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WO2008078249A1 - Agents anti-inflammatoires - Google Patents

Agents anti-inflammatoires Download PDF

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Publication number
WO2008078249A1
WO2008078249A1 PCT/IB2007/055140 IB2007055140W WO2008078249A1 WO 2008078249 A1 WO2008078249 A1 WO 2008078249A1 IB 2007055140 W IB2007055140 W IB 2007055140W WO 2008078249 A1 WO2008078249 A1 WO 2008078249A1
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Prior art keywords
compound
formula
methyl
pyrimidin
alkyl
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Inventor
Ashwani Kumar Verma
Venkata P. Palle
Sanjay Malhotra
Rakesh Kumar Singh
Arti Walia
Malini Bajpai
Puneet Chopra
Abhijit Ray
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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 dioxolyl derivatives as anti-inflammatory agents and processes for the synthesis of the same.
  • the compounds of this invention are useful for inhibition and 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 of the present invention and the methods of treating 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.
  • 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 i.e., therapies that aim to inhibit or restore the activity of specific cytokines.
  • drugs that block inflammatory cytokines such as tumor necrosis factor-alpha (TNF- ⁇ ) are among the most successful agents being introduced to the market.
  • TNF- ⁇ tumor necrosis factor-alpha
  • Elevated levels of proinflammatory cytokines viz TNF- ⁇ and IL- ⁇ are associated with the pathogenesis of many immune mediated inflammatory disorders like sepsis, rheumatoid arthritis, inflammatory bowel disease, type-I diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis. Inflammation is regulated by a large number of pro- and anti-inflammatory mediators, which include cytokines, eicosanoids, nitric oxide and reactive oxygen species. The central role of these inflammatory mediators in the pathogenesis of both chronic and acute inflammatory diseases has been documented.
  • inflammatory disorders were treated primarily with relatively non-selective anti-inflammatory agents, such as corticosteroids and various non-steroidal anti-inflammatory drugs.
  • therapies have been developed that specifically interfere with the action of selected proinflammatory mediators, such as TNF- ⁇ and PGE-2.
  • TNF- ⁇ and PGE-2 selected proinflammatory mediators, such as TNF- ⁇ and PGE-2.
  • TNF- ⁇ tumour- necrosis factor- ⁇
  • Etanercept Enbrel; Amgen/Wyeth
  • Infliximab Remicade; Centocor
  • Adalimumab Humira; Abbott
  • IL-1 Kineret -an interleukin-1 receptor antagonist
  • current injectable therapies have associated limitations and risks, including the potential for increased malignancies and infections and increased congestive heart failure.
  • 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 kinase (ERK) & the c-jun N-terminal kinases (JNK).
  • ERK extracellular regulated kinase
  • JNK c-jun N-terminal kinases
  • 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 was first identified as a tyrosine phosphorylated protein in LPS (Lipopolysaccharide) stimulated macrophages.
  • LPS Lipopolysaccharide
  • 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-1 release from LPS stimulated monocytes.
  • p38 ⁇ additional members of the p38 MAPK family were cloned by homology, including the p38 ⁇ , p38 ⁇ and p38 ⁇ .
  • the p38 pathway controls the activity of multiple transcription factors and the expression of many genes.
  • p38 Inhibitors have been shown to effectively block both TNF- ⁇ and IL-1 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.
  • GM-CSF and 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 a 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.
  • WO 01/44258 discloses bone-targeting groups useful for treating a variety of disorders and conditions.
  • WO 02/18380 and U.S. Patent Nos. 6,518,276 and 6,506,749 disclose 7-oxopyridopyrimidines as inhibitors of cell proliferation.
  • WO 02/18379 discloses 7-oxo-pyridopyrimidines, a process for their manufacture, pharmaceutical preparation and method of use.
  • WO02/064594 discloses pyridopyrimidines and their derivatives.
  • WO 03/057165 describes compositions and methods for prevention and treatment of amyloid- ⁇ -peptide related disorders.
  • U.S. Patent No. 6,316,464 discloses compounds as p38 kinase inhibitors.
  • 6,451,804 discloses heteroalkylamino-substituted bicyclic nitrogen heterocycles.
  • U.S. Patent No. 6,696,566 discloses 6-substituted pyridopyrimidines useful for the treatment of p38-mediated disorders.
