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WO2004111044A1 - Composes tricycliques efficaces dans le traitement des affections inflammatoires et allergiques : leur procede de preparation - Google Patents

Composes tricycliques efficaces dans le traitement des affections inflammatoires et allergiques : leur procede de preparation Download PDF

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Publication number
WO2004111044A1
WO2004111044A1 PCT/IB2004/001643 IB2004001643W WO2004111044A1 WO 2004111044 A1 WO2004111044 A1 WO 2004111044A1 IB 2004001643 W IB2004001643 W IB 2004001643W WO 2004111044 A1 WO2004111044 A1 WO 2004111044A1
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Gopalan Balasubramanian
Laxmikant Atmaram Gharat
Aftab Dawoodbhai Lakdawala
Raghu Ram Anupindi
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Glenmark Pharmaceuticals Ltd
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Glenmark Pharmaceuticals Ltd
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    • 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
    • C07D405/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel heterocyclic compounds, their analogs, their tautomers, their regioisomers, their stereoisomers, their enantiomers, their diasteromers, their polymorphs, their pharmaceutically acceptable salts, their appropriate N-oxides, their pharmaceutically acceptable solvates and their pharmaceutical compositions containing them.
  • the present invention more particularly relates to novel Phosphodiesterase type 4 (PDE4) inhibitors of the formula (1), their analogs, their tautomers, their enantiomers, their diasteromers, their regioisomers, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their appropriate oxides, their pharmaceutically acceptable solvates and the pharmaceutical compositions containing them.
  • PDE4 Phosphodiesterase type 4
  • the present invention provides a compound of formula (1)
  • Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring;
  • Ar is optionally substituted phenyl, optionally substituted pyridyl or optionally substituted pyridyl-N-oxide in which optional substituents (one or more) may be same or different and are independently selected from the groups consisting of hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino or mono or di substituted or unsubstituted al
  • R 4 is hydrogen, substituted or unsubstituted alkyl, hydroxyl, -OR a , substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic ring;
  • the present invention also relates to a process for the preparation of the above said novel heterocyclic compounds of the formula (1) as defined above.
  • the compounds of general formula (1) more particularly, down regulate or inhibit the production of TNF- ⁇ as they are PDE4 inhibitors and therefore are useful in the treatment of variety of allergic and inflammatory diseases including asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjuctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, diabetes, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, 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)
  • Airway inflammation characterizes a number of severe lung diseases including asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Events leading to airway obstruction include edema of airway walls, infiltration of inflammatory cells into the lung, production of various inflammatory mediators and increased mucous production.
  • the airways of asthmatic patients are infiltrated by inflammatory leukocytes, of which the eosinophil is the most prominent component. The magnitude of asthmatic reactions is correlated with the number of eosinophils present in lungs.
  • eosinophils The accumulation of eosinophils is found dramatically in the lungs of asthmatic patients although there are very few in the lungs of a normal individual. They are capable of lysing and activating cells and destroying tissues. When activated, they synthesize and release inflammatory cytokines such as IL-1, IL-3, TNF- ⁇ and inflammatory mediators such as PAF, LTD4 and related oxygen species that can produce edema and bronchoconstriction.
  • Tumor necrosis factor (TNF- ⁇ ) was also known to be involved in the pathogenesis of a number of autoimmune and inflammatory diseases. Consequently, manipulation of the cytokine signaling or biosynthetic pathways associated with these proteins may provide therapeutic benefit in those disease states.
  • TNF- ⁇ production in pro-inflammatory cells becomes attenuated by an elevation of intracellular cyclic adenosine 3',5'-monophosphate (cAMP).
  • cAMP cyclic adenosine 3',5'-monophosphate
  • PDE phosphodiesterase family of enzymes.
  • the phosphodiesterase enzymes play an integral role in cell signaling mechanisms by hydrolyzing cAMP and cGP to their inactive 5' forms. Inhibition of PDE enzymes thus results in an elevation of cAMP and /or cGP levels and alters intracellular responses to extra cellular signals by affecting the processes mediated by cyclic nucleotides.
  • PDEs The mammalian cyclic nucleotide phosphodiesterases (PDEs) are classified into ten families on the basis of their amino acid sequences and/or DNA sequence, substrate specificity and sensitivity to pharmacological agents [Soderling, S.H., Bayuga, S.J., and Beavo, J.A., Proc. Natl. Acad. Sci., USA, 96, 7071-7076 (1999); Fujishige, K, Kotera, J., Michibata, H., Yuasa, K., Takebayashi, Si, Okamura, K. and Omori, K., J. Biol. Chem., 274, 18438-18445 (1999) herein incorporated by reference in their entirety]. Many cell types express more than one PDE and distribution of isoenzymes between the cells varies markedly. Therefore development of highly isoenzyme selective PDE inhibitors provides a unique opportunity for selective manipulation of various pathophysiological processes.
