WO2006129158A2 - 3 - indazolyl - isoxazoline derivatives as inhibitors of phosphodiesterase type - i - Google Patents

3 - indazolyl - isoxazoline derivatives as inhibitors of phosphodiesterase type - i Download PDF

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WO2006129158A2
WO2006129158A2 PCT/IB2006/001383 IB2006001383W WO2006129158A2 WO 2006129158 A2 WO2006129158 A2 WO 2006129158A2 IB 2006001383 W IB2006001383 W IB 2006001383W WO 2006129158 A2 WO2006129158 A2 WO 2006129158A2
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compound
formula
cyclopentyl
azaspiro
oxa
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PCT/IB2006/001383
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French (fr)
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WO2006129158B1 (en
WO2006129158A3 (en
Inventor
Venkata P. Palle
Sarala Balachandran
Lalit Kumar Baregama
Saswati Chakladar
Sarika Ramnani
Nagarajan Muthukamal
Abhijit Ray
Sunanda G. Dastidar
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Ranbaxy Laboratories Limited
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Priority to EP06744776A priority Critical patent/EP1891060A2/en
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Publication of WO2006129158A3 publication Critical patent/WO2006129158A3/en
Publication of WO2006129158B1 publication Critical patent/WO2006129158B1/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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to isoxazoline derivatives, which can be used as selective inhibitors of phosphodiesterase (PDE) type IV.
  • PDE phosphodiesterase
  • Compounds disclosed herein can be useful in treating AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis or other inflammatory diseases especially in humans.
  • COPD chronic obstructive pulmonary disease
  • psoriasis psoriasis
  • allergic rhinitis shock
  • atopic dermatitis Crohn's disease
  • ARDS adult respiratory distress syndrome
  • eosinophilic granuloma allergic conjunctivitis
  • osteoarthritis ulcerative co
  • cyclic adenosine-3 ',5 '-monophosphate exhibits an important role of acting as an intracellular secondary messenger (E. W. Sutherland, and T. W. Roll, Pharmacol.Rev,1960,12, 265). Its intracellular hydrolysis to adenosine 5 '-monophosphate (AMP) causes number of inflammatory conditions which are not limited to psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis.
  • ARDS adult respiratory distress syndrome
  • PDE cyclic nucleotide phosphodiesterases
  • PDE I, PDE II, PDE III, PDE IV, and PDE VII all use cAMP as a substrate, only the PDE IV and PDE VII types are highly selective for hydrolysis of cAMP.
  • Inhibitors of PDE, particularly the PDE IV inhibitors, such as rolipram or Ro- 1724 are therefore known as cAMP-enhancers.
  • Immune cells contain type IV and type III PDE, the PDE IV type being prevalent in human mononuclear cells. Thus the inhibition of phosphodiesterase type IV has been a target for modulation and, accordingly, for therapeutic intervention in a range of disease processes.
  • WO 03/47520 discloses substituted amino methyl factor Xa inhibitors.
  • US 2003176421, EP 1040829 discloses prokinetic agents for treating gastric hypomotility and related disorders.
  • WO 02/50070 discloses piperidine derivatives as subtype selective N- methyl-D-aspartate antagonists.
  • EP 1251128 discloses cyclohexylamine derivatives as subtype selective N-methyl-D-aspartate antagonists.
  • WO 00/59902 disclose aryl sulfonyls as factor Xa inhibitors.
  • WO 01/19798 discloses novel compounds as factor Xa inhibitors.
  • WO 99/23076, WO 99/23077 discloses indazole bioisostere replacement of catechol in therapeutically active compounds.
  • WO 97/49702 and WO 98/09961 disclose indazole derivatives and their use as inhibitor of phosphodiesterase type IV and production of tumor necrosis factor (TNF).
  • WO 97/48697 discloses substituted azabicyclo compounds and their use as inhibitors of the production of TNF and cyclic AMP phosphodiesterase.
  • WO 99/57951, US 6,339,099 discloses guanidine mimics as factor Xa inhibitor.
  • R 1 and R 2 can independently be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy, halogen or -OH; and
  • l-Cyclopentyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole Compound No. 1
  • l-Cyclopentyl-3-methyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole Compound No. 1
  • compositions comprising a therapeutically effective amount of one or more compounds described herein and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • provided are methods of treating AIDS, asthma, arthritis, bronchitis, chronic obstructer pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds described herein.
  • methods of preventing, inhibiting or suppressing inflammatory conditions comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds described herein.
  • processes for preparing a compound of Formula VII or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, diastereomer or N-oxide comprising the steps of:
  • hal can be Br, Cl or I
  • R 1 and R 2 can independently be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy, halogen or -OH;
  • R z can be -CH 2 COOalkyl
  • Re can be -COOalkyl or R z and Rq together join to form a cycloalkyl ring, wherein the cycloalkyl ring optionally contains one or more heteroatoms selected from oxygen or sulphur (when R 2 is -COOR 5 and R q is -CH 2 COOR 5 ); and Rs can be alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, aralkyl, heterocyclylalkyl or heteroarylalkyl.
  • processes for preparing a compound of Formula X or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, diastereomer or N-oxide thereof comprising the steps of:
  • R 1 and R 2 can be independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy, halogen or -OH; and 1383
  • t can be 0 or 1.
  • the present invention provides isoxazoline derivatives, which can be used in treating AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis or other inflammatory diseases, as well as processes for synthesizing such compounds.
  • COPD chronic obstructive pulmonary disease
  • psoriasis psoriasis
  • allergic rhinitis shock
  • atopic dermatitis Crohn's disease
  • ARDS adult respiratory distress syndrome
  • eosinophilic granuloma allergic conjunctivitis
  • osteoarthritis osteoarthritis
  • ulcerative colitis or other inflammatory diseases as well as processes for synthesizing such compounds.
  • compositions comprising compounds described herein and optionally one or more pharmaceutically acceptable carriers or diluents can be used in treating AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome, eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis or other inflammatory diseases.
  • COPD chronic obstructive pulmonary disease
  • R 1 and R 2 can independently be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy, halogen or -OH;
  • methods for the treatment or prophylaxis of inflammatory diseases comprising administering to a patient in need thereof an effective amount of one or more compounds described herein.
  • AIDS chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • psoriasis psoriasis
  • allergic rhinitis shock, atopic dermatitis, Crohn's disease
  • ARDS adult respiratory distress syndrome
  • eosinophilic granuloma allergic conjunctivitis
  • osteoarthritis ulcerative colitis or other inflammatory diseases
  • the compounds described herein were tested as phosphodiesterase type IV inhibitors. Therefore, pharmaceutical compositions for the possible treatment of diabetes and diabetes- associated complications are provided. In addition, the compounds can be administered orally or parenterally. The following definitions apply to terms as used herein.
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. Groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, n-hexyl, n-decyl, 006/001383
  • 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 (e.g, -CH 2 CH 2 CH 2 or - CH(CH 3 )CH 2 ) and the like.
  • substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl
  • 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.
  • 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 the heteroatom, the triple bond cannot be alpha to the heteroatom.
  • cycloalkyl refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a monocyclic ring or polycyclic (fused, spiro or bridged) rings, which may optionally contain one or more olefinic bonds, unless or otherwise constrained.
  • Such cycloalkyl groups include, by way of example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, or polycyclic ring structures such as, tricyclo[3.3.1.1]decane, bicyclo[2.2.2]octane, bicyclo[4.4.0]decane, bicyclo[4.3.0]nonane, bicyclo[3.3.0]octane, bicyclo [2.2.1] heptane and the like, or cyclic alkyl groups to which is fused an aryl group, for example indane, and the like.
  • aralkyl refers to aryl linked through an alkyl portion and the alkyl portion contains carbon atoms from 1-6 and aryl is the same as defined below.
  • aralkyl groups include benzyl and the like.
  • R 5 is the same
  • aryloxy refers to the group O-aryl, wherein aryl is the same as defined above.
  • heteroaryl refers to an aromatic monocyclic or polycyclic (fused, spiro or bridged) ring system containing 1-8 heteroatom(s) independently selected from N, O or S.
  • substituent(s) selected from halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl,
  • the substituents can be attached to the ring atom, be it carbon or heteroatom.
  • heteroaryl groups include pyridinyl, pyridazinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, carbazolyl, isobenzofuranyl, thianthrene, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, imidazolyl, tetrazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzoxazinonyl, benzothiazinonyl and the like.
  • heterocyclyl refers to nonaromatic monocyclic or polycyclic ring (fused, spiro or bridged) system having 1 to 8 heteroatoms selected from O, S or N.
  • heterocycles containing sulphur oxidized sulphur heterocycles containing SO or SO 2 are also included.
  • the substituents can be attached to the ring atom via carbon atom or heteroatom.
  • the heterocyclyl ring may optionally contain one or more olef ⁇ nic bond(s).
  • heterocyclyl groups include tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, piperidinyl, isoxazolinyl, thiazolinyl, thiazolidinonyl, oxazolinyl or oxazolidinonyl.
  • heteroarylalkyl refers to heteroaryl group linked through alkyl portion, wherein the alkyl and heteroaryl are the same as defined earlier.
  • heterocyclylalkyl refers to heterocyclyl group linked through alkyl portion, wherein the alkyl and heterocyclyl are the same as defined earlier.
  • halogen refers to fluorine, chlorine, bromine or iodine
  • leaving group generally refers to groups that exhibit the desirable properties of being labile under the defined synthetic conditions and also, being easily separated from synthetic products under defined conditions. Examples of such leaving groups include, but are not limited to, hal (Cl, Br, I), triflate, tosylate, 4- bromophenylsulfonate, 4-nitrophenylsulfonate, mesylate and the like.
  • protecting groups refers to known moieties which have the desirable property of preventing specific chemical reaction at a site on the molecule undergoing chemical modification intended to be left unaffected by the particular chemical modification. Also the term protecting group, unless or other specified may be used with groups such as hydroxy, amino, carboxy and examples of such 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 group employed is not so critical so long as the derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed at the appropriate point without disrupting the remainder of the molecule.
  • Each stereogenic 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.
  • 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.
  • 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.
  • the compounds of Formulae V, VI and VII can be prepared by following the procedure as described in Scheme I.
  • a compound of Formula I (wherein hal is Br, Cl or I; R 1 and R 2 are the same as described above) can be formylated to form a compound of Formula II.
