EP2097379A1 - Carboxamide derivatives as ion channel modulators - Google Patents

Carboxamide derivatives as ion channel modulators

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Publication number
EP2097379A1
EP2097379A1 EP07865495A EP07865495A EP2097379A1 EP 2097379 A1 EP2097379 A1 EP 2097379A1 EP 07865495 A EP07865495 A EP 07865495A EP 07865495 A EP07865495 A EP 07865495A EP 2097379 A1 EP2097379 A1 EP 2097379A1
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European Patent Office
Prior art keywords
phenyl
group
ylmethyl
pyridin
methyl
Prior art date
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EP07865495A
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German (de)
French (fr)
Inventor
Robert Zelle
Hormoz Mazdiyasni
Vincent Galullo
Christopher Todd Baker
Paul Will
Jinsong Guo
Danielle Soenen
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 EP2097379A1 publication Critical patent/EP2097379A1/en
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    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

Definitions

  • the present teachings relate to certain substituted benzamides and related 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 CH 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.
  • CH 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.
  • 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,
  • 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 0 2 6 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 ⁇ 2 ⁇ subunits, thereby inhibiting presynaptic calcium currents.
  • the present teachings also provide methods of making the compounds of formula (I), and methods of using the compounds of formula (I) 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 generally include administering a therapeutically effective amount of a compound of formula (I) 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, Na v 1.1 , Na v 1.2, Na v 1.3, Na v 1.7, Na v 1.8, and Na v 1.9.
  • Ca v 2.2 voltage-gated calcium channel refers to a voltage-gated calcium channel containing at least one Ca v 2.2 O 1 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 C 1-6 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 C 1-6 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.
  • 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.
  • 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- 7 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.
  • One or more 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 /-/,3H)-dione, pyridin-2(1 H)-one, and the like.
  • oxo groups such as piperidone, oxazolidinone, pyrimidine-2,4(1 /-/,3H)-dione, pyridin-2(1 H)-one, and the like.
  • Examples of 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 C , -C 2-6 alkyl-OR c , -C 2
  • 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 Ci-6 haloalkyl group, and a Ci -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:
  • 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.
  • a “leaving group” (“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
  • TsO toluenesulfonyl group, TsO
  • mesylate methanesulfonyl group, MsO
  • brosylate p- bromobenzenesulfonyl group, BsO
  • nosylate 4-nitrobenzenesulfonyl group, NsO
  • water H 2 O
  • ammonia NH 3
  • triflate trifluoromethanesulfonyl group, OTf
  • 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.
  • substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges.
  • the term "Ci -6 alkyl" is specifically intended to individually disclose Ci, C 2 , C 3 , C 4 , C 5 , C 6 , CrC 6 , CrC 5 , CrC 4 , CrC 3 , CrC 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 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.
  • X is selected from -NR C -, -O-, -CR a Rt > -, a divalent Ci -6 alkoxy group, a divalent Ci -6 alkyl group, a divalent C 2-6 alkenyl group, and a covalent bond;
  • R 1 at each occurrence, is independently selected from a halogen, -CN, - OR C , -C(O)OR C , -NR d R ⁇ , -S(O) m NR d R ⁇ , -N(R C )C(O)R C , -NO 2 , a phenyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group;
  • R 2 is C 3-6 cycloalkyl, benzyl, indole, phenyl, or a bicyclic aryl group, wherein
  • phenyl, benzyl, and cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, phenyl, C 1-6 alkyl, a C 1-6 alkoxy group, C 1-6 haloalkyl, C 1-6 haloalkoxy, -OCH 2 -phenyl, -CN, -C(0)0R c , -OH, -C(O)NH 2 , NHCORc, and -NR d R ⁇ ;
  • Ar-R 3 is selected from:
  • R 3 is selected from a halogen, a a piperidin-4-yl group, C 1-10 alkyl group, a C 1- io alkoxy group, a C 1-10 haloalkyl group, a C 1-10 haloalkoxy group, a -C(O)R 0 group,, C 3-6 cycloalkyl, and -Y-NR f R g , 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;
  • nitrogen ring atom of the piperidin-4-yl is optionally substituted with -C(O)O-C 1-6 alkyl;
  • Y at each occurrence, is independently a divalent C 1-6 alkyl group or a covalent bond; R a and R b taken together with the carbon atom to which they are bonded form a C 3-6 cycloalkyl group;
  • R c , R d and R ⁇ at each occurrence, independently are H, Ci -6 haloalkyl, or a Ci -6 alkyl group;
  • R f and R 9 at each occurrence, independently are selected from H, -C(O)R C , -
  • R f and R 9 taken together with the nitrogen atom to which they are bonded form a 5-7 membered cycloheteroalkyl group or a 5-7 membered heteroaryl group, the 5-7 membered cycloheteroalkyl group and the 5-7 membered heteroaryl group containing up to two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein
  • a sulfur atom in the ring optionally is substituted with 1 or 2 oxo groups
  • 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 ⁇ ,-S(O) 2 -Ci -6 alkyl, -C 2-6 alkyl-(5-7 membered cycloheteroalkyl), Ci -6 alkyl, C 3-8 cycloalkyl, -Y-(phenyl) q , or 5-7 membered heteroaryl,
  • one or more carbon atoms in the ring optionally are independently substituted with -C(O)-NR d R ⁇ , -Y-ORc, -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 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, Ci -6 alkyl, Ci -6 haloalkyl, and Ci -6 alkoxy;
  • 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 Ci -6 alkyl;
  • n 0, 1 , or 2;
  • n O, 1 , 2, or 3;
  • p is 1 , 2, 3, or 4;
  • q is 1 , 2, or 3;
  • R 2 is cycloalkyl and p is 2, then Ar-R 3 is not .
  • X can be selected from -NH-, -O-, and a covalent bond. In accordance with some embodiments, X can be selected from -CH(CH 3 )-, - C(CH 3 ) 2 -, and a cyclobutylgroup.
  • R 1 can be selected from a halogen, a Ci -6 alkyl group, a Ci -6 haloalkyl group, a phenyl group, and a Ci -6 alkoxy group.
  • R 1 can be selected from F, Cl, CH 3 , CF 3 , OH, -0-CH 3 , a phenyl group, and a t-butyl group.
  • R 1 can be selected from a hydroxyl group, CN, -S(O) 2 NH 2 , - C(O)OH, -C(O)CH 3 , -NHC(O)-Ci -6 alkyl group, and a nitro group.
  • R 1 can be -NO 2 , -CN, -CO 2 CH 3 , -S(O) 2 NH 2 , or - NHC(O)CH 3 .
  • R 2 can be a phenyl group optionally substituted with 1-2 substituents independently selected from a halogen, a Ci -6 alkyl group, a phenyl group, a Ci -6 alkoxy group, a Ci -6 haloalkyl group, and a -OCH 2 -phenyl group.
  • R 2 can be a 4-fluorophenyl group, a 4-chlorophenyl group, a 4- methylphenyl group, a 3-methylphenyl group, a 2-methylphenyl group, a 4-fluoro-2- methylphenyl group, a 5-chloro-2-methyl group, a 3,5-dichlorophenyl group, a 2,3- dichlorophenyl group, a 3,5-dimethylphenyl group, a 2,6-dimethylphenyl group, a 3- cyanophenyl group, a 3-tert-butylphenyl group, a 2-isopropyl-phenyl group, a 3- isopropyl-phenyl group, a biphenyl-2-yl group, a biphenyl-4-yl group, a 4- benzyloxyphenyl group, a 3-chloro-2-methoxyphenyl group, a 3-trifluoromethylphenyl group, or
  • R 2 can be a phenyl group optionally substituted with 1-2 substituents independently selected from, -CN, -C(0)0R c , -OH, -C(O)NH 2 , NHCOR C , and -NR d R ⁇ wherein R c , R d and R ⁇ are as defined above.
  • R 2 can be a 2-carbamoylphenyl group, a 3-carbamoylphenyl group, a 4-carbamoylphenyl group, a 4-hydroxyphenyl, 3-acetamidophenyl, a 3-tert-butoxycarbonylphenyl group, a 4-tert- butoxycarbonylphenyl group, or a 3-carboxylphenyl group.
  • R 2 can be selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • R 2 can be a 1-naphthyl group, a 1 H-indol-5- yl group, or a quinolin-6-yl group.
  • Ar-R 3 can be:
  • 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-C 1-6 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, a -C(O)-phenyl group, an N(Ci -6 alkyl)-Y-(5-7 membered cycloheteroalkyl), 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
  • R 3 can be a diethylamino group, a diphenylamino group, a methyl(2-pyridin-2- ylethyl)amino group, a methyl(2-morpholin-4-ylethyl)amino group, a methyl(4- chlorobenzoyl)amino group, a 2-(dimethylamino)ethyl](methyl)amino, or a cyclopropyl(ethyl)amino group.
  • R 3 can be an optionally substituted 5-7 membered cycloheteroalkyl group or an optionally substituted 5-7 membered heteroaryl group as described herein.
  • 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, wherein each of these groups can include a nitrogen ring atom optionally substituted with -C(O)R C , -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 -Y-(phenyl) q group, a Ci -6 alkyl group, or a 5-7 membered heteroaryl group, a carbon ring
  • 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 0 , -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, a -Y-(phenyl) q group, or a 5-7 membered heteroaryl group.
  • R 3 can be a 4-methylpiperazin-1-yl group, a 4-(4- fluorophenyl) piperazin-1-yl group, a 4-[bis(4-fluorophenyl)methyl]piperazin-1-yl group, a 4-pyridin-2-ylpiperazin-1-yl group, or a 4-(methylsulfonyl)piperazin-1-yl group.
  • R 3 can be a 1-pipe ⁇ dinyl 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 4-(hydroxymethyl)piperidin- 1-yl group
  • R 3 can be a trifluoromethyl group, chloro, a 2,2,2-trifluoroethoxy group, or a cyclohexyl group
  • R 3 can be an optionally substituted piperidin-4-yl group, such as, for example, a 1-tert-butoxycarbonyl-piperidin-4-yl 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.
  • salts of the compounds 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 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-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine).
  • metal salts such as alkali metal or al
  • 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.
  • salts can be formed using organic and inorganic acids.
  • 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-Ci -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. C 7- - I2 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. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, the entire disclosures of which are incorporated by reference herein for all purposes.
  • 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. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated.
  • process conditions i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.
  • Optimum reaction conditions may vary with the particular reactants or solvent used, but one skilled in the art can determine such conditions by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds described 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.
  • aryl acid (II) is coupled with the desired amine (III) to provide a compound of Formula (I).
  • Many aryl acids and their derivatives are commercially available or can otherwise be prepared by literature methods.
  • 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.
  • Scheme 2 illustrates a method for preparing compounds of formula (I) where X is
  • Scheme 3 illustrates a method for preparing compounds of formula (I) where X is
  • R 3 group can be incorporated in the last step of the synthesis, as illustrated in Scheme 4 below.
  • Z e.g., halide or acetate
  • LG e.g.,Cl, Br, or I
  • alkylation of a protected amine (X) with a compound of formula (Villa) provides the protected alkylated amine (Xl).
  • Displacement of the leaving group on compound (Xl) with the appropriate amine (R 3 , wherein R 3 is NR f R g ) provides the amine-substituted aryl derivative (XII).
  • alkylation of the protected amine (X) with a compound of formula (VIIIb) provides the amine-substituted aryl derivative (XII) 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 6 below.
  • LG e.g., Cl, Br or I
  • a substituted acid halide, anhydride or activated carboxylic acid derivative (XIIIa or XIIIb) is reacted with the appropriate amine R 2 -NH 2 to provide the amide (XIVa or XIVb).
  • amide (XIVb) displacement of the leaving group (LG) with the appropriate amine (R 3 , wherein R 3 is NR f R g ) provides amide (XIVa).
  • the amide (XIVa) 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.
  • 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 such as, for example, those described in Remington's Pharmaceutical
  • 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 in powders, 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
  • 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.
  • 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
  • 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, intra- articular 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 f , R 9 , and substitutents on R 2 and R 3 , among others as appropriate and in accordance with the teachings herein.
  • R can be selected from, for example, R f , R 9 , and substitutents on R 2 and R 3 , among others as appropriate and in accordance with the teachings herein.
  • Ar represents an aryl group in accordance with the teachings herein, and any of the alkyl, aryl and cylcloalkyl groups may be substituted in accordance with the teachings herein.
  • the 6-diethylamino-N-(4-fluorophenyl)-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 2 PREPARATION OF CYCLOPROPYL- ⁇ 5-[(4- FLUOROPHENYLAMINO)-METHYL]-PYRIDIN-2-YL ⁇ -ETHYL-AMINE
  • Step III Preparation of [3-(cyclopropyl-ethyl-amino)-benzyl]-(4-fluorophenyl)- 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.
  • EXAMPLE 8 PREPARATION OF (4-FLUOROPHENYL)- ⁇ -PI PERIDI N-I -YL- PYRI M I D I N-5-YLM ETH YL)-AM I N E
  • 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- fluorophenyl)-(2-piperidin-1-yl-pyrimidin-5-ylmethyl)-amine (0.93 g, 3.25 mmol) as a yellow oil.
  • EXAMPLE 1 1 PREPARATION OF (4-FLUOROPHENYL)- ⁇ -PI PERI DIN-I -YL- TH IAZOL-S-YLMETHYL)-AMI NE DI HYDROCHLORIDE
  • Step 1 To a stirred solution of 6-chloronicotinaldehyde (3.0 g, 21.2 mmol) and 4- fluoroaniline (2.0 mL, 21.2 mmol) in dichloromethane (70 mL) was added acetic acid (3.6 mL) and the resulting solution was stirred overnight at room temperature. Sodium triacetoxyborohydride (9.0 g, 42.4 mmol) was added and the solution was stirred an additional hour. The reaction was quenched with 1 N NaOH solution and extracted with dichloromethane.
  • Step 2 To a stirred solution of 2,2,2-trifluoroethanol (0.42 g, 4.2 mmol) in DMF (3 mL) at 0 0 C was added sodium hydride (0.17 g, 4.20 mmol) and the resulting solution was stirred 15 minutes. To this was added N-[(6-chloropyridin-3-yl)methyl]-4- fluoroaniline (0.20 g, 0.85 mmol) and the resulting solution was heated over 3 days at
  • EXAMPLE 16 4-(CHLOROMETHYL)-N-CYCLOPROPYL-N-ETHYL-I 1 S-THIAZOL-
  • 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).
  • Part I A: Preparation of 4-chloro-N-(4-fluorophenyl)-benzamide
  • the free base (309 mg, 0.75 mmol) was treated with 1% aqueous trifluoroacetic acid, and lyophilized to provide 4-chloro-N-(6-diethylamino-pyridin-3-yl-methyl)-N-(4- fluorophenyl)-benzamide trifluoroacetate (394 mg, 1.44 mmol) as a gummy solid.
  • EXAMPLE 20 PREPARATION OF 4-CHLORO-N-(4-FLUOROPHENYL)-N-(2- PI PERIDI N-I -YL-THIAZOL ⁇ -YL-METHYL)-BENZAMI DE HYDROCHLORIDE
  • 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. ⁇ feurosc/.,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 25 ⁇ l of compound which is diluted in HBSS with 1% DMSO.

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Abstract

The present teachings provide compounds of Formula (I) wherein Ar, R1, R2, R3, X, p and n are defined herein. The present teachings also provide processes for producing said compounds and methods of treating a pathological condition or disorder, or alleviating a symptom thereof, using said compounds. The compounds can be useful in modulating ion channel activity including treating a variety of conditions associated with the abnormal modulation of one or more voltage-gated calcium channels.

Description

CARBOXAMIDE DERIVATIVES AS ION CHANNEL MODULATORS
This application claims the benefit of U.S. Provisional Application Ser. No. 60/874,206, filed December 1 1 , 2006, the entire disclosure of which is incorporated herein by reference, and of U.S. Provisional Application Ser. No. 60/874,102, filed December 1 1 , 2006.
FIELD OF THE INVENTION
The present teachings relate to certain substituted benzamides and related derivatives, processes for their preparation, and their use in therapeutic treatments.
BACKGROUND OF THE INVENTION
All cells rely on the regulated movement of inorganic ions across cell membranes to perform essential physiological functions. Electrical excitability, synaptic plasticity, and signal transduction are examples of processes in which changes in ion concentration play a critical role. In general, the 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+, Ca2+, 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 Ca2+ 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, Ca2+, and phosphorylation).
The Cav2 family of voltage-gated calcium channels consists of 3 main subtypes Cav2.1 (P or Q-type calcium currents), Cav2.2 (N-type calcium currents), and Cav2.3 (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 Cav2 channels is a widespread and highly efficacious means of regulating neurotransmission. The subunit composition of the Cav2 channels is defined by their CH subunit, which forms the pore and contains the voltage-sensing gates (CH2.1 , αi2.2, and αi2.3, also known as diA, CHB, and diE, respectively) and the β and α2 subunits.
Genetic or pharmacological perturbations in 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). The growing number of identified ion channels and understanding of their complexity will assist in future efforts at therapies, that can modify ion channel function.
