EP2234983A1 - 4-imidazolidinones comme inhibiteurs du canal potassique kv1.5 - Google Patents

4-imidazolidinones comme inhibiteurs du canal potassique kv1.5

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Publication number
EP2234983A1
EP2234983A1 EP08861246A EP08861246A EP2234983A1 EP 2234983 A1 EP2234983 A1 EP 2234983A1 EP 08861246 A EP08861246 A EP 08861246A EP 08861246 A EP08861246 A EP 08861246A EP 2234983 A1 EP2234983 A1 EP 2234983A1
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EP
European Patent Office
Prior art keywords
alkyl
compound
ethyl
methoxyphenyl
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP08861246A
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German (de)
English (en)
Inventor
Benjamin E. Blass
John M. Janusz
James M. Ii Ridgeway
Shengde Wu
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Wyeth LLC
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Wyeth LLC
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Publication date
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Publication of EP2234983A1 publication Critical patent/EP2234983A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics

Definitions

  • the present invention relates to compounds that are effective as Kv1.5 potassium channel inhibitors
  • the present invention also relates to compositions comprising 5 certain Kv1 5 potassium channel inhibitors, and to methods for treating cardiac arrhythmia
  • Atrial fibrillation is a frequently encountered cardiac arrhythmia in the clinical setting It affects nearly 3 million people in the United States and its prevalence
  • Certain atrial-selective antiarrhythmic agents offer one possibility of increased therapeutic efficacy and safety by minimizing cardiac proarrhythmia inherent in conventional antiarrhythmic therapies
  • Kv1 5 potassium channel include: Brendel, J , et al , Curr Med Chem. 2003, 1 , 273-
  • the present invention provides compounds of Formula (Ia) or (Ib):
  • Ar 1 is a C 6 -C 10 aryl ring or a 5-14 membered heteroaryl ring, each of which is optionally substituted with 1 , 2, 3 or 4 substituents independently selected from Cr 6 alkyl, F, Cl, Br, I, C 3 - 6 cycloalkyl C,- 6 alkoxy, OH, NH 2 , NH(C 1 ⁇ alkyl), N(C 1 e alkyl) 2 , NO 2 , C 1 3 haloalkyl, SH, SCL 6 alkyl and CN,
  • Ar 2 is a C 6 -C 10 aryl ring or a 5-14 membered heteroaryl ring, each of which is optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C r6 alkyl, F, Cl, Br, I, C 3 - 6 cycloalkyl, C r6 alkoxy, OH, NH 2 , NH(C 1 6 alkyl), N(C 1 6 alkyl) 2 , NO 2 , C 1 3 haloalkyl, SH, -SC 1 6 alkyl and CN,
  • each X is independently -CR 3 R 4 -,
  • each L is independently -CR 5 R 6 -,
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from H, halogen and C 1-6 alkyl optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C 1 - B alkyl, F 1 CI, Br, I, C r ⁇ alkoxy, OH, NH 2 , NO 2 , C 1 3 haloalkyl, SH, S-C 1 6 alkyl and CN;
  • R 7 and R 8 are each independently selected from H and C r6 alkyl optionally substituted with 1 , 2, 3 or 4 substituents independently selected from F, Cl, Br, I, C r6 alkoxy, OH, NH 2 , NO 2 , C 1 3 haloalkyl, SH, -SCL 6 alkyl, CN, C 3 . 10 cycloalkyl, a 3-10 membered heterocyclyl ring, C 6 -, C 10 -aryl ring, and a 5-10 membered heteroaryl ring;
  • Y is a countenon
  • n 1 , 2, 3, 4 or 5
  • compositions comprising an effective amount of one or more compounds of Formula (Ia) or (Ib) and one or more excipients.
  • the present invention also provides a method for treating or preventing cardiac arrhythmias, for example atrial arrhythmia, including but not limited to, atrial fibrillation and atrial flutter, said method comprising administering to a subject an effective amount of a compound of Formula (Ia) or (Ib) according to the present invention.
  • the present invention also provides a method for treating or preventing cardiac arrhythmias, for example atrial arrhythmia, including but not limited to, atrial fibrillation and atrial flutter, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds of Formula (Ia) or (Ib) according to the present invention and one or more excipients.
