WO2005021523A1 - Piperazine substituted compounds used as calcium channel blockers - Google Patents

Piperazine substituted compounds used as calcium channel blockers Download PDF

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Publication number
WO2005021523A1
WO2005021523A1 PCT/CA2004/001629 CA2004001629W WO2005021523A1 WO 2005021523 A1 WO2005021523 A1 WO 2005021523A1 CA 2004001629 W CA2004001629 W CA 2004001629W WO 2005021523 A1 WO2005021523 A1 WO 2005021523A1
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WO
WIPO (PCT)
Prior art keywords
diphenyl
piperazin
propan
phenyl
aryl
Prior art date
Application number
PCT/CA2004/001629
Other languages
English (en)
French (fr)
Other versions
WO2005021523A8 (en
Inventor
Terrance P. Snutch
Gerald W. Zamponi
Hassan Pajouhesh
Hossein Pajouhesh
Francesco Belardetti
Original Assignee
Neuromed Technologies, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Neuromed Technologies, Inc. filed Critical Neuromed Technologies, Inc.
Priority to EP04761792A priority Critical patent/EP1670775A4/en
Priority to MXPA06002467A priority patent/MXPA06002467A/es
Priority to BRPI0414094-0A priority patent/BRPI0414094A/pt
Priority to JP2006525016A priority patent/JP2007504174A/ja
Priority to AU2004268711A priority patent/AU2004268711A1/en
Priority to NZ546254A priority patent/NZ546254A/en
Priority to CA002537487A priority patent/CA2537487A1/en
Publication of WO2005021523A1 publication Critical patent/WO2005021523A1/en
Publication of WO2005021523A8 publication Critical patent/WO2005021523A8/en
Priority to IL174025A priority patent/IL174025A0/en

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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
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    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the invention relates to compounds useful in treating conditions associated with abnormal calcium channel function. More specifically, the invention concerns compounds containing substituted or unsubstituted derivatives of 6-membered heterocyclic moieties that are useful in treatment of conditions such as stroke and pain.
  • Calcium channels mediate a variety of normal physiological functions, and are also implicated in a number of human disorders.
  • Examples of calcium-mediated human disorders include but are not limited to congenital migraine, cerebellar ataxia, angina, epilepsy, hypertension, ischemia, and some arrhythmias.
  • the clinical treatment of some of these disorders has been aided by the development of therapeutic calcium channel antagonists (e.g., dihydropyridines, phenylalkyl amines, and benzothiazapines all target L-type calcium channels) (Janis and Triggle, 1991).
  • therapeutic calcium channel antagonists e.g., dihydropyridines, phenylalkyl amines, and benzothiazapines all target L-type calcium channels
  • T-type (or low voltage-activated) channels describe a broad class of molecules that transiently activate at negative potentials and are highly sensitive to changes in resting potential.
  • L-, N- and P/Q-type channels activate at more positive potentials (high voltage- activated) and display diverse kinetics and voltage-dependent properties (Catterall (2000); Huguenard (1996)).
  • L-type channels can be distinguished by their sensitivity to several classes of small organic molecules used therapeutically, including dihydropyridines (DHP's), phenylalkylamines and benzothiazepines.
  • DHP's dihydropyridines
  • phenylalkylamines phenylalkylamines
  • benzothiazepines are high affinity targets for certain peptide toxins produced by venous spiders and marine snails: N-type channels are blocked by the ⁇ -conopeptides ⁇ -conotoxin GVIA ( ⁇ -CTx-GVIA) isolated from Conus geographus and ⁇ -conotoxin MVIIA ( ⁇ -CTx-MVIIA) isolated from Conus magus, while P/Q-type channels are resistant to ⁇ -CTx-MVIIA but are sensitive to the funnel web spider peptide, ⁇ -agatoxin IVA ( ⁇ -Aga-IVA).
  • R-type calcium channels are sensitive to block by the tarantula toxin, SNX-482.
  • Neuronal high voltage-activated calcium channels are composed of a large (>200 kDa) pore-forming oti subunit that is the target of identified pharmacological agents, a cytoplasmically localized ⁇ 50-70 kDa ⁇ subunit that tightly binds the ⁇ subunit and modulates channel biophysical properties, and an ⁇ 170 kDa ⁇ 2 ⁇ subunit (reviewed by Stea, et al. (1994); Catterall (2000)).
  • ⁇ i subunit genes expressed in the nervous system have been identified and shown to encode all of the major classes of native calcium currents (Table 1).
  • mice null for the die N type calcium channel gene have been reported by several independent groups (Ino, et al. (2001); Kim, et al. (2001); Saegusa, et al. (2001); Hatakeyama, et al. (2001)).