  • the compound of Formula II can be reacted with hydroxylamine hydrochloride to form a compound of Formula III.
  • the compound of Formula III can be reacted with a compound of Formula IV [wherein R z is -CH 2 COOalkyl; Rq is -COOalkyl or R z and Rq may together join to form a cycloalkyl ring wherein the ring may optionally contain heteroatom selected from oxygen or sulphur] to form a compound of Formula V.
  • the compound of Formula V can be reduced (when R 2 is -COOR 5 and Rq is -CH 2 COORs) to form a compound of Formula VI.
  • the compound of Formula VI can be cyclized to form a
  • Compounds of Formula I can be formylated to form compounds of Formula II in the presence of one or more formylating agents, for example, dimethylformamide, triformamide, tris (diformylamino)methane, tris(dichloromethyl)amine or N,N,N,N-tetraformyl hydrazine.
  • the formylation reaction can also be carried out in the presence of one or more bases, for example, butyl lithium, pyridine, N-methylmorpholine or mixtures thereof.
  • the reaction can also be carried out in one or more organic solvents, for example, tetrahydrofuran, dimethylformamide, dioxane, diethylether or mixtures thereof.
  • Compounds of Formula II can be reacted with hydroxylamine hydrochloride to form compounds of Formula III in the presence of one or more bases, for example, sodium acetate, sodium carbonate, ammonium acetate, potassium carbonate or mixtures thereof.
  • bases for example, sodium acetate, sodium carbonate, ammonium acetate, potassium carbonate or mixtures thereof.
  • the reaction can also be carried out in one or more organic solvents, for example, ethanol, methanol, propanol, isopropylalcohol or mixtures thereof.
  • Compounds of Formula III can be reacted with compounds of Formula IV to form compounds of Formula V with one or more oxidants, for example, sodium hypochlorite, N- chlorosuccinimide, tert-butoxy chloride or mixtures thereof.
  • the reaction can also be carried out in the presence of one or more optional bases, for example, triethylamine, butyl lithium, N-methylmorpholine, diisopropylethylamine or mixtures thereof.
  • the reaction can also be carried out in one or more organic solvents, for example, tetrahydrofuran, dimethylformamide, diethylether, dioxane or mixtures thereof.
  • Compounds of Formula V can be reduced (when R z is -COOR 5 and R q is — CH 2 COORs) to form compounds of Formula VI in the presence of one or more reducing agents, for example, sodium borohydride, sodium cyanoborohydride or mixtures thereof.
  • the reduction reaction can also be carried out in one or more organic solvents, for example, tetrahydrofuran, dimethylformamide, diethylether, dioxane or mixtures thereof.
  • Compounds of Formula VI can be ring cyclized to form compounds of Formula VII in the presence of a redox couple.
  • the oxidizing part of the redox couple can be selected from diisopropylazodicarboxylate (DIAD), diethylazodicarboxylate (DEAD), N 5 N 5 N', N'- tetramethylazodicarboxylate (TMAD) 5 l,l'-(azodicarbonyl) dipiperidine (ADDP), cyanomethylenetributylphosphorane (CMBP) 5 4,7-dimethyl-3,5,7-hexahydro-l,2 5 4,7- tetrazocin-3,8-dione (DHTD) orN,N,N' 5 N,'-tetraisopropylazodicarboxamide (TIPA).
  • DIAD diisopropylazodicarboxylate
  • DEAD diethylazodicarboxylate
  • TMAD N 5 N 5 N
  • the reduction part of the redox couple can be a phosphine reagent selected from trialkylphosphine (such as tributylphosphine), triarylphosphine (such as triphenylphosphine), tricycloalkylphosphine (such as triscyclohexylphosphine) or tetraheteroarylphosphine.
  • Phosphine reagents having a combination of aryl, alkyl or heteroaryl substituents may also be used (such as diphenylpyridylphosphine).
  • the reaction can also be carried out in one or more organic solvents, for example, tetrahydrofuran, dimethylformamide, dioxane, diethyl ether or mixtures thereof.
  • Compounds prepared following Scheme I include, for example: l-Cyclopentyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole (Compound No. 1), l-Cyclopentyl-3-methyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole (Compound No. 2), l-Cyclopentyl-3-ethyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole (Compound No.
  • the compounds of Formula IX and X can be prepared by following the procedure as depicted in Scheme II.
  • a compound of Formula III (where R 1 and R 2 are the same as depicted earlier) can be reacted with a compound of Formula VIII to form a compound of Formula IX (where t is O or 1).
  • the compound of Formula VIII can be deprotected to form a compound of Formula X.
  • Compounds of Formula III can be reacted with compounds of Formula VIII to form compounds of Formula IX in the presence of one or more oxidants, for example sodium hypochlorite, N-chlorosuccinimide, tert-butoxy chloride or mixtures thereof.
  • the reaction can also be carried out in the presence of one or more optional bases, for example, triethylamine, butyl lithium, N-methylmorpholine, diisopropylethylamine or mixtures thereof.
  • the reaction can also be carried out in one or more organic solvents, for example, tetrahydrofuran, dimethylformarnide, diethylether, dioxane or mixtures thereof.
  • Compounds of Formula IX can be deprotected to form compounds of Formula X in the presence of one or more deprotection agents, for example, methanol in hydrochloric acid or ethanol in hydrochloric acid.
  • Compounds prepared following Scheme II include, for example: 3-(l-Cyclopentyl-lH-indazol-6-yl)-l-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylate (Compound No. 10), rert-butyl 3-(l-cyclopentyl-3-methyl-lH-indazol-6-yl)-l-oxa-2,8-diazaspiro[4.5]dec-2-ene-8- carboxylate (Compound No.
  • Compounds of Formula Ia and pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides thereof may be advantageously used in combination with one or more other therapeutic agents.
  • other therapeutic agents include one or more of corticosteroids, beta agonists, leukotriene antagonists, 5-lipoxygenase inhibitors, chemokine inhibitors, muscarinic receptor antagonists or mixtures thereof.
  • compositions described herein can be produced and administered in dosage units, each unit containing a specified amount of one or more compounds described herein and/or one or more pharmaceutically acceptable addition salt thereof.
  • the dosage may be varied over wide limits, as the compounds are effective at low dosage levels and relatively free of toxicity.
  • Such compounds may be administered in the low micromolar concentration, which is therapeutically effective, and the dosage may be increased as desired up to the maximum dosage tolerated by the patient.
  • the compounds described herein can be produced and formulated as racemic mixtures, enantiomers, diastereomers, rotamers, N-Oxides, polymorphs, solvates and pharmaceutically acceptable salts, as well as the active metabolites.
  • Pharmaceutical compositions comprising the compounds described herein or metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with one or more pharmaceutically acceptable carriers and optionally included excipients can also be produced. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims. Examples
  • Step a l-Cyclopentyl-l ⁇ -indazole- ⁇ -carboxaldehyde
  • Step b l-Cvclopentyl-lH-indazole-6-carboxaldehyde oxime
  • Tetrahydrofuran (5 ml) was added to a mixture of compound obtained from step b above (300 mg, 1.310 mmol) and dimethyl-2-methylenesuccinate (414 mg, 2.620 mmol) and the reaction mixture was stirred for 10 minutes at room temperature.
  • Sodium hypochlorite (3 ml) was added with vigorous stirring to the reaction mixture and then further stirred for 15 hours.
  • the solvent was evaporated under reduced pressure and the residue was extracted with ethyl acetate.
  • the organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure.
  • the residue thus obtained was purified by column chromatography using ethyl acetate in hexane solvent mixture as eluent to furnish the title compound. Yield: 410 mg.
  • Step d 2-f3-(l-Cyclopentyl-lH-mdazol-6-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5- yl] ethanol (Compound No . 21 )
  • Sodium borohydride (0.296 g, 7.792 mmol) was added to a solution of the compound obtained from step c above (0.500 g, 1.298 mmol) in tetrahydrofuran and stirred for 15 minutes at 0-5 0 C.
  • Methanol 1.0 ml was added to the resulting reaction mixture.
  • the reaction mixture was stirred for 14 hours at room temperature, quenched with ammonium chloride solution and extracted with ethyl acetate.
  • Example 5 Synthesis of hydrochloride salt of 3-(l-cyclopentyl-lH-indazol-6-yl)-l-oxa-2,8- diazaspiro[4.5]dec-2-ene (Compound No. 16)
  • a solution of the Compound No. 10 (0.21Og, 0.495mmol) obtained in Example 4 in methanolic hydrochloric acid (5.9 ml, 29.3 mmol) was stirred at room temperature for 14 hours. The solvent was evaporated under reduced pressure and the residue thus obtained was washed with ether and dried under high vacuum to furnish the title compound. Yield: 0.090 g- Mass (m/z): 325.2 (M + +!).
  • Example 6 Efficacy of Compounds as PDE IV Inhibitors PDE-IV Enzyme Assay The efficacy of compounds as PDE-4 inhibitor was determined by an enzyme assay (Burnouf et al; J. Med. Chem. 2000, 43:4850-4867).
  • the PDE-4 enzyme source used was U937 cell cytosolic fraction prepared by sonication. The enzyme reaction was carried out, with the cytosolic fraction as the enzyme source, in the presence of cAMP (1 ⁇ M) at 3O 0 C in the presence or absence of NCE for 45 -60 min. An aliquot of this reaction mixture was taken further for the ELISA assay to determine level of cAMP in the sample. The concentration of the cAMP in the sample directly correlates with the degree of PDE-4 enzyme inhibition.
  • PDE-IV enzyme assay results were expressed as percent control and the IC 5O values of compounds disclosed herein were from about 0.1 nM to about 10,000 nM, from about 0.1 nM to about 2600 nM, from about 0.1 nM to about 215 nM, and even from about 0.1 nM to about 35 nM.
  • the level of TNF- ⁇ in treated wells was compared with the vehicle treated controls and inhibitory potency of compound was expressed as ICs 0 values calculated by using Graph pad prism and were from about 385 nM to about 8400 nM, from about 385 nM to about 2400 nM and even from about 385 nM to about 1600 nM.

Abstract

The present invention relates to isoxazoline derivatives, of formula (I a) which can be used as selective inhibitors of phosphodiesterase (PDE) type IV. Compounds disclosed herein can be useful in treating AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis or other inflammatory diseases especially in humans. Processes for preparing compounds described herein are provided, as well as pharmaceutical compositions comprising compounds described herein, and their use as phosphodiesterase (PDE) type IV inhibitors.

