methods and intermediates for the preparation of bile acid derivatives

专利摘要:
The present description relates to methods and new intermediates useful in the preparation of a compound of formula I (I),or its pharmaceutically acceptable salt, hydrate, solvate or conjugate of amino acid, sulfate or glucuronide or prodrug.
公开号:BR112019027458A2
申请号:R112019027458-8
申请日:2018-06-22
公开日:2020-07-07
发明作者:Roberto Pellicciari；Antimo Gioiello；Gabriel Galvin；Ronald D. Lewis；Matthew Yanik；Myoung Goo Kim；Fred Ronald Leusink；Bartjan Koning；Thomas Hensel
申请人:Intercept Pharmaceuticals, Inc.；
IPC主号:

专利说明:

[001] [001] Bile acids (BAs) and their derivatives have been shown to modulate the farnesoid X receptor (FXR) and regulate FXR-mediated diseases and conditions (Gioiello, et al., Curr. Top. Med. Chem. 14 (2014) , 2159). Such natural bile acids such as chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA) and their taurine and glycine conjugates are known FXR ligands. A semisynthetic bile acid analogue, 3α, 7α-dihydroxy-6α-ethyl-5β-cholan-24-oic acid (6-ethyl-chenodeoxycholic acid (6a-ECDCA) or obeticolic acid (OCA)), disclosed in WO 2002/75298 is a highly potent FXR modulator, which is currently marketed as OCALIVA® for the treatment of primary biliary cholangitis (PBC). Another semisynthetic bile acid analogue, 3α, 7α, 11β-trihydroxy-6α-ethyl-5β-colan-24-oic acid (compound 100), although being a potent FXR agonist, also showed specificity against the receptor coupled to TGR5 G protein (GP-BAR1, M-BAR, GPBAR or GPR131).
[002] [002] The identification of potent and selective bile acid FXR agonists is essential not only to further explore the physiological roles and pathological implications of bile acid signaling, but also to advance new therapeutic opportunities associated with selective receptor modulation by bile acid analogs. More effective and selective bile acid based FXR agonists may demonstrate added therapeutic value by avoiding potential side effects associated with TGR5 activation (eg, itching, gallbladder filling and cholesterol gallstone formation) (Pellicciari et al., J. Med. Chem. 59 (2016), 9201-9214).
[003] [003] Methods of synthesis of compound 100 and its analogs have been described in WO 2014/184271 and more recently in WO 2017/062763. However, there remains a need for more efficient methods of preparing selective FXR modulators, such as compound 100 and its analogs, including processes with a reduced number of steps, increased yields, and providing high purity of intermediates and final products. The present application addresses this need. SUMMARY OF THE INVENTION
[004] [004] The present invention provides methods of preparing bile acid derivatives.
[005] [005] In one aspect, the present description refers to a method of preparing a compound of formula II, or a salt, solvate or conjugate of amino acid, sulfate or glucuronide or pharmaceutically acceptable prodrug, in which: R1, R2, R2, R3, R4, R5, R6, R7, R8, R9, R10, m, nep are as described herein.
[006] [006] In another aspect, the present description refers to a method of preparing a compound of formula II:
[007] [007] In another aspect, the present description relates to a method of preparing a compound of the formula III: III, or a salt, solvate or conjugate of amino acid, sulfate or glucuronide or pharmaceutically acceptable prodrug, wherein: R1 , R2, R4, R5, R7, R8, R9, R10, m, nep are as described herein.
[008] [008] Unless otherwise defined, all technical and scientific terms used here have the same meaning as commonly understood by a person skilled in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. The materials, methods and examples are illustrative only and are not intended to be limiting. In case of conflict, this specification, including definitions, will monitor. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. All publications, patent applications, patents and other references mentioned here are incorporated by reference. The references cited here are not accepted as being prior art to the claimed invention.
[009] [009] Other features and advantages of the invention will be apparent from the following detailed description.
[0010] [0010] Certain terms used in the specification and claims are collected here.
[0011] [0011] As used herein, the phrase "a compound of the description" refers to a compound of any of the formulas I, Ia, Ib, I-9, II, III, IIIa, IIIb, C2, D5, 44, 44a , 45 and 100 or any other compound explicitly disclosed here.
[0012] [0012] The term "C1-C6 alkyl" or "Alq" or "alkyl", as used herein, refers to a fraction of straight or branched chain hydrocarbons having 1, 2, 3, 4, 5 or 6 atoms carbon. Examples of C1-C6 alkyl fractions include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, and n -hexila. "C1-C4 alkyl" refers to a fraction of straight or branched chain hydrocarbons having 1, 2, 3 or 4 carbon atoms.
[0013] [0013] The term "alkenyl" refers to a fraction of straight or branched chain hydrocarbons containing at least one carbon-carbon double bond. Both the trans and cis isomers of the carbon-carbon double bond are encompassed under the term "alkenyl". Examples of alkenyl fractions include, but are not limited to, vinyl, allyl, 1-butenyl, 2-butenyl, 3-butenyl and 2-hexenyl.
[0014] [0014] As used here, "alkynyl" refers to a fraction of straight or branched chain hydrocarbons containing at least one carbon-carbon triple bond. Examples of alkynyl fractions include, but are not limited to, ethynyl, 2-propynyl, 5-but-1-en-3-inyl and 3-hexynyl.
[0015] [0015] The term "alkoxy" refers to a saturated straight or branched chain hydrocarbon covalently attached to an oxygen atom. Examples of alkoxy fractions include, but are not limited to, methoxy, ethoxy, isopropyloxy, n-propoxy, n-butoxy, t-butoxy and pentoxy.
[0016] [0016] As used here, the term "halogen" or "Hal" refers to fluorine, bromine, chlorine and iodine.
[0017] [0017] As used herein, "carbocycle", "carbocyclic" or "carbocyclic ring" is intended to include any stable monocyclic or bicyclic ring having the specified number of carbons, any of which can be saturated, unsaturated or aromatic. Carbocyclic ring includes cycloalkyl and aryl. For example, a C3-C8 carbocyclic ring is intended to include a monocyclic or bicyclic ring having 3, 4, 5, 6, 7 or 8 carbon atoms. Examples of carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl and phenyl.
[0018] [0018] As used herein, "heterocycle", "heterocyclic" or "heterocyclic group" includes any ring structure (saturated, unsaturated or aromatic) that contains at least one ring hetero atom (eg, N, O or S). Heterocycle includes heterocycloalkyl and heteroaryl. Examples of heterocycles include, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, oxetane, pyran, tetrahydropyran, azetidine and tetrahydrofuran. Examples of heterocyclic groups include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, tetrahydrofuran, furanyl, furazanil, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenila, indolinyl, indolizine, indolizine, indolizine isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, pyridinyl, pyridyl and pyrimidinyl.
[0019] [0019] As used here, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic mono- or multi-ring hydrocarbon system (eg, fused, bridged or spiro rings) having 3 to 10 carbon atoms (e.g., C3-C6). Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
[0020] [0020] As used here, any recited fraction that includes, but is not limited to, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring, heterocyclic ring, cycloalkyl, etc., can be optionally substituted. The term "optionally substituted" refers to the indicated fraction which may or may not be substituted and which, when substituted, is mono-, di- or tri-substituted, such as with 1, 2 or 3 substituents. In some cases, the substituent is halogen or OH.
[0021] [0021] As used here, the term "protecting group" refers to an appropriate fraction to mask, for example, a hydroxyl functionality, which is stable / non-reactive under reaction conditions (eg, not reactive with an agent used in the reaction). One skilled in the art will recognize the particular fractions employed to protect certain functional groups, e.g., hydroxyl group, instead of another functionality, e.g., carboxylic acid. Protective group reagents include, but are not limited to, acylating agents (eg, acetic anhydride, benzoyl chloride, pivaloyl chloride, etc.), silylating agents (eg, TMS-Cl, TES- Cl, TBDMS-Cl, etc.), ether-forming reagents (MOM-Cl, MEM-Cl, dihydropyran, ethyl vinyl ether, haloalkanes such as iodomethane, bromomethane, iodoethane, bromoethane, etc.), chloroformates (chloroform) methyl, ethyl chloroformate, isobutyl chloroformate, benzyl chloroformate, etc.), in the presence of an appropriate base (eg carbonate salts, bicarbonate salts, pyridine, triethylamine, diisopropyl ethylamine, N -
[0022] [0022] As used here, the term "labile group" or "LG" refers to a labile functionality that has a propensity to dissociate from carbon (eg, Cl, Br, I, sulfonated alcohols such as methanesulfonates, p-toluenesulfonates, trifluoromethanesulfonates, trifluoroacetates, sulphorylated alcohols, phosphorylated alcohols, etc.). The labile groups can be substituted by another functional group or eliminated, e.g., to produce an unsaturated compound, such as, for example, a compound of formula B.
[0023] [0023] As used herein, the term "pharmaceutically acceptable salt" refers to base addition salts including, but not limited to, alkali metal salts selected from sodium, lithium or potassium salts, or selected alkaline earth metal salts of calcium or magnesium. Base addition salts additionally include salts of inorganic and organic amines including, but not limited to, ammonium, methylammonium, ethylammonium, diethylammonium, triethylammonium, lysine, arginine, N-methylglucamine and choline. Conventional non-toxic salts also include those, but are not limited to those, derived from inorganic and organic acids selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethanedisulfonic, fumaric , gluco-heptonic, gluconic, glutamic, glycolic, glycoliarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, iodridic, hydroximalic, hydroxinphtoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanolic, mandelic, methanolic, mandelic, mandelic, methanolic, mandelic, methanolic, mandelic, mandelic, methanolic, mandelic, mandelic, mandelic, mandelic, mandelic, mandelic, mandilic, mandelic, mandelic, mandelic, mandelic, mandelic, mandelic, mandelic.
[0024] [0024] "Solvate", as used herein, refers to a form of adding solvents of a compound of formula (A) that contains stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more water molecules with one of the substances in which water retains its molecular state as H2O, such a combination being able to form one or more hydrates.
[0025] [0025] The phrase "pharmaceutically acceptable carrier" is recognized in the art and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in loading or transportation from any composition in question from one organ, or body part, to another organ or body part. Each vehicle is "acceptable" in the sense of being compatible with the other ingredients of the composition in question and not harmful to the patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffered solutions; and (21) other compatible non-toxic substances used in pharmaceutical formulations.
[0026] [0026] As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient that is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes excipients acceptable for veterinary use as well as human pharmaceutical use.
[0027] [0027] A "pharmaceutical composition" is a formulation containing a compound of formula (A) or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump in an aerosol inhaler or a bottle. The amount of active ingredient (e.g., a formulation of a compound of the invention or its salts) in a unit dose of the composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it may be necessary to make routine variations to the dosage depending, for example, on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, ocular, ophthalmic, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal and the like. Dosage forms for topical or transdermal administration of a compound of this application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalers. In another embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or propellants that are required.
[0028] [0028] As used herein, the term "amino acid conjugates" refers to conjugates of a compound of the description with any suitable amino acid. Taurine (-NH (CH2) 2SO3H), glycine (- NHCH2CO2H) and sarcosine (-N (CH3) CH2CO2H) are examples of amino acid conjugates. Suitable amino acid conjugates of the compounds have the added advantage of enhanced integrity in the bile or intestinal fluids. Suitable amino acids include, are not limited to, taurine, glycine and sarcosine. The amino acid conjugates of the compounds of the description can be prepared according to methods known in the art. For example, a free or protected bile acid or bile acid derivative can be coupled to an amino acid (protected or unprotected), eg, amino acid glycine, sarcosine or taurine, using standard peptide coupling conditions (eg ., in the presence of a base (eg, triethylamine, diisopropyl ethylamine (DIPEA), etc.) and specific coupling reagents, for example, N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), 4- (4,6-Dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholine (DMTMM) chloride (DMTMM), etc.
[0029] [0029] As defined herein, the term "metabolite" refers to glucuronidated and sulfated derivatives of the compounds described herein, wherein one or more fractions of glucuronic acid or sulfate are linked to the compound of the invention. Glucuronic acid fractions can be linked to the compounds through glycosidic bonds with the hydroxyl groups of the compounds (eg, 3-hydroxyl, 7-hydroxyl,
[0030] [0030] The term "prodrug", as used herein, refers to a bile acid derivative or compound that, after administration, is metabolized (i.e., converted within the body) to a pharmacologically active drug. Inactive prodrugs are pharmacologically inactive medications that are metabolized in an active form within the body. Rather than administering a drug directly, a corresponding prodrug could be used instead to improve how a drug is absorbed, distributed, metabolized and excreted (ADME). Prodrugs are often designed to improve bioavailability when a drug itself is poorly absorbed from the gastrointestinal tract. A prodrug can be used to improve how selectively the drug interacts with cells or processes that are not its intended target. This can reduce adverse or unintended effects of a drug, especially important in treatments having serious unwanted and undesirable side effects.
[0031] [0031] The term "treat", as used herein, refers to alleviating, alleviating, reducing, eliminating, modulating or improving, i.e., causing regression of the disease state or condition.
[0032] [0032] The term "prevent", as used here, refers to completely or almost completely preventing a disease state or condition from occurring in a patient or subject, especially when the patient or subject is predisposed to or at risk of contracting a disease state or condition. Prevention may also include inhibiting, i.e., preventing the development, of a disease state or condition, and alleviating or ameliorating, i.e., causing regression of the disease state or condition, for example when the disease state or condition may already be present.
[0033] [0033] The phrase "reduce the risk of", as used here, refers to decreasing the possibility or probability that a disease of the central nervous system, inflammatory disease and / or metabolic disease will occur in a patient, especially when the subject is predisposed for such an occurrence.
[0034] [0034] "Combination therapy" (or "co-therapy") refers to the administration of a compound of the description and at least a second agent as part of a specific treatment regimen designed to provide the beneficial effect from the coercion of these therapeutic agents (ie, the compound of the description and at least a second agent). The beneficial effect of the combination includes, but is not limited to, coercion of pharmacokinetics or pharmacodynamics resulting from the combination of therapeutic agents. The administration of these therapeutic agents in combination is typically carried out over a defined period of time (usually minutes, hours, days or weeks depending on the selected combination). "Combination therapy" may, but is not generally intended to, encompass the administration of two or more of these therapeutic agents as part of separate monotherapeutic regimens that incidentally and arbitrarily result in the combinations of the present application. "Combination therapy" is intended to encompass the administration of these therapeutic agents in a sequential manner, that is, in which each therapeutic agent is administered at a different time, as well as the administration of these therapeutic agents, or at least two of the therapeutic agents , in a substantially simultaneous manner. Substantially simultaneous administration can be achieved, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple unique capsules for each of the therapeutic agents. The sequential or substantially simultaneous administration of each therapeutic agent can be carried out by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes and direct absorption through mucous membrane tissues. Therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the selected combination can be administered by intravenous injection while the other therapeutic agents of the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally or all therapeutic agents can be administered by intravenous injection. The sequence in which therapeutic agents are administered is not strictly critical.
[0035] [0035] "Combination therapy" also encompasses the administration of therapeutic agents as described above in additional combination with other biologically active ingredients and drug-free therapies (eg, surgery or mechanical treatments). Where combination therapy additionally comprises drug-free treatment, drug-free treatment can be conducted at any appropriate time as long as a beneficial effect is achieved from the constraint of the combination of therapeutic agents and drug-free treatment. For example, in appropriate cases, the beneficial effect is still achieved when the drug-free treatment is temporarily removed from the administration of the therapeutic agents, perhaps for days or even weeks. As used herein, "combination therapy" means that a compound of the application can be administered in conjunction with another therapeutic agent. "In conjunction with" refers to the administration of one treatment modality in addition to another treatment modality, such as administration of a compound of the application as described herein in addition to administration of another therapeutic agent to the same subject. As such, "in conjunction with" refers to the administration of a treatment modality before, during or after the distribution of a treatment modality to the subject.
[0036] [0036] An "effective amount" of a compound of the description, or a combination of compounds, is an amount (amount or concentration) of compound or compounds. In one embodiment, when a therapeutically effective amount of a compound is administered to a subject in need of treatment, symptoms arising from the disease improve immediately or after administration of the compound one or more times. The amount of the compound to be administered to a subject will depend on the particular dysfunction, the mode of administration, co-administered compounds, if any, and the characteristics of the subject, such as general health, other diseases, age, sex, genotype, body weight and tolerance to drugs. The skilled person will be able to determine appropriate dosages depending on these and other factors.
[0037] [0037] The term "prophylactically effective amount" means an amount (amount or concentration) of a compound of the present description, or a combination of compounds, which is administered to prevent or reduce the risk of a disease - in other words, an amount necessary to provide a preventive or prophylactic effect. The amount of the present compound to be administered to a subject will depend on the particular dysfunction, the mode of administration, co-administered compounds, if any, and the characteristics of the subject, such as general health, other diseases, age, sex, genotype, body weight and tolerance to drugs. The skilled person will be able to determine appropriate dosages depending on these and other factors.
[0038] [0038] A "subject" includes mammals, eg, humans, pets (eg, dogs, cats, birds and the like), farm animals (eg, cows, sheep, pigs, horses and the like) and laboratory animals (eg, rats, mice, guinea pigs and the like). The subject is typically human.
[0039] [0039] As used here, farnesoid X receptor or FXR refers to all mammalian forms of such a receptor including, for example, alternative processing isoforms and naturally occurring isoforms (see, eg, Huber et al., Gene 290 : 35-43 (2002)). Representative FXR species include, without limitation, rat FXR (GenBank Access No. NM 021745), mouse FXR (GenBank Access No. NM 009108) and human FXR (GenBank Access No. NM 005123).
[0040] [0040] The term "about" as used here when referring to a measurable value such as a quantity, a time duration and the like is intended to encompass variations of ± 20% or ± 10%, in some embodiments ± 5%, in some embodiments ± 1% and, in some embodiments, ± 0.1% from the specified value, as such variations are appropriate for practicing the disclosed methods or for preparing and using the disclosed compounds and in the claimed methods. Methods of the Invention
[0041] [0041] In one aspect, the present description relates to a method of preparing a compound of formula I:
[0042] [0042] According to Scheme A, the process of preparing the compound of formula I comprises the steps of 1) optional protection of a compound of formula I-1 to provide the compound of formula I-2; 2) treating the compound of the formula I-1 or I-2 with an appropriate activating agent to provide a compound of the formula I-3, where LG is a labile group; 3) treating the compound of formula I-3 with a base to prepare a compound of formula I-4; 4) reacting a compound of formula I-4 with a halogenating reagent (e.g., brominated) to provide a compound of formula I-5; 5) reacting the compound of formula I-5 with an oxidizing agent to prepare a compound of formula I-6; 6) reacting the compound of formula I-6 with a reducing agent to prepare the compound of formula I-7 (dehalogenation or reducing debromation); 7) optional deprotection of the compound of formula I-7 to obtain the compound of formula I-8; and 8) reacting the compound of formula I-7 or I-8 with a reducing agent to provide the compound of formula I-9 or I.
[0043] [0043] Some embodiments of the present description relate to a method of preparing a compound of formula I: I, or a salt, solvate or conjugate of amino acid, sulfate or glucuronide or pharmaceutically acceptable prodrug, wherein R1, R2, R3 , R4, R5, R6, R8, R9, R10, m, nep are as described here and R7 is OH, OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, CO2H, C (O) NHOH, NH (CH2) 2SO3H , NHCH2CO2H or tetrazolyl, oxadiazolyl,
[0044] [0044] According to Scheme A-I, the process of preparing the compound of formula I comprises the steps of 1) optional protection of a compound of formula I-1 to provide the compound of formula I-2; 2) treating the compound of the formula I-1 or I-2 with an appropriate activating agent to provide a compound of the formula I-3, where LG is a labile group; 3) treating the compound of formula I-3 with a base to prepare a compound of formula I-4; 4) reacting a compound of formula I-4 with a halogenating reagent (e.g., brominated or iodizing) to provide a compound of formula I-5a; 5) reacting the compound of formula I-5a with an oxidizing agent to prepare a compound of formula I-6a; 6) reacting the compound of the formula I-6a with a reducing agent to prepare the compound of the formula I-7 (dehalogenation, e.g., disruption or deiodination, reducing); 7) optional deprotection of the compound of formula I-7 to obtain the compound of formula I-8; and 8) reacting the compound of formula I-7 or I-8 with a reducing agent to provide the compound of formula I-9 or I. In one embodiment, X is, where R8, R9 and R10 are as described herein. In certain embodiments, Hal is iodine. In some modalities, Hal is bromine.
[0045] [0045] In some embodiments, the compounds of the description, or their pharmaceutically acceptable salts, solvates or conjugates of amino acids, are isotopically labeled (or radiolabeled). Examples of isotopes that can be incorporated into compounds of the description, or their pharmaceutically acceptable salts, solvates or amino acid conjugates, include isotopes of hydrogen, carbon, nitrogen, fluorine, such as 2H, 3H, 11 C, 13 C, 14C and 18 F. In some embodiments, the compounds of the description are deuterated, ie, incorporate 2H, tritiated, ie, incorporate 3H, and radiolabeled with 14 carbon-14, ie, C. The compounds of the description isotopically labeled, or their salts, solvates or conjugates of pharmaceutically acceptable amino acids, can generally be prepared by carrying out the procedures disclosed in the Schemes and / or the Examples, by replacing a readily available isotopically labeled reagent with a non-isotopically labeled reagent.
