WO2000059886A2 - Benzimidazole abd imidazolophyridine derivaties, their preparation and their use as selective modulators of bradykinin b2 (=bk-2) receptors - Google Patents
Benzimidazole abd imidazolophyridine derivaties, their preparation and their use as selective modulators of bradykinin b2 (=bk-2) receptors Download PDFInfo
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Definitions
- Aryl and Hetroaryl Fused Aminoalkyl-Imidazole Derivatives Selective Modulators of Bradykinin B 2 Receptors BACKGROUND OF THE INVENTION
- This invention relates to aryl and heteroaryl fused aminoalkylimidazole derivatives which, when appropriately substituted, are selective modulators of Bradykinin B 2 receptors.
- This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating a variety of central and peripheral disorders. Additionally, compounds of this invention are useful as positive controls in assays for BK-2 receptor activity and when appropriately labeled as probes for the localization of BK-2 receptors in tissue sections.
- BK Background Bradykinin
- ys-BK closely related decapeptide kallidin
- bradykinin receptor subtypes The existence of two bradykinin receptor subtypes was initially proposed by Regoli and Barabe ( Pharmacol . Rev. , 1980, 1-46) and this hypothesis had been unequivocally confirmed within the last six years.
- Both BK and kallidin activate the B 2 receptor while only kallidin is active at the B. receptor.
- both compounds are rapidly cleaved to produce B. receptor agonists, and then further degraded by kinases to produce inactive peptides.
- the instability of BK and kallidin suggests that these peptides act locally.
- Both receptors are expressed in a number of peripheral tissues as well as in the CNS.
- the B 2 receptor is expressed constitutively in a variety of tissues (Regoli et al . , Bur. J. Pharmacol . , 1981, 105 - 115) and accounts for the majority of the acute pharmacological effects of bradykinin.
- the B receptor is inducibly expressed (Regoli et al . , Eur. J. Pharmacol . , 1981, 105 - 115; Deblois et al . , Immunopharmacology, 1989, 187-98; arceau, Immunopharmacology, 1995, 1 - 26.) and appears to act predominantly in pathophysiological conditions (Dray and Perkins, J. Neurophysiol . , 1993, 256-272).
- the BK-1 receptor has been especially implicated in persistent hyperalgesia and chronic inflammation.
- Bradykinin is an effector of a number of inflammatory responses including bronchoconstriction, plasma extravasation, release of prostaglandins/leukotrienes, smooth muscle contraction/relaxation and nociception (Burch et al., Med. Res . Rev. 1990, 237-269) . Bradykinin and the related peptide kallidin have been implicated in a number of disease conditions, including but not limited to pain (Whalley et al., Naunyn. Schmiedeherg ' s Arch . Pharmc. , 1987, 652-655), rhinitis, anaphylaxis, inflammatory bowel disease, vascular permeability (Schachter et al . , Br.
- bradykinin has been implicated in increased glucose uptake, and decreased blood glucose concentration
- agonists of the BK-2 receptor may be useful in the treatment of Type II diabetes.
- Unterberg et al . J " Cereb. Blood Flow Metab. , 1984, 574-585) report an increased permeability of the blood- brain barrier due to bradykinin.
- agonists of the BK-2 receptor could also be used to increase the brain levels of pharmaceutical compounds used to treat central nervous system disorders when administered with these compounds. Therefore, compounds that modulate the bradykinin B 2 (BK-2) receptor as agonists or antagonists would have considerable therapeutic benefit .
- bradykinin receptors A number of tissues and cultured cell lines has been assessed for the presence of bradykinin receptors using radiolabeled bradykinin or a radiolabeled bradykinin analogue as a probe (See Hall, Gen . Pharma . , 1997, 28: 1-6, for a compilation of such studies.).
- bradykinin and its analogues exhibit high affinity for bradykinin receptors there are some difficulties in using these ligands as receptor localization probes.
- Bradykinin binds to both BK-1 and BK-2 receptors and therefore cannot be used to distinguish receptor subtypes.
