EP2344477A1 - Niedermolekulare bradykinin b2-rezeptormodulatoren - Google Patents

Niedermolekulare bradykinin b2-rezeptormodulatoren

Info

Publication number
EP2344477A1
EP2344477A1 EP09778657A EP09778657A EP2344477A1 EP 2344477 A1 EP2344477 A1 EP 2344477A1 EP 09778657 A EP09778657 A EP 09778657A EP 09778657 A EP09778657 A EP 09778657A EP 2344477 A1 EP2344477 A1 EP 2344477A1
Authority
EP
European Patent Office
Prior art keywords
methyl
pyridin
yloxymethyl
quinolin
ylmethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09778657A
Other languages
English (en)
French (fr)
Inventor
Christoph Gibson
Karsten Schnatbaum
Thomas Tradler
Jochen Pfeifer
Dirk Scharn
Ulf Reimer
Uwe Richter
Gerd Hummel
Ulrich Reineke
Elsa Locardi
Matthias Paschke
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jerini AG
Original Assignee
Jerini AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jerini AG filed Critical Jerini AG
Priority to EP09778657A priority Critical patent/EP2344477A1/de
Publication of EP2344477A1 publication Critical patent/EP2344477A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to novel 8-(heteroarylmethoxy)quinoline compounds, compositions containing the same and the use of said compounds. These compounds act as selective modulators of bradykinin (BK) B2 receptors and can therefore be used in pharmaceutical compositions for the treatment of conditions responsive to BK B2 receptor modulation. Compounds of the invention are also useful as probes for the localization of BK B2 receptors and as standards in assays for BK B2 receptor binding.
  • BK bradykinin
  • Bradykinin is a vasoactive nonapeptide, H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe- Arg-OH, formed by the action of various plasma enzymes such as kallikrein on kininogens. In some aspects, it has some similar actions to that of histamine, and like histamine is released from venules rather than arterioles.
  • BK receptors Two types are recognized in mammals, Bl and B2 (Leeb-Lundberg, et al Pharmacol. Rev. 2005, 57, 27-77).
  • the actions of BK mediated by the B2 receptor are important physiological functions, such as increases in vascular permeability, modulation of inflammatory responses and pain as well as vasoactive effects (vasodilatation, vasoconstriction).
  • These effects at the B2 receptor are responsible for BK's role in numerous diseases, such as inflammation, cardiovascular disease, and pain.
  • agents that block the binding of BK to its B2 receptor can inhibit or at least alleviate the pathogenic events.
  • BK B2 receptor antagonists Numerous peptide and non-peptide antagonists of BK B2 receptor have been described in the prior art. For instance, WO 2006/40004, WO 03/103671, WO 03/87090, WO00/23439, WO 00/50418, WO 99/64039, WO 97/41104, WO 97/28153, WO 97/07115, WO 96/13485, EP 0 795 547, EP 0 796 848, EP 0 867 432, and EP 1 213 289 disclose quinoline compounds that are BK B2 receptor antagonists. In view of the severe conditions associated with a pathophysiological level of bradykinin, both acute and chronic, there is still a need for highly selective B2 receptor modulators having improved properties.
  • the problem underlying the present invention is to provide highly selective B2 receptor modulators, preferably having improved properties.
  • R is Cl, F, or methoxy
  • R 3 is methyl, methoxy, hydroxymethyl, H, or absent;
  • R 4 is methyl, ethyl, HO, H, or absent;
  • a 1 is C or N
  • a 2 is C or N
  • R 6 is H or OH
  • the compound is selected from the group consisting of
  • the problem under lying the instant invention is solved in a first embodiment by a pharmaceutical composition that comprises one or more compounds according to the first aspect and, optionally, at least one carrier substance, excipient and/or adjuvant.
  • the pharmaceutical composition is formulated as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a solution, a transdermal patch or a pharmaceutical delivery device.
  • the problem under lying the instant invention is solved in a first embodiment by a method of inhibiting binding of BK to a BK B2 receptor in vitro, the method comprising contacting the BK B2 receptor with at least one compound according to the first aspect or a salt thereof, under conditions and in an amount sufficient to detectably inhibit binding of BK or any other substance to the BK B2 receptor.
  • the problem under lying the instant invention is solved in a first embodiment by a method for localizing or detecting a BK B2 receptor in a tissue, preferably a tissue section, in vitro, comprising:
  • the compound is radiolabeled, fluorescence-labeled or luminescence-labeled, or labeled with an antibody.
  • the problem under lying the instant invention is solved in a first embodiment by the use of a compound or of a pharmaceutical composition according to the first or second aspect for the manufacture of a medicament for the treatment and/or prevention of a disease or a condition.
  • condition or disease is responsive to BK B2 receptor modulation.
  • the condition is skin disorders; eye diseases; ear diseases; mouth, throat and respiratory diseases; gastrointestinal diseases; liver, gallbladder and pancreatic diseases; urinary tract and kidney diseases; diseases of male genitale organs and female genitale organs; diseases of the hormone system; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic diseases; disorders of the central nervous system; brain disorders; musculoskeletal system diseases; allergy disorders; pain; infectious diseases; inflammatory disorders; injuries; immunology disorders; cancers; hereditary diseases; or edema.
  • the problem under lying the instant invention is solved in a first embodiment by a method for the treatment of a subject which is in need of such treatment, comprising the administration of a compound or of a pharmaceutical composition according to the first or second aspect.
  • the problem under lying the instant invention is solved in a first embodiment by the compound or a pharmacologically acceptable salt, solvate or hydrate thereof according to the first aspect for use in a method of treatment of a disease or condition.
  • condition or disease is responsive to BK B2 receptor modulation.
