WO2011119704A1 - Antagonistes de trpv4 - Google Patents

Antagonistes de trpv4 Download PDF

Info

Publication number
WO2011119704A1
WO2011119704A1 PCT/US2011/029584 US2011029584W WO2011119704A1 WO 2011119704 A1 WO2011119704 A1 WO 2011119704A1 US 2011029584 W US2011029584 W US 2011029584W WO 2011119704 A1 WO2011119704 A1 WO 2011119704A1
Authority
WO
WIPO (PCT)
Prior art keywords
trifluoromethyl
phenyl
quinolinecarboxamide
phenylcyclopropyl
methyl
Prior art date
Application number
PCT/US2011/029584
Other languages
English (en)
Inventor
Carl A. Brooks
Mui Cheung
Hilary S. Eidam
Ryan M Fox
Mark A. Hilfker
Eric S. Manas
Guosen Ye
Original Assignee
Glaxosmithkline Llc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Glaxosmithkline Llc filed Critical Glaxosmithkline Llc
Publication of WO2011119704A1 publication Critical patent/WO2011119704A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to quinoline analogs, pharmaceutical compositions containing them and their use as TRPV4 antagonists.
  • 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 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; Alessandri-Haber et al., 2006. J Neurosci 26: 3864-3874), genetic motor neuron disorders (Auer-Grumbach et al., 2009. Nat Genet. PMID: 20037588; Deng et al., 2009. Nat Genet PMID: 20037587;
  • 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 Formula (I) as TRPV4 antagonists.
  • this invention provides for the use of the compounds of Formula (I) 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 (hyperreactivity/hyporeactivity), fecal incontinence, irritable bowel syndrome (IBS), constipation, intestinal pain and cramping, celiac disease, lactose intolerance, and flatulence.
  • 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 anti-inflammatory 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
  • Ri is independently Ci -6 alkyl or C 3- 6 cycloalkyl
  • R 2 is independently OH, OCi -4 alkyl, Ci -4 alkyl, CH 2 OH, F, CH 2 OCi -4 alkyl, CF 3 , or CF 2 H;
  • R 3 is morpholinyl, piperidinyl, pyrrolidinyl, or hexahydroazepinyl, all of which may be unsubstituted or substituted by one or two R 2 ;
  • R 3 is N(Ci-6 alkyl) 2 , wherein Ci -6 alkyl may be unsubstituted or substituted by OH or -OCH 3 ;
  • R 4 is independently CF 3 , halo, Ci -3 alkyl or OCi -3 alkyl;
  • R 5 is independently , S0 2 Ri, NH 2 , NHS0 2 Ri, NRiSOzRi, C(0)NH 2 , C(0)NHR 2 , halo, cyano, CF 3 , C1-6 alkyl, C 2-4 alkenyl, pyrrolidinyl, morpholinyl, piperidinyl, phenyl, pyridyl, pyrazolyl, oxazolyl, tetrazolyl, pyrrolyl, piperazinyl, pyrimidinyl, OH, OCH 2 CH 2 OH, OCH 2 CH 2 ORi, OCF 3, OCH 2 CF 3, OCH 2 CN, ORi or CH 2 R 7 ;
  • pyrrolidinyl morpholinyl, piperidinyl, phenyl, pyridyl, pyrazolyl, oxazolyl, tetrazolyl, pyrrolyl, piperazinyl or pyrimidinyl may be unsubstituted or substituted with one or two halo, OH, ORi or R ⁇
  • R 5 groups may be combined to form , ;
  • R 6 is independently halo, methyl, or OMe
  • R 7 is pyrrolidinyl, morpholinyl, or piperidinyl
  • n is independently 0, 1 , or 2;
  • X is N or C
  • y is independently 0, 1 or 2;
  • Alkyl refers to a monovalent saturated hydrocarbon chain having the specified number of member atoms.
  • C 1-4 alkyl refers to an alkyl group having from 1 to 4 member atoms.
  • Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches.
  • Alkyl includes methyl, ethyl, propyl,
  • Cycloalkyl refers to a monovalent saturated or unsaturated hydrocarbon ring having the specified number of member atoms.
  • C 3 - 6 cycloalkyl refers to a cycloalkyl group having from 3 to 6 member atoms.
  • Unsaturated cycloalkyl groups have one or more carbon-carbon double bonds within the ring. Cycloalkyl groups are not aromatic.
  • Cycloalkyl includes cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.
  • 'halogen' and 'halo' include fluorine, chlorine, bromine and iodine, and fluoro, chloro, bromo, and iodo, respectively.
  • Substituted in reference to a group indicates that one or more hydrogen atom attached to a member atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term “substituted” includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is stated that a group may contain one or more
  • substituents one or more (as appropriate) member atoms within the group may be substituted.