  • B N type null mice were viable, fertile and showed normal motor coordination.
  • peripheral body temperature, blood pressure and heart rate in the N type gene knock out mice were all normal (Saegusa, et al. (2001)).
  • the baroreflex mediated by the sympathetic nervous system was reduced after bilateral carotid occlusion (Ino, et al. (2001)).
  • mice were examined for other behavioral changes and were found to be normal except for exhibiting significantly lower anxiety related behaviors (Saegusa, et al. (2001)), suggesting the N type channel may be a potential target for mood disorders as well as pain.
  • mice lacking functional N type channels exhibit marked decreases in the chronic and inflammatory pain responses.
  • mice lacking N type channels generally showed normal acute nociceptive responses.
  • Two examples of either FDA approved or investigational drug that act on N type channel are gabapentin and ziconotide.
  • Gabapentin, 1 (aminomethyl) cyclohexaneacetic acid (Neurontin®), is an anticonvulsant originally found to be active in a number of animal seizure models (Taylor, et al. (1998)). Subsequent work has demonstrated that gabapentin is also successful at preventing hyperalgesia in a number of different animal pain models, including chronic constriction injury (CCI), heat hyperalgesia, inflammation, diabetic neuropathy, static and dynamic mechanoallodynia associated with postoperative pain (Taylor, et al. (1998); Cesena & Calcutt (1999); Field, et al. (1999); Cheng, J K., et al.
  • CCI chronic constriction injury
  • gabapentin While its mechanism of action is incompletely understood, current evidence suggests that gabapentin does not directly interact with GABA receptors in many neuronal systems, but rather modulates the activity of high threshold calcium channels. Gabapentin has been shown to bind to the calcium channel ⁇ 2 ⁇ ancillary subunit, although it remains to be determined whether this interaction accounts for its therapeutic effects in neuropathic pain. [0012] In humans, gabapentin exhibits clinically effective anti hyperalgesic activity against a wide ranging of neuropathic pain conditions. Numerous open label case studies and three large double blind trials suggest gabapentin might be useful in the treatment of pain.
  • Ziconotide (Prialt®; SNX 111) is a synthetic analgesic derived from the cone snail peptide Conus magus MVIIA that has been shown to reversibly block N type calcium channels.
  • the selective block of N type channels via intrathecal administration of Ziconotide significantly depresses the formalin phase 2 response, thermal hyperalgesia, mechanical allodynia and post surgical pain (Malmberg and Yaksh (1994); Bowersox, et al. (1996); Sluka (1998); Wang, et al. (1998)).
  • Ziconotide has been evaluated in a number of clinical trials via intrathecal administration for the treatment of a variety of conditions including post herpetic neuralgia, phantom limb syndrome, HIV related neuropathic pain and intractable cancer pain (reviewed in athur (2000)).
  • phase II and III clinical trials with patients unresponsive to intrathecal 381092000656 opiates Ziconotide has significantly reduced pain scores and in a number of specific instances resulted in relief after many years of continuous pain.
  • Ziconotide is also being examined for the management of severe post operative pain as well as for brain damage following stroke and severe head trauma (Heading (1999)).
  • T type calcium channels are highly expressed in tissues of the cardiovascular system. Mibefradil, a calcium channel blocker 10 30 fold selective for T type over L type channels, was approved for use in hypertension and angina. It was withdrawn from the market shortly after launch due to interactions with other drugs (Heady, et al. (2001)). [0017] Growing evidence suggests T type calcium channels may also be involved in pain.
  • A An essential component of these molecules is represented by A, which must be an antioxidant; the piperazine or 381092000656 piperidine itself is said to be important.
  • the exemplified compounds contain a benzhydril substituent, based on known calcium channel blockers (see below).
  • U.S. Pat. No. 5,703,071 discloses compounds said to be useful in treating ischemic diseases.
  • a mandatory portion of the molecule is a tropolone residue, with substituents such as piperazine derivatives, including their benzhydril derivatives.
  • U.S. Pat. No. 5,428,038 discloses compounds indicated to exhibit a neural protective and antiallergic effect. These compounds are coumarin derivatives which may include derivatives of piperazine and other six membered heterocycles.
  • a permitted substituent on the heterocycle is diphenylhydroxymethyl.
  • approaches in the art for various indications which may involve calcium channel blocking activity have employed compounds which incidentally contain piperidine or piperazine moieties substituted with benzhydril but mandate additional substituents to maintain functionality.
  • Certain compounds containing both benzhydril moieties and piperidine or piperazine are known to be calcium channel antagonists and neuroleptic drugs.
