EP2091917A1 - Modulateurs de canaux ioniques - Google Patents

Modulateurs de canaux ioniques

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Publication number
EP2091917A1
EP2091917A1 EP07865491A EP07865491A EP2091917A1 EP 2091917 A1 EP2091917 A1 EP 2091917A1 EP 07865491 A EP07865491 A EP 07865491A EP 07865491 A EP07865491 A EP 07865491A EP 2091917 A1 EP2091917 A1 EP 2091917A1
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EP
European Patent Office
Prior art keywords
group
phenyl
methyl
amino
fluoro
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.)
Withdrawn
Application number
EP07865491A
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German (de)
English (en)
Inventor
Christopher Todd Baker
Paul Will
Robert Zelle
Hormoz Mazdiyasni
Vincent P. Galullo
Jinsong Guo
Andrew Fensome
Jeffrey Curtis Kern
William Jay Moore
Edward George Melenski
Justin Kaplan
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Wyeth LLC
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Wyeth LLC
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Publication of EP2091917A1 publication Critical patent/EP2091917A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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 carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

Definitions

  • the present teachings relate to certain amino acid derivatives, processes for their preparation, and their use in therapeutic treatments.
  • ion channels that permit these changes are proteinaceous pores consisting of one or multiple subunits, each containing two or more membrane-spanning domains. Most ion channels have selectivity for specific ions, primarily Na + , K + , Ca 2+ , or Cl " , by virtue of physical preferences for size and charge. Electrochemical forces, rather than active transport, drive ions across membranes, thus a single channel may allow the passage of millions of ions per second.
  • Channel opening, or "gating" is tightly controlled by changes in voltage or by ligand binding, depending on the subclass of channel. Ion channels are attractive therapeutic targets due to their involvement in so many physiological processes, yet the generation of drugs with specificity for particular channels in particular tissue types remains a major challenge.
  • Voltage-gated ion channels open in response to changes in membrane potential. For example, depolarization of excitable cells such as neurons results in a transient influx of Na + ions, which propagates nerve impulses. This change in membrane potential is sensed by voltage-gated K + channels, which then allow an efflux of K + ions. The efflux of K + ions repolarizes the membrane. Other cell types rely on voltage-gated Ca 2+ channels to generate action potentials. Voltage-gated ion channels also perform important functions in non-excitable cells, such as the regulation of secretory, homeostatic, and mitogenic processes.
  • Ligand-gated ion channels can be opened by extracellular stimuli such as neurotransmitters (e.g., glutamate, serotonin, and acetylcholine), or intracellular stimuli (e.g., cAMP, Ca 2+ , and phosphorylation).
  • extracellular stimuli such as neurotransmitters (e.g., glutamate, serotonin, and acetylcholine), or intracellular stimuli (e.g., cAMP, Ca 2+ , and phosphorylation).
  • the Ca v 2 family of voltage-gated calcium channels consists of 3 main subtypes Ca v 2.1 (P or Q-type calcium currents), Ca v 2.2 (N-type calcium currents), and Ca v 2.3 (R-type calcium currents). These currents are found almost exclusively in the central nervous system (CNS), peripheral nervous system (PNS) and neuroendocrine cells, and constitute the predominant forms of presynaptic voltage-gated calcium current. Presynaptic calcium entry is modulated by many types of G-protein coupled receptors (GPCRs) and modulation of Ca v 2 channels is a widespread and highly efficacious means of regulating neurotransmission.
  • GPCRs G-protein coupled receptors
  • the subunit composition of the Ca v 2 channels is defined by their ⁇ i subunit, which forms the pore and contains the voltage-sensing gates (CH2.1 , ⁇ i2.2, and ⁇ i2.3, also known as di A , CH B , and di E , respectively) and the ⁇ and ⁇ 2 subunits.
  • ⁇ i subunit which forms the pore and contains the voltage-sensing gates (CH2.1 , ⁇ i2.2, and ⁇ i2.3, also known as di A , CH B , and di E , respectively) and the ⁇ and ⁇ 2 subunits.
  • ion channel function can have dramatic clinical consequences. Long QT syndrome, epilepsy, cystic fibrosis, and episodic ataxia are a few examples of heritable diseases resulting from mutations in ion channel subunits. Toxic side effects such as arrhythmia and seizure, which can be triggered by certain drugs, can be due to interference with ion channel function (Sirois, J. E. and Atchison, W.D. (1996), Neurotoxicology, 17(1 ): 63-84; Keating, MT. (1996), Science, 272: 681-685).
  • Drugs are useful for the therapeutic modulation of ion channel activity, and have applications in treatment of many pathological conditions, including hypertension, angina pectoris, myocardial ischemia, asthma, bladder overactivity, alopecia, pain, heart failure, dysmenorrhea, type Il diabetes, arrhythmia, graft rejection, seizure, convulsions, epilepsy, stroke, gastric hypermotility, psychoses, cancer, muscular dystrophy, and narcolepsy (Coghlan, MJ. et al. (2001 ), J. Med. Chem., 44: 1627-1653; Ackerman, MJ. and Clapham, D. E. (1997), N. Eng. J. Med., 336: 1575-1586).
  • pathological conditions including hypertension, angina pectoris, myocardial ischemia, asthma, bladder overactivity, alopecia, pain, heart failure, dysmenorrhea, type Il diabetes, arrhythmia, graft rejection, seizure, con
  • Therapeutic modulation of Ca v 2 channel activity has applications in treatment of many pathological conditions. All primary sensory afferents provide input to neurons in the dorsal horns of the spinal cord and in dorsal root ganglia neurons in the dorsal horn, and calcium influx through Ca v 2.2 channels triggers the release of neurotransmitters from presynaptic nerve terminals in the spinal cord. Hence, blockade of Ca v 2.2 channels is expected to be broadly efficacious because these channels are in a common pathway downstream from the wide variety of receptors that mediate pain (Julius, D. and Basbaum, A.I. (2001 ), Nature, 413: 203-216).
  • Ca v 2.2 channels are found in the periphery and mediate catecholamine release from sympathetic neurons and adrenal chroffin cells. Some forms of hypertension result from elevated sympathetic tone. Ca v 2.2 modulators could be particularly effective in treating this disorder. Although complete block of Ca v 2.2 channels can cause hypotension or impair baroreceptor reflexes, partial inhibition by Ca v 2.2 modulators might reduce hypertension with minimal reflex tachycardia (Uneyama, O. D. (1999), Int. J. MoI. Med, 3: 455-466).
  • Overactive bladder is characterized by storage symptoms such as urgency, frequency, and nocturia, with or without urge incontinence, resulting from the overactivity of the detrusor muscle in the bladder. OAB can lead to urge incontinence.
  • the etiology of OAB and painful bladder syndrome is unknown, although disturbances in nerves, smooth muscle and urothelium can cause OAB (Steers, W., Rev. Urol., 4: S7-S18). There is evidence to suggest that reduction of bladder hyperactivity may be indirectly effected by inhibition of Ca v 2.2 and/or Ca v 1 channels.
  • gabapentin was designed as a metabologically stable GABA mimetic, but most studies find no effect on the GABA receptors.
  • the ⁇ 2 ⁇ subunit of voltage-gated calcium channels has been identified as a high affinity binding site for gabapentin in the CNS.
  • gabapentin could inhibit neurotransmission in the spinal cord by interfering with the function of the c ⁇ subunits, thereby inhibiting presynaptic calcium currents.
