WO2009115874A2 - Novel heterocyclic compounds, pharmaceutical compositions containing them and processes for their preparation - Google Patents

Novel heterocyclic compounds, pharmaceutical compositions containing them and processes for their preparation Download PDF

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WO2009115874A2
WO2009115874A2 PCT/IB2009/000190 IB2009000190W WO2009115874A2 WO 2009115874 A2 WO2009115874 A2 WO 2009115874A2 IB 2009000190 W IB2009000190 W IB 2009000190W WO 2009115874 A2 WO2009115874 A2 WO 2009115874A2
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methoxy
methyl
compound
carbonitrile
carbazol
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PCT/IB2009/000190
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French (fr)
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WO2009115874A3 (en
Inventor
Balasubramanian Gopalan
Pal Manojit
Hanumantappa Havale Shrikant
Kodimuthali Arumugam
Kumar Singh Santosh
Vidyawant Gupta Rajesh
Kumar Tokala Ranjeet
Mungara Anitha
Chandra Chary Bathoju
Lal Jabaris Sobhana George Sugin
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Matrix Laboratories Ltd.
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Publication of WO2009115874A2 publication Critical patent/WO2009115874A2/en
Publication of WO2009115874A3 publication Critical patent/WO2009115874A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • Novel heterocyclic compounds novel heterocyclic compounds, pharmaceutical compositions containing them and processes for their preparation
  • the present invention relates to novel heterocyclic compounds that may be useful as phosphodiesterase inhibitors (PDEs) in particular phosphodiesterase type 4 inhibitors represented by formula I, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, their enantiomers, their appropriate N-oxides, their pharmaceutically acceptable salts, their pharmaceutically acceptable hydrates, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them and their use in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor(TNF- ⁇ ).
  • PDEs phosphodiesterase inhibitors
  • TNF- ⁇ Tumor Necrosis Factor
  • Bronchial asthma is a complex multifactorial disease characterized by hyperactivity of the respiratory tract to external stimuli.
  • Airway inflammation leads to a number of severe lung diseases including Asthma and Chronic Obstructive Pulmonary Diseases (COPD, also known as Chronic Obstructive Airway Disease, Chronic Obstructive lung Disease or chronic airflow limitation and chronic airflow obstruction.).
  • COPD Chronic Obstructive Pulmonary Diseases
  • the airflow limitation is usually progressive and associated with abnormal inflammatory response of the lungs to noxious particles or gases.
  • cyclic nucleotides mainly cAMP and cGMP which in turn are synthesized by adenylyl cyclases (ACs) and guanylate cyclases (GCs).
  • ACs adenylyl cyclases
  • GCs guanylate cyclases
  • PDEs Phosphodiesterases
  • PDEs are classified according to their nucleotide selectivity. All 4 PDE4 isoforms possess upstream conserved regions (UCRs) which appear to modulate dimerisation and may bind to signaling molecules such as lipids. At least 18 different splice variants of the 4 PDE4 isoforms exist. Because of the critical role of cAMP in mediating cytokine responses, cAMP specific PDE (PDE-4) plays an important role in the progression of inflammatory diseases. Many of the mediators of inflammatory response such as T cells, B cells, monocytes, neutrophils, eosinophils and macrophages have PDE4 enzymes as their primary cAMP specific PDE.
  • UCRs upstream conserved regions
  • inflammatory diseases that are implicated by these cellular mediators are asthma, chronic obstructive pulmonary diseases (COPD), rheumatoid arthritis, inflammatory bowel disease, Crohn's disease and multiple sclerosis. Consequently, the development of PDE4 inhibitors as therapeutic agents for these diseases has been a major pharmaceutical focus.
  • PDE4 indirectly controls the degree of bronchodilation.
  • cAMP is a negative regulator of the primary activating pathways such as cytokine release by T-cells. Inhibition of the PDE4 isozymes in these cells results in elevated cAMP levels and consequent inactivation of the inflammatory response.
  • elevated cAMP levels In addition to the direct role of cAMP in inflammatory cell function, elevated cAMP levels also lead to smooth muscle relaxation. Consequently inhibition of PDE4 activity leading to higher cAMP levels causes bronchodilation thereby alleviating symptoms of respiratory diseases such as asthma or COPD.
  • Patent application WO93/19749 claims the compounds of formula I which are useful for allergy and inflammatory states.
  • Patent US5811455 claims the compounds of formulae AA and BB
  • Patent application WO2006011024 claims the compounds of generic formula
  • One of the representative compounds is as given below and the compounds of the invention are claimed for asthma and chronic obstructive pulmonary disease apart from other disease states.
  • PDE4 As described above, as regulation of intracellular signaling is coordinated by PDE4, it has become a validated target for the development of therapeutics for inflammatory diseases such as asthma and COPD. PDE4 also has been shown to be a potential target for depression, memory enhancement, cardiovascular disease and osteogenesis.
  • R 1 is selected from
  • X represents O, S or NR 4 ; Y represents O, S, NR 4 or can be absent; X 1 and X 2 independently represent hydrogen, hydroxy, amino, nitro, cyano and optionally substituted groups selected from alkyl, alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, alkyl hydroxy, alkyl halo, alkyl amino, alkenyl amino, alkenyl amino alkyl, guanidyl, ureidyl, CR 5 R 6 R7, CR 5 R 6 OR 7 , CR 5 R 6 C(O)R 7 , CR 5 R 6 C(O)C(O)OR 7 , CR 5 R 6 C(O)OR 7 , (CR 5 R 6 ) n C(O)R 7 , CR 5 R 6 C(O)NR 7 R 8 , CR 5 R 6 S(O) m R 7 , CR 5 R 6 N R 7 R 8 ,
  • Nonlimiting examples of such cyclic groups include but are not limited to pyrazole, imidazole, imidazolidine, triazole, tetrazole, pyrrolidine, pyrrole, thiophene, thiazole, oxazole, isoxazole, furan, tetrahydrothiophene, tetrahydrofuran, thiazolidine, oxazolidine, piperazine, morpholine, thiomorpholine, piperidine, pyridine, pyrazine, pyrimidine, pyridazine;
  • X 3 represents hydrogen, cyano, Ci -4 alkyl, C 2 _ 4 alkenyl, C 2-4 alkynyl, alkylhalo, nitro, alkylnitro, alkyl carboxy, alkylcarbonyl, CH 2 NR 5r R>6 ,,CH 2 OR , C 3 -C 4 cyclo alkyl, OR 5 , R
  • X 4 represents O, NR 5 , N-OR 5 , NCR 5 R 6 R 7 , NOR 8 , NNR 7 R 8 , NCN, NNR 5 C(X)NR 7 R 8 or X 4 may be dimethyl ketal, diethyl ketal, 1,3-dithiane, 1,3- dithiolane, 1,3-dioxane, 5,5-dimethyl-[l,3]dioxane or 1,3-dioxolane; or
  • X 1 and X 4 can form a 5 to 7 membered cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl.
  • Nonlimiting examples of such cyclic groups include but are not limited to pyrazole, imidazole, imidazolidine, triazole, tetrazole, pyrrolidine, pyrrole, thiophene, thiazole, oxazole, isoxazole, furan, tetrahydrothiophene, tetrahydrofuran, thiazolidine, oxazolidine, piperazine, morpholine, thiomorpholine, piperidine, pyridine, pyrazine, pyrimidine, pyridazine;
  • R 2 and R 3 are independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, alkylamino ,alkyl hydroxy, alkyl halo, nitro, amino, cyano, formyl, carboxy, carbamoyl, acyl, halogen, ureidyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, acylamino, alkanoylamino, CR 5 R 6 R 7 , CR 5 R 6 OR 7 , CR 5 R 6 C(O)R 7 , CR 5 R 6 C(O)C(O)OR 7 , CR 5 R 6 C(O)OR 7 , (CR 5 R 6 ) n C(O)R 7 , CR 5 R 6 C(O)NR 7 R 8 , CR 5 R 6 S(O) m R 7 , CR 5 R
  • R 4 represents hydrogen, hydroxyl, alkyl, SO 2 CH 3 , SO 2 PhCH 3 or a protecting group; or when X represents NR 4 , then R 2 and R 4 may form a 6 to 7 membered substituted or unsubstituted heterocyclic ring;
  • R 5 , R 6 , R 7 , R 8 may be independently selected from hydrogen, Cj-C 6 straight or branched alkyl, dialkyl, C 2 -C 6 straight or branched alkenyl, alkylamino, alkyl halo, alkyl hydroxy, acyl, alkoxy, carboxy, sulfonyl, sulfinyl, thio, sulfamido, amido, NH(CO)R 7 , nitro, amino, halo, hydroxy, ureidyl, guanidyl; or
  • R 7 and R 8 when attached to Nitrogen as NR 7 R 8 may together with the nitrogen atom to which they are attached form a 5 to 7 membered optionally substituted ,saturated, partially saturated or unsaturated ring optionally containing at least one additional heteroatom selected from O, NR 5 or S;
  • R' and R' ' independently represent hydrogen, hydroxyl, halo, cyano, substituted or unsubstituted alkyl, alkoxy, haloalkyl, CONH 2 , COOH; or
  • R' and R" together with the carbon atoms to which they are attached form a C 5 to C 8 ring system selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and the substitutions on the said cycloalkyl, heterocyclyl, aryl, heteroaryl include but not limited to halo, cyano, haloalkyl, amino, amido, NHSO 2 Me, etc.; r represents an integer O, 1, 2 or 3; s represents an integer 0, 1 or 2; m represents an integer 0, 1 or 2; n represents an integer 0, 1 or 2; dotted line [ — ] inside the ring in general formula (I) represents an optional double bond; and their analogues, derivatives, tautomers, stereoisomers, enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically
  • R 4 and R 2 form an optionally substituted 6 to 7 membered ring such as
  • the compounds of the present invention may inhibit or regulate the TNF alpha production and are useful in the treatment of allergic and inflammatory diseases including asthma, allergic conditions, allergic conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, diabetes, Crohn's disease allergic rhinitis endotoxic shock and adult respiratory distress syndrome.
  • allergic and inflammatory diseases including asthma, allergic conditions, allergic conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, diabetes, Crohn's disease allergic rhinitis endotoxic shock and adult respiratory distress syndrome.
  • COPD chronic obstructive pulmonary disease
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon that may be substituted or unsubstituted.
  • alkyl include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, isobutyl, etc.
  • alkenyl used herein, either alone or in combination with other radicals, denotes a straight or branched C 2 -C 6 aliphatic hydrocarbon chain containing one or more carbon to carbon double bonds that may be optionally substituted with multiple degrees of substitution being allowed.
  • alkenyl includes dienes and trienes of straight and branched chains and are selected form vinyl allyl, 2- butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3hexenyl, 4- hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, and 6- heptenyl.
  • alkynyl used herein, either alone or in combination with other radicals, denotes a straight or branched chain aliphatic hydrocarbon containing two to eight carbons with one or more triple bonds which may be substituted or unsubstituted.
  • alkynyl includes di-and tri-ynes, such as ethynyl, 1- propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.
  • acyl refers to the group-C(O)R d where R d is alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl each as herein defined and examples of which include acetoyl, propanoyl, butanoyl, iso-butanoyl, pentanoyl, benzoyl, etc., which may be substituted or unsubstituted.
  • acylamino used herein represents -NHC(O)R d where R d is as defined above and examples of which include CH 3 CONH-, C 6 H 5 CONH-, Cl 2 C 6 H 3 CONH-, etc.
  • Alkoxy refers to a group -OR 0 where R c is alkyl as herein defined.
  • Representative examples include but are not limited to methoxy, ethoxy, etc.
  • Alkylamino refers to the group - N(R c ) 2 where one R 0 is alkyl and the other R c independently is H or alkyl as herein defined.
  • Alkylhalo refers to the group 'R c -halogen' where R 0 is alkyl defined as above and halogen is selected from Fluorine, Chlorine, Bromine and Iodine and it can be haloalkyl, dihaloalkyl, trihaloalkyl or polyhaloalkyl like methylene chloride, CF 3 , CHF 2 , CF 2 -CF 3 etc.
  • Halogen refers to Fluorine, Chlorine, Bromine or Iodine.
  • Alkylhydroxy or hydroxyalkyl refer to the group R 0 OH where R 0 is alkyl as herein defined and the representative examples include but are not limited to hydroxy methyl, hydroxy ethyl, hydroxy propyl, etc.
  • Aryl refers to optionally substituted aromatic ring system having the carbon atoms in the range of five to ten carbon atoms and they may be monocyclic, bicyclic or polycyclic and unsaturated or partially saturated and one or more carbons may optionally be replaced by one or more heteroatoms selected from N, O and S.
  • exemplary aryl groups include phenyl, naphthyl, indanyl, biphenyl, etc.
  • cycloalkyl used herein, either alone or in combination with other radicals, denotes mono, bicyclic or polycyclic saturated, partially saturated hydrocarbon ring system of about 3 to 12 carbon atoms which may be substituted or unsubstituted.
  • exemplary "cycloalkyl” groups include, but are not limited to cyclopopyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, perhydronapthyl, adamantyl, noradamantyl and spirobicyclic groups such as spiro (4,4)non-2-yl.
  • cycloalkylalkyl refers to a cycloalkyl ring containing 3 to 12 carbon atoms directly attached to an alkyl group which is then attached to the main structure at any carbon atom in the alkyl group that results in a stable structure such as cyclopropylmethyl, cyclobutylmethyl, etc.
  • Heteroaryl refers to monocyclic aromatic ring systems or fused bicyclic aromatic ring systems comprising two or more aromatic rings preferably two to three ring systems. These heteroaryl rings contain one or more nitrogen, sulfur and or oxygen atoms where N-oxides sulfur oxides and dioxides are permissible heteroatom substitutions.
  • the term includes ring(s) optionally substituted with halo, nitro, amino, alkoxy, alkyl sulfonyl amino, alkylcarbonylamino, carboxy, alkyl carbonoyl, hydroxy, and alkyl groups.
  • heteroaryl groups include furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, chromanyl, iso chromanyl, etc.
  • Heterocyclyl refers to a stable 3 to 15 membered ring that is either saturated or has one or more degrees of unsaturation or unsaturated. These heterocyclic rings contain one or more heteroatoms selected from the group consisting of nitrogen, sulfur and/or oxygen atoms where N-oxides, sulfur oxides and dioxides are permissible heteroatom substitutions. Such a ring may be optionally fused to one or more of other heterocyclic ring(s), aryl ring(s) or cycloalkyl ring(s).
  • Examples of such groups may be selected from the group comprising azetidinyl, acridinyl, pyrazolyl, imidazolyl, triazolyl, pyrrolyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, pyrazinyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorphonilyl, pyridazinyl, indolyl, isoindolyl, quinolinyl, chromanyl, etc.
  • Heterocyclylalkyl refers to a heterocyclic ring radical defined above directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at carbon atom in the alkyl group that results in the creation of a stable structure.
  • the substituents in the aforementioned "substituted” groups cannot be further substituted.
  • substituent on “substituted alkyl” is "substituted aryl”
  • substituent on "substituted aryl” cannot be “substituted alkenyl”.
  • Stereoisomers refer to certain compounds described herein containing one or more chiral centres or may otherwise be capable of existing as multiple stereoisomers.
  • the scope of the present invention includes pure stereoisomers as well as mixtures of stereoisomers, such as purified enantiomers/diastereomers or enantiomerically/diastereomerically enriched mixtures.
  • Bioisosteres refers to compounds or groups that possess near molecular shapes and volumes, approximately the same distribution of electrons and which exhibit similar physical properties such as hydrophobicity. Bioisosteric compounds affect the same biochemically associated systems as agonist or antagonists and thereby produce biological properties that are related to each other.
  • “Pharmaceutically acceptable salts” forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, 2-dimethylaminoethanol, isopropylamine, morpholine, piperazine, piperidine, procaine, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, pyrimidine, spermidine, etc.; chiral bases like alkylphenylamine, glycinol, phenyl glycinol, etc.; salts of natural amino acids such as glycine
  • Salts may include acid addition salts where appropriate, such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, etc.
  • “Pharmaceutically acceptable solvates” may be hydrates or comprising other solvents of crystallization such as alcohols.
  • Compounds of the invention or “present invention” refers to the compounds of the present invention represented by general formula (I) as herein defined, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, their enantiomers, their appropriate N-oxides, their pharmaceutically acceptable salts, their pharmaceutically acceptable hydrates, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.
  • the present invention also relates to a process for the preparation of the novel heterocyclic compounds of general formula (I).
  • the compounds of the present invention may inhibit or regulate TNF alpha production and are useful in the treatment of allergic and inflammatory diseases including asthma, inflammatory diseases, allergic conditions, allergic conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, diabetes, Crohn's disease, allergic rhinitis endotoxic shock and adult respiratory distress syndrome.
  • allergic and inflammatory diseases including asthma, inflammatory diseases, allergic conditions, allergic conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, diabetes, Crohn's disease, allergic rhinitis endotoxic shock and adult respiratory distress syndrome.
  • COPD chronic obstructive pulmonary disease
  • Another embodiment of the present invention is a method of treating an inflammatory disease, disorder or condition associated with undesirable inflammatory immune response or a disease or condition induced by or associated with an excessive secretion of TNF- ⁇ and PDE4 in humans.
  • This method includes administering to the human a therapeutically effective amount of a compound according to the general formula (I).
  • Method of treating includes preventing or delaying the appearance of clinical symptoms, inhibiting the state disorder or condition, relieving the disease causing regression of the disease.
  • the compound of formula E is made using the normal conventional methods.
  • the compound of general formula E is then treated with methyl acrylate in the presence of a suitable base such as 1,1,3,3-tetramethyl guanidine, triton B (benzyltrimethylammonium hydroxide) in the presence of a suitable solvent such as dimethyl sulphoxide, acetonitrile and dimethyl formamide (DMF) to give the compound of general formula F.
  • a suitable base such as 1,1,3,3-tetramethyl guanidine, triton B (benzyltrimethylammonium hydroxide)
  • a suitable solvent such as dimethyl sulphoxide, acetonitrile and dimethyl formamide (DMF)
  • the compound of general formula F is then converted to the compound of general formula G by internal cyclization in the presence of a suitable base such as sodium hydride, potassium hydride, sodium or potassium methoxide, etc., and an appropriate solvent such as dimethoxyethane (DME)
  • the compound of general formula (I) wherein R 1 is cyclohexanone is obtained from the compound of general formula G by treatment with a suitable inorganic salt such as sodium halides, lithium halides and potassium halides in a suitable solvent system such as dimethyl sulphoxide and water.
  • a suitable inorganic salt such as sodium halides, lithium halides and potassium halides in a suitable solvent system such as dimethyl sulphoxide and water.
  • a suitable solvent system such as dimethyl sulphoxide and water.
  • the compound of general formula G is converted to the compound of general formula H which in turn is converted to the compound of general formula I upon treatment with dimethylformamide dimethylacetal in the presence of a suitable solvent such as dimethyl formamide and benzene.
  • Compound of general formula I is then converted to a compound of general formula (I) using a reagent such as hydrazine hydrate, phenyl hydrazine, methyl hydrazine, hydroxylamine hydrochloride, salts of guanidine, guanidine acetic acid, acetimidine hydrochloride, salts of formamidine in the presence of a suitable solvent such as ethanol, methanol, n-butanol, toluene, benzene, dioxane and the like.
  • a suitable solvent such as ethanol, methanol, n-butanol, toluene, benzene, dioxane and the like.
  • the intermediate AI (wherein X 3 , Y, R 2 and R 4 are as described above and T hydrogen or halo, nitro or alkylhalo) can be synthesized according to the general synthetic scheme Ia.
  • the compound AC is prepared as per the Scheme mentioned in - Chem Pharm. Bull 29(3), 699-710 ( 1981 ).
  • the compound of formula AC is then converted to compound of formula AD by treating with palladium carbon in the presence of suitable solvent such as diphenylether, xylene, toluene, chloroform, dichloromethane, etc. or in the presence of copper bromide in a suitable solvent such as acetonitrile, ethylacetate, etc. under heating.
  • suitable solvent such as diphenylether, xylene, toluene, chloroform, dichloromethane, etc.
  • copper bromide in a suitable solvent such as acetonitrile, ethylacetate, etc. under heating.
  • the compound of formula AD is converted to compound of formula AE by treating with suitable base such as sodium hydride, sodium or potassium hydroxide and in the presence of suitable reagent such as methyl iodide, dimethylsulfate in a suitable solvent such as dimethyl formamide, water, etc.
  • suitable base such as sodium hydride, sodium or potassium hydroxide
  • suitable reagent such as methyl iodide, dimethylsulfate in a suitable solvent such as dimethyl formamide, water, etc.
  • the compound of formula AE is converted to the compound of formula AF by treatment with dichloromethylmethyl ether in the presence of titanium tetrachloride and dichloromethane or phosphorousoxy chloride in dimethyl formamide.
  • Compound of formula AF is converted to the compound of formula AG by reduction with sodium borohydride in the presence of a suitable solvent system such as tetrahydrofuran or methanol or lithiumaluminium hydride in the presence of THF.
  • Compound of formula AG is converted to compound of formula AH by chlorination using suitable chlorinating agents such as thionyl chloride, phosphorousoxychloride, phosphorous trichloride, carbon tetrachloride and triphenylphosphine in the presence of a suitable solvent such as ethyl acetate, THF, DMF, DCM or EDC.
  • suitable chlorinating agents such as thionyl chloride, phosphorousoxychloride, phosphorous trichloride, carbon tetrachloride and triphenylphosphine in the presence of a suitable solvent such as ethyl acetate, THF, DMF, DCM or EDC.
  • Compound of formula AH is converted to compound of general formula AI by treatment with sodium or potassium cyanide in the presence of dimethylformamide.
  • the compound of general formula AI (which is equivalent to E of scheme 1), is converted to compound of general formula (I) by the method mentioned in synthetic scheme 1.
  • the intermediate AI (substituted tetrahydro carbazole) can be prepared using the literature reference Canadian journal of research (1950), 28B, 443-452 which is then converted to the compound of formula E using palladium carbon in the presence of suitable solvent such as diphenyl ether, xylene, toluene, chloroform, etc.
  • the compound of formula 1 can be reacted with cyclopentyl bromide in presence of a suitable base such as anhydrous potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, etc. and a suitable solvent such as dimethyl formamide, dimethyl sulfoxide, acetonitrile, etc. to afford the compound of general formula 2.
  • a suitable base such as anhydrous potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, etc.
  • a suitable solvent such as dimethyl formamide, dimethyl sulfoxide, acetonitrile, etc.
  • the compound of general formula 3 can be converted to the compound of general formula 4 by treatment with fluoronitrobenzene in the presence of suitable base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium or potassium alkoxide, etc. and suitable solvent such as dimethyl formamide, dimethyl sulfoxide, acetonitrile, etc..
  • suitable base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium or potassium alkoxide, etc.
  • suitable solvent such as dimethyl formamide, dimethyl sulfoxide, acetonitrile, etc.
  • the compound of general formula 4 can then be cyclised to the compound of general formula 5 using palladium acetate in the presence of suitable base like anhydrous sodium carbonate, potassium carbonate, etc. and suitable solvent such as dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, acetonitrile, etc.
  • the compound of general formula 5 can then be reduced using conventional reducing agents such as sodium borohydride, lithium aluminum hydride, etc. in the presence of suitable solvent such as tetrahydrofuran, methanol, and dimethyl sulfoxide to obtain the compound of general formula 6.
  • suitable solvent such as tetrahydrofuran, methanol, and dimethyl sulfoxide
  • Halogenation of the compound of general formula 6 using suitable reagents such as thionyl chloride and phosphorus chloride in the presence of suitable solvent such as dichloromethane and ethyl acetate afford compound of general formula 7.
  • the compound of general formula 7 can be made by treating the compound of general formula 6 with triphenylphosphine/carbon tetrachloride or carbon tetrabromide.
  • the compound of general formula 7 can be treated with sodium or potassium cyanide in the presence of suitable solvent system such as dimethyl formamide, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, etc. to afford the compound of general formula 8.
  • suitable solvent system such as dimethyl formamide, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, etc.
  • suitable bases like triton B, l,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, sodium hydride, etc. in presence of suitable solvent such as acetonitrile, dimethyl formamide, dimethyl sulfoxide, etc. to obtain the compound of general formula 9.
  • the compound of general formula 10 can be obtained by treating compound of general formula 9 with sodium hydride, sodium ethoxide, or/and??
  • conversion of the compound of general formula 11 to the compound of general formula 12 can be made by treating with hydrogen halides such as hydrogen bromide, hydrogen chloride or hydrogen iodide in presence of suitable solvent such as glacial acetic acid, dichloromethane, benzene, etc. Alternatively, it can be made by treatment with boron tribromide in dichloromethane.
  • the compound of general formula 12 can be converted to the compound of general formula 13 by treatment with chlorodifluoromethane gas in the presence of suitable bases such as anhydrous sodium carbonate, potassium carbonate, etc. and suitable solvents such as dry dimethyl formamide, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, etc.
  • suitable bases such as anhydrous sodium carbonate, potassium carbonate, etc.
  • suitable solvents such as dry dimethyl formamide, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, etc.
  • the compound of general formula 13 can be treated with triethylamine followed by N 5 N- dimethylformamide dimethylacetal (DMFDMA) in presence of suitable solvent such as benzene, toluene, dimethyl formamide, etc.
  • DMFDMA N 5 N- dimethylformamide dimethylacetal
  • the compound of general formula 14 which in-turn can be treated with formamidine hydrochloride in presence of a suitable solvent such as dry dimethylformamide, dimethyl acetamide, dimethyl sulfoxide, etc. to obtain the compound of general formula 15.
  • a suitable solvent such as dry dimethylformamide, dimethyl acetamide, dimethyl sulfoxide, etc.
  • the ompound of general formula 15 can be reduced by hydrogenation using regular catalytic agents such as Raney nickel in presence of suitable solvent such as ethyl acetate, methanol, ethanol, 1,4-dioxane, etc. to obtain the compound of general formula 16.
  • the compound of general formula 15 can be treated with iron or zinc powder/ammonium chloride in a suitable solvent such as tetrahydrofuran, ethanol, methanol, etc. to obtain the compound of general formula 16.
  • the compound of general formula 16 can then be treated with methane sulphonyl chloride in presence of suitable base such as pyridine, triethylamine, etc. and suitable solvent such as dry tetrahydrofuran, dichloromethane, etc. to produce compound of general formula (I).
  • suitable base such as pyridine, triethylamine, etc.
  • suitable solvent such as dry tetrahydrofuran, dichloromethane, etc.
  • stereo isomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomeric form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, etc. wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives, etc.
  • Different polymorphs of a compound of general formula (I) of the present invention may be prepared by crystallization of the compound of formula (I) under different conditions. For example, making use of commonly used solvents or their mixtures for recrystallization, crystallization at different temperature ranges, different cooling techniques like very fast to very slow cooling during crystallization procedure, exposure to room temperature, heating or melting the compound followed by gradual cooling, etc.
  • the presence of polymorphs may be determined by one or more methods such as solid probe NMR spectroscopy, DSC, TGA, Powder X-Ray diffraction and IR.
  • the present invention also provides pharmaceutical compositions containing the compounds of the invention as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their polymorphs, their enantiomers, their diastereomers, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates in combination with the suitable pharmaceutically acceptable carriers, diluents.
  • the pharmaceutical compositions according to the present invention are useful for the treatment of allergic and inflammatory diseases including asthma, inflammatory diseases, allergic conditions, allergic conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, diabetes, Crohn's disease, allergic rhinitis endotoxic shock and adult respiratory distress syndrome and related diseases.
  • the pharmaceutical composition may be tablets, capsules, powders, syrups, solutions, suspensions, sprays, etc. and may contain flavorants, sweeteners, etc. in suitable solid or liquid carriers, diluents, or in a suitable sterile media to form injectable solutions or suspensions.
  • any reactive group in the substrate molecule may be protected according to any conventional procedure known in the prior art.
  • Suitable protecting groups comprise N-Boc, N-Cbz, N-Fmoc, alkyl, benzophenoneimine for protection of amino groups, acetal protection for aldehydes, and ketal protection for ketones.
  • the invention also encompasses prodrugs of compounds of the invention, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances.
  • prodrugs will be functional derivatives of compounds of the invention, which are readily convertible in vivo into compounds of the invention.
  • the invention also encompasses the active metabolites of the compounds of the present invention of general formula (I). Examples
  • Step-2 preparation of (7-Methoxy-l-tosyl-lH-indoI-4-yl) methanol To a solution of 7-methoxy-l-tosyl-lH-indole-4-carbaldehyde (16.8 g, 0.051 mol) in methanol (150 ml) was added sodium borohydride (2.8 g, 0.076 mol) portion wise at 0-5 0 C over a period of 30 minutes and the mixture was stirred at the same temperature for 1 hour.
  • Step-3 Preparation of 4-(Chloromethyl)-7-methoxy-l-tosyl-lH-indole
  • a solution of (7-methoxy-l-tosyl-lH-indol-4-yl) methanol (16.Og, 0.0483 mol) in ethyl acetate (350 ml) was added a solution of thionyl chloride (SOCl 2 ) (7.19 ml, 0.0966 mol) in ethyl acetate (50 ml) at -4O 0 C for 2 hours and the mixture was stirred for an additional 20 minutes.
  • SOCl 2 thionyl chloride
  • Step-1 Preparation of Benzyl 4-(cyanomethyl)-lH-indole-l-carboxylate
  • Step-1 Preparation of Benzyl 4-formyl-lH-indole-l-carboxylate
  • KHMDS potassium hexamethyldisilazane
  • Step-2 Preparation of Benzyl 4-(hydroxymethyl)-lH-indole-l-carboxylate The title compound was prepared following a similar procedure as described in step
  • Step-4 Preparation of Benzyl 4-(cyanomethyl)-lH-indole-l-carboxylate
  • the title compound was prepared following a similar procedure as described in step 3 of intermediate 1 and obtained as an off-white solid.
  • Step 3 Preparation of 6-Fluoro-2,3.4,9-tetrahydro-carbazol-l-one
  • acetonitrile 600 ml
  • concentrated sulphuric acid 20 ml
  • the mixture was refluxed for 2 hours.
