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WO2006016237A2 - Dérivés hétérocycliques faisant office d’agents anti-inflammatoires - Google Patents

Dérivés hétérocycliques faisant office d’agents anti-inflammatoires Download PDF

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Publication number
WO2006016237A2
WO2006016237A2 PCT/IB2005/002292 IB2005002292W WO2006016237A2 WO 2006016237 A2 WO2006016237 A2 WO 2006016237A2 IB 2005002292 W IB2005002292 W IB 2005002292W WO 2006016237 A2 WO2006016237 A2 WO 2006016237A2
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Prior art keywords
compound
methyl
phenyl
carbonyl
carboxylic acid
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WO2006016237A3 (fr
Inventor
Venkata P. Palle
Ashwani Kumar Verma
Mohammad Salman
Rakesh Kumar Singh
Yogesh Bhaskarrao Waman
Geeta Sharma
Abhijit Ray
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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]

Definitions

  • the present invention relates to some heterocyclic derivatives as anti-inflammatory agents.
  • the compounds of this invention can be useful, for inhibition and/or prevention of inflammation and associated pathologies including inflammatory and autoimmune diseases such as sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis.
  • This invention also relates to pharmacological compositions containing the compounds disclosed herein and the methods of treating and/or preventing sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis, and other inflammatory and/or autoimmune disorders, using the compounds.
  • cytokines a unique class of intercellular regulatory proteins, in the pathogenesis of many diseases have been investigated.
  • Cytokines play a crucial role in initiating, maintaining, and regulating immunological and inflammatory processes. Advances in our understanding of their role in immune and inflammatory disorders have led to the development of cytokine-based therapies —that is, therapies that aim to inhibit or restore the activity of specific cytokines. Drugs that block inflammatory cytokines, such as tumor necrosis factor-alpha (TNF- ⁇ ), have been introduced to the market.
  • TNF- ⁇ tumor necrosis factor-alpha
  • Elevated levels of proinflammatory cytokines viz TNF- ⁇ and IL-I ⁇ are associated with the pathogenesis of many immune mediated inflammatory disorders like sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis, mflammation is regulated by a large number of pro- and anti-inflammatory mediators, which include cytokines, eicosanoids, nitric oxide, and reactive oxygen species.
  • pro- and anti-inflammatory mediators include cytokines, eicosanoids, nitric oxide, and reactive oxygen species.
  • inflammatory disorders were treated primarily with relatively non-selective anti ⁇ inflammatory agents, such as corticosteroids and various non-steroidal anti-inflammatory drugs.
  • the p38 mitogen activated protein kinase regulates cytokine levels and therefore plays a central role in both the cellular infiltration and activation responses associated with inflammatory diseases.
  • the p38 MAPK is a member of a large family of MAPK' s whose signaling pathways also include the extracellular regulated kinases (ERK) & the c-jun N terminal kinases (INK).
  • MAP kinases are Serine Threonine Kinases that transduce environmental stimuli to the nucleus and they themselves are activated by upstream MAPK kinases by phosphorylation on both Tyrosine and Threonine residues.
  • p38 ⁇ MAPK The MAPK pathways are involved in alterations in cell physiology resulting from a variety of stimuli and control cell death, cell cycle machinery, gene transcription and protein translation.
  • p38 ⁇ MAPK was first identified as a tyrosine phosphorylated protein in LPS (Lipopolysaccharide) stimulated macrophages.
  • the human p38 ⁇ MAPK was identified as the target of pyridinyl imidazole compounds (cytokine suppressive anti- inflammatory drugs) that were known to block TNF- ⁇ and IL-I release from LPS stimulated monocytes.
  • p38 ⁇ additional members of the p38MAPK family were cloned by homology, including the p38 ⁇ , p38 ⁇ and p38 ⁇ .
  • p38 pathway controls the activity of multiple transcription factor s and the expression of many genes.
  • p38 inhibitors have been shown to effectively block both TNF- ⁇ and IL-I biosynthesis by LPS stimulated human monocytes.
  • p38 MAPk also plays a role in the production of IL-4, IL-6, IL-8 and IL-12.
