WO2007016784A1 - Nouveau 1,2,3-tπazolylméthyle-benzothiophène substitués ou -indole et leur utilisation en tant qu’inhibiteurs de biosynthèse leukotπène - Google Patents

Nouveau 1,2,3-tπazolylméthyle-benzothiophène substitués ou -indole et leur utilisation en tant qu’inhibiteurs de biosynthèse leukotπène Download PDF

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WO2007016784A1
WO2007016784A1 PCT/CA2006/001306 CA2006001306W WO2007016784A1 WO 2007016784 A1 WO2007016784 A1 WO 2007016784A1 CA 2006001306 W CA2006001306 W CA 2006001306W WO 2007016784 A1 WO2007016784 A1 WO 2007016784A1
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compound
group
substituted
alkyl
phenyl
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PCT/CA2006/001306
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English (en)
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Carl Berthelette
Claude Dufresne
Lianhai Li
Zhaoyin Wang
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Merck Frosst Canada Ltd.
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Priority to AU2006279211A priority Critical patent/AU2006279211A1/en
Priority to JP2008525348A priority patent/JP2009504575A/ja
Priority to EP06775086A priority patent/EP1915369A4/fr
Priority to CA002618586A priority patent/CA2618586A1/fr
Priority to US11/990,193 priority patent/US20100137371A1/en
Publication of WO2007016784A1 publication Critical patent/WO2007016784A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the instant invention involves novel compounds which are useful as inhibitors of leukot ⁇ ene biosynthesis.
  • leukot ⁇ ene biosynthesis inhibitors are those known to act through inhibition of 5 -lipoxygenase (5-LO).
  • the major leukotrienes are Leukot ⁇ ene B4 (abbreviated as LTB4), LTC4, LTD4 and LTE4.
  • LTB4 The major leukotrienes
  • LTC4 The major leukotrienes
  • LTC4 The major leukotrienes
  • LTC4 The major leukotrienes
  • LT A4 The biosynthesis of these leukotrienes begins with the action of the enzyme 5 -lipoxygenases on arachidonic acid to produce the epoxide known as Leukot ⁇ ene A4 (LT A4), which is converted to the other leukotrienes by subsequent enzymatic steps. Further details of the biosynthesis as well as the metabolism of the leukotrienes are to be found in the book Leukotrienes and Lipoxygenases, ed. J. Rokach, Elsevier, Amsterdam (1989). The actions of the leukotrienes in living systems and their contribution to various diseases states are also discussed m the book
  • 5-LO inhibitors have been sought for the treatment of allergic rhinitis, asthma and inflammatory conditions including arthritis.
  • a 5-LO inhibitor is the marketed drug zileuton (ZYLOFT®) which is indicated for the treatment of asthma.
  • ZYLOFT® the marketed drug zileuton
  • 5-LO may be an important contributor to the atherogenic process; see Mehrabian, M. et al., Circulation Research, 2002 JuI 26, 91(2):120-126.
  • the instant invention addresses that need by providing novel 5-LO inhibitors which are useful for inhibiting leukot ⁇ ene biosynthesis.
  • the instant invention relates to compounds of Formula I which are leukot ⁇ ene biosynthesis inhibitors, methods for their preparation, and methods and pharmaceutical formulations for using these compounds m mammals, especially humans
  • the compounds of Formula I are useful as pharmaceutical agents to slow or halt atherogenesis. Therefore, the instant invention provides a method for treating atherosclerosis, which includes halting or slowing the progression of atherosclerotic disease once it has become clinically evident, comprising administering a therapeutically effective amount of a compound of Formula I to a patient in need of such treatment.
  • the instant invention also provides methods for preventing or reducing the risk of developing atherosclerosis and atherosclerotic disease events, comprising administering a prophylactically effective amount of a compound of Formula I to a patient who is at risk of developing atherosclerosis or having an atherosclerotic disease event
  • the instant invention involves the use of compounds of Formula I as antiasthmatic, anti-allergic, anti-inflammatory and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis, and allograft rejection.
  • the instant invention provides methods of treatment comprising administering a therapeutically effective amount of a compound of Formula I to a patient in need of the above-desc ⁇ bed treatments.
  • the instant invention further provides the use of a compound of Formula I in combination with other therapeutically effective agents. Additional embodiments will be evident from the following detailed description.
  • A is selected from the group consisting of -Cl and phenyl optionally mono- or di-substituted with a substituent independently selected at each occurrence from the group consisting of (i) -F (n) -Cl, (in) -Ci _3alkyl optionally substituted with one or more of halo for example including -CF3, (iv)
  • -OC1 - ⁇ alkyl optionally substituted with one or more of halo for example including -OCHF2 and -OCF3, (v) -OC3_6cycloalkyl, (vi) -C3_6cycloalkyl, (vii) -CH2OH, (vin) -COOR.5, (ix) -CN and (x) -NR5R5a ; n is an integer selected from zero, 1 and 2; Rl is selected from the group consisting of (1) -H, (11) -Br, (111) -Cl, (iv) -COCi- ⁇ alkyl, (v)
  • -COOCi_6alkyl (vi) -COOCs- ⁇ cycloalkyl, (vii) -S ⁇ 2Ci-6alkyl, (vin) -SO2NR 5 R 5 , (i ⁇ ) -CONR5R5, (x) -CN, (xi) -Q -6alkyl optionally mono- or di-substituted with a substituent independently selected at each occurrence from the group consisting of -OH and -F, (xii) phenyl optionally mono- or di- substituted with a substituent independently selected at each occurrence from the group consisting of -OH and -F, (x ⁇ i) tetrazolyl optionally substituted with methyl, (xiv) 1 ,2,4-oxadiazolyl optionally substituted with methyl, and (xv) pyridmyl optionally substituted with methyl;
  • R2 IS selected from the group consisting of -H, -OH, -F, -Ci _3alkyl, -0C].3alkyl and -OC(O)-C i-3alkyl
  • R3 IS selected from the group consisting of -H, -Ci_6alkyl, -Ci- ⁇ alkyl substituted with one or more of fluoro including for example but not limited to -Cl-6perfluoroalkyl such as -CF3 and -CF2CF3, -Ci-6alkyl substituted with R6, phenyl, -C2-6alkenyl, -C3_6cycloalkyl and -C5_7cycloalkenyl;
  • R4 IS selected from the group consisting of -H, -Ci _6alkyl, -Ci- ⁇ alkyl substituted with one or more of fluoro including for example but not limited to -C 1 -6perfluoroalkyl such as -CF3 and -CF2CF3, -Ci-6alkyl substituted with R6, phenyl, -C2-6alkenyl, -C3_6cycloalkyl and -Cs ⁇ cycloalkenyl; R5 IS independently selected at each occurrence from the group consisting of -H, -Ci_6 alkyl and -C3_6cycloalkyl,
  • R5a is independently selected at each occurrence from the group consisting of -H, -Ci -6 alkyl, -C3_6cycloalkyl and -COOR5, and
  • R6 IS independently selected at each occurrence from the group consisting of -COOR ⁇ , -C(O)H, -CN, -CR5R50H, -OR5, -S-Ci.6alkyl and -S- C3-6 cycloalkyl.
  • R6 IS independently selected at each occurrence from the group consisting of -COOR ⁇ , -C(O)H, -CN, -CR5R50H, -OR5, -S-Ci.6alkyl and -S- C3-6 cycloalkyl.
  • Ia and Ib is a class of compounds wherein "A" is selected from the group consisting of phenyl and phenyl mono-substituted at the 3- or 4-position, and particularly wherein the substituent at the 3- or 4-position on the phenyl is selected from -Cl and -F, and more particularly wherein the substituent is -F.
  • R.2 is selected from the group consisting of -H, -OH , -F, -Ci- 3alkyl, -OCH3, and -OC(O)CH3
  • R 3 is selected from the group consisting of -H, -Ci_6alkyl, -Ci_6alkyl substituted with one or more of fluoro, -C3_6cycloalkyl and phenyl
  • R.4 is selected from the group consisting of -H, -C 1 -6 alkyl, -C 1 -6 alkyl substituted with one or more of fluoro, -C 1 -6 alkyl substituted with R6 and -C3_6cycloalkyl.
  • each class is compounds wherein R.2 is selected from -H and -OH; R 3 is selected from -CH3 -C2H5, -Ci_2alkyl substituted with fluoro particularly -CF3 and -CF2CF3, and cyclopropyl; and R.4 IS selected from -CH3 5 -CH2CH3, -Ci_2alkyl substituted with fluoro particularly -CF3 and -CF2CF3, cyclopropyl and -O ⁇ COOCi ⁇ alkyl.
