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WO2009111680A1 - Antagonistes de trpv4 - Google Patents

Antagonistes de trpv4 Download PDF

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Publication number
WO2009111680A1
WO2009111680A1 PCT/US2009/036265 US2009036265W WO2009111680A1 WO 2009111680 A1 WO2009111680 A1 WO 2009111680A1 US 2009036265 W US2009036265 W US 2009036265W WO 2009111680 A1 WO2009111680 A1 WO 2009111680A1
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Prior art keywords
amino
carboxamide
diazabicyclo
carbonyl
sulfonyl
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English (en)
Inventor
Mui Cheung
Zhimin Du
Hilary Schenck Eidam
Ryan Michael Fox
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to diazabicyclo[2.2.1]hept-2-yl analogs, pharmaceutical compositions containing them and their use as TRPV4 antagonists.
  • 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. This increases the end diastolic pressure and pulmonary blood pressure, placing the septal barrier at risk, which serves to separate the circulatory aqueous environment and the alveolar airspaces of the lung. 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 a member of the Transient Receptor Potential (TRP) superfamily of cation channels (Plant TD, Strotmann R. 2007. Handb Exp Pharmacol 179: 189-205) and is activated by heat, demonstrating spontaneous activity at physiological temperatures (Guler et al. 2002. J Neurosci 22: 6408-6414). TRPV4 is also activated by physical cell stress (Strotmann et al. 2000. Nat Cell Biol 2: 695-702), through phospholipase A2 activation and production of arachidonic acid and epoxyeicosatrienoic acids (Vriens et al. 2004. Proc Natl Acad Sci U S A 101 : 396-401 ).
  • TRP Transient Receptor Potential
  • TRPV4 is expressed in the lung (Delany et al. 2001. Physiol. Genomics 4: 165-174) and has been shown to mediated Ca 2+ entry in isolated endothelial cells (Vriens et al. 2005. Circ Res 97: 908-15). Endothelial cells are responsible for forming the capillary vessels that mediate oxygen/carbon dioxide exchange, contributing to the septal barrier in the lung. Activation of TRPV4 channels results in contraction of endothelial cells in culture and cardiovascular collapse in vivo, at least partially due to the enhanced filtration at the septal barrier resulting in lung edema and hemorrage (Alvarez et al. 2006. Circ Res 99: 988-95).
  • TRPV4 channels have recently been implicated in urinary bladder function (Birder L, et al. 2007. J Pharmacol Exp Ther 323: 227-235.; Gevaert et al. 2007 J Clin Invest. 117: 3453-62) 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.
  • the etiology is complex but generally results from dysfunctions of bladder based myogenic and/or neurogenic mechanisms, alterations in control of bladder contractility and/or firing of bladder neurons. TRPV4 channels expressed within bladder smooth muscle cells (Birder L, et al. 2007.
  • TRPV4 expression in urothelial cells of the bladder regulate the release of transmitters, (Birder L, et al. 2007. J Pharmacol Exp Ther 323: 227-235.; Gevaert et al. 2007 J Clin Invest. 117: 3453-62) that are known to sensitize sensory afferent nerves controlling bladder activity. TRPV4 is also likely to be expressed directly on afferent nerves providing a direct neuronal stimulation of the bladder (Facer et al. 2007. BMC Neurol. 7: 11 ). These data suggest a clinically beneficialal 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 been recently implicated in a number of other physiological/pathophysiological processes in which TRPV4 antagonists are likely to provide significant clinical benefit these include various aspects of pain (Todaka et al. 2004. J Biol Chem 279: 35133-35138; Grant et al. 2007. J Physiol 578: 715-733; Alessandri-Haber et al. 2006. J Neurosci 26: 3864-3874), cardiovascular disease (Earley et al. 2005. Circ Res 97: 1270-9; Yang et al. 2006. Am. J Physiol. 290:L1267-L1276), and osteoarthritis (Muramatsu et al. 2007. J. Biol. Chem. 282: 32158-67).
  • this invention provides for diazabicyclo[2.2.1]hept-2-yl analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing them.
