WO2006028590A1 - 1,1,2,2-tetra (hetero) arylethanes or 1,1,2-tri (hetero) aryl-2-heterocyclylethanes as potassium channel inhibitors - Google Patents
1,1,2,2-tetra (hetero) arylethanes or 1,1,2-tri (hetero) aryl-2-heterocyclylethanes as potassium channel inhibitors Download PDFInfo
- Publication number
- WO2006028590A1 WO2006028590A1 PCT/US2005/026334 US2005026334W WO2006028590A1 WO 2006028590 A1 WO2006028590 A1 WO 2006028590A1 US 2005026334 W US2005026334 W US 2005026334W WO 2006028590 A1 WO2006028590 A1 WO 2006028590A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ring
- heteroaryl ring
- independently selected
- group
- heteroaryl
- Prior art date
Links
- 0 *c1**(*)ccc1 Chemical compound *c1**(*)ccc1 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
Definitions
- the present invention relates broadly to compounds that are useful as potassium channel inhibitors.
- Compounds in mis class may be useful as KvI.5 antagonists for treating and preventing cardiac arrhythmias, and the like.
- Atrial fibrillation is the most common sustained cardiac arrhythmia in clinical practice and is likely to increase in prevalence with the aging of the population. While AF is rarely fatal, it can impair cardiac function and lead to complications such as the development of congestive heart failure, thromboembolism, or ventricular fibrillation.
- Drug therapy for ventricular arrhythmia includes Class Ia (eg. procainamide, quinidine), Class Ic (eg. flecainide, propafenone), and Class III (amiodarone) agents, which pose significant risks of proarrhythmia.
- Class Ia eg. procainamide, quinidine
- Class Ic eg. flecainide, propafenone
- Class III amiodarone
- Class HI antiarrhythmic agents cause a selective prolongation of the APD without significant depression of cardiac conduction or contractile function.
- the only selective Class IH drug approved for clinical use in atrial fibrillation is dofetilide, which mediates its anti-arrhythmic effects by blocking I KX , the rapidly activating component of I ⁇ found in both atrium and ventricle in humans (Mounsey, JP, DiMarco, JP, Circulation, 102:2665-2670). Since I K ,.
- blockers increase APD and refractoriness both in atria and ventricle without affecting conduction per se, theoretically they represent potentially useful agents for the treatment of arrhythmias like AF (Torp-Pedersen, et al, Expert Opin. Invest. Drugs, 9:2695-2704, 2000). However, these agents have the major liability of an enhanced risk of proarrhythmia at slow heart rates.
- the ultrarapid delayed rectifier K + current, I Kur has been observed specifically in human atrium and not in ventricle.
- the molecular correlate of I ⁇ ur in the human atrium is the potassium channel designated KvI.5.
- I Kur is believed to contribute significantly to repolarization in human atrium. Consequently, a specific blocker of I Kur , that is a compound which blocks KvI.5, would overcome the shortcoming of other compounds by prolonging refractoriness through retardation of the repolarization in the human atrium without causing the delays in ventricular repolarization that underlie arrhythmogenic afterdepolarizations and acquired long QT syndrome observed during treatment with current Class III drugs.
- KvI.5 blockers exhibiting these properties have been described (Peukert et al, J. Med. Chem., 4(5:486-498, 2003; Knobloch et al, Namyn-Schmedieberg's Arch. Pharmacol. 3 ⁇ 5 ⁇ 5:482-287, 2002; Merck & Co., Inc. WO0224655, 2002).
- the compounds described in this invention represent a novel structural class of KvI .5 antagonist.
- the invention concerns compounds of formula I which antagonizes the KvI.5 potassium channel:
- the compounds of this invention are useful in the treatment and prevention of cardiac arrhythmias, and the like. Also within the scope of this invention are pharmaceutical formulations comprising a compound of Formula I and a pharmaceutical carrier.
- the invention concerns compounds of formula I which antagonizes the KvI.5 potassium channel:
- A, B and C are independently selected from the group consisting of:
- heteroaryl ring wherein the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is selected from the group consisting of: a) a 5-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S, b) a 6-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S, and c) an 8-, 9- or 10-membered unsaturated bicyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S, said aryl and heteroaryl ring is unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein any
- heteroaryl ring wherein the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is selected from the group consisting of: a) a 5-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S, b) a 6-membered unsaturated monocyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S, and c) an 8-, 9- or 10-membered unsaturated bicyclic ring with 1, 2, 3, or 4 heteroatom ring atoms selected from the group consisting of N, O or S, and
- X and Y are independently selected from the group consisting of H and OR5;
- R a in each instance in which it appears, is independently selected from the group consisting of hydrogen,
- Ci-C ⁇ alkyl and halogen
- R5 in each instance in which it appears, is independently selected from the group consisting of hydrogen, unsubstituted or substituted Ci-C ⁇ alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted aryl, and unsubstituted or substituted heterocyclyl;
- m is independently 0, 1 or 2; and n is independently 0, 1, 2, 3, 4, 5 or 6.
- A is a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, wherein the heteroaryl ring is a 6-membered unsaturated monocyclic ring with 1 or 2 N ring atoms, said heteroaryl ring is unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R.4, or tetrasubstituted with groups independently selected from R.4, and wherein any stable N heteroaryl ring atom is unsubstituted or substituted with oxo, said heteroaryl ring R4 substitutions being on one or more heteroaryl ring carbon atoms;
- B is a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is a 6-membered unsaturated monocyclic ring with 1 or 2 N atoms, said heteroaryl ring is unsubstituted, mono-substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein any stable N heteroaryl ring atom is unsubstituted or substituted with oxo, said heteroaryl ring R4 substitutions being on one or more heteroaryl ring carbon atoms;
- C is selected from the group consisting of 1) an aryl ring, and 2) a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, wherein the heteroaryl ring is a 6-membered unsaturated monocyclic ring with 1 N atom, said aryl and heteroaryl ring is unsubstituted, mono- substituted with R4, disubstituted with groups independently selected from R4, trisubstituted with groups independently selected from R4, or tetrasubstituted with groups independently selected from R4, and wherein any stable N heteroaryl or heterocyclic ring atom is unsubstituted or substituted with oxo, said heteroaryl ring R4 substitutions being on one or more heteroaryl ring carbon atoms; and D is a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is a 6-membered unsaturated monocyclic
- a preferred embodiment of the invention is a compound wherein X is selected from the group consisting of hydrogen and -OH; Y is selected from the group consisting of hydrogen and -OH; A is selected from
- An example of a compound of the invention is a compound selected from the group consisting of
- the above-listed compounds are active in one or more of the assays for KvI .5 described below.