  • Ia and Ib is a class of compounds wherein "A" is selected from the group consisting of phenyl and phenyl mono-substituted at the 3- or 4-position, and particularly wherein the substituent at the 3- or 4-position on the phenyl is selected from -Cl and -F, and more particularly wherein the substituent is -F, and R 1 is selected from - COOR 5 , -CONR 5 R 5 , -SO 2 -C 1 6 -alkyl and -SO 2 NR 5 R 5 .
  • R 2 is selected from the group consisting of -H, -OH , -F, -Ci-3alkyl, -OCH3, and - OC(O)CH3
  • R 3 is selected from the group consisting of -H, -Ci-6alkyl, -Ci-6alkyl substituted with one or more of fluoro, -C3-6cycloalkyl and phenyl
  • R4 IS selected from the group consisting of -H, -Ci _6alkyl, -Ci -galkyl substituted with one or more of fluoro, -Ci- ⁇ alkyl substituted with R6 and -C3.
  • each class is compounds wherein R2 IS selected from -H and -OH, R3 IS selected from -CH3 ? -C2H5, -Ci-2alkyl substituted with fluoro particularly -CF3 and -CF2CF3, and cyclopropyl; and R4 IS selected from -CE ⁇ -CH2CH3, -Ci -2alkyl substituted with fluoro particularly -CF3 and -CF2CF3, cyclopropyl and -CH2COOC 1 _4alkyl
  • Ia and Ib is a class of compounds wherein R 1 is selected from -COOR 5 , -CONR 5 R 5 , -SO 2 -C 1 6 alkyl and -SO 2 NR 5 R 5 .
  • R2 IS selected from the group consisting of -H, - OH , -F, -CiJjalkyl, -OCH3, and -OC(O)CH3
  • R3 IS selected from the group consisting of -H, -Q- ⁇ alkyl, -Ci_6alkyl substituted with one or more of fluoro, -C3_6cycloalkyl and phenyl
  • each class are compounds wherein R2 IS selected from -H and -OH; R3 IS selected from -CH3 5 -C2H5, -Ci_2alkyl substituted with fluoro particularly -CF3 and -CF2CF3, and cyclopropyl; and R4 IS selected from -CH3 ? -CH2CH3, -Ci-2alkyl substituted with fluoro particularly -CF3 and -CF2CF3, cyclopropyl and -CH2COOCi-4alkyl.
  • Ia and Ib is a class of compounds wherein R2 IS selected from the group consisting of -H, -OH , -F, -Ci_3alkyl, -OCH3, and - OC(O)CH3.
  • R2 IS selected from the group consisting of -H, -OH , -F, -Ci_3alkyl, -OCH3, and - OC(O)CH3.
  • R2 IS selected from the group consisting of -H, -OH , -F, -Ci_3alkyl, -OCH3, and - OC(O)CH3.
  • R2 IS selected from the group consisting of -H, -OH , -F, -Ci_3alkyl, -OCH3, and - OC(O)CH3.
  • R2 IS selected from the group consisting of -H, -OH , -F, -Ci_3alkyl, -OCH3, and -
  • Ia and Ib is a class of compounds wherein R3 IS selected from the group consisting of -H, -Ci- ⁇ alkyl, -Ci_6alkyl substituted with one or more of fluoro, -C3-6cycloalkyl and phenyl.
  • R3 IS selected from -CH3 5 -C2H5, -Ci_2alkyl substituted with fluoro particularly -CF3 and - CF2CF3, and cyclopropyl.
  • each of the embodiments defined by Formulas I, Ia and Ib is a class of compounds wherein R4 IS selected from the group consisting of -H, -Ci-6alkyl, -Ci-6alkyl substituted with one or more of fluoro, -Ci- ⁇ alkyl substituted with R6 and -C3_6cycloalkyl.
  • R4 IS selected from -CH3 ; -CH2CH3, -Ci_2alkyl substituted with fluoro particularly -CF3 and -CF2CF3, cyclopropyl and -CH2COOCi_4alkyl.
  • Ia and Ib is a class of compounds wherein R2 IS selected from the group consisting of -H, -OH , -F, -Ci .3 alkyl, -OCH3, and - OC(O)CH3; R.3 IS selected from the group consisting of -H, -Ci-6alkyl, -Ci - ⁇ alkyl substituted with one or more of fluoro, -C3-6cycloalkyl and phenyl; and R4 IS selected from the group consisting of -H, -Ci_6alkyl, -Ci_6alkyl substituted with one or more of fluoro, -Ci _6alkyl substituted with R.6 and -C?,- 6cycloalkyl.
  • R2 IS selected from -H and -OH
  • R ⁇ IS selected from -CH3 -C2H5, -Ci_2alkyl substituted with fluoro particularly -CF3 and -CF2CF3, and cyclopropyl
  • R4 IS selected from -Ct ⁇ -CH2CH3, -Ci-2alkyl substituted with fluoro particularly -CF3 and -CF2CF3, cyclopropyl and -CH2COOCi-4alkyl.
  • MS mass spectral
  • Examples of compounds within the scope of Formula Ia include but are not limited to those in Table 1 as well as pharmaceutically acceptable salts, esters and solvates of the compounds.
  • Examples of compounds within the scope of Formula Ib include but are not limited to those in Table 2 as well as pharmaceutically acceptable salts, esters and solvates of the compounds.
  • the term "pharmaceutically acceptable salts” refers to non-toxic salts of the compounds employed m this invention which can generally be prepared by reacting the free acid with a suitable organic or inorganic base, particularly those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as those salts formed from amines such as ammonia, ethylenediamme, N-methylglucamme, lysine, arginme, ornithine, choline, N,N'-dibenzylethylenediamme, chloroprocame, diethanolamme, procaine, N-benzylphenethylamine, 1-p- chlorobenzyl-2-pyrrolidme-l '-yl-methylbenzimidazole, diethylamme, p ⁇ erazine, mo ⁇ holme, 2,4,4- t ⁇ methyl-2-pentamme and t ⁇ s(hydroxymethyl)aminomethane
  • Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfomc, fuma ⁇ c, gluconic, glutamic, hydrobromic, hydrochloric, lsethiomc, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfu ⁇ c, and tartaric acids
  • esters of carboxyhc acid de ⁇ vatives can be employed.
  • pharmaceutically acceptable esters include, but are not limited to, -C] .4 alkyl (e.g., methyl, ethyl), pivaloyloxymethyl and -Cl -4 alkyl substituted with phenyl, dimethylammo and acetylammo.
  • Acyl derivatives of alcohol groups such as -O-acetyl, -O-pivaloyl, -O-benzoyl and -O- ammoacyl can similarly be employed. Included are those esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics of pharmaceutical compounds for use as pro-drugs or sustained-release or formulations.
  • Some of the compounds described herein contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, diastereoisome ⁇ c mixtures and individual diastereoisomers.
  • the present invention includes all such possible isomers m racemic, racemic mixture and resolved, enantiome ⁇ cally pure forms and the pharmaceutically acceptable salts thereof.
  • some of the crystalline forms of compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates and hydrates are likewise encompassed withm the scope of this invention
  • Some of the compounds described herein contain olef ⁇ nic double bonds.
  • the invention includes both E and Z geometric isomers.
  • Compounds of this invention may be separated into their individual diastereoisomers by, e.g , fractional crystallization from suitable solvents, e g., methylene chlo ⁇ de/hexanes or EtOAc/hexanes, or via chiral chromatography using an optically active stationary phase.
  • suitable solvents e g., methylene chlo ⁇ de/hexanes or EtOAc/hexanes
  • Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are de ⁇ vatized, if necessary, with a reagent containing a stereogemc center of known configuration.
  • any stereoisomer of a compound of this invention may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration.
  • alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e g , methyl (Me), ethyl (Et), n-propyl (Pr), n-butyl (Bu), n-pentyl, n-hexyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), secbutyl (s-Bu), tertbutyl (t-Bu), lsopentyl, isohexyl and the like.
  • Cycloalkyl means a monocyclic saturated carbocyclic ring, having the specified number of carbon atoms, e.g , 3, 4, 5 or 6 carbon atoms.
  • Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C2-6alkenyl refers to a straight or branched 2-6 carbon chain with at least one carbon-carbon double bond.
