AU2006334359A1 - 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 Download PDF

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AU2006334359A1
AU2006334359A1 AU2006334359A AU2006334359A AU2006334359A1 AU 2006334359 A1 AU2006334359 A1 AU 2006334359A1 AU 2006334359 A AU2006334359 A AU 2006334359A AU 2006334359 A AU2006334359 A AU 2006334359A AU 2006334359 A1 AU2006334359 A1 AU 2006334359A1
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substituted
alkyl
group
independently hydrogen
hydroxyl
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AU2006334359A2 (en
Inventor
Monica Banez Coronel
Ana Estevez Braun
Angel Gutierrez Ravelo
Juan Carlos Lacal Sanjuan
Elisa Perez Sacau
Ana Ramirez De Molina
Dulce Yazmin Mesa Siverio
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Consejo Superior de Investigaciones Cientificas CSIC
Universidad de La Laguna
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Consejo Superior de Investigaciones Cientificas CSIC
Universidad de La Laguna
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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
    • A61K31/21—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
    • 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
    • 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

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  • Health & Medical Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Communicable Diseases (AREA)
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  • Tropical Medicine & Parasitology (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Description

WO 2007/077203 PCT/EP2006/070276 1 TRITERPENEQUINONE AND TRITERPENEPHENOL DERIVATIVES AND THEIR APPLICATION FOR THE TREATMENT OF TUMORS AND PARASITIC DISEASES FIELD OF THE INVENTION 5 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 10 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. 15 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 20 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, 25 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 30 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 35 oncogenes in human carcinogenesis and that ChoK inhibition has been shown to be a new and effective antitumor strategy in cells WO 2007/077203 PCT/EP2006/070276 2 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 5 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., 10 Jim6nez B. and Lacal J.C. Oncogene 8, 2959-2968 (1993); Jim6nez 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., Nifez, M. C., Khaless, F., Gallo, M. A., Espinosa, A., Lacal, J. C. Oncogene, 15, 2289-2301 (1997)]. This 15 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 20 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 (W098/05644) . However, these 25 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 30 human models with leukemia [Nagase, M., Oto, J., Sugiyama, S., Yube, K., Takaishi, and Sakato, N., Biosci. Biotechnol. Biochem 67, 1883 (2003)1 . 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 35 sense, application US 2004/0220267 describes celastrol and pristimerin derivatives which allow improving the toxicity problem.
WO 2007/077203 PCT/EP2006/070276 3 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 5 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 10 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. 15 Thus, in one aspect the present invention relates to the use of a compound of formula (I):
R
10
R
9 R 1 * R i~ R12 R7
CH
3 -lIR 6 ( ) H CH 3 (A) (Bj H 3 C R R,
R
2 (I) where: 20 RI, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 and R 1 2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI
C
1 2 alkyl; substituted or non-substituted C 6 -Co aryl; a N(R') (R'') amino group, where R' and R' are independently hydrogen or a C 1
-C
1 2 alkyl group; an OCOR group, where R is 25 (CH 2
)
2 COOH or (CH 2
)
2
CO
2
CH
2
CH
3 ; or each pair can form a (C=O) group together with the carbon to which they are attached;
R
9 and RIO are independently hydrogen; substituted or non substituted C 1
-C
1 2 alkyl; C 6
-C
1 o aryl; a COR"' group (where R"' is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 30 alkyl; substituted or non-substituted C 6 -Co aryl; 0-C-C 1 2 alkyl; WO 2007/077203 PCT/EP2006/070276 4 or N(RIv) (Rv) amino, where RIv and Rv are independently hydrogen or a C 1
-C
1 2 alkyl group) ; a (CH 2 ) n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group; 5 the bond :------- means a double bond or a single bond; and where the tricyclic structure is selected from the following structures: 10
R
14
R
13
R
1 4
R
13
R
14
R
13 Ris R Rs 1R R o""Ri,'""" R, ""' 0 R 20 0 R 20 0 R17 R17 R,,O aR,,O ,R1,,O R 23
R
18 Ric R 21
R
22
R
18
R
21 (a) (b) (c)
R
13
R
14
R
13
R
1 4
R
1 3 15l hR 15 n -R 1 R R R 161" R
R
2 4
R
25 R 4 CH
R
20 R20
CH
3 CCHHf R20\' R20 CH R20' R1,' / R20"' H R20'\"R
R
23 23 R 23
R
18
R
21
RI
8 ' R 1 8
R
21 RP' R 1 8
R
21 (d) (e) (f) where:
R
13 , R 1 4 r R 15 , R 16 , R 21 , R 2 2 and R 2 3 are independently hydrogen; 15 hydroxyl; halogen; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6
-CI
0 aryl; a N(RvI) (RvII) amino group, where RvI and RvII are independently hydrogen or a CI-C 12 alkyl group; an OCORvIII group, where RvIII is (CH 2 ) 2 COOH or WO 2007/077203 PCT/EP2006/070276 5
(CH
2
)
2
CO
2
CH
2
CH
3 ; 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;
R
17 is hydrogen or methyl; 5 R 18 and R 18 , are independently hydrogen; hydroxyl; halogen; Ci-C 1 2 alkyl; C 6
-C
1 0 aryl; CORIx (where RIx is hydrogen; hydroxyl; Ci-C 1 2 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a CI-C 1 2 alkyl group; or CI-C 12 alcoxyl); or trifluoromethyl; 10 R 19 , R 19 , R 20 and R 20 , are independently hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a CORxI group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6
-C
0 aryl; or N(RxulI) (RxV) amino, where RxIII and RxV are independently hydrogen or a Ci-C 1 2 alkyl 15 group); a [(C 1
-C
1 2 )alkyl-O-(C 1
-C
1 2 )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;
R
24 and R 25 are independently hydrogen, hydroxyl or halogen; 20 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. 25 In another aspect, the present invention refers to the use of a compound of formula (II): R7 R8 R6 *. R R2 R3 Rs R,, R4 R1o R23 C _'12 RR8 3 , *"liR13 / R17 *-, R14 R22 R19 R16 R1s 21 R20 (II) 30 WO 2007/077203 PCT/EP2006/070276 6 where:
R
1 , R 2 , R 3 , R 4 , Rs, Re, Rg, Ro 0 , R 11 , R 12 , R 13 , R 14 , R 1 is, R 16 , R 17 , R 1 8 ,
R
19 and R 20 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 12 alkyl; substituted or non 5 substituted C 6
-C
1 0 aryl; a N(RxV) (RxvI) amino group, where Rxv and
R
x are independently hydrogen or a CI-C 12 alkyl group; or each pair can form a carboxyl (C=O) group together with the carbon to which they are attached;
R
7 and R 8 are independently hydrogen; substituted or non 10 substituted CI-C 1 2 alkyl; C 6
-C
0 aryl; a COR xv I group (where R xv I is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6
-C
0 lo aryl; 0-CI-C 12 alkyl; or N(RxvI l ) (RxIx) amino, where R xv
I
l and RxIx are independently hydrogen or a C 1
-C
1 2 alkyl group) ; a (CH 2 )n-OH carbinol group 15 (where n is an integer comprised between 1 and 10); or together form a methylene group,
R
2 1 and R 2 4 are independently substituted or non-substituted C 1 C 1 2 alkyl; a COR xx group (where R xx is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
1 2 alkyl; substituted or non 20 substituted C 6
-C
1 0 aryl; or N(RxxI) (Rxx") amino, where R xx ' and RxxII 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;
R
2 2 and R 2 3 are: 25 - hydrogen; substituted or non-substituted CI-C 1 2 alkyl; a CORxxIII group (where RxxIII is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6 -Co 0 aryl; or N(RxxIv) (Rxxv) amino, where RxxIv and R xxv are independently hydrogen or a C 1
-C
12 alkyl 30 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 2 3 ' respectively, where R 22 ' and R 23 ' are independently hydrogen; substituted or non-substituted C 1 35 C 12 alkyl; a COR xxw group (where R xx is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or WO 2007/077203 PCT/EP2006/070276 7 non-substituted C 6 -Co 0 aryl; or N(RxxvII) (RxxvIII) amino, where
R
xxv n and R xxv I 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 5 in the meta position with respect to R 20 . 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. 10 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. 15 In another aspect the present invention relates to compounds of general formula (I):
R
1 0
R
9
R
1
-
""\R8 R 1 2 R CH3
(I
6 20 where:
R
1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 and R 1 2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci ( ) H CH35 '//iR4 (A)(8 HC R,,R BjHCR, R2 20 where: RI, R2, R3, R4r R5, R6, R7, R8, RII and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI
C
1 2 alkyl; substituted or non-substituted C 6
-CI
0 aryl; a N(R') (R'') amino group, where R' and R'' are independently 25 hydrogen or a C 1
-C
1 2 alkyl group; an OCOR group, where R is
(CH
2
)
2 COOH or (CH 2
)
2
CO
2
CH
2
CH
3 ; 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 1
-C
12 alkyl; C 6
-C
1 0 aryl; a COR''' group (where R''' 30 is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 WO 2007/077203 PCT/EP2006/070276 8 alkyl; substituted or non-substituted C 6
-CI
0 aryl; 0-CI-C 12 alkyl; or N(RI") (RV) amino, where RIV and Rv are independently hydrogen or a CI-C 12 alkyl group) ; a (CH2) n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a 5 methylene group; the bond ------- means a double bond or a single bond; and where the tricyclic structure 10 is selected from the following structures:
R
14
R
13
R
1 4
R
13
R
1 4
R
1 3 Ri R Is I Ri 15 Re""Rj,'"'" RI '"'I 0 R 20 0 R 20 0 Ray R17
R
19 0 R 19 0 -- R 1 O 23 R18 RI, R 21
R
22 Rip R 21 (a) (b) (c) Ri R 14
R
13
R
1 4
R
13 R 15h
R
24 1R2 R20'CH R20 CH 3 R20\s""" R201"""" CH 3 R20" Rq, Rl,' R I\R R,' $ F R23R * 2 3 R, ' 2 3
R
18
R
2 1
R
18 ' R 1 8
R
21 Rio' R 1 8
R
21 (d) (e) (f) where: 15 R 13 , R 1 4 r R 15 , R 16 , R 21 , R 22 and R 23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6 -CIo aryl; a N(RvI) (RVII) amino group, where RV and RVII are independently hydrogen or a CI-C 12 WO 2007/077203 PCT/EP2006/070276 9 alkyl group; an OCOR"III group, where RvIII is (CH 2
)
2 COOH or
(CH
2
)
2
CO
2
CH
2
CH
3 ; 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; 5 R17 is hydrogen or methyl;
R
18 and R 18 , are independently hydrogen; hydroxyl; halogen; C1-C 1 2 alkyl; C 6 -Co 0 aryl; CORIx (where RIx is hydrogen; hydroxyl; C1-C 1 2 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a C 1
-C
1 2 alkyl group; or C 1
-C
12 alcoxyl); or 10 trifluoromethyl;
R
19 , R 19 , R 20 and R 20 , are independently hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
1 2 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; or N(RxI) (RxIv) amino, 15 where RxIII and RxIv are independently hydrogen or a C1-C 1 2 alkyl group); a [(C 1
-C
1 2 )alkyl-O-(C 1
-C
1 2 )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; 20 R 24 and R 25 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 25 formula (I) is not: - 10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-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-11-oxo 30 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-11 oxo-1,2,3,4,4a,5,6,6a,11,12b, 13,14,14a,14b 35 tetradecahydro-picene-2-carboxylic acid methyl ester; WO 2007/077203 PCT/EP2006/070276 10 - 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 5 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; 10 - 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 15 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 20 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; 25 - 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 30 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 35 2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a tetradecahydro-picen-3-yl ester; WO 2007/077203 PCT/EP2006/070276 11 - 3,10-Dihydroxy-2,4a,6a,9,12b,14a-hexamethyl-11 oxo-1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b tetradecahydro-picene-2-carboxylic acid methyl ester; 5 - 10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-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 R 1 9 and R 2 0 are 10 independently hydrogen or an acyl group, then: - R 5 is hydroxyl; or - R 2 1 and R 2 2 form a C=O group together with the carbon to which they are attached and R 10 is not COOH. 15 - when the tricyclic structure is (c) and R 19 and R 20 are both CH 3 , then R 15 and R 16 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 20 formula (II): R7 R8
R
6 where : 25 RR, R 2 , R 3 , R 4 , R 5 , R, R ,, R2 R, R 2 , R5 3 , R 4 , R, R, R, R, R23 C12 Iz R18 -..mR13 / R 17 ''z R 14 R22 R19 R16 R1s R21 R20 where: 25 RI, R2, R3, R4r R51 R,1 R9, Rjor RIu, R12r R13, R14r RIs, R16, R17, RIu,
RI
9 and R 2 0 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1
-C
1 2 alkyl; substituted or non substituted C 6 -Co 0 aryl; a N(Rxv) (RxvI) amino group, where Rxv and
R
x " are independently hydrogen or a C 1
-C
12 alkyl group; or each WO 2007/077203 PCT/EP2006/070276 12 pair can form a carboxyl (C=O) group together with the carbon to which they are attached;
R
7 and R 8 are independently hydrogen; substituted or non substituted CI-C 12 alkyl; C 6
-C
0 aryl; a CORxv group (where Rxv 5 is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6
-C
0 lo aryl; 0-CI-C 1 2 alkyl; or N(RxvIII) (RxIx) amino, where R xv I I I and RxIx are independently hydrogen or a C-C 12 alkyl group); a (CH 2 )n-OH carbinol group (where n is an integer comprised between 1 and 10); or together 10 form a methylene group,
R
21 and R 24 are independently substituted or non-substituted Cj
C
12 alkyl; a COR xx group (where R xx is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non substituted C 6
-C
1 0 aryl; or N(Rxx) (RxxII) amino, where R xxl and RxxII 15 are independently hydrogen or a C 1
-C
12 alkyl group) ; a [(Cl
C
12 )alkyl-O-(C 1
-C
1 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 CI-C 1 2 alkyl; a 20 CORxxIII group (where RxxIII is hydrogen; hydroxyl; substituted or non-substituted C-C 12 alkyl; substituted or non-substituted C 6
-C
0 lo aryl; or N(RxxIv) (Rxxv) amino, where RxxIv and R xxv are independently hydrogen or a CI-C 12 alkyl group); a [(C 1
-C
12 )alkyl-O-(C 1
-C
1 2 )alkyl-]n group (where n is 25 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 2 3 ' respectively, where R 22 ' and R 23 ' are independently hydrogen; substituted or non-substituted C 1 C 12 alkyl; a COR x w l group (where R xxw is hydrogen; hydroxyl; 30 substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; or N(Rxxv w I) (RxxvII) amino, where
R
xx v w and R xxw n are independently hydrogen or a CI-C 12 alkyl group); a [(C-C 1 2 )alkyl-O-(C 1
-C
2 )alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl when R 24 is 35 in the meta position with respect to R 20
.
WO 2007/077203 PCT/EP2006/070276 13 or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof. In another aspect, the invention is directed to a 5 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 10 to a patient. DETAILED DESCRIPTION OF THE INVENTION One object of the present invention is the use of a compound of formula (I) ,RR
R
1 0
R
9
CH
3
R
7 - -111R "ll 6 R5 (7) H CH 3 ""'"R4 (A) (8) H3C -, R3 R,
R
2 15 (I) where: RI, R 2 , R 3 , R 4 , R 5 , R,, R,, R,, RII and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI 20 C 12 alkyl; substituted or non-substituted C 6 -CIo aryl; a N(R') (R'') amino group, where R' and R' are independently hydrogen or a C 1
-C
12 alkyl group; an OCOR group, where R is
(CH
2
)
2 COOH or (CH 2
)
2
CO
2
CH
2
CH
3 ; or each pair can form a (C=O) group together with the carbon to which they are attached; 25 R 9 and RIO are independently hydrogen; substituted or non substituted C 1
-C
12 alkyl; C 6 -C.o aryl; a COR' group (where R' is hydrogen; hydroxyl; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6 -Co aryl; O-C-C 12 alkyl; or N(RIv) (RV) amino, where RIv and RV are independently hydrogen 30 or a CI-C 1 2 alkyl group); a (CH 2 )n-OH carbinol group (where n is WO 2007/077203 PCT/EP2006/070276 14 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 5 is selected from the following structures:
R
14
R
1 3
R
14
R
13
R
14
R
1 3 Ris Rs R 1 5 R~a'""R16"""R,el' O R 20 0 R 20 0 0R17 R,0 R17R R,,O R,,O .,R1,O R23
R
1 8 RI, R 21
R
22
R
18
R
21 (a) (b) (c)
R
13
R
1 4
R
1 3
R
1 4
R
1 3 982 23 R2
R
1 4. R2' R24 R 21
R
18
R
1 8
R
21
R
1 ' R 1 8
R
21 (d) (e) (f) 10 where:
R
13 , R 14 , Ri 5 , Ri 6 , R 21 , R 22 and R 23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6
-C
10 aryl; a N(RvI) (RVI) amino 15 group, where RvI and RvII are independently hydrogen or a Ci-C 12 alkyl group; an OCORvIIn group, where RvIIn is (CH 2 ) 2 COOH or
(CH
2
)
2
CO
2
CH
2
CH
3 ; or each pair can form a (C=O) group together with WO 2007/077203 PCT/EP2006/070276 15 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;
R
17 is hydrogen or methyl;
R
18 and R 18 , are independently hydrogen; hydroxyl; halogen; Ci-C 1 2 5 alkyl; C 6
-C
1 0 aryl; CORIx (where RIx is hydrogen; hydroxyl; Ci-C 1 2 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a C 1
-C
1 2 alkyl group; or Ci-C 12 alcoxyl); or trifluoromethyl;
R
19 , R 19 ,, R 2 0 and R 20 , are independently hydrogen; substituted or 10 non-substituted C 1
-C
12 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6
-C
0 aryl; or N(RxIII) (RxV) amino, where RxIII and RxV are independently hydrogen or a Ci-C 1 2 alkyl group); a [(CI-C 12 )alkyl-O-(CI-C 12 )alkyl-]n group (where n is 15 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;
R
24 and R 25 are independently hydrogen, hydroxyl or halogen; 20 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 25 of formula (I) used in the prevention and/or treatment of a ChoK mediated disease or condition is a compound of formula (Ia): Rio R R R il (Ia) where R 13 R 12\0 R R1 R 1, CH3, 7, 01 "'11R, R17 H, CH3Rs R R1 R2 Ri,O R8 (la) where WO 2007/077203 PCT/EP2006/070276 16
R
1 , R 2 , R 3 , R 4 , Rs, Re, R,, R,, Rn and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI
C
12 alkyl; substituted or non-substituted C 6
-C
0 aryl; a N(R') (R'') amino group, where R' and R'' are independently 5 hydrogen or a CI-C 12 alkyl group; an OCOR group, where R is
(CH
2
)
2 COOH or (CH 2
)
2
CO
2
CH
2
CH
3 ; 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 CI-C 12 alkyl; C 6
-CI
0 aryl; a COR''' group (where R''' 10 is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6
-CI
0 aryl; 0-CI-C 12 alkyl; or N(RI") (RV) amino, where RI" and Rv are independently hydrogen or a CI-C 12 alkyl group); a (CH 2 )n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a 15 methylene group,
R
13 , R 1 4 , R 15 is and R 16 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C-C 12 alkyl; substituted or non-substituted C 6
-CI
0 aryl; a N(RvI) (RvII) amino group, where Rvi and R v n are independently hydrogen or a CI-C 12 alkyl group; an 20 OCOR w III group, where RvIII is (CH 2
)
2 COOH or (CH 2
)
2
CO
2
CH
2
CH
3 ; or each pair can form a (C=O) group together with the carbon to which they are attached;
R
1 7 is hydrogen or methyl; RIO is hydrogen; hydroxyl; halogen; C 1
-C
12 alkyl; C 6 -CIo aryl; CORIx 25 (where RIx is hydrogen; hydroxyl; C 1
-C
12 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a C 1
-C
12 alkyl group; or C 1
-C
12 alcoxyl); or trifluoromethyl;
R
19 is hydrogen; substituted or non-substituted C 1
-C
1 2 alkyl; a
COR
x group (where R x n is hydrogen; hydroxyl; substituted or 30 non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6 C 10 O aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a C 1
-C
12 alkyl group); a [(C 1
-C
12 )alkyl
O-(C
1
-C
1 2 )alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl; and 35 the bond ------- means a double bond or a single bond.