- bradykinin and many of its peptide analogues are susceptible to rapid degradation by kininases, leading to experimental difficulties.
- Nonpeptidic ligands are not susceptible to kininase activity. Therefore, small molecules that bind with high affinity and high selectivity to BK-2 receptors are especially desirable tools for BK-2 localization studies.
- This invention provides compounds of Formula I (shown below) and pharmaceutical compositions comprising compounds of Formula I.
- Preferred compounds of the invention exhibit high selectivity for G-coupled protein receptors, especially bradykinin B 2 receptors .
- Preferred compounds of Formula I also bind with high affinity to these receptors .
- the invention further provides methods of treating patients suffering from certain inflammatory disorders and other conditions mediated by bradykinin.
- the invention also provides methods of treating patients (humans and non-humans) suffering from conditions in which agonism of the BK-2 receptor may prove beneficial.
- Treatment of humans, domesticated companion animals (pets) or livestock animals suffering such conditions with an effective amount of a compound of the invention is contemplated by the invention.
- the invention provides methods of using compounds of this invention as positive controls in assays for BK-2 receptor activity and using appropriately labeled compounds of the invention as probes for the localization of BK-2 receptors in tissue sections.
- the invention is directed to compounds of Formula I :
- R- L is not 3-fluorobenzyl and represents (i) (C 2 -C 6 ) alkenyl; or (ii) R. represents aryl (C ⁇ C g ) alkyl or heteroaryl (C ⁇ C 6 ) alkyl, where the ring portion of each is optionally substituted with one, two or three groups independently selected from halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (C.-C 6 ) alkyl, hydroxy (C ⁇ C g ) alkyl, amino, mono- or di alkylamino, amino (C.-C 6 ) alkyl, mono- or di C 6 ) alkylamino alkoxy, or (iii) OR 7/ 0(CH 2 ) n C(0)R 7 O (CH 2 ) r- R7R8 .
- R7 and Rs are the same or different and represent hydrogen, S0 2 Me, or alkyl; or R7 and Rs together with the nitrogen to which they are attached form a 5 , 6 or 7 membered carbocyclic ring where up to two of the members are optionally hetero atoms selected from oxygen, sulfur and nitrogen, and where each member is optionally substituted with (C x -
- R 3 represents alkyl
- R 4 represents halogen or trifluoromethyl
- R 5 and R 6 are the same or different and represent hydrogen, trifluoromethyl, trifluoromethoxy, cyano, (C ⁇ C alkyl, halogen, (C.-Cg) alkylamino alkyl, mono or dKC j -
- R7 and Rs are the same or different and represent hydrogen, S0 2 Me, or (C.-Cg) alkyl; or R7 and Rs together with the nitrogen to which they are attached form a 5, 6 or 7 membered carbocyclic ring where up to two of the members are optionally hetero atoms selected from oxygen, sulfur and nitrogen, and where each member is optionally substituted with (C x - C 6 ) alkyl;
- X represents a bond or CH 2 , where the CH 2 is optionally mono- or disubstituted with a alkyl or alkoxy; and
- A, B, C and D are the same or different and represent CH or N with the proviso that not more than two of A, B, C and D represent N.
- Preferred compounds of the inventions are modulators of G-coupled protein receptors, especially BK-2 receptors. These compounds are therefore useful in the diagnosis and treatment of renal diseases, heart failure, hypertension, Meniere's disease, vaginal inflammation and pain, peripheral circulatory disorders, climacteric disturbance, retinochoroidal circulatroy disorders, myocardial ischemia, myocardial infarction, postmyocardial infarction syndrome, angina pectoris, restenosis after percutaneous transluminal coronary angioplasty, hepatitis, liver cirrhosis, pancreatitis, ileus, diabetes, diabetic complications, male infertility or glaucoma, or for the increase of permeability of blood-brain barrier, pain, asthma and rhinitis.
- the invention provides methods for treating and/or preventing the above-listed disorders, which methods comprise administration to a patient in need thereof of an effective amount of a compound of Formula I.
- the invention provides intermediates useful in the preparation of the compounds of Formula I .
