WO1999032115A1 - Modulateurs des recepteurs de la ryanodine contenant des 2-(aryl)-4,7-dioxobenzothiazoles et leurs analogues - Google Patents

Modulateurs des recepteurs de la ryanodine contenant des 2-(aryl)-4,7-dioxobenzothiazoles et leurs analogues Download PDF

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WO1999032115A1
WO1999032115A1 PCT/US1998/027002 US9827002W WO9932115A1 WO 1999032115 A1 WO1999032115 A1 WO 1999032115A1 US 9827002 W US9827002 W US 9827002W WO 9932115 A1 WO9932115 A1 WO 9932115A1
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substituents
electron
group
compound
substituent
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PCT/US1998/027002
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English (en)
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Keshore R. Bidasee
Henry R. Besch, Jr.
Yvette A. Jackson
Michael A. Lyon
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Advanced Research And Technology Institute, Inc.
The University Of The West Indies
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Priority to AU20039/99A priority Critical patent/AU2003999A/en
Publication of WO1999032115A1 publication Critical patent/WO1999032115A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2

Definitions

  • the present invention relates generally to novel compounds that modulate ryanodine receptors, as might be particularly useful in pesticides or as a therapeutic agent .
  • ryanodine which is the major alkaloid from Ryania speciosa Vahl, has aided in the identification, localization, and cloning of three different forms of mammalian ryanodine- sensitive calcium- release channels (ryanodine receptors or CRCs) : RyRl, which is predominant in skeletal muscle, RyR2 which is predominant in the heart and the brain, and RyR3 which was first identified in the brain but subsequently found to be ubiquitously distributed, with the highest expression occurring in the diaphragm.
  • CRCs mammalian ryanodine receptors
  • Ryanodine was also instrumental in identifying the ⁇ and ⁇ isofor s of RyRl in avian and amphibian muscles .
  • ryanodine has been and still continues to be used as a high affinity probe for mammalian and non- mammalian ryanodine receptors, it is well known in the art that this compound is ill-suited for use as a therapeutic agent or as the major component of pesticides for a number of reasons.
  • ryanodine is not only highly toxic to non-vertebrates, as evidenced by the use of Ryania as an insecticide, but also to vertebrates. In this respect, studies have shown that 300 nmol/kg i.v. of ryanodine is lethal to rats.
  • ryanodine is a complex, hexacyclic, polyhydroxy, diterpene alkaloid (Trinidad and Brazil are the major sources, yields ⁇ _ 0.1% w/w of plant tissue) .
  • ryanodine receptors exhibit an undesirable concentration-dependent biphasic response upon treatment with ryanodine.
  • ryanodine Because of its extremely slow on and off kinetics from the receptors, many investigators, especially those studying actions at the single channel level, use concentrations of ryanodine significantly higher than its K d value to study its functional effects. At these high concentrations, ryanodine may open some calcium-release channels but may undesirably close others, thereby confounding interpretation of the results.
  • exogenous substances such as eudostomins, caffeine, dantrolene, halothane and imperatoxins, as well as endogenous ligands, such as calcium and magnesium ions, cyclic adenosine diphosphate- ribose (cADP-ribose) , FK binding proteins (FKBP12) , and calmodulin, are known to have modulatory effects on ryanodine receptors, their affinities and efficacies vary significantly among the three types of mammalian ryanodine receptors (RyRl, RyR2 , and RyR3 ) .
  • these ligands do not interact at the ryanodine binding site(s) on the receptors. With the exception of eudostomins and imperatoxins, all of these ligands have affinities in the micromolar range.
  • ryanodine has not been satisfactory for therapeutic uses because of its high mammalian toxicity. Also of disadvantage are the extremely slow association and dissociation kinetics of ryanodine. In addition, it was not possible even to explore the therapeutic potential of selectively activating or deactivating ryanodine receptors because of ryanodine ' s concentration-dependent biphasic effect on CRCs . It also bears mentioning that total chemical synthesis of ryanodine is beyond the state of the art .
