WO2012037349A2 - Composés - Google Patents

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Publication number
WO2012037349A2
WO2012037349A2 PCT/US2011/051761 US2011051761W WO2012037349A2 WO 2012037349 A2 WO2012037349 A2 WO 2012037349A2 US 2011051761 W US2011051761 W US 2011051761W WO 2012037349 A2 WO2012037349 A2 WO 2012037349A2
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WIPO (PCT)
Prior art keywords
compound
methyl
formula
dihydro
phenyl
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PCT/US2011/051761
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English (en)
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WO2012037349A3 (fr
Inventor
Jason W. Dodson
Joseph Paul Marino Jr.
John Jeffrey Mcatee
Lamont Roscoe Terrell
David G. Washburn
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Glaxosmithkline Llc
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Publication of WO2012037349A2 publication Critical patent/WO2012037349A2/fr
Publication of WO2012037349A3 publication Critical patent/WO2012037349A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to 2-(amino)-thiazole-4-carboxamide compounds, pharmaceutical compositions containing them, and their use as TRPC3 and/or TRPC6 ion channel blockers and for the treatment of conditions which benefit from the blockade of the TRPC3 and/or TRPC6 ion channels.
  • Heart failure occurs when the heart can no longer provide adequate blood flow or blood pressure to meet the body's demands. This condition triggers a number of compensatory mechanisms including changes in cardiac function and structure such as ventricular remodeling. Compared to healthy controls, patients with heart failure frequently have ventricular hypertrophy, dilation, and fibrosis. This ventricular remodeling can lead to diastolic dysfunction, systolic dysfunction, pulmonary congestion and edema. The mechanisms that contribute to ventricular remodeling remain unclear but abnormal calcium handling in cardiac myocytes is a dominant, common characteristic of the myocyardium in heart failure.
  • TRP transient receptor potential
  • TRPC3 and TRPC6 channels are composed of 4 subunits in either homomeric or heteromeric conformation. Heterotetramers may form between TRPC channels and possibly with channels from other TRP families (K. Kiselyov, R.L. Patterson, Frontiers in Bioscience 14 (2009), 45-58; M.L. Villereal, Sem Cell Dev Biol 17 (2006), 618-629; J.Y. Park, E.M. Hwang, O. Yarishkin, J.H. Seo, E. Kim, J. Yoo, G.S. Yi, D.G. Kim, N.
  • TRPC3 and TRPC6 are nonselective, calcium-permeable cation channels that are activated by diacylglycerol and a G-protein coupled receptor- phospholipase C signaling pathway.
  • TRPC3 and TRPC6 are widely expressed including in brain, heart, lung, skeletal muscle, adipose, bone, blood vessels, and kidney (A. Riccio, A.D. Medhurst, C. Mattei, R.E. Kelsell, A.R. Calver, A.D. Randall, CD. Benham, M.N. Pangalos, Mol Br Res 109 (2002), 95-104).
  • TRPC3 and TRPC6 contribute to a variety of cellular functions in myocytes, endothelium, epithelium, chondrocytes, lymphocytes, neuronal cells, and tumors. Some of these cellular functions include hypertrophy, contraction, proliferation, apoptosis, differentiation, chemoattraction, survival, neurotransmission, activation, and migration (B. Nilius, G. Owslanik, T. Voets, J.A. Peters, Physiol Rev 87 (2007), 165-217; J. Abramowitz, L. Birnbaumer, FASEB J 2 (2009), 297-328).
  • TRPC3 or TRPC6 siRNA decreases calcium influx, expression of hypertrophy-associated genes, actin reorganization and protein synthesis in neonatal rat cardiomyocytes treated with angiotensin II or phenylephrine (K. Kuwahara, Y. Wang, J. McAnally, J.A. Richardson, R. Bassel-Duby, J.A. Hill, E.N. Olson, J Clin Invest 1 16 (2006), 31 14-3125; J.S. Brenner, R.E. Domnetsch, PLos ONE 8 (2007), e802; N. Onohara, M. Nishida, R. Inoue, H.
  • TRPC3 and TRPC6 may play an important role in a variety of other pathophysiological states.
  • Human genetic and preclinical studies indicate that TRPC3 and/or TRPC6 contribute to pulmonary hypertension (Y. Yu, I. Fantozzi, C.V. Remillard, J.W. Landsberg, N. Kunichika,, O. Platoshyn, D.D. Tigno, P.A. Thistlethwaite, L.J. Rubin, J.S-J. Yuan, Proc Natl Acad Sci 101 (2004), 13861 -13866), essential hypertension (F. Thilo, D. Baumunk, H. Krause, M. Schrader, K. Miller, C.
  • Pulmonary Circulation AEME (2010); 661 :137-154
  • chronic obstructive pulmonary disease S. Li, J. Westwick, C. Poll, Cell Calcium 33 (2003), 551-558
  • pulmonary edema X. Yao and C.J. Garland. Circ Res (2005); 97:854-863; D.L. Cioffi et al., "Membrane Receptors, Channels, and Transporters in Pulmonary Circulation” AEME (2010); 661 :137-154, G.U. Ahmmed and A.B. Malik. Pflugers Arch-Eur J Phys (2005); 451 :131-142; A. Kerem et al. Circ Res (2010); 106:1 103-1 1 16), focal segmental glomerulosclerosis (N. Mukerji, T.V.
