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.
• the L, N, P and Q-type channels activate at more positive potentials (high voltage activated) and display diverse kinetics and voltage-dependent properties. There is some overlap in biophysical properties ofthe high voltage-activated channels, consequently phannacological profiles are useful to further distinguish them. Whether the Q- and P-type channels are distinct molecular entities is controversial. Several types of calcium conductances do not fall neatly into any ofthe above categories and there is variability of properties even within a category suggesting that additional calcium channels subtypes remain to be classified.
• neuronal high voltage activated calcium channels are heterooligomeric complexes consisting of at least three distinct subunits ( ⁇ i, ⁇ ⁇ and ⁇ ).
• the ⁇ i subunit is the major pore-forming subunit and contains the voltage sensor and binding sites for calcium channel antagonists.
• the mainly extracellular ⁇ x 2 is disulfide-linked to the transmembrane ⁇ subunit and both are derived from the same gene and are proteolytically cleaved in vivo.
• the ⁇ subunit is a nonglycosylated, hydrophilic protein with a high affinity of binding to a cytoplasmic region ofthe ⁇ i subunit.
• a fourth subunit, ⁇ is unique to L-type calcium channels expressed in skeletal muscle T-rubules.
• XI A channels are ofthe P/Q type; ⁇ iB represents N; ⁇ ic, tx'io, CU IF and ⁇ is represent L; OC IE represents a novel type of calcium conductance, and (Xio- ⁇ n represent members ofthe T-type family.
• N-type channels which are mainly localized to neurons, have been disclosed, for example, in U.S. Patent No. 5,623,051, the disclosure of which is incorporated herein by reference.
• N-type channels possess a site for binding syntaxin, a protein anchored in the presynaptic membrane. Blocking this interaction also blocks the presynaptic response to calcium influx.
• syntaxin a protein anchored in the presynaptic membrane. Blocking this interaction also blocks the presynaptic response to calcium influx.
• compounds that block the interaction between syntaxin and this binding site would be useful in neural protection and analgesia.
• Such compounds have the added advantage of enhanced specificity for presynaptic calcium channel effects.
• U.S. Patent No. 5,646,149 describes calcium channel antagonists ofthe formula A-Y-B wherein B contains a piperazine or piperidine ring directly linked to Y.
• A which must be an antioxidant; the piperazine or piperidine itself is said to be important.
• the exemplified compounds contain a benzhydril substituent, based on known calcium channel blockers (see below).
• the antioxidant can be a phenyl group containing methoxy and/or hydroxyl substituents.
• the antioxidant In the few compounds where there is an alkylene chain between the CH to which the two phenyl groups are bound and the heterocycle, the antioxidant must be coupled to the heterocycle through an unsubstituted alkylene and in most of these cases the antioxidant is a bicyclic system. Where the antioxidant can simply be a phenyl moiety coupled through an alkynylene, the linker from the heterocycle to the phenyl moieties contains no more than six atoms in the chain.
• U.S. Patent No. 5,703,071 discloses compounds said to be useful in treating ischemic diseases. A mandatory portion of the molecule is a tropolone residue; among the substituents permitted are piperazine derivatives, including their benzhydril derivatives.
• 5,428,038 discloses compounds which are said to exert 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.
• 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. It has also been shown that fluspirilene binds to sites on L-type calcium channels (King, V.K., et al, J. Biol. Chem.
• Lomerizine as developed by Kanebo, K.K., is a known calcium channel blocker; Lomerizine is, however, not specific for N-type channels. A review of publications concerning Lomerizine is found in Dooley, D., Current Opinion in CPNS Investigational Drugs (1999) 1:116-125.
• the present invention is based on the recognition that the combination of a six- membered heterocyclic ring containing at least one nitrogen said nitrogen coupled through a linker to a benzhydril moiety results in effective calcium channel blocking activity. In some cases enhanced specificity for N-type channels and/or T-type channels, or decreased specificity for L-type channels is shown.
