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    • 专利摘要:
    Compounds derived from vitamin D. The present invention relates to compounds derived from vitamin D. More specifically, it refers to complex derivatives of vitamin D with multiple substitutions, methods of obtaining and uses thereof. These derivatives present greater rigidity in certain positions. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2714628A1
    申请号:ES201731367
    申请日:2017-11-29
    公开日:2019-05-29
    发明作者:Ponte Rita Sigüeiro；Mosquera Antonio Mourino
    申请人:Universidade de Santiago de Compostela；
    IPC主号:
    专利说明:

    [0001]
    [0002] Compounds derived from vitamin D
    [0003]
    [0004] Sector of the technique
    [0005]
    [0006] The present invention relates to compounds derived from vitamin D. More specifically, it refers to complex derivatives of vitamin D with multiple substitutions, methods of obtaining and uses thereof.
    [0007]
    [0008] Background of the invention
    [0009]
    [0010] 1,25a-dihydroxyvitamin D3 (1,25D) is the most active metabolite of vitamin D. It exerts its biological actions by specifically joining its nuclear receptor, the vitamin D receptor (VDR). The endocrine system of vitamin D plays a fundamental role in a wide range of biological actions. For example, in the regulation of phospho-calcium metabolism, stimulating the intestinal absorption of these essential minerals and their mobilization in the osseous tissue, promotes cell differentiation and inhibits the cellular proliferation of several tumor cells, suggesting its possible use in the cancer treatment. However, as an antitumor agent, it has serious limitations due to its calcemic activity.
    [0011]
    [0012] On the other hand, some derivatives of vitamin D have been synthesized with high restrictions of rotation in the side chain by the introduction of an alkyne group in said side chain (Org.Lett., 2003, vol.5, 22, 4033-4036 ). However, although these structures are capable of stabilizing the complex formed with the VDR receptor, they do not activate the genetic transcription as much as 1,25D.
    [0013]
    [0014] Thus, there is still a need for non-hypercalcemic derivatives of vitamin D that bind to the VDR receptor in order to achieve greater efficacy in obtaining selective analogues.
    [0015]
    [0016] Brief description of the invention
    [0017]
    [0018] The authors of the present invention have designed new compounds derived from vitamin D. Specifically, they have designed compounds derived from vitamin D that have greater substitution in the C-17 position. In addition one of the substituents of the C-17 position is a chain with greater rigidity than that of the vitamin. One of the advantages of these compounds with greater stiffness and steric hindrance in the side chain, either because one of the substituents provides greater rigidity given its conformation, or because in the C-17 position there are two substituents that allows greater stability in the complexation with the VDR receptor .
    [0019]
    [0020] Thus, one aspect of the invention is directed to a compound of formula (I) or one of its stereoisomers, or its pharmaceutically acceptable salts,
    [0021]
    [0022]
    [0023]
    [0024] wherein R1 is (Ci-Ci2) alkyl, (Ci-Ci2) alkenyl, (Ci-Ci2) alkynyl, (Ci-Ci2) heteroalkyl, (C2-Ci2) heteroalkenyl or (Ci-Ci2) heteroalkynyl,
    [0025] each of R and R is independently selected from (Ci-Ci2) alkyl, (Ci-Ci2) alkenyl, (Ci-Ci2) alkynyl,
    [0026]
    [0027] R4 is selected from hydrogen, (Ci-Ci2) alkyl, (Ci-Ci2) hydroxyalkyl, (C2-Ci2) alkenyl, (C2-Ci2) hydroxyalkenyl, (C2-Ci2) alkynyl, (C2-Ci2) hydroxyalkynyl, ( Ci-Ci2) heteroalkyl, (C2-Ci2) heteroalkenyl, (Ci-Ci2) heteroalkynyl, (C6-Ci0) aryl, (C3-Ci5) heteroaryl, (C6-Cio) aryl (Ci-Ci2) alkyl, (Ci-) Ci2) alkylacyl, (C6-Ci0) aryl acyl, (Ci-Ci2) alkoxy, (C6-Ci0) aryloxy (Ci-Ci2) alkylcarboxy, (C6-Ci0) arylcarboxy, (Ci-Ci2) carbocycle, (C 3 - Ci5) heterocycle, -O- (Ci-Ci2) alkyl and -O- (Ci-Ci2) heteroalkyl,
    [0028]
    [0029] each of P and P is independently selected from hydrogen, -OH, (Ci-Ci2) alkoxy, (C6-Ci0) aryloxy, (Ci-Ci2) alkylcarboxy, (C6-Ci0) arylcarboxy and -OSiRaRbRc, where each of Ra, Rb and Rc are selected from among (CiCi 2 ) alkyl, (C6-Cio) aryl, (C6-Cio) aryl, (Ci-Ci 2 ) alkyl, (Ci-Ci 2 ) alkoxy, (C6-Cio) aryloxy and (C 3 -Ci 5) heterocycle , Y
    [0030]
    [0031] X 1 and X 2 * are hydrogen or form together with the carbon atom to which a methylene group is attached (= CH 2).
    [0032]
    [0033] Another aspect of the invention is directed to a process for the preparation of a compound of formula (I), which comprises reacting a compound of formula (II) with a compound of formula (Ilia) in the presence of a base,
    [0034]
    [0035]
    [0036] where R 1, R 2, R 3, 4 R, Pi, P 2, X, X are as described above.
    [0037] Another aspect of the invention is directed to an alternative process for the preparation of a compound of formula (I) comprising:
    [0038] (a) reacting a compound of formula (II) with a compound of formula (IIIb) in the presence of a base, and
    [0039] (b) reaction of the intermediate obtained in step (a) with a compound of formula RM and / or R3M,
    [0040]
    [0041]
    [0042] where R6 is selected from (Ci-Ci 2 ) alkyl and (C6-Cio) aryl,
    [0043] Hal is a halogen of between chlorine, bromine, iodine,
    [0044] M is a metal or a metal halide, and
    [0045] R, R, R, R, P1, P2, X, X are as described above.
    [0046] Another aspect of the invention is directed to a compound of formula (I) as described above, for use as a medicament.
    [0047] In another aspect the invention is directed to a compound of formula (I), for use in the treatment of diseases or conditions related to vitamin D deficiency. In a particular embodiment, diseases or conditions related to vitamin D deficiency they are selected from the group consisting of rickets, osteoporosis, osteodystrophy, osteomalacia and fractures.
    [0048] In another particular embodiment, the invention is directed to a compound of formula (I), as described above, for use in the treatment of psoriasis, diabetes, autoimmune, degenerative, endocrinological, cardiovascular, metabolic, infectious, or tumor diseases. . In another particular embodiment, the invention is directed to a compound of formula (I), as described above, for use in the treatment of neoplastic diseases. In a more particular embodiment, the neoplastic diseases are selected from the group consisting of breast, ovarian, prostate, lung, leukemia, solid tumors and hematological tumors.
    [0049] In another particular embodiment, the invention is directed to the combination of at least one compound of formula (I), as described above, and at least one antineoplastic compound.
    [0050]
    [0051] In a further aspect the invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), as described above, together with one or more pharmaceutically acceptable excipients or carriers.