Description

INHIBITORS OF PHOSPHODIESTERASE TYPE-IV
Field of the Invention
The present invention relates to isoxazoline derivatives, which can be used as selective inhibitors of phosphodiesterase (PDE) type IV. Compounds disclosed herein can be useful in treating AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis or other inflammatory diseases especially in humans. Processes for preparing compounds described herein are provided, as well as pharmaceutical compositions comprising compounds described herein, and their use as phosphodiesterase (PDE) type IV inhibitors.
Background of the Invention
It is known that cyclic adenosine-3 ',5 '-monophosphate (cAMP) exhibits an important role of acting as an intracellular secondary messenger (E. W. Sutherland, and T. W. Roll, Pharmacol.Rev,1960,12, 265). Its intracellular hydrolysis to adenosine 5 '-monophosphate (AMP) causes number of inflammatory conditions which are not limited to psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis. The most important role in the control of cAMP (as well as of cGMP) levels is played by cyclic nucleotide phosphodiesterases (PDE) which represent a biochemically and functionally, highly variable superfamily of the enzyme; eleven distinct families with more than twenty five gene products are currently recognized. Although PDE I, PDE II, PDE III, PDE IV, and PDE VII all use cAMP as a substrate, only the PDE IV and PDE VII types are highly selective for hydrolysis of cAMP. Inhibitors of PDE, particularly the PDE IV inhibitors, such as rolipram or Ro- 1724 are therefore known as cAMP-enhancers. Immune cells contain type IV and type III PDE, the PDE IV type being prevalent in human mononuclear cells. Thus the inhibition of phosphodiesterase type IV has been a target for modulation and, accordingly, for therapeutic intervention in a range of disease processes.
The initial observation that xanthine derivatives, theophylline and caffeine inhibit the hydrolysis of cAMP led to the discovery of the required hydrolytic activity in the cyclic nucleotide phosphodiesterase (PDE) enzymes. More recently, distinct classes of PDE have been recognized (J. A. Bervo and D.H. Reifsnyder, TIPS, 1990,11,150), and their selective inhibition has led to improved drug therapy (CD. Nicholus, R.A. Challiss and M. Shahid, TIPS, 1991, 12, 19). Thus it was recognized that inhibition of PDE IV could lead to inhibition of inflammatory mediator release (M.W. Verghese et. al, J. MoI. Cell. Cardiol., 1989, 12 (Suppl.II), S 61).
WO 03/47520 discloses substituted amino methyl factor Xa inhibitors. US 2003176421, EP 1040829 discloses prokinetic agents for treating gastric hypomotility and related disorders. WO 02/50070 discloses piperidine derivatives as subtype selective N- methyl-D-aspartate antagonists. EP 1251128 discloses cyclohexylamine derivatives as subtype selective N-methyl-D-aspartate antagonists. WO 00/59902 disclose aryl sulfonyls as factor Xa inhibitors. WO 01/19798 discloses novel compounds as factor Xa inhibitors. WO 99/23076, WO 99/23077 discloses indazole bioisostere replacement of catechol in therapeutically active compounds. WO 97/49702 and WO 98/09961 disclose indazole derivatives and their use as inhibitor of phosphodiesterase type IV and production of tumor necrosis factor (TNF). WO 97/48697 discloses substituted azabicyclo compounds and their use as inhibitors of the production of TNF and cyclic AMP phosphodiesterase. WO 99/57951, US 6,339,099 discloses guanidine mimics as factor Xa inhibitor.
In view of the above, there remains a need for novel PDE IV inhibitors. Summary of the Invention Provided are compounds having the structure of Formula Ia,
Figure imgf000004_0001
Formula Ia
R1 and R2 can independently be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy, halogen or -OH; and
R3 and R4 can independently be selected from hydroxyalkyl or R3 and R4 together join to form mono or bicyclic ring containing 3-12 carbon atom, wherein the ring optionally contains 1-3 heteroatoms selected from oxygen, sulphur or-NRa (wherein Ra can be hydrogen, aralkyl, -(C=O)OC(CH3)3, - (=O)OC(CH3)2CHBr2 or -C(=O)OC(CH3)2CC13).
In another aspect, provided are compounds selected from: l-Cyclopentyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole (Compound No. 1), l-Cyclopentyl-3-methyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole (Compound No.
2), l-Cyclopentyl-3-ethyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole (Compound No.
3), l-Cyclopentyl-6-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No. 4), l-Cyclopentyl-3-methyl-6-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No.
5), l-Cyclopentyl-3-ethyl-6-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No.
6),
3-(l-Cyclopentyl-lH-indazol-6-yl)-l-oxa-2-azaspiro[4.5]dec-2-ene (Compound No. 7),
3 -( 1 -Cyclopentyl-3 -methyl- lH-indazol-6-yl)- 1 -oxa-2-azaspiro [4.5] dec-2-ene (Compound No .
8), 3-(l-Cyclopentyl-3-ethyl-lH-indazol-6-yl)-l-oxa-2-azaspiro[4.5]dec-2-ene (Compound No.
9),
3-(l-Cyclopentyl-lH-indazol-6-yl)-l-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylate
(Compound No. 10), Zert-butyl 3-(l-cyclopentyl-3-methyl-lH-indazol-6-yl)-l-oxa-2,8-diazaspiro[4.5]dec-2-ene-8- carboxylate (Compound No. 11),
Zert-butyl 3-(l-cyclopentyl-3-ethyl-lH-indazol-6-yl)-l-oxa-2,8-diazaspiro[4.5]dec-2-ene-8- carboxylate (Compound No. 12), l-Cyclopentyl-6-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No. 13), l-Cyclopentyl-6-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)-3-methyl-lH-indazole
(Compound No. 14), l-Cyclopentyl-6-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)-3-ethyl-lH-indazole (Compound
No. 15),
Hydrochloride salt of 3-(l-cyclopentyl-lH-indazol-6-yl)-l-oxa-2,8-diazaspiro[4.5]dec-2-ene (Compound No. 16),
Hydrochloride salt of 3 -( 1 -cyclopentyl-3 -methyl- lH-indazol-6-yl)- 1 -oxa-2 ,8- diazaspiro[4.5]dec-2-ene (Compound No. 17),
Hydrochloride salt of 3-(l-cyclopentyl-3-ethyl-lH-indazol-6-yl)-l-oxa-2,8- diazaspiro[4.5]dec-2-ene (Compound No. 18), 2-[3-(l-Cyclopentyl-3-methyl-lH-indazol-6-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5- yljethanol (Compound No. 19),
2-[3-(l-Cyclopentyl-3-ethyl-lH-indazol-6-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5- yl]ethanol (Compound No. 20),
2-[3-(l-Cyclopentyl-lH-indazol-6-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5-yl]ethanol (Compound No. 21),
3-(l-Cyclopentyl-3-methyl-lH-indazol-6-yl)-l,8-dioxa-2-azaspiro[4.5]dec-2-ene (Compound
No. 22),
3-(l-Cyclopentyl-3-ethyl-lH-indazol-6-yl)-l,8-dioxa-2-azaspiro[4.5]dec-2-ene (Compound
No. 23), 3-Ethyl-l-methyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole (CompoundNo. 24), 3-Ethyl-l-methyl-6-(l -oxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No. 25), 3-(3-Ethyl-l-methyl-lH-indazol-6-yl)-l-oxa-2-azaspiro[4.5]dec-2-ene (Compound No. 26), 2-[3-(3-Ethyl-l-methyl-lH-indazol-6-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5- yl]ethanol (Compound No. 27), 6-(l,7-Dioxa-2-azaspiro[4.4]non-2-en-3-yl)-3-ethyl-l-methyl-lH-indazole (Compound No. 28), l,3-Dimethyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole (Compound No. 29), l,3-Dimethyl-6-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No. 30), 3-(l,3-Dimethyl-lH-indazol-6-yl)-l-oxa-2-azaspiro[4.5]dec-2-ene (Compound No. 31), 2-[3-(l,3-Dimethyl-lH-indazol-6-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5-yl]ethanol (Compound No. 32),
6-(l,7-Dioxa-2-azaspiro[4.4]non-2-en-3-yl)-l,3-dimethyl-lH-indazole (Compound No. 33), l-Cyclopentyl-3-ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No. 34), 3 -( 1 -Cyclopentyl-3 -ethyl- lH-indazol-5 -yl)- 1 -oxa-2-azaspiro [4.5] dec-2-ene (Compound No . 35),
2-[3-(l-Cyclopentyl-3-ethyl-lH-indazol-5-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5- yl]ethanol (Compound No. 36), or l-Cyclopentyl-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)-3-ethyl-lH-indazole (Compound No. 37).
In another aspect, provided are pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds described herein and one or more pharmaceutically acceptable carriers, excipients or diluents.
In another aspect, provided are methods of treating AIDS, asthma, arthritis, bronchitis, chronic obstructer pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds described herein In yet another aspect, provided are methods of preventing, inhibiting or suppressing inflammatory conditions comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds described herein.
In another aspect, provided are processes for preparing a compound of Formula VII or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, diastereomer or N-oxide comprising the steps of:
a. formylating a compound of Formula I
Figure imgf000007_0001
Formula I to form a compound of Formula II
Figure imgf000007_0002
Formula Il b. reacting the compound of Formula II with hydroxylamine hydrochloride to form a compound of Formula III,
Figure imgf000007_0003
Formula III c. reacting the compound of Formula III with a compound of Formula IV
Figure imgf000007_0004
Formula IV to form a compound of Formula V,
Figure imgf000008_0001
Formula V c. reducing the compound of Formula V to form a compound of Formula VI,
Figure imgf000008_0002
Formula Vl d. cyclizing a compound of Formula VI to form a compound of Formula VII,
Figure imgf000008_0003
Formula VIl
wherein
hal can be Br, Cl or I;
R1 and R2 can independently be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy, halogen or -OH;
Rz can be -CH2COOalkyl;
Re can be -COOalkyl or Rz and Rq together join to form a cycloalkyl ring, wherein the cycloalkyl ring optionally contains one or more heteroatoms selected from oxygen or sulphur (when R2 is -COOR5 and Rq is -CH2COOR5); and Rs can be alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, aralkyl, heterocyclylalkyl or heteroarylalkyl.
