US 2004O2298.03A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0229803 A1 Stephenson et al. (43) Pub. Date: Nov. 18, 2004
(54) COMPOSITIONS OF A Related U.S. Application Data CYCLOOXYGENASE-2 SELECTIVE INHIBITOR AND A POTASSIUM ION (60) Provisional application No. 60/465,068, filed on Apr. CHANNEL MODULATOR FOR THE 24, 2003. Provisional application No. 60/464,775, TREATMENT OF PAIN, INFLAMMATION filed on Apr. 23, 2003. Provisional application No. OR INFLAMMATION MEDIATED 60/464,609, filed on Apr. 22, 2003. DSORDERS Publication Classification (75) Inventors: Diane T. Stephenson, Groton, CT (US); Duncan P. Taylor, Bridgewater, (51) Int. Cl.' ...... A61K 38/17; A61K 31/415; NJ (US) A61K 31/50 (52) U.S. Cl...... 514/12; 514/247; 514/406; Correspondence Address: 514/571 SENNIGER POWERS LEAVITT AND ROEDEL (57) ABSTRACT ONE METROPOLITAN SQUARE 16TH FLOOR The present invention provides compositions and methods ST LOUIS, MO 63102 (US) for the treatment of pain, inflammation or inflammation mediated disorders in a Subject. More particularly, the (73) Assignee: Pharmacia Corporation invention provides a combination therapy for the treatment of pain, inflammation or inflammation mediated disorders (21) Appl. No.: 10/828,734 comprising the administration to a Subject of a potassium ion channel modulator in combination with a cyclooxygenase-2 (22) Filed: Apr. 21, 2004 Selective inhibitor. US 2004/0229803 A1 Nov. 18, 2004
COMPOSITIONS OF A CYCLOOXYGENASE-2 pain-based receptors within the human body. For example, SELECTIVE INHIBITOR AND A POTASSIUM ION morphine and most other opioid analgesicS elicit an inhibi CHANNEL MODULATOR FOR THE TREATMENT tory neuronal effect within central nervous and gastrointes OF PAIN, INFLAMMATION OR INFLAMMATION tinal (GI) systems by interacting with areas of the brain MEDIATED DSORDERS receiving input from the Spinal pain-transmitting pathways containing opioid receptors. By Suppressing neuronal activ CROSS REFERENCE TO RELATED ity at these receptor points, opioid narcotics produce anal APPLICATION gesia and control the pain threshold within a human patient. 0001. This application claims priority from the following 0007 Opioid narcotics, however, have several negative Provisional Applications: Serial No. 60/465,068 filed on side effects that severely limit their therapeutic value. These Apr. 24, 2003, Serial No. 60/464,775 filed on Apr. 23, 2003, Side effects include drowsiness, lethargy, difficulty in being and Serial No. 60/464,609 filed on Apr. 22, 2003, all of mobile, respiratory depression, excessive central nervous which are hereby incorporated by reference in their entirety. System depression, weakness in the extremities, and dizzi neSS. In addition, patients being treated with opioids also FIELD OF THE INVENTION may develop tolerance to the agent, requiring higher doses, 0002 The present invention provides methods and com or addition of other opioids to the pain treatment regimen. positions related to the treatment of pain, inflammation or The larger effective dosage may in turn lead to the devel inflammation mediated disorders. More particularly, the opment of physical and psychological addiction. Further, invention is directed toward a combination therapy for the other typical Side effects of opioid analgesics include miosis, treatment of pain, inflammation or inflammation mediated or constriction of the pupils, nausea, vomiting, prolongation disorders comprising the administration to a Subject of a of Stomach emptying time, and decreased propulsive con potassium ion channel modulator in combination with a tractions of the Small intestine. cyclooxygenase-2 Selective inhibitor. 0008. Several studies demonstrate that potassium chan BACKGROUND OF THE INVENTION nels may contribute to Signal transmission in the brain and Spinal cord, and opioids action may be related to potassium 0.003 Pain is a sensory experience distinct from sensa channel function (Asano T, et al., (1996) Masui Novem tions of touch, preSSure, heat and cold. It is often described ber;45(11): 1342-6). In one study, for example, it was dem by Sufferers by Such terms as bright, dull, aching, pricking, onstrated that potassium ion channel modulator administra cutting or burning and is generally considered to include tion to mice showed significant anesthetic effect for the both the original Sensation and the reaction to that Sensation. treatment of chronic pain (Beekwilder M., et al., (2002) J. Pain Sensation is complex and variable. Often experiences Pharmacol. Exp. Ther. (304)(2):531-38). In another study, it considered painful by one Subject may not be equally painful was demonstrated that potassium ion channels provide a to another and may vary in the same Subject depending on common link between numerous neurotransmitter receptors the circumstances presented. This range of Sensations, as and the regulation of Synaptic transmission (Blednov et al., well as the variation in perception of pain by different (2003) PNAS January:(100)(1):277-82). individuals, renders a precise definition of pain difficult, however, many individuals Suffer with Severe and continu 0009. As an alternative to opioid analgesics, a number of ous pain. non-narcotic based drugs may be utilized to treat mild to moderate pain. Generally Speaking, non-narcotic drugs can 0004 Pain can be caused by the stimulation of nocicep be given over longer periods of time compared to opioid tive receptors and transmitted over intact neural pathways, analgesics because of their lower central nervous System and in which case the pain is termed “nociceptive' pain. Gen respiratory depressive effects. Examples of non-narcotic erally Speaking, there are two different types of nociceptive drugs employed to treat pain include acetylsalicylic acid Stimuli that are intense enough to be perceived as pain. One (aspirin), centrally acting alpha antiadrenergic agents, diflu type, Somatic pain, consists of an intense, localized, Sharp or Sinal, Salsalate, acetaminophen, and nonsteroidal anti-in Stinging Sensation. Somatic pain is mediated by fast-con flammatory agents Such as ibuprofen, naproxen, and feno ducting, lightly myelinated A-delta fibers that have a high profen. These agents all generally relieve pain through threshold (i.e. require a strong mechanical Stimulus to sense prostaglandin Synthesis inhibition resulting in a decrease in pain) and enter into the spinal cord through the dorsal horn pain receptor Stimulation. of the central nervous System where they terminate in the Spinal cord. 0010 Non-narcotic drugs also have several negative side effects that Severely limit their therapeutic value. Aspirin, for 0005 The second type of pain, sometimes referred to as example, has been shown through epidemiological data to Visceral pain, is characterized as a diffuse, dull, aching or be a factor in the occurrence of Reye's Syndrome. In burning Sensation. Visceral pain is mediated largely by addition, Salicylates have been shown to cause gastrointes unmyelinated, slower-conducting C-fibers that are poly tinal upset, gastrointestinal hemorrhage, and anti-platelet modal (i.e., mediate mechanical, thermal, or chemical effects. Acetaminophen has been linked to liver damage, Stimuli). C-fibers also enter the spinal cord through the kidney damage, and hematological effects Such as hemolytic dorsal horn of the central nervous System where they ter anemia, neutropenia, and leukopenia. Moreover, nonsteroi minate in the Spinal cord. Both Somatic and Visceral pain can dal anti-inflammatory agents also exhibit numerous negative be sensed centrally and peripherally within the human body Side effects as well, ranging from gastrointestinal distress, and may be either acute or chronic. gastrointestinal hemorrhage, and kidney damage when 0006. A number of analgesics reduce both central and administered at a therapeutically effective dosage for the peripheral Sensitization through interaction with the various treatment of pain. US 2004/0229803 A1 Nov. 18, 2004
SUMMARY OF THE INVENTION 0.011 Among the several aspects of the invention is provided a method for the treatment of pain, inflammation or inflammation-mediated disorders in a Subject. The method comprises administering to the Subject a cyclooxygenase-2 Selective inhibitor or an isomer, a pharmaceutically accept able Salt, ester, or prodrug thereof in combination with a potassium channel modulator or pharmaceutically accept able Salt or prodrug thereof. 0012. In one embodiment, the cyclooxygenase-2 selec tive inhibitor is a member of the chromene class of com 0024 wherein pounds. For example, the chromene compound may be a 0025 A is selected from the group consisting of partially compound of the formula: unsaturated or unsaturated heterocyclyl and partially unsat urated or unsaturated carbocyclic rings,
0026) R' is selected from the group consisting of hetero (I) cyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R is optionally Substituted at a Substitutable position with one or more radicals Selected from alkyl, haloalkyl, cyano, car boxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkdxyalkyl, alkyl Sulfinyl, halo, alkoxy and alkylthio; 0027 R is selected from the group consisting of methyl 0013 wherein: or amino; and 0.014) n is an integer which is 0, 1, 2, 3 or 4; 0028) R is selected from the group consisting of a radical Selected from H, halo, alkyl, alkenyl, alkynyl, OXO, cyano, 0015) G is O, S or NR; carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, 0016 R is alkyl; cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthio 0017) R' is selected from the group consisting of H and alkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkyl aryl; carbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxy alkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, 0018) R is selected from the group consisting of car alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, boxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-ary alkoxycarbonyl, laminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N- 0019 R is selected from the group consisting of aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylami haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally noalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl Substituted with one or more radicals Selected from alky N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, lthio, nitro and alkylsulfonyl, and aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, 0020 each R" is independently selected from the group aminoSulfonyl, alkylaminoSulfonyl, N-arylaminosulfonyl, consisting of H, halo, alkyl, aralkyl, alkoxy, aryloxy, het arylsulfonyl, N-alkyl-N-arylaminosulfonyl. eroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, het 0029. In one embodiment, the potassium ion channel eroarylamino, heteroarylalkylamino, nitro, amino, amino modulator is a potassium ion channel blocker. In one alter Sulfonyl, alkylaminoSulfonyl, arylaminosulfonyl, heteroary native of this embodiment, the potassium ion channel laminosulfonyl, aralkylaminoSulfonyl, blocker is a Voltage-gated potassium channel blocker. In heteroaralkylaminoSulfonyl, heterocycloSulfonyl, alkylsul another alternative of this embodiment, the potassium ion fonyl, hydroxyarylcarbonyl, nitroaryl, optionally Substituted channel blocker is a calcium-activated potassium channel aryl, optionally Substituted heteroaryl, aralkylcarbonyl, het blocker. In a further alternative of this embodiment, the eroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcar potassium ion channel blocker is an ATP-Sensitive potas bonyl; sium channel blocker. In a still further alternative of this embodiment, the potassium ion channel blocker is a two 0021) or wherein R* together with the carbon atoms to pore potassium channel blocker. which it is attached and the remainder of ring E forms a 0030. In another embodiment, the potassium ion channel naphthyl radical; modulator is a potassium ion channel opener. In one alter 0022 or prodrug thereof. native of this embodiment, the potassium ion channel opener is a Voltage-gated potassium channel opener. In another 0023. In another embodiment, the cyclooxygenase-2 alternative of this embodiment, the potassium ion channel Selective inhibitor or an isomer, a pharmaceutically accept opener is a calcium-activated potassium channel opener. In able Salt, ester, or prodrug thereof comprises a compound of a further alternative of this embodiment, the potassium ion the formula: channel opener is an ATP-Sensitive potassium channel US 2004/0229803 A1 Nov. 18, 2004