Therapeutic modulation of Cav2 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 Cav2.2 channels triggers the release of neurotransmitters from presynaptic nerve terminals in the spinal cord. Hence, blockade of Cav2.2 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). Indeed, intrathecal injection of the Cav2.2-selective conotoxin ziconitide (SNX-11 1 ) has been shown to be effective against both neuropathic pain and inflammatory pain in animals and man (Bowersox, S. S. et al. (1996), J. Pharmacol. Exp. Ther., 279: 1243-1249). Ziconotide has also been shown to be effective as a neuroprotective agent in rat models of global or focal ischemia (Colburne, F. et al. (1999), Stroke, 30: 662-668). Thus, it is reasonable to conclude that modulation of Cav2.2 can have implications in the treatment of neuroprotection and/or stroke.
Cav2.2 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. Cav2.2 modulators could be particularly effective in treating this disorder. Although complete block of Cav2.2 channels can cause hypotension or impair baroreceptor reflexes, partial inhibition by Cav2.2 modulators might reduce hypertension with minimal reflex tachycardia (Uneyama, O. D. (1999), Int. J. MoI. Med., 3: 455-466).
Overactive bladder (OAB) 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 Cav2.2 and/or Cav1 channels.
The localization of Cav2.1 channels in the superficial laminae of the dorsal horn of the spinal cord suggests involvement of these channels in the perception and maintenance of certain forms of pain (Vanegas, H. and Schaible, H. (2000), Pain, 85: 9-18). Complete elimination of Cav2.1 calcium currents alters synaptic transmission, resulting in severe ataxia. Gabapentin has been used clinically for many years as an add-on therapy for the treatment of epilepsy. In recent years, it has emerged as a leading treatment of neuropathic pain. Clinical trials have shown gabapentin to be effective for the treatment of post-herpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, migrane and fibromyalgia (Mellegers, P. G. et al. (2001 ), CHn. J. Pain, 17: 284-295). Gabapentin was designed as a metabologically stable GABA mimetic, but most studies find no effect on the GABA receptors. The 026 subunit of voltage-gated calcium channels has been identified as a high affinity binding site for gabapentin in the CNS. There is evidence that suggests that gabapentin could inhibit neurotransmission in the spinal cord by interfering with the function of the α2δ subunits, thereby inhibiting presynaptic calcium currents.
SUMMARY OF THE INVENTION
The present teachings relate to compounds of formula (I):
and pharmaceutically acceptable salts, hydrates, and esters thereof, wherein Ar, R1, R2, R3, X, p and n are defined as described herein.
The present teachings also provide methods of making the compounds of formula (I), and methods of using the compounds of formula (I) 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 generally include administering a therapeutically effective amount of a compound of formula (I) to a mammal.
DETAILED DESCRIPTION OF THE INVENTION
Embodiments of the present invention provide compounds that can modulate the activity of ion channels in a mammal, for example, Cav2.2 voltage-gated calcium channels, and can treat a variety of pathological conditions, states, disorders or diseases.
Unless otherwise indicated, the following terms are held to have the following meanings as used herein.
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, Cav1 .1 , CaJ .2, CaJ .3, Cav2.1 , Cav2.2, Cav2.3, Ca«3.1 , Cav3.2, Nav1.1 , Nav1.2, Nav1.3, Nav1.7, Nav1.8, and Nav1.9. As used herein, "Cav2.2 voltage-gated calcium channel" refers to a voltage-gated calcium channel containing at least one Cav2.2 O1 subunit. The phrase "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 Cav2.2 voltage-gated calcium channels.
As used herein, "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.
As used herein, "oxo" refers to a double-bonded oxygen (i.e., =0).
As used herein, "alkyl" refers to a straight-chain or branched saturated hydrocarbon group. Examples of 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. In various embodiments, an alkyl group has 1-6 carbon atoms, and is referred to as a "Ci-6 alkyl group." Examples of 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 C3-6 alkyl group, i.e., a branched lower alkyl group. Examples of branched lower alkyl groups include, but are not limited to:
isopropyl, isobutyl, sec-butyl, terf-butyl, isopentyl, neopentyl, and tert-pentyl. As used here, a divalent C1-6 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 C1-6 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.
As used herein, "alkenyl" refers to a straight-chain or branched alkyl group having one or more carbon-carbon double bonds. Examples of 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 C3-6 alkenyl group,.
The term "alkynyl" refers to a straight-chain or branched alkyl group having one or more carbon-carbon triple bonds. Examples of 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 C3-6 alkynyl group,
As used herein, "alkoxy" refers to an -O-alkyl group wherein the alkyl group may be a straight or branched chain. Examples of 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-).
As used herein, "haloalkyl" refers to an alkyl group having one or more halogen substituents. Examples of haloalkyl groups include, but are not limited to, -CF3, -C2F5, -CHF2, -CH2F, -CCI3, -CHCI2, -CH2CI, -C2CI5, and the like. Perhaloalkyl groups, i.e., alkyl groups wherein all of the hydrogen atoms are replaced with halogen atoms (e.g., CF3 and C2F5), are included within the definition of "haloalkyl."
As used herein, "haloalkoxy" refers to an alkoxy group having one or more halogen substituents. Examples of haloalkoxy groups include, but are not limited to, -OCF3, -OC2F5, -OCHF2, and the like.
As used herein, "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. In various embodiments, a cycloalkyl group has 3-6 carbon atoms, and is referred to as a "C3-6 cycloalkyl group." Examples of C3-6 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.
As used herein, "heteroatom" refers to an atom of any element other than carbon or hydrogen and includes, for example, nitrogen, oxygen, sulfur, phosphorus, and selenium.
As used herein, "cycloheteroalkyl" refers to a non-aromatic cycloalkyl group having 5- 7 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. One or more 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 /-/,3H)-dione, pyridin-2(1 H)-one, and the like. Examples of 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. For example, in some embodiments, 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)-NRdRΘ, -Y-ORC, -Y-NRdRΘ, 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)RC, -C2-6 alkyl-ORc, -C2-6 alkyl-NRdRΘ, -Y- C(O)NRdRΘ, an -S(O)2-Ci-6 alkyl group, a -C2-6 alkyl— (5-7 membered cycloheteroalkyl) group, or a 5-7 membered heteroaryl group, wherein Y, Rc, Rd, and RΘ are as defined hereinbelow. Further, 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.
As used herein, "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. In some embodiments, 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. Examples of 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. Examples of 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). Other examples of aryl groups include, but are not limited to, benzodioxanyl, benzodioxolyl, chromanyl, indolinyl groups, and the like. In some embodiments, aryl groups optionally contain up to three independently selected substitution groups. For example, a phenyl group, in some embodiments, can be optionally substituted with 1 to 3 substituents independently selected from a halogen, CN, -C(O)ORC, -NRdRΘ, a Ci-6 alkyl group, a Ci-6 haloalkyl group, and a Ci-6 alkoxy group, wherein Rc, Rd, and RΘ are as defined hereinbelow.
As used herein, "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. Generally, heteroaryl rings do not contain 0-0, S-S, or S-O bonds. However, 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). Examples of heteroaryl groups include, for example, the 5-membered monocyclic and 5-6 bicyclic ring systems shown below:
where K is 0, S, NH, or NR'; and R' can be selected from a halogen, a C1-6 alkyl group, a C(O)RC group, a C2-6 alkyl-ORc group, a C2-6 alkyl-NRdRΘ group, a -Y- C(O)NRdRΘ group, an S(O)2-C1-6 alkyl group, a 5-7 membered heteroaryl group, and a C2-6 alkyl— (5-7 membered cycloheteroalkyl) group, where Y, Rc, Rd and RΘ are as defined hereinbelow. Examples of such 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, pteridine, purine, oxazolopyridine, thiazolopyridine, imidazopyridine, furopyridine, thienopyridine, pyridopyrimidine, pyridopyrazine, pyridopyridazine, thienothiazole, thienoxazole, and thienoimidazole. Further examples of heteroaryl groups include, but are not limited to, 4,5,6,7-tetrahydroindole, tetrahydroquinoline, benzothienopyridine, benzofuropyridine, and the like. In some embodiments, heteroaryl groups can be substituted with up to three independently selected substitution groups. For example, in some embodiments, 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 C1-6 alkyl group, -C(O)-NRdRΘ, -Y-ORC, -Y-NRdRΘ, 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, Rc, Rd, and RΘ are as defined hereinbelow. Further, 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.
Aa "divalent group" is defined herein as a linking group capable of forming a covalent bond with two other moieties. As used herein, a "leaving group" ("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. Examples of 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 (H2O), ammonia (NH3), and triflate (trifluoromethanesulfonyl group, OTf).
As used herein, a "protecting group" ("PtG") refers to modification of a functional group that reduces the reactivity of the functional group in an unwanted reaction. Examples of protecting groups for amines include, but are not limited to, tert- butyloxycarbonyl (t-BOC), benzyl (Bn), and carbobenzyloxy (Cbz) groups. Examples of protecting groups for carbonyls include, but are not limited to, acetals and ketals. Examples of 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.
At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term "Ci-6 alkyl" is specifically intended to individually disclose Ci, C2, C3, C4, C5, C6, CrC6, CrC5, CrC4, CrC3, CrC2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl. By way of another example, 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.
The present teachings provide compounds of formula (I):
and pharmaceutically acceptable salts, hydrates and esters thereof, wherein:
X is selected from -NRC-, -O-, -CRaRt>-, a divalent Ci-6 alkoxy group, a divalent Ci-6 alkyl group, a divalent C2-6 alkenyl group, and a covalent bond; R1, at each occurrence, is independently selected from a halogen, -CN, - ORC, -C(O)ORC, -NRdRΘ, -S(O)mNRdRΘ, -N(RC)C(O)RC, -NO2, a phenyl group, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group;
R2 is C3-6 cycloalkyl, benzyl, indole, phenyl, or a bicyclic aryl group, wherein
wherein the phenyl, benzyl, and cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, phenyl, C1-6 alkyl, a C1-6 alkoxy group, C1-6 haloalkyl, C1-6 haloalkoxy, -OCH2-phenyl, -CN, -C(0)0Rc, -OH, -C(O)NH2, NHCORc, and -NRdRΘ;
Ar-R3 is selected from:
R3 is selected from a halogen, a a piperidin-4-yl group, C1-10 alkyl group, a C1- io alkoxy group, a C1-10 haloalkyl group, a C1-10 haloalkoxy group, a -C(O)R0 group,, C3-6 cycloalkyl, and -Y-NRfRg, wherein
the CMO alkyl group and the CMO alkoxy group are optionally substituted with from 1-3 substitutents selected from a halogen, a phenyl group, and -OH;
wherein the nitrogen ring atom of the piperidin-4-yl is optionally substituted with -C(O)O-C1-6 alkyl;
Y, at each occurrence, is independently a divalent C1-6 alkyl group or a covalent bond; Ra and Rb taken together with the carbon atom to which they are bonded form a C3-6 cycloalkyl group;
Rc, Rd and RΘ, at each occurrence, independently are H, Ci-6 haloalkyl, or a Ci-6 alkyl group;
Rf and R9, at each occurrence, independently are selected from H, -C(O)RC, -
C2-6 alkyl-ORc, -C2-6 alkyl-NRdRΘ, a CM0 alkyl group, a C3-6 cycloalkyl group, a -Y-phenyl group, a -C(O)-phenyl group, a -Y-(5-7 membered cycloheteroalkyl), a -Y-(5-7 membered heteroaryl) group, and a -C2-6 alkyl— O-Y-(5-7 membered heteroaryl) group,
alternatively, Rf and R9 taken together with the nitrogen atom to which they are bonded form a 5-7 membered cycloheteroalkyl group or a 5-7 membered heteroaryl group, the 5-7 membered cycloheteroalkyl group and the 5-7 membered heteroaryl group containing up to two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein
a sulfur atom in the ring optionally is substituted with 1 or 2 oxo groups;
one or more nitrogen atoms in the ring optionally are independently substituted with -C(O)RC, -C2-6 alkyl-ORc, -C2-6 alkyl-NRdRΘ, -Y- C(O)NRdRΘ,-S(O)2-Ci-6 alkyl, -C2-6 alkyl-(5-7 membered cycloheteroalkyl), Ci-6 alkyl, C3-8 cycloalkyl, -Y-(phenyl)q, or 5-7 membered heteroaryl,
one or more carbon atoms in the ring optionally are independently substituted with -C(O)-NRdRΘ, -Y-ORc, -Y-NRdRΘ, 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 each of the phenyl groups appearing anywhere in said Rf and R9 is optionally substituted with 1 to 3 substituents independently selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, and Ci-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 Rf and R9 is optionally substituted with 1 to 3 substituents independently selected from halogen and Ci-6 alkyl;
m is 0, 1 , or 2;
n is O, 1 , 2, or 3;
p is 1 , 2, 3, or 4; and
q is 1 , 2, or 3;
with the proviso is
R2 is cycloalkyl and p is 2, then Ar-R3 is not .
In some embodiments, X can be selected from -CH2-, -CH2-O-, -0-CH2-, -CH2CH2CH2-O-, -CH2CH2-, and -CH=CH-.
In accordance with other embodiments, X can be selected from -NH-, -O-, and a covalent bond. In accordance with some embodiments, X can be selected from -CH(CH3)-, - C(CH3)2-, and a cyclobutylgroup.
In certain embodiments, R1 can be selected from a halogen, a Ci-6 alkyl group, a Ci-6 haloalkyl group, a phenyl group, and a Ci-6 alkoxy group. In particular embodiments, R1 can be selected from F, Cl, CH3, CF3, OH, -0-CH3, a phenyl group, and a t-butyl group.
In certain embodiments, R1 can be selected from a hydroxyl group, CN, -S(O)2NH2, - C(O)OH, -C(O)CH3, -NHC(O)-Ci-6 alkyl group, and a nitro group. In accordance with some embodiments, R1 can be -NO2, -CN, -CO2CH3, -S(O)2NH2, or - NHC(O)CH3.
In some embodiments, R2 can be a phenyl group optionally substituted with 1-2 substituents independently selected from a halogen, a Ci-6 alkyl group, a phenyl group, a Ci-6 alkoxy group, a Ci-6 haloalkyl group, and a -OCH2-phenyl group. For example, R2 can be a 4-fluorophenyl group, a 4-chlorophenyl group, a 4- methylphenyl group, a 3-methylphenyl group, a 2-methylphenyl group, a 4-fluoro-2- methylphenyl group, a 5-chloro-2-methyl group, a 3,5-dichlorophenyl group, a 2,3- dichlorophenyl group, a 3,5-dimethylphenyl group, a 2,6-dimethylphenyl group, a 3- cyanophenyl group, a 3-tert-butylphenyl group, a 2-isopropyl-phenyl group, a 3- isopropyl-phenyl group, a biphenyl-2-yl group, a biphenyl-4-yl group, a 4- benzyloxyphenyl group, a 3-chloro-2-methoxyphenyl group, a 3-trifluoromethylphenyl group, or a 4-trifluoromethylphenyl group.
In some embodiments, R2 can be a phenyl group optionally substituted with 1-2 substituents independently selected from, -CN, -C(0)0Rc, -OH, -C(O)NH2, NHCORC, and -NRdRΘ wherein Rc, Rd and RΘ are as defined above. For example, R2 can be a 2-carbamoylphenyl group, a 3-carbamoylphenyl group, a 4-carbamoylphenyl group, a 4-hydroxyphenyl, 3-acetamidophenyl, a 3-tert-butoxycarbonylphenyl group, a 4-tert- butoxycarbonylphenyl group, or a 3-carboxylphenyl group. In other embodiments, R2 can be selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
In accordance with some embodiments, R2 can be a 1-naphthyl group, a 1 H-indol-5- yl group, or a quinolin-6-yl group.
In certain embodiments, Ar-R3 can be:
wherein R3 is as defined above.
In some embodiments, R3 can be NRfRg, wherein Rf and R9 are as defined above. In particular embodiments, R3 can be selected from NH2, an NH-C1-6 alkyl group, an N(Ci-6 alkyl)2 group wherein the Ci-6 alkyl groups do not need to be the same,, an NH-C3-6 cycloalkyl group, an N(Ci-6 alkyl)— C3-6 cycloalkyl group, an N(Ci-6 alkyl)-C2-6 alkyl-ORc group, a -C(O)-phenyl group, an N(Ci-6 alkyl)-Y-(5-7 membered cycloheteroalkyl), 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)-C2-6 alkyl-O-Y-(5-7 membered heteroaryl) group, wherein each of the phenyl group, the 5-7 membered cycloheteroalkyl group, and the 5-7 membered heteroaryl group immediately above is optionally substituted with 1 to 3 substituents independently selected from a halogen and a Ci-6 alkyl group, and Y and Rc are as defined above. For example, R3 can be a diethylamino group, a diphenylamino group, a methyl(2-pyridin-2- ylethyl)amino group, a methyl(2-morpholin-4-ylethyl)amino group, a methyl(4- chlorobenzoyl)amino group, a 2-(dimethylamino)ethyl](methyl)amino, or a cyclopropyl(ethyl)amino group. In other embodiments, R3 can be an optionally substituted 5-7 membered cycloheteroalkyl group or an optionally substituted 5-7 membered heteroaryl group as described herein. In certain embodiments, R3 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, wherein each of these groups can include a nitrogen ring atom optionally substituted with -C(O)RC, -C2-6 alkyl-ORc, -C2-6 alkyl-NRdRΘ, -Y-C(O)NRdRΘ, an -S(O)2-Ci-6 alkyl group, a - C2-6 alkyl— (5-7 membered cycloheteroalkyl) group, a -Y-(phenyl)q group, a Ci-6 alkyl group, or a 5-7 membered heteroaryl group, a carbon ring atom optionally substituted with -C(O)-NRdRΘ, -Y-ORc, -Y-NRdRΘ, 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 a sulfur ring atom optionally substituted with 1 or 2 oxo groups, wherein each of the phenyl groups immediately above is 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 groups, the 5-7 membered heteroaryl groups, and the 5- 9 membered heteroaryl groups immediately above is optionally substituted with 1 to 3 substituents independently selected from a halogen and a Ci-6 alkyl group, wherein Y, Rc, Rd and RΘ are as defined above.
