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WO2010031589A1 - Small molecule bradykinin b2 receptor modulators - Google Patents

Small molecule bradykinin b2 receptor modulators Download PDF

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Publication number
WO2010031589A1
WO2010031589A1 PCT/EP2009/006842 EP2009006842W WO2010031589A1 WO 2010031589 A1 WO2010031589 A1 WO 2010031589A1 EP 2009006842 W EP2009006842 W EP 2009006842W WO 2010031589 A1 WO2010031589 A1 WO 2010031589A1
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WO
WIPO (PCT)
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.)
Ceased
Application number
PCT/EP2009/006842
Other languages
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
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Filing date
Publication date
Application filed by Jerini AG filed Critical Jerini AG
Priority to EP09778657A priority Critical patent/EP2344477A1/en
Publication of WO2010031589A1 publication Critical patent/WO2010031589A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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 composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials.
  • stabilizing agents such as hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.
  • 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.
  • Inhalant compositions may comprise liquid or powdered compositions containing the active ingredient that are suitable for nebulization and intrabronchial use, or aerosol compositions administered via an aerosol unit dispensing metered doses.
  • Suitable liquid compositions comprise the active ingredient in an aqueous, pharmaceutically acceptable inhalant solvent, e.g., isotonic saline or bacteriostatic water.
  • the solutions are administered by means of a pump or squeeze-actuated nebulized spray dispenser, or by any other conventional means for causing or enabling the requisite dosage amount of the liquid composition to be inhaled into the patient's lungs.
  • Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
  • 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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Abstract

The present invention is related to a compound of the formula (I): or a pharmacologically acceptable salt, solvate, or hydrate thereof, wherein R1 is: (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n), (o), (p), (q), (r), (s); R2 is C1, F, or methoxy; R3 is methyl, methoxy, hydroxymethyl, H, or absent; R4 is methyl, ethyl, HO, H, or absent; A1 is C or N; A2 is C or N; R6 is H or OH; R5 is: (t), (u), (v), (w), (x), (y), (z).

Description

Small molecule bradykinin B2 receptor modulators
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.
Bradykinin (BK) 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.
Two types of BK receptors 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. Hence agents that block the binding of BK to its B2 receptor can inhibit or at least alleviate the pathogenic events.
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.
Therefore, the problem underlying the present invention is to provide highly selective B2 receptor modulators, preferably having improved properties.
The problem underlying the present invention is solved by the subject matter of the attached independent claims. Preferred embodiments may be taken from the dependent claims.
More specifically, in a first aspect, the problem under lying the instant invention is solved in a first embodiment by a compound of the formula (I):
Figure imgf000004_0001
or a pharmacologically acceptable salt, solvate, or hydrate thereof, wherein
R1 is
Figure imgf000005_0001
Figure imgf000005_0002
R is Cl, F, or methoxy;
R3 is methyl, methoxy, hydroxymethyl, H, or absent;
R4 is methyl, ethyl, HO, H, or absent;
A1 is C or N;
A2 is C or N;
R6 is H or OH; and
R5 is
Figure imgf000006_0001
In a second embodiment of the first aspect which is also an embodiment of the first embodiment, the compound is selected from the group consisting of
l-{4-Chloro-3-[4-(4-hydroxymethyl-lH-pyrazol-3-yl)-2-methyl-quinolin-8- yloxymethyl]-6-methyl-pyridin-2-ylmethyl}-3-trifluoromethyl-lH-pyridin-2-one, l-{4-Chloro-3-[4-(4-hydroxymethyl-thiazol-5-yl)-2-methyl-quinolin-8-yloxymethyl]-6- methyl-pyridin-2-ylmethyl } -3 -trifluoromethyl- 1 H-pyridin-2-one,
1 - {4-Chloro-3 - [4-(4-hydroxymethyl-pyrazol- 1 -yl)-2-methyl-quinolin-8-yloxymethyl] - 6-methyl-pyridin-2-ylmethyl } -3 -trifluoromethyl- 1 H-pyridin-2-one, l-{4-Chloro-6-methoxy-3-[2-methyl-4-(2-methyl-2H-[l,2,4]triazol-3-yl)-quinolin-8- yloxymethyl]-pyridin-2-ylmethyl } -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile, l-{4-Chloro-6-methoxy-3-[2-methyl-4-(4-methyl-lH-pyrazol-3-yl)-quinolin-8- yloxymethyl]-pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile,
1 - {4-Chloro-6-methoxy-3-[2-methyl-4-(5-methyl- 1 H-imidazol-4-yl)-quinolin-8- yloxymethyl]-pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile, l-{5-Fluoro-4-[2-methyl-4-(4-methyl-lH-pyrazol-3-yl)-quinolin-8-yloxymethyl]- pyridin-3 -ylmethyl } -3 -trifluoromethyl- 1 H-pyridin-2-one, l-{4-[4-(5-Chloro-thiazol-4-yl)-2-methyl-quinolin-8-yloxymethyl]-5-fluoro-pyridin-3- ylmethyl} -3 -trifluoromethyl- 1 H-pyridin-2-one, l-{5-Fluoro-4-[2-methyl-4-(4-methyl-lH-pyrazol-3-yl)-quinolin-8-yloxymethyl]- pyridin-3 -ylmethyl } -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile, l-{4-[4-(5-Chloro-thiazol-4-yl)-2-methyl-quinolin-8-yloxymethyl]-5-fluoro-pyridin-3- ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile, l-{4-Chloro-3-[4-(4-methoxymethyl-5-methyl-lH-pyrazol-3-yl)-2-methyl-quinolin-8- yloxymethyl] -6-methyl-pyridin-2-ylmethyl } -2 -oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile, l-{4-Chloro-3-[4-(4-methoxymethyl-5-methyl-lH-pyrazol-3-yl)-2-methyl-quinolin-8- yloxymethyl] -6-methyl-pyridin-2-ylmethyl } -3 -trifluoromethyl- 1 H-pyridin-2-one, l-{4-[4-(5-Chloro-thiazol-4-yl)-2-methyl-quinolin-8-yloxymethyl]-5-fluoro-2-methyl- pyridin-3 -ylmethyl} -3 -trifluoromethyl- 1 H-pyridin-2-one, l-{5-Fluoro-2-methyl-4-[2-methyl-4-(4-methyl-lH-pyrazol-3-yl)-quinolin-8- yloxymethyl] -pyridin-3 -ylmethyl } -3 -trifluoromethyl- 1 H-pyridin-2-one,
1 - {4-Chloro-6-methyl-3 - [2-methyl-4-(l -methyl- 1 H-pyrazol-3 -yl)-quinolin-8- yloxymethyl]-pyridin-2 -ylmethyl } -3 -trifluoromethyl- 1 H-pyridin-2-one,
1 - {4-Chloro-6-methyl-3 - [2-methyl-4-( 1 -methyl- 1 H-pyrazol-3 -yl)-quinolin-8- yloxymethyl]-pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile,
1 - {4-Chloro-3 - [4-(4-fluoro-pyrazol- 1 -yl)-2-methyl-quinolin-8-yloxymethyl]-6- methoxy-pyridin-2-ylmethyl } -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile, l-{5-Fluoro-2-hydroxy-4-[2-methyl-4-(4-methyl-2H-pyrazol-3-yl)-quinolin-8- yloxymethyl]-pyridin-3-ylmethyl}-3-trifluoromethyl-lH-pyridin-2-one,
5-{8-[5-Fluoro-2-hydroxy-3-(2-oxo-3-trifluoromethyl-2H-pyridin-l-ylmethyl)-pyridin- 4-ylmethoxy] -2-methyl-quinolin-4-yl} - 1 -methyl- 1 H-pyrrole-2 -carbonitrile, l-{4-Chloro-3-[4-(4-hydroxymethyl-5-methyl-lH-pyrazol-3-yl)-2-methyl-quinolin-8- yloxymethyl]-6-methyl-pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile, l-{4-Chloro-3-[4-(4-hydroxymethyl-5-methyl-lH-pyrazol-3-yl)-2-methyl-quinolin-8- yloxymethyl]-6-methyl-pyridin-2-ylmethyl } -3 -trifluoromethyl- 1 H-pyridin-2-one, l-{4-Chloro-3-[4-(4-chloro-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]-6-methyl- pyridin-2 -ylmethyl} -2-oxo- 1 ,2-dihydro-pyridine-3-carbonitrile, l-{4-Chloro-3-[4-(4-methoxy-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]-6- methyl-pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile, l-{5-Fluoro-2-methyl-4-[2-methyl-4-(4-methyl-lH-pyrazol-3-yl)-quinolin-8- yloxymethyl] -pyridin-3 -ylmethyl } -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile, l-{4-[4-(5-Chloro-thiazol-4-yl)-2-methyl-quinolin-8-yloxymethyl]-5-fluoro-2-methyl- pyridin-3 -ylmethyl } -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile,
