b, 8a, 11, 12b, 14a-hexamethyl- 2,10-dioxo-2, 6b, 7, 8, 8a, 9, 10 , 11, 12 , 12a, 12b, 13, 14 , 14a- tetradecahydro-picene-3-yl) benzoic acid ester (C5) ; - 3, 9, 10-trihydroxy-6b, 8a, 11, 12b, 14a-hexamethyl- 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14 , 14a-dodecahydro-6bH- picene-2-one (C6) .
In another preferred embodiment, the compounds of formula (Ia) comprise a substructure having the following formula (Ia") :
( I a " ) where :
R7 and Rg are independently hydrogen, hydroxyl, halogen, substituted or non-substituted Ci-Ci2 alkyl, substituted or non- substituted C6-Ci0 aryl, a N (R') (R'') amino group, where R' and R' ' are independently hydrogen or a Cx-Ci2 alkyl group, or each pair can form a (C=O) group together with the carbon to which they are attached; Ri5 is hydrogen or halogen;
Ri9 is hydrogen, substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6- Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl- 0- (Ci-Ci2) 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-hexamethyl-
7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14 , 14a-dodecahydro-6bH-picen- 2-one; - 3-Hydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene- 2,10-dione.
Particular examples of 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);
- 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- picene-3-yl acetic acid ester (C8);
- 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- picene-3-yl nicotinic acid ester (C9) ;
- 3, 10-dihydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14 , 14a-dodecahydro-6bH- picene-2-one (ClO);
- 3-hydroxy-4 , 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 12a, 12b, 13, 14, 14a-octahydro-6bff, 9ff-picene-2, 10- dione (CIl) .
In another preferred embodiment, the compounds of formula [Ia) comprise a substructure having the following formula :ia'") :
(Ia'") where :
R7 is hydrogen, hydroxyl, halogen, substituted or non- substituted Cx-Ci2 alkyl, substituted or non-substituted C6-Ci0 aryl, or a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; and
Ri9 is substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Ci-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) 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-
1,2, 3, 4, 4a, 5, 6, 6a, 11, 12b, 13, 14, 14a, 14b-tetradecahydro- picene-2-carboxylic acid methyl ester; - 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.
Particular examples of 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) ;
10-dimethylcarbamoyloxy-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 (C14) . In another particular aspect, the invention is directed to compounds of formula (Ib) :
(Ib) where : Ri, R2, R3, R4, R5, Rε, R7, Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a Ci-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Ri0 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group,
Ri3, Ri4, Ri5, Ri6, R2i, R22 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; Ri7 is hydrogen or methyl;
Ri8 is hydrogen; hydroxyl; halogen; Cx-Ci2 alkyl; C6-C10 aryl; CORIX (where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N (Rx) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-C12 alcoxyl) ; or trifluoromethyl;
R19 and R20 are independently hydrogen, substituted or non- substituted Cx-C12 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl-O- (C1-C12) 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 R19 and R20 are independently hydrogen or an acyl group, then: R5 is hydroxyl; or
R21 and R22 form a C=O group together with the carbon to which they are attached and R10 is not COOH.
In another preferred embodiment, the compounds of formula (Ib) comprise a substructure having the following formula (Ib') :
(Ib') where :
Ri9 and R20 are independently substituted or non-substituted C1- C12 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Ci-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; or N(Rxlil) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group) ; a [ (Ci- Ci2) alkyl-0- (Ci-Ci2) 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).
In another preferred embodiment, the compounds of formula (Ib) comprise a substructure having the following formula (Ib") :
where : Ri8 is hydrogen; hydroxyl ; halogen; Ci-Ci2 alkyl ; C6-Ci0 aryl ; COR IX
(where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N (Rx) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-Ci2 alcoxyl) ; or trifluoromethyl; Ri9 is hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6- C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-C12 alkyl group); a [ (Cx-C12) alkyl- 0- (Cx-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl;
R23 is hydrogen; hydroxyl; halogen; substituted or non- substituted C1-C12 alkyl; substituted or non-substituted C6-C10 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a C1-C12alkyl group.
Particular examples of this substructure (Ib'') are:
7,10, ll-trihydroxy-2 , 4a, 6a, 9, 12b, 14a-hexamethyl-8-oxo- 1,2, 3, 4, 4a, 5, 6, 6a, 8, 12b, 13, 14 , 14a, 14b-tetradecahydro- picene-2-carboxylic acid methyl ester (F16);
9-formyl-10 , 11-dihydroxy-2 , 4a, 6a, 12b, 14a-pentamethyl-8- oxo-1, 2, 3, 4, 4a, 5, 6, 6a, 8 , 12b, 13, 14 , 14a, 14b-tetradecahydro- picene-2-carboxylic acid methyl ester (C17); ll-hydroxy-10- (2-methoxy-ethoxymethoxy) -2, 4a, 6a, 9, 12b, 14a- hexamethyl-8-oxo-l,2,3, 4, 4a, 5, 6, 6a, 8, 12b, 13, 14, 14a, 14b- tetradecahydro-picene-2-carboxylic acid methyl ester (C18) .
In another particular aspect, the invention is directed to compounds of formula (Ic) :
(Ic) where : Ri, R2, R3, R4, R5, R6, R7, Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
R9 and Ri0 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Cx-Ci2 alkyl group) ; a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group; Ri3, Ri4, Ri5, Ri6, R2i and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R18 is hydrogen; hydroxyl; halogen; Cx-C12 alkyl; C6-C10 aryl; CORIX (where RIX is hydrogen; hydroxyl; C1-C12 alkyl; N (Rx) (RXI) amino, where Rx and RXI are independently hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl) ; or trif luoromethyl; Ri9 and R20 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Ci-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) 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 R19 and R20 are both CH3, then R15 and Ri6 do not form a C=O group together with the carbon to which they are attached.
In a preferred embodiment, the compounds of formula (Ic) comprise a substructure having the following formula (Ic') :
(IC) where :
Ri9 and R20 are independently hydrogen; substituted or non- substituted Cx-Ci2 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3) or trifluoromethyl; and the bond means a double bond or a single bond.
Particular examples of this substructure (Ic') are: 10, ll-dihydroxy-2 , 4a, 6a, 9, 14a-pentamethyl-
1, 4, 4a, 5, 6, 6a, 13, 14 , 14a, 14b-decahydro-2H-picene-3-one
(C19) ;
10, ll-dihydroxy-2 , 4a, 6a, 9, 14a-pentamethyl-
4a, 5, 6, 6a, 13, 14 , 14a, 14b-octahydro-4H-picene-3-one (C20) .
In another preferred embodiment, the compounds of formula
[Ic) comprise a substructure having the following formula lie") :
(Ic") where :
Ri9 and R2o are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Ci-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-0- (Ci-Ci2) 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-
1,2, 3, 4, 4a, 5, 6, 6a, 13, 14,14a, 14b-dodecahydro-picene-2-carboxylic acid methyl ester (C21) .
In another particular aspect, the invention is directed to compounds of formula (Id) :
( Id) where : Ri, R2, R3, R4, R5, R6, R7, Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
R9 and Ri0 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Ci-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group, Ri3? Ri5? R21 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl ; a N (R VI \ ) / (TR1VI I i amino group, where
RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O ) group together with the carbon to which they are attached; R18 is hydrogen; hydroxyl ; halogen; Cx-C12 alkyl ; C6-C10 aryl ; CORIX (where RIX i s hydrogen; hydroxyl ; C1-C12 alkyl ; N (Rx) (RXI ) amino , where Rx and RXI are independently hydrogen or a C1-C12 alkyl group ; or C1-C12 alcoxyl ) ; or tri f luoromethyl ; Ri9, Rig', R20 and R20- are independently hydrogen; substituted or non-substituted Ci-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 and R25 are independently hydrogen, hydroxyl or halogen; and the bond means a double bond or a single bond.
In a preferred embodiment, the compounds of formula (Id) comprise a substructure having the following formula (Id') :
(Id') where :
R5 and R6 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R' ' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
Rig, Rig-, R20 and R20- are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-C12 alkyl; substituted or non-substituted C6-C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 and R25 are independently hydrogen, hydroxyl or halogen.
Particular examples of 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-
6b, 7, 8, 8a, 9,11, 12 , 12a, 12b, 14b-decahydro-lH-picene-2 , 3, 10- trione (C23) .
In another preferred embodiment, the compounds of formula (Id) comprise a substructure having the following formula (Id") :
(Id") where : Ri9, Ri9', R20 and R20- are independently hydrogen; substituted or non-substituted Ci-Ci2 alkyl; a COR group (where Rx is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 and R25 are independently hydrogen, hydroxyl or halogen. A particular example of this substructure (Id'') is 12- bromo-2 ,4a, 6a, 9, 12a, 14a-hexamethyl-10 , 11-dioxo-
1,2, 3, 4, 4a, 5, 6, 6a, 10, 11, 12, 12a, 14a, 14b-tetradecahydro-picene-2- carboxylic acid methyl ester (C24) . In another particular aspect, the invention is directed to compounds of formula (Ie) :
(Ie) where:
Ri, R2, R3, R4, R5, R6, Ri, Rs, Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx- C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Ri0 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or an alkyl group Ci-Ci2); a carbinol group (CH2) n-0H (where n is an integer comprised between 1 and 10); or together form a methylene group; Ri3, Ri4, Ri5, Ri6, R2x and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
Ri8 and Ri8' are independently hydrogen; hydroxyl; halogen; Ci-Ci2 alkyl; C6-Ci0 aryl; CORIX (where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N(RX) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-Ci2 alcoxyl); or trifluoromethyl ;
Ri9, Ri9', R2o and R20. are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-C10 aryl; or N(R' XII I v / RXIV) ammo , where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3) ; trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to which they are attached;
R24 is hydrogen, hydroxyl or halogen; and the bond means a double bond or a single bond.