  • ovarian cancer S.L. Yang, Q. Cao, K.C. Zhou, Y.J. Feng, Y.Z. Wang, Oncogene 28 (2009), 1320-1328
  • breast cancer E. Aydar, S. Yeo, M. Djamgoz, C. Palmer, Cancer Cell Int 9 (2009), 23
  • gastric cancer R. Cai, X. Ding, K. Zhou, Y. Shi, R. Ge, G. Ren, Y. Jin, Y. Wang, Int J Cancer 125 (2009), 2281-2287
  • esophageal cancer Y. Shi, X. Ding, Z.H.
  • TRPC3 and TRPC6 channels may be useful in the treatment of these and other cardiovascular, respiratory, renal, and musculo-skeletal diseases, and types of cancer.
  • the present invention relates to the discovery that certain compounds are TRPC3 and/or TRPC6 ion channel blockers (i.e., inhibit TRPC3 and/or TRPC6 ion channel activity), and therefore may be useful in treating diseases to which TRPC3 and/or TRPC6 activity contribute.
  • the present invention provides for novel compounds of Formula I and salts, e.g. pharmaceutically acceptable salts, thereof:
  • Y is N or CR", wherein R" is H or a group R5;
  • R4 is an optional substituent independently selected from halo, (Ci -6 )alkyl, trifluoromethyl, (C 1-6 )alkylthio, -OH, -C0 2 H, phenyl, cyano, -(C 1-6 )N(R a )(R b ), and (C 1-6 )alkoxy; n is an integer of from 0-3;
  • R5 is an optional substituent independently selected from (Ci -6 )alkoxy, halo, and cyano; and m is an integer of from 0-3;
  • R2 is H, D, halo, or (C 1-4 )alkyl
  • R3 is a monocyclic, carbocyclic or heterocyclic ring selected from phenyl and pyridinyl; either of which may be optionally substituted with one to three substituents independently selected from D, (Ci -6 )alkyl, (Ci -6 )alkoxy, halo, trifluoromethoxy, trifluoromethyl, cyano, -N(R a )(R b ), morpholinyl, -S0 2 R c , and -S0 2 N(R d )(R e ); or R3 is a bicyclic ring system (A):
  • ring (a) is saturated or unsaturated
  • R' is independently selected from H, D, (Ci -6 )alkyl, (Ci -6 )alkoxy, halo,
  • R a -R e are independently selected from H and (C 1-6 )alkyl.
  • the present invention provides for pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the invention provides for the use of a compound of Formula I or a pharmaceutically acceptable salt thereof as an antagonist or inhibitor of TRPC3 and/or TRPC6 ion channel activity (e.g. in in vitro or in vivo assays or in a subject in need thereof).
  • the invention provides for the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for treating a disease, e.g. cardiovascular, respiratory, renal, or musculo-skeletal disease or cancer, to which TRPC3 and/or TRPC6 ion channel activity contribute.
  • a disease e.g. cardiovascular, respiratory, renal, or musculo-skeletal disease or cancer
  • the invention provides for the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for treating cardiac hypertrophy, heart failure, chronic renal failure, pulmonary hypertension, essential hypertension, cardiac arrhythmia, asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary edema, focal segmental glomerulosclerosis, other kidney diseases, osteoarthritis, Duchenne or other muscular dystrophy, cystic fibrosis, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, or glioma.
  • Alkyl refers to a monovalent, saturated, linear or branched hydrocarbon group having the specified number of member carbon atoms.
  • (Ci -6 )alkyl as used herein refers to an alkyl group having from 1 to 6 member atoms.
  • Branched alkyl groups include hydrocarbon chains having one, two, or three branches. Examples of alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, sec-butyl, t- butyl), pentyl (n-pentyl, isopentyl, neopentyl), and hexyl.
  • alkoxy refers to a group containing an alkyl radical attached through an oxygen linking atom.
  • alkoxy groups include (Ci -4 )alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy and t-butoxy (or methoxyl, ethoxyl, etc.)
  • Alkylthio refers to a group containing an alkyl radical attached through a sulfur linking atom.
  • exemplary alkylthio groups include (Ci -4 )alkylthio groups such as methylthio-, ethylthio-, n-propylthio-, isopropylthio-, n-butylthio-, s-butylthio-, and t-butylthio-.
  • Carbocyclyl or “carbocyclic” refers to a 3-12 (e.g. 5-7) membered monocyclic or fused 8-12 membered bicyclic hydrocarbon ring which may be saturated or unsaturated, and aromatic or non-aromatic. Carbocyclyl includes aryl and cycloalkyl.
  • Cycloalkyl refers to a monovalent, saturated monocyclic hydrocarbon ring having the specified number of carbon atoms in the ring.
  • (C 3-7 )cycloalkyl refers to a monovalent, saturated monocyclic hydrocarbon ring having 3 to 7 ring carbon atoms.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Aryl refers to a 6-12 membered monocyclic or fused bicyclic hydrocarbon ring, wherein at least one ring is aromatic. Examples of such groups include phenyl, naphthyl, tetrahydronaphthalenyl and indanyl.
  • Heterocyclyl refers to a 4-7 (e.g. 5-7) membered monocyclic ring or a fused 8-12 membered bicyclic ring which may be saturated or unsaturated, aromatic or non-aromatic, containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulphur. Heterocyclyl includes heteroaryl.
  • Examples of such monocyclic rings include pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dioxolanyl, dioxanyl, oxathiolanyl, oxathianyl, dithianyl, dihydrofuranyl, tetrahydrofuranyl,
  • dihydropyranyl dihydropyranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, diazepanyl, and azepanyl.
