EP1242398A2 - Inhibiteurs calciques partiellement satures - Google Patents

Inhibiteurs calciques partiellement satures

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Publication number
EP1242398A2
EP1242398A2 EP00988532A EP00988532A EP1242398A2 EP 1242398 A2 EP1242398 A2 EP 1242398A2 EP 00988532 A EP00988532 A EP 00988532A EP 00988532 A EP00988532 A EP 00988532A EP 1242398 A2 EP1242398 A2 EP 1242398A2
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EP
European Patent Office
Prior art keywords
substituted
unsubstituted
rings
aliphatic cyclic
aromatic
Prior art date
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Application number
EP00988532A
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German (de)
English (en)
Inventor
Terrance P. Snutch
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Taro Pharmaceuticals Inc
Original Assignee
Neuromed Technologies Inc
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Filing date
Publication date
Application filed by Neuromed Technologies Inc filed Critical Neuromed Technologies Inc
Publication of EP1242398A2 publication Critical patent/EP1242398A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures

Definitions

  • the invention relates to compounds useful in treating conditions associated with calcium channel function. More specifically, the invention concerns compounds containing benzhydril and 6-membered heterocyclic moieties that are useful in treatment of conditions such as stroke and pain.
  • 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.
  • 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 of the high voltage- activated channels, consequently pharmacological profiles are useful to further distinguish them.
  • L-type channels are sensitive to dihydropyridine agonists and antagonists
  • N-type channels are blocked by the Conus geographus peptide toxin
  • ⁇ -conotoxin GNIA and P-type channels are blocked by the peptide ⁇ -agatoxin IV A from the venom of the funnel web spider, Agelenopsis aperta.
  • Q-type high voltage-activated calcium channel
  • Biochemical analyses show that neuronal high voltage activated calcium channels are heterooligomeric complexes consisting of three distinct subunits (oti, ⁇ 2 ⁇ and ⁇ ) (reviewed by De Waard, M. et al. Ion Channels (1997) vol. 4, Narahashi, T. ed. Plenum Press, NY).
  • the ⁇ i subunit is the major pore-forming subunit and contains the voltage sensor and binding sites for calcium channel antagonists.
  • the mainly extracellular 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 of the ⁇ i subunit.
  • a fourth subunit, ⁇ is unique to L-type calcium channels expressed in skeletal muscle T-tubules. The isolation and characterization of ⁇ -subunit-encoding cDNAs is described in U.S. Patent No. 5,386,025 which is incorporated herein by reference.
  • ⁇ A channels are of the P/Q type; ⁇ B represents N; a ⁇ c, O ⁇ ' . D. C* I F and ⁇ is represent L; ⁇ E represents a novel type of calcium conductance, and ⁇ i G - ⁇ represent members of the T-type family, reviewed in Stea, A. et al. in Handbook of Receptors and Channels (1994), North, R.A. ed. CRC Press; Perez-Reyes, et al. Nature (1998) 391 :896-900;
  • N-type channels which are synaptic channels
  • 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 of the formula A-Y-B wherein B contains a piperazine or piperidine ring directly linked to
  • A An essential component of these molecules is represented by 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).
  • 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.
  • U.S. Patent No. 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.
  • 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 ci USA (1983) 80:5122-5125 describes antischizophrenic neuroleptic drugs such as lidoflazine, fluspirilene, pimozide, clopimozide, and penfluridol.
  • 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 compounds comprising a six-membered heterocyclic ring containing at least one nitrogen coupled to two hydrophobic clusters (each cluster coupled optionally through a linker) provide calcium channel blocking activity.
  • these compounds are particularly useful for treating stroke and pain.
  • compounds useful in treating indications associated with excessive calcium channel activity and combinatorial libraries that contain these compounds can be prepared.
  • the invention relates to compounds useful in treating conditions such as stroke, 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 of the invention are derivatives of piperidine or piperazine linked to hydrophobic substituents which enhance the calcium channel blocking activity.