  • a single member atom within the group may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom.
  • Suitable substituents are defined herein for each substituted or optionally substituted group.
  • the compounds of Formula (I) 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 according to Formula (I) 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 according to Formula (I) 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,
  • compounds according to Formula (I) 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, succinic acid, malic acid, malonic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, tannic acid, formic acid, stearic acid, lactic acid, ascorbic acid, methanesulfonic acid, p-toluenesulfonic acid, oleic acid, lauric acid, and the like.
  • a compound of Formula (I) or “the compound of Formula (I)” refers to one or more compounds according to Formula (I).
  • the compound of Formula (I) 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 nonaqueous 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.
  • 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. Representative Embodiments
  • Ri is independently Ci -6 alkyl or C 3- 6 cycloalkyl
  • R 2 is independently OH, OCi -4 alkyl, Ci -4 alkyl, F or CF 3 ;
  • R 3 is morpholinyl, piperidinyl or pyrrolidinyl, all of which may be unsubstituted or substituted by one or two R 2 ;
  • R 4 is independently CF 3 , halo or OCi -3 alkyl
  • R 5 is independently
  • OCH2CH2OR1 OCF 3, OCH 2 CF 3, OCH 2 CN, ORi or CH 2 R 7 ;
  • pyrrolidinyl morpholinyl, piperidinyl, phenyl, pyridyl, pyrazolyl, oxazolyl, tetrazolyl, pyrrolyl, piperazinyl or pyrimidinyl may be unsubstituted or substituted with one or or two adjacent R 5 groups may be combined to form °Cr , ;
  • R 6 is independently halo, methyl, or OMe
  • R 7 is pyrrolidinyl, morpholinyl, or piperidinyl
  • n is independently 0, 1 , or 2;
  • X is N
  • y is independently 1 or 2.
  • Ri is independently Ci -6 alkyl or C 3- 6 cycloalkyl
  • R 2 is independently OH, OC1-4 alkyl, Ci -4 alkyl, F or CF 3 ;
  • R 3 is morpholinyl or piperidinyl which may be unsubstituted or substituted by one or two R 2 ;
  • R 4 is independently CF 3 ;
  • R 5 is independently
  • pyrrolidinyl morpholinyl, piperidinyl, phenyl, pyridyl, pyrazolyl, tetrazolyl, pyrrolyl, piperazinyl or pyrimidinyl may be unsubstituted or substituted with one or two OR 1 n is independently 0 or 1 ;
  • X is N
  • y is independently 1 or 2.
  • Ri is independently C 1-6 alkyl or C 3-6 cycloalkyl
  • R 2 is independently OH, OMe, Me or F;
  • R 3 is morpholinyl or piperidinyl which may be unsubstituted or substituted by one or two R 2 ;
  • R 4 is independently CF 3 ;
  • R 5 is independently
  • pyrrolidinyl, morpholinyl, piperidinyl, phenyl, pyridyl, pyrazolyl, tetrazolyl, pyrrolyl, piperazinyl or pyrimidinyl may be unsubstituted or substituted with one or two ORi n is independently 0 or 1 ;
  • X is N
  • y is independently 1 or 2.
  • a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions.
  • the protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound.
  • suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts,
  • a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.
  • the compounds of Formula I can be prepared in a multi-step sequence starting with formation of a substituted 3-methyl-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid by reaction of an appropriately substituted 1 H-indole-2,3-dione with KOH in refluxing ethanol.
  • the quinoline is treated with /V-bromosuccinimide and benzoyl peroxide in carbon tetrachloride followed by an appropriate amine in acetonitrile to afford the corresponding tertiary amine.
  • the compounds of Formula I can be prepared via the multistep sequence outlined in Scheme 2.
  • the substituted 3-methyl-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid derivative can be prepared from the appropriately substituted aniline, 3-(trifluoromethyl)benzaldehyde, and 2-oxobutanoic acid.
  • the methyl ester can be formed by first forming the acid chloride with oxalyl chloride and treating that intermediate with methanol.
  • the compounds of Formula I can also be prepared as outlined in Scheme 3.
  • Nucleophilic aromatic substitution of 5-F substituted methyl 3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate with a thioether followed by oxidation with m-CPBA provides the sulfone.