  • the condition is skin disorders; eye diseases; ear diseases; mouth, throat and respiratory diseases; gastrointestinal diseases; liver, gallbladder and pancreatic diseases; urinary tract and kidney diseases; diseases of male genitale organs and female genitale organs; diseases of the hormone system; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic diseases; disorders of the central nervous system; brain disorders; musculoskeletal system diseases; allergy disorders; pain; infectious diseases; inflammatory disorders; injuries; immunology disorders; cancers; hereditary diseases; or edema.
  • BK B2 receptor modulators provided herein exhibit high activity on human BK B2 receptor (i.e., an inhibition constant (IC 50 ) for competition with binding of labelled BK to human BK B2 receptor of less than 5 micromolar) or very high activity on human BK B2 receptor (i.e., an IC 5O for competition with the binding of labelled BK to human BK B2 receptor of preferably less than 50 nanomolar).
  • IC 50 inhibition constant
  • such modulators exhibit a high activity on BK B2 receptors of species other than human, e.g. rat, mouse, gerbil, guinea pig, rabbit, dog, cat, pig, or cynomolgus monkey.
  • the activity and more specifically pharmacological activity of the B2 receptor modulators according to the present invention can be assessed using appropriate in vitro assays.
  • the IC 50 values of the modulators according to the present invention for B2 receptor may be determined via a radioligand binding assay, such as the assay provided in Example 50, which is thus an embodiment of a standard in vitro BK B2 receptor- mediated assay.
  • Inhibitory effects of the B2 receptor modulators provided herein for B2 receptor may be determined, for example, via calcium mobilization assay, such as the assay provided in Example 51.
  • Preferred compounds of the invention have an IC 50 (half-maximal inhibitory concentration) of about 5 micromolar or less, still more preferably an IC 50 of about 500 nM or less, or even 50 nM or less, even more preferably an IC 50 of about 10 nM or less, or even 1 nanomolar or less in the assays mentioned above.
  • the present invention further provides, within other aspects, pharmaceutical compositions comprising at least one BK B2 receptor modulator as described herein, i.e. a compound accordint to the present invention, in combination with a physiologically acceptable carrier or excipient. Processes for preparing such pharmaceutical compositions are also provided. Such compositions are particularly useful in the treatment of B2 receptor- mediated diseases and conditions as described below.
  • Recited compounds are further intended to encompass compounds in which one or more atoms are replaced with an isotope (i.e., an atom having the same atomic number but a different mass number).
  • isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 11 C, 13 C, and 14 C.
  • 8-(heteroarylmethoxy)quinoline refers to the compounds according to the present invention and more preferably according to table 1 provided herein, as well as salts and preferably pharmaceutically acceptable salts thereof.
  • a “pharmaceutically acceptable salt” of a compound disclosed herein is an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication.
  • Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids.
  • Suitable pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzene sulfonic, ethane disulfonic, 2- hydroxyethylsulfonic, nitric, benzoic, 2-acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic such as acetic, HOOC-(CH 2 ) n -COOH where n is any integer from O to —4 ⁇ i.e., 0, 1, 2, 3, or 4) and the like.
  • acids such as hydrochloric
  • pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium.
  • a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, is preferred.
  • each compound according to the present invention and more preferably according to table 1 may, but need not, be present or used as a hydrate, solvate or non-covalent complex.
  • the various crystal forms and polymorphs are within the scope of the present invention, as are prodrugs of the compounds according to the present invention and more preferably according to table 1 provided herein.
  • a “prodrug” is a compound that may not fully satisfy the structural requirements of the compounds provided herein, but is modified in vivo, following administration to a subject or patient, to produce a compound according to the present invention and more preferably according to table 1 provided herein.
  • a prodrug may be an acylated derivative of a compound as provided herein.
  • Prodrugs include compounds wherein hydroxy, carboxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively.
  • prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein.
  • Prodrugs of the compounds provided herein may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to generate the parent compounds.
  • a wording defining the limits of a range of length such as, e. g., "from 1 to 5" means any integer from 1 to 5, i. e. 1, 2, 3, 4 and 5.
  • any range defined by two integers explicitly mentioned is meant to comprise and disclose any integer defining said limits and any integer comprised in said range.
  • the present invention also comprises all isotopes of atoms of the described compounds.
  • Isotopes are atoms having the same atomic number but different mass numbers.
  • tritium and deuterium are isotopes of hydrogen.
  • Examples for carbon isotopes are 11 C, 13 C and 14 C.
  • the therapeutic use of compounds according to the present invention and more preferably according to table 1, their pharmacologically acceptable salts, solvates or hydrates and also formulations and pharmaceutical compositions containing the same are within the scope of the present invention.
  • the present invention also relates to the use of the compounds accordint to the present invention and more preferably according to table 1 as active ingredients in the preparation or manufacture of a medicament.
  • compositions according to the present invention comprise at least one compound according to the present invention and more preferably according to table 1 and, optionally, one or more carrier substances, excipients and/or adjuvants.
  • Pharmaceutical compositions may additionally comprise, for example, one or more of water, buffers ⁇ e.g., neutral buffered saline or phosphate buffered saline), ethanol, mineral oil, vegetable oil, dimethylsulfoxide, carbohydrates ⁇ e.g., glucose, mannose, sucrose or dextrans), mannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and/or preservatives.
  • buffers ⁇ e.g., neutral buffered saline or phosphate buffered saline
  • ethanol mineral oil
  • vegetable oil dimethylsulfoxide
  • carbohydrates ⁇ e.g., glucose, mannose, sucrose or dextrans
  • one or more other active ingredients may (but need not) be included in the pharmaceutical compositions provided herein.
  • the compounds of the invention may advantageously be employed in combination with an antibiotic, anti-fungal, or anti-viral agent, an antihistamine, a non-steroidal anti-inflammatory drug, a disease modifying anti-rheumatic drug, a cytostatic drug, a drug with smooth muscle activity modulatory activity or mixtures of the aforementioned.
