TRITERPENEQUINONE AND TRITERPENEPHENOL DERIVATIVES AND THEIR APPLICATION FOR THE TREATMENT OF TUMORS AND PARASITIC DISEASES

DERIVES DE TRITERPENEQUINONE ET DE TRITERPENEPHENOL ET LEUR APPLICATION POUR LE TRAITEMENT DE TUMEURS ET DE MALADIES PARASITAIRES

English Abstract

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

French Abstract

La présente invention concerne des dérivés de triterpènequinone et de triterpènephénol, leurs sels promédicaments, solvates ou stéréo-isomères pharmaceutiquement acceptables, en tant qu'agents bloquants sélectifs de l'enzyme choline kinase, des compositions pharmaceutiques les contenant et leur utilisation pour le traitement de tumeurs et de maladies parasitaires ou de maladies causées par des virus, des bactéries ou des champignons.

Claims

86
CLAIMS
1.- Use of a compound of formula (I):
<IMG>
where:
R1, R2, R3, R4, R5, R6, R7, R8, R11 and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted C1-
C12 alkyl; substituted or non-substituted C6-C10 aryl; a
N(R')(R'') amino group, where R' and R'' are independently
hydrogen or a C1-C12 alkyl group; an OCOR group, where R is
(CH2)2COOH or (CH2)2CO2CH2CH3; or each pair can form a (C=O) group
together with the carbon to which they are attached;
R9 and R10 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R'''
is hydrogen; hydroxyl; substituted or non-substituted C1-C12
alkyl; substituted or non-substituted C6-C10 aryl; O-C1-C12 alkyl;
or N(R IV)(R V) amino, where R IV and R V are independently hydrogen
or a C1-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;
the bond <IMG> means a double bond or a single bond;
and where the tricyclic structure
<IMG>
is selected from the following structures:

87
<IMG>
where:
R13, R14, R15, R16, R21, R22 and R23 are independently hydrogen;
hydroxyl; halogen; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; a N(R VI)(R VII) amino
group, where R VI and R VII are independently hydrogen or a C1-C12
alkyl group; an OCOR VIII group, where R VIII is (CH2)2COOH or
(CH2)2CO2CH2CH3; 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;
R17 is hydrogen or methyl;
R18 and R18' are independently hydrogen; hydroxyl; halogen; C1-C12
alkyl; C6-C10 aryl; COR IX (where R IX is hydrogen; hydroxyl; C1-C12
alkyl; N(R X)(R XI) amino, where R X and R XI are independently
hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl) or
trifluoromethyl;
R19, R19', R20 and R20' are independently hydrogen; substituted or
non-substituted C1-C12 alkyl; a COR XII group (where R XII is
hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII)(R XIV) amino,

88
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 and R25 are independently hydrogen, hydroxyl or halogen;
or a pharmaceutically acceptable salt, derivative, prodrug,
solvate or stereoisomer thereof, in the manufacture of a
medicament for the prevention and/or treatment of ChoK mediated
disease or condition.
2.- Use according to claim 1 wherein the compound of formula (I)
is a compound of formula (Ia):
<IMG>
where
R1, R2, R3, R4, R5, R6, R7, R8, R11 and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted C1-
C12 alkyl; substituted or non-substituted C6-C10 aryl; a
N(R')(R'') amino group, where R' and R'' are independently
hydrogen or a C1-C12 alkyl group; an OCOR group, where R is
(CH2)2COOH or (CH2)2CO2CH2CH3; or each pair can form a (C=O) group
together with the carbon to which they are attached;
R9 and R10 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R'''
is hydrogen; hydroxyl; substituted or non-substituted C1-C12
alkyl; substituted or non-substituted C6-C10 aryl; O-C1-C12 alkyl;
or N(R IV) (R V) amino, where R IV and R V are independently hydrogen

89
or a C1-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, R14, R15 and R16 are independently hydrogen; hydroxyl;
halogen; substituted or non-substituted C1-C12 alkyl; substituted
or non-substituted C6-C10 aryl; a N(R VI)(R VII) amino group, where
R VI and R VII are independently hydrogen or a C1-C12 alkyl group; an
OCOR VIII group, where R VIII is (CH2)2COOH or (CH2)2CO2CH2CH3; or each
pair can form a (C=O) group together with the carbon to which
they are attached;
R17 is hydrogen or methyl;
R18 is hydrogen; hydroxyl; halogen; C1-C12 alkyl; C6-C10 aryl; COR IX
(where R IX is hydrogen; hydroxyl; C1-C12 alkyl; N(R X)(R XI) amino,
where R X and R XI are independently hydrogen or a C1-C12 alkyl
group; or C1-C12alcoxyl); or trifluoromethyl;
R19 is hydrogen; substituted or non-substituted C1-C12 alkyl; a
COR XII group (where R XII is hydrogen; hydroxyl; substituted or
non-substituted C1-C12 alkyl; substituted or non-substituted C6-
C10 aryl; or N(R XIII)(R XIV) amino, where R XIII and R XIV are
independently hydrogen or a C1-C12 alkyl group); a [(C1-C12)alkyl-
O-(C1-C12)alkyl-]n group (where n is comprised between 1 and 3);
or trifluoromethyl; and
the bond <IMG> means a double bond or a single bond.
3.- Use according to claim 2 wherein the compound of formula
(Ia) is a compound of formula (Ia'):
<IMG>
where

90
R5 is hydroxyl or a OCOR group where R is (CH2)2COOH or
(CH2)2CO2CH2CH3;
R7 and R8 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; a N(R')(R'') amino group, where R' and
R'' are independently hydrogen or a C1-C12 alkyl group; or each
pair can form a (C=O) group together with the carbon to which
they are attached;
R12 is independently hydrogen or a halogen; and
R19 is hydrogen; substituted or non-substituted C1-C12 alkyl; a
COR XII group (where R XII is hydrogen; hydroxyl; substituted or
non-substituted C1-C12 alkyl; substituted or non-substituted C6-
C10 aryl; or N(R XIII)(R XIV) amino, where R XIII and R XIV are
independently hydrogen or a C1-C12 alkyl group); a [(C1-C12)alkyl-
O-(C1-C12)alkyl-]n group (where n is comprised between 1 and 3);
or trifluoromethyl; and
the bond <IMG> means a double bond or a single bond.
4.- Use according to claim 3 wherein the compound of formula
(Ia') is:
- 3,9-Dihydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-
2,10-dione;
- Acetic acid 9-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-2,10-
dioxo-2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- 9-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-
picene-3-yl propionic acid ester;
- Dodecanoic acid 9-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-
2,10-dioxo-2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- Dimethyl-carbamic acid 9-hydroxy-4,6b,8a,11,12b,14a-
hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-
picen-3-yl ester;

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-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-
picene-3-yl) benzoic acid ester;
- 14-Bromo-3,7,9-trihydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-
2,10-dione;
- 12-bromo-9-hydroxy-6b,8a,11,12b,14a-hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-
picene-3-yl dimethyl-carbamic acid ester;
- 4-bromo-(12-bromo-9-hydroxy-6b,8a,11,12b,14a-hexamethyl-
2,10-dioxo-2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picene-3-yl) benzoic acid ester;
- 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-
7,8,8a,9,10,11,12,12a,12b,13,14,14a-dodecahydro-6bH-
picene-2-one;
- Succinic acid mono-(10-hydroxy-2,4a,6a,9,12b,14a-
hexamethyl-3,11-dioxo-
1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro-
picen-4-yl) ester;
- Succinic acid ethyl ester 10-hydroxy-2,4a,6a,9,12b,14a-
hexamethyl-3,11-dioxo-
1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro-
picen-4-yl ester.
5.- Use according to claim 2 wherein the compound of formula
(Ia) is a compound of formula (Ia''):

92
<IMG>
where:
R7 and R8 are independently hydrogen, hydroxyl, halogen,
substituted or non-substituted C1-C12 alkyl, substituted or non-
substituted C6-C10 aryl, a N(R')(R'') amino group, where R' and
R'' are independently hydrogen or a C1-C12 alkyl group, or each
pair can form a (C=O) group together with the carbon to which
they are attached;
R15 is hydrogen or halogen;
R19 is hydrogen, substituted or non-substituted C1-C12 alkyl; a
COR XII group (where R XII is hydrogen; hydroxyl; substituted or
non-substituted C1-C12 alkyl; substituted or non-substituted C6-
C10 aryl; or N(R XIII)(R XIV) amino, where R XIII and R XIV are
independently hydrogen or a C1-C12 alkyl group); a [(C1-C12)alkyl-
O-(C1-C12)alkyl-]n group (where n is comprised between 1 and 3);
or trifluoromethyl; and
the bond <IMG> means a double bond or a single bond.
6.- Use according to claim 5 wherein the compound of formula
(Ia'') is:
-14-bromo-3-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-
2,10-dione;
-4,6b,8a,11,12b,14a-hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-
picene-3-yl acetic acid ester;

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-
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
7.- Use according to claim 2 wherein the compound of formula
(Ia) is a compound of formula (Ia"'):
<IMG>
where:
R7 is hydrogen, hydroxyl, halogen, substituted or non-
substituted C1-C12 alkyl, substituted or non-substituted C6-C10
aryl, or a N(R')(R") amino group, where R' and R" are
independently hydrogen or a C1-C12 alkyl group; and
R19 is substituted or non-substituted C1-C12 alkyl; a COR XII group
(where R XII is hydrogen; hydroxyl; substituted or non-substituted
C1-C12 alkyl; substituted or non-substituted C6-C10 aryl; or
N(R XIII) (R XIV) amino, where R XIII and R XIV are independently hydrogen
or a C1-C12 alkyl group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group
(where n is comprised between 1 and 3); or trifluoromethyl;
with the proviso that when R19 is hydrogen, R7 is not hydrogen.

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-
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-
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
9.- Use according to clam 1 wherein the compound of formula (I)
is a compound of formula (Ib):
<IMG>
where:
R1, R2, R3, R4, R5, R6, R7, R8, R11 and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted C1-
C12 alkyl; substituted or non-substituted C6-C10 aryl; a
N(R')(R'') amino group, where R' and R" are independently
hydrogen or a C1-C12 alkyl group; or each pair can form a (C=O)
group together with the carbon to which they are attached;
R9 and R10 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R'''

95
is hydrogen; hydroxyl; substituted or non-substituted C1-C12
alkyl; substituted or non-substituted C6-C10 aryl; O-C1-C12 alkyl;
or N(R IV) (R V) amino, where R IV and R V are independently hydrogen
or a C1-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, R14, R15, R16, R21, R22 and R23 are independently hydrogen;
hydroxyl; halogen; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; a N(R VI) (R VII) amino
group, where R VI and R VII are independently hydrogen or a C1-C12
alkyl group; or each pair can form a (C=O) group together with
the carbon to which they are attached;
R17 is hydrogen or methyl;
R18 is hydrogen; hydroxyl; halogen; C1-C12 alkyl; C6-C10 aryl; COR IX
(where R IX is hydrogen; hydroxyl; C1-C12 alkyl; N(R X) (R XI) amino,
where R X and R XI are independently hydrogen or a C1-C12 alkyl
group; or C1-C12 alcoxyl); or trifluoromethyl;
R19 and R20 are independently hydrogen, substituted or non-
substituted C1-C12 alkyl; a COR XII group (where R XII is hydrogen;
hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII) (R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group) ; a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); or trifluoromethyl; and
the bond <IMG> 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'):

96
<IMG>
where:
R19 and R20 are independently substituted or non-substituted C1-
C12 alkyl; a COR XII group (where R XII is hydrogen; hydroxyl;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; or N(R XIII) (R XIV) amino, where R XIII and R XIV
are independently hydrogen or a C1-C12 alkyl group); a [(C1-
C12)alkyl-O-(C1-C12)alkyl-]n group (where n is comprised between 1
and 3); or trifluoromethyl.
11.- Use according to claim 10 wherein the compound of formula
(Ib') is 4-nitro-(3-dimethylcarbamoyloxy-5,9-dihydroxy-
4,6b,8a,11,12b,14a-hexamethyl-10-oxo-
5,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-picene-
2-yl) benzoic acid ester.
12.- Use according to claim 9 wherein the compound of formula
(Ib) is a compound of formula (Ib"):
<IMG>

97
where:
R18 is hydrogen; hydroxyl; halogen; C1-C12 alkyl; C6-C10 aryl; COR IX
(where R IX is hydrogen; hydroxyl; C1-C12 alkyl; N(R X) (R XI) amino,
where R X and R XI are independently hydrogen or a C1-C12 alkyl
group; or C1-C12 alcoxyl); or trifluoromethyl;
R19 is hydrogen; substituted or non-substituted C1-C12 alkyl; a
COR XII group (where R XII is hydrogen; hydroxyl; substituted or
non-substituted C1-C12 alkyl; substituted or non-substituted C6-
C10 aryl; or N(R XIII) (R XIV) amino, where R XIII and R XIV are
independently hydrogen or a C1-C12 alkyl group) ; a [(C1-C12)alkyl-
O-(C1-C12)alkyl-]n group (where n is comprised between 1 and 3);
or trifluoromethyl;
R23 is hydrogen; hydroxyl; halogen; substituted or non-
substituted C1-C12 alkyl; substituted or non-substituted C6-C10
aryl; a N(R VI) (R VII) amino group, where R VI and R VII are
independently hydrogen or a C1-C12alkyl group.
13.- Use according to claim 12 wherein the compound of formula
(Ib'') is:
- 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-
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
14.- Use according to claim 1 wherein the compound of formula
(I) is a compound of formula (Ic):

98
<IMG>
where:
R1, R2, R3, R4, R5, R6, R7, R8, R11 and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted C1-
C12 alkyl; substituted or non-substituted C6-C10 aryl; a
N(R')(R'') amino group, where R' and R" are independently
hydrogen or a C1-C12 alkyl group; or each pair can form a (C=O)
group together with the carbon to which they are attached;
R9 and R10 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R'''
is hydrogen; hydroxyl; substituted or non-substituted C1-C12
alkyl; substituted or non-substituted C6-C10 aryl; O-C1-C12 alkyl;
or N(R IV) (R V) amino, where R IV and R V are independently hydrogen
or a C1-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, R14, R15, R16, R21 and R23 are independently hydrogen;
hydroxyl; halogen; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; a N(R VI) (R VII) amino
group, where R VI and R VII are independently hydrogen or a C1-C12
alkyl group; or each pair can form a (C=O) group together with
the carbon to which they are attached;
R18 is hydrogen; hydroxyl; halogen; C1-C12 alkyl; C6-C10 aryl; COR IX
(where R IX is hydrogen; hydroxyl; C1-C12 alkyl; N(R X) (R XI) amino,
where R X and R XI are independently hydrogen or a C1-C12 alkyl
group; or C1-Cl2 alcoxyl); or trifluoromethyl;

99
R19 and R20 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; a COR XII group (where R XII is hydrogen;
hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII) (R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); or trifluoromethyl; and
the bond <IMG> means a double bond or a single bond.
15. Use according to claim 14 wherein the compound of formula
(Ic) is a compound of formula (Ic'):
<IMG>
where:
R19 and R20 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; a COR XII group (where R XII is hydrogen;
hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII) (R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3) or trifluoromethyl; and
the bond <IMG> means a double bond or a single bond.
16.- Use according to claim 15 wherein the compound of formula
(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.

100
17.- Use according to claim 14 wherein the compound of formula
(Ic) is a compound of formula (Ic"):
<IMG>
where:
R19 and R20 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; a COR XII group (where R XII is hydrogen;
hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII) (R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); or trifluoromethyl.
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.
19.- Use according to claim 1 wherein the compound of formula
(I) is a compound of formula (Id):

101
<IMG>
where:
R1, R2, R3, R4, R5, R6, R7, R8, R11 and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted C1-
C12 alkyl; substituted or non-substituted C6-C10 aryl; a
N(R')(R'') amino group, where R' and R" are independently
hydrogen or a C1-C12 alkyl group; or each pair can form a (C=O)
group together with the carbon to which they are attached;
R9 and R10 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R'''
is hydrogen; hydroxyl; substituted or non-substituted C1-C12
alkyl; substituted or non-substituted C6-C10 aryl; O-C1-C12 alkyl;
or N(R IV) (R V) amino, where R IV and R V are independently hydrogen
or a C1-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, R15, R21 and R23 are independently hydrogen; hydroxyl;
halogen; substituted or non-substituted C1-C12 alkyl; substituted
or non-substituted C6-C10 aryl; a N(R VI) (R VII) amino group, where
R VI and R VII are independently hydrogen or a C1-C12 alkyl group; or
each pair can form a (C=O) group together with the carbon to
which they are attached;
R18 is hydrogen; hydroxyl; halogen; C1-C12 alkyl; C6-C10 aryl; COR IX
(where R IX is hydrogen; hydroxyl; C1-C12 alkyl; N(R X) (R XI) amino,
where R X and R XI are independently hydrogen or a C1-C12 alkyl
group; or C1-C12 alcoxyl); or trifluoromethyl;

102
R19, R19', R20 and R20' are independently hydrogen; substituted or
non-substituted C1-C12 alkyl; a COR XII group (where R XII is
hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII) (R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 and R25 are independently hydrogen, hydroxyl or halogen; and
the bond <IMG> 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'):
<IMG>
where:
R5 and R6 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; a N(R')(R") amino group, where R' and
R'' are independently hydrogen or a C1-C12 alkyl group; or each
pair can form a (C=O) group together with the carbon to which
they are attached;
R19, R19', R20 and R20' are independently hydrogen; substituted or
non-substituted C1-C12 alkyl; a COR XII group (where R XII is
hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII) (R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is

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;
R24 and R25 are independently hydrogen, hydroxyl or halogen.
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-
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
(Id) is a compound of formula (Id''):
<IMG>
where:
R19, R19', R20 and R20' are independently hydrogen; substituted or
non-substituted C1-C12 alkyl; a COR XII group (where R XII is
hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII)(R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12) alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 and R25 are independently hydrogen, hydroxyl or halogen.

