• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    Preparation procedure of (-) - englerin A, analogs and intermediates. The present invention relates to a process for obtaining the compound (-) - englerin A and analogous compounds thereof of formula III, wherein the groups R1-R6they have the meaning described in the description. Also, the present invention relates to the analogous compounds mentioned and their use in the treatment of cancer, as well as to the reaction intermediates. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2661549A1
    申请号:ES201631261
    申请日:2016-09-28
    公开日:2018-04-02
    发明作者:Fernando José LÓPEZ GARCÍA；José Luis Mascareñas Cid；Ronald Nelson GONZÁLEZ；Moises GULÍAS COSTA；Soraya LEARTE AYMAMÍ
    申请人:Universidade de Santiago de Compostela；Consejo Superior de Investigaciones Cientificas CSIC；
    IPC主号:
    专利说明:

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    Preparation procedure for (-) - englerin A, analogues and intermediates
    DESCRIPTION
    The present invention relates to a process for obtaining the compound (-) - englerin A and similar compounds thereof. Also, the present invention relates to the aforementioned analogous compounds and their use in the treatment of cancer, as well as to the reaction intermediates.
    STATE OF THE TECHNIQUE
    Over the past few years, sesquiterpene (-) - englerin A (EA, figure 1) has attracted the attention of chemists, biologists and physicists for its potent and selective activity as a growth inhibitor of renal cancer cells (GI 20 nM) (see R. Ratnayake, D. Covell, TT Ransom, KR Gustafson, JA Beutler, Org. Lett. 2009, 11, 57).
    image 1
    Figure 1
    Since the isolation of compound EA in 2009 (see previous reference) different formal and total syntheses have been described.
    WO 2009/088854 describes the isolation of Englerin A and Englerin B by extraction and purification by HPLC. This document also describes a hemisynthetic route for the preparation of various derivatives of the ester group of the natural compound from cinnamoyl.
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    Willot has described a total synthesis of (+) - englerin A from trans monoterpene, cis-nepelactone (see M. Willot et al. Anqewandte Chemie. International Edition, 2009, vol. 48, pp. 9105-9108).
    On the other hand, Echavarren has described the synthesis of (-) - englerin A by an asymmetric epoxidation of Sharpless from geraniol (Echavarren et al WO 2011/120886). In this synthesis, a gold-catalyzed ketoenin cycloisomerization is used to obtain the EA bicarbobiclo directly.
    This and other syntheses have the disadvantage that in order to generate the centers resulting from the fusion of the rings with the correct stereochemistry, isomerizations involving the destruction and generation of stereocenters and the need to separate isomers have to be carried out.
    In addition, the syntheses that have been described to date have numerous drawbacks. Some of them are long (more than 20 synthetic stages) and consequently have low overall yields. Others, despite being shorter, also have low overall yields or do not constitute an efficient method to synthesize structural analogs of englerin A since they start from chiral natural products from which the (-) englerina is made. In particular, none of the syntheses described to date allow obtaining a wide range of EA derivatives with different modifications in the five-member ring.
    Therefore, it would be desirable to have an EA preparation procedure to overcome these limitations.