  • the present invention comprises novel substituted 2- (aryl) -4 , 7-dioxobenzothiazole derivatives (herein termed "BQTs”) given by the formula:
  • these analogues can include substitutions on the C 2 phenyl at the 2', 3', 4', 5', and 6' positions denoted as R 2 -R 6 , as well as substitutions on positions 5 and 6 of the benzoquinone moiety denoted as Y 5 and Y s .
  • the substituents on the phenyl moiety will vary from electron donating (for example, alkyl, such as methyl, ethyl, propyl, and butyl) to electron withdrawing functionalities (for example, acyl, cyano, or fluoro) , as well as substituents that can modulate the electron density of the phenyl moiety (for example, amino, alkoxy, such as methoxy and ethoxy, halogen, especially iodo, chloro, and bromo, as well as hydroxy) .
  • Functional groups may be inserted into these positions as mono- , di-, tri-, tetra-, or penta- substitutions.
  • the substituents on the benzoquinone moiety will vary from electron donating (for example, alkyl, such as methyl, ethyl, propyl, and butyl) to electron withdrawing functionalities (for example, acyl, cyano, or fluoro) , as well as substituents that can modulate the electron density of the benzoquinone moiety (for example, amino, alkoxy, such as methoxy and ethoxy, cyclic aromatic, halogen, especially iodo, chloro, and bromo, hydroxy, and heterocyclic substituents) .
  • Functional groups may be inserted into these positions as mono- or di- substitutions.
  • Compounds according to the present invention exhibit a very high affinity for binding to ryanodine-sensitive calcium-release channels from muscle (RyRs) and an appreciable ability to alter the patency ("openness") of these channels. Therefore, these compounds (i) are suitable as molecular probes for RyRs, and it is also contemplated that these compounds (ii) have use in beneficially altering the concentrations of intracellular free calcium upon introduction into an organism, thereby ameliorating the underlying etiology for a wide array of cellular pathologies, by a mechanism or mode of action different from those of existing drugs, and (iii) have use as pesticides. Moreover, these compounds are of far simpler structure than ryanodine but carry its pharmacological actions.
  • novel ligands with simple chemical structures that bind specifically to and activate endoplasmic/sarcoplasmic reticulum calcium-release channels were synthesized.
  • activator- selective ryanoids are less toxic than ryanodine to rats when given intravenously. Since the novel ligands of the present invention preferentially activate ryanodine receptors, it is likely that they are less toxic and can be used to investigate the therapeutic potential of selectively activating or opening ryanodine receptors.
  • activator-selective ryanoids were more toxic than ryanodine to insects.
  • the compounds of the present invention are molecules of simple chemical structure, and can be easily synthesized from common laboratory reagents, therefore reducing significantly the problem of supply and cost .
  • the simple chemical structures of the compounds of the present invention interact at ryanodine binding sites and activate ryanodine receptors. These compounds have been specifically synthesized to investigate the therapeutic potential of selectively activating ryanodine receptors.
  • the compounds of the present invention predominantly activate ryanodine receptors, they are expected to exhibit high insect toxicity, but low mammalian toxicity, thereby making them useful as pesticides.
  • FIG. 1 illustrates a synthetic scheme for preparing exemplary compounds in accordance with the present invention. Detailed Description of the Preferred Embodiments
  • BQT's novel 2-(aryl) 4 , 7-dioxobenzothiazoles
  • R 2 -R 6 are independently selected from the group consisting of hydrogen, electron donating substituents, electron withdrawing substituents, and electron modulating substituents; and Y 5 and Y s are independently selected from the group consisting of hydrogen, electron donating substituents, electron withdrawing substituents, and electron modulating substituents, or Y 5 and Y 6 together comprise a fused cyclic substituent (fused to the quinone ring at positions 5 and 6) having from 4 to 8 atoms in the ring skeleton (including heteroatoms) , defining a carbocyclic or a heterocyclic, aromatic or non-aromatic, ring, optionally substituted with a substituent selected from the group consisting of electron donating substituents, electron withdrawing substituents, and electron modulating substituents; and suitable salts thereof.