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.
24.- Use according to claim 1 wherein the compound of formula
(I) is a compound of formula (Ie) :
<IMG>
where:
R1, R2, R3, R4, R5, R6, R7, R8, R11 and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted C1-
C12 alkyl; substituted or non-substituted C6-C10 aryl; a
N(R')(R'') amino group, where R' and R'' are independently
hydrogen or a C1-C12 alkyl group; or each pair can form a (C=O)
group together with the carbon to which they are attached;
R9 and R10 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R'''
is hydrogen; hydroxyl; substituted or non-substituted C1-C12
alkyl; substituted or non-substituted C6-C10 aryl; O-C1-C12 alkyl;
or N(R IV)(R V) amino, where R IV and R V are independently hydrogen
or an alkyl group C1-C12); a carbinol group (CH2)n-OH (where n is
an integer comprised between 1 and 10); or together form a
methylene group;
R13, R14, R15, R16, R21 and R23 are independently hydrogen;
hydroxyl; halogen; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-C10 aryl; a N(R VI)(R VII) amino
group, where R VI and R VII are independently hydrogen or a C1-C12

105
alkyl group; or each pair can form a (C=O) group together with
the carbon to which they are attached;
R18 and R18' are independently hydrogen; hydroxyl; halogen; C1-C12
alkyl; C6-C10 aryl; COR IX (where R IX is hydrogen; hydroxyl; C1-C12
alkyl; N(R X) (R XI) amino, where R X and R XI are independently
hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl); or
trifluoromethyl;
R19m R19', R20 and R20' are independently hydrogen; substituted or
non-substituted C1-C12 alkyl; a COR XII group (where R XII is
hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII)(RXIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 is hydrogen, hydroxyl or halogen; and
the bond <IMG> means a double bond or a single bond.
25.- Use according to claim 24 wherein the compound of formula
(Ie) is a compound of formula (Ie'):
<IMG>
where:
R18 and R18' are independently hydrogen; hydroxyl; halogen; C1-C12
alkyl; C6-C10 aryl; COR IX (where R IX is hydrogen; hydroxyl; C1-C12
alkyl; N(R X) (R XI) amino, where R X and R XI are independently
hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl) or
trifluoromethyl;

106
R19, R19', R20 and R20' are independently hydrogen; substituted or
non-substituted C1-C12 alkyl; a COR XII group (where R XII is
hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII)(R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12) alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 is hydrogen, hydroxyl or halogen.
26.- Use according to claim 25 wherein the compound of formula
(Ie') is 9-hydroxy-2,4a,6a,9,12b-hexamethyl-10,11-dioxo-
1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydro-
picene-2-carboxylic acid methyl ester.
27.- Use according to claim 1 wherein the compound of formula
(I) is a compound of formula (If):
<IMG>
where:
R1, R2, R3, R4, R5, R6, R7, R8, R11 and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted C1-
C12 alkyl; substituted or non-substituted C6-C10 aryl; a
N(R')(R'') amino group, where R' and R'' are independently
hydrogen or a C1-C12 alkyl group; or each pair can form a (C=O)
group together with the carbon to which they are attached;

107
R9 and R10 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R'''
is hydrogen; hydroxyl; substituted or non-substituted C1-C12
alkyl; substituted or non-substituted C6-C10 aryl; O-C1-C12 alkyl;
or N(R IV)(R V) amino, where R IV and R V are independently hydrogen
or a C1-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, R14, R15, R21 and R23 are independently hydrogen; hydroxyl;
halogen; substituted or non-substituted C1-C12 alkyl; substituted
or non-substituted C6-C10 aryl; a N(R VI)(R VIII) amino group, where
R XI and R XII are independently hydrogen or a C1-C12 alkyl group; or
each pair can form a (C=O) group together with the carbon to
which they are attached;
R18 and R18' are independently hydrogen; hydroxyl; halogen; C1-C12
alkyl; C6-C10 aryl; COR IX (where R IX is hydrogen; hydroxyl; C1-C12
alkyl; N(R X)(R XI) amino, where R X and R XI are independently
hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl) or
trifluoromethyl;
R19, R19', R20 and R20' are independently hydrogen; substituted or
non-substituted C1-C12 alkyl; a COR XII group (where R XII is
hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII) (R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 is hydrogen, hydroxyl or halogen; and
the bond <IMG> 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'):

108
<IMG>
where:
R18 and R18' are independently hydrogen; hydroxyl; halogen; C1-C12
alkyl; C6-C10 aryl; COR IX (where R IX is hydrogen; hydroxyl; C1-C12
alkyl; N(R X) (R XI) amino, where R X and R XI are independently
hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl); or
trifluoromethyl;
R19, R19', R20 and R20' are independently hydrogen; substituted or
non-substituted C1-C12 alkyl; a COR XII group (where R XII is
hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII)(R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a group C=O group together with the carbon
to which they are attached;
R24 is hydrogen, hydroxyl or halogen.
29.- Use according to claim 28 wherein the compound of formula
(If') is 9-hydroxy-2,4a,6a,6b,9-hexamethyl-10,11-dioxo-
1,2,3,4,4a,5,6,6a,6b,8a,9,10,11,14,14a,14b-hexadecahydro-picene-
2-carboxylic acid methyl ester.
30.- Use of a compound of formula (II):

109
<IMG>
where:
R1, R2, R3, R4, R5, R6r R9r R10, R11, R12, R13, R14, R15, R16, R17, R18,
R19 and R20 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; a N(R XV)(R XVI) amino group, where R XV and
R XVI are independently hydrogen or a C1-C12 alkyl group; or each
pair can form a carboxyl (C=O) group together with the carbon to
which they are attached;
R7 and R8 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; C6-C10 aryl; a COR XVII group (where R XVII
is hydrogen; hydroxyl; substituted or non-substituted C1-C12
alkyl; substituted or non-substituted C6-C10 aryl; O-C1-C12 alkyl;
or N(R XVIII)(R XIX) amino, where R XVIII and R XIX are independently
hydrogen or a C1-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,
R21 and R24 are independently substituted or non-substituted C1-
C12 alkyl; a COR XX group (where R XX is hydrogen; hydroxyl;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; or N(R XXI)(R XXII) amino, where R XXI and R XXII
are independently hydrogen or a C1-C12 alkyl group); a [(C1-
C12) alkyl-O-(C1-C12)alkyl-]n group (where n is comprised between 1
and 3); or trifluoromethyl;
R22 and R23 are:
- hydrogen; substituted or non-substituted C1-C12 alkyl; a
COR XXIII group (where R XXIII is hydrogen; hydroxyl;
substituted or non-substituted C1-C12 alkyl; substituted or

110
non-substituted C6-C10 aryl; or N(R XXIV) (R XXV) amino, where
R XXIV and R XXV are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); or trifluoromethyl when R24 is
in the para position with respect to R20; or
OR22' and OR23' respectively, where R22' and R23' are
independently hydrogen; substituted or non-substituted C1-
C12 alkyl; a COR XXVI group (where R XXVI is hydrogen; hydroxyl;
substituted or non-substituted C1-C12 alkyl; substituted or
non-substituted C6-C10 aryl; or N(R XXVII)(R XXVIII) amino, where
R XXVII and R XXVIII are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); or trifluoromethyl when R24 is
in the meta position with respect to R20.
or a pharmaceutically acceptable salt, derivative, prodrug,
solvate or stereoisomer thereof, in the manufacture of a
medicament for the prevention and/or treatment of a ChoK
mediated disease or condition.
31.- Use according to claim 30 wherein the compound of formula
(II) is a compound of formula (IIa):
<IMG>
where:
R1, R2, R3, R4, R5, R6, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18,
R19 and R20 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; a N(R XV)(R XVI) amino group, where R XV and
R XVI are independently hydrogen or a C1-C12 alkyl group; or each

111
pair can form a carboxyl (C=O) group together with the carbon to
which they are attached;
R7 and R8 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; C6-C10 aryl; a COR XVII group (where R XVII
is hydrogen; hydroxyl; substituted or non-substituted C1-C12
alkyl; substituted or non-substituted C6-C10 aryl; O-C1-C12 alkyl;
or N(R XVIII)(R XIX) amino, where R XVIII and R XIX are independently
hydrogen or a C1-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,
R21 and R24 are independently substituted or non-substituted C1-
C12 alkyl; a COR XX group (where R XX is hydrogen; hydroxyl;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; or N(R XXI)(R XXII) amino, where R XXI and R XXII
are independently hydrogen or a C1-C12 alkyl group); a [(C1-
C12)alkyl-O-(C1-C12)alkyl-]n group (where n is comprised between 1
and 3); or trifluoromethyl;
R22 and R23 are:
- hydrogen; substituted or non-substituted C1-C12 alkyl; a
COR XXIII group (where R XXIII is hydrogen; hydroxyl;
substituted or non-substituted C1-C12 alkyl; substituted or
non-substituted C6-C10 aryl; or N(R XXIV)(R XXV) amino, where
R XXIV and R XXV are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); or trifluoromethyl when R24 is
in the para position with respect to R20; or
- OR22' and OR23' respectively, where R22' and R23' are
independently hydrogen; substituted or non-substituted C1-
C12 alkyl; a COR XXVI group (where R XXVI is hydrogen; hydroxyl;
substituted or non-substituted C1-C12 alkyl; substituted or
non-substituted C6-C10 aryl; or N(R XXVII) (R XXVIII) amino, where
R XXVIV and R XXVIII are independently hydrogen or a C1-C12 alkyl
group); a[(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); or trifluoromethyl when R24 is
in the meta position with respect to R20.

112
32.- Use according to claim 31 wherein the compound of formula
(IIa) is a compound of formula (IIa'):
<IMG>
where:
R19 and R20 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; a N(R XV)(R XVI) amino group, where R XV and
R XVI are independently hydrogen or a C1-C12 alkyl group; or each
pair can form a (C=O) carboxyl group together with the carbon to
which they are attached;
R21 and R24 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; a N(R XXI)(R XXII) amino group, where R XXI and
R XXII are independently hydrogen or a C1-C12 alkyl group; or each
pair can form a (C=O) carboxyl group together with the carbon to
which they are attached;
R22 and R23 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; a N(R XXIV)(R XXV) amino group, where R XXIV
and R XXV are independently hydrogen or a C1-C12 alkyl group; or
each pair can form a (C=O) carboxyl group together with the
carbon to which they are attached.
33.- Use according to claim 32 wherein the compound of formula
(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.
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

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
mediated disease or condition to be prevented and/or treated is
a parasitic disease, more preferably caused
by Plasmodium or Trypanosoma.
36. Use according to any one of claims 1 to 33 wherein the ChoK
mediated disease or condition to be prevented and/or treated is
a parasitic disease, more preferably is a parasitic disease
caused by a bacterial disease, preferably caused by
Streptococcus.
37. Use according to any one of claims 1 to 33 wherein the ChoK
mediated disease or condition to be prevented and/or treated is
a fungal disease, preferably caused by Candida.
38. A compound of formula (I):
<IMG>
where:
R1, R2, R3, R4, R5, R6, R7, R8, R11 and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted C1-
C12 alkyl; substituted or non-substituted C6-C10 aryl; a
N(R')(R'') amino group, where R' and R'' are independently
hydrogen or a C1-C12 alkyl group; an OCOR group, where R is
(CH2)2COOH or (CH2)2CO2CH2CH3; or each pair can form a (C=O) group
together with the carbon to which they are attached;

114
R9 and R10 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R'''
is hydrogen; hydroxyl; substituted or non-substituted C1-C12
alkyl; substituted or non-substituted C6-C10 aryl; O-C1-C12 alkyl;
or N(R IV)(R V) amino, where R IV and R V are independently hydrogen
or a C1-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;
the bond <IMG> means a double bond or a single bond;
and where the tricyclic structure
<IMG>
is selected from the following structures:
<IMG>
where:
R13, R14, R15, R16, R21, R22 and R23 are independently hydrogen;
hydroxyl; halogen; substituted or non-substituted C1-C12 alkyl;

115
substituted or non-substituted C6-C10 aryl; a N(R VI)(R VII) amino
group, where R VI and R VII are independently hydrogen or a C1-C12
alkyl group; an OCOR VIII group, where R VIII is (CH2)2COOH or
(CH2)2CO2CH2CH3; 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;
R17 is hydrogen or methyl;
R18 and R18, are independently hydrogen; hydroxyl; halogen; C1-C12
alkyl; C6-C10 aryl; COR IX (where R IX is hydrogen; hydroxyl; C1-C12
alkyl; N(R X)(R XI) amino, where R X and R XI are independently
hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl); or
trifluoromethyl;
R19, R19', R20 and R20' are independently hydrogen; substituted or
non-substituted C1-C12 alkyl; a COR XII group (where R XII is
hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII)(R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group) ; a [(C1-C12) alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 and R25 are independently hydrogen, hydroxyl or halogen;
or a pharmaceutically acceptable salt, derivative, prodrug,
solvate or stereoisomer thereof, with the following provisos:
- when the tricyclic structure is (a) then the compound of
formula (I) is not:
- 10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-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-
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-

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-
picene-2,10-dione;
- 3,9-Dihydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-
picene-2,10-dione;
- 3,7,9-Trihydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-
picene-2,10-dione;
- 14-Bromo-3,7,9-trihydroxy-4,6b,8a,11,12b,14a-
hexamethyl-7,8,8a,11,12,12a,12b,13,14,14a-
decahydro-6bH,9H-picene-2,10-dione;
- Succinic acid mono-(10-hydroxy-2,4a,6a,9,12b,14a-
hexamethyl-3,11-dioxo-
1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-
tetradecahydro-picen-4-yl) ester;
- Succinic acid ethyl ester 10-hydroxy-
2,4a,6a,9,12b,14a-hexamethyl-3,11-dioxo-
1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-
tetradecahydro-picen-4-yl ester;
- Acetic acid 9-hydroxy-4,6b,8a,11,12b,14a-
hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- Dodecanoic acid 9-hydroxy-4,6b,8a,11,12b,14a-
hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- Dimethyl-carbamic acid 9-hydroxy-
4,6b,8a,11,12b,14a-hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- Nicotinic acid 9-hydroxy-4,6b,8a,11,12b,14a-
hexamethyl-2,10-dioxo-

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-
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.
- when the tricyclic structure is (b) and R19 and R20 are
independently hydrogen or an acyl group, then:
- R5 is hydroxyl; or
- R21 and R22 form a C=O group together with the
carbon to which they are attached and R10 is not
COOH.
- when the tricyclic structure is (c) and R19 and R20 are
both CH3, then R15 and R16 do not form a C=O group together
with the carbon to which they are attached.
39. A compound according to claim 38 of formula (Ia):
<IMG>
where
R1, R2, R3, R4, R5, R6, R7, R8, R11 and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted C1-
C12 alkyl; substituted or non-substituted C6-C10 aryl; a
N(R')(R'') amino group, where R' and R'' are independently
hydrogen or a C1-C12 alkyl group; an OCOR group, where R is

118
(CH2)2COOH or (CH2)2CO2CH2CH3; or each pair can form a (C=O) group
together with the carbon to which they are attached;
R9 and R10 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R'''
is hydrogen; hydroxyl; substituted or non-substituted C1-C12
alkyl; substituted or non-substituted C6-C10 aryl; O-C1-C12 alkyl;
or N(R IV)(R V) amino, where R IV and R V are independently hydrogen
or a C1-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, R14, R15 and R16 are independently hydrogen; hydroxyl;
halogen; substituted or non-substituted C1-C12 alkyl; substituted
or non-substituted C6-C10 aryl; a N(R VI)(R VII) amino group, where
R VI1 and R VII are independently hydrogen or a C1-C12 alkyl group; an
OCOR VIII group, where R VIII is (CH2)2COOH or (CH2)2CO2CH2CH3; or each
pair can form a (C=O) group together with the carbon to which
they are attached;
R17 is hydrogen or methyl;
R18 is hydrogen; hydroxyl; halogen; C1-C12 alkyl; C6-C10 aryl; COR IX
(where R IX is hydrogen; hydroxyl; C1-C12 alkyl; N(R X)(R XI) amino,
where R X and R XI are independently hydrogen or a C1-C12 alkyl
group; or C1-C12alcoxyl); or trifluoromethyl;
R19 is hydrogen; substituted or non-substituted C1-C12 alkyl; a
COR XII group (where R XII is hydrogen; hydroxyl; substituted or
non-substituted C1-C12 alkyl; substituted or non-substituted C6-
C10 aryl; or N(R XIII)(R XIV) amino, where R XIII and R XIV are
independently hydrogen or a C1-C12 alkyl group); a [(C1-C12)alkyl-
O-(C1-C12)alkyl-]n group (where n is comprised between 1 and 3);
or trifluoromethyl; and
the bond <IMG> 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;

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-
1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro-
picene-2-carboxylic acid methyl ester;
- 3-Hydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-2,10-
dione;
- 3,9-Dihydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-2,10-
dione;
- 3,7,9-Trihydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-2,10-
dione;
- 14-Bromo-3,7,9-trihydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-2,10-
dione;
- Succinic acid mono-(10-hydroxy-2,4a,6a,9,12b,14a-hexamethyl-
3,11-dioxo-1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-
tetradecahydro-picen-4-yl) ester;
- Succinic acid ethyl ester 10-hydroxy-2,4a,6a,9,12b,14a-
hexamethyl-3,11-dioxo-
1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro-picen-
4-yl ester;
- Acetic acid 9-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-2,10-
dioxo-2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- Dodecanoic acid 9-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-
2,10-dioxo-2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- Dimethyl-carbamic acid 9-hydroxy-4,6b,8a,11,12b,14a-
hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-
picen-3-yl ester;

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-
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.
40. A compound according to claim 39 of formula (Ia'):
<IMG>
where
R5 is hydroxyl or a OCOR group where R is (CH2)2COOH or
(CH2)2CO2CH2CH3;
R7 and R8 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; a N(R')(R'') amino group, where R' and
R'' are independently hydrogen or a C1-C12 alkyl group; or each
pair can form a(C=O) group together with the carbon to which
they are attached;
R12 is independently hydrogen or a halogen; and
R19 is hydrogen; substituted or non-substituted C1-C12 alkyl; a
COR XII group (where R XII is hydrogen; hydroxyl; substituted or
non-substituted C1-C12 alkyl; substituted or non-substituted C6-
C10 aryl; or N(R XIII)(R X IV) amino, where R XIII and R XIV are
independently hydrogen or a C1-C12 alkyl group); a [(C1-C12)alkyl-

121
O-(C1-C12)alkyl-]n group (where n is comprised between 1 and 3);
or trifluoromethyl; and
the bond <IMG> means a double bond or a single bond,
with the proviso that the compound of formula (Ia') is not:
- 3,9-Dihydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-
2,10-dione;
- 14-Bromo-3,7,9-trihydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-
2,10-dione;
- Succinic acid mono-(10-hydroxy-2,4a,6a,9,12b,14a-
hexamethyl-3,11-dioxo-
1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro-
picen-4-yl) ester;
- Succinic acid ethyl ester 10-hydroxy-2,4a,6a,9,12b,14a-
hexamethyl-3,11-dioxo-
1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro-
picen-4-yl ester;
- Acetic acid 9-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-2,10-
dioxo-2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- Dodecanoic acid 9-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-
2,10-dioxo-2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- Dimethyl-carbamic acid 9-hydroxy-4,6b,8a,11,12b,14a-
hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-
picen-3-yl ester;
- Nicotinic acid 9-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-
2,10-dioxo-2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester.
41. A compound according to claim 40 which is:
- 9-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-
picene-3-yl propionic acid ester;

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-
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;
- 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-
picene-2-one.
42. A compound according to claim 39 of formula (Ia''):
<IMG>
where:
R7 and R8 are independently hydrogen, hydroxyl, halogen,
substituted or non-substituted C1-C12 alkyl, substituted or non-
substituted C6-C10 aryl, a N(R')(R'') amino group, where R' and
R'' are independently hydrogen or a C1-C12 alkyl group, or each
pair can form a (C=O) group together with the carbon to which
they are attached;
R15 is hydrogen or halogen;

123
R19 is hydrogen, substituted or non-substituted C1-C12 alkyl; a
COR XII group (where R XII is hydrogen; hydroxyl; substituted or
non-substituted C1-C12 alkyl; substituted or non-substituted C6-
C10 aryl; or N(R XIII) (R XIV) amino, where R XIII and R XIV are
independently hydrogen or a C1-C12 alkyl group); a [(C1-C12) alkyl-
O-(C1-C12) alkyl-]n group (where n is comprised between 1 and 3);
or trifluoromethyl; and
the bond <IMG> means a double bond or a single bond,
with the proviso that the compound of formula (Ia") is not:
- 3-Hydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,9,10,11,12,12a,12b,13,14,14a-dodecahydro-6bH-picen-
2-one;
- 3-Hydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-
2,10-dione.
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-
2,10-dione;
-4,6b,8a,11,12b,14a-hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-
picene-3-yl acetic acid ester;
-4,6b,8a,11,12b,14a-hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-
picene-3-yl nicotinic acid ester;
-3,10-dihydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,9,10,11,12,12a,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.
44. A compound according to claim 39 of formula (Ia"'):

124
<IMG>
where:
R7 is hydrogen, hydroxyl, halogen, substituted or non-
substituted C1-C12 alkyl, substituted or non-substituted C6-C10
aryl, or a N(R')(R") amino group, where R' and R" are
independently hydrogen or a C1-C12 alkyl group; and
R19 is substituted or non-substituted C1-C12 alkyl; a COR XII group
(where R XII is hydrogen; hydroxyl; substituted or non-substituted
C1-C12 alkyl; substituted or non-substituted C6-C10 aryl; or
N(R XIII) (R XIV) amino, where R XIII and R XIV are independently hydrogen
or a C1-C12 alkyl group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group
(where n is comprised between 1 and 3); or trifluoromethyl;
with the proviso that the compound of formula (Ia"') is not:
- 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-
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-
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):

125
<IMG>
where:
R1, R2, R3, R4, R5, R6, R7, R8, R11 and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted C1-
C12 alkyl; substituted or non-substituted C6-C10 aryl; a
N(R')(R'') amino group, where R' and R'' are independently
hydrogen or a C1-C12 alkyl group; or each pair can form a (C=O)
group together with the carbon to which they are attached;
R9 and R10 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R'''
is hydrogen; hydroxyl; substituted or non-substituted C1-C12
alkyl; substituted or non-substituted C6-C10 aryl; O-C1-C12 alkyl;
or N(R IV) (R V) amino, where R IV and R V are independently hydrogen
or a C1-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, R14, R15, R16, R21, R22 and R23 are independently hydrogen;
hydroxyl; halogen; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; a N(R VI) (R VII) amino
group, where R VI and R VII are independently hydrogen or a C1-C12
alkyl group; or each pair can form a (C=O) group together with
the carbon to which they are attached;
R17 is hydrogen or methyl;
R18 is hydrogen; hydroxyl; halogen; C1-C12 alkyl; C6-C10 aryl; COR IX
(where R IX is hydrogen; hydroxyl; C1-C12 alkyl; N(R X) (R XI) amino,
where R X and R XI are independently hydrogen or a C1-C12 alkyl
group; or C1-C12 alcoxyl); or trifluoromethyl;

