EP2220087A1 - Composés d'imidazoazépinone énantiomériquement enrichis - Google Patents

Composés d'imidazoazépinone énantiomériquement enrichis

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Publication number
EP2220087A1
EP2220087A1 EP07867469A EP07867469A EP2220087A1 EP 2220087 A1 EP2220087 A1 EP 2220087A1 EP 07867469 A EP07867469 A EP 07867469A EP 07867469 A EP07867469 A EP 07867469A EP 2220087 A1 EP2220087 A1 EP 2220087A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutically acceptable
compound
alkyl
group
acceptable salts
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07867469A
Other languages
German (de)
English (en)
Inventor
Mark Spyvee
Christina J. Shaffer
Boris M. Seletsky
Shawn Schiller
Jia Liu
Xiang-Yi Li Li
Qian Chen
Roch Boivin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eisai R&D Management Co Ltd
Original Assignee
Eisai R&D Management Co Ltd
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Filing date
Publication date
Application filed by Eisai R&D Management Co Ltd filed Critical Eisai R&D Management Co Ltd
Publication of EP2220087A1 publication Critical patent/EP2220087A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • Thp naive CD4+ T helper precursor
  • ThI Type 1 T helper
  • Th2 Type 2 T helper
  • ThI cells are defined both by their distinct functional abilities and by unique cytokine profiles. Specifically, ThI cells produce interferon-gamma, interleukin (IL)- 2, and tumor necrosis factor (TNF)-beta, which activate macrophages and are responsible for cell-mediated immunity and phagocyte-dependent protective responses.
  • IL interleukin
  • TNF tumor necrosis factor
  • Th2 cells are known to produce IL-4, IL-5, IL-6, IL-9, IL-IO and IL- 13, which are responsible for strong antibody production, eosinophil activation, and inhibition of several macrophage functions, thus providing phagocyte-independent protective responses. Accordingly, ThI and Th2 cells are associated with different immunopathological responses.
  • IL-4 promotes Th2 differentiation and simultaneously blocks ThI development.
  • IL- 12, IL- 18 and IFN-gamma are the cytokines critical for the development of ThI cells. Accordingly, the cytokines themselves form a positive and negative feedback system that drives Th polarization and keeps a balance between ThI and Th2.
  • ThI cells are involved in the pathogenesis of a variety of organ- specific autoimmune disorders, Crohn's disease, Helicobacter pylori-induced peptic ulcer, acute kidney allograft rejection, and unexplained recurrent abortions.
  • allergen-specific Th2 responses are responsible for atopic disorders in genetically susceptible individuals.
  • Th2 responses against still unknown antigens predominate in Omenn's syndrome, idiopathic pulmonary fibrosis, and progressive systemic sclerosis.
  • Thl/Th2 paradigm provides a rationale for the development of strategies for the therapy of allergic and autoimmune disorders.
  • a first aspect of the present invention is an enantiomerically pure compound (sometimes referred to as an "active compound” herein) of Formula I:
  • R 1 is C 1-3 alkyl
  • X is methylene, ethylene, propylene, ethenylene, propenylene, or butenylene;
  • R 5 is phenyl, pyrrolyl, benzimidazolyl, oxazolyl, isoxazolyl, imidazothiazolyl, quinolinyl, isoquinolinyl, indazolyl, pyridinyl, imidazopyridinyl, indolyl, benzotriazolyl, imidazolyl, benzofuranyl, benzothiadiazolyl, pyridimidinyl, benzopyranonyl, thiazolyl, thiadiazolyl, furyl, thienyl, pyrazolyl, quinoxalinyl, or naphthyl, and substituted with between 0 and 5 substituents independently selected from Cj -4 alkyl, C 1-3 alkoxy, hydroxyl,
  • R 8 is H, methyl, ethyl, propyl, (Ci -3 alkoxy)Ci -3 alkyl, (Ci -3 alkylthio)Ci -3 alkyl,
  • R is substituted with between 0 and 3 substituents independently selected from methyl, ethyl, halo, hydroxyl, Ci -3 alkoxy, Ci -3 alkylthio, (Ci -3 alkoxy)Ci -3 alkyl, (Ci -3 alkylthio)Ci -3 alkyl, C 1-3 hydroxyalkyl, (Ci -3 mercaptoalkyl)phenyl, benzyl, furyl, imidazolyl, pyrazolyl, pyrrolyl, isothiazolyl, isooxazolyl, pyridyl, and thienyl; and
  • each of R a , R b , and R c is independently selected from hydrogen, hydroxyl, methoxy, benzyloxy, fluoro, chloro, amino, methylamino, dimethylamino, and phenoxy;
  • a second aspect of the present invention is a composition comprising an active compound as described herein in a pharmaceutically acceptable carrier.