In a preferred embodiment, the compounds of formula lie) comprise a substructure having the following formula (Ie' ) :
(Ie') where :
Ri8 and Ri8- are independently hydrogen; hydroxyl; halogen; Cx-Ci2 alkyl; C6-C10 aryl; CORIX (where RIX is hydrogen; hydroxyl; Cx-C12 alkyl; N(RX) (RXI) amino, where Rx and RXI are independently hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl); or trifluoromethyl ; Ri9, Rig', R20 and R20- are independently hydrogen; substituted or non-substituted Ci-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 is hydrogen, hydroxyl or halogen.
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) .
In another particular aspect, the invention is directed to compounds of formula (If) :
(If)
where :
Ri, R2, R3, R4, R5, R6, R7, R8, Rn and Ri2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Ri0 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, Ri3, Ri4, R15, R2i and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a C1-C12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R18 and Ri8- are independently hydrogen; hydroxyl; halogen; C1-C12 alkyl; C6-Ci0 aryl; CORIX (where RIX is hydrogen; hydroxyl; C1-C12 alkyl; N(RX) (RXI) amino, where Rx and RXI are independently hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl); or trifluoromethyl ; R19, R19', R20 and R20- are independently hydrogen; substituted or non-substituted C1-C12 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3) ; trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 is hydrogen, hydroxyl or halogen; and the bond means a double bond or a single bond.
In a preferred embodiment, the compounds of formula (If) comprise a substructure having the following formula (If ) :
( I f ) where :
Ri8 and Ri8- are independently hydrogen ; hydroxyl ; halogen ; Ci-Ci2 alkyl ; C6-Ci0 aryl ; C0RIX (where RIX i s hydrogen ; hydroxyl ; Cx-Ci2 alkyl ; N ( RX ) ( RXI ) amino , where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group ; or Cx-Ci2 alcoxyl ) ; or trifluoromethyl ;
Rig, Rig-, R20 and R20- are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-0- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3) ; trifluoromethyl; or each 19-19' or
20-20' pair can form a group C=O group together with the carbon to which they are attached;
R24 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).
Another aspect of the invention is formed by compounds of formula (II) :
where :
Rl I R∑ Λ R3 Λ R4 1 R5 Λ Rδ Λ Rθ Λ RlO Λ Rll Λ Rl2 1 Rl3 Λ Rl4 Λ Rl5 Λ Rl6 Λ Rl7 r Rlβ Λ
RI9 and R2o are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl ; a N ( R XXVV N) ( / πRXVI N amino group, where Rxv and
Rx are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a carboxyl (C=O) group together with the carbon to which they are attached;
R7 and R8 are independently hydrogen; substituted or non- substituted Cx-Ci2 alkyl; C6-Ci0 aryl; a CORXVI1 group (where RXVI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RXVI11) (RXIX) amino, where RXVI11 anc} RXIX are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group,
R2i and R24 are independently substituted or non-substituted Ci- Ci2 alkyl; a CORXX group (where Rxx is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl ; or N ( R XXXXI1 N) ( / -RT1XXI I , amino , where RXXI and R XXII are independently hydrogen or a Cx-Ci2 alkyl group) ; a [ (Cx- C12) alkyl-O- (Cx-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; R22 and R23 are: hydrogen; substituted or non-substituted Cx-C12 alkyl; a
COR XXIII group (where R XXI11 -j_s hydrogen; hydroxyl; substituted or non-substituted Cx-C12 alkyl; substituted or non-substituted C6-Ci0 aryl; or N (RXXIV) (Rxxv) amino, where
RXXIV and Rxxv are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R24 is in the para position with respect to R20; or
OR22' and OR23' respectively, where R22' and R23' are independently hydrogen; substituted or non-substituted C1-
Ci2 alkyl; a CORXXVI group (where RXXVI is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N (RXXVI1) (RXXVI11) amino, where RXXVI1 and RXXVI11 are independently hydrogen or a Ci-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R24 is in the meta position with respect to R20. or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof.
In one particular aspect, the invention is directed to compounds of formula (Ha) :
( H a ) where :
Rl 1 R-2 Λ R-3 Λ R4 1 R5 Λ Rδ Λ Rθ Λ RlO Λ Rll Λ Rl2 1 Rl3 Λ Rl4 ? Rl5 Λ Rl6 Λ Rl7 I Rlβ Λ
Rig and R20 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N(RXV) (RXVI) amino group, where Rxv and RXVI are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a carboxyl (C=O) group together with the carbon to which they are attached; R7 and R8 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a CORXVI1 group (where RXVI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RXVI11) (RXIX) amino, where RXVI11 and RXIX are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group,
R2i and R24 are independently substituted or non-substituted C1- Ci2 alkyl; a CORXX group (where Rxx is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; or N(RXXI) (RXXI1) amino, where RXXI and RXXI1 are independently hydrogen or a Cx-Ci2 alkyl group) ; a [ (C1- Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; R22 and R23 are: hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a COR XXIII group (where R XXI11 -j_s hydrogen; hydroxyl; substituted or non-substituted Cx-C12 alkyl; substituted or non-substituted C6-C10 aryl; or N (RXXIV) (Rxxv) amino, where RXXIV and Rxxv are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R24 is in the para position with respect to R20; or - OR22' and OR23' respectively, where R22' and R23' are independently hydrogen; substituted or non-substituted C1- C12 alkyl; a CORXXVI group (where RXXVI is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-C10 aryl; or N (RXXVI1) (RXXVI11) amino, where R χχvii and R XXVIII are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R24 is in the meta position with respect to R20.
In a preferred embodiment, the compounds of formula (Ha) comprise a substructure having the following formula (Ha') :
( Ha ' ) where :
Ri9 and R20 are independently hydrogen ; hydroxyl ; halogen ; substituted or non- substituted Ci-Ci2 alkyl ; substituted or non- substituted C6-Ci0 aryl; a N(R XXVV N) (/πRXVIv amino group, where R and
RA are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) carboxyl group together with the carbon to which they are attached;
R2i and R24 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N(RXXI) (RXXI1) amino group, where RXXI and
Rx are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) carboxyl group together with the carbon to which they are attached;
R22 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N(RXXIV) (Rxxv) amino group, where RXXIV and Rxxv are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) carboxyl group together with the carbon to which they are attached.
A particular example of 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) .
In another aspect 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. c) By means of an already studied process, C-25 will be transformed in a fluoromethyl group and the subsequent functional group transformations will allow reaching the indicated groups. d) The use of heterolytic and homolytic halogenation reactions together with chemoselective oxidation processes and the introduction of nitrogens by means of the use of azides forms parts of any of the methods to be used for obtaining the objectives. e) Taking advantage of the functionalizations in C-Il, the previously studied methodology will be used to obtain C11-C12 double bonds which will serve as a functional group to apply a FGT (Functional Group Transformations) to them for the purpose of preparing the envisaged compounds . f) The C-15 and C16 positions have been functionalized by carrying out allylic oxidation reactions from double bonds in ring E or in ring C and from then onwards, the application of FGT. g) The C-19, C-20, C-21 and C-22 positions can be partially functionalized in some starting substrates and the chemistry for introducing functional groups in this ring has been widely elaborated. Particular examples of the present invention are described in the preparation example section, nevertheless a person skilled in the art would achieve synthesizing any of the described compounds by conventional synthetic compounds of the state of the art.
The term "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. However, it will be observed that 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.
For example, pharmaceutically acceptable 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. Examples of 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 . Examples of 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.
Any compound which is a prodrug of a compound of formula (I) or of formula (II) is within the scope of the invention. The term "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 . "Textbook of Drug design and Discovery" Taylor & Francis (April 2002) . 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. In a particular embodiment, 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 .
The different substituents selected for the different compounds of the invention provide a series of factors considerably affecting the values of log P. Thus, 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') ,
(Ia"), (Ia'"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id),
(Id'), (Id"), (Ie), (Ie'), (If), (If), (II), (Ha), (Ha') or mixtures thereof, 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.
The pharmaceutical 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 .
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.
The pharmaceutical 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.
For their application in therapy, 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. In the same manner 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"),
(Ic), (Ic'), (Ic"), (Id), (Id'), (Id"), (Ie), (Ie'), (If),
(If), (II), (Ha), (Ha') or mixtures thereof, or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof for use in the treatment of cancer, parasitic diseases, bacterial diseases or fungal diseases. The following examples are given only as an additional illustration of the invention, they must not be interpreted as limiting the invention as it is defined in the claims.
EXAMPLES
PREPARATION EXAMPLES
Example 1
Compound C3 : 12-bromo-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 300 g of Maytenus amazonica root bark were extracted in 2 liters of a n-hexane-ethyl ether 1:1 solvent mixture in soxhlet equipment under reflux for 48 hours, obtaining 70 grams of a reddish solid after evaporating the solvent. The extract was chromatographed on a sephadex LH-20 column, using a n-hexane- CHCl3-MeOH 2:1:1 mixture as eluent . 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 22β-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.