  • p38 MAPk is also critical for cell response to certain cytokines. Treatment of human neutrophils with GM-CSF, TNF- ⁇ or TGF- ⁇ results in p38 activation.
  • TNF- ⁇ are potent enhancers of neutrophil respiratory activity suggesting a role for p38 MAPk in respiratory burst.
  • p38 has also been implicated in the induction of cyclooxygenase-2 (COX-2) in LPS induced monocytes.
  • COX-2 enzyme is the key enzyme in the production of prostaglandins from arachidonic acid.
  • Inhibitors of p38 MAP kinase are also expected to inhibit COX-2 expression. Accordingly inhibitors of cytokine synthesis would be expected to be effective in disorders currently treated with NSAID's. These disorders include acute and chronic pain as well as symptoms of inflammation and cardiovascular disease.
  • Compounds, which modulate release of one or more of the aforementioned inflammatory cytokines can be useful in treating diseases associated with the release of these cytokines.
  • PCT application WO 00/12074, WO 01/64676 and U.S. Patent No. 6,410,540 disclose compounds that are described as being useful in treating inflammation.
  • the disclosed compounds include N-containing heterocycles.
  • U.S. Patent No. 6,541,477 discloses methods for treating conditions mediated by p38 ⁇ kinase.
  • U.S. application 2002/0115671 discloses compounds that are said to be useful in treating inflammation and cardiac conditions.
  • the disclosed compounds include N containing heterocycles.
  • Heterocyclic derivatives which can be used for the for inhibition and prevention of inflammation and associated pathologies such as sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis, are disclosed herein.
  • Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N- oxides of these compounds having the same type of activity are also provided.
  • compositions containing the compounds, and which may also contain pharmaceutically acceptable carriers or diluents, which may be used for the treatment of inflammatory and autoimmune diseases such as such as sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis are also provided.
  • X can be oxygen, sulphur, or -NR (wherein R can be alkyl, or aryl).
  • Each of r and p represents an integer from 0-4, with the proviso that both r and p cannot be zero at the same time.
  • Z can be nitrogen, or -CH.
  • W can be alkylene, alkenylene, or alkynylene (wherein when Z is nitrogen double bond of said alkenylene or triple bond of said alkynylene cannot be attached directly to Z atom).
  • R 1 and R 2 can independently be hydrogen, cyano, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, acyl, aryloxy, cycloalkyl, aryl, aralkyl, carboxy, -COOR 3 (wherein R 3 can be alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl), -NR p Rq (wherein R p and R q can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl, or R p and Rq may also together join to form a hetero
  • Ar 1 and Ar 2 can independently be aryl, heteroaryl, or heterocyclyl.
  • Ar 1 can be phenyl
  • W can be methylene
  • Z can be -CH-
  • t and m can be 1
  • Q can be carbonyl
  • Ar 2 can be 1,2-, 1,3-, or 1,4-disubstituted phenyl
  • r can be 0,
  • p can be 1
  • X can be oxygen.
  • R 1 can be alkyl (e.g., methyl)
  • Ar 2 can be a trisubstituted phenyl.
  • a second aspect there are provided methods for the treatment of mammals suffering from inflammation and associated pathologies.
  • methods for the treatment of mammals suffering from inflammatory diseases and associated pathologies including sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis.
  • the compounds provided herein are screened as p38 kinase inhibitors.
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t- butyl, n-hexyl, n-decyl, tetradecyl, and the like.
  • Alkyl may further be substituted with one or more substituents selected from alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryloxy, aralkyloxy, heteroaryloxy, aminosulfonyl, -
  • alkylene refers to a diradical branched or unbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms. This term is exemplified by groups such as methylene, ethylene, propylene isomers and the like.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 20 carbon atoms with cis or trans geometry. In the event that alkenyl is attached to the heteroatom, the double bond cannot be alpha to the heteroatom. Conjugated or unconjugated multiply unsaturated systems are also contemplated.
  • alkenylene refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 6 carbon atoms with cis or trans geometry. In the event that alkenylene is attached to a heteroatom, any double bond cannot be alpha to the heteroatom.