opener. In a still further alternative of this embodiment, the Examples of Such radicals include methyl, ethyl, n-propyl, potassium ion channel opener is a two-pore potassium isopropyl, n-butyl, isobutyl, Sec-butyl, tert-butyl, pentyl, channel opener. iso-amyl, hexyl and the like. 0031. Other aspects of the invention are described in 0039 The term “alkylamino” is an amino group that has more detail below. been substituted with one or two alkyl radicals. Preferred are “lower N-alkylamino' radicals having alkyl portions having ABBREVIATIONS AND DEFINITIONS 1 to 6 carbon atoms. Suitable lower alkylamino may be mono or dialkylamino such as N-methylamino, N-ethy 0.032 The term “acyl is a radical provided by the residue lamino, N,N-dimethylamino, N,N-diethylamino or the like. after removal of hydroxyl from an organic acid. Examples of Such acyl radicals include alkanoyl and aroyl radicals. 0040. The term “alkylaminoalkyl” is a radical having one Examples of Such lower alkanoyl radicals include formyl, or more alkyl radicals attached to an aminoalkyl radical. acetyl, propionyl, butyryl, isobutyryl, Valeryl, isoValeryl, pivaloyl, heXanoyl, and trifluoroacetyl. 0041. The term “alkylaminocarbonyl' is an aminocarbo nyl group that has been Substituted with one or two alkyl 0033. The term “alkenyl' is a linear or branched radical radicals on the amino nitrogen atom. Preferred are "N-alky having at least one carbon-carbon double bond of two to laminocarbonyl"N,N-dialkylaminocarbonyl radicals. about twenty carbon atoms or, preferably, two to about More preferred are “lower N-alkylaminocarbonyl"lower twelve carbon atoms. More preferred alkyl radicals are N,N-dialkylaminocarbonyl' radicals with lower alkyl por “lower alkenyl' radicals having two to about six carbon tions as defined above. atoms. Examples of alkenyl radicals include ethenyl, pro penyl, allyl, propenyl, butenyl and 4-methylbutenyl. 0042. The terms “alkylcarbonyl”, “arylcarbonyl” and “aralkylcarbonyl' include radicals having alkyl, aryl and 0034) The terms “alkenyl” and “lower alkenyl” also are aralkyl radicals, as defined above, attached to a carbonyl radicals having "cis" and “trans' orientations, or alterna radical. Examples of Such radicals include Substituted or tively, “E” and “Z” orientations. The term “cycloalkyl is a unsubstituted methylcarbonyl, ethylcarbonyl, phenylcarbo Saturated carbocyclic radical having three to twelve carbon nyl and benzylcarbonyl. atoms. More preferred cycloalkyl radicals are “lower cycloalkyl radicals having three to about eight carbon 0043. The term “alkylthio' is a radical containing a linear atoms. Examples of Such radicals include cyclopropyl, or branched alkyl radical, of one to about ten carbon atoms cyclobutyl, cyclopentyl and cyclohexyl. attached to a divalent sulfur atom. More preferred alkylthio radicals are “lower alkylthio' radicals having alkyl radicals 0035) The terms “alkoxy” and “alkyloxy” are linear or of one to six carbon atoms. Examples of Such lower alky branched oxy-containing radicals each having alkyl portions lthio radicals are methylthio, ethylthio, propylthio, butylthio of one to about ten carbon atoms. More preferred alkoxy and hexylthio. radicals are “lower alkoxy' radicals having one to six carbon atoms. Examples of Such radicals include methoxy, ethoxy, 0044) The term “alkylthioalkyl is a radical containing an propoxy, butoxy and tert-butoxy. alkylthio radical attached through the divalent Sulfur atom to an alkyl radical of one to about ten carbon atoms. More 0.036 The term “alkoxyalkyl” is an alkyl radical having preferred alkylthioalkyl radicals are “lower alkylthioalkyl one or more alkoxy radicals attached to the alkyl radical, that radicals having alkyl radicals of one to six carbon atoms. is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. The Examples of Such lower alkylthioalkyl radicals include “alkoxy' radicals may be further substituted with one or methylthiomethyl. more halo atoms, Such as fluoro, chloro or bromo, to provide haloalkoxy radicals. More preferred haloalkoxy radicals are 004.5 The term “alkylsulfinyl' is a radical containing a “lower haloalkoxy' radicals having one to six carbon atoms linear or branched alkyl radical, of one to ten carbon atoms, and one or more halo radicals. Examples of Such radicals attached to a divalent -S(=O)- radical. More preferred include fluoromethoxy, chloromethoxy, trifluoromethoxy, alkylsulfinyl radicals are “lower alkylsulfinyl' radicals hav trifluoroethoxy, fluoroethoxy and fluoropropoxy. ing alkyl radicals of one to Six carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, 0037. The term “alkoxycarbonyl' is a radical containing ethylsulfinyl, butylsulfinyl and hexylsulfinyl. an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. More preferred are “lower 0046) The term “alkynyl' is a linear or branched radical alkoxycarbonyl radicals with alkyl porions having 1 to 6 having two to about twenty carbon atoms or, preferably, two carbons. Examples of Such lower alkoxycarbonyl (ester) to about twelve carbon atoms. More preferred alkynyl radicals include Substituted or unsubstituted methoxycarbo radicals are “lower alkynyl' radicals having two to about ten nyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and carbon atoms. Most preferred are lower alkynyl radicals hexyloxycarbonyl. having two to about Six carbon atoms. Examples of Such 0.038. Where used, either alone or within other terms such radicals include propargyl, butynyl, and the like. as “haloalkyl”, “alkylsulfonyl”, “alkoxyalkyl” and 0047 The term “aminoalkyl is an alkyl radical substi “hydroxyalkyl', the term “alkyl” is a linear, cyclic or tuted with one or more amino radicals. More preferred are branched radical having one to about twenty carbon atoms “lower aminoalkyl radicals. Examples of Such radicals or, preferably, one to about twelve carbon atoms. More include aminomethyl, aminoethyl, and the like. preferred alkyl radicals are “lower alkyl radicals having one to about ten carbon atoms. Most preferred are lower 0048. The term “aminocarbonyl' is an amide group of the alkyl radicals having one to about six carbon atoms. formula –C(=O)NH2. US 2004/0229803 A1 Nov. 18, 2004
0049. The term “aralkoxy” is an aralkyl radical attached radical with halo. Examples of such lower carboxyalkyl through an oxygen atom to other radicals. radicals include carboxymethyl, carboxyethyl and carbox ypropyl. 0050. The term “aralkoxyalkyl” is an aralkoxy radical attached through an oxygen atom to an alkyl radical. 0063. The term “cycloalkenyl' is a partially unsaturated carbocyclic radical having three to twelve carbon atoms. 0051. The term “aralkyl is an aryl-substituted alkyl More preferred cycloalkenyl radicals are “lower cycloalk radical Such as benzyl, diphenylmethyl, triphenylmethyl, enyl' radicals having four to about eight carbon atoms. phenylethyl, and diphenylethyl. The aryl in Said aralkyl may Examples of Such radicals include cyclobutenyl, cyclopen be additionally substituted with halo, alkyl, alkoxy, halko tenyl, cyclopentadienyl, and cyclohexenyl. alkyl and haloalkoxy. The terms benzyl and phenylmethyl are interchangeable. 0064. The term “cyclooxygenase-2 selective inhibitor” is a compound able to inhibit cyclooxygenase-2 without Sig 0.052 The term “aralkylamino” is an aralkyl radical nificant inhibition of cyclooxygenase-1. Typically, it attached through an amino nitrogen atom to other radicals. includes compounds that have a cyclooxygenase-2 ICso of The terms “N-arylaminoalkyl and “N-aryl-N-alkyl-ami less than about 0.2 micro molar, and also have a Selectivity noalkyl are amino groups which have been Substituted with ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 one aryl radical or one aryl and one alkyl radical, respec inhibition of at least 50, and more typically, of at least 100. tively, and having the amino group attached to an alkyl Even more typically, the compounds have a cyclooxyge radical. Examples of Such radicals include N-phenylami nase-1 ICso of greater than about 1 micro molar, and more nomethyl and N-phenyl-N-methylaminomethyl. preferably of greater than 10 micro molar. Inhibitors of the 0053) The term “aralkylthio” is an aralkyl radical cyclooxygenase pathway in the metabolism of arachidonic attached to a Sulfur atom. acid used in the present method may inhibit enzyme activity through a variety of mechanisms. By the way of example, 0.054 The term “aralkylthioalkyl is an aralkylthio radi and without limitation, the inhibitors used in the methods cal attached through a Sulfur atom to an alkyl radical. described herein may block the enzyme activity directly by 0055. The term “aroyl” is an aryl radical with a carbonyl acting as a Substrate for the enzyme. radical as defined above. Examples of aroyl include benzoyl, 0065. The term “halo' is a halogen such as fluorine, naphthoyl, and the like and the aryl in Said aroyl may be chlorine, bromine or iodine. additionally Substituted. 0066. The term “haloalkyl” is a radical wherein any one 0056. The term “aryl', alone or in combination, is a or more of the alkyl carbon atoms is substituted with halo as carbocyclic aromatic System containing one, two or three defined above. Specifically included are monohaloalkyl, rings wherein Such rings may be attached together in a dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl pendent manner or may be fused. The term “aryl' includes radical, for one example, may have either an iodo, bromo, aromatic radicals. Such as phenyl, naphthyl, tetrahydronaph chloro or fluoro atom within the radical. Dihalo and poly thyl, indane and biphenyl. Aryl moieties may also be Sub haloalkyl radicals may have two or more of the same halo Stituted at a Substitutable position with one or more Sub atoms or a combination of different halo radicals. "Lower Stituents Selected independently from alkyl, alkoxyalkyl, haloalkyl is a radical having 1-6 carbon atoms. Examples alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, ami of haloalkyl radicals include fluoromethyl, difluoromethyl, nocarbonylalkyl, alkoxy, aralkoxy, hydroxyl, amino, halo, trifluoromethyl, chloromethyl, dichloromethyl, trichlorom nitro, alkylamino, acyl, cyano, carboxy, aminocarbonyl, ethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, alkoxycarbonyl and aralkoxycarbonyl. difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. 0057 The term “arylamino” is an amino group, which has been Substituted with one or two aryl radicals, Such as 0067. The term “heteroaryl' is an unsaturated heterocy N-phenylamino. The “arylamino” radicals may be further clyl radical. Examples of unsaturated heterocyclyl radicals, Substituted on the aryl ring portion of the radical. also termed "heteroaryl” radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitro 0.058. The term “aryloxyalkyl” is a radical having an aryl gen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, radical attached to an alkyl radical through a divalent pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triaz OXygen atom. olyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3- 0059. The term “arylthioalkyl is a radical having an aryl triazolyl, etc.) tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, radical attached to an alkyl radical through a divalent Sulfur etc.), etc.; unsaturated condensed heterocyclyl group con atOm. taining 1 to 5 nitrogen atoms, for example, indolyl, isolin dolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, 0060. The term “carbonyl', whether used alone or with indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g., tetra other terms, such as “alkoxycarbonyl', is -(C=O)-. Zolo1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-mem bered heteromonocyclic group containing an oxygen atom, 0061 The terms “carboxy” or “carboxyl”, whether used for example, pyranyl, furyl, etc.; unsaturated 3 to 6-mem alone or with other terms, Such as “carboxyalkyl', is bered heteromonocyclic group containing a Sulfur atom, for -CO2H. example, thienyl, etc.; unsaturated 3- to 6-membered het 0062) The term “carboxyalkyl is an alkyl radical Sub eromonocyclic group containing 1 to 2 oxygen atoms and 1 stituted with a carboxy radical. More preferred are “lower to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, carboxyalkyl” which are lower alkyl radicals as defined oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1.2, above, and may be additionally substituted on the alkyl 5-oxadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl US 2004/0229803 A1 Nov. 18, 2004 group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen ammonium cations, including in part, trimethylamine, atoms (e.g. benzoxazolyl, benzoxadiazolyl, etc.).; unsatur diethylamine, N,N'-dibenzy 1ethylenediamine, chlorop ated 3 to 6-membered heteromonocyclic group containing 1 rocaine, choline, diethanolamine, ethylenediamine, meglu to 2 Sulfur atoms and 1 to 3 nitrogen atoms, for example, mine (N-methylglucamine) and procaine. Exemplary phar thiazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadia maceutically acceptable acids include without limitation Zolyl, 1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed hydrochloric acid, hydrobromic acid, phosphoric acid, Sul heterocyclyl group containing 1 to 2 Sulfur atoms and 1 to furic acid, methaneSulfonic acid, acetic acid, formic acid, 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl, tartaric acid, maleic acid, malic acid, citric acid, isocitric etc.) and the like. The term also includes radicals where acid, Succinic acid, lactic acid, gluconic acid, glucuronic heterocyclyl radicals are fused with aryl radicals. Examples acid, pyruvic acid, oxalacetic acid, fumaric acid, propionic of Such fused bicyclic