  • the invention is directed to therapeutic methods that employ compounds of the formulas or
  • each Z is independently N or CH, but one Z must be N; wherein n 1 is 1 and n 2 is 0 or 1 ;
  • X 1 and X 2 are linkers
  • Ar represents one or two substituted or unsubstituted aromatic or heteroaromatic rings
  • Cy represents one or two substituted or unsubstituted aliphatic cyclic or heterocyclic rings, or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic ring and one substituted or unsubstituted aromatic or heteroaromatic ring; each of Y a and Y b is two substituted or unsubstituted aromatic or heteroaromatic rings, or can be two substituted or unsubstituted aliphatic cyclic or heterocyclic rings or consists of one substituted or unsubstituted aliphatic cyclic or heterocyclic ring and one substituted or unsubstituted aromatic or heteroaromatic ring; with the proviso that said rings cannot both be phenyl when both Ar includes a single phenyl ring and X 1 contains less than 5C; and with the proviso that formula (lb) must contain at least one aromatic or heteroaromatic ring; l 1 is O or 1 ; R 1 is substituted
  • the invention is directed to methods to antagonize calcium channel activity using the compounds of formulas (la) or (lb) and thus to treat associated conditions. It will be noted that the conditions may be associated with abnormal calcium channel activity, or the subject may have normal calcium channel function which nevertheless results in an undesirable physical or metabolic state that can be benefited by lowering calcium transport. In another aspect, the invention is directed to pharmaceutical compositions containing these compounds.
  • the invention is also directed to combinatorial libraries containing the compounds of formulas (la) or (lb) and to methods to screen these libraries for members containing particularly potent calcium channel blocking activity including blocking activity for channels of a particular type.
  • the compounds of formulas (la) or (lb), useful in the methods of the invention exert their desirable effects through their ability to antagonize the activity of calcium channels, including those which are synaptic in their activity. While the compounds of formulas (la) or (lb) generally have this activity, the availability of a multiplicity of calcium channel blockers permits a nuanced selection of compounds for particular disorders. Thus, the availability of this class of compounds provides not only a genus of general utility in indications that are affected by excessive calcium channel activity, but also provides a large number of compounds which can be mined and manipulated for specific interaction with particular forms of calcium channels.
  • 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.”
  • activation 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
  • Blockers of sodium channels are useful as local anesthetics, and in treating cardiac arrhythmias, as anticonvulsants, and in treating hyperkalemic periodic paralysis.
  • Potassium channel blockers are useful in treating hypertension and cardiac arrhythmias; various other receptors are associated with psychoses, schizophrenia, depression, and apnea.
  • the library of compounds of the invention is useful in standard screening techniques as a source of effective pharmaceutical compounds.
  • the compounds of the invention may be synthesized using conventional methods. Illustrative of such methods are the following schemes.
  • the piperazine derivatives of the invention are prepared conveniently by synthetic routes wherein one of the linkers, X 1 or X 2 , is supplied as a carboxylic acid or carboxylic acid derivative and is coupled to piperazine already bound to the remaining substituent.
  • these compounds are prepared by Reaction Scheme 1 illustrated below for the embodiment wherein Ar is benzhydril and is depicted as R.
  • the intermediate amide product can be reduced as shown, if desired, using a suitable reducing agent.
  • the piperazine ring nitrogen shown coupled to R is protected with t-butyl carbonate (BOC) which can then be removed and replaced with a different substituent as shown in Reaction Scheme 2 and then reduced, for example, with BH 3 .
  • EDC represents ethyldicyclohexylcarbodiimide
  • LAH represents lithium aluminum hydride
  • TFA is trifluoroacetic acid.
  • carboxylates are commercially available including instances which include cyclic aliphatics. Where they are not, they can be prepared by a Wittig reaction and reduced as desired, as shown in Reaction Scheme 3, which illustrates preparation of the benzhydril embodiment using benzophenone. However, phenylcyclohexylketone or dicyclohexylketone can be substituted for benzophenone to obtain the corresponding embodiments wherein the substituent coupled to linker is symbolized by Cy in formula (lb).
  • LiHMDS represents lithium hexamethyl disilazide.
