WO2023288123A1 - Procédés et intermédiaires pour la préparation d'acide 3.alpha.,7.alpha.,11.bêta.-trihydroxy-6.alpha.-éthyl-5.bêta.-cholan-24-oïque - Google Patents

Procédés et intermédiaires pour la préparation d'acide 3.alpha.,7.alpha.,11.bêta.-trihydroxy-6.alpha.-éthyl-5.bêta.-cholan-24-oïque Download PDF

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WO2023288123A1
WO2023288123A1 PCT/US2022/037426 US2022037426W WO2023288123A1 WO 2023288123 A1 WO2023288123 A1 WO 2023288123A1 US 2022037426 W US2022037426 W US 2022037426W WO 2023288123 A1 WO2023288123 A1 WO 2023288123A1
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compound
disease
present application
conjugate
carried out
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PCT/US2022/037426
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English (en)
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Gabriel Galvin
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Interecept Pharmaceuticals, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/001—Oxiranes

Definitions

  • Bile acids modulate famesoid X receptor (FXR) and regulate FXR-mediated diseases and conditions.
  • Natural bile acids such as chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), and the taurine and glycine conjugates thereof are known FXR ligands.
  • PBC primary biliary cholangitis
  • the present application provides methods of preparing bile acid derivatives.
  • the present application relates to a method of preparing a compound of formula I: or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, wherein R 1 , R 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , m, n, and p are as described herein.
  • the present application relates to a method of preparing a compound of formula II: or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, wherein R 1 , R 2 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , m, n, and p are as described herein.
  • the present application relates to a method of preparing a compound of formula III: or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, wherein R 2 , R 4 , R 5 , R 7 , R 8 , R 9 , R 10 , m, n, and p are as described herein.
  • the present application relates to Compound A, Compound B, Compound B’, Compound C, Compound C’, Compound D, Compound El, Compound EG, Compound El”, EE”, Compound E2a, Compound E2b, Compound E3a, Compound E3b, or Compound F.
  • the present application relates to Compound A-l, Compound B-l, Compound B-E, Compound C, Compound C’, Compound D, Compound El, Compound EE, Compound El”, Compound EE”, Compound E2a, Compound E2b, Compound E3a, Compound E3b, or Compound F.
  • a compound of the disclosure or “a compound of the application” refers to a compound of any one of formulae 1, 1-9, 1-9a, II, III, Ilia, or Illb, or any other compound explicitly disclosed herein.
  • C1-C6 alkyl or “Aik” or “alkyl”, as used herein, refers to a straight- chain or branched hydrocarbon moiety having 1, 2, 3, 4, 5, or 6 carbon atoms.
  • Ci-Ce alkyl moieties include, but are not limited to, methyl, ethyl, «-propyl, isopropyl, cyclopropyl, «-butyl, isobutyl, sec-butyl, /-butyl, «-pentyl, isopentyl, and «-hexyl.
  • C1-C4 alkyl refers to a straight-chain or branched hydrocarbon moiety having 1, 2, 3, or 4 carbon atoms.
  • alkenyl refers to a straight-chain or branched hydrocarbon moiety 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”.
  • alkenyl moieties include, but are not limited to, vinyl, allyl, 1-butenyl, 2-butenyl, 3- butenyl, and 2-hexenyl.
  • alkynyl refers to a straight-chain or branched hydrocarbon moiety containing at least one carbon-carbon triple bond.
  • alkynyl moieties include, but are not limited to, ethynyl, 2-propynyl, 5-but-l-en-3-ynyl, and 3-hexynyl.
  • alkoxy refers to a straight-chain or branched saturated hydrocarbon covalently attached to an oxygen atom.
  • alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropyloxy, «-propoxy, «-butoxy, /-butoxy, and pentoxy.
  • halogen or “Hal” refers to fluorine, bromine, chlorine, and iodine.
  • Carbocycle 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 may be saturated, unsaturated, or aromatic.
  • Carbocyclic ring includes cycloalkyl and aryl.
  • a C3-C8 carbocyclic ring is intended to include a monocyclic or bicyclic ring having 3,4, 5, 6, 7, or 8 carbon atoms.
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, and phenyl.
  • heterocycle includes any ring structure (saturated, unsaturated, or aromatic) which contains at least one ring heteroatom (e.g ., 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.
  • heterocyclic groups include, but are not limited to, benzimidazolyl, benzofuranyl, benzothiofuranyl, tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, pyridinyl, pyridyl, and pyrimidinyl.
  • cycloalkyl refers to a saturated or unsaturated nonaromatic hydrocarbon mono- or multi-ring (e.g., fused, bridged, or spiro rings) system having 3 to 10 carbon atoms (e.g, C3-C6).
  • cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • any recited moiety which 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 moiety which may or may not be substituted, and when substituted is mono-, di-, or tri- substituted, such as with 1, 2, or 3 substituents. In some instances, the substituent is halogen or OH.
  • protecting group refers to an appropriate moiety for masking, for example, a hydroxyl functionality, which is stable/non-reactive under the reaction condition (e.g, non-reactive with an agent used in the reaction).
  • a hydroxyl functionality which is stable/non-reactive under the reaction condition (e.g, non-reactive with an agent used in the reaction).
  • moieties employed for protecting certain functional groups e.g, hydroxyl group, instead of another functionality, e.g, carboxylic acid.
  • the protecting group reagents include, but are not limited to, acylating agents (e.g, acetic anhydride, benzoyl chloride, pivaloyl chloride, etc.), silylating agents (e.g ., TMS-C1, TES- Cl, TBDMS-C1, etc.), ether forming reagents (MOM-C1, MEM-C1, dihydropyran, ethyl vinyl ether, haloalkanes such as iodomethane, bromomethane, iodoethane, bromoethane, etc.), chloroformates (methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, benzyl chloroformate, etc.), in the presence of an appropriate base (e.g., carbonate salts, bicarbonate salts, pyridine, triethylamine, diisopropyl ethylamine, N-methylmorpho
  • an ester-based solvent e.g, methyl acetate, ethyl acetate, isopropyl acetate, ethyl formate, methyl trifluoroacetate, methyl propionate, etc.
  • an acid e.g, methanesulfonic acid, p-toluenesulfonic acid, cone sulfuric acid, etc.
  • LG refers to a labile functionality that has a propensity to dissociate from carbon (e.g, Cl, Br, I, sulfonated alcohols such as methane sulfonates, p-toluenesulfonates, trifluoromethane sulfonates, trifluoroacetates, sulforylated alcohols, phosphorylated alcohols, etc.).
  • the leaving groups can be either replaced with another functional group or eliminated, e.g, to produce an unsaturated compound.
  • phrases “pharmaceutically acceptable carrier” is art-recognized, 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 carrying or transporting any subject composition from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically acceptable carrier is non-pyrogenic.
  • materials which may 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, com 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)
  • pharmaceutically acceptable excipient refers to an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutical composition” is a formulation containing a compound of the present application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • 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 on an aerosol inhaler, or a vial.
  • the quantity of active ingredient e.g ., a formulation of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof
  • a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • active ingredient e.g ., a formulation of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof
  • the dosage will also depend on the route of administration.
  • routes including oral, ocular, ophthalmic, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of this application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
  • amino acid conjugates refers to conjugates of a compound of the application with any suitable amino acid.
  • Taurine -NH ⁇ CThjiSCbH
  • glycine -NHCH2CO2H
  • sarcosine -N ⁇ CHajCtfcCC H
  • Suitable amino acid conjugates of the compounds have the added advantage of enhanced integrity in bile or intestinal fluids.
  • Suitable amino acids include, but are not limited to taurine, glycine, and sarcosine.
  • the amino acid conjugates of the compounds of the application can be prepared according to methods known in the art.
  • a free or protected bile acid or bile acid derivative can be coupled to an amino acid (protected or unprotected), e.g ., glycine, sarcosine, or taurine amino acid, using standard peptide coupling conditions (e.g, in the presence of a base (e.g, tri ethyl amine, diisopropyl ethylamine (DIPEA), etc.) and specific coupling reagents, for example, N-Ethoxycarbonyl- 2-ethoxy-l,2-dihydroquinoline (EEDQ), 4-(4,6-Dimethoxy-l,3,5-triazin-2-yl)-4- methylmorpholinium chloride (DMTMM), etc.).
  • a base e.g, tri ethyl amine, diisopropyl ethylamine (DIPEA), etc.
  • specific coupling reagents for example, N-Ethoxycarbonyl- 2-e
  • the term “metabolite” refers to glucuroni dated and sulfated derivatives of the compounds described herein, wherein one or more glucuronic acid or sulfate moieties are linked to the compound of the application.
  • Glucuronic acid moieties may be linked to the compounds through glycosidic bonds with the hydroxyl groups of the compounds (e.g, 3-hydroxyl, 7-hydroxyl, 11-hydroxyl, and/or the hydroxyl of the R 7 group).
  • Sulfated derivatives of the compounds may be formed through sulfation of the hydroxyl groups (e.g, 3-hydroxyl, 7-hydroxyl, 11-hydroxyl, and/or the hydroxyl of the R 7 group).
  • metabolites include, but are not limited to, 3-O-glucuronide, 7-0- glucuronide, 11-O-glucuronide, 3-0-7-0-diglucuronide, 3-0-11-O-triglucuronide, 7-0-11- O-triglucuronide, and 3-0-7-0-11-O-triglucuronide, of the compounds described herein, and 3-sulfate, 7-sulfate, 11-sulfate, 3, 7-bi sulfate, 3, 11-bi sulfate, 7, 11-bi sulfate, and 3,7,11- trisulfate, of the compounds described herein.
  • glucuronides have similar or even greater biological activity compared to their corresponding parent drug molecules.
  • active glucuronide is morphine 6-0-glucuronide, which has even more analgesic action than morphine.
  • the Koenigs-Knorr reaction is one of the most widely applied methods for the synthesis of alkyl and aryl O-glucuronide compounds.
  • the aglycone starting alcohol or phenol
  • the substrate molecule has multiple glucuronidation sites
  • chemical synthesis can yield a mixture of mono- and polyglucuronides unless the unwanted glucuronidation sites are protected.
  • the reaction gives glucuronides in variable yields depending on the catalyst, solvent, aglycone, and the ratio of the starting materials used.
  • prodrug refers to a bile acid derivative or compound that, after administration, is metabolized (z.e., converted within the body) into a pharmacologically active drug.
  • Inactive prodrugs are pharmacologically inactive medications that are metabolized into an active form within the body. Instead of administering a drug directly, a corresponding prodrug might be used instead to improve how a medicine 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 may 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 severe unintended and undesirable side effects.
  • treating refers to relieving, lessening, reducing, eliminating, modulating, or ameliorating, z.e., causing regression of the disease state or condition.
  • preventing refers to completely or almost completely stop a disease state or condition, from occurring in a patient or subject, especially when the patient or subject is predisposed to such or at risk of contracting a disease state or condition.
  • Preventing can also include inhibiting, z.e., arresting the development, of a disease state or condition, and relieving or ameliorating, z.e., causing regression of the disease state or condition, for example when the disease state or condition may already be present.
  • reducing the risk of refers to lowering the likelihood or probability of a central nervous system disease, inflammatory disease and/or metabolic disease from occurring in a patient, especially when the subject is predisposed to such occurrence.
  • “Combination therapy” refers to the administration of a compound of the application and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents (i.e., the compound of the application and at least a second agent).
  • the beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
  • Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
  • “Combination therapy” may, but generally is not, intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present application.