  • the mixture was diluted with water (750 ml) and stirred for 10 minutes, filtered and dried under vacuum to afford the title compound (21 g, yield 99.1%) as orange colored solid.
  • Step 4 Preparation of 6-Fluoro-9H-carbazol-l-ol To the solution of compound of step 3 (1Og, 0.05 mole) in diphenylether (1.2 /) was added 10% Pd/C (5g) and the mixture was refluxed for 5 hours. The mixture was then filtered, concentrated and the crude product was purified to afford the title compound (4g, yield 40.4%) as an off-white solid.
  • Step 6 Preparation of 6-Fluoro-l-methoxy-9-metb.yl-9H-carbazo.e-4- carbaldehyde
  • DCM DCM
  • titanium tetrachloride 1.38 ml, 0.01 mole
  • the mixture was stirred for 10 min and then dichloromethyl methyl ether (0.65 ml, 0.01 mole) was added. After stirring for 30 min.
  • Step 7 Preparation of (6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yI)-methanol To the solution of compound of step 5 (1.54 g, 5.99 mmole) in THF (50 ml), was added sodium borohydride (360 mg, 9.51 mmole) portion wise at room temperature.
  • Step 8 Preparation of (6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)- acetonitrile
  • a solution of (6-fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-methanol (50 mg, 0.19 mmol) in ethyl acetate (5 ml) was cooled to -10 0 C and thionyl chloride (0.02 ml, 0.23 mmol) was added drop wise. The reaction mass was stirred for 2 hours at the same temperature and then concentrated under vacuum. The residue was dissolved in DMF (5 ml) and sodium cyanide (10 mg, 0.20 mmol) was added at room temperature.
  • Step 2 Preparation of 2-Bromo-4-cyclopentoxy-3-hydroxybenzaldehyde Compound of step 1 (18gm, 0.087mol) was dissolved in glacial acetic acid (540ml). Anhydrous sodium acetate (14.31 gm, 0.174mol) was added to the above solution followed by powdered iron (396mg). The system was flushed thoroughly with nitrogen.
  • Step 3 Preparation of 2-Bromo-4-cyclopentoxy-3-(4-nitrophenoxy) benzaldehyde To a stirred solution of compound of step 2 (26gm,0.091 moles) and potassium carbonate (31.5gm, 0.228mole) in dry dimethylformamide (260 ml) was added fluoronitrobenzene (10.16ml, 0.095mole) and then above reaction mixture was stirred at 14O 0 C for 5 hours. After completion of reaction, the reaction mixture was cooled to room temperature and the contents were poured in to water (750ml) and extracted with ethyl acetate (3X500ml).
  • Step 4 Preparation of 4-cyclopentoxy-8-nitro-l-formyl dibenzo [b, d] furan
  • a solution of compound of step 3 (26.12gm, 0.064mol) in dimethylformamide (200ml), anhydrous sodium carbonate (20.45gm, 0.193mol) and Pd(II) acetate (1.44gm, O.OO ⁇ mol) was heated and stirred under nitrogen at 13O 0 C for 7hours. After completion of reaction, the reaction mixture was filtered through celite bed, and then to the filtrate, water (500ml) was added and extracted with ethyl acetate (3X250ml).
  • Step 5 Preparation of (4-Cyclopentyloxy-8-nitro-dibenzofuran-l-yl)-methanol
  • sodium borohydride 0.584gm, 0.015mole
  • the mixture was then allowed to stir at room temperature for 3 hours and then quenched with a saturated solution of ammonium chloride (150ml).
  • the mixture was extracted with ethyl acetate (3X150ml).
  • step 7 To a solution of sodium hydride (1.344gm, 0.0336mole) in dry dimethoxyethane (250ml) was added the compound of step 7 (5.69gm, 0.01 lmole) in dimethoxyethane (25ml) drop wise over a period of 20 minutes at room temperature under nitrogen. The mixture was then allowed to stir at room temperature for 2 hours and then quenched with a saturated solution of ammonium chloride (200ml). The mixture was then extracted with ethyl acetate (3 X 250ml). The organic layers were collected, combined dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the title compound (5.3gm, yield-98%) as a solid.
  • Step 1 Preparation of l-(-4-Cyclopentyloxy-8-nitro-dibenzofuran-l-yl)-4-oxo- cyclohexane carbonitrile
  • Step-1 Preparation of 3-(2-Bromo-4-trifluoromethyl-phenoxy)-4-methoxy- benzaldehyde
  • Step 2 Preparation of 4-Methoxy-8-trifluoromethyl-dibenzofuran-l- carbaldehyde A solution of the product from step 1 (11.5 gm, 0.030 mol) in DMF (80 ml), anhydrous sodium carbonate (9.8 gm, 0.091 mol) and Pd(II) acetate (0.689 gm,
  • step 2 To a cold solution of the product of step 2 (4.5 gm, 0.015 moles) in dry THF (25 ml) was added sodium borohydride (0.640gm, 0.016 moles) portion wise at O 0 C under nitrogen. The mixture was then allowed to stir at room temperature for 3 hrs and then quenched with saturated solution of ammonium chloride (50 ml). The mixture was extracted with ethyl acetate (3X75 ml). The organic layers were collected, combined, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the title compound (4.3 gm, yield-94.9 %) as a solid.
  • step 3 To a cold solution of step 3 (5.8 gm, 0.019 moles) in 200 ml of dry DCM, thionyl chloride (2.86 ml, 0.039 moles) was added drop wise over a period of 15 min, under nitrogen atmosphere. After addition, the reaction mixture was brought to room temperature and allowed to stir for 3 hrs. After completion of the reaction, excess thionyl chloride and DCM was evaporated under vacuum completely and the product was not isolated. To the non-isolated compound obtained above was added dry DMF (150 ml) and sodium cyanide (2.13 gm, 0.043 moles) at room temperature and the reaction mixture was allowed to stir for 2 hrs.
  • dry DMF 150 ml
  • sodium cyanide (2.13 gm, 0.043 moles
  • Step 5 Preparation of 4-Cyano-4-(4-Methoxy-8-trifluoromethyl-dibenzofuran-l- yl) hepatanedioic acid dimethylester To a solution of step 4 (2.7gm, 0.0088 moles) in acetonitrile (20 ml) was added
  • Triton B (0.8 ml, 0.004 moles) at room temperature, the reaction mixture was heated to reflux (85 0 C), at reflux temperature was added drop wise methyl acrylate (8.45 ml, 0.088 moles) and then the reaction was maintained at reflux for 5 hrs. After completion of the reaction, the reaction mass was evaporated under vacuum. The crude product was purified by column chromatography using 5-10% ethyl acetate- hexane to obtain the title compound (2.53 gm, yield-60 %) as a pale yellow solid.
  • Step 6 Preparation of 5-Cyano-5-(4-methoxy-8-trifluoromethyl-dibenzofuran-l- yl)-2-oxo-cyclohexanecarboxylic acid methyl ester
  • sodium hydride (1.56 gm, 0.032 moles) in dry DME (50 ml) was added drop wise the product of step 5 (5.20 gm, 0.010 moles) by dissolving it in DME (50 ml) over a period of 20 min at room temperature under nitrogen.
  • the mixture was then allowed to stir at room temperature for 2 hrs and then quenched with a saturated solution of ammonium chloride (100 ml).
  • Step 2 Preparation of 3-dimethylaminomethyIene-l-(4-methoxy-8- trifluoromethyl-dibenzofuran-l-yl ⁇ -oxo-cyclohexanecarbonitrile
  • Step-1 Preparation of Benzyl-4-(l,5-dimethoxycarbonyl-3-cyanopentan-3-yl)- lH-indole-1-carboxylate
  • Step-3 Preparation of l-(lH-Indol-4-yl)-4-oxocyclohexanecarbonitrile
  • H 2 O 10.8 ml
  • sodium chloride 7.5 g, 129.3 mmol
  • the mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (3 x 100 ml). The organic layers were collected, combined, washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (3.Og, 63.8 %) as an off-white solid.
  • Step-4 Preparation of l ⁇ l-Methyl-lH-indoM-yl ⁇ -oxocyclohexanecarbonitrile
  • cesium carbonate 415 mg, 1.27 mmol
  • methyl iodide 71 ⁇ l, 1.09 mmol
  • N,N- dimethylformamide dimethylacetal (DMFDMA) (0.5 ml, 3.96 mmol) and the mixture was stirred for 1 hour at 110-120 0 C under a nitrogen atmosphere.
  • the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layers were collected, combined, washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the crude enamine intermediate (600 mg) as a brown solid which was dissolved in ethanol (8 ml).
  • Step 1 Preparation of 4,5,6,7-Tetrahydro-5-(lH-indol-4-yl)-2H-indazole-5- carbonitrile
  • N,N-dimethylformamide 6 ml
  • N, N- dimethylformamide dimethylacetal 447 ⁇ l, 3.36 mmol
  • Step-1 Preparation of Dimethyl 4-cyano-4-(7-methoxy-l-tosyl-lH-indol-4- yl)heptanedioate
  • the title compound was prepared using intermediate 1, following a similar procedure as mentioned in step 1 of example 1 as a white solid.
  • Step-2 Preparation of Methyl-5-cyano-5-(7-methoxy-l-tosyl-lH-indol-4-yl)-2- oxocyclohexanecarboxylate
  • Step-3 Preparation of l-(7-Methoxy-l-tosyl-lH-indol-4-yl)-4-oxocycIohexane- carbonitrile
  • Step-4 Preparation of 4,5,6,7-Tetrahydro-5-(7-methoxy-l-tosyl-lH-indol-4-yl)- 2H-indazole-5-carbonitrile
  • the title compound was prepared following a similar procedure as mentioned in step 5 of example 1 as an off-white solid.
  • Step-1 Preparation of Dimethyl 4-cyano-4-(7-methoxy-l-tosyl-lH-indol-4-yl) heptanedioate
  • the title compound was prepared using intermediate 1, following a similar procedure as mentioned in step 1 of example 1 as a white solid.
  • Step-2 Preparation of Dimethyl 4-cyano-4-(7-methoxyl-lH-indol-4-yl)- heptanedioate
  • the title compound was prepared following a similar procedure as mentioned in step 5 of example 3 as a white solid (120 mg, 22 %).
  • Step-3 Preparation of Dimethyl 4-cyano-4-(7-methoxy-l-methyl-lH-indol-4-yl) heptanedioate To a solution of compound of step 2 (3.0 g, 8.37 mmol) in N,N-dimethylformamide
  • Step-4 Preparation of Methyl-5-cyano-5-(7-methoxy-l-methyl-lH-indol-4-yl)-2- oxocyclo-hexane-carboxylate
  • the title compound was prepared following a similar procedure as mentioned in step
  • Step-5 Preparation of l-(7-Methoxy-l-methyl-lH-indol-4-yl)-4-oxocyclohexane- carbonitrile
  • the title compound was prepared following a similar procedure as mentioned in step 5 of example 1 as a yellow powder (160 mg, 30 %).
  • Step 1 Preparation of 4-hydroxy-l-(7-methoxy-lH-indol-4-yl)- cyclohexanecarbonitrile
  • Step 2 Preparation of l-(7-methoxy-lH-indol-4-yl)-4-oxocyclohexanecarbonitrile
  • Step 1 Preparation of 4-(6-FIuoro-l-methoxy-9-methyl-9H-carbazol-4-yl)- heptanedioic acid dimethyl ester
  • Step 3 Preparation of 4-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)- cyclohexanone
  • the title compound was prepared following a similar procedure mentioned in step 3 of example 1.
  • Step 1 Preparation of 4-(l-methoxy-9-methyl-9H-carbazol-4-yl)-heptanedioic acid dimethyl ester
  • Step 3 Preparation of 4-(l-methoxy-9-methyl-9H-carbazol-4-yl)-cycIohexanone Prepared according to the procedure mentioned in step 3 of example 1 to afford the desired product as a pale yellow solid.
  • Step 1 Preparation of 3-dimethylaminomethylene-l-(6-fluoro-l-methoxy-9- methyl-9H-carbazol-4-yl)-4-oxo-cyclohexanecarbonitrile
  • Step 2 Preparation of 6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yI)-5,6,7,8- tetrahydroquinazoIine-6-carbonitrile
  • DMA dimethyl methacrylate
  • aqueous sodium bicarbonate 10 ml
  • the mixture was extracted with dichloromethane (3 x 5 ml).
  • the combined organic layer was washed with water (3 x 10 ml), dried over anhydrous Na 2 SO 4 and concentrated.
  • the residue was purified by column chromatography to afford the desired product (60 mg, yield 64.8%) as a pale yellow solid.
  • Step 1 Preparation of 3-Dimethylaminomethylene-l-(6-fluoro-l-methoxy-9- methyl-9H-carbazol-4-yl)-4-oxo-cyclohexanecarbonitrile
  • the title compound was prepared according to a similar procedure mentioned in step 1 of example 9.
  • Step 2 Preparation of 2-Amino-6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4- yl)-5,6,7,8-tetrahydroquinazoline-6-carbonitrile
  • Step 1 Preparation of 3-Dimethylaminomethylene-l-(6-fluoro-l-methoxy-9- methyl-9H-carbazoI-4-yl)-4-oxo-cyclohexanecarbonitrile
  • Step 2 Preparation of 5-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-4,5,6,7- tetrahydro-2H-indazole-5-carbonitrile
  • Step 1 Preparation of 3-Dimethylaminomethylene-l-(6-fluoro-l-methoxy-9- methyl-9H-carbazol-4-yl)-4-oxo-cyclohexanecarbonitrile
  • the title compound was prepared according to a similar procedure mentioned in step 1 of example 9.
  • Step 2 Preparation of 5-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-4,5,6,7- tetrahydro-benzo [c] isoxazole-5-carbonitrile
  • hydroxylamine.HCl 21 mg, 0.30 mmole
  • sodium ethoxide 20 mg, 0.30 mmole
  • the reaction mass was concentrated under vacuum, diluted with water (10 ml) and extracted with ethyl acetate (3 X 5 ml). The combined organic layer was washed with water (3 x 10 ml), dried over anhydrous Na 2 SO 4 and concentrated.
  • the crude product was purified by column chromatography to afford the desired product (60 mg, yield 64.5 %) as a pale yellow solid.
  • Step 1 Preparation of 3-Dimethylaminomethylene-l-(6-fluoro-l-methoxy-9- methyl-9H-carbazol-4-yl)-4-oxo-cyclohexanecarbonitrile
  • Step 2 Preparation of 6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-2- methyl-5,6,7,8-tetrahydroquinazoline-6-carbonitrile
  • step 1 To a stirred solution of step 1 (100 mg, 0.25 mmole) in ethanol (3 ml) was added acetamidine.HCl (47 mg, 0.50 mmole) followed by sodium methoxide (27 mg, 0.50 mmole) at RT. After refluxing for 2h (the starting material was absent by TLC) the reaction mass was concentrated at 40 0 C under vacuum, diluted with water (10 ml) and extracted with dichloromethane (3 x 5 ml). The combined organic layer was washed with water (3 x 10 ml), dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography to afford the desired product (50 mg, yield 50 %) as a pale yellow solid.
  • Step 1 Preparation of 3-Dimethylaminomethylene-l-(l-methoxy-9-methyl-9H- carbazol-4-yl)-4-oxo-cyclohexanecarbonitrile
  • Step 2 Preparation of 6-(l-methoxy-9-methyl-9H-carbazoI-4-yl)-5,6,7,8- tetrahydroquinazoline-6-carbonitrile
  • the starting material was absent by TLC and the reaction mass was cooled to RT. To this was added aqueous sodium bicarbonate (10 ml) and the mixture was extracted with dichloromethane (3 x 5 ml).
  • Step 1 Preparation of 3-Dimethylaminomethylene-l-(l-methoxy-9-methyI-9/T- carbazol-4-yl)-4-oxo-cyclohexanecarbonitrile
  • Step 2 Preparation of 2-Amino-6-(l-methoxy-9-methyl-9H-carbazoI-4-yl)-5,6,7,8- tetrahydroquinazoline-6-carbonitriIe
  • step 1 To a stirred solution of step 1 (110 mg, 0.28 mmole) in ethanol (3 ml) was added guanidine.HCl (29.8 mg, 0.31 mmole) followed by sodium ethoxide (23.2 mg, 0.34 mmole) at RT. After refluxing for 2h (the starting material was absent by TLC) the reaction mass was concentrated under vacuum, diluted with water (10 ml) and extracted with ethyl acetate (3 x 5 ml). The combined organic layer was washed with water (3 x 10 ml), dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by column chromatography to afford the desired product (95 mg, yield 87.3 %) as a pale yellow solid.
  • Step 1 Preparation of 3-dimethylaminomethylene-l-(l-methoxy-9-methyl-9//- carbazol-4-yl)-4-oxo-cyclohexanecarbonitrile
  • Step 2 Preparation of 5-(l-methoxy-9-methyl-9H-carbazol-4-yl)-4,5,6,7- tetrahydro-2H-indazole-5-carbonitrile
  • the starting material was absent by TLC and the reaction mass was concentrated at 4O 0 C under vacuum.
  • Water (10 ml) was added and the mixture was extracted with dichloromethane (3 x 5 ml). The combined organic layer was washed with water (3 X 10 ml), dried over anhydrous Na 2 SO 4 and concentrated.
  • the crude product was purified by column chromatography to afford the desired product (63 mg, yield 68.5 %) as an off-yellow solid.
  • Step 1 Preparation of 3-Dimethylaminomethylene-l-(l-methoxy-9-methyl-9//- carbazol-4-yl)-4-oxo-cyclohexanecarbonitrile
  • Step 2 Preparation of 5-(l-methoxy-9-methyl-9H-carbazol-4-yl)-4,5,6,7- tetrahydro-benzo [c] isoxazole-5-carbonitriIe
  • Step 1 Preparation of 4-cyano-4-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4- yl)-heptanedioic acid dimethyl ester
  • Step 2 Preparation of 5-cyano-5-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4- yl)-2-oxo cyclohexanecarboxylic acid methyl ester
  • step 2 To a stirred solution of the product of step 1 (175 mg, 0.40 mmole) in dimethoxyethane (5 ml), was added 60% NaH in paraffin oil (20 mg, 0.50 mmole) and stirred for 1 hour at room temperature (the starting material was absent by TLC). The reaction mass was quenched with water (10 ml) and extracted with ethyl acetate (2 x 20 ml). The combined organic layer was dried the organic layer over anhydrous Na 2 SO 4 and concentrated to the desired product (125 mg, yield 77.2%) as a pale yellow solid.
  • Step 1 Preparation of 4-(l-methoxy-9-methyl-9H-carbazol-4-yl)-heptanedioic acid dimethyl ester
  • Step 1 Preparation of (l-Methoxy-9-methyl-6-nitro-9//-carbazol-4-yl)-methanoI: To a suspension of l-methoxy-9-methyl-6-nitro-9H-carbazole-4-carboxylic acid (this compound is prepared as per the procedure mentioned in US20070105855) (13 g, 43.33 mmol) in dry tetrahydrofuran (T ⁇ F) (1340 ml) was added borane dimethylsulfide complex (21.4 ml, 281.66 mmol) slowly at 0 C for one hour under a nitrogen atmosphere and then the mixture was stirred at room temperature for 18 hours. The reaction was monitored by TLC (50 % EtOAc/hexane).
  • Step 2 Preparation of 4-Chloromethyl-l-methoxy-9-methyl-6-nitro-9/- r - carbazole: To a suspension of (1 -methoxy-9-methyl-6-nitro-9H-carbazol-4-yl)-methanol (7.2 g, 26.2 mmol) in EtOAc (1050 ml) was added SOCl 2 (39.0 ml, 524.4 mmol) slowly at room temperature for 30 minutes and then the mixture was stirred at the same temperature for 2 hours. The reaction was monitored by TLC (50 % EtOAc/hexane). After completion of the reaction EtOAc was removed under vacuum and the residue was treated with ethyl acetate (20 ml) which was completely removed again.
  • Step 4 Preparation of 4-Cyano-4-(l-methoxy-9-methyl-6-nitro-9//-carbazol-4- yl)-heptanedioic acid dimethyl ester: To a suspension of (l-methoxy-9-methyl-6-nitro-9H-carbazol-4-yl)-acetonitrile (4.0 g, 13.55 mmol) in DMSO (120 ml) was added methyl acrylate (23.3 ml, 271 mmol) followed by 1 ,8-diazabicycloundec-7-ene (DBU) (4.5 g, 29.83 mmol) at room temperature and the mixture was stirred for 4 hours at the same temperature.
  • DBU 1 ,8-diazabicycloundec-7-ene
  • the reaction mass was cooled to 15 0 C, diluted with water (400 ml) and extracted with ethyl acetate (8 x 200 ml). The combined ethyl acetate layer was collected, washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated under vacuum.
  • the crude product was purified by column chromatography using silica gel (100-200) and 10 % ethyl acetate/ hexane to afford the title compound (2.2 g, 35 %). mp: 166-168 0 C.
  • Step 1 Preparation of l-(-4-difluoromethoxy-8-nitro-dibenzofuran-l-yl)-4-oxo- cyclohexane carbonitrile
  • step 1 To a solution of step 1 (0.150g, 0.0003mole) in benzene (25ml) and 2 drops of triethylamine was added N 5 N- dimethylformamide dimethylacetal (0.08ml, 0.0005mole) at room temperature under nitrogen. Reaction mixture was heated to reflux. Methanol was removed azeotropically using benzene as a solvent utilizing the Dean and Stark apparatus and fresh benzene (40ml) was added and the same operation was repeated until the starting material was absent by TLC. After completion of the reaction, the reaction mass was evaporated under vacuum to obtain the title compound in crude product as a brown residue (0.0150gm), taken as such for the next step without purification.
  • Step 3 Preparation of 6-(-4-difluoromethoxy-8-nitro-dibenzofuran-l-yl)-5, 6,7, 8- tetrahydro-quinazolin-6-yl)-6-carbonitrile
  • Step 4 Preparation of 6-(8-Amino-4-difluoromethoxy-dibenzofuran-l-yl)-5, 6,7, S-tetrahydro-quinazoIin- ⁇ -yty- ⁇ -carbonitrile
  • a solution of compound of step 3 (0.017gm, 0.038mmoles) in ethyl acetate (3ml) was added a catalytic quantity of Raney Nickel and then hydrogenated under hydrogen with balloon pressure over a period of 12 hours. After completion of the reaction, the reaction mixture was filtered through celite bed and concentrated under vacuum to obtain the title compound (0.014gm, yield- 88 %).
  • Step 5 Preparation of N-[9-(6-Cyano-5, 6,7, 8-tetrahydro-quinazolin-6-yl)-6- difluoro-methoxy-dibenzofuran-2-yl]-methane sulfonamide
  • pyridine 0.02ml, 0.24mmole
  • the reaction mixture was stirred for 10 minutes and was added methanesulfonyl chloride (0.01ml, 0.12mmole). The reaction mixture was allowed to stir for 2 hours at room temperature.
  • reaction mass was diluted with water (10ml) and extracted with ethyl acetate (3 X 30ml). The combined organic layer was washed with water dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography using chloroform to obtain the title compound (0.012gm, yield-71.8 %) as a yellow solid.
  • Step 1 Preparation of l-(-4-methoxy-8-nitro-dibenzofuran-l-yI)-4-oxo- cyclohexane carbonitrile A solution of intermediate 7 (0.840gm, 0.0024mole) and anhydrous potassium carbonate (0.992gm, 0.0071 mole) in dry dimethylformamide (15ml) was stirred at room temperature for 15 minutes. To that, methyl iodide (0.23ml, 0.003mole) was added drop wise over a period of 10 minutes at room temperature, and then the reaction mixture was allowed to stir for 2 hours at room temperature.
  • reaction mass was diluted with water (50ml) and extracted with ethyl acetate (3 X 75ml). The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under vacuum to obtain the title compound (0.700gm, yield-80%) as a yellow solid.
  • Step 2 Preparation of l-(-4-methoxy-8-nitro-dibenzofuran-l-yl)-3- dimethylaminomethylene-4-oxo-cyclohexane carbonitrile
  • the reaction mixture was heated to reflux. Methanol was removed azeotropically using benzene as a solvent utilizing the Dean and Stark apparatus and fresh benzene (40ml) was added and the same operation was repeated until the starting material was absent by TLC. After completion of the reaction, the reaction mass was evaporated under vacuum to get the desired crude product as a brown residue (0.120gm), taken as such for the next step without purification.
  • Step 3 Preparation of 6-(-4-methoxy-8-nitro-dibenzofuran-l-yI)-5, 6,7, 8- tetrahydro-quinazolin-6-yl)-6-carbonitrile
  • a solution of crude product obtained in step 2 (0.115gm, 0.0002 mole) in dry dimethylformamide (5ml) was added Formamidine.HCl (0.02 lgm, 0.00025mole) at room temperature and then the reaction mixture was heated to 14O 0 C and maintained at 14O 0 C for 2 hours. After completion of the reaction, the reaction mass was diluted with water (20ml) and extracted with ethyl acetate (3 X 30ml). The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under vacuum to obtain the title compound (0.033gm, yield-35.2%) as a yellow solid.
  • Step 4 Preparation of 6-(8-Amino-4-methoxy-dibenzofuran-l-yl)-5, 6,7, 8- tetrahydro-quinazolin-6-yl)-6-carbonitrile
  • ethyl acetate 10ml
  • methanol ImI
  • a catalytic quantity of Raney Nickel was added to a solution of compound of step 3 (0.050gm, 0.012mmole) in ethyl acetate (10ml) and methanol (ImI) and then hydrogenated under hydrogen gas with balloon pressure over a period of 12 hours. After completion of thr reaction, the reaction mixture was filtered through celite bed and the filtrate was concentrated under vacuum to obtain the title compound (0.043gm, yield- 93 %).
  • HEK 293 cells were routinely maintained in T-25 cm2 flasks. One day prior to transfection, cells were seeded in a 6 well cell culture plate (Corning) at a seeding density of 1.3 - 1.4 x 10 6 cells/well. Cells were transfected for 5 h using lipofectamine-2000, as per manufacturer instructions with total 4.0 ⁇ g of plasmid DNA/well. PDE4 expression plasmid in each well was 10%-50% of total plasmid DNA for respective subtype selective expression plasmids.
  • Each well was transfected with PDE4 expression plasmid (10-50%), pCREluc plasmid (20-50%), pSV-D gal plasmid (20-30%) and empty vector to make up total DNA concentration.
  • medium was removed and cells were trypsinized, counted and seeded in 96 well plates at a seeding density of 40000 cells/well in complete medium (DMEM with 10% FBS, Ix penicillin-streptomycin). Plate was incubated in CO 2 incubator set to 37 0 C and 5% CO 2 for overnight. Next day, cells were incubated with respective inhibitors for 30-45 minute, followed by stimulation with 5 ⁇ M forskolin for 4 h incubation in incubator.
  • TNF- ⁇ Tumor necrosis factor- ⁇
  • Fresh blood was collected in Heparinzed tubes by venipuncture from male volunteers with consent. The subjects had no apparent inflammatory conditions and had not taken any NSAID for at least 4 days prior to blood collection. 487.5 ⁇ l of blood in triplicate were pre-incubated with 2.5 ⁇ l of test compound at different concentrations (0, 0.001, 0.003, 0.01, 0.03 0.1, 0.3, 1, 3, lO ⁇ M) and vehicle (DMSO) at 37 0 C for 15 min, and this was followed by incubation blood with lO ⁇ l lipopolysaccharide (final concentration l ⁇ g/ml) diluted in 0.1% bovine serum albumin diluted in phosphate buffer saline) for 24 hrs at 37 0 C. PBS was used as a blank. After the incubation period, the samples were centrifuged at 1500xg at 4 0 C for 10 min. Plasma TNF-alpha was quantified ELISA (R&D System).

Abstract

The present invention relates to novel heterocyclic compounds of general formula (I) that are phosphodiesterase inhibitors (PDEs), in particular phosphodiesterase type 4 inhibitors. These novel PDEs are useful in the treatment of inflammatory diseases (such as asthma, COPD, allergic rhinitis, allergic conjunctivitis, respiratory distress syndrome, chronic bronchitis, nephritis, rheumatoid spondylitis, osteoarthritis, atopic dermatitis, eosinophilic granuloma, psoriasis, rheumatoid septic shock, ulcerative colitis, multiple sclerosis, chronic inflammation, Crohn's syndrome and central nervous system(CNS) disorders) as well as disorders or conditions generally characterized by or associated with an excessive secretion of TNF-α and Phosphodiesterase 4 (PDE IV).

Description

Novel heterocyclic compounds, pharmaceutical compositions containing them and processes for their preparation
This application claims priority to Indian patent application Nos. 656/CHE/2008 filed on March 17, 2008 and 2228/CHE/2008 filed on September 12, 2008, the contents of which are incorporated by reference in their entirety
Field of invention
The present invention relates to novel heterocyclic compounds that may be useful as phosphodiesterase inhibitors (PDEs) in particular phosphodiesterase type 4 inhibitors represented by formula I, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, their enantiomers, their appropriate N-oxides, their pharmaceutically acceptable salts, their pharmaceutically acceptable hydrates, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them and their use in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor(TNF-α).
Background of the invention Bronchial asthma is a complex multifactorial disease characterized by hyperactivity of the respiratory tract to external stimuli. Airway inflammation leads to a number of severe lung diseases including Asthma and Chronic Obstructive Pulmonary Diseases (COPD, also known as Chronic Obstructive Airway Disease, Chronic Obstructive lung Disease or chronic airflow limitation and chronic airflow obstruction.). The airflow limitation is usually progressive and associated with abnormal inflammatory response of the lungs to noxious particles or gases.