126
R19 and R20 are independently hydrogen, substituted or non-
substituted C1-C12 alkyl; a COR XII group (where R XII is hydrogen;
hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII) (R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12) alkyl-O-(C1-C12) alkyl-]n group (where n is
comprised between 1 and 3); or trifluoromethyl; and
the bond <IMG> means a double bond or a single bond,
with the proviso that when R19 and R20 are independently hydrogen
or an acyl group, then:
R5 is hydroxyl; or
R21 and R22 form a C=O group together with the carbon to
which they are attached and R10 is not COOH.
47. A compound according to claim 46 of formula (Ib'):
<IMG>
where:
R19 and R20 are independently substituted or non-substituted C1-
C12 alkyl; a COR XII group (where R XII is hydrogen; hydroxyl;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; or N(R XIII) (R XIV) amino, where R XIII and R XIV
are independently hydrogen or a C1-C12 alkyl group); a [(C1-
C12)alkyl-O-(C1-C12)alkyl-]n group (where n is comprised between 1
and 3); or trifluoromethyl.
48. A compound according to claim 47 which is 4-nitro-(3-
dimethylcarbamoyloxy-5,9-dihydroxy-4,6b,8a,11,12b,14a-

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''):
<IMG>
where:
R18 is hydrogen; hydroxyl; halogen; C1-C12 alkyl; C6-C10 aryl; COR IX
(where R IX is hydrogen; hydroxyl; C1-C12 alkyl; N(R X) (R XI) amino,
where R X and R XI are independently hydrogen or a C1-C12 alkyl
group; or C1-C12 alcoxyl); or trifluoromethyl;
R19 is hydrogen; substituted or non-substituted C1-C12 alkyl; a
COR XII group (where R XII is hydrogen; hydroxyl; substituted or
non-substituted C1-C12 alkyl; substituted or non-substituted C6-
C10 aryl; or N(R XIII) (R XIV) amino, where R XIII and R XIV are
independently hydrogen or a C1-C12 alkyl group); a [(C1-C12)alkyl-
O-(C1-C12)alkyl-]n group (where n is comprised between 1 and 3);
or trifluoromethyl;
R23 is hydrogen; hydroxyl; halogen; substituted or non-
substituted C1-C12 alkyl; substituted or non-substituted C6-C10
aryl; a N(R VI) (R VII) amino group, where R VI and R VII are
independently hydrogen or a C1-C12alkyl group.
50. A compound according to claim 49 which is:
- 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;

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-
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):
<IMG>
where:
R1, R2, R3, R4, R5, R6, R7, R8, R11 and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted C1-
C12 alkyl; substituted or non-substituted C6-C10 aryl; a
N(R')(R'') amino group, where R' and R" are independently
hydrogen or a C1-C12 alkyl group; or each pair can form a (C=O)
group together with the carbon to which they are attached;
R9 and R10 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R'''
is hydrogen; hydroxyl; substituted or non-substituted C1-C12
alkyl; substituted or non-substituted C6-C10 aryl; O-C1-C12 alkyl;
or N(R IV) (R V) amino, where R IV and R V are independently hydrogen
or a C1-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, R14, R15, R16, R21 and R23 are independently hydrogen;
hydroxyl; halogen; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; a N(R VI) (R VII) amino

129
group, where R VI and R VII are independently hydrogen or a C1-C12
alkyl group; or each pair can form a (C=O) group together with
the carbon to which they are attached;
R18 is hydrogen; hydroxyl; halogen; C1-C12 alkyl; C6-C10 aryl; COR IX
(where R IX is hydrogen; hydroxyl; C1-C12 alkyl; N(R X) (R XI) amino,
where R X and R XI are independently hydrogen or a C1-C12 alkyl
group; or C1-C12 alcoxyl); or trifluoromethyl;
R19 and R20 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; a COR XII group (where R XII is hydrogen;
hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII) (R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); or trifluoromethyl; and
the bond <IMG> means a double bond or a single bond,
with the proviso that when R19 and R20 are both CH3, then R15 and
R16 do not form a C=O group together with the carbon to which
they are attached.
52. A compound according to claim 51 of formula (Ic'):
<IMG>
where:
R19 and R20 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; a COR XII group (where R XII is hydrogen;
hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII) (R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl

130
group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3) or trifluoromethyl; and
the bond <IMG> means a double bond or a single bond.
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.
54. A compound according to claim 51 of formula (Ic"):
<IMG>
where:
R19 and R20 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; a COR XII group (where R XII is hydrogen;
hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII) (R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); or trifluoromethyl.
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-
dodecahydro-picene-2-carboxylic acid methyl ester.
56. A compound according to claim 38 of formula (Id):

131
<IMG>
where:
R1, R2, R3, R4, R5, R6, R7, R8, R11 and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted C1-
C12 alkyl; substituted or non-substituted C6-C10 aryl; a
N(R')(R'') amino group, where R' and R'' are independently
hydrogen or a C1-C12 alkyl group; or each pair can form a (C=O)
group together with the carbon to which they are attached;
R9 and R10 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R'''
is hydrogen; hydroxyl; substituted or non-substituted C1-C12
alkyl; substituted or non-substituted C6-C10 aryl; O-C1-C12 alkyl;
or N(R IV) (R V) amino, where R IV and R V are independently hydrogen
or a C1-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, R15, R21 and R23 are independently hydrogen; hydroxyl;
halogen; substituted or non-substituted C1-C12 alkyl; substituted
or non-substituted C6-C10 aryl; a N(R VI) (R VII) amino group, where
R VI and R VII are independently hydrogen or a C1-C12 alkyl group; or
each pair can form a (C=O) group together with the carbon to
which they are attached;
R18 is hydrogen; hydroxyl; halogen; C1-C12 alkyl; C6-C10 aryl; COR IX
(where R IX is hydrogen; hydroxyl; C1-C12 alkyl; N(R X) (R XI) amino,
where R X and R XI are independently hydrogen or a C1-C12 alkyl
group; or C1-Cl2 alcoxyl); or trifluoromethyl;

132
R19, R19', R20 and R20' are independently hydrogen; substituted or
non-substituted C1-C12 alkyl; a COR XII group (where R XII is
hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII) (R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 and R25 are independently hydrogen, hydroxyl or halogen; and
the bond <IMG> means a double bond or a single bond.
57. A compound according to claim 56 of formula (Id'):
<IMG>
where:
R5 and R6 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; a N(R')(R") amino group, where R' and
R'' are independently hydrogen or a C1-C12 alkyl group; or each
pair can form a (C=O) group together with the carbon to which
they are attached;
R19, R19', R20 and R20' are independently hydrogen; substituted or
non-substituted C1-C12 alkyl; a COR XII group (where R XII is
hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII) (R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group); a [(C1-C12)alkyl-O-(C1-C12)alkyl-]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or

133
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 and R25 are independently hydrogen, hydroxyl or halogen.
58. A compound according to claim 57 which is:
- 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-
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''):
<IMG>
where:
R19, R19', R20 and R20, are independently hydrogen; substituted or
non-substituted C1-C12 alkyl; a COR XII group (where R XII is
hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII) (R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group) ; a [(C1-C12) alkyl-O- (C1-C12) alkyl-]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 and R25 are independently hydrogen, hydroxyl or halogen.
60. A compound according to claim 59 which is 12-bromo-
2,4a,6a,9,12a,14a-hexamethyl-10,11-dioxo-

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 (Ie):
<IMG>
where:
R1, R2, R3, R4, R5, R6, R7, R8, R11 and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted C1-
C12 alkyl; substituted or non-substituted C6-C10 aryl; a
N(R')(R'') amino group, where R' and R'' are independently
hydrogen or a C1-C12 alkyl group; or each pair can form a(C=0)
group together with the carbon to which they are attached;
R9 and R10 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R'''
is hydrogen; hydroxyl; substituted or non-substituted C1-C12
alkyl; substituted or non-substituted C6-C10 aryl; O-C1-C12 alkyl;
or N(R IV) (R V) amino, where R IV and R V are independently hydrogen
or an alkyl group C1-C12) ; a carbinol group (CH2)n-OH (where n is
an integer comprised between 1 and 10); or together form a
methylene group;
R13, R14, R15, R16, R21 and R23 are independently hydrogen;
hydroxyl; halogen; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; a N(R VI) (R VII) amino
group, where R VI and R VII are independently hydrogen or a C1-C12

135
alkyl group; or each pair can form a(C=O) group together with
the carbon to which they are attached;
R18 and R18' are independently hydrogen; hydroxyl; halogen; C1-C12
alkyl; C6-C10 aryl; COR IX (where R IX is hydrogen; hydroxyl; C1-C12
alkyl; N(R X) (R XI) amino, where R X and R XI are independently
hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl); or
trifluoromethyl;
R19, R19', R20 and R20' are independently hydrogen; substituted or
non-substituted C1-C12 alkyl; a COR XII group (where R XII is
hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII) (R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group) ; a [(C1-C12) alkyl-O- (C1-C12) alkyl-]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 is hydrogen, hydroxyl or halogen; and
the bond ~ means a double bond or a single bond.
62. A compound according to claim 61 of formula (Ie'):
<IMG>
where:
R18 and R18' are independently hydrogen; hydroxyl; halogen; C1-C12
alkyl; C6-C10 aryl; COR IX (where R IX is hydrogen; hydroxyl; C1-C12
alkyl; N(R X) (R XI) amino, where R X and R IX are independently
hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl) or
trifluoromethyl;

136
R19, R19', R20 and R20, are independently hydrogen; substituted or
non-substituted C1-C12 alkyl; a COR XII group (where R XII is
hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII) (R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group) ; a [(C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 is hydrogen, hydroxyl or halogen.
63. A compound according to claim 62 which is 9-hydroxy-
2,4a,6a,9,12b-hexamethyl-10,11-dioxo-
1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydro-
picene-2-carboxylic acid methyl ester.
64. A compound according to claim 38 of formula (If):
<IMG>
where:
R1, R2, R3, R4, R5, R6, R7, R8, R11 and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted C1-
C12 alkyl; substituted or non-substituted C6-C10 aryl; a
N(R')(R'') amino group, where R' and R'' are independently
hydrogen or a C1-C12 alkyl group; or each pair can form a(C=0)
group together with the carbon to which they are attached;

137
R9 and R10 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; C6-C10 aryl; a COR''' group (where R'''
is hydrogen; hydroxyl; substituted or non-substituted C1-C12
alkyl; substituted or non-substituted C6-C10 aryl; O-C1-C12 alkyl;
or N(R IV) (R V) amino, where R IV and R V are independently hydrogen
or a C1-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, R14, R15, R21 and R23 are independently hydrogen; hydroxyl;
halogen; substituted or non-substituted C1-C12 alkyl; substituted
or non-substituted C6-C10 aryl; a N(R41) (R411) amino group, where
R VI and R VII are independently hydrogen or a C1-C12 alkyl group; or
each pair can form a(C=O) group together with the carbon to
which they are attached;
R18 and R18' are independently hydrogen; hydroxyl; halogen; C1-C12
alkyl; C6-C10 aryl; COR IX (where R IX is hydrogen; hydroxyl; C1-C12
alkyl; N(R X) (R XI) amino, where R X and R XI are independently
hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl) or
trifluoromethyl;
R19, R19', R20 and R20, are independently hydrogen; substituted or
non-substituted C1-C12 alkyl; a COR XII group (where R XII is
hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII) (R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group) ; a [(C1-C12) alkyl-O- (C1-C12) alkyl-]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 is hydrogen, hydroxyl or halogen; and
the bond ~ means a double bond or a single bond.
65. A compound according to claim 64 of formula (If'):

138
<IMG>
where:
R18 and R18' are independently hydrogen; hydroxyl; halogen; C1-C12
alkyl; C6-C10 aryl; COR IX (where R IX is hydrogen; hydroxyl; C1-C12
alkyl; N(R X) (R XI) amino, where R X and R XI are independently
hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl); or
trifluoromethyl;
R19, R19', R20 and R20, are independently hydrogen; substituted or
non-substituted C1-C12 alkyl; a COR XII group (where R XII is
hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-C10 aryl; or N(R XIII) (R XIV) amino,
where R XIII and R XIV are independently hydrogen or a C1-C12 alkyl
group) ; a [(C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a group C=O group together with the carbon
to which they are attached;
R24 is hydrogen, hydroxyl or halogen.
66. A compound according to claim 65 which is the 9-hydroxy-
2,4a,6a,6b,9-hexamethyl-10,11-dioxo-
1,2,3,4,4a,5,6,6a,6b,8a,9,10,11,14,14a,14b-hexadecahydro-picene-
2-carboxylic acid methyl ester.
67. A compound of formula (II):

139
<IMG>
where:
R1, R2, R3, R4, R5, R6, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18,
R19 and R20 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; a N(R XV) (R XVI) amino group, where R XV and
R XVI are independently hydrogen or a C1-C12 alkyl group; or each
pair can form a carboxyl (C=O) group together with the carbon to
which they are attached;
R7 and R8 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; C6-C10 aryl; a COR XVII group (where R XVII
is hydrogen; hydroxyl; substituted or non-substituted C1-C12
alkyl; substituted or non-substituted C6-C10 aryl; O-C1-C12 alkyl;
or N(R XVIII) (R XIX) amino, where R XVIII and R XIX are independently
hydrogen or a C1-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,
R21 and R24 are independently substituted or non-substituted C1-
C12 alkyl; a COR XX group (where R XX is hydrogen; hydroxyl;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; or N(R XXI) (R XXII) amino, where R XXI and R XXII
are independently hydrogen or a C1-C12 alkyl group); a [(C1-
C12) alkyl-O- (C1-C12) alkyl-] n group (where n is comprised between 1
and 3); or trifluoromethyl;
R22 and R23 are:
- hydrogen; substituted or non-substituted C1-C12 alkyl; a
COR XXIII group (where R XXIII is hydrogen; hydroxyl;
substituted or non-substituted C1-C12 alkyl; substituted or

140
non-substituted C6-C10 aryl; or N(R XXIV) (R XXV) amino, where
R XXIV and R XXV are independently hydrogen or a C1-C12 alkyl
group) ; a[(C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is
comprised between 1 and 3); or trifluoromethyl when R24 is
in the para position with respect to R20; or
- OR22' and OR23' respectively, where R22' and R23' are
independently hydrogen; substituted or non-substituted C1-
C12 alkyl; a COR XXVI group (where R XXVI is hydrogen; hydroxyl;
substituted or non-substituted C1-C12 alkyl; substituted or
non-substituted C6-C10 aryl; or N(R XXVIII) (R XXVIII) amino, where
R XXVII and R XXVIII are independently hydrogen or a C1-C12 alkyl
group) ; a[(C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is
comprised between 1 and 3); or trifluoromethyl when R24 is
in the meta position with respect to R20.
or a pharmaceutically acceptable salt, derivative, prodrug,
solvate or stereoisomer thereof.
68. A compound according to claim 67 of formula (IIa):
<IMG>
where:
R1, R2, R3, R4, R5, R6, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18,
R19 and R20 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; a N(R XV) (R XVI) amino group, where R XV and
R XVI are independently hydrogen or a C1-C12 alkyl group; or each
pair can form a carboxyl (C=O) group together with the carbon to
which they are attached;
R7 and R8 are independently hydrogen; substituted or non-
substituted C1-C12 alkyl; C6-C10 aryl; a COR XVII group (where R XVII

141
is hydrogen; hydroxyl; substituted or non-substituted C1-C12
alkyl; substituted or non-substituted C6-C10 aryl; O-C1-C12 alkyl;
or N(R XVIII) (R XIX) amino, where R XVIII and R XIX are independently
hydrogen or a C1-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,
R21 and R24 are independently substituted or non-substituted C1-
C12 alkyl; a COR XX group (where R XX is hydrogen; hydroxyl;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; or N(R XXI) (R XXII) amino, where R XXI and R XXII
are independently hydrogen or a C1-C12 alkyl group); a[(C1-
C12) alkyl-O- (C1-C12) alkyl-]n group (where n is comprised between 1
and 3); or trifluoromethyl;
R22 and R23 are:
- hydrogen; substituted or non-substituted C1-C12 alkyl; a
COR XXIII group (where R XXIII is hydrogen; hydroxyl;
substituted or non-substituted C1-C12 alkyl; substituted or
non-substituted C6-C10 aryl; or N(R XXIV) (R XXV) amino, where
R XXIV and R XXV are independently hydrogen or a C1-C12 alkyl
group) ; a[(C1-C12) alkyl-O- (C1-C12) alkyl-] n group (where n is
comprised between 1 and 3); or trifluoromethyl when R24 is
in the para position with respect to R20; or
OR22' and OR23' respectively, where R22' and R23' are independently
hydrogen; substituted or non-substituted C1-C12 alkyl; a COR XXVI
group (where R XXVI is hydrogen; hydroxyl; substituted or non-
substituted C1-C12 alkyl; substituted or non-substituted C6-C10
aryl; or N(R XXVII) (R XXVIII) amino, where R XXVII and R XXVIII are
independently hydrogen or a C1-C12 alkyl group) ; a[(C1-C12) alkyl-
O- (C1-C12) alkyl-] n group (where n is comprised between 1 and 3) ;
or trifluoromethyl when R24 is in the meta position with respect
to R20.
69. A compound according to claim 68 of formula (IIa'):

142
<IMG>
where:
R19 and R20 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; a N(R XV) (R XVI) amino group, where R XV and
R XVI are independently hydrogen or a C1-C12 alkyl group; or each
pair can form a(C=O) carboxyl group together with the carbon to
which they are attached;
R21 and R24 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted C1-C12 alkyl; substituted or non-
substituted C6-C10 aryl; a N(R XXI) (R XXII) amino group, where R XXI and
R XXII are independently hydrogen or a C1-C12alkyl group; or each
pair can form a(C=O) carboxyl group together with the carbon to
which they are attached;
R22 and R23 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted C XXIV) (R XXV) amino group, where R XXIV
and R XXV are independently hydrogen or a C1-C12 alkyl group; or
each pair can form a(C=O) carboxyl group together with the
carbon to which they are attached.
70.- A pharmaceutical composition which comprises a compound of
formula (I) or (II) as defined in any one of claims 38 to 69 or
mixtures thereof, or a pharmaceutically acceptable salt,
derivative, prodrug, solvate or stereoisomer thereof together
with a pharmaceutically acceptable carrier, adjuvant or vehicle
for the administration to a patient.
71.- A compound as defined in any one of claims 38 to 69 or
mixtures thereof, or a pharmaceutically acceptable salt,

143
derivative, prodrug, solvate or stereoisomer thereof for use in
the treatment of a ChoK mediated disease or condition.

Description

CA 02635318 2008-06-26
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1
TRITERPENEQUINONE AND TRITERPENEPHENOL DERIVATIVES AND THEIR
APPLICATION FOR THE TREATMENT OF TUMORS AND PARASITIC DISEASES
FIELD OF THE INVENTION
The invention generally relates to triterpenequinone and
triterpenephenol derivatives blocking the biosynthesis of
phosphorylcholine by means of the selective blocking of the
choline kinase enzyme in tumor cells or in cells affected by
parasitic infection, and which are consequently applicable in
the treatment of tumors and parasitic diseases or diseases
caused by viruses, bacteria and fungi in animals, including
human beings, as well as to a method for preparing the compounds
of the invention.
BACKGROUND OF THE INVENTION
Choline kinase is the first enzyme of the Kennedy pathway
or the phospatidylcholine (PC) synthesis pathway, and it
phosphorylates choline to phosphorylcholine (PCho) using
adenosine 5'-triphosphate (ATP) as a phosphate group donor. Ras
genes form a family of the so-called oncogenes which have been
widely studied since they are activated in 25-30% of all human
tumors and in several of them in 90%. Ras proteins have an
important role in the transmission of intracellular signals due
to their involvement in the regulation of cell proliferation,
terminal differentiation and senescence. The transformation
mediated by different oncogenes, among which the ras oncogenes
stand out, induces high choline kinase activity levels,
resulting in an abnormal increase in the intracellular levels of
its product, PCho. Complementary facts support the role of ChoK
in the generation of human tumors, as studies using nuclear
magnetic resonance (NMR) techniques have shown high PCho levels
in human tumor tissues with respect to normal tissues including
breast, colon, lung and prostate tumors, among others. It is
common knowledge that ras is one of the most deeply studied
oncogenes in human carcinogenesis and that ChoK inhibition has
been shown to be a new and effective antitumor strategy in cells

CA 02635318 2008-06-26
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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
phosphorylcholine in an individual or combined manner would
allow the development of effective antitumor therapies.
In this sense, the research on ChoK inhibitors has
identified Hemicholinium-3 (HC-3) as a relatively potent and
selective blocking agent [Cuadrado A., Carnero A., Dolfi F.,
Jimenez B. and Lacal J.C. Oncogene 8, 2959-2968 (1993); Jimenez
B., del Peso L., Montaner S., Esteve P. and Lacal J.C. J. Cell
Biochem. 57, 141-149 (1995); Hernandez-Alcoceba, R., Saniger,
L., Campos, J., Nunez, M. C., Khaless, F., Gallo, M. A.,
Espinosa, A., Lacal, J. C. Oncogene, 15, 2289-2301 (1997)]. This
choline homologue with a biphenyl structure has been used for
designing new antitumor drugs, nevertheless, due to the fact
that HC-3 is a potent respiratory paralyzing agent, it is not a
good candidate for its use in clinical practice. The synthesis
of some derivatives has been based on structural modifications
of HC-3 improving the inhibitory activity of the ChoK enzyme and
partly eliminating its toxic effects.
Bisquaternized symmetric compounds derived from pyridinium
have also been used and their ability to inhibit PCho production
in entire cells has been evaluated (W098/05644) . However, these
derivatives have high toxicity levels limiting their extended
therapeutic application.
On the other hand, it is known that the compounds called
celastrol and pristimerin, formed by a pentacyclic triterpene
structure, induce apoptosis, said activity having been proved in
human models with leukemia [Nagase, M., Oto, J., Sugiyama, S.,
Yube, K., Takaishi, and Sakato, N., Biosci. Biotechnol. Biochem
67, 1883 (2003)]. Nevertheless, these compounds show a serious
toxicity at cell level which makes their development as useful
drugs in the treatment of tumor conditions impossible. In this
sense, application US 2004/0220267 describes celastrol and
pristimerin derivatives which allow improving the toxicity
problem.