WO 2007/077203 PCT/EP2006/070276 17 In a preferred embodiment, the compounds of formula (la) used in the invention comprise a substructure having the following formula (Ia'):
CH
3 R2/
R
7
CH
3 H RqRO
R
19 0 * CH, 5 (Ia') where
R
5 is hydroxyl or a OCOR group where R is (CH 2 ) 2 COOH or
(CH
2 ) 2
CO
2
CH
2
CH
3 ;
R
7 and R 8 are independently hydrogen; hydroxyl; halogen; 10 substituted or non-substituted CI-C 12 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 C 1
-C
12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; 15 R 12 is independently hydrogen or a halogen; and
RI
9 is hydrogen; substituted or non-substituted CI-C 1 2 alkyl; a COR
X
I group (where R x " is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6 CI 0 aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are 20 independently hydrogen or a CI-C 1 2 alkyl group); a [(C 1
-C
2 )alkyl
O-(C
1
-C
1 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. 25 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; WO 2007/077203 PCT/EP2006/070276 18 - 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 5 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; 10 - 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 15 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); 20 - 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 25 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 (CS); - 12-bromo-3,9-dihydroxy-6b,8a,11,12b,14a-hexamethyl 30 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,9,10,11,12,12a,12b,13,14,14a-dodecahydro-6bH picene-2-one (C6); 35 - Succinic acid mono-(10-hydroxy-2,4a,6a,9,12b,14a hexamethyl-3,11-dioxo- WO 2007/077203 PCT/EP2006/070276 19 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 5 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''): CH3O R7 gCH3 RqR1O
R
19 0 " ' 10 CH, (Ia'') where:
R
7 and R 8 are independently hydrogen, hydroxyl, halogen, substituted or non-substituted CI-C 12 alkyl, substituted or non 15 substituted C 6
-CI
0 aryl, a N(R') (R'') amino group, where R' and R'' are independently hydrogen or a C 1
-C
12 alkyl group, or each pair can form a (C=O) group together with the carbon to which they are attached;
R
15 is hydrogen or halogen; 20 RI 9 is hydrogen, substituted or non-substituted CL-C 12 alkyl; a CORXII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6 CI 0 aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a C 1
-C
1 2 alkyl group); a [(C 1
-C
1 2 )alkyl 25 O-(C 1
-C
1 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. Particular examples of this substructure (Ia'') are: WO 2007/077203 PCT/EP2006/070276 20 -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 (C7); -4,6b,8a,11,12b,14a-hexamethyl-2,10-dioxo 5 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); 10 -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 (C0l); -3-hydroxy-4,6b,8a,11,12b,14a-hexamethyl 7,8,8a,12a,12b,13,14,14a-octahydro-6bH,9H-picene-2,10 15 dione (ClI). In another preferred embodiment, the compounds of formula (Ia) used in the present invention comprise a substructure having the following formula (Ia'''):
H
3 C 1COOCH 3
R
7
CH
3
CH
3 0
CH
3 1 CH 3
R
1 9 0 20 CH 3 (Ia''') where:
R
7 is hydrogen, hydroxyl, halogen, substituted or non substituted C 1
-C
12 alkyl, substituted or non-substituted C 6
-C
0 25 aryl, or a N(R')(R'') amino group, where R' and R'"' are independently hydrogen or a C-C 12 alkyl group; and
R
1 9 is substituted or non-substituted C-C 12 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted
C
1
-C
12 alkyl; substituted or non-substituted C 6
-C
0 aryl; or WO 2007/077203 PCT/EP2006/070276 21 N(RxIII) (RxIv) amino, where RxIII and R xIv ' are independently hydrogen or a C 1
-C
1 2 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. 5 Particular examples of this substructure (Ia''') are: - 10-hydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-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-11-oxo 10 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-11-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); 15 - 10-dimethylcarbamoyloxy-2,4a,6a,9,12b,14a-hexamethyl-11 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 20 compound of formula (I) used in the prevention and/or treatment of a ChoK mediated disease or condition is a compound of formula (Ib): R1o R9
R
1 1,, R 4 R 1 1 2 / 1 1 1 , 1 , - s R 7 R1 3 CH3,R RiRi ""'IR6iiii 25 (Ib) where: R16"" H CH3 Rs R200 **wi/R4 R17R 1 , R 2 , R 3 , R 4 , R, R, R, RHC, R and R 2 are independently I I R, R2 R190 R23 R18 R21 R22 25 (Ib) where: R1, R2, R3, R4r R5, R6, R7, R8, R11 and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cj
C
12 alkyl; substituted or non-substituted C 6
-C
10 aryl; a WO 2007/077203 PCT/EP2006/070276 22 N(R') (R'') amino group, where R' and R'' are independently hydrogen or a CI-C 1 2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
R
9 and R 10 are independently hydrogen; substituted or non 5 substituted CI-C 1 2 alkyl; C 6
-CI
0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6
-CI
0 aryl; 0-CI-C 12 alkyl; or N(RIv) (Rv) amino, where RIv and Rv are independently hydrogen or a CI-C 12 alkyl group) ; a (CH 2 ) n-OH carbinol group (where n is 10 an integer comprised between 1 and 10); or together form a methylene group,
R
13 , R 1 4 , Ris, R 16 , R 21 , R 22 and R 23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 2 alkyl; substituted or non-substituted C 6
-CI
0 aryl; a N(RvI) (RvII) amino 15 group, where RvI and RvII are independently hydrogen or a CI-C 1 2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
R
1 7 is hydrogen or methyl;
R
18 is hydrogen; hydroxyl; halogen; CI-C 1 2 alkyl; C 6 -CIo aryl; CORIx 20 (where RIx is hydrogen; hydroxyl; CI-C 1 2 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a CI-C 1 2 alkyl group; or CI-C 2 alcoxyl); or trifluoromethyl;
R
1 9 and R 20 are independently hydrogen, substituted or non substituted CI-C 12 alkyl; a CORxII group (where RxII is hydrogen; 25 hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6
-CI
0 aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a CI-C 1 2 alkyl group); a [(CI-C 12 )alkyl-O-(CI-C 1 2 )alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and 30 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'): WO 2007/077203 PCT/EP2006/070276 23
CH
3 0
OH
3 OH
CH
3 R200 CH3 CH3 R190 CH3 OH (Ib') where:
R
19 and R 20 are independently substituted or non-substituted C 1 5 C 12 alkyl; a CORxn group (where Rx is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non substituted C 6 -Co 0 aryl; or N(Rx I) (R x "v) amino, where RxIII and Rxiv are independently hydrogen or a CT-C12 alkyl group); a [(Cl
C
1 2)alkyl-O-(C 1
-C
1 2)alkyl-]n group (where n is comprised between 1 10 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 15 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' '):
H
3 COOQ CH 3
CH
3
CH
3 HO
CH
3 1 CH 3
R
19 0 R23
R
18 0 ~R 3 O 20 (Ib' ') where: WO 2007/077203 PCT/EP2006/070276 24
R
18 is hydrogen; hydroxyl; halogen; CI-C 1 2 alkyl; C 6
-CI
0 aryl; CORIx (where RIx is hydrogen; hydroxyl; CI-C 12 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a CI-C 1 2 alkyl group; or CI-C 12 alcoxyl); or trifluoromethyl; 5 R 19 is hydrogen; substituted or non-substituted C 1
-C
1 2 alkyl; a
COR
x group (where R x " is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6 CIo aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a C 1
-C
1 2 alkyl group); a [(C 1
-C
1 2 )alkyl 10 O-(C 1
-C
1 2 )alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl;
R
23 is hydrogen; hydroxyl; halogen; substituted or non substituted C 1
-C
12 alkyl; substituted or non-substituted C 6
-C
0 aryl; a N(RvI) (RvII) amino group, where RVI and RvII are 15 independently hydrogen or a C 1
-C
12 alkyl group. Particular examples of this substructure (Ib'') are: - 7,10,11-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 20 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); - 11-hydroxy-10-(2-methoxy-ethoxymethoxy)-2,4a,6a,9,12b,14a 25 hexamethyl-8-oxo-1,2,3,4,4a,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 30 compound of formula (I) used in the prevention and/or treatment of a ChoK mediated disease or condition is a compound of formula (Ic): WO 2007/077203 PCT/EP2006/070276 25 R1o R9 ..... .... .. .... ... ..... .. R 8 R, (Ic) where : 5 RR1, R 2 , R 3 , R4, R, R 6 , R, R 8 , R13 and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci
C
12 alkyl; substituted or non-substituted C 6
-C
10 aryl; a N(R') (R'') amino group, where R' and R'' are independently hydrogen or a C 1
-C
12 alkyl group; or each pair can form a (C-O) 10 group together with the carbon to which they are attached;
R
9 and R 10 are independently hydrogen; substituted or non substituted C 1
-C
1 2 alkyl; C 6
-C
10 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6
-C
10 aryl; 0-C 1
-C
1 2 alkyl; 15 or N(R ') (R') amino, where R ' and R' are independently hydrogen or a C 1
-C
1 2 alkyl group) ; a (CH 2 )n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group;
R
13 , R 1 , R 1 5 , R 1 6 , R 21 and R 23 are independently hydrogen; Ris"" ""R6 R16H CH3R R20020 hydroxyl; halogen; substituted or non-substituted C-C 2 alkyl; 3C R3 I R, R2 R190 R23 R18 R21 (Ic) where: 5 RI, R2, R3, R4r R5, R6, R7, R,, RnI and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI C12 alkyl; substituted or non-substituted C-C-C a aryl; amino N(R')(R) amino group, where R' and R are independently hydrogen or a C-C 12 hydrogen or a CC12 alkyl group; or each pair can form a (C=)-O) group together with 10 group together with the carbon to which they are attached; R9 and RIO are independently hydrogen; substituted or non sub25 R 8 is hydrogen;d CC2 alkyl; C-Clo aryl; a COR group (w h er e R X (where Ris hydrogen; hydroxyl; C-C 12 substituted or non-substituted C(Rx) (RX) aminoC2 alkyl; substituted or non-substituted C6-CIo aryl; O-CI-C12 alkyl; 15 or N(R")(R) amino, where R" and R are independently hydrogen or a C-C 2 alkyl group; or C-C 1 2 alkyl groupyl) ; ora (CH2) nH carbinol group (where n istrifluoromethyl; an integer comprised between 1 and 10) ; or together form a methylene group; R13, R14r RIs, R16, R21 and R23 are independently hydrogen; 20 hydroxyl; halogen; substituted or non-substituted CI-(12 alkyl; substituted or non-substituted C6-CIo aryl; a N (Rv") (RvnI) amino group, where Rv" and Rv" are independently hydrogen or a CI-C12 alkyl group; or each pair can form a (C=0) group together with the carbon to which they are attached; 25 RIO is hydrogen; hydroxyl; halogen; C -C12 alkyl; C6-CIo aryl; COR"x (where RIx is hydrogen; hydroxyl; C -C12 alkyl; N (Rx) (Rxx) amino, where Rx and Rx" are independently hydrogen or a CI-C12 alkyl group; Or CI-C12 alCOxyl) ; or trifluoromethyl; WO 2007/077203 PCT/EP2006/070276 26
R
19 and R 20 are independently hydrogen; substituted or non substituted C 1
-C
12 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted Ci-C 1 2 alkyl; substituted or non-substituted C 6
-C
0 aryl; or N(RxIII) (RxV) amino, 5 where RxIII and RxV are independently hydrogen or a Ci-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. 10 In an embodiment, the compounds of formula (Ic) used in the present invention comprise a substructure having the following formula (Ic'):
CH
3 0
CH
3
CH
3
R
19 0
CH
3
R
20 0
CH
3 (Ic') 15 where:
R
1 9 and R 20 are independently hydrogen; substituted or non substituted C 1
-C
12 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; or N(RxIII) (Rxv) amino, 20 where RxIII and RxIv are independently hydrogen or a C 1
-C
12 alkyl group); a [(CI-C 12 )alkyl-O-(CI-C 1 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. 25 Particular examples of this substructure (Ic') are: - 10,11-dihydroxy-2,4a,6a,9,14a-pentamethyl 1,4,4a,5,6,6a,13,14,14a,14b-decahydro-2H-picene-3-one (C19); WO 2007/077203 PCT/EP2006/070276 27 - 10,11-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 5 (Ic) used in the present invention comprise a substructure having the following formula (Ic''):
H
3 -C00CH 3
CH
3
CH
3
R
1 9 0
CH
3
R
20 0
CH
3 (Ic' where: 10 R 19 and R 2 0 are independently hydrogen; substituted or non substituted C 1
-C
12 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted C1-C 1 2 alkyl; substituted or non-substituted C 6 -Ca aryl; or N(RxIII) (Rxv) amino, where RxIII and RxIv are independently hydrogen or a C-C 1 2 alkyl 15 group); a [(C-C 1 2 )alkyl-O-(C 1
-C
12 )alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl. A particular example of this substructure (Ic") is 10,11 dihydroxy-2,4a,6a,9,14a-pentamethyl 1,2,3,4,4a,5,6,6a,13,14,14a,14b-dodecahydro-picene-2-carboxylic 20 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 25 (Id): WO 2007/077203 PCT/EP2006/070276 28 R1i R9 R, R11, y R 8 R13 HR7 (Id) R1s """11IR6 where : 5 RR24, R 2 , R, R, R, R, R25, R, R and R 2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci
C
12 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; a N(R') (R'') amino group, where R' and R'' are independently hydrogen or a C 1
-C
12 alkyl group; or each pair can form a (C-O) 10 group together with the carbon to which they are attached;
R
9 and R 10 are independently hydrogen; substituted or non substituted C 1
-C
1 2 alkyl; C 6
-C
10 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6
-C
10 aryl; 0-C 1
-C
12 alkyl; 15 or N(R ') (R') amino, where R v and R' are independently hydrogen or a C 1
-C
1 2 alkyl group); a (CH 2 )OH CH3carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group, R20 3C b R3 R, R 15 , R 21 and R 2 R, are independently hydrogen; hydroxyl;R2 R 19' 2 R23 R19 R18 R21 (Id) where: 5 RI, R2, R3, R4r R5, R6, R7, R,, RnI and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C-C 2 alkyl; substituted C12 alkyl; substituted or non-substituted CC-C 1 0 aryl; a N(RV) (RV) amino group, where N(R') (R" ) amino group, where R' and R" are independently R and R are independently hydrogen or a C 1
-C
1 2 alkyl group; or each pair can form a (C=) 10each pair can form a (C-O) group together with the carbon to which they are attached; Which theyand RIO are attachindependently hydrogen; substituted or non sub25 R 18 is hydrogen;d CC2 alkyl; C-Clo aryl; a COR-C 1 0 aryl; CORx (wis hydrogen; hydroxxyyl; substituted or non-substituted C) amino,2 alkyl; substituted or non-substituted C6-CIo aryl; O-CI-C12 alkyl; 15 or N(R")(R) amino, where R" and R are independently hydrogen or a C-C 1 2 alkyl group; or C 1
-C
1 2 al grcoxylup) ; ora (CH2) nH carbinol group (where n istrifluoromethyl; an integer comprised between 1 and 10) ; or together form a methylene group, R13,r RIs, R21 and R23 are independently hydrogen; hydroxyl; 20 halogen; substituted or non-substituted CI-C12 alkyl; substituted or non-substituted C6-CIo aryl; a N(R") (Rv" ) amino group, where R v and Rv" are independently hydrogen or a CI-C12 alkyl group; or each pair can form a (C=0) group together with the carbon to which they are attached; 25 RIO is hydrogen; hydroxyl; halogen; C -C12 alkyl; C6-CIo aryl; COR"x (where RIx is hydrogen; hydroxyl; CI-C12 alkyl; N (Rx) (Rxx) amino, where Rx and Rx" are independently hydrogen or a CI-C12 alkyl group; Or CI-C12 alCOxyl) ; or trifluoromethyl; WO 2007/077203 PCT/EP2006/070276 29
R
19 , R 19 ,, R 2 0 and R 20 , are independently hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a CORxII group (where Rx is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6
-C
0 aryl; or N(RxII) (Rx"V) amino, 5 where RxIII and RxV are independently hydrogen or a Ci-C 1 2 alkyl group); a [(C 1
-C
1 2 )alkyl-O-(C 1
-C
1 2 )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; 10 R 24 and R 25 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 15 following formula (Id'):
CH
3 0
CH
3 R5 R24 R25 R , C,_CH3 CH36 R20' R20 CH3 R19 CH3 (Id') where: Rs and R 6 are independently hydrogen; hydroxyl; halogen; 20 substituted or non-substituted C 1
-C
12 alkyl; substituted or non substituted C 6
-C
0 aryl; a N(R') (R' ' ) 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; 25 R 19 , R 19 i, R 20 and R 20 , are independently hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6
-C
0 aryl; or N(RxII) (Rxv) amino, where RxIII and RxIv are independently hydrogen or a Ci-C 1 2 alkyl WO 2007/077203 PCT/EP2006/070276 30 group); a [(C 1
-C
12 )alkyl-O-(C 1
-C
12 )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; 5 R 24 and R 25 are independently hydrogen, hydroxyl or halogen. Particular examples of this substructure (Id') are: - 1-bromo-9-hydroxy-4,6b,8a,11,12b,14b-hexamethyl 6b,7,8,8a,9,11,12,12a,12b,14b-decahydro-1H-picene-2,3,10 trione (C22); 10 - 1-bromo-4,6b,8a,11,12b,14b-hexamethyl 6b,7,8,8a,9,11,12,12a,12b,14b-decahydro-1H-picene-2,3,10 trione (C23). In another preferred embodiment, the compounds of formula (Id) used in the present invention comprise a substructure 15 having the following formula (Id''):
H
3 C COOCH 3
CH
3
R
2 4
R
25 ,2, CH 3
CH
3 R20' R20 CH3 R19' CH3 (Id"r) where:
R
19 , R 19 ,, R 20 and R 20 , are independently hydrogen; substituted or 20 non-substituted C 1
-C
12 alkyl; a CORXII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6
-C
0 aryl; or N(RxII) (Rxv) amino, where RxIII and RxIv are independently hydrogen or a Ci-C 1 2 alkyl group); a [(C 1
-C
12 )alkyl-O-(CI-C 1 2 )alkyl-]n group (where n is 25 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;
R
24 and R 25 are independently hydrogen, hydroxyl or halogen.
WO 2007/077203 PCT/EP2006/070276 31 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). 5 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 (le):
R
10
R
9 RRR11
R
12 /l1,,,1, - ,\R8 R14 R13 CH 3 R7 ~Ri R24 R R20 R20CH 3 I H 3 C 'sR R '
RR
2 * # ,,R23 R1 9 ; 10 R 18 ' R 1 8
R
21 (le) where: RI, R 2 , R 3 , R 4 , Rs, Re, R 7 , R 8 , R 1 1 and R 1 2 are independently 15 hydrogen; hydroxyl; halogen; substituted or non-substituted CI
C
1 2 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; a N(R') (R'') amino group, where R' and R'' are independently hydrogen or a C 1
-C
1 2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; 20 R 9 and R 10 are independently hydrogen; substituted or non substituted CI-C 12 alkyl; C 6
-CI
0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6
-CI
0 aryl; 0-CI-C 12 alkyl; or N(RIv) (Rv) amino, where RIv and Rv are independently hydrogen 25 or an alkyl group CI-C 1 2 ); a carbinol group (CH 2 )n-OH (where n is an integer comprised between 1 and 10); or together form a methylene group;
R
1 3 , R 1 4 , Ris, R 16 , R 2 1 and R 2 3 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 1 2 alkyl; WO 2007/077203 PCT/EP2006/070276 32 substituted or non-substituted C 6 -Co 0 aryl; a N(RvI) (RvII) amino group, where R"I and RvII are independently hydrogen or a C 1
-C
12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; 5 R 18 and R 18 , are independently hydrogen; hydroxyl; halogen; C1-C 1 2 alkyl; C 6 -Co 0 aryl; CORIx (where RIx is hydrogen; hydroxyl; C1-C 1 2 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a C 1
-C
1 2 alkyl group; or C 1
-C
12 alcoxyl); or trifluoromethyl; 10 R 19 , R 19 i, R 20 and R 20 , are independently hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C1-C 1 2 alkyl; substituted or non-substituted C 6 -Co 0 aryl; or N(RxII) (RXIV) amino, where RxIII and RxIv are independently hydrogen or a C1-C 1 2 alkyl 15 group); a [(C 1
-C
1 2 )alkyl-O-(C 1
-C
1 2 )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;
R
24 is hydrogen, hydroxyl or halogen; and 20 the bond ---- means a double bond or a single bond. In a preferred embodiment, the compounds of formula (le) used in the present invention comprise a substructure having the following formula (le'):
H
3 C COOCH 3
CH
3 R24 R20,
CH
3
R
20 1ne11". CH 3 CH 3 R19 25 R 8
R
18 (le') where:
R
18 and R 18 , are independently hydrogen; hydroxyl; halogen; C 1
-C
1 2 alkyl; C 6
-C
1 o aryl; CORIx (where RIx is hydrogen; hydroxyl; CI-C 1 2 WO 2007/077203 PCT/EP2006/070276 33 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a C 1
-C
1 2 alkyl group; or Ci-C 12 alcoxyl); or trifluoromethyl;
R
19 , R 19 , R 20 and R 20 , are independently hydrogen; substituted or 5 non-substituted C 1
-C
12 alkyl; a CORXII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted Ci-C 1 2 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; or N(RxIn) (Rxv) amino, where RxIII and RxIv are independently hydrogen or a CI-C 1 2 alkyl group); a [(CI-C 1 2 )alkyl-O-(CI-C 1 2 )alkyl-] n group (where n is 10 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;
R
24 is hydrogen, hydroxyl or halogen. 15 A particular example of this substructure (le') 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). 20 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): RRio R9 ~Ri ^*, R11 * - '~ 14 3 CH3 R7 R1s "'"R6 25 (If) where : , 2 CH3 H CH3R5 R 2 0 ' 3fl R R20"" 3C b R3 R ' ' R,4 R 2 Z , R23 R19 R18' R18 R21 25 where: WO 2007/077203 PCT/EP2006/070276 34
R
1 , R 2 , R 3 , R 4 , Rs, Re, R,, R,, Ro and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI
C
1 2 alkyl; substituted or non-substituted C 6
-C
0 aryl; a N(R') (R'') amino group, where R' and R'' are independently 5 hydrogen or a C 1
-C
1 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 CI-C 1 2 alkyl; C 6
-CI
0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 10 alkyl; substituted or non-substituted C 6
-CI
0 aryl; 0-CI-C 12 alkyl; or N(RI") (RV) amino, where RI" and Rv are independently hydrogen or a CI-C 12 alkyl group) ; a (CH 2 ) n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, 15 R 13 , R 14 , Ris, R 2 1 and R 2 3 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6
-C
10 aryl; a N(RvI) (RvII) amino group, where Rvi and R v n are independently hydrogen or a CI-C 12 alkyl group; or each pair can form a (C=O) group together with the carbon to 20 which they are attached;
R
18 and R 18 , are independently hydrogen; hydroxyl; halogen; CI-C 12 alkyl; C 6
-CI
0 aryl; CORIx (where RIx is hydrogen; hydroxyl; CI-C 12 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a CI-C 12 alkyl group; or CI-C 12 alcoxyl); or 25 trifluoromethyl;
R
19 , R 19 ,, R 20 and R 20 , are independently hydrogen; substituted or non-substituted CI-C 12 alkyl; a CORXII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6
-CI
0 aryl; or N(RxIII) (RxIv) amino, 30 where RxIII and RxIv are independently hydrogen or a CI-C 12 alkyl group); a [(CI-C 12 )alkyl-O-(CI-C 12 )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; 35 R 24 is hydrogen, hydroxyl or halogen; and the bond ------- means a double bond or a single bond.