[0046] [0046] In certain embodiments, the present description refers to a method of preparing a compound of formula I or I-9, where R1 is alpha-hydroxy, compound of formula I-9a: I-9a, or a compound thereof salt, solvate or amino acid, sulfate or glucuronide conjugate or pharmaceutically acceptable prodrug, wherein R2-R10 are as described herein.
[0047] [0047] In some embodiments, the compound of formula I or I-9 or I-9a, where R7 is OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, CO2H, C (O) NHOH, tetrazolyl, oxadiazolyl, thiadiazolyl , 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidinedionyl, thiazolidinedionyl, 3-hydroxy-isoxazolyl, 3-hydroxy-isothiazolyl, pyrimidine, 3,5-difluoro-4 -hydroxyphenyl or 2,4-difluoro-3-hydroxyphenyl, all of which can be optionally additionally substituted, can be prepared using synthetic procedures described in WO 2017/062763, US20160130297, US20160145295, US20160145296, US20160185815, US20160229886, US20160289262 and US20160289262 and US 081285 or using another procedure known in the art. The method currently disclosed provides an efficient synthesis of intermediates that can be further elaborated up to several side chain analogs, including, but not limited to, compounds with the following side chains:
[0048] [0048] In one of the modalities, in Scheme AI, step 1) is protection of a compound of formula I-1 to provide compound of formula I-2, where R11 is a protecting group and step 2) is treatment of compound of formula I-1 or I-2 with an appropriate activating agent to provide a compound of formula I-3, where LG is a labile group, which can be carried out sequentially in a vessel without isolation of intermediates through a telescopic process (two-step procedure, a vessel).
[0049] [0049] In certain embodiments, this description relates to a method of preparing a compound of formula I:
[0050] [0050] In certain embodiments, the compound of formula I is a compound of formula I-9
[0051] [0051] In one embodiment, the method of preparing a compound of the formula I or I-9 comprises alternative steps from the compound of the formula I-5 (eg, I-5b) as shown in Scheme A1. Scheme A1:
[0052] [0052] According to Scheme A1, the method of preparing a compound of formula I or I-9 starting from a compound of formula I-5 (e.g., I-5b) comprises the steps of: 1) reaction of the compound of formula I-5b with a reducing agent to prepare the compound of formula I-5c (Step 5b; reducing dehalogenation (eg, debromation, deiodination, etc.); 2) reaction of the formula compound I-5c with a reducing agent to provide the compound of formula I-5d (Step 6b; reduction of ketone in the presence of protecting groups at C3);
[0053] [0053] In some embodiments, step 6b or other C7 ketone reductions are conducted in the presence of protective groups in C3 through, for example, reduction of borohydride or catalytic hydrogenation.
[0054] [0054] In some embodiments, the deprotection of X in step 7b (eg, R7 is methyl ester) and removal of the protecting group R11 in C3 can be done selectively and occur in a step-by-step manner or can occur simultaneously . In one embodiment, the C3 hydroxy can be protected as, for example, an alkyloxycarbonyl, then both the protecting group X of the side chain (eg, R7 methyl ester) and the protecting group C3 hydroxy can be removed simultaneously under basic conditions. In other embodiments, the C3 hydroxy can be protected as, for example, a pivolate, then the side chain protecting group X (eg, R7 is methyl ester) can be removed by maintaining the hydroxy protective group first. C3 intact. Step-by-step deprotection allows isolation of penultimate intermediates of compound I or I-9 (eg, 100), thereby providing alternative opportunities for purification (eg, crystallization) of intermediates (eg, compounds of formula I-5d) and final products (eg compounds of formula I or I-9).
[0055] [0055] In some embodiments, the order of steps 6b and 7b can be reversed, such that the deprotection step as described above can occur before the ketone reduction step.
[0056] [0056] In one embodiment, the compound of formula I-7a can be prepared from compound I-4 (e.g., where R2 and R3 form a carbonyl). In a certain embodiment, the compound of formula I-7a can be prepared from compound I-4 (e.g., where R2 and R3 form a carbonyl) using a telescopic procedure. In some embodiments, the method of preparing the compound of formula I or I-9 comprises alternative steps from the compound of formula I-7 (e.g., I-7a) as shown in Scheme A2. Scheme A2:
[0057] [0057] According to Scheme A2, an alternative process for preparing the compound of formula I or I-9 starting from the compound of formula I-7a comprises the steps of: 1) reacting the compound of formula I-7a with a reducing agent to provide the compound of formula I-8a (Step 6c); 2) deprotection of the compound of formula I-8a to obtain the compound of formula I or I-9 (Step 7c).
[0058] [0058] The synthetic processes of the present description can tolerate a wide variety of functional groups, therefore, several substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain cases to further convert the compound into a pharmaceutically acceptable salt, ester, prodrug or amino acid, sulfate or glucuronide conjugate.
[0059] [0059] In one embodiment, the compound of formula I-1 is a compound of formula A A '.
[0060] [0060] In one of the embodiments, the compound of formula I-1 is the compound of formula A A.
[0061] [0061] In one of the embodiments, the compound of formula I-1 is the compound of formula A "A".
[0062] [0062] In one of the embodiments, the compound of formula I-1 is the compound of formula A1 A '' '.
[0063] [0063] In one of the embodiments, the compound of formula I-1 is the compound of formula 1
[0064] [0064] In one embodiment, the present description relates to a process for preparing the compound of the formula C2 as shown in Scheme 1.
[0065] [0065] In some embodiments, step 1) comprises simultaneous protection of hydroxy C3 and R7 with protecting groups R11 suitable to provide the compound of formula A1 (e.g., R7 can be protected as a terminal methyl ester and C3 hydroxide protected as an acetoxy group).
[0066] [0066] According to Scheme 1, the process of preparing the compound of formula C2 comprises the steps of 1) protecting a compound of formula A to provide a compound of formula A1; 2) treating the compound of formula A1 with an appropriate activating agent to provide a compound of formula A2, where LG is a labile group; 3) treating the compound of formula A2 with a base to prepare a compound of formula B; 4) reacting a compound of formula B with a brominated reagent to provide a compound of formula B1; 5) reacting the compound of formula B1 with an oxidizing agent to prepare a compound of formula B2; 6) reaction of the compound of formula B2 with a reducing agent to prepare a compound of formula C (dehalogenation or reducing debromation); 7) deprotection of the compound of formula C to obtain a compound of formula C1; and 8) reacting the compound of formula C1 with a reducing agent to provide a compound of formula C2.
[0067] [0067] In one of the modalities, compound A is compound A '' '.
[0068] [0068] In certain embodiments, the present description relates to a process for preparing the compound of the formula C2 as shown in Scheme 1A. Scheme 1A:
[0069] [0069] According to Scheme 1A, the process of preparing the compound of formula C2 comprises the steps of 1) protecting a compound of formula A to provide a compound of formula A1; 2) treating the compound of formula A1 with an appropriate activating agent to provide a compound of formula A2, where LG is a labile group; 3) treating the compound of formula A2 with a base to prepare a compound of formula B; 4) reacting a compound of formula B with a halogenating reagent (e.g., brominated or iodizing) to provide a compound of formula B1a; 5) reacting the compound of formula B1a with an oxidizing agent to prepare a compound of formula B2a; 6) reaction of the compound of the formula B2a with a reducing agent to prepare a compound of the formula C (dehalogenation, e.g., debromation or deiodination, reducing); 7) deprotection of the compound of formula C to obtain a compound of formula C1; and 8) reacting the compound of formula C1 with a reducing agent to provide a compound of formula C2.
[0070] [0070] In some modalities, X is, where R8, R9 and R10 are as described here. In certain embodiments, the compound of formula A is a compound of formula A '' '.
[0071] [0071] In some embodiments, the present description relates to a process for preparing the compound of formula A2 as shown in Scheme 1A-1, comprising the following steps: 1) protecting a compound of formula A to provide a compound of formula A1 and 2) treating the compound of formula A1 with an appropriate activating agent to provide a compound of formula A2, where LG is a labile group.
[0072] These two steps can be performed sequentially without processing or isolating the intermediate compound of formula A1 (i.e., a telescopic procedure or in two steps, one step) thereby improving the overall efficiency of manufacturing operations. Scheme 1A-1:
[0073] [0073] In some modalities, X is, where R8, R9 and R10 are as described here. In certain embodiments, the compound of formula A is a compound of formula A '' '.
[0074] [0074] In some embodiments, the compound of formula I-9 or C2 is further transformed into the compound of formula I, where R 7 is OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, C (O) NHOH, tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo- 1,2,4-thiadiazolyl, oxazolidinedionyl, thiazolidinedionionyl, 3-hydroxy-isoxazolyl, 3-hydroxy-isothiazolyl or 2,4-difluoro- 3-hydroxyphenyl, and R1 is alkoxy or oxo using known synthetic procedures.
[0075] [0075] In some embodiments, the compound of formula I-9 or C2 is further transformed into the compound of formula I, where R 7 is OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, CO2H, C (O) NHOH, tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidinedionyl, thiazolidinedionyl, 3-hydroxy-isoxazolyl, 3-hydroxy-isothiazolyl, pyrimidine, 3, 5-difluoro-4-hydroxyphenyl or 2,4-difluoro-3-hydroxyphenyl, all of which can be optionally additionally substituted, and R 1 is alkoxy or oxo using synthetic procedures described in WO 2017/062763, US20160130297, US20160145295, US20160145296, US20160185815, US20160229886, US20160289262 and WO2018 / 081285 or using another procedure known in the art.
[0076] [0076] For example, compounds where R7 is tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidinedione, thiazolidinedione, 3-hydroxy-isoxa- zolyl, 3-hydroxy-isothiazolyl or 2,4-difluoro-3-hydroxyphenyl can be prepared from the corresponding carboxylic acid through a coupling with the required R7-containing boronic acids: (1).
[0077] [0077] In some embodiments, the protecting group R11 is selected from C (O) -C1-C4 alkyl, C1-C6 alkoxycarbonyl, aryloxycarbonyl, benzoyl, benzyl, pivaloyl, tetrahydropyranyl ether, tetrahydrofuranyl ether, 2 -methoxyethoxymethyl, methoxymethyl ether, ethoxyethyl ether, p-methoxybenzyl ether, methylthiomethyl ether, triphenylmethyl, dimethoxytrityl, methoxytrityl and optionally substituted silyl ether. In one embodiment, the silyl ether is selected from trimethylsilyl ether, triethylsilyl ether, triisopropylsilyl ether, tert-butyldimethylsilyl ether and tert-butyldiphenylsilyl ether. In one embodiment, the protecting group R11 is benzoyl or acetyl. In one embodiment, the protecting group R11 is C (O) -C1-C4 alkyl. In one embodiment, the protecting group R11 is acetyl. In some modalities, R11 is H.
[0078] [0078] The compounds of formula I can be prepared in 6 to 9 stages with an overall yield of about 40 to about 60%. In one embodiment, the overall yield of the compound of formula I, I-9 or C2 is about 50%. Various modifications to the Scheme A or Scheme A-I process are disclosed in Schemes 1-13. In some respects, the present description relates to a method of preparing the compound of formula B from the compound of formula A1 in one step, the method comprising the steps shown in Scheme 2. Scheme 2:, where R4, R11 and X are as described here.
[0079] [0079] In some embodiments, the Scheme 2 step is performed on a C7 protected compound, as, for example, shown in Scheme 2a. Scheme 2a:
[0080] [0080] In some embodiments, the compound of formula A1 is treated with a dehydrating reagent (eg, phosphorus oxychloride (POCl3), PCl5, P2O5, Burgess reagent, dicyclohexylcarbodiimide (DCC), chloride 2-chloro-1,3-dimethylimidazolinium (DMC), H3PO4, etc.) in the presence of a base (eg, pyridine, lutidine, triethylamine, diisopropylethyl amine, LiBr, Li2CO3, AcOK, trimethylpyridine, etc. .) to provide the compound of formula B. In some embodiments, the reaction is taken into account at about 40 ° C, about 45 ° C, about 50 ° C, about 55 ° C or about 60 ° C . In some embodiments, the compound of formula B prepared by the dehydration reaction is obtained in about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95 % or more than 95% yield. The compound of formula B can be purified (eg, by chromatography or crystallization) or used for the next step without purification. In one embodiment, the compound of formula B is crystallized and optionally recrystallized. In one embodiment, the compound of formula B is used without purification.
[0081] [0081] In some embodiments, the compound of formula A1 is first converted to the compound of formula A2 as shown in step 2 of Scheme 1. In some embodiments, C12-alcohol A1 is treated with an activating reagent (or an electrophile , eg, mesyl chloride (methanesulfonyl), tosyl chloride (toluenesulfonyl), trifluoromethanesulfonic anhydride (triflic), thionyl chloride, SO3-pyridine, phosphoryl chloride, phosphoryl bromide, nonafluorobutyl chloride or any other reagent a suitable labile group at position C12) in the presence of a base (eg, pyridine, triethylamine, diisopropylethylamine (DIPEA), imidazole, etc.) at about 20 ° C, about 25 ° C, about 30 ° C, about 35 ° C, about 40 ° C, about 45 ° C, about 50 ° C, about 55 ° C, about 60 ° C, about 65 ° C or up to reflux of an appropriate reaction solvent (eg, pyridine, methylene chloride (DCM), etc.). In some embodiments, an additional base can be used as a nucleophilic catalyst (eg, 4-dimethylaminopyridine (DMAP)).
[0082] [0082] In some modalities, about 2 equivalents, about
[0083] [0083] In some embodiments, the compound of formula A2 is prepared in about 50%, about 60%, about 70%, about 80%, about 85%, about 90%, about 95% or more than 95% yield. In one embodiment, the compound of formula A2 can be prepared in quantitative yield, e.g., about 100%. In one embodiment, the compound of formula A2 is used without purification.
[0084] [0084] In some embodiments, the compound of formula A2 is treated with a suitable base to provide the compound of formula B. In some embodiments, suitable bases include, but are not limited to, metal alkoxides (e.g., tertiary) - potassium butoxide (t-BuOK), sodium amylate, etc.), acetate salts (eg, potassium acetate (KOAc), lithium acetate (LiOAc), sodium acetate (NaOAc) or acetate cesium (CsOAc)), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), imidazole, pyridine, etc.
[0085] [0085] In some embodiments, the elimination reaction from step 3 of Scheme 1 is carried out in a suitable solvent, such as high boiling solvent (eg, hexamethylphosphoramide (HMPA), 1,3-dimethyl -3,4,5,6-tetrahydro-2-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO),
[0086] [0086] In some embodiments, the compound of formula B is prepared in about 60%, about 70%, about 80%, about 85%, about 90%, about 95% or more than 95% income. In one embodiment, the compound of formula B can be prepared in quantitative yield, e.g., about 100%. In one embodiment, the compound of formula B is used without purification. In some embodiments, the compound of formula B is purified by chromatography or crystallization. In one embodiment, the compound of formula B is crystallized from a suitable organic solvent (eg, heptanes, n-heptane, hexanes, ethyl acetate, methanol, water). In one embodiment, the purity of the isolated compound of formula B is about 80%, about 85%, about 90%, about 95% or more than 95% (by weight). In one embodiment, the purity of the compound of formula B is about 97%. In one embodiment, the purity of the compound of formula B is more than about 97%.
[0087] [0087] Some embodiments of the present description relate to methods of converting the compound of formula B into the compound of formula C. In certain embodiments, the compound of formula B is treated with an oxidizing agent to provide the compound of formula C in one step single (step 4a):
[0088] [0088] In some embodiments, the oxidation step can be performed on compounds protected at C-7, where C7 is OR11.
[0089] [0089] In certain embodiments, the compound of formula B is contacted with a metal salt or metal complex (eg, salts or complexes of ruthenium, rhodium, vanadium, molybdenum, platinum, iron, iridium, etc.) , in the presence of an oxidizer (eg, molecular oxygen, hydrogen peroxide, tert-butyl hydroperoxide, etc.) to generate the compound of formula C.
[0090] [0090] In one of the modalities, the compound of the formula C can be prepared through Wacker type oxidation. The compound of formula B in a suitable organic solvent (eg, dimethylformamide, dimethylacetamide, 1,2-diethoxyethane, etc.), optionally containing water, is treated with a catalytic amount of a palladium salt (eg ., PdCl2, Pd (Quinox) Cl2, etc.), optionally in the presence of a copper salt (eg, CuCl, CuCl2, Cu (OAc) 2, etc.) or a silver salt (eg ., AgOAc, AgSbF6, etc.) and an oxidizer (eg, molecular oxygen, tert-butyl hydrogen peroxide, etc.) to provide the compound of formula C.
[0091] [0091] In certain embodiments, the compound of formula B is contacted with a metal salt or metal complex (eg, ruthenium, rhodium, vanadium, molybdenum, platinum, iron, iridium salts or complexes, etc.) , in the presence of an oxidizer (eg, molecular oxygen, hydrogen peroxide, tert-butyl hydroperoxide, etc.) to generate the compound of formula C. In one of the embodiments, the compound of formula B is contacted with a bromide-containing salt (eg, LiBr, NaBr, KBr, CsBr, tetraalkylammonium bromide, etc.) and an oxidant (eg, H2O2, Oxone or other peroxysulfate salts, mCPBA, peracetic acid, periodate sodium, periodic acid, etc.) to provide the compound of formula C. Suitable solvents include, but are not limited to, acetone, acetic acid and mixtures thereof. Optionally, the solvents used for bromination can contain water.
[0092] [0092] In one of the embodiments, the compound of formula B is contacted with a hypobromite salt (eg LiOBr, NaOBr, KOBr, tetraalkylammonium hypobromite, Ca (OBr) 2, etc.) or bromite (eg LiO2Br, NaO2Br, KO2Br, tetraalkylammonium hypobromite, Ca (BrO2) 2, etc.) in a suitable organic solvent (eg, acetone, acetic acid, etc.), optionally in presence of water, to generate the compound of formula C. In some embodiments, the present description refers to a method of preparing the compound of formula C as shown in Scheme 1 and Scheme 3. Scheme 3:, where R4, R11 and X are as described here. According to the Scheme
[0093] [0093] In certain embodiments, the description refers to a method of preparing compound C according to Scheme 3A comprising the following steps: 1) contacting the compound of formula B with a halogenating reagent (eg, N-bromosuccinimide, N-iodosuccinimide, etc.) in the presence of an alcohol (eg, methanol, ethanol, isopropanol, etc.) to form an intermediate a vicinal halo ether (eg, bromine or iodine) of formula B '(step 4b); 2) treatment of the vicinal B 'halo (eg, bromine or iodine) ether with a suitable base (eg, DBU, triethyl amine, metal alkoxide bases, etc.) to generate an ether of alkoxy enol B '' through halogen elimination (step 5b); and 3) treatment of the alkoxy enol ether with an acid in the presence of water, the compound of formula C is generated by hydrolysis of the alkoxy enol ether B '' (step 6b). Scheme 3A.
[0094] [0094] In some embodiments, the present description relates to a method of preparing the compound of formula C as shown in Scheme 3B. Scheme 3B:, where R4, R11 and X are as described here.
[0095] [0095] According to Scheme 3B, the process of preparing the compound of the formula C comprises the steps of 4) reaction of the compound of the formula B with a halogenating reagent (eg, bromance or iodine) to provide the compounds of formula B1a (step 4c); 5) reacting the compound of formula B1a with an oxidizing agent to prepare the compound of formula B2a (step 5c); and 6) reacting the compound of the formula B2a with a reducing agent to prepare the compound of the formula C (step 6c; halogenation, e.g., disruption or deiodination, reducing).
[0096] [0096] The present description also relates to the methods described here that apply alternatively to compounds protected in C7, i.e., C7 is replaced by OR11 instead of oxo groups.
[0097] [0097] Some modalities of the present description relate to the manipulation of protection and / or deprotection steps for the ease of purification (eg, by crystallization) of intermediates. In some embodiments, the presence of R7 as COOH protected with methyl ester facilitates the purification of intermediates including the penultimate intermediate. In some embodiments, the retention of the protecting group at C3 facilitates the purification of intermediates including the penultimate compounds.
[0098] [0098] In certain embodiments, the compound of formula B in a suitable organic solvent (eg, THF, acetonitrile (ACN), methyl acetate (AcOMe), dichloromethane (DCM), acetone, etc. or mixtures thereof) optionally containing water and / or optionally containing a buffer salt (eg, potassium phosphate, sodium acetate, sodium bicarbonate, etc.) is treated with a halogenating reagent (halogen donor reagent) to generate the compound of the formula B1, B 'or B1a. In some embodiments, the halogenating reagent is a brooding reagent (bromine donor reagent). In some embodiments, the halogenating reagent is an iodizing reagent (iodine donor reagent).
[0099] [0099] In certain embodiments, the compound of formula B in a suitable organic solvent (eg, THF, acetonitrile (ACN), methyl acetate (AcOMe), dichloromethane (DCM), acetone, etc. or mixtures thereof) optionally containing water and / or optionally containing a buffer salt (eg, potassium phosphate, sodium acetate, sodium bicarbonate, etc.) is treated with an iodizing agent (bromine donor reagent) to generate the compound of the formula B1.