- R. is as defined above for Formula I; and R 3 is C 3 -C 6 alkyl, preferably n-butyl, isoamyl, or n-pentyl; R 4 is chloro or fluoro; and R a and R b independently represent hydrogen or alkoxy.
- More preferred compounds of Formula II are where R is benzyl mono- or disubstituted on the ring portion with
- (C.-Cg) alkyl halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, alkyl, hydroxy ( C ⁇ -C 6 ) alkyl , amino, mono- or di.C- . - C 6 ) alkylamino, aminomethyl, mono- or ditC,-
- R7 and Rs are the same or different and represent hydrogen, S0 Me, or alkyl; or R7 and Rs together with the nitrogen to which they are attached form a 5, 6 or 7 membered carbocyclic ring where up to two of the members are optionally hetero atoms selected from oxygen, sulfur and nitrogen, and where each member is optionally substituted with (C j -Cg) alkyl; except that R x is not 3-fluorobenzyl .
- R 4 is chloro and R a and R b are independently C 1 -C 6 alkoxy, most preferably C--C 3 alkoxy.
- Particularly preferred compounds of Formula II are those where R 3 is butyl or isoamyl, i.e, 3 -methylbutyl , R 4 is chloro, and R a and R b are independently C 1 -C 2 alkoxy, most preferably methoxy.
- the present invention encompasses compounds of the Formula III.
- R ⁇ is as defined above for Formula I; and R 3 is C 3 or C 6 alkyl, preferably n-butyl, isoamyl, or n- pentyl ; R 4 is chloro or fluoro; and R a and R b independently represent hydrogen or alkoxy.
- More preferred compounds of Formula II are where R. is benzyl mono- or disubstituted on the ring portion with alkyl, halogen, nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, alkyl, hydroxy ( ⁇ -C 6 ) alkyl , amino, mono- or dKC ⁇ C 6 ) alkylamino, aminomethyl, mono- or di(C 1 - C 6 ) alkylamino (C ⁇ C g ) alkyl, or mono- or di(C
- R 4 is chloro and R a and R b are independently C 1 -C 6 alkoxy, most preferably C- . -C 3 alkoxy.
- Particularly preferred compounds of Formula III are those where R 3 is butyl or isoamyl, i.e, 3 -methylbutyl, R 4 is chloro, and R a and R b are methoxy.
- R x groups in Formulae II and III are benzyl substituted in the 2- or 3 -positions of its phenyl ring with hydroxy, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, ⁇ - [4- ( (C-- C 6 ) alkyl) piperazinyl] (C 1 -C 4 ) alkoxy, methyl sulfonate, 3- halopropoxy, carboxymethoxy, 2-, 3-, or 4-pyridyl (Ci-Cg) alkyl, preferably 2-, 3-, or 4-pyridyl (C.-C 2 ) alkyl, 3- pyrrolidinyl (Cx-Cg) alkoxy; tetrazolyl, halogen, preferably bromo, fluoro or chloro, alkylamino (C.-C 6 ) alkoxy, preferably 3- (methylamino)propoxy or 2- (ethylamino) ethoxy,
- R. groups of the invention are 2-fluoro-, 2-bromo- or 2-chloro-5-nitrobenzyl, 3,5- dihalobenzyl where the halogen is chloro or fluoro, 5- hydroxy (C- -C 2 ) alkyl-2 - ( x -C 3 ) alkoxybenzyl , 5- ( C 2 -C 4 ) alkanoyl-2 -
- R : groups include alkenyl groups such as allyl or l-buten-2- or 3-yl.
- R. groups include 2- or 3- pyridyl .
- co-substitution as used herein is meant the terminal position on, for example, an alkyl chain.
- examples of such groups are 3-hydroxypropyl, 5-morpholin-4-ylpentyl, 3- piperazinylpropoxy, and 4 -methoxybutyl .
- alkyl By “alkyl”, “lower alkyl”, and “ (C 1 -C 6 ) alkyl” in the
- alkyl groups having 1-6 carbon atoms such as, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2- pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, -hexyl, and 3- methylpentyl .