WO 2007/077203 PCT/EP2006/070276 35 In a preferred embodiment, the compounds of formula (If) used in the present invention comprise a substructure having the following formula (If'):
H
3 C COOCH 3
CH
3 R0
CH
3
CH
3
R
20 III
CH
3
R
19 '
R,
8
R
18 5 (If') where:
R
18 and R 1 8, are independently hydrogen; hydroxyl; halogen; C 1
-C
12 alkyl; C 6
-C
0 aryl; CORIx (where RIx is hydrogen; hydroxyl; Ci-C 12 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently 10 hydrogen or a C 1
-C
12 alkyl group; or Ci-C 12 alcoxyl); or trifluoromethyl;
R
19 , R 19 , R 20 and R 20 , are independently hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a CORXII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 alkyl; 15 substituted or non-substituted C 6
-C
0 aryl; or N(RxIII) (Rxv) amino, where RxIII and RxIv are independently hydrogen or a Ci-C 1 2 alkyl group); a [(CI-C 12 )alkyl-O-(CI-C 12 )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 20 to which they are attached;
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 25 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 WO 2007/077203 PCT/EP2006/070276 36 of a ChoK mediated disease or condition is a compound of formula (IIa): R7 R8 1 S6 Ris RR3 R5//,,o1 (Iha) 5 where:
R
1 , R 2 , R 3 , R 4 , Rs, Re, R, Rio, R 11 , R 1 2 , R 1 3 , R 14 , R 1 s, Ri, R 17 , R 1 8 ,
R
19 and R 20 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 12 alkyl; substituted or non substituted C 6
-CI
0 aryl; a N(Rx") (Rx"VI) amino group, where Rx" and 10 R xv " are independently hydrogen or a CI-C 12 alkyl group; or each pair can form a carboxyl (C=O) group together with the carbon to which they are attached;
R
7 and R 8 are independently hydrogen; substituted or non substituted CI-C 12 alkyl; C 6
-CI
0 aryl; a COR xv I group (where R xv I 15 is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6
-CI
0 aryl; 0-CI-C 12 alkyl; or N(RxvIII) (RxIx) amino, where RxvIl and RxIx are independently hydrogen or a C 1
-C
1 2 alkyl group) ; a (CH 2 )n-OH carbinol group (where n is an integer comprised between 1 and 10); or together 20 form a methylene group,
R
21 and R 24 are independently substituted or non-substituted Cj
C
1 2 alkyl; a COR xx group (where R xx is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non substituted C 6 -Co 0 aryl; or N(RxxI) (RxxII) amino, where R xx ' and RxxII 25 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;
R
2 2 and R 2 3 are: - hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a 30 CORxxIII group (where RxxIII is hydrogen; hydroxyl; WO 2007/077203 PCT/EP2006/070276 37 substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6
-C
0 lo aryl; or N(RxxIv) (Rxxv) amino, where
R
xx iv 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 5 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 2 3 ' respectively, where R 22 ' and R 23 ' are independently hydrogen; substituted or non-substituted Cj
C
12 alkyl; a COR xxv l group (where R xxw is hydrogen; hydroxyl; 10 substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; or N(RxxvII) (RxxvIII) amino, where
R
xxv n and R xxv Iw are independently hydrogen or a C 1
-C
12 alkyl group); a [(C-C 12 )alkyl-O-(C-C 12 )alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl when R 24 is 15 in the meta position with respect to R 20 . In a preferred embodiment, the compounds of formula (IIa) used in the present invention comprise a substructure having the following formula (IIa'):
H
3 C ,,COOCH 3 R24 R23 11 CH3 R22 R19 2 021 R20 (IIa') where:
R
19 and R 20 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1
-C
12 alkyl; substituted or non 25 substituted C 6
-C
0 lo aryl; a N(Rxv) (Rxv) amino group, where Rxv and
R
x w are independently hydrogen or a CI-C 12 alkyl group; or each pair can form a (C=O) carboxyl group together with the carbon to which they are attached;
R
2 1 and R 24 are independently hydrogen; hydroxyl; halogen; 30 substituted or non-substituted C 1
-C
12 alkyl; substituted or non substituted C 6
-C
1 0 aryl; a N(Rxx) (RxxII) amino group, where RxxI and WO 2007/077203 PCT/EP2006/070276 38 RxxII are independently hydrogen or a CI-C 12 alkyl group; or each pair can form a (C=O) carboxyl group together with the carbon to which they are attached;
R
22 and R 23 are independently hydrogen; hydroxyl; halogen; 5 substituted or non-substituted C 1
-C
12 alkyl; substituted or non substituted C 6
-C
10 aryl; a N(RXXIV) (RxxV) amino group, where R xx Iv and RxxV are independently hydrogen or a C 1
-C
12 alkyl group; or each pair can form a (C=O) carboxyl group together with the carbon to which they are attached. 10 A particular example of this substructure (IIa') is: - 8-[2-(6,7-dihydroxy-1,5-dimethyl-naphthalen-2-yl)-ethyl]-2,4a tetramethyl-1,2,3,4,4a,5,6,7-octahydro-naphthalen-2-carboxylic acid methyl ester (C27). 15 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 20 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, 25 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 30 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 35 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 WO 2007/077203 PCT/EP2006/070276 39 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. 5 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, 10 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 15 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):
R
10
R
9 R *
R
12 R7
CH
3
-
"millR 6 ( ) H CH3R ""'tR4 (A) (B) H 3 C R3 R,
R
2 20 (I) where:
R
1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cl 25 C 12 alkyl; substituted or non-substituted C 6
-C
1 o aryl; a N(R') (R'') amino group, where R' and R' are independently hydrogen or a C 1
-C
12 alkyl group; an OCOR group, where R is
(CH
2
)
2 COOH or (CH 2
)
2
CO
2
CH
2
CH
3 ; or each pair can form a (C=O) group together with the carbon to which they are attached; WO 2007/077203 PCT/EP2006/070276 40
R
9 and R 10 are independently hydrogen; substituted or non substituted CI-C 12 alkyl; C 6
-CI
0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6
-CI
0 aryl; 0-CI-C 12 alkyl; 5 or N(RI") (RV) amino, where RI" and Rv are independently hydrogen or a CI-C 12 alkyl group) ; a (CH 2 ) n-OH 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; 10 and where the tricyclic structure is selected from the following structures:
R
14
R
13
R
14
R
13
R
1 4
R
13 Rs Rs I R 1 5 R "Ri,"""" R1 \W", 0 R 20 0 R 20 0 R7R17 R,,O R1,,O R1,,O R 23
R
18 Ric R 21
R
22 Rip R 21 (a) (b) (c)
R
1 3
R
1 4
R
1 3
R
1 4
R
1 3 6 R
R
20 2 CHR20
R
20
CH
3 R20"""" R20 CH 3 R20'"" R R 1 R'R ' Ri, R R 2 3 23 Rip R 21 Ris' R 1 8
R
2 1 Rio' R 1 8
R
21 (d) (e) (f) 15 where:
R
13 , R 14 , RI 5 , R 16 , R 21 , R 22 and R 23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 1 2 alkyl; WO 2007/077203 PCT/EP2006/070276 41 substituted or non-substituted C 6 -Co 0 aryl; a N(R"I) (RvII) amino group, where R"I and RvII are independently hydrogen or a C 1
-C
12 alkyl group; an OCORvIII group, where RvIII is (CH 2
)
2 COOH or
(CH
2
)
2
CO
2
CH
2
CH
3 ; or each pair can form a (C=O) group together with 5 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;
R
17 is hydrogen or methyl;
R
18 and R 18 , are independently hydrogen; hydroxyl; halogen; C 1
-C
1 2 alkyl; C 6 -Co 0 aryl; CORIx (where RIx is hydrogen; hydroxyl; C 1
-C
1 2 10 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a C 1
-C
1 2 alkyl group; or CI-C 12 alcoxyl); or trifluoromethyl;
R
19 , R 19 , R 20 and R 20 , are independently hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a CORXII group (where RxII is 15 hydrogen; hydroxyl; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a C 1
-C
1 2 alkyl group); a [(C 1
-C
12 )alkyl-O-(C 1
-C
12 )alkyl-]n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20 20-20' pair can form a C=O group together with the carbon to which they are attached;
R
24 and R 25 are independently hydrogen, hydroxyl or halogen; or a pharmaceutically acceptable salt, derivative, prodrug, 25 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-11-oxo 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b 30 tetradecahydro-picene-2-carboxylic acid; - 10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b tetradecahydro-picene-2-carboxylic acid methyl ester; 35 - 3,10-Dihydroxy-2,4a,6a,9,12b,14a-hexamethyl-11 oxo-1,2,3,4,4a,5,6,6a,11,12b, 13,14,14a,14b- WO 2007/077203 PCT/EP2006/070276 42 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 5 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 10 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; 15 - 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 20 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 25 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 30 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; 35 - Nicotinic acid 9-hydroxy-4,6b,8a,11,12b,14a hexamethyl-2,10-dioxo- WO 2007/077203 PCT/EP2006/070276 43 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-11 oxo-1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b 5 tetradecahydro-picene-2-carboxylic acid methyl ester; - 10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b tetradecahydro-picene-2-carboxylic acid methyl 10 ester. - when the tricyclic structure is (b) and R 1 9 and R 20 are independently hydrogen or an acyl group, then: - Rs is hydroxyl; or - R 2 1 and R 2 2 form a C=O group together with the 15 carbon to which they are attached and R 10 is not COOH. - when the tricyclic structure is (c) and R 1 9 and R 20 are both CH 3 , then R 15 is and R 16 do not form a C=O group together with the carbon to which they are attached. 20 In one particular aspect, the invention is directed to compounds of formula (Ia): R1o R, R R R R3R12 R R R CH (Ia) 25 where RI, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R,, R and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1 C 12 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; a N(R') (R'') amino group, where R' and R'' are independently WO 2007/077203 PCT/EP2006/070276 44 hydrogen or a CI-C 12 alkyl group; an OCOR group, where R is
(CH
2
)
2 COOH or (CH 2
)
2
CO
2
CH
2
CH
3 ; or each pair can form a (C=O) group together with the carbon to which they are attached;
R
9 and R 10 are independently hydrogen; substituted or non 5 substituted CI-C 12 alkyl; C 6
-CI
0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6
-CI
0 aryl; 0-CI-C 1 2 alkyl; or N(RIv) (Rv) amino, where RIv and Rv are independently hydrogen or a CI-C 12 alkyl group); a (CH 2 )n-OH carbinol group (where n is 10 an integer comprised between 1 and 10); or together form a methylene group,
R
13 , R 14 , R 15 is and R 16 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"I) (R"VII) amino group, where 15 RVI and R v n are independently hydrogen or a CI-C 12 alkyl group; an OCORvIII group, where RvIII is (CH 2
)
2 COOH or (CH 2
)
2
CO
2
CH
2
CH
3 ; or each pair can form a (C=O) group together with the carbon to which they are attached;
R
1 7 is hydrogen or methyl; 20 R 18 is hydrogen; hydroxyl; halogen; CI-C 12 alkyl; C 6
-CI
0 aryl; CORIx (where RIx is hydrogen; hydroxyl; CI-C 12 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a CI-C 12 alkyl group; or C 1
-C
1 2 alcoxyl); or trifluoromethyl;
R
19 is hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a 25 CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C-C 12 alkyl; substituted or non-substituted C 6 CI 0 aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a CI-C 12 alkyl group); a [(C 1
-C
12 )alkyl
O-(C
1
-C
1 2 )alkyl-]n group (where n is comprised between 1 and 3); 30 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-11-oxo 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro 35 picene-2-carboxylic acid; WO 2007/077203 PCT/EP2006/070276 45 - 10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-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-11-oxo 5 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; 10 - 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 15 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 20 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 25 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 30 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 35 picen-3-yl ester; WO 2007/077203 PCT/EP2006/070276 46 - 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. 5 In a preferred embodiment, the compounds of formula (Ia) comprise a substructure having the following formula (Ia'):
CH
3
R
12 ,,, R7
CH
3 R
R
5
CH
3 0
CH
3 1 CH 3
R
1 9 0
CH
3 (Ia') where 10 R 5 is hydroxyl or a OCOR group where R is (CH 2
)
2 COOH or
(CH
2 ) 2
CO
2
CH
2
CH
3 ;
R
7 and R 8 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1
-C
12 alkyl; substituted or non substituted C 6 -Co aryl; a N (R' ) (R' ' ) amino group, where R' and 15 R'' are independently hydrogen or a C 1
-C
12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
R
12 is independently hydrogen or a halogen; and
RI
9 is hydrogen; substituted or non-substituted C-C 12 alkyl; a 20 CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6 CIO aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a C 1
-C
1 2 alkyl group); a [(C 1
-C
12 )alkyl
O-(C
1 -Cu 2 )alkyl-]n group (where n is comprised between 1 and 3); 25 or trifluoromethyl; and the bond ------- means a double bond or a single bond, with the proviso that the compound of formula (Ia') is not: WO 2007/077203 PCT/EP2006/070276 47 - 10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-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-11-oxo 5 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-11-oxo 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro picene-2-carboxylic acid methyl ester; 10 - 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 15 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 20 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; 25 - 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 30 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; 35 - Dimethyl-carbamic acid 9-hydroxy-4,6b,8a,11,12b,14a hexamethyl-2,10-dioxo- WO 2007/077203 PCT/EP2006/070276 48 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 5 tetradecahydro-picen-3-yl ester; - 3,10-Dihydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-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-11-oxo 10 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 15 2,6b,7,8,8a,9,10,11,12,12a,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); 20 - 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 25 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 (CS); - 3,9,10-trihydroxy-6b,8a,11,12b,14a-hexamethyl 30 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'' ): WO 2007/077203 PCT/EP2006/070276 49 CH3 R7 CH3 iR R1s CH3 0 CH31 CH3
R
1 9 0
CH
3 (Ia' F where: R, and R 8 are independently hydrogen, hydroxyl, halogen, 5 substituted or non-substituted CI-C 12 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 C 1
-C
12 alkyl group, or each pair can form a (C-O) group together with the carbon to which they are attached; 10 R 15 is hydrogen or halogen;
RI
9 is hydrogen, substituted or non-substituted CI-C 12 alkyl; a COR
X
I group (where R x " is hydrogen; hydroxyl; substituted or non-substituted C-C 12 alkyl; substituted or non-substituted C 6 CI 0 aryl; or N(Rx ) (R x v ) amino, where Rx and Rxv are 15 independently hydrogen or a C 1
-C
12 alkyl group); a [(C-C) alkyl
O-(C
1
-C
1 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: 20 - 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 25 2,10-dione. Particular examples of this substructure (Ia'') are: WO 2007/077203 PCT/EP2006/070276 50 -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 (C7); -4,6b,8a,11,12b,14a-hexamethyl-2,10-dioxo 5 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); 10 -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 (C0l); -3-hydroxy-4,6b,8a,11,12b,14a-hexamethyl 7,8,8a,12a,12b,13,14,14a-octahydro-6bH,9H-picene-2,10 15 dione (ClI). In another preferred embodiment, the compounds of formula (Ia) comprise a substructure having the following formula (Ia'''):
H
3 C 1COOCH 3
R
7
CH
3
CH
3 0
CH
3 1 CH 3
R
1 9 0 20 CH 3 (Ia''') where:
R
7 is hydrogen, hydroxyl, halogen, substituted or non substituted C 1
-C
12 alkyl, substituted or non-substituted C 6
-C
0 25 aryl, or a N(R')(R'') amino group, where R' and R'"' are independently hydrogen or a C-C 12 alkyl group; and
R
1 9 is substituted or non-substituted C-C 12 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted
C
1
-C
12 alkyl; substituted or non-substituted C 6
-C
0 aryl; or WO 2007/077203 PCT/EP2006/070276 51 N(RxIII) (RxIv) amino, where RxIII and R xI v ' are independently hydrogen or a C 1
-C
1 2 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; with the proviso that the compound of formula (Ia''') is not: 5 - 3,10-Dihydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-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-11-oxo 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro 10 picene-2-carboxylic acid methyl ester. Particular examples of this substructure (Ia''') are: - 2,4a,6a,9,12b,14a-hexamethyl-11-oxo-10-propionyloxy 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro 15 picene-2-carboxylic acid methyl ester (C13); - 10-dimethylcarbamoyloxy-2,4a,6a,9,12b,14a-hexamethyl-11 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 20 compounds of formula (Ib): R1o R9 (Rb) where: 25 R 1 , R 2 , R, R 4 , R, R, R, R1, R 1 3 and R 2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci
C
12 alkyl; substituted or non-substituted C 6
-C
10 aryl; a N(R') (R'') amino group, where R' and R'' are independently R1s ?""R6 R16 .... H CH3 Rs R200 ""'/R4 R17 H3C -,R3 I I R, R2 R190 R23 R18 R21 R22 (Ib) where: 25 R1, R2, R3, R4r R5, R6, R,, Re, R11 and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cj C12 alkyl; substituted or non-substituted C6-Clo aryl; a N(R') (R" ) amino group, where R' and R" are independently WO 2007/077203 PCT/EP2006/070276 52 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;
R
9 and R 10 are independently hydrogen; substituted or non substituted CI-C 1 2 alkyl; C 6
-CI
0 aryl; a COR''' group (where R''' 5 is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6
-CI
0 aryl; 0-CI-C 12 alkyl; or N(RI") (RV) amino, where RI" and Rv are independently hydrogen or a CI-C 12 alkyl group) ; a (CH 2 ) n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a 10 methylene group,
R
13 , R 1 4 , Ris, R 16 , R 21 , R 22 and R 23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 2 alkyl; substituted or non-substituted C 6
-CI
0 aryl; a N(RvI) (RvII) amino group, where RvI and RvII are independently hydrogen or a CI-C 12 15 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
R
1 7 is hydrogen or methyl;
R
18 is hydrogen; hydroxyl; halogen; CI-C 1 2 alkyl; C 6 -CIo aryl; CORIx (where RIx is hydrogen; hydroxyl; CI-C 1 2 alkyl; N(Rx) (RxI) amino, 20 where Rx and RxI are independently hydrogen or a CI-C 1 2 alkyl group; or CI-C 2 alcoxyl); or trifluoromethyl;
R
1 9 and R 20 are independently hydrogen, substituted or non substituted CI-C 12 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted CI-C 2 alkyl; 25 substituted or non-substituted C 6
-CI
0 aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a CI-C 12 alkyl group); a [(CI-C 12 )alkyl-O-(CI-C 1 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, 30 with the proviso that when RI 9 and R 20 are independently hydrogen or an acyl group, then: Rs is hydroxyl; or
R
21 and R 22 form a C=O group together with the carbon to which they are attached and RI 0 is not COOH. 35 In another preferred embodiment, the compounds of formula (Ib) comprise a substructure having the following formula (Ib'): WO 2007/077203 PCT/EP2006/070276 53
CH
3 0
OH
3 OH
CH
3 R200 C H CH 3 R190 C H3 OH (Ib') where:
R
19 and R 20 are independently substituted or non-substituted C 1 5 C 12 alkyl; a CORxn group (where Rx is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non substituted C 6 -Co 0 aryl; or N(Rx I) (R x "v) amino, where RxIII and Rxiv are independently hydrogen or a CT-C12 alkyl group); a [(Cl
C
1 2)alkyl-O-(C 1
-C
1 2)alkyl-]n group (where n is comprised between 1 10 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 15 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' '):
H
3 COOQ CH 3
CH
3
CH
3 HO
CH
3 1 CH 3
R
19 0 R23
R
18 0 ~R 3 O 20 (Ib' ') where: WO 2007/077203 PCT/EP2006/070276 54
R
18 is hydrogen; hydroxyl; halogen; CI-C 1 2 alkyl; C 6
-CI
0 aryl; CORIx (where RIx is hydrogen; hydroxyl; CI-C 12 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a CI-C 1 2 alkyl group; or CI-C 12 alcoxyl); or trifluoromethyl; 5 R 19 is hydrogen; substituted or non-substituted C 1
-C
1 2 alkyl; a
COR
x group (where R x " is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6 C 10 O aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a C 1
-C
1 2 alkyl group); a [(C 1
-C
1 2 )alkyl 10 O-(C 1
-C
12 )alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl;
R
23 is hydrogen; hydroxyl; halogen; substituted or non substituted C 1
-C
12 alkyl; substituted or non-substituted C 6
-C
0 aryl; a N(RvI) (RvII) amino group, where RVI and RvII are 15 independently hydrogen or a C 1
-C
12 alkyl group. Particular examples of this substructure (Ib'') are: - 7,10,11-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 20 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); - 11-hydroxy-10-(2-methoxy-ethoxymethoxy)-2,4a,6a,9,12b,14a 25 hexamethyl-8-oxo-1,2,3,4,4a,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 30 compounds of formula (Ic): WO 2007/077203 PCT/EP2006/070276 55 R1o R9 (Ic) where : 5 RR1, R 2 , R 3 , R4, R, R 6 , R, R, R13 and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci
C
12 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; a N(R') (R'') amino group, where R' and R'' are independently hydrogen or a C 1
-C
12 alkyl group; or each pair can form a (C-O) 10 group together with the carbon to which they are attached;
R
9 and R 10 are independently hydrogen; substituted or non substituted C 1