    [0052]
    [0053] Detailed description of the invention
    [0054]
    [0055] Definitions
    [0056]
    [0057] "(Ci-Ci 2 ) Alkyl" refers to a straight or branched hydrocarbon chain, formed by
    [0058] carbon and hydrogen atoms, without unsaturation, from 1 to 12, preferably six, more preferably from one to four carbon atoms, and which is attached to the remainder of the molecule by a single bond, which optionally may be labeled isotopically so that one or more hydrogen s are replaced by deuterium (H) or tritium (H) and / or one or more carbons are replaced by carbon-11 (11C), carbon-13 (13C) or carbon-14 (14C), optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a (C1-C12) alkylcarboxy group, a (C6-C10) arylcarboxy group, a (C1-C12) alkoxy group, a cyano group, a nitro group , a (C1-C12) thioalkoxy group, a (C1-C12) heteroalkyl group, a (C3-C15) heterocyclic group or CF3. Examples of alkyl groups include without limitation methyl, trifluoromethyl, trideuteromethyl, ethyl, "-propyl, z-propyl," -butyl, t-butyl, "-pentyl, cyclopropyl, etc.
    [0059] "(C1-C12) Carbocycle" refers to a closed hydrocarbon chain formed by carbon and hydrogen atoms, without unsaturation, from 1 to 12, preferably eight, more preferably from five to eight carbon atoms, and which is attached to the remainder of the molecule by a single bond, which optionally can be labeled isotopically so that one or more hydrogen s are replaced by deuterium (2H) or tritium (3H) and / or one or more carbons are replaced by carbon-11 (11C) , carbon-13 (13C) or carbon-14 (14C).
    [0060]
    [0061] "(C2-C12) Alkenyl" refers to a straight or branched hydrocarbon chain, formed by carbon and hydrogen atoms, containing at least one unsaturated, conjugated or no, from 2 to 12, preferably from two to eight, more preferably from two to four carbon atoms, and which is attached to the remainder of the molecule by a single bond and which optionally may be isotopically labeled so that one or more hydrogen s are replaced by 2H or 3H and / or one or more carbons are replaced by 11C, 13C or 14C. The alkenyl radicals may be optionally substituted by one or more substituents such as a halogen atom, a carboxy group, a (C1-C12) alkoxy group, a cyano group, a nitro group, a (C1-C12) thioalkoxy group, a group (C1-C12) heteroalkyl, a (C3-C15) heterocyclic group or CF3. Examples of alkenyl groups include without limitation vinyl, allyl, butenyl (e.g., 1-butenyl, 2-butenyl, 3-butenyl), or pentenyl (e.g., 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl ).
    [0062]
    [0063] "(C2-C12) Alkynyl" refers to a straight or branched hydrocarbon chain, formed by carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, conjugated or not, from two to twelve, preferably two to eight, more preferably from two to four carbon atoms, and which is attached to the remainder of the molecule by a single bond, such as -CCH, -CH2CCH, -CCCH3, -CH2CCCH3, and which may optionally be isotopically labeled so that one or more hydrogen is replaced by 2H or 3H and / or one or more carbons are replaced by 11C, 13C or 14C. The alkynyl radicals may be optionally substituted by one or more substituents such as a halogen atom, a carboxy group, a (C1-C12) alkoxy group, a cyano group, a nitro group, a (C1-C12) thioalkoxy group, a group (C3-C 15) heterociciclo or CF3.
    [0064] "(C1-C12) Hydroxyalkyl" refers to a straight or branched, cyclic or acyclic hydrocarbon chain formed by carbon and hydrogen atoms, without unsaturation, from 1 to 12, preferably from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, which is substituted by a hydroxyl group, optionally protected by a protecting group as described in Wuts, PGM, Greene, TW; "Protective Groups in Organic Synthesis", 4rd Ed., John Wiley & Sons, Inc. 2007, New Jersey, pages 24-222. Preferably, the chain is branched and the hydroxyl group is protected with alkylethers and esters, such as for example methoxymethylether, methoxymethylether, benzyloxymethylether, methylthiomethylether, trimethylsilylethoxymethylether, acetate, pivalate, benzoate, p-nitrobenzoate. Examples of substituted hydroxyalkyl include, without limitation, 5-methyl-5-hydroxyhexyl and 6-methyl-6-hydroxyheptyl, 5-ethyl-5-hydroxyheptyl and 6-ethyl-6-hydroxyoctyl.
    [0065] Examples of unsubstituted hydroxyalkyls include without limitation 5-hydroxyhexyl and 6-hydroxyheptyl, 5-hydroxyheptyl and 6-hydroxyoctyl.
    [0066]
    [0067] "(C1-C12) Hydroxyalkenyl" refers to a straight or branched hydrocarbon chain, formed by carbon and hydrogen atoms, containing at least one unsaturation, conjugated or not, from 2 to 12, preferably from two to eight, more preferably of two to four carbon atoms, and which is bound to the rest of the molecule by a single bond and which optionally can be labeled isotopically so that one or more
    [0068] Hydrogen s are replaced by H or H and / or one or more carbons are replaced by C, C or 14C. The alkenyl radicals may be optionally substituted by one or more substituents such as a halogen atom, a carboxy group, a (C 1 -C 12) alkoxy group, a cyano group, a nitro group, a (C 1 -C 12) thioalkoxy group, a (C1-C12) heteroalkyl group, a (C3-C15) heterocyclic group.
    [0069]
    [0070] "(C1-C12) Hydroxyalkynyl" refers to a straight or branched hydrocarbon chain, formed by carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, conjugated or not, from two to twelve, preferably two to eight, more preferably from two to four carbon atoms, and which is attached to the remainder of the molecule by a single bond, such as -CCH, -CH2CCH, -CCCH3, -CH2CCCH3, and which optionally may be labeled isotopically so that one or more hydrogen s are replaced by 2H or 3H and / or one or more carbons are replaced by 11C, 13C or 14C. The alkynyl radicals may be optionally substituted by one or more substituents such as a halogen atom, a carboxy group, a (C1-C12) alkoxy group, a cyano group, a nitro group, a (C1-C12) thioalkoxy group, a group (C3-C15) heterocycle or CF3.
    [0071] "(C6-C10) Aryl" refers to an aromatic hydrocarbon of 6 to 10 carbon atoms, such as phenyl or naphthyl, and which may optionally be isotopically labeled so that one or more hydrogen is replaced by 2H or 3H and / or one or more carbons are replaced by 11C, 13C or 14C. The aryl radicals may be optionally substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a carboxy group, a (C1-C12) alkoxy group, a cyano group, a nitro group, a group (C1-C12) thioalkoxy, a (C1-C12) alkyl or CF3 group.
    [0072]
    [0073] M (C6-C10) Aryl (C1-C12) alkyl "refers to one or more aryl groups attached to the remainder of the molecule by an alkyl radical, for example, benzyl, 3- (phenyl) -propyl, etc.
    [0074] "(C 3 -Ci 5 ) Heterocycle" refers to a stable ring of 3 to 15 members formed by
    [0075] carbon atoms and between 1 to 5 heteroatoms chosen from nitrogen, oxygen and sulfur, preferably a 4- to 8-membered ring formed by one or more heteroatoms, and more preferably a 5-6 membered ring with one or more heteroatoms. For the purposes of this invention, the heterocyclic groups may be monocyclic, bicyclic or tricyclic systems, which may include fused rings; and the nitrogen or sulfur atom in the heterocyclic ring may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocycle radical may be partially or fully saturated. The radicals (C3-C15) heterocycles can be aromatic (for example, they can have one or more aromatic rings) in which case they are considered as "(C3-C15) heteroaryls" for the purposes of the present invention. The heterocyclic ring may be substituted by one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a carboxy group, a (C1-C12) alkoxy group, a (C1-C12) alkyl group, a group (C1-C12) thioalkoxy, a cyano group, a nitro group or CF3. Examples of such heterocycles include without limitation, furan, thiophene, pyrrole, imidazole, triazole, isothiazole, benzothiophene, benzofuran, indole, benzoimidazole, tetrahydrofuran.
    [0076]
    [0077] "(C1-C12) Alkoxy" refers to a radical of formula -O- (C1-C12) alkyl, for example, methoxy, ethoxy, propoxy, etc.