  • “Combination therapy” is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be affected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
  • the sequence in which the therapeutic agents are administered is not narrowly critical.
  • Combination therapy also embraces the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g surgery or mechanical treatments).
  • the combination therapy further comprises a non-drug treatment
  • the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved.
  • the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
  • “combination therapy” means that a compound of the application can be administered in conjunction with another therapeutic agent.
  • “In conjunction with” refers to 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 administration of one treatment modality before, during, or after delivery of a second treatment modality to the subject.
  • an “effective amount” of a compound of the application, or a combination of compounds is an amount (quantity or concentration) of compound or compounds.
  • a therapeutically effective amount of a compound is administered to a subject in need of treatment symptoms arising from the disease are ameliorated 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 disorder, the mode of administration, coadministered 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 artisan will be able to determine appropriate dosages depending on these and other factors.
  • prophylactically effective amount means an amount (quantity or concentration) of a compound of the present application, or a combination of compounds, that is administered to prevent or reduce the risk of a disease - in other words, an amount needed to provide a preventative or prophylactic effect.
  • amount of the present compound to be administered to a subject will depend on the particular disorder, the mode of administration, coadministered 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 artisan will be able to determine appropriate dosages depending on these and other factors.
  • a “subject” includes mammals, e.g ., humans, companion animals (e.g. , dogs, cats, birds, and the like), farm animals (e.g, cows, sheep, pigs, horses, and the like), and laboratory animals (e.g, rats, mice, guinea pigs, and the like). Typically, the subject is human.
  • companion animals e.g. , dogs, cats, birds, and the like
  • farm animals e.g, cows, sheep, pigs, horses, and the like
  • laboratory animals e.g, rats, mice, guinea pigs, and the like.
  • the subject is human.
  • farnesoid X receptor or FXR refers to all mammalian forms of such receptor including, for example, alternative splice isoforms and naturally occurring isoforms (see, e.g, Huber etal., Gene 290:35-43 (2002)).
  • Representative FXR species include, without limitation rat FXR (GenBank Accession No. NM 021745), mouse FXR (GenBank Accession No. NM 009108), and human FXR (GenBank Accession No. NM 005123).
  • the present application relates to a method of preparing a compound of formula I: or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, wherein: each is independently a single bond or a double bond;
  • R 1 is OH, alkoxy, or oxo
  • R 2 and R 3 are each independently H, OH, OSO3H, 00(0)03 ⁇ 4, OPO3H2, halogen, or alkyl optionally substituted with one or more halogen or OH; or
  • R 2 and R 3 taken together with the carbon atom to which they are attached form a carbonyl
  • R 4 is H, halogen, alkyl optionally substituted with one or more halogen or OH, alkenyl, or alkynyl;
  • R 5 and R 6 are each independently H, OH, OSO 3 H, 0C(0)CH 3 , OPO 3 H 2 , halogen, or alkyl optionally substituted with one or more halogen or OH; or
  • R 5 and R 6 taken together with the carbon atom to which they are attached form a carbonyl
  • R 7 is OH, OSO 3 H, SO 3 H, OSO 2 NH 2 , SO 2 NH 2 , OPO 3 H 2 , PO 3 H 2 , CO 2 H, C(0)NH0H, NH(CH 2 ) 2 S0 3 H, NHCH 2 CO 2 H, tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-
  • R 8 , R 9 , and R 10 are each independently H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH; or
  • R 10 is H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH; and R 8 and R 9 , 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; or R 8 is H, OH, halogen, or alkyl optionally substituted with one or more halogen or OH; and R 9 and R 10 , 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 at least one of the following steps:
  • Step 1-1 Converting Compound A-l to Compound B-l:
  • Step 4-1 Converting Compound D to Compound El :
  • Step 5-1 Converting Compound El to Compound F:
  • the present application relates to a method of preparing a compound of formula I: or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, wherein R 1 , R 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , m, n, and p are each as defined above, the method comprising at least one of the following steps: Step 1-2. Converting Compound A to Compound B:
  • Step 4-1 Converting Compound D to Compound El :
  • the present application relates to a method of preparing a compound of formula I: or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, wherein R 1 , R 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , m, n, and p are each as defined above, the method comprising at least one of the following steps: Step 1-2. Converting Compound A to Compound B:
  • Step 4-2a Converting Compound D to Compound E2a:
  • Step 4-2b Converting Compound E2a to Compound E2b:
  • Step 5-2 Hydrogenating Compound E2b to form Compound F:
  • Step 6 converting Compound F to Compound 100:
  • the present application relates to a method of preparing a compound of formula I: or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, wherein R 1 , R 2 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , m, n, and p are each as defined above, the method comprising at least one of the following steps: Step 1-2. Converting Compound A to Compound B:
  • Step 4-3 a Converting Compound D to Compound E3a:
  • Step 4-3b Converting Compound E3a to Compound E3b:
  • Step 5-3 Hydrogenating Compound E3b to form Compound F:
  • Step 1-1 comprises converting Compound A-l to Compound B-l by mixing Compound A with a monooxygenase.
  • the monooxygenase is a cytochrome P450 enzyme (“CYP450”).
  • the CYP450 is an animal CYP450, i.e., a CYP450 obtained from an animal.
  • the CYP450 is a plant CYP450, i.e., a CYP450 obtained from a plant.
  • Step 1-1 comprises converting Compound A-l to Compound B-l under microbial conditions.
  • Step 1-1 comprises converting Compound A-l to Compound B-l by mixing Compound A with a natural or genetically modified mircroorganism (e.g. a bacterium, a fungus, an algae, a prokaryotic cell, a eukaryotic cell, an insect caell, or a mammalian cell (e.g. a human cell)) which expresses a cytochrome P450 monooxygenase (e.g. CYP7A, more prefereably CYP11B1) or other enzyme capable of catalyzing a stereoselective oxidation reaction.
  • a natural or genetically modified mircroorganism e.g. a bacterium, a fungus, an algae, a prokaryotic cell, a eukaryotic cell, an insect caell, or a mammalian cell (e.g. a human cell
  • the stereoselective oxidative catalysis by a cytochrome P450 monooxygenase or other enzyme is conducted by a microorganism.
  • the microorganism is selected from the group consisting of Absidia, Aspergillus , Cephalosporium , Cunningamella , Curvularia , Diplodia , Dothideales , Fusarium , Gibberella , Helminthosporium , Hypocreales , Mucor, Mucorales, Rhizopus , Saccharomyces .
  • the microorganism is selected from Cephalosporium aphidicola , Cladosporium herbarum , Colletotrichum lini , Fusarium culmorum , A. moniliforme , A.
  • the Hypocreaceae family e.g, Fusarium sp.
  • the Mucoraceae family e.g, Rhizopus nig
  • Rhodococcus pyridinivorans Rhodococcus erythropolis, Rhodococcus opacus, Rhodococcus ruber, Rhodococcus globerulus, Rhodococcus wratislaviensis
  • Pseudomonas sp. e.g, Pseudomonas syringiae, Pseudomonas fluorescens
  • Lactobacillus sp. e.g, Lactobacillus mesenter, Lactobacillus sake, Lactobacillus farciminis, Lactobacillus kefiri
  • Burkholderia sp e.g, Rhodococcus pyridinivorans, Rhodococcus erythropolis, Rhodococcus opacus, Rhodococcus ruber, Rhodococcus globerulus, Rhodococcus wratislaviensis
  • Pseudomonas sp. e.g
  • Xanthobacter sp e.g. , Xanthobacter autotrophicus, Xanthobacter tagetidis ), Furasium sp.
  • Chlorophyceae e.g., Dunaliella minuta, Coccomyxa elongata, Trebouxia decolorans, Chlorella ellipsoidea, Chlorella saccharophila, Chlorella pringsheimii, Trebouxia sp., Dunaliella primolectd
  • Prasinophyceae e.g, Tetraselmis tetrathele, Tetraselmis chui, Tetraselmis sueica, Pyramimonas gelidicold
  • Cyanobacteria e.g, Anacystis nidulans, Fremyella diplosiphon, Cvanidium caldarium, Microcystis aeruginosa, Anabaena cylindrica, Spirulina platensis, Spirulina sp., Calothrix sp., Nostoc commune
  • Chrysophyceaceae e.g., Dunaliella
  • Chrysotila stipitata Hymenomomas carterae,Coccolithus pelagicus, Nitzschia longissima, Melosira granulats, Thalassionema nitzschoides, Nitzschia frustulum, Chaetoceros simplex, Skeletonema costatum, Thalassiosira fluviatilis, Fragilaria sp., Asterionella glacialis, Biddulphia sinensis, Ciclotella nana, Vavicula pelliculosa, Nitzschia closterium, Phaeodactylum tricornutum, Phaeodactylum tricornutum, Stauroneis amphioxys, Nitzschia ovalis, Biddulphia aurita, Chaetoceros sp., Thalassiosira pseudonana, Thalassiosira pseudonana,
  • the microorganism is Curvularia lunata VKPM F-981. In one embodiment, the microorganism is Curvularia lunata VKPM F-981 as disclosed in Andryushina, V.A., Yaderets, V.V., Stytsenko, T.S. etal. Effect of the steroid molecule structure on the direction of its hydroxylation by the fungus Curvularia lunata. Appl Biochem Microbiol 49, 386-394 (2013) In one embodiment, Step 2-1 further comprises Steps 2-la and 2-lb:
  • Step 2- la Olefmation of compound B-l and installation of a protected carboxy group to form Compound B-G
  • Step 2-lb Protecting the Cl 1 hydroxy group of Compound B-G to produce Compound C
  • the olefmation of Step 2- la is a Wittig reaction. In one embodiment, the olefmation of Step 2- la is a Horner Wadsworth Emmons reaction.
  • Step 2-lb comprises reacting the hydroxy group with an agent to form a protecting group selected from acetyl, benzoyl, b-methoxyethoxymethylether, dimethoxytrityl, methyl ether, methoxymethyl ether, methoxyethyl ether, ethoxyethyl ether, ethoxymethyl ether, allyl ether, /-butyl ether, methoxytrityl, / -methoxybenzyl ether, methylthiomethyl ether, tetrahydropyranyl ether, tetrahydrofuranyl ether, trityl, silyl ether ( e.g ., trimethyl silyl (TMS), /-butyldimethylsilyl (TBDMS), tri-iso-propylsilyloxymethyl (TOM), and triisopropyl silyl (TIPS) ethers), methyl ester, pivalo
  • the agent is an acylating agent (e.g., acetic anhydride, benzoyl chloride, pivaloyl chloride, etc.), a silylating agent (e.g, TMS-C1, TES-C1, TBDMS-C1, etc.), an ether forming reagent (e.g, MOM-C1, MEM-Cl, dihydropyran, ethyl vinyl ether, haloalkanes such as iodomethane, bromomethane, iodoethane, bromoethane, etc.), or a chloroformate (methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, benzyl chloroformate, etc.).
  • acylating agent e.g., acetic anhydride, benzoyl chloride, pivaloyl chloride, etc.
  • a silylating agent e.g, TMS-C1,
  • the agent is selected from MOM-C1, MEM-Cl, dihydropyran, ethyl vinyl ether, /-butyldiphenylsilyl, methoxymethyl acetal, benzylhailde (e.g, benzyl fluoride, benzyl chloride, benzylbromide, or benzyliodide), benzoylhailde (e.g, benzoylfluoride, benzoyl chloride, benzoylbromide, or benzoyliodide), and haloalkane ( e.g ., iodomethane, bromom ethane, iodoethane, or bromoethane).