  • the present teachings also provide methods of making the compounds of formula (I) and pharmaceutically acceptable salts, hydrates, and esters thereof, and methods of using the compounds of formula (I) and pharmaceutically acceptable salts, hydrates, and esters thereof for the therapeutic modulation of ion channel function, and treatment of one or more conditions, particularly those mediated by certain calcium channel subtype targets.
  • the methods of using the compounds and pharmaceutically acceptable salts, hydrates, and esters thereof generally include administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, or ester thereof, to a mammal.
  • Embodiments of the present invention provide compounds that can modulate the activity of ion channels in a mammal, for example, Ca v 2.2 voltage-gated calcium channels, and can treat a variety of pathological conditions, states, disorders or diseases.
  • the term “mammal” refers to any warm blooded species, such as a human.
  • the term “ion channel” includes at least voltage-gated calcium channels and voltage- gated sodium channels such as, without limitation, Ca v 1.1 , CaJ .2, CaJ .3, Ca v 2.1 , Ca v 2.2, Ca v 2.3, Ca «3.1 , Ca v 3.2, NaJ .1 , NaJ .2, NaJ .3, NaJ .7, NaJ .8, and NaJ .9.
  • “Ca v 2.2 voltage-gated calcium channel” refers to a voltage-gated calcium channel containing at least one Ca v 2.2 CH subunit.
  • ion channel mediated condition refers to any condition or pathological state of a mammal or any disease present in a mammal that can be treated, or the symptoms of which can be alleviated, by modulation of the activity of one or more ion channels such as Ca v 2.2 voltage-gated calcium channels.
  • halo or halogen refers to fluoro, chloro, bromo, and iodo.
  • alkyl refers to a straight-chain or branched saturated hydrocarbon group.
  • alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n- propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl groups (e.g., n-pentyl, isopentyl, neopentyl), and the like.
  • a lower alkyl group typically has up to 6 carbon atoms.
  • an alkyl group has 1-6 carbon atoms, and is referred to as a "Ci -6 alkyl group.”
  • Ci -6 alkyl groups include, but are not limited to, methyl, ethyl, propyl (e.g., n-propyl and isopropyl), and butyl groups (e.g., n-butyl, isobutyl, s-butyl, t-butyl).
  • a branched alkyl group has at least 3 carbon atoms (e.g., an isopropyl group) and up to 6 carbon atoms, e.g. it is a C 3-6 alkyl group, i.e., a branched lower alkyl group. Examples of branched lower alkyl groups include, but are not limited to:
  • a divalent Ci -6 alkyl group can be a straight chain or branched alkyl group, which as a linking group is capable of forming a covalent bond with two other moieties.
  • Examples of a divalent Ci -6 alkyl group include, for example, a methylene group, an ethylene group, an ethylidene group, an n-propylene group, an isopropylene group, an isobutylene group, a s-butylene group, an n-butylene group, and a t-butylene group.
  • alkenyl refers to a straight-chain or branched alkyl group having one or more carbon-carbon double bonds.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl groups, and the like.
  • the one or more carbon-carbon double bonds can be internal (such as in 2-butene) or terminal (such as in 1-butene).
  • a branched alkenyl group has at least 3 carbon atoms, and in various embodiments, has up to 6 carbon atoms, e.g. it is a C 3-6 alkenyl group.
  • alkynyl refers to a straight-chain or branched alkyl group having one or more carbon-carbon triple bonds.
  • alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
  • the one or more carbon- carbon triple bonds can be internal (such as in 2-butyne) or terminal (such as in 1- butyne).
  • the alkynyl group is suitably a C 3-6 alkynyl group.
  • alkoxy refers to an -O-alkyl group wherein the alkyl group may be a straight or branched chain.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy groups, and the like.
  • a divalent alkoxy group means an alkoxy group which, as a linking group, is capable of forming a covalent bond with two other moieties (-O-alkyl-).
  • haloalkyl refers to an alkyl group having one or more halogen substituents.
  • haloalkyl groups include, but are not limited to, -CF 3 , -C 2 F 5 , -CHF 2 , -CH 2 F, -CCI 3 , -CHCI 2 , -CH 2 CI, -C 2 CI 5 , and the like.
  • Perhaloalkyl groups i.e., alkyl groups wherein all of the hydrogen atoms are replaced with halogen atoms (e.g., CF 3 and C 2 F 5 ), are included within the definition of "haloalkyl.”
  • haloalkoxy refers to an alkoxy group having one or more halogen substituents. Examples of haloalkoxy groups include, but are not limited to, -OCF 3 , -OC 2 F 5 , -OCHF 2 , and the like.
  • cycloalkyl refers to a non-aromatic carbocyclic group including cyclized alkyl, alkenyl, and alkynyl groups.
  • a cycloalkyl group 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.
  • a cycloalkyl group has 3-6 carbon atoms, and is referred to as a "C 3-6 cycloalkyl group.”
  • C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutyl, cyclobutylmethyl, cyclobutylethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and cyclohexadienyl groups, as well as their homologs, isomers, and the like.
  • cycloalkyl groups are moieties that have one or more aromatic rings fused (Ae., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane (i.e., an indanyl group), cyclohexane (i.e., a tetrahydronaphthyl group), and the like.
  • cycloalkyl groups can be substituted with 1 to 3 substituents independently selected from a Ci -6 alkyl group and a -Y-phenyl group, wherein the phenyl group is optionally substituted with 1 to 3 substituted independently selected from a halogen and a C 1-6 alkoxyl group, and Y is as defined hereinbelow.
  • heteroatom refers to an atom of any element other than carbon or hydrogen and includes, for example, nitrogen, oxygen, sulfur, phosphorus, and selenium.
  • cycloheteroalkyl refers to a non-aromatic cycloalkyl group having 5- 10 ring atoms, among which 1 to 3 ring atoms are heteroatoms independently selected from oxygen (O), nitrogen (N) and sulfur (S), and that optionally contains one or more, e.g., two, double or triple bonds. Also included in the definition of cycloheteroalkyl are moieties that have one or more aromatic rings fused (Ae., have a bond in common with) to the cycloheteroalkyl group.
  • cycloheteroalkyl groups include, among others, morpholine, thiomorpholine, pyran, imidazolidine, imidazoline, oxazolidine, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, tetrahydroisoquinoline, benzimidazoline, chromane, chromene, indolinetetrahydroquinoline, and the like.
  • N or S atoms in a cycloheteroalkyl ring can be oxidized (e.g., morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S,S-dioxide).
  • Cycloheteroalkyl groups can also contain one or more oxo groups, such as piperidone, oxazolidinone, pyrimidine-2,4(1 H,3/-/)-dione, pyridin-2(1 H)-one, and the like.
  • cycloheteroalkyl groups include, among others, morpholine, thiomorpholine, pyran, imidazolidine, imidazoline, oxazolidine, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, and the like.
  • a cycloheteroalkyl group can be optionally substituted.