In another aspect, provided are processes for preparing a compound of Formula X or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, diastereomer or N-oxide thereof comprising the steps of:
a. reacting a compound of Formula III
Figure imgf000009_0001
with a compound of Formula VIII
Figure imgf000009_0002
Formula VIlI to form a compound of Formula IX, and
Figure imgf000009_0003
Formula IX b. deprotecting a compound of Formula IX to form a compound of Formula X,
Figure imgf000009_0004
Formula X wherein R1 and R2 can be independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy, halogen or -OH; and 1383
t can be 0 or 1.
Detailed Description of the Invention
The present invention provides isoxazoline derivatives, which can be used in treating AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis or other inflammatory diseases, as well as processes for synthesizing such compounds.
Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-oxides of such compounds described herein having the same type of activity are also provided.
Pharmaceutical compositions comprising compounds described herein and optionally one or more pharmaceutically acceptable carriers or diluents can be used in treating AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome, eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis or other inflammatory diseases.
Other aspects will be set forth in the 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, provided are compounds having the structure of Formula Ia:
Figure imgf000010_0001
or their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-oxides, wherein
R1 and R2 can independently be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy, halogen or -OH; R3 and R4 can independently be hydroxyalkyl or R3 and R4 may together join to form mono or bicyclic ring containing 3-12 carbon atoms, wherein the ring may optionally contain 1-3 heteroatoms selected from oxygen, sulphur or -NRa (wherein Ra is hydrogen, aralkyl, -(C=O)OC(CH3)3, -C(=O)OC(CH3)2CHBr2 or - C(=O)OC(CH3)2CC13); In accordance with a second aspect, provided are methods for the treatment or prophylaxis of inflammatory diseases comprising administering to a patient in need thereof an effective amount of one or more compounds described herein.
In accordance with a third aspect, provided are methods for the treatment or prophylaxis of AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis or other inflammatory diseases comprising administering to a patient in need thereof an effective amount of one or more compounds described herein.
In accordance with a fourth aspect, provided are processes for preparing compounds described herein.
The compounds described herein were tested as phosphodiesterase type IV inhibitors. Therefore, pharmaceutical compositions for the possible treatment of diabetes and diabetes- associated complications are provided. In addition, the compounds can be administered orally or parenterally. 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. Groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n-pentyl, n-hexyl, n-decyl, 006/001383
11 tetradecyl, and the like exemplify this term. Alkyl groups may further be substituted with one or more substituents selected from alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, thioacyl, acyloxy, cycloalkyloxy, heterocyclyloxy, azido, cyano, halogen, hydroxy, thiol, aryloxy, heteroaryloxy, aminosulfonyl, -COOR5 (wherein R5 is alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, aralkyl, heterocyclylalkyl or heteroarylalkyl), -NHR2, -NRxRy, -C(=O)NRxRy, - OC(=O)NRxRy (wherein R2 is the same as defined earlier; Rx and Ry are independently selected from R5 or Rx and Ry may together join to form cycloalkyl, heteroaryl or heterocyclyl ring), nitro, or -S(O)1nR6 (wherein m is an integer from 0-2 and R6 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or NRxRy). Unless otherwise constrained, all substituents may be further substituted by 1-3 substituents selected from alkyl, -COOR5, -NHR2, -NRxRy, -C(=0)NRxRy, -0C(=0)NRxRy, hydroxy, alkoxy, halogen, CF3, cyano or -S(O)mR6. Alkyls groups may also be interrupted by 1-5 atoms or groups independently selected from oxygen, sulfur or -NRa- (where Ra is selected from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, acyl, aralkyl, -COOR5, - SO2R6, -C(=O)NRxRy).
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 (e.g, -CH2CH2CH2 or - CH(CH3)CH2) and the like. Alkylene groups may further be substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, thioacyl, acyloxy, cycloalkyloxy, heterocyclyloxy, azido, cyano, halogen, hydroxy, thiol, aryloxy, heteroaryloxy, aminosulfonyl, -COOR5 (wherein R5 is the same as defined earlier), -NHR2, - NRxRy, -C(=O)NRxRy, -0C(=0)NRxRy (wherein R2, Rx and Ry are the same as defined earlier), nitro, or -S(O)H1R6 (wherein m and R6 is the same as defined earlier). Unless otherwise constrained, all substituents may be further substituted by 1-3 substituents selected from alkyl, -COOR5, -NHR2, -NRxRy, -C(=0)NRxRy, -OC(O)NRxRy, hydroxy, alkoxy, halogen, -CF3, cyano or -S(O)1nR6. Alkylene groups may also be interrupted by 1-5 atoms of groups independently selected from oxygen, sulfur or -NRa (wherein Ra is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl, -COOR5, - SO2R6, -C(=0)NRxRy).
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. Alkenyl groups may further be substituted with one or more substituents selected from the group alkyl, alkynyl, alkoxy, cycloalkyl, acyl, thioacyl, acyloxy, cycloalkyloxy, heterocyclyloxy, heteroaryloxy, -COOR5 (wherein R5 is the same as defined earlier), -NHR2, -NRxRy, -C(=0)NRxRy, -0C(=0)NRxRy (wherein R2, Rx and Ry are the same as defined earlier), azido, cyano, halogen, hydroxy, thiol, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, aminosulfonyl, alkoxyamino, nitro, or -S(O)H1R6 (wherein R6 and m are the same as defined earlier). Unless otherwise constrained, all substituents may optionally be further substituted by 1-3 substituents selected from alkyl, -COOR5, hydroxy, alkoxy, halogen, -CF3, cyano, -NHR2, -NRxRy, -C(=0)NRxRy, -0C(=0)NRxRy or -S(O)1nR6.
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 the heteroatom, the triple bond cannot be alpha to the heteroatom. Alkynyl groups may further be substituted with one or more substituents selected from alkyl, alkenyl, alkoxy, cycloalkyl, acyl, thioacyl, acyloxy, azido, cyano, halogen, hydroxy, thiol, heteroaryloxy, heterocyclyloxy, cycloalkyloxy, aryl, aralkyl, aryloxy, aminosulfonyl, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, -COOR5 (wherein R5 is the same as defined earlier), -NHR2, -NRxRy, -C(=0)NRxRy, -OC(=O)NRxRy (wherein R2, Rx and Ry are the same as defined earlier), or -S(O)H1R6 (wherein R6 and m are the same as defined earlier). Unless otherwise constrained, all substituents may optionally be further substituted by 1-3 substituents selected from alkyl, -COOR5, hydroxy, alkoxy, halogen, -CF3, -NHR2, - NRxRy, -C(=0)NRxRy, -C(=0)NRxRy, cyano or -S(O)1nR6.
The term "cycloalkyl" unless otherwise specified refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a monocyclic ring or polycyclic (fused, spiro or bridged) rings, which may optionally contain one or more olefinic bonds, unless or otherwise constrained. Such cycloalkyl groups include, by way of example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like, or polycyclic ring structures such as, tricyclo[3.3.1.1]decane, bicyclo[2.2.2]octane, bicyclo[4.4.0]decane, bicyclo[4.3.0]nonane, bicyclo[3.3.0]octane, bicyclo [2.2.1] heptane and the like, or cyclic alkyl groups to which is fused an aryl group, for example indane, and the like. Cycloalkyl groups may further be substituted with one or more substituents selected alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, thioacyl, acyloxy, heteroaryloxy, heterocyclyloxy, azido, cyano, halogen, hydroxy, thiol, aryl, aralkyl, aryloxy, aminosulfonyl, -COOR5 (wherein R5 is the same as defined earlier), -NHRZj -NRxRy, -C(=0)NRxRy, -
OC(=O)NRxRy (wherein R2, Rx and Ry are the same as defined earlier), nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, or S(O)1nR6 (wherein R6 and m are the same as defined earlier). Unless otherwise constrained, all substituents may optionally be further substituted by 1-3 substituents selected from alkyl, hydroxy, alkoxy, halogen, CF3, -NHR2, - NRxRy, -C(=0)NRxRy, -0C(=0)NRxRy, cyano or -S(O)1nR6.
The term "aralkyl" unless otherwise specified refers to aryl linked through an alkyl portion and the alkyl portion contains carbon atoms from 1-6 and aryl is the same as defined below. The examples of aralkyl groups include benzyl and the like.
The term "aryl" unless otherwise specified refers to a carbocyclic aromatic group, for example, phenyl, naphthyl or anthryl ring and the like optionally substituted with 1 to 3 substituents selected from halogen (F, Cl, Br, I), hydroxy, -COOR5 (wherein R5 is the same as defined earlier), alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, heterocyclyloxy, heteroaryloxy, cycloalkyloxy, acyl, thioacyl, aryloxy, cyano, nitro, -NRxRy, -C(=O)NRxRy, -NHR2, -(SO)1nR6 (wherein R2, R6, Rx, Ry and m are the same as defined earlier), aryl, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl. Aryl groups may optionally be fused with cycloalkyl groups, heteroaryl groups or heterocyclyl groups.
The term "aryloxy" unless otherwise specified refers to the group O-aryl, wherein aryl is the same as defined above. The term "heteroaryl" unless otherwise specified refers to an aromatic monocyclic or polycyclic (fused, spiro or bridged) ring system containing 1-8 heteroatom(s) independently selected from N, O or S. Heteroaryl rings can optionally be substituted with 1 to 3 substituent(s) selected from halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, aryloxy, cycloalkyloxy, acyl, thioacyl, -COOR5 (wherein R5 is the same as defined earlier), aryl, alkoxy, aralkyl, cyano, nitro, -NHR2, -NRxR5,, -C(=O)NRxRy, -S(O)mR6> or -OC(=O)NRxRy (wherein m, Rz, R61Rx and Ry are the same as defined earlier). Unless otherwise constrained, the substituents can be attached to the ring atom, be it carbon or heteroatom. Examples of heteroaryl groups include pyridinyl, pyridazinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, carbazolyl, isobenzofuranyl, thianthrene, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, imidazolyl, tetrazolyl, quinolinyl, isoquinolinyl, quinazolinyl, benzoxazinonyl, benzothiazinonyl and the like.