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Nevertheless, there is a great need to develop compounds
that provide a high inhibitory activity of the ChoK enzyme for
the purpose of allowing their use for the treatment of tumors,
while at the same time they considerably reduce their toxicity
against compounds of the state of the art.
BRIEF DESCRIPTION OF THE INVENTION
After laborious research, the authors of the present
invention have found that certain modifications in the structure
of the previously described compounds celastrol and pristimerin
allow providing compounds acting as blocking agents of the
biosynthesis of phosphorylcholine by means of the selective
blocking of the choline kinase (ChoK) enzyme and which have
shown to be a new and effective antitumor strategy in human
tumor cells.
Thus, in one aspect the present invention relates to the
use of a compound of formula (I):
R:o Rg
R~~
,,\\\R8
R12i
CH3 R7
Rs
H CH3R5
R
a
HsC R
R, R2
(I)
where:
Rl, R2, R3, R4, R5, R6, R7 , R8, Rll and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-
C12 alkyl; substituted or non-substituted C6-Clo aryl; a
N(R')(R ') amino group, where R' and R" are independently
hydrogen or a Cl-C12 alkyl group; an OCOR group, where R is
(CH2) 2COOH or (CH2) 2CO2CH2CH3; or each pair can form a(C=0) group
together with the carbon to which they are attached;
R9 and Rlo are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a COR' '' group (where R' ''
is hydrogen; hydroxyl; substituted or non-substituted Cl-Clz
alkyl; substituted or non-substituted C6-Clo aryl; 0-C1-C12 alkyl;

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4
or N(R14) (R ) amino, where RI4 and R' are independently hydrogen
or a Cl-Clz alkyl group); a(CH2)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
is selected from the following structures:
R14 R13 R14 R13 R14 Ris
R R R15
R a"" Rtr;Rwu'~'
0 RzoO RzoO
R17 R1;
R,,O R,,O R,,)O Rz3
Ria Ria R21 R22 Rje, R21
(a) (b) (c)
Ri3 Ria Ris R1a Ris
Ri5
R15 RR1~RzRiS
Rza Rz5 CH ;
R20 CH, R R
zozoRz~"0 Rzo ,,,. Rzo HRj~' R
R,~' Rzs Rzs Rzs
RRi RIe Rz1 RI e" R18 R21 Rip, Rz,
(d) (e) (f)
where:
R13, R14, R15, R16, R21, R22 and R23 are independently hydrogen;
hydroxyl; halogen; substituted or non-substituted Cl-Clz alkyl;
substituted or non-substituted C6-Clo aryl; a N(R41) (R411) amino
group, where R41 and R411 are independently hydrogen or a Cl-Clz
alkyl group; an OCOR III group, where R III is (CH2) 2COOH or

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(CH2) 2CO2CH2CH3; or each pair can form a(C=0) 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;
R17 is hydrogen or methyl;
5 R18 and R18, are independently hydrogen; hydroxyl; halogen; Cl-C12
alkyl; C6-Clo aryl; CORIX (where RIX is hydrogen; hydroxyl; Cl-C12
alkyl; N(RX) (RXI) amino, where RX and RXI are independently
hydrogen or a Cl-C12 alkyl group; or Cl-C12 alcoxyl); or
trifluoromethyl;
R19r R19,, R20 and R20, are independently hydrogen; substituted or
non-substituted Cl-C12 alkyl; a CORXII group (where RXII is
hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 and R25 are independently hydrogen, hydroxyl or halogen;
or a pharmaceutically acceptable salt, derivative, prodrug,
solvate or stereoisomer thereof, in the manufacture of a
medicament for the treatment and/or prevention of a ChoK
mediated disease or condition.
In another aspect, the present invention refers to the use
of a compound of formula (II) :
R7 R8
R
s \\\Ro
R2 RJ R5
:17
22 R19 R18 R15
R21 R20
(II)

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6
where:
Rlr R2, R3, R4, R5, R6r R9r Rlor Rllr R1zr R13r R14r R15r R16r R17r Rl8r
R19 and R20 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted Cl-C12 alkyl; substituted or non-
substituted C6-Clo aryl; a N(Rxv) (Rxvz) amino group, where Rxv and
Rxvl are independently hydrogen or a Cl-C12 alkyl group; or each
pair can form a carboxyl (C=O) group together with the carbon to
which they are attached;
R7 and R8 are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a CORxvII group (where Rxvzz
is hydrogen; hydroxyl; substituted or non-substituted Cl-Clz
alkyl; substituted or non-substituted C6-Clo aryl; 0-C1-C12 alkyl;
or N(Rxvzzz) (Rxzx) amino, where RxvIII and Rxlx are independently
hydrogen or a Cl-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,
R21 and R24 are independently substituted or non-substituted Cl-
C12 alkyl; a CORxx group (where Rxx is hydrogen; hydroxyl;
substituted or non-substituted Cl-C12 alkyl; substituted or non-
substituted C6-Clo aryl; or N(Rxxz) (Rxxzz) amino, where Rxxl and Rxxzz
are independently hydrogen or a Cl-C12 alkyl group); a[(Cl-
C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is comprised between 1
and 3); or trifluoromethyl;
R22 and R23 are:
- hydrogen; substituted or non-substituted Cl-C12 alkyl; a
CORxxIII group (where RxxIII is hydrogen; hydroxyl;
substituted or non-substituted Cl-C12 alkyl; substituted or
non-substituted C6-Clo aryl; or N(Rxxzv) (Rxxv) amino, where
Rxxiv and Rxxv are independently hydrogen or a Cl-C12 alkyl
group) ; a[(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is
comprised between 1 and 3); or trifluoromethyl when R24 is
in the para position with respect to R20; or
OR22' and OR23' respectively, where R22' and R23' are
independently hydrogen; substituted or non-substituted Cl-
C12 alkyl; a CORxxvz group (where Rxxvz is hydrogen; hydroxyl;
substituted or non-substituted Cl-C12 alkyl; substituted or

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7
non-substituted C6-Clo aryl; or N(Rxxvzz) (Rxxvzzz) amino, where
Rxxviz and Rxxvzzz are independently hydrogen or a Cl-C12 alkyl
group) ; a[(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is
comprised between 1 and 3); or trifluoromethyl when R24 is
in the meta position with respect to R20=
or a pharmaceutically acceptable salt, derivative, prodrug,
solvate or stereoisomer thereof, in the manufacture of a
medicament for the treatment and/or prevention of a ChoK
mediated disease or condition.
In a particular embodiment, the disease or condition is
cancer. In another particular embodiment the disease is a
parasitic disease. In another particular embodiment the disease
is a bacterial disease. Finally, in another particular
embodiment the disease is a fungal disease.
In another aspect the present invention relates to
compounds of general formula (I):
Rlo Ro
R~~
,\\\R8
R12i
CH3 R7
Rs
H CH3R5
R
a
) H3C R~
h3
R, R2
(I)
where:
Rl, R2, R3, R4, R5, R6, R7, R8, Rll and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-
C12 alkyl; substituted or non-substituted C6-Clo aryl; a
N(R')(R ') amino group, where R' and R" are independently
hydrogen or a Cl-C12 alkyl group; an OCOR group, where R is
(CH2) 2COOH or (CH2) 2CO2CH2CH3; or each pair can form a(C=0) group
together with the carbon to which they are attached;
R9 and Rlo are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a COR' '' group (where R' ''
is hydrogen; hydroxyl; substituted or non-substituted Cl-Cl2

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8
alkyl; substituted or non-substituted C6-Clo aryl; O-Cl-C12 alkyl;
or N(R14) (R ) amino, where RI4 and R are independently hydrogen
or a Cl-Clz alkyl group); a(CH2)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
is selected from the following structures:
R14 Ris R14 R13 Riz R1z
R RI s R,5
r i6
R R ' R \ \ õ =
0 RzzO R20O
R1;
R17
R zO R1eO R,,O Rz.,
R18 Ria R21 R22 Rie R21
(a) (b) (c)
Ris R14 Ris Ria Ris
Ri,
R~5 RRGim,,, R,5
Rza Rz~CH Rza
CH;
RzCi' R20 Rz*R'
R20 \~Rzo '
'~ CH Rzo ,
RI,' Rl~' RRRz Rz3 Rzs
19 R1e Rz1 R1e' R,e 21 RieRie Rz,
(d) (e) (f)
where:
R13, R14, R15, R16, R21, R22 and R23 are independently hydrogen;
hydroxyl; halogen; substituted or non-substituted Cl-Clz alkyl;
substituted or non-substituted C6-Clo aryl; a N(R41) (R411) amino
group, where R41 and R411 are independently hydrogen or a Cl-Clz

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9
alkyl group; an OCOR III group, where R III is (CH2) 2COOH or
(CH2) 2CO2CH2CH3; or each pair can form a(C=0) 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;
R17 is hydrogen or methyl;
R18 and R18, are independently hydrogen; hydroxyl; halogen; Cl-C12
alkyl; C6-Clo aryl; CORIX (where RIX is hydrogen; hydroxyl; Cl-C12
alkyl; N(RX) (RXI) amino, where RX and RXI are independently
hydrogen or a Cl-C12 alkyl group; or Cl-C12 alcoxyl) or
trifluoromethyl;
R19r R19,, R20 and R20, are independently hydrogen; substituted or
non-substituted Cl-C12 alkyl; a CORXII group (where RXII is
hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) alkyl- ]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 and R25 are independently hydrogen, hydroxyl or halogen;
or a pharmaceutically acceptable salt, derivative, prodrug,
solvate or stereoisomer thereof, with the following provisos:
- when the tricyclic structure is (a) then the compound of
formula (I) is not:
- 10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-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-
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;

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- 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-
1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-
tetradecahydro-picen-4-yl) ester;
- Succinic acid ethyl ester 10-hydroxy-
2,4a,6a,9,12b,14a-hexamethyl-3,11-dioxo-
1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-
tetradecahydro-picen-4-yl ester;
- Acetic acid 9-hydroxy-4,6b,8a,11,12b,14a-
hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- Dodecanoic acid 9-hydroxy-4,6b,8a,11,12b,14a-
hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- Dimethyl-carbamic acid 9-hydroxy-
4,6b,8a,11,12b,14a-hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- Nicotinic acid 9-hydroxy-4,6b,8a,11,12b,14a-
hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;

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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;
- 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 R19 and R20 are
independently hydrogen or an acyl group, then:
- R5 is hydroxyl; or
- R21 and R22 form a C=O group together with the
carbon to which they are attached and Rlo is not
COOH.
- when the tricyclic structure is (c) and R19 and R20 are
both CH3, then R15 and R16 do not form a C=O group together
with the carbon to which they are attached.
In another aspect, the invention relates to a compound of
formula (II):
R7 R8
R6
R2 RJ R5
:::1
Rl9 R16 R15
R21 R20
(II)
where:
Rlr R2, R3, R4, R51 R61 R9r Rlor Rllr R12r R13r R14r R15r R16r Rl7r Rlar
R19 and R20 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted Cl-C12 alkyl; substituted or non-
substituted C6-Clo aryl; a N(Rxv) (Rxvz) amino group, where RX4 and
RX41 are independently hydrogen or a Cl-C12 alkyl group; or each

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12
pair can form a carboxyl (C=O) group together with the carbon to
which they are attached;
R7 and R8 are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a CORxvII group (where Rxvzz
is hydrogen; hydroxyl; substituted or non-substituted Cl-Clz
alkyl; substituted or non-substituted C6-Clo aryl; 0-C1-C12 alkyl;
or N(Rxvzzz) (Rxzx) amino, where RxvIII and Rxlx are independently
hydrogen or a Cl-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,
R21 and R24 are independently substituted or non-substituted Cl-
C12 alkyl; a CORxx group (where Rxx is hydrogen; hydroxyl;
substituted or non-substituted Cl-C12 alkyl; substituted or non-
substituted C6-Clo aryl; or N(Rxxz) (Rxxzz) amino, where Rxxl and Rxxzz
are independently hydrogen or a Cl-C12 alkyl group) ; a[(Cl-
C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is comprised between 1
and 3); or trifluoromethyl;
R22 and R23 are:
- hydrogen; substituted or non-substituted Cl-C12 alkyl; a
CORxxIII group (where RxxIII is hydrogen; hydroxyl;
substituted or non-substituted Cl-C12 alkyl; substituted or
non-substituted C6-Clo aryl; or N(Rxxzv) (Rxxv) amino, where
Rxxzv and Rxxv are independently hydrogen or a Cl-C12 alkyl
group) ; a[(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is
comprised between 1 and 3); or trifluoromethyl when R24 is
in the para position with respect to R20; or
- OR22' and OR23' respectively, where R22' and R23' are
independently hydrogen; substituted or non-substituted Cl-
C12 alkyl; a CORxxvz group (where Rxxvz is hydrogen; hydroxyl;
substituted or non-substituted Cl-C12 alkyl; substituted or
non-substituted C6-Clo aryl; or N(Rxxvzz) (Rxxvzzz) amino, where
Rxxviz and Rxxvzzz are independently hydrogen or a Cl-C12 alkyl
group) ; a[(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is
comprised between 1 and 3); or trifluoromethyl when R24 is
in the meta position with respect to Rzo=

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13
or a pharmaceutically acceptable salt, derivative, prodrug,
solvate or stereoisomer thereof.
In another aspect, the invention is directed to a
pharmaceutical composition comprising a compound of formula (I),
or a compound of formula (II), or mixtures thereof, or a
pharmaceutically acceptable salt, derivative, prodrug, solvate
or stereoisomer thereof together with a pharmaceutically
acceptable carrier, adjuvant or vehicle, for the administration
to a patient.
DETAILED DESCRIPTION OF THE INVENTION
One object of the present invention is the use of a
compound of formula (I)
Rlo Ro
Rll
Ra
,o\R12i
CH3 R7
,~~11nRs
H CH3R5
""Ra
NsC R3
R, R2
(I)
where:
Rl, R2, R3, R4, R5, R6, R,, R8, Rll and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-
C12 alkyl; substituted or non-substituted C6-Clo aryl; a
N(R')(R ') amino group, where R' and R" are independently
hydrogen or a Cl-C12 alkyl group; an OCOR group, where R is
(CH2) 2COOH or (CH2) 2CO2CH2CH3; or each pair can form a(C=0) group
together with the carbon to which they are attached;
R9 and Rlo are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a COR' '' group (where R' ''
is hydrogen; hydroxyl; substituted or non-substituted Cl-Cl2
alkyl; substituted or non-substituted C6-Clo aryl; O-Cl-C12 alkyl;
or N(R14) (R ) amino, where RI4 and R are independently hydrogen
or a Cl-C12 alkyl group); a(CH2)n-OH carbinol group (where n is

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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
is selected from the following structures:
R14 R13 R14 R13 R14 Rjs
Ris RIs R~5
Rr~~ ,,,,. R o ,,,, R ~~",,,.
w
0 RzzO R20O
R17 R;
R ,0 R1z0 Rlc) O r R R18 R1o R21 R22 R18 R21
(a) (b) (c)
Ri R 14 Ris R 14 Ris
R15 RR16RR~5
Rza Rz~CH za
CH,
Rzo Rz0 Rz0 ~
R2 ~~~~,,,. R20 "\~,,,,. CH Rzo """.~
,
R~~~ Rlc' Rlc'
R2, Rzs Rzs
Ri Ri Ri
Rje R21 R18' R~e R21 Rje~ ~R1e R21
(d) (e) (f)
where:
R13f R14f R15f R16, R21, R22 and R23 are independently hydrogen;
hydroxyl; halogen; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; a N(R41) (R411) amino
group, where R41 and R411 are independently hydrogen or a Cl-Clz
alkyl group; an OCOR III group, where R III is (CH2) 2COOH or
(CH2) 2CO2CH2CH3; or each pair can form a (C=O) group together with

CA 02635318 2008-06-26
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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;
R17 is hydrogen or methyl;
R18 and R18, are independently hydrogen; hydroxyl; halogen; Cl-Clz
5 alkyl; C6-Clo aryl; CORIX (where RIX is hydrogen; hydroxyl; Cl-Clz
alkyl; N(RX) (RXI) amino, where RX and RXI are independently
hydrogen or a Cl-C12 alkyl group; or Cl-C12 alcoxyl); or
trifluoromethyl;
R19r R19,, R20 and R20, are independently hydrogen; substituted or
10 non-substituted Cl-C12 alkyl; a CORXII group (where RXII is
hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-O- (Cl-C12) 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;
R24 and R25 are independently hydrogen, hydroxyl or halogen;
or a pharmaceutically acceptable salt, derivative, prodrug,
solvate or stereoisomer thereof, in the manufacture of a
medicament for the treatment and/or prevention of a ChoK
mediated disease or condition.
In a particular embodiment of the invention, the compound
of formula (I) used in the prevention and/or treatment of a ChoK
mediated disease or condition is a compound of formula (Ia):
Rio Ry
Rll
opRa
Ris
R~a~ CH3 ~
Ris /11,
= -111iiRa
H CH3Rs
O ~10Ra
R H3C '~ Rs
R i R2
R1gO
Ria
(Ia)
where

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16
Rl, R2, R3, R4, R5, R6, R,, R8, Rll and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-
C12 alkyl; substituted or non-substituted C6-Clo aryl; a
N(R')(R ') amino group, where R' and R" are independently
hydrogen or a Cl-C12 alkyl group; an OCOR group, where R is
(CH2) 2COOH or (CH2) 2CO2CH2CH3; or each pair can form a(C=0) group
together with the carbon to which they are attached;
R9 and Rlo are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a COR' '' group (where R' ''
is hydrogen; hydroxyl; substituted or non-substituted Cl-Clz
alkyl; substituted or non-substituted C6-Clo aryl; 0-C1-C12 alkyl;
or N(R14) (R ) amino, where RI4 and R are independently hydrogen
or a Cl-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, R14, R15 and R16 are independently hydrogen; hydroxyl;
halogen; substituted or non-substituted Cl-C12 alkyl; substituted
or non-substituted C6-Clo aryl; a N(R41) (R411) amino group, where
R41 and R411 are independently hydrogen or a Cl-C12 alkyl group; an
OCOR III group, where R III is (CH2) 2COOH or (CH2) 2CO2CH2CH3; or each
pair can form a(C=0) group together with the carbon to which
they are attached;
R17 is hydrogen or methyl;
R18 is hydrogen; hydroxyl; halogen; Cl-C12 alkyl; C6-Clo aryl; CORIX
(where RIX is hydrogen; hydroxyl; Cl-C12 alkyl; N(RX) (RXI) amino,
where RX and RXI are independently hydrogen or a Cl-C12 alkyl
group; or Cl-C12alcoxyl); or trifluoromethyl;
R19 is hydrogen; substituted or non-substituted Cl-C12 alkyl; a
CORXII group (where RXII is hydrogen; hydroxyl; substituted or
non-substituted Cl-C12 alkyl; substituted or non-substituted C6-
Clo aryl; or N(RXIII) (RXI ) amino, where RXIII and RX14 are
independently hydrogen or a Cl-C12 alkyl group) ; a[(Cl-C12) alkyl-
0- (Cl-C12) alkyl-] n group (where n is comprised between 1 and 3) ;
or trifluoromethyl; and
the bond ------ means a double bond or a single bond.

