WO2004050624A1 - Substituted 1h-pyridine-2-one derivatives - Google Patents

Substituted 1h-pyridine-2-one derivatives Download PDF

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WO2004050624A1
WO2004050624A1 PCT/KR2003/002615 KR0302615W WO2004050624A1 WO 2004050624 A1 WO2004050624 A1 WO 2004050624A1 KR 0302615 W KR0302615 W KR 0302615W WO 2004050624 A1 WO2004050624 A1 WO 2004050624A1
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compound
amino
cyclohexyl
pyridine
phenyl
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PCT/KR2003/002615
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French (fr)
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Bon Am Koo
Woong Hyun Nam
Woo Sang Hong
Hyoung Sik Seo
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C & C Research Laboratories
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Priority to AU2003284704A priority Critical patent/AU2003284704A1/en
Priority to KR1020057009630A priority patent/KR101154431B1/en
Priority to JP2004556961A priority patent/JP4628107B2/en
Publication of WO2004050624A1 publication Critical patent/WO2004050624A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • the present invention relates to novel compounds, e.g., novel substituted 1H- pyridine-2-one derivatives useful for the preparation of medicine treating a variety of allergic or inflammatory diseases, particularly the disease where phosphodiesterase-4 inhibitors are used as main therapeutic agents.
  • the medicine is useful particularly as an anti-inflammatory agent, an anti-allergic agent, a bronchodilator, an anti-asthmatic agent, or a TNF- ⁇ suppressor.
  • Cyclic adenosine 3',5'-monophosphate acts as a second messenger within cells, and mediates cellular responses to many different primary signals such as hormone, neurotransmitter or autacoid. Many of the primary signals exert their effect through the enzymes that participate in the synthesis of cAMP, and the resulting increase in cAMP level produce markedly different effect in various types of cells for example, metabolysis, muscle contraction or secretions of cellular substances. The actual cellular responses to cAMP vary among different cell types.
  • cAMP level Another point of regulation of cAMP level is the hydrolysis of cAMP to adenosine 5'-monophosphate.
  • the hydrolysis reaction is catalyzed by cyclic nucleotide phosphodiesterases (PDE) resulting in the termination of cAMP's role as a messenger.
  • PDE cyclic nucleotide phosphodiesterases
  • PDE 1 to 11 11 families of PDE have been identified in mammalian cells (named PDE 1 to 11), which were grouped into the corresponding family according to their specificity towards hydrolysis of cAMP or cGMP, their structures, their kinetic behaviors, their sensitivity to regulation by calcium, calmodulin or cGMP, and their selective inhibition by various compounds (for references, see Beavo J.A. et al (1990) Trends Pharmacol. Sci., 150-155; Beavo J.A. et al (1944); Molecular Pharmacol., 399-405).
  • PDE4 is one of the cAMP-specific isoenzymes and it has been shown that its functions are inhibited by Rolipram.
  • the non-specific as well as specific PDE inhibitor compounds have been known.
  • the non-specific PDE inhibitors as with the case of a particular methylxanthin such as theophyline act not only on PDEs residing in the target cells, but also on PDEs in other cells resulting in low remedy index.
  • specific inhibitors work selectively so that some PDE families are inhibited selectively by various inhibitors. Therefore, hydrolysis of cyclic nucleotide is mitigated only in the cells where PDE families sensitive to certain inhibitors are found thus increasing the intracellular concentration of cAMP.
  • Phosphodiesterase 4 Phosphodiesterase 4
  • tissues including central nervous system, heart, vascular endothelium, and smooth muscles of blood vessel, air route, bone marrow gland and lymph gland.
  • the increased level of cAMP in inflammatory cells results in the suppression of cell activities: the suppression of synthesis and the secretion of many intracellular substances in mast mastocyte, monocyte, polymorphonuclear acidophil and basophil, the suppression of chemical taxis and degranulation of polymorphonuclear neutrophil and acidophil, and the suppression of proliferation and differentiation of lymphocyte.
  • Cytokines particularly TNFs(Tumor Necrosis Factor) and interleukins that are produced by various leucocytes such as T-lymphocytes and polymorphonuclear acidophils play an important role in the development of inflammatory state in cells, particularly hypersensitivity reaction induced by the allergen in the respiratory tract.
  • the cAMP introduced into the cells of airway causes the contraction of airway smooth muscle, and the PDE4 inhibitors cause the relaxation of the such contracted bronchi.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic bronchitis
  • Ariflo has also many disadvantages. Particularly, it has been reported that there were severe side effects such as nausea and emesis in patients administered with 20mg of Ariflo (for references, see Murdoch et al., Am J Respir Crit Care Med 1998, 157:A409). Therefore the side effects observed in such a low dosage would severely restricted its therapeutic utility and cause much inconveniences to patient who have to take them on a daily basis.
  • potent and selective PDE4 inhibitors are strongly desired, namely the inhibitors that do not have specificity on other family members of PDE, and that do not cause side effects in the therapeutic dosage range while maintaining the activity of preventing the acute deterioration of lung function associated with COPD through the direct functional activities of bronchodilation and anti-inflammation, and of curing the gradual deterioration of lung function associated with disease, thus improving the quality of life of the patients.
  • the present invention relates to substituted lH-pyridine-2-one derivatives of formula (1)
  • R is selected from the group consisting of C 6 -C 12 aryl, C 3 -C 8 cycloalkyl, and saturated or unsaturated C 2 -C ⁇ mono- or poly-heterocyclyl containing 1 to 3 heteroatoms, which may be substituted by one or two R 7 's;
  • R 2 is selected from the group consisting of C 6 -C, 2 aryl, C 3 -C 8 cycloalkyl, and saturated or unsaturated C 2 -C ⁇ mono- or poly-heterocyclyl containing 1 to 3 heteroatoms, which may be substituted by one or two R 8 's;
  • R 3 and R 4 which may be identical or different, are selected from the group consisting of hydrogen, C,-C 6 alkyl, and C 2 -C 7 alkylcarbonyl;
  • R 5 and R ⁇ which may be identical or different, are selected from the group consisting of hydrogen, C,-C 6 alkyl, C 2 -C 7 alkylcarbonyl, and C 2 -C 7 alkoxy carbonyl;
  • R 7 is selected from the group consisting of hydrogen, C,-C 6 alkyl, C,-C 6 alkoxy, C 2 -C 7 alkoxycarbonyl, C 6 -C 12 aryl, C,-C 5 heteroaryl containing
  • R 8 is selected from the group consisting of hydrogen, C,-C 6 alkyl, C,-C 6 alkoxy, hydroxy, halogen, CN, and CO 2 H; R, and R 4 may be selectively linked to form an aromatic ring.
  • the compounds according to the present invention are useful as phosphodiesterase (PDE) enzyme inhibitors, particularly a PDE4 inhibitor, more particularly a selective inhibitor.
  • PDE phosphodiesterase
  • an alkyl group and an alkyl residue in the other groups (e.g., alkoxy) described in the invention may be linear or branched.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • the C 3 -C 8 cycloalkyl group used in the invention is, for example, preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, most preferably, cyclohexyl.
  • the saturated or unsaturated C 2 -C Intel mono- or poly-heterocyclyl group containing 1 to 3 heteroatoms used in the invention is, for example, preferably, thienyl, thiazolyl, imidazolyl, benzoimidazolyl, triazolyl, tetrahydropyranyl, pyridinyl, furanyl, pyranyl, pyrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, isothiazolyl, isooxazolyl, pyridazinyl, isobenzopyranyl, chromenyl, indolyl, indazolyl, quinolinyl, purinyl, pyrolinyl, chromanyl, pyrazolidinyl, piperidinyl, piperazinyl, most preferably, imidazolyl.
  • the C 6 -C 12 aryl group used in the invention is, for example, preferably, phenyl, naphthyl, most preferably, phenyl.
  • phenyl preferably, phenyl, naphthyl, most preferably, phenyl.
  • compounds of formula (1) according to the present invention mention can be made of the following compounds: l-amino-6-cyclohexyl-4-phenyl-lH-pyridine-2-one (Compound 1); l-amino-4,6-bis(cyclohexyl)-lH-pyridine-2-one (Compound 2);
  • the compounds of formula (1) according to the present invention can also form pharmaceutically acceptable salts.
  • Such pharmaceutically acceptable salts include acid addition salts produced by acids to form non-toxic acid addition salts containing pharmaceutically acceptable anion, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid and the like, organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and the like, sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalsulfonic acid and the like, as well as salts with alkali metals such as sodium, potassium and the like.
  • salts with other organic acids such as hydrochloric
  • Novel compounds of formula (1) as defined above can be prepared by the following method. Accordingly, another object of the present invention is to provide a method for producing compounds of formula (1).
  • a compound of formula (1) can be produced by a process comprising the steps of:
  • the condensation reactions of a compound of formula (9) and a compound of formula (8) are carried out in the presence of an adequate solvent and condensing agent according to a conventional method.
  • a conventional solvent which does not adversely affect the reaction can be generally employed as a solvent, and preferable examples are polar, aprotic solvent such as tetrahydrofuran, acetonitrile, dimethoxyethane, particularly preferably dimethoxyethane.
  • the base added to the reaction is a conventional base such as potassium tert-butoxide, sodium ethoxide, sodium hydride, preferably sodium hydride.
  • the reaction is carried out at temperature between room temperature and 100°C , preferably at 100 ° C for about 5 to 24 hours, preferably 8 hours.
  • the compound of formula (7) obtained by the above-mentioned method is subjected to a cyclization according to a conventional method in the presence of an adequate solvent and a catalyst.
  • a conventional solvent which does not adversely affect the reaction can be generally employed as a solvent, and preferable examples are a polar, aprotic solvent such as tetrahydrofuran, ethyl ether, dimethoxyethane, particularly preferably ethyl ether.
  • the general anhydride preferably trifluoroacetyl anhydride is used to obtain cyclized alcoholic compounds of formula 6.
  • the reaction is carried out at temperature between room temperature and 100 ° C , preferably at room temperature for about half an hour to 10 hours, preferably 2 hours.
  • a usual halogenating compound preferably tribromophosphine in the mixture of solvents of dimethylformamide and ethyl ether to substitute an alcohol at 4-position of the reactant with Br and then bromide of formula (5) is obtained.
  • the reaction is carried out at temperature between room temperature and 60 ° C , preferably at 60 ° C with the starting temperature being at 0 ° C for one hour to 24 hours, preferably 8 hours.
  • a base such as potassium carbonate, sodium hydrocarbonate, preferably potassium carbonate in aprotic solvent such as tetrahydrofuran, acetonitrile, diemethylformamide, preferably acetonitrile, in the present of a catalyst such as sodium iodide or potassium iodide, preferably potassium iodide to give the coupled compound of formula (3).
  • the reaction is carried out at between room temperature and reflux condition, preferably at the reflux temperature for 2 to 20 hours, preferably 5 hours.
  • the compound of formula (1) according to the present invention has an excellent selectivity and inhibitory activity on PDE4 as stated above. Accordingly, the present invention relates to PDE4 inhibitor composition comprising an effective amount of the compound of formula (1) as the active component, pharmaceutically acceptable salts thereof, stereochemical isomers and pharmaceutically acceptable carrier.
  • the compositions according to the present invention exhibit the strong inhibitory activity on PDE4, it is useful as a therapeutic agent to treat COPD, asthma, chronic bronchitis, psoriasis, ulcerative colitis, Crohn's disease (local ileitis), arteriosclerosis, rheumatoid arthritis, osteoporosis, bone arthritis, depression, memory loss, inflammation mediated by chronic necrosis and the others mediated by PDE4.
  • the compound according to the present invention can be prepared as pharmaceutical compositions suitable for oral or parenteral administration.
  • Said pharmaceutical compositions can be formulated for oral administration as a powder, a granule, a tablet, a capsule, a syrup or a suspension; or for parenteral administration by injection as a solution, a emulsion or a suspension. It also can be formulated in a form suitable for administration by inhalation as an aerosol to be sprayed into respirator or for rectal administration as a suppository.
  • the pharmaceutical composition can be prepared by blending the compounds of the present invention as the active ingredient together with a pharmaceutically acceptable carrier, receptor, binding agent, stabilizer and diluent.
  • a pharmaceutically acceptable buffer solution, dissolution adjuvant or isotonic agent can be mixed with the composition of the present invention.
  • the dosage and time of administration will vary depending on the types of disease, disease state, age, weight and the type of administration.
  • daily dosage of 0.1 ⁇ 2000mg for an adult, preferably 1 ⁇ 200 mg is administered once daily or several times a day divided in equal amount.
  • composition according to the present invention is non-toxic.
  • a white solid (0.40g, 70%) was obtained by reacting 6-cyclohexyl-3-methyl-4- phenyl-pyrane-2-one (0.54g, 2.01 mmol) in the same manner as in Example 1 (e).
  • 3-Oxo-butyric acid ethyl ester (4.5 lg, 0.0347mol) was dissolved in diethyl ether (50mL) and then cooled down to -78 ° C .
  • LDA lithium diisopropylamide
  • N,N,N',N'- Tetramethylethylenediamine (4.03g, 0.0337mol) was slowly added dropwise and stirred while elevating temperature to 0 ° C over 3 hours.
  • reaction solution was cooled down to room temperature, the solvent was distilled off under reduced pressure followed by adding water (200mL), and the resulting solution was stirred at room temperature for 2 hours.
  • the reaction solution was then acidified with 2N HC1 aqueous solution and extracted twice with ethyl acetate (200mL). The extract was dried over MgSO 4 , filtered, and distilled under reduced pressure.
  • the resulting residue was purified by the column chromatography on silica gel using n-hexane:ethylacetate (2 : 1) as eluent. The fractions containing the product were then combined and evaporated to give a colorless liquid (7.5g, 44%).
  • 6-Cycloheptyl-4-imidazole-l-yl-lH-pyridine-2-one (630mg, 2.44mmol) was dissolved in ethanol (20mL) in a lOOmL flask, and then hydrazine hydrate (1.2mL, 24.4mmol) was added dropwise thereto followed by stirring at room temperature for 24 hours.
  • the reaction solution was then distilled under reduced pressure. Subsequently, the residue was purified by column chromatography on silica gel using MC.MeOH (30:1) as eluent. The fractions containing the products were then combined and evaporated to give a milky solid (32.6g, 47%).
  • 6-Cyclohexyl-4-naphthalene-l-yl-pyrane-2-one 160mg, 0.525mmol was dissolved in a mixture solvent of EtOH (3mL) and MC (lmL) in a 50mL flask, and hydrazine hydrate (0.3mL, 5.25mmol) was added dropwise thereto. Then, the reaction solution was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography on silica gel using MC:MeOH (50:1) as eluent.
  • 6-Cyclohexyl-4-[l,2,3]triazol-l-yl-pyrane-2-one (184mg, 0.750mmol) was dissolved in EtOH (lOmL) in a 25mL flask, and hydrazine hydrate (0.4mL, 7.5mmol) was added dropwise thereto. After the reaction solution was stirred at room temperature for 24 hours, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel using hexane:ethylacetate (2:1) as eluent .
  • 6-Cyclohexyl-4-(4-methylimidazole)-l-yl-pyrane-2-one (165mg, 0.606mmol) was dissolved in EtOH (lOmL) in a 25mL flask. After hydrazine hydrate (0.3 lmL, 6.1mmol) was added dropwise thereto, the solution was stirred at room temperature for 24 hours. Then, the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography on silica gel using MC:MeOH (10:1) as eluent.