  • U.S. Patent No. 6,479,507 discloses p38 kinase inhibitors.
  • U.S. Publication No. 2003/0153586 discloses 7-oxo-pyridopyridopyrimidines for the treatment of p38-mediated disorders.
  • WO 03/00270 discloses pyridopyrimidones and uses thereof.
  • U.S. Patent No. 6,630,485 discloses p38 kinase inhibitors, pharmaceutical compositions containing them, method for their use, and methods for preparing these compounds.
  • the present invention provides dioxolyl derivatives, useful for the 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.
  • 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 are provided, which may be used for the treatment of 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.
  • 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.
  • a compound having the structure of Formula I and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, polymorphs, metabolites; wherein R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl; when R n is oxygen or sulphur
  • R 2 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl or heteroarylalkyl; when R m is -NH, -N-acyl, -N(CN), -N(NO 2 ), -C(R 3 ) 2 , or -CH(NO 2 )
  • R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heteroarylalkyl or heterocyclylalkyl;
  • R 4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aral
  • R 5 is alkyl, alkenyl, alkynyl, cycloalkyl, -NR p R q ;
  • R 6 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroarylalkyl or heterocyclylalkyl;
  • R 7 and R 8 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heteroarylalkyl or heterocyclylalkyl;
  • Z is a direct bond, oxygen, sulphur, -NH or -(CH 2 ) n ;
  • n is an integer selected from 0-3;
  • R x and R y are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryl, aralkyl, -SO 2 R 5 , heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl; and
  • R p and R q are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl; R p and R q may also together join to form a heterocyclyl ring.
  • a method for the treatment of mammal 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.
  • compositions containing the compounds which may also contain pharmaceutically acceptable carriers or diluents, which may be used for the treatment of 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.
  • 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.
  • 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.
  • a process for the preparation of compounds disclosed herein there is provided a process for the preparation of compounds disclosed herein.
  • the compounds of the present invention are screened as p38 kinase inhibitor
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms.
  • This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n- decyl, tetradecyl, and the like.
  • R ⁇ and R ⁇ are independently selected from hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or carboxy ⁇ , nitro or -SO m R ⁇ (wherein m is an integer from 0-2 and R ⁇ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl).
  • alkylene refers to a diradical branched or unbranched saturated hydrocarbon chain having from 1 to 6 carbon atoms and one or more hydrogen can optionally be substituted with alkyl, hydroxy, halogen or oximes. This term can be exemplified by groups such as methylene, ethylene, propylene isomers (e.g., -CH 2 CH 2 CH 2 and -CH(CH 3 )CH 2 ) and the like.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans or geminal geometry.
  • Alkenyl groups can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and -NR ⁇ - (wherein R ⁇ is the same as defined earlier), In the event that alkenyl is attached to a heteroatom, the double bond cannot be alpha to the heteroatom.
  • alkenylene refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 6 carbon atoms with cis, trans or geminal geometry. In the event that alkenylene is attached to the heteroatom, the 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 I.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms.
  • Alkynyl groups can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and -NR ⁇ - (wherein R ⁇ is the same as defined earlier). In the event that alkynyl groups are attached to a heteroatom, the triple bond cannot be alpha to the heteroatom.
  • alkynylene refers to a diradical of a triply- unsaturated hydrocarbon, preferably having from 2 to 6 carbon atoms. In the event that alkynylene is attached to the heteroatom, the triple 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 I.
  • 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 otherwise constrained by the definition.
  • Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like or multiple ring structures, including adamantanyl, and bicyclo [2.2.1] heptane or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like.
  • Cycloalkylalkyl refers to alkyl-cycloalkyl group linked through alkyl portion, wherein the alkyl and cycloalkyl are the same as defined earlier.
  • alkoxy denotes the group O-alkyl, wherein alkyl is the same as defined above.
  • aryl refers to aromatic system having 6 to 14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are carbocyclic aromatic groups.
  • Aryl groups optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S.
  • Groups such as phenyl, naphthyl, anthryl, biphenyl, and the like exemplify this term.
  • alkenyl refers to alkenyl-aryl linked through alkenyl (wherein alkenyl is as defined above) portion and the alkenyl portion contains 1 to 6 carbon atoms and aryl is as defined below.
  • aryloxy denotes the group O-aryl, wherein aryl is as defined above.
  • heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazoly], triazinyl, furanyl, benzofuranyl, indolyl, benzthiazinyl, benzthiazinonyl, benzoxazinyl, benzoxazinonyl, quinazonyl, carbazolyl phenothiazinyl, phenoxazinyl, benzothiazolyl or benzoxazolyl, and the like.
  • Heterocyclyl can optionally include rings having one or more double bonds. Such ring systems can be mono-, bi- or tricyclic. Carbonyl or sulfonyl group can replace carbon atom(s) of heterocyclyl. Unless otherwise constrained by the definition, the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring. Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefinic bond(s).
  • heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, benzoxazinyl, benzthiazinyl, imidazolyl, benzimidazolyl, tetrazolyl, carbaxolyl, indolyl, phenoxazinyl, phenothiazinyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, thiazolidinyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl, tetrahydropyranyl, piperazinyl, 3H-imidazo[4,5-b]pyridine, isoquinolinyl, lH-pyrrolo[2,3-b]pyridine or piperazinyl and the like.
  • Heteroarylalkyl refers to alkyl-heteroaryl group linked through alkyl portion, wherein the alkyl and heteroaryl are as defined earlier.
  • ' ⁇ eterocyclylalkyl refers to alkyl-heterocyclyl group linked through alkyl portion, wherein the alkyl and heterocyclyl are as defined earlier.
  • leaving group refers to groups that exhibit or potentially exhibit the properties of being labile under the synthetic conditions and also, of being readily separated from synthetic products under defined conditions.
  • leaving groups include, but are not limited to, halogen (e.g. , F, Cl, Br, I), triflates, tosylate, mesylates, alkoxy, thioalkoxy, or hydroxy radicals and the like.
  • protecting groups refers to moieties that prevent chemical reaction at a location of a molecule intended to be left unaffected during chemical modification of such molecule. Unless otherwise specified, protecting groups may be used on groups, such as hydroxy, amino, or carboxy. Examples of protecting groups are found in T. W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2 nd Ed., John Wiley and Sons, New York, N. Y., which is incorporated herein by reference. The species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting groups employed are not critical, as long as the derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed without disrupting the remainder of the molecule.
  • pharmaceutically acceptable salts refers to derivatives of compounds that can be modified by forming their corresponding acid or base salts.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acids salts of basic residues (such as amines), or alkali or organic salts of acidic residues (such as carboxylic acids), and the like.
  • pharmaceutically acceptable salts can also refer to a salt prepared from pharmaceutically acceptable non-toxic inorganic or organic acid. Examples of such inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitrous, nitric, carbonic, sulfuric, phosphoric acid, and the like.
  • organic acids include, but are not limited to aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic, benzenesulfonic, panthenic, toluenesulfonic, 2-hydroxyethanesulfonic acid and the like.
  • the compounds of the present invention may be prepared by techniques well known in the art and familiar to a practitioner skilled in art of this invention.
  • the compounds of the present invention may be prepared by processes described herein, which are not the only means by which the compounds described 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 XI can be prepared by following, for example, the reaction sequence as depicted in Scheme L