    DESCRIPTION OF THE INVENTION
    In a first aspect, the present invention relates to a process for obtaining a compound of formula I:
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    image2
    each -— independently represents a single or double bond with the proviso that both -— do not represent a double bond simultaneously;
    R1 represents H, OH, -OP1, = O, -CN, halogen, -NR7R7, -N3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or Cy1;
    each R2 and R3 independently represent H or C1-6 alkyl;
    R4 represents H or P2;
    R5 represents C1-6 alkyl;
    R6 represents Cy2-C1-6 alkyl-CO-, Cy2-C2-6 alkenyl-CO-, Cy2-C1-6 or Cy2OCO-, where the alkyl or alkenyl moiety of each of the R6 groups are optionally and independently substituted by one or more halogen groups or -OH; each R7 independently represents H, C1-6 alkyl or two R7 groups on an N atom join to form a Cy3 group; Y
    each Cy1 and Cy2 independently represent a carbocyclic aromatic ring of 6 to 10 members or each Cy1 and Cy2 independently represent a heteroaromatic ring of 5 or 6 members containing 1 to 3 heteroatoms selected from N, O and S, where each Cy1 and Cy2 independently is bound to the rest of the molecule through any available N or C atom, and where each Cy1 and Cy2 independently is optionally substituted by one or more halogen groups, -C1-6 alkyl, -OC1-6 alkyl or halo -C1-6 alkyl;
    Cy3 represents a 5- or 6-membered heteroaryl containing 1 to 3 N atoms, where Cy3 is attached to the rest of the molecule through the N atom of the group -NR7R7 and where Cy3 is optionally substituted by one or more R8 groups ; each R8 independently represents hydrogen, C1-6 alkyl or Cy2; each P1 and P2 independently represent -Si (R9) 3, methoxymethyl (MOM), tetrahydropyranyl (THP), benzyl (Bn), -COR10, -COCy1, -SO2R11, -SO2Cy1,
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    benzyloxymethyl ether, methylthiomethyl ether, trimethylsilylethoxymethyl ether or para-methoxybenzyl (PMB);
    each R9 independently represents phenyl or C1-6 alkyl,
    R10 represents C1-6 alkyl, halo C1-6 alkyl, -CH2OH, -CH2OC1-6 alkyl or -CH2OP1; and R11 represents C1-6 alkyl or halo-C1-6 alkyl,
    which comprises the reaction between a compound of formula II and a PtCl2 catalyst
    and P (C6F 5) 3:
    Pr
    image3
    II
    where:
    P3 represents -Si (R9) 3, methoxymethyl (MOM), tetrahydropyranyl (THP), benzyl
    (Bn), -COR10, -COCy1, -SO2R11, -SO2Cy or para-methoxybenzyl (PMB); Y
    Cy1, R2, R3 and R5 R9 and R10 have the meaning described for a compound of formula I.
    In another embodiment the invention relates to the process defined above, where P3 is selected from ferc-butyldimethylsilyl (TBS), trimethylsilyl (TMS), triethylsilyl (TES), ferc-butyldiphenylsilyl (TBDPS) and triisopropylsilyl (TIPS), and preferably where P3 represents ferc-butyldimethylsilyl (TBS).
    In another embodiment the invention relates to the process defined above, where the molar ratio between PtCl2 and P (C6F5) 3 is between 2: 1 and 1: 2, and preferably is 1: 1.
    In another embodiment the invention relates to the process defined above, where the molar ratio between the compound of formula II, PtCl2 and P (C6F5) 3 is between 100: 1: 1 and 10: 1: 1 respectively, and preferably 20 : 1: 1 respectively.
    In another embodiment the invention relates to the process defined above, which further comprises the dihydroxylation step of a compound of formula IV, and optionally protective and / or deprotection reactions, for obtaining a compound of formula V:
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    PiO | _ | Pr
    image4
    R120 | - | Pr
    IV
    where:
    R12 represents hydrogen or P1, and
    P1, R2, R3, R4 and R5 have the meaning described for a compound of formula I.
    image5
    V
    In another embodiment the invention relates to a procedure defined above, which further comprises the steps:
    a) epoxidation of a compound of formula V; Y
    b) transanulation, and optionally protection and / or deprotection, to obtain a compound of formula la.
    image6
    OR4
    the
    where P3, R2-R6 have the meaning described for a compound of formula I.
    In another embodiment the invention relates to the process defined above, which further comprises an additional reaction selected from the following:
    a) reaction of a compound of formula la with a compound of formula (R13) 2CuM to obtain a compound of formula Ib:
    image7
    R13 represents halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or Cy1;
    M represents Li or MgX; Y
    X represents halogen, -OSO2R11 or -CN; Y
    R11 has the meaning described for a compound of formula I; or
    b) oxidation of a compound of formula la, to obtain a compound of formula lc,
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    O H Re ¡Pr
    image8
    Ic
    wherein R2-R6 has the meaning described for a compound of formula I; Y
    optionally, reaction with a base and a triflating agent to obtain a compound of formula Id:
    ORr, r
    image9
    Id
    wherein R2-R6 has the meaning described for a compound of formula I; Y
    optionally, reaction of a compound of formula Id of "cross-coupling" of Suzuki, preferably with an organometallic compound of formula R14B (OH) 2, by catalysis by a complex of Pd or Ni, to obtain a compound of formula Ie,
    image10
    or4
    Ie
    wherein R2-R6 has the meaning described for a compound of formula I; and R14 represents C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl or Cy1; or
    c) reaction of a compound of formula Ia with a cyanide to obtain a compound 20 of formula I wherein R 1 represents a cyano group; or
    d) reaction of a compound of formula Ia with an azide, to obtain the compound of formula I where R 1 represents azide; or
    e) fluoridation of a compound of formula la, to obtain the compound of formula I, where R 1 represents fluorine.
