WO2011091410A1 - Antagonistes de trpv4 - Google Patents

Antagonistes de trpv4 Download PDF

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Publication number
WO2011091410A1
WO2011091410A1 PCT/US2011/022380 US2011022380W WO2011091410A1 WO 2011091410 A1 WO2011091410 A1 WO 2011091410A1 US 2011022380 W US2011022380 W US 2011022380W WO 2011091410 A1 WO2011091410 A1 WO 2011091410A1
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alkyl
phenyl
carbonyl
substituted
independently
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PCT/US2011/022380
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WO2011091410A8 (fr
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Hilary Schneck Eidam
Ryan Michael Fox
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Glaxos Smithkline Llc
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    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to indole or benzothiophene 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 indole or benzothiophene analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them.
  • this invention provides for the use of the compounds of
  • 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 and osteoarthritis.
  • 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 of Formula (I):
  • R-i is C 1-3 alkyl, C 1-3 alkoxy, CF 3 , halo, S0 2 C 1-3 alkyl, N(R 4 ) 2 , OCF 3 , or CN;
  • R 2 is C 1-4 alkyl, -CH 2 C 3-6 cycloalkyl, or -CH 2 -phenyl;
  • OCi -5 alkyl, d -5 alkyl, C(0)NR 4 Ci -5 alkyl, S0 2 NR 4 Ci -5 alkyl, phenyl, morpholinyl, pyrimidinyl, dihydropyranyl, tetrahydropyranyl, pyridizinyl, pyrazinyl, oxazolyl, pyrollyl, C 3-6 cycloalkyl, cyclohexenyl, piperazinyl, pyrrolidinyl, piperadinyl, and pyridyl may be unsubstituted or substituted with one, two, or three substituents selected from the group consisting of: OR 4 , R 4 , OCF 3 , halo, CF 3 , CN, N(R 4 ) 2 , morpholinyl, piperidinyl, pyrollidinyl, piperazinyl, tetrazolyl, C0 2 C 1
  • X is a bond or CH 2 ;
  • Y is NR 4 or S
  • R 4 is independently H or C1-3 alkyl
  • R 5 is independently H or C1-5 alkyl
  • R is independently
  • R 7 is independently H or C 1-4 alkyl
  • i 0, 1 , 2, or 3;
  • 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 (n-propyl and isopropyl), and butyl (n-butyl, isobutyl, and t-butyl).
  • CycloalkyI 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.
  • Alkoxy refers to an -0-C 1-3 alkyl group wherein C 1-3 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, and the like.
  • 'halogen' and 'halo' mean 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. In addition, 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, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.
  • 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, 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.
  • 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 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.
  • polymorphs may exhibit 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.
  • 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.
  • Ri is Ci-3 alkyl, d -3 alkoxy, CF 3 , halo, S0 2 Ci -3 alkyl, N(R 4 ) 2 , OCF 3 , or CN;
  • R 2 is Ci -4 alkyl, -CH 2 C 3 - 6 cycloalkyl, or -CH 2 -phenyl;
  • R 3 is
  • OCi -5 alkyl, d -5 alkyl, C(0)NR 4 Ci -5 alkyl, S0 2 NR 4 Ci -5 alkyl, phenyl, morpholinyl, pyrimidinyl, dihydropyranyl, tetrahydropyranyl, pyridizinyl, pyrazinyl, oxazolyl, pyrollyl, C 3-6 cycloalkyl, cyclohexenyl, piperazinyl, pyrrolidinyl, piperadinyl, and pyridyl may be unsubstituted or substituted with one, two, or three substituents selected from the group consisting of: OR 4 , R 4 , OCF 3 , halo, CF 3 , CN, N(R 4 ) 2 , morpholinyl, piperidinyl, pyrollidinyl, piperazinyl, tetrazolyl, C0 2 Ci
  • X is a bond or CH 2 ;
  • Y is NR 4 or S
  • R 4 is independently H or C1-3 alkyl
  • R 5 is independently H or C1-5 alkyl
  • R is independently
  • R 7 is independently H or C1-4 alkyl
  • i 0, 1 , 2, or 3.
  • R-i is C 1-3 alkyl, C 1-3 alkoxy, CF 3 , halo, OCF 3 , or CN;
  • R 2 is C 1-4 alkyl, -CH 2 C 3-6 cycloalkyl, or -CH 2 -phenyl;
  • R 3 is:
  • phenyl or pyridyl may be unsubstituted or substituted with one, two, or three substituents selected from the group consisting of: OR 4 , R 4 , OCF 3 , halo, CF 3 , CN, N (R 4 ) 2 , C0 2 Ci -3 alkyl, and S0 2 Ci -3 alkyl; G is
  • X is a bond or CH 2 ;
  • Y is NR 4 or S
  • R 4 is independently H or C 1 -3 alkyl
  • R 5 is hydrogen
  • R is independently
  • R 7 is independently H or C 1-4 alkyl
  • i 0, 1 , 2, or 3.
  • R-i is CF 3 , halo, OCF 3 , or CN;
  • R 2 is Ci- 4 alkyl
  • phenyl, morpholinyl, pyrimidinyl, dihydropyranyl, C 3-6 cycloalkyl, cyclohexenyl, piperazinyl, pyrrolidinyl, piperadinyl, and pyridyl may be unsubstituted or substituted with one, two, or three substituents selected from the group consisting of: OR 4 , R 4 , OCF 3 , halo, CF 3 , CN, N(R 4 ) 2 , C0 2 Ci -3 alkyl, and S0 2 Ci -3 alkyl;
  • X is a bond
  • Y is NR 4 or S
  • R 4 is independently C 3 alkyl
  • R 5 is hydrogen
  • R is independently
  • R 7 is independently H or alkyl
  • i 0, 1 , or 2.
  • Ri is CF 3 , halo, OCF 3 , or CN;
  • R 2 is C 1-4 alkyl
  • R 3 is:
  • phenyl and pyridyl may be unsubstituted or substituted with one, two, or three substituents selected from the group consisting of: OR 4 , R 4 , OCF 3 , halo, CF 3 , CN, N(R 4 ) 2 , C0 2 Ci -3 alkyl, and S0 2 Ci -3 alkyl;
  • X is a bond
  • Y is NR 4 or S
  • R 4 is independently C 3 alkyl
  • R 5 is hydrogen or Ci- 3 alkyl
  • R is independently
