WO2011119693A1 - Antagonistes de trpv4 - Google Patents

Antagonistes de trpv4 Download PDF

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Publication number
WO2011119693A1
WO2011119693A1 PCT/US2011/029570 US2011029570W WO2011119693A1 WO 2011119693 A1 WO2011119693 A1 WO 2011119693A1 US 2011029570 W US2011029570 W US 2011029570W WO 2011119693 A1 WO2011119693 A1 WO 2011119693A1
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WIPO (PCT)
Prior art keywords
trifluoromethyl
phenyl
quinolinecarboxamide
phenylethyl
bipiperidin
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PCT/US2011/029570
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English (en)
Inventor
Carl A. Brooks
Mui Cheung
Ryan M. Fox
Krista B. Goodman
Mark A. Hilfiker
Guosen Ye
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Glaxosmithkline Llc
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Publication of WO2011119693A1 publication Critical patent/WO2011119693A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings

Definitions

  • the present invention relates to quinoline analogs, pharmaceutical compositions containing them and their use as TRPV4 antagonists.
  • TRPV4 is a member of the Transient Receptor Potential (TRP) superfamily of cation channels and is activated by heat, demonstrating spontaneous activity at physiological temperatures (Guler et al., 2002. J Neurosci 22. 6408-6414). Consistent with its polymodal activation property TRPV4 is also activated by hypotonicity and physical cell stress/pressure (Strotmann et al., 2000. Nat Cell Biol 2: 695-702), through a mechanism involving phospholipase A2 activation, arachidonic acid and epoxyeicosatrienoic acid generation (Vriens et al., 2004.
  • TRP Transient Receptor Potential
  • tyrosine kinase activity may also regulate TRPV4 (Wegierski et al., 2009. J Biol Chem. 284: 2923-33).
  • Heart failure results in the decreased ability of the left ventricle to pump blood into the peripheral circulation as indicated by a reduced ejection fraction and/or left ventricular dialation. This increases the left ventricular end diastolic pressure resulting in enhanced pulmonary blood pressures. This places the septal barrier, which separates the circulatory aqueous environment and the alveolar airspaces of the lung, at risk. Increased pulmonary pressure results in the flow of fluid from the pulmonary circulation into the alveolar space resulting in lung edema/congestion, as is observed in patients with congestive heart failure.
  • TRPV4 is expressed in the lung (Delany et al., 2001. Physiol. Genomics 4: 165- 174) and has been shown to mediate Ca 2+ entry in isolated endothelial cells and in intact lungs (Jian et al., 2009 Am J Respir Cell Mol Biol 38: 386-92). Endothelial cells are responsible for forming the capillary vessels that mediate oxygen/carbon dioxide exchange and contribute to the septal barrier in the lung.
  • TRPV4 channels Activation of TRPV4 channels results in contraction of endothelial cells in culture and cardiovascular collapse in vivo (Willette et al., 2008 J Pharmacol Exp Ther 325: 466-74), at least partially due to the enhanced filtration at the septal barrier evoking lung edema and hemorrage (Alvarez et al., 2006. Circ Res 99: 988-95). Indeed filtration at the septal barrier is increased in response to increased vascular and/or airway pressures and this response is dependent on the activity of TRPV4 channels (Jian et al., 2008 Am J Respir Cell Mol Biol 38: 386-92). Overall this suggests a clinical benefit of inhibiting TRPV4 function in the treatment of heart failure associated lung congestion.
  • TRPV4 function in pulmonary-based pathologies presenting with symptoms including lung edema/congestion, infection, inflammation, pulmonary remodeling and/or altered airway reactivity.
  • a genetic link between TRPV4 and chronic obstructive pulmonary disorder (COPD) has recently been identified (Zhu et al., 2009. Hum Mol Genetics, 18: 2053-62) suggesting potential efficacy for TRPV4 modulation in treatment of COPD with or without coincident emphysema.
  • Enhanced TRPV4 activity is also a key driver in ventilator-induced lung injury (Hamanaka et al., 2007.
  • TRPV4 activation may underlie pathologies involved in acute respiratory distress syndrome (ARDS), pulmonary fibrosis and asthma (Liedtke & Simon, 2004. Am J Physiol 287: 269-71 ).