  • C5-7 cycloalkenyl as used herein means a non-aromatic monocyclic ring having from 5 to 7 carbon atoms in the ring with at least one carbon-carbon double bond
  • halo or halogen are meant to include fluoro, chloro, bromo and iodo, unless otherwise noted. Fluoro and chloro are preferred, and fluoro is most preferred.
  • optionally substituted means "unsubstituted or substituted," and therefore, the generic structural formulas described herein encompass compounds containing the specified optional substituent as well as compounds that do not contain the optional substituent.
  • tetrazolyl optionally substituted with methyl encompasses unsubstituted tetrazolyl and tetrazolyl substituted with methyl.
  • Each va ⁇ able is independently defined each time it occurs within the gene ⁇ c structural formula definitions. For example, when Rl is -SO2NR5R5 5 R5 IS independently selected at each occurrence and each R ⁇ can be the same or different.
  • substituted is intended to encompass mono- and poly-substitution on the specified moiety, unless otherwise specified.
  • a mono-substituted moiety has one substituent, while a poly-susbtituted moiety has more than one substituent wherein each carbon atom, as well as heteroatom such as nitrogen if present, that is available for substitution in the moiety may independently be unsubstituted, mono- or poly-substituted such that it results in the creation of a stable structure.
  • “-Ci- ⁇ alkyl optionally substituted with fluoro” includes but is not limited to -CH3, -CH2F, -CHF2, -CF3 and -CH2CF3.
  • this invention provides a method for preventing the synthesis, the action, or the release of leukotrienes in a mammal which comprises administering to said mammal a 5-LO inhibitory effective amount of a compound of this invention.
  • 5-LO inhibitory activity can be measured using the Human 5-Lipoxygenase Enzyme Assay and 5 -Lipoxygenase Human Whole Blood Assay described herein.
  • leukotrienes are potent inflammatory mediators
  • method of treating an inflammatory condition in a mammal which comprises administering a therapeutically effective amount of a compound of this invention to a mammal in need of such treatment.
  • the inhibition of the mammalian biosynthesis of leukotrienes also indicates that the compounds and pharmaceutical compositions thereof are useful to treat, prevent or ameliorate atherosclerosis in mammals, and especially m humans. Therefore, the compounds of this invention can be used for the treatment of atherosclerosis comprising administering a therapeutically effective amount of a compound of this invention to a patient in need of such treatment.
  • the method of this invention serves to prevent or slow new atherosclerotic lesion or plaque formation, and to prevent or slow progression of existing lesions or plaques, as well as to cause regression of existing lesions or plaques Accordingly, one aspect of this invention encompassed withm the scope of treatment of atherosclerosis involves a method for halting or slowing the progression of atherosclerosis, including halting or slowing atherosclerotic plaque progression, comprising administering a therapeutically effective amount of a compound of this invention to a patient in need of such treatment.
  • This method includes halting or slowing progression of atherosclerotic plaques existing at the time the instant treatment is begun (i.e., "existing atherosclerotic plaques"), as well as halting or slowing formation of new atherosclerotic plaques in patients with atherosclerosis.
  • Another aspect of this invention encompassed within the scope of treatment of atherosclerosis involves a method for effecting regression of atherosclerosis, including effecting regression of atherosclerotic plaques existing at the time the instant treatment is begun, comprising administering a therapeutically effective amount of a compound of this invention to a patient in need of such treatment.
  • this invention provides a method for preventing or reducing the risk of atherosclerotic plaque rupture comprising administering a prophylactically effective amount of a compound of this invention to a patient having atherosclerotic plaque.
  • This invention also involves a method for preventing or reducing the risk of developing atherosclerosis, comprising administering a prophylactically effective amount of a compound of this invention to a patient in need of such treatment, including, for example, a patient who is at risk for developing atherosclerosis
  • Atherosclerosis is characterized by the deposition of atheromatous plaques containing cholesterol and lipids on the innermost layer of the walls of large and medium-sized arteries.
  • Atherosclerosis encompasses vascular diseases and conditions that are recognized and understood by physicians practicing in the relevant fields of medicine.
  • Atherosclerotic cardiovascular disease including restenosis following revascularization procedures, coronary heart disease (also known as coronary artery disease or ischemic heart disease), cerebrovascular disease including multi-infarct dementia, and peripheral vessel disease including erectile dysfunction, are all clinical manifestations of atherosclerosis and are therefore encompassed by the terms "atherosclerosis” and "atherosclerotic disease.”
  • a compound of the instant invention may be administered to prevent or reduce the risk of occurrence, or recurrence where the potential exists, of a coronary heart disease (CHD) event, a cerebrovascular event, and/or intermittent claudication.
  • CHD coronary heart disease
  • Coronary heart disease events are intended to include CHD death, myocardial infarction (i.e., a heart attack), and coronary revascularization procedures. Cerebrovascular events are intended to include ischemic or hemorrhagic stroke (also known as cerebrovascular accidents) and transient ischemic attacks. Intermittent claudication is a clinical manifestation of peripheral vessel disease.
  • the term "atherosclerotic disease event" as used herein is intended to encompass coronary heart disease events, cerebrovascular events, and intermittent claudication. It is intended that persons who have previously experienced one or more non-fatal atherosclerotic disease events are those for whom the potential for recurrence of such an event exists.
  • the instant invention also provides a method for preventing or reducing the risk of a first or subsequent occurrence of an atherosclerotic disease event comprising the administration of a prophylactically effective amount of a compound of this invention to a patient in need of such treatment, such as a patient who is at risk for such an event.
  • a patient in need of such treatment may already have atherosclerotic disease at the time of administration, or may be at risk for developing it.
  • This invention also provides a method for treating, preventing, or ameliorating angina and/or myocardial ischemia, comprising administering a therapeutically or prophylactically effective amount, as appropriate, of a compound of this invention to a patient in need of such treatment.
  • the activity of the instant compounds as leukotriene biosynthesis inhibitors makes them useful for treating, preventing, or ameliorating: 1) pulmonary disorders including diseases such as asthma, chronic bronchitis, and related obstructive airway diseases, 2) allergies and allergic reactions such as allergic rhinitis, contact dermatitis, allergic conjunctivitis, and the like, 3) inflammation such as arthritis or inflammatory bowel disease, 4) pain, 5) skm disorders such as atopic eczema, and the like, 6) cardiovascular disorders such hypertension, platelet aggregation and the like, 7) renal insufficiency arising from ischaemia induced by immunological or chemical (cyclosporin) etiology and 8) migraine or cluster headache, 9) ocular conditions such as uveitis, 10) hepatitis resulting from chemical, immunological or infectious stimuli, 11) trauma or shock states such as burn injuries, endotoxemia and the like, 12) allograft rejection, 13) prevention of side effects
  • the compounds of this invention can be administered to patients, including adult and pediatric patients, for the prophylaxis of asthma and for chronic treatment of asthma.
  • the compounds of this invention can be administered to patients, including adult and pediatric patients, for the treatment of asthma' (1) as an alternative to low-dose inhaled corticosteroids (ICS) for patients with mild persistent asthma, (2) as concomitant therapy with low-dose inhaled corticosteroids (ICS) for patients with mild persistent asthma, or (3) as concomitant therapy in patients with persistent asthma who are inadequately controlled on inhaled corticosteroids (ICS) or on combined ICS/long-actmg beta-agonist (LABA) therapy
  • ICS low-dose inhaled corticosteroids
  • LAA long-actmg beta-agonist
  • the compounds can be used for treatment of asthmatic patients including, but not limited to, steroid resistant/non-responder asthmatics, asthmatics for whom leukot ⁇ ene modifiers have previously failed, smoking asthmatics, and aspirin sensitive asthmatics
  • the compounds can be administered to patients to (1) improve FEVl (Forced Expitory Volume in one minute), (2) improve morning and evening PEF (Peak Expitory flow), (3) reduce beta- agonist use (measured by puffs/day), (4) reduce inhaled / systemic steroid use. (5) improve daytime asthma symptoms, (6) reduce number of nocturnal awakenings, 7) improve asthma control days, (8) reduce number of asthma exacerbations, wherein an exacerbation is defined as: requiring systemic steroid, an emergency room visit, hospitalization, an unscheduled asthma related doctor visit, decrease in A.M. PEF by >20% or A.M.
  • the compounds of this invention can be administered to patients, including adult and pediatric patients, for the relief of symptoms of allergic rhinitis, including seasonal allergic rhinitis.