  • Gould, R. J., et al., Proc Natl Acad Sci USA (1983) 80:5122 5125 describes antischizophrenic neuroleptic drugs such as lidoflazine, fluspirilene, pimozide, clopimozide, and penfluridol.
  • patent publication 2002/0019389 published 14 February 2002 discloses what are characterized as urea derivatives useful as anticancer agents.
  • these derivatives are piperazines wherein one ring nitrogen forms a urea with a benzhydril group. Certain of these compounds contain 3,5 dimethylphenyl or benzhydril coupled to the alternate piperazine nitrogen. These compounds are described simply as anticancer agents and are not reported to have any effects on calcium ion channels or any indications mediated by such channels.
  • the foregoing publications are listed for convenience, and are not to be construed as prior art.
  • the present invention provides additional compounds which comprise benzhydril coupled to an acetyl group in turn coupled to a piperazine ring.
  • the piperazine ring is, in turn, substituted by a variety of substituents, none of them antioxidants. These compounds are effective in blocking calcium ion channels. 381092000656
  • the invention relates to compounds useful in treating conditions such as stroke, anxiety, overactive bladder, inflammatory bowel disease, irritable bowel syndrome, interstitial colitis, head trauma, migraine, chronic, neuropathic and acute pain, drug and alcohol addiction, neurodegenerative disorders, psychoses, sleep disorders, depression, epilepsy, diabetes, cancer, male contraception, hypertension, pulmonary hypertension, cardiac arrhythmias, congestive heart failure, angina pectoris and other indications associated with calcium metabolism, including synaptic calcium channel-mediated functions.
  • the invention is directed to compounds of the formula
  • each R -R is independently a non-interfering substituent; wherein a combination of R 2 and R 3 may form a bridge between phenyl groups which may be a bond, a CR group, an NR group, O, or S wherein the S is optionally oxidized; n is 0-4 and n and n are independently 0-5; and wherein X is selected from the group consisting of: (a) optionally substituted alkyl (1-12C) or optionally substituted alkenyl (2-12C) optionally including one or more N, O or S with the proviso that any N included in a ring is secondary or is tertiary solely because of an alkyl substitution; (b) optionally substituted aryl, provided that if n 1 is 0, and aryl is phenyl or pyridyl, said aryl must contain at least one substituent and wherein if said aryl is phenyl and contains only one substituent,
  • alkyl, alkenyl, or alkynyl comprises at least one cyclic moiety, the number of C contained maybe as many as 15, again wherein one or more C may be replaced by a heteroatom.
  • R'-R 3 may independently be in the form of an acyl, amide, or ester linkage with the ring carbon to which it is bound.
  • "Non-interfering substituents” also include halo, CF 3 , OCF 3 , CN, NO 2 , NR 2 , OR, SR, COOR, or CONR 2 , wherein R is H or optionally substituted alkyl, alkenyl, alkynyl, aryl, or arylalkyl as described above.
  • Two substituents at adjacent positions on the same ring may form a 3-7 membered saturated or unsaturated ring fused to said substituted ring, said fused ring optionally itself substituted and optionally contains one or more heteroatoms (N, S, O).
  • R 1 may be keto ifn 1 is 1 or 2.
  • the invention is also directed to methods to modulate calcium channel activity, preferably N type and T-type channel activity, using the compounds of formula (1).
  • the invention is directed to pharmaceutical compositions containing the compounds of formula (1). 381092000656
  • Figure 1 is a graph showing the selectivity of compound P24 of the invention for N-type, P/Q-type and L-type channels.
  • Figure 2 is a graph showing the selectivity of compound P28 of the invention for N-type, P/Q-type and L-type channels.
  • the compounds of formula (1) useful in the methods of the invention exert their desirable effects through their ability to modulate the activity of N-type and/or T-type calcium channels. This makes them useful for treatment of certain conditions.
  • Such conditions where antagonist activity is desired are stroke, epilepsy, head trauma, migraine, inflammatory bowel disease and chronic, neuropathic and acute pain.
  • Calcium flux is also implicated in other neurological disorders such as schizophrenia, anxiety, depression, other psychoses, and neural degenerative disorders.
  • Other treatable conditions include cardiovascular conditions such as hypertension and cardiac arrhythmias.
  • T-type calcium channels have been implicated in certain types of cancer, diabetes, infertility and sexual dysfunction.
  • the members of the genus of compounds of formula (1) exhibit high affinity for N-type channels and/or T-type channels. Thus, as described below, they are screened for their ability to interact with N-type and T-type channels as an initial indication of desirable function. It is desirable that the compounds exhibit IC 50 values of ⁇ 1 ⁇ M.