[00100] [00100] In certain embodiments, the solvent is a mixed solvent system. In some embodiments, the solvent is a THF / water, AcOMe / water or ACN / water system. In one embodiment, the solvent is an acetonitrile-water system. In one embodiment, the solvent is a THF-water system. In one embodiment, the solvent is an ethyl acetate-water system. In certain embodiments, the solvents in a mixed solvent system are mixed in a fixed ratio, including, but not limited to, eg, 5: 1, 4.5: 1, 4: 1, 3.5: 1 , 3: 1, 2.5: 1, 2: 1,1,5: 1, or 1: 1 (organic solvent: water). In an additional embodiment, the solvent is a three-solvent system. In one embodiment, the solvent system is acetone-THF-water. In certain embodiments, the solvents in a mixed three-solvent system are mixed in a fixed ratio, including, but not limited to, eg, 1.5: 3: 1, 1: 3: 1.5, or 1: 3: 1, 1.5: 4: 1, 1: 4: 1.5, 1: 4: 1, 1.5: 5: 1, 1: 5: 1.5, 1: 5: 1 ( organic solvent 1: organic solvent 2: water).
[00101] [00101] In some embodiments, the brominated reagent is an electrophilic brominated reagent. In one embodiment, the bromine reagent is bromine. Bromine reagents or bromine donor reagents are commercially available or can be easily synthesized by an expert. Electrophilic brominated reagents include, but are not limited to, phenylselene bromide, phenylselene tribromide, pyridinium tribromide, N-bromophthalimide, N-bromosaccharin, acetyl-hypobromite, N-bromacetamide, tetramethylammonium tribromide, dibromo-hydroidine 1,3-dibromo-5,5-dimethylhydantoin (DBDMH)), tribromoisocyanuric acid, dibromoisocyanuric acid, dibromamine-T (N, N-dibromo-p-toluenesulfonamide), dibromamine-B, N-bromosuccinimide (NBS), dimethylaminopyridine bromide and bromodichloroisocyanuric acid (BDCCA):
[00102] [00102] In certain embodiments, the brooding agent (reagent or donor) is dibromohydantoin (1,3-dibromo-5,5-dimethylhydantoin (DBDMH)), N-bromosuccinimide (NBS), N-bromosaccharin, dibromamin -T or bromodichloroisocyanuric acid (BDCCA). In one of the modalities, the brominated reagent is dibromamine-T. In another embodiment, the brooding reagent is 1,3-dibromo-5,5-dimethylhydantoin (DBDMH). In another embodiment, the brooding reagent is NBS. In one embodiment, NBS is used in combination with NH 4OAc (eg, catalytic, about 0.1 to about 0.2 equivalents (eq.), Including about 0.11, about 0, 12, about 0.13, about 0.14, about 0.15, about 0.16, about 0.17, about 0.18, about 0.19, or about 0.2 eq .). In some embodiments, the stoichiometry of the brominated reagent is about 1.0 to about 2.5 eq., Including about 1.05, about 1.1, about 1.15, about 1.2, about 1.25, about 1.3,
[00103] [00103] In one aspect of the invention, the brominated reagent is optionally used in the presence of a nucleophilic organocatalyst. Nucleophilic organocatalysts include, but are not limited to, dimethylformamide, dimethylacetamide, tetramethylguanidine, dimethylaminopyridine and N-bromoamidine (e.g. + -iso-amarine).
[00104] [00104] In some embodiments, the bromohydration (hydroxy-bromination) reaction of step 4 is carried out at about -50 ° C, about -40 ° C, about -30 ° C, about -20 ° C, about -10 ° C, about -5 ° C, about 0 ° C, about 5 ° C, about 10 oC, about 15 oC or about 20 oC.
[00105] [00105] In certain embodiments, the bromohydration reaction of step 4 is carried out from about 5 ºC to about 10 ºC.
[00106] [00106] In some embodiments, the compound of formula B1, bromohydrin, is obtained in about 50%, in about 55%, in about 60%, in about 65%, about 70%, about 75 %, about 80%, about 85%, about 90%, about 95% or more than 95% yield. In one embodiment, the compound of formula B1 can be purified or used without purification. In one embodiment, compound B1 is obtained in about 63% yield using a methyl acetate-water solvent system.
[00107] [00107] In some embodiments, the compound of formula B1 is treated with a reducing agent (eg, sodium bisulfite, sodium thiosulfate, trimethylphosphite, etc.) to stabilize the compound of formula B1 during processing and isolation. In certain embodiments, the reducing agent is a mild reducing agent. In one embodiment, the reducing agent may be replaced by an additional oxidizer (eg, NaOCl, tert-butyl hydroperoxide, hydrogen peroxide, peracetic acid, sodium periodate, etc.) and, optionally, in the presence of a oxidation catalyst (eg, chromium salts, TEMPO, etc.), to generate the compound of formula B2, without isolating the compound of formula B1. The product can be extracted in a suitable organic solvent (eg, ethyl acetate, methyl and tert-butyl ether, dichloromethane, etc.) and concentrated as necessary for the next reaction steps.
[00108] [00108] In some embodiments, the halogenating reagent is an electrophilic halogenating reagent. In some embodiments, the iodizing reagent is an electrophilic iodizing reagent. In one embodiment, the iodizing reagent is iodine. In another embodiment, the iodizing reagent is N-iodosuccinimide (NIS). Halogenating reagents (eg, brooding or iodizing reagents) are commercially available or can be easily synthesized by an expert. Iodine reagents or iodine donor reagents are commercially available or can be easily synthesized by an expert. Electrophilic iodizing reagents include, but are not limited to, HOI generated in situ from iodine in the presence of water, iodine in the presence of aqueous cerium sulfate, NaIO4 with sodium bisulfite, N-iodosuccinimide, I-Cl, IF, etc., with or without an oxidizing agent (eg, HIO3, HIO4, H5IO6, HClO4, HNO3, H2SO4, trifluoroacetic acid, trichloroacetic acid, etc.).
[00109] [00109] In certain embodiments, the iodizing agent (reagent or donor) is N-iodosuccinimide (NIS). In one embodiment, NIS is used in combination with catalytic or non-catalytic (eg catalytic, about 0.1 to about 0.3 equivalents (eq.), Including about 0, H5IO6, HClO4 or H2SO4 , 11, about 0.12, about 0.13, about 0.14, about 0.15, about 0.16, about 0.17, about 0.18, about 0.19 , about 0.2 eq, about 0.21 eq, about 0.22 eq, about
[00110] [00110] In certain embodiments, the compound of formula B in a suitable organic solvent (eg, THF, acetonitrile (ACN), methyl acetate (AcOMe), dichloromethane (DCM), acetone, methyl ether and tert- butyl (MTBE), dioxane, etc. or their mixtures) optionally containing water and / or optionally containing a buffer salt (eg, potassium phosphate, sodium acetate, sodium bicarbonate, etc.) is treated with a iodizing agent (iodine donor reagent) to generate the compound of formula B1a.
[00111] [00111] In certain embodiments, the solvent is a mixed solvent system. In some embodiments, the solvent is a system of dioxane / water, MTBE / water or ACN / water. In one embodiment, the solvent is a dioxane-water system. In one embodiment, the solvent is an MTBE-water system containing trifluoroacetic acid. In one of the modalities, the solvent is an MTBE-water system. In certain embodiments, the solvents in an MTBE-water system are mixed at a fixed ratio, including, but not limited to, eg, 20: 1, 19: 1, 18: 1, 17: 1, 16 : 1, 15: 1, 14: 1, 13: 1, 12: 1, 11: 1, 10: 1, 9: 1, 8: 1, 7: 1, 6: 1, 5: 1, 4,5 : 1, 4: 1, 3,5: 1, 3: 1, 2,5: 1, 2: 1,1,5: 1, or 1: 1 (organic solvent: water). In certain embodiments, the solvents in a dioxane-water system are mixed in a fixed ratio, including, but not limited to, eg, 10: 1, 9: 1, 8: 1, 7: 1, 6 : 1, 5: 1, 4,5: 1, 4: 1, 3,5: 1, 3: 1, 2,5: 1, 2: 1,1,5: 1, or 1: 1 (organic solvent :Water).
[00112] [00112] In some embodiments, the iodine-hydration (hydroxy-iodation) reaction from step 4 is carried out at about -10 ° C, about -5 ° C, about 0 ° C, about 5 ° C, about 10 ° C, about 15 ° C, about 20 ° C, about 25 ° C, about 30 oC, about 35 oC, about 40 oC, at about 45 ºC or 50 ºC.
[00113] [00113] In certain embodiments, the iodine hydration reaction in step 4 is carried out from about 0 ° C to about 5 ° C.
[00114] [00114] In some embodiments, the compound of the formula B1a (eg, iodohydrin when Hal is iodine) is obtained in about 50%, in about 55%, in about 60%, in about 65% , about 70%, about 75%, about 80%, about 85%, about 90%, about 95% or more than 95% yield. In one embodiment, the compound of formula B1a can be purified or used without purification. In one embodiment, compound B1a is obtained in about 90% yield using a dioxane-water solvent system.
[00115] [00115] In some embodiments, the compound of the formula B1a is treated with a reducing agent (eg, sodium bisulfite, sodium thiosulfate, trimethylphosphite, etc.) to stabilize the compound of the formula B1a during processing and isolation. In certain embodiments, the reducing agent is a mild reducing agent. In one embodiment, the reducing agent may be replaced by an additional oxidizer (eg, NaOCl, tert-butyl hydroperoxide, hydrogen peroxide, peracetic acid, sodium periodate, etc.) and, optionally, in the presence of a oxidation catalyst (eg, ruthenium salts, chromium salts, TEMPO, etc.), to generate the compound of formula B2a, without isolating the compound of formula B1a. The product can be extracted in a suitable organic solvent (eg, ethyl acetate, methyl and tert-butyl ether, dichloromethane, etc.) and concentrated as necessary for the next reaction steps.
[00116] [00116] In certain embodiments, a compound of formula B1 in a suitable organic solvent (eg, methyl and tert-butyl ether, THF, dichloromethane, ethyl acetate, acetonitrile, etc .; or a mixture thereof), optionally containing water, it is contacted with an oxidizer to generate the compound of the formula B2. The product can be extracted in a suitable organic solvent (eg, ethyl acetate, methyl and tert-butyl ether, dichloromethane, etc.) and concentrated as necessary for the next reaction steps.
[00117] [00117] In certain embodiments, a compound of the formula B1a (eg, iodohydrin when Hal is iodine) in a suitable organic solvent (eg, methyl and tert-butyl ether, THF, dichloromethane, acetate of ethyl, acetonitrile, etc., or a mixture thereof), optionally containing water, is contacted with an oxidizer to generate the compound of formula B2a. The product can be extracted in a suitable organic solvent (eg, ethyl acetate, methyl and tert-butyl ether, dichloromethane, etc.) and concentrated as necessary for the next reaction steps.
[00118] [00118] In some embodiments, oxidizing agents include, but are not limited to, chromic acid or chromium salts (eg, Na2Cr2O7), manganese salts (eg, KMnO4), silver salts (eg eg Ag2CO3), iron salts (eg, K2FeO4), cerium salts (eg, Ce (SO4) 2), ruthenium salts (eg, Na2RuO4) and N derivatives -bromine (eg, N-bromosuccinimide, dimethyl dibromohydantoin, N-bromoacetamide, etc.) in stoichiometric excess or in catalytic amounts in combination with a co-oxidant (eg, ammonium nitrate, peroxide hydrogen, tert-butyl hydroperoxide, peracetic acid, NaOCl, Ca (OCl) 2, etc.). In some embodiments, the oxidizing agent can be used in the absence of metal salts. In certain embodiments, the oxidant can be used during the bromination step to directly convert the intermediate compound of formula B1 into a compound of formula B2.
[00119] [00119] In some embodiments, oxidizing agents include, but are not limited to, chromic acid or chromium salts (eg, Na2Cr2O7), manganese salts (eg, KMnO4), silver salts (eg eg Ag2CO3), iron salts (eg, K2FeO4), cerium salts (eg, Ce (SO4) 2), ruthenium salts (eg, Na2RuO4) and N derivatives -halo (eg, N-iodosuccinimide, N-bromosuccinimide, dimethyl dibromohydantoin, N-bromoacetamide, etc.) in stoichiometric excess or in catalytic amounts in combination with a co-oxidant (eg nitrate ammonium, hydrogen peroxide, tert-butyl hydroperoxide, peracetic acid, NaOCl, Ca (OCl) 2, etc.). In some embodiments, the oxidizing agent can be used in the absence of metal salts. In certain embodiments, the oxidant can be employed during the halogenation step, e.g., iodination to directly convert the intermediate compound of formula B1a into a compound of formula B2a.
[00120] [00120] The compound of the formula B2, bromoketone, is obtained in about 80%, in about 85%, in about 90%, in about 95% or more than 95% in yield. In one embodiment, the compound of formula B2 is prepared in quantitative yield, eg, about 100%. In one embodiment, the compound of formula B2 can be purified or used without purification.
[00121] [00121] In some embodiments, the compound of formula B2 in a suitable organic solvent (i.e., acetic acid, methanol, THF, etc.), optionally containing water, is contacted with a reducing agent to generate the compound of formula C.
[00122] [00122] In some embodiments, the compound of the formula B2a, halocetone (eg, bromoketone or iodocetone) is obtained in about 80%, in about 85%, in about 90%, in about 95% or more than 95% yield. In one embodiment, the compound of formula B2a is prepared in quantitative yield, eg, about
[00123] [00123] In some embodiments, the compound of formula B2a in a suitable organic solvent (i.e., acetic acid, methanol, THF, etc.), optionally containing water, is contacted with a reducing agent to generate the compound of formula C.
[00124] [00124] Suitable reducing agents include, but are not limited to, organosilanes (e.g., triethylsilane, hexamethyldisilane, etc.), trialkyl phosphines (e.g., triethyl phosphine, tributyl phosphine, etc.) , triphenyl phosphine, 1,3-dialkyl-2-phenylbenzimidazolines (e.g., 1,3-dimethyl-2-phenylbenzimidazoline), iodide salts (e.g., LiI, NaI, KI, CsI, etc.) ) in the presence of a Lewis acid (eg, BF3), hydroiodic acid, zinc-copper pair, zero valence metals (eg, Li0, Na0, K0, Ca0, Al0, Fe0, Zn0, etc. .) and their corresponding lower valence metal salts (eg, low valence salts of chromium, tin, samarium, manganese, titanium such as CrCl2, SnCl2, SmI2, Mn (OAc) 3, TiCl3, respectively) , aniline or substituted anilines (eg, PhNH2, PhNHMe, etc.) and hydrogen in the presence of a catalyst (eg, palladium, platinum, ruthenium, iron, nickel, etc.). In one embodiment, the breakdown is carried out using Zn (powder) in the presence of acetate salt (eg, AcONa) in a suitable solvent (eg, AcOH) and elevated temperature (eg, reflux) ). The diketone compound of formula C is obtained in about 70%, in about 75%, in about 80%, in about 85%, about 90%, in about 95% or more than 95% of Yield. In one embodiment, the compound of formula C is prepared in quantitative yield, eg, about 100%. In one embodiment, the compound of formula C can be purified or used without purification.
[00125] [00125] One of the embodiments of the present description relates to a method of preparing the compound of formula B2 'comprising the steps shown in Scheme 4.
[00126] [00126] In one embodiment, the present description relates to a method of preparing the compound of formula B2 'comprising the steps shown in Scheme 4A. Scheme 4A: where R4, R11 and X are as described here. The halogenated compound (eg, brominated or iodinated) of the formula B1a (halohydrin, eg, bromohydrin or iodohydrin) in a suitable organic solvent (eg, ethanol, acetic acid, etc. or its mixture) can be treated with a metal catalyst or reagent (eg Raney® Nickel (Raney Ni or Ra-Ni) or zero valence zinc or magnesium) or, optionally, in the presence of hydrogen and a catalyst (eg, Pd, Pt, Rh, Ni and their salts, etc.), to generate a compound of the formula B2 '.
[00127] [00127] The halogenated compound of the formula B1 or B1a (halohydrin or iodohydrin or bromohydrin) in a suitable organic solvent (eg, ethanol, acetic acid, etc. or its mixture) can be treated with a metal catalyst or reagent (eg, Nickel Raney®, Ni Raney, Ra-Ni) or, optionally, in the presence of hydrogen and a catalyst (eg, Pd, Pt, Rh, Ni and their salts , etc.), to generate a compound of the formula B2 or B2a. The brominated compound of the formula B1 (bromohydrin)
[00128] [00128] In one embodiment, the present description relates to a method of preparing the compound of formula C comprising the steps shown in Scheme 5. Scheme 5:
[00129] [00129] The method of preparing the compound of formula C in Scheme 5 comprises the steps of: 4a) reacting a compound of formula B with a borane reagent to prepare a compound of formula B1 '; 5a) reacting the compound of formula B1 'with an oxidizing reagent to provide a compound of formula B2'; and 6a) reaction of the compound of formula B2 'with oxidizing reagent to prepare the compound of formula C.
[00130] [00130] In certain embodiments of the present description, the compound of formula B in an aprotic organic solvent (eg, THF, dichloromethane, 1,2-diethoxyethane, heptane, etc.) is contacted with a borane reagent to form a compound of the formula B1 '. After completion of the reaction, the mixture is contacted with an oxidizer to form a compound of the formula B2 'carrying an alcohol in C-11. The mixture can be processed by solvent extraction in a suitable organic solvent (eg, ethyl acetate, dichloromethane, methyl and tert-butyl ether, etc.), and the resulting solution is concentrated as needed or exchanged of buffers for a more appropriate solvent. A solution of the compound of formula B2 'is then contacted with an oxidizer to generate the compound of formula C.
[00131] [00131] Borane reagents ("B") include, but are not limited to, BH3 and its complexes (eg, BH3-THF, BH3-DMS, BH3-NH3, etc.), monoalkylboranes of the alkylBH2 structure (eg, mono-texyl borane, mono-isopinocanfeyl borane, etc.), dialkylboranes of the dialkylBH structure (eg, disiamylborane, ditexylborane, dicyclopentylborane, 9-BBN, etc.), mono-chloroborane and its complexes (eg, ClBH2-THF, ClBH2-DMS, etc.), dichloroborane and its complexes (eg, Cl2BH-THF, Cl2BH-DMS, etc.) and catecholborane.
[00132] [00132] Oxidizing agents, for oxidizing the compound of formula B1 ', include, but are not limited to, hydrogen peroxide, tert-butyl hydroperoxide, Oxone and molecular oxygen.
[00133] [00133] Oxidizing agents, for oxidizing the compound of formula B2 ', include, but are not limited to, chromic acid or chromium salts (eg, Na2Cr2O7), manganese salts (eg, KMnO4) , silver salts (eg, Ag2CO3), iron salts (eg, K2FeO4), cerium salts (eg, Ce (SO4) 2), ruthenium salts (eg, Na2RuO4), etc. in stoichiometric excess or in catalytic amounts in combination with a co-oxidant (eg, ammonium nitrate, hydrogen peroxide, tert-butyl hydroperoxide, peracetic acid, NaOCl, Ca (OCl) 2, NaIO4, H5IO6, etc. .). In some embodiments, the oxidizing agent can be used in the absence of metal salts. In some embodiments, an oxidation catalyst, for example TEMPO, can be employed.
[00134] [00134] In some embodiments, the present description relates to a method of preparing the compound of the formula C2 according to the process of Scheme 5, wherein R4, R11 and X are as described here. Scheme 6:
[00135] [00135] According to Scheme 6, the process of preparing the compound of formula C2 comprises the steps of: 7) deprotecting the compound of formula C to provide the compound of formula C1 or a pharmaceutically acceptable salt thereof; and 8) reacting the compound of formula C1 with a reducing reagent to prepare a compound of formula C2.
[00136] [00136] In some embodiments, the reducing reagents in step 8 include but are not limited to NaBH4, NaCNBH3, LiBH4, (i-Bu2AlH) 2, L-selectride, K-selectride. In one embodiment, the reducing reagent is NaBH4 or LiBH4. Reducing agents can be used in combination with added reagents such as, but not limited to, CeCl3, CoCl2 and other Lewis acids, which can be used to enhance a ketone reduction, including, but not limited to, salts of zinc (II), calcium (II), magnesium (II), aluminum (III).
[00137] [00137] In some embodiments, at least 2 molar equivalents of the reducing agent are used. In some embodiments, about 2 equivalents to about 3 equivalents of the reducing agent are used. In another embodiment, the molar ratio (or molar equivalent) is about 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8 , 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4 , 1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0 equivalents.
[00138] [00138] The reduction is carried out in a suitable solvent. In one embodiment, the reduction is carried out in water. In one embodiment, the reduction is carried out in an alcoholic solvent. In one embodiment, the alcoholic solvent is methanol. In one embodiment, the alcoholic solvent is isopropanol. In one embodiment, the alcoholic solvent is ethanol. In one embodiment, the reduction is carried out in the presence of a base. In one embodiment, the base is sodium hydroxide. In one embodiment, the base is sodium hydroxide and the solvent is water.
[00139] [00139] In one embodiment, the reduction in step 8 is carried out in a period of time between about 2 hours and about 50 hours, e.g., about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 25 hours, about 30 hours, about 35 hours, about 40 hours, about 45 hours or about 50 hours.
[00140] [00140] In one embodiment, the reduction in step 8 is carried out at a temperature of between about 15 oC and between about 100 oC, as well as any intermediate temperature rise, eg, at about 20oC, at about 25 oC, about 30 oC, about 40 oC, about 50 oC, about 60 oC, about 70 oC, about 80 oC, about 90 oC or about 100 oC.
[00141] [00141] In one embodiment, the reduction is carried out at a temperature of between about -10 ° C and about 15 ° C, e.g., about -10 ° C, about -5 ° C, about 0 ° C, about 3 ° C, about 5 ° C, about 7 ° C, about 10 ° C or about 15 ° C, as well as any intermediate temperature increase. In one embodiment, the reduction is carried out at about 5 ºC.