  • the compounds of the present invention may also be used to treat or prevent mammalian (especially, human) disease states such as erosive gastritis; erosive esophagitis; diarrhea; cerebral spasm; premature labor; spontaneous abortion; dysmenorrhea, ischemia; noxious agent-induced damage or necrosis of hepatic, pancreatic, renal, or myocardial tissue, liver parenchymal damage caused by hepatoxic agents such as CCI4 and D-galactosamme, ischemic renal failure; disease-induced hepatic damage; bile salt induced pancreatic or gastric damage; trauma- or stress-induced cell damage; and glycerol-induced renal failure
  • Leukotriene biosynthesis inhibitors also act as inhibitors of tumor metastasis and exhibit cytoprotective action.
  • the cytoprotective activity of a compound may be observed in both animals and man by noting the increased resistance of the gastrointestinal mucosa to the noxious effects of strong irritants, for example, the ulcerogenic effects of aspirin or indomethacin
  • animal studies show that cytoprotective compounds will prevent gastric lesions induced by oral administration of strong acids, strong bases, ethanol, hypertonic saline solutions, and the like.
  • Two assays can be used to measure cytoprotective ability These assays are: (A) an ethanol-induced lesion assay and (B) an mdomethacin-mduced ulcer assay and are described m EP 140,684.
  • the compounds of the invention would be useful to reduce the gastric erosion caused by co-admmistration of a cyclooxygenase-2 selective inhibitor such as rofecoxib (VIOXX®), eto ⁇ coxib (ARCOXIATM), and celecoxib (CELEBREX®) and low-dose aspirin.
  • a cyclooxygenase-2 selective inhibitor such as rofecoxib (VIOXX®), eto ⁇ coxib (ARCOXIATM), and celecoxib (CELEBREX®) and low-dose aspirin.
  • the compounds of this invention can also be used for the treatment of chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the presence of neutrophils is mediated in part by LTB4, and treatment with the instant compounds could be used to reduce neutrophilic inflammation in patients with COPD and reduce the rate of COPD exacerbations.
  • the compounds of this invention could be used for daily, preferably once-daily, maintenance treatment of airflow obstruction associated with COPD, including chronic bronchitis and emphysema.
  • patient includes mammals, especially humans, who use the instant active agents for the prevention or treatment of a medical condition.
  • Administering of the drug to the patient includes both self-administration and administration to the patient by another person.
  • the patient may be in need of treatment for an existing disease or medical condition, or may desire prophylactic treatment to prevent or reduce the risk for diseases and medical conditions affected by inhibition of leukot ⁇ ene biosynthesis.
  • terapéuticaally effective amount is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • prophylactically effective amount is intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.
  • the magnitude of prophylactic or therapeutic dose of a compound of this invention will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound and its route of administration. It will also vary according to the age, weight and response of the individual patient.
  • a specific daily dosage amount can simultaneously be both a therapeutically effective amount, e.g., for treatment to slow progression of existing atherosclerosis, and a prophylactically effective amount, e.g., for prevention of an atherosclerotic disease event or formation of new lesions.
  • the daily dose range for anti-asthmatic, anti-inflammatory, anti-allergic or anti- atherosclerotic use and generally, uses other than cytoprotection he within the range of from about 0 001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 10 mg per kg, and most preferably 0.1 to 1 mg per kg, in single or divided doses.
  • a suitable daily dosage range for antiasthmatic, anti-inflammatory, anti-allergic or anti-atherosclerotic use is, e.g., from about 0.01 mg to about 100 mg of a compound of this invention per kg of body weight per day, and preferably from about 0.1 mg to about 10 mg per kg.
  • a suitable daily dosage range is from 0.1 mg to about 100 mg, preferably from about 1 mg to about 100 mg, and more preferably from about 10 mg to about 100 mg, of a compound of this invention per kg of body weight per day.
  • a suitable daily dosage range for anti-asthmatic, antiinflammatory, anti-atherosclerotic or anti-allergic use is from about 0.001 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of a compound of this invention per kg of body weight per day and for cytoprotective use from about 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 1 mg to about 10 mg) of a compound of this invention per kg of body weight per day.
  • ophthalmic preparations for ocular administration comprising 0.001-1% by weight solutions or suspensions of the compounds of this invention in an acceptable ophthalmic formulation may be used.
  • a compound of this invention to be used as a cytoprotective agent will depend on, inter alia, whether it is being administered to heal damaged cells or to avoid future damage, on the nature of the damaged cells (e.g., gastrointestinal ulcerations vs. nephrotic necrosis), and on the nature of the causative agent.
  • An example of the use of a compound of this invention in avoiding future damage would be co-admmistration of a compound of this invention with an NSAID that might otherwise cause such damage (for example, lndomethacin).
  • the compound of this invention is administered from 30 minutes prior up to 30 minutes after administration of the NSAID.
  • compositions of the present invention comp ⁇ se a compound of this invention as an active ingredient and a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • oral formulation is preferred.
  • compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient They may be conveniently presented in unit dosage form and prepared by any of the methods well-known m the art of pharmacy.
  • the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers
  • the compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device.
  • the preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of this invention m suitable propellants, such as fluorocarbons or hydrocarbons
  • Suitable topical formulations of a compound of this invention include transdermal devices, aerosols, creams, ointments, lotions, dusting powders, and the like.
  • the compounds of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like m the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or earners such as starches, sugars, microcrystalhne cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like m the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
  • the compounds of this invention may also be administered by controlled release means and/or delivery devices such as those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; and 5,366,738 the disclosures of which are incorporated herein by reference.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion.
  • compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation
  • a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • each tablet, cachet or capsule contains from about 1 mg to about 500 mg of the active ingredient, for example but not limited to 10 mg, 20mg, 30mg, 40mg, 50 mg and 75mg.
  • the instant invention also encompasses a process for preparing a pharmaceutical composition comprising combining a compound of this invention with a pharmaceutically acceptable carrier. Also encompassed is the pharmaceutical composition which is made by combining a compound of this invention with a pharmaceutically acceptable carrier
  • a therapeutically effective amount of a compound of this invention can be used for the preparation of a medicament useful for treating or preventing any of the medical conditions described herein, in dosage amounts desc ⁇ bed herein.
  • a compound of this invention can be used for the preparation of a medicament useful for preventing or reducing the risk of developing atherosclerotic disease, halting or slowing the progression of atherosclerotic disease once it has become clinically manifest, and preventing or reducing the risk of a first or subsequent occurrence of an atherosclerotic disease event.
  • a compound of this invention can be used for the preparation of a medicament useful for the treatment of asthma, allergies and allergic conditions, inflammation, COPD or erosive gastritis.
  • the medicament comprised of a compound of this invention may also be prepared with one or more additional active agents, such as those described below.
  • One or more additional active agents may be used m combination with the compounds of this invention m a single dosage formulation, or the active agents of the combination may be administered to the patient in separate dosage formulations, which allows for concurrent or sequential administration of the active agents.
  • reference herein to compounds of this invention being used in combination with other active agents or used as part of combination therapy or the like encompasses both a single pharmaceutical composition comprised of a compound of this invention with one or more additional active agents, as well as a pharmaceutical composition comprised of a compound of this invention administered as part of a combination therapy with one or more other separately formulated active agents.
  • the pharmaceutical compositions of the present invention can also contain other active agents (i.e., ingredients) and the pharmaceutical compositions comprised of a compound of this invention may be used for combination therapy with one or more other separately formulated active agents, such as cyclooxygenase inhibitors, non-steroidal anti -inflammatory drugs (NSAIDs), peripheral analgesic agents such as zomepirac diflumsal and the like.
  • active agents such as cyclooxygenase inhibitors, non-steroidal anti -inflammatory drugs (NSAIDs), peripheral analgesic agents such as zomepirac diflumsal and the like.
  • NSAIDs non-steroidal anti -inflammatory drugs
  • peripheral analgesic agents such as zomepirac diflumsal and the like.
  • the weight ratio of the compound of this invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • NSAIDs can be characterized into five groups: (1) propionic acid derivatives; (2) acetic acid derivatives; (3) fenamic acid derivatives; (4)oxicams; and (5)biphenylcarboxyhc acid derivatives; or a pharmaceutically acceptable salt thereof.
  • the propionic acid derivatives which may be used comprise: alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, lbuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozm, pirprofen, prano-profen, suprofen, tiaprofenic acid, and tioxaprofen.
  • Structurally related propionic acid derivatives having similar analgesic and antiinflammatory properties are also intended to be included m this group.
  • ⁇ as defined herein are non-narcotic analgesics/non-steroidal antiinflammatory drugs having a free -CH(CH3)COOH or -CH2CH2COOH group (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g., -CH(CH3)COO " Na + or -CH2CH2COO-Na + ), typically attached directly or via a carbonyl function to a ring system, preferably to an aromatic ring system.
