AU2006334359A2 - Triterpenequinone and triterpenephenol derivatives and their application for the treatment of tumors and parasitic diseases - Google Patents
Triterpenequinone and triterpenephenol derivatives and their application for the treatment of tumors and parasitic diseases Download PDFInfo
- Publication number
- AU2006334359A2 AU2006334359A2 AU2006334359A AU2006334359A AU2006334359A2 AU 2006334359 A2 AU2006334359 A2 AU 2006334359A2 AU 2006334359 A AU2006334359 A AU 2006334359A AU 2006334359 A AU2006334359 A AU 2006334359A AU 2006334359 A2 AU2006334359 A2 AU 2006334359A2
- Authority
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- Australia
- Prior art keywords
- substituted
- alkyl
- group
- hexamethyl
- independently hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 206010028980 Neoplasm Diseases 0.000 title claims description 14
- 208000030852 Parasitic disease Diseases 0.000 title claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 437
- 239000001257 hydrogen Substances 0.000 claims description 437
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 348
- 125000000217 alkyl group Chemical group 0.000 claims description 316
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 205
- 125000003118 aryl group Chemical group 0.000 claims description 175
- 150000001875 compounds Chemical class 0.000 claims description 131
- 229910052736 halogen Inorganic materials 0.000 claims description 105
- 150000002367 halogens Chemical class 0.000 claims description 105
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 100
- 229910052799 carbon Inorganic materials 0.000 claims description 83
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 81
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 77
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 60
- 125000003277 amino group Chemical group 0.000 claims description 59
- 201000010099 disease Diseases 0.000 claims description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 28
- 150000002431 hydrogen Chemical class 0.000 claims description 28
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 16
- -1 nicotinic acid ester Chemical class 0.000 claims description 16
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 13
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- 239000001384 succinic acid Substances 0.000 claims description 7
- WSTYNZDAOAEEKG-UHFFFAOYSA-N 3-hydroxy-4,6a,6b,8a,11,14a-hexamethyl-7,8,9,11,12,12a,13,14-octahydropicene-2,10-dione Chemical compound CC1=C(O)C(=O)C=C2C(CCC3(C4CC(C(CC4(CCC33C)C)=O)C)C)(C)C3=CC=C21 WSTYNZDAOAEEKG-UHFFFAOYSA-N 0.000 claims description 6
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- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
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- 125000005605 benzo group Chemical group 0.000 claims 2
- VKPJRDFHXPLERI-UHFFFAOYSA-N (4,6a,6b,8a,11,14a-hexamethyl-2,10-dioxo-7,8,9,11,12,12a,13,14-octahydropicen-3-yl) acetate Chemical compound CC1=C(OC(C)=O)C(=O)C=C2C(CCC3(C4CC(C(CC4(CCC33C)C)=O)C)C)(C)C3=CC=C21 VKPJRDFHXPLERI-UHFFFAOYSA-N 0.000 claims 1
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- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
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Description
WO 2007/077203 PCT/EP2006/070276 1 TRITERPENEQUINONE AND TRITERPENEPHENOL DERIVATIVES AND THEIR APPLICATION FOR THE TREATMENT OF TUMORS AND PARASITIC DISEASES FIELD OF THE INVENTION The invention generally relates to triterpenecuinone 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 onccgenes 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 WO 2007/077203 PCT/EP2006/070276 2 transformed by oncogenes. These first observations were later extrapolated in vivo in nude mice.
In view of this data, the design of compounds directly affecting choline kinase activity or the enzyme activated by 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 Carnero Dolfi F., Jim6nez B. and Lacal J.C. Oncogene 8, 2959-2968 (1993); Jimenez del Peso Montaner Esteve P. and Lacal J.C. J. Cell Biochem. 57, 141-149 (1995); Hernandez-Alcoceba, Saniger, Campos, Nuiez, M. Khaless, Gallo, M. A., Espinosa, 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 respiratcry 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, Oto, Sugiyama, S., Yube, Takaishi, and Sakato, 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.
WO 2007/077203 PCT/EP2006/070276 3 Nevertheless, there is a great need to develop compounds that provide a high inhibitory activity of the ChoK enzyme for the purpose of allowing their use for the treatment of tumors, while at the same time they considerably reduce their toxicity 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)
where: Ri, R 2 Rs, R4, RS, R, Rare ndependen R1 hydrogen; hydroxyl; halogen; substituted or non-substituted Ci- 2 alky; sustituted or nonsustituted C aryl; a amino group, where R' and are independently
CH,
hydrogen or a Ci-C 1 F alkyl grcup; an OCOR group, where R is
(CH
2 )2COOH or (CH) 2
CO
2
CH
2 CH; or each pair can form a group C R where: together with the carbon to which they are attached; R R2 R3 R4 R R Rr R and RR 1 are independently hydrogen; su ituted or non substituted Ci-C 1 2 alkyl; C 6 -Ci0 aryl; a COR''' group (where ihydrogen; hydroxyl; halogen; substituted or non-substituted C-C 2 alky l; substitut ed or non-substituted C-C ary; -CC aryl; a 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)2CC2CH2CH3; or each pair can form a group together with the carbon to which they are attached; R and Rjo are independently hydrogen; substituted or nonsubstituted Cl-C22 alkyl; C6-Clo aryl; a COR"' group (where R"' is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-Clo aryl; O-C -C12 alkyl; WO 2007/077203 PCT/EP2006/070276 4 or N(RI) (Rv) amino, where RTV and R v are independently hydrogen or a C 1
-C
1 2 alkyl group); a (CH2),-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: where:
R
1 3, R 1 4 RIr, RI 2 R21, R22 and are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-C alkyl; substituted or non-substituted CG-Co aryl; a N(R"
I
(R
C 1 amino group, where R" I and R" I I are independently hydrogen or a C 1
-C
12 alkyl group; an OCOR v group, where R v is (CH2) 2COOH or WO 2007/077203 PCT/EP2006/070276 (CH2)C 2 C2CH 3 or each pair can form a group together with the carbon to which they are attached or each pair can form a group together with the carbon to which they are attached;
R
1 7 is hydrogen or methyl; Ri 1 and R18, are independently hydrogen; hydroxyl; halogen; Ci-Calkyl; C6-Cic aryl; CORI x (where RIX is hydrogen; hydroxyl; C 1
-C
1 2 alkyl; N(RX) (R"
I
amino, where R x and R- are independently hydrogen or a CI-C12 alkyl group; or CI-C12 alcoxyl); or trifluoromethyl; R19, R1,, R20 and R20, are independently hydrogen; substituted or non-substituted C 1 alkyl; a COR"
I
group (where R x is hydrogen; hydroxyl; substituted or non-substituted C-C12 alkyl; substituted or non-substituted C 6 -Cio aryl; or N(RXII) (R x IV) amino, where R x II I and R XIV are independently hydrogen or a Cl-C1 2 alkyl group); a [(CL-C12)alkyl-O-(C 1 -C2) alkyl-]n group (where n is comprised between 1 and trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached;
R
24 and R 25 are independently hydrogen, hydroxyl or halogen; or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof, in the manufacture of a medicament for the treatment and/or prevention of a ChoK mediated disease or condition.
In another aspect, the present invention refers to the use of a compound of formula (II):
(II)
WO 2007/077203 PCT/EP2006/070276 6 where:
R
1
R
2
R
3
R
4 Ri, Ro, R, R R 11
R
12 R 3
R
14 R, R 6
R
17 Rla, RLD and R2 0 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 12 alkyl; substituted or nonsubstituted Cs-C-o aryl; a (Rx v amino group, where R" v and
R
xV are independently hydrogen or a CI-C 1 2 alkyl group; or each pair can form a carboxyl group together with the carbon to which they are attached; R, and R 8 are independently hydrogen; substituted or nonsubstituted Ci-C 12 alkyl; C 6 -Clo aryl; a COR v 2 group (where R' v l is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
1 alkyl; substituted or non-substituted C 6
-C
10 aryl; O-C--C, 1 alkyl; or N(RXv 1 1
(R
xx amino, where R x III and R x X are independently hydrogen or a CI-C12 alkyl group); a (CH2)n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, R21 and R24 are independently substituted or non-substituted C1- C12 alkyl; a COR x group (where R" is hydrogen; hydroxyl; substituted or non-substituted CI-C 1 2 alkyl; substituted or nonsubstituted Cs-C10 aryl; or N(R x I
(R
xx x amino, where R xx and R x are independently hydrogen or a Ci-Ci, alkyl group); a [(Ci- C12)alkyl-O-(C1-C 1 2)alkyl-]n group (where n is comprised between 1 and or trifluoromethyl; R22 and R2 3 are: -hydrogen; substituted or non-substituted CI-C 1 2 alkyl; a CORxxII group (where R x is hydrogen; hydroxyl; substituted or non-substituted C 1 -C12 alkyl; substituted or non-substituted C 6 -Co1 aryl; or N(RXXT) amino, where
R
x x and R x x are independently hydrogen or a C1-C 1 2 alkyl group); a [(C 1
-C
1 2)alkyl-O-(C 1 -C,2)alkyl-]n, group (where n is comprised between 1 and or trifluoromethyl when R2 4 is in the para position with respect to R2o; or OR22' and OR2 3 respectively, where R22' and R2 3 are independently hydrogen; substituted or non-substituted Cj- C12 alkyl; a CO x v I group (where R" x v is hydrogen; hydroxyl; substituted or non-substituted C 1 -C12 alkyl; substituted or WO 2007/077203 PCT/EP2006/070276 7 non-substituted C 6 -Clo aryl; or N(R"" v
(R
x xv II) amino, where
R
x x 1 1 and Rxv'z are independently hydrogen or a C 1
-C
1 2 alkyl group); a (Ci-C2)alkyl-0-(Ci-C 1 2 )alkyl-]n group (where n is comprised between 1 and or trifluoromethyl when R 2 4 is in the meta posi-ion with respect to Ro 0 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 Rio R 9 (RI1
CH
3 H R, R, where:
R
1
R
2
R
3
R
4 Rs, R 6
R
7 RE, Rn and R- 2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cj-
C
12 alkyl; substituted or non-substituted C 6 -Cio aryl; a amino group, where R' and are independently hydrogen or a C 1
-C
1 2 alkyl group; an OCOR group, where R is (CH2)2COOH or (CH2) 2
CO
2
CH
2
CH
3 or each pair can form a group together with the carbon to which they are attached; RD and Rjo are independently hydrogen; substituted or nonsubstituted Cl-C 1 s alkyl; Cs-Co aryl; a COR''' group (where is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 WO 2007/077203 PCT/EP2006/070276 8 alkyl; substituted or non-substituted C 6
-C
10 aryl; 0-C-C 12 alkyl; or N(RIV)(R v amino, where R IV and Rv are independently hydrogen or a Ci-C 12 alkyl group); a (CHA)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 0 is selected from the following structures:
R
14
R
1 3
R
1 R200R RI, R 2
R
where: Ri, R1 R Ri 1 Ri, R 2 and R,:i are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1
-C
1 2 alkyl; substituted or non-substituted CE-Cio aryl; a N(R
I
(RI
1 amino group, where RV' and R VI I are independently hydrogen or a C 1 -C12 WO 2007/077203 PCT/EP2006/070276 9 alkyl group; an OCOR v "I group, where RVIII is (CH 2 2COOH or (CH2) 2 C2H2CH 3 or each pair can form a group together with the carbon to which they are attached or each pair can form a group together with the carbon to which they are attached;
R
17 is hydrogen or methyl;
R
1 8 and Ri 6 are independently hydrogen; hydroxyl; halogen; Ci-C-2 alkyl; Co-Cic aryl; COR Ix (where R I is hydrogen; hydroxyl; Ci-C12 alkyl; N(RX) amino, where R x and R x are independently hydrogen or a C1-C12 alkyl group; or C1-C12 alcoxyl); or trifluoromethyl; RI, RI,, and R 6 are independently hydrogen; substituted or non-substituted Ci-C12 alkyl; a COR"' group (where R x I is hydrogen; hydroxyl; substituted or non-substituted Ci-C12 alkyl; substituted or non-substituted C6-C0 aryl; or N(R x I I) (R x I amino, where R x I I and R x Iv are independently hydrogen or a CI-C12 alkyl group); a [(Ci-CL,)alkyl-O-(C1-Cl,)alkyl-]n group (where n is comprised between 1 and trifluoromethyl; or each 19-19' or 20-20' pair can form a C=0 group together with the carbon to which they are attached;
R
2 4 and R2 5 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 then the compound of formula 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,14btetradecahydro-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,14btetradecahydro-picene-2-carboxylic acid methyl ester; -3,10-Dihydroxy-2,4a,6a,9,12b,14a-hexamethyl-lloxo-1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14btetradecahydro-picene-2-carboxylic acid methyl ester; WO 2007/077203 WO 207/07203PCT!EP2006/070276 3-Hydraxy-4,Bb,Ba,11,12b,14a-hexamethyi- 7,8, Ba, 11, 12, 12a, 12b, 13, 14, 14a-decahydra-BbH, 9Hpicene-2, 3,9-Dihydrcxy-4,6b,8a,11,12b,14a-hexamethyla, 11, 12, 12a, 12b, 13, 14, 14a-decahydra-BbH, 9Hpicene-2, 3,7,9-Trihydrcxy-4,6b,8a,11,12b,14a-hexamemhyl- 7,3, a, 11, 12, 12a, 12b, 13, 14, 14a-decahydrao-BbH, OHpicene-2, 14-Brarna-3,7,9-trihydraxy-4,6b,8a,11,12b,14ahexamethyl-7,8, Ba, 11,12, 12a,12b, 13, 14,14adecahydra-BbH, 9H-picene-2, Succinic acid mana-(10-hydraoxy-2,4a,Ba,9,12b,14a hexamethyl-3, li-diaxa- 1,2,3,4, 4a, 5,6, Ba, 11, 12b, 13, 14, 14a, 14bterradecahydra-picen-4-yi) ester; Succinic acid ethyl ester 2, 4a, Ba, 9,12b, 14a-hexamethyl-3, li-diaxa- 1,2,3,4, 4a, 5,6, Ba, 11, 12b, 13, 14, 14a, 14btetrdecahydrc-picen-4-yi ester; Acetic acid 9-hydraxy-4,6b,8a,I hexarnethyi-2, lO-diaxa- 2, 6b, 7,B, a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a terradecahydrc-picen-3-yi ester; Dadecanaic acid 9-hydraxy-4, 6b, Ba,' hexamethyi-2, lO-diaxa- 2, 6b, 7,81 Ba, 9,10,11,12, 12a, 12b, 13, 14, 14a terradecahydra-picen-3-yi ester; Dimethyl-car-bamic acid 4,6b,Ba,11,12b,14a-hexamethyl-2,10-diaxa 2,Bb, 7, B, a, 9,10, 11, 12, 12a, 12b, 13, 14, 14a terradecahydrc-picen-3-yl ester; Nicatinic acid 9-hydraxy-4, 6b, Ba,I hexamethyl-2, lO-diaxa- 2,Eb, 7,B, Ba, 9,10, 11, 12, 12a, 12b, 13, 14, 14a terradecahydrc-picen-3-yl ester; 0-hyd-raxy- 1, 12b, 14a- 1, 12b, 14a- 9 -hyd-raxy- 1, 12b, 14a- WO 2007/077203 PCT/EP2006/070276 11 -3,10-Dihydroxy-2,4a,6a,9,12b,14a-hexamethyl-1loxo-1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14btetradecahydro-picene-2-carboxylic acid methyl ester; 10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-ll-oxo- 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14btetradecahydro-picene-2-carboxylic acid methyl ester.
when the tricyclic structure is and R- 9 and R 20 are independently hydrogen or an acyl group, then:
R
5 is hydroxyl; or
R
2 1 and R 22 form a C=0 group together with the carbon to which they are attached and Rio is not
COOH.
when the tricyclic structure is and and R 20 are both CH 3 then R, 5 and Ri 6 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 R, 22 R59 RRg RI R21
(II)
where: R1, R2, R 3 R4, Rs, RG, RD, Rio, R 1
R
12
R
13 R14, R15, R 6, R 1 7 R13,
R
1 9 and R2 0 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1
-C
1 2 alkyl; substituted or nonsubstituted Cs-Cio aryl; a N(R (R x I amino group, where R" 7 and R" are independently hydrogen or a C 1
-C
12 alkyl group; or each WO 2007/077203 PCT/EP2006/070276 12 pair can form a carboxyl group together with the carbon to which they are attached;
R
7 and Rg are independently hydrogen; substituted or nonsubstituted C 1
-C
12 alkyl; CE-C 1 0 aryl; a COR xv I group (where R
VI
is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6 -Cio aryl; 0C-C 1 2 alkyl; or N(RN"l) (R x x amino, where R I 1 and R xzx are independently hydrogen or a CI-C 12 alkyl group); a (CH 2 -OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group,
R
2 i and R;4 are independently substituted or non-substituted Ci-
C
12 alkyl; a CORx' group (where R x is hydrogen; hydroxyl; substituted or non-substituted CI-C 12 alkyl; substituted or nonsubstituted C 6
-C
10 aryl; or N(RXl) (R xx amino, where R xxl and Rx xI l are independently hydrogen or a Ci-C 12 alkyl group); a [(CI- Cl 2 )alkyl-O-(C 1 -Cli)alkyl-], group (where n is comprised between 1 and or trifluoromethyl;
R
22 and R 23 are: hydrogen; substituted or non-substituted CI-C 1 2 alkyl; a CORXXI group (where R x 1 1 is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6 -Clo aryl; or N(R x x hI) (R" x amino, where Rxy v 1 and Rxx' are independently hydrogen or a CI-C 1 2 alkyl group); a [(Ci-C 1 2)alkyl-0- (C-C2)alkyl-]n group (where n is comprised between 1 and or trifluoromethyl when R 24 is in the para posiion with respect to Ro 2 or
-OR
22 and OR 2 3 respectively, where R22' and R23' are independently hydrogen; substituted or non-substituted Cj-
C
12 alkyl; a COR x "s I group (where R xx v is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted Cs-C 1 o aryl; or N(R vTT) (Rx-TT) amino, where
R
x xvI and R x v II are independently hydrogen or a CI-C 1 2 alkyl group); a [(C1-C12)alkyl-0-(Ci-Ci2)alkyl-]n group (where n is comprised between 1 and or trifluoromethyl when R 24 is in the meta posinion with respect to R 20 WO 2007/077203 PCT/EP2006/070276 13 or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof.