Many biological responses are mediated by levels of cyclic nucleotides, mainly cAMP and cGMP which in turn are synthesized by adenylyl cyclases (ACs) and guanylate cyclases (GCs). To regulate levels of c AMP and cGMP, all cells have Phosphodiesterases (PDEs) that hydrolyze cAMP and cGMP to 5'-AMP and 5'- GMP. In humans there are 21 different PDE isoforms that are classified into 11 different groups. Basically these PDEs fall into three categories like those that are specific to (i) cAMP, (ii) cGMP and (iii) those that act on both cAMP and cGMP. These 11 groups of PDEs are classified according to their nucleotide selectivity. All 4 PDE4 isoforms possess upstream conserved regions (UCRs) which appear to modulate dimerisation and may bind to signaling molecules such as lipids. At least 18 different splice variants of the 4 PDE4 isoforms exist. Because of the critical role of cAMP in mediating cytokine responses, cAMP specific PDE (PDE-4) plays an important role in the progression of inflammatory diseases. Many of the mediators of inflammatory response such as T cells, B cells, monocytes, neutrophils, eosinophils and macrophages have PDE4 enzymes as their primary cAMP specific PDE. Among the inflammatory diseases that are implicated by these cellular mediators are asthma, chronic obstructive pulmonary diseases (COPD), rheumatoid arthritis, inflammatory bowel disease, Crohn's disease and multiple sclerosis. Consequently, the development of PDE4 inhibitors as therapeutic agents for these diseases has been a major pharmaceutical focus. PDE4 indirectly controls the degree of bronchodilation. In inflammatory cells cAMP is a negative regulator of the primary activating pathways such as cytokine release by T-cells. Inhibition of the PDE4 isozymes in these cells results in elevated cAMP levels and consequent inactivation of the inflammatory response. In addition to the direct role of cAMP in inflammatory cell function, elevated cAMP levels also lead to smooth muscle relaxation. Consequently inhibition of PDE4 activity leading to higher cAMP levels causes bronchodilation thereby alleviating symptoms of respiratory diseases such as asthma or COPD.
Also, inhibition of PDE4 enzymes increase levels of cAMP, which modulates the activity of most of the cells that contribute to the pathophysiology of allergic asthma. Elevation of c AMP would produce beneficial effects, some of which include, apart from airway smooth muscle relaxation, inhibition of mast cell mediator release, suppression of neutrophil degranulation, inhibition of basophil degranulation and inhibition of monocyte and macrophage activation. The connection between PDE4 activity and cognition has been speculated ever since the discovery that the cAMP-regulating dunce gene of the fruit fly encodes a PDE4 homologue(Λtøw/-e, 1981,289,5793, 79-l;J.molbiol, 1991,222,3,553-565). Current drug discovery efforts involved the design of the PDE4 inhibitors with reduced side effects at the same time maintaining the anti-inflammatory properties of rolipram. Compounds like Cilomilast, roflumilast, Lirimilast and AWD- 12-281 belong to the second generation PDE4 inhibitors.
1. Patent application WO93/19749 claims the compounds of formula I which are useful for allergy and inflammatory states.
Where X4 is
One of the representative examples of this patent is as given below.
Figure imgf000005_0002
2. Patent US5811455 claims the compounds of formulae AA and BB
Figure imgf000006_0001
One of the representative examples of this invention is
Figure imgf000006_0002
4. Patent application WO2006011024 claims the compounds of generic formula
Figure imgf000006_0003
One of the representative compounds is as given below and the compounds of the invention are claimed for asthma and chronic obstructive pulmonary disease apart from other disease states.
Figure imgf000006_0004
OCH,
Challenges that are facing the PDE4 inhibitors are mainly nausea, vomiting, and increased gastric acid secretion, which may be because of selectivity towards binding sites. Based on the prior art reports, compounds with selectivity for the high- affinity rolipram binding site causes side effects, where as compounds with selectivity for the low-affinity rolipram binding site are expected to have better therapeutic effects compared to rolipram (J. Biol. Chem. 1992,267(3):1798-1804; J. Biol. Chem. 1999,274(17): 11796-11810). Other side effects include cardiac dysarhythmias, vasculitis and osteoporosis.
As described above, as regulation of intracellular signaling is coordinated by PDE4, it has become a validated target for the development of therapeutics for inflammatory diseases such as asthma and COPD. PDE4 also has been shown to be a potential target for depression, memory enhancement, cardiovascular disease and osteogenesis.
During the course of our research aimed at the development of novel antiasthmatic compounds having potential PDE4 inhibitory activity, we have filed a WTO patent application in India bearing No. 1647/MUM/2006 dated September 11 , 2006, and PCT application No. PCT/IB2007/002596 dated September 10, 2007, and 656/CHE/2008 dated March 14, 2008, are incorporated herein by reference in their entireties, for a novel series of heterocyclic compounds useful for the treatment of inflammatory and allergic disorders.
Summary of the invention
According to the present invention, the compounds are represented by the general formula (I)
Figure imgf000007_0001
General Formula (I)
Wherein
R1 is selected from
Figure imgf000008_0001
X represents O, S or NR4; Y represents O, S, NR4 or can be absent; X1 and X2 independently represent hydrogen, hydroxy, amino, nitro, cyano and optionally substituted groups selected from alkyl, alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, alkyl hydroxy, alkyl halo, alkyl amino, alkenyl amino, alkenyl amino alkyl, guanidyl, ureidyl, CR5R6R7, CR5R6OR7, CR5R6C(O)R7, CR5R6C(O)C(O)OR7, CR5R6C(O)OR7, (CR5R6)nC(O)R7, CR5R6C(O)NR7R8, CR5R6S(O)mR7, CR5R6N R7R8, CR5R6CN, CR5R6R7, CR5R6NR7S(O)01R5, CR5R6N R7C(X)R5,
CR5R6NR7S(O)01NR7R8, CR5R6NR7C(O)NR7R8, CR5R6NR7C(O)C(O)OR7, CR5R6NR7C(S)NR7R8, CR5R6NR7C(NCN)NR7R8, NR5R6, NR5S(O)1nR6, NR5S(O)1nNR5, NR5C(O)R6, NR5C(O)OR6, NR5C(O)NR7R8, NR5C(S)NR7R8, NR5C(O)NR6S(O)mR7, C(NR5)R6, C(NNR5C(X)NR7R8)R5, C(NNR5S(O)mR6)R5, C(NR5)NR7R8, C(NCN)SR5, C(NOR5)R6, C(O)OR5, C(O)NR5R6, C(O)N R7R8, C(O)NR5N R7R8, C(O)R5, OR5, OC(O)R5, OC(O)NR7R8, OS(O)mR5, SO2, SO3H, S(O)mR5, S(R5), S(O)01NR7R8; or when X1 and X2 are adjacent to each other, they may together form a 4 to 7 membered cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl. Nonlimiting examples of such cyclic groups include but are not limited to pyrazole, imidazole, imidazolidine, triazole, tetrazole, pyrrolidine, pyrrole, thiophene, thiazole, oxazole, isoxazole, furan, tetrahydrothiophene, tetrahydrofuran, thiazolidine, oxazolidine, piperazine, morpholine, thiomorpholine, piperidine, pyridine, pyrazine, pyrimidine, pyridazine; X3 represents hydrogen, cyano, Ci-4 alkyl, C2_4alkenyl, C2-4alkynyl, alkylhalo, nitro, alkylnitro, alkyl carboxy, alkylcarbonyl, CH2NR 5r R>6 ,,CH2OR , C3-C4 cyclo alkyl, OR5, R5OR6, NR5R6, NR5R6NO2, C(O)OR5, C(O)NR7R8, C(O)R5, CH2NHC(O)C(O)NH2, CHNR5, CHN=OR5, NHCN, CH(CN)2, CH(CN)R5;
X4 represents O, NR5, N-OR5, NCR5R6R7, NOR8, NNR7R8, NCN, NNR5C(X)NR7R8 or X4 may be dimethyl ketal, diethyl ketal, 1,3-dithiane, 1,3- dithiolane, 1,3-dioxane, 5,5-dimethyl-[l,3]dioxane or 1,3-dioxolane; or
X1 and X4 can form a 5 to 7 membered cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl. Nonlimiting examples of such cyclic groups include but are not limited to pyrazole, imidazole, imidazolidine, triazole, tetrazole, pyrrolidine, pyrrole, thiophene, thiazole, oxazole, isoxazole, furan, tetrahydrothiophene, tetrahydrofuran, thiazolidine, oxazolidine, piperazine, morpholine, thiomorpholine, piperidine, pyridine, pyrazine, pyrimidine, pyridazine;
R2 and R3 are independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, alkylamino ,alkyl hydroxy, alkyl halo, nitro, amino, cyano, formyl, carboxy, carbamoyl, acyl, halogen, ureidyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, acylamino, alkanoylamino, CR5R6R7, CR5R6OR7, CR5R6C(O)R7, CR5R6C(O)C(O)OR7, CR5R6C(O)OR7, (CR5R6)nC(O)R7, CR5R6C(O)NR7R8, CR5R6S(O)mR7, CR5R6NR7R8, CR5R6CN, CR5R6R7, CR5R6NR7S(O)01R5, CR5R6NR7C(X)R5, CR5R6NR7S(O)1nNR7R8,
CR5R6NR7C(O)NR7R8, CR5R6NR7C(O)C(O)OR7, CR5R6NRTC(S)N R7R8, CR5R6NR7C(NCN)N R7R8, NR5R6, NR5, NR5S(O)01R6, NR5S(O)1nNR5, NR5C(O)R6, NR5C(O)OR6, NR5C(O)NR7R8, NR5C(S)NR7R8, NR5C(O)NR6S(O)mR7, C(NR5)R6, C(NNR5C(X)NR7R8)R5, C(NN R5S(O)mR6)R5, C(NR5)NR7R8, C(NCN)SR5, C(NOR5)R6, C(O)OR5, C(O)NR5R6, C(O)NR7R8, C(O)NR5NR7R8, C(O)R5, OR5, OC(O)R5, OC(O)NR7R8, OS(O)01R5, SO2, SO3H, S(O)01R5, S(R5), S(O)01NR7R8;
R4 represents hydrogen, hydroxyl, alkyl, SO2CH3, SO2PhCH3 or a protecting group; or when X represents NR4, then R2 and R4 may form a 6 to 7 membered substituted or unsubstituted heterocyclic ring;
R5, R6, R7, R8 may be independently selected from hydrogen, Cj-C6 straight or branched alkyl, dialkyl, C2-C6 straight or branched alkenyl, alkylamino, alkyl halo, alkyl hydroxy, acyl, alkoxy, carboxy, sulfonyl, sulfinyl, thio, sulfamido, amido, NH(CO)R7, nitro, amino, halo, hydroxy, ureidyl, guanidyl; or
R7 and R8 when attached to Nitrogen as NR7R8 may together with the nitrogen atom to which they are attached form a 5 to 7 membered optionally substituted ,saturated, partially saturated or unsaturated ring optionally containing at least one additional heteroatom selected from O, NR5 or S;
R' and R' ' independently represent hydrogen, hydroxyl, halo, cyano, substituted or unsubstituted alkyl, alkoxy, haloalkyl, CONH2, COOH; or
R' and R" together with the carbon atoms to which they are attached form a C5 to C8 ring system selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and the substitutions on the said cycloalkyl, heterocyclyl, aryl, heteroaryl include but not limited to halo, cyano, haloalkyl, amino, amido, NHSO2Me, etc.; r represents an integer O, 1, 2 or 3; s represents an integer 0, 1 or 2; m represents an integer 0, 1 or 2; n represents an integer 0, 1 or 2; dotted line [ — ] inside the ring in general formula (I) represents an optional double bond; and their analogues, derivatives, tautomers, stereoisomers, enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable hydrates, pharmaceutically acceptable solvates, pharmaceutical compositions, N-oxides and bioisosteres.
Preferred is a compound of general formula (I) wherein X is NR4 Further preferred is a compound of general formula (I) wherein Y is O Further preferred is a compound of general formula (I) wherein Y is absent Further preferred is a compound of general formula (I) wherein R1 is selected from
Figure imgf000011_0001
Further preferred is a compound of general formula (I) wherein R2 is hydrogen
Further preferred is a compound of general formula (I) wherein R2 is alkyl
Further preferred is a compound of general formula (I) wherein R2 is methyl Further preferred is a compound of general formula (I) wherein R2 is haloalkyl
Further preferred is a compound of general formula (I) wherein R2 is difluoromethane
Further preferred is a compound of general formula (I) wherein R3 is hydrogen
Further preferred is a compound of general formula (I) wherein R4 is hydrogen
Further preferred is a compound of general formula (I) wherein R4 is alkyl
Further preferred is a compound of general formula (I) wherein R4 is methyl Further preferred is a compound of general formula (I) wherein R4 is ethyl
Further preferred is a compound of general formula (I) wherein R4 is SO2CH3
Further preferred is a compound of general formula (I) wherein R4 is
SO2PhC CHH33
Further preferred is a compound of general formula (I) wherein X3 is cyano
Further preferred is a compound of general formula (I) wherein X4 is oxygen Further preferred is a compound of general formula (I) wherein R' and R' ' together with the carbon atoms to which they are attached form a six member substituted or unsubstituted aryl group wherein the aryl group is phenyl and the substitutions are selected from NHSO2Me, CF3
Also preferred are the compounds of general formula (I) where X and X form a 4 to 7 membered ring with optional substitutions such as
Figure imgf000012_0001
Also preferred are the compounds of general formula (I) where X is NR4 then R4 and R2 form an optionally substituted 6 to 7 membered ring such as
Figure imgf000012_0002
Representative compounds of the present invention are specified below. The present invention should not be construed to be limited to them a) 4, 5, 6, 7-Tetrahydro-5-(l-methyl-lH-indol-4-yl)-2H-indazole- 5-carbonitrile b) 4, 5, 6, 7-Tetrahydro-5-(lH-indol-4-yl)-2H-indazole-5-carbonitrile c) 4, 5, 6, 7-Tetrahydro-5-(7-methoxy-lH-indol-4-yl)-2H-indazole-5 -carbonitrile d) l-(7-Methoxy-l-methyl-lH-indol-4-yl)-4-oxocyclohexanecarbonitrile e) 4, 5, 6, 7-Tetrahydro-5-(7-methoxy-l-methyl-lH-indol-4-yl)-2H-indazole-5- carbonitrile J) l-(7-methoxy-lH-indol-4-yl)-4-oxocyclohexanecarbonitrile g) 4-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-cyclohexanone h) 4-(l-methoxy-9-methyl-9H-carbazol-4-yl)-cyclohexanone i) 6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-5, 6, 7, 8- tetrahydroquinazoline-6-carbonitrile j) 2-Amino-6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-5, 6, 7, 8- tetrahydroquinazoline-6-carbonitrile k) 5-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-4, 5, 6, 7-tetrahydro-2H- indazole-5-carbonitrile I) 5-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-4,5,6, 7-tetrahydro- benzo[c]isoxazole-5-carbonitrile m) 6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-2-methyl-5, 6, 7, 8- tetrahydroquinazoline-6-carbonitrile n) 6-(l-methoxy-9-methyl-9H-carbazol-4-yl)-5, 6, 7, 8-tetrahydroquinazoline-6- carbonitrile o) 2-Amino-6-(l -methoxy-9-methyl-9H-carbazol-4-yl)-5 , 6, 7, 8- tetrahydroquinazoline-6-carbonitrile p) 5-(l-methoxy-9-methyl-9H-carbazol-4-yl)-4, 5, 6, 7-tetrahydro-2H-indazole-5- carbonitrile q) 5-(l-methoxy-9-methyl-9H-carbazol-4-yl)-4,5,6, 7-tetrahydro- benzo[c]isoxazole-5-carbonitrile r) 6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-4-oxo-3, 4, 5, 6, 7, 8- hexahydroquinazoline-6-carbonitrile s) 2-Amino-6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-4-oxo- 3,4, 5, 6, 7, 8-hexahydroquinazoline-6-carbonitrile t) 5-(6-Fluoro- 1 -methoxy-9-methyl-9H-carbazol-4-yl)-3-oxo-3 , 3a, 4, 5, 6, 7- hexahydro-2H-indazole-5-carbonitrile u) 6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol~4-yl)-2-methyl-4-oxo-
3, 4, 5, 6, 7, S-hexahydroquinazoline-ό-carbonitrile v) 2-Amino-6-(l -methoxy-9-methyl-9H-carbazol-4-yl)-4-oxo-3 , 4, 5, 6, 7, 8- hexahydroquinazoline-6-carbonitrile w) 5-(l -methoxy-9-methyl-9H-carbazol-4-yl)-3-oxo-3 , 3a, 4, 5, 6, 7-hexahydro-2H- indazole-5-carbonitrile x) l-(l-Methoxy-9-methyl-6-nitro-9H-carbazol-4-yl)-4-oxo- cyclohexanecarbonitrile y) 6-(l-Methoxy-9-methyl-6-nitro-9H-carbazol-4-yl)-5, 6, 7, 8-tetrahydro- quinazoline-6-carbonitrile z) N-[5-(6-Cyano-5, 6, 7, 8-tetrahydro-quinazolin-6-yl)-8-methoxy-9-methyl-9H- carbazol-3-yl]-methanesulfonamide aa) N-[5-(l-Cyano-4-oxo-cyclohexyl)-8-methoxy-9-methyl-9H-carbazol-3-yl]- methanesulfonamide bb) 2-Amino-6-(l -methoxy-9-methyl-6-nitro-9H-carbazol-4-yl)-5 , 6, 7,8- tetrahydro-quinazoline-6-carbonitrile cc) N-[9-(6-Cyano-5, 6, 7, 8-tetrahydro-quinazolin-6-yl)-6-difluoromethoxy- dibenzofuran-2-yl] -methane sulfonamide dd) N-[9-(6-Cyano-5, 6, 7, 8-tetrahydro-quinazolin-6-yl)-6-methoxy- dibenzofuran-2-yl] -methane sulfonamide ee) 6-(4-Methoxy-8-trifluoromethyl-dibenzofuran-l-yl)-5, 6, 7,8-tetrahydro- quinazoline-6-carbonitrile ff) 1- (4-Methoxy-8-trifluoromethyl-dibenzofuran- 1 -yl) -4-oxo- cyclohexanecaronitrile gg) 5-(4-Methoxy-8-trifluoromethyl-dibenzofuran- 1 -yl)-3-oxo-3 , 3a,4,5,6, 7- hexahydro-2H-indazole-5-carbonitrile hh) 2-Amino-6-(4-Methoxy-8-trifluoromethyl-dibenzofuran-l-yl)-5, 6, 7, 8- tetrahydro-quinazoline-6-carbonitrile H) 6-(4-Methoxy-8-trifluoromethyl-dibenzofuran-l-yl)-2-methyl-5, 6, 7, 8- tetrahydro-quinazoline-6-carbonitrile Present invention also relates to a process for the preparation of the novel heterocyclic compounds of general formula (I).
The compounds of the present invention may inhibit or regulate the TNF alpha production and are useful in the treatment of allergic and inflammatory diseases including asthma, allergic conditions, allergic conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, diabetes, Crohn's disease allergic rhinitis endotoxic shock and adult respiratory distress syndrome. The compounds of the present invention are particularly useful for the treatment of asthma and chronic obstructive pulmonary disease (COPD).
Detailed description of the invention: Definitions:
The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon that may be substituted or unsubstituted. Examples of "alkyl" include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, isobutyl, etc.
The term "alkenyl" used herein, either alone or in combination with other radicals, denotes a straight or branched C2-C6 aliphatic hydrocarbon chain containing one or more carbon to carbon double bonds that may be optionally substituted with multiple degrees of substitution being allowed. The term "alkenyl" includes dienes and trienes of straight and branched chains and are selected form vinyl allyl, 2- butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3hexenyl, 4- hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, and 6- heptenyl. The term "alkynyl" used herein, either alone or in combination with other radicals, denotes a straight or branched chain aliphatic hydrocarbon containing two to eight carbons with one or more triple bonds which may be substituted or unsubstituted. The term "alkynyl" includes di-and tri-ynes, such as ethynyl, 1- propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.
The term "acyl" refers to the group-C(O)Rd where Rd is alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl each as herein defined and examples of which include acetoyl, propanoyl, butanoyl, iso-butanoyl, pentanoyl, benzoyl, etc., which may be substituted or unsubstituted.
The term "acylamino" used herein represents -NHC(O)Rd where Rd is as defined above and examples of which include CH3CONH-, C6H5CONH-, Cl2C6H3CONH-, etc. "Alkoxy" refers to a group -OR0 where Rc is alkyl as herein defined.
Representative examples include but are not limited to methoxy, ethoxy, etc.
"Alkylamino" refers to the group - N(Rc)2 where one R0 is alkyl and the other Rc independently is H or alkyl as herein defined.
"Alkylhalo" refers to the group 'Rc-halogen' where R0 is alkyl defined as above and halogen is selected from Fluorine, Chlorine, Bromine and Iodine and it can be haloalkyl, dihaloalkyl, trihaloalkyl or polyhaloalkyl like methylene chloride, CF3, CHF2, CF2-CF3 etc.
"Halogen" refers to Fluorine, Chlorine, Bromine or Iodine.
"Alkylhydroxy or hydroxyalkyl" refer to the group R0OH where R0 is alkyl as herein defined and the representative examples include but are not limited to hydroxy methyl, hydroxy ethyl, hydroxy propyl, etc.
"Aryl" refers to optionally substituted aromatic ring system having the carbon atoms in the range of five to ten carbon atoms and they may be monocyclic, bicyclic or polycyclic and unsaturated or partially saturated and one or more carbons may optionally be replaced by one or more heteroatoms selected from N, O and S. Exemplary aryl groups include phenyl, naphthyl, indanyl, biphenyl, etc.
The term "cycloalkyl" used herein, either alone or in combination with other radicals, denotes mono, bicyclic or polycyclic saturated, partially saturated hydrocarbon ring system of about 3 to 12 carbon atoms which may be substituted or unsubstituted. Exemplary "cycloalkyl" groups include, but are not limited to cyclopopyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, perhydronapthyl, adamantyl, noradamantyl and spirobicyclic groups such as spiro (4,4)non-2-yl. The term "cycloalkylalkyl" refers to a cycloalkyl ring containing 3 to 12 carbon atoms directly attached to an alkyl group which is then attached to the main structure at any carbon atom in the alkyl group that results in a stable structure such as cyclopropylmethyl, cyclobutylmethyl, etc.
"Heteroaryl "refers to monocyclic aromatic ring systems or fused bicyclic aromatic ring systems comprising two or more aromatic rings preferably two to three ring systems. These heteroaryl rings contain one or more nitrogen, sulfur and or oxygen atoms where N-oxides sulfur oxides and dioxides are permissible heteroatom substitutions. The term includes ring(s) optionally substituted with halo, nitro, amino, alkoxy, alkyl sulfonyl amino, alkylcarbonylamino, carboxy, alkyl carbonoyl, hydroxy, and alkyl groups. Examples of heteroaryl groups include furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, chromanyl, iso chromanyl, etc.
"Heterocyclyl" refers to a stable 3 to 15 membered ring that is either saturated or has one or more degrees of unsaturation or unsaturated. These heterocyclic rings contain one or more heteroatoms selected from the group consisting of nitrogen, sulfur and/or oxygen atoms where N-oxides, sulfur oxides and dioxides are permissible heteroatom substitutions. Such a ring may be optionally fused to one or more of other heterocyclic ring(s), aryl ring(s) or cycloalkyl ring(s). Examples of such groups may be selected from the group comprising azetidinyl, acridinyl, pyrazolyl, imidazolyl, triazolyl, pyrrolyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, pyrazinyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, morpholinyl, thiomorphonilyl, pyridazinyl, indolyl, isoindolyl, quinolinyl, chromanyl, etc. "Heterocyclylalkyl" refers to a heterocyclic ring radical defined above directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at carbon atom in the alkyl group that results in the creation of a stable structure. Unless otherwise specified, the term "substituted" as used herein refers to substitution with any one or any combination of the following substituents: hydroxy, halo, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, - COOR5, -C(O)R5, -C(S)R5, -C(O)NR5R6, -C(O)ONR5R6, -NR5CONR6R7, -
N(R5)SOR6, -N(R5)SO2R6, -(=N-N(R5)R6), - NR5C(O)OR6, -NR5R6, -NR5C(O)R6, - NR5C(S)R6, -NR5C(S)NR6R7, -SONR5R6, -SO2NR5R6, -OR5, -OR5C(O)NR6R7, - OR5C(O)OR6, -OC(O)R5, -OC(O)NR5R6, -R5NR6C(O)R7, -R5OR6, -R5C(O)OR6, - R5C(O)NR6R7, -R5C(O)R6, -R5OC(O)R5, -SR5, -SOR5, -SO2R5, and -ONO2, wherein R5, R6 and R7 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring. According to one embodiment, the substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl" the substituent on "substituted aryl" cannot be "substituted alkenyl".
"Stereoisomers" refer to certain compounds described herein containing one or more chiral centres or may otherwise be capable of existing as multiple stereoisomers. The scope of the present invention includes pure stereoisomers as well as mixtures of stereoisomers, such as purified enantiomers/diastereomers or enantiomerically/diastereomerically enriched mixtures.
"Bioisosteres" refers to compounds or groups that possess near molecular shapes and volumes, approximately the same distribution of electrons and which exhibit similar physical properties such as hydrophobicity. Bioisosteric compounds affect the same biochemically associated systems as agonist or antagonists and thereby produce biological properties that are related to each other.
"Pharmaceutically acceptable salts" forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, 2-dimethylaminoethanol, isopropylamine, morpholine, piperazine, piperidine, procaine, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, choline hydroxide, dicyclohexylamine, metformin, benzylamine, phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, pyrimidine, spermidine, etc.; chiral bases like alkylphenylamine, glycinol, phenyl glycinol, etc.; salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, lysine, arginine, serine, threonine, phenylalanine; unnatural amino acids such as D- isomers or substituted amino acids; salts of acidic amino acids such as aspartic acid, glutamic acid; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts. Salts may include acid addition salts where appropriate, such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, etc. "Pharmaceutically acceptable solvates" may be hydrates or comprising other solvents of crystallization such as alcohols.
"Compounds of the invention" or "present invention" refers to the compounds of the present invention represented by general formula (I) as herein defined, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, their enantiomers, their appropriate N-oxides, their pharmaceutically acceptable salts, their pharmaceutically acceptable hydrates, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. The present invention also relates to a process for the preparation of the novel heterocyclic compounds of general formula (I).
The compounds of the present invention may inhibit or regulate TNF alpha production and are useful in the treatment of allergic and inflammatory diseases including asthma, inflammatory diseases, allergic conditions, allergic conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, diabetes, Crohn's disease, allergic rhinitis endotoxic shock and adult respiratory distress syndrome. The compounds of present invention are particularly useful for the treatment of asthma and chronic obstructive pulmonary disease (COPD).
Another embodiment of the present invention is a method of treating an inflammatory disease, disorder or condition associated with undesirable inflammatory immune response or a disease or condition induced by or associated with an excessive secretion of TNF-α and PDE4 in humans. This method includes administering to the human a therapeutically effective amount of a compound according to the general formula (I). "Method of treating" includes preventing or delaying the appearance of clinical symptoms, inhibiting the state disorder or condition, relieving the disease causing regression of the disease. General method of preparation
The compounds of general formula (I) can be synthesized by the schemes illustrated below:
The compounds of general formula (I), where X is NR4 (wherein R4 can be hydrogen or alkyl such as methyl or a protecting group such as tosyl, benzyl, chlorobenzoyl); X3 is cyano; Y can be either absent or O, S or NR4; R1 as mentioned above; R can be hydrogen or alkyl; R , R' and R" are as mentioned above, can be synthesized as described in the general synthetic scheme 1
Figure imgf000021_0001
General Formula (I)
In the above mentioned scheme, the compound of formula E is made using the normal conventional methods. The compound of general formula E is then treated with methyl acrylate in the presence of a suitable base such as 1,1,3,3-tetramethyl guanidine, triton B (benzyltrimethylammonium hydroxide) in the presence of a suitable solvent such as dimethyl sulphoxide, acetonitrile and dimethyl formamide (DMF) to give the compound of general formula F. The compound of general formula F is then converted to the compound of general formula G by internal cyclization in the presence of a suitable base such as sodium hydride, potassium hydride, sodium or potassium methoxide, etc., and an appropriate solvent such as dimethoxyethane (DME) and DMF. The compound of general formula (I) wherein R1 is cyclohexanone is obtained from the compound of general formula G by treatment with a suitable inorganic salt such as sodium halides, lithium halides and potassium halides in a suitable solvent system such as dimethyl sulphoxide and water. Alternately the compound of general formula G is converted to the compound of general formula H which in turn is converted to the compound of general formula I upon treatment with dimethylformamide dimethylacetal in the presence of a suitable solvent such as dimethyl formamide and benzene. Compound of general formula I is then converted to a compound of general formula (I) using a reagent such as hydrazine hydrate, phenyl hydrazine, methyl hydrazine, hydroxylamine hydrochloride, salts of guanidine, guanidine acetic acid, acetimidine hydrochloride, salts of formamidine in the presence of a suitable solvent such as ethanol, methanol, n-butanol, toluene, benzene, dioxane and the like.
In yet another embodiment the intermediate AI, (wherein X3, Y, R2 and R4 are as described above and T hydrogen or halo, nitro or alkylhalo) can be synthesized according to the general synthetic scheme Ia.
Scheme Ia
Figure imgf000023_0001
In the above mentioned Scheme Ia, the compound AC is prepared as per the Scheme mentioned in - Chem Pharm. Bull 29(3), 699-710 ( 1981 ). The compound of formula AC is then converted to compound of formula AD by treating with palladium carbon in the presence of suitable solvent such as diphenylether, xylene, toluene, chloroform, dichloromethane, etc. or in the presence of copper bromide in a suitable solvent such as acetonitrile, ethylacetate, etc. under heating. The compound of formula AD is converted to compound of formula AE by treating with suitable base such as sodium hydride, sodium or potassium hydroxide and in the presence of suitable reagent such as methyl iodide, dimethylsulfate in a suitable solvent such as dimethyl formamide, water, etc. The compound of formula AE is converted to the compound of formula AF by treatment with dichloromethylmethyl ether in the presence of titanium tetrachloride and dichloromethane or phosphorousoxy chloride in dimethyl formamide. Compound of formula AF is converted to the compound of formula AG by reduction with sodium borohydride in the presence of a suitable solvent system such as tetrahydrofuran or methanol or lithiumaluminium hydride in the presence of THF. Compound of formula AG is converted to compound of formula AH by chlorination using suitable chlorinating agents such as thionyl chloride, phosphorousoxychloride, phosphorous trichloride, carbon tetrachloride and triphenylphosphine in the presence of a suitable solvent such as ethyl acetate, THF, DMF, DCM or EDC. Compound of formula AH is converted to compound of general formula AI by treatment with sodium or potassium cyanide in the presence of dimethylformamide. The compound of general formula AI (which is equivalent to E of scheme 1), is converted to compound of general formula (I) by the method mentioned in synthetic scheme 1.