342 mg (0.78 mmoles) of 22β-hydroxy-tingenone in 50 ml of dry CH2Cl2, under an inert atmosphere and at 00C were treated with 1.5 eq of BBr3 (IM) . The reaction mixture was followed by thin layer chromatography, and was left stirring for 30 minutes until the starting product ran out. After this time, 50 ml of cold distilled water was added and the mixture was stirred for another 30 minutes. Then, an extraction with CH2Cl2 was carried out. The organic phases were dried with anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by LH-20 sephadex chromatography using ji-hexane : chloroform:methanol 2:1:1 mixture as eluent and in a silica gel chromatography column using n-hexane-ethyl acetate 7:3 as eluent. Ill mg (27%) of product C3 was obtained. 1H NMR (300 MHz, CDCl3) δ 0.50 (3H, s, Me-27); 1.16 (3H, d, J= 5.9 Hz, Me-30); 1.29 (3H, s, Me-26); 1.36 (3H, s, Me-28); 1.44 (3H, s, Me-25); 2.20 (3H, s, Me-23) ; 2.61 (IH, m, H-20); 3.70 (IH, d, J= 2.9 Hz, H-22); 4.03 (IH, dd, J1= 2.6, J2= 10.2 Hz, H- 19); 6.32 (IH, d, J= 7.2 Hz, H-7); 6.50 (IH, d, J= 1.3 Hz, H-I); 7.00 (IH, dd, J1= 1.3, J2= 7.1 Hz, H-6). 13C NMR (75 MHz, CDCl3) δ 10.2 (c, C-23); 20.3 (c, C-27); 20.9 (c, C-30); 21.7 (c, C-26); 27.9 (t, C-16); 28.0 (t, C-15) ; 28.9 (t, C-12); 30.9 (c, C-28); 33.4 (t, C-Il); 37.9 (c, C-25) ; 40.0 (d, C-20); 40.4 (s, C-14); 42.7 (s, C-9) ; 44.4 (s, C-13) ; 45.5 (s, C-17); 48.7 (d, C-18); 76.6 (d, C-19); 77.2 (d, C-22); 118.6 (d, C-7); 119.6 (d, C-I); 127.7 (s, C-5); 133.7 (d, C-6) ; 146.1 (s, C-4); 149.5 (s, C-3) ; 164.1 (s, C-IO); 167.9 (s, C-8); 178.4 (s, C-2); 216.5 (s, C- 21). High resolution MS Calculated for (M+-Br) C28H36O4 436.2614, observed 436.2695. Example 2
Compound C7 : 14-Bromo-3-hydroxy-4 , 6b, 8a, 11, 12b, 14a-hexamethyl- 7 , 8 , 8a, 11 , 12 , 12a, 12b, 13 , 14 , 14a-decahydro-6bH, 9H-picene-2 , 10- dione 100 mg (0.23 mmoles) of 22β-hydroxy-tingenone, obtained according to example 1, were dissolved in 10 ml of CH2Cl2 and were treated with 82 mg of NBS (2eq) for 2h at room temperature. The reaction mixture was followed by TLC and when there was no more starting product, an extraction with CH2Cl2 was carried out. The organic phase was dried with anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using n- hexane:AcOEt mixtures in polarity increasing from 10% to 60% as an eluent to obtain: 1.2 mg (1%) of compound C7 and a mixture of other compounds.
1H NMR (300 MHz, CDCl3) δ 0.99 (3H, s, Me-28); 1.00 (3H, d, J= 5.2 Hz, Me-30); 1.01 (3H, s, Me-27); 1.38 (3H, s, Me-26); 1.76 (3H, s, Me-25); 2.20 (3H, s, Me-23); 4.81 (IH, dd, J1= 6.7 Hz, J2= 12.0 Hz, H-Il); 6.28 (IH, d, J= 7.0 Hz, H-7); 6.89 (IH, d, J= 7.0 Hz, H-6) ; 7.35 (IH, s, H-I) .. 13C NMR (75 MHz, CDCl3) δ 10.2 (c, C-23) ; 14.9 (c, C-30) ; 19.5 (c, C-27) ; 21.2 (c, C-26) ; 28.3 (t, C-15); 31.7 (t, C-16); 32.0 (c, C-28); 35.0 (t, C-19); 37.6 (c, C-25); 38.1 (s, C-13) ; 41.6 (d, C-18); 42.4 (s, C-14); 42.8 (d, C-20); 44.3 (s, C-17); 44.9 (t, C-12); 46.8 (s, C-9) ; 51.6 (t, C-22); 58.3 (d, C-Il); 117.9 (s, C-4); 118.4 (d, C-7); 121.1 (d, C-I); 129.6 (s, C-5) ; 131.4 (d, C-6); 152.9 (s, C-3) ; 162.7 (s, C-IO); 165.4 (s, C-8); 178.3 (s, C-2); 212.8 (s, C- 21). High resolution MS Calculated for C28H35BrO3 498.1770, observed 498.1801. Example 3 Compound C8: (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) acetic acid ester
300 g of Maytenus amazonica root bark were extracted in 2 liters of a n-hexane-ethyl ether 1:1 solvent mixture in soxhlet equipment under reflux for 48 hours, obtaining 70 grams of a reddish solid after evaporating the solvent. The extract was chromatographed on a sephadex LH-20 column, using a n-hexane- CHCl3-MeOH 2:1:1 mixture as eluent . 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 called tingenone was obtained.
40 mg (0.096 mmoles) of tingenone in 10 ml of dry CH2Cl2 were treated with 0.04 ml (3 eq) of dry Et3N and 0.01 ml (1.5 eq) of acetyl chloride. The reaction was carried out at room temperature, followed by TLC and stirred for 2h. The process described in the previous reactions was followed. The raw product was purified by preparative chromatography on silica gel using n-hexane : AcOEt (2:3) as a mobile phase, to give 24 mg
(54%) of product C8. The residue was starting product.
1H NMR (300 MHz, CDCl3) δ 7.08 (IH, dd, J1= 1.3, J2= 7.0 Hz, H- 6) ;
6.50 (IH, d, J=I.4 Hz, H-I) ; 6.35 (IH, d, J= 7.1 Hz, H-7) ; 2.49
(IH, m, H-20) ; 2.36 (3H, s, Me-COO) ; 2.16 (3H, s, Me-23) ; 1.52 (3H, s, Me-25) ; 1.35 (3H, s, Me-26) ; 1.00 (3H, s, Me-27) ; 0.99 (3H, d, J= 6.2 Hz, Me-30) ; 0.98 (3H, s, Me-28) . 13C NMR (75 MHz, CDCl3) δ 11.1 (c, C-23) ; 14.8 (c, C-30) ; 19.5 (c, C-27) ; 20.3 (c, CH3COO) ; 21.6 (c, C-26) ; 28.2 (t, C-15) ; 29.6 (t, C-12) ;
31.8 (t, C-19) ; 32.3 (c, C-28) ; 33.6 (t, C-Il) ; 35.2 (t, C-16) ;
37.9 (s, C-17) ; 38.8 (c, C-25) ; 40.2 (s, C-13) ; 41.7 (d, C-20) ; 42.2 (s, C-9) ; 43.3 (d, C-18) ; 44.6 (s, C-14) ; 52.3 (t, C-22) ;
117.6 (d, C-7) ; 122.9 (d, C-I) ; 126.4 (s, C-5) ; 133.5 (s, C-4) ; 134.9 (d, C-6) ; 142.8 (s, C-3) ; 162.9 (s, C-IO) ; 168.5 (s, CH3COO) ; 170.4 (s, C-8) ; 177.3 (s, C-2) ; 213.4 (s, C-21) . High resolution MS Calculated for C30H38O4 462.2770, observed 462.2784. Example 4
Compound C9: (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) nicotinic acid ester
98 mg (0.23 mmoles) of tingenone (obtained according to example 3) were dissolved in 10 ml of dry CH2CI2 and were treated with 0.097 ml (3 eq) of dry Et3N, 62.12 mg (1.5 eq) of nicotyl chloride and catalytic amounts of DMAP. The reaction was carried out at room temperature, followed by TLC and stirred for 20 minutes. The process described in the previous reactions was followed and the raw product was purified by preparative chromatography on silica gel using CH2Cl2:AcOEt (1:1) as a mobile phase, to give 55 mg (46%) of product C9. The residue was starting product. 1H NMR (300 MHz, CDCl3) δ 9.37 (IH, dd, J1= 0.9, J2= 2.1 Hz, HJ ; 8.81 (IH, dd, J1= 1.7, J2= 4.9 Hz, Hd) ; 8.43 (IH, dd, J1= 1.9, J2= 8.2 Hz, Hb) ; 7.44 (IH, m, Hc) ; 7.13 (IH, dd, J1= 1.2, J2= 7.0 Hz, H-6); 6.53 (IH, d, J=I .3 Hz, H-I); 6.38 (IH, d, J= 7.1 Hz, H-7); 2.49 (IH, m, H-20); 2.22 (3H, s, Me-23); 1.54 (3H, s, Me-25) ; 1.35 (3H, s, Me-26); 0.99 (3H, s, Me-27); 0.97 (3H, d, J= 6.6 Hz, Me-30) ; 0.95 (3H, s, Me-28) . 13C NMR (75 MHz, CDCl3) δ 11.23 (c, C-23) ; 14.84 (c, C-30) ; 19.54 (c, C-27) ; 21.59 (c, C-26) ; 28.26 (t, C-15) ; 29.63 (t, C-12) ; 31.78 (t, C-19) ; 32.30 (c, C- 28) ; 33.69 (t, C-Il) ; 35.23 (t, C-16) ; 37.91 (s, C-17) ; 38.81 (c, C-25) ; 40.23 (s, C-13) ; 41.65 (d, C-20) ; 42.29 (s, C-9) ; 43.26 (d, C-18) ; 44.64 (s, C-14) ; 52.26 (t, C-22) ; 117.6 (d, C- 7) ; 123.0 (d, C-I) ; 123.2 (d, CH-Ar) ; 125.0 (s, C-Ar) ; 126.3 (s, C-5); 133.8 (s, C-4); 135.2 (d, C-6) ; 137.6 (d, CH-Ar); 142.7 (s, C-3); 151.3 (d, N-CH); 153.7 (d, N-CH); 162.8 (s, C-IO); 162.9 (s, OCO-Nic); 170.7 (s, C-8); 176.8 (s, C-2); 213.3 (s, C- 21). High resolution MS Calculated for C34H39NO4 525.2879, observed 525.2899. Example 5
Compound C12 : 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-picen- 2-carboxylic acid methyl ester. 1500 g of Salacia root bark were extracted in 2 liters of a ji-hexane-ethyl ether 1:1 solvent mixture, obtaining 5 grams of a reddish extract after evaporating the solvent. The extract was chromatographed on several silica gel columns, from which compound C12 was obtained. Example 6
Compound C14 : lO-Dimethylcarbamoyloxy-2 ,4a, 6a, 9, 12b, 14a- hexamethyl-ll-oxo-1 , 2 , 3 , 4 , 4a, 5 , 6 , 6a , 11 , 12b, 13 , 14 , 14a, 14b- tetradecahydro-picen-2-carboxylic acid methyl ester
300 g of Maytenus amazonica root bark were extracted in 2 liters of a n-hexane-ethyl ether 1:1 solvent mixture in soxhlet equipment under reflux for 48 hours, obtaining 70 grams of a reddish solid after evaporating the solvent. The extract was chromatographed on a sephadex LH-20 column, using a n-hexane- CHCl3-MeOH 2:1:1 mixture as eluent . 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 called pristimerin was obtained. 65 mg (0.14 mmoles) of pristimerin in 5 ml of dry CH2CI2 were treated with 0.062 ml (3 eq) of dry Et3N, 0.02 ml (1.5 eq) of N, N-dimethylcarbamoyl chloride and catalytic amounts of DMAP. The reaction was carried out at 0°C and under an inert atmosphere, followed by TLC and stirred for 24h. Then 5% diluted hydrochloric acid was added until neutralization. Then the organic phase was extracted with CH2Cl2 and was dried with anhydrous magnesium sulfate. It was filtered and concentrated under reduced pressure. The raw product was purified by preparative chromatography using n-hexane : AcOEt (2:3) as a mobile phase to yield 36 mg (48%) of product C14. The residue corresponded to starting product. 1H NMR (300 MHz, CDCl3) δ 7.00 (IH, dd, J1= 1.4, J2= 7.0 Hz, H- 6) ; 6.46 (IH, d, J= 1.4 Hz, H-I); 6.29 (IH, d, J= 7.2 Hz, H-7); 3.56 (3H, s, OMe); 3.13 (s, N-CH3); 3.00 (s, N-CH3); 2.17 (3H, s, Me- 23); 1.46 (3H, s, Me-25); 1.26 (3H, s, Me-26); 1.17 (3H, s, Me- 30); 1.09 (3H, s, Me-28); 0.54 (3H, s, Me-27). 13C NMR (75 MHz, CDCl3) δ 10.97 (c, C-23) ; 18.09 (c, C-27); 21.63 (c, C-26); 28.39 (t, C-15) ; 29.38 (t, C-12); 29.67 (t, C-21); 30.29 (s, C- 17); 30.61 (t, C-19); 31.34 (c, C-28); 32.40 (c, C-30); 33.45 (t, C-Il); 34.49 (t, C-22); 36.15 (t, C-16); 36.57 (c, N-CH3); 36.58 (c, N-CH3); 37.99 (c, C-25); 38.99 (s, C-13); 40.14 (s, C- 20); 42.23 (s, C-9) ; 44.07 (d, C-18); 44.87 (s, C-14); 51.34 (q, OCH3); 117.5 (d, C-7); 122.9 (d, C-I); 126.5 (s, C-4); 133.1 (s, C-5); 134.5 (d, C-6); 143.0 (s, C-3); 153.9 (s, OCON); 162.6 (s, C-IO); 170.8 (s, C-8); 178.3 (s, C-2); 178.4 (s, C-29). High resolution MS Calculated for C33H45NO5 535.3298, observed 535.3294.