radicals include benzofuran, ben acid, aspartic acid, glutamic acid, benzoic acid, and the like. Zothiophene, and the like. Said "heterocyclyl group” may 0073. The term “prodrug” refers to a chemical compound have 1 to 3 Substituents Such as alkyl, hydroxyl, halo, that can be converted into a therapeutic compound by alkoxy, OXO, amino and alkylamino. metabolic or simple chemical processes within the body of 0068 The term “heterocyclyl is a saturated, partially the Subject. For example, a class of prodrugs of COX-2 unsaturated and unsaturated heteroatom-containing ring inhibitors is described in U.S. Pat. No. 5,932,598, herein shaped radical, where the heteroatoms may be Selected from incorporated by reference. nitrogen, Sulfur and oxygen. Examples of Saturated hetero cyclyl radicals include Saturated 3 to 6-membered hetero 0074 The term “subject” for purposes of treatment monocylic group containing 1 to 4 nitrogen atoms (e.g. includes any human or animal Subject who is in need of Such pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); treatment. The Subject can be a domestic livestock Species, Saturated 3 to 6-membered heteromonocyclic group contain a laboratory animal Species, a Zoo animal or a companion ing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. animal. In one embodiment, the Subject is a mammal. In morpholinyl, etc.); Saturated 3 to 6-membered heteromono another embodiment, the mammal is a human being. cyclic group containing 1 to 2 Sulfur atoms and 1 to 3 0075) The term “sulfonyl', whether used alone or linked nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of par to other terms Such as alkylsulfonyl, is a divalent radical tially unsaturated heterocyclyl radicals include dihy -SO-. “Alkylsulfonyl” is an alkyl radical attached to a drothiophene, dihydropyran, dihydrofuran and dihydrothia sulfonyl radical, where alkyl is defined as above. More Zole. preferred alkylsulfonyl radicals are “lower alkylsulfonyl 0069. The term “heterocyclylalkyl” is a Saturated and radicals having one to six carbon atoms. Examples of Such partially unsaturated heterocyclyl-Substituted alkyl radical, lower alkylsulfonyl radicals include methylsulfonyl, ethyl Such as pyrrolidinylmethyl, and heteroaryl-Substituted alkyl sulfonyl and propylsulfonyl. The “alkylsulfonyl radicals radicals, Such as pyridylmethyl, quinolylmethyl, thienylm may be further substituted with one or more halo atoms, ethyl, furylethyl, and quinolylethyl. The heteroaryl in said Such as fluoro, chloro or bromo, to provide haloalkylsulfonyl heteroaralkyl may be additionally substituted with halo, radicals. The terms “sulfamyl”, “aminosulfonyl' and “sul alkyl, alkoxy, halkoalkyl and haloalkoxy. fonamidyll” are NHOS-. 0076. The phrase “therapeutically-effective' is intended 0070 The term “hydrido” is a single hydrogen atom (H). to qualify the amount of each agent (i.e. the amount of This hydrido radical may be attached, for example, to an cyclooxygenase-2 Selective inhibitor and the amount of oxygen atom to form a hydroxyl radical or two hydrido potassium ion channel modulator) which will achieve the radicals may be attached to a carbon atom to form a goal of improvement in disorder Severity and the frequency methylene (-CH2-) radical. of incidence over no treatment or treatment of each agent by 0071. The term “hydroxyalkyl” is a linear or branched itself. alkyl radical having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl DESCRIPTION OF THE PREFERRED radicals. More preferred hydroxyalkyl radicals are “lower EMBODIMENTS hydroxyalkyl radicals having one to Six carbon atoms and 0077. The present invention provides a combination one or more hydroxyl radicals. Examples of Such radicals therapy comprising the administration to a Subject of a include hydroxymethyl, hydroxyethyl, hydroxypropyl, therapeutically effective amount of a COX-2 selective hydroxybutyl and hydroxyhexyl. inhibitor in combination with a therapeutically effective 0.072 The term “pharmaceutically acceptable” is used amount of a potassium ion channel modulator. The combi adjectivally herein to mean that the modified noun is appro nation therapy may be used to treat a pain, inflammation or priate for use in a pharmaceutical product; that is the an inflammation mediated disorder. When administered as “pharmaceutically acceptable' material is relatively Safe part of a combination therapy, the COX-2 selective inhibitor and/or non-toxic, though not necessarily providing a sepa together with the potassium ion channel modulator provide rable therapeutic benefit by itself. Pharmaceutically accept enhanced treatment options as compared to administration able cations include metallic ions and organic ions. More of either the potassium ion channel modulator or the COX-2 preferred metallic ions include, but are not limited to appro Selective inhibitor alone. priate alkali metal Salts, alkaline earth metal Salts and other physiologically acceptable metal ions. Exemplary ions CYCLOOXYGENASE-2 SELECTIVE include aluminum, calcium, lithium, magnesium, potassium, INHIBITORS Sodium and Zinc in their usual Valences. Preferred organic 0078. A number of suitable cyclooxygenase-2 selective ions include protonated tertiary amines and quaternary inhibitors or an isomer, a pharmaceutically acceptable Salt, US 2004/0229803 A1 Nov. 18, 2004 ester, or prodrug thereof, may be employed in the compo 0082 wherein: Sition of the current invention. In one embodiment, the cyclooxygenase-2 Selective inhibitor can be, for example, 0083 n is an integer which is 0, 1, 2, 3 or 4; the cyclooxygenase-2 Selective inhibitor meloxicam, For 0084) G is O, S or NR; mula B-1 (CAS registry number 71125-38-7) or an isomer, 0085 R is alkyl; a pharmaceutically acceptable Salt, ester, or prodrug of a 0086) R' is selected from the group consisting of H and compound having Formula B-1. aryl; 0087 R’ is selected from the group consisting of car B-1 boxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl, 0088 R is selected from the group consisting of N - ), haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally N Substituted with one or more radicals Selected from alky S CH lthio, nitro and alkylsulfonyl, and / \, 0089 each R" is independently selected from the group consisting of H, halo, alkyl, aralkyl, alkoxy, aryloxy, het eroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, 0079. In yet another embodiment, the cyclooxygenase-2 haloalkoxy, alkylamino, arylamino, aralkylamino, het Selective inhibitor is the cyclooxygenase-2 Selective inhibi eroarylamino, heteroarylalkylamino, nitro, amino, amino tor, 6-5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl) Sulfonyl, alkylaminoSulfonyl, arylaminosulfonyl, heteroary methyl-3(2H)-pyridazinone, Formula B-2 (CAS registry laminoSulfonyl, aralkylaminoSulfonyl, number 179382-91-3) or an isomer, a pharmaceutically heteroaralkylaminoSulfonyl, heterocycloSulfonyl, alkylsul acceptable Salt, ester, or prodrug of a compound having fonyl, hydroxyarylcarbonyl, nitroaryl, optionally Substituted Formula B-2. aryl, optionally Substituted heteroaryl, aralkylcarbonyl, het eroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcar bonyl; B-2 1. th O 0090 or R' together with the carbon atoms to which it is N N attached and the remainder of ring E forms a naphthyl radical. in Sry 0091. The cyclooxygenase-2 selective inhibitor may also O 2 Cl be a compound of Formula (I) or an isomer, a pharmaceu CH tically acceptable Salt, ester, or prodrug thereof, wherein: 0092 n is an integer which is 0, 1, 2, 3 or 4; 0080. In still another embodiment the cyclooxygenase-2 0.093 G is O, S or NR; Selective inhibitor is a chromene compound that is a Sub Stituted benzopyran or a Substituted benzopyran analog, and 0094) R' is H; even more typically, Selected from the group consisting of 0.095 R is alkyl; Substituted benzothiopyrans, dihydroquinolines, dihy dronaphthalenes or a compound having Formula I shown 0096), R is selected from the group consisting of car below and possessing, by way of example and not limitation, boxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and the structures disclosed in Table 1X. Furthermore, benzopy alkoxycarbonyl, ran cyclooxygenase-2 Selective inhibitors useful in the prac 0097 R is selected from the group consisting of tice of the present methods are described in U.S. Pat. Nos. haloalkyl, alkyl, aralkyl, cycloalkyl and aryl, wherein 6,034,256 and 6,077,850 herein incorporated by reference in haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl each is inde their entirety. pendently optionally Substituted with one or more radicals 0081. In another embodiment, the cyclooxygenase-2 Selected from the group consisting of alkylthio, nitro and Selective inhibitor is a chromene compound represented by alkylsulfonyl; and Formula I or an isomer, a pharmaceutically acceptable Salt, 0.098 each R" is independently selected from the group ester, or prodrug thereof: consisting of hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, het (I) eroarylamino, heteroarylalkylamino, nitro, amino, amino Sulfonyl, alkylaminoSulfonyl, arylaminosulfonyl, heteroary laminoSulfonyl, aralkylaminoSulfonyl, heteroaralkylaminoSulfonyl, heterocycloSulfonyl, alkylsul fonyl, optionally Substituted aryl, optionally Substituted het eroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or wherein R* together with ring E forms a naphthyl radical. US 2004/0229803 A1 Nov. 18, 2004
0099. In a further embodiment, the cyclooxygenase-2 phenylacetyl or phenyl; or wherein R* together with the selective inhibitor may also be a compound of Formula (I), carbon atoms to which it is attached and the remainder of or an isomer, a pharmaceutically acceptable Salt, ester, or ring E forms a naphthyl radical. prodrug thereof, wherein: 0115 The cyclooxygenase-2 selective inhibitor may also 0100 n is an integer which is 0, 1, 2, 3 or 4; be a compound of Formula (I) or an isomer, a pharmaceu 0101 G is oxygen or sulfur; tically acceptable Salt, ester, or prodrug thereof wherein: 0102) R' is H; 0116 n is an integer which is 0, 1, 2, 3 or 4; 0103 R’ is carboxyl, lower alkyl, lower aralkyl or lower 0117 R is trifluoromethyl or pentafluoroethyl; and alkoxycarbonyl, 0118 each R" is independently H, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, methoxy, trifluo 0104 R is lower haloalkyl, lower cycloalkyl or phenyl; romethyl, trifluoromethoxy, N-phenylmethylaminosulfonyl, and N-phenylethylaminosulfonyl, N-(2-furylmethyl)aminosul 0105 each R" is H, halo, lower alkyl, lower alkoxy, lower fonyl, N,N-dimethylaminosulfonyl, N-methylaminosulfo haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino, nyl, N-(2,2-dimethylethyl)aminosulfonyl, dimethylamino aminosulfonyl, lower alkylaminosulfonyl, 5-membered het Sulfonyl, 2-methylpropylaminoSulfonyl, eroarylalkylaminoSulfonyl, 6-membered heteroarylalky N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, or laminosulfonyl, lower aralkylaminoSulfonyl, 5-membered phenyl; or wherein R" together with the carbon atoms to nitrogen-containing heterocycloSulfonyl, 6-membered-ni which it is attached and the remainder of ring E forms a trogen containing heterocycloSulfonyl, lower alkylsulfonyl, naphthyl radical. optionally Substituted phenyl, lower aralkylcarbonyl, or 0119). In yet another embodiment, the cyclooxygenase-2 lower alkylcarbonyl; or selective inhibitor used in connection with the method(s) of 0106) R' together with the carbon atoms to which it is the present invention can also be a compound having the attached and the remainder of ring E forms a naphthyl Structure of Formula (I) or an isomer, a pharmaceutically radical. acceptable Salt, ester, or prodrug thereof wherein: 0107 The cyclooxygenase-2 selective inhibitor may also 0120) n =4; be a compound of Formula (I) or an isomer, a pharmaceu tically acceptable Salt, ester, or prodrug thereof wherein: 0121 G is O or S; 01.08 R is carboxyl; 0122) R' is H; 0109 R is lower haloalkyl; and 0123 R is COH; 0110 each R" is H, halo, lower alkyl, lower haloalkyl, 0.124 R is lower haloalkyl; lower haloalkoxy, lower alkylamino, amino, aminoSulfonyl, 0125 a first R' corresponding to R' is hydrido or halo; lower alkylaminosulfonyl, 5-membered heteroarylalkylami 0126 a second R'corresponding to R' is H, halo, lower noSulfonyl, 6-membered heteroarylalkylaminoSulfonyl, alkyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbo lower aralkylaminoSulfonyl, lower alkylsulfonyl, 6-mem nyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, bered nitrogen-containing heterocycloSulfonyl, optionally lower aralkylaminoSulfonyl, lower heteroaralkylaminoSul Substituted phenyl, lower aralkylcarbonyl, or lower alkyl fonyl, 5-membered nitrogen-containing heterocycloSulfo carbonyl; or wherein R* together with ring E forms a nyl, or 6-membered nitrogen-containing heterocycloSulfo naphthyl radical. nyl, 0111. The cyclooxygenase-2 selective inhibitor may also be a compound of Formula (I) or an isomer, a pharmaceu 0127 a third R' corresponding to R' is H, lower alkyl, tically acceptable Salt, ester, or prodrug thereof wherein: halo, lower alkoxy, or aryl; and 0128 a fourth R" corresponding to R' is