  • this invention provides for the use of the compounds of Formula (I) as TRPV4 antagonists.
  • this invention provides for the use of the compounds of Formula (I) for treating and preventing conditions associated with TRPV4 imbalance.
  • this invention provides for the use of the compounds of Formula (I) for the treatment or prevention of atherosclerosis, disorders related to intestinal edema, post-surgical abdominal edema, local and systemic edema, fluid retention, hypertension, inflammation, bone loss associated with immobilization and congestive heart failure, pulmonary disorders, sinusitis/rhinitis, asthma, overactive bladder, pain, 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 Il receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal anti-inflammatory drugs, bronchodilators, Leukotriene antagonist, HMG-CoA reductase inhibitors and dual non-selective ⁇ -adrenoceptor and ⁇ -
  • agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension Il receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, beta
  • the present invention is a.
  • R 1 is H, C 1-4 alkyl, CH 2 -C 3-6 cycloalkyl, or CH 2 -phenyl;
  • R 2 is independently hydrogen, or C 1-4 alkyl which may be unsubstituted or substituted with
  • R 3 is H or C 1 - S alkyl
  • R 4 is NH-Phenyl which maybe unsubstituted or substituted with C 1-3 alkyl, or halogen, or
  • R 4 is:
  • R 5 and R 6 are independently hydrogen or C 1-3 alkyl which may be unsubstituted or substituted with OH, CO 2 H, CO 2 NH 2 , or CN;
  • R 7 is a bond or C 3-6 cycloalkyl; provided when R 7 is C 3-6 cycloalkyl, Y is C(O); and further provided that when Y is C(O)O, R 7 is a bond;
  • Ar is phenyl, pyridine, thienyl, or naphthalene, all of which may be unsubstituted or substituted with one to four substituents chosen from: C r3 alkyl, CN, NO 2 , NH 2 , N 3 ,
  • X is CH 2 or C(O); and Y is SO 2 , SO 2 CH 2 , C(O)NH, C(O)O, CR 5 R 6 , C(O), or C(O)CR 5 R 6 ; or a pharmaceutically acceptable salt thereof.
  • Alkyl refers to a monovalent saturated hydrocarbon chain having the specified number of member atoms.
  • Ci -6 alkyl refers to an alkyl group having from 1 to 6 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), butyl (n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl.
  • 'C 3-6 cycloalkyl' refers to a saturated monocyclic hydrocarbon ring of 3 to 6 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl and the like.
  • 'halogen' and 'halo' include fluorine, chlorine, bromine and iodine, and fluoro, chloro, bromo, and iodo, respectively.
  • Substituted in reference to a group indicates that one or more hydrogen atom attached to a member atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term “substituted” includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is stated that a group may contain one or more substituents, one or more (as appropriate) member atoms within the group may be substituted. 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.
  • compositions according to Formula (I) may be prepared in situ during the final isolation and purification of the compound, or by separately reacting 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, 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 arangement, 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.
  • R 1 is H, C 1-4 alkyl, CH 2 -C 3-6 cycloalkyl, or CH 2 -phenyl;
  • R 2 is independently hydrogen, or Ci -4 alkyl which may be unsubstituted or substituted with
  • R 3 is H or C 1 -3 alkyl
  • R 4 is NH-Phenyl which maybe unsubstituted or substituted with d- 3 alkyl, or halogen, or
  • R 4 is:
  • R 5 and R 6 are independently hydrogen or Ci -3 alkyl which may be unsubstituted or substituted with OH, CO 2 H, CO 2 NH 2 , or CN;
  • R 7 is a bond or C 3-6 cycloalkyl; provided when R 7 is C 3-6 cycloalkyl, Y is C(O)O; and further provided that when R 7 is a bond, Y is not C(O)O;
  • Ar is phenyl, pyridine, thienyl, or naphthalene, all of which may be unsubstituted or substituted with one to four substituents chosen from: d- 3 alkyl, CN, NO 2 , NH 2 , N 3 ,
  • X is CH 2 or C(O);
  • Y is SO 2 , SO 2 CH 2 , C(O)NH, C(O)O, CR 5 R 6 , or C(O)CR 5 R 6 ; or a pharmaceutically acceptable salt thereof.