  • bicyclic rings examples include indolinyl, isoindolinyl, benzopyranyl, quinuclidinyl, 2,3,4,5-tetrahydro- 1 H-3-benzazepine, tetrahydroisoquinolinyl, benzodioxolyl, 2,3-dihydro-1 ,4-benzodioxinyl, benzoxazolyl, 3,4-dihydro-2H-1 ,5-benzodioxepinyl, 2H-1 ,4-benzoxazinyl, and 1 ,2,3,4- tetrahydroquinolinyl.
  • Heteroaryl refers to a 5-7 (e.g. 5-6) membered monocyclic aromatic or a fused 8-10 membered bicyclic aromatic ring, containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulphur.
  • Examples of such monocyclic aromatic rings include thienyl, furyl, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, triazinyl, and tetrazinyl.
  • fused aromatic rings include quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, pteridinyl, cinnolinyl, phthalazinyl, naphthyridinyl, indolyl, isoindolyl, azaindolyl, indolizinyl, indazolyl, purinyl, pyrrolopyridinyl, furopyridinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzoimidazolyl, benzooxazolyl,
  • D is deuterium (also referred to as 2 H).
  • 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 atoms 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. Where two or more substituents may be present, it is to be understood that each substituent is independently selected from the defined group of substituents, unless otherwise indicated.
  • Optionally substituted or “optional substituent” indicates that a group, such as alkyl, phenyl, cycloalkyl, heterocycloalkyl, heteroaryl, carbocyclic, heterocyclic etc., may be unsubstituted, or the group may be substituted with one or more substituents as defined.
  • the compounds of Formula I may have one or more asymmetric carbon atoms 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 without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio. It will be recognized that compounds, materials, compositions and dosage forms of the invention may be acceptable in veterinary applications, provided they are suitable for use in contact with the tissues of (non-human) animals without excessive toxicity, irritation, or other problem or complication, within the scope of sound veterinary judgment and commensurate with a reasonable benefit/risk ratio.
  • salts of the compounds according to Formula I may be prepared. These salts may be prepared in situ during the 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.
  • the salts of the compounds of Formula I are preferably pharmaceutically acceptable.
  • the compounds of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt.
  • Suitable pharmaceutically acceptable salts can include acid or base addition salts.
  • suitable salts see Berge et al, J. Pharm. Sci., 1977, 66, 1-19.
  • a pharmaceutical acceptable salt may be readily prepared by using a desired acid or base as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent used during preparation.
  • compounds according to Formula I may contain an acidic functional group and are, therefore, capable of forming base addition salts by treatment with a suitable base.
  • bases include:
  • hydroxides, carbonates, and bicarbonates of alkali metals or alkaline earth metals such as sodium, potassium, lithium, calcium, magnesium, aluminium, and zinc
  • 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,
  • a pharmaceutically acceptable base addition salt can be formed by reaction of a compound of Formula I with a suitable inorganic or organic base (optionally in a suitable solvent such as an organic solvent), to give the base addition salt which is usually isolated for example by crystallisation and filtration.
  • compounds according to Formula I may contain a basic functional group and are therefore capable of forming 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 pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of Formula I with a suitable inorganic or organic acid, optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration.
  • the invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the salts of the compounds of Formula I.
  • 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. The skilled artisan will further appreciate that certain compounds of the invention that exist in crystalline form, including the various solvates thereof, 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. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.
  • the invention comprises a novel compound of Formula I:
  • R1 is:
  • Y is N or CR", wherein R" is H or a group R5;
  • R4 is an optional substituent independently selected from halo, (C 1-6 )alkyl, trifluoromethyl, (C 1-6 )alkylthio, -OH, -C0 2 H, phenyl, cyano, -(C 1-6 )N(R a )(R b ), and (C 1-6 )alkoxy;
  • n is an integer of from 0-3;
  • R5 is an optional substituent independently selected from (Ci -6 )alkoxy, halo, and cyano; and m is an integer of from 0-3;
  • R2 is H, D, halo, or (C 1-4 )alkyl
  • R3 is a monocyclic, carbocyclic or heterocyclic ring selected from phenyl and pyridinyl; either of which may be optionally substituted with one to three substituents independently selected from D, (Ci -6 )alkyl, (Ci -6 )alkoxy, halo, trifluoromethoxy,
  • R3 is a bicyclic ring system (A):
  • ring (a) is saturated or unsaturated
  • R a -R e are independently selected from H and (Ci -6 )alkyl.
  • Y of R1 is N (R1 is optionally substituted 7,8-dihydro-1 ,6- naphthyridin-6(5H)-yl).
  • Y of R1 is CR" where R" is defined as above (R1 is optionally substituted 3,4-dihydroisoquinolin-2(1 H)-yl).
  • m is 0, 1 or 2.
  • m is an integer of from 1-3 (e.g., 1 or 2) and R5 is independently selected from (Ci -6 )alkoxy, halo, and cyano (e.g. methoxy, chloro, fluoro, bromo, and cyano).
  • n 0, 1 or 2.
  • n is an integer of from 1 -3 (e.g., 1 or 2) and R4 comprises at least one (C 1-6 )alkyl group (e.g., methyl).
  • the at least one alkyl group is in the 2-position of R1 , relative to the piperidine N.
  • n is 1 and R4 is methyl, and in some more particular such embodiments, methyl is in the 2-position of R1 , relative to the piperidine N. In some such embodiments, m is 0.