  • ARDS acute respiratory distress syndrome
  • pulmonary fibrosis fibrosis
  • asthma pulmonary fibrosis
  • Am J Physiol 287: 269-71 A potential clinical benefit for TRPV4 blockers in the treatment of sinusitis, as well as allergic and non-allergic rhinitis is also supported (Bhargave et al., 2008. Am J Rhinol 22:7-12).
  • TRPV4 channels have recently been implicated in urinary bladder function (Thorneloe et al., 2008. J Pharmacol Exp Ther 326 : 432-42) and are likely to provide therapeutic benefit for conditions of bladder overactivity, characterized by an increased urge to urinate and an enhancement of micturition frequency. These data suggest a clinically beneficial effect of inhibiting TRPV4, located on multiple cell types, on urinary bladder function that is likely to be effective in bladder disorders such as overactive bladder, interstitial cystitis and painful bladder syndrome.
  • TRPV4 has in recent years been implicated in a number of other physiological/pathophysiological processes in which TRPV4 antagonists are likely to provide significant clinical benefit. These include various aspects of pain (Todaka et al., 2004. J Biol Chem 279: 35133-35138; Grant et al., 2007. J Physiol 578: 715-733;
  • this invention provides for quinoline analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them.
  • this invention provides for the use of the compounds of the invention as TRPV4 antagonists.
  • this invention provides for the use of the compounds of the invention for treating and preventing conditions associated with TRPV4 imbalance.
  • this invention provides for the use of the compounds of Formula (I) for the treatment or prevention of atherosclerosis, disorders related to intestinal edema, post-surgical abdominal edema, local and systemic edema, fluid retention, sepsis, hypertension, inflammation, bone related dysfunctions and congestive heart failure, pulmonary disorders, chronic obstructive pulmonary disorder, ventilator induced lung injury, high altitude induced pulmonary edema, acute respiratory distress syndrome, pulmonary fibrosis, sinusitis/rhinitis, asthma, overactive bladder, pain, motor neuron disorders, genetic gain of function disorders, cardiovascular disease, renal dysfunction, osteoarthritis Crohn's disease, colitis, diarrhea, intestinal irregularity
  • hyporeactivity/hyporeactivity fecal incontinence
  • IBS irritable bowel syndrome
  • the TRPV4 antagonist may be administered alone or in conjunction with one or more other therapeutic agents, eg. agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension II receptor antagonists, vasopeptidase inhibitors, vasopressin receptor modulators, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal antiinflammatory drugs, bronchodilators, anti-histamines, leukotriene antagonist, HMG-CoA reductase inhibitors, dual non-selective ⁇ -adrenoceptor and a-
  • agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (
  • the present invention provides for compounds selected from the group consisting of: 6-amino-3- ⁇ [4-(4-morpholinyl)-1 -piperidinyl]methyl ⁇ -2-[3-(trifluoromethyl)phenyl]-N- [(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 6-[(methylsulfonyl)amino]-3- ⁇ [4-(4-morpholinyl)-1 -piperidinyl]methyl ⁇ -2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-trifluoro-1 -phenylethyl]-4-quinolinecarboxamide; 6-[(ethylsulfonyl)amino]-3- ⁇ [4-(4-morpholinyl)-1-piperidinyl]methyl ⁇ -2-[3- (trifluoromethyl)phenyl]-N-[(1 R)-2,2,2-tri
  • the compounds of the invention may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts of the compounds of the invention may be prepared. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately treating the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • compounds of the invention may contain an acidic functional group and are, therefore, capable of forming pharmaceutically acceptable base addition salts by treatment with a suitable base.
  • bases include a) hydroxides, carbonates, and bicarbonates of sodium, potassium, lithium, calcium, magnesium, aluminium, and zinc; and b) primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.
  • compounds of the invention may contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid.
  • suitable acids include pharmaceutically acceptable inorganic acids and organic acids.