    [0078]
    [0079] "(C1-C12) Thioalkoxy" refers to a radical of formula -S- (C1-C12) alkyl, for example, thiomethoxy, thioethoxy, thiopropoxy, etc.
    [0080]
    [0081] "(C6-C10) Aryloxy" refers to a radical of formula -O- (C6-C1o) aryl, for example phenoxy, benzyloxy, etc.
    [0082]
    [0083] "(C1-C12) Alkylcarboxy" refers to an alkyl group that is attached to the remainder of the molecule by the oxygen of a carboxy group (-CO2-).
    [0084]
    [0085] "(C6-C10) Arilcarboxi" refers to an aryl group that is joined to the rest of the molecule by the oxygen of a carboxy group (-CO2-).
    [0086]
    [0087] "(C1-C12) Alkylaryl" refers to an alkyl group that is attached to the remainder of the molecule by a carbonyl group (-CO-).
    [0088] "(C6-C10) Arylacil" refers to an aryl group that is attached to the rest of the molecule by a carbonyl group (-CO-).
    [0089]
    [0090] "(C1-C12) Heteroalkyl" refers to an alkyl group in which one or more carbons are substituted by heteroatoms, preferably from 1 to 5, wherein the heteroatom may be selected from oxygen, sulfur, selenium, tellurium, nitrogen, phosphorus, arsenic.
    [0091]
    [0092] "(C1-C12) Heteroalkenyl" refers to an alkenyl group in which one or more carbons are substituted by heteroatoms, preferably from 1 to 5, wherein the heteroatom may be selected from oxygen, sulfur, selenium, tellurium, nitrogen, phosphorus, arsenic.
    [0093] "(C1-C12) Heteroalkynyl" refers to an alkynyl group in which one or more carbons are substituted by heteroatoms, preferably from 1 to 5, wherein the heteroatom may be selected from oxygen, sulfur, selenium, tellurium, nitrogen, phosphorus, arsenic.
    [0094] The compounds of the present invention can include diastereoisomers and / or enantiomers, depending on the presence of chiral centers, or isomers depending on the presence of multiple bonds (for example Z, E). Said isomers, diastereomers, enantiomers and their mixtures are within the scope of the present invention.
    [0095]
    [0096] The phrase "pharmaceutically acceptable salt" as used in the present description refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention. Examples of pharmaceutically acceptable salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, iohydric acid, sulfuric acid, nitric acid and phosphoric acid; and organic acids such as methanesulfonic acid, benzenesulphonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, Ethanesulfonic acid, aspartic acid and glutamic acid.
    [0097]
    [0098] Exemplary salts include, but are not limited to, salts of sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate. isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, ptoluensulfonate and pamoate (i.e., 1,1'-methylene-bis- (2-hydroxy-3-naphthoate)). A salt Pharmaceutically acceptable may comprise the inclusion of another molecule such as an acetate ion, a succinate ion or another counterion. The counterion may be an organic or inorganic part that stabilizes the charge of the main compound. On the other hand, a pharmaceutically acceptable salt may have more than one atom charged in its structure. Cases in which multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counterions. Therefore, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterions.
    [0099]
    [0100] If the compound of the invention is a base, it is possible to prepare the desired pharmaceutically acceptable salt by any method available in the art, for example, by treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, acid. sulfuric acid, nitric acid, methanesulphonic acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidilic acid, such as glucuronic acid or galacturonic acid, an α-hydroxy acid, such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
    [0101]
    [0102] If the compound of the invention is an acid, it is possible to prepare the desired pharmaceutically acceptable salt by any suitable method, for example, by treatment of the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), a alkali metal dioxide or an alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and the derived inorganic salts of sodium, calcium, potassium, magnesium, iron, copper, zinc, aluminum and lithium.
    [0103]
    [0104] Typically the salt is a mesylate, a hydrochloride, a phosphate, a benzenesulfonate, oxaloacetate or a sulfate. More typically, the salt is a mesylate or a hydrochloride.
    [0105] The salts, for example, salts with any of the inorganic or organic acids mentioned above, can be monosal or bis-salts. Thus, for example, the mesylate salt may be the mono-mesylate or the bis-mesylate.
    [0106]
    [0107] Compounds of formula (I)
    [0108]
    [0109] The compounds of formula (I) of the present invention bind specifically to the vitamin VDR receptor. They are also highly functionalized and said functionalization gives them rigidity and greater stability in their union with the receiver.
    [0110]
    [0111] In a particular embodiment, P 1 and P 2 in a compound of formula (I) are -OH or -OSiRaRbRc, wherein each of Ra, Rb and Rc are as described above.
    [0112] In another particular embodiment, X 1 and X 2 in a compound of formula (I) together form the carbon atom to which a methylene group (= CH 2) are attached. In another particular embodiment, R and R in a compound of formula (I) are a (Ci-Ci2) alkyl.
    [0113]
    [0114] Of special interest for the invention are the compounds of formula (I) wherein R 2 and R 3 are trifluoromethyl- (C 1 -C 6) alkyl, and more particularly, trifluoromethyl.
    [0115]
    [0116] The isotopic derivatives of the compounds of the invention are useful for use as internal standards in different techniques of mass spectrometry or high performance liquid chromatography coupled to nuclear magnetic resonance. The compounds of the invention that incorporate H or H are also useful as radiopharmaceuticals, for example but without limitation, to carry out "in vivo" diagnosis and investigation techniques by imaging, allowing the external detection of the biodistribution of the radiopharmaceutical within the organism. .
    [0117]
    [0118] In the present invention, a compound that "incorporates isotopic label" refers to a compound of the invention wherein between 1 and 6 hydrogen atoms are substituted by isotopes of hydrogen, deuterium or tritium, and / or from 1 to 3 atoms. of carbon are substituted by isotopes, such as 11C, 13C or 14C.
    [0119] Thus, in a particular embodiment the compounds of formula (I), have been defined as above, incorporate isotopic label. In a more preferred embodiment, the isotopic label is selected from 2 H, 3 H and 13 C.
    [0120]
    [0121] In a particular embodiment, a compound of formula (I) incorporates isotopic labeling in R and R. In a particular embodiment, the isotopic labeling in R and R are equal and selects from the group consisting of 2 Hn- (Ci-Ci2) alkyl, 3 Hn- (Ci-Ci2) alkyl, where n has a value between 1 and 6. In a particular embodiment, the isotopic label in R and R is selected from the group consisting of (C1-C4) alkyl. In a more particular realization, R and R are trideuteromethyl.
    [0122]
    [0123] In another aspect the invention is directed to the use of compounds of formula (I) as defined above, characterized in that they incorporate isotopic labeling, as internal standards in spectroscopic and spectrometric techniques. The invention also relates to the compounds of formula (I) have been previously defined, characterized in that they incorporate isotopic labeling, for use as internal standards in spectroscopic and spectrometric techniques.
    [0124]
    [0125] In another aspect, the invention relates to the compounds of formula (I), as defined above, characterized in that they incorporate isotopic label selected from H and H for use as radiopharmaceuticals. A radiopharmaceutical can serve, for example, but without limitation, to carry out "in vivo" diagnosis and investigation techniques by image, allowing external detection of the biodistribution of the radiopharmaceutical within the organism. Alternatively, the invention relates to the use of the compounds of formula (I), as defined above, characterized in that they incorporate isotopic label selected from H and H as radiopharmaceuticals.
    [0126]
    [0127] Preparation of the compounds of formula (I)
    [0128]
    [0129] The compounds of formula (I) of the present invention can be prepared by a process comprising reacting a compound of formula (II) with a compound of formula (III) in the presence of a base,
    [0130] where R 1, R 2, R 3, 4 R, Pi, P 2, X, X are as described above.