1 - {5-Fluoro-4-[4-(4-fluoro-pyrazol- 1 -yl)-2-methyl-quinolin-8-yloxymethyl]-2-methyl- pyridin-3-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile, l-{5-Fluoro-4-[4-(4-fluoro-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]-2-methyl- pyridin-3 -ylmethyl } -3 -trifluoromethyl- 1 H-pyridin-2-one, l-{2-Ethyl-5-fluoro-4-[2-methyl-4-(4-methyl-2H-pyrazol-3-yl)-quinolin-8- yloxymethyl] -pyridin-3 -ylmethyl } -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile, l-{2-Ethyl-5-fluoro-4-[4-(4-fluoro-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]- pyridin-3 -ylmethyl } -2-oxo- 1 ,2-dihydro-pyridine-3-carbonitrile, l-{4-Chloro-3-[4-(4-cyano-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]-6-methyl- pyridin-2-yhτiethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile,
1 -( 1 - {4-Chloro-6-methoxy-3 - [2-methyl-4-(2-methyl-2H- [ 1 ,2,4]triazol-3 -yl)-quinolin-8- yloxymethyl]-pyridin-2-yl}-ethyl)-2-oxo-l,2-dihydro-pyridine-3-carbonitrile,
1 -[4-Chloro-6-methyl-3-(2-methyl-4-pyrazol- 1 -yl-quinolin-8-yloxymethyl)-pyridin-2- ylmethyl] -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile, l-[4-Chloro-6-methyl-3-(2-methyl-4-pyrazol-l-yl-quinolin-8-yloxymethyl)-pyridin-2- ylmethyl] -3 -trifluoromethyl- 1 H-pyridin-2-one, l-{4-Chloro-3-[4-(4-fluoro-5-methyl-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]- 6-methyl-pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile, l-{5-Chloro-4-[4-(4-fluoro-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]-2-methyl- pyridin-3 -ylmethyl } -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile,
1 - { 3 - [4-(5-Cyano- 1 -methyl- 1 H-pyrrol-2-yl)-2-methyl-quinolin-8-yloxymethyl]-4- methoxy-6-methyl-pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile,
1 -( 1 - {4-Chloro-3 - [4-(4-fluoro-pyrazol- 1 -yl)-2-methyl-quinolin-8-yloxymethyl] -pyridin- 2-yl}-ethyl)-2-oxo-l,2-dihydro-pyridine-3-carbonitrile,
1 - { 4-Chloro-3 - [4-(4-fluoro-pyrazol- 1 -yl)-2-methy 1-quinolin- 8-y loxymethyl] -6- hydroxymethyl-pyridin-2 -ylmethyl } -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile,
Isobutyric acid 4-chloro-6-methyl-3 - [2-methyl-4-(4-methyl- 1 H-pyrazol-3 -yl)-quinolin- 8-yloxymethyl]-pyridin-2-ylmethyl ester,
Acetic acid 4-chloro-6-methyl-3-[2-methyl-4-(4-methyl-lH-pyrazol-3-yl)-quinolin-8- yloxymethyl]-pyridin-2 -ylmethyl ester, Acetic acid 1 - {4-chloro-3-[2-methyl-4-(4-methyl- 1 H-pyrazol-3-yl)-quinolin-8- yloxymethyl]-pyridin-2-yl} -ethyl ester,
Acetic acid 4-chloro-3-[2-methyl-4-(4-methyl-lH-pyrazol-3-yl)-quinolin-8- yloxymethyl] -pyridin-2-ylmethyl ester,
Isobutyric acid 1 - {4-chloro-3-[2-methyl-4-(4-methyl- 1 H-pyrazol-3-yl)-quinolin-8- yloxymethyl]-pyridin-2-yl}-ethyl ester,
1 - {4-Chloro-3-[4-(4-cyano-pyrazol- 1 -yl)-2-methyl-quinolin-8-yloxymethyl]-6- methoxy-pyridin-2 -ylmethyl } -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile, l-{4-Chloro-6-methoxy-3-[2-methyl-4-(3-methyl-isoxazol-4-yl)-quinolin-8- yloxymethyl]-pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile,
1 - {4-Chloro-3-[4-(5-chloro-pyrazol- 1 -yl)-2-methyl-quinolin-8-yloxymethyl]-6-methyl- pyridin-2-ylmethyl} -2-oxo- 1 ,2-dihydro-pyridine-3-carbonitrile,
1 -( 1 - { 4-Chloro-3 - [4-(4-cyano-pyrazol- 1 -yl)-2-methyl-quinolin-8-yloxymethyl] -pyridin- 2-yl } -ethyl)-2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile, l-{4-Chloro-3-[4-(4-fluoro-pyrazol-l-yl)-2-hydroxymethyl-quinolin-8-yloxymethyl]-6- methyl-pyridin-2 -ylmethyl } -2-oxo- 1 ,2-dihydro-pyridine-3-carbonitrile, or l-{4-Chloro-3-[4-(4-methoxy-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]-pyridin- 2-yhnethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile
In a second aspect, 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.
In a second embodiment of the second aspect which is also an embodiment of the first embodiment of the second aspect, 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.
In a third aspect, 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.
In a fourth aspect, 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:
(a) contacting a tissue sample containing the BK B2 receptor with a detectably labeled compound according to the first aspect under conditions that permit binding of the compound to the BK B2 receptor; and
(b) detecting the bound compound.
In a second embodiment of the fourth aspect which is also an embodiment of the first embodiment of the fourth aspect, the compound is radiolabeled, fluorescence-labeled or luminescence-labeled, or labeled with an antibody.
In a fifth aspect, 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.
In a second embodiment of the fifth aspect which is also an embodiment of the first embodiment of the fifth aspect, the condition or disease is responsive to BK B2 receptor modulation.
In a third embodiment of the fifth aspect which is also an embodiment of the first embodiment of the fifth aspect, 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.
In a sixth aspect, 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.
hi a seventh 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.
In a second embodiment of the seventh aspect which is also an embodiment of the first embodiment of the seventh aspect, the condition or disease is responsive to BK B2 receptor modulation.
In a third embodiment of the seventh aspect which is also an embodiment of the first and the second embodiment of the seventh aspect, 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.
It is to be acknowledged that, if not explicitely indicated to the contrary, the terms compounds according to the invention, compounds according to table 1, BK B2 receptor modulators provided herein, BK B2 antagonists and agonist provided herein, or similar respective expressions, are used interchangeably herein. BK B2 receptor modulators provided herein exhibit high activity on human BK B2 receptor (i.e., an inhibition constant (IC50) 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 IC5O for competition with the binding of labelled BK to human BK B2 receptor of preferably less than 50 nanomolar). In certain embodiments, 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. For instance, the IC50 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 IC50 (half-maximal inhibitory concentration) of about 5 micromolar or less, still more preferably an IC50 of about 500 nM or less, or even 50 nM or less, even more preferably an IC50 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.
These and other aspects of the present invention will become apparent upon reference to the following detailed description. Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise specified) all of the optical isomers and mixtures thereof are encompassed. Compounds with two or more asymmetric elements can also be present as mixtures of diastereomers. In addition, compounds with carbon-carbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. Where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms. 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). By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 11C, 13C, and 14C.
Compounds according to the formulas provided herein, which have one or more stereogenic centers, have an enantiomeric excess of at least 50%. For example, such compounds may have an enantiomeric excess of at least 60%, 70%, 80%, 85%, 90%, 95%, or 98%. Some embodiments of the compounds have an enantiomeric excess of at least 99%. It will be apparent that single enantiomers (optically active forms) can be obtained by asymmetric synthesis, synthesis from optically pure precursors or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral HPLC column.
The term "8-(heteroarylmethoxy)quinoline", as used herein, 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-(CH2)n-COOH where n is any integer from O to —4 {i.e., 0, 1, 2, 3, or 4) and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those of ordinary skill in the art will recognize further pharmaceutically acceptable salts for the compounds provided herein. In general, 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. Generally, the use of nonaqueous media, such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile, is preferred.