  • the compounds of the present invention can be further derivatized with a sugar moiety, for example, but not limited to, a 5 or a 6 membered ring.
  • the sugar is preferably a natural sugar.
  • the derivatization with the sugar could aid the solubilization of the compounds.
  • Non-aromatic carbocyclic rings include ring systems such as, for example, cyclobutene, cyclobutadiene, cyclopentene, cyclopentadiene, cyclohexene, cycloheptene, cyclooctene, and the like.
  • Aromatic carbocyclic rings include ring systems such as, for example, benzene, naphthalene, and the like.
  • the aromatic ring can be optionally substituted, including rings such as, for example, toluene, xylene (ortho, meta, or para), ethylbenzene, isobutylbenzene, n-propylbenzene, and the like.
  • Non-aromatic heterocyclic rings include ring systems such as, for example, piperidine, tetrahydropyridine, pyran, tetrahydrofuran, dihydrofuran, pyrrolidine, and the like.
  • Aromatic heterocyclic rings include ring systems such as, for example, pyridine, pyrimidine, furan, thiophene, oxazole, pyrazole, imidazole, thiazole, and the like.
  • electron donating substituent refers to a functional group which has a tendency to donate electron density, including, for example, alkyl substituents (e.g., methyl, propyl, isobutyl), alkenyl substituents (e.g., 2-butenyl), and alkynyl substituents (e.g., propargyl) , and the like.
  • alkyl substituents e.g., methyl, propyl, isobutyl
  • alkenyl substituents e.g., 2-butenyl
  • alkynyl substituents e.g., propargyl
  • alkyl means a straight-chain or branched-chain alkyl group which, unless otherwise specified, contains a chain from about 1 to about 20 carbon atoms, preferably from about 1 to about 10 carbon atoms, more preferably from about 1 to about 8 carbon atoms, and even more preferably from about 1 to about 6 carbon atoms.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, ⁇ -butyl, sec-butyl, isobutyl, tert- butyl, pentyl, isoamyl, hexyl, octyl, dodecanyl, and the like.
  • alkenyl and alkynyl refer to straight-chain or branched-chain groups which preferably contain chains from about 1 to about 20 carbon atoms, preferably from about 1 to about 10 carbon atoms, more preferably from about 1 to about 8 carbon atoms, and even more preferably from about 1 to about 6 carbon atoms.
  • electron withdrawing substituent refers to a functional group that has a tendency to withdraw electron density, including, for example, cyano, acyl , carbonyl, fluoro, nitro, sulfonyl, trihalomethyl, and the like.
  • electron modulating substituent refers to a functional group which has a tendency to modulate electron density, that is, a functional group including, for example, amino, hydroxy, alkoxy, aryl (monocyclic or polycyclic, such as, but not limited to, phenyl and naphthyl) substituents, heterocyclic substituents
  • Suitable salts include salts derived from acids such as, for example, hydrochloric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic ,acid, and the like.
  • the electron donating substituent is preferably an alkyl substituent.
  • the electron withdrawing substituent is preferably a substituent selected from the group consisting of acyl (e.g., acetyl, propionyl, butyryl, isobutyryl, and the like) cyano, nitro, and fluoro, and is more preferably, cyano, nitro, or fluoro.
  • the electron modulating substituent is preferably selected from the group consisting of amino (e.g., NH 2 , alkylamino, and dialkylamino, such as, but not limited to, methylamino, dimethylamino, and the like) , alkoxy (preferably C ⁇ -C ⁇ 0 alkoxy), halogen, and hydroxy.
  • Y 5 and Y 6 together comprise a fused cyclic substituent (fused to the quinone ring at positions 5 and 6)
  • there are preferably about 5-7 atoms in the ring skeleton (including heteroatoms) preferably 5 or 6 atoms, and even more preferably 6 atoms .