  • the resulting sulfone-substituted methyl 3- methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate is treated with N- bromosuccinimide and benzoyl peroxide in carbon tetrachloride followed by an appropriate amine in acetonitrile to afford the corresponding tertiary amine.
  • the sulfone derivatives can be prepared by copper- mediated coupling of 5-Br substituted methyl 3-methyl-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylate with an appropriate substituted sulfinate.
  • the resulting sulfone- substituted methyl 3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate is treated with /V-bromosuccinimide and benzoyl peroxide in carbon tetrachloride followed by an appropriate amine in acetonitrile to afford the corresponding tertiary amine.
  • the methyl ester can be hydrolyzed under basic conditions to provide the corresponding acid. Coupling of the acid with (l-phenylcyclopropyl)amine ethanedioate in the presence of T3P provides compounds of Formula I.
  • Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallization, chromatography, H.P.L.C. or SCF of a stereoisomeric mixture. Pure stereoisomer of the agent may also be prepared from the corresponding optically pure intermediate or by resolution, such as H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallization of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
  • 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 and osteoarthritis.
  • 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.
  • BHK/AC9_DMEM/F12 conditioned (Baby Hamster Kidney) cells are transduced with
  • 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. 10 uL of test compound diluted in HBSS/H 2 0 (-1 :2.3) + 0.01 % Chaps is added to the plate, incubated for 10 min at room temperature in the dark, and then 10 uL of hypotonic buffer (H 2 0 + 1.5mM CaCI 2 + ⁇ 68 mM NaCI; 140 mOsm stock/260mOsm FAC) is used to test the inhibition of the hypotonicity-induced activation. Reaction is measured on a heated stage (37 degrees) using the FLIPRtetra.
  • 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, osteoarthritis Crohn's disease, colitis, diarrhea, intestinal irregularity
  • 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 according to Formula I 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.
  • treatment 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
  • 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. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.
  • 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
  • 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 administration chosen. 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 pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition.
  • 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 pharmaceutical 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
  • compositions 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 Company).
  • 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. corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (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 anti-inflammatory drugs, bronchodilators, anti-histamines, leukotriene antagonists, HMG-CoA reductase inhibitors, dual non-selective ⁇ -adrenoceptor and a-
  • the naming program used is ACD Name Pro 6.02.
  • 2,2,2-Trichloroethane-1 , 1-diol (79.7 g, 481.86 mmol) and Na 2 S0 4 (550 g, 3.87 mol) were dissolved in water and warmed to 35°C.
  • a warm solution of 2-bromoaniline (74 g, 430.23 mmol) in water was added, followed by 35% aqueous HCI (75 ml.) and
  • This diazonium intermediate was poured into a solution of copper(l) chloride (18.27 g, 185 mmol) in water (90 mL) and concentrated HCI (90 mL) at 0°C. The reaction was stirred for 15 min at 0°C, warmed to 60°C, and stirred for an additional 15 min. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was transferred to a separatory funnel and extracted with Et 2 0 (3 x 500 mL). The combined ethereal extracts were washed with brine, dried over Na 2 S0 4 , filtered, and concentrated to afford the crude product. The crude material was purified via column chromatography (ISCO, 3:1
  • Propiophenone (4.52 mL, 34.0 mmol) was added and the reaction was heated to reflux for 18 h.