- alkoxy "lower alkoxy”
- (C ⁇ Cg) alkoxy in the
- present invention is meant straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
- halogen in the present invention is meant fluorine, bromine, chlorine, and iodine.
- heteroaryl is meant one or more aromatic ring systems of 5-, 6-, or 7-membered rings containing at least one and up to four heteroatoms selected from nitrogen, oxygen, or sulfur.
- heteroaryl groups include, for example, thienyl , furanyl, thiazolyl, imidazolyl, (is) oxazolyl, pyridyl, pyrimidinyl, (iso) quinolinyl, napthyridinyl, benzimidazolyl, benzoxazolyl .
- Preferred heteroaryls are thiazolyl and pyridyl .
- aryl is meant an aromatic carbocyclic group having a single ring (e.g., phenyl), multiple rings (e.g., biphenyl) , or multiple condensed rings in which at least one is aromatic, (e.g., 1, 2, 3 , 4-tetrahydronaphthyl, naphthyl, anthryl, or .phenanthryl) , which is optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, and hydroxy.
- a preferred aryl is phenyl.
- Preferred alkylamino groups are methylamino and ethylamino; preferred di alkylamino groups are diethylamino and dimethylamino; preferred amino alkyl groups are aminomethyl and 2-aminoethyl; preferred mono- and di (C x -C 6 ) alkylamino (C x -C 6 ) alkyl groups are methylaminomethyl , dimethylaminomethyl , ethylaminomethyl ; and 2- (ethylamino) ethyl .
- the compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
- These compounds can be, for example, racemates or optically active forms.
- the single enantiomers, i.e., optically active forms can be obtained by asymmetric synthesis 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.
- Representative compounds of the present invention, which are encompassed by Formula I include, but are not limited to the compounds described in the Examples and their pharmaceutically acceptable acid addition salts.
- the free base can be obtained by basifying a solution of the acid salt.
- an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds .
- Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH 2 ) n-COOH where n is 0-4, and the like.
- acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOC- (CH 2 ) n-COOH where n is 0-4, and the like.
- the present invention also encompasses the acylated prodrugs of the compounds of Formula I.
- acylated prodrugs of the compounds of Formula I Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I .
- Selective agonists or antagonists of the bradykinin B 2 receptor provide compounds useful in treatment of renal diseases, heart failure, hypertension, Meniere's disease, vaginal inflammation and pain, peripheral circulatory disorders, climacteric disturbance, retinochoroidal circulatroy disorders, myocardial ischemia, myocardial infarction, postmyocardial infarction syndrome, angina pectoris, restenosis after percutaneous transluminal coronary angioplasty, hepatitis, liver cirrhosis, pancreatitis, ileus, diabetes, diabetic complications, male infertility or glaucoma, or for the increase of permeability of blood-brain barrier, pain, asthma, rhinitis.
- the invention provides methods of treating patients suffering from such disorders with an amount of a compound of the invention sufficient to reduce the symptoms of the disorder.
- Bradykinin has been shown to increase the permeability of blood-brain barrier and blood-brain tumor barrier.
- the invention provides a method of increasing the brain concentration of a CNS active compound which comprises administering to a patient in need of such treatment a compound of the invention, that is a selective agonist of the BK-2 receptor, along with a CNS active compound, and thereby increasing the brain concentration of the CNS active compound.
- the invention provides a method of increasing the brain concentration of anti-cancer and anti-tumor agents which comprises administering a patient suffering from brain cancer or a brain tumor a compound of the invention that is a selective agonist of the BK-2 receptor, along with an anti- cancer and anti-tumor agent, and thereby increasing the brain concentration of the anti-cancer or anti-tumor agent.
- the compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles .
- parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
- a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier.
- One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
- the pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
- compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
- Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets .
- excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for e ' xample starch, gelatin or acacia, and lubricating agents, for example 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.
- 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 is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- water or an oil medium for example peanut oil, liquid paraffin or olive oil.
- Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol , or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoole
- the aqueous suspensions may also contain 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, for example 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, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations.