[00142] [00142] Deprotection reagents for step 7 depend on the protective groups chosen and can be selected from standard reagents known to those skilled in the art (including reagents discussed here).
[00143] [00143] In certain embodiments, the Scheme 1 process provides a compound of formula II:
[00144] [00144] In certain embodiments, the Scheme 1 process provides a compound of formula III:
[00145] [00145] In some embodiments, the present description relates to a method of preparing a compound of the formula IIIa: IIIa or a salt, solvate or conjugate of the amino acid, sulfate or glucuronide or pharmaceutically acceptable prodrug.
[00146] [00146] In some embodiments, the present description relates to a method of preparing a compound of formula IIIb:
[00147] [00147] In certain embodiments, the Scheme 1 process provides a compound of the formula 100: 100 or a salt, solvate or conjugate of amino acid, sulfate or glucuronide or pharmaceutically acceptable prodrug.
[00148] [00148] In one aspect, the present description relates to a method of preparing a compound of the formula Ia: Ia, or a pharmaceutically acceptable salt, solvate or amino acid, sulfate or glucuronide conjugate thereof, wherein: the bond dashed (----) represents double or single bond, where a double bond exists between C12-C13 or C13-C14 or C13-C17; R2 and R3 are each independently H, OH, OSO3H, OCOCH3, OPO3H2, halogen or alkyl optionally substituted by one or more halogens or OH, or R2 and R3 taken together with the carbon atom to which they are attached form a carbonyl; R4 is H, halogen, alkyl optionally substituted by one or more halogens or OH, alkenyl or alkynyl; R5 and R6 are each independently H, OH, OSO3H, OCOCH3, OPO3H2, halogen or alkyl optionally substituted by one or more halogens or OH, or R5 and R6 taken together with the carbon atom to which they are attached form a carbonyl; R7 is OH, OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, CO2H, C (O) NHOH, NH (CH2) 2SO3H, NHCH2CO2H or tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazol 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxy-isoxazolyl, 3-hydroxy-isothiazolyl, pyrimidine, 3,5-difluoro-4-hydroxyphenyl or 2,4-difluoro- 3- optionally substituted hydroxyphenyl; R8, R9 and R10 are each independently H, OH, halogen or alkyl optionally substituted by one or more halogens or OH, or R8 and R9 taken together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring with 3 to 6 members comprising 1 or 2 heteroatoms selected from N, O and S, or R9 and R10 taken together with the carbon atoms to which they are attached form a 3 to 6 membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O and S; m is 0, 1 or 2; n is 0 or 1; and p is 0 or 1.
[00149] [00149] In certain respects, the compound of formula Ia is a compound of formula Ib:
[00150] [00150] In some embodiments, a compound of formula Ia or Ib is the compound of formula D5 D5 or its salt, hydrate, solvate or conjugate of amino acid, sulfate or glucuronide or pharmaceutically acceptable prodrug, where: R7 is OH, OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, CO2H, C (O) NHOH, NH (CH2) 2SO3H, NHCH2CO2H or tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1, 2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxy-isoxazolyl, 3-hydroxy-isothiazolyl, pyrimidine, 3,5-difluoro-4-hydroxyphenyl or optionally substituted 2,4-difluoro-3-hydroxyphenyl; R8, R9 and R10 are each independently H, OH, halogen or alkyl optionally substituted by one or more halogens or OH, or R8 and R9 taken together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring with 3 to 6 members comprising 1 or 2 heteroatoms selected from N, O and S, or R9 and R10 taken together with the carbon atoms to which they are attached form a 3 to 6 membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O and S; m is 0, 1 or 2; n is 0 or 1; and p is 0 or 1.
[00151] [00151] In some embodiments, the present description relates to a method of preparing the compound of formula Ia (or Ib) having a structure of formula D5; the method comprising steps 1-8 as shown in Scheme 7. The compound of formula Ia (or Ib) can be prepared according to a synthetic scheme analogous to Scheme
[00152] [00152] According to scheme 7, the method of preparing the compound of formula Ia comprises the steps of a) protecting a compound of formula D to prepare a compound of formula D1; b) reacting the compound of the formula D1 with an activating reagent to convert the C-12 alcohol into a labile group, thus preparing a compound of the formula D2; c) reacting the compound of the formula D2 with a base to prepare the compound of the formula D3; d) reacting a compound of the formula D3 with a hydrogen source in the presence of a hydrogenation catalyst to generate a compound of the formula D4; and e) reacting a compound of formula D4 with deprotecting reagents and a reducing agent to prepare a compound of formula D5,
[00153] [00153] The activating agent includes, but is not limited to, ethanesulfonyl chloride, trifluoromethanesulfonic anhydride, nonafluorobutanesulfonyl chloride, thionyl chloride, SO3-pyridine, phosphoryl chloride, phosphoryl bromide, etc., in the presence of a suitable base (eg, pyridine, triethylamine, imidazole, etc.) to generate the intermediate compound of the formula D2, where LG is a labile group (eg, sulfonate derivative, phosphonyl derivative, halide, etc.).
[00154] [00154] The basis for rearranging the compound of formula D2 may include, but is not limited to, acetate salts (e.g., LiOAc, NaOAc, KOAc, CsOAc), DBU, metal alkoxides (e.g. , potassium tert-butoxide, sodium amylate, etc.), imidazole, pyridine, etc., in a high-boiling solvent (eg, HMPA, DMPU, DMI, DMSO, DMF, DMA, NMP, etc.) or appropriate low boiling solvent (eg DCM, MTBE, THF, etc.). The optimum temperature for rearranging the compound of formula D2 can vary from about –20 ° C to about 120 ° C, depending on the nature of the labile group that is generated. Alternatively, the activating agent, base and temperature can be chosen to promote the direct conversion of the compound of formula D1 into the compound of formula D3 in a single step without isolation of the compound of formula D2.
[00155] [00155] The hydrogen source and catalyst for the hydrogenation of the compound of the formula D3 may include, but are not limited to, combinations of hydrogen, formic acid, ammonium formate, hydrazine, etc., in the presence of catalytic palladium, platinum , nickel, etc. on solid support (eg, carbon, silica gel, alumina, SMOPEX® (polyolefin fiber grafted with mercaptoethylacrylate), diatomaceous earth, etc.), optionally in a form of salt or organic solvate.
[00156] [00156] Deprotection reagents can be chosen from standard reagents known to those skilled in the art and are dependent on the chosen protecting groups. For example, for a C-3 acyl or carbonate protecting group and side chain acid ester protecting group, a metal hydroxide (eg LiOH, NaOH, KOH, CsOH, etc.) can be removed to removing the C-3 acyl function while removing the side chain ester functionality. In the subsequent step, the intermediate can be reduced with a reducing agent which can include, but is not limited to, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, etc., optionally in the presence of sodium hydroxide. aqueous sodium. Alternatively, the reduction step can be carried out prior to deprotection, and the reducing agents may include, in addition to the aforementioned borohydride reagents, borane complexes and their mono- and disubstituted derivatives (eg, BH3 THF, texylborane , disiamylborane, catecholborane, etc.), followed by treatment with an appropriate deprotection reagent to generate the compound of formula D5.
[00157] [00157] In one embodiment, the compound of formula Ia is compound D3 or its unprotected analog.
[00158] [00158] In one embodiment, the compound of formula Ia is compound 44.
[00159] [00159] In one of the embodiments, the compound of formula 44 is compound 44a.
[00160] [00160] In one embodiment, the compound of formula Ia is compound D5 or a pharmaceutically acceptable salt, solvate or amino acid, sulfate or glucuronide conjugate thereof.
[00161] [00161] In one of the modality, the compound of the formula Ib is the compound 45.
[00162] [00162] In some respects, the present description refers to a method of preparing the compound of formula I, the method comprising the steps as shown in Scheme 8. Scheme 8:
[00163] [00163] In one embodiment, the compound of formula E is prepared from the compound of formula A in 7 steps based on the procedure previously disclosed in Pellicciari et al., J. Med Chem. 59 (2016) 9201-9214.
[00164] [00164] In some embodiments, a compound of formula E undergoes 12-keto transposition to provide a compound of formula F1. In one embodiment, a compound of formula F1 is prepared according to Scheme 9. Scheme 9:,
[00165] [00165] According to Scheme 9, the process of preparing a compound of formula F1 comprises the steps of: a) reacting the compound of formula E with a nitrating reagent to prepare a compound of formula E1; b) reducing the compound of the formula E1 in acidic media to provide a compound of the formula E2; c) conversion of the compound of formula E2 into the compound of formula F1 with oxidative and reducing methods.
[00166] [00166] In some respects, a compound of the formula E1 is prepared by reaction with nitrating agents (eg, n-butyl nitrate, nitrocyclohexadienones, thionyl nitrate, etc.) in the presence of an acid (p eg HNO3, acetic acid, HF, etc.) or a base (eg, t-butoxide, etc.). In some embodiments, the reaction is carried out at about 25 ° C, about 35 ° C, about 45 ° C or about 55 ° C.
[00167] [00167] Some modalities of the present description relate to methods of converting a compound of the formula E1 into E2 by using reducing agents (eg, NaBH4, NaCNBH3, LiBH4, i-Bu2AlH, etc.) in basic media or acids. In some embodiments, the reaction is carried out at about 0 ° C, about 25 ° C, about 35 ° C, about 45 ° C or about 55 ° C or up to the reflux temperature of an appropriate solvent ( eg methylene chloride, methanol, etc.).
[00168] [00168] In certain embodiments, a compound of the formula E2 is converted to the compound of the formula F1 by Nef reaction using reagents that include, but are not limited to, oxone, TiCl3, DBU, KMnO4 / KOH and KH / Me3SiCl. Alternatively, the compound of formula E1 can be converted to nitroalkene of formula E2 by reduction with reducing agents (eg, NaBH4, NaCNBH3, LiBH4, etc.) in the presence of cerium trichloride (Stork G. et al. Tet. Lett. 25 (1984) 5367). The compound of formula F1 is converted to the compound of formula C2 as shown in Scheme 8 and described here (through deprotection and reduction, also shown in Schemes 1-6 described here).
[00169] [00169] In one of the embodiments, a compound of the formula F1 is prepared according to Scheme 10. Scheme 10: where R4, R11 and X are as described here. According to Scheme 10, the process of preparing a compound of formula F1 comprises the following steps: a) treatment of the compound of formula E with a hydrazide reagent to give a compound of formula E1 '; b) reacting a compound of the formula E1 'with an alkyl lithium reagent to give vinylsilane of the formula E2'; c) oxidizing a compound of the formula E2 'to an epoxide of the formula E3'; d) reduction of the compound of the formula E3 'in β-silyl alcohol of the formula E4'; e) treating the compound of formula E4 'with oxidizing agents and operating under hydrolytic desilylation conditions to form the compound of formula F1.
[00170] [00170] In some respects, a compound of the formula E1 'is prepared from compound E by reaction with hydrazide reagents (eg, benzenesulfonyl hydrazide, nicotinic hydrazide,
[00171] [00171] Some embodiments disclosed in the present application relate to methods of converting a compound of the formula E1 'to E2' using alkyl lithium reagents (e.g., n-butyllithium, lithium diisopropyl amide, ethylene , t-butylithium, etc.), a base (e.g., trimethylamine, tetramethylenediamine, pyridine, diethylamine, lutidine, etc.) and silylating agents (e.g., chlorotrimethylsilane, methyl dichlorosilane, methyldiethoxysilane, methyldimethoxysilane, trichlorosilane, trichlorosilane , trimethoxysilane, etc.) in pure conditions or in an appropriate solvent (eg, tetrahydrofuran, methyl tetrahydrofuran, diethyl ether) at low temperature (about -78 ° C, about -65 ° C, about -55 ° C, about -45 ° C, about -35 ° C, about -25 ° C, about -15 ° C or about 0 ° C).
[00172] [00172] In certain embodiments, a compound of the formula E2 'is converted to a compound of the formula E3' using oxidizing reagents including but not limited to m-chloroperbenzoic acid, peracetic acid, H2O2, oxone, tert-butyl hydroperoxide, etc. . in an appropriate solvent (eg, dichloromethane, ethyl acetate, acetonitrile, acetone, water / acetonitrile, toluene, etc.).
[00173] [00173] In some embodiments, an E2 'compound is reacted with reducing agents (e.g., LiAlH4, LiBH4, NaBH4, Na (BH3CN), lithium and aluminum hexahydride, etc.) to provide the compound of the formula E4 '.
[00174] [00174] In some embodiments, the oxidation of β-silyl alcohol of the formula E4 'with chromium reagents (eg, sodium dichromate, potassium dichromate, chromium trioxide) in strongly acidic media with in situ generation chromic acid generates the compound of the formula F1. The compound of formula F1 is converted to the compound of formula C2 as shown in Scheme 8 and described here (through deprotection and reduction, also shown in Schemes 1-6 described here).
[00175] [00175] In one embodiment, a compound of the formula F1 is prepared according to Scheme 11. Scheme 11:, where R4, R11 and X are as described here.
[00176] [00176] According to Scheme 11, the method for preparing a compound of formula F1 is based on the following steps: a) treatment of the compound of formula E with thiolation agents to form a compound of formula E3 ''; b) reducing a compound of the formula E3 '' to a compound of the formula E4 ''; c) conversion of E4 '' to the corresponding C12 acetate and hydrolysis to give the compound of formula F1; In certain embodiments, a compound of the formula E3 '' is prepared from a compound of the formula E by reaction with thiolation agents including, but not limited to, 1,3-propanedithiol, di-p-toluenesulfonate in the presence of a base (eg, potassium acetate, sodium acetate, sodium hydride, t-butoxide, etc.).
[00177] [00177] In another embodiment, a compound of the formula E3 '' is reduced by means of reducing agents including, but not limited to, LiAlH4, NaBH4, NaCNBH3, LiBH4, i-Bu2AlH, etc.) to give a compound of the formula E4 ''. In some embodiments, the reaction is carried out at about 0 ° C, about 25 ° C, about 35 ° C, about 45 ° C or about 55 ° C or up to the reflux temperature of an appropriate solvent ( eg methylene chloride, methanol, etc.).
[00178] [00178] In some respects, a compound of the formula E4 '' is converted into a compound of the formula F1 by means of hydrolysis with reducing agents (eg, Ca / NH3, Li / NH3, Na / NH3, Li / EDA , etc.). The compound of formula F1 is converted to the compound of formula C2 as shown in Scheme 8 and described here (through deprotection and reduction, also shown in Schemes 1-6 described here).
[00179] [00179] In some embodiments, a compound of the formula E4 '' 'on transformation of 11.12-epoxidation / opening to provide a compound of the formula H. In one of the embodiments, a compound of the formula H is prepared according to Scheme 12. Scheme 12:
[00180] [00180] According to Scheme 12, the process of preparing a compound of the formula C2 comprises the following steps: a) bromination of the compound of the formula E to prepare a compound of the formula E4 '' '; b) reducing a compound of the formula E4 '' 'in basic media to provide a compound of the formula F2; c) opening a reducing epoxide ring to form a compound of the formula H; d) deprotection to provide the compound of the formula C2.
[00181] [00181] In one of the embodiments, the compound of the formula F2 is prepared from the compound of the formula E in 3 steps based on the procedure previously disclosed in Pellicciari et al., J. Med Chem. 59 (2016) 9201-9214. Alternatively, a compound of the formula F2 is prepared using oxidizing reagents (m-chloroperbenzoic acid, peracetic acid, H2O2, oxone, tert-butyl hydroperoxide, etc.) in an appropriate solvent (eg, dichloromethane, ethyl acetate, acetonitrile, acetone, water / acetonitrile, toluene, etc.). The compound of formula H is converted to the compound of formula C2 as shown and described here.
[00182] [00182] In certain embodiments, a compound of the formula H is prepared from a compound of the formula F2 by hydrogenolysis in a suitable organic solvent (eg, ethanol, acetic acid, tetrahydrofuran, pyridine, water, etc.). or its mixture) can be treated with a metal catalyst or reagent (eg, Raney® Nickel, Raney Ni, Ra-Ni)) or, optionally, in the presence of hydrogen and a catalyst (eg , Pd, Pt, Rh, Ni and their salts, etc.). In certain embodiments, the metal reagent can be used alone in stoichiometric amounts or in catalytic amounts in the presence of hydrogen. In other embodiments, the reaction can be conducted under hydrogenation by catalytic transfer using hydrogen donors (1,3-cyclohexadiene, 1,7-octadiene, cyclohexene, ammonium formate, potassium formate, formic acid, ethanol, i-propanol, etc.). In one embodiment, hydrogenation and hydrogenation by catalytic transfer are performed under continuous flow conditions.
[00183] [00183] In other embodiments, the compound of the formula F2 is reacted with dissolving metals (eg, lithium, sodium, potassium, etc.) in an appropriate solvent (eg, ethylenediamine, ammonia, ethanol, methanol, etc.) at room temperature, about 30 ° C, about 40 ° C or about 50 ° C or with metal hydrides (eg, NaBH4, NaCNBH3, LiBH4, NaH, tributyltin hydride, i-Bu2AlH ) coupled with Lewis acids (eg, AlBr3, AlCl3, BCl3, BF3, C4H8BF3O4, CH4BF3O, BF3 · C2H6O, C4H8BF3O, SnCl4, AlCl12Ti3, Cl4Ti, Bi (OTf) 3, MgClO4, Zn, etc. organic solvents (dichloromethane, tetrahydrofuran, diethyl ether, dimethoxyethane, dimethoxymethane, methanol, ethanol, water, etc. or mixtures).
[00184] [00184] In some embodiments, a compound of formula E undergoes a transformation of 9.11-epoxidation / opening to provide a compound of formula C2. In one embodiment, a compound of formula C2 is prepared according to Scheme 13.
[00185] [00185] According to Scheme 13, the process of preparing a compound of formula C2 comprises the following steps: a) oxidizing the compound of formula E to prepare a compound of formula E5; b) reducing a compound of formula E5 to a compound of formula E6; c) epoxidation of a compound of the formula E6 to a compound of the formula F3; d) reducing a compound of the formula F3 to a compound of the formula H; e) deprotection of a compound of formula H to prepare a compound of formula C2.
[00186] [00186] In one embodiment, the compound of formula E5 is prepared from a compound of formula E based on the procedure previously disclosed by Fieser et al., J. Am. Chem. Soc. 73 (1951) 4133.
[00187] [00187] In certain embodiments, a compound of the formula E5 is reacted with reducing reagents (eg, NaBH4, NaCNBH3, LiBH4, NaH, tributyltin hydride, i-Bu2AlH, t-butylaminoborane, triethylsilane)
[00188] [00188] In some embodiments, the compound of the formula E6 is synthesized according to the procedure previously disclosed in Hicks et al., J. Biol. Chem. (1945) 633-640.
[00189] [00189] In other embodiments, the reaction of the compound of the formula E6 is oxidized by means of peroxides (eg, m-chloroperbenzoic acid, peracetic acid, H2O2, oxone, t-butyl hydroperoxide, t-butylperoxybenzoate, dioxide manganese, etc.) in an appropriate solvent (eg, dichloromethane, ethyl acetate, acetonitrile, acetone, water / acetonitrile, toluene, etc.).
[00190] [00190] In one of the modalities, the epoxide of the formula F3 is subjected to hydrogenolysis in a suitable organic solvent (eg, ethanol, acetic acid, tetrahydrofuran, pyridine, water, etc. or its mixture). with a metal catalyst or reagent (eg, Nickel Raney®, Ni Raney, Ra-Ni)) or, optionally, in the presence of hydrogen and a catalyst (eg, Pd, Pt, Rh, Ni and salts, etc.). In certain embodiments, the metal reagents can be used alone in stoichiometric amounts or in catalytic amounts in the presence of hydrogen. In other embodiments, the reaction can be conducted under hydrogenation by catalytic transfer using hydrogen donors (eg, 1,3-cyclohexadiene, 1,7-
[00191] [00191] In other embodiments, the compound of the formula F3 is reacted with dissolving metals (lithium, sodium, potassium, etc.) in an appropriate solvent (ethylenediamine, ammonia, ethanol, methanol, etc.) at room temperature, about 30 ° C, about 40 ° C or about 50 ° C or with metal hydrides (e.g., NaBH4, NaCNBH3, LiBH4, NaH, tributyltin hydride, (i-Bu2AlH) 2) coupled with Lewis acids ( e.g., AlBr3, AlCl3, BCl3, BF3, C4H8BF3O4, CH4BF3O, BF3 · C2H6O, C4H8BF3O, SnCl4, AlCl12Ti3, TiCl4, Bi (OTf) 3, MgClO4, ZnI, etc.) in organic solvents (dichloromethane) hydrofuran, diethyl ether, dimethoxyethane, dimethoxyethane, methanol, ethanol, water, etc. or mixtures).
[00192] [00192] In some respects, the present description relates to a method of preparing the compound of formula F1 as shown in Scheme 14. Scheme 14:
[00193] [00193] According to Scheme 14, the compound synthesis of formula F1 comprises the steps of a) reacting a compound of formula E6 with a brominated reagent to provide a compound of formula E7; b) reacting the compound of the formula E7 with an oxidizing agent to prepare a compound of the formula E8; c) reaction of the compound of formula E8 with a reducing agent to prepare a compound of formula F1 (dehalogenation or reducing debromation);
[00194] [00194] In one of the embodiments, the compound of the formula F1 is prepared according to Scheme 14 using the methods shown in Schemes 3-5 and described here. In one embodiment, the Formula F1 compound is prepared in 3 steps from the Formula E6 compound following the procedure previously reported in Hicks et al., J. Biol. Chem. (1946) 641-644. The compound of formula F1 is converted to the compound of formula C2 as shown in Scheme 12 and described here.