• the compounds are useful for treating stroke and pain and other calcium channel-associated disorders, as further described below. By focusing on these moieties, compounds useful in treating indications associated with calcium channel activity are prepared.
• the invention relates to compounds useful in treating conditions such as stroke, anxiety, overactive bladder, inflammatory bowel disease, head trauma, migraine, chronic, neuropathic and acute pain, epilepsy, hypertension, cardiac arrhythmias, and other indications associated with calcium metabolism, including synaptic calcium channel- mediated functions.
• the compounds ofthe invention are benzhydril derivatives of piperazine with substituents that enhance the calcium channel blocking activity ofthe compounds.
• the invention is directed to compounds ofthe formula
• Ar is phenyl, a six-membered or five-membered ring which is heteroaromatic or a fused aromatic or heteroaromatic system, each of which may optionally be substituted with one or more non-interfering substituents;
• X 1 is a linker containing 1-5 members; n is 0 or 1 ; each R ⁇ R 3 is independently a non-interfering non-hydrogen substituent; each 1 is independently 0-5 ; m is 0-4;
• X 2 is a linker comprising a chain of at least 5 members
• A is H, OR, SR, NR 2 , or halo wherein R is H or lower alkyl (1-6C); with the proviso that
• Ar is an optionally substituted five- or six-membered heteroaryl substituent or an optionally substituted fused aromatic or heteroaromatic substituent;
• n 0;
• X 2 is a chain of at least 6 members
• X contains at least one heteroatom selected from N, S and O;
• A is OR, SR, NR 2 or halo, wherein R is H or lower alkyl (1 -6C) and/or (h) Ar is substituted with at least one t-butyl moiety or at least one substituted alkoxy; and/or
• X 1 includes at least one heteroatom selected from O, N and S.
• the compounds are ofthe formula:
• the invention is directed to the compounds of formula
• R is a carboxylic acid group or ester or amide thereof and Ar, R 2 -R 3 , X 1 , 1, n, X 2 and A are defined as above.
• the substituents R -R , on Ar or on substituted alkoxy independently include, as well, one or more halo, CF 3 , CN, OCF, N0 2 , NR 2 , OR, SR, COOR, and/or CONR 2 , wherein R is H or optionally substituted alkyl, alkenyl, alkynyl, aryl, arylalkyl, or arylalkenyl, as described above, and wherein S may be oxidized, and wherein 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 containing one or more heteroatoms (N, S, O) and wherein said fused ring may further be fused to an additional aromatic moiety, as shown, for instance, in compound P35.
• R 2 and R 3 may form a bond or a bridge between the phenyl groups on which they reside -e.g., R 2 and R 3 together may be a bond or one or more CR 2 groups, an NR group, an O, or S wherein the S is optionally oxidized, or combinations thereof.
• 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) and thus to treat certain undesirable physiological conditions; these conditions are associated with abnormal calcium channel activity.
• the invention is directed to pharmaceutical compositions containing these compounds, and to the use of these compounds for the preparation of medicaments for the treatment of conditions requiring modulation of calcium channel activity.
• Figure 1 shows illustrative compounds ofthe invention.
• Figure 2 is a graph showing the selectivity of compound PI 8 ofthe invention for N, PQ, T and L type channels.
• Figure 3 is a graph showing the selectivity of compound P36 ofthe invention for N, PQ, T and L type channels.
• Figure 4 is a graph showing the selectivity of compound P 104 of the invention for N, PQ, T and L type channels.
• the compounds of formula (1) useful in the methods ofthe 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.
• conditions where antagonist activity is desired are stroke, anxiety, epilepsy, head trauma, migraine, inflammatory bowel disease, overactive bladder and chronic, neuropathic and acute pain.
• Calcium flux is also implicated in other neurological disorders such as schizophrenia, anxiety, depression, other psychoses, neural degenerative disorders and drug and alcohol addiction and withdrawal.
• 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.