    [0131] In a particular embodiment, the base may be an organic base such as, for example, (C1-C12) alkyl lithium, potassium alkoxide, alkali hydrides or alkaline earth hydrides. In a preferred embodiment the base is hexyl lithium or butyl lithium. In other embodiments, the base may be an inorganic base, such as, for example, potassium oxide or sodium hydride.
    [0132] In a particular embodiment the compound of formula (III) is isotopically labeled. In a more particular embodiment, between 1 to 3 carbons of a compound of formula (III) are substituted by 11C, 13C and 14C isotopes.
    [0133] Another aspect of the invention is directed to an alternative process for the preparation of a compound of formula (I) comprising:
    [0134] (a) reacting a compound of formula (II) with a compound of formula (IIIb) in the presence of a base, and
    [0135] (b) reaction of the intermediate obtained in step (a) with a compound of formula RM and / or R3M,
    [0136]
    [0137]
    [0138] where R6 is selected from (Ci-Ci 2 ) alkyl and (C6-Cio) aryl,
    [0139] Hal is a halogen of between chlorine, bromine, iodine,
    [0140] M is a metal or a metal halide, and
    [0141] R, R, R, R, P1, P2, X, X are as described above. In a particular embodiment, the compounds of formula R 2 M or R 3 M are selected from among alkyl lithium, magnesium halides and dialkylcinnates.
    [0142]
    [0143] The compounds of formula (II) wherein X and X form together with the carbon atom to which a methylene group is attached (= CH2), can be prepared by a process comprising a coupling between a compound of formula (IVa) with a compound of formula (V) in the presence of a metal catalyst,
    [0144]
    [0145]
    [0146]
    [0147] wherein R5 is selected from hydrogen and -SiRaRbRc, wherein each of Ra, Rb and Rc are selected from (C1-C12) alkyl, (C6-C10) aryl, (C6-C10) aryl, (C1-C12) alkyl, (C1-C12) alkoxy, (C6-C10) aryloxy and (C3-C15) heterocycle,
    [0148] Za is selected from di (Ci-Ci 2 ) alkoxyboron, di (Ci-Ci 2 ) alkylboron, indium halide, di (C 1 -C 12) alkylindium, di (C 1 -C 12) arylindium, (C 1 -C 12) alkyl ( C6-C10) arylindium, lithium, zinc halide and (C1-C12) alkylcycline.
    [0149] Y is a halogen or an electron attractive group selected load from the group comprising (C1-C12) alkylsulfonate, (C6-C10) aryl sulfonate, triflate and phosphate, R1, R4, P 1 and P 2 are as described above.
    [0150]
    [0151] The compounds of formula (V) can be prepared as described in ES2331289B2, J.Med.Chem., 2000, 43, 4247-4265 and Chem. Eur. J. 2010, 16, 1432-1435 which are incorporated by reference.
    [0152]
    [0153] The compounds of formula (II) wherein X and X are hydrogen, can be prepared by a process comprising a coupling between a compound of formula (IVb) and a compound of formula (VI) in the presence of a metal catalyst,
    [0154]
    [0155]
    [0156]
    [0157] wherein R5 is selected from hydrogen and -SiRaRbRc, wherein each of Ra, Rb and Rc are selected from (C1-C12) alkyl, (C6-C10) aryl, (C6-C10) aryl, (C1-C12) alkyl, (C1-C12) alkoxy, (C6-C10) aryloxy and (C3-C15) heterocycle,
    [0158] Zb is selected from chlorine, bromine iodine,
    [0159] W is selected from (C1-C12) alkylsulfonate, (C6-C10) arylsulfonate, halogen, methylene alkylsulfone and methylene arylsulfone,
    [0160] R1, R4, P1 and P2 are as described above.
    [0161]
    [0162] In a particular embodiment, the metal catalyst of the coupling reaction is selected from the typical group of catalysts for a coupling reaction, for example and without limiting sense, (Ph3P) 2PdCl2, Pd (OAc) 2, PdCl2, Pd ( PPh3) 4, Pd (dba) 2, Ni (PPh3) 4, Pd2 (dba) 3, Cu compounds and Hf compounds.
    [0163] Compounds (VI) can be prepared as described in " Novel synthetic approach to 19-nor-1a, 25-dihydroxyvitamin D3 and its derivatives by Suzuki-Miyaura coupling in solution and on solid support", Organic Letters (2001), 3 ( 24), 3975-3977 and " Preparation of 2-hydroxy A-ring precursors for synthesis of vitamin D3 analogues from lyxose" , Tetrahedron Letters, (2015), 56 (18), 2315-2318, which are incorporated by reference.
    [0164]
    [0165] A compound of formula (IVb) can be transformed into a compound of formula (IVa) by transforming functional group Z. Thus, in a particular embodiment the invention relates to a process for obtaining a compound of formula (IVa) a starting from a compound of formula (IVb) by a) a metalation reaction, and b) exchange of the metal by a group selected from dialkoxyboron, dialkylboron, indium halide, diarylindium, alkylarylindium and zinc halide.
    [0166]
    [0167] A person skilled in the art knows the conditions for carrying out said transformation, as for example, the substitution of the bromide can be carried out by metalation with an organolithic, subsequent trapping with boron isopropoxide and exchange of the boron substituents (Org. Lett. 2003 (5) 523-525), it can also be carried out by a Suzuki reaction by coupling, for example with bis (pinacol) diborane in the presence of a palladium catalyst, such as, for example, Pd (OAc) 2, Pd (PPh 3 ) 4, Pd (dppf) Cl 2, in the presence of a base such as, for example, sodium carbonate, barium hydroxide, potassium phosphate, cesium carbonate, potassium carbonate, thallium hydroxide, cesium fluoride, potassium fluoride, sodium hydroxide. (J. Am. Chem. Soc. 2002 (27) 8001-8006). A person skilled in the art also knows other possibilities such as, for example, the bromide substitution can be carried out by metalation with an organolithic, subsequent reaction with indium trichloride (Org Lett, 2004 (6) 4555-4558). In another example, the substitution of the bromide can be carried out by metalation with an organolithic, subsequent reaction with zinc dichloride (Synlett 2003 861-863). In another example, the iodide substitution can be carried out by direct zinc metalation, subsequent reaction with the copper (I) cyanide complex (lithium chloride (Angew, Chem. Int. Ed. 2006 (45) 6040-6044). ).
    [0168]
    [0169] The invention is also directed to the process for preparing the compounds of formula (IVb) comprising:
    [0170]
    [0171] a) epoxidation of a compound of formula (VII),
    [0172]
    [0173] b) opening the epoxide obtained in step a) with a reducing reagent,
    [0174] c) oxidation of the resulting hydroxyl in step b),
    [0175] d) deprotonation until obtaining an alkynyl group,
    [0176] e) iodization,
    [0177] f) coupling with HC = C SiRaRbRc,
    [0178] g) oxidation,
    [0179] h) halogenation,
    [0180]
    [0181] and optionally between some of the described steps is carried out protections and deprotections of hydroxyl groups,
    [0182]
    [0183] where Ra, Rb and Rc are as described above.
    [0184]
    [0185] Protections and deprotections are common to those skilled in the art in the field of organic compound synthesis and the reaction conditions are described in Wuts, P. G. M., Greene, T. W .; "Protective Groups in Organic Synthesis", 4th Ed., John Wiley & Sons, Inc. 2007, New Jersey.
    [0186]
    [0187] The invention is also directed to the method of preparing the compounds of formula (VII) comprising the reaction of a compound of formula (VIII) with a compound R1-Li,
    [0188]
    [0189]
    [0190]
    [0191] where P4 is a good outgoing group, and
    [0192]
    [0193] R1, Ra, Rb and Rc are as described above.