In yet another embodiment the intermediate AI (substituted tetrahydro carbazole) can be prepared using the literature reference Canadian journal of research (1950), 28B, 443-452 which is then converted to the compound of formula E using palladium carbon in the presence of suitable solvent such as diphenyl ether, xylene, toluene, chloroform, etc.
The compounds of general formula (I) wherein X is O; X3 is cyano; Y is O; R is as mentioned above; R can be alkyl or haloalkyl; R is as mentioned above, R' and R" together with the carbon atoms to which they are attached form a substituted aryl group wherein the substitution can be NO2, NHSO2Me or CF3, can be synthesized as described in the general synthetic scheme 2 and 2a.
Scheme 2
Figure imgf000024_0001
In the above mentioned scheme, the compound of formula 1 can be reacted with cyclopentyl bromide in presence of a suitable base such as anhydrous potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, etc. and a suitable solvent such as dimethyl formamide, dimethyl sulfoxide, acetonitrile, etc. to afford the compound of general formula 2. The compound of general formula 2 can then be brominated to attain the compound of general formula 3 using conventional methods such as treatment with bromine solution in glacial acetic acid. The compound of general formula 3 can be converted to the compound of general formula 4 by treatment with fluoronitrobenzene in the presence of suitable base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium or potassium alkoxide, etc. and suitable solvent such as dimethyl formamide, dimethyl sulfoxide, acetonitrile, etc.. The compound of general formula 4 can then be cyclised to the compound of general formula 5 using palladium acetate in the presence of suitable base like anhydrous sodium carbonate, potassium carbonate, etc. and suitable solvent such as dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, acetonitrile, etc. The compound of general formula 5 can then be reduced using conventional reducing agents such as sodium borohydride, lithium aluminum hydride, etc. in the presence of suitable solvent such as tetrahydrofuran, methanol, and dimethyl sulfoxide to obtain the compound of general formula 6. Halogenation of the compound of general formula 6 using suitable reagents such as thionyl chloride and phosphorus chloride in the presence of suitable solvent such as dichloromethane and ethyl acetate afford compound of general formula 7. Alternatively, the compound of general formula 7 can be made by treating the compound of general formula 6 with triphenylphosphine/carbon tetrachloride or carbon tetrabromide. The compound of general formula 7 can be treated with sodium or potassium cyanide in the presence of suitable solvent system such as dimethyl formamide, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, etc. to afford the compound of general formula 8. The compound of general formula 8 is treated with suitable bases like triton B, l,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, sodium hydride, etc. in presence of suitable solvent such as acetonitrile, dimethyl formamide, dimethyl sulfoxide, etc. to obtain the compound of general formula 9. The compound of general formula 10 can be obtained by treating compound of general formula 9 with sodium hydride, sodium ethoxide, or/and?? sodium methoxide in the presence of suitable solvent such as dry dimethoxyethane, ethanol, methanol, etc. The compound of general formula 10 can then be converted to the compound of general formula 11 using suitable salts such sodium chloride, lithium chloride, etc. in presence of suitable solvent such as dimethyl formamide, dimethyl sulphoxide, etc. Conversion of the compound of general formula 11 to the compound of general formula 12 can be made by treating with hydrogen halides such as hydrogen bromide, hydrogen chloride or hydrogen iodide in presence of suitable solvent such as glacial acetic acid, dichloromethane, benzene, etc. Alternatively, it can be made by treatment with boron tribromide in dichloromethane. The compound of general formula 12 can be converted to the compound of general formula 13 by treatment with chlorodifluoromethane gas in the presence of suitable bases such as anhydrous sodium carbonate, potassium carbonate, etc. and suitable solvents such as dry dimethyl formamide, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, etc. The compound of general formula 13 can be treated with triethylamine followed by N5N- dimethylformamide dimethylacetal (DMFDMA) in presence of suitable solvent such as benzene, toluene, dimethyl formamide, etc. to produce the compound of general formula 14 which in-turn can be treated with formamidine hydrochloride in presence of a suitable solvent such as dry dimethylformamide, dimethyl acetamide, dimethyl sulfoxide, etc. to obtain the compound of general formula 15. The ompound of general formula 15 can be reduced by hydrogenation using regular catalytic agents such as Raney nickel in presence of suitable solvent such as ethyl acetate, methanol, ethanol, 1,4-dioxane, etc. to obtain the compound of general formula 16. Alternatively the compound of general formula 15 can be treated with iron or zinc powder/ammonium chloride in a suitable solvent such as tetrahydrofuran, ethanol, methanol, etc. to obtain the compound of general formula 16. The compound of general formula 16 can then be treated with methane sulphonyl chloride in presence of suitable base such as pyridine, triethylamine, etc. and suitable solvent such as dry tetrahydrofuran, dichloromethane, etc. to produce compound of general formula (I). Scheme 2a
Figure imgf000027_0001
General formula (I)
The stereo isomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomeric form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, etc. wherever applicable or chiral bases such as brucine, cinchona alkaloids and their derivatives, etc.
Different polymorphs of a compound of general formula (I) of the present invention may be prepared by crystallization of the compound of formula (I) under different conditions. For example, making use of commonly used solvents or their mixtures for recrystallization, crystallization at different temperature ranges, different cooling techniques like very fast to very slow cooling during crystallization procedure, exposure to room temperature, heating or melting the compound followed by gradual cooling, etc. The presence of polymorphs may be determined by one or more methods such as solid probe NMR spectroscopy, DSC, TGA, Powder X-Ray diffraction and IR.
The present invention also provides pharmaceutical compositions containing the compounds of the invention as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their polymorphs, their enantiomers, their diastereomers, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates in combination with the suitable pharmaceutically acceptable carriers, diluents. The pharmaceutical compositions according to the present invention are useful for the treatment of allergic and inflammatory diseases including asthma, inflammatory diseases, allergic conditions, allergic conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, diabetes, Crohn's disease, allergic rhinitis endotoxic shock and adult respiratory distress syndrome and related diseases. The pharmaceutical composition may be tablets, capsules, powders, syrups, solutions, suspensions, sprays, etc. and may contain flavorants, sweeteners, etc. in suitable solid or liquid carriers, diluents, or in a suitable sterile media to form injectable solutions or suspensions.
It is understood that in any of the above schemes any reactive group in the substrate molecule may be protected according to any conventional procedure known in the prior art. Suitable protecting groups comprise N-Boc, N-Cbz, N-Fmoc, alkyl, benzophenoneimine for protection of amino groups, acetal protection for aldehydes, and ketal protection for ketones.
The invention also encompasses prodrugs of compounds of the invention, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of compounds of the invention, which are readily convertible in vivo into compounds of the invention.
The invention also encompasses the active metabolites of the compounds of the present invention of general formula (I). Examples
Preparation of Intermediates
Intermediate 1: Preparation of 4-(Cyanomethyl)-7-methoxy-l-tosyl-lH-indole Step-1 : Preparation of 7-Methoxy-l-tosyl-lH-indole-4-carbaldehyde To a solution of 7-methoxy-lH-indole-4-carbaldehyde (10. Og, 0.057 mol) in dichloromethane (100 ml) was added powdered sodium hydroxide (7.3g, 0.182 mol) at 0 0C followed by tetrabutylammonium bisulphate (0.5g). To this mixture a suspension of p-tolunesulphonyl chloride (13.6 g, 0.071mol) in dichloromethane (86 ml) was added at 0 0C for a period of 30 min and the mixture was stirred at 5-10 0C for 1 hour. The reaction mixture was filtered through celite and washed with dichloromethane (3 x 50 ml). The filtrate was collected and concentrated. The crude product was dissolved in refluxing ethyl acetate (95 ml), cooled to room temperature and hexane (160 ml) was added drop wise. The crystalline solid precipitated, was filtered and dried under vacuum to afford the off-white title compound (17.Og, 90.4%). IR (cm"'): 3435.39, 2845.70, 1679.45, 1579.2, 1531.23, 1378.92, 1364.60, 1290.13, 1172.54, 949.57, 670.4.
1H NMR (300 MHz, DMSOd6) δ 2.3 (s, 3 H), 3.78 (s, 3 H), 7.0 (d, 1 H, J= 8.4 Hz), 7.4 (m, 3 H), 7.76-7.83 (m, 3 H), 8.0 (d, 1 H, J= 3.9 Hz), 10.0 (s, 1 H); Step-2: preparation of (7-Methoxy-l-tosyl-lH-indoI-4-yl) methanol To a solution of 7-methoxy-l-tosyl-lH-indole-4-carbaldehyde (16.8 g, 0.051 mol) in methanol (150 ml) was added sodium borohydride (2.8 g, 0.076 mol) portion wise at 0-5 0C over a period of 30 minutes and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was then treated with ammonium chloride solution and extracted with chloroform (3 x 100 ml). The combined organic layers were washed with brine, dried with anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (16.2g, 95.85 %) as a white solid. IR (cm-'): 3435.12, 1614.59, 1499.68, 1348.68, 1175.99, 670.17. IH NMR (300 MHz, DMSOd6) δ 2.35 (s, 3 H), 3.6 (s, 3 H), 4.6 (d, 2 H, J= 5.7 Hz), 5.1 (t, 1 H, OH, D2O exchangeable proton), 6.7 (d, 1 H, J= 8.1 Hz), 6.8 (d, 1 H, J= 3.9 Hz), 7.1 (d, 1 H, J= 8.1 Hz), 7.4 (d, 2 H, J= 8.4 Hz), 7.7 (d, 2 H, J= 8.4 Hz), 7.8 (d, I H, J= 3.9 Hz);
Step-3 : Preparation of 4-(Chloromethyl)-7-methoxy-l-tosyl-lH-indole To a solution of (7-methoxy-l-tosyl-lH-indol-4-yl) methanol (16.Og, 0.0483 mol) in ethyl acetate (350 ml) was added a solution of thionyl chloride (SOCl2) (7.19 ml, 0.0966 mol) in ethyl acetate (50 ml) at -4O0C for 2 hours and the mixture was stirred for an additional 20 minutes. The reaction mixture was warmed to room temperature and ethyl acetate was removed completely under vacuum at 40 0C to afford the crude chloro compound which was used in the next step without purification. IR (cm 1): 2947.41, 2874.48, 1606.95, 1593.78, 1498.9, 1356.76, 1171.06, 1133.43, 1084.17, 668.88.
1H NMR (300 MHz, DMSO-d6) δ 2.3 (s, 3 H), 3.6 (s, 3 H), 4.98 (s, 2 H), 6.7 (d, 1 H, J= 8.1 Hz), 6.9 (d, 1 H, J= 3.6 Hz), 7.2 (d, 1 H, J= 8.1 Hz), 7.4 (d, 2 H, J= 8.1 Hz), 7.7 (d, 2 H, J= 8.4 Hz), 7.9 (d, 1 H, J= 3.9 Hz); Step-4: Preparation of 4-(Cyanomethyl)-7-methoxy-l-tosyl-lH-indole
To a solution of crude 4-(chloromethyl)-7-methoxy-l-tosyl-lH-indole (16.8 g, 0.049 mol) in iV.N-dimethyl formamide (90 ml) was added sodium cyanide (4.7g, 0.0966 mol) and the mixture was stirred at room temperature for 3 hours. To this mixture was added saturated ferrous sulfate solution and the mixture was filtered through celite and washed with chloroform. The filtrate was collected, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum to afford the cyano compound (15.0 g, 91%). IR (Cm"1): 3157.67, 2966.87, 2245.26, 1594.03, 1500.50, 1355.41, 1289.62, 1244.22, 1140.65, 669.33. 1H NMR (300 MHz, DMSOd6) δ 2.3 (s, 3 H), 3.6 (s, 3 H), 4.1 (s, 2 H), 6.8 (d, 1 H, J = 8.1 Hz), 6.9 (d, 1 H, J= 3.9 Hz), 7.1 (d, 1 H, J= 8.1 Hz), 7.4 (d, 2 H3 J= 8.1 Hz), 7.7 (d, 2 H, J= 8.1 Hz), 7.9 (d, 1 H, J= 3.6 Hz);
Intermediate 2: Preparation of Benzyl 4-(cyanomethyl)-lH-indole-l-carboxylate Step-1 : Preparation of Benzyl 4-formyl-lH-indole-l-carboxylate To a solution of lH-indole-4-carbaldehyde (12g, 82.75 mmol) in dry tetrahydrofuran (THF) (330 ml) was added potassium hexamethyldisilazane (KHMDS) (33.0 g, 165.5 mmol) at -78 0C in portion wise followed by a tetrahydrofuran solution of benzyl chloroformate (17.6 ml, 124.12 mmol) during a period of 1.0 hour at the same temperature. The mixture was stirred for an additional 2 hours at the same temperature, diluted with cold water (100 ml) followed by ethyl acetate (200 ml) and allowed to warm to room temperature. The mixture was extracted with ethyl acetate (2 x 100 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography using 5% ethyl acetate/hexane as eluant to afford the title compound (12.0 g, 52%) as colorless oil which solidifies when stored in a refrigerator. 1H NMR (300 MHz, CDCl3) δ 5.47 (s, 2 H), 7.28-7.5 (m, 7 H), 7.7 (d, 1 H, J= 0.9 Hz), 7.8 (d,
1 H, J= 3.6 Hz), 8.5 (d, 1 H3 J= 8.1 Hz), 10.2 (s, 1 H).
Step-2: Preparation of Benzyl 4-(hydroxymethyl)-lH-indole-l-carboxylate The title compound was prepared following a similar procedure as described in step
2 of intermediate 1 and obtained as colorless viscous oil which solidified when stored in a refrigerator. IR (cm"1): 3304.58, 1732.37, 1528.8, 1486.06, 1433.27, 1399.51, 1347.57, 1275.50, 1128.54, 1051.71, 762.97. 1H NMR (300 MHz, CDCl3) δ 4.9 (s, 2 H), 5.4 (s, 2 H), 6.7 (dd, IH, J1 = 0.6 Hz, J2 = 3.9 Hz), 7.2-7.35 (m, 2 H), 7.36-7.45 (m, 3 H), 7.46-7.5 (m, 2 H), 7.6 (d, 1 H, J= 3.6 Hz), 8.1 (d, 1 H, J= 8.1 Hz). Step-3: Preparation of Benzyl 4-(chloromethyl)-lH-indole-l-carboxylate The title compound was prepared following a similar procedure as described in step
3 of intermediate 1 and obtained as a brown viscous mass. IR (cm"1): 3447, 1730.95, 1434.99, 1398.54, 1349.52, 1280.78, 1258.12, 1161.49, 1125.01, 1050.35, 762.09. 1H NMR (300 MHz, CDCl3) δ 4.8 (s, 2 H), 5.4 (s, 2 H), 6.7 (d, IH, J= 3.9 Hz), 7.2- 7.34 (m, 2 H), 7.36-7.5 (m, 5 H), 7.7 (d, 1 H, J= 3.9 Hz), 8.1 (d, 1 H, J= 7.8 Hz). Step-4: Preparation of Benzyl 4-(cyanomethyl)-lH-indole-l-carboxylate The title compound was prepared following a similar procedure as described in step 3 of intermediate 1 and obtained as an off-white solid. IR (cm"1): 3448.72, 2250.9, 1733.52, 1489.83, 1434.53, 1337.99, 1277.44, 1127.1, 1048.88, 975.39, 766.38, 752.16, 695.75. 1H NMR (300 MHz, CDCl3) δ 3.9 (s, 2 H), 5.4 (s, 2 H), 6.6 (d, IH, J = 3.6 Hz), 7.2-7.37 (m, 3 H), 7.38-7.5 (m, 5 H), 7.7 (d, 1 H, J= 3.9 Hz), 8.1 (d, 1 H, J= 8.1 Hz).
Intermediate 3: Preparation of (1- Methoxy-9-methyl-6-trifluoromethyl-9H- carbazole-4-yl)-acetonitrile
The title compound was prepared according to the procedure depicted in WO 2006011024 and US20050027129. IR (cm'1, KBr) 3436, 2923, 2853, 2247, 1627, 1548, 1466, 1330, 1271, 1097, 795. 1H NMR (300 MHz, CDCl3) δ 4.0 (s, 3H), 4.22 (s, 3H), 4.29 (s, 2H), 6.90 (d, J= 8.1 Hz, IH), 7.50 (m, 2H), 7.70 (d, J = 8.1 Hz, IH), 8.24 (s, IH).
Intermediate 4: Preparation of (6-Fluoro-l-methoxy-9-methyl-9H-carbazoI-4- yl)-acetonitrile
Stepl: Preparation of 2-Hydroxymethylene-cyclohexanone
To a solution of cyclohexanone (25 g, 0.26 mole) in THF (1 litre) was added ethyl formate (25.48 g, 0.34 mole), and then 60% sodium hydride in paraffin oil (12.24 g, 0.31 mole) at 10-20 0C and the mixture was stirred for overnight at room temperature. After completion of the reaction, the reaction mixture was filtered and the solid was washed with dry tetrahydrofuram (200 ml), dried under vacuum to give the desired product (32.1 g, yield 100%) as off-white solid. 1H NMR (300 MHz, OMSO-d6): δ 1.40 - 1.56 (m, 4H), 1.86 -1.90 (m, 2H), 2.06-2.11 (m, 2H), 9.18 (s, IH) Step 2: Preparation of 2-[(4-Fluoro-phenyl)-hydrazono]-cycIohexanone
To the solution of 4-fluoroaniline (38 g, 0.34 mole) in water (300 ml) and cone, hydrochloric acid (71.3 ml, 0.68 mole), was added a solution of sodium nitrite (23.5 g, 0.34 mole) dissolved in water (80 ml) drop wise at 1O0C. The mixture was stirred for 30 min. at the same temperature and then a solution of compound of step 1 (43.09 g, 0.34 mole) in methanol (130 ml) followed by sodium acetate (70 g, 0.85 mole) and sodium carbonate (10.87 g, 0.10 mole) was added. The mixture was stirred for 30 minutes at room temperature. The mixture was extracted with dichloromethane (300 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford the crude product which, on purification by column chromatography, afforded the desired product (23 g, yield 30.7%) as orange colored solid. 1H NMR (300 MHz, CDCl3): δ 1.82 - 1.97 (m, 4H), 2.50 - 2.69 (m, 4H), 6.96 - 7.10 (m, 2H), 7.17 - 7.34 (m, 2H), 13. 82 (s, IH) Step 3: Preparation of 6-Fluoro-2,3.4,9-tetrahydro-carbazol-l-one To the solution of compound of step 2 (23 g, 0.10 mole) in acetonitrile (600 ml) was added concentrated sulphuric acid (20 ml) and the mixture was refluxed for 2 hours. After completion of the reaction (indicated by TLC using 10% ethyl acetate/n-hexane as eluant), the mixture was diluted with water (750 ml) and stirred for 10 minutes, filtered and dried under vacuum to afford the title compound (21 g, yield 99.1%) as orange colored solid. 1H NMR (300 MHz, CDCl3): δ 2.26 - 2.33 (m, 2H), 2.67 (t, J= 6.1 Hz, 2H), 2.98 (t, J= 6.1 Hz, 2H), 7.11 - 7.18 (m, IH), 7.27 - 7.38 (m, 2H), 8.74 (s, IH)
Step 4: Preparation of 6-Fluoro-9H-carbazol-l-ol To the solution of compound of step 3 (1Og, 0.05 mole) in diphenylether (1.2 /) was added 10% Pd/C (5g) and the mixture was refluxed for 5 hours. The mixture was then filtered, concentrated and the crude product was purified to afford the title compound (4g, yield 40.4%) as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 6.85 (d, J= 7.6 Hz, IH), 7.06 (t, J= 7.7 Hz, IH), 7.12 - 7.19 (m, IH), 7.35 - 7.40 (m, IH), 7.60 - 7.71 (m, IH) Step 5: Preparation of 6-FIuoro-l-methoxy-9-methyl-9H-carbazole
To the solution of compound of step 4 (4.36 g, 0.02 mole) in dimethylformamide (50 ml), was added 60% sodium hydride in paraffin oil (2.08 g, 0.05 mole) at 0 0C and the mixture was stirred for 30 min. at 0 0C. Methyl iodide (3.36 ml, 0.05 mole) was added to this mixture and the reaction mass was stirred for 30 minutes at 0 0C. The mixture was quenched with water (250 ml) and extracted with dichloromethane (200 ml). The organic layer was collected, washed with water (5 X 100 ml), dried over anhydrous sodium sulfate and concentrated to give the desired product (4.2g, yield 84.7%) as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 3.96 (s, 3H), 4.08 (s, 3H), 6.85 (d, J= 7.7, IH), 7.06 (t, J= 7.8 Hz, IH), 7.12 - 7.24 (m, 2H), 7.56 (d, J = 7.7 Hz, IH), 7.61 - 7.64 (m, IH)
Step 6: Preparation of 6-Fluoro-l-methoxy-9-metb.yl-9H-carbazo.e-4- carbaldehyde A solution of compound of step 5 (1.39 g, 0.01 mole) in DCM (50 ml) was cooled to 0 0C and titanium tetrachloride (1.38 ml, 0.01 mole) was added. The mixture was stirred for 10 min and then dichloromethyl methyl ether (0.65 ml, 0.01 mole) was added. After stirring for 30 min. at 0 0C (the starting material was absent by TLC) the mixture was treated with 20 % aqueous NaHCO3 solution (100 ml) and extracted in dichloromethane (2 X 50 ml). The organic layers were collected, combined, dried over anhydrous sodium sulfate and concentrated to give a mixture of products (1.54 g) that was directly taken for the next step without purification. Step 7: Preparation of (6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yI)-methanol To the solution of compound of step 5 (1.54 g, 5.99 mmole) in THF (50 ml), was added sodium borohydride (360 mg, 9.51 mmole) portion wise at room temperature. After 2 hours stirring at room temperature (the starting material was absent by TLC) the reaction was diluted with water (100 ml). After extraction with ethyl acetate (2X50 ml), drying over anhydrous sodium sulfate, and being concentrated, the crude product was purified by column chromatography to afford the desired product (750 mg, yield 47.8% with respect to compound of 5) as a white solid. 1H NMR (300 MHz, DMSO-J6): δ 3.95 (s, 3H), 4.13 (s, 3H), 4.92 (d, J= 5.2 Hz, 2H), 5.23 (s, IH), 6.99 (d, J= 8.01 Hz, IH), 7.07 (d, J= 7.99 Hz, IH), 7.31 (m, IH), 7.55 - 7.60 (m, IH), 7.90 (dd, J= 2.5 Hz5 J= 10.1 Hz, IH)
Step 8: Preparation of (6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)- acetonitrile A solution of (6-fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-methanol (50 mg, 0.19 mmol) in ethyl acetate (5 ml) was cooled to -100C and thionyl chloride (0.02 ml, 0.23 mmol) was added drop wise. The reaction mass was stirred for 2 hours at the same temperature and then concentrated under vacuum. The residue was dissolved in DMF (5 ml) and sodium cyanide (10 mg, 0.20 mmol) was added at room temperature. After 1 hour stirring at room temperature (the starting material was absent by TLC) the reaction mixture was quenched in water (5 ml) and extracted in ethyl acetate (2 X 5 ml). The combined organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuum. The crude product was purified to afford the title compound (20 mg, yield 38.7%) as a white solid. 1H NMR (300 MHz, DMSO-^s): δ 3.97 (s, 3H), 4.15 (s, 3H), 4.50 (s, 2H), 7.04 - 7.13 (m, 2H), 7.35 - 7.42 (m, IH), 7.62 - 7.67 (m, IH), 7.94 (dd, J= 10.0 and 2.4 Hz, IH) IR (KBr) (cm-l): 3436, 2935, 2251, 1583, 1523, 1482, 1313, 1261, 1186, 1087, 1028, 887.
Intermediate 5: Preparation of (l-Methoxy-9-methyl-9H-carbazoI-4-yI)- acetonitrile
Prepared this intermediate as per the procedure depicted in "Canadian journal of research (1950), 28B, 443-452". 1H NMR (300 MHz, CDCl3): δ 3.99 (s, 3H), 4.18 (s, 3H), 4.24 (s, 2H), 6.89 (d, J= 8.1 Hz, IH), 7.15 (d, J= 8.1 Hz, IH), 7.27 (m, IH), 7.43 - 7.54 (m, 2H), 8.01 (d, J= 7.9 Hz, IH)
Intermediate 6: Preparation of 5-Cyano-5-(4-Cyclopentyloxy-8-nitro- dibenzofuran-l-yl)-2-oxo-cyclohexane carboxylic acid methyl ester Step 1 : Preparation of 4-Cyclopentoxy-3-hydroxybenzaldehyde
A suspension of 3, 4-dihydroxybenzaldehyde (5gms, 0.0362mol), anhydrous potassium carbonate (6gms, 0.0434mol) and cyclopentyl bromide (6.5gms, 0.0434mol) in dry dimethylformamide DMF (50ml) was heated and stirred at 8O0C for 24 hours. The reaction mixture was then cooled and diluted with water (500ml), acidified with IN HCl and extracted with ethyl acetate (3XlOOmI). The combined ethyl acetate layer was washed with 5% sodium bicarbonate and brine and dried on sodium sulfate, filtered and the solvent removed to get a residue which was purified by column chromatography on silica gel using 10% ethyl acetate in hexane as the eluent to obtain the title compound (5gms, yield-67.11%) as a white solid.
1H NMR (300 MHz, CDCl3) δ 1.62-2.06 (m, 8H), 4.90-4.95 (m, IH), 5.73 (s, IH), 6.95 (d, J= 8.2 Hz, IH), 7.40-7.50 (m, 2H), 9.80 (s, IH). Step 2: Preparation of 2-Bromo-4-cyclopentoxy-3-hydroxybenzaldehyde Compound of step 1 (18gm, 0.087mol) was dissolved in glacial acetic acid (540ml). Anhydrous sodium acetate (14.31 gm, 0.174mol) was added to the above solution followed by powdered iron (396mg). The system was flushed thoroughly with nitrogen. A solution of bromine (5ml, 0.096mole) in glacial acetic acid (40ml) was added to the above stirred suspension at 150C, over a period of 15 minutes. The reaction mixture was stirred at 150C for 45 minutes. The reaction mixture was poured into aqueous 2% sodium bisulphate (500ml) solution and stirred for 10 minutes. The precipitated solid was filtered, washed with water (300ml) and dried to obtain the title compound (24gm, yield-96.1%) as a solid.
1H NMR (300 MHz, CDCl3) δ 1.61-2.03 (m, 8H), 4.91-4.97 (m, IH), 6.07 (s, IH), 6.89 (d, J= 8.6 Hz, IH), 7.50 (d, J= 8.6 Hz, IH), 10.25 (s, IH). Step 3: Preparation of 2-Bromo-4-cyclopentoxy-3-(4-nitrophenoxy) benzaldehyde To a stirred solution of compound of step 2 (26gm,0.091 moles) and potassium carbonate (31.5gm, 0.228mole) in dry dimethylformamide (260 ml) was added fluoronitrobenzene (10.16ml, 0.095mole) and then above reaction mixture was stirred at 14O0C for 5 hours. After completion of reaction, the reaction mixture was cooled to room temperature and the contents were poured in to water (750ml) and extracted with ethyl acetate (3X500ml). The organic extracts were combined and washed with IN aqueous sodium hydroxide solution, water and brine, dried with sodium sulfate, filtered and solvent evaporated under vacuum to obtain the title compound (32gm, yield-86%) as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 1.40-1.50 (m, 2H), 1.59-1.70 (m,4H), 1.73-1.80 (m,2H), 4.81-4.85(m, IH), 6.90-6.95 (m, 2H), 7.04 (d, J= 8.8 Hz, IH), 7.90 (d, J= 8.8 Hz, IH), 8.17-8.23 (m, 2H), 10.26 (s, IH).
Step 4: Preparation of 4-cyclopentoxy-8-nitro-l-formyl dibenzo [b, d] furan A solution of compound of step 3 (26.12gm, 0.064mol) in dimethylformamide (200ml), anhydrous sodium carbonate (20.45gm, 0.193mol) and Pd(II) acetate (1.44gm, O.OOόmol) was heated and stirred under nitrogen at 13O0C for 7hours. After completion of reaction, the reaction mixture was filtered through celite bed, and then to the filtrate, water (500ml) was added and extracted with ethyl acetate (3X250ml). The combined organic layer was washed with 5% HCl (250ml), followed by water and dried with sodium sulfate, filtered and the solvent evaporated under vacuum to obtain the title compound (13.6gm, yield-65%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 1.60-1.79 (m, 2H), 1.80-1.99 (m, 4 H), 2.09-2.10 (m, 2H), 5.15 (m, IH), 7.19 (d, J= 8.3 Hz, IH), 7.74 (d, J= 9 Hz, IH), 7.88 (d, J= 8.3, IH), 8.46 (dd, J= 8.7Hz, 1.9Hz IH), 10.02 (s, IH), 10.17 (s, IH).
Step 5: Preparation of (4-Cyclopentyloxy-8-nitro-dibenzofuran-l-yl)-methanol To a cold solution of compound of step 4 (5gm, 0.015mole) in dry tetrahydrofuran (200ml) was added sodium borohydride (0.584gm, 0.015mole) portion wise at O0C under nitrogen. The mixture was then allowed to stir at room temperature for 3 hours and then quenched with a saturated solution of ammonium chloride (150ml). The mixture was extracted with ethyl acetate (3X150ml). The organic layers were collected, combined, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the title compound (3.5gm, yield-69.5%) as a solid. 1H NMR (300 MHz, CDCl3) δ 1.57-1.73 (m, 2H), 1.89-1.99 (m, 4 H), 2.03-2.10 (m, 2H), 5.02-5.16 (m, IH), 5.16 (s, 2H), 7.04 (d, J= 8.2 Hz, IH), 7.30 (d, J= 8.3 Hz, IH), 7.73 (d, J= 9 Hz, IH), 8.42 (dd, J= 9.0 Hz, 2.3 Hz, IH), 9.08 (d, J= 2.2 Hz, IH), Step 6: Preparation of (4-Cyclopentyloxy-8-nitro-dibenzofuran-l-yl)-acetonitriIe To a cold solution of compound of step 5 (3.9gm, 0.01 lmole) in dichloromethane (250 ml) was added thionyl chloride (1.74ml, 0.023mole) drop wise with stirring at O0C under nitrogen atmosphere. The mixture was allowed to stir at room temperature for 2 hours. After completion of the reaction, the solvent was evaporated completely under vacuum and the residue was dissolved in dry dimethylformamide (100ml). To this was added sodium cyanide (1.29gm, 0.026mole) portion wise and the mixture was allowed to stir at room temperature for lδhours. After completion of the reaction, the mixture was quenched with water (350ml) and extracted with ethyl acetate (3 X 200ml). The organic layers were collected, combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography using 5-10% ethyl acetate-hexane as an eluent to obtain the title compound (3.59gm, yield-90 %) as a solid.