• N-type and T-type channels are associated with particular conditions.
• the association of N-type and T-type channels in conditions associated with neural transmission would indicate that compounds ofthe invention which target N-type or T-type receptors are most useful in these conditions.
• these conditions are:
• the members ofthe 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/or 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 50 is the concentration which inhibits 50% ofthe calcium, barium or other permeant divalent cation flux at a particular applied potential.
• 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 blocking inhibitors diminish the current exhibited at the peak flow and can also accelerate the rate of current decay.
• activation inhibition 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 ofthe 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 ofthe channels are unavailable for opening (inactivated).
• “Inactivation” type inhibitors increase the percentage of receptors that are in an inactivated state.
• Resting channel block is the inhibition ofthe 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.
• the compounds ofthe invention modulate the activity of calcium channels; in general, said modulation is the inhibition ofthe ability ofthe channel to transport calcium.
• modulation is the inhibition ofthe ability ofthe 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 activated, and the effect ofthe compound on this activation (either positive or negative) is assessed. Typical assays are described hereinbelow.
• alkyl straight-chain, branched-chain and cyclic monovalent substituents, containing only C and H when they are unsubstituted or unless otherwise noted. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentyl ethyl, 2- ⁇ ropenyl, 3-butynyl, and the like.
• the alkyl, alkenyl and alkynyl substituents contain 1-lOC (alkyl) or 2-10C (alkenyl or alkynyl). Preferably they contain 1-6C (lower alkyl) or 2-6C (lower alkenyl or lower alkynyl).
• 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.
• 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; “heteroaromatic” also refers to monocyclic or fused bicyclic ring systems containing one or more heteroatoms selected from O, S and N. The inclusion of a heteroatom permits inclusion of 5-membered rings as well as 6-membered rings.
• 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. Typically, the ring systems 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.
• any alkyl, alkenyl, alkynyl, acyl, or aryl group contained in a substituent 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.
• this alkyl may optionally be substituted by the remaining substituents listed as substituents where this makes chemical sense, and where this does not underaiine 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.
• Ar is preferably optionally substituted phenyl, 2-, 3- or 4-pyridyl, indolyl, 2- or 4-pyrimidyl, pyridazinyl, benzotriazolyl or benzimidazolyl. More preferably Ar is phenyl, pyridyl, or pyrimidyl. Most preferably Ar is phenyl.
• Each of these embodiments may optionally be substituted with a group defined above such as alkyl, alkenyl, alkynyl, aryl, O-aryl, O-alkylaryl, O-aroyl, NR-aryl, N-alkylaryl, NR-aroyl, halo, OR, NR 2 , SR, -OOCR, -NROCR, RCO, -COOR, -CONR 2 , and/or S0 2 NR , wherein each R is independently H or alkyl (1-8C), and/or by -CN, -CF 3 , and/or N0 2 . Alkyl, alkenyl, alkynyl and aryl portions of these may be further substituted by similar substituents.
• R 1 0 and carboxy.
• Preferred embodiments of R and R include alkoxy, halo, and alkyl.
• the compounds ofthe invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
• These salts maybe acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms ofthe compounds ofthe 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 ofthe appropriate salts are well-established in the art.
• the compounds ofthe 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.
• Reaction Scheme 2 is used to prepare compounds ofthe invention within the embodiment of formula (2). Variations in R, and substitutions for the fluoro substituents in compound 6 will result in variants having corresponding variations in the compounds shown as 8 above.
• compounds PI, P2, P3, P4, P5, P6, P7, P8, P39, P9, P10, P11, P12, P13, P14 and PI 5 may be synthesized using this approach.
• Reaction Scheme 3 shows synthesis of compounds ofthe invention which comprise tertiary butyl substituents in Ar.
• Reaction Scheme 4 shows synthesis of compounds ofthe invention which comprise a keto substitution on the piperazine ring, such as in compounds P48-P57.