In particular embodiments, R3 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.
In some embodiments, R3 can be a 1 -piperazinyl group having a nitrogen atom in the ring optionally substituted with -C(O)R0, -C2-6 alkyl-ORc, -C2-6 alkyl-NRdRΘ, -Ci-6 alkyl-C(O)NRdRΘ, an S(O)2-Ci-6 alkyl group, a -C2-6 alkyl-(5-7 membered cycloheteroalkyl) group, a Ci-6 alkyl group, a -Y-(phenyl)q group, or a 5-7 membered heteroaryl group. For example, R3 can be a 4-methylpiperazin-1-yl group, a 4-(4- fluorophenyl) piperazin-1-yl group, a 4-[bis(4-fluorophenyl)methyl]piperazin-1-yl group, a 4-pyridin-2-ylpiperazin-1-yl group, or a 4-(methylsulfonyl)piperazin-1-yl group. In other embodiments, R3 can be a 1-pipeιϊdinyl group having a carbon atom in the ring optionally substituted with -NRdRΘ, -C(O)-NRdRΘ, -Y-ORC, a 5-7 cycloheteroalkyl group, a 5-9 membered heteroaryl group, or a -Y-O-(5-7 membered heteroaryl) group. For example, R3 can be a 4-(hydroxymethyl)piperidin- 1-yl group
In accordance with some embodiments, R3 can be a trifluoromethyl group, chloro, a 2,2,2-trifluoroethoxy group, or a cyclohexyl group
According to some embodiments, R3 can be an optionally substituted piperidin-4-yl group, such as, for example, a 1-tert-butoxycarbonyl-piperidin-4-yl 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.
TABLE 1
,3-
Pharmaceutically acceptable salts of the compounds 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 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-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCO3, Na2CO3, KHCO3, K2CO3, Cs2CO3, LiOH, NaOH, KOH, NaH2PO4, Na2HPO4, and Na3PO4. Internal salts also can be formed. Similarly, when a compound disclosed herein contains a basic moiety, salts can be formed using organic and inorganic acids. For example, 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.
Pharmaceutically acceptable 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. However, other esters such as phenyl-Ci-5 alkyl may be employed if desired. Examples of pharmaceutically acceptable esters include, but are not limited to, C2-C6 alkyl esters such as methyl esters and ethyl esters. Pharmaceutically acceptable 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--I2 acids such as benzoic acid. The aliphatic and aromatic acids may optionally be substituted by one or more Ci-4 alkyl groups.
Also provided in accordance with the present teachings are prodrugs of the compounds disclosed herein. As used herein, "prodrug" 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. Examples of 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. Examples of 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. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, the entire disclosures of which are incorporated by reference herein for all purposes.
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. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but one skilled in the art can determine such conditions by routine optimization procedures. Those skilled in the art of organic synthesis will recognize that the nature and order of the synthetic steps presented may be varied for the purpose of optimizing the formation of the compounds described 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. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected. One skilled in the art of organic synthesis can readily selected suitable solvents.
It is understood by those skilled in the art of organic synthesis that the various functionalities present on the molecule must be consistent with the chemical transformation proposed. This may necessitate routine judgment as to the order of synthetic steps, and the need for protecting groups for remote functionalities. One skilled in the art can readily determine the need for protection and deprotection and select appropriate protecting groups. The chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991 , the entire disclosure of which is herein incorporated by reference. The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography.
In the schemes provided herein, unless expressed to the contrary, variables in chemical formulae are as defined in other formulae herein. For example, Ar, R1, R2, R3, X and n in the schemes are defined as in any of the formulae herein, except where defined otherwise in the schemes.
One method for preparing compounds of formula (I) where X is a covalent bond involves the coupling of an aryl acid or acid derivative (II) with an appropriate amine (III) as shown in Scheme 1 below:
SCHEME 1
An aryl acid (II), or alternatively an activated acid derivative, is coupled with the desired amine (III) to provide a compound of Formula (I). Many aryl acids and their derivatives are commercially available or can otherwise be prepared by literature methods.
Examples of 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.
Scheme 2 illustrates a method for preparing compounds of formula (I) where X is
-NRC- and Rc is H, by coupling an optionally substituted isocyanatobenzene compound (IV) with the desired amine (III).
SCHEME 2
Scheme 3 illustrates a method for preparing compounds of formula (I) where X is
-O-, by coupling an optionally substituted phenyl formate (V) with the desired amine (III). SCHEME 3
Alternatively the R3 group can be incorporated in the last step of the synthesis, as illustrated in Scheme 4 below.
SCHEME 4
(VI) (VII) (IX) (I)
Z: e.g., halide or acetate LG: e.g.,Cl, Br, or I
In this scheme, an acid halide, anhydride or activated acid derivative (Vl) is reacted with the appropriate amine (R2-NH2) to provide the amide (VII). Alkylation of the resulting amide (VII) with a compound of formula (VIII) provides the substituted amide (IX). Compounds of formula (VIII) are either commercially available or can otherwise be readily synthesized. Displacement of the leaving group on the substituted amide (IX) with the desired R3 group provides a compound of Formula (I).
The amine (III) can be synthesized as described in Scheme 5 below. SCHEME 5
(X) (VIIIb)
In this scheme, alkylation of a protected amine (X) with a compound of formula (Villa) provides the protected alkylated amine (Xl). Displacement of the leaving group on compound (Xl) with the appropriate amine (R3, wherein R3 is NRfRg) provides the amine-substituted aryl derivative (XII). Alternatively, alkylation of the protected amine (X) with a compound of formula (VIIIb) provides the amine-substituted aryl derivative (XII) directly. Removal of the protecting group (PtG) under standard conditions provides the desired amine (III).
Alternatively, 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 6 below.
SCHEME 6
LG: e.g., Cl, Br or I In this scheme, a substituted acid halide, anhydride or activated carboxylic acid derivative (XIIIa or XIIIb) is reacted with the appropriate amine R2-NH2 to provide the amide (XIVa or XIVb). In the case of amide (XIVb), displacement of the leaving group (LG) with the appropriate amine (R3, wherein R3 is NRfRg) provides amide (XIVa). Finally, the amide (XIVa) is reduced under standard conditions to provide the desired amine (III).
A third approach commences with a substituted aryl compound (XV), as illustrated in Scheme 7 below.
SCHEME 7
X O Reductive
LG^ , Me2NCHO M AAmcinattiioonn Rl N Ar-R3
^Ar-R3 ► H^^AArr--RR33 Z ► ϊ I.
R2-NH2 H
(XV) (in)
(XVI)
More specifically, conversion of a compound of formula (XV) to the corresponding organometallic derivative and treatment with dimethylformamide (Me2NCHO) provides the aryl aldehyde (Ia). Reductive amination with the appropriate amine (R2- NH2) provides the desired amine (III).
Evaluation of representative compounds according to embodiments of this invention indicated that the compounds of the present teachings can modulate the activity of ion channels in a mammal, for example, Cav2.2 voltage-gated calcium channels.
A variety of pathological conditions, states, disorders or diseases can be treated by modulating the activity of certain ion channels. As used herein, "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 Cav2.2 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.
By way of non-limiting examples, 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.
Examples of 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.
Examples of 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.
Examples of 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.
Examples of pain 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. One skilled in the art will recognize that these pain types can overlap one another. For example, 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 types of pain listed above can be acute (short duration) or chronic (regularly reoccuring or persistent), centralized or peripheral, and can be with or without peripheral or central sensitization.
Accordingly, 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. In some embodiments, 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. As used herein, "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.
For example, 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 thalamic conditions.
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. As used herein, the term "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.
One skilled in the art will also recognize that at least some of the types of pain described above can be attributed to a condition associated with the abnormal activity of one or more 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. As used 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. As used herein, "therapeutically effective" refers to a substance or an amount that elicits a desirable biological activity or effect.
In some embodiments, 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). For example, 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, Cav2.2 voltage-gated calcium channels. In some embodiments, such methods include contacting a Cav2.2 voltage- gated calcium channel with a compound disclosed herein. In certain embodiments, the methods include monitoring the activity of ion channels. In various embodiments, the present teachings relate to methods of modulating the activity of an ion channel such as a Cav2.2 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). As used herein, "pharmaceutically effective" refers to an amount that can elicit an intended biological activity or effect.
When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that 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. In therapeutic applications, 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.
The present teachings also provide pharmaceutical compositions comprising at least one compound described herein and one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of such 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. As used herein, "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. Accordingly, 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. In powders, the carrier can be a finely divided solid, which is an admixture with a finely divided active compound. In tablets, 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.
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. 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. Examples of 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). For parenteral administration, 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.
Preferably the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, 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. Alternatively, 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).
In some cases, it may be desirable to administer a compound directly to the airways of the patient in the form of a dry powder or an aerosol. For administration by intranasal or intrabronchial inhalation, 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, intra- articular 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. In preferred embodiments, 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. A variety of 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. For example, the compounds described herein can be administered in the form of liposomes. As is known in the art, 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.
To increase the effectiveness of compounds of the present teachings, it can be desirable to combine a compound with other agents effective in the treatment of the target disease. For inflammatory diseases, other active compounds (i.e., other active ingredients or agents) effective in their treatment, and particularly in the treatment of asthma and arthritis, 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.
Throughout the description, where 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 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.
In the application, where 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.
The use of the singular herein includes the plural (and vice versa) unless specifically stated otherwise. In addition, where the use of the term "about" is before a quantitative value, the present teachings also include the specific quantitative value itself, unless specifically stated otherwise.
It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present teachings remain operable. Moreover, two or more steps or actions may be conducted simultaneously.
Compounds described herein can contain an asymmetric atom (also referred as a chiral center), and 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.
Throughout the specification, structures may or may not be presented with chemical names. Where any question arises as to nomenclature, the structure prevails.
Aspects of the present teachings can be further understood in light of the following examples, which should not be construed as limiting the scope of the present teachings in any way. More specifically, the following examples illustrate various synthetic routes that can be used to prepare reagents and intermediates, including appropriate amines and carboxylic acids, that can be used to prepare compounds of formula (I).
EXAMPLES
Amines of formula R2NH(CH2)pArR3, including those provided in the following examples and others commercially available or prepared according to procedures known in the art, 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.
Compound Numbers 1-291 were prepared in accordance with Representative Schemes 1-18 and the following specific examples of analogous compounds using the appropriate starting materials. Selected compounds are shown in Table 2 below.
It is understood by those skilled in the art of organic synthesis that the 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.
While certain acyl chlorides are illustrated in the representative schemes as examples of activated acid derivatives useful for acylation of amines, other reagents for amide bond formation as known in the art can be utilized in the preparation of compounds of formula (I) in accordance with the teachings herein.
In some cases, 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. Those skilled in the art will also appreciate that 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.
One of skill in the art of organic chemistry would recognize that reference to 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, Rf, R9, and substitutents on R2 and R3, among others as appropriate and in accordance with the teachings herein. In the following schemes,
Ar represents an aryl group in accordance with the teachings herein, and any of the alkyl, aryl and cylcloalkyl groups may be substituted in accordance with the teachings herein.
When reference is made to HPLC retention time, the following HPLC conditions were used:
HPLC A: Waters Xterra RP18, 3.5u, 150 x 4.6 mm; Temperature 40 0C; Flow Rate1.2 mL/min; Mobile Phase Comp. 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10min, hold 4min; Injection Volume 5 μL; Detector Wavelength 210-37O nM.
HPLC B: Nucleodur C18 EC, 4.6 x 250 mm, Mobile phase: A = MeCN, 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; Temperature 50 0C; Diluent: MeOH; and
HPLC C: Mobile phase gradient = 5% acetonitrile / 95% ammonium acetate (10 mM) to 95% acetonitrile / 5% ammonium acetate (10 mM) over 2.5 min, hold for 1.5 min, then re-equilibrate. Column = Keystone Aquasil™ C18 column (2 x 50 mm, 5 mM). Detection = 214 nm and 254 nm. REPRESENTATIVE SCHEME 1
REPRESENTATIVE SCHEME 2 REPRESENTATIVE SCHEME 3
REPRESENTATIVE SCHEME 4
REPRESENTATIVE SCHEME 5
REPRESENTATIVE SCHEME 6 ine
REPRESENTATIVE SCHEME 7
REPRESENTATIVE SCHEME 8
REPRESENTATIVE SCHEME 9
REPRESENTATIVE SCHEME 10
REPRESENTATIVE SCHEME 11 REPRESENTATIVE SCHEME 12
REPRESENTATIVE SCHEME 13
REPRESENTATIVE SCHEME 14 REPRESENTATIVE SCHEME 15
REPRESENTATIVE SCHEME 16
REPRESENTATIVE SCHEME 17
REPRESENTATIVE SCHEME 18 EXAMPLE 1A: PREPARATION OF (5-[(4-FLUOROPHENYLAMI NO)-METHYL]-
PYRIDIN-2-YL}-DIETHYLAMINE
NaAIH(OCH2CH2OMe)2
Part I: Preparation of 6-chloro-N-(4-fluorophenyl)-nicotinamide
To a solution of 4-fluoroaniline (15.8 g, 142 mmol) in dichloromethane (450 mL) at 0°C was slowly added a solution of 6-chloro-nicotinoyl chloride (25 g, 142 mmol) in dichloromethane (50 mL), followed by triethylamine (23.7 mL, 170 mmol). After the addition was complete, the reaction was stirred at 0°C for 30 minutes, followed by warming to room temperature. After stirring for 30 minutes, the resulting solid was filtered, washed with water and dried under reduced pressure to provide 6-chloro-N- (4-fluorophenyl)-nicotinamide (35 g, 139.6 mmol) as a white solid.
Part II: Preparation of N-(4-fluorophenyl)-6-iodo-nicotinamide
To a solution of 6-chloro-N-(4-fluorophenyl)-nicotinamide (6.4 g, 25.5 mmol) in acetone (130 mL) was added sodium iodide (38.2 g, 255.3 mmol) followed by the dropwise addition of acetyl chloride (7.3 ml_, 102 mmol). The yellow mixture was heated at reflux for 1 hour. The reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate (10 ml.) and 1 N sodium hydroxide (10 ml_). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide N-(4-fluorophenyl)-6-iodo- nicotinamide (6.76 g, 19.8 mmol) as a white solid.
Part III: Preparation of 6-diethylamino-N-(4-fluorophenyl)-nicotinamide
A mixture of N-(4-fluorophenyl)-6-iodo-nicotinamide (684 mg, 2 mmol), diethylamine hydrochloride (0.326 g, 4 mmol), and potassium carbonate (91 1 mg, 6.6 mmol) in 1- methyl-2-pyrrolidinone (2 ml.) was heated at 140°C in a sealed tube for 65 hours.
After cooling to room temperature, a saturated aqueous sodium bicarbonate solution
(5 ml.) was added, followed by extraction into ethyl acetate (5 ml_). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 6-diethylamino-N-(4-fluorophenyl)-nicotinamide as a solid which was used directly in the next reaction without further purification.
Part IV: Preparation of {5-[(4-fluorophenylamino)-methyl]-pyridin-2-yl}-diethyl-amine
The 6-diethylamino-N-(4-fluorophenyl)-nicotinamide was suspended in a mixture of toluene (5 ml.) and tetrahydrofuran (10 ml.) and stirred at 00C. 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 500C for 1 hour. The mixture was cooled to room temperature and quenched by the slow addition of an aqueous saturated sodium bicarbonate solution (10 ml.) and 6N sodium hydroxide (10 ml.) followed by extraction into ethyl acetate (30 ml_). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide {5-[(4- fluorophenylamino)-methyl]-pyridin-2-yl}diethyl-amine (300 mg, 1.2 mmol) as an oil. EXAMPLE 1 B: ALTERNATIVE PREPARATION OF {5-[(4- FLUOROPHENYLAMINO)-METHYL]-PYRIDIN-2-YL}-DIETHYL-AMINE
DIHYDROCHLORIDE
Part I: Preparation of (6-chloro-1-oxy-pyridin-3-ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester
To a solution of (6-chloro-pyridin-3-ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester (1 g, 2.97 mmol) in chloroform (10 mL) was added m-chloroperbenzoic acid (1 g, 4.5 mmol) and the reaction heated at 50°C for 6 hours. (6-Chloro-pyridin-3- ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester can be prepared analogously to (6-bromo-pyridin-2-ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester following the procedures described in Example 3 infra. The reaction was cooled to room temperature, diluted with dichloromethane (6 mL), and washed with 3N sodium hydroxide (6 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. Purification by chromatography (silica gel; 3:7 ethyl acetate:hexane) provided (6-chloro-1-oxy- pyridin-3-ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester (1 g, 2.8 mmol) as a colorless oil.