  • Representative pharmaceutically acceptable acids include hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, sulfonic acid, phosphoric acid, acetic acid, hydroxyacetic acid, phenylacetic acid, propionic acid, butyric acid, valeric acid, maleic acid, acrylic acid, fumaric acid, malic acid, malonic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, tannic acid, formic acid, stearic acid, lactic acid, ascorbic acid, methylsulfonic acid, p-toluenesulfonic acid, oleic acid, lauric acid, and the like.
  • the compounds of the invention may exist in solid or liquid form. In the solid state, it may exist in crystalline or noncrystalline form, or as a mixture thereof.
  • pharmaceutically acceptable solvates may be formed for crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization.
  • Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice.
  • Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The invention includes all such solvates.
  • polymorphism i.e. the capacity to occur in different crystalline structures. These different crystalline forms are typically known as "polymorphs.”
  • the invention includes all such polymorphs. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • the subject invention also includes isotopically-labelled compounds, which are identical to those recited in formula (I) 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 usually found in nature.
  • isotopes that can be incorporated into compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2H, 3H, 1 1 C, 13C, 14C, 15N, 170, 180, 31 P, 32P, 35S, 18F, 36CI, 1231 and 1251.
  • Isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. 1 1 C and 18F isotopes are particularly useful in PET
  • Isotopically labelled compounds of formula I and following of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • the compounds according to Formula I are TRPV4 antagonists, and are useful in the treatment or prevention of atherosclerosis, disorders related to intestinal edema, post-surgical abdominal edema, local and systemic edema, fluid retention, sepsis, hypertension, inflammation, bone related dysfunctions and congestive heart failure, pulmonary disorders, chronic obstructive pulmonary disorder, ventilator induced lung injury, high altitude induced pulmonary edema, acute respiratory distress syndrome, pulmonary fibrosis, sinusitis/rhinitis, asthma, overactive bladder, pain, motor neuron disorders, genetic gain of function disorders, cardiovascular disease, renal dysfunction, osteoarthritis, Crohn's disease, colitis, diarrhea, intestinal irregularity
  • the biological activity of the compounds according to Formula I can be determined using any suitable assay for determining the activity of a candidate compound as a TRPV4 antagonist, as well as tissue and in vivo models.
  • TRP channel activation/opening results in an influx of divalent and monovalent cations including calcium.
  • the resulting changes in intracellular calcium are monitored using a calcium selective fluorescent dye Fluo4 (MDS Analytical Technologies).
  • Dye loaded cells are initially exposed to test compound to verify a lack of agonist activity. Cells are subsequently activated by addition of an agonist and inhibition of the agonist-induced activation is recorded.
  • Human embryonic kidney 293 cells stably expressing the macrophage scavenger receptor class II (HEK-293-MSR-II) and transduced with 1 % BacMam (J. P. Condreay, S.M. Witherspoon, W.C. Clay and T.A.
  • virus expressing the human TRPV4 gene are plated at 15000 cells/well in a volume of 50 uL in a 384 well poly-D lysine coated plate. Cells are incubated for 24 hours at 37 degrees and 5% C0 2 . Media is then aspirated using a Tecan Plate- washer and replaced with 20 uL of dye loading buffer: HBSS, 500 uM Brilliant Black (MDS Analytical Technologies), 2 uM Fluo-4. Dye loaded plates are then incubated in the dark at room temperature for 1 -1 .5 hours.
  • BHK/AC9_DMEM/F12 conditioned (Baby Hamster Kidney) cells are transduced with 2% BacMam virus expressing the human TRPV4 gene and are plated at 10K cells per well in a volume of 50 uL in 384 well poly-D-lysine coated plates. Cells are incubated for 18-24 hours at 37 degrees and 5% C0 2. The following day, the media is aspirated using a Tecan Plate-washer and replaced with 20uL of dye loading buffer: HBSS buffer, 2.5 mM Probenecid, 500 uM Brilliant Black, 2 uM Fluo-4. The dye loaded cells are incubated for 1-1 .5 hours at room temperature in the dark.
