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  Vitamin d3 analog useful for the treatment of osteoporosisUSPTO Application #: 20060135491Title: Vitamin d3 analog useful for the treatment of osteoporosis Abstract: The present invention relates to the vitamin D3 analog (1R,3R)-5-{(E)-(2R, 5R)-2-[2-(4-hydroxy-4-methylpentyl)-spiro[4.5]dec-7-ylidene]-ethylidene}-cyclohexane-1,3-diol which is useful in the treatment of osteoporosis. (end of abstract)
Agent: Clark & Elbing LLP - Boston, MA, US Inventors: Roger Bouillon, Pierre De Clercq, Wim Schepens, Maurits Vandewalle, Annemieke Verstuyf USPTO Applicaton #: 20060135491 - Class: 514167000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Ortho-hydroxybenzoic Acid (i.e., Salicyclic Acid) Or Derivative Doai, 9,10-seco- Cyclopentanohydrophenanthrene Ring System (e.g., Vitamin D, Etc.) Doai The Patent Description & Claims data below is from USPTO Patent Application 20060135491. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority under Title 35, United States Code 119(e) from Provisional Application Ser. No. 60/633,670, filed Dec. 6, 2004, which is hereby incorporated by reference. FIELD OF THE INVENTION [0002] The present invention relates to the vitamin D.sub.3 analog (1R,3R)-5-{(E)-(2R, 5R)-2-[2-(4-hydroxy-4-methylpentyl)-spiro[4.5]dec-7-ylidene]-ethyli-dene}- -cyclohexane-1,3-diol which is useful in the treatment of bone disorders, more in particular -osteoporosis. The present invention further relates to compositions, more in particular pharmaceutical compositions comprising said vitamin D.sub.3 analog, to a method of treating humans with said analog, and to a process for preparing said analog. DESCRIPTION OF THE DRAWING [0003] FIG. 1 shows the effect on bone (A) and serum calcium (B) levels of ovariectomized Spargue-Dawley rats upon treatment with the compound of the present invention, (1R,3R)-5-{(E)-(2R,5R)-2-[2-(4-hydroxy-4-methylpentyl)-spiro[4.5]dec-7-yl- idene]-ethylidene}-cyclohexane-1,3-diol at different dosages. DETAILED DESCRIPTION OF THE INVENTION [0004] The present invention relates to the vitamin D.sub.3 analog (1R,3R)-5-{(E)-(2R, 5R)-2-[2-(4-hydroxy-4-methylpentyl)-spiro[4.5]dec-7-ylidene]-ethylidene}-- cyclohexane-1,3-diol having the formula: [0005] For the purposes of the present invention, in order to describe in detail aspects of the vitamin D.sub.3 analog disclosed herein, the following numbering system is used when referring to the carbon atoms which comprise said analog. [0006] The following stereochemistry has been assigned to carbons 1, 3, 13, and 21 of said analog: [0007] The analog of the present invention comprises an upper CF-Ring scaffold connected to a lower A-Ring scaffold as depicted herein below. [0008] The upper CF-Ring scaffold having the (R,R) stereochemistry at carbons 13 and 21 is prepared via key intermediates 10 and 14a. Once formed the CF-Ring scaffold is coupled with the lower A-Ring scaffold. [0009] The following is a detailed description of a process for preparing (1R,3R)-5-{(E)-(2R,5R)-2-[2-(4-hydroxy-4-methylpentyl)-spiro[4.5]dec-7-yl- idene]-ethylidene}-cyclohexane-1,3-diol. The present invention also relates to a number of intermediates, most of them having a specific stereochemistry, and which are useful in the preparation of the final vitamin D.sub.3 analog of this invention. The preparation and the detailed formulae of a first set of these intermediates are shown in the following scheme I comprising a sequence of eleven process steps for making pure isomers of 1,4-dioxa-dispiro[4.1.5.3]pentadec-8-ene. Each step will now be illustrated in details, based on specific starting compounds, reactive agents, catalysts, solvents, temperature ranges and the-like, but the skilled person will readily understand that the specific materials and conditions disclosed herein may be replaced with similar or equivalent materials and conditions without significantly altering the resulting product of the relevant step, except maybe for the reaction yield of such step. Scheme I [0010] Synthesis of a pure isomer of 1,4-dioxa-dispiro[4.1.5.3]pentadec-8-ene starts, as a first step (a), with the halogenation, preferably the bromination, of 3-ethoxy-cyclohex-2-enone, e.g. according to the procedure disclosed by Hara et al. in J. Am. Chem. Soc. (1 999) 121, 3072-3082: (preferred reagents and conditions for step (a): N-bromosuccinimide as a reagent, CH.sub.2Cl.sub.2 as a solvent; temperature range from about 0.degree. C. to about 40.degree. C.). [0011] In a second step (b), the 2-bromo-3-ethoxy-cyclohex-2-enone resulting from step (a) is n-butylated for instance, but without limitation, by means of 1-chloro-4-methoxybutane (the latter may be prepared according to the procedures disclosed by Hara et al. in J. Org. Chem. (1975) 40, 2786-2791 and by De Buyck et al. in Bull. Soc. Chim. Belg. (1992) 101, 807-815) in the presence of an effective amount of an organometallic derivative such as a Grignard reagent. In a more specific embodiment in order to improve butylation yield, said step may additionally be performed in the presence of a stoechiometric amount of cerium trichloride. This specific embodiment is believed to result in the formation of an organocerium active species as shown in the scheme below, although said presumed active species was not isolated: (preferred reagents and conditions for step (b): THF as a solvent; temperature range from about 