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17
In a preferred embodiment, the compounds of formula (Ia)
used in the invention comprise a substructure having the
following formula (Ia'):
CH,,
R12/,,, R7
CH3
R5
CH,,
O ~
CH ; CH,,
~ ~
R19O
CH,,
(Ia')
where
R5 is hydroxyl or a OCOR group where R is (CH2) 2COOH or
(CH2) 2CO2CH2CH3;
R7 and R8 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted Cl-C12 alkyl; substituted or non-
substituted C6-Clo aryl; a N(R' )(R" ) amino group, where R' and
R" are independently hydrogen or a Cl-C12 alkyl group; or each
pair can form a(C=0) group together with the carbon to which
they are attached;
R12 is independently hydrogen or a halogen; and
R19 is hydrogen; substituted or non-substituted Cl-C12 alkyl; a
CORXII group (where RXII is hydrogen; hydroxyl; substituted or
non-substituted Cl-C12 alkyl; substituted or non-substituted C6-
Clo aryl; or N(RXIII) (RXI ) amino, where RXIII and RX14 are
independently hydrogen or a Cl-C12 alkyl group) ; a[(Cl-C12) alkyl-
0- (Cl-C12) alkyl-] n group (where n is comprised between 1 and 3) ;
or trifluoromethyl; and
the bond ------ means a double bond or a single bond.
Particular examples of this substructure (Ia') are:
- 3,9-Dihydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-
2,10-dione;

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- Acetic acid 9-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-2,10-
dioxo-2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- 9-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-
picene-3-yl propionic acid ester (C1);
- Dodecanoic acid 9-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-
2,10-dioxo-2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- Dimethyl-carbamic acid 9-hydroxy-4,6b,8a,11,12b,14a-
hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-
picen-3-yl ester;
- Nicotinic acid 9-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-
2,10-dioxo-2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- 4-bromo-(9-hydroxy-6b,8a,11,12b,14a-hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-
picene-3-yl) benzoic acid ester (C2) ;
- 14-Bromo-3,7,9-trihydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-
2,10-dione;
- 12-bromo-9-hydroxy-6b,8a,11,12b,14a-hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-
picene-3-yl dimethyl-carbamic acid ester (C4);
- 4-bromo-(12-bromo-9-hydroxy-6b,8a,11,12b,14a-hexamethyl-
2,10-dioxo-2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picene-3-yl) benzoic acid ester (C5);
- 12-bromo-3,9-dihydroxy-6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-
2,10-dione (C3);
- 3,9,10-trihydroxy-6b,8a,11,12b,14a-hexamethyl-
7,8,8a,9,10,11,12,12a,12b,13,14,14a-dodecahydro-6bH-
picene-2-one (C6);
- Succinic acid mono-(10-hydroxy-2,4a,6a,9,12b,14a-
hexamethyl-3,11-dioxo-

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1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro-
picen-4-yl) ester;
- Succinic acid ethyl ester 10-hydroxy-2,4a,6a,9,12b,14a-
hexamethyl-3,11-dioxo-
1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro-
picen-4-yl ester.
In another preferred embodiment, the compounds of formula
(Ia) used in the present invention comprise a substructure
having the following formula (Ia "):
CH;
R7
C_H3
R15
CH;
O
CH,, CH,,
R190
H;
(Ia" )
where:
R7 and R8 are independently hydrogen, hydroxyl, halogen,
substituted or non-substituted Cl-C12 alkyl, substituted or non-
substituted C6-Clo aryl, a N(R' )(R" ) amino group, where R' and
R'' are independently hydrogen or a Cl-C12 alkyl group, or each
pair can form a(C=0) group together with the carbon to which
they are attached;
R15 is hydrogen or halogen;
R19 is hydrogen, substituted or non-substituted Cl-C12 alkyl; a
CORXII group (where RXII is hydrogen; hydroxyl; substituted or
non-substituted Cl-C12 alkyl; substituted or non-substituted C6-
Clo aryl; or N(RXIII) (RXI ) amino, where RXIII and RX14 are
independently hydrogen or a Cl-C12 alkyl group) ; a[(Cl-C12) alkyl-
0- (Cl-C12) alkyl-] n group (where n is comprised between 1 and 3) ;
or trifluoromethyl; and
the bond ------ means a double bond or a single bond.
Particular examples of this substructure (Ia'') are:

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-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 (C10);
-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 (C11) .
In another preferred embodiment, the compounds of formula
(Ia) used in the present invention comprise a substructure
having the following formula (Ia "'):
H;C ,COOCH;
R7
CH~
CH3
O ~
CH~ CH;
~ ~ J
R19O
20 H;
(Ia,,,)
where:
R7 is hydrogen, hydroxyl, halogen, substituted or non-
substituted Cl-C12 alkyl, substituted or non-substituted C6-Clo
aryl, or a N(R' )(R" ) amino group, where R' and R" are
independently hydrogen or a Cl-C12 alkyl group; and
R19 is substituted or non-substituted Cl-C12 alkyl; a CORXII group
(where RXII is hydrogen; hydroxyl; substituted or non-substituted
Cl-C12 alkyl; substituted or non-substituted C6-Clo aryl; or

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N(RXIII) (RXI ) amino, where RXIII and RX14 are independently hydrogen
or a Cl-C12 alkyl group) ; a[(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group
(where n is comprised between 1 and 3); or trifluoromethyl.
Particular examples of this substructure (Ia "') are:
- 10-hydroxy-2,4a,6a,9,12b,14a-hexamethyl-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-
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);
- 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
compound of formula (I) used in the prevention and/or treatment
of a ChoK mediated disease or condition is a compound of formula
(Ib) :
Rio Ro
R i i
12m1,,, R
R~qR~~ CH3 R7
R15 R6
R 16\"",,,,
H CH3 RS
R200 ,,,,/R
a
1 R~~ NsC R3
R1 R2
RioO R23
R18 R21 R22
(Ib)
where:
Rl, R2, R3, R4, R5, R6, R7, R8, Rll and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-
C12 alkyl; substituted or non-substituted C6-Clo aryl; a

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22
N(R')(R ' ) amino group, where R' and R" are independently
hydrogen or a Cl-C12 alkyl group; or each pair can form a(C=0)
group together with the carbon to which they are attached;
R9 and Rlo are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a COR' '' group (where R' ''
is hydrogen; hydroxyl; substituted or non-substituted Cl-Clz
alkyl; substituted or non-substituted C6-Clo aryl; 0-C1-C12 alkyl;
or N(R14) (R ) amino, where RI4 and R' are independently hydrogen
or a Cl-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, R14, R15, R16, R21, R22 and R23 are independently hydrogen;
hydroxyl; halogen; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; a N(R41) (R411) amino
group, where R41 and R411 are independently hydrogen or a Cl-Clz
alkyl group; or each pair can form a(C=0) group together with
the carbon to which they are attached;
R17 is hydrogen or methyl;
R18 is hydrogen; hydroxyl; halogen; Cl-C12 alkyl; C6-Clo aryl; CORIX
(where RIX is hydrogen; hydroxyl; Cl-C12 alkyl; N(RX) (RXI) amino,
where RX and RXI are independently hydrogen or a Cl-C12 alkyl
group; or Cl-Cl2alcoxyl); or trifluoromethyl;
R19 and R20 are independently hydrogen, substituted or non-
substituted Cl-C12 alkyl; a CORXII group (where RXII is hydrogen;
hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is
comprised between 1 and 3); or trifluoromethyl; and
the bond ------ means a double bond or a single bond.
In a preferred embodiment, the compounds of formula (Ib)
used in the present invention comprise a substructure having the
following formula (Ib'):

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23
CH3
O
CH3
OH
CH;
R200
CH; CH3
R19O
CH; OH
(Ib')
where:
R19 and R20 are independently substituted or non-substituted Cl-
C12 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl;
substituted or non-substituted Cl-C12 alkyl; substituted or non-
substituted C6-Clo aryl; or N(RxIII) (RxI ) amino, where RxIII and Rxzv
are independently hydrogen or a Cl-C12 alkyl group); a[(Cl-
C12) alkyl-O- (Cl-C12) alkyl-] n group (where n is comprised between 1
and 3); or trifluoromethyl.
A particular example of this substructure (Ib') is 4-nitro-
(3-dimethylcarbamoyloxy-5,9-dihydroxy-4,6b,8a,11,12b,14a-
hexamethyl-10-oxo-5,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picene-2-yl) benzoic acid ester (C15).
In another preferred embodiment, the compounds of formula
(Ib) comprise a substructure having the following formula
(Ib"):
H3COOC CH;
H~
CH;
HO I CH~ CH;
R190 R2s
R18 O
(Ib" )
where:

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R18 is hydrogen; hydroxyl; halogen; Cl-C12 alkyl; C6-Clo aryl; CORIX
(where RIX is hydrogen; hydroxyl; Cl-C12 alkyl; N(RX) (RXI) amino,
where RX and RXI are independently hydrogen or a Cl-C12 alkyl
group; or Cl-C12alcoxyl); or trifluoromethyl;
R19 is hydrogen; substituted or non-substituted Cl-C12 alkyl; a
CORXII group (where RXII is hydrogen; hydroxyl; substituted or
non-substituted Cl-C12 alkyl; substituted or non-substituted C6-
Clo aryl; or N(RXIII) (RXI ) amino, where RXIII and RX14 are
independently hydrogen or a Cl-C12 alkyl group) ; a[(Cl-C12) alkyl-
0- (Cl-C12) alkyl-] n group (where n is comprised between 1 and 3) ;
or trifluoromethyl;
R23 is hydrogen; hydroxyl; halogen; substituted or non-
substituted Cl-C12 alkyl; substituted or non-substituted C6-Clo
aryl; a N(R41) (R411) amino group, where R 1 and R411 are
independently hydrogen or a Cl-Cl2alkyl 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-
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-
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
compound of formula (I) used in the prevention and/or treatment
of a ChoK mediated disease or condition is a compound of formula
(Ic) :

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Rlo Ro
R ll
R1,,~111\ Ra
R13
4 R1 H~ R7
C
R15 = ., Rs
R 16\" " H CHRS
R200 ""'/iRa
I 3C R3
R, R2
R90 R23
R18 R21
(Ic)
where:
5 Rl, R2, R3, R4, R5, R6, R7, R8, Rll and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-
C12 alkyl; substituted or non-substituted C6-Clo aryl; a
N(R')(R ') amino group, where R' and R" are independently
hydrogen or a Cl-C12 alkyl group; or each pair can form a(C=0)
10 group together with the carbon to which they are attached;
R9 and Rlo are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a COR' '' group (where R' ''
is hydrogen; hydroxyl; substituted or non-substituted Cl-Clz
alkyl; substituted or non-substituted C6-Clo aryl; 0-C1-C12 alkyl;
15 or N(R14) (R ) amino, where RI4 and R are independently hydrogen
or a Cl-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, R14, R15, R16, R21 and R23 are independently hydrogen;
20 hydroxyl; halogen; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; a N(R41) (R411) amino
group, where R41 and R411 are independently hydrogen or a Cl-Clz
alkyl group; or each pair can form a(C=0) group together with
the carbon to which they are attached;
25 R18 is hydrogen; hydroxyl; halogen; Cl-C12 alkyl; C6-Clo aryl; CORIX
(where RIX is hydrogen; hydroxyl; Cl-C12 alkyl; N(RX) (RXI) amino,
where RX and RXI are independently hydrogen or a Cl-C12 alkyl
group; or Cl-Cl2alcoxyl); or trifluoromethyl;

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R19 and R20 are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; a CORXII group (where RXII is hydrogen;
hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) alkyl- ]n group (where n is
comprised between 1 and 3); or trifluoromethyl; and
the bond ------ means a double bond or a single bond.
In an embodiment, the compounds of formula (Ic) used in the
present invention comprise a substructure having the following
formula (Ic'):
CH3
0
CH3
CH3
R19O
CH3
R200
CH3
(Ic')
where:
R19 and R20 are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; a CORXII group (where RXII is hydrogen;
hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is
comprised between 1 and 3) or trifluoromethyl; and
the bond ------ means a double bond or a single bond.
Particular examples of this substructure (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) ;

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- 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
(Ic) used in the present invention comprise a substructure
having the following formula (Ic"):
H3 ,C --COOCH~
CH~
CH;
R190 CH3
R200
CH3
(Ic" )
where:
R19 and R20 are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; a CORXII group (where RXII is hydrogen;
hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) 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
acid methyl ester.
In another particular embodiment of the invention, the
compound of formula (I) used in the prevention and/or treatment
of a ChoK mediated disease or condition is a compound of formula
(Id) :

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Rlo Ro
R 11
R12m,,,, Ra
R13 CH~ R~
R15 nRs
R24 R25 C H CHR5
R2o
R20 ;C R3
R, R2
R1o' ; R2s
Rjo
R18 R21
(Id)
where:
Rl, R2, R3, R4, R5, R6, R7, R8, Rll and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-
C12 alkyl; substituted or non-substituted C6-Clo aryl; a
N(R')(R ') amino group, where R' and R" are independently
hydrogen or a Cl-C12 alkyl group; or each pair can form a(C=0)
group together with the carbon to which they are attached;
R9 and Rlo are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a COR' '' group (where R' ''
is hydrogen; hydroxyl; substituted or non-substituted Cl-Cl2
alkyl; substituted or non-substituted C6-Clo aryl; 0-C1-C12 alkyl;
or N(R14) (R ) amino, where RI4 and R are independently hydrogen
or a Cl-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, R15, R21 and R23 are independently hydrogen; hydroxyl;
halogen; substituted or non-substituted Cl-C12 alkyl; substituted
or non-substituted C6-Clo aryl; a N(R41) (R411) amino group, where
R41 and R411 are independently hydrogen or a Cl-C12 alkyl group; or
each pair can form a(C=0) group together with the carbon to
which they are attached;
R18 is hydrogen; hydroxyl; halogen; Cl-C12 alkyl; C6-Clo aryl; CORIX
(where RIX is hydrogen; hydroxyl; Cl-C12 alkyl; N(RX) (RXI) amino,
where RX and RXI are independently hydrogen or a Cl-C12 alkyl
group; or Cl-Cl2alcoxyl); or trifluoromethyl;

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29
R19r R19,, R20 and R20, are independently hydrogen; substituted or
non-substituted Cl-C12 alkyl; a CORXII group (where RXII is
hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) alkyl- ]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 and R25 are independently hydrogen, hydroxyl or halogen; and
the bond ------ means a double bond or a single bond.
In a preferred embodiment, the compounds of formula (Id)
used in the present invention comprise a substructure having the
following formula (Id'):
CH3
O
R
R ~ R%~ 2 CH~
6
R20'
R20ii~ õ CH3
Rlg'
\; ~ R~~
CH3
(Id')
where:
R5 and R6 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted Cl-C12 alkyl; substituted or non-
substituted C6-Clo aryl; a N(R' )(R" ) amino group, where R' and
R" are independently hydrogen or a Cl-C12 alkyl group; or each
pair can form a(C=0) group together with the carbon to which
they are attached;
R19r R19,, R20 and R20, are independently hydrogen; substituted or
non-substituted Cl-C12 alkyl; a CORXII group (where RXII is
hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl

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group) ; a [(Cl-C12) alkyl-0- (Cl-C12) alkyl-] 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 R24 and R25 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-lH-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-lH-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;C C00CH;
CH~
R24 R25
, CH~ CJ'C H;
R 2o~
R20~~ii õ
CH;
\; ~
Rlg'
R~~
CH3
(Id" )
where:
R19r R19,, R20 and R20, are independently hydrogen; substituted or
20 non-substituted Cl-C12 alkyl; a CORXII group (where RXII is
hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) 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;
R24 and R25 are independently hydrogen, hydroxyl or halogen.

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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).
In another particular embodiment of the invention, the
compound of formula (I) used in the prevention and/or treatment
of a ChoK mediated disease or condition is a compound of formula
(Ie) :
Rlo Ro
R11
R12nn,,,. ,"\\\Ra
R14 R13 CH R7
R~6R15 ;
_ ~nR
R2a
H CHRS s
R20 /iRa
R20\\\\",,.
H I NsC R
R, R2
R1 '
R23
Rlo '
R18' R18 R21
(Ie)
where:
Rl, R2, R3, R4, R5, R6, R7, R8, Rll and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-
C12 alkyl; substituted or non-substituted C6-Clo aryl; a
N(R')(R ') amino group, where R' and R" are independently
hydrogen or a Cl-C12 alkyl group; or each pair can form a(C=0)
group together with the carbon to which they are attached;
R9 and Rlo are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a COR' '' group (where R' ''
is hydrogen; hydroxyl; substituted or non-substituted Cl-Clz
alkyl; substituted or non-substituted C6-Clo aryl; 0-C1-C12 alkyl;
or N(R14) (R ) amino, where RI4 and R' are independently hydrogen
or an alkyl group Cl-C12) ; a carbinol group (CH2) n-OH (where n is
an integer comprised between 1 and 10); or together form a
methylene group;
R13, R14, R15, R16, R21 and R23 are independently hydrogen;
hydroxyl; halogen; substituted or non-substituted Cl-C12 alkyl;

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32
substituted or non-substituted C6-Clo aryl; a N(RvI) (RvII) amino
group, where RvI and RvII are independently hydrogen or a Cl-Clz
alkyl group; or each pair can form a(C=0) group together with
the carbon to which they are attached;
R18 and R18, are independently hydrogen; hydroxyl; halogen; Cl-Clz
alkyl; C6-Clo aryl; CORIx (where RIx is hydrogen; hydroxyl; Cl-Clz
alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently
hydrogen or a Cl-C12 alkyl group; or Cl-C12 alcoxyl); or
trifluoromethyl;
R19r R19,, R20 and R20, are independently hydrogen; substituted or
non-substituted Cl-C12 alkyl; a CORxII group (where RxII is
hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(Rxzzz) (Rxzv' amino,
where RxIII and Rxlv are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) alkyl- ]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 is hydrogen, hydroxyl or halogen; and
the bond ------ means a double bond or a single bond.
In a preferred embodiment, the compounds of formula (Ie)
used in the present invention comprise a substructure having the
following formula (Ie'):
H3C ,COOCH;
CH~
Rza
Rzo' CH;
R2011ii1".
CH3 CH;
Rlo
\\\,.
Rio
R, 8 R18
(1e')
where:
R18 and R18, are independently hydrogen; hydroxyl; halogen; Cl-Clz
alkyl; C6-Clo aryl; CORIx (where RIx is hydrogen; hydroxyl; Cl-Clz

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33
alkyl; N(RX) (RXI) amino, where RX and RXI are independently
hydrogen or a Cl-C12 alkyl group; or Cl-C12 alcoxyl); or
trifluoromethyl;
R19r R19,, R20 and R20, are independently hydrogen; substituted or
non-substituted Cl-C12 alkyl; a CORXII group (where RXII is
hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) alkyl- ]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 is hydrogen, hydroxyl or halogen.
A particular example of this substructure (Ie') is 9-
hydroxy-2,4a,6a,9,12b-hexamethyl-10,11-dioxo-
1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydro-
picene-2-carboxylic acid methyl ester (C25).
In another particular embodiment of the invention, the
compound of formula (I) used in the prevention and/or treatment
of a ChoK mediated disease or condition is a compound of formula
(If) :
Rlo Ro
R11
R12um,,, Ra
R1;
R14 CH~ R7
R15 R6
R2a
CH~ H CHR5
R2o
R20""" ;C Rs
Rio' R, R2
R23
Rlo
R1g' R18 R21
(If)
where:

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34
Rl, R2, R3, R4, R5, R6, R,, R8, Rll and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-
C12 alkyl; substituted or non-substituted C6-Clo aryl; a
N(R')(R ') amino group, where R' and R" are independently
hydrogen or a Cl-C12 alkyl group; or each pair can form a(C=0)
group together with the carbon to which they are attached;
R9 and Rlo are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a COR' '' group (where R' ''
is hydrogen; hydroxyl; substituted or non-substituted Cl-Clz
alkyl; substituted or non-substituted C6-Clo aryl; 0-C1-C12 alkyl;
or N(R14) (R ) amino, where RI4 and R are independently hydrogen
or a Cl-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, R14, R15, R21 and R23 are independently hydrogen; hydroxyl;
halogen; substituted or non-substituted Cl-C12 alkyl; substituted
or non-substituted C6-Clo aryl; a N(R41) (R411) amino group, where
R41 and R411 are independently hydrogen or a Cl-C12 alkyl group; or
each pair can form a(C=0) group together with the carbon to
which they are attached;
R18 and R18, are independently hydrogen; hydroxyl; halogen; Cl-Clz
alkyl; C6-Clo aryl; CORIX (where RIX is hydrogen; hydroxyl; Cl-Clz
alkyl; N(RX) (RXI) amino, where RX and RXI are independently
hydrogen or a Cl-C12 alkyl group; or Cl-C12 alcoxyl) or
trifluoromethyl;
R19r R19,, R20 and R20, are independently hydrogen; substituted or
non-substituted Cl-C12 alkyl; a CORXII group (where RXII is
hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) alkyl- ]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 is hydrogen, hydroxyl or halogen; and
the bond ------ means a double bond or a single bond.