-C
1 2 alkyl; C 6
-C
1 0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6
-C
10 aryl; 0-C 1
-C
12 alkyl; 15 or N(R ') (R') amino, where R ' and R' are independently hydrogen or a C 1
-C
1 2 alkyl group) ; a (CH 2 )n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group;
R
13 , R 1 , R 1 5 , R 1 6 , R 21 and R 23 are independently hydrogen; Ris"" ""R6 R16H CH3R R20020 hydroxyl; halogen; substituted or non-substituted C-C 2 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; a N(RV w ) (RV ) amino group, where RV and RV x 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; 3C R3 I R, R2 25 R 1 8 is hydrogen; hydroxyl; halogen; CR-C 1 2 alkyl; C3-C 0 aryl; COR R18 R21 (Ic) where: 5 RI, R2, R3, R4r R5, R6, R7, R,, RnI and R12 are independently (where R is hydrogen; hydroxyl; Calogen; substituted or non-substituted C(RX) amino, C12 alkyl; substituted or non-substituted C6-Cha aryl; a N(R')(R) amino group, where R' and R are independently hydrogen or a C-C 1 2 alkyl hydrogeup; or C-C 2 alcoxC12 alkyl group; r trifluoro each pair can form a (C=yl;) 10 group together with the carbon to which they are attached; R9 and RIO are independently hydrogen; substituted or non substituted CI-C12 alkyl; C6-CIo aryl; a COR"' group (where R"' is hydrogen; hydroxyl; substituted or non-substituted CI-C12 alkyl; substituted or non-substituted C6-CIo aryl; O-CI-C12 alkyl; 15 or N(RI")(R") amino, where RI" and Rv are independently hydrogen or a CI-C12 alkyl group) ; a (CH2) n-OH carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group; R13, R14r RIs, R16, R21 and R23 are independently hydrogen; 20 hydroxyl; halogen; substituted or non-substituted CI-(12 alkyl; substituted or non-substituted C6-CIo aryl; a N (Rv") (RvnI) amino group, where Rv" and Rv" are independently hydrogen or a CI-C12 alkyl group; or each pair can form a (C=0) group together with the carbon to which they are attached; 25 RIO is hydrogen; hydroxyl; halogen; C -C12 alkyl; C6-CIo aryl; COR"x (where RIx is hydrogen; hydroxyl; C -C12 alkyl; N (Rx) (Rxx) amino, where Rx and Rx" are independently hydrogen or a CI-C12 alkyl group; Or CI-C12 alCOxyl) ; or trifluoromethyl; WO 2007/077203 PCT/EP2006/070276 56
R
19 and R 20 are independently hydrogen; substituted or non substituted C 1
-C
12 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted Ci-C 1 2 alkyl; substituted or non-substituted C 6
-C
0 aryl; or N(RxIII) (Rx"V) amino, 5 where RxIII and RxV are independently hydrogen or a Ci-C 1 2 alkyl group); a [(C 1
-C
1 2 )alkyl-O-(C 1
-C
1 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 when R 1 9 and R 2 0 are both CH 3 , then R 15 is and 10 R 16 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'):
CH
3 0
CH
3
CH
3
R
19 0
CH
3
R
20 0 15 CH 3 (Ic') where:
R
19 and R 2 o are independently hydrogen; substituted or non substituted C 1
-C
12 alkyl; a CORXII group (where RXII is hydrogen; 20 hydroxyl; substituted or non-substituted C1-C 1 2 alkyl; substituted or non-substituted C 6
-C
0 aryl; or N(RxIII) (Rxv) amino, where RxIII and RxIv are independently hydrogen or a C-C 1 2 alkyl group); a [(C-C 12 )alkyl-O-(C 1
-C
1 2 )alkyl-]n group (where n is comprised between 1 and 3) or trifluoromethyl; and 25 the bond ------- means a double bond or a single bond. Particular examples of this substructure (Ic') are: WO 2007/077203 PCT/EP2006/070276 57 - 10,11-dihydroxy-2,4a,6a,9,14a-pentamethyl 1,4,4a,5,6,6a,13,14,14a,14b-decahydro-2H-picene-3-one (C19); - 10,11-dihydroxy-2,4a,6a,9,14a-pentamethyl 5 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 (Ic"''):
H
3 C 4COOCH 3
CH
3
CH
3
R
1 9 0
CH
3
R
20 0
CH
3 10 (Ic'') where:
R
19 and R 20 are independently hydrogen; substituted or non substituted C 1
-C
12 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; 15 substituted or non-substituted C 6
-C
1 0 aryl; or N(RxII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a C1-C 1 2 alkyl group); a [(C 1
-C
1 2 )alkyl-O-(C 1
-C
1 2 )alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl. 20 A particular example of this substructure (Ic'') is 10,11 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 25 compounds of formula (Id): WO 2007/077203 PCT/EP2006/070276 58 R1i R9 R, R11, y R 8 R13 HR7 (Id) R1s """11IR6 where : 5 RR24, R 2 , R, R, R, R, R25, R, R and R 2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci
C
12 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; a N(R') (R'') amino group, where R' and R'' are independently hydrogen or a C 1
-C
12 alkyl group; or each pair can form a (C-O) 10 group together with the carbon to which they are attached;
R
9 and R 10 are independently hydrogen; substituted or non substituted C 1
-C
1 2 alkyl; C 6
-C
10 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6
-C
10 aryl; 0-C 1
-C
12 alkyl; 15 or N(R ') (R') amino, where R v and R' are independently hydrogen or a C 1
-C
1 2 alkyl group); a (CH 2 )OH CH3carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group, R20 3C b R3 R, R 15 , R 21 and R 2 R, are independently hydrogen; hydroxyl;R2 R 19' 2 R23 R19 R18 R21 (Id) where: 5 RI, R2, R3, R4r R5, R6, R7, R,, RnI and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C-C 2 alkyl; substituted C12 alkyl; substituted or non-substituted CC-C 1 0 aryl; a N(RV) (RV) amino group, where N(R') (R" ) amino group, where R' and R" are independently R and R are independently hydrogen or a C 1
-C
1 2 alkyl group; or each pair can form a (C=) 10each pair can form a (C-O) group together with the carbon to which they are attached; Which theyand RIO are attachindependently hydrogen; substituted or non sub25 R 18 is hydrogen;d CC2 alkyl; C-Clo aryl; a COR-C 1 0 aryl; CORx (wis hydrogen; hydroxxyyl; substituted or non-substituted C) amino,2 alkyl; substituted or non-substituted C6-CIo aryl; O-CI-C12 alkyl; 15 or N(R")(R) amino, where R" and R are independently hydrogen or a C-C 1 2 alkyl group; or C 1
-C
1 2 al grcoxylup) ; ora (CH2) nH carbinol group (where n istrifluoromethyl; an integer comprised between 1 and 10) ; or together form a methylene group, R13,r RIs, R21 and R23 are independently hydrogen; hydroxyl; 20 halogen; substituted or non-substituted CI-C12 alkyl; substituted or non-substituted C6-CIo aryl; a N(R") (Rv" ) amino group, where R v and Rv" are independently hydrogen or a CI-C12 alkyl group; or each pair can form a (C=0) group together with the carbon to which they are attached; 25 RIO is hydrogen; hydroxyl; halogen; C -C12 alkyl; C6-CIo aryl; COR"x (where RIx is hydrogen; hydroxyl; CI-C12 alkyl; N (Rx) (Rxx) amino, where Rx and Rx" are independently hydrogen or a CI-C12 alkyl group; Or CI-C12 alCOxyl) ; or trifluoromethyl; WO 2007/077203 PCT/EP2006/070276 59
R
19 , R 19 ,, R 2 0 and R 20 , are independently hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a CORxII group (where Rx is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6
-C
0 aryl; or N(RxIII) (Rx"V) amino, 5 where RxIII and RxV are independently hydrogen or a Ci-C 1 2 alkyl group); a [(C 1
-C
1 2 )alkyl-O-(C 1
-C
1 2 )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; 10 R 24 and R 25 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'):
CH
3 0
CH
3 - R5 R24 R25 R ,20' CH3 CH36 R20 CH3 R1 15 CH3 (Id') where: Rs and R 6 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1
-C
12 alkyl; substituted or non 20 substituted C 6
-C
0 aryl; a N(R')(R'') amino group, where R' and R'' are independently hydrogen or a C 1
-C
12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
R
19 , R 19 , R 20 and R 20 , are independently hydrogen; substituted or 25 non-substituted C 1
-C
12 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6
-C
0 aryl; or N(RxIII) (Rxv) amino, where RxIII and RxIv are independently hydrogen or a Ci-C 1 2 alkyl group); a [(CI-C 12 )alkyl-O-(CI-C 12 )alkyl-]n group (where n is WO 2007/077203 PCT/EP2006/070276 60 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;
R
24 and R 25 are independently hydrogen, hydroxyl or halogen. 5 Particular examples of this substructure (Id') are: - 1-bromo-9-hydroxy-4,6b,8a,11,12b,14b-hexamethyl 6b,7,8,8a,9,11,12,12a,12b,14b-decahydro-1H-picene-2,3,10 trione (C22); - 1-bromo-4,6b,8a,11,12b,14b-hexamethyl 10 6b,7,8,8a,9,11,12,12a,12b,14b-decahydro-1H-picene-2,3,10 trione (C23). In another preferred embodiment, the compounds of formula (Id) comprise a substructure having the following formula (Id''):
H
3 C COOCH 3
CH
3 FR24 R25 , R25 CH3 CH3 R20' R20 CH3 R19 R R19 15 CH 3 (Id") where:
R
19 , R 19 ,, R 2 o and R 20 , are independently hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a CORxII group (where RxII is 20 hydrogen; hydroxyl; substituted or non-substituted C1-C 1 2 alkyl; substituted or non-substituted C 6
-C
1 a aryl; or N(RxIII) (Rxv) amino, where RxIII and RxIv are independently hydrogen or a C1-C 1 2 alkyl group); a [(C-C 1 2 )alkyl-O-(C 1
-C
12 )alkyl-]n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 25 20-20' pair can form a C=O group together with the carbon to which they are attached;
R
24 and R 25 are independently hydrogen, hydroxyl or halogen.
WO 2007/077203 PCT/EP2006/070276 61 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). 5 In another particular aspect, the invention is directed to compounds of formula (le):
R
10
R
9 R1R R1 R 12 i,, R1R14 CH 3 R7
R
1 6 /7, J*IR6 R24 R R, H CH3
R
1 19
R
18 ' R 1 8
R
21 (le) 10 where: RI, R 2 , R 3 , R 4 , Rs, Re, R 7 , R 8 , Rn and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI
C
12 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; a N(R') (R'') amino group, where R' and R'' are independently 15 hydrogen or a C 1
-C
12 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 CI-C 12 alkyl; C 6
-CI
0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted CI-C 1 2 20 alkyl; substituted or non-substituted C 6
-CI
0 aryl; 0-CI-C 12 alkyl; or N(RIv) (Rv) amino, where RIv and Rv are independently hydrogen or an alkyl group CI-C 12 ); a carbinol group (CH 2 )n-OH (where n is an integer comprised between 1 and 10); or together form a methylene group; 25 R 13 , R 14 , Ris, R 16 , R 21 and R 23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6
-CI
0 aryl; a N(RvI) (RvII) amino group, where Rv and RvII are independently hydrogen or a CI-C 12 WO 2007/077203 PCT/EP2006/070276 62 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached;
R
18 and R 18 ' are independently hydrogen; hydroxyl; halogen; Ci-C 1 2 alkyl; C 6
-C
1 0 aryl; CORIx (where RIx is hydrogen; hydroxyl; Ci-C 1 2 5 alkyl; N(Rx) (Rx l ) amino, where Rx and RxI are independently hydrogen or a C 1
-C
1 2 alkyl group; or Ci-C 12 alcoxyl); or trifluoromethyl;
R
19 , R 19 ,, R 2 0 and R 20 , are independently hydrogen; substituted or non-substituted CI-C 12 alkyl; a CORxII group (where RxII is 10 hydrogen; hydroxyl; substituted or non-substituted Ci-C 1 2 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; or N(RXIII) (RXIV) amino, where RxIII and RxV are independently hydrogen or a Ci-C 1 2 alkyl group); a [(CI-C 12 )alkyl-O-(CI-C 12 )alkyl-]n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 15 20-20' pair can form a C=O group together with the carbon to which they are attached;
R
24 is hydrogen, hydroxyl or halogen; and the bond = ------- means a double bond or a single bond. 20 In a preferred embodiment, the compounds of formula (le) comprise a substructure having the following formula (le'):
H
3 C COOCH 3
CH
3 RR24 9 R20, CH3 R20 1nn1. Rig' CH3 CH3
R
18 ' R 18 (le') where: 25 R 18 and R 18 , are independently hydrogen; hydroxyl; halogen; C 1
-C
1 2 alkyl; C 6
-C
1 0 aryl; CORIx (where RIx is hydrogen; hydroxyl; Ci-C 1 2 alkyl; N(Rx) (Rx l ) amino, where Rx and RxI are independently hydrogen or a C 1
-C
1 2 alkyl group; or Ci-C 12 alcoxyl); or trifluoromethyl; WO 2007/077203 PCT/EP2006/070276 63
R
19 , R 19 ,, R 2 0 and R 20 , are independently hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a CORXII group (where Rx is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6
-C
0 aryl; or N(RxII) (RxV) amino, 5 where RxIII and RxV are independently hydrogen or a Ci-C 1 2 alkyl group); a [(C 1
-C
1 2 )alkyl-O-(C 1
-C
1 2 )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; 10 R 24 is hydrogen, hydroxyl or halogen. A particular example of this substructure (le') 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 15 picene-2-carboxylic acid methyl ester (C25). In another particular aspect, the invention is directed to compounds of formula (If): R Ro 1 R9 R14 13 C R7
CH
3 H R 1 " R6 R24 I R , 24 CH3 H CH35 R20' ""'R43 R20\\\\"" 3C ' R3 RR R2 R19R R~R23 R18' R18 R21 20 (If) where:
R
1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R,, R 11 and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1 25 C 12 alkyl; substituted or non-substituted C 6
-C
0 aryl; a N(R') (R'') amino group, where R' and R'' are independently hydrogen or a C 1
-C
12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; WO 2007/077203 PCT/EP2006/070276 64
R
9 and R 10 are independently hydrogen; substituted or non substituted CI-C 12 alkyl; C 6
-CI
0 aryl; a COR''' group (where R'' is hydrogen; hydroxyl; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6
-CI
0 aryl; 0-CI-C 12 alkyl; 5 or N(RI") (RV) amino, where RI" and Rv are independently hydrogen or a CI-C 12 alkyl group) ; a (CH 2 ) n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group,
R
13 , R 14 , Ris, R 2 1 and R 2 3 are independently hydrogen; hydroxyl; 10 halogen; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6
-CI
0 aryl; a N(RvI) (RvII) amino group, where RVI and R v n 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; 15 R 18 and R 18 , are independently hydrogen; hydroxyl; halogen; CI-C 12 alkyl; C 6
-CI
0 aryl; CORIx (where RIx is hydrogen; hydroxyl; CI-C 1 2 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a CI-C 12 alkyl group; or Ci-C 1 2 alcoxyl); or trifluoromethyl; 20 R 19 , R 19 , R 20 and R 20 , are independently hydrogen; substituted or non-substituted CI-C 12 alkyl; a CORII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6
-CI
0 aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a CI-C 12 alkyl 25 group); a [(CI-C 12 )alkyl-O-(CI-C 12 )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;
R
24 is hydrogen, hydroxyl or halogen; and 30 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'): WO 2007/077203 PCT/EP2006/070276 65
H
3 C .C00CH 3
CH
3 R24C RCH 3
CH
3
R
20 I'..
CH
3
R
19 ' R 9i,,g ...
R
18
R
18 (If') where:
R
18 and R 18 , are independently hydrogen; hydroxyl; halogen; C 1
-C
1 2 5 alkyl; C 6 -Co 0 aryl; CORIx (where RIx is hydrogen; hydroxyl; C1-C 1 2 alkyl; N(Rx) (Rx ) amino, where Rx and Rx are independently hydrogen or a C 1
-C
1 2 alkyl group; or C 1
-C
12 alcoxyl); or trifluoromethyl;
R
19 , R 19 , R 20 and R 20 , are independently hydrogen; substituted or 10 non-substituted C 1
-C
12 alkyl; a CORX group (where Rx is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; or N(Rxn) (R x V) amino, where R x I and RxV are independently hydrogen or a C1-C 1 2 alkyl group); a [(C 1
-C
12 )alkyl-O-(C 1
-C
12 )alkyl-]n group (where n is 15 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;
R
2 4 is hydrogen, hydroxyl or halogen. 20 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 25 formula (II): WO 2007/077203 PCT/EP2006/070276 66 R7 R8 R6 R2 R3 R6 (II) R 1, R4 R1o where: 5 R 1 , R 2 , R 3 , R4, R 5 , R 6 , Rg, R 1 o, R, R 12
R
13 R14 , R 15 , R 16 , R 1 , R 18 ,
R
19 and R 20 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 12 alkyl; substituted or non substituted C 6
-CI
0 aryl; a N(Rx") (Rx" ) amino group, where Rx" and
R
x " are independently hydrogen or a CI-C12 alkyl group; or each 10 pair can form a carboxyl (C-O) group together with the carbon to which they are attached; R7 and R 8 are independently hydrogen; substituted or non substituted CI-C 12 alkyl; C 6
-CI
0 aryl; a COR xv I group (where R xv I is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 15 alkyl; substituted or non-substituted C 6
-CI
0 aryl; 0-CI-C 12 alkyl; or N(Rxv l ) (R x x ) amino, where RxvIl and R x x are independently hydrogen or a CI-C 1 2 alkyl group); a (CH 2 )n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, 20 R 21 and R 2 4 are independently substituted or non-substituted Cj
C
1 2 alkyl; a COR xx group (where R xx is hydrogen; hydroxyl; substituted or non-substituted CI-C12 alkyl; substituted or non substituted C 6 -Co 0 aryl; or N(Rxx ) (R xx ") amino, where R xx l and RxxI are independently hydrogen or a C 1
-C
12 alkyl group); a [(C 1 25 C 1 2)alkyl-O-(C 1
-C
1 2)alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl;
R
2 2 and R 2 3 are: - hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a
COR
xx ii I group (where R xx ii I is hydrogen; hydroxyl; 30 substituted or non-substituted C 1
-C
12 alkyl; substituted or WO 2007/077203 PCT/EP2006/070276 67 non-substituted C 6 -Co 0 aryl; or N(RxxIv) (Rxxv) amino, where RxxIv and R xxv are independently hydrogen or a C 1
-C
12 alkyl group); a [(C 1
-C
1 2 )alkyl-O-(C 1
-C
1 2 )alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl when R 24 is 5 in the para position with respect to R 20 ; or
OR
2 2 ' and OR 2 3 ' respectively, where R 2 2 ' and R 2 3 ' are independently hydrogen; substituted or non-substituted C 1 C 1 2 alkyl; a COR xx v w group (where R xxw is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or 10 non-substituted C 6
-C
1 0 aryl; or N(RxxvI) (RxxvI) amino, where
R
xxv n and Rx xv I are independently hydrogen or a C 1
-C
1 2 alkyl group); a [(C 1
-C
1 2 )alkyl-O-(C 1
-C
1 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 . 15 or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof. In one particular aspect, the invention is directed to compounds of formula (IIa): R7 R R R6 R9 R24 RR2RR4Ro R23 tilR11 202 R22 R19 Rj7 1 R1 20 R21 R20 R16 R1s (Ha) where:
R
1 , R 2 , R 3 , R 4 , Rs, Re, R 9 , Ro 0 , R 11 , R 1 2 , R 13 , R 1 4 , R 15 , R 16 , R 17 , R 18 ,
R
19 and R 20 are independently hydrogen; hydroxyl; halogen; 25 substituted or non-substituted C 1
-C
12 alkyl; substituted or non substituted C 6
-C
1 0 aryl; a N(Rxv) (Rxv) amino group, where Rxv and
R
x are independently hydrogen or a C 1
-C
12 alkyl group; or each pair can form a carboxyl (C=O) group together with the carbon to which they are attached; WO 2007/077203 PCT/EP2006/070276 68
R
7 and R 8 are independently hydrogen; substituted or non substituted C 1
-C
12 alkyl; C 6
-C
0 lo aryl; a COR x v w group (where Rxv is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6
-C
0 lo aryl; 0-C 1
-C
12 alkyl; 5 or N(RxvII) (RxIx) amino, where R xv i n and RxIx are independently hydrogen or a C 1
-C
12 alkyl group); a (CH 2 )n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group,
R
21 and R 24 are independently substituted or non-substituted C 1 10 C 12 alkyl; a COR xx group (where R xx is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non substituted C 6
-C
1 0 aryl; or N(Rxx) (RxxII) amino, where R xxl and RxxII are independently hydrogen or a C 1
-C
12 alkyl group); a [(Cl
C
12 )alkyl-O-(C 1
-C
12 )alkyl-]n group (where n is comprised between 1 15 and 3); or trifluoromethyl;
R
22 and R 23 are: - hydrogen; substituted or non-substituted Ci-C 1 2 alkyl; a CORxxIII group (where RxxIII is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or 20 non-substituted C 6
-C
0 lo aryl; or N(RxxIv) (Rxxv) amino, where
R
xx Iv and R xxv are independently hydrogen or a CI-C 12 alkyl group); a [(C-C 12 )alkyl-O-(C-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 25 - OR 22 ' and OR 2 3 ' respectively, where R 22 ' and R 23 ' are independently hydrogen; substituted or non-substituted Cj
C
12 alkyl; a COR x w l group (where R xxw is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; or N(Rxxv w I) (RxxvII) amino, where 30 RxxvI and R xxw n 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 . 35 In a preferred embodiment, the compounds of formula (IIa) comprise a substructure having the following formula (IIa'): WO 2007/077203 PCT/EP2006/070276 69
H
3 C "-COOCH 3 R24 R23 CH3 R22 R19 R21 R20 (IIa' where:
R
19 and R 20 are independently hydrogen; hydroxyl; halogen; 5 substituted or non-substituted C 1
-C
12 alkyl; substituted or non substituted C 6
-C
10 aryl; a N(Rxv) (RxV ) amino group, where Rxv and
R
x are independently hydrogen or a C 1
-C
1 2 alkyl group; or each pair can form a (C-O) carboxyl group together with the carbon to which they are attached; 10 R21 and R24 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1
-C
12 alkyl; substituted or non substituted C 6
-C
0 aryl; a N(Rxx ) (R xx I) amino group, where Rxx and
R
xx are independently hydrogen or a C-C 12 alkyl group; or each pair can form a (C-O) carboxyl group together with the carbon to 15 which they are attached;
R
22 and R 23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1
-C
12 alkyl; substituted or non substituted C 6
-C
0 aryl; a N(Rxxiv) (Rxxv) amino group, where R xx iv and Rxxv are independently hydrogen or a C 1
-C
12 alkyl group; or 20 each pair can form a (C-O) carboxyl group together with the carbon to which they are attached. A particular example of this substructure (IIa') is: - 8-[2-(6,7-dihydroxy-1,5-dimethyl-naphthalen-2-yl)-ethyl]-2,4a 25 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: 30 a) The usual methodology for the chemoselective introduction in the hydroxyl in C-3 of the natural WO 2007/077203 PCT/EP2006/070276 70 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 5 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 10 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 15 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 20 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-11, the previously studied methodology will be used to obtain 25 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 30 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 35 chemistry for introducing functional groups in this ring has been widely elaborated.