  • compositions may be formulated for any appropriate manner of administration, including, for example, topical (e.g., transdermal or ocular), oral, buccal, nasal, vaginal, rectal or parenteral administration.
  • parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, as well as any similar injection or infusion technique.
  • compositions in a form suitable for oral use are preferred.
  • compositions provided herein may be formulated as a lyophilizate.
  • Formulation for topical administration may be preferred for certain conditions (e.g., in the treatment of skin conditions such as burns or itch).
  • Compositions intended for oral use may further comprise one or more components such as sweetening agents, flavoring agents, coloring agents and/or preserving agents in order to provide appealing and palatable preparations.
  • Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets.
  • excipients include, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents (e.g., corn starch or alginic acid), binding agents (e.g., starch, gelatin or acacia) and lubricating agents (e.g., magnesium stearate, stearic acid or talc).
  • inert diluents e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents e.g., corn starch or
  • 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 such as glyceryl monosterate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient, i.e. any of the compounds according to the present invention and more preferably according to table 1, is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).
  • an oil medium e.g., peanut oil, liquid paraffin or olive oil
  • Aqueous suspensions contain the active ingredient(s) in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia); and dispersing or wetting agents (e.g., naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monoole
  • Aqueous suspensions may also comprise one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents such as sucrose or saccharin.
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil (e.g., arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavoring agents may be added to provide palatable oral preparations.
  • Such suspensions may be preserved by the addition of an anti-oxidant such as 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 may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil (e.g., olive oil or arachis oil), a mineral oil (e.g., liquid paraffin) or a mixture thereof.
  • Suitable emulsifying agents include naturally-occurring gums (e.g., gum acacia or gum tragacanth), naturally-occurring phosphatides (e.g., soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol), anhydrides (e.g., sorbitan monoleate) and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide (e.g., polyoxyethylene sorbitan monoleate).
  • An emulsion may also comprise one or more sweetening and/or flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.
  • Compounds may be formulated for local or topical administration, such as for topical application to the skin or mucous membranes, such as in the eye.
  • Formulations for topical administration typically comprise a topical vehicle combined with active agent(s), with or without additional optional components.
  • Suitable topical vehicles and additional components are well known in the art, and it will be apparent that the choice of a vehicle will depend on the particular physical form and mode of delivery.
  • Topical vehicles include water; organic solvents such as alcohols (e.g., ethanol or isopropyl alcohol) or glycerin; glycols (e.g., butylene, isoprene or propylene glycol); aliphatic alcohols (e.g., lanolin); mixtures of water and organic solvents and mixtures of organic solvents such as alcohol and glycerin; lipid-based materials such as fatty acids, acylglycerols (including oils, such as mineral oil, and fats of natural or synthetic origin), phosphoglycerides, sphingolipids and waxes; protein-based materials such as collagen and gelatin; silicone-based materials (both non-volatile and volatile); and hydrocarbon-based materials such as microsponges and polymer matrices.
  • organic solvents such as alcohols (e.g., ethanol or isopropyl alcohol) or glycerin
  • glycols e.g., butylene, isoprene or
  • a topical formulation may be prepared in a variety of physical forms including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids, emulsions, sprays and skin patches.
  • the physical appearance and viscosity of such forms can be governed by the presence and amount of emulsifier(s) and viscosity adjuster(s) present in the formulation.
  • Solids are generally firm and non-pourable and commonly are formulated as bars or sticks, or in particulate form; solids can be opaque or transparent, and optionally can contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Creams and lotions are often similar to one another, differing mainly in their viscosity; both lotions and creams may be opaque, translucent or clear and often contain emulsifiers, solvents, and viscosity adjusting agents, as well as moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Gels can be prepared with a range of viscosities, from thick or high viscosity to thin or low viscosity.
  • These formulations may also contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Liquids are thinner than creams, lotions, or gels and often do not contain emulsifiers.
  • Liquid topical products often contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Suitable emulsifiers for use in topical formulations include, but are not limited to, ionic emulsifiers, cetearyl alcohol, non-ionic emulsifiers like polyoxyethylene oleyl ether, PEG- 40 stearate, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol, PEG-100 stearate and glyceryl stearate.
  • Suitable viscosity adjusting agents include, but are not limited to, protective colloids or non-ionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffin, and cetyl palmitate.
  • a gel composition may be formed by the addition of a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquaterniums, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or ammoniated glycyrrhizinate.
  • a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquaterniums, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or ammoniated glycyrrhizinate.
  • Suitable surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants.
  • dimethicone copolyol polysorbate 20
  • polysorbate 40 polysorbate 60
  • polysorbate 80 lauramide DEA, cocamide DEA, and cocamide MEA
  • lauramide DEA lauramide DEA
  • cocamide DEA cocamide MEA
  • oleyl betaine cocamidopropyl phosphatidyl PG- dimonium chloride
  • ammonium laureth sulfate may be used within topical formulations.
  • Suitable preservatives include, but are not limited to, antimicrobials such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate/ascorbic acid and propyl gallate.
  • Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, and butylene glycol.
  • Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate and mineral oils.
  • Suitable fragrances and colors include, but are not limited to, FD&C Red No. 40 and FD&C Yellow No. 5.
  • Other suitable additional ingredients that may be included in a topical formulation include, but are not limited to, abrasives, absorbents, anti-caking agents, anti-foaming agents, anti-static agents, astringents (e.g., witch hazel, alcohol and herbal extracts such as chamomile extract), binders/excipients, buffering agents, chelating agents, film forming agents, conditioning agents, propellants, opacifying agents, pH adjusters and protectants.
  • An example of a suitable topical vehicle for formulation of a gel is: hydroxypropylcellulose (2.1%); 70/30 isopropyl alcohol/water (90.9%); propylene glycol (5.1%); and Polysorbate 80 (1.9%).