  • the alkenylene group can be connected by two bonds to the rest of the structure of compound of Formula Ia.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2 to 20 carbon atoms. In the event that alkynyl is attached to a heteroatom, any triple bond cannot be alpha to the heteroatom.
  • alkynylene refers to a diradical of an unsaturated hydrocarbon, preferably having from 2 to 6 carbon atoms. In the event that alkynylene is attached to a heteroatom, any triple bond cannot be alpha to the heteroatom.
  • the alkenylene group is connected by two bonds to the rest of the structure of compound of Formula Ia.
  • cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless or otherwise constrained by the definition.
  • the cycloalkyl group may optionally contain 1-3 heteroatoms selected from the group consisting of O, N or S such as oxazoline, isoxazoline, thiazoline, and the like.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures such as adamantanyl, and bicyclo (2.2.1) heptane, or cyclic alkyl groups to which is fused an aryl group, for example indane, and the like. Fused or spiro rings are also contemplated.
  • alkoxy denotes the group O-alkyl wherein alkyl is the same as defined above.
  • aralkyl refers to alkyl-aryl linked through alkyl (wherein alkyl is the same as defined above) portion and the alkyl portion contains carbon atoms from 1-6 and aryl is as defined below.
  • alkyl is the same as defined above
  • alkyl portion contains carbon atoms from 1-6 and aryl is as defined below.
  • aralkyl groups are benzyl and the like.
  • substituents selected from halogen (F, Cl, Br, I),
  • aryl group may optionally be fused with cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from the group consisting of O, N, S.
  • aryloxy denotes the group O-aryl wherein aryl is the same as defined above.
  • aralkyloxy denotes the group O-aralkyl wherein aralkyl is the same as defined above.
  • heteroaryl refers to an aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 ring atoms, with one or more heteroatom(s) independently selected from the group consisting of N, O and S optionally substituted with 1 to 3 substituent(s) selected from the group consisting of halogen (F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, -COOR 3 (wherein R 3 is the same as defined earlier), aryl, alkoxy, aralkyl, cyano, nitro, -NR x Ry, -C(O)NR x Ry and -NHC(O)NR x Ry , -S(O) 01 R 4 , -OC(O)NR x Ry (wherein m,
  • the substituents are attached to the ring atom, be it carbon or heteroatom.
  • heteroaryl groups are pyridinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, tetrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, and the like.
  • heterocyclyl ring may optionally contain one or more olefinic bond(s).
  • heterocyclyl groups are tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, piperidinyl, pyrrolidinyl, morpholinyl or piperazinyl.
  • Heteroarylalkyl refers to alkyl-heteroaryl group linked through alkyl portion, wherein the alkyl and heteroaryl are the same as defined earlier.
  • Heterocyclylalkyl refers to alkyl-heterocyclyl group linked through alkyl portion, wherein the alkyl and heterocyclyl are the same as defined earlier.
  • leaving group generally refers to groups that exhibit the properties of being labile under the defined synthetic conditions and also, of being easily separated from synthetic products under defined conditions. Examples of such leaving groups include, but are not limited to halogen (F, Cl, Br, I), triflates, tosylate, mesylates, alkoxy, thioalkoxy, hydroxy radicals and the like.
  • the compounds provided herein can contain one or more asymmetric carbon atoms and thus occur as racemates and racemic mixtures, single enantiomers, diastereomieric mixtures and individual diastereomers. AU such isomeric forms of these compounds are expressly included in the present invention.
  • Each stereo genie carbon may be of the R or S configuration.
  • the specific compounds exemplified in this application may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral center or mixtures thereof are envisioned as part of the invention.
  • amino acids and amino acid side chains may be depicted in a particular configuration, both natural and unnatural forms are envisioned as part of the invention.
  • Suitable inorganic base addition salts include, but are not limited to aluminium, calcium. Lithium, magnesium, potassium, sodium and zinc salts.
  • Suitable organic base addition salts include, but are not limited to primary, secondary and tertiary amines, cyclic amines, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine and procaine salts.
  • the pharmaceutically acceptable salts may be prepared by the conventional methods known in the prior art.