  • the present invention also provides methods for treating or preventing diseases or conditions associated with cardiac arrhythmias, including but not limited to, thromboembolism, stroke, and heart failure
  • the methods comprise administering to a subject an effective amount of a compound of Formula (Ia) or (Ib) according to the present invention.
  • the present invention further provides methods for treating or preventing diseases or conditions associated with cardiac arrhythmias, including but not limited to, thromboembolism, stroke, and heart failure, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds of Formula (Ia) or (Ib) according to the present invention and one or more excipients
  • the present invention also provides a method for inducing cardioversion, said method comprising administering to a subject an effective amount of a compound Formula (Ia) or (Ib) according to the present invention.
  • the present invention also provides a method for inhibiting Kv1 5 potassium channel in a subject comprising administering a therapeutically effective amount of a compound of Formula (Ia) or (Ib) to the subject
  • the present invention also provides a method for treating or preventing a disorder associated with inhibition of Kv1 5 potassium channel in a subject comprising administering a therapeutically effective amount of a compound of Formula (Ia) or (Ib) to the subject
  • these compounds are useful in treating atrial arrhythmia, thromboembolism, stroke or cardiac failure
  • Kv1 5 potassium channel inhibitors of the present invention are capable of treating and preventing arrhythmia in the atrial portion of the human heart or in the heart of certain animals It has been discovered that functional Kv1 5 potassium channels are found in human atrial tissue but not in human ventricular myocytes Without wishing to be limited by theory, it is believed the inhibition of the Kv1 5 voltage-gated Shaker-like potassium (K * ) ion channel can ameliorate, abate, or otherwise cause to be controlled, atrial fibrillation and flutter without prolonging ventricular repolarization
  • compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present invention also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps
  • alkyl whether used alone or as part of a substituent group refers to a saturated straight and branched carbon chain having 1 to 20 carbon atoms or any number within this range, for example, 1 to 6 carbon atoms or 1 to 4 carbon atoms. Designated numbers of carbon atoms (e.g.
  • C 1 6 shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent
  • alkyl groups include methyl, ethyl, n-propyl, jso-propyl, n-butyl, sec-butyl, (so-butyl, fert-butyl, and the like Where so indicated, alkyl groups can be optionally substituted.
  • substituent groups with multiple alkyl groups such as N(C 1 . 6 alkyl) 2 , the alkyl groups may be the same or different
  • alkoxy refers to groups of formula -Oalkyl. Designated numbers of carbon atoms (e.g. -OCi 6 ) shall refer independently to the number of carbon atoms in the alkoxy group Non-limiting examples of alkyl groups include methoxy, ethoxy, n-propoxy, /so-propoxy, n-butoxy, sec-butoxy, /so-butoxy, ferf-butoxy, and the like. Where so indicated, alkoxy groups can be optionally substituted
  • alkenyl and alkynyl groups refer to straight and branched carbon chains having 2 or more carbon atoms, preferably 2 to 20, having at least one carbon-carbon double bond (“alkenyl”) or at least one carbon-carbon triple bond (“alkynyl”). Where so indicated, alkenyl and alkynyl groups can be optionally substituted
  • alkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also 2- methylethenyl), isopropenyl (also 2-methylethen-2-yl), buten-4-yl, and the like.
  • alkynyl groups include ethynyl, prop-2-ynyl (also propargyl), propyn-1-yl, and 2-methyl-hex-4-yn-1-yl
  • cycloalkyl refers to a non-aromatic hydrocarbon ring including cyclized alkyl, alkenyl, or alkynyl groups, e.g., having from 3 to 14 ring carbon atoms, for example, from 3 to 7 or 3 to 6 ring carbon atoms, and optionally containing one or more (e.g , 1 , 2, or 3) double or triple bonds
  • Cycloalkyl groups can be monocyclic (e g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure Where so indicated, cycloalkyl rings can be optionally substituted
  • Nonlimiting examples of cycloalkyl groups include: cyclopropyl, cycloprop
  • Haloalkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms.
  • halogen refers to F, Cl, Br and I
  • Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e g , -CF 3 , -CF 2 CF 3 )
  • the halogens can be the same (e g , CHF 2 , -CF 3 ) or different (e g , CF 2 CI) Where so indicated, haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen.
  • haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups
  • aryl wherein used alone or as part of another group, is defined herein as an aromatic monocyclic ring of 6 carbons or an aromatic polycyclic ring of from 10 to 14 carbons
  • Aryl groups include but are not limited to, for example, phenyl or naphthyl (e.g., naphthylen-1-yl or naphthylen-2-yl) Where so indicated, aryl groups may be optionally substituted with one or more substituents
  • Aryl groups also include, but are not limited to for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e g , bicyclo[4.2 0]octa-1 ,3,5- trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings
  • heterocyclic refers herein as groups having one or more rings (e g , 1 , 2 or 3 rings) and having from 3 to 20 atoms (e g , 3 to 10 atoms, 3 to 6 atoms) wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S), and wherein the ring that includes the heteroatom is non-aromatic
  • the non- heteroatom bearing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl).
  • heterocyclyl groups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S)
  • N nitrogen
  • O oxygen
  • S sulfur
  • One or more N or S atoms in a heterocyclyl group can be oxidized (e g , N ⁇ O " , S(O), SO 2 ) Where so indicated, heterocyclyl groups can be optionally substituted
  • Non-limiting examples of monocyclic heterocyclyl groups include, for example diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydro-1H-azep ⁇ nyl, 2,3-dihydro-1H- ⁇ ndole, and 1 ,2,3,4-te
  • Non-limiting examples of heterocyclic groups having 2 or more rings include, for example. hexahydro-1H-pyrrol ⁇ z ⁇ nyl, 3a,4,5,6,7,7a-hexahydro-1H- benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1 ,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1H- cyclooctalbjpyrrolyl.
  • heteroaryl whether used alone or as part of another group, is defined herein as a single or fused ring system having from 5 to 20 atoms (e.g., 5 to 10 atoms, 5 to 6 atoms) wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic.
  • the non-heteroatom bearing ring may be a carbocycle (e g , ⁇ J-Dihydro-SH-cyclopentapy ⁇ midine) or aryl (e g , benzofuranyl, benzothiophenyl, indolyl).
  • exemplary heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S).
  • N nitrogen
  • O oxygen
  • S sulfur
  • One or more N or S atoms in a heteroaryl group can be oxidized (e g , N ⁇ O , S(O), SO 2 ).
  • heteroaryl groups can be substituted
  • monocyclic heteroaryl rings include, for example 1 ,2,3,4-tetrazolyl, [1 ,2,3]tr ⁇ azolyl, [1 ,2,4]tr ⁇ azolyl, triazinyl, thiazolyl, 1H- imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, and pyridinyl.
  • heteroaryl rings containing 2 or more fused rings include 1 benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztnazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 5H-pyrrolo[3,2-c/]pyrimidinyl, 7H-pyrrolo[2,3- d]pyr ⁇ m ⁇ d ⁇ nyl, pyr ⁇ do[2,3-d]pyr ⁇ m ⁇ d ⁇ nyl, 2-phenylbenzo[d]thiazolyl, 1H- ⁇ ndolyl, 4,5,6,7- tetrahydro-1-H- ⁇ ndolyl, quinoxalinyl, 5-methylqu ⁇ noxal ⁇ nyl, quinazolinyl, quinolinyl, and isoquinolinyl
  • heteroaryl group as described above is C 1 -C 5 heteroaryl, which is a monocyclic aromatic ring having 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), and sulfur (S).
  • C 1 -C 5 heteroaryl examples include, but are not limited to for example, triazinyl, thiazol-2-yl, th ⁇ azol-4-yl, ⁇ m ⁇ dazol-1-yl, 1H- ⁇ m ⁇ dazol-2-yl, 1H- ⁇ m ⁇ dazol-4-yl, ⁇ soxazol ⁇ n-5-yl, furan-2-yl, furan-3-yl, th ⁇ ophen-2-yl, th ⁇ ophen-4-yl, pyr ⁇ mid ⁇ n-2-yl, pyrim ⁇ d ⁇ n-4-yl, pyrim ⁇ din-5-yl, pyr ⁇ d ⁇ n-2-yl, pyr ⁇ d ⁇ n-3-yl, and pyr ⁇ d ⁇ n-4-yl.
  • fused ring groups, spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring
  • 1 ,2,3,4-tetrahydroqu ⁇ noline having the formula is, for the purposes of the present invention, considered a heterocyclyl group
  • 6,7- Dihydro- ⁇ H-cyclopentapyrimidine having the formula is, for the purposes of the present invention, considered a heteroaryl group.