  • a compound of Formula II [wherein hal is halogen (Cl, Br or I)] can be reacted with a compound of Formula III (wherein R d is hydrogen, optionally substituted alkyl, cycloalkyl, or aryl) to give a compound of Formula IV, which can undergo reduction to give a compound of Formula V, which can be further oxidized to give a compound of Formula VI, which can be reacted with an ester of Formula VII (wherein R 1 is alkyl; R 1 and Z are the same as defined earlier) to give a compound of Formula VIII, which can be oxidized to give a compound of Formula IX (where R e is optionally substituted alkyl, cycloalkyl, aralkyl or aryl).
  • the compound of formula VIII (when R d is hydrogen) can be reacted with Formula XIII to give a compound of Formula XII (where R f is optionally substituted aralkyl).
  • the compound of Formula XII can be oxidized to give a compound of Formula IX (where R e is optionally substituted R d and R f ) which can be reacted with a compound of Formula X (wherein R 3 and R 4 are the same as defined earlier) to give a compound of Formula XL
  • reaction of a compound of Formula II with a compound of Formula III to give a compound of Formula IV is carried out in an organic solvent, for example tetrahydrofuran, N,N-dimethylformamide, dioxane or diethyl ether in the presence of a base, for example, triethylamine, tributylamine, N-ethyldiisopropylamine, N- methylmorpholine or pyridine.
  • organic solvent for example tetrahydrofuran, N,N-dimethylformamide, dioxane or diethyl ether
  • a base for example, triethylamine, tributylamine, N-ethyldiisopropylamine, N- methylmorpholine or pyridine.
  • the reduction of compound of Formula IV to give a compound of Formula V can be carried out in an organic solvent, for example, tetrahydrofuran, N,N- dimethylformamide, dioxane or diethylether with reducing agent, for example, lithium aluminium hydride, lithium borohydride, sodium cyanoborohydride or sodium borohydride.
  • organic solvent for example, tetrahydrofuran, N,N- dimethylformamide, dioxane or diethylether
  • reducing agent for example, lithium aluminium hydride, lithium borohydride, sodium cyanoborohydride or sodium borohydride.
  • the oxidation of a compound of Formula V to give a compound of Formula VI can be carried out in an organic solvent, for example, dichloromethane, dichloroethane, carbon tetrachloride or chloroform with an oxidizing agent for example, manganese dioxide, potassium permanganate, Dess-Martin periodinane (DMP), pyridinium dichromate (PDC), pyridinium chlorochromate (PCC) or chromic anhydride, although numerous other methods could be employed (see, for example, Advanced Organic Chemistry, 4 th Edn., Merck, John Wiley & Sons, 1992).
  • an organic solvent for example, dichloromethane, dichloroethane, carbon tetrachloride or chloroform
  • an oxidizing agent for example, manganese dioxide, potassium permanganate, Dess-Martin periodinane (DMP), pyridinium dichromate (PDC), pyridinium chlorochromate (PCC) or chromic an
  • reaction of a compound of Formula VI with a compound of Formula VII to give a compound of Formula VIII can be carried out in an organic solvent, for example, N- methylpyrrolidinone, N,N-dimethylformamide, dimethylsulphoxide, tetrahydrofuran, diethylether or dioxane in the presence of a base, for example, potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate, lithium bicarbonate, sodium bicarbonate, sodium hydride, potassium hydride, potassium tert-butoxide or sodium tert- butoxide.
  • organic solvent for example, N- methylpyrrolidinone, N,N-dimethylformamide, dimethylsulphoxide, tetrahydrofuran, diethylether or dioxane
  • a base for example, potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate, lithium bicarbonate, sodium bicarbonate, sodium hydride, potassium hydride, potassium tert-butoxid
  • reaction of compound of Formula VIII (when R d is hydrogen) with compound of Formula XIII to give a compound of Formula XII can be carried out in an organic solvent, for example, N-methylpyrrolidinone, N,N-dimethylformamide, dimethylsulphoxide, tetrahydrofuran, diethylether or dioxane in the presence of a base, for example, potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate, lithium bicarbonate, sodium bicarbonate, sodium hydride, potassium hydride, potassium tert-butoxide or sodium tert-butoxide.
  • organic solvent for example, N-methylpyrrolidinone, N,N-dimethylformamide, dimethylsulphoxide, tetrahydrofuran, diethylether or dioxane