It will be apparent that 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. In addition, 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. For example, 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. Examples of 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.
As used herein 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. In other words, 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. For example, 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.
The pharmaceutical 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. Furthermore, one or more other active ingredients may (but need not) be included in the pharmaceutical compositions provided herein. For instance, 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.
Pharmaceutical 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. The term 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. In certain embodiments, compositions in a form suitable for oral use are preferred. Such forms include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Within yet other embodiments, 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. Such 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). 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. For example, 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).
Aqueous suspensions contain the active ingredient(s) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such 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 monooleate). 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.
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. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical 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.
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. A composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials. Examples of such components are described in Martindale~The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences. Formulations may comprise microcapsules, such as hydroxymethylcellulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.
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, like those of lotions and creams, 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. Suitable surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants. For example, one or more of dimethicone copolyol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocamidopropyl phosphatidyl PG- dimonium chloride, and 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. For inhalation formulations, 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. 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.
Inhalant compositions may comprise liquid or powdered compositions containing the active ingredient that are suitable for nebulization and intrabronchial use, or aerosol compositions administered via an aerosol unit dispensing metered doses. Suitable liquid compositions comprise the active ingredient in an aqueous, pharmaceutically acceptable inhalant solvent, e.g., isotonic saline or bacteriostatic water. The solutions are administered by means of a pump or squeeze-actuated nebulized spray dispenser, or by any other conventional means for causing or enabling the requisite dosage amount of the liquid composition to be inhaled into the patient's lungs. Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
Formulations or compositions suitable for nasal administration, wherein the carrier is a solid, 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.
Pharmaceutical 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.
Pharmaceutical 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). 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.
For the prevention and/or treatment of diseases mediated by BK or analogues thereof, 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.
It will be understood, however, that 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.
The 8-(heteroarylmethoxy)quinolines provided herein may preferably be used as antagonists of BK B2 receptors in a variety of applications, both in vitro and in vivo. B2 receptor antagonists according to the present invention 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 according to the present invention 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.
In the following the various diseases and conditions that are responsive to BK B2 receptor modulation and the use of the compounds according to the present invention in specific methodology and diagnostics are further specified.
Skin disorders: Within the present application the term "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. Exp Dermatol. 2004; 13 Suppl 4:22-6) neurodermatitis, radiation damage, sunburn, pruritus, itching, urticaria (EP0622361; Frigas, E.; Park, M. Immunol. Allergy Clin. North Am. 2006, 26, 739-51; Luquin, E.; Kaplan, A. P.; Ferrer, M. Clin. Exp. Allergy 2005, 55, 456-60; Kaplan, A. P.; Greaves, M. W. J. Am. Acad. Dermatol. 2005, 53, 373-88; quiz 389-92), psoriasis, mycosis, tissue ulceration, epidermolysis bullosa, wounds including abnormal wound healing, burns (Nwariaku, F. E.; Sikes, P. J.; Lightfoot, E.; Mileski, W. J.; Baxter, C. Burns 1996, 22, 324-7; Neely, A. N.; Imwalle, A. R.; Holder, I. A. Burns 1996, 22, 520-3), frostbite, skin inflammation and edema caused by venoms, alopecia, hair squama, corn, wart and panaris.
Eye diseases: Within the present application the term "eye diseases" encompasses, but is not limited to, inflammatory disorders such as scleritis, conjunctivitis, chemosis, iritis, 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: Within the present application the term "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: Within the present application the term "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 and, in particular, byssinosis, bronchitis, cough, trachitis, congestion, pneumonia, eosinophilc lung infiltrate, chronic eosinophilic pneumonia, idiopathic pulmonary fibrosis and other fibrotic lung diseases, treatment related fibrotic lung disease e.g. related to radiation, methotrexate, chemotherapy, amiodarone or nitrofurantoin, sarcoidosis, acute respiratory distress syndrome (ARDS), asthma of whatever type (Akbary, A. M.; Wirth, K. J.; Scholkens, B. A. Immunopharmacology 1996, 33, 238-42; WO 00/75107 A2), etiology, or pathogenesis, or 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, wheezy 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, pleurisy, tuberculosis, exposure to high altitude i.e. acute mountain sickness and preferably high altitude pulmonary edema (HAPE).
Gastrointestinal diseases: Within the present application the term "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.
Liver, gallbladder and pancreatic diseases (Cugno, M.; Salerno. F.; Nussberger. J.; Bottasso. B.: Lorenzano. E.: Agostoni. A. Clin. Sci. (Lond) 2001. 101. 651-7: WO 01/56995 Al: EP0797997 Bl: Wirth. K. J.: Bickel. M.: Hropot. M.: Gunzler. V.: Heitsch. H.: Ruppert. P.: Scholkens. B. A. Eur. J. Pharmacol. 1997. 337. 45-53): Within the present application the term "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.
Urinary tract and kidney diseases: Within the present application the term "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. Urol. 1994, 152, 874-8; Rosamilia, A.; Clements, J. A.; Dwyer, P. L.; Kende, M.; Campbell, D. J. J. Urol. 1999, 162, 129-34), irritable bladder, overactive bladder (WO 2007003411 A2), incontinence including but not limited to stress-, urge and reflex incontinence, benign prostate hyperplasia (Srinivasan, D.; Kosaka, A.H.;,Daniels, D.V.; Ford, A.P.; Bhattacharya, A. Eur J Pharmacol. 2004, 504(3):155-67), urethritis, inflammatory 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: Within the present application the term "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: Within the present application the term "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: Within the present application the term "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. P.; Feener, E. P. Nat. Med 2007, 13, 181-8; Tranos, P. G.; Wickremasinghe, S. S.; Stangos, N. T.; Topouzis, F.; Tsinopoulos, L; Pavesio, C. E. Surv. Ophthalmol 2004, 49, 470-90), diabetic nephropathy and diabetic neuropathy, insulin resistance and diabetic ulceration, diseases of the proteo- and purine metabolism such as gout and disorder of lipometabolism.
Cardiovascular diseases: Within the present application the term "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. 2005 Jul;289(l):H251-7) 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. Am J Obstet Gynecol. 2005 Oct;193(4):1508-12.). systemic inflammatory response syndrome (SIRS) including SIRS caused by heartlung bypass during surgery, sepsis and internal and external complications during cardiopulmonal bypass surgery (including but not limited to adverse hemodynamic effects following protamine sulfate reversal of heparine (Pretorius, M.; Scholl, F.G.; McFarlane, J.A.; Murphey, L.J.; Brown, NJ..C///I Pharmacol Ther. 2005 Nov;78(5):477-85).
Blood diseases: Within the present application the term "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: Within the present application the term "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.
Musculoskeletal system diseases: Within the present application the term "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, musculoskeletal pain and hardening, spinal disk syndrome. Allergy disorders: Within the present application the term "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: Within the present application the term "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. Inflamm. Res. 2003, 52, 164-9; Petersen, M.; Eckert, A. S.; Segond von Banchet, G.; Heppelmann, B.; Klusch, A.; Kniffki, K. D. Neuroscience 1998, 83, 949- 59; Birklein, F.; Schmelz, M.; Schifter, S.; Weber, M. Neurology 2001, 57, 2179-84; Weber, M.; Birklein, F.; Neundorfer, B.; Schmelz, M. Pain 2001, 91, 251-7), causalgia, morbus sudeck, reflex sympathetic dystrophy), diabetic peripheral neuropathy, post-herpetic neuralgia, trigeminal neuralgia, cancer-related pain, pain associated with rheumatoid arthritis, osteoarthritis (Bond, A. P.; Lemon, M.; Dieppe, P. A.; Bhoola, K. D. Immunopharmacology 1997, 36, 209-16; Cassim, B.; Naidoo, S.; Ramsaroop, R.; Bhoola, K. D. Immunopharmacology 1997, 36, 121-5; Calixto, J. B.; Cabrini, D. A.; Ferreira, J.; Campos, M. M. Pain 2000, 87, 1-5; Kaneyama, K.; Segami, N.; Sato, J.; Fujimura, K.; Nagao, T.; Yoshimura, H. J. Oral. Maxillofac. Surg. 2007, 65, 242-7), teno-synovitis, gout, menstruation and angina, fibromyalgia, ocular pain, back pain, headache, cluster headache, migraine (Ebersberger, A.; Ringkamp, M.; Reeh, P.W.; Handwerker, H.O. J Neurophysiol. 1997 Jun;77(6):3122-33.), hyperalgesia, and fever. Furthermore, compounds of the invention are useful as analgesic agent for use during general and monitored anesthesia. Infectious diseases: Within the present application the term "infectious diseases" encompasses, but is not limited to, diseases including those mediated by bacteria, viruses, fungi, parasites, protozoa, prions or mycobacterial infections. Particularly, 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 Examples of 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: Within the present application the term "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: Within the present application the term "injuries" encompasses, but is not limited to, multiple trauma, head trauma, lung injuries, external, internal and surgery wounds.