  • a pharmaceutically acceptable salt group e.g., -CH(CH3)COO " Na + or -CH2CH2COO-Na +
  • acetic acid derivatives which may be used comprise: mdomethacin, which is a preferred NSAID, acemetacm, alclofenac, chdanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, lbufenac, isoxepac, oxpinac, suhndac, tiopmac, tolmetin, zidometacin, and zomepirac.
  • mdomethacin which is a preferred NSAID
  • acemetacm alclofenac
  • chdanac diclofenac
  • fenclofenac fenclozic acid
  • fentiazac furofenac
  • lbufenac isoxepac
  • oxpinac suhndac
  • tiopmac tolmetin
  • zidometacin zidome
  • acetic acid derivatives having similar analgesic and anti-mflammatory properties are also intended to be encompassed by this group.
  • acetic acid derivatives as defined herein are nonnarcotic analgesics/non-steroidal anti-mflammatory drugs having a free -CH2COOH group (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g., -CH2COO ⁇ Na + ), typically attached directly to a ring system, preferably to an aromatic or heteroaromatic ⁇ ng system.
  • fenamic acid derivatives which may be used comprise: flufenamic acid, meclofenamic acid, mefenamic acid, mflumic acid and tolfenamic acid. Structurally related fenamic acid de ⁇ vatives having similar analgesic and anti-mflammatory properties are also intended to be encompassed by this group.
  • "fenamic acid derivatives" as defined herein are non-narcotic analgesics/non-steroidal anti-mflammatory drugs which contain the basic structure:
  • biphenylcarboxyhc acid de ⁇ vatives which can be used comprise: diflunisal and flufenisal. Structurally related brphenyl-carboxyhc acid de ⁇ vatives having similar analgesic and antiinflammatory properties are also intended to be encompassed by this group.
  • brphenyl-carboxyhc acid derivatives as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs which contain the basic structure:
  • oxicams as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs which have the general formula:
  • R is an aryl or heteroaryl ring system.
  • NSAIDs may also be used: amfenac sodium, ammoprofen, anitrazafen, antrafenme, auranofm, bendazac lysmate, benzydanme, beprozin, broperamole, bufezolac, cmmetacm, ciproquazone, cloximate, dazidamine, deboxamet, delmetacin, detomidme, dexmdoprofen, diacerem, di-fisalamine, difenpyramide, emorfazone, enfenamic acid, enohcam, epinzole, etersalate, etodolac, etofenamate, fanetizole mesylate, fenclorac, fendosal, fenflumizole, feprazone, floctafenine, flunixm, flunoxaprofen, fluproquazone, fopirtoline, fosfo
  • NSADDs designated by company code number (see e.g , Pharmaprojects), may also be used: 480156S, AA861, AD1590, AFP802, AFP860, AI77B, AP504, AU8001, BPPC, BW540C, CHINOIN 127, CNlOO, EB382, EL5O8, F1044, GV3658, ITFl 82,
  • NSAIDs which may also be used include the salicylates, specifically acetyl salicylic acid and the phenylbutazones, and pharmaceutically acceptable salts thereof.
  • other preferred NSAIDs are acetyl salicylic acid, diclofenac, fenbufen, fenoprofen, flurbiprofen, lbuprofen, ketoprofen, naproxen, phenylbutazone, piroxicam, suhndac, and tolmetm
  • Pharmaceutical compositions and combinations comprising compounds of this invention may also contain inhibitors of the biosynthesis of the leukotrienes such as are disclosed in EP 138,481 (April 24,1985), EP 115,394 (August 8, 1984), EP 136,893 (April 10, 1985), and EP 140,709 (May 8, 1985), which are hereby incorporated herein by reference.
  • the compounds of this invention may also be used in combination with leukotriene antagonists such as those disclosed m EP 106,565 (April 25, 1984) and EP 104,885 (April 4, 1984) which are hereby incorporated herein by reference and others known m the art such as those disclosed in EP Application Nos. 56,172 (July 21, 1982) and 61,800 (June 10, 1982); and in U.K. Patent Specification No. 2,058,785 (April 15, 1981), which are hereby incorporated herein by reference.
  • leukotriene antagonists such as those disclosed m EP 106,565 (April 25, 1984) and EP 104,885 (April 4, 1984) which are hereby incorporated herein by reference and others known m the art such as those disclosed in EP Application Nos. 56,172 (July 21, 1982) and 61,800 (June 10, 1982); and in U.K. Patent Specification No. 2,058,785 (April 15, 1981), which are hereby incorporated herein by reference.
  • compositions and combinations comprising compounds of this invention may also contain as the second active ingredient, or be used m combination therapy with, prostaglandin antagonists such as those disclosed in EP 1 1,067 (May 28, 1980) or thromboxane antagonists such as those disclosed m U.S. Pat. 4,237,160. They may also contain or be used with histidme decarboxylase inhibitors such as ⁇ -fluoromethylhistidme, desc ⁇ bed m U.S. Pat. 4,325,961.
  • the compounds of this invention may also be advantageously combined with an Hi or H2-receptor antagonist, such as for instance acetamazole, aminothiadiazoles disclosed in EP 40,696 (December 2, 1981), benadryl, cimetidme, famotidine, framamine, histadyl, phenergan, ranitidine, terfenadine and like compounds, such as those disclosed in U.S. Patent Nos. 4,283,408; 4,362,736; and 4,394,508.
  • the pharmaceutical compositions may also contain or be used in combination with a K + /H + ATPase inhibitor such as omeprazole, disclosed m U.S. Pat. 4,255,431, and the like.
  • Compounds of this invention may also be usefully combined with most cell stabilizing agents, such as l,3-bis(2-carboxychromon-5-yloxy)-2- hydroxypropane and related compounds desc ⁇ bed in British Patent Specifications 1,144,905 and 1 ,144,906
  • Another useful pharmaceutical composition comprises compounds of this invention m combination with serotonin antagonists such as methysergide, the serotonin antagonists desc ⁇ bed in
  • compositions of this invention in combination with anti-cholmergics such as ipratropium bromide and tiotropium, bronchodilators such as the beta agonist salbutamol, metaproterenol, terbutahne, fenoterol, salmeterol, formoterol and the like, and the anti-asthmatic drugs theophylline, choline theophyllmate and enprofylhne, the calcium antagonists nifedipine, diltiazem, nitrendipine, verapamil, nrmodipme, felodipme, etc , and the corticosteroids, hydrocortisone, methylpredmsolone, betamethasone, dexamethasone, beclomethasone, and the like
  • anti-cholmergics such as ipratropium bromide and tiotropium
  • bronchodilators such as the beta agonist salbutamol, metaprotereno
  • compounds of this invention can be used m combination with orally inhaled corticosteroids, such as beclomethasone (e g. QV AR® Inhalation Aerosol), budesomde (e g.
  • Pulmicort Respules Pulmicort Respules
  • flunisolide e.g., AEROBE® and AEROBID®-M Inhaler System
  • fluticasone e g., FLOVENT® DISKUS® inhalation powder, FLOVENT® HFA Inhalation Aerosol
  • mometasone e.g , ASMANEX® TWISTHALER®
  • triamcinolone e.g., AZMACORT® Inhalation Aerosol
  • inhaled corticosteroid/LABA products such as fluticasone propionate/salmeterol (e.g., ADVAIR DISKUS®).
  • the instant compounds could also be used m combination with leukot ⁇ ene receptor antagonists such as montelukast (e g., SINGULAIR®); phosphodiesterase 4 (PDE4) inhibitors such as roflumilast, N-Cyclo ⁇ ropyl-l-[3-(l- oxido-3 -py ⁇ dmylethynyl)phenyl]- 1 ,4-dihydro[ 1 ,8]naphthy ⁇ dm-4-one-3 -carboxamide and the compounds disclosed in PCT Publication WO2003/018579; and Very Late Antigen 4 (VLA4) inhibitors such as the compounds disclosed in U.S. Pat. No.
  • VLA4 Very Late Antigen 4
  • 6,229,011, particularly R411 N-(2-Chloro-6- methylbenzoyl)-4-[(2,6- dichlorobenzoyl) amino]-L-phenylalanine-2-(diethylammo)ethyl ester which is an ester pro-drug of the active moiety, N-(2-chloro-6-methylbenzoyl)-4- [(2,6-dichlorobenzoyl)ammo]-L- phenylalamne), and the compounds disclosed in PCT publication WO2006/023396.