  • aryl ring When a fused ring unit contains heteroatoms in both a saturated and an aryl ring, the aryl ring will predominate and determine the type of category to which the ring is assigned For example, 1 ,2,3,4-tetrahydro-[1 ,8]naphthyridine having the formula:
  • treat and “treating,” as used herein, refer to partially or completely alleviating, inhibiting, ameliorating and/or relieving a condition from which a patient is suspected to suffer
  • terapéuticaally effective refers to a substance or an amount that elicits a desirable biological activity or effect.
  • the terms “subject” or “patient” are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals Accordingly, the term “subject” or “patient” as used herein means any mammalian patient or subject to which the compounds of the invention can be administered.
  • accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, but are not limited to for example, conventional work-ups to determine risk factors that may be associated with the targeted or suspected disease or condition.
  • substituted is used throughout the specification
  • substituted is defined herein as a moiety, whether acyclic or cyclic, which has one or more (e g. 1- 10) hydrogen atoms replaced by a substituent as defined herein below.
  • Substituents include those that are capable of replacing one or two hydrogen atoms of a single moiety at a time, and also those that can replace two hydrogen atoms on two adjacent carbons to form said substituent
  • substituents that replace single hydrogen atoms includes, for example, halogen, hydroxyl, and the like
  • a two hydrogen atom replacement includes carbonyl, oximino, and the like
  • Substituents that replace two hydrogen atoms from adjacent carbon atoms include, for example, epoxy, and the like
  • any number of its hydrogen atoms can be replaced, as described above
  • difluoromethyl is a substituted C 1 alkyl
  • t ⁇ fluoromethyl is a substituted C 1 alkyl
  • 4 -hydroxyphenyl is a substituted aryl ring
  • (N,N-dimethyl-5-am ⁇ no)octanyl is a substituted C 8 alkyl
  • 3- guanidinopropyl is
  • C 1 6 alkyl is specifically intended to individually disclose C 1 , C 2 , C 3 , C 4 , C 5 , Ce, C 1 -Cs, C 1 -Cs, C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 alkyl.
  • the present invention provides compounds of Formula (Ia) or (Ib)
  • Ar 1 is a C 6 -Ci 0 aryl ring or a 5-14 membered heteroaryl ring, each of which is optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C r6 alkyl, F, Cl, Br, I, C 3 - 6 cycloalkyl, C r6 alkoxy, OH, NH 2 , NH(C 1 6 alkyl), N(C 1 6 alkyl) 2 , NO 2 , C 1 3 haloalkyl, SH, SCL 6 alkyl and CN
  • Ar 2 is a C 6 -C 10 aryl ring or a 5-14 membered heteroaryl ring, each of which is optionally substituted with 1 , 2, 3 or 4 substituents independently selected from d- 6 alkyl, F, Cl, Br, I, C 3 - 6 cycloalkyl, d-e alkoxy, OH, NH 2 , NH(d. 6 alkyl), N
  • each X is independently -CR 3 R 4 -,
  • each L is independently -CR 5 R 6 -,
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from H, halogen and C r ⁇ alkyl optionally substituted with 1 , 2, 3 or 4 substituents independently selected from Cr 6 alkyl, F, Cl, Br, I, C r6 alkoxy, OH, NH 2 , NO 2 , C 1 3 haloalkyl, SH, S-C 1 6 alkyl and CN,
  • R 7 and R 8 are each independently selected from H and C 1 - S alkyl optionally substituted with 1 , 2, 3 or 4 substituents independently selected from F, Cl, Br, I, C r6 alkoxy, OH, NH 2 , NO 2 , C 1 3 haloalkyl, SH, SC 1 6 alkyl, CN, C 3 10 cycloalkyl, a 3-10 membered heterocyclyl ring, C 6 -, C 10 -aryl ring, and a 5-10 membered heteroaryl ring,
  • Y is a countenon
  • n 1 , 2, 3, 4 or 5
  • p O, 1 , 2, 3 or 4
  • Ar 1 is a substituted C 6 -C 10 -aryl ring or a 5-14 membered heteroaryl ring, each of which is substituted with at least one substituent independently selected from d- 6 alkyl, F, Cl, Br, I, C 3 - 6 cycloalkyl, C 1 - O alkoxy, OH, NH 2 , NH(C 1 6 alkyl), N(C 1 6 alkyl) 2 , NO 2 , C 1 3 haloalkyl, SH, SC 1 6 alkyl and CN
  • each aryl or heteroaryl ring is further optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C r6 alkyl, F, Cl, Br, I, C 3 - 6 cycloalkyl, C r6 alkoxy, OH, NH 2 , NH(C 1 6 alkyl), N(C 1 6 alkyl) 2 , NO 2 , C 1 3
  • both Ar 1 and Ar 2 are independently a C 6 -C 1D -aryl ring or a 5-14 membered heteroaryl ring, substituted with at least one substituent independently selected from C r6 alkyl, F, Cl, Br, I, Cr 6 alkoxy, OH, NH 2 , NH(C 1 6 alkyl), N(d. 6 alkyl) 2 , NO 2 , C 1 3 haloalkyl, SH, SC 1 e alkyl and CN.
