WO2014008458A2 - N-substituted benzamides and methods of use thereof - Google Patents

N-substituted benzamides and methods of use thereof Download PDF

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Publication number
WO2014008458A2
WO2014008458A2 PCT/US2013/049423 US2013049423W WO2014008458A2 WO 2014008458 A2 WO2014008458 A2 WO 2014008458A2 US 2013049423 W US2013049423 W US 2013049423W WO 2014008458 A2 WO2014008458 A2 WO 2014008458A2
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WIPO (PCT)
Prior art keywords
compound
alkyl
group
pain
formula
Prior art date
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PCT/US2013/049423
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English (en)
French (fr)
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WO2014008458A3 (en
Inventor
Christoph Martin Dehnhardt
Sultan Chowdhury
Thilo FOCKEN
Michael Edward Grimwood
Ivan William Hemeon
Brian Safina
Daniel P. Sutherlin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xenon Pharmaceuticals Inc
Genentech Inc
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Xenon Pharmaceuticals Inc
Genentech Inc
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Priority to EP13812904.4A priority Critical patent/EP2870138B1/en
Priority to US14/413,218 priority patent/US10071957B2/en
Priority to HK15110498.9A priority patent/HK1209736B/xx
Priority to MX2015000164A priority patent/MX2015000164A/es
Priority to BR112015000187A priority patent/BR112015000187A2/pt
Priority to CN201380046120.9A priority patent/CN104797555B/zh
Priority to CA2878478A priority patent/CA2878478A1/en
Priority to JP2015520701A priority patent/JP6309519B2/ja
Application filed by Xenon Pharmaceuticals Inc, Genentech Inc filed Critical Xenon Pharmaceuticals Inc
Priority to RU2015103913A priority patent/RU2015103913A/ru
Priority to KR1020157002962A priority patent/KR101663436B1/ko
Publication of WO2014008458A2 publication Critical patent/WO2014008458A2/en
Publication of WO2014008458A3 publication Critical patent/WO2014008458A3/en
Anticipated expiration legal-status Critical
Priority to US16/057,693 priority patent/US20180346416A1/en
Ceased legal-status Critical Current