EX VIVO ASSAYS OF HUMAN CHOK ACTIVITY
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 MgCl2, 10 mM ATP and 200 μM of choline in the presence of methyl [14C] -choline chloride (50-60 μCi/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. The 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) ] .
These assays were carried out with the compounds of the invention C3, C7, C8, C9, ClO, C12 and C14 as well as with another eight compounds known in the state of the art (IS 2 117 950) . The results are summarized in table I.
From the obtained results it is concluded that the compounds of the invention allow considerably and selectively reducing the activity of the choline kinase (ChoK) enzyme in cell models. CELL PROLIFERATION ASSAYS
HT-29 cells were seeded in 24-well plates (35 H 103 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. C, Khaless, F., Gallo, M. A., Espmosa, A., Lacal, J. C. Oncogene, 15, 2289-2301 (1997)]. Briefly, the cells were washed with TD buffer and were fixed with 1% glutaraldehyde for 15 mm. After washing again with TD, the cell nuclei were stained with 0.1% Crystal Violet for at least 30 mm and were washed 3 times with distilled water. The adsorbed dye was resuspended in 10% acetic acid and the absorbance at 595 nm was determined in a spectrometer. The obtained results are summarized in the form of an IC50 value, i.e. the concentration of the compound required to cause a 50% inhibition. 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 IC50 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, Cl1 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.
The following table summarizes the results obtained in the conducted assays and which are shown as an example.
Table I
From the data of table I it is observed that the compounds of the present invention have similar antiproliferative values against cells derived from cultured tumors.

Claims

1.- Use of a compound of formula (I) :
(D where :
R1, R2, R3, R4, R5, R6, R7, Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-C10 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a C1-C12 alkyl group; an OCOR group, where R is (CH2) 2COOH or (CH2) 2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and R10 are independently hydrogen; substituted or non- substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-C10 aryl; 0-C1-C12 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a C1-C12 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group; the bond means a double bond or a single bond; and where the tricyclic structure
is selected from the following structures
(a) (b) (c;
(d) (e) (f)
where :
Ri3, Ri4, Ri5, Ri6, R2i, R22 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) ammo group, where RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group; an 0C0RVI11 group, where RVI11 is (CH2) 2COOH or (CH2J2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached or each pair can form a (C=O) group together with the carbon to which they are attached;
Ri7 is hydrogen or methyl;
Ri 8 and Ri8- are independently hydrogen; hydroxyl; halogen; Cx-Ci2 alkyl; C6-Ci0 aryl; C0RIX (where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N(RX) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-Ci2 alcoxyl) ; or trif luoromethyl ;
R19, R19-, R20 and R20- are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a C0RXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-C10 aryl; or N(RXI11) (RXIV) ammo, where RXI11 and RXIV are independently hydrogen or a Ci-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached;
R24 and R25 are independently hydrogen, hydroxyl or halogen;
or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof, in the manufacture of a medicament for the prevention and/or treatment of ChoK mediated disease or condition.
2.- Use according to claim I wherein the compound of formula (I! is a compound of formula (Ia) :
(Ia) where
Ri, R2, R3, R4, R5, R6, R7, Re, Rn and Ri2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; an OCOR group, where R is (CH2) 2COOH or (CH2) 2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Ri0 are independently hydrogen; substituted or non- substituted Cx-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Ci-Ci2 alkyl group); a (CH2) n~0H carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group,
Ri3, Ri4, Ri5 and Ri6 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where
RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group; an
OCORVI11 group , where RVii i i s ( CH2 J 2COOH or ( CH2 J 2CO2CH2CH3 ; or each pai r can form a ( C=O ) group together with the carbon to which they are attached ; Ri 7 i s hydrogen or methyl ;
Ri 8 i s hydrogen ; hydroxyl ; halogen ; Cx-Ci2 alkyl ; C6-Ci0 aryl ; CORIX
(where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N (Rx) (RXI) amino, where Rx and RXI are independently hydrogen or a Ci-Ci2 alkyl group; or Cx-Ci2 alcoxyl) ; or trifluoromethyl;
Ri9 is hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a
CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-C12 alkyl; substituted or non-substituted C6-
C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-C12 alkyl group); a [ (Cx-C12) alkyl-
0- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond.
3.- Use according to claim 2 wherein the compound of formula (Ia) is a compound of formula (Ia') :
:ia') where R5 is hydroxyl or a OCOR group where R is (CH2) 2COOH or
(CHz)2CO2CH2CH3;
R7 and R8 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and
R' ' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
Ri2 is independently hydrogen or a halogen; and Ri9 is hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a
CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-
Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Cx-C12) alkyl- 0- (Cx-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond.
4.- Use according to claim 3 wherein the compound of formula (Ia') is:
3, 9-Dihydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-
2,10-dione;
- Acetic 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;
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- picene-3-yl propionic acid ester; - Dodecanoic 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;
Dimethyl-carbamic acid 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- picen-3-yl ester; 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;
4-bromo- ( 9-hydroxy- 6b, 8a, 11 , 12b, 14a-hexamethyl-2 , 10-dioxo- 2, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a-tetradecahydro- picene-3-yl) benzoic acid ester;
14-Bromo-3, 7, 9-trihydroxy-4 , 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-
2 , 10-dione; - 12-bromo-9-hydroxy-6b,8a, ll,12b,14a-hexamethyl-2, 10-dioxo-
2, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a-tetradecahydro- picene-3-yl dimethyl-carbamic acid ester;
4-bromo- (12-bromo-9-hydroxy-6b, 8a, 11, 12b, 14a-hexamethyl-
2,10-dioxo-2, 6b, 7, 8, 8a, 9, 10 , 11, 12 , 12a, 12b, 13, 14 , 14a- tetradecahydro-picene-3-yl) benzoic acid ester;
- 12-bromo-3, 9-dihydroxy-6b, 8a, 11 , 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bff, 9ff-picene- 2, 10-dione;
- 3, 9, 10-trihydroxy-6b, 8a, 11, 12b, 14a-hexamethyl- 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14 , 14a-dodecahydro-6bH- picene-2-one;
Succinic acid mono- (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;
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.
5.- Use according to claim 2 wherein the compound of formula (Ia) is a compound of formula (Ia''):
( I a " ) where :
R7 and Rg are independently hydrogen, hydroxyl, halogen, substituted or non-substituted Ci-Ci2 alkyl, substituted or non- substituted C6-Ci0 aryl, a N (R') (R'') amino group, where R' and R' ' are independently hydrogen or a Cx-Ci2 alkyl group, or each pair can form a (C=O) group together with the carbon to which they are attached; Ri5 is hydrogen or halogen;
Ri9 is hydrogen, substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6- Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl- 0- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond.
6.- Use according to claim 5 wherein the compound of formula (Ia") is:
- 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; - 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- picene-3-yl acetic acid ester; - 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- picene-3-yl nicotinic acid ester;
- 3, 10-dihydroxy-4, 6b, 8a, 11 , 12b, 14a-hexamethyl- 7,8,8a, 9,10,ll,12,12a,12b,13,14,14a-dodecahydro-6bH- picene-2-one;
- 3-hydroxy-4 , 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 12a, 12b, 13, 14, 14a-octahydro-6bff, 9ff-picene-2, 10- dione
7.- Use according to claim 2 wherein the compound of formula (Ia) is a compound of formula (Ia'''):
(Ia'") where :
R7 is hydrogen, hydroxyl, halogen, substituted or non- substituted Ci-Ci2 alkyl, substituted or non-substituted C6-Ci0 aryl, or a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; and
Ri9 is substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; with the proviso that when Ri9 is hydrogen, R7 is not hydrogen.