  • additional active agents such as anti-atherosclerotic agents, anti-diabetes agents, anti -obesity agents and agents used for the treatment of metabolic syndrome, may be used m combination with the compounds of this invention.
  • the additional active agent or agents can be lipid altering compounds such as HMG-CoA reductase inhibitors, or agents having other pharmaceutical activities, or agents that have both hpid-alte ⁇ ng effects and other pharmaceutical activities.
  • HMG-CoA reductase inhibitors useful for this purpose include statins in their lactonized or dihydroxy open acid forms and pharmaceutically acceptable salts and esters thereof, including but not limited to lovastatin (MEVACOR®; see US Patent No.
  • simvastatin ZOCOR®; see US Patent No. 4,444,784
  • dihydroxy open-acid simvastatin particularly the ammonium or calcium salts thereof
  • pravastatin particularly the sodium salt thereof
  • PRA VACHOL® see US Patent No. 4,346,227)
  • fluvastatin particularly the sodium salt thereof see US Patent No. 5,354,772
  • atorvastatm particularly the calcium salt thereof
  • NK- 104 see PCT international publication number WO 97/23200
  • CRESTOR® see US Patent No 5,260,440
  • Additional active agents which may be employed in combination with a compound of this invention include but are not limited to HMG-CoA synthase inhibitors; cholesterol absorption inhibitors such as ezetimibe (ZETIA®) which is l-(4-fluorophenyl)-3(R)-[3(S)-(4- fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidmone, described m U S.
  • HMG-CoA synthase inhibitors cholesterol absorption inhibitors
  • ZTIA® ezetimibe which is l-(4-fluorophenyl)-3(R)-[3(S)-(4- fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidmone, described m U S.
  • Anti-obesity agents can be employed in combination with a compound of this invention including, but not limited to, sibutramine, orhstat, topiramate, naltrexone, bup ⁇ opion, phentermine, and phentermme/topiramate combination (QNEXA®); NPY5 antagonists; Acetyl-CoA Carboxylase-1 and -2 (ACC) inhibitors; MCHlR antagonists; and CBl antagonists/inverse agonists such as those described m WO03/077847 and WO05/000809.
  • Additional anti-diabetes agents which may be employed in combination with a compound of this invention include but are not limited to DPP-4 (dipeptidylpeptidase-4) inhibitors such as sitaghptm (JANUVIA®) and vildaghptin (GAL VUS®); sulfonylureas e.g., chlorpropamide, tolazamide, glybu ⁇ de, glipizide, and glimepi ⁇ de; biguanides, e.g., metformin; alpha-glucosidase inhibitors e.g., acarbose and mightol; meglitmides e.g , repaghnide; glucagon-receptor agonists; and glucokmase activators.
  • DPP-4 dipeptidylpeptidase-4 inhibitors
  • sitaghptm JNUVIA®
  • vildaghptin GAL VUS®
  • Compounds of this invention can be tested using the following assays to determine their mammalian leukot ⁇ ene biosynthesis inhibiting activity.
  • Representative tested compounds of this invention were shown to be inhibitors of leukot ⁇ ene biosynthesis, with most having an IC50 less than or equal to 4 ⁇ M in the Human 5 -Lipoxygenase Enzyme Assay, described below, with preferred compounds tested in this assay having an IC50 less than or equal to 0.100 ⁇ M.
  • the representative tested compounds were also shown to have activity as 5-LO inhibitors in the 5 -Lipoxygenase Human Whole Blood Assay, described below, with most having an IC50 less than or equal to 5 ⁇ M, and preferred compounds having an IC50 of less than or equal to 0.500 ⁇ M.
  • the activity of 5-hpoxygenase was measured using a spectrophotomet ⁇ c assay and recombinant human 5 -lipoxygenase as a source of enzyme.
  • Human 5 -lipoxygenase was purified from Sf9 cells infected with the recombinant baculovuzaffles rvH5LO (8-1) containing the coding sequence for human 5 -lipoxygenase as described by Percival et al., (Eur. J. Biochem 210, 109-117, 1992).
  • the enzymatic activity was measured using a spectrophotomet ⁇ c assay from the optimal rate of conjugated diene formation (absorbance at 238 nm) using the procedure described m Riendeau et al. (Biochem. Pharmacol. 38, 2313-2321, 1989) with minor modifications.
  • the incubation mixture contained 25 mM potassium phosphate, pH 7.5, 0.1 mM EDTA, 0.3 mM CaCl 2 , 24 ⁇ g/ml phosphatidylcholine, 0.1 mM ATP, 0.5 mM DTT, 20 ⁇ M arachidonic acid (2 ⁇ l from a 100-fold solution in ethanol), inhibitor (2 ⁇ l aliquot from a 100-fold solution m DMSO) and an aliquot of purified 5 -lipoxygenase. Reactions were initiated by the addition of the pu ⁇ fied 5-hpoxygenase and the rate of conjugated diene production was followed for 5 minutes at room temperature. The reaction was performed m a Costar UV plate (Cat.
  • Fresh blood is collected in hepa ⁇ nized tubes by venipuncture from volunteers with consent. The subjects have no apparent inflammatory conditions and have not taken any nonsteroidal anti-inflammatory drugs for at least 4 days prior to blood collection. 250 ⁇ l ahquots of blood are pre- incubated with either 0 5 ⁇ l of vehicle (DMSO) or test compound at 37°C for 15 minutes. This is followed by incubation of the blood with 5 ⁇ l of either plasma or a 1.25 mM solution of the calcium ionophore A23187 (Sigma, St Louis, Mo, USA) m plasma. The latter solution is prepared by cent ⁇ fugmg approximately 10 mis of blood from each donor and collecting the plasma.
  • a 5OmM stock solution of A23187 in DMSO is diluted 40-fold m plasma to yield a 1.25 mM working solution.
  • Five ⁇ ls of this working solution is added to each appropriate 250 ⁇ l-ahquot of blood of the same donor from which the plasma was prepared to give a final concentration of 25 ⁇ M of A23187.
  • the blood is then incubated at 37 0 C for 30 minutes. Following incubation, the blood is centrifuged at 150Og at 4 0 C for 10 minutes. Plasma is then collected from all samples and stored at 4 0 C until time of enzyme immunosorbent assay (EIA). All samples are tested for the production of leukotriene B4 (LTB4) using the LTB4 EIA kit from Assay Designs (Ann Arbor, MI, USA) according to the manufacturer's instructions.
  • EIA enzyme immunosorbent assay
  • the final aromatic ring is introduced via a Suzuki cross-coupling reaction;
  • the solvent is preferably 1,4-dioxane: water at a ratio of 100:1-1.5, and the reaction is preferably quenched with 2N NaOH when using any intermediate that is stable to NaOH.
  • the methyl ester can be saponified using standard conditions and, m turn, can be coupled with a variety of alcohols or amines using standard protocols to form the corresponding esters or amides.
  • the intermediate carboxyhc acid can also be decarboxylated by treatment with copper in refluxing quinohne.
  • the methyl ester substituent of the benzothiophene can be modified into a number of other groups as illustrated in Schemes 3 and 4.
  • the ester can be reduced to the primary alcohol by treatment with DIBAL as highlighted m Scheme 3.
  • This alcohol can be oxidized to the corresponding aldehyde through the action OfMnO 2 .
  • the methyl ester of the 3- chlorobenzothiophene intermediate can be reduced as desc ⁇ bed above with DIBAL and the resulting alcohol oxidized to the corresponding aldehyde.
  • This aldehyde can be converted into a nitrile by first treating with hydroxylamme followed by CDI.
  • Suzuki cross-coupling of the 2-cyano-3- chlorobenzothiophene with a variety of boronic acids can be accomplished following standards methods.
  • Unsubstituted and substituted phenylbormic acids are commercially available or can prepared from the corresponding bromide following standard literature procedures such as that desc ⁇ bed in Byrant, J.A. et. al., J Org Chem. 1990, 55, 4622-4634.
  • Scheme 6 highlights a number of additional transformations of the benzothiophenes that can be accomplished.
  • Scheme 6a illustrates treatment of the methyl ester with excess methyl lithium to generate the corresponding tertiary alcohol
  • Schemes 6b and 6c highlight two approaches to generate the primary amide by either treating the methyl ester with pre-mixed NH4C1-A1C13 or, alternatively, oxidation of the corresponding nitrile
  • the 2-bromobenzothiophene can be converted into a methyl sulphone, as shown in Scheme 6d, by treatment with methyl sulfinic acid sodium salt and CuI in hot DMF.