  • Phosphodiesterase type 4 is an enzyme which regulates activities in cells which lead to inflammation in the lungs.
  • PDE4 a cAMP-specific and Ca +2 -independent enzyme, is a key isozyme in the hydrolysis of cAMP in mast cells, basophils, eosinophils, monocytes and lymphocytes.
  • the association between cAMP elevation in inflammatory cells with airway smooth muscle relaxation and inhibition of mediator release has led to widespread interest in the design of PDE4 inhibitors [Trophy,TJ., Am. J. Respir. Crit. Care Med., 157, 351-370 (1998) herein incorporated by reference in their entirety].
  • TNF- ⁇ production has been implicated in mediating or exacerbating a number of undesirable physiological conditions such as diseases including osteoarthritis, and other arthritic conditions; septic shock, endotoxic shock, respiratory distress syndrome and bone resorption diseases since TNF- ⁇ also participates in the onset and progress of autoimmune diseases, PDE4 inhibitors may find utility as therapeutic agents for rheumatoid arthritis, multiple sclerosis and Crohn's disease. [Nature Medicine, 1, 211-214 (1995) and ibid., 244-248 herein incorporated by reference in their entirety] .
  • PDE-4 exists in two distinct forms which represent different conformations. They are designated as High affinity Rolipram binding site PDE-4H and low affinity Rolipram binding site PDE-4L [Jacobitz, S., McLaughlin, M.M., Livi, G.P., Burman, M., Trophy, T.J., Mol. Pharmaco., 50, 891-899 (1996) herein incorporated by reference in their entirety]. It was shown that certain side effects (vomiting and gastric acid secretion) are associated with inhibition of PDE-4H whereas some beneficial actions are associated with PDE-4L inhibition.
  • Ar is substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic ring or substituted or unsubstituted heteroaryl ring;
  • Ar is optionally substituted phenyl, optionally substituted pyridyl or optionally substituted pyridyl-N-oxide in which optional substituents (one or more) may be same or different and are independently selected from the groups consisting of hydrogen, hydroxyl, halogen, cyano, nitro, carboxyl, trifluoroalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted amino or mono or di substituted or unsubstituted alkylamino
  • L represents O, S or NR a ; wherein R a represents in the above; wherein P represents O or S; wherein n represents 0 -4; X is O, S(O) m or R a
  • B represents O, S or NR a
  • R 4 is hydrogen, substituted or unsubstituted alkyl, hydroxyl, -OR a , substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic ring;
  • the present invention also relates to a process for the preparation of the above said novel heterocyclic compounds of the formula (1) as defined above.
  • the compounds of general formula (1) more particularly, down regulate or inhibit the production of TNF- ⁇ as they are PDE4 inhibitors and therefore are useful in the treatment of variety of allergic and inflammatory diseases including asthma, chronic bronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjuctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, diabetes, ulcerative colitis, Crohn's disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, 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)
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1- methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like .
  • Alkenyl refers to aliphatic hydrocarbon group containing a carbon- carbon double bond and which may be a straight or branched or branched chain having about 2 to about 10 carbon atoms in the e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso- propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl and the like.
  • Alkynyl refers to straight or branched chain hydrocarbyl radicals having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms (with radicals having in the range of about 2 up to 10 carbon atoms presently being preferred) e.g., ethynyl, propynyl, butnyl and the like.
  • Alkoxy denotes alkyl group as defined above attached via oxygen linkage to the rest of the molecule. Representative examples of those groups are -OCH 3 , -OC 2 H 5 and the like.
  • Alkylcarbonyl denotes alkyl group as defined above attached via carbonyl linkage to the rest of the molecule. Representative examples of those groups are -C(0)CH 3 , - C(0)C 2 H 5 and the like.
  • Alkoxycarbonyl denotes alkoxy group as defined above attached via carbonyl linkage to the rest of the molecule. Representative examples of those groups are -C(0)-OCH 3 , - C(O)-OC 2 H 5 and the like.
  • Alkylcarbonyloxy denotes alkylcarbonyl group as defined above attached via oxygen linkage to the rest of the molecule. Representative examples of those groups are -0-C(O)CH 3 , - 0-C(0)C 2 H 5 and the like.
  • Alkylamino denotes alkyl group as defined above attached via amino linkage to the rest of the molecule. Representative examples of those groups are - NH 2 CH 3 , - -NH(CH 3 ) 2 , -N(CH 3 ) 3 and the like.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and examples of multicycic cycloalkyl groups include perhydronapththyl, adamantyl and norbornyl groups bridged cyclic group or spirobicyclic groups e.g sprio (4,4) non-2-yl.