  • each aryl or heteroaryl ring is further optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C r6 alkyl, F, Cl, Br, I, C r6 alkyl, OH, NH 2 , NH(C 1 6 alkyl), N(C 1 6 alkyl) 2 , NO 2 , C 1 3 haloalkyl, SH, -SC 1 6 alkyl and CN.
  • each R 1 , R 2 , R 3 and R 4 is H
  • R 5 and R 6 are each H
  • L is CH 2 . In some further embodiments, p is 2
  • Ar 1 is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from Cr 6 alkyl, halogen, C 1-6 alkoxy, OH, NH 2 , NH(C 1 6 alkyl), N(C 1 6 alkyl) 2 , NO 2 , C 1 3 haloalkyl, SH, SC 1 6 alkyl and CN
  • Ar 1 is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from Cr 6 alkyl, halogen, C r6 alkoxy, OH, and CF 3
  • Ar 1 is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from methyl, F, Cl and methoxy
  • Ar 1 is phenyl optionally substituted with 1 , 2 or 3 methoxy groups
  • Ar 1 is para-substituted phenyl In some embodiments,
  • Ar 2 is phenyl optionally substituted with 1 , 2, or 3 substituents independently selected from C r6 alkyl, halogen, C 3 - 6 cycloalkyl, C,- 6 alkoxy, OH, NH 2 , NH(C 1 6 alkyl), N(CL 6 alkyl) 2 , NO 2 , C 1 3 haloalkyl, SH, -S-C 1 6 alkyl and CN
  • Ar 2 is phenyl optionally substituted with 1 , 2 or 3 substitutents independently selected from C r6 alkyl, halogen, N(C 1 6 alkyl) 2 , and CF 3 .
  • Ar 2 is para-substituted phenyl In some embodiments, Ar 2 is phenyl substituted at the 4-position with methyl, ethyl, isopropyl, t-butyl, F, Cl, CF 3 , dimethylamino, diethylamino, or diisopropylamino.
  • Ar 2 is 5-14 membered heteroaryl ring optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C r6 alkyl, halogen, C 3 - 6 cycloalkyl, C 1 ⁇ alkoxy, OH, NH- 2 , NH(C 1 6 alkyl), N(C 1 6 alkyl) 2 , NO 2 , C 1 3 haloalkyl, SH, S-C 1 6 alkyl and CN
  • Ar 2 is pyrimidinyl optionally substituted with 1 , 2, or 3 substituents independently selected from Ci- 6 alkyl, halogen, C r6 alkoxy, OH, NH 2 , NH(C 1 6 alkyl), N(C 1 6 alkyl) 2 , NO 2 , C 1 3 haloalkyl, SH, -S-C 1 e alkyl and CN
  • substituents independently selected from Ci- 6 alkyl, halogen, C r6 alkoxy
  • Ar 1 is 5-14 membered heteroaryl optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C r6 alkyl, halogen, C r6 alkoxy, OH, NH 2 , NH(C 1 6 alkyl), N(C 1 6 alkyl)(C 1 6 alkyl), NO 2 , d_ 3 haloalkyl, S-C 1 6 alkyl and CN
  • Ar 1 is pyrimidinyl optionally substituted with 1 , 2, or 3 substituents independently selected from C r6 alkyl, halogen, C r6 alkoxy, OH, NH 2 , NH(C 1 6 alkyl), N(C 1 6 alkyi ⁇ Ci.