  • the compounds provided herein may be prepared by techniques well known in the art and familiar to a practitioner skilled in art of this invention. Li addition, the compounds provided herein may be prepared by the process described herein, this process is not the only means by which the compounds may be synthesized. Further, the various synthetic steps described herein may be performed in an alternate sequence in order to give the desired compounds.
  • the compounds of Formula VI can be prepared by Scheme I.
  • a compound of Formula I (wherein 1 is an integer from 0-2 and Ar 1 , W, Z and m are the same as defined earlier) is reacted with a compound of Formula II (wherein K and R 3 are the same as defined earlier) to furnish a compound of Formula III, which is reacted with hydroxylamine hydrochloride to furnish a compound of Formula IV, which is reacted with a compound of Formula V (wherein B is hydrogen or alkyl and P is cyano, -COOR 3 (wherein R 3 is same as defined earlier) or -CH 2 OH) to furnish a compound of Formula VI.
  • the compound of Formula I can be reacted with a compound of Formula II to give a compound of Formula III in an organic solvent, such as tetrahydrofuran, dimethylformamide or dioxane, with a condensing agent, such as l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide, in the presence of an organic base, such as N-methylmorpholine, diisopropylethylamine or triethylamine.
  • a compound of Formula I can be reacted with an "activated derivative of carboxylic acid" to furnish a compound of Formula III (when k is O).
  • the compound of Formula III can be reacted with hydroxylamine hydrochloride to give a compound of Formula IV in an organic solvent, such as ethanol, methanol, propanol or isopropylalcohol, in the presence of an organic base, such as pyridine, N- methylmorpholine or diisopropylethylamine.
  • an organic solvent such as ethanol, methanol, propanol or isopropylalcohol
  • the compound of Formula IV can be reacted with a compound of Formula V to give a compound of Formula VI in an organic solvent such as tetrahydrofuran, dimethylformamide, chloroform, carbon tetrachloride or dioxane with oxidants such as, sodium hypochlorite, N-chlorosuccinimide or tert-butoxychloride in the presence of an optional base such as, pyridine, butyl lithium, N-methylmorpholine, diisopropylethylamine or triethylamine.
  • an organic solvent such as tetrahydrofuran, dimethylformamide, chloroform, carbon tetrachloride or dioxane
  • oxidants such as, sodium hypochlorite, N-chlorosuccinimide or tert-butoxychloride
  • an optional base such as, pyridine, butyl lithium, N-methylmorpholine, diisopropylethylamine or triethy
  • esters are specified one skilled in the art would optionally hydrolyze them to their respective acids, for example hydrolysis of alkyl esters (such as ethyl, methyl or benzyl ester) to their corresponding acids can be carried out in the presence of a base for example lithium hydroxide, sodium hydroxide or potassium hydroxide. Alternatively hydrolysis of benzyl ester can be carried out hydrogenatically using catalysts for example palladium on carbon or platinum on carbon. The esters such as tert-butyl can be hydrolyzed to their corresponding acids in the presence of acid for example trifluoroacetic acid or hydrochloric acid.
  • alkyl esters such as ethyl, methyl or benzyl ester
  • benzyl ester can be carried out hydrogenatically using catalysts for example palladium on carbon or platinum on carbon.
  • the esters such as tert-butyl can be hydrolyzed to their corresponding acids in the presence of acid for example trifluoroacetic acid or
  • the compound of Formula IX can be prepared, for example, by Scheme II, thus
  • Path a The compound of Formula VII (wherein An, R 3 , W, Z, 1, m and k are the same as defined earlier) reacts with a compound of Formula VIII (wherein R p and R q are the same as defined earlier) to give a compound of Formula IX.
  • Path b The compound of Formula VII undergoes hydrolysis to give a compound of Formula X, which is reacted with a compound of Formula VIII to give a compound of Formula IX.
  • the compound of Formula VII (Path a) can be reacted with a compound of Formula VIII to furnish a compound of Formula IX in an organic solvent, such as tetrahydrofuran, dimethylformamide, diethyl ether or dioxane.
  • an organic solvent such as tetrahydrofuran, dimethylformamide, diethyl ether or dioxane.