  • a third aspect of the present invention is a method of treating rheumatoid arthritis in a subject in need thereof, comprising administering to the subject an active compound as described herein in a treatment effective amount, along with the use of an active compound as described herein for the manufacture of a medicament for treating rheumatoid arthritis in a subject in need thereof.
  • a fourth aspect of the present invention is a method of treating multiple sclerosis in a subject in need thereof, comprising administering to said subject, an active compound as described herein in a treatment effective amount, along with the use of an active compound as described herein for the manufacture of a medicament for treating multiple sclerosis in a subject in need thereof.
  • a fifth aspect of the invention is a method of treating an autoimmune disease in a subject in need thereof, comprising administering to the subject an active compound as described herein in a treatment effective amount, along with the use of an active compound as described herein for the manufacture of a medicament for treating an autoimmune disease in a subject in need thereof, wherein the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, type 1 diabetes mellitus, psoriasis, and atherosclerosis.
  • Enantiomerically pure as used herein means a stereomerically pure compound, or composition of a compound, the compound having one chiral center.
  • “Stereomerically pure” as used herein means a compound or composition thereof that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound.
  • a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
  • a stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. See, e.g., US Patent No. 7,189,715.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • Alkyl or "alkyl group,” as used herein, means a straight-chain (i.e., unbranched), branched, or cyclic hydrocarbon chain that is completely saturated.
  • alkyl groups contain 1-3 carbon atoms.
  • alkyl groups contain 2-3 carbon atoms, and in yet other embodiments alkyl groups contain 1-2 carbon atoms.
  • the term “alkyl” or “alkyl group” refers to a cycloalkyl group, also known as carbocycle.
  • Exemplary Ci -3 alkyl groups include methyl, ethyl, propyl, isopropyl, and cyclopropyl.
  • alkenyl or "alkenyl group,” as used herein, refers to a straight-chain (i.e., unbranched), branched, or cyclic hydrocarbon chain that has one or more double bonds.
  • alkenyl groups contain 2-4 carbon atoms.
  • alkenyl groups contain 3-4 carbon atoms, and in yet other embodiments alkenyl groups contain 2-3 carbon atoms.
  • the term alkenyl refers to a straight chain hydrocarbon having two double bonds, also referred to as "diene.”
  • alkenyl or “alkenyl group” refers to a cycloalkenyl group.
  • alkoxy refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur
  • alkylthio (alkylthio) atom
  • Methylene ethylene
  • ethylene ethylene
  • propylene as used herein refer to the bivalent moieties -CH 2 -, -CH 2 CH 2 -, and -CH 2 CH 2 CH 2 -, respectively.
  • Alkylidene refers to a bivalent hydrocarbon group formed by mono or dialkyl substitution of methylene.
  • an alkylidene group has 1-6 carbon atoms.
  • an alkylidene group has 2-6, 1-5, 2-4, or 1-3 carbon atoms.
  • alkenylidene refers to a bivalent hydrocarbon group having one or more double bonds formed by mono or dialkenyl substitution of methylene. In certain embodiments, an alkenylidene group has 2-6 carbon atoms. In other embodiments, an alkenylidene group has
  • an alkenylidene has two double bonds.
  • Ci -6 alkyl ester or amide refers to a C] -6 alkyl ester or a Ci -6 alkyl amide where each Ci -6 alkyl group is as defined above.
  • C 2-6 alkenyl ester or amide refers to a C 2-6 alkenyl ester or a C 2-6 alkenyl amide where each C 2-6 alkenyl group is as defined above.
  • Treatment refers to reversing, alleviating, delaying the onset of, inhibiting the progress of, or preventing a disease or disorder as described herein.