  • one or more carbon ring atoms of a cycloheteroalkyl group can bear a substituent independently selected from a halogen, a Ci -6 alkyl group, -C(O)-NR d R ⁇ , -Y-OR C , -Y-NR d R ⁇ , a -Y-phenyl group, a -Y-(5-7 cycloheteroalkyl) group, a -Y-(5-9 membered heteroaryl) group, or a -Y-O-(5-7 membered heteroaryl) group, and/or one or more nitrogen ring atoms of a cycloheteroalkyl group can bear a substituent independently selected from a halogen, a Ci -6 alkyl group, -C(O)R 0 , -C 2-6 alkyl-OR c , -C 2-6 alkyl-NR d R ⁇ , -Y-
  • each of the phenyl substituents immediately above can be optionally substituted with 1 to 3 substituents independently selected from a halogen, a Ci -6 alkyl group, a Ci -6 haloalkyl group, and a Ci -6 alkoxy group, and each of the 5-7 membered cycloheteroalkyl substituents, the 5-7 membered heteroaryl substituents, and the 5-9 membered heteroaryl substituents immediately above can be optionally substituted with 1 to 3 substituents independently selected from a halogen and a Ci -6 alkyl group.
  • aryl refers to an aromatic monocyclic hydrocarbon ring system or a polycyclic ring system in which two or more aromatic hydrocarbon rings are fused (i.e., having a bond in common with) together or at least one aromatic monocyclic hydrocarbon ring is fused to one or more cycloalkyl and/or cycloheteroalkyl rings.
  • An aryl group can have from 6 to 14 carbon atoms in its ring system, which can include multiple fused rings.
  • a polycyclic aryl group can have from 7 to 14 carbon atoms. Any suitable ring position of the aryl group can be covalently linked to the defined chemical structure.
  • aryl groups having only aromatic carbocyclic ring(s) include, but are not limited to, phenyl, 1-naphthyl (bicyclic), 2-naphthyl (bicyclic), anthracenyl (tricyclic), phenanthrenyl (tricyclic) and like groups.
  • polycyclic ring systems in which at least one aromatic carbocyclic ring is fused to one or more cycloalkyl and/or cycloheteroalkyl rings include, among others, benzo derivatives of cyclopentane (i.e., an indanyl group, which is a 5,6-bicyclic cycloalkyl/aromatic ring system), cyclohexane (i.e., a tetrahydronaphthyl group, which is a 6,6-bicyclic cycloalkyl/aromatic ring system), imidazoline (i.e., a benzimidazolinyl group, which is a 5,6-bicyclic cycloheteroalkyl/aromatic ring system), and pyran (i.e., a chromenyl group, which is a 6,6-bicyclic cycloheteroalkyl/aromatic ring system).
  • aryl groups include, but are not limited to, benzodioxanyl, benzodioxolyl, chromanyl, indolinyl groups, and the like.
  • aryl groups optionally contain up to three independently selected substitution groups.
  • a phenyl group in some embodiments, can be optionally substituted with 1 to 3 substituents independently selected from a halogen, CN, -C(O)OR C , -NR d R ⁇ , a Ci -6 alkyl group, a C 1-6 haloalkyl group, and a C 1-6 alkoxy group, wherein R c , R d , and R ⁇ are as defined hereinbelow.
  • heteroaryl refers to an aromatic monocyclic ring system or a polycyclic ring system where at least one of the rings present in the ring system is aromatic, containing 5-7 or 5-9 ring atoms, among which 1 to 3 ring atoms are heteroatoms independently selected from oxygen (O), nitrogen (N) and sulfur (S).
  • Polycyclic heteroaryl groups include two or more heteroaryl rings fused together, and monocyclic heteroaryl rings fused to one or more aromatic carbocyclic rings, non- aromatic carbocyclic rings, and/or non-aromatic cycloheteroalkyl rings.
  • the heteroaryl group can be attached to the defined chemical structure at any heteroatom or carbon atom that results in a stable structure.
  • heteroaryl rings do not contain 0-0, S-S, or S-O bonds.
  • one or more N or S atoms in a heteroaryl group can be oxidized (e.g., pyridine N-oxide, thiophene S-oxide, thiophene S, S- dioxide).
  • heteroaryl groups include, for example, the 5-membered monocyclic and 5-6 bicyclic ring systems shown below: where K is O, S, NH, or NR'; and R' can be selected from a halogen, a C 1-6 alkyl group, a C(O)R C group, a C 2-6 alkyl-OR c group, a C 2-6 alkyl-NR d R ⁇ group, a -Y- C(O)NR d R ⁇ group, an S(O) 2 -C 1-6 alkyl group, a 5-7 membered heteroaryl group, and a C 2-6 alkyl— (5-7 membered cycloheteroalkyl) group, where Y, R c , R d and R ⁇ are as defined hereinbelow.
  • heteroaryl rings include, but are not limited to, pyrrole, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, triazole, tetrazole, pyrazole, imidazole, isothiazole, thiazole, thiadiazole, isoxazole, oxazole, oxadiazole, indole, isoindole, benzofuran, benzothiophene, quinoline, 2- methylquinoline, isoquinoline, quinoxaline, quinazoline, benzotriazole, benzimidazole, benzothiazole, benzisothiazole, benzisoxazole, benzoxadiazole, benzoxazole, cinnoline, 1 H-indazole, 2H-indazole, indolizine, isobenzofuran, naphthyridine, phthalazine,
  • heteroaryl groups include, but are not limited to, 4,5,6,7-tetrahydroindole, tetrahydroquinoline, benzothienopyridine, benzofuropyridine, and the like.
  • heteroaryl groups can be substituted with up to three independently selected substitution groups.
  • one or more nitrogen atoms can be substituted with independently selected R' groups as defined above, and/or one or more carbon ring atoms of a cycloheteroalkyl group can bear a substituent independently selected from a halogen, a C 1-6 alkyl group, -C(O)-NR d R ⁇ , -Y-OR C , -Y-NR d R ⁇ , a -Y-phenyl group, a -Y-(5-7 cycloheteroalkyl) group, a -Y-(5- 9 membered heteroaryl) group, or a -Y-O-(5-7 membered heteroaryl) group, wherein Y, R c , R d , and R ⁇ are as defined hereinbelow.
  • each of the phenyl substituents immediately above can be optionally substituted with 1 to 3 substituents independently selected from a halogen, a Ci -6 alkyl group, a Ci -6 haloalkyl group, and a Ci -6 alkoxy group, and each of the 5-7 membered cycloheteroalkyl substituents, the 5-7 membered heteroaryl substituents, and the 5-9 membered heteroaryl substituents immediately above can be optionally substituted with 1 to 3 substituents independently selected from a halogen and a Ci -6 alkyl group.
  • a “divalent group” is defined herein as a linking group capable of forming a covalent bond with two other moieties.
  • LG refers to a charged or uncharged atom (or group of atoms) that can be displaced as a stable species as a result of, for example, a substitution or elimination reaction.
  • leaving groups include, but are not limited to, halide (e.g., Cl, Br, I), tosylate (toluenesulfonyl group, TsO), mesylate (methanesulfonyl group, MsO), brosylate (p-bromobenzenesulfonyl group, BsO), nosylate (4-nitrobenzenesulfonyl group, NsO), water (H 2 O), ammonia (NH 3 ), and triflate (trifluoromethanesulfonyl group, OTf).
  • halide e.g., Cl, Br, I
  • tosylate toluenesulfonyl group, TsO
  • mesylate methanesulfonyl group,
  • a "protecting group” refers to modification of a functional group that reduces the reactivity of the functional group in an unwanted reaction.
  • protecting groups for amines include, but are not limited to, tert- butyloxycarbonyl (t-BOC), benzyl (Bn), and carbobenzyloxy (Cbz) groups.