  • the compounds of the invention are TRPV4 antagonists, and are useful in the treatment or prevention of atherosclerosis, disorders related to atherosclerosis, disorders related to intestinal edema, post-surgical abdominal edema, local and systemic edema, fluid retention, sepsis, hypertension, inflammation, bone related dysfunctions and congestive heart failure, pulmonary disorders, chronic obstructive pulmonary disorder, ventilator induced lung injury, high altitude induced pulmonary edema, acute respiratory distress syndrome, pulmonary fibrosis, sinusitis/rhinitis, asthma, overactive bladder, pain, motor neuron disorders, genetic gain of function disorders, cardiovascular disease, renal dysfunction and osteoarthritis. Accordingly, in another aspect the invention is directed to methods of treating such conditions.
  • the methods of treatment of the invention comprise administering a safe and effective amount of a compound of the invention or a pharmaceutically-acceptable salt thereof to a patient in need thereof.
  • treat in reference to a condition means: (1 ) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.
  • prevention of a condition includes prevention of the condition.
  • prevention is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.
  • safe and effective amount in reference to a compound of the invention or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment.
  • a safe and effective amount of a compound will vary with the particular compound chosen (e.g.
  • patient refers to a human or other animal.
  • the compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.
  • Typical daily dosages may vary depending upon the particular route of
  • Typical dosages for oral administration range from 1 mg to 1000 mg per person per dose.
  • a prodrug of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo.
  • Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (C) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound.
  • Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
  • the compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically-acceptable excipient.
  • compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention.
  • the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg.
  • compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
  • pharmaceutically-acceptable excipient means a
  • each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in
  • compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
  • dosage forms include those adapted for (1 ) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets
  • parenteral administration such as sterile solutions, suspensions, and powders for reconstitution
  • transdermal administration such as transdermal patches
  • rectal administration
  • Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen.
  • suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition.
  • certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms.
  • Certain pharmaceutically- acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body.
  • Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.
  • Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
  • excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, hemectants, chel
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • the oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose.
  • the oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.
  • the compounds may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension II receptor antagonists, vasopeptidase inhibitors, vasopressin receptor modulators, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal antiinflammatory drugs, bronchodilators, anti-histamines, leukotriene antagonist, HMG-CoA reductase inhibitors, dual non-selective ⁇ -adrenoceptor and a-
  • ACE angiotensin converting enzyme
  • J are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double triplet), m (multiplet), br (broad).
  • the naming program used is ACD Name Pro 6.02.
  • Methyl 3-methyl-6-nitro-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (5.7 g, 14.60 mmol) was suspended in carbon tetrachloride (60 mL) and /V-bromosuccinimide (2.86 g, 16.06 mmol) and benzoyl peroxide (0.354 g, 1 .460 mmol) were added. The mixture was heated to 100°C overnight. The solvent was removed in vacuo to afford a brown oil, which was dissolved in acetonitrile (60 mL).
  • the resultant black suspension was heated to 70°C for 2 h.
  • the reaction mixture was cooled to room temperature, filtered through Celite ® , washed with methanol, and concentrated to a volume of 80 mL of methanol.
  • Fresh ammonium formate (3.59 g, 57.0 mmol) and 10% Pt/C (1.140 mmol) were added and the reaction heated back to reflux for 1 h and then at 4°C overnight.
  • the reaction mixture was filtered through Celite ® , washed with methanol, and concentrated in vacuo. The residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate.
  • Methanesulfonyl chloride (0.139 ml_, 1 .787 mmol) was added to a stirred solution of 6-amino-3- ⁇ [4-(4-morpholinyl)-1 -piperidinyl]methyl ⁇ -2-[3-(trifluoromethyl)phenyl]-/ ⁇ /-[(1 R)- 2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (1 g, 1 .489 mmol) in pyridine (10 ml_). The mixture was heated to 100 °C for 3 h. Additional mesyl chloride (0.139 ml_, 1.787 mmol) was added and the mixture was heated to 100 °C for an hour.
  • A/JV-diisopropylethylamine (6.09 mL, 34.8 mmol) was added and the mixture was stirred overnight at room temperature and then allowed to stand at room temperature for 1 week. The solvent was removed under reduced pressure and the residue was partitioned between methylene chloride and 10% sodium carbonate solution. The phases were separated and the organic phase was washed twice more with a 10% sodium carbonate solution. The organic phase was then extracted with 2N HCI (3 times). The combined aqueous extracts were cooled in a ice bath and the pH was adjusted to -12 with 6N NaOH. The resulting emulsion was extracted with methylene chloride (3 times). The combined organic extracts were washed with brine, dried, and concentrated in vacuo.