- Another embodiment of the invention is a method of treating or preventing a condition in a mammal, the treatment or prevention of which is effected or facilitated by K V 1.5 inhibition, which comprises administering an amount of a compound of Formula I that is effective at inhibiting K v l.5.
- a preferred embodiment is a method of treating or preventing cardiac arrhythmias, e.g. atrial fibrillation, atrial flutter, atrial arrhythmia, and supraventricular tachycardia, in a mammal, which comprises administering a therapeutically effective amount of a compound of Formula I.
- cardiac arrhythmias e.g. atrial fibrillation, atrial flutter, atrial arrhythmia, and supraventricular tachycardia
- Another preferred embodiment is a method of preventing thromboembolic events, such as stroke.
- Another preferred embodiment is a method of preventing congestive heart failure.
- Another preferred embodiment is a method of treating or preventing immunodepression or a disorder involving immunodepression, such as AIDS, cancer, senile dementia, trauma (including wound healing, surgery and shock) chronic bacterial infection, certain central nervous system disorders, and conditions including resistance by transplantation of organs or tissue, graft-versus-host diseases brought about by medulla ossium transplantation.
- a method for treating or preventing immunodepression by administering a compound of the invention with an immunosuppresant compound.
- Another preferred embodiment is a method of treating or preventing gliomas including those of lower and higher malignancy, preferably those of higher malignancy.
- Another preferred embodiment is a method for inducing in a patient having atrial fibrillation, a condition of normal sinus rhythm, in which the induced rhythm corresponds to the rhythm that would be considered normal for an individual sharing with the patient similar size and age characteristics, which comprises treating the patient with a compound of the invention.
- Another preferred embodiment is a method for treating tachycardia, (i.e., rapid heart rate e.g. 100 beats per minute) in a patient which comprises treating the patient with an antitachycardia device (e.g. a defibrillator or a pacemaker) in combination with a compound of Claim 1.
- an antitachycardia device e.g. a defibrillator or a pacemaker
- the present invention also encompasses a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and the compound of Formula I or a pharmaceutically acceptable crystal form or hydrate thereof.
- a preferred embodiment is a pharmaceutical composition of the compound of Formula I 5 comprising, in addition, a second agent.
- the compounds of the present invention may have chiral centers, e.g. one chiral center (providing for two stereoisomers, (R) and (S)), or two chiral centers (providing for up to four stereoisomers, (R,R), (S 5 S), (R 5 S), and (S 5 R)).
- This invention includes all of the optical isomers and mixtures thereof. Whenever the isomeric composition is unspecified, all possible isomers are included.
- Tautomers of compounds defined in Formula I are also included within the scope of the present invention.
- alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbon atoms. Commonly used abbreviations for alkyl groups are used throughout the specification, e.g. methyl may be represented by “Me” or CH 3 , ethyl may be represented by “Et” or CH 2 CH 3 , propyl may be represented by “Pr” or CH 2 CH 2 CH 3 , butyl may be represented by "Bu” or CH 2 CH 2 CH 2 CH 3 , etc.
- C i-6 alkyl (or “C1-C6 alkyl”) for example, means linear or branched chain alkyl groups, including all isomers, having the specified number of carbon atoms.
- Ci.g alkyl includes all of the hexyl alkyl and penryl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
- C 1.4 alkyl means n-, iso, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
- alkoxy represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
- alkenyl includes both branched and straight chain unsaturated hydrocarbon groups containing at least two carbon atoms joined by a double bond.
- C2-5 alkenyl (or “C2-C5 alkenyl) for example, means linear or branched chain alkenyl groups having from 2 to 5 carbon atoms and includes all of the pentenyl isomers as well as 1-butenyl, 2-butenyl, 3-butenyl, 1-propenyl, 2-propenyl, and ethenyl (or ethylenyl). Similar terms such as “C2-3 alkenyl” have an analogous meaning.
- alkynyl includes both branched and straight chain unsaturated hydrocarbon groups containing at least two carbon atoms joined by a triple bond.
- the alkyne acetlyene is represented, for example, by "CHCH” or alternatively, by "HC ⁇ CH”.
- C2.5 alkynyl (or “C2-C5 alkynyl”) for example, means linear or branched chain alkynyl groups having from 2 to 5 carbon atoms and includes all of the pentynyl isomers as well as 1-butynyl, 2-butynyl, 3-butynyl, 1-pro ⁇ ynyl, 2-propynyl, and ethynyl (or acetylenyl). Similar terms such as “C2-3 alkynyl” have an analogous meaning.
- alkyl, alkenyl and alkynyl groups are unsubstituted or substituted with 1 to 3 substituents on each carbon atom, with halo, C1-C20 alkyl, CF3, NH2, N(Ci-Ce alkyl)2, NO2, oxo, CN, N3, -OH, -O(Ci-C6 alkyl), C3- Cio cycloalkyl, C2-C6 alkenyl,
- C 0 as employed in expressions such as "C 0 - 6 alkyl" means a direct covalent bond.
- an integer defining the presence of a certain number of atoms in a group is equal to zero, it means that the atoms adjacent thereto are connected directly by a bond.
- C3.8 cycloalkyl (or “C3-C8 cycloalkyl”) means a cyclic ring of an alkane having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl).
- C3-7 cycloalkyl "C3- 6 cycloalkyl”
- C5-7 cycloalkyl and the like have analogous meanings.
- halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro (F), chloro (Cl), bromo (Br), and iodo (I)).
