Substituted imidazoles as selective modulators of bradykinin B2 receptors

FIELD OF THE INVENTION

[0002] This invention relates to certain imidazoles which, when appropriately substituted, are selective modulators of Bradykinin B2 receptors (BK-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.

BACKGROUND

[0003] Bradykinin (BK), a nonapeptide, and the closely related decapeptide kallidin (Lys-BK), are produced by proteolytic cleavage of high molecular weight kininogen by plasma kallikreins. The effects of bradykinin and kallidin are mediated by specific seven transmembrane G-protein coupled receptors.

[0004] The existence of two bradykinin receptor subtypes has been unequivocally confirmed within the last six years. The expression and cloning of a rat bradykinin receptor, now known to be a BK-2 receptor, was first reported followed by the cloning and pharmacological characterization of a human BK-2 receptor. The expression and cloning of a human bradykinin (B1) receptor has also been described.

[0005] Both BK and kallidin activate the B2 receptor while only kallidin is active at the B1 receptor. However, both compounds are rapidly cleaved to produce B1 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 Central Nervous System (CNS).

[0006] The B2 receptor is expressed constitutively in a variety of tissues and accounts for the majority of the acute pharmacological effects of bradykinin. The B1 receptor is inducibly expressed and appears to act predominantly in pathophysiological conditions. The BK-1 receptor has been especially implicated in persistent hyperalgesia and chronic inflammation.

[0007] Bradykinin is an effector of a number of inflammatory responses including bronchoconstriction, plasma extravasation, release of prostaglandins/leukotrienes, smooth muscle contraction/relaxation and nociception. Bradykinin and the related peptide kallidin have been implicated in a number of disease conditions, including but not limited to pain, rhinitis, anaphylaxis, inflammatory bowel disease, vascular permeability, algesia, vasodilataion, inflammatory response, hypotension associated with sepsis, bronchopulmonary disorders including asthma, and increased cell proliferation. Antagonists of the BK-2 receptor are useful in treating these conditions. Additionally bradykinin has been implicated in increased glucose uptake, and decreased blood glucose concentration. Therefore agonists of the BK-2 receptor may be useful in the treatment of Type II diabetes. An increased permeability of the blood-brain barrier due to bradykinin has also been reported. Thus, agonists of the BK-2 receptor may 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 B2 (BK-2) receptor as agonists or antagonists would have considerable therapeutic benefit.

[0008] A number of tissues and cultured cell lines have 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.). Although 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. Also 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.

DESCRIPTION OF THE RELATED ART

[0009] Various compounds have been prepared as modulators of BK-2 receptors. The following disclose non-peptidic compounds that modulate Bradykinin B2 receptors: EP-622361-A1, WO 98/42672, WO 97/41104, WO 97/28153, WO 96/13485, EP-596406-A1, EP-835659-A1, EP-808-838-A1, EP-796-848-A1, WO 98/03503, WO 97/24349, U.S. Pat. No. 5,438,064, U.S. Pat. No. 5,216,165, U.S. Pat. No. 5,212,182, WO 97/30048, EP 790239-A1, U.S. Pat. No. 5,510,380 and U.S. Pat. No. 5,817,756.

[0010] The compounds most closely related structurally to those of the present invention are a series of 2-[(methylamino)methyl]-4,5-dialkyl-1H-imidazoles described as vitronectin receptor antagonists and disclosed in international patent applications WO 99/06049 and WO 97/24119. These compounds are also discussed by Keenan et. al. (Bioorg. Med. Chem. Lett. (1998), 9(22): 3165-3170) and by Reader (Synlett (1998), (10): 1077-1078). The compounds described in these publications are not disclosed as bradykinin antagonists and they are not contained in the present invention.

SUMMARY OF THE INVENTION

[0011] This invention provides novel compounds of Formula I (shown below) and pharmaceutical compositions comprising compounds of Formula I. Such compounds exhibit high selectivity for bradykinin B2 receptors. Compounds of Formula I also bind with high affinity to these receptors.

[0012] 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.

[0013] In a separate aspect, 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.

[0014] A broad aspect of the invention is directed to compounds of Formula I:

[0015] or the pharmaceutically acceptable non-toxic salts thereof wherein:

[0016] R1 is arylalkyl, preferably benzyl (with the proviso that R1 may not be 3-Fluorobenzyl), heteroarylalkyl preferably quinolinylmethyl or picolyl, or allyl, each of which which is optionally substituted directly or through a O(CH2)n linker (where n=1, 2, 3 or 4) with up to three substituents independently selected from:

[0017] (i) halogen (with the proviso that R1 may not be 3-Fluorobenzyl), nitro, trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, C1-C6 alkyl, amino, C1-C6 alkoxy, aminomethyl, mono or di(C1-C6)alkylamino, mono or dialkylaminomethyl, (wherein each alkyl is independently lower (C1-C6) alkyl),

[0018] (ii) C1-C6alkoxyNR8R9, NR8R9, NR8COR9, CONR8R9,

[0019] wherein R8 and R9 are the same or different and represent hydrogen, straight or branched chain lower alkyl, or R8 and R9 form a 5, 6, or 7 membered heterocyclic ring, which is optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C1-C6 alkyl, amino, mono or di(C1-C6)alkylamino, or C1-C6 alkoxy,

[0020] (iii) O(CH2)nCO2RA wherein n=1, 2, 3, 4, CORA, and CO2RA,

[0021] wherein RA represents hydrogen, or straight or branched chain lower alkyl,

[0022] (iv) SO2RA, NHSO2RA, SO2NHRA, SO2NHCORA, CONHSO2RA,

[0023] wherein RA represents hydrogen, or straight or branched chain lower alkyl,

[0024] (v) tetrazole, triazole, imidazole, thiazole, oxazole, thiophene, and pyridyl;

[0025] R2 and R3 are the same or different and represent

[0026] (i) halogen, trifluoromethyl, trifluoromethoxy, lower alkoxy having 1-6 carbon atoms, lower alkyl, amino methyl, mono or dialkylaminomethyl, wherein each alkyl is independently lower (C1-C6) alkyl,

[0027] (ii) C1-C6alkoxyNR8′R9′, NR8′R9′, CONR8′R9′, NR8′COR9′, wherein R8′ and R9′ are the same or different and represent hydrogen or straight or branched chain lower alkyl, or R8′ and R9′ is a 5, 6, or 7 membered heterocyclic ring, optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C1-C6 alkyl, amino, mono or di(C1-C6)alkylamino, or C1-C6 alkoxy,

[0028] (iii) O(CH2)nCO2RA′ where n=1, 2, 3, 4, CORA′, or CO2RA′,

[0029] wherein RA′ represents hydrogen or straight or branched chain lower alkyl; or

[0030] R2 and R3 may be taken together to form a carbocyclic or heterocyclic saturated ring;

[0031] R4 represents straight or branched chain lower alkyl;

[0032] R5 represents halogen or trifluoromethyl;