  • benzylhailde e.g, benzyl fluoride, benzyl chloride, benzylbromide, or benzyliodide
  • benzoylhailde e.g, benzo
  • the agent in Step 2- lb is a silylating agent.
  • the agent is TMS-C1.
  • the agent is TES-C1.
  • the agent is TBDMS-C1.
  • the agent is TIPS-Cl.
  • the agent is TOM-C1.
  • the agent is TMS-OTf.
  • the agent is TES-OTf.
  • the agent is TBDMS-OTf.
  • the agent is TIPS-OTf.
  • the agent is TOM-OTf.
  • the hydroxy protecting group is a silyl ether.
  • the silyl ether is TMS.
  • the silyl ether is TBDMS.
  • the silyl ether is TES.
  • the silyl ether is TIPS.
  • the silyl ether is TOM.
  • the reaction of Step 2-lb is carried out for greater than 12 hours. In one embodiment, the reaction is carried out for between 12 and 24 hours. In one embodiment, the reaction is carried out between 16 and 20 hours. In one embodiment, the reaction is carried out for about 18 hours.
  • Step 2-2 comprises protecting the hydroxy group and/or carboxyl group in Compound B with a protecting group. In some embodiments, Step 2-2 comprises protecting the hydroxy group in Compound B with a protecting group. In some embodiments, Step 2-2 comprises protecting the carboxyl group in Compound B with a protecting group. In some embodiments, Step 2-2 comprises protecting the hydroxy group in Compound B with a protecting group and protecting the carboxyl group in Compound B with a protecting group. In some embodiments, Step 2-2 comprises protecting the carboxyl group in Compound B with a protecting group, followed by protecting the hydroxy group in Compound B with a protecting group. Protecting groups for carrying out Step 2-2 are well known in the art.
  • Step 2-2 further comprises Steps 2-2a and 2-2b:
  • Step 2 -2a Protecting the carboxy group of Compound B to produce Compound B’
  • Step 2 -2b Protecting the Cl 1 hydroxy group of Compound B’ to produce Compound C
  • Step 2-2a comprises reacting the carboxyl group with an agent to form a protecting group selected from methyl ester, benzyl ester, /-butyl ester, silyl ester, orthoester, and oxazoline.
  • the agent is an acylating agent (e.g ., acetic anhydride, benzoyl chloride, pivaloyl chloride, etc.), a silylating agent (e.g., TMS-C1, TES- Cl, TBDMS-C1, etc.), or a chloroformate (methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, benzyl chloroformate, etc.).
  • acylating agent e.g ., acetic anhydride, benzoyl chloride, pivaloyl chloride, etc.
  • a silylating agent e.g., TMS-C1, TES- Cl, TBDMS-C1, etc.
  • Step 2-2a comprises dissolving Compound B in an alcoholic solvent and adding a catalytic amount of acid.
  • the alcoholic solvent is selected from methanol, ethanol, and isopropanol.
  • the alcoholic solvent is methanol.
  • the acid is selected from H2SO4, HC1, methanesulfonic acid, and toluenesulfonic acid.
  • Step 2-2a is conducted at a temperature between ambient and reflux. In one embodiment, Step 2-2a is conducted at ambient temperature. In one embodiment, Step 2-2a is conducted at reflux.
  • Step 2-2b comprises reacting the hydroxy group with an agent to form a protecting group selected from acetyl, benzoyl, b-methoxyethoxymethylether, dimethoxytrityl, methyl ether, methoxymethyl ether, methoxyethyl ether, ethoxyethyl ether, ethoxymethyl ether, allyl ether, /-butyl ether, methoxytrityl, /;-methoxybenzyl ether, methylthiomethyl ether, tetrahydropyranyl ether, tetrahydrofuranyl ether, trityl, silyl ether (e.g., trimethyl silyl (TMS), /-butyl di methyl si lyl (TBDMS), tri-iso-propylsilyloxymethyl (TOM), and triisopropyl silyl (TIPS) ethers), methyl ester, pivaloyl,
  • the agent is an acylating agent (e.g, acetic anhydride, benzoyl chloride, pivaloyl chloride, etc.), a silylating agent (e.g, TMS-C1, TES-C1, TBDMS-C1, etc.), an ether forming reagent (e.g, MOM-C1, MEM-C1, dihydropyran, ethyl vinyl ether, haloalkanes such as iodomethane, bromomethane, iodoethane, bromoethane, etc.), or a chloroformate (methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, benzyl chloroformate, etc.).
  • acylating agent e.g, acetic anhydride, benzoyl chloride, pivaloyl chloride, etc.
  • a silylating agent e.g, TMS-C1, TES-
  • the agent is selected from MOM-C1, MEM-C1, dihydropyran, ethyl vinyl ether, /-butyl di phenyl si lyl , methoxymethyl acetal, benzylhailde (e.g, benzyl fluoride, benzyl chloride, benzylbromide, or benzyliodide), benzoylhailde (e.g, benzoylfluoride, benzoyl chloride, benzoylbromide, or benzoyliodide), and haloalkane (e.g, iodomethane, bromomethane, iodoethane, or bromoethane).
  • benzylhailde e.g, benzyl fluoride, benzyl chloride, benzylbromide, or benzyliodide
  • benzoylhailde e.g, benzoylfluor
  • the agent in Step 2-2b is a silylating agent.
  • the agent is TMS-C1.
  • the agent is TES-C1.
  • the agent is TBDMS-C1.
  • the agent is TIPS-Cl.
  • the agent is TOM-C1.
  • the agent is TMS-OTf.
  • the agent is TES-OTf.
  • the agent is TBDMS-OTf.
  • the agent is TIPS-OTf.
  • the agent is TOM-OTf.
  • the hydroxy protecting group is a silyl ether.
  • the silyl ether is TMS.
  • the silyl ether is TBDMS.
  • the silyl ether is TES.
  • the silyl ether is TIPS.
  • the silyl ether is TOM.
  • the reaction of Step 2-2b is carried out for greater than 12 hours. In one embodiment, the reaction is carried out for between 12 and 24 hours. In one embodiment, the reaction is carried out between 16 and 20 hours. In one embodiment, the reaction is carried out for about 18 hours.
  • the protecting reaction is carried out in the presence of an appropriate solvent.
  • the protection reaction is carried out in the presence of a basic solvent (e.g. pyridine, pyridine derivatives, trialkylamines, N- methylmorpholine, etc.).
  • the protecting reaction is carried out in the presence of an appropriate base (e.g, carbonate salts, bicarbonate salts, pyridine, triethylamine, diisopropyl ethylamine, N-methylmorpholine, etc.).
  • the protecting reaction is carried out in the presence of an ester-based solvent (e.g ., methyl acetate, ethyl acetate, isopropyl acetate, ethyl formate, methyl trifluoroacetate, methyl propionate, etc.).
  • an ester-based solvent e.g ., methyl acetate, ethyl acetate, isopropyl acetate, ethyl formate, methyl trifluoroacetate, methyl propionate, etc.
  • the ester-based solvent is used in conjunction with an acid (e.g., methanesulfonic acid, p-toluenesulfonic acid, cone sulfuric acid, etc.).
  • Step 3 further comprises Steps 3a and 3b: Step 3a. Oxidizing Compound C to form Compound C’
  • Step 3a comprises reacting Compound C with an oxidant to form compound D.
  • the oxidant is a 1-4 benzoquinone derivative.
  • the oxidant is chloranil.
  • the oxidant is 2,3-dichloro- 5,6-dicyano-l,4-benzoquinone (DDQ).
  • Step 3a comprises treatment with N-bromosuccinimide or dibromo-dimethylhydantoin, followed by treatment with a base.
  • the Step 3a is carried out in the presence of an appropriate solvent.
  • the solvent is an organic solvent.
  • the solvent is a polar organic solvent.
  • the solvent is a polar protic organic solvent.
  • the solvent is an alcohol.
  • the solvent is methanol.
  • the solvent is ethanol.
  • the solvent is isopropanol.
  • the solvent is butanol.
  • the solvent is isobutanol, tert- butanol, or .svc-butanol.
  • Step 3a is carried out at a temperature above room temperature.
  • the temperature is between 40 °C and 100 °C. In one embodiment, the temperature is between 40 °C and 80 °C. In one embodiment, the temperature is between 40 °C and 60 °C.
  • Step 3a is carried out for between 1 and 8 hours. In one embodiment, Step 3a is carried out for between 2 and 7 hours. In one embodiment, Step 3a is carried out for between 3 and 6 hours. In one embodiment, Step 3a is carried out for between 4 and 6 hours. In one embodiment, Step 3a is carried out for between 4 and 5 hours.
  • Step 3b comprises reacting Compound C’ with an oxidant.
  • the oxidant is an peroxide-based oxidant.
  • the oxidant is a peroxide.
  • the oxidant is a peroxy acid.
  • the oxidant is a peroxycarboxylic acid.
  • the oxidant is peroxybenzoic acid.
  • the oxidant is peracetic acid.
  • the oxidant is trifluoroperacetic acid.
  • the oxidant is dimethyldioxirane.
  • the oxidant is methyl(trifluoromethyl)dioxirane.
  • the oxidant is weto-chloroperoxybenzoic acid (mCPBA).
  • Step 3b is carried out in the presence of a radical scavenger.
  • the radical scavenger is a phenolic antioxidant.
  • the radical scavenger is butylated hydroxytoluene (BHT, also known as 2,6-di-/er/-butyl-4- methylphenol)
  • the radical scavenger is butylated hydroxyanisole (BHA, which comprises a mixture of 2-/er/-butyl-4-hydroxyanisole and 3-/er/-butyl-4- hydroxyanisole).
  • the radical scavenger is tertiary butylhydroquinone (TBHQ).
  • Step 3b is carried out in the presence of an appropriate solvent.
  • the solvent is an organic solvent.
  • the solvent is an aqueous solvent.
  • the solvent is a mixture of organic and aqueous solvents.
  • the organic solvent is a polar solvent.
  • the organic solvent is a polar aprotic solvent.
  • the organic solvent is an ester-based solvent.
  • the organic solvent is isopropyl acetate.
  • the organic solvent is ethyl acetate.
  • the aqueous solvent is water. In one embodiment, the solvent is a mixture of water and ethyl acetate.
  • Step 3b is carried out at a temperature above room temperature.
  • the temperature is between 40 °C and 100 °C. In one embodiment, the temperature is between 70 °C and 100 °C. In one embodiment, the temperature is between 70 °C and 80 °C.
  • Step 3b is carried out for between 1 and 5 hours. In one embodiment, Step 3b is carried out for between 1 and 4 hours. In one embodiment, Step 3b is carried out for between 2 and 4 hours. In one embodiment, Step 3b is carried out for between 2 and 3 hours.
  • Step 4-1 comprises alkylating Compound D with an organometallic reagent to form Compound El.
  • the organometallic reagent is an alkykllithium reagent.
  • the organometallic reagent is a Gilman reagent formed by reaction of an alkyl lithium compound of the following formula:
  • R 4 -Li wherein R 4 is as defined in formula I, and a copper (I) salt, including a copper (I) halide such as copper (I) iodide.
  • Step 4-1 is carried out in an organic solvent.
  • the reaction is carried out in a polar organic solvent.
  • the reaction is carried out in a polar aprotic solvent.
  • the reaction is carried out in an ether solvent.
  • the reaction is carried out in THF.
  • the reaction is carried out in cyclopentyl methyl ether.
  • the reaction is carried out in 2-methyl THF.
  • the reaction is carried out in tBME.
  • the reaction is carried out in diethyl ether.
