US20090130076A1 - Substituted benzoazole pde4 inhibitors for treating pulmonary and cardiovascular disorders - Google Patents

Substituted benzoazole pde4 inhibitors for treating pulmonary and cardiovascular disorders Download PDF

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US20090130076A1
US20090130076A1 US12/275,164 US27516408A US2009130076A1 US 20090130076 A1 US20090130076 A1 US 20090130076A1 US 27516408 A US27516408 A US 27516408A US 2009130076 A1 US2009130076 A1 US 2009130076A1
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Jasbir Singh
Mark E. Gurney
Alex Burgin
Alexander Kiselyov
Munagala Rao
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Decode Genetics ehf
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Decode Genetics ehf
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Assigned to DECODE GENETICS EHF reassignment DECODE GENETICS EHF ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: RAO, MUNAGALA, BURGIN, ALEX, KISELYOV, ALEX, SINGH, JASBIR, GURNEY, MARK E.
Assigned to SAGA INVESTMENTS LLC reassignment SAGA INVESTMENTS LLC GRANT OF PATENT SECURITY INTEREST Assignors: DECODE GENETICS EHF (IN ICELANDIC: ISLENSK ERFDAGREINING EHF)
Priority to US13/454,487 priority patent/US20120207729A1/en
Priority to US14/288,470 priority patent/US20140275553A1/en
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    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D277/62—Benzothiazoles
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    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to substituted benzothiazoles, benzoxazoles—and their counterparts having pyridine and pyrimidine rings replacing the benzene ring—that are useful for treating stroke, myocardial infarct, and cardiovascular inflammatory conditions, to pharmaceutical compositions comprising these compounds, and to methods for the treatment of stroke, myocardial infarct, and cardiovascular inflammatory conditions in a mammal.
  • PDE4 is the major cAMP-metabolizing enzyme found in inflammatory and immune cells.
  • PDE4 inhibitors have proven potential as anti-inflammatory drugs, especially in inflammatory pulmonary diseases such as asthma, COPD and rhinitis. They suppress the release of cytokines and other inflammatory signals and inhibit the production of reactive oxygen species.
  • a large number of PDE4 inhibitors have been developed for a variety of clinical indications (Torphy and Page. 2000. TIPS 21, 157-159; Burnouf and Pruniaux. 2002. Curr. Pharm. Design 8, 1255-1296; Lipworth. 2005. Lancet 365, 167-175).
  • PDE4 inhibitors have been in development as a novel anti-inflammatory therapy since the 1980s with asthma and chronic obstructive pulmonary disease (COPD) being primary indications.
  • COPD chronic obstructive pulmonary disease
  • PDE4 inhibitors of various structural classes including cilomilast, filaminast, lirimilast, piclamilast, tofimilast . . . has been discontinued due to lack of efficacy.
  • a primary problem is the low therapeutic ratio of these compounds, which severely limits the dose that can be given.
  • the compounds of the present invention are non-competitive inhibitors of cAMP while being gene-specific inhibitors (PDE4D), and, based on the target rationale and in vitro potency, a person of skill in the art would expect the compounds to be useful as anti-inflammatory agents for the treatment, amelioration or prevention of inflammatory diseases and of complications arising therefrom and useful as CNS agents for amelioration of the cognitive decline in Alzheimer's disease, Parkinson's disease, the treatment of schizophrenia and depression, and neuroprotective in Huntington's disease.
  • PDE4D gene-specific inhibitors
  • the present invention relates to compounds exhibiting PDE4 enzyme inhibition, having the formulae Ia, Ib or Ic:
  • U is selected from the group consisting of —S— and —O—;
  • V is selected from the group consisting of H, CH 3 , NH 2 , and CF 3 ;
  • X is selected from the group consisting of CH, C—F, C—Cl, C—Br, C—I, C—NH 2 , C—OH, C—OCH 3 , N, and N—O;
  • Y is selected from the group consisting of N, CH, CF and C-lower alkyl;
  • R 1 is H or lower alkyl;
  • R 2 is selected from the group consisting of H, alkyl, OH, NH 2 , and OCH 3 ;
  • B is an optionally substituted, mono- or bicyclic aryl or heteroaryl;
  • A is an optionally substituted heterocycle or an optionally substituted carbocycle; and
  • a 1 is chosen from
  • R 40 is chosen from H, halogen, OH, NH 2 and CH 3 ;
  • substituents on the heterocycle or carbocycle are chosen from hydroxy, carboxy, carboxyalkyl, carboxyalkoxy, carboxyalkylthio, alkoxycarbonyl, carboxyalkylcarbonylamino, carboxyalkylaminocarbonylamino, guanidino, the residue of an amino acid and the residue of an N-methylated amino acid.
  • a pharmaceutical composition comprising a compound as described herein, and a pharmaceutically acceptable carrier, excipient or diluent therefore.
  • the salt should be a pharmaceutically acceptable salt.
  • the invention relates to methods for the treatment or prophylaxis of a disease or condition mediated by peripheral (i.e. outside the CNS) phosphodiesterase-4.
  • the methods comprise administering to a mammal a therapeutically effective amount of a compound having the general formula I.
  • the disease or condition may be related to allergic, acute or chronic inflammation.
  • the disease may be, for example, atherosclerosis, thrombosis, stroke, acute coronary syndrome, stable angina, peripheral vascular disease, critical leg ischemia, intermittent claudication, abdominal aortic aneurysm or myocardial infarction.