  • the compound of Formula VII (Path b) can be hydrolyzed to furnish a compound of Formula X in an organic solvent, such as tetrahydrofuran, dimethylformamide, methanol or ethanol, in the presence of base, such as lithium hydroxide, potassium hydroxide or sodium hydroxide.
  • organic solvent such as tetrahydrofuran, dimethylformamide, methanol or ethanol
  • base such as lithium hydroxide, potassium hydroxide or sodium hydroxide.
  • the compound of Formula X can be reacted with a compound of Formula VIII to furnish a compound of Formula IX in an organic solvent, such as tetrahydrofuran, dimethylforniamide, diethylether or dioxane, with condensing agent, such as l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or dicyclohexyl carbodiimide, in the presence of base, such as N-methylmorpholine, diisopropylethylamine or triethylamine.
  • organic solvent such as tetrahydrofuran, dimethylforniamide, diethylether or dioxane
  • condensing agent such as l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or dicyclohexyl carbodiimide
  • base such as N-methylmorpholine, diisopropylethyl
  • the compound of Formula XIII can be prepared, for example, by Scheme III, thus a compound of Formula XI (wherein Ar, Z, W, 1, m and K same as defined earlier and B is H or alkyl) is reacted with a compound of Formula XII (wherein hal is Cl, Br or I and G is alkyl or aralkyl) to give a compound of Formula XIII.
  • the compound of Formula XI can be reacted with a compound of Formula XII to give a compound of Formula XIII in an organic solvent, such as tetrahydrofuran, dimethylformamide, acetonitrile, acetone or dioxane, in the presence of a base such as sodium hydride, lithium hydride, potassium carbonate or calcium hydride.
  • an organic solvent such as tetrahydrofuran, dimethylformamide, acetonitrile, acetone or dioxane
  • a base such as sodium hydride, lithium hydride, potassium carbonate or calcium hydride.
  • the compound of Formula XV can be prepared by following the procedure as depicted in Scheme IV.
  • a compound of Formula XIV can be reacted with a compound of Formula Ro-hal (wherein R 0 Is alkyl, aryl, cycloalkyl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl and hal are the same as defined earlier) to give a compound of Formula XV.
  • a compound of Formula Ro-hal wherein R 0 Is alkyl, aryl, cycloalkyl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl and hal are the same as defined earlier
  • reaction of a compound of Formula XIV with a compound of Formula R ⁇ -hal to give a compound of Formula XV can be carried out in an organic solvent such as, dimethylformamide, tetrahydrofuran, diethyl ether or dioxane in the presence of a base such as, sodium hydride, potassium tert-butoxide, potassium carbonate or cesium carbonate.
  • organic solvent such as, dimethylformamide, tetrahydrofuran, diethyl ether or dioxane
  • a base such as, sodium hydride, potassium tert-butoxide, potassium carbonate or cesium carbonate.
  • compositions of the present invention comprise a pharmaceutically effective amount of a compound described herein formulated together with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carriers is intended to include non-toxic, inert solid, semi-solid or liquid filter, diluent, encapsulating material or formulation auxiliary of any type. Solid form preparation for oral administrations, include capsules, tablets, pills, powders, granules, and suppositories.
  • the active compound can be mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate, dicalcium phosphate and/or a filler or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid; binders such as carboxymethylcellulose, alginates, gelatins, polyvinylpyrolidinone, sucrose, acacia; disintegrating agents such as a agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates and sodium carbonate, absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol, glycerol, monostearate; adsorbents such as kaolin; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium lauryl sulphate and mixtures thereof.
  • pharmaceutically acceptable excipient or carrier such as sodium citrate, dicalcium phosphate
  • the dosage form may also comprise buffering agents.
  • Solid preparations of tablets, capsules, pills, granules can be prepared with coating and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art.
  • Liquid form preparations for oral administration can include pharmaceutically acceptable emulsions, solution, suspensions, syrups and elixirs.
  • the active compound can be mixed with water or other solvent, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as cottonseed, groundnut, corn, germ, olive, castor and Sesame oil), glycerol, and fatty acid esters of sorbitan and mixtures thereof.
  • oral compositions can also include adjuvants such as wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents.