  • protecting groups for carbonyls include, but are not limited to, acetals and ketals.
  • protecting groups for carboxylic acids include, but are not limited to, methyl esters, benzyl esters, te/t-butyl esters, and silyl esters. See Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991 , the entire disclosure of which is incorporated by reference herein for all purposes.
  • C 1-6 alkyl is specifically intended to individually disclose Ci, C 2 , C3, C 4 , C5, C 6 , Ci-C 6 , C 1 -C5, C 1 -C 4 , C 1 -C3, C 1 -C 2 , C 2 -C 6 , C 2 -C5, 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 term "5-9 membered heteroaryl group” is specifically intended to individually disclose a heteroaryl group having 5, 6, 7, 8, 9, 5-9, 5-8, 5-7, 5-6, 6-9, 6- 8, 6-7, 7-9, 7-8, and 8-9 ring atoms.
  • R 1 and R 1 are independently H, a C MO alkyl group, or a -Y-phenyl group, wherein
  • Ci-io alkyl group is optionally substituted with a 5-9 membered heteroaryl group
  • R 1 and R 1 together form an oxo group
  • R 2 is a C 3-6 cycloalkyl group, a benzyl group, an indole group, or a phenyl group, wherein the phenyl group and the benzyl group are each optionally substituted with 1 to 3 substituents independently selected from a halogen, a Ci -6 alkyl group, a Ci -6 alkoxy group, a Ci -6 haloalkyl group, a Ci -6 haloalkoxy group, -OCH 2 -C 6 H 5 , CN, -C(O)OR C , -OH, and -NR d R ⁇ ; and -NR d R ⁇ , and the
  • Ar-R is selected from:
  • R 3 is selected from a halogen, a C MO alkyl group, a C MO alkoxy group, a C M 0 haloalkyl group, a C MO haloalkoxy group, a -C(O)R C group, a piperidin-4-yl group, a C 3-6 cycloalkyl group, a phenyl group, and a -Y-NR f R g group;; wherein the C MO alkyl group and the C MO alkoxy group are optionally substituted with from 1-3 substitutents selected from a halogen, a phenyl group, and -OH, and the nitrogen ring atom of the piperidin-4-yl group is optionally substituted with -C(O)O-d -6 alkyl;
  • R 4 and R 4 are independently H, a Ci -6 alkyl group, a -C(O)OCi -6 alkyl group, or a -Y-phenyl group, where the phenyl group is optionally substituted with 1 to 3 substituents independently selected from a halogen, CN, -C(O)OR C , a Ci -6 alkyl group, and -NR d R ⁇ ; or
  • R 4 and R 4 taken together with the nitrogen atom to which they are bonded form a 5-7 membered cycloheteroalkyl group, where the 5-7 membered cycloheteroalkyl group is optionally substituted with 1 to 3 substituents selected from a halogen or a Ci -6 alkyl group;
  • Y at each occurrence, is independently a divalent Ci -6 alkyl group or a covalent bond
  • R c , R d and R ⁇ at each occurrence, independently are H or a Ci -6 alkyl group; and R f and R 9 , at each occurrence, independently are selected from H, -C(O)R C , - C 2 - 6 alkyl-OR c , -C 2-6 alkyl-NR d R ⁇ , a C 1-10 alkyl group, a C 3-6 cycloalkyl group, a -Y-phenyl group, a -C(O)-phenyl group, a -Y-(5-7 membered cycloheteroalkyl) group, a -Y-(5-7 membered heteroaryl) group, and a -C 2-6 alkyl-O-Y-(5-7 membered heteroaryl) group, or
  • R f and R 9 taken together with the nitrogen atom to which they are bonded form a 5-8 membered cycloheteroalkyl group or a 5-7 membered heteroaryl group, the 5-8 membered cycloheteroalkyl group and the 5-7 membered heteroaryl group containing up to two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, whereinany sulfur atom in the ring optionally is substituted with 1 or 2 oxo groups; wherein
  • one or more nitrogen atoms in the ring optionally are independently substituted with -C(O)R C , -C 2-6 alkyl-OR c , -C 2-6 alkyl-NR d R ⁇ , -Y- C(O)NR d R ⁇ , an -S(O) 2 -C 1-6 alkyl group, a -C 1-6 alkyl-(phenyl) n group, a -C 2-6 alkyl— (5-7 membered cycloheteroalkyl) group, a C 1-6 alkyl group, a -Y-(phenyl) q group, C 3- S cycloalkyl, a -C(O)O-C 1-6 alkyl group, or a 5-7 membered heteroaryl group,
  • one or more carbon atoms in the ring optionally are independently substituted with CN, -C(O)-NR d R ⁇ , -Y-OR c , -Y-NR d R ⁇ , -Y- (phenyl) q , a -Y-(5-7 cycloheteroalkyl) group, a -Y-(5-9 membered heteroaryl) group, an oxo group, CN, C 3-8 cycloalkyl, a C 1-6 alkyl group, or a -Y-O-(5-7 membered heteroaryl) group;
  • each of the phenyl groups appearing anywhere in said R f and R 9 is optionally substituted with 1 to 3 substituents independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy, and each of the 5-7 membered cycloheteroalkyl groups, the 5-7 membered heteroaryl groups, and the 5-9 membered heteroaryl groups appearing anywhere in said R f and R 9 is optionally substituted with 1 to 3 substituents independently selected from halogen and C 1-6 alkyl; n is 1 , 2, or 3;
  • q is 1 , 2, or 3;
  • p 1 , 2, 3, or 4.
  • R 1 and R 1 independently can be H, an isobutyl group, or a benzyl group. In certain embodiments, at least one of R 1 and R 1 can be H. In other embodiments, R 1 and R 1 together can form an oxo group.
  • R 2 can be a phenyl group optionally substituted with 1-2 substituents independently selected from a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, CN, -C(O)OR C , and -NR d R ⁇ , wherein R c , R d and R ⁇ are as defined above.
  • R 2 can be a 4-fluorophenyl group, a 4-chlorophenyl group, a 4- methoxyphenyl group, a 4-methylphenyl group, a 4-fluoro-2-methylphenyl group, or a 4-dimethylaminophenyl group.
  • p is 1.
  • p is 3.
  • Ar-R 3 can be:
  • Ar-R 3 can be: wherein R is as defined above.
  • Ar-R 3 can be any organic radical
  • R 3 is as defined above.
  • R 3 can be NR f R g , wherein R f and R 9 are as defined above.