- compositions 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, for example sweetening, flavoring and coloring agents, may also be present.
- compositions of the invention may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
- Suitable emulsifying agents may " be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate.
- the emulsions may also contain sweetening and flavoring agents.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1, 3-butanediol .
- Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono-or diglycerides .
- fatty acids such as oleic acid find use in the preparation of injectables .
- the compounds of general Formula I may also be administered in the form of suppositories for rectal administration of the drug.
- These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- Such materials are cocoa butter and polyethylene glycols.
- Compounds of general Formula I may be administered parenterally in a sterile medium.
- the drug depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
- adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
- Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day) .
- 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.
- Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of chronic conditions, a dosage regimen of 1 or 2 times daily is particularly preferred. For the treatment of acute disorders, a single dose that rapidly reaches effective concentrations is desirable. 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 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, low toxicity, low serum protein binding and desirable in vitro and in vivo half- lifes. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat periphereal disorders are often preferred. Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers . Toxicity to cultured hepatocyctes may be used to predict compound toxicity.
- Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously.
- Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcova, et al. (Journal of Chromatography B ⁇ (1996) volume 677, pages 1-27) .
- Compound half-life is inversely proportional to the frequency of dosage of a compound.
- In vitro half-lifes of compounds may be predicted from assays of microsomal half- life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127) .
- the present invention also pertains to packaged pharmaceutical compositions for treating disorders responsive to BK-2 receptor modulation, e.g., treatment asthma, pain or rhinitis by BK-2 receptor modulation.
- the packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one BK-2 receptor modulator as described supra and instructions for using the treating disorder responsive to BK-2 receptor modulation in the patient.
- the present invention also pertains to methods of inhibiting the binding of bradykinin to the BK-2 receptor which methods involve contacting a compound of the invention with cells expressing BK-2 receptors, wherein the compound is present at a concentration sufficient to inhibit bradykinin binding to cells expressing a cloned human Bradykinin receptor in vitro and to methods for altering the signal- tranducing activity of BK-2 receptors, said method comprising exposing cells expressing such receptor to an effective amount of a compound of the invention.
- the invention furthermore provides methods of using compounds of this invention as positive controls in assays for receptor activity and using appropriately labeled compounds of the invention as probes for the localization of receptors, particularly BK-2 receptors, in tissue sections. Such probes are useful for in vitro studies, such as binding assays and autoradiography of tissue sections and for in vivo techniques such as PET and SPECT scans .
- the invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in hem.
- the starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available organic compounds, or prepared using well known synthetic methods . Representative examples of methods for preparing intermediates of the invention are set forth below.
- the reaction solution is dilluted with 300 mL of ethyl acetate and then washed with 2 X 60 mL water, 1 X 60 mL sat. NaHC0 3 , and 1 X 60 mL of brine.
- the resulting organic layer is dried over anhydrous Na 2 S0 4 and the solvent removed in vacuo.
- the residue is treated with 150 mL of methanol and 1.1 g of NaOR at reflux for 2 hours and then allowed to cool to room temperature for 2 hours.
- the resulting solution is evaporated under reduced pressure and partioned between ethyl acetate 200 mL and water 100 mL.
- the solution is evaporated under reduced pressure, the residue is diluted with 30 mL of ethyl acetate, washed with 2 X 10 mL water and 1 X 10 mL brine, dried over anhydrous Na 2 S0 4 and the solvent is removed in vacuo.
- the residue is dissolved in anhydrous 1-methyl-2-pyrrolidinone at 100 mg/ mL and 1 mL of the solution is treated with an excess of N- methyl piperazine at 50 °C for 16 hr.
- the resulting solution is cooled to room temperature, washed with 3 X ImL water and 1 X 1 mL brine, dried over anhydrous Na 2 S0 4 and the solvent is removed in vacuo.
- This assay is a standard assay of BK-2 receptor binding, and is used to determine the high affinity of compounds of this invention for the BK-2 (bradykinin B 2 ) receptor.