  • R 1 is Ci -4 alkyl
  • R 2 is independently hydrogen, or Ci -4 alkyl;
  • R 3 is H or Ci-3 alkyl;
  • R 4 is indole or benzothiophene; both of which may be unsubstituted or substituted with halogen, Ci -3 alkyl, or CF 3 ,
  • R 7 is a bond;
  • Ar is phenyl which may be unsubstituted or substituted with one to four substituents chosen from: C r3 alkyl, OCi- 3 alkyl, CF 3, or halogen; G is
  • X is CH 2 or C(O); and Y is SO 2 ; or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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 synthesis of the compounds of the general formula (I) and pharmaceutically acceptable derivatives and salts thereof may be accomplished as outlined below in Schemes 1-6.
  • the groups are as defined above for compounds of formula (I) unless otherwise indicated.
  • Starting materials are commercially available or are made from commercially available starting materials using methods known to those skilled in the art.
  • target molecules can be prepared from ⁇ /-Boc-(1 R,4R)-2,5-diazabicyclo[2.2.1]heptane or N- Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane respectively (Scheme 1 ).
  • the free secondary amine of the diamine core can be coupled to an appropriate carboxylic acid intermediate 2 under conditions common to the art such as EDC in the presence of a base such as ⁇ /-methylmorpholine or triethylamine, and a coupling modifier such as, but not limited to, HOOBt to provide the amide intermediate 3.
  • a base such as ⁇ /-methylmorpholine or triethylamine
  • a coupling modifier such as, but not limited to, HOOBt
  • BOC deprotection of intermediate 3 under standard conditions such as by treatment with an acid such as hydrochloric acid in 1 ,4-dioxane and methanol or TFA in dichloromethane provides the amine intermediate 4.
  • BOC-protected amide intermediate 5 Removal of the BOC protecting group 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 yielding intermediate 6. Subsequent treatment of intermediate 6 with an electrophilic reagent such as, but not limited to, 2,4-dichlorophenylsulfonyl chloride in the presence of an amine base such as triethylamine under conditions common to the art provides the compound of Formula (I). This results in a mixture of diastereomers when R1 is not H and contains substitutents such as tert-butyl. The corresponding diastereomers may be separated by H. P. L. C.
  • target molecules can also be prepared from ⁇ /-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane according to Scheme 2.
  • the free secondary amine of ⁇ /-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane 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 ⁇ /-methylmorpholine or triethylamine, and a coupling modifier such as HOBt to provide the amide intermediate 7. Subsequent CBz deprotection under standard conditions such as by treatment with Pd/C under an H 2 atmosphere in MeOH provides the amine intermediate 8.
  • intermediate 8 Treatment of intermediate 8 with an electrophilic reagent such as, but not limited to, 2,4-dichlorophenylsulfonyl chloride in the presence of an amine base such as triethylamine under conditions common to the art yielding intermediate 9. Subsequent BOC deprotection of intermediate 9 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 the intermediate 10.
  • an electrophilic reagent such as, but not limited to, 2,4-dichlorophenylsulfonyl chloride in the presence of an amine base such as triethylamine under conditions common to the art yielding intermediate 9.
  • an amine base such as triethylamine
  • BOC deprotection of intermediate 9 can be accomplished under conditions common to the art such as treatment with an acid such as hydrochloric acid in 1 ,4-dioxane and m
  • intermediate 10 Treatment of intermediate 10 with a carboxylic acid such as, but not limited to, BOC-glycine 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 BOC-protected amide intermediate 11. Removal of the BOC protecting group of intermediate 11 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 yielding intermediate 12.
  • a carboxylic acid such as, but not limited to, BOC-glycine 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
  • Removal of the BOC protecting group of intermediate 11 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 dichloromethan
  • intermediate 12 Subsequent treatment of intermediate 12 with a carboxylic acid such as, but not limited to, 1-benzothiophene-2-carboxylic acid under conditions common to the art such as EDC in the presence of a base such as ⁇ /-methylmorpholine and a coupling modifier such as HOBt provides the compound of Formula (I).