  • Selective PDE4 inhibitors of the invention are also useful for treating asthma and Chronic Obstructive Pulmonary Disease (COPD).
  • COPD Chronic Obstructive Pulmonary Disease
  • Compounds of the invention, which inhibit tumor growth and metastases, also find utility in the treatment and prevention of cancer, including esophageal cancer, brain cancer, pancreatic cancer, and colon cancer.
  • alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. A combination would be, for example, cyclopropylmethyl.
  • Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl and the like. Preferred alkyl groups are those of C 20 or below; C 1 to C 8 are more preferred.
  • Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl and the like.
  • C 1 to C 20 hydrocarbon includes alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl. Hydrocarbon refers to any substituent comprised of hydrogen and carbon as the only elemental constituents.
  • carbocycle is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state.
  • C 3 -C 10 carbocycle refers to both non-aromatic and aromatic systems, including such systems as cyclopropane, benzene, cyclopentene and cyclohexene;
  • C 8 -C 12 carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene.
  • Carbocycle if not otherwise limited, refers to monocycles, bicycles and polycycles.
  • Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched or cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons. For the purpose of this application, alkoxy and lower alkoxy include methylenedioxy and ethylenedioxy. Alkoxyalkyl refers to ether groups of from 3 to 8 atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an alkyl.
  • Alkoxyaryl refers to alkoxy substituents attached to an aryl, wherein the aryl is attached to the parent structure.
  • Arylalkoxy refers to aryl substituents attached to an oxygen, wherein the oxygen is attached to the parent structure.
  • Substituted arylalkoxy refers to a substituted aryl substituent attached to an oxygen, wherein the oxygen is attached to the parent structure.
  • Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy; 3,6,9-trioxadecyl; 2,6,7-trioxabicyclo[2.2.2]octane and the like.
  • the term oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 196, but without the restriction of 127(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds); it does not refer to doubly bonded oxygen, as would be found in carbonyl groups.
  • thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons has been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.
  • acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality.
  • One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Lower-acyl refers to groups containing one to four carbons.
  • the double bonded oxygen, when referred to as a substituent itself is called “oxo”.
  • Aryl and heteroaryl mean (i) a phenyl group (or benzene) or a monocyclic 5- or 6-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, N, or S; (ii) a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-4 heteroatoms selected from O, N, or S; or (iii) a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-5 heteroatoms selected from O, N, or S.
  • Aryl, as understood herein, includes residues in which one or more rings are aromatic, but not all need be.
  • aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
  • Arylalkyl refers to a substituent in which an aryl residue is attached to the parent structure through alkyl. Examples are benzyl, phenethyl and the like. Heteroarylalkyl refers to a substituent in which a heteroaryl residue is attached to the parent structure through alkyl.
  • the alkyl group of an arylalkyl or a heteroarylalkyl is an alkyl group of from 1 to 6 carbons. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like.
  • Heterocycle means a cycloalkyl or aryl carbocycle residue in which from one to three carbons is replaced by a heteroatom selected from the group consisting of N, O and S.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • a heterocycle may be non-aromatic or aromatic. It is to be noted that heteroaryl is a subset of heterocycle in which the heterocycle is aromatic.
  • heterocyclic residues that fall within the scope of the invention include pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), morpholine, thiazole, pyridine (including 2-oxopyridine), pyridine N-oxide, pyrimidine, thiophene (i.e.
  • furan oxazole, oxazoline, oxazolidine, isoxazolidine, isoxazole, dioxane, azetidine, piperazine, piperidine, pyrrolidine, pyridazine, azepine, pyrazolidine, imidazole, imidazoline, imidazolidine, imidazolopyridine, pyrazine, thiazolidine, isothiazole, 1,2-thiazine-1,1-dioxide, quinuclidine, isothiazolidine, benzimidazole, thiadiazole, benzopyran, benzothiazole, benzotriazole, benzoxazole, tetrahydrofuran, tetrahydropyran, benzothiene, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, oxadiazole, triazole
  • An oxygen heterocycle is a heterocycle containing at least one oxygen in the ring; it may contain additional oxygens, as well as other heteroatoms.
  • Oxygen heterocycles found in the examples of the invention include tetrahydrofuran, benzodioxole, morpholine, isoxazole and 2,6,7-trioxabicyclo[2.2.2]octane.
  • a sulphur heterocycle is a heterocycle containing at least one sulphur in the ring; it may contain additional sulphurs, as well as other heteroatoms.
  • a nitrogen heterocycle is a heterocycle containing at least one nitrogen in the ring; it may contain additional nitrogens, as well as other heteroatoms.
  • substituted refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical.
  • substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl (i.e.
  • oxo phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, carboxyalkyl, carboxyalkoxy, carboxyalkylthio, alkoxycarbonyl [—C( ⁇ O)O-alkyl], alkoxycarbonylamino [—NHC( ⁇ O)O-alkyl], alkoxycarbonylaminoalkyl [-alkyl-NHC( ⁇ O)O-alkyl], carboxyalkylcarbonylamino [—NHC( ⁇ O)-alkyl-COOH], carboxamido [—C( ⁇ O)NH 2 ], aminocarbonyloxy [—OC( ⁇ O)NH 2 ], alkylaminocarbonyl [—C( ⁇ O)NH-alkyl], dialkylaminocarbonyl [—C( ⁇ O)N(alkyl) 2 ], aminocarbonylalkyl [-alkyl
  • oxo is included among the substituents referred to in “optionally substituted”, it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl). Additional substituents that are considered within the scope of the term, particularly for R 1 , are the are the residues of amino acids, amino acid amides, protected residues of aminoacids and their amides, and N-methylated (mono- or di-, as appropriate) amino acids and amino acid amides.