8.- Use according to claim 7 wherein the compound of formula (Ia' " ) is:
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; 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;
(lO-dimethylcarbamoyloxy-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
9.- Use according to clam 1 wherein the compound of formula (I) is a compound of formula (Ib) :
( Ib ) where :
R1, R2, R3, R4, R5, R6, R7, Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-C10 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a C1-C12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and R10 are independently hydrogen; substituted or non- substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group,
Ri3, Ri4, Ri5, Ri6, R2i, R22 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where R and R are independently hydrogen or a Ci-C 12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
Ri7 is hydrogen or methyl;
Ri8 is hydrogen; hydroxyl; halogen; Cx-Ci2 alkyl; C6-Ci0 aryl; CORIX (where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N (Rx) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-C12 alcoxyl) ; or trifluoromethyl;
R19 and R20 are independently hydrogen, substituted or non- substituted Cx-C12 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-C12 alkyl; substituted or non-substituted C6-C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-C12 alkyl group); a [ (C1-C12) alkyl-O- (Cx-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond.
10.- Use according to claim 9 wherein the compound of formula (Ib) is a compound of formula (Ib') :
(Ib') where :
Ri9 and R20 are independently substituted or non-substituted C1- C12 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Ci-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; or N(Rxlil) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group) ; a [ (Ci- Ci2) alkyl-0- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl .
11.- Use according to claim 10 wherein the compound of formula (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.
12.- Use according to claim 9 wherein the compound of formula (Ib) is a compound of formula (Ib'') :
:ib") where :
Ri8 is hydrogen; hydroxyl; halogen; Ci-Ci2 alkyl; C6-Ci0 aryl; CORIX (where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N (Rx) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-Ci2 alcoxyl) ; or trifluoromethyl;
Ri9 is hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6- C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-C12 alkyl group); a [ (Cx-C12) alkyl- 0- (Cx-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl;
R23 is hydrogen; hydroxyl; halogen; substituted or non- substituted C1-C12 alkyl; substituted or non-substituted C6-C10 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a C1-C12alkyl group.
13.- Use according to claim 12 wherein the compound of formula (Ib") is: - 7, 10, ll-trihydroxy-2, 4a, 6a, 9, 12b, 14a-hexamethyl-8-oxo- 1,2, 3, 4, 4a, 5, 6, 6a, 8, 12b, 13, 14 , 14a, 14b-tetradecahydro- picene-2-carboxylic acid methyl ester;
9-formyl-10 , 11-dihydroxy-2 , 4a, 6a, 12b, 14a-pentamethyl-8- oxo-1, 2, 3, 4, 4a, 5, 6, 6a, 8 , 12b, 13, 14 , 14a, 14b-tetradecahydro- picene-2-carboxylic acid methyl ester; ll-hydroxy-10- (2-methoxy-ethoxymethoxy) -2, 4a, 6a, 9, 12b, 14a- hexamethyl-8-oxo-l,2,3, 4, 4a, 5, 6, 6a, 8, 12b, 13, 14, 14a, 14b- tetradecahydro-picene-2-carboxylic acid methyl ester
14.- Use according to claim 1 wherein the compound of formula (I) is a compound of formula (Ic) :
( Ic ) where : Ri, R2, R3, R4, R5, R6, R7, Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
R9 and Ri0 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group; Ri3, Ri4, Ri5, Ri6, R2i and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R18 is hydrogen; hydroxyl; halogen; Cx-C12 alkyl; C6-C10 aryl; CORIX (where RIX is hydrogen; hydroxyl; C1-C12 alkyl; N (Rx) (RXI) amino, where Rx and RXI are independently hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl) ; or trifluoromethyl; Ri9 and R20 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Ci-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond.
15. Use according to claim 14 wherein the compound of formula (Ic) is a compound of formula (Ic') :
(IC) where :
Ri9 and R20 are independently hydrogen; substituted or non- substituted Cx-Ci2 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Ci-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where is comprised between 1 and 3) or trifluoromethyl; and the bond means a double bond or a single bond.
16.- Use according to claim 15 wherein the compound of formula (Ic') is:
10, ll-dihydroxy-2 , 4a, 6a, 9, 14a-pentamethyl-
1,4, 4a, 5, 6, 6a, 13, 14,14a, 14b-decahydro-2H-picene-3-one;
10, ll-dihydroxy-2 , 4a, 6a, 9, 14a-pentamethyl-
4a, 5, 6, 6a, 13, 14 , 14a, 14b-octahydro-4H-picene-3-one .
17.- Use according to claim 14 wherein the compound of formula (Ic) is a compound of formula (Ic''):
(Ic") where :
Ri9 and R20 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-0- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl .
18.- Use according to claim 17 wherein the compound of formula
[1C is 10, ll-dihydroxy-2 , 4a, 6a, 9, 14a-pentamethyl-
1,2, 3, 4, 4a, 5, 6, 6a, 13, 14,14a, 14b-dodecahydro-picene-2-carboxylic acid methyl ester.
19.- Use according to claim 1 wherein the compound of formula (I) is a compound of formula (Id) :
(Id) where : Ri, R2, R3, R4, R5, R6, R7, Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
R9 and Ri0 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Ci-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group, Ri3? Ri5? R21 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl ; a N (R VI \ ) / ( TR1VI I i amino group, where
RVI and RVI1 are independently hydrogen or a Cx-Ci2 al kyl group ; or each pair can form a ( C=O ) group together with the carbon to whi ch they are attached ; R18 i s hydrogen ; hydroxyl ; halogen ; Cx-C12 alkyl ; C6-C10 aryl ; CORIX (where RIX i s hydrogen ; hydroxyl ; C1-C12 alkyl ; N (Rx) (RXI ) amino , where Rx and RXI are independently hydrogen or a C1-C12 alkyl group ; or C1-C12 al coxyl ) ; or tri f luoromethyl ; Ri9, Rig', R20 and R20- are independently hydrogen; substituted or non-substituted Ci-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 and R25 are independently hydrogen, hydroxyl or halogen; and the bond means a double bond or a single bond.
20.- Use according to claim 19 wherein the compound of formula (Id) is a compound of formula (Id') :
(Id') where :
R5 and R6 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R' ' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
Rig, Rig-, R20 and R20- are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-C12 alkyl; substituted or non-substituted C6-C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached;
R24 and R25 are independently hydrogen, hydroxyl or halogen.
21.- Use according to calim 20 wherein the compound of formula (Id') is: 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;
- l-bromo-4, 6b, 8a, 11, 12b, 14b-hexamethyl-6b, 7, 8, 8a, 9, 11, 12, 12a, 12b, 14b-decahydro-lH-picene-2, 3, 10-trione .
22.- Use according to claim 19 wherein the compound of formula (Id) is a compound of formula (Id''):
(Id") where :
Ri9, Ri9', R20 and R20- are independently hydrogen; substituted or non-substituted Ci-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 and R25 are independently hydrogen, hydroxyl or halogen.
23.- Use according to claim 22 wherein the compound of formula (Id") is 12-bromo-2, 4a, 6a, 9, 12a, 14a-hexamethyl-10, 11-dioxo- 1,2, 3, 4, 4a, 5, 6, 6a, 10, 11, 12, 12a, 14a, 14b-tetradecahydro-picene-2- carboxylic acid methyl ester.
24.- Use according to claim 1 wherein the compound of formula (I) is a compound of formula (Ie) :
( Ie ) where :
Ri, R2, R3, R4, R5, R6, R7, Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx- C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Ri0 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or an alkyl group Ci-Ci2); a carbinol group (CH2) n-0H (where n is an integer comprised between 1 and 10); or together form a methylene group;
Ri3, Ri4, Ri5, Ri6, R2i and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
Ri8 and Ri8- are independently hydrogen; hydroxyl; halogen; Ci-Ci2 alkyl; C6-Ci0 aryl; CORIX (where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N(RX) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-Ci2 alcoxyl); or trifluoromethyl ;
Ri9, Ri9', R2o and R20. are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-C10 aryl; or N(R' XII I v / RXIV) ammo , where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3) ; trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to which they are attached;
R24 is hydrogen, hydroxyl or halogen; and the bond means a double bond or a single bond.
25.- Use according to claim 24 wherein the compound of formula (Ie) is a compound of formula (Ie') :
(Ie') where :
Ri8 and Ri8- are independently hydrogen; hydroxyl; halogen; Cx-Ci2 alkyl; C6-C10 aryl; CORIX (where RIX is hydrogen; hydroxyl; Cx-C12 alkyl; N(RX) (RXI) amino, where Rx and RXI are independently hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl); or trifluoromethyl ; Ri9, Rig', R20 and R20- are independently hydrogen; substituted or non-substituted Ci-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 is hydrogen, hydroxyl or halogen.
26.- Use according to claim 25 wherein the compound of formula (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.
27.- Use according to claim 1 wherein the compound of formula (I) is a compound of formula (If) :
(if)
where :
Ri, R2, R3, R4, R5, R6, R7, R8, Rn and Ri2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci- Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Ri0 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, Ri3, Ri4, R15, R2i and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a C1-C12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R18 and Ri8- are independently hydrogen; hydroxyl; halogen; C1-C12 alkyl; C6-Ci0 aryl; CORIX (where RIX is hydrogen; hydroxyl; C1-C12 alkyl; N(RX) (RXI) amino, where Rx and RXI are independently hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl); or trifluoromethyl ; R19, R19', R20 and R20- are independently hydrogen; substituted or non-substituted C1-C12 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3) ; trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 is hydrogen, hydroxyl or halogen; and the bond means a double bond or a single bond.