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In a preferred embodiment, the compounds of formula (If)
used in the present invention comprise a substructure having the
following formula (If'):
H;C 'COOCH;
CH~
R2a
CH3 CH;
R19
R20' R20i~~~
CH;
R lg'
9
R, 8R1a
5 (If'~
where:
R18 and R18, are independently hydrogen; hydroxyl; halogen; Cl-Clz
alkyl; C6-Clo aryl; CORIX (where RIX is hydrogen; hydroxyl; Cl-Clz
alkyl; N(RX) (RXI) amino, where RX and RXI are independently
10 hydrogen or a Cl-C12 alkyl group; or Cl-C12 alcoxyl); or
trifluoromethyl;
R19r R19,, R20 and R20, are independently hydrogen; substituted or
non-substituted Cl-C12 alkyl; a CORXII group (where RXII is
hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
15 substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-O- (Cl-C12) 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;
R24 is hydrogen, hydroxyl or halogen.
A particular example of this substructure (If') is the 9-
hydroxy-2,4a,6a,6b,9-hexamethyl-10,11-dioxo-
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

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36
of a ChoK mediated disease or condition is a compound of formula
(IIa) :
R7 R8
R6
Rg
R5 in/,,,
;
R2~ 2 R
R
a R1o
R
R23 "'IR11
Cr13,12
R16 -11ii1IR13
R22 R19 R17 R14
R21 R20 R16 R15
(IIa)
where:
Rlr R2, R3, R4, R5, R6r R9r Rlor Rllr R12r R13r R14r R15r R16r R17r R1ar
R19 and R20 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted Cl-C12 alkyl; substituted or non-
substituted C6-Clo aryl; a N(Rxv) (Rxvz) amino group, where Rxv and
Rxvl are independently hydrogen or a Cl-C12 alkyl group; or each
pair can form a carboxyl (C=O) group together with the carbon to
which they are attached;
R7 and R8 are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a CORxvII group (where Rxvzz
is hydrogen; hydroxyl; substituted or non-substituted Cl-C12
alkyl; substituted or non-substituted C6-Clo aryl; O-Cl-C12 alkyl;
or N(Rxvzzz) (Rxzx) amino, where RxvIII and Rxlx are independently
hydrogen or a Cl-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,
R21 and R24 are independently substituted or non-substituted Cl-
C12 alkyl; a CORxx group (where Rxx is hydrogen; hydroxyl;
substituted or non-substituted Cl-C12 alkyl; substituted or non-
substituted C6-Clo aryl; or N(Rxxz) (Rxxzz) amino, where Rxxl and Rxxzz
are independently hydrogen or a Cl-C12 alkyl group) ; a[(Cl-
C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is comprised between 1
and 3); or trifluoromethyl;
R22 and R23 are:
- hydrogen; substituted or non-substituted Cl-C12 alkyl; a
CORxxIII group (where RxxIII is hydrogen; hydroxyl;

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37
substituted or non-substituted Cl-C12 alkyl; substituted or
non-substituted C6-Clo aryl; or N(Rxxzv) (Rxxv) amino, where
Rxxiv and Rxxv are independently hydrogen or a Cl-C12 alkyl
group) ; a[(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is
comprised between 1 and 3); or trifluoromethyl when R24 is
in the para position with respect to R20; or
OR22' and OR23' respectively, where R22' and R23' are
independently hydrogen; substituted or non-substituted Cl-
C12 alkyl; a CORxxvz group (where Rxxvz is hydrogen; hydroxyl;
substituted or non-substituted Cl-C12 alkyl; substituted or
non-substituted C6-Clo aryl; or N(Rxxvzz) (Rxxvzzz) amino, where
Rxxviz and Rxxvzzz are independently hydrogen or a Cl-C12 alkyl
group) ; a[(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is
comprised between 1 and 3); or trifluoromethyl when R24 is
in the meta position with respect to Rzo=
In a preferred embodiment, the compounds of formula (IIa)
used in the present invention comprise a substructure having the
following formula (IIa'):
H3C '--COOCH;
R2a
R23 11 CH3
R22 R19
R21 R20
(IIa')
where:
R19 and R20 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted Cl-C12 alkyl; substituted or non-
substituted C6-Clo aryl; a N(Rxv) (Rxvz) amino group, where Rxv and
Rxvl are independently hydrogen or a Cl-C12 alkyl group; or each
pair can form a(C=0) carboxyl group together with the carbon to
which they are attached;
R21 and R24 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted Cl-C12 alkyl; substituted or non-
substituted C6-Clo aryl; a N(Rxxz) (Rxxzz) amino group, where Rxxl and

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38
RxxII are inde endentl h dro en or a C C alk 1 rou
p Y Y g ~- ~z Y g p; or each
pair can form a(C=0) carboxyl group together with the carbon to
which they are attached;
R22 and R23 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted Cl-Clz alkyl; substituted or non-
substituted C6-Clo aryl; a N(Rxxzv) (Rxxv) amino group, where Rxxzv
and Rxxv are independently hydrogen or a Cl-Clz alkyl group; or
each pair can form a(C=0) 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-
tetramethyl-1,2,3,4,4a,5,6,7-octahydro-naphthalen-2-carboxylic
acid methyl ester (C27).
The compounds of the invention act as blocking agents of
the biosynthesis of phosphorylcholine by means of the selective
blocking of the choline kinase (ChoK) enzyme and have shown a
selective effect on signaling pathways necessary for the
transformation by certain oncogenes which do not affect normal
cells with the same intensity and therefore leave a sufficient
margin for a greater efficacy in the tumor treatment.
Accordingly, in a particular embodiment, the Chok mediated
disease or condition to be prevented or treated is cancer,
preferably selected from breast, lung, colorectal and pancreatic
cancer.
On the other hand, the biological assays carried out allow
extending the use of the compounds described in the present
invention for the treatment of viral, parasitic, bacterial and
fungal conditions because some parasites such as Plasmodium
falciparum or Trypanosoma cruci, some viruses such as
adenovirus, bacteria such as Streptococcus pneumoniae and fungi
such as Candida albicans require the metabolic
phosphatidylcholine synthesis pathway through choline kinase to
complete its infective cycles in humans and animals. In this
sense, the bibliographic background supports the role of the
ChoK enzyme in the intracellular metabolism of certain

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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.
Consequently, in another embodiment the ChoK mediated
disease or condition to be prevented and/or treated is a viral
disease, preferably that caused by Adenovirus.
In another embodiment the ChoK mediated disease or
condition to be prevented and/or treated is a parasitic disease,
preferably that caused by Plasmodium or Trypanosoma.
In another embodiment the ChoK mediated disease or
condition to be prevented and/or treated is bacterial disease,
preferably that caused by Streptococcus.
In another embodiment the ChoK mediated disease or
condition to be prevented and/or treated is a fungal disease,
preferably that caused by Candida.
Another object of the present invention are the compounds
of general formula (I):
Rlo Ro
Rll
R12i R8
CH ,.. R7
-111iRs
(~ H CH3R5
R
a
~ ~~ Hsc R3
R, R2
(I)
where:
Rl, R2, R3, R4, R5, R6, R7, R8, Rll and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-
C12 alkyl; substituted or non-substituted C6-Clo aryl; a
N(R')(R ') amino group, where R' and R" are independently
hydrogen or a Cl-C12 alkyl group; an OCOR group, where R is
(CH2) 2COOH or (CH2) 2CO2CH2CH3; or each pair can form a(C=0) group
together with the carbon to which they are attached;

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R9 and Rlo are independently hydrogen; substituted or non-
substituted Cl-Clz alkyl; C6-Clo aryl; a COR' '' group (where R' ''
is hydrogen; hydroxyl; substituted or non-substituted Cl-Clz
alkyl; substituted or non-substituted C6-Clo aryl; 0-Cl-Clz alkyl;
5 or N(R14) (R ) amino, where RI4 and R are independently hydrogen
or a Cl-Clz alkyl group); a(CH2)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:
R14 R13 R14 R13 R14 Ris
R RI s R15
tr;~~oõ~ Rw \o ,,,.
R
tr,
0 RzoO Rzo0
R R17
R zO R,,o R,,)O Rz3
Ria Ria R21 R22 Ria R21
(a) (b) (c)
R 13 Ria Ris R1a Ris
R15 RR1~Rza RiS
Rza RzSCH
CH,
R2~j Rz0 Rzo
R ,,,. Rzo """,. ~ Rzo "'~=.
o CH,
R~~ ~ Ric' Ric'
R2; Rz. Rz.
R~~ R~~ R
Rie R21 Rie~ ~Rip, R21 Rie' Rip, Rz,
(d) (e) (f)
where:
R13, R14, R15, R16, R21, R22 and R23 are independently hydrogen;
hydroxyl; halogen; substituted or non-substituted Cl-Clz alkyl;

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41
substituted or non-substituted C6-Clo aryl; a N(R41) (R411) amino
group, where R41 and R411 are independently hydrogen or a Cl-C12
alkyl group; an OCOR III group, where R III is (CH2) 2COOH or
(CH2) 2CO2CH2CH3; or each pair can form a(C=0) 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;
R17 is hydrogen or methyl;
R18 and R18, are independently hydrogen; hydroxyl; halogen; Cl-C12
alkyl; C6-Clo aryl; CORIX (where RIX is hydrogen; hydroxyl; Cl-C12
alkyl; N(RX) (RXI) amino, where RX and RXI are independently
hydrogen or a Cl-C12 alkyl group; or Cl-C12 alcoxyl); or
trifluoromethyl;
R19r R19,, R20 and R20, are independently hydrogen; substituted or
non-substituted Cl-C12 alkyl; a CORXII group (where RXII is
hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 and R25 are independently hydrogen, hydroxyl or halogen;
or a pharmaceutically acceptable salt, derivative, prodrug,
solvate or stereoisomer thereof, with the following provisos:
- when the tricyclic structure is (a) then the compound of
formula (I) is not:
- 10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-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-
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-

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tetradecahydro-picene-2-carboxylic acid methyl
ester;
- 3-Hydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-
picene-2,10-dione;
- 3,9-Dihydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-
picene-2,10-dione;
- 3,7,9-Trihydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-
picene-2,10-dione;
- 14-Bromo-3,7,9-trihydroxy-4,6b,8a,11,12b,14a-
hexamethyl-7,8,8a,11,12,12a,12b,13,14,14a-
decahydro-6bH,9H-picene-2,10-dione;
- Succinic acid mono-(10-hydroxy-2,4a,6a,9,12b,14a-
hexamethyl-3,11-dioxo-
1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-
tetradecahydro-picen-4-yl) ester;
- Succinic acid ethyl ester 10-hydroxy-
2,4a,6a,9,12b,14a-hexamethyl-3,11-dioxo-
1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-
tetradecahydro-picen-4-yl ester;
- Acetic acid 9-hydroxy-4,6b,8a,11,12b,14a-
hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- Dodecanoic acid 9-hydroxy-4,6b,8a,11,12b,14a-
hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- Dimethyl-carbamic acid 9-hydroxy-
4,6b,8a,11,12b,14a-hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- Nicotinic acid 9-hydroxy-4,6b,8a,11,12b,14a-
hexamethyl-2,10-dioxo-

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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-
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.
- when the tricyclic structure is (b) and R19 and R20 are
independently hydrogen or an acyl group, then:
- R5 is hydroxyl; or
- R21 and R22 form a C=O group together with the
carbon to which they are attached and Rlo is not
COOH.
- when the tricyclic structure is (c) and R19 and R20 are
both CH3, then R15 and R16 do not form a C=O group together
with the carbon to which they are attached.
In one particular aspect, the invention is directed to
compounds of formula (Ia):
Rio Ro
R> > Ra
Ris Ri2iii111,,. ,-' JR7
Ris -11iiRo
CH3 Rs
O
H3C R3
R i R2
R1gO
R18
(Ia)
where
Rl, R2, R3, R4, R5, R6, R7, R8, Rll and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-
C12 alkyl; substituted or non-substituted Co-Clo aryl; a
N(R')(R ') amino group, where R' and R" are independently

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44
hydrogen or a Cl-C12 alkyl group; an OCOR group, where R is
(CH2) 2COOH or (CH2) 2CO2CH2CH3; or each pair can form a(C=0) group
together with the carbon to which they are attached;
R9 and Rlo are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a COR' '' group (where R' ''
is hydrogen; hydroxyl; substituted or non-substituted Cl-Clz
alkyl; substituted or non-substituted C6-Clo aryl; 0-C1-C12 alkyl;
or N(R14) (R ) amino, where RI4 and R' are independently hydrogen
or a Cl-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, R14, R15 and R16 are independently hydrogen; hydroxyl;
halogen; substituted or non-substituted Cl-C12 alkyl; substituted
or non-substituted C6-Clo aryl; a N(R41) (R411) amino group, where
R41 and R411 are independently hydrogen or a Cl-C12 alkyl group; an
OCOR III group, where R III is (CH2) 2COOH or (CH2) 2CO2CH2CH3; or each
pair can form a(C=0) group together with the carbon to which
they are attached;
R17 is hydrogen or methyl;
R18 is hydrogen; hydroxyl; halogen; Cl-C12 alkyl; C6-Clo aryl; CORIX
(where RIX is hydrogen; hydroxyl; Cl-C12 alkyl; N(RX) (RXI) amino,
where RX and RXI are independently hydrogen or a Cl-C12 alkyl
group; or Cl-C12alcoxyl); or trifluoromethyl;
R19 is hydrogen; substituted or non-substituted Cl-C12 alkyl; a
CORXII group (where RXII is hydrogen; hydroxyl; substituted or
non-substituted Cl-C12 alkyl; substituted or non-substituted C6-
Clo aryl; or N(RXIII) (RXI ) amino, where RXIII and RX14 are
independently hydrogen or a Cl-C12 alkyl group) ; a[(Cl-C12) alkyl-
0- (Cl-C12) alkyl-] n group (where n is comprised between 1 and 3) ;
or trifluoromethyl; and
the bond ------ means a double bond or a single bond,
with the proviso that the compound of formula (Ia) is not:
- 10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-11-oxo-
1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro-
picene-2-carboxylic acid;

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- 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;

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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.
In a preferred embodiment, the compounds of formula (Ia)
comprise a substructure having the following formula (Ia'):
CH3
R7
CH3
R5
CH3
CH;
O *61
R19O CH3
(Ia')
where
R5 is hydroxyl or a OCOR group where R is (CH2) 2COOH or
(CH2) 2CO2CH2CH3;
R7 and R8 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted Cl-C12 alkyl; substituted or non-
substituted C6-Clo aryl; a N(R' )(R" ) amino group, where R' and
R" are independently hydrogen or a Cl-C12 alkyl group; or each
pair can form a(C=0) group together with the carbon to which
they are attached;
R12 is independently hydrogen or a halogen; and
R19 is hydrogen; substituted or non-substituted Cl-C12 alkyl; a
CORXII group (where RXII is hydrogen; hydroxyl; substituted or
non-substituted Cl-C12 alkyl; substituted or non-substituted C6-
Clo aryl; or N(RXIII) (RXI ) amino, where RXIII and RX14 are
independently hydrogen or a Cl-C12 alkyl group) ; a[(Cl-C12) alkyl-
0- (Cl-C12) alkyl-] n group (where n is comprised between 1 and 3) ;
or trifluoromethyl; and
the bond ------ means a double bond or a single bond,
with the proviso that the compound of formula (Ia') is not:

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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-
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;
- 3-Hydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-2,10-
dione;
- 3,9-Dihydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-2,10-
dione;
- 3,7,9-Trihydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-2,10-
dione;
- 14-Bromo-3,7,9-trihydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-2,10-
dione;
- Succinic acid mono-(10-hydroxy-2,4a,6a,9,12b,14a-hexamethyl-
3,11-dioxo-1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-
tetradecahydro-picen-4-yl) ester;
- Succinic acid ethyl ester 10-hydroxy-2,4a,6a,9,12b,14a-
hexamethyl-3,11-dioxo-
1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro-picen-
4-yl ester;
- Acetic acid 9-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-2,10-
dioxo-2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- Dodecanoic acid 9-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-
2,10-dioxo-2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picen-3-yl ester;
- Dimethyl-carbamic acid 9-hydroxy-4,6b,8a,11,12b,14a-
hexamethyl-2,10-dioxo-

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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-
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-
1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro-
picene-2-carboxylic acid methyl ester.
Particular examples of this substructure (Ia') are:
- 9-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-
picene-3-yl propionic acid ester (C1);
- 4-bromo-(9-hydroxy-6b,8a,11,12b,14a-hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-
picene-3-yl) benzoic acid ester (C2);
- 12-bromo-3,9-dihydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-
2,10-dione (C3);
- 12-bromo-9-hydroxy-6b,8a,11,12b,14a-hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-
picene-3-yl dimethyl-carbamic acid ester (C4);
- 4-bromo-(12-bromo-9-hydroxy-6b,8a,11,12b,14a-hexamethyl-
2,10-dioxo-2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picene-3-yl) benzoic acid ester (C5);
- 3,9,10-trihydroxy-6b,8a,11,12b,14a-hexamethyl-
7,8,8a,9,10,11,12,12a,12b,13,14,14a-dodecahydro-6bH-
picene-2-one (C6).
In another preferred embodiment, the compounds of formula
(Ia) comprise a substructure having the following formula
(Ia"):

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CH3
R7
~~uRa
C_H~
R15 =
CH3
O
CHJ~ CH3
R19O
C H;
(Ia" )
where:
R7 and R8 are independently hydrogen, hydroxyl, halogen,
substituted or non-substituted Cl-C12 alkyl, substituted or non-
substituted C6-Clo aryl, a N(R' )(R" ) amino group, where R' and
R'' are independently hydrogen or a Cl-C12 alkyl group, or each
pair can form a(C=0) group together with the carbon to which
they are attached;
R15 is hydrogen or halogen;
R19 is hydrogen, substituted or non-substituted Cl-C12 alkyl; a
CORXII group (where RXII is hydrogen; hydroxyl; substituted or
non-substituted Cl-C12 alkyl; substituted or non-substituted C6-
Clo aryl; or N(RXIII) (RXI ) amino, where RXIII and RX14 are
independently hydrogen or a Cl-C12 alkyl group) ; a[(Cl-C12) alkyl-
0- (Cl-C12) alkyl-] n group (where n is comprised between 1 and 3) ;
or trifluoromethyl; and
the bond ------ means a double bond or a single bond,
with the proviso that the compound of formula (Ia ") is not:
- 3-Hydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,9,10,11,12,12a,12b,13,14,14a-dodecahydro-6bH-picen-
2-one;
- 3-Hydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-
2,10-dione.
Particular examples of this substructure (Ia'') are:

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-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 (C10);
-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 (C11) .
In another preferred embodiment, the compounds of formula
(Ia) comprise a substructure having the following formula
(Ia,,,) :
H;C ,COOCH;
R7
CH~
CH3
O ~
CH~ CH;
~ ~ J
R19O
20 H;
(Ia,,,)
where:
R7 is hydrogen, hydroxyl, halogen, substituted or non-
substituted Cl-C12 alkyl, substituted or non-substituted C6-Clo
25 aryl, or a N(R' )(R" ) amino group, where R' and R" are
independently hydrogen or a Cl-C12 alkyl group; and
R19 is substituted or non-substituted Cl-C12 alkyl; a CORXII group
(where RXII is hydrogen; hydroxyl; substituted or non-substituted
Cl-C12 alkyl; substituted or non-substituted C6-Clo aryl; or

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N(RXIII) (RXI ) amino, where RXIII and RX14 are independently hydrogen
or a Cl-C12 alkyl group) ; a[(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group
(where n is comprised between 1 and 3); or trifluoromethyl;
with the proviso that the compound of formula (Ia "') is not:
- 3,10-Dihydroxy-2,4a,6a,9,12b,14a-hexamethyl-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-
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-
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
compounds of formula (Ib):
Rlo Ro
R ll
R1,,~111\ Ra
R13
R~~ DH R~
R15 R6
R16' .......
H CH3R5
R200 ""'/iRa
I I R17 NsC R3
R, R2
R1oO R23
R18 R21 R22
(Ib)
where:
Rl, R2, R3, R4, R5, R6, R7, R8, Rll and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-
C12 alkyl; substituted or non-substituted C6-Clo aryl; a
N(R')(R ') amino group, where R' and R" are independently