  • Y 5 and Y 6 together comprise a fused cyclic substituent, it is preferably a heterocyclic ring, preferably comprising about 5-7 atoms in the ring skeleton (including heteroatoms) , more preferably 5 or 6 atoms .
  • the fused cyclic substituent is a 6 - numbered ring, it is most preferably a pyridine ring.
  • the present invention is drawn to a BQT of the formula:
  • R 4 is selected from the group consisting of hydrogen, electron donating substituents, electron withdrawing substituents, and electron modulating substituents; and Y 5 and Y s are independently selected from the group consisting of electron donating substituents, electron withdrawing substituents, and electron modulating substituents, or Y 5 and Y s together comprise a fused cyclic substituent (fused to the quinone ring at positions 5 and 6) having from 4 to 8 atoms in the ring skeleton (including heteroatoms) , defining carbocyclic or heterocyclic, aromatic or non-aromatic, ring, optionally substituted with a substituent selected from the group consisting of electron donating substituents, electron withdrawing substituents, and electron modulating substituents; and salts thereof.
  • the present invention further provides a pesticidal or therapeutic (pharmaceutical) composition
  • a pesticidal or therapeutic (pharmaceutical) composition comprising a compound of the present invention and any acceptable carrier therefor.
  • inventive compounds generally do not exhibit high water solubility, carriers such as a form of cyclodextrin and other encapsulating agents, for example, can be used to deliver the inventive compounds and compositions to the desired site(s) of action, as will be apparent to one of ordinary skill in the art.
  • compositions of the present invention may be in a pharmaceutical form suitable for oral use such as, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of compositions, and such compositions can contain one or more agents including, for example, sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide a pharmaceutically elegant and/or palatable preparation. Tablets can contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets.
  • excipients can include, for example, inert diluents such as, for example, calcium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as, for example, maize starch or alginic acid; binding agents such as, for example, starch, gelatine or acacia, and lubricating agents such as, for example, stearic acid or talc.
  • the tablets may be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material for example, glyceryl monostearate or glyceryl distearate, alone or with a wax, may be employed.
  • Formulations for oral use also can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example arachis oil, peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions typically contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include suspending agents, for example, sodium carboxymethyl cellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia.
  • Dispersing or wetting agents may include natural-occurring phosphatides, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol , or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, for example, polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyoxyethylene sorbitan mono-oleate.
  • natural-occurring phosphatides for example, lecithin
  • condensation products of an alkylene oxide with fatty acids for example polyoxyethylene stearate
  • condensation products of ethylene oxide with long chain aliphatic alcohols for example heptadecaethyleneoxycetanol
  • the aqueous suspensions also can contain one or more preservatives, for example, ethyl or n-propyl p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents such as, for example, sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oil suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions can be preserved by the addition of an antioxidant such as, for example, ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • compositions of the present invention also can be in the form of oil-in-water emulsions.
  • the oily phase can be a vegetable oil, for example, olive oil or arachis oils, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacantn, naturally-occurring phosphatides, for example soya bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan mono-oleate, and condensation products of the said partial esters and ethylene oxide, for example polyoxyethylene sorbitan mono-oleate.
  • the emulsions also can contain sweetening and flavoring agents.
  • compositions of the present invention can be in the form of syrups and elixirs, which are typically formulated with sweetening agents such as, for example, glycerol, sorbitol or sucrose. Such formulations also can contain a demulcent, a preservative and flavoring and coloring agents .
  • compositions can be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleagenous suspension.
  • Suitable suspensions for parenteral administration can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • Formulations suitable for parenteral administration also can include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non- aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the sterile injectable preparation can be in the form of a solution or a suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in water or 1, 3-butanediol .
  • acceptable vehicles and solvents that can be employed, for example, are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides .
  • fatty acids such as, for example, oleic acid find use in the preparation of injectables.