28.- Use according to claim 27 wherein the compound of formula (If) is a compound of formula (If) :
( I f ) where :
Ri8 and Ri8- are independently hydrogen ; hydroxyl ; halogen ; Ci-Ci2 alkyl ; C6-Ci0 aryl ; C0RIX (where RIX i s hydrogen ; hydroxyl ; Cx-Ci2 alkyl ; N ( RX ) ( RXI ) amino , where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group ; or Cx-Ci2 alcoxyl ) ; or trifluoromethyl ;
Rig, Rig-, R20 and R20- are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3) ; trifluoromethyl; or each 19-19' or
20-20' pair can form a group C=O group together with the carbon to which they are attached;
R24 is hydrogen, hydroxyl or halogen.
29.- Use according to claim 28 wherein the compound of formula (If) is 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.
30.- Use of a compound of formula (II) :
where :
Rl I R∑ Λ R3 Λ R4 1 R5 Λ Rδ Λ Rθ Λ RlO Λ Rll Λ Rl2 1 Rl3 Λ Rl4 Λ Rl5 Λ Rl6 Λ Rl7 r Rlβ Λ
RI9 and R2o are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl ; a N ( R XXVV N) ( / πRXVI N amino group, where Rxv and
Rx are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a carboxyl (C=O) group together with the carbon to which they are attached;
R7 and R8 are independently hydrogen; substituted or non- substituted Cx-Ci2 alkyl; C6-Ci0 aryl; a CORXVI1 group (where RXVI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RXVI11) (RXIX) amino, where RXVI11 anc} RXIX are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group,
R2i and R24 are independently substituted or non-substituted Ci- Ci2 alkyl; a CORXX group (where Rxx is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl ; or N ( R XXXXI1 N) ( / -RT1XXI I , amino , where RXXI and R XXII are independently hydrogen or a Cx-Ci2 alkyl group) ; a [ (Cx- C12) alkyl-O- (Cx-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; R22 and R23 are: hydrogen; substituted or non-substituted Cx-C12 alkyl; a
COR XXIII group (where R XXI11 -j_s hydrogen; hydroxyl; substituted or non-substituted Cx-C12 alkyl; substituted or non-substituted CK-CI aryl; or N (RXXIV) (Rxxv) amino, where
RXXIV and Rxxv are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R24 is in the para position with respect to R20; or
OR22' and OR23' respectively, where R22' and R23' are independently hydrogen; substituted or non-substituted C1- Ci2 alkyl; a CORXXVI group (where RXXVI is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N (RXXVI1) (RXXVI11) amino, where RXXVI1 and RXXVI11 are independently hydrogen or a Ci-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R24 is in the meta position with respect to R20. or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof, in the manufacture of a medicament for the prevention and/or treatment of a ChoK mediated disease or condition.
31.- Use according to claim 30 wherein the compound of formula (II) is a compound of formula (Ha) :
(Ha) where :
Rl I R-2 Λ R-3 Λ R4 I R5 Λ Rδ Λ Rθ Λ RlO Λ Rll Λ Rl2 1 Rl3 Λ Rl4 ? Rl5 Λ Rl6 Λ Rl7 I Rlβ Λ
RI9 and R20 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N(RXV) (RXVI) amino group, where Rxv and
Rx are independently hydrogen or a Cx-Ci2 alkyl group ; or each pair can form a carboxyl (C=O) group together with the carbon to which they are attached;
R7 and R8 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a CORXVI1 group (where RXVI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RXVI11) (RXIX) amino, where RXVI11 and RXIX are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group,
R2i and R24 are independently substituted or non-substituted C1- Ci2 alkyl; a CORXX group (where Rxx is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; or N(RXXI) (RXXI1) amino, where RXXI and RXXI1 are independently hydrogen or a Cx-Ci2 alkyl group) ; a [ (C1- Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; R22 and R23 are: hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXXI11 group (where RXXI11 ±S hydrogen; hydroxyl; substituted or non-substituted Cx-C12 alkyl; substituted or non-substituted C6-C10 aryl; or N (RXXIV) (Rxxv) amino, where
RXXIV and Rxxv are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R24 is in the para position with respect to R20; or
OR22' and OR23' respectively, where R22' and R23' are independently hydrogen; substituted or non-substituted C1-
C12 alkyl; a CORXXVI group (where RXXVI is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-C10 aryl; or N (RXXVI1) (RXXVI11) amino, where
RXXVI1 and RXXVI11 are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R24 is in the meta position with respect to R20.
32.- Use according to claim 31 wherein the compound of formula (Ha) is a compound of formula (Ha') :
( Ha ' ) where :
Ri9 and R2o are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N(RXV) (RXVI) amino group, where Rxv and RXVI are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) carboxyl group together with the carbon to which they are attached;
R2i and R24 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N(RXXI) (RXXI1) amino group, where RXXI and RXXI1 are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) carboxyl group together with the carbon to which they are attached;
R22 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N(RXXIV) (Rxxv) amino group, where RXXIV and Rxxv are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) carboxyl group together with the carbon to which they are attached.
33.- Use according to claim 32 wherein the compound of formula (Ha') is 8- [ 2- ( 6 , 7-dihydroxy-l , 5-dimethyl-naphthalen-2-yl) - ethyl] -2, 4a-tetramethyl-l ,2, 3, 4, 4a, 5, 6, 7-octahydro-naphthalen-2- carboxylic acid methyl ester.
34. Use according to any one of claims 1 to 33 wherein the ChoK mediated disease or condition to be prevented and/or treated is cancer, preferably selected from breast, lung, colorectal and pancreatic cancer.
35. Use according to any one of claims 1 to 33 wherein the ChoK mediated disease or condition to be prevented and/or treated is a parasitic disease, more preferably caused by Plasmodium or Trypanosoma .
36. Use according to any one of claims 1 to 33 wherein the ChoK mediated disease or condition to be prevented and/or treated is a parasitic disease, more preferably is a parasitic disease caused by a bacterial disease, preferably caused by Streptococcus .
37. Use according to any one of claims 1 to 33 wherein the ChoK mediated disease or condition to be prevented and/or treated is a fungal disease, preferably caused by Candida.
38. A compound of formula (I) :
(D where :
Ri, R2, R3, R4, R5, Rβr R7, Re? Rn and Ri2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; an OCOR group, where R is (CH2) 2COOH or (CH2) 2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Ri0 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) ammo, where RIV and Rv are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbmol group (where n is an integer comprised between 1 and 10); or together form a methylene group; the bond means a double bond or a single bond; and where the tricyclic structure
is selected from the following structures:
(a) (b ) ( c ;
( d) ( e ) ( f )
where :
Ri3, Ri4, Ri5, Ri6, R2i, R22 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group; an OCORVI11 group, where RVI11 is (CH2) 2COOH or (CH2J2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached or each pair can form a (C=O) group together with the carbon to which they are attached; Ri7 is hydrogen or methyl;
Ri8 and Ri8. are independently hydrogen; hydroxyl; halogen; Cx-Ci2 alkyl; C6-Ci0 aryl; CORIX (where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N(RX) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-Ci2 alcoxyl); or trifluoromethyl ;
R19, R19-, R20 and R20- are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-C12 alkyl group); a [ (Cx-C12) alkyl-O- (Cx-C12) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 and R25 are independently hydrogen, hydroxyl or halogen;
or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof, with the following provisos:
- when the tricyclic structure is (a) then the compound of formula (I) is not:
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; - 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;
3-Hydroxy-4 , 6b, 8a, 11, 12b, 14a-hexamethyl- 7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H- picene-2, 10-dione;
3, 9-Dihydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H- picene-2, 10-dione;
- 3,7, 9-Trihydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl- 7,8,8a,ll,12,12a,12b,13,14,14a-decahydro-6bH,9H- picene-2, 10-dione;
- 14-Bromo-3, 7, 9-trihydroxy-4 , 6b, 8a, 11, 12b, 14a- hexamethyl-7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a- decahydro-6bH, 9H-picene-2 , 10-dione; - Succinic acid mono- (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;
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;
- Acetic 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;
Dodecanoic 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;
Dimethyl-carbamic 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; - 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;
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;
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 .
- when the tricyclic structure is (b) and Ri9 and R2o are independently hydrogen or an acyl group, then:
R5 is hydroxyl; or
R2i and R22 form a C=O group together with the carbon to which they are attached and Ri0 is not
COOH.
- when the tricyclic structure is (c) and Ri9 and R20 are both CH3, then R15 and Ri6 do not form a C=O group together with the carbon to which they are attached.
39. A compound according to claim 38 of formula (Ia)
: ia ) where
R1, R2, R3, R4, R5, R6, R7, Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a C1-C12 alkyl group; an OCOR group, where R is (CH2) 2COOH or (CHz)2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Ri0 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Ci-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group,
Ri3, Ri4, Ri5 and R16 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group; an OCORVI11 group, where RVI11 is (CH2) 2COOH or (CH2) 2CO2CH2CH3; or each pair can form a (C=O) group together with the carbon to which they are attached; Ri7 is hydrogen or methyl; Ri8 is hydrogen; hydroxyl; halogen; Cx-Ci2 alkyl; C6-Ci0 aryl; CORIX (where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N (Rx) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-C12 alcoxyl) ; or trifluoromethyl;
R19 is hydrogen; substituted or non-substituted Cx-C12 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-C12 alkyl; substituted or non-substituted C6- C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-C12 alkyl group); a [ (Cx-C12) alkyl- 0- (C1-C12) 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-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;
- 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;
- 3-Hydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-2, 10- dione; - 3, 9-Dihydroxy-4, 6b, 8a,ll, 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-2, 10- dione;
- 3,7, 9-Trihydroxy-4, 6b, 8a, 11 , 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-2, 10- dione;
- 14-Bromo-3, 7, 9-trihydroxy-4 , 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-2, 10- dione;
- Succinic acid mono- (10-hydroxy-2 , 4a, 6a, 9, 12b, 14a-hexamethyl- 3,ll-dioxo-l,2,3,4,4a,5,6,6a,ll,12b,13,14,14a,14b- tetradecahydro-picen-4-yl) 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;
- Acetic 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;
- Dodecanoic 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;
- Dimethyl-carbamic 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; - 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;
- 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;
- 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.