  • alkyl sulphone adducts can be generated by using the appropriate sulfinic acid sodium salt coupling partner (alkyl-SO2Na)
  • the bromide intermediate can be coupled with a variety of boronic acids or organostannanes to generate the corresponding 2-aryl or heterocyclic adducts (see Scheme 11)
  • the bromide can be converted into sulphonamides by first generating the 2-lithio species by treatment with BuLi, quenching this anion with sulfur dioxide, chlo ⁇ nation with NCS and finally treatment with an amine.
  • Schemes 6e and 6f illustrate that the sulfur atom of the benzothiophene ring can be oxidized to the corresponding sulfoxide or sulphone by treatment with either hydrogen peroxide or MCPBA, respectively.
  • the synthesis of 2-sulfonamide benzothiophenes is illustrated in Scheme 7. Hydrolysis of the acid chlo ⁇ de followed by decarboxylation generates the 2-hydro-benzothiophene This intermediate can be deprotonated at the 2-position with the aid of a strong, base such as BuLi, and the resulting anion reacted with sulphur dioxide.
  • Scheme 9 illustrates the preparation of 2-oxadiazolebenzothiophene analogs
  • This intermediate can be further elaborated to introduce the triazole unit as previously described.
  • chlo ⁇ nation of a benzothiophene such as methyl 3 -phenyl- 1- benzothiophene-6-carboxylate, provides the corresponding 2-chloro derivative
  • the methyl ester can be elaborated to introduce the t ⁇ azole ring system as previously described
  • Scheme 12 illustrates the synthesis of 5-LO inhibitors of Formula Ib.
  • the phenyl group was N-coupled to methyl 5-methyl-lH-mdole-2-carboxylate using standard methods Benzyhc bromination followed by azide displacement provides the corresponding benzyhc azide. Exposure of this azide with an alkyne in the presence of CuI generates the t ⁇ azole ring system. Saponification of the methyl ester provides the carboxylic acid which, under standard conditions, can be transformed into a carboxamide or the corresponding mt ⁇ le Alternatively, the acid can be transformed into a variety of esters or amides by following procedures outlined above in the previous schemes.
  • Scheme 13 illustrates a alternate synthesis of compounds of formula Ia wherein Rl is -COOCi- ⁇ alkyl, -COOC3-6cycloalkyl or -CONR5R5 which is preferred for chiral synthesis of the final products.
  • Starting material 3-chloro-6-methyl-l -benzothiophene -2 -carbonyl chlo ⁇ de 2 is made according to the procedure m T. Higa and AJ. Krubsack, J. Org. Chem, 1976, 41, 3399-3403.
  • Compound 2 can be este ⁇ fied to 3 with an alkyl alcohol, for example methanol, using DMAP at 0 0 C under an inert (e.g.
  • amide forms of 3 can also be prepared by adding a mixture of an appropriate amine (4 eq, for example NH2Ci-6alkyl) m CH2CI2 to the carbonyl chloride 2 (leq) under an inert (e.g. nitrogen) atmosphere at
  • Benzyhc bromination of 4 followed by azide displacement generates the azide intermediate 6, using procedures similar to that descnbed m Scheme 2 and Example 1, steps 2 and 3.
  • the benzyhc bromination of 4 (1 eq) can be performed using solvents such as carbon tetrachloride or benzene, employing about 1.1 eq. of NBS, and from about 0.05 to about 0.3 eq. of benzoylperoxide m a single portion or two portions.
  • the azide displacement can be performed using about 1 to 2 eq of sodium azide
  • the coupled product 10 can be prepared by treating a mixture of 6 (1 eq) and 9 (1 1 eq) at rt in a solvent such as THF under an inert (e.g., nitrogen) atmosphere with DIPEA (5 eq) and copper(I) iodide (1.5 eq) followed by isolation of the product
  • DIPEA e.g., nitrogen
  • copper(I) iodide 1.5 eq
  • the product is isolated using standard techniques, e g., by removing the solvent, re-dissolvmg in EtOAc and filtering through a silica gel pad.
  • the product can be further purified using flash chromatography such as the COMBI-FLASH® system (an automated flash chromatography system from Teledyne Isco) as described in many of the examples below
  • flash chromatography such as the COMBI-FLASH® system (an automated flash chromatography system from Teledyne Isco) as described in many of the examples below
  • base such as sodium hydroxide
  • 2M, 1 7 eq sodium hydroxide
  • EtOAc EtOAc
  • the product is isolated using standard techniques, e g , extracting with EtOAc, washing the combined organic layers with water, a saturated NaHC ⁇ 3 solution, then brine, drying over a drying agent such as Na2SO4, then concentrating the resulting material
  • the product can be further purified using flash chromatography such as the COMBI-FLASH® system For compound IJ.
  • -C(O)R 1 a an alkyl ester
  • additional modifications to the alkyl ester group can be performed as noted in the Schemes above
  • -C(O)R 1 a is an alkyl-substituted amide, such as -NH-t-butyl
  • the alkyl group can be readily removed by treatment with TFA with or without additional solvent to provide the corresponding primary amine.
  • Scheme 14 illustrates a method for making racemic 1 -ethyl- l-(tnfluoromethyl)prop-2-yn- 1-yl 4-nitrobenzoate 8 which can be chromatographically resolved to obtain 9
  • the chiral intermediate 9 can be used for the chiral synthesis of compounds of this invention as described in Scheme 13.
  • Compound 8 was prepared by adding n-butylhthium (1 eq) to a stirring mixture of ethynyl(t ⁇ methyl)silane (1.2 eq) in THF using standard conditions, e.g., at -78°C under an inert (e.g., nitrogen) atmosphere, followed by stirring at -78°C for about an hour and then at rt for about an hour.
  • the reaction was quenched by the addition of a saturated NaHCO3 solution at 0 0 C .
  • the organic layer was separated and the aqueous phase was extracted with ether/hexane (1 : 1). The organic layers were combined, washed with brme, dried over Na 2 SO 4 .
  • the solvent was removed by careful distillation.
  • the crude thus obtained was re-dissolved in THF (200 mL, 1 M) under atmosphere of nitrogen at 0 0 C, tetrabutylammonium fluoride IM THF (238 mL, 238 mmol, 1 2 eq) was added dropwise. The resulting mixture was stirred at rt for 2 h.
  • the reaction was quenched by the addition of brme.
  • Step 5 methyl 3-chloro-6-( ⁇ 4-[l-hydroxy-l-(t ⁇ fluoromethyl)pro ⁇ yl]-lH-l,2,3-t ⁇ azol-l-yl ⁇ methyl)-l- benzothiophene-2-carboxylate
  • Step 1 2-( 1 - ⁇ [3-chloro-2-(hydroxymethyl)- 1 -benzothien-6-yl]methyl ⁇ - IH- 1 ,2,3 -triazol-4-yl)- 1,1,1- trifluorobutan-2-ol
  • Step 2 3-chloro-6-( ⁇ 4-[l-hydroxy-l-(trifluoromethyl)propyl]-lH-l ,2,3-triazol-l-yl ⁇ methyl)-l- benzothiophene-2-carbonit ⁇ le
  • Step 3 3 -(3 -fluorophenyl)-6-( ⁇ 4-[ 1 -hydroxy- 1 -(t ⁇ fluoromethyl)propyl] - 1 H- 1 ,2,3 -triazol- 1 -yl ⁇ methyl)- 1 -benzothiophene-2-carbomt ⁇ le
  • Step 2 methyl 3-(4-fluorophenyl)-l-benzothiophene-6-carboxylate
  • Step 4 2-( 1 - ⁇ [2-bromo-3-(4-fluorophenyl)- 1 -benzothien-6-yl]methyl ⁇ -IH- 1 ,2,3-t ⁇ azol-4-yl)- 1,1,1- trifluorobutan-2-ol
  • 2-bromo-3-(4-fluorophenyl)-l-benzothiophene-6-carboxylate 9.57 g, 26.2 mmol
  • DIBAL- ⁇ 52.7 mL, 79 mmol, 3 eq
  • the resulting mixture was stirred at - 30 0 C forl h.
  • the reaction was quenched by the addition of a saturated NaHCO 3 solution.
  • the organic layer was separated and the aqueous phase was extracted with EtOAc.
  • the organic layers were combined, washed with brine, and dried over Na 2 SO 4 .
  • the solvent was removed by evaporation and the crude thus obtained was re-dissolved in DMF (25 mL) under atmosphere of nitrogen at rt and sodium azide (3.08 g, 47.4 mmol, 10 eq) was added.