[00195] [00195] In some embodiments, the starting material of formula E or E6 in Schemes 9-14 can be replaced by a compound having a ketone (or oxo group) instead of an OR 11 group in C7 as shown, for example, in Schemes 1-6.
[00196] [00196] In some embodiments, methods of preparing the compounds of formulas F1, F2 and F3 may use procedures known in the art including those disclosed in Hassner, et al., J. Org. Chem. 33 (1968), 1733-1739; Paquette, et al., J. Org. Chem. 45 (1980), 3017; Fristad, et al., J. Org. Chem. 45 (1980), 3028; Marshall, et al., J. Org. Chem. 34 (1969), 4188; and Constantin, et al., J. Am. Chem. Soc. 74 (1952), 3908.
[00197] [00197] In certain embodiments, this description refers to a method of preparing the compound of formula I according to the following biocatalytic processes: where R11 is a protecting group, X is,
[00198] [00198] In one of the modalities, the biocatalytic method provides the compound 100 (from obeticolic acid (OCA)):.
[00199] [00199] A wide variety of microbial organisms is able to catabolize xenobiotics. Organisms that are capable of biooxidation can be extracted from mesophiles or extremophiles, including but not limited to prokaryotes and eukaryotes of the wild type or genetically modified. In some cases, the organisms are classified in the same genus but differ in type strain based on the source of isolation or growing conditions. Examples of microbial organisms include, but are not limited to, the following: bacteria, yeasts, fungi, algae and molds. Fermentation can take place during any phase of the microbial life cycle including the lag phase, exponential phase or stationary phase, using aerobic and anaerobic conditions. Suitable organisms include, but are not limited to, Streptomyces diastatochromogenes, Streptomyces griseus, Streptomyces sp, Streptomyces rimosus, Streptomyces albidoflavus, Streptomyces avermitilis, Streptomyces fradiae, Streptomyces griseolus, Streptomyces griseolus, Streptomyces, Streptomyces, Streptomyces Rhizopus stolonifer, Absidia coerulea, Beauveria bassiana, Cunninghamella elegans, Rhizopus oryzae, Gliocladium roseum, Verticillium lecanii, Fusarium oxysporum, Curvularia lunata,
[00200] [00200] In one of the modalities, the microorganisms are grown in conical centrifuge tubes of about 50 ml containing about 10 ml of the required culture medium. In some embodiments, the growth media may be Nutrient Broth (eg, 15 g Peptone, 3 g Yeast Extract, 6 g NaCl, 1 g Glucose); Gym Streptomyces Media (eg, 4 g of Glucose, 4 g of Yeast Extract, 10 g of Malt Extract); Malt extract peptone (eg, 30 g Malt extract, 3 g Peptone); or Potato dextrose media (eg, 30 g of potato extract, 10 g of glucose). After inoculation of media from microbial glycerol stocks, cultures are incubated for 7 days at about 28 ° C with shaking. After that, about 1 mL of each microbial culture was transferred to the wells of plates with 96 deep wells. The plates are incubated at about 28 ºC with shaking for 48 hours before adding OCA dissolved in DMSO (to a final concentration of about 2 mg / ml). The plates are incubated for an additional 36 hours before adding about 1 ml of 100% acetonitrile, after which the plates are incubated at room temperature before centrifugation at 9,000 × g for 15 mins. About 200 μL of supernatant is transferred to a clean 96-well plate before analysis by UHPLC (ultra high performance liquid chromatography). In one embodiment, the biotransformation process may use the method (s) reported in Ishida, et al., Chem. Pharm. Bull. 46 (1998), 12-16 for the natural product 3α, 7α, 11α-trihydroxy-5β-colan-24-oico (11α-OH CDCA).
[00201] [00201] In one of the embodiments, the present description provides compounds of the formula I I, Ia, Ib, I-9, II, III, IIIa, IIIb, C2 or D5, where R4 is in the α position. In one embodiment, the present description provides compounds of the formula I, Ia, Ib, I-9, II, III, IIIa, IIIb, C2 or D5, wherein R4 is C1-C4 alkyl. In one embodiment, the present description provides compounds of the formula I, Ia, Ib, I-9, II, III, IIIa, IIIb, C2 or D5, wherein R4 is methyl, ethyl or propyl. In one embodiment, R4 is ethyl. In another modality, R4 is alpha-ethyl. In one embodiment, the present description provides compounds of the formula I, Ia, Ib, I-9, II, III, IIIa, IIIb, C2 or D5, where R4 is H or halogen. In one embodiment, the present description provides compounds of the formula I, Ia, Ib, I-9, II, III, IIIa, IIIb, C2 or D5, wherein R4 is C1-C6 alkyl optionally substituted by one or more halogens or OH. In one embodiment, the present description provides compounds of the formula I, Ia, Ib, I-9, II, III, IIIa, IIIb, C2 or D5, wherein R4 is C2-C6 alkenyl or C2-C6 alkynyl.
[00202] [00202] In one embodiment, the present description provides compounds of the formula I, Ia, Ib, I-9, II, III, IIIa, IIIb, C2 or D5, where R7 is OH, OSO3H, SO3H, OSO2NH2, SO2NH2 , OPO3H2, PO3H2, CO2H or C (O) NHOH.
[00203] [00203] In one embodiment, this description provides compounds of the formula I, Ia, Ib, I-9, II, III, IIIa, IIIb, C2 or D5, where R7 is OH, OSO3H, OSO2NH2, OPO3H2 or CO2H .
[00204] [00204] In one embodiment, the present description provides compounds of the formula I, Ia, Ib, I-9, II, III, IIIa, IIIb, C2 or D5, where R7 is OH.
[00205] [00205] In one embodiment, the present description provides compounds of the formula I, Ia, Ib, I-9, II, III, IIIa, IIIb, C2 or D5, where R7 is CO2H.
[00206] [00206] In one embodiment, the present description provides compounds of the formula I, Ia, Ib, I-9, II, III, IIIa, IIIb, C2 or D5, where R7 is OSO3H.
[00207] [00207] In one embodiment, the present description provides compounds of the formula I, Ia, Ib, I-9, II, III, IIIa, IIIb, C2 or D5, where R7 is SO3H.
[00208] [00208] In one embodiment, the present description provides compounds of the formula I, Ia, Ib, I-9, II, III, IIIa, IIIb, C2 or D5, where R7 is OSO2NH2 or SO2NH2.
[00209] [00209] In one embodiment, the present description provides compounds of the formula I, Ia, Ib, I-9, II, III, IIIa, IIIb, C2 or D5, where R7 is OPO3H2, PO3H2 or C (O) NHOH .
[00210] [00210] In one embodiment, the present description provides compounds of the formula I, Ia, Ib, I-9, II, III, IIIa, IIIb, C2 or D5, wherein R7 is tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo -1,2,4-oxadiazolyl, 5-oxo- 1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxy-isoxazolyl, 3-hydroxy-isothiazolyl or 2,4-difluoro-3-hydroxyphenyl .
[00211] [00211] In one embodiment, the present description provides compounds of the formula I, Ia, Ib, I-9, II, III, IIIa, IIIb, C2 or D5, where R7 is OH, OSO3H, OSO2NH2, OPO3H2, CO2H , tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxy-isoxazolyl, 3-hydroxy-isothiazolyl or 2,4-difluoro-3-hydroxyphenyl.
[00212] [00212] In one embodiment, the present description provides compounds of formula I, where R5 is OSO3H, OCOCH3 or OPO3H2.
[00213] [00213] In one embodiment, the present description provides compounds of formula I, in which R5 and R6 taken together with the carbon atom to which they are attached form a carbonyl.
[00214] [00214] In one embodiment, the present description provides compounds of the formula I, Ia, Ib, I-9, II, III, C2 or D5, where m is 0.
[00215] [00215] In one embodiment, the present description provides compounds of the formula I, Ia, Ib, I-9, II, III, C2 or D5, where m is 1.
[00216] [00216] In one embodiment, the present description provides compounds of formula I, Ia, Ib, I-9, II, III, C2 or D5, where m is 2.
[00217] [00217] In one embodiment, the present description provides compounds of the formula I, Ia, Ib, I-9, II, III, C2 or D5, where n is 1.
[00218] [00218] In one embodiment, the present description provides compounds of I, Ia, Ib, I-9, II, III, C2 or D5, where p is 0.
[00219] [00219] In one of the embodiments, the present description provides compounds of the formula I, Ia, Ib, I-9, II, C2 or D5, where R1 is in the β position (beta position).
[00220] [00220] In one embodiment, the compound prepared by the methods of the present description is compound 100:
[00221] [00221] In one aspect, the method of the present application produces a substantially pure compound of formula I or a pharmaceutically acceptable salt thereof. The term "purity" as used herein refers to the amount of the compound of formula I based on analytical methods commonly used in the art (eg, HPLC). In some embodiments, the compound of formula I has a purity of more than about 90%. In one embodiment, the compound of formula I has a purity of more than about 95%. In one embodiment, the compound of formula I has a purity of more than about 98%. For example, the purity of the synthesized compound of Formula I is about 96.0%, about 97.0%, about 98.0%, about 99.0% or about 100%. For example, the purity of the synthesized compound of formula I is 98.5%, 99.0% or 99.5%. In one embodiment, purity is determined by HPLC.
[00222] [00222] The present application provides methods for the synthesis of highly pure compounds of formula I that are safe and that can produce compounds of formula I on a large scale. In one embodiment, the method of the present application produces compounds of formula I in high yield (> 98%) and with a limited number of impurities.
[00223] [00223] The compounds of the description have asymmetric centers and can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolving racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present description. The cis and trans geometric isomers of the compounds of the description and can be isolated as a mixture of isomers or as separate isomeric forms. All chiral diastereoisomeric, racemic and isomeric geometric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present description and intermediates prepared therein are considered to be part of the present description. All tautomers of the compounds shown or described are also considered to be part of the present description. In addition, the description also includes metabolites of the compounds described herein.
[00224] [00224] The description also comprises isotopically labeled compounds of the description, or their pharmaceutically acceptable salts, solvates or amino acid conjugates, which are identical to those referred to in the application formulas and following, except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the description, or their pharmaceutically acceptable salts, solvates or amino acid conjugates, include isotopes of hydrogen, carbon, nitrogen, fluorine, such as 2H, 3H, 11C, 13C, 14C and 18F.
[00225] Deuterated, i.e., 2H, tritiated, i.e., 3H, and carbon-14, i.e., C, isotopes can be used for their ease of preparation and detectability. In addition, substitution with heavier isotopes such as deuterium, ie, 2H, may give rise to certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, therefore, may be used in some circumstances . The compounds of the isotopically labeled description, or their pharmaceutically acceptable salts, solvates or conjugates of amino acids, can generally be prepared by carrying out the procedures disclosed in the Schemes and / or the Examples, by replacing a readily available isotopically labeled reagent with a non-reactive reagent. isotopically labeled. However, one skilled in the art will recognize that not all isotopes can be included by replacing the isotopically labeled reagent. In one embodiment, the compounds of the description, or their pharmaceutically acceptable salts, solvates or conjugates of amino acids, are not isotopically labeled. In one embodiment, the deuterated compounds of the description are useful for bioanalytical assays. In another embodiment, the compounds of the description, or their pharmaceutically acceptable salts, solvates or conjugates of amino acids, are radiolabeled. Pharmaceutical Compositions
[00226] [00226] A "pharmaceutical composition" is a formulation containing one or more compounds of the description in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. It may be advantageous to formulate compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages for the subject to be treated, each unit containing a predetermined amount of active reagent calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for unit dosage forms is dictated by, and is directly dependent on, the unique characteristics of the active reagent and the particular therapeutic effect to be achieved and limitations inherent in the technique of composing such an active agent for the treatment of individuals.
[00227] Possible formulations include those suitable for oral, sublingual, buccal, parenteral (e.g., subcutaneous, intramuscular or intravenous), rectal, topical administration including transdermal, intranasal and by inhalation. The most suitable means of administration for a particular patient will depend on the nature and severity of the disease being treated or the nature of the therapy being used and the nature of the active compound but, where possible, oral administration can be used for the prevention and treatment of FXR-mediated diseases and conditions. Formulations suitable for oral administration can be provided as discrete units, such as tablets, capsules, cachets, dragees, each containing a predetermined amount of the active compound; as powders or granules;
[00228] [00228] Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution can be isotonic with the blood of the intended recipient. Additional formulations suitable for parenteral administration include formulations containing physiologically suitable cosolvents and / or complexing agents such as surfactants and cyclodextrins. Oil-in-water emulsions are also suitable formulations for parenteral formulations. Although such solutions can be administered intravenously, they can also be administered by subcutaneous or intramuscular injection.
[00229] [00229] Formulations suitable for rectal administration can be provided as unit dose suppositories comprising the active principle in one or more solid vehicles forming the suppository base, for example, cocoa butter.
[00230] [00230] Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols and oils. Suitable vehicles for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols and combinations thereof.
[00231] [00231] The formulations of the description can be prepared by any suitable method, typically by mixing by uniformly and intimately adding the active compound with finely divided liquids or solid vehicles or both, in the required proportions and then, if necessary, molding the resulting mixture into desired shape.
[00232] [00232] For example, a tablet can be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent or surfactant dispersing agent, or by molding an intimate blend of powdered active ingredient and inert liquid thinner. Formulations suitable for administration by inhalation include fine particulate dust or mists that can be generated by various types of pressurized aerosols, nebulizers or metered dose insufflators.
[00233] [00233] For pulmonary administration through the mouth, the particle size of the powder or droplets is typically in the range of 0.5-10 μm or can be about 1-5 μm, to ensure distribution in the bronchial tree. For nasal administration, a particle size in the range of 10-500 μm can be used to ensure retention in the nasal cavity.
[00234] [00234] Calibrated dose inhalers are pressurized aerosol dispensers, typically containing a formulation of a suspension or solution of the active ingredient in a liquefied propellant. During use, these devices discharge the formulation through a valve adapted to deliver a calibrated volume, typically 10 to 150 μm, to produce a spray of fine particles containing the active ingredient. Suitable propellants include certain chlorofluorocarbon compounds, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof. The formulation may additionally contain one or more co-solvents, for example, surfactants in ethanol, such as oleic acid or sorbitan trioleate, suitable antioxidants and flavoring agents.
[00235] [00235] Nebulizers are commercially available devices that transform solutions or suspensions of the active ingredient into a therapeutic aerosol mist by accelerating a compressed gas, typically air or oxygen, through a narrow venturi orifice, or by stirring ultrasonic. Formulations suitable for use in nebulizers consist of the active ingredient in a liquid carrier and comprise up to 40% w / w of the formulation, preferably less than 20% w / w. The vehicle is typically water or a dilute aqueous alcoholic solution, preferably made isotonic with body fluids by the addition of, for example, sodium chloride. Optional additives include preservatives if the formulation is not prepared in a sterile manner, for example, methyl hydroxy benzoate, antioxidants, flavoring agents, volatile oils, buffering agents and surfactants.
[00236] [00236] Formulations suitable for administration by insufflation include finely crushed powders that can be distributed by means of an insufflator or taken to the nasal cavity in the form of a snuff. In the insufflator, the powder is contained in capsules or cartridges, typically made of gelatin or plastic, which are punctured or opened in situ and the powder distributed by air extracted through the device after inhalation or by means of a manually operated pump. The powder used in the insufflator consists merely of the active ingredient or a combination of powders comprising the active ingredient, a suitable diluent for the powder, such as lactose, and an optional surfactant. The active ingredient typically comprises from 0.1 to 100% w / w of the formulation.
[00237] [00237] In a further embodiment, the present description provides a pharmaceutical composition comprising, as an active ingredient, a compound of the description together with, and / or in admixture with, at least one pharmaceutical carrier or diluent. These pharmaceutical compositions can be used to prevent or treat previous diseases or conditions.
[00238] [00238] The vehicle is pharmaceutically acceptable and must be compatible with, i.e., cannot have a detrimental effect on, the other ingredients in the composition. The carrier can be a solid or a liquid and is preferably formulated as a unit dose formulation; for example, a tablet that can contain from 0.05 to 95% by weight of the active ingredient. If desired, other physiologically active ingredients can also be incorporated into the pharmaceutical compositions of the description.
[00239] [00239] In addition to the ingredients specifically mentioned above, the formulations of the present description may include other agents known to those skilled in the art of pharmacy, taking into account the type of formulation in question. For example, formulations suitable for oral administration may include flavoring agents and formulations suitable for intranasal administration may include perfumes.
[00240] [00240] In one embodiment, the present description provides a pharmaceutical composition comprising the compounds of formula I and a pharmaceutically acceptable carrier or excipient. Treatment Methods
[00241] [00241] The compounds of the description (e.g., compounds of formulas I, Ia, Ib, I-9, II, III, IIIa, IIIb, C2, D5, 44, 44a, 45 and 100) are useful for therapy in subjects such as mammals, including humans. In particular, the compounds of the description are useful in a method of treating or preventing a disease or condition in a subject comprising administering to the subject with their need for an effective amount of a compound of the description or a salt, solvate or amino acid conjugate thereof. pharmaceutically acceptable. In one embodiment, the disease or condition is mediated by FXR (eg, FXR plays a role in the onset or progress of the disease or condition). In one embodiment, the disease or condition is mediated by decreased FXR activity. In one embodiment, the disease or condition is selected from cardiovascular disease, chronic liver disease, lipid dysfunction, gastrointestinal disease, kidney disease, metabolic disease, cancer and neurological disease.
[00242] [00242] In one embodiment, the description refers to a method of treating or preventing cardiovascular disease in a subject, comprising administering to the subject with his need for an effective amount of a compound of the description or a salt, solvate or conjugate thereof pharmaceutically acceptable amino acid. In one embodiment, the description refers to a method of treating cardiovascular disease. In one embodiment, cardiovascular disease is selected from atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesteremia, hyperlipidemia, hyperlipoproteinemia and hypertriglyceridemia.
[00243] [00243] The term "hyperlipidemia" refers to the presence of an abnormally high level of lipids in the blood. Hyperlipidemia can appear in at least three forms: (1) hypercholesterolemia, i.e., an elevated cholesterol level; (2) hypertriglyceridemia, i.e., a high level of triglycerides; and (3) combined hyperlipidemia, i.e., a combination of hypercholesterolemia and hypertriglyceridemia.
[00244] [00244] The term "dyslipidemia" refers to abnormal levels of lipoproteins in the blood plasma including very low and / or high levels of lipoproteins (eg, high levels of LDL, VLDL and very low levels of HDL).
[00245] [00245] In one embodiment, the description refers to a selected method of regulating cholesterol levels or modulating cholesterol metabolism, catabolism, absorption of dietary cholesterol and reverse cholesterol transport in a subject,
[00246] [00246] In another embodiment, the description refers to a method of treating or preventing a disease by affecting the levels of cholesterol, triglycerides or bile acids in a subject, comprising administering to the subject with his need for an effective amount of a compound of the description or a pharmaceutically acceptable salt, solvate or amino acid conjugate thereof.
[00247] [00247] In one embodiment, the description refers to a method of decreasing triglycerides in a subject, comprising administering to the subject with his need for an effective amount of a compound of the description or a salt, solvate or pharmaceutically conjugated amino acid thereof acceptable.
[00248] [00248] In one embodiment, the description refers to a method of treating or preventing a disease state associated with a high level of cholesterol in a subject, comprising administering to the subject with his need for an effective amount of a compound of the description or a pharmaceutically acceptable salt, solvate or amino acid conjugate thereof. In one embodiment, the description refers to a method of treating a disease state associated with a high level of cholesterol in a subject. In one embodiment, the description refers to a method of preventing a disease state associated with a high level of cholesterol in a subject. In one embodiment, the disease state is selected from coronary artery disease, angina pectoris, carotid artery disease, strokes, cerebral arteriosclerosis and xanthoma.
[00249] [00249] In one embodiment, the description refers to a method of treating or preventing lipid dysfunction in a subject,
[00250] [00250] Lipid dysfunctions are the term for abnormalities in cholesterol and triglycerides. Abnormalities of lipids are associated with an increased risk of vascular disease and especially heart attacks and strokes. Abnormalities in lipid dysfunction are a combination of genetic predisposition as well as the nature of food intake. Many lipid disorders are associated with being overweight. Lipid dysfunctions can also be associated with other diseases including diabetes, metabolic syndrome (sometimes called insulin resistance syndrome), underactive thyroid or the result of certain medications (such as those used for anti-rejection regimes in people who have undergone transplants).
[00251] [00251] In one embodiment, the description refers to a method of treating or preventing one or more symptoms of disease affecting the metabolism of lipids (ie, lipodystrophy) in a subject, comprising administration to the subject with his need for a quantity efficacy of a compound of the description or a pharmaceutically acceptable salt, solvate or amino acid conjugate thereof. In one embodiment, the description refers to a method of treating one or more symptoms of a disease affecting lipid metabolism. In one embodiment, the description refers to a method of preventing one or more symptoms of a disease by affecting lipid metabolism.