In another aspect, the invention is directed to a pharmaceutical composition comprising a compound of formula or a compound of formula 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) Rio Rg
R
10 p
(I)
RI, R, R3, R4, R, R, R7, R, R and R, are independently R6 C H
CH
aino group, where R' and are independently R, R,
(I)
where:
R
1
R
2
R
3
R
4
R
5
R
6
R
7 9 REr R1 and R- are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C-
C
1 2 akyl; substituted or non-substituted C 6
-C
1 0 aryl; a amino group, where R' and R' are independently hydrogen or a C-C 1 alkyl group; an OCOR group, where R is (CH2)2COOH or (CH)2C;CH 2
CH
3 or each pair can form a group together with the carbon to which they are attached; R, and R 1 o are independently hydrogen; substituted or nonsubstituted C 1
-C
1 2 alkyl; C 6 -Clo aryl; a COR"' group (where R"' is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
1 2 alkyl; substituted or non-substituted C 6
-C
10 aryl; O-C -C 1 2 alkyl; or N(RIV)(R') amino, where RTV and R are independently hydrogen or a C 1
-C
12 alkyl group); a (CH),-OH carbinol group (where n is WO 2007/077203 PCT/EP2006/070276 14 an integer comprised between 1 and 10); or together form a methylene group; the bond means a double bond or a single bond; and where the tricyclic structure is selected from the following structures:
R
14
R
13
R
14
R
13
R
14
R
13 R RR, R O R 2 0 0
R
R R I7
R
19 O R 19 0 R 19 0 A 23 R cO O10 R2 R Ri R, 2
R
22 R R, 21 (c) R Ri 4 Ri, R 1 4
R
1> Rs /1 R 2 CH ROHR I CH 3 R RC R iR'9R2 R 2 R
R
1 I R 2 R R R Ri 8
RI
8
R
2 1 (f) 0 where:
R
1 3
R
14 R, R G 15
R
21
R
22 and R 2 3 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-Ci 2 alkyl; substituted or non-substituted C 6 -Clo aryl; a amino group, where R"I and R"'I are independently hydrogen or a Ci-Ci alkyl group; an OCOR"II group, where R V 1 II is (CH2) COOH or (CH2)2CO2CH2CH 3 or each pair can form a group together with WO 2007/077203 PCT/EP2006/070276 the carbon to which they are attached or each pair can form a group together with the carbon to which they are attached;
R
1 7 is hydrogen or methyl;
R
18 and Ri8, are independently hydrogen; hydroxyl; halogen; Cl-Calkyl; C6-Cic aryl; COR
I
(where R" X is hydrogen; hydroxyl; C 1 -C12 alkyl; N(RX) amino, where R x and R- are independently hydrogen or a C 1 -C12 alkyl group; or C 1
-C
12 alcoxyl); or trifluoromethyl; Ri 9 R1S, R 20 and R20, are independently hydrogen; substituted or non-substituted C 1 -C12 alkyl; a COR"- group (where R x 5 is hydrogen; hydroxyl; substituted or non-substituted Ci-C], alkyl; substituted or non-substituted C 6 -Clo aryl; or N(R x I II
(R
x amino, where R x I and R x IV are independently hydrogen or a Ci-C12 alkyl group); a [(CL-C12)alkyl-O- (C-C12) alkyl-] group (where n is comprised between 1 and trifluoromethyl; or each 19-19' or 20-20' pair can form a C=0 group together with the carbon to which they are attached; R24 and R2 5 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 used in the prevention and/or treatment of a ChoK mediated disease or condition is a compound of formula (Ia): (Ia) where WO 2007/077203 PCT/EP2006/070276 16 RI, R2, R3, R4, Rs, RE, Rn and R- are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci- C12 alkyl; substituted or non-substituted Cs-Cio aryl; a amino group, where R' and are independently hydrogen or a CI-C12 alkyl group; an OCOR group, where R is (CH2)2COOH or (CH2)2C02CH2CH3; or each pair can form a group together with the carbon to which they are attached; R9 and Rio are independently hydrogen; substituted or nonsubstituted C,-C2, alkyl; C5-Cio aryl; a COR''' group (where is hydrogen; hydroxyl; substituted or non-substituted Ci-C 1 2 alkyl; substituted or non-substituted C,-C 1 aryl; O-C-C alkyl; or N(R 1 I
(R
v amino, where R Iv and R v are independently hydrogen or a Ci-C12 alkyl group); a (CH2)n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, R4, and are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C12 alkyl; substituted or non-substituted C6-Cio aryl; a (R v I) amino group, where R" and are independently hydrogen or a Cl-C2 alkyl group; an
OCOR'
1 11 group, where R"II is (CH2)2COOH or (CH2)2CO2CH2CH,; or each pair can form a group together with the carbon to which they are attached; R17 is hydrogen or methyl; R18 is hydrogen; hydroxyl; halogen; Ci-C12 alkyl; C6-Cio aryl; COR
I
(where R" is hydrogen; hydroxyl; Ci-Ci, alkyl; N(R) (R x amino, where R x and R x are independently hydrogen or a alkyl group; or C,-C12 alcoxyl); or trifluoromethyl; RIK is hydrogen; substituted or non-substituted CL-C 1 2 alkyl; a CORXI group (where is hydrogen; hydroxyl; substituted or non-substituted C--C 1 2 alkyl; substituted or non-substituted Cs- Cli aryl; or N (R x (R"xI) amino, where R x II and R x v are independently hydrogen or a CI-C2 alkyl group); a [(Ci-C12)alkyl- 0-(CI-Ci2)alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond.
WO 2007/077203 PCT/EP2006/070276 17 In a preferred embodiment, the compounds of formula (la) used in the invention comprise a substructure having the following formula
CH
3
R,
OHH
3 0CH o CH
CH
3 (la') where Rs is hydroxyl or a OCOR group where R is (CH2) COOH or
(CH
2 2 C02CH 2
CH
3
R
7 and Re are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 2
-C
1 alkyl; substituted or nonsubstituted CG-C 1 0 aryl; a amino group, where R' and are independently hydrogen or a CI-C 12 alkyl group; or each pair can form a group together with the carbon to which they are attached;
R
12 is independently hydrogen or a halogen; and Ri, is hydrogen; substituted or non-substituted CL-C 1 2 alkyl; a CORII group (where R' is hydrogen; hydroxyl; substituted or non-substituted C-_C 12 alkyl; substituted or non-substituted Cs- Cio aryl; or N (R x
(R"
x amino, where R x I I I and R x I" are independently hydrogen or a Ci-C], alkyl group); a alkyl- O-(Ci-Ci2)alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond.
Particular examples of this substructure are: 3,9-Dihydroxy-4,6b,8a,11,12b,14a-hexamethyl- 7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene- 2,10-dione; WO 2007/077203 WO 207/07203PCT!EP2006/070276 18 Acetic acid 9-hydr-oxy-4,6b,8a,11,12b,14a-hexamethyl-2,10 dioxo-2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14atetradecahydro-picen-3-yl ester; 9-hydlroxy-4,6b,8a,11,12b,14a-hexamethyl-2,10-dicxo- 2,Gb,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydropicene-3-yl propionic acid ester (Cl); Dodecanoic acid 9-hydroxy-4,6b,8a,11,12b,14-hexaieth-yl 2, 10-dicxo-2, 6b, 7,8, 8a, 9,10,11,12, 12a, 12b, 13, 14, 14atetradecahydro-picen-3-yl ester; Dimethyl-carbamic acid 9-hydroxy-4,6b,8a,11,12b,14a hexarnethyl-2, lO-dioxo- 2, 6b, 7,8, 8a, 9,10,11, 12, 12a, 12b, 13, 14, 14a-tetradecahydropicen-3-yl ester; Nicctinic acidl 9-hydroxy-4,6b,8a,11,12b,14a-hexamethyl 2,10-dicxo-2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14atetradecahydro-picen-3-yl ester; 4-brcmo-(9-hyd-roxy-6b,8a,11,12b,14a-hexamethyi-2,10-dioxo- 2,Gb, 7,8, 8a, 9,10,11, 12, 12a, 12b, 13, 14, 14a-tetradecahydropicene-3-yl) bensoic acid ester (C2); 14-Bromrt-3,7,9-trihydroxy-4,b,8a,11,12b,14a-hexamethyl- 7,8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene- 2,10-diane; 12-bromc-9-hydroxy-6b,8a,11,12b,14a-hexamethyl-2,10-dioxo- 2,Gb, 7,8, 8a, 9,10,11,12, 12a, 12b, 13, 14, 14a-tetradecahydropicene-3-yl dimer-hyl-carbamic acid ester (C4); 4-brcmo-(12-bromo-9-hydrcxy-Gb,8a,11,12b,14a-hexamethyl- 2, 10-dicxo-2, 6b, 7,8, 8a, 9,10,11,12, 12a, 12b, 13, 14, 14atetradecahydro-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-diane (C3); 3,9,10-t-rihydraxy-6b,8a,11,12b,14a-hexamethyl- 7,8, 8a, 9,10,11,12, 12a, 12b, 13, 14, 14a-dodecahydrao-6bHpicene-2-one (C6) Succinic acid mono-(10-hydr-oxy-2,4a,6a,9,12b,14a hexamethyl-3, li-dioxo- WO 2007/077203 PCT/EP2006/070276 19 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydropicen-4-yl) ester; Succinic acid ethyl ester 10-hydroxy-2,4a,6a,9,12b,14ahexamethyl-3,11-dioxo- 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydropicen-4-yl ester.
In another preferred embodiment, the compounds of formula (Ia) used in the present invention comprise a substructure having the following formula CHs gH "RCH 3
CH
R,,o
CH,
(la") where:
R
7 and R 8 are independently hydrogen, hydroxyl, halogen, substituted or non-substituted CI-C 1 2 alkyl, substituted or nonsubstituted C 6 -Cio aryl, a amino group, where R' and R" are independently hydrogen or a CI-C 1 2 alkyl group, or each pair can form a group together with the carbon to which they are attached;
R
15 is hydrogen or halogen;
R
19 is hydrogen, substituted or non-substituted CI-C 1 2 alkyl; a
COR
x x group (where RK" is hydrogen; hydroxyl; substituted or non-substituted C--C 12 alkyl; substituted or non-substituted Cs- Cl aryl; or N (R x amino, where R X and R x v are independently hydrogen or a CI-C2 alkyl group); a [(Cl-C12)alkyl- 0-(Cl-Ci2)alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond.
Particular examples of this substructure are: WO 2007/077203 PCT/EP2006/070276 -14-bromo-3-hydroxy-4,6b, a,11,12b,14a-hexamethyl- 7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene- 2,10-dione (27); -4,6b,8a,11,12b,14a-hexamethyl-2,10-dioxo- 2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-tetradecahydropicene-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-tetradecahydropicene-3-yl nicorinic acid ester (C9); -3,10-dihydroxy-4,6b,8a,11,12b,14a-hexamethyl- 7,8,8a,9,10,11,12,12a,12b,13,14,14a-dodecahydro-6bHpicene-2-one -3-hydroxy-4,6b,8a,11,12b,14a-hexamethyl- 7,8,8a,12a,12b,13,14,14a-octahydro-6bH,9H-picene-2,10dione (C11).
In another preferred embodiment, the compounds of formula (Ia) used in the present invention comprise a substructure having the following formula where: R7 is hydrogen, hydroxyl, halogen, substituted or nonsubstituted C--Ci alkyl, substituted or non-substituted Ch-C] aryl, or a amino group, where R' and are independently hydrogen or a C 1 -Ci2 alkyl group; and R9, is substituted or non-substituted CI-C 1 alkyl; a COR II group (where R"I is hydrogen; hydroxyl; substituted or non-substituted Ci-Cl2 alkyl; substituted or non-substituted C 6
-CI
0 aryl; or WO 2007/077203 WO 207/07203PCT!EP2006/070276 21 N (RxIII) (RxTv) amino, where RxIII and R,' 7 are independently hydrogen or a C 1
-C
12 alkyl group) a (C 1
-C
1 2 alkyl-O- (C 1
-C
1 2 alkyl-], group (where n is comprised hetween 1 and or trifluoromethyl.
Particular examples of this suhstructure are: lO-hydroxy-2, 4a, Ga, 9,l2h, 14a-hexamethyl-ll-oxo- 1, 2,3, 4, 4a, 5,6,Ga, 11, 12b, 13, 14, 14a, 14b-recr-adecahydlropicene-2-carboxylic arid methyl ester; 3,lQ-dihydroxy-2,4a,6a,9,12b,14a-hexamethyl-ll-oxo- 1, 2,3, 4, 4a, 5, 6,Ga, 11, 12b, 13, 14, 14a, 14b-tetoradecahydlropicene-2-carboxylic arid methyl ester (C12); 2,4a,6a,9,12b,14a-hexamethyl-ll-oxo)-l0-propionyloxy- 1, 2,3, 4, 4a, 5,6, 6a, 11, 12b, 13, 14, 14a, 14b-recr-adecahydlropicene-2-carboxylic acid methyl ester (C13); lO-dimethylcarhamoyloxy-2,4a,6a,9,12h,14a-hexamethyl-lloxo-l, 2,3, 4, 4a, 5, 6, a, 11, 12h, 13, 14, 14a, 14b-tetradecahydropicene-2-carboxylic acid methyl ester (C14).
In another particular compound of formula used of a ChcK mediated disease or (Ih): Dmbodiment of the invention, rho in the prevention and/or creatment condition is a compound of formula (Ih) where:
R.
1
R
2
R
3
R
4
R
6
R,,
hydrogen; hydroxyl; halogen;
C
12 alkyl; substituted or Re, R 11 and R 12 are independently suhstituted or non-suhstituted C 1 non-substituted C 6
-C
1 0 aryl; a WO 2007/077203 PCT/EP2006/070276 22 amino group, where R' and are independently hydrogen or a Ci-C12 alkyl group; or each pair can form a (C=0) group together with the carbon to which they are attached; R9 and Rio are independently hydrogen; substituted or nonsubstituted Ci-C12 alkyl; Cs-Clo aryl; a COR''' group (where is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted Cc-C0o aryl; 0-Ci-C2 alkyl; or N(RI) amino, where RI and R' are independently hydrogen or a C1-C12 alkyl group); a (CH 2 )n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group,
R
13 R14, R 1 Ri 6
R
2 1
R
2 2 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-C12 alkyl; substituted or non-substituted CE-Cio aryl; a (R' 7 I amino group, where and R
VI
are independently hydrogen or a C1-C12 alkyl group; or each pair can form a group together with the carbon to which they are attached;
R
1 7 is hydrogen or methyl;
R
1 8 is hydrogen; hydroxyl; halogen; Ci-C12 alkyl; Ce-C-o aryl; COR
IX
(where R 1 is hydrogen; hydroxyl; Ci-C12 alkyl; N(R x
(R
x amino, where R x and R x are independently hydrogen or a Ci-C], alkyl group; or Ci-C2 alcoxyl); or trifluoromethyl; RI9 and R2 0 are independently hydrogen, substituted or nonsubstituted C1-C12 alkyl; a COR x group (where R x II is hydrogen; hydroxyl; substituted or non-substituted Ci-C alkyl; substituted or non-substituted Ch-C() aryl; or N(R x 1 1 1 (Rx
P
amino, where R X 1 and R x
I
v are independently hydrogen or a C1-C2 alkyl group); a [(CL-Ci2)alkyl-O-(CI-C12) alkyl-] group (where n is comprised between 1 and 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 WO 2007/077203 WO 207/07203PCT!EP2006/070276 23
OH
3 0
OH
3
OH
OH
3
R,
0 0 ICH-11
CH,
R
19 0
CH
3
OH
(Ib') where: RID anid R 0 o are independently substituted o- non-substituted Cj-
C
12 alkyl; a CORX", group (where R is hydrogen; hydroxyl; substituted or non-substituted CI-CI2 alkyl; substituted or nonsubstituted CG-Cic aryl; or N(RX amino, where Rx" and RX\v are independently hydrogen or a C2_ 1 alkyl group) a [(C 1
C
1 2)alkyl-O-(C 1 -Cj2)alkyl-], group (where n is comprised between 1 and or trifluoromethyl.