  • treatment may be administered after one or more symptoms have developed.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • Patient or "subject”, as used herein, means an animal subject, preferably a mammalian subject (e.g., dog, cat, horse, cow, sheep, goat, monkey, etc.), and particularly human subjects (including both male and female subjects, and including neonatal, infant, juvenile, adolescent, adult and geriatric subjects).
  • mammalian subject e.g., dog, cat, horse, cow, sheep, goat, monkey, etc.
  • human subjects including both male and female subjects, and including neonatal, infant, juvenile, adolescent, adult and geriatric subjects.
  • “Pharmaceutically acceptable carrier” refers to a nontoxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, cyclodextrins, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-
  • structures depicted herein are also meant to include all enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • active compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention.
  • substituted refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent.
  • a substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • the present invention provides enantiomerically pure compounds, or active compounds, of Formula I: or more particularly Formula Ia or Formula Ib:
  • R 1 is C 1-3 alkyl
  • X is methylene, ethylene, propylene, ethenylene, propenylene, or butenylene;
  • R 5 is phenyl, pyrrolyl, benzimidazolyl, oxazolyl, isoxazolyl, imidazothiazolyl, quinolinyl, isoquinolinyl, indazolyl, pyridinyl, imidazopyridinyl, indolyl, benzotriazolyl, imidazolyl, benzofuranyl, benzothiadiazolyl, pyridimidinyl, benzopyranonyl, thiazolyl, thiadiazolyl, furyl, thienyl, pyrazolyl, quinoxalinyl, or naphthyl, and substituted with between 0 and 5 substituents independently selected from Ci -4 alkyl, Cj -3 alkoxy, hydroxyl, Ci -3 alkylthio, cyclopropyl, cyclopropylmethyl, trifluoromethoxy, 5-methylisoxazolyl, pyrazolyl, benz
  • R 1 is Ci -2 alkyl
  • R 5 is phenyl, pyrrolyl, benzimidazolyl, oxazolyl, isoxazolyl, imidazothiazolyl, quinolinyl, isoquinolinyl, indazolyl, pyridinyl, imidazopyridinyl, indolyl, benzotriazolyl, imidazolyl, benzofuranyl, benzothiadiazolyl, pyridimidinyl, benzopyranonyl, thiazolyl, thiadiazolyl, furyl, thienyl, pyrazolyl, quinoxalinyl, or naphthyl, and substituted with between 0 and 5 substituents independently selected from Ci -4 alkyl, Ci -3 alkoxy, hydroxyl, Ci -3 alkylthio, cyclopropyl, cyclopropylmethyl, trifluoromethoxy, 5-methylisoxazolyl, pyrazolyl, benzy
  • R is, methyl, ethyl, or propyl, wherein R8 is substituted with from 0 and 3 hydroxyl substituents;
  • X is methylene or ethylene
  • R a R b and R c are each independently selected from the group consisting of H and methoxy. or a pharmaceutically acceptable salt, a Ci -6 alkyl ester or amide, or a C 2-6 alkenyl ester or amide thereof.
  • R 1 is methyl
  • R is phenyl, pyrrolyl or pyrazolyl, each of which is substituted 0, 1 or 2 times with methyl
  • R 8 is ethyl
  • X is methylene
  • R a and R c are each methoxy
  • R b is H; or pharmaceutically acceptable salt thereof.
  • Active compounds of the present invention include pharmaceutically acceptable salts of the foregoing.
  • Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2- naphthalenesulf
  • Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N+(Ci -4 alkyl) 4 salts.
  • alkali metal e.g., sodium and potassium
  • alkaline earth metal e.g., magnesium
  • ammonium e.g., sodium and potassium
  • N+(Ci -4 alkyl) 4 salts e.g., sodium and potassium
  • alkaline earth metal e.g., magnesium
  • ammonium e.g., sodium and potassium
  • N+(Ci -4 alkyl) 4 salts e.g., sodium and potassium
  • ammonium e.g., sodium and potassium
  • N+(Ci -4 alkyl) 4 salts e.g., sodium and potassium
  • ammonium e.g., sodium and potassium
  • N+(Ci -4 alkyl) 4 salts e.g., sodium and potassium
  • Active compounds of the present invention can be combined with a pharmaceutically acceptable carrier to provide pharmaceutical formulations thereof.
  • a pharmaceutically acceptable carrier to provide pharmaceutical formulations thereof.
