WO2006016237A2 - Heterocyclic derivatives as anti-inflammatory agents - Google Patents

Heterocyclic derivatives as anti-inflammatory agents 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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compound
methyl
phenyl
carbonyl
carboxylic acid
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PCT/IB2005/002292
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French (fr)
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WO2006016237A3 (en
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 Limited
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Publication of WO2006016237A3 publication Critical patent/WO2006016237A3/en

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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.

Abstract

The present invention relates to some heterocyclic derivatives having the structure of formula (Ia) wherein Ar1, Ar2, W, Q, Z, X, R1, R2, m, p, r and t are as defined in the description 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.

Description

HETEROCYCLIC DERIVATIVES AS ANTI-INFLAMMATORY AGENTS
Field of the Invention
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.
Background of the Invention
During the last decade, the roles played by 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-α), have been introduced to the market.
Elevated levels of proinflammatory cytokines viz TNF-α and IL-I α 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. Until a few years ago, inflammatory disorders were treated primarily with relatively non-selective anti¬ inflammatory agents, such as corticosteroids and various non-steroidal anti-inflammatory drugs. In recent years, specific interference with the action of selected pro-inflammatory mediators, such as TNFα and PGE2 has been used in therapy. These specific anti- inflammatory therapies have been used in the treatment of rheumatoid arthritis, inflammatory bowel disease, and several other inflammatory diseases.
The p38 mitogen activated protein kinase (p38MAPK) 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. 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. p38α MAPK was first identified as a tyrosine phosphorylated protein in LPS (Lipopolysaccharide) stimulated macrophages. The human p38α MAPK was identified as the target of pyridinyl imidazole compounds (cytokine suppressive anti- inflammatory drugs) that were known to block TNF-α and IL-I release from LPS stimulated monocytes. After the cloning of first p38MAPK (p38α), additional members of the p38MAPK family were cloned by homology, including the p38α, p38β and p38γ.
The p38 pathway controls the activity of multiple transcription factor s and the expression of many genes. There is ample evidence implicating a pivotal role for p38 in inflammatory processes mediated by IL- 1 and TNF-α. p38 inhibitors have been shown to effectively block both TNF-α and IL-I biosynthesis by LPS stimulated human monocytes. hi addition, 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-α or TGF-α results in p38 activation. GM-CSF and
TNF-α 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 p38α 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.
Summary of the Invention 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.
Pharmaceutical 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.
Other aspects will be set forth in accompanying description which follows and in part will be apparent from the description or may be learnt by the practice of the invention.
In accordance with one aspect, there is provided a compound having the structure of Formula Ia - A -
Figure imgf000005_0001
Formula Ia
and its pharmaceutically accepted salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides wherein 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.
Q can be alkylene, alkenylene, alkynylene, or -C(=T) (wherein T can be oxygen, sulphur, - N(CN), -N(NO2), or -CH(NO2)) (wherein double bond of said alkenylene or triple bond of said alkynylene cannot be attached directly to N atom).
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).
The subscript m is an integer from 0-3, and the subscript t is an integer from 0-4. R1 and R2 can independently be hydrogen, cyano, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, acyl, aryloxy, cycloalkyl, aryl, aralkyl, carboxy, -COOR3 (wherein R3 can be alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl), -NRpRq (wherein Rp and Rq can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl, or Rp and Rq may also together join to form a heterocyclic ring), -OC(=O)NRxRy [wherein Rx and Ry can independently be hydrogen, hydroxy (excepting that both Rx and Ry cannot be -OH at the same time), alkyl, cycloalkyl, alkoxy, hydroxyalkyl, aryloxy, heterocyclylalkyl, aralkyloxy, aryl, aralkyl, or -SO2R4 (wherein R4 can be alkyl, alkenyl, alkynyl, cycloalkyl, -NRpRq wherein Rp and Rq as defined above, aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, or heteroarylalkyl), or Rx and Ry may also together join to form a heterocyclyl or heteroaryl ring], -NRj(C=O)ORs (wherein Rs can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl , aralkyl, heterocyclylalkyl, or heteroarylalkyl, and wherein Rj can be hydrogen, lower (C1-C6) alkyl, lower (C3-C6) cycloalkyl, lower (C1-C3) aralkyl, aryl, heteroaryl, heteroarylalkyl, or lieterocyclylalkyl), NRjYRu (wherein Y can be -C(=O), -C(=S) or SO2, Rj is as defined above, and Ru can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl), -NRj (=T)NRxRy (wherein Rj, T, Rx and Ry are as defined above), -C(=K)NRxRy (wherein K is O or S), -CH2ORS (wherein R3 is the same as defined above), heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl.
Ar1 and Ar2 can independently be aryl, heteroaryl, or heterocyclyl.
In some particular embodiments, for example, Ar1 can be phenyl, W can be methylene, Z can be -CH-, t and m can be 1, Q can be carbonyl, Ar2 can be 1,2-, 1,3-, or 1,4-disubstituted phenyl, r can be 0, p can be 1, and X can be oxygen. Of such compounds, R1 can be alkyl (e.g., methyl), and R2 can be COOR3 or C(=K)NRxRy. In other particular embodiments, Ar2 can be a trisubstituted phenyl.
In accordance with a second aspect, there are provided methods for the treatment of mammals suffering from inflammation and associated pathologies. hi accordance with a third aspect, there are provided 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.
In accordance with a fourth aspect, there are provided processes for the prepration of compounds provided herein.
In accordance with a fifth aspect, the compounds provided herein are screened as p38 kinase inhibitors.
The following definitions apply to terms as used herein
The term "alkyl " unless otherwise specified, 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, -
COOR3 (wherein R3 is the same as defined earlier), -NHC(=O)RX, -NRxRy, -C(=O)NRxRy, -NHC(=O)NRxRy, -C(=O)heteroaryl, C(=O)heterocyclyl, -OC(=O)NRxRy (wherein Rx and Ry are the same as defined earlier), nitro, -S(O)01R4 (wherein m is an integer from 0-2 and R4 is the same as defined earlier). Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents chosen from alkyl, carboxy, - COOR3 (wherein R3 is the same as defined earlier), -NRxRy, -C(=O)NRxRy, -O-
C(=O)NRxRy; -NHC(=O)NRxRy (wherein Rx and Ry are the same as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, and -S(O)nIR4 (where R4 and m are the same as defined earlier). Alkyl groups as defined above may also be interrupted by 1-5 atoms of groups independently chosen from oxygen, sulfur and -NRa- [where Ra is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl, -C(=O)OR3 (wherein R3 is the same as defined earlier), S(O)2R4 (where R4 is as defined earlier) or - C(=O)NRxRy (wherein Rx and Ry are as defined earlier)]. Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents chosen from alkyl, carboxy, -NRxRy, -C(=O)NRxRy, -OC(=O)NRxRy (wherein Rx and Ry are the same as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, and -S(O)1nR4 (where m and R4 are the same as defined earlier).
The term "alkylene," unless otherwise specified, 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. Alkylene may further be substituted with one or more substituents such as alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryloxy, heteroaryloxy, aminosulfonyl, -COOR3 (wherein R3 is the same as defined earlier), - NHC(=O)RX, -NRxRy, -C(=0)NRxRy, -NHC(=0)NRxRy, -C(=O)heteroaryl, C(=O)heterocyclyl, -0C(=0)NRxRy (wherein Rx and Ry are the same as defined earlier), nitro, -S(O)It1R4 (wherein m is an integer from 0-2 and R4 is the same as defined earlier). Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents chosen from alkyl, carboxy, -COOR3 (wherein R3 is the same as defined earlier), -NRxRy, -C(=O)NRxRy, -O-C(=O)NRxRy, -NHC(=0)NRxRy (wherein Rx and Ry are the same as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, and -
S(O)mR6 (where R6 and m are the same as defined earlier). Alkylene groups as defined above may also be interrupted by 1-5 atoms of groups independently chosen from oxygen, sulfur and -NEIa [where Ra is chosen from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl, -C(=O)OR3 (wherein R3 is the same as defined earlier), -S(O)InR4 (where R4Is as defined earlier) or -C(=O)NRxRy (wherein Rx and Ry are as defined earlier)]. Unless otherwise constrained by the definition, all substituents may be further substituted by 1-3 substituents chosen from alkyl, carboxy, -NRxRy, - C(=O)NRxRy, -OC(=O)NRxRy (wherein Rx and Ry are the same as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, and -S(O)1nR4 (where m and R4 are the same as defined earlier).
The term "alkenyl," unless otherwise specified, 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.
Alkenyl may further be substituted with one or more substituents selected alkyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, -NHC(=O)RX, -NRxRy, -
C(=O)NRxRy, -NHC(=O)NRxRy , -OC(=O)NRxRy (wherein Rx and Ry are the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, -COOR3 (wherein R3 is the same as defined earlier), arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, alkoxyamino, nitro, S(O)mR4 (wherein R4 and m are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, -COOR3 (wherein R3 is the same as defined earlier), hydroxy, alkoxy, halogen, -CF3, cyano, -NRxRy, - C(=O)NRxRy, -O-C(=O)NRxRy (wherein Rx and Ry are the same as defined earlier) and - S(O)1nR4 (where R4 and m are the same as defined earlier).
The term "alkenylene" unless otherwise specified, 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. Alkenylene may further be substituted with one or more substituents selected from the group consisting of alkyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, - NHC(=O)RX, -NRxRy, -C(=O)NRxRy, -NHC(=O)NRxRy , -OC(=O)NRxRy (wherein Rx and Ry are the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, -COOR3 (wherein R3 is the same as defined earlier), arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, alkoxyamino, nitro, -S(O)1nR4 (wherein R4 and m are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, - COOR3 (wherein R3 is the same as defined earlier), hydroxy, alkoxy, halogen, -CF3, cyano, -NRxRy, -C(=O)NRxRy, -OC(=0)NRxRy (wherein Rx and Ry are the same as defined earlier) and -S(O)1nR4 (where R4 and m are the same as defined earlier).
The term "alkynyl," unless otherwise specified, 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. Alkynyl may further be substituted with one or more substituents selected from alkyl, alkenyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, - COOR3 wherein R3 is the same as defined earlier, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, nitro, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroarylalkyl, -NHC(=O)RX -NRxRy, -NHC(=O)NRxRy, -C(=O)NRxRy, -O-C(=O)NRxRy (wherein Rx and Ry are the same as defined earlier), -S(O)InR4 (wherein R4 and m are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, -COOR3 (wherein R3 is the same as defined earlier), hydroxy, alkoxy, halogen, CF3, -NRxRy, -C(=O)NRxRy, - NHC(=O)NRxRy, -C(=O)NRxRy (wherein Rx and Ry are the same as defined earlier), cyano, and -S(O)1nR4 (where R4 and m are the same as defined earlier).
The term "alkynylene," unless otherwise specified, 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. Alkynylene may further be substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, nitro, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroarylalkyl, -NHC(=O)RX -NRxRy, - NHC(O)NRxRy , -C(=0)NRxRy, -0C(=0)NRxRy (wherein Rx and Ry are the same as defined earlier), -S(O)]T1R4 (wherein R4 and m are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, -COOR3 (wherein R3 is the same as defined earlier), hydroxy, alkoxy, halogen, CF3, -NRxRy, -C(=0)NRxRy, - NHC(=0)NRxRy, -C(=0)NRxRy (wherein Rx and Ry are the same as defined earlier), cyano, and -S(O)1nR4 (where R4 and m are the same as defined earlier).
The term "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. Cycloalkyl may further be substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, -COOR3 (wherein R3 is the same as defined earlier), arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, -NRxRy, - NHC(=0)NRxRy, -NHC(=O)RX, -C(=0)NRxRy, -0C(=0)NRxRy (wherein Rx and Ry are the same as defined earlier), nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, -S(O)1TiR4 (wherein R4 and m are the same as defined earlier). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, carboxy, hydroxy, alkoxy, halogen, CF3, -NRxRy, -C(=0)NRxRy, -NHC(=0)NRxRy, -0C(=0)NRxRy (wherein Rx and Ry are the same as defined earlier), cyano, and -S(O)1nR4 (where R4 and m are the same as defined earlier). The term "alkoxy" denotes the group O-alkyl wherein alkyl is the same as defined above.
The term "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. The examples of aralkyl groups are benzyl and the like.
The term "aryl" herein refers to a carbocyclic aromatic group, for example phenyl, biphenyl or naphthyl ring and the like optionally substituted with 1 to 3 substituents selected from halogen (F, Cl, Br, I), hydroxy, carboxy, -COOR3 (wherein R3 is the same as defined earlier), alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, cyano, nitro, - NHC(O)Rx, -NRxRy, -C(=O)NRxRy, -NHC(O)NRxRy, -(SO)01R4 (wherein R4, Rx, Ry and m are the same as defined earlier), carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl. The 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. The term "aryloxy" denotes the group O-aryl wherein aryl is the same as defined above.
The term "aralkyloxy" denotes the group O-aralkyl wherein aralkyl is the same as defined above.
The term "carboxy" as defined herein refers to -C(O)OH. The term "heteroaryl" unless and otherwise specified 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, -COOR3 (wherein R3 is the same as defined earlier), aryl, alkoxy, aralkyl, cyano, nitro, -NRxRy, -C(O)NRxRy and -NHC(O)NRxRy , -S(O)01R4, -OC(O)NRxRy (wherein m, R4, Rx and Ry are the same as defined earlier). Unless otherwise constrained by the definition, the substituents are attached to the ring atom, be it carbon or heteroatom. Examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, tetrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, and the like. The term "heterocyclyl" unless and otherwise specified, refers to a non-aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms in which 1 to 3 carbon atoms in a ring are replaced by heteroatoms selected from O, S or N, and are optionally benzo fused or fused heteroaryl of 5-6 ring members and/or are optionally substituted wherein the substituents are selected from halogen (F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, alkoxy, alkaryl, cyano, nitro, oxo, carboxy, -COOR3 (wherein R3 is the same as defined earlier), -C(=O)NRxRy, -S(O)H1R4, -OC(=O)NRxRy, - NHC(=O)NRxRy -NRxRy (wherein m, R4, Rx and Ry are the same as defined earlier). Unless otherwise constrained by the definition, the substituents are attached to the ring atom, be it carbon or heteroatom. Also unless or otherwise constrained by the definition the heterocyclyl ring may optionally contain one or more olefinic bond(s). Examples of heterocyclyl groups are tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, piperidinyl, pyrrolidinyl, morpholinyl or piperazinyl. The term "Heteroarylalkyl" refers to alkyl-heteroaryl group linked through alkyl portion, wherein the alkyl and heteroaryl are the same as defined earlier.
The term "Heterocyclylalkyl" refers to alkyl-heterocyclyl group linked through alkyl portion, wherein the alkyl and heterocyclyl are the same as defined earlier.
The term "acyl" refers to -C(=O)R" wherein R" is selected from alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl.