A particular example of this substruoture is 4-nitro- 9-dihvdroxy-4, 6b, 8a, 11, 12b, 14a- 6b, 7,8, 8a, 9,10,11,12, 12a, 12b, 13, 14, 14atetradecahydro-picene-2 yl) benzoic acid ester In another preferred embodiment, the compounds of formula (Ib) comprise a substr-ucture having the followina formula (Ib''
H
3 COOC_ OH 3 gH 3
CH-
HO
OH1 C 3 R R23
R
1 8 0 (Ib'f where: WO 2007/077203 PCT/EP2006/070276 24
R
1 I is hydrogen; hydroxyl; halogen; Ci-C12 alkyl; C 6 -C-o aryl; CORIX (where RI" is hydrogen; hydroxyl; Ci-C 1 2 alkyl; N(R) (R X I amino, where R x and R
X
are independently hydrogen or a CI-C 12 alkyl group; or C 1
-C
1 2 alcoxyl); or trifluoromethyl; RI9 is hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a
COR
x I group (where RI" is hydrogen; hydroxyl; substituted or non-substituted C--C 2 alkyl; substituted or non-substituted Cs- Cio aryl; or N (R x amino, where Rx I I I and RXIv are independently hydrogen or a Ci-C 12 alkyl group); a [(Ci-C 1 2)alkyl- O-(CL-CI2)alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl;
R
23 is hydrogen; hydroxyl; halogen; substituted or nonsubstituted C -C 1 2 alkyl; substituted or non-substituted C 6 -Co 0 aryl; a N(RVI) (R amino group, where R and R" v are independently hydrogen or a C1-C12alkyl group.
Particular examples of this substructure 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-tetradecahydropicene-2-carboxylic acid methyl ester (F16); 9-formyl-l0,11-dihydroxy-2,4a,6a,12b,14a-pentamethyl-8oxo-1,2,3,4,4a,5,6,6a,8,12b,13,14,14a,14b-tetradecahydropicene-2-carboxylic acid methyl ester (C17); ll-hydroxy-10-(2-methoxy-ethoxymethoxy)-2,4a,6a,9,12b,14ahexamethyl-8-oxo-l,2,3,4,4a,5,6,6a,8,12b,13,14,14a,14btetradecahydro-picene-2-carboxylic acid methyl ester (C18).
In another particular embodiment of the invention, the compound of formula used in the prevention and/or treatment of a ChcK mediated disease or condition is a compound of formula (Ic): WO 2007/077203 PCT/EP2006/070276 R(I
R
(1C) R, R, R, R, R, R and R are independen hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-
C
1 2 alkyl; substituted or non-substituted CG-Co aryl; a amino group, where R' and are independently hydrogen or a Ci-C 1 2 alkyl group; or each pair can form a (C-0) group together with the carbon to which they are attached; R9 and Ri, are independently hydrogen; substituted or nonsubstituted Ci-C 1 i alkyl; Cs-C10 aryl; a COR''' group (where is hydrogen; hydroxyl; substituted or non substituted C- Ci2 alkyl; substituted or non-substituted C 6
-C
11 aryl; 0-C--Ci7 alkyl; or N(R v amino, where R and R v are independently hydrogen or a Ci-C2 alkyl group); a (CH2)n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group; H Ra Rill R21 (Ic) where: R, R4, R3 RI, R 6
R
1 andR R R and R ae independently hydrogen; 2 hydroxyl; halogen; halogen; substituted or non-substituted C-C alky Salkyl; substituted or non-substituted C-C-Ci aryl; a N(R) amino group,) amino group, where iR' andetly hydrogeen or a C-Cy hydrogen or aalkyl group; or each pair can form a group together with group together with the carbon to which they are attached; R9 and Rjo are independently hydrogen; substituted or nonsub is hydrogen; hydroxlkyl; C-Clo aryl; a COR aoup (Chearyl; CR" is hydrogen; hydroxyl; substituted or nonsubstituted C(RC) amino, alkyl; substituted or non-substituted C(-Cjo aryl; O-C--CI2 alkyl; or N(RR) amino, where R and R are independently hydrogen or a C-C alky or a C-C-C2 alkyl group); a (CH-OH binol group (where n istrifluoromethyl; an integer comprised between 1 and 10); or together form a methylene group; R13r R-4, R15r R16, R21 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C -Cjo aryl; a 711) amino group, where R" and Rv" are independently hydrogen or a C1-C12 alkyl group; or each pair can form a group together with the carbon to which they are attached; R18 is hydrogen; hydroxyl; halogen; C2-C12 alkyl; CE-Co aryl; CORIX (where RI" is hydrogen; hydroxyl; C-C12 alkyl; N(Rx)(RXI) amino, where Rx and Rx' are independently hydrogen or a CI-C12 alkyl group; or alcoxyl); or trifluoromethyl; WO 2007/077203 PCT/EP2006/070276
R
1 9 and R 20 are independently hydrogen; substituted or nonsubstituted C 1
-C
12 alkyl; a CORx
I
group (where RxII is hydrogen; hydroxyl; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6 -Cio aryl; or N(RIII) (R x amino, where R X 1 and R'v are independently hydrogen or a CI-C 1 2 alkyl group); a [(CL-C 12 )alkyl-O-(Ci-C 12 )alkyl-]n group (where n is comprised between 1 and or trifluoromethyl; and the bond means a double bond or a single bond.
In present formula an embodiment, the invention comprise compounds of formula (Ic) used in the a substructure having the following (Ic') where: Ri, and R2o are independently hydrogen; substitu substituted C 1
-C
12 alkyl; a CORXII group (where RXII hydroxyl; substituted or non-substituted Ci substituted or non-substituted Cg-Clo aryl; or N(RX 1 11 where R II I and R" v are independently hydrogen or group); a [(CL-C 1 2)alkyl-O-(Ci-C12) alkyl-]n group comprised between 1 and 3) or trifluoromethyl; and the bond means a double bond or a single bond.
ted is -C1 2
(R
SCi (whe or nonhydrogen; alkyl; xI) amino, -Cl] alkyl ire n is Particular examples of this substructure are: 10,11-dihydroxy-2,4a,6a,9,14a-pentamethyl- 1,4,4a,5,6,6a,13,14,14a,14b-decahydro-2H-picene-3-one (C19); WO 2007/077203 PCT/EP2006/070276 27 10,11-dihydroxy-2,4a,6a,9,14a-pentamethyl- 4a,5,6,6a,13,14,14a,14b-octahydro-4H-picene-3-one In another preferred embodiment, the compounds of formula (Ic) used in the present invention comprise a substructure having the following formula H3C 400CH- CH3 CH3 CCH3H (Ic") where: R19 and R2 0 are independently hydrogen; substituted or nonsubstituted C 1
-C
12 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
1 2 alkyl; substituted or non-substituted Cg-Clo aryl; or N(R x amino, where R x and Rx" are independently hydrogen or a C 1
-C
1 2 alkyl group); a [(CL-Ci2)alkyl-- (Ci-C2) alkyl-], group (where n is comprised between 1 and or trifluoromethyl.
A particular example of this substructure is 10,11dihydroxy-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 used in the prevention and/or treatment of a ChoK mediated disease or condition is a compound of formula (Id): WO 2007/077203 PCT/EP2006/070276 28 Rio R9 CH3 7 R1 ""H1rR, RAI R SR, R 2 Rai R'1 (Id) where: RI, R2, R 3 R4, R, R6, R Re, Ri and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-
C
1 2 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; a amino group, where R' and are independently hydrogen or a Ci-C 1 2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Rio are independently hydrogen; substituted or nonsubstituted CI-C 1 2 alkyl; Cs-Cio aryl; a COR"' group (where R' is hydrogen; hydroxyl; substituted or non-substituted C1_C12 alkyl; substituted or non-substituted CE-Cio aryl; 0-C--C 1 2 alkyl; or N(RV) (R v amino, where R" and Rv are independently hydrogen or a Ci-C12 alkyl group); a (CH2)n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, R1 3 Ris, R2 1 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C12 alkyl; substituted or non-substituted C 6 -Clo aryl; a N(R v I
(R
v I) amino group, where
R"
V and R 7 T are independently hydrogen or a Ci-C 1 2 alkyl group; or each pair can form a (C O) group together with the carbon to which they are attached; R1e is hydrogen; hydroxyl; halogen; Ci-C 1 2 alkyl; C 6 -Co- aryl; COR Ix (where R
I
is hydrogen; hydroxyl; Ci-C12 alkyl; N(R x (Rx) amino, where R x and R x are independently hydrogen or a CI-C12 alkyl group; or Ci-C12 alcoxyl); or trifluoromethyl; WO 2007/077203 PCT/EP2006/070276 29
R
1 9, R 1
R
20 and R 20 are independently hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a CORx" group (where R x is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non-substituted C 6 -Cio aryl; or N(R x11
(R
x y) amino, where R X 1 and Rtv are independently hydrogen or a CI-C 12 alkyl group); a [(CL-C 12 )alkyl-O-(Ci-C 12 )alkyl-] group (where n is comprised between 1 and trifluoromethyl; or each 19-19' or 20-20' pair can form a C=0 group together with the carbon to which they are attached; R2 4 and R 25 are independently hydrogen, hydroxyl or halogen; and the bond means a double bond or a single bond.
In a preferred embodiment, the compounds of formula (Id) used in the present invention comprise a substructure having the following formula
CH,
0 HH3
RR
R
24
R
25
R
e CH 3 CH36
R
20
H
R
1 9
CHH
3 (Id') where: Rs and R 6 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-Ci> alkyl; substituted or nonsubstituted C 6
-CI
1 aryl; a amino group, where R' and R" are independently hydrogen or a C 1
-C
1 2 alkyl group; or each pair can form a group together with the carbon to which they are attached; Rig, Ris,, R 20 and R 20 o are independently hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a COR" group (where R x is hydrogen; hydroxyl; substituted or non-substituted C2-C?2 alkyl; substituted or non-substituted C 6
-C
0 o aryl; or N(R xx x
(R
x amino, where R X T and R
X
IV are independently hydrogen or a C 1
-C
1 2 alkyl WO 2007/077203 PCT/EP2006/070276 group); a [(C-C 12 alkyl-0- (C 1
-C
12 alkyl-] n group (where n is comprised between 1 and trifluoromethyl; or each 19-19' or 20-20' pair can form a C=O group together with the carbon to which they are attached; R21 and R 25 are independently hydrogen, hydroxyl or halogen.
Particular examples of this substructure are: l-bromo-9-hydroxy-4,6b,8a,11,12b,14b-hexamethyl- 6b,7,8,8a,9,11,12,12a,12b,14b-decahydro-lH-picene-2,3,10trione (C22); l-bromo-4,6b,8a,11,12b,14b-hexamethyl- 6b,7,8,8a,9,11,12,12a,12b,14b-decahydro-1H-picene-2,3,10trione (C23).
In another preferred embodiment, the compounds of formula (Id) used in the present invention comprise a substructure having the following formula
H
3 C COOCH 3 CH3 C H 3 R19' R19 CH3 (Id where: R1I, R 10
R
2 0 and R 20 are independently hydrogen; substituted or non-substituted Ci-Ci alkyl; a COR" x group (where R x I is hydrogen; hydroxyl; substituted or non-substituted Ci-C 1 2 alkyl; substituted or non-substituted C 6 -Ci0 aryl; or N(RIII) (RIv) amino, where R XII I and R x IV are independently hydrogen or a CI-C 1 2 alkyl group); a [(C 1
-C
12 alkyl-O- (C-C 12 alkyl-] n group (where n is comprised between 1 and trifluoromethyl; or each 19-19' or 20-20' pair can form a C=0 group together with the carbon to which they are attached;
R
24 and R2 5 are independently hydrogen, hydroxyl or halogen.
WO 2007/077203 PCT/EP2006/070276 31 A particular example of this substructure is 12bromo-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-2carboxylic acid methyl ester (C24).
In another particular embodiment of the invention, the compound of formula used in the prevention and/or treatment of a ChoK mediated disease or condition is a compound of formula (le): Ri O R1 1 R 1 3 12 R g14 CH3 R7 R, 2 R, 6 R, and 12 are independenly
R
2 4 H RH Salkyl; substituted or non-substituted -0 aryl; a
R-'R
Rio -RR R 2 Rl8b Ri8 R21 (Ie) where: R1, R2, R3, R4, Rs, R, R Ra, R1 and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cj- C12 alkyl; substituted or non-substituted Cs-Clo aryl; a amino group, where R' and 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 Rio are independently hydrogen; substituted or nonsubstituted CI-C12 alkyl; Co-Clo aryl; a COR'' group (where is hydrogen; hydroxyl; substituted or non-substituted Ci-C12 alkyl; substituted or non-substituted CE-CIo aryl; O-C -C12 alkyl; or N(RIV) (R v amino, where R' v and Rv are independently hydrogen or an alkyl group CI-C-2); a carbinol group (CH2)n-OH (where n is an integer comprised between 1 and 10); or together form a methylene group; RIB, R- 4 Ri 5 Ri 6 R2 1 and R2 3 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-C12 alkyl; WO 2007/077203 PCT/EP2006/070276 32 substituted or non-substituted C 6 -Ci 0 aryl; a N(R' 7
(R'
1 amino group, where R' and R V are independently hydrogen or a C 1 -Ci2 alkyl group; or each pair can form a group together with the carbon to which they are attached;
R
1 i and R18, are independently hydrogen; hydroxyl; halogen; Ci-C,alkyl; C6-Cic aryl; COR Ix (where R I x is hydrogen; hydroxyl; Ci-C 1 2 alkyl; N(R x
(R"
I
amino, where R x and R- are independently hydrogen or a CI-C12 alkyl group; or CI-C 1 alcoxyl); or trifluoromethyl;
R
1 9, R20 and R20, are independently hydrogen; substituted or non-substituted C 1
-C
1 alkyl; a COR
I
group (where R x is hydrogen; hydroxyl; substituted or non-substituted C-C12 alkyl; substituted or non-substituted C 6 -Clo aryl; or N(RXIII) (RXIV amino, where R x I I I and R x IV are independently hydrogen or a C1-Cz2 alkyl group); a [(CL-Cz2)alkyl-O-(C 1 -C2) alkyl-]n group (where n is comprised between 1 and 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
H
3 C COOCH
CH
3 R24 R2i
CH
3
R
2
R,'
R
18
R
1 s (le') where: R1 8 and R18, are independently hydrogen; hydroxyl; halogen; Cl-C-2 alkyl; C,-Cl aryl; COR I x (where R I x is hydrogen; hydroxyl; Ci-C, WO 2007/077203 PCT/EP2006/070276 33 alkyl; N(Rx) (RxI) amino, where R x and RX are independently hydrogen or a C 1
-C
12 alkyl group; or C 1
-C
12 alcoxyl); or trifluoromethyl; Ri 9 Rlos, R 2 0 and R 2 0 are independently hydrogen; substituted or non-substituted C 1
-C
1 2 alkyl; a COR"- group (where Rx" is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
2 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; or N(RIII) (R x I amino, where R x II I and RX" I are independently hydrogen or a C 1
-C
1 2 alkyl group); a [(C 1 -Cl 2 )alkyl-O-(C 1
-C
12 alkyl-] n group (where n is comprised between 1 and trifluoromethyl; or each 19-19' or 20-20' pair can form a C=0 group together with the carbon to which they are attached;
R
2 4 is hydrogen, hydroxyl or halogen.
A particular example of this substructure is 9hydroxy-2,4a,6a,9,12b-hexamethyl-10,11-dioxo- 1,2,3,4,4a,5,6,6a,9,1C,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylic acid methyl ester In another particular embodiment of the invention, the compound of formula used in the prevention and/or treatment of a ChoK mediated disease or condition is a compound of formula (If): R R 9 R 1 3 ^?24 1R 2 CH 3 H CH3 R2 4
R
1
R
1
R
2 S 9R 23
R
15 RI R 2 1 (If) where: WO 2007/077203 PCT/EP2006/070276 34 RI, R2, R 3
R
4 Rs, R 6 RE, Rn and R_ are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci- C12 alkyl; substituted or non-substituted Cs-Cio aryl; a amino group, where R' and are independently hydrogen or a Ci-C12 alkyl group; or each pair can form a (C=0) group together with the carbon to which they are attached; R, and R 1 i are independently hydrogen; substituted or nonsubstituted CI-C12 alkyl; Cs-CIo aryl; a COR"' group (where is hydrogen; hydroxyl; substituted or non-substituted C-C12 alkyl; substituted or non-substituted CE-Ci0 aryl; 0-C--C2 alkyl; or N(RIV) (R v amino, where RIV and R v are independently hydrogen or a CI-C12 alkyl group); a (CH-)n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group,
R
13
R_
4 R1s, R2 1 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-Ci, alkyl; substituted or non-substituted C6-Clo aryl; a N(R 1 T) (R
VTT
amino group, where R" and R V 1 are independently hydrogen or a Cl-C12 alkyl group; or each pair can form a group together with the carbon to which they are attached; Ri and Ri, are independently hydrogen; hydroxyl; halogen; Ci-Calkyl; CG-Cic aryl; CORI x (where RI is hydrogen; hydroxyl; C1-C12 alkyl; N(RX) amino, where R x and R- are independently hydrogen or a CI-Ci2 alkyl group; or CI-C12 alcoxyl); or trifluoromethyl; Ri,, Ri,, and are independently hydrogen; substituted or non-substituted CI-C12 alkyl; a COR group (where R x is hydrogen; hydroxyl; substituted or non-substituted C1-C1s alkyl; substituted or non-substituted C6-Clo aryl; or N(RxIII) (R x I amino, where R I I I and R x I are independently hydrogen or a C1-C12 alkyl group); a [(Ci-C 1 2 alkyl-0- (Ci-C2) alkyl-] group (where n is comprised between 1 and trifluoromethyl; or each 19-19' or 20-20' pair can form a C=0 group together with the carbon to which they are attached; R2 1 is hydrogen, hydroxyl or halogen; and the bond means a double bond or a single bond.