  • An example of a suitable topical vehicle for formulation as a foam is: cetyl alcohol (1.1%); stearyl alcohol (0.5%; Quaternium 52 (1.0%); propylene glycol (2.0%); Ethanol 95 PGF3 (61.05%); deionized water (30.05%); P75 hydrocarbon propellant (4.30%). AU percents are by weight.
  • Typical modes of delivery for topical compositions include application using the fingers; application using a physical applicator such as a cloth, tissue, swab, stick or brush; spraying (including mist, aerosol or foam spraying); dropper application; sprinkling; soaking; and rinsing.
  • Controlled release vehicles can also be used, and compositions may be formulated for transdermal administration as a transdermal patch.
  • a pharmaceutical composition may be formulated as inhaled formulations, including sprays, mists, or aerosols. Such formulations are particularly useful for the treatment of asthma or other respiratory conditions.
  • the compounds provided herein may be delivered via any inhalation methods known to those skilled in the art.
  • Such inhalation methods and devices include, but are not limited to, metered dose inhalers with propellants such as CFC or HFA or propellants that are physiologically and environmentally acceptable.
  • propellants such as CFC or HFA or propellants that are physiologically and environmentally acceptable.
  • Other suitable devices are breath operated inhalers, multidose dry powder inhalers and aerosol nebulizers.
  • Aerosol formulations for use in the subject method typically include propellants, surfactants and co-solvents and may be filled into conventional aerosol containers that are closed by a suitable metering valve.
  • Formulations or compositions suitable for nasal administration include a coarse powder having a particle size, for example, in the range of 20 to 500 microns which is administered in the manner in which snuff is administered (i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose).
  • Suitable powder compositions include, by way of illustration, powdered preparations of the active ingredient thoroughly intermixed with lactose or other inert powders acceptable for intrabronchial administration.
  • the powder compositions can be administered via an aerosol dispenser or encased in a breakable capsule which may be inserted by the patient into a device that punctures the capsule and blows the powder out in a steady stream suitable for inhalation.
  • compositions may also be prepared in the form of suppositories (e.g., for rectal administration).
  • Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • compositions may be formulated as sustained release formulations (i.e., a formulation such as a capsule that effects a slow release of modulator following administration).
  • sustained release formulations i.e., a formulation such as a capsule that effects a slow release of modulator following administration.
  • Such formulations may generally be prepared using well known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site.
  • Carriers for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of modulator release.
  • the amount of modulator contained within a sustained release formulation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.
  • the dose of the biologically active compound according to the invention may vary within wide limits and may be adjusted to individual requirements.
  • Active compounds according to the present invention are generally administered in a therapeutically effective amount. Preferred doses range from about 0.1 mg to about 140 mg per kilogram of body weight per day (about 0.5 mg to about 7 g per patient per day).
  • the daily dose may be administered as a single dose or in a plurality of doses.
  • the amount of active ingredient that may 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. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination (i.e. other drugs being used to treat the patient) and the severity of the particular disease undergoing therapy.
  • Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, such that the preferred oral dosage forms discussed above can provide therapeutically effective levels of the compound in vivo.
  • B2 receptor antagonists may be used to inhibit the binding of BK B2 receptor ligands (e.g., BK) to BK B2 receptor in vitro or in vivo.
  • BK B2 receptor modulator(s), i.e. antagonists and agonists, respectively, provided herein are preferably administered to a patient (e.g., a human) orally or topically, and are present within at least one body fluid or tissue of the patient while modulating BK B2 receptor activity.
  • BK B2 receptor modulators are particularly useful for the treatment and/or prevention and/or prophylaxis of conditions or diseases that are responsive to BK B2 receptor modulation including skin disorders; eye diseases; ear diseases; mouth, throat and respiratory diseases; gastrointestinal diseases; liver, gallbladder and pancreatic diseases; urinary tract and kidney diseases; diseases of male genitale organs and female genitale organs; diseases of the hormone system; metabolic diseases; cardiovascular diseases; blood diseases; lymphatic diseases; disorders of the central nervous system; brain disorders; musculoskeletal system diseases; allergy disorders; pain; infectious diseases; inflammatory disorders; injuries; immunology disorders; cancers; hereditary diseases, edema or capillary leak syndrome(s), and for the use in specific methodology. It is within the present invention that the compounds according to the invention are used as or for the manufacture of a diagnostic agent, whereby such diagnostic agent is for the diagnosis of the diseases and conditions which can be addressed by the compounds of the present invention for therapeutic purposes as disclosed herein.
  • skin disorders encompasses, but is not limited to, disorders such as skin aging, skin efflorescences including pressure sores, decubital ulcers, irritated, sensitive and dysaesthetic skin, erythema, rash, skin edema, psoriasis, eczema, lichen, bacterial, viral, fungal and parasites induced skin infections including furuncle, abscess, phlegmon, erysipelas, folliculitis and impetigo, lice, scabies and herpes simplex, acne, exanthema, dermatitis including atopic dermatitis, allergic contact dermatitis (Scholzen, T.E.; Luger, T.A.
  • Eye diseases encompasses, but is not limited to, inflammatory disorders such as scleritis, conjunctivitis, chemosis, ulceris, iridocyclitis, uveitis, chorioretinitis, as well as disorders such as retinochoroidal circulatory disorders, bacterial eye infections, unspecific conjunctivitis and eye irritations, retinopathy of prematurity, proliferative vitreoretinopathy, macular degeneration (including age related macular degeneration and including both wet and dry forms), corneal diseases including corneal graft rejection, corneal injury, corneal scarring, corneal ulceration, corneal haze, keratoconus, glaucoma (preferably open angle glaucoma), myopia, ocular hypertension, ocular vessel damage, angiogenesis, eye fibrosis ⁇ e.g.