"Substituted amino" unless and otherwise specified refers to a group -N(Rk)2 wherein each Rk is independently selected from hydrogen (provided that both Rk groups are not hydrogen (defined as "amino")), alkyl, alkenyl, alkynyl, aralkyl, carboxy, -COOR3 wherein R3 is the same as defined earlier, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, acyl, -S(O)nVR4 (wherein m and R4 is the same as defined above), -C(=Rv)NRxRy (wherein Rv is O or S, Rx and Ry are the same as defined earlier) or -NHC(=Rv)NRχRy (wherein Rv, Rx and Ry are the same as defined earlier).
Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents chosen from alkyl, aralkyl, cycloalkyl, aryl, carboxy, -COOR3 wherein R3 is the same as defined earlier heteroaryl, heterocyclyl, carboxy, hydroxy, alkoxy, halogen, CF3, cyano, -C(=Rv)NRxRy, -OC(=O)NRxRy (wherein Rx, Ry and Rv are the same as defined earlier) and -OC(=Rv)NRxRy), -S(O)nIR4 (where m and R4 are the same as defined above).
The term "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. Although 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. Although 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.
The term "pharmaceutically acceptable salts" refers to salts of the free acids, which possess the desired pharmacological activity of the free acid and which are neither biologically nor otherwise undesirable. 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 salt forms differ from the compound described herein in certain physical properties such as solubility, but the salts are otherwise equivalent for the purpose of this invention. Detailed Description of the Invention
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.
Scheme 1
condensation Ar1-W * »-• A Arr11--WW--ZZ N t —
Figure imgf000014_0001
V
Figure imgf000014_0002
Figure imgf000014_0003
The compounds of Formula VI can be prepared by Scheme I. Thus a compound of Formula I (wherein 1 is an integer from 0-2 and Ar1, W, Z and m are the same as defined earlier) is reacted with a compound of Formula II (wherein K and R3 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, -COOR3 (wherein R3 is same as defined earlier) or -CH2OH) 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. Alternatively, 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. 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.
Representative compounds prepared following Scheme I are:
3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid methyl ester (Compound No. 1); 3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid methyl ester (Compound No. 6);
(4-Benzylpiperidin-l-yl)-[4-(5-hydroxymethyl-4,5-dihydroisoxazole-3- yl)phenyl]methanone (Compound No. 23);
(4-Benzylpiperidin-l-yl)-[4-(5-hydroxymethyl-5-methyl-4,5-dihydroisoxazol-3- yl]phenyl)methanone (Compound No. 24);
3-[2-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid methyl ester (Compound No. 30);
4-{4-[(4-Benzylpiperidin-l-yl)carbonyl]phenyl}-5-methyl-4,5-dihydroisoxazole-5- carbonitrile (compound No. 43);
Ethyl 4-{4-[(4-benzylpiperidin-l-yl)carbonyl]phenyl}-4,5-dihydroisoxazole-5-carboxylate (Compound No. 44);
Methyl3-{3-[(4-benzylpiperidin-l-yl)carbonyl]-4-methoxyphenyl}-5-methyl-4,5- dihydroisoxazole-5-carboxylate (Compound No. 65);
Methyl 3-(3-{[4-(4-fluorobenzyl)piperidin-l-yl]carbonyl}-4-methoxyphenyl)-5-methyl- 4,5-dihydroisoxazole-5-carboxylate (Compound No. 70).
Also, in all the above representative examples wherever 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.
Scheme Il
Figure imgf000016_0001
Formula VII
Figure imgf000016_0002
Formula IX
Figure imgf000016_0003
The compound of Formula IX can be prepared, for example, by Scheme II, thus
Path a: The compound of Formula VII (wherein An, R3, W, Z, 1, m and k are the same as defined earlier) reacts with a compound of Formula VIII (wherein Rp and Rq 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.
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.
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.
Representative compounds prepared following Scheme II, Path a are: 3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid amide (Compound No. 3);
3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid methylamide (Compound No. 4);
3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid methylamide (Compound No. 5);
3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid amide (Compound No. 8);
3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid cyclopropylamide (Compound No. 9); 3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid propylamide (Compound No. 10);
3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid cyclohexylamide (Compound No. 11);
3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid (2-hydroxy-ethyl)amide (Compound No. 12);
3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid benzylamide (Compound No. 13);
3 - [3 -(4-B enzylpiperidine- 1 -carbonyl)phenyl] -5 -methyl-4,5 -dihydroisoxazole-5-carboxylic acid isopropylamide (Compound No. 14); 3-[3-(4-Benzylpiperidine- 1 -carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid ethylamide (Compound No. 15); 3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- yl}pyrrolidin-l-ylmethanone (Compound No. 16);
3-[4-(4-Benzyl-piperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid butylamide (Compound No. 22);
3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid prop-2-ynylamide (Compound No. 26); 3-[2-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-metliyl-4,5-dihydro-isoxazole-5- carboxylic acid methylamide (Compound No. 31);
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid isopropylamide (Compound No. 32);
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid cyclopropylamide (Compound No. 33);
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid benzylamide (Compound No. 34);
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid (2-hydroxy-ethyl)-amide (Compound No. 35); 3-[4-(4-Benzyl-piperidine- 1 -carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid cyclohexylamide (Compound No. 37);
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid ethylamide (Compound No. 38); *
3-[4-(4-Benzyl-ρiperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid propylamide (Compound No. 39);
3-[4-(4-Benzyl-ρiperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid cyclopentylamide (Compound No. 42);
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid (3-methyl-butyl)-amide (Compound No. 45); 3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid allylamide (Compound No. 46);
(4-Benzyl-piperidin-l-yl)-{2-[5-methyl-5-(pyrrolidine-l-carbonyl)-4,5-dihydro-isoxazol- 3 -yl] -phenyl} -methanone (Compound No. 55);
3-[2-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid propylamide (Compound No. 56); 3-[2-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid (2-hydroxy-ethyl)-amide (Compound No. 57);
3-[2-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid ethylamide (Compound No. 58);
3-[2-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid cyclopropylamide (Compound No. 59); (4-Benzyl-piperidin- 1 -yl)- {3-[5-(2-hydroxymethyl-pyrrolidine-l -carbonyl)-5-methyl-4,5- dihydro-isoxazol-3 -yl] -phenyl} -methanone (Compound No. 61);
3-[3-(4-Benzyl-piperidine-l-carbonyl)-2-methoxy-phenyl]-5-methyl-4,5-dihydro- isoxazole-5-carboxylic acid cyclopropylamide (Compound No. 64);
(4-Benzyl-piperidin-l-yl)-{2-methoxy-5-[5-methyl-5-(pyrrolidine-l-carbonyl)-4,5- dihydro-isoxazol-3-yl]-phenyl}-methanone (Compound No. 66);
(4-Benzyl-piperidin-l-yl)-{5-[5-(2-hydroxymethyl-pyrrolidine-l-carbonyl)-5-methyl-4,5- dihydro-isoxazol-3-yl]-2-methoxy-phenyl}-methanone (Compound No. 67);
[4-(4-Fluoro-benzyl)-piperidin-l-yl]-{5-[5-(2-hydroxymethyl-pyrrolidine-l-carbonyl)-5- methyl-4,5-dihydro-isoxazol-3-yl]-2-methoxy-phenyl}-methanone (Compound No. 68); 3-{3-[4-(4-Fluoro-benzyl)-piperidine-l-carbonyl)-4-methoxy-phenyl}-5-methyl-4,5- dihydro-isoxazole-5-carboxylic acid methylamide (Compound No. 69);
4-{3-[4-(4-Fluoro-benzyl)-piperidine-l-carbonyl)-4-methoxy-phenyl}-5-methyl-4,5- dihydro-isoxazole-5-carboxylic acid amide (Compound No. 71);
4- {3-[4-(4-Fluoro-benzyl)-piperidine- 1 -carbonyl)-4-methoxy-phenyl} -5-methyl-4,5- dihydro-isoxazole-5-carboxylic acid ethylamide (Compound No. 72);
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid (2-pyrrolidin-l-yl-ethyl)-amide (Compound No. 73);
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid (3-morpholin-4-yl-propyl)-amide (Compound No. 74).
Representative compounds prepared following Scheme II, Path b are:
3-[4-(4-Benzylpiρeridine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid (Compound No. 2);
3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid (Compound No. 7); 3 - [4-(4-B enzylpiperidine- 1 -carbonyl)phenyl] -5 -methyl-4,5 -dihydroisoxazole-5 -carboxylic acid hydroxyamide (Compound No. 17);
3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid (2-methylene-pent-3-enyloxy)amide (Compound No. 18);
3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid methoxyamide (Compound No. 19);
3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid dimethylamide (Compound No. 20);
3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid diisopropylamide (Compound No. 21);
3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid tert-butylamide (Compound No. 25);
3- {2-[(4-Benzylpiperidin- 1 -yl)carbonyl]phenyl} -5-methyl-4,5-dihydroisoxazole-5- carboxylic acid (Compound No. 29);
(4-Benzyl-piperidm-l-yl)-{4-[5-methyl-5-(pyrrolidine-l-carbonyl)-4,5-dihydro-isoxazol- 3 -yl] -phenyl} -methanone (Compound No. 36); (4-Benzyl-piperidin- 1 -yl)- {4-[5-methyl-5-(morpholine-4-carbonyl)-4,5-dihydro-isoxazol- 3-yl]-phenyl}-methanone (Compound No. 40);
3-[4-(4-Benzyl-piperidme-l-carbonyl)-pb.enyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid diethylamide (Compound No. 41);
(4-Benzyl-piperidin- 1 -yl)- {4-[5-(2-hydroxymethyl-pyrrolidine- 1 -carbonyl)-5-methyl-4,5- dihydro-isoxazol-3-yl]-phenyl}-methanone (Compound No. 53); l-{3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carbonyl}-pyrrolidine-2-carboxylic acid methyl ester (Compound No. 54);
(4-Benzyl-piperidine-l-yl)-{4-[5-methyl-5-(piperidine-l-carbonyl)-4,5-dihydro-isoxazole- 3-yl]-phenyl} -methanone (Compound No. 75);
3-[4-(4-Benzyl-piperidine- 1 -carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid phenylamide (Compound No. 76). Scheme III
Figure imgf000021_0001
Fonmula Xl Formula XIII
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.
Representative compounds prepared following Scheme III are:
(4-Benzylpiperidin-l-yl)-[4-(5-hydroxymethyl-5-methyl-4,5-dihydroisoxazol-3- yl)phenyl]methanone (Compound No. 24);
[4-(5-Benzyloxymethyl-5-methyl-4,5-dihydroisoxazol-3-yl)phenyl]-(4-benzylpiperidin-l- yl)methanone (Compound No. 28).
Scheme IV
Figure imgf000021_0002
Formula XlV Formula XV
The compound of Formula XV can be prepared by following the procedure as depicted in Scheme IV. Thus a compound of Formula XIV can be reacted with a compound of Formula Ro-hal (wherein R0Is alkyl, aryl, cycloalkyl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl and hal are the same as defined earlier) to give a compound of Formula XV. The reaction of a compound of Formula XIV with a compound of Formula Rς-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.
Representative compounds prepared following Scheme IV are:
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid benzyl-ethyl-amide (Compound No. 47); 3-[4-(4-Benzyl-piperidine- 1 -carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid ethyl-methyl-amide (Compound No. 48);
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid cyclopropyl-ethyl-amide (Compound No. 49);
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid cyclopropyl-methyl-amide (Compound No. 50);
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid benzyl-cyclopropyl-amide (Compound No. 51);
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid ethyl-propyl-amide (Compound No. 52); 3-[3-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-2,5-dihydro-isoxazole-5- carboxylic acid benzyl-methyl-amide (Compound No. 60);
3 - [3 -(4-B enzyl-piperidine- 1 -carbonyl)-phenyl] -5 -methyl-4, 5 -dihydro-isoxazole-5- carboxylic acid cyclopropyl-methyl-amide (Compound No. 62);
3-[3-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid ethyl-methyl-amide (Compound No. 63).
Particular compounds which can be produced by Scheme I, are listed in the Table below:
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
The compounds described herein have pharmacological activity, and therefore may be administered to an animal for treatment orally, parenterally, topically, rectally, internasally, subcutaneously or transdermally. The pharmaceutical compositions of the present invention comprise a pharmaceutically effective amount of a compound described herein formulated together with one or more pharmaceutically acceptable carriers. The term "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. For solid form preparations, 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.
In case of capsules, tablets, or pills 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. For liquid form preparations, 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. Besides inert diluents, 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. Among the acceptable vehicles and solvents that may be employed are 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. In such forms, 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.
EXPERIMENTAL
Synthesis of 4-(4-fluorobenzyl)piperidine
Step a: Synthesis of diethyl (4-fluorobenzyl)phosphonate
A mixture of the compound 4-fluorobenzyl bromide (1.50 g, 8.4 mmol) and triethylphosphite (1.20 g, 9.32 mmol) was stirred at 150 °C for 8 hours to furnish the title compound (2.2 g). This compound was used as such in the next step without purification.
Step b: Synthesis of l-benzyI-4-(4-fIuorobenzylidene)piperidine
To a solution of the compound obtained from step a above (0.38 g, 1.72 mmol) and N- benzyl-4-piperidone (0.326 g, 1.72 mmol) in dimethylformamide (3 ml) was added sodium hydride (0.10 g, 4.3 mol) at 0°C and stirred for overnight. The reaction mixture was quenched with ice-cold water followed by the addition of ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to furnish the title compound (0.40 g).
Step c: synthesis of 4-(4-fluorobenzyl)piperidine To a solution of the compound obtained from step b above (0.280 g, lmol) in methanol (20 ml) was added ammonium formate (0.63 g, 10.0 mmol) and palladium on carbon (0.3 g) under nitrogen atmosphere. 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). Scheme I:
Example 1: Synthesis of 3-[4-(4-benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5- dihydroisoxazole-5-carboxylic acid methyl ester (Compound No. 1)
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 0C followed by the addition of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.9 g, 10 mmol). The resulting reaction mixture was stirred for 10 minutes at same temperature and thereafter warmed up to room temperature and stirred overnight. The solvent was removed under reduced pressure and the residue thus obtained was collected in ethyl acetate and extracted with water. The organic layer was collected, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography using 30% ethyl acetate in hexane as eluent to furnish the title compound (2.4 g).
1H NMR (CDCl3, 300MHz) δ: 10.04 (s, IH, CHO), 7.94-7.90 (d, 2H, J=12.0Hz, Ar-H), 7.68-7.56 (m, 2H, Ar-H), 7.31-7.13 (m, 5H, Ar-H), 4.73 (brs, IH), 3.66 (s, IH), 2.98 (brs, IH), 2.84 (brs, IH), 2.75 (s, 2H), 1.85-1.80 (brs, 2H) and 1.28-1.23 (m, 3H).
Step b: Synthesis of 3-(4-benzyIpiperidine-l-carbonyl)benzaIdehyde oxime. To a solution of the compound obtained from step a above (1.90 g, 6.18 mmol) in ethanol and pyridine solution (1:1, 5 ml), was added 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).