Part II: Preparation of (6-diethylamino-1-oxy-pyridin-3-ylmethyl)-(4-fluorophenyl)- carbamic acid terf-butyl ester
(6-Chloro-1-oxy-pyridin-3-ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester (1 g, 2.8 mmol) and diethyl amine (2.9 ml_, 28.4 mmol) were combined in a sealed tube. The reaction was heated at 130°C overnight. The reaction was cooled to room temperature and concentrated under reduced pressure. Purification by chromatography (silica gel; ethyl acetate) provided (6-diethylamino-1-oxy-pyridin-3- ylmethyl)-(4-fluorophenyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester (1 g, 2.5 mmol) as a brown oil.
Part III: Preparation of (6-diethylamino-pyridin-3-ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester
(6-Diethylamino-1-oxy-pyridin-3-ylmethyl)-(4-fluorophenyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester (1 g, 2.5 mmol) was dissolved in chloroform (10 ml_). Phosphorous trichloride (336 μl_, 3.85 mmol) was added, and the reaction was stirred at room temperature for 45 minutes. The reaction mixture was diluted with dichloromethane (10 ml.) and washed with 3N sodium hydroxide (20 ml_). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. Purification by chromatography (silica gel; 1 :9 ethyl acetate:hexane) provided (6-diethylamino-pyridin-3-ylmethyl)-(4-fluorophenyl)- carbamic acid terf-butyl ester (920 mg, 2.5 mmol) as a colorless oil.
Part IV: Preparation of {5-[(4-fluorophenylamino)-methyl]-pyridin-2-yl}-diethyl-amine dihydrochloride
To a solution of (6-diethylamino-pyridin-3-ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester (900 mg, 2.4 mmol) in methanol (10 ml.) was added gaseous hydrochloric acid at 00C. The reaction was allowed to warm to room temperature and stirred for 30 minutes. The reaction was concentrated to provide {5-[(4- fluorophenylamino)-methyl]-pyridin-2-yl}-diethyl-amine dihydrochloride (665 mg, 2.4 mmol) as a white solid.
EXAMPLE 2: PREPARATION OF CYCLOPROPYL-{5-[(4- FLUOROPHENYLAMINO)-METHYL]-PYRIDIN-2-YL}-ETHYL-AMINE
DIHYDROCHLORIDE
Part I: Preparation of 6-cyclopropylamino-nicotinic acid ethyl ester
A mixture of ethyl-6-chloro-nicotinate (10 g, 53.9 mmol) in cyclopropyl amine (10 mL) was heated in a sealed tube at 800C for 12 hours. The reaction was cooled and the mixture purified by chromatography (silica gel; ethyl acetate : hexane gradient elution) to provide 6-cyclopropylamino-nicotinic acid ethyl ester (6.9 g, 32.2 mmol) as an oil.
Part II: Preparation of 6-(cyclopropyl-ethyl-amino)-nicotinic acid ethyl ester
To a solution of 6-cyclopropylamino-nicotinic acid ethyl ester (6.9 g, 32.2 mmol) in anhydrous tetrahydrofuran (80 mL) containing dimethyl formamide (50 μL) at 0°C was added sodium hydride (60% dispersion in mineral oil, 1.85 g, 48.3 mmol). The reaction was allowed to warm to room temperature and stirred for 30 minutes. The reaction was treated with ethyl iodide (3.0 ml_, 48.3 mmol) and the reaction allowed to stir overnight. The reaction was quenched by the addition of water (10 ml_), followed by extraction with ethyl acetate (2 x 50 ml_). The organic phases were combined, washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica gel; ethyl acetate:hexane gradient elution) provided 6- (cyclopropyl-ethyl-amino)-nicotinic acid ethyl ester (6.45 g, 27.5 mmol) as an oil.
Part III: Preparation of 6-(cyclopropyl-ethyl-amino)-N-(4-fluorophenyl)-nicotinamide
To a solution of 4-fluoroaniline (4.65 ml_, 35.8 mmol) in toluene (50 ml.) was slowly added 2M trimethylaluminum in toluene (16.5 ml_, 33 mmol) and the reaction allowed to stir for 1 hour. A solution of 6-(cyclopropyl-ethyl-amino)-nicotinic acid ethyl ester (6.45g, 27.5 mmol) in toluene (25 ml.) was added and the reaction heated to 600C. After 12 hours, the reaction was cooled to room temperature and quenched by the dropwise addition of methanol. The reaction was concentrated under reduced pressure and the residue taken up into ethyl acetate (100 ml_). The organic phase was washed with saturated sodium bicarbonate (25 ml_), saturated potassium- sodium tartrate (25 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica gel; ethyl acetate:hexane gradient elution) provided 6-(cyclopropyl-ethyl-amino)-N-(4- fluorophenyl)-nicotinamide (7.25 g, 24.1 mmol).
Part IV: Preparation of cyclopropyl-{5-[(4-fluorophenylamino)-methyl]-pyridin-2-yl}- ethyl-amine dihydrochloride
To a mixture of 6-(cyclopropyl-ethyl-amino)-N-(4-fluorophenyl)-nicotinamide (7.25 g, 24.1 mmol) in toluene (20 ml.) and anhydrous tetrahydrofuran (40 ml.) at 00C was slowly added sodium bis(2-methoxyethoxy)aluminum hydride (65 wt.% in toluene, 16 ml_). The reaction was allowed to warm to room temperature and stirred for 15 minutes followed by heating at 500C for 1 hour. The mixture was cooled to room temperature and quenched by the slow addition of an aqueous saturated sodium bicarbonate solution (20 mL) and 6N sodium hydroxide (20 ml.) followed by extraction into ethyl acetate (60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica gel; ethyl acetate:hexane gradient elution) provided cyclopropyl-{5-[(4-fluorophenylamino)-methyl]-pyridin-2-yl}-ethyl-amine (8.0 g, 23.1 mmol).
The free base was treated with ethereal hydrochloric acid to provide cyclopropyl-{5- [(4-fluorophenylamino)-methyl]-pyridin-2-yl}-ethyl-amine dihydrochloride (6.8 g, 23.1 mmol) as a white solid.
EXAMPLE 3: PREPARATION OF DIETHYL-{6-[(4-FLUOROPHENYLAMINO)-
METHYL]-PYRI DI N^-YLJ-AMI NE DIHYDROCHLORI DE
Part I: Preparation of 2-bromo-6-chloromethyl-pyridine
To a solution of (6-bromo-pyridin-2-yl)-methanol (1.5 g, 8.0 mmol) in chloroform (10 mL) was added dropwise sulfuryl choride (1.29 mL, 16 mmol) and the reaction stirred overnight. The reaction was concentrated under reduced pressure to provide a yellow semi-solid. The material was triturated with diethyl ether/hexanes and the solid collected to provide 2-bromo-6-chloromethyl-pyridine (900 mg, 4.37 mmol) as a sticky white solid. Part II: Preparation of (6-bromo-pyridin-2-ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester
To a solution of (4-fluorophenyl)-carbamic acid terf-butyl ester (60144-53-8, 750 mg, 3.55 mmol) in tetrahydrofuran (10 ml.) was added sodium hydride (60% dispersion in mineral oil, 150 mg, 3.9 mmol). After 30 minutes, tetra-n-butylammonium iodide (51 mg, 0.36 mmol) and 2-bromo-6-chloromethyl-pyridine (804 mg, 3.9 mmol) was added to the reaction and the mixture was heated to 70°C. After 1 hour, the reaction was cooled to room temperature, quenched with saturated sodium bicarbonate (10 ml.) and extracted with ethyl acetate (2 x 15 ml_). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (silica gel; 10% ethyl acetate in hexanes) provided (6-bromo-pyridin-2-ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester (700 mg, 1.84 mmol) as an oil which solidified upon standing.
Part III: Preparation of (6-bromo-1-oxy-pyridin-2-ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester
To a solution of (6-bromo-pyridin-2-ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester (700 mg, 1.84 mmol) in chloroform (8 ml.) was added m-chloroperbenzoic acid (477 mg, 2.76 mmol) and the reaction heated to 500C. After stirring overnight, the reaction was cooled to room temperature, diluted with chloroform (10 ml.) and washed with 3N sodium hydroxide (5 ml_). The layers were separated and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide a yellow solid upon standing. Purification by chromatography (silica gel; 10-20% ethyl acetate in chloroform) provided (6-bromo-1- oxy-pyridin-2-ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester (400 mg, 1.0 mmol) as a white solid.
Part IV: Preparation of (6-diethylamino-1-oxy-pyridin-2-ylmethyl)-(4-fluorophenyl)- carbamic acid terf-butyl ester A suspension of (6-bromo-1-oxy-pyridin-2-ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester (400 mg, 1.0 mmol) in diethylamine (7 mL) was heated to 1300C in a sealed tube. After stirring overnight, the reaction was cooled to room temperature and partitioned between brine (10 mL) and ethyl acetate (15 mL). The layers were separated and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide a dark liquid. Flash chromatography (silica gel; 30-75% ethyl acetate in chloroform) provided (6- diethylamino-1-oxy-pyridin-2-ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester (230 mg, 0.59 mmol) as a light yellow oil.
Part V: Preparation of diethyl-{6-[(4-fluorophenylamino)-methyl]-pyridin-2-yl}-amine dihydrochloride
To a solution of (6-diethylamino-1-oxy-pyridin-2-ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester (230 mg, 0.59 mmol) in chloroform (2 mL) was added phosphorous trichloride (121 mg, 0.89 mmol). After stirring for 1 hour, the reaction was diluted with chloroform (10 mL) and washed with 3N sodium hydroxide (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide a yellow oil. The oil was dissolved in chloroform (2 mL) and treated with trifluoroacetic acid (1 mL) and allowed to stir for 1 hour. The reaction was concentrated under reduced pressure and the residue treated with ethereal hydrochloric acid. The resulting solid was collected to provide diethyl-{6-[(4-fluorophenylamino)-methyl]-pyridin-2-yl}-amine dihydrochloride (182 mg, 0.59 mmol) as a white solid.
EXAMPLE 4: PREPARATION OF ETHYL-CYCLOPROPYL-{[4-(4- FLUOROPHENYLAMINO)-M ETHYL]-PH ENYL}-AMI N E
Part I: Preparation of (4-fluorophenyl)-carbamic acid te/t-butyl ester
A mixture of 4-fluoroaniline (4.2 mL, 44.1 mmol) and carbonic acid di-terf-butyl ester (1 1.55 g, 52.9 mmol) in toluene (100 mL) was heated at reflux overnight. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was triturated with hexanes to provide (4- fluorophenyl)-carbamic acid terf-butyl ester (8.4 g, 39.8 mmol) as an off-white solid.
Part II: Preparation of (4-fluorophenyl)-(4-iodo-benzyl)-carbamic acid terf-butyl ester
A solution of (4-fluorophenyl)-carbamic acid terf-butyl ester (9.98 g, 47.3 mmol) in anhydrous tetrahydrofuran (150 mL) was cooled to 0°C and treated with sodium hydride (60% dispersion in mineral oil, 2.3 g, 56.8 mmol). The mixture was warmed to room temperature and stirred for 30 minutes. To the reaction was added 1- bromomethyl-4-iodo-benzene (14.0 g, 47.3 mmol) and the mixture was allowed to stir at room temperature overnight. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, washed with brine (50 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica gel; 5% ethyl acetate in hexanes) provided (4-fluorophenyl)-(4-iodo-benzyl)-carbamic acid terf-butyl ester (18 g, 42.1 mmol) as a colorless oil.
Part III: Preparation of (4-cyclopropylamino-benzyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester
A mixture of (4-fluorophenyl)-(4-iodo-benzyl)-carbamic acid terf-butyl ester (10 g, 23.4 mmol), cyclopropylamine (4.86 ml_, 70.2 mmol), copper (I) iodide (445 mg, 2.34 mmol), potassium carbonate (6.5 g, 46.8 mmol), and L-proline (540 mg, 4.68 mmol) were combined in dimethylsulfoxide (100 ml.) and heated at 80°C for 5 hours. The reaction mixture was cooled, diluted with water (50 ml_), and extracted with ethyl acetate (2 x 100 ml_). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The (4-cyclopropylamino-benzyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester was used in the next step without further purification.
Part IV: Preparation of [4-(cyclopropyl-ethyl-amino)-benzyl]-(4-fluorophenyl)-carbamic acid terf-butyl ester
To the (4-cyclopropylamino-benzyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester from the previous step in dichloromethane (100 ml.) was added acetaldehyde (1.44 ml_, 25.7 mmol) and acetic acid (1.6 ml_, 28.1 mmol). The solution was stirred at room temperature for 30 minutes, followed by the addition of sodium triacetoxyborohydride (2.0 g, 9.4 mmol). After 30 minutes, another portion of sodium triacetoxyborohydride (2.0 g, 9.4 mmol) was added. A third portion of sodium triacetoxyborohydride (2.0 g, 9.4 mmol) was added and the reaction stirred for 30 minutes. The 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; 10% ethyl acetate in hexanes) provided [4-(cyclopropyl-ethyl-amino)-benzyl]-(4-fluorophenyl)-carbamic acid terf-butyl ester a yellow oil, which was used directly in the next reaction.
Part V: Preparation of ethyl-cyclopropyl-{[4-(4-fluorophenylamino)-methyl]-phenyl}- amine
To a solution of [4-(cyclopropyl-ethyl-amino)-benzyl]-(4-fluorophenyl)-carbamic acid te/t-butyl ester from the previous step in dichloromethane (20 ml.) was added trifluoroacetic acid (20 ml.) at 0°C. The solution was warmed up to room temperature and stirred for 30 minutes. The reaction was concentrated to dryness under reduced pressure and the residue was dissolved in dichloromethane (20 ml_). The organic layer was washed with 3N sodium hydroxide (10 ml_), dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. Flash chromatography (silica gel; 10% ethyl acetate in hexanes) provided ethyl- cyclopropyl-{[4-(4-fluorophenylamino)-methyl]-phenyl}-amine (6 g, 21.1 mmol) as a yellow oil.
EXAMPLE 5: PREPARATION OF DIETHYL-{[4-(4-FLUOROPHENYLAMINO)-
METHYL]-PH ENYL}-AMI N E DIHYDROCHLORIDE
Part I: Preparation of 4-diethylamino-N-(4-fluorophenyl)-benzamide To a solution of 4-diethylamino-benzoic acid (1.0 g, 5.2 mmol) and N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide (1.4 g, 9.4 mmol) in pyridine (10 ml.) was added 4-fluoroaniline (446 μl_, 4.7 mmol) and the reaction stirred overnight. The reaction was concentrated under reduced pressure to provide a red oil, which was partitioned between saturated sodium bicarbonate, and hexanes and flash ethyl acetate. The resulting precipitate was collected and dried under reduced pressure to provide 4-diethylamino-N-(4-fluorophenyl)-benzamide (1.2 g, 4.2 mmol) as a white solid.
Part II: Preparation of diethyl-{[4-(4-fluorophenylamino)-methyl]-phenyl}-amine dihydrochloride
To a solution of 4-diethylamino-N-(4-fluorophenyl)-benzamide (600 mg, 2.1 mmol) in anhydrous tetrahydrofuran (10 ml.) was added dropwise 1 M borane tetrahydrofuran complex (6.3 ml_, 6.3 mmol). The reaction was heated to reflux and stirred for 3 hours. The reaction was cooled to room temperature and treated with saturated hydrochloric acid in methanol (6 ml.) and heated to reflux for 3 hours. The reaction was cooled to room temperature and the resulting precipitate filtered and dried to provide diethyl-{[4-(4-fluorophenylamino)-methyl]-phenyl}-amine dihydrochloride (622 mg, 1.8 mmol) as a white solid.
EXAMPLE 6: PREPARATION OF ETHYL-CYCLOPROPYL-{[3-(4- FLUOROPHENYLAMINO)-M ETHYL]-PHENYL)}AMINE
ine
Part I: Preparation of (4-fluorophenyl)-(3-iodo-benzyl)-carbamic acid te/t-butyl ester
A solution of (4-fluorophenyl)-carbamic acid terf-butyl ester (5 g, 47.3 mmol) in anhydrous tetrahydrofuran (80 mL) was cooled to 0°C and treated with sodium hydride (60% dispersion in mineral oil, 1.1 g, 28.4 mmol). The mixture was warmed to room temperature and stirred for 30 minutes. To the reaction was added 1- bromomethyl-3-iodo-benzene (7.0 g, 23.7 mmol) and the mixture was allowed to stir at room temperature overnight. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica gel; 5% ethyl acetate in hexanes) provided (4-fluorophenyl)-(3-iodo-benzyl)-carbamic acid terf-butyl ester (9 g, 21.1 mmol) as a colorless oil, which was contaminated with residual (4-fluorophenyl)-carbamic acid te/t-butyl ester. Part II: Preparation of (3-cyclopropylamino-benzyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester
A mixture of (4-fluorophenyl)-(3-iodo-benzyl)-carbamic acid terf-butyl ester (5.8 g,
13.6 mmol), cyclopropylamine (3.8 mL, 54.4 mmol), copper (I) iodide (260 mg, 1.36 mmol), potassium carbonate (7.5 g, 54.4 mmol), and L-proline (313 mg, 2.72 mmol) were combined in dimethylsulfoxide (60 mL) and heated at 80°C for 4 hours. The reaction mixture was cooled, diluted with water (50 mL), and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The (3-cyclopropylamino-benzyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester was used in the next step without further purification.