WO 2007/077203 PCT/EP2006/070276 In a preferred embodiment, the compounds of formula (If) used in the present invention comprise a substructure having the following formula
H
3 C COOCH 3 R 9
R
18
R
18 (If') where:
R
12 and R28, are independently hydrogen; hydroxyl; halogen; C 1 -C-2 alkyl; C6-Cic aryl; COR x (where RI is hydrogen; hydroxyl; CL-Ci2 alkyl; N(R
X
(R"
x amino, where R x and R x are independently hydrogen or a C 1 -C12 alkyl group; or C1-C12 alcoxyl); or trifluoromethyl;
R
19 R19,, R 20 and R20, are independently hydrogen; substituted or non-substituted Ci-C. alkyl; a CORx" group (where R x is hydrogen; hydroxyl; substituted or non-substituted CI-C12 alkyl; substituted or non-substituted CG-Cio aryl; or N(R x x II) (RXI) amino, where R x II and RxTv are independently hydrogen or a C1-C12 alkyl group); a [(CL-C12)alkyl-O-(C1-C12) alkyl-] group (where n is comprised between 1 and trifluoromethyl; or each 19-19' or 20-20' pair can form a group C=0 group together with the carbon to which they are attached; R24 is hydrogen, hydroxyl or halogen.
A particular example of this substructure is the 9hydroxy-2,4a,6a,6b,9-hexamethyl-lO,11-dioxo- 1,2,3,4,4a,5,6,6a,6b,ea,9,10,11,14,14a,14b-hexadecahydro-picene- 2-carboxylic acid methyl ester (C26).
In another particular embodiment of the invention, the compound of formula (II) used in the prevention and/or treatment WO 2007/077203 PCT/EP2006/070276 36 of a ChoK mediated disease or condition is a compound of formula (IIa):
R
1
R
1
R,
R5 where: 2R23 R22 R R,7 \1 R 1 4 R21 R2c R (IIa) where:
R
1
R
2
R
3
R
4 Rs 5 R6r R, Rlor R 11
R
1 2
R
1 3 R14, R 1 5 1 Rl 6
R
1 7 r R 1 8, Ri, and are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1
-C
12 alkyl; substituted or nonsubstituted Cs-C-0 aryl; a N(R x
(R
x I amino group, where R x and RXVI are independently hydrogen or a C 1
-C
12 alkyl group; or each pair can form a carboxyl group together with the carbon to which they are attached; R, and R8 are independently hydrogen; substituted or nonsubstituted C 1
-C
12 alkyl; Ce-Co1 aryl; a COR v II group (where Rx'
I
is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
1 2 alkyl; substituted or non-substituted C 6 -Clo aryl; O-Ci-C 12 alkyl; or N(R x v n
I
(RIX) amino, where R x v II and RXIX are independently hydrogen or a C 1
-C
12 alkyl group); a (CH 2 -OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group,
R
2 1 and R2 1 are independently substituted or non-substituted C 1
C
1 2 alkyl; a COR x group (where R x x is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
1 2 alkyl; substituted or nonsubstituted Cs-C10 aryl; or N(R x x
(R
xx amino, where R x and Rx" x are independently hydrogen or a C 1
-C
1 2 alkyl group); a [(C 1
C
12 )alkyl-O-(C 1 -C12)alkyl-]n group (where n is comprised between 1 and or trifluoromethyl; R22 and R2 3 are: hydrogen; substituted or non-substituted CI-C;2 alkyl; a
COR
x x x group (where R"" x is hydrogen; hydroxyl; WO 2007/077203 PCT/EP2006/070276 37 substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; or N(R x x v (Rxx) amino, where R and R"
X
are independently hydrogen or a Ci-C 12 alkyl group); a [(C 1
-C
1 2)alkyl-0-(C 1
-C
1 2)alkyl-]n group (where n is comprised between 1 and or trifluoromethyl when R 24 is in the para posirion with respect to R 2 0 or
OR
22 and OR 2 3 respectively, where R22' and R 23 are independently hydrogen; substituted or non-substituted CL-
C
12 alkyl; a COR x lI" group (where RXx v is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
1 2 alkyl; substituted or non-substituted 0 6
-C
1 o aryl; or N(R"Xv I I (Rxxv
I
I) amino, where I I and R xxv I II are independently hydrogen or a C 1
-C
12 alkyl group); a [(C 1
-C
12 )alkyl-O-(C 1
-C
2 )alkyl-]n group (where n is comprised between 1 and or trifluoromethyl when R2 4 is in the meta posirion with respect to R 20 In a preferred embodiment, the compounds of formula (IIa) used in the present invention comprise a substructure having the following formula (IIa'):
H
3 C COOCH 3 R24 R21 (IIa') where:
R
1 9 and R2 0 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 12 alkyl; substituted or nonsubstituted Cs-C0o aryl; a N(R x
(R
xvI amino group, where R xv and
R""
1 are independently hydrogen or a C 1
-C
12 alkyl group; or each pair can form a carboxyl group together with the carbon to which they are attached;
R
21 and R2 4 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-C 12 alkyl; substituted or nonsubstituted C 6 -Cio aryl; a N(Rxx") (R x x I) amino group, where R'" 1 and WO 2007/077203 PCT/EP2006/070276 38 R""I are independently hydrogen or a C 1
-C
1 2 alkyl group; or each pair can form a carboxyl group together with the carbon to which they are attached; R22 and R 23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1
-C
12 alkyl; substituted or nonsubstituted C 6 -Ci 0 aryl; a N(Rxx"v) (R xx v) amino group, where R x v and R xxv are independently hydrogen or a C 1
-C
12 alkyl group; or each pair can form a carboxyl group together with the carbon to which they are attached.
A particular example of this substructure (IIa') is: 8-[2-(6,7-dihydroxy-l,5-dimethyl-naphthalen-2-yl)-ethyl]-2,4atetramethyl-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, -he bibliographic background supports the role of the ChoK enzyme in the intracellular metabolism of certain WO 2007/077203 PCT/EP2006/070276 39 nucleosides in Hep-G2 cells, the use of said enzyme as an enzymatic marker in parasitic diseases and the participation thereof in the biosynthesis of important phospholipids in viruses, bacteria and fungi.
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 S H CH 3
R,
R, R
(I)
where:
R
1
R
2
R
3
R
4
R
5
R
6
R
7 RE, R11 and R- 2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-
C
12 alkyl; substituted or non-substituted C 6
-C
0 aryl; a amino group, where R' and are independently hydrogen or a C 1
-C
12 alkyl group; an OCOR group, where R is (CH2)2COOH or (CH2)2CO2CH 2
CH
3 or each pair can form a group together with the carbon to which they are attached; WO 2007/077203 PCT/EP2006/070276 RO and R 10 are independently hydrogen; substituted or nonsubstituted C 1
-C
1 2 alkyl; Cs-Cio aryl; a COR''' group (where is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted CE-C 10 aryl; 0-CI-C 1 2 alkyl; or N(R
I
V) amino, where R
I
V and Rv are independently hydrogen or a C1-C 12 alkyl group); a (CH) 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; 0 and where the tricyclic structure is selected from the following structures:
R
14
R
13
R
14 R, R 14
R
13 RRO R ~R 19 R
R
9 0 R R Rig° R!O R 3 R R 21
R
22 R R 21 (c) 13 1 4
R
13 14
R
13 RH R20 C 1 c R' R -R Ri 8
R
21
R
1 8
R
18
R
21 R R 15
R
2 (f) where:
R
13 Ri4, Rs 5
R
1 6, R 21
R
22 and R2 3 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-C 12 alkyl; WO 2007/077203 PCT/EP2006/070276 41 substituted or non-substituted C 6 -Cio aryl; a N(R 7
(R'
7 1 amino group, where R' and R"I are independently hydrogen or a C1-C12 alkyl group; an OCOR v group, where Rv 2 is (CH2) 2COOH or (CH2)02COH 2
CH
3 or each pair can form a group together with the carbon to which they are attached or each pair can form a group together with the carbon to which they are attached;
R
1 is hydrogen or methyl;
R
1 I and Ria, are independently hydrogen; hydroxyl; halogen; Cl-Calkyl; C6-Cic aryl; COR Ix (where R I is hydrogen; hydroxyl; Ci-C12 alkyl; N(Rx) amino, where R x and R x are independently hydrogen or a C 1
-C
1 alkyl group; or Ci-Ci, alcoxyl); or trifluoromethyl;
R
19 R19,, R20 and R20o are independently hydrogen; substituted or non-substituted CI-C12 alkyl; a COR x group (where R x I is hydrogen; hydroxyl; substituted or non-substituted Ci-C,1 alkyl; substituted or non-substituted Ch-C]( aryl; or N(R x I) (R x amino, where R T TT and R" TV are independently hydrogen or a CI-C12 alkyl group); a [(CL-C12)alkyl-O-(Ci-C12) alkyl-] group (where n is comprised between 1 and trifluoromethyl; or each 19-19' or 20-20' pair can form a C=0 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 then the compound of formula is not: 10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-ll-oxo- 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14btetradecahydro-picene-2-carboxylic acid; 10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-ll-oxo- 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14btetradecahydro-picene-2-carboxylic acid methyl ester; 3,10-Dihydroxy-2,4a,6a,9,12b,14a-hexamethyl-1loxo-1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b- WO 2007/077203 WO 207/07203PCT!EP2006/070276 tecradecahydrc-picene-2-carboxylic acid me ester; 3-Hydroxy-4,6b,8a,11,12b,14a-hexamethyi- 7,8, 8a, 11, 12, 12a, 12b, 13,14, 14a-decahydro-6bH, 9H picene-2, lO-dione; 3,9-Dihydrcxy-4,6b,8a,11,12b,14a-hexamethyl- 7,8, 8a,11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H picene-2, lO-dione; 3,7,9-Trihydroxy-4,6b,8a,11,12b,14a-hexamechyl- 7,8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H picene-2, lO-dione; 14-Bromo-3,7,9-trihydroxy-4,6b,8a,11,12b,14ahexamethyl-7, 8, 8a, 11, 12, 12a, 12b, 13, 14, 14adecahydro-6bH, 9H-picene-2, iC-dione; Succinic acid mono-(10-hyd-oxy-2,4a,6a,9,12b, hexamethyl-3, li-dioxo- 1,2,3,4, 4a, 5,6, 8a, 11, 12b, 13, 14, 14a, 14btetradecahydrc-picen-4-yl) ester; thvl 1 4a -Succinic acid ethyl ester 2, 4a, 6a, 9, 12b, 14a-hexamethyl-3, li-dioxo- 1,2,3,4, 4a, 5,6, 6a, 11, 12b, 13, 14, 14a, 14btet-radecahydrc-picen-4-yl ester; C' -hydroxy Acetic acid 9-hydroxy-4,6b,8a,11,12b,14a hexamethyl-2, lO-dioxo- 2, 6b, 7, 8,8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14atetrdecahydrc-picen-3-yl ester; Dodecancic acid 9-hydroxy-4,6b,8a,11,12b,14a hexamethyl-2, lO-dioxo- 2,Gb, 7,8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14atetradecahydrc-picen-3-yl ester; Dimethyl-ca-bamic acid 9-hydroxy 4, 6b, 8a, 11, 12b, 14a-hexamechyl-2, lO-dioxo- 2, 6b, 7, 8,8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14atetradecahydrc-picen-3-yl ester; Nicotinic acid 9-hydroxy-4,Gb,8a,11,12b,14a hexamethyl-2, lO-dioxo- WO 2007/077203 PCT/EP2006/070276 43 2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14atetradecahydro-picen-3-yl ester; 3,10-Dihydroxy-2,4a,6a,9,12b,14a-hexamethyl-1loxo-1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14btetradecahydro-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,14btetradecahydro-picene-2-carboxylic acid methyl ester.
when the tricyclic structure is and R- 9 and R2 0 are independently hydrogen or an acyl group, then: Rs is hydroxyl; or R2 1 and R22 form a C=O group together with the carbon to which they are attached and Ri 0 is not
COOH.
when the tricyclic structure is and R and R2 0 are both CHa, then R, and R 16 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):
R
1 R R R
R
13
R
1 2 1 3 11 14o R,3 R I, CH, R18 (Ia) where R1, R 2 R3, R 4 Rs, R, R 7 RE, R 1 and R_2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1
C
12 alkyl; substituted or non-substituted C6-C 0 o aryl; a amino group, where R' and are independently WO 2007/077203 PCT/EP2006/070276 44 hydrogen or a Ci-C12 alkyl group; an OCOR group, where R is (CH2)2COOH or (CH2)2C02CH2CH3; or each pair can form a group together with the carbon to which they are attached; R9 and Rio are independently hydrogen; substituted or nonsubstituted Ci-C2 alkyl; Cs-Clo aryl; a COR''' group (where is hydrogen; hydroxyl; substituted or non-substituted C 1 -C12 alkyl; substituted or non-substituted Cc-C0o aryl; 0-C--C12 alkyl; or N(RI) amino, where R IV and R' are independently hydrogen or a C 1
-C
1 2 alkyl group); a (CH2)n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group,
R
13
R
14 RI and Ri, are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-C 1 2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; a (R v II amino group, where
R
v and R
V
are independently hydrogen or a Cl-C12 alkyl group; an
OCOR
1 II group, where R vI I I is COOH or (CH,),CO,CHCHCH:; or each pair can form a group together with the carbon to which they are attached;
R
1 is hydrogen or methyl; R18 is hydrogen; hydroxyl; halogen; CI-C,2 alkyl; C 6 -Cio aryl; COR"
I
(where RI" is hydrogen; hydroxyl; Ci-C 1 alkyl; N(R x (RxK) amino, where R x and R x are independently hydrogen or a CI-C12 alkyl group; or C,-C12 alcoxyl); or trifluoromethyl; RI9 is hydrogen; substituted or non-substituted CL-C12 alkyl; a CORxf- group (where is hydrogen; hydroxyl; substituted or non-substituted alkyl; substituted or non-substituted C,- Cio aryl; or N (R x amino, where R
X
'I
1 and R X v are independently hydrogen or a CI-C2 alkyl group); a [(Ci-Ci2)alkyl- O-(Ci-C12)alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond, with the proviso that the compound of formula (Ia) is not: 10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-ll-oxo- 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tetradecahydro picene-2-carboxylic acid; WO 2007/077203 WO 207/07203PCT!EP2006/070276 lO-Hyd-raxy-2, 4a, 6a, 9, 12h,14a-hexamethyl-l1-axa- 1, 2, 3, 4,4a, 5, 6,6a, 11, 12h, 13, 14, 14a, l4b-tetradiecahydrapiceae-2-carbaxylic acid methyl ester; 3,10-Dihydraxy-2,4a,6a,9,12h,14a-hexamerhyl-11-axal,2,3,4,4a,5, 6, 6a,l1,12b,13,14,14a,14h-retr-adecahydrapicene-2-carbaxylic acid methyl ester; 3-Hydraxy-4,6b,8a,l1,12h,14a-hexamethyl- 7,8, Ba, 11, 12, 12a, 12b, 13, 14, 14a-deaahydra-6bH, 9H-piaene-2, diane; 3,9-Dlhydraxy-4,6b,8a,11,12t,14a-hexamerhyl- 7,8, Ba, 11, 12, 12a, 12b, 13, 14, 14a-decahydra-EbH, 9H-picene-2, diane; 3,7,9-Trihydraxy-4,6b,8a,1l,12h,14a-hexamethyl- 7,8, Ba, 11, 12, 12a, 12h, 13, 14, 14a-decahydra-6hH, 9H-picene-2, diane; 14-Brama-3,7,9-crihiydraxy-4,6b,8a,1l,12b,14a-hexamethyl- 7,8, Ba, 11, 12, 12a, 12b, 13, 14, 14a-decahydra-EbH, 9H-piaene-2, diane; Succinic acid mana- (10-hyd-raxy-2,4a,6a, 9,12b,14a-hexamethyl 3, 1l-diaxa)-1, 2,3,4, 4a, 5,6, 6a, 11, 12h, 13, 14, 14a, 14htatradaaahydra-piacn-4-yl) aster; Succinic acid ethyl escer l0-hydraoxy-2,4a,6a,9,12h,14a hexamethyl-3, li-diaxa- 1,2,3,4, 4a, 5,6, 6a,l1,12b, 13,14, 14a, l4b-retr-adecahydra-picen- 4-yl ester; Acetic acid 9-hydraxy-4,6h,8a,ll,12h,14a-hexamethyl-2,10 diaxa-2, 6b, 7,8, Sa, 9,10,11,12, 12a, 12b, 13, 14, 14atetradecahydra-picen-3-yl ester; Dadecanaic acid 9-hydraxy-4,6b,8a,ll,12h,14a-hexamethyl 2,l0-diaxa-2, 6h,7,8,8a, 9,lQ,ll,12,12a,12h,13,14,14atetradecahydra-picen-3-yl ester; Dimethyl-carbamia acid 9-hydraxy-4, 6b, 8a, 11, 12h, 14a hexamethyl-2, lO-dioxa- 2, 6h,7,8, 8a, 9,10,11,12, 12a, 12b, 13, 14, 14a-tetradecahvdrapiceai-3-yl esrer; WO 2007/077203 PCT/EP2006/070276 46 Nicotinic acid 9-hydroxy-4,6b,8a,11,12b,14a-hexamethyl-2,10dioxo-2,6b,7,8,8a,9,10,11,12,12a,12b,13,14,14atetradecahydro-picen-3-yl ester.