WO 2007/077203 PCT/EP2006/070276 71 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 5 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 10 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 15 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 20 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 25 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 30 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 35 amino acid salts. The particularly preferred derivatives or prodrugs are those increasing the bioavailability of the compounds of this WO 2007/077203 PCT/EP2006/070276 72 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 5 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 10 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, 15 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). 20 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 25 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). 30 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 35 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 WO 2007/077203 PCT/EP2006/070276 73 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 5 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 10 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), (IIa) , (IIa') or mixtures thereof, a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof together 15 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, 20 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, 25 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 30 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 35 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 WO 2007/077203 PCT/EP2006/070276 74 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, 5 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 10 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. 15 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. 20 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 25 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 30 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 35 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 WO 2007/077203 PCT/EP2006/070276 75 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 5 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 10 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 15 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 20 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. 25 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 30 formula (I), (Ia), (Ia'), (Ia''), (Ia'''), (Ib), (Ib'), (Ib''), (Ic), (Ic'), (Ic''), (Id), (Id'), (Id''), (Ie), (Ie'), (If), (If'), (II), (IIa), (IIa') or mixtures thereof, or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof for use in the treatment of cancer, 35 parasitic diseases, bacterial diseases or fungal diseases.
WO 2007/077203 PCT/EP2006/070276 76 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. 5 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 10 300 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 15 CHC13-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 20 starting compound 22f-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 22f-hydroxy-tingenone in 50 ml of dry CH 2 C1 2 , under an inert atmosphere and at 0 0 C were treated 25 with 1.5 eq of BBr 3 (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 CH 2 C1 2 was carried 30 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 n-hexane:chloroform:methanol 2:1:1 mixture as eluent and in a silica gel chromatography column using n-hexane-ethyl acetate 35 7:3 as eluent. 111 mg (27%) of product C3 was obtained.
WO 2007/077203 PCT/EP2006/070276 77 11H NMR (300 MHz, CDCl 3 ) 6 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 (1H, m, H-20); 3.70 (1H, d, J= 2.9 Hz, H-22); 4.03 (1H, dd, J 1 = 2.6, J 2 = 10.2 Hz, H 5 19); 6.32 (1H, d, J= 7.2 Hz, H-7); 6.50 (1H, d, J= 1.3 Hz, H-1); 7.00 (1H, dd, J,= 1.3, J 2 = 7.1 Hz, H-6). 13 C NMR (75 MHz, CDCl 3 ) 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-11); 37.9 (c, C-25); 40.0 (d, C-20); 40.4 (s, C-14); 10 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-1); 127.7 (s, C-5); 133.7 (d, C-6); 146.1 (s, C-4); 149.5 (s, C-3); 164.1 (s, C-10); 167.9 (s, C-8); 178.4 (s, C-2); 216.5 (s, C 21). High resolution MS Calculated for (M+-Br) C 28
H
36 0 4 436.2614, 15 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 20 100 mg (0.23 mmoles) of 22p-hydroxy-tingenone, obtained according to example 1, were dissolved in 10 ml of CH 2 C1 2 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 CH 2 C1 2 was carried out. 25 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 30 other compounds. 1H NMR (300 MHz, CDCl 3 ) 6 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 (1H, dd, J= 6.7 Hz,
J
2 = 12.0 Hz, H-11); 6.28 (1IH, d, J= 7.0 Hz, H-7); 6.89 (1IH, d, 35 J= 7.0 Hz, H-6); 7.35 (1H, s, H-1).. 3C NMR (75 MHz, CDCl 3 ) 6 10.2 (c, C-23); 14.9 (c, C-30); 19.5 (c, C-27); 21.2 (c, C-26); WO 2007/077203 PCT/EP2006/070276 78 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-11); 117.9 (s, C-4); 118.4 (d, C-7); 5 121.1 (d, C-1); 129.6 (s, C-5); 131.4 (d, C-6); 152.9 (s, C-3); 162.7 (s, C-10); 165.4 (s, C-8); 178.3 (s, C-2); 212.8 (s, C 21) . High resolution MS Calculated for C 28 Ha 35 BrO 3 498.1770, observed 498.1801. Example 3 10 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 15 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 CHC13-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 20 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 CH 2 C12 25 were treated with 0.04 ml (3 eq) of dry Et 3 N 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 30 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, CDCl 3 ) 8 7.08 (1H, dd, J 1 = 1.3, J 2 = 7.0 Hz, H-6); 6.50 (1H, d, J=-1.4 Hz, H-1); 6.35 (1H, d, J= 7.1 Hz, H-7); 2.49 (1H, m, H-20); 2.36 (3H, s, Me-COO); 2.16 (3H, s, Me-23); 1.52 35 (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) .
13 C NMR (75 MHz, WO 2007/077203 PCT/EP2006/070276 79 CDCl 3 ) 6 11.1 (c, C-23); 14.8 (c, C-30); 19.5 (c, C-27); 20.3 (c, CH 3 COO) 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-11); 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); 5 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-1); 126.4 (s, C-5); 133.5 (s, C-4); 134.9 (d, C-6); 142.8 (s, C-3); 162.9 (s, C-10); 168.5 (s,
CH
3 COO) ; 170.4 (s, C-8) ; 177.3 (s, C-2) ; 213.4 (s, C-21) . High resolution MS Calculated for C 30
H
3 8 0 4 462.2770, observed 462.2784. 10 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 15 example 3) were dissolved in 10 ml of dry CH 2 C1 2 and were treated with 0.097 ml (3 eq) of dry Et 3 N, 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 20 followed and the raw product was purified by preparative chromatography on silica gel using CH 2 Cl 2 :AcOEt (1:1) as a mobile phase, to give 55 mg (46%) of product C9. The residue was starting product. 1H NMR (300 MHz, CDCl 3 ) 8 9.37 (1H, dd, J 1 ,= 0.9, J 2 = 2.1 Hz, Ha); 25 8.81 (1H, dd, J 1 = 1.7, J 2 = 4.9 Hz, Hd); 8.43 (1H, dd, J= 1.9, J 2 = 8.2 Hz, Hb); 7.44 (1H, m, He); 7.13 (1H, dd, J 1 = 1.2, J 2 = 7.0 Hz, H-6); 6.53 (1H, d, J=1.3 Hz, H-1); 6.38 (1H, d, J= 7.1 Hz, H-7); 2.49 (1H, 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 30 Hz, Me-30); 0.95 (3H, s, Me-28). 13 C NMR (75 MHz, CDCl 3 ) 6 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-11); 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); 35 43.26 (d, C-18); 44.64 (s, C-14); 52.26 (t, C-22); 117.6 (d, C 7); 123.0 (d, C-1); 123.2 (d, CH-Ar); 125.0 (s, C-Ar); 126.3 (s, WO 2007/077203 PCT/EP2006/070276 80 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-10); 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 C 3 4
H
39 N0 4 525.2879, 5 observed 525.2899. Example 5 Compound C12: 3,10-dihydroxy-2,4a,6a,9,12b,14a-hexamethyl-11 oxo-1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro-picen 2-carboxylic acid methyl ester. 10 1500 g of Salacia root bark were extracted in 2 liters of a n-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. 15 Example 6 Compound C14: 10-Dimethylcarbamoyloxy-2,4a,6a,9,12b,14a hexamethyl-11-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 20 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 CHC13-MeOH 2:1:1 mixture as eluent. A total of 41 fractions were 25 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. 30 65 mg (0.14 mmoles) of pristimerin in 5 ml of dry CH 2 C1 2 were treated with 0.062 ml (3 eq) of dry Et 3 N, 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 35 hydrochloric acid was added until neutralization. Then the organic phase was extracted with CH 2 C1 2 and was dried with anhydrous magnesium sulfate. It was filtered and concentrated WO 2007/077203 PCT/EP2006/070276 81 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. 5 H NMR (300 MHz, CDCl 3 ) 8 7.00 (1H, dd, J 1 = 1.4, J 2 = 7.0 Hz, H-6); 6.46 (1IH, d, J= 1.4 Hz, H-1); 6.29 (1IH, d, J= 7.2 Hz, H-7); 3.56 (3H, s, OMe); 3.13 (s, N-CH 3 ); 3.00 (s, N-CH 3 ); 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) .
13 C NMR (75 MHz, 10 CDCl 3 ) 6 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-11) ; 34.49 (t, C-22); 36.15 (t, C-16); 36.57(c, N-CH 3 ); 36.58(c, N-CH 3 ); 37.99 (c, C-25); 38.99 (s, C-13); 40.14 (s, C 15 20); 42.23 (s, C-9); 44.07 (d, C-18); 44.87 (s, C-14); 51.34 (q,
OCH
3 ); 117.5 (d, C-7); 122.9 (d, C-1); 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-10); 170.8 (s, C-8); 178.3 (s, C-2) ; 178.4 (s, C-29) . High resolution MS Calculated for C 3 3
H
45
NO
5 535.3298, observed 20 535.3294. EX VIVO ASSAYS OF HUMAN CHOK ACTIVITY Recombinant human alpha-i choline kinase expressed in E. coli in the assay of the buffer (100 mM Tris-HCl pH 8.0, 100 mM MgCl 2 , 10 mM ATP and 200 pM of choline in the presence of 25 methyl[14C]-choline chloride (50-60 pCi/mmol) were used for the ex vivo assays. The reactions were carried out at 370 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 30 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 35 invention C3, C7, C8, C9, C10, C12 and C14 as well as with WO 2007/077203 PCT/EP2006/070276 82 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 5 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 10 3 cells/well) and were incubated for 24 h. Then, the cells were 10 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 15 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., Nuifez, M. C., Khaless, F., Gallo, M. A., Espinosa, A., Lacal, J. C. Oncogene, 15, 2289-2301 (1997)]. Briefly, the cells were washed with TD 20 buffer and were fixed with 1% glutaraldehyde for 15 min. After washing again with TD, the cell nuclei were stained with 0.1% Crystal Violet for at least 30 min 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 25 spectrometer. The obtained results are summarized in the form of an ICs 0 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 30 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 35 structure.
WO 2007/077203 PCT/EP2006/070276 83 These assays are carried out with the compounds of the invention C3, C7, C8, C9, C10, 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. 5 The following table summarizes the results obtained in the conducted assays and which are shown as an example. Table I
IC
50 ex vivo No. Code IC 50 HT-29 (pM) (PiM) 1 C3 3.3 8.8 2 C7 13.6 27.5 3 C8 5.3 26.4 4 C9 8.8 13.3 5 C 11.2 25.9 6 C12 7.4 3.8 7 C14 7.1 11.3 8 3,9-dihydroxy 4, 6b, 8a, 11, 12b, 14a amhexamethyl- 1 7,8,8a,11,12,12a,12b,1 4.9 6.5 a3,14, 14a-decahydro 6bH, 9H-picen-2, 10 dione 9 (9-hydroxy 4, 6b, 8a, 11, 12b, 14a hexamethyl-2,10O-dioxo 2, 6b, 7,8, 8a, 9,10,11,12, 4.8 11.1 12a, 12b, 13, 14, 14a tetradecahydro-picen-3 yl) acetic acid methyl ester 1 9-hydroxy 5.2 9.6 4, 6b, 8a, 11, 12b, 14a- WO 2007/077203 PCT/EP2006/070276 84 hexamethyl-2, 1-dioxo 2, 6b, 7,8, 8a, 9,10,11,12 14.6 17.0 12a,12b,13, 14, 14a tetradecahydro-picen 2}t -III 7- 8-a 9 i i l- - I 3-yl dodecanoic acid ester 11 (9-hydroxy 4, 6b, 8a, 11,12b, 14a hexamethyl-2, 1-dioxo 2,6b,7,8,8a,9,10,11,12, 14.6 17.0 12a, 12b, 13, 14, 14a t} t} al 4 1 -a 5 : 6- r)} i 1 c tetradecahydro-picen-3 yl) dimethyl-carbamic acid ester 12 (9-hydroxy 4, 6b, 8a,11, 12b, 14a hexamethyl-2,10O-dioxo 2,6b,7,8, 8a,9,10,11,12, 8.6 7.2 12a, 12b, 13,14, 14a tetradecahydro-picen-3 yl) nicotinic acid ester 13 14-bromo-3, 9-dihydroxy 4,6b, 8a, 11,12b,14a hexamethyl 10.8 12.1 7,8, 8a, 11, 12, 12a, 12b, 13 ,14, 14a-decahydro 6bH, 9H-picen-2, 10-dione 14 mono-(13-bromo-10 h yd roxy 2, 4a, 6a, 9, 12b, 14a hexamethyl-3,11l-dioxo 4.7 11.3 1,2,3,4, 4a, 5,6, 6a, 11,12 b, 13, 14, 14a, 14b tetradecahydro-picen-4 yl) succinic acid ester WO 2007/077203 PCT/EP2006/070276 85 15 13-bromo-10-hydroxy 2, 4a, 6a, 9, 12b, 14a hexamethyl-3, 1i-dioxo 1,2,3,4,4a, 5, 6,6a,11, 12 2.1 4.1 b, 13, 14, 14a, 14b tetradecahydr-picen-4 yl ethylsuccinic acid ester 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 (38)

1.- Use of a compound of formula (I): R 10 R 9 R * R 12 R7 CH 3 .. illR 6 ) H CH3R5 ,"',it//R4 (A) (B) H 3 C R3 R, R 2 5 (I) where: RI, R 2 , R 3 , R 4 , R 5 , R 6 , R,, R,, RII and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1 10 C 12 alkyl; substituted or non-substituted C 6 -C 1 a aryl; a N(R') (R'') amino group, where R' and R' are independently hydrogen or a C 1 -C 1 2 alkyl group; an OCOR group, where R is (CH 2 ) 2 COOH or (CH 2 ) 2 CO 2 CH 2 CH 3 ; or each pair can form a (C=O) group together with the carbon to which they are attached; 15 R 9 and RIO are independently hydrogen; substituted or non substituted C 1 -C 12 alkyl; C 6 -Co aryl; a COR"' group (where R"' is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -Co aryl; 0-C-C 12 alkyl; or N(RI") (RV) amino, where RI" and RV are independently hydrogen 20 or a C 1 -C 12 alkyl group); a (CH 2 )n-OH 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 25 is selected from the following structures: WO 2007/077203 PCT/EP2006/070276 87 R 14 R 13 R 1 4 R 13 R 14 R 1 3 Ri Rs I R 1 R 1 6 R R 16 0 R 20 0 R 20 0 R 17 R17 R 1 ,O R 1 ,O - R 1 O R23 RI, RI, R 21 R 22 RIp R 21 (a) (b) (c) R 1 3 R 1 4 R 1 3 R 1 4 R 1 3 R 1 R R 15 R 15 RR RR 2 R24 R CH 3 R20 R20 R R204 RR 9 R' R20\""" R20"""" R20\\" R ' ;/R1'Ic R1,' ReR23 RR R23 RR R23 R 1 8 R 21 R 1 8 ' R 1 8 R 21 R 1 8 ' R 1 8 R 21 (d) (e) (f) where: R 13 , R 1 4r R 15 is, R 16 , R 21 , R 2 2 and R 2 3 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 1 2 alkyl; 5 substituted or non-substituted C 6 -CI 0 aryl; a N(R ) (Rvn) amino group, where Rv and Rvn are independently hydrogen or a CI-C 12 alkyl group; an OCORvI group, where Rvu is (CH 2 ) 2 COOH or (CH2) 2 CO 2 CH 2 CH 3 ; or each pair can form a (C-O) group together with the carbon to which they are attached or each pair can form a 10 (C-O) group together with the carbon to which they are attached; R 1 7 is hydrogen or methyl; R 18 and R 18 , are independently hydrogen; hydroxyl; halogen; CI-C 1 2 alkyl; C 6 -CI 0 aryl; CORIx (where RIx is hydrogen; hydroxyl; CI-C 1 2 alkyl; N (Rx) (Rx ) amino, where Rx and R xl are independently 15 hydrogen or a CI-C 1 2 alkyl group; or CI-C 12 alcoxyl); or trifluoromethyl; R 19 , R 19 ,, R 2 0 and R 20 , are independently hydrogen; substituted or non-substituted CI-C 12 alkyl; a CORxn group (where Rxn is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; 20 substituted or non-substituted C 6 -CI 0 aryl; or N(RxIn) (Rxv) amino, WO 2007/077203 PCT/EP2006/070276 88 where RxIII and RxIv are independently hydrogen or a C 1 -C 12 alkyl group); a [(C 1 -C 12 )alkyl-O-(C 1 -C 1 2 )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 5 which they are attached; R 24 and R 25 are independently hydrogen, hydroxyl or halogen; or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof, in the manufacture of a 10 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): Rio R, R43R piln.,- is ..milR, Re CHs R q R14 RO R211s. R, 15 (la) where R 1 , R 2 , R 3 , R 4 , Rs, Re, R 7 , R , Rn and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1 20 C 12 alkyl; substituted or non-substituted C 6 -C 0 aryl; a N(R') (R'') amino group, where R' and R'' are independently hydrogen or a C 1 -C 12 alkyl group; an OCOR group, where R is (CH 2 ) 2 COOH or (CH 2 ) 2 CO 2 CH 2 CH 3 ; or each pair can form a (C=O) group together with the carbon to which they are attached; 25 R 9 and R 10 are independently hydrogen; substituted or non substituted C 1 -C 1 2 alkyl; C 6 -C 10 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 2 alkyl; substituted or non-substituted C 6 -C 10 aryl; 0-C 1 -C 12 alkyl; or N(RIv) (Rv) amino, where RIv and Rv are independently hydrogen WO 2007/077203 PCT/EP2006/070276 89 or a CI-C 12 alkyl group) ; a (CH 2 ) n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, R 13 , R 14 , R 15 and R 16 are independently hydrogen; hydroxyl; 5 halogen; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -CI 0 aryl; a N(R"I) (R"VII) amino group, where Rvi and R v n are independently hydrogen or a CI-C 12 alkyl group; an OCORvIII group, where RvIII is (CH 2 ) 2 COOH or (CH 2 ) 2 CO 2 CH 2 CH 3 ; or each pair can form a (C=O) group together with the carbon to which 10 they are attached; R 17 is hydrogen or methyl; R 18 is hydrogen; hydroxyl; halogen; CI-C 12 alkyl; C 6 -CIo aryl; CORIx (where RIx is hydrogen; hydroxyl; CI-C 12 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a CI-C 12 alkyl 15 group; or C 1 -C 1 2 alcoxyl); or trifluoromethyl; R 19 is hydrogen; substituted or non-substituted C-C 1 2 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 CI 0 aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are 20 independently hydrogen or a CI-C 12 alkyl group); a [(C 1 -C 12 )alkyl O-(C 1 -C 1 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. 25 3.- Use according to claim 2 wherein the compound of formula (Ia) is a compound of formula (Ia'): CH 3 R,,, R 7 CH 3 R Rs CH 3 0 CH 3 CH 3 R 1 9 0 CH 3 (Ia') where WO 2007/077203 PCT/EP2006/070276 90 Rs is hydroxyl or a OCOR group where R is (CH 2 ) 2 COOH or (CH 2 ) 2 CO 2 CH 2 CH 3 ; R 7 and R 8 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 12 alkyl; substituted or non 5 substituted C 6 -CI 0 aryl; a N(R') (R'') 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; R 12 is independently hydrogen or a halogen; and 10 RI 9 is hydrogen; substituted or non-substituted CI-C 12 alkyl; a COR x I group (where R x " is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 CI 0 aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a CI-C 12 alkyl group); a [(C 1 -C 12 )alkyl 15 O-(C 1 -C 1 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. 4.- Use according to claim 3 wherein the compound of formula 20 (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 25 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; 30 - 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 35 2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro picen-3-yl ester; WO 2007/077203 PCT/EP2006/070276 91 - 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 5 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; 10 - 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 15 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-6bH,9H-picene 2,10-dione; - 3,9,10-trihydroxy-6b,8a,11,12b,14a-hexamethyl 20 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 25 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. 