Step III: Preparation of [3-(cyclopropyl-ethyl-amino)-benzyl]-(4-fluorophenyl)- carbamic acid terf-butyl ester
To the (3-cyclopropylamino-benzyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester from the previous step in dichloromethane (30 mL) was added acetaldehyde (840 μL,
15 mmol) and acetic acid (933 μL, 16.3 mmol). The solution was stirred at room temperature for 30 minutes, followed by the addition of sodium triacetoxyborohydride
(3.5 g, 16.32 mmol). After 30 minutes, another portion of sodium triacetoxyborohydride (3.5 g, 16.32 mmol) was added. A third portion of sodium triacetoxyborohydride (3.5 g, 16.32 mmol) was added and the reaction stirred for 30 minutes. The 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; 10% ethyl acetate in hexanes) provided (3-(cyclopropyl-ethyl-amino)-benzyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester a yellow oil, which was used directly in the next reaction.
Part IV: Preparation of ethyl-cyclopropyl-{[3-(4-fluorophenylamino)-methyl]-phenyl}- amine To a solution of [3-(cyclopropyl-ethyl-amino)-benzyl]-(4-fluorophenyl)-carbamic acid terf-butyl ester from the previous step in dichloromethane (20 ml.) was added trifluoroacetic acid (20 ml.) at 0°C. The solution was warmed to room temperature and stirred for 30 minutes. The reaction was concentrated to dryness under reduced pressure and the residue was dissolved in dichloromethane (20 ml_). The organic layer was washed with 3N sodium hydroxide (10 ml_), dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. Flash chromatography (silica gel; 10% ethyl acetate in hexanes) provided ethyl- cyclopropyl-{[3-(4-fluorophenylamino)-methyl]-phenyl}-amine (3.4 g, 12 mmol) as a yellow oil.
EXAMPLE 7: PREPARATION OF (4-FLUOROPHENYL)-[4-(4-METHYL-PIPERAZIN-
1-YL)-BENZYL]-AMINE
PhMe
Part I: Preparation of N-(4-fluorophenyl)-4-(4-methyl-piperazin-1-yl)-benzamide
To a solution of 4-fluoroaniline (15.8 g, 142 mmol) in dichloromethane (200 mL) at 00C was added dropwise a solution of 4-(4-methylpiperazin-1-yl)-benzoyl chloride (25 g, 142 mmol). As a precipitate formed, the reaction was slowly diluted with additional dichloromethane (300 mL). Triethylamine (23.7 mL, 170 mmol) was added and the reaction was stirred for 30 minutes. The reaction was then warmed to room temperature and stirred for 30 minutes. The resulting precipitate was filtered and washed with water. The filtrate was treated with water, upon which additional precipitates formed. The precipitate was collected and combined with the previously obtained precipitate. The material was dried under reduced pressure overnight to provide N-(4-fluorophenyl)-4-(4-methyl-piperazin-1-yl)-benzamide (35 g, 140 mmol) as a white solid.
Part II: Preparation of (4-fluorophenyl)-[4-(4-methyl-piperazin-1-yl)-benzyl]-amine
To a solution of N-(4-fluorophenyl)-4-(4-methyl-piperazin-1-yl)-benzamide (7.6 g, 24.2 mmol) in anhydrous toluene (50 ml.) and anhydrous terahydrofuran (25 ml.) at 00C was added dropwise sodium bis(2-methoxyethoxy)aluminum hydride (65 wt.% in toluene, 22 ml_). After the addition was complete the reaction was heated to reflux and stirred for 1 hour. The reaction was cooled to 00C and treated by dropwise addition of 6N sodium hydroxide (50 ml_). 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. The material was treated with dichloromethane and hexanes to provide (4-fluorophenyl)-[4-(4- methyl-piperazin-1-yl)-benzyl]-amine (5.7 g, 19 mmol) as a white solid.
EXAMPLE 8: PREPARATION OF (4-FLUOROPHENYL)-^-PI PERIDI N-I -YL- PYRI M I D I N-5-YLM ETH YL)-AM I N E
Part I: Preparation of 5-bromo-2-piperidin-1-yl-pyrimidine
To solution of 5-bromo-2-chloro-pyrimidine (3.0 g, 15.5 mmol) in dichloromethane (30 mL) at room temperature was added piperidine (1.53 mL, 15.5 mmol) followed by the dropwise addition of triethylamine (3.23 mL, 23.3 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with dichloromethane (20 mL), washed with a saturated aqueous sodium bicarbonate solution (50 mL), followed by brine (50 mL). The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (silica gel; 5% ethyl acetate in hexanes) provided 5-bromo-2-piperidin-1-yl-pyrimidine as a white solid (3.74g, 15.5 mmol).
Part II: Preparation of 2-piperidin-1-yl-pyrimidine-5-carbaldehyde
To a solution of 5-bromo-2-piperidin-1-yl-pyrimidine (1.3 g, 5.4 mmol) in anhydrous tetrahydrofuran (30 mL) at -78°C was added 1.6 M n-butyl lithium in hexanes (3.7 mL, 5.93 mmol). The mixture was stirred at a temperature below -70°C for 1 hour. Dimethylformamide (4.2 mL, 53.9 mmol) was added dropwise and the reaction was stirred at a temperature below -70°C for 1 hour. The reaction was quenched with saturated ammonium chloride (10 mL), diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 ml_). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to provide a viscous brown oil. Flash chromatography (silica gel; 5-30% ethyl acetate in hexanes) provided 2-piperidin-1-yl-pyrimidine-5-carbaldehyde (0.76 g, 4.0 mmol) as a white solid.
Part III: Preparation of (4-fluorophenyl)-(2-piperidin-1-yl-pyrimidin-5-ylmethyl)-amine
2-Piperidin-1-yl-pyrimidine-5-carbaldehyde (0.76 g, 4.0 mmol), 4-fluoroaniline (0.76 ml_, 8.0 mmol), and acetic acid (0.25 ml_, 4.4 mmol) were combined in dichloromethane (8 ml_). The solution was stirred at room temperature for 30 minutes, followed by the addition of sodium triacetoxyborohydride (0.28 mg, 1.32 mmol). After 30 minutes, another portion of sodium triacetoxyborohydride (0.28 mg, 1.32 mmol) was added. A third portion of sodium triacetoxyborohydride (0.28 mg, 1.32 mmol) was added and the reaction stirred for 30 minutes. The 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- fluorophenyl)-(2-piperidin-1-yl-pyrimidin-5-ylmethyl)-amine (0.93 g, 3.25 mmol) as a yellow oil.
EXAMPLE 9: PREPARATION OF (4-FLUOROPHENYL)-^-PYRROLI DI N-I -YL- THIAZOL-S-YLMETHYL)-AMI NE DI HYDROCHLORIDE
Part I: Preparation of 2-chloro-5-chloromethyl thiazole
To a solution of 2-chloro-thiazol-5-yl-methanol (1 g, 6.7 mmol) in chloroform (10 mL) was added thionyl chloride (1.6g, 13.4 mmol), and the reaction was allowed to stir at room temperature overnight. The solvent was removed under reduced pressure to afford a cloudy oil (1.1g, 6.5 mmol) which was used directly in the next reaction without further purification.
Part II: Preparation of 2-chloro-thiazol-5-ylmethyl-4-fluorophenylcarbamic acid tert- butyl ester
To a solution of 4-fluorophenylcarbamic acid te/t-butyl ester (1.3 g, 6.2 mmol) in anhydrous tetrahydrofuran (15 mL) was added sodium hydride (60% dispersion in mineral oil, 261 mg, 6.8 mmol). After the initial gas evolution had ceased, the reaction was allowed to stir for 15 minutes. Tetra-n-butylammonium iodide (227 mg, 0.6 mmol) was then added followed by addition of the 2-chloro-5-chloromethyl thiazole prepared above. The mixture was heated to reflux for 1 hour. After cooling, the reaction was carefully neutralized with cold saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (2 x 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to provide a dark oil. Flash chromatography (silica gel; 5%- 10% ethyl acetate in hexanes) provided 2-chloro-thiazol-5-ylmethyl-4- fluorophenylcarbamic acid te/t-butyl ester (1.5 g, 4.4 mmol) as a yellow oil.
Part III: Preparation of 4-fluorophenyl-2-pyrrolidin-1-yl-thiazol-5-ylmethylcarbamic acid terf-butyl ester
A solution of 2-chloro-thiazol-5-ylmethyl-4-fluorophenylcarbamic acid tert-butyl ester (1.5 g, 4.4 mmol) in pyrrolidine (1.6 ml_, 22 mmol) was heated in a sealed tube to 13O0C and stirred overnight. After cooling, the reaction was partitioned between water and ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to provide 4-fluorophenyl-2-pyrrolidin-1-yl-thiazol-5-ylmethylcarbamic acid terf-butyl ester as a yellow oil.
Part IV: Preparation of (4-fluorophenyl)-(2-pyrrolidin-1-yl-thiazol-5-ylmethyl)-amine dihydrochloride
To the free base of 4-fluorophenyl-2-pyrrolidin-1-yl-thiazol-5-ylmethylcarbamic acid terf-butyl ester in dichloromethane (10 ml.) was added trifluoroacetic acid (4 ml.) and the reaction was stirred at room temperature for 3 hours. After removing the solvent under reduced pressure, the resulting oil was dissolved in diethyl ether and treated with excess ethereal hydrochloric acid. The resulting solid was collected by filtration and dried to provide (4-fluorophenyl)-(2-pyrrolidin-1-yl-thiazol-5-ylmethyl)-amine dihydrochloride (274 mg, 1.2 mmol) as a white solid.
EXAMPLE 10: PREPARATION OF (4-FLUOROPHENYL)-^-PI PERI DIN-I -YL- TH IAZOL^-YLMETHYL)-AMI NE DI HYDROCHLORIDE
Part I: Preparation of 1-(4-chloromethyl-thiazol-2-yl)-piperidine
A suspension of piperidine-1-carbothioamide (1.0 g, 6.9 mmol) and 1 ,3-dichloro- propan-2-one (876 mg, 6.9 mmol) in ethanol (10 mL) was heated to 800C and the reaction monitored by liquid chromatography (LC)/mass spectrometry (MS). After 1 hour, the reaction was cooled and the solvent was removed under reduced pressure to provide a pinkish-violet liquid. The liquid was dissolved into ice water (10 mL) and slowly treated with solid sodium bicarbonate, upon which a white precipitate formed. The solid was collected by filtration and dried under reduced pressure. The solid was triturated with hexane and filtered. The filtrate was collected, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to afford 1- (4-chloromethyl-thiazol-2-yl)-piperidine (1.1 g, 5.1 mmol) as an off-white solid.
Part II: Preparation of (4-fluorophenyl)-(2-piperidin-1-yl-thiazol-4-ylmethyl)-carbamic acid terf-butyl ester
To a solution of 4-fluorophenylcarbamic acid terf-butyl ester (1.02 g, 4.6 mmol) in tetrahydrofuran (15 mL) was added sodium hydride (60% dispersion in mineral oil, 206 mg, 5.1 mmol). After the initial gas evolution had ceased, the reaction was allowed to stir for 15 minutes. Tetra-n-butylammonium iodide (189 mg, 0.5 mmol) was then added followed by the addition of 1-(4-chloromethyl-thiazol-2-yl)-piperidine (1.1 g, 5.1 mmol) prepared above. The mixture was heated to reflux for 1 hour. After cooling, the reaction was carefully neutralized with cold saturated sodium bicarbonate (10 ml.) and extracted with ethyl acetate (2 x 20 ml_). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to provide an oil. Flash chromatography (silica gel; 10% ethyl acetate in hexanes) provided (4-fluorophenyl)-(2-piperidin-1-yl-thiazol-4- ylmethyl)-carbamic acid terf-butyl ester (1.25 g, 3.2 mmol) as a white solid.
Part III: Preparation of (4-fluorophenyl)-(2-piperidin-1-yl-thiazol-4-ylmethyl)-amine dihydrochloride
To a solution of (4-fluorophenyl)-(2-piperidin-1-yl-thiazol-4-ylmethyl)-carbamic acid terf-butyl ester (1.25 g, 3.2 mmol) in dichloromethane (15 ml.) was added trifluoroacetic acid (4 ml.) and the reaction was stirred at room temperature for 1.5 hours. After removing the solvent under reduced pressure, the resulting oil was dissolved in diethyl ether and treated with excess ethereal hydrochloric acid. The resulting solid was collected by filtration and dried to provide (4-fluorophenyl)-(2- piperidin-1-yl-thiazol-4-ylmethyl)-amine dihydrochloride (1.05 g, 3.2 mmol) as a white solid.
EXAMPLE 1 1 : PREPARATION OF (4-FLUOROPHENYL)-^-PI PERI DIN-I -YL- TH IAZOL-S-YLMETHYL)-AMI NE DI HYDROCHLORIDE
Part I: Preparation of (2-chloro-thiazol-5-ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester
To a solution of 2-chloro-thiazol-5-yl-methanol (1 g, 6.7 mmol) in chloroform (10 mL) was added thionyl chloride (1.6 g, 13.4 mmol), and the reaction was allowed to stir at room temperature overnight. The solvent was removed under reduced pressure to afford a cloudy oil (1.1 g, 6.5 mmol) which was used directly in the next reaction without further purification.
To a solution of (4-fluorophenyl)-carbamic acid te/t-butyl ester (1.3 g, 6.2 mmol) in anhydrous tetrahydrofuran (15 mL) was added sodium hydride (60% dispersion in mineral oil, 261 mg, 6.8 mmol). After the initial gas evolution had ceased, the reaction was allowed to stir for 15 minutes. Tetra-n-butylammonium iodide (227 mg, 0.6 mmol) was then added followed by addition of 2-chloro-5-chloromethyl thiazole prepared above. The mixture was heated to reflux for 1 hour. After cooling, the reaction was carefully neutralized with cold saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (2 x 20 ml_). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to provide a dark oil. Flash chromatography (silica gel; 5%-10% ethyl acetate in hexanes) provided (2-chloro-thiazol-5-ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester as a yellow oil (1.5 g, 4.4 mmol).
Part II: Preparation of (4-fluorophenyl)-(2-piperidin-1-yl-thiazol-5-ylmethyl)-carbamic acid terf-butyl ester
A solution of (2-chloro-thiazol-5-ylmethyl)-(4-fluorophenyl)-carbamic acid terf-butyl ester (1.5 g, 4.4 mmol) in piperidine (10 ml.) was heated in a sealed tube to 13O0C and stirred overnight. After cooling, the reaction was partitioned between water and ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to obtain a yellow oil. Flash chromatography (silica gel; 10%-20% ethyl acetate in hexanes) provided (4-fluorophenyl)-(2-piperidin-1-yl-thiazol-5-ylmethyl)-carbamic acid terf-butyl ester as a light yellow oil (981 mg, 2.6 mmol).
Part III: Preparation of (4-fluorophenyl)-(2-piperidin-1-yl-thiazol-5-ylmethyl)-amine dihydrochloride
To a solution of (4-fluorophenyl)-(2-piperidin-1-yl-thiazol-5-ylmethyl)-carbamic acid terf-butyl ester (981 mg, 2.6 mmol) in dichloromethane (10 ml.) was added trifluoroacetic acid (4 ml.) and the reaction was stirred at room temperature for 3 hours. After removing the solvent under reduced pressure, the resulting oil was dissolved in diethyl ether and treated with excess ethereal hydrochloric acid. The resulting solid was collected by filtration and dried to provide (4-fluorophenyl)-(2- piperidin-1-yl-thiazol-5-ylmethyl)-amine dihydrochloride as a white solid (472 mg, 1.7 mmol). EXAMPLE 12: 4-((I H-I NDOL-S-YLAMI NO)METHYL)-N-CYCLOPROPYL-N-
ETHYLTHIAZOL-2-AMINE
To a stirred solution of 2-[cyclopropyl(ethyl)amino]-1 ,3-thiazole-4-carbaldehyde (0.19 g, 0.97 mmol) and 5-aminoindole (0.13 g, 1.00 mmol) in THF (3 mL) was added acetic acid (0.1 mL) and the resulting solution was stirred overnight at room temperature. Sodium triacetoxyborohydride (0.41 g, 1.95 mmol) was added and the solution was stirred an additional hour. The reaction was quenched with sat. sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was concentrated and flash column separation using 10-50% ethyl acetate / hexane gave
N-({2-[cyclopropyl(ethyl)amino]-1 ,3-thiazol-4-yl}methyl)-1 H-indol-5-amine as a white solid. (0.21 g, 56%).