The term "heterocyclyl" unless otherwise specified refers to nonaromatic monocyclic or polycyclic ring (fused, spiro or bridged) system having 1 to 8 heteroatoms selected from O, S or N. For heterocycles containing sulphur, oxidized sulphur heterocycles containing SO or SO2 are also included. The heterocyclyl ring system can be optionally benzofused or fused with heteroaryl and/or are optionally substituted, wherein the substituents are selected from halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, thioacyl, aryl, alkoxy, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, aryloxy, cyano, nitro, -COOR5 (wherein R5 is the same as defined earlier), -C(=0)NRxRy, S(O)1nR6, -0C(=0)NRxRy, -NHR2, or -NRxRy (wherein m, R2, Rx and Ry are the same as defined earlier). Unless or otherwise constrained, the substituents can be attached to the ring atom via carbon atom or heteroatom. Also, unless otherwise constrained the heterocyclyl ring may optionally contain one or more olefϊnic bond(s). Examples of heterocyclyl groups include tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, piperidinyl, isoxazolinyl, thiazolinyl, thiazolidinonyl, oxazolinyl or oxazolidinonyl.
The term "heteroarylalkyl" unless otherwise specified refers to heteroaryl group linked through alkyl portion, wherein the alkyl and heteroaryl are the same as defined earlier. The term "heterocyclylalkyl" unless otherwise specified refers to heterocyclyl group linked through alkyl portion, wherein the alkyl and heterocyclyl are the same as defined earlier.
The term "acyl" unless otherwise specified refers to — C(=0)R" wherein R" is selected from the group alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl .
The term "thioacyl" unless otherwise specified refers to — C(=S)R" wherein R" is the same as defined above;
The term "halogen " unless otherwise specified refers to fluorine, chlorine, bromine or iodine;
The term "leaving group " unless otherwise specified generally refers to groups that exhibit the desirable properties of being labile under the defined synthetic conditions and also, being easily separated from synthetic products under defined conditions. Examples of such leaving groups include, but are not limited to, hal (Cl, Br, I), triflate, tosylate, 4- bromophenylsulfonate, 4-nitrophenylsulfonate, mesylate and the like.
The term "protecting groups" unless otherwise specified refers to known moieties which have the desirable property of preventing specific chemical reaction at a site on the molecule undergoing chemical modification intended to be left unaffected by the particular chemical modification. Also the term protecting group, unless or other specified may be used with groups such as hydroxy, amino, carboxy and examples of such groups are found in T. W. Greene and P.G.M. Wuts, "Protective groups in organic synthesis", 2nd 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 group employed is not so critical so long as the derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed at the appropriate point without disrupting the remainder of the molecule.
Compounds described herein contain one or more asymmetric carbon atoms and thus can exist as racemic mixtures, enantiomers or diastereomers. These compounds also exist as conformers/rotamers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic 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.
The term "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.
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.
Compounds described herein may be prepared by techniques well known in the art and familiar to a practitioner skilled in art of this invention, hi addition, compounds described herein may be prepared by processes described herein, although such processes 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 form the desired compounds.
Scheme I
V
Figure imgf000018_0001
The compounds of Formulae V, VI and VII can be prepared by following the procedure as described in Scheme I. Thus a compound of Formula I (wherein hal is Br, Cl or I; R1 and R2 are the same as described above) can be formylated to form a compound of Formula II. The compound of Formula II can be reacted with hydroxylamine hydrochloride to form a compound of Formula III. The compound of Formula III can be reacted with a compound of Formula IV [wherein Rz is -CH2COOalkyl; Rq is -COOalkyl or Rz and Rq may together join to form a cycloalkyl ring wherein the ring may optionally contain heteroatom selected from oxygen or sulphur] to form a compound of Formula V. The compound of Formula V can be reduced (when R2 is -COOR5 and Rq is -CH2COORs) to form a compound of Formula VI. The compound of Formula VI can be cyclized to form a compound of Formula VII.
Compounds of Formula I can be formylated to form compounds of Formula II in the presence of one or more formylating agents, for example, dimethylformamide, triformamide, tris (diformylamino)methane, tris(dichloromethyl)amine or N,N,N,N-tetraformyl hydrazine. The formylation reaction can also be carried out in the presence of one or more bases, for example, butyl lithium, pyridine, N-methylmorpholine or mixtures thereof. The reaction can also be carried out in one or more organic solvents, for example, tetrahydrofuran, dimethylformamide, dioxane, diethylether or mixtures thereof. Compounds of Formula II can be reacted with hydroxylamine hydrochloride to form compounds of Formula III in the presence of one or more bases, for example, sodium acetate, sodium carbonate, ammonium acetate, potassium carbonate or mixtures thereof. The reaction can also be carried out in one or more organic solvents, for example, ethanol, methanol, propanol, isopropylalcohol or mixtures thereof.
Compounds of Formula III can be reacted with compounds of Formula IV to form compounds of Formula V with one or more oxidants, for example, sodium hypochlorite, N- chlorosuccinimide, tert-butoxy chloride or mixtures thereof. The reaction can also be carried out in the presence of one or more optional bases, for example, triethylamine, butyl lithium, N-methylmorpholine, diisopropylethylamine or mixtures thereof. The reaction can also be carried out in one or more organic solvents, for example, tetrahydrofuran, dimethylformamide, diethylether, dioxane or mixtures thereof.
Compounds of Formula V can be reduced (when Rz is -COOR5 and Rq is — CH2COORs) to form compounds of Formula VI in the presence of one or more reducing agents, for example, sodium borohydride, sodium cyanoborohydride or mixtures thereof. The reduction reaction can also be carried out in one or more organic solvents, for example, tetrahydrofuran, dimethylformamide, diethylether, dioxane or mixtures thereof.
Compounds of Formula VI can be ring cyclized to form compounds of Formula VII in the presence of a redox couple. The oxidizing part of the redox couple can be selected from diisopropylazodicarboxylate (DIAD), diethylazodicarboxylate (DEAD), N5N5N', N'- tetramethylazodicarboxylate (TMAD)5 l,l'-(azodicarbonyl) dipiperidine (ADDP), cyanomethylenetributylphosphorane (CMBP)5 4,7-dimethyl-3,5,7-hexahydro-l,254,7- tetrazocin-3,8-dione (DHTD) orN,N,N'5N,'-tetraisopropylazodicarboxamide (TIPA). The reduction part of the redox couple can be a phosphine reagent selected from trialkylphosphine (such as tributylphosphine), triarylphosphine (such as triphenylphosphine), tricycloalkylphosphine (such as triscyclohexylphosphine) or tetraheteroarylphosphine. Phosphine reagents having a combination of aryl, alkyl or heteroaryl substituents may also be used (such as diphenylpyridylphosphine). The reaction can also be carried out in one or more organic solvents, for example, tetrahydrofuran, dimethylformamide, dioxane, diethyl ether or mixtures thereof.
Compounds prepared following Scheme I include, for example: l-Cyclopentyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole (Compound No. 1), l-Cyclopentyl-3-methyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole (Compound No. 2), l-Cyclopentyl-3-ethyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole (Compound No. 3), l-Cyclopentyl-6-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No. 4), l-Cyclopentyl-3-methyl-6-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No. 5), l-Cyclopentyl-3-ethyl-6-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No. 6), 3-(l-Cyclopentyl-lH-indazol-6-yl)-l-oxa-2-azaspiro[4.5]dec-2-ene (Compound No. 7), 3-(l-Cyclopentyl-3-methyl-lH-indazol-6-yl)-l-oxa-2-azaspiro[4.5]dec-2-ene (Compound No. 8),
3-(l-Cyclopentyl-3-ethyl-lH-indazol-6-yl)-l-oxa-2-azaspiro[4.5]dec-2-ene (Compound No. 9), l-Cyclopentyl-6-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No. 13), l-Cyclopentyl-6-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)-3-methyl-lH-indazole (Compound No. 14), l-Cyclopentyl-6-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)-3-ethyl-lH-indazole (Compound No. 15),
2-[3-(l -Cyclopentyl-3 -methyl- lH-indazol-6-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5- yl]ethanol (Compound No. 19), 2-[3-(l-Cyclopentyl-3-ethyl-lH-indazol-6-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5- yl]ethanol (Compound No. 20),
2-[3-(l-Cyclopentyl-lH-indazol-6-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5-yl]ethanol (Compound No. 21), 3-(l-Cyclopentyl-3-methyl-lH-indazol-6-yl)-l,8-dioxa-2-azaspiro[4.5]dec-2-ene (Compound No. 22),
3-(l-Cyclopentyl-3-ethyl-lH-indazol-6-yl)-l,8-dioxa-2-azaspiro[4.5]dec-2-ene (Compound No. 23),
3-Ethyl-l-methyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole (Compound No. 24), 3-Ethyl-l-methyl-6-(l-oxa-2-azasρiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No. 25), 3-(3-Ethyl-l-methyl-lH-indazol-6-yl)-l-oxa-2-azaspiro[4.5]dec-2-ene (Compound No. 26),
2-[3-(3-Ethyl-l-methyl-lH-indazol-6-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5- yl]ethanol (Compound No. 27),
6-( 1 ,7-Dioxa-2-azaspiro [4.4]non-2-en-3 -yl)-3 -ethyl- 1 -methyl- lH-indazole (Compound No . 28), l,3-Dimethyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole (Compound No. 29), l,3-Dimethyl-6-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No. 30), 3-(l,3-Dimethyl-lH-indazol-6-yl)-l-oxa-2-azaspiro[4.5]dec-2-ene (Compound No. 31)5
2-[3-(l,3-Dimethyl-lH-indazol-6-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5-yl]ethanol (Compound No. 32),
6-(l,7-Dioxa-2-azaspiro[4.4]non-2-en-3-yl)-l,3-dimethyl-lH-indazole (Compound No. 33), l-Cyclopentyl-3-ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No. 34),
3-(l-Cyclopentyl-3-ethyl-lH-indazol-5-yl)-l-oxa-2-azaspiro[4.5]dec-2-ene (Compound No. 35), 3
21
2-[3-(l-Cyclopentyl-3-ethyl-lH-indazol-5-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5- yl]ethanol (Compound No. 36), l-Cyclopentyl-5-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)-3-ethyl-lH-indazole (Compound No. 37), or their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers or polymorphs.
Scheme Il
Figure imgf000022_0001
The compounds of Formula IX and X can be prepared by following the procedure as depicted in Scheme II. Thus, a compound of Formula III (where R1 and R2 are the same as depicted earlier) can be reacted with a compound of Formula VIII to form a compound of Formula IX (where t is O or 1). The compound of Formula VIII can be deprotected to form a compound of Formula X.