- Binding Buffer 50mM Tris, pH 7.0 (4 °C) , 0.14 grams per liter bacitracin (approx. 50,000 units of activity/liter, lot# 103746 from Amersham) , and 10 "6 M captopril.
- Ligand Preparation 0.25 nM 3 H-Bradykinin is used. 10 ⁇ l of stock + 100 nnl of binding buffer gives approximately 600 cpm / 5 ul aliquot.
- Baculovirus-infected S_f9 cells expressing recombinant human bradykinin B 2 receptors are harvested 48 hours post infection via centrifugation at 3000 x g. Cells are washed with ice-cold PBS and stored at -70 °C until needed. Frozen cell pellets are resuspended in ice cold Washing Buffer (50mM Tris pH 7.0) and homogenized via POLYTRON for 30 seconds at setting 5. Membranes are centrifuged at 40,000 x g for 10 min. Pellets are resuspended in Washing Buffer with the aid of a polytron and centrifuged again. Membranes are resuspended in binding buffer at a concentration of 133 ⁇ g/ml . This corresponds to 20 ⁇ g of protein per 150 ⁇ l .
- incubations When measuring non-specific binding, incubations contain 150 ⁇ l of Sf9 cell membranes prepared as described above, 50 ⁇ l 3 H-Bradykinin (0.25 nM) , 25 ⁇ l unlabeled bradykinin at 1 ⁇ M final concentration and 2 ⁇ l DMSO. Incubations for determining test compound binding contain 175 ⁇ l of S-f9 cell membranes, 50 ⁇ l 3 H-Bradykinin (0.25 nM) , and test compound in 2 ⁇ l DMSO. The concentration of the test compound is generally 1 ⁇ M for displacement studies. The binding reaction components are incubated for 2 hrs at 4 °C in Falcon U bottom plates .
- compounds of the invention have Ki's of less than 1 uM, preferred compounds of the invention exhibit Ki values of less than 500 nM and more preferred compounds of the invention exhibit Ki values of less than 100 nM.
- the agonist and antagonist properties of the compounds of the invention can be evaluated by the following assay.
- Forty-eight hours prior to assay the cell growth media is replaced with another medium that does not contain the tetracycline.
- Twenty-four hours prior to experiment sodium butyrate is added to a final concentration of 10 mM.
- Agonist-induced (bradykinin) calcium mobilization is monitored using either Fluoroskan Ascent (Labsystems) or FLIPR (Molecular Devices) instruments.
- the agonists either bradykinin or drug candidates, are added to the cells and fluorescence responses are continuously recorded for up to 5 min.
- compounds at a concentration of 1 uM in DMSO, are preincubated with the cells for up to 30 minutes prior to administration of the bradykinin agonist .
- Bradykinin agonist is generally applied at a concentration suffiencient to induce 50% maximal activity. Responses are recorded for up to 5 min.
- y is the maximum fluorescence signal
- x is the concentration of the agonist or antagonist
- a is the Emax
- b corresponds to the EC 50 or IC 50 value
- c is the Hill coefficient.
- the compounds of the invention are prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope.
- the radioisotope is preferably selected from of at least one of carbon (preferably 14 C) , hydrogen (preferably 3 H) , sulfur (preferably 35 S) , or iodine (preferably 125 I) .
- Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds. Such suppliers include Amersham Corporation, Arlington Heights, IL; Cambridge Isotope Laboratories, Inc.
- Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the compound of the invention as substrate. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate.
- Example 8 Use of compounds of the invention as probes for BK-2 receptors in cultured cells and tissue samples
- the presence of BK-2 receptors in cultured cells or tissue samples may be ascertained by the procedures described by Hall and Morton in the chapter entitled "Immunopharmacology of the Bradykinin Receptor” of The Handbook of Immunopharmacology - The Kinin Systems (1997) Academic Press, S.C. Farmer, editor, using radiolabeled compounds of the invention prepared as described in the preceding Example 7.