1H NMR (CDCl3, 300MHz) δ: 8.10 (s, IH), 7.69 (s, IH), 7.57-7.54 (m, IH, Ar-H), 7.40- 7.12 (m, 8H, Ar-H), 4.69 (brs, IH), 3.68 (brs, IH), 2.94 (brs, IH), 2.73 (brs, IH), 2.56 (brs, 2H), 1.80-1.77 (m, 2H) and 1.25 (m, 3H).
Step c: Synthesis of 3-[4-(4-benzyIpiperidine-l-carbonyI)phenyl]-5~methyl-4,5- dihydroisoxazol-5-carboxyIic acid methyl ester. To a solution of the compound obtained form step b above (1.0 g, 3.11 mmol) in dry tetrahydrofuran (5 ml), was added methyl methacrylate (0.534 g, 6.22 mmol) and stirred at room temperature under nitrogen atmosphere. To the reaction mixture thus obtained, was added aqueous solution of sodium hypochlorite (4%, 5 ml) dropwise and stirred for 36 hours. The reaction mixture was concentrated under reduced pressure and the residue thus obtained was collected in ethyl acetate. The organic layer was extracted with water and dried over anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure and the residue thus obtained was purified by column chromatography using 20% ethyl acetate in hexane as eluent to furnish the title compound (0.7 g).
1H NMR (CDCl3, 300MHz) δ: 7.64-7.62 (d, J=6.0 Hz, 2H, Ar-H), 7.38-7.36 (d, J=6.0Hz, 2H, Ar-H), 7.26-7.07 (m, 5H, Ar-H), 4.62 (brs, IH), 3.86-3.81 (d, J=15.0Hz,lH), 3.76 (s, 3H), 3.69-3.60 (m, IH), 3.19-3.13 (d, J=18.0Hz, IH), 2.89 (m, IH), 2.69-2.67 (m, IH), 2.51 (brs, 2H), 1.75-1.73 (m, 2H) and 1.68-1.59 (m, 6H). IR (DCM): 2929, 1740, 1629, 1440, 1286, 1105 and 966 cm"1
Analogs of 3-[4-(4-benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole- 5-carboxylic acid methyl ester (Compound No. 1) described below, can be prepared by using appropriate carboxaldehyde in place of 3-carboxaldehyde and acrylate in place of methylmethacrylate, respectively, as applicable in each case. 3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid methyl ester (Compound No. 6)
1H NMR (CDCl3, 300MHz) δ: 7.72-7.65 (m, 2H, Ar-H), 7.46-7.42 (m, 2H, Ar-H), 7.31- 7.12 (m, 5H, Ar-H), 4.67 (brs, IH), 3.91-3.86 (d, IH), 3.81 (s, 3H), 3.68 (brs, IH), 3.24- 3.18 (d, IH), 2.76 (brs, IH), 2.76-2.72 (m, IH), 2.59-2.56 (m, 2H), 1.81-1.77 (m, 2H), 1.72 (s, 3H) and 1.32-1.25 (m, 3H).
IR (DCM): 3447, 2929, 2361, 1740, 1630, 1447, 1286, 1107 and 967cm"1
(4-Benzylpiperidin-l-yl)-[4-(5-hydroxymethyl-4,5-dihydroisoxazol-3- yl)phenyl]methanone (Compound No. 23)
1H NMR (CDCl3, 300MHz) δ: 7.78-7.71 (m, 2H, Ar-H), 7.48-7.46 (d, 2H, J=6.3Hz, Ar- H), 7.48-7.17 (m, 5H, Ar-H), 4.95-4.92 (m, 2H), 3.95-3.90 (m, 2H), 3.76-3.70 (m, 2H), 3.53-3.31 (m, IH), 2.50-2.30 (m, 2H), 2.63-2.61 (d, 2H, J=6.0Hz), 1.86-1.82 (m, 6H) and 1.30 (m, IH).
IR (DCM): 3396, 2921, 1616 and 1450 cm"1
(4-Benzylpiperidin-l-yl)-[4-(5-hydroxymethyl-5-methyl-4,5-dihydroisoxazol-3-yl)- phenyl]methanone (Compound No. 24)
1H NMR (CDCl3, 300MHz) δ: 7.64-7.62 (d, 2H, J=6.0Hz, Ar-H), 7.39-7.36 (d, 2H, J=9.0Hz, Ar-H), 7.27-7.08 (m, 5H, Ar-H), 4.70 (brs, IH), 3.73-3.68 (m, 2H), 3.57-3.42 (m, 2H), 2.99-2.94 (d, 2H, J=15.0Hz), 2.68 (brm, IH), 2.52 (s, 2H), 2.02-1.96 (dd, IH, J=6.0Hz each), 1.75-1.74 (d, 2H, J=3.0Hz), 1.58 (s, 3H) and 1.24-1.21 (brm, 2H). 3-[2-(4-Benzylpiperidine-l-carbonyl)plienyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid methyl ester (Compound No. 30)
1H NMR (CDCl3, 300MHz) δ: 7.45-7.37 (m, 3H, Ar-H), 7.29-7.11 (m, 6H, Ar-H), 4.72- 4.68 (d, IH, J=12.0Hz, -CH2Ph), 3.80 (brs, 4H, -OCH3 & -CH), 3.38-3.34 (d, IH, J=12.0Hz, -CH2Ph), 3.15 (brm, IH), 2.92-2.84 (t, IH, J=12.0Hz), 2.71-2.67 (t, IH, J=12.0Hz), 2.57-2.55 (brs, 2H), 1.79-1.75 (m, 2H), 1.68-1.25 (m, 4H), and 1.17-1.11 (m, 2H).
IR (DCM): 3464, 2931, 1740, 1632, 1435, 1200, 1108, 913 and 750 cm"1. Mass (positive ion mode) m/z: 421 [M++l].
4- {4- [(4-B enzylpiperidin- 1 -yl)carbonyl]phenyl} -5 -methyl-4, 5 -dihydroisoxazole-5 - carbonitrile (compound No. 43)
1H NMR (CDCl3, 300MHz) δ: 7.67-7.65 (d, 2H, J=6.0Hz, Ar-H), 7.46-7.44 (d, 2H, J=6.0Hz, Ar-H), 7.28-7.12 (m, 5H, Ar-H), 4.68 (m, IH, -CH2Ph), 3.88-3.82 (d, IH, J=18.0Hz), 3.65 (m, IH, -CH2Ph), 3.44-3.38 (d, IH, J=18.0Hz), 2.95 (m, IH), 2.73 (m, IH), 2.57 (brs, 2H), 1.91 (s, 3H, -CH3), 1.80 (m, 2H) and 1.37-1.26 (m, 3H). Mass (positive ion mode) m/z: 388 [M+H-I].
Ethyl 4-{4-[(4-benzylpiperidin-l-yl)carbonyl]phenyl}-4,5-dihydroisoxazole-5-carboxylate (Compound No. 44)
1H NMR (CDCl3, 300MHz) δ: 7.72-7.69 (d, 2H, J=9.0Hz, Ar-H), 7.44-7.42 (d, 2H, J=6.0Hz, Ar-H), 7.36-7.12 (m, 5H, Ar-H), 5.21-5.15 (m, IH), 4.67 (m, IH, -CH2Ph), 4.31- 4.24 (m, 2H), 4.11-4.07 (m, IH)5 3.65-3.61 (m, 3H), 2.90 (m, IH), 2.7 (m, IH), 2.56 (bra, 2H), 2.05-2.04 (m, 2H), 1.35-1.25 (m, 3H) and 0.97-0.88 (m, 3H).
Mass (positive ion mode) m/z: 421 [M++!].
Methyl 3-{3-[(4-benzylpiperidin-l-yl)carbonyl]-4-methoxyphenyl}-5-methyl-4,5- dihydroisoxazole-5-carboxylate (Compound No. 65)
1H NMR (CDCl3, 300MHz) δ: 7.54-7.48 (m, 2H, Ar-H), 122-1.19 (m, 5H, Ar-H), 6.94- 6.90 (m, IH, Ar-H), 4.76-4.72 (d, IH, J=12.0Hz), 4.13-4.11 (m, IH), 3.89-3.79 (m, 6H), 3.40-3.44 (d, IH, J=12.0Hz), 3.2-3.1 (m, IH), 2.9-2.8 (m, IH), 2.72-2.69 (m, IH), 2.56 (brs, 2H), 1.77-1.69 (m, 5H) and 1.33-1.23 (m, 3H). Mass (positive ion mode) m/z: 451 [M++l].
Methyl 3-(3-{[4-(4-fluorobenzyl)piperidin-l-yl]carbonyl}-4-methoxyphenyl)-5-methyl- 4,5-dihydroisoxazole-5-carboxylate (Compound No. 70)
1H NMR (CDCl3, 300MHz) δ: 7.88-7.39 (m, 2H, Ar-H), 7.08-6.90 (m, 5H, Ar-H), 4.77- 4.73 (m, IH), 3.92-3.80 (m, 6H), 3.45-3.41 (d, IH, J=12.0Hz), 2.72-2.64 (m, 2H), 2.66- 2.64 (m, 2H), 2.56-2.54 (m, 2H), 2.08-2.05 (m, 2H), 1.72 (s, 3H) and 1.15-0.88 (m, 3H).
Mass (positive ion mode) m/z: 469 [M+l]. Scheme II, path a:
Example 2: Synthesis of 3-[3-(4-benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5- dihydroisoxazoI-5-yl)pyrrolidin-l-ylmethanone (Compound No. 16) To a solution of the Compound No. 1 (0.12 g, 0.28 mmol) in tetrahydrofuran (1 ml), was added 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).
1B. NMR (CDCl3, 300MHz) δ: 7.70-7.67 (m, 2H, Ar-H), 7.46-7.41 (m, 2H, Ar-H), 7.31- 7.13 (m, 5H, Ar-H), 4.69 (brs, IH), 4.27-4.22 (d, IH, J=15.0Hz), 3.87-3.76 (m, 3H), 3.53- 3.49 (m, 2H), 3.18-3.12 (d, IH, J=18.0Hz), 2.95 (brs, IH), 2.72 (bs, IH), 2.57 (brs, 2H), 2.04-1.75 (m, 6H), 1.7 (brs, 3H) and 1.70 (brs, 3H). IR (DCM): 3455, 2926, 1630, 1430, 1287 and 921cm"1
Analogs of 3-[3-(4-benzylρiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazol-5- yl)pyrrolidin-l-ylmethanone (Compound No. 16) described below, can be prepared by using appropriate amine in place of pyrrolidine, respectively, as applicable in each case. 3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazol-5-carboxylic acid amide (Compound No. 3)
1H NMR (CDCl3, 300MHz) δ: 7.72-7.69 (d, 2H, J=9.0Hz, Ax-H), 7.41-7.38 (d, 2H, J=9.0Hz, Ar-H), 7.20-7.10 (m, 5H, Ar-H), 4.54 (bra, IH), 3.75-3.58 (m, 2H), 3.00 (m, IH), 2.78-2.75 (m, IH), 2.54-2.52 (m, 2H), 1.81-1.53 (m, 6H) and 1.23-1.16 (m, 3H). IR: (DCM): 3471, 2929, 1736, 1688, 1456, 1356, 1286, 1103 and 966 cm 1
3 - [4-(4-Benzylpiperidine- 1 -carbonyl)phenyl] -5 -methyl-4, 5 -dihydroisoxazole-5 -carboxylic acid methylamide (Compound No. 4)
1H NMR (CDCl3, 300MHz) δ: 7.67-7.64 (d, 2H, J=9.0Hz, Ar-H), 7.44-7.41 (d, 2H, J=9.0Hz, Ar-H), 7.31-7.12 (m, 5H, Ar-H), 6.88-6.86 (bra, IH, -NH), 4.67 (brs, IH), 3.86- 3.80 (d, IH, J=18.0Hz), 3.72 (brs, IH), 3.26-3.20 (d, IH, J=18.0Hz), 2.84-2.82 (brs, 3H), 2.72 (brs, IH), 2.57 (brs, 2H), 1.81-1.73 (m, 5H) and 1.25-1.11 (m, 4H).
IR (DCM): 3854, 3424, 2954, 2364, 1626, 1539, 1442, 1356, 1208 and 966 cm"1
3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-diliydroisoxazole-5-carboxylic acid methylamide (Compound No. 5) 1H NMR (CDCl3, 300MHz) δ: 7.67-7.64 (m, 2H, Ar-H), 7.44-7.42 (m, 2H, Ar-H), 7.31- 7.13 (m, 5H, Ar-H), 6.86 (brs, IH, -NH), 4.67 (brs, IH), 3.86-3.80 (d, IH, J=18.0Hz), 3.76 (brs, IH), 3.25-3.19 (d, IH, J=18.0Hz), 2.97 (brs, IH), 2.84 (brs, 3H), 2.72 (brs, IH), 2.59- 2.57 (m, 2H), 1.83-1.72 (m, 4H), 1.72-1.64 (brs, 3H) and 1.29-1.21 (m, IH).
IR (KBr): 3422, 2928, 1672, 1534, 1287, 1054 and 967 cm"1 3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid amide (Compound No. 8)
1H NMR (CDCl3, 300MHz) δ: 7.67-7.65 (m, 2H, Ar-H), 7.44-7.43 (m, 2H, Ar-H), 7.31- 7.12 (m, 5H, Ar-H), 6.78 (brs, IH, -NH), 5.35 (brs, IH, -NH), 4.67 (brs, IH), 3.87-3.81 (d, IH, J=18.0Hz), 3.66 (brs, IH), 3.26-3.21 (d, IH, J=18.0Hz ) 2.95 (brs, IH), 2.72 (brs, IH), 2.58-2.56 (m, 2H), 1.83-1.75 (m, 5H) and 1.30-1.25 (m, 3H).
IR (DCM): 3471, 2927, 1686, 1625, 1450, 1287, 1098 and 966 cm"1
3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid cyclopropylamide (Compound No. 9)
1H NMR (CDCl3, 300MHz) δ: 7.65-7.64 (m, 2H, Ar-H), 7.44-7.42 (m, 2H, Ar-H), 7.31- 7.13 (m, 5H, Ar-H), 6.86 (brs, IH, -NH), 4.67 (brs, IH), 3.86-3.80 (d, IH, J=18.0Hz), 3.67 (brs, IH), 3.24-3.19 (d, IH, J=18.0Hz), 2.98 (brs, IH), 2.77-2.71 (m, IH), 2.57 (m, 2H), 1.81-1.77 (m, 2H), 1.70 (brs, 4H), 1.61 (brs, 3H), 0.80-0.77 (m, 2H) and 0.53-0.51 (m, 2H).
IR (DCM): 3314, 2928, 2361, 1629, 1515, 1364, 1199 and 967 cm"1
3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid propylamide (Compound No. 10)
1H NMR (CDCl3, 300MHz) δ: 7.68-7.64 (m, 2H, Ar-H), 7.46-7.42 (m, 2H, Ar-H), 7.30- 7.12 (m, 5H, Ar-H), 6.86 (brs, IH, -NH), 4.69 (brs, IH), 3.85-3.79 (d, IH, J=18.0Hz), 3.72 (brs, IH), 3.28-3.15 (m, 3H), 2.97 (brs, IH), 2.72 (brs, IH), 2.57 (brs, 2H), 1.81-1.72 (m, 5H), 1.65 (brs, 2H), 1.59-1.50 (m, 3H) and 1.28-1.23 (m, 3H).