Compounds of Formula III can be reacted with compounds of Formula VIII to form compounds of Formula IX in the presence of one or more oxidants, for example sodium hypochlorite, N-chlorosuccinimide, tert-butoxy chloride or mixtures thereof. The reaction can also be carried out in the presence of one or more optional bases, for example, triethylamine, butyl lithium, N-methylmorpholine, diisopropylethylamine or mixtures thereof. The reaction can also be carried out in one or more organic solvents, for example, tetrahydrofuran, dimethylformarnide, diethylether, dioxane or mixtures thereof. Compounds of Formula IX can be deprotected to form compounds of Formula X in the presence of one or more deprotection agents, for example, methanol in hydrochloric acid or ethanol in hydrochloric acid.
Compounds prepared following Scheme II include, for example: 3-(l-Cyclopentyl-lH-indazol-6-yl)-l-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylate (Compound No. 10), rert-butyl 3-(l-cyclopentyl-3-methyl-lH-indazol-6-yl)-l-oxa-2,8-diazaspiro[4.5]dec-2-ene-8- carboxylate (Compound No. 11), rert-butyl 3-(l-cyclopentyl-3-ethyl-lH-indazol-6-yl)-l-oxa-2,8-diazaspiro[4.5]dec-2-ene-8- carboxylate (Compound No. 12),
Hydrochloride salt of 3-(l-cyclopentyl-lH-indazol-6-yl)-l-oxa-2,8-diazaspiro[4.5]dec-2-ene (Compound No. 16),
Hydrochloride salt of 3-(l-cyclopentyl-3-methyl-lH-indazol-6-yl)-l-oxa-258- diazaspiro[4.5]dec-2-ene (Compound No. 17),
Hydrochloride salt of 3-(l-cyclopentyl-3-ethyl-lH-indazol-6-yl)-l-oxa-2,8- diazaspiro[4.5]dec-2-ene (Compound No. 18) or their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers or polymorphs. In the above schemes, where specific reagents, for example, acids, bases, solvents, condensing agents, hydrolyzing agents etc. are disclosed, it is to be understood that other reagents (acids, bases, solvents, condensing agents, hydrolyzing agents, etc, known to those skilled in an art may also be used. Similarly, reaction temperatures and durations of the reactions may be readily adjusted according to desired needs. Compounds of Formula Ia and pharmaceutically acceptable salts, pharmaceutically acceptable solvates, stereoisomers, tautomers, racemates, prodrugs, metabolites, polymorphs or N-oxides thereof may be advantageously used in combination with one or more other therapeutic agents. Examples of other therapeutic agents include one or more of corticosteroids, beta agonists, leukotriene antagonists, 5-lipoxygenase inhibitors, chemokine inhibitors, muscarinic receptor antagonists or mixtures thereof.
Because of their valuable pharmacological properties, compounds described herein may be administered to an animal for treatment by any route of administration and more particularly by oral or parenteral routes. Pharmaceutical compositions described herein can be produced and administered in dosage units, each unit containing a specified amount of one or more compounds described herein and/or one or more pharmaceutically acceptable addition salt thereof. The dosage may be varied over wide limits, as the compounds are effective at low dosage levels and relatively free of toxicity. Such compounds may be administered in the low micromolar concentration, which is therapeutically effective, and the dosage may be increased as desired up to the maximum dosage tolerated by the patient.
The compounds described herein can be produced and formulated as racemic mixtures, enantiomers, diastereomers, rotamers, N-Oxides, polymorphs, solvates and pharmaceutically acceptable salts, as well as the active metabolites. Pharmaceutical compositions comprising the compounds described herein or metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates or pharmaceutically acceptable salts thereof, in combination with one or more pharmaceutically acceptable carriers and optionally included excipients can also be produced. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims. Examples
Synthesis of 6-bromo- 1 -cvclopentyl- 1 H-indazole. 6-bromo- 1 -cyclopentyl-3 -methyl- 1 H- indazole and 6-bromo- l-cvclopentyl-3 -ethyl- lH-indazole
The title compounds were prepared following the procedure as described in U.S. Patent No. 6,262,040 or Synthesis, 1999, 4, 588-592. Example 1 : 2-[3-(l -Cyclopentyl- lH-mdazol-6-ylV5-(hydroxymethylV4,5-dihydroisoxazol-5- yl]ethanol (Compound No. 21)
Step a: l-Cyclopentyl-lΗ-indazole-ό-carboxaldehyde
A solution of the compound ό-bromo-l-cyclopentyl-lΗ-indazole (1.19 g, 4.15 mmol) in dry tetrahydrofuran (10 ml) was stirred at -78 °C for 15 minutes followed by the addition of butyl lithium (0.532 g, 8.3 mmol). The reaction mixture was again stirred for 30 minutes at -78 °C followed by the dropwise addition of dimethylformamide (1.212 g, 16.6 mmol). The reaction mixture was stirred for 30 minutes at the same temperature followed by stirring at room temperature for 1 hour. The reaction mixture was quenched with hydrochloric acid (IN) and extracted with ethyl acetate and water. The organic layer was collected, washed with brine and dried over anhydrous sodium sulphate. The reaction mixture was filtered and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography to furnish the title compound. Yield: 0.465g. Mass (m/z): 215 (M++!). 1HNMR (CDCl3):δ 10.07 (IH, s), 8.23 (IH, s), 8.03 (IH, s), 7.7 (IH, d), 7.62 (IH, d), 5.00 (IH, m), 1.2-2.3 (m, 8H).
Step b: l-Cvclopentyl-lH-indazole-6-carboxaldehyde oxime
Hydroxylamine hydrochloride (311.7 mg, 4.48 mmol) and sodium acetate (367 mg,
4.48 mmol) and ethanol (10 ml) was added to a compound obtained from step a above (240 mg, 1.121 mmol). The reaction mixture was stirred for 18 hours. The solvent was evaporated under reduced pressure and extracted the compound with ethyl acetate.
The organic layer was collected, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using ethyl acetate in hexane solvent mixture as eluent to furnish the title compound. Yield: 260 mg.
Mass (m/z): 230.13 (M++l).
1HNMR (CDCl3):δ 8.28 (s, IH), 7.99 (s, IH), 7.71-7.70 (d,lH), 7.61 (s, IH), 7.45-7.42 (dd,
IH), 5.05-4.98 (m, IH), 2.2-1.75 (m, 8H). Step c: 3-(l-Cyclopentyl-lH-mdazol-6-yl)-5-methoxycarbonylmethyl-4,5-dihydroisoxazole- 5-carboxylic acid methyl ester
Tetrahydrofuran (5 ml) was added to a mixture of compound obtained from step b above (300 mg, 1.310 mmol) and dimethyl-2-methylenesuccinate (414 mg, 2.620 mmol) and the reaction mixture was stirred for 10 minutes at room temperature. Sodium hypochlorite (3 ml) was added with vigorous stirring to the reaction mixture and then further stirred for 15 hours. The solvent was evaporated under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using ethyl acetate in hexane solvent mixture as eluent to furnish the title compound. Yield: 410 mg.
Mass (m/z): 386.10 (M++l).
Step d: 2-f3-(l-Cyclopentyl-lH-mdazol-6-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5- yl] ethanol (Compound No . 21 ) Sodium borohydride (0.296 g, 7.792 mmol) was added to a solution of the compound obtained from step c above (0.500 g, 1.298 mmol) in tetrahydrofuran and stirred for 15 minutes at 0-5 0C. Methanol (1.0 ml) was added to the resulting reaction mixture. The reaction mixture was stirred for 14 hours at room temperature, quenched with ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography using 40 % ethyl acetate in hexane as eluent to furnish the title compound. Yield: 0.390 g. Mass (m/z): 330.10 (M++l).
Following compounds were prepared similarly using the appropriate corresponding starting materials, 2-r3-(l-Cyclopentyl-3-methyl-lH-indazol-6-yl)-5-(hvdroxymethylV4.5-dihvdroisoxazol-5- yliethanol (Compound No. 19)
Mass (m/z): 344.3 (M++!).
2-[3-(l-Cyclopentyl-3-ethyl-lH-indazol-6-yl')-5-('hvdroxymethyl')-4,5-dihvdroisoxazol-5- yllethanol (Compound No. 20)
Mass (m/z): 358.4 (M++!).
2-[3-(3-Ethyl-l-methyl-lH-indazol-6-yl)-5-(hydroxymethyl)-4,5-dihvdroisoxazol-5- vi]ethanol (Compound No. 27)
Mass (m/z): 304.1 (M++!). 2-r3-(1.3-Dimethyl-lH-indazol-6-yl)-5-(hvdroxymethyl)-4,5-dihvdroisoxazol-5-yllethanol (Compound No. 32)
Mass (m/z): 290.2 (M++1).
2-r3-(l-Cvclopentyl-3-ethyl-lH-mdazol-5-yl)-5-(hvdroxymethyl)-4,5-dihydroisoxazol-5- yllethanol (Compound No. 36) Mass (m/z): 358.2(M++1).
Example 2: Synthesis of l-cyclopentyl-6-(l,7-dioxa-2-azaspiro|~4.4'|non-2-en-3-yD-lH- indazole (Compound No. 13)
A solution of succinimide (0.117g, l.lδlmmol) and triphenylphosphine (0.326g, 1.244mmol) in tetrahydrofuran (10ml) was stirred at 0-5 0C for 15 minutes followed by the addition of Compound No. 21 (0.390g, 1.185mmol) obtained in Example 1. The reaction mixture was stirred at 0-5 °C for 15 minutes followed by the addition of diisopropylazodicarboxylate (0.31 Ig, 1.540mmol). The resulting reaction mixture was stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure and the residue thus obtained was purified by column chromatography using 10-25 % ethyl acetate in hexane as eluent to furnish the title compound. Yield: 0.110 g. Mass (m/z): 312.1 (M++l).
Following compounds were prepared similarly using the appropriate corresponding starting materials, l-Cyclopentyl-6-rL7-dioxa-2-azaspiro[4.41non-2-en-3-ylV3-methyl-lH-indazole
(Compound No. 14) Mass (m/z): 326.2 (M++!). l-Cyclopentyl-6-(l,7-dioxa-2-azaspiror4.41non-2-en-3-yl)-3-ethyl-lH-indazole (Compound No. 15)
Mass (m/z): 340.3 (M++l).