  • R 3 can be selected from NH 2 , an NH-Ci -6 alkyl group, an N(Ci -6 alkyl) 2 group wherein the Ci -6 alkyl groups do not need to be the same, an NH-C 3-6 cycloalkyl group, an N(Ci -6 alkyl)— C 3-6 cycloalkyl group, an N(Ci -6 alkyl)-C 2-6 alkyl-OR c group, an N(Ci -6 alkyl)- Y-(5-7 membered cycloheteroalkyl) group, an N(Ci -6 alkyl)-phenyl group, an N(phenyl) 2 group, an N(Ci -6 alkyl)- Y-(5-7 membered heteroaryl) group, and an N(Ci -6 alkyl)-C 2-6 al
  • R 3 can be an optionally substituted 5-7 membered cycloheteroalkyl group or an optionally substituted 5-7 membered heteroaryl group, where each of these groups can include a nitrogen ring atom optionally substituted with -C(O)Rc, -C 2-6 alkyl-ORc, -C 2-6 alkyl-NR d R ⁇ , -Y-C(O)NR d R ⁇ , an -S(O) 2 -Ci -6 alkyl group, a -C 2-6 alkyl— (5-7 membered cycloheteroalkyl) group, a Ci -6 alkyl group, or a 5-7 membered heteroaryl group; a carbon ring atom optionally substituted with - C(O)-NR d R ⁇ , -Y-OR c , -Y-NR d R ⁇ , a -Y-phenyl group, a -Y-(5-7
  • R 3 can be selected from a diazepanyl group, an imidazolyl group, a morpholinyl group, a piperidinyl group, a piperazinyl group, a pyridyl group, a pyrrolidyl group, and a thiomorpholinyl group, where each of these groups can be optionally substituted as described above.
  • R 3 can be selected from a 1-[1 ,4]diazepanyl group, a 1- imidazolyl group, a 4-morpholinyl group, a 1 -piperidinyl group, a 1 -piperazinyl group, a 4-pyridyl group, a 1 -pyrrolidyl group, and a 4-thiomorpholinyl group, wherein each of these groups can be optionally substituted as described above.
  • R 3 can be a 1 -piperazinyl group having a nitrogen atom in the ring optionally substituted with -C(O)R C , -C 2-6 alkyl-OR c , -C 2-6 alkyl-NR d R ⁇ , -Ci -6 alkyl-C(O)NR d R ⁇ , an S(O) 2 -Ci -6 alkyl group, a -C 2-6 alkyl-(5-7 membered cycloheteroalkyl) group, a Ci -6 alkyl group, or a 5-7 membered heteroaryl group.
  • R 3 can be a 4-methyl piperazin-1-yl group.
  • R 3 can be a 1 -piperidinyl group having a carbon atom in the ring optionally substituted with -NR d R ⁇ , -C(O)-NR d R ⁇ , -Y-OR C , a 5-7 cycloheteroalkyl group, a 5-9 membered heteroaryl group, or a -Y-O-(5-7 membered heteroaryl) group.
  • R 3 can be a C 3-6 cycloalkyl group or a phenyl group; for example, R 3 can be a cyclohexyl group.
  • R 4 and R 4 independently can be H, a methyl group, or a benzyl group.
  • R 4 and R 4 together with the nitrogen atom to which they are bonded can form a 1-pyrrolidinyl group.
  • R 4 and R 4 independently can be H, a t-butyl group, or a 4-chlorophenyl group, for example, when R 1 and R 1 together form an oxo group.
  • Representative compounds of formula (I) in accordance with embodiments of the present invention include, but are not limited to, the compounds presented in Table 1 below.
  • compositions of formula (I), which can have an acidic moiety can be formed using organic and inorganic bases. Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens 5 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
  • inorganic bases include NaHCO 3 , Na 2 CO 3 , KHCO 3 , K 2 CO 3 , Cs 2 CO 3 , LiOH, NaOH, KOH, NaH 2 PO 4 , Na 2 HPO 4 , and Na 3 PO 4 .
  • Internal salts also can be formed. Similarly, when a compound disclosed herein contains a basic moiety, salts can be formed using organic and
  • salts can be formed from the following acids: acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, 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, and as well as other known pharmaceutically acceptable acids.
  • esters in the present invention refer to non-toxic esters of the compounds of formula (I), preferably the alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters, of which the methyl ester is preferred.
  • alkyl esters such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl esters, of which the methyl ester is preferred.
  • other esters such as phenyl-C 1-5 alkyl may be employed if desired.
  • examples of pharmaceutically acceptable esters include, but are not limited to, C 2 -C 6 alkyl esters such as methyl esters and ethyl esters.
  • esters include esters made with aliphatic carboxylic acids, preferably those with a linear chain of between two and six carbon atoms, preferably acetic acid, and made with aromatic carboxylic acids, e.g. C7- 12 acids such as benzoic acid.
  • the aliphatic and aromatic acids may optionally be substituted by one or more Ci -4 alkyl groups.
  • prodrugs of the compounds disclosed herein refers to a moiety that produces, generates or releases a compound of the present teachings when administered to a mammalian subject.
  • Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either by routine manipulation or in vivo, from the parent compounds.
  • prodrugs include compounds as described herein that contain one or more molecular moieties appended to a hydroxyl, amino, sulfhydryl, or carboxyl group of the compound, and that when administered to a mammalian subject, is cleaved in vivo to form the free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively.
  • prodrugs can include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present teachings. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S.
  • Carboxylic acid amide compounds of formula (I) in accordance with the present invention can be prepared as outlined in the schemes below and as illustrated in the examples, from (a) commercially available starting materials, (b) compounds known in the literature, or readily prepared intermediates using literature procedures, or (c) new intermediates described in the schemes and experimental procedures herein.
  • Reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformation being effected.
  • 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.
  • suitable solvents for a particular reaction step can be selected.
  • suitable solvents One skilled in the art of organic synthesis can readily selected suitable solvents.
  • 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), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry
  • chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
  • amino acid (II) is coupled with the desired amine (III) to provide a compound of Formula (I).
  • Many natural amino acids e.g., all of the standard amino acids
  • derivatives e.g., N-substituted derivatives
  • activated acid derivatives include, for example, acid chlorides, esters, acylimidazoles, anhydrides; these activated acid derivatives can be generated in situ or as isolated compounds.
  • Representative activating agents include, but are not limited to, sulfuryl chloride, thionyl chloride, 2-chloro-4,6-dimethoxy-1 ,3,5-triazine, and carbodiimides such as 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide and dicyclohexyl carbodiimide; for examples of amide bond formation and acid activation, see Montalbetti C.A.G.N. and Falque, V. (2005), Tetrahedron, 61 (46): 10827-10852, the entire disclosure of which is herein incorporated by reference.
  • the amine (III) can be synthesized as described in Scheme 2 below.
  • PtG e.g., tert-butyloxycarbonyl LG: e.g., Cl, Br, or I
  • alkylation of a protected amine (V) with a compound of formula (IVa) provides the protected alkylated amine (Vl).
  • Displacement of the leaving group on compound (Vl) with the appropriate amine (R 3 , wherein R 3 is NR f R g ) provides the amine-substituted aryl derivative (VII).
  • R 3 is NR f R g
  • alkylation of the protected amine (V) with a compound of formula (IVb) provides the amine-substituted aryl derivative (VII) directly. Removal of the protecting group (PtG) under standard conditions provides the desired amine (III).
  • the amine (III) can be synthesized from commercially available substituted acid halides, anhydrides or other activated carboxylic acid derivatives (Villa or VIIIb), as illustrated in Scheme 3 below.
  • Z e.g, halide, acetate LG: e.g, Cl, Br, or I p: 0, 1, 2, or 3
  • a substituted acid halide, anhydride or activated carboxylic acid derivative (Villa or VIIIb) is reacted with the appropriate amine R 2 -NH 2 to provide the amide (IXa or IXb).
  • amide (IXb) displacement of the leaving group (LG) with the appropriate amine (R 3 , wherein R 3 is NR f R g ) provides amide (IXa).
  • the amide (IXa) is reduced under standard conditions to provide the desired amine (III).