  • the reaction proceeds smoothly with benzophenone and phenylcyclohexylketone; use of dicyclohexylketone results in an aberrant molecular weight as measured by mass spectrometry, but nevertheless provides product.
  • reagents in the above-referenced scheme may or may not contain substitutions on the aromatic or cyclic aliphatic moieties.
  • compounds in the bis-4-fluorophenyl butylidine series are commercially available and Reaction Scheme 4 illustrates the preparation of these compounds.
  • R represents Y a and may include a portion of the linker, X 1 , which linker includes CH 2 NH.
  • each Z is independently N or CH, but one Z must be N.
  • R 1 is alkyl (1-6C) aryl (6-10C) or arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of N, P, O, S, and halo.
  • R 1 may also be the "substituents" halo, OR, SR, NR 2 , OOCR, NROCR, COR, COOR, CONR 2 , CF 3 , CN or NO 2 , wherein R is H or alkyl (1-6C).
  • These "substituents” may also be present on the alkyl, aryl or arylalkyl moieties contained in Formulas la and lb; aryl groups may also contain alkyl substituents.
  • R 1 Preferred embodiments of R 1 include phenyl, phenylalkyl, F, Cl, Br, I, CF 3 , OR, NR and alkyl. Particularly preferred are F, OMe, NH 2 , NMe 2 , NHOAc, CONH 2 , Br, COOEt, and COOMe, as well as methyl. Preferably, however, l 1 is 0. As n 2 may be 0 or 1, X 2 may be present or not. X 1 and X 2 are suitable linkers containing 1-lOC which may be saturated or unsaturated and may contain a ring. The linker may also contain one or two heteroatoms selected from N, O and S and may be substituted with the "substituents" listed above.
  • formulas (la) and (lb) are similar, except that compounds of formula (la) contain more mandated aromatic substituents linked to the heterocyclic 6-membered ring and those of (lb) contain more aliphatic cyclic or heterocyclic moieties.
  • X 2 represents a linker which spaces the
  • Ar or Cy moiety from Z preferably at a distance of 3-20A, and may contain at least one heteroatom which is nitrogen or oxygen. Included in such linkers are amines and carbonyl functionalities, including amides. The linker may also be unsaturated or may be an alkylene group.
  • X 1 spaces the Y a or Y b from the nitrogen of the heterocyclic ring at a distance of 3-20A.
  • X 1 or X 2 when linked to two aromatic or heterocyclic or other cyclic moieties, as is always the case for Y a and Y b , X 1 or X 2 must accommodate this and a typical embodiment is -(CH 2 ) 0 - 6 -CH-CH(CH 2 ) 0 - 6 CO, or -CH(CH 2 ) 0 - 7 .
  • X 2 is (CH 2 ) ⁇ _ 8 , (CH 2 ),. 5 CO(CH 2 )o-3, (CH 2 )i. 5 NH(CH 2 )o-3, (CH 2 ) 0 - 5 CONH(CH 2 )o.3, and (CH 2 ) 1 . 5 NHCO(CH 2 ) 0 -3, with accommodation as required for two rings.
  • Preferred for X 1 are CH(CH ) M O and CH(CH 2 ) ⁇ _ 9 CO.
  • halogenation of the compounds of the invention is helpful in modulating the in vivo half-life, and it may be advantageous to include halogen- substituted rings in the compounds.
  • substituents include alkyl (1-6C), aryl (6- IOC) or arylalkyl (7-16C) optionally containing 1-4 heteroatoms selected from the group consisting of halo, N, P, O, and S or may be the "substituents" halo, OR, SR, NR 2 , OOCR, NROCR, COR, COOR, CONR 2 , CF 3 , CN or NO 2 , wherein R is H or alkyl (1-6C).
  • substituents may also be present on the alkyl, aryl or arylalkyl or other cyclic moieties; aryl or other cyclic moieties groups may also contain alkyl substituents.
  • Typical heteroaromatic moieties include pyridyl, pyrimidyl, quinolyl and the like.