  • the compounds of the present invention also can be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include, for example, cocoa butter and polyethylene glycols.
  • Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, and foams.
  • Formulations suitable for topical administration may be presented as creams, gels, pastes, or foams, containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • inventive compounds can be made into aerosol formulations to be administered via inhalation or as a pesticide.
  • aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non- pressured preparations such as in a nebulizer or an atomizer.
  • the formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • any suitable dosage level can be employed in the compositions of the present invention.
  • the dose administered to a pest or animal (in the latter respect, particularly a human) should be sufficient to effect a prophylactic, pesticidal, or therapeutic response in the animal over a reasonable time frame.
  • the amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • One skilled in the art will recognize that the specific dosage level for any particular patient will depend upon a variety of factors including, for example, the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • the size of the dose will also be determined by the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular compound. Other factors which effect the specific dosage include, for example, bioavailability, metabolic profile, and the pharmacodynamics associated with the particular compound to be administered in a particular patient. Suitable doses and dosage regimens can be determined by comparisons, for example, with similarly-acting agents or as will be apparent to one of ordinary skill in the art.
  • the dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the animal over a reasonable time frame.
  • the dose will be determined by the strength of the particular composition employed and the condition of the animal, as well as the body weight of the animal to be treated.
  • the size of the dose will also be determined by the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular compound.
  • Other factors which effect the specific dosage include, for example, bioavailability, metabolic profile, and the pharmacodynamics associated with the particular compound to be administered in a particular patient.
  • the specific dosage level for any particular patient will depend upon a variety of factors including, for example, the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, the severity of the symptoms presented prior to or during the course of therapy, and the like.
  • the present invention further provides a method of altering the concentration of intracellular free calcium in a living organism (e.g., a vertebrate), which method comprises exposing the organism to an intracellular free calcium concentration altering-effective amount of a compound of the present invention.
  • inventive compounds and methods will have use in treating diseases (including conditions), such as, but not limited to, congestive heart failure, migraine headaches, hypertension, premature abortions, and Parkinson's and Alzheimer's diseases (particularly at early stages) .
  • the compound can be diluted with an acceptable diluent (e.g., a carrier, as described above) for enhancing the uptake of the compound by the organism.
  • BQTs can also complement ryanodine as in vi tro probes of ryanodine receptors. Direct comparisons of the effects of BQTs on ryanodine receptors can be made with those of ryanodine.
  • BQT #1 (set forth below) was synthesized in four steps, starting with readily available 2 , 5-dimethoxy aniline using the procedure schematically depicted in Figure 1. a) Benzoyl amide of 2 , 5-dimethoxyaniline (2a)
  • Benzoyl chloride (1.5 mL) was added to a solution of 2, 5-dimethoxyaniline (la) (2.0 g, 13.2 mmol) in dry toluene (12 mL) and dry pyridine (10 mL) .
  • the solution was heated on a water bath at 60-70 °C for 1 hour.
  • the mixture was cooled to room temperature and poured into aqueous layer was extracted with toluene (3 x 10 mL) .
  • the combined toluene layers were dried over MgS0 4 , filtered, and the toluene removed on a rotary evaporator.
  • Lawesson's reagent (2.0 g, 4.94 mmol) was stirred in dry toluene (5 mL) , to which was added N-2,5- dimethoxyphenylbenzamide (2a) (1.0 g, 3.89 mmol) in dry toluene (5 mL) .
  • the mixture was heated under an atmosphere of nitrogen at 70-80 °C for 2 hours.
  • the solvent was evaporated and the thioamide was purified by column chromatography [dichloromethane : hexane (3:1)] to yield bright yellow crystals (90% yield), m.p. 58 °C - 61 °C.