  • cycloalkylalkyl refers to cyclic ring-containing radicals containing in the range of about 3 up to 8 carbon atoms directly attached to alkyl group which then attached to the main structure at any carbon from alkyl group that results in the creation of a stable structure, such as cyclopropylmethyl, cyclobuylethyl, cyclopentylethyl, and the like.
  • cycloalkenyl refers to cyclic ring-containing radicals containing in the range of about 3 up to 8 carbon atoms with atleast one carbon- carbon double bond such as cyclopropenyl, cyclobutenyl, cyclopentenyl and the like.
  • aryl refers to aromatic radicals having in the range of 6 up to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, biphenyl and the like.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH 2 C 6 H 5 , -C 2 H 5 C 6 H 5 and the like.
  • Heterocyclic ring refers to a stable 3- to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated ot aromatic.
  • heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofumyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl
  • Heteroaryl refers to heterocyclic ring radical as defined above.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • Heteroarylalkyl refers to heteroaryl ring radical as defined above directly bonded to alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom from alkyl group that results in the creation of a stable structure.
  • Heterocyclyi refers to a heterocylic ring radical as defined above.
  • the heterocylyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • Heterocyclylalkyl refers to a heterocylic ring radical as defined above directly bonded to 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.
  • cyclic ring refers to a cyclic group containing 3-10 carbon atoms
  • protecting group refers to CBZ or BOC and the like
  • Halogen refers to radicals of Fluorine, Chlorine, Bromine, Iodine
  • Preferred inflammatory disorders are chosen from the group consisting of asthma, bronchial asthma, chronic obstructive pulmonary disease, allergic rhinitis, eosinophilic granuloma, nephritis, rheumatoid arthritis, cystic fibrosis, chronic bronchitis, multiple sclerosis, Crohns disease, psoraisis, uticaria, adult vernal cojunctivitis, respiratory distress syndrome, rhematoid spondylitis, osteoarthritis, gouty arthritis, uteltis, allergic conjunctivitis, inflammatory bowel conditions, ulcerative coalitis, eczema, atopic dermatitis and chronic inflammation. Further preferred are allergic inflammatory conditions.
  • inflamatory disorders include, but are not limited to, chronic abstractive pulmonary disease (COPD) and asthma.
  • COPD chronic abstractive pulmonary disease
  • inflammatory conditions and immune disorders selected from the group consisting of inflammatory conditions or immune disorders of the lungs, joints, eyes, bowels, skin and heart.
  • inflammatory conditions chosen from the group consisting of bronchial asthma, nepritis, and allergic rhinitis.
  • Another object of the invention is a method for abating inflammation in an affected organ or tissue including delivering to the organ or tissue a therapeutically effective amount of a compound represented by a compound according to Formula 1.
  • Another object of the invention is a method of treating diseases of the central nervous system in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound according to Formula 1.
  • Preferred diseases of the central nervous system are chosen from the group consisting of depression, amnesia, dementia, Alzheimers disease, cardiac failure, shock and cerebrovascular disease.
  • Another object of the invention is a method of treating insulin resistant diabetes in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound according to Formula 1.
  • Treating" or “treatment” of a state, disorder or condition includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
  • Symptoms and signs of inflammation associated with specific conditions include:
  • insulin-dependent diabetes mellitus- insulitis this condition can lead to a variety of complications with an inflammatory component, including: retinopathy, neuropathy, nephropathy; coronary artery disease, peripheral vascular disease, and cerebrovascular disease;
  • inflammatory skin disorders such as , eczema, other dermatites (e.g., atopic, contact), psoriasis, burns induced by UV radiation (sun rays and similar UV sources)- erythema, pain, scaling, swelling, tenderness; • inflammatory bowel disease, such as Crohn's disease, ulcerative colitis- pain, diarrhea, constipation, rectal bleeding, fever, arthritis;
  • lung injury such as that which occurs in adult respiratory distress syndrome- shortness of breath, hyperventilation, decreased oxygenation, pulmonary infiltrates
  • inflammation accompanying infection such as sepsis, septic shock, toxic shock syndrome- fever, respiratory failure, tachycardia, hypotension, leukocytosis;
  • nephritis e.g., glomerulonephritis
  • oliguria e.g., urinalysis
  • vascular disease such as atherosclerosis and restenosis- pain, loss of sensation, diminished pulses, loss of function and alloimmunity leading to transplant rejection- pain, tenderness, fever.
  • Subclinical symptoms include without limitation diagnostic markers for inflammation the appearance of which may precede the manifestation of clinical symptoms.