  • ion channel mediated condition refers to any condition or pathological state of a mammal or any disease present in a mammal that can be treated, or the symptoms of which can be alleviated, by modulation of the activity of one or more ion channels such as Ca v 2.2 voltage-gated calcium channels.
  • An ion channel mediated condition can be attributed to the abnormal functioning of one or more ion channels.
  • An ion channel can be functioning abnormally when, for example, the ion channel exhibits abnormally increased or decreased activation.
  • ion channel mediated conditions include conditions associated with neuronal hyperexcitability, conditions associated with abnormal glutamate regulation, pain, convulsions, epilepsy, stroke, anxiety disorders, neuronal disorders, traumatic brain injury, angina, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, diabetes, urinary incontinence, hot flush, thermal disregulation, and combinations thereof.
  • conditions associated with neuronal hyperexcitability include, but are not limited to, convulsions, including neonatal convulsions, epilepsy, episodic ataxia, myokymia, cerebral ischemia, cerebral palsy, stroke, traumatic brain injury, traumatic spinal cord injury, asphyxia, anoxia, prolonged cardiac surgery, and combinations thereof.
  • conditions associated with the abnormal regulation of glutamate include, but are not limited to, hypoglycemia or diseases associated with abnormal glutamate regulation such as, without limitation, Parkinson's disease, Huntingdon's disease, Alzheimer's disease, amyotrophic lateral sclerosis, AIDS-related dementia, and combinations thereof.
  • anxiety disorders include, but are not limited to, agoraphobia, panic disorder, specific phobia, social phobia, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, separation anxiety disorder, substance-induced anxiety disorder, and anxiety disorder not otherwise specified.
  • pain examples include, but are not limited to various types of nociceptic or neuropathic pain, such as, without limitation, inflammatory pain, musculoskeletal pain, bony pain, lumbosacral pain, neck or upper back pain, visceral pain, somatic pain, pain associated with diabetic neuropathy, cancer pain, pain caused by injury or surgery such as burn pain, headaches such as migraines or tension headaches, and combinations of these pains.
  • nociceptic or neuropathic pain such as, without limitation, inflammatory pain, musculoskeletal pain, bony pain, lumbosacral pain, neck or upper back pain, visceral pain, somatic pain, pain associated with diabetic neuropathy, cancer pain, pain caused by injury or surgery such as burn pain, headaches such as migraines or tension headaches, and combinations of these pains.
  • a pain caused by inflammation can also be visceral or musculoskeletal in nature.
  • Other examples of pain include those related to conditions of hyperalgesia, allodynia, or both
  • the compounds of the present teachings can be useful for the treatment of a pathological condition, disorder or disease, and the alleviation of a symptom thereof, in a mammal, for example, a human.
  • the pathological condition, disorder or disease, or a symptom thereof can be, but is not limited to, one of the various ion channel mediated conditions described above.
  • the compounds of the present teachings can be used for pain therapy, including treating, by way of non-limiting examples, the various types of pain described above.
  • "treating" refers to partially or completely alleviating, inhibiting, preventing and/or ameliorating the condition.
  • the present teachings therefore include use of the compounds disclosed herein as active therapeutic substances for the treatment of a variety of ion channel mediated conditions as well as for pain therapy.
  • the compounds disclosed herein can be useful for treating the various conditions associated with neuronal hyperexcitability, the various conditions associated with abnormal glutamate regulation, the various anxiety and neuronal disorders, angina, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, diabetes, urinary incontinence, and combinations thereof, as described above.
  • the compounds disclosed herein also can be useful for treating pain, including chronic pain that is neuropathic pain associated with damage to or pathological changes in the peripheral nervous system or the central nervous system; visceral pain associated with, by way of non-limiting examples, the abdominal, pelvic, and/or perineal regions or pancreatitis;, musculoskeletal pain; bony pain associated with, by way of non-limiting examples, bone or joint degenerating disorders such as osteoarthritis, rheumatoid arthritis, or spinal stenosis; cancer pain; musculoskeletal pain associated with, by way of non-limiting examples, the lower or upper back, spine, fibromylagia, temporomandibular joint, or myofascial pain syndrome; headaches such migraine or tension headaches; pain associated with infections such as HIV or shingles, sickle cell anemia, autoimmune disorders, multiple sclerosis, and inflammation in accordance with the methods described herein.
  • Inflammatory pain can be associated with a variety of medical conditions such as osteoarthritis, rheumatoid arthritis, surgery, or injury.
  • Neuropathic pain may be associated with, for example, diabetic neuropathy, peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, casualgia, thalamic syndrome, nerve root avulsion, or nerve damage cause by injury resulting in peripheral and/or central sensitization such as phantom limb pain, reflex sympathetic dystrophy or postthoracotomy pain, cancer, chemical injury, toxins, nutritional deficiencies, or viral or bacterial infections such as shingles or HIV, or combinations thereof.
  • the methods of use for compounds of this invention further include treatments in which the neuropathic pain is a condition secondary to metastatic infiltration, adiposis dolorosa, burns, or central pain conditions related to
  • Chronic pain may be associated with diabetes, post traumatic pain of amputation, lower back pain, spinal cord damage, cancer, chemical injury, chemotherapy induced peripheral neuropathy, toxins, major surgery, peripheral nerve damage due to traumatic injury, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, causalgia, thalamic syndrome, nerve root avulsion, reflex sympathetic dystrophy or post thoracotomy pain, nutritional deficiencies, viral infection, bacterial infection, metastatic infiltration, adiposis dolorosa, burns, central pain conditions related to thalamic conditions; and any combination thereof.
  • chronic pain refers to centralized or peripheral pain that is intense, localized, sharp, or stinging, and/or dull, aching, diffuse, or burning in nature and that occurs for extended periods of time (i.e., persistent and/or regularly reoccurring), including, for the purpose of the present invention, neuropathic pain and cancer pain.
  • Chronic pain includes neuropathic pain, hyperalgesia, and/or allodynia.
  • ion channels such as, but not limited to, the abnormal regulation of glutamate.
  • the present teachings therefore include methods of administering to a mammal a therapeutically effective amount of a compound disclosed herein.
  • administer or “administering” refers to either directly administering a compound of the present teachings or a pharmaceutical composition containing the compound, or administering the compound or pharmaceutical composition indirectly via a prodrug derivative or analog which will form an equivalent amount of the active compound or substance within the body.
  • the methods also can include identifying a mammal in need of such treatment, and administering a therapeutically effective amount of a compound disclosed herein to the mammal in need thereof.
  • therapeutically effective refers to a substance or an amount that elicits a desirable biological activity or effect.
  • the method includes administering to a mammal a pharmaceutical composition that comprises a compound disclosed herein in combination or association with a pharmaceutically acceptable carrier.
  • the compound of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment of such condition(s).
  • the other therapeutically effective compounds can include a cardiovascular disease agent and/or a nervous system disease agent.
  • a nervous system disease agent can be a peripheral nervous system (PNS) disease agent and/or a central nervous (CNS) disease agent.
  • the present teachings also relate to in vitro or in vivo methods of modulating the activity of ion channels including, but not limited to, Ca v 2.2 voltage-gated calcium channels.
  • such methods include contacting a Ca v 2.2 voltage- gated calcium channel with a compound disclosed herein.
  • the methods include monitoring the activity of ion channels.