IR (DCM): 3337, 2931, 2361, 1669, 1525, 1365, 1286, 1054 and 966 cm"1
3-[3-(4-Benzylpiperidme-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid cyclohexylamide (CompoundNo. il)
1H NMR (CDCl3, 300MHz) δ: 7.68-7.65 (d, 2H, J=9.0Hz Ar-H), 7.44-7.42 (d, 2H, J=9.0Hz, Ar-H), 7.31-7.12 (m, 5H, Ar-H), 6.73-6.70 (d, IH, J=9.0Hz, -NH), 4.67 (brs, IH), 3.84-3.78 (d, IH, J=18.0Hz), 3.72-3.66 (m, IH), 3.24-3.18 (d, IH, J=18.0Hz), 2.97 (brs, IH), 2.77 (brs, IH), 2.57 (brs, 2H), 1.90-1.58 (m, 13H) and 1.35-1.28 (m, 5H). IR (DCM): 3854, 3413, 2930, 2361, 1633, 1519, 1365, 1286 and 966 cm"1
3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid (2-hydroxyethyl)amide (Compound No. 12) 1H NMR (CDCl3, 300MHz) δ: 7.64 (brs, 2H, Ar-H), 7.43-7.42 (m, 2H, Ar-H), 7.30-7.12 (m, 5H, Ar-H), 3.85-3.70 (m, 3H), 3.50-3.35 (m, 2H), 3.27-3.21 (d, IH, J=18.0Hz), 2.95- 2.73 (brs, 2H), 2.57 (brs, 2H), 1.73-1.40 (m, 8H) and 1.28-1.23 (m, 2H).
IR: 3416, 2930, 2361, 1624, 1287 and 1056 cm'1 3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid benzylamide (Compound No. 13)
1HNMR (CDCl3, 300MHz) δ: 4.67-7.65 (m, 2H, Ar-H), 7.44-7.42 (m, 2H, Ar-H), 7.33- 7.12 (m, 1OH, Ar-H), 4.70 (brs, IH), 4.56-4.49 (m, IH), 4.38-4.32 (m, IH), 3.89-3.83 (d, IH, J=18.0Hz), 3.67 (brs, IH), 3.28-3.22 (d, IH, J=18.0Hz), 2.95 (brs, IH), 2.73 (brs, IH), 2.57 (brs, 2H), 1.75 (brs, 4H), 1.63 (brs, 3H) and 1.27-1.23 (m, IH).
IR (DCM): 3336, 2926, 2361, 1670, 1522, 1363, 1286, 1054 and 966 cm"1
3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid isopropylamide (Compound No. 14)
1H NMR (CDCl3, 300MHz) δ: 7.67-7.65 (d, 2H, J=6.0Hz Ar-H), 7.44-7.42 (d, 2H, J=6.0Hz, Ar-H), 7.31-6.65 (m, 5H, Ar-H), 4.69 (brs, IH), 4.06-3.99 (m, IH), 3.84-3.78 (d, IH, J=18.0Hz), 3.79 (brs, IH), 3.24-3.18 (d, IH, J=18.0Hz), 2.99 (brs, IH), 2.72 (brs, IH), 2.59-2.57 (brs, 2H), 1.81-1.66 (m, 7H) and 1.32-1.12 (m, 7H).
IR (DCM): 3414, 2973, 2929, 1630, 1518, 1450, 1367, 1287, 1205, 1085 and 967 cm"1
3 - [3 -(4-B enzylpiperidine- 1 -carbonyl)phenyl] -5-methyl-4, 5 -dihydroisoxazole-5 -carboxylic acid ethylamide (Compound No. 15)
1H NMR (CDCl3, 300MHz) δ: 7.83-7.64 (m, 2H, Ar-H), 7.44-7.42 (m, 2H, Ar-H), 7.31-
7.12 (m, 5H, Ar-H), 6.82 (brs, IH, -NH), 4.69 (brs, IH), 3.85-3.79 (d, IH, J=18.0Hz), 3.65 (brs, IH), 3.37-3.19 (m, 3H), 2.97 (brs, IH), 2.72 (brs, IH), 2.57 (brs, 2H), 1.81-1.65 (m, 8H) and 1.28-1.13 (m, 3H). IR (DCM): 3421, 2937, 1629, 1528, 1448, 1366, 1287, 1266, 1098 and 913 cm"1
3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- yl}pyrrolidin-l-ylmethanone (Compound No. 16)
1H NMR (CDCl3, 300MHz) δ: 7.70-7.67 (m, 2H, Ar-H), 7.46-7.41 (m, 2H, Ar-H), 7.31-
7.13 (m, 5H, Ar-H), 4.69 (brs, IH), 4.27-4.22 (d, IH, J=15.0Hz), 3.87-3.76 (m, 3H), 3.53- 3.49 (m, 2H), 3.18-3.12 (d, IH, J=18.0Hz), 2.95 (brs, IH), 2.72 (brs, IH), 2.57 (brs, 2H), 2.04-1.75 (m, 6H), 1.7 (brs, 3H) and 1.70 (brs, 3H).
IR (DCM): 3455, 2926, 1630, 1430, 1287 and 921 cm"1
3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid butylamide (Compound No. 22)
1H NMR (CDCl3, 300MHz) δ: 7.67-7.65 (d, 2H, J=9.0Hz, Ar-H), 7.41-7.44 (d, 2H, J-9.0Hz, Ar-H), 7.31-7.12 (m, 5H, Ar-H), 6.86-6.82 (brs, IH, N-H), 4.7 (brs, IH), 3.85- 3.80 (d, IH), 3.70 (brs, IH), 3.32-3.19 (m, 3H), 2.94 (brs, IH), 2.71 (brs, IH), 2.57 (brs, 2H), 1.72 (m, 5H), 1.37-1.26 (m, 6H) and 0.96-0.86 (m, 5H). IR: 3421, 2928, 2857, 1628, 1529, 1443, 1285 and 1099 cm4
3 - [4-(4-B enzylpiperidine- 1 -carbonyl)phenyl] -5 -methyl-4, 5 -dihydroisoxazole-5-carboxylic acid prop-2-ynylamide (Compound No. 26)
1H NMR (CDCl3, 300MHz) δ: 7.66-7.64 (d, 2H, J=6.0Hz, Ar-H), 7.43-7.40 (d, 2H, J=9.0Hz, Ar-H), 7.30-7.11 (m, 4H, Ar-H), 7.06-7.03(m, 3H), 4.70 (brs, IH), 4.08-3.99 (m, 2H), 3.84-3.78 (d, IH, J=18.0Hz), 3.64 (brs, IH), 3.26-3.20 (d, IH, J=18.0Hz), 3.00-2.56 (m, 2H), 2.56 (s, 2H), 2.24-2.22 (t, IH, J=3.0Hz ), 1.80-1.73 (m, 5H) and 1.24-1.16 (m, 3H).
IR (DCM): 3302, 2921, 2361, 1673, 1624, 1516 and 1445 cm"1
3-[2-(4-Benzyl-piperidine-l-carbonyl)-pb.enyl]-5-metriyl-4,5-dihydro-isoxazole-5- carboxylic acid methylamide (Compound No. 31)
1H NMR (CDCl3, 300MHz) δ: 7.40-7.35 (m, 3H, Ar-H), 7.23-7.07 (m, 6H, Ar-H), 4.69- 4.65 (m, IH, -CH2Ph), 3.80 (m, IH), 3.38-3.34 (m, IH, -CH2Ph), 3.15 (m, IH), 2.84-2.73 (m, 5H, -NCH3 & 2x-CH), 2.52-2.50 (brs, 2H), 1.93 (m, 2H), 1.63 (s, 3H) and 1.25-1.20 (m, 3H). Mass (positive ion mode) m/z: 421 [M++l].
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid isopropylamide (Compound No. 32)
1H NMR (CDCl3, 300MHz) δ: 7.69-7.65 (m, 2H, Ar-H), 7.43-7.41 (m, 2H, Ar-H), 7.28- 7.1 (m, 5H, Ar-H), 7.28-7.1 (m, IH, -NH & D2O exchangeable), 4.67-4.64 (m, IH, - CH2Ph), 4.03-4.01 (m, IH), 3.91 (m, 2H), 3.84-3.79 (m, IH), 3.24-3.18 (m, IH), 2.93-2.85 (m, IH), 2.76-2.68 (m, IH), 2.58-2.56 (brs, 2H), 1.8-1.71 (m, 4H) and 1.19-1.14 (m, 9H). Mass (positive ion mode) m/z: 448 [M++l]. m.pt: 95-96.4 °C. 3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid cyclopropylamide (Compound No. 33)
1H NMR (CDCl3, 300MHz) δ: 7.67-7.64 (d, 2H, J=9.0Hz, Ar-H), 7.43-7.41 (d, 2H, J=6.0Hz, Ar-H), 7.31-7.12 (m, 5H, Ar-H), 6.87-6.86 (brs, IH, Ar-H), 4.67-4.63 (m, IH, - CH2Ph), 3.86-3.80 (d, J=18.0Hz, IH), 3.64 (m, IH), 3.24-3.18 (d, J=18.0Hz, IH), 2.93- 2.85 (m, IH), 2.76-2.70 (m, 2H), 2.58-2.56 (brs, 2H), 1.80-1.78 (m, 2H), 1.70 (s, 3H), 1.29-1.25 (m, 3H), 0.80-0.75 (m, 2H) and 0.53-0.52 (m, 2H). Mass (positive ion mode) m/z: 446 [M+H-I]. m.pt: 60-62.4 °C
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid benzylamide (Compound No. 34)
1H NMR (CDCl3, 300MHz) δ: 7.67-7.65 (d, 2H, J=6.0Hz, Ar-H), 7.44-7.41 (d, 2H, J=9.0Hz, Ar-H), 7.32-7.12 (m, HH, Ar-H & -NH), 4.67 (m, IH, -CH2Ph)5 4.56-4.49 (m, IH, -CH2Ph), 4.39-4.32 (m, IH, -CH2Ph), 3.90-3.84 (d, IH, J=18.0Hz), 3.66 (m, IH, - CH2Ph), 3.28-3.23 (d, IH, J=18.0Hz), 2.93-7.0 (m, 2H), 2.57 (brs, 2H), 1.84-1.76 (m, 5H) andl.29-1.25 (m, 3H).
Mass (positive ion mode) m/z: 496 [M++l]. m.pt: 61-63 °C.
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid (2-hydroxy-ethyl)-amide (Compound No. 35) 1H NMR (CDCl3, 300MHz) δ: 7.68-7.65 (d, 2H, J=9.0Hz, Ar-H), 7.44-7.41 (d, 2H, J=9.0Hz, Ar-H), 7.31-7.12 (m, 6H, Ar-H & -NH), 6.20 (m, IH, -OH), 4.67 (m, IH, - CH2Ph), 3.86-3.80 (d, J=I 8.0Hz, IH), 3.72-3.69 (m, 3H, -CH2Ph & -OCH2), 3.48-3.38 (m, 2H, -NCH2), 3.27-3.22 (d, IH, J=15.0Hz), 2.60 (m, IH), 2.73 (m, IH), 2.57 (brs, 2H), 1.82-1.60 (m, 5H) and 1.29-1.26 (m, 3H). Mass (positive ion mode) m/z: 450 [M++!]. 3-[4-(4-Benzyl-piperidine-l-carbonyl)-ph.enyl]-5-metliyl-4,5-dihydro-isoxazole-5- carboxylic acid cyclohexylamide (Compound No. 37)
1H NMR (CDCl3, 300MHz) δ: 7.67-7.64 (d, 2H, J=9.0Hz, Ar-H), 7.43-7.41 (d, 2H, J=6.0Hz, Ar-H), 7.35-7.12 (m, 4H, Ar-H), 6.73-6.71 (d, IH, J=6.0Hz, Ar-H), 4.70 (m, IH5 -CH2Ph), 3.84-3.78 (d, IH, J=18.0Hz), 3.75-3.69 (m, 2H), 3.24-3.18 (d, IH, J=18.0Hz), 2.94-2.72 (m, 2H), 2.58 (brs, 2H), 1.93-1.59 (m, 9H) and 1.42-1.12(m, 9H). Mass (positive ion mode) m/z: 488 [M++l]. m.pt: 133.4-134.2 0C
3-[4-(4-Benzyl-piperidine-l-carbonyl)-plienyl]-5-metliyl-4,5-dihydro-isoxazole-5- carboxylic acid ethylamide (Compound No. 38)
1H NMR (CDCl3, 300MHz) δ: 7.66 (m, 2H, Ar-H), 7.43 (m, 2H, Ar-H), 7.28-7.12 (m, 5H, Ar-H & INH), 6.83 (s, IH, Ar-H), 4.69 (m, IH, -CH2Ph), 3.85-3.80 (d, IH, J=I 8.0Hz), 3.66 (m, IH, -CH2Ph), 3.34-3.19 (m, 3H), 2.94 (m, IH), 2.74 (m, IH), 2.57 (brs, 2H), 1.79-1.72 (m, 5H), 1.42-1.12 (m, 3H) and 1.17-1.13 (m, 3H, -CH3). Mass (positive ion mode) m/z: 434 [M++l]. m.pt: 112-115.4 0C
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid propylamide (Compound No. 39)
1H NMR (CDCl3, 300MHz) δ: 7.67-7.64 (d, 2H, Ar-H), 7.43-7.41 (d, 2H, Ar-H), 7.31- 7.12 (m, 5H, Ar-H & NH), 6.88-6.85 (m, IH, Ar-H), 4.68 (m, IH, -CH2Ph), 3.85-3.80 (d, IH), 3.64 (m, IH, -CH2Ph), 3.28-3.1 (m, 3H), 2.90-2.70 (m, 2H), 2.58-2.57 (brs, 2H), 1.80-1.72 (m, 5H), 1.62-1.49 (m, 2H), 1.28-1.25 (m, 3H) and 0.93-0.88 (m, 3H, -CH3).
Mass (positive ion mode) m/z: 448 [M++l].
m.pt: 75-77 0C. 3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid cyclopentylamide (Compound No. 42)
1H NMR (CDCl3, 300MHz) δ: 7.68-7.65 (d, 2H, J=9.0Hz, Ar-H), 7.44-7 '.41 (d, 2H, J=9.0Hz, Ar-H), 7.31-7.12 (m, 4H, Ar-H & INH), 6.79-6.76 (d, IH, J=9.0Hz, Ar-H), 4.67 (m, IH, -CH2Ph), 4.19-4.12 (m, IH), 3.85-3.80 (d, IH, J=18.0Hz), 3.66 (m, IH), 3.24-3.18 (d, IH, J=I 8.0Hz), 2.94 (m, IH), 2.73 (m, IH), 2.57 (brs, 2H), 2.00-1.94 (m, 2H), 1.78- 1.61 (m, 10H) and 1.46-1.26 (m, 4H).