  • Substituents that are considered within the scope of the term, particularly for A, are the are the residues of amino acids, amino acid amides and protected residues of aminoacids and their amides, as well as the following specific residues: —CH 3 , —CH 2 CF 3 , —CF 3 , —CHO, —COOH, —CN, halogen, —OH, —OEt, —C( ⁇ O)NH 2 , —C( ⁇ O)NHEt, —C( ⁇ O)NMe 2 -COOCH 3 , —COOEt, —CH 2 NHC( ⁇ O)NH 2 , —CH(CH 3 )NHC( ⁇ O)NH 2 , —CH 2 NHC( ⁇ O)H, —CH 2 NHC( ⁇ O)CH 3 , —CH 2 C( ⁇ O)NH 2 , —CH 2 COOH, —CH 2 COOEt, —CH 2 NHC( ⁇ O)OEt, —CH
  • a residue of an amino acid, amino acid amide”, etc. refers to an amino acid etc. minus the functional groups that are considered part of the bond to the parent structure.
  • BB-03 illustrated below:
  • haloalkyl and haloalkoxy mean alkyl or alkoxy, respectively, substituted with one or more halogen atoms.
  • alkylcarbonyl and alkoxycarbonyl mean —C( ⁇ O)alkyl or —C(O)alkoxy, respectively.
  • halogen means fluorine, chlorine, bromine or iodine. In one embodiment, halogen may be fluorine or chlorine.
  • the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • Radioisotopes of hydrogen, carbon, phosphorous, fluorine, and chlorine include 2 H, 3 H, 13 C, 14 C, 15 N, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention.
  • Tritiated, i.e. 3 H, and carbon-14, i.e., 14 C, radioisotopes are particularly preferred for their ease in preparation and detectability.
  • Radiolabeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radiolabeled reagent.
  • a compound is intended to include salts, solvates, co-crystals and inclusion complexes of that compound as well as any stereoisomeric form, or a mixture of any such forms of that compound in any ratio.
  • a compound as described herein including in the contexts of pharmaceutical compositions, methods of treatment, and compounds per se, is provided as the salt form.
  • the recitation “a compound of formula I” as depicted above, in which R 1 is imidazolyl would include imidazolium salts.
  • the term “compound of formula I” refers to the compound or a pharmaceutically acceptable salt thereof.
  • the compounds described herein may contain asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present invention is meant to include all such possible isomers, in any ratio from racemic to optically pure forms.
  • Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the prefix “rac” refers to a racemate.
  • solvate refers to a compound of Formula I in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered.
  • suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate.
  • solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions.
  • Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19 th Ed. (1995) volume 1, page 176-177, which is incorporated herein by reference. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic, are specifically encompassed within the claims.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Suitable pharmaceutically acceptable anions for the compounds of the present invention include acetate, benzenesulfonate (besylate), benzoate, bicarbonate, bisulfate, carbonate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, glycolate, bromide, chloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, trifluoroacetate, p-toluenesulfonate, acetamidobenzoate, adipate, alginate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, calcium edetate, camphorate, camsylate, caprate, caproate, caprylate, cinnamate,
  • suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • a protecting group refers to a group, which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable.
  • the protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or “deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere.
  • the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.
  • the starting materials are either commercially available, synthesized as described in the examples or may be obtained by the methods well known to persons of skill in the art.
  • PDE4 inhibitors have been shown to be effective therapeutic agents in clinical studies. For example, administration of cilomilast and roflumilast (PDE4 inhibitors) to patients suffering from asthma and COPD showed initially excellent results, although the effect of cilomilast disappeared on long-term trial [Lipworth, Lancet 365, 167-175 (2005)]. Genetic studies have clearly demonstrated an association between PDE4D and ischemic stroke (Gretarsdottir et al. 2003. Nature Genetics. 35, 1-8). Selective PDE4 inhibitors (e.g. rolipram) are also useful for treating bone loss [Yao et al., J. Musculoskelet. Neuronal Interact. 7, 119-130 (2007)].
  • a PDE4 inhibitor YM976 was shown to ameliorate the effects of experimentally-induced interstitial cystitis in rats, resulting in a decrease in the frequency of urination and an increase in the volume of urine at each time of urination [Kitta et al., BJU Int. 102, 1472-1476 (2008)].
  • the compounds, compositions and methods of the present invention may be useful in treating cancer.
  • Phosphodiesterase activity has been shown to be associated with hematological malignancies [Lerner et al., Biochem. J. 393, 21-41 (2006); Ogawa et al., Blood 99, 3390-3397 (2002)].
  • the compounds, compositions and methods of the present invention may be employed as imaging agents and in other ways for diagnosis and/or treatment.
  • immobilization of compounds of the invention on solid support could be of utility for affinity purification and modification of compounds of the invention with chemically active groups may be used for protein labeling.