  • anterior subcapsular fibrosis posterior subcapsular opacities, posterior capsular opacities, corneal haze after laser surgery, subconjunctival scarring after glaucoma surgery), proliferative vitreoretinopathy (PVR), bacterial ocular infections including hordeolum and ptilosis.
  • Ear diseases encompasses, but is not limited to, disorders such as Meniere's disease, inflammation of the middle ear, inflammation of the external auditory canal and acute hearing loss.
  • Mouth, throat and respiratory diseases encompasses, but is not limited to, disorders such as inflammation of the oral mucosa and gums including aphta and stomatitis, parodontitis, epiglottitis, pharyngitis, laryngotracheitis, tonsillitis, common cold, angina, rhinitis including seasonal allergic rhinitis or perennial allergic rhinitis, rhinorrea, sinusitis of whatever type, etiology or pathogenesis or sinusitis that is a member selected from the group consisting of purulent or nonpurulent sinusitis, acute and chronic sinusitis and ethmoid, frontal, maxillary or sphenoid sinusitis, expectoration, pneumoconiosis of whatever type or genesis, including for example aluminosis, anthracosis, asbestosis, chalicosis, siderosis, silicosis, tabacosis
  • asthma that is a member selected from the group of atopic asthma, non-atopic asthma, allergic and non-allergic asthma, extrinsic asthma caused by environmental factors, intrinsic asthma caused by pathophysiologic disturbances, bronchial asthma, IgE-mediated asthma, essential asthma and essential asthma of unknown or inapparent cause, true asthma, emphysematous asthma, exercise-induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal or viral infection, incipient asthma, whez infant syndrome, bronchial hyperreactivity, chronic obstructive pulmonary disease (COPD), COPD that is characterized by irreversible, progressive airways obstruction, acute respiratory distress syndrome (ARDS) and exacerbation of airways hyperreactivity consequent to other drug therapy, dyspnea, hyperoxic alveolar injury, pulmonary emphysema, ple
  • Gastrointestinal diseases encompasses, but is not limited to, disorders including esophagitis, gastritis, irritable stomach, gastric and duodenal ulcer, ileus, colon irritable, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, enteritis, hypertensive gastro- and colopathy, colitis, peritonitis, appendicitis, rectitis, gastrointestinal hemorrhage caused by a portal hypertension, collateral circulation or hyperemia, postgastrectomy dumping- syndrome, digestion discomfort, diarrhea, hemorrhoids, worm diseases, abdominal colic and colic of parts of the gastrointestinal system.
  • disorders including esophagitis, gastritis, irritable stomach, gastric and duodenal ulcer, ileus, colon irritable, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, enteritis, hypertensive gastro- and colopathy, colitis, peritonitis, appendicitis, rectitis, gastrointestinal hemor
  • liver and gallbladder diseases encompasses, but is not limited to, disorders such as hepatitis, cirrhosis of the liver, liver fibrosis (e.g. due to viral (HBV/HCV) infections, toxins (alcohol), fatty liver, bile stasis, hypoxia), portal hypertension, hepatorenal syndrome, hepatogenic edema, cholangitis, cholecystitis, acute and chronic pancreatitis, and biliary colic.
  • disorders such as hepatitis, cirrhosis of the liver, liver fibrosis (e.g. due to viral (HBV/HCV) infections, toxins (alcohol), fatty liver, bile stasis, hypoxia), portal hypertension, hepatorenal syndrome, hepatogenic edema, cholangitis, cholecystitis, acute and chronic pancreatitis, and biliary colic.
  • Urinary tract and kidney diseases encompasses, but is not limited to, urinary tract infections such as acute and chronic cystitis, interstitial cystitis (Campbell, D. J. Clin. Exp. Pharmacol. Physiol. 2001, 28, 1060-5; Meini, S.; Patacchini, R.; Giuliani, S.; Lazzeri, M.; Turini, D.; Maggi, C. A.; Lecci, A. Eur. J. Pharmacol. 2000, 388, 177-82; Zuraw, B. L.; Sugimoto, S.; Parsons, C. L.; Hugli, T.; Lotz, M.; Koziol, J. J.
  • kidney diseases including glomerulonephritis, glomerular disease of the kidney, interstitial nephritis, pyelonephritis, diuresis, proteinuria, natriuresis, calciuresis, disorders of water balance, disorders of electrolyte balance, disorders of acid-base balance and renal colic, renal fibrosis, and chronic renal allograft dysfunction.
  • Diseases of male genitale organs and female genitale organs encompasses, but is not limited, to altered sperm mobility, male infertility, orchitis, prostatitis, prostate enhancement, mastitis, inflammatory pelvis diseases, vaginal infections and pain, adnexitis, colpitis, soft ulcus, syphilis, clap and ovarian hyperstimulation syndrome (Ujioka, T.; Matsuura, K.; Tanaka, N.; Okamura, H. Hum Reprod. 1998 Nov;13(l l):3009-15.).
  • Diseases of the hormone system encompasses, but is not limited to, menstrual disorders and pain, climacteric disturbance, emesis, premature uterine contractions, premature labor, endometriosis, endometritis, myoma.
  • Metabolic diseases encompasses, but is not limited to, disorders such as diabetes, including non-insulin dependent diabetes mellitus, diabetic retinopathy, diabetic macular edema (Speicher, M. A.; Danis, R. P.; Criswell, M.; Pratt, L. Expert Opin. Emerg. Drugs 2003, 8, 239-50; Gao, B. B.; Clermont, A.; Rook, S.; Fonda, S. J.; Srinivasan, V. J.; Wojtkowski, M.; Fujimoto, J. G.; Avery, R. L.; Arrigg, P. G.; Bursell, S. E.; Aiello, L.