  • One class of subclinical symptoms is immunological symptoms, such as the invasion or accumulation in an organ or tissue of proinflammatory lymphoid cells or the presence locally or peripherally of activated pro-inflammatory lymphoid cells recognizing a pathogen or an antigen specific to the organ or tissue. Activation of lymphoid cells can be measured by techniques known in the art.
  • Delivery a therapeutically effective amount of an active ingredient to a particular location within a host means causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished , e.g., by local or by systemic administration of the active ingredient to the host.
  • a subject or "a patient” or “a host” refers to mammalian animals, preferably human.
  • Pharmaceutically acceptable salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, choline hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, thiamine, spermidine, and the like; chiral bases like alkylphenylamine, glycinol, phenyl glycinol and the like, salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, omithine, lysine, arginine, serine, and the like; unnatural amino acids such as
  • Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, benzoates, salicylates, , benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • Pharmaceutically acceptable solvates may be hydrates or comprise other solvents of crystallization such as alcohols.
  • the compounds according to the invention may be prepared by the following processes.
  • the present invention discloses a process for the preparation of compounds of general formula (1).
  • the compound of the formula 10 (obtained from ref. J Org. Chem.; 1986; 51; 1821-1829) is alkylated using appropriate alkyl halide or alkyl mesylate or alkyl tosylate under standard basic conditions to obtain the intermediate of the general formula 11.
  • the intermediate of the general formula 11 is then acylated to the intermediate of the formula 12 by appropriate acylation techniques practiced in the literature.
  • Willegerodt-Kindler rearrangement of the intermediate of the general formula 12 provides the intermediate of the general formula 13 which is oxidized to the dicarbonyl ester intermediate 14 using appropriate oxidizing agent like selenium dioxide.
  • the intermediate of the formula 14 is hydrolyzed using standard acidic or basic conditions reported in the literature to the dicarbonyl acid intermediate 15.
  • the compounds of formula la are obtained by reacting the appropriately activated carboxylic acid (acid halide or mixed anhydride or active ester ) intermediate of the general formula 15 with the optionally substituted aryl or heteroaryl amines (ArNHR 4 ) under appropriate basic conditions reported in the literature.
  • the desired compounds of the formula la obtained are then converted into their salts and/or the N-oxides and, if desired, salts of the compounds of the formula la obtained are then converted into the free compounds
  • the intermediate of the formula 11 can be directly acylated under appropriate Lewis acidic condition with ethyl oxalyl chloride to the intermediate of the formula 14 which can then be converted to the desired compounds of the formula la as described in the synthetic scheme I.
  • the desired compounds of the formula la obtained are then converted into their salts and/or the N-oxides and, if desired, salts of the compounds of the formula la obtained are then converted into the free compounds
  • N-oxidation is carried out in a manner likewise familiar to the person skilled in the art, e.g with the aid of m-chloroperoxybenzoic acid in dichloromethane at room temperature.
  • the person skilled in the art is familiar with the reaction conditions which are necessary for carrying out the process on the basis of his expert knowledge.
  • the substances according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuum and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as column chromatography on a suitable support material.
  • Salts are obtained by dissolving the free compound in a suitable solvent, e.g in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added.
  • a suitable solvent e.g in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added.
  • the salts are obtained by filtering, reprecepiting, precipitating with a non-solvent for the addition salt or by evaporating the solvent. Salts obtained can be converted by basification or by acidifying into the free compounds which, in turn can be converted into salts.
  • the ethereal solvents used in the above described processes for the preparation of compounds of the formula la are selected from diethyl ether, 1,2- dimethoxyethane, tetrahydrofuran, diisopropyl ether, 1,4 dioxane and the like.
  • the chlorinated solvent which may be employed may be selected from dichloromethane, 1,2- dichloroethane, chloroform, carbontetrachloride and the like .
  • the aromatic solvents which may be employed may be selected from benzene, toluene.
  • the alchoholic solvents which may be employed may be selected from methanol, ethanol, n-propanol, iso propanol, tert.butanol and the like.
  • the aprotic solvents which may be employed may be selected from N, N-dimethylformamide, dimethyl sulfoxide and the like.
  • the compounds prepared in the above described processes are obtained in pure form by using well known techniques such as crystallization using solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, iso propanol, water or their combinations, or column chromatography using Alumina or silica gel and eluting the column with solvents such as hexane, petroleum ether (pet.ether), chloroform, ethyl acetate, acetone, methanol or their combinations.
  • solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, iso propanol, water or their combinations
  • solvents such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethan
  • polymorphs of a compound of general formula (1) forming part of this invention may be prepared by crystallization of compound of formula (1) under different conditions, example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures, various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe nmr spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the present invention provides novel heterocyclic compounds, their analogs, their tautomers, their regioisomers, their stereoisomers, their enantiomers, their diastreomers, their polymorphs, their pharmaceutically acceptable salts, their appropriate N-oxides and their pharmaceutically acceptable solvates.
  • the present invention also provides pharmaceutical compositions, containing compounds of the general formula (1) as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their enantiomers, their diasteromers, their pharmaceutically acceptable salts or their pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like.
  • the pharmaceutical compositions according to this invention can be used for the treatment of allergic disorders.
  • some of the compounds of the general formula (1) defined above according to the invention can contain one or more asymmetrically substituted carbon atoms.
  • the presence of one or more of these asymmetric centers in the compounds of the general formula (1) can give rise to stereoisomers and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers and their mixtures, including racemic mixtures.
  • the invention may also contain E & Z geometrical isomers wherever possible in the compounds of the general formula (1) which includes the single isomer or mixture of both the isomers
  • the pharmaceutical compositions may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like and may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • the active compounds of the formula (1) will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the compounds of the formula (1) can be combined with a suitable solid, liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
  • the compounds of the formula (1) can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • injectable solutions or suspensions for example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds of the formula (1).
  • the injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • the compounds can also be administered by inhalation when application within the respiratory tract is intended.
  • Formulation of the present compounds is especially significant for respiratory inhalation, wherein the compound of Formula (1) is to be delivered in the form of an aerosol under pressure. It is preferred to micronize the compound of Formula (1) after it has been homogenised, e.g., in lactose, glucose, higher fatty acids, sodium salt of dioctylsulfosuccinic acid or, most preferably, in carboxymethyl cellulose, in order to achieve a microparticle size of 5 ⁇ m or less for the majority of particles.
  • the aerosol can be mixed with a gas or a liquid propellant for dispensing the active substance.
  • An inhaler or atomizer or nebulizer may be used. Such devices are known. See, e.g., Newman et al., Tliorax, 1985, 40:61-676; Berenberg, M., J. Asthma USA, 1985, 22:87-92; incorporated herein by reference in their entirety.
  • a Bird nebulizer can also be used. See also U.S. Patents 6,402,733; 6,273,086; and 6,228,346, incorporated herein by reference in their entirety.
  • the compound of the structure (1) for inhalation is preferably formulated in the form of a dry powder with micronized particles.
  • the compounds of the invention may also be used in a metered dose inhaler using methods disclosed in U.S. Patent 6, 131,566, incorporated herein by reference in its entirety.
  • compositions of the present invention may also contain or be co-administered with one or more known drugs selected from other clinically useful therapeutic agents.
  • dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from 0.05mg to about lOOOmg preferably from about 0.5mg to about 250mg of the compounds admixed with a pharmaceutically acceptable carrier or diluent.
  • Step 2 l-(4-methoxydibenzo[ ⁇ , ⁇ ]furan-l-yI)-l-ethanone 4-methoxydibenzo[6, d]fux (100 mg, 0.555 mmol) was dissolved in chloroform (4 ml) and cooled to 5°C. Anhydrous aluminum chloride (200 mg, 1.515 mmol) was added to the reaction mixture and was stirred for 10 min at 5°C. A solution of acetyl chloride (70 mg, 0.833 mmol) in chloroform (2 ml) was added dropwise to the reaction mixture and was stirred at 5-10°C for 1 h.
  • Step 3 Ethyl 2-(4-methoxydibenzo [#, ⁇ /] furan-l-yl)acetate l-(4-methoxydibenzo[ ⁇ ,c?]furan-l-yl)-l-ethanone (100 mg, 0.416 mmol), triethylorthoformate (2 ml), lead tetraacetate (185 mg, 0.416 mmol), 70% aqueous perchloric acid (120 mg, 0.832 mmol) were mixed and heated to 60-70°C for 7 h. Reaction mixture was cooled to room temperature, diluted with water (25 ml) and extracted with chloroform (2 x 25 ml).
  • Step 4 Ethyl 2-(4-methoxydibenzo[6,rf]furan-l-yl)-2-oxoacetate
  • Ethyl 2-(4-methoxydibenzo[ ⁇ ,(t furan-l-yl)acetate (100 mg, 0.352 mmol) was dissolved in xylenes (7 ml).
  • Selenium dioxide 190 mg, 1.76 mmol
  • the xylene was distilled off and the residue obtained was tritutrated with chloroform (30 ml) and filtered through celite bed. Chloroform was evaporated to get a sticky solid which was purified by silica gel column chromatography using 8 % ethyl acetate in petroleum ether to give the product (45 mg); mp: 191-193°C.