  • the present teachings relate to methods of modulating the activity of an ion channel such as a Ca v 2.2 voltage-gated calcium channel that include in vitro or in vivo administration of a pharmaceutically effective amount of one or more compounds of formula (I).
  • pharmaceutically effective refers to an amount that can elicit an intended biological activity or effect.
  • an effective dosage can vary depending upon the particular compound utilized, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated.
  • a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to treat the symptoms of the disease and its complications.
  • the dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician.
  • the variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.
  • compositions comprising at least one compound described herein and one or more pharmaceutically acceptable carriers, excipients, or diluents.
  • pharmaceutically acceptable carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, PA (1985), the entire disclosure of which is incorporated by reference herein for all purposes.
  • pharmaceutically acceptable refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient.
  • pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable.
  • Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.
  • Compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.
  • Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials.
  • the compounds can be formulated in conventional manner, for example, in a manner similar to that used for known antiinflammatory agents.
  • Oral formulations containing an active compound disclosed herein can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions.
  • the carrier can be a finely divided solid, which is an admixture with a finely divided active compound.
  • an active compound can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets can contain up to about 99% or greater of the active compound.
  • Capsules can contain mixtures of active compound(s) with inert filler(s) and/or diluent(s) such as the pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.
  • inert filler(s) and/or diluent(s) such as the pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.
  • Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins.
  • pharmaceutically acceptable diluents including
  • Surface modifying agents can include nonionic and anionic surface modifying agents.
  • Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidol silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine.
  • Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the active compound(s).
  • the oral formulation can also consist of administering an active compound in water or fruit juice, containing appropriate solubilizers or emulisifiers as needed.
  • Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, and elixirs.
  • An active compound described herein can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators.
  • liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly containing additives as described above, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil).
  • the carrier can be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions, can be utilized by, for example, intrathecal, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • Compositions for oral administration can be in either liquid or solid form.
  • the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories.
  • the pharmaceutical composition can be sub-divided in unit dose(s) containing appropriate quantities of the active compound.
  • the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be a capsule or tablet itself, or it can comprise the appropriate number of any such compositions in package form.
  • Such unit dosage form may contain from about 1 mg/kg of active compound to about 500 mg/kg of active compound, and can be given in a single dose or in two or more doses.
  • Such doses can be administered in any manner useful in directing the active compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.
  • Such administrations can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (e.g., rectal and vaginal).
  • the compounds of the present teachings can be formulated, for example, into an aqueous or partially aqueous solution.
  • Compounds described herein can be administered enterally or parenterally (such as, without limitation, interperitoneal, intramuscular, intravascular, intrathecal, intraarticular or subcuteaneous injection or infusion).
  • Solutions or suspensions of these active compounds or pharmaceutically acceptable salts thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl-propylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.
  • the pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form is sterile and its viscosity permits it to flow through a syringe.
  • the form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (e.g., rectal and vaginal). Topical formulations that deliver active compound(s) through the epidermis can be useful for localized treatment of inflammation and arthritis.
  • Transdermal administration can be accomplished through the use of a transdermal patch containing an active compound and a carrier that can be inert to the active compound, can be non-toxic to the skin, and can allow delivery of the active compound for systemic absorption into the blood stream via the skin.
  • the carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
  • the creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active compound can also be suitable.
  • occlusive devices can be used to release the active compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the active compound with or without a carrier, or a matrix containing the active compound.
  • Other occlusive devices are known in the literature.
  • Compounds described herein can be administered into a body cavity, (e.g., rectally or vaginally) in the form of a conventional suppository.
  • Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin.
  • Water-soluble suppository bases such as polyethylene glycols of various molecular weights, can also be used.
  • Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo.
  • Lipid formulations and nanocapsules can be prepared by methods known in the art.
  • the compounds described herein can be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances, and are formed by mono or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any nontoxic, pharmacologically acceptable lipid capable of forming liposomes can be used.
  • a compound can be desirable to combine a compound with other agents effective in the treatment of the target disease.
  • other active compounds i.e., other active ingredients or agents
  • active compounds of the present teachings can be administered with active compounds of the present teachings.
  • the other agents can be administered at the same time or at different times than the compounds disclosed herein.
  • compositions of the present teachings also can 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.
  • an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from a group consisting of two or more of the recited elements or components.
  • 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 optical isomers (enantiomers) and diastereomers (geometric isomers), 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, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis.
  • the present teachings also encompass cis and trans isomers of compounds containing 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.
  • Amines of formula R 2 NH(CH 2 ) p ArR 3 can be coupled with various carboxylic acids and acid derivatives to provide compounds of formula (I).
  • Useful carboxylic acids and activated derivatives include those provided in the following examples as well as those that are commercially available or prepared according to procedures known in the art.
  • substitution patterns of the starting materials determines the substitution patterns of the products, and the skilled practioner will be able to exercise routine judgment for the selection of suitable starting materials in order to prepare specific products, the order of synthetic steps, and the need for protecting groups for remote functionalities.
  • the compounds were isolated as hydrochloride salts prepared via standard protocols using anhydrous hydrogen chloride as a gas, or as a solution in dioxane or diethyl ether.
  • the protonation state of the test compound is in accordance with the pH of the assay conditions, typically buffered as specified in the assay protocols, and not of the salt form or free base of the compound as synthesized.
  • R in the following representative schemes is a generic representation, that R wherever it appears does not have to be the same at each occurrence, and R can be selected from, for example, R 1 , R 1 , R 4 , R 4 , R f , R 9 , and substitutents on R 2 and R 3 , among others as appropriate and in accordance with the teachings herein.
  • HPLC B Nucleodur C18 EC, 4.6 x 250 mm
  • B 0.1% aqueous formic acid
  • Time/%B 0/90, 3/90, 8/20, 15/20, 18/90, 20/90
  • Flow 1.0 mL/min
  • Diluent MeOH
  • the 6-diethylamino-N-(4-fluoro-phenyl)-nicotinamide was suspended in a mixture of toluene (5 ml.) and tetrahydrofuran (10 ml.) and stirred at 0 0 C.
  • To the reaction was slowly added sodium bis(2-methoxyethoxy)aluminum hydride (65 wt.% in toluene, 1.8 ml_). The reaction was allowed to warm to room temperature and stirred for 15 minutes followed by heating at 50 0 C for 1 hour.
  • EXAMPLE 1 B ALTERNATIVE PREPARATION OF ⁇ 5-[(4-FLUORO- PHENYLAMINO)-METHYL]-PYRIDIN-2-YL ⁇ -DIETHYL-AMINE DIHYDROCHLORIDE
  • Flash chromatography (silica gel; 30-75% ethyl acetate in chloroform) provided (6- diethylamino-1-oxy-pyridin-2-ylmethyl)-(4-fluoro-phenyl)-carbamic acid terf-butyl ester (230 mg, 0.59 mmol) as a light yellow oil.
  • Step III Preparation of [3-(cyclopropyl-ethyl-amino)-benzyl]-(4-fluoro-phenyl)- carbamic acid terf-butyl ester
  • the reaction was warmed to room temperature, diluted with toluene (50 ml.) and stirred for 2 hours. The layers were separated and the aqueous phase washed with toluene (50 ml_). The organic phases were combined, washed with saturated sodium bicarbonate (30 ml_), water (30 ml_), and brine (30 ml_). The organic phase was filtered through a pad of Celite ® and the Celite ® pad washed with ethyl acetate. The organic filtrates were combined and concentrated under reduced pressure to provide a yellow solid.