- Ci-6 haloalkyl (which may alternatively be referred to as "C ⁇ -Cg haloalkyl” or “halogenated C1-C6 alkyl”) means a Cl to Cg linear or branched alkyl group as defined above with one or more halogen substituents.
- C1-4 haloalkyl has an analogous meaning.
- Cj. 6 fluoroalkyl has an analogous meaning except that the halogen substituents are restricted to fluoro. Suitable fluoroalkyls include the series (CH2) ⁇ 4CF3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3- trifluoro-n-propyl, etc.).
- carbocycle (and variations thereof such as “carbocyclic” or “carbocyclyl”) as used herein, unless otherwise indicated, refers to (i) a C3 to Cg monocyclic, saturated or unsaturated ring or (ii) a C7 to Cj2 bicyclic saturated or unsaturated ring system. Each ring in (ii) is either independent of, or fused to, the other ring, and each ring is saturated or unsaturated.
- the carbocycle may be attached to the rest of the molecule at any carbon atom which results in a stable compound.
- fused bicyclic carbocycles are a subset of the carbocycles; i.e., the term "fused bicyclic carbocycle” generally refers to a Cj to CiO bicyclic ring system in which each ring is saturated or unsaturated and two adjacent carbon atoms are shared by each of the rings in the ring system.
- a fused bicyclic carbocycle in which one ring is saturated and the other is saturated is a saturated bicyclic ring system.
- a fused bicyclic carbocycle in which one ring is benzene and the other is saturated is an unsaturated bicyclic ring system.
- a fused bicyclic carbocycle in which one ring is benzene and the other is unsaturated is an unsaturated ring system.
- Saturated carbocyclic rings are also referred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc.
- carbocycle is unsubstituted or substituted with C 1-6 alkyl, Ci_6 alkenyl, Ci. 6 alkynyl, aryl, halogen, NH2 or OH.
- a subset of the fused bicyclic unsaturated carbocycles are those bicyclic carbocycles in which one ring is a benzene ring and the other ring is saturated or unsaturated, with attachment via any carbon atom that results in a stable compound. Representative examples of this subset include the following:
- aryl refers to aromatic mono- and poly-carbocyclic ring systems, wherein the individual carbocyclic rings in the polyring systems are fused or attached to each other via a single bond.
- Suitable aryl groups include phenyl, naphthyl, and biphenylenyl.
- heterocycle broadly refers to (i) a stable 4- to 8-membered, saturated or unsaturated monocyclic ring, or (ii) a stable 7- to 12-membered bicyclic ring system, wherein each ring in (ii) is independent of, or fused to, the other ring or rings and each ring is saturated or unsaturated, and the monocyclic ring or bicyclic ring system contains one or more heteroatoms (e.g., from 1 to 6 heteroatoms, or from 1 to 4 heteroatoms) selected from N, O and S and a balance of carbon atoms (the monocyclic ring typically contains at least one carbon atom and the ring systems typically contain at least two carbon atoms); and wherein any one or more of the nitrogen and sulfur heteroatoms is optionally oxidized, and any one or more of the nitrogen heteroatoms is optionally quaternized.
- heteroatoms e.g., from 1 to 6 heteroatoms, or from 1 to 4 heteroatoms
- the heterocyclic ring may be attached at any heteroatom or carbon atom, provided that attachment results in the creation of a stable structure.
- the heterocyclic ring has substituents, it is understood that the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results.
- cycloalkyl, aryl and heterocycle groups are unsubstituted or substituted.
- substituted C3-C10 cycloalkyl “substituted aryl” and “substituted heterocycle” are intended to include the cyclic group containing from 1 to 3 substituents in addition to the point of attachment to the rest of the compound.
- the substituents are selected from the group which includes, but is not limited to, halo, C1-C20 alkyl, CF3, NH2, N(Ci-C6 alkyl) 2 , NO2, oxo, CN, N3, -OH, -O(Ci-C6 alkyl), C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (Co-C 6 alkyl) S(0) ⁇ -2-, aryl-S(0) ⁇ -2-, (Co-C 6 alkyl)S(O) 0 - 2(C 0 -C 6 alkyl)-, (Co-C 6 alkyl)C(O)NH-, H 2 N-C(NH)-, -0(Ci-C 6 aikyl)CF 35 (C 0 -C 6 alkyl)C(O)-, (C 0 - C 6 alkyl)OC(O)-, (C 0
- saturated heterocyclics form a subset of the heterocycles; i.e., the term “saturated heterocyclic” generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is saturated.
- saturated heterocyclic ring refers to a 4- to 8-membered saturated monocyclic ring or a stable 7- to 12-membered bicyclic ring system which consists of carbon atoms and one or more heteroatoms selected from N, O and S.
- Representative examples include piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl).
- Heteroaromatics form another subset of the heterocycles; i.e., the term “heteroaromatic” (alternatively “heteroaryl”) generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is an aromatic ring system.
- the term “heteroaromatic ring” refers a 5- or 6-membered monocyclic aromatic ring or a 7- to 12-membered bicyclic which consists of carbon atoms and one or more heteroatoms selected from N, O and S.
- substituted heteroaryl rings containing at least one nitrogen atom e.g., pyridine
- substitutions can be those resulting in N-oxide formation.
- heteroaromatic rings include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.
- bicyclic heterocycles include benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl,
- phenyl having as a substituent methylenedioxy attached to two adjacent carbon atoms.
- an “unsaturated” ring is a partially or fully unsaturated ring.
- an “unsaturated monocyclic Cg carbocycle” refers to cyclohexene, cyclohexadiene, and benzene.
- heterocycle described as containing from “1 to 4 heteroatoms” means the heterocycle can contain 1, 2, 3 or 4 heteroatoms.
- substituted e.g., as in "aryl which is optionally substituted with one or more substituents "
- substituents include mono- and poly-substitution by a named substituent to the extent such single and multiple substitution (including multiple substitution at the same site) is chemically allowed.