  • a carboxylic acid such as, but not limited to, 1-benzothiophene-2-carboxylic acid under conditions common to the art such as EDC in the presence of a base such as ⁇ /-methylmorpholine and a coupling modifier such as HOBt provides the compound of Formula (I).
  • Intermediate 12 can also be treated with an appropriate isocyanate in dichloromethane to afford the corresponding urea of the compound of Formula (I).
  • target molecules can be prepared from ⁇ /-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane according to Scheme 3.
  • the free secondary amine of ⁇ /-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane can be coupled to a carboxylic acid such as, but not limited to, ⁇ /-Fmoc glycine under conditions common to the art such as EDC in the presence of a base such as ⁇ /-methylmorpholine or triethylamine, and a coupling modifier such as HOBt to provide the amide intermediate 13.
  • a carboxylic acid such as, but not limited to, ⁇ /-Fmoc glycine under conditions common to the art such as EDC in the presence of a base such as ⁇ /-methylmorpholine or triethylamine, and a coupling modifier such as HOBt
  • Subsequent BOC deprotection of intermediate 13 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 dich
  • intermediate 14 Treatment of intermediate 14 with an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as ⁇ /-methylmorpholine and a coupling modifier such as HOBt provides the BOC-protected amide intermediate 15. Subsequent BOC deprotection of intermediate 15 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 the intermediate 16. Treatment of intermediate 16 with an appropriate electrophilic reagent in the presence of an amine base such as triethylamine under conditions common to the art yields intermediate 17.
  • target molecules can be prepared from ⁇ /-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane according to Scheme 4.
  • the free secondary amine of ⁇ /-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane 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 ⁇ /-methylmorpholine or triethylamine, a coupling modifier such as HOBt to provide the amide intermediate 7.
  • a coupling modifier such as HOBt
  • BOC deprotection of intermediate 7 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 the amine intermediate 18.
  • intermediate 18 Treatment of intermediate 18 with an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as ⁇ /-methylmorpholine and a coupling modifier such as HOBt provides intermediate 19. Subsequent CBz deprotection of intermediate 19 under standard conditions such as by treatment with Pd/C in the presence of ammonium formate in EtOH provides the amine intermediate 20. Treatment of the amine intermediate 20 with an electrophilic reagent in the presence of an amine base such as triethylamine under conditions common to the art yields intermediate 11.
  • Subsequent BOC deprotection of intermediate 11 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 the free amine intermediate 12.
  • Treatment of intermediate 12 with a carboxylic acid under conditions common to the art such as EDC in the presence of a base such as ⁇ /-methylmorpholine and a coupling modifier such as HOBt provides the compound of Formula (I).
  • target molecules can be prepared from ⁇ /-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane according to Scheme 5.
  • the free secondary amine of ⁇ /-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane 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 ⁇ /-methylmorpholine or triethylamine, a coupling modifier such as HOBt to provide the amide intermediate 7.
  • a coupling modifier such as HOBt
  • 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 the amine intermediate 21.
  • intermediate 21 Treatment of intermediate 21 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 BOC-protected amide intermediate 22. 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 the amine intermediate 23. Treatment of intermediate 23 with an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as ⁇ /-methylmorpholine and a coupling modifier such as HOBt provides the BOC-protected amide intermediate 24.
  • an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as ⁇ /-methylmorpholine and a coupling modifier such as HOBt provides the BOC-protected amide intermediate 24.
  • target molecules can be prepared from ⁇ /-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane (Scheme 6).
  • the free secondary amine of ⁇ /-Boc-(1 S,4S)-2,5-diazabicyclo[2.2.1]heptane 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 ⁇ /-methylmorpholine or triethylamine, a coupling modifier such as HOBt to provide the amide intermediate 25.