  • Step 2 Ethyl 2-(4-isopropyloxydibenzo[6, «7]furan-l-yl)-2-oxoacetate was synthesized as described in step 2 of intermediate 2 using 4-Isopropyloxy dibenzo[ ⁇ ,c(jfuran instead of 4-Ethoxydibenzo[ ⁇ ,cT
  • Step 1 4-Cyclopentyloxydibenzo[6, ⁇ flfuran was synthesized as described in step 1 of intermediate 2 using cyclopentyl bromide instead of ethyl bromide.
  • Step 2 Ethyl 2-(4-cyclopentyloxydibenzo[ ⁇ , ⁇ f
  • Step 3 2-(4-cycIopentyloxydibenzo[6, ⁇ /]furan-l-yI)-2-oxoacetic acid was synthesized by hydrolysis of Ethyl 2-(4-cyclopentyloxydibenzo[t>, ⁇ furan-l-yl)-2- oxoacetate ( from step 2 above) as described in step 3 of intermediate 3.
  • Example 2 was synthesized as described for example 1 using intermediate 1 and 4- aminopyridine.
  • the crude product was purified by silica gel column chromatography using 30 % acetone in chloroform, mp: 224°C IR (KBr): 3133, 2932, 1689, 1667, 1597, 1563, 1518, 1400, 1280, 1189, 1107, 1010,
  • Example 3 was synthesized as described for example 1 using intermediate 1 and 3- aminopyridine.
  • the crade product was purified by silica gel column chromatography using 30 % acetone in chloroform, mp: 209°C
  • Example 4 was synthesized as described for example 1 using intermediate 2 and 4- amino-3,5-dichloropyridine.
  • the crude product was purified by silica gel column chromatography using 10 % ethyl acetate in chloroform, mp: 268°C
  • Example 5 was synthesized as described for example 1 using intermediate 2 and 4- aminopyridine.
  • Example 6 was synthesized as described for example 1 using intermediate 2 and 3- aminopyridine.
  • the crade product was purified by silica gel column chromatography using 20 % ethyl acetate in chloroform, mp: 207°C
  • Example 7 was synthesized as described for example 1 using intermediate 3 and 4- amino-3,5-dichloropyridine.
  • the crude product was purified by silica gel column chromatography using 40 % ethyl acetate in petroleum ether. mp:176°C IR (KBr): 3432, 3084, 2927, 2865, 1670, 1635, 1600, 1554, 1400, 1278, 1168, 1107, 1010, 768, 535m "1
  • Example 8 was synthesized as described for example 1 using intermediate 4 and 3,5- dichloro-4-aminopyridine. The crude product was purified by silica gel column chromatography using 10 % ethyl acetate in chloroform, mp: 201°C
  • Example was synthesized as described for example 1 using intermediate 4 and 4- aminopyridine.
  • the crade product was purified by silica gel column chromatography using 15 % ethyl acetate in chloroform, mp: 189°C IR (KBr): 3068, 2964, 2874, 1691, 1595, 1515, 1398, 1229, 1281, 1209, 1162, 1015, 996, 752, 502 cm "1 .
  • Example' 10 was synthesized as described for example 1 using intermediate 4 and 3- aminopyridine.
  • the crade product was purified by silica gel column chromatography using 15 % ethyl acetate in chloroform, mp: 191°C IR (KBr): 3193, 3066, 2958, 2735, 1672, 1567, 1449, 1399, 1273, 1169, 1107, 1072, 981, 748, 538. cm "1
  • Example 11 was synthesized as described for example 1 using intermediate 5 and 3,5- dichloro-4-aminopyridine.
  • the crude product was purified by silica gel column chromatography using 5 % ethyl acetate in chloroform, mp: 206°C IR (KBr): 3165, 3100, 2952, 1698, 1671, 1560, 1510, 1449, 1400, 1282, 1274, 1183, 1155, 1108, 917, 892, 748. cm "1
  • Example 12 was synthesized as described for example 1 using intermediate 5 and 4- aminopyridine.
  • the crade product was purified by silica gel column chromatography using 15 % ethyl acetate in chloroform, mp: 215°C IR (KBr): 3162, 3031, 2961, 1687, 159, 1520, 1401, 1283, 1207, 1156, 1106, 1057, 1001, 857, 822, 741.
  • Example 13 was synthesized as described for example 1 using intermediate 5 and 3- aminopyridine.
  • the crade product was purified by silica gel column chromatography using 15 % ethyl acetate in chloroform, mp: 174°C IR (KBr): 3234, 3075, 2987, 2849, 1675, 1575, 1432, 1390, 1283, 1273, 1168, 1184, 1108, 1044, 809, 749 cm "1
  • PDE4 enzyme converts [ 3 H] cAMP to the corresponding [ 3 H] 5'- AMP in proportion to the amount of PDE4 present.