1H NMR (300 MHz, CDCl3) δ 1.57-1.73 (m, 2H), 1.85-1.96 (m, 2 H), 1.99-2.03 (m, 4H), 4.22 (s, 2H), 5.02-5.06 (m, IH), 7.08 (d, J= 8.3 Hz, IH), 7.39 (d, J= 8.3, IH), 7.78 (d, J= 9.1 Hz, IH), 8.46 (dd, J= 9.1 Hz, 2.3Hz, IH), 8.82 (d, J= 2.1 Hz, IH), Step 7: Preparation of 4-Cyano-4-(4-Cyclopentyloxy-8-nitro-dibenzofuran-l-yl)- heptanedioic acid di methyl ester
To a solution of compound of step 6 (2.4gm, 0.007moles) in acetonitrile (60ml) was added triton B (0.14ml) at room temperature. Reaction mixture was heated to reflux (850C), at reflux temperature was added drop wise methyl acrylate (6.8ml, 0.07 lmole) and then the reaction was maintained at reflux for 5 hours. After completion of the reaction, the reaction mass was evaporated under vacuum. The crude product was purified by column chromatography by using 5-10% ethyl acetate- hexane to obtain the title compound (5.69gm, yield-83.6 %) as a solid. 1H NMR (SOO MHZ, CDCl3) δ 1.71-1.75 (m, 2H), 1.89-1.94 (m, 2 H), 1.98-2.03 (m, 4H), 2.38-2.43 (m, 2H), 2.54-2.67 (m, 4H), 2.78-2.83 (m, 2H), 3.57 (s, 6H), 5.01- 5.04 (m, IH), 7.06 (d, J= 8.5 Hz, IH), 7.47 (d, J= 8.5 Hz, IH), 7.79 (d, J= 9.07 Hz, IH), 8.46 (dd, J= 9.1 Hz, 1.9 Hz, IH), 9.19 (s, IH) Step 8: Preparation of 5-Cyano-5-(4-Cyclopentyloxy-8-nitro-dibenzofuran-l-yl)- 2-oxo-cyclohexane carboxylic acid methyl ester
To a solution of sodium hydride (1.344gm, 0.0336mole) in dry dimethoxyethane (250ml) was added the compound of step 7 (5.69gm, 0.01 lmole) in dimethoxyethane (25ml) drop wise over a period of 20 minutes at room temperature under nitrogen. The mixture was then allowed to stir at room temperature for 2 hours and then quenched with a saturated solution of ammonium chloride (200ml). The mixture was then extracted with ethyl acetate (3 X 250ml). The organic layers were collected, combined dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the title compound (5.3gm, yield-98%) as a solid.
1H NMR (300 MHz, CDCl3) δ 1.64-1.76 (m, 2H), 1.85-1.96 (m, 2 H), 1.86-2.04 (m, 4H), 2.41-2.63 (m, 2H), 2.63-2.69 (m, IH), 2.92-2.97 (m, 2H), 3.45 (d, J= 16 Hz, IH), 3.83 (s, 3H), 5.01-5.07 (m, IH), 7.06 (d, J= 8.5 Hz, IH), 7.32 (d, J= 8.5 Hz, IH), 7.79 (d, J= 9.1 Hz, IH), 8.45 (dd, J= 9.1Hz, 2.1Hz, IH), 9.19 (d, J= 2.1 Hz, IH), 12.36 (s,lH)
Intermediate 7: Preparation of l-(-4-Hydroxy-8-nitro-dibenzofuran-l-yl)-4-oxo- cyclohexane carbonitrile
Step 1 : Preparation of l-(-4-Cyclopentyloxy-8-nitro-dibenzofuran-l-yl)-4-oxo- cyclohexane carbonitrile
To a solution of intermediate 1 (5.3gm, 0.01 lmole) in dimethylsulphoxide (50ml), was added water(4ml), sodium chloride (4.2gm, 0.072mole) and then the reaction mass was heated to 14O0C, and maintained atl40°C for 5 hours. After completion of the reaction, the reaction mixture was brought to room temperature and quenched with cold water (150ml). The mixture was then extracted with ethyl acetate (3 X 250 ml). The organic layers were collected, combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude was purified by column chromatography using 5-10% ethyl acetate-hexane to obtain the title compound (2.7gm, yield 58%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 1.70-1.79 (m, 2H), 1.89-1.93 (m, 2 H), 1.97-2.04 (m, 4H), 2.27-2.37 (m, 2H), 2.70-2.75 (m, 2H), 2.97-2.98 (m, 2H), 3.02-3.21 (m, 2H), 5.02-5.06 (m, IH), 7.08 (d, J= 8.5 Hz, IH), 7.26-7.30 (m, IH), 7.80 (d, J= 9.1 Hz, IH), 8.47 (dd, J = 9. IHz, 2. IHz, IH), 9.26 (d, J= 2.0, IH) Step 2: Preparation of l-(-4-Hydroxy-8-nitro-dibenzofuran-l-yl)-4-oxo- cyclohexane carbonitrile
To a solution of the product from step 1 (200mg, 0.0004mole) in glacial acetic acid (3ml), was added 33% HBr in acetic acid (ImI) at room temperature, and then reaction mixture was heated to 8O0C and maintained at 8O0C for 5 hours. After completion of the reaction, the reaction mixture was quenched with ice cold water (10ml). The mixture was then extracted with ethyl acetate (3 X 50ml). The organic layers were collected, combined, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the title compound (162 mg, yield 97%) as a solid. 1H NMR (300 MHz, DMSCM6) δ 2.40-2.57 (m, 6H), 2.89-2.92 (m, 2H), 7.15 (d, J = 8.5 Hz, IH), 7.36 (d, J= 8.5 Hz, IH), 8.07 (d, J= 9.1Hz, IH), 8.51 (dd, J= 8.8, 1.6Hz, IH), 9.13 (d, J= 1.5 Hz, IH), 10.87 (s, IH)
Intermediate 8: Preparation of 5-Cyano-5-(4-methoxy-8-trifluoromethyl- dibenzofuran-l-yl)-2-oxo-cyclohexanecarboxylic acid methyl ester
Step-1: Preparation of 3-(2-Bromo-4-trifluoromethyl-phenoxy)-4-methoxy- benzaldehyde
To a stirred solution of Isovanillin (5 gm, 0.0328 moles) and Potassium carbonate (13.6 gm, 0.0985 moles) in dry DMF (20 ml) was added 3-Bromo-4- Fluorobenzotrifluoride (8.065 gm, 0.0331 moles) over a period of 15 min at room temperature under nitrogen atmosphere, and then above reaction mixture was stirred at 14O0C for 5 hrs. After completion of reaction, the reaction mixture was cooled to room temperature and the contents were poured in to water (100 ml) and extracted with ethyl acetate (3XlOOmI). The organic extracts were combined and washed with IN sodium hydroxide, water and brine, dried with sodium sulfate, filtered and solvent evaporated under vacuum to obtain the title compound (11.58 gm, yield-
94%) a pale yellow solid.
1H NMR (300 MHz, CDCl3) δ 3.92 (s, 3H), 6.75 (d, J= 8.6 Hz, IH), 7.15 (d, J= 8.5 Hz, IH), 7.45 (d, J= 8.6 Hz, IH), 7.54 (d, J = 1.9 Hz, IH), 7.77 (dd, J=8.4 Hz, J=I.9
Hz, IH,), 7.90 (s, IH), 9.87 (s, IH)
MS (M++!): 376
Step 2: Preparation of 4-Methoxy-8-trifluoromethyl-dibenzofuran-l- carbaldehyde A solution of the product from step 1 (11.5 gm, 0.030 mol) in DMF (80 ml), anhydrous sodium carbonate (9.8 gm, 0.091 mol) and Pd(II) acetate (0.689 gm,
0.0030 mol), was heated and stirred under nitrogen at 13O0C for 7hrs. After completion of the reaction, the reaction mixture was filtered through celite bed, and then to the filtrate, water (500ml) was added and extracted with ethyl acetate (3X250ml). The combined organic layer was washed with water (250ml) and dried with sodium sulfate, filtered and the solvent evaporated under vacuum to obtain the title compound (4.5gm, yield-53.5 %) as a yellow solid.
1H NMR (300 MHz, CDCl3) δ 4.18 (s, 3H), 7.18 (d, J= 8.4 Hz, IH), 7.74 (d, J= 8.7
Hz, IH), 7.82 (d, J= 8.7 Hz, IH), 7.88 (d, J= 8.4 Hz, IH), 9.41 (d, J= 1.8 Hz, IH), 10.71 (s, IH)
MS (M++l): 295.1
Step 3: Preparation of (4-Methoxy-8-trifluoromethyl-dibenzofuran-l-yl)~ methanol
To a cold solution of the product of step 2 (4.5 gm, 0.015 moles) in dry THF (25 ml) was added sodium borohydride (0.640gm, 0.016 moles) portion wise at O0C under nitrogen. The mixture was then allowed to stir at room temperature for 3 hrs and then quenched with saturated solution of ammonium chloride (50 ml). The mixture was extracted with ethyl acetate (3X75 ml). The organic layers were collected, combined, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the title compound (4.3 gm, yield-94.9 %) as a solid.
1H NMR (300 MHz, CDCl3) δ 4.08 (s, 3H), 5.12 (s, 2H), 7.00 (d, J= 8.2 Hz, IH), 7.28 (d, J= 8.2 Hz, IH), 7.70-7.77 (m, 2H), 8.43 (s, IH) MS (M++l): 297
Step 4: Preparation of (4-Methoxy-8-trifluoromethyl-dibenzofuran-l-yl)~ acetonitrile
To a cold solution of step 3 (5.8 gm, 0.019 moles) in 200 ml of dry DCM, thionyl chloride (2.86 ml, 0.039 moles) was added drop wise over a period of 15 min, under nitrogen atmosphere. After addition, the reaction mixture was brought to room temperature and allowed to stir for 3 hrs. After completion of the reaction, excess thionyl chloride and DCM was evaporated under vacuum completely and the product was not isolated. To the non-isolated compound obtained above was added dry DMF (150 ml) and sodium cyanide (2.13 gm, 0.043 moles) at room temperature and the reaction mixture was allowed to stir for 2 hrs. After completion of the reaction, the reaction mixture was diluted with water (600 ml) and extracted with ethyl acetate (3X500 ml). The combined organic layer was washed with water (500 ml), dried with sodium sulphate and concentrated under vacuum to obtain the title compound (5.7 gm, yield- 95.3%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 4.09 (s, 3H), 4.20 (s, 2H), 7.06 (d, J= 8.3 Hz, IH), 7.38 (d, J= 8.3 Hz, IH), 7.75-7.82 (m, 2H), 8.17 (s, IH) MS (M++!): 306
Step 5: Preparation of 4-Cyano-4-(4-Methoxy-8-trifluoromethyl-dibenzofuran-l- yl) hepatanedioic acid dimethylester To a solution of step 4 (2.7gm, 0.0088 moles) in acetonitrile (20 ml) was added
Triton B (0.8 ml, 0.004 moles) at room temperature, the reaction mixture was heated to reflux (850C), at reflux temperature was added drop wise methyl acrylate (8.45 ml, 0.088 moles) and then the reaction was maintained at reflux for 5 hrs. After completion of the reaction, the reaction mass was evaporated under vacuum. The crude product was purified by column chromatography using 5-10% ethyl acetate- hexane to obtain the title compound (2.53 gm, yield-60 %) as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 2.40-2.56 (m, 2H), 2.58-2.66 (m, 4H), 2.76-2.82 (m, 2H), 3.63 (s, 6H), 4.09 (s, 3H), 7.05 (d, J= 8.6, IH), 7.50 (d, J= 8.6 Hz, IH), 7.79- 7.80 (m, 2H), 8.51 (s, IH) MS (M++l): 478
Step 6: Preparation of 5-Cyano-5-(4-methoxy-8-trifluoromethyl-dibenzofuran-l- yl)-2-oxo-cyclohexanecarboxylic acid methyl ester To a solution of sodium hydride (1.56 gm, 0.032 moles) in dry DME (50 ml) was added drop wise the product of step 5 (5.20 gm, 0.010 moles) by dissolving it in DME (50 ml) over a period of 20 min at room temperature under nitrogen. The mixture was then allowed to stir at room temperature for 2 hrs and then quenched with a saturated solution of ammonium chloride (100 ml). The mixture was then extracted with ethyl acetate (3 X 250 ml). The organic layers were collected, combined, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the title compound (3.4 gm, yield-65.8 %) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 2.40-2.67 (m, 3H), 2.84-2.89 (m, 2H), 3.50 (d, J= 16.6 Hz, IH), 3.80 (s, 3H), 4.10 (s, 3H), 7.05 (d, J= 8.5 Hz, IH), 7.32 (d, J= 8.5 Hz, IH), 7.79 (m, 2H), 8.51 (s, IH), 12.34 (s, IH) MS (M++l): 446
Intermediate 9: Preparation of 3-Dimethylaminomethylene-l-(4-methoxy-8- trifluoromethyl-dibenzofuran-l-yl)-4-oxo-cyclohexanecarbonitrile Step 1: Preparation of l-(4-Methoxy-8-trifluoromethyl-dibenzofuran-l-yl)-4-oxo- cyclohexane-caronitrile
To a solution of intermediate 8 (3.4 gm, 0.0076 moles) in dimethyl sulphoxide (DMSO)(IO ml), was added water(l ml), sodium chloride (2.9 gm, 0.049 moles) and then the reaction mass was heated to 14O0C, and maintained at 14O0C for 5 hours. After completion of the reaction, the reaction mixture was brought to room temperature and quenched with cold water (50 ml). The mixture was then extracted with ethyl acetate (3 X 75 ml). The organic layers were collected, combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography using 5-10% ethyl acetate-hexane to obtain the title compound (1.9 gm, yield 65 %) as a yellow solid.
Step 2: Preparation of 3-dimethylaminomethyIene-l-(4-methoxy-8- trifluoromethyl-dibenzofuran-l-yl^-oxo-cyclohexanecarbonitrile
A solution of the product step 1 (0.40Og, 0.0010 moles) in benzene (10 ml) and 2 drops of triethylamine was added DMFDMA (0.2 ml, 0.0015 moles) at room temperature under nitrogen. The reaction mixture was heated to HO0C. The benzene was removed using the Dean and Stark apparatus and fresh benzene (10 ml) was added 3 to 4 times, this process was continued for 6 hours. After completion of the reaction, the reaction mass was evaporated under vacuum to obtain the title compound as a brown residue (0.411 gm), which, is further used as such without purification.
Example 1
Figure imgf000045_0001
Step-1: Preparation of Benzyl-4-(l,5-dimethoxycarbonyl-3-cyanopentan-3-yl)- lH-indole-1-carboxylate
To a solution of intermediate 2 (2.3 g, 7.93 mmol) in DMSO (20 ml) was added 1,1,3,3-tetramethyl guanidine (0.5 ml, 3.96 mmol) and methyl acrylate (7.1 ml, 79.3 mmol) at 10-15 0C and the mixture was stirred at room temperature for about one and half hours. The mixture was cooled to 1O0C, diluted with water and extracted with ethyl acetate. The organic layers were collected, combined, washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography to afford the title compound (3.3 g, 90.65 %) as a white solid. IR (Cm-1): 3445.15, 2956.39, 2237.09, 1744.64, 1730.68, 1426.84, 1395.78, 1345.64, 1279.23, 1252.46, 1215.28, 1132.97, 1053.04, 762.35.
1H NMR (300 MHz, CDCl3) δ 2.09-2.14 (m, 2 H), 2.42-2.55 (m, 4 H), 2.59-2.65 (m, 2 H), 3.57 (s, 6 H), 5.4 (s, 2 H), 6.8 (d, IH, J= 3.6 Hz), 7.3-7.49 (m, 7H), 7.7 (d, 1 H, J= 3.9 Hz), 8.2 (d, 1 H, J= 8.1 Hz). Step-2: Preparation of Methyl 5-cyano-5-(lH-indol-4-yl)-2- oxocyclohexanecarboxylate
To a solution of compound of step 1 (2.8 g, 6.08 mmol) in 1 ,2-dimethoxyethane (DME, 65 ml) was added sodium hydride (876 mg, 18.24 mmol, 55%) portion wise in 30 minutes at 0 0C and the mixture was stirred at the same temperature for 2 hours. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layers were collected, combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography using 10% ethyl acetate- hexane to afford the title compound (2.6 g, 70 %) as a white solid. IR (Cm"1): 3340.72, 2233.31, 1662.58, 1606.62, 1444.29, 1339.79, 1292.94, 1222.10, 1100.67, 787.24, 754.21. 1H NMR (300 MHz, CDCl3) δ 1.23-1.34 (m, 1 H), 2.42-2.51 (m, 3 H), 2.82-2.93 (m, 2 H), 3.2 (br d, 1 H, J= 16.2 Hz), 3.78 (s, 3 H), 6.8 (br s, 1 H), 7.1-7.3 (m, 3 H), 7.4 (d, 1 H, J= 7.4 Hz), 8.3 (br s, 1 H).
Step-3: Preparation of l-(lH-Indol-4-yl)-4-oxocyclohexanecarbonitrile To a solution of compound of step 2 (5.9 g, 19.9 mmol) in dimethyl sulfoxide (80 ml) was added H2O (10.8 ml) followed by sodium chloride (7.5 g, 129.3 mmol) at room temperature and the mixture was stirred at 145-1500C for 5 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (3 x 100 ml). The organic layers were collected, combined, washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (3.Og, 63.8 %) as an off-white solid.
IR (Cm"1): 3274.67, 2230.30, 1707.40, 1413.71, 1359.89, 1338.74, 1286.54, 901.29,
750.46.
1H NMR (300 MHz, CDCl3) δ 2.5 (m, 4 H), 2.64-2.85 (m, 4 H), 6.7 (s, 1 H), 7.1 (m,
2 H), 7.5 (m, 2 H), 11.3 (br s, 1 H). Step-4: Preparation of l^l-Methyl-lH-indoM-yl^-oxocyclohexanecarbonitrile To a solution of compound of step 3 (200 mg, 0.84 mmol) in N,N-dimethyl formamide (2 ml) was added cesium carbonate (415 mg, 1.27 mmol) at room temperature followed by methyl iodide (71 μl, 1.09 mmol) and the mixture was stirred for one and half hours. The reaction mass was diluted with water and extracted with ethyl acetate (3 x 20 ml). The organic layers were collected, combined, washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was crystallized from 30% ethyl acetate-hexane to afford the title compound (180 mg, 85 %) as an off- white solid. IR (Cm-1): 3412.94, 2951.96, 2232.62, 1720.33, 1514.44, 1426.02, 1338.62, 1293.37, 1249.31, 1221.03, 754.27.
1H NMR (300 MHz, CDCl3) δ 2.4-2.49 (m, 4 H), 2.64-2.80 (m, 4 H), 3.8 (s, 3 H), 6.7 (d, 1 H, J= 3.3 Hz), 7.1 (m, 2 H), 7.5 (m, 2 H). MS m/z [M+l] 253.0, [M+Na] 275.0. Step-5: Preparation of 4,5,6,7-Tetrahydro-5-(l-methyl-lH-indol-4-yl)-2H- indazole- 5-carbonitrile
To a solution of compound of step 4 (500 mg, 1.98 mmol) in N, N- dimethylformamide (8 ml) was added N,N- dimethylformamide dimethylacetal (DMFDMA) (0.5 ml, 3.96 mmol) and the mixture was stirred for 1 hour at 110-120 0C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layers were collected, combined, washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the crude enamine intermediate (600 mg) as a brown solid which was dissolved in ethanol (8 ml). To this solution was added hydrazine hydrate (117 mg, 2.34 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with ethyl acetate (3 x 50 ml). The organic layers were collected, combined, washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography using silica gel, eluted with 1% MeOH-CHCl3 to give the title compound (130 mg, 24 %) as yellow powder, mp: 203-205 0C. IR (Cm-1): 3269.97, 2926.79, 2854.56, 2231.14, 1606.77, 1515.83, 1498.26, 1436.46, 1340.98, 1298.22, 749.93. 1H NMR (300 MHz, CDCl3) δ 2.69-2.62 (m, 2 H), 2.89-2.80 (m, 1 H), 3.14-3.09 (m, 1 H), 3.53-3.3 (ABq, J1 = 15.9 Hz, J2 = 46.5 Hz, 2 H), 3.8 (s, 3 H), 6.8 (dd, J1 = 0.6 Hz, J2 = 3.3 Hz, IH), 7.3 (m, IH), 7.1 (m, 3H), 7.4 (br s, IH). Example 2
Figure imgf000048_0001
Step 1: Preparation of 4,5,6,7-Tetrahydro-5-(lH-indol-4-yl)-2H-indazole-5- carbonitrile To a solution of l-(lH-indol-4-yl)-4-oxocyclohexanecarbonitrile (400 mg, 1.68 mmol) in N,N-dimethylformamide (6 ml) was added N, N- dimethylformamide dimethylacetal (DMFDMA, 447 μl, 3.36 mmol) and the mixture was stirred for 1 hour at 110-120 0C under nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under vacuum to afford crude enamine intermediate (400 mg) as a brown solid which was suspended in ethanol (4 ml). To this solution was added hydrazine hydrate (62 μl, 1.22 mmol) and the mixture was stirred at 55-60 0C for about 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography to obtain the title compound (140 mg, 31.8 %) as a yellow powder, mp: 133-135 0C. IR (cm'1): 3409.36, 2929.77, 2234.44, 1613.45, 1505.56, 1436.24, 1413.35, 1339.77, 1088.57, 753.44.
1H NMR (300 MHz, CDCl3 + CD3OD) δ 2.7-2.65 (m, IH), 2.92-2.83 (m, IH), 3.15- 3.07 (m, 1 H), 3.5-3.3 (ABq, J1 = 15.6 Hz, J2 = 39.9 Hz, 2H), 6.8 (m, IH), 7.1 (m, 2H), 7.3 (m, IH), 7.4 (m, IH). Example 3
Figure imgf000049_0001
Step-1: Preparation of Dimethyl 4-cyano-4-(7-methoxy-l-tosyl-lH-indol-4- yl)heptanedioate The title compound was prepared using intermediate 1, following a similar procedure as mentioned in step 1 of example 1 as a white solid.
IR (Cm'1): 3448.03, 2956.11, 2231.92, 1746.74, 1732.08, 1375.38, 1175.94, 1144.57,
614.79.
1H NMR (300 MHz, CDCl3) δ 2.11-2.15 (m, 2 H), 2.38-2.61 (m, 6 H), 2.4 (s, 3 H), 3.5 (s, 6 H), 3.6 (s, 3 H), 6.6 (d, 1 H, J= 8.4 Hz), 6.8 (d, 1 H5 J= 3.9 Hz), 7.2-7.31
(m, 3 H), 7.7 (d, 2 H, J= 8.4 Hz), 7.9 (d, 1 H, J= 3.9 Hz).
Step-2: Preparation of Methyl-5-cyano-5-(7-methoxy-l-tosyl-lH-indol-4-yl)-2- oxocyclohexanecarboxylate
The title compound was prepared following a similar procedure as mentioned in step 2 of example 1 as a white solid.
IR (cm"'): 3435.65, 2942.38, 2230.13, 1665.21, 1626.06, 1497.05, 1443.15, 1357.18,
1291.32, 667.91.
1H NMR (300 MHz, CDCl3) δ 1.2 (m, 1 H), 2.35-2.47 (m, 3 H), 2.4 (s, 3 H), 2.75-2.9
(m, 2 H), 3.2 (br d, 1 H, J= 16.5 Hz), 3.7 (s, 3 H), 3.8 (s, 3 H), 6.6 (d, 1 H, J= 8.4 Hz), 7.0 (d, 1 H, J= 3.9 Hz), 7.1 (d, 1 H, J= 8.4 Hz), 7.3 (d, 1 H, J= 8.4 Hz), 7.7 (d,
1 H, J= 8.4 Hz), 7.9 (d, 1 H, J= 3.6 Hz);
Step-3: Preparation of l-(7-Methoxy-l-tosyl-lH-indol-4-yl)-4-oxocycIohexane- carbonitrile
The title compound was prepared following a similar procedure as mentioned in step 3 of example 1 as an off-white solid. IR (Cm-1): 2961.70, 2941.17, 2234.16, 1716.99, 1495.36, 1373.4, 1357.62, 1289.51, 1244.53, 1170.21, 1143.32, 680.67, 657.14.
1H NMR (300 MHz, CDCl3) δ 2.33-2.33 (m, 2 H), 2.4 (s, 3 H), 2.57-2.62 (m, 2 H), 2.69-2.76 (m, 2 H), 2.92-3.0 (m, 2 H), 3.68 (s, 3 H), 6.6 (d, 1 H, J= 8.4 Hz), 7.0 (d, 1 H, J= 3.9 Hz), 7.1 (d, 1 H, J= 8.4 Hz), 7.3 (d, 1 H, J= 8.1 Hz), 7.7 (d, 1 H, J= 8.1 Hz), 7.9 (d, I H, J= 3.9 Hz);
Step-4: Preparation of 4,5,6,7-Tetrahydro-5-(7-methoxy-l-tosyl-lH-indol-4-yl)- 2H-indazole-5-carbonitrile The title compound was prepared following a similar procedure as mentioned in step 5 of example 1 as an off-white solid.
IR (cm'1): 3391.79, 2930.43, 2853.94, 2233.13, 1584.29, 1373.5, 1357.76, 1289.75, 1243.49, 1171.56, 1141.53, 1087.17, 681.01, 664.95. 1H NMR (300 MHz, CDCl3) δ 2.4 (s, 3 H), 2.51-2.57 (m, 2 H), 2.8 (m, 1 H), 3.1 (m, 1 H), 3.4 (m, 2 H), 3.67 (s, 3 H), 6.6 (d, 1 H, J= 8.4 Hz), 7.0 (d, 1 H, J= 3.9 Hz), 7.1 (d, 1 H, J= 8.7 Hz), 7.3 (d, 2 H, J= 8.4 Hz), 7.4 (s, 1 H), 7.7 (d, 2 H, J= 8.1 Hz), 7.9 (d, 1 H, J= 3.9 Hz); Step-5: Preparation of 4,5,6,7-Tetrahydro-5-(7-methoxy-lH-indol-4-yl)-2H- indazole-5 -carbonitrile
To a solution of compound of step 4 (420 mg, 0.94 mmol) in 35% dichlomethane- methanol (30 ml) was added Mg (226 mg, 9.4 mmol) at room temperature and the mixture was stirred at the same temperature for 4 hours. The mixture was treated with saturated ammonium chloride solution at 10 0C, filtered through celite bed and washed with dichlomethane. From the filtrate, the dichloromethane layer was separated and the aqueous layer was extracted with dichlomethane (2 x 30 ml). The organic layers were collected, combined, washed with water followed by brine, dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by silica gel column chromatography using 1% MeOH-CHCl3 to give the title compound (140 mg, 51 %) as an off-white solid. HPLC purity: 98.57 %. IR (cm"1): 3402.04 (br), 2933.13, 2853.80, 2233.68 (CN), 1626.04, 1577.44, 1524.58, 1500.90, 1444.59, 1417.95, 1347.55, 1278.47, 1083.61, 960.59. 1H NMR (300 MHz, CDCl3) δ 2.65-2.59 (m, 2H), 2.88-2.80 (m, IH), 3.13-3.08 (m, IH), 3.49- 3.29 (ABq, 2H, J1 = 43.65 Hz, J2 = 15.9 Hz ), 3.97 (s, 3H), 6.59 (d, IH, J= 8.1 Hz), 6.8 (dd, IH, Ji = 3.15 Hz, J2 = 2.1 Hz), 7.1 (d, IH, J= 8.1 Hz), 7.2 (t, IH, J= 3.0 Hz), 7.4 (s, IH), 8.55 (br s, IH, NH);
Example 4
Figure imgf000051_0001
Step-1: Preparation of Dimethyl 4-cyano-4-(7-methoxy-l-tosyl-lH-indol-4-yl) heptanedioate The title compound was prepared using intermediate 1, following a similar procedure as mentioned in step 1 of example 1 as a white solid.
IR (Cm"1): 3448.03, 2956.11, 2231.92, 1746.74, 1732.08, 1375.38, 1175.94, 1144.57,
614.79.
1H NMR (300 MHz, CDCl3) δ 2.11-2.15 (m, 2 H), 2.38-2.61 (m, 6 H), 2.4 (s, 3 H), 3.5 (s, 6 H), 3.6 (s, 3 H), 6.6 (d, 1 H, J= 8.4 Hz), 6.8 (d, 1 H, J= 3.9 Hz), 7.2-7.31
(m, 3 H), 7.7 (d, 2 H, J= 8.4 Hz), 7.9 (d, 1 H, J= 3.9 Hz).
Step-2: Preparation of Dimethyl 4-cyano-4-(7-methoxyl-lH-indol-4-yl)- heptanedioate
The title compound was prepared following a similar procedure as mentioned in step 5 of example 3 as a white solid (120 mg, 22 %).
IR (cm-'): 3436.07, 3103.20, 2963.32, 2933.75, 2898.64, 2244.88, 1731.64, 1581.64,
1524.82, 1507.82, 1259.84.