H, halo, lower 0112 n is an integer which is 0, 1, 2, 3 or 4; alkyl, lower alkoxy, and aryl; 0113 R is fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, dif 0129 wherein Formula (I) is represented by Formula luoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, (Ia): difluoromethyl, or trifluoromethyl; and 0114 each R" is H., chloro, fluoro, bromo, iodo, methyl, (Ia) ethyl, isopropyl, tert-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tertbutyloxy, trifluorom ethyl, difluoromethyl, trifluoromethoxy, amino, N,N-dim R1 CO2H ethylamino, N,N-diethylamino, N-phenylmethylaminosul fonyl, N-phenylethylaminosulfonyl, N-(2- furylmethyl)aminosulfonyl, nitro, N,N- R11 G R8 dimethylaminoSulfonyl, aminoSulfonyl, R12 N-methylaminosulfonyl, N-ethylsulfonyl, 2,2-dimethyl ethylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-me thylpropyl)aminosulfonyl, N-morpholinosulfonyl, methyl 0.130. The cyclooxygenase-2 selective inhibitor used in Sulfonyl, benzylcarbonyl, 2,2-dimethylpropylcarbonyl, connection with the method(s) of the present invention can US 2004/0229803 A1 Nov. 18, 2004 also be a compound of having the structure of Formula (Ia) or an isomer, a pharmaceutically acceptable Salt, ester, or TABLE 1X-continued prodrug thereof wherein: EXAMPLES OF CHROMENE CYCLOOXYGENASE-2 0131) R' is trifluoromethyl or pentafluoroethyl; SELECTIVE INHIBITORS AS EMBODIMENTS Compound 0132) R' is H, chloro, or fluoro; Number Structural Formula 0133) R' is H., chloro, bromo, fluoro, iodo, methyl, B-6 O tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dim ethylaminoSulfonyl, isopropylaminoSulfonyl, methylamino Sulfonyl, benzylaminoSulfonyl, phenylethylaminoSulfonyl, O N OH methylpropylaminoSulfonyl, methylsulfonyl, or morpholi O CF noSulfonyl, 2-Trifluoromethyl-2H-naphtho2,3-b 0134) R' is H, methyl, ethyl, isopropyl, tert-butyl, pyran-3-carboxylic acid chloro, methoxy, diethylamino, or phenyl; and B-7 O 0135) R' is H, chloro, bromo, fluoro, methyl, ethyl, ON Cl tert-butyl, methoxy, or phenyl. 0.136 Examples of exemplary chromene cyclooxyge Ol O OcO CF nase-2 selective inhibitors are depicted in Table 1X below. 6-Chloro-7-(4-nitrophenoxy)-2-(trifluoromethyl)-2H-1- benzopyran-3-carboxylic acid TABLE 1X B-8 O
EXAMPLES OF CHROMENE CYCLOOXYGENASE-2 C SELECTIVE INHIBITORS AS EMBODIMENTS N OH
Compound O CF Number Structural Formula C ((S)-6,8-Dichloro-2-(trifluoromethyl)- B-3 O 2H-1-benzopyran-3-carboxylic acid
ON B-9 N OH
O CF O 6-Nitro-2-trifluoromethyl-2H-1- C benzopyran-3-carboxylic acid O N OH B-4 O O CF Cl 6-Chloro-2-(trifluoromethyl)-4-phenyl-2H N OH 1-benzopyran-3-carboxylic acid
B-10 O O O CF CH 6-Chloro-8-methyl-2-trifluoromethyl O O N OH 2H-1-benzopyran-3-carboxylic acid HO O CF 6-(4-Hydroxybenzoyl)-2-(trifluoromethyl)- B-5 O 2H-1-benzopyran-3-carboxylic acid
C B-11 O N OH 1. S FC N OH O CF
S CF ((S)-6-Chloro-7-(1,1-dimethylethyl)-2-(trifluoro 2-(Trifluoromethyl)-6-(trifluoromethyl)thio methyl-2H-1-benzopyran-3-carboxylic acid 2H-1-benzothiopyran-3-carboxylic acid US 2004/0229803 A1 Nov. 18, 2004
0.137 In a further embodiment, the cyclooxygenase-2 TABLE 1X-continued selective inhibitor is selected from the class of tricyclic EXAMPLES OF CHROMENE CYCLOOXYGENASE-2 cyclooxygenase-2 Selective inhibitors represented by the SELECTIVE INHIBITORS AS EMBODIMENTS general Structure of Formula I. or an isomer, a pharmaceu tically acceptable Salt, ester, or prodrug thereof wherein: Compound Number Structural Formula
B-12 O II O O Cl \/ N OH R21 R1 S CF A1 C R3 6.8-Dichloro-2-trifluoromethyl-2H-1- benzothiopyran-3-carboxylic acid B-13 O 0.138 A is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsat N OH urated or unsaturated carbocyclic rings, 0139) R' is selected from the group consisting of hetero S CF cyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R' is 6-(1,1-Dimethylethyl)-2-(trifluoromethyl)- 2H-1-benzothiopyran-3-carboxylic acid optionally Substituted at a Substitutable position with one or more radicals Selected from alkyl, haloalkyl, cyano, car B-14 O boxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkyl F N OH Sulfinyl, halo, alkoxy and alkylthio; 0140 R is selected from the group consisting of methyl F N CF H or amino; and 6,7-Difluoro-1,2-dihydro-2-(trifluoro methyl)-3-quinolinecarboxylic acid 0141 R is selected from the group consisting of a radical Selected from H, halo, alkyl, alkenyl, alkynyl, OXO, cyano, B-15 O carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, Cl N OH cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthio alkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkyl carbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxy CF alkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, CH alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, 6-Chloro-1,2-dihydro-1-methyl-2-(trifluoro alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-ary methyl)-3-quinolinecarboxylic acid laminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, B-16 O alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N- aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylami C N N OH noalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, 2 aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, N N CF H aminoSulfonyl, alkylaminoSulfonyl, N-arylaminosulfonyl, 6-Chloro-2-(trifluoromethyl)-1,2-dihydro arylsulfonyl, N-alkyl-N-arylaminosulfonyl. 1.8 naphthyridine-3-carboxylic acid 0142. In another embodiment, the cyclooxygenase-2 B-17 O selective inhibitor represented by the above Formula II is Cl Selected from the group of compounds illustrated in Table N OH 2X, consisting of celecoxib (B-18; U.S. Pat. No. 5,466,823; CAS No. 169590-42-5), valdecoxib (B-19; U.S. Pat. No. N CF H 3 5,633,272; CAS No. 181695-72-7), deracoxib (B-20; U.S. ((S)-6-Chloro-1,2-dihydro-2-(trifluoro Pat. No. 5,521,207; CAS No. 169590-41-4), rofecoxib methyl)-3-quinolinecarboxylic acid (B-21; CAS No. 162011-90-7), etoricoxib (MK-663; B-22; PCT publication WO 98/03484), tilmacoxib (JTE-522; B-23; CAS No. 180200-68-4). US 2004/0229803 A1 Nov. 18, 2004 10
TABLE 2X TABLE 2X-continued
EXAMPLES OF TRICYCLIC CYCLOOXYGENASE-2 EXAMPLES OF TRICYCLIC CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS SELECTIVE INHIBITORS AS EMBODIMENTS Compound Number Structural Formula Compound Number Structural Formula B-23 V A” -S B-18 O. O HN \/ CH HN1 3 o
N / \ S.CF N 3
CF 0143. In still another embodiment, the cyclooxygenase-2 Selective inhibitor is Selected from the group consisting of B-19 O. O celecoxib, rofecoxib and etoricoxib. V/ 1S 0144. In yet another embodiment, the cyclooxygenase-2 HN selective inhibitor is parecoxib (B-24, U.S. Pat. No. 5,932, 598, CAS No. 198470-84-7), which is a therapeutically effective prodrug of the tricyclic cyclooxygenase-2 Selective / \ inhibitor Valdecoxib, B-19, may be advantageously HC -N employed as a Source of a cyclooxygenase inhibitor (U.S. 3 O Pat. No. 5,932,598, herein incorporated by reference).
B-2O F B-24 O. O O. O \/ VW -S OCH S HN Ol HN1 N O
HC o1 CHF 0145 One form of parecoxib- is0 sodium parecoxib. B-21 O. O 0146 In another embodiment of the invention, the com V/ pound having the formula B-25 or an isomer, a pharmaceu HC1 S tically acceptable Salt, ester, or prodrug of a compound having formula B-25 that has been previously described in o International Publication number WO 00/24719 (which is herein incorporated by reference) is another tricyclic cyclooxygenase-2 Selective inhibitor that may be advanta O O geously employed.
B-25 F B-22 V / O S 21 CH HO O N F HN N N-N 2
/ \ N o OSMe C 0147 Another cyclooxygenase-2 selective inhibitor that is useful in connection with the method(s) of the present invention is N-(2-cyclohexyloxynitrophenyl)-methane Sul US 2004/0229803 A1 Nov. 18, 2004 fonamide (NS-398) having a structure shown below as B-26, 0159) R' and Rare hydrogen; and or an isomer, a pharmaceutically acceptable Salt, ester, or prodrug of a compound having formula B-26. 0160 and R is methyl. 0.161 In yet another embodiment, the cyclooxygenase-2 selective inhibitor is represented by Formula (IV) or an B-26 isomer, a pharmaceutically acceptable Salt, ester, or prodrug thereof: ON
(IV)
HNya CO R23 R24
0162 wherein: 0.148. In yet a further embodiment, the cyclooxygenase-2 selective inhibitor used in connection with the method(s) of 0163 X is O or S; the present invention can be Selected from the class of 0164. J is a carbocycle or a heterocycle; phenylacetic acid derivative cyclooxygenase-2 Selective inhibitorS represented by the general Structure of Formula 0165 R’ is NHSOCH or F; (III) or an isomer, a pharmaceutically acceptable Salt, ester, 0166 R’ is H, NO, or F; and or prodrug thereof: 0167) R' is H, NHSOCH, or (SOCH)CH. 0168 According to another embodiment, the cyclooxy (III) genase-2 Selective inhibitors used in the present method(s) R18 O have the structural Formula (V) or an isomer, a pharmaceu tically acceptable Salt, ester, or prodrug thereof: OH NH
R R21 (V)
R18 R20 R19
0149 wherein: 0150 R is methyl or ethyl; 0151) R7 is chloro or fluoro; 0152) R" is hydrogen or fluoro; 0169 wherein: 0153) R' is hydrogen, fluoro, chloro, methyl, ethyl, 0170 T and M independently are phenyl, naphthyl, a methoxy, ethoxy or hydroxy, radical derived from a heterocycle comprising 5 to 6 mem bers and possessing from 1 to 4 heteroatoms, or a radical 0154) R' is hydrogen or fluoro; and derived from a Saturated hydrocarbon ring having from 3 to 0155) R' is chloro, fluoro, trifluoromethyl or methyl, 7 carbon atoms, provided that R'7, R, R'' and Rare not all fluoro when 0171 Q', Q, L' or L are independently hydrogen, R" is ethyl and R' is H. halogen, lower alkyl having from 1 to 6 carbon atoms, 0156 Another phenylacetic acid derivative cyclooxyge trifluoromethyl, or lower methoxy having from 1 to 6 carbon nase-2 Selective inhibitor used in connection with the meth atoms, and od(s) of the present invention is a compound that has the 0172 at least one of Q', Q, L' or L is in the para designation of COX 189 (lumiracoxib; B-211) and that has position and is -S(O), R, wherein n is 0,1, or 2 and R is the structure shown in Formula (III) or an isomer, a phar a lower alkyl radical having 1 to 6 carbon atoms or a lower maceutically acceptable Salt, ester, or prodrug thereof haloalkyl radical having from 1 to 6 carbon atoms, or an wherein: -SONH; or, O157) R" is ethyl; 0173 Q' and Q are methylenedioxy; or 0158 R7 and R'' are chloro; 0174) L' and L are methylenedioxy; and US 2004/0229803 A1 Nov. 18, 2004
0175 R,R,R', and Rare independently hydrogen, 0196) 7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3- halogen, lower alkyl radical having from 1 to 6 carbon carboxylic acid (B41); atoms, lower haloalkyl radical having from 1 to 6 carbon 0.197 6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopy atoms, or an aromatic radical Selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl, or, ran-3-carboxylic acid (B42); 0198 6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopy 0176 R and R are O; or, ran-3-carboxylic acid (B-43); 0177) R-7 and Rare O; or, 0199 6-chloro-7-phenyl-2-trifluoromethyl-2H-1-ben 0178 R, R, together with the carbon atom to which Zopyran-3-carboxylic acid (B44); they are attached, form a Saturated hydrocarbon ring having 0200 6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran from 3 to 7 carbon atoms; or, 3-carboxylic acid (B45); 0179 R7, R, together with the carbon atom to which they are attached, form a Saturated hydrocarbon ring having 0201 6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran from 3 to 7 carbon atoms. 3-carboxylic acid (B46); 0180. In another embodiment, the compounds N-(2-cy 0202 6-chloro-8-methyl-2-trifluoromethyl-2H-1-ben clohexyloxynitrophenyl)methane Sulfonamide, and (E)-4- Zopyran-3-carboxylic acid (B47); (4-methylphenyl)(tetrahydro-2-oxo-3-furanylidene) 0203 8-chloro-6-methyl-2-trifluoromethyl-2H-1-ben methylbenzenesulfonamide or an isomer, a pharmaceuti Zopyran-3-carboxylic acid (B-48) cally acceptable Salt, ester, or prodrug thereof having the Structure of Formula (V) are employed as cyclooxygenase-2 0204 8-chloro-6-methoxy-2-trifluoromethyl-2H-1-ben Selective inhibitors. Zopyran-3-carboxylic acid (B49); 0181. In a further embodiment, compounds that are use 0205 6-bromo-8-chloro-2-trifluoromethyl-2H-1-ben ful for the cyclooxygenase-2 Selective inhibitor or an isomer, Zopyran-3-carboxylic acid (B-50); a pharmaceutically acceptable Salt, ester, or prodrug thereof 0206 8-bromo-6-fluoro-2-trifluoromethyl-2H-1-ben used in connection with the method(s) of the present inven Zopyran-3-carboxylic acid (B-51); tion, the structures for which are set forth in Table 3X below, 0207 8-bromo-6-methyl-2-trifluoromethyl-2H-1-ben include, but are not limited to: Zopyran-3-carboxylic acid (B-52); 0182 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3- 0208 8-bromo-5-fluoro-2-trifluoromethyl-2H-1-ben carboxylic acid (B-27); Zopyran-3-carboxylic acid (B-53); 0183 6-chloro-7-methyl-2-trifluoromethyl-2H-1-ben 0209) 6-chloro-8-fluoro-2-trifluoromethyl-2H-1-ben Zopyran-3-carboxylic acid (B-28); Zopyran-3-carboxylic acid (B-54); 0184 8-(1-methylethyl)-2-trifluoromethyl-2H-1-ben 0210 6-bromo-8-methoxy-2-trifluoromethyl-2H-1-ben Zopyran-3-carboxylic acid (B-29); Zopyran-3-carboxylic acid (B-55); 0185. 