  • cholinesterase inhibitors e.g. tacrine, huperzine, donepezil
  • NMDA antagonists e.g. lanicemine, remacemide, neramexane, memantine
  • calpain inhibitors e.g. CEP-3122
  • antioxidants e.g. vitamin E, coenzyme Q10 and agents that have shown clinical efficacy but whose mechanism is unclear (e.g. dimebon).
  • Compounds of formula I may also be administered together with one or more of the following agents to improve cognition: amisulpride, atomoxetine, bromocryptine, buspirone, caffeine, chlorpromazine, clonidine, clozapine, diazepam, flumazenil, fluoxetine, galantamine, guanfacine, methylphenidate, idazoxan, modafinil, olanzapine, paroxetine, pergolide, phenserine, quetiapine, risperidone, rivastigmine, SGS742 and sulpiride.
  • the terms “methods of treating or preventing” mean amelioration, prevention or relief from the symptoms and/or effects associated with disorders.
  • preventing refers to administering a medicament beforehand to forestall or obtund an acute episode.
  • prevent is not an absolute term.
  • prophylactic administration of a drug to substantially diminish the likelihood or seriousness of a condition, and this is the sense intended in applicants' claims.
  • treatment of a patient is intended to include prophylaxis.
  • mamal is used in its dictionary sense. Humans are included in the group of mammals, and humans would be the preferred subjects of the methods.
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration.
  • the most suitable route may depend upon the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association a compound of formula I or a pharmaceutically acceptable salt or solvate thereof (“active ingredient”) with the carrier, which constitutes one or more accessory ingredients.
  • active ingredient a pharmaceutically acceptable salt or solvate thereof
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations 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; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made 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 a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, 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.
  • the tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
  • the pharmaceutical compositions may include a “pharmaceutically acceptable inert carrier”, and this expression is intended to include one or more inert excipients, which include starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and the like. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques, “Pharmaceutically acceptable carrier” also encompasses controlled release means.
  • compositions may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, and the like. Any such optional ingredient must be compatible with the compound of formula I to insure the stability of the formulation.
  • the composition may contain other additives as needed, including for example lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, and the like, and hydrates thereof, and amino acids, for example alanine, glycine and betaine, and peptides and proteins, for example albumen.
  • additives including for example lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, and the like, and hydrates thereof, and amino
  • excipients for use as the pharmaceutically acceptable carriers and the pharmaceutically acceptable inert carriers and the aforementioned additional ingredients include, but are not limited to binders, fillers, disintegrants, lubricants, anti-microbial agents, and coating agents.
  • the dose range for adult humans is generally from 0.005 mg to 10 g/day orally. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of formula I which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity.
  • a dosage unit (e.g. an oral dosage unit) can include from, for example, 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, 1 to 300 mg, 1 to 500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, 5 to 100 mg (e.g.
  • the agents can be administered, e.g., by intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection, topical, sublingual, intraarticular (in the joints), intradermal, buccal, ophthalmic (including intraocular), intranasally (including using a cannula), or by other routes.
  • the agents can be administered orally, e.g., as a tablet or cachet containing a predetermined amount of the active ingredient, gel, pellet, paste, syrup, bolus, electuary, slurry, capsule, powder, granules, as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, via a micellar formulation (see, e.g.
  • the agents can also be administered transdermally (i.e. via reservoir-type or matrix-type patches, microneedles, thermal poration, hypodermic needles, iontophoresis, electroporation, ultrasound or other forms of sonophoresis, jet injection, or a combination of any of the preceding methods (Prausnitz et al. 2004, Nature Reviews Drug Discovery 3:115)).
  • the agents can be administered locally, for example, at the site of injury to an injured blood vessel.
  • the agents can be coated on a stent.
  • the agents can be administered using high-velocity transdermal particle injection techniques using the hydrogel particle formulation described in U.S. 20020061336. Additional particle formulations are described in WO 00/45792, WO 00/53160, and WO 02/19989. An example of a transdermal formulation containing plaster and the absorption promoter dimethylisosorbide can be found in WO 89/04179.
  • WO 96/11705 provides formulations suitable for transdermal administration.
  • the agents can be administered in the form a suppository or by other vaginal or rectal means.
  • the agents can be administered in a transmembrane formulation as described in WO 90/07923.
  • the agents can be administered non-invasively via the dehydrated particles described in U.S. Pat. No.
  • the agent can be administered in an enteric-coated drug formulation as described in WO 02/49621.
  • the agents can be administered intranasally using the formulation described in U.S. Pat. No. 5,179,079.
  • Formulations suitable for parenteral injection are described in WO 00/62759.
  • the agents can be administered using the casein formulation described in U.S. 20030206939 and WO 00/06108.
  • the agents can be administered using the particulate formulations described in U.S. 20020034536.
  • the agents can be administered by pulmonary route utilizing several techniques including but not limited to intratracheal instillation (delivery of solution into the lungs by syringe), intratracheal delivery of liposomes, insufflation (administration of powder formulation by syringe or any other similar device into the lungs) and aerosol inhalation.
  • Aerosols e.g., jet or ultrasonic nebulizers, metered-dose inhalers (MDIs), and dry-Powder inhalers (DPIs)
  • MDIs metered-dose inhalers
  • DPIs dry-Powder inhalers
  • Aerosol formulations are stable dispersions or suspensions of solid material and liquid droplets in a gaseous medium and can be placed into pressurized acceptable propellants, such as hydrofluoroalkanes (HFAs, i.e. HFA-134a and HFA-227, or a mixture thereof), dichlorodifluoromethane (or other chlorofluorocarbon propellants such as a mixture of Propellants 11, 12, and/or 114), propane, nitrogen, and the like.