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    Another aspect of the invention relates to a compound of formula NI:
    image11
    III
    where:
    R1 represents -OH, -OP1, = O, -CN, halogen, -NR7R7, -N3, -C2-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or Cy1; Y
    R2 to R7, Cy1, and ---- have the meaning described for a compound of formula I.
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    In another embodiment the invention relates to a compound of formula III, which is a compound of formula IIIa:
    image12
    IIIa
    where R1 to R5 and -— have the meaning described for a compound of formula III.
    In another embodiment the invention relates to a compound of formula III, where each ---- represents a single bond.
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    R6O
    image13
    IlIb
    5 where -—, R1-R6 have the meaning described for a compound of formula III.
    In another embodiment the invention relates to a compound of formula III, which is a compound of formula IIIc:
    image14
    IIIc
    where R1-R6 have the meaning described for a compound of formula III.
    In another embodiment the invention relates to a compound of formula III, which is a compound of formula IIId:
    RrO
    image15
    IIId
    where R1-R6 have the meaning described for a compound of formula III.
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    image16
    where R2-R6 has the meaning described for a compound of formula III.
    In another embodiment the invention relates to a compound of formula III, wherein:
    Each ---- represents a simple link; Y
    R1 represents F, Cl, I, isobutyl, n-butyl, n-hexyl, -N3, = O or -OTs.
    In another embodiment the invention relates to a compound of formula III, wherein each R2 and R3 represent H.
    In another embodiment the invention relates to a compound of formula III, wherein: each ---- represents a single bond;
    R1 represents F, Cl, I, isobutyl, n-butyl, n-hexyl, -N3, = O or -OTs; and each R2 and R3 represent H.
    In another embodiment the invention relates to a compound of formula III, wherein R4 represents P2.
    In another embodiment the invention relates to a compound of formula III, wherein R4 represents -COCH2OH.
    In another embodiment the invention relates to a compound of formula III, wherein: each ---- represents a single bond;
    R1 represents F, Cl, I, isobutyl, n-butyl, n-hexyl, -N3, = O or -OTs; each R2 and R3 represent H; Y
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    R4 represents P2, and preferably R4 represents -COCH2OH.
    In another embodiment the invention relates to a compound of formula III, wherein:
    R4 represents P2; Y
    P2 represents -COR10, -COCy1, -SO2R11, -SO2Cy1, benzyloxymethyl ether, methylthiomethyl ether, trimethylsilyloxymethyl ether or para-methoxybenzyl (PMB),
    preferably -COR10, -COCy1, -SO2R11, -SO2Cy1 or para-methoxybenzyl (PMB), more preferably -COR10, -COCy1, -SO2R11o -SO2Cy1, even more
    preferably -COR10 or -COCy1, and even more preferably -COR10.
    In another embodiment the invention relates to a compound of formula III, wherein:
    R4 represents P2; Y
    P2 represents -COR10, -COCy1, -SO2R11, -SO2Cy1, benzyloxymethyl ether, methylthiomethyl ether, trimethylsilyloxymethyl ether or para-methoxybenzyl (PMB),
    preferably -COR10, -COCy1, -SO2R11, -SO2Cy1 or para-methoxybenzyl (PMB), more preferably -COR10, -COCy1, -SO2R11o -SO2Cy1, even more
    preferably -COR10 or -COCy1, and even more preferably -COR10; and R10 represents -CH2OH, -CH2OC1-6 alkyl or -CH2OP1, and preferably -CH2OH.
    In another embodiment the invention relates to a compound of formula III, wherein R 5 represents methyl.
    In another embodiment the invention relates to a compound of formula III, wherein: each ---- represents a single bond;
    R1 represents F, Cl, I, isobutyl, n-butyl, n-hexyl, -N3, = O or -OTs; and R5 represents methyl.
    In another embodiment the invention relates to a compound of formula III, wherein: each R2 and R3 represent H; and R5 represents methyl.
    In another embodiment the invention relates to a compound of formula III, wherein:
    R4 represents P2, and preferably R4 represents -COCH2OH; and R5 represents methyl.