- the pyridyl-N-oxide portion is structurally depicted using conventional representations such as
- Ri is a defined variable
- RJ is a defined variable
- the value of Ri may differ in each instance in which it occurs, and the value of RJ may differ in each instance in which it occurs.
- Ri and RJ are independently selected from the group consisting of methyl, ethyl, propyl and butyl
- (CR ⁇ RJ)2 can be
- Pharmaceutically acceptable salts include both the metallic (inorganic) salts and organic salts; a list of which is given in Remington's Pharmaceutical Sciences, 17th Edition, pg. 1418 (1985). It is well known to one skilled in the art that an appropriate salt form is chosen based on physical and chemical stability, flowability, hydro-scopicity and solubility.
- pharmaceutically acceptable salts include, but are not limited to salts of inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate or salts of an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p- toluenesulfonate or palmoate, salicylate and stearate.
- pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium (especially ammonium salts with secondary amines).
- Preferred salts of this invention for the reasons cited above include potassium, sodium, calcium and ammonium salts.
- crystal forms, hydrates and solvates of the compounds of Formula I are crystal forms, hydrates and solvates of the compounds of Formula I.
- the racemic mixture was separated by ChiralPak AD (30 % iPrOH in Hexane + DEA 1 mL/L).
- the first peak was enantiomer A of 2-bromo-6-[l-(4-fluorophenyl)-2,2-dipyridin-3- ylethyljpyridine; HRMS m/z (M+H) Calcd.: 434.0663, found: 434.0648.
- the second peak was enantiomer B of 2-bromo-6-[l-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]pyridine; HRMS m/z (M+H) Calcd.: 434.0633, found: 434.0646.
- Enantiomer B of N- ⁇ 6-[l-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]pyridin-2-yl ⁇ methanesulfonamide (HRMS m/z (M+H) Calcd.: 449.1442, found: 449.1459) was synthesized using the method described above except with enantiomer B of 2-bromo-6-[l-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]pyridine.
- the first peak was enantiomer A of 3-[l-(6- bromopyridin-2-yI)-2,2-dipyridin-3-ylethyl]benzonitrile
- the second peak was enantiomer B of 3-[l- (6-bromopyridin-2-yl)-2,2-dipyridin-3-ylethyl]benzonitrile.
- Enantiomer B of N- ⁇ 6-[l-(3-cyanophenyl)-2,2-dipyridin-3- ylethyl]pyridin-2-yl ⁇ methanesulfonamide (HRMS m/z (M+H) Calcd.: 456.1489, found: 456.1469) was synthesized using the method described above except with enantiomer B of 3-[l-(6-bromopyridin-2-yl)- 2,2-dipyridin-3-ylethyl]benzonitrile.
- the racemic mixture was separated by ChiralPak AD (40% EtOH in Hexanes +DEA 1 mL/L).
- the first peak was enantiomer A of 2-bromo-6-[l-(6-methoxypyridin-2-yl)- 2,2-dipyridin-3-ylethyl]pyridine
- the second peak was enantiomer B of 2-bromo-6-[l-(6- methoxypyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyridine.
- the mixture was cooled to rt and diluted with CHCI 3 .
- the mixture was filtered through a pad of celite and washed with CHCl 3 and EtOAc.
- the filterate was concentrated and purified by silica gel chromatography (1-5% MeOH in CH2Q2).
- the mixture was then purified by acidic reverse phase HPLC (95% H 2 0:5% CH 3 CN to 100 % CH 3 CN + 0.1% TFA).
- the fractions were concentrated then quenched with saturated aqueous, sodium bicarbonate, and extracted 3x with EtOAc. The combined organic were dried (anhd.
- Enantiomer B of N- ⁇ 6-[l-(6-methoxypyridin-2-yl)-2,2-dipyridin-3- ylethyl]pyridin-2-yl ⁇ methanesulfonamide (LRMS m/z (M+H) Calcd.: 462.1595, found 462.1597) was synthesized using the method described above except with enantiomer B of 2-bromo-6-[l-(6- methoxypyridin-2-yl)-2,2-dipyridin-3-ylethyl]pyridine.
- EXAMPLE 1-4 (R and S)-3-Fl -r2-aminopvrimidin-4-vlV2,2-dipvridin-3-vlethvllbenzonitrile
- the racemic mixture was separated by Chiralcel OD (50% /-PrOH in hexane).
- the first peak was (-)-3- [l-(2-aminopyrimidin-4-yl)-2,2-dipyridin-3-ylethyl]benzonitrile.
- the second peak was (+)-3-[l-(2- aminopyrimidin-4-yl)-2,2-dipyridin-3-ylethyl]benzonitrile.
- Lithium hexamethyldisilazide solution (8.39 mL of IM in tetrahydrofuran, 8.39 mmol) was added to dry T ⁇ F and cooled to -78 0 C. Methyl phenylacetate (1.15 mL, 7.99 mmol) was added dropwise, and the reaction stirred for 15 minutes. A solution of l-benzyl-5-ethoxy-3,4-dihydro-2H-pyrrolium tetrafluoroborate in 5 mL of tetrahydrofuran was added dropwise, and after one hour the reaction was allowed to warm to room temperature. The mixture was quenched with saturated NaHCO 3 solution, warmed to ambient temperature and poured into water.
- 3-Bromopyridine (0.790 mL, 8.20 mmol) was dissolved in 30 mL of dry Et2 ⁇ 3 and was cooled to -78 0 C.
- ra-Butyl lithium (3.28 mL, 2.5M solution in hexanes, 8.20 mmol) was added dropwise via syringe over 10 minutes.
- a solution of tert-butyl 2-(2-methoxy-2-oxo-l- phenylethyl)pyrrolidine-l-carboxylate (0.524 g, 1.64 mmol) in 5 mL of ether was added dropwise.
- KvI.5 inhibitors and antiarrhythmics were evaluated and found to exhibit activity in the KvI .5 assays, thereby demonstrating and confirming the utility of the compounds of this invention as KvI.5 inhibitors and antiarrhythmics.
- Compounds of this type may exhibit forward rate-dependence, blocking the outward K + currents to a greater extent or preferentially at faster rates of depolarization or heart rates.