Immunology disorders: Within the present application the term "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: Within the present application the term "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 carcinoid tumors), Hodgkin's disease, non-Hodkin's lymphomas, multiple myeloma, hematopoetic malignancies including leukemias and lymphomas including lymphocytic, granulocytic and monocytic lymphomas, tumor invasion, metastasis, ascites, tumor growth and angiogenesis.
Hereditary diseases: Within the present application the term "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: Within the present application the term "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.
Capillary leak svndrome(s): Within the present application the term "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.
Methodology and diagnostics: 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.
The present invention also pertains to methods for altering the signal-transducing activity of bradykinin receptors in vitro and in vivo. For instance, 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. As used herein, the term "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.
It is also 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.
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 present invention is now further illustrated by the following examples from which further features, embodiments and advantages of the present invention may be taken. EXAMPLES
Preparation of Compounds:
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.
Abbreviations used in the following examples are as follows:
BK is bradykinin
BSA is bovine serum albumin cpm is counts per minute
DCM is dichloromethane
DIBAL is diisobutylaluminum hydride
DMF is dimethylformamide
DMSO is dimethylsulfoxide
EA is ethyl acetate
ELISA is enzyme-linked immunosorbentimmosorbent assay
HBSS is Hanks' balanced salt solution
HPLC is high performance liquid chromatography
LDA is lithium diisoprpylamide
PBS is phosphate-buffered saline
PIPES is piperazine-N,N'-bis(2-ethanesulfonic acid)
RT is room temperature
THF is tetrahydrofuran
THP is tetrahydropyranyl
TFA is trifluoroacetate or trifluoroacetic acid The compounds shown in the following Table 1 are representative examples of compounds of formula (I) according to the present invention.
Table 1:
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0002
Figure imgf000041_0001
Figure imgf000042_0001
Specific examples for the preparation of compounds of the present invention and preferably according to table 1 are provided in the following examples. Unless otherwise specified all starting materials and reagents are of standard commercial grade, and are used without further purification, or are readily prepared from such materials by routine methods. Those skilled in the art of organic synthesis will recognize that starting materials and reaction conditions may be varied including additional steps employed to produce compounds encompassed by 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
A. 2,4,6-Trichloro-nicotinic acid methyl ester
A solution of 2,4,6-trichloro-pyridine (2004 mg, 10.98 mmol) in Et2O (2O mL) was cooled to -78 0C and w-butyllithium (1.6 M in hexane, 7.6 mL, 12.08 mmol) were added dropwise over a period of 10 min. The reaction mixture was stirred for 1 h at -78 0C before it was transferd via a canula to a second flask containing methylchloroformate (935 μl, 12.08 mmol) dissolved in Et2O (2O mL) at -70 0C. The reaction mixture was allowed to warm to RT over 25 min. Then the reaction was quenched by the addition of water (20 mL) and extracted with Et2O (3x 20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EA) to give the title compound. MS (m/z): 239.2
B. (2,4,6-Trichloro-pyridin-3-yl)-methanol
To a stirred solution of 2,4,6-Trichloro-nicotinic acid methyl ester (1.826 g, 7.59 mmol) in THF (36 mL) was added dropwise DIBAL (1.5 M in toluene, 30.4 mL, 45.6 mmol) at - 5 °C. The reaction mixture was stirred for 30 min at 0 °C before it was cooled down to - 20 °C and MeOH (30 ml) and water (30 mL) were added subsequently. The solvents were removed in vacuo, the residue was partitioned between water and EA and extracted with EA (3x 30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound which was used in the next step without further purification. C. 2,4,6-Trichloro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridine
To (2,4,6-Trichloro-pyridin-3-yl)-methanol (1.68 g, 7.59 mmol) dissolved in anhydrous DCM (18 mL) 3,4-dihydro-2H-pyran (789 μL, 8.70 mmol) and (+/-)- 10-camphersulfonic acid (2.02 g, 8.70 mmol) were added and the solution was stirred for 2 h. The mixture was washed with saturated NaHCO3 (50 mL) and the organic layer was separated and the aqueous solution extracted with DCM (2x 5OmL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with hexane/EA to provide the title compound. MS (m/z): 297.9 [M+H+]
D. 2,4-Dichloro-6-methoxy-3-(tetrahydro-pyran-2-yloxymethyl)-pyridine
Under argon atmosphere a freshly prepared solution of NaOMe (131 mg, 2.42 mmol) in THF (8 mL) was added to a solution of 2,4,6-Trichloro-3-(tetrahydro-pyran-2- yloxymethyl)-pyridine in THF (2 mL). The reaction mixture was stirred for 2 h at RT, then water (5 mL) was added and it was extracted with DCM (3x 10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EA) to give the title compound together with the 2-methoxy-regioisomer. MS (m/z): 291.9 [M+H+]
E. 4-Chloro-6-methoxy-3-(tetrahydro-pyran-2-yloxymethyl)-2-vinyl-pyridine 2,4-Dichloro-6-methoxy-3 -(tetrahydro-pyran-2-yloxymethyl)-pyridine (312 mg,
1.07 mmol) was dissolved in of 1 ,2-dimethoxyethane (20 mL). K2CO3 (177 mg, 1.28 mmol) and 2,4,6-trivinyl-cyclotriboroxane pyridine complex (103 mg, 0.43 mmol) were added and the reaction mixture was degassed two times before the addition of Pd((PPh3)4 (123 mg, 0.11 mmol). The reaction mixture was stirred at 100 °C for 18 h. Saturated NaHCO3 (7 mL) was added and the mixture was extracted with DCM (3x 20 mL). The solvents were removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with hexane/EA) to give the title compound. MS (m/z): 283.9 [M+H*]
F. [4-Chloro-6-methoxy-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-yl]-methanol 4-Chloro-6-methoxy-3-(tetrahydro-pyran-2-yloxymethyl)-2-vinyl-pyridine (173 mg, 0.61 mmol) was dissolved in DCM (120 mL) and cooled to -50 0C. A gentle flow of ozone was bubbled through the reaction mixture until the colour of the solution changed to slight blue. NaBH4 (232 mg, 6.1 mmol) dissolved in MeOH (5 mL) was added and the reaction was allowed to warm to RT over a period of 1 h. Water (20 mL) was added and the mixture was extracted with DCM (3x 20 mL). The combined organic fractions were washed with brine and dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EA) to give the title compound. MS (m/z): 287.9 [M+H+]
G. l-[4-Chloro-6-methoxy-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-ylmethyl]-2- oxo- 1 ,2-dihydro-pyridine-3-carbonitrile
[4-Chloro-6-methoxy-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-yl]-methanol (33 mg, 0.11 mmol) was dissolved in DCM (2 mL) and cooled to 0 °C. NEt3 (48 μL, 0.34 mmol) and methanesulfonic acid anhydridel (22 mg, 0.13 mmol) were added and the reaction mixture was stirred for 50 min at RT. After removal of the solvents in vacuo, the residue was dissolved in DMF (1 mL) and CsCO3 (187 mg, 0.57 mmol) and 2-hydroxy- nicotinonitrile (27.6 mg, 0.23 mmol) were added. After stirring for 1 h at RT the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EA) to give the title compound. MS (m/z): 389.7 [M+H+]