  • the particular choice of carrier and formulation will depend upon the particular route of administration for which the composition is intended.
  • compositions of the present invention may be suitable for oral, parenteral, inhalation spray, topical, rectal, nasal, buccal, vaginal or implanted reservoir administration, etc.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdermal patches may also be used.
  • the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.
  • the pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • the pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions of this invention are formulated for oral administration.
  • Active compounds of the present invention may be administered to patients or subjects to treat a variety of different condition, particularly patients or subjects afflicted with:
  • Active compounds may be administered to subjects by any suitable route, including orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • the active compounds are administered to the subjects in a treatment effective, or therapeutically effective, amount.
  • the amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, and the particular route of administration.
  • the compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • the compositions of the present invention provide a dosage of between 0.01 mg and 50 mg is provided. In other embodiments, a dosage of between 0.1 and 25 mg or between 5 mg and 40 mg is provided.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
  • Microwave assisted reactions were carried out using an Emrys Liberator instrument supplied by Biotage Corporation. Solvent removal was carried out using either a B ⁇ chi rotary evaporator or a Genevac centrifugal evaporator. Analytical and preparative chromatography was carried out using a Waters autopurification instrument using either normal phase or reverse phase HPLC columns, under either acidic, neutral, or basic conditions. Compounds were estimated to be >90% pure, as determined by area percent of ELSD chromatograms. NMR spectra were recorded using a Varian 300 MHz spectrometer. [0063] General methods and experimentals for preparing compounds of the present invention are set forth below. In certain cases, a particular compound is described by way of example. However, it will be appreciated that in each case a series of compounds of the present invention were prepared in accordance with the schemes and experimentals described below.
  • ER-811160 As depicted in Scheme 1 above, a solution of potassium cyanide (22.5 g, 0.335 mol) in water (50 mL) was added dropwise over 5 minutes to a solution of 1- Boc-piperidone (32.48 g, 0.1598 mol) and ammonium carbonate (33.8 g, 0.351 mol) in water (90 mL) and methanol (110 mL). An off-white precipitate began to form soon after addition was complete. The reaction flask was sealed and the suspension stirred at room temperature for 72 hours. The resultant pale yellow precipitate was filtered and was washed with small portions of water to give ER-811160 (37.1 g, 86%) as a colorless solid.
  • Scheme 2 As depicted in Scheme 1 above, a solution of potassium cyanide (22.5 g, 0.335 mol) in water (50 mL) was added dropwise over 5 minutes to a solution of 1- Boc-piperidone (32.48 g, 0.1598 mol)
  • ER-818039 As depicted in Scheme 2 above, a suspension of ER-81 1160 (30.0 g, 0.11 1 mol), 3,5-dimethoxybenzyl bromide (30.9 g, 0.134 mol), and potassium carbonate (18.5 g, 0.134 mol) in acetone (555 mL) was heated under reflux overnight. The reaction solution was cooled to room temperature, filtered and concentrated in vacuo. The crude orange residue was dissolved in a minimal amount of MTBE (250 mL). A small amount of hexanes was added (50 mL) and the product allowed to precipitate out (over ⁇ 2 hours) as a colorless solid which was isolated by vacuum filtration. The filter cake was washed with small amounts of MTBE, and dried in vacuo to provide ER-818039 (39.6g, 85%) as a colorless solid.
  • ER-823143-01 As depicted in Scheme 3 above, to a 1-neck round-bottom flask containing ER-818039 (2.15 g, 0.00512 mol) was slowly added a solution of 4N HCl in 1,4- dioxane (3.8 mL, 0.049 mol). The starting material slowly dissolved over 20 minutes and a colorless precipitate formed after 30 minutes. MTBE (3 ml) was then added. After 2 hours, the reaction was filtered and washed with MTBE, which provided ER-823143-01 (1.81 g, 99%) as a colorless solid.
  • ER-817098 As depicted in Scheme 4 above, to a suspension of ER-823143-01 (41.5 mg, 0.000117 mol) and 4A molecular sieves in 1 ,2-dimethoxyethane (0.5 mL, 0.004 mol) under an atmosphere of nitrogen was added 3,5-dimethoxybenzaldehyde (21.3 mg, 0.000128 mol) followed by triethylamine (16.2 ⁇ L, 0.000117 mol). The reaction was stirred for 1 hour. Sodium triacetoxyborohydride (34.6 mg, 0.000163 mol) was added, and the reaction was stirred overnight. Silica gel flash chromatography yielded ER-817098 (45.3 mg, 83%) as a colorless solid.