EXAMPLE 13: 4-FLUORO-N-((6-(TRIFLUOROMETHYL)PYRIDIN-3-
YL)METHYL)ANILINE
To a stirred solution of 6-(trifluoromethyl)pyridine-3-carboxaldehyde (1.0 g, 5.71 mmol) and 4-fluoroaniline (0.64 g, 5.71 mmol) in dichloromethane (2 mL) was added acetic acid (1.2 mL) and the resulting solution was stirred overnight at room temperature. Sodium triacetoxyborohydride (2.4 g, 11.4 mmol) was added and the solution was stirred an additional hour. The reaction was quenched with 1 N NaOH solution and extracted with dichloromethane. The organic layer was concentrated and flash column separation using 0-20% ethyl acetate/ hexane to give 4-fluoro-N- {[6-(trifluoromethyl)pyridin-3-yl]methyl}aniline as an oil. (0.98 g, 64%)
EXAMPLE 14: 4-FLUORO-N-((6-(2,2,2-TRIFLUOROETHOXY)PYRIDIN-3-
YL)METHYL)ANILINE
Step 1 : To a stirred solution of 6-chloronicotinaldehyde (3.0 g, 21.2 mmol) and 4- fluoroaniline (2.0 mL, 21.2 mmol) in dichloromethane (70 mL) was added acetic acid (3.6 mL) and the resulting solution was stirred overnight at room temperature. Sodium triacetoxyborohydride (9.0 g, 42.4 mmol) was added and the solution was stirred an additional hour. The reaction was quenched with 1 N NaOH solution and extracted with dichloromethane. The organic layer was concentrated and flash column separation using 10-30% ethyl acetate/ hexane gave N-[(6-chloropyridin-3- yl)methyl]-4-fluoroaniline as a white solid. (4.29 g, 86%)
Step 2: To a stirred solution of 2,2,2-trifluoroethanol (0.42 g, 4.2 mmol) in DMF (3 mL) at 00C was added sodium hydride (0.17 g, 4.20 mmol) and the resulting solution was stirred 15 minutes. To this was added N-[(6-chloropyridin-3-yl)methyl]-4- fluoroaniline (0.20 g, 0.85 mmol) and the resulting solution was heated over 3 days at
600C. The reaction was allowed to cool, diluted with water and extracted several times with ethyl acetate. The combined organic phase was concentrated and flash column separation using 0-20% ethyl acetate/ hexane gave 4-fluoro-N-((6-(2,2,2- trifluoroethoxy)pyridin-3-yl)methyl)aniline as an oil. (0.16 g, 65%) EXAMPLE 15: 4-FLUORO-N-(2-(2-MORPHOLINOTHIAZOL-4-YL)ETHYL)ANILINE
LiAlH4 f V-N. diethylether
Part I: Preparation of ethyl (2-morpholin-4-yl-1 ,3-thiazol-4-yl)acetate
A mixture of ethylmalonylchloride (4.76 mL, 35 mmol) and morpholine-4-carbothioic acid amide (5.0 g, 34.2 mmol) in ethanol (40 mL) was heated to 80 0C for 3 hours.
The mixture was cooled, ethanol evaporated, and diluted with saturated sodium bicarbonate, and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate and the reaction mixture purified by chromatography (silica gel; ethylacetate/hexane, 1 :1 ) to provide ethyl (2-morpholin-4-yl-1 ,3-thiazol-4-yl)acetate (9 g, quantitative)
Part II: Preparation of N-(4-fluorophenyl)-2-(2-morpholin-4-yl-1 ,3-thiazol-4- yl)acetamide
A mixture of ethyl (2-morpholin-4-yl-1 ,3-thiazol-4-yl)acetate (1.0 g, 4.65 mmol) and 4- fluoroaniline(0.55 mL, 5.8 mmol) was dissolved in toluene (13 mL) at room temperature. 2M Trimethylaluminum (2.5 mL, 5 mmol) was added dropwise, and the mixture was heated to 60 0C for 3 hours. The mixture was cooled, quenched with methanol, and the solvent evaporated under reduced pressure. The residue was partitioned between saturated sodium bicarbonate and ethyl acetate. The organic layer was collected, washed with saturated potassium-sodium tartrate, dried over magnesium sulfate, and concentrated. The residue was purified by chromatography (silica gel; 10%-50% ethylacetate/hexane, gradient elution) to provide N-(4-fluorophenyl)-2-(2-morpholin-4-yl-1 ,3-thiazol-4-yl)acetamide (0.93Og, 62%).
Part III: Preparation of 4-fluoro-N-[2-(2-morpholin-4-yl-1 ,3-thiazol-4-yl)ethyl]aniline
To a mixture of N-(4-fluorophenyl)-2-(2-morpholin-4-yl-1 ,3-thiazol-4-yl)acetamide (0.90Og, 2.8 mmol) in anhydrous diethylether (30 ml.) at 0 0C was slowly added 1 M lithium aluminum hydride (5 ml_). The reaction was allowed to warm to room temperature and stirring continued 7 hours. The mixture was quenched sequentially with water (0.2 ml_), 2N NaOH (.2 ml_), and water (0.6 ml_). The mixture was filtered through celite and the filtrate concentrated. The residue was purified by chromatography (silica gel; 20%-50% ethylacetate/hexane, gradient elution) to provide 4-fluoro-N-[2-(2-morpholin-4-yl-1 ,3-thiazol-4-yl)ethyl]aniline (0.52Og, 60%).
EXAMPLE 16: 4-(CHLOROMETHYL)-N-CYCLOPROPYL-N-ETHYL-I 1S-THIAZOL-
2-AMINE
B0C20 NaH, DMF,
2. 2N NaOH reflux, 48 hrs.
Step 1. tert-butyl cyclopropylcarbamate
To a solution of cylcopropylamine (6.0 g, 0.10 mol) and triethylamine (14.6 ml, 0.10 mol) in dichloromethane (250 mL) was slowly added di-tertbutyldicarbonate (22.9 g, 0.10 mol) in dichloromethane (100 mL). After stirring overnight at room temperature, the mixture was poured into water, the organic layer was separated, washed with water, dried (MgSO4) and evaporated to afford the product (15.48 g, 0.098 mol).
Step 2. tert-butyl cyclopropyl(ethyl)carbamate
tert-butyl cyclopropylcarbamate (14.24 g, 0.092 mmol) in dry DMF (100 mL) was cooled to 0 oC, and treated with sodium hydride (60% dispersion in oil, 3.79 g, 0.095 mol). After the addition was complete, ethyl iodide (8.0 mL, 100 mmol) was added dropwise. The mixture was then stirred overnight at room temperature, then pured into water, extracted with diethyl ether, the organic layer was washed with water, dried (MgSO4) and evaporated to afford the product as an oil (17.74 g, 0.092 mol).
Step 3. N-ethylcyclopropanamine 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).
Step 4. 1-cyclopropyl-i-ethylthiourea
To a mixture of cyclohexylethylamine hydrochloride (10.5 g, 87.5 mmol) and triethylamine (12.2 ml_, 87.7 mmol) in tetrahydrofuran was added benzoylisothiocyanate (11.9 ml_, 90.4 mmol) and reluxed 3 hours. The mixture was cooled, and partitioned between water and ethyl acetate. The organic layer was collected, dried over magnesium sulfate, and evaporated. The residue was dissolved in tetrahydrofuran/ethanol (300 ml_); 2N NaOH (60 ml.) was added and the mixture refluxed 48 hours. The mixture was partitioned between water and ethyl acetate. The organic layer was collected, dried over magnesium sulfate, and evaporated. The resultant oil was scratched with hexanes/ether to provide 1-cyclopropyl-i- ethylthiourea (9.5 g, 75 %).
Step 5. 4-(chloromethyl)-N-cyclopropyl-N-ethyl-1 ,3-thiazol-2-amine
A mixture of 1-cyclopropyl-i-ethylthiourea (9.5 g, 66.2 mmol) and 1 ,3 dichloroacetone (8.6 g, 68 mmol) in ethanol (100 ml.) was refluxed 8 hours. The solvent evaporated under reduced pressure and the residue was partitioned between saturated sodium bicarbonate and ethyl acetate. The organic layer was collected, dried over magnesium sulfate, and concentrated. The residue was purified by chromatography (silica gel; 1/5 ethylacetate/hexane) to provide 4-(chloromethyl)-N- cyclopropyl-N-ethyl-1 ,3-thiazol-2-amine (8.0 g, 56 %).
EXAMPLE 17 PREPARATION OF 4-CHLORO-N-(4-FLUOROPHENYL)-N-[6-(4-
METHYL-PI PERAZI N-I -YL)-PYRI DI N-S-YL-METHYL]-BENZAMI DE
HYDROCHLORIDE (COMPOUND NO. 1 )
Part I: A: Preparation of 4-chloro-N-(4-fluorophenyl)-benzamide
To a solution of 4-fluoroaniline (2.58 g, 23.2 mmol) in dichloromethane (30 mL) at 0°C was added 4-chlorobenzoyl chloride (2.98 mL, 23.2 mmol), followed by the dropwise addition of triethylamine (3.9 mL, 27.9 mmol). The reaction was allowed to warm to room temperature and stirred for 30 minutes. The reaction was diluted with dichloromethane (20 mL), washed with a saturated aqueous sodium bicarbonate solution (50 mL), followed by brine (50 mL). The organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide a solid. The solid was washed with hexanes to provide 4-chloro-Λ/-(4- fluorophenyl)-benzamide (5.38 g, 21.5 mmol) as a white solid. Part II: Preparation of 4-chloro-N-(6-chloro-pyridin-3-yl-methyl)-N-(4-fluorophenyl)- benzamide
To a solution of 4-chloro-N-(4-fluorophenyl)-benzamide (1.0 g, 4 mmol) in dimethylformamide (10 ml.) at room temperature was added sodium hydride (60% oil dispersion, 241 mg, 6 mmol). The reaction was stirred for 15 minutes or until gas evolution ceased. The reaction temperature was raised to 90°C for 15 minutes followed by addition of 2-chloro-5-chloromethyl pyridine (0.98 g, 6 mmol). After stirring at 90°C for 30 minutes, the mixture was cooled to room temperature and then slowly poured into a 2N sodium hydroxide solution (10 ml_). The aqueous medium was extracted with ethyl acetate (3 x 20 ml_). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to provide a viscous brown oil (0.8 g, 2.1 mmol). This material was used directly in the next reaction without further purification.
Part III: Preparation of 4-chloro-N-(4-fluorophenyl)-N-[6-(4-methyl-piperazin-1-yl)- pyridin-3-yl-methyl]-benzamide hydrochloride
4-Chloro-N-(6-chloropyridin-3-yl-methyl)-N-(4-fluorophenyl)-benzamide (0.8 g, 2.1 mmol, crude) was dissolved in N-methylpiperazine (4 ml_). The resulting mixture was heated at 130°C overnight in a sealed tube. The reaction was cooled, diluted with brine (20 ml_), and extracted with ethyl acetate (3 x 20 ml_). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to provide a dark brown oil. Flash chromatography (silica gel; 5-20% methanol in dichloromethane) provided a light yellow oil.
The resulting oil was dissolved in diethyl ether (10 ml.) and a saturated hydrochloric acid solution in diethyl ether (6 ml.) was added. The solvent was removed under reduced pressure to provide 4-chloro-N-(4-fluorophenyl)-N-[6-(4-methyl-piperazin-1- yl)-pyridin-3-yl-methyl]-benzamide hydrochloride (0.4 g, 0.9 mmol) as a white solid. EXAMPLE 18 PREPARATION OF 4-CHLORO-N-(6-DIETHYLAMINO-PYRIDIN-3- YL-METHYL)-N-^-FLUOROPHENYL)-BENZAMI DE TRI FLUOROACETATE
(COMPOUND NO. 2)
To a solution of {5-[(4-fluorophenylamino)-methyl]-pyridin-2-yl}-diethylamine (407 mg, 1.49 mmol) in anhydrous tetrahyrofuran (7.5 mL) at 00C was added 4-chlorobenzoyl chloride (230 μL, 1.79 mmol) and triethylamine (250 μL, 1.79 mmol). The reaction was warmed to room temperature and stirred for 1 hour. The reaction was quenched with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (2 x 10 mL). The organic phases were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by chromatography (silica gel; 1 :2 ethyl acetate in hexane) provided 4- chloro-N-(6-diethylamino-pyridin-3-yl-methyl)-N-(4-fluorophenyl)-benzamide (594 mg, 1.44 mmol).
The free base (309 mg, 0.75 mmol) was treated with 1% aqueous trifluoroacetic acid, and lyophilized to provide 4-chloro-N-(6-diethylamino-pyridin-3-yl-methyl)-N-(4- fluorophenyl)-benzamide trifluoroacetate (394 mg, 1.44 mmol) as a gummy solid.
EXAMPLE 19: PREPARATION OF 4-CHLORO-N-(4-FLUOROPHENYL)-N-(2- PYRROLI DI N-I -YL-THIAZOL-S-YL-METHYL)-BENZAMI DE HYDROCHLORIDE
(COMPOUND NO. 3)
To a solution of (4-fluorophenyl)-(2-pyrrolidin-1-yl-thiazol-5-yl-methyl)-amine (180 mg, 0.65 mmol) in dichloromethane (7.5 mL) was added 4-chlorobenzoyl chloride (125 μL, 0.98 mmol) and triethylamine (270 μL, 1.95 mmol). The reaction was stirred for 30 minutes. The reaction was quenched with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (2 x 10 mL). The organic phases were combined, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by chromatography (silica gel; 10% methanol in dichloromethane) provided 4-chloro-N-(4-fluorophenyl)-N-(2- pyrrolidin-1-yl-thiazol-5-yl-methyl)-benzamide (229 mg, 0.55 mmol).
Treatment of the free base with ethereal hydrochloric acid provided 4-chloro-N-(4- fluorophenyl)-N-(2-pyrrolidin-1-yl-thiazol-5-yl-methyl)-benzamide hydrochloride (250 mg, 0.55 mmol) as a white solid.
EXAMPLE 20: PREPARATION OF 4-CHLORO-N-(4-FLUOROPHENYL)-N-(2- PI PERIDI N-I -YL-THIAZOL^-YL-METHYL)-BENZAMI DE HYDROCHLORIDE
(COMPOUND NO. 4)
To a solution of 4-chloro-N-(4-fluorophenyl)-benzamide (250 mg, 1 mmol) in anhydrous tetrahydrofuran (6 mL) was added sodium hydride (60% oil dispersion, 0.241 mg, 6 mmol). The reaction was stirred for 15 minutes or until gas evolution ceased. To the reaction was added 1-(4-chloromethyl-thiazol-2-yl)-piperidine (239 mg, 1.1 mmol) and tetra-n-butylammonium iodide (74 mg, 0.2 mmol), and the reaction was heated to 80°C. After stirring for 2 hours, the reaction was cooled to room temperature and slowly quenched with saturated sodium bicarbonate (10 mL). The aqueous phase was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure to provide a dark yellow oil. Purification by chromatography (silica gel; 20-30% ethyl acetate in hexane) provided 4-chloro-N-(4- fluorophenyl)-N-(2-piperidin-1-yl-thiazol-4-yl-methyl)-benzamide (249 mg, 0.58 mmol). MS (base): m/z 430 [M+H]; HPLC (base): tr = 3.4 min.
Treatment of the free base with ethereal hydrochloric acid provided 4-chloro-N-(4- fluorophenyl)-N-(2-piperidin-1-yl-thiazol-4-yl-methyl)-benzamide hydrochloride (250 mg, 0.58 mmol) as a white foam. EXAMPLE 21 : PREPARATION OF 2-(4-CHLOROPHENYL)-N-(4-
FLUOROPHENYL)-N-[6-(4-METHYL-PIPERAZIN-1-YL)-PYRIDIN-3-YLMETHYL]-
ISOBUTYRAMIDE HYDROCHLORIDE (COMPOUND NO. 34)
To a suspension of 2-(4-chlorophenyl)-2-methyl propanoic acid (199 mg, 1 mmol) in chloroform (5 mL) was added thionyl chloride (220 μL, 3 mmol) and the reaction heated to reflux for 1 hour. The reaction was cooled and concentrated under reduced pressure to provide 2-(4-chlorophenyl)-2-methyl-propionyl chloride.
To a solution of 2-(4-chlorophenyl)-2-methyl-propionyl chloride in dichloromethane (5 mL) and diisopropyl amine (700 μL, 5 mmol) was added (4-fluorophenyl)-[6-(4- methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-amine (180 mg, 0.6 mmol). After stirring for 30 minutes, the reaction was quenched with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (2 x 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by reverse phase chromatography and isolation of the free base provided 2-(4-chlorophenyl)-N-(4-fluorophenyl)-N-[6-(4-methyl-piperazin-1 -yl)- pyridin-3-ylmethyl]-isobutyramide. MS (base): m/z 481 [M+H]; HPLC (base): tr = 2.7 min. Treatment of the free base with ethereal hydrochloric acid provided 2-(4- chlorophenyl)-N-(4-fluorophenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]- isobutyramide hydrochloride (300 mg, 0.58 mmol) as a white solid.
EXAMPLE 22: PREPARATION OF 1-(4-CHLOROPHENYL)-
CYCLOBUTANECARBOXYLIC ACID (4-FLUOROPHENYL)-[6-(4-METHYL-
PI PERAZI N-I -YL)-PYRI DI N-S-YLMETHYL]-AMI DE HYDROCHLORI DE
(COMPOUND NO. 35)
To a suspension of 1-(4-chlorophenyl)-1-cyclobutane carboxylic acid (211 mg, 1 mmol) in chloroform (5 mL) was added thionyl chloride (220 μL, 3 mmol) and the reaction heated to reflux for 1 hour. The reaction was cooled and concentrated under reduced pressure to provide 1-(4-chlorophenyl)-cyclobutanecarbonyl chloride.