[0033] R6, R7 and R7′ are the same or different and represent

[0034] (i) hydrogen, trifluoromethyl, trifluoromethoxy, nitrile, C1-C10 alkyl, C1-C10 alkoxy (with the proviso that R6, R7, or R7′ may not be C1-C10 alkoxy when located ortho to Y), C1-C6alkylthio, halogen, aminomethyl, di(C1-C6)alkylamino, mono or diC1-C6alkylaminomethyl, or

[0035] (ii) C1-C6 alkoxyaminoalkyl where the amino is mono or disubstituted with straight or branched chain lower alkyl;

[0036] (iii) or any two adjacent R6, R7 or R7′ may be joined to form a 5 to 7 membered ring containing 1 or 2 oxygen atoms where the remaining ring members are carbon; or

[0037] R5 and R6 are joined to form a 5, 6, or 7 membered carbocyclic or heterocyclic aromatic ring which is optionally substituted with up to four substituents selected from:

[0038] (i) halogen, nitro, trifluoromethyl, cyano, hydroxyl, C1-C6 alkyl, amino, C1-C6 alkoxy, aminomethyl, alkylaminomethyl, mono or di(C1-C6)alkylamino, mono or dialkylaminomethyl, wherein each alkyl is independently lower (C1-C6) alkyl,

[0039] (ii) C1-C6alkoxyNR8″R9″, NR8″R9″, CONR8″R9″, NR8″COR9″, where R8″ and R9″ are the same or different and represent hydrogen or straight or branched chain lower alkyl, or R8″ and R9″ can be a 5, 6, or 7 membered heterocyclic ring, which is optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, lower alkyl, amino, mono or di(C1-C6)alkylamino, or C1-C6 alkoxy,

[0040] (iii) O(CH2)nCO2RA″ where n=1, 2, 3, 4, CORA″, or CO2RA″, wherein RA″ represents hydrogen or straight or branched chain lower alkyl; and R7 and R7′ are as defined above; and

[0041] Y represents a bond or CH2, when Y=CH2 it may be mono or disubstituted with a straight or branched chain lower alkyl, or straight or branched chain lower alkoxy having 1-6 carbon atoms.

DETAILED DESCRIPTION OF THE INVENTION

[0042] The novel compounds of Formula I may be comprised of compounds of general Formula Ia:

[0043] or the pharmaceutically acceptable non-toxic salts thereof wherein: R1, R2, R3, R4, and Y are as defined above;

[0044] R5 represents halogen, hydrogen, or trifluoromethyl; and

[0045] R6, R7 and R7′ are the same or different and represent hydrogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, lower alkyl having 1-10 carbon atoms, C1-C10 alkoxy (with the proviso that R6, R7, or R7′ may not be C1-C10 alkoxy when located ortho to Y in Formula Ia), halogen, aminomethyl, mono or dialkylaminomethyl where each alkyl is independently lower (C1-C6) alkyl, and C1-C6 alkoxyaminoalkyl where the amino is mono or disubstituted with straight or branched chain lower alkyl having 1-6 carbon atoms.

[0046] Preferred compounds of the invention are comprised of compounds of Formula I or Formula Ia, and the pharmaceutically acceptable salts thereof, wherein R1, R4, R5, R6, R7, R7′ and Y are as defined for Formula I or Formula Ia with the restriction that R2 and R3 do not form a carbocyclic or heterocyclic ring.

[0047] Other novel compounds of Formula I may be comprised of compounds of general Formula Ib:

[0048] or the pharmaceutically acceptable non-toxic salts thereof wherein: R1, R2, R3, R4, and Y are as defined above;

[0049] R5 is part of an aromatic ring formed with R6;

[0050] R6 is part of an 5, 6, or 7 membered aromatic ring which is optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C1-C6 alkyl, amino, or mono or di(C1-C6)alkylamino, C1-C6 alkoxy, aminomethyl, alkylaminomethyl or mono or dialkylaminomethyl where each alkyl is independently lower (C1-C6) alkyl, C1-C6 alkoxyaminoalkyl (for example OCH2CH2NR8″R9″), NR8″R9″, CONR8″R9″, NR8″COR9″, where R8″ and R9″ are the same or different and represent hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms, additionally R8″ and R9″ can be a 5, 6, or 7 membered heterocyclic ring, which may be optionally substituted with halogen, nitro, trifluoromethyl, cyano, hydroxyl, C1-C6 alkyl, amino, mono or di(C1-C6)alkylamino, or C1-C6 alkoxy;

[0051] O(CH2)nCO2R8″ where n=1, 2, 3, 4, COR8″, or CO2R8″, where R8″ represents hydrogen or straight or branched chain lower alkyl having 1-6 carbon atoms; and

[0052] R7 and R7′ represent hydrogen, trifluoromethyl, trifluoromethoxy, cyano or nitro, lower alkyl having 1-10 carbon atoms, C1-C10 alkoxy (with the proviso that R6, R7, or R7′ may not be C1-C10 alkoxy when located ortho to Y in Formula Ib), halogen, aminomethyl, mono or dialkylaminomethyl where each alkyl is independently lower (C1-C6) alkyl, or C1-C6 alkoxyaminoalkyl where the amino is mono or disubstituted with straight or branched chain lower alkyl having 1-6 carbon atoms.

[0053] Preferred compounds of Formula Ib include those compound in which R1, R4, R5, R6, R7, and R7′ are as defined for Formula Ib and R2 and R3 are defined as for Formula Ib with the restriction that R2 and R3 do not form a ring.

[0054] One preferred embodiment of the present invention encompasses compounds of Formula II and the pharmaceutically acceptable salts thereof;

[0055] wherein R1 and R4 are as defined above.

[0056] In a more preferred embodiment the invention encompasses compounds of Formula II and the pharmaceutically acceptable salts thereof wherein R4 is isoamyl or n-pentyl, and R1 is as defined above.

[0057] In another preferred embodiment, the present invention encompasses compounds of Formula III, and the pharmaceutically acceptable salts thereof;

[0058] wherein R1 and R4 are as defined above.

[0059] In a more preferred embodiment the invention encompasses compounds of Formula III and the pharmaceutically acceptable salts thereof wherein R4 is iso amyl or n-pentyl, and R1 is as defined above.

[0060] In certain situations, 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. In these situations, 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.

[0061] 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. In addition, if the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, 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.

[0062] 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—(CH2)n—COOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.

[0063] The present invention also encompasses the 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.

[0064] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R*, then said group may optionally be substituted with up to two R* groups and R* at each occurrence is selected independently from the definition of R*. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[0065] The term “aryl” in the present invention means a monocyclic or bicyclic aromatic group having preferably 6 to 10 carbon atoms, such as, for example, phenyl or naphthyl.

[0066] By “arylalkyl” or “heteroarylalkyl” in the present invention is meant a branched or straight-chain alkyl group having from 1 to about 6 carbon atoms and substituted on one of the carbon atoms by an optionally substituted aryl or heteroaryl ring, such as, for example, benzyl, phenethyl, methylpyridyl, ethylpyridyl, and the like.

[0067] By “alkyl” in the present invention is meant C1-C10 alkyl, i.e., straight or branched chain alkyl groups having 1-10 carbon atoms, preferably 1-6 carbon atoms (C1-C6 alkyl), such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. Preferred C1-C10 alkyl groups are methyl, ethyl, propyl, butyl, cyclopropyl or cyclopropylmethyl.