  • a yellow oil (0.13g, 63%) was obtained by reacting 4-bromo-6-cyclohexyl- pyrane-2-one (0.20g, 0.778mmol) with 2-methyl imidazole (0.19g, 2.33mmol) in the same manner as in Example 22 (a).
  • a yellow solid (126mg, 60%) was obtained by reacting 4-bromo-6-cyclohexyl- pyrane-2-one (0.20g, 0.778mmol) with 2-ethylimidazole (0.22g, 2.33mmol) in the same manner as in Example 22 (a).
  • ⁇ -NMR(CDC1 3 ); ⁇ 7.06(m, 1H), 6.98(m, 1H), 6.04(m, 2H), 2.80(q, 2H),
  • a white solid (35mg, 45%) was obtained by reacting 6-cyclohexyl-4-(2-ethyl- imidazole- l-yl)-lH-pyridine-2-one (80mg, 0.274mmol) in the same manner as in Example 1 (e).
  • a light yellow solid (60mg, 50%) was obtained by reacting l-(6-cyclohexyl-2- oxo-2H-pyrrane-4-yl)-lH-imidazole-4-carboxylic acid ethyl ester (0.12g, 0.379mmol) in the same manner as in Example 1 (e).
  • a yellow solid (0.15g, 66%) was obtained by reacting 4-bromo-6-cyclohexyl- pyrane-2-one (0.20g, 0.778mmol) with benzimidazole (0.18g, 1.55mmol) in the same manner as in Example 22 (a).
  • a white solid (13mg, 41%) was obtained by reacting 3-phenyl-isochromene-l-one (30mg, 0.13mmol) in the same manner as in Example 1 (e).
  • a white solid (52mg, 89%) was obtained by reacting 2-(l-benzoyl-2-oxo-propyl)- benzoic acid (43mg, 0.15mmol) in the same manner as in Example 34 (a).
  • a white solid (0.036g, 54%) was obtained by reacting 4-acetyl-3 -phenyl isochromene-1-one (0.06g, 0.13mmol) in the same manner as in Example 1 (e).
  • a 500mL flask was equipped with a reflux apparatus.
  • NaH 7.0g, 0.174mol
  • DME dimethoxyethane
  • DME dimethoxyethane
  • a solution of 4-methoxycyclohexane carboxylic acid methyl ester (lOg, 0.058mol) and 3-oxo-butyric acid ethyl ester (9.0g, 0.069mol) diluted with dimethoxyethane (DME: 70mL) was slowly added thereto over 30 minutes, and then the resulting solution was refluxed for 8 hours.
  • reaction solution was cooled down to room temperature, the solvent was distilled off under reduced pressure followed by adding water (70mL). Then, the solution was stirred at room temperature for 2 hours.
  • the reaction solution was acidified with 2N HC1 aqueous solution and was then extracted twice with ethyl acetate (lOOmL). The extract was dried over anhydrous MgSO 4 followed by filtration, and the filtrate was distilled under reduced pressure.
  • the residue was purified by column chromatography on silica gel using n-hexane:ethylacetate (1 :1) as eluent. The fractions containing the product were combined and evaporated to give a colorless liquid (10.22g, 73%).
  • Dimethyl formamide (DMF: 200 mL) was introduced in a 1000 mL flask and then cooled down to -10 ° C . Subsequently, a solution of PBr 3 (9.1mL, 0.097mol) diluted with ether (200mL) was added dropwise thereto over 60 minutes. After 30 minutes, a solution of 4-hydroxy-6-(4-methoxy-cyclohexyl)-pyrane-2-one (5.44g, 0.024mol) dissolved with DMF (lOOmL) was slowly added dropwise thereto over 30 minutes. After elevating the reaction temperature to 60 ° C, the solution was heated at the same temperature for 10 hours. The reaction solution was cooled down to room temperature followed by adding water.
  • Example 1 (d) 90% was obtained by reacting 4-bromo-6-cyclohexyl-pyrane-2-one (219mg, 0.817mmol) in the same manner as in Example 1 (d). Then, 200mg of the title compound was reacted in the same manner as in Example 1 (e) to obtain the title compound of 4-(l-amino-6- cyclohexyl-2-oxo-l ,2-dihydro-pyridine-4-yl)-benzonitrile (78mg, 37%).
  • a light yellow solid (13mg, 59%) was obtained by reacting N-[3-6-cyclohexyl-2- oxo-2H-pyrane-4-yl)-phenyl]-acetamide (21mg, 0.0674mmol) in the same manner as in Example 1 (e).
  • reaction solution was heated to the reflux temperature and stirred for 18 hours.
  • the solution was cooled down to room temperature and concentrated under reduced pressure.
  • the residue was purified by column chromatography on silica gel using n- hexane:ethylacetate (5:1) as eluent. The fractions containing the product were combined and evaporated to give a pale yellow solid (340mg, 63%).
  • a light yellow solid (98mg, 55%) was obtained by reacting 6-(6-cyclohexyl-2- oxo-2H-pyrane-4-yl)-nicotinonitrile (170mg, 0.606mmol) in the same manner as in Example 1 (e).
  • EXAMPLE 46 Synthesis of 1 -( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydro-pyridine-4-yl)- 1 H-imidazole-4- carboxlic acid methyl ester (Compound 51) a) Synthesis of l-(6-cyclohexyl-2-oxo-2H-pyrane-4-yl)-lH-imidazole-4-carboxlic acid methyl ester lH-Imidazole-4-carboxlic acid methyl ester (293.8mg, 2.33mmol), 4-bromo-6- cyclohexyl-pyrane-2-one (300mg, 1.17mmol) and potassium carbonate (483.8mg, 3.50mmol) were introduced into a 50mL flask, and the flask was then filled with nitrogen gas.
  • Lungs of a rat male, 200-300g was extracted and immediately placed into the buffer solution [50mM TRIS HCl (pH 6.5), 2mM EDTA, 5mM 2-mercaptoethanol, 2mM benzamidine and lO ⁇ M Leupeptin].
  • the extracted lungs were first cut into fine pieces with scissors and then homogenized by a polytron.
  • the homogenized lungs prepared as above were centrifuged by 35,000g for an hour.
  • the resulting supernatant was collected and then applied to diethylaminoethyl(DEAE)-sepharose column and PDE4 enzymes were eluted with a linearly increasing salt gradient running from 50mM to lOOOmM sodium acetate (Flow rate : 3mL/min., volume of the fractional distillation: 5mL).
  • PDE4 enzymes were eluted with a linearly increasing salt gradient running from 50mM to lOOOmM sodium acetate (Flow rate : 3mL/min., volume of the fractional distillation: 5mL).
  • bovine serum albumin To each fraction prepared as above was added bovine serum albumin to the final concentration of 0.1 % and fractions showing PDE4 activity were collected and stored until use.
  • the buffer solution for analysis was prepared [50mM TRIS HCl (pH 6.5), 5mM MgCl 2 , 4mM 2-mercaptoethanol and 0.15mg/mL bovine serum albumin (BSA)], and all the analyses were carried out in the presence of cGMP in order to inhibit any remaining, if any, PDE3 activity.
  • the final reaction volume was lOO ⁇ L and 0.25 ⁇ M [ 3 H]cAMP was added as a substrate.
  • the reaction was carried out at 30 ° C for 30 minutes and was terminated by placing the sample in boiling water bath for 1 min followed by a immediate transfer onto an ice bath.
  • Brain of a rat male, 200-300g was extracted and immediately placed into the buffer solution [50mM TRIS HCl (pH 8.0), 2mM MgCl 2 , O.lmM DTT and lO ⁇ M Leupeptin].
  • the brains were first cut into fine pieces with scissors and then homogenized by a polytron.
  • the homogenized brains prepared as above were centrifuged by 45,000g for an hour.
  • the resulting pellets were collected and resuspended in buffer solution [50mM TRIS HCl (pH 8.0), 2mM MgCl 2 ] and aliquoted and stored at -20 ° C until use.
  • the buffer solution for analysis was prepared [50mM TRIS HCl (pH 8.0), 5mM MgCl 2 and 0.05mM 5'-AMP] and the reactions were carried out in the final volume of 200 ⁇ L and 200 ⁇ g of homogenized brains was added to each well. Finally, [ 3 H]-( ⁇ ) Rolipram was added to the final concentration of 3nM thereto and the samples were incubated at 30 ° C for an hour. Subsequently the bound Rolipram was removed by passing the resulting solution through the filter by centrifugation (3000 rpm, 3minutes). The non-specific bindings were determined in the presence of lO ⁇ M RP73401. The radioactivity was then determined by liquid-scintillation counting. The decrease in the amount of radioactivity caused by the compounds according to the present invention was expressed in the percent of reduction at each concentration and the concentration of the compound at which it shows 50% inhibition (IC 50 ) was also calculated.
  • the compounds of the present invention exhibit potent PDE4 inhibition activity, and furthermore, they do not show any side effects such as nausea and emesis in the therapeutic dosage range. Therefore, the compounds according to the present invention can be useful for preventing the acute deterioration of lung function associated with COPD through the direct functional activities of bronchodilation and anti -inflammation as well as for curing the gradual deterioration of lung function associated with disease and thus improving the quality of life of the patients.

Abstract

The present invention relates to substituted 1H-pyridine-2-one derivatives of formula (1) and pharmaceutically acceptable salts thereof, which are useful for the treatment of chronic obstructive pulmonary disease, asthma, chronic bronchitis, psoriasis, ulcerative colitis, Crohn's disease (local ileitis), arteriosclerosis, rheumatoid arthritis, osteoporosis, bone arthritis, depression, memory loss, inflammation mediated by chronic necrosis and the others mediated by PDE4: (I)

Description

SUBSTITUTED 1H-PYRIDINE-2-ONE DERIVATIVES
TECHNICAL FIELD
The present invention relates to novel compounds, e.g., novel substituted 1H- pyridine-2-one derivatives useful for the preparation of medicine treating a variety of allergic or inflammatory diseases, particularly the disease where phosphodiesterase-4 inhibitors are used as main therapeutic agents. The medicine is useful particularly as an anti-inflammatory agent, an anti-allergic agent, a bronchodilator, an anti-asthmatic agent, or a TNF-α suppressor.
BACKGROUND OF THE INVENTION
Cyclic adenosine 3',5'-monophosphate (cAMP) acts as a second messenger within cells, and mediates cellular responses to many different primary signals such as hormone, neurotransmitter or autacoid. Many of the primary signals exert their effect through the enzymes that participate in the synthesis of cAMP, and the resulting increase in cAMP level produce markedly different effect in various types of cells for example, metabolysis, muscle contraction or secretions of cellular substances. The actual cellular responses to cAMP vary among different cell types.
Another point of regulation of cAMP level is the hydrolysis of cAMP to adenosine 5'-monophosphate. The hydrolysis reaction is catalyzed by cyclic nucleotide phosphodiesterases (PDE) resulting in the termination of cAMP's role as a messenger.
To date, 11 families of PDE have been identified in mammalian cells (named PDE 1 to 11), which were grouped into the corresponding family according to their specificity towards hydrolysis of cAMP or cGMP, their structures, their kinetic behaviors, their sensitivity to regulation by calcium, calmodulin or cGMP, and their selective inhibition by various compounds (for references, see Beavo J.A. et al (1990) Trends Pharmacol. Sci., 150-155; Beavo J.A. et al (1944); Molecular Pharmacol., 399-405). Among them, PDE4 is one of the cAMP-specific isoenzymes and it has been shown that its functions are inhibited by Rolipram.
The non-specific as well as specific PDE inhibitor compounds have been known. The non-specific PDE inhibitors as with the case of a particular methylxanthin such as theophyline act not only on PDEs residing in the target cells, but also on PDEs in other cells resulting in low remedy index. On the contrary, specific inhibitors work selectively so that some PDE families are inhibited selectively by various inhibitors. Therefore, hydrolysis of cyclic nucleotide is mitigated only in the cells where PDE families sensitive to certain inhibitors are found thus increasing the intracellular concentration of cAMP.
The specific advantageous properties of Phosphodiesterase 4 (PDE4) are known in many different types of tissues including central nervous system, heart, vascular endothelium, and smooth muscles of blood vessel, air route, bone marrow gland and lymph gland.
The increased level of cAMP in inflammatory cells results in the suppression of cell activities: the suppression of synthesis and the secretion of many intracellular substances in mast mastocyte, monocyte, polymorphonuclear acidophil and basophil, the suppression of chemical taxis and degranulation of polymorphonuclear neutrophil and acidophil, and the suppression of proliferation and differentiation of lymphocyte.
Cytokines, particularly TNFs(Tumor Necrosis Factor) and interleukins that are produced by various leucocytes such as T-lymphocytes and polymorphonuclear acidophils play an important role in the development of inflammatory state in cells, particularly hypersensitivity reaction induced by the allergen in the respiratory tract.
In addition, the cAMP introduced into the cells of airway causes the contraction of airway smooth muscle, and the PDE4 inhibitors cause the relaxation of the such contracted bronchi.
The chronic obstructive pulmonary disease (COPD) is a disease which develops and progresses gradually and is characterized by abnormalities in the lung structure that permanently obstruct airflow (related to the excessive inflammatory reactions in the respiratory tract and the increased number of neutrophils). Even though some symptoms of COPD can be relieved by using a bronchodilator, the damages in lungs are permanent in majority of cases.
The clinical symptoms of COPD varies from a recoverable simple bronchitis to an irrecoverable chronic respiratory failure depending on the severity of lung disease. Generally, two major distinct diseases are involved with COPD: emphysema and/or chronic bronchitis (associated with excessive inflammatory reactions in the respiratory tract and increased number of neutrophils).
Today, COPD is the fourth leading cause of death for people aged over 45 in the United States and the numbers are increasing worldwide. And it is also predicted that the numbers who suffer from COPD will be increased by three times in next ten years in countries such as China and Southeast Asia where male smoking rate is very high. Korea is also not an exception that considering the highest smoking rate in youth in the world, it is expected that there will be a steady increase in the prevalence rate of COPD for considerable periods of time. However, despite of its many serious problems associated, studies are still underway to understand the underlying mechanisms of COPD and thus the cure has yet to be discovered. Therefore the treatment is mainly focused on relieving the symptoms or slowing down its progression. Currently treatments available to help manage the disease include smoking cessation or medical treatments using drugs such as bronchodilators and anti-inflammatory agents, or both depending on the progression of the disease state. However, the progression of the disease is not substantially affected with those treatments described above.
On the other hand, in terms of pharmaceutical development, many efforts have been made to develop therapeutic agents based on the findings from studies of the various underlying mechanisms of COPD. However, much progress has not been made despite of the intensive efforts for the last 10 years and for example, clinical trials with neutrophil leukocyte elastase as a therapeutic agent were not very successful. Currently the development of pharmaceutical agents are towards treating the symptoms associated with COPD such as chronic coughs, shortness of breath, productive cough accompanied by a excessive mucus formation in airway and reducing the risk of chances to develop acute deterioration of lung function caused by COPD. Although therapeutic agents such as CCR5 receptor, LTB4 agonist, IL-8-regulating agent which are based on the new anti- inflammatory mechanism have been developed, there have been no clinical reports that shows good therapeutic effects on COPD as well as no reports on drug approval.