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52
hydrogen or a Cl-C12 alkyl group; or each pair can form a(C=0)
group together with the carbon to which they are attached;
R9 and Rlo are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a COR' '' group (where R' ''
is hydrogen; hydroxyl; substituted or non-substituted Cl-Clz
alkyl; substituted or non-substituted C6-Clo aryl; 0-C1-C12 alkyl;
or N(R14) (R ) amino, where RI4 and R are independently hydrogen
or a Cl-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, R14, R15, R16, R21, R22 and R23 are independently hydrogen;
hydroxyl; halogen; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; a N(R41) (R411) amino
group, where R41 and R411 are independently hydrogen or a Cl-Clz
alkyl group; or each pair can form a(C=0) group together with
the carbon to which they are attached;
R17 is hydrogen or methyl;
R18 is hydrogen; hydroxyl; halogen; Cl-C12 alkyl; C6-Clo aryl; CORIX
(where RIX is hydrogen; hydroxyl; Cl-C12 alkyl; N(RX) (RXI) amino,
where RX and RXI are independently hydrogen or a Cl-C12 alkyl
group; or Cl-C12 alcoxyl) ; or trifluoromethyl;
R19 and R20 are independently hydrogen, substituted or non-
substituted Cl-C12 alkyl; a CORXII group (where RXII is hydrogen;
hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is
comprised between 1 and 3); or trifluoromethyl; and
the bond ------ means a double bond or a single bond,
with the proviso that when R19 and R20 are independently hydrogen
or an acyl group, then:
R5 is hydroxyl; or
R21 and R22 form a C=O group together with the carbon to
which they are attached and Rlo is not COOH.
In another preferred embodiment, the compounds of formula
(Ib) comprise a substructure having the following formula (Ib'):

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CH3
O
CH~
OH
CH;
R200
CH~ CH;
R19O
CH; OH
(Ib')
where:
R19 and R20 are independently substituted or non-substituted Cl-
C12 alkyl; a CORxII group (where RxII is hydrogen; hydroxyl;
substituted or non-substituted Cl-C12 alkyl; substituted or non-
substituted C6-Clo aryl; or N(RxIII) (RxI ) amino, where RxIII and Rxzv
are independently hydrogen or a Cl-C12 alkyl group); a[(Cl-
C12) alkyl-O- (Cl-C12) alkyl-] n group (where n is comprised between 1
and 3); or trifluoromethyl.
A particular example of this substructure (Ib') is 4-nitro-
(3-dimethylcarbamoyloxy-5,9-dihydroxy-4,6b,8a,11,12b,14a-
hexamethyl-10-oxo-5,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-
tetradecahydro-picene-2-yl) benzoic acid ester (C15).
In another preferred embodiment, the compounds of formula
(Ib) comprise a substructure having the following formula
(Ib"):
H3COOC CH;
H~
CH;
HO I CH~ CH;
R190 R2s
R18 O
(Ib" )
where:

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R18 is hydrogen; hydroxyl; halogen; Cl-C12 alkyl; C6-Clo aryl; CORIX
(where RIX is hydrogen; hydroxyl; Cl-C12 alkyl; N(RX) (RXI) amino,
where RX and RXI are independently hydrogen or a Cl-C12 alkyl
group; or Cl-C12alcoxyl); or trifluoromethyl;
R19 is hydrogen; substituted or non-substituted Cl-C12 alkyl; a
CORXII group (where RXII is hydrogen; hydroxyl; substituted or
non-substituted Cl-C12 alkyl; substituted or non-substituted C6-
Clo aryl; or N(RXIII) (RXI ) amino, where RXIII and RX14 are
independently hydrogen or a Cl-C12 alkyl group) ; a[(Cl-C12) alkyl-
0- (Cl-C12) alkyl-] n group (where n is comprised between 1 and 3) ;
or trifluoromethyl;
R23 is hydrogen; hydroxyl; halogen; substituted or non-
substituted Cl-C12 alkyl; substituted or non-substituted C6-Clo
aryl; a N(R41) (R411) amino group, where R 1 and R411 are
independently hydrogen or a Cl-Cl2alkyl 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-
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-
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
compounds of formula (Ic):

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Rlo Ro
R ll
R12iu,,,, ,,~111\ Ra
R13
R1 4 H~ R7
C
R15 = ., Rs
R 16\" " H CHRS
R200 ""'/iRa
I 3C R3
R, R2
R1oO Rz3
R18 R21
(Ic)
where:
5 Rl, R2, R3, R4, R5, R6, R7, R8, Rll and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-
C12 alkyl; substituted or non-substituted C6-Clo aryl; a
N(R')(R ') amino group, where R' and R" are independently
hydrogen or a Cl-C12 alkyl group; or each pair can form a(C=0)
10 group together with the carbon to which they are attached;
R9 and Rlo are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a COR' '' group (where R' ''
is hydrogen; hydroxyl; substituted or non-substituted Cl-Clz
alkyl; substituted or non-substituted C6-Clo aryl; 0-C1-C12 alkyl;
15 or N(R14) (R ) amino, where RI4 and R are independently hydrogen
or a Cl-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, R14, R15, R16, R21 and R23 are independently hydrogen;
20 hydroxyl; halogen; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; a N(R41) (R411) amino
group, where R41 and R411 are independently hydrogen or a Cl-Clz
alkyl group; or each pair can form a(C=0) group together with
the carbon to which they are attached;
25 R18 is hydrogen; hydroxyl; halogen; Cl-C12 alkyl; C6-Clo aryl; CORIX
(where RIX is hydrogen; hydroxyl; Cl-C12 alkyl; N(RX) (RXI) amino,
where RX and RXI are independently hydrogen or a Cl-C12 alkyl
group; or Cl-Cl2alcoxyl); or trifluoromethyl;

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R19 and R20 are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; a CORXII group (where RXII is hydrogen;
hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) alkyl- ]n group (where n is
comprised between 1 and 3); or trifluoromethyl; and
the bond ------ means a double bond or a single bond,
with the proviso that when R19 and R20 are both CH3, then R15 and
R16 do not form a C=O group together with the carbon to which
they are attached.
In a preferred embodiment, the compounds of formula (Ic)
comprise a substructure having the following formula (Ic'):
CH3
0
CH~
CH3
R19O
CH3
R200
CH3
(Ic')
where:
R19 and R20 are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; a CORXII group (where RXII is hydrogen;
hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is
comprised between 1 and 3) or trifluoromethyl; and
the bond ------ means a double bond or a single bond.
Particular examples of this substructure (Ic') are:

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- 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-
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"):
H3C \--COOCH3
CH~
CH3
R190 CH3
R200
CH3
(Ic" )
where:
R19 and R20 are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; a CORXII group (where RXII is hydrogen;
hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) 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
acid methyl ester (C21).
In another particular aspect, the invention is directed to
compounds of formula (Id):

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Rlo Ro
R 11
R12m,,,, Ra
R13 CH~ R~
R15 nRs
R24 R25 C H CHR5
R2o
R20 ;C R3
R, R2
R1o' ; R2s
Rjo
R18 R21
(Id)
where:
Rl, R2, R3, R4, R5, R6, R7, R8, Rll and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-
C12 alkyl; substituted or non-substituted C6-Clo aryl; a
N(R')(R ') amino group, where R' and R" are independently
hydrogen or a Cl-C12 alkyl group; or each pair can form a(C=0)
group together with the carbon to which they are attached;
R9 and Rlo are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a COR' '' group (where R' ''
is hydrogen; hydroxyl; substituted or non-substituted Cl-Cl2
alkyl; substituted or non-substituted C6-Clo aryl; 0-C1-C12 alkyl;
or N(R14) (R ) amino, where RI4 and R are independently hydrogen
or a Cl-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, R15, R21 and R23 are independently hydrogen; hydroxyl;
halogen; substituted or non-substituted Cl-C12 alkyl; substituted
or non-substituted C6-Clo aryl; a N(R41) (R411) amino group, where
R41 and R411 are independently hydrogen or a Cl-C12 alkyl group; or
each pair can form a(C=0) group together with the carbon to
which they are attached;
R18 is hydrogen; hydroxyl; halogen; Cl-C12 alkyl; C6-Clo aryl; CORIX
(where RIX is hydrogen; hydroxyl; Cl-C12 alkyl; N(RX) (RXI) amino,
where RX and RXI are independently hydrogen or a Cl-C12 alkyl
group; or Cl-Cl2alcoxyl); or trifluoromethyl;

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R19r R19,, R20 and R20, are independently hydrogen; substituted or
non-substituted Cl-C12 alkyl; a CORXII group (where RXII is
hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) alkyl- ]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 and R25 are independently hydrogen, hydroxyl or halogen; 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'):
CH3
O
C_H~
= R5
R%4RCH; HR6
R2o
R20u~
CH3
Rig'
Rlg
CH;
(Id')
where:
R5 and R6 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted Cl-C12 alkyl; substituted or non-
substituted C6-Clo aryl; a N(R' )(R" ) amino group, where R' and
R" are independently hydrogen or a Cl-C12 alkyl group; or each
pair can form a(C=0) group together with the carbon to which
they are attached;
R19r R19,, R20 and R20, are independently hydrogen; substituted or
non-substituted Cl-C12 alkyl; a CORXII group (where RXII is
hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is

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comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 and R25 are independently hydrogen, hydroxyl or halogen.
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-lH-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-lH-picene-2,3,10-
trione (C23).
In another preferred embodiment, the compounds of formula
(Id) comprise a substructure having the following formula
(Id"):
H3C OOCH;
CH~
R24 R25
CH~ CH;
R20' R20~~ii
CH3
Rlo'
Rlo
15 CH;
(Id" )
where:
R19r R19,, R20 and R20, are independently hydrogen; substituted or
non-substituted Cl-C12 alkyl; a CORXII group (where RXII is
20 hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) 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;
R24 and R25 are independently hydrogen, hydroxyl or halogen.

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A particular example of this substructure (Id ' ) is 12-
bromo-2,4a,6a,9,12a,14a-hexamethyl-10,11-dioxo-
1,2,3,4,4a,5,6,6a,10,11,12,12a,14a,14b-tetradecahydro-picene-2-
carboxylic acid methyl ester (C24).
In another particular aspect, the invention is directed to
compounds of formula (Ie):
R1o Ro
R11
R12u~~,,,
R13
R14 CH R7
R15 ;
,111nR6
16
R2a
H CHRS
R2o' "/R
a
\\\~~~,,,
R20 CH , H3C R3
R1o' R1 R2
~ R23
R1o
R1g' R18 R21
(Ie)
where:
Rl, R2, R3, R4, R5, R6, R7, R8, Rll and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-
C12 alkyl; substituted or non-substituted C6-Clo aryl; a
N(R')(R ') amino group, where R' and R" are independently
hydrogen or a Cl-C12 alkyl group; or each pair can form a(C=0)
group together with the carbon to which they are attached;
R9 and Rlo are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a COR' '' group (where R' ''
is hydrogen; hydroxyl; substituted or non-substituted Cl-Cl2
alkyl; substituted or non-substituted C6-Clo aryl; 0-C1-C12 alkyl;
or N(R14) (R ) amino, where RI4 and R are independently hydrogen
or an alkyl group Cl-C12) ; a carbinol group (CH2) n-OH (where n is
an integer comprised between 1 and 10); or together form a
methylene group;
R13, R14, R15, R16, R21 and R23 are independently hydrogen;
hydroxyl; halogen; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; a N(R41) (R411) amino
group, where R41 and R411 are independently hydrogen or a Cl-Cl2

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62
alkyl group; or each pair can form a (C=O) group together with
the carbon to which they are attached;
R18 and R18' are independently hydrogen; hydroxyl; halogen; Cl-Clz
alkyl; C6-Clo aryl; CORIx (where RIx is hydrogen; hydroxyl; Cl-Clz
alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently
hydrogen or a Cl-C12 alkyl group; or Cl-C12 alcoxyl); or
trifluoromethyl;
R19r R19,, R20 and R20, are independently hydrogen; substituted or
non-substituted Cl-C12 alkyl; a CORxII group (where RxII is
hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(Rxzzz) (Rxzv' amino,
where RxIII and Rxlv are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-O- (Cl-C12) alkyl-] n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 is hydrogen, hydroxyl or halogen; and
the bond ------ means a double bond or a single bond.
In a preferred embodiment, the compounds of formula (Ie)
comprise a substructure having the following formula (Ie'):
H3C ,COOCH;
CH~
R2a
CH;
R20'
R2011ii1".
CH~ CH;
Rlg
.~'Rig ";
R18' R18
(1e')
where:
R18 and R18, are independently hydrogen; hydroxyl; halogen; Cl-Clz
alkyl; C6-Clo aryl; CORIx (where RIx is hydrogen; hydroxyl; Cl-Clz
alkyl; N(Rx) (RxI) amino, where Rx and RxI are independently
hydrogen or a Cl-C12 alkyl group; or Cl-C12 alcoxyl) or
trifluoromethyl;

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R19r R19,, R20 and R20, are independently hydrogen; substituted or
non-substituted Cl-C12 alkyl; a CORXII group (where RXII is
hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) alkyl- ]n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 is hydrogen, hydroxyl or halogen.
A particular example of this substructure (Ie') is 9-
hydroxy-2,4a,6a,9,12b-hexamethyl-10,11-dioxo-
1,2,3,4,4a,5,6,6a,9,10,11,12b,13,14,14a,14b-hexadecahydro-
picene-2-carboxylic acid methyl ester (C25).
In another particular aspect, the invention is directed to
compounds of formula (If):
Rlo Ro R12m,,,, ,,\\\ Ra
R1a 131
R~
CH3
R15 = R6
R2a
CH~ H CHR5
R20
""'/iRa
\\\\~,,,.
R20 3C Rs
R, R2
Rlo'
R2s
R1o
R1g' R18 R21
(If)
where:
Rl, R2, R3, R4, R5, R6, R,, R8, Rll and R12 are independently
hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-
C12 alkyl; substituted or non-substituted C6-Clo aryl; a
N(R')(R ') amino group, where R' and R" are independently
hydrogen or a Cl-C12 alkyl group; or each pair can form a(C=0)
group together with the carbon to which they are attached;

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R9 and Rlo are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a COR' '' group (where R' ''
is hydrogen; hydroxyl; substituted or non-substituted Cl-Clz
alkyl; substituted or non-substituted C6-Clo aryl; 0-C1-C12 alkyl;
or N(R14) (R ) amino, where RI4 and R are independently hydrogen
or a Cl-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, R14, R15, R21 and R23 are independently hydrogen; hydroxyl;
halogen; substituted or non-substituted Cl-C12 alkyl; substituted
or non-substituted C6-Clo aryl; a N(R41) (R411) amino group, where
R41 and R411 are independently hydrogen or a Cl-C12 alkyl group; or
each pair can form a(C=0) group together with the carbon to
which they are attached;
R18 and R18, are independently hydrogen; hydroxyl; halogen; Cl-Clz
alkyl; C6-Clo aryl; CORIX (where RIX is hydrogen; hydroxyl; Cl-Clz
alkyl; N(RX) (RXI) amino, where RX and RXI are independently
hydrogen or a Cl-C12 alkyl group; or Cl-C12 alcoxyl); or
trifluoromethyl;
R19r R19,, R20 and R20, are independently hydrogen; substituted or
non-substituted Cl-C12 alkyl; a CORXII group (where RXII is
hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is
comprised between 1 and 3); trifluoromethyl; or each 19-19' or
20-20' pair can form a C=O group together with the carbon to
which they are attached;
R24 is hydrogen, hydroxyl or halogen; and
the bond ------ means a double bond or a single bond.
In a preferred embodiment, the compounds of formula (If)
comprise a substructure having the following formula (If'):

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H3C \COOCH;
CH~
R2a
CH3 CH3
R2o'
R20i~~
CH3
Rlg
R ~~
R18 R18
(If')
where:
R18 and R18, are independently hydrogen; hydroxyl; halogen; Cl-Clz
5 alkyl; C6-Clo aryl; CORIX (where RIX is hydrogen; hydroxyl; Cl-Clz
alkyl; N(RX) (RXI) amino, where RX and RXI are independently
hydrogen or a Cl-C12 alkyl group; or Cl-C12 alcoxyl); or
trifluoromethyl;
R19r R19,, R20 and R20, are independently hydrogen; substituted or
10 non-substituted Cl-C12 alkyl; a CORXII group (where RXII is
hydrogen; hydroxyl; substituted or non-substituted Cl-C12 alkyl;
substituted or non-substituted C6-Clo aryl; or N(RXIII) (RXI ) amino,
where RXIII and RX14 are independently hydrogen or a Cl-C12 alkyl
group) ; a [(Cl-C12) alkyl-O- (Cl-C12) 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;
R24 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):

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R7 R8
R
s \Ro
R2 RJ R5
::1
2 R19 R16 R15
R21 R20
(11)
where:
R, R2, R3, R4, R5, R6i R9i Rloi Rlli R12i R13i R14i R15i R16i R17i Rlai
R19 and R20 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted Cl-C12 alkyl; substituted or non-
substituted C6-Clo aryl; a N(Rxv) (Rxvz) amino group, where Rxv and
Rxvl are independently hydrogen or a Cl-C12 alkyl group; or each
pair can form a carboxyl (C=O) group together with the carbon to
which they are attached;
R7 and R8 are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a CORxvII group (where Rxvzz
is hydrogen; hydroxyl; substituted or non-substituted Cl-C12
alkyl; substituted or non-substituted C6-Clo aryl; O-Cl-C12 alkyl;
or N(Rxvzzz) (Rxzx) amino, where RxvIII and Rxlx are independently
hydrogen or a Cl-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,
R21 and R24 are independently substituted or non-substituted Cl-
C12 alkyl; a CORxx group (where Rxx is hydrogen; hydroxyl;
substituted or non-substituted Cl-C12 alkyl; substituted or non-
substituted C6-Clo aryl; or N(Rxxz) (Rxxzz) amino, where Rxxl and Rxxzz
are independently hydrogen or a Cl-C12 alkyl group); a[(Cl-
C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is comprised between 1
and 3); or trifluoromethyl;
R22 and R23 are:
- hydrogen; substituted or non-substituted Cl-C12 alkyl; a
CORxxIII group (where RxxIII is hydrogen; hydroxyl;
substituted or non-substituted Cl-C12 alkyl; substituted or

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non-substituted C6-Clo aryl; or N(Rxxzv) (Rxxv) amino, where
Rxxiv and Rxxv are independently hydrogen or a Cl-C12 alkyl
group) ; a[(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is
comprised between 1 and 3); or trifluoromethyl when R24 is
in the para position with respect to R20; or
OR22' and OR23' respectively, where R22' and R23' are
independently hydrogen; substituted or non-substituted Cl-
C12 alkyl; a CORxxvz group (where Rxxvz is hydrogen; hydroxyl;
substituted or non-substituted Cl-C12 alkyl; substituted or
non-substituted C6-Clo aryl; or N(Rxxvzz) (Rxxvzzz) amino, where
Rxxviz and Rxxvzzz are independently hydrogen or a Cl-C12 alkyl
group) ; a[(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is
comprised between 1 and 3); or trifluoromethyl when R24 is
in the meta position with respect to R20=
or a pharmaceutically acceptable salt, derivative, prodrug,
solvate or stereoisomer thereof.
In one particular aspect, the invention is directed to
compounds of formula (IIa):
R7 R8
R
s '\\Rg
R 2 R R5 nu",,.
R
24
a R1o
R23 WR11
Cr~12
18
~~'~
R22 R19 R17 R14
R16 R15
2 0 R21 R20
(IIa)
where:
Rlr R2, R3, R4, R5, R6, R9r Rlor Rllr R12r R13r R14r R15r R16r R17r R18r
R19 and R20 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted Cl-C12 alkyl; substituted or non-
substituted C6-Clo aryl; a N(Rxv) (Rxvz) amino group, where Rxv and
Rxvl are independently hydrogen or a Cl-C12 alkyl group; or each
pair can form a carboxyl (C=O) group together with the carbon to
which they are attached;

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R7 and R8 are independently hydrogen; substituted or non-
substituted Cl-C12 alkyl; C6-Clo aryl; a CORxvII group (where Rxvzz
is hydrogen; hydroxyl; substituted or non-substituted Cl-Clz
alkyl; substituted or non-substituted C6-Clo aryl; 0-C1-C12 alkyl;
or N(Rxvzzz) (Rxzx) amino, where RxvIII and Rxlx are independently
hydrogen or a Cl-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,
R21 and R24 are independently substituted or non-substituted Cl-
C12 alkyl; a CORxx group (where Rxx is hydrogen; hydroxyl;
substituted or non-substituted Cl-C12 alkyl; substituted or non-
substituted C6-Clo aryl; or N(Rxxz) (Rxxzz) amino, where Rxxl and Rxxzz
are independently hydrogen or a Cl-C12 alkyl group); a[(Cl-
C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is comprised between 1
and 3); or trifluoromethyl;
R22 and R23 are:
- hydrogen; substituted or non-substituted Cl-C12 alkyl; a
CORxxIII group (where RxxIII is hydrogen; hydroxyl;
substituted or non-substituted Cl-C12 alkyl; substituted or
non-substituted C6-Clo aryl; or N(Rxxzv) (Rxxv) amino, where
Rxxzv and Rxxv are independently hydrogen or a Cl-C12 alkyl
group) ; a[(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is
comprised between 1 and 3); or trifluoromethyl when R24 is
in the para position with respect to R20; or
- OR22' and OR23' respectively, where R22' and R23' are
independently hydrogen; substituted or non-substituted Cl-
C12 alkyl; a CORxxvz group (where Rxxvz is hydrogen; hydroxyl;
substituted or non-substituted Cl-C12 alkyl; substituted or
non-substituted C6-Clo aryl; or N(Rxxvzz) (Rxxvzzz) amino, where
Rxxviz and Rxxvzzz are independently hydrogen or a Cl-C12 alkyl
group) ; a[(Cl-C12) alkyl-0- (Cl-C12) alkyl-] n group (where n is
comprised between 1 and 3); or trifluoromethyl when R24 is
in the meta position with respect to Rzo=
In a preferred embodiment, the compounds of formula (IIa)
comprise a substructure having the following formula (IIa'):

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H3C '--COOCH;
Rz4
R23
CH;
R22 R19
R21 R20
(IIa')
where:
R19 and R20 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted Cl-C1z alkyl; substituted or non-
substituted C6-Clo aryl; a N(Rxv) (Rxvz) amino group, where Rxv and
Rxvl are independently hydrogen or a Cl-Clz alkyl group; or each
pair can form a (C=O) carboxyl group together with the carbon to
which they are attached;
R21 and R24 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted Cl-Clz alkyl; substituted or non-
substituted C6-Clo aryl; a N(Rxxz) (Rxxzz) amino group, where Rxxl and
RxxII are inde endentl h dro en or a C C alk 1 rou
p Y Y g ~- ~z Y g p; or each
pair can form a (C=O) carboxyl group together with the carbon to
which they are attached;
R22 and R23 are independently hydrogen; hydroxyl; halogen;
substituted or non-substituted Cl-Clz alkyl; substituted or non-
substituted C6-Clo aryl; a N(Rxxzv) (Rxxv) amino group, where Rxxzv
and Rxxv are independently hydrogen or a Cl-Clz alkyl group; or
each pair can form a (C=O) carboxyl group together with the
carbon to which they are attached.
A particular example of this substructure (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).
In another aspect the present invention relates to a
process for preparing compounds of formula (I) comprising the
following features:
a) The usual methodology for the chemoselective
introduction in the hydroxyl in C-3 of the natural

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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.