  • ER-817116 As depicted in Scheme 5 above, to a solution of ER-817098-00 (50.0 mg, 0.000106 mol) and l-bromo-2-methoxyethane (15.6 ⁇ L, 0.000160 mol) in N- methylpyrrolidinone (1.0 mL, 0.010 mol) was added 1.0 M lithium hexamethyldisilazide solution in tetrahydrofuran (0.16 mL). The temperature ⁇ vas increased to at 80°C and the reaction mixture stirred overnight. The reaction mixture was cooled to room temperature, quenched with water and then extracted several times with MTBE.
  • ER-823914 As depicted in Scheme 7 above, to a solution of ER-823143-01 (5.03 g, 0.0141 mol) in tetrahydrofuran (30.0 mL, 0.370 mol) at -78°C was slowly added 1.0 M of allylmagnesium bromide in ether (71 mL). The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was cooled to -78°C, treated dropwise with trifluoroacetic acid (21.8 mL, 0.283 mol), and then concentrated in vacuo to a small residual volume. Triethylamine was added to neutralize residual TFA and the mixture then concentrated in vacuo to dryness.
  • ER-823915 As depicted in Scheme 8 above, to a solution of ER-823914 (2.20 g, 0.00496 mol) in N,N-Dimethylformamide (12.4 mL, 0.160 mol) was added sodium hydride (298 mg, 0.00744 mol) followed by iodoethane (607 ⁇ L, 0.00744 mol). The reaction mixture was stirred overnight then quenched with water and extracted several times with MTBE. The MTBE extracts were combined and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (eluent: 40% hexanes in ethyl acetate) provided ER-823915 (0.80 g, 34%) as a colorless foam.
  • ER-823917-01 As depicted in Scheme 9 above, ER-823915 (799.2 mg, 0.001695 mol) was dissolved in a solution of 4 M hydrogen chloride in 1,4-dioxane (10 mL). The reaction mixture was stirred overnight and then concentrated in vacuo to provide ER-823917- 01 (0.69g, quantitative) as an orange solid.
  • ER-824184 & ER-824185 As depicted in Scheme 10 above, a solution of ER- 823915 (200 mg) in acetonitrile (1 ml) was injected onto a CHIRALP AK® AS-H SFC column (30 mm x 250 mm, 5 micron particle size) and eluted with 95 : 5 n-heptane : i- propanol at a flow rate of 40 ml/min. Eluted fractions were detected using a UV detector with the wavelength set at 290 run. The first eluting fraction was isolated and concentrated by rotary evaporation in vacuo to afford ER-824184; the second eluting fraction was isolated and concentrated by rotary evaporation in vacuo to afford ER-824185.
  • ER-824188-01 As depicted in Scheme 11 above, ER-824184 (25.33 g, 0.05371 mol) was dissolved in a solution of 4 M hydrogen chloride in 1,4-dioxane (135 mL). The reaction mixture was stirred overnight and then concentrated in vacuo to provide ER-824188-01 (21.9 g, quantitative) as an orange solid. Single crystal X-ray diffraction analysis of ER-824188-01 showed the absolute configuration of the stereocenter to be S, as depicted in Scheme 11.
  • ER-824280-01 As depicted in Scheme 12 above, ER-824185 (457.2 mg, 0.0009695 mol) was dissolved in a solution of 4 M hydrogen chloride in 1,4-dioxane (2.5 mL). The reaction mixture was stirred overnight and then concentrated in vacuo to provide ER-824280-01 (383.2 mg, 97%) as an orange solid. Single crystal X-ray diffraction analysis of a Mosher amide derivative of ER-824188-01 showed the absolute configuration of the stereocenter to be R, as depicted in Scheme 11.