  • Cardiovascular diseases encompasses, but is not limited to, disorders including vascular permeability, vasodilation, peripheral circulatory disorders, arterial circulatory disorders including aortic aneurysm, abdominal aortic aneurysm, brain aortic aneurysm, hypertension and hypotension associated with sepsis, restenosis after percutaneous transluminal coronary angioplasty, atherosclerosis including atherosclerotic plaque rupture (Fernando, A.N.; Fernando, L.P.; Fukuda, Y.; Kaplan, A.P. Am J Physiol Heart Circ Physiol.
  • hemangioma hemangioma, angiofibroma, venous disorders such as thrombosis, varicosity, phlebitis, thrombophlebitis, phlebothrombosis, cardiopathy, congestive heart failure, carcinoid syndrome, angina pectoris, cardiac dysrhythmias, inflammatory heart diseases including endocarditis, pericarditis and constrictive pericarditis, myocarditis, myocardial infarct, postmyocardial infarction syndrome, left ventricular dilation, post ischemic reperfusion injury, shock and collapse including septic, allergic, post traumatic and hemodynamic shock, amniotic fluid embolism (Robillard, J.; Gauvin, F.; Molinaro, G.; Leduc, L.; Adam, A.; Rivard, G.E.
  • SIRS systemic inflammatory response syndrome
  • Blood diseases encompasses, but is not limited to, disorders such as coagulation, disseminated intravascular coagulopathy, hemorrhage, hemorrhagic diathesis, hypercholesterolemia and hyperlipemia.
  • Lymphatic diseases within the present application the tem "Lymphatic diseases” as used herein encompasses, but is not limited to, splenomegaly, lymphangitis, lymphadenitis and hyperplastic adenoids.
  • Disorders of the central nervous system within the present application the term “disorders of the central nervous system” encompasses, but is not limited to, disorders such as inflammatory diseases of the central nervous system including encephalitis, meningitis, encephalomyelitis, meningoencephalitis; hydrocephalus, amyotrophic lateral sclerosis, spinal cord trauma, spinal cord edema, demyelinating diseases of the nervous system, multiple sclerosis, acute and chronic neuro-degenerative disorders including Alzheimer's disease and Parkinson's disease, neuritis and peripheral neuropathy, depressions, anorexia, anxiety and schizophrenia.
  • Brain disorders encompasses, but is not limited to, disorders including nootropic or cognition enhancement, cerebral amyloid angiopathy, stroke, head and brain trauma, traumatic brain injury (Marmarou, A.; Guy, M.; Murphey, L.; Roy, F.; Layani, L.; Combal, J.P.; Marquer, C; American Brain Injury Consortium J Neurotrauma 2005 Dec;22(12): 1444-55) cerebral heat damage, cerebral ischemia, cerebral hemorrhage, post traumatic and post ischemic cerebral edema, general brain edema, acute mountain sickness and preferably high altitude cerebral edema (HACE), cytotoxic brain edema, vasogenic brain edema, post-surgical brain edema, brain edema associated with metabolic diseases,_increase of permeability of blood-brain barrier or blood-brain tumor barrier.
  • HACE high altitude cerebral edema
  • cytotoxic brain edema vasogenic brain edema
  • Musculoskeletal system diseases encompasses, but is not limited to, disorders such as inflammatory musculoskeletal disorders, arthrosis, osteoarthrosis, osteoarthritis, chondroporosis after joint trauma or relatively long immobilization of a joint after meniscus or patella injuries or torn ligaments, rheumatoid arthritis of whatever type, etiology, or pathogenesis including acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthtritis, Lyme arthritis, proliferative arthritis, vertebral arthritis, septic arthritis, psoriatic arthritis, chronic polyarthritis, rheumatism, Sjogren's syndrome, lumbago, spondylitis, spondylarthritis, ankylosing spondylitis, osteomyelitis, sprain, teno-synovitis, inflammation-induced bone resorption, fracture or the like, osteoporosis
  • allergy disorders encompasses, but is not limited to, disorders such as general allergic reactions, food allergy, anaphylactic shock, allergic contact hypersensitivity, allergic skin reactions, allergic asthma, vernal conjunctivitis and seasonal or perennial allergic rhinitis (Summers, C.W.; Pumphrey, R.S.; Woods, C.N.; McDowell, G.; Pemberton, P.W.; Arkwright, P.D. J Allergy Clin Immunol. 2008)
  • Pain encompasses, but is not limited to, centrally and peripherally mediated pain, vascular pain, visceral pain, inflammatory mediated pain, neuralgic pain, referred pain, nociceptive pain, reflectory pain, psychosomatic pain, acute pain such as caused by acute injury, trauma or surgery of bones, muscle, tissue, soft tissue, organs, pain after insectbites, post-stroke pain syndrome, post- surgery pain, progressive disease related pain, chronic pain such as caused by neuropathic pain conditions (including but not limited to complex regional pain syndrome (WO00/75107 A2; Yamaguchi-Sase, S.; Hayashi, L; Okamoto, H.; Nara, Y.; Matsuzaki, S.; Hoka, S.; Majima, M.
  • Infectious diseases encompasses, but is not limited to, diseases including those mediated by bacteria, viruses, fungi, parasites, protozoa, prions or mycobacterial infections.
  • the present invention is useful for the treatment of bacterial infections caused by Streptococcus, Escherichia, Salmonella, Staphylococcus, Klebsiella, Moracella, Haemophilus and Yersinia.
  • Examples of bacterial infections intended to be within the scope of the present invention include, but are not limited to diseases such as pestis, sepsis, epidemic typhus, food poisoning, tetanus, scarlet red, whooping cough, diphtheria.
  • Examples of viral infections intended to be within the scope of the present invention include, but are not limited to diseases such chickenpox and herpes zoster, AIDS, influenza, small pox, and children diseases such as measles, rubella, mumps, acute anterior poliomyelitis.