In a preferred embodiment, the compounds of formula (Ia) comprise a substructure having the following formula
CH
3 R 12
R
7 H CH R0 CH CH,
R,,O
CH
3 (la') where Rs is hydroxyl or a OCOR group where R is (CH 2 COOH or
(CH
2 2 CO2CH 2
CH
3
R
7 and Re are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1
-C
12 alkyl; substituted or nonsubstituted C 6
-C
0 aryl; a amino group, where R' and are independently hydrogen or a CI-C 1 2 alkyl group; or each pair can form a group together with the carbon to which they are attached;
R
12 is independently hydrogen or a halogen; and RI9 is hydrogen; substituted or non-substituted CI-C 1 2 alkyl; a CORxII group (where RAI is hydrogen; hydroxyl; substituted or non-substituted C--C 1 2 alkyl; substituted or non-substituted C 6
C
0 o aryl; or N amino, where R x i 1 and R x L are independently hydrogen or a C1-C], alkyl group); a [(C1-C 2 ,)alkyl- 0-(C 1
-C
1 2)alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond, with the proviso that the compound of formula is not: WO 2007/077203 WO 207/07203PCT!EP2006/070276 47 l0-Hydroxy-2, 4a, 6a, 9, 12b,14a-hexamethyl-1l-oxo- 1,2,3,4, 4a, 5, 6,6a,11,12h, 13,14, 14a, 14h-tet-adiecahydropicene-2-carboxylic acid; 10-Hydroxy-2, 4a, 6a, 9, 12h,14a-hexamethyl-11-oxo- 1,2,3,4,4a,5, 6, 6a,11,12b,13,14,14a,14b-tetr-adecahydropicene-2-carboxylic acid methyl estec; 3,l0-Dihydroxy-2,4a,6a,9,12b,14a-hexamethyl-1l-cxo- 1,2,3,4, 4a, 5, 6, 6,11,12b, 13,14, 14a, 14b-tetc-adecaihyd-ropicerie-2-carboxylic acid methyl estec; 3-Hydroxy-4,6b,8a,11,12b,14a-hexamethyl- 7,8, Ba, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-2, dione; 3,9-Dihydroxy-4,6b,8a.11,12b,14a-hexamethyl- 7,8, Ba, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene-2, diane; 3,7,9-Trihydroxy-4,6b,8a.11,12b,14a-hexamethyl- 7,8, Ba, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6hH, 9H-picene-2, dione; 14-Bromo-3,7,9-trih-ydroxy-4,6b,8a,11,12b,14a-hexamethyl- 7,8,Ba,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picenle-2,1Cdiane; Succinic acid mono- (10-hydroxy-2,4a,6a, 9,12b,14a-hexamethyl 3, 1l-dicxo-1, 2,3,4, 4a, 5,6, 6a, 11, 12b, 13, 14, 14a, 14btetradecahydro-picen-4-yl) ester; Succinic acid ethyl ester lQ-hydr-oxy-2,4a,6a,9,12h,14a hexamethyl-3, li-dioxo- 1,2,3,4,4a,5,6,6a,11,12b.13,14,14a,14b-tet-adecahydro-picen- 4-yl ester; Acetic acid 9-hydroxy-4,6h,8a.ll,12h,14a-hexamethyl-2,l0 dicxo-2, 6b, 7,8, 8a, 9,10,11, 12, 12a, 12b, 13, 14, 14atetradecahydro-picen-3-yl ester; Dadecanaic acid 9-hydraxy-4,6b,8a,l1,12h,14a-hexamethyl 2, lQ-dicxa-2, 6b,7,8, 8a, 9, 10,11, 12, 12a,12b,13, 14, 14atetradecahydro-plcen-3-yl ester; Dimethyl-carbamic acid 9-hydroxy-4,6b,8a,1l,12h,14a hexamethyl-2, WO 2007/077203 WO 207/07203PCT!EP2006/070276 48 2, 6b, 7,8, 8a, 9, 10, 11, 12, 12a, 12b, 13, 14, 14a-tetradecahvdropicen-3-y1 ester; Nicotinic acid 9-hyd-oxy-4,6b,8a,1l,12b,14a-hexamethyl-2,10dioxo-2, 6b, 7,8, 8a, 9,10,11, 12, 12a, 12b, 13, 14, 14atetradecahydro-picen-3-yl ester; 3,l0-Dihydroxy-2,4a,6a,9,12b,14a-hexamethyl-1l-cxo- 1,2,3,4, 4a, 5, 6,6a,11,12b, 13,14, 14a, 14b-tetr-adecahydropicene-2-carboxylic acid methyl ester; l0-Hydroxy-2, 4a, 6a, 9, 12b, 14a-hexamethyl-ll-oxol,2,3,4,4a,5, 6, Oa,11,12b,13,14,14a,14b-tetr-adecahydropicene-2-carboxylic acid methyl ester.
Particular examples of this substructure are: 9-hydroxy-4,6b,8a,ll,12b,14a-hexamethyl-2,l0-dioxo- 2,6b,7,8,8a,9,10,ll,12,12a,12b,13,14,14a-tetradecahydropicene-3-yl propionic acid ester (Cl); 4-brcmo-(9-hydroxy-6b,8a,ll,12b,14a-hexamethyl-2,l0-dioxo- 2, 6b, 7,8, 8a, 9,10,11,12, 12a, 12b, 13, 14, 14a-tetradecahydropicene-3-yl) benzoic acid ester (C2); 12-bromc-3,9-dlhydroxy-4,6b,8a,ll,12b,14a-hexamethyl- 7,8, 8a, 11, 12, 12a, 12b, 13, 14, 14a-decahydro-6bH, 9H-picene- 2,10-d-iane (C3); 12-bromc-9-hydroxy-6b,8a,ll,12b,14a-hexamethyl-2,l0-dioxo- 2, 6b, 7,8, 8a, 9,10,11,12, 12a, 12b, 13, 14, 14a-tetradecahydropicene-3-yl d:imec-hyl-carbamic acid ester (C4); 4-bromo-(12-bromo-9-hydrcxy-6b,8a,1l,12b,14a-hexamethyl- 2, l0-dioxo-2, 6b, 7,8, 8a, 9,10,11,12, 12a, 12b, 13, 14, 14atetradecahydro-picene-3-yl) benzoic acid ester 3,9,l0-trihydroxy-6b,8a,ll,12b,14a-hexamethyl- 7,8, 8a, 9,10,11,12, 12a, 12b, 13, 14, 14a-dodecahydr-o-6bHpicene-2-one (C6).
In another preferred embodiment, the compounds of formula (Ia) ccmprise a substr-ucture having the followina formula WO 2007/077203 PCT/EP2006/070276 49
CH
3
R,
1
CH
3 0 CH CH
R
1 9 0
CH
3 (Ia") where: R7 and Re are independently hydrogen, hydroxyl, halogen, substituted or non-substituted C 1 -C12 alkyl, substituted or nonsubstituted C 6 -Cl0 aryl, a amino group, where R' and are independently hydrogen or a C 1 -C12 alkyl group, or each pair can form a group together with the carbon to which they are attached; Ri. is hydrogen or halogen; RI, is hydrogen, substituted or non-substituted C1-C 1 2 alkyl; a
COR
x I group (where RIr is hydrogen; hydroxyl; substituted or non-substituted C--C, 2 alkyl; substituted or non-substituted C6- Clo aryl; or N (RX amino, where Rx l l i and Rx
L
are independently hydrogen or a Ci-Ci2 alkyl group); a [(CI-Ci2)alkyl- O-(Ci-Ci2)alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl; and the bond means a double bond or a single bond, with the proviso that the compound of formula is not: 3-Hydroxy-4,6b,8a,ll,12b,14a-hexamethyl- 7,8,8a,9,10,11,12,12a,12b,13,14,14a-dodecahydro-6bH-picen- 2-one; 3-Hydroxy-4,6b,8a,11,12b, 14a-hexamethyl- 7,8,8a,11,12,12a,12b,13,14,14a-decahydro-6bH,9H-picene- 2,10-dione.
Par-icular examples of this substructure are: WO 2007/077203 PCT!EP2006/070276 -14-bromc-3-hydroxy-4, b,Ba,11,12b,14a-hexamethyl- 7,8,Ba,11,12,12a,12b,13,14,14a-decahydro-BbH,9H-picene- 2,10-diane (27); -4,b,Ba,11,12b,14a-hexamethyl-2,lO-dioxo- 2, b,7,8,Sa,9,10,11,12,12a,12b,13,14,14a-etradocahydro picene-3-yl acetic acid ester (C8); -4,Sb, a,11,12b,14a-hexamethyl-2,10-dioxo- 2, b,7,8,8a,9,10,11,12,12a,12b,13,14,14a-cetradecahydro picene-3-yl nicorinic acid ester (C9); -3,10-dihydroxy-4,6b,8a,11,12b,14a-hexamethyl- 7,8,Ba,9,10,11,12,12a,12b,13,14,14a-dodecahydro-SbHpicene-2-one -3-hydroxy-4,Sb,Sa,11,12b,14a-hexamethyl- 7,8,Ba,12a,12b,13,14,14a-octahydro-SbH,9H-picene-2,10dione (C11).
In another preferred embodiment, the compounds of (Ia) ccmprise a substructure having the followino formula formula where: R7 is hydrogen, hydroxyl, halogen, substituted or nonsubstituted C-C> alkyl, substituted or non-substituted C6-C 22 aryl, or a amino group, whera R' and ara independently hydrogen or a C 1 -C alkyl group; and
R
1 is subsrituted or non-substituted 0>-C 1 alkyl; a CORII group (where VII is hydrogen; hydroxyl; suhstitured or non-substituted C>-Ci2 alkyl; substituted or non-substituted C 6
-C>
0 aryl; or WO 2007/077203 PCT!EP2006/070276 0- N(RXIII) (RXTv) amino, where RXIII and R'I' are independently hydrogen or a C 1
-C
1 2 alkyl group); a (C 1
-C
1 2 alkyl-O- (C 1
-C
1 2 alkyl-],, group (where n is comprised between 1 and or trifluoromethyl; with the proviso that the compound of formula is not: 3,l0-Dihydroxy-2,4a,Ca,9,12b,14a-hexamethyl-ll-oxo- 1,2,3,4,4a,5,6, a,11,12h,13,14,14a,14h-tetradecahydropicene-2-carboxylic acid methyl ester; 10-Hydroxy-2,4a,6a,9,12b,14a-hexamethyl-ll-oxo- 1,2,3,4,4a,5,6,Ca,11,12b,13,14,14a,14b-tetradecahydropicene-2-carboxylic acid methyl ester.
Particular examples of this substructure are: 2,4a,6a,9,12h,14a-hexamethyl-11-oxo-10-propicnyloxy- 1,2,3,4,4a,5,6,6a,11,12b,13,14,14a,14b-tecradecahydropicene-2-carhoxylic acid methyl ester (C13); 10-dimethylcarbamoyloxy-2,4a,6a,9,12b,14a-hexamethyl-lloxo-1,2,3,4,4a,5,6,6a,11,12h,13,14,14a, 14-tetradecahydropicene-2-carhoxylic acid methyl ester (C14).
In another particular aspect, the invention is directed to compounds of formula (Tb):
R
10
R,
OH
3 R1 R1 CHR7 H
R
1 7H 3
C
R
1 9 0B
R
18
RR
1
R
22 (Ib) where:
R
1
R
2
R
3
R
4 RF, R 6 1 Rj, R 3
R
11 and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1
C
1 2 alkyl; substituted or non-substituted C 6
-C
0 aryl; a amino group, where R' and are independently WO 2007/077203 PCT/EP2006/070276 hydrogen or a Ci-C12 alkyl group; or each pair can form a (C=0) group together with the carbon to which they are attached; RD and R 1 i are independently hydrogen; substituted or nonsubstituted C1-C2 alkyl; Cs-Cio aryl; a COR''' group (where R'' is hydrogen; hydroxyl; substituted or non-substituted Ci-C12 alkyl; substituted or non-substituted C6-Cio aryl; 0-Ci-C12 alkyl; or N(RIV) (R v amino, where R Iv and Rv are independently hydrogen or a C1-C12 alkyl group); a (CH2),-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, RID, Ri 4 Ri, Ri, and R>D are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Cl-C12 alkyl; substituted or non-substituted CE-Clo aryl; a N(R I) amino group, where R"V and R
V
II are independently hydrogen or a C1-C12 alkyl group; or each pair can form a group together with the carbon to which they are attached; R,1 is hydrogen or methyl; R1e is hydrogen; hydroxyl; halogen; Ci-C12 alkyl; C6-Co aryl; COR Ix (where R is hydrogen; hydroxyl; C1-C12 alkyl; N(R x (RK) amino, where R x and R" are independently hydrogen or a CI-C12 alkyl group; or Ci-C], alcoxyl); or trifluoromethyl; R19 and R2o are independently hydrogen, substituted or nonsubstituted C1-C12 alkyl; a COR x x group (where R" x is hydrogen; hydroxyl; substituted or non-substituted CI-C12 alkyl; substituted or non-substituted C-Clo aryl; or N(RX"K) amino, where R
X
II and R x v are independently hydrogen or a Ci-Ci, alkyl group); a [(CL-C12)alkyl-- (CI-C12)alkyl-]n group (where n is comprised between 1 and or trifluoromethyl; and the bond means a double bond or a single bond, with the proviso -hat when R,9 and R 20 are independently hydrogen or an acyl group, then: is hydroxyl; or
R
2 1 and R22 form a C=0 group together with the carbon to which they are artached and R 1 i is not COOH.
In another preferred embodiment, the compounds of formula (Ib) comprise a substructure having the following formula WO 2007/077203 WO 207/07203PCT!EP2006/070276 53
OH
3 0
COH
3 O H
OH
3
R,
0 0
CH,
R
19 0
CH
3
OH
(Ib') where: RID anid R 0 o are independently substituted o- non-substituted Cj-
C
12 alkyl; a CORX", group (where R is hydrogen; hydroxyl; substituted or non-substituted CI-CI2 alkyl; substituted or nonsubstituted CG-Cic aryl; or N(RX amino, where Rx" and RX\v are independently hydrogen or a C2_ 1 alkyl group) a [(C 1
C
1 2)alkyl-O-(C 1 -Cj2)alkyl-], group (where n is comprised between 1 and or trifluoromethyl.
A particular example of this substruoture is 4-nitro- 9-dihvdroxy-4, 6b, 8a, 11, 12b, 14a- 6b, 7,8, 8a, 9,10,11,12, 12a, 12b, 13, 14, 14atetradecahydro-picene-2 yl) benzoic acid ester In another preferred embodiment, the compounds of formula (Ib) comprise a substr-ucture having the followina formula (Ib''
H
3 COOC_ OH 3 gH 3
CH-
HO
R
1 8 0 (Ib'f where: WO 2007/077203 PCT/EP2006/070276 54
R
1 is hydrogen; hydroxyl; halogen; Ci-C12 alkyl; C 6 -C-o aryl; CORIX (where RI" is hydrogen; hydroxyl; Ci-C 1 2 alkyl; N(R) (R X I amino, where R x and R
X
are independently hydrogen or a CI-C 12 alkyl group; or C 1
-C
1 2 alcoxyl); or trifluoromethyl; RI9 is hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a
COR
x I group (where RI" is hydrogen; hydroxyl; substituted or non-substituted C--C 2 alkyl; substituted or non-substituted Cs- Cio aryl; or N (R x amino, where Rx I I I and RXIv are independently hydrogen or a Ci-C 12 alkyl group); a [(Ci-C 1 2)alkyl- O-(CL-CI2)alkyl-]n group (where n is comprised between 1 and 3); or trifluoromethyl;
R
23 is hydrogen; hydroxyl; halogen; substituted or nonsubstituted C -C 1 2 alkyl; substituted or non-substituted C 6 -Co 0 aryl; a N(RVI) amino group, where R and R" v are independently hydrogen or a C1-C12alkyl group.
Particular examples of this substructure 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-tetradecahydropicene-2-carboxylic acid methyl ester (F16); 9-formyl-l0,11-dihydroxy-2,4a,6a,12b,14a-pentamethyl-8oxo-1,2,3,4,4a,5,6,6a,8,12b,13,14,14a,14b-tetradecahydropicene-2-carboxylic acid methyl ester (C17); ll-hydroxy-10-(2-methoxy-ethoxymethoxy)-2,4a,6a,9,12b,14ahexamethyl-8-oxo-l,2,3,4,4a,5,6,6a,8,12b,13,14,14a,14btetradecahydro-picene-2-carboxylic acid methyl ester (C18).