  • a coupling modifier such as HOBt
  • intermediate 26 Treatment of intermediate 26 with an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as ⁇ /-methylmorpholine and a coupling modifier such as HOBt provides the amide intermediate 3A. 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 4A.
  • an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base such as ⁇ /-methylmorpholine and a coupling modifier such as HOBt provides the amide intermediate 3A.
  • 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 4A.
  • intermediate 4A Treatment of intermediate 4A with an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base and a coupling modifier or treatment with an aliphatic bromide under conditions common to the art such as diisopropylethylamine in acetonitrile provides intermediate 27. 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 the amine intermediate 28. Treatment of the amine with an appropriate electrophilic reagent such as appropriately substituted sulfonyl chloride in the presence of an amine base such as triethylamine under conditions common to the art provides the compound of Formula (I).
  • an appropriate carboxylic acid under conditions common to the art such as EDC in the presence of a base and a coupling modifier or treatment with an aliphatic bromide under conditions common to the art such as diisoprop
  • Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography, H. P. L. C. or SCF of a stereoisomeric mixture.
  • Pure stereoisomer of the agent may also be prepared from the corresponding optically pure intermediate or by resolution, such as H. P. L. C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
  • the compounds according to Formula I are TRPV4 antagonists, and are useful in the treatment or prevention of atherosclerosis, disorders related to intestinal edema, post-surgical abdominal edema, local and systemic edema, fluid retention, hypertension, inflammation, bone loss associated with immobilization and congestive heart failure, pulmonary disorders, sinusitis/rhinitis, asthma, overactive bladder, pain, 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.
  • the biological activity of the compounds of Formula (I) are demonstrated by the following tests. Liqand-qated assay:
  • 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 (InvitrogenTM).
  • 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 Il (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 5OuL in a 384 well poly-D lysine coated plate. Cells are incubated for 24 to 48 hours at 37 degrees and 5% CO 2 . Media is then removed from the cells and replaced with 2OuL of dye loading buffer: HBSS, 50OuM Brilliant Black (Molecular Devices), 2uM Fluo-4 (Molecular Devices). Dye loaded plates are then incubated in the dark at room temperature for 1-1.5 hours.
  • 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 (InvitrogenTM).
  • Dye loaded cells are initially exposed to test compound to verify a lack of agonist activity. Cells are subsequently activated by addition of a hypotonic buffer and inhibition of the hypotonicity-induced activation is recorded.
  • 50 uL of HEK293 cells stably transformed with human TRPV4 are plated at 3OK cells per well in 384 well poly-D-lysine coated plates.
  • the media is removed and replaced with 50 uL of dye loading buffer (Fluo-4 from Invitrogen diluted 1 :500 in DMEM/F12) then the cells are incubated for 1.5 hours at room temperature in the dark.
  • Dye is then removed and replaced with 50 uL of 310mOsm isotonic buffer (130 mM NaCI, 2.5 mM KCI, 1 mg/mL D-glucose, 10 mM Hepes, 1.2 mM MgCI 2 , 1.5 mM CaCI 2 , 0.25% DMSO, pH 7.4) and incubated in dark at room temp for an additional hour.
  • Test compounds are diluted in isotonic buffer to a final DMSO concentration of 0.25%.
  • 25 uL of diluted compound is added 30 seconds after start.
  • 25 uL of 110-115 mOsm hypotonic buffer 2.5 mM KCI, 1 mg/mL D-glucose, 10 mM Hepes, 1.2 mM MgCI 2 , 1.5 mM CaCI 2 , 0.25% DMSO, 80 mM mannitol, pH 7.4 is added.
  • Signal is recorded for a total of 20 minutes with reads every 4.5 seconds.
  • the compounds of the invention are TRPV4 antagonists, and are useful in the treatment or prevention of atherosclerosis, disorders related to intestinal edema, postsurgical abdominal edema, local and systemic edema, fluid retention, hypertension, inflammation, bone loss associated with immobilization and congestive heart failure, pulmonary disorders, sinusitis/rhinitis, asthma, overactive bladder, pain, 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.
  • treatment of a condition includes prevention of the condition.