  • HFAs hydrofluoroalkanes
  • HFA-134a and HFA-227 or a mixture thereof
  • dichlorodifluoromethane or other chlorofluorocarbon propellants such as a mixture of Propellants 11, 12, and/or 114
  • propane nitrogen, and the like.
  • Pulmonary formulations may include permeation enhancers such as fatty acids, and saccharides, chelating agents, enzyme inhibitors (e.g., protease inhibitors), adjuvants (e.g., glycocholate, surfactin, span 85, and nafamostat), preservatives (e.g., benzalkonium chloride or chlorobutanol), and ethanol (normally up to 5% but possibly up to 20%, by weight). Ethanol is commonly included in aerosol compositions as it can improve the function of the metering valve and in some cases also improve the stability of the dispersion. Pulmonary formulations may also include surfactants which include but are not limited to bile salts and those described in U.S. Pat. No.
  • the surfactants described in U.S. Pat. No. 6,524,557 e.g., a C 8 -C 16 fatty acid salt, a bile salt, a phospholipid, or alkyl saccharide are advantageous in that some of them also reportedly enhance absorption of the compound in the formulation.
  • dry powder formulations comprising a therapeutically effective amount of active compound blended with an appropriate carrier and adapted for use in connection with a dry-Powder inhaler.
  • Absorption enhancers which can be added to dry powder formulations of the present invention include those described in U.S. Pat. No. 6,632,456.
  • WO 02/080884 describes new methods for the surface modification of powders.
  • Aerosol formulations may include U.S. Pat. No. 5,230,884, U.S. Pat. No. 5,292,499, WO 017/8694, WO 01/78696, U.S. 2003019437, U.S. 20030165436, and WO 96/40089 (which includes vegetable oil).
  • Sustained release formulations suitable for inhalation are described in U.S. 20010036481A1, 20030232019A1, and U.S. 20040018243A1 as well as in WO 01/13891, WO 02/067902, WO 03/072080, and WO 03/079885.
  • Pulmonary formulations containing microparticles are described in WO 03/015750, U.S.
  • Pulmonary formulations containing stable glassy state powder are described in U.S. 20020141945 and U.S. Pat. No. 6,309,671.
  • Other aerosol formulations are described in EP 1338272A1 WO 90/09781, U.S. Pat. No. 5,348,730, U.S. Pat. No. 6,436,367, WO 91/04011, and U.S. Pat. No. 6,294,153 and U.S. Pat. No. 6,290,987 describes a liposomal based formulation that can be administered via aerosol or other means.
  • Powder formulations for inhalation are described in U.S. 20030053960 and WO 01/60341.
  • the agents can be administered intranasally as described in U.S. 20010038824.
  • Solutions of medicament in buffered saline and similar vehicles are commonly employed to generate an aerosol in a nebulizer.
  • Simple nebulizers operate on Bernoulli's principle and employ a stream of air or oxygen to generate the spray particles.
  • More complex nebulizers employ ultrasound to create the spray particles. Both types are well known in the art and are described in standard textbooks of pharmacy such as Sprowls' American Pharmacy and Remington's The Science and Practice of Pharmacy.
  • Other devices for generating aerosols employ compressed gases, usually hydrofluorocarbons and chlorofluorocarbons, which are mixed with the medicament and any necessary excipients in a pressurized container, these devices are likewise described in standard textbooks such as Sprowls and Remington.
  • the agent can be incorporated into a liposome to improve half-life.
  • the agent can also be conjugated to polyethylene glycol (PEG) chains.
  • PEG polyethylene glycol
  • Methods for pegylation and additional formulations containing PEG-conjugates i.e. PEG-based hydrogels, PEG modified liposomes
  • the agent can be administered via a nanocochleate or cochleate delivery vehicle (BioDelivery Sciences International).
  • the agents can be delivered transmucosally (i.e. across a mucosal surface such as the vagina, eye or nose) using formulations such as that described in U.S. Pat. No. 5,204,108.
  • the agents can be formulated in microcapsules as described in WO 88/01165.
  • the agent can be administered intra-orally using the formulations described in U.S. 20020055496, WO 00/47203, and U.S. Pat. No. 6,495,120.
  • the agent can be delivered using nanoemulsion formulations described in WO 01/91728A2.
  • compounds of formula I may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.
  • the invention relates to compounds of formula Ia, Ib or Ic:
  • Y is CH. In accordance with other embodiments, Y is N.
  • U is S. In accordance with other embodiments, U is O.
  • V is selected from H, CH 3 and NH 2 . In accordance with some embodiments, V is H. In accordance with some embodiments, V is CH 3 . In accordance with some embodiments, V is NH 2 .
  • B is phenyl which has a substituent at the 3-position, the 4-position and at both the 3- and 4-positions.
  • B is selected from 3-chlorophenyl, 3-nitrophenyl, 3-cyanophenyl, 3-bromophenyl, 3-acetylphenyl, 3-trifluoromethylphenyl, and 3-methylthiophenyl.
  • B is benzo[c][1,2,5]oxadiazol-5-yl and benzo[d][1,3]dioxol-5-yl.