    In another embodiment the invention relates to a compound of formula III, wherein:
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    each -— represents a simple link;
    R1 represents F, Cl, I, isobutyl, n-butyl, n-hexyl, -N3, = O or -OTs; each R2 and R3 represent H; and R5 represents methyl.
    In another embodiment the invention relates to a compound of formula III, wherein: each ---- represents a single bond;
    R1 represents F, Cl, I, isobutyl, n-butyl, n-hexyl, -N3, = O or -OTs; each R2 and R3 represent H;
    R4 represents P2, and preferably R4 represents -COCH2OH; and R5 represents methyl.
    In another embodiment the invention relates to a compound of formula III, wherein R 6 represents cinnamoyl, cinnamon, 3-phenylpropyl, 3-phenylpropanoyl, benzyloxycarbonyl, N-benzylaminocarbonyl, N-benzylaminothiocarbonyl, wherein the phenyl moiety of each of the R6 groups it is optionally substituted by one or more C1-6 alkyl groups, -OC1-6 alkyl or halogen, and where the alkyl or alkenyl moiety of each of the R6 groups are optionally and independently substituted by one or more halogen groups or -OH.
    In another embodiment the invention relates to a compound of formula III, wherein: each ---- represents a single bond;
    R1 represents F, Cl, I, isobutyl, n-butyl, n-hexyl, -N3, = O or -OTs; and R6 represents cinnamoyl, cinnamonyl, 3-phenylpropyl, 3-phenylpropanoyl, benzyloxycarbonyl, N-benzylaminocarbonyl, N-benzylaminothiocarbonyl, where the phenyl moiety of each of the R6 groups is optionally substituted by one or more C1-6 alkyl groups, - OC1-6 alkyl or halogen, and where the alkyl or alkenyl moiety of each of the R6 groups are optionally and independently substituted by one or more halogen or -OH groups.
    In another embodiment the invention relates to a compound of formula III, wherein: each R2 and R3 represent H; Y
    R6 represents cinnamoyl, cinnamonyl, 3-phenylpropyl, 3-phenylpropanoyl, benzyloxycarbonyl, N-benzylaminocarbonyl, N-benzylaminothiocarbonyl, where the phenyl moiety of each of the R6 groups is optionally substituted by one or more C1-6 alkyl groups, - OC1 -6 alkyl or halogen, and where the alkyl or alkenyl moiety of each of the
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    R6 groups are optionally and independently substituted by one or more halogen groups or -OH.
    In another embodiment the invention relates to a compound of formula III, wherein:
    R4 represents P2, and preferably R4 represents -COCH2OH;
    R5 represents methyl; Y
    R6 represents cinnamoyl, cinnamonyl, 3-phenylpropyl, 3-phenylpropanoyl, benzyloxycarbonyl, N-benzylaminocarbonyl, N-benzylaminothiocarbonyl, where the phenyl moiety of each of the R6 groups is optionally substituted by one or more C1-6 alkyl groups, - OC1 -6 alkyl or halogen, and wherein the alkyl or alkenyl moiety of each of the R6 groups are optionally and independently substituted by one or more halogen groups or -OH.
    In another embodiment the invention relates to a compound of formula III, wherein:
    R5 represents methyl; Y
    R6 represents cinnamoyl, cinnamonyl, 3-phenylpropyl, 3-phenylpropanoyl, benzyloxycarbonyl, N-benzylaminocarbonyl, N-benzylaminothiocarbonyl, where the phenyl moiety of each of the R6 groups is optionally substituted by one or more C1-6 alkyl groups, - OC1 -6 alkyl or halogen, and wherein the alkyl or alkenyl moiety of each of the R6 groups are optionally and independently substituted by one or more halogen groups or -OH.
    In another embodiment the invention relates to a compound of formula III, wherein: each ---- represents a single bond;
    R1 represents F, Cl, I, isobutyl, n-butyl, n-hexyl, -N3, = O or -Ots; each R2 and R3 represent H;
    R4 represents P2, and preferably R4 represents -COCH2OH;
    R5 represents methyl; Y
    R6 represents cinnamoyl, cinnamonyl, 3-phenylpropyl, 3-phenylpropanoyl, benzyloxycarbonyl, N-benzylaminocarbonyl, N-benzylaminothiocarbonyl, where the phenyl moiety of each of the R6 groups is optionally substituted by one or more C1-6 alkyl groups, - OC1 -6 alkyl or halogen, and wherein the alkyl or alkenyl moiety of each of the R6 groups are optionally and independently substituted by one or more halogen groups or -OH.