To a solution of 1-(4-chlorophenyl)-cyclobutanecarbonyl chloride in dichloromethane (5 mL) and diisopropyl amine (700 μL, 5 mmol) was added (4-fluorophenyl)-[6-(4- methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-amine (150 mg, 0.5 mmol). After stirring for
30 minutes, the reaction was quenched with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (2 x 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by reverse phase chromatography and isolation of the free base provided 1-(4-chlorophenyl)-N-(4-fluorophenyl)-N-((6-(4-methylpiperazin-1- yl)pyridin-3-yl)methyl)cyclobutanecarboxamide.
Treatment of the free base with ethereal hydrochloric acid provided 1-(4- chlorophenyl)-cyclobutanecarboxylic acid (4-fluorophenyl)-[6-(4-methyl-piperazin-1- yl)-pyridin-3-ylmethyl]-amide hydrochloride (238mg, 0.45 mmol ) as a white solid.
EXAMPLE 23. 4-CHLORO-N-{[6-(DIPHENYLAMINO)PYRIDIN-3-YL]METHYL}-N-(4- FLUOROPHENYL)BENZAMIDE (COMPOUND NO. 273)
Preparation of 4-chloro-Λ/-{[6-(diphenylamino)pyridin-3-yl]methyl}-Λ/-(4- fluorophenyl)benzamide
To a stirred solution of 4-chloro-Λ/-[(6-chloropyridin-3-yl)methyl]-Λ/-(4- fluorophenyl)benzamide (0.10 g, 0.26 mmol) and diphenylamine (0.05 g, 0.26 mmol) in toluene (5 mL) was added Pd2(dba)3 (0.01 g, 0.015 mmol) and BINAP (0.03 g, 0.04 mmol) and cesium carbonate (0.13 g, 0.40 mmol) and the resulting solution was heated to 1000C for 2 days. The mixture was partitioned between 1.0 N NaOH solution and ethyl acetate. The organic phase was concentrated. Flash column separation using 0-30% ethyl acetate/hexane gave 4-chloro-Λ/-{[6- (diphenylamino)pyridin-3-yl]methyl}-Λ/-(4-fluorophenyl)benzamide as a white solid. (0.03 g, 22%). TABLE 2A
TABLE 2B.
EXAMPLE 24: PHARMACOLOGICAL TESTING
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. Oocyte Assay
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. Λfeurosc/.,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., Cav2.2 subfamily) whereby the modulation of the calcium channel was measured for each tested compound. For measuring compound potency on Cav2.2, a train of five depolarizing pulses of 20-30 ms to about +10 mV was applied at a frequency of 5 Hz from a holding potential of -100 mV every 30 seconds. The 50% inhibitory concentration (IC50) of the test compounds was calculated by measuring the current obtained at the fifth pulse (P5).
HEK Assay
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 105 cells in 2 ml. in a 6-well plate, incubated for one night, and achieved a -30-40% confluence. In a small sterile tube, sufficient serum-free medium was added as diluent for FuGENE Transfection Reagent (Roche Applied Science, Indianapolis, IN) to a total volume of 100 μl_. To this medium was added 3 μl_ of FuGENE 6 Reagent. The mixture was tapped gently to mix. To the prediluted FuGENE 6 Reagent was added 2 μg of DNA solution (0.8- 2.0 μg/μL). The DNA/Fugene 6 mixture was gently pipeted to mix the contents and incubated for about 15 minutes at room temperature. The complex mixture was then added to the HEK-293T/17 cells, distributed around the well, and swirled to ensure even dispersal. The cells were returned to the incubator for 24 hours. The transfected cells were then replated at density 2.5 x 105 in a 35 mm dish with 5 glass coverslips and grew in low serum (1%) media for 24 hours. Coverslips with isolated cells were then transferred into a chamber, and calcium channel (e.g., L-type, N-type, etc.) current or other currents for counter screening were recorded from the transiently transfected HEK-293T/17 cells. The whole-cell voltage clamp configuration of the patch clamp technique was employed to evaluate voltage-dependent calcium currents essentially as described by Thompson and Wong (1991 ), J. Physiol., 439: 671-689, the entire disclosure of which is herein incorporated by reference. To record calcium channel (e.g., L-type, N-type, etc.) currents for evaluation of inhibitory potency of compounds (steady-state concentration-response analysis), five pulses of 20-30 ms voltage steps to about +10 mV (the peak of the current voltage relationship) were delivered at five Hz every 30 second from a holding potential at -10OmV. In order to obtain an estimate of the degree of use-dependent block of the test compounds, IC50 values were determined at the first and fifth pulse of the train (P1 and P5, respectively, in Table 2). Compound evaluations were carried out essentially as described by Sah D. W. and Bean B. P. (1994), MoI. Pharmacol., 45:84-92, the entire disclosure of which is herein incorporated by reference.
FLIPR Assay
TSA201 cells stably transfected with human Cav2.2 (composed of the subunits α1 , β3 and α2δ) and human Kir2.3 to enhance the FLIPR Ca2+ signal were used. These cells were plated on 384-well collagen-coated plates (BD Bioscience, Franklin Lakes, NJ) at a density of 2x104 cells/well one day prior to the FLIPR assay. For each assay plate, 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 4μM in the presence of Pluronic F-127 (Invitrogen, Carlsbad, CA). Culture media is removed and replaced with 25μl 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 25μl of HBSS (Invitrogen, Carlsbad, CA). The HBSS is then aspirated and replaced with 25μl of compound which is diluted in HBSS with 1% DMSO. Compounds are incubated on the cells for 15 minutes. The cells are then depolarized with 25μl of 14OmM KCI solution (also containing 2mM CaCI2 and 1OmM HEPES). The final concentration of KCI on the cells is 7OmM. The results for selected compounds are summarized in Tables 3 and 4 below. Data presented represent the average value when one or more samples were tested.
TABLE 3
TABLE 4 Variations, modifications, and other implementations of what is described herein will occur to those of ordinary skill in the art without departing from the spirit and the essential characteristics of the present teachings. It is not intended that the present invention be limited to the illustrated embodiments but rather by the following claims, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

WHAT IS CLAIMED IS:
1. A compound of formula (I)
or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein:
X is selected from -NRC-, -O-, -CRaRt>-, a divalent Ci-6 alkoxy group, a divalent Ci-6 alkyl group, a divalent C2-6 alkenyl group, and a covalent bond;
R1, at each occurrence, is independently selected from halogen, -CN, -ORC, - C(O)ORC, -NRdRΘ, -S(O)mNRdRΘ, -N(RC)C(O)RC, -NO2, phenyl, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 haloalkyl and Ci-6 haloalkoxy;
R2 is C3-6 cycloalkyl, benzyl, indole, phenyl, or a bicyclic aryl group, wherein wherein the phenyl, benzyl, and cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen, phenyl, C1-6 alkyl, a C1-6 alkoxy group, C1-6 haloalkyl, C1-6 haloalkoxy, -OCH2-phenyl, -CN, -C(O)ORC, -OH, -C(O)NH2, NHCORc, and -NRdRΘ;
Ar-R3 is selected from:
R3 is selected from a halogen, a a piperidin-4-yl group, C1-10 alkyl group, a C1-10 alkoxy group, a C1-10 haloalkyl group, a C1-10 haloalkoxy group, a -C(O)RC group,, C3-6 cycloalkyl, and -Y-NRfRg, wherein
the C1-10 alkyl group and the C1-10 alkoxy group are optionally substituted with from 1-3 substitutents selected from a halogen, a phenyl group, and -OH;
wherein the nitrogen ring atom of the piperidin-4-yl is optionally substituted with -C(O)O-C1-6 alkyl;
Y, at each occurrence, is independently a divalent C1-6 alkyl group or a covalent bond;
Ra and Rb taken together with the carbon atom to which they are bonded form C3- 6 cycloalkyl;
Rc, Rd and RΘ, at each occurrence, independently are H, C1-6 haloalkyl, or a C1-6 alkyl group; and Rf and R9, at each occurrence, independently are selected from H, -C(O)RC, -C2-6 alkyl-ORc, -C2-6 alkyl-NRdRΘ, C1-10 alkyl, C3-6 cycloalkyl, -Y-phenyl, -C(O)- phenyl, -Y-(5-7 membered cycloheteroalkyl), -Y-(5-7 membered heteroaryl), and a -C2-6 alkyl-O-Y-(5-7 membered heteroaryl), or
alternatively, Rf and R9 taken together with the nitrogen atom to which they are bonded form a 5-7 membered cycloheteroalkyl group or a 5-7 membered heteroaryl group, the 5-7 membered cycloheteroalkyl group and the 5-7 membered heteroaryl group containing up to two ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein
any sulfur atom in the ring optionally is substituted with 1 or 2 oxo groups;
one or more nitrogen atoms in the ring optionally are independently substituted with -C(O)RC, -C2-6 alkyl-ORc, -C2-6 alkyl-NRdRΘ, -Y-
C(O)NRdRΘ,-S(O)2-C1-6 alkyl, -C2-6 alkyl-(5-7 membered cycloheteroalkyl), C1-6 alkyl, C3-8 cycloalkyl, -Y-(phenyl)q, or 5-7 membered heteroaryl,
one or more carbon atoms in the ring optionally are independently substituted with -C(O)-NRdRΘ, -Y-ORC, -Y-NRdRΘ, -Y-(phenyl)q,-Y-(5-7 cycloheteroalkyl), -Y-(5-9 membered heteroaryl), or -Y-O-(5-7 membered heteroaryl); and wherein
each of the phenyl groups appearing anywhere in said Rf and R9 is optionally substituted with 1 to 3 substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, and C1-6 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 Rf and R9 is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-6 alkyl; m is 0, 1 , or 2;
n is O, 1 , 2, or 3;
p is 1 , 2, 3, or 4; and
q is 1 , 2, or 3;
R2 is cycloalkyl and p is 2, then Ar-R3 is not N R3
2. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein X is selected from -NH-, -O- -CH2-, -CH2-O-, -0-CH2-, -CH2CH2CH2-O-, -CH2CH2-, and -CH=CH-.
3. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein X is a covalent bond.
4. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein X is selected from -CH(CH3)-, -C(CH3)2-, and cyclobutyl.
5. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R1 is selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 haloalkoxy, phenyl, and Ci-6 alkoxy.
6. The compound of claim 5, wherein R1 is selected from F, Cl, CH3, CF3, -0-CH3, phenyl, and t-butyl.
7. The compound of claim 1 , wherein R1 is selected from -OH, CN, -S(O)2NH2, - C(O)OH, -C(O)CH3, -NHC(O)-Ci-6 alkyl, and -NO2.
8. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R2 is phenyl optionally substituted with 1 to 2 substituents independently selected from halogen, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 haloalkyl, C1- 6 haloalkoxy, and -OCH2-phenyl.
9. The compound of claim 8 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R2 is selected from 4-fluorophenyl group, a 4-chlorophenyl group, a 4-methylphenyl group, a 3-methylphenyl group, a 2-methylphenyl group, a 4-fluoro-2- methylphenyl group, a 5-chloro-2-methyl group, a 3,5-dichlorophenyl group, a 2,3- dichlorophenyl group, a 3,5-dimethylphenyl group, a 2,6-dimethylphenyl group, a 3- cyanophenyl group, a 3-tert-butylphenyl group, a 2-isopropyl-phenyl group, a 3- isopropyl-phenyl group, a biphenyl-2-yl group, a biphenyl-4-yl group, a 4- benzyloxyphenyl group, a 3-chloro-2-methoxyphenyl group, a 3-trifluoromethylphenyl group, and a 4-trifluoromethylphenyl group.
10. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R2 is phenyl optionally substituted with 1 to 2 substituents independently selected from, -CN, -C(0)0Rc, -OH, -C(O)NH2, NHCORC, and -NRdRΘ wherein Rc, Rd and RΘ are as defined above.
11. The compound of claim 10 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R2 is selected from a 2-carbamoylphenyl group, a 3- carbamoylphenyl group, a 4-carbamoylphenyl group, 4-hydroxyphenyl, 3- acetamidophenyl, a 3-tert-butoxycarbonylphenyl group, a 4-tert- butoxycarbonylphenyl group, and a 3-carboxylphenyl group.
12. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or ester tthheerreeooff,, wwhheerreeiinn RR22 is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
13. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R2 is a 1-naphthyl group, a 1 H-indol-5-yl group, or a quinolin-6-yl group.
14. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein Ar-R3 is selected from:
wherein R is as defined in claim 1.
15. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R3 is NRfRg, wherein Rf and R9 are as defined in claim 1.
16. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R3 is selected from NH2, NH-Ci-6 alkyl, N(Ci-6 alkyl)2, NH-C3-6 cycloalkyl, N(Ci-6 alkyl)-C3-6 cycloalkyl, N(Ci-6 alkyl)-C2-6 alkyl-ORc, -C(O)-phenyl, N(Ci-6 alkyl)-Y-(5-7 membered cycloheteroalkyl), N(Ci-6 alkyl)-phenyl, N(phenyl)2, N(Ci-6 alkyl)-Y-(5-7 membered heteroaryl), and N(Ci-6 alkyl)-C2-6 alkyl-O-Y-(5-7 membered heteroaryl), wherein each of phenyl, the 5-7 membered cycloheteroalkyl group, and the 5-7 heteroaryl group is optionally substituted with 1 to 3 substituents independently selected from halogen and Ci-6 alkyl, wherein Y and Rc are as defined in claim 1.
17. The compound of claim 16 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R3 is selected from a diethylamino group, a diphenylamino group, a methyl(2-pyridin-2-ylethyl)amino group, a methyl(2-morpholin-4-ylethyl)amino group, a methyl(4-chlorobenzoyl)amino group, a 2-(dimethylamino)ethyl](methyl)amino, and a cyclopropyl(ethyl)amino group.
18. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R3 is an optionally substituted 5-7 membered cycloheteroalkyl group or an optionally substituted 5-7 membered heteroaryl group as defined in claim 1.
19. The compound of claim 18 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R3 is 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, wherein each of these groups optionally includes a nitrogen ring atom substituted with -C(O)RC, -C2-6 alkyl-ORc, - C2-6 alkyl-NRdRΘ, -Y-C(O)N RdRΘ, an -S(O)2-C1-6 alkyl group, a -C2-6 alkyl— (5-7 membered cycloheteroalkyl) group, Ci-6 alkyl, C3-8 cycloalkyl, or a 5-7 membered heteroaryl group, a carbon ring atom substituted with -C(O)-N RdRΘ, -Y-ORC, -Y- NRdRΘ, -Y-phenyl, a -Y-(5-7 cycloheteroalkyl) group, a -Y-(5-9 membered heteroaryl) group, or a -Y-O-(5-7 membered heteroaryl) group, and/or a sulfur ring atom substituted with 1 or 2 oxo groups, wherein each of the phenyl groups immediately above is optionally substituted with 1 to 3 substituents independently selected from halogen, Ci-6 alkyl, Ci-6 haloalkyl, and a Ci-6 alkoxy group, and each of the 5-7 membered cycloheteroalkyl groups, the 5-7 membered heteroaryl groups, and the 5-9 membered heteroaryl groups immediately above is optionally substituted with 1 to 3 substituents independently selected from halogen and Ci-6 alkyl, and wherein Y, Rc, Rd and RΘ are as defined in claim 1.
20. The compound of claim 19 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R3 is a 1 -piperazinyl group having a nitrogen atom in the ring optionally substituted with -C(O)RC, C3-8 cycloalkyl, -C2-6 alkyl-ORc, -C2-6 alkyl— NRdRΘ, -Ci-6 alkyl-C(O)NRdRΘ, S(O)2-Ci-6 alkyl, -C2-6 alkyl— (5-7 membered cycloheteroalkyl), CM O alkyl, or a 5-7 membered heteroaryl group, wherein Rc, Rd and RΘ are as defined in claim 1.
21. The compound according to claim 20 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R3 is selected from a 4-methylpiperazin-1-yl group, a 4-(4-fluorophenyl) piperazin-1-yl group, a 4-[bis(4-fluorophenyl)methyl]piperazin-1- yl group, a 4-pyridin-2-ylpiperazin-1-yl group, and a 4-(methylsulfonyl)piperazin-1-yl group.
22. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate or ester thereof, wherein R3 is selected from trifluoromethyl, chloro, 2,2,2-trifluoroethoxy, and cyclohexyl.