0.degree. C. to about 40.degree. C. after refluxing to create the Grignard reagent; magnesium, 1-chloro-4-methoxybutane and cerium trichloride as active reagents). [0012] In a third step (c), the 2-bromo-3-(4-methoxybutyl)-cyclohex-2-enone resulting from step (b) is stereoselectively reduced by means of an effective amount of a reducing agent in the presence of a catalytic amount of a suitable stereoselective reduction catalyst. Suitable reducing agents for this reduction step include, but are not limited to, borane, catecholborane and borohydride reagents. Suitable stereoselective reduction catalyst for this reduction step include, but are not limited to, substantially pure methyloxazaborolidinone isomers and metal complexes, either monometallic, homobimetallic or heterobimetallic, such as lithium aluminum hydrides or transition metal complexes, having one or more chiral ligand. The skilled person understands that this step is very; important for the present invention since it determines the success of the whole synthetic route up to the desired following stereoisomeric intermediates and the desired vitamin D.sub.3 analog of the invention. Therefore the skilled person, based on the general knowledge relating to reducing catalysts and agents, will make a careful selection of the reaction conditions in view of various considerations such as reaction yield, productivity and, mainly, enantiomeric excess of one stereoisomer of the resulting product with respect to the other stereoisomer. (preferred reagents and conditions for step (c) as shown above: (R)-methyloxazaborolidinone as a catalyst, catecholborane as a reducing agent, toluene as a solvent; temperature range from about -95.degree. C. to about 25.degree. C., more preferably from -78.degree. C. to about 0.degree. C). [0013] In a fourth step (d), the 2-bromo-3-(4-methoxybutyl)-cyclohex-2-enol stereoisomer resulting from step (c) is submitted to a 3,3-sigmatropic rearrangement by means of a dimethylamino-dimethylacetal (preferably in an at least stoechiometric amount), preferably in the presence of a suitable solvent: (preferred reagents and: conditions for step (d) include: (CH.sub.3).sub.2N[CCH.sub.3(OCH.sub.3).sub.2] as a reagent, toluene as a solvent; temperature: reflux of the solvent). [0014] In a fifth step (e), the 2-[2-bromo-1-(4-methoxybutyl)-cyclohex-2-enyl]-N,N-dimethylacetamide stereoisomer resulting from step (d) is reduced by means of a reducing agent such as a metal hydride, preferably in the presence of a suitable solvent and optionally in the presence of a free radical initiator: (preferred reagents and conditions for step (e): BU.sub.3SnH as the reducing agent, azobis-isobutyronitrile as a free radical initiator; THF a solvent; temperature: reflux of the solvent). [0015] In a sixth step (f), the 2-[1-(4-methoxybutyl)-cyclohex-2-enyl]-N,N-dimethylacetamide stereoisomer resulting from step (e) is submitted to ether cleavage, preferably in the presence of a Lewis acid reagent, a nucleophile reagent and an effective amount of suitable catalyst such as a crown ether. (preferred reagents and conditions for step (f) include: BBr.sub.3 as a Lewis acid, Nal as a nucleophilic reagent, and 15-crown-5 as a catalyst, CH.sub.2Cl.sub.2 as a solvent; temperature range from about -40.degree. C. to about -20.degree. C.). [0016] In a seventh step (g), the 2-[1-(4-hydroxybutyl)-cyclohex-2-enyl]-N,N-dimethylacetamide stereoisomer resulting from step (f) is oxidized in the presence of a suitable oxidation reagent, preferably a chromium (VI) compound, preferably at moderate temperature and in the presence of a suitable solvent: (preferred reagents and conditions for step (g) include: pyridinium dichromate as an oxidation reagent, DMF as a solvent; temperature range from about 10.degree. C. to about 40.degree. C.). [0017] In an eighth step (h), the 4-(1-dimethylcarbamoylmethyl-cyclohex-2-enyl)-butyric acid stereoisomer resulting from step (g) is esterified, preferably in two sub-steps including first a strong base at elevated temperatures, and secondly the presence of an aliphatic alcohol optionally in the presence of an effective amount of an esterification catalyst: (preferred reagents and conditions for step (h) include: first. (i) KOH, dioxane/water mixture as a solvent, temperature range from about 160.degree. C. to about 240.degree. C.; then (ii) diazomethane (CH.sub.2N.sub.2), MeOH). [0018] In a ninth step (i), the 4-(1-dimethylcarbamoylmethyl-cyclohex-2-enyl)-butyric acid methyl ester stereoisomer resulting from step (h) is submitted to a Dieckmann condensation into a .beta.-keto ester preferably in the presence of a strong base such as a sodium alkoxide or a lithium amide, and optionally in the presence of a suitable solvent: (preferred reagents and conditions for step (i) include: lithium diisopropylamide as a base, THF as a solvent; temperature range from about -80.degree. C. to about 40.degree. C.). [0019] In a tenth step (1), the 2-hydroxy-spiro[5.5]undecan-2,7-diene-3-carboxylic acid methyl ester stereoisomer resulting from step (i) is submitted to oxidative decarboxylation, preferably in the presence of an oxidative agent: (preferred reagents and conditions for step (1) include: NaCl, water, and DMSO both as a solvent and an oxidative agent; temperature range from about 140.degree. C. to about 180.degree. C.). Continue reading... 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