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    • C07C307/04—Diamides of sulfuric acids
    • C07C307/06—Diamides of sulfuric acids having nitrogen atoms of the sulfamide groups bound to acyclic carbon atoms
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • X 1 and X 2 are each independently selected from the group consisting of absent, -0-, -S-,-S(0)-, -S(0) 2 - -N(H)-, and -N(R x1 )- wherein R xl is C 1-8 alkyl, C 1-8 acyl or -S(0) 2 (C 1-g alkyl), and wherein if the subscript m is 0 then one of X 1 or X 2 is absent;
  • each alpha-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(0)(OH) 2 , -P(0)(0(Ci.6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).
  • Metabolite products typically are identified by preparing a radiolabeled (e.g., 14 C or 3 H) isotope of a compound of the invention, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples.
  • a detectable dose e.g., greater than about 0.5 mg/kg
  • an animal such as rat, mouse, guinea pig, monkey, or to man
  • sufficient time for metabolism to occur typically about 30 seconds to 30 hours
  • isolating its conversion products from the urine, blood or other biological samples typically isolating its conversion products from the urine, blood or other biological samples.
  • a ring represents a 6-10 membered aryl or a 5-10 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S;
  • D 1 is C(R D1 ) and D 3 is C(R D3 ).
  • D is CH or N.
  • one or more of R , R and R is each independently selected from the group consisting of F, CI, -CN, Ci -g alkyl, Ci.g haloalkyl, Q-g alkoxy, C 3 .8 cycloalkyl, -i heterocycloalkyl, phenyl and 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with from 1 to 3 substituents selected from F, CI, -CN, C alkyl, C haloalkyl and CM alkoxy; and the remainder of R D2 , R D3 and R 04 are each H.
  • a compound of formula I is a compound of formula Ie:
  • D 1 is CH or N; and E is C(R A ) or N.
  • R N is hydrogen, Cj alkyl or C ]Jt haloalkyl
  • D 3 is N or C(R D3 );
  • R D1 , R D2 , R D3 and R m are independently selected from the group consisting of H, F, CI, -CN, C 2-8 alkenyl, C 3-8 cycloalkyl, C 2-7 heterocycloalkyl, and 5-6 membered heteroarylcomprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with from 1 to 3 substituents selected from F, CI, Br, I, -CN, CM alkyl, C M haloalkyl and C ⁇ alkoxy and said C 2-7 heterocycloalkyl is further optionally substituted with from 1 to 3 substituents selected from F and -OH.
  • Compound of formula (XIV) can be made from the benzoic acid compounds of formula ( ⁇ ) using protecting methodology as described in references such as 'Greene's Protective Groups in Organic Synthesis'.
  • Compounds of formula (XXIX) can be made according to step (xxix) in Scheme 3 by activation of the benzoic acid group of formula (XXX) with reagents such as oxalyl chloride, carbonyl di-imidazole (CDI), propylphosphonic anhydride, a uronium based amide coupling agent or a carbodiimide reagent followed by displacement with a sulfonamide of formula (HI) in the presence of a nucleophilic base such as DBU, N, N-diisopropylethylamine or triethylamine in a suitable solvent such a tetrahydrofuran or
  • reagents such as oxalyl chloride, carbonyl di-imidazole (CDI), propylphosphonic anhydride, a uronium based amide coupling agent or a carbodiimide reagent followed by displacement with a sulfonamide of formula (HI
  • the invention provides for pharmaceutical compositions (or medicaments) comprising a compound of Formula I or an embodiment thereof, and its stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts, or prodrugs thereof) and a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention provides for preparing compositions (or medicaments) comprising compounds of the invention.
  • the invention provides for administering compounds of Formula I or its embodiments and compositions comprising compounds of Formula I or an embodiment thereof to a patient (e.g., a human patient) in need thereof.
  • the compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • Formulations for rectal administration can be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • certain embodiments of the invention provide for a compound of formula I (or an embodiment thereof) to traverse the blood-brain barrier.
  • Certain neurodegenerative diseases are associated with an increase in permeability of the blood-brain barrier, such that a compound of formula I (or an embodiment thereof) can be readily introduced to the brain.
  • the blood-brain barrier remains intact, several art-known approaches exist for transporting molecules across it, including, but not limited to, physical methods, lipid-based methods, and receptor and channel-based methods.
  • Physical methods of transporting a compound of formula I (or an embodiment thereof) across the blood-brain barrier include, but are not limited to, circumventing the blood- brain barrier entirely, or by creating openings in the blood-brain barrier.
  • eiythamatosis granulomatous disease, olivo-ponto-cerebellar atrophy, spinocerebellar ataxia, episodic ataxia, myokymia, progressive pallidal atrophy, progressive supranuclear palsy and spasticity, traumatic brain injury, cerebral oedema, hydrocephalus injury, spinal cord injury, anorexia nervosa, bulimia, Prader-Willi syndrome, obesity, optic neuritis, cataract, retinal haemorrhage, ischaemic retinopathy, retinitis pigmentosa, acute and chronic glaucoma, macular degeneration, retinal artery occlusion, Chorea, Huntington's chorea, cerebral edema, proctitis, post-herpetic neuralgia, eudynia, heat sensitivity, sarcoidosis, irritable bowel syndrome, Tourette syndrome, Lesch-Nyhan Syndrome, Brugado
  • the compounds of the invention can also be useful for treating pruritus.
  • the rationale for treating itch with inhibitors of voltage-gated sodium channels, especially NaV1.7, is as follows:
  • One embodiment of this embodiment is wherein the disease or condition is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, childbirth pain, labor pain, neurogenic bladder, ulcerative colitis, chronic pain, persistent pain, peripherally mediated pain, centrally mediated pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, and combinations thereof.
  • Another embodiment of the invention is the method of treating pruritus in a mammal, preferably a human, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of an embodiment of a compound of the invention, as set forth above, as a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, as set forth above, as a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient.
  • the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number.
  • isotopically-labeled (i.e., radiolabelled) compounds of formula (I) are considered to be within the scope of this invention.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • FRET based voltage sensors are used to measure the ability of a test compound to directly block Na influx.
  • HTS systems include the VIPRTM II FRET system (Life Technologies, or Aurora Biosciences Corporation, San Diego, CA, a division of Vertex Pharmaceuticals, Inc.) which may be used in conjunction with FRET dyes, also available from Aurora Biosciences.
  • This assay measures sub-second responses to voltage changes. There is no requirement for a modifier of channel function.
  • the assay measures depolarization and hyperpolarizations, and provides ratiometric outputs for quantification.
  • a somewhat less expensive MTS version of this assay employs the
  • alpha-adrenergics e.g., doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, and 4-amino-6,7-dimethoxy-2-(5- methane
  • cyclopropylboronic acid (13.4 g, 156 mmol), tricyclohexylphosphine tetrafluoroborate (6.92 g, 18.8 mmol), and palladium(II) acetate trimer (2.11 g, 9.4 mmol).
  • the reaction vessel was evacuated and released to an argon atmosphere twice, then heated to reflux under an argon atmosphere for 2 h.
  • the reaction mixture was cooled to ambient temperature, filtered through a pad of diatomaceous earth and rinsed with ethyl acetate (400 mL).

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HK15110498.9A HK1209736B (en) 2012-07-06 2013-07-05 N-substituted benzamides and methods of use thereof
MX2015000164A MX2015000164A (es) 2012-07-06 2013-07-05 Benzamidas n-sustituidas y metodos para usarlas.
BR112015000187A BR112015000187A2 (pt) 2012-07-06 2013-07-05 benzamidas substituídas com n e métodos de uso das mesmas
CN201380046120.9A CN104797555B (zh) 2012-07-06 2013-07-05 N‑取代的苯甲酰胺及其使用方法
JP2015520701A JP6309519B2 (ja) 2012-07-06 2013-07-05 Ｎ置換ベンズアミド及びその使用方法
RU2015103913A RU2015103913A (ru) 2012-07-06 2013-07-05 N-замещенные бензамиды и способы их применение
EP13812904.4A EP2870138B1 (en) 2012-07-06 2013-07-05 N-substituted benzamides and methods of use thereof
US14/413,218 US10071957B2 (en) 2012-07-06 2013-07-05 N-substituted benzamides and methods of use thereof
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US20150322002A1 (en) 2015-11-12
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WO2014008458A3 (en) 2014-04-17
CN104797555A (zh) 2015-07-22
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US20180346416A1 (en) 2018-12-06
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