  • Injectable preparations such as sterile injections, aqueous or oleaginous suspensions may be formulated according to the art using suitable dispersing or wetting and suspending agents.
  • suitable dispersing or wetting and suspending agents include water, Ringer's solution, U.S.P. and isotonic sodium chloride.
  • Dosage forms for tropical or transdermal administration of compounds described herein include ointments, pastes, creams, lotions, gel, powders, solutions, spray, inhalants or patches.
  • the active compound can be admixed under sterile conditions with pharmaceutically acceptable carriers and any preservatives or buffers as may be desired. Ophthalmic formulation, eardrops, eye ointments, powders and solutions are also included herein.
  • the pharmaceutical preparation may be in unit dosage form.
  • the preparation maybe subdivided into unit doses containing appropriate quantities of active component.
  • Unit dosage forms can be packaged preparations, the package containing discrete capsules, powders, in vials or ampoules and ointments, capsules, cachets, tablets, gel creams or it can be the appropriate number of any packaged forms.
  • Formulations disclosed herein may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known to the art.
  • Step b Synthesis of l-benzyI-4-(4-fIuorobenzylidene)piperidine
  • Step c synthesis of 4-(4-fluorobenzyl)piperidine
  • ammonium formate (0.63 g, 10.0 mmol)
  • palladium on carbon 0.3 g
  • the mixture was refluxed for 3 hours and subsequently cooled to room temperature.
  • the mixture was filtered through celite pad and washed with methanol. The filtrate was concentrated under reduced pressure to furnish the title compound (0.07 g).
  • Step a Synthesis of 3-(4-benzylpiperidine-l-carbonyl)benzaldehyde To a solution of 3-carboxaldehyde (1.5 g, 10 mmol) in dry tetrahydrofuran (10 ml) under argon atmosphere, was added N-methylmorpholine (2.52 g, 25 mmol) and 4-benzyl piperidine (1.75 g, 10 mmol). The reaction mixture was stirred for 30 minutes at 0-5 0 C followed by the addition of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.9 g, 10 mmol).
  • Step b Synthesis of 3-(4-benzyIpiperidine-l-carbonyl)benzaIdehyde oxime.
  • hydroxyl amine hydrochloride (0.64 g, 9.28 mmol) under nitrogen atmosphere.
  • the reaction mixture was stirred for overnight followed by removal of solvent under reduced pressure.
  • the residue was diluted with ice- cold water and extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulphate and concentrated to furnish the title compound (1.78 g).
  • Step c Synthesis of 3-[4-(4-benzyIpiperidine-l-carbonyI)phenyl]-5 ⁇ methyl-4,5- dihydroisoxazol-5-carboxyIic acid methyl ester.
  • methyl methacrylate 0.534 g, 6.22 mmol
  • aqueous solution of sodium hypochlorite 4%, 5 ml
  • the reaction mixture was concentrated under reduced pressure and the residue thus obtained was collected in ethyl acetate.
  • Example 2 Synthesis of 3-[3-(4-benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5- dihydroisoxazoI-5-yl)pyrrolidin-l-ylmethanone (Compound No. 16)
  • pyrrolidine 0.45 g, 5.71 mmol
  • the reaction mixture was stirred at 40 °C for overnight.
  • the reaction mixture was diluted with ethyl acetate and extracted with water.
  • the organic layer was collected and concentrated under reduced pressure.
  • the residue thus obtained was purified by column chromatography using 80% ethyl acetate in hexane as eluent to furnish the title compound (0.128 g).
  • Analogue of (4-benzylpiperidin-l-yl)-[4-(5-methoxymethyl-5-methyl-4,5- dihydroisoxazol-3-yl)phenyl]methanone (Compound No. 27) described below, can be prepared by replacing appropriate alkyl halide group in place of methyl iodide, respectively, as applicable in each case.
  • PBM cells 0.1 ml, 2 million/ml were co-incubated with 0.1 ml of compound (10 -0.41 ⁇ M, final concentration) for 1 hour in flat bottom 96 well microliter plate.
  • Compounds were dissolved in DMSO initially and diluted in TCM for a final concentration of 0.1% DMSO.