  • Typical aliphatic heterocycles include, for example, piperidinyl, piperazinyl, tetrahydrofuranyl, pyranyl, and the like.
  • Preferred embodiments of Y a and Y b include two cyclohexyl residues or a cyclohexyl and a phenyl residue.
  • aromatic, heteroaromatic, cyclic aliphatic, and heterocyclic aliphatic moieties may be substituted or unsubstituted.
  • Typical "substituents" include halo, OR, SR, NR 2 , OOCR, NROCR, COR, COOR, CONR 2 , CF 3 , CN or NO 2 , wherein R is H or alkyl (1 -6C).
  • alkyl 1-6C
  • aryl (6- IOC)
  • arylalkyl 7-16C
  • Aryl residues or other cyclic residues may also be substituted by alkyl.
  • Preferred substituents include halo, CF 3 , OR, NR 2 , COONR 2 , COOR, and the like.
  • preferred embodiments of Ar include two phenyl moieties or a single phenyl moiety.
  • preferred embodiments of Cy include a single cyclohexyl, a cyclohexyl and phenyl moiety, or two cyclohexyl moieties.
  • Y a is two substituted or unsubstituted phenyl
  • X' is CH(CH 2 ) 5 or CH(CH 2 ) 4 CO
  • Z is N
  • X 2 is CH 2 and n 2 is O or 1.
  • Ar is preferably an optionally substituted ring which is phenyl, pyrimidyl, especially 2-pyrimidyl or pyridyl, especially 2-pyridyl.
  • the invention compounds may also be supplied as pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts include the acid addition salts which can be formed from inorganic acids such as hydrochloric, sulfuric, and phosphoric acid or from organic acids such as acetic, propionic, glutamic, glutaric, as well as acid ion-exchange resins. If the compounds contain carboxyl groups, the salts of the carboxyl groups may also be included, typical pharmaceutically acceptable salts are sodium, potassium, or calcium salts if appropriate, or salts with inorganic bases such as caffeine.
  • the compounds of the invention can be formulated as pharmaceutical or veterinary compositions.
  • 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
  • the compounds of formulas (la) and (lb) may be used alone, as mixtures of two or more compounds of formulas (la) and (lb) or in combination with other pharmaceuticals.
  • 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.
  • 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.
  • sustained release systems for drugs have also been devised. See, for example, U.S. Patent No. 5,624,677.
  • 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.
  • 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.
  • the compounds of the invention can be synthesized individually using methods known in the art per se, or as members of a combinatorial library.
  • Y a or Yb is coupled, along with any linking moiety, to the nitrogen of the piperazine or piperidine ring.
  • This ring itself is generally appropriately substituted with (X 2 )n-Ar or (X 2 ) n -Cy prior to this coupling.
  • Y a (X 1 ) folki or Y (X')ni is supplied containing a suitable electron- withdrawing leaving group, thus effecting the coupling to the ring nitrogen.
  • the libraries contain compounds with various embodiments of R 1 , X 1 , X 2 , Ar, Cy, Y and Z, along with appropriate substituents. These 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. In addition, using standard screening protocols, the libraries may be screened for compounds which block additional channels such as sodium channels, potassium channels and the like.
  • 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 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 measured in the presence of the appropriate agonist and the ability of the 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, K- 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.
  • Example 1 Assay of N-Type Calcium Channel Blocking Activity Antagonist activity was measured using whole cell patch recordings on human embryonic kidney cells either stably or transiently expressing rat ⁇ i ⁇ + ⁇ + ⁇ i b channels with 5 mM barium as a charge carrier.
  • HEK 293 For transient expression, host cells, such as human embryonic kidney cells, HEK 293 (ATCC# CRL 1573) are grown in standard DMEM medium supplemented with 2 mM glutamine and 10% fetal bovine serum. HEK 293 cells are transfected by a standard calcium-phosphate-DNA coprecipitation method using the rat ⁇ i B + ⁇ i b + ⁇ ⁇ N-type calcium channel subunits in a vertebrate expression vector (for example, see Current Protocols in Molecular Biology).