  • reaction mixture was basified with 1 N sodium hydroxide to pH 10 and extracted with dichloromethane (2 x 50 ml_). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to provide a yellow oil. Flash chromatography (silica gel; 5-30% ethyl acetate in hexanes) provided (4- fluoro-phenyl)-(2-piperidin-1-yl-pyrimidin-5-ylmethyl)-amine (0.93 g, 3.25 mmol) as a yellow oil.
  • EXAMPLE 1 1 PREPARATION OF (4-FL-UORO-PHENYL)- ⁇ -PI PERI DI N-I -YL-- TH IAZOL-S-YLMETHYL)-AMI NE DI HYDROCHLORIDE
  • tert-butyl cyclopropyl(ethyl)carbamate (15 g, 0.081 mol) was treated with hydrogen chloride (4N in dioxane, 200 ml_). After 16 h, the reaction was evaporated and the residue triturated with diethylether, then hexane. The solid was then dried under vacuum to afford the product (8.67 g, 72 mmol).
  • EXAMPLE 15 PREPARATION OF 4-METHYL-2-METHYLAMINO-PENTANOIC ACID [4-(CYCLOPROPYL(ETHYL)AMI NO)BENZYL]-( ⁇ FLUORO-PHENYL)-AMI DE DIHYDROCHLORIDE (COMPOUND NO. 1 )
  • Flash chromatography (silica gel; 5-50% ethyl acetate in hexanes) provided (1- ⁇ [4-(cyclopropyl-ethyl-amino)-benzyl]-(4-fluoro- phenyl)-carbamoyl ⁇ -3-methyl-butyl)-methyl-carbamic acid tert-butyl ester (102 mg, 0.2 mmol) as a colorless oil.
  • EXAMPLE 17 PREPARATION OF 4-METHYL-2-METHYLAMINO-PENTANOIC ACI D [S-(CYCLOPROPYL-ETHYL-AMINO)-BENZYL]-( ⁇ FLUORO-PHENYL)-AMI DE DIHYDROCHLORI DE (COMPOUND S)
  • the resisue was diluted with ethyl acetate (40 mL), and washed with water (2 x 20 mL), saturated sodium bicarbonate (20 mL), and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to provide a yellow oil.
  • Flash chromatography (silica gel; 5-50% ethyl acetate in hexanes) provided (1 - ⁇ [3-(cyclopropyl-ethyl-amino)-benzyl]-(4-fluoro-phenyl)- carbamoyl ⁇ -3-methyl-butyl)-methyl-carbamic acid tert-butyl ester (300 mg, 0.59 mmol) as a colorless oil.
  • DIHYDROCHLORIDE COMPONENT 4
  • EXAMPLE 19 PREPARATION OF 4-METHYL-2-METHYLAMINO-PENTANOIC ACID [6-(CYCLOPROPYL-ETHYL-AMI NO)-PYRI Dl N-3-YLMETHYL]-(4-FLUORO- PHENYL)-AMIDE DIHYDROCHLORIDE (COMPOUND 5)
  • EXAMPLE 20 PREPARATION OF 2-DIMETHYLAMINO-4-METHYL-PENTANOIC ACID [6-(CYCLOPROPYL-ETHYL-AMI NO)-PYRI Dl N-3-YLMETHYL]-(4-FLUORO- PHENYL)-AMIDE DIHYDROCHLORIDE (COMPOUND 6)
  • DIHYDROCHLORIDE (COMPOUND 9)
  • EXAMPLE 24 PREPARATION OF 2-AMINO-N-(6-(CYCLOPROPYL-ETHYL- AMINO)-PYRIDIN-3-YLMETHYL)-N-(4-FLUORO-PHENYL)-3-PHENYL-
  • PROPIONAMIDE DIHYDROCHLORIDE (COMPOUND 10)
  • Representative compounds of formula (I) are screened for activity against calcium channel targets in several standard pharmacological test procedures. Based on the activity shown in the standard pharmacological test procedures, the compounds of the present teachings can be useful as ion channel modulators.
  • This assay was essentially performed as described in Lin et al. (1997), Neuron 18(1 1 ): 153-166; Pan J. and Lipsombe D. (2000), J. ⁇ /eurosc/.,20(13): 4768-75; and Xu W. and Lipscombe D. (2001 ), J. Neurosci., 21 (16): 5944-5951 , the entire disclosures of which are herein incorporated by reference, using Xenopus oocyte heterologeous expression system.
  • the assay was performed on various calcium channels (e.g., Ca v 2.2 subfamily) whereby the modulation of the calcium channel was measured for each tested compound.
  • IC 50 50% inhibitory concentration
  • HEK-293T/17 cells were transiently transfected in a similar manner as described in FuGENE 6 Package Insert Version 7, April 2002, Roche Applied Science, Indianapolis, IN.
  • the cells were plated at 2.5 x 10 5 cells in 2 ml. in a 6-well plate, incubated for one night, and achieved a -30-40% confluence.
  • sufficient serum-free medium was added as diluent for FuGENE Transfection Reagent (Roche Applied Science, Indianapolis, IN) to a total volume of 100 ⁇ l_.
  • To this medium was added 3 ⁇ l_ of FuGENE 6 Reagent. The mixture was tapped gently to mix.
  • TSA201 cells stably transfected with human Ca v 2.2 (composed of the subunits ⁇ 1 , ⁇ 3 and ⁇ 2 ⁇ ) and human Kir2.3 to enhance the FLIPR Ca 2+ signal were used. These cells were plated on 384-well collagen-coated plates (BD Bioscience, Franklin Lakes, NJ) at a density of 2x10 4 cells/well one day prior to the FLIPR assay.
  • FLUO-4 dye (Invitrogen, Carlsbad, CA) was diluted in 12 mL of Dulbecco's Modified Eagle's Medium (Invitrogen, Carlsbad, CA) to a final concentration of 4 ⁇ M in the presence of Pluronic F-127 (Invitrogen, Carlsbad, CA). Culture media is removed and replaced with 25 ⁇ l of the FLUO-4 dye solution and incubated for one hour at room temperature. The cell plate is then placed on the FLIPR where the dye is aspirated off and replaced with 25 ⁇ l of HBSS (Invitrogen, Carlsbad, CA). The HBSS is then aspirated and replaced with 25Dl of compound which is diluted in HBSS with 1% DMSO.

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Abstract

La présente invention concerne des composés de formule (I) et des sels, hydrates et esters acceptables du point de vue pharmaceutique de ceux-ci, dans laquelle Ar, R1, R1', R2, R3, R4, R4' et p sont tels que définis ici. La présente invention concerne également des procédés servant à produire lesdits composés et leurs sels, hydrates et esters acceptables du point de vue pharmaceutique et des procédés de traitement d'une affection ou d'un trouble pathologique, ou de soulagement d'un symptôme de celui-ci, utilisant lesdits composés y compris leurs sels, hydrates et esters acceptables du point de vue pharmaceutique. Les composés peuvent être utiles pour moduler l'activité de canaux ioniques par exemple pour traiter un grand nombre d'affections associées à la modulation anormale d'un ou plusieurs canaux calciques dépendants d'un potentiel d'action.
EP07865491A 2006-12-11 2007-12-11 Modulateurs de canaux ioniques Withdrawn EP2091917A1 (fr)

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