  • R1 is substituted as in the Examples herein.
  • R1 is 7,8-dihydro-1 ,6-naphthyridin-6(5H)-yl; 5-methyl-7,8- dihydro-1 ,6-naphthyridin-6(5H)-yl; 3,4-dihydroisoquinolin-2(1 H)-yl; or 1-methyl-3,4- dihydroisoquinolin-2(1 H)-yl.
  • R2 is H, methyl, chloro or fluoro. In some more particular embodiments, R2 is H or methyl.
  • R3 is selected from:
  • R3 is unsubstituted phenyl.
  • R3 is phenyl substituted in accordance with Formula I .
  • R3 is phenyl optionally substituted with one to three (e.g. 1 -2) substituents independently selected from D, (Ci -6 )alkyl, halo, trifluoromethoxy,
  • R3 is phenyl substituted with 1 -3 (e.g. 1 -2) substituents independently selected from fluoro, chloro, methoxy, methyl, propan-2-yl, cyano, dimethylamino, trifluoromethoxy, and morpholinyl.
  • substituents are independently selected from fluoro, chloro, methyl, propan-2-yl, cyano, dimethylamino, trifluoromethoxy, and morpholinyl.
  • R3 is phenyl substituted at least in the 2-position (relative to the aniline N), including for example 2,4-substituted phenyl wherein the substituents may be as defined for Formula I (and in particular embodiments, selected from fluoro, chloro, methoxy, methyl, propan-2-yl, cyano, dimethylamino, trifluoromethoxy, and morpholinyl).
  • R3 is 2-fluorophenyl optionally further substituted in accordance with Formula I .
  • R3 is 2-fluoro-4-cyanophenyl; 2-fluoro-4- chlorophenyl; or 2-fluoro-4-trifluoromethoxyphenyl.
  • R3 is unsubstituted 1 ,3-benzodioxol-5-yl.
  • R3 is 1 ,3-benzodioxol-5-yl substituted in accordance with Formula I, for example wherein the benzo ring is substituted in the 2 position (relative to the point of attachment of R3 to the aniline N) with fluoro and optionally further substituted in accordance with Formula I .
  • R1 is 7,8-dihydro-1 ,6-naphthyridin-6(5H)-yl or 5-methyl-7,8-dihydro-1 ,6-naphthyridin-6(5H)- yi;
  • R2 is H or methyl
  • R3 is 1 ,3-benzodioxol-5-yl. In other embodiments:
  • R1 is 7,8-dihydro-1 ,6-naphthyridin-6(5H)-yl or 5-methyl-7,8-dihydro-1 ,6-naphthyridin-6(5H)- yi;
  • R2 is H or methyl
  • R3 is 2-fluorophenyl further substituted in the 4-position with a substituent selected from D, (Ci -6 )alkyl, (Ci -6 )alkoxy, halo, trifluoromethoxy, trifluoromethyl, cyano, -N(R a )(R b ), morpholinyl, -S0 2 R c , and -S0 2 N(R d )(R e ) as defined for general Formula I (in particular embodiments, 4-cyano, 4-chloro, or 4-trifluoromethoxy).
  • a substituent selected from D, (Ci -6 )alkyl, (Ci -6 )alkoxy, halo, trifluoromethoxy, trifluoromethyl, cyano, -N(R a )(R b ), morpholinyl, -S0 2 R c , and -S0 2 N(R d )(R e ) as defined
  • R1 is 3,4-dihydroisoquinolin-2(1 H)-yl or 1-methyl-3,4-dihydroisoquinolin-2(1 H)-yl;
  • R2 is H or methyl
  • R3 is 1 ,3-benzodioxol-5-yl.
  • R1 is 3,4-dihydroisoquinolin-2(1 H)-yl or 1-methyl-3,4-dihydroisoquinolin-2(1 H)-yl;
  • R2 is H or methyl
  • R3 is 2-fluorophenyl further substituted in the 4-position with a substituent selected from D, (C 1-6 )alkyl, (C 1-6 )alkoxy, halo, trifluoromethoxy, trifluoromethyl, cyano, -N(R a )(R b ), morpholinyl, -S0 2 R c , and -S0 2 N(R d )(R e ) as defined for general Formula I (in particular embodiments, 4-cyano, 4-chloro, or 4-trifluoromethoxy).
  • a substituent selected from D, (C 1-6 )alkyl, (C 1-6 )alkoxy, halo, trifluoromethoxy, trifluoromethyl, cyano, -N(R a )(R b ), morpholinyl, -S0 2 R c , and -S0 2 N(R d )(R e ) as defined for general Formula I
  • a compound of the invention is a salt (including
  • the compound of Formula I is a compound represented by any one of the Examples herein below, including in free base form or salt form (including pharmaceutically acceptable salts).
  • a compound of Formula I is not:
  • the present invention is intended to include novel compositions and uses of these compounds, as well novel compositions and uses of any compounds of Formula I which may be known in the art.
  • 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 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.
  • Scheme 1 represents a general reaction scheme for preparing general compounds according to Formula I (depicted as compound 1.6).
  • a reagent 1.2 commercially available or made from commercially available starting materials using methods known to those skilled in the art
  • ethanol or equivalent solvent
  • R2 alkyl group such as an ethyl group
  • compound 1.3 is treated with base such as NaOH or equivalent and solvent such as ethanol at temperatures between 0°C to 80°C to yield intermediate 1.4.