  • prevention is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to 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. consider the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.
  • patient refers to a human or other animal.
  • the compounds of the invention may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation.
  • Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion.
  • Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.
  • Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages.
  • Topical administration includes application to the skin as well as intraocular, otic, intravaginal, and intranasal administration.
  • the compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens including the duration such regimens are 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 administration chosen. Typical dosages for oral administration range from 1 mg to 1000 mg per person per dose.
  • a prodrug of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo.
  • Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (C) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome or overcome a side effect or other difficulty encountered with the compound.
  • Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
  • the compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in another aspect the invention is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically-acceptable excipient.
  • compositions of the invention may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups.
  • the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of the invention.
  • the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg.
  • compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. For example, in certain embodiments the pharmaceutical compositions of the invention contain two compounds of the invention. In addition, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds.
  • pharmaceutically-acceptable excipient means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
  • each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.
  • 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, chelating agents
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
  • the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler.
  • Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate.
  • the oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g.
  • 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 endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotension Il receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, beta blocker, aldosterone antagonists, iontropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal anti-inflammatory drugs, bronchodilators, Leukotriene antagonist, HMG-CoA reductase inhibitors and dual non-selective ⁇ -adrenoceptor and ⁇ -
  • ACE angiotensin converting enzyme
  • the naming program used is ACD Name Pro 6.02.
  • DIEA ⁇ /, ⁇ /-diisopropylethylamine
  • DCM dichloromethane
  • DMSO dimethylsulfoxide
  • EDCI 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide
  • Fmoc (9-fluorenylmethoxycarbonyl); HOBT (1-hydroxybenzotriazole);
  • HOOBt Hydrochloro-3,4-dihydro-4-oxo-1 ,2,3-benzotriazine
  • NMM ⁇ /-methyl morpholine
  • TFA trifluoroacetic acid
  • Example 65 ⁇ /-K1 S)A -ffl1 S.4S)-5- ⁇ r(2.4-dichlorophenyl)sulfonvnamino>acetvn-2.5- diazabicvclor2.2.nhept-2-vncarbonyl>-3-methylbutyl)-1-methyl-1H-indole-2- carboxamide
  • Triethylamine (4.36 mL, 31.29 mmol) and 2,4-dichlorobenzenesulfonyl chloride (2.81 g, 1 1.47 mmol) were added to a solution of 9H-fluoren-9-ylmethyl ((1 S)-1- ⁇ [(1 S,4S)-5- (aminoacetyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl ⁇ -3-methylbutyl)carbamate (5.5 g,
  • Ethanol 120 mL was added to a 250 ml flask followed by 1 ,1-dimethylethyl [(1 S)-2,2- dimethyl-1-( ⁇ (1 S,4S)-5-[( ⁇ [(phenylmethyl)oxy]carbonyl ⁇ amino)acetyl]-2,5- diazabicyclo[2.2.1]hept-2-yl ⁇ carbonyl)propyl]carbamate (6.28 g, 12.5 mmol), ammonium formate (3.94 g, 62.5 mmol) and 10% Pd/C (1.330 g). The reaction mixture was stirred overnight, then filtered over celite eluting with ethanol.
  • the compounds in Table 4 were prepared by a method similar to the one described for the preparation of ⁇ /-[(1 S)-1-( ⁇ (1 S,4S)-5-[( ⁇ [5-chloro-2-(methyloxy)phenyl]sulfonyl ⁇ amino)acetyl]- 2,5-diazabicyclo[2.2.1]hept-2-yl ⁇ carbonyl)-2,2-dimethylpropyl]-1 /-/-indole-2-carboxamide or Scheme 5.
  • these analogous examples may involve variations in synthetic procedure.
  • the reaction mixture was allowed to stir for 2 h, then diluted with CH 2 CI 2 and washed with saturated NaHCO 3 , 1 N HCI, saturated NaHCO 3 .
  • the organic layer was passed through a phase separator and concentrated.
  • the residue was dissolved in DCM (20 mL) and TFA (20 mL) was added.