- Such a compound could be identified in electrophysiological studies as described below. For example, during a train of depolarizations delivered at frequencies of 1 Hz and 3 Hz, the block is "rate-dependent" if the amount of block observed during a 10 second train at 3 Hz is greater than that at 1 Hz.
- a KvI .5 blocker may also display use-dependence, during which the block of the outward K + currents increases with use, or during repetitive depolarization of a cardiac cell.
- Use dependence of block occurs to a greater extent with each successive depolarization in a train or sequence of pulses or depolarizations at a given rate or frequency. For example, during a train of 10 depolarizations at a frequency of 1 Hz, the block is "use-dependent" if the amount of block is greater for the 10 th pulse than for the 1 st pulse of the train.
- a Kvl.5 blocker may exhibit both use- dependence and rate-dependence.
- a Kvl.5 blocker may also be identified through electrophysiological studies of native I Kur using cardiac myocytes or other tissue from various species including, but not limited to, human, rat, mouse, dog, monkey, ferret, rabbit, guinea pig, or goat.
- native tissues Kvl.5 may exist as a homo- oligomer, or as a hetero-oligomer with other Kv family members, or may exist in a complex with a ⁇ - subunit.
- Compounds of mis invention may block KvI .5 homo- or hetero-oligomers or KvI .5 in complexes with ⁇ -subunits.
- the high throughput Kvl.5 planar patch clamp assay is a systematic primary screen. It confirms activity and provides a functional measure of the potency of agents that specifically affect Kvl.5 potassium channels. Kiss et al. (Assay and Drug Dev. Tech., 1(1-2): 127-135,2003) and Schroeder et al. (J. of Biomol. Screen., 8(l);50-64, 2003) describe the use of this instrument for Kvl.5 as well as other voltage gated ion channels.
- CHO Chinese hamster ovary cells
- CHO stably expressing the human KvI .5 potassium channel alpha subunit, cloned from human heart, are grown to 90-100% confluence in Ham's F12 medium supplemented with 10% FBS, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin, 1000 ⁇ g/ml G-418 sulfate.
- Cells are subcultured by treatment with Versene, then suspended in phosphate-buffered saline (PBS) and centrifuged The cell pellet is resuspended in PBS and the resulting suspension placed in the cell reservoir of the IonWorksTM HT instrument.
- PBS phosphate-buffered saline
- Electrophysiological recordings are performed with intracellular solution containing (mM): K-gluconate 100, KCl 40, MgCl 2 3.2, EGTA 3, N-2-hydroxylethylpiperazine-N 1 -2- ethanesulphonic acid (HEPES) 5, adjusted to pH 7.3.
- Amphotericin (Sigma) is prepared as 30 mg/ml stock solution and diluted to a final working concentration of 0.1 mg/ml in internal buffer solution.
- the external solution is Dulbecco's PBS (Invitrogen) and contains (mM): CaCl 2 0.90, KCl 2.67, K 3 PO 4 1.47, MgCl 2 0.50, NaCl 138, Na 3 PO 4 8.10 and has a pH of 7.4. All compounds are prepared as 10 mM stock solutions in DMSO. Compounds are diluted into external buffer, then transferred from the drug plate to the Patchplate during the experiment (final DMSO concentration ⁇ 0.66% vol.).
- Kvl.5 ionic currents are recorded at room temperature.
- Membrane currents are amplified (RMS ⁇ 10pA) and sampled at 10 kHz.
- Leak subtraction was performed in all experiments by applying a 160 ms hyperpolarizing (10 mV) pre-pulses 200 ms before the test pulses to measure leak conductance.
- the patch clamp stimulus protocol is as follows:
- Patchplate wells are loaded with 3.5 ⁇ L of external buffer.
- Planar micropipette hole resistances is determined by applying a 10 mV, 160 ms potential difference across each hole (Hole test). 3. Cells are pipetted into the Patchplate and form high resistance seals with the 1-2 ⁇ m holes at the bottom of each Patchplate well. A seal test scan is performed to determine how many of the Patchplate wells have cells that have formed seals.
- intracellular solution containing amphotericin is circulated for 4 minutes on the bottom side of the Patchplate.
- Pre-compound addition test pulse is applied to each well on the Patchplate. Protocol: Cells are voltage clamped at a membrane holding potential of -80 mV for 15 seconds. This is followed by application of a 5 Hz stimulus train (27 x 150 ms depolarizations to +40 mV). The membrane potential steps to +40 mV evoke outward (positive) ionic currents.
- Protocol Cells are voltage clamped at a membrane holding potential of -80 mV for 15 seconds. This is followed by application of a 5 Hz stimulus train (27 x 150 ms depolarizations to +40 mV).
- baseline metric the mean current at -70 mV from 5 to 45 ms before the first depolarization to +40 mV
- pre-read peak metric is ⁇ 400 pA.
- the above-listed compounds provide > 20% inhibition at a concentration of 33 ⁇ M or less in the high throughput KvI.5 planar patch clamp assay described above.
- This assay identifies agents that specifically block the human Kv 1.5 K+ channel heterologously expressed in CHO cells as measured by Rb + efflux using Flame Atomic Absorption Spectroscopy (FAAS).
- FAAS Flame Atomic Absorption Spectroscopy
- CHO cells expressing human KvI.5 are cultured as described above, then harvested with trypsin-EDTA and washed with medium.
- the cells are washed 5 times with 200 ⁇ l Hank's Balanced Salt Solution (HBSS) followed by the addition of 100 ⁇ l HBSS containing test compound or 0.5 % DMSO.
- HBSS Hank's Balanced Salt Solution
- Rb content is measured in samples of supernatant (SUP) and lysate (LYS) using an ICR-8000 automated AAS instrument (Aurora Biomed, Vancouver, BC).
- % FLUX 100%*(SUP/(LYS+SUP)).