  • reaction of intermediate 1.4 with an amine 1.5 (commercially available or made from commercially available starting materials using methods known to those skilled in the art), a coupling reagent (such as 1 H-1 ,2,3-benzotriazol-1 -yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) reagent), and a base (such as DIEA) in a solvent (such as DMF) at temperatures between 0°C to 80°C provides compounds 1.6 according to Formula I.
  • a coupling reagent such as 1 H-1 ,2,3-benzotriazol-1 -yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) reagent
  • Scheme 2 represents an alternative general reaction scheme for preparing certain compounds according to Formula I (depicted as compound 2.6).
  • Treatment of intermediate 2.1 with aniline 2.2 in a solvent (such as ethanol) at temperatures between 0 to 150 °C under standard microwave conditions yields intermediate 2.3.
  • Treatment of intermediate 2.3 with a base (such as LiOH) in a THF/MeOH mixture provides intermediate 2.4.
  • reaction of intermediate 2.4 with an amine 2.5 (commercially available or made from commercially available starting materials using methods known to those skilled in the art), a coupling reagent (such as 1 H-1 ,2,3-benzotriazol-1 -yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) reagent), and a base (such as DIEA) in a solvent (such as DMF) at temperatures between 0°C to 80°C provides compounds 2.6 according to Formula I.
  • a coupling reagent such as 1 H-1 ,2,3-benzotriazol-1 -yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) reagent
  • Scheme 3 represents a general scheme to incorporate either a chlorine or fluorine group onto the thiazole ring.
  • Treatment of amide 3.1 with BOC 2 0 in a solvent and base yields the protected amide 3.2.
  • Treatment of intermediate 3.2 with Selectfluor ® (1- chloromethyl-4-fluoro-1 ,4-diazoniabicyclo [2.2.2] octane bis-(tetrafluoroborate); Air Products & Chemicals Inc.) in a solvent yields the desired fluorinated compound 3.3.
  • Treatment of 3.2 with N-chlorosuccinimide in a solvent followed by TFA deprotection of the BOC protecting group yields the desired chloro compound 3.4.
  • Scheme 4 represents an alternative general scheme to incorporate a fluorine or chlorine group onto the thiazole ring.
  • Treatment of amide 4.1 with Selectfluor ® in a solvent such as CH 3 CN yields the desired amide 4.2.
  • Chloro analogs 4.3 can be synthesized directly from 4.1 by treatment with NCS in a solvent.
  • Scheme 5 represents two general syntheses for thioureas that are used in the synthesis of the desired compounds according to the Formula I described previously.
  • Treatment of aniline 5.1 with benzoyl isothiocyanate in a solvent such as CH 3 CN or CH 2 CI 2 yields the intermediate 5.2.
  • Treatment of intermediate 5.2 with a base in a solvent at temperatures between 0 to 100 °C yields thiourea 5.3.
  • reaction of aniline 5.1 with ammonium thiocyanate in an acid such as HCI yields the desired thiourea 5.3.
  • the compounds of the invention are TRPC3 and/or TRPC6 blockers or inhibitors, and therefore may be useful for treatment of conditions or diseases to which TRPC3 and/or TRPC6 ion channel activity contribute.
  • the biological activity of compounds of Formula I can be determined using any suitable assay for determining the activity of a candidate compound as a TRPC3 and/or TRPC6 inhibitor, as well as tissue and in vivo models.
  • the biological activity of compounds of Formula I may be demonstrated by one or more of the following tests.
  • TRPC3 and TRPC6 channel opening causes an influx of predominantly calcium and sodium cations that result in a change in the electrical potential across the cell membrane. This change in membrane potential can be monitored using membrane potential dyes.
  • HEK-293-MSRII macrophage scavenging receptor - MSRII
  • BacMam vector J. P. Condreay, S.M. Witherspoon, W.C. Clay, T.A. Kost, Proc Nat Acad Sci 96 (1999), 127-132
  • TRPC3 For TRPC3, cells are resuspended in DMEM/F12 (Dulbecco's Modified Eagle Medium, Nutrient Mixture F-12, available from Invitrogen Life Science) with 10% FBS (fetal bovine serum) to a final density of 300,000 cells/mL when incubated for 24 hours prior to experiments, or to 200,000 cells/mL when incubated for 48 hours prior to experiments.
  • FBS fetal bovine serum
  • BacMam virus expressing TRPC3 is added at 1 % v/v ratio prior to incubation.
  • TRPC6 cells are resuspended in DMEM/F12 with 10% FBS to a final density of 300,000 cells/mL.
  • TRPC6 BacMam virus plus 0.5% muscarinic receptor type 1 BacMam are transduced together.
  • Cells plus BacMam virus are plated at either 10K/well or 15K/well in 50 ⁇ _, as per above into 384-well polystrene plates. Cells are grown for 24 hours or 48 hours at 37°C plus 5% C0 2 .
  • a compound of the invention has a mean TRPC3 and/or TRPC6 IC 50 of ⁇ 10 ⁇ (e.g., ⁇ 5 ⁇ ).
  • TRPC3 and TRPC6 channel activation results in ionic current which can be measured using the whole-cell patch-clamp technique.
  • Intracellular AIF 4 is used to activate human TRPC3 or TRPC6 current in transduced HEK293F cells as previously described (R. Kraft, Biochem Biophys Res Commun 361 (2007), 230-6).
  • HEK293F cells are sub-cultured in 6-well plates at 50-70% confluency.