Recently, second generation of selective Phosphodiesterase 4 inhibitors has been proposed as a potentially effective therapeutic agents for COPD (for references, see Doherty, Chemical Biology 1999, 3:466-473; Mohammed et al., Anti-inflammatory & Immunology Investigational Drugs 1999 l(l):l-28 ; Schmidt et al., Clinical and Experimental Allergy, 29, supplement 2, 99-109). Among the various types of recently developed PDE4 inhibitors, it has been suggested that Ariflo from GSK (orally administered PDE4 inhibitor) has the potential to treat COPD (for references, see Nieman et al., Am. J. Respir. Crit. Care Med. 1998, 157: A413 ; Underwood et al., Eur. Respir. J. 1998, 12:86s; Compton et al., Am. J. Respir. Crit. Care Med. 1999, 159:A522). Further refer to the oral report by Compton in the conference of European Respiratory Society held in Madrid on October 12, 1999 as well as the oral report by Torphy and Underwood in the 4th world conference as to the inflammation held in Paris on June 27-30, 1999. Ariflo is currently under phase 3 clinical trial for the treatment of COPD.
However, it must be indicated that Ariflo has also many disadvantages. Particularly, it has been reported that there were severe side effects such as nausea and emesis in patients administered with 20mg of Ariflo (for references, see Murdoch et al., Am J Respir Crit Care Med 1998, 157:A409). Therefore the side effects observed in such a low dosage would severely restricted its therapeutic utility and cause much inconveniences to patient who have to take them on a daily basis.
Thus, the intensive studies have been done in various aspect of COPD to develop a potent and stable PDE4 inhibitor in recent several years. However, this was hampered by the fact that many potential PDE4 inhibitors have been shown not to be very selective so that they also have the activity on PDEs belong to other families. Moreover, there were reports that it is the inhibitory function on PDE4 in the central nervous system that causes the side effects such as nausea and emesis, even though underlying mechanisms are yet to be clarified. Considering the various functions exerted by cAMP, currently the major problems are the side effects at the therapeutic dosage range of PDE4 inhibitor and the less selectiveness of PDE4 inhibitors. Under these circumstances, the development of potent and selective PDE4 inhibitors are strongly desired, namely the inhibitors that do not have specificity on other family members of PDE, and that do not cause side effects in the therapeutic dosage range while maintaining the activity of preventing the acute deterioration of lung function associated with COPD through the direct functional activities of bronchodilation and anti-inflammation, and of curing the gradual deterioration of lung function associated with disease, thus improving the quality of life of the patients.
SUMMARY OF THE INVENTION
The present invention relates to substituted lH-pyridine-2-one derivatives of formula (1)
Figure imgf000007_0001
(1) as well as racemics, isomers and pharmaceutically acceptable salts thereof, in which:
R, is selected from the group consisting of C6-C12 aryl, C3-C8 cycloalkyl, and saturated or unsaturated C2-Cπ mono- or poly-heterocyclyl containing 1 to 3 heteroatoms, which may be substituted by one or two R7's;
R2 is selected from the group consisting of C6-C,2 aryl, C3-C8 cycloalkyl, and saturated or unsaturated C2-Cπ mono- or poly-heterocyclyl containing 1 to 3 heteroatoms, which may be substituted by one or two R8's; R3 and R4, which may be identical or different, are selected from the group consisting of hydrogen, C,-C6 alkyl, and C2-C7 alkylcarbonyl; R5 and R^, which may be identical or different, are selected from the group consisting of hydrogen, C,-C6 alkyl, C2-C7 alkylcarbonyl, and C2-C7 alkoxy carbonyl; R7 is selected from the group consisting of hydrogen, C,-C6 alkyl, C,-C6 alkoxy, C2-C7 alkoxycarbonyl, C6-C12 aryl, C,-C5 heteroaryl containing 1 to 4 heteroatoms, halogen, CN, CF3, CO2H, CONH2, CONHNH2, and NHCOCH3;
R8 is selected from the group consisting of hydrogen, C,-C6 alkyl, C,-C6 alkoxy, hydroxy, halogen, CN, and CO2H; R, and R4 may be selectively linked to form an aromatic ring. The compounds according to the present invention are useful as phosphodiesterase (PDE) enzyme inhibitors, particularly a PDE4 inhibitor, more particularly a selective inhibitor.
DETAILED DESCRIPTION OF THE INVENTION
Unless indicated otherwise, an alkyl group and an alkyl residue in the other groups (e.g., alkoxy) described in the invention may be linear or branched. Further, halogen includes fluorine, chlorine, bromine and iodine.
The C3-C8 cycloalkyl group used in the invention is, for example, preferably, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, most preferably, cyclohexyl.
The saturated or unsaturated C2-C„ mono- or poly-heterocyclyl group containing 1 to 3 heteroatoms used in the invention is, for example, preferably, thienyl, thiazolyl, imidazolyl, benzoimidazolyl, triazolyl, tetrahydropyranyl, pyridinyl, furanyl, pyranyl, pyrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, isothiazolyl, isooxazolyl, pyridazinyl, isobenzopyranyl, chromenyl, indolyl, indazolyl, quinolinyl, purinyl, pyrolinyl, chromanyl, pyrazolidinyl, piperidinyl, piperazinyl, most preferably, imidazolyl.
The C6-C12 aryl group used in the invention is, for example, preferably, phenyl, naphthyl, most preferably, phenyl. As representative examples of compounds of formula (1) according to the present invention, mention can be made of the following compounds: l-amino-6-cyclohexyl-4-phenyl-lH-pyridine-2-one (Compound 1); l-amino-4,6-bis(cyclohexyl)-lH-pyridine-2-one (Compound 2);
1 -amino-6-cyclohexyl-5-methyl-4-phenyl- 1 H-pyridine-2-one (Compound 3); l-amino-6-cyclohexyl-3-methyl-4-phenyl-lH-pyridine-2-one (Compound 4);
1 -amino-6-(2-methoxyphenyl)-4-phenyl- 1 H-pyridine-2-one (Compound 5);
1 -amino-6-(3-methoxyphenyl)-4-phenyl- 1 H-pyridine-2-one (Compound 6);
1 -amino-6-(4-fluorophenyl)-4-phenyl- 1 H-pyridine-2-one (Compound 7);
1 -amino-6-(3 ,4-dimethoxyphenyl)-4-phenyl- 1 H-pyridine-2-one (Compound 8) ; 1 -amino-4-phenyl-6-o-toyl- 1 H-pyridine-2-one (Compound 9); l-amino-6-cyclopropyl-4-phenyl-lH-pyridine-2-one (Compound 10); l-amino-6-cyclopentyl-4-phenyl-lH-pyridine-2-one (Compound 11);
1 -amino-4-phenyl-6-(tetrahydropyran-4-yl)- 1 H-pyridine-2-one (Compound 12); 1 -amino-6-(4-methoxyphenyl)-4-phenyl- 1 H-pyridine-2-one (Compound 13);
1 -amino-6-cycloheptyl-4-imidazole- 1 -yl- 1 H-pyridine-2-one (Compound 14);
1 -amino-4-(4-fluorophenyl)-6-phenyl- 1 H-pyridine-2-one (Compound 15); l-amino-4-cyclopentyl-6-phenyl-lH-pyridine-2-one (Compound 16); 1 -amino-6-cyclohexyl-4-naphthalene- 1 -yl- 1 H-pyridine-2-one (Compound 17); l-methylamino-4,6-diphenyl-lH-pyridine-2-one (Compound 18);
1 -amino-6-cyclohexyl-4-imidazole- 1 -yl- 1 H-pyridine-2-one (Compound 19);
1 -amino-6-cyclohexyl-4-[ 1 ,2,3]triazol- 1 -yl- 1 H-pyridine-2-one (Compound 20);
1 -amino-6-cyclopentyl-4-(imidazole)- 1 -yl- 1 H-pyridine-2-one (Compound 21); 1 -amino-6-cyclohexyl-4-( 1 ,2,4-triazol)- 1 -yl- 1 H-pyridine-2-one (Compound 22);
1 -amino-6-cyclohexyl-4-(3 -methylpyrol)- 1 -yl- 1 H-pyridine-2-one (Compound 23);
1 -amino-6-cyclohexyl-4-(4-methylimidazole)- 1 -yl- 1 H-pyridine-2-one (Compound 24); 1 -amino-6-cyclohexyl-4-(4-phenylimidazole)- 1 -yl- 1 H-pyridine-2-one (Compound
25); l-amino-6-cyclohexyl-4-pyrazol-l-yl-lH-pyridine-2-one (Compound 26);
1 -amino-6-cyclohexyl-4-(2-methylimidazole- 1 -yl)- 1 H-pyridine-2-one (Compound 27); 1 -amino-6-cyclohexyl-4-(2-ethylimidazole- 1 -yl)- 1 H-pyridine-2-one (Compound
28);
1 -(amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)- 1 H-imidazole-4- carboxylic acid hydrazide (Compound 29); l-amino-4-benzimidazole-l-yl-6-cyclohexyl-lH-pyridine-2-one (Compound 30);
2-amino-3-phenyl-2H-isoquinoline-l-one (Compound 31);
4-acetyl-2-amino-3-phenyl-2H-isoquinoline-l-one (Compound 32);
1 -amino-4-imidazole- 1 -yl-6-(4-methoxycyclohexyl)- 1 H-pyridine-2-one (Compound 33);
1 -amino-6-(4-hydroxycyclohexyl)-4-imidazole- 1 -yl- 1 H-pyridine-2-one (Compound 34);
4-(l-amino-2-oxo-6-phenyl-l,2-dihydropyridine-4-yl)-benzonitrile (Compound 35); 4-(l-amino-2-oxo-6-phenyl-l,2-dihydropyridine-4-yl)-benzoic acid (Compound
36);
4-( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)-benzonitrile (Compound 37);
4-( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)-benzoic acid (Compound 38);
4-( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)-benzaimde (Compound 39);
1 -amino-6-cyclohexyl-4-(4-trifluoromethylimidazole- 1 -yl)- 1 H-pyridine-2-one (Compound 40); 1 -( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)- 1 H-imidazole-4- carbonitrile (Compound 41);
1 -( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)- 1 H-imidazole-4- carboxylic acid amide (Compound 42); (6-cyclohexyl-4-imidazole- 1 -yl-2-oxo-2H-pyridine- 1 -yl)-carbamic acid methyl ester (Compound 43);
4-( 1 -amino-4-imidazole- 1 -yl-6-oxo- 1 ,6-dihydropyridine-2-yl)-cyclohexane- carbonitrile (Compound 44); 4-( 1 -amino-4-imidazole- 1 -yl-6-oxo- 1 ,6-dihydropyridine-2-yl)-cyclohexane- carboxylic acid (Compound 45); r-amino-6'-cyclohexyl-rH-[2,4']bipyridinyl-2'-one (Compound 46);
N-[3-( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)-phenyl]-acetarnide (Compound 47); 1 '-amino-6'-cyclohexyl-2'-oxo- 1 ',2'-dihydro-[2,4']bipyridinyl-5-carbonitrile
(Compound 48);
1 '-amino-6'-cyclohexyl-2'-oxo- 1 ',2'-dihydro-[2,4']bipyridinyl-5-carboxylic acid amide (Compound 49);
1 -(1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)- 1 H-imidazole-4- carboxylic acid (Compound 50);
1 -( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)- 1 H-imidazole-4- carboxylic acid methyl ester (Compound 51);
4-(l -amino-6-oxo-4-phenyl-l ,6-dihydropyridine-2-yl)-benzoic acid (Compound 52); 4-( 1 -amino-6-oxo-4-phenyl- 1 ,6-dihydropyridine-2-yl)-benzonitrile (Compound
53);
3-(l-amino-6-cyclohexyl-2-oxo-l,2-dihydropyridine-4-yl)-benzoic acid
(Compound 54); 3-(l-amino-6-cyclohexyl-2-oxo-l,2-dihydropyridine-4-yl)-benzonitrile (Compound 55); and
1 -amino-6-cy clohexyl-4-[4-(5H-tetrazol-5-yl)-phenyl]- 1 H-pyridine-2-one
(Compound 56). The compounds of formula (1) according to the present invention can also form pharmaceutically acceptable salts. Such pharmaceutically acceptable salts include acid addition salts produced by acids to form non-toxic acid addition salts containing pharmaceutically acceptable anion, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid and the like, organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid and the like, sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalsulfonic acid and the like, as well as salts with alkali metals such as sodium, potassium and the like. In addition, mention can be made of salts with other acids or bases which has been known and used in the art related to aromatic amidine derivatives or lactam derivatives. They are produced by a conventional conversion process.
Novel compounds of formula (1) as defined above can be prepared by the following method. Accordingly, another object of the present invention is to provide a method for producing compounds of formula (1).
More specifically, a compound of formula (1) can be produced by a process comprising the steps of:
Figure imgf000014_0001
(1) a) subjecting a compound of formula (9) to a condensation reaction
Figure imgf000014_0002
(9) with a compound of formula (8)
Figure imgf000014_0003
(8) to obtain a compound of formula (7),
Figure imgf000014_0004
(7) b) conducting a cyclization reaction of the compound of formula (7) to obtain a compound of formula (6),
Figure imgf000015_0001
(6) c) halogenating the compound of formula (6) to obtain a compound of formula (5),
Figure imgf000015_0002
(5) d) coupling the compound of formula (5) with a compound of formula (4)
R,-H
(4) to obtain a substituted compound of formula (3), and
Figure imgf000015_0003
(3) e) substituting the compound of formula (3) with a compound of formula (2)
R5R6N-NH2
(2) to obtain a compound of formula (1), wherein R„ R2, R3, R4, R5 and R6 are the same as defined above and X represents a reactive leaving group, preferably, hydroxy or halogen. The method for preparation is described more specifically hereinbelow.
The condensation reactions of a compound of formula (9) and a compound of formula (8) are carried out in the presence of an adequate solvent and condensing agent according to a conventional method. In the reaction, a conventional solvent which does not adversely affect the reaction can be generally employed as a solvent, and preferable examples are polar, aprotic solvent such as tetrahydrofuran, acetonitrile, dimethoxyethane, particularly preferably dimethoxyethane. The base added to the reaction is a conventional base such as potassium tert-butoxide, sodium ethoxide, sodium hydride, preferably sodium hydride. The reaction is carried out at temperature between room temperature and 100°C , preferably at 100°C for about 5 to 24 hours, preferably 8 hours.
The compound of formula (9) and the compound of formula (8) used as the starting materials can be prepared by referring to the methods described in the literatures :
[JACS. 89.25. 1967. 6623-6628; Tetrahedron, 52. 16. 1967. 5799-5804; Yakugaku Zashi,
87. 1967. 1209; Chem. Ber, 27. 1894. 1141], or are commercially available from the chemical company such as Sigma Aldrich, Merck etc.
In the next step, the compound of formula (7) obtained by the above-mentioned method is subjected to a cyclization according to a conventional method in the presence of an adequate solvent and a catalyst. In the reaction, a conventional solvent which does not adversely affect the reaction can be generally employed as a solvent, and preferable examples are a polar, aprotic solvent such as tetrahydrofuran, ethyl ether, dimethoxyethane, particularly preferably ethyl ether. As the catalyst, the general anhydride, preferably trifluoroacetyl anhydride is used to obtain cyclized alcoholic compounds of formula 6. The reaction is carried out at temperature between room temperature and 100°C , preferably at room temperature for about half an hour to 10 hours, preferably 2 hours.
To the compound of formula (6) is added a usual halogenating compound, preferably tribromophosphine in the mixture of solvents of dimethylformamide and ethyl ether to substitute an alcohol at 4-position of the reactant with Br and then bromide of formula (5) is obtained. The reaction is carried out at temperature between room temperature and 60 °C , preferably at 60 °C with the starting temperature being at 0°C for one hour to 24 hours, preferably 8 hours.