  • Ethanesulfonyl chloride (0.081 ml_, 0.851 mmol) was added to a stirred yellow solution of methyl 6-amino-3- ⁇ [4-(4-morpholinyl)-1 -piperidinyl]methyl ⁇ -2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (300 mg, 0.568 mmol) in pyridine (3 ml.) in two portions. The mixture was stirred for 30 min. The reaction mixture was concentrated and azeotroped with methanol twice to give a brown oil.
  • Acetyl chloride (0.021 g, 0.267 mmol) was added to a stirred solution of 6-amino-3- ⁇ [4-(4-morpholinyl)-1-piperidinyl]methyl ⁇ -2-[3-(trifluoromethyl)phenyl]-/ ⁇ /-[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (150 mg, 0.223 mmol, Example 2) and /V,/V-diisopropylethylamine (0.1 17 mL, 0.670 mmol) in dichloromethane (5 mL). The reaction mixture was stirred for 30 min. Additional acetyl chloride was added (0.017 g,
  • Example 8 and analogous sulfonamides may also be prepared using the procedure described below:
  • Methyl 6-bromo-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (72g, 170 mmol) was added to a 1 L flask and azeotroped (3 times) with benzene to remove any residual water.
  • NBS (36.3 g, 204 mmol) and diphenylperoxyanhydride (4.1 1 g, 16.97 mmol) were added followed by carbon tetrachloride (800 mLI). The solution was heated to reflux fori .5 h, cooled to room temperature, and concentrated to a minimal volume (-200 ml.) to afford a light yellow slurry.
  • Acetonitrile 700 ml. was added to the slurry followed by 4-(4-piperidinyl)morpholine (30.3 g, 178 mmol) and DIEA (35.6 ml_, 204 mmol). The solution was stirred for one hour at room temperature, and the solution was concentrated to a volume of -200 ml. Water (1 L) and dichloromethane (500 ml.) were added. The two layers were separated, and the aqueous phase was extracted with dichloromethane (2 x 300 ml_). The combined dichloromethane extracts were concentrated, and the residue was dissolved in 2N HCI (1.75L).
  • the HCI solution was transferred to a separatory funnel and washed with dichloromethane (2 x 500 mLI).
  • the dichloromethane extracts were washed with 200 ml 2N HCI.
  • the combined HCI solutions were made basic with 6N
  • the thick slurry was filtered, and the filter cake was washed with 250 ml. iPrOH.
  • the solid was dried under reduced pressure and azeotroped with toluene to afford 41 g (48%) of the title compound as a white solid.
  • the yellow filtrate was concentrated under reduced pressure and azeotroped with toluene.
  • iPrOH 250 ml. was added to the residue, the mixture was heated until the solid was dissolved, and the resulting solution was allowed to cool with stirring.
  • the thick slurry was stirred at room temperature overnight, and the solid was collected by filtration to afford 32 g (37%) as an off white solid.
  • Methanesulfonyl chloride (0.035 mL, 0.448 mmol) was added to a stirred solution of 6-amino-3-(1 ,4'-bipiperidin-1 '-ylmethyl)-2-[3-(trifluoromethyl)phenyl]-/ ⁇ /-[(1 R)-2,2,2- trifluoro-1 -phenylethyl]-4-quinolinecarboxamide (0.200 g, 0.299 mmol, Example 10) in pyridine (2 mL). The reaction mixture was heated in the microwave at 140°C for 20 min. The solvent was removed under reduced pressure.
  • 6-Bromo-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (16 g, 39.0 mmol) was suspended in toluene (160 ml.) and methanol (40 ml_). The brown suspension was cooled to 0 °C. 2N TMS-diazomethane in diethyl ether (19.50 ml_, 39.0 mmol) was added portionwise over 10 min. The resulting mixture was stirred for 1 h. The solvents were removed in vacuo and the resultant solid was again suspended in toluene (160 ml.) and methanol (40 ml_).
  • Methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-bromo-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (2.1 g, 3.56 mmol) was suspended in methanol (20 ml.) and water (10 ml_). Potassium hydroxide (1.596 g, 28.5 mmol) was added in one portion and the reaction mixture was heated to reflux overnight. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The suspension became a solution. The reaction mixture was cooled, the methanol was removed in vacuo, and the residue was diluted with dichloromethane.
  • Phenylboronic acid (0.124 g, 1.061 mmol)
  • methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6- bromo-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.500 g, 0.847 mmol)
  • PdCI 2 dppf PdCI 2 dppf
  • 2N Na 2 C0 3 in dioxane were heated to 160 °C in the microwave for 10 min.
  • the reaction mixture was diluted with water and methylene chloride and filtered through Celite ® .
  • the phases were separated, and the aqueous phase was extracted twice with methylene chloride.
  • Methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-bromo-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate 200 mg, 0.339 mmol
  • 4-methoxypiperidine 46.8 mg, 0.406 mmol
  • palladium(ll) acetate 7.60 mg, 0.034 mmol
  • cesium carbonate 221 mg, 0.677 mmol
  • di-t-butylbiphenylphosphine (20.19 mg, 0.068 mmol) were weighed into a microwave vial and suspended in dioxane.
  • Methyl 3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-[4-(methyloxy)-1 -piperidinyl]-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (61.5 mg, 0.0984 mmol) was dissolved in 2 ml. of 1 N HCI and 1 ml. of THF. The solution was heated to 100°C in the microwave for 15 minutes. The reaction mixture was diluted with dichloromethane and sat. aqueous NaHC0 3 . The layers were shaken and separated. The organic phase was dried over MgS0 4 , filtered, and concentrated to afford 60 mg of crude acid. The residue was dissolved in 1 ml.
  • the aqueous phase was acidified to pH 7 and washed with ethyl acetate.
  • the aqueous phase was acidified to pH 3 and washed with ethyl acetate.
  • the organic phases were combined, dried over MgS0 4 , filtered, and concentrated to give 6- (ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (2.16 g, >99% yield) as a light orange solid.
  • Methyl-3-(1 ,4'-bipiperidin-1 '-ylmethyl)-6-(ethyloxy)-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (0.934 g, 1 .681 mmol) was dissolved in methanol (9.04 ml_), tetrahydrofuran (3.01 ml_), and water (3.01 ml_). Potassium hydroxide (0.472 g, 8.40 mmol) was added and the reaction mixture was heated to 70°C. After 3 days the reaction was cooled to room temperature and concentrated. The crude product was suspended in ethyl acetate and water.
  • the reaction mixture was allowed to stir at 0°C for 2 h before it was quenched with water and stirred for 30 min. The phases were separated, and the organic phase was concentrated to crude yellow product.
  • the crude product was purified via HPLC (Waters, Sunfire 30 x 100 mm, 15-70% CH 3 CN/H 2 0 with 0.1 % TFA). The product fractions were concentrated and dissolved in methylene chloride.
  • Potassium hydroxide (1 .527 g, 27.2 mmol) was added to a solution of methyl 3- (1 ,4'-bipiperidin-1 '-ylmethyl)-7-(propyloxy)-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate (3.1 g, 5.44 mmol) in methanol (30 mL) and water (10 mL). The mixture was heated to reflux for 5 hours. The solvent was removed under reduced pressure, and the residue was adjusted to pH ⁇ 5-6 with 2N HCI and extracted with methylene chloride (3 times).
  • the residue was dissolved in methanol and purified via HPLC (Gilson, Sunfire Prep C18 OBD, 30 x 150 mm, 10-100% CH 3 CN/H 2 0 with 0.1 % TFA). The residue was diluted with water (3 mL), neutralized with Na 2 C0 3 , and extracted with ethyl acetate.
  • Example 37 was prepared as described for Example 37, using the quinoline synthesis conditions in Example 15 in place of the first step above. As is appreciated by those skilled in the art, this analogous example may involve variations in general reaction conditions.