6-chloro-8-(1-methylethyl)-2-trifluoromethyl-2H 0211) 6-(phenylmethyl)aminosulfonyl-2-trifluorom 1-benzopyran-3-carboxylic acid (B-30); ethyl-2H-1-benzopyran-3-carboxylic acid (B-56); 0186 2-trifluoromethyl-3H-naphtho2,1-bipyran-3-car 0212 6-(dimethylamino)sulfonyl-2-trifluoromethyl boxylic acid (B-31); 2H-1-benzopyran-3-carboxylic acid (B-57); 0187 7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1- 0213 6-(methylamino)sulfonyl-2-trifluoromethyl-2H benzopyran-3-carboxylic acid (B-32); 1-benzopyran-3-carboxylic acid (B-58); 0188 6-bromo-2-trifluoromethyl-2H-1-benzopyran-3- 0214) 6-(4-morpholino)sulfonyl-2-trifluoromethyl-2H carboxylic acid (B-33); 1-benzopyran-3-carboxylic acid (B-59); 0189 8-chloro-2-trifluoromethyl-2H-1-benzopyran-3- 0215 6-(1,1-dimethylethyl)aminosulfonyl-2-trifluo carboxylic acid (B-34); romethyl-2H-1-benzopyran-3-carboxylic acid (B-60); 0190. 6-trifluoromethoxy-2-trifluoromethyl-2H-1-ben 0216) 6-(2-methylpropyl)aminosulfonyl-2-trifluorom Zopyran-3-carboxylic acid (B-35); ethyl-2H-1-benzopyran-3-carboxylic acid (B-61); 0191) 5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran 0217 6-methylsulfonyl-2-trifluoromethyl-2H-1-ben 3-carboxylic acid (B-36); Zopyran-3-carboxylic acid (B-62); 0.192 8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3- 0218 8-chloro-6-(phenylmethyl)aminosulfonyl-2-tri carboxylic acid (B-37); fluoromethyl-2H-1-benzopyran-3-carboxylic acid (B-63); 0193 7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran 0219) 6-phenylacetyl-2-trifluoromethyl-2H-1-benzopy 3-carboxylic acid (B-38); ran-3-carboxylic acid (B-64); 0194 6,8-bis(dimethylethyl)-2-trifluoromethyl-2H-1- 0220 6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran benzopyran-3-carboxylic acid (B-39); 3-carboxylic acid (B-65); 0195 7-(1-methylethyl)-2-trifluoromethyl-2H-1-ben 0221 8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1- Zopyran-3-carboxylic acid (B40); benzopyran-3-carboxylic acid (B-66);
US 2004/0229803 A1 Nov. 18, 2004 17
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS Compound Number Structural Formula
B-28 O
Cl
O
6-chloro-7-methyl-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-29
8-(1-methylethyl)-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-30 Cl
O F 2 F F HO O 6-chloro-8-(1-methylethyl)-2-trifluoromethyl 2H-1-benzopyran-3-carboxylic acid;
B-31
2-trifluoromethyl-3H-naphtho 2,1-bipyran-3-carboxylic acid;
B-32 O
N OH F O F F 7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid; US 2004/0229803 A1 Nov. 18, 2004 18
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-33 O
Br
O
6-bromo-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-34 C
8-chloro-2-trifluoromethyl 2H-1-benzopyran-3-carboxylic acid;
B-35 O \ lo
F x^^F --SonF O F F 6-trifluoromethoxy-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-36 C O
Cl O
5,7-dichloro-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-37
8-phenyl-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid; US 2004/0229803 A1 Nov. 18, 2004 19
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-38 O
N OH F O F F 7,8-dimethyl-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-39 O OH F F 21 F O
6.8-bis(dimethylethyl)-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-40 O
N OH F O F F 7-(1-methylethyl)-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-41
7-phenyl-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-42 O
C N OH F O F F 6-chloro-7-ethyl-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid; US 2004/0229803 A1 Nov. 18, 2004 2O
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-43 C
O F 2 F F HO O 6-chloro-8-ethyl-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-44
6-chloro-7-phenyl-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-45 O
Cl N OH F Cl O F F 6,7-dichloro-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-46 O
Cl N OH F O F C F 6,8-dichloro-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-47 O
Cl N OH F O F F 6-chloro-8-methyl-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid; US 2004/0229803 A1 Nov. 18, 2004 21
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-48 O
Cl F 8-chloro-6-methyl-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-49 O
O 1. N OH F O F C F 8-chloro-6-methoxy-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-50 O
Br N OH F O F Cl F 6-bromo-8-chloro-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-51 O
F N OH F O F Br F 8-bromo-6-fluoro-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-52 O
N OH F O F Br F 8-bromo-6-methyl-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid; US 2004/0229803 A1 Nov. 18, 2004 22
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-53 Br
O F F 2 F F HO O 8-bromo-5-fluoro-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-54 O
Cl
F F 6-chloro-8-fluoro-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-55
6-bromo-8-methoxy-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-56
6-(phenylmethyl)aminosulfonyl-2-trifluoromethyl 2H-1-benzopyran-3-carboxylic acid; US 2004/0229803 A1 Nov. 18, 2004 23
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-57 F F O
F O HO N 4. M n1 O O 6-(dimethylamino)sulfonyl-2-trifluoromethyl 2H-1-benzopyran-3-carboxylic acid;
B-58 F F O F O HO N 4. M n1 O O H 6-(methylamino)sulfonyl-2-trifluoromethyl 2H-1-benzopyran-3-carboxylic acid;
B-59
6-(4-morpholino)sulfonyl-2-trifluoromethyl 2H-1-benzopyran-3-carboxylic acid;
B-60 HN sA NoN V / HO O F
F F 6-(1,1-dimethylethyl)aminosulfonyl-2-trifluoromethyl 2H-1-benzopyran-3-carboxylic acid; US 2004/0229803 A1 Nov. 18, 2004 24
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-61
6-(2-methylpropyl)aminosulfonyl-2-trifluoromethyl 2H-1-benzopyran-3-carboxylic acid;
F F O F HO N / 4. N 6-methylsulfonyl-2-trifluoromethyl 2H-1-benzopyran-3-carboxylic acid;
B-63 N/H O O M N OH O F
O F Cl F 8-chloro-6-(phenylmethyl)aminosulfonyl-2-trifluoromethyl 2H-1-benzopyran-3-carboxylic acid;
B-64
O 6-phenylacetyl-2-trifluoromethyl 2H-1-benzopyran-3-carboxylic acid;
B-65
Br
Br F 6,8-dibromo-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
US 2004/0229803 A1 Nov. 18, 2004 26
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-71 O
O
6-iodo-2-trifluoromethyl-2H-1- benzopyran-3-carboxylic acid;
B-72
7-(1,1-dimethylethyl)-2-pentafluoroethyl-2H-1- benzopyran-3-carboxylic acid;
B-73 O
Cl
6-chloro-2-trifluoromethyl-2H-1- benzothiopyran-3-carboxylic acid;
B-74 Me
OESEO
C 3-(3-chloro-phenyl)-(4-methanesulfonyl-phenyl)-methylene dihydro-furan-2-one or MBS-347070;
US 2004/0229803 A1 Nov. 18, 2004
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-79 C
O e N S-NH N O No 4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)- 1H-pyrazol-1-yl)benzenesulfonamide;
B-8O
's /so HN 4-(3,5-bis(4-methylphenyl)- 1H-pyrazol-1-yl)benzenesulfonamide;
B-81
's/So, HN 4-(5-(4-chlorophenyl)-3-phenyl 1H-pyrazol-1-yl)benzenesulfonamide;
US 2004/0229803 A1 Nov. 18, 2004 31
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-89
sy’so HN 4-5-(4-fluorophenyl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl)benzenesulfonamide;
B-90
45-(4-methoxyphenyl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl)benzenesulfonamide;
B-91
C
4-5-(4-chlorophenyl)-3-(difluoromethyl)- 1H-pyrazol-1-yl)benzenesulfonamide; US 2004/0229803 A1 Nov. 18, 2004 32
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-92
4-5-(4-methylphenyl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl)benzenesulfonamide;
B-93 F
C 4-4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl)benzenesulfonamide;
B-94 F F
s / So HN 4-3-(difluoromethyl)-5-(4-methylphenyl)- 1H-pyrazol-1-yl)benzenesulfonamide; US 2004/0229803 A1 Nov. 18, 2004 33
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-95
F 4-3-(difluoromethyl)-5-phenyl 1H-pyrazol-1-yl)benzenesulfonamide;
B-96 F F
s/So, HN 4-3-(difluoromethyl)-5-(4-methoxyphenyl)- 1H-pyrazol-1-ylbenzenesulfonamide;
B-97 N Y, N
O Ns F M so HN 4-3-cyan-5-(4-fluorophenyl)- 1H-pyrazol-1-yl)benzenesulfonamide;
US 2004/0229803 A1 Nov. 18, 2004 35
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-101 HO Y, N
O Ns Cl M so HN 4-5-(4-chlorophenyl)-3-(hydroxymethyl)- 1H-pyrazol-1-yl)benzenesulfonamide;
B-102
sy’so HN 4-5-(4-N,N-dimethylamino)phenyl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl)benzenesulfonamide;
B-103
Cx 5-(4-fluorophenyl)-6-4-(methylsulfonyl) phenylspiro[2.4]hept-5-ene;
US 2004/0229803 A1 Nov. 18, 2004 38
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-112 E
N \
S V O Cl
1VO 2-(2-chlorophenyl)-4-(4-fluorophenyl)-5- (4-methylsulfonylphenyl)thiazole;
B-113 F SX \,
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)- 2-methylthiazole;
B-114
4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)- 2-trifluoromethylthiazole;
US 2004/0229803 A1 Nov. 18, 2004 40
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-119 F SX HeF N F O\, 1. \, 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)- 2-trifluoromethylthiazole;
B-120
OESEO
1-methylsulfonyl-4-1,1-dimethyl-4-(4-fluorophenyl) cyclopenta-2,4-dien-3-ylbenzene:So B-121 ne- (O O
4-4-(4-fluorophenyl)-1,1-dimethylcyclopenta 2,4-dien-3-ylbenzenesulfonamide;
B-122 2Ye
F V 5-(4-fluorophenyl)-6-4-(methylsulfonyl)phenyl spiro2.4 hepta-4,6-diene; US 2004/0229803 A1 Nov. 18, 2004 41
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula B-123 { S-C
OESEO
4-6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-5-yl) benzenesulfonamide;
B-124
6-(4-fluorophenyl)-2-methoxy-5-4-(methylsulfonyl) phenyl-pyridine-3-carbonitrile;
B-125 On / F s
N 2-bromo-6-(4-fluorophenyl)-5-4-(methylsulfonyl) phenyl-pyridine-3-carbonitrile;
US 2004/0229803 A1 Nov. 18, 2004 48
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-148 Cl
O NN -S N F le O F F 1-4-(methylsulfonyl)phenyl-2-(3-chlorophenyl)- 4-trifluoromethyl-1H-imidazole;
B-149 C
O NN HN-S N F le O
4-2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazol 1-ylbenzenesulfonamide;
B-150
O SN HN-S N F le O F F 4-2-phenyl-4-trifluoromethyl-1H-imidazol 1-ylbenzenesulfonamide;
B-151
4-2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl 1H-imidazol-1-yl)benzenesulfonamide;
US 2004/0229803 A1 Nov. 18, 2004 52
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-161
5-(4-fluorophenyl)-2-methoxy-4-4-(methylsulfonyl)phenyl 6-(trifluoromethyl)pyridine;
B-162
2-ethoxy-5-(4-fluorophenyl)-4-4-(methylsulfonyl)phenyl 6-(trifluoromethyl)pyridine;
B-163 O , O O rs N 2
F F F F 5-(4-fluorophenyl)-4-4-(methylsulfonyl)phenyl 2-(2-propynyloxy)-6-(trifluoromethyl)pyridine; US 2004/0229803 A1 Nov. 18, 2004 53
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-164
2-bromo-5-(4-fluorophenyl)-4-4-(methylsulfonyl)phenyl 6-(trifluoromethyl)pyridine;
B-165 F
F
O M Sn M NH2 O C
1. O 4-2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl benzenesulfonamide;
B-166
F
1-(4-fluorophenyl)-2-4-methylsulfonyl) phenylbenzene: US 2004/0229803 A1 Nov. 18, 2004 54
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-167
5-difluoromethyl-4-(4-methylsulfonylphenyl)- 3-phenylisoxazole;
B-168
O MN O\, NH1 \O 4-3-ethyl-5-phenylisoxazol-4-yl) benzenesulfonamide;
B-169
4-5-difluoromethyl-3-phenylisoxazol 4-yl)benzenesulfonamide;
B-170
4-5-hydroxymethyl-3-phenylisoxazol-4-yl) benzenesulfonamide; US 2004/0229803 A1 Nov. 18, 2004 55
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-171 O MN V
4-5-methyl-3-phenyl-isoxazol-4-yl) benzenesulfonamide;
B-172
1-2-(4-fluorophenyl)cyclopenten-1-yl)-4- (methylsulfonyl)benzene:
B-173 os/S S.O ( ) C-C, 1-2-(4-fluoro-2-methylphenyl)cyclopenten 1-yl)-4-(methylsulfonyl)benzene: B-174 os/ (SSn C-C 1-2-(4-chlorophenyl)cyclopenten 1-yl)-4-(methylsulfonyl)benzene: US 2004/0229803 A1 Nov. 18, 2004 56
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula B-175 os/ s
Cl Cl 1-2-(2,4-dichlorophenyl)cyclopenten 1-yl)-4-(methylsulfonyl)benzene:
B-176
F
F 1-2-(4-trifloromethylphenyl)cyclopenten 1-yl)-4-(methylsulfonyl)benzene:
B-177
S
1-2-(4-methylthiophenyl)cyclopenten 1-yl)-4-(methylsulfonyl)benzene: US 2004/0229803 A1 Nov. 18, 2004 57
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS Compound Number Structural Formula B-178 N / C 1-2-(4-fluorophenyl)-4,4-dimethylcyclopenten- 1-yl)-4-(methylsulfonyl)benzene:
B-179 O NH2- M C 4-2-(4-fluorophenyl)-4,4-dimethylcyclopenten- 1-ylbenzenesulfonamide;
B-18O O NA C. 1-2-(3-chlorophenyl)-4,4-dimethylcyclopenten- 1-yl)-4-(methylsulfonyl)benzene:
B-181 O NH3-N- M C 4-2-(4-chlorophenyl)-4,4-dimethylcyclopenten- 1-ylbenzenesulfonamide; US 2004/0229803 A1 Nov. 18, 2004 58
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-182 NH2 's ( ( ) S. Cy O 4-2-(4-fluorophenyl)cyclopenten 1-ylbenzenesulfonamide;
B-183 NH2
O-O 4-2-(4-chlorophenyl)cyclopenten 1-ylbenzenesulfonamide;
B-184 os/S S.O ( ) O 1-2-(4-methoxyphenyl)cyclopenten 1-yl)-4-(methylsulfonyl)benzene: B-185 C 21 F O 4. AS F O 1-2-(2,3-difluorophenyl)cyclopenten 1-yl)-4-(methylsulfonyl)benzene: US 2004/0229803 A1 Nov. 18, 2004 59
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-186 NH2
O
4-2-(3-fluoro-4-methoxyphenyl)cyclopenten 1-ylbenzenesulfonamide;
B-187 's (noSa
Cl
1-2-(3-chloro-4-methoxyphenyl)cyclopenten 1-yl)-4-(methylsulfonyl)benzene:
B-188 NH2 's/S.