  • the reaction mixture was concentrated in vacuo to provide a gummy residue.
  • the residue was dissolved in water (-250 mL) and washed with diethyl ether (2 x 100 mL).
  • the aqueous phase was chilled in an ice bath, made acidic with glacial acetic acid, and solids were collected by filtration.
  • the solid was dissolved in hot acetic acid ( ⁇ 30 mL), the resulting solution was cooled to room temperature, and water was added slowly to precipitate the product.
  • This material was purified via reverse phase HPLC (Gilson, Sunfire Prep C18 OBD 30 x 150 mm, 25 mL/min, 10-100% CH 3 CN/H 2 0 with 0.1 % TFA over 10 min) to afford 3-(1 ,4'- bipiperidin-1 '-ylmethyl)-2-phenyl-/ ⁇ /-(1 -phenylcyclopropyl)-4-quinolinecarboxamide as the TFA salt.
  • This material was partitioned between ethyl acetate and 10% aqueous sodium carbonate.
  • Restek PFPP 30 x 100 column 40-70 % MeOH/water, ammonium acetate over 13 min.
  • Methyl 7-bromo-8-fluoro-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (12 g, 27.13 mmol), benzoyl peroxide (3.28 g, 13.57 mmol) and NBS (5.3 g, 29.84 mmol) were dissolved in carbon tetrachloride (120 mL) and refluxed for 18 h.
  • Triethylamine (8.05 mL, 57.8 mmol) was added slowly. The resulting mixture was stirred overnight. The solvent was removed, the residue was diluted with saturated aqueous NaHC0 3 and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na 2 S0 4 , filtered, and concentration in vacuo.
  • 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 three 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.
  • 6-(ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid To a mixture of 6-(ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (2.16 g, 5.75 mmol) in dichloromethane (19.17 mL) at 0°C was added oxalyl chloride (6.33 mL, 12.65 mmol) dropwise. Two drops of DMF were added. An additional 10 mL of THF was added to aid in solubility. The reaction mixture was stirred at 0°C for 1 h. Methanol (15 mL) was added slowly to the reaction mixture.
  • Methyl 6-(ethyloxy)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1 .8 g, 4.62 mmol) was dissolved in carbon tetrachloride (23 mL). /V-Bromosuccinimide (1.070 g, 6.01 mmol) and benzoyl peroxide (0.1 12 g, 0.462 mmol) were added, and the reaction was heated to 100°C for 24 h. The reaction was filtered, cooled to room temperature, and concentrated. The oil was dissolved in 24 mL MeCN. Half of the solution (12 mL) was treated with 4-morpholinylpiperidine (0.787 g, 4.62 mmol).
  • Methyl-6-(ethyloxy)-3- ⁇ [4-(4-morpholinyl)-1 -piperidinyl]methyl ⁇ -2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.750 g, 1.345 mmol) was dissolved in methanol (9.037 ml_), tetrahydrofuran (3.01 ml.) and water (3.01 ml_). Potassium hydroxide (0.377 g, 6.73 mmol) was added, and the reaction was heated to 70°C. After 7 days the reaction was cooled to room temperature and concentrated. The crude product was suspended in ethyl acetate and washed with water.
  • the crude product was purified via reverse phase HPLC (Waters, Sunfire 30 x 100 mm column, 20-60% CH 3 CN/H 2 0 with 0.1 % TFA).
  • the product fractions were concentrated, dissolved in methylene chloride, washed with saturated aqueous NaHC0 3 solution, and passed through a phase separator.
  • the organic phase was concentrated to give 6-(ethyloxy)-3- ⁇ [4-(4-morpholinyl)-1-piperidinyl]methyl ⁇ -/ ⁇ /-(1- phenylcyclopropyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide (0.021 g, 17% yield) as a white solid.
  • Oxalyl chloride (2.55 g, 20.07 mmol) was dissolved in CH 2 CI 2 and cooled to
  • the aqueous phase was acidified to pH 5 and concentrated in vacuo.
  • the residue was diluted with ethyl acetate, filtered, and concentrated in vacuo.
  • the crude material was purified via reverse phase HPLC (19-49% CH 3 CN/H 2 0 with 0.1 % TFA) to give 3- ⁇ [4-(1 -piperidinyl)cyclohexyl]methyl ⁇ -2-[3-(trifluoromethyl)phenyl]-4- quinolinecarboxylic acid (0.130 g, 56% yield) as a yellow solid.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des analogues de quinoléine, des compositions pharmaceutiques les contenant et leur utilisation en tant qu'antagonistes de TRPV4.
PCT/US2011/029584 2010-03-23 2011-03-23 Antagonistes de trpv4 WO2011119704A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US31643310P 2010-03-23 2010-03-23
US61/316,433 2010-03-23