  • the reaction was stirred at room temperature for 30 minutes before concentrating.
  • the reaction mixture was added to a SPE R60530B-20X (5 g column), washed with MeOH (10 mL) and NH 3 /MeOH (10 mL) and concentrated to afford 5 g of the product: LCMS (m/z): 356.2 (M+H).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L’invention concerne les analogues du diazabicyclo[2.2.1]hept-2-yle, des compositions pharmaceutiques les contenant et leur utilisation en tant qu’antagonistes de TRPV4.
PCT/US2009/036265 2008-03-07 2009-03-06 Antagonistes de trpv4 Ceased WO2009111680A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011091407A1 (fr) * 2010-01-25 2011-07-28 Glaxosmithkline Llp Antagonistes de trpv4
WO2014089013A1 (fr) 2012-12-03 2014-06-12 Indiana University Research And Technology Corporation Utilisation d'antagonistes de trpv4 pour l'amélioration de l'hydrocéphalie, et matériaux et procédés afférents
US9340500B2 (en) 2011-04-20 2016-05-17 Shionogi & Co., Ltd. Aromatic heterocyclic derivative having TRPV4-inhibiting activity
US9708338B2 (en) 2013-09-25 2017-07-18 Shionogi & Co., Ltd. Aromatic heterocyclylamine derivative having TRPV4-inhibiting activity
WO2018156401A1 (fr) 2017-02-24 2018-08-30 Indiana University Research And Technology Corporation Procédés d'inhibition de la kinase 1 induite par les glucocorticoïdes sériques (sgk1) en tant que traitement des maladies de l'équilibre salin et hydrique
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
CN114478359A (zh) * 2022-03-17 2022-05-13 河南大学 氨基甲酸酯类trpv1拮抗/faah抑制双靶点药物及其制备方法和应用

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US5091383A (en) * 1985-09-18 1992-02-25 Pfizer Inc. Substituted bridged diazabicycloalkyl quinolone carboxylic acids
US20070259856A1 (en) * 2004-09-07 2007-11-08 Sanjay Kumar Method for Activating Trpv4 Channel Receptors by Agonists

Patent Citations (2)

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US5091383A (en) * 1985-09-18 1992-02-25 Pfizer Inc. Substituted bridged diazabicycloalkyl quinolone carboxylic acids
US20070259856A1 (en) * 2004-09-07 2007-11-08 Sanjay Kumar Method for Activating Trpv4 Channel Receptors by Agonists

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011091407A1 (fr) * 2010-01-25 2011-07-28 Glaxosmithkline Llp Antagonistes de trpv4
US9340500B2 (en) 2011-04-20 2016-05-17 Shionogi & Co., Ltd. Aromatic heterocyclic derivative having TRPV4-inhibiting activity
WO2014089013A1 (fr) 2012-12-03 2014-06-12 Indiana University Research And Technology Corporation Utilisation d'antagonistes de trpv4 pour l'amélioration de l'hydrocéphalie, et matériaux et procédés afférents
US9708338B2 (en) 2013-09-25 2017-07-18 Shionogi & Co., Ltd. Aromatic heterocyclylamine derivative having TRPV4-inhibiting activity
WO2018156401A1 (fr) 2017-02-24 2018-08-30 Indiana University Research And Technology Corporation Procédés d'inhibition de la kinase 1 induite par les glucocorticoïdes sériques (sgk1) en tant que traitement des maladies de l'équilibre salin et hydrique
US11701358B2 (en) 2017-02-24 2023-07-18 Indiana University Research And Technology Corporation Methods of inhibiting serum glucocorticoid induced kinase 1 (SGKI) as a treatment for salt and water balance diseases
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
CN114478359A (zh) * 2022-03-17 2022-05-13 河南大学 氨基甲酸酯类trpv1拮抗/faah抑制双靶点药物及其制备方法和应用
CN114478359B (zh) * 2022-03-17 2023-09-29 河南大学 氨基甲酸酯类trpv1拮抗/faah抑制双靶点药物及其制备方法和应用

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