  • R 1 and R 2 are both H. In some embodiments, R 1 is H and R 2 is OH.
  • A is optionally substituted phenyl; in other embodiments A is selected from the group consisting of optionally substituted 5- and 6-membered ring nitrogen heterocycles. In accordance with some embodiments of the invention, A is selected from the group consisting of optionally substituted pyridinyl, phenyl, morpholin-4-yl, piperazin-1-yl, piperidiny-1-yl, imidazol-1-yl, pyrazol-1-yl, and pyrazol-5-yl.
  • X is selected from the group consisting of CH, C—F, C—OH and N.
  • the compounds are of formula
  • a 2 is phenyl, five-membered heteroaryl, six-membered heteroaryl, 4-7 membered non-aryl heterocycle or fused bicycle;
  • R 7 is H or F
  • R 8 is chosen from halogen, nitro, acetyl, hydroxyethyl, amino, methylthio, trifluoromethyl, methoxymethyl, methoxycarbonyl, trifluoromethoxy, cyano and 1,3,4-thiadiazol-2-yl, or taken together R 7 and R 8 are methylenedioxy, ⁇ N—O—N ⁇ , —NH—CH ⁇ N— or difluoromethylenedioxy; R 14 is chosen from H, halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxyalkyl, carboxyalkoxy, carboxyalkylthio, alkoxycarbony
  • R 14a is chosen from hydroxy, carboxy, alkoxycarbonyl, carboxyalkylcarbonylamino, carboxyalkylaminocarbonylamino, guanidino, the residue of an amino acid and the residue of an N-methylated amino acid, 5-tetrazolyl and monocyclic heterocycle substituted with any of the foregoing; alternatively, R 14a may be chosen from —COOH, —OH, —COOCH 3 , —COOEt, —CH 2 COOH, —CH 2 COOEt, —CH 2 NHC( ⁇ O)OEt, —CH 2 NHC( ⁇ O)C( ⁇ O)NH 2 , —NHCH 2 COOH, —OCH(CH 3 )COOH, —SCH 2 COOH, —N(CH 3 )CH 2 COOH, —NHSO 2 NH 2 , —NHC( ⁇ O)CH 2 CH 2 COOH, —NHC
  • a 2 is a monocyclic heterocycle attached to a monocyclic heterocycle substituted with a carboxylic acid is found in example BB-01 below:
  • Exemplary carboxyalkoxy and carboxyalkylthio are lactic acid and thioglycolic acid respectively.
  • Exemplary amino acids are glycine, alanine and proline.
  • the compound is selected from the following:
  • Ia, Ib and Ic are useful as PDE4 inhibitors. It may be found upon examination that species and genera not presently excluded are not patentable to the inventors in this application because of prior art. In this case, the exclusion of species and genera in applicants' claims are to be considered artifacts of patent prosecution and not reflective of the inventors' concept or description of their invention.
  • the invention in a composition aspect, is all active compounds of formula Ia, Ib and Ic, except those that are in the public's possession.
  • compounds of formula Ia, Ib and Ic may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.
  • Table 1 above lists compounds representative of embodiments of the invention. Processes for obtaining compounds of formula I are presented below. Other compounds of formula I may be prepared in analogous fashion to those whose synthesis is exemplified herein. The procedures below illustrate such methods. Furthermore, although the syntheses depicted herein may result in the preparation of enantiomers having a particular stereochemistry, included within the scope of the present invention are compounds of formula I in any stereoisomeric form, and preparation of compounds of formula I in stereoisomeric forms other than those depicted herein would be obvious to one of ordinary skill in the chemical arts based on the procedures presented herein.
  • Generally compounds of the Formula I can be prepared by sequential introduction of substitution at the 4 and 6 positions of the benzoazoles.
  • the introduction of the substituents at the C4 position to form a C—C bond can be accomplished by organometallic coupling protocols (e.g. Suzuki, Stille reaction) or by displacement of a halogen using metal assisted displacement with a cyclic or heterocyclic NH compound forming a C—N bond at the C4 position of the benzoazole.
  • organometallic coupling protocols e.g. Suzuki, Stille reaction
  • metal assisted displacement with a cyclic or heterocyclic NH compound forming a C—N bond at the C4 position of the benzoazole.
  • G1 Scheme 1
  • the substituent at the C-6 position can be introduced by a wide variety of approaches. These chemistries employed depend of the 1-carbon functionality (CH3, CHO, COOR′, CN etc.) present at the C-6.
  • substituents at C6 or C4 could be carried in either sequence, i.e. formation of C4 substituent followed by C6 (route A, G1->G2) or vice versa (route B, G1-.G5).
  • Either of these substituents may carry additional functional groups which could be further derivatized through standard functional group transformation chemistries that are well know in the art. Some of these include formation of amide, sulfonamide, ureas, imidazolone, oxazolones, and carbamates from appropriate amine, carboxylic acid, alcohols or phenol groups.
  • the R1 group contains an ortho-halo N-heterocycles (e.g 2-halo pyridine or 2-halo-pyrimidine) G8, a nucleophilic displacement of the halo (or -OTf, ONf derived from pyridin-2-one) groups.
  • these nucleophile include an amine (primary, sec. tert.; acyclic or cyclic including) or NH-containing heteroaryl (for example, substituted imidazole or pyrazole); or alcohol/thiol allowing incorporation of additional —O, —S or —N linked substituents to provide G9.