  • Ar 1 is pyr ⁇ m ⁇ d ⁇ n-5-yl optionally sibstituted with NH 2 , NH(C 1 s alkyl), or N(C 6 alkyl)(Ci 6 alkyl). In some embodiments, Ar 1 is pyr ⁇ m ⁇ d ⁇ n-5-yl optionally substituted with diethylamino In some embodiments, Ar 1 is pyr ⁇ m ⁇ d ⁇ n-5-yl optionally substituted with NH 2 , NH(C 1 - S alkyl), or N(C 1 6 alkyl) 2 . In some embodiments, Ar 1 is pyrimidin-5-yl optionally substituted with diethylamino
  • R 7 is H, C 1-6 alkyl optionally substituted with halogen, C 3 10 cycloalkyl, a 3-10 membered heterocyclyl, C 6 -C 10 aryl, or a 5-10 membered heteroaryl.
  • R 7 is H, C 1 - 6 alkyl or cyclopropylmethyl
  • R 7 and R ⁇ are each independently C r6 alkyl
  • R 7 and R 8 are each methyl.
  • n is 1, 2, 3 or 4
  • R 3 at each occurrence, is H, and R 4 , at each occurrence, is H.
  • each L is - CH 2 -; and Ar 1 is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from C r6 alkyl, halogen, C r6 alkoxy, OH, NH 2 , NH(C 1 6 alkyl), N(C 1 6 alkyl) 2 , and C 1 ⁇ haloalkyl
  • Ar 1 is 4- methoxyphenyl
  • Ar 2 is phenyl optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C r6 alkyl, halogen, C r6 alkoxy, OH, NH 2 , NH(C 1 6 alkyl), N(C 1 6 alkyl) 2 , NO 2 , C 1 ⁇ haloalkyl, SH, S-C 1 6 alkyl and CN.
  • Ar 2 is phenyl substituted at the 4-position with methyl, ethyl, isopropyl, t-butyl, F, Cl, CF 3 , dimethylamino, diethylamino, or diisopropylamino.
  • Ar 2 is a 5-14 membered heteroaryl ring optionally substituted with 1 , 2, 3 or 4 substituents independently selected from Cr 6 alkyl, halogen, C r6 alkoxy, OH, NH 2 , NH(C 1 6 alkyl), N(C 1 6 alkyl) 2 , NO 2 , C 1 3 haloalkyl, SH, -S-C 6 alkyl and CN
  • Ar 2 is pyrimidinyl optionally substituted with 1 , 2, or 3 substituents independently selected from Ci- 6 alkyl, halogen, Cr 6 alkoxy, OH, NH 2 , NH(C 1 6 alkyl), N(CL 6 alkyl) 2 , NO 2 , C 1 3 haloalkyl, SH, S-CL 6 alkyl and CN
  • R 7 is H, C r6 alkyl, or cyclopropylmethyl
  • R 7 and R 8 are each
  • asymmetric atom also referred as a chiral center
  • some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers.
  • the present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
  • Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include, but are not limited to for example, chiral chromatography, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis.
  • the present invention also includes cis and trans or E/Z isomers of compounds of Formula (Ia) or (Ib)conta ⁇ n ⁇ ng alkenyl moieties (e g , alkenes and imines) It is also understood that the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography
  • salts of compounds of the present invention can be formed using organic and inorganic bases Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts, ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e g , ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, d ⁇ -, or t ⁇ hydroxy lower alkylamine (e.g., mono-, d ⁇ - or triethanolamine) Specific non-limiting examples of inorganic
  • salts can be formed using organic and inorganic acids
  • salts can be formed from the following acids acetic, propionic, lactic, benzenesulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, camphorsulfonic, carbonic, as well as other known pharmaceutically acceptable acids.
  • the compounds described herein may be administered to humans and other animals orally, parenteral! ⁇ sublingually, by aerosohzation or inhalation spray, rectally, intracisternally, intravaginally, intraperitoneally, bucally, intrathecal ⁇ or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired
  • parenteral as used herein includes subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, or infusion techniques Topical administration may also involve the use of transdermal administration such as transdermal patches or ionophoresis devices
  • compositions for use in the present invention can be in the form of sterile, non-pyrogenic liquid solutions or suspensions, coated capsules, suppositories, lyophilized powders, transdermal patches or other forms known in the art.