  • the present invention is useful for the treatment of protozoa and parasites infections caused by Schistosoma mansoni, Dermatofagoides farinae and Plasmodium inducing Malaria
  • prion infections intended to be within the scope of the present invention include, but are not limited to diseases such bovine spongiform encephalopathy (BSE), Creutzfeldt Jacob disease and kuru.
  • Inflammatory disorders encompasses, but is not limited to, disorders such as acute-phase reaction, local and systemic inflammation and inflammation caused by other diseases whatever type, etiology or pathogenesis and caused by those inflammatory diseases specified within this application.
  • injuries encompasses, but is not limited to, multiple trauma, head trauma, lung injuries, external, internal and surgery wounds.
  • Immunology disorders encompasses, but is not limited to, disorders such as hyperesthesia, autoimmune disorders, graft rejection in transplantation, transplant toxicity, granulomatous inflammation / tissue remodelling, myasthenia gravis, immunosuppression, immune-complex diseases, over- and underproduction of antibodies, vasculitis.
  • cancers encompasses, but is not limited to, disorders such as solid tumor cancer including breast cancer, lung cancer (non- small-cell lung cancer and small-cell lung cancer), prostate cancer, cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx), esophagus, stomach, small intestine, large intestine, colon, rectum, gallbladder and biliary passages, pancreas, larynx, lung, bone, osteosarcoma, connective tissue, skin cancer including Kaposi's syndrome, melanoma and skin metastasis, epidermoid cancer, basal cell carcinoma, cervix uteri, corpus endometrium, cancer of ovary, testis, bladder, ureter and urethra, kidney, eye, brain and central nervous system, pseudotumor cerebri, sarcoma, sarcoid, thyroid and other endocrine glands (including but not limited to car
  • Hereditary diseases encompasses, but is not limited to, disorders such as hereditary angioedema (Davis, A. E. et al., 3rd Transfus. Apher. Sci. 2003, 29, 195-203; Zuraw, B. L. Immunol. Allergy Clin. North Am. 2006, 26, 691-708; Bas, M. et al. Allergy 2006, 61, 1490-2) and angioneurotic edema, chondrocalcinosis, Huntington's disease, mucoviscidosis.
  • Edema encompasses, but is not limited to, general edema and edema caused by inflammation, other drugs, e.g. drug induced angioedema (Mathelier-Fusade, P. Clin. Rev. Allergy Immunol. 2006, 30, 19-23; Finley, C. J. et al. Am. J. Emerg. Med 1992, 10, 550-2; Bielory, L. et al. Allergy Proc. 1992, 13, 85-7), infection, burns, injuries, trauma, frostbite, surgery, distorsions, fractures, exposure to high altitude (e.g. high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE)), hereditary, autoimmune and other diseases and disorders, particularly but not limited to those disorders specified in this application.
  • drugs e.g. drug induced angioedema (Mathelier-Fusade, P. Clin. Rev. Allergy Immunol. 2006, 30, 19
  • Capillary leak syndrome(s) encompasses, but is not limited to, systemic capillary leak syndrome in sepsis (Marx, G. Eur J Anaesthesiol. 2003 20(6):429-42; Traber, D.L. Crit Care Med. 2000, 28(3):882-3), burn (Jonkam, CC; Enkhbaatar, P.; Nakano, Y.; Boehm, T.; Wang, J.; Nussberger, J. Esechie, A.; Traber, L.D.; Herndon, D.; Traber, D.L.. Shock. 2007 Dec;28(6):704-9), allergy, drug/toxin-induced conditions, organ transplantation and IL-2 cytokine therapy.
  • Compounds of the invention can be labelled by isotopes, fluorescence or luminescence markers, antibodies or antibody fragments, any other affinity label like nanobodies, aptamers, peptides etc., enzymes or enzyme substrates.
  • These labelled compounds of this invention are useful for mapping the location of bradykinin receptors in vivo, ex vivo, in vitro and in situ (e.g. in tissue sections via autoradiography) and as radiotracers for positron emission tomography (PET) imaging, single photon emission computerized tomography (SPECT) and the like to characterize those receptors in living subjects or other materials.
  • PET positron emission tomography
  • SPECT single photon emission computerized tomography
  • the present invention also pertains to methods for altering the signal-transducing activity of bradykinin receptors in vitro and in vivo.
  • compounds of the present invention and labelled derivatives thereof can be used as standard and reagent in determining the ability of a potential pharmaceutical to bind to the BK B2 receptor.
  • the present invention also provides methods for localizing or detecting a BK B2 receptor in a tissue, preferably a tissue section, which methods involve contacting the tissue sample containing BK B2 receptor with a detectably labelled compound according to the present invention under conditions that permit binding of the compound to the BK B2 receptor and detecting the bound compound.
  • Such methods and their respective conditions are known to those skilled in the art and include, for example, the radioligand binding assay disclosed in example 50.
  • the present invention also provides methods of inhibiting the binding of BK or any other B2 receptor ligand to a BK B2 receptor which methods involve contacting a solution containing a BK B2 receptor antagonist compound disclosed herein with cells expressing BK B2 receptor under conditions and in an amount sufficient to detectably inhibit binding of BK or any other substance to BK B2 receptor.
  • Such methods and their respective conditions are known to those skilled in the art and include, for example, the calcium mobilization assay disclosed in example 51.
  • the present invention further provides methods for treating patients suffering from conditions responsive to BK B2 receptor modulation as mentioned above.
  • treatment encompasses both disease-modifying treatment and symptomatic treatment, either of which may be prophylactic (i.e., before the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms) or therapeutic (i.e., after the onset of symptoms, in order to reduce the severity and/or duration of symptoms).
  • a condition is "responsive to BK B2 receptor modulation” if modulation of BK B2 receptor activity results in alleviation of the condition or a symptom thereof.