1H NMR (300 MHz, DMSOd6) δ 3.8 (s, 3 H), 4.0 (s, 3 H), 4.05 (s, 2H), 6.4 (br s, 1
H), 6.6 (d, J= 7.8 Hz, 1 H), 6.9 (d, J= 7.5 Hz, 1 H), 7.2 (br s, 1 H). Step-3: Preparation of Dimethyl 4-cyano-4-(7-methoxy-l-methyl-lH-indol-4-yl) heptanedioate To a solution of compound of step 2 (3.0 g, 8.37 mmol) in N,N-dimethylformamide
(25 ml) was added powdered sodium hydroxide (161 mg, 4.02 mmol) at 0 0C followed by methyl iodide (0.8 ml, 12.56 mmol). The mixture was then stirred for 2 hours at the same temperature, quenched with acetic acid, diluted with water and extracted with ethyl acetate (3 x 50 ml). The organic layers were collected, combined, washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford the title compound (2.7 g, 86.8 %) as an off- white solid. IR (cm-1): 3450.81, 2953.16, 2235.44, 1737.52, 1576.54,
1508.19, 1437.68, 1296.44, 1270.73, 1199.09, 1175.75, 1093, 31, 727.90. 1H NMR (300 MHz, CDCl3) δ 2.1 (m, 2 H), 2.3-2.6 (m, 4H), 2.65-2.8 (m, 2 H), 3.6
(s, 6 H), 3.9 (s, 3 H), 4.06 (s, 3 H), 6.5 (m, 2 H), 6.9 (d, 1 H, J= 3.0 Hz), 7.1 (d, 1 H,
J= 8.1 Hz);
Step-4: Preparation of Methyl-5-cyano-5-(7-methoxy-l-methyl-lH-indol-4-yl)-2- oxocyclo-hexane-carboxylate The title compound was prepared following a similar procedure as mentioned in step
2 of example 1 as a white solid.
IR (cm"'): 2959.37, 2937.38, 2224.81, 1663.22, 1612.39, 1505.02, 1443.63, 1294.83,
1273.84, 1215.83, 1091.48, 798.18.
1H NMR (300 MHz, CDCl3) δ 1.25 (m, 1 H), 2.38-2.46 (m, 3 H), 2.78-2.94 (m, 2 H), 3.2 (br d, 1 H, J= 16.2 Hz), 3.7 (s, 3 H), 3.9 (s, 3 H), 4.06 (s, 3 H), 6.5 (d, 1 H, J =
8.1 Hz), 6.7 (d, 1 H, J= 3.3 Hz), 6.9 (d, 1 H, J= 8.1 Hz), 7.0 (d, 1 H, J= 3.0 Hz).
Step-5: Preparation of l-(7-Methoxy-l-methyl-lH-indol-4-yl)-4-oxocyclohexane- carbonitrile
The title compound was prepared following a similar procedure as mentioned in step 3 of example 1 as an off-white solid.
IR (cm"1): 3401.32, 2938.10, 2907.83, 2840.92, 2233.14, 1717.58, 1572.80, 1505.01,
1467.86, 1429.99, 1292.68, 1272.11. 1H NMR (300 MHz, CDCl3) δ 2.42-2.32 (m, 2H), 2.61-2.55 (m, 2H), 2.81-2.74 (m, 2H), 3.05-2.93 (m, 2H), 3.9 (s, 3H), 4.07 (s, 3H), 6.5 (d, IH, J= 8.1 Hz), 6.7 (d, IH, J= 3.0 Hz), 6.9 (d, IH, J= 8.1 Hz), 7.0 (d, IH, J= 3.3 Hz).
Example 5
Figure imgf000053_0001
Preparation of 4,5,6,7-Tetrahydro-5-(7-methoxy-l-methyl-lH-indol-4-yl)-2H- indazole-5-carbonitrile
The title compound was prepared following a similar procedure as mentioned in step 5 of example 1 as a yellow powder (160 mg, 30 %).
IR (Cm-1): 3167.49, 2933.22, 2231.81 (CN), 1733.66, 1610.72, 1575.06, 1507.03, 1400.47, 1359.44, 1297.85, 1269.42, 1103.24, 964.04, 794.87. 1H NMR (300 MHz, CDCl3) δ 2.63-2.58 (m, 2H), 2.86-2.77 (m, IH), 3.14-3.06 (m, IH), 3.49-3.26 (ABq, 2H, J, = 52.05 Hz, J2 = 15.9 Hz), 3.92 (s, 3H), 4.0 (s, 3H), 6.5 (d, IH, J= 8.1 Hz), 6.7 (d, IH, J= 3.3 Hz), 7.4 (s, IH), 7.0(m, 2H).
Example 6
Figure imgf000053_0002
Step 1: Preparation of 4-hydroxy-l-(7-methoxy-lH-indol-4-yl)- cyclohexanecarbonitrile
The title compound was prepared by using the compound prepared in step 3 of example 3 and following a similar procedure as mentioned in step 5 of example 3. Step 2: Preparation of l-(7-methoxy-lH-indol-4-yl)-4-oxocyclohexanecarbonitrile
To a solution of compound of step 1 (400 mg, 1.48 mmol) in dichloromethane (10 ml) was added pyridinium chlorochromate (PCC) (638 mg, 2.96 mmol) at 0 0C and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and filtered through celite. The filtrate was concentrated under vacuum and the crude product was purified by column chromatography using silica gel eluted with 15 % ethyl acetate-hexane to give the title compound (168 mg, 42.8 %) as an off-white powder.
IR (Cm"1): 3380.22, 2949.13, 2925.66, 2236.84, 1708.08, 1574.66, 1523.93, 1504.73, 1273.55741.80. 1H NMR (300 MHz, CDCl3) δ 2.47-2.36 (m, 2H), 2.63-2.56 (m, 2H), 2.80-2.73 (m, 2H), 3.06-2.94 (m, 2H), 3.9 (s, 3H), 6.59 (d, IH, J= 8.1 Hz), 6.8 (dd, IH, J1 = 3.15 Hz, J2= 2.1 Hz), 7.0 (d, IH, J= 8.1 Hz), 7.2 (t, IH5 J= 2.8 Hz), 8.58 (br s, IH, NH).
Figure imgf000054_0001
Step 1 : Preparation of 4-(6-FIuoro-l-methoxy-9-methyl-9H-carbazol-4-yl)- heptanedioic acid dimethyl ester
The title compound was prepared using intermediate 4, according to a similar procedure mentioned in step 1 of example 1. In this example triton B was used as the base instead of 1,1,3,3-tetramethyl guanidine under reflux.
1H NMR (300 MHz, DMSO-J6): δ 2.4 - 2.8 (m, 8H), 3.50 (s, 6H), 3.99 (s, 3H), 4.20 (s, 3H), 7.09 - 7.17 (m, 2H), 7.40 - 7.46 (m, IH), 7.7 - 7.74 (m, IH), 8.05 (d, J = 10.7 Hz, IH). Step2: Preparation of 5-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-2-oxo cyclohexanecarboxylic acid methyl ester
The title compound was prepared following a similar procedure mentioned in step 2 of example 1 at room temperature instead of 0 0C. 1H NMR (300 MHz, OMSO-d6): δ 2.64 - 2.90 (m, 4H), 3.20 - 3.5 5 (m, 2H), 3.76 (s,
3H), 3.99 (s, 3H), 4.21 (s, 3H), 7.1 - 7.20 (m, 2H), 7.40 - 7.50 (m, IH), 7.7 - 7.79
(m, IH), 7.89 (d, J= 9.2 Hz, IH), 12.14 (s, IH).
Step 3: Preparation of 4-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)- cyclohexanone The title compound was prepared following a similar procedure mentioned in step 3 of example 1.
IR (KBr) (cm"1): 3436, 2951,2720, 2221, 1727, 1581, 1486, 1317, 1272, 1240,
1194, 905, 802.1HNMR (300 MHz, CDCl3): δ 2.24 - 2.34 (m, 2H), 2.65 - 2.71 (m,
2H), 3.07 - 3.15 (m, 4H), 4.01 (s, 3H), 4.22 (s, 3H), 6.90 (d, J= 8.4 Hz, IH), 7.07 (d, J= 8.4 Hz, IH), 7.26 - 7.32 (m, IH), 7.39 - 7.44 (m, IH), 8.08 (d, J= 9.2 Hz, IH).
Example 8
Figure imgf000055_0001
Step 1 : Preparation of 4-(l-methoxy-9-methyl-9H-carbazol-4-yl)-heptanedioic acid dimethyl ester
The title compound was prepared using intermediate 5, according to the procedure mentioned in step 1 of example 1. In this example triton B was the base used instead of 1,1,3,3-tetramethyl guanidine under reflux. 1H NMR (300 MHz, CD3OD): δ 2.2 - 2.8 (m, 8H), 4.02 (s, 6H), 4.22 (s, 3H, s), 4.57 (s, 3H), 7.03 (d, J= 8.3 Hz, IH), 7.24 - 7.34 (m, 2H), 7.47 - 7.58 (m, 2H), 8.33 (d, J = 7.7 Hz, IH)
Step2: Preparation of 5-(l-methoxy-9-methyl-9H-carbazol-4-yl)-2-oxocyclohexane carboxylic acid methyl ester
Prepared according to the procedure mentioned in step 2 of example 1 to afford the desired product as a pale yellow solid at RT instead of 0 0C. 1H NMR (300 MHz, CDCl3): δ 2.64 - 2.90 (m, 4H), 3.20 - 3.5 5 (m, 2H), 3.78 (s, 3H), 4.01 (s, 3H), 4.23 (s, 3H), 6.90 (d, J= 8.4 Hz, IH), 7.16 - 7.19 (m, IH), 7.30 - 7.32 (m, IH), 7.49 - 7.53 (m, 2H), 8.30 (d, J= 8.2 Hz, IH), 12.33 (s, IH).
Step 3: Preparation of 4-(l-methoxy-9-methyl-9H-carbazol-4-yl)-cycIohexanone Prepared according to the procedure mentioned in step 3 of example 1 to afford the desired product as a pale yellow solid. IR (KBr) (cm-1): 3421, 2959, 2224, 1719, 1574, 1474, 1322, 1274, 1247, 1104, 1017, 799, 754.
1H NMR (300 MHz, CDCl3): δ 2.28 - 2.37 (m, 2H), 2.64 - 2.70 (m, 2H), 3.00 - 3.15 (m, 4H), 4.01 (s, 3H), 4.24 (s, 3H), 6.90 (d, J= 8.3 Hz, IH), 7.10 (d, J= 8.3 Hz, IH), 7.31 - 7.36 (m, IH), 7.48 - 7.57 (m, 2H), 8.39 (d, J= 8.3 Hz, IH).
Example 9
Figure imgf000056_0001
Step 1 : Preparation of 3-dimethylaminomethylene-l-(6-fluoro-l-methoxy-9- methyl-9H-carbazol-4-yl)-4-oxo-cyclohexanecarbonitrile
A stirred solution of 4-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)- cyclohexanone (example 7) (Ig, 2.46 mmole) in DMF (7 ml) and DMA.DMF (588 mg, 4.93 mmole) was heated to 110° C. After 2h, the starting material was absent by TLC and the reaction mass was cooled to RT. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (3 X 25 ml). The combined organic layer was washed with water (3 x 75 ml), dried over anhydrous Na2SO4 and concentrated at 40 0C under vacuum. The crude product was purified by column chromatography to give the title compound (900 mg, yield 77.8%).
Step 2: Preparation of 6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yI)-5,6,7,8- tetrahydroquinazoIine-6-carbonitrile To a solution of the product from step 1 (100 mg, 0.24 mmole) and formamidine acetate (256 mg, 2.46 mmole) in DMA (3 ml) was stirred under microwave in a micro oven for 10 minutes. The reaction mass was cooled to room temperature and aqueous sodium bicarbonate (10 ml) was added. The mixture was extracted with dichloromethane (3 x 5 ml). The combined organic layer was washed with water (3 x 10 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to afford the desired product (60 mg, yield 64.8%) as a pale yellow solid.
1H NMR (300 MHz, DMSO-J6): δ 2.43 - 2.62 (m, IH), 2.90 - 3.35 (m, 3H), 3.65 (d, J= 15.6 Hz, IH), 3.85 (d, J= 16.3 Hz, IH), 4.00 (s, 3H), 4.22 (s, 3H), 7.08 - 7.17 (m, 2H), 7.41 - 7.48 (m, IH), 7.72 - 7.76 (m, IH), 7.95 (dd, J= 11.1 Hz and 2.0 Hz, IH), 8.76 (s, IH), 9.03 (s, IH).
IR (KBr) (cm "'): 3435, 2990, 2227, 1779, 1602, 1578, 1512, 1486, 1458, 1392, 1313, 1274, 1242, 1200, 1026, 783. Example 10
Figure imgf000058_0001
Step 1: Preparation of 3-Dimethylaminomethylene-l-(6-fluoro-l-methoxy-9- methyl-9H-carbazol-4-yl)-4-oxo-cyclohexanecarbonitrile The title compound was prepared according to a similar procedure mentioned in step 1 of example 9.
Step 2: Preparation of 2-Amino-6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4- yl)-5,6,7,8-tetrahydroquinazoline-6-carbonitrile
To a stirred solution of the product of step 1 (90 mg, 0.22 mmole) in ethanol (3 ml) was added guanidine.HCl (23 mg, 0.24 mmole) followed by sodium ethoxide (18.1 mg, 0.26) at RT. After refluxing for 2h (the starting material was absent by TLC) the reaction mixture was concentrated at 400C under vacuum, diluted with water (10 ml) and extracted with dichloromethane (3 x 5 ml). The combined organic layer was washed with water (3 X 10 ml), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography to afford the desired product (50 mg, yield 56 %) as a pale yellow solid.
1H NMR (300 MHz, DMSO- d6): δ 2.43 - 2.50 (m, IH), 2.80 - 3.10 (m, 3H), 3.22 - 3.37 (m, IH), 3.57 - 3.62 (m, IH), 3.99 (s, 3H), 4.21 (s, 3H), 6.51 (s, 2H), 7.08 - 7.18 (m, 2H), 7.41 - 7.47 (m, IH), 7.71 - 7.76 (m, IH), 7.90 - 7.95 (dd, J= 11.2 Hz and 2.3 Hz, IH), 8.18 (s, IH).
IR (KBr) (cm "'): 3420, 3179, 2933, 2231, 1657, 1599, 1579, 1510, 1484, 1462, 1391, 1315, 1270, 1241, 1199, 1027, 793. Example 11
Figure imgf000059_0001
Step 1: Preparation of 3-Dimethylaminomethylene-l-(6-fluoro-l-methoxy-9- methyl-9H-carbazoI-4-yl)-4-oxo-cyclohexanecarbonitrile
The title compound was prepared according to a similar procedure mentioned in step
1 of example 9.
Step 2: Preparation of 5-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-4,5,6,7- tetrahydro-2H-indazole-5-carbonitrile
A solution of the product of step 1 (90 mg, 0.22 mmole) and hydrazine hydrate (13 mg, 0.26 mmole) in ethanol (3 ml) was refiuxed for 6h. The starting material was absent by TLC and the reaction mass was concentrated at 400C under vacuum. The mixture was diluted with water (10 ml) and extracted with dichloromethane (3 x 5 ml). The combined organic layer was washed with water (3 x 10 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to afford the desired product (65 mg, yield 78.3 %) as a pale yellow solid.
Example 12
Figure imgf000059_0002
Step 1 : Preparation of 3-Dimethylaminomethylene-l-(6-fluoro-l-methoxy-9- methyl-9H-carbazol-4-yl)-4-oxo-cyclohexanecarbonitrile The title compound was prepared according to a similar procedure mentioned in step 1 of example 9.
Step 2; Preparation of 5-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-4,5,6,7- tetrahydro-benzo [c] isoxazole-5-carbonitrile To a stirred solution of hydroxylamine.HCl (21 mg, 0.30 mmole) in ethanol (3 ml) and sodium ethoxide (20 mg, 0.30 mmole) was added the product of step 1 (100 mg, 0.25 mmole) at RT. After stirring for 1 h (the starting material was absent by TLC) the reaction mass was concentrated under vacuum, diluted with water (10 ml) and extracted with ethyl acetate (3 X 5 ml). The combined organic layer was washed with water (3 x 10 ml), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography to afford the desired product (60 mg, yield 64.5 %) as a pale yellow solid.
1H NMR (300 MHz, DMSO- d6): δ 2.2 - 3.50 (m, 6H), 3.98 (s, 3H), 4.19 (s, 3H), 7.04 - 7.13 (m, 2H), 7.41 - 7.47 (m, IH), 7.70 - 7.75 (m, 2H), 7.93 (dd, J= 1 1.0 Hz and 2.08 Hz, IH).
IR (KBr) (cm"1): 3436, 2938, 2231, 1627, 1579, 1513, 1484, 1463, 1315, 1274, 1190,907.
Figure imgf000060_0001
Step 1: Preparation of 3-Dimethylaminomethylene-l-(6-fluoro-l-methoxy-9- methyl-9H-carbazol-4-yl)-4-oxo-cyclohexanecarbonitrile
The title compound was prepared according to a similar procedure mentioned in step 1 of example 9. Step 2: Preparation of 6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-2- methyl-5,6,7,8-tetrahydroquinazoline-6-carbonitrile
To a stirred solution of step 1 (100 mg, 0.25 mmole) in ethanol (3 ml) was added acetamidine.HCl (47 mg, 0.50 mmole) followed by sodium methoxide (27 mg, 0.50 mmole) at RT. After refluxing for 2h (the starting material was absent by TLC) the reaction mass was concentrated at 400C under vacuum, diluted with water (10 ml) and extracted with dichloromethane (3 x 5 ml). The combined organic layer was washed with water (3 x 10 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to afford the desired product (50 mg, yield 50 %) as a pale yellow solid.
1H NMR (300 MHz, DMSO- d6): δ 2.50 - 2.60 (m, 3H), 2.80 - 3.30 (m, 3H), 3.58 (d, J= 16.5 Hz, IH), 3.80 (d, J= 16.5 Hz, IH), 3.99 (s, 3H), 4.22 (s, 3H), 7.08 - 7.17 (m, 2H), 7.42 - 7.48 (m, IH), 7.72 - 7.77 (m, IH), 7.95 (d, J= 11.1 Hz, IH), 8.64 (s, IH). IR (KBr) (cm Λ): 3434, 2942, 2226, 1735, 1580, 1556, 1484, 1434, 1315, 1273, 1199,1187,920,792.
Example 14
Figure imgf000061_0001
Step 1: Preparation of 3-Dimethylaminomethylene-l-(l-methoxy-9-methyl-9H- carbazol-4-yl)-4-oxo-cyclohexanecarbonitrile
A solution of 4-(l-methoxy-9-methyl-9H-carbazol-4-yl)-heptanedioic acid dimethyl ester
(example 8) (530 mg, 1.59 mmole) and DMA.DMF (379.9 mg, 3.19 mmole) in benzene (10 ml) was stirred and refluxed. After 2hours, the reaction mass was concentrated at 40° C under vacuum and the crude product was purified by column chromatography to yield the title compound (270 mg, yield 43.6%) and the starting material (290 mg, 54.7%)
Step 2: Preparation of 6-(l-methoxy-9-methyl-9H-carbazoI-4-yl)-5,6,7,8- tetrahydroquinazoline-6-carbonitrile A mixture of the product of step 1 (104 mg, 0.27 mmole) in DMA (3 ml) and formamidine acetate (419.2 mg, 4.03 mmole) was exposed to microwave for 10 min in a household micro oven. The starting material was absent by TLC and the reaction mass was cooled to RT. To this was added aqueous sodium bicarbonate (10 ml) and the mixture was extracted with dichloromethane (3 x 5 ml). The combined organic layer was washed with water (3 x 10 ml), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography to yield the desired product (79 mg, yield 79.8%) as an off-yellow solid. 1H NMR (300 MHz, CDCl3): δ 2.43 - 3.70 (m, 6H), 4.02 (s, 3H), 4.25 (s, 3H), 6.88 (d, J= 8.0 Hz, IH), 7.06 (d, J= 8.6 Hz, IH), 7.33 (t, J= 6.7, IH), 7.50 - 7.59 (m, 2H), 8.34 (d, J= 8.3 Hz, IH), 8.69 (s, IH), 9.15 (s, IH).
IR (KBr) (cm ^1): 3431, 2927, 2857, 2225, 1731, 1616, 1575, 1553, 1509, 1475, 1395, 1321, 1279, 1246, 749, 731.
Example 15
Figure imgf000062_0001
Step 1: Preparation of 3-Dimethylaminomethylene-l-(l-methoxy-9-methyI-9/T- carbazol-4-yl)-4-oxo-cyclohexanecarbonitrile
The title compound was prepared according to a similar procedure mentioned in step 1 of example 14. Step 2: Preparation of 2-Amino-6-(l-methoxy-9-methyl-9H-carbazoI-4-yl)-5,6,7,8- tetrahydroquinazoline-6-carbonitriIe
To a stirred solution of step 1 (110 mg, 0.28 mmole) in ethanol (3 ml) was added guanidine.HCl (29.8 mg, 0.31 mmole) followed by sodium ethoxide (23.2 mg, 0.34 mmole) at RT. After refluxing for 2h (the starting material was absent by TLC) the reaction mass was concentrated under vacuum, diluted with water (10 ml) and extracted with ethyl acetate (3 x 5 ml). The combined organic layer was washed with water (3 x 10 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to afford the desired product (95 mg, yield 87.3 %) as a pale yellow solid.
1H NMR (300 MHz, CDCl3): δ 2.43 - 3.70 (m, 6H), 4.00 (s, 3H), 4.21 (s, 3H), 6.50 (s, 2H), 7.09 (d, J= 8.4 Hz, IH), 7.17 (d, J= 8.3 Hz, IH), 7.31 (t, J= 7.6 Hz, IH), 7.54 (t, J= 7.7 Hz, IH), 7.69 (d, J= 8.3 Hz, IH), 8.17 (s, IH), 8.26 (d, J= 8.2 Hz, IH). IR (KBr) (cm A): 3395, 3330, 3175, 2934, 2225, 1662, 1599, 1574, 1474, 1323, 1295,1272,1108,793,754.
Example 16
Figure imgf000063_0001
Step 1: Preparation of 3-dimethylaminomethylene-l-(l-methoxy-9-methyl-9//- carbazol-4-yl)-4-oxo-cyclohexanecarbonitrile
The title compound was prepared according to a similar procedure mentioned in step 1 of example 14.
Step 2: Preparation of 5-(l-methoxy-9-methyl-9H-carbazol-4-yl)-4,5,6,7- tetrahydro-2H-indazole-5-carbonitrile A solution of the product from step 1 (100 mg, 0.26 mmole) and hydrazine hydrate (15.5 mg, 0.31 mmole) in ethanol (4 ml) was refluxed for 2h. The starting material was absent by TLC and the reaction mass was concentrated at 4O0C under vacuum. Water (10 ml) was added and the mixture was extracted with dichloromethane (3 x 5 ml). The combined organic layer was washed with water (3 X 10 ml), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by column chromatography to afford the desired product (63 mg, yield 68.5 %) as an off-yellow solid.
1H NMR (300 MHz, DMSO- d6): δ 2.39 - 3.58 (m, 6H), 4.00 (s, 3H), 4.21 (s, 3H), 7.07 (d, J= 8.4 Hz, IH), 7.22 - 7.30 (m, 2H), 7.50 - 7.55 (m, 2H), 7.67 (d, J= 8.1 Hz, IH), 8.23 (d, J= 7.0 Hz, IH), 12.58 (s, IH).
IR (KBr) (cm "■): 3393, 2932, 2854, 2230, 1616, 1574, 1508, 1475, 1395, 1323, 1275,1102,1020,957,752,735.
Example 17
Figure imgf000064_0001
Step 1: Preparation of 3-Dimethylaminomethylene-l-(l-methoxy-9-methyl-9//- carbazol-4-yl)-4-oxo-cyclohexanecarbonitrile
The title compound was prepared according to a similar procedure mentioned in step 1 of example 14.
Step 2: Preparation of 5-(l-methoxy-9-methyl-9H-carbazol-4-yl)-4,5,6,7- tetrahydro-benzo [c] isoxazole-5-carbonitriIe
To a stirred solution of hydroxylamine.HCl (20mg, 0.28 mmole) and sodium ethoxide (19.3 mg, 0.28 mmole) in ethanol (5ml) was added compound of step 1 (100 mg, 0.25 mmole) at RT. After stirring for 16 h (the starting material was absent by TLC) the reaction mass was concentrated under vacuum, diluted with water (10 ml) and extracted with ethyl acetate (3 x 5 ml). The combined organic layer was washed with water (3 x 10 ml), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to afford the desired product (60 mg, yield 65 %).
1H NMR (300 MHz, CDCl3): δ 2.00 - 3.68 (m, 6H), 3.99 (s, 3H), 4.22 (s, 3H), 6.86 (d, J= 8.2 Hz, IH), 6.99 (d, J= 8.1 Hz, IH), 7.34 (t, J= 7.08, IH), 7.41 - 7.56 (m, 3H), 8.35 (d, J= 8 Hz, IH).
IR (KBr) (cm ■'): 3308, 2956, 2923, 2853, 2225, 1713, 1573, 1509, 1465, 1398, 1322,1276,1188,1021,754.
Example 18
Figure imgf000065_0001
Step 1 : Preparation of 4-cyano-4-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4- yl)-heptanedioic acid dimethyl ester
The title compound was prepared using intermediate 4, according to a similar procedure mentioned in step 1 of example 1. In this example triton B was implemented as the base instead of 1,1,3,3-tetramethyl guanidine under reflux. 1H NMR (300 MHz, DMSO-afc): δ 2.4 - 2.8 (m, 8H), 3.50 (s, 6H), 3.99 (s, 3H), 4.20 (s, 3H), 7.09 - 7.17 (m, 2H), 7.40 - 7.46 (m, IH), 7.7 - 7.74 (m, IH), 8.05 (d, J = 10.7 Hz, IH).
Step 2: Preparation of 5-cyano-5-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4- yl)-2-oxo cyclohexanecarboxylic acid methyl ester To a stirred solution of the product of step 1 (175 mg, 0.40 mmole) in dimethoxyethane (5 ml), was added 60% NaH in paraffin oil (20 mg, 0.50 mmole) and stirred for 1 hour at room temperature (the starting material was absent by TLC). The reaction mass was quenched with water (10 ml) and extracted with ethyl acetate (2 x 20 ml). The combined organic layer was dried the organic layer over anhydrous Na2SO4 and concentrated to the desired product (125 mg, yield 77.2%) as a pale yellow solid.
1H NMR (300 MHz, DMSO-J6): δ 2.64 - 2.90 (m, 4H), 3.20 - 3.5 5 (m, 2H), 3.76 (s, 3H), 3.99 (s, 3H), 4.21 (s, 3H), 7.1 - 7.20 (m, 2H), 7.40 - 7.50 (m, IH), 7.7 - 7.79 (m, IH), 7.89 (d, J= 9.2 Hz, IH), 12.14 (s, IH) MS: 409.3 (M++l) Step 3: Preparation of 6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-4-oxo- 3,4,5,6,7,8-hexahydroquinazoline-6-carbonitrile
A mixture of intermediate 1 (100 mg, 0.25 mmole) and formamidine acetate (255 mg, 2.5 mmole) in DMA (3 ml) was exposed to microwave for 10 min in a household micro oven. The reaction mass was cooled to room temperature, diluted with water (10 ml) and extracted with dichloromethane (3 x 5 ml). The combined organic layer was washed with water (3 x 10 ml), dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by column chromatography to yield the desired product (65 mg, yield 66%) as an off-yellow solid. 1K NMR (300 MHz, DMSO- d6): δ 2.70 - 3.80 (m, 6H), 3.99 (s, 3H), 4.21 (s, 3H), 7.02 - 7.12 (m, 2H), 7.44 (t, J= 7.9 Hz, IH), 7.71 - 7.76 (m, IH), 7.93 (d, J= 11.4 Hz, IH), 8.12 (s, IH), 12.55 (s, IH). IR (KBr) (Cm -1): 3435, 2915, 2230, 1644, 1579, 1484, 1315, 1271, 1191, 1086, 795. Example 19
Figure imgf000067_0001
Preparation of 2-Amino-6-(6-Fluoro-l-methoxy-9-methyI-9H-carbazol-4-yl)-4- oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carbonitrile To a stirred solution of the product from step 2 of example 18 (90 mg, 0.22 mmole) in ethanol (3 ml) was added guanidine.HCl (26 mg, 0.27 mmole) followed by sodium ethoxide (20 mg, 0.29 mmole) at room temperature. After refluxing for 4hours (the starting material was absent by TLC) the reaction mass was concentrated under vacuum, diluted with water (10 ml) and extracted with ethyl acetate (3 x 5 ml). The combined organic layer was washed with water (3 x 10 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to yield the desired product (65 mg, yield 52 %)
1H NMR (300 MHz, DMSO- d6): δ 2.30 - 3.70 (m, 6H), 3.99 (s, 3H), 4.21 (s, 3H), 6.44 (s, 2H), 7.09 - 7.16 (m, 2H), 7.39 - 7.46 (m, IH), 7.70 - 7.75 (m, IH), 7.90 (d, J= 8.9 Hz, IH), 10.89 (s, IH).
IR (KBr) (cm ^1): 3445, 2927, 2229, 1652, 1484, 1390, 1270, 1192, 1038, 777.
Example 20
Figure imgf000067_0002
Preparation of 5-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-3-oxo- 3,3a,4,5,6,7-hexahydro-2H-indazole-5-carbonitrile A solution of compound of step 2 of example 18 (100 mg, 0.25 mmole) and hydrazine hydrate (18 mg, 0.36 mmole) in ethanol (3 ml) was refluxed for 6h (the starting material was absent by TLC). The reaction mass was concentrated under vacuum, diluted with water (10 ml) and extracted with dichloromethane (3 x 5 ml). The combined organic layer was washed with water (3 x 10 ml), dried and concentrated under vacuum. The residue was purified by column chromatography to afford the desired product (70 mg, yield 73.2 %).