    [0194]
    [0195] In a particular reaction, P4 is phenylcarbamate, o-methoxyphenylcarbamate, p-methoxyphenylcarbamate, o-diphenylphosphanylbenzoate, benzoate, pivalate.
    [0196] The invention is also directed to the compounds of formula (II)
    [0197]
    [0198]
    [0199]
    [0200] where R1, R4, P1, P2, X1 and X2 are as described above.
    [0201]
    [0202] The invention is also directed to the compounds of formula (IV)
    [0203]
    [0204]
    [0205]
    [0206] wherein R5 is selected from hydrogen and -SiRaRbRc, wherein each of Ra, Rb and Rc are selected from (C1-C12) alkyl, (C6-C10) aryl, (C1-C12) alkyl,
    [0207] (C1-C12) alkoxy, (C6-C10) aryloxy and (C3-C15) heterocycle,
    [0208] P3 is selected from di (C1-C12) alkoxyboron, di (C1-C12) alkylboron, indium halide, di (C1-C12) alkylindium, di (C1-C12) arylindium, (C1-C12) alkyl (C6-) C10) arylindium, lithium, zinc halide, (C1-C12) alkylcinc, chlorine, bromine and iodine, and
    [0209] R1 as described above.
    [0210] The invention is also directed to the compounds of formula (V)
    [0211]
    [0212]
    [0213] where R7 is-SiRaRbRc, wherein each of Ra, Rb and Rc are selected from (Ci-Ci 2 ) alkyl, (C 6 -C 10 ) aryl, (C 6 -C 10 ) aryl, (C 1 -C) 12 ) alkyl, (C 1 -C 12 ) alkoxy, (C 6 -C 10) aryloxy and (C 3 -C 15 ) heterocycle, and
    [0214]
    [0215] R1 as described above.
    [0216]
    [0217] The following examples serve to illustrate the present invention, although they should not be considered a limitation thereof.
    [0218]
    [0219] General procedures
    [0220]
    [0221] To determine the purity of the synthesized vitamin D analogs, an HPLC analysis (> 95%) was used. All the synthesized analogues present a single peak in HPLC (Phenomenex Luna 5u Silica (2) 100A, 250x21.2 mm, normal phase, isocratic).
    [0222]
    [0223] Preparation of # erc-butyl {[(1 ^, 3a ^, 4A, 7aA) -1,7a-dimethyl-1-vinyloctahydro-1H-inden-4-yl] oxy} dimethylsilane (5)
    [0224]
    [0225]
    [0226]
    [0227]
    [0228] A solution of nBuLi in hexanes (2.6 mL, 1.3 M) was added dropwise over a solution of alcohol 3 (1 g, 3.22 mmol) in Et2O (30 mL) cooled to -30 ° C. After 10 min, phenyl isocyanate was dropped (PhNCO, 0.40 mL, 3.54 mmol). The reaction mixture was removed from the bath and stirred at room temperature for 2.5 h. Next, it was added in a single CuCN portion (0.29 g, 3.22 mmol). The mixture was stirred at room temperature for 1 h and then cooled to 0 ° C. After 5 min, a solution of MeLi in Et2O (2.4 mL, 1.5 M) was added slowly and dropwise. After 15 min, the yellow suspension was removed from the bath and stirred at room temperature protected from light for 48 h. The black reaction was stopped by the addition of a saturated aqueous solution of NH 4 Cl (20 mL). The aqueous phase was extracted with MTBE (50 mL) and the organic phase combined dry, filter and concentrate. The residue was purified by flash chromatography on SiO2 column, 0-5% AcOEt / hexanes) to give carbamate 4 (0.474 g, 34%, yellow oil) and alkene 5 (0.506 g, 51%, colorless oil). 5: * H NMR (250 MHz, CDCl 3): 5 5.92 (dd, J = 17.2, J2 = 10.3, 1H, = CH), 4.94 (d, J = 10.3, 1H, = CH 2 cis), 4.92 (d , J = 17.2, 1H, = CH 2 trans), 4.10 (sa, 1H, H-8), 2.01 (t, J = 10.5, 1H, H-9), 1.85-1.56 (m, 4H), 1.51- 1.23 (m, 6H), 0.94 (s, 6H, Me-28 and Me-18), 0.90 (s, 9H, Me 3 CSi), 0.03 (s, 3H, MeSi), 0.02 (s, 3H, MeSi) .
    [0229]
    [0230] Preparation of # erc-butyl - {[(1 ^, 3â, 4 ^, 7a »V) -1,7a-dimethyl-1- (oxiran-2-yl) octahydro-1H-inden-4-yl] oxy} dimethylsilane ( 6)
    [0231]
    [0232]
    [0233]
    [0234]
    [0235] NaHCO3 (0.480 g, 5.71 mmol) was added over a solution of alkene 5 (1.1 g, 3.57 mmol) in CH2Cl2 (35 mL). After 5 min, m-chloroperbenzoic acid (mCPBA, 0.740 g, 4.28 mmol) was added in a single portion. The resulting white suspension was stirred at room temperature and in the absence of light for 12 h. The reaction was stopped by the addition of H2O (20 mL). The aqueous phase was extracted with CH2Cl2 (60 mL) and the combined organic phase was dried, filtered and concentrated to dryness. The residue flash column chromatography (SiO2, 5% EtOAc / hexanes) to mix epoxide s 6 (1.10 g, 95%, colorless oil) was purified. 1 H NMR (250 MHz, CDCl 3): 54.06 (br s, 2H, 2xH-8), 2.89 (t, J = 3.4, 1H, H-22), 2.81 (t, J = 3.5, 1H, H-22) , 2.74 (t, J = 3.7, 1H, H-22), 2.66 (t, J = 4.2, 1H, H-22), 2.59 (t, J = 4.6, 1H, H-20), 2.25 (dd, J = 4.8, J 2 = 3.0, 1H, H-20), 1.89-1.20 (m, 2x11H), 1.10 (s, 3H, Me-28), 1.09 (s, 3H, Me-28), 0.88 (s) , 9H, Me3CSi), 0.87 (s, 9H, Me3CSi), 0.87 (s, 3H, Me-18), 0.85 (s, 3H, Me-18), 0.00 (s, 3H, MeSi), 0.02 (s, 3H, MeSi), -0.01 (s, 3H, MeSi), -0.02 (s, 3H, MeSi).
    [0236]
    [0237] Preparation of 1 - {(1 ^, 3â, 4 ^, 7a »V) -4 - (# erc-butyldimethylsilyloxy) -1,7a-dimethyloctahydro-1H-inden-1-yl} ethan-1-ol (7)
    [0238]
    [0239]
    [0240] A solution of LiAlH4 (3.3 mL, 2M) in THF was carefully dripped over a solution of epoxies 6 (0.850 g, 2.62 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 2 h. Then, it was cooled to 0 ° C and an aqueous solution of HCl (15 mL, 10%) was added. The aqueous phase was extracted with MTBE (30 mL) and the combined organic phase was dried, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, 5% AcOEt / hexanes) to give the mixture of alcohols 7 (0.843 g, 98%, colorless oil). LRMS ([ESI-TOF] +, m / z,%): 349.2 ([M + Na] +, 17), 347.2 ([M + Na-2H] +, 100), 309.2 ([M-OH] + , 4), 281.0 ([M-Month] +, 11), 279 ([M-Me 2 -OH] +, 13). HRMS ([ESI-TOF] +, m / z): calculated for C 19 H 38 O 2 SiNa (M + Na), 349.2539; found 349.2546.