Mass (positive ion mode) m/z: 474 [M++l]. m.pt: 135.3 -135.9 0C 3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-diliydro-isoxazole-5- carboxylic acid (3-methyl-butyl)-amide (Compound No. 45)
1H NMR (CDCl3, 300MHz) δ: 7.63-7.60 (d, 2H, J=9.0Hz, Ar-H), 7.39-7.37 (d, 2H, J=6.0Hz, Ar-H), 7.26-7.08 (m, 5H, Ar-H & -NH), 6.76 (m, IH, Ar-H), 4.70 (m, IH, - CH2Ph), 3.81-3.75 (d, IH, J=18.0Hz), 3.69 (m, IH, -CH2Ph), 3.29-3.15 (m, 3H), 2.90 (m, IH), 2.70 (m, IH), 2.54 (brs, 2H), 1.76-1.68 (m, 5H), 1.58-1.54 (m, 2H), 1.39-1.32 (m, 2H), 1.21 (m, 2H) and 0.87-0.84 (m, 6H).
Mass (positive ion mode) m/z: 476 [M++l]. m.pt: 116.3-117.4 0C.
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid allylamide (Compound No. 46)
1H NMR (CDCl3, 300MHz) δ: 7.67-7.65 (d, 2H, J=9.0Hz, Ar-H), 7.44-7.41 (d, 2H, J=9.0Hz, Ar-H), 7.31-7.12 (m, 5H, Ar-H & -NH) 6.96 (m, IH, Ar-H), 5.80 (m, IH), 5.19- 5.11 (m, 2H), 4.70 (m, IH), 3.90-3.81 (m, 3H), 3.73 (m, IH), 3.26-3.21 (d, IH, J=18.0Hz), 2.90 (m, IH), 2.70(m, IH), 2.57 (brs, 2H), 1.80-1.74 (m, 5H) and 1.25 (m, 3H). Mass (positive ion mode) m/z: 446 [M++l]. m.pt: 128.7-130.1 °C.
(4-Benzyl-piperidin- 1 -yl)- {2-[5-methyl-5-(pyrrolidine- 1 -carbonyl)-4,5-dihydro-isoxazol- 3-yl]-phenyl}-methanone (Compound No. 55)
1H NMR (CDCl3, 300MHz) δ: 7.60-7.36 (m, 3H, Ar-H), 7.21-7.13 (m, 6H, Ar-H), 4.73- 4.69 (d, IH, J=12.0Hz), 4.21-4.15 (d, IH, J=18.0Hz), 3.83-3.64 (m, 2H), 3.49-3.10 (m, 4H), 2.87-2.74 (m, 2H), 2.57-2.54 (m, 2H), 1.96-1.80 (m, 2H), 1.78 (s, 3H) and 1.28-1.25 (m, 7H).
Mass (positive ion mode) m/z: 460 [M++!]. 3-[2-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid propylamide (Compound No. 56)
1H NMR (CDCl3, 300MHz) δ: 7.47-7.37 (m, 3H, Ar-H), 7.21-7.19 (m, 4H, Ar-H), 7.13- 7.11 (m, 2H, Ar-H), 6.8 (brs, IH, Ar-H), 4.73-4.69 (m, IH, J=12.0Hz), 3.83-3.77 (d, IH, J=18.0Hz), 3.38-3.14 (m, 4H), 2.72-2.55 (m, 2H), 2.54-2.50 (m, 2H), 1.76-1.68 (m, 2H), 1.59 (s, 3H), 1.25 (s, 4H) and 0.97-0.85 (m, 4H).
Mass (positive ion mode) m/z: 448 [M++l].
3-[2-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid (2-hydroxy-ethyl)-amide (Compound No. 57) 1H NMR (CDCl3, 300MHz) δ: 7.42-7.16 (m, 1OH, Ar-H), 4.6-4.5 (m, IH), 3.72-3.44 (m, 3H), 3.42-3.36 (m, 4H), 2.94-2.92 (m, IH5), 2.75-2.73 (m, IH), 2.61-2.54 (m, 2H), 2.08- 2.05 (m, 2H), 2.00 (s, 3H) and 1.90-1.21 (m, 3H).
Mass (positive ion mode) m/z: 450 [M++!].
3-[2-(4-Benzyl-piperidine-l-carbonyl)-pb.enyl]-5-methyl-4,5-diliydro-isoxazole-5- carboxylic acid ethylamide (Compound No. 58)
1H NMR (CDCl3, 300MHz) δ: 7.42 (brs, 3H, Ar-H), 7.21-7.11 (m, 6H, Ar-H), 6.80 (brs, IH, Ar-H), 4.73 (brs, IH), 3.83-3.77 (m, IH), 3.34-3.18 (m, 4H), 2.86-2.74 (m, 2H), 2.56 (brs, 2H), 1.53-1.49 (m, 2H), 1.30 (3H, s), 1.25-1.15 (5H, m) and 1.00-0.87 (IH, m).
Mass (positive ion mode) m/z: 434 [M++l]. 3-[2-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-diliydro-isoxazole-5- carboxylic acid cyclopropylamide (Compound No. 59)
1H NMR (CDCl3, 300MHz) δ: 7.46-7.37 (m, 3H, Ar-H), 7.21-7.11 (m, 6H, Ar-H), 6.86 (brs, IH, Ar-H), 4.73-4.68 (d, IH, J=15.0Hz), 3.83-3.77 (m, IH), 3.39-3.34 (d, IH, J=15.0Hz), 3.23-3.17 (d, IH, J=18.0Hz), 2.88-2.82 (m, IH), 2.73-2.72 (m, 2H,), 2.60-2.56 (m, 2H,), 1.73 ( brs, 2H), 1.66 ( s, 3H), 1.29-1.25 (m, 3H,), 0.87-0.76 ( m, 2H) and 0.53 (brs, 2H).
Mass (positive ion mode) m/z: 446 [M++l].
(4-Benzyl-piperidin-l-yl)-{3-[5-(2-hydroxymethyl-pyrrolidme-l-carbonyl)-5-methyl-4,5- dihydro-isoxazol-3-yl]-phenyl}-methanone (Compound No. 61) 1H NMR (CDCl3, 300MHz) δ: 7.72-7.67 (m, 2H, Ar-H), 7.54-7.52 (m, IH, Ar-H), 7.44- 7.42 (2H, m, Ar-H), 7.19-7.12 (m, 4H, Ar-H), 4.4 (brs, IH), 4.28-4.2 (m, 4H), 4.1-3.9 (m, IH), 3.68-3.61 (m, 2H), 3.16-3.12 (m, IH), 2.70-2.60 (m, 2H), 2.58-2.56 (m, 2H,), 1.74- 1.66 (m, 5H), 1.41-1.32 (m, 3H) and 0.94-0.88 (m, 4H). Mass (positive ion mode) m/z: 490 [M++l].
3-[3-(4-Benzyl-piperidine-l-carbonyl)-2-methoxy-phenyl]-5-metliyl-4,5-dihydro- isoxazole-5-carboxylic acid cyclopropylamide (Compound No. 64)
1H NMR (CDCl3, 300MHz) δ: 7.67-7.62 (m, IH, Ar-H), 7.34-7.14 (m, 6H, Ar-H), 6.9 (brs, IH, Ar-H), 4.78-4.74 (d, IH, _Λ=12.0Hz), 3.8 (s, 3H), 3.48-3.36 (m, 2H), 3.10-2.90 (m, IH), 2.73 (brs, 2H), 2.57 (brs, IH), 2.32-2.20 (m, IH), 1.42-1.33 (m, 5H), 0.88 (m, 3H) and 0.52 (brs, 2H).
Mass (positive ion mode) m/z: 476 [M+H-I].
(4-Benzyl-piperidin-l-yl)-{2-methoxy-5-[5-methyl-5-(pyrrolidme-l-carbonyl)-4,5- dihydro-isoxazol-3-yl]-phenyl}-methanone (Compound No. 66) 1H NMR (CDCl3, 300MHz) δ: 7.68-7.52 (m, 2H, Ar-H), 7.21-7.12 (m, 5H, Ar-H), 6.92- 6.89 (m, IH, Ar-H), 4.76-4.72 (d, IH, J=12.0Hz), 4.40-4.30 (m, IH), 3.85 (s, 3H), 3.83 (m, IH), 3.51-3.39 (m, 4H), 2.90-2.80 (m, IH), 2.79-2.65 (m, IH), 2.60-2.59 (m, IH), 2.58-2.56 (m, 2H), 2.56 (s, 2H), 2.05-1.77 (m, 4H), 1.69 (s, 3H) and 1.28-1.25 (m, 3H).
Mass (positive ion mode) m/z: 490 [M++l]. (4-Benzyl-piperidin-l-yl)-{5-[5-(2-hydroxymethyl-pyrrolidine-l-carbonyl)-5-metliyl-4,5- dihydro-isoxazol-3-yl]-2-methoxy-phenyl}-methanone (Compound No. 67)
1HNMR (CDCl3, 300MHz) δ: 7.71-7.59 (m, 2H, Ar-H), 7.21-7.12 (m, 5H, Ar-H), 6.90- 6.89 (IH, m, Ar-H), 4.76-4.72 (d, IH, J=12.0Hz, -CHPh,), 4.28-4.18 (m, 3H,), 4.15 (brs, IH), 3.80 (s, 3H, -OCH3), 3.68-3.60 (m, 3H), 3.40-2.70 (m, 3H), 2.58-2.56 (d, 2H, J=6.00Hz), 2.06-2.04 (m, 2H), 1.92-1.90 (m, 2H), 1.77-1.65 (m, 6H) and 1.60-1.53 (m, 2H).
Mass (positive ion mode) m/z: 520 [M++l].
[4-(4-Fluoro-benzyl)-piperidin-l-yl]-{5-[5-(2-hydroxymethyl-pyrrolidine-l-carbonyl)-5- methyl-4,5-dihydro-isoxazol-3-yl]-2-methoxy-phenyl}-methanone (Compound No. 68) 1H NMR (CDCl3, 300MHz) δ: 7.71-7.36 (m, 2H, Ar-H), 7.08-6.94 (m, 5H, Ar-H), 4.77- 4.73 (d, IH, J=12.0Hz), 4.28-4.14, (m, 3H), 3.86 (s, 3H)5 3.66-3.59 (m, 3H), 3.45-3.41 (m, 2H), 3.20-3.10 (m, IH), 3.00-2.90 (m, IH), 2.55-2.53 (m, 2H), 2.04-1.9 (m, 2H), 1.73-1.42 (m, 7H) and 1.25 (m, 3H). Mass (positive ion mode) m/z: 538 [M++l].
3-{3-[4-(4-Fluoro-benzyl)-piperidine-l-carbonyl)-4-methoxy-phenyl}-5-metliyl-4,5- dihydro-isoxazole-5-carboxylic acid methylamide (Compound No. 69)
1H NMR (CDCl3, 300MHz) δ: 7.66-7.36 (m, 2H, Ar-H), 7.08-6.93 (m, 6H5Ar-H), 4.77- 4.73 (d, lH, J=12.0Hz), 3.86-3.78 (m, 5H), 3.43-3.39 (d, IH, J=12.0Hz), 2.84-2.54 (m, 5H), 2.08-2.05 (m, 2H), 1.72-1.33 (m, 5H) and 1.26-1.06 (m, 3H).
Mass (positive ion mode) m/z: 468 [M++l].
4- {3-[4-(4-Fluoro-benzyl)-piperidine- 1 -carbonyl)-4-methoxy-phenyl} -5-methyl-4,5- dihydro-isoxazole-5-carboxylic acid amide (Compound No. 71)
1H NMR (CDCl3, 300MHz) δ: 7.64-7.42 (m5 3H5 Ar-H)5 7.08-6.81 (m, 4H, Ar-H), 5.59 (brs, -IH, -NH2), 4.77-4.73 (d, IH, J=12.0Hz, -NCH), 3.92-3.80 (d, 4H, -OCH3 & -NCH),
3.59 (brs, 2H, -NCH2), 3.43-3.39 (d, 2H,-CH2Ph), 3.00 (brs, IH, -CH), 2.71-2.68 (d, 2H, J=9.00, -CH2), 2.55-2.53 (d, 4H, J=6.0Hz, 2x-CH2) and 1.74 (s, 3H, -CH3).
Mass (positive ion mode) m/z: 454 [M++l].
4-{3-[4-(4-Fluoro-benzyl)-piperidine-l-carbonyl)-4-methoxy-phenyl}-5-methyl-4,5- dihydro-isoxazole-5-carboxylic acid ethylamide (Compound No. 72)
1H NMR (CDCl3, 300MHz) δ: 7.63-7.49 (m, 2H, Ar-H), 7.11-6.85 (m, 5H, Ar-H), 4.77- 4.73 (d, IH, J=12.0Hz, -NCH), 3.86-3.84 (d, IH, J=6.0Hz, -NCH), 3.79 (s, 3H, -OCH3),
3.60 (brs, IH, -NCH), 3.49-3.20 (m, 3H, -NCH & -NCH2), 2.56-2.51 (t, 2H, J=9.0Hz, - CH2Ph), 2.08-2.04 (t, 2H, J=6.0Hz), 1.72-1.69 (m, 6H, -CH3, -CH2 & -CH), 1.23 (t, 3H, - CH3)
Mass (positive ion mode) m/z: 482 [M++l].
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid (2-pyrrolidin-l-yl-ethyl)-amide (Compound No. 73) 1H NMR (CDCl3, 300 MHz)δ: 7.67-7.65 (d, J=6.0Hz, 2H, Ar-H), 7.43-7.40 (d, J=9.0Hz, 2H, Ar-H), 7.31-7.12 (m, 5H, Ar-H), 4.8 (brs, IH5-CHPh), 3.86-3.80 (d, J=18.0Hz, IH), 3.70 (brs, IH5-CHPh), 3.40-3.38 (m, 2H), 3.25-3.19 (d, J=18.0Hz, IH)5 2.85 (m, 2H)5 2.65-2.50 (m, 8H) and 1.80-1.12 (m, 12H). Mass (positive ion mode) m/z: 503 [M++l]
IR (DCM): 3418, 2931, 1629, 1528, 1444, 1287 and 752 cm"1
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid (3-morpholin-4-yl-propyl)-amide (Compound No. 74)
1H NMR (CDCl3, 300 MHz)δ: 8.08 (s, IH5 -NH)5 7.67-7.64 (d, J=9.0Hz, 2H, Ar-H), 7.43- 7.40 (d, J=9.0Hz, 2H, Ar-H), 7.31-7.12 (m, 6H, Ar-H), 4.7 (brs, IH, -CHPh), 3.84-3.78 (m, 5H, 2x-OCH2 & -CH), 3.71 (m, 2H), 3.42-3.18 (m, 3H), 2.90 (brs, IH)5 2.70 (brs, IH)5 2.56 (s, 2H)5 2.45-2.41 (m, 6H, 3x-NCH2), 1.96 (m, IH), 1.79-1.68 (m, 5H) and 1.25-1.11 (m, 3H).