[0068] By “lower alkyl” in the present invention is meant C1-C6 alkyl, i.e., straight or branched chain alkyl groups having 1-6 carbon atoms.

[0069] By “alkoxy” or “lower alkoxy” in the present invention is meant C1-C6 alkoxy, i.e., 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-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

[0070] By “halogen” in the present invention is meant fluorine, bromine, chlorine, and iodine.

[0071] By “(hetero) cyclic ring” is meant a ring that is either aliphatic or aromatic and optionally contains at least one hetero atom. Hetero atoms include nitrogen, sulfur, and oxygen. Examples of such (hetero) cyclic rings are cyclohexyl, cyclopentyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, etc.

[0072] By “heteroaryl” (aromatic heterocycle) in the present invention is meant one or more aromatic ring systems of 5-, 6-, or 7-membered rings containing at least one and up to four hetero atoms selected from nitrogen, oxygen, or sulfur. Such heteroaryl groups include, for example, thienyl, furanyl, thiazolyl, imidazolyl, (is)oxazolyl, pyridyl, pyrimidinyl, imidazolyl, (iso)quinolinyl, naphthyridinyl, benzimidazolyl, and benzoxazolyl.

[0073] Specific examples of heteroaryl groups are the following:

[0074] wherein:

[0075] L is nitrogen or —CR11;

[0076] T is —NR19, oxygen, or sulfur;

[0077] R11 and R11′ are the same or different and are selected from: hydrogen, halogen, hydroxy, C1-C6 alkyl, (C1-C6)alkoxy, amino, or mono- or di(C1-C6)alkylamino;

[0078] R12, R12′, and R13 are the same or different and are selected from hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, amino, mono- or di(C1-C6)alkylamino, hydroxy, or trifluoromethyl; and

[0079] R19 is hydrogen, or lower alkyl having 1-6 carbon atoms.

[0080] The structure of Formula I as shown in the specification and as used in the claims includes all possible tautomers and rotamers.

[0081] The invention also provides pharmaceutical composition comprising compounds of the invention.

[0082] The invention also provides packaged pharmaceutical compositions comprising pharmaceutical compositions of the invention in a container and instructions for using the composition to treat a patient in need thereof. In one embodiment, the instructions are for using the composition for treating a patient suffering from a physiological disorder associated with an excess of or insufficient amount of bradykinin. The patient may be suffering, for example, from renal disease, heart failure, hypertension, Meniere's disease, vaginal inflammation and pain, peripheral circulatory disorders, climacteric disturbance, retinochoroidal circulatory 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, asthma, rhinitis, brain cancer, or a brain tumor.

[0083] The invention further provides methods of treating patients in suffering from an inflammatory disorder with an amount of a compound of the invention sufficient to alter the symptoms of the inflammatory disorder. Inflammatory disorders that may be treated with a selective antagonist of the BK-2 receptor include restenosis after percutaneous transluminal coronary angioplasty, rhinitis, inflammation associated with brain trauma, stroke, sepsis, anaphylaxis, Meniere's disease, pancreatitis, ileus, inflammatory bowel disease, and bronchopulmonary disorders including asthma. The invention also provides methods of treating patients suffering from pain with a pain-reducing amount of a compound of the invention. Painful conditions that may be treated with an antagonist of the BK-2 receptor, include, but are not limited to inflammatory pain, postoperative pain, and vaginal inflammation and pain. The invention further provides a method of treating patients suffering from hypertension with an amount of compound of the invention sufficient to reduce blood pressure. Selective antagonists of the BK-2 receptor are useful as anti-hypertensives.

[0084] In a further aspect the invention provide a method of treating a patient suffering from Type II (adult-onset) diabetes with an amount of a compound of the invention sufficient to alter the symptoms. Selective agonists of the BK-2 receptor are useful for treating type II diabetes. The invention also provides methods of treating patients suffering from circulatory or cardiovascular disorders with an amount of a compound of the invention, that is a selective agonist of the BK-2 receptor, sufficient to reduce the symptoms of the circulatory of cardiovascular disorder. Such circulatory or cardiovascular disorders include, but are not limited to heart failure, peripheral circulatory disorders, myocardial infarction, postmyocardial infarction syndrome, angina pectoris, retinochoroidal circulatory disorders, and myocardial ischemia. Selective agonists of the BK-2 stimulate NO release and as such are useful for treating climacteric disturbance and male infertility. 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 disorder.

[0085] 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 compounds which comprises administering 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. In a particularly preferred embodiment 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 a anti-cancer and anti-tumor agent, and thereby increasing the brain concentration of the anti-cancer or anti-tumor agent.

[0086] Patients include human and non-human animals, such as domestic pets and farm animals (for example, dogs, cats, swine, sheep, horses, cattle, etc.).

[0087] The present invention also pertains to methods of inhibiting the binding of bradykinin to the bradykinin receptors, especially BK-2 receptors which methods involve contacting a compound of the invention with cells expressing bradykinon receptors, (preferably BK-2 receptors) wherein the compound is present at a concentration sufficient to inhibit the binding of bradykinin to bradykinin receptors in vitro. This method includes inhibiting the binding of bradykinin to bradykinin receptors in vivo, e.g., in a patient given an amount of a compound of formula I or any of the subformulae thereof, that would be sufficient to inhibit the binding of bradykinon to BK-2 receptors in vitro. The amount of a compound that would be sufficient to inhibit the binding bradykinin to the BK-2 receptor may be readily determined via a BK-2 receptor binding assay, such as the assay described in Example 8. The BK-2 receptors used to determine in vitro binding may be obtained from a variety of sources, for example from preparations of rat brain or from cells expressing cloned human BK-2 receptors.

[0088] The present invention also pertains to methods for altering the signal-transducing activity of bradykinin receptors, said method comprising exposing cells expressing such receptors to an effective amount of a compound of the invention. This method includes altering the signal-transducing activity of BK-2 receptors in vivo, e.g., in a patient given an amount of a compound of formula I, or the subformulae thereof, that would be sufficient to alter the signal-transducing activity of BK-2 receptors in vitro. The amount of a compound that would be sufficient to alter the signal-transducing activity of bradykinin receptors may be determined via a bradykinin receptor signal transduction assay, such as the assay described in Example 9. The bradykinin receptor ligands (i.e. the compounds of the invention) provided by this invention and labeled derivatives thereof are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the BK-2 receptor.

[0089] Isotopically-labeled compounds of this invention, which are identical to those recited in formula I, or the subformulae thereof, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature, are also useful for mapping the location of bradykinin receptors (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 such receptors in living subjects. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. In addition, substitution with heavy isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of formula Ia, or the subformulae thereof, of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

Pharmaceutical Preparations

[0090] 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. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like. In addition, there is provided 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.

[0091] 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 preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These 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 example 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. In some cases such coatings may be prepared by known techniques so as 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.

[0092] 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.

[0093] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such 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 monooleate. 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.

[0094] 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 and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

[0095] 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.

[0096] Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil or a mineral oil 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.

[0097] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose 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 that 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0098] The compounds of general Formula I may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These 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. Such materials are cocoa butter and polyethylene glycols.