[00252] [00252] In one embodiment, the description refers to a method of decreasing the accumulation of lipids in a subject, comprising administration to the subject with his need for an effective amount of a compound of the description or a salt, solvate or conjugate thereof. pharmaceutically acceptable amino acid.
[00253] [00253] In one embodiment, the description refers to a method of treating or preventing liver disease in a subject, comprising administering to the subject in need of an effective amount of a compound of the invention or a salt, solvate or conjugate thereof pharmaceutically acceptable amino acid. In one embodiment, the description refers to a method of treating chronic liver disease. In one embodiment, the description refers to a method of preventing chronic liver disease. In one embodiment, FXR-mediated liver disease is selected from cholestatic liver disease such as primary biliary cirrhosis (PBC), also known as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), chronic liver disease, fatty liver disease non-alcoholic (NAFLD), non-alcoholic steatohepatitis (NASH), hepatitis C infection, alcoholic liver disease, liver damage due to progressive fibrosis and liver fibrosis. Other examples of FXR-mediated diseases also include portal hypertension, bile acid diarrhea, hyperlipidemia, high LDL cholesterol, high HDL cholesterol, high triglycerides and cardiovascular disease. Other liver diseases include cerebrotendinous xanthomatosis (CTX), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), bacterial overgrowth or sepsis-associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, graft versus disease host associated with liver transplantation, liver regeneration from live donor transplantation, congenital liver fibrosis, choledocholithiasis, granulomatous liver disease, intra or extrahepatic malignancy,
[00254] [00254] In one embodiment, the description refers to a method of treating or preventing one or more symptoms of cholestasis, including complications of cholestasis in a subject, comprising administering to the subject in need of an effective amount of a compound of the description or a pharmaceutically acceptable salt, solvate or amino acid or prodrug conjugate thereof. In one embodiment, the description refers to a method of treating one or more symptoms of cholestasis. In one embodiment, the description refers to the prevention of one or more symptoms of cholestasis.
[00255] [00255] Cholestasis is typically caused by factors within the liver (intrahepatic) or outside the liver (extrahepatic) and leads to the accumulation of bile salts, bile pigment bilirubin and lipids in the bloodstream instead of being eliminated normally. Intrahepatic cholestasis is characterized by the widespread blockage of small ducts or by dysfunctions such as hepatitis, which impair the body's ability to eliminate bile. Intrahepatic cholestasis can also be caused by alcoholic liver disease, primary biliary cirrhosis, cancer that has spread (metastasized) from another part of the body, primary sclerosing cholangitis, gallstones, biliary colic and acute cholecystitis. It can also occur as a complication of surgery, severe injury, cystic fibrosis, infection or intravenous feeding or be drug-induced. Cholestasis can also occur as a complication of pregnancy and often develops during the second and third trimesters. Extrahepatic cholestasis is most often caused by choledocholithiasis (Bile Duct Stones), benign biliary restrictions (non-cancerous narrowing of the common duct), cholangiocarcinoma (dutch carcinoma) and pancreatic carcinoma. Extrahepatic cholestasis can occur as a side effect of many medications.
[00256] [00256] A compound of the description can be used for treatment or prevention of one or more symptoms of intrahepatic or extrahepatic cholestasis including, without limitation, biliary atresia, obstetric cholestasis, neonatal cholestasis, drug-induced cholestasis, cholestasis arising from Hepatitis C infection, chronic cholestatic liver disease such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC).
[00257] [00257] In one embodiment, the description refers to a method of enhancing liver regeneration in a subject, comprising administering to the subject with their need for an effective amount of a compound of the description or a salt, solvate or amino acid conjugate thereof or pharmaceutically acceptable prodrug. In one embodiment, the method is to enhance liver regeneration for liver transplantation.
[00258] [00258] In one embodiment, the description refers to a method of treating or preventing fibrosis in a subject, comprising administering to the subject with his need for an effective amount of a compound of the description or a salt, solvate or conjugate thereof. pharmaceutically acceptable amino acid or prodrug. In one embodiment, the description refers to a method of treating fibrosis. In one embodiment, the description refers to a fibrosis prevention method.
[00259] [00259] Accordingly, as used here, the term fibrosis refers to all recognized fibrotic dysfunctions, including fibrosis due to pathological conditions or diseases, fibrosis due to physical trauma ("traumatic fibrosis"), fibrosis due to radiation injury and fibrosis due to exposure to chemotherapeutics. As used herein, the term "organ fibrosis" includes, but is not limited to, liver fibrosis, kidney fibrosis, lung fibrosis, and intestinal fibrosis. "Traumatic fibrosis" includes, but is not limited to, surgery-derived fibrosis (surgical scarring), accidental physical trauma, burns, and hypertrophic scarring.
[00260] [00260] As used herein, "liver fibrosis" includes liver fibrosis due to any cause, including but not limited to virally induced liver fibrosis such as that due to the hepatitis B or C virus; exposure to alcohol (alcoholic liver disease), certain pharmaceutical compounds including but not limited to methotrexate, some chemotherapeutic agents and chronic ingestion of compounds with arsenic or vitamin A in megadoses, oxidative stress, radiation therapy against cancer or certain industrial chemicals including but not limited to limited to carbon tetrachloride and dimethylnitrosamine; and diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, fatty liver, obesity, non-alcoholic steatohepatitis, cystic fibrosis, hemochromatosis, autoimmune hepatitis and steatohepatitis. Current therapy for liver fibrosis is mainly aimed at removing the causative agent, eg, removing excess iron (eg, in the case of hemochromatosis), decreasing the viral load (eg, in the case of of chronic viral hepatitis) or elimination or decreased exposure to toxins (eg, in the case of alcoholic liver disease). Anti-inflammatory drugs such as corticosteroids and colchicine are also known for use in the treatment of inflammation that can lead to liver fibrosis. As is known in the art, liver fibrosis can be clinically classified into five stages of severity (S0, S1, S2, S3 and S4), usually based on histological examination of a biopsy sample. S0 indicates absence of fibrosis, whereas S4 indicates cirrhosis. Although there are several criteria for scaling the severity of hepatic fibrosis, in general the initial stages of fibrosis are identified by localized, discrete areas of scarring in a port (zone) of the liver, whereas later stages of fibrosis are identified by bridging fibrosis (scar that crosses areas of the liver).
[00261] [00261] In one embodiment, the description refers to a method of treating or preventing organ fibrosis in a subject, comprising administering to the subject in need of an effective amount of a compound of the invention or a salt, solvate thereof or pharmaceutically acceptable amino acid conjugate. In one embodiment, fibrosis is liver fibrosis.
[00262] [00262] In one embodiment, the description refers to a method of treating or preventing gastrointestinal disease in a subject, comprising administering to the subject in need of an effective amount of a compound of the description or a salt, solvate or conjugate thereof pharmaceutically acceptable amino acid or prodrug. In one embodiment, the description refers to a method of treating gastrointestinal disease. In one embodiment, the description refers to a method of preventing gastrointestinal disease. In one embodiment, gastrointestinal disease is selected from inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), bacterial overgrowth, malabsorption, post-radiation colitis and microscopic colitis. In one embodiment, inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis.
[00263] [00263] In one embodiment, the description refers to a method of treating or preventing kidney disease in a subject, comprising administering to the subject with his need for an effective amount of a compound of the invention or a salt, solvate or conjugate thereof pharmaceutically acceptable amino acid. In one embodiment, the description refers to a method of treating kidney disease. In one embodiment, the description refers to a method of preventing kidney disease. In one embodiment, kidney disease is selected from diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis and polycystic kidney disease.
[00264] [00264] In one embodiment, the description refers to a method of treating or preventing metabolic disease in a subject, comprising administering to the subject with his need for an effective amount of a compound of the invention or a salt, solvate or conjugate thereof pharmaceutically acceptable amino acid. In one embodiment, the description refers to a method of treating kidney disease. In one embodiment, the description refers to a method of preventing kidney disease. In one embodiment, metabolic disease is selected from insulin resistance, hyperglycemia, diabetes mellitus, diabetes and obesity. In one embodiment, diabetes mellitus is type I diabetes. In one embodiment, diabetes mellitus is type II diabetes.
[00265] [00265] Diabetes mellitus, commonly called diabetes, refers to a disease or condition that is generally characterized by metabolic defects in the production and use of glucose that result in an inability to maintain proper blood sugar levels in the body.
[00266] [00266] In the case of type II diabetes, the disease is characterized by insulin resistance, in which insulin loses its ability to exert its biological effects over a wide range of concentrations. This resistance to insulin responsiveness results in insufficient activation of insulin in glucose uptake, oxidation and storage in muscles and inadequate repression of insulin in lipolysis in adipose tissue and in the production and secretion of glucose in the liver. The resulting condition is high blood glucose, which is called "hyperglycemia". Uncontrolled hyperglycemia is associated with increased and premature mortality due to an increased risk of microvascular and macrovascular diseases, including retinopathy (the reduction or loss of vision due to damage to blood vessels in the eyes); neuropathy (nerve damage and foot problems due to damage to blood vessels in the nervous system); and nephropathy (kidney disease due to damage to blood vessels in the kidneys), hypertension, cerebral vascular disease and coronary heart disease. Therefore, controlling glucose homeostasis is a critically important approach to the treatment of diabetes.
[00267] [00267] It was hypothesized that insulin resistance unifies the grouping of hypertension, glucose intolerance, hyperinsulinemia, increased levels of triglycerides and decreased HDL cholesterol and central and global obesity. The association of insulin resistance with glucose intolerance, an increase in plasma triglyceride concentrations and a decrease in high-density lipoprotein cholesterol, hypertension, hyperuricemia, smaller and more dense low-density lipoprotein particles and higher levels in Circulation of plasminogen-1 activator inhibitor has been referred to as "Syndrome X". Accordingly, methods of treating or preventing any dysfunctions related to insulin resistance are provided, including the grouping of disease states, conditions or dysfunctions that constitute "Syndrome X". In one embodiment, the description relates to a method of treating or preventing metabolic syndrome in a subject, comprising administering to the subject with his need for an effective amount of a compound of the invention or a pharmaceutically salt, solvate or amino acid conjugate thereof. acceptable. In one embodiment, the description refers to a method of treating metabolic syndrome. In another embodiment, the description refers to a method of preventing metabolic syndrome.
[00268] [00268] In one embodiment, the description refers to a method of treating or preventing cancer in a subject, comprising administering to the subject with his need for an effective amount of a compound of the invention or a salt, solvate or conjugate thereof. pharmaceutically acceptable amino acid. In one embodiment, the description refers to a method of treating cancer. In one embodiment, the description refers to a cancer prevention method. In one embodiment, the cancer is selected from hepatocellular carcinoma, colorectal cancer, gastric cancer, kidney cancer, prostate cancer, adrenal cancer, pancreatic cancer, breast cancer, bladder cancer, salivary gland cancer, ovarian cancer, cancer of the uterine body and lung cancer. In one embodiment, cancer is a hepatocellular carcinoma. In one embodiment, cancer is colorectal cancer. In one embodiment, cancer is gastric cancer. In one embodiment, cancer is kidney cancer. In one embodiment, cancer is prostate cancer. In one embodiment, cancer is adrenal cancer. In one embodiment, cancer is pancreatic cancer. In one embodiment, cancer is breast cancer. In one embodiment, cancer is bladder cancer. In one embodiment, cancer is cancer of the salivary glands. In one embodiment, cancer is ovarian cancer. In one embodiment, cancer is cancer of the uterine body. In one embodiment, cancer is lung cancer.
[00269] [00269] In another embodiment, at least one of an agent selected from Sorafenib, Sunitinib, Erlotinib or Imatinib is co-administered with the compound of the description to treat cancer. In one embodiment, at least one of an agent selected from Abarelix, Aldeleucine, Allopurinol, Altretamine, Amifostine, Anastozole, Bevacizumab, Capecitabine, Carboplatin, Cisplatin, Docetaxel, Doxorubicin, Erlotinib, Exemestane, 5-Fluoritol, Goserelin, Irinotecan, Ditosylate
[00270] [00270] The appropriate treatment for cancers depends on the type of cell from which the tumor was derived, the stage and severity of the malignancy and the genetic abnormality that contributes to the tumor.
[00271] [00271] Cancer scheduling systems describe the extent of cancer progression. In general, scheduling systems describe how far the tumor has spread and place patients with similar prognosis and treatment in the same scheduling group. There are generally worse prognosis for tumors that have become invasive or metastasized.
[00272] [00272] In a type of scheduling system, cases are grouped into four stages, denoted by Roman numbers I to IV. In stage I, cancers are often localized and are usually curable. The cancers in stages II and IIIA are usually more advanced and may have invaded the surrounding tissues and spread to lymph nodes. Stage IV cancers include metastatic cancers that have spread to sites outside the lymph nodes.
[00273] [00273] Another scheduling system is the TNM scheduling that represents the categories: Tumor, Nodules and Metastases. In this system, malignancies are described according to the severity of the individual categories. For example, T classifies the extent of a primary tumor from 0 to 4 with 0 representing a malignancy that has no invasive activity and 4 representing a malignancy that has invaded other organs by extension from the original site. N classifies the extent of lymph node involvement as 0 representing a malignancy without any lymph node involvement and 4 representing a malignancy with extensive lymph node involvement. M classifies the extent of metastasis from 0 to 1 with 0 representing a malignancy without metastasis and 1 representing a malignancy with metastasis.
[00274] [00274] These scheduling systems or variations of these scheduling systems or other suitable scheduling systems can be used to describe a tumor such as a hepatocellular carcinoma. Only a few options are available for the treatment of hepatocellular cancer depending on the stage and characteristics of the cancer. Treatments include surgery, treatment with Sorafenib and targeted therapies. In general, surgery is the first line of treatment for hepatocellular cancer located at an early stage. Additional systemic treatments can be used to treat invasive and metastatic tumors.
[00275] [00275] In one embodiment, the description refers to a method of treating or preventing gallstones in a subject, comprising administering to the subject in need of an effective amount of a compound of the invention or a salt, solvate or conjugate thereof pharmaceutically acceptable amino acid. In one embodiment, the description refers to a method of treating gallstones. In one embodiment, the description refers to a method of preventing gallstones.
[00276] [00276] A gallstone is a crystalline concretion formed inside the gallbladder by accretion of bile components. These calculations are formed in the gallbladder but can pass distally to other parts of the biliary tract such as the cystic duct, common bile duct, pancreatic duct or Vater's ampoule. Rarely, in cases of severe inflammation, gallstones can corrode the gallbladder and pass into the adherent intestine, potentially causing an obstruction called the bile ileum. The presence of gallstones in the gallbladder can lead to acute cholecystitis, an inflammatory condition characterized by retention of bile in the gallbladder and often secondary infection by intestinal microorganisms, predominantly Escherichia coli, and species of Bacteroides.
[00277] [00277] The presence of gallstones in other parts of the biliary tract can cause obstruction in the bile ducts, which can lead to serious conditions such as ascending cholangitis or pancreatitis. In one embodiment, the description refers to a method of treating or preventing cholesterol kidney stone disease in a subject, comprising administering to the subject with his need for an effective amount of a compound of the description or a salt, solvate thereof or pharmaceutically acceptable amino acid conjugate. In one embodiment, the description refers to a method of treating cholesterol kidney stone disease. In one embodiment, the description refers to a method of preventing cholesterol kidney stone disease.
[00278] [00278] In one embodiment, the description refers to a method of treating or preventing neurological disease in a subject, comprising administering to the subject with his need for an effective amount of a compound of the invention or a salt, solvate or conjugate thereof pharmaceutically acceptable amino acid. In one embodiment, the description refers to a method of treating neurological disease. In one embodiment, the description refers to a method of preventing neurological disease. In one embodiment, the neurological disease is stroke.
[00279] [00279] In one embodiment, the description refers to a method as described here and additionally in which the compound is administered via a selected route of oral, parenteral, intramuscular, intranasal, sublingual, intratracheal, inhalation, ocular, vaginal, rectal and intracerebroventricular. In one embodiment, the route is oral.
[00280] [00280] In one embodiment, the compound used in one or more of the methods described here is an FXR agonist. In one embodiment, the compound is a selective FXR agonist. In another embodiment, the compound does not activate TGR5. In one embodiment, the compound does not activate other nuclear receptors involved in metabolic pathways (eg, as measured by an AlphaScreen assay). In one embodiment, such other nuclear receptors involved in metabolic pathways are selected from LXRβ, PXR, CAR, PPARα, PPARδ, PPARγRAR, RARα, VDR, TR, PR, RXR, GR and ER. In one embodiment, the compound induces apoptosis.
[00281] [00281] In one embodiment, the description refers to a method of regulating the level of expression of one or more genes involved in bile acid homeostasis.
[00282] [00282] In one embodiment, the description refers to a method of subregulating the level of expression of one or more genes selected from CYP7αl and SREBP-IC in a cell by administering to the cell a compound of the description. In one embodiment, the description refers to a method of overregulating the level of expression of one or more genes selected from OSTα, OSTβ, BSEP, SHP, UGT2B4, MRP2, FGF-19, PPARγ, PLTP, APOCII and PEPCK in one cell by administering to the cell a compound of the description.
[00283] [00283] The description also relates to the manufacture of a drug for the treatment or prevention of a disease or condition (eg, a disease or condition mediated by FXR), wherein the drug comprises a compound of the description or one thereof pharmaceutically acceptable salt, solvate or amino acid conjugate. In one embodiment, the description refers to the manufacture of a medicament for treating or preventing any of the diseases or conditions described above, wherein the medicament comprises a compound of the description or a pharmaceutically acceptable salt, solvate or amino acid conjugate thereof.
[00284] [00284] The description also relates to a composition for use in a method for treating or preventing a disease or condition (e.g., an FXR-mediated disease or condition), wherein the composition comprises a compound of the description or a pharmaceutically acceptable salt, solvate or amino acid conjugate thereof. In one embodiment, the description refers to a composition for use in a method for treating or preventing any of the diseases or conditions described above, wherein the composition comprises a compound of the description or a salt, solvate or amino acid conjugate thereof. pharmaceutically acceptable.
[00285] [00285] The methods of the description comprise the step of administering an effective amount of a compound of the description. As used herein, the term "effective amount" refers to an amount of a compound of the description that is sufficient to achieve the aforementioned effect. Accordingly, an effective amount of a compound of the description used in a method for the prevention or treatment of FXR-mediated diseases or conditions will be an amount sufficient to prevent or treat the FXR-mediated disease or condition.
[00286] [00286] Similarly, an effective amount of a compound of the description for use in a method for the prevention or treatment of cholestatic liver disease or increased bile flow will be an amount sufficient to increase bile flow to the intestine. The amount of the description compound that is required to achieve the desired biological effect will depend on a number of factors such as the intended use, the means of administration and the recipient and will ultimately be at the discretion of the attending physician or vet. In general, a typical daily dose for the treatment of an FXR-mediated disease and condition, for example, can be expected to range from about 0.01 mg / kg to about 100 mg / kg.
[00287] [00287] In one embodiment, the present description proves a method of treating or preventing a disease or condition in a subject in need comprising administering an effective amount of the compound of formula I or a salt, solvate or amino acid conjugate pharmaceutically acceptable, and where the disease or condition is mediated by FXR.
[00288] [00288] In one of the embodiments, the present description proves a method of treating or preventing a disease or condition in a subject with his need comprising administering an effective amount of the compound of formula I, in which the disease is selected from cardiovascular disease , chronic liver disease, lipid dysfunction, gastrointestinal disease, kidney disease, metabolic disease, cancer and neurological disease.
[00289] [00289] In one of the embodiments, the present description proves a method of treatment or prevention of a disease or condition in a subject with his need comprising administering an effective amount of the compound of formula I, wherein the disease is cardiovascular disease selected from atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesteremia, hyperlipidemia, hyperlipoproteinemia and hypertriglyceridemia.
[00290] [00290] In one embodiment, the present description proves a method of treating or preventing a disease or condition in a subject in need comprising administering an effective amount of the compound of formula I, wherein the disease is liver disease selected from a cholestatic liver disease such as primary biliary cirrhosis (PBC), also known as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), chronic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH ), hepatitis C infection, alcoholic liver disease, liver damage due to progressive fibrosis and liver fibrosis. Other examples of FXR-mediated diseases also include portal hypertension, bile acid diarrhea, hyperlipidemia, high LDL cholesterol, high HDL cholesterol, high triglycerides and cardiovascular disease. Other liver diseases include cerebrotendinous xanthomatosis (CTX), drug-induced cholestasis, intrahepatic cholestasis of pregnancy, parenteral nutrition-associated cholestasis (PNAC), bacterial overgrowth or sepsis-associated cholestasis, autoimmune hepatitis, chronic viral hepatitis, graft versus disease host associated with liver transplantation, liver regeneration from living donor transplantation, congenital liver fibrosis, choledocholithiasis, granulomatous liver disease, intra or extrahepatic malignancy, Sjögren's syndrome, Sarcoidosis, Wilson's disease, Gaucher disease, hemochromatosis and alpha deficiency 1-antitrypsin.
[00291] [00291] In one of the embodiments, the present description proves a method of treatment or prevention of a disease or condition in a subject with his need comprising administering an effective amount of the compound of formula I, wherein the disease is gastrointestinal disease selected from inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), bacterial overgrowth, malabsorption, post-radiation colitis and microscopic colitis.
[00292] [00292] In one embodiment, the present description proves a method of treating or preventing a disease or condition in a subject in need comprising administering an effective amount of the compound of formula I, wherein the inflammatory bowel disease is a disease Crohn's disease or ulcerative colitis.