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00919946A EP1165518A2 (en) | 1999-04-02 | 2000-03-31 | Benzimidazole and imidazolopyridine derivatives, their preparation and their use as selective modulators of bradykinin b2 (= bk-2) receptors |
AU40553/00A AU4055300A (en) | 1999-04-02 | 2000-03-31 | Aryl and heteroaryl fused aminoalkyl-imidazole derivatives: selective modulators of Bradykinin B2 receptors |
CA002369544A CA2369544A1 (en) | 1999-04-02 | 2000-03-31 | Aryl and heteroaryl fused aminoalkyl-imidazole derivatives:selective modulators of bradykinin b2 receptors |
JP2000609398A JP2002541145A (en) | 1999-04-02 | 2000-03-31 | Aryl and heteroaryl fused aminoalkyl-imidazole derivatives: Bradykinin B2 receptor selective modulators |
Applications Claiming Priority (4)
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US12750599P | 1999-04-02 | 1999-04-02 | |
US28532799A | 1999-04-02 | 1999-04-02 | |
US60/127,505 | 1999-04-02 | ||
US09/285,327 | 1999-04-02 |
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WO2000059886A2 true WO2000059886A2 (en) | 2000-10-12 |
WO2000059886A3 WO2000059886A3 (en) | 2001-09-13 |
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PCT/US2000/008568 WO2000059886A2 (en) | 1999-04-02 | 2000-03-31 | Benzimidazole abd imidazolophyridine derivaties, their preparation and their use as selective modulators of bradykinin b2 (=bk-2) receptors |
Country Status (5)
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EP (1) | EP1165518A2 (en) |
JP (1) | JP2002541145A (en) |
AU (1) | AU4055300A (en) |
CA (1) | CA2369544A1 (en) |
WO (1) | WO2000059886A2 (en) |
Cited By (9)
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WO2001056995A1 (en) * | 2000-01-18 | 2001-08-09 | Nuerogen Corporation | Substituted imidazoles as selective modulators of bradykinin b2 receptors |
WO2002028839A1 (en) * | 2000-10-06 | 2002-04-11 | Neurogen Corporation | Benzimidazole and indole derivatives as crf receptor modulators |
WO2003006438A1 (en) * | 2001-07-09 | 2003-01-23 | Schering Aktiengesellschaft | Benzimidazole derivatives for treating microglia-activation associated diseases such as inflammatory, allergic, infectious or autoimmune diseases |
WO2005042497A2 (en) | 2003-10-28 | 2005-05-12 | Vertex Pharmaceuticals, Incorporated | Benzimidazoles useful as modulators of ion channels |
US6903126B2 (en) | 2001-07-09 | 2005-06-07 | Schering Ag | 1-Aryl-2-N-, S- or O-substituted benzimidazole derivatives, their use for the production of pharmaceutical agents as well as pharmaceutical preparations that contain these derivatives |
US6906075B2 (en) | 2002-01-10 | 2005-06-14 | Neurogen Corp. | Melanin concentrating hormone receptor ligands: substituted benzoimidazole analogues |
US6916819B2 (en) | 2000-12-21 | 2005-07-12 | Neurogen Corporation | Benzimidazole and pyridylimidazole derivatives |
WO2010089084A1 (en) * | 2009-02-04 | 2010-08-12 | Grünenthal GmbH | Substituted indole compounds as bradykinin receptor 1 modulators |
CN113906020A (en) * | 2019-05-23 | 2022-01-07 | 法瓦里斯有限责任公司 | (R) -3- (chloro-5-fluoro-2- ((4- (1H-pyrazol-1-yl) -2-methylquinolin-8-yloxy) methyl) phenyl) morpholine derivatives and related compounds as Bradykinin (BK) B2 receptor antagonists for the treatment of skin disorders |
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WO1997011069A1 (en) * | 1995-09-18 | 1997-03-27 | Fujisawa Pharmaceutical Co., Ltd. | Heterocyclic compounds as bradykinin antagonists |
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WO2000059887A1 (en) * | 1999-04-02 | 2000-10-12 | Neurogen Corporation | Aryl and heteroaryl fused aminoalkyl-imidazole derivatives and their use as antidiabetics |