23. A compound according to claim 1 selected from:
4-Chloro-N-(4-fluoro-phenyl)-N-[6-(4-methyl-piperazin-1 -yl)-pyridin-3-ylmethyl]- benzamide;
4-Chloro-N-(6-diethylamino-pyridin-3-ylmethyl)-N-(4-fluoro-phenyl)-benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-(2-piperidin-1-yl-thiazol-4-ylmethyl)-benzamide;
2-Methyl-N-(4-methyl-phenyl)-N-(4-amino-phenylmethyl)-benzamide;
4-Chloro-N-cyclopentyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]- benzamide;
4-Chloro-N-cyclobutyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]- benzamide;
N-Cyclopentyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-benzamide;
N-Cyclopentyl-3,4,5-trimethoxy-N-{[6-(4-methylpiperazin-1-yl)pyridin-3- yl]methyl}benzamide; 5-Fluoro-N-(4-fluoro-phenyl)-2-methyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- ylmethyl]-benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-{6-[methyl-(2-pyridin-2-yl-ethyl)-amino]-pyridin-3- ylmethyl}-benzamide;
N-(4-Fluoro-phenyl)-2-methoxy-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]- benzamide;
N-(4-Fluoro-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-benzamide;
N-(4-Fluoro-phenyl)-3-methoxy-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]- benzamide;
N-(4-Fluoro-phenyl)-2-methyl-N-[6-(4-methyl-piperazin-1 -yl)-pyιϊdin-3-ylmethyl]- benzamide;
2-Fluoro-N-(4-fluoro-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]- benzamide;
N-(4-Fluoro-phenyl)-4-methyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]- benzamide;
5-Fluoro-N-(4-fluoro-phenyl)-2-methoxy-N-[6-(4-methyl-piperazin-1-yl)-pyιϊdin-3- ylmethyl]-benzamide;
N-(4-Fluoro-phenyl)-2,4-dimethyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- ylmethyl]-benzamide;
4-Chloro-N-(4-fluoro-phenyl)-2-methoxy-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- ylmethyl]-benzamide; N-(4-Fluoro-phenyl)-2,5-dimethoxy-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- ylmethyl]-benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyridin-3- ylmethyl}-benzamide;
N-(4-Fluoro-phenyl)-4-methoxy-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]- benzamide;
N-(4-Fluoro-phenyl)-3-methyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]- benzamide;
3-Chloro-N-(4-fluoro-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]- benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-{6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-3- ylmethyl}-benzamide;
4-Chloro-N-(4-fluoro-2-methyl-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- ylmethyl]-benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-{6-[methyl-(2-morpholin-4-yl-ethyl)-amino]-pyridin-
3-ylmethyl}-benzamide;
N-(4-Fluoro-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-4- trifluoromethyl-benzamide;
4-Cyano-N-(4-fluoro-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]- benzamide;
4-Acetylamino-N-(4-fluoro-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- ylmethyl]-benz7amide; 4-Chloro-N-(4-fluoro-phenyl)-N-(6-morpholin-4-yl-pyridin-3-ylmethyl)-benzamide;
4-Chloro-N-{6-[(2-methoxylethyl)-methyl-amino]-pyridin-3-ylmethyl}-N-(4-fluoro- phenyl)-benzamide;
N-(4-Fluoro-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-4- sulfamoyl-benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-[6-(4-methyl-[1 ,4]diazepan-1-yl)-pyridin-3- ylmethyl]-benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-[6-(4-chlorobenzoyl-methyl-amino)-pyridin-3- ylmethyl]-benzamide;
4-Chloro-N-[6-(4-methyl-piperazin-1 -yl)-pyridin-3-ylmethyl]-N-m-tolyl-benzamide;
4-Chloro-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-N-o-tolyl-benzamide;
4-Chloro-N-(3,5-dimethyl-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- ylmethyl]-benzamide;
4-Chloro-N-(2-isopropyl-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- ylmethyl]-benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-[6-(4-pyridin-2-yl-piperazin-1-yl)-pyridin-3- ylmethyl]-benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-(6-piperazin-1-yl-pyridin-3-ylmethyl)-benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-(6-thiomorpholin-4-yl-pyridin-3-ylmethyl)- benzamide; N-(4-Fluoro-phenyl)-2-hydroxy-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]- benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-{6-[4-(2-methoxy-ethyl)-piperazin-1-yl]-pyridin-3- ylmethyl}-benzamide;
4-Chloro-N-[6-(4-dimethylcarbamoylmethyl-piperazin-1-yl)-pyridin-3-ylmethyl]-N-
(4-fluoro-phenyl)-benzamide;
4-Chloro-N-{6-[(2-dimethylamino-ethyl)-methyl-amino]-pyridin-3-ylmethyl}-N-(4- fluoro-phenyl)-benzamide;
4-Chloro-N-[6-(1 ,1-dioxo-1λ6-thiomorpholin-4-yl)-pyridin-3-ylmethyl]-N-(4-fluoro- phenyl)-benzamide;
4-Chloro-N-(4-chloro-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]- benzamide;
4-Chloro-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-N-p-tolyl-benzamide;
N-(4-Chloro-phenyl)-4-methyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]- benzamide;
N-[6-(4-Acetyl-piperazin-1-yl)-pyridin-3-ylmethyl]-4-chloro-N-(4-fluoro-phenyl)- benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-{6-[methyl-(2-pyridin-3-yl-ethyl)-amino]-pyridin-3- ylmethyl}-benzamide;
4-Chloro-N-(3-isopropyl-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- ylmethyl]-benzamide; 4-Chloro-N-(2,6-dimethyl-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- ylmethyl]-benzamide;
4-Chloro-N-{6-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-pyridin-3-ylmethyl}-N-(4- fluoro-phenyl)-benzamide;
5'-{[(4-Chloro-benzoyl)-(4-fluoro-phenyl)-amino]-methyl}-3,4,5,6-tetrahydro-2H-
[1 ,2']bipyridinyl-4-carboxylic acid amide;
4-(5-{[(4-Chloro-benzoyl)-(4-fluoro-phenyl)-amino]-methyl}-pyridin-2-yl)- piperazine-1-carboxylic acid ethylamide;
4-Chloro-N-(4-fluoro-phenyl)-N-[6-(4-isopropyl-piperazin-1-yl)-pyridin-3-ylmethyl]- benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-{6-[4-(2-morpholin-4-yl-ethyl)-piperazin-1-yl]- pyridin-3-ylmethyl}-benzamide;
N-(6-Piperazin-1-yl-pyridin-3-ylmethyl)-N-p-tolyl-benzamide;
N-[6-(4-Methanesulfonyl-piperazin-1-yl)-pyridin-3-ylmethyl]-N-p-tolyl-benzamide;
N-[4-(1 H-Benzoimidazol-2-yl)-3,4,5,6-tetrahydro-2H-[1 ,2']bipyridinyl-5'-ylmethyl]-
4-chloro-N-(4-fluoro-phenyl)-benzamide;
N-[6-(4-Acetyl-piperazin-1-yl)-pyridin-3-ylmethyl]-N-p-tolyl-benzamide;
4-Chloro-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-N-phenyl-benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-(6-pyrrolidin-1-yl-pyridin-3-ylmethyl)-benzamide; 4-Chloro-N-(4-fluoro-phenyl)-N-[6-(4-methanesulfonyl-piperazin-1-yl)-pyridin-3- ylmethyl]-benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-(6-imidazol-1-yl-pyridin-3-ylmethyl)-benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-[6-(3-methylamino-pyrrolidin-1-yl)-pyridin-3- ylmethyl]-benzamide;
4-Chloro-N-(6-diethylaminomethyl-pyridin-3-ylmethyl)-N-(4-fluoro-phenyl)- benzamide;
4-Chloro-N-(6-dimethylamino-pyridin-3-ylmethyl)-N-(4-fluoro-phenyl)-benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-(2-methyl-thiazol-4-ylmethyl)-benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-(6-methylamino-pyridin-3-ylmethyl)-benzamide;
4-Chloro-N-(6-cyclopropylamino-pyridin-3-ylmethyl)-N-(4-fluoro-phenyl)- benzamide;
4-Chloro-N-[6-(cyclopropyl-methyl-amino)-pyridin-3-ylmethyl]-N-(4-fluoro-phenyl)- benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-(2-morpholin-4-yl-thiazol-4-ylmethyl)-benzamide;
N-(4-Fluoro-phenyl)-N-(2-morpholin-4-yl-thiazol-4-ylmethyl)-benzamide;
N-(4-Fluoro-phenyl)-4-methyl-N-(2-morpholin-4-yl-thiazol-4-ylmethyl)-benzamide; 4-Chloro-N-(4-fluoro-phenyl)-N-(2-pyridin-4-yl-thiazol-4-ylmethyl)-benzamide;
4-Chloro-N-(2-diethylamino-thiazol-4-ylmethyl)-N-(4-fluoro-phenyl)-benzamide;
3-(4-Chloro-phenyl)-1-(4-fluoro-phenyl)-1-[6-(4-methyl-piperazin-1-yl)-pyridin-3- ylmethyl]-urea;
3-(3,4-Dimethoxy-phenyl)-1-(4-fluoro-phenyl)-1-[6-(4-methyl-piperazin-1-yl)- pyridin-3-ylmethyl]-urea;
3-(5-Chloro-2-methoxy-phenyl)-1-(4-fluoro-phenyl)-1-[6-(4-methyl-piperazin-1-yl)- pyridin-3-ylmethyl]-urea;
(4-Fluoro-phenyl)-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-carbamic acid 4- chloro-phenyl ester;
N-Cyclopentyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-3-phenyl- propionamide;
N-Cyclopropyl-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-3-phenyl- propionamide;
N-Cyclopentyl-N-[6-(4-methyl-piperazin-1 -yl)-pyιϊdin-3-ylmethyl]-2-phenyl- acetamide;
N-(4-Fluoro-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-3-phenyl- propionamide;
3-(2-Chloro-phenyl)-N-(4-fluoro-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- ylmethyl]-acrylamide; 2-(4-Chloro-phenyl)-N-(4-fluoro-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- ylmethyl]-acetamide;
N-(4-Fluoro-phenyl)-2-phenyl-N-(2-piperidin-1-yl-thiazol-4-ylmethyl)-acetamide;
2-(4-Chloro-phenoxy)-N-(4-fluoro-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- ylmethyl]-acetamide;
2-(4-Chloro-phenyl)-N-(4-fluoro-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- ylmethyl]-isobutyramide;
1 -(4-Chloro-phenyl)-cyclobutanecarboxylic acid (4-fluoro-phenyl)-[6-(4-methyl- piperazin-1-yl)-pyridin-3-ylmethyl]-amide;
2-(4-Chloro-phenyl)-N-(4-fluoro-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3- ylmethyl]-propionamide;
N-(4-Fluoro-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-3-phenyl- butyramide;
2-(4-Chloro-phenyl)-N-[6-(4-methyl-piperazin-1-yl)-pyridin-3-ylmethyl]-N-phenyl- isobutyramide;
1 -(4-Methoxy-phenyl)-cyclopentanecarboxylic acid (4-fluoro-phenyl)-[6-(4-methyl- piperazin-1-yl)-pyridin-3-ylmethyl]-amide;
and pharmaceutically acceptable salts, hydrates, and esters thereof.
24. A pharmaceutical composition comprising the compound of any one of claims 1- 23 or a pharmaceutically acceptable salt, hydrate or ester thereof and a pharmaceutically acceptable carrier or excipient.
25. The pharmaceutical composition of claim 24, further comprising an additional therapeutic agent.
26. A method of treating a disease or disease symptom selected from angina, hypertension, congestive heart failure, myocardial ischemia, and arrhythmia, the method comprising administering to a subject a therapeutically effective amount of the compound of any of claims 1-23 or a pharmaceutically acceptable salt, hydrate, or ester thereof.
27. A method of treating a disease or disease symptom selected from stroke, convulsion, epilepsy, traumatic brain injury, and neuronal disorder, the method comprising administering to a subject a therapeutically effective amount of the compound of any of claims 1-23 or a pharmaceutically acceptable salt, hydrate, or ester thereof.
28. A method of treating a disease or disease symptom selected from diabetes, urinary incontinence, hot flush, and thermal disregulation, the method comprising administering to a subject a therapeutically effective amount of the compound of any of claims 1-23 or a pharmaceutically acceptable salt, hydrate, or ester thereof.
29. A method of treating pain in a subject, the method comprising administering to a subject a therapeutically effective amount of the compound of any of claims 1-23 or a pharmaceutically acceptable salt, hydrate, or ester thereof.
30. A method of claim 29 wherein said pain is chronic pain.
31. A method of claim 30 wherein said chronic pain is 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, or a combination thereof.
32. A method of claim 29 wherein said pain is chronic back pain.
33. A method of claim 29 wherein said pain is neuropathic pain.
34. A method of claim 29 wherein said pain is associated with diabetic neuropathy.
35. A method of claim 29 wherein said pain is associated with post-herpetic neuropathy.
36. A method of claim 29 wherein said pain is associated with post-herpetic fibromyalgia.
37. A method of treating a disease or disease symptom modulated by calcium channel Cav2, the method comprising administering to a subject a therapeutically effective amount of the compound of any of claims 1-23 or a pharmaceutically acceptable salt, hydrate, or ester thereof.
38. The method of claim 37, wherein the disease or disease symptom is modulated by calcium channel Cav2.
39. The method of claim 38, wherein the disease or disease symptom is modulated by calcium channel Cav2.2.
40. The method of any one of claims 26-39, wherein the subject is a mammal.
41. A method of modulating calcium channel activity in a subject, the method comprising administering the compound of any one of claims 1-23, or a pharmaceutically acceptable salt, hydrate or ester thereof, to a subject.
42. A method for making a compound of formula (I) according to claim 1 and pharmaceutically acceptable salts thereof, comprising
(a) reacting a carboxylic acid compound of formula (II)
(H) with an activating agent; and
(b) coupling the resultant activated acid with an amine of formula (III)
(III)
43. The method according to claim 42, wherein the activating agent is selected from thionyl chloride, 2-chloro-4,6-dimethoxy-1 ,3,5-triazine, 1-[3-(dimethylamino)propyl]-3- ethyl-carbodiimide and dicyclohexyl carbodiimide.
44. A method of treating a disease or disease symptom selected from angina, hypertension, congestive heart failure, myocardial ischemia, and arrhythmia, the method comprising administering to a subject a therapeutically effective amount of a compound of formula (Ia),
or a pharmaceutically acceptable salt, hydrate or ester thereof and a pharmaceutically acceptable carrier or excipient, wherein
R1, R2, R3, X, p, and
are as defined in claim 1.
45. A method of treating a disease or disease symptom selected from stroke, convulsion, epilepsy, traumatic brain injury, and neuronal disorder, the method comprising administering to a subject a therapeutically effective amount of the compound of formula (Ia) as defined in claim 44 or a pharmaceutically acceptable salt, hydrate, or ester thereof.
46. A method of treating a disease or disease symptom selected from diabetes, urinary incontinence, hot flush, and thermal disregulation, the method comprising administering to a subject a therapeutically effective amount of the compound of formula (Ia) as defined in claim 44 or a pharmaceutically acceptable salt, hydrate, or ester thereof.
47. A method of treating pain in a subject, the method comprising administering to a subject a therapeutically effective amount of compound of formula (Ia) as defined in claim 44 or a pharmaceutically acceptable salt, hydrate, or ester thereof.
48. A method of claim 47 wherein said pain is chronic pain.
49. A method of claim 48 wherein said chronic pain is 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, or a combination thereof.
50. A method of claim 47 wherein said pain is chronic back pain.
51. A method of claim 47 wherein said pain is neuropathic pain.
52. A method of claim 47 wherein said pain is associated with diabetic neuropathy.
53. A method of claim 47 wherein said pain is associated with post-herpetic neuropathy.
54. A method of claim 47 wherein said pain is associated with post-herpetic fibromyalgia.
55. A method of treating a disease or disease symptom modulated by calcium channel Cav2, the method comprising administering to a subject a therapeutically effective amount of the compound of formula (Ia) as defined in claim 44 or a pharmaceutically acceptable salt, hydrate, or ester thereof.
56. The method of claim 55, wherein the disease or disease symptom is modulated by calcium channel Cav2.2.
57. A method of modulating calcium channel activity in a subject, the method comprising administering the compound of formula (Ia) as defined in claim 44, or a pharmaceutically acceptable salt, hydrate or ester thereof, to a subject.
58. The method of any one of claims 44-57, wherein the subject is a mammal.
59. The method of any one of claims 44-57, wherein the compound of formula (Ia) is selected from
4-Chloro-N-(4-fluoro-phenyl)-N-(2-pyrrolidin-1 -yl-thiazol-5-ylmethyl)-benzamide;
4-Chloro-N-(4-fluoro-phenyl)-N-[2-(4-methyl-piperazin-1-yl)-thiazol-5-ylmethyl]- benzamide;
and pharmaceutically acceptable salts, hydrates, and esters thereof.
60. A compound as defined in any one of claims 1 to 23 for use in the treatment of a disease or disease symptom selected from angina, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, stroke, convulsion, epilepsy, traumatic brain injury, neuronal disorder, urinary incontinence, hot flush, thermal disregulation, pain or a disease or disease symptom modulated by calcium channel Cav2, or the modulation of calcium channel activity in a subject.
61. Use of a compound as defined in any one of claims 1 to 23 in the preparation of a medication for the treatment of a disease or disease symptom selected from angina, hypertension, congestive heart failure, myocardial ischemia, arrhythmia, stroke, convulsion, epilepsy, traumatic brain injury, neuronal disorder, urinary incontinence, hot flush, thermal disregulation, pain or a disease or disease symptom modulated by calcium channel Cav2, or the modulation of calcium channel activity in a subject.
EP07865495A 2006-12-11 2007-12-11 Carboxamide derivatives as ion channel modulators Withdrawn EP2097379A1 (en)

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