3-(l-Cyclopentyl-3-methyl-lH-indazol-6-yl)-l,8-dioxa-2-azaspiro[4.51dec-2-ene (Compound
No. 22)
Mass (m/z): 340.3 (M^+l). 3-(l-Cyclopentyl-3-ethyl-lH-indazol-6-yl)-l,8-dioxa-2-azaspiro[4.5]dec-2-ene (Compound No. 23)
Mass (m/z): 354.3 (M++l).
6-(l,7-Dioxa-2-azaspiro["4.41non-2-en-3-yl)-3-ethyl-l-methyl-lH-indazole (Compound No. 28) 6-(l,7-Dioxa-2-azaspiro[4.41non-2-en-3-yl)-l,3-dimethyl-lH-indazole (Compound No. 33) l-Cyclopentyl-5-(1.7-dioxa-2-azaspiro["4.41non-2-en-3-yl)-3-ethyl-lH-indazole (Compound
No. 37)
Mass (m/z): 340.1 (M++l).
Example 3: Synthesis of l-Cyclopentyl-6-(5-oxa-6-azaspirof3.41oct-6-en-7-yl)-lH-indazole (Compound No. 1)
The title compound was prepared following the procedure as described in Example 1, step c, by using methylenecyclobutane in place of dimethyl 2-methylenesuccinate. Mass (m/z): 296.10 (M++l).
Following compounds were prepared similarly using the appropriate corresponding starting materials, l-Cvclopentyl-3-methyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole (Compound No. 2}
Mass (m/z): 310.20 (M++l). l-Cvclopentyl-3-ethyl-6-(5-oxa-6-azaspiror3.41oct-6-en-7-yl)-lH-indazole (Compound No. 3) Mass (m/z): 324.30 (M++!). l-Cyclopentyl-6-(l-oxa-2-azaspiro[4.41non-2-en-3-yl)-lH-indazole (Compound No. 4) Mass (Wz): 310.10 (M++!). l-Cyclopentyl-3-methyl-6-(l-oxa-2-azaspiro[4.4]non-2-en-3-ylVlH-indazole (Compound No. 5}
Mass (m/z): 324.40 (M++l). 1 -Cyclopentyl-3 -ethyl-6-( 1 -oxa-2-azaspiro [4.4]non-2-en-3 - yl)- lH-indazole (Compound No . 6)
Mass (m/z): 338.30 (M++l).
3-(l-Cyclopentyl-lH-indazol-6-yl)-l-oxa-2-azaspiro[4.51dec-2-ene (Compound No. 7) Mass (m/z): 324.10 (M++!). 3-(l-Cyclopentyl-3-methyl-lH-indazol-6-ylVl-oxa-2-azaspiror4.51dec-2-ene (Compound No. 8} Mass (m/z): 338.30 (M++l).
3 -( 1 -Cyclopentyl-3 -ethyl- lH-indazol-6- ylV 1 -oxa-2-azaspiro [4.5"|dec-2-ene (Compound No . 9) Mass (m/z): 352.40 (M++!).
3-Ethyl-l-methyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-ylVlH-indazole (Compound No. 24)
Mass (m/z): 270.1 (M++!).
3-Ethyl-l-methyl-6-(l-oxa-2-azaspirof4.41non-2-en-3-yl)-lH-indazole (Compound No. 25)
Mass (m/z): 284.2 (M++!). 3-(3-Ethyl-l-methyl-lH-mdazol-6-yl)-l-oxa-2-azaspiro[4.51dec-2-ene (Compound No. 26)
Mass (m/z): 298.1 (M++!). l,3-Dimethyl-6-(5-oxa-6-azaspirof3.41oct-6-en-7-yl)-lH-indazole (Compound No. 29)
Mass (m/z): 256.2 (M++!).
13-Dimethyl-6-(l-oxa-2-azaspiro[4.41non-2-en-3-yl)-lH-indazole (Compound No. 30) Mass (m/z): 270.2 (M++l).
3-(l ,3-Dimethyl-lH-indazol-6-yl)-l-oxa-2-azaspiro[4.51dec-2-ene (Compound No. 31)
Mass (m/z): 284.2 (M++l).
1 -Cvclopentyl-3 -ethyl-5-( 1 -oxa-2-azaspiro["4.4~|non-2-en-3 -yl)- lH-indazole (Compound No. 34) Mass (m/z): 338.2 (M++l).
3 -(I -Cyclopentyl-3 -ethyl- lH-indazol-5 -yl)- 1 -oxa-2-azaspiro [4.5] dec-2-ene (Compound No . 35}
Mass (m/z): 352.1 (M++l). 006/001383
29
Example 4: Synthesis of fert-butyl 3-(l-cyclopentyl-lH-indazol-6-yl>l-oxa-2.8- diazaspiro[4.51dec-2-ene-8-carboxylate (Compound No. 10)
The title compound was prepared following the procedure as described in Example 1 (step c), by using tert-butyl 4-methylene piperidine-1-carboxylate in place of dimethyl 2- methylenesuccinate.
Mass (m/z): 425.2 (M++l).
The following compounds were prepared similarly using the appropriate corresponding starting materials,
7'ert-butyl 3-(l-cvclopentyl-3-methyl-lH-indazol-6-ylVl-oxa-2,8-diazaspiror4.5'|dec-2-ene-8- carboxylate (Compound No. 11)
Tert-butyl 3-(l-cyclopentyl-3-ethyl-lH-indazol-6-ylVl-oxa-2,8-diazaspirof4.5]dec-2-ene-8- carboxylate (Compound No. 12)
Example 5: Synthesis of hydrochloride salt of 3-(l-cyclopentyl-lH-indazol-6-yl)-l-oxa-2,8- diazaspiro[4.5]dec-2-ene (Compound No. 16) A solution of the Compound No. 10 (0.21Og, 0.495mmol) obtained in Example 4 in methanolic hydrochloric acid (5.9 ml, 29.3 mmol) was stirred at room temperature for 14 hours. The solvent was evaporated under reduced pressure and the residue thus obtained was washed with ether and dried under high vacuum to furnish the title compound. Yield: 0.090 g- Mass (m/z): 325.2 (M++!).
The following compounds were prepared similarly using the appropriate corresponding starting materials,
Hydrochloride salt of 3-(l-cyclopentyl-3-methyl-lH-indazol-6-ylVl-oxa-2,8- diazaspiro|~4.5]dec-2-ene (Compound No. 17) Mass (m/z): 339.3 (M+H-I-Cl)
Hydrochloride salt of 3 -( 1 -cvclopentyl-3 -ethyl- lH-indazol-6- vD- 1 -oxa-2 s 8- diazaspiro[4.51dec-2-ene (Compound No. 18)
Mass (m/z): 353.4 (M+H-I).
Example 6. Efficacy of Compounds as PDE IV Inhibitors PDE-IV Enzyme Assay The efficacy of compounds as PDE-4 inhibitor was determined by an enzyme assay (Burnouf et al; J. Med. Chem. 2000, 43:4850-4867). The PDE-4 enzyme source used was U937 cell cytosolic fraction prepared by sonication. The enzyme reaction was carried out, with the cytosolic fraction as the enzyme source, in the presence of cAMP (1 μM) at 3O0C in the presence or absence of NCE for 45 -60 min. An aliquot of this reaction mixture was taken further for the ELISA assay to determine level of cAMP in the sample. The concentration of the cAMP in the sample directly correlates with the degree of PDE-4 enzyme inhibition.
PDE-IV enzyme assay results were expressed as percent control and the IC5O values of compounds disclosed herein were from about 0.1 nM to about 10,000 nM, from about 0.1 nM to about 2600 nM, from about 0.1 nM to about 215 nM, and even from about 0.1 nM to about 35 nM.
Whole Blood Assay for TNF-α release
Human whole blood was collected in vacutainer tubes containing heparin or EDTA as an anti coagulant. 0.1 ml blood per well was co-incubated with 20 μl of compound (final DMSO concentration of 0.2 %) for 10 min in a flat bottom 96 well microtiter plate.
Compounds were dissolved in DMSO initially and diluted in medium for a final concentration of 0.2% DMSO. LPS (1 μg/ml, final concentration) was then added at a volume of 10 μl per well. After 30 min, 20 μl of fetal calf serum (final concentration of 10%) was added to each well. Samples were incubated overnight at 370C in an atmosphere of 5% CO2 and 95% air. Supernatant were then removed, diluted 1 :20 with PBS and tested by ELISA for TNF-α release using a commercial kit (e.g. BD Biosciences).
The level of TNF-α in treated wells was compared with the vehicle treated controls and inhibitory potency of compound was expressed as ICs0 values calculated by using Graph pad prism and were from about 385 nM to about 8400 nM, from about 385 nM to about 2400 nM and even from about 385 nM to about 1600 nM.