  • the IC 5 0 is the concentration which inhibits 50% of the calcium flux at a particular applied potential.
  • N-type channels Illustrative conditions mediated by N-type channels are: Chronic pain Neuropathic pain Diabetic peripheral neuropathy Post-herpetic neuralgia Trigeminal neuralgia AIDS related neuropathy Cancer pain Inflammatory pain Osteoarthritis pain Rheumatoid arthritis pain Fibromyalgia Acute pain Nociceptive pain Post-operative pain Mood disorders Anxiety disorders Generalized anxiety disorder Social anxiety disorder Panic disorder Obsessive compulsive disorder Post- traumatic stress syndrome Depression Addiction Cocaine dependence and withdrawal Opioid dependence and withdrawal Alcohol dependence and withdrawal Nicotine dependence and withdrawal Gastrointestinal disorders Inflammatory bowel disease Irritable bowel syndrome Genitourinary disorders Urinary incontinence Interstitial colitis Sexual dysfunction
  • T-type channels Illustrative of conditions mediated by T-type channels are: Cardiovascular disease Hypertension Arrhythmia Atrial fibrillation Congestive heart failure Angina pectoris Epilepsy Partial seizures Temporal lobe epilepsy Absence seizures Generalized seizures Tonic/clonic seizures Diabetes Cancer Chronic pain Neuropathic pain Diabetic peripheral neuropathy Post-herpetic neuralgia Trigeminal neuralgia Cancer pain AIDS related neuropathy Inflammatory pain Osteoarthritis pain Rheumatoid arthritis pain Fibromyalgia Acute pain Nociceptive pain Post-operative pain
  • open channel blockage is conveniently demonstrated when displayed calcium channels are maintained at an artificially negative resting potential of about -100 mV (as distinguished from the typical endogenous resting maintained potential of about -70 mV).
  • open channel 381092000656 blocking inhibitors diminish the current exhibited at the peak flow and can also accelerate the rate of current decay.
  • This type of inhibition is distinguished from a second type of block, referred to herein as "inactivation inhibition.”
  • inactivation inhibition When maintained at less negative resting potentials, such as the physiologically important potential of -70 mV, a certain percentage of the channels may undergo conformational change, rendering them incapable of being activated — i.e., opened — by the abrupt depolarization. Thus, the peak current due to calcium ion flow will be diminished not because the open channel is blocked, but because some of the channels are unavailable for opening (inactivated).
  • “Inactivation” type inhibitors increase the percentage of receptors that are in an inactivated state.
  • a third type of inhibition is designated "resting channel block”.
  • Resting channel block is the inhibition of the channel that occurs in the absence of membrane depolarization, that would normally lead to opening or inactivation. For example, resting channel blockers would diminish the peak current amplitude during the very first depolarization after drug application without additional inhibition during the depolarization. [0040] In order to be maximally useful in treatment, it is also helpful to assess the side reactions which might occur. Thus, in addition to being able to modulate a particular calcium channel, it is desirable that the compound has very low activity with respect to the HERG K + channel which is expressed in the heart. Compounds that block this channel with high potency may cause reactions which are fatal. Thus, for a compound that modulates the calcium channel, it should also be shown that the HERG K + channel is not inhibited.
  • the compound will be evaluated for calcium ion channel type specificity by comparing its activity among the various types of calcium channels, and specificity for one particular channel type is preferred. The compounds which progress through these tests successfully are then examined in animal models as actual drug candidates.
  • alkyl alkenyl
  • alkynyl alkynyl
  • substituents on the basic structures of formula (1) are described above. These include alkyl, alkenyl, alkynyl, etc., substituents.
  • alkyl alkenyl
  • alkynyl straight-chain, branched-chain and cyclic monovalent substituents, containing only C and H when they are 381092000656 unsubstituted or unless otherwise noted. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl, 2-propenyl, 3-butynyl, and the like.
  • the alkyl, alkenyl and alkynyl substituents contain 1-lOC (alkyl) or 2-12C (alkenyl or alkynyl). They may contain 1-6C (lower alkyl) or 2-6C (lower alkenyl or lower alkynyl), however, when the alkyl, alkenyl or alkynyl groups contain rings, they may contain as many as 18C, some of which may optionally be replaced by heteroatoms. [0043] Heteroalkyl, heteroalkenyl and heteroalkynyl are similarly defined but may contain one or more O, S or N heteroatoms or combinations thereof within the backbone residue.
  • alkyl, alkenyl and alkynyl include those wherein heteroatoms are contained when thus specified.