H. 1 -(4-Chloro-3 -chloromethyl-6-methoxy-pyridin-2-ylmethyl)-2-oxo- 1 ,2-dihydro- pyridine-3 -carbonitrile l-[4-Chloro-6-methoxy-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-ylmethyl]-2- oxo-l,2-dihydro-pyridine-3 -carbonitrile (35 mg, 0.90 mmol) was dissolved in DCM (2 mL). SOCl2 (33 μL, 4.49 mmol) and water (2 μL) were added and the reaction mixture was stirred for 1 h at RT. After removal of the solvents in vacuo the resulting title compound was used for the next reaction without purification. MS (m/z): 323.8 [M-I-H+] I. 4-(4-Fluoro-pyrazol- 1 -yl)-2-methyl-quinolin-8-ol
A mixture of 4-Chloro-2-methyl-quinolin-8-ol (30 mg, 0.15 mmol) and 4-Fluoro-lH- pyrazole (Shi, Xifeng; Ishihara, Takashi; Yamanaka, Ηiroki; Gupton, John T. Tetrahedron Letters 1995, 36, 1527-1530) (33 mg, 0.39 mmol) in NMP (25 μL) was stirred at 150 °C for 90 min. The crude product was purified by reversed phase ΗPLC using a gradient of acetonitrile in water with 0.1 % TFA to give the title compound as the TFA salt. MS (m/z):
Figure imgf000046_0001
J. l-{4-Chloro-3-[4-(4-fluoro-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]-6- methoxy-pyridin-2-ylmethyl } -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile
A solution of 4-(4-Fluoro-pyrazol-l-yl)-2-methyl-quinolin-8-ol (5 mg, 21 μmol), l-(4- Chloro-3-chloromethyl-6-methoxy-pyridin-2-ylmethyl)-2-oxo-l,2-dihydro-pyridine-3- carbonitrile (7 mg, 23 μmol) and Cs2CO3 (21 mg, 63 μmol) in DMF (1 mL) was stirred for at RT 3 h. After removal of the solvent in vacuo the residue was purified by reversed phase ΗPLC using a gradient of acetonitrile in water with 0.1 % TFA to give the title compound as the TFA salt. MS (m/z): 530.9 [M+Η+]
Example 23 : Synthesis of l-{4-Chloro-3-[4-(4-methoxy-pyrazol-l-yl)-2-methyl- quinolin-8-yloxymethyl]-6-methyl-pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3- carbonitrile
A. l-Ben2yl-lH-pyrazol-4-ol l-Benzyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lΗ-pyrazole (700 mg,
2.46 mmol) was dissolved in THF (6 mL) and cooled to 0 0C. NaOH (2 M in water, 4.93 mmol, 2.5 mL) and H2O2 (30% in water, 503 μl, 4.93 mmol) were added and the reaction mixture was stirred at RT for 45 min. Then the pH was adjusted to 2 by the addition of aqueous HCl (2 M) and the mixture was extracted with DCM (3x 10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EA) to give the title compound. MS (m/z): 175.0 [M+H+] B . 1 -Benzyl-4-methoxy- 1 H-pyrazole
To a solution of 1 -Benzyl- lH-pyrazol-4-ol (200 mg, 1.15 mmol) and Cs2CO3 (524 mg, 1.61 mmol) in DMF (5 mL) was added MeI (100 μL, 1.61 mmol). After stirring at RT for 75 min the solvents were removed in vacuo and the residue was purified by flash chromatography on silica gel (elution with hexane/EA) to give the title compound. MS (m/z): 189.0 [M+Η*]
C. 4-Methoxy-l H-pyrazole
1 -Benzyl-4-methoxy- 1 H-pyrazole (38 mg, 0.2 mmol) was dissolved in MeOH (4.5 mL) and aqueous HCl (1 M, 0.5 ml), Pd(OH)2 (7.6 mg, 0.05 mmol) was added and the vigorously stirred solution was evacuated and subsequently flushed with H2 from a balloon three times. After 90 min Pd(OH)2 (40 mg, 0.28 mmol) was added and the reaction mixture was stirred under a H2-atmosphere for 16 h, filtered and the filtrate concentrated in vacuo. The crude product was used in the next step without further purification. MS (m/z): 98.9 [M-HH+]
D. 4-(4-Methoxy-pyrazol- 1 -yl)-2-methyl-quinolin-8-ol
Reaction of 4-Chloro-2-methyl-quinolin-8-ol (32 mg, 0.16 mmol) and 4-Methoxy-lH- pyrazole (16 mg, 0.16 mmol) according to procedure described for the synthesis of 4-(4- Fluoro-pyrazol-l-yl)-2-methyl-quinolin-8-ol gave the title compound which was used for the next reaction without purification. MS (m/z): 256.0 [M-I-H+]
E. (2,4-Dichloro-6-methyl-pyridin-3 -yl)-methanol 2,4-Dichloro-6-methyl-nicotinic acid ethyl ester (550 mg, 2.35 mmol) was reduced according to procedure described for the synthesis of (2,4,6-Trichloro-pyridin-3-yl)- methanol to give the title compound afer purification by flash chromatography on silica gel (elution with hexane/EA) MS (m/z): 192.0 [M+H4]
F. 2,4-Dichloro-6-methyl-3 -(tetrahydro-pyran-2-yloxymethyl)-pyridine (2,4-Dichloro-6-methyl-pyridin-3-yl)-methanol (391 mg, 2.04 mmol) was THP- protected according to procedure described for the synthesis of 2,4,6-Trichloro-3- (tetrahydro-pyran-2-yloxymethyl)-pyridine to yield after purification by flash chromatography on silica gel (elution with hexane/EA) the title compound. MS (m/z): 275.9 [M+H*]
G. 4-Chloro-6-methyl-3-(tetrahydro-pyran-2-yloxymethyl)-2-vinyl-pyridine 2,4-Dichloro-6-methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridine (239 mg,
0.89 mmol) was vinylated according to procedure described for the synthesis of 4-Chloro-6- methoxy-3-(tetrahydro-pyran-2-yloxymethyl)-2-vinyl-pyridine to provide after purification by flash chromatography on silica gel (elution with hexane/EA) the title compound. MS (m/z): 267.9 [M+H+]
H. [4-Chloro-6-methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-yl]-methanol 4-Chloro-6-methyl-3 -(tetrahydro-pyran-2-yloxymethyl)-2-vinyl-pyridine (306 mg,
1.14 mmol) was subjected to ozonolysis and subsequent reduction according to procedure described for the synthesis of [4-Chloro-6-methoxy-3-(tetrahydro-pyran-2-yloxymethyl)- pyridin-2-yl]-methanol to yield after purification by flash chromatography on silica gel (elution with hexane/EA) the title compound. MS (m/z): 271.9 [M+H*]
I. l-[4-Chloro-6-methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-ylmethyl]-2- oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile
[4-Chloro-6-methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-yl]-methanol (141 mg, 0.52 mmol) was alkylated according to procedure described for the synthesis of 1- [4-Chloro-6-methoxy-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-ylmethyl]-2-oxo-l,2- dihydro-pyridine-3 -carbonitrile. Purification by flash chromatography on silica gel (elution with hexane/EA) yielded the title compound. MS (m/z): 373.7 [M+H*]
J. 1 -(4-Chloro-3-chloromethyl-6-methyl-pyridin-2-ylmethyl)-2-oxo- 1 ,2-dihydro- pyridine-3 -carbonitrile l-[4-Chloro-6-methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-ylmethyl]-2-oxo- l,2-dihydro-pyridine-3-carbonitrile (60 mg, 0.16 mmol) was chlorinated according to procedure described for the synthesis of l-(4-Chloro-3-chloromethyl-6-methoxy-pyridin-2- ylmethyl)-2-oxo-l,2-dihydro-pyridine-3-carbonitrile to provide the title compound which was used in the next step without purification. MS (m/z): 307.9 [MH-H+]
K. 1 - { 4-Chloro-3 - [4-(4-methoxy-pyrazol- 1 -yl)-2-methyl-quinolin- 8-yloxymethyl] -6- methyl-pyridin-2-ylmethyl } -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile
1 -(4-Chloro-3-chloromethyl-6-methyl-pyridin-2-ylmethyl)-2-oxo- 1 ,2-dihydro-pyridine- 3 -carbonitrile (6 mg, 19.6 μmol) and 4-(4-Methoxy-pyrazol-l-yl)-2-methyl-quinolin-8-ol (5 mg, 19.6 μmol) were coupled according to procedure described for the 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. Purification by reversed phase HPLC using a gradient of acetonitrile in water with 0.1 % TFA to give the title compound as the TFA salt. MS (m/z): 527.0 [M+H+]
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
A. 5-(8-Ηydroxy-2-methyl-quinolin-4-yl)-l-methyl-lH-pyrrole-2- LDA (1.8 M in heptanr/ TΗF/ethylbenzene, 0.44 mL, 0.79 mmol) was added dropwise to a stirred solution of 1 -methyl- lΗ-pyrrole-2-carbonitrile (84 mg, 0.79 mmol) in anhydrous THF (60 mL) at -87 0C. The reaction mixture was allowed to warm to -60 °C. A solution of ZnCl2 (290 mg, 2.13 mmol) in anhydrous THF (2.1 mL) was than added dropwise at -90 °C. The reaction mixture was allowed to reach -30 0C and was than transferred to a suspension of Pd(PPtLt)4 (25.5 mg, 22 μmol) 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 NH3 solution and the aqueous layer was extracted with DCM (2x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with DCM/MeOH 20:1) to give the title compound. MS (m/z): 264.2 [M+H*].