    [0241]
    [0242] Preparation of 1 - {(1 A, 3aK, 4A, 7aA) -4- (tert-Butyldimethylsilyloxy) -1,7a-dimethyloctahydro-1 H -inden-1-yl} ethan-1-one (8)
    [0243]
    [0244]
    [0245]
    [0246]
    [0247] Dess-Martin periodinane (DMP, 1.6 g, 3.70 mmol) was added over a solution of the alcohols 7 (0.460 g, 3.37 mmol) in CH2Cl2 (30 mL). The reaction mixture was stirred at room temperature for 1.5 h. The reaction was stopped by the addition of a saturated aqueous solution of NaCl (15 mL). The aqueous phase was extracted with CH2Cl2 (45 mL) and the combined organic phase was dried, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, 3% AcOEt / hexanes) to give ketone 8 (1.1 g, 99%). 1 H NMR (250 MHz, CDCh): 54.03 (br s, 1H, H-8), 2.62 (dd, Ji = 13.5, J = 10.5, 1H, H-9), 2.05 (s, 3H, Me-22) , 1.83-1.29 (m, 9H), 1.21-1.11 (m, 1H), 1.06 (s, 3H, Me-28), 0.87 (s, 3H, Me-18), 0.82 (s, 9H, MesCSi), -0.03 (s, 3H, MeSi), -0.05 (s, 3H, MeSi).
    [0248] Preparation of trifluoromethanesulfonate of 1 - {(1S, 3aR, 4S, 7aS) -4- (tertbutyldimethylsilyloxy) -1,7a-dimethyloctahydro-1H-inden-1-yl} -vinyl (9).
    [0249]
    [0250]
    [0251]
    [0252]
    [0253] A solution of sodium bis (trimethylsilyl) amide in hexanes (NaHMDS, 1.5 mL,, 2M) was dropped over a solution of ketone 8 (0.650 g, 2.0 mmol) in THF (20 mL) cooled to -78 ° C. After 1 h, a solution of A- (2-pyridyl) -triflimide (2.15 g, 6.0 mmol) in THF (10 mL) was added. The temperature of the reaction mixture was allowed to slowly rise to room temperature overnight. The reaction was stopped by the addition of a saturated aqueous solution of NaCl (30 mL). The aqueous phase was extracted with CH2Cl2 (60 mL) and the combined organic phase was dried, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, hexanes) to give triflate 9 (0.728 g, 83%).
    [0254] 1 H NMR (400 MHz, CDCh): 55.12 (d, J = 4.5, 1H, = CH 2 ), 4.95 (d, J = 4.5, 1H, = CH 2 ), 4.07 (sa, 1H, H-8), 2.08 (tt, Ji = 11.5, J 2 = 7.9, 1H, H-9), 1.89-1.59 (m, 4H), 1.55-1.28 (m, 5H), 1.17 (s, 3H, Me-28), 1.03 (s, 3H, Me-18), 0.89 (s, 9H, Me 3 CSi), 0.02 (s, 3H, MeSi), 0.01 (s, 3H, MeSi).
    [0255]
    [0256] Preparation of tert-butyldimethylsilyloxy of (1R, 3aR, 4S, 7aS) -1-ethynyl-1,7-dimethyloctahydro-1H-inden-4-yl (10).
    [0257]
    [0258]
    [0259]
    [0260] A solution of sodium hexamethyldisilazanide (NaHMDS, 1.5 mL, 3.1 mmol, 2M) in hexanes was dropped over a solution cooled to -78 ° C of triflate 9 (0.710 g, 1.55 mmol) in THF (15 mL). After 15 min, the bath was removed and the mixture was stirred at room temperature for 1 h. The reaction was stopped by the addition of a saturated aqueous solution NaCl (20 mL). The aqueous phase was extracted with MTBE (40 mL) and the combined organic phase was dried, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, hexanes) to give alkyne 10 (0.460 g, 96%). * H NMR (250 MHz, CDCf): 5 4.08 (s, 1H, H-8), 2.11 (m, 1H, H-9), 2.12 (s, 1H, C-22), 1.89-1.03 (m, 16H), 1.20 (s, 3H, Me-28), 1.15 (s, 3H, Me-18), 0.89 (s, 9H, Me 3 CSi), 0.02 (s, 3H, MeSi), 0.00 (s, 3H , Me if).
    [0261]
    [0262] Preparation of tert-butyldimethylsilyloxy of (1 ^, 3a ^, 4 ^, 7a ^) - 1- (iodoetinyl) -1,7adimetiloctahydro-1H-inden-4-yl (11)
    [0263]
    [0264]
    [0265]
    [0266]
    [0267] A solution of -BuLi in hexanes (8.3 mL, 12.4 mmol, 1.5M) was dropped over a solution cooled to -78 ° C of the 10- alkyne (0.9 g, 3.1 mmol) in THF (30 mL). After 1 h, iodine (3.9 g, 15.5 mmol) was added in one portion. The reaction mixture was allowed to stir at ambient temperature for 12 h. The reaction was stopped by the addition of a saturated aqueous solution of NaCl (20 mL). The aqueous phase was extracted with MTBE (40 mL) and the combined organic phase was dried, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, hexanes) to give iodide 11 (1.20 g, 95%). * H NMR (250 MHz, CDCf): 5 4.07 (s, 1H, H-8), 2.12 (t, J = 12.2, 1H, H-9), 1.84-1.07 (m, 10H), 1.18 (s, 3H, Me-28), 1.15 (s, 3H, Me-18), 0.89 (s, 9H, MesCSi), 0.02 (s, 3H, MeSi), 0.00 (s, 3H, MeSi).
    [0268]
    [0269] Preparation of tert -butyl {[(1 * V, 3a, ^ 4, ^ 7 a * S) -1,7 a-dimethyl-1 - ((trimethylsilyl) buta-1,3-diin-1-yl) octahydro -1H-inden-4-yl] oxy} dimethylsilane (12).
    [0270]
    [0271]
    [0272] CuI (88 mg, 0.46 mmol) was added over a solution of compound 11 (1.0 g, 2.32 mmol) and trimethylsilylacetylene (1 mL, 6.96 mmol) in piperidine (10 mL) cooled to 0 ° C. After 5 min, it is removed from the bath and the mixture is stirred at room temperature for 7 h. The reaction was stopped by the addition of a saturated aqueous solution of NH 4 Cl (8 mL). The aqueous phase was extracted with MTBE (40 mL) and the combined organic phase was dried, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, hexanes) and then by preparative HPLC (Luna 5 pm column, SiO2, 250x210 mm, hexanes) to give the diino 12 (0.576 g, 62%). 1 H NMR (250 MHz, CDCl 3): 54.06 (br s, 1H, H-8), 2.13 (t, J = 12.2, 1H, H-9), 1.85-1.07 (m, 10H), 1.19 (s, 3H , Me-28), 1.14 (s, 3H, Me-18), 0.88 (s, 9H, Me 3 CSi), 0.17 (s, 9H, Me 3 Si), 0.02 (s, 3H, MeSi), 0.00 ( s, 3H, MeSi).
    [0273] Preparation of (1A, 3aK, 4A, 7aA) -1,7a-dimethyl-1 - ((trimethylsilyl) buta-1,3-diin-1-yl) octahydro-1H-inden-4-ol (13)
    [0274]
    [0275]
    [0276]
    [0277]
    [0278] HF (2 mL, 48% aq.) Was added to a solution of 12 (0.350 g, 0.87 mmol) in CH3CN (6 mL) and CH2Cl2 (3 mL). The mixture was stirred at room temperature for 1 h. The reaction was stopped by slow addition of a saturated solution of NaHCO3 (20 mL). The aqueous phase was extracted with CH2Cl2 (20 mL) and the combined organic phase was dried, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, 5% EtOAchexanes) to provide 13 (0.247 g, 98%). * H NMR (250 MHz, CDCl 3): 54.12 (br s, 1H, H-8), 2.12 (br t, J = 12.1, 1H, H-9), 1.90-1.01 (m, 11H), 1.18 (s, 3H, Me-28), 1.14 (s, 3H, Me -18), 0.15 (s, 9H, Me 3 Si).