  • Example 1(a) -1(d) Applying the procedure of Example 1(a) -1(d), except using, as the starting material, 4 -methyl benzoyl chloride (p-toluoyl chloride) instead of benzoyl chloride, the BQT #2 compound (set forth below) was prepared. (Yield -22% from 2b), m.p. 203 °C-206 °C,
  • Example 1 (a) -1 (d) Applying the procedure of Example 1 (a) -1 (d) , except using, as a starting material, 4-chlorobenzoyl chloride instead of benzoyl chloride, the BQT #3 compound (set forth below) was prepared. (Yield -40% from 2c), m.p. 222 °C-224 °C, IR(KBr disc) : v max 1650 cm “1 and 1675 cm “1 .
  • BQT#4 and BQT#5 are isomeric forms of thiazolo [4, 5-g] quinolinequinone (BQT#4 and BQT#5, set forth below), i.e., derivatives of BQT#1 which possess a fused para-methyl pyridine ring on the 5 and 6 positions.
  • R 4 H ( BQT#4 ;
  • R 4 H ( BQT#5 l
  • binding affinities of BQT#1, BQT#2, BQT#3 , BQT#4 , BQT#5, and their synthetic precursors were determined in traditional relative binding affinity assays, with results summarized in Table 1.
  • Sarcoplasmic reticulum membrane vesicles (JSRV) from rabbit skeletal muscle (RyRl) (0.1 mg/mL) were incubated in binding buffer (500 mM KCl, 20 mM Tris.HCl, 0.2 mM CaCl 2 , pH 7.4 at 37 °C) containing 6.7 nM [ 3 H] ryanodine and varying concentrations of BQTs (up to 10,000 nM) for 2 hours at 37°C.
  • the vesicles were filtered through Whatman GF/C filters (0.45 ⁇ m) using a cell harvester (Brandel Model M-24R) and the JSRV remaining on the filters were washed with 3 X 3 mL ice- cold binding buffer (pH 7.4 at O °C) .
  • the filters were then placed in scintillation cocktail, vortexed, allowed to stand overnight, and the [ 3 H] ryanodine bound to RyRs was quantified by liquid scintillation counting.
  • Nonspecific binding was determined simultaneously by incubating JSRV with a concentration of the respective BQT, 10-fold higher than the highest concentration used in the binding assay.
  • Efflux was allowed to continue for 3 seconds and then stopped by further diluting the vesicles six-fold into an ice-cold stop solution (140 mM NaCl, 20 mM HEPES, 0.1 mM EGTA, 5 mM MgCl 2 and 0.01 mM ruthenium red) and rapidly filtering.
  • the vesicles on the filters were then washed with 3 X 3 mL rinse solution (identical to stop solution except without ruthenium red) and the 45 Ca 2+ remaining inside the vesicles were determined by liquid scintillation counting.
  • the ensemble functional patency of RyRs to calcium efflux is inversely related to the amount of calcium ( 45 Ca 2+ ) remaining in the vesicles; the lower the amount of 45 Ca 2+ remaining in the vesicles the greater the ensemble functional patency of RyRs to calcium efflux and vice versa .
  • BQT#2 (2- (4-methylphenyl) -4, 7-benzoquinonethiazole) did not exhibit a significant ability to close the channels.
  • Electron withdrawing groups, electron donating groups, and electron modulating groups can be substituted for Y 5 and Y 6 by using synthetic methods that are available to those of ordinary skill in the art.
  • desired substituents can be introduced at Y 5 and/or Y 6 by way of the synthesis illustrated in FIG. 1, for example, by replacing 2,5- dimethoxy aniline with a suitably substituted 2,5- dimethoxy aniline.
  • electron donating groups, electron withdrawing groups, and electron modulating groups can be substituted for R 2 -R 6 by using synthetic methods that are available to those of ordinary skill in the art.
  • desired substituents can be introduced at R 2 -R s by way of the synthesis depicted in FIG. 1, for example, by substituting reactants (e.g., benzoyl chloride, p-toluoyl chloride, or p-methyl benzoyl chloride) with suitably substituted analogues of such reactants .