B. [4-Methoxy-6-methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-yl]-methanol [4-Chloro-6-methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-yl]-methanol
(150 mg, 0.55 mmol) was converted into the methoxy-pyridine according to procedure described for the synthesis of 2,4-Dichloro-6-methoxy-3-(tetrahydro-pyran-2-yloxymethyl)- pyridine. Purification by flash chromatography on silica gel (elution with EA) yielded the title compound. MS (m/z): 268.0 [MH-H+]
C. 1 -(3-Chloromethyl-4-methoxy-6-methyl-pyridin-2-ylmethyl)-2-oxo- 1 ,2-dihydro- pyridine-3 -carbonitrile
[4-Methoxy-6-methyl-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-yl]-methanol (40 mg, 0.15 mmol) was alkylated according to procedure described for the synthesis of 1 - [4-Chloro-6-methoxy-3 -(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-ylmethyl] -2-oxo- 1 ,2- dihydro-pyridine-3 -carbonitrile (MS (m/z): 369.8 [M+H+])and subsequently chlorinated according to procedure described for the synthesis of l-(4-Chloro-3-chloromethyl-6- methoxy-pyridin-2-ylmethyl)-2-oxo-l,2-dihydro-pyridine-3-carbonitrile to provide the title compound which was used in the next step without purification. MS (m/z): 303.9 [TvM-H+]
D. 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-l,2-dihydro-pyridine-3-carbonitrile
1 -(3-Chloromethyl-4-methoxy-6-methyl-pyridin-2-ylmethyl)-2-oxo- 1 ,2-dihydro- pyridine-3-carbonitrile (3.5 mg, 11 μmol) and 5-(8-Ηydroxy-2-methyl-quinolin-4-yl)-l- methyl-lH-pyrrole-2-carbonitrile (3 mg, 11 μmol) were coupled according to procedure described for the 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. Purification by reversed phase HPLC using a gradient of acetonitrile in water with 0.1 % TFA gave the title compound as the TFA salt. MS (m/z): 531.0 [IVH-H+]
Example 44: Synthesis of l-{4-Chloro-3-[4-(4-cyano-pyrazol-l-yl)-2-methyl-quinolin- 8-yloxymethyl]-6-methoxy-pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile
A. 1 -(8-Hydroxy-2-methyl-quinolin-4-yl)- 1 H-pyrazole-4-carbonitrile lH-Pyrazole-4-carbonitrile (Jachak, Madhukar; Kriessmann, Ulrike; Mittelbach,
Martin; Junek, Hans; Monatshefte fuer Chemie 1993, 124; 199-208) (103 mg, 1.10 mmol) was reacted with 4-Chloro-2-methyl-quinolin-8-ol (164 mg, 0.85 mmol) according to procedure described for the synthesis of 4-(4-Fluoro-pyrazol-l-yl)-2-methyl-quinolin-8-ol. Purification by flash chromatography on silica gel (elution with DCM/MeOH 40:1) gave the title compound. MS (m/z): 251.1 [M+HT].
B. l-{4-Chloro-3-[4-(4-cyano-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]-6- methoxy-pyridin-2-ylmethyl } -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile l-(8-Hydroxy-2-methyl-quinolin-4-yl)-lH-pyrazole-4-carbonitrile (4.7 mg, 18.6 μmol) was coupled with l-(4-Chloro-3-chloromethyl-6-methoxy-pyridin-2-yhnethyl)-2-oxo-l,2- dihydro-pyridine-3-carbonitrile (6.0 mg, 18.6 μmol) according to procedure described for the 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. Purification by reversed phase ΗPLC using a gradient of acetonitrile in water with 0.1 % TFA provided the title compound as the TFA salt. MS (m/z): 538.0 [M+Η+]
Example 47: Synthesis of l-(l-{4-Chloro-3-[4-(4-cyano-pyrazol-l-yl)-2-methyl- quinolin-8-yloxymethyl]-pyridin-2-yl}-ethyl)-2-oxo-l,2-dihydro-pyridine-3-carbonitrile
A. 2,4-Dichloro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridine
NaBH4 (1.12 g, 29.55 mmol) was added to a stirred solution 2,4-Dichloro-pyridine-3- carbaldehyde (4 g, 22.73 mmol) in ethanol (10O mL). After stirring for 1 h at room temperature, the reaction was quenched by the addition of saturated NaHCO3 solution (30 mL) and concentrated in vacuo, the residue was partitioned between EA (100 mL) and water (50 mL). The mixture was extracted with EA (3x 50 mL), washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give (2,4-Dichloro-pyridin-3-yl)- methanol (MS (m/z): 178.2 [M+H"1"]). The crude product was THP-protected according to procedure described for the synthesis of 2,4,6-Trichloro-3-(tetrahydro-pyran-2- yloxymethyl)-pyridine to yield after purification by flash chromatography on silica gel (elution with hexane/EA) the title compound. MS (m/z): 262.0 [M-I-H+]
B. [4-Chloro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-yl]-methanol 2,4-Dichloro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridine (1.71 g, 6.53 mmol) was vinylated according to procedure described for the synthesis of 4-Chloro-6-methoxy-3- (tetrahydro-pyran-2-yloxymethyl)-2 -vinyl -pyridine and subsequently subjected to ozonolysis according to procedure described for the synthesis of [4-Chloro-6-methoxy-3- (tetrahydro-pyran-2-yloxymethyl)-pyridin-2-yl] -methanol to yield after purification by flash chromatography on silica gel (elution with hexane/EA) the title compound. MS (m/z): 257.8 [M+H*]
C. 4-Chloro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridine-2-carbaldehyde
To a solution of [4-Chloro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-yl]-methanol (150 mg, 0.58 mmol) in THF (5 mL) was added Dess-Martin-periodinane (370 mg, 0.87 mmol)and the reaction mixture was stirred for 2 h at RT. Saturated NaHCO3 solution (20 mL) was added and the mixture was extracted with EA (2x 50 mL), washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound which was used in the next reaction without purification. MS (m/z): 255.7 [M+H*]
D. 1 -[4-Chloro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-yl]-ethanol
To a solution of 4-Chloro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridine-2-carbaldehyde (148 mg, 0.58 mmol) in THF (6 mL) was added methylmagnesium bromide (3 M in Et2O, 582 μl, 1.74 mmol) It was stirred for lO min before saturated NaHCO3 solution (3O mL) was added and the mixture was extracted with DCM (2x 25 mL), washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (elution with DCM/MeOH) gave the title compound. MS (m/z): 271.8[M+H+]
E. 1 -[ 1 -(4-Chloro-3-chloromethyl-pyridin-2-yl)-ethyl]-2-oxo- 1 ,2-dihydro-pyridine-3- carbonitrile l-[4-Chloro-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-yl]-ethanol (120 mg,
0.44 mmol) was alkylated according to procedure described for the synthesis of l-[4- Chloro-6-methoxy-3-(tetrahydro-pyran-2-yloxymethyl)-pyridin-2-ylmethyl]-2-oxo-l,2- dihydro-pyridine-3-carbonitrile (MS (m/z): 373.7 [M+H+])and subsequently chlorinated according to procedure described for the synthesis of l-(4-Chloro-3-chloromethyl-6- methoxy-pyridin-2-ylmethyl)-2-oxo-l,2-dihydro-pyridine-3-carbonitrile to provide the title compound which was used in the next step without purification. MS (m/z): 307.8 [MH-H+]
F. l-(l-{4-Chloro-3-[4-(4-cyano-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]- pyridin-2-yl}-ethyl)-2-oxo-l,2-dihydro-pyridine-3-carbonitrile l-(8-Hydroxy-2-methyl-quinolin-4-yl)-lH-pyrazole-4-carbonitrile (8 mg, 32 μmol) and l-[l-(4-Chloro-3-chloromethyl-pyridin-2-yl)-ethyl]-2-oxo-l,2-dihydro-pyridine-3- carbonitrile (4.9 mg, 16 μmol) were coupled according to procedure described for the synthesis of l-{4-Chloro-3-[4-(4-fluoro-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]-6- methoxy-pyridin-2-ylmethyl}-2-oxo- 1 ,2-dihydro-pyridine-3-carbonitrile. Purification by reversed phase HPLC using a gradient of acetonitrile in water with 0.1 % TFA gave the title compound as the TFA salt. MS (m/z): 522.1 [M-I-H+]
Example 50: Radioligand binding assay
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 CaCl2, 1 mM MgCl2, pH 7.4; with following inhibitors:
2 mM bacitracin, 0.8 mM 1,10-phenanthrolin, 100 μM captopril. Before starting the experiment, [3H]BK is added to obtain a final concentration of 2 nM.