  • the reaction is carried out in a mixture of two or more of the foregoing solvents
  • the organometallic reagent is a Grignard reagent: R 4 MgX, where R 4 is as defined in formula I, and X is halogen.
  • the Grignard reagent is ethylmagnesium bromide.
  • Step 4-1 is carried out in the presence of a zinc (II) salt, such as zinc chloride, and a catalytic amount of a copper (I) or copper(II) salt or complex, such as copper (I) chloride, copper (II) chloride, or a copper(I) or copper (II) acetyl acetonate (acac) complex.
  • a zinc (II) salt such as zinc chloride
  • a catalytic amount of a copper (I) or copper(II) salt or complex such as copper (I) chloride, copper (II) chloride, or a copper(I) or copper (II) acetyl acetonate (acac) complex.
  • Step 4-1 may be carried out in an organic solvent, for example, an ether such as THF, cyclopentyl methyl ether, 2-methyl THF, methyl tert-butyl ether (tBME), or diethyl ether or a mixture thereof.
  • the reaction is carried out in a polar organic solvent.
  • the reaction is carried out in a polar aprotic solvent.
  • the reaction is carried out in an ether solvent.
  • the reaction is carried out in THF.
  • the reaction is carried out in cyclopentyl methyl ether.
  • the reaction is carried out in 2-methyl THF.
  • the reaction is carried out in tBME.
  • the reaction is carried out in diethyl ether.
  • the reaction is carried out in a mixture of two or more of the foregoing solvents.
  • Step 4-1 is carried out at a temperature below room temperature.
  • the temperature is between -78 °C and 0 °C.
  • the temperature is between -40 °C and 0 °C.
  • the temperature is between -20 °C and 0 °C.
  • the temperature is between - 20°C and -10 °C. In one embodiment, the temperature is about -20 °C.
  • Step 4-1 is carried out between 30 minutes and 2 hours. In one embodiment, Step 4-1 is carried out between 30 and 90 minutes. In one embodiment, Step 4-1 is carried out between 60 and 90 minutes.
  • Step 4-2a comprises reacting Compound D with an acetylide to form Compound E2a.
  • the acetylide is a lithium acetylide, a copper acetylide, a calcium carbide, or a silver acetylide.
  • the acetylide is a lithium acetylide.
  • the lithium acetylide is a lithium alkylsilyl acetylide.
  • the lithium alkylsilyl acetylide is lithium trimethyl silyl acetylide.
  • the reaction between Compound D and acetylide is carried out in the presence of a Lewis acid.
  • the Lewis acid is an aluminum based Lewis acid, a boron based Lewis acid, an iron based Lewis acid, a tin based Lewis acid, or a zinc based Lewis acid.
  • the Lewis acid is AIBn, AICL, aluminum isopropoxide, BCL, boron trichloride methyl sulfide, BF3, boron trifluoride acetic acid, boron trifluoride dibutyl etherate, boron trifluoride acetonitrile, boron trifluoride diethyl etherate, boron trifluoride methyl etherate, boron trifluoride methyl sulfide, FeBn, FeCL, ZnCh, or SnCL.
  • the Lewis acid is ZnCh or BF3.
  • Step 4-2b comprises treating Compound E2a with a isomerization catalyst to form Compound E2b.
  • the isomerization catalyst is Fe(CO)s, Pd(OAc)2, a ruthenium salt, a Lewis acid, or a protic acid.
  • Step 4-3a comprises reacting Compound D with a vinyl Grignard reagent to form Compound E3a.
  • the vinyl Grignard reagent is ethenylmagnesium bromide.
  • the reaction between Compound D and vinyl Grignard reagent is carried out in the presence of a Lewis acid.
  • the Lewis acid is an aluminum based Lewis acid, a boron based Lewis acid, an iron based Lewis acid, a tin based Lewis acid, or a zinc based Lewis acid.
  • the Lewis acid is AIBn, AlCb, aluminum isopropoxide, BCb, boron trichloride methyl sulfide, BF3, boron trifluoride acetic acid, boron trifluoride dibutyl etherate, boron trifluoride acetonitrile, boron trifluoride diethyl etherate, boron trifluoride methyl etherate, boron trifluoride methyl sulfide, FeBn, FeCL, ZnCh, or SnCL.
  • the Lewis acid is ZnCh or BF3.
  • Step 4-3b comprises treating Compound E3a with a isomerization catalyst to form Compound E3b.
  • the isomerization catalyst is Fe(CO)s, Pd(OAc)2, a ruthenium salt, a Lewis acid, or a protic acid.
  • Step 5-1 comprises Step 5- la.
  • Step 5-la Reducing Compound El to form Compound EL:
  • Step 5- la comprises reacting Compound El with a hydrogenating agent to form Compound EG.
  • the hydrogenating agent is hydrogen gas, an alcohol (e.g ., methanol, ethanol, or isopropanol), or an acid (e.g, formic acid).
  • the hydrogenating agent is hydrogen gas.
  • Step 5- la is carried out in the presence of a catalyst.
  • Catalysts for hydrogenation is well known in the art.
  • the catalyst is a nickel-, platinum-, palladium-, rhodium-, or ruthenium-based catalyst.
  • the catalyst is Pd/C, Pd/CaCCE, Pd/AhCE, Pd/Pt, or Raney nickel.
  • Step 5- la is carried out in the presence of an organic solvent, for example, an alcoholic solvent such as methanol, ethanol or isopropanol; ethyl acetate; pyridine; acetic acid; cyclopentyl methyl ether (CPME); or N,N-dimethylformamide (DMF).
  • the solvent is a polar organic solvent.
  • the organic solvent is a polar protic solvent.
  • the organic solvent is a polar aprotic solvent.
  • the organic solvent is an alcohol.
  • the organic solvent is methanol.
  • the organic solvent is ethanol.
  • the organic solvent is is isopropanol.
  • the organic solvent is ethyl acetate. In some embodiments, the organic solvent is pyridine. In some embodiments, the organic solvent is acetic acid. In some embodiments, the organic solvent is CPME. In some embodiments, the organic solvent is DMF. In some embodiments, the organic solvent is DMSO. In some embodiments, the organic solvent is THF. In some embodiments, the organic solvent is dichloromethane. In some embodiments, the organic solvent is acetonitrile.
  • the organic solvent may optionally be mixed with a co-solvent such as acetone or water and/or a base such as triethylamine. In some embodiments, Step 5- la is carried out at ambient pressure. In some embodiments, Step 5- la is carried out at elevated pressure.
  • Step 5- la is carried out at a temperature below room temperature.
  • the temperature is between -20 and 20 °C.
  • the temperature is between -10 and 10 °C.
  • the temperature is between 0 and 10 °C.
  • the temperature is between 0 and 5 °C.
  • Step 5-la is carried out for between 1-10 hours. In some embodiments, Step 5- la is carried out for between 1-5 hours. In some embodiments, Step 5- la is carried out for between 2-5 hours. In some embodiments, Step 5- la is carried out for between 3-5 hours.
  • Step 5-1 further comprises Step 5-lb Step 5-lb. Oxidizing the 7-hydroxyl in Compound EG to form Compound El”:
  • Step 5-lb may be carried out with any suitable methods known in the art.
  • Step 5- lb is carried out in the presence of an oxidant and a co-oxidant.
  • the oxidant is an iodine-based oxidant.
  • the co-oxidant is a ruthenium salt.
  • Step 5-lb is carried out in the presence of RuCh and H5IO6.
  • the RuCl ⁇ is present in a sub-stoichiometric quantity.
  • the oxidization reagent is a Dess-Martin periodinane ( 1,1,1 -triacetoxy- 1,1- dihydro- 1,2-benziodoxol) oxidation.
  • the Dess-Martin periodinane oxidation is carried out in a chlorinated solvent such as chloroform or dichloromethane.
  • the oxidization reaction comprises reaction with hypochlorite, for example, sodium hypochlorite, under acidic conditions, for example, provided by acetic acid.
  • the oxidization reaction is carried out in an aqueous solvent.
  • the oxidization reaction is a Jones reaction using sodium dichromate or chromic trioxide in dilute sulfuric acid.
  • Step 5-lb is carried out at a temperature below room temperature.
  • the temperature is between -20 and 20 °C.
  • the temperature is between -10 and 10 °C.
  • the temperature is between 0 and 10 °C.
  • the temperature is between 0 and 5 °C.
  • Step 5-1 further comprises Step 5-lc.
  • Step 5-lc involves deprotection of the Cl 1 alcohol by treating Compound El” with a deprotecting agent.
  • the deprotecting agent is a fluoride-based deprotecting agent.
  • the deprotecting agent is NFER
  • Step 5-lc is carried out at a temperature above room temperature.
  • the temperature is between 40 °C and 100 °C.
  • the temperature is between 30 °C and 60 °C.
  • the temperature is between 35 °C and 45 °C. In one embodiment, the temperature about 40 °C.
  • Step 5-lc is carried out for about 1-8 hours. In some embodiments, Step 5-lc is carried out for about 2-7 hours. In some embodiments, Step 5- lc is carried out for about 3-6 hours. In some embodiments, Step 5-lc is carried out for about 4-6 hours.
  • Step 5-1 further comprises Step 5-ld.
  • Step 5-ld comprises treating Compound EG” with a base.
  • the base is an inorganic salt.
  • the base is NaOH.
  • the base is used as an aqueous solution.
  • the base used is a 10% aqueous solution of NaOH.
  • the base is used above room temperature.
  • the base is used in the presence of a polar protic solvent.
  • the base is used in the presence of an alcoholic solvent.
  • the alcoholic solvent is methanol.
  • the alcoholic solvent is ethanol.
  • the alcoholic solvent is is isopropanol.
  • Step 5-ld is carried out at a temperature above room temperature.
  • the temperature is between 30 °C and 100 °C. In one embodiment, the temperature is between 30 °C and 60 °C. In one embodiment, the temperature is between 45 °C and 55 °C. In one embodiment, the temperature about 50 °C.
  • Step 5-ld comprises treating Compound EG” with a isomerization catalyst.
  • the isomerization catalyst is Fe(CO)s, Pd(OAc)2, a ruthenium salt, a Lewis acid, or a protic acid.
  • the isomerization comprises treating Compound El” with a base.
  • Step 5-2 comprises reacting Compound E2b with a hydrogenating agent to form Compound F.
  • the hydrogenating agent is hydrogen gas, an alcohol (e.g ., methanol, ethanol, or isopropanol), or an acid (e.g, formic acid).
  • the hydrogenating agent is hydrogen gas.
  • the hydrogenation of Compound E2b is carried out in the presence of a catalyst.
  • Catalysts for hydrogenation is well known in the art.
  • the catalyst is a nickel-, platinum-, palladium-, rhodium-, or ruthenium-based catalyst.
  • the catalyst is Pd/C, Pd/CaCCE, Pd/AhCE, Pd/Pt, or Raney nickel.
  • the hydrogenation of Compound E2b is carried out in the presence of an organic solvent, which may be an alcoholic solvent such as methanol, ethanol or isopropanol; ethyl acetate; pyridine; acetic acid; cyclopentyl methyl ether (CPME); or N,N-dimethylformamide (DMF).
  • the organic solvent may optionally be mixed with a co-solvent such as acetone or water and/or a base such as triethylamine.
  • Step 5-3 comprises reacting Compound E3b with a hydrogenating agent to form Compound F.
  • the hydrogenating agent is hydrogen gas, an alcohol (e.g ., methanol, ethanol, or isopropanol), or an acid (e.g, formic acid).
  • the hydrogenating agent is hydrogen gas.