Claims

We Claim: 1. A compound having the structure of Formula Ia,
Figure imgf000032_0001
Formula Ia R1 and R2 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy, halogen or -OH; and R3 and R4 are independently selected from hydroxyalkyl or R3 and R4 together join to form mono or bicyclic ring containing 3-12 carbon atom, wherein the ring optionally contains 1-3 heteroatoms selected from oxygen, sulphur or -NRa (wherein Ra is hydrogen, aralkyl, -(C=O)OC(CH3)3, -(=O)OC(CH3)2CHBr2 or - C(=O)OC(CH3)2CC13). 2. A compound selected from: l-Cyclopentyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole (CompoundNo. 1), l-Cyclopentyl-3-methyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole (Compound No. 2), 1 -Cyclopentyl-3 -ethyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)- lH-indazole (Compound No. 3), l-Cyclopentyl-6-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (CompoundNo. 4), l-Cyclopentyl-3-methyl-6-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No. 5), l-Cyclopentyl-3-ethyl-6-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No. 6), 3-(l-Cyclopentyl-lH-indazol-6-yl)-l-oxa-2-azaspiro[4.5]dec-2-ene (CompoundNo. 7), 3-(l-Cyclopentyl-3-methyl-lH-indazol-6-yl)-l-oxa-2-azaspiro[4.5]dec-2-ene (Compound No. 8), 3-(l-Cyclopentyl-3-ethyl-lH-indazol-6-yl)-l-oxa-2-azaspiro[4.5]dec-2-ene (Compound No. 9), 3-(l-Cyclopentyl-lH-indazol-6-yl)-l-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylate (Compound No. 10), rert-butyl 3-(l-cyclopentyl-3-methyl-lH-indazol-6-yl)-l-oxa-2,8-diazaspiro[4.5]dec-2-ene-8- carboxylate (Compound No. 11), rert-butyl 3-(l-cyclopentyl-3-etliyl-lH-indazol-6-yl)-l-oxa-2,8-diazaspiro[4.5]dec-2-ene-8- carboxylate (Compound No. 12), l-Cyclopentyl-6-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No. 13), l-Cyclopentyl-6-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)-3-methyl-lH-indazole (Compound No. 14), l-Cyclopentyl-6-(l,7-dioxa-2-azaspiro[4.4]non-2-en-3-yl)-3-ethyl-lH-indazole (Compound No. 15), Hydrochloride salt of 3-(l-cyclopentyl-lH-indazol-6-yl)-l-oxa-2,8-diazaspiro[4.5]dec-2-ene (Compound No. 16), Hydrochloride salt of 3-(l-cyclopentyl-3-methyl-lH-indazol-6-yl)-l-oxa-2,8- diazaspiro[4.5]dec-2-ene (Compound No. 17), Hydrochloride salt of 3-(l-cyclopentyl-3-ethyl-lH-indazol-6-yl)-l-oxa-2,8- diazaspiro[4.5]dec-2-ene (Compound No. 18), 2-[3-(l-Cyclopentyl-3-methyl-lH-indazol-6-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5- yl]ethanol (Compound No. 19), 2-[3-(l-Cyclopentyl-3-ethyl-lH-indazol-6-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5- yl]ethanol (Compound No. 20), 2-[3-(l -Cyclopentyl- lH-indazol-6-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5-yl]ethanol (Compound No. 21), 3 -( 1 -Cyclopentyl-3 -methyl- lH-indazol-6-yl)- 1 , 8-dioxa-2-azaspiro [4.5]dec-2-ene (Compound No. 22), 3 -( 1 -Cyclopentyl-3 -ethyl- lH-indazol-6-yl)- 1 , 8 -dioxa-2-azaspiro [4.5] dec-2-ene (Compound No. 23), 3-Ethyl-l-methyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)-lH-indazole (Compound No. 24), 3
33 3-Ethyl-l-methyl-6-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No. 25), 3-(3-Ethyl-l-methyl-lH-indazol-6-yl)-l-oxa-2-azaspiro[4.5]dec-2-ene (Compound No. 26), 2-[3-(3-Ethyl-l-methyl-lH-indazol-6-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5- yl]ethanol (Compound No. 27), 6-(l,7-Dioxa-2-azaspiro[4.4]non-2-en-3-yl)-3-ethyl-l-methyl-lH-indazole (Compound No. 28), 1 ,3-Dimethyl-6-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)- lH-indazole (Compound No. 29), l,3-Dimethyl-6-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (CompoundNo. 30), 3-(l,3-Dimethyl-lH-indazol-6-yl)-l-oxa-2-azaspiro[4.5]dec-2-ene (CompoundNo. 31), 2-[3-(l,3-Dimethyl-lH-indazol-6-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5-yl]ethanol (CompoundNo. 32), 6-(l,7-Dioxa-2-azaspiro[4.4]non-2-en-3-yl)-l,3-dimethyl-lH-indazole (CompoundNo. 33), l-Cyclopentyl-3-ethyl-5-(l-oxa-2-azaspiro[4.4]non-2-en-3-yl)-lH-indazole (Compound No. 34), 3-(l-Cyclopentyl-3-ethyl-lH-indazol-5-yl)-l-oxa-2-azaspiro[4.5]dec-2-ene (Compound No. 35), 2-[3-(l-Cyclopentyl-3-ethyl-lH-indazol-5-yl)-5-(hydroxymethyl)-4,5-dihydroisoxazol-5- yl]ethanol (Compound No. 36), or 1 -Cyclopentyl-5 -(1 ,7-dioxa-2-azaspiro[4.4]non-2-en-3 -yl)-3 -ethyl- lH-indazole (Compound No. 37). 3. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula Ia and one or more pharmaceutically acceptable carriers, excipients or diluents, wherein the compound of Formula Ia is:
Figure imgf000034_0001
5 R1 and R2 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,
6 aralkyl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy, halogen or -OH; and
7 R3 and R4 are independently selected from hydroxyalkyl or R3 and R4 together join to
8 form mono or bicyclic ring containing 3-12 carbon atom, wherein the ring
9 optionally contains 1-3 heteroatoms selected from oxygen, sulphur or -NRa 0 (wherein Ra is hydrogen, aralkyl, -(C=O)OC(CH3)3, -(=O)OC(CH3)2CHBr2 or - 1 C(=O)OC(CH3)2CC13).
1 4. A method of treating AIDS, asthma, arthritis, bronchitis, chronic obstructer pulmonary
2 disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult
3 respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis,
4 osteoarthritis, ulcerative colitis comprising administering to a patient in need thereof a
5 therapeutically effective amount of a compound of Formula Ia:
Figure imgf000035_0001
g Formula Ia
7 R1 and R2 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,
8 aralkyl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy, halogen or -OH; and
9 R3 and R4 are independently selected from hydroxyalkyl or R3 and R4 together join to 0 form mono or bicyclic ring containing 3-12 carbon atom, wherein the ring 1 optionally contains 1-3 heteroatoms selected from oxygen, sulphur or -NRa 2 (wherein Ra is hydrogen, aralkyl, -(C=O)OC(CH3)3, -(=O)OC(CH3)2CHBr2 or - 3 C(=O)OC(CH3)2CC13).
1 5. A method of preventing, inhibiting or suppressing an inflammatory condition
2 comprising administering to a patient in need thereof a therapeutically effective amount of a
3 compound of Formula Ia: 006/001383
35
Figure imgf000036_0001
Formula Ia
R1 and R2 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy, halogen or -OH; and
R3 and R4 are independently selected from hydroxyalkyl or R3 and R4 together join to form mono or bicyclic ring containing 3-12 carbon atom, wherein the ring optionally contains 1-3 heteroatoms selected from oxygen, sulphur or-NRa (wherein Ra is hydrogen, aralkyl, -(C=O)OC(CH3)3, -(=O)OC(CH3)2CHBr2 or - C(=O)OC(CH3)2CC13).
6. A process for preparing a compound of Formula VII or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomef , diastereomer or N-oxide comprising the steps of:
a. formylating a compound of Formula I
Figure imgf000036_0002
Formula I to form a compound of Formula II
Figure imgf000036_0003
Formula Il b. reacting the compound of Formula II with hydroxylamine hydrochloride to form a compound of Formula III,
Figure imgf000037_0001
Formula III c. reacting the compound of Formula III with a compound of Formula IV
Figure imgf000037_0002
Formula IV to form a compound of Formula V,
Figure imgf000037_0003
Formula V c. reducing the compound of Formula V to form a compound of Formula VI,
Figure imgf000037_0004
Formula Vl d. cyclizing a compound of Formula VI to form a compound of Formula VII,
Figure imgf000037_0005
Formula VII
wherein
hal is Br, Cl or I; 6 001383
37 R1 and R2 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy, halogen or -OH;
Rz is -CH2COOalkyl;
Rq is -COOalkyl or Rz and Rq together join to form a cycloalkyl ring, wherein the cycloalkyl ring optionally contains one or more heteroatoms selected from oxygen or sulphur (when R2 is -COOR5 and Rq is -CH2COOR5); and R5 is alkyl, aryl, cycloalkyl, heteroaryl, heterocyclyl, aralkyl, heterocyclylalkyl or heteroarylalkyl.
7. A process for preparing a compound of Formula X or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enantiomer, diastereomer or N-oxide thereof comprising the steps of:
a. reacting a compound of Formula III
Figure imgf000038_0001
Formula III with a compound of Formula VIII
Figure imgf000038_0002
Formula VlIl to form a compound of Formula IX, and
Figure imgf000038_0003
Formula IX b. deprotecting a compound of Formula IX to form a compound of Formula X,
Figure imgf000039_0001
Formula X wherein R1 and R2 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocyclyl, cycloalkyl, alkoxy, halogen or -OH; and
t is O or 1.
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WO2009022746A1 (en) * 2007-08-10 2009-02-19 Nippon Soda Co., Ltd. Nitrogen-containing heterocyclic compound and pest control agent
US8293738B2 (en) 2010-05-12 2012-10-23 Abbott Laboratories Indazole inhibitors of kinase

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WO1997049702A1 (en) * 1996-06-25 1997-12-31 Pfizer Inc. Substituted indazole derivatives and their use as phosphodiesterase (pde) type iv and tumor necrosis factor (tnf) inhibitors
WO1998009961A1 (en) * 1996-09-04 1998-03-12 Pfizer Inc. Indazole derivatives and their use as inhibitors of phosphodiesterase (pde) type iv and the production of tumor necrosis factor (tnf)
WO2001047915A1 (en) * 1999-12-23 2001-07-05 Icos Corporation Cyclic amp-specific phosphodiesterase inhibitors

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WO1997049702A1 (en) * 1996-06-25 1997-12-31 Pfizer Inc. Substituted indazole derivatives and their use as phosphodiesterase (pde) type iv and tumor necrosis factor (tnf) inhibitors
WO1998009961A1 (en) * 1996-09-04 1998-03-12 Pfizer Inc. Indazole derivatives and their use as inhibitors of phosphodiesterase (pde) type iv and the production of tumor necrosis factor (tnf)
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Publication number Priority date Publication date Assignee Title
WO2007029077A1 (en) * 2005-09-05 2007-03-15 Ranbaxy Laboratories Limited Substituted indazoles as inhibitors of phosphodiesterase type-iv
US7781460B2 (en) 2005-09-05 2010-08-24 Ranbaxy Laboratories Limited Substituted indazoles as inhibitors of phosphodiesterase type-IV
WO2009022746A1 (en) * 2007-08-10 2009-02-19 Nippon Soda Co., Ltd. Nitrogen-containing heterocyclic compound and pest control agent
US8288393B2 (en) 2007-08-10 2012-10-16 Nippon Soda Co., Ltd. Nitrogen-containing heterocyclic compound and pest control agent
JP5128600B2 (en) * 2007-08-10 2013-01-23 日本曹達株式会社 Nitrogen-containing heterocyclic compounds and pest control agents
US8293738B2 (en) 2010-05-12 2012-10-23 Abbott Laboratories Indazole inhibitors of kinase

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