  • BacMam virus expressing the human TRPC3 or human TRPC6 gene is added to the well with volume to volume concentration of 4-12%. Cells are incubated overnight at 37°C and 5% C0 2 .
  • the transduced cells are detached from the well using trypsin solution (0.25% trypsin+0.1 % EDTA (ethylenediaminetetraacetic acid)) and stored in culture medium at room temperature for patch-clamp experiments within 5 hours. All current recordings are conducted at room temperature ( ⁇ 22°C). Cells are placed in a small chamber and continuously perfused with an external solution ( ⁇ 3 mL/min).
  • trypsin solution 0.25% trypsin+0.1 % EDTA (ethylenediaminetetraacetic acid)
  • EDTA ethylenediaminetetraacetic acid
  • TRPC3 or TRPC6 current desensitization of TRPC3 or TRPC6 current.
  • Cell membrane capacitance is canceled electronically and the series resistance is compensated by about 70%.
  • a ramp voltage protocol is applied every 10 seconds for as long as the experiment lasts.
  • the ramp protocol is stepped from a holding voltage of -60 mV to -80 mV for 40 ms and then depolarized to +80 mV in 400 ms, and stepped back to holding voltage after spending 40 ms at +80 mV.
  • TRPC3 or TRPC6 current gradually increases as the cell is dialyzed with the internal solution containing AIF 4 " .
  • the recording chamber is perfused with the EGTA external solution containing a test compound. At each drug concentration, sufficient time is allowed for the drug effect to reach steady-state.
  • Positive control is either 2-[4-[(2,5- difluorophenyl)methoxy]phenoxy-5-ethoxyaniline (See e.g., WO99/020598), or 4-(3,4- dihydro-2(1 H)-isoquinolinylcarbonyl)-/ ⁇ /-[4-(methyloxy)phenyl]-1 ,3-thiazol-2-amine
  • 4-(3,4-dihydro-2(1 H)- isoquinolinylcarbonyl)-/V-[4-(methyloxy)phenyl]-1 ,3-thiazol-2-amine is commercially available from Interchim Inc., San Pedro CA; Zelinsky Institute, Newark DE; Ryan Scientific, Inc., Mt. Pleasant SC; ASINEX Corp., Winston-Salem NC; and Aurora Fine Chemicals LLC and ChemDiv, Inc., both of San Diego; CA.
  • TRPC3 or TRPC6 current is measured as the average current at +80 mV.
  • the time course of current is plotted for the whole experiment.
  • Percent inhibition 100 x (1 - l D / l c ), where l D is the current amplitude measured at the end of a particular drug concentration and lc is the control current amplitude measured before drug application.
  • Zero current (background) level is set at the end of positive control compound perfusion or at the very beginning before AIF 4 " activated TRPC3 or TRPC6 current.
  • AXOPATCH 200B amplifier and pCLAMP software (version 8, Molecular Devices) are used for data acquisition. The average percent inhibition at each drug concentration is calculated first. Then, the average data are fit using a 4-parameter logistic equation (Origin 7.0 software) to calculate the IC 50 values.
  • Atrial naturietic factor A common hypertrophic response in cardiac myocytes is the increased expression of atrial naturietic factor (ANF) which can be modulated by anti-hypertrophic compounds (E. Bush, J. FielitzJ, L. Melvin, M. Martinez-Arnold, T.A. McKinsey, R. Plichta, E.N. Olson, Proc Nat Acad Sci 101 (2004), 2870-5; D.M. Eble, M. Qui, S. Waldschmidt, P.A. Lucchesi, K.L. Byron, A. M.
  • ANF mRNA or protein is measured by quantifying ANF (Nppa/ANF) messenger RNA levels by Real Time -Polymerase Chain Reaction (RT-PCR) or by high content imaging, respectively.
  • RT-PCR Real Time -Polymerase Chain Reaction
  • NRVM neonatal rat ventricular myocytes
  • NRVM are isolated from cardiac ventricles of 2-3 day old Sprague-Dawley pups and minced with scissors or a Mcllwain tissue chopper to 5 mm cubes. Cells are dissociated from the cubes by incubation in 0.1 % pancreatin in PBS (phosphate buffered saline) at 37°C for 200 minutes with agitation, changing the digestion solution every 20 minutes.
  • PBS phosphate buffered saline
  • tissue are incubated at 37°C for 120 minutes with agitation, changing the digestion solution every 20 minutes, discarding the first two isolates.
  • Cell isolates are stored on ice until all fractions have been collected.
  • the crude cell isolates are then pooled and resuspended in two aliquots of 12.5 ml. of 1.082 g/ml_ Percoll in DMEM/F12 containing 15 mM HEPES, pH 7.4. After transfer to a centrifuge tube, 12.5 ml. of 1 .062 and 1 .050 g/mL Percoll, respectively, are layered on top.
  • ANF is stimulated with phenylephrine and measured using high content imaging.
  • high content imaging assays cells plated on clear-bottom tissue culture dishes are
  • R-phenylephrine (PE) agonist Five microliters of 100 ⁇ R-phenylephrine (PE) agonist is then added to each well. Cells are incubated for 48 hours directly in a 5% C0 2 incubator at 37°C or are placed inside a humidity-controlling chamber within the incubator. Cells are fixed with 10% formalin for 15 minutes at room temperature, and fixative is washed away using 3 washes of 100 ⁇ _ PBS on a BioTek platewasher. After blocking with 50 ⁇ _ of 3% BSA (bovine serum albumin) in PBS + 0.1 % Tween-20 for 72 hours at 4°C, the cells are stained with primary antibodies against ANF (Rabbit IgG) in blocking solution.