  • R 7 is independently H or Ci -2 alkyl
  • i 0, 1 , or 2.
  • Ri is C 1-3 alkyl, C 1-3 alkoxy, CF 3 , halo, S0 2 C 1-3 alkyl, N(R 4 ) 2 , OCF 3 , or CN;
  • R 2 is C 1-4 alkyl, -CH 2 C 3-6 cycloalkyl, or -CH 2 -phenyl;
  • C(0)NR 4 C 1-5 alkyl C(0)NHphenyl, C(0)R 6 , C0 2 C 1-3 alkyl, S0 2 C 1-3 alkyl, S0 2 phenyl, S0 2 NR 4 C 1-5 alkyl, -O-phenyl, phenyl, morpholinyl, pyrimidinyl, tetrahydropyranyl, pyridizinyl, oxazolyl, pyrazinyl, pyrrolyl, tetrazolyl, oxadiazolyl, triazolyl, dihydropyranyl, C 3- 6 cycloalkyl, cyclohexenyl, piperazinyl, pyrrolidinyl, piperadinyl, and pyridyl;
  • OCi -5 alkyl, d -5 alkyl, C(0)NR 4 Ci -5 alkyl, S0 2 NR 4 Ci -5 alkyl, phenyl, morpholinyl, pyrimidinyl, dihydropyranyl, tetrahydropyranyl, pyridizinyl, pyrazinyl, oxazolyl, pyrollyl, C 3- 6 cycloalkyl, cyclohexenyl, piperazinyl, pyrrolidinyl, piperadinyl, and pyridyl may be unsubstituted or substituted with one, two, or three substituents selected from the group consisting of: OR 4 , R 4 , OCF 3 , halo, CF 3 , CN, N(R 4 ) 2 , morpholinyl, piperidinyl, pyrollidinyl, piperazinyl, tetrazolyl, C0 2 Ci
  • G is all of which may be unsubstituted or substituted by one or two substituents selected from the group consisting of: C ⁇ alkyl, OH, C(0)OH, CtC -O-C ⁇ alkyl, CH 2 OR 5 , CH 2 NHR 5 , oxo, or F;
  • X is a bond or CH 2 ;
  • Y is NR 4 or S
  • R 4 is independently H or C1-3 alkyl
  • R 5 is hydrogen or d- 5 alkyl
  • R is independently
  • R 7 is independently H or Ci -2 alkyl; and i is 0, 1 , 2, or 3.
  • Ri is Ci-3 alkyl, Ci -3 alkoxy, CF 3 , halo, or CN;
  • R 2 is Ci-4 alkyl
  • C(0)NR 4 C 1-5 alkyl C(0)NHphenyl, C(0)R 6 , C0 2 C 1-3 alkyl, S0 2 C 1-3 alkyl, S0 2 phenyl, S0 2 NR 4 C 1-5 alkyl, -O-phenyl, phenyl, morpholinyl, pyrimidinyl, tetrahydropyranyl, pyridizinyl, oxazolyl, pyrazinyl, pyrrolyl, tetrazolyl, oxadiazolyl, triazolyl, dihydropyranyl, C 3- 6 cycloalkyl, cyclohexenyl, piperazinyl, pyrrolidinyl, piperadinyl, and pyridyl;
  • C 3-6 cycloalkyl, piperazinyl, pyrrolidinyl, piperadinyl, and pyridyl may be unsubstituted or substituted with one, two, or three substituents selected from the group consisting of: OR 4 , R 4 , OCF 3 , halo, CF 3 , CN, N(R 4 ) 2 , morpholinyl, piperidinyl, pyrollidinyl, piperazinyl, tetrazolyl, C0 2 Ci -4 alkyl, S0 2 NHCi -3 alkyl, C(0)N(R 4 ) 2 , NHS0 2 Ci -3 alkyl and S0 2 Ci -3 alkyl; G is
  • X is a bond
  • Y is NR 4 or S
  • R 4 is independently H or Ci- 3 alkyl
  • R 5 is hydrogen or C1-5 alkyl
  • R is independently
  • R 7 is independently H or Ci -2 alkyl
  • i 0, 1 , 2, or 3. It is to be understood that the present invention covers all combinations of particular groups described hereinabove. Specific examples of compounds of the present invention include the following:
  • 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, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999).
  • 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 free secondary amine of appropriately substituted diamine core can be coupled to an appropriate carboxylic acid 1 under conditions common to the art such as EDC in the presence of a base such as /V-methylmorpholine or triethylamine, a coupling modifier such as HOBt to provide the amide intermediate 2. Subsequent CBz
  • the free amine of appropriately substituted diamine core can be coupled to an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as /V-methylmorpholine or triethylamine, a coupling modifier such as HOBt to provide the amide intermediate 6.
  • a coupling modifier such as HOBt
  • Subsequent Boc deprotection can be accomplished under conditions common to the art such as treatment with an acid such as hydrochloric acid in 1 ,4-dioxane and methanol or TFA in dichloromethane to provide intermediate 7.
  • Treatment of intermediate 7 with an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as N- methylmorpholine and a coupling modifier such as HOBt provides the amide intermediate 8.
  • the free amine of an appropriately substituted diamine core can be coupled to an appropriate carboxylic acid 10 under conditions common to the art such as EDC in the presence of a base such as /V-methylmorpholine or triethylamine, a coupling modifier such as HOBt to provide the amide intermediate 11.
  • a coupling modifier such as HOBt
  • Subsequent Boc deprotection can be accomplished under conditions common to the art such as treatment with an acid such as hydrochloric acid in 1 ,4-dioxane and methanol or TFA in dichloromethane to provide intermediate 12.
  • Treatment of intermediate 12 with an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as N- methylmorpholine and a coupling modifier such as HOBt provides the amide intermediate 13.
  • 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. 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 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.
  • 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
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
  • the compound of the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration.
  • 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
  • A/-3-azetidinyl-5-phenyl-2-pyridinecarboxamide To a 100 ml flask was added 1 , 1- dimethylethyl 3- ⁇ [(5-phenyl-2-pyridinyl)carbonyl]amino ⁇ -1 -azetidinecarboxylate (1.5 g, 4.1 mmol) followed by dichloromethane (DCM) (20 mL) and TFA (8.17 mL, 106 mmol). The solution was stirred at room temperature overnight, concentrated then passed over an SCX cartridge to remove the TFA eluting with methanol, then 2N NH 3 -methanol.
  • DCM dichloromethane