  • acyl encompasses the definitions of alkyl, alkenyl, alkynyl, each of which is coupled to an additional residue through a carbonyl group. Heteroacyl includes the related heteroforms.
  • "Aromatic” moiety or “aryl” moiety refers to a monocyclic or fused bicyclic moiety such as phenyl or naphthyl which may also be heteroaromatic; “heteroaromatic” also refers to monocyclic or fused bicyclic ring systems containing one or more heteroatoms selected from O, S and N.
  • heteroatom permits inclusion of 5-membered rings as well as 6-membered rings.
  • typical aromatic/heteroaromatic systems include pyridyl, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl and the like. Because tautomers are theoretically possible, phthalimido is also considered aromatic. Any monocyclic or fused ring bicyclic system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system is included in this definition.
  • ring systems typically contain 5-12 ring member atoms.
  • arylalkyl and heteroarylalkyl refer to aromatic and heteroaromatic systems which are coupled to another residue through a carbon chain, including substituted or unsubstituted, saturated or unsaturated, carbon chains, typically of 1-8C, or the hetero forms thereof. These carbon chains may also include a carbonyl group, thus making them able to provide substituents as an acyl or heteroacyl moiety.
  • Carbocylcyl refers to a 4-7 membered ring, said ring members being only C atoms, which ring may be saturated or unsaturated.
  • any alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, acyl, carbocyclyl or aryl group or heteroforms as defined in formula (1) or contained in a substituent 81092000656 may itself optionally be substituted by additional substituents.
  • the nature of these substituents is similar to those recited with regard to the primary substituents themselves.
  • alkyl may optionally be substituted by the remaining substituents listed as substituents where this makes chemical sense, and where this does not undermine the size limit of alkyl per se; e.g., alkyl substituted by alkyl or by alkenyl would simply extend the upper limit of carbon atoms for these embodiments.
  • alkyl substituted by aryl, amino, alkoxy, and the like would be included.
  • Non-interfering substituents on aryl groups in general include, but are not limited to, optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, and acyl, as well as halo, -CN, -CF 3 , -NO, -NO 2 , -OR, -NR 2 , -SR, -SOR, -SO 2 R, -OCOR, -NRCOR, -NRCONR 2 , -NRCOOR, -OCONR 2 , -RCO, -COOR, -NRSOR, -NRSO 2 R, -SO3R, -CONR 2 , -SO 2 NR 2 , wherein each R is independently H or alkyl (1-8C), and the like.
  • the compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
  • These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases.
  • Suitable pharmaceutically acceptable acids and bases are well-known in the art, i.e., acids such as hydrochloric, sulphuric, citric, acetic, or tartaric acids and bases such as potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, and the like. Methods for preparation of the appropriate salts are well-established in the art.
  • the compounds of the invention contain one or more chiral centers.
  • the invention includes the isolated stereoisomeric forms as well as mixtures of stereoisomers in varying degrees of chiral purity.
  • the compounds of the invention may also be conjugated to additional entities such as polyethylene glycol (PEG), a targeting agent such as an antibody or ligand, a solid matrix such as derivatized cellulose, and the like.
  • the compounds of the invention modulate the activity of calcium channels; in general, said modulation is the inhibition of the ability of the channel to transport calcium.
  • modulation is the inhibition of the ability of the channel to transport calcium.
  • the effect of a particular compound on calcium channel activity can readily be ascertained in a routine assay whereby the conditions are arranged so that the channel is 381092000656 activated, and the effect of the compound on this activation (either positive or negative) is assessed. Typical assays are described hereinbelow.
  • the compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
  • salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases.
  • Suitable pharmaceutically acceptable acids and bases are well-known in the art, such as hydrochloric, sulphuric, citric, acidic, or tartaric acids and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, and the like. Methods for preparation of the appropriate salts are well-established in the art, as are methods of conjugation.
  • the compounds of the invention may be synthesized using conventional methods. Illustrative of such methods are Schemes 1 to 3.:
  • Reaction Scheme 1 was used to prepare compounds P6-P8, P25, P30-P32, P36-P42 of the invention.
  • Reaction Scheme 2 was used to prepare compounds P9 and PI 0 of the invention.
  • Reaction Scheme 3 was used to prepare compounds P 1 -P5, P 12-P24, P27-P29, P33-P35 of the invention.
  • Particularly preferred embodiments of Formula (1) are those wherein only zero, one or two of the depicted rings are substituted and wherein the number of substituents on a single ring is three or less.