  • sterile injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenteral ⁇ acceptable diluent or solvent
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides
  • fatty acids such as oleic acid find use in the preparation of injectables
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • Formulations comprising crystalline forms of the compositions described herein for slow absorption from subcutaneous or intramuscular injection are provided herein Additionally, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the compounds in an oil vehicle Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations may also be prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissues
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrohdinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, acetyl alcohol and
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like
  • the solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art They may optionally contain opacifying agents and can also be of a composition that they release the active ⁇ ngredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner
  • embedding compositions examples include polymeric substances and waxes
  • the compounds described herein can also be in micro-encapsulated form with one or more excipients as noted above
  • the solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e g , tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose
  • the dosage forms may also comprise buffering agents They may optionally contain opacifying agents and can also be of a composition that they release the active ⁇ ngredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, EtOAc, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof Besides inert diluents, the oral compositions
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required Ophthalmic formulations, ear drops, and the like are also contemplated as being within the scope of this invention
  • compositions of the invention may also be formulated for delivery as a liquid aerosol or inhalable dry powder
  • Liquid aerosol formulations may be nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles
  • Effective amounts of the compounds of the invention generally include any amount sufficient to detectably modulate Kv1 5 potassium channel activity, or to alleviate symptoms of diseases associated with Kv1 5 potassium channel activity or susceptible to Kv1 5 potassium channel activity modulation
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration It will be understood, however, that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy The therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.
  • kits that include one or more compounds of the invention are provided.
  • Representative kits include a compound described herein (e g , a compound of Formula Ia or Ib) and a package insert or other labeling including directions for treating or preventing atrial arrhythmia, thromboembolism, stroke, or cardiac failure by administering an effective amount of a compound of the present invention
  • kits that include one or more compounds of the invention are provided.
  • Representative kits include a compound described herein (e g , a compound of Formula Ia or Ib) and a package insert or other labeling including directions for inhibiting Kv1 5 potassium channel by administering an effective amount of a compound of the present invention
  • kits that include one or more compounds of the invention are provided.
  • Representative kits include a compound described herein (e g , a compound of Formula Ia or Ib) and a package insert or other labeling including directions for inducing cardioversion by administering an effective amount of a compound of the present invention
  • the Kv1 5 potassium channel inhibitors of the present invention are 5-spirocyclic-4- imidazolidinones, and include all enantiomeric and diasteriomeric forms and salts of compounds having the formula (Ia) or (Ib).
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e g , 1 H or 13 C), infrared spectroscopy, spectrophotometry (e g , UV-visible), mass spectrometry, or by chromatography such as high-performance liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC)
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e g , 1 H or 13 C), infrared spectroscopy, spectrophotometry (e g , UV-visible), mass spectrometry, or by chromatography such as high-performance liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC)
  • Preparation of the compounds can involve protection and deprotection of various chemical groups
  • the chemistry of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 4th Ed (John Wiley & Sons, 2007), the entire disclosure of which is incorporated by reference herein for all purposes
  • the reactions or the processes described herein can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i e , temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent
  • suitable solvents for a particular reaction step can be selected.
  • the compounds of these teachings can be prepared by methods known in the art
  • the reagents used in the preparation of the compounds of these teachings can be either commercially obtained or can be prepared by standard procedures described in the literature
  • compounds of the present invention can be prepared according to the method illustrated in Scheme 1
  • the amine-protected amino acid A contains an -NH-PG group.
  • the amine-protected amino acid may have the formula
  • Z is -NH-PG
  • Z may be a protected amino group of the formula
  • PG 1 and PG 2 are each a protecting group functionality, which may be, as an example, a carbonyl group.
  • Z may be a phthalimido group.
  • Amine-protected amino acid A (wherein PG is an amine protecting group) is treated with amine Ar 1 -(L) P -NH 2 under amide coupling conditions.
  • Suitable amide coupling conditions include the use of a coupling reagent such as a carbodiimide (e g , N-(3- dimethylaminopropyl)-N'-ethylcarbodnmide hydrochloride (EDAC) or dicyclohexylcarbodiimide (DCC)), or PyBOP.