  • BSA bovine serum albumin
  • a GE InCell 1000 fitted with a DAPI/FITC/Texas Red dichroic mirror is used to image the cells using epiflourescence, with the following settings: Hoechst channel, 360 nm/40 nm excitation filter, 460 nm/40 nm emission filter, 100 ms; Alexa 488 channel, 480 nm/40 nm excitation filter, 545 nm/50 nm excitation filter, 150 ms; Alexa 647 channel, 600 nm/50 nm excitation, 700 nm/75 nm emission, 800 ms. Five to eight fields per well are imaged and analyzed.
  • ANF protein content is defined as the number of ANF-positive spots per cell or as the number of ANF- positive spots within 4 microns of the nucleus.
  • Average responses per well are expressed as the percent of response in hypertrophic control wells (i.e. wells treated with 10 ⁇ PE and vehicle only) and plotted against the log of the concentration of compound. These dose-response curves are fitted and IC 5 o values are calculated using a four-parameter dose- response curve in Graph Pad Prism software.
  • NRVM are stimulated with PE in the presence and absence of test compounds. Isolated NRVM are plated at a seeding density of 10,000 or 25,000 cells/well in 384 or 96 well-dishes precoated with 0.2% gelatin, respectively. Cells are maintained in 50 ⁇ _ plating medium containing 3:1 mix of DMEM:M199 and 15% fetal bovine serum supplemented with 0.1 % Neutridoma, penicillin, streptomycin and 1 mM L-glutamine.
  • RT-PCR is conducted to quantify levels of Nppal ANF mRNA and the internal control Gapdh mRNA using the probes Rn00561661_m1 (Applied Biosystems) and Rn99999916 s1 (Applied Biosystems), respectively.
  • the reaction is run on a 7900HT Fast Real-Time PCR system (Applied biosystems).
  • ANF mRNA expression values are normalized to the internal control GAPDH, and calculated as percent inhibition versus PE treated controls. The values are plotted against the log concentration of the compound to obtain the IC 50 values using the four-parameter dose-response curve provided in GraphPad Prism software.
  • Compounds listed in Examples 3, 9, 1 1 and 42 herein were tested according to the above assay, and exhibited plC 50 values which were between 1-10 ⁇ (e.g., -5-10 ⁇ ).
  • the compounds of the invention are TRPC3 and/or TRPC6 inhibitors. These compounds may be particularly useful for treatment of diseases (conditions) mediated at least in part by TRPC3 and/or TRPC6, specifically by inhibition of TRPC3 and/or TRPC6 activity. In some embodiments, such diseases are selected from cardiovascular, respiratory, renal, or musculo-skeletal disease or cancer, to which TRPC3 and/or TRPC6 ion channel activity contribute.
  • a compound of the invention is used for treating a condition selected from cardiac hypertrophy, heart failure, chronic renal failure, pulmonary
  • hypertension essential hypertension, cardiac arrhythmia, asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease, pulmonary edema, focal segmental glomerulosclerosis, other kidney diseases, osteoarthritis, Duchenne or other muscular dystrophy, cystic fibrosis, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, and glioma.
  • the methods of treatment of the invention comprise administering an effective amount of a compound according to Formula I or a pharmaceutically-acceptable salt thereof to a patient in need thereof.
  • the present invention provides a method of treating diseases mediated by TRPC3 and/or TRPC6, specifically by inhibition of TRPC3 and/or TRPC6, for example those diseases mentioned herein above, which comprises administering an effective amount of a compound according to Formula I or a pharmaceutically-acceptable salt thereof to a patient (e.g. human) in need thereof.
  • the invention also provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases mediated by TRPC3 and/or TRPC6, specifically by inhibition of TRPC3 and/or TRPC6, for example those diseases mentioned herein above.
  • the invention also provides the use of a compound of Formula I, or a
  • treat in reference to a condition means at least the mitigation of a disease condition in a patient.
  • the methods of treatment for mitigation of a disease condition include the use of the compounds of the invention in any conventionally acceptable manner, for example for prevention, retardation, prophylaxis, therapy or cure of a disease.
  • Treatment may include (1 ) amelioration or prevention of the condition or one or more of the biological manifestations of the condition, (2) interference 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) alleviation of one or more of the symptoms or effects associated with the condition, or (4) slowing 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.
  • prevention refers 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.
  • an 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.
  • An 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 or “subject” 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.
  • a compound of the invention is administered intravenously, transdermally, by inhalation, or orally.
  • 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
  • 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.
  • Methods of treatment of the invention may be achieved using the compounds of the invention as a monotherapy, or in dual or multiple combination therapy with one or more therapeutic agents or therapies.
  • one or more compounds of the invention may be used in combination.
  • One or more compounds of the invention may also be used with one or more other therapeutic agents or therapies.