Publications (1)

Publication Number Publication Date
WO2011119704A1 true WO2011119704A1 (fr) 2011-09-29

Family

ID=44673595

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/029584 WO2011119704A1 (fr) 2010-03-23 2011-03-23 Antagonistes de trpv4

Country Status (1)

Country Link
WO (1) WO2011119704A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103159636A (zh) * 2013-04-05 2013-06-19 李兴惠 氨甲基己酸衍生物和用途
WO2013169396A1 (fr) * 2012-05-11 2013-11-14 The University Of Utah Research Foundation Composés ayant une activité trpv4, compositions et procédés associés de ces composés
WO2014060432A1 (fr) 2012-10-16 2014-04-24 Almirall, S.A. Dérivés de pyrrolotriazinone en tant qu'inhibiteurs des pi3k
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
WO2019121357A1 (fr) * 2017-12-19 2019-06-27 F. Hoffmann-La Roche Ag Nouveaux composés de quinoléine pour le traitement et la prophylaxie d'une maladie à virus de l'hépatite b
US10738016B2 (en) 2015-10-13 2020-08-11 H. Lee Moffitt Cancer Center And Research Institute, Inc. BRD4-kinase inhibitors as cancer therapeutics
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
EP4142874A1 (fr) * 2020-04-30 2023-03-08 RaQualia Pharma Inc. Dérivés de pyrimidin-4 (3h)-one utilisés en tant qu'antagonistes de trpv4

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007071055A1 (fr) * 2005-12-21 2007-06-28 Painceptor Pharma Corporation Compositions et procedes de modulation de canaux ioniques commandes par porte
WO2009000085A1 (fr) * 2007-06-27 2008-12-31 Painceptor Pharma Corporation Dérivés de quinoline et de quinazoline utiles comme modulateurs des canaux ioniques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007071055A1 (fr) * 2005-12-21 2007-06-28 Painceptor Pharma Corporation Compositions et procedes de modulation de canaux ioniques commandes par porte
WO2009000085A1 (fr) * 2007-06-27 2008-12-31 Painceptor Pharma Corporation Dérivés de quinoline et de quinazoline utiles comme modulateurs des canaux ioniques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
VRIENS ET AL.: "Determinants of 4alpha-Phorbol Sensitivity in Transmembrane Domains 3 and 4 of the Cation Channel TRPV4.", JBC, vol. 282, no. 17, 2007, pages 12796 - 12803 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9499533B2 (en) 2012-03-27 2016-11-22 Shionogi & Co., Ltd. Aromatic 5-membered heterocyclic derivative having TRPV4-Inhibiting activity
WO2013169396A1 (fr) * 2012-05-11 2013-11-14 The University Of Utah Research Foundation Composés ayant une activité trpv4, compositions et procédés associés de ces composés
EP2847164A4 (fr) * 2012-05-11 2015-09-23 Univ Utah Res Found Composés ayant une activité trpv4, compositions et procédés associés de ces composés
WO2014060432A1 (fr) 2012-10-16 2014-04-24 Almirall, S.A. Dérivés de pyrrolotriazinone en tant qu'inhibiteurs des pi3k
CN103159636A (zh) * 2013-04-05 2013-06-19 李兴惠 氨甲基己酸衍生物和用途
CN103159636B (zh) * 2013-04-05 2015-02-25 李兴惠 氨甲基己酸衍生物和用途
US9708338B2 (en) 2013-09-25 2017-07-18 Shionogi & Co., Ltd. Aromatic heterocyclylamine derivative having TRPV4-inhibiting activity
US10738016B2 (en) 2015-10-13 2020-08-11 H. Lee Moffitt Cancer Center And Research Institute, Inc. BRD4-kinase inhibitors as cancer therapeutics
US11643396B2 (en) 2015-10-13 2023-05-09 H. Lee Moffitt Cancer Center And Research Institute, Inc. BRD4-kinase inhibitors as cancer therapeutics
WO2019121357A1 (fr) * 2017-12-19 2019-06-27 F. Hoffmann-La Roche Ag Nouveaux composés de quinoléine pour le traitement et la prophylaxie d'une maladie à virus de l'hépatite b
EP4142874A1 (fr) * 2020-04-30 2023-03-08 RaQualia Pharma Inc. Dérivés de pyrimidin-4 (3h)-one utilisés en tant qu'antagonistes de trpv4
EP4142874A4 (fr) * 2020-04-30 2024-05-22 Raqualia Pharma Inc Dérivés de pyrimidin-4 (3h)-one utilisés en tant qu'antagonistes de trpv4
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