[0099] 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. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

[0100] 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.

[0101] 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.

[0102] 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-lives. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat peripheral disorders are often preferred.

[0103] 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 hepatocytes 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.

[0104] Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcová, et al. (Journal of Chromatography B 1996, 677, 1-27).

[0105] Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition 1998, 26, 1120-1127).

[0106] As discussed above, preferred compounds of the invention exhibit good activity in in vitro Bradykinin receptor binding assays, especially BK-2 receptor binding assays, and specifically the assay as specified in Example 8, which follows. References herein to “in vitro BK-2 receptor binding assay” are intended to refer to that protocol as defined in Example 8 which follows.

[0107] For administration to non-human animals, the composition may also be added to the animal feed or drinking water. It will be convenient to formulate these animal feed and drinking water compositions so that the animal takes in an appropriate quantity of the composition along with its diet. It will also be convenient to present the composition as a premix for addition to the feed or drinking water.

EXAMPLES

[0108] Compounds of the invention can be prepared using the reactions depicted in Schemes 1 to 3.

[0109] In Scheme 1, L represents an appropriate leaving group such as chloride, bromide, iodide or mesylate. The groups R1, R2, R3, R4, R5, R6, R7, R7′ and Y are as defined as Formula I.

[0110] Alternatively, appropriately protected forms of R1, R2, R3, R4, R5, R6, R7 and R7′ may be employed. In such cases, an additional deprotection step is employed to obtain the final product. Suitable protecting groups and conditions are readily available (e.g. “Protective Groups in Organic Synthesis” by T. W. Greene). Suitable conditions for carrying out the transformations in Scheme 1 are exemplified but not limited to those given in Example 1. Those skilled in the art will realize that alternate synthetic methods may be employed to accomplish the reactions in Scheme 1.

[0111] In Scheme 2, L represents an appropriate leaving group such as chloride, bromide, iodide or mesylate. The groups R1, R2, R3, R4, R5, R6, R7, R7′ and Y are as defined as Formula I.

[0112] Alternatively, appropriately protected forms of R1, R2, R3, R4, R5, R6, R7 and R7′ may be employed. In such cases, an additional deprotection step is employed to obtain the final product. Suitable protecting groups and conditions are readily available (e.g. “Protective Groups in Organic Synthesis” by T. W. Greene). Suitable conditions for carrying out the transformations in Scheme 2 are exemplified but not limited to those given in Example 2. Those skilled in the art will realize that alternate synthetic methods may be employed to accomplish the reactions in Scheme 2.

[0113] In Scheme 3, Z represents hydrogen, bromine, chorine or other substituents consistent with the definition of R1 in Formula I. The groups R1, R2, R3, R4, R5, R6, R7, R7′ and Y are as defined as Formula I. Alternatively, appropriately protected forms of R1, R2, R3, R4, R5, R6, R7 and R7′ may be employed. In such cases, an additional deprotection step is employed to obtain the final product. Suitable protecting groups and conditions are readily available (e.g. “Protective Groups in Organic Synthesis” by T. W. Greene). The compound RIL is an electrophile chosen so as to produce substitution in compound 11 that is consistent with Formula I. In some cases RI in 11 may be further modified by a chemical transformation. Examples include but are not limited to hydrolysis of ester or cyano groups in RI. Suitable conditions for carrying out the transformations in Scheme 3 are exemplified in Example 3. Those skilled in the art will realize that alternate synthetic methods may be employed to accomplish the reactions in Scheme 3.

[0114] Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention, as demonstrated by the following examples.

[0115] The following examples illustrate the general procedures for the preparation of compounds of the invention using the reactions outlined above in Schemes 1-3. These examples are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described in them.

Example 1

General Procedure for the Preparation of Substituted Imidazoles as Outlined in Scheme 1

Preparation of (2-Chloro-3,4-dimethoxyphenyl)-N-({1-[(2-chlorophenyl)methyl]-4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide

[0116]

[0117] To a solution of 4.89 g (0.027 mol) of 4,5-dimethylimidazole hydrobromide and 5.7 g (0.028 mol) of 2-chlorobenzyl bromide in 20 ml of DMF is added 6 ml of 50% potassium hydroxide aqueous solution dropwise. Then the reaction mixture is stirred at RT under nitrogen overnight. The reaction mixture is poured into ether (100 ml)/ water (50 ml). The ether layer is separated, washed with water (10 ml×2), dried over anhydrous sodium sulfate and evaporated in vacuo. The raw material is subjected to chromatography on silica gel using dichloromethane-methanol (10:1) as eluent to give 2.67 g (44%) of 1-(2′-chlorobenzyl)-4,5-dimethylimidazole as a pale yellow oil. MS m/z (M++1) 221; 1H-NMR 400 MHz(δ, CDCl3): 2.00 (3H, s), 2.20 (3H, s), 5.07 (2H, s), 6.59 (1H, dd, J=9.2, 2 Hz), 7.17 (1H, td, J=8, 1.2 Hz), 7.23 (1H, td, J=8, 1.6 Hz), 7.38 (2H, dd, J=7.2, 1.6 Hz) ppm.

[0118] To a solution of 10 ml of glacial acetic acid and 10 ml of 37% formaldehyde is added 2.67 g (0.012 mol) of 1-(2′-chlorobenzyl)-4,5-dimethylimidazole. The mixture is stirred and heated in a sealed tube at 125-130° C. (oil bath temperature) overnight. After cooling, the solvent is evaporated in vacuo. The residue is subjected to chromatography on silica gel using dichloromethane-methanol (10:1) as eluent to give 2.39 g (79%) of 1-(2′-chlorobenzyl)-4,5-dimethyl-2-hydroxymethylimidazole as colorless powder. MS m/z (M++1) 251; 1H-NMR 400 MHz(δ, CDCl3): 1.94 (3H, s), 2.11 (3H, s), 4.53 (2H, s), 5.26 (2H, s), 6.42 (1H, dd, J=8, 1.2 Hz), 7.14(1H, td, J=8, 1.2Hz), 7.21 (1H, td, J=7.4, 1.6 Hz), 7.39 (1H, dd, J=8, 1.2 Hz) ppm.

[0119] To 3 ml of thionyl chloride is added 2.39 g (9.5 mmol) of 1-(2′-chlorobenzyl)-4,5-dimethyl-2-hydroxymethyl-imidazole. The mixture is heated at 50° C. for about 5 min., and the thionyl chloride is evaporated in vacuo. The residue is dissolved in 10 ml of dichloromethane, then evaporated in vacuo. This is repeated twice to give 1-(2′-chlorobenzyl)-4,5-dimethyl-2-chloromethylimidazole as a cream colored foam which is used in next step without further purification.