1H NMR (300 MHz, DMSO- d6): δ 2.40 - 3.50 (m, 6H), 3.99 (s, 3H), 4.21 (s, 3H), 7.11 (d, J= 8.4 Hz, IH), 7.23 (d, J= 6.5Hz, IH), 7.42 (t, J = 8.8 Hz, IH), 7.70 - 7.74 (m, IH), 7.87 (m, IH), 11.32 (s, IH)
IR (KBr) (cm ■'): 3436, 2934, 2230, 1625, 1580, 1484, 1384, 1315, 1273, 1241, 1191,934.
Example 21
Figure imgf000068_0001
Preparation of 6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-2-methyl-4- oxo-3,4,5,6,7,8-hexahydroquinazoline-6-carbonitrile
To a stirred solution of compound of step 2 of example 18 (100 mg, 0.25 mmole) in methanol (3 ml) was added acetamidine.HCl (46 mg, 0.50 mmole) followed by sodium methoxide (27 mg, 0.50 mmole) at room temperature and the mixture was refluxed for 2h. After completion of the reaction (indicated by TLC) the reaction mass was concentrated at 4O0C under vacuum, diluted with water (10 ml) and extracted with dichloromethane (3 x 5 ml). The combined organic layer was washed with water (3 x 10 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to afford the desired product (70 mg, yield
68.6 %) as a pale yellow solid.
1H NMR (300 MHz, DMSO- d6): δ 2.25 (s, 3H), 2.44 - 2.94 (m, 4H), 3.56 - 3.62 (m,
2H), 3.99 (s, 3H), 4.21 (s, 3H), 7.09 - 7.15 (m, 2H), 7.40 - 7.46 (m, IH), 7.70 - 7.75
(m, IH), 7.90 - 7.94 (m, IH).
IR (KBr) (Cm -1): 3423, 2934, 2841, 2233, 1651, 1611, 1580, 1513, 1483, 1315,
1240, 1192, 1028, 925, 864.
Example 22
Figure imgf000069_0001
Step 1 : Preparation of 4-(l-methoxy-9-methyl-9H-carbazol-4-yl)-heptanedioic acid dimethyl ester
The title compound was prepared using intermediate 5, according to a similar procedure mentioned in step 1 of example 1. In this example triton B was used as the base instead of 1 , 1 ,3,3-tetramethyl guanidine under reflux.
1H NMR (300 MHz, CD3OD): δ 2.2 - 2.8 (m, 8H), 4.02 (s, 6H), 4.22 (s, 3H), 4.57 (s, 3H), 7.03 (d, J= 8.3 Hz, IH), 7.24 - 7.34 (m, 2H), 7.47 - 7.58 (m, 2H), 8.33 (d, J= 7.7 Hz, IH) Step 2: Preparation of 5-(l-methoxy-9-methyl-9H-carbazol-4-yl)-2- oxocyclohexane carboxylic acid methyl ester
To a stirred solution of compound of step 1 (190 mg, 0.45 mmole) in dimethoxy ethane (3 ml), was added 60% NaH in paraffin oil (20 mg, 0.5 mmole) and the mixture was stirred for 2 h at RT. The reaction was monitored by TLC. After disappearance of starting material the reaction mass was quenched with water (10 ml) and extracted with ethyl acetate (2 x 10 ml). The combined organic layer was dried over anhydrous Na2SO4, concentrated and dried to afford the desired product as a pale yellow solid (100 mg, yield 57%).
1H NMR (300 MHz, CDCl3): δ 2.64 - 2.90 (m, 4H), 3.20 - 3.5 5 (m, 2H), 3.78 (s, 3H), 4.01 (s, 3H), 4.23 (s, 3H), 6.90 (d, J= 8.4 Hz, IH), 7.16 - 7.19 (m, IH), 7.30 - 7.32 (m, IH), 7.49 - 7.53 (m, 2H), 8.30 (d, J= 8.2 Hz, IH), 12.33 (s, IH)
Step 3: Preparation of 2-Amino-6-(l-methoxy-9-methyl-9H-carbazol-4-yl)-4-oxo-
3,4,5,6,7,8-hexahydroquinazoline-6-carbonitrile
To a stirred solution of the product of step 2 (200 mg, 0.51 mmole) in ethanol (10 ml) was added guanidine.HCl (59 mg, 0.61 mmole) followed by sodium ethoxide (45 mg, 0.66 mmole) at RT. After refluxing for 8h (the starting material was absent by TLC) the reaction mass was concentrated at 4O0C under vacuum, diluted with water (10 ml) and extracted with ethyl acetate (3 x 5 ml). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to afford the desired product (110 mg, yield 53.9 %).
1H NMR (300 MHz, DMSO- d6): δ 2.37 - 3.55 (m, 6H), 3.99 (s, 3H), 4.20 (s, 3H), 6.43 (s, 2H), 7.07 - 7.16 (m, 2H), 7.27 (t, J= 7.6 Hz, IH), 7.52 (t, J= 7.6 Hz, IH), 7.68 (d, J= 8.2 Hz, IH), 8.23 (d, J= 8.3 Hz, IH), 10.88 (s, IH). IR (KBr) (cm ■'): 3430, 2933, 2228, 1637, 1509, 1475, 1385, 1324, 1272, 1111, 1029, 752.
Example 23
Figure imgf000071_0001
Preparation of 5-(l-methoxy-9-methyl-9H-carbazol-4-yl)-3-oxo-3,3a,4,5,6,7- hexahydro-2H-indazole-5-carbonitrile
A solution of compound of step 2 of example 22 (120 mg, 0.31 mmole) and hydrazine hydrate (23 mg, 0.46 mmole) in ethanol (10 ml) was refluxed for 2h. After completion of the reaction (indicated by TLC) the reaction mass was concentrated, diluted with water (10 ml) and extracted with ethyl acetate (3 x 5 ml). The combined organic layer was washed with water (3 x 10 ml), dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to afford the desired product (75 mg, yield 65.8 %) as a pale yellow solid. 1H NMR (300 MHz, DMSO- d6): δ 2.30 - 3.60 (m, 6H), 4.00 (s, 3H), 4.20 (s, 3H), 7.09 (d, J= 8.4 Hz, IH), 7.23 - 7.30 (m, 2H), 7.52 (t, J= 7.62 Hz, IH), 7.67 (d, J= 8.2 Hz, IH), 8.20 (d, J= 8.4 Hz, IH), 11.35 (s, IH)
IR (KBr) (cm "'): 3435, 2933, 2229, 1627, 1577, 1485, 1385, 1314, 1272, 1189,935.
Example 24
Figure imgf000071_0002
Step 1 : Preparation of (l-Methoxy-9-methyl-6-nitro-9//-carbazol-4-yl)-methanoI: To a suspension of l-methoxy-9-methyl-6-nitro-9H-carbazole-4-carboxylic acid (this compound is prepared as per the procedure mentioned in US20070105855) (13 g, 43.33 mmol) in dry tetrahydrofuran (TΗF) (1340 ml) was added borane dimethylsulfide complex (21.4 ml, 281.66 mmol) slowly at 0 C for one hour under a nitrogen atmosphere and then the mixture was stirred at room temperature for 18 hours. The reaction was monitored by TLC (50 % EtOAc/hexane). The reaction mass was concentrated under vacuum at 30 C and to the resulting solid was added cold potassium carbonate (K2CO3) solution (60 g in 200 ml water) at 0-5 0C in 1 hour. The precipitated solid was filtered after 30 minutes, washed with water and dried under vacuum at 5O0C for 8 hours to afford the titled compound (10.65 g, 87 %). mp: 211-213.6°C. IR (KBR) cπfl 3369, 2838, 1620, 1579, 1513, 1325, 1307, 1263, 1075. 1H NMR (300 MHz, OMSO-d6) δ 3.9 (s, 3 H), 4.2 (s, 3 H), 5.0 (d, 2 H, J = 6.0 Hz, D2O exchangable), 5.3 (t, 1 H, J = 6.0 Hz), 7.1 (d, I H1 J = 0.03 Hz), 7.2 (d, 1 H, J = 9.0 Hz), 7.7 (d, 1 H, J = 9.0 Hz), 8.3 (dd, 1 Hz, J = 3.0 Hz, 9.0 Hz), 9.0 (d, 1 H, J = 3.0 Hz).
Step 2: Preparation of 4-Chloromethyl-l-methoxy-9-methyl-6-nitro-9/-r- carbazole: To a suspension of (1 -methoxy-9-methyl-6-nitro-9H-carbazol-4-yl)-methanol (7.2 g, 26.2 mmol) in EtOAc (1050 ml) was added SOCl2 (39.0 ml, 524.4 mmol) slowly at room temperature for 30 minutes and then the mixture was stirred at the same temperature for 2 hours. The reaction was monitored by TLC (50 % EtOAc/hexane). After completion of the reaction EtOAc was removed under vacuum and the residue was treated with ethyl acetate (20 ml) which was completely removed again. A small amount of product was isolated by triturating it with hexane for characterization purposes and the remaining amount was directly taken for the next step. DSC: 1H NMR (300 MHz, DMSO-d6) δ 4.0 (s, 3 H), 4.2 (s, 3 H), 5.3 (s, 2 H), 7.1 (d, 1 H, J = 9.0 Hz), 7.3 (d, 1 H, J = 9.0 Hz), 7.8 (d, 1 H, J = 9.0 Hz), 8.3 (dd, 1 Hz, J = 3.0 Hz, 9.0 Hz), 9.0 (d, I H, J = 3.0 Hz).
Step 3: Preparation of (l-Methoxy-9-methyl-6-nitro-9JΪ-carbazol-4-yl)- acetonitrile:
To a solution of 4-chloromethyl-l-methoxy-9-methyl-6-nitro-9//-carbazole in DMF
(240 ml) was added sodium cyanide (NaCN) (2.4 g, 49.0 mmol) and the mixture was stirred at room temperature for 18 hours. The reaction mass was then diluted with water (2.0 liter) and the precipitated solid was filtered. The solid was washed with water and dried under vacuum at 55 0C for 8 hours to give the cyano compound (6.1 g, 84.7 %). mp: 266.5-267.5 0C. IR (KBR) cml 3436.12, 2256.74, 1504.56, 1335.25, 1314.86, 1268.94, 1075.46, 796.01. DSC: 285.48°C. 1H NMR (300 MHz, DMSOd6) δ 4.0 (s, 3 H), 4.2 (s, 3 H), 4.6 (s, 2 H), 7.1 (d, 1 H, J = 9.0 Hz), 7.2 (d, 1 H, J = 9.0 Hz), 7.8 (d, 1 H, J = 9.0 Hz), 8.3 (d, 1 Hz, J = 9.0 Hz, 9.0 Hz), 9.0 (s, 1 H). Step 4: Preparation of 4-Cyano-4-(l-methoxy-9-methyl-6-nitro-9//-carbazol-4- yl)-heptanedioic acid dimethyl ester: To a suspension of (l-methoxy-9-methyl-6-nitro-9H-carbazol-4-yl)-acetonitrile (4.0 g, 13.55 mmol) in DMSO (120 ml) was added methyl acrylate (23.3 ml, 271 mmol) followed by 1 ,8-diazabicycloundec-7-ene (DBU) (4.5 g, 29.83 mmol) at room temperature and the mixture was stirred for 4 hours at the same temperature. The reaction mass was cooled to 15 0C, diluted with water (400 ml) and extracted with ethyl acetate (8 x 200 ml). The combined ethyl acetate layer was collected, washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography using silica gel (100-200) and 10 % ethyl acetate/ hexane to afford the title compound (2.2 g, 35 %). mp: 166-168 0C. IR (KBR) cm"l 3453.59, 2953.70, 2930.91, 2228.51, 1745.21, 1573.51, 1509.27, 1327.24, 1313.55, 808.15. 1H NMR (SOO MHZ5 CDCI3) O 2.3-2.7 (m, 6 H), 2.8-3.1 (m, 2 H), 3.6 (s, 6 H), 4.0 (s, 3 H), 4.2 (s, 3 H), 7.0 (d, 1 H, J = 9.0 Hz), 7.36 (m, 1 H), 7.5 (d, 1 H, J = 9.0 Hz), 8.4 (dd, 1 Hz, J = 3.0 Hz, 9.0 Hz), 9.3 (br s, 1 H). Step 5: Preparation of 5-Cyano-5-(l-methoxy-9-methyl-6-nitro-9//-carbazol-4- yl)-2-oxo-cyclohexanecarboxylic acid methyl ester:
To a solution of 4-cyano-4-(l-methoxy-9-methyl-6-nitro-9H-carbazol-4-yl)- heptanedioic acid dimethyl ester (2.0 g, 4.2 mmol) in dry DMF (40 ml) was added sodium hydride (NaH) (287 mg, 5.99 mmol, 50 %) portion wise at 0 0C for 5 minutes and the mixture was stirred at the same temperature for 1 hour. To this mixture was added saturated ammonium chloride. The mixture was then diluted with water, extracted with 20% MeOH/CHCl3 (6 x 200 ml) and concentrated under vacuum. The residue was treated with water (200 ml) and the precipitated solid was filtered, washed with water and dried under vacuum to afford the title compound (1.4 g, 75.2 %). mp: 215-216.5 0C. IR (KBR) cm l 3436.04, 2954.18, 2924.16, 2228.63, 1664.32, 1619.61, 1572.51, 1514.36, 1313.66, 1220.6, 1077.19. 1H NMR (SOO MHZ5 CDCI3) O 2.41-2.53 (m, 2 H), 2.72-2.77 (m, 1 H), 2.88-3.0 (m, 3 H), 3.5 (d, 1 H, J = 18.0 Hz), 3.8 (s, 3 H), 4.0 (s, 3 H), 4.2 (s, 3 H), 7.0 (d, 1 H, J = 9 Hz), 7.5 (d, 1 H, J = 9 Hz), 8.4 (dd, 1 H, J = 3.0 Hz, & 9.0 Hz), 9.3 (d, 1 H, J = 3 Hz), 12.3 (s, 1 H). Step 6: Preparation of l-(l-Methoxy-9-methyl-6-nitro-9//-carbazol-4-yl)-4-oxo- cyclohexanecarbonitrile:
To a solution of 5-cyano-5-(l-methoxy-9-methyl-6-nitro-9H-carbazol-4-yl)-2-oxo- cyclohexanecarboxylic acid methyl ester (1.0 g, 2.29 mmol) in DMSO (35 ml) was added LiBr (257 mg, 2.98 mmol) at room temperature and the mixture was stirred at 130 0C for 5 hours. The reaction was monitored by TLC (50 % EtOAc/hexane). After cooling to RT the reaction mixture was diluted with water (280 ml) and extracted with 20% MeOΗ/CΗCl3 (6 x 100 ml). The organic layers were collected, combined and concentrated under vacuum. The concentrated mass containing dimethyl sulphoxide (DMSO) was diluted with 100ml of water and the precipitated solid was filtered, washed with water and dried under vacuum at 50 0C which was purified by column chromatography to afford the title compound (600 mg, 69.28 %). mp: 227- 229 0C. IR (KBR) cm"l 3430.69, 2960.55, 2921.48, 2227.56, 1725.73, 1618.16, 1569.43, 1516.11, 1310.38, 1270.94, 1072.27. 1H NMR (300 MHz, CDCl3) δ 2.25- 2.34 (m, 2 H), 2.70-2.76 (m, 2 H), 3.09-3.25 (m, 4 H), 4.0 (s, 3H), 4.29 (s, 3 H), 7.0 (d, 1 H, J = 9 Hz), 7.2 (d, 1 H, J = 9 Hz), 7.5 (d, 1 H, J = 9 Hz), 8.4 (dd, 1 H, J = 3.0 Hz, & 9.0 Hz), 9.45 (d, 1 H, J = 3 Hz). Example 25
Figure imgf000075_0001
Preparation of 6-(l-Methoxy-9-methyl-6-nitro-9//-carbazol-4-yl)-5,6,7,8- tetrahydro-quinazoline-6-carbonitrile: To a solution of compound of example 24 (100 mg, 0.265 mmol) in DMF (5 ml) was added DMF.DMA (70.6 μl, 0.53 mmol) at room temperature and the mixture was stirred at 110 0C for 2 hours. The reaction was monitored by TLC (5 % MeOH/CHCl3). The mixture was diluted with cold water (30 ml) and then extracted with ethyl acetate (5 x 20 ml). The combined organic layers were washed with water (3 x 20 ml), dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude enamine intermediate which was treated with formamidine acetate (273 mg, 2.65 mmol) in N, TV-dimethyl acetamide (2 ml) under MW for 10 minutes. After completion of the reaction, [monitored by TLC (5 % MeOH/CHCl3)], the reaction mass was diluted with cold water and extracted with ethyl acetate (4 x 20 ml). The combined organic layer was washed with water, brine, then dried over anhydrous Na2SO4 and concentrated under vacuum. The crude solid was purified by column chromatography (100-200 silica gel) using CHCl3 to afford the title compound (80 mg, 72 %). 1H NMR (300 MHz, CDCl3) δ 2.63-2.68 (m, 1 H), 3.01-3.08 (m, 2 H), 3.46 (m, 1 H), 3.6 (d, 1 H, J = 15 Hz), 3.8 ((d, 1 H, J = 15 Hz), 4.0 (s, 3 H), 4.3 (s, 3 H), 6.9 (d, 1 H, J = 9.0 Hz), 7.1 (d, 1 H, J = 9.0 Hz), 7.5 (d, 1 H, J = 9.0 Hz), 8.4 (d, 1 H, J = 9.0 Hz), 8.6 (s, 1 H), 9.1 (s, 1 H), 9.4 (s, 1 H). Example 26
Figure imgf000076_0001
Preparation of N- [5-(6-Cy ano-5,6,7,8-tetrahydro-quinazolin-6-y l)-8-methoxy-9- methyl-9H-carbazol-3-yl]-methanesulfonamide: To a suspension of compound of example 25 (150 mg, 0.353 mmol) in EtOΗ/water (15 ml, 2:1) was added iron powder (150 mg, 2.68 mmol) and ammonium chloride (NH4Cl) (150 mg, 2.80 mmol) and the mixture was refluxed for 3 hours. After completion of the reaction, [monitored by TLC (5 % MeOH/CHCl3)], the mixture was cooled to room temperature and filtered. The residue was washed with chloroform. The filtrate was collected, diluted with water and extracted with chloroform. The combined organic layer was washed with brine and dried over anhydrous Na2SO4. After concentrating under vacuum, the crude amine was dissolved in methylene dichloride - tetrahydrofuran (MDC-THF) (8 ml, 1 :1) and cooled to 0 0C. To this was added mesyl chloride (MsCl) (76.4 μl, 0.939 mmol) in tetrahydrofuran (THF) (1 ml) and pyridine (247.5 μl, 3.13 mmol) and the mixture was stirred at the same temperature for one hour. The reaction mass was diluted with water (20 ml) and extracted with chloroform (3 x 30 ml). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate (Na2SO4) and concentrated under vacuum to give the crude product which was purified by column chromatography (100-200 silica gel) using 0.2 % MeOH/CHCl3 to afford the title compound as a yellow solid (40 mg, 28 %). IR (KBr) cm"1 3430.82, 3247.82, 2933.50, 2226.50, 1660.00, 1577.06, 1485.54, 1463.24, 1401.48, 1325.63, 1278.85, 1152.54, 973.02. HPLC Purity: 98.42 %. 1H NMR (300 MHz, CDCl3) δ 2.57-2.63 (m, 1 H), 2.9 (d, 1 H, J = 21 Hz), 3.0 (s, 3 H), 3.08-3.10 (m, 1 H), 3.43- 3.53 (m, 2 H), 3.9 (d, 1 H, J = 18 Hz), 4.0 (s, 3 H), 4.2 (s, 3 H), 6.5 (s, 1 H), 6.9 (d, 1 H, J = 9.0 Hz), 7.0 (d, 1 H, J = 9.0 Hz), 7.4 (dd, 1 H, J = 3.0 Hz, 9.0 Hz), 7.5 (d, 1 H, J = 9.0 Hz), 8.3 (s, 1 H), 8.6 (br s, 1 H), 9.0 (br s, 1 H).
Example 27
Figure imgf000077_0001
Preparation ofiV-[5-(l-Cyano-4-oxo-cyclohexyl)-8-methoxy-9-methyl-9/-r- carbazol-3-yl]-methanesulfonamide:
To a suspension of l-(l-methoxy-9-methyl-6-nitro-9H-carbazol-4-yl)-4-oxo- cyclohexanecarbonitrile (100 mg, 0.265 mmol) in EtOH-THF-H2O (20 ml, 2:1 :0.5) was added iron powder (100 mg, 1.79 mmol) and NH4Cl (100 mg, 1.869 mmol) and the mixture was refluxed for 3 hours. After completion of the reaction, [monitored by TLC (5 % MeOH/CHCl3)], the reaction mass was cooled to room temperature and then filtered through celite bed. The bed was washed with chloroform. The filtrate was collected, diluted with water and extracted with chloroform. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude amine was dissolved in tetrahydrofuran (THF) (5 ml) and cooled to 0 0C. To this was added mesyl chloride (MsCl) (76.4 μl, 0.939 mmol) dissolved in tetrahydrofuran (THF) (1 ml) and pyridine (247.5 μl, 3.13 mmol) and the mixture was stirred at the same temperature for 2 hours. The reaction mass was diluted with water (20 ml) and extracted with ethyl acetate (3 x 40 ml). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude product which was purified by column chromatography (100-200 silica gel) using 0.1 % MeOH/CHCl3. The recovered product was crystallized with methanol (3 ml) to afford the title compound as a yellow solid (32 mg, 20 %). IR (KBR) cml 3430. 5, 2227.79, 1707.19, 1635.3, 1574.97, 1487.82, 1154.96. 1H NMR (300 MHz, CDCl3) δ 2.2 (m, 2 H), 2.7 (m, 2 H), 3.08 (s, 3 H), 3.0-3.15 (m, 4 H), 4.0 (s, 3 H), 4.2 (s, 3 H), 6.6 (s, 1 H), 6.9 (d, 1 H, J = 9.0 Hz), 7.0 (d, I H1 J = 9.0 Hz), 7.3 (d, 1 H, J = 9.0 Hz), 7.4 (d, 1 H, J = 9.0 Hz), 8.4 (s, 1 H).
Example 28
Figure imgf000078_0001
Preparation of 2-Amino-6-(l-methoxy-9-methyl-6-nitro-9//-carbazol-4-yl)- 5,6,7,8-tetrahydro-quinazoline-6-carbonitrile:
To the solution of l-(l-methoxy-9-methyl-6-nitro-9H-carbazol-4-yl)-4-oxo- cyclohexanecarbonitrile (250 mg, 0.663 mmol) in DMF (10 ml) was added
DMF.DMA (176.5 μl, 1.326 mmol) at room temperature and the mixture was stirred at 110 0C for 2 hours. The reaction was monitored by TLC (5 % MeOΗ/CΗCl3). The reaction mass was diluted with cold water (30 ml) and extracted with ethyl acetate (3 x 40 ml). The combined organic layers were washed with water (3 x 20 ml), dried over anhydrous Na2SO4 and concentrated under vacuum to afford the crude enamine (270 mg) intermediate which was directly treated with guanidine hydrochloride (83 mg, 0.862 mmol) and sodium ethoxide (63 mg, 0.92 mmol) in ethanol (10 ml) at 75- 80 0C for 1 hour. After completion of the reaction, [monitored by TLC (5 % MeOH/CHCl3)], the reaction mass was concentrated under vacuum and purified by column chromatography (100-200 silica gel) using CHCl3 to give the title compound (92 mg, 32 %). mp: >314 0C. HPLC purity: 98.67 %.
IR (KBR) cml 3468.04, 3312.02, 3187.42, 2935.89, 2227.41, 1629.23, 1572.96, 1509.21, 1480.40, 1312.09, 1275.08, 1076.14. 1H NMR (300 MHz, DMSO-d6) δ 2.28-3.0 (m, 4 H), 3.3 (d, 1 H, J = 15 Hz), 3.6 (d, 1 H, J = 15 Hz), 4.08 (s, 3 H), 4.29 (s, 3 H), 6.5 (s, 1 H), 7.2 (d, 1 H, J = 9.0 Hz), 7.3 (d, I H1 J = 9.0 Hz)J.9 (d, 1 H, J = 9.0 Hz), 8.2 (s, 1 H), 8.4 (d, 1 H, J = 3.0 Hz), 9.2 (d, 1 H, J = 3.0 Hz). Example 29
Preparation of N-[9-(6-Cyano-5, 6,7, 8-tetrahydro-quinazolin-6-yl)-6-difluoro- methoxy-dibenzofuran-2-yl]-methane sulfonamide
Figure imgf000079_0001
Step 1: Preparation of l-(-4-difluoromethoxy-8-nitro-dibenzofuran-l-yl)-4-oxo- cyclohexane carbonitrile
A solution of intermediate 7 (0.350gm, 0.0004mole) and anhydrous potassium carbonate (0.188gm, 0.0013mole) in dry dimethylformamide (5ml) was stirred at room temperature for 10 minutes. Chlorodifluoromethane gas was purged into the reaction mixture for 45 minutes and then the reaction mixture was allowed to stir for 18 hours. After completion of the reaction, the reaction mass was diluted with water (30ml) and extracted with ethyl acetate (3 X 30ml). The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under vacuum to obtain the title compound (0.158gm, yield-87%) as a yellow solid.
1H NMR (300 MHz, CDCl3) δ 2.31-2.40 (m, 2H), 2.73-2.88 (m, 2H), 2.95-2.98 (m, 2H), 3.03-3.22 (m, 2H), 6.83 (t, J= 72 Hz, IH), 7.37 (d, J= 8.6 Hz, IH), 7.48 (d, J= 8.2 Hz, IH), 7.83 (d, J= 9.1Hz, IH), 8.54 (d, J= 9.2 Hz, IH), 9.28 (s, IH) Step 2: Preparation of l-(-4-difluoromethoxy-8-nitro-dibenzofuran-l-yl)-3- dimethyl-aminomethylene^-oxo-cyclohexane carbonitrile
To a solution of step 1 (0.150g, 0.0003mole) in benzene (25ml) and 2 drops of triethylamine was added N5N- dimethylformamide dimethylacetal (0.08ml, 0.0005mole) at room temperature under nitrogen. Reaction mixture was heated to reflux. Methanol was removed azeotropically using benzene as a solvent utilizing the Dean and Stark apparatus and fresh benzene (40ml) was added and the same operation was repeated until the starting material was absent by TLC. After completion of the reaction, the reaction mass was evaporated under vacuum to obtain the title compound in crude product as a brown residue (0.0150gm), taken as such for the next step without purification.
Step 3: Preparation of 6-(-4-difluoromethoxy-8-nitro-dibenzofuran-l-yl)-5, 6,7, 8- tetrahydro-quinazolin-6-yl)-6-carbonitrile
A solution of crude compound from step 2 (0.150gm, 0.0003) and dry dimethylformamide (5ml) was added Formamidine HCl ( 0.029gm, 0.00036mole) at room temperature and then the reaction mixture was heated to 14O0C and maintained at 14O0C for 2 hours. After completion of the reaction, the reaction mass was diluted with water (20ml) and extracted with ethyl acetate (3 X 30ml). The combined organic layer was washed with water, dried over sodium sulfate, filtered and concentrated under vacuum to obtain the title compound (0.038gm, yield-26.5%) as a yellow solid. 1H NMR (300 MHz, DMSO-J6) δ 2.68-3.20 (m, 4H), 3.71 (d, J= 16 Hz, IH), 3.90 (d, J= 16 Hz, IH), 7.55 (t, J= 73 Hz, IH), 7.57 (d, J= 8.3 Hz5IH), 7.66 (d, J= 8.3 Hz, IH), 8.20 (d, J= 9.1Hz, IH), 8.60 (dd, J= 9.2Hz, 1.9Hz, IH), 8.78 (s, IH), 9.07 (s, IH), 9.14 (d, J= 1.8 Hz, IH),
Step 4: Preparation of 6-(8-Amino-4-difluoromethoxy-dibenzofuran-l-yl)-5, 6,7, S-tetrahydro-quinazoIin-β-yty-ό-carbonitrile A solution of compound of step 3 (0.017gm, 0.038mmoles) in ethyl acetate (3ml) was added a catalytic quantity of Raney Nickel and then hydrogenated under hydrogen with balloon pressure over a period of 12 hours. After completion of the reaction, the reaction mixture was filtered through celite bed and concentrated under vacuum to obtain the title compound (0.014gm, yield- 88 %). 1H NMR (300 MHz, CDCl3) δ 2.63-3.16 (m, 4H), 3.47 (d, J= 16 Hz, IH), 3.84 (d, J = 16 Hz, IH), 6.83 (t, J= 73 Hz, IH), 6.84-7.08 (m, 3H), 7.40-7.50 (m, 2H), 8.61 (s, IH), 9.11 (s, IH)
Step 5: Preparation of N-[9-(6-Cyano-5, 6,7, 8-tetrahydro-quinazolin-6-yl)-6- difluoro-methoxy-dibenzofuran-2-yl]-methane sulfonamide A solution of compound of step 4 (0.014gm, 0.034mmole) in dry tetrahydrofuran (2ml) was added pyridine (0.02ml, 0.24mmole) at 1O0C. The reaction mixture was stirred for 10 minutes and was added methanesulfonyl chloride (0.01ml, 0.12mmole). The reaction mixture was allowed to stir for 2 hours at room temperature. After completion of the reaction, the reaction mass was diluted with water (10ml) and extracted with ethyl acetate (3 X 30ml). The combined organic layer was washed with water dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography using chloroform to obtain the title compound (0.012gm, yield-71.8 %) as a yellow solid. 1H NMR (300 MHz, DMS(W6) δ 2.91 (s, 3H), 3.00-3.35 (m, 4H), 3.70 (d, J= 16 Hz, IH), 3.84 (d, J= 16 Hz5 IH), 7.45 (t, J= 73 Hz, IH), 7.47-7.57 (m, 3H), 7.91 (d, J= 8.9 Hz, IH), 8.24 (s, IH), 8.72 (s, IH), 9.06 (s, IH), 10.06 (s, IH).