-
2000
- 2000-03-31 JP JP2000609398A patent/JP2002541145A/en active Pending
- 2000-03-31 EP EP00919946A patent/EP1165518A2/en not_active Withdrawn
- 2000-03-31 AU AU40553/00A patent/AU4055300A/en not_active Abandoned
- 2000-03-31 WO PCT/US2000/008568 patent/WO2000059886A2/en not_active Application Discontinuation
- 2000-03-31 CA CA002369544A patent/CA2369544A1/en not_active Abandoned
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Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
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US6509366B2 (en) | 2000-01-18 | 2003-01-21 | Neurogen Corporation | Substituted imidazoles as selective modulators of Bradykinin B2 receptors |
WO2001056995A1 (en) * | 2000-01-18 | 2001-08-09 | Nuerogen Corporation | Substituted imidazoles as selective modulators of bradykinin b2 receptors |
WO2002028839A1 (en) * | 2000-10-06 | 2002-04-11 | Neurogen Corporation | Benzimidazole and indole derivatives as crf receptor modulators |
US7300945B2 (en) | 2000-12-21 | 2007-11-27 | Neurogen Corporation | Benzimidazole and pyridylimidazole derivatives |
US6916819B2 (en) | 2000-12-21 | 2005-07-12 | Neurogen Corporation | Benzimidazole and pyridylimidazole derivatives |
US7196202B2 (en) | 2001-07-09 | 2007-03-27 | Schering Ag | 1-aryl-2-N-, S- or O-substituted benzimidazole derivatives, their use for the production of pharmaceutical agents as well as pharmaceutical preparations that contain these derivatives |
WO2003006438A1 (en) * | 2001-07-09 | 2003-01-23 | Schering Aktiengesellschaft | Benzimidazole derivatives for treating microglia-activation associated diseases such as inflammatory, allergic, infectious or autoimmune diseases |
US6903126B2 (en) | 2001-07-09 | 2005-06-07 | Schering Ag | 1-Aryl-2-N-, S- or O-substituted benzimidazole derivatives, their use for the production of pharmaceutical agents as well as pharmaceutical preparations that contain these derivatives |
US6906075B2 (en) | 2002-01-10 | 2005-06-14 | Neurogen Corp. | Melanin concentrating hormone receptor ligands: substituted benzoimidazole analogues |
WO2005042497A3 (en) * | 2003-10-28 | 2005-07-21 | Vertex Pharma | Benzimidazoles useful as modulators of ion channels |
WO2005042497A2 (en) | 2003-10-28 | 2005-05-12 | Vertex Pharmaceuticals, Incorporated | Benzimidazoles useful as modulators of ion channels |
US7309716B2 (en) | 2003-10-28 | 2007-12-18 | Vertex Pharmaceuticals Incorporated | Benzimidazoles useful as modulators of ion channels |
US7705031B2 (en) | 2003-10-28 | 2010-04-27 | Vertex Pharmaceuticals Incorporated | Benzimidazoles useful as modulators of ion channels |
WO2010089084A1 (en) * | 2009-02-04 | 2010-08-12 | Grünenthal GmbH | Substituted indole compounds as bradykinin receptor 1 modulators |
US8492559B2 (en) | 2009-02-04 | 2013-07-23 | Gruenenthal Gmbh | Substituted indole compounds |
CN113906020A (en) * | 2019-05-23 | 2022-01-07 | 法瓦里斯有限责任公司 | (R) -3- (chloro-5-fluoro-2- ((4- (1H-pyrazol-1-yl) -2-methylquinolin-8-yloxy) methyl) phenyl) morpholine derivatives and related compounds as Bradykinin (BK) B2 receptor antagonists for the treatment of skin disorders |
CN113906020B (en) * | 2019-05-23 | 2024-03-12 | 法瓦里斯有限责任公司 | Cyclic bradykinin B2 receptor antagonists |
Also Published As
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EP1165518A2 (en) | 2002-01-02 |
WO2000059886A3 (en) | 2001-09-13 |
AU4055300A (en) | 2000-10-23 |
CA2369544A1 (en) | 2000-10-12 |
JP2002541145A (en) | 2002-12-03 |
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