  • the resulting mixture was stirred at rt for 3 h.
  • the reaction was quenched by the addition of water and extracted with EtOAc.
  • Step 2 methyl 5 -bromomethyl-1 -phenyl- lH-indole-2-carboxylate
  • Step 4 methyl 5-( ⁇ 4-[ 1 -hydroxy-1 -(t ⁇ fluoromethyl)propyl]- 1 H- 1 ,2,3-t ⁇ azol- 1 -yl ⁇ methyl)- 1 -phenyl-
  • Step 1 5 -( ⁇ 4-[ 1 -hydroxy- 1 -(trifluoromethyl)propyl]- 1 H- 1 ,2,3 -triazol- 1 -yl ⁇ methyl)- 1 -phenyl- 1 H- indole-2-carboxylic acid
  • Step 2 5 -( ⁇ 4-[ 1 -hydroxy- 1 -(t ⁇ fluoromethyl)propyl] - 1 H- 1 ,2,3-triazol- 1 -yl Jmethyl)- 1 -phenyl- 1 H- mdole-2-carboxarmde

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Abstract

La présente invention se rapporte à des composés de formule I qui sont des inhibiteurs de biosynthèse de leukotπene. Z est un cycle fusionné (optionnellement sulfo-oxydisé) ou un noyau pyrolle fusionné, R2-R4 sont choisis parmi divers substituants. Les composés de la formule I sont utiles en tant qu’agents anti-athéroscléreux, anti-asthmatiques, anti-allergiques, anti-inflammatoires et cytoprotecteurs.
PCT/CA2006/001306 2003-06-11 2006-08-08 Nouveau 1,2,3-tπazolylméthyle-benzothiophène substitués ou -indole et leur utilisation en tant qu’inhibiteurs de biosynthèse leukotπène WO2007016784A1 (fr)

Priority Applications (5)

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AU2006279211A AU2006279211A1 (en) 2005-08-11 2006-08-08 Novel substituted 1,2,3-triazolylmethyl-benzothiophene or -indole and their use as leukotriene biosynthesis inhibitors
JP2008525348A JP2009504575A (ja) 2005-08-11 2006-08-08 新規の置換された１，２，３，−トリアゾリルメチル−ベンゾチオフェン又は−インドール並びにロイコトリエン生合成阻害剤としてのそれらの使用
EP06775086A EP1915369A4 (fr) 2005-08-11 2006-08-08 Nouveau 1,2,3-t ii azolylméthyle-benzothiophène substitués ou -indole et leur utilisation en tant qu'inhibiteurs de biosynthèse leukotiiène
CA002618586A CA2618586A1 (fr) 2005-08-11 2006-08-08 Nouveau 1,2,3-t.pi.azolylmethyle-benzothiophene substitues ou -indole et leur utilisation en tant qu'inhibiteurs de biosynthese leukot.pi.ene
US11/990,193 US20100137371A1 (en) 2003-06-11 2006-08-08 Novel Pharmaceutical Compounds

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011017350A2 (fr) 2009-08-04 2011-02-10 Amira Pharmaceuticals, Inc. Composés en tant qu'antagonistes du récepteur de l'acide lysophosphatidique
WO2011041694A2 (fr) 2009-10-01 2011-04-07 Amira Pharmaceuticals, Inc. Composés utiles comme antagonistes du récepteur de l'acide lysophosphatidique (lpa)
US7960409B2 (en) 2007-02-05 2011-06-14 Merck Sharp & Dohme Corp. Pharmaceutical phenylquinoline and chromen-2-one triazole compounds
WO2012078593A2 (fr) 2010-12-07 2012-06-14 Amira Pharmaceuticals, Inc. Antagonistes des récepteurs de l'acide lysophosphatidique et utilisations de ceux-ci
WO2012078805A1 (fr) 2010-12-07 2012-06-14 Amira Pharmaceuticals, Inc. Antagoniste lpa1 polycyclique et utilisations de celui-ci
WO2012138797A1 (fr) 2011-04-05 2012-10-11 Amira Pharmaceuticals, Inc. Composés à base de 3- ou 5-biphényl-4-ylisoxazole utiles pour le traitement de la fibrose, de la douleur, du cancer et de troubles respiratoires, allergiques, de troubles du système nerveux ou de troubles cardiovasculaires
WO2012166415A1 (fr) 2011-05-27 2012-12-06 Amira Pharmaceuticals, Inc. Inhibiteurs hétérocycliques d'autotaxine et leurs utilisations
US11072585B2 (en) 2015-03-06 2021-07-27 Pharmakea, Inc. Fluorinated lysyl oxidase-like 2 inhibitors and uses thereof
EP4052707A1 (fr) 2016-09-07 2022-09-07 Pharmakea, Inc. Utilisations d'un inhibiteur d'homologue 2 de lysyl-oxydase
US11459309B2 (en) 2016-09-07 2022-10-04 Pharmakea, Inc. Crystalline forms of a lysyl oxidase-like 2 inhibitor and methods of making

Citations (2)

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EP0778275A1 (fr) * 1991-01-23 1997-06-11 MERCK SHARP & DOHME LTD. Procédé pour la préparation de dérivés d'imidazole, triazole et tetrazole et leur utilisation comme agonistes sélectifs des récepteurs 5-HT-1
CA2527769A1 (fr) * 2003-06-11 2004-12-16 Merck Frosst Canada Ltd. Derives de 7- (1,3-thiazol-2-yl)thio !coumarine et utilisation de ceux-ci en tant qu'inhibiteurs de la biosynthese des leucotrienes

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EP0778275A1 (fr) * 1991-01-23 1997-06-11 MERCK SHARP & DOHME LTD. Procédé pour la préparation de dérivés d'imidazole, triazole et tetrazole et leur utilisation comme agonistes sélectifs des récepteurs 5-HT-1
CA2527769A1 (fr) * 2003-06-11 2004-12-16 Merck Frosst Canada Ltd. Derives de 7- (1,3-thiazol-2-yl)thio !coumarine et utilisation de ceux-ci en tant qu'inhibiteurs de la biosynthese des leucotrienes

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See also references of EP1915369A4 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7960409B2 (en) 2007-02-05 2011-06-14 Merck Sharp & Dohme Corp. Pharmaceutical phenylquinoline and chromen-2-one triazole compounds
WO2011017350A2 (fr) 2009-08-04 2011-02-10 Amira Pharmaceuticals, Inc. Composés en tant qu'antagonistes du récepteur de l'acide lysophosphatidique
WO2011041694A2 (fr) 2009-10-01 2011-04-07 Amira Pharmaceuticals, Inc. Composés utiles comme antagonistes du récepteur de l'acide lysophosphatidique (lpa)
WO2012078593A2 (fr) 2010-12-07 2012-06-14 Amira Pharmaceuticals, Inc. Antagonistes des récepteurs de l'acide lysophosphatidique et utilisations de ceux-ci
WO2012078805A1 (fr) 2010-12-07 2012-06-14 Amira Pharmaceuticals, Inc. Antagoniste lpa1 polycyclique et utilisations de celui-ci
EP3360552A1 (fr) 2010-12-07 2018-08-15 Amira Pharmaceuticals, Inc. Antagoniste lpa1 polycyclique et utilisations de celui-ci
WO2012138797A1 (fr) 2011-04-05 2012-10-11 Amira Pharmaceuticals, Inc. Composés à base de 3- ou 5-biphényl-4-ylisoxazole utiles pour le traitement de la fibrose, de la douleur, du cancer et de troubles respiratoires, allergiques, de troubles du système nerveux ou de troubles cardiovasculaires
WO2012166415A1 (fr) 2011-05-27 2012-12-06 Amira Pharmaceuticals, Inc. Inhibiteurs hétérocycliques d'autotaxine et leurs utilisations
US11072585B2 (en) 2015-03-06 2021-07-27 Pharmakea, Inc. Fluorinated lysyl oxidase-like 2 inhibitors and uses thereof
EP4052707A1 (fr) 2016-09-07 2022-09-07 Pharmakea, Inc. Utilisations d'un inhibiteur d'homologue 2 de lysyl-oxydase
US11459309B2 (en) 2016-09-07 2022-10-04 Pharmakea, Inc. Crystalline forms of a lysyl oxidase-like 2 inhibitor and methods of making
US11793797B2 (en) 2016-09-07 2023-10-24 Pharmakea, Inc. Uses of a lysyl oxidase-like 2 inhibitor

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