Example 30 Preparation of N- [9-(6-Cy ano-5,6,7,8-tetrahydro-quinazolin-6-y l)-6-methoxy- dibenzofuran-2-yl]-methane sulfonamide
Figure imgf000081_0001
Step 1: Preparation of l-(-4-methoxy-8-nitro-dibenzofuran-l-yI)-4-oxo- cyclohexane carbonitrile A solution of intermediate 7 (0.840gm, 0.0024mole) and anhydrous potassium carbonate (0.992gm, 0.0071 mole) in dry dimethylformamide (15ml) was stirred at room temperature for 15 minutes. To that, methyl iodide (0.23ml, 0.003mole) was added drop wise over a period of 10 minutes at room temperature, and then the reaction mixture was allowed to stir for 2 hours at room temperature. After completion of the reaction, the reaction mass was diluted with water (50ml) and extracted with ethyl acetate (3 X 75ml). The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under vacuum to obtain the title compound (0.700gm, yield-80%) as a yellow solid. 1H NMR (300 MHz, DMSO-^6) δ 2.44-2.58 (m, 4H), 2.83-2.88 (m, 4H), 4.05 (s, 3H), 7.38 (d, J= 8.6 Hz, IH), 7.49 (d, J= 8.6 Hz, IH), 8.10 (d, J= 9.1Hz, IH), 8.52 (dd, J= 9.1Hz, 2.1Hz, IH), 9.15 (d, J= 1.9 Hz, IH)
Step 2: Preparation of l-(-4-methoxy-8-nitro-dibenzofuran-l-yl)-3- dimethylaminomethylene-4-oxo-cyclohexane carbonitrile A solution of compound of step 1 (0.20Og, 0.0005mole) in benzene (50ml) and 2 drops of triethylamine was added N5N- dimethylformamide dimethylacetal (0.1ml, O.OOOδmole) at room temperature under nitrogen. The reaction mixture was heated to reflux. Methanol was removed azeotropically using benzene as a solvent utilizing the Dean and Stark apparatus and fresh benzene (40ml) was added and the same operation was repeated until the starting material was absent by TLC. After completion of the reaction, the reaction mass was evaporated under vacuum to get the desired crude product as a brown residue (0.120gm), taken as such for the next step without purification.
Step 3: Preparation of 6-(-4-methoxy-8-nitro-dibenzofuran-l-yI)-5, 6,7, 8- tetrahydro-quinazolin-6-yl)-6-carbonitrile To a solution of crude product obtained in step 2 (0.115gm, 0.0002 mole) in dry dimethylformamide (5ml) was added Formamidine.HCl (0.02 lgm, 0.00025mole) at room temperature and then the reaction mixture was heated to 14O0C and maintained at 14O0C for 2 hours. After completion of the reaction, the reaction mass was diluted with water (20ml) and extracted with ethyl acetate (3 X 30ml). The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under vacuum to obtain the title compound (0.033gm, yield-35.2%) as a yellow solid.
1H NMR (300 MHz, DMSO-J6) δ 2.93-3.18 (m, 2H), 3.21-3.48 (m, 2H), 3.67 (d, J = 16.6 Hz, IH), 3.88 (d, J= 16.6 Hz, IH), 4.05 (s, 3H), 7.38 (d, J= 8.6 Hz, IH), 7.46 (d, J= 8.6 Hz, IH), 8.12 (d, J= 9.1Hz, IH), 8.54 (dd, J= 9.1Hz, 2.1Hz, IH), 8.78 (s,
IH), 9.06 (s, IH), 9.1 (d, J= 1.9 Hz, IH),
Step 4: Preparation of 6-(8-Amino-4-methoxy-dibenzofuran-l-yl)-5, 6,7, 8- tetrahydro-quinazolin-6-yl)-6-carbonitrile To a solution of compound of step 3 (0.050gm, 0.012mmole) in ethyl acetate (10ml) and methanol (ImI) was added a catalytic quantity of Raney Nickel and then hydrogenated under hydrogen gas with balloon pressure over a period of 12 hours. After completion of thr reaction, the reaction mixture was filtered through celite bed and the filtrate was concentrated under vacuum to obtain the title compound (0.043gm, yield- 93 %).
1H NMR (300 MHz, DMSO-J6) δ 2.94-3.06 (m, 4H), 3.63 (d, J= 16.2 Hz, IH), 3.80 (d, J= 16.2 Hz, IH), 3.98 (s, 3H), 5.23 (s, 2H), 6.86 (d, J= 8.5 Hz, IH), 7.15 (d, J= 9 Hz, IH), 7.29 (d, J= 8.6Hz, IH), 7.38 (s, IH), 7.47 (d, J= 8.5Hz, IH), 8.74 (s, IH), 9.04 (s, IH), Step 5: Preparation of N-[9-(6-Cyano-5, 6,7, 8-tetrahydro-quinazolin-6-yl)-6- methoxy-dibenzofuran-2-yl]-methane sulfonamide
To a solution of compound of step 4 (0.040gm, O.OlOmmole) in dry tetrahydrofuran (3ml) was added pyridine (0.1ml, O.lOmmole) at 1O0C. The reaction mixture was stirred for 10 minutes and was added methane sulfonyl chloride (0.01ml, 0.13mmole). The reaction mixture was allowed to stir for 2 hours at room temperature. After completion of the reaction, the reaction mass was diluted with water (10ml) and extracted with ethyl acetate (3 X 30ml). The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by column chromatography using chloroform as an eluent to obtain the title compound (0.018gm, yield-37.1 %) as a yellow solid.
1H NMR (300 MHz, CDCl3) δ 2.52-2.63 (m, IH), 2.95-3.07 (m, IH), 3.10 (s, 3H), 3.07-3.16 (m, IH), 3.49-3.56 (m, 2H), 3.85 (d, J= 16.4 Hz, IH), 4.09 (s, 3H), 6.82 (s, IH), 7.01 (d, J= 8.6Hz, IH), 7.22-7.33 (m, 2H), 7.70 (d, J= 8.8Hz, IH), 8.28 (s, IH), 8.64 (s, IH), 9.10 (s, IH)
Example 31
Figure imgf000084_0001
Preparation of 1 -(4-Methoxy-8-trifluoromethyl-dibenzofuran-l-yl)-4-oxo- cyclohexane-caronitrile
To a solution of intermediate 8 (3.4 gm, 0.0076 moles) in dimethyl sulphoxide (DMSO)(IO ml), was added water(l ml), sodium chloride (2.9 gm, 0.049 moles) and then the reaction mass was heated to 14O0C, and maintained at 14O0C for 5 hrs. After completion of the reaction, the reaction mixture was brought to room temperature and quenched with cold water (50 ml). The mixture was then extracted with ethyl acetate (3 X 75 ml). The organic layers were collected, combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography using 5-10% ethyl acetate-hexane to obtain the title compound (1.9 gm, yield 65 %) as a yellow solid.
1H NMR (300 MHz, CDCl3) δ 2.27-2.38 (m, 2H), 2.68-2.74 (m, 2H), 2.95-3.15 (m, 4H), 4.10 (s, 3H), 7.06 (d, J= 8.6 Hz, IH), 7.30 (d, J= 8.6 Hz, IH), 7.81-7.82 (m, 2H), 8.58 (s IH) MS (M++l): 388 Example 32
Figure imgf000085_0001
Preparation of 5-(4-Methoxy-8-trifluoromethyl-dibenzofuran-l-yl)-3-oxo-3, 3a,4,5,6,7-hexahydro-2H-indazole-5-carbonitrile A mixture of intermediate 8 (0.050 gm, 0.0001 mole), hydrazine hydrate (0.01 ml,
0.0002 mole) and triethylamine (0.04 ml, 0.0003 mole) in methanol (5 ml) was stirred at reflux for 2 hrs. After completion of reaction, methanol was evaporated under vacuum and the residue was partitioned between ethyl acetate (20ml) and water (20ml). The ethyl acetate layer was washed with water followed by brine, and the organic layer was evaporated under vacuum to obtain the title compound (0.042 gm, yield-87.8 %) as a pale yellow solid.
Η-NMR (300MHZ, DMSO-J6) δ 2.50-2.54 (m, IH), 2.67-2.89 (m, 4H), 3.05 (d, J = 15.4 Hz, IH), 4.04 (s, 3H), 7.34 (d, J= 8.6 Hz, IH), 7.47 (d, J= 8.6 Hz, IH), 7.99 (d, J= 8.6, IH), 8.09 (d, J= 8.6 Hz, IH), 8.48 (s, IH), 9.64 (s, IH), 11.32 (s, IH) MS (M++1): 428
Example 33
Figure imgf000085_0002
Preparation of 6-(4-Methoxy-8-trifluoromethyl-dibenzofuran-l-yl)-5,6,7,8- tetrahydro-quinazoline-6-carbonitrile
A solution of crude intermediate 9 (0.420 gm, 0.0009) and dry DMF (5ml) was added Formamidine HCl ( 0.082gm, 0.001 moles) at RT and then the reaction mixture was heated to 14O0C and maintained at 14O0C for 2 hrs. After completion of the reaction, the reaction mass was diluted with water (20ml) and extracted with ethyl acetate (3 X 30ml). The combined organic layer was washed with water, dried over sodium sulfate, filtered and concentrated under vacuum to get the desired product (0.040 gm, yield-26.5%) as a yellow solid.
'H-NMR (300MHz, CDCl3) δ 2.57-2.66 (m, IH), 2.90-2.96 (m, IH), 3.01-3.11 (m, IH), 3.37-3.49 (m, IH), 3.54 (d, J= 16.6 Hz, IH), 3.81 (d, J= 16.6 Hz, IH), 4.10 (s, 3H), 7.03 (d, J= 8.4 Hz, IH), 7.26 (d, J= 8.4 Hz, IH), 7.82 (m, 2H), 8.56-8.62 (m, 2H), 9.11 (s, IH)
Example 34
Figure imgf000086_0001
Preparation of 2-Amino-6-(4-Methoxy-8-trifluoromethyl-dibenzofuran-l-yl)-5,6,7,8- tetrahydro-quinazoline-6-carbonitrile
To a mixture of intermediate 9 (70 mg, 0.00015 moles), Guanidine HCl (20 mg, 0.0002 moles) and Sodium ethoxide (15 mg, 0.0002 moles) in 5 ml ethanol, was heated at reflux for 2 hr. After completion of the reaction, the mixture was cooled to room temperature and then evaporated the solvent under vacuum. The crude residue was purified by column chromatography to get 13 (30 mg, yield-81%) as an off- white solid product. 'H-NMR (300MHz, DMSO-fl?6) δ 2.50-2.60 (m, IH), 2.75-2.85 (m, 2H), 2.90-3.10 (m, IH), 3.30-3.40 (m, IH), 3.55-3.70 (m, IH), 4.04 (s, 3H), 6.53 (s, 2H), 7.34 (d, J = 8.6 Hz, IH), 7.42 (d, J= 8.6 Hz, IH), 8.02 (d, J= 8.6Hz, IH), 8.10 (d, J= 8.6 Hz, IH), 8.17 (s, IH), 8.50 (s, IH) Example 35
Figure imgf000087_0001
Preparation of 6-(4-Methoxy-8-trifluoromethyl-dibenzofuran-l-yl)-2-methyl-5, 6, 7, S-tetrahydro-quinazoline-β-carbonitrile To a mixture of intermediate 9 (70 mg, 0.00015 moles), Acetamidine HCl (37.4 mg, 0.0003 moles) and Sodium methoxide (30 mg, 0.0005 moles) in 3 ml methanol, was stirred at RT for 3 hrs. After completion of the reaction, the reaction mixture was evaporated under vacuum. The crude residue was purified by column chromatography to obtain the title compound (28 mg, yield-40.5%) as an off-white solid product.
'H-NMR (300MHz, DMSO-^6) δ 2.65 (s, 3H), 2.79-3.20 (m, 4H), 3.60 (d, J= 16.4 Hz, IH), 3.79 (d, J= 16.8 Hz, IH), 4.04 (s, 3H), 7.34 (d, J= 8.6 Hz, IH), 7.41 (d, J= 8.6 Hz, IH), 8.06 (d, J= 8.7 Hz, IH), 8.11 (d, J= 8.7 Hz, IH), 8.51 (s, IH), 8.64 (s, IH) In Vitro Assay
Cell based cAMP reporter assay for screening PDE4 subtype specific inhibitors: HEK 293 cells were routinely maintained in T-25 cm2 flasks. One day prior to transfection, cells were seeded in a 6 well cell culture plate (Corning) at a seeding density of 1.3 - 1.4 x 106 cells/well. Cells were transfected for 5 h using lipofectamine-2000, as per manufacturer instructions with total 4.0 μg of plasmid DNA/well. PDE4 expression plasmid in each well was 10%-50% of total plasmid DNA for respective subtype selective expression plasmids. Each well was transfected with PDE4 expression plasmid (10-50%), pCREluc plasmid (20-50%), pSV-D gal plasmid (20-30%) and empty vector to make up total DNA concentration. After 5 h of transfection, medium was removed and cells were trypsinized, counted and seeded in 96 well plates at a seeding density of 40000 cells/well in complete medium (DMEM with 10% FBS, Ix penicillin-streptomycin). Plate was incubated in CO2 incubator set to 370C and 5% CO2 for overnight. Next day, cells were incubated with respective inhibitors for 30-45 minute, followed by stimulation with 5μM forskolin for 4 h incubation in incubator. After 4 h, plate was taken out of incubator and medium was removed manually using pipette. Cells were lysed (120μl/well) with Ix reporter lysis buffer (Promega, Inc. USA), for 15 min with moderate shaking on shaker at RT, followed by centrifugation at 4000 rpm for 8 -10 min at 220C. Supernatant was transferred (40μl, each) to White/Black luminescence plate and normal flat bottom plate, for Luciferase/Luminescence detection assay and D -gal assay respectively. Luminescence readings were taken in a Perkin Elmer Victor Light.
The percentage inhibition of PDE 4B with respect to rolipram is depicted in the table below:
Figure imgf000088_0001
Tumor necrosis factor-α (TNF-α) in a human whole blood
Fresh blood was collected in Heparinzed tubes by venipuncture from male volunteers with consent. The subjects had no apparent inflammatory conditions and had not taken any NSAID for at least 4 days prior to blood collection. 487.5 μl of blood in triplicate were pre-incubated with 2.5μl of test compound at different concentrations (0, 0.001, 0.003, 0.01, 0.03 0.1, 0.3, 1, 3, lOμM) and vehicle (DMSO) at 370C for 15 min, and this was followed by incubation blood with lOμl lipopolysaccharide (final concentration lμg/ml) diluted in 0.1% bovine serum albumin diluted in phosphate buffer saline) for 24 hrs at 370C. PBS was used as a blank. After the incubation period, the samples were centrifuged at 1500xg at 4 0C for 10 min. Plasma TNF-alpha was quantified ELISA (R&D System).
Examples 29 and 33 inhibited 50% of LPS induce TNF-alpha production in Whole blood with a concentration of 0.41 ± 0.02 and 0.092 ± 0.01 μM (N=3) respectively.

Claims

1. A compound of formula (I)
Figure imgf000090_0001
Formula (I) Wherein
R1 is selected from
Figure imgf000090_0002
X represents O, S or NR4;
Y represents O, S, NR4 or can be absent;
XI and X2 independently represent hydrogen, hydroxy, amino, nitro, cyano and optionally substituted groups selected from alkyl, alkoxy, C2-C6-alkenyl, C2-C6- alkynyl, alkyl hydroxy, alkyl halo, alkyl amino, alkenyl amino, alkenyl amino alkyl, guanidyl, ureidyl, CR5R6R7, CR5R6OR7, CR5R6C(O)R7, CR5R6C(O)C(O)OR7, CR5R6C(O)OR7, (CR5R6)nC(O)R7, CR5R6C(O)NR7R8, CR5R6S(O)1nR7, CR5R6N R7R8, CR5R6CN, CR5R6R7, CR5R6NR7S(O)1nR5, CR5R6NR7C(X)R5, CR5R6NR7S(O)1nNR7R8, CR5R6NR7C(O)NR7R8, CR5R6NR7C(O)C(O)OR7, CR5R6NR7C(S)NR7R8, CR5R6NR7C(NCN)NR7R8, NR5R6, NR5S(O)01R6,
NR5S(O)01NR5, NR5C(O)R6, NR5C(O)OR6, NR5C(O)NR7R8, NR5C(S)NR7R8, NR5C(O)NR6S(O)mR7, C(NR5)R6, C(NNR5C(X)NR7R8)R5, C(NNR5S(O)mR6)R5, C(NR5)NR7R8, C(NCN)SR5, C(NOR5)R6, C(O)OR5, C(O)NR5R6, C(O)NR7R8, C(O)NR5NR7R8, C(O)R5, OR5, OC(O)R5, OC(O)NR7R8, OS(O)01R5, SO2, SO3H, S(O)mR5, S(R5), S(O)1nNR7R8; or when X1 and X2 are adjacent to each other, they may together form a 4 to 7- membered cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl; nonlimiting examples of such cyclic group include but are not limited to pyrazole, imidazole, imidazolidine, triazole, tetrazole, pyrrolidine, pyrrole, thiophene, thiazole, oxazole, isoxazole, furan, tetrahydrothiophene, tetrahydrofuran, thiazolidine, oxazolidine, piperazine, morpholine, thiomorpholine, piperidine, pyridine, pyrazine, pyrimidine, pyridazine; X3 represents hydrogen, cyano, C1-4-alkyl, C2^»-alkenyl, C2-4-alkynyl, alkylhalo, nitro, alkylnitro, alkyl carboxy, alkylcarbonyl or tetrazole CH2NR5R6,CH2OR5,C3- C4-cycloalkyl, OR5, R5OR6, NR5R6, C(O)OR5, C(O)NR7R8, C(O)R5 , CH2NHC(O)C(O) NH2, CHNR5, CHN=OR5, NHCN, CH(CN)2, CH(CN)R5 ; X4 represents O, NR5, N-OR5, NCR5R6R7, NOR7, NOR5R6, NNR7R8, NCN, NNR5C(X)NR7R8 or X4 may be dimethyl ketal, diethyl ketal, 1,3-dithiane, 1,3- dithiolane, 1,3-dioxane, 5,5-dimethyl-[l,3]dioxane or 1,3-dioxolane; or X1 and X4 can form a 5 to 7-membered cyclic group selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl; nonlimiting examples of such cyclic groups include but are not limited to pyrazole, imidazole, imidazolidine, triazole, tetrazole, pyrrolidine, pyrrole, thiophene, thiazole, oxazole, isoxazole, furan, tetrahydro thiophene, tetrahydrofuran, thiazolidine, oxazolidine, piperazine, morpholine, thiomorpholine, piperidine, pyridine, pyrazine, pyrimidine, pyridazine; R2 and R3 are independently selected from hydrogen, hydroxyl, substituted or unsubstituted alkyl, alkoxy, alkenyl, alkynyl, alkylamino ,alkyl hydroxy, alkyl halo, nitro, amino, cyano, formyl, carboxy, carbamoyl, acyl, halogen, ureidyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, acylamino, alkanoylamino, CR5R6R7, CR5R6OR7, CR5R6C(O)R7, CR5R6C(O)C(O)OR7, CR5R6C(O)OR7, (CR5R6)nC(O)R7, CR5R6C(O)NR7R8, CR5R6S(O)1nR7, CR5R6NR7R8, CR5R6CN, CR5R6R7, CR5R6NR7S(O)111R5, CR5R6NR7C(X)R5, CR5R6NR7S(O)1nNR7R8, CR5R6NR7C(O)NR7R8, CR5R6NR7C(O)C(O)OR7, CR5R6NRVC(S)NR7R8, CR5R6NR7C(NCN)NR7R8, NR5R6, NR5, NR5S(O)1nR6, NR5S(O)1nNR5, NR5C(O)R6, NR5C(O)OR6, NR5C(O)NR7R8, NR5C(S)NR7R8,
NR5C(O)NR6S(O)1nR7, C(NR5)R6, C(NNR5C(X)N R7R8)R5, C(NN R5S(O)mR6)R5, C(NR5)N R7R8, C(NCN)SR5, C(NOR5)R6, C(O)OR5, C(O)NR5R6, C(O)NR7R8, C(O)NR5NR7R8, C(O)R5, OR5, OC(O)R5, OC(O)NR7R8, OS(O)1nR5, SO2, SO3H, S(O)1nR5, S(R5), S(O)01NR7R8; R4 represents hydrogen, hydroxy., alkyl, SO2CH3, SO2PhCH3 or a protecting group; R5, R6, R7, R8 may be independently selected from hydrogen, CrC6-straight or branched alkyl, dialkyl, C2-C6 straight or branched alkenyl, alkylamino, alkyl halo, alkyl hydroxy, acyl, alkoxy, carboxy, sulfonyl, sulfinyl, thio, sulfamido, amido, NH(CO)R7, nitro, amino, halogens, hydroxy, ureidyl, guanidyl; or R7 and R8 when attached to Nitrogen as NR7R8 may together with the nitrogen atom to which they are attached form a 5 to 7-membered ring; optionally substituted, saturated, partially saturated or unsaturated ring optionally containing at least one additional heteroatom selected from O, NR5 or S; R' and R" independently represent hydrogen, hydroxyl, halo, cyano, substituted or unsubstituted alkyl, alkoxy, haloalkyl, CONH2, COOH; or R' and R" together with the carbon atoms to which they are attached form a C5 to C8 ring system selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and the substitutions on the said cycloalkyl, heterocyclyl, aryl, heteroaryl include but not limited to halo, cyano, haloalkyl, amino, amido, NHSO2Me and the like;
r represents an integer O, 1, 2 or 3; s represents an integer O, 1 or 2; m represents an integer O, 1 or 2; n represents an integer O, 1 or 2; dotted line [ — ] inside the ring in general formula (I) represents an optional double bond; and their analogues, derivatives, tautomers, stereoisomers, enantiomers, diastereomers, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable hydrates, pharmaceutically acceptable solvates, pharmaceutical compositions, N-oxides and bioisosteres.
2. A compound according to claim 1, wherein X is NR4 and Y is O.
3. A compound according to claim 1, wherein X is O.
4. A compound according to claim 1, wherein X3 is cyano.
5. A compound according to claim 1, wherein R1 is selected from
Figure imgf000093_0001
and X1 and X2 form a 4 to 7 membered ring with optional substitutions such is selected from
Figure imgf000093_0002
6. A compound according to claim 1, wherein R2 is methyl.
7. A compound according to claim 1, wherein R2 is difluoromethyl.
8. A compound according to claim 1, wherein R and R" independently represent hydrogen.
9. A compound according to claim 1, wherein R and R" together with the carbon atoms to which they are attached form a substituted phenyl ring.
10. A compound according to claim 9, wherein the substitution on the phenyl ring NHSO2Me.
11. A compound according to claim 9, wherein the substitution on the phenyl ring CF3.
12. A compound according to claim 1, wherein the compound is selected from 4,5,6,7-Tetrahydro-5-(l-methyl-lH-indol-4-yl)-2H-indazole- 5-carbonitrile 4, 5, 6, 7-Tetrahydro-5-(lH-indol-4-yl)-2H-indazole-5-carbonitrile 4,5,6,7-Tetrahydro-5-(7-methoxy-lH-indol-4-yl)-2H-indazole-5 -carbonitrile
1 -(7-Methoxy- 1 -methyl- 1 H-indol-4-yl)-4-oxocyclohexanecarbonitrile
4,5,6,7-Tetrahydro-5-(7-methoxy-l-methyl-lH-indol-4-yl)-2H-indazole-5- carbonitrile
1 -(7-methoxy- 1 H-indol-4-yl)-4-oxocyclohexanecarbonitrile 4-(6-Fluoro- 1 -methoxy-9-methyl-9H-carbazol-4-yl)-cyclohexanone
4-( 1 -methoxy-9-methyl-9H-carbazol-4-yl)-cyclohexanone
6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-5,6,7,8-tetrahydroquinazoline-6- carbonitrile 2-Amino-6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-5,6,7,8- tetrahydroquinazoline-6-carbonitrile
5-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-4,5,6,7-tetrahydro-2H-indazole-
5-carbonitrile 5-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-4,5,6,7-tetrahydro- benzo [c] isoxazole-5-carbonitrile
6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-2-methyl-5,6,7,8- tetrahydroquinazoline-6-carbonitrile
6-(l-methoxy-9-methyl-9H-carbazol-4-yl)-5,6,7,8-tetrahydroquinazoline-6- carbonitrile
2-Amino-6-(l-methoxy-9-methyl-9H-carbazol-4-yl)-5,6,7,8-tetrahydroquinazoline-
6-carbonitrile
5-(l-methoxy-9-methyl-9H-carbazol-4-yl)-4,5,6,7-tetrahydro-2H-indazole-5- carbonitrile 5-(l-methoxy-9-methyl-9H-carbazol-4-yl)-4,5,6,7-tetrahydro-benzo[c]isoxazole-5- carbonitrile
6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-4-oxo-3,4,5,6,7,8- hexahydroquinazoline-6-carbonitrile
2-Amino-6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-4-oxo-3 ,4,5,6,7, 8- hexahydroquinazoline-6-carbonitrile
5-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-3-oxo-3,3a,4,5,6,7-hexahydro-
2H-indazole-5-carbonitrile
6-(6-Fluoro-l-methoxy-9-methyl-9H-carbazol-4-yl)-2-methyl-4-oxo-3,4,5,6,7,8- hexahydroquinazoline-6-carbonitrile 2-Amino-6-(l-methoxy-9-methyl-9H-carbazol-4-yl)-4-oxo-3,4,5,6,7,8- hexahydroquinazoline-6-carbonitrile
5-(l-methoxy-9-methyl-9H-carbazol-4-yl)-3-oxo-3,3a,4,5,6,7-hexahydro-2H- indazole-5-carbonitrile
1 -( 1 -Methoxy-9-methyl-6-nitro-9H-carbazol-4-yl)-4-oxo-cyclohexanecarbonitrile 6-(l-Methoxy-9-methyl-6-nitro-9H-carbazol-4-yl)-5,6,7,8-tetrahydro-quinazoline-6- carbonitrile
N-[5-(6-Cyano-5,6,7,8-tetrahydro-quinazolin-6-yl)-8-methoxy-9-methyl-9H- carbazol-3 -yl] -methanesulfonamide N-[5-(l-Cyano-4-oxo-cyclohexyl)-8-methoxy-9-methyl-9H-carbazol-3-yl]- methanesulfonamide
2-Amino-6-(l-methoxy-9-methyl-6-nitro-9H-carbazol-4-yl)-5,6,7,8-tetrahydro- quinazoline-6-carbonitrile
N-[9-(6-Cyano-5, 6,7, 8-tetrahydro-quinazolin-6-yl)-6-difluorornethoxy- dibenzofuran-2-yl] -methane sulfonamide
N-[9-(6-Cyano-5, 6,7, 8-tetrahydro-quinazolin-6-yl)-6-methoxy-dibenzofuran-2-yl]- methane sulfonamide
6-(4-Methoxy-8-trifluoromethyl-dibenzofuran-l-yl)-5,6,7,8-tetrahydro-quinazoline-
6-carbonitrile 1 -(4-Methoxy-8-trifluoromethyl-dibenzofuran- 1 -yl)-4-oxo-cyclohexanecaronitrile
5-(4-Methoxy-8-trifluoromethyl-dibenzofuran- 1 -yl)-3-oxo-3 , 3a,4,5,6,7-hexahydro-
2H-indazole-5-carbonitrile
2- Amino-6-(4-Methoxy-8-trifluoromethyl-dibenzofuran- 1 -yl)-5 ,6,7,8-tetrahydro- quinazoline-6-carbonitrile 6-(4-Methoxy-8-trifluoromethyl-dibenzofuran-l-yl)-2-methyl-5, 6, 7, 8-tetrahydro- quinazoline-6-carbonitrile
13. A process for preparing a compound of general formula (I) or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, enaontiomer, diastereiomer or N-oxide thereof comprising at least one of the steps of
a. preparing the compound of general formula E wherein X3, R' and R" are as defined in claim 1 using regular conventional methods known in the literature
Figure imgf000097_0001
b. treatment of the compound of general formula E with methyl acrylate in presence of suitable base such as 1,1,3,3-tetramethyl guanidine or triton B in presence of suitable solvent like dimethyl sulphoxide to afford the compound of general formula F
Figure imgf000097_0002
c. cyclising the compound of general formula F to form the compound of general formula G using suitable base such as sodium hydride
Figure imgf000097_0003
d. conversion of a compound of general formula G to a compound of general formula (I) wherein X, Y, R' R' ' R2 are as defined in claim 1 and R1 is cyclohexanone
Figure imgf000097_0004
General Formula (I) e. alternately, conversion of the compound of general formula G to compound of general formula I using dimethylformamide dimethylacetal in suitable solvent such as benzene
Figure imgf000098_0001
i f. conversion of a compound of general formula I to a compound of general formula (I) wherein R1 is as defined in claim 4 by using suitable reagent such as hydrazone hydrate or phenyl hydrazine in the presence of suitable solvent such as ethanol.
14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition according to claim 14 or a pharmaceutically acceptable salt thereof for use as a Phosphodiesterase 4 (PDE IV) inhibitor.
16. A method for treating an inflammatory disease, disorder or condition characterized by or associated with an excessive secretion of TNF-α and
Phosphodiesterase 4 (PDE IV), which comprises administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1.
17. The method according to claim 16, wherein said inflammatory conditions and disorders are chosen from the group comprising asthma, COPD, allergic rhinitis, allergic conjunctivitis, respiratory distress syndrome, chronic bronchitis, nephritis, rheumatoid spondylitis, osteoarthritis, atopic dermatitis, eosinophilic granuloma, psoriasis, rheumatoid septic shock, ulcerative colitis, multiple sclerosis, chronic inflammation, Crohn's syndrome and central nervous system(CNS) disorders.
18. The use of the compound according to claims 1 to 12, in a medicament for the treatment of inflammatory conditions and disorders chosen from the group comprising asthma, COPD, allergic rhinitis, allergic conjunctivitis, respiratory distress syndrome, chronic bronchitis, nephritis, rheumatoid spondylitis, osteoarthritis, atopic dermatitis, eosinophilic granuloma, psoriasis, rheumatoid septic shock, ulcerative colitis, multiple sclerosis, chronic inflammation, Crohn's syndrome and , central nervous system (CNS) disorders.
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