- % INH 100%*(l-(A-B)/(C-B)), where A is % FLUX in the presence of tested compound, B is % FLUX in the presence of 10 mM (6-methoxy-2-methyl-l-oxo-4- phenyl-l ⁇ -dihydroisoquinolin-S-y ⁇ -N ⁇ N-dimethylmethanaminium chloride, C is % FLUX in the presence of 0.25% DMSO.
- the above-listed compounds provide > 25% inhibition at a concentration of 25 ⁇ M or less in the AAS assay described above.
- the compounds of this invention can be administered for the treatment or prevention of afflictions, diseases and illnesses according to the invention by any means that effects contact of the active ingredient compound with the site of action in the body of a warm-blooded animal.
- administration can be oral, topical, including transdermal, ocular, buccal, intranasal, inhalation, intravaginal, rectal, intracisternal and parenteral.
- parenteral refers to modes of administration which include subcutaneous, intravenous, intramuscular, intraarticular injection or infusion, intrasternal and intraperitoneal.
- the compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
- a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.
- the dosage administered will be dependent on the age, health and weight of the recipient, the extent of disease, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired.
- a daily dosage of active ingredient compound will be from about 1-500 milligrams per day. Ordinarily, from 10 to 100 milligrams per day in one or more applications is effective to obtain desired results.
- These dosages are the effective amounts for the treatment and prevention of afflictions, diseases and illnesses described above, e.g., cardiac arrhythmias such as atrial fibrillation, atrial flutter, atrial arrhythmia, and supraventricular tachycardia, thromboembolic events such as stroke and congestive heart failure, and immunodepression.
- the active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, troches, dragees, granules and powders, or in liquid dosage forms, such as elixirs, syrups, emulsions, dispersions, and suspensions.
- the active ingredient can also be administered parenterally, in sterile liquid dosage forms, such as dispersions, suspensions or solutions.
- dosages forms that can also be used to administer the active ingredient as an ointment, cream, drops, transdermal patch or powder for topical administration, as an ophthalmic solution or suspension formation, i.e., eye drops, for ocular administration, as an aerosol spray or powder composition for inhalation or intranasal administration, or as a cream, ointment, spray or suppository for rectal or vaginal administration.
- Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
- powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
- Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
- Li general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene gycols are suitable carriers for parenteral solutions.
- Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances.
- Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
- citric acid and its salts and sodium EDTA are also used.
- parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.
- Suitable pharmaceutical carriers are described in Remington 's Pharmaceutical Sciences, A. Osol, a standard reference text in this field.
- the compounds of the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers.
- the compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device.
- the preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of Formula I in suitable propellants, such as fluorocarbons or hydrocarbons.
- MDI metered dose inhalation
- an ophthalmic preparation may be formulated with an appropriate weight percent solution or suspension of the compounds of Formula I in an appropriate ophthalmic vehicle, such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye.
- Useful pharmaceutical dosage-forms for administration of the compounds of this invention include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injectables, and oral suspensions.
- a large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
- a mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient.
- the capsules are washed and dried.
- a large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose.
- Appropriate coatings may be applied to increase palatability or delay absorption.
- a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol. The solution is made to volume with water for injection and sterilized.
- An aqueous suspension is prepared for oral administration so that each 5 milliliters contain 100 milligrams of finely divided active ingredient, 100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin.
- the same dosage forms can generally be used when the compounds of this invention are administered stepwise or in conjunction with another therapeutic agent.
- the dosage form and administration route should be selected depending on the compatibility of the combined drugs.
- coadministration is understood to include the administration of the two agents concomitantly or sequentially, or alternatively as a fixed dose combination of the two active components.
- Compounds of the invention can be administered as the sole active ingredient or in combination with a second active ingredient, including other antiarrhythmic agents having KvI.5 blocking activities such as quinidine, propafenone, ambasilide, amiodarone, flecainide, sotalol, bretylium, dofetilide, almokalant, bepridil, clofilium, other compounds having Kv 1.5 blocking activities such as clotrimazole, ketoconazole, bupivacaine, erythromycin, verapamil, nifedipine, zatebradine, bisindolylmaleimide, or other cardiovascular agents such as, but not limited to, ACE inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril erbumine, quinapril, ramipril, and trandolapril, angio
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MX2007001188A MX2007001188A (en) | 2004-07-29 | 2005-07-25 | 1,1,2,2-tetra (hetero) arylethanes or 1,1,2-tri (hetero) aryl-2-heterocyclylethanes as potassium channel inhibitors. |