  • 6-Bromohexanoic acid (7.08 g, 36.3 mM) and triphenylphosphine (10 g, 38.2 mM) was mixed in dry CH 3 CN (40 ml).
  • the reaction mixture was heated to reflux overnight and allowed to cool to RT.
  • the solution was concentrated under reduced pressure to give a viscous gel.
  • Approximately 75 ml of THF was added to the reaction mixture and the walls of the flask were scratched with a spatula to start crystallization.
  • the resulting solid was filtered under vacuum, washed with THF and dried under reduced pressure and used without further purification.
  • the product from the above reaction (1.5 g) was suspended in dry THF and the flask purged with N and cooled to -78°C.
  • LiHMDS lithium hexamethyldisilazide
  • the combined aqueous base fractions were acidified with cone. HC1 to a pH of 4.
  • the water layer was extracted with ether (3x) and the combined organic fractions dried over Na 2 SO 4 .
  • the ether was evaporated to dryness under reduced pressure to give a colorless oil that crystallized on standing to give a waxy solid. NMR and MS showed this material was clean enough to continue without further purification.
  • the alkene was dissolved in 30 ml MeOH and mixed with 5% Pd-C and placed in a Parr hydrogenator. The reaction vessel was purged with hydrogen and pressurized to 60 PSIG and reacted at RT for 5h. The reaction mixture was sampled and analyzed by TLC.
  • the reaction mixture was resubjected to the reaction conditions. After the reaction was done the solution was filtered through a plug of celite and the methanol filtrate was concentrated under vacuum.
  • the substituted BOC piperazine (65 mg, 0.15 mM) was dissolved in TFA (25%) in CH 2 C1 , 3 ml) in a dry 20 ml vial.
  • the vial was loosely capped to allow for the release of CO 2 .
  • the mixture was allowed to react for lh then concentrated under vacuum.
  • the residue was sampled for MS and showed the molecular ion for the free amine.
  • the residue was redissolved in THF and reacted with cyclohexanecarbonyl chloride (46 mg, 42 ⁇ l, 0.31 mM) and DIEA (57 mg, 77.7 ⁇ ) and stirred at RT for 2h.
  • the reaction mixture was diluted with EtOAc and extracted with water (3x), 10% NaOH (6x), 10% HC1 (3x), brine (lx) and dried over sodium sulphate.
  • the product was generally clean enough after work up but could be further purified via column
  • Example 2 Using the procedure set forth in Example 1, various compounds of the invention were tested for their ability to block N-type calcium channels. The results are shown in Tables 1 and 2, where IC 5 o is given in ⁇ M (micromolar). In all cases, l 1 is 0, both Z are N, both n 1 and n 2 are 1.
  • N-type calcium channel blocking activity is assayed in human embryonic kidney cells, HEK 293, stably transfected with the rat brain N-type calcium channel subunits ( iB + &2 ⁇ + ⁇ b cDNA subunits).
  • iB + &2 ⁇ + ⁇ b cDNA subunits the rat brain N-type calcium channel subunits
  • N-type calcium channels (C-IB + dz ⁇ cDNA subunits) and P/Q-type channels ⁇ 1A + &2 ⁇ + ⁇ b cDNA subunits) are transiently expressed in HEK 293 cells.
  • DMEM Dulbecco's modified eagle medium
  • 10%o fetal bovine serum 200 U/ml penicillin and 0.2 mg/ml streptomycin at 37°C with 5% CO 2 .
  • 85% confluency cells are split with 0.25% trypsin 1 mM EDTA and plated at 10%> confluency on glass coverslips.
  • the medium is replaced and the cells transiently transfected using a standard calcium phosphate protocol and the appropriate calcium channel cDNAs.
  • Fresh DMEM is supplied and the cells transferred to 28 0 C/5%> CO 2 . Cells are incubated for 1 to 2 days to whole cell recording.