30 5.- Use according to claim 2 wherein the compound of formula (Ia) is a compound of formula (Ia''): WO 2007/077203 PCT/EP2006/070276 92 CH3 R7 CH3 iR R1s CH3 0 CH31 CH3 R 1 9 0 CH 3 (Ia' F where: R, and R 8 are independently hydrogen, hydroxyl, halogen, 5 substituted or non-substituted CI-C 12 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 C 1 -C 12 alkyl group, or each pair can form a (C-O) group together with the carbon to which they are attached; 10 R 15 is hydrogen or halogen; RI 9 is hydrogen, substituted or non-substituted CI-C 12 alkyl; a COR X I group (where R x " is hydrogen; hydroxyl; substituted or non-substituted C-C 12 alkyl; substituted or non-substituted C 6 CI 0 aryl; or N(Rx ) (R x v ) amino, where Rx and Rxv are 15 independently hydrogen or a C 1 -C 12 alkyl group); a [(C-C) alkyl O-(C 1 -C 1 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. 20 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-6bH,9H-picene 2,10-dione; 25 -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; WO 2007/077203 PCT/EP2006/070276 93 -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 5 7,8,8a,9,10,11,12,12a,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 10 7.- Use according to claim 2 wherein the compound of formula (Ia) is a compound of formula (Ia'''): H 3 C COOCH 3 R 7 CH 3 CH 3 O CH 3 CH3 R 1 9 0 * CH 3 15 (Ia''') where: R 7 is hydrogen, hydroxyl, halogen, substituted or non substituted CI-C 12 alkyl, substituted or non-substituted C 6 -CI 0 aryl, or a N(R')(R'') amino group, where R' and R'' are 20 independently hydrogen or a C 1 -C 1 2 alkyl group; and R 1 9 is substituted or non-substituted C 1 -C 12 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -C 1 0 aryl; or N(RxIII) (RxIv) amino, where RxIII and Rxa v are independently hydrogen 25 or a C 1 -C 12 alkyl group); a [(C-C 12 )alkyl-O-(C-C 12 )alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl; with the proviso that when R 19 is hydrogen, R 7 is not hydrogen. WO 2007/077203 PCT/EP2006/070276 94 8.- Use according to claim 7 wherein the compound of formula (Ia''')is: - 10-hydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro 5 picene-2-carboxylic acid methyl ester; - 3,10-dihydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-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-11-oxo-10-propionyloxy 10 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-11 oxo-1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro picene-2-carboxylic) acid methyl ester 15 9.- Use according to clam 1 wherein the compound of formula (I) is a compound of formula (Ib): R20 R9 where:, R R 1 1 a Re R1441 CH3,R R1s ? ""R6 R16"" H CH3 Rs R200 ''t//R4 R17 HC , R3 I I R, R2 R190 R23 R18 R21 R22 20 (Ib) where: RI, R2, R3, R4r R5, R6, R7, R,, RII and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI C 12 alkyl; substituted or non-substituted C 6 -Co aryl; a 25 N(R') (R'') amino group, where R' and R' are independently hydrogen or a C 1 -C 12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R 9 and RIO are independently hydrogen; substituted or non substituted C-C 12 alkyl; C 6 -Co aryl; a COR"' group (where R"' WO 2007/077203 PCT/EP2006/070276 95 is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6 -C 0 lo aryl; 0-CI-C 1 2 alkyl; or N(RI") (RV) amino, where RIV and Rv are independently hydrogen or a CI-C 12 alkyl group) ; a (CH 2 ) n-OH carbinol group (where n is 5 an integer comprised between 1 and 10); or together form a methylene group, R 13 , R 1 4 , R 15 is, R 16 , R 21 , R 22 and R 23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6 -C 0 lo aryl; a N(R) (RvII) amino 10 group, where RvI and RvII 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; R 17 is hydrogen or methyl; R 18 is hydrogen; hydroxyl; halogen; CI-C 12 alkyl; C 6 -Cio aryl; CORIx 15 (where RIx is hydrogen; hydroxyl; CI-C 12 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a CI-C 12 alkyl group; or C 1 -C 12 alcoxyl); or trifluoromethyl; R 19 and R 20 are independently hydrogen, substituted or non substituted CI-C 12 alkyl; a CORxII group (where RxII is hydrogen; 20 hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6 -Cl 0 aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a CI-C 12 alkyl group); a [(CI-C 12 )alkyl-O-(CI-C 1 2 )alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; and 25 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'): WO 2007/077203 PCT/EP2006/070276 96 CH 3 0 OH 3 OH CH 3 R200 C H CH 3 R190 C H3 OH (Ib') where: R 19 and R 20 are independently substituted or non-substituted C 1 5 C 12 alkyl; a CORxn group (where Rx is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non substituted C 6 -C 0 aryl; or N(RxIII) (R x "v) amino, where RxIII and Rxiv are independently hydrogen or a C-C12 alkyl group); a [(Cl C 1 2)alkyl-O-(C 1 -C 1 2)alkyl-]n group (where n is comprised between 1 10 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 15 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''): H 3 COOC CH 3 CH 3 CH 3 HO CH 3 1 CH 3 R 19 0 R23 20 R 18 0 (Ib' ') WO 2007/077203 PCT/EP2006/070276 97 where: R 18 is hydrogen; hydroxyl; halogen; C 1 -C 1 2 alkyl; C 6 -CIo aryl; CORIx (where RIx is hydrogen; hydroxyl; C 1 -C 12 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a CI-C 1 2 alkyl 5 group; or C 1 -C 12 alcoxyl); or trifluoromethyl; R 1 9 is hydrogen; substituted or non-substituted C 1 -C 1 2 alkyl; a COR x group (where R x " is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 C 10 O aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are 10 independently hydrogen or a C 1 -C 1 2 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; R 23 is hydrogen; hydroxyl; halogen; substituted or non substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -C 0 15 aryl; a N(RvI) (RvII) amino group, where RVI and RvII are independently hydrogen or a C 1 -C 12 alkyl group. 13.- Use according to claim 12 wherein the compound of formula (Ib'') is: 20 - 7,10,11-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 25 picene-2-carboxylic acid methyl ester; - 11-hydroxy-10-(2-methoxy-ethoxymethoxy)-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 30 14.- Use according to claim 1 wherein the compound of formula (I) is a compound of formula (Ic): WO 2007/077203 PCT/EP2006/070276 98 R1o R9 (Ic) where : 5 RR1, R 2 , R 3 , R4, R, R 6 , R, R, R13 and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci C 12 alkyl; substituted or non-substituted C 6 -C 1 0 aryl; a N(R') (R'') amino group, where R' and R'' are independently hydrogen or a C 1 -C 12 alkyl group; or each pair can form a (C-O) 10 group together with the carbon to which they are attached; R 9 and R 10 are independently hydrogen; substituted or non substituted C 1 -C 1 2 alkyl; C 6 -C 1 0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6 -C 10 aryl; 0-C 1 -C 12 alkyl; 15 or N(R ') (R') amino, where R ' and R' are independently hydrogen or a C 1 -C 1 2 alkyl group) ; a (CH 2 )n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group; R 13 , R 1 , R 1 5 , R 1 6 , R 21 and R 23 are independently hydrogen; Ris"" ""R6 R16H CH3R R20020 hydroxyl; halogen; substituted or non-substituted C-C 2 alkyl; substituted or non-substituted C 6 -C 1 0 aryl; a N(RV w ) (RV ) amino group, where RV and RV x 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; 3C R3 I R, R2 25 R 1 8 is hydrogen; hydroxyl; halogen; CR-C 1 2 alkyl; C3-C 0 aryl; COR R18 R21 (Ic) where: 5 RI, R2, R3, R4r R5, R6, R7, R,, RnI and R12 are independently (where R is hydrogen; hydroxyl; Calogen; substituted or non-substituted C(RX) amino, C12 alkyl; substituted or non-substituted C6-Cha aryl; a N(R')(R) amino group, where R' and R are independently hydrogen or a C-C 1 2 alkyl hydrogeup; or C-C 2 alcoxC12 alkyl group; r trifluoro each pair can form a (C=yl;) 10 group together with the carbon to which they are attached; R9 and RIO are independently hydrogen; substituted or non substituted CI-C12 alkyl; C6-CIo aryl; a COR"' group (where R"' is hydrogen; hydroxyl; substituted or non-substituted CI-C12 alkyl; substituted or non-substituted C6-CIo aryl; O-CI-C12 alkyl; 15 or N(RI")(R") amino, where RI" and Rv are independently hydrogen or a CI-C12 alkyl group) ; a (CH2) n-OH carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group; R13, R14r RIs, R16, R21 and R23 are independently hydrogen; 20 hydroxyl; halogen; substituted or non-substituted CI-(12 alkyl; substituted or non-substituted C6-CIo aryl; a N (Rv") (RvnI) amino group, where Rv" and Rv" are independently hydrogen or a CI-C12 alkyl group; or each pair can form a (C=0) group together with the carbon to which they are attached; 25 RIO is hydrogen; hydroxyl; halogen; C -C12 alkyl; C6-CIo aryl; COR"x (where RIx is hydrogen; hydroxyl; C -C12 alkyl; N (Rx) (Rxx) amino, where Rx and Rx" are independently hydrogen or a CI-C12 alkyl group; Or CI-C12 alCOxyl) ; or trifluoromethyl; WO 2007/077203 PCT/EP2006/070276 99 R 19 and R 20 are independently hydrogen; substituted or non substituted C 1 -C 12 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted Ci-C 1 2 alkyl; substituted or non-substituted C 6 -C 0 aryl; or N(RxIII) (Rx"V) amino, 5 where RxIII and RxV are independently hydrogen or a Ci-C 1 2 alkyl group); a [(C 1 -C 1 2 )alkyl-O-(C 1 -C 1 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. 10 15. Use according to claim 14 wherein the compound of formula (Ic) is a compound of formula (Ic'): CH 3 0 CH 3 CH 3 R 19 0 CH 3 R 20 0 CH 3 (Ic') where: 15 R 19 and R 20 are independently hydrogen; substituted or non substituted C 1 -C 12 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted C1-C 1 2 alkyl; substituted or non-substituted C 6 -C 1 0 aryl; or N(RxIII) (Rx"V) amino, where RxIII and RxV are independently hydrogen or a Ci-C 1 2 alkyl 20 group); a [(CI-C 12 )alkyl-O-(CI-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. 16.- Use according to claim 15 wherein the compound of formula 25 (Ic') is: - 10,11-dihydroxy-2,4a,6a,9,14a-pentamethyl 1,4,4a,5,6,6a,13,14,14a,14b-decahydro-2H-picene-3-one; - 10,11-dihydroxy-2,4a,6a,9,14a-pentamethyl 4a,5,6,6a,13,14,14a,14b-octahydro-4H-picene-3-one. WO 2007/077203 PCT/EP2006/070276 100 17.- Use according to claim 14 wherein the compound of formula (Ic) is a compound of formula (Ic''): H 3 C COOCH 3 CH 3 CH 3 R 1 9 0 CH 3 R 20 0 CH 3 5 (Ic'') where: R 19 and R 20 are independently hydrogen; substituted or non substituted CI-C 12 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; 10 substituted or non-substituted C 6 -C 1 0 aryl; or N(RxII) (Rxv) amino, where RxIII and Rxv are independently hydrogen or a Ci-C 1 2 alkyl group); a [(C 1 -C 1 2 )alkyl-O-(C 1 -C 12 )alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl. 15 18.- Use according to claim 17 wherein the compound of formula (Ic'') is 10,11-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. 20 19.- Use according to claim 1 wherein the compound of formula (I) is a compound of formula (Id): WO 2007/077203 PCT/EP2006/070276 101 R1i R9 R, R11, y R 8 R13 HR7 (Id) R1s """11IR6 where : 5 RR24, R 2 , R, R, R, R, R25, R, R and R 2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci C 12 alkyl; substituted or non-substituted C 6 -C 1 0 aryl; a N(R') (R'') amino group, where R' and R'' are independently hydrogen or a C 1 -C 12 alkyl group; or each pair can form a (C-O) 10 group together with the carbon to which they are attached; R 9 and R 10 are independently hydrogen; substituted or non substituted C 1 -C 1 2 alkyl; C 6 -C 10 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6 -C 10 aryl; 0-C 1 -C 12 alkyl; 15 or N(R ') (R') amino, where R v and R' are independently hydrogen or a C 1 -C 1 2 alkyl group); a (CH 2 )OH CH3carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group, R20 3C b R3 R, R 15 , R 21 and R 2 R, are independently hydrogen; hydroxyl;R2 R 19' 2 R23 R19 R18 R21 (Id) where: 5 RI, R2, R3, R4r R5, R6, R7, R,, RnI and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C-C 2 alkyl; substituted C12 alkyl; substituted or non-substituted CC-C 1 0 aryl; a N(RV) (RV) amino group, where N(R') (R" ) amino group, where R' and R" are independently R and R are independently hydrogen or a C 1 -C 1 2 alkyl group; or each pair can form a (C=) 10each pair can form a (C-O) group together with the carbon to which they are attached; Which theyand RIO are attachindependently hydrogen; substituted or non sub25 R 18 is hydrogen;d CC2 alkyl; C-Clo aryl; a COR g roup (where Rx (wis hydrogen; hydroxxyyl; substituted or non-substituted C) amino,2 alkyl; substituted or non-substituted C6-CIo aryl; O-CI-C12 alkyl; 15 or N(R")(R) amino, where R" and R are independently hydrogen or a C-C 1 2 alkyl group; or C 1 -C 1 2 al grcoxylup) ; ora (CH2) nH carbinol group (where n istrifluoromethyl; an integer comprised between 1 and 10) ; or together form a methylene group, R13,r RIs, R21 and R23 are independently hydrogen; hydroxyl; 20 halogen; substituted or non-substituted CI-C12 alkyl; substituted or non-substituted C6-CIo aryl; a N(R") (Rv" ) amino group, where R v and Rv" are independently hydrogen or a CI-C12 alkyl group; or each pair can form a (C=0) group together with the carbon to which they are attached; 25 RIO is hydrogen; hydroxyl; halogen; C -C12 alkyl; C6-CIo aryl; COR"x (where RIx is hydrogen; hydroxyl; CI-C12 alkyl; N (Rx) (Rxx) amino, where Rx and Rx" are independently hydrogen or a CI-C12 alkyl group; Or CI-C12 alCOxyl) ; or trifluoromethyl; WO 2007/077203 PCT/EP2006/070276 102 R 19 , R 19 ,, R 2 0 and R 20 , are independently hydrogen; substituted or non-substituted C 1 -C 12 alkyl; a CORxII group (where Rx is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6 -C 0 aryl; or N(RxIII) (Rx"V) amino, 5 where RxIII and RxV are independently hydrogen or a Ci-C 1 2 alkyl group); a [(C 1 -C 1 2 )alkyl-O-(C 1 -C 1 2 )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; 10 R 24 and R 25 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'): CH 3 0 CH 3 - R5 R24 R25 R ,20' CH3 CH36 R20 CH3 R1 15 CH3 (Id') where: Rs and R 6 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1 -C 12 alkyl; substituted or non 20 substituted C 6 -C 0 aryl; a N(R')(R'') amino group, where R' and R'' are independently hydrogen or a C 1 -C 12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R 19 , R 19 , R 20 and R 20 , are independently hydrogen; substituted or 25 non-substituted C 1 -C 12 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -C 0 aryl; or N(RxIII) (Rx"V) amino, where RxIII and RxV are independently hydrogen or a Ci-C 1 2 alkyl group); a [(CI-C 12 )alkyl-O-(CI-C 12 )alkyl-]n group (where n is WO 2007/077203 PCT/EP2006/070276 103 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; R 24 and R 25 are independently hydrogen, hydroxyl or halogen. 5
21.- Use according to calim 20 wherein the compound of formula (Id') is: - 1-bromo-9-hydroxy-4,6b,8a,11,12b,14b-hexamethyl 6b,7,8,8a,9,11,12,12a,12b,14b-decahydro-1H-picene-2,3,10 10 trione; - 1-bromo-4,6b,8a,11,12b,14b-hexamethyl-6b,7,8,8a,9, 11,12,12a,12b,14b-decahydro-1H-picene-2,3,10-trione.
22.- Use according to claim 19 wherein the compound of formula 15 (Id) is a compound of formula (Id''): H 3 C \COOCH 3 CH 3 R 2 4 R 25 ,2, CH 3 CH 3 R20' R20 CH3 R19' CH3 (Id"r) where: R 19 , R 19 ,, R2o and R 20 , are independently hydrogen; substituted or 20 non-substituted C 1 -C 12 alkyl; a CORXII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -CIo aryl; or N(RxIII) (RxV) amino, where RxIII and RxV are independently hydrogen or a CI-C 1 2 alkyl group); a [(C-C 12 )alkyl-O-(C 1 -C 1 2 )alkyl-]n group (where n is 25 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; R 24 and R 25 are independently hydrogen, hydroxyl or halogen. WO 2007/077203 PCT/EP2006/070276 104
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. 5
24.- Use according to claim 1 wherein the compound of formula (I) is a compound of formula (le): R 10 R 9 .. R12/l11,,,, ,R8 R14 CH 3 R 7 R 1 6 /7, "anR6 R24 R5 ,20 H CH35 R20R i 0**(ieR R2, ,CH 3 I H 3 C Rn R 3 R19 $R R 2 3 R 1 8 ' R 1 8 R 21 10 (le) where: RI, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , RnI and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI C 12 alkyl; substituted or non-substituted C 6 -C 1 a aryl; a 15 N(R') (R'') amino group, where R' and R'' are independently hydrogen or a CL-C 12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R 9 and RiO 0 are independently hydrogen; substituted or non substituted CI-C 1 2 alkyl; C 6 -CI 0 aryl; a COR''' group (where R''' 20 is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6 -CI 0 aryl; O-CI-C 12 alkyl; or N(RI") (RV) amino, where RI" and Rv are independently hydrogen or an alkyl group CL-C 1 2 ); a carbinol group (CH 2 )n-OH (where n is an integer comprised between 1 and 10); or together form a 25 methylene group; R 13 , R 14 , RI 5 s, R 16 , R 21 and R 23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-CI 1 2 alkyl; substituted or non-substituted C 6 -CIo aryl; a N(RI) (RvII) amino group, where Rv and RvII are independently hydrogen or a CI-C 1 2 WO 2007/077203 PCT/EP2006/070276 105 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R 18 and R 18 , are independently hydrogen; hydroxyl; halogen; CI-C 1 2 alkyl; C 6 -CI 0 aryl; CORIx (where RIx is hydrogen; hydroxyl; CI-C 1 2 5 alkyl; N(Rx) (Rx l ) amino, where Rx and RxI are independently hydrogen or a CI-C 1 2 alkyl group; or Ci-C 12 alcoxyl); or trifluoromethyl; R 19 , R 19 ,, R 2 0 and R 20 , are independently hydrogen; substituted or non-substituted CI-C 12 alkyl; a CORxII group (where RxII is 10 hydrogen; hydroxyl; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6 -CI 0 aryl; or N(RxIII) (RXIV) amino, where RxIII and RxV are independently hydrogen or a CI-C 1 2 alkyl group); a [(CI-C 12 )alkyl-O-(CI-C 12 )alkyl-]n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 15 20-20' pair can form a C=O group together with the carbon to which they are attached; R 24 is hydrogen, hydroxyl or halogen; and the bond = ------- means a double bond or a single bond. 20 25.- Use according to claim 24 wherein the compound of formula (le) is a compound of formula (le'): H 3 C COOCH 3 CH 3 RR24 9 R20, CH3 R20 1nn1. Rig' CH3 CH3 R 18 ' R 18 (le') where: 25 R 18 and R 18 , are independently hydrogen; hydroxyl; halogen; CI-C 1 2 alkyl; C 6 -CI 0 aryl; CORIx (where RIx is hydrogen; hydroxyl; CI-C 1 2 alkyl; N(Rx) (Rx l ) amino, where Rx and RxI are independently hydrogen or a CI-C 1 2 alkyl group; or Ci-C 12 alcoxyl); or trifluoromethyl; WO 2007/077203 PCT/EP2006/070276 106 R 19 , R 19 ,, R 2 0 and R 20 , are independently hydrogen; substituted or non-substituted C 1 -C 12 alkyl; a CORxII group (where Rx is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6 -C 0 aryl; or N(RxII) (RxV) amino, 5 where RxIII and RxV are independently hydrogen or a Ci-C 1 2 alkyl group); a [(C 1 -C 1 2 )alkyl-O-(C 1 -C 1 2 )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; 10 R 24 is hydrogen, hydroxyl or halogen.
26.- Use according to claim 25 wherein the compound of formula (le') 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 15 picene-2-carboxylic acid methyl ester.