BRPI0513793-4A BRPI0513793A (en) | 2004-07-29 | 2005-07-25 | pharmaceutically acceptable compound or salt thereof, method of treating a condition in a mammal, pharmaceutical formulation, and pharmaceutical composition |
IL180846A IL180846A0 (en) | 2004-07-29 | 2007-01-21 | 1,1,2,2-tetra (hetero) arylethanes or 1,1,2-tri (hetero) aryl-2-heterocyclylethanes as potassium channel inhibitors |
NO20071107A NO20071107L (en) | 2004-07-29 | 2007-02-27 | 1,1,2,2-tetra (hetero) arylethanes or 1,1,2-tri (hetero) aryl-2-heterocyclylethanes as potassium channel inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US59218104P | 2004-07-29 | 2004-07-29 | |
US60/592,181 | 2004-07-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006028590A1 true WO2006028590A1 (en) | 2006-03-16 |
Family
ID=35613661
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2005/026334 WO2006028590A1 (en) | 2004-07-29 | 2005-07-25 | 1,1,2,2-tetra (hetero) arylethanes or 1,1,2-tri (hetero) aryl-2-heterocyclylethanes as potassium channel inhibitors |
Country Status (15)
Country | Link |
---|---|
KR (1) | KR20070043985A (en) |
AR (1) | AR049847A1 (en) |
BR (1) | BRPI0513793A (en) |
CR (1) | CR8876A (en) |
EC (1) | ECSP077208A (en) |
IL (1) | IL180846A0 (en) |
MA (1) | MA28980B1 (en) |
MX (1) | MX2007001188A (en) |
NO (1) | NO20071107L (en) |
PE (1) | PE20060382A1 (en) |
RU (1) | RU2344134C2 (en) |
TW (1) | TW200607493A (en) |
UA (1) | UA88018C2 (en) |
WO (1) | WO2006028590A1 (en) |
ZA (1) | ZA200700477B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9238666B2 (en) | 2012-06-11 | 2016-01-19 | Bristol-Myers Squibb Company | Phosphoramidic acid prodrugs of 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl] pyridine-3-sulfonamide |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BRPI1009313A2 (en) * | 2009-03-18 | 2018-01-30 | Medicure Int Inc | transdermal pharmaceutical preparation and administration of tirofiban |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003059873A1 (en) * | 2002-01-04 | 2003-07-24 | Poseidon Pharmaceuticals A/S | Potassium channel modulators |
-
2005
- 2005-07-19 AR ARP050102975A patent/AR049847A1/en unknown
- 2005-07-22 PE PE2005000858A patent/PE20060382A1/en not_active Application Discontinuation
- 2005-07-22 TW TW094125011A patent/TW200607493A/en unknown
- 2005-07-25 WO PCT/US2005/026334 patent/WO2006028590A1/en active Application Filing
- 2005-07-25 MX MX2007001188A patent/MX2007001188A/en unknown
- 2005-07-25 UA UAA200702125A patent/UA88018C2/en unknown
- 2005-07-25 RU RU2007107408/04A patent/RU2344134C2/en not_active IP Right Cessation
- 2005-07-25 BR BRPI0513793-4A patent/BRPI0513793A/en not_active IP Right Cessation
- 2005-07-25 KR KR1020077002228A patent/KR20070043985A/en not_active Application Discontinuation
-
2007
- 2007-01-16 ZA ZA200700477A patent/ZA200700477B/en unknown
- 2007-01-21 IL IL180846A patent/IL180846A0/en unknown
- 2007-01-25 CR CR8876A patent/CR8876A/en not_active Application Discontinuation
- 2007-01-26 EC EC2007007208A patent/ECSP077208A/en unknown
- 2007-02-21 MA MA29689A patent/MA28980B1/en unknown
- 2007-02-27 NO NO20071107A patent/NO20071107L/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003059873A1 (en) * | 2002-01-04 | 2003-07-24 | Poseidon Pharmaceuticals A/S | Potassium channel modulators |
Non-Patent Citations (27)
Title |
---|
A. RICHARDSON, JR. ET AL.: "Triarylpyridylethanols and Triarylpyridylethylenes. Chemistry and Antifertility Effects", JOURNAL OF MEDICINAL CHEMISTRY., vol. 18, no. 7, 1975, AMERICAN CHEMICAL SOCIETY. WASHINGTON; US, pages 689 - 691, XP002365173 * |
D'ALESSANDRO, D. M. ET AL.: "Mono- and di-nuclear complexes of the ligands 3,4-di(2-pyridyl)-1,2,5-oxadiazole and 3,4-di(2-pyridyl)-1,2,5-thiadiazole; new bridges allowing unusually strong metal-metal interactions", AUSTRALIAN JOURNAL OF CHEMISTRY., vol. 56, no. 7, 2003, CSIRO PUBLISHING, MELBOURNE; AU, pages 657 - 664 * |
DATABASE BEILSTEIN [online] Beilstein Institut zur Foerderung der chemischen Wissenschaften; XP002365390, retrieved from XFIRE Database accession no. 9712968/BRN * |
DATABASE BEILSTEIN [online] Beilstein Institut zur Foerderung der chemischen Wissenschaften; XP002365391, retrieved from XFIRE Database accession no. 6423228/BRN * |
DATABASE BEILSTEIN [online] Beilstein Institut zur Foerderung der chemischen Wissenschaften; XP002365394, retrieved from XFIRE Database accession no. 1025723/BRN * |
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002365392, retrieved from STN Database accession no. 1957:71471 * |
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002365393, retrieved from STN Database accession no. 1964:16544 * |
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002365395, retrieved from STN Database accession no. 1970:43371 * |
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002365396, retrieved from STN Database accession no. 1974:26410 * |
E. F. PRATT ET AL.: "Oxidation by Solids. II. The Preparation of Either Tetraarylethanes or Diaryl Ketones by the Oxidation of Diarylmethanes with Manganese Dioxide", JOURNAL OF ORGANIC CHEMISTRY., vol. 28, 1963, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC; US, pages 638 - 642, XP002365162 * |
E. V. BROWN ET AL.: "Photochemical Preparation and rearrangement of Some Symmetrical Methoxypyridyl Phenyl Glycols (Pinacols)", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 8, no. 6, 1971, PROVO, UT; US, pages 967 - 973, XP002365170 * |
E. V. BROWN ET AL.: "Pinacol Reanrrangement of Quinoline Analogs of Benzopinacol and Evidence for Rearrangement under the Conditions of Electron Impact", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 6, no. 4, 1969, PROVO, UT; US, pages 567 - 570, XP002365161 * |
F. J. VILLANI ET AL.: "Hypocholesteremic Agents. I. Substituted Stilbazoles and Dihydrostilbazoles", JOURNAL OF MEDICINAL CHEMISTRY., vol. 13, no. 3, 1970, AMERICAN CHEMICAL SOCIETY. WASHINGTON; US, pages 359 - 366, XP002365172 * |