  • Patients may include but are not limited to primates (especially humans), domesticated companion animals (such as dogs, cats, horses) and livestock (such as cattle, pigs, sheep), with dosages as described herein.
  • the compounds according to the invention are used as or for the manufacture of a diagnostic agent, whereby such diagnostic agent is for the diagnosis of the diseases and conditions which can be addressed by the compounds of the present invention for therapeutic purposes as disclosed herein.
  • the compounds according to the present invention and preferably those disclosed in table 1 have improved properties when compared to BK B2 receptor antagonists known in the state of the art, especially, improved selectivity, low toxicity, low drug drug interaction, improved bioavailability (especially with regard to oral administration), improved metabolic stability, improved stability in microsomal degradation assay, and improved solubility.
  • the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis.
  • the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below.
  • Each of the references cited below are hereby incorporated herein by reference.
  • BK is bradykinin
  • BSA bovine serum albumin cpm is counts per minute
  • DIBAL is diisobutylaluminum hydride
  • DMSO dimethylsulfoxide
  • EA is ethyl acetate
  • ELISA enzyme-linked immunosorbentimmosorbent assay
  • HBSS Hanks' balanced salt solution
  • HPLC high performance liquid chromatography
  • LDA lithium diisoprpylamide
  • PBS is phosphate-buffered saline
  • PIPES is piperazine-N,N'-bis(2-ethanesulfonic acid)
  • THF is tetrahydrofuran
  • THP is tetrahydropyranyl
  • TFA is trifluoroacetate or trifluoroacetic acid
  • Table 1 are representative examples of compounds of formula (I) according to the present invention.
  • Example 17 Synthesis of l- ⁇ 4-Chloro-3-[4-(4-fluoro-pyrazol-l-yl)-2-methyl-quinolin- 8-yloxymethyl]-6-methoxy-pyridin-2-ylmethyl ⁇ -2-oxo-l,2-dihydro-pyridine-3-carbonitrile
  • Example 36 Synthesis of l- ⁇ 3-[4-(5-Cyano-l -methyl- lH-pyrrol-2-yl)-2-methyl- quinolin-8-yloxymethyl]-4-methoxy-6-methyl-pyridin-2-ylmethyl ⁇ -2-oxo- 1 ,2-dihydro- pyridine-3 -carbonitrile
  • the reaction mixture was allowed to reach -30 0 C and was than transferred to a suspension of Pd(PPtLt) 4 (25.5 mg, 22 ⁇ mol) and 4-bromo-2-methyl-quinolin-8-ol (75 mg, 0.32 mmol) in anhydrous dioxane (1.5 mL). After stirring for 1 h at 80 °C, the reaction mixture was cooled to room temperature, MeOH (0.5 mL) was added and the solvent was removed in vacuo. The residue was partitioned between DCM (10 mL) and water (5 mL). The pH of the aqueous layer was adjusted to 11 by the addition of concentrated aqueous NH 3 solution and the aqueous layer was extracted with DCM (2x 10 mL).
  • the following assay is defined herein as a standard in vitro B2 receptor binding assay.
  • the pharmaceutical utility of compounds of this invention is indicated by detection of activity in the following assay for BK B2 receptor activity.
  • the B2 receptor binding assay is performed using the following experimental settings. Incubation buffer: Consists of: 40 mM PIPES, 109 mM NaCl, 5 mM KCl, 0.1% glucose, 0.05% BSA, 2 mM CaCl 2 , 1 mM MgCl 2 , pH 7.4; with following inhibitors:
  • test compounds to incubation buffer and preparation of serial dilutions: 10 ⁇ L of a 10 mM stock solution of the individual test compounds in DMSO was diluted in 90 ⁇ L DMSO, resulting in a compound concentration of 1 mM in 100% DMSO. 7.5 ⁇ L of this (1 mM) compound solution was then added to 242.5 ⁇ L of incubation buffer (contains 2 nM [ 3 H]BK, see above), resulting in a test compound concentration of 30 ⁇ M. A 10 ⁇ M compound solution was prepared by addition of 2.5 ⁇ L of the 1 mM compound solution to 247.5 ⁇ L incubation buffer.
  • Coating with cells 96-well cell culture-trays were treated with 0.01% poly-D-lysin hydrobromide in PBS for at least 1 hour. Afterwards, HEK293 cells that stably express recombinant human B2R (10 pmol/mg protein) were added and cultivated for 1-3 days until at least 90% confluence was reached.
  • wash steps Then, multiwell-trays were stored on ice and the culture medium was removed using a 12-channel rack of an ELIS A- wash device. Afterwards, ice-cold PBS (10x-stock solution, 1:10 diluted, pH adjusted to 7.4) was added starting at the front of the plate (until wells are half-filled) and this wash procedure is repeated 3 times.
  • Incubation with compound and read-out 100 ⁇ L each of the incubation buffer containing [ 3 H]BK and serial dilutions of test/control compounds/controls or 50 ⁇ M BK, respectively, were added to the rinsed cells on ice. After 90 minutes incubation on ice, the incubation medium was removed and the cells were washed 4 times with ice-cold PBS.
  • Examples 1-49 have been tested in this assay and found to exhibit IC 50 values of less than or equal to 5 micromolar. Most preferred compounds according to the present invention exhibited IC 5O values of less than 50 nanomolar.
  • Preparation of cell-coated plates and loading of the cells with calcium dye 50.000 HF- 15 cells (passage 12) were added per well of a black, clear bottom 96 well plate. After incubation overnight, cells were washed with HBSS (37 0 C) and 100 ⁇ L of HBSS were left per well. Then, 100 ⁇ L of a freshly prepared calcium dye (Ca3, Molecular Devices) solution containing 2.5 mM probenicide were added per well. Cells then were incubated for 60 minutes at 37°C.
  • HBSS 37 0 C
  • a freshly prepared calcium dye Ca3, Molecular Devices

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