  • Oxalyl chloride (29.0 g, 228 mmol) was added to a suspension of 7-hydroxy-3- methyl-6-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (20.5 g, 54.3 mmol) in methylene chloride (150 mL) at 0°C. DMF (5 drops) was added, and the reaction mixture was stirred for 6 h. Methanol was added, and the reaction mixture was warmed to room temperature and stirred for 2.5 d.
  • Triethylamine (6.70 mL, 48.1 mmol) was added slowly, and the mixture was stirred overnight. The solvent was removed under reduced pressure. The residue was diluted with saturated aqueous NaHC0 3 and extracted with ethyl acetate. The phases were separated, and the organic phase was washed with brine, dried over Na 2 S0 4 , filtered, and concentrated in vacuo. The crude material was purified via column
  • the reaction mixture was cooled and concentrated in vacuo to give a cream oily solid, which was partitioned between water (-100 mL) and CH 2 CI 2 (200 mL). The phases were separated the aqueous phase was extracted three more times with CH 2 CI 2 . The combined organic extracts were washed with brine (twice), dried, and concentrated in vacuo to afford the title compound as a light brown solid (4.3g, 10.1 1 mmol, 29.7 % yield).
  • the aqueous phase was washed once with CH 2 CI 2 and cooled in an ice bath, and the pH was adjusted to ⁇ 1 1 with 6N NaOH.
  • the basic aqueous phase was extracted with CH 2 CI 2 (three times) and the combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford a yellow solid:
  • the solid was purified by ISCO silica gel chromatography (40g) eluting with 0 ⁇ 20% CH 2 CI 2 /MeOH to afford: the title compound as a yellow solid (930 mg, 1.428 mmol, 34.0 % yield). MS (m/z) 619.2 (M+H + ).
  • the reaction was quenched with a small amount of water, concentrated in vacuo, dissolved in MeOH and purified by Waters reverse phase HPLC (20% to 60% MeCN, 0.1 %TFA, 16mins, 50ml/min, Sunfire column). The purified fractions were combined and diluted with dichloromethane and 10% sodium carbonate solution. The phases were separated, and the aqueous phase was extracted once more with
  • the reaction mixture was concentrated, the resulting yellow oil was dissolved in acetonitrile (20 mL), 4-(4- piperidinyl)morpholine (0.813 g, 4.77 mmol) was added in one portion, and the solution was stirred for 3 hours.
  • the reaction mixture was concentrated in vacuo, the residue was partitioned between CH 2 CI 2 ( ⁇ 75 ml) and 10% aqueous sodium carbonate solution, and the layers were separated.
  • the organic phase was washed twice more with carbonate solution.
  • the organic phase was extracted three times with 30 ml aqueous 2N HCI, and the combined acidic aqueous extracts were washed once with CH 2 CI 2 .
  • T3P (0.245 mL, 0.386 mmol) was added in one portion and the resultant mixture was stirred for one hour.
  • the reaction mixture was concentrated in vacuo, and the residue was dissolved in methanol and purified by Waters reverse phase HPLC (20% to 60% MeCN, 0.1 %TFA, 16mins,
  • Methyl 6-[(dimethylamino)sulfonyl]-3- ⁇ [4-(4-morpholinyl)-1-piperidinyl]methyl ⁇ -2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (900 mg, 1.450 mmol, contaminated with -30% methyl 6-[(methylamino)sulfonyl]-3- ⁇ [4-(4-morpholinyl)-1 -piperidinyl]methyl ⁇ -2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate, synthesis described in Example 45) was dissolved in methanol (10 ml.) to give a yellow solution.
  • Tetrahydrofuran (2 mL) (2 mL) was added DIPEA (0.613 mL, 3.51 mmol). The mixture was stirred at 50°C overnight. The reaction mixture was concentrated to remove THF, and the residue was dissolved in DMSO and purified via HPLC (Waters, Sunfire,
  • Example 48 The following example was prepared using a procedure analogous to that described in Example 48, substituting 3-isopropoxyaniline for 3-[(2-methylpropyl)oxy]aniline in the first step. As is appreciated by those skilled in the art, this analogous example may involve variations in general reaction conditions.