Cl
4-2-(3-chloro-4-fluorophenyl)cyclopenten 1-ylbenzenesulfonamide;
US 2004/0229803 A1 Nov. 18, 2004 61
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula B-193 \ 2O 2 21S
F 4-(4-fluorophenyl)-5-4-(methylsulfonyl) phenyl)-2-phenyloxazole;
B-194 F
O \, 1. V O 4-(4-fluorophenyl)-2-methyl-5-4- (methylsulfonyl)phenyloxazole;
B-195 F
o- O 4-5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl 4-oxazolylbenzensulfonamide;
B-196 O
Cl
O
6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H 1-benzopyran-3-carboxylic acid; US 2004/0229803 A1 Nov. 18, 2004 62
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-197 O
C N OH F O F F 6-chloro-8-methyl-2-trifluoromethyl-2H 1-benzopyran-3-carboxylic acid;
B-198 F
5,5-dimethyl-3-(3-fluorophenyl)-4- methysulfonyl-2(5H)-furanone;
B-199 O
Cl N OH F S F F 6-chloro-2-trifluoromethyl-2H 1-benzothiopyran-3-carboxylic acid;
s / SoSa NH2 4-5-(4-chlorophenyl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl)benzenesulfonamide; US 2004/0229803 A1 Nov. 18, 2004 63
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
O ns/ SoSa NH2 4-5-(4-methylphenyl)-3-(trifluoromethyl)- 1H-pyrazol-1-yl)benzenesulfonamide;
N
Cl S F 4. YNH, - O 4-5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)- 1H-pyrazol-1-yl)benzenesulfonamide;
O SN -S N | le F O
F F 3-1-4-(methylsulfonyl)phenyl-4-trifluoromethyl 1H-imidazol-2-yl)pyridine; US 2004/0229803 A1 Nov. 18, 2004 64
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
2-methyl-5-1-4-(methylsulfonyl)phenyl-4- trifluoromethyl-1H-imidazol-2-yl)pyridine;
B-205 7 N
S.
O NN NH-S N le F O
4-2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)- 1H-imidazol-1-yl)benzenesulfonamide;
4-5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide;
4-5-hydroxymethyl-3-phenylisoxazol-4-yl)benzenesulfonamide; US 2004/0229803 A1 Nov. 18, 2004 65
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-208 F
O F
N I FF OFSFO
2-trifluoromethyl-5-(3,4-difluorophenyl)- 4-oxazoylbenzenesulfonamide;
a S
B-210 F
OESEO
4-5-(2-fluoro-4-methoxyphenyl)-2-trifluoromethyl 4-oxazoylbenzenesulfonamide;
B-211 HOC YCH, C
NH
HC F US 2004/0229803 A1 Nov. 18, 2004 66
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-212 O | S-CH HN1 3 O O NO2 N-(4-nitro-2-phenoxy-phenyl)-methanesulfonamide or Nimesulide
B-213 F
NH
OSEO
N-6-(2,4-difluoro-phenoxy)-1-oxo-inden-5-yl)- methanesulfonamide or Flosulide
B-214 F
F O S
Nat
ORSFO
N-6-(2,4-difluoro-phenylsulfanyl)-1-oxo-1H-inden-5-yl)- methanesulfonamide, soldium salt, or L-745337
B-215 O F N4 / /YNE1 O S S N-5-(4-fluoro-phenylsulfanyl)-thiophen-2-yl)- methanesulfonamide or RWJ-63556
US 2004/0229803 A1 Nov. 18, 2004
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-234 F
F Me-S 2NNN O N y O M--ch-cu-o Me
B-235 O
O=S-NH2
F -N \ F FC
B-236 H
H O- H H-
CHSO
B-237 H
H
CHSO US 2004/0229803 A1 Nov. 18, 2004 70
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS Compound Number Structural Formula
B-238 H
CHSO B-239 HO
H H
NO F
CHSO 3. B-240
H H H
NO CH
CHSO
B-241 3.
H H H
NO CF
CHSO
B-242 3. HCO H H
NO H
CHSO US 2004/0229803 A1 Nov. 18, 2004
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS
Compound Number Structural Formula
B-243 H
F O O H. H.
N H
CHSO
B-244 H
F O O F. H.
N H
CHSO
B-245 H HCO
N H
CHSO
B-246 H
HCO O 9 HCO H
N H
CHSO US 2004/0229803 A1 Nov. 18, 2004 72
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS Compound Number Structural Formula B-247
HCO H F
NO H
CHSO
B-248 3.
F H H
NO CH
CHSO
B-249 3.
F H H
NO CHO
CHSO 3.
F H H
NO CF
CHSO
B-251 3. HCO H H
NO F
CHSO US 2004/0229803 A1 Nov. 18, 2004 73
TABLE 3X-continued
EXAMPLES OF CYCLOOXYGENASE-2 SELECTIVE INHIBITORS AS EMBODIMENTS Compound Number Structural Formula
B-252 F
F O H H
N
CHSO
0399. The cyclooxygenase-2 selective inhibitor droxybenzoic, phenylacetic, mandelic, embonic (pamoic), employed in the present invention can exist in tautomeric, methaneSulfonic, ethaneSulfonic, benzeneSulfonic, pan geometric or Stereoisomeric forms. Generally Speaking, Suit tothenic, 2-hydroxyethaneSulfonic, toluenesulfonic, Sulfa able cyclooxygenase-2 Selective inhibitors that are in tauto nilic, cyclohexylaminoSulfonic, Stearic, algenic, hydroxybu meric, geometric or Stereoisomeric forms are those com tyric, Salicylic, galactaric and galacturonic acid. Suitable pounds that inhibit cyclooxygenase-2 activity by about 25%, pharmaceutically-acceptable base addition Salts of com more typically by about 50%, and even more typically, by pounds of use in the present methods include metallic Salts about 75% or more when present at a concentration of 100 made from aluminum, calcium, lithium, magnesium, potas tiM or less. The present invention contemplates all Such sium, Sodium and Zinc or organic salts made from N,N'- compounds, including cis- and trans-geometric isomers, E dibenzylethylenediamine, chloroprocaine, choline, dietha and Z-geometric isomers, R- and S-enantiomers, diastere nolamine, ethylenediamine, meglumine omers, d-isomers, I-isomers, the racemic mixtures thereof (N-methylglucamine) and procaine. All of these salts may be and other mixtures thereof. Pharmaceutically acceptable prepared by conventional means from the corresponding Salts of Such tautomeric, geometric or Stereoisomeric forms compound by reacting, for example, the appropriate acid or are also included within the invention. The terms “cis' and base with the compound of any Formula set forth herein. “trans', as used herein, denote a form of geometric isom 04.01 The cyclooxygenase-2 selective inhibitors of the erism in which two carbon atoms connected by a double present invention can be formulated into pharmaceutical bond will each have a hydrogenatom on the same side of the compositions and administered by a number of different double bond ("cis") or on opposite sides of the double bond means that will deliver a therapeutically effective dose. Such (“trans'). Some of the compounds described contain alkenyl compositions can be administered orally, parenterally, by groups, and are meant to include both cis and trans or “E” inhalation Spray, rectally, intradermally, transdermally, or and “Z” geometric forms. Furthermore, some of the com topically in dosage unit formulations containing conven pounds described contain one or more Stereocenters and are tional nontoxic pharmaceutically acceptable carriers, adju meant to include R, S, and mixtures or R and S forms for Vants, and vehicles as desired. Topical administration may each Stereocenter present. also involve the use of transdermal administration Such as 0400. The cyclooxygenase-2 selective inhibitors utilized transdermal patches or iontophoresis devices. The term in the present invention may be in the form of free bases or parenteral as used herein includes Subcutaneous, intrave pharmaceutically acceptable acid addition Salts thereof. The nous, intramuscular, or intrasternal injection, or infusion term "pharmaceutically-acceptable Salts' are Salts com techniques. Formulation of drugs is discussed in, for monly used to form alkali metal Salts and to form addition example, Hoover, John E., Remington's Pharmaceutical salts of free acids or free bases. The nature of the salt may Sciences, Mack Publishing Co., Easton, Pa. (1975), and vary, provided that it is pharmaceutically acceptable. Suit Liberman, H. A. and Lachman, L., Eds., Pharmaceutical able pharmaceutically acceptable acid addition Salts of com Dosage Forms, Marcel Decker, New York, N.Y. (1980). pounds for use in the present methods may be prepared from 0402. Injectable preparations, for example, Sterile inject an inorganic acid or from an organic acid. Examples of Such able aqueous or oleaginous Suspensions, can be formulated inorganic acids are hydrochloric, hydrobromic, hydroiodic, according to the known art using Suitable dispersing or nitric, carbonic, Sulfuric and phosphoric acid. Appropriate wetting agents and Suspending agents. The Sterile injectable organic acids may be selected from aliphatic, cycloaliphatic, preparation may also be a sterile injectable Solution or aromatic, araliphatic, heterocyclic, carboxylic and Sulfonic Suspension in a nontoxic parenterally acceptable diluent or classes of organic acids, examples of which are formic, Solvent. Among the acceptable vehicles and Solvents that acetic, propionic, Succinic, glycolic, gluconic, lactic, malic, may be employed are water, Ringer's Solution, and isotonic tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyru Sodium chloride Solution. In addition, Sterile, fixed oils are Vic, aspartic, glutamic, benzoic, anthranilic, meSylic, 4-hy conventionally employed as a Solvent or Suspending US 2004/0229803 A1 Nov. 18, 2004 74 medium. For this purpose, any bland fixed oil may be 50 mg/kg body weight and even more typically, from about employed, including Synthetic mono- or diglycerides. In 1 to 20 mg/kg body weight, may be appropriate. The daily addition, fatty acids Such as oleic acid are useful in the dose is generally administered in one to about four doses per preparation of injectables. Dimethyl acetamide, Surfactants day. including ionic and non-ionic detergents, and polyethylene glycols can be used. Mixtures of Solvents and wetting agents 0408. In one embodiment, when the cyclooxygenase-2 Such as those discussed above are also useful. Selective inhibitor comprises rofecoxib, it is typical that the amount used is within a range of from about 0.15 to about 0403 Suppositories for rectal administration of the com 1.0 mg/day kg, and even more typically, from about 0.18 to pounds discussed herein can be prepared by mixing the about 0.4 mg/day kg. active agent with a Suitable non-irritating excipient Such as cocoa butter, Synthetic mono-, di-, or triglycerides, fatty 04.09. In still another embodiment, when the cyclooxy acids, or polyethylene glycols which are Solid at ordinary genase-2 Selective inhibitor comprises etoricoxib, it is typi temperatures but liquid at the rectal temperature, and which cal that the amount used is within a range of from about 0.5 will therefore melt in the rectum and release the drug. to about 5 mg/day kg, and even more typically, from about 0.8 to about 4 mg/day kg. 04.04 Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In 0410. Further, when the cyclooxygenase-2 selective Such Solid dosage forms, the compounds are ordinarily inhibitor comprises celecoxib, it is typical that the amount combined with one or more adjuvants appropriate to the used is within a range of from about 1 to about 20 indicated route of administration. If administered per OS, the mg/day kg, even more typically, from about 1.4 to about 8.6 compounds can be admixed with lactose, Sucrose, Starch mg/day kg, and yet more typically, from about 2 to about 3 powder, cellulose esters of alkanoic acids, cellulose alkyl mg/day kg. esters, talc, Stearic acid, magnesium Stearate, magnesium 0411 When the cyclooxygenase-2 selective inhibitor oxide, Sodium and calcium Salts of phosphoric and Sulfuric comprises Valdecoxib, it is typical that the amount used is acids, gelatin, acacia gum, Sodium alginate, polyvinylpyr within a range of from about 0.1 to about 5 mg/day kg, and rolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules even more typically, from about 0.8 to about 4 mg/day kg. or tablets can contain a controlled-release formulation as can 0412. In a further embodiment, when the cyclooxyge be provided in a dispersion of active compound in hydrox nase-2 Selective inhibitor comprises parecoxib, it is typical ypropylmethyl cellulose. In the case of capsules, tablets, and that the amount used is within a range of from about 0.1 to pills, the dosage forms can also comprise buffering agents about 5 mg/day kg, and even more typically, from about 1 to Such as Sodium citrate, or magnesium or calcium carbonate about 3 mg/day kg. orbicarbonate. Tablets and pills can additionally be prepared with enteric coatings. 