27.- Use according to claim 1 wherein the compound of formula (I) is a compound of formula (If): R1o R9 ......... R 12.....i.ng, .... ask~ R14 13 C R7 CH 3 H Rs R 1 " IR6 , 2 CH3 H CH3R5 R20' ",,R43 R20""3"' 3 R3 R19 " ,,R2R3 R2 R19 $ R18' R18 R21 20 (If) where: R 1 , R 2 , R 3 , R 4 , Rs, Re, R 7 , R,, R 11 and R 1 2 are independently 25 hydrogen; hydroxyl; halogen; substituted or non-substituted Cj C 1 2 alkyl; substituted or non-substituted C 6 -C 1 0 aryl; a N(R') (R'') amino group, where R' and R'' are independently hydrogen or a C 1 -C 12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; WO 2007/077203 PCT/EP2006/070276 107 R 9 and R 10 are independently hydrogen; substituted or non substituted CI-C 12 alkyl; C 6 -CI 0 aryl; a COR''' group (where R'' is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6 -CI 0 aryl; 0-CI-C 12 alkyl; 5 or N(RI") (RV) amino, where RI" and Rv are independently hydrogen or a CI-C 12 alkyl group) ; a (CH 2 ) n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, R 13 , R 14 , Ris, R 2 1 and R 2 3 are independently hydrogen; hydroxyl; 10 halogen; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -CI 0 aryl; a N(RvI) (RvII) amino group, where RvI and RvII 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; 15 R 18 and R 18 , are independently hydrogen; hydroxyl; halogen; CI-C 12 alkyl; C 6 -CI 0 aryl; CORIx (where RIx is hydrogen; hydroxyl; CI-C 1 2 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a CI-C 12 alkyl group; or Ci-C 1 2 alcoxyl); or trifluoromethyl; 20 R 19 , R 19 , R 20 and R 20 , are independently hydrogen; substituted or non-substituted CI-C 12 alkyl; a CORXII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -CI 0 aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a CI-C 12 alkyl 25 group); a [(CI-C 12 )alkyl-O-(CI-C 12 )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; R 24 is hydrogen, hydroxyl or halogen; and 30 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'): WO 2007/077203 PCT/EP2006/070276 108 H 3 C .C00CH 3 CH 3 R24C RCH 3 CH 3 R 20 I'.. CH 3 R 19 ' R 9i,,g ... R 18 R 18 (If') where: R 18 and R 18 , are independently hydrogen; hydroxyl; halogen; C 1 -C 1 2 5 alkyl; C 6 -Co 0 aryl; CORIx (where RIx is hydrogen; hydroxyl; CI-C 1 2 alkyl; N(Rx) (R xI ) amino, where Rx and Rx are independently hydrogen or a C 1 -C 1 2 alkyl group; or C 1 -C 12 alcoxyl); or trifluoromethyl; R 19 , R 19 , R 20 and R 20 , are independently hydrogen; substituted or 10 non-substituted C 1 -C 12 alkyl; a CORX group (where Rx is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -C 1 0 aryl; or N(Rx I ) (R x V) amino, where R x I and RxV are independently hydrogen or a CI-C 1 2 alkyl group); a [(C 1 -C 12 )alkyl-O-(C 1 -C 12 )alkyl-]n group (where n is 15 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; R 2 4 is hydrogen, hydroxyl or halogen. 20 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. 25 30.- Use of a compound of formula (II): WO 2007/077203 PCT/EP2006/070276 109 R7 R8 RR6 R2 R3 R6 (II) R,, R4 R1o where: 5 R 1 , R 2 , R 3 , R4, R 5 , R 6 , Rg, R 1 o, R, R 12 R 13 R14 , R 15 , R 16 , R 1 , R 18 , R 19 and R 20 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 12 alkyl; substituted or non substituted C 6 -CI 0 aryl; a N(Rx") (Rx" ) amino group, where Rx" and R x " are independently hydrogen or a CI-C12 alkyl group; or each 10 pair can form a carboxyl (C-O) group together with the carbon to which they are attached; R7 and R 8 are independently hydrogen; substituted or non substituted CI-C 12 alkyl; C 6 -CI 0 aryl; a COR xv I group (where R xv I is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 15 alkyl; substituted or non-substituted C 6 -CI 0 aryl; 0-CI-C 12 alkyl; or N(Rxv l ) (R x x ) amino, where RxvIl and R x x are independently hydrogen or a CI-C 1 2 alkyl group); a (CH 2 )n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, 20 R 21 and R 2 4 are independently substituted or non-substituted Cj C 1 2 alkyl; a COR xx group (where R xx is hydrogen; hydroxyl; substituted or non-substituted CI-C12 alkyl; substituted or non substituted C 6 -Co 0 aryl; or N(Rxx ) (R xx ") amino, where R xx l and RxxI are independently hydrogen or a C 1 -C 12 alkyl group); a [(C 1 25 C 1 2)alkyl-O-(C 1 -C 1 2)alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl; R 2 2 and R 2 3 are: - hydrogen; substituted or non-substituted C 1 -C 12 alkyl; a COR xx ii I group (where R xx ii I is hydrogen; hydroxyl; 30 substituted or non-substituted C 1 -C 12 alkyl; substituted or WO 2007/077203 PCT/EP2006/070276 110 non-substituted C 6 -Co 0 aryl; or N(RxxIv) (Rxxv) amino, where RxxIv 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 5 in the para position with respect to R 20 ; or OR 2 2 ' and OR 2 3 ' respectively, where R 2 2 ' and R 2 3 ' are independently hydrogen; substituted or non-substituted C 1 C 1 2 alkyl; a COR xx v w group (where R xxw is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or 10 non-substituted C 6 -C 1 0 aryl; or N(RxxvI) (RxxvIn) amino, where R xxv n and Rx xv I are independently hydrogen or a C 1 -C 1 2 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 . 15 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. 20 31.- Use according to claim 30 wherein the compound of formula (II) is a compound of formula (IIa): R7 R8 R 6 R 24 R R4 R 10 io R23 t"I/R1 R12 R22 R19 R17 1, R14 R21 R20 R16 R1s (IIa) where: 25 R 1 , R 2 , R 3 , R 4 , Rs, Re, R 9 , Rio, R 11 , R 1 2 , R 13 , R 1 4 , R 15 s, R 16 , R 17 , R 18 , R 1 9 and R 20 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1 -C 12 alkyl; substituted or non substituted C 6 -Clo aryl; a N(Rxv) (Rxv) amino group, where Rxv and R xw are independently hydrogen or a C 1 -C 12 alkyl group; or each WO 2007/077203 PCT/EP2006/070276 111 pair can form a carboxyl (C=O) group together with the carbon to which they are attached; R 7 and R 8 are independently hydrogen; substituted or non substituted CI-C 12 alkyl; C 6 -C 0 aryl; a CORxv group (where Rxv 5 is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6 -C 0 lo aryl; 0-CI-C 1 2 alkyl; or N(RxvIII) (RxIx) amino, where R xv I I I and RxIx are independently hydrogen or a C-C 12 alkyl group); a (CH 2 )n-OH carbinol group (where n is an integer comprised between 1 and 10); or together 10 form a methylene group, R 21 and R 24 are independently substituted or non-substituted Cj C 12 alkyl; a COR xx group (where R xx is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non substituted C 6 -C 1 0 aryl; or N(Rxx) (RxxII) amino, where R xxl and RxxII 15 are independently hydrogen or a C 1 -C 12 alkyl group) ; a [(Cl C 12 )alkyl-O-(C 1 -C 1 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 CI-C 1 2 alkyl; a 20 CORxxIII group (where RxxIII is hydrogen; hydroxyl; substituted or non-substituted C-C 12 alkyl; substituted or non-substituted C 6 -C 0 lo aryl; or N(RxxIv) (Rxxv) amino, where R xx Iv and R xxv are independently hydrogen or a CI-C 12 alkyl group); a [(C 1 -C 12 )alkyl-O-(C 1 -C 1 2 )alkyl-]n group (where n is 25 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 2 3 ' respectively, where R 22 ' and R 23 ' are independently hydrogen; substituted or non-substituted C 1 C 12 alkyl; a COR x w l group (where R xxw is hydrogen; hydroxyl; 30 substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6 -C 1 0 aryl; or N(Rxxv w I) (RxxvII) amino, where R xx v w and R xxw n are independently hydrogen or a CI-C 12 alkyl group); a [(C-C 1 2 )alkyl-O-(C 1 -C 2 )alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl when R 2 4 is 35 in the meta position with respect to R 20 . WO 2007/077203 PCT/EP2006/070276 112
32.- Use according to claim 31 wherein the compound of formula (IIa) is a compound of formula (IIa'): H 3 C COOCH 3 R24 R23 11CH 3 R22 R19 R21 R20 (IIa') 5 where: R 19 and R 20 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 12 alkyl; substituted or non substituted C 6 -CI 0 aryl; a N(Rx") (Rx"VI) amino group, where Rx" and R x are independently hydrogen or a CI-C 12 alkyl group; or each 10 pair can form a (C=O) carboxyl group together with the carbon to which they are attached; R 21 and R 24 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1 -C 12 alkyl; substituted or non substituted C 6 -C 1 o aryl; a N(Rxx) (Rxx") amino group, where RxxI and 15 RxxII are independently hydrogen or a CI-C 12 alkyl group; or each pair can form a (C=O) carboxyl group together with the carbon to which they are attached; R 22 and R 23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1 -C 12 alkyl; substituted or non 20 substituted C 6 -C 1 o aryl; a N(RxxIv) (Rxxv) amino group, where R xx Iv and Rxxv are independently hydrogen or a CI-C 12 alkyl group; or each pair can form a (C=O) carboxyl group together with the carbon to which they are attached. 25 33.- Use according to claim 32 wherein the compound of formula (IIa') is 8-[2-(6,7-dihydroxy-1,5-dimethyl-naphthalen-2-yl) ethyl]-2,4a-tetramethyl-1,2,3,4,4a,5,6,7-octahydro-naphthalen-2 carboxylic acid methyl ester. 30 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 WO 2007/077203 PCT/EP2006/070276 113 cancer, preferably selected from breast, lung, colorectal and pancreatic cancer.
35. Use according to any one of claims 1 to 33 wherein the ChoK 5 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 10 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. 15 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): R 1 0 R 9 R R 1 R 2 20 (I) where: R 1 , R 2 r R 3 , R 4 r Rs, R 6 , R 7 , R 8 , Rn 1 and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci 25 C 12 alkyl; substituted or non-substituted C 6 -C 1 aryl; a N(R') (R'') amino group, where R' and R'' are independently hydrogen or a C 1 -C 12 alkyl group; an OCOR group, where R is (CH 2 ) 2 COOH or (CH 2 ) 2 CO 2 CH 2 CH 3 ; or each pair can form a (C=0) group together with the carbon to which they are attached; CHiii i iR 6 Rz, R, R3,R4, , Re T, R, R2adR2ae neednl hydrogen; hydroxyl; halogen; substituted or non-substituted Cj 25 C12 alkyl; substituted or non-substituted C6CI0 aryl; a N(R') (R'') amino group, where R' and R'' are independently hydrogen or a CI-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; WO 2007/077203 PCT/EP2006/070276 114 R 9 and R 10 are independently hydrogen; substituted or non substituted CI-C 12 alkyl; C 6 -CI 0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6 -CI 0 aryl; 0-CI-C 12 alkyl; 5 or N(RI") (RV) amino, where RI" and Rv are independently hydrogen or a CI-C 12 alkyl group) ; a (CH 2 ) n-OH 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; 10 and where the tricyclic structure is selected from the following structures: R 14 R 13 R 14 R 13 R 1 4 R 13 Rs Rs I R 1 5 R "Ri,"""" R1 \W", 0 R 20 0 R 20 0 R7R17 R,,O R1,,O R1,,O R 23 R 18 Ric R 21 R 22 R 1 i R 21 (a) (b) (c) R 1 3 R14 R 1 3 R 1 4 R 1 3 6 R 1 5 R R 1 5 R R 16 Ri , R 21 R 4 2 18 R 21 RR2' R 1 8 R 21 (d) (e) (f) 15 where: R 13 , R 14 r R 1 s, R 16 , R 21 r R 22 and R 23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-C 12 alkyl; WO 2007/077203 PCT/EP2006/070276 115 substituted or non-substituted C 6 -Co 0 aryl; a N(R"I) (RvII) amino group, where R"I and RvII are independently hydrogen or a C 1 -C 12 alkyl group; an OCORvIII group, where RvIII is (CH 2 ) 2 COOH or (CH 2 ) 2 CO 2 CH 2 CH 3 ; or each pair can form a (C=O) group together with 5 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; R 17 is hydrogen or methyl; R 18 and R 18 , are independently hydrogen; hydroxyl; halogen; C 1 -C 1 2 alkyl; C 6 -Co 0 aryl; CORIx (where RIx is hydrogen; hydroxyl; C 1 -C 1 2 10 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a C 1 -C 1 2 alkyl group; or CI-C 12 alcoxyl); or trifluoromethyl; R 19 , R 19 , R 20 and R 20 , are independently hydrogen; substituted or non-substituted C 1 -C 12 alkyl; a CORXII group (where RxII is 15 hydrogen; hydroxyl; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6 -C 1 0 aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a C 1 -C 1 2 alkyl group); a [(C 1 -C 12 )alkyl-O-(C 1 -C 12 )alkyl-]n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 20 20-20' pair can form a C=O group together with the carbon to which they are attached; R 24 and R 25 are independently hydrogen, hydroxyl or halogen; or a pharmaceutically acceptable salt, derivative, prodrug, 25 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-11-oxo 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b 30 tetradecahydro-picene-2-carboxylic acid; - 10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b tetradecahydro-picene-2-carboxylic acid methyl ester; 35 - 3,10-Dihydroxy-2,4a,6a,9,12b,14a-hexamethyl-11 oxo-1,2,3,4,4a,5,6,6a,11,12b, 13,14,14a,14b- WO 2007/077203 PCT/EP2006/070276 116 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 5 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 10 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; 15 - 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 20 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 25 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 30 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; 35 - Nicotinic acid 9-hydroxy-4,6b,8a,11,12b,14a hexamethyl-2,10-dioxo- WO 2007/077203 PCT/EP2006/070276 117 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-11 oxo-1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b 5 tetradecahydro-picene-2-carboxylic acid methyl ester; - 10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b tetradecahydro-picene-2-carboxylic acid methyl 10 ester. - when the tricyclic structure is (b) and R 19 and R 20 are independently hydrogen or an acyl group, then: - Rs is hydroxyl; or - R 21 and R 22 form a C=O group together with the 15 carbon to which they are attached and R 10 is not COOH. - when the tricyclic structure is (c) and R 19 and R 20 are both CH 3 , then R 15 is and R 16 do not form a C=O group together with the carbon to which they are attached. 20
39. A compound according to claim 38 of formula (Ia): R1o R R R R, (Ia) where 25 R 1 , R 2 , R, R 4 , R, R, R 1, R, R12 and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1 C 12 alkyl; substituted or non-substituted C 6 -C 1 0 aryl; a N(R') (R'') amino group, where R' and R'' are independently hydrogen or a C 1 -C 12 alkyl group; an OCOR group, where R is Rf" HCH3 R5 RH3C ,R R1 7 R , R 2 R1Re (la) where 25 RI, R2, R3, R4r R5, R6, R,, Re, RII and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI C12 alkyl; substituted or non-substituted C6-Cla aryl; a N(R') (R" ) amino group, where R' and R" are independently hydrogen or a CI-C12 alkyl group; an OCOR group, where R is WO 2007/077203 PCT/EP2006/070276 118 (CH 2 ) 2 COOH or (CH 2 ) 2 CO 2 CH 2 CH 3 ; or each pair can form a (C=O) group together with the carbon to which they are attached; R 9 and R 10 are independently hydrogen; substituted or non substituted CI-C 12 alkyl; C 6 -CI 0 aryl; a COR''' group (where R'' 5 is hydrogen; hydroxyl; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6 -CI 0 aryl; 0-CI-C 12 alkyl; or N(RI") (RV) amino, where RI" and Rv are independently hydrogen or a CI-C 12 alkyl group); a (CH 2 )n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a 10 methylene group, R 13 , R 14 , R 15 is and R 16 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(RvI) (RvII) amino group, where RVI and R v n are independently hydrogen or a CI-C 12 alkyl group; an 15 OCORVIII group, where RvIII is (CH 2 ) 2 COOH or (CH 2 ) 2 CO 2 CH 2 CH 3 ; or each pair can form a (C=O) group together with the carbon to which they are attached; R 1 7 is hydrogen or methyl; R 18 is hydrogen; hydroxyl; halogen; CI-C 12 alkyl; C 6 -CIo aryl; CORIx 20 (where RIx is hydrogen; hydroxyl; CI-C 12 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a CI-C 12 alkyl group; or C 1 -C 12 alcoxyl); or trifluoromethyl; R 19 is hydrogen; substituted or non-substituted C 1 -C 12 alkyl; a COR x n group (where R x " is hydrogen; hydroxyl; substituted or 25 non-substituted C-C 12 alkyl; substituted or non-substituted C 6 CI 0 aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a CI-C 12 alkyl group); a [(C 1 -C 12 )alkyl O-(C 1 -C 1 2 )alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl; and 30 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-11-oxo 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro picene-2-carboxylic acid; WO 2007/077203 PCT/EP2006/070276 119 - 10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-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-11-oxo 5 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; 10 - 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 15 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 20 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 25 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 30 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 35 picen-3-yl ester; WO 2007/077203 PCT/EP2006/070276 120 - 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-11-oxo 5 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-11-oxo 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro picene-2-carboxylic acid methyl ester. 10
40. A compound according to claim 39 of formula (Ia'): CH 3 R 1 2 ///, R 7 gH 3 iR R 5 CH 3 0 CH 3 CH 3 R 1 9 0 CH 3 (Ia') where 15 R 5 is hydroxyl or a OCOR group where R is (CH 2 ) 2 COOH or (CH 2 ) 2 CO 2 CH 2 CH 3 ; R 7 and R 8 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 12 alkyl; substituted or non substituted C 6 -CI 0 aryl; a N(R') (R' ' ) amino group, where R' and 20 R'' are independently hydrogen or a C 1 -C 12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R 12 is independently hydrogen or a halogen; and RI 9 is hydrogen; substituted or non-substituted CI-C 1 2 alkyl; a 25 COR x I group (where R x is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 CI 0 aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a CI-C 1 2 alkyl group); a [(C 1 -C 12 )alkyl- WO 2007/077203 PCT/EP2006/070276 121 O-(C 1 -C 1 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: 5 - 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 10 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; 15 - 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 20 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; 25 - 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 30 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 35 2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro picene-3-yl propionic acid ester; WO 2007/077203 PCT/EP2006/070276 122 - 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 5 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; 10 - 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-6bH 15 picene-2-one.
42. A compound according to claim 39 of formula (Ia''): CH3 R7 R 1 R15 CH3 CH31 CH3 R190 CH3 (Ia' ' 20 where: R 7 and R 8 are independently hydrogen, hydroxyl, halogen, substituted or non-substituted CI-C 12 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 C 1 -C 12 alkyl group, or each 25 pair can form a (C=O) group together with the carbon to which they are attached; R 15 is hydrogen or halogen; WO 2007/077203 PCT/EP2006/070276 123 R 1 9 is hydrogen, substituted or non-substituted CI-C 12 alkyl; a COR x I group (where R x " is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6 C 10 O aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are 5 independently hydrogen or a C 1 -C 12 alkyl group); a [(C 1 -C 12 )alkyl O-(C 1 -C 1 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: 10 - 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 15 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-6bH,9H-picene 20 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 25 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,9,10,11,12,12a,12b,13,14,14a-dodecahydro-6bH picene-2-one; 30 -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'''): WO 2007/077203 PCT/EP2006/070276 124 H 3 C COOCH 3 R7 CH 3 CH 3 0 CH 3 CH 3 R 19 0 *6T CH 3 (Ia' where: R, is hydrogen, hydroxyl, halogen, substituted or non 5 substituted C 1 -C 12 alkyl, substituted or non-substituted C 6 -C 0 aryl, or a N(R')(R') amino group, where R' and R" are independently hydrogen or a C 1 -C 1 2 alkyl group; and R 19 is substituted or non-substituted C 1 -C 12 alkyl; a CORxn group (where RxI is hydrogen; hydroxyl; substituted or non-substituted 10 C 1 -C 12 alkyl; substituted or non-substituted C 6 -C 0 aryl; or N(Rxu) (Rxv) amino, where Rxn and RxV are independently hydrogen or a CI-C 12 alkyl group); a [ (C 1 -C 1 2 ) alkyl-O- (C 1 -C 12 ) alkyl-] n group (where n is comprised between 1 and 3); or trifluoromethyl; with the proviso that the compound of formula (Ia"') is not: 15 - 3,10-Dihydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-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-11-oxo 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro 20 picene-2-carboxylic acid methyl ester.
45. A compound according to claim 44 which is: - 2,4a,6a,9,12b,14a-hexamethyl-11-oxo-10-propionyloxy 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro 25 picene-2-carboxylic acid methyl ester; - 10-dimethylcarbamoyloxy-2,4a,6a,9,12b,14a-hexamethyl-11 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): WO2007/077203 PCT/EP2006/070276 125 R1o R9 RIb) R14 R13 ad R7 R1s ?""R6 R16"" H CH3 Rs R200 ""'//R4 R17 H3C 4R3 I I R, R2 R190 R23 R18 R21 R22 (Ib) where: 5 RI, R2, R3, R4r R5, R6, R7, R,, RnI and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI C 12 alkyl; substituted or non-substituted C 6 -C 1 a aryl; a N(R') (R'') amino group, where R' and R' are independently hydrogen or a C 1 -C 12 alkyl group; or each pair can form a (C=O) 10 group together with the carbon to which they are attached; R 9 and RIO are independently hydrogen; substituted or non substituted C 1 -C 12 alkyl; C 6 -C.o aryl; a COR"' group (where R"' is hydrogen; hydroxyl; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6 -C 1 o aryl; 0-C-C 1 2 alkyl; 15 or N(R ") (R") amino, where RI" and R' are independently hydrogen or a C-C 12 alkyl group) ; a (CH 2 ) nOH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, R 13 , R14r, RI 5 , R 16 , R 21 , R 22 and R 23 are independently hydrogen; 20 hydroxyl; halogen; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6 -C- aryl; a N(RV) (Rvn) amino group, where Rv and Rv are independently hydrogen or a CI-C 1 2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; 25 R 1 7 is hydrogen or methyl; Ru is hydrogen; hydroxyl; halogen; C -C 12 alkyl; C 6 -C aryl; CORx (where RIx is hydrogen; hydroxyl; C-C 12 alkyl; N(Rx) (Rx) amino, where Rx and Rx are independently hydrogen or a CI-C 1 2 alkyl group; or C-C 12 alcoxyl) ; or trifluoromethyl; WO 2007/077203 PCT/EP2006/070276 126 R 19 and R 20 are independently hydrogen, substituted or non substituted CI-C 12 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6 -CI 0 aryl; or N(RxIII) (RxV) amino, 5 where RxIII and RxIV are independently hydrogen or a CI-C 1 2 alkyl group); a [(CI-C 12 )alkyl-O-(CI-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 RI 9 and R 20 are independently hydrogen 10 or an acyl group, then: Rs is hydroxyl; or R 21 and R 2 2 form a C=O group together with the carbon to which they are attached and RI 0 is not COOH. 15 47. A compound according to claim 46 of formula (Ib'): CH 3 0 CH 3 OH CH 3 R200 CH3, CH3, R190 CH3 OH (Ib') where: R 1 9 and R 20 are independently substituted or non-substituted CI 20 C 1 2 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non substituted C 6 -Co 0 aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv 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 25 and 3); or trifluoromethyl.
48. A compound according to claim 47 which is 4-nitro-(3 dimethylcarbamoyloxy-5,9-dihydroxy-4,6b,8a,11,12b,14a- WO 2007/077203 PCT/EP2006/070276 127 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''): H 3 COOC 0 .CH 3 CH 3 CH 3 HO CH3 CH 3 R 19 0 R23 5 R 18 0 (Ib'') where: R 18 is hydrogen; hydroxyl; halogen; C 1 -C 12 alkyl; C 6 -Cjo aryl; CORIx (where RIx is hydrogen; hydroxyl; C 1 -C 12 alkyl; N(Rx) (RxI) amino, 10 where Rx and RxI are independently hydrogen or a CI-C 12 alkyl group; or C 1 -C 12 alcoxyl); or trifluoromethyl; R 19 is hydrogen; substituted or non-substituted C 1 -C 12 alkyl; a CORXII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 15 Co 10 aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv 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; R 23 is hydrogen; hydroxyl; halogen; substituted or non 20 substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -C0o aryl; a N(RVI) (RvII) amino group, where RVI and RvII are independently hydrogen or a C 1 -C 12 alkyl group.