  • the coupling conditions comprise a coupling agent and a hydroxylated moiety (e g , N-hydroxybenzotriazole (HOBt), (HOAt) or pentafluorophenol).
  • Any suitable amide coupling conditions known in the art may be employed. Removal of the protecting group PG yields compound B Any suitable amine protecting group (e g , ferf-butoxy carbonyl, benzyloxy carbonyl, etc.) and corresponding deprotection conditions (e.g., treatment with acid (e.g., HCI, TFA) or hydrogenation (e g , palladium catalyzed hydrogenation)) may be used (see, e g , T W Greene, Protective Groups in Organic Synthesis, 4 TH Ed (John Wiley and Sons, 2007) Compound B is condensed with aldehyde Ai ⁇ -CHO in the presence of a base to produce 4-imidazolidinone C Alkylation of C yields 4 - ⁇ m ⁇ dazol ⁇ d ⁇ none D Any suitable alkylation conditions may be employed, including, for example, treatment with an alkyl halide (e.g., alkyl iodide, alkyl bromide, al
  • Compound C may be treated with an appropriate base (e g , sodium hydride) in the presence of at least two equivalents of an alkylating agent (e g , alkyl halide, alkyl sulfonate, etc ) in a suitable solvent (e g , DMF) to yield compound E
  • an alkylating agent e g , alkyl halide, alkyl sulfonate, etc
  • a suitable solvent e g , DMF
  • monoalkylated 4- ⁇ m ⁇ dazol ⁇ d ⁇ none D may be treated with an appropriate base (e g sodium hydride) and an alkylating agent (e g alkyl halide, alkyl sulfonate, etc ) in a suitable solvent (e g DMF) to produce compound E.
  • Example 1 Preparation of 6-(4-ferf-butylphenyl)-7-[2-(4-methoxyphenyl)ethyl]-5- methyl-5,7-d ⁇ azasp ⁇ ro[3.4]octan-8-one (Compound #9 in Table 1)
  • Step 1 860 mg (4 mmol) of Boc amino acid 1 and 4-methoxyphenethyl amine (604 mg, 4 mmol) were dissolved in 10 DMF at room temperature and 2 05 g (4 mmol) of
  • Step 2 The light brown oil was dissolved in 20 ml of methanol, 676 mg of 4-t- butylbenzaldehyde was added, followed by 1.38 g K 2 CO 3 , and the reaction was heated to reflux. After 18 hours, the reaction was allowed to cool to room temperature, the solution was filtered, and the resulting solution was stripped of solvent.
  • Kv1 5 currents are recorded by the whole cell mode of patch clamp electrophysiologic Kv1 - 5 is stably over expressed in HEK cells.
  • Microelectrodes are pulled from borosilicate glass (TW150) and heat polished (tip resistance, 1 5 to 3 megaohms)
  • the external solution is standard Tyrodes solution
  • the internal (microelectrode) solution contained: 1 10 mM KCI, 5 mM K 2 ATP, 5 mM K 4 BAPTA, 1 mM MgCI 2 and 10 mM HEPES, adjusted to pH 7 2 with KOH.
  • Command potentials are applied for 1 second to +6OmV from a holding potential of -70 mV using Axon software (pClamp 8 1) and hardware (Axopatch 1D, 200B)
  • Compounds are prepared as 10-2OmM DMSO stocks and diluted to appropriate test concentrations After stable currents are achieved, compounds are perfused onto the cells and the cells are pulsed every 5 seconds until no further changes in current are evident at a given compound concentration Inhibition is measured at the end of the 1 second pulses and expressed relative to controls Kv1 5 inhibition is estimated by single point determinations done at 1 ⁇ M Generally following this procedure, results for representative compounds according to the present invention are listed in Table Il below.

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Abstract

La présente invention concerne des 4-imidazolidinones de formule (Ia) ou (Ib) qui sont utiles comme inhibiteurs du canal potassique KV1.5 fournissant une activité antiarythmique exclusivement atriale. L'invention concerne en outre des compositions et des procédés pour traiter l'antiarythmie exclusivement atriale.
EP08861246A 2007-12-19 2008-12-18 4-imidazolidinones comme inhibiteurs du canal potassique kv1.5 Withdrawn EP2234983A1 (fr)

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