  • an appropriately functionalized pyridine can be converted to corresponding 2-OTf or 2-ONf which could then participate in similar chemistries.
  • the R1 group could also be assembled form an acyclic intermediate (Scheme A3) to form a heterocylic or heteroaromatic ring.
  • Scheme A3 acyclic intermediate
  • examples of these chemistries include formation of 5-membered heteroaryls (G12) such as oxadiazole, thiadiazole, triazole form acyl hydrazide (G11); thiazole from 2-halo-ketone or dipolar cycloaddition reactions when the C4 or C6 substituent is an olefin or acetylic group (G10->G13)).
  • 6-membered heteroaryl or heterocyclic rings could be formed using Diels-Alder or hetero-Diels-Alder chemistries using appropriately substituted alkyl aryl ether bearing either a dienophile or a diene at C4 or C6 position.
  • R1 The diverse selection of substituents present in R1 could be formed by standard functional group transformations that are well know in the art. Some of these include formation of amide, sulfonamide, ureas, imidazolone, oxazolones, carbamates from the alkoxy-biaryl fragments bearing and appropriate amine, carboxylic acid, alcohols or phenol groups.
  • R1 group contains an ortho-halo pyridine or pyrimidine for example, the nucleophilic displacement of the halo (or -OTf, ONf derived from pyridone) groups. Examples of the nucleophile include an amine (primary, sec.
  • tert. acyclic or cyclic including), alcohol or HN-containing heterocylic groups (for example, substituted imidazole or pyrazole).
  • HN-containing heterocylic groups for example, substituted imidazole or pyrazole.
  • Scheme 1 provides an outline of the synthesis of example 1.
  • Step-1 (86). To 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (0.2 g, 0.91 mmol) in pyridine (2.5 mL) was added ethyl chloroformate (0.15 g, 1.36 mmol)). The reaction mixture was stirred at room temperature for 18 b, concentrated. Water (1.0 mL) and saturated NaHCO 3 solution (1.0 mL) was added, stirred for 1.0 h, filtered, washed with water, dried to afford 0.16 g (60%) of (86), as white solid.
  • BA-40 To (84) (0.08 g, 0.22 mmol), MR-75 (0.1 g, 0.34 mmol), (PPh 3 ) 4 Pd (0.026 g, 0.02 mmol) and K 2 PO 4 (0.095 g, 0.45 mmol) was added DME (3.0 mL), and EtOH—H 2 O (1:1, 1.0 mL). Ar gas was bubbled through the stirred reaction for 5 min. The reaction was stirred at 160° C. for 20 minutes using microwave oven (Biotage Initiator II). The reaction was cooled to room temperature, concentrated.
  • Step-1 [1-[4-(3-Chloro-phenyl)-5-fluoro-benzothiazol-6-ylmethyl]-piperidin-4-yl]-carbamic Acid tert-butyl Ester. (87)
  • Step-2 [1-[4-(3-Chloro-phenyl)-5-fluoro-benzothiazol-6-ylmethyl]-piperidin-4-yl]-carbamic Acid tert-butyl Ester.
  • BA-47 [1-[4-(3-Chloro-phenyl)-5-fluoro-benzothiazol-6-ylmethyl]-piperidin-4-yl]-carbamic Acid tert-butyl Ester.
  • Methods of the invention parallel the compositions and formulations.
  • the methods comprise administering to a patient in need of treatment a therapeutically effective amount of a compound according to the invention.
  • the present invention also provides a method for inhibiting phosphodiesterase 4.
  • In-vitro assay for PDE4 enzymes The in-vitro activity of PDE4 enzymes and the in-vitro potency of therapeutic agents described in the present invention was measured using a real-time, enzyme-coupled spectrophotometric assay. By using three different coupling enzymes, the product of the PDE4 reaction is coupled to the oxidation of the reduced form ⁇ -nicotinamide adenine dinucleotide (NADH), which dissipation can be monitored spectrophotometrically at 340 nM.
  • NADH ⁇ -nicotinamide adenine dinucleotide
  • Buffer A containing 50 mM Tris, pH 8.0, 16 mM MgCl 2 and 80 mM KCl is prepared and stored at room temperature.
  • Buffer B containing 50 mM Tris, pH 8.0 is prepared and stored at room temperature.
  • Stock solutions of the following reagents are prepared in Buffer B and stored at ⁇ 20° C.: Adenosine-5′-triphosphate (ATP), cyclic adenosine-5′-monophosphate (cAMP), phosphoenolpyruvate (PEP) and NADH.
  • ATP Adenosine-5′-triphosphate
  • cAMP cyclic adenosine-5′-monophosphate
  • PEP phosphoenolpyruvate
  • NADH NADH
  • An assay mix is prepared by mixing Buffer A, trichloroethylphosphine (TCEP), ATP, PEP, NADH, myokinase (MK), pyruvate kinase (PK), lactate dehydroganese (LDH) and PDE4 to a final volume of 20 mL, which is enough for a single 96-well assay plate.
  • Assay mix 180 ⁇ L
  • test article (10 ⁇ L) in 1:1 DMSO/H 2 O mixture is pre-incubated at room temperature for 10 min. The enzymatic reaction is initiated by addition of cAMP (10 ⁇ L).