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

Abstract

La présente invention concerne des analogues d'indole ou de benzothiophène, des compositions pharmaceutiques contenant ceux-ci et leur utilisation en tant qu'antagonistes de TRPV4.
PCT/US2011/022380 2010-01-25 2011-01-25 Antagonistes de trpv4 WO2011091410A1 (fr)

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Cited By (5)

* 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
US9708338B2 (en) 2013-09-25 2017-07-18 Shionogi & Co., Ltd. Aromatic heterocyclylamine derivative having TRPV4-inhibiting activity
US10351532B2 (en) 2014-12-29 2019-07-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
AU2015306643B2 (en) * 2014-08-28 2020-05-07 X-Chem, Inc. Soluble epoxide hydrolase inhibitors and uses thereof
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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WO2007070865A2 (fr) * 2005-12-15 2007-06-21 Smithkline Beecham Corporation Composes innovants

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WO2006029154A2 (fr) * 2004-09-07 2006-03-16 Smithkline Beecham Corporation Nouveaux composes
WO2007070865A2 (fr) * 2005-12-15 2007-06-21 Smithkline Beecham Corporation Composes innovants

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Cited By (7)

* 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
US9708338B2 (en) 2013-09-25 2017-07-18 Shionogi & Co., Ltd. Aromatic heterocyclylamine derivative having TRPV4-inhibiting activity
AU2015306643B2 (en) * 2014-08-28 2020-05-07 X-Chem, Inc. Soluble epoxide hydrolase inhibitors and uses thereof
US10351532B2 (en) 2014-12-29 2019-07-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
US10961200B2 (en) 2014-12-29 2021-03-30 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
US11247971B2 (en) 2014-12-29 2022-02-15 The Trustees Of The University Of Pennsylvania Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
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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