[0120] To a solution of 7 ml (60 mmol) of isoamylamine in 3 ml of acetonitrile is added slowly a solution of 1-(2′-chlorobenzyl)-4,5-dimethyl-2-chloromethylimidazole in 10 ml of acetonitrile followed by added 1.5 g (10.8 mmol) of potassium carbonate powder. The reaction mixture is stirred overnight at room temperature under nitrogen and excess isoamylamine is evaporated in vacuo. The residue is dissolved in 50 ml of ethyl acetate and 25 ml of water. The ethyl acetate layer is separated, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product is purified by preparative TLC [silica gel, chloroform-methanol-ammonium hydroxide (90:10:1)] to give 1.39 g (46%) of N-[(4,5-dimethylimidazol-2-yl)methyl]-(3-methylbutyl)amine as a yellow oil. MS m/z (M++1) 320; 1H-NMR 400 MHz(δ, CDCl3): 0.81 (6H, d, J=6.4 Hz), 1.25 (2H, m), 1.51 (1H, m), 1.96 (3H, s), 2.17 (3H, s), 2.56 (2H, m), 3.68 (2H, s), 5.21 (2H, s), 6.39 (1H, d, J=7.6 Hz), 7.13 (1H, m), 7.19 (1H, m), 7.37 (1H, m) ppm.

[0121] To a solution of 210 mg (0.66 mmol) of N-[(4,5-dimethylimidazol-2-yl)methyl]-(3-methylbutyl)amine in 5 ml of chloroform (stabilized with amylenes) is added 170 mg (0.84 mmol) of 2-chloro-3,4-dimethoxybenzoyl chloride and 1 ml of triethylamine. The reaction mixture is stirred at RT under nitrogen overnight and evaporated in vacuo. The residue is dissolved in 20 ml of ethyl acetate and 10 ml of water. The ethyl acetate layer is separated, washed with brine (5 ml×2), dried over anhydrous sodium sulfate, and the solvent is evaporated in vacuo. The crude product is purified by preparative TLC [silica gel, chloroform-methanol-ammonia hydroxide (95:4.5:0.5)] to give the title compound as a colorless oil. MS m/z (M++1) 518; 1H-NMR 400 MHz(δ, CDCl3): 0.61 and 0.88 (6H, d, J=6 Hz, the ratio of two peaks is 4/1), 1.26 (2H, m), 1.36 (1H, m), 1.89 and 1.94 (3H, s, the ratio of two peaks is 1/4), 2.14 and 2.17 (3H, s, the ratio of two peaks is 1/4), 3.04 (2H, br), 3.74 and 3.80 (3H, s, the ratio of two peaks is 1/4), 3.78 and 3.82 (3H, s, the ratio of two peaks is 1/4), 4.72, 4.84, 5.17, 5.47 (4H, 4 br), 6.30 (2H, d, J=8.4 Hz), 6.67 (1H, d, J=8.8 Hz), 7.15 (1H, td, J=7.2, 1.2 Hz), 7.21 (1H. td, J=7.2, 1.2 Hz), 7.38 (1H, dd, J=7.2, 1.2 Hz) ppm.

Example 2

General Procedure for the Preparation of Substituted Imidazoles as Outlined in Scheme 2

Preparation of (2-Chloro-3,4-dimethoxyphenyl)-N-({1-[(2-methoxyphenyl)methyl]-4,5-dimethylimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide

[0122]

[0123] A mixture of 3.35 g (27 mmol) of 4,5-dimethyl-2-imidazolecarboxaldehyde, 9.0 mL (77 mmol) of isoamylamine, 200 mL of ethanol, and 0.20 g of platinum dioxide is hydrogenated under 50 psi of pressure at 22° C. for 24 h. The solution is filtered, and the volatiles are evaporated under reduced pressure to give 5.17 g (98%) of N-[(4,5-dimethylimidazol-2-yl)methyl]-(3-methylbutyl)amine. Mass Spec m/z (M++1) 196.

[0124] A mixture of 4.50 g (20 mmol) of 2-chloro-3,4-dimethoxybenzoic acid, 5 mL of chloroform, 0.2 mL of pyridine, and 5.8 mL (80 mmol) of thionyl chloride is stirred at 40° C. for 1 h. The volatiles are thoroughly evaporated. A solution of the residue in 10 mL of chloroform is added dropwise to a solution of 2.73 g (14 mmol) of N-[(4,5-dimethylimidazol-2-yl)methyl]-3-methylbutylamine in 20 mL of anhydrous pyridine stirred under nitrogen at −20° C. The obtained mixture is allowed to warm up slowly, and it is stirred then at 20° C. for 20 h.

[0125] The reaction mixture is poured into 50 mL of water and extracted with 50 mL of chloroform. The extract is washed with 50 mL of 5% NaCO3, and the solvent is evaporated. The residue is dissolved in 20 mL of ethanol, treated with 2 mL of 10N NaOH, and stirred at 60° C. for 1 h. The mixture is poured into 50 mL of 5% NaCO3 and extracted with 50 mL of chloroform. The solvent is evaporated under reduced pressure. The crude product is purified by column chromatography on 100 g of silica gel using chloroform-methanol—28% ammonium hydroxide (95:4.5:0.5, v/v/v) as an eluent to give 2.42 g (44%) of (2-chloro-3,4-dimethoxyphenyl)-N-[(4,5-dimethylimidazol-2-yl)methyl]-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M++1) 394.

[0126] A mixture of 0.74 g (1.9 mmol) of (2-chloro-3,4-dimethoxyphenyl)-N-(3,4-dimethylimidazol-2-yl)methyl-N-(3-methylbutyl)carboxamide, 0.94 g (6.0 mmol) of 2-methoxybenzyl chloride, 10 mL of dimethylformamide and 0.63 mL (8.0 mmol) of 50% KOH is stirred vigorously under nitrogen at 40° C. for 20 h. The reaction mixture is poured into 100 mL of water and extracted with 50 mL of chloroform. The extract is washed with 100 mL of water, and the solvent is evaporated under reduced pressure. The residue is diluted with 50 mL of xylenes, and the volatiles are thoroughly evaporated under reduced pressure. Column chromatography of the residue on 30 g of silica gel using chloroform-diethyl ether (98:2, v/v) as an eluent afforded 646 mg (67%) of the title compound as a cream colored foam. Mass Spec m/z (M++1) 514.

Example 3

General Procedure for the Preparation of Substituted Imidazoles as Outlined in Scheme 3

Preparation of (2-chloro-3,4-dimethoxyphenyl)-N-{3,4-dimethyl-1-[(2-hydroxyphenyl)methyl]imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide

[0127]

[0128] A mixture of 1.89 g (4.8 mmol) of (2-chloro-3,4-dimethoxyphenyl)-N-(3,4-dimethylimidazol-2-yl)methyl-N-(3-methylbutyl)carboxamide, 0.74 g (6.0 mmol) of 2-hydroxybenzyl alcohol, 50 mL of toluene, 0.10 g of p-toluenesulfonic acid monohydrate, and 15 g of molecular sieves 5A is gently stirred and heated under nitrogen at 100° C. for 24 h. Another portion of 2-hydroxybenzyl alcohol (0.37 g, 3.0 mmol) is added, and heating at 100° C. is continued for additional 24 h. The molecular sieves are filtered off and washed with 20 mL of ethyl acetate-methanol (4:1). The filtrate and washings are combined, and the solvent is evaporated under reduced pressure. The crude material is purified by column chromatography on 75 g of silica gel using chloroform-methanol-acetic acid (96:3:1) as an eluent to give 1.74 g (72%) of the title compound. Mass Spec m/z (M++1) 500.