40. A compound according to claim 39 of formula (Ia') :
(Ia' where
R5 is hydroxyl or OCOR group where R is (CH2) 2COOH or (CHz)2CO2CH2CH3;
R7 and Rg are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R' ' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
Ri2 is independently hydrogen or a halogen; and
Ri9 is hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6- Cio aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Cx-C12) alkyl- O- (Ci-Ci2) 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, 9-Dihydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-
2, 10-dione;
- 14-Bromo-3, 7, 9-trihydroxy-4 , 6b, 8a, 11, 12b, 14a-hexamethyl- 7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene- 2, 10-dione;
- Succinic acid mono- (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; - 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;
- Acetic 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;
- Dodecanoic 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; - Dimethyl-carbamic 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;
- 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.
41. A compound according to claim 40 which is:
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- picene-3-yl propionic acid ester; 4-bromo- ( 9-hydroxy- 6b, 8a, 11 , 12b, 14a-hexamethyl-2 , 10-dioxo-
2, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a-tetradecahydro- picene-3-yl) benzoic acid ester;
12-bromo-3, 9-dihydroxy-4 , 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bff, 9ff-picene-
2, 10-dione;
12-bromo-9-hydroxy-6b, 8a, 11, 12b, 14a-hexamethyl-2, 10-dioxo-
2, 6b, 7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a-tetradecahydro- picene-3-yl dimethyl-carbamic acid ester;
4-bromo- (12-bromo-9-hydroxy-6b, 8a, 11, 12b, 14a-hexamethyl-
2,10-dioxo-2, 6b, 7, 8, 8a, 9, 10 , 11, 12 , 12a, 12b, 13, 14 , 14a- tetradecahydro-picene-3-yl) benzoic acid ester;
3, 9, 10-trihydroxy-6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14 , 14a-dodecahydro-6bff- picene-2-one .
42. A compound according to claim 39 of formula (Ia'
(Ia") where:
R7 and R8 are independently hydrogen, hydroxyl, halogen, substituted or non-substituted Ci-Ci2 alkyl, substituted or non- substituted C6-Ci0 aryl, a N (R') (R'') amino group, where R' and R' ' are independently hydrogen or a Cx-Ci2 alkyl group, or each pair can form a (C=O) group together with the carbon to which they are attached; Ri5 is hydrogen or halogen; Ri9 is hydrogen, substituted or non-substituted Ci-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6- Cio aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl- 0- (Ci-Ci2) 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,ll, 12b, 14a-hexamethyl-
7, 8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14 , 14a-dodecahydro-6bH-picen- 2-one; - 3-Hydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene- 2,10-dione.
43. A compound according to claim 42 which is:
- 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;
- 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- picene-3-yl acetic acid ester;
- 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 nicotinic acid ester;
- 3, 10-dihydroxy-4, 6b, 8a, 11 , 12b, 14a-hexamethyl- 7,8,8a, 9,10,ll,12,12a,12b,13,14,14a-dodecahydro-6bH- picene-2-one; - 3-hydroxy-4, 6b, 8a, 11, 12b, 14a-hexamethyl-
7, 8, 8a, 12a, 12b, 13, 14, 14a-octahydro-6bH, 9H-picene-2, 10- dione .
44. A compound according to claim 39 of formula (Ia''') :
(Ia'") where :
R7 is hydrogen, hydroxyl, halogen, substituted or non- substituted Ci-Ci2 alkyl, substituted or non-substituted C6-Ci0 aryl, or a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; and
R- is substituted or non-substituted Cx-Ci2 alkyl; a COR group
(where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or
N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) 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-
1,2, 3, 4, 4a, 5, 6, 6a, 11, 12b, 13, 14, 14a, 14b-tetradecahydro- picene-2-carboxylic acid methyl ester; - 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.
45. A compound according to claim 44 which is:
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;
10-dimethylcarbamoyloxy-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.
46. A compound according to claim 38 of formula (Ib) :
( Ib ) where : Ri, R2, R3, R4, R5, R6, R7, Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx- C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R' ) (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
R9 and Ri0 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, Ri3, Ri4, Ri5, Ri6, R2i, R22 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R17 is hydrogen or methyl;
R18 is hydrogen; hydroxyl; halogen; Cx-Ci2 alkyl; C6-Ci0 aryl; CORIX (where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N (Rx) (RXI) amino, where Rx and RXI are independently hydrogen or a CX-CX2 alkyl group; or Cx-C12 alcoxyl) ; or trifluoromethyl; Ri9 and R20 are independently hydrogen, substituted or non- substituted Ci-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) 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 Ri9 and R20 are independently hydrogen or an acyl group, then: R5 is hydroxyl; or
R2i and R22 form a C=O group together with the carbon to which they are attached and Ri0 is not COOH.
47. A compound according to claim 46 of formula (Ib'
( Ib ' ) where :
Ri9 and R20 are independently substituted or non- substituted C1- Ci2 al kyl ; a C0RXI 1 group (where RXI 1 i s hydrogen ; hydroxyl ; substituted or non- substituted Cx-Ci2 alkyl ; substituted or non- substituted C6-Ci0 aryl; or N(R XXIiIiIis) /(πRX-IV ι amino, where RXI11 and R are independently hydrogen or a Cx-Ci2 alkyl group) ; a [ (Ci- Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl .
48. A compound according to claim 47 which is 4-nitro- (3- dimethy1carbamoyloxy-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.
49. A compound according to claim 46 of formula (Ib'') :
where :
Ri8 is hydrogen; hydroxyl; halogen; Ci-Ci2 alkyl; C6-Ci0 aryl; CORIX (where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N (Rx) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-Ci2 alcoxyl) ; or trifluoromethyl;
Ri9 is hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6- C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-C12 alkyl group); a [ (Cx-C12) alkyl- 0- (Cx-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl;
R23 is hydrogen; hydroxyl; halogen; substituted or non- substituted C1-C12 alkyl; substituted or non-substituted C6-C10 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a C1-C12alkyl group.
50. A compound according to claim 49 which is: - 7 , 10 , ll-trihydroxy-2 , 4a, 6a, 9, 12b, 14a-hexamethyl-8-oxo- 1,2, 3, 4, 4a, 5, 6, 6a, 8, 12b, 13, 14 , 14a, 14b-tetradecahydro- picene-2-carboxylic acid methyl ester; 9-formyl-10 , 11-dihydroxy-2 , 4a, 6a, 12b, 14a-pentamethyl-8- oxo-1, 2, 3, 4, 4a, 5, 6, 6a, 8 , 12b, 13, 14 , 14a, 14b-tetradecahydro- picene-2-carboxylic acid methyl ester; ll-hydroxy-10- (2-methoxy-ethoxymethoxy) -2, 4a, 6a, 9, 12b, 14a- hexamethyl-8-oxo-l,2,3, 4, 4a, 5, 6, 6a, 8, 12b, 13, 14, 14a, 14b- tetradecahydro-picene-2-carboxylic acid methyl ester.
51. A compound according to claim 38 of formula (Ic) :
(Ic) where :
Ri, R2, R3, R4, R5, R6, R7, Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Ri0 are independently hydrogen; substituted or non- substituted Cx-Ci2 alkyl; C6-Ci0 aryl; a COR"' group (where R'" is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group;
Ri3, Ri4, R15, Ri6, R2i and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a Ci-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
Ri8 is hydrogen; hydroxyl; halogen; Cx-Ci2 alkyl; C6-Ci0 aryl; CORIX (where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N (Rx) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-Ci2 alcoxyl) ; or trifluoromethyl;
Ri9 and R20 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Ci-Ci2 alkyl;
^-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, XIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Cx-C12) alkyl-O- (Cx-C12) 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 R19 and R20 are both CH3, then R15 and R16 do not form a C=O group together with the carbon to which they are attached.
52. A compound according to claim 51 of formula (Ic') :
( I C ) where :
R19 and R20 are independently hydrogen ; substituted or non- substituted C1-C12 al kyl ; a CORXI I group (where RXI I i s hydrogen ; hydroxyl ; substituted or non- substituted C1-C12 al kyl ; substituted or non- substituted C6-C10 aryl ; or N ( RXI11 ) (RXIV) amino , where RXI11 and RXIV are independently hydrogen or a C1-C12 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where is comprised between 1 and 3) or trifluoromethyl; and the bond means a double bond or a single bond.
53. A compound according to claim 52 which is:
10, ll-dihydroxy-2 , 4a, 6a, 9, 14a-pentamethyl-
1,4, 4a, 5, 6, 6a, 13, 14,14a, 14b-decahydro-2fl-picene-3-one;
10, ll-dihydroxy-2 , 4a, 6a, 9, 14a-pentamethyl-
4a, 5, 6, 6a, 13, 14 , 14a, 14b-octahydro-4H-picene-3-one .
54. A compound according to claim 51 of formula (Ic''
(Ic") where :
Ri9 and R2o are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl .
55. A compound according to claim 54 which is 10 , 11-dihydroxy- 2,4a, 6a, 9, 14a-pentamethyl-l , 2 , 3, 4 , 4a, 5, 6, 6a, 13, 14, 14a, 14b- dodecahydro-picene-2-carboxylic acid methyl ester.
56. A compound according to claim 38 of formula (Id) :
(Id) where : Ri, R2, R3, R4, R5, R6, R7, Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
R9 and Ri0 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Ci-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group, Ri3? Ri5? R21 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl ; a N (R VI \ ) / ( TR1VI I i amino group, where
RVI and RVI1 are independently hydrogen or a Cx-Ci2 al kyl group ; or each pair can form a ( C=O ) group together with the carbon to whi ch they are attached ; R18 i s hydrogen ; hydroxyl ; halogen ; Cx-C12 alkyl ; C6-C10 aryl ; CORIX (where RIX i s hydrogen ; hydroxyl ; C1-C12 alkyl ; N (Rx) (RXI ) amino , where Rx and RXI are independently hydrogen or a C1-C12 alkyl group ; or C1-C12 al coxyl ) ; or tri f luoromethyl ; Ri9, Ri9', R20 and R20- are independently hydrogen; substituted or non-substituted Ci-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 and R25 are independently hydrogen, hydroxyl or halogen; and the bond means a double bond or a single bond.