  • the [ 3 H] 5'-AMP then was quantitatively converted to free [ 3 H] adenosine and phosphate by the action of snake venom 5'-nucleotidase.
  • the amount of [ 3 H] adenosine liberated is proportional to PDE4 activity.
  • the assay was performed with modification of the method of Thompson and Appleman (Biochemistry; 1971; 10; 311-316) and Schwartz and Passoneau (Proc. Natl. Acad. Sci. U.S.A. 1974; 71; 3844-3848), both references incorporated herein by reference in their entirety, at 34°C.
  • the reaction mixture contained 12.5mM of Tris, 5 mM MgCl 2 , 1 ⁇ M cAMP (cold) and 3 H cAMP (0.1 uCi), (Amersham).
  • Stock solutions of the compounds to be investigated were prepared in DMSO in concentrations such that the DMSO content in the test samples did not exceed 0.05 % by volume to avoid affecting the PDE4 activity.
  • Drag samples were then added in the reaction mixture (25 ⁇ l/tube).
  • the assay was initiated by addition of enzyme mix (75 ⁇ l) and the mixture was incubated for 20 minutes at 34° C.
  • the reaction was stopped by boiling the tubes for 2 mins at 100°C in a water bath. After cooling on ice for 5 minutes and addition of 50 ug/reaction of 5'-nucleotidase snake venom from Crotalus atrox incubation was carried out again for 20 min. at 34°C.
  • the unreacted substrate was separated from ( 3 H) Adenosine by addition of Dowex AG 1-X8 ( Biorad Lab), (400 ul) which was prequilibrated (1:1:1) in water and ethanol.
  • Reaction mixture was then thoroughly mixed, placed on ice for 15 minutes, vortexed and centrifuged at 14,000 r.p.m. for 2 mins. After centrifugation, a sample of the supernatant was taken and added in 24 well optiplates containing Scintillant (1 ml) and mixed well. The samples in the plates were then determined for radioactivity in a Top Counter and the PDE4 activity was estimated. PDE4 enzyme was present in quantities that yield ⁇ 30% total hydrolysis of substrate (linear assay conditions).
  • Phosphodiesterase enzymes namely, PDE l(Ca.sup.2+/calmodulin-dependent), PDE 2(cGP-stimulated), PDE 3 (cGP-inhibited), PDE 5 (cGP-specific) and PDE 6 (cGP- specific, photoreceptor).
  • Results were expressed as percent inhibition (IC50) in nM/uM concentrations.
  • IC50 values were determined from the concentration curves by nonlinear regression analysis.

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Abstract

La présente invention concerne de nouveaux composés hétérocycliques, leurs analogues, leurs tautomères, leurs régioisomères, leurs stéréoisomères, leurs énantiomères, leurs diastéréomères, leurs polymorphes, leurs sels pharmaceutiquement acceptables, leurs N-oxydes appropriés, leurs solvates pharmaceutiquement acceptables et leurs compositions pharmaceutiques les contenant. La présente invention concerne plus particulièrement de nouveaux inhibiteurs de la phosphodiestérase de type 4 (PDE4) répondant à la formule (1), leurs analogues, leurs tautomères, leurs énantiomères, leurs diastéréomères, leurs régioisomères, leurs stéréoisomères, leurs polymorphes, leurs sels pharmaceutiquement acceptables, leurs N-oxydes appropriés, leurs solvates pharmaceutiquement acceptables et les compositions pharmaceutiques les contenant.