Preparation of Ethyl {2-[(2-{[(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino]methyl}-4,5-dimethylimidazol-1-yl)methyl]phenoxy}acetate

[0129]

[0130] A mixture of 0.55 g (1.1 mmol) of (2-chloro-3,4-dimethoxyphenyl)-N-{3,4-dimethyl-1-[(2-hydroxyphenyl)-methyl]imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide, 0.24 mL (2.2 mmol) of ethyl bromoacetate, 0.69 g (5.0 mmol) of K2CO3, and 5 mL of anhydrous dimethylformamide is stirred under nitrogen at 22° C. for 20 h. The reaction mixture is poured onto 50 g of crushed ice, acidified to pH 6 with 1M HCl, and extracted with hexanes-ethyl acetate (25 mL of each). The extract is washed with water (2×50 mL), dried over MgSO4, and the solvents are evaporated under reduced pressure. The residue is purified by column chromatography on 30 g of silica gel using ethyl acetate as an eluent to give 0.51 g (79%) of the title compound. Mass Spec m/z (M++1) 586.

Preparation of {2-[(2-{[(2-Chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino]methyl}-4,5-dimethylimidazol-1-yl)methyl]phenoxy}acetic acid

[0131]

[0132] A solution of 58 mg of {2-[(2-{[(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino]methyl}-4,5-dimethylimidazol-1-yl)methyl]phenoxy}acetate in 2 mL of 5N HCl is heated under reflux for 15 min. The volatiles are evaporated under reduced pressure, and the residue is dried in a vacuum oven at 90° C. to give 59 mg of the title compound as the hydrochloride salt. Mass Spec m/z (M++1) 558.

Example 4

Alternate Alkylation Conditions for Substituted Imidazoles Prepared in Scheme 2

Preparation of (2-Chloro-3,4-dimethoxyphenyl)-N-{3,4-dimethyl-1-[(2-cyanophenyl)methyl]imidazol-2-yl}methyl-N-(3-methylbutyl) carboxamide

[0133]

[0134] A mixture of 197 mg (0.50 mmol) of (2-chloro-3,4-dimethoxyphenyl)-N-(3,4-dimethylimidazol-2-yl)methyl-N-(3-methylbutyl)carboxamide, 147 mg (0.75 mmol) of α-bromo-o-tolunitrile, 3 mL of DMF, and 415 mg (3 mmol) of K2CO3 is stirred under nitrogen at 22° C. for 24 h. The reaction mixture is poured into 30 mL of water and extracted with 30 mL of diethyl ether. The extract is washed with water (2×20 mL), and the solvent is evaporated. The residue is dissolved in 20 mL of xylenes, and the volatiles are thoroughly evaporated in vacuo. The crude product is purified by column chromatography on 24 g of silica gel using chloroform-diethyl ether (85:15) as an eluent to give 181 mg (71% yield) of the title compound. Mass Spec m/z (M++1) 509.

Example 5

Preparation of 2-{2-{[(2-Chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carbonylamino}methyl]-4,5-dimethylimidazol-1-yl)methyl}benzoic acid

[0135]

[0136] A mixture of 140 mg (0.27 mmol) of (2-Chloro-3,4-dimethoxyphenyl)-N-{3,4-dimethyl-1-[(2-cyanophenyl)methyl] imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide, 2.0 mL of ethanol and 1.0 mL of 50% KOH is stirred under nitrogen at 80° C. for 18 h. The reaction mixture is poured into 30 g of ice-water, acidified to pH 5 with 1M HCl, and extracted with 20 mL of ethyl acetate. The extract is washed with 10 mL of water, and the solvent is evaporated under reduced pressure. The residue is triturated with 2 mL of acetone, and the crystals are separated by decantation to give 112 mg (78%) of the title compound. Mass Spec m/z (M++1) 528.

Example 6

Preparation of (2-Chloro-3,4-dimethoxyphenyl)-N-{3,4-dimethyl-1-[(2-[cyanomethoxy]phenyl)methyl]imidazol-2yl}methyl-N-(3-methylbutyl)carboxamide

[0137]

[0138] A mixture of 250 mg (0.50 mmol) of (2-chloro-3,4-dimethoxyphenyl)-N-(3,4-dimethylimidazol-2-yl)methyl-N-(3-methylbutyl)carboxamide, 52 μL of chloroacetonitrile (0.75 mmol), 276 mg (2.0 mmol) of K2CO3, and 3 mL of anhydrous DMF is stirred under nitrogen at 22° C. for 24 h and poured into 10% NaCl. The mixture is extracted with 20 mL of ethyl acetate. The extract is concentrated under reduced pressure, diluted with 20 mL of xylenes, and the volatiles are thoroughly evaporated. The crude product is purified by chromatography on 30 g of silica gel using chloroform-methanol—28% ammonium hydroxide (98:1.8:0.2, v/v/v) for elution to afford 113 mg (42% yield) of the title compound. Mass Spec m/z (M++1) 539.

[0139] Using the above procedures, the following compounds were prepared according to Schemes 1, 2 and 3:

[0140] (a) (2-Chloro-3,4-dimethoxyphenyl)-N-{[1-benzyl-4,5-dimethylimidazol-2-yl]methyl}-N-(3-methylbutyl) carboxamide. Mass Spec m/z (M++1) 484.

[0141] (b) (2-Chloro-3,4-dimethoxyphenyl-N-({4,5-dimethyl-1-[(2-methylphenyl)methyl]}imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M++1) 498.

[0142] (c) (2-Chloro-3,4-dimethoxyphenyl-N-[(4,5-dimethyl-1-{[2-(trifluoromethyl)phenyl]methyl}imidazol-2-yl)methyl]-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M++1) 552.

[0143] (d) N-{[4,5-Dichloro-1-benzylimidazol-2-yl]methyl}(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M++1) 524.

[0144] (e) N-({4,5-Dichloro-1-[(2-chlorophenyl)methyl]imidazol-2-yl}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M++1) 560.

[0145] (f) N-({4,5-Dichloro-1-[(2-methylphenyl)methyl]imidazol-2-yl]methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M++1) 540.

[0146] (g) (2-Chloro-3,4-dimethoxyphenyl)-N-{3,4-diethyl-1-[(pyridin-2-yl)methyl]imidazol-2-yl}methyl-N(3-methylbutyl) carboxamide. Mass Spec m/z (M++1) 513.

[0147] (h) 2-Chloro-3,4-dimethoxyphenyl)-N-{3,4-dimethyl-1-[quinolin-2-yl)methyl]imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M++1) 535.

[0148] (i) (2-Chloro-3,4-dimethoxyphenyl)-N-{4,5-diethyl-1-[(5-ethyl-2-methoxyphenyl)methyl]imidazol-2-yl}methyl-N-(3-methylbutyl)carboxamide. Mass Spec m/z(M++1)570.

[0149] (j) (2-Chloro-3,4-dimethoxyphenyl)-N-{3,4-dimethyl-1-[(5-bromo-2-hydroxyphenyl)methyl]imidazol-2-yl}methyl-N-(3-methylbutyl) carboxamide. Mass Spec m/z (M++1) 579.