  • Particularly preferred substituents for the phenyl rings shown include halo, especially fluoro or chloro,; CF 3 ; optionally substituted, optionally heteroatom-containing alkyl, alkenyl, aryl, alkyl aryl, alkenyl aryl, phenoxy, and the like. Where the substituents on these moieties contain alkyl or aryl groups, these also may optionally be substituted.
  • X is alkyl and is in a cyclic form, and thus may contain up to 15C, wherein one or more of said C may optionally be replaced by a heteroatom.
  • X comprises a heteroaryl moiety, such as pyridyl, pyrimidyl, benzimidazole, benzothiazole and the like.
  • X is arylalkyl wherein the alkyl group is substituted by an aromatic or other cyclic moiety; especially preferred are those embodiments wherein the alkyl portion is methylene substituted by a cyclic moiety.
  • X is arylalkyl, the aryl portion is phenyl and is multiply substituted or is substituted by a substituent that comprises an additional aryl moiety.
  • the compounds of the invention can be synthesized individually using methods known in the art per se, or as members of a combinatorial library. [0064] Synthesis of combinatorial libraries is now commonplace in the art. Suitable descriptions of such syntheses are found, for example, in Wentworth, Jr., P., et al, Current Opinion in Biol. (1993) 9:109-115; Salemme, F.R., et al, Structure (1997) 5:319-324.
  • the libraries contain compounds with various substituents and various degrees of unsaturation, as well as different chain lengths.
  • the libraries which contain, as few as 10, but typically several hundred members to several thousand members, may then be screened for compounds which are particularly effective against a specific subtype of calcium channel, i.e., the N-type channel.
  • the libraries may be screened for compounds which block additional channels or receptors such as sodium channels, potassium channels and the like.
  • Methods of performing these screening functions are well known in the art. These methods can also be used for individually ascertaining the ability of a compound to agonize or antagonize the channel.
  • the channel to be targeted is expressed at the surface of a recombinant host cell such as human embryonic kidney cells.
  • the ability of the members of the library to bind the channel to be tested is measured, for example, by the ability of the compound in the library to displace a labeled binding ligand such as the ligand normally associated with the channel or an antibody to the channel. More typically, ability to antagonize the channel is 1 92 measured in the presence of calcium ion and the ability of the compound to interfere with the signal generated is measured using standard techniques.
  • one method involves the bmding of radiolabeled agents that interact with the calcium channel and subsequent analysis of equilibrium binding measurements including, but not limited to, on rates, off rates, I j values and competitive binding by other molecules.
  • Another method involves the screening for the effects of compounds by electrophysiological assay whereby individual cells are impaled with a microelectrode and currents through the calcium channel are recorded before and after application of the compound of interest.
  • Another method high-throughput spectrophotometric assay, utilizes loading of the cell lines with a fluorescent dye sensitive to intracellular calcium concentration and subsequent examination of the effects of compounds on the ability of depolarization by potassium chloride or other means to alter intracellular calcium levels.
  • a more definitive assay can be used to distinguish inhibitors of calcium flow which operate as open channel blockers, as opposed to those that operate by promoting inactivation of the channel. The methods to distinguish these types of inhibition are more particularly described in the examples below.
  • open-channel blockers are assessed by measuring the level of peak current when depolarization is imposed on a background resting potential of about -100 mV in the presence and absence of the candidate compound. Successful open-channel blockers will reduce the peak current observed and may accelerate the decay of this current.
  • Compounds that are inactivated channel blockers are generally determined by their ability to shift the voltage dependence of inactivation towards more negative potentials. This is also reflected in their ability to reduce peak currents at more depolarized holding potentials (e.g., -70 mV) and at higher frequencies of stimulation, e.g., 0.2 Hz vs. 0.03 Hz.
  • the compounds of the invention can be formulated as pharmaceutical or veterinary compositions.
  • the mode of administration, and the type of treatment desired ⁇ e.g., prevention, prophylaxis, therapy; the compounds are formulated in ways consonant with these parameters. 381092000656
  • Formulations may be prepared in a manner suitable for systemic administration or topical or local administration.
  • Systemic formulations include those designed for injection (e.g., intramuscular, intravenous or subcutaneous injection) or may be prepared for transdermal, transmucosal, or oral administration.
  • the formulation will generally include a diluent as well as, in some cases, adjuvants, buffers, preservatives and the like.
  • the compounds can be administered also in liposomal compositions or as microemulsions.
  • formulations can be prepared in conventional forms as liquid solutions or suspensions or as solid forms suitable for solution or suspension in liquid prior to injection or as emulsions.
  • Suitable excipients include, for example, water, saline, dextrose, glycerol and the like.
  • Such compositions may also contain amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as, for example, sodium acetate, sorbitan monolaurate, and so forth.