To the compound of formula (5) and the compound of formula 4 are added a base such as potassium carbonate, sodium hydrocarbonate, preferably potassium carbonate in aprotic solvent such as tetrahydrofuran, acetonitrile, diemethylformamide, preferably acetonitrile, in the present of a catalyst such as sodium iodide or potassium iodide, preferably potassium iodide to give the coupled compound of formula (3). The reaction is carried out at between room temperature and reflux condition, preferably at the reflux temperature for 2 to 20 hours, preferably 5 hours. To the compound of formula (3) is added the compound of formula (2) in a polar, aprotic solvent such as ethanol, methanol, water, dimethylformamide, preferably ethanol and the compound of formula (3) in the resulting mixture is substituted to obtain the compound of formula (1). The reaction is carried out at between room temperature and reflux condition, preferably at room temperature for 5 to 48 hours, preferably 8 hours. The processes as set forth above will be more specifically explained by examples hereinbelow.
On the other hand, the compound of formula (1) according to the present invention has an excellent selectivity and inhibitory activity on PDE4 as stated above. Accordingly, the present invention relates to PDE4 inhibitor composition comprising an effective amount of the compound of formula (1) as the active component, pharmaceutically acceptable salts thereof, stereochemical isomers and pharmaceutically acceptable carrier. As the compositions according to the present invention exhibit the strong inhibitory activity on PDE4, it is useful as a therapeutic agent to treat COPD, asthma, chronic bronchitis, psoriasis, ulcerative colitis, Crohn's disease (local ileitis), arteriosclerosis, rheumatoid arthritis, osteoporosis, bone arthritis, depression, memory loss, inflammation mediated by chronic necrosis and the others mediated by PDE4. The compound according to the present invention can be prepared as pharmaceutical compositions suitable for oral or parenteral administration. Said pharmaceutical compositions can be formulated for oral administration as a powder, a granule, a tablet, a capsule, a syrup or a suspension; or for parenteral administration by injection as a solution, a emulsion or a suspension. It also can be formulated in a form suitable for administration by inhalation as an aerosol to be sprayed into respirator or for rectal administration as a suppository.
The pharmaceutical composition can be prepared by blending the compounds of the present invention as the active ingredient together with a pharmaceutically acceptable carrier, receptor, binding agent, stabilizer and diluent. When the compounds of the present invention are employed in the form of an injection, a pharmaceutically acceptable buffer solution, dissolution adjuvant or isotonic agent can be mixed with the composition of the present invention.
The dosage and time of administration will vary depending on the types of disease, disease state, age, weight and the type of administration. For said composition, daily dosage of 0.1 ~2000mg for an adult, preferably 1 ~200 mg is administered once daily or several times a day divided in equal amount.
For the toxicity test, 10 mice were administered with lOOmg/kg of composition according to present invention and the condition of the mice was observed one day after the administration. All the mice survived and none of them has developed any severe disease indicating that the composition according to the present invention is non-toxic.
The present invention is described in more detail in reference to Examples, However, Examples are just to exemplify the embodiment of the present invention and thus the scope of the present invention is not limited to the examples by any means.
EXAMPLES EXAMPLE 1 Synthesis of l-amino-6-cyclohexyl-4-phenyl-lH-pyridine-2-one (Compound 1) a) Synthesis of 5-cyclohexyl-3,5-dioxo-pentanoic acid
NaH (42g, 1.053mol) was introduced into a 500mL flask equipped with the reflux apparatus, diluted with dimethoxyethane (DME, 250mL), and then heated up to 100°C under reflux. After an hour, a solution of cyclohexane carboxylic acid ethyl ester (50g, 0.351 mol) and 3-oxo-butyric acid ethyl ester (50g, 0.386mol) diluted with DME (250 mL) was slowly added over 30 minutes, and then refluxed for 8 hours. The reaction solution was cooled down to room temperature, and then the solvent was distilled off under reduced pressure followed by adding water (200mL). Then, the solution was stirred at room temperature for 2 hours, acidified with a 2N HC1 aqueous solution, and extracted twice with ethyl acetate (200mL). After the extract was dried over MgSO4 and filtered, the filtrate was distilled under reduced pressure. The residue was purified by column chromatography on silica gel using n-hexane:ethylacetate (1 : 1) as eluent. The fractions containing the product were combined and evaporated to dryness to give a colorless liquid (52g, 70%).
Η-NMR(CDC13); 5 = 5.63(s, lH), 3.35(s, lH), 2.15(m, 1H), 1.9-1.15(m, 10H).
MS(ESI); 213(M++1). b) Synthesis of 6-cyclohexyl-4-hydroxy-pyrane-2-one
In a 500mL flask, 5-cyclohexyl-3,5-dioxo-pentanoic acid (30g, 0.142 mol) was dissolved in ether (200mL), and the solution was cooled down to 0°C . Subsequently, trifluoroacetic acid anhydride [(TFA)2O: 40mL, 0.284mol] was slowly added dropwise over 30 minutes. After two hours, the reaction solution was distilled under reduced pressure, and the residue was purified by column chromatography on silica gel using methylene chloride (MC):methanol (MeOH) (30:1) as eluent. The fractions containing the product were combined and evaporated to give a milky solid (27g, 99%).
Η-NMR(CDC13); δ = 5.98(d, 1H), 5.08(d, lH), 2.44(m, 1H), 2.05- 1.10(m, 10H). MS(ESI); 195(M++1). c) Synthesis of 4-bromo-6-cyclohexyl-pyrane-2-one
Dimethyl formamide (DMF: lOmL) was introduced in a lOOmL flask, cooled down to -10°C , and subsequently, a PBr3 (0.7mL, 7.688mmol) solution diluted with ether
(lOmL) was added dropwise thereto over 10 minutes. After 10 minutes, a solution of 6- cyclohexyl-4-hydroxy-pyrane-2-one (373mg, 1.922mmol) dissolved in DMF (7mL) was slowly added dropwise over 30 minutes. The reaction solution was heated at 60 °C for 10 hours. After the reaction solution was cooled down to room temperature, water was added, and then the solution was extracted with ethyl acetate. After the extract was dried over MgSO4 and filtered, the filtrate was distilled under reduced pressure. The residue was purified by column chromatography on silica gel using n-hexane:ethylacetate (10:1) as eluent. The fractions containing the product were combined and evaporated to give a light yellow solid (241mg, 49%).
Η-NMR(CDC13); δ = 6.34(d, 1H), 5.88(d, 1H), 2.44(m, 1H), 2.05-1.10(m, 10H). MS(ESI); 258(M++1). d) Synthesis of 6-cyclohexyl-4-phenyl-pyrane-2-one 4-Bromo-6-cyclohexyl-pyrane-2-one (3.04g, 11.8mmol) was dissolved in a dried
THF (25mL), and Pd(PPh3)4 (300mg) was added thereto. Then, 0.5 M solution of phenyl zinc chloride (71mL, 17.7mmol).was added dropwise. After an hour, aqueous NH4C1 (20mL) was added, and the mixture solution was extracted twice with ethyl acetate (lOOmL). After the extract was dried over MgSO4 and filtered, the filtrate was distilled under reduced pressure. The residue was purified by column chromatography on silica gel using n-hexane:ethylacetate (5: 1) as eluent. The fractions containing the product were combined and evaporated to give white solid (2.15g, 71%).
Η-NMR CDCl,); δ = 7.58(m, 2H), 7.48(m, 3H), 6.75(d, 1H), 6.43(d, 1H), 3.33(m, 1H), 2.02-1.15(m, 10H). MS(ESI); 255(M++1). e) Synthesis of l-amino-6-cyclohexyl-4-phenyl-lH-pyridine-2-one 6-Cyclohexyl-4-phenyl-pyrane-2-one (2.0g, 7.874mmol) was dissolved in ethanol
(50mL). After hydrazine hydrate (4.0mL, 78.74mmol) was added dropwise thereto, the solution was stirred at room temperature for 10 hours. The reaction solution was distilled under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (50:1) as eluent. The fractions containing the product were combined and evaporated to dryness to give milky solid (1.42g, 68%). Η-NMR(CDC13); δ = 7.58(m, 2H), 7.48(m, 3H), 6.75(d, 1H), 6.43(d, 1H),
5.12(s, 2H), 3.33(m, 1H), 2.02-1.15(m, 10H).
MS(ESI); 269(M++1). EXAMPLE 2
Synthesis of l-amino-4,6-bis(cyclohexyl)-lH-pyridine-2-one (Compound 2) a) Synthesis of 4,6-bis(cyclohexyl)-pyrane-2-one
The title compound of 4,6-bis(cyclohexyl)-ρyrane-2-one (760mg, 89%) was obtained by reacting 4-bromo-6-cyclohexyl-pyrane-2-one (840mg, 3.27mmol) with cyclohexyl zinc chloride (25mL, 6.53mmol) in the same manner as in Example 1 (d).
Η-NMR(CDC13); δ = 5.92(s, 1H), 5.84(s, 1H), 2.37-2.32(m, 1H), 2.25-2.20(m, 1H), 1.97-1.70(m, 10H), 1.43-1.19(m, 10H). b) Synthesis of l-amino-4,6-bis(cyclohexyl)-lH-pyridine-2-one
The title compound of l-amino-4,6-bis(cyclohexyl)-lH-pyridine-2-one (91mg, 54%) was obtained by reacting 4,6-bis(cyclohexyl)-pyrane-2-one (160mg, 0.615mmol) in the same manner as in Example 1 (e). Η-NMR(CDC13); δ = 6.34(s, 1H), 5.93(s, 1H), 4.98(s, 2H), 3.19-3.08(m, 1H),
2.37-2.23(m, 1H), 1.98-1.65(m, 10H), 1.50-1.22(m, 10H).
MS(ESI); 275(M++1), 549(2M++1). EXAMPLE 3 Synthesis of l-amino-6-cyclohexyl-5-methyl-4-phenyl-lH-pyridine-2-one (Compound 3) a) Synthesis of 6-cyclohexyl-4-hydroxy-5-methyl-pyrane-2-one
The title compound of 6-cyclohexyl-4-hydroxy-5-methyl-pyrane-2-one (1.35g, 20%) was obtained by reacting cyclohexane carboxylic acid methyl ester (4.62g, 32.5mmol) with ethyl propioacetate (5.15g, 35.7mmol) in the same manner as in Example 1 (a).
Η-NMR(CDC13); δ = 5.61(s, 1H), 2.73-2.66(m, 1H), 1.96(s, 3H), 1.85-1.26(m, 10H). b) Synthesis of 4-bromo-6-cyclohexyl-5-methyl-pyrane-2-one The title compound of 4-bromo-6-cyclohexyl-5-methyl-pyrane-2-one (956mg,
54%) was obtained by reacting 6-cyclohexyl-4-hydroxy-5-methyl-pyrane-2-one (1.35g, 6.48mmol) in the same manner as in Example 1 (c).
Η-NMR(CDC13); δ = 6.57(s, 1H), 2.71-2.66(m, 1H), 2.13(s, 3H), 1.88-1.26(m, 10H). c) Synthesis of 6-cyclohexyl-5-methyl-4-phenyl-pyrane-2-one
The title compound of 6-cyclohexyl-5-methyl-4-phenyl-pyrane-2-one (360mg, 39%) was obtained by reacting 4-bromo-6-cyclohexyl-5-methyl-pyrane-2-one (940mg, 3.47mmol) in the same manner as in Example 1 (d).
Η-NMR(CDC13); δ = 7.44-7.23(m, 5H), 6.06(s, 1H), 2.74-2.69(m, 1H), 1.86(s, 3H), 1.78-1.26(m, 1 OH). d) Synthesis of l-amino-6-cyclohexyl-5-methyl-4-phenyl-lH-pyridine-2-one The title compound of l-amino-6-cyclohexyl-5-methyl-4-phenyl-lH-pyridine-2- one (191mg, 51%) was obtained by reacting 6-cyclohexyl-5-methyl-4-phenyl-pyrane-2- one (355mg, 1.32mmol) in the same manner as in Example 1 (e).
Η-NMR(CDC13); δ = 7.52-7.42(m, 5H), 6.18(s, 1H), 3.36-3.32(m, 1H), 2.04- l.ll(m, 10H), 1.58(s, 3H).
MS(ESI); 283(M++1). EXAMPLE 4
Synthesis of l-amino-6-cyclohexyl-3-methyl-4-phenyl-lH-pyridine-2-one (Cpompound 4) a) Synthesis of 6-cyclohexyl-4-hydroxy-3-methyl-pyrane-2-one
60%-NaH (4.65g, O.llόmol) was suspended in DME (70mL) and then heated to 70 °C under reflux. Subsequently, a solution of cyclohexane carboxylic acid methyl ester (5.00g, 0.0352mol) and 2-methyl-3-oxo-butyric acid ethyl ester (90%, 6.20g, 0.0387mol) diluted with DME (30mL) was added thereto over 45 minutes and then heated under reflux for 18 hours. After the resulting solution was cooled down to room temperature, the solvent was distilled off under reduced pressure. Then, water (50mL) was added thereto and the resulting solution was stirred for 2 hours. After a 2N HC1 solution was added thereto for acidification followed by extraction with ethyl acetate (50mL* 2), the resulting organic layer was washed with a saturated NaCl solution (50mL). The organic layer was dried over MgSO4, filtered, and then concentrated under a reduced pressure. The resulting residue was purified by recrystallization from ethyl acetate/n-hexane to obtain white solid (4.80g, 66%). Η-NMR(CDC13); δ = 8.46(brs, 1H), 6.02(s, 1H), 2.35(m, 1H), 1.96(s, 3H), 1.90-
1.15(m, 10H).
MS = 209[M+H], 231[M+Na]. b) Synthesis of 4-bromo-6-cyclohexyl-3-methyl-pyrane-2-one A white solid (1.89g, 75%) was obtained by reacting 6-cyclohexyl-4-hydroxy-3- methyl-pyrane-2-one (1.93g, 0.00927mol) in the same manner as in Example 1 (c).
Η-NMR(CDC13); δ = 6.14(s, lH), 2.40(m, 1H), 2.04(s, 3H), 1.95-1.20(m, 10H). c) Synthesis of 6-cyclohexyl-3-methyl-4-phenyl-pyrane-2-one A milky caramel-like substance (0.55g, 56%) was obtained by reacting 4-bromo-
6-cyclohexyl-3-methyl-pyrane-2-one (l.OOg, 3.69mmol) in the same manner as in Example 1 (d).
Η-NMR(CDC13); δ = 7.40(m, 4H), 7.30(m, 2H), 5.92(s, 1H), 2.40(m, 1H), 2.04(s, 3H), 1.98-1.70(m, 4H), 1.46-1.20(m, 6H). d) Synthesis of l-amino-6-cyclohexyl-3-methyl-4-phenyl-lH-pyridine-2-one
A white solid (0.40g, 70%) was obtained by reacting 6-cyclohexyl-3-methyl-4- phenyl-pyrane-2-one (0.54g, 2.01 mmol) in the same manner as in Example 1 (e).
Η-NMR(CDC13); δ = 7.38(m, 4H), 7.26(m, 2H), 6.00(s, 1H), 5.16(s, 2H), 3.16(m, 1H), 2.08(s, 3H), 1.99-1.74(m, 4H), 1.50-1.20(m, 6H). MS = 283[M+H], 565[2M+H].