Mass (positive ion mode) m/z: 533 [M++l]. IR (DCM): 3422, 2933, 1625, 1524, 1445, 1116, 910 and 752 cm'1. Scheme II, Path b:
Example 3: Synthesis of 3-[4-(4-benzylpiperidme-l-carbonyl)phenyl]-5-methyl-4,5- dihydroisoxazole-5-carboxylic acid (Compound No. 2)
To a solution of the Compound No. 1 in tetrahydrofuran (5 ml), was added aqueous lithium hydroxide (4.5 equiv.) at 0 0C and the resulting reaction mixture was stirred at room temperature for about 30 minutes. The reaction mixture was allowed to warm up to room temperature for 2-3 hours. The solvent was removed under reduced pressure and the aqueous layer was cooled at 0 °C. To the reaction mixture was added hydrochloric acid drop wise (10 ml, 2 N). The white precipitate thus obtained was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound.
1H NMR (CDCl3, 300MHz) δ: 7.66-7.63 (d, 2H, J=9.0Hz, Ar-H), 7.44-7.41 (d, 2H, J=9.0Hz, Ar-H), 7.31-7.12 (m, 5H, Ar-H), 4.72-4.69 (m, IH), 3.75-3.69 (d, IH, J=18.0Hz), 3.64 (m, IH), 3.23-3.17 (d, IH, J=18.0Hz), 2.96 (m, IH), 2.74 (m, 4H) and 1.63-1.60 (brs, 2H).
IR (KBr): 3486, 2921, 2366, 1735, 1601, 1357, 1285, 1184 and 967 cm-1
The analogs of 3-[4-(4-benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5- dihydroisoxazole-5-carboxylic acid (Compound No. 2) described below, can be prepared by replacing Compound No. 6 in place of compound No. 1, respectively, as applicable in each case.
3 - [3 -(4-Benzylpiperidine- 1 -carbonyl)phenyl] -5 -methyl-4, 5 -dihydroisoxazole-5 -carboxylic acid (Compound No. 7) 1H NMR (CDCl3, 300MHz) δ: 7.73-7.64 (m, 2H, Ar-H), 7.43-7.38 (m, 2H, Ar-H), 7.29- 7.10 (m, 5H, Ar-H), 4.70-4.67 (d, IH, J=9.0Hz), 3.84-3.78 (d, IH, J=18.0Hz), 3.70-3.66 (d, IH, J=12.0Hz), 3.22-3.16 (d, IH, J=18.0Hz), 2.95 (brs, IH), 2.77-2.70 (m, IH), 2.55 (brs, 2H), 1.80-1.77 (brs, 2H), 1.69 (brs, 3H) and 1.30-1.16 (m, 3H).
IR (KBr): 3447, 2926, 2364, 1735, 1602, 1452, 1287, 1190 and 966 cm-1. 3-{2-[(4-Benzylpiperidin-l-yl)carbonyl]phenyl}-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid (Compound No. 29)
1H NMR (CDCl3, 300MHz) δ: 7.48-7.37 (m, 3H, Ar-H), 7.28-7.10 (m, 6H, Ar-H), 4.70- 4.66 (d, lH, J=12.0Hz, -CH2Ph), 3.85-3.79 (d, lH, J=18.0Hz), 3.39-3.35 (d, IH, J=12.0Hz, -CH2Ph), 3.26-3.20 (d, IH, J=I 8.0Hz), 2.93-2.85 (m, IH), 2.76-2.68 (m, IH), 2.57-2.55 (brs, 2H), 1.68 (m, 3H), 1.52-1.43 (m, IH) and 1.28-1.12 (m, 2H).
IR (DCM): 3447, 2930, 2535, 1946, 1733, 1588, 1453, 1269, 1192 and 917 cm'1. Mass (positive ion mode) m/z: 407 [M +1]. m.pt: 68.7-70.4 °C
Example 4: Synthesis of 3-[4-(4-benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5- dihydroisoxazole-5-carboxylic acid methoxyamide (Compound No. 19)
To a solution of the compound No.2 (0.1 g, 0.246 mmol) in dry tetrahydrofuran (5.0 ml), was added methoxylamine hydrochloride (0.020 g, 0.258 mmol), N- methylmorpholine (0.069 g, 0.61 mmol) and hydroxybenzotriazole (0.033 g, 0.24 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 20 minutes followed by the addition of l-(3-dimethylaminopropyl)-3-etliyl-carbodiiniide hydrochloride (0.049 g, 0.0248 mmol) and the reaction mixture was allowed to stir for overnight. The solvent was evaporated under reduced pressure and the residue was collected in ethylacetate. The organic layer was extracted with water, collected, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the little compound (0.078 g).
1H NMR (CDCl3, 300MHz) δ: 9.29 (brs, IH, -NH), 7.67-7.64 (d, 2H, J=9.0Hz, Ar-H), 7.45-7.42 (d, 2H, J=9.0Hz, Ar-H), 7.31-7.12 (m, 5H, Ar-H), 4.7 (brs, IH), 3.89-3.83 (d, IH, J=18.0Hz), 3.78 (s, 3H), 3.68 (brs, IH), 3.29-3.23 (d, IH5 J=18.0Hz), 2.92 (brs, IH), 2.68 (brs, IH), 2.57 (brs, 2H), 1.63 (s, 3H), 1.43 (s, IH) and 1.28-1.17 (m, 4H).
IR (DCM): 3453, 1658 and 1443 cm4
The analogs of 3-[4-(4-benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5- dihydroisoxazole-5-carboxylic acid methoxyamide (Compound No. 19) described below, can be prepared by replacing appropriate amine in place of methoxylamine hydrochloride, respectively as applicable in each case.
3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid hydroxyamide (Compound No. 17)
1H NMR (CDCl3, 300MHz) δ: 7.62-7.59 (d, 2H, J=9.0Hz, Ar-H), 7.41-7.38 (d, 2H, J=9.0Hz, Ar-H), 7.30-6.97 (m, 5H), 4.66 (brs, IH), 3.83-3.77 (d, IH, J=I 8.0Hz), 3.65 (brs, IH), 3.28-3.22 (d, IH, J=18.0Hz), 2.94 (brs, IH), 2.75 (brs, 2H), 2.57 (brs, 2H), 1.82- 1.61 (m, 3H), 1.43 (s, IH) and 1.28-1.11 (m, 4H).
IR (DCM): 3443, 2921, 2851, 1626, 1448, 1358, 1286, 1100 and 910 cm"1
3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid (2-methylene-pent-3-enyloxy)amide (Compound No. 18) 1H NMR (CDCl3, 300MHz) δ: 9.10 (brs, IH, -NH), 7.65-7.62 (d, 2H, J=9.0Hz, Ar-H), 7.44-7.20 (m, 1OH, Ar-H), 7.15-7.12 (d, 2H, J=9.0Hz, Ar-H), 4.91 (s, 2H), 4.69 (s, 2H), 3.84-3.78 (d, lH, J=18.0Hz), 3.65 (brs, IH), 3.25-3.19 (d, lH, J=18.0Hz), 3.06 (brs, IH), 2.57 (brs, 2H), 2.27 (brs, IH), 1.89-1.63 (m, 4H), 1.43 (s, IH) and 1.25-1.10 (m, 2H).
IR (DCM): 3451, 2929, 1626, 1449, 1359, 1286 and 908 cm"1 3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid methoxyamide (Compound No. 20)
1H NMR (CDCl3, 300MHz) δ: 7.59-7.57 (d, 2H, J=9.0Hz, Ar-H), 7.39-7.36 (d, 2H, J=9.0Hz, Ar-H), 7.34-7.12 (m, 5H, Ar-H), 4.78 (brs, IH), 4.38-4.32 (d, IH, J=I 8.0Hz)5 3.63-3.60 (m, IH), 3.31 (s, 3H, -NCH3), 3.14-3.08 (d, IH, J=18.0Hz), 3.01-2.99 (s, 3H), 2.76 (brs, 3H), 2.58-2.56 (d, 2H, J=4.0Hz), 1.80-1.60 (m, 5H) and 1.28-1.41 (m, 4H).
IR (DCM): 3447, 2921, 1631 and 1446 cm"1
3-[4-(4-Benzylpiperidme-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid diisopropylamide (Compound No. 21) 1H NMR (CDCl3, 300MHz) δ: 7.67-7.65 (d, 2H, J=8.4Hz, Ar-H), 7.43-7.41 (d, 2H,
J=8.4Hz, Ar-H), 7.31-7.12 (m, 5H, Ar-H), 4.70 (brs, IH), 4.8 (m, IH), 3.84-3.59 (m, 3H), 3.24-3.18 (d, IH, J=18.0Hz), 2.90 (brs, IH), 2.74 (brs, IH), 2.56 (brs, 2H) and 1.81-1.02 (m, 19H).
3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5-carboxylic acid tertbutyl amide (Compound No. 25)
1H NMR (CDCl3, 300MHz) δ: 7.68-7.65 (d, 2H, J=9.0Hz, Ar-H), 7.43-7.40 (d, 2H, J=9.0Hz, Ar-H), 7.35-7.17 (m, 3H, Ar-H), 7.14-7.11 (d, 2H, J=9.0Hz), 4.75 (m, IH), 3.77- 3.63 (m, IH), 3.63-3.59 (m, 2H), 3.20-3.14 (d, 2H, J=18.0Hz), 2.80-2.77 (m, 2H), 2.57- 2.56 (d, 2H, J=3.0Hz), 1.90 (s, IH), 1.80 (s, 2H), 1.72-1.40 (m, 4H, -CH3 & -CH) and 1.28-1.25 (m, 13H).
IR (DCM): 2925, 1734, 1631 and 1517 cm"1.
(4-Benzyl-piperidin-l-yl)-{4-[5-methyl-5-(pyrrolidine-l-carbonyl)-4,5-diliydro-isoxazol- 3-yl]-phenyl}-methanone (Compound No. 36)
1H NMR (CDCl3, 300MHz) δ: 7.70-7.67 (d, 2H, J=9.0Hz, Ar-H), 7.43-7.40 (d, 2H, J=9.0Hz, Ar-H), 7.31-7.12 (m, 5H, Ar-H), 4.69 (m, IH, -CH2Ph), 4.28-4.22 (d, IH, J=18.0Hz), 3.87-3.74 (m, 2H, -NCH2), 3.53-3.48 (m, 2H, -NCH2), 3.17-3.11 (d, IH, J=I 8.0Hz), 2.90-2.70 (m, 2H), 2.58-2.56 (brs, 2H), 1.99-1.77 (m, 6H), 1.64 (s, 3H) and 1.25 (m, 3H).
Mass (positive ion mode) m/z: 460 [M++!]. m.pt: 80-82.6 0C.
(4-Benzyl-piperidin-l-yl)-{4-[5-methyl-5-(morpholine-4-carbonyl)-4,5-dihydro-isoxazol- 3-yl]-phenyl}-methanone (Compound No. 40)
1H NMR (CDCl3, 300MHz) δ: 7.68-7.14 (m, 9H, Ar-H), 4.70 (m, IH3 -CH2Ph), 4.42-4.37 (d, IH), 4.10 (m, IH, -CH2Ph), 3.74-3.60 (m, 8H), 3.15-3.09 (m, IH), 2.93 (m, IH), 2.72 (m, IH), 2.57 (bs, 2H), 1.80-1.70 (m, 2H) and 1.25 (m, 6H).
Mass (positive ion mode) m/z: 476 [M++l]. m.pt: 105.3-106.6 °C.
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid diethylamide (Compound No. 41)
1H NMR (CDCl3, 300MHz) δ: 7.71-7.68 (d, 2H, J-9.0Hz, Ar-H), 7.43-7.40 (d, 2H, J=9.0Hz, Ar-H), 7.36-7.12 (m, 5H, Ar-H), 4.69 (brs, IH, -CH2Ph), 4.40-4.34 (d, 4H, J=18.0Hz), 3.16-3.10 (d, IH, J=18.0Hz), 2.95 (m, IH), 2.80 (m, IH), 2.57 (m, 2H), 2.04- 2.01 (m, 2H), 1.80-1.60 (m, 3H) and 1.43-1.12 (m, 9H). Mass (+ve ion mode, m/z) : 462 [M++ 1 ] .
(4-Benzyl-piperidin-l-yl)-{4-[5-(2-hydroxymethyl-pyrrolidine-l-carbonyl)-5-methyl-4,5- dihydro-isoxazol-3-yl]-phenyl}-methanone (Compound No. 53)
1H NMR (CDCl3, 300MHz) δ: 7.70-7.68 (d, 2H, J=6.0Hz, Ar-H), 7.44-7.41 (d, 2H, J=9.0Hz, Ar-H), 7.31-7.12 (m, 5H, Ar-H), 4.69 (m, IH, -CH2Ph), 4.30-4.22 (m, 3H), 3.68- 3.58 (m, 4H), 3.22-3.12 (m, IH), 2.90(m, IH), 2.7 (m, IH), 2.58-2.57 (brs, 2H), 2.01-1.91 (m, 4H), 1.80-1.56 (m, 5H) and 1.25-1.18 (m, 3H).
Mass (positive ion mode) m/z: 490 [M++l]. l-{3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carbonyl}-pyrrolidine-2-carboxylic acid methyl ester (Compound No. 54) 1H NMR (CDCl3, 300MHz) δ: 7.71-7.63 (m, 2H, Ar-H), 7.44-7.40 (m, 2H, Ar-H), 7.31- 7.12 (m, 5H, Ar-H), 4.70 (m, IH), 4.5 (m, IH), 4.25 (m, IH), 4.06 (m, 2H), 3.82-3.69 (m, 4H), 3.15 (m, IH), 2.90 (m, IH), 2.7 (m, IH), 2.57 (brs, 2H), 2.10-1.88 (m, 4H), 1.80-1.68 (m, 5H) and 1.33-1.26 (m, 3H). Mass (positive ion mode) m/z: 518 [M++l].
(4-Benzyl-piperidine- 1 -yl)- {4-[5-methyl-5 -(piperidine- 1 -carbonyl)-4,5 -dihydro-isoxazole- 3-yl]-phenyl}-methanone (Compound No. 75)
1H NMR (CDCl3, 300MHz) δ: 7.71-7.68 (d, J=9.0Hz, 2H, Ar-H), 7.43-7.40 (d, J=9.0Hz, 2H, Ar-H), 7.31-7.12 (m, 5H, Ar-H), 4.70 (brs, IH, -CHPh), 4.46-4.40 (d, J=I 8.0Hz, IH), 3.90 (m, IH), 3.70 (m, 2H), 3.68 (m, 2H), 3.56-3.52 (m, 2H), 3.40-3.37 (d, J=9.0Hz, IH), 3.13 (brs, IH), 3.08 (brs, IH), 2.57 (s, 2H), 2.08 (s, 2H, -CH3), 1.8-1.56 (m, 3H) and 1.43- 1.22 (m, 10H).