0413 Those skilled in the art will appreciate that dosages may also be determined with guidance from Goodman & 04.05 For therapeutic purposes, formulations for Goldman's The Pharmacological Basis of Therapeutics, parenteral administration can be in the form of aqueous or Ninth Edition (1996), Appendix II, pp. 1707-1711 and from non-aqueous isotonic Sterile injection Solutions or Suspen Goodman & Goldman's The Pharmacological Basis of Sions. These Solutions and Suspensions can be prepared from Therapeutics, Tenth Edition (2001), Appendix II, pp. 475 Sterile powders or granules having one or more of the 493. carriers or diluents mentioned for use in the formulations for oral administration. The compounds can be dissolved in POTASSIUM ION CHANNEL MODULATORS water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, Sesame oil, benzyl alcohol, 0414. In addition to a cyclooxygenase-2 selective inhibi Sodium chloride, and/or various buffers. Other adjuvants and tor, the composition of the invention also comprises a modes of administration are well and widely known in the therapeutically effective amount of a potassium ion channel pharmaceutical art. modulator or a pharmaceutically acceptable Salt or prodrug thereof. A number of potassium ion channel modulators may 0406 Liquid dosage forms for oral administration can be employed in the present invention. include pharmaceutically acceptable emulsions, Solutions, Suspensions, Syrups, and elixirs containing inert diluents 0415. In one aspect of the invention, the potassium ion commonly used in the art, Such as water. Such compositions channel modulator is a potassium ion channel blocker. In can also comprise adjuvants, Such as wetting agents, emul one embodiment, the potassium ion channel blocker is a Sifying and Suspending agents, and Sweetening, flavoring, Voltage-gated potassium channel blocker. In one alternative and perfuming agents. of this embodiment, the potassium ion channel blocker is Selected from the group consisting of dendrotoxin, dendro 0407. The amount of active ingredient that can be com toxin I, dendrotoxin K, alpha-dendrotoxin, beta-dendro bined with the carrier materials to produce a Single dosage toxin, gamma-dendrotoxin, margatoxin, Stichodactyla toxin, of the cyclooxygenase-2 Selective inhibitor will vary depending upon the patient and the particular mode of and tityustoxin K, or a pharmaceutically acceptable Salt or administration. In general, the pharmaceutical compositions prodrug thereof. may contain a cyclooxygenase-2 Selective inhibitor in the 0416) In another embodiment, the potassium ion channel range of about 0.1 to 2000 mg, more typically, in the range blocker is a calcium-activated potassium channel blocker. In of about 0.5 to 500 mg and still more typically, between one alternative of this embodiment, the potassium ion chan about 1 and 200 mg. A daily dose of about 0.01 to 100 mg/kg nel blocker is Selected from the group consisting of apamin, body weight, or more typically, between about 0.1 and about charylotoxin, clotrimazole, dequalinium chloride, iberi US 2004/0229803 A1 Nov. 18, 2004 75 otoxin, kaliotoxin, neuropeptide Y, noxiustoxin, and peni one alternative of this embodiment, the potassium ion chan trem A, or a pharmaceutically acceptable Salt or prodrug nel opener is Selected from the group consisting of NS1619, thereof. NS004, SCA4D, DHS-1, NS1608, Maxi-k dial, and 0417. In a further embodiment, the potassium ion channel CGS7184, or a pharmaceutically acceptable Salt or prodrug blocker is an ATP-sensitive potassium channel blocker. In thereof. one alternative of this embodiment, the potassium ion chan nel blocker is Selected from the group consisting of tolbuta 0420. In a further embodiment, the potassium ion channel mide, chlorpropamide, glibenclamide, glipizide, nateglini opener is an ATP-Sensitive potassium channel opener. In one ide, repaglinide, glyburide, and tolaZamide, or a alternative of this embodiment, the potassium ion channel pharmaceutically acceptable Salt or prodrug thereof. opener is Selected from the group consisting of minoxidil, 0418. In another aspect of the invention, the potassium diaZOxide, pinacidil, cromakalim, nicorandil, aprilkalim, ion channel modulator is a potassium ion channel opener. In ZD6169, bimakalim, BRL55834, levcromakalim, BMS one embodiment, the potassium ion channel opener is a 180448, and RP66471, or a pharmaceutically acceptable salt Voltage-gated potassium channel opener. In one alternative or prodrug thereof. of this embodiment, the Voltage-gated potassium channel opener is Selected from the group consisting of BMS 0421. In a further embodiment, compounds that are use 204352, and N-(3R,4S)-6-cyano-3,4-dihydro-3-hydroxy-2, ful for the potassium ion channel blocker or a pharmaceu 2-dimethyl-2H-1-benzopyran-4-yl)-N-methyl. tically acceptable Salt or prodrug thereof in connection with 0419. In another embodiment, the potassium ion channel the present invention include, but are not limited to, the opener is a calcium-activated potassium channel opener. In compounds set forth in Table 4B below:
TABLE 4B
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
1. Acecainide 32795-44-1
C-NH-CH-CH-NEt
AcNH Benzamide, 4-(acetylamino)-N-2-(diethylamino)ethyl 2 AL 275 No name available. No structure available. 33.1677-71 5
3 Alinidine ST 33178-86-8 567 Cl r N N
Y)HN C
1H-Imidazol-2-amine, N-(2,6-dichlorophenyl)-4,5-dihydro-N-2-propenyl
4 N-allyl OH 1572OO-09 secoboldine 4 MeO
Me MeO CH-CH-N-CH-CH=CH
HO
2,6-Phenanthrenediol, 3,5-dimethoxy-8-2-(methyl-2- propenylamino)ethyl US 2004/0229803 A1 Nov. 18, 2004 76
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
5 Almokalant H & 123955-1O 234/09 N 2 N- 1n 1a r O - OH
Benzonitrile, 4-3-ethyl 3-(propylsulfinyl)propylamino-2- hydroxypropoxy
6 AM92O16 OH Me 178894-81 O O-CH-CH-CH-N-CH-CH
Me -- NH C O Cl
Methanesulfonamide, N-4-3-2-(3,4-dichlorophenyl)ethylmet hylamino-2-hydroxypropoxylphenyl-, monobenzoate (salt)
7 Ambasilide LU Ph-CHN 83991-25-7 47110 N O
N-C
NH2
3,7-Diazabicyclo3.3.1nonane, 3-(4-aminobenzoyl)-7-(phenylmethyl)-
8 AN 132 O 105668-70 O NH-C-CH-CH-NH-CH-CH-N(Pr-i) Me Me
Propanamide, 3-2-bis(1-methylethyl)aminoethylamino-N-(2,6- dimethylphenyl)-phosphate(1:2) 9 ARH 050642 No name available. No structure available No CAS RN
10 AWD 12-260 H 10861O-89 EtN-(CH2)5-N Nn 21 NN 5 2 n. NC
3,4'-Bipyridine-5-carbonitrile, 6-3-(diethylamino)propylamino US 2004/0229803 A1 Nov. 18, 2004 77
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
11 AWD 23-111 221 639-91 AWD 160275 NO 4 (HCl) (Oxalate salt) 2264-08-59 Cul N-1N1 /- 9 (oxalate)
Benzamide, N-2-(dicyclohexylamino)-2-oxoethyl-N-3- (diethylamino)propyl-4-nitro-, monohydrochloride 12 AZD 7009 No name available. No structure available No CAS RN
13 AZDF 265 Ph H. O. CO2H 8390.1-4O-O CH-N-C-CH N
Benzoic acid, 4-2-oxo-2-phenyl 2-(1- piperidinyl)phenylmethylaminoethyl
14 Azimilide C 149888-94 8
O N--N-N 2,4-Imidazolidinedione, 1-5-(4-chlorophenyl)-2- furanylmethyleneamino-3-4-(4-methyl-1-piperazinyl)butyl-, dihydrochloride
15 Bepridil i-BuO-CH Ph CH-CH-N-CH-Ph ( N) 1-Pyrrolidineethanamine, B-(2-methylpropoxy) methyl-N-phenyl-N- (phenylmethyl) US 2004/0229803 A1 Nov. 18, 2004 78
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
16 Bertosamil 126825-36 3
Spirocyclohexane-19-3,7diazabicyclo3.3.1 nonane),3'-(1- methylethyl)-7-(2-methylpropyl)-
17 BIA O388 337359-07 6
CH-C-NH-CH-CH-CHPh MeO n N
MeO 1-Isoquinolineacetamide, C-cyclohexyl-N-(3,3-diphenylpropyl)-3,4- dihydro-6,7-dimethoxy
18 BMS. 2087.82 O Me Me 212380-81 9
N
S(+)enantiomer Benzamide, 4-(3-butyl-1,2,4-oxadiazol-5-yl)-N-(2,2- dimethylcyclopentyl)methyl-, (+)-
19 BMS. 208783 O Me Me 212380-82 O
N
R(-)enantiomer Benzamide, 4-(3-butyl-1,2,4-oxadiazol-5-yl)-N-(2,2- dimethylcyclopentyl)methyl-, (-)-
2O BRBI 28 89398-07-2
N YCH-Ph 3-Thia-7-azabicyclo3.3.1nonane, 7-(phenylmethyl)-, perchlorate
US 2004/0229803 A1 Nov. 18, 2004 8O
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number 26 PyrozolineChangrolin Nn 72O63-47-9 2N
NH N- - C CH-N OH
Phenol, 2,6-bis(1-pyrrolidinylmethyl)-4-(4-quinazolinylamino)-
27 CHF 1522 OMe 10238-21-8 Cyclo-dextrin O complex of glibenclamide C-NH-CH-CH O O i NH-C-NH O C
Benzamide, 5-chloro-N-2-4- (cyclohexylamino)carbonylaminosulfonylphenylethyl-2-methoxy
28 Chromanol 293 O Me 163.163-23 isomer 3 Me R NC S OH
Et N NS1 NM,na O O
Ethanesulfonamide, N-(3R,4S)-6-cyano-3,4-dihydro-3-hydroxy-2,2- dimethyl-2H-1-benzopyran-4-yl-N-methyl-, rel
29 Clamikalant O S 158751-64 HMR 1883 5 HMR 1098 OES-NH-C-NHMe (Nasalt) OMe OMe
C-NH-CH-CH
C
Benzamide, 5-chloro-2-methoxy-N-(2-4-methoxy-3- (methylamino)thioxomethylaminosulfonylphenylethyl US 2004/0229803 A1 Nov. 18, 2004 81
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
30 Clausenamide Me Ph 103541-15 (racemic) 7 O N S R OH R H
HO Ph
2-Pyrrolidinone, 3-hydroxy-5-(R)-hydroxyphenylmethyl-1-methyl-4- phenyl-(3R,4S,5S)-rel
31 (-) clausenamide Me Ph O O N R S OH S H
HO Ph
2-Pyrrolidinone, 3-hydroxy-5-(S)-hydroxyphenylmethyl-1-methyl-4- phenyl-, (3S,4R,5R)-
32 Clofilium LY Et 68379-02-2 150378 C (CH2)4- – (CH2)5-CH Et
Benzenebutanaminium, 4-chloro-N,N-diethyl-N-heptyl
33 CNS 1237 OMe 1742.32-22 5
t = NH NH