Addition of test compounds to incubation buffer and preparation of serial dilutions: 10 μL of a 10 mM stock solution of the individual test compounds in DMSO was diluted in 90 μL DMSO, resulting in a compound concentration of 1 mM in 100% DMSO. 7.5 μL of this (1 mM) compound solution was then added to 242.5 μL of incubation buffer (contains 2 nM [3H]BK, see above), resulting in a test compound concentration of 30 μM. A 10 μM compound solution was prepared by addition of 2.5 μL of the 1 mM compound solution to 247.5 μL incubation buffer. Based on these 30 μM and 10 μM compound solutions in incubation buffer, further dilutions were prepared by serial 1:10 dilution with incubation buffer (containing 2 nM [3H]BK, see above) steps resulting in 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003 and 0.001 μM compound solutions. For determination of non-specific binding 1.25 μL of a 10 mM BK solution was added to 248.8 μL incubation buffer (contains 2 nM [3H]BK). For determination of total binding, incubation buffer with [3H]BK but without compound was used. Beside of compounds to be tested, appropriate controls were prepared in the same way.
Procedure:
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 μL each of the incubation buffer containing [3H]BK and serial dilutions of test/control compounds/controls or 50 μM 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. In order to dissociate surface-bound [3H]BK, 200 μL 0.2 M acetic acid/0.5 M NaCl, pH 2.7 were added subsequently, followed by a further incubation step on ice for 10 minutes. Afterwards, the supernatants were transferred into 6 mL scintillation vials; 0.9 mL scintillation fluid were added each and the amount of [3H]BK was determined by analysis in a beta-counter (cpm, counting time 1 min). For analysis of results, the cpm determined for non-specific binding were subtracted from the total counts and the cpm values for each compound dilution were used for curve fit and IC50 calculation.
The compounds shown in Examples 1-49 have been tested in this assay and found to exhibit IC50 values of less than or equal to 5 micromolar. Most preferred compounds according to the present invention exhibited IC5O values of less than 50 nanomolar.
Example 51 : Calcium mobilization assay
Inhibitory effects of test compounds on BK-mediated calcium mobilization were tested on HF- 15 primary human fibroblasts.
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 (370C) and 100 μL of HBSS were left per well. Then, 100 μL 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.
Preparation of serial dilutions and incubation with test compounds: Based on 5 mM stock solutions in 100% DMSO (and pre-dilutions in 100% DMSO if necessary), serial 1 :3 dilutions of test compounds and controls are prepared in 100% DMSO. Concentration range to be used was chosen to be between 2 mM and 1 nM, dependent on the optimal concentration range for each compound. 2.5 μL of the compound/control dilutions then were added per well of the cell-coated assay plate, already containing 200 μL HBSS/dye solution. Subsequently, cells were pre-incubated with compounds /controls for 25 minutes at 25°C.
Calcium mobilization and analysis of results: After pre-incubation with compounds /controls for 25 minutes, calcium mobilization was tested in a Flexstation device (Molecular Devices). 20 seconds after start of the continous recording of fluorescence signals, 50 μL of a 25 nM BK solution in HBSS were added per well by the liquid-handling system of the device. Height of the resulting peak over baseline (relative fluorescence units [RFU] max- min) was used for calculation of inhibitory effects of test compounds on BK-mediated calcium mobilization. Percent inhibition was calculated by comparison of the obtained RFU max-min values for the blanks (only BK, no antagonist) with the values obtained for the antagonist-treated cells. Percent inhibition values each referring to a certain concentration of antagonist were used for curve fit and IC50 calculation.
Most preferred compounds according to the present invention according to table 1 exhibited IC50 values of less than 50 nanomolar in this assay.
The features of the present invention disclosed in the specification, the claims and/or the drawings may both separately and in any combination thereof be material for realizing the invention in various forms thereof.

Claims

Claims
1. A compound of the formula (I):
Figure imgf000057_0001
or a pharmacologically acceptable salt, solvate, or hydrate thereof, wherein
R1 is
Figure imgf000058_0001
Figure imgf000058_0002
R2 is Cl, F, or methoxy;
R3 is methyl, methoxy, hydroxymethyl, H, or absent;
R4 is methyl, ethyl, HO, H, or absent;
A1 is C or N;
A2 is C or N;
R6 is H or OH; R5 is
Figure imgf000059_0001
2. The compound according to claim 1, wherein the compound is selected from the group consisting of
1 -{4-Chloro-3-[4-(4-hydroxymethyl- 1 H-pyrazol-3-yl)-2-methyl-quinolin-8-yloxymethyl]-6- methyl-pyridin-2-ylmethyl } -3 -trifluoromethyl- 1 H-pyridin-2-one, l-{4-Chloro-3-[4-(4-hydroxymethyl-thiazol-5-yl)-2-methyl-quinolin-8-yloxymethyl]-6- methyl-pyridin-2-ylmethyl}-3-trifluoromethyl-lH-pyridin-2-one,
1 - {4-Chloro-3 - [4-(4-hydroxymethyl-pyrazol- 1 -yl)-2-methyl-quinolin-8-yloxymethyl] -6- methyl-pyridin-2-ylmethyl}-3-trifluoromethyl-l H-pyridin-2-one, l-{4-Chloro-6-methoxy-3-[2-methyl-4-(2-methyl-2H-[l,2,4]triazol-3-yl)-quinolin-8- yloxymethyl]-pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile, l-{4-Chloro-6-methoxy-3-[2-methyl-4-(4-methyl-lH-pyrazol-3-yl)-quinolin-8- yloxymethyl]-pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile, l-{4-Chloro-6-methoxy-3-[2-methyl-4-(5-methyl-lH-imidazol-4-yl)-quinolin-8- yloxymethyl]-pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile,
1 - { 5-Fluoro-4-[2-methyl-4-(4-methyl- 1 H-pyrazol-3-yl)-quinolin-8-yloxymethyl]-pyridin-3- ylmethyl } -3 -trifluoromethyl- 1 H-pyridin-2-one, l-{4-[4-(5-Chloro-thiazol-4-yl)-2-methyl-quinolin-8-yloxyniethyl]-5-fluoro-pyridin-3- ylmethyl}-3-trifluoromethyl-lH-pyridin-2-one, l-{5-Fluoro-4-[2-methyl-4-(4-methyl-lH-pyrazol-3-yl)-quinolin-8-yloxymethyl]-pyridin-3- ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile, l-{4-[4-(5-Chloro-thiazol-4-yl)-2-methyl-quinolin-8-yloxymethyl]-5-fluoro-pyridin-3- ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile, l-{4-Chloro-3-[4-(4-methoxymethyl-5-methyl-lH-pyrazol-3-yl)-2-methyl-quinolin-8- yloxymethyl]-6-methyl-pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile, l-{4-Chloro-3-[4-(4-methoxymethyl-5-methyl-lH-pyrazol-3-yl)-2-methyl-quinolin-8- yloxymethyl] -6-methyl-pyridin-2-ylmethyl } -3 -trifluoromethyl- 1 H-pyridin-2-one, l-{4-[4-(5-Chloro-thiazol-4-yl)-2-methyl-quinolin-8-yloxymethyl]-5-fluoro-2-methyl- pyridin-3 -ylmethyl } -3 -trifluoromethyl- 1 H-pyridin-2-one, l-{5-Fluoro-2-methyl-4-[2-methyl-4-(4-methyl-lH-pyrazol-3-yl)-quinolin-8-yloxymethyl]- pyridin-3 -ylmethyl} -3 -trifluoromethyl- 1 H-pyridin-2-one, l-{4-Chloro-6-methyl-3-[2-methyl-4-(l-methyl-lH-pyrazol-3-yl)-quinolin-8-yloxymethyl]- pyridin-2-ylmethyl}-3-trifluoromethyl-lH-pyridin-2-one, l-{4-Chloro-6-methyl-3-[2-methyl-4-(l-methyl-lH-pyrazol-3-yl)-quinolin-8-yloxymethyl]- pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile,