[00293] [00293] In one of the embodiments, the present description proves a method of treatment or prevention of a disease or condition in a subject with his need comprising administering an effective amount of the compound of formula I, wherein the disease is kidney disease selected from diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis and polycystic kidney disease.
[00294] [00294] In one of the embodiments, the present description proves a method of treatment or prevention of a disease or condition in a subject with his need comprising administration of an effective amount of the compound of formula I, wherein the disease is a metabolic disease selected from insulin resistance, hyperglycemia, diabetes mellitus, diabetes and obesity.
[00295] [00295] In one of the embodiments, the present description proves a method of treatment or prevention of a disease or condition in a subject with his need comprising administering an effective amount of the compound of formula I, in which the disease is cancer selected from carcinoma hepatocellular, colorectal cancer, gastric cancer, kidney cancer, prostate cancer, adrenal cancer, pancreatic cancer, breast cancer, bladder cancer, salivary gland cancer, ovarian cancer, uterine body cancer and lung cancer. EXAMPLES
[00296] [00296] The following examples are intended to illustrate certain embodiments of the present invention, but do not exemplify the full scope of the invention. Example 1. Synthesis of compound 100:
[00297] [00297] Tracks 1-3 can also be carried out with other protecting groups in hydroxy C3. Exemplary Route 4:
[00298] [00298] Pathways 4 can also be carried out with other protecting groups on hydroxy C3 (eg, OAc). Example 1-1: methyl 3α, 12α-Dihydroxy-6α-ethyl-7-oxo-5β-colan-24-oate (2)
[00299] [00299] To a stirring solution of 6-ethyl-7-ketocholic acid (1.25 g, 57.52 mmol) in CH2Cl2 (340 mL) was added MeOH (23 mL) followed by pTSA · H2O (1.1 g, 5.75 mmol). The resulting solution was heated at 40 ° C for 20 h. The reaction mixture was poured into a mixture of brine (500 ml) and NaHCO3 (1.5 g). CH2Cl2 (500 ml) and brine (200 ml) were added, the layers were separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give 24.91 g (97%) as an off-white solid (compound 2). ES-API Pos: 466.2 [M + H2O]. 1H-NMR (300 MHz, CDCl3): δ 0.68 (s, 3H, 18-CH3), 0.80 (t, 3H, 26-CH3), 0.96 (d, 3H, 21-CH3), 1.20 (s, 3H, 19-CH3), 3.43-3.59 (3, 1H, 3-CH), 3.66 (s, 3H, CO2CH3), 3.99 (ls, 1H, 12 - CH). Alternative procedure for preparing compound 2:
[00300] [00300] To a suspension of 6-ethyl-7-ketocholic acid (1, 2.5 kg, 5.75 mol) in MeOH (12 L) was added H2SO4 conc. (16.1 ml; 0.29 mol) and the mixture was heated to 65 ° C for 3 h. The mixture was cooled, the pH was adjusted with 1 N NaOH (aq) to ca. pH 9, and water (12.5 L) was added to precipitate the product. The solids were filtered, washed with 1: 1 MeOH-water and dried in vacuo. Compound 2 (2.37 kg) was produced in 91.8% yield. (e.g., Via 4). Example 1-2: Methyl 3α-acetoxy-12α-hydroxy-6α-ethyl-7-oxo-5β-colan-24- oate (18)
[00301] [00301] To a stirred suspension of compound 2 (24.9 g, 55.5 mmol) in MeOAc (660 mL) was added pTsOH · H2O (1.01 g, 5.33 mmol). The resulting solution was heated to 75 ° C for 4 days. EtOAc (950 ml) was added. The mixture was washed with saturated NaHCO 3,
[00302] [00302] A solution of compound 2 (2.36 kg, 5.26 mol) in MeOAc (20 L) was added pTsOH · H2O (100 g, 0.526 mol). The mixture was heated to reflux for 13-65 h, then the solvents were distilled and fresh MeOAc was added and the reflux continued. This was repeated three times until the reaction was complete. The mixture was concentrated and DCM (23.6 L) was added. The organic layer was washed with water (23.6 L), 8% NaHCO3 (aq) (23.6 L) followed by saturated aqueous NaCl (11.8 L). The organic layer was separated and dried over Na2SO4, then filtered and concentrated to a final volume of 11.7 L. The DCM solution of compound 18 was used directly in the next step. Example 1-3: Methyl 3α-acetoxy-6α-ethyl-7-keto-12α - ((methylsulfonyl) oxy) -5β- colan-24-oate (32)
[00303] [00303] To a solution of compound 18 (27.2 g, 55.43 mmol) in pyridine (270 ml) at room temperature was added MsCl (8.58 ml, 110.87 mmol). The reaction was stirred at 20-30 ° C overnight. The reaction mixture was poured into ice water and EtOAc (1 L) was added. The phases were separated and the aqueous phase was extracted with EtOAc (3 × 150 ml). The combined organic phases were washed with aq. 2 M (3 × 150 mL). The combined organic phases were washed with sat. NaHCO3. (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. More EtOAc was added to remove the pyridine and the crude was dried under reduced pressure for three hours providing 31.13 g (99%) of product 32 as an off-white solid. 1H-NMR (400 MHz, CDCl3): δ 0.75-0.81 (m, 6H, 18-CH3, 26-CH3), 0.96 (d, J = 6.4 Hz, 3H, 21-CH3 ), 1.21 (s, 3H, 19-CH3), 2.01 (s, 3H, OCOCH3), 3.04 (s, 3H, OSO2CH3), 3.67 (s, 3H, CO2CH3), 4, 59-4.62 (m, 1H, 3-CH), 5.10 (s, 1H, 12-CH). Alternative Procedure:
[00304] [00304] To a DCM solution of compound 18 (11.7 L, ca. 5.26 mol) were added pyridine (2.13 L, 26.3 mol) and MsCl (0.814 L, 10.52 mol) at 15-25 ° C. The mixture was stirred for 96 h, then diluted with DCM (12 L) and water (12 L). The organic layer was washed twice with aq. at 2 N (12 L), 8% NaHCO3 (aq) (12 L), then dried over Na2SO4, then concentrated to a final volume of 7.1 L. MTBE (24 L) was added in portions and concentrated to a final volume of 8 L. The resulting suspension was cooled and filtered in vacuo. The solids were washed with MTBE-heptane 1: 1, then dried in vacuo to give compound 32 (2.576 kg) in 86.1% yield.
[00305] [00305] Alternatively, mesylate 32b can be prepared through a telescoped process, a vessel procedure using ethyl chloroformate as a protecting group for C3-OH as shown in Example 1-3b. The ethyl carbonate protecting group that can be installed with high selectivity provides a more crystalline solid and overcomes possible problems with the completion of the reaction on a larger scale. (Route 4) Example 1-3a: 3α- (Ethoxycarbonyl) oxy-12α- (methanesulfonyl) oxy-6α-
[00306] [00306] To a solution of 3-acetate 32 (45 g, 78.8 mmol) in HMPA (HMPT or DMPU) (500 mL) was added KOAc (64 g, 652 mmol). After stirring with a suspended stirrer for 15 h at 98 ° C, 1HRMN showed approximately 70% conversion. Heating was continued for an additional 24 h and the mixture was cooled to room temperature. Water (2 L) and heptanes (600 ml) were added. The organic layer was separated and the aqueous layer was extracted with heptanes (200 ml). The combined organic layers were washed with aq. sat. (300 ml) and brine (200 ml). The organic layer was dried over Na2SO4, treated with active carbon (3 g) and concentrated to provide 40 g (with some residual heptanes; about 98% yield) of crude compound 19. The material was acceptable in purity based on 1H-NMR. The material was analyzed by 1H-NMR and LCMS. ES-API Pos: 490.8 [M + H2O]. 1H-NMR (400 MHz, CDCl3): δ 0.74 (s, 3H, 18-CH3), 0.82 (t, J = 7.3 Hz, 3H, 26-CH3), 1.00 (d, J = 6.3 Hz, 3H, 21-CH3), 1.16 (s, 3H, 19-CH3), 2.02 (s, 3H, OCOCH3), 3.66 (s, 3H, CO2CH3), 4 , 63-4.68 (m, 1H, 3-CH), 5.32 (d, J = 10.3 Hz, 1H, 12-CH), 6.18 (dd, J1 = 2.4 Hz, J2 = 10.3 Hz, 1H, 11-CH).
[00307] [00307] Alternatively, compound 19 can be prepared according to the following procedure:
[00308] [00308] To a solution of 3-acetate 18 (0.5 g, 1.02 mmol) in pyridine
[00309] Alternatively, compound 19 can be prepared according to the following procedure:
[00310] [00310] To a solution of compound 32 (2.59 kg, 4.55 mol) in DMSO (20.2 L) was added CsOAc (3.93 kg, 20.5 mol) and the mixture was heated to 90- 100 ° C for 16-20 h. The mixture was cooled to room temperature and added to cold water (62.1 L) over 0.5-1 h. The resulting suspension was filtered, washed with water (3 x 20 L), then dried in vacuo. The solids were absorbed in EtOAc and chromatographed on silica gel (10% EtOAc-Heptane). The product-rich fractions were pooled and concentrated to give compound 19 (1.69 kg) as a solid in 79% yield. (Via 3)
[00311] [00311] Alternatively, Compound 19b can be prepared according to Example 1-4a. Example 1-4a: Δ11,12-3α- (Ethoxycarbonyl) oxy-6α-ethyl-5β-colan-24-oate (19b)
[00312] [00312] To a solution of 3α- (ethoxycarbonyl) oxy-12α- (methanesulfonyl) oxy-6α-ethyl-7-oxo-5β-colan-24-oate (32b) (14.4 g, 25.3 mmol) in DMSO (150 mL) CsOAc (19.6 g, 102 mmol) was added. The mixture was stirred at 90-100 ° C for 18 hours before being cooled to room temperature. The mixture was added to water (500 ml) and the resulting precipitate was filtered, washed with water and dried in the funnel. A 5.9 g portion of crude compound 19b was dissolved in MeOH (5.9 ml) at reflux. Water (3 ml) was added and the mixture was cooled to 25-35 ° C and the product precipitated. Additional water (56 ml) was added at 20-25 ° C, the suspension was stirred for 1.5 h, then filtered in vacuo and washed with water and dried in vacuo. Compound 19b (5.64 g) was isolated in 88.7% yield (from compound 32b). 1H-NMR (300 MHz, CDCl3): δ 0.75 (s, 3H, 18-CH3), 0.82 (t, J = 7.3 Hz, 3H, 26-CH3), 1.00 (d, J = 6.3 Hz, 3H, 21-CH3), 1.17 (s, 3H, 19-CH3), 1.29 (t, J = 7.3 Hz, 3H OC (O) OCH2CH3), 3, 66 (s, 3H, CO2CH3), 4.15 (q, 2H, OC (O) OCH2CH3), 4.38-4.64 (m, 1H, 3-CH), 5.33 (d, J = 10 , 3 Hz, 1H, 12-CH), 6.18 (dd, J1 = 2.3 Hz, J2 = 10.3 Hz, 1H, 11-CH). (Route 4) Example 1-4b: Δ11.12 Methyl -3α- (Etoxicarbonyl) oxy-6α-ethyl-5β-colan-24-oate (19b)
[00313] [00313] Cs2CO3 (278.6 g, 855.1 mmol) and AcOH (41.08 g, 39.1 mL, 684.0 mmol) were mixed in DMSO (1 L) and stirred for 30 min at 50-70 ° C. Methyl 3α- (ethoxycarbonyl) -12α- (methanesulfonyl) oxy-6α-ethyl-7-oxo-5β-cholan-24-oate (32b) (102.4 g, 171.0 mmol) was added and the mixture it was stirred at 90 ° C for 18 hours. The mixture was cooled to room temperature and then slowly added to 4 L of pre-cooled water (0-5 ° C) containing 200 ml of concentrated HCl. The off-white precipitate was filtered, washed with water (3 × 1 L) and dried on a vacuum filter. The solids were absorbed into heptanes (2 L) and heated. The remaining water was removed and the solution containing insoluble brown tar was filtered over a layer of Celite. The resulting filtrate was concentrated to give compound 19b (84.9 g, 98.8%) as a light brown solid. Example 1-5: Methyl 3α-acetoxy-12-bromo-6α-ethyl-7-keto-11-hydroxy-5β-cholan-24-oate (21)
[00314] [00314] To a solution of compound 19 (53.5 g, 113 mmol) in MeCN (455 ml) and H2O (116 ml) was added NBS (24.13 g, 135 mmol) of about -5 ° C at about 5 ° C in portions over 25 min. After complete addition, the mixture was stirred at room temperature. After 1.5 h, the mixture was poured into aq. 2.5% (1.5 L) and stirred at room temperature. The mixture was extracted with 10: 1 EtOAc: heptanes
[00315] [00315] Alternatively, to a water-cooled solution of compound 19 (1.5 g, 3.17 mmol) in THF (11 mL) and H2O (4 mL) was added NBS (677 mg, 3.8 mmol ) in portions over 5 min. at 20 ° C. At the end of the addition, the color remained slightly orange. After complete addition, the mixture was stirred at room temperature. After 18 h, the mixture was poured into aq. 2.5% (20 mL) and stirred at room temperature. To the mixture, brine (10 ml) was added and the mixture was extracted with 10: 1 EtOAc: heptanes (40 ml and 20 ml). The combined organic layer was washed with aq. 10% (15 ml), brine (20 ml), dried over Na2SO4, filtered and concentrated to give compound 21 (1.86 g) as a yellowish foam containing some EtOAc. This material was used without purification in the next reaction step.
[00316] [00316] Alternatively, compound 21 can be prepared according to the following procedure:
[00317] [00317] Dibromamine-T (TsNBr2): To a solution of Chloramine-T (10 g, 40.7 mmol) in 200 mL of water was added bromine (2 mL, 6.24 g, 78 mmol) in a dropwise manner the drop. After the addition was complete, the mixture was stirred for 2 h. The mixture was filtered and the filtrate was washed with water (2 × 20 ml) and dried in vacuo to provide 12 g (90% yield) of dibromamine-T.
[00318] [00318] To a solution of compound 19 (416 mg, 1 mmol) in MeCN (4 mL) and H2O (1 mL) was added dibromamin-T (329 mg, 1 mmol) in portions. After the addition was complete, the mixture was stirred at room temperature for about 5 to about 30 min. The mixture was quenched with sodium thiosulfate (284 mg, 1.8 mmol), diluted with water (20 mL) and extracted with EtOAc. The organic layer was washed with 10% NaHCO3, dried over Na2SO4, filtered and concentrated to produce crude compound 21.
[00319] Alternatively, iodination of compound 19 using an iodizing agent such as N-iodosuccinimide in the presence of TFA, followed by selective destrifluoroacetylation of intermediate 21c, can generate halohydrin (iodohydrin) 21a. The procedure is shown in Example 1-5a. Example 1-5a: Methyl 3α-acetoxy-6α-ethyl-12-iodo-7-keto-11β-trifluoroacetoxy-5β-cholan-24-oate (21a)
[00320] [00320] To a mixture of compound 19 (10.0 g, 21.16 mmol), N-iodosuccinimide (6.66 g, 29.62 mmol), MTBE (100 mL) and water (6.47 mL) at 5-15 ° C, trifluoroacetic acid (8.1 mL, 105.8 mmol) was loaded. The mixture was heated to 20-25 ° C and stirred until completion of the reaction (within 7 h). A 0.5 M sodium bisulfite solution (50 ml) was added and the organic layer was separated and washed with saturated aqueous NaHCO3. To the MTBE solution containing compound 21c, water (1 ml) and triethylamine (4.42 ml, 31.74 mmol) were added and stirred at 20-25 ° C until completion of the reaction (within 74 h). The pH was adjusted with acetic acid as needed until pH 5-7 was reached. The organic layer was washed with water (2 x 30.0 ml), then concentrated in vacuo to generate iodohydrin 21a (12.7 g,
[00321] [00321] Alternatively, iodination of compound 19b using an iodizing agent such as NIS in the presence of H5IO6 can generate halohydrin 21b in a single step. The procedure is shown in Example 1-5b. Example 1-5b: methyl 3α- (ethoxycarbonyl) oxy-6α-ethyl-11β-hydroxy-12-iodo-7-keto-5β-colan-24-oate (21b)
[00322] [00322] To a stirred mixture of compound 19b (4.1 g, 8.16 mmol), H5IO6 (0.45 g, 1.63 mmol), dioxane (41 mL) and water (10.3 mL) at 0 -5 ° C M-iodosuccinimide (2.75 g, 12.24 mmol) was added. The mixture was stirred at 0-5 ° C until completion of the reaction (within 3 h), then treated with 10% by weight aqueous sodium bisulfite (20.5 ml), diluted with methanol (41 ml), then ice water (0-5 ° C) is added. The resulting precipitate was filtered and dried in vacuo to give 5.4 g of the wet compound 21b which was used directly in the next step (reducing dehalogenation step). 1H-NMR (300 MHz, CDCl3): δ 0.82 (t, J = 7.3 Hz, 3H, 26-CH3), 1.05 (d, 3H, 21-CH3), 1.10 (s, 3H, 18-CH3), 1.29 (t, J = 7.3 Hz, 3H OC (O) OCH2CH3), 1.41 (s, 3H, 19-CH3), 2.01 (s, 3H, OCOCH3 ), 3.66 (s, 3H, CO2CH3), 4.16 (q, 2H, OC (O) OCH2CH3), 4.39- 4.59 (m, 2H, 3-CH, 11-CH), 4 , 64 (d, J = 7.3 Hz, 1H, 12-CH). Example 1-6: Methyl 3α-acetoxy-12-bromo-6α-ethyl-7,11-diceto-5β-colan-24- oate (22)
[00323] [00323] To a stirred solution cooled in an ice bath of bromohydrin 21 (crude, about 113 mmol) at 6 ° C in acetone (1 L) was added dropwise the Jones reagent (32 mL) over approximately 15 min. The reaction mixture was stirred for 30 min at 6 ° C. Isopropanol (45 ml) was added dropwise. After addition, the reaction was stirred for 30 min. and filtered through Celite®. The filtrate was concentrated under reduced pressure, absorbed in CH2Cl2 (700 ml), washed with water (400 ml), aq. 10% (100 ml) and dried over Na2SO4 and concentrated under reduced pressure to give compound 22 (55 g). ES-API Pos: 584.2 [M + H2O]. 1H-NMR (200 MHz, CDCl3): δ 0.77-0.85 (m, 6H, 18-CH3, 26-CH3), 0.96 (d, J = 6.1 Hz, 3H, 21-CH3 ), 1.45 (s, 3H, 19-CH3), 2.02 (s, 3H, OCOCH3), 3.68 (s, 3H, CO2CH3), 4.28 (s, 1H, 12-CH), 4.59-4.70 (m, 1H, 3-CH). Example 1-7: Methyl 3α-acetoxy-6α-ethyl-7,11-diceto-5β-colan-24-oate (23a)
[00324] [00324] To a stirring solution of compound 22 (crude, about 113 mmol) in AcOH (1.2 L) was added NaOAc (64.5 g, 786 mmol) and Zn (56 g, 850 mmol). The resulting suspension was heated slowly to 78 ° C. After 5 h, a 1 H-NMR sample showed total consumption of compound 22. The reaction mixture was allowed to cool to room temperature and EtOAc (2.5 L) was added to the reaction mixture and the resulting suspension was filtered. The filtrate was washed with brine (2 × 500 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give crude compound 23a. This crude material was suspended in CH2Cl2 (250 ml), purified by column chromatography (SiO2, 2.5 kg, EtOAc: heptanes 1: 4) and analyzed by 1H-NMR and LCMS. ES-API Pos: 506.8 [M + H2O]. 1 H-NMR (400 MHz, CDCl3): δ 0.60 (s, 3H, 18-CH3), 0.77 (t, J = 7.3 Hz, 3H, 26-CH3), 0.86 (d , J = 5.2 Hz, 3H, 21-CH3), 1.41 (s, 3H, 19-CH3), 1.96 (s, 3H, OCOCH3), 3.64 (s, 3H, CO2CH3), 4.58-4.63 (m, 1H, 3-CH).
[00325] [00325] Alternatively, compound 23a can be prepared using a telescoped process, where compound 22 is prepared without isolation of intermediate 21 and compound 23a is prepared without isolation of compound 22. The telescoped procedure is shown below. Telescopic Procedure: methyl 3α-Acetoxy-6α-ethyl-7,11-diceto-5β-colan- 24-oate (23a)
[00326] [00326] A solution of compound 19 (1.67 kg, 3.53 mol) in acetone (3.3 L), THF (10 L) and water (3.3 L) was sparged with nitrogen and cooled to 0- 5 ° C. Dibromodimethyl hydantoin (DBH) (1.11 kg, 3.88 mol) was added in portions over 0.5 h. The mixture was stirred in the absence of light at 5-15 ° C until the reaction was complete (within 12 h). The initial reaction mixture containing compound 21 was added to a pre-cooled (0-5 ° C), stirred mixture of DBH (1.01 kg, 3.53 mol), NaOAc (0.58 kg, 7.06 mol ) and RuCl3 (22 g, 0.106 mol) in acetonitrile (4.2 L) and water (4.2 L) over 0.5 h. The mixture was stirred at 4-10 ° C until completion of the reaction (within 4 h). The reaction was quenched with 2.5% by weight NaHSO3 (18 L) and partitioned with EtOAc (18 L). The aqueous layer was backwashed with EtOAc and the combined organic layers were washed with 10% by weight Na 2 SO 4 (aq) (2 x 10 L). The EtOAc solution of compound 22 was concentrated to a final volume of 8.4 L.