  • Systemic administration may also include relatively noninvasive methods such as the use of suppositories, transdermal patches, transmucosal delivery and intranasal administration.
  • Oral administration is also suitable for compounds of the invention. Suitable forms include syrups, capsules, tablets, as in understood in the art.
  • the dosage of the compounds of the invention is typically 0.1-15 mg/kg, preferably 0.1-1 mg/kg. However, dosage levels are highly dependent on the nature of the condition, the condition of the patient, the judgment of the practitioner, and the frequency and mode of administration.
  • K 2 CO 3 (1.07g, 7.78 mmol) was added to a solution of 2,4-difluoro ⁇ henol(0.84g, 6.48 mmol) in dry DMF (15 ml). 2-Bromoethanol (0.8 lg, 6.48 mmol) was added, and the mixture was heated overnight at 120°C. The mixture was cooled, taken up in EtOAc, extracted with water (20 ml), saturated NaCl (4x 20 ml), dried over MgSO , and evaporated under reduced pressure. The product was purified by column chromatography on silica (Hexane:EtOAc 3: 1 ) to give the desired product in 63% yield
  • N-type calcium channel blocking activity was assayed in human embryonic kidney cells, HEK 293, stably transfected with the rat brain N-type calcium channel subunits (ai ⁇ + a 2 d + ⁇ ib cDNA subunits).
  • N-type calcium channels (ai ⁇ + a 2 a +Bi b cDNA subunits)
  • L-type channels a ⁇ c + 2 d + ⁇ ib cDNA subunits
  • P/Q-type channels a i A + a 2 a + ⁇ ib cDNA subunits
  • DMEM Dulbecco's modified eagle medium
  • Antagonist activity was measured using whole cell patch recordings on human embryonic kidney cells either stably or transiently expressing rat ⁇ iB+ ⁇ 2 b+ ⁇ ib channels (N-type channels) with 5 mM barium as a charge carrier.
  • host cells such as human embryonic kidney cells, HEK 293 (ATCC# CRL 1573) were grown in standard DMEM medium supplemented with 2 mM glutamine and 10% fetal bovine serum.
  • HEK 293 cells were transfected by a standard calcium- phosphate-DNA coprecipitation method using the rat ⁇ + ⁇ i b + ⁇ * 2 o " N-type calcium channel subunits in a vertebrate expression vector (for example, see Current Protocols in Molecular Biology).
  • a standard calcium- phosphate-DNA coprecipitation method using the rat ⁇ + ⁇ i b + ⁇ * 2 o " N-type calcium channel subunits in a vertebrate expression vector (for example, see Current Protocols in Molecular Biology).
  • the culture medium was removed and replaced with external recording solution (see below).
  • Whole cell patch clamp experiments were performed using an Axopatch 200B amplifier (Axon Instruments, Burlingame, CA) linked to an IBM compatible personal computer equipped with pCLAMP software.
  • Borosilicate glass patch pipettes (Sutter Instrument Co., Novato, CA) were polished (Microforge, Narishige, Japan) to a resistance of about 4 M ⁇ when filled with cesium methanesulfonate internal solution (composition in MM: 109 CsCH 3 SO 4 , 4 MgCl 2 , 9 EGTA, 9 HEPES, pH 7.2). Cells were bathed in 5 M Ba** (in mM: 5 BaCl 2 , 1 MgCl 2 , 10 HEPES, 40 tetraethylammonium chloride, 10 glucose, 87.5 CsCl pH 7.2).
  • Example 7 Block of a in T-tvpe Channels
  • Standard patch-clamp techniques were employed to identify blockers of T-type currents. Briefly, previously described HEK cell lines stably expressing human aic subunits were used for all the recordings (passage #: 4-20, 37° C, 5% CO 2 ). To obtain T-type currents, plastic dishes containing semi-confluent cells were positioned on the stage of a ZEISS AXIOVERT S 100 microscope after replacing the culture medium with external solution (see below). Whole-cell patches were obtained using pipettes (borosilicate glass with filament, O.D. 1.5 mm, I.D.: 0.86 mm, 10 cm length), fabricated on a SUTTER P-97 puller with resistance values of ⁇ 5 MO (see below for internal medium).
  • T-type currents were reliably obtained by using two voltage protocols: (1) “non-inactivating", and (2) “inactivation” [0099]
  • the holding potential is set at -110 mV and with a pre-pulse at -100 mV for 1 second prior to the test pulse at -40 mV for 50 ms.
  • the pre-pulse is at approximately -85 mV for 1 second, which inactivates about 15% of the T-type channels.