  • the hydrogenation of Compound E3b is carried out in the presence of a catalyst.
  • Catalysts for hydrogenation is well known in the art.
  • the catalyst is a nickel-, platinum-, palladium-, rhodium-, or ruthenium-based catalyst.
  • the catalyst is Pd/C, Pd/CaCCE, Pd/AhCE, Pd/Pt, or Raney nickel.
  • the hydrogenation of Compound E3b is carried out in the presence of an organic solvent, which may be an alcoholic solvent such as methanol, ethanol or isopropanol; ethyl acetate; pyridine; acetic acid; cyclopentyl methyl ether (CPME); or N,N-dimethylformamide (DMF).
  • the organic solvent may optionally be mixed with a co-solvent such as acetone or water and/or a base such as triethylamine.
  • Step 6 comprises reacting Compound F with a reducing agent to reduce the 7-keto to 7-OH and the 3-keto to 3-OH.
  • Step 6 reduction of Compound F comprises reducing the 7-keto to 7-a-OH.
  • Step 6 reduction of Compound F comprises reducing the 3-keto to 3-a-OH.
  • Step 6 reduction of Compound F comprises reducing the 7-keto to 7-a-OH and the 3-keto to 3-a-OH.
  • the reducing agent is a hydride.
  • the reducing agent is lithium aluminum hydride (LiAlH4).
  • the reducing agent is sodium borohydride (NaBHi).
  • the reducing agent is hydrogen gas (without or with a suitable catalyst).
  • the reducing agent is sodium amalgam (Na(Hg)).
  • the reducing agent is sodium-lead alloy (Na + Pb).
  • the reducing agent is zinc amalgam (Zn(Hg)).
  • the reducing agent is diborane.
  • the reducing agent is compounds containing the Fe2+ ion, such as iron(II) sulfate, compounds containing the Sn2+ ion, such as tin(II) chloride.
  • the reducing agent is sulfite.
  • the reducing agent is a dithionate ( e.g ., Na 2 S 2 0 6 ).
  • the reducing agent is a thiosulfate (e.g., Na 2 S 2 C> 3 ).
  • the reducing agent is an iodide.
  • the reducing agent is hydrazine, diisobutylaluminium hydride.
  • the reducing agent is oxalic acid. In one embodiment, the reducing agent is formic acid. In one embodiment, the reducing agent is ascorbic acid. In one embodiment, the reducing agent is phosphites. In one embodiment, the reducing agent is hypophosphites. In one embodiment, the reducing agent is phosphorous acid. In one embodiment, the reducing agent is carbon monoxide. In one embodiment, the reducing agent is carbon (C). In one embodiment, the reducing agent is or tris-2- carboxyethylphosphine hydrochloride (TCEP). In one embodiment, the reducing agent is NaBH 4.
  • TCEP tris-2- carboxyethylphosphine hydrochloride
  • Step 6 is carried out under a basic condition. In one embodiment, Step 6 is carried out in the presence of a strong base. In one embodiment, the strong base is sodium. In one embodiment, the strong base is potassium hydroxide.
  • the solvent comprises tetrahydrofuran, water, or a mixture thereof.
  • the solvent is an aqueous solvent.
  • the solvent is water.
  • Step 6 is carried out at a temperature above room temperature.
  • the temperature is between 50 °C and 100 °C.
  • the temperature is between 80 °C and 10 °C.
  • the temperature is between 90 °C and 100 °C.
  • the temperature is between 90 °C and 95 °C.
  • Step 6 is carried out for about 1-8 hours. In some embodiments, Step 6 is carried out for about 1-7 hours. In some embodiments, Step 6 is carried out for about 2-6 hours. In some embodiments, Step 6 is carried out for about 3-6 hours.
  • compounds of the application, or pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof are isotopically labeled (or radiolabeled).
  • isotopes that can be incorporated into compounds of the application, or pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof include isotopes of hydrogen, carbon, nitrogen, fluorine, such as 2 H, 3 ⁇ 4, U C, 13 C , 14 C, and 18 F.
  • compounds of the application are deuterated, i.e., incorporate 2 H, tritiated, i.e., incorporate 3 ⁇ 4, and radiolabeled with carbon-14, i.e., 14 C.
  • Isotopically labeled compounds of the application, or pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof can generally be prepared by carrying out the procedures herein, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • the present application relates to a method of preparing a compound of formula 1-9 or I-9a: or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, wherein R 2 -R 10 are as described herein.
  • the presently disclosed method provides an efficient synthesis of intermediates that can be further elaborated to various side chain analogs, including, but not limited to compounds with the following side chains: where Z is any same or different appropriate substituent, Y is a heteroatom (e.g., O, N, or S), and he is any appropriate heterocycle (e.g., aromatic or non-aromatic 4-6-memberd ring), which, for example, can include, but is not limited to the following groups
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-1.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-1 and Step 3, and optionally Step 2-1.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-1, Step 3, Step 4-1, and optionally Step 2-1.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-1, Step 3, Step 4-1, Step 5-1, and optionally Step 2-1.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-1, Step 3, Step 4-1, Step 5-1, Step 6, and optionally Step 2-1.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-1, Step 3, Step 4-2a, Step 4-2b, and optionally Step 2-1.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-1, Step 3, Step 4-2a, Step 4-2b, Step 5-2, and optionally Step 2-1.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-1, Step 3, Step 4-2a, Step 4-2b, Step 5-2, Step 6, and optionally Step 2-1.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-1, Step 3, Step 4-3a, Step 4-3b, and optionally Step 2-1.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-1, Step 3, Step 4-3a, Step 4-3b, Step 5-3, and optionally Step 2-1.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-1, Step 3, Step 4-3a, Step 4-3b, Step 5-3, Step 6, and optionally Step 2-1.
  • Step 2-1 the protecting groups (PG) shown in Compound C, Compound D, Compound El, Compound EG, Compound El”, Compound E2a, Compound E2b, Compound E3a, Compound E3b, and Compound F, would be replaced with H.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-2.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 3.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 4-1, Step 4- 2a and Step 4-2b, or Step 4-3 a and Step 4-3b.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 5-1, Step 5- 2, or Step 5-3. In certain embodiments, the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 6.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-2 and Step 3, and optionally Step 2-2.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-2, Step 3, Step 4-1, and optionally Step 2-2.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-2, Step 3, Step 4-1, Step 5-1, and optionally Step 2-2.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-2, Step 3, Step 4-1, Step 5-1, Step 6, and optionally Step 2-2.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-2, Step 3, Step 4-2a, Step 4-2b, and optionally Step 2-2.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-2, Step 3, Step 4-2a, Step 4-2b, Step 5-2, and optionally Step 2-2.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-2, Step 3, Step 4-2a, Step 4-2b, Step 5-2, Step 6, and optionally Step 2-2.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-2, Step 3, Step 4-3a, Step 4-3b, and optionally Step 2-2.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-2, Step 3, Step 4-3a, Step 4-3b, Step 5-3, and optionally Step 2-2.
  • the present application relates to a method of preparing a compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, comprising Step 1-2, Step 3, Step 4-3a, Step 4-3b, Step 5-3, Step 6, and optionally Step 2-2.
  • Step 2-2 when Step 2-2 is omitted, the protecting groups (PG) shown in Compound C, Compound D, Compound El, Compound EG, Compound El”, Compound E2a, Compound E2b, Compound E3a, Compound E3b, and Compound F, would be replaced with H.
  • the synthetic processes of the present application can tolerate a wide variety of functional groups, therefore various 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 instances to further convert the compound to a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the present application relates to Compound A, Compound B, Compound B’, Compound C, Compound C’, Compound D, Compound El, Compound EE, Compound El”, EE”, Compound E2a, Compound E2b, Compound E3a, Compound E3b, or Compound F.
  • the present application relates to Compound A-l, Compound B-l, Compound B-E, Compound C, Compound C’, Compound D, Compound El, Compound EE, Compound El”, EE”, Compound E2a, Compound E2b, Compound E3a, Compound E3b, or Compound F.
  • the present application relates to Compound B. In one embodiment, the present application relates to Compound B ⁇
  • the present application relates to Compound B-l.
  • the present application relates to Compound B-G
  • the present application relates to Compound C.
  • the present application relates to Compound C’.
  • the present application relates to Compound D.
  • the present application relates to Compound El, Compound EG, Compound El”, or Compound EE”.
  • the present application relates to Compound E2a or Compound
  • the present application relates to Compound E3a or Compound
  • the present application relates to Compound F.
  • the compound of formula 1-9 or I-9a is further transformed into the compound of formula I, wherein R 7 is OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, C(0)NH0H, tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-l,2,4- oxadiazolyl, 5-oxo-l,2,4-thiadiazolyl, oxazolidinedionyl, thiazolidinedionyl, 3- hydroxyisoxazolyl, 3-hydroxyisothiazolyl, or 2,4-difluoro-3-hydroxyphenyl, and R 1 is alkoxy or oxo using known synthetic procedures.
  • the compound of formula 1-9 or I-9a is further transformed into the compound of formula I, wherein R 7 is OSO3H, SO3H, OSO2NH2, SO2NH2, OPO3H2, PO3H2, CO2H, C(0)NH0H, tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-l,2,4-oxadiazolyl, 5-oxo-l,2,4-thiadiazolyl, oxazolidinedionyl, thiazolidinedionyl, 3-hydroxyisoxazolyl, 3-hydroxyisothiazolyl, pyrimidine, 3,5-difluoro-4-hydroxyphenyl or 2,4-difluoro-3-hydroxyphenyl, all of which can be optionally further substituted, and R 1 is alkoxy or oxo using synthetic procedures described in WO 2017/062763, US20160130297, US20160145295, US20160145296, US2016
  • compounds wherein R 7 is tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo- 1,2,4-oxadiazolyl, 5-oxo-l,2,4-thiadiazolyl, oxazolidinedionyl, thiazolidinedionyl, 3- hydroxyisoxa-zolyl, 3-hydroxyisothiazolyl, or 2,4-difluoro-3-hydroxyphenyl can be prepared from the corresponding carboxylic acid via a coupling with the required R 7 - containing boronic acids:
  • R 11 protecting group is selected from C(0)Ci-C 4 alkyl, Ci- C 6 alkoxycarbonyl, optionally substituted aryloxycarbonyl, benzoyl, benzyl, pivaloyl, tetrahydropyranyl ether, tetrahydrofuranyl, 2-methoxyethoxymethyl ether, methoxymethyl ether, ethoxyethyl ether, p-methoxybenzyl ether, methylthiomethyl ether, triphenylmethyl, dimethoxytrityl, methoxytrityl, and silyl ether.
  • the silyl ether is selected from trimethyl silyl ether, triethylsilyl ether, triisopropyl silyl ether, tert- butyldimethylsilyl ether, and /c77-buty 1 di pheny 1 si 1 y 1 ether.
  • the R 11 protecting group is benzoyl or acetyl. In one embodiment, the R 11 protecting group is C(0)Ci-C 4 alkyl. In one embodiment, the R 11 protecting group is acetyl. In some embodiments R 11 is H.
  • the process of the present application provides a compound of formula II: or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the process of present application provides a compound of formula III: in, or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the present application relates to a method of making a compound of formula Ilia: Ilia, or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the present application relates to a method of making a compound of formula Illb: mb, or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • Organisms which are capable of biooxidation can be drawn from both mesophiles or extremeophiles, including but not limited to either wild type or genetically modified prokaryotes and eukaryotes. In some cases, the organisms are classified in the same genus but differ in type strain based on isolation source or growth conditions. Examples of microbial organisms include but are not limited to the following: bacteria, yeast, fungi, algea, and molds. Fermentation can take place during any phase of the microbial lifecycle including the lag phase, exponential phase, or stationary phase, using either aerobic and anaerobic conditions. Table 1 shows several references that identified microorganisms capable of biooxidation of sterioid derivatives.