  • the external and internal recording solutions contain, respectively, 5 mM BaCl 2 , 1 mM MgCl 2 , 10 mM HEPES, 40 mM TEAC1, 10 mM glucose, 87.5 mM CsCl (pH 7.2) and 108 mM CsMS, 4 mM MgCl 2 , 9 mM EGTA, 9 mM HEPES (pH 7.2).

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Abstract

L'invention concerne des composé représentés par la formule (1a) ou (1b) ou leurs sels, dans lesquelles chaque Z est indépendamment N ou CH, mais un Z doit être N; dans lesquelles n1 est 1 et n2 est 0 ou 1; X1 et X2 sont des segments de liaison; Ar représente un ou deux anneaux aromatiques ou hétéroaromatiques substitués ou non substitués, et Cy représente un ou deux anneaux aliphatiques cycliques ou hétérocycliques substitués ou non substitués, ou est composé d'un anneau aliphatique cyclique ou hétérocyclique substitué ou non substitué et d'un anneau aromatique ou hétéroaromatique substitué ou non substitué; Y¿a? et Yb sont deux anneaux aromatiques ou hétéroaromatiques substitués ou non substitués, ou peuvent être deux anneaux aliphatiques cycliques ou hétérocycliques substitués ou non substitués, ou sont composés d'un anneau aliphatique cyclique ou hétérocyclique substitué ou non substitué et d'un anneau aromatique ou hétéroaromatique substitué ou non substitué; à condition que lesdits anneaux ne soient pas tous les deux un phényle lorsque les deux Ar comprennent un seul anneau de phényle et X?1¿ contient moins de 5C; et à condition que la formule (1b) contienne au moins un anneau aromatique ou hétéroaromatique; 11 est 0 ou 1; R1 est un alkyle (1-6C) substitué ou non substitué, un aryle (6-10C) substitué ou non substitué ou un arylalkyle (7-16C) substitué ou non substitué contenant éventuellement 1-4 hétéroatomes sélectionnés dans le groupe composé de halo, N, P, O, et S ou pouvant être indépendamment halo, OR, SR, NR¿2?, OOCR, NROCR, COR, COOR, CONR2, CF3, CN ou NO2, R étant H ou alkyle (1-6C).
EP00988532A 1999-12-20 2000-12-20 Inhibiteurs calciques partiellement satures Withdrawn EP1242398A2 (fr)

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US47692999A 1999-12-30 1999-12-30
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Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUP0501182A3 (en) 2003-04-24 2011-08-29 Incyte Corp Aza spiro alkane derivatives as inhibitors of metallproteases and pharmaceutical compositions containing them
MXPA06000795A (es) 2003-07-22 2006-08-23 Arena Pharm Inc Derivados de diaril y arilheteroaril urea como moduladores del receptor 5-ht2a de serotonina utiles para la profilaxis y tratamiento de desordenes relacionados con el mismo.
GEP20094638B (en) 2004-06-15 2009-03-10 Pfizer Benzimidazolone carboxylic acid derivatives
US7737163B2 (en) 2004-06-15 2010-06-15 Pfizer Inc. Benzimidazolone carboxylic acid derivatives
WO2006024160A1 (fr) 2004-08-30 2006-03-09 Neuromed Pharmaceuticals Ltd. Dérivés de l'urée agissant comme agents bloquant un canal de calcium
US7511077B2 (en) 2005-02-09 2009-03-31 Neuromed Pharmaceuticals Ltd. Diamine calcium channel blockers
EA012615B1 (ru) 2005-02-22 2009-10-30 Пфайзер Инк. Производные оксииндола в качестве агонистов 5-htрецептора
US20100168103A1 (en) * 2006-09-14 2010-07-01 Neuromed Pharmaceuticals Ltd. Diaryl piperidine compounds as calcium channel blockers
TWI415845B (zh) 2006-10-03 2013-11-21 Arena Pharm Inc 用於治療與５-ｈｔ2ａ血清素受體相關聯病症之作為５-ｈｔ2ａ血清素受體之調節劑的吡唑衍生物