• Reaction Scheme 5 shows synthesis of compounds ofthe invention which comprise a various substitutions on the piperazine ring, such as in compounds P36 and P47.
• the compounds ofthe invention can be synthesized individually using methods known in the artj ⁇ er.s'e, or as members of a combinatorial library. [0053] 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 ofthe library to bind the channel to be tested is measured, for example, by the ability ofthe 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 measured in the presence of calcium, barium or other permeant divalent cation and the ability ofthe compound to interfere with the signal generated is measured using standard techniques.
• one method involves the binding 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, Kd 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 ofthe 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 ofthe 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 ofthe channel or as resting channel blockers. 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 ofthe 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. Finally, resting channel blockers would diminish the peak current amplitude during the very first depolarization after drug application without additional inhibition during the depolarization.
• the compounds ofthe invention can be formulated as pharmaceutical of 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.
• a summary of such techniques is found in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton, PA, incorporated herein by reference.
• the compounds of formula (1) may be used alone, as mixtures of two or more compounds of fonnula (1) or in combination with other pharmaceuticals. Depending on the mode of administration, the compounds will be formulated into suitable compositions to permit facile delivery.
• 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 ofthe invention. Suitable forms include syrups, capsules, tablets, as is understood in the art.
• the dosage ofthe compounds of the invention is typically 0.1-15 mg/kg, preferably 0.1-1 mg/kg.
• dosage levels are highly dependent on the nature ofthe condition, drug efficacy, the condition ofthe 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 3,4,dimethoxyphenol (l.Og, 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 4 , and evaporated under reduced pressure. The product was purified by column chromatography on silica (Hexane:EtOAc 3:1) to give the desired product in 60% yield.
• Antagonist activity was measured using whole cell patch recordings on human embryonic kidney cells either stably or transiently expressing rat N-type channels ( ⁇ XI B + ⁇ 2 b+ ⁇ ib subunits) with 5 mM barium as a charge carrier.
• cells either stably or transiently expressing rat L-type channels ( ⁇ ]C + ⁇ 2 ⁇ + Si b cDNA subunits) and P/Q-type channels ( ⁇ A + ⁇ 2 s + ⁇ b cDNA subunits)
• HEK 293 For transient expression, 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 + ⁇ i b + ⁇ 2 ⁇ N-type calcium channel subunits in a vertebrate expression vector (for example, see Current Protocols in Molecular Biology).
• Example 10 The methods of Example 10 were followed with slight modifications as will be apparent from the description below.
• ⁇ -type calcium channel blocking activity was assayed in human embryonic kidney cells, HEK 293, stably transfected with the rat brain ⁇ -type calcium channel subunits ( i ⁇ + ⁇ _ ⁇ +/3ib cD ⁇ A subunits).
• ⁇ -type calcium channels i B + 0_s + ⁇ b cD ⁇ A subunits
• L-type channels ⁇ ic + 2 ⁇ + ⁇ . b cD ⁇ A subunits
• P/Q-type channels a JA + ckt, + ⁇ b cD ⁇ A subunits
• DMEM Dulbecco's modified eagle medium
• Standard patch-clamp techniques were employed to identify blockers of T-type currents. Briefly, previously described HEK cell lines stably expressing human ⁇ io 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 SI 00 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 M ⁇ (see below for internal medium).
• T-type currents are reliably obtained by using two voltage protocols: “non-inactivating", and “inactivating"
• 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% ofthe T-type channels, as shown below.
• test pulse - 40 mV, 50 ms 0.067 HH
• Vholding ⁇ -IO rnV non-inactivating pre-pulse -100 mV, 1 second u
• 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-inactivating" pre-pulse was used to examine the resting block of a compound. The “inactivating” protocol was employed to study voltage-dependent block. However, the initial data were obtained using the non-inactivating protocol. IC 50 value of PI 8 was found to be 0.022 ⁇ M under this protocol.
• Results are shown in Table 5 for some ofthe invention compounds.
• Table 5 Block of otic T-type Channels

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