1 - {4-Chloro-3-[4-(4-fluoro-pyrazol- 1 -yl)-2-methyl-quinolin-8-yloxymethyl]-6-methoxy- pyridin-2 -ylmethyl} -2-oxo- 1 ,2-dihydro-pyridine-3-carbonitrile, l-{5-Fluoro-2-hydroxy-4-[2-methyl-4-(4-methyl-2H-pyrazol-3-yl)-quinolin-8- yloxymethyl] -pyridin-3 -ylmethyl } -3 -trifluoromethyl- 1 H-pyridin-2-one,
5-{8-[5-Fluoro-2-hydroxy-3-(2-oxo-3-trifluoromethyl-2H-pyridin-l-ylmethyl)-pyridin-4- ylmethoxy]-2-methyl-quinolin-4-yl } - 1 -methyl- 1 H-pyrrole-2-carbonitrile, l-{4-Chloro-3-[4-(4-hydroxymethyl-5-methyl-lH-pyrazol-3-yl)-2-methyl-quinolin-8- yloxymethyl]-6-methyl-pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile,
1 - {4-Chloro-3 - [4-(4-hydroxymethyl-5 -methyl- 1 H-pyrazol-3 -yl)-2-methyl-quinolin-8- yloxymethyl] -6-methyl-pyridin-2-ylmethyl } -3 -trifluoromethyl- 1 H-pyridin-2-one, l-{4-Chloro-3-[4-(4-chloro-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]-6-methyl- pyridin-2-ylmethyl} -2-oxo- 1 ,2-dihydro-pyridine-3-carbonitrile, l-{4-Chloro-3-[4-(4-methoxy-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]-6-methyl- pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile,
1 - {5-Fluoro-2-methyl-4-[2-methyl-4-(4-methyl- 1 H-pyrazol-3-yl)-quinolin-8-yloxymethyl]- pyridin-3-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile, l-{4-[4-(5-Chloro-thiazol-4-yl)-2-methyl-quinolin-8-yloxymethyl]-5-fluoro-2-methyl- pyridin-3-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile,
1 - { 5-Fluoro-4- [4-(4-fluoro-pyrazol- 1 -yl)-2-methyl-quinolin-8-yloxymethyl]-2-methyl- pyridin-3 -ylmethyl} -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile, l-{5-Fluoro-4-[4-(4-fluoro-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]-2 -methyl- pyridin-3 -ylmethyl } -3 -trifluoromethyl- 1 H-pyridin-2-one, l-{2-Ethyl-5-fluoro-4-[2-methyl-4-(4-methyl-2H-pyrazol-3-yl)-quinolin-8-yloxymethyl]- pyridin-3 -ylmethyl } -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile, l-{2-Ethyl-5-fluoro-4-[4-(4-fluoro-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]- pyridin-3 -ylmethyl } -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile,
1 - {4-Chloro-3-[4-(4-cyano-pyrazol- 1 -yl)-2-methyl-quinolin-8-yloxymethyl]-6-methyl- pyridin-2-ylmethyl} -2-oxo- 1 ,2-dihydro-pyridine-3-carbonitrile, l-(l-{4-Chloro-6-methoxy-3-[2-methyl-4-(2-methyl-2H-[l,2,4]triazol-3-yl)-quinolin-8- yloxymethyl]-pyridin-2-yl}-ethyl)-2-oxo-l,2-dihydro-pyridine-3-carbonitrile, l-[4-Chloro-6-methyl-3-(2-methyl-4-pyrazol-l-yl-quinolin-8-yloxymethyl)-pyridin-2- ylmethyl] -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile, l-[4-Chloro-6-methyl-3-(2-methyl-4-pyrazol-l-yl-quinolin-8-yloxymethyl)-pyridin-2- ylmethyl] -3 -trifluoromethyl- 1 H-pyridin-2-one, l-{4-Chloro-3-[4-(4-fluoro-5-methyl-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]-6- methyl-pyridin-2-ylmethyl } -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile, l-{5-Chloro-4-[4-(4-fluoro-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]-2-methyl- pyridin-3-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile, 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, l-(l-{4-Chloro-3-[4-(4-fluoro-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]-pyridin-2- yl } -ethyl)-2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile, 1 - {4-Chloro-3-[4-(4-fluoro-pyrazol- 1 -yl)-2-methyl-quinolin-8-yloxymethyl]-6- hydroxymethyl-pyridin-2-ylmethyl } -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile,
Isobutyric acid 4-chloro-6-methyl-3-[2-methyl-4-(4-methyl-lH-pyrazol-3-yl)-quinolin-8- yloxymethyl] -pyridin-2-ylmethyl ester,
Acetic acid 4-chloro-6-methyl-3- [2-methyl-4-(4-methyl- 1 H-pyrazol-3 -yl)-quinolin-8- yloxymethyl]-pyridin-2-ylmethyl ester,
Acetic acid 1 -{4-chloro-3-[2-methyl-4-(4-methyl-lH-pyrazol-3-yl)-quinolin-8- yloxymethyl]-pyridin-2-yl}-ethyl ester,
Acetic acid 4-chloro-3-[2-methyl-4-(4-methyl- 1 H-pyrazol-3-yl)-quinolin-8-yloxymethyl]- pyridin-2-ylmethyl ester,
Isobutyric acid 1 -{4-chloro-3-[2-methyl-4-(4-methyl-lH-pyrazol-3-yl)-quinolin-8- yloxymethyl]-pyridin-2-yl}-ethyl ester, l-{4-Chloro-3-[4-(4-cyano-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]-6-methoxy- pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile, l-{4-Chloro-6-methoxy-3-[2-methyl-4-(3-methyl-isoxazol-4-yl)-quinolin-8-yloxymethyl]- pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile,
1 - {4-Chloro-3 - [4-(5-chloro-pyrazol- 1 -yl)-2-methyl-quinolin-8-yloxymethyl] -6-methyl- pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile, l-(l-{4-Chloro-3-[4-(4-cyano-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]-pyridin-2- yl } -ethyl)-2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile, l-{4-Chloro-3-[4-(4-fluoro-pyrazol-l-yl)-2-hydroxymethyl-quinolin-8-yloxymethyl]-6- methyl-pyridin-2-ylmethyl}-2-oxo-l,2-dihydro-pyridine-3-carbonitrile, or l-{4-Chloro-3-[4-(4-methoxy-pyrazol-l-yl)-2-methyl-quinolin-8-yloxymethyl]-pyridin-2- ylmethyl} -2-oxo- 1 ,2-dihydro-pyridine-3 -carbonitrile
3. A pharmaceutical composition that comprises one or more compounds according to claim 1 or 2 and, optionally, at least one carrier substance, excipient and/or adjuvant.
4. The pharmaceutical composition according to claim 3, wherein 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.
5. 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 claim 1 or 2 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.
6. A method for localizing or detecting a BK B2 receptor in a tissue, preferably a tissue section, in vitro, comprising:
(a) contacting a tissue sample containing the BK B2 receptor with a detectably labeled compound according to claim 1 or 2 under conditions that permit binding of the compound to the BK B2 receptor; and
(b) detecting the bound compound.
7. The method according to claim 6, wherein the compound is radiolabeled, fluorescence- labeled or luminescence-labeled, or labeled with an antibody.
8. Use of a compound or of a pharmaceutical composition according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment and/or prevention of a disease or a condition.
9. Use according to claim 8, wherein the condition or disease is responsive to BK B2 receptor modulation.
10. The use according to claim 8or 9, wherein 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.
11. 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 any of claims 1 to 4.
12. The compound or a pharmacologically acceptable salt, solvate or hydrate thereof according to claim 1 or 2 for use in a method of treatment of a disease or condition.
13. The compound according to claim 12, wherein the condition or disease is responsive to BK B2 receptor modulation.
14. The compound according to any of claims 12 to 13, wherein 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.
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