  • LPS (CaI biochem, 20ng/ml, final concentration) was then added at volume of 0.010 ml. Cultures were incubated overnight at 37 0 C. Supernatant was then removed and tested by ELISA for TNF- ⁇ release. Viability was analyzed using MTT.
  • 0.1 ml of 0.25mg/ml of MTT was added to remaining 0.1 ml of cells.
  • the cells were incubated at 37 0 C for 2-4 hours, then the O.D was measured at 490-650 nm.

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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur certains dérivés hétérocycliques faisant office d'agents anti-inflammatoires. Les composés de la présente invention peuvent servir à l'inhibition et/ou la prévention des inflammations et des pathologies associées, comme les maladies inflammatoires et auto-immunes comme l'état septique, l'arthrite rhumatismale, les gastroentérites, le diabète de type-1, l'asthme, les troubles pulmonaires obstructifs chroniques, le rejet d'organes transplantés et le psoriasis. La présente invention porte également sur des compositions pharmacologiques contenant les composés divulgués ici et les procédés de traitement et/ou de prévention de l'état septique, de l'arthrite rhumatismale, des gastroentérites, du diabète de type-1, de l'asthme, des troubles pulmonaires obstructifs chroniques, du rejet d'organes transplantés et du psoriasis et d'autres troubles inflammatoires et/ou auto-immunes à l'aide des composés.
PCT/IB2005/002292 2004-08-04 2005-08-02 Dérivés hétérocycliques faisant office d’agents anti-inflammatoires Ceased WO2006016237A2 (fr)

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US60/598,621 2004-08-04

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EP1958947A1 (fr) 2007-02-15 2008-08-20 Ranbaxy Laboratories Limited Inhibiteurs de la phosphodiestérase de type 4
WO2010032437A1 (fr) * 2008-09-18 2010-03-25 日本曹達株式会社 Composé hétérocyclique contenant de l'azote et agent de lutte contre les animaux nuisibles
WO2012130798A1 (fr) 2011-03-31 2012-10-04 Bayer Cropscience Ag 3-phénylisoxazolino-5-carboxamides et 3-phénylisoxazolino-5-thioamides à activité herbicide et fongicide
US8420666B2 (en) 2007-03-14 2013-04-16 Ranbaxy Laboratories Limited Pyrazolo (3, 4-B) pyridine derivatives as phosphodiesterase inhibitors
WO2018228985A1 (fr) 2017-06-13 2018-12-20 Bayer Aktiengesellschaft 3-phénylisoxazoline-5-carboxamides d'acides carboxyliques et d'esters de tétrahydro- et dihydrofurane à effet herbicide
WO2018228986A1 (fr) 2017-06-13 2018-12-20 Bayer Aktiengesellschaft 3-phénylisoxazoline-5-carboxamides d'amides d'acide carboxylique de tétrahydro- et dihydrofurane à effet herbicide
WO2019034602A1 (fr) 2017-08-17 2019-02-21 Bayer Aktiengesellschaft 3-phényl-5-trifluorométhylisoxazoline-5-carboxamides d'acides carboxyliques et d'esters de cyclopentyle efficaces en tant qu'herbicides
WO2019145245A1 (fr) 2018-01-25 2019-08-01 Bayer Aktiengesellschaft 3-phényl-isoxazoline-5-carboxamides de dérivés d'acide cyclopentényl-carboxylique à action herbicide
WO2020182723A1 (fr) 2019-03-12 2020-09-17 Bayer Aktiengesellschaft 3-phényl-isoxazoline-5-carboxamides d'esters d'acide cyclopentényl-carboxylique soufrés à action herbicide

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DE4407134A1 (de) * 1994-03-04 1995-09-07 Thomae Gmbh Dr K Benzylpiperazine, deren Salze, diese Verbindungen enthaltende Arzneimittel und deren Verwendung sowie Verfahren zu ihrer Herstellung