  • ER-819924 As depicted in Scheme 13 above, ER-824188-01 (62.4 mg, 0.000153 mol) and N-methylpyrrole-2-carbaldehyde (0.000229 mol) were dissolved/suspended in N 5 N- dimethylformamide (0.62 mL). After stirring for 30 minutes, sodium triacetoxyborohydride (47.8 mg, 0.000214 mol) was added. The reaction mixture was stirred overnight then purified by reverse phase chromatography to afford ER-819924 (71.1 mg, 83.4%) as an oil.
  • ER-819925 As depicted in Scheme 14 above, ER-824280-01 (59.5 mg, 0.000146 mol and N-methylpyrrole-2-carbaldehyde (0.000219 mol) were dissolved/suspended in N 5 N'- dimethylformamide (0.60 mL). After stirring for 30 minutes, sodium triacetoxyborohydride (45.6 mg, 0.000204 mol) was added. The reaction mixture was stirred overnight then purified by reverse phase chromatography to afford ER-819925 (51.9 mg, 76.6%) as an oil.
  • ER-819762 As depicted in Scheme 15 above, a solution of ER-824188-01 (5.7 g, 0.0140 mol), l,8-diazabicyclo[5.4.0]undec-7-ene (4.4 mL, 0.029 mol) and 3,5- dimethylbenzyl bromide (4.7 g, 0.024 mol) in N,N-dimethylformamide (50 mL) was heated at 97 C overnight. An aqueous work-up and purification by flash chromatography provided ER-819762 (4.86 g, 71 %) as colorless solid.
  • ER-819762-01 As depicted in Scheme 16 above, a solution of ER-819762 (4.77 g, 0.00974 mol), Acetonitrile (10 mL) and IM HCl in Water (11 mL) was stirred at room temperature for approximately 5 minutes. The solution was concentrated to provide ER- 819762-01 (5.1 g, quantitative) as a colorless crystalline solid after lyophilization. Single crystal X-ray diffraction analysis of ER-819762-01 showed the absolute configuration of the stereocenter to be S, as depicted in Scheme 16.
  • Scheme 17 Single crystal X-ray diffraction analysis of ER-819762-01 showed the absolute configuration of the stereocenter to be S, as depicted in Scheme 16.
  • ER-819763 As depicted in Scheme 17 above, a solution of ER-824280-01 (66.9 g, 0.1640 mol), l,8-diazabicyclo[5.4.0]undec-7-ene (54 mL, 0.361 mol) and 3,5- dimethylbenzyl chloride (42.4 g, 0.213 mol) in N-Methylpyrrolidinone (669 mL) was heated at 72 C for 2 hours. After cooling, water was added to precipitate the desired product. Filtration and drying under vacuum provided ER-819763 (74.4g, 92%) as colorless solid.
  • ER-824102 As depicted in Scheme 18 above, to a solution of ER-823143-01 (4.00 g, 0.0112 mol) in N,N-dimethylformamide (25 mL) at room temperature was added alpha- bromomesitylene (3.13 g, 0.0157 mol) followed by DBU (4.37 mL, 0.0292 mol). After stirring for 1 hour, reaction was quenched with half-saturated aq. NH4C1, diluted with ethyl acetate, and stirred for Ih to give two clear layers. Organic layer was separated, aq. layer was extracted with ethyl acetate (2x). Combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Crystallization from MTBE afforded ER-824102 (4.30 g, 87%) as a colorless solid.
  • ER-819929 As depicted in Scheme 19 above, to a solution of ER-824102 (3.72 g, 0.0085 mol) in tetrahydrofuran (35 mL) at -65 0 C was added 1.0 M allylmagnesium bromide in ether (25.5 mL, 0.0255 mol) over 10 min keeping internal temperature below -50°C. The reaction mixture was allowed to warm to 0 0 C. After 3 h at 0 0 C, reaction was quenched with saturated aq. NH4C1, diluted with ethyl acetate and water, stirred for 10 min to give two clear layers. Organic layer was separated, aq. layer was extracted with ethyl acetate. Combined extracts were washed with water, brine, dried over Na2SO4, filtered, concentrated in vacuo to give crude product ER-819929 (4.15 g, quantitative) as a colorless solid that was used for next step without further purification.