  • a base for example, potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate, lithium bicarbonate, sodium bicarbonate, sodium hydride, potassium hydride,
  • the oxidation of a compound of Formula VIII to give a compound of Formula IX can be carried out with m-chloroperbenzoic acid or oxone (KHSO 5 ) in an organic solvent, for example, chloroform, carbon tetrachloride, dichloromethane, ethanol or tetrahydrofuran.
  • KHSO 5 m-chloroperbenzoic acid or oxone
  • the oxidation of compound of Formula XII to give a compound of Formula IX can be carried out with m-chloroperbenzoic acid or oxone (KHSO 5 ) in an organic solvent, for example, chloroform, carbon tetrachloride, dichloromethane, ethanol or tetrahydrofuran.
  • KHSO 5 m-chloroperbenzoic acid or oxone
  • reaction of a compound of Formula IX with a compound of Formula X to give a compound of Formula XI can be carried in the presence of a base, for example, pyridine, 2,6-lutidine, N-methylmorpholine, N-ethyldiisopropylamine, sodium hydride or triethylamine.
  • a base for example, pyridine, 2,6-lutidine, N-methylmorpholine, N-ethyldiisopropylamine, sodium hydride or triethylamine.
  • a compound of Formula VIIl can be reacted directly with a compound of Formula X to give a compound of Formula XI.
  • Step 4 (4R,5R)-5-(Hydroxymethyl)-N-isopropyl-1,3-dioxolane-4-carboxamide
  • sodium borohydride (1.696 g, 44.651 mmol) at 0 °C and stirred at room temperature overnight.
  • the reaction mixture was concentrated under reduced pressure and the residue so obtained was collected with ethyl acetate.
  • the ethyl acetate layer was washed with a saturated solution of aminonium chloride, dried over anhydrous sodium sulphate, filtered and evaporated under vacuum to afford the title compound as yellow oil. Yield: 3.20 g.
  • Step 5 (4R,5R)-N-Isopropyl-5-[(methylsulfonyl)methyl]-1,3-dioxolane-4- carboxamide
  • dichloromethane 20 ml
  • triethyl amine 4.216 g, 41.666 mmol
  • methanesulfonyl chloride 2.726 g, 23.809 mmol
  • Step 1 4-Methylamino-2-methylthio-pyrimidine-5-carboxylic acid ethyl ester To a suspension of ethyl-4-chloro-2-methylthio-5-pyrimidine-carboxylate
  • Step 5 6-(2-Chlorophenyl)-2-methanesulphonyl-8-methyI-8H-pyrido[2,3-d]pyrimidin-7-one
  • Example 3 Synthesis of 8-trifluoromethoxybenzyl-6-(2-methylphenyl)-2- (methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one
  • sodium hydride 50% dispersion in oil, 0.039 g, 0.972 mmol
  • 2-methylsulfanyl-6-(2-methylphenyl)-8H-pyrido[2,3- d]pyrimidin-7one (0.250 g, 0.883 mmol) was added at 0 °C and allowed the reaction mixture to come to room temperature.
  • Mass spectrum (m/z, positive ion mode): 538 [M + +1+2] and 536 [M + +1];
  • Mass spectrum (m/z, positive ion mode): 540 [M + +1+2] and 538 [M + +1];
  • Mass spectrum (m/z, positive ion mode): 498 [M + +1+2] and 496 [M + +1];
  • Example 5 P38 Inhibition Assays p38 MAP Kinase inhibitory potential was evaluated utilizing the proprietary IQ technology (Pierce, Rockford, IL). The assay incorporates an iron-containing compound that binds specifically to phosphate groups present on the fluorescent dye-labelled phosphorylated peptides, which in this case is the Epidermal
  • EGFR Growth Factor Receptor
  • This interfacial layer was washed by adding 5 ml of RPMI 1640 and centrifuged at 3000 rpm for 10 minutes at room temperature. The cell pellet was resuspended in a definite volume of RPMI 1640 and cells were counted using a haemocytometer.
  • the plate was incubated for 30 minutes at room temperature on rotatory shaker at 200 rpm. 50 ⁇ l of LPS (4 ⁇ g/ml) was added to each well except negative LPS control wells. The plate was incubated for IS minutes at room temperature on rotatory shaker at 200 rpm. Further, 30 ⁇ l of RPMI 1640 with 10 % FCS was added to all wells to make up the volume to 200 ⁇ l. AU NCE's and controls were set up in duplicate. The plate was incubated at 37 °C in a CO 2 incubator overnight. At the end of the incubation period, the plate was centrifuged at 3000 rpm for 10 minutes at 20° C. The supernatant was removed and preceded for (TNF- ⁇ ) estimation using a commercially available ELISA kit following the instructions given in the kit insert. A dose response curve was generated with different concentrations of inhibitor and the IC50 was calculated using Graph Pad Prism.
  • IC 50 from about 10,000 nM to about 70 nM, for example, from about 1000 nM to about 70 nM, or from about 500 nM to about 70 nM, or from about 200 nM to about 70 nM.
  • Compound Nos. 2, 5, 6, 15, 17, 18 and 20 exhibited cell-based assay results with IC 50 of from about 10,000 nM to about 200 nM, for example, from about 800 nM to about 200 nM.