Mass (positive ion mode) m/z: 474 [M +1]. IR (DCM): 3423, 2918, 2362, 1649, 1649, 1219, 1029 and 772 cm"1
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid phenylamide (Compound No. 76)
1H NMR (CDCl3, 300MHz) δ: 8.61 (s, IH, -NH), 7.69-7.66 (d, J=9.0Hz, 2H, Ar-H), 7.59- 7.56 (d, J=9.0Hz, 2H, Ar-H), 7.36-7.11 (m, 8H, Ar-H), 4.66 (brs, IH, -CHPh)3 3.97-3.92 (d, J=45.0Hz, IH, -CH), 3.6 (brs, IH, -CHPh), 3.34-3.28 (d, J=18.0Hz, IH, -CH), 2.90 (brs, IH, -CH), 2.7 (brs, IH, -CH), 2.57 (s, 2H), 1.82-1.77 (brs, 3H), 1.72-1.70 (brs, 2H) and 1.33-1.18 (m, 3H).
Mass (positive ion mode) m/z: 482 [M++l].
Scheme III:
Example 5: Synthesis of (4-benzylpiperidin-l-yl)-[4-('5-methoxymethyl-5-methyl-4,5- dihvdroisoxazol-3-vDphenvHmethanone (Compound No. 27)
To the solution of compound No. 24 (0.10 g, 0.25 mmol) in dry tetrahydrofuran (5.0 ml) at -150C under nitrogen atmosphere, was added sodium hydride (0.025 g, 0.50 mmol) and the reaction mixture was stirred at the same temperature for 3 hours. To the reaction mixture was added methyl iodide (0.072 g, 0.50 mmol) and reaction mixture was stirred at the same temperature for 30 minutes and then allowed to warm to room temp and stirred overnight. Excess of sodium hydride was decomposed carefully with chilled water and the reaction mixture was collected in ethyl acetate and extracted with water. The organic layer was collected and dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 15% ethyl acetate in hexane as eluent to furnish the title compound (0.085 g). 1H NMR (CDCl3, 300MHz) δ: 7.61-7.58 (d, 2H, J=8.1Hz, Ar-H), 7.34-7.31 (d, 2H, J=8.4Hz, Ar-H), 7.23-7.04 (m, 5H, Ar-H), 4.52-4.50 (m, IH), 3.60-3.56 (m, IH), 3.43- 3.37 (m, 2H), 3.34-3.32 (brs, 3H, -OCH3), 2.92-2.86 (m, 2H), 2.62-2.60 (brm, 2H), 2.50- 2.48 (m, 2H), 1.72-1.70 (brm, 2H), 1.54 (s, 4H) and 1.29-1.17 (m, 3H).
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.
(4-Benzylpiperidin-l-yl)-[4-(5-benzyloxymethyl-5-methyl-4,5-dihydroisoxazol-3- yl)phenyl]methanone (Compound No. 28) 1H NMR (CDCl3, 300MHz) δ: 7.61-7.59 (d, 2H, J=6.0Hz, Ar-H), 7.35-7.32 (d, 2H,
J=9.0Hz, Ar-H), 7.28-7.05 (m, 13H, Ar-H), 4.59-4.49 (m, 3H), 3.59-3.54 (brm, IH), 3.52- 3.43 (m, 2H), 3.40-3.35 d, IH, J=45.0Hz), 2.94-2.88 (d, 2H, J=18.0Hz), 2.73-2.71 (m, 2H), 2.51-2.49 (brm, 2H), 1.72-1.71 (brm, 2H), 1.18 (s, 3H, -CH3) and 1.09 (brs, 5H).
Scheme IV: Example 6: Synthesis of 3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5- dihydro-isoxazole-5-carboxylic acid benzyl-ethyl-amide ("Compound No. 47)
1H NMR (CDCl3, 300MHz) δ: 7.72-7.70 (d, 3H, J=6.0Hz, Ar-H), 7.44-7.12 (m, HH, Ar- H), 4.96-4.91 (d, IH, J=15.0Hz, -CH2Ph), 4.72-4.67 (d, IH, J=15.0Hz, -CH2Ph), 4.51-4.40 (d, IH, J=18.0Hz, -CH2Ph), 4.30-4.25 (d, IH, J=15.0Hz), 3.7 (m, IH, -CH2Ph), 3.48 (m, 2H, -CH2N), 3.37-3.28 (m, IH), 3.21-3.20 (m, IH), 2.94 (m, IH), 2.70 (m, IH), 2.58-2.57 (brs, 2H), 1.77-1.67 (m, 5H), 1.32-1.25 (m, 3H) and 1.09-1.04 (m, 3H).
Mass (positive ion mode) m/z: 524 [M++l]. Following compounds were prepared similarly,
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid ethyl-methyl-amide (Compound No. 48) 1H NMR (CDCl3, 300MHz) δ: 7.74-7.71 (d, 2H, J=9.0Hz Ar-H)3 7.46-7.44 (d, 2H, J=6.0Hz, Ar-H), 7.34-7.16 (m, 5H, Ar-H), 4.70 (m, IH, -CH2Ph), 4.44-4.38 (d, IH, J=18.0Hz), 3.67 (m, IH), 3.52-3.42 (m, 2H), 3.30 (s, IH), 3.19-3.13 (d, IH, J=18.0Hz), 2.97 (s, 3H, -NCH3), 2.52-2.50 (m, IH), 2.62-2.60 (brs, 2H), 1.83-1.73 (m, 5H), 1.19-1.14 (m, 3H) and 0.91-0.88 (m, 3H).
Mass (positive ion mode) m/z: 448 [M++l].
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-diliydro-isoxazole-5- carboxylic acid cyclopropyl-ethyl-amide (Compound No. 49) 1R NMR (CDCl3, 300MHz) δ: 7.70-7.68 (d, 2H, J=6.0Hz, Ar-H), 7.43-7.40 (d, 2H,
J=9.0Hz, Ar-H), 7.31-7.12 (m, 5H, Ar-H), 4.68 (m, IH, -CH2Ph), 4.45 (m, IH), 3.66 (m, IH, -CH2Ph & 2H, -NCH2), 3.15-3.09 (m, IH), 2.90 (m, IH), 2.7 (m, IH), 2.56 (brs, 2H), 1.77-1.56 (m, 5H), 1.32-1.25 (m, 6H), 0.88-0.85 (m, 2H) and 0.60 (m, 2H).
Mass (positive ion mode) m/z: 474 [M++l]. 3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid cyclopropyl-methyl-amide (Compound No. 50)
1H NMR (CDCl3, 300MHz) δ: 7.70-7.67 (d, 2H, J=9.0Hz, Ar-H), 7.43-7.40 (d, 2H, J=9.0Hz, Ar-H), 7.31-7.12 (m, 5H, Ar-H), 4.70 (m, IH, -CH2Ph), 4.28 (m, IH), 3.70 (m, IH, -CH2Ph), 3.19-3.13 (m, 3H), 2.93 (m, IH), 2.74 (m, IH), 2.58-2.57 (brs, 2H), 1.79- 1.60 (m, 5H), 1.33-1.26 (m, 3H), 0.88-0.80 (m, 2H) and 0.64 (m, 2H).
Mass (positive ion mode) m/z: 460 [M++l].
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid benzyl-cyclopropyl-amide (Compound No. 51)
1H NMR (CDCl3, 300MHz) δ: 7.70-7.68 (d, 2H, J=6.0Hz, Ar-H), 7.44-7.41 (d, 2H, J=9.0Hz, Ar-H), 7.35-7.12 (m, 1OH, Ar-H), 4.89-4.70 (m, 3H), 4.30 (m, IH), 3.67 (m, IH), 3.22-3.17 (m, IH), 2.94 (m, IH), 2.72 (m, IH)5 2.56 (brs, 2H), 2.08-1.42 (m, 5H), 1.32-1.25 (m, 3H), 0.98 (m, 3H) and 0.87-0.74 (m, 4H).
Mass (positive ion mode) m/z: 556 [M++!]. 3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid ethyl-propyl-amide (Compound No. 52)
1H NMR (CDCl3, 300MHz) δ: 7.71-7.68 (d, 2H, J=9.0Hz, Ar-H), 7.43-7.40 (d, 2H, J=9.0Hz, Ar-H), 7.31-7.12 (m, 5H, Ar-H), 4.70 (m, IH, -CH2Ph), 4.40-4.34 (d, IH, J=18.0Hz), 3.70-3.60 (m, IH, -CH2Ph), 3.45-3.35 (m, 2H), 3.30 (m, IH), 3.23-3.16 (m, IH), 2.90 (m, IH), 2.73 (m, IH), 2.58-2.56 (brs, 2H), 1.78-1.70 (m, 5H), 1.32-1.25 (m, 3H), 1.16-1.14 (m, 3H) and 0.96-0.88 (m, 5H).
Mass (positive ion mode) m/z: 476 [M++l].
3-[3-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-2,5-dihydro-isoxazole-5- carboxylic acid benzyl-methyl-amide (Compound No. 60)
1H NMR (CDCl3, 300MHz) δ: 7.62 (s, 2H, Ar-H), 7.42-7.13 (m, 12H, Ar-H), 4.78-4.70 (m, IH), 4.50-4.40 (m, 2H), 3.68 (brs, IH), 3.15 (s, 3H), 2.95-2.73 (m, 4H), 2.58-2.57 (m, 2H), 1.75-1.74 (m, 5H) and 1.42-1.41 (m, 3H).
Mass (positive ion mode) m/z: 510 [M++l]. 3-[3-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid cyclopropyl-methyl-amide (Compound No. 62)
1H NMR (CDCl3, 300MHz) δ: 7.71-7.67 (m, 2H, Ar-H), 7.52 (s, 2H, Ar-H), 7.20-7.13 (m, 5H, Ar-H), 4.40 (brs, IH), 4.23-4.20 (m, 2H), 3.60 (brs, IH), 3.19-3.13 (m, 3H), 2.96-2.87 (m, 2H), 2.70-2.60 (m, IH), 2.59-2.57 (m, 2H), 1.72-1.56 (m, 5H), 0.95-0.92 (m, 5H) and 0.60 (m, 2H).
Mass (positive ion mode) m/z: 460 [M +1].
3-[3-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid ethyl-methyl-amide (Compound No. 63)
1H NMR (CDCl3, 300MHz) δ: 7.67 (s, 2H, Ar-H), 7.41 (s, 2H, Ar-H), 7.22-7.19 (m, 3H, Ar-H), 7.15-7.13 (m, 2H, Ar-H), 4.40 (brs, IH), 4.35-4.34 (d, IH, J=3.0Hz), 3.60 (brs, IH), 3.48-3.41 (m, 2H), 3.26-3.16 (m, IH), 2.90 (s, 3H), 2.58-2.56 (m, 2H), 2.40 (brs, IH), 2.30-2.20 (m, IH), 1.80-1.71 (m, 5H), 1.33-1.28 (m, 3H) and 1.6-1.11 (m, 3H).
Mass (positive ion mode) m/z: 448 [M++!]. CeIl based Assay for TNF-α release
Method of isolation of Human Peripheral Blood Mononuclear Cells:
Human whole blood was collected in vacutainer tubes containing EDTA as an anti coagulant. A blood sample (7 ml) was carefully layered over 5 ml PMN Cell Isolation Medium (Robbins Scientific) in a 15 ml round bottom centrifuge tubes. The sample was centrifuged at 450-500 x g for 30-35 minutes in a swing-out rotor at room temperature. After centrifugation the top band of cells were removed and washed 3 times with PBS w/o calcium or magnesium. The cells were centrifuged at 40Ox g for 10 minutes at room temperature. The cells were resuspended in Macrophage Serum Free Medium (Gibco BRL) at concentration of 2 million cells/ml.
LPS stimulation of Human PBMNCs :
PBM cells (0.1 ml, 2 million/ml) were co-incubated with 0.1 ml of compound (10 -0.41μM, 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 0C. Supernatant was then removed and tested by ELISA for TNF-α release. Viability was analyzed using MTT. After 0.1 ml supernatant was collected, 0.1 ml of 0.25mg/ml of MTT was added to remaining 0.1 ml of cells. The cells were incubated at 37 0C for 2-4 hours, then the O.D was measured at 490-650 nm.