  • the reaction mixture was cooled to room temperature, combined with an identical reaction run on 0.088 mmol scale, and concentrated to dryness.
  • the residue was dissolved in ethyl acetate, and the solution was washed once with water, twice with 1 N NaOH, once with water, and once with brine.
  • the organic phase was dried over sodium sulfate, filtered and concentrated.
  • the residue was purified by preparative HPLC (60-90% CH 3 CN/H 2 0 + 0.1 % TFA over 21 min, 15 mL/min, VYA 2515 305 column). Fractions containing the product were made basic with saturated NaHC0 3 , concentrated to remove acetonitrile, and extracted three times with dichloromethane.

Abstract

La présente invention concerne des analogues d'indole ou de benzothiophène, des compositions pharmaceutiques les contenant et leur utilisation comme antagonistes de TRPV4.
PCT/US2011/029570 2010-03-23 2011-03-23 Antagonistes de trpv4 WO2011119693A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130012499A1 (en) * 2010-03-23 2013-01-10 Glaxosmithkline Llc Trpv4 antagonists
CN105481702A (zh) * 2015-11-27 2016-04-13 浙江鸿盛化工有限公司 一锅法合成间氨基苯乙醚的方法
US9499533B2 (en) 2012-03-27 2016-11-22 Shionogi & Co., Ltd. Aromatic 5-membered heterocyclic derivative having TRPV4-Inhibiting activity
US9708338B2 (en) 2013-09-25 2017-07-18 Shionogi & Co., Ltd. Aromatic heterocyclylamine derivative having TRPV4-inhibiting activity
WO2021014415A3 (fr) * 2019-07-25 2021-03-04 Curadev Pharma Pvt. Ltd. Inhibiteurs à petites molécules de l'acétyl-coenzyme a synthétase à chaîne courte 2 (acss2)
WO2022014707A1 (fr) 2020-07-16 2022-01-20 ラクオリア創薬株式会社 Inhibiteur de trpv4 en tant que médicament thérapeutique pour une maladie oculaire

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050070574A1 (en) * 2000-11-28 2005-03-31 Glaxosmithkline Spa And Laboratoire Novel compounds
US20070129363A1 (en) * 2000-11-06 2007-06-07 Astrazeneca Ab N-type calcium channel antagonists for the treatment of pain

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070129363A1 (en) * 2000-11-06 2007-06-07 Astrazeneca Ab N-type calcium channel antagonists for the treatment of pain
US20050070574A1 (en) * 2000-11-28 2005-03-31 Glaxosmithkline Spa And Laboratoire Novel compounds

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130012499A1 (en) * 2010-03-23 2013-01-10 Glaxosmithkline Llc Trpv4 antagonists
US8658636B2 (en) * 2010-03-23 2014-02-25 GlaxoSmithKline, LLC TRPV4 antagonists
US9499533B2 (en) 2012-03-27 2016-11-22 Shionogi & Co., Ltd. Aromatic 5-membered heterocyclic derivative having TRPV4-Inhibiting activity
US9708338B2 (en) 2013-09-25 2017-07-18 Shionogi & Co., Ltd. Aromatic heterocyclylamine derivative having TRPV4-inhibiting activity
CN105481702A (zh) * 2015-11-27 2016-04-13 浙江鸿盛化工有限公司 一锅法合成间氨基苯乙醚的方法
CN105481702B (zh) * 2015-11-27 2018-05-11 浙江鸿盛化工有限公司 一锅法合成间氨基苯乙醚的方法
WO2021014415A3 (fr) * 2019-07-25 2021-03-04 Curadev Pharma Pvt. Ltd. Inhibiteurs à petites molécules de l'acétyl-coenzyme a synthétase à chaîne courte 2 (acss2)
CN114269720A (zh) * 2019-07-25 2022-04-01 库拉德夫制药私人有限公司 乙酰辅酶a合成酶短链2(acss2)的小分子抑制剂
WO2022014707A1 (fr) 2020-07-16 2022-01-20 ラクオリア創薬株式会社 Inhibiteur de trpv4 en tant que médicament thérapeutique pour une maladie oculaire

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