  • test pulse - 40 mV, 50 ms 0.067 Hz
  • Vholding 110 ⁇ > v non-inactivated pre-pulse: -100 mV, 1 second
  • Test compounds were dissolved in external solution, 0.1-0.01 % DMSO. After -10 min rest, they were applied by gravity close to the cell using a WPI microfil tubing. The "non- inactivated" pre-pulse was used to examine the resting block of a compound. The "inactivated” protocol was employed to study voltage-dependent block. However, the initial data shown below were mainly obtained using the non-inactivated protocol only. IC 50 values are shown for various compounds of the invention in the following table.

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PCT/CA2004/001629 2003-09-03 2004-09-03 Piperazine substituted compounds used as calcium channel blockers WO2005021523A1 (en)

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EP04761792A EP1670775A4 (en) 2003-09-03 2004-09-03 PIPERAZINE-SUBSTITUTED COMPOUNDS AS CALCIUM CHANNEL BLOCKERS
MXPA06002467A MXPA06002467A (es) 2003-09-03 2004-09-03 Compuestos sustituidos con piperazina usados como bloqueadores del canal de calcio.
BRPI0414094-0A BRPI0414094A (pt) 2003-09-03 2004-09-03 compostos de piperazina substituìdos usados como bloqueadores do canal de cálcio
JP2006525016A JP2007504174A (ja) 2003-09-03 2004-09-03 カルシウムチャネル遮断薬として使用されるピペラジン置換化合物
AU2004268711A AU2004268711A1 (en) 2003-09-03 2004-09-03 Piperazine substituted compounds used as calcium channel blockers
NZ546254A NZ546254A (en) 2003-09-03 2004-09-03 Piperazine substituted compounds used as calcium channel blockers
CA002537487A CA2537487A1 (en) 2003-09-03 2004-09-03 Piperazine substituted compounds used as calcium channel blockers
IL174025A IL174025A0 (en) 2003-09-03 2006-03-01 Piperazine subtituted compounds used as calcium channel blockers

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US10/655,393 US7186726B2 (en) 1998-06-30 2003-09-03 Preferentially substituted calcium channel blockers

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WO2008050200A1 (en) * 2006-10-24 2008-05-02 Pfizer Products Inc. Oxadiazole compounds as calcium channel antagonists
WO2008087421A2 (en) * 2007-01-17 2008-07-24 King's College London Male contraceptive
WO2008143263A1 (ja) 2007-05-22 2008-11-27 Astellas Pharma Inc. １位置換テトラヒドロイソキノリン化合物
WO2009132454A1 (en) * 2008-04-28 2009-11-05 Neuromed Pharmaceuticals Ltd. Di-t-butylphenyl piperazines as calcium channel blockers
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US7705002B2 (en) 2005-05-19 2010-04-27 Vertex Pharmaceuticals Incorporated Biaryls useful as modulators of ion channels
WO2006124865A3 (en) * 2005-05-19 2007-01-11 Vertex Pharma Biaryls derivatives useful as modulators of ion channels
WO2006124865A2 (en) * 2005-05-19 2006-11-23 Vertex Pharmaceuticals Incorporated Biaryls derivatives useful as modulators of ion channels
US8329702B2 (en) 2005-05-31 2012-12-11 Vertex Pharmaceuticals Incorporated Heterocycles useful as modulators of ion channels
US7880008B2 (en) 2005-05-31 2011-02-01 Vertex Pharmaceuticals Incorporated Heterocycles useful as modulators of ion channels
WO2007118323A1 (en) * 2006-04-17 2007-10-25 Neuromed Pharmaceuticals Ltd. Isoxazole derivatives as calcium channel blockers
WO2008050200A1 (en) * 2006-10-24 2008-05-02 Pfizer Products Inc. Oxadiazole compounds as calcium channel antagonists
WO2008087421A3 (en) * 2007-01-17 2009-07-23 King's College London Male contraceptive
WO2008087421A2 (en) * 2007-01-17 2008-07-24 King's College London Male contraceptive
US8927579B2 (en) 2007-01-17 2015-01-06 Nnaemkea Ikechukwu Amobi Male contraceptive
WO2008143263A1 (ja) 2007-05-22 2008-11-27 Astellas Pharma Inc. １位置換テトラヒドロイソキノリン化合物
US8263607B2 (en) 2007-05-22 2012-09-11 Astellas Pharma Inc. 1-substituted tetrahydroisoquinoline compound
WO2009132454A1 (en) * 2008-04-28 2009-11-05 Neuromed Pharmaceuticals Ltd. Di-t-butylphenyl piperazines as calcium channel blockers

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