EXAMPLE 5 Synthesis of l-amino-6-(2-methoxy-phenyl)-4-phenyl-lH-pyridine-2-one (Cpompound 5) a) Synthesis of 5-(2-methoxy-phenyl)-3,5-dioxo-pentanoic acid
The title compound of 5-(2-methoxy-phenyl)-3,5-dioxo-pentanoic acid (2.1g, 60%) was obtained by reacting 2-methoxy benzoic acid ethyl ester (5g, 0.03mol) with 3- oxo-butyric acid ethyl ester (2g, 0.015mol) in the same manner as in Example 1 (a). Η-NMR(CDC13); δ = 7.5-7.0(m, 4H), 6.4(s, 1H), 3.84(s, 3H), 3.5(s, 2H). b) Synthesis of 4-hydroxy-6-(2-methoxy-phenyl)-pyrane-2-one The title compound of 4-hydroxy-6-(2-methoxy-phenyl)pyrane-2-one (1.7g, 92%) was obtained by reacting 5-(2-methoxy-phenyl)-3,5-dioxo-pentanoic acid (2g, 8.474mmol) in the same manner as in Example 1 (b).
Η-NMR(CDC13); δ = 7.92(dd, 1H), 7.46(m, 1H), 7.0 l(m, 3H), 5.5(d, 1H), 3.94(s, 3H). c) Synthesis of 4-bromo-6-(2-methoxy-phenyl)-pyrane-2-one
The title compound of 4-bromo-6-(2-methoxy-phenyl)-pyrane-2-one (281mg, 46%) was obtained by reacting 4-hydroxy-6-(2-methoxy-phenyl)pyrane-2-one (300mg,1.376mmol) in the same manner as in Example 1 (c). 'H-NMR CDCh ; δ = 7.96(dd, 1H), 7.45(m, 1H), 7.33(d, 1H), 7.00(m, 2H),
6.55(d, 1H), 3.94(s, 3H). d) Synthesis of 6-(2-methoxy-phenyl)-pyrane-2-one
The title compound of 6-(2-methoxy-phenyl)-pyrane-2-one (72mg, 50%) was obtained by reacting 4-bromo-6-(2-methoxy-phenyl)pyrane-2-one (147mg,0.523mmol) in the same manner as in Example 1 (d).
Η-NMR(CDC13); δ = 8.1-6.9(m, 9H), 7.4(d, 1H), 6.48(d, 1H), 3.99(s, 3H). e) Synthesis of l-amino-6-(2-mcthoxy-phenyl)-4-phenyl-lH-pyridine-2-one
The title compound of l-amino-6-(2-methoxy-phenyl)-4-phenyl-lH-pyridine-2- one(36mg, 48%) was obtained by reacting 6-(2-methoxy-phenyl)pyrane-2-one(70mg, 0.25mmol) in the same manner as in Example 1 (e).
Η-NMR(CDC13); δ = 7.70-6.80(m, 10H), 6.40(m, 1H), 5.62(s, 2H), 3.94(s, 3H). MS(ESI); 293(M++1). EXAMPLE 6
Synthesis of l-amino-6-(3-methoxy-phenyl)-4-phenyl-lH-pyridine-2-one (Compound 6) a) Synthesis of 5-(3-methoxy-phenyl)-3,5-dioxo-pentanoic acid
The title compound of 5-(3-methoxy-phenyl)-3,5-dioxo-pentanoic acid (2.3g, 65%) was obtained by reacting 3-methoxy benzoic acid ethyl ester (5g, 0.03mol) in the same manner as in Example 1 (a).
Η-NMR(CDC13); δ = 7.50-7.00(m, 4H), 6.24(s, 1H), 3.87(s, 3H), 3.52(s, 2H). b) Synthesis of 4-hydroxy-6-(3-methoxy-phenyl)-pyrane-2-one
The title compound of 4-hydroxy-6-(3-methoxy-phenyl)pyrane-2-one (760mg, 91%) was obtained by reacting 5-(3-methoxy-phenyl)-3,5-dioxo-pentanoic acid (900mg, 3.81mmol) in the same manner as in Example 1 (b).
Η-NMR(CDC13); δ = 7.4(m, 3H), 7.06(m, 1H), 6.63(d, 1H), 6.37(d, 1H), 3.88(s, 3H). c) Synthesis of 6-(3-methoxy-phenyl)-4-phenyl-pyrane-2-one The compound of 4-bromo-6-(3-methoxy-phenyl)-pyrane-2-one (138mg, 36%) was obtained by reacting 4-hydroxy-6-(3-methoxy-phenyl)pyrane-2-one (300mg,1.376mmol) in the same manner as in Example 1 (c). Subsequently, the title compound of 6-(3-methoxy-phenyl)-4-phenyl-pyrane-2-one (86mg, 70%) was obtained by reacting 4-bromo-6-(3-methoxy-phenyl)-pyrane-2-one (124mg,0.441 mmol) in the same manner as in Example 1 (d).
Η-NMR(CDC13); δ - 7.7-7.3(m, 9H), 6.95(d, 1H), 6.49(d, 1H), 3.9(s, 3H). d) Synthesis of l-amino-6-(3-methoxy-phenyl)-4-phenyl-lH-pyridine-2-one
The title compound "of l-amino-6-(3-methoxy-phenyl)-4-phenyl-lH-pyridine-2- one (88mg, 68%) was obtained by reacting 6-(3-methoxy-phenyl)-4-phenyl-pyrane-2-one (125mg,0.449mmol) in the same manner as in Example 1 (e).
Η-NMR(CDC13); δ = 7.65-7.0(m, 9H), 6.88(d, 1H), 6.49(d, 1H), 5.38(s, 2H), 3.89(s, 3H). MS(ESI): 293(M++1).
EXAMPLE 7 Synthesis of l-amino-6-(4-fluoro-phenyl)-4-phenyl-lH-pyridine-2-one (Cpompound 7) a) Synthesis of 5-(4-fluoro-phenyl)-3,5-dioxo-pentanoic acid
The title compound of 6-(4-fluoro-phenyl)-4-phenyl-pyrane-2-one was obtained from 4-fluoro-benzoic acid ethyl ester by carrying out the same processes in order as in Example 1 (a), (b), (c) and (d).
Η-NMR(CDC13); δ = 7.92(m, 2H), 7.63(m, 2H), 7.50(m, 3H), 7.16(m, 2H), 6.94(d, 1H), 6.44(d, 1H).
MS(ESI): 267(M++1). b) Synthesis of l-amino-6-(4-fluoro-phenyl)-4-phenyl-lH-pyridine-2-one
The title compound of l-amino-6-(4-fluoro-phenyl)-4-phenyl-lH-pyridine-2-one (12mg, 64%) was obtained by reacting 6-(4-fluoro-phenyl)-4-phenyl-pyrane-2-one (18mg, 0.067mmol) in the same manner as in Example 1 (e).
Η-NMR(CDC13); δ = 7.60(m, 4H), 7.46(m, 3H), 7.14(m, 2H), 6.89(d, 1H), 6.45(d, 1H), 5.20(s, 2H).
MS(ESI): 281(M++1). EXAMPLE 8 Synthesis of l-amino-6-(3,4-dimethoxy-phenyl)-4-phenyl-lH-pyridine-2-one (Compound 8} a) Synthesis of 4-bromo-6-(3,4-dimethoxy-phenyl)-pyrane-2-one
The title compound of 4-bromo-6-(3,4-dimethoxy-phenyl)-pyrane-2-one was obtained from 3,4-dimethoxy-benzoic acid ethyl ester by carrying out the same processes in order as in Example 1 (a), (b) and (c)
Η-NMR(CDC13); δ = 7.43(d, 1H), 7.24(m, 1H), 6.65-6.41(m, 3H), 3.93(s, 3H), 3.84(s, 3H). b) Synthesis of 6-(3,4-dimethoxy-phenyl)-4-phenyl-pyrane-2-one
The title compound of 6-(3,4-dimethoxy-phenyl)-4-phenyl-pyrane-2-one (24mg, 81%) was obtained by reacting 4-bromo-6-(3,4-dimethoxy-phenyl)-pyrane-2-one (30mg, 0.096mmol) in the same manner as in Example 1 (d).
Η-NMR(CDC13); δ = 7.99(d, 1H), 7.63(m, 2H), 7.52(m, 3H), 7.36(d, 1H), 6.63(dd, 1H), 6.56(d, 1H), 6.48(d, 1H), 3.95(s, 3H), 3.89(s, 3H).
MS(ESI): 309(M++1). c) Synthesis of l-amino-6-(3,4-dimethoxy-phenyl)-4-phenyl-lH-pyridine-2-one
The title compound of l-amino-6-(3,4-dimethoxy-phenyl)-4-phenyl-lH-pyridine- 2-one(16mg, 75%) was obtained by reacting 6-(3,4-dimethoxy-phenyl)-4-phenyl-pyrane-2- one (20mg, 0.064mmol) in the same manner as in Example 1 (e).
'H-NMR CDCUJ; δ = 7.7-7.3(m, 5H), 6.89(d, 1H), 6.6(m, 2H), 6.43(d, 1H), 5.2(s, 2H), 3.78(s, 6H).
MS(ESI): 323(M++1). EXAMPLE 9 Synthesis of l-amino-4-phenyl-6-o-toyl-lH-pyridine-2-one (Compound 9) a) Synthesis of 4-hydroxy-6-o-toyl-pyrane-2-one
The title compound of 4-hydroxy-6-o-toyl-pyrane-2-one was obtained from 2- methoxy-benzoic acid ethyl ester by carrying out the same processes in order as in Example 1 (a) and (b). Η-NMR(CDC13); δ = 7.6-7.2(m, 4H), 6.45(s, 2H), 2.5(s, 3H). b) Synthesis of 4-bromo-6-o-toyl-pyrane-2-one
The title compound of 4-bromo-6-o-toyl-pyrane-2-one (300mg, 40%) was obtained by reacting 4-hydroxy-6-o-toyl-pyrane-2-one (546mg, 2.698mmol) in the same manner as in Example 1 (c). Η-NMR(CDC13); δ = 7.93(dd, 1H), 7.45(m, 1H), 7.33(d, 1H), 7.05(m, 2H),
6.54(d, 1H), 3.98(s, 3H). c) Synthesis of 4-phenyl-6-o-toyl-pyrane-2-one
The title compound of 4-phenyl-6-o-toyl-pyrane-2-one (147mg, 71%) was obtained by reacting 4-bromo-6-o-toyl-pyrane-2-one (210mg, 0.795mmol) in the same manner as in Example 1 (d).
Η-NMR(CDC13); δ = 7.7-6.8(m, 9H), 6.63(d, 1H), 6.5(d, 1H), 2.53(s, 3H). MS(ESI): 263(M++1). d) Synthesis of l-amino-4-phenyl-6-o-toyl-lH-pyridine-2-one
The title compound of l-amino-4-phenyl-6-o-toyl-lH-pyridine-2-one (102mg, 48%) was obtained by reacting 4-phenyl-6-o-toyl-pyrane-2-one (200mg, 0.763mmol) in the same manner as in Example 1 (e).
Η-NMR(CDC13); δ = 7.7-7.2(m, 9H), 6.92(d, 1H), 6.43(d, 1H), 5.24(s, 2H), 2.3(s, 3H). MS(ESI): 277(M++1). EXAMPLE 10 Synthesis of l-amino-6-cyclopropyl-4-phenyl-lH-pyridine-2-one (Compound 10) a) Synthesis of 5-cyclopropyl-3,5-dioxo-pentanoic acid The title compound of 5-cyclopropyl-3,5-dioxo-pentanoic acid (4.5g, 53%) was obtained by reacting cyclopropane carboxylic acid methyl ester (5g, 49.9mmol) in the same manner as in Example 1 (a).
Η-NMR(CDC13); δ = 5.74(s, 1H), 3.38(s, 2H), 1.67-1.62(m, 1H), 1.19-0.97(m, 4H). b) Synthesis of 4-bromo-6-cyclopropyl-pyrane-2-one
The intermediate of 6-cyclopropyl-4-hydroxy-pyrane-2-one (3.04g, 76%) was obtained by reacting 5-cyclopropyl-3,5-dioxo-pentanoic acid (4.5g, 26.4mmol) in the same manner as in Example 1 (b). Then, the title compound of 4-bromo-6-cyclopropyl-pyrane- 2-one (2.47g, 58%) was obtained by the reaction in the same manner as in Example 1 (c). Η-NMR(CDC13); δ = 6.37(d, 1H, J=1.5Hz), 6.25(s, 1H), 1.79-1.70(m, 1H),
1.16-0.99(m, 4H). c) Synthesis of 6-cyclopropyl-4-phenyl-pyrane-2-one
The title compound of 6-cyclopropyl-4-phenyl-pyrane-2-one (540mg, 78%) was obtained by reacting 4-bromo-6-cyclopropyl-pyrane-2-one (700mg, 3.26mmol) in the same manner as in Example 1 (d).
Η-NMR(CDC13); δ - 7.59-7.56(m, 2H), 7.50-7.46(m, 3H), 6.36(d, 1H, J=1.9Hz), 6.28(d, 1H, J=1.4Hz), 1.89-1.82(m, 1H), 1.18-0.99(m, 4H). d) Synthesis of l-amino-6-cyclopropyl-4-phenyl-lH-pyridine-2-one The title compound of l-amino-6-cyclopropyl-4-phenyl-lH-pyridine-2-one (114mg, 67%) was obtained by reacting 6-cyclopropyl-4-phenyl-pyrane-2-one (160mg, 0.754mmol) in the same manner as in Example 1 (e).
Η-N RCCDCla); δ = 7.55-7.41 (m, 5H), 6.72(d, 1H, J=2.0Hz), 6.14(d, 1H, J=1.8Hz), 5.53(s, 2H), 2.37-2.3 l(m, 1H), 1.18-0.82(m, 4H).
MS(ESI); 227(M++1). EXAMPLE 11 Synthesis of l-amino-6-cyclopentyl-4-phenyl-lH-pyridine-2-one (Cpompound 11) a) Synthesis of 5-cyclopentyl-3,5-dioxo-pentanoic acid The title compound of 5-cyclopentyl-3,5-dioxo-pentanoic acid (6.35g, 41%) was obtained by reacting cyclopentane carboxylic acid methyl ester (lOg, 78.0mmol) in the same manner as in Example 1 (a).
Η-NMR(CDC13); δ = 5.62(s, 1H), 3.43(s, 2H), 2.74-2.65(m, 1H), 1.85-1.56(m, 8H). b) Synthesis of 6-cyclopentyl-4-hydroxy-pyrane-2-one
The title compound of 6-cyclopentyl-4-hydroxy-pyrane-2-one (1.76g, 52%) was obtained by reacting 5-cyclopentyl-3,5-dioxo-pentanoic acid (3.7g,18.7mmol) in the same manner as in Example 1 (b).
Η-NMR(CDC13); δ = 6.01(s, 1H), 5.56(s, 1H), 2.90-2.85(m, 1H), 1.99-1.94(m, 2H), 1.79-1.63(m, 8H). c) Synthesis of 4-bromo-6-cyclopropyl-pyrane-2-one
The title compound of 4-bromo-6-cyclopentyl-pyrane-2-one (1.05g, 62%) was obtained by reacting 6-cyclopentyl-4-hydroxy-pyrane-2-one (1.25g, 6.94mmol) in the same manner as in Example 1 (c).
Η-NMR(CDC13); δ = 6.44(d, 1H, J=1.4Hz), 6.20(d, 1H, J=1.5Hz), 2.89-2.83(m, lH), 2.02-1.63(m, 8H). d) Synthesis of 6-cyclopentyl-4-phenyl-pyrane-2-one The title compound of 6-cyclopentyl-4-phenyl-pyrane-2-one (327mg, 33%) was obtained by reacting 4-bromo-6-cyclopentyl-pyrane-2-one (lg, 4.11 mmol) in the same manner as in Example 1 (d).