  • ER-819930 As depicted in Scheme 20 above, a solution of ER-819929 (37 mg, 0.000077 mol) in trifluoroacetic acid (0.5 mL) was stirred at room temperature for 16 hours. Dark brown-red reaction mixture was diluted with EtOAc (5 mL), neutralized with sat aq NaHCO3 (5 mL, careful: gas evolution). Two-layer mixture was stirred for 10 min to give two clear, almost colorless layers. The organic layer was separated; the aq layer was extracted with EtOAc. Combined organic extracts were dried over Na2SO4, filtered, concentrated in vacuo. Purification by flash chromatography eluting with 1:1 Heptane-EtOAc, 1 :3 Heptane-EtOAc, 100% EtOAc afforded ER-819930 (26 mg, 73%) as a colorless solid.
  • ER-820006 and ER-820007 As depicted in Scheme 21 above, to a solution of ER-819930 (110 mg, 0.000238 mol) and methallyl bromide (72 ⁇ L, 0.000715 mol) in DMF (1.5 mL,) was added 1.0 M lithium hexamethyldisilazide solution in tetrahydrofuran (0.52 mL, 0.00052 mol). After stirring for 18 h at rt, reaction mixture was diluted with MTBE, quenched with half-saturated aq NH 4 Cl. Aq. layer was separated, extracted with MTBE. Combined extracts were dried over Na 2 SO 4 , filtered, concentrated in vacuo.
  • ER-819786 and ER-819787 As depicted in Scheme 22 above, a 5 mL microwave reactor vial equipped with a stir bar was charged with ER-819930 (110 mg, 0.000238 mol), DMF (1.5 mL), 2-(2-bromoethoxy)tetrahydro-2H-pyran (108 ⁇ L, 0.000715 mol) and 1.00 M of lithium hexamethyldisilazide in tetrahydrofuran (520 ⁇ L, 0.00052 mol). The reactor vial was microwaved at 200°C for 15 min.
  • ER-819993 and ER-819994 As depicted in Scheme 23 above, a 5 mL microwave reactor vial equipped with a stir bar was charged with ER-819930 (110 mg, 0.000238 mol), DMF (1.5 mL), ((4S)-2,2-dimethyl-l,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (205 mg, 0.000715 mol) and 1.00 M of lithium hexamethyldisilazide in tetrahydrofuran (520 ⁇ L, 0.00052 mol). The reactor vial was heated by microwave irradiation at 200°C for 15 min.
  • ER-81990 As depicted in Scheme 24 above, a solution of ER-824220-00 (51.8 mg, 0.000139 mol), triethylamine (97 ⁇ L, 0.00070 mol), 4-dimethylaminopyridine (3.4 mg, 0.000028 mol) and (R)-(-)- ⁇ -Methoxy- ⁇ -trifluoromethylphenylacetyl chloride (0.052 mL, 0.00028 mol) in Methylene Chloride (500 ⁇ L) was stirred at room temperature for 5 hours.
  • HEKT-bet-luc assay This assay measures a T-bet dependent reporter (luciferase) activity in engineered HEK cells that express a human T-bet and a T-box responsive element driving luciferase reporter.
  • HEKT-bet cells were plated at 2xlO4/well in 96-well plate and compound was added into cell culture for 24 hours. Luciferase activity was measured by adding 50 ⁇ l of Steady-Glo reagent (Promega) and samples were read in Victor V reader (PerkinElmer). The activity of compound was determined by comparing compound treated samples to non-compound treated vehicle controls. The IC 50 values were calculated utilizing a maximum value corresponding to the amount of luciferase in the absence of a test compound and a minimum value corresponding to a test compound value obtained at maximum inhibition.
  • Exemplary compounds of the present invention were assayed according to the methods set forth above in the HEKT-bet-luc assay described above.
  • Table 2 below set forth exemplary compounds of the present invention having an IC 50 of up to the indicated amount ( ⁇ M) as determined by the normalized HEKT-bet-luc assay described above.
  • Table 2 ICso Values of Exemplary Compounds
  • mice were injected i.v. with 1 mg of anti-type II collagen antibody at day 0, and 3 days later 25 ⁇ g of LPS was injected i.p. with active compound and methotrexate (MTX) was given once daily PO from day 0 to day 7. Arthritis score and body weight was monitored over the course of study.
  • MTX methotrexate

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Abstract

La présente invention concerne un composé de formule (I) énantiomériquement pur, ainsi que des formulations pharmaceutiques le contenant et ses procédés d'utilisation.
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