Guanidine, N-5-acenaphthylenyl-N'-(4-methoxy-1-naphthalenyl)- 34 CP 92713 No name available. No structure available No CAS RN 35 CP3O8408 No name available. No structure available No CAS US 2004/0229803 A1 Nov. 18, 2004 82
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
36 CP339818 CH-Ph 185855-91 8
1-Pentanamine, N-1-(phenylmethyl)-4-(1H)-quinolinylidene 37 CP 366660 No name available. No structure available No CAS RN
38 CPU 86O17 p-\ 149088-32 4 O
N MeO CH2 C OMe
Cl 6H-Benzog-1,3-benzodioxolo.5,6-aquinolizinium, 7-(4- chlorophenyl)methyl-5,8,13,13a-tetrahydro-9,10-dimethoxy-choloride
39 Dexsotalol OH 3O236-32-9 BMY O57631D d-sotalol S NHP O\/ O Me1 NN H Methanesulfonamide, N-4-(1S)-1-hydroxy-2-(1- methylethyl)aminoethylphenyl 40 Dicentrine /- 517-66-8 O MeO O
MeO N H Me 5 H-Benzog-1,3-benzodioxoloé,5,4-dequinoline, 6,7,7a,8-tetrahydro 10,11-dimethoxy-7-methyl-,(7aS)- US 2004/0229803 A1 Nov. 18, 2004 83
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
41 DKAHI 269 OMe 186097-54
OMe
HCI MeO
OMe
2H-3-Benzazepin-2-one,3-(3S)-1-2-(3,4-dimethoxyphenyl)ethyl-3- piperidinylmethyl-1,3,4,5-tetrahydro-7,8-dimethoxy monohydrochloride
42 DMP 543 F N 160588-45 DPC 543 21 4 N 21 N CH2 CH2 n. F
O
9(1OH)-Anthracenone,10,10-bis(2-fluoro-4-pyridinyl)methyl
43 Dofetilide O 115256-11
Me-S-NH NH-S-Me Me O-CH-CH-N-CH-CH
Methanesulfonamide, N-4-2-methyl 2-4- (methylsulfonyl)aminophenoxyethylaminoethylphenyl
44 DPI 201106 78573-03-2
N CN
NH
1H-Indole-2-carbonitrile,4-3-4-(diphenylmethyl)-1-piperazinyl-2- hydroxypropoxy US 2004/0229803 A1 Nov. 18, 2004 84
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
45 Dronedarone O Bu-n O-(CH2)3-N(Bu-n) 141626-36 SR 33589 O O | C Me-S-NH O
Methanesulfonamide, N-2-butyl-3-4-3- (dibutylamino)propoxybenzoyl-5-benzofuranyl
46 E 4031 113559-13 O 21 n1 MV O O
O Methanesulfonamide, N-(4-1-2-(6-methyl-2-pyridinyl)ethyl-4- piperidinylcarbonylphenyl-dihydrochloride
47 EGIS 7229 OMe 190333-92 7
Cl OMe Me NH- (CH2)- N-CH-CH
N O H 3(2H)-Pyridazinone.5-chloro-4-3-2-(3,4- dimethoxyphenyl)ethylmethylaminopropyl amino-,(2E)-2-butenedioate(1:1) 48 (+/-) Ersentilide 128264-20 O C. O-ulOH
Methanesulfonamide, N-4-2-hydroxy-3-2-4-(1H-imidazol-1- yl)phenoxyethylaminopropoxyphenyl
49 (S)-ersentilide N 125279-79 ( N) O O S
Me
Methanesulfonamide, N-4-(2S)-2-hydroxy-3-2-4-(1H-imidazol-1- yl)phenoxyethylaminopropoxyphenyl US 2004/0229803 A1 Nov. 18, 2004 85
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
50 Evodiamine (S) O 518-17-2
\"\ S N N H / Me Indolo2',3',3,4pyrido 2,1-biquinazolin-5(7H)-one, 8,13,13b,14 tetrahydro-1 4-methyl-(13bS)- 51 Fampiridine 4- N 504-24-5 aminopyridine 21 EL 970 N
NH2 4-Pyridinamine 52 Fosinoprilat O 95399-71-6
HOC N % \-cia, Ph S OH S
L-Proline, 4-cyclohexyl-I-hydroxy(4-phenylbutyl)phosphinylacetyl-, (4S)- 53 GEA857 O 120493-42 Me 7 S Pr O Me Cl NH2 L-Valine, 2-(4-chlorophenyl)-1,1-dimethylethyl ester 54 Glemanserin CH-CH-Ph 107703-78 MDL 11939 N 6
HO-CH
Ph 4-Piperidinemethanol, C-phenyl-1-(2-phenylethyl)-
SS GLG V 13 i- 155O29-33 Prn N O 7
3,7-Diazabicyclo3.3.1 nanone, 3-4-(1H-imidazol-1-yl)benzoyl-7-(1- methylethyl)-, diperchlorate US 2004/0229803 A1 Nov. 18, 2004 86
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
56 Glipizide 29094-61-9 K 4024 TK 132O Me r i-Si-c-st ---N-a-ch, O Pyrazinecarboxamide, N-(2-4- (cyclohexylamino)carbonylaminosulfonylphenylethyl-5-methyl
57 GYK 16638 O 307556-59 8 OMe NH-S-Me Me Me O O-CH-CH-N-CH-CH
OMe
# HC Methanesulfonamide, N-4-2-2-(2,6-dimethoxyphenoxy)-1- methylethylmethylaminoethylphenyl-, monohydrochloride
58 HA 7 Ph-CH 2O1943-88 6 O N OMe
O O FuroI2,3-biguinoline-3,4(2H.9H)-dione, 7-methoxy-9-(phenylmethyl)-
59 HMR 1372 O S 260971-17 3 ORS-NH-C-NHMe
OMe O t-Bu C-NH-CH-CH
OMe Benzamide, 5-(1,1-dimethylethyl)-2-methoxy-N-(2-4-methoxy-3- (methylamino)thioxomethylaminosulfonylphenylethyl
60 O S 181272-10 6 C ORS-NH-C-NHMe O-CH-CH-OMe O C-NH-CH-CH
OMe Benzamide, 5-chloro-2-methoxy-N-(2-4-(2-methoxyethoxy)-3- (methylamino)thioxomethylaminosulfonylphenylethyl US 2004/0229803 A1 Nov. 18, 2004 87
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
61. HMR 1556 22.3749-46 O
Methanesulfonamide, N-(3R,4S)-3,4-dihydro-3-hydroxy-2,2-dimethyl-6- (4,4,4-trifluorobutoxy)-2H-1-benzopyran-4-yl-N-methyl
62 Hydroxy OH 624-OO-O Me-(CH2)4-CH-(CH2)-COH
Decanoic acid, 5-hydroxy
63 Ibutilide U OH Et 122647-31 70226E 8 (solatol analog) N Me 1 n 1 O O (CH2)5 (CH2)2 Me1\/ NN H
Methanesulfonamide, N-4-4-(ethylheptylamino)-1- hydroxybutylphenyl
64 ICA 17043 O 289656-45 F 7 – NH2 F
Phf
Benzeneacetamide, 4-fluoro-O-(4-fluorophenyl)-O-phenyl
65 ICI 181037 138779-29 O
t-Bu
Acetamide, 2-2-2-(dimethylamino)-1-5-(1,1-dimethylethyl)-2- methoxyphenyl-1-hydroxypropylphenoxy-, (R,R)- US 2004/0229803 A1 Nov. 18, 2004 88
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
66 IK Channel O Me 223749-45 Blocker 9 Me (CH2)3 R FC1 No S OH Etn-NN /S \ Me O O
Ethanesulfonamide, N-(3R,4S)-3,4-dihydro-3-hydroxy-2,2-dimethyl-6- (4,4,4-trifluorobutoxy)-2H-1-benzopyran-4-yl-N-methyl
67 Ipazilide O 115436-73 WIN 2 54177 2\ N CH-C-NH-(CH3)3-NEt,
Ph Ph 1H-Pyrazole-1-acetamide, N-3-(diethylamino)propyl-4,5-diphenyl
68 Ipidacrine NIK NH2 62732-44-9 247 21
N N
1H-Cyclopentablquinolin-9-amine, 2,3,5,6,7,8-hexahydro
69 Ivabradine MeO O OMe 155974-00 Me 8 l N MeO - 1 No.1 OMe
2H-3-Benzazepin-2-one, 3-3-(7S)-3,4-dimethoxybicyclo4.2.0 octa 1,3,5-trien-7-ylmethylmethylaminopropyl-1,3,4,5-tetrahydro-7,8- dimethoxy
7O JKL 1073A 549-21-3 Oxy-berberine; O -\ 8-Oxo O berberine; 8-Oxy berberine; Berlambine N
N MeO
OMe O
8H-Benzog-1,3-benzodioxolo.5,6-aquinolizin-8-one, 5,6-dihydro-9,10 dimethoxy
US 2004/0229803 A1 Nov. 18, 2004 91
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
Correolide
80 L 768673 FC 177954-68 Ph 6 N21 FC R O N H NS-CF3 O
Benzeneacetamide, N-(3R)-2,3-dihydro-2-oxo-5-phenyl-1-(2,2,2- trifluoroethyl)-1H-1,4-benzodiazepin-3-yl-2,4-bis(trifluoromethyl)-
81 Levosemotiadil 116476-17 SA3212 6 SD 3212 (1:1 salt) 116476-16 5 OMe
O
2H-1,4-Benzothiazin-3 (4H)-one, 2-2-3-2-(1,3-benzodioxol-5- yloxy)ethylmethylaminopropoxy-5-methoxyphenyl-4-methyl-, (2S)-, (2E)-2-butenedioate (1:1)
82 Liriodenine 475-75-2
8H-Benzog-1,3-benzodioxoloé,5,4-dequinolin-8-one
US 2004/0229803 A1 Nov. 18, 2004 93
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
88 MK 499 CN 150481-98 L 706OOO 4
N O
Me -- NH O OH
Methanesulfonamide, N-(4R)-1'-(2R)-6-cyano-1,2,3,4-tetrahydro-2- naphthalenyl-3,4-dihydro-4-hydroxyspiro2H-1-benzopyran-2,4- piperidin-6-yl-, rel
89 N36O1 Me 113826-99 6 (maleate salt) aC-N riN N N Me n
l-cis-cis-1)N- N-C
OMe
OMe
1H-Benzimidazole-2-carboxamide, 1-2-4-(3,4-dimethoxybenzoyl)-1- piperazinylethyl-N-(4,6-dimethyl-2-pyridinyl)-N-methyl-(9CI)
90 Nateglinide AY 105816-04 4166 4 YMO26 SDZDN 608
CO2H O
D-Phenylalanine, N-trans-4-(1-methylethyl)cyclohexylcarbonyl
91 Nibentan O Ph 157832-56 9 C-NH-CH-(CH2)4-NEt
ON
# HC Benzamide, N-5-(diethylamino)-1-phenylpentyl-4-nitro-, monohydrochloride US 2004/0229803 A1 Nov. 18, 2004 94
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
92 Nifekalant ON Me 130636-43 MS 551 CH-CH-OH O (HCl) N O 130656-51 8 (CH2)-N-CH2-CH-NH Y (HCl) N Me
O 2,4(1H,3H)-Pyrimidinedione, 6-2-(2-hydroxyethyl)3-(4- nitrophenyl)propylaminolethylamino-1,3-dimethyl
93 NIP 142 ON 344609-47 8 (no structure) MeO 2O3OO2-75-75 HN 9
Benzeneacetamide, N-4-(cyclopropylamino)-3,4-dihydro-3-hydroxy 2,2-dimethyl-7-nitro-2H-1-benzopyran-6-yl-4-methoxy-, (3R-trans)-
94 NSOO4 C 141797-92 H 4 FC OriN OH 2H-Benzimidazol-2-one, 1-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-5- (trifluoromethyl)- 95 NS 1546 No name available. No structure available No CAS RN
96 OPC88117 Me 113225-73 3 H N O 1. " 2(1H)-Quinolinone, 8-methyl-3-(4-methyl-1-piperazinyl)-, monohydrochloride
97 ORG 2O781 169107-07 7
HO
HO Estra-1,3,5(10)-triene-2,3,16-triol, 17-(methylamino)-, (16C, 17(3)-
US 2004/0229803 A1 Nov. 18, 2004 96
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
103 Pyrido triazoles S No CAS RN NYu-N 2
N N
NN | H N O
No name available
104 Repaglinide CO2H 135062-02 NN 623 1. AGEE 623
N Bu-l OEt
Benzoic acid, 2-ethoxy-4-2-(1S)-3-methyl-1-2-(1-piperidinyl)phenyl butylamino-2-oxoethyl
105 Rimonabant C 168273-06 SR 141716 O 1.
Cl
Cl
1H-Pyrazole-3-carboxamide, 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)- 4-methyl-N-1-piperidinyl
106 Risotilide O Pr 12O688-08 6 S-N-CH-CH-NHPr-i
O O
Me-S-NH
O
Benzenesulfonamide, N-(1-methylethyl)-N-2-(1- methylethyl)aminoethyl-4-(methylsulfonyl)amino US 2004/0229803 A1 Nov. 18, 2004 97
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
107 RO-O34563 No CAS RN -)-CC, No name available
108 Ropivacaine Me 84057-95-4 AL 281 LEA103
NH
Me O S n-P1 N 2-Piperidinecarboxamide, N-(2,6-dimethylphenyl)-1-propyl-, (2S)- 109 RP 58866 121277-95 O
COCH2 CH2
N
HCI
MeO
OMe Piperidine, 1-2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl-4-(3,4- dimethoxyphenyl)-, hydrochloride
110 RP 66784 O. O 137392-34 8
Cyclohexanecarbothioamide, N-methyl-2-2- (phenylsulfonyl)aminoethyl-1-(3-pyridinyl)-, trans US 2004/0229803 A1 Nov. 18, 2004 98
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
111 RSD 1 OOO 169191-56 4
O
N
O 1-Naphthaleneacetic acid, (1R,2R)-2-(4-morpholinyl)cyclohexyl ester, rel
112 RSD 1019 O 169191-65 5
N
O O
Br Benzeneacetic acid, 4-bromo-, (1R,2R)-2-(4-morpholinyl)cyclohexyl ester, rel 113. RW 2881O NO 329040-80 O 4 ON N-C CH-CH-N Piperazine, 1-(4-nitrobenzoyl-4-2-(4-nitrophenyl)ethyl
114 RX 871024 Ph 142872-83 1. H N O N 1H-Indole, 2-(4,5-dihydro-1H-imidazol-2-yl)-1-phenyl
115 S. 9947 332378-43 N1 n 5 NH-CH-CH 21
Ph-CH-O-C-NH-CH O Carbamic acid, 2-2-(2-pyridinyl)ethylaminocarbonyl 1,1'-biphenyl 2-yl)methyl-, phenylmethyl ester US 2004/0229803 A1 Nov. 18, 2004 99
TABLE 4B-continued
EXAMPLES OF POTASSIUM ION CHANNEL BLOCKERS AS EMBODIMENTS
CAS Common Structure Registry ID Name Chemical Name Number
116 S 16260 MeO O OMe 167072-91 5
N N MeODOJ N N(CH-51 OMe 2H-3-Benzazepin-2-one, 3-3-III (7R)-3,4-dimethoxybicyclo4.2.0 octa 1,3,5-trien-7-ylmethylmethylaminopropyl-1,3,4,5-tetrahydro-7,8- dimethoxy
117 Salicylaldoxime CHEN-OH 94-67-7
OH Benzaldehyde, 2-hydroxy-, Oxime
118 SB 23.7376 OMe 1792.58-59 4 ON OMe O C-NH-(CH2)-NH-CH-CH
Benzamide, N-3-2-(3,4-dimethoxyphenyl)ethylaminopropyl-4-nitro
119 Sematilide O 101526-83 CK 1752 4 ZK 110516 C-NH-CH-CH-NEt O
Me-S-NH
O Benzamide, N-2-(diethylamino)ethyl-4-(methylsulfonyl)amino
120 Sinominine 115-53-7
MeO OH O Morphinan-6-one, 7,8-didehydro-4-hydroxy-3,7-dimethoxy-17-methyl-, (9a, 13a,14C)-
121 Sotalol OH No CAS RN CH-CH-NHPr-i O
Me-S-NH
O Methanesulfonamide, N-(4-1-hydroxy-2-(1- methylethyl)aminoethylphenyl