PCT/IB2004/001643 2003-06-17 2004-06-16 Composes tricycliques efficaces dans le traitement des affections inflammatoires et allergiques : leur procede de preparation Ceased WO2004111044A1 (fr)

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WO2007007886A1 (fr) * 2005-07-11 2007-01-18 Mitsubishi Tanabe Pharma Corporation Derive d'oxime et ses preparations
WO2008052734A1 (fr) 2006-10-30 2008-05-08 Novartis Ag Composés hétérocycliques en tant qu'agents anti-inflammatoires
US7511150B2 (en) 2006-07-06 2009-03-31 Forest Laboratories Holdings Limited Synthesis of heterocyclic compounds
WO2009087224A1 (fr) 2008-01-11 2009-07-16 Novartis Ag Pyrimidines utilisés en tant qu'inhibiteurs de kinase
JP2010502689A (ja) * 2006-09-11 2010-01-28 マトリックス ラボラトリーズ リミテッド Ｐｄｅ−４およびｐｄｅ−１０の阻害剤としてのジベンゾフラン誘導体
EP2286813A2 (fr) 2006-01-31 2011-02-23 Novartis AG Utilisation de dérivés de naphthyridine comme medicaments
WO2012034095A1 (fr) 2010-09-09 2012-03-15 Irm Llc Composés et compositions comme inhibiteurs de trk
WO2012034091A1 (fr) 2010-09-09 2012-03-15 Irm Llc Composés et compositions à titre d'inhibiteurs de trk
WO2012116217A1 (fr) 2011-02-25 2012-08-30 Irm Llc Composés et compositions en tant qu'inhibiteurs de trk
WO2018041935A1 (fr) * 2016-09-02 2018-03-08 Igm Group B.V. Glyoxylates polycycliques utilisés en tant que photo-initiateurs
CN108084128A (zh) * 2017-12-28 2018-05-29 福建中医药大学 一种二苯并呋喃衍生物及其制备方法和用途
EP3603634A1 (fr) 2004-05-18 2020-02-05 Novartis AG Composition pharmaceutique comprenant du glycopyrrolate et un agoniste du récepteur beta2 adrénergique

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WO2002072567A2 (fr) * 2001-03-13 2002-09-19 Glenmark Pharmaceuticals Limited Nouveaux composes heterocycliques utiles dans le traitement des troubles allergiques inflammatoires; procede de leur preparation et compositions pharmaceutiques les contenant

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WO1994008995A1 (fr) * 1992-10-13 1994-04-28 Smithkline Beecham Plc Derives heterocycliques condenses d'acide benzoique utilises comme antagonistes des recepteurs 5-ht¿4?
US20020128290A1 (en) * 1995-05-19 2002-09-12 Etsuo Ohshima Derivatives of benzofuran or benzodioxole
WO1998009934A1 (fr) * 1996-09-04 1998-03-12 Warner-Lambert Company Inhibiteurs de metalloproteinases matricielles et leurs utilisations pharmaceutiques
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3603634A1 (fr) 2004-05-18 2020-02-05 Novartis AG Composition pharmaceutique comprenant du glycopyrrolate et un agoniste du récepteur beta2 adrénergique
CN101218237B (zh) * 2005-07-11 2012-03-28 田边三菱制药株式会社 肟衍生物及其制备方法
US7514439B2 (en) 2005-07-11 2009-04-07 Mitsubishi Tanabe Pharma Corporation Oxime derivative and preparations thereof
WO2007007886A1 (fr) * 2005-07-11 2007-01-18 Mitsubishi Tanabe Pharma Corporation Derive d'oxime et ses preparations
AU2006267387B2 (en) * 2005-07-11 2010-11-18 Mitsubishi Tanabe Pharma Corporation An oxime derivative and preparations thereof
US8119626B2 (en) 2005-07-11 2012-02-21 Mitsubishi Tanabe Pharma Corporation Oxime derivative and preparations thereof
EP2286813A2 (fr) 2006-01-31 2011-02-23 Novartis AG Utilisation de dérivés de naphthyridine comme medicaments
US7511150B2 (en) 2006-07-06 2009-03-31 Forest Laboratories Holdings Limited Synthesis of heterocyclic compounds
JP2010502689A (ja) * 2006-09-11 2010-01-28 マトリックス ラボラトリーズ リミテッド Ｐｄｅ−４およびｐｄｅ−１０の阻害剤としてのジベンゾフラン誘導体
WO2008052734A1 (fr) 2006-10-30 2008-05-08 Novartis Ag Composés hétérocycliques en tant qu'agents anti-inflammatoires
WO2009087224A1 (fr) 2008-01-11 2009-07-16 Novartis Ag Pyrimidines utilisés en tant qu'inhibiteurs de kinase
WO2012034091A1 (fr) 2010-09-09 2012-03-15 Irm Llc Composés et compositions à titre d'inhibiteurs de trk
WO2012034095A1 (fr) 2010-09-09 2012-03-15 Irm Llc Composés et compositions comme inhibiteurs de trk
WO2012116217A1 (fr) 2011-02-25 2012-08-30 Irm Llc Composés et compositions en tant qu'inhibiteurs de trk
WO2018041935A1 (fr) * 2016-09-02 2018-03-08 Igm Group B.V. Glyoxylates polycycliques utilisés en tant que photo-initiateurs
US10597515B2 (en) 2016-09-02 2020-03-24 Igm Group B.V. Polycyclic glyoxylates as photoinitiators
CN108084128A (zh) * 2017-12-28 2018-05-29 福建中医药大学 一种二苯并呋喃衍生物及其制备方法和用途
CN108084128B (zh) * 2017-12-28 2020-01-03 福建中医药大学 一种二苯并呋喃衍生物及其制备方法和用途

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