Η-NMR(CDC13); δ = 7.59-7.47(m, 5H), 6.36-6.32(m, 2H), 2.98-2.93(m, 1H), 2.07-1.70(m, 8H). e) Synthesis of l-amino-6-cyclopentyl-4-phenyl-lH-pyridine-2-one
The title compound of l-amino-6-cyclopentyl-4-phenyl-lH-pyridine-2-one (176mg, 52%) was obtained by reacting 6-cyclopentyl-4-phenyl-pyrane-2-one (320mg, 1.33mmol) in the same manner as in Example 1 (e).
Η-NMR(CDC13); δ - 7.58-7.43(m, 5H), 6.72(d, 1H, J=2.0Hz), 6.38(d, 1H, J=1.8Hz), 5.15(s, 2H), 3.62-3.57(m, 1H), 2.18-2.15(m, 2H), 1.84-1.66(m, 6H).
MS(ESI); 255(M++1). EXAMPLE 12 Synthesis of l-amino-4-phenyl-6-(tetrahydropyrane-4-yl)-lH-pyridine-2-one (Compound
IS a) Synthesis of 5-hydroxy-3-oxo-5-(tetrahydropyrane-4-yl)-pent-4-enoic acid ethyl ester
3-Oxo-butyric acid ethyl ester (4.5 lg, 0.0347mol) was dissolved in diethyl ether (50mL) and then cooled down to -78 °C . To the resulting solution, lithium diisopropylamide (LDA: 2.0M in hexane; 43.4mL, 0.0868mol) and N,N,N',N'- Tetramethylethylenediamine (4.03g, 0.0337mol) was slowly added dropwise and stirred while elevating temperature to 0°C over 3 hours. Subsequently, a solution of tetrahydropyrane-4-carboxylic acid methyl ester (5.00g, 0.0347mol) diluted with diethyl ether (50mL) was slowly added dropwise thereto and stirred at room temperature for 18 hours. Acetic acid (5mL) was then added to the reaction solution and stirred at room temperature for 10 minutes. Then, the precipitated solid was filtered and dried to obtain yellow solid (5.20g, 62%).
Η-NMR(CDC13); δ = 5.62(s, 1H), 4.20(m, 2H), 4.02(m, 2H), 3.48-3.36(m, 4H), 2.46(m, 1H), 1.80-1.70(m, 4H), 1.28(m, 3H). b) Synthesis of 4-hydroxy-3',4',5',6'-tetrahydro-2'H-[2,4']-bipyranyl-6-one
5-Hydroxy-3-oxo-5-(tetrahydropyrane-4-yl)-pent-4-enoic acid ethyl ester (2.50g, 0.0103mol) was heated to 150 — 160 °C under reduced pressure and stirred for 30 minutes. After the reaction solution was cooled down to room temperature, diethyl ether (15mL) was added thereto followed by stirring for 10 minutes. Subsequently, the precipitated solid was filtered, washed with diethyl ether, and then dried to obtain a yellow solid (1.24g, 61%).
Η-NMR(CDCl3+DMSO-d6); δ = 5.80(s, 1H), 5.45(s, 1H), 4.02(m, 2H), 3.45(m, 2H), 2.60(m, 1H), 1.86-1.65(m, 4H). c) Synthesis of 4-bromo-3',4',5',6'-tetrahydro-2'H-[2,4']-bipyranyl-6-one
The title compound as a yellow solid (1.30g, 79%) was obtained by reacting 4- hydroxy-3^4^5\6^etrahydro-2Η-[2,4']-bipyranyl-6-one (1.24g, 6.32mmol) in the same manner as in Example 1 (c). Η-NMR(CDC13); δ = 6.50(s, 1H), 6.16(s, 1H), 4.06(m, 2H), 3.46(m, 2H), 2.68(m, 1H), 1.88-1.68(m, 4H). d) Synthesis of 4-phenyl-3',4',5',6'-tetrahydro-2'H-[2,4']-bipyranyl-6-one
The title compound as a white solid (0.57g, 46%) was obtained by reacting 4- bromo-3',4,,5',6'-tetrahydro-2Η-[2,4,]-bipyranyl-6-one (1.25g, 4.82mol) in the same manner as in Example 1 (d).
Η-NMR(CDC13); δ = 7.56-7.42(m, 5H), 6.38(s, 1H), 6.26(s, 1H), 4.06(m, 2H), 3.46(m, 2H), 2.72(m, 1H), 1.96-1.75(m, 4H). e) Synthesis of l-amino-4-phenyl-6-(tetrahydro-pyrane-4-yl)-lH-pyridine-2-one The title compound as a light yellow solid (0.34g, 58%) was obtained by reacting
4-phenyl-3',4',5,,6'-tetrahydro-2Η-[2,4']-bipyranyl-6-one (0.56g, 2.18mmol) in the same manner as in Example 1 (e).
Η-NMR(CDC13); δ = 7.56-7.42(m, 5H), 6.74(s, 1H), 6.32(s, 1H), 4.98(s, 2H), 4.10(m, 2H), 3.62-3.45(m, 3H), 1.95-1.72(m, 4H). MS = 271[M+H], 293[M+Na].
EXAMPLE 13
Synthesis of l-amino-6-(4-methoxyphenyl)-4-phenyl-lH-pyridine-2-one (Compound 13) a) Synthesis of 4-bromo-6-(4-methoxyphenyl)-pyrane-2-one The title compound as a yellow solid (0.38g, 58%) was obtained by reacting 4- hydroxy-6-(4-methoxyphenyl)-pyrane-2-one (0.50g, 2.29mmol) in the same manner as in Example 1 (c).
Η-NMR(CDC13); δ =3.87(s, 3H), 6.49(d, 1H, J=1.7Hz), 6.72(d, 1H, J=1.7Hz), 6.94-6.99(m, 2H), 7.74-7.79(m, 2H). b) Synthesis of 6-(4-methoxyphenyl)-4-phenyl-pyrane-2-one
The title compound as a yellow solid (0.18g, 98%) was obtained by reacting 4- bromo-6-(4-methoxyphenyl)-ρyrane-2-one (0.18g, 0.65mmol) in the same manner as in Example 1 (d). Η-NMR(CDC13); δ = 3.88(s, 3H), 6.41(d, 1H, J=1.5Hz), 6.85(d, 1H, J=1.5Hz),
6.96-7.01(m, 2H), 7.49-7.53(m, 3H), 7.63-7.66(m, 2H), 7.83-7.88(m, 2H). c) Synthesis of l-amino-6-(4-methoxyphenyl)-4-phenyl-lH-pyridine-2-one
The title compound as a white solid (44mg, 42%) was obtained by reacting 6-(4- methoxyphenyl)-4-phenyl-pyrane-2-one (0.1 Og, 0.36mmol) in the same manner as in Example 1 (e).
Η-NMR(CDC13); δ = 3.85(s, 3H), 5.30(bs, 2H), 6.42(d, 1H, J=1.9Hz), 6.82(d, 1H, J=1.9Hz), 6.98(d, 2H, J=8.8Hz), 7.41-7.46(m, 3H), 7.51(d, 2H, J=8.8Hz), 7.55-7.59(m, 2H).
MS(ESI) : 293[M+H], 315[M+Na], 585[2M+H]. EXAMPLE 14
Synthesis of l-amino-6-cycloheptyl-4-imidazole-l-yl-lH-pyridine-2-one (Compound 14) a) Synthesis of 5-cycloheptyl-3,5-dioxo-pentanoic acid
To a 500mL flask equipped with a refluxing apparatus was added NaH (42g, 1.053mol), diluted with dimethoxy ethane (DME: 250mL) and then heated up to 100°C under reflux. After an hour, a solution of cycloheptane carboxylic acid ethyl ester (11.8g, 0.076mol) and 3-oxo-butyric acid ethyl ester (lOg, 0.076mol) diluted with DME (150mL) was slowly added thereto over 30 minutes and refluxed for 8 hours. After the reaction solution was cooled down to room temperature, the solvent was distilled off under reduced pressure followed by adding water (200mL), and the resulting solution was stirred at room temperature for 2 hours. The reaction solution was then acidified with 2N HC1 aqueous solution and extracted twice with ethyl acetate (200mL). The extract was dried over MgSO4, filtered, and distilled under reduced pressure. The resulting residue was purified by the column chromatography on silica gel using n-hexane:ethylacetate (2 : 1) as eluent. The fractions containing the product were then combined and evaporated to give a colorless liquid (7.5g, 44%).
Η-NMR(CDC13); δ = 5.58(s, 1H), 3.42(s, 1H), 2.35(m, 1H), 1.9-1.15(m, 12H).
MS(ESI); 223(M++1). b) Synthesis of 6-cycloheptyl-4-hydroxy-pyrane-2-one
5-Cycloheptyl-3,5-dioxo-pentanoic acid (7.0g, 30.97mmol) was dissolved in ether (lOOmL) in a 500mL flask and cooled down to 0°C . Subsequently, trifluoroacetic acid anhydride [(TFA)2O: 8.75mL, 61.9mmol] was slowly added dropwise over 30 minutes. After two hours, the reaction solution was distilled under reduced pressure, and the resulting residue was purified by column chromatography on silica gel using MC:MeOH (30:1) as eluent. The fractions containing the product were then combined and evaporated to give a milky solid (4.68g, 73%).
Η-NMR(CDC13); δ = 5.95(s, 1H), 5.02(s, 1H), 2.54(m, 1H), 2.00-1.40(m, 12H).
MS(ESI); 209(M++1). c) Synthesis of 4-bromo-6-cycloheptyl-pyrane-2-one
Dimethyl formamide (DMF: lOOmL) was added into a lOOmL flask and then cooled down to -10°C . Then, a solution of PBr3 (7.6mL, 80.76mmol) diluted with ether (50mL) was added dropwise thereto over 10 minutes. After 10 minutes, a solution of 6- cycloheptyl-4-hydroxy-pyrane-2-one (4.2g, 20.19mmol) dissolved in DMF (40mL) was slowly added dropwise thereto over 30 minutes. The reaction temperature was then elevated to 60 °C, and the solution was heated at the same temperature for 10 hours. Subsequently, the reaction solution was cooled down to room temperature and water was added thereto followed by an extraction with ethyl acetate. The resulting extract was then dried over MgSO4 and filtered followed by distillation under reduced pressure. The resulting residue was purified by column chromatography on silica gel using n- hexane:ethylacetate (3 : 1) as eluent. The fractions containing the product were then combined and evaporated to give a light yellow solid (1.14g, 21%). Η-NMR(CDC13); δ - 6.48(s, 1H), 6.12(s, 1H), 2.52(m, 1H), 2.1-1.4(m, 12H).
MS(ESI); 272(M"+1). d) Synthesis of 6-cycloheptyl-4-imidazole-l-yl-lH-pyridine-2-one
4-Bromo-6-cycloheptyl-pyrane-2-one (1.14g, 4.2mmol) and imidazole (860mg, 12.62mmol) were dissolved in CH3CN (40mL) in a lOOmL flask, and then K2CO3 (1.74g, 12.6mmol) and KI (670mg, 4.2mmol) were added thereto followed by heating under reflux. After 8 hours, the reaction solution was cooled down to room temperature and filtered. The resulting filtrate was then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (30:1) as eluent. The fractions containing the product were then combined and evaporated to give a milky solid (672mg, 67%).
Η-NMR(CDC13); δ - 8.01(s, 1H), 7.3(m, 2H), 6.19(d, 1H), 6.12(d, 1H), 2.65(m, 1H), 2.15-I.41(m, 12H).
MS(ESI); 269(M++1). e) Synthesis of l-amino-6-cycloheptyl-4-imidazole-l-yl-lH-pyridine-2-one
6-Cycloheptyl-4-imidazole-l-yl-lH-pyridine-2-one (630mg, 2.44mmol) was dissolved in ethanol (20mL) in a lOOmL flask, and then hydrazine hydrate (1.2mL, 24.4mmol) was added dropwise thereto followed by stirring at room temperature for 24 hours. The reaction solution was then distilled under reduced pressure. Subsequently, the residue was purified by column chromatography on silica gel using MC.MeOH (30:1) as eluent. The fractions containing the products were then combined and evaporated to give a milky solid (32.6g, 47%).
Η-NMR(CDC13); δ = 8.12(s, 1H), 7.35(m, 2H), 6.32(d, 1H), 6.23(d, 1H), 2.7 l(m, 1H), 2.1-1.4(m, 12H).
MS(ESI); 283(M++1). EXAMPLE 15 Synthesis of l-amino-4-(4-fluorophenyl)-6-phenyl-lH-pyridine-2-one (Compound 15) a) Synthesis of 4-(4-fluorophenyl)-6-phenyl-pyrane-2-one The title compound of 4-(4-fluorophenyl)-6-phenyl-pyrane-2-one (37mg, 71%) was obtained by reacting 4-bromo-6-phenyl-pyrane-2-one (50mg, 0.199mmol) with 4- fluorophenyl zinc chloride (0.299mmol) in the same manner as in Example 1 (d).
Η-NMR(CDC13); δ = 7.9(m, 2H), 7.69(m, 2H), 7.52(m, 3H), 7.3(m, 2H), 6.95(d, 1H), 6.47(d, 1H). b) Synthesis of l-amino-4-(4-fluorophenyl)-6-phenyl-lH-pyridine-2-one
The title compound of l-amino-4-(4-fluoroρhenyl)-6-phenyl-lH-pyridine-2- one(21mg, 81%) was obtained by reacting 4-(4-fluorophenyl)-6-phenyl-pyrane-2-one (25mg, 0.0938mmol) in the same manner as in Example 1 (e). Η-NMR(CDC13); δ = 7.57(m, 7H), 7.15(m, 2H), 6.84(d, 1H), 6.43(d, 1H), 5.3(s, 2H).
MS(ESI): 281(M++1). EXAMPLE 16 Synthesis of l-amino-4-cyclopentyl-6-phenyl-lH-pyridine-2-one (Compound 16) a) Synthesis of 4-cyclopentyl-6-phenyl-pyrane-2-one
The title compound of 4-cyclopentyl-6-phenyl-pyrane-2-one (50mg, 52%) was obtained by reacting 4-bromo-6-phenyl-pyrane-2-one (103mg, 0.41 mmol) with cyclopentyl zinc chloride (0.615mmol) in the same manner as in Example 1 (d). Η-NMR(CDC13); δ = 7.84(m, 2H), 7.45(m, 3H), 6.57(d, 1H), 6.13(d, 1H),
2.85(m, 1H), 2.1(m, 2H), 1.9-1.55(m, 6H). b) Synthesis of l-amino-4-cyclopentyl-6-phenyl-lH-pyridine-2-one
The title compound of l-amino-4-cyclopentyl-6-phenyl-lH-pyridine-2-one (llmg, 66%) was obtained by reacting 4-cyclpentyl-6-phenyl-pyrane-2-one (15mg, 0.0624mmol) in the same manner as in Example 1 (e).
Η-NMR(CDC13); δ = 7.75(m, 2H), 7.5(m, 3H), 6.57(d, 1H), 6.13(d, 1H), 2.8(m, 1H), 2.2-1.5(m, 8H).