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    In another embodiment the invention relates to a compound of formula NI, where each R7 independently represents H or C1-6 alkyl.
    In another embodiment the invention relates to a compound of formula III, wherein:
    R1 represents -NR7R7;
    two R7 groups on an atom of N join to form a Cy3 group.
    In another embodiment the invention relates to a compound of formula III, wherein:
    R1 represents -NR7R7;
    two R7 groups on an N atom join to form a Cy3 group; and Cy3 represents triazole.
    In another embodiment the invention relates to a compound of formula III, wherein R 10 represents -CH 2 OH.
    In another embodiment the invention relates to a compound of formula III, where Cy1 represents a 5-membered heteroaryl containing 1 to 3 N atoms, where Cy1 is attached to the rest of the molecule through the N atom of the group - NR7R7 and where Cy1 is optionally substituted by one or more R8 groups, and preferably where Cy1 represents a triazole ring.
    In another embodiment the invention relates to a compound of formula III selected from:
    image17
    1 B;
    image18
    OH 1c;
    iBu
    O ^^ Ph
    image19
    OH id;
    image20
    OH ie;
    OH ig;
    OR,
    image21
    1 hour;
    权利要求:
    Claims (21)
    [1]
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    1. Procedure for obtaining a compound of formula I:
    image 1
    where:
    each -— independently represents a single or double bond with the proviso that both -— do not represent a double bond simultaneously;
    R1 represents H, OH, -OP1, = O, -CN, halogen, -NR7R7, -N3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or Cy1;
    each R2 and R3 independently represent H or C1-6 alkyl;
    R4 represents H or P2;
    R5 represents C1-6 alkyl;
    R6 represents Cy2-C1-6 alkyl-CO-, Cy2-C2-6 alkenyl-CO-, Cy2-C1-6 or Cy2OCO-, where the alkyl or alkenyl moiety of each of the R6 groups is optionally and independently substituted by one or more halogen groups or -OH; each R7 independently represents H, C1-6 alkyl or two R7 groups on an N atom join to form a Cy3 group; Y
    each Cy1 and Cy2 independently represent a carbocyclic aromatic ring of 6 to 10 members or each Cy1 and Cy2 independently represent a heteroaromatic ring of 5 or 6 members containing 1 to 3 heteroatoms selected from N, O and S, where each Cy1 and Cy2 independently is bound to the rest of the molecule through any available N or C atom, and where each Cy1 and Cy2 independently is optionally substituted by one or more halogen groups, -C1-6 alkyl, -OC1-6 alkyl or halo -C1-6 alkyl;
    Cy3 represents a 5- or 6-membered heteroaryl containing 1 to 3 N atoms, where Cy3 is attached to the rest of the molecule through the N atom of the group -NR7R7 and where Cy3 is optionally substituted by one or more R8 groups ; each R8 independently represents hydrogen, C1-6 alkyl or Cy2;
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    each P1 and P2 independently represent -Si (R9) 3, methoxymethyl (MOM), tetrahydropyranyl (THP), benzyl (Bn), -COR10, -COCy1, -SO2R11, -SO2Cy1, benzyloxymethyl ether, methylthiomethyl ether, trimethylsilylmethoxymethyl or para-methoxymethyl PMB);
    each R9 independently represents phenyl or C1-6 alkyl,
    R10 represents C1-6 alkyl, halo C1-6 alkyl, -CH2OH, -CH2OC1-6 alkyl or -CH2OP1; and R11 represents C1-6 alkyl or halo-C1-6 alkyl,
    which comprises the reaction between a compound of formula II and a PtCl2 catalyst
    and P (C6F 5) 3:
    iPr
    image2
    II
    where:
    P3 represents -Si (R9) 3, methoxymethyl (MOM), tetrahydropyranyl (THP), benzyl
    (Bn), -COR10, -COCy1, -SO2R11, -SO2Cy or para-methoxybenzyl (PMB); Y
    Cy1, R2, R3 and R5 R9 and R10 have the meaning described for a compound of formula I.