In another particular aspect, the invention is directed to compounds of formula (Ic): WO 2007/077203 PCT/EP2006/070276 Ri RR R R 1 and R ae independenly R H3 R R I" H SI 3C R3 RI R RO R
R,,O
(Ic) where: Ri, R2, R3, RI, Rs, R6, R7, RE, R12 and R_2 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-
C
1 2 alkyl; substituted or non-substituted C 6 -CIo aryl; a amino group, where R' and are independently hydrogen or a CI-C 1 2 alkyl group; or each pair can form a (C=0) group together with the carbon to which they are attached; R9 and Rio are independently hydrogen; substituted or nonsubstituted CI-C 1 2 alkyl; Cs-Cio aryl; a COR''' group (where is hydrogen; hydroxyl; substituted or non-substituted C1_C12 alkyl; substituted or non-substituted C 6 -Cio aryl; O-C--CI2 alkyl; or N(R' v amino, where R I and R' are independently hydrogen or a Ci-C12 alkyl group); a (CH2)n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group; R1 3 R-4, R1s, RIG, R21 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-C12 alkyl; substituted or non-substituted Ce-Cio aryl; a N(R' v
(R
1 amino group, where R" and R v are independently hydrogen or a Cl-C12 alkyl group; or each pair can form a group together with the carbon to which they are attached; Ri8 is hydrogen; hydroxyl; halogen; Ci-C 12 alkyl; Ce-Co aryl; COR
IX
(where R I is hydrogen; hydroxyl; C C 1 2 alkyl; N(R x (RX) amino, where R x and Rx' are independently hydrogen or a Ci-C12 alkyl group; or Ci-Ci] alcoxyl); or trifluoromethyl; WO 2007/077203 PCT/EP2006/070276
R
1 9 and R 20 are independently hydrogen; substituted or nonsubstituted C 1
-C
12 alkyl; a COR"
I
group (where RxII is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
1 2 alkyl; substituted or non-substituted C 6 -Cio aryl; or N(RXII) (R x amino, where R X 1 and R'v are independently hydrogen or a C 1
-C
1 2 alkyl group); a [(CL-C 12 )alkyl-O-(Ci-C 12 )alkyl-]n group (where n is comprised between 1 and or trifluoromethyl; and the bond means a double bond or a single bond, with the proviso that when and R 20 are both CH 3 then R 5 and 0 R 16 do not form a C=O group together with the carbon to which they are attached.
In comprise a preferred embodiment, the compounds of formula (Ic) a substructure having the following formula (Ic') where:
R
1 9 and R2o are independently hydrogen; substituted or nonsubstituted Ci-C 12 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted Ci-C> alkyl; substituted or non-substituted C 6 -Cio aryl; or N(RXIII) (R x amino, where R x I" and R x yI are independently hydrogen or a Ci-C 1 2 alkyl group); a [(CL-C 1 2 )alkyl-O- (Ci-C 12 alkyl-]n group (where n is comprised between 1 and 3) or trifluoromethyl; and the bond means a double bond or a single bond.
Particular examples of this substructure are: WO 2007/077203 PCT/EP2006/070276 57 10,11-dihydroxy-2,4a,6a,9,14a-pentamethyl- 1,4,4a,5,6,6a,13,14,14a,14b-decahydro-2H-picene-3-one (C19); S10,11-dihydroxy-2,4a,6a,9,14a-pentamethyl- 4a,5,6,6a,13,14,14a,14b-octahydro-4H-picene-3-one In another preferred embodiment, the compounds of formula (Ic) ccmprise a substructure having the following formula
H
3 C ,COOCH
I
CI-I
S[ CH, R 1 p SI CHs CH3 (Ic") where: R19 and R2o are independently hydrogen; substituted or nonsubstituted C 1
-C
12 alkyl; a CORXII group (where RXII is hydrogen; hydroxyl; substituted or non-substituted CI-C 1 2 alkyl; substituted or non-substituted C 6 aryl; or N(R x (RXI") amino, where R x and R x IV are independently hydrogen or a Ci-C 1 alkyl group); a [(Cl-C 12 )alkyl-O- (CI-C 12 alkyl-]n group (where n is comprised between 1 and or trifluoromethyl.
A particular example of this substructure is 10,11dihydroxy-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): WO 2007/077203 PCT/EP2006/070276 58 Rio R9 R 1
R,
CH3 7 ""11R, R4 R, a Re e R0 J H CH '"R4 R203 R3 R, R 2 Ril R'1 (Id) where: Ri, R2, R3, R4, RE, Rs, R, Re, Rii and R12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-
C
1 2 alkyl; substituted or non-substituted C 6
-C
1 0 aryl; a amino group, where R' and are independently hydrogen or a Ci-C 1 2 alkyl group; or each pair can form a (C=O) group together with the carbon to which they are attached; R9 and Rio are independently hydrogen; substituted or nonsubstituted CI-C 1 2 alkyl; Cs-Cio aryl; a COR"' group (where R' is hydrogen; hydroxyl; substituted or non-substituted C1_C12 alkyl; substituted or non-substituted CE-Cio aryl; 0-C--C 1 2 alkyl; or N(RV) (R v amino, where R" and Rv are independently hydrogen or a Ci-C12 alkyl group); a (CH2)n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, R1 3 Ris, R2 1 and R23 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C12 alkyl; substituted or non-substituted C 6 -Clo aryl; a N(R v I
(R
v I) amino group, where
R"
V and R 7 T are independently hydrogen or a Ci-C 1 2 alkyl group; or each pair can form a (C O) group together with the carbon to which they are attached; R1e is hydrogen; hydroxyl; halogen; Ci-C 1 2 alkyl; C 6 -Co- aryl; COR Ix (where R
I
is hydrogen; hydroxyl; Ci-C12 alkyl; N(R x (Rx) amino, where R x and R x are independently hydrogen or a CI-C12 alkyl group; or Ci-C12 alcoxyl); or trifluoromethyl; WO 2007/077203 PCT/EP2006/070276 59
R
1 9, R 1
R
20 and R 20 are independently hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a CORx"I group (where RX1 is hydrogen; hydroxyl; substituted or non-substituted Ci-C 1 2 alkyl; substituted or non-substituted C 6 -Cio aryl; or N(R x 11
(R
x v amino, where R X 1 and R'v are independently hydrogen or a CI-C 12 alkyl group); a [(CL-C 12 )alkyl-O-(Ci-C 12 )alkyl-] group (where n is comprised between 1 and trifluoromethyl; or each 19-19' or 20-20' pair can form a C=0 group together with the carbon to which they are attached; R2 4 and R 25 are independently hydrogen, hydroxyl or halogen; and the bond means a double bond or a single bond.
In a preferred embodiment, the compounds of formula (Id) comprise a substructure having the following formula
CH
3
OH
3
R
2 4
R
2 5
R
e CH 3 CH36 OH 3 9
CH
3 (Id') where:
R
5 and R 6 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1
-C
12 alkyl; substituted or nonsubstituted C 6 aryl; a amino group, where R' and are independently hydrogen or a C 1
-C
1 2 alkyl group; or each pair can form a group together with the carbon to which they are attached;
R
19
R
19
R
20 and R20, are independently hydrogen; substituted or non-substituted CI-C 1 2 alkyl; a COR'" group (where R x is hydrogen; hydroxyl; substituted or non-substituted C2-C2 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; or N(Rx"I) (R x V amino, where R x M and R x "I are independently hydrogen or a C1-C12 alkyl group); a [(CL-C2) alkyl-O- (C-C 1 2 alkyl-] group (where n is WO 2007/077203 PCT/EP2006/070276 comprised between 1 and trifluoromethyl; or each 19-19' or 20-20' pair can form a C=0 group together with the carbon to which they are attached;
R
24 and R 25 are independently hydrogen, hydroxyl or halogen.
Particular examples of this substructure are: l-bromo-9-hydroxy-4,6b,8a,11,12b,14b-hexamethyl- 6b,7,8,8a,9,11,12,12a,12b,14b-decahydro-lH-picene-2,3,10trione (C22); l-bromo-4,6b,8a,11,12b,14b-hexamethyl- 6b,7,8,8a,9,11,12,12a,12b,14b-decahydro-1H-picene-2,3,10trione (C23).
In another preferred embodiment, the compounds of formula (Id) comprise a substructure having the following formula H3C 0OOCH 3
CH,
CH3 (Id") where:
R
1 I, RIo,, R 2 0 and R 20 are independently hydrogen; substituted or non-substituted CI-C 1 2 alkyl; a COR-" group (where Rx" is hydrogen; hydroxyl; substituted or non-substituted Ci-C1 alkyl; substituted or non-substituted C 6 -Clo aryl; or N(RXIII) (R x amino, where R x I I I and R x IV are independently hydrogen or a CI-C 1 2 alkyl group); a [(CL-C 1 2 )alkyl-O-(CI-C 12 alkyl-],, group (where n is comprised between 1 and trifluoromethyl; or each 19-19' or 20-20' pair can form a C=0 group together with the carbon to which they are attached;
R
24 and R 25 are independently hydrogen, hydroxyl or halogen.
WO 2007/077203 PCT/EP2006/070276 o0 A particular example of this substructure is 12bromo-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-2carboxylic acid methyl ester (C24).
In another particular aspect, the invention is directed to compounds of formula (Ie): RIO Rg
R
R R R
R
R0 CH sC R3 Ro R R (Ie) where:
R
I
R
2
R
3
R
4 R, ,R 6 Rs, R and R 12 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci- C12 alkyl; substituted or non-substituted C 6 -Ci 0 aryl; a amino group, where R' and are independently hydrogen or a CI-C1s alkyl group; or each pair can form a (C=0) group together with the carbon to which they are attached; R9 and Rio are independently hydrogen; substituted or nonsubstituted Cl-Ci2 alkyl; Cs-Clo aryl; a COR''' group (where is hydrogen; hydroxyl; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted C6-Ci0 aryl; 0-C--C12 alkyl; or N(R
I
(R
v amino, where R Iv and R v are independently hydrogen or an alkyl group CI-C-2); a carbinol group (CH2)n-OH (where n is an integer comprised between 1 and 10); or together form a methylene group; R1 3
R-
4
R
15
R
1 6 R2 1 and R2 3 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted Ci-C12 alkyl; substituted or non-substituted C-Clo aryl; a (R" 1 amino group, where R" and are independently hydrogen or a Ci-C12 WO 2007/077203 PCT/EP2006/070276 alkyl group; or each pair can form a group together with the carbon to which they are attached; Ri 1 and R 18 are independently hydrogen; hydroxyl; halogen; Cl-C 2 alkyl; C 6 -CIC aryl; COR' x (where R' x is hydrogen; hydroxyl; C 1 -C1 2 alkyl; N(RX) amino, where R x and Rx are independently hydrogen or a C 1
-C
12 alkyl group; or Ci-C 12 alcoxyl); or trifluoromethyl;
R
1 9
R
2 0 and R20, are independently hydrogen; substituted or non-substituted C 1
-C
1 2 alkyl; a CORX'- group (where R x I is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted CO-CIs] aryl; or N(RXIIIR~'I) amino, where R x III and Rx
I
are independently hydrogen or a CI-C 1 2 alkyl group); a [(CL-C 12 )alkyl-O-(C1-C 12 )alkyl-]n group (where n is comprised between 1 and trifluoromethyl; or each 19-19' or 20-20' pair can form a C-0 group together with the carbon to which they are attached;
R
2 4 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
H
3 C COOCH 3
CH
3
R
24 R*4 C H 3 R 0 CH31 CH 3 RD' f' Ri 1 Ri 1 (le') where:
R
1 3 and R18e are independently hydrogen; hydroxyl; halogen; Cl-C- 2 alkyl; C6-CIC aryl; COR Ix (where R Ix is hydrogen; hydroxyl; Ci-C 1 2 alkyl; N(R x amino, where R x and R x are independently hydrogen or a CI-C 1 2 alkyl group; or CI-C12 alcoxyl); or trifluoromethyl; WO 2007/077203 PCT/EP2006/070276 63
R
1 9, R 1
R
2 0 and R 2 0 are independently hydrogen; substituted or non-substituted C 1
-C
12 alkyl; a CORx"I group (where R x is hydrogen; hydroxyl; substituted or non-substituted Ci-C 1 2 alkyl; substituted or non-substituted C 6 -Cio aryl; or N(R x 11
(R
x I amino, where and Rx I are independently hydrogen or a C 1
-C
12 alkyl group); a [(CL-C 12 )alkyl-O-(C-1C 12 )alkyl-]n group (where n is comprised between 1 and trifluoromethyl; or each 19-19' or 20-20' pair can form a C=0 group together with the carbon to which they are attached; R24 is hydrogen, hydroxyl or halogen.
A particular example of this substructure is 9hydroxy-2,4a,6a,9,12b-hexamethyl-10,11-dioxo- 1,2,3,4,4a,5,6,6a,9,1C,11,12b,13,14,14a,14b-hexadecahydropicene-2-carboxylic acid methyl ester In another particular aspect, the invention is directed to compounds of formula (If): Rio R, R R 12 i, R 1 CH, R7 R24 R
H
3 R
R
1 9
R
1 8
R
1 8
R
21 (If) where: Ri, R2, R 3
R
4 R, R, R 7 RE, Rn and R, are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1
C
12 alkyl; substituted or non-substituted C 6
-C
0 o aryl; a amino group, where R' and are independently hydrogen or a C 1
-C
1 2 alkyl group; or each pair can form a (C-O) group together with the carbon to which they are attached; WO 2007/077203 PCT/EP2006/070276 64 R9 and R 10 are independently hydrogen; substituted or nonsubstituted C 1
-C
12 alkyl; Cs-Co aryl; a COR'' group (where is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted CE-C 1 0 aryl; 0-CI-C 1 2 alkyl; or N(RV) amino, where R
I
V and Rv are independently hydrogen or a -C1C2 alkyl group); a (CH2)n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, R1 3
R_
4
R
15
R
2 1 and R 2 3 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C1-C12 alkyl; substituted or non-substituted Ch-CI() aryl; a N(Rv") (R v n) amino group, where
R"
I and R vII are independently hydrogen or a C 1
-C
1 2 alkyl group; or each pair can form a group together with the carbon to which they are attached; R18 and R 18 are independently hydrogen; hydroxyl; halogen; Cl-C-2 alkyl; aryl; COR Ix (where R Ix is hydrogen; hydroxyl; C 1 -Cl> alkyl; N(RX) (R
T
amino, where Rx and R X are independently hydrogen or a C 1
-C
1 2 alkyl group; or C1-C12 alcoxyl); or trifluoromethyl; R19, R1g,, R2 0 and R20, are independently hydrogen; substituted or non-substituted Ci-C] alkyl; a COR'" group (where R x 1 is hydrogen; hydroxyl; substituted or non-substituted C2-C,2 alkyl; substituted or non-substituted C 6 -Cio aryl; or N(R x x 1
(R"
v amino, where R x PII and R x v are independently hydrogen or a C 1 -C12 alkyl group); a [(C 1
-C
1 i)alkyl-O-(C 1
-C
1 i) alkyl-], group (where n is comprised between 1 and trifluoromethyl; or each 19-19' or 20-20' pair can form a C=0 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 WO 2007/077203 PCT/EP2006/070276
H
3 C COOCH 3
OH
3 CCHH3 S OH3CH
R
20
OH,
R
1 9
R
18
R
18 (If') where:
R
18 and Rie' are independently hydrogen; hydroxyl; halogen; Cl-C-2 alkyl; CG-C1c aryl; COR I x (where R I x is hydrogen; hydroxyl; C1-C12 alkyl; N(R x
(R
x amino, where R x and R are independently hydrogen or a CI-C 12 alkyl group; or Ci-C12 alcoxyl); or trifluoromethyl;
R
1 9, R, 1
R
2 0 and R20, are independently hydrogen; substituted or non-substituted C 1
-C
1 2 alkyl; a COR x group (where RXr is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
1 2 alkyl; substituted or non-substituted C6-Cio aryl; or N(R x x
(R
xv amino, where RxIII and R x are independently hydrogen or a Ci-Ci> alkyl group); a [(CL-C 1 2 )alkyl-O-(C 1
-C
12 alkyl-] group (where n is comprised between 1 and 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; R2 is hydrogen, hydroxyl or halogen.
A particular example of this substructure is the 9 hydroxy-2,4a,6a,6b,9-hexamethyl-lO,11-dioxo- 1,2,3,4,4a,5,6,6a,6b, a,9,10,11,14,14a,14b-hexadecahydro-picene- 2-carboxylic acid methyl ester (C26).
Another aspect of the invention is formed by compounds of formula (II): WO 2007/077203 PCT/EP2006/070276
(II)
where: RI, R2, R3, R4, R 5
R
6 Rs, Rio RII, R 1 2, Rl3, R 1 4 R 1 5 R 6, R 1 Rl3,
R
1 i and Ro are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CI-C 1 2 alkyl; substituted or nonsubstituted C6-Cro aryl; a N(R x
(R
xv amino group, where Rx" and
R
x are independently hydrogen or a Ci-C2 alkyl group; or each pair can form a carboxyl group together with the carbon to which they are attached; R, and R 8 are independently hydrogen; substituted or nonsubstituted C 1 -C12 alkyl; CE-Cio aryl; a CORx"I group (where R xv I is hydrogen; hydroxyl; substituted or non-substituted Ci-C2 alkyl; substituted or non-substituted C 1 -Clo aryl; 0-C -C12 alkyl; or N(R xv n l
(R
x x amino, where R' v II and R x s x are independently hydrogen or a CI-C 1 2 alkyl group); a (CH 2 )n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, R21 and R24 are independently substituted or non-substituted Ci-
C
12 alkyl; a CORX group (where R is hydrogen; hydroxyl; substituted or non-substituted CI-C 1 2 alkyl; substituted or nonsubstituted CG-C 1 0 aryl; or N(Rxx) (R xx x) amino, where Rxx and R x x I are independently hydrogen or a C 1 -C12 alkyl group); a [(Cl-
C
1 2)alkyl-O-(C 1 -C12)alkyl-]n group (where n is comprised between 1 and or trifluoromethyl;
R
22 and R 23 are: hydrogen; substituted or non-substituted CI-C 1 alkyl; a CORXX I group (where R x "II is hydrogen; hydroxyl; substituted or non-substituted CI-C12 alkyl; substituted or WO 2007/077203 PCT/EP2006/070276 67 non-substituted C 6 -Co aryl; or N(RxxO) (R x amino, where
R"
xx and R" xx are independently hydrogen or a C 1
-C
12 alkyl group); a [(Ci-C 2 )alkyl-0-(Ci-C 1 2)alkyl-]n group (where n is comprised between 1 and or trifluoromethyl when R 2 4 is in the para posiion with respect to R;o; or
OR
22 and OR 2 3 respectively, where R 2 2 and R 2 3 are independently hydrogen; substituted or non-substituted C 1
C
12 alkyl; a COR'" VT group (where R VT is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
1 2 alkyl; substituted or non-substituted Ce-C 1 o aryl; or N(R" xvII
(R
x x "II) amino, where
R
x x 'Ir and Rx x v -I are independently hydrogen or a C1-C 1 2 alkyl group); a [(C 1
-C
12 )alkyl-0-(C 1 -C)alkyl-]n group (where n is comprised between 1 and 3) or trifluoromethyl when R 2 4 is in the meta posirion with respect to R2 0 or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof.