    [0279]
    [0280] Preparation of (1A, 3aK, 7aA) -1,7a-dimethyl-1 - [(trimethylsilyl) buta-1,3-diin-1-yl] octahydro-4H-inden-4-one (14)
    [0281]
    [0282]
    [0283]
    [0284] Pyridinium dichromate (PDC, 960 mg, 2.55 mmol) was added over a solution of alcohol 13 (245 mg, 0.85 mmol) in CH2Cl2 (15 mL). The suspension was stirred at 23 ° C for 5 h. The reaction mixture was diluted with Et2O, stirred for 15 min and filtered through a layer of Celite®. The organic filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (SiO2, 5% EtOAc / hexanes) to provide ketone 14 (247 mg, 98%). * H NMR (250 MHz, CDCl3): 52.64 (t, J = 9.1, 1H, H-9), 2.39-1.79 (m, 6H), 1.76-1.50 (m, 4H), 1.26 (s, 3H, Me). -28), 0.86 (s, 3H, Me-18), 0.17 (s, 9H, Me 3 Si).
    [0285]
    [0286] Preparation of {[(1A, 3aK, 7aA, E ') - 4- (bromomethylene) -1,7a-dimethyloctahydro-1H-inden-1-yl] buta-1,3-diin-1-yl} trimethylsilane ).
    [0287]
    [0288]
    [0289]
    [0290]
    [0291] A suspension of (Ph3PCH2Br) Br (2.45 g, 5.58 mmol) in toluene (20 mL) was sonicated for 30 min (two periods of 15 min). The suspension was cooled to -15 ° C and a solution of KOffiu in THF (5.5 mL, 1M) was added dropwise. The mixture was stirred for 2 h at 15 ° C, then tempering at 0 ° C and re-cooling to -15 ° C and stirring for 15 min. A solution of ketone 14 (0.2 g, 0.70 mmol, 1 equiv) in THF (5 mL) was cooled to 0 ° C and transferred with a cannula onto the suspension of the chilled ilide at -15 ° C. The mixture was stirred at -15 ° C for 1 h, and at 0 ° C for another hour. The reaction was stopped by slow addition of a saturated solution of NH 4 Cl (1 mL). The mixture was purified directly by flash column chromatography (SiO2, hexanes) to give 15 (0.140 g, 55%).
    [0292] 1H NMR (250 MHz, CDCfi): 55.67 (s, 1H, H-7), 2.91 (d, J = 10.7, 1H, H-9), 2.20 (m, 2H), 1.76-1.40 (m, 8H) , 1.23 (s, 3H, Me-28), 0.81 (s, 3H, Me-18), 0.18 (s, 9H, Me2Si).
    [0293] Preparation of {[((1A, 3aA, 7aA, E) -1,7a-dimethyl-4 - [(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) methylene] - Octahydro-1H-inden-1-yl] buta-1,3-diin-1-yl} trimethylsilane (16)
    [0294]
    [0295]
    [0296]
    [0297]
    [0298] A solution of t-BuLi in pentane (0.48 mL, 1.46M) was added slowly to a solution of 15 (120 mg, 0.33 mmol) in THF / toluene (6 mL, 1: 3) cooled to -78 ° C. The yellow reaction mixture was stirred at -78 ° C for 1 h and then B (O / -Pr ) 3 (0.12 mL, 0.50 mmol) was slowly added dropwise. After 2 h, pinacol (0.051 g, 0.43 mmol) was added. The cryogenic bath was removed and the reaction mixture was stirred at room temperature for 1 h. The reaction was stopped by the addition of H2O (10 mL). The aqueous phase was extracted with MTBE (30 mL). The combined organic phase is dried, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, 1% EtOAc / Hexane) to give 16 (0.106 g, 78%). * H NMR (250 MHz, CDCfi): 54.93 (s, 1H, H-7), 3.19 (dd, J = 9.8, J 2 = 3.8, 1H), 2.28 (t, J = 7.3, 1H), 2.13 ( br t, J = 11.3, 1H), 1.74-1.41 (m, 8H), 1.25 (s, 12H, 2 x Me 2 COB), 1.23 (s, 3H, Me-28), 0.78 (s, 3H, Me -18), 0.16 (s, 9H, Me2Si).
    [0299]
    [0300] Preparation of {[(1 ^, 3A, Z) -5- {2 - [(1A, 3aA, 7aA, ^) - 1- (buta-1,3-diin-1-yl) -1,7adimethyloctahydro-4H -inden-4-ylidene] ethylidene} -4-methylenecyclohexane-1,3-diyl] bis (oxy)} bis (tert-butyldimethylsilane) (19).
    [0301]
    [0302]
    [0303]
    [0304]
    [0305] An aqueous solution of K3PO4 (1.5 mL, 2 M) was added to a solution of 16 (70 mg, 0.17 mmol) and of enoltriphalte 17 (100 mg, 0.193 mmol) in THF (2.5 mL). PdCl2 (PPh3) 2 CH2Cl2 (6.0 mg, 0.0085 mmol, 0.05 equiv) was then added. The reaction mixture was stirred for 1 h. The reaction was stopped by the addition of H2O (10 mL). The aqueous phase was extracted with hexanes (30 mL). The combined organic phase is dried, filtered, concentrated and filtered through a layer of silica gel. The residue (18) was redissolved in MeOH (2 mL) and THF (1 mL). Then K2CO3 (70 mg, 0.51 mmol) was added. The resulting suspension was stirred at room temperature overnight. The reaction was stopped by addition of saturated aqueous solution of NH 4 Cl (5 mL) and of H 2 O (5 mL). The mixture was concentrated to a small volume and extracted with MTBE (30 mL). The combined organic phase is dried, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, hexanes) to provide 19 [63 mg, 65% (2 steps)]. 1 H NMR (250 MHz, CDCl 3): 56.23 (d, J = 11.1, 1 H, H-7), 6.03 (d, J = 11.1, 1 H, H-6), 5.17 (s, 1 H, H-19), 4.85 (s, 1H, H-19), 4.36 (dd, J 1 = 6.0, J2 = 3.9, H-1), 4.20 (dt, J = 10.7, J 2 = 3.6, 1H, H-3), 2.85 (m, 1H), 2.46 (dd, J 1 = 13.1, J 2 = 3.4, 1H), 2.34-2.08 (m, 2H), 2.03 (s, 1H, = CH), 1.95-1.39 (m, 10H) , 1.25 (s, 3H, Me-28), 0.87 (s, 18H, 2xMe3CSi), 0.79 (s, 3H, Me-18), 0.06 (s, 12H, 4xMeSi).