CA2282390A1 (fr) * 1997-04-17 1998-10-22 Yukio Fujisawa Composition thermogenique et composes thermogeniques a base de benzazepine
EP1107758A2 (fr) * 1998-08-28 2001-06-20 Scios Inc. INHIBITEURS DE p38-APLHA KINASE
WO2001064676A2 (fr) * 2000-02-28 2001-09-07 Scios, Inc. INHIBITEURS DE LA P38-α KINASE
AU2001294824A1 (en) * 2000-09-29 2002-04-08 Millennium Pharmaceuticals, Inc. Piperazine based inhibitors of factor xa

Cited By (18)

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EP1958947A1 (fr) 2007-02-15 2008-08-20 Ranbaxy Laboratories Limited Inhibiteurs de la phosphodiestérase de type 4
US8420666B2 (en) 2007-03-14 2013-04-16 Ranbaxy Laboratories Limited Pyrazolo (3, 4-B) pyridine derivatives as phosphodiesterase inhibitors
US8598367B2 (en) 2008-09-18 2013-12-03 Nippon Soda Co., Ltd. Nitrogen-containing heterocyclic compound and pest control agent
WO2010032437A1 (fr) * 2008-09-18 2010-03-25 日本曹達株式会社 Composé hétérocyclique contenant de l'azote et agent de lutte contre les animaux nuisibles
US20110166358A1 (en) * 2008-09-18 2011-07-07 Nippon Soda Co., Ltd. Nitrogen-containing heterocyclic compound and pest control agent
AU2009294050B2 (en) * 2008-09-18 2011-11-17 Nippon Soda Co., Ltd. Nitrogen-containing heterocyclic compound and pest control agent
US8362257B2 (en) 2008-09-18 2013-01-29 Nippon Soda Co., Ltd. Nitrogen-containing heterocyclic compound and pest control agent
JP5307819B2 (ja) * 2008-09-18 2013-10-02 日本曹達株式会社 含窒素複素環化合物および有害生物防除剤
WO2012130798A1 (fr) 2011-03-31 2012-10-04 Bayer Cropscience Ag 3-phénylisoxazolino-5-carboxamides et 3-phénylisoxazolino-5-thioamides à activité herbicide et fongicide
WO2018228985A1 (fr) 2017-06-13 2018-12-20 Bayer Aktiengesellschaft 3-phénylisoxazoline-5-carboxamides d'acides carboxyliques et d'esters de tétrahydro- et dihydrofurane à effet herbicide
WO2018228986A1 (fr) 2017-06-13 2018-12-20 Bayer Aktiengesellschaft 3-phénylisoxazoline-5-carboxamides d'amides d'acide carboxylique de tétrahydro- et dihydrofurane à effet herbicide
US11597724B2 (en) 2017-06-13 2023-03-07 Bayer Aktiengesellschaft Herbicidally active 3-phenylisoxazoline-5-carboxamides of tetrahydro and dihydrofuran carboxylic acids and esters
US11613522B2 (en) 2017-06-13 2023-03-28 Bayer Aktiengesellschaft Herbicidally active 3-phenylisoxazoline-5-carboxamides of tetrahydro- and dihydrofurancarboxamides
WO2019034602A1 (fr) 2017-08-17 2019-02-21 Bayer Aktiengesellschaft 3-phényl-5-trifluorométhylisoxazoline-5-carboxamides d'acides carboxyliques et d'esters de cyclopentyle efficaces en tant qu'herbicides
WO2019145245A1 (fr) 2018-01-25 2019-08-01 Bayer Aktiengesellschaft 3-phényl-isoxazoline-5-carboxamides de dérivés d'acide cyclopentényl-carboxylique à action herbicide
US12319664B2 (en) 2018-01-25 2025-06-03 Bayer Aktiengesellschaft Herbicidally active 3-phenylisoxazoline-5-carboxamides of cyclopentenylcarboxylic acid derivatives
WO2020182723A1 (fr) 2019-03-12 2020-09-17 Bayer Aktiengesellschaft 3-phényl-isoxazoline-5-carboxamides d'esters d'acide cyclopentényl-carboxylique soufrés à action herbicide
US12185723B2 (en) 2019-03-12 2025-01-07 Bayer Aktiengesellschaft Herbicidally active 3-phenylisoxazoline-5-carboxamides of s-containing cyclopentenylcarboxylic esters

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