The results of in- vitro tests are listed in Table-II
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001

Claims

We Claim: 1. A compound having the structure of Formula Ia
Figure imgf000058_0001
Formula Ia and its pharmaceutically accepted salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, polymorphs or N-oxides wherein 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. Q can be alkylene, alkenylene, alkynylene, or -C(=T) (wherein T can be oxygen, sulphur, -N(CN), -N(NO2), or -CH(NO2)) (wherein double bond of said alkenylene or triple bond of said alkynylene cannot be attached directly to N atom). 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). The subscript m is an integer from 0-3, and the subscript t is an integer from 0-4. R1 and R2 can independently be hydrogen, cyano, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, aryloxy, cycloalkyl, aryl, aralkyl, carboxy, -COOR3 (wherein R3 can be alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl), -NRpRq (wherein Rp and Rq can independently be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl, or Rp and Rq may also together join to form a heterocyclic ring), -OC(=O)NRxRy [wherein Rx and Ry can independently be hydrogen, hydroxy (excepting that both Rx and Ry cannot be -OH at the same time), alkyl, cycloalkyl, alkoxy, hydroxyalkyl, aryloxy, aralkyloxy, aryl, aralkyl, or -SO2R4 (wherein R4 can be alkyl, alkenyl, alkynyl, cycloalkyl, -NRpRq wherein Rp and. Rq as defined above, aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, or heteroarylalkyl), or Rx and Ry may also together join to form a heterocyclyl or heteroaryl ring],
Figure imgf000059_0001
(wherein R5 can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl , aralkyl, heterocyclylalkyl, or heteroarylalkyl, and wherein Rj can be hydrogen, lower (C1-C6) alkyl, lower (C3- C6) cycloalkyl, lower (C1-C3) aralkyl, aryl, heteroaryl, heteroarylalkyl, or heterocyclylalkyl), NRjYRu (wherein Y can be -C(=O), -C(=S) or -SO2, Rj is as defined above, and Ru can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl), -NRj (=T)NRxRy (wherein Rj, T, Rx and Ry are as defined above), -C(=K)NRxRy (wherein K is O or S), -CH2OR5 (wherein Rs is the same as defined above), heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl. "Ar1 and Ar2 can independently be aryl, heteroaryl, or heterocyclyl. 2. The compound of claim 1, wherein Ar1 is phenyl, W is methylene, Z is -CH-, t and m are 1, Q is carbonyl, Ar2 is 1,2-, 1,3-, or 1,4-disubstituted phenyl, r is 0, p is 1, and X is oxygen. 3. The compound of claim 2, WrIeTeUi R1 is alkyl. 4. The compound of claim 3, wherein R1 is methyl and R2 is COOR3 or C(=K)NRxRy. 5. The compound of claim 1, wherein Ar2 is trisubstituted phenyl. 6. The compound of claim 5, wherein Ar2 is substituted with alkoxy. 7. A compound selected from 3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid methyl ester (Compound No. 1),
3-[4-(4-benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid, 3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid amide (Compound No. 3), 3 - [4-(4-Benzylpiperidine- 1 -carbonyl)phenyl] -5 -methyl-4, 5 -dihydroisoxazole-5 - carboxylic acid methylamide (Compound No. 4), 3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid methylamide (Compound No. 5), 3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid methyl ester (Compound No. 6), 3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid (Compound No. 7), 3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid amide (Compound No. 8), 3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-metliyl-4,5-diliydroisoxazole-5- carboxylic acid cyclopropylamide (Compound No. 9), 3 - [3 -(4-B enzylpiperidine- 1 -carbonyl)phenyl] -5 -methyl-4, 5-dihydroisoxazole-5 - carboxylic acid propylamide (Compound No. 10), 3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid cyclohexylamide (Compound No. 11), 3-[3-(4-Benzylpiperidme-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid (2-hydroxy-ethyl)amide (Compound No. 12), 3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid benzylamide (Compound No. 13), 3 - [3 -(4-B enzylpiperidine- 1 -carbonyl)phenyl] -5 -methyl-4, 5 -dihydroisoxazole-5 - carboxylic acid isopropylamide (Compound No. 14), 3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid ethylamide (Compound No. 15), 3-[3-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- yl}pyrrolidin-l-ylmethanone (Compound No. 16), 3 - [4-(4-B enzylpiperidine- 1 -carbonyl)phenyl] -5 -methyl-4, 5 -dihydroisoxazole-5 - carboxylic acid hydroxyamide (Compound No. 17),
3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid (2-methylene-pent-3-enyloxy)amide (Compound No. 18), 3-[4-(4-Benzylρiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid methoxyamide (Compound No. 19), 3-[4-(4-Benzylpiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid dimethylamide (Compound No. 20),
3-[4-(4-Benzylρiperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid diisopropylamide (Compound No. 21), 3-[4-(4-Benzyl-piperidine-l-carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid butylamide (Compound No. 22), (4-Benzylpiperidin-l-yl)-[4-(5-hydroxymethyl-4,5-diliydroisoxazole-3- yl)phenyl]methanone (Compound No. 23), (4-Benzylpiperidin-l-yl)-[4-(5-hydroxymethyl-5-methyl-4,5-dihydroisoxazol-3- yl]phenyl)methanone (Compound No. 24), 3 - [4-(4-B enzylpiperidine- 1 -carbonyl)phenyl] -5 -methyl-4, 5 -dihydroisoxazole-5 - carboxylic acid tert-butyl amide (Compound No. 25), 3-[4-(4-Benzylpiperidine- 1 -carbonyl)phenyl]-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid prop-2-ynylamide (Compound No. 26), (4-benzylpiperidin-l-yl)-[4-(5-methoxymethyl-5-methyl-4,5-dihydroisoxazol-3- yl)phenyl]methanone (Compound No. 27), [4-(5 -Benzyloxymethyl-5 -methyl-4,5 -dihydroisoxazol-3 -yl)phenyl] -(4- benzylpiperidin-l-yl)methanone (Compound No. 28), 3-{2-[(4-Benzylpiperidin-l-yl)carbonyl]phenyl}-5-methyl-4,5-dihydroisoxazole-5- carboxylic acid (Compound No. 29), 3 - [2-(4-B enzylpiperidine- 1 -carbonyl)phenyl] -5 -methyl-4,5 -dihydroisoxazole-5 - carboxylic acid methyl ester (Compound No. 30) 3-[2-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid methylamide (Compound No. 31), 3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid isopropylamide (Compound No. 32),
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid cyclopropylamide (Compound No. 33),
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid benzylamide (Compound No. 34),
3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid (2-hydroxy-ethyl)-amide (Compound No. 35),
(4-Benzyl-piperidin-l-yl)-{4-[5-methyl-5-(pyrrolidine-l-carbonyl)-4,5-dihydro- isoxazol-3-yl]-phenyl}-methanone (Compound No. 36), 3 - [4-(4-B enzyl-piperidine- 1 -carbonyl)-phenyl] -5 -methyl-4,5 -dihydro-isoxazole-5 - carboxylic acid cyclohexylamide (Compound No. 37), 3-[4-(4-Benzyl-piperidine- 1 -carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5- carboxylic acid ethylamide (Compound No. 38), 114 3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5-
115 carboxylic acid propylamide (Compound No. 39), 116
117 (4-Benzyl-piperidin-l-yl)-{4-[5-methyl-5-(morpholme-4-carbonyl)-4,5-dihydro-
118 isoxazol-3-yl]-phenyl} -methanone (Compound No. 40), 119
120 3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-metliyl-4,5-diliydro-isoxazole-5-
121 carboxylic acid diethylamide (Compound No. 41), 122
123 3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5-
124 carboxylic acid cyclopentylamide (Compound No. 42), 125
126 4-{4-[(4-Benzylpiperidin-l-yl)carbonyl]phenyl}-5-methyl-4,5-dihydroisoxazole-5-
127 carbonitrile (compound No. 43), 128
129 Ethyl 4-{4-[(4-benzylpiperidin-l-yl)carbonyl]phenyl}-4,5-dihydiOisoxazole-5-
130 carboxylate (Compound No. 44) 131
132 3-[4-(4-Benzyl-piperidine- 1 -carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5-
133 carboxylic acid (3-methyl-butyl)-amide (Compound No. 45), 134
135 3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5-
136 carboxylic acid allylamide (Compound No. 46), 137
138 3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-diriydro-isoxazole-5-
139 carboxylic acid benzyl-ethyl-amide (Compound No. 47), 140
141 3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5-
142 carboxylic acid ethyl-methyl-amide (Compound No. 48), 143
144 3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5-
145 carboxylic acid cyclopropyl-ethyl-amide (Compound No. 49), 146
147 3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5-
148 carboxylic acid cyclopropyl-methyl-amide (Compound No. 50), 149
150 3-[4-(4-Benzyl-piperidine- 1 -carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5-
151 carboxylic acid benzyl-cyclopropyl-amide (Compound No. 51), 152
153 3-[4-(4-Benzyl-piperidine- 1 -carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5-
154 carboxylic acid ethyl-propyl-amide (Compound No. 52), 155
156 (4-Benzyl-piρeridin- 1 -yl)- {4-[5-(2-hydroxymethyl-pyrrolidine- 1 -carbonyl)-5-
157 methyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-methanone (Compound No. 53), 158
159 l-{3-[4-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-
160 isoxazole-5-carbonyl} -pyrrolidine-2-carboxylic acid methyl ester (Compound No.
161 54), 162 163 (4-Benzyl-piperidin-l-yl)-{2-[5-methyl-5-(pyrrolidine-l-carbonyl)-4,5-dihydro-
164 isoxazol-3 -yl] -phenyl} -methanone (Compound No . 55), 165
166 3-[2-(4-Benzyl-piperidine- 1 -carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5-
167 carboxylic acid propylamide (Compound No. 56), 168
169 3-[2-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5-
170 carboxylic acid (2-hydroxy-ethyl)-amide (Compound No. 57), 171
172 3-[2-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5-
173 carboxylic acid ethylamide (Compound No. 58), 174
175 3-[2-(4-Benzyl-piperidine-l-carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5-
176 carboxylic acid cyclopropylamide (Compound No. 59), 177
178 3-[3-(4-Benzyl-piperidine-l-carbonyl)-plienyl]-5-methyl-2,5-dihydro-isoxazole-5-
179 carboxylic acid benzyl-methyl-amide (Compound No. 60), 180
181 (4-Benzyl-piperidin- 1 -yl)- {3-[5-(2-hydroxymethyl-pyrrolidine- 1 -carbonyl)-5-
182 methyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-methanone (Compound No. 61), 183
184 3-[3-(4-Benzyl-piperidine- 1 -carbonyl)-phenyl]-5-methyl-4,5-dihydro-isoxazole-5-
185 carboxylic acid ethyl-methyl-amide (Compound No. 63), 186
187 3-[3-(4-Benzyl-piperidine-l -carbonyl)-2-methoxy-phenyl]-5-methyl-4,5-dihydro-
188 isoxazole-5-carboxylic acid cyclopropylamide (Compound No. 64), 189
190 Methyl 3-{3-[(4-benzylpiperidin-l-yl)carbonyl]-4-methoxyphenyl}-5-methyl-4,5-
191 dihydroisoxazole-5-carboxylate (Compound No. 65), 192
193 (4-Benzyl-piperidin-l-yl)-{2-methoxy-5-[5-methyl-5-(pyrrolidine-l-carbonyl)-4,5-
194 dihydro-isoxazol-3-yl]-phenyl} -methanone (Compound No. 66), 195
196 (4-Benzyl-piperidin-l-yl)-{5-[5-(2-hydroxymethyl-pyrrolidine-l-carbonyl)-5-
197 methyl-4,5-dihydro-isoxazol-3-yl]-2-methoxy-phenyl} -methanone (Compound
198 No. 67), 199
200 [4-(4-Fluoro-benzyl)-piperidin- 1 -yl]- {5-[5-(2-hydroxymethyl-pyrrolidine- 1 -
201 carbonyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-2-methoxy-phenyl}-methanone
202 (Compound No. 68), 203
204 3-{3-[4-(4-Fluoro-benzyl)-piperidine-l-carbonyl)-4-methoxy-phenyl}-5-methyl-
205 4,5-dihydro-isoxazole-5-carboxylic acid methylamide (Compound No. 69), 206
207 Methyl 3-(3- {[4-(4-fluorobenzyl)piperidin- 1 -yl]carbonyl} -4-methoxyphenyl)-5-
208 methyl-4,5-dihydroisoxazole-5-carboxylate (Compound No. 70), 209
210 4- {3-[4-(4-Fluoro-benzyl)-piperidine- 1 -carbonyl)-4-methoxy-phenyl} -5-methyl-
211 4,5-dihydro-isoxazole-5-carboxylic acid amide (Compound No. 71), 212 4-{3-[4-(4-Fluoro-benzyl)-piperidine-l-carbonyl)-4-methoxy-phenyl}-5-methyl-
213 4,5-dihydro-isoxazole-5-carboxylic acid ethylamide (Compound No. 72).
1 8. A method of treating a mammal suffering from inflammation or associated
2 pathologies, the method comprising administration to the mammal a
3 therapeutically effective amount of a compound of claim 1, or a pharmaceutically
4 acceptable salt thereof.
1 9. The method of claim 8, further comprising administration of the compound of
2 claim 1 or a pharmaceutically acceptable salt thereof in a pharmaceutical
3 composition, comprising a pharmaceutically acceptable carrier.
1 10. A method of treating mammals suffering from inflammatory diseases and
2 associated pathologies selected from sepsis, rheumatoid arthritis, inflammatory
3 bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder,
4 organ transplant rejection and psoriasis, the method comprising administration to
5 the mammal a therapeutically effective amount of a compound of claim 1, or a
6 pharmaceutically acceptable salt thereof.
1 11. The method of claim 10, further comprising administration of the compound of
2 claim 1 or a pharmaceutically acceptable salt thereof in a pharmaceutical
3 composition, comprising a pharmaceutically acceptable carrier.
1 12. A method of preparing a compound of Formula VI,
Figure imgf000064_0001
6 wherein
7 Z is nitrogen, or -CH;
8 W is alkylene, alkenylene, or alkynylene;
9 the subscript m is an integer from 0-3, and the subscript 1 is an integer from 0-2;
10 Ar1 is aryl, heteroaryl, or heterocyclyl;
11 K is O or S; 12 B is hydrogen or alkyl; and
13 P is -COOR3 (wherein R3 is alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl,
14 heterocyclyl, or heteroaryl) or CH2OH,
15 the method comprising:
16 a) reacting a compound of Formula I
17 A Δr1 — W , — Z T2"Λ NH
18 (CW
Formula I
19
20 (where Ar1, W, Z, 1 and m are as defined) with a compound of Formula II
21 (where K is as defined)
22
Figure imgf000065_0001
23 Formula Il
24 to produce a compound of Formula III;
25
Figure imgf000065_0002
26 b) reacting the compound of Formula III with hydroxylamine hydrochloride to
27 produce a compound of Formula IV;
Figure imgf000065_0003
29 c) reacting the compound of Formula IV with a compound of Formula V
30 (where B and P
31 are the same as defined earlier) /B
H2C=C^ ~ry Formula V
33 to produce a compound of Formula VI.
Figure imgf000066_0001
1 13. A method of producing a compound of Formula IX
2
3 4
Figure imgf000066_0002
C Formula IX
6 wherein
7 Z is nitrogen or -CH;
8 W is alkylene, alkenylene, or alkynylene;
9 the subscript m is an integer from 0-3, and the subscript 1 is an integer from 0-2;
10 Ar1 is aryl, heteroaryl, or heterocyclyl;
11 K is O or S;
12 Rp and Rq are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,
13 aralkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, or Rp and Rq may also
14 together join to form a heterocyclic ring;
15 the method comprising: 16 reacting a compound of Formula VII with a compound of Formula VIII (NHRpRq, wherein Rp and Rq are as defined) to produce the compound of Formula IX.
Figure imgf000067_0001
Formula VII
14. A method of producing a compound of Formula IX wherein Z is nitrogen or -CH; W is alkylene, alkenylene, or alkynylene; the subscript m is an integer from 0-3, and the subscript 1 is an integer from 0-2; Ar1 is aryl, heteroaryl, or heterocyclyl; K is O or S; Rp and Rq are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, or heterocyclylalkyl, or Rp and Rq may also together join to form a heterocyclic ring; the method comprising: a) hydro lyzing a compound of Formula VII to give a compound of Formula X; and
Figure imgf000068_0001
b) reacting the compound of Formula X with a compound of Formula VIII (NHRpRq, wherein Rp and Rq are as defined) to produce the compound of Formula IX.
15. A method of making a compound of Formula XIII
Scheme III
Figure imgf000068_0002
wherein Z is nitrogen or -CH; W is alkylene, alkenylene, or alkynylene; the subscript m is an integer from 0-3, and the subscript 1 is an integer from 0-2; Ar1 is aryl, heteroaryl, or heterocyclyl; K is O or S; B is hydrogen or alkyl; and G is alkyl or aralkyl, the method comprising reacting a compound of Formula XI with a compound of Formula XII (hal-G, wherein hal is a halogen and G is as defined) to produce the compound of Formula XIII.
16. A method of making a compound of Formula XV
Scheme IV
Figure imgf000069_0001
Formula XlV Formula XV
wherein Z is nitrogen or -CH; W is alkylene, alkenylene, or alkynylene; the subscript m is an integer from 0-3, and the subscript 1 is an integer from 0-2; Ar1 is aryl, heteroaryl, or heterocyclyl; K is O or S; Rc is alkyl, aryl, cycloalkyl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl; hal is Cl, Br or I; the method comprising reacting a compound of Formula XIV with a compound of Formula Rc-hal to produce a compound of Formula XV.
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