  • reactants e.g., benzoyl chlor

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Abstract

On décrit des composés, des compositions, et des procédés concernant de nouveaux dérivés de 2-(aryl)-4,7-dioxobenzothiazole substitué.
PCT/US1998/027002 1997-12-19 1998-12-18 Modulateurs des recepteurs de la ryanodine contenant des 2-(aryl)-4,7-dioxobenzothiazoles et leurs analogues WO1999032115A1 (fr)

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WO2001074810A2 (fr) * 2000-03-31 2001-10-11 Ortho Mcneil Pharmaceutical, Inc. Procede d'utilisation de 2-aryloxyalkylaminobenzoxazoles et de 2-aryloxyalkylaminobenzothiazoles comme antagonistes vis-a-vis du recepteur h3
WO2002022122A1 (fr) * 2000-09-15 2002-03-21 Novo Nordisk A/S Utilisation de composes pour le traitement de l'obesite
US6908929B2 (en) 2000-03-31 2005-06-21 Ortho-Mcneil Pharmaceutical, Inc. Phenyl-substituted imidazopyridines
CN100422159C (zh) * 2003-08-18 2008-10-01 索尔瓦药物有限公司 Bifeprunox甲磺酸盐的稳定的多晶型物
CN100425600C (zh) * 2001-12-27 2008-10-15 科学研究和应用咨询公司 苯并噻唑－和苯并唑－4,7－二酮衍生物及其作为cdc25磷酸酯酶抑制剂的用途
US8710045B2 (en) 2004-01-22 2014-04-29 The Trustees Of Columbia University In The City Of New York Agents for preventing and treating disorders involving modulation of the ryanodine receptors

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001074810A2 (fr) * 2000-03-31 2001-10-11 Ortho Mcneil Pharmaceutical, Inc. Procede d'utilisation de 2-aryloxyalkylaminobenzoxazoles et de 2-aryloxyalkylaminobenzothiazoles comme antagonistes vis-a-vis du recepteur h3
WO2001074810A3 (fr) * 2000-03-31 2002-04-04 Ortho Mcneil Pharm Inc Procede d'utilisation de 2-aryloxyalkylaminobenzoxazoles et de 2-aryloxyalkylaminobenzothiazoles comme antagonistes vis-a-vis du recepteur h3
US6436939B2 (en) 2000-03-31 2002-08-20 Ortho-Mcneil Pharmaceutical, Inc. Method for using 2-aryloxyalkylaminobenzoxazoles and 2-aryloxyalkylaminobenzothiazoles as H3 antagonists
US6908929B2 (en) 2000-03-31 2005-06-21 Ortho-Mcneil Pharmaceutical, Inc. Phenyl-substituted imidazopyridines
US7041828B2 (en) 2000-03-31 2006-05-09 Breitenbucher J Guy Phenyl-substituted imidazopyridines
US7041827B2 (en) 2000-03-31 2006-05-09 Breitenbucher J Guy Phenyl-substituted imidazopyridines
US7087757B2 (en) 2000-03-31 2006-08-08 Ortho-Mcneil Pharmaceutical, Inc. Phenyl-substituted imidazopyridines
US7199117B2 (en) 2000-03-31 2007-04-03 Ortho-Mcneil Pharmaceutical, Inc. Phenyl-substituted imidazopyridines
WO2002022122A1 (fr) * 2000-09-15 2002-03-21 Novo Nordisk A/S Utilisation de composes pour le traitement de l'obesite
CN100425600C (zh) * 2001-12-27 2008-10-15 科学研究和应用咨询公司 苯并噻唑－和苯并唑－4,7－二酮衍生物及其作为cdc25磷酸酯酶抑制剂的用途
CN100422159C (zh) * 2003-08-18 2008-10-01 索尔瓦药物有限公司 Bifeprunox甲磺酸盐的稳定的多晶型物
US8710045B2 (en) 2004-01-22 2014-04-29 The Trustees Of Columbia University In The City Of New York Agents for preventing and treating disorders involving modulation of the ryanodine receptors

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