    [0306]
    [0307] Preparation of (1.K, 3 »S, Z) -5- {2 - [(1» S, 3 & S, 7 & S, E ') - 1- (5-hydroxy-5-methylhexa-1,3-diin- 1-yl) -1,7a-dimethyloctahydro-4 H -inden-4-ylidene] ethylidene} -4-methylene cyclohexane-1,3-diol (21)
    [0308]
    [0309]
    [0310] A solution of n-HexLi in hexanes (0.045 mL, 2.3M) was added dropwise over a solution cooled to -78 ° C of compound 19 (0.030 g, 0.052 mmol) in THF (1 mL). After stirring for 1 h, dry acetone was added dropwise (0.020 mL, 0.273 mmol). The reaction mixture was stirred while slowly reaching room temperature. The reaction was stopped by addition of saturated aqueous NH 4 Cl solution (10 mL). The mixture was concentrated to a small volume and extracted with MTBE (3x10 mL). The combined organic phase is dried, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, 5% EtOAc / hexanes) to provide 21 [0.030 g, 93%]. The protected analogue 20 (30 mg, 0.047 mmol) was dissolved in THF (1 mL) under argon. A solution of TBAF in THF (0.140 mL, 1M) was added. The mixture was stirred at room temperature. After 48 h, the reaction was stopped by addition of saturated aqueous NH 4 Cl solution (5 mL). The aqueous phase was extracted with EtOAc (15 mL). The combined organic phase is dried, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, 50% EtOAc / hexanes) and repurified by HPLC (Phenomenex SiO2, Preparative Moon 5 gm, 20% z-PrOH / Hexanes) to give 21 (0.014 g, 67%) . 1 H NMR (250 MHz, CDCf): 5 6.36 (d, J = 11.0, 1H, H-7), 6.03 (d, J = 11.4, 1H, H-6), 5.32 (s, 1H, H-19). ), 4.98 (s, 1H, H-19), 4.43 (t, J = 5.7, H-1), 4.23 (m, 1H, H-3), 2.85 (d, J = 10.9, 1H), 2.60 ( d, J = 11.4, 1H), 2.39-1.85 (m, 5H), 1.74-1.44 (m, 11H), 1.52 (s, 6H, Me-26 and Me-27), 1.24 (s, 3H, Me- 28), 0.79 (s, 3H, Me-18).
    [0311]
    [0312] Preparation of (1 ^, 3A, Z) -5- {2 - [(1A, 3aA, 7aA, E) -1,7a-dimethyl-1- (6,6,6-trifluoro-5-hydroxy-5- (trifluoromethyl) hexa-1,3-diin-1-yl) octahydro-4H-inden-4-ylidene] ethylidene]} - 4-methylene-cyclohexane-1,3-diol (23)
    [0313]
    [0314]
    [0315] A solution of n-HexLi in hexanes (0.060 mL, 2.3M) was added dropwise over a solution cooled to -78 ° C of compound 19 (0.040 g, 0.069 mmol) in THF (1 mL). After stirring for 1 h, a solution cooled to -78 ° C of hexafluoroacetone in THF (1 mL), obtained by dissolving the hexafluoroacetone (10 drops) collected in a trap cooled with dry ice in THF, was added via cannula. mL) cooled to -78 ° C. The reaction mixture was stirred for 30 min at -78 ° C in the dark. The reaction was stopped by addition of saturated aqueous NH 4 Cl solution (10 mL). The mixture was concentrated to a small volume and extracted with MTBE (30 mL). The combined organic phase is dried, filtered and concentrated. The residue (22, 33 mg, 0.044 mmol) was dissolved in THF (1 mL) under argon. A solution of TBAF in THF (0.150 mL, 1M) was added. The mixture was stirred at room temperature in the dark. After 24 h, the reaction was stopped by addition of saturated aqueous solution of NH 4 Cl (5 mL). The aqueous phase was extracted with EtOAc (15 mL). The combined organic phase is dried, filtered and concentrated. The residue was purified by flash column chromatography (SiO2, 60% EtOAc / hexanes) and repurified by HPLC (Phenomenex SiO2, Preparative Moon 5 gm, 20% z-PrOH / Hexanes) to give 23 (0.020 g, 57%) . 1 H NMR (250 MHz, CDCh): 56.36 (d, J = 11.2, 1H, H-7), 6.03 (d, J = 11.4, 1H, H-6), 5.33 (s, 1H, H-19) , 4.99 (s, 1H, H-19), 4.44 (t, J = 6.0, H-1), 4.25 (m, 1H, H-3), 2.85 (d, J = 11.7, 1H), 2.60 (d , J = 13.5, 1H), 2.43-2.10 (m, 3H), 2.10-1.84 (m, 3H), 1.84-1.41 (m 10H), 1.27 (s, 3H, Me-28), 0.80 (s, 3H) , Me-18).
    权利要求:
    Claims (22)
    [1]
    1. Compound of formula (I), or one of its stereoisomers, or its pharmaceutically acceptable salts,

    [2]
    2. Compues according to claim 1, wherein P1 and P2 are -OH or -OSiRaRbRc, wherein each of Ra, Rb and Rc are as described in claim 1.
    [3]
    3. Compound according to claim 1, wherein X and X together with the carbon atom to which a methylene group (= CH2) are attached.
    [4]
    4. Compues according to claim 1, wherein R 2 and R 3 are a (C 1 -C 12) alkyl.
    [5]
    5. Compues according to claim 1, wherein R and R are trifluoromethyl.
    [6]
    6. Compues according to claim 1, which incorporates isotopic labeling.
    [7]
    7. Compues according to claim 1, wherein R and R are the same and are selected from the group consisting of Hn- (C1-C12) alkyl, Hn- (C1-C12) alkyl, where n has a value between 1 and 6 .
    [8]
    8. Process for the preparation of a compound of formula (I), as described in claim 1, which comprises reacting a compound of formula (II) with a compound of formula (IIIa) in the presence of a base,

    [9]
    9. Process for the preparation of a compound of formula (I), as described in claim 1, comprising:
    (a) reacting a compound of formula (II) with a compound of formula (IIIb) in the presence of a base, and
    (b) reaction of the intermediate obtained in step (a) with a compound of formula R2M and / or R3M,

    [10]
    10. Compound of formula (I) as described in claim 1, for use as a medicament.
    [11]
    11. Compound of formula (I) as described in claim 1n, for use in the treatment of diseases or conditions related to vitamin D deficiency.
    [12]
    12. The compound of formula (I) according to claim 11, wherein the diseases or conditions related to vitamin D deficiency are selected from the group consisting of rickets, osteoporosis, osteodystrophy, osteomalacia and fractures.
    [13]
    13. Compound of formula (I), s any of claims 1 to 7, for use in the treatment of psoriasis, diabetes, autoimmune, degenerative, endocrinological, cardiovascular, metabolic, infectious, or tumor diseases.
    [14]
    14. Compound of formula (I), according to any of claims 1 to 7, for use in the treatment of neoplastic diseases.
    [15]
    15. Compound of formula s (eIg) in the claim 14, wherein the neoplasic diseases are selected from the group consisting of breast, ovarian, prostate, lung, leukemia, solid tumors and hematological tumors.
    [16]
    16. Combination of at least one compound of formula (I), as defined in any of claims 1 to 7, and at least one antineoplastic compound.
    [17]
    17. Use of a compound of formula (I), as defined in claim 6 or 7, as an internal standard in spectroscopic and spectrometric techniques.
    [18]
    18. Use of a compound of formula (I), as defined in claim 6 or 7, for the preparation of a radiopharmaceutical.
    [19]
    19. Compound of formula (II)

    [20]
    20. Compound of formula (IV) (IV)

    [21]
    21. Compound of formula (V)

    [22]
    22. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), as defined in any one of claims 1 to 7, together with one or more pharmaceutically acceptable excipients or carriers.
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    同族专利:
    公开号 | 公开日
    ES2714628B2|2019-10-02|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO1996030338A1|1995-03-31|1996-10-03|The Johns-Hopkins University|1-substituted vitamin d3 analogues|
    WO2004098612A2|2003-05-07|2004-11-18|Ab Science|Calcitriol analogs of uses thereof|
    EP2682386A1|2011-03-02|2014-01-08|Nihon University|Novel vitamin d receptor modulator with partial agonist activity|
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