50. A compound according to claim 49 which is: 25 - 7,10,11-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; WO 2007/077203 PCT/EP2006/070276 128 - 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; - 11-hydroxy-10-(2-methoxy-ethoxymethoxy)-2,4a,6a,9,12b,14a 5 hexamethyl-8-oxo-1,2,3,4,4a,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): R0 R9 (Ic) where : R1 R8, R12////,,, , ,~ RR14, R 2 , R 3 , R 4 , R, R 6 , R 7 , R, R13 and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci 15 C 12 alkyl; substituted or non-substituted C 6 -C 1 0 aryl; a N(R') (R'') amino group, where R' and R'' are independently hydrogen or a C 1 -C 12 alkyl group; or each pair can form a (C-O) group together with the carbon to which they are attached; R 9 and R 10 are independently hydrogen; substituted or non R1s '""R6 R16H CH3R R20020 substituted C-C 1 2 alkyl; C-C 0 aryl; a COR''' group (where R''' 3C , R3 I R, R2 R190 R23 R8 R21 10 (Ic) where: RI, R2, R3, R4r R5, R6, R7, R8, RnI and R12 are independently is hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 2 15 C12 alkyl; substituted or non-substituted C-C 0 aryl; 1 -C 12 alkyl; a or N(RV) (RV) amino , where RIV and RV are independently hydrogen hydrogen ora C-C 1 2 a ClkylC2 alkyl group; or each pair cangroup (where n is(C=) group25 an integeter comprised between arbon to which they are attached;r form a methylene group; R 13 , R 14 , R, a re independently hydrogen; substituted or non 20 substituted C -C12 alkyl; C6-Clo aryl; a COR"' group (where R"' is hydrogen; hydroxylhalogen; substituted or non-substituted CC-C2 alkyl; alkyl; substituted or non-substituted C-C-C 0 aryl; Ca N(RC2) (RV) alkymino or N(RI") (R") amino, where RI" and Rv are independently hydrogen or a CI-C12 alkyl group) ; a (CH2) n-OH carbinol group (where n is 25 an integer comprised between 1 and 10) ; or together form a methylene group; R13, R14r RIs, R16, R21 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CL-C12 alkyl; substituted or non-substituted C6-CIo aryl; a N (Rv") (RvnI) amino WO 2007/077203 PCT/EP2006/070276 129 group, where R w and RvI are independently hydrogen or a C 1 -C 12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R 18 is hydrogen; hydroxyl; halogen; C 1 -C 12 alkyl; C 6 -Cjo aryl; CORIx 5 (where RIx is hydrogen; hydroxyl; C 1 -C 12 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a CI-C 12 alkyl group; or C 1 -C 1 2 alcoxyl); or trifluoromethyl; R 19 and R 20 are independently hydrogen; substituted or non substituted C 1 -C 12 alkyl; a CORxII group (where RxII is hydrogen; 10 hydroxyl; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6 -C 1 0 aryl; or N(RxIII) (RxIV) amino, where RxIII and RxIV are independently hydrogen or a CI-C 12 alkyl group); a [(C 1 -C 12 )alkyl-O-(C 1 -C 1 2 )alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl; and 15 the bond =------- means a double bond or a single bond, with the proviso that when R 1 9 and R 20 are both CH 3 , then R 15 and R 16 do not form a C=O group together with the carbon to which they are attached. 20 52. A compound according to claim 51 of formula (Ic'): CH 3 0 CH 3 CH 3 R 19 0 CH 3 R 20 0 CH 3 (Ic') where: R 19 and R 20 are independently hydrogen; substituted or non 25 substituted C 1 -C 12 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6 -C 1 0 aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a CI-C 12 alkyl WO 2007/077203 PCT/EP2006/070276 130 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. 5 53. A compound according to claim 52 which is: - 10,11-dihydroxy-2,4a,6a,9,14a-pentamethyl 1,4,4a,5,6,6a,13,14,14a,14b-decahydro-2H-picene-3-one; - 10,11-dihydroxy-2,4a,6a,9,14a-pentamethyl 4a,5,6,6a,13,14,14a,14b-octahydro-4H-picene-3-one. 10
54. A compound according to claim 51 of formula (Ic''): H 3 C COOCH 3 CH 3 CH 3 R 1 9 0 CH 3 R 20 0 CH 3 (Ic' where: 15 R 19 and R 20 are independently hydrogen; substituted or non substituted C 1 -C 12 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6 -C 1 a aryl; or N(RxIIn) (Rxv) amino, where RxIII and RxIv are independently hydrogen or a C 1 -C 12 alkyl 20 group); a [(C 1 -C 1 2 )alkyl-O-(C 1 -C 1 2 )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-1,2,3,4,4a,5,6,6a,13,14,14a,14b 25 dodecahydro-picene-2-carboxylic acid methyl ester.
56. A compound according to claim 38 of formula (Id): WO 2007/077203 PCT/EP2006/070276 131 R1i R9 R, R11, y R 8 R13 HR7 (Id) R1s """11IR6 where : 5 RR24, R 2 , R, R, R, R, R25, R, R and R 2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci C 12 alkyl; substituted or non-substituted C 6 -C 1 0 aryl; a N(R') (R'') amino group, where R' and R'' are independently hydrogen or a C 1 -C 12 alkyl group; or each pair can form a (C-O) 10 group together with the carbon to which they are attached; R 9 and R 10 are independently hydrogen; substituted or non substituted C 1 -C 1 2 alkyl; C 6 -C 10 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6 -C 10 aryl; 0-C 1 -C 12 alkyl; 15 or N(R ') (R') amino, where R v and R' are independently hydrogen or a C 1 -C 1 2 alkyl group); a (CH 2 )OH CH3carbinol group (where n is an integer comprised between 1 and 10) ; or together form a methylene group, R20 3C b R3 R, R 15 , R 21 and R 2 R, are independently hydrogen; hydroxyl;R2 R 19' 2 R23 R19 R18 R21 (Id) where: 5 RI, R2, R3, R4r R5, R6, R7, R,, RnI and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C-C 2 alkyl; substituted C12 alkyl; substituted or non-substituted CC-C 1 0 aryl; a N(RV) (RV) amino group, where N(R') (R" ) amino group, where R' and R" are independently R and R are independently hydrogen or a C 1 -C 1 2 alkyl group; or each pair can form a (C=) 10each pair can form a (C-O) group together with the carbon to which they are attached; Which theyand RIO are attachindependently hydrogen; substituted or non sub25 R 18 is hydrogen;d CC2 alkyl; C-Clo aryl; a COR g roup (where Rx (wis hydrogen; hydroxxyyl; substituted or non-substituted C) amino,2 alkyl; substituted or non-substituted C6-CIo aryl; O-CI-C12 alkyl; 15 or N(R")(R) amino, where R" and R are independently hydrogen or a C-C 1 2 alkyl group; or C 1 -C 1 2 al grcoxylup) ; ora (CH2) nH carbinol group (where n istrifluoromethyl; an integer comprised between 1 and 10) ; or together form a methylene group, R13,r RIs, R21 and R23 are independently hydrogen; hydroxyl; 20 halogen; substituted or non-substituted CI-C12 alkyl; substituted or non-substituted C6-CIo aryl; a N(R") (Rv" ) amino group, where R v and Rv" are independently hydrogen or a CI-C12 alkyl group; or each pair can form a (C=0) group together with the carbon to which they are attached; 25 RIO is hydrogen; hydroxyl; halogen; C -C12 alkyl; C6-CIo aryl; COR"x (where RIx is hydrogen; hydroxyl; CI-C12 alkyl; N (Rx) (Rxx) amino, where Rx and Rx" are independently hydrogen or a CI-C12 alkyl group; Or CI-C12 alCOxyl) ; or trifluoromethyl; WO 2007/077203 PCT/EP2006/070276 132 R 19 , R 19 ,, R 2 0 and R 20 , are independently hydrogen; substituted or non-substituted C 1 -C 12 alkyl; a CORxII group (where Rx is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6 -C 0 aryl; or N(RxIII) (Rx"V) amino, 5 where RxIII and RxV are independently hydrogen or a Ci-C 1 2 alkyl group); a [(C 1 -C 1 2 )alkyl-O-(C 1 -C 1 2 )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; 10 R 24 and R 25 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'): CH 3 0 CH 3 -R5 R2415 (Id')R25 ,20' CH3 CH36 R20 CH3 R19 CH3 15 (Id') where: Rs and R 6 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1 -C 12 alkyl; substituted or non substituted C 6 -C 0 aryl; a N(R') (R' ' ) amino group, where R' and 20 R'' are independently hydrogen or a C 1 -C 12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R 19 , R 19 ,, R 20 and R 20 , are independently hydrogen; substituted or non-substituted C 1 -C 12 alkyl; a CORxII group (where RxII is 25 hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6 -C 0 aryl; or N(RxIII) (Rx"V) amino, where RxIII and RxV are independently hydrogen or a Ci-C 1 2 alkyl group); a [(CI-C 12 )alkyl-O-(CI-C 12 )alkyl-]n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or WO 2007/077203 PCT/EP2006/070276 133 20-20' pair can form a C=O group together with the carbon to which they are attached; R 24 and R 25 are independently hydrogen, hydroxyl or halogen. 5 58. A compound according to claim 57 which is: - 1-bromo-9-hydroxy-4,6b,8a,11,12b,14b-hexamethyl 6b,7,8,8a,9,11,12,12a,12b,14b-decahydro-1H-picene-2,3,10 trione; - 1-bromo-4,6b,8a,11,12b,14b-hexamethyl 10 6b,7,8,8a,9,11,12,12a,12b,14b-decahydro-1H-picene-2,3,10 trione.
59. A compound according to claim 56 of formula (Id''): H 3 C \COOCH 3 CH 3 R 24 R 25 , R,, CH 3 CH 3 R 2 0 ' R20 CH3 C R 1 9 CH 3 15 (Id'') where: R 19 , R 19 , R 20 and R 20 ' are independently hydrogen; substituted or non-substituted C 1 -C 12 alkyl; a COR xi group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 1 2 alkyl; 20 substituted or non-substituted C 6 -Ca aryl; or N(RxIII) (RxyV) amino, where RxIII and Rxyv are independently hydrogen or a C 1 -C 1 2 alkyl group); a [(CI-C 1 2 )alkyl-O-(CI-C 1 2 )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 25 which they are attached; R 24 and R 25 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- WO 2007/077203 PCT/EP2006/070276 134 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 (le): 5 R 10 R 9 R1R R1 R 12 i,, R, R14 CH 3 R7 R 1 6 //, R24 R R, H CH3 R 1 19 R 18 ' R 1 8 R 21 (le) 10 where: RI, R 2 , R 3 , R 4 , Rs, Re, R 7 , R 8 , Rn and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI C 12 alkyl; substituted or non-substituted C 6 -C 1 0 aryl; a N(R') (R'') amino group, where R' and R'' are independently 15 hydrogen or a C 1 -C 12 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 CI-C 12 alkyl; C 6 -CI 0 aryl; a COR''' group (where R''' is hydrogen; hydroxyl; substituted or non-substituted CI-C 1 2 20 alkyl; substituted or non-substituted C 6 -CI 0 aryl; 0-CI-C 12 alkyl; or N(RI") (RV) amino, where RI" and Rv are independently hydrogen or an alkyl group CI-C 1 2 ); a carbinol group (CH 2 )n-OH (where n is an integer comprised between 1 and 10); or together form a methylene group; 25 R 13 , R 14 , Ris, R 16 , R 21 and R 23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6 -CI 0 aryl; a N(RI) (RvII) amino group, where Rv and RvII are independently hydrogen or a CI-C 12 WO 2007/077203 PCT/EP2006/070276 135 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R 18 and R 18 , are independently hydrogen; hydroxyl; halogen; CI-C 1 2 alkyl; C 6 -CI 0 aryl; CORIx (where RIx is hydrogen; hydroxyl; CI-C 1 2 5 alkyl; N(Rx) (Rx l ) amino, where Rx and RxI are independently hydrogen or a CI-C 1 2 alkyl group; or Ci-C 12 alcoxyl); or trifluoromethyl; R 19 , R 19 ,, R 2 0 and R 20 , are independently hydrogen; substituted or non-substituted CI-C 12 alkyl; a CORxII group (where RxII is 10 hydrogen; hydroxyl; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6 -CI 0 aryl; or N(RxIII) (RXIV) amino, where RxIII and RxV are independently hydrogen or a CI-C 1 2 alkyl group); a [(CI-C 12 )alkyl-O-(CI-C 12 )alkyl-]n group (where n is comprised between 1 and 3); trifluoromethyl; or each 19-19' or 15 20-20' pair can form a C=O group together with the carbon to which they are attached; R 24 is hydrogen, hydroxyl or halogen; and the bond = ------- means a double bond or a single bond. 20 62. A compound according to claim 61 of formula (le'): H 3 C COOCH 3 CH 3 R24 R20, CH 3 R 20 CH 3 I CH 3 R 18 ' R 18 (le') where: R 18 and R 18 , are independently hydrogen; hydroxyl; halogen; C 1 -C 1 2 25 alkyl; C 6 -Co aryl; CORIx (where RIx is hydrogen; hydroxyl; CI-C 1 2 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a C 1 -C 1 2 alkyl group; or CI-C 12 alcoxyl); or trifluoromethyl; WO 2007/077203 PCT/EP2006/070276 136 R 19 , R 19 ,, R 2 0 and R 20 , are independently hydrogen; substituted or non-substituted C 1 -C 12 alkyl; a CORxI group (where Rx is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6 -C 0 aryl; or N(RxII) (RxV) amino, 5 where RxIII and RxV are independently hydrogen or a Ci-C 1 2 alkyl group); a [(C 1 -C 1 2 )alkyl-O-(C 1 -C 1 2 )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; 10 R 24 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 15 picene-2-carboxylic acid methyl ester.
64. A compound according to claim 38 of formula (If): R Ro 1 R9 R14 13 C R7 CH 3 H R 1 " R6 R24 I R , 24 CH3 H CH35 R20' ""'R43 R20\\\\"" 3C ' R3 RR R2 R19R R~R23 R18' R18 R21 20 (If) where: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R,, R 11 and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1 25 C 12 alkyl; substituted or non-substituted C 6 -C 0 aryl; a N(R') (R'') amino group, where R' and R'' are independently hydrogen or a C 1 -C 12 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; WO 2007/077203 PCT/EP2006/070276 137 R 9 and R 10 are independently hydrogen; substituted or non substituted CI-C 12 alkyl; C 6 -CI 0 aryl; a COR''' group (where R'' is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6 -CI 0 aryl; 0-CI-C 12 alkyl; 5 or N(RI") (RV) amino, where RI" and Rv are independently hydrogen or a CI-C 12 alkyl group) ; a (CH 2 ) n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, R 13 , R 14 , Ris, R 2 1 and R 2 3 are independently hydrogen; hydroxyl; 10 halogen; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -CI 0 aryl; a N(RvI) (RvII) amino group, where RvI and RvII 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; 15 R 18 and R 18 , are independently hydrogen; hydroxyl; halogen; CI-C 12 alkyl; C 6 -CI 0 aryl; CORIx (where RIx is hydrogen; hydroxyl; CI-C 1 2 alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently hydrogen or a CI-C 12 alkyl group; or Ci-C 1 2 alcoxyl); or trifluoromethyl; 20 R 19 , R 19 , R 20 and R 20 , are independently hydrogen; substituted or non-substituted CI-C 12 alkyl; a CORXII group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -CI 0 aryl; or N(RxIII) (RxIv) amino, where RxIII and RxIv are independently hydrogen or a CI-C 12 alkyl 25 group); a [(CI-C 12 )alkyl-O-(CI-C 12 )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; R 24 is hydrogen, hydroxyl or halogen; and 30 the bond ------- means a double bond or a single bond.
65. A compound according to claim 64 of formula (If'): WO 2007/077203 PCT/EP2006/070276 138 H 3 C .C00CH 3 CH 3 R24C RCH 3 CH 3 R 20 I'.. CH 3 R 19 ' R 9i,,g ... R 18 R 18 (If') where: R 18 and R 18 , are independently hydrogen; hydroxyl; halogen; C 1 -C 1 2 5 alkyl; C 6 -Co 0 aryl; CORIx (where RIx is hydrogen; hydroxyl; CI-C 1 2 alkyl; N(Rx) (R xI ) amino, where Rx and Rx are independently hydrogen or a C 1 -C 1 2 alkyl group; or C 1 -C 12 alcoxyl); or trifluoromethyl; R 19 , R 19 , R 20 and R 20 , are independently hydrogen; substituted or 10 non-substituted C 1 -C 12 alkyl; a CORX group (where Rx is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -C 1 0 aryl; or N(Rx I ) (R x V) amino, where R x I and RxV are independently hydrogen or a CI-C 1 2 alkyl group); a [(C 1 -C 12 )alkyl-O-(C 1 -C 12 )alkyl-]n group (where n is 15 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; R 2 4 is hydrogen, hydroxyl or halogen. 20 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. 25 67. A compound of formula (II): WO 2007/077203 PCT/EP2006/070276 139 R7 R8 RR6 R2 R3 R6 (II) R,, R4 R1o where: 5 R 1 , R 2 , R 3 , R4, R 5 , R 6 , Rg, R 1 o, R, R 12 R 13 R14 , R 15 , R 16 , R 1 , R 18 , R 19 and R 20 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 12 alkyl; substituted or non substituted C 6 -CI 0 aryl; a N(Rx") (Rx" ) amino group, where Rx" and R x " are independently hydrogen or a CI-C12 alkyl group; or each 10 pair can form a carboxyl (C-O) group together with the carbon to which they are attached; R7 and R 8 are independently hydrogen; substituted or non substituted CI-C 12 alkyl; C 6 -CI 0 aryl; a COR xv I group (where R xv I is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 15 alkyl; substituted or non-substituted C 6 -CI 0 aryl; 0-CI-C 12 alkyl; or N(Rxv l ) (R x x ) amino, where RxvIl and R x x are independently hydrogen or a CI-C 1 2 alkyl group); a (CH 2 )n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, 20 R 21 and R 2 4 are independently substituted or non-substituted Cj C 1 2 alkyl; a COR xx group (where R xx is hydrogen; hydroxyl; substituted or non-substituted CI-C12 alkyl; substituted or non substituted C 6 -Co 0 aryl; or N(Rxx ) (R xx ") amino, where R xx l and RxxI are independently hydrogen or a C 1 -C 12 alkyl group); a [(C 1 25 C 1 2)alkyl-O-(C 1 -C 1 2)alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl; R 2 2 and R 2 3 are: - hydrogen; substituted or non-substituted C 1 -C 12 alkyl; a COR xx ii I group (where R xx ii I is hydrogen; hydroxyl; 30 substituted or non-substituted C 1 -C 12 alkyl; substituted or WO 2007/077203 PCT/EP2006/070276 140 non-substituted C 6 -Co 0 aryl; or N(RxxIv) (Rxxv) amino, where RxxIv 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 5 in the para position with respect to R 20 ; or OR 2 2 ' and OR 2 3 ' respectively, where R 2 2 ' and R 2 3 ' are independently hydrogen; substituted or non-substituted C 1 C 1 2 alkyl; a COR xx v w group (where R xxw is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or 10 non-substituted C 6 -C 1 0 aryl; or N(RxxvI) (RxxvI) amino, where R xxv n and Rx xv I are independently hydrogen or a C 1 -C 1 2 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 . 15 or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof.
68. A compound according to claim 67 of formula (IIa): R7 R R6 R9 R24 R4io C 12 R18 /1 R22 R19 Ray 1 R1 R21 R20 R16 R1s 20 (Ha) where: R 1 , R 2 , R 3 , R 4 , Rs, Re, Rg, Rior, R , R 1 2 , R 13 , R 1 4 , R 15 s, R 16 , R 17 , R 18 , R 19 and R 20 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1 -C 12 alkyl; substituted or non 25 substituted C 6 -C 1 0 aryl; a N(Rxv) (Rxv) amino group, where Rxv and R x are independently hydrogen or a CI-C 12 alkyl group; or each pair can form a carboxyl (C=O) group together with the carbon to which they are attached; R 7 and R 8 are independently hydrogen; substituted or non 30 substituted CI-C 1 2 alkyl; C 6 -C 0 lo aryl; a COR xv n group (where R xv n WO 2007/077203 PCT/EP2006/070276 141 is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or non-substituted C 6 -C 0 lo aryl; 0-CI-C 12 alkyl; or N(RxvI l ) (RxIx) amino, where R xv I l and RxIx are independently hydrogen or a C 1 -C 1 2 alkyl group); a (CH 2 )n-OH carbinol group 5 (where n is an integer comprised between 1 and 10); or together form a methylene group, R 2 1 and R 24 are independently substituted or non-substituted Cj C 12 alkyl; a CORxx group (where R xx is hydrogen; hydroxyl; substituted or non-substituted C-C 1 2 alkyl; substituted or non 10 substituted C 6 -C 1 0 aryl; or N(Rxx) (Rxx") amino, where R xxl and RxxII are independently hydrogen or a C 1 -C 12 alkyl group); a [(Cl C 12 )alkyl-O-(C 1 -C 12 )alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl; R 22 and R 23 are: 15 - hydrogen; substituted or non-substituted C-C 12 alkyl; a CORxxIII group (where RxxIII is hydrogen; hydroxyl; substituted or non-substituted C 1 -C 12 alkyl; substituted or non-substituted C 6 -C 0 lo aryl; or N(RxxIv) (Rxxv) amino, where R xx iv and R xxv are independently hydrogen or a CI-C 12 alkyl 20 group); a [(C-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 2 3 ' are independently hydrogen; substituted or non-substituted CI-C 12 alkyl; a COR xxw 25 group (where R xxw is hydrogen; hydroxyl; substituted or non substituted CI-C 12 alkyl; substituted or non-substituted C 6 -C 0 aryl; or N (RxxvI) (RxxvIll) amino, where R xxv I and RxxvIII are independently hydrogen or a CI-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); 30 or trifluoromethyl when R 24 is in the meta position with respect to R 20 .
69. A compound according to claim 68 of formula (IIa'): WO 2007/077203 PCT/EP2006/070276 142 H 3 C "-COOCH 3 R24 R23 CH3 R22 R19 R21 R20 (IIa' where: R 19 and R 20 are independently hydrogen; hydroxyl; halogen; 5 substituted or non-substituted C 1 -C 12 alkyl; substituted or non substituted C 6 -C 10 aryl; a N(Rxv) (RxV ) amino group, where Rxv and R x are independently hydrogen or a C 1 -C 1 2 alkyl group; or each pair can form a (C-O) carboxyl group together with the carbon to which they are attached; 10 R21 and R24 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1 -C 12 alkyl; substituted or non substituted C 6 -C 0 aryl; a N(Rxx ) (R xx I) amino group, where Rxx and R xx are independently hydrogen or a C-C 12 alkyl group; or each pair can form a (C-O) carboxyl group together with the carbon to 15 which they are attached; R 22 and R 23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1 -C 12 alkyl; substituted or non substituted C 6 -C 0 aryl; a N(Rxxiv) (Rxxv) amino group, where R xx iv and Rxxv are independently hydrogen or a C 1 -C 12 alkyl group; or 20 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 25 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. 30 71.- A compound as defined in any one of claims 38 to 69 or mixtures thereof, or a pharmaceutically acceptable salt, WO 2007/077203 PCT/EP2006/070276 143 derivative, prodrug, solvate or stereoisomer thereof for use in the treatment of a ChoK mediated disease or condition.
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