  • the 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 platensis, Streptomyces violascens, Streptomyces ochraceiscleroticus, Methylobacterium extorquens, Methylophaga thalassica, Rhizopus stolonifer, Absidia coerulea , Beauveria has si ana, Cunninghamella elegans, Rhizopus oryzae, Gliocladium roseum, Verticillium lecanii, Fusarium oxysporum, Curvularia lunata, Mortierella isabellina, Cunninghamella blakeslee
  • the microorganisms are grown in about 50 ml conical centrifuge tubes containing about 10 ml of the required growth medium.
  • the growth media can be Nutrient Broth (e.g. , 15 g Peptone, 3 g Yeast extract, 6 g NaCl, 1 g Glucose); Gym Streptomyces media (e.g, 4 g Glucose, 4 g Yeast extract, 10 g Malt extract); Malt extract peptone ( e.g ., 30 g Malt extract, 3 g Peptone); or Potato dextrose media (e.g., 30 g Potato extract, 10 g Glucose).
  • the cultures are incubated for 7 days at about 28°C with shaking. After that, about 1 ml of each microbial culture was transferred into the wells of deep 96 well plates. The plates are incubated at about 28 °C with agitation for 48 hours before addition of OCA dissolved in DMSO (to the final concentration of about 2 mg/ml). The plates are incubated for a further 36 hours before addition of about 1 ml of 100% acetonitrile, after which the plates are incubated at room temperature before centrifugation at 9,000 xg for 15 mins.
  • the biotransformation process can utilize the method(s) reported in Ishida, et ah, Chem. Pharm. Bull. 46 (1998), 12-16 for natural product 3a,7a,1 la-trihydroxy-5 -cholan-24-oic acid (1 la-OH CDCA).
  • R 4 is in the a-position.
  • the present application provides compounds of formula 1, 1-9, 1-9a, II, III, Ilia, or Illb, wherein R 4 is C 1 -C 4 alkyl.
  • the present application provides compounds of formula 1, 1-9, 1-9a, II, III, Ilia, or Illb, wherein R 4 is methyl, ethyl, or propyl.
  • R 4 is ethyl.
  • R 4 is alpha-ethyl.
  • the present application provides compounds of formula 1, 1-9, 1-9a, II, III, Ilia, or Illb, wherein R 4 is H or halogen. In one of the embodiments, the present application provides compounds of formula 1, 1-9, 1-9a, II, III, Ilia, or Illb, wherein R 4 is C1-C6 alkyl optionally substituted with one or more halogen or OH. In one of the embodiments, the present application provides compounds of formula 1, 1-9, 1-9a, II, III, Ilia, or Illb, wherein R 4 is C2-C6 alkenyl or C2-C6 alkynyl.
  • R 7 is OH, OSO 3 H, SO 3 H, OSO 2 NH 2 , SO 2 NH 2 , OPO 3 H 2 , PO 3 H 2 , CO 2 H, or C(0)NHOH.
  • the present application provides compounds of formula 1, 1-9, 1-9a, II, III, Ilia, or Illb, wherein R 7 is OH, OSO 3 H, OSO 2 NH 2 , OPO 3 H 2 , or C0 2 H. In one of the embodiments, the present application provides compounds of formula 1, 1-9, 1-9a, II, III, Ilia, or Illb, wherein R 7 is OH, OSO 3 H, OSO 2 NH 2 , OPO 3 H 2 , or C0 2 H. In one of the embodiments, the present application provides compounds of formula 1, 1-9, 1-9a, II, III, Ilia, or Illb, wherein R 7 is OH, OSO 3 H, OSO 2 NH 2 , OPO 3 H 2 , or C0 2 H. In one of the embodiments, the present application provides compounds of formula 1, 1-9, 1-9a, II, III, Ilia, or Illb, wherein R 7 is OH, OSO 3 H, OSO 2 NH 2
  • R 7 is 0S0 3 H.
  • R 7 is OSO2NH2 or SO2NH2.
  • R 7 is OPO 3 H 2 , PO 3 H 2 , or C(0)NH0H.
  • R 7 is tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-
  • the present application provides compounds of formula 1, 1-9, 1-9a, II, III, Ilia, or Illb, wherein R 7 is OH, OSO 3 H, OSO 2 NH 2 , OPO 3 H 2 , C0 2 H, tetrazolyl, oxadiazolyl, thiadiazolyl, 5-oxo-l,2,4-oxadiazolyl, 5-oxo-l,2,4-thiadiazolyl, oxazolidine-dionyl, thiazolidine-dionyl, 3-hydroxyisoxazolyl, 3-hydroxyisothiazolyl, or
  • R 5 is OSO 3 H, 0C(0)CH , or OPO 3 H 2 .
  • the present application provides compounds of formula I, la, lb, 1-9, II, or III, wherein m is 0.
  • the present application provides compounds of formula I, la, lb, 1-9, II, or III, wherein m is 1. In one of the embodiments, the present application provides compounds of formula I, la, lb, 1-9, II, or III, wherein m is 2.
  • the present application provides compounds of formula I, la, lb, 1-9, II, or III, wherein n is 1.
  • the present application provides compounds of I, la, lb, 1-9, II, or III, wherein p is 0.
  • the present application provides compounds of formula I, la, lb, 1-9, or II, , wherein R 1 is in the b-position (beta-position).
  • the compound prepared by the methods of the present application is Compound 100:
  • the method of the present application produces a substantially pure compound of formula I, or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the term “purity” as used herein refers to the amount of compound of formula I based on analytic methods commonly used in the art (e.g ., HPLC).
  • the compound of formula I has a purity of greater than about 90%.
  • the compound of formula I has a purity of greater than about 95%.
  • the compound of formula I has a purity of greater than about 98%.
  • 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%.
  • the purity of the synthesized compound of formula I is 98.5%, 99.0%, or 99.5%.
  • the purity is determined by HPLC.
  • the present application provides methods for the synthesis of highly pure compounds of formula I which are safe and which can produce compounds of formula I on a large scale.
  • the method of the present application produces compounds of formula I in high yield (>98%) and with limited number of impurities.
  • the compounds of the application 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 resolution of 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 application.
  • Cis and trans geometric isomers of the compounds of the application can be isolated as a mixture of isomers or as separate isomeric forms. All chiral, diastereomeric, racemic, and geometric isomeric forms of a structure are intended, unless specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present application and intermediates made therein are considered to be part of the present application. All tautomers of shown or described compounds are also considered to be part of the present application. Furthermore, the application also includes metabolites of the compounds described herein.
  • the application also comprehends isotopically-labeled compounds of the application, or pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, which are identical to those recited in formulae of the application and following, but 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.
  • isotopes that can be incorporated into compounds of the application, or pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof include isotopes of hydrogen, carbon, nitrogen, fluorine, such as 2 H, 3 ⁇ 4, U C, 13 C, 14 C, and 18 F.
  • Deuterated, i.e., 2 H, tritiated, /. e. , 3 ⁇ 4, and carbon-14, /. e. , 14 C, isotopes may be used for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be used in some circumstances.
  • Isotopically labeled compounds of the application, or pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. However, one skilled in the art will recognize that not all isotopes can be included by substitution of the non-isotopically labeled reagent. In one embodiment, compounds of the application, or pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof are not isotopically labeled.
  • deuterated compounds of the application are useful for bioanalytical assays.
  • compounds of the application, or pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof are radiolabeled.
  • a "pharmaceutical composition” is a formulation containing one or more compounds of the application in a form suitable for administration to a subject.
  • the pharmaceutical composition is in bulk or in unit dosage form. It can be advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active reagent calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms are dictated by and directly dependent on the unique characteristics of the active reagent and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active agent for the treatment of individuals.
  • Possible formulations include those suitable for oral, sublingual, buccal, parenteral (e.g, subcutaneous, intramuscular, or intravenous), rectal, topical including transdermal, intranasal and inhalation administration. 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 on the nature of the active compound, but where possible, oral administration may be used for the prevention and treatment of FXR mediated diseases and conditions.
  • Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in- water or water-in-oil emulsions.
  • Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically a flavored base, such as sugar and acacia or tragacanth and pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose acacia.
  • Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution may be isotonic with the blood of the intended recipient. Additional formulations suitable for parenteral administration include formulations containing physiologically suitable co-solvents and/or complexing agents such as surfactants and cyclodextrins. Oil- in-water emulsions are also suitable formulations for parenteral formulations. Although such solutions may be administered intravenously, they may also be administered by subcutaneous or intramuscular injection.
  • Formulations suitable for rectal administration may be provided as unit-dose suppositories comprising the active ingredient in one or more solid carriers forming the suppository base, for example, cocoa butter.
  • Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, sprays, aerosols, and oils.
  • Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof.
  • Formulations of the application may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound with liquids or finely divided solid carriers or both, in the required proportions and then, if necessary, shaping the resulting mixture into the desired shape.
  • a tablet may 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 surface-active dispersing agent, or by molding an intimate mixture of powdered active ingredient and inert liquid diluent.
  • Suitable formulations for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols, nebulizers, or insufflators.
  • the particle size of the powder or droplets is typically in the range of 0.5-10 pm, or may be about 1-5 pm, to ensure delivery into the bronchial tree.
  • a particle size in the range of 10-500 pm may be used to ensure retention in the nasal cavity.
  • Metered dose inhalers are pressurized aerosol dispensers, typically containing a suspension or solution formulation of the active ingredient in a liquefied propellant.
  • these devices discharge the formulation through a valve adapted to deliver a metered volume, typically from 10 to 150 pm, to produce a fine particle spray 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, ethanol surfactants, such as oleic acid or sorbitan trioleate, anti-oxidants, and suitable flavoring agents.
  • Nebulizers are commercially available devices that transform solutions or suspensions of the active ingredient into a therapeutic aerosol mist either by means of acceleration of a compressed gas typically air or oxygen, through a narrow venturi orifice, or by means of ultrasonic agitation.
  • Suitable formulations 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 carrier 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 sterile, for example, methyl hydroxy-benzoate, anti-oxidants, flavoring agents, volatile oils, buffering agents, and surfactants.
  • Suitable formulations for administration by insufflation include finely comminuted powders which may be delivered by means of an insufflator or taken into the nasal cavity in the manner of a snuff.
  • the powder is contained in capsules or cartridges, typically made of gelatin or plastic, which are either pierced or opened in situ and the powder delivered by air drawn through the device upon inhalation or by means of a manually- operated pump.
  • the powder employed in the insufflator consists either solely of the active ingredient or of a powder blend comprising the active ingredient, a suitable powder diluent, such as lactose, and an optional surfactant.
  • the active ingredient typically comprises from 0.1 to 100 % w/w of the formulation.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising, as active ingredient, a compound of the application together, and/or in admixture, with at least one pharmaceutical carrier or diluent.
  • These pharmaceutical compositions may be used in the prevention or treatment of the foregoing diseases or conditions.
  • the carrier is pharmaceutically acceptable and must be compatible with, i.e., not have a deleterious effect upon, the other ingredients in the composition.
  • the carrier may be a solid or liquid and is preferably formulated as a unit dose formulation, for example, a tablet which may contain from 0.05 to 95% by weight of the active ingredient. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the application.