G. N. WALKER: "Palladium-catalyzed hydrogenation of pyridines", JOURNAL OF ORGANIC CHEMISTRY., vol. 27, 1962, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC; US, pages 2966 - 2967 * |
H. E. ZIMMERMAN ET AL.: "Control of the Stereochemistry of Kinetic Protonation: Intramolecular Proton Delivery", JOURNAL OF ORGANIC CHEMISTRY., vol. 64, 1999, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC; US, pages 6635 - 6645, XP002365169 * |
J. J. EISCH ET AL.: "Coordination-Induced Reductive Elimination and Titanium(II) Carbenoid Transfer in Reactions of Dialkyltitanium(IV) Complexes with Unsaturated Organic Substrates", ORGANOMETALLICS., vol. 22, 2003, ACS, WASHINGTON, DC; US, pages 24 - 26, XP002365167 * |
K. K. CHIU ET AL.: "Infrared and Raman spectra of 1,2-bis(4-pyridyl)ethanes", SPECTROCHIMICA ACTA. PART A: MOLECULAR AND BIOMOLECULAR SPECTROSCOPY, vol. 29, no. 11, 1973, ELSEVIER, AMSTERDAM; NL, pages 1947 - 1952 * |
K. K. CHIU ET AL.: "Reaction of substituted pyridines with free tert-butoxy radicals", JOURNAL OF THE CHEMICAL SOCIETY, SECTION C: ORGANIC CHEMISTRY., vol. 19, 1969, CHEMICAL SOCIETY. LETCHWORTH; GB, pages 2758 - 2761 * |
M. ABE ET AL.: "Oxidative Ring-Opening Reaction of Cyclopropanone Acetals with Carbonyl Compounds via Photoinduced Electron Transfer. Generation of a .beta.-Carbonyl Radical Species and Its Application to the Synthesis of .gamma.-Hydroxy Ester Derivatives", JOURNAL OF ORGANIC CHEMISTRY., vol. 60, 1965, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC; US, pages 3065 - 3073, XP002365168 * |
M. L. BLACK ET AL.: "2-(2-Pyridyl-)-1,2-diaryl alkanols as hypocholesteremic agents", JOURNAL OF MEDICINAL CHEMISTRY., vol. 10, no. 4, 1967, AMERICAN CHEMICAL SOCIETY. WASHINGTON; US, pages 565 - 575, XP002365171 * |
M. R. KAGELMAN ET AL.: "The Pinacol Rearrangement in the Heterocyclic Series. I. Pyridine Analogs of Benzopinacol", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 75, 1953, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC; US, pages 4649 - 4651, XP002365163 * |
N. D. HEINDEL ET AL.: "Dimeric Photoreduction in 2-Methylbenzophenones", TETRAHEDRON LETTERS, no. 32, 1968, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM. NL, pages 3579 - 3582, XP002365164 * |
R. HABERL ET AL.: "1,2-Di-.alphy.-pyridyl-1,2-diphenylethane", MONATSHEFTE FUER CHEMIE., vol. 88, 1957, SPRINGER VERLAG, VIENNA; AT, pages 47 - 51 * |
S. BANK ET AL.: "Substituent Effect on the Electrochemical Oxidation of Arylmethyl Anions. 4. Effect of Pyridine Rings", JOURNAL OF ORGANIC CHEMISTRY., vol. 52, 1987, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC; US, pages 5105 - 5111, XP002365166 * |
STEEL, P. J. ET AL.: "Coordination chemistry of di-2-pyridylmethane and related bridging ligands with silver(I), copper(II), palladium(II) and zinc(II)", DALTON TRANSACTIONS., no. 23, 2003, RSC PUBLISHING, CAMBRIDGE; GB, pages 4505 - 4515 * |
V. J. TRAYNELIS ET AL.: "Reactions of 4-Alkylpyridine N-Oxides with Dimethyl Sulphoxide", TETRAHEDRON LETTERS, no. 42, 1969, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM; NL, pages 3619 - 3622, XP002365165 * |
W. CZUBA: "Effects of substituent groups on the rearrangement of 3-nitroaminopyridine derivatives", BULLETIN DE L'ACADEMIE POLONAISE DES SCIENCES. SERIE DES SCIENCES CHIMIQUES., vol. 8, no. 6, 1960, WARSZAW; PL, pages 281 - 284 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9238666B2 (en) | 2012-06-11 | 2016-01-19 | Bristol-Myers Squibb Company | Phosphoramidic acid prodrugs of 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl] pyridine-3-sulfonamide |
Also Published As
Publication number | Publication date |
---|---|
NO20071107L (en) | 2007-04-19 |
ZA200700477B (en) | 2009-08-26 |
CR8876A (en) | 2007-08-28 |
RU2344134C2 (en) | 2009-01-20 |
KR20070043985A (en) | 2007-04-26 |
IL180846A0 (en) | 2007-06-03 |
RU2007107408A (en) | 2008-09-10 |
MA28980B1 (en) | 2007-11-01 |
PE20060382A1 (en) | 2006-05-15 |
ECSP077208A (en) | 2007-02-28 |
BRPI0513793A (en) | 2008-05-13 |
UA88018C2 (en) | 2009-09-10 |
TW200607493A (en) | 2006-03-01 |
MX2007001188A (en) | 2007-03-21 |
AR049847A1 (en) | 2006-09-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2004276236B2 (en) | Isoquinolinone potassium channel inhibitors | |
CA2626402C (en) | Potassium channel inhibitors | |
CA2539707C (en) | Quinoline potassium channel inhibitors | |
CA2539853C (en) | Isoquinolinone potassium channel inhibitors | |
EP1776355B1 (en) | Potassium channel inhibitors | |
US8067607B2 (en) | Potassium channel inhibitors | |
US8030332B2 (en) | Potassium channel inhibitors | |
WO2006028590A1 (en) | 1,1,2,2-tetra (hetero) arylethanes or 1,1,2-tri (hetero) aryl-2-heterocyclylethanes as potassium channel inhibitors | |
AU2007210014B2 (en) | Potassium channel inhibitors | |
US8278317B2 (en) | Potassium channel inhibitors | |
AU2007210013B2 (en) | Potassium channel inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 180846 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 552757 Country of ref document: NZ Ref document number: 12007500230 Country of ref document: PH |
|
WWE | Wipo information: entry into national phase |
Ref document number: 07007300 Country of ref document: CO Ref document number: CR2007-008876 Country of ref document: CR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 451.07 Country of ref document: BZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: DZP2007000063 Country of ref document: DZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020077002228 Country of ref document: KR Ref document number: MX/a/2007/001188 Country of ref document: MX |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1200700226 Country of ref document: VN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2007107408 Country of ref document: RU |
|
122 | Ep: pct application non-entry in european phase | ||
ENP | Entry into the national phase |
Ref document number: PI0513793 Country of ref document: BR |