MS(ESI): 255(M++1). EXAMPLE 17 Synthesis of l-amino-6-cyclohexyl-4-naphthalene-l-yl-lH-pyridine-2-one (Compound 17) a) Synthesis of 6-cyclohexyl-4-naphthalene-l-yl-pyrane-2-one 4-Bromo-6-pyrane-2-one (126mg, 0.49mmol) was dissolved in THF (2.0mL) in a lOOmL flask, and Pd(PPh3)4 (20mg) was added thereto followed by stirring at room temperature. After 5 minutes, 2-naphthyl zinc chloride (lOmL, 2mmol, an excess amount) was slowly added and stirred further at room temperature for 1 day. To the reaction solution, NH4C1 aqueous solution (15mL) was added, and then the resulting solution was extracted twice with ethyl acetate (20mL each). The extract was dried over MgSO4 and then filtered. The filtrate was distilled under reduced pressure. The residue was purified by column chromatography on silica gel using n-hexane:ethylacetate (10:1) as eluent. The fractions containing the product were combined and evaporated to give the title compound of 6-cyclohexyl-4-naphthalene-l-yl-pyrane-2-one (143mg, 96%).
Η-NMR(CDC13); δ = 7.92(m, 3H), 7.54(m, 3H), 7.4(d, 1H), 6.8(d, 1H), 6.68(d, 1H), 2.5(m, 1H), 2.2-l.l(m, 10H).
MS(ESI): 305(M++1). b) Synthesis of l-amino-6-cyclohexyl-4-naphthalene-l-yl-lH-pyrane-2-one
6-Cyclohexyl-4-naphthalene-l-yl-pyrane-2-one (160mg, 0.525mmol) was dissolved in a mixture solvent of EtOH (3mL) and MC (lmL) in a 50mL flask, and hydrazine hydrate (0.3mL, 5.25mmol) was added dropwise thereto. Then, the reaction solution was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography on silica gel using MC:MeOH (50:1) as eluent. The fractions containing the product were combined and evaporated to give the title compound of l-amino-6-cyclohexyl-4- naphthalene- 1 -yl- 1 H-pyrane-2-one ( 128mg, 76%).
*H-NMR(CDC13); δ = 7.92(m, 3H), 7.6-7.4(m, 4H), 6.67(d, 1H), 6.35(d, 1H), 3.3(m, 1H), 2.1-I.l(m, 19H).
MS(ESI): 319(M++1). EXAMPLE 18
Synthesis of l-methylamino-4,6-diphenyl-lH-pyridine-2-one (Compound 18) l-Amino-4,6-diphenyl-lH-pyrane-2-one (30mg, 0.114mmol) and p- chlorosulfonyl methyl ether (24μL, 0.114mmol) were dissolved in CH3CN (15mL) in a 50mL flask and then stirred at 65 °C for 1 day. The reaction solution was cooled down to room temperature and then filtered. The separated residue was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethylacetate:hexane (4:1) as eluent. The fractions containing the product were combined and evaporated to give the title compound of l-methylamino-4,6-diphenyl-lH-pyridine-2-one (17mg, 55%).
1H-NMR(CDC13); δ = 7.68-7.56(m, 5H), 7.52-7.40(m, 5H), 6.90(s, 1H), 6.44(s, 1H), 2.44(d, 3H). EXAMPLE 19 Synthesis of l-amino-6-cyclohexyl-4-imidazole-l-yl-lH-pyridine-2-one (Compound 19) a) Synthesis of 6-cyclohexyl-4-imidazole-l-yl-lH-pyridine-2-one
4-Bromo-6-cyclohexyl-pyrane-2-one (2.18g, 9.727mmol) and imidazole (1.98g, 29.2mmol) were dissolved in CH3CN (lOOmL) in a 250mL flask. After K2CO3 (4.03g, 29.181mmol) and KI (161mg, 0.972mmol) were added thereto, the reaction solution was heated under reflux. After 8 hours, the solution was cooled down to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (30:1) as eluent. The fractions containing the product were combined and evaporated to give a milky solid (2.36g, 99%). Η-NMR(CDC13); δ = 8.1(s, 1H), 7.3(d, 1H), 6.15(d, 1H), 2.5(m, 1H), 2.15- 1.1 (m, 10H).
MS(ESI); 245(M++1). b) Synthesis of l-amino-6-cyclohexyl-4-imidazole-l-yl-lH-pyridine-2-one 6-Cyclohexyl-4-imidazole-l-yl-lH-pyridine-2-one (2.6g, lO.όmmol) was dissolved in a mixed solvent of EtOH (50mL) and MC (20mL) in a lOOmL flask. After hydrazine hydrate (5.4mL, 106.55mmol) was added dropwise thereto, the reaction solution was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (30:1) as eluent. The fractions containing the product were combined and evaporated to give a milky solid (1.92g, 70%).
Η-NMR(CDC13); δ = 7.92(s, 1H), 7.3(s, 1H), 7.2(s, 1H), 6.52(d, 1H), 6.16(d, 1H), 5.04(s, 1H), 3.3(m, 1H), 2.1-1.9(m, 5H), 1.6-1. l(m, 5H).
MS(ESI); 259(M++1). EXAMPLE 20
Synthesis of l-amino-6-cyclohexyl-4-[l,2,3]triazol-l-yl-lH-pyridine-2-one (Compound 20) a) Synthesis of 6-cyclohexyl-4-[l,2,3]triazol-l-yl-lH-pyrane-2-one
4-Bromo-6-pyrane-2-one (200mg, 0.778mmol) and lH-[l,2,3]triazol (135μL, 2.334mmol) were dissolved in CH3CN (15mL) in a 50mL flask. After K2CO3 (323mg,
2.334mmol) and KI (13mg) were added thereto, the reaction solution was stirred at 100°C for 3 hours. The reaction solution was cooled down to room temperature and then filtered.
The obtained residue was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using n-hexane:ethylacetate (5: 1) as eluent. The fractions containing the product were combined and evaporatied to give the title compound of 6-cyclohexyl-4-[l,2,3]triazol-l-yl- lH-pyrane-2-one (187mg, 100%). Η-NMR(CDC13); δ = 7.9(s, 2H), 6.9(d, 1H), 6.8(d, 1H), 2.5(m, 1H), 2.1(m, 2H),
1.9(m, 2H), 1.78(m, 1H), 1.6-1.2(m, 5H).
MS(ESI): 246(M++1). b) Synthesis of l-amino-6-cyclohexyl-4-[l,2,3]triazol-l-yl-lH-pyridine-2-one
6-Cyclohexyl-4-[l,2,3]triazol-l-yl-pyrane-2-one (184mg, 0.750mmol) was dissolved in EtOH (lOmL) in a 25mL flask, and hydrazine hydrate (0.4mL, 7.5mmol) was added dropwise thereto. After the reaction solution was stirred at room temperature for 24 hours, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel using hexane:ethylacetate (2:1) as eluent . The fractions containing the product were combined and evaporated to give the title compound of l-amino-6-cyclohexyl-4-[l,2,3]triazol-l-yl-lH-pyridine-2-one (1 lOmg, 55%).
'H-NMR (CDC13); δ = 7.88(s, 2H), 7.2(d, 1H), 6.94(d, 1H), 5.1(s, 2H), 3.3(m, 1H), 2.2-I.2(m, 10H).
MS(ESI ): 260(M++1). EXAMPLE 21 Synthesis of l-amino-6-cyclopentyl-4-(imidazole)-l-yl-lH-pyridine-2-one (Compound 21) a) Synthesis of 6-cyclopentyl-4-imidazole-l-yl-lH-pyridine-2-one
The title compound of 6-cyclopentyl-4-(imidazole)-l-yl-lH-pyridine-2-one (500mg, 65%) was obtained by reacting 4-bromo-6-cyclopentyl-pyrane-2-one (810mg, 3.33mmol) in the same manner as in Example 22 (a).
Η-NMR(CDC13); δ = 7.97(s, 1H), 7.30-7.25(m, 2H), 6.24(d, 1H, J=2.1Hz), 6.11(d, 1H, J=2.2Hz), 3.00-2.97(m, 1H), 2.08-1.63(m, 8H). b) Synthesis of l-amino-6-cyclopentyl-4-(imidazole)-l-yl-lH-pyridine-2-one The title compound of l-amino-6-cyclopentyl-4-(imidazole)-l-yl-lH-pyridine-2- one(296mg, 57%) was obtained by reacting 6-cyclopentyl-4-(imidazole)-l-yl-lH-pyridine- 2-one (490mg, 2.13mmol) in the same manner as in Example 1 (e).
Η-NMR(CDC13); δ = 7.92(s, 1H), 7.31-7.21(m, 2H), 6.50(d, 1H, J=2.0Hz), 6.22(d, 1H, J=1.9Hz), 5.08(s, 2H), 3.63-3.58(m, 1H), 2.28-1.60(m, 8H). MS(ESI); 245(M++1).
EXAMPLE 22
Synthesis of l-amino-6-cyclohexyl-4-(l,2,4-triazol)-l-yl-lH-pyridine-2-one (Compound 22)
' a) Synthesis of 6-cyclohexyl-4-(l,2,4-triazol)-l-yl-lH-pyridine-2-one The title compound of 6-cyclohexyl-4-(l,2,4-triazol)-l-yl-lH-pyridine-2- one(280mg, 98%) was obtained by reacting 4-bromo-6-cyclohexyl-pyrane-2-one (300mg, 1.17mmol) in the same manner as in Example 22 (a).
Η-NMR(CDC13); δ = 8.66(s, 1H), 8.14(s, 1H), 6.59(d, 1H, J=1.9Hz), 6.45(d, 1H, J=2.3Hz), 2.56-2.48(m, 1H), 2.05-1.22(m, 10H). b) Synthesis of l-amino-6-cyclohexyl-4-(l,2,4-triazol)-l-yl-lH-pyridine-2-one
The title compound of l-amino-6-cyclohexyl-4-(l,2,4-triazol)-l-yl-lH-pyridine- 2-one (159mg, 56%) was obtained by reacting 6-cyclohexyl-4-(l,2,4-triazol)-l-yl-lH- pyridine-2-one (268mg, 1.09mmol) in the same manner as in Example 1 (e). Η-NMR(CDC13); δ = 8.61(s, 1H), 8.1 l(s, 1H), 6.77(d, 1H, J=2.2Hz), 6.61(d, 1H, J=2.2Hz), 5.09(s, 2H), 3.32-3.25(m, 1H), 2.03-1.26(m, 10H).
MS(ESI); 260(M++1). EXAMPLE 23 Synthesis of 1 -amino-6-cyclohexyl-4-[3-(methyl)pyrrole]- 1 -yl- 1 H-pyridine-2-one (Compound 23) a) Synthesis of 6-cyclohexyl-4-[3-(methyl)pyrrole]-l-yl-lH-pyridine-2-one
The title compound of 6-cyclohexyl-4-[3-(methyl)pyrrole]-l-yl-lH-pyridine-2- one(237mg, 79%) was obtained by reacting 4-bromo-6-cyclohexyl-pyrane-2-one (300mg, 1.17mmol) in the same manner as in Example 22 (a).
Η-NMR(CDC13); δ = 7.63(d, 1H, J=1.5Hz), 6.75(d, 1H, J=1.5Hz), 6.26(s, 1H), 6.13(d, 1H, J=1.8Hz), 2.54(s, 3H), 2.52-2.48(m, 1H), 2.04-1.25(m, 10H). b) Synthesis of l-amino-6-cyclohexyl-4-[3-(methyl)pyrrole]l-yl-lH-pyridine-2- one The title compound of l-amino-6-cyclohexyl-4-[3-(methyl)pyrrole]-l-yl-lH- pyridine-2-one (120mg, 57%) was obtained by reacting 6-cyclohexyl-4-[3- (methyl)pyrrole]-l-yl-lH-pyridine-2-one (200mg, 0.774mmol) in the same manner as in Example 1 (e). lH-NMR(CDCl3); δ = 7.60(s, 1H), 6.58(d, 1H, J=2.6Hz), 6.52(d, 1H, J=2.6Hz), 6.22(s, 1H), 5.06(s, 2H), 3.25-3.21(m, 1H), 2.48(s, 3H), 2.04-1.24(m, 10H). MS(ESI); 273(M++1). EXAMPLE 24 Synthesis of 1 -amino-6-cyclohexyl-4-(4-methylimidazole)- 1 -yl- 1 H-pyridine-2-one (Compound 24) a) Synthesis of 6-cyclohexyl-4-(4-methylimidazole)- 1 -yl- 1 H-pyrane-2-one 4-Bromo-6-pyrane-2-one (200mg, 0.778mmol) and 4-methyl-imidazole (193μL,
2.334mmol) were dissolved in CH3CN (15mL) in a 50mL flask. After K2CO3 (323mg, 2.334mmol) and KI (13mg) were added thereto, the reaction solution was stirred at 100°C for 3 hours. The reaction solution was cooled down to room temperature and then filtered. The obtained residue was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (30:1) as eluent. The fractions containing the product were combined and evaporated to give the title compound of 6-cyclohexyl-4-(4- methylimidazole)-l-yl-lH-pyrane-2-one (165mg, 78%).
Η-NMR(CDC13); δ = 7.96(s, 1H), 7.76(s, 1H), 6.76(s, 1H,), 6.56(d, 1H, J=2.3Hz), 6.26(d, 1H), 2.56-2.40(m, 1H), 2.10-1.14(m, 10H). b) Synthesis of l-amino-6-cyclohexyl-4-(4-methylimidazole)-l-yl-lH-pyridine-2- one
6-Cyclohexyl-4-(4-methylimidazole)-l-yl-pyrane-2-one (165mg, 0.606mmol) was dissolved in EtOH (lOmL) in a 25mL flask. After hydrazine hydrate (0.3 lmL, 6.1mmol) was added dropwise thereto, the solution was stirred at room temperature for 24 hours. Then, the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography on silica gel using MC:MeOH (10:1) as eluent. The fractions containing the product were combined and evaporated to give the title compound of l-amino-6-cyclohexyl-4-(4-methylimidazole)-l-yl-lH-pyridine-2-one (lOOmg, 37%).
Η-NMR(CDC13); δ - 7.98(s, 1H), 7.80(s, 1H), 6.80(d, 1H, J=2.2Hz), 6.68(d, 1H, J=2.2Hz), 6.52(d, 1H), 5.09(s, 2H), 3.32-3.20(m, 1H), 2.08-1.20(m, 10H). EXAMPLE 25
Synthesis of 1 -amino-6-cyclohexyl-4-(4-phenylimidazole)- 1 -yl- 1 H-pyridine-2-one (Compound 25) a) Synthesis of 6-cyclohexyl-4-(4-phenylimidazole)- 1 -yl- 1 H-pyrane-2-one
The title compound of 6-cyclohexyl-4-(4-phenylimidazole)-l-yl-lH-pyrane-2-one (189mg, 76%) was obtained by reacting 4-bromo-6-cyclohexyl-pyrane-2-one (200mg, 0.78mmol) in the same manner as in Example 22 (a).
Η-NMR(CDC13); δ = 8.03(s, 1H), 7.90-7.78(d, 2H, J=1.5Hz), 7.58(s, 1H), 7.50- 7.35(m, 3H), 6.23(s, 1H), 6.15(s, 1H) 2.60-2.45(m, 1H), 2.10-1.16(m, 10H). b) Synthesis of l-amino-6-cyclohexyl-4-(4-phenylimidazole)-l-yl-lH-pyridine-2- one
The title compound of l-amino-6-cyclohexyl-4-(4-phenylimidazole)-l-yl-lH- pyridine-2-one (150mg, 45%) was obtained by reacting 6-cyclohexyl-4-(4-ρhenyl imidazole)-l-yl-lH-pyrane-2-one (189mg, 0.59mmol) in the same manner as in Example 1 (e).