[0150] (k) (2-Chloro-3,4-dimethoxyphenyl)-N-{3,4-dimethyl-1-[(5-chloro-2-hydroxyphenyl)methyl]imidazol-2-yl}methyl-N-(3-methylbutyl) carboxamide. Mass Spec m/z (M++1) 534.

[0151] (l) (2-Chloro-3,4-dimethoxyphenyl)-N-({3-[(2-chlorophenyl)methyl](3,4,5,6,7-pentahydrobenzimidazol-2-yl)}methyl)-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M++1) 544.

Example 7

Additional Compounds of the Invention

[0152] Additional Compounds of the invention which may be prepared by the methods outlined in Reaction Schemes 1, 2, and 3 are shown in Table I.

Ex #R10R11R12R13R14R15R161

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

100

393

394

395

396

101

397

398

399

400

102

401

402

403

404

103

405

406

407

408

104

409

410

411

412

105

413

414

415

106

416

417

418

107

419

420

421

108

422

423

424

109

425

426

427

110

428

429

430

111

431

432

433

112

434

435

436

113

437

438

439

114

440

441

442

115

443

444

445

116

446

447

448

117

449

450

451

452

118

453

454

455

456

119

457

458

459

460

120

461

462

463

464

121

465

466

467

468

122

469

470

471

472

123

473

474

475

476

124

477

478

479

480

125

481

482

483

484

126

485

486

487

488

127

489

490

491

492

128

493

494

495

496

129

497

498

499

500

130

501

502

503

504

131

505

506

507

508

132

509

510

511

512

133

513

514

515

134

516

517

518

135

519

520

521

136

522

523

524

137

525

526

527

138

528

529

530

139

531

532

533

140

534

535

536

141

537

538

539

142

540

541

542

143

543

544

545

144

546

547

548

145

549

550

551

552

146

553

554

555

556

147

557

558

559

560

148

561

562

563

564

149

565

566

567

568

150

569

570

571

572

151

573

574

575

576

152

577

578

579

580

153

581

582

583

584

154

585

586

587

588

155

589

590

591

592

156

593

594

595

596

157

597

598

599

600

158

601

602

603

604

159

605

606

607

608

160

609

610

611

612

161

613

614

615

162

616

617

618

163

619

620

621

164

622

623

624

165

625

626

627

166

628

629

630

167

631

632

633

168

634

635

636

169

637

638

639

170

640

641

642

171

643

644

645

172

646

647

648

173

649

650

651

174

652

653

654

175

655

656

657

176

658

659

660

177

661

662

663

178

664

665

666

179

667

668

669

180

670

671

672

181

673

674

675

182

676

677

678

183

679

680

681

184

682

683

684

185

685

686

687

186

688

689

690

187

691

692

693

188

694

695

696

189

697

698

699

700

190

701

702

703

704

191

705

706

707

708

192

709

710

711

712

193

713

714

715

716

194

717

718

719

720

195

721

722

723

724

196

725

726

727

728

197

729

730

731

732

198

733

734

735

736

199

737

738

739

740

200

741

742

743

744

201

745

746

747

748

749

202

750

751

752

753

754

203

755

756

757

758

759

204

760

761

762

763

764

205

765

766

767

206

768

769

770

207

771

772

773

208

774

775

776

209

777

778

779

210

780

781

782

211

783

784

785

212

786

787

788

213

789

790

791

214

792

793

794

215

795

796

797

216

798

799

800

217

801

802

803

218

804

805

806

219

807

808

809

220

810

811

812

221

813

814

815

222

816

817

818

223

819

820

821

224

822

823

824

225

825

826

827

828

226

829

830

831

832

227

833

834

835

836

228

837

838

839

840

229

841

842

843

844

230

845

846

847

848

231

849

850

851

852

232

853

854

855

856

233

857

858

859

860

234

861

862

863

864

235

865

866

867

868

236

869

870

871

872

237

873

874

875

876

238

877

878

879

880

239

881

882

883

884

240

885

886

887

888

241

889

890

891

892

242

893

894

895

896

243

897

898

899

900

244

901

902

903

904

245

905

906

907

908

246

909

910

911

912

247

913

914

915

916

248

917

918

919

920

249

921

922

923

924

250

925

926

927

928

251

929

930

931

932

252

933

934

935

936

253

937

938

939

940

254

941

942

943

944

255

945

946

947

948

256

949

950

951

952

257

953

954

955

258

956

957

958

259

959

960

961

260

962

963

964

261

965

966

967

262

968

969

970

263

971

972

973

264

974

975

976

265

977

978

979

266

980

981

982

267

983

984

985

268

986

987

988

269

989

990

991

992

270

993

994

995

996

271

997

998

999

1000

272

1001

1002

1003

1004

273

1005

1006

1007

1008

274

1009

1010

1011

1012

275

1013

1014

1015

1016

276

1017

1018

1019

1020

277

1021

1022

1023

1024

278

1025

1026

1027

1028

279

1029

1030

1031

1032

280

1033

1034

1035

1036

281

1037

1038

1039

1040

282

1041

1042

1043

1044

283

1045

1046

1047

1048

284

1049

1050

1051

1052

285

1053

1054

1055

1056

286

1057

1058

1059

1060

287

1061

1062

1063

1064

288

1065

1066

1067

1068

289

1069

1070

1071

290

1072

1073

1074

291

1075

1076

1077

292

1078

1079

1080

293

1081

1082

1083

294

1084

1085

1086

295

1087

1088

1089

296

1090

1091

1092

297

1093

1094

1095

298

1096

1097

1098

299

1099

1100

1101

300

1102

1103

1104

301

1105

1106

1107

302

1108

1109

1110

303

1111

1112

1113

304

1114

1115

1116

305

1117

1118

1119

306

1120

1121

1122

307

1123

1124

1125

308

1126

1127

1128

309

1129

1130

1131

310

1132

1133

1134

311

1135

1136

1137

312

1138

1139

1140

313

1141

1142

1143

314

1144

1145

1146

315

1147

1148

1149

316

1150

1151

1152

317

1153

1154

1155

318

1156

1157

1158

319

1159

1160

1161

320

1162

1163

1164

321

1165

1166

1167

322

1168

1169

1170

323

1171

1172

1173

324

1174

1175

1176

325

1177

1178

1179

326

1180

1181

1182

327

1183

1184

1185

328

1186

1187

1188

329

1189

1190

1191

1192

330

1193

1194

1195

1196

331

1197

1198

1199

1200

332

1201

1202

1203

1204

333

1205

1206

1207

1208

334

1209

1210

1211

1212

335

1213

1214

1215

1216

336

1217

1218

1219

1220

337

1221

1222

1223

1224

1225

338

1226

1227

1228

1229

1230

339

1231

1232

1233

1234

1235

340

1236

1237

1238

1239

1240

341

1241

1242

1243

1244

1245

342

1246

1247

1248

1249

1250

343

1251

1252

1253

1254

1255

344

1256

1257

1258

1259

1260

345

1261

1262

1263

346

1264

1265

1266

347

1267

1268

1269

348

1270

1271

1272

349

1273

1274

1275

350

1276

1277

1278

351

1279

1280

1281

352

1282

1283

1284

353

1285

1286

1287

354

1288

1289

1290

355

1291

1292

1293

356

1294

1295

1296

357

1297

1298

1299

358

1300

1301

1302

359

1303

1304

1305

360

1306