MY148880A (en) 2006-10-20 2013-06-14 Astrazeneca Ab N-(2-hydroxyethyl)-n-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)piperidin-4-ylidene)methyl)benzamide, the process of making it as well as its use for the treatment of pain, anxiety and depression
ES2421237T7 (es) 2007-08-15 2013-09-30 Arena Pharmaceuticals, Inc. Derivados de imidazo[1,2-a]piridin como moduladores del receptor serotoninérgico 5ht2a en el tratamiento de trastornos relacionados con el mismo
WO2009123714A2 (fr) 2008-04-02 2009-10-08 Arena Pharmaceuticals, Inc. Procédés de préparation de dérivés de pyrazole utiles comme modulateurs du récepteur de la sérotonine 5-ht<sb>2a</sb>
WO2010062321A1 (fr) 2008-10-28 2010-06-03 Arena Pharmaceuticals, Inc. Procédés utiles pour la préparation de 1-[3-(4-bromo-2-méthyl-2h-pyrazol-3-yl)-4-méthoxy-phényl]-3-(2,4-difluoro‑phényl)-urée, et formes cristallines associées
LT2364142T (lt) 2008-10-28 2018-06-25 Arena Pharmaceuticals, Inc. 5-ht2a serotonino receptoriaus moduliatoriaus kompozicijos, naudotinos su juo susijusių sutrikimų gydymui
EP2578569B1 (fr) * 2010-05-27 2015-10-28 ASKA Pharmaceutical Co., Ltd. Composé hétérocyclique et antagoniste du récepteur h1
EP3288527B1 (fr) 2015-04-28 2020-02-19 Unilever PLC, a company registered in England and Wales under company no. 41424 of Composés d'aralkylcarboxamidoalkylamine et compositions de soins personnels les comprenant
MX2017013690A (es) * 2015-04-28 2018-03-02 Unilever Nv Compuestos de n-aralquilcarbonil-piperazina y -homopiperazina y composciones para el cuidado personal que comprenden los mismos.
EP4119141A1 (fr) 2015-06-12 2023-01-18 Axovant Sciences GmbH Nelotanserin pour la prophylaxie et le traitement d'un trouble du comportement en sommeil paradoxal
CA2992518A1 (fr) 2015-07-15 2017-01-19 Axovant Sciences Gmbh Derives d'arylheretoaryl uree en tant que modulateurs du recepteur serotoninergique 5-ht2a utiles pour la prophylaxie et le traitement d'hallucinations associees a une maladie neurodegenerative

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5703071A (en) * 1990-08-29 1997-12-30 Pharmacia & Upjohn Company Tropolone derivatives and pharmaceutical composition thereof for preventing and treating ischemic diseases
DE4111861A1 (de) * 1991-04-11 1992-10-15 Schwabe Willmar Gmbh & Co Benzopyranone, verfahren zu ihrer herstellung und verwendung
WO1992020661A1 (fr) * 1991-05-22 1992-11-26 Merck & Co., Inc. N, n-diacylpiperazines
WO1995015958A1 (fr) * 1993-12-08 1995-06-15 Alcon Laboratories, Inc. Composes presentant une puissante activite d'antagonistes du calcium et d'antioxydants et leur utilisation en tant qu'agents cytoprotecteurs
CA2294011A1 (fr) * 1997-06-16 1998-12-23 Janssen Pharmaceutica N.V. Utilisation d'analogues de draflazine dans le traitement de la douleur
AU1600599A (en) * 1998-02-27 1999-09-15 Warner-Lambert Company Heterocyclic substituted aniline calcium channel blockers
US6011035A (en) * 1998-06-30 2000-01-04 Neuromed Technologies Inc. Calcium channel blockers

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0146166A2 *

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JP2003518107A (ja) 2003-06-03
AU2495701A (en) 2001-07-03
NO20022948L (no) 2002-08-19
NO20022948D0 (no) 2002-06-19
CA2397681A1 (fr) 2001-06-28
MXPA02006137A (es) 2002-12-05
AU784848B2 (en) 2006-07-06
WO2001046166A2 (fr) 2001-06-28
CA2397681C (fr) 2011-03-15
NO326939B1 (no) 2009-03-16

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