  • a compound of the invention may be used in combination with a loop diuretic (e.g., bumetanide, furosemide, torsemide), thiazide diuretic (e.g.,
  • chlorothiazide chlorthalidone, hydrochlorothiazide, indapamide, metolazone
  • potassium- sparing diuretic e.g., amiloride, triamterene
  • arginine vasopressin antagonist e.g., satavaptan, tolvaptan, lixivaptan, conivaptan
  • angiotensin receptor blocker e.g.,
  • angiotensin converting enzyme inhibitor e.g., captopril, enalapril, lisinopril, ramilpril, perindopril, foxinopril
  • cardiac glycoside e.g., digoxin, digitalis
  • beta adrenergic receptor antagonist e.g., carvedilol, bisoprolol, metoprolol
  • beta adrenergic receptor agonist e.g., dobutamine
  • phosphodiesterase inhibitor e.g., sildenafil
  • aldosterone receptor antagonist e.g., sprinolactone, eplerenone
  • hydralazine nitrate, renin inhibitor (e.g., aliskiren), ryanodine receptor activator, calcium sensitizer, sarcoplasmic reticulum calcium ATPase activator, and/or
  • One or more compounds from a given class, or from different classes may be used in combination with a compound of the invention. Use in combination includes combination products (e.g. dosage forms) as well as regimens. Accordingly, the compounds may be combined in a single composition, or may be in different compositions which are administered to a patient concurrently or at different times.
  • the present invention includes the use of a compound of Formula I or salt thereof as an inhibitor (or antagonist/blocker) of TRPC3 and/or TRPC6 ion channel activity (e.g. in in vitro or in vivo assays or in a subject in need thereof).
  • compounds of Formula I may be used to identify compounds which inhibit TRPC3 and/or TRPC6 ion channel activity, for example by using a compound of Formula I as a control compound in an assay or model which measures TRPC3 and/or TRPC6 ion channel activity, including any of the biological assays described herein.
  • the compounds of the invention will normally, but not necessarily, be formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and a pharmaceutically-acceptable excipient.
  • compositions of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection.
  • pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains an effective amount of a compound of the invention.
  • compositions of the invention typically contain from 1 mg to 1000 mg of a compound of the invention.
  • 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 (including, e.g., those described herein). Conversely, the pharmaceutical compositions of the invention typically contain more than one pharmaceutically-acceptable excipient. However, in certain embodiments, the pharmaceutical compositions of the invention contain one
  • pharmaceutically-acceptable excipient means a pharmaceutically acceptable material which is included in the composition for a purpose other than
  • an excipient may be involved in giving form or consistency to the pharmaceutical composition, such as forming a vehicle or carrier for a compound of the invention.
  • 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 aerosols 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 such as suppositories
  • 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 of the invention (or other compounds) 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, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, humectants, 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, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, humectants, 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, e.g., 18 th Ed.), Remington: The Science and Practice of Pharmacy (Lippincott Williams & Wilkins.
  • 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.
  • HPLC data was recorded on an Agilent 1 100 series HPLC system with C-18 reverse phase column (Eclipse XDB-C18, 4.6 x 250 mm, 5 micron) running a gradient of 1-99% MeCN/H20 (+0.1 % TFA) over 12 minutes.
  • Flash column chromatography was performed on silica gel.
  • the naming program used is ACD Name Pro 6.02.
  • N Normal and refers to the number of equivalents of reagent per liter of solution
  • Step 1 ethyl 2-r(2-chlorophenyl)aminol-1 ,3-thiazole-4-carboxylate
  • Step 2 2-r(2-chlorophenyl)aminol-1 ,3-thiazole-4-carboxylic acid
  • Step 1 ethyl 2-[(2-fluorophenyl)aminol-1 ,3-thiazole-4-carboxylate
  • Step 2 2-r(2-fluorophenyl)aminol-1 ,3-thiazole-4-carboxylic acid
  • Step 1 N-r(2,3-dihvdro-1 ,4-benzodioxin-6-ylamino)carbonothioyllbenzamide
  • Step 2 N-(2,3-dihvdro-1 ,4-benzodioxin-6-yl)thiourea
  • Step l 5-fluoro-1 ,3-benzodioxole
  • Step 2 5-fluoro-6-nitro-1 ,3-benzodioxole
  • Step 3 (6-fluoro-1 ,3-benzodioxol-5-yl)amine
  • Step 1 5-nitro-1 ,3-benzodioxole-d2
  • Step 2 1 ,3-benzodioxol-5-amine-d2
  • reaction mixture was then purified by reverse-phase HPLC (Sunfire, 30 X 100 mm, 50 mL/min, A: acetonitrile (0.1 % TFA) B: water (0.1 % TFA), A: 15 to 70% over 25 min, UV detection at 214 nm) to yield the titled compound (286 mg, 0.78mmol). MS m/e 366 [M+1 ] + .

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Abstract

composés, compositions pharmaceutiques les contenant, et leur utilisation pour traiter les affections médiées par les canaux ioniques TRPC3 et/ou TRPC6.
PCT/US2011/051761 2010-09-17 2011-09-15 Composés WO2012037349A2 (fr)

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WO2014016766A1 (fr) 2012-07-25 2014-01-30 Glenmark Pharmaceuticals S.A. Utilisation de dérivés de la guanidine comme modulateurs des canaux trpc
WO2017123759A1 (fr) * 2016-01-12 2017-07-20 Zanella Fabian Formulation de milieu cellulaire pour la stabilisation de cellules
WO2019158572A1 (fr) * 2018-02-15 2019-08-22 Boehringer Ingelheim International Gmbh Inhibiteurs de trpc6
KR20220154773A (ko) 2020-04-16 2022-11-22 데이진 화-마 가부시키가이샤 아릴 또는 헤테로아릴 유도체
US12059408B2 (en) 2020-08-13 2024-08-13 Boehringer Ingelheim International Gmbh Treatment of cognitive impairment associated with schizophrenia

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