  • formulations of the present application may include other agents known to those skilled in the art of pharmacy, having regard for the type of formulation in issue.
  • formulations suitable for oral administration may include flavoring agents and formulations suitable for intranasal administration may include perfumes.
  • the present application provides a pharmaceutical composition comprising the compounds of formula I and a pharmaceutically acceptable carrier or excipient.
  • the compounds of the application are useful for therapy in subjects such as mammals, including humans.
  • the compounds of the application are useful in a method of treating or preventing a disease or condition in a subject comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the disease or condition is FXR-mediated (e.g., FXR plays a role in the initiation or progress of the disease or condition).
  • the disease or condition is mediated by decreased FXR activity.
  • the disease or condition is selected from cardiovascular disease, chronic liver disease, lipid disorder, gastrointestinal disease, renal disease, metabolic disease, cancer, and neurological disease.
  • the application relates to a method of treating or preventing cardiovascular disease in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of treating cardiovascular disease.
  • cardiovascular disease selected from atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesteremia, hyperlipidemia, hyperlipoproteinemia, and hypertriglyceridemia.
  • hyperlipidemia refers to the presence of an abnormally elevated level of lipids in the blood. Hyperlipidemia can appear in at least three forms: (1) hypercholesterolemia, i.e., an elevated cholesterol level; (2) hypertriglyceridemia, /. e. , an elevated triglyceride level; and (3) combined hyperlipidemia, i.e., a combination of hypercholesterolemia and hypertriglyceridemia.
  • dislipidemia refers to abnormal levels of lipoproteins in blood plasma including both depressed and/or elevated levels of lipoproteins (e.g ., elevated levels of LDL, VLDL and depressed levels of HDL).
  • the application relates to a method selected from reducing cholesterol levels or modulating cholesterol metabolism, catabolism, absorption of dietary cholesterol, and reverse cholesterol transport in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of treating or preventing a disease affecting cholesterol, triglyceride, or bile acid levels in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of lowering triglycerides in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of treating or preventing a disease state associated with an elevated cholesterol level in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of treating a disease state associated with an elevated cholesterol level in a subject.
  • the application relates to a method of preventing a disease state associated with an elevated cholesterol level in a subject.
  • the disease state is selected from coronary artery disease, angina pectoris, carotid artery disease, strokes, cerebral arteriosclerosis, and xanthoma.
  • the application relates to a method of treating or preventing a lipid disorder in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of treating a lipid disorder.
  • the application relates to a method of preventing a lipid disorder.
  • Lipid disorders are the term for abnormalities of cholesterol and triglycerides.
  • Lipid abnormalities are associated with an increased risk for vascular disease, and especially heart attacks and strokes. Abnormalities in lipid disorders are a combination of genetic predisposition as well as the nature of dietary intake. Many lipid disorders are associated with being overweight. Lipid disorders may also be associated with other diseases including diabetes, the metabolic syndrome (sometimes called the insulin resistance syndrome), underactive thyroid or the result of certain medications (such as those used for anti -rejection regimens in people who have had transplants).
  • the metabolic syndrome sometimes called the insulin resistance syndrome
  • underactive thyroid or the result of certain medications (such as those used for anti -rejection regimens in people who have had transplants).
  • the application relates to a method of treating or preventing one or more symptoms of disease affecting lipid metabolism (z.e., lipodystrophy) in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of treating one or more symptoms of a disease affecting lipid metabolism.
  • the application relates to a method of preventing one or more symptoms of a disease affecting lipid metabolism.
  • the application relates to a method of decreasing lipid accumulation in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of treating or preventing liver disease in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of treating chronic liver disease.
  • the application relates to a method of preventing chronic liver disease.
  • the FXR mediated liver disease is 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, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis C infection, alcoholic liver disease, liver damage due to progressive fibrosis, and liver fibrosis.
  • PBC primary biliary cirrhosis
  • PSC primary biliary cholangitis
  • NAFLD nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • 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.
  • 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, liver transplant associated graft versus host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, Sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis, and alpha 1 -antitrypsin deficiency.
  • CX cerebrotendinous xanthomatosis
  • PNAC parenteral nutrition associated cholestasis
  • autoimmune hepatitis chronic viral hepatitis
  • liver transplant associated graft versus host disease living
  • the application relates 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 thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of treating one or more symptoms of cholestasis.
  • the application relates to preventing one or more symptoms of cholestasis.
  • Intrahepatic 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 blood stream instead of being eliminated normally.
  • Intrahepatic cholestasis is characterized by widespread blockage of small ducts or by disorders, such as hepatitis, that impair the body's ability to eliminate bile.
  • Intrahepatic cholestasis may 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, serious injury, cystic fibrosis, infection, or intravenous feeding or be drug induced. Cholestasis may 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 strictures (non-cancerous narrowing of the common duct), cholangiocarcinoma (ductal carcinoma), and pancreatic carcinoma. Extrahepatic cholestasis can occur as a side effect of many medications.
  • a compound of the application may be used for treating or preventing 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).
  • PBC primary biliary cirrhosis
  • PSC primary sclerosing cholangitis
  • the application relates to a method of enhancing liver regeneration in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the method is enhancing liver regeneration for liver transplantation.
  • the application relates to a method of treating or preventing fibrosis in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of treating fibrosis.
  • the application relates to a method of preventing fibrosis.
  • fibrosis refers to all recognized fibrotic disorders, including fibrosis due to pathological conditions or diseases, fibrosis due to physical trauma (“traumatic fibrosis”), fibrosis due to radiation damage, and fibrosis due to exposure to chemotherapeutics.
  • organ fibrosis includes but is not limited to liver fibrosis, fibrosis of the kidneys, fibrosis of lung, and fibrosis of the intestine.
  • Traumatic fibrosis includes but is not limited to fibrosis secondary to surgery (surgical scarring), accidental physical trauma, bums, and hypertrophic scarring.
  • liver fibrosis includes liver fibrosis due to any cause, including but not limited to virally-induced liver fibrosis such as that due to hepatitis B or C vims; exposure to alcohol (alcoholic liver disease), certain pharmaceutical compounds including but not limited to methotrexate, some chemotherapeutic agents, and chronic ingestion of arsenicals or vitamin A in megadoses, oxidative stress, cancer radiation therapy or certain industrial chemicals including but not 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, auto-immune hepatitis, and steatohepatitis.
  • diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, fatty liver, obesity, non-alcoholic steatohepatitis, cystic
  • liver fibrosis Current therapy in liver fibrosis is primarily directed at removing the causal agent, e.g ., removing excess iron (e.g, in the case of hemochromatosis), decreasing viral load (e.g, in the case of chronic viral hepatitis), or eliminating or decreasing exposure to toxins (e.g, in the case of alcoholic liver disease).
  • Anti-inflammatory drugs such as corticosteroids and colchicine are also known for use in treating inflammation that can lead to liver fibrosis.
  • liver fibrosis may be clinically classified into five stages of severity (SO, SI, S2, S3, and S4), usually based on histological examination of a biopsy specimen. SO indicates no fibrosis, whereas S4 indicates cirrhosis.
  • liver fibrosis While various criteria for staging the severity of liver fibrosis exist, in general early stages of fibrosis are identified by discrete, localized areas of scarring in one portal (zone) of the liver, whereas later stages of fibrosis are identified by bridging fibrosis (scarring that crosses zones of the liver).
  • the application relates to a method of treating or preventing organ fibrosis in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the fibrosis is liver fibrosis.
  • the application relates to a method of treating or preventing gastrointestinal disease in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of treating gastrointestinal disease.
  • the application relates to a method of preventing gastrointestinal disease.
  • the gastrointestinal disease is selected from inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), bacterial overgrowth, malabsorption, post-radiation colitis, and microscopic colitis.
  • the inflammatory bowel disease is selected from Crohn's disease and ulcerative colitis.
  • the application relates to a method of treating or preventing renal disease in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of treating renal disease.
  • the application relates to a method of preventing renal disease.
  • the renal disease is selected from diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, and polycystic kidney disease.
  • FSGS focal segmental glomerulosclerosis
  • hypertensive nephrosclerosis chronic glomerulonephritis
  • chronic transplant glomerulopathy chronic interstitial nephritis
  • chronic interstitial nephritis chronic interstitial nephritis
  • polycystic kidney disease polycystic kidney disease
  • the application relates to a method of treating or preventing metabolic disease in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of treating renal disease.
  • the application relates to a method of preventing renal disease.
  • the metabolic disease is selected from insulin resistance, hyperglycemia, diabetes mellitus, diabesity, and obesity.
  • the diabetes mellitus is type I diabetes.
  • the diabetes mellitus is type II diabetes.
  • Diabetes mellitus commonly called diabetes, refers to a disease or condition that is generally characterized by metabolic defects in production and utilization of glucose which result in the failure to maintain appropriate blood sugar levels in the body.
  • type II diabetes the disease is characterized by insulin resistance, in which insulin loses its ability to exert its biological effects across a broad range of concentrations.
  • This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in liver.
  • the resulting condition is elevated blood glucose, which is called "hyperglycemia”.
  • Uncontrolled hyperglycemia is associated with increased and premature mortality due to an increased risk for microvascular and macrovascular diseases, including retinopathy (the impairment or loss of vision due to blood vessel damage in the eyes); neuropathy (nerve damage and foot problems due to blood vessel damage to the nervous system); and nephropathy (kidney disease due to blood vessel damage in the kidneys), hypertension, cerebrovascular disease, and coronary heart disease. Therefore, control of glucose homeostasis is a critically important approach for the treatment of diabetes.
  • Insulin resistance has been hypothesized to unify the clustering of hypertension, glucose intolerance, hyperinsulinemia, increased levels of triglyceride and decreased HDL cholesterol, and central and overall obesity.
  • the association of insulin resistance with glucose intolerance, an increase in plasma triglyceride and a decrease in high-density lipoprotein cholesterol concentrations, hypertension, hyperuricemia, smaller denser low- density lipoprotein particles, and higher circulating levels of plasminogen activator inhibitor- 1, has been referred to as "Syndrome X". Accordingly, methods of treating or preventing any disorders related to insulin resistance including the cluster of disease states, conditions or disorders that make up "Syndrome X" are provided.
  • the application relates to a method of treating or preventing metabolic syndrome in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of treating metabolic syndrome.
  • the application relates to a method of preventing metabolic syndrome.
  • the application relates to a method of treating or preventing cancer in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of treating cancer.
  • the application relates to a method of preventing cancer.
  • the cancer is selected from hepatocellular carcinoma, colorectal cancer, gastric cancer, renal cancer, prostate cancer, adrenal cancer, pancreatic cancer, breast cancer, bladder cancer, salivary gland cancer, ovarian cancer, uterine body cancer, and lung cancer.
  • the cancer is hepatocellular carcinoma. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is renal cancer. In one embodiment, the cancer is prostate cancer. In one embodiment, the cancer is adrenal cancer. In one embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is bladder cancer. In one embodiment, the cancer is salivary gland cancer. In one embodiment, the cancer is ovarian cancer. In one embodiment, the cancer is uterine body cancer. In one embodiment, the cancer is lung cancer.
  • At least one of an agent selected from Sorafenib, Sunitinib, Erlotinib, or Imatinib is co-administered with the compound of the application to treat cancer.