    [2]
    2. The process according to claim 1, wherein P3 is selected from tert-butyldimethylsilyl (TBS), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS) and triisopropylsilyl (TIPS).
    [3]
    3. The process according to claim 2, wherein P3 represents tert-butyldimethylsilyl (TBS).
    [4]
    4. The method according to any of claims 1 to 3, wherein the molar ratio between PtCl2 and P (C6F5) 3 is between 2: 1 and 1: 2.
    [5]
    5. The method according to claim 4, wherein the molar ratio between PtCl2 and P (C6F5) 3 is 1: 1.
    [6]
    6. The process according to any of claims 1 to 5, wherein the molar ratio between the compound of formula II, PtCl2 and P (C6F5) 3 is between 100: 1: 1 and 10: 1: 1 respectively.
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    [7]
    7. The process according to claim 6, wherein the molar ratio between the compound of formula II, PtCl2 and P (C6F5) 3 is 20: 1: 1 respectively.
    [8]
    8. The process according to any one of claims 1 to 7, further comprising the dihydroxylation step of a compound of formula IV, and optionally protective and / or deprotection reactions, for obtaining a compound of formula V:
    image3
    . , or4
    '3 R5 IV R5 OH v
    where:
    R12 represents hydrogen or P1, and
    P1, R2, R3, R4 and R5 have the meaning described for a compound of formula
    image4
    I.
    [9]
    9. A compound of formula NI:
    image5
    where:
    R1 represents -OH, -OP1, = O, -CN, halogen, -NR7R7, -N3, -C2-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or Cy1; Y
    R2 to R7, Cy1, and ---- have the meaning described for a compound of formula I.
    [10]
    10. The compound according to claim 9, wherein:
    Each ---- represents a simple link; Y
    R1 represents F, Cl, I, isobutyl, n-butyl, n-hexyl, -N3, = O or -OTs.
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    [11]
    11. The compound according to any of claims 9 or 10, wherein each R2 and R3 represent H.
    [12]
    12. The compound according to any of claims 9 to 11, wherein R4 represents -COCH2OH.
    [13]
    13. The compound according to any of claims 9 to 12, wherein R5 represents methyl.
    [14]
    14. The compound according to any of claims 9 to 13, wherein R6 represents cinnamoyl, cinnamonyl, 3-phenylpropyl, 3-phenylpropanoyl, benzyloxycarbonyl, N-benzylaminocarbonyl, N-benzylaminothiocarbonyl, wherein the phenyl moiety of each of the R6 groups is optionally substituted by one or more C1-6 alkyl groups, -OC1-6 alkyl or halogen, and where the alkyl or alkenyl moiety of each of the R6 groups are optionally and independently substituted by one or more halogen groups or -OH.
    [15]
    15. The compound according to any of claims 9 to 14, wherein R10 represents -CH2OH.
    [16]
    16. The compound according to any of claims 9 to 15, wherein Cy1 represents a 5-membered heteroaryl containing 1 to 3 N atoms, where Cy1 is attached to the rest of the molecule through the N atom of the group - NR7R7 and where Cy1 is optionally substituted by one or more R8 groups.
    [17]
    17. The compound according to claim 16, wherein Cy1 represents a triazole ring.
    [18]
    18. The compound according to claim 9 selected from:
    image6
    OH 1b;
    image7
    OH 1c;
    OH id;
    image8
    OH ie;
    OH ig;
    image9
    1 hour;
    ToPl HO (n
    TsO | _ | - 'Pr
    'OPMB 11b;
    l-HH (3 'Pr
    H ¿OH
    12f;
    H i
    M HO / D
    N3 h - 'Pr
    12g;
    OPMB i3h;
    HQ / r
    H i 0Piv 15¡;
    . HQ to.
    H £ OPÍV
    I5g; Y
    n, uh9 f
    H £ OPÍV
    15h
    image10
    image11
    image12
    image13
    image14
    [19]
    19. A pharmaceutical composition comprising at least a therapeutically effective amount of a compound of formula III described in any of claims 9 to 18 and one or more excipients or carriers
    5 pharmaceutically acceptable.
    [20]
    20. Use of a compound of formula III described in any of claims 9 to 18 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament.
    10
    [21]
    21. Use of a compound of formula III described in any of claims 9 to 18 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer and HIV.
    22. The use according to claim 21, for the treatment of renal cancer.
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