1307

1308

361

1309

1310

1311

1312

362

1313

1314

1315

1316

363

1317

1318

1319

1320

364

1321

1322

1323

1324

365

1325

1326

1327

1328

366

1329

1330

1331

1332

367

1333

1334

1335

1336

368

1337

1338

1339

1340

369

1341

1342

1343

370

1344

1345

1346

371

1347

1348

1349

372

1350

1351

1352

373

1353

1354

1355

374

1356

1357

1358

375

1359

1360

1361

376

1362

1363

1364

377

1365

1366

1367

378

1368

1369

1370

379

1371

1372

1373

380

1374

1375

1376

381

1377

1378

1379

382

1380

1381

1382

383

1383

1384

1385

384

1386

1387

1388

385

1389

1390

1391

386

1392

1393

1394

387

1395

1396

1397

388

1398

1399

1400

389

1401

1402

1403

390

1404

1405

1406

391

1407

1408

1409

392

1410

1411

1412

393

1413

1414

1415

394

1416

1417

1418

395

1419

1420

1421

396

1422

1423

1424

397

1425

1426

1427

398

1428

1429

1430

399

1431

1432

1433

400

1434

1435

1436

401

1437

1438

1439

402

1440

1441

1442

403

1443

1444

1445

404

1446

1447

1448

Example 8

Ligand Binding Assay on Sf9 cell membranes expressing the BK-2 receptor

[0153] This assay is used to determine the high affinity of compounds of this invention for the BK-2 (bradykinin B2) receptor.

[0154] Binding Buffer: 50 mM Tris 7.0 (cold), 0.14 grams per liter bacitracin (approx. 50,000 units of activity/liter, lot# 103746 from Amersham), and 10−6 M captopril. Captopril is purchased from Sigma C-4042, 2.17 mg in 10 ml of milli-Q water produces a 10−3 M stock. Stock can be stored for 3 weeks in the refrigerator. 1.0 ml of stock per liter buffer=10−6 M final concentration.

[0155] Ligand Preparation: 0.25 nM 3H-Bradykinin is used. 10 μl of stock+100 ml of binding buffer gives approximately 600 cpm/5 μl aliquot.

[0156] Non-Specific Preparation: NS binding is defined by unlabeled bradykinin at 1 μM final concentration. Aliquots are stored at −20 ° C. in 0.5% BSA at a concentration of 10−3 M. Aliquots are then diluted 1:100 for an intermediate concentration of 10−5 M.

[0157] Baculovirus-infected Sf9 cells expressing recombinant human bradykinin B2 receptors are harvested 48 hours post infection via centrifugation at 3000×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 (50 mM Tris pH 7.0) and homogenized via POLYTRON for 30 seconds at setting 5. Membranes are centrifuged at 40,000×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 μg/ml. This corresponds to 20 μg of protein per 150 μl.

[0158] When measuring non-specific binding, incubations contain 150 μl of Sf9 cell membranes prepared as described above, 50 μl 3H-Bradykinin (0.25 nM), 25 μl unlabeled bradykinin at 1 μM final concentration and 2 μl DMSO. Incubations for determining test compound binding contain 175 μl of Sf9 cell membranes, 50 μl 3H-Bradykinin (0.25 nM), and test compound in 2 μl DMSO. The concentration of the test compound is generally 1 μM for displacement studies. The binding reaction components are incubated for 2 hrs at 4° C. in Falcon U bottom plates. Plates are harvested on the microbeta harvester onto 0.5% PEI pretreated unifilters. After harvesting, the filters are dried overnight. 17 μl of beta-scint is added to each well before the unifilters are counted in the microbeta counters. Data are collected in duplicate determinations, averaged and % inhibition of total specific binding is calculated. Total Specific Binding=Total−Nonspecific. In some cases, the amounts of unlabeled drug is varied and total displacement curves of binding are carried out. Data are converted to a form for the calculation of IC50 and Hill Coefficient (nH). Ki's are subsequently determined by the Cheng-Prusoff equation (Cheng, Y. C.; Prusoff, W. C. Biochem. Pharmacol. 1972, 22, 3099-3108). In the described assay, preferred compounds of the invention have Ki's of less than 1 μM, more preferred compounds of the invention exhibit Ki values of less than 500 nM and even more preferred compounds of the invention exhibit Ki values of less than 100 nM.

Example 9

BK-2 Receptor Mediated Calcium Mobilization

[0159] The agonist and antagonist properties of the compounds of the invention can be evaluated by the following assay.

[0160] CHO cells stably expressing the BK-2 receptor are grown in Ham's F-12 media supplemented with 250 μg/ml G418, 1 μg/ml tetracycline, 7 μg/ml puromycin, 10% fetal bovine serum and 25 mM Hepes, pH=7.4. 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. On the day of assay, cells, grown to 70-90% confluency in 96-well plates, are washed with Krebs-Ringer buffer (25 mM HEPES, 5 mM KCl, 0.96 mM NaH2PO4, 1 mM MgSO4, 2 mM CaCl2, 5 mM glucose, and 1 mM probenecid, pH 7.4) and are then incubated for 1-2 hours in the above buffer supplemented with Fluo3-AM (2.5 ñ 10 (g/ml; Teflabs) at 37° C. in an environment containing 5% CO2. The wells are then washed twice with Krebs-Ringers buffer. 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. For the examination of antagonist drug candidates, compounds, at a concentration of 1 μM 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 sufficient to induce 50% maximal activity. Responses are recorded for up to 5 min. Kaleidagraph software (Synergy Software, Reading, Pa.) is utilized to fit the data to the equation y=a*(1/(1+(b/x)c)) to determine the EC50 value or IC50 value for the response. In this equation, y is the maximum fluorescence signal, x is the concentration of the agonist or antagonist, a is the Emax, b corresponds to the EC50 or IC50 value, and, finally, c is the Hill coefficient.

Example 10

Preparation of Radiolabeled Probe Compounds of the Invention

[0161] 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 14C), hydrogen (preferably 3H), sulfur (preferably 35S), or iodine (preferably 125I). 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, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRI International, Menlo Park, Calif.; Wizard Laboratories, West Sacramento, Calif.; ChemSyn Laboratories, Lexena, Kans.; American Radiolabeled Chemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea, Calif.

[0162] 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 11

Use of Compounds of the Invention as Probes for BK-2 Receptors in Cultured Cells and Tissue Samples

[0163] 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. Fanner, editor, using radiolabeled compounds of the invention prepared as described in the preceding Example 9.

[0164] The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification.

Substituted imidazoles as selective modulators of bradykinin B2 receptors

Information

Publication Number

Date Filed

Date Published

Inventors

CPC

US Classifications

International Classifications

Abstract

Description

Claims

Parent Case Info

Provisional Applications (1)