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Particular examples of the present invention are described
in the preparation example section, nevertheless a person
skilled in the art would achieve synthesizing any of the
described compounds by conventional synthetic compounds of the
state of the art.
The term "pharmaceutically acceptable salts, solvates,
prodrugs" refers to any pharmaceutically salt, ester, solvate or
any other compound which when administered to a receptor is able
to provide (directly or indirectly) a compound as described in
the present document. However, it will be observed that
pharmaceutically unacceptable salts are also within the scope of
the invention because the latter can be useful in the
preparation of pharmaceutically acceptable salts. The
preparation of salts, prodrugs and derivatives can be carried
out by means of methods known in the art.
For example, pharmaceutically acceptable salts of compounds
provided in the present document are synthesized by means of
conventional chemical methods from an original compound
containing a basic or acid residue. Such salts are generally
prepared, for example, by reacting the free acid or base forms
of the compounds with a stoichiometric amount of the suitable
base or acid in water or an organic solvent or a mixture of
both. Non-aqueous media such as ether, ethyl acetate, ethanol,
isopropanol or acetonitrile are generally preferred. Examples of
acid addition salts include mineral acid addition salts such as
for example, hydrochloride, bromohydrate, iodohydrate, sulfate,
nitrate, phosphate and organic acid addition salts such as for
example, acetate, maleate, fumarate, citrate, oxalate,
succinate, tartrate, malate, mandelate, methanesulfonate and p-
toluenesulfonate. Examples of base addition salts include
inorganic salts such as for example sodium, potassium, calcium,
ammonium, magnesium, aluminium and lithium salts and organic
base salts such as for example ethylenediamine, ethanolamine,
N,N-dialkylenethanolamine, triethanolamine, glucamine and basic
amino acid salts.
The particularly preferred derivatives or prodrugs are
those increasing the bioavailability of the compounds of this

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invention when such compounds are administered to a patient (for
example, by making a compound administered orally be absorbed
more easily by blood), or enhancing the release of the original
compound in a biological compartment (for example, the brain or
the lymphatic system) in relation to the original species.
Any compound which is a prodrug of a compound of formula
(I) or of formula (II) is within the scope of the invention. The
term "prodrug" is used in its widest sense and includes those
derivatives which are converted in vivo into the compounds of
the invention. Such derivatives are evident for the persons
skilled in the art and depending on the functional groups
present in the molecule and without limitation, include the
following derivatives of the present compounds: esters, amino
acid esters, phosphate esters, metal salt sulfonate esters,
carbamates and amides. Examples of methods for producing a
prodrug of a given active compound are known by the person
skilled in the art and can be found for example in Krogsgaard-
Larsen et al. "Textbook of Drug design and Discovery" Taylor &
Francis (April 2002).
The compounds of the invention can be in crystalline form
as free compounds or as solvates and it is intended that both of
them are within the scope of the present invention. The
solvation methods are generally known in the art. The suitable
solvates are pharmaceutically acceptable solvates. In a
particular embodiment, the solvate is a hydrate.
The compounds of the present invention represented by the
formula (I) described previously can include enantiomers,
depending on the presence of chiral centers on a C, or isomers,
depending on the presence of multiple bonds (for example, Z, E).
The individual isomers, enantiomers or diastereoisomers and the
mixtures thereof are included within the scope of the present
invention.
The different substituents selected for the different
compounds of the invention provide a series of factors
considerably affecting the values of log P. Thus, hydroxyl
groups act as hydrogen bond donors and intra or intermolecular
links can be established even in the case of phenols. The

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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
nucleophiles on the molecule and in most cases significantly
modify its polarity and polarizability and the presence of
additional alkyl and/or aryl groups increases the lypophilicity
of the molecules.
The present invention additionally provides pharmaceutical
compositions comprising a compound of formula (I), (Ia), (Ia'),
(Ia" ) , (Ia,, , ) , (Ib) , (Ib' ) , (Ib" ) , (Ic) , (Ic' ) , (Ic' ) , (Id) ,
( I d ' (Id " ) , (1e), (1e'(If) , (If'), (II) , (IIa), (IIa') or
mixtures thereof, a pharmaceutically acceptable salt,
derivative, prodrug, solvate or stereoisomer thereof together
with a pharmaceutically acceptable carrier, adjuvant or vehicle
for the administration to a patient.
The pharmaceutical compositions can be administered by any
suitable administration route, for example an oral, topical,
rectal or parenteral route (including subcutaneous,
intraperitoneal, intradermal, intramuscular and intravenous
route).
Suitable pharmaceutical forms for oral administration
include any solid composition (tablets, pastilles, capsules,
granules, etc.) or liquid composition (solutions, suspensions,
emulsions, syrups, etc.) and can contain conventional excipients
known in the art, such as binding agents, for example syrup,
acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone;
fillers, for example lactose, sugar, cornstarch, calcium
fosfate, sorbitol or glycine; lubricants for the preparation of
tablets, for example magnesium stearate, disintegrants, for
example starch, polyvinylpirrolidone, sodium starch glycolate or
microcrystalline cellulose; or pharmaceutically acceptable
wetting agents such as sodium laurylsulfate.
Solid oral compositions can be prepared by means of
conventional methods for mixing, filling or preparing tablets.
The repeated mixing operations can be used to distribute the
active ingredient through the entire compositions by using large

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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,
particularly with an enteric coating.
The pharmaceutical compositions can also be adapted for
parenteral administration such as sterile solutions, suspensions
or lyophilized products in a suitable unitary pharmaceutical
form. Suitable excipients such as bulk agents, buffering agents
or surfactants can be used.
The mentioned formulations will be prepared using usual
methods such as those described or referred to in Spanish
Pharmacopoeia and the Pharmacopoeia of the United States and in
similar reference texts.
The administration of the compounds or compositions used in
the present invention can be by any suitable method, such as
intravenous infusion, oral preparations and intraperitoneal and
intravenous administration. Nevertheless, the preferred
administration route will depend on the patient's condition.
Oral administration is preferred due to the comfort for the
patient and the chronic character of the diseases which are to
be treated.
For their application in therapy, the compounds of formula
(I) and formula (II) will preferably be found in
pharmaceutically acceptable or substantially pure form, i.e. the
compounds of formula (I) and formula (II) have a
pharmaceutically acceptable purity level excluding the
pharmaceutically acceptable excipients and not including
material considered to be toxic at the normal dosage levels. The
purity levels for a compound of formula (I) or for a compound of
formula (II) preferably exceed 50%, more preferably exceed 70%,
more preferable exceed 90%. In a preferred embodiment, they
exceed 95%.
The therapeutically effective amount of the compound of
formula (I) or of the compound of formula (II) to be
administered will generally depend, among other factors, on the
individual who is to be treated, on the severity of the disease

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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.

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The following examples are given only as an additional
illustration of the invention, they must not be interpreted as
limiting the invention as it is defined in the claims.
EXAMPLES
PREPARATION EXAMPLES
Example 1
Compound C3: 12-bromo-3,9-dihydroxy-6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picen-2,10-dione
300 g of Maytenus amazonica root bark were extracted in 2
liters of a n-hexane-ethyl ether 1:1 solvent mixture in soxhlet
equipment under reflux for 48 hours, obtaining 70 grams of a
reddish solid after evaporating the solvent. The extract was
chromatographed on a sephadex LH-20 column, using a n-hexane-
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
starting compound 22(3-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 22(3-hydroxy-tingenone in 50 ml of
dry CH2C12, under an inert atmosphere and at 0 C were treated
with 1.5 eq of BBr3 (1M) . 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 CH2C12 was carried
out. The organic phases were dried with anhydrous magnesium
sulfate and the solvent was evaporated under reduced pressure.
The residue was purified by LH-20 sephadex chromatography using
n-hexane:chloroform:methanol 2:1:1 mixture as eluent and in a
silica gel chromatography column using n-hexane-ethyl acetate
7:3 as eluent. 111 mg (27%) of product C3 was obtained.

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1H NMR (300 MHz, CDC13) S 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, J1= 2. 6, J2= 10.2 Hz, H-
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, J1= 1.3, J2= 7.1 Hz, H-6) . 13C NMR (75 MHz, CDC13) $
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);
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) C28H3604 436.2614,
observed 436.2695.
Example 2
Compound C7: 14-Bromo-3-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-
7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene-2,10-
dione
100 mg (0.23 mmoles) of 22(3-hydroxy-tingenone, obtained
according to example 1, were dissolved in 10 ml of CH2C12 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 CH2C12 was carried out.
The organic phase was dried with anhydrous magnesium sulfate and
the solvent was evaporated under reduced pressure. The residue
was purified by column chromatography on silica gel, using n-
hexane:AcOEt mixtures in polarity increasing from 10% to 60% as
an eluent to obtain: 1.2 mg (1%) of compound C7 and a mixture of
other compounds.
1H NMR (300 MHz, CDC13) S 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, J1= 6.7 Hz,
J2= 12.0 Hz, H-11); 6.28 (1H, d, J= 7.0 Hz, H - 7 ) ; 6.89 (1H, d,
J= 7.0 Hz, H-6) ; 7.35 (1H, s, H-1).. 13C NMR (75 MHz, CDC13) S
10.2 (c, C-23); 14.9 (c, C-30); 19.5 (c, C-27); 21.2 (c, C-26);

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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) ;
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 C28H35BrO3 498.1770,
observed 498.1801.
Example 3
Compound C8: (4,6b,8a,11,12b,14a-hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-picen-3-
yl) acetic acid ester
300 g of Maytenus amazonica root bark were extracted in 2
liters of a n-hexane-ethyl ether 1:1 solvent mixture in soxhlet
equipment under reflux for 48 hours, obtaining 70 grams of a
reddish solid after evaporating the solvent. The extract was
chromatographed on a sephadex LH-20 column, using a n-hexane-
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
starting compound called tingenone was obtained.
40 mg (0.096 mmoles) of tingenone in 10 ml of dry CH2C12
were treated with 0.04 ml (3 eq) of dry Et3N and 0.01 ml (1.5
eq) of acetyl chloride. The reaction was carried out at room
temperature, followed by TLC and stirred for 2h. The process
described in the previous reactions was followed. The raw
product was purified by preparative chromatography on silica gel
using n-hexane:AcOEt (2:3) as a mobile phase, to give 24 mg
(54%) of product C8. The residue was starting product.
'H NMR (300 MHz, CDC13) 8 7.08 (1H, dd, J1= 1.3, J2= 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-C00); 2.16 (3H, s, Me-23); 1.52
(3H, s, Me-25); 1.35 (3H, s, Me-26); 1.00 (3H, s, Me-27); 0.99
(3H, d, J- 6.2 Hz, Me-30) ; 0.98 (3H, s, Me-28) . 13C NMR (75 MHz,

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CDC13) S 11.1 (c, C-23); 14.8 (c, C-30); 19.5 (c, C-27) ; 20.3
(c, CH3C00); 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);
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,
CH3CO0); 170.4 (s, C-8) ; 177.3 (s, C-2) ; 213.4 (s, C-21) . High
resolution MS Calculated for C30H3804 462.2770, observed 462.2784.
Example 4
Compound C9: (4,6b,8a,11,12b,14a-hexamethyl-2,10-dioxo-
2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydro-picen-3-
yl) nicotinic acid ester
98 mg (0.23 mmoles) of tingenone (obtained according to
example 3) were dissolved in 10 ml of dry CH2C12 and were treated
with 0.097 ml (3 eq) of dry Et3N, 62.12 mg (1.5 eq) of nicotyl
chloride and catalytic amounts of DMAP. The reaction was carried
out at room temperature, followed by TLC and stirred for 20
minutes. The process described in the previous reactions was
followed and the raw product was purified by preparative
chromatography on silica gel using CH2C12:AcOEt (1:1) as a mobile
phase, to give 55 mg (46%) of product C9. The residue was
starting product.
'H NMR (300 MHz, CDC13) S 9.37 (1H, dd, J1= 0.9, J2= 2.1 Hz, Ha) ;
8.81 (1H, dd, J1= 1.7, J2= 4. 9 Hz, Hd) ; 8. 43 (1H, dd, J1= 1. 9, J2=
8.2 Hz, Hb) ; 7.44 (1H, m, HC) ; 7.13 (1H, dd, J1= 1.2, J2= 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
Hz, Me-30) ; 0. 95 (3H, s, Me-28) . 13C NMR (75 MHz, CDC13) 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);
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,

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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 C34H39NO4 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 CH2C12
were treated with 0.062 ml (3 eq) of dry Et3N, 0.02 ml (1.5 eq)
of N,N-dimethylcarbamoyl chloride and catalytic amounts of DMAP.
The reaction was carried out at 0'C and under an inert
atmosphere, followed by TLC and stirred for 24h. Then 5% diluted
35 hydrochloric acid was added until neutralization. Then the
organic phase was extracted with CH2C12 and was dried with
anhydrous magnesium sulfate. It was filtered and concentrated

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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.
'H NMR (300 MHz, CDC13) S 7.00 (1H, dd, J1= 1. 4, J2= 7.0 Hz, H-6) ;
6.46 (1H, d, J= 1. 4 Hz, H-1) ; 6.29 (1H, d, J= 7.2 Hz, H-7) ; 3.56
(3H, s, OMe) ; 3.13 (s, N-CH3) ; 3. 00 (s, N-CH3) ; 2.17 (3H, s, Me-
23); 1.46 (3H, s, Me-25); 1.26 (3H, s, Me-26); 1.17 (3H, s, Me-
30); 1.09 (3H, s, Me-28) ; 0.54 (3H, s, Me-27) . 13C NMR (75 MHz,
CDC13) 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-CH3) ;
36.58(c, N-CH3); 37.99 (c, C-25); 38.99 (s, C-13); 40.14 (s, C-
20) ; 42.23 (s, C-9) ; 44.07 (d, C-18) ; 44.87 (s, C-14) ; 51.34 (q,
OCH3); 117.5 (d, C-7) 122.9 (d, C-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 C33H45N05 535.3298, observed
535.3294.
EX VIVO ASSAYS OF HUMAN CHOK ACTIVITY
Recombinant human alpha-1 choline kinase expressed in E.
coli in the assay of the buffer (100 mM Tris-HC1 pH 8.0, 100 mM
MgC12, 10 mM ATP and 200 M of choline in the presence of
methyl [ 14C ] -choline chloride (50-60 Ci/mmol) were used for the
ex vivo assays. The reactions were carried out at 37 C for 30
min and were stopped with trichloroacetic acid cooled with ice
at a final 16% concentration. The samples were washed with
diethyl ether saturated with water and were lyophilized. The
hydrophilic choline derivatives were resolved in thin layer
chromatography plates according to a described process [Ramirez,
A., Penalva, V., Lucas, L., Lacal, J.C. Oncogene 21, 937-946
(2002)].
These assays were carried out with the compounds of the
invention C3, C7, C8, C9, C10, C12 and C14 as well as with

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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
reducing the activity of the choline kinase (ChoK) enzyme in
cell models.
CELL PROLIFERATION ASSAYS
HT-29 cells were seeded in 24-well plates (35 H 103
cells/well) and were incubated for 24 h. Then, the cells were
treated with different concentrations of ChoK inhibitors in the
usual culture medium. Three days later, the wells were aspirated
and both fresh medium and more drug was added, and the cells
were kept for 3 more days. The quantification of the cells
remaining in each well was carried out by means of the Crystal
Violet method [Gillies, R. J., Didier, N., Denton, M. Anal.
Biochem. 159, 109-113 (1986)], with some modifications
[Hernandez-Alcoceba, R., Saniger, L., Campos, J., Nunez, M. C.,
Khaless, F., Gallo, M. A., Espinosa, A., Lacal, J. C. Oncogene,
15, 2289-2301 (1997)]. Briefly, the cells were washed with TD
buffer and were fixed with 1% glutaraldehyde for 15 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
spectrometer. The obtained results are summarized in the form of
an IC50 value, i.e. the concentration of the compound required to
cause a 50% inhibition. This value is determined by the
iterative adjustment of the curve. Two values were determined
for each point of the curve, the experiment was repeated two or
three times and the average values were estimated. In the few
cases in which the two values differed by more than 50%, a third
experiment was carried out to determine the real value. The IC50
value as a measurement of the potency is used to relate the
biological activity of the compounds with their chemical
structure.

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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.
The following table summarizes the results obtained in the
conducted assays and which are shown as an example.
Table I
IC50 ex vivo
No. Code IC50 HT-2 9( M)
(NM)
3.3
13.6 % F,
5.3 =1
4 8.8
1 11.2 ~ .
7.4
11 7.1 11.3
r-r1ih, 1
1,
amr-.tl1...,;1-
11,1% l11};,1 4.1 r,.r :};H, ',H ri l 4, (;b, ; , 11, 11};, 14a -
am:-.t1 :1-l, 1)- li
4.8 11.1
1~;a, 1~};, 1 1 1 , 14;a-
t-.t - , 1- a1 -:,1- -pi -.i - ;-
al) fii : a-~i~1 in-filj~,rl
r-. -
t
1 ~_i 1~'Trl-
5.2
4 , ~};, :õ , 11, 1 1}_;, 1 1;a-

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WO 2007/077203 PCT/EP2006/070276
84
m: tlr,;l li _ :
1;; li};, 1 11, 11
tit - _i!=1 1':_: r,l
4, };, 11, 11};, 14a -
-_ m-t1 l l ) li _ _
14.6 17.0
114 , 1 1a
ti-t i 1 r Cl -r;i ri
yl dim-th,rl a -}"amir
t
1% 1
1, };, , 11, 12};, 14 1 :- _xaint lr%1-'l li
8.6 7.2
11_=i, 11 14 , 14
1) i iili _ i 1
t
114-} m 1 il - 1:__
}, };, 11, 11};, 1 1a -
rrn: t11-,71-
10.8 12.1
14 , 14 i 1c-
},H, H r i n 1( li:_ r:
14 m i~o (1
-;
4_i, , 11},, 1 1i-
1 :-_ lrn:-t1i,-1-, 11- li
4.7 11.3
1, 1, 1. , , , r.; , 11, 1%
}", 1},, 1 1, 14 a, 1};-
t-t ~l1 a1 -: 1 .- -r,i -r - 1-
;l) z=: ii i= i 1 t

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WO 2007/077203 PCT/EP2006/070276
1r 1 } m 1( 1 ;-
1 llt;, 14
tl-1-11- li
1, 4 1 1 1
2.1 4.1
},,1 11,11; 11};-
t t 1. 17 ,1 -r;i 1-
-,7 1 -tlj 1 lz= iiii:= a _ i 1
t
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.