In one particular aspect, the invention is directed to compounds of formula (IIa): R7 R R R R5/i,,
R
R24 R, R4R 10 C 1 3R R R1 Rv 1 14
R
1
R
2
R
3
R
4 1 Rs 5
R
6 Ro 0 r R 1 1 R 1 2
R
1 3
R
1 4
R
1 5
R
6
R
1 7 R18,
R
1 9 and R 2 o are independently hydrogen; hydroxyl; halogen; substituted or non-substituted CL-C 12 alkyl; substituted or nonsubstituted Cs-CI0 aryl; a N(R x
(R
x I 1 amino group, where R xv and
R
x 1 are independently hydrogen or a C 1
-C
12 alkyl group; or each pair can form a carboxyl group together with the carbon to which they are attached; WO 2007/077203 PCT/EP2006/070276 68 R7 and R8 are independently hydrogen; substituted or nonsubstituted C 1
-C
12 alkyl; CE-C 1 0 aryl; a COR" v1 1 group (where R x s is hydrogen; hydroxyl; substituted or non-substituted Ci-C12 alkyl; substituted or non-substituted CE-Ci 0 aryl; 0-CI-C 1 2 alkyl; or N(RxvyI) (Ri) amino, where Rx v 1 and Rxx are independently hydrogen or a C 1
-C
12 alkyl group); a (CH 2 )n-OH carbinol group (where n is an integer comprised between 1 and 10); or together form a methylene group, R21 and R24 are independently substituted or non-substituted Ci-
C
12 alkyl; a CORxx group (where R xx is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
1 alkyl; substituted or nonsubstituted C 6 -Ci 0 aryl; or N(RXa) (R xx II) amino, where R xx and R x z
I
are independently hydrogen or a Ci-C 1 2 alkyl group); a [(Ci-
C
1 2)alkyl-O-(C 1 -C1)alkyl-]n group (where n is comprised between 1 and or trifluoromethyl; R, and R 3 are: hydrogen; substituted or non-substituted Ci-Cl2 alkyl; a CORx T group (where R""KT is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6 -Cio aryl; or N(R xx I v
(R>
x amino, where
R
x x and R x x are independently hydrogen or a CI-C 12 alkyl group); a [(C 1 -C1 2 )alkyl-0-(C-C 1 2)alkyl-] group (where n is comprised between 1 and or trifluoromethyl when R 24 is in the para posicion with respect to R2o; or
OR
22 and OR 23 respectively, where R22' and R23' are independently hydrogen; substituted or non-substituted C 1
C
12 alkyl; a COR x vI group (where R xw1 is hydrogen; hydroxyl; substituted or non-substituted C 1
-C
12 alkyl; substituted or non-substituted C 6 -Clo aryl; or N(R'" w n) (R xxvI amino, where RPxxn" and RxxvI are independently hydrogen or a C 1
-C
12 alkyl group); a [(Ci-C12)alkyl-O-(C-C 1 2)alkyl-]n group (where n is comprised between 1 and or trifluoromethyl when R2 4 is in the meta posicion with respect to R2o.
In a preferred embodiment, the compounds of formula (IIa) comprise a substructure having the following formula (IIa'): WO 2007/077203 PCT/EP2006/070276 69
H
3 C COOCH 3 RR24 HC 3 R21 (IIa') where:
R
1 9 and R2o are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1 -C12 alkyl; substituted or nonsubstituted Cs-C-a aryl; a (Rv
I
amino group, where RX" and
R"
w are independently hydrogen or a C1-Ci2 alkyl group; or each pair can form a carboxyl group together with the carbon to which they are attached;
R
2 1 and R24 are independently hydrogen; hydroxyl; halogen; substituted or non-substituted C 1
-C
1 I alkyl; substituted or nonsubstituted C6-Cio aryl; a N(RX
I
(R
x x u) amino group, where R x and
R""
I I are independently hydrogen or a C 1 -C12 alkyl group; or each pair can form a 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 nonsubstituted Cc-Co aryl; a N(Rx Tv (Rxx v amino group, where Rxxv and R x v are independently hydrogen or a C-Ci2 alkyl group; or each pair can form a 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 comprising the following features: a) The usual methodology for the chemoselective introduction in the hydroxyl in C-3 of the natural WO 2007/077203 PCT/EP2006/070276 Friedelane derivative of the chemical family of pristimerin-related methylene triterpenequinones requires an analysis of the basicity conditions for abstracting the phenolic proton and subsequent reaction with the indicated acylation agents or agents of another type. It is relevant that if the pH control is not appropriate, reactions on C-6 that complicate the synthetic process occur.
b) The method for the chemoselective introduction in C-23 of the indicated groups will be carried out by controlled oxidation with specific reagents for allyl aromatic systems and subsequent transformations of the functionality thus obtained.
c) By means of an already studied process, C-25 will be transformed in a fluoromethyl group and the subsequent functional group transformations will allow reaching the indicated groups.
d) The use of heterolytic and homolytic halogenation reactions together with chemoselective oxidation processes and the introduction of nitrogens by means of the use of azides forms parts of any of the methods to be used for obtaining the objectives.
e) Taking advantage of the functionalizations in C-ll, the previously studied methodology will be used to obtain C11-C12 double bonds which will serve as a functional group to apply a FGT (Functional Group Transformations) to them for the purpose of preparing the envisaged compounds.
f) The C-15 and C16 positions have been functionalized by carrying out allylic oxidation reactions from double bonds in ring E or in ring C and from then onwards, the application of FGT.
g) The C-19, C-20, C-21 and C-22 positions can be partially functionalized in some starting substrates and the chemistry for introducing functional groups in this ring has been widely elaborated.
WO 2007/077203 PCT/EP2006/070276 71 Particular examples of the present invention are described in the preparation example section, nevertheless a person skilled in the art would achieve synthesizing any of the described compounds by conventional synthetic compounds of the 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, -or 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 ptoluenesulfonate. 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 WO 2007/077203 PCT/EP2006/070276 72 invention when such compounds are administered to a patient (for example, by making a compound administered orally be absorbed more easily by blood), or enhancing the release of the original compound in a biological compartment (for example, the brain or the lymphatic system) in relation to the original species.
Any compound which is a prodrug of a compound of formula 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 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 hycrogen bond donors and intra or intermolecular links can be established even in the case of phenols. The WO 2007/077203 PCT/EP2006/070276 73 presence of carbonyl or carboxyl groups generates proton acceptor groups in the molecule. The presence of halogens generates very deficient carbons and considerably modifies the biological properties. The amino groups generate good 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 (Ia" (Ia" (Ib" (Ic) (Ic" (Id), (Id" (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 WO 2007/077203 PCT/EP2006/070276 74 amounts of filler agents. Such operations are conventional in the art. The tablets can be prepared, for example by means of wet or dry granulation and can be optionally coated according to methods well known in normal pharmaceutical practice, 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 and formula (II) will preferably be found in pharmaceutically acceptable or substantially pure form, i.e. the compounds of formula 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 or for a compound of formula (II) preferably exceed 50%, more preferably exceed more preferable exceed 90%. In a preferred embodiment, they exceed The therapeutically effective amount of the compound of formula or of the compound of formula (II) to be administered will generally depend, among other factors, on the individual who is to be treated, on the severity of the disease WO 2007/077203 PCT/EP2006/070276 said individual suffers from, on the administration form chosen etc. For this reason, the doses mentioned in this invention must be considered as guides for the person skilled in the art and the latter must adjust the doses according to the variables mentioned previously. Nevertheless, a compound of formula (I) can be administered once or more times a day, for example, 1, 2, 3 or 4 times a day in a typical daily total amount comprised between 1 and 200 mg/kg body mass/day, preferably 1-10 mg/kg body mass/day. In the same manner a compound of formula (II) can be administered once or more times a day, for example, 1, 2, 3 or 4 times a day in a typical daily total amount comprised between 1 and 200 mg/kg body mass/day, preferably 1-10 mg/kg body mass/day.
The compounds described in this invention, their pharmaceutically acceptable salts, prodrugs and/or solvates, as well as the pharmaceutical compositions containing them can be used together with other additional drugs to provide a combination therapy. Said additional drugs can form part of the same pharmaceutical composition or can alternatively be provided in the form of a separate composition for its simultaneous or non-simultaneous administration with the pharmaceutical composition comprising a compound of formula or of formula or a pharmaceutically acceptable prodrug, solvate or salt thereof.
The other drugs can form part of the same composition or be provided as a separate composition for its administration at the same time or at different times.
A last object of the invention is formed by a compound of formula (Ib" (Ic" (Id" (If), (IIa), (IIa') or mixtures thereof, or a pharmaceutically acceptable salt, derivative, prodrug, solvate or stereoisomer thereof for use in the treatment of cancer, parasitic diseases, bacterial diseases or fungal diseases.
WO 2007/077203 PCT/EP2006/070276 76 The following examples are given only as an additional illustration of the invention, they must not be interpreted as limiting the invention as it is defined in the claims.
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 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 22p-hydroxy-tingenone or [3,9-dihydroxy- 6b,8a,11,12b,14a-hexamethyl-7,8,8a,11,12,12a,12b,13,14,14adecahydro-6bH,9H-picen-2,10-dione] was obtained.
342 mg (0.78 mmoles) of 22p-hydroxy-tingenone in 50 ml of dry CHiCl, under an inert atmosphere and at 0°C were treated with 1.5 eq of BBr 3 The reaction mixture was followed by thin layer chromatography, and was left stirring for 30 minutes until the starting product ran out. After this time, 50 ml of cold distilled water was added and the mixture was stirred for another 30 minutes. Then, an extraction with CH 2 Cl2 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 of product C3 was obtained.
WO 2007/077203 PCT/EP2006/070276 77 1H NMR (300 MHz, CDC13) 8 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, JZ= 10.2 Hz, H- 19); 6.32 (1H, d, J- 7.2 Hz, 6.50 (1H, d, J- 1.3 Hz, H-1); 7.00 (1H, dd, J 1 1.3, J2= 7.1 Hz, 13C NMR (75 MHz, CDCl 3 6 10.2 C-23); 20.3 C-27); 20.9 C-30); 21.7 C-26); 27.9 C-16); 28.0 C-15); 28.9 C-12); 30.9 C-28); 33.4 C-11); 37.9 C-25); 40.0 C-20); 40.4 C-14); 42.7 44.4 C-13); 45.5 C-17); 48.7 C-18); 76.6 C-19); 77.2 C-22); 118.6 119.6 C-1); 127.7 133.7 146.1 149.5 C-3); 164.1 C-10); 167.9 178.4 216.5 C- 21). High resolution MS Calculated for (M-Br) C 28
H
36 0 4 436.2614, 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-2,10dione 100 mg (0.23 mmoles) of 223-hydroxy-tingenone, obtained according to example 1, were dissolved in 10 ml of CH 2 C12 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 CHC1 2 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 nhexane:AcOEt mixtures in polarity increasing from 10% to 60% as an eluent to obtain: 1.2 mg of compound C7 and a mixture of other compounds.
1 H NMR (300 MHz, CDC13) 6 0.99 (3H, s, Me-28); 1.00 (3H, d, J- 5.2 Hz, Me-30); 1.01 (3H, s, Me-27); 1.38 (3H, s, Me-26); 1.76 (3H, s, Me-25); 2.20 (3H, s, Me-23); 4.81 (1H, dd, J= 6.7 Hz, J2= 12.0 Hz, H-ll); 6.28 (1H, d, J= 7.0 Hz, 6.89 (1H, d, J= 7.0 Hz, 7.35 (1H, s, "C NMR (75 MHz, CDCl 3 6 10.2 C-23); 14.9 C-30); 19.5 C-27); 21.2 C-26); WO 2007/077203 PCT/EP2006/070276 78 28.3 C-15); 31.7 C-16); 32.0 C-28); 35.0 C-19); 37.6 C-25); 38.1 C-13); 41.6 C-18); 42.4 C-14); 42.8 C-20); 44.3 C-17); 44.9 C-12); 46.8 C-9); 51.6 C-22); 58.3 C-ll); 117.9 118.4 C-7); 121.1 129.6 131.4 152.9 C-3); 162.7 C-10); 165.4 178.3 212.8 C- 21). High resolution MS Calculated for C 28
H
3 aBrOs 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-3yl) 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 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.
mg (0.096 mmoles) of ringenone in 10 ml of dry CH 2 C12 were treated with 0.04 ml (3 eq) of dry EtN and 0.01 ml 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 as a mobile phase, to give 24 mg of product C8. The residue was starting product.
1H NMR (300 MHz, CDC1 3 6 7.08 (1H, dd, Ji= 1.3, 7.0 Hz, H-6); 6.50 (1E, d, J-1.4 Hz, 6.35 (1H, d, J- 7.1 Hz, 2.49 (1H, m, H-20); 2.36 (3H, s, Me-COO); 2.16 (3H, s, Me-23); 1.52 (3H, s, Me-25); 1.35 (3H, s, Me-26); 1.00 (3H, s, Me-27); 0.99 (3H, d, J- 6.2 Hz, Me-30); 0.98 (3H, s, Me-28) 13C NMR (75 MHz, WO 2007/077203 PCT/EP2006/070276 79 CDC1 3 8 11.1 C-23); 14.8 C-30); 19.5 C-27); 20.3
CH
3 COO) 21.6 C-26) 28.2 C-15) 29.6 C-12); 31.8 C-19); 32.3 C-28); 33.6 C-l1 35.2 C-16); 37.9 C-17); 38.8 C-25); 40.2 C-13); 41.7 42.2 43.3 C-18); 44.6 C-14); 52.3 C-22); 117.6 122.9 126.4 133.5 C-4); 134.9 142.8 162.9 C-10); 168.5 (s,
CH
3 COO); 170.4 177.3 213.4 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-3yl) nicotinic acid ester 98 mg (0.23 mmcles) of tingenone (obtained according to example 3) were dissolved in 10 ml of dry CH>Cl, and were treated with 0.097 ml (3 eq) of dry EtsN, 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 minutes. The process described in the previous reactions was followed and the raw product was purified by preparative chromatography on silica gel using CH 2 C12:AcOEt as a mobile phase, to give 55 mg of product C9. The residue was starting product.
1H NMR (300 MHz, CDCl 3 8 9.37 (1H, dd, J= 0.9, Jz= 2.1 Hz, Ha); 8.81 (1H, dd, J 1 1.7, J 2 4.9 Hz, Hd); 8.43 (1H, dd, J= 1.9, J2 8.2 Hz, Hb); 7.44 (1H, m, He); 7.13 (1H, dd, J 1 1.2, J 2 7.0 Hz, 6.53 (1H, d, J-1.3 Hz, 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, 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). 13 C NMR (75 MHz, CDC13) 6 11.23 C-23); 14.84 C-30); 19.54 C-27); 21.59 C-26); 28.26 C-15); 29.63 C-12); 31.78 C-19); 32.30 C- 28); 33.69 C-ll); 35.23 C-16); 37.91 C-17); 38.81 C-25); 40.23 C-13); 41.65 C-20) 42.29 C-9); 43.26 C-18); 44.64 C-14); 52.26 C-22); 117.6 C- 123.0 123.2 CH-Ar); 125.0 C-Ar); 126.3 (s, WO 2007/077203 PCT/EP2006/070276 133.8 135.2 137.6 CH-Ar); 142.7 C-3) 151.3 N-CH); 153.7 N-CH); 162.8 162.9 OCO-Nic); 170.7 176.8 213.3 C- 21) High resolution MS Calculated for C 34
H
39 N0 4 525.2879, observed 525.2899.
Example Compound C12: 3,10-dihydroxy-2,4a,6a,9,12b,14a-hexamethyl-1loxo-1,2,3,4,4a,5,6,6a,ll,12b,13,14,14a,14b-tetradecahydro-picen- 2-carboxylic acid methyl ester.
1500 g of Salacia root bark were extracted in 2 liters of a n-hexane-ethyl ether 1:1 solven: mixture, obtaining 5 grams of a reddish extract after evaporating the solvent. The extract was chromatographed on several silica gel columns, from which compound C12 was obtained.
Example 6 Compound C14: 10-Dimethylcarbamoyloxy-2,4a,6a,9,12b,14ahexamethyl-ll-oxo-l,2,3,4,4a,5,6,6a,ll,12b,13,14,14a,14btetradecahydro-picen-2-carboxylic acid methyl ester 300 g of Maytenus amazonica root bark were extracted in 2 liters of a n-hexane-ethyl ether 1:1 solvent mixture in soxhlet equipment under reflux for 48 hours, obtaining 70 grams of a reddish solid after evaporating the solvent. The extract was chromatographed on a sephadex LH-20 column, using a n-hexane- CHC13-MeOH 2:1:1 mixture as eluent. A total of 41 fractions were obtained which were gathered in seven groups B, C, D, E, F and G) according to thin layer chromatography. These groups were in turn fractioned in sephadex LH-20 columns, in medium pressure silica gel columns and in preparation plates, from which the starting compound called pristimerin was obtained.