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  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur des dérivés pyrido-pyrimidin-2-yl-aminométhyl-dioxolylés en tant qu'agents anti-inflammatoires. Les composés de cette invention ont été utiles pour l'inhibition et la prévention d'une inflammation et de pathologies associées comprenant les maladies inflammatoires et auto-immunes telles que la septicémie, la polyarthrite rhumatoïde, une maladie intestinale inflammatoire, le diabète de type 1, l'asthme, le trouble pulmonaire obstructif chronique, un rejet de transplantation d'organes et le psoriasis. Cette invention porte également sur des compositions pharmacologiques contenant les composés de la présente invention et sur les procédés de traitement de la septicémie, de la polyarthrite rhumatoïde, de la maladie intestinale inflammatoire, du diabète de type 1, de l'asthme, du trouble pulmonaire obstructif chronique, d'un rejet de transplantation d'organes et du psoriasis, et d'autres troubles inflammatoires et/ou auto-immuns, à l'aide des composés.
PCT/IB2007/055140 2006-12-21 2007-12-15 Agents anti-inflammatoires Ceased WO2008078249A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2753/DEL/2006 2006-12-21
IN2753DE2006 2006-12-21

Publications (1)

Publication Number Publication Date
WO2008078249A1 true WO2008078249A1 (fr) 2008-07-03

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PCT/IB2007/055140 Ceased WO2008078249A1 (fr) 2006-12-21 2007-12-15 Agents anti-inflammatoires

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WO (1) WO2008078249A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020243376A1 (fr) * 2019-05-31 2020-12-03 Agios Pharmaceuticals, Inc. Inhibiteurs hétérobicycliques de mat2a et procédés d'utilisation pour le traitement du cancer

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002018380A1 (fr) * 2000-08-31 2002-03-07 F. Hoffmann-La Roche Ag 7 oxo pyridopyrimidines comme inhibiteurs d'une proliferation cellulaire
WO2002064594A2 (fr) * 2001-02-12 2002-08-22 F. Hoffmann-La Roche Ag Pyrido-pyrimidines substituees en position 6
US20020137756A1 (en) * 2000-08-31 2002-09-26 Chen Jian Jeffrey 7-oxo-pyridopyrimidines (I)
WO2005034869A2 (fr) * 2003-10-08 2005-04-21 Irm Llc Composes et compositions convenant comme inhibiteurs de proteine-kinases

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002018380A1 (fr) * 2000-08-31 2002-03-07 F. Hoffmann-La Roche Ag 7 oxo pyridopyrimidines comme inhibiteurs d'une proliferation cellulaire
US20020137756A1 (en) * 2000-08-31 2002-09-26 Chen Jian Jeffrey 7-oxo-pyridopyrimidines (I)
WO2002064594A2 (fr) * 2001-02-12 2002-08-22 F. Hoffmann-La Roche Ag Pyrido-pyrimidines substituees en position 6
WO2005034869A2 (fr) * 2003-10-08 2005-04-21 Irm Llc Composes et compositions convenant comme inhibiteurs de proteine-kinases

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020243376A1 (fr) * 2019-05-31 2020-12-03 Agios Pharmaceuticals, Inc. Inhibiteurs hétérobicycliques de mat2a et procédés d'utilisation pour le traitement du cancer

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