57. A compound according to claim 56 of formula (Id'
(Id') where :
R5 and R6 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
Ri9, Ri9', R2o and R20- are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-C12 alkyl; substituted or non-substituted C6-C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached;
R24 and R25 are independently hydrogen, hydroxyl or halogen.
58. A compound according to claim 57 which is: 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; l-bromo-4, 6b, 8a, 11, 12b, 14b-hexamethyl- 6b, 7, 8, 8a, 9, 11, 12 , 12a, 12b, 14b-decahydro-lH-picene-2 , 3, 10- trione .
59. A compound according to claim 56 of formula (Id
(Id") where :
Rig, Rig-, R2O and R20- are independently hydrogen; substituted or non-substituted Ci-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached;
R24 and R25 are independently hydrogen, hydroxyl or halogen.
60. A compound according to claim 59 which is 12-bromo- 2, 4a, 6a, 9, 12a, 14a-hexamethyl-10 , 11-dioxo- 1,2, 3, 4, 4a, 5, 6, 6a, 10, 11, 12, 12a, 14a, 14b-tetradecahydro-picene-2- carboxylic acid methyl ester.
61. A compound according to claim 38 of formula (Ie) :
( Ie ) where :
Ri, R2, R3, R4, R5, R6, R7, Re? Rn and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Ri0 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Ci-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or an alkyl group Ci-Ci2); a carbinol group (CH2) n-0H (where n is an integer comprised between 1 and 10); or together form a methylene group; Ri3, Ri4, Ri5, Ri6, R2x and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a Ci-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
Ri8 and Ri8- are independently hydrogen; hydroxyl; halogen; Ci-Ci2 alkyl; C6-Ci0 aryl; CORIX (where RIX is hydrogen; hydroxyl; Cx-Ci2 alkyl; N(RX) (RXI) amino, where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group; or Cx-Ci2 alcoxyl); or trifluoromethyl ;
Ri9, Ri9', R2o and R20. are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-C10 aryl; or N(R' XII I v / RXIV) ammo , where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3) ; trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to which they are attached;
R24 is hydrogen, hydroxyl or halogen; and the bond means a double bond or a single bond.
62. A compound according to claim 61 of formula (Ie'
( Ie ' ) where :
Ri 8 and Ri8- are independently hydrogen ; hydroxyl ; halogen ; Cx-Ci2 alkyl ; C6-C10 aryl ; CORIX (where RIX i s hydrogen ; hydroxyl ; Cx-C12 alkyl ; N ( RX ) ( RXI ) amino , where Rx and RXI are independently hydrogen or a C1-C12 alkyl group ; or C1-C12 alcoxyl ) ; or tri f luoromethyl ; Ri9, Rig', R20 and R20- are independently hydrogen; substituted or non-substituted Ci-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 is hydrogen, hydroxyl or halogen.
63. A compound according to claim 62 which 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.
64. A compound according to claim 38 of formula (If)
(If)
where :
Ri, R2, R3, R4, R5, R6, R7, R8, Rn and Ri2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1- Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; a N (R') (R'') amino group, where R' and R'' are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Ri0 are independently hydrogen; substituted or non- substituted Ci-Ci2 alkyl; C6-Ci0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RIV) (Rv) amino, where RIV and Rv are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, Ri3, Ri4, R15, R2i and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-Ci0 aryl; a N(RVI) (RVI1) amino group, where RVI and RVI1 are independently hydrogen or a C1-C12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R18 and Ri8- are independently hydrogen; hydroxyl; halogen; C1-C12 alkyl; C6-Ci0 aryl; CORIX (where RIX is hydrogen; hydroxyl; C1-C12 alkyl; N(RX) (RXI) amino, where Rx and RXI are independently hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl); or trifluoromethyl ; R19, R19', R20 and R20- are independently hydrogen; substituted or non-substituted C1-C12 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-Ci0 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a C1-C12 alkyl group); a [ (C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3) ; trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R24 is hydrogen, hydroxyl or halogen; and the bond means a double bond or a single bond.
65. A compound according to claim 64 of formula (If) :
( I f ) where :
Ri8 and Ri8- are independently hydrogen ; hydroxyl ; halogen ; Ci-Ci2 alkyl ; C6-Ci0 aryl ; C0RIX (where RIX i s hydrogen ; hydroxyl ; Cx-Ci2 alkyl ; N ( RX ) ( RXI ) amino , where Rx and RXI are independently hydrogen or a Cx-Ci2 alkyl group ; or Cx-Ci2 alcoxyl ) ; or trifluoromethyl ;
Rig, Rig-, R20 and R20- are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXI1 group (where RXI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-C10 aryl; or N(RXI11) (RXIV) amino, where RXI11 and RXIV are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-0- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3) ; trifluoromethyl; or each 19-19' or
20-20' pair can form a group C=O group together with the carbon to which they are attached;
R24 is hydrogen, hydroxyl or halogen.
66. A compound according to claim 65 which 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.
67. A compound of formula (II) :
where :
Rl I R∑ Λ R3 Λ R4 1 R5 Λ Rδ Λ Rθ Λ RlO Λ Rll Λ Rl2 1 Rl3 Λ Rl4 Λ Rl5 Λ Rl6 Λ Rl7 r Rlβ Λ
RI9 and R2o are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl ; a N ( R XXVV N) ( / πRXVI N amino group, where Rxv and
Rx are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a carboxyl (C=O) group together with the carbon to which they are attached;
R7 and R8 are independently hydrogen; substituted or non- substituted Cx-Ci2 alkyl; C6-Ci0 aryl; a CORXVI1 group (where RXVI1 is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RXVI11) (RXIX) amino, where RXVI11 anc} RXIX are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group,
R2i and R24 are independently substituted or non-substituted Ci- Ci2 alkyl; a CORXX group (where Rxx is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl ; or N ( R XXXXI1 N) ( / -RT1XXI I , amino , where RXXI and R XXII are independently hydrogen or a Cx-Ci2 alkyl group) ; a [ (Cx- C12) alkyl-O- (Cx-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; R22 and R23 are: hydrogen; substituted or non-substituted Cx-C12 alkyl; a
COR XXIII group (where R XXI11 -j_s hydrogen; hydroxyl; substituted or non-substituted Cx-C12 alkyl; substituted or non-substituted CK-CI aryl; or N (RXXIV) (Rxxv) amino, where
RXXIV and Rxxv are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R24 is in the para position with respect to R20; or
OR22' and OR23' respectively, where R22' and R23' are independently hydrogen; substituted or non-substituted C1- Ci2 alkyl; a CORXXVI group (where RXXVI is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; or N (RXXVI1) (RXXVI11) amino, where RXXVI1 and RXXVI11 are independently hydrogen or a Ci-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R24 is in the meta position with respect to R20. or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof.
A compound according to claim 67 of formula (Ha) :
( H a ) where :
Rl I R-2Λ R-3Λ R4 I RδΛ RδΛ R9Λ RlO I Ri Ri Ri Ri Ri Ri Ri Ri
Ri9 and R20 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N(RXV) (RXVI) amino group, where Rxv and RXVI are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a carboxyl (C=O) group together with the carbon to which they are attached;
R7 and R8 are independently hydrogen; substituted or non- substituted Cx-Ci2 alkyl; C6-Ci0 aryl; a CORXVI1 group (where RXVI1 is hydrogen; hydroxyl; substituted or non-substituted Ci-Ci2 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-Ci-Ci2 alkyl; or N(RXVI11) (RXIX) amino, where RXVI11 and RXIX are independently hydrogen or a Cx-Ci2 alkyl group); a (CH2) n-0H carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group,
R2i and R24 are independently substituted or non-substituted C1- Ci2 alkyl; a CORXX group (where Rxx is hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; or N(RXXI) (RXXI1) amino, where RXXI and RXXI1 are independently hydrogen or a Cx-Ci2 alkyl group) ; a [ (Cx- Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; R22 and R23 are: - hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a COR XXIII group (where R XXI11 -j_s hydrogen; hydroxyl; substituted or non-substituted Cx-Ci2 alkyl; substituted or non-substituted C6-C10 aryl; or N (RXXIV) (Rxxv) amino, where RXXIV and Rxxv are independently hydrogen or a Cx-Ci2 alkyl group); a [ (Ci-Ci2) alkyl-O- (Ci-Ci2) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R24 is in the para position with respect to R20; or
OR22' and OR23' respectively, where R22' and R23' are independently hydrogen; substituted or non-substituted Cx-Ci2 alkyl; a CORXXVI group (where RXXVI ±S hydrogen; hydroxyl; substituted or non- substituted Cx-C12 alkyl; substituted or non-substituted C6-C 10 aryl; or N (RXXVI1) (RXXVI11) amino, where RXXVI1 and RXXVI11 are independently hydrogen or a Cx-C12 alkyl group); a [ (Cx-C12) alkyl- 0- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl when R24 is in the meta position with respect to R20.
69. A compound according to claim 68 of formula (Ha') :
( Ha ' ) where :
Ri9 and R20 are independently hydrogen ; hydroxyl ; halogen ; substituted or non- substituted Ci-Ci2 alkyl ; substituted or non- substituted C6-Ci0 aryl; a N(R XXVV N) (/πRXVIv amino group, where R and
RA are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) carboxyl group together with the carbon to which they are attached;
R2i and R24 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N(RXXI) (RXXI1) amino group, where RXXI and
Rx are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) carboxyl group together with the carbon to which they are attached;
R22 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cx-Ci2 alkyl; substituted or non- substituted C6-Ci0 aryl; a N(RXXIV) (Rxxv) amino group, where RXXIV and Rxxv are independently hydrogen or a Cx-Ci2 alkyl group; or each pair can form a (C=O) carboxyl group together with the carbon to which they are attached.
70.- A pharmaceutical composition which comprises a compound of formula (I) or (II) as defined in any one of claims 38 to 69 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.
71.- A compound as defined in any one of claims 38 to 69 or mixtures thereof, or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof for use in the treatment of a ChoK mediated disease or condition.
EP06830856A 2005-12-30 2006-12-29 Triterpenequinone and triterpenephenol derivatives and their application for the treatment of tumors and parasitic diseases Withdrawn EP1976533A2 (en)

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