65 mg (0.14 mmoles) of pristimerin in 5 ml of dry CH 2 C1 2 were treated with 0.062 ml (3 eq) of dry Et 3 N, 0.02 ml (1.5 eq) of N,N-dimethylcarbamoyl chloride and catalytic amounts of DMAP.
The reaction was carried out at and under an inert atmosphere, followed by TLC and stirred for 24h. Then 5% diluted hydrochloric acid was added until neutralization. Then the organic phase was extracted with CH 2 C12 and was dried with anhydrous magnesium sulfate. It was filtered and concentrated WO 2007/077203 PCT/EP2006/070276 81 under reduced pressure. The raw product was purified by preparative chronatography using n-hexane:AcOEt as a mobile phase to yield 36 mg of product C14. The residue corresponded to starting product.
1H NMR (300 MHz, CDC13) 8 7.00 (1H, dd, J5= 1.4, 7.0 Hz, H-6); 6.46 (1H, d, J- 1.4 Hz, 6.29 (1H, d, J- 7.2 Hz, 3.56 (3H, s, OMe); 3.13 N-CH3); 3.00 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- 1.09 (3H, s, Me-28); 0.54 (3H, s, Me-27). 1C NMR (75 MHz, CDC13) 6 10.97 C-23); 18.09 C-27); 21.63 C-26); 28.39 C-15); 29.38 C-12); 29.67 C-21); 30.29 C- 17); 30.61 C-19); 31.34 C-28); 32.40 C-30); 33.45 C-11); 34.49 C-22); 36.15 C-16); 36.57(c, N-CH3); 36.58(c, N-CHJ); 37.99 C-25); 38.99 C-13); 40.14 C- 20); 42.23 44.07 C-18); 44.87 C-14); 51.34 (q, OCH3); 117.5 122.9 126.5 133.1 (s, 134.5 143.0 153.9 OCON); 162.6 (s, 170.8 178.3 C-2) 178.4 C-29). High resolution MS Calculated for C 33
H
45 N0 5 535.3298, observed 535.3294.
EX VIVO ASSAYS OF HUMAN CHOK ACTIVITY Recombinant human alpha-i choline kinase expressed in E.
coli in the assay of the buffer (100 mM Tris-HC1 pH 8.0, 100 mM MgC12, 10 mM ATP and 200 [LM of choline in the presence of methyl[" 4 C]-choline chloride (50-60 pCi/mmol) were used for the ex vivo assays. The reactions were carried out at 370 C for 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, Penalva, Lucas, 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 WO 2007/077203 PCT/EP2006/070276 82 another eight compounds known in the state of the art (IS 2 117 950). The results are summarized in table I.
From the obtained results it is concluded that the compounds of the invention allow considerably and selectively 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. Didier, Denton, M. Anal.
Biochem. 159, 109-113 (1986)], with some modifications [Hernandez-Alcoceba, Saniger, Campos, Nuiez, M. C., Khaless, Gallo, M. Espinosa, Lacal, J. C. Oncogene, 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 IC 50 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 ICo0 value as a measurement of the potency is used to relate the biological activity of the compounds with their chemical structure.
WO 2007/077203 PCT/EP2006/070276 83 These assays are carried out with the compounds of the invention C3, C7, C8, C9, C10, C12 and C14 as well as with another eight compounds known in the state of the art (ES 2 117 950). The results are summarized in table I.
The following table summarizes the results obtained in the conducted assays and which are shown as an example.
Table I
IC
5 0 ex vivo No. Code IC 5 0 HT-29 (pM) (pM) 1 C 3.3 8.8 2 C7 13.6 27.5 3 C8 5.3 26.4 4 C9 8.8 13.3 C10 11.2 25.9 6 C12 7.4 3.8 7 C4 7.1 11.3 8 3,9-dihydroxy- 4,6b, a,11,12b,14ahexamethyl- 7,8,8a, ,12,12a,12b,4.9 3,14,14a-decahydro- 6bH,9H-picen-2,10dione 9 (9-hydroxy- 4,6b,8a,11,12b,14ahexamethyl-2,10-dioxo- 2,6b,7,8,8a,9,10,11,12, 4.8 11.1 12a,12b,13,14,14atetradecahydro-picen-3yl) acetic acid methyl ester 9-hydroxy- 5.2 9.6 4,6b,Ba,11,12b,14a- WO 2007/077203 WO 207/07203PCT!EP2006/070276 2, 4 6b ,10 1,1 'T a ,T 1,1,1a 4, 6b,8a, 1, 12b 11a 144, 17.0 h 42a -2I, 1, 14 1: 4 tetIdeTa 1-plcenI 4, 8b, 8a, 11, 14aI 2, 1b 3 14, 14tetraea r-ie- 4- WO 2007/077203 PCT/EP2006/070276 13-brcmo 10 hydroxy 2,4a,a,9,12b, 14ahexamethyl-3, l-dioxo- 1,2,3144a,5,6,6a,11,12 2.1 4.1 b, 13,14, 14a, 14btetradecahydro-picen-4yl ethylsuccinic acid ester From the data of table I it is observed that the compounds of the present invention have similar antiproliferative values against cells derived from cultured tumors.
Claims (3)
1. A compound of formula CH 3 R 1 R 7 OH 3 H3H (Ia') where R 5 is hydroxyl or a OCOR group where R is (CH 2 2 COOH or (CH 2 2 CO 2 CH 2 CH 3 R 7 and R 8 are independently hydrogen; hydroxyl; halogen; substituted or non- substituted Cl-C 12 alkyl; substituted or non-substituted C 6 -C 10 aryl; a amino group, where R' and R" are independently hydrogen or a CI-C 12 alkyl group; or each pair can form a group together with the carbon to which they are attached; R 1 2 is independently hydrogen or a halogen; and Rig is hydrogen; substituted or non-substituted CI-C 1 2 alkyl; a CORxII group (where Rx is hydrogen; hydroxyl; substituted or non-substituted C,-C, 2 alkyl; substituted or non-substituted C 6 -Cio aryl; or N(Rx 1 1 )(RxIv) amino, where Rx.II and Rx'v are independently hydrogen or a CI-C1 2 alkyl group); a [(CI-CI 2 )alkyl-O-(CI-C 2 )alkyl-],, group (where n is comprised between I and or trifluoromethyl; and the bond---means a double bond or a single bond, with the proviso that the compound of formnula is not: 3,9-Dihydroxy-4,6b,8a, 11,1 2b, 14a-hexamethyl-7,8,8a, 11,12,1 2a, 12b, 13,14,1 4a- decahydro-6bH,9H-picene-2, I 0-dione; 1 4-Bromo-3,7,9-trihydroxy-4,6b,8a, 11I, 1 2b, 1 4a-hexamethyl- 7,8,8a, 11, 12,1 2a, 1 2b, 1 3,14,1 4a-decahydro-6bH,9H-picene-2, I 0-dione; Succinic acid mono-( I O-hydroxy-2,4a,6a,9,1I2b, 1 4a-hexamethyl-3, 11 -dioxo- 1 ,2,3,4,4a,5,6,6a, 11, 1 2b, 13,14,1 4a, I 4b-tetradecahydro-picen-4-yl) ester; 00 0/ -Succinic acid ethyl ester Il0-hydroxy-2,4a,6a,9,12b, 14a-hexamethyl-3,1 I1-dioxo- 1,2,3,4, 4a, 5,6,6 a, 1 1, 1 2b, I13,14,14a,1I4b-tetradecahydro-picen-4-yi ester; -Acetic acid 9-hydroxy-4,6b,8a, 11, 1 2b, I 4a-hexamethyl-2, 1 0-dioxo- 2,6b,7,8,8a,9,10,1 l,12,12a,1I2b,1I3,14,14a-tetradecahydro-picen-3-y ester; -Dodecanoic acid 9-hydroxy-4,6b, 8a, 11, 1 2b, 1 4a-hexamethyl-2, 1 0-dioxo- 2,6b,7,8,8a,9, 10,11,12,1 2a, 1 2b, 1 3,14,1 4a-tetradecahydro-picen-3-yI ester; -Dimethyl-carbamic acid 9-hydroxy-4,6b,8a, 11, 1 2b, 1 4a-hexamethyl-2, 1 0-dioxo- 2,6b,7,8,8a,9, 10,11,12,1 2a,lI 2b, 1 3,14, 14a-tetradecahydro-picen-3-yl ester; -Nicotinic acid 9-hydroxy-4,6b, 8a, 11, 1 2b, I 4a-hexamethyl-2, 1 0-dioxo- ri 2,6b,7,8, 8a,9, 10,11,12,1 2a, I 2b, 1 3,14,1 4a-tetradecahydro-picen-3-yl ester.
2. A compound according to claim 1 which is:
9-hydroxy-4,6b, 8a, 11, 1 2b, 1 4a-hexamethyl-2, 1 0-dioxo- 2,6b,7,8,8a,9, 10,11,12,1 2a, 12b, 13,14,1 4a-tetradecahydro-picene-3-yl propionic acid ester; 4-bromo-(9-hydroxy-6b,8a, 11, 1 2b, 1 4a-hexamethyl-2, 1 0-dioxo- 2,6b,7,8,8a,9, 10,11,12,1 2a, I 2b, 1 3,14,1 4a-tetradecahydro-picene-3-yl) benzo ic acid ester; 1 2-bromo-3,9-dihydroxy-4,6b,8a, 11, 1 2b, 1 4a-hexamethyl- 7,8,8a, 1 1, 12,1 2a, I 2b, 1 3,14,1 4a-decahydro-6bH,9H-picene-2,1 I -dione; 1 2-bromo-9-hydroxy-6b,8a, 11, 1 2b, 1 4a-hexamethyl-2, I 0-dioxo- 2,6b,7,8, 8a,9, 10,11,1 2,1 2a, 12b, 13,14,1 4a-tetradecahydro-picene-3-yI dimethyl- carbamic acid ester; 4-bromo-( 1 2-bromo-9-hydroxy-6b,8a, 11, 1 2b, 1 4a-hexamethyl-2, 1 0-dioxo- 2,6b,7, 8, 8a,9, 10,11,12,1 2a, 1 2b, 1 3,14,1 4a-tetradecahydro-picene-3-y1) benzo ic acid ester; 3,9,1 0-trihydroxy-6b, 8a, 11],1 2b, 1 4a-hexamethyl- 7,8,8a,9, 10,11,12,1 2a, I 2b, 1 3,14,1 4a-dodecahydro-6bH-picene-2-one. 0 O 3. A compound of formula SI ICH C1 (Ia") where: R 7 and R 8 are independently hydrogen, hydroxyl, halogen, substituted or non- substituted CI-C 2 alkyl, substituted or non-substituted C 6 -CIO aryl, a amino group, where R' and R" are independently hydrogen or a CI-CI 2 alkyl group, or each pair can form a group together with the carbon to which they are attached; Ri 5 is hydrogen or halogen; R 1 9 is hydrogen, substituted or non-substituted CI-C 1 2 alkyl; a CORxI group (where RxII is hydrogen; hydroxyl; substituted or non-substituted Ci-C 12 alkyl; substituted or non- substituted C 6 -Clo aryl; or N(RX)(Rxiv) amino, where Rx" and RxIV are independently hydrogen or a CI-C 12 alkyl group); a [(Ci-Cl 2 )alkyl-O-(CI-Cl2)alkyl-]n group (where n is comprised between 1 and or trifluoromethyl; and the bond means a double bond or a single bond, with the proviso that the compound of formula 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; Acetic acid 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 (tingenone acetate); -Benzo ic acid 4,6b,8a, 11, 12b, 1 4a-hexamethyl-2, I 0-dioxo- 2,6b,7,8,8a,9,I0,l 1,12,12a,1I2b,1I3,14,14a-tetradecahydro-picen-3-y ester (tingenone benzoate) 4. A compound according to claim 3 which is: 1 4-bromo-3-hydroxy-4,6b,8a, 11, 1 2b, 1 4a-hexamethyl- 7,8,8a, 11, 12,1 2a, 1 2b, 1 3,14,1 4a-decahydro-6bH,9H-picene-2,1 I -dione; 4,6b, 8a, 11, 1 2b, 1 4a-hexamethyl-2, 1 0-dioxo- ID2,6b,7,8,8a,9, 10,11,12,1 2a,1I2b, 13,14,1 4a-tetradecahydro-picene-3-yl acetic acid ester; -4,6b,8a, 11, 1 2b, 1 4a-hexamethyl-2, 1 0-dioxo- 2,6b,7,8,8a,9,1O,1 l,l 2 ,12a,lI2b,1I3,14,14a-tetradecahydro-picene-3-yl nicotinic acid ester; 3) 31 O-dihydroxy-4,6b,8a, 11, 1 2b, 1 4a-hexamethyl- 7,8,8a,9, 10,11,12,1 2a, 1 2b, 13,14,1 4a-dodecahydro-6bH-picene-2-one; -3-hydroxy-4,6b,8a, 11, 12b, I 4a-hexamethyl-7, 8,8a, I 2a, 1 2b, 1 3,14,1 4a-octahydro- 6bH,9H-picene-2, 1 0-dione. A compound which is: 2,4a,6a,9,]I2b, 1 4a-hexamethyl- I11 -oxo- 1 0-propionyloxy- 1 ,2,3,4,4a,5,6,6a, 11,1 2b, 13,14,1 4a,1I4b-tetradecahydro-picene-2-carboxylic acid methyl ester; 1 0-dimethylcarbamoyloxy-2,4a,6a,9,1I2b, I 4a-hexamethyl- 11I -oxo- 1 ,2,3,4,4a,5,6,6a, 11,1 2b, 13,14,1 4a,1I4b-tetradecahydro-picene-2-carboxylic acid methyl ester. 6. Use of a compound as defined in any of claims I to 5 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. 00 O 7. Use according to claim 6 wherein the ChoK mediated disease or condition to be prevented and/or treated is cancer, preferably selected from breast, lung, colorectal and pancreatic cancer. 8. Use according to claim 6 wherein the ChoK mediated disease or condition to be t prevented and/or treated is a parasitic disease, more preferably caused by Plasmodium or Trypanosoma. IND 9. Use according to claim 6 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. Use according to claim 6 wherein the ChoK mediated disease or condition to be prevented and/or treated is a fungal disease, preferably caused by Candida.
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ES200503263A ES2277568B1 (en) | 2005-12-30 | 2005-12-30 | DERIVATIVES OF TRITERPENOQUINONA AND TRITERPENOFENOLES AND ITS APPLICATION FOR THE TREATMENT OF TUMORS AND PARASITARY DISEASES. |
ESP200503263 | 2005-12-30 | ||
PCT/EP2006/070276 WO2007077203A2 (en) | 2005-12-30 | 2006-12-29 | Triterpenequinone and triterpenephenol derivatives and their application for the treatment of tumors and parasitic diseases |
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AU (1) | AU2006334359A1 (en) |
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CA (1) | CA2635318A1 (en) |
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US7776894B2 (en) | 2007-08-17 | 2010-08-17 | Burnham Institute For Medical Research | Compositions and methods for inhibiting growth and metastasis of melanoma |
CN101434635B (en) * | 2007-11-16 | 2012-05-16 | 上海华拓医药科技发展股份有限公司 | Water-soluble phenolic triterpenoid with antineoplastic activity and preparation thereof |
US20100068302A1 (en) * | 2008-09-17 | 2010-03-18 | Traslational Cancer Drugs Pharma, S.L. | Methods and compositions for the treatment of cancer |
WO2010049173A1 (en) * | 2008-10-31 | 2010-05-06 | Cenix Bioscience Gmbh | Use of inhibitors of host kinases for the treatment of infectious diseases |
US8691977B2 (en) * | 2010-08-23 | 2014-04-08 | Neupharma, Inc. | Certain chemical entities, compositions, and methods |
EP3364956A4 (en) | 2015-10-23 | 2019-05-01 | ERX Pharmaceuticals, Inc. | Analogs of celastrol |
EP3480207A4 (en) | 2016-07-04 | 2020-03-11 | Xiamen University | Orphan nuclear receptor nur77 ligand and application thereof |
US10683292B2 (en) | 2016-07-25 | 2020-06-16 | Nerviano Medical Sciences S.R.L. | Purine and 3-deazapurine analogues as choline kinase inhibitors |
JP7178401B2 (en) | 2017-07-11 | 2022-11-25 | ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ | Pyrazoloquinazoline derivatives as choline kinase inhibitors |
WO2020257658A1 (en) | 2019-06-20 | 2020-12-24 | University Of Iowa Research Foundation | Nanoparticles comprising quinone w methides and compositions for use |
CN113827599A (en) * | 2021-09-23 | 2021-12-24 | 天津国际生物医药联合研究院 | Potential application of demethylzelaronal in resisting dengue virus infection |
CN116023426A (en) * | 2022-12-30 | 2023-04-28 | 上海海洋大学 | Norzeranal derivative and application thereof in preparation of anticancer drugs |
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AU2006334359A1 (en) | 2007-07-12 |
EP1976533A2 (en) | 2008-10-08 |
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CA2635318A1 (en) | 2007-07-12 |
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KR20080083044A (en) | 2008-09-12 |
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