  • at least one of an agent selected from Abarelix, Aldeleukin, Allopurinol, Altretamine, Amifostine, Anastozole, Bevacizumab, Capecitabine, Carboplatin, Cisplatin, Docetaxel, Doxorubicin, Erlotinib, Exemestane, 5-Fluorouracil, Fulvestrant, Gemcitabine, Goserelin Acetate, Irinotecan, Lapatinib Ditosylate, Letozole, Leucovorin, Levamisole, Oxaliplatin, Paclitaxel, Panitumumab, Pemetrexed Disodium, Profimer Sodium, Tamoxifen, Topotecan, and Trastuzumab is
  • Cancer staging systems describe the extent of cancer progression. In general, the staging systems describe how far the tumor has spread and puts patients with similar prognosis and treatment in the same staging group. In general, there are poorer prognoses for tumors that have become invasive or metastasized.
  • stage I cancers are often localized and are usually curable.
  • Stage II and IIIA cancers 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 of lymph nodes.
  • TNM staging which stands for the categories: Tumor, Nodes, and Metastases.
  • 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 does not have 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 with 0 representing a malignancy with no 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 with no metastases and 1 representing a malignancy with metastases.
  • staging systems or variations of these staging systems or other suitable staging systems may be used to describe a tumor such as hepatocellular carcinoma. Few options only are available for the treatment of hepatocellular cancer depending on the stage and features of the cancer. Treatments include surgery, treatment with Sorafenib, and targeted therapies. In general, surgery is the first line of treatment for early stage localized hepatocellular cancer. Additional systemic treatments may be used to treat invasive and metastatic tumors.
  • the application relates to a method of treating or preventing gallstones in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of treating gallstones.
  • the application relates to a method of preventing gallstones.
  • a gallstone is a crystalline concretion formed within the gallbladder by accretion of bile components. These calculi are formed in the gallbladder but may distally pass into other parts of the biliary tract such as the cystic duct, common bile duct, pancreatic duct, or the ampulla of Vater. Rarely, in cases of severe inflammation, gallstones may erode through the gallbladder into adherent bowel potentially causing an obstruction termed gallstone ileus.
  • Presence of gallstones in the gallbladder may 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 Bacteroides species.
  • Presence of gallstones in other parts of the biliary tract can cause obstruction of the bile ducts, which can lead to serious conditions such as ascending cholangitis or pancreatitis.
  • the application relates to a method of treating or preventing cholesterol gallstone disease in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of treating cholesterol gallstone disease.
  • the application relates to a method of preventing cholesterol gallstone disease.
  • the application relates to a method of treating or preventing neurological disease in a subject, comprising administering to the subject in need thereof an effective amount of a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application relates to a method of treating neurological disease.
  • the application relates to a method of preventing neurological disease.
  • the neurological disease is stroke.
  • the application relates to a method as described herein and further wherein, the compound is administered by a route selected from oral, parenteral, intramuscular, intranasal, sublingual, intratracheal, inhalation, ocular, vaginal, rectal, and intracerebroventricular.
  • the route is oral.
  • the compound utilized in one or more of the methods described herein is an FXR agonist.
  • the compound is a selective FXR agonist.
  • the compound does not activate TGR5.
  • the compound does not activate other nuclear receptors involved in metabolic pathways (e.g ., as measured by an AlphaScreen assay).
  • such other nuclear receptors involved in metabolic pathways are selected from LXRp, PXR, CAR, PPARa, PPAR5, PPARy, RAR, RARa, VDR, TR, PR, RXR, GR, and ER.
  • the compound induces apoptosis.
  • the application relates to a method of regulating the expression level of one or more genes involved in bile acid homeostasis.
  • the application relates to a method of down regulating the expression level of one or more genes selected from CYP7al and SREBP-IC in a cell by administering to the cell a compound of the application. In one embodiment, the application relates to a method of up regulating the expression level of one or more genes selected from OSTa, OSTp, BSEP, SHP, UGT2B4, MRP2, FGF-19, PPARy, PLTP, APOCII, and PEPCK in a cell by administering to the cell a compound of the application.
  • the application also relates to the manufacture of a medicament for treating or preventing a disease or condition (e.g., a disease or condition mediated by FXR), wherein the medicament comprises a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • a disease or condition e.g., a disease or condition mediated by FXR
  • the application relates to the manufacture of a medicament for treating or preventing any one of the diseases or conditions described herein above, wherein the medicament comprises a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the application also relates to a composition for use in a method for treating or preventing a disease or condition (e.g, a disease or condition mediated by FXR), wherein the composition comprises a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • a disease or condition e.g, a disease or condition mediated by FXR
  • the application relates to a composition for use in a method for treating or preventing any one of the diseases or conditions described herein above, wherein the composition comprises a compound of the application or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof.
  • the methods of the application comprise the step of administering an effective amount of a compound of the application.
  • an "effective amount" refers to an amount of a compound of the application which is sufficient to achieve the stated effect. Accordingly, an effective amount of a compound of the application 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.
  • an effective amount of a compound of the application for use in a method for the prevention or treatment of a cholestatic liver disease or increasing bile flow will be an amount sufficient to increase bile flow to the intestine.
  • the amount of the compound of the application which is required to achieve the desired biological effect will depend on a number of factors such as the use for which it is intended, the means of administration, and the recipient, and will be ultimately at the discretion of the attendant physician or veterinarian.
  • a typical daily dose for the treatment of a FXR mediated disease and condition may be expected to lie in the range of from about 0.01 mg/kg to about 100 mg/kg. This dose may be administered as a single unit dose or as several separate unit doses or as a continuous infusion. Similar dosages would be applicable for the treatment of other diseases, conditions and therapies including the prevention and treatment of cholestatic liver diseases.
  • the present application proves a method of treating or preventing a disease or condition in a subject in need thereof comprising administering an effective amount of the compound of formula I or a pharmaceutically acceptable salt, solvate, amino acid conjugate, sulfate, glucuronide conjugate, or prodrug thereof, and wherein the disease or condition is mediated by FXR.
  • the present application proves a method of treating or preventing a disease or condition in a subject in need thereof comprising administering an effective amount of the compound of formula I, wherein the disease is selected from cardiovascular disease, chronic liver disease, lipid disorder, gastrointestinal disease, renal disease, metabolic disease, cancer, and neurological disease.
  • the present application proves a method of treating or preventing a disease or condition in a subject in need thereof 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.
  • cardiovascular disease selected from atherosclerosis, arteriosclerosis, dyslipidemia, hypercholesteremia, hyperlipidemia, hyperlipoproteinemia, and hypertriglyceridemia.
  • the present application proves a method of treating or preventing a disease or condition in a subject in need thereof 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, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), hepatitis C infection, alcoholic liver disease, liver damage due to progressive fibrosis, and liver fibrosis.
  • PBC primary biliary cirrhosis
  • PSC primary biliary cholangitis
  • NASH nonalcoholic fatty liver disease
  • hepatitis C infection alcoholic liver disease
  • liver damage due to progressive fibrosis and liver fibrosis.
  • FXR mediated diseases also include portal hypertension, bile acid diarrhea, hyperlipidemia, high LDL-cholesterol, high HDL cholesterol, high triglycerides, and cardiovascular disease.
  • 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, liver transplant associated graft versus host disease, living donor transplant liver regeneration, congenital hepatic fibrosis, choledocholithiasis, granulomatous liver disease, intra- or extrahepatic malignancy, Sjogren's syndrome, Sarcoidosis, Wilson's disease, Gaucher' s disease, hemochromatosis, and alpha 1 -antitrypsin deficiency.
  • CX cerebrotendinous x
  • the present application proves a method of treating or preventing a disease or condition in a subject in need thereof 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.
  • IBD inflammatory bowel disease
  • IBS irritable bowel syndrome
  • bacterial overgrowth malabsorption
  • malabsorption post-radiation colitis
  • microscopic colitis microscopic colitis
  • the present application proves a method of treating or preventing a disease or condition in a subject in need thereof comprising administering an effective amount of the compound of formula I, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
  • the present application proves a method of treating or preventing a disease or condition in a subject in need thereof comprising administering an effective amount of the compound of formula I, wherein the disease is renal disease selected from diabetic nephropathy, focal segmental glomerulosclerosis (FSGS), hypertensive nephrosclerosis, chronic glomerulonephritis, chronic transplant glomerulopathy, chronic interstitial nephritis, and polycystic kidney disease.
  • FSGS focal segmental glomerulosclerosis
  • the present application proves a method of treating or preventing a disease or condition in a subject in need thereof comprising administering an effective amount of the compound of formula I, wherein the disease is metabolic disease selected from insulin resistance, hyperglycemia, diabetes mellitus, diabesity, and obesity.
  • the present application proves a method of treating or preventing a disease or condition in a subject in need thereof comprising administering an effective amount of the compound of formula I, wherein the disease is cancer selected from hepatocellular carcinoma, colorectal cancer, gastric cancer, renal cancer, prostate cancer, adrenal cancer, pancreatic cancer, breast cancer, bladder cancer, salivary gland cancer, ovarian cancer, uterine body cancer, and lung cancer.
  • the disease is cancer selected from hepatocellular carcinoma, colorectal cancer, gastric cancer, renal cancer, prostate cancer, adrenal cancer, pancreatic cancer, breast cancer, bladder cancer, salivary gland cancer, ovarian cancer, uterine body cancer, and lung cancer.
  • Example 1 Compound 20 may be prepared by, e.g. bioconversion from a plant sterol.
  • Compound 21 may be converted to compound 22 by olefmation using techniques known in the art, such as those disclosed in US 2,624,748 and Uekawa et al. (2004) Short- step Synthesis of Chenodiol from Stigmasterol. Bioscience, biotechnology, and biochemistry, 68, 1332-1337.
  • Example 4 A solution of EtMgBr in THF (1M, 1.85 mL, 1.85 mmol, 1.9 equiv.) was added portionwise to a pre-cooled (-20 °C) solution of ZnCh (0.5M, 1.85 mL, 0.93 mmol, 0.96 equiv.) in THF (1.85 mL). Copper iodide (9.2 mg, 0.048 mmol, 0.05 equiv.) was added in one portion, followed by portionwise addition of 25c (513 mg, 0.97 mmol) in THF (1.85 mL). The reaction was stirred at -20 °C for 60-90 min.
  • the organic layer was concentrated under vacuum and diluted with methanol diluted with methanol and concentrated to an oil.
  • the mixture was stirred for 3- 6 h and cooled to ambient temperature, quenched with HC1 and extracted with MTBE, and the MTBE layer was washed with water and the aqueous layers were discarded.
  • the product was isolated from the MTBE layer by warming to 50 °C, then adding heptane (20- 30% v/v).
  • the mixture was cooled to 15-20 °C and filtered and dried to produce Compound 100 as a solid (227 mg, 0.52 mmol, 80% yield).
  • Compound 100 can be isolated from water by stirring the MTBE layer was stirred with INNaOH (aq) (2-2.5 equiv.) for 30 min, then separating and collecting the aqueous layer.
  • the MTBE layer is washed with water and then discarded, while and the aqueous washings are combined with the basic aqueous layer.
  • the combined aqueous layers are concentrated under vacuum to remove residual MTBE and the residue is diluted with water and acidified to pH 2-3 with IN HC1 (aq).
  • the suspension is heated to 40 °C for 30-60 min, then cooled.
  • the suspension is filtered, washed with water and dried under vacuum to afford Compound 100.

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Abstract

La présente invention concerne des procédés et de nouveaux intermédiaires utiles dans la préparation d'un composé de formule 100 (composé 100).
PCT/US2022/037426 2021-07-16 2022-07-18 Procédés et intermédiaires pour la préparation d'acide 3.alpha.,7.alpha.,11.bêta.-trihydroxy-6.alpha.-éthyl-5.bêta.-cholan-24-oïque WO2023288123A1 (fr)

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