Similar Documents

Publication Publication Date Title
WO2011119704A1 (fr) Antagonistes de trpv4
AU2015233654B2 (en) Heteroaryl Syk inhibitors
JP7337951B2 (ja) 癌を治療するための窒素含有芳香族ヘテロ環アミド誘導体
TWI605040B (zh) 作為ｍＧｌｕＲ２負向異位性調節劑之喹啉甲醯胺及喹啉甲腈衍生物、組合物及其用途
RU2629194C2 (ru) Производные 1,5- и 1,7-нафтиридина, полезные при лечении заболеваний, опосредованных fgfr
KR101936851B1 (ko) 단백질 키나아제 저해제인 신규 피라졸로피리딘 유도체 또는 인다졸 유도체
EP2197438B1 (fr) Composés hétérocycliques comme antagonistes du récepteur crth2
JP5607046B2 (ja) Ｔｒｐｖ４拮抗薬
EP3144308B1 (fr) Composé hétérocyclique contenant de l'azote
JP6738795B2 (ja) 新規な置換ピリミジン化合物
JP6771246B2 (ja) それに関連する障害の治療または予防に有用なβ−３アドレナリン受容体調節剤
JP6868011B2 (ja) ピラゾリル置換ヘテロアリール及び医薬としてのその使用
WO2016011979A1 (fr) Dérivé 7h-pyrrolo[2,3-d]pyrimidine 2,4-disubstituté, procédé de préparation et utilisation médicinale de ce dernier
CA2870347A1 (fr) Derives de 3,4-dihydro-2h-pyrido[1,2-a]pyrazine-1,6-dione substitues pouvant etre utilises pour le traitement de (entre autres) la maladie d'alzheimer
AU2016284654A1 (en) 2,3-dihydro-4h-1,3-benzoxazin-4-one derivatives as modulators of cholinergic muscarinic M1 receptor
TW201307302A (zh) 作為ｃｒｔｈ２受體調節劑之喹□啉及氮雜喹□啉
KR20140041733A (ko) Trpv4 길항제
KR20190005877A (ko) Trpv4 길항제
CN113454081A (zh) 咪唑并吡啶基化合物及其用于治疗增生性疾病的用途
JP2022141918A (ja) 複素環化合物
US8658636B2 (en) TRPV4 antagonists
TW201620913A (zh) 作為PARP抑制劑的4H-吡唑並[1,5-α]苯並咪唑化合物的類似物
EP1968976A1 (fr) Derives de pyrazolo [4,3-c] pyridine substitues agissant comme inhibiteurs de kinase
AU2012271661A1 (en) Cycloalkyl-fused tetrahydroquinolines as CRTH2 receptor modulators
WO2011119693A1 (fr) Antagonistes de trpv4

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11760130

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11760130

Country of ref document: EP

Kind code of ref document: A1