[00327] [00327] To a vessel containing NaOAc (1.16 kg, 14.12 mol) and powdered zinc (1.15 kg, 17.65 mol) was added a solution of compound 22 in EtOAc (8.4 L) followed by by glacial AcOH (8 L). The mixture was heated to 70-80 ° C and stirred until completion of the reaction (within 4 h). The mixture was cooled to room temperature and filtered through Celite®, and Celite® was washed with EtOAc (3 x 4 L). The filtrate was washed sequentially with water (10 L), 8% NaHCO3 (aq) (2 x 10 L) and water (10 L). The organic layer was dried over Na2SO4, concentrated to a residue (1.74 kg) and chromatographed on silica gel (5- 10% EtOAc-Heptane). The product-rich fractions were pooled and concentrated to give compound 23a (0.882 kg) in 51.1% yield (from compound 19). Fractions containing compound 19 (a by-product of the reaction) were pooled and concentrated to give 0.266 kg of recovered compound 19. Example 1-8: 3α-hydroxy-7,11-diceto-6α-ethyl-5β-colan-24-oic acid (40)
[00328] [00328] To a stirring solution of compound 23a (9.7 g, 19.8 mmol) in MeOH (170 mL) was added NaOH (9 g, 225 mmol). The resulting solution was heated at 45 ° C for 18 h. 1H-NMR showed total conversion. The mixture was concentrated to approximately 30 ml. Water (150 ml) was added. The mixture was cooled in an ice bath and aq. to 3 N was added dropwise until pH <2. The resulting suspension was stirred for an additional 0.5 h. The product was filtered off, washed with water (20 ml) and dried in vacuo to give 9.45 g of compound 40 as a beige solid (about 100% yield), which was used without purification in the next reaction step. ES-API Pos: 450.6 [M + H2O]. 1H-NMR (400 MHz, CDCl3): δ 0.63 (s, 3H, 18-CH3), 0.81 (t, J = 7.2 Hz, 3H, 26-CH3), 0.91 (d, J = 5.2 Hz, 3H, 21-CH3), 1.44 (s, 3H, 19-CH3), 3.55-3.59 (m, 1H, 3-CH). Example 1-9: 3α, 7α, 11β-trihydroxy-6α-ethyl-5β-colan-24-oic acid (100)
[00329] [00329] To a chilled solution in a stirred ice bath of diketone 40 (about 6.7 g, 15.5 mmol) in a mixture of THF (160 mL) and water (30 mL), NaBH4 (3.48 g , 91 mmol) was added in small portions. The resulting solution was stirred for 18 h at room temperature. 1H-NMR showed total conversion. Brine (40 ml), EtOAc (100 ml) and aq. 2 N (up to pH <2) were added, the layers were separated. The aqueous layer was extracted again with EtOAc (100 ml). The combined organic extracts were washed with brine (25 ml), dried over Na2SO4 and concentrated under reduced pressure to give 6.2 g of compound 100. The final product was purified by column chromatography. ES-API Neg: 435.5 [M-H]. 1 H-NMR (400 MHz, CD3OD): δ 0.89-0.92 (s, 6H, 18-CH3, 26-CH3), 1.00
[00330] [00330] To a solution of compound 23a (442 mg, 0.91 mmol) in THF / MeOH (9 mL, 1: 1), CeCl3.7H2O (674 mg, 1.81 mmol) and LiBH4 (69 mg, 3 , 62 mmol) were sequentially added in one portion at 0 ° C. The resulting mixture was stirred at 0 ° C for 4 h. The mixture was diluted with CH2Cl2 (15 mL) and quenched at 0 ° C by adding H2O (15 mL) and 3 N HCl (15 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2 x 15 ml). The combined organic extracts were washed with H2O (20 ml), brine (20 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude (444 mg) was dissolved in MeOH / H2O (4.5 ml, 9: 1) and stirred overnight at room temperature in the presence of NaOH (360 mg, 9.01 mmol). The mixture was concentrated under reduced pressure and the residue was dissolved in CH2Cl2 (20 ml) and acidified with 3N HCl. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3 x 20 ml). The combined organic extracts were washed with H2O (30 ml), brine (30 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel giving 272 mg of pure compound 100 (0.62 mmol). ES- API Neg: 435.5 [M-H]. 1H-NMR (400 MHz, CD3OD): δ 0.89-0.92 (s, 6H,
[00331] [00331] To a solution of methyl 3α-acetoxy-7-keto-Δ11,12-6α-ethyl-5β-cholan-24-oate (19) (1.1 g, 2.4 mmol) in THF / H2O (24 mL, 4: 1), freshly crystallized N-iodosuccinimide (807 mg, 3.59 mmol) and Jones reagent (2.4 mL) were sequentially added at room temperature and the resulting mixture was refluxed for 1 H. The mixture was allowed to cool to room temperature and was then quenched by adding MeOH (25 ml) and 5% w / v aqueous solution of Na2S2O3 (25 ml). The mixture was diluted with EtOAc and filtered on a pad of Celite. The organic phase was washed with saturated aqueous NaHCO3, H2O, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude (1.39 g, 95% recovery) was dissolved in AcOH (24 mL) and refluxed for 1.5 h in the presence of NaOAc (1.18 g, 14.3 mmol) and Zn powder ( 1.17 g, 17.9 mmol). The suspension was allowed to cool to room temperature and was filtered on a short pad of Celite. The mixture was diluted with EtOAc and washed with H2O, aqueous saturated solution of NaHCO3, H2O, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure giving the crude diceto intermediate 23a (1.07 g, 92% recovery) as pale yellow solid. To a solution of 3α-acetoxy-7,11-diceto-6α-ethyl-5β-colan-24-oate (23a) (442 mg, 0.91 mmol) in anhydrous THF / MeOH (9 mL, 1: 1), CeCl3.7H2O (674 mg, 1.81 mmol) and LiBH4 (69 mg, 3.62 mmol) were sequentially added in one portion at 0 ° C and the resulting mixture was stirred at 0 ° C for 4 h. The mixture was diluted with CH2Cl2 and quenched at 0 ° C by adding H2O and 3N HCl. The phases were separated and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were washed with H2O, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude (444 mg) was dissolved in MeOH / H2O (4.5 ml, 9: 1) and stirred overnight at room temperature in the presence of NaOH (360 mg). The mixture was concentrated under reduced pressure and the residue was dissolved in CH2Cl2 and acidified with 3 N HCl (pH = 2). The phases were separated and the aqueous phase was extracted with CH2Cl2. The combined organic extracts were washed with H2O, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel, giving 280 mg of compound 100. Alternative Procedure:
[00332] [00332] A solution of compound 40 (0.736 kg, 1.70 mol) in water (6.94 L) containing 50% by weight NaOH (0.734 kg, 9.18 mol) was heated to 74-80 ° C. A solution of NaBH4 (0.135 kg, 3.57 mol) in water (0.37 L) containing 50% by weight NaOH (68 g, 0.85 mol) was added and the mixture was stirred until completion of the reaction ( within 21 h). The mixture was cooled and MTBE (7.3 L) was loaded, followed by the addition of 3 N HCl (aq) (ca. 4.4 L) until pH 2 was reached. The organic layer was discarded and the organic layer was washed with water (5.4 L), then dried over Na2SO4 and concentrated to 1.2 L. The product solution was diluted with heptane (0.25 L) and chromatographed on silica gel (MTBE-Heptane 75- 80%). The product-containing fractions were concentrated to a solid and dissolved in water (5 L) containing 50% by weight NaOH (0.242 kg). The solution was concentrated in vacuo to remove ca. 2.2 L of distillates. The mixture was acidified to pH 2 with 2 N HCl (1.55 L) and the suspension was further diluted with water (3 L). The suspension was heated to 40 ° C for 1 h,
[00333] [00333] A synthesis analogous to that shown in Exemplary Route 4 can proceed through intermediate 47a, which can be prepared by reducing dehalogenation of the compound of formula 21a under mild hydrogenation conditions in the presence of catalytic palladium and a base as shown in Example 1 -10. Example 1-10: Methyl 3α-acetoxy-6α-ethyl-11β-hydroxy-7-keto-5β-colan-24-oate (47a)
[00334] [00334] A mixture of compound 21a (100 mg, 0.16 mmol), Pd / C (12 mg), imidazole (54.5 mg, 0.80 mmol), MTBE (1.5 mL) and water (1 mL) was stirred under a hydrogen atmosphere (1 atm) at 20-25 ⁰C. The mixture was stirred at 20-25 ° C until completion of the reaction. The mixture was filtered through Celite® and Celite® was washed with MTBE (2 ml). The organic layer was separated and washed with water (2 x 1 ml), then concentrated to generate compound 47a (67 mg) in 78.5% yield.
[00335] Alternatively, as shown in Route 4, the reducing dehalogenation of the compound of formula 21b under mild hydrogenation conditions in the presence of catalytic palladium and a base can produce compound 47b as shown in Example 1-10a. Example 1-10a: methyl 3α- (ethoxycarbonyl) oxy-6α-ethyl-11β-hydroxy-7-keto-5β-colan-24-oate (47b)
[00336] [00336] A mixture of compound 21b (5.4 g, wet weight), NaOAc (3.35 g, 40.8 mmol), Pd / C (0.41 g) in MeOH (82 mL) was stirred under a hydrogen atmosphere (0.5 to 2 bar) at 20-25 ⁰C until the reaction is complete (within 18 h). The mixture was filtered over Celite® and the filtrate was added to a cold solution (0-5 ⁰C) of 0.2% by weight sodium bisulfite (aq). The resulting solids were filtered, washed with water and dried in vacuo to give compound 47b (3.6 g) as a solid in 84.8% yield (2-step yield from compound 19b). 1H-NMR (300 MHz, CDCl3): δ 0.81 (t, J = 7.3 Hz, 3H, 26-CH3), 0.88 (s, 3H, 18-CH3), 0.91 (d, 3H, 21-CH3), 1.28 (t, J = 7.3 Hz, 3H OC (O) OCH2CH3), 1.46 (s, 3H, 19-CH3), 3.66 (s, 3H, CO2CH3 ), 4.00 - 4.24 (m, 3H, OC (O) OCH2CH3, 11-CH), 4.39-4.69 (m, 1H, 3-CH). Example 1-11: methyl 3α- (ethoxycarbonyl) oxy-6α-ethyl-7α, 11β-dihydroxy-5β-cholan- 24-oate (49b)
[00337] [00337] A solution of compound 47b (3.6 g, 6.91 mmol) in methanol (72 mL) was cooled to 0-5 ° C with stirring. To the cold solution, NaBH4 (0.522 g, 13.82 mmol) was added in portions and continued to stir at 0-5⁰C until the reaction was completed (within 1.5 h). The reaction was quenched with 1 N HCl and the resulting precipitate was filtered, washed with water and dried in vacuo to generate compound 49b (3.26 g) as a solid in 90% yield. 1H-NMR (300 MHz, CDCl3): δ
[00338] [00338] To a solution of compound 49b (1.5 g, 2.8 mmol) in methanol (15 mL) at room temperature with stirring was added LiOH (0.20 g, 8.4 mmol). The mixture was heated to 30-35 ° C and was stirred until completion of the reaction (within 36 h). Water (20 ml) was added and the mixture was concentrated in vacuo. The residue was diluted with water (20 ml) and MTBE (40 ml), then acidified with 1 N HCl (aq) until pH 1-2. The solids were filtered in vacuo and washed with water, then dried in vacuo to generate compound 100 (1.1 g, 2.5 mmol) in 91% yield. Example 2-1: 3α, 7α-dihydroxy-6α-ethyl-12β-methyl-13-nor-5β-cholan-24-oic acid (45)
[00339] [00339] To a solution of compound 18 (49 mg, 0.1 mmol) in anhydrous DCM (0.5 ml) and pyridine (2.4 eq) at -15 ~ -10 ⁰C was added Tf2O (1.1 eq ). The reaction was gradually warmed to 0 - 5 ⁰C and stirred for 2 h, then gradually warmed to room temperature and stirred for an additional 15 h. The reaction was diluted with ethyl acetate and washed with 1 N HCl (aq), aqueous NaHCO3 and saturated aqueous NaCl. The organic layer was dried over Na2SO4, concentrated and chromatographed on silica gel (10% ethyl acetate in heptanes) to give 40 mg of compound 44 as a mixture of regioisomers (85% yield). ES-API Pos: 473.2 [M + 1]; 413.2 [M - OAc]. 1H- NMR (300 MHz, CDCl3): δ 0.84 (t, 3H, 26-CH3), 0.98 (d, 3H, 21-CH3), 1.14 (s, 3H, 19-CH3), 1.59 (s, 3H, 18-CH3), 2.00 (s, 3H, -OCOCH3), 3.66 (s, 3H, CO2CH3), 4.63-4.67 (m, 1H, 3- CH).
[00340] [00340] The product (compound 44) is dissolved in methanol and 5% palladium on carbon is added. The mixture is stirred in the presence of hydrogen pressure until the hydrogenation is complete. The product mixture is filtered and treated with excess LiOH until the reaction is complete. The mixture was quenched with HCl (aq) and the product was extracted with DCM, washed with water, dried over Na2SO4 and concentrated to dryness. The product from the previous step was dissolved in aqueous NaOH and contacted with NaBH4 and stirred until the reaction was complete. The reaction is quenched with HCl (aq) and extracted in ethyl acetate, washed with water and dried over Na2SO4. The ethyl acetate solution was concentrated to dryness to generate 20 mg of Compound 45. ES-API Pos: 492.2 [M + H2O]. 1H-NMR (300 MHz, CDCl3): δ 0.75-0.90 (m, 6H, C18-CH3 / 26-CH3), 0.93 (d, 3H, 21-CH3), 1.14 (s , 3H, 19-CH3), 1.98 (s, 3H, -OCOCH3), 3.64 (s, 3H, CO2CH3), 4.55-4.69 (m, 1H, 3-CH).

权利要求:
Claims (1)
[1]
1. Method of preparing a compound characterized by the fact that it has formula I
I or its salt, hydrate, solvate or conjugate of amino acid, sulfate or glucuronide or pharmaceutically acceptable prodrug, wherein: R1 is OH, alkoxy or oxo; R2 and R3 are each independently H, OH, OSO3H, OCOCH3, OPO3H2, halogen or alkyl optionally substituted by one or more halogens or OH, or R2 and R3 taken together with the carbon atom to which they are attached form a carbonyl; R4 is H, halogen, alkyl optionally substituted by one or more halogens or OH, alkenyl or alkynyl; R5 and R6 are each independently H, OH, OSO3H, OCOCH3, OPO3H2, halogen or alkyl optionally substituted by one or more halogens or OH, or R5 and R6 taken together with the carbon atom to which they are attached form a carbonyl; R7 is OH, OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, CO2H, C (O) NHOH, NH (CH2) 2SO3H, NHCH2CO2H or tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazol 5-oxo-1,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxy-isoxazolyl, 3-hydroxy-isothiazolyl, pyrimidine, 3,5-difluoro-4-hydroxyphenyl or 2,4-difluoro- Optionally substituted 3-hydroxyphenyl; R8, R9 and R10 are each independently H, OH, halogen or alkyl optionally substituted by one or more halogens or OH, or R8 and R9 taken together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring with 3 to 6 members comprising 1 or 2 heteroatoms selected from N, O and S, or R9 and R10 taken together with the carbon atoms to which they are attached form a 3 to 6 membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O and S; m is 0, 1 or 2; n is 0 or 1; and P is 0 or 1; the method comprising the step of reacting a compound of formula I-4 with a halogenating reagent to provide a compound of formula I-5a, where X is, where R7, R8, R9 and R10 can be protected by R11 or another group protector.
2. Method according to claim 1, characterized by the fact that the compound of formula I is the compound of formula I-9 I-9 or its salt, hydrate, solvate or amino acid conjugate,
sulfate or glucuronide or pharmaceutically acceptable prodrug.
3. Method according to claim 1, characterized by the fact that the compound of formula I is the compound of formula II
II or its salt, hydrate, solvate or conjugate of amino acid, sulfate or glucuronide or pharmaceutically acceptable prodrug.
4. Method according to claim 1, characterized by the fact that the compound of formula I is the compound of formula III
III or its salt, hydrate, solvate or conjugate of amino acid, sulfate or glucuronide or pharmaceutically acceptable prodrug, where it is R2 and R5 and OH.
5. Method according to claim 1, characterized by the fact that the compound of formula I is the compound of formula 100
100.
6. Method according to claim 1,
characterized by the fact that the halogenating agent is a brooding agent.
7. Method according to claim 1, characterized by the fact that the halogenating reagent is an iodizing reagent.
Method according to claim 1, characterized in that it further comprises conversion of the compound of the formula I-1 into the compound of the formula I-4 comprising the steps of 1) protecting the compound of the formula I-1 to provide the compound of the formula I-2; 2) forming a C12 labile group to provide the compound of formula I-3; and 3) elimination of the C12 labile group to provide the alkene compound of formula I-4.
9. Method according to claim 1, characterized in that it further comprises converting the compound of formula I-5a into the compound of formula I-6a comprising the step of 5) reacting the compound of formula I-5a with an agent oxidant to prepare a compound of formula I-6a.
Method according to claim 9, characterized in that it further comprises converting the compound of formula I-6a into the compound of formula I-7 comprising step 6) reacting the compound of formula I-6a with an agent reducing agent to prepare the compound of formula I-7.
11. Method according to claim 10, characterized in that it further comprises conversion of the compound of formula I-7 into the compound of formula I comprising the steps of 7) optional deprotection of the compound of formula I-7 to obtain the compound of formula I-8 and 8) reaction of the compound of formula I-7 or I-8 with a reducing agent to provide the compound of formula I.
12. Method according to claim 1, characterized in that it further comprises conversion of the compound of the formula I-5 or I-5b into the compound of the formula I comprising the steps of: 4) reaction of the compound of the formula I-5b with a reducing agent to prepare the compound of formula I-5c; 5) reacting the compound of formula I-5c with a reducing agent to provide the compound of formula I-5d; and 6) deprotection of the compound of formula I-5d to provide the compound of formula I.
13. Method according to claim 10, characterized in that it further comprises conversion of the compound of the formula I-7 or I-7a into the compound of the formula I comprising the steps of: 3) reaction of the compound of the formula I-7a with a reducing agent to provide the compound of formula I-8a; 4) deprotection of the compound of formula I-8a to obtain the compound of formula I.
14. Method according to claim 6, characterized by the fact that the brominated agent is N-bromosuccinimide.
15. Method according to claim 7, characterized by the fact that the iodizing agent is N-iodosuccinimide.
16. Method according to claim 9, characterized by the fact that the oxidizing agent is RuCl3.
17. Method according to claim 10, characterized by the fact that the reducing agent is zinc metal.
18. Method according to claim 11, characterized by the fact that the reducing agent is sodium borohydride.
19. Method of preparing a compound characterized by the fact that it has the formula D5 D5 or its salt, hydrate, solvate or conjugate of amino acid, sulfate or glucuronide or pharmaceutically acceptable prodrug, in which: R7 is OH, OSO3H, SO3H, OSO2NH2 , SO2NH2, OPO3H2, PO3H2, CO2H, C (O) NHOH, NH (CH2) 2SO3H, NHCH2CO2H or tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-1,2,4-oxadiazolyl, 5-oxo-1,2,4 - thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxy-isoxazolyl, 3-hydroxy-isothiazolyl, pyrimidine, 3,5-difluoro-4-hydroxyphenyl or optionally substituted 2,4-difluoro-3-hydroxyphenyl; R8, R9 and R10 are each independently H, OH, halogen or alkyl optionally substituted by one or more halogens or OH, or R8 and R9 taken together with the carbon atoms to which they are attached form a carbocyclic or heterocyclic ring with 3 to 6 members comprising 1 or 2 heteroatoms selected from N, O and S, or R9 and R10 taken together with the carbon atoms to which they are attached form a 3 to 6 membered carbocyclic or heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O and S;
m is 0, 1 or 2; n is 0 or 1; and P is 0 or 1; the method comprising the steps of a) protecting a compound of formula D to prepare a compound of formula D1; b) reacting the compound of the formula D1 with an activating reagent to convert the C-12 alcohol into a labile group, thus preparing a compound of the formula D2; c) reacting the compound of the formula D2 with a base to prepare the compound of the formula D3; d) reacting a compound of the formula D3 with a hydrogen source in the presence of a hydrogenation catalyst to generate a compound of the formula D4; and e) reaction of a compound of the formula D4 with deprotecting reagents and a reducing agent to prepare a compound of the formula D5, where R11 is a protecting group, X is, where R7, R8, R9 and R10 can be protected by R11 or other protective group.
20. Method according to claim 20,
characterized by the fact that the compound of formula D5 is the compound of formula 45
45.

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法律状态:
2021-07-13| B15K| Others concerning applications: alteration of classification|Free format text: AS CLASSIFICACOES ANTERIORES ERAM: C07J 41/00 , C07J 43/00 Ipc: C07J 41/00 (2006.01), C07J 43/00 (2006.01), A61P 1 |

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2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201762523937P| true| 2017-06-23|2017-06-23|

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US62/523,937|2017-06-23|

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PCT/US2018/039148|WO2018237350A1|2017-06-23|2018-06-22|Methods and intermediates for the preparation of bile acid derivatives|

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