  • Final concentration of all components in the assay (200 ⁇ L/well) are as follows: 10 mM MgCl 2 , 50 mM KCl, 5 mM TCEP, 2.5% DMSO, 0.4 mM NADH, 1 mM PEP, 0.04 mM ATP, 5 units MK, 1 unit PK, 1 unit LDH and appropriate amount of PDE4.
  • Reaction progress curves are monitored in a plate reader capable of measuring light absorbance at 340 nM. A decrease in light absorbance at 340 nm is due to oxidation of NADH. Positive controls containing no test article and negative controls containing no test article and no cAMP are included on every assay plate. Reaction rates are determined from the slopes of the linear portions of the progress curves.
  • the activity of PDE4 inhibitors described in the present invention can be measured using in an ex-vivo assay measuring leukotriene E4 (LTE4) in human whole blood after Sephadex stimulation.
  • LTE4 leukotriene E4
  • the anti-inflammatory activity of therapeutic agents of the present invention is demonstrated by the inhibition of eosinophil activation as measured by sephadex bead stimulated LTE4 production in whole human blood.
  • 356 ⁇ l of heparinized human whole blood (Vacutainer tube #6480) is added to wells of a 96 well plate.
  • 4 ⁇ l of a series of compound dilutions in triplicates, suspension mixed and allowed to incubate at 37° C. for 15 min with gentle shaking.
  • blood samples are stimulated by adding 40 ⁇ L of Sephadex G-15 beads (Sigma-Aldrich, Sweden). The beads are predissolved in PBS (0.16 g/mL PBS). After mixing, the suspension is incubated at 37° C. for 90 min. Then, 8 ⁇ L of 15% EDTA/PBS is added to each sample, mixed and plate centrifuged for 5 min at 115 ⁇ g at 21° C. and supernatants taken. In each plate, 10 positive controls and 10 negative controls are used, containing DMSO instead of compound solution. The positive controls are stimulated with Sephadex as described for the samples, and in the negative controls (unstimulated), Sephadex solution is replaced by PBS. LTE 4 levels in the resulting plasma samples are determined using a commercial enzyme-linked immunoassay (Cayman Chemical Company, Ann Arbor, Mich.) according to the manufacturer's instructions.

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CN109053623A (zh) * 2018-08-27 2018-12-21 济南悟通生物科技有限公司 一种4-甲基-5-噻唑甲醛的新型制备方法
JPWO2018008718A1 (ja) * 2016-07-07 2019-04-18 保土谷化学工業株式会社 ベンゾアゾール環構造を有する化合物および有機エレクトロルミネッセンス素子
CN112047960A (zh) * 2015-07-02 2020-12-08 豪夫迈·罗氏有限公司 苯并氧氮杂*噁唑烷酮化合物及其使用方法
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US20090136473A1 (en) * 2007-11-21 2009-05-28 Decode Genetics Ehf Biaryl pde4 inhibitors for treating pulmonary and cardiovascular disorders
US20090324569A1 (en) * 2007-11-21 2009-12-31 Decode Genetics Ehf Biaryl pde4 inhibitors for treating inflammatory, cardiovascular and cns disorders
US20120207729A1 (en) * 2007-11-21 2012-08-16 Decode Genetics Ehf Substituted benzoazole pde4 inhibitors for treating pulmonary and cardiovascular disorders
US8791267B2 (en) 2007-11-21 2014-07-29 Decode Genetics Ehf Biaryl PDE4 inhibitors for treating inflammatory, cardiovascular and CNS disorders
EP3345902A1 (en) 2013-03-14 2018-07-11 Dart NeuroScience (Cayman) Ltd Substituted pyridine and pyrazine compounds as pde4 inhibitors
US9120770B2 (en) 2013-03-14 2015-09-01 Dart Neuroscience (Cayman) Ltd. Substituted pyridine and pyrazine compounds as PDE4 inhibitors
US9573937B2 (en) 2013-03-14 2017-02-21 Dart Neuroscience (Cayman) Ltd. Substituted pyridine and pyrazine compounds as PDE4 inhibitors
US9040692B2 (en) 2013-03-14 2015-05-26 Dart Neuroscience (Cayman) Ltd. Substituted pyridine and pyrazine compounds as PDE4 inhibitors
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CN112047960A (zh) * 2015-07-02 2020-12-08 豪夫迈·罗氏有限公司 苯并氧氮杂*噁唑烷酮化合物及其使用方法
WO2017089347A1 (en) 2015-11-25 2017-06-01 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and pharmaceutical compositions for the treatment of braf inhibitor resistant melanomas
JPWO2018008718A1 (ja) * 2016-07-07 2019-04-18 保土谷化学工業株式会社 ベンゾアゾール環構造を有する化合物および有機エレクトロルミネッセンス素子
CN109790132A (zh) * 2016-07-07 2019-05-21 保土谷化学工业株式会社 具有苯并唑环结构的化合物及有机电致发光元件
JP7430486B2 (ja) 2016-07-07 2024-02-13 保土谷化学工業株式会社 ベンゾアゾール環構造を有する化合物および有機エレクトロルミネッセンス素子
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CN109053623A (zh) * 2018-08-27 2018-12-21 济南悟通生物科技有限公司 一种4-甲基-5-噻唑甲醛的新型制备方法
WO2022172037A1 (en) * 2021-02-15 2022-08-18 Mironid Limited Compounds and their use as pde4 activators

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