'H-NMR CDCy; δ = 7.98(s, 1H), 7.90-7.80(d, 2H, J=1.5Hz), 7.58(s, 1H), 7.50- 7.35(m, 3H), 6.58(s, 1H), 6.23(s, 1H), 5.06(s, 2H), 3.36-3.25(m, 1H), 2.10-1.20(m, 10H). EXAMPLE 26 Synthesis of l-amino-6-cyclohexyl-4-pyrazole-l-yl-lH-pyridine-2-one (Compound 26) a) Synthesis of 6-cyclohexyl-4-pyrazole-l-yl-lH-pyrane-2-one
The title compound of 6-cyclohexyl-4-pyrazole-l-yl-lH-pyrane-2-one (130mg, 68%) was obtained by reacting 4-bromo-6-cyclohexyl-pyrane-2-one (200mg, 0.78mmol) in the same manner as in Example 22 (a).
Η-NMR(CDC13); δ = 7.96(s, 1H), 7.76(s, 1H), 6.76(s, 1H,), 6.56(d, 1H, J=2.3Hz), 6.26(d, 1H), 2.56-2.40(m, 1H), 2.10-1.14(m, 10H). b) Synthesis of l-amino-6-cyclohexyl-4-pyrazole-l-yl-lH-pyridine-2-one The title compound of l-amino-6-cyclohexyl-4-pyrazole-l-yl-lH-pyridine-2-one
(80mg, 31%) was obtained by reacting 6-cyclohexyl-4-pyrazole-l-yl-lH-pyane-2-one (200mg, 0.78mmol) in the same manner as in Example 1 (e).
Η-NMR(CDC13); δ = 7.98(s, 1H), 7.80(s, 1H), 6.80(d, 1H, J=2.2Hz), 6.68(d, 1H, J=2.2Hz), 6.52(d, 1H), 5.09(s, 2H), 3.32-3.20(m, 1H), 2.08-1.20(m, 10H). EXAMPLE 27
Synthesis of 1 -amino-6-cyclohexyl-4-(2-meτhylimidazole- 1 -yl)- 1 H-pyridine-2-one (Compound 27) a) Synthesis of 6-cyclohexyl-4-(2-methylimidazole- 1 -yl)- 1 H-pyridine-2-one
A yellow oil (0.13g, 63%) was obtained by reacting 4-bromo-6-cyclohexyl- pyrane-2-one (0.20g, 0.778mmol) with 2-methyl imidazole (0.19g, 2.33mmol) in the same manner as in Example 22 (a).
Η-NMR(CDC13); δ = 7.02(m, 2H), 6.04(s, 2H), 2.55(s, 3H), 2.48(m, 1H), 2.05- 1.75(m, 4H), 1.50-1.20(m, 6H). b) Synthesis of l-amino-6-cyclohexyl-4-(2-methylimidazole-l-yl)-lH-pyridine-2- one
A white solid (66mg, 57%) was obtained by reacting 6-cyclohexyl-4-(2- methylimidazole-l-yl)-lH-pyridine-2-one (O.l lg, 0.426mmol) in the same manner as in Example 1 (e). Η-NMR(CDC13); δ = 7.02(m, 2H), 6.42(s, 1H), 6.04(s, 1H), 5.06(s, 2H), 3.25(m, 1H), 2.46(s, 3H), 2.05-1.75(m, 4H), 1.50-1.20(m, 6H). EXAMPLE 28
Synthesis of l-amino-6-cyclohexyl-4-(2-ethylimidazole-l-yl)-lH-pyridine-2-one (Compound 28) a) Synthesis of 6-cyclohexyl-4-(2-ethylimidazole- 1 -yl)- 1 H-pyridine-2-one
A yellow solid (126mg, 60%) was obtained by reacting 4-bromo-6-cyclohexyl- pyrane-2-one (0.20g, 0.778mmol) with 2-ethylimidazole (0.22g, 2.33mmol) in the same manner as in Example 22 (a). Η-NMR(CDC13); δ = 7.06(m, 1H), 6.98(m, 1H), 6.04(m, 2H), 2.80(q, 2H),
2.50(m, 1H), 2.05-1.75(m, 4H), 1.50-1.20(m, 9H). b) Synthesis of l-amino-6-cyclohexyl-4-(2-ethyl-imidazole-l-yl)-lH-pyridine-2- one
A white solid (35mg, 45%) was obtained by reacting 6-cyclohexyl-4-(2-ethyl- imidazole- l-yl)-lH-pyridine-2-one (80mg, 0.274mmol) in the same manner as in Example 1 (e).
'H-NMRtCDCy; δ = 7.06(m, 1H), 6.96(m, 1H), 6.42(s, 1H), 6.05(s, 1H), 5.06(s, 2H), 3.25(m, 1H), 2.75(q, 2H), 2.05-1.75(m, 4H), 1.50-1.20(m, 9H). EXAMPLE 29 Synthesis of 1 -(amino-6-cyclohexyl-2-oxo- 1 ,2-dihydro-pyridine-4-yl)- 1 H-imidazole-4- carboxylic acid hydrazide (Compound 29) a) Synthesis of l-(6-cyclohexyl-2-oxo-2H-pyrane-4-yl)-lH-imidazole-4- carboxylic acid ethyl ester A pale yellow solid (125mg, 72%) was obtained by reacting 4-bromo-6- cyclohexyl-pyrane-2-one (0.14g, 0.546mmol) with lH-imidazole-4-carboxylic acid ethyl ester (0.15g, 1.09mmol) in the same manner as in Example 22 (a).
Η-NMR(CDC13); δ = 7.95(m, 2H), 6.18(m, 2H), 4.40(q, 2H), 2.50(m, 1H), 2.05- 1.70(m, 4H), 1.50-1.20(m, 9H). b) Synthesis of l-(amino-6-cyclohexyl-2-oxo-l,2-dihydro-pyridine-4-yl)-lH- imidazole-4-carboxylic acid hydrazide
A light yellow solid (60mg, 50%) was obtained by reacting l-(6-cyclohexyl-2- oxo-2H-pyrrane-4-yl)-lH-imidazole-4-carboxylic acid ethyl ester (0.12g, 0.379mmol) in the same manner as in Example 1 (e).
Η-NMR(CDC13); δ = 8.32(brs, 1H), 7.95(m, 1H), 7.86(m, 1H), 6.55(m, 1H), 6.15(m, 1H), 5.08(s, 2H), 4.05(brs, 2H), 3.26(m, 1H), 2.05-1.70(m, 4H), 1.50-1.20(m, 6H).
MS = 317[M+H], 339[M+Na]. EXAMPLE 30 Synthesis of l-amino-4-benzimidazole-l-yl-6-cyclohexyl-lH-pyridine-2-one (Compound 30) a) Synthesis of 4-benzimidazole-l-yl-6-cyclohexyl-pyrane-2-one
A yellow solid (0.15g, 66%) was obtained by reacting 4-bromo-6-cyclohexyl- pyrane-2-one (0.20g, 0.778mmol) with benzimidazole (0.18g, 1.55mmol) in the same manner as in Example 22 (a).
Η-NMR(CDC13); δ = 8.16(s, 1H), 7.85(m, 1H), 7.68(m, 1H), 7.40(m, 2H), 6.32(m, 2H), 2.55(m, 1H), 2.10-1.70(m, 4H), 1.55-1.25(m, 6H). b) Synthesis of l-amino-4-benzimidazole-l-yl-6-cyclohexyl-lH-pyridine-2-one A light yellow solid (75mg, 51%) was obtained by reacting 4-benzimidazole-l-yl- 6-cyclohexyl-pyrane-2-one (0.14g, 0.476mmol) in the same manner as in Example 1 (e).
Η-NMR CDCL ; δ = 8.15(s, 1H), 7.86(m, 1H), 7.65(m, 1H), 7.38(m, 2H), 6.66(m, 1H), 6.30(m, 1H), 5.06(s, 1H), 3.30(m, 1H), 2.05-1.75(m, 4H), 1.55-1.25(m, 6H). MS = 309[M+H], 331 [M+Na].
EXAMPLE 31 Synthesis of 2-amino-3-phenyl-2H-isoquinoline-l-one (Compound 31) a) Synthesis of 3-phenyl-isochromene-l-one 2-(2-Oxo-2-phenylethyl)-benzoic acid (O.057g, 0.24mmol) was dissolved in acetic anhydride ( OmL) and then refluxed for an hour. After the reaction solution was cooled to 0°C, a saturated solution of sodium bicarbonate and ethyl acetate were added thereto and then the organic layer was separated. The organic layer was washed with a saturated solution of sodium chloride, dried over anhydrous MgSO4, filtered, and then concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using ethylacetate/n-hexane (1 : 15) as eluent to give a white solid (30mg, 57%). 'H-NMR(CDC13); δ = 6.97(s, 1H), 7.40-7.53(m, 5H), 7.70-7.76(m, 1H), 7.87- 7.92(m, 2H), 8.32(d, 1H, J=8.2Hz). b) Synthesis of 2-amino-3-phenyl-2H-isoquinoline-l-one
A white solid (13mg, 41%) was obtained by reacting 3-phenyl-isochromene-l-one (30mg, 0.13mmol) in the same manner as in Example 1 (e).
Η-NMR(CDC13); δ = 4.06(s, 2H), 7.32(d, 1H, J=7.5Hz), 7.38-7.45(m, 4H), 7.54(dt, 1H, J=1.5 and 7.5Hz), 7.80-7.85(m, 2H), 8.03(d, 1H, J=7.9Hz), 8.81(s, 1H). MS (ESI) : 237[M+H], 473[2M+H]. EXAMPLE 32
Synthesis of 4-acetyl-2-amino-3-phenyl-2H-isoquinoline-l-one (Compound 32) a) Synthesis of 4-acetyl-3-phenyl-isochromene-l-one
A white solid (52mg, 89%) was obtained by reacting 2-(l-benzoyl-2-oxo-propyl)- benzoic acid (43mg, 0.15mmol) in the same manner as in Example 34 (a).
'H-NMR (CDC13); δ = 2.17(s, 3H), 7.13(d, 1H, J=8.1Hz), 7.48-7.53(m, 3H), 7.57-7.70(m, 2H), 7.93-7.96(m, 2H), 8.34(dd, 1H, J=1.0 and 7.9Hz). b) Synthesis of 4-acetyl-2-amino-3-phenyl-2H-isoquinoline-l-one
A white solid (0.036g, 54%) was obtained by reacting 4-acetyl-3 -phenyl isochromene-1-one (0.06g, 0.13mmol) in the same manner as in Example 1 (e).
'H-NMR (CDC13); δ = 2.37(s, 3H), 5.06(s, 2H), 7.20(d, 1H, J=7.6Hz), 7.41- 7.56(m, 5H), 7.91(d, 2H, J= 7.1Hz), 8.45(dd, 1H, J-1.3 and 7.6Hz).
MS (ESI): 279[M+H], 557[2M+H]. EXAMPLE 33 Synthesis of 1 -amino-6-(4-hydroxy-cyclohexyl-4-imidazole- 1 -yl- 1 H-pyridine-2-one a) Synthesis of 5-(4-methoxy-cyclohexyl)-3,5-dioxo-pentanoic acid
A 500mL flask was equipped with a reflux apparatus. Into the flask, NaH (7.0g, 0.174mol) was introduced, diluted with dimethoxyethane (DME: 180mL), and heated up to 100U under reflux. After an hour, a solution of 4-methoxycyclohexane carboxylic acid methyl ester (lOg, 0.058mol) and 3-oxo-butyric acid ethyl ester (9.0g, 0.069mol) diluted with dimethoxyethane (DME: 70mL) was slowly added thereto over 30 minutes, and then the resulting solution was refluxed for 8 hours. After the reaction solution was cooled down to room temperature, the solvent was distilled off under reduced pressure followed by adding water (70mL). Then, the solution was stirred at room temperature for 2 hours. The reaction solution was acidified with 2N HC1 aqueous solution and was then extracted twice with ethyl acetate (lOOmL). The extract was dried over anhydrous MgSO4 followed by filtration, and the filtrate was distilled under reduced pressure. The residue was purified by column chromatography on silica gel using n-hexane:ethylacetate (1 :1) as eluent. The fractions containing the product were combined and evaporated to give a colorless liquid (10.22g, 73%).
Η-NMR(CDC13); δ = 5.62(s, 2H), 5.25(s, 1H), 3.38(s, 3H), 3.17(m, 1H), 2.20- 1.07(m, 9H). b) Synthesis of 4-hydroxy-6-(4-methoxy-cyclohexyl)-pyrane-2-one
5-(4-Methoxy-cyclohexyl)-3,5-dioxo-pentanoic acid (95mg, 0.392mmol) was dissolved in ether (20mL) in a 500 mL flask, and the solution was cooled down to 0°C . Subsequently, trifluoroacetic anhydride [(TFA)2O; lllμL, 0.785mmol] was slowly added dropwise over a minutes. After 15 hours, the reaction solution was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using methylene chloride/methanol (MC:MeOH=20:l) as eluent. The fractions containing the product were combined and evaporated to give a milky solid (58mg, 67%).
Η-NMR(CDCl3); δ =5.96(s, 1H), 5.52(s, 1H), 3.50-3.24(ss, 3H), 3.15(m, 1H), 2.50-1.10(m, 9H). c) Synthesis of 4-bromo-6-(4-methoxy-cyclohexyl)-pyrane-2-one
Dimethyl formamide (DMF: 200 mL) was introduced in a 1000 mL flask and then cooled down to -10°C . Subsequently, a solution of PBr3 (9.1mL, 0.097mol) diluted with ether (200mL) was added dropwise thereto over 60 minutes. After 30 minutes, a solution of 4-hydroxy-6-(4-methoxy-cyclohexyl)-pyrane-2-one (5.44g, 0.024mol) dissolved with DMF (lOOmL) was slowly added dropwise thereto over 30 minutes. After elevating the reaction temperature to 60 °C, the solution was heated at the same temperature for 10 hours. The reaction solution was cooled down to room temperature followed by adding water. Then, the solution was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4 followed by filtration. The filtrate was distilled under reduced pressure. The residue was purified by column chromatography on silica gel using n-hexane:ethylacetate (10:1) as eluent. The fractions containing the product were combined and evaporated to give a light yellow solid (3.5g, 68%). Η-NMR(CDC13); δ =6.45(d, 1H), 6.16(d, 1H), 3.49(m, 1H), 3.30(s, 3H), 2.45(m,
1H), 2.02(m, 2H), 1.73(m, 4H), 1.47(m, 2H). d) Synthesis of 4-imidazole- 1 -yl-6-(4-methoxy-cyclohexyl)-pyrane-2-one 4-Bromo-6-(4-methoxy-cyclohexyl)-pyrane-2-one (2.10g, 7.31 mmol) and imidazole (1.52g, 21.95mmol) were dissolved in acetonitrile (50mL) in a 100 mL flask, and then K2CO3 (3.03g, 21.95mmol) and KI (121mg, 0.731 mmol) were added thereto. The resulting mixture was heated under reflux. After 15 hours, the reaction solution was cooled down to room temperature followed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using methylene chloride:methanol (20:1) as eluent. The fractions containing the product were combined and evaporated to obtain a white solid (2.01 g, 100%).
Η-NMR(CDC13); δ =7.97(s, 1H), 7.3(s, 2H), 7.22(s, 1H), 6.19(d,lH), 6.12(d, 1H), 3.37(s, 3H), 2.65-1. ll(m, 10H). e) Synthesis of l-amino-4-imidazole-l-yl-6-(4-methoxy-cyclohexyl)-lH-pyridine- 2-one (Compound 33)
4-Imidazole-l-yl-6-(4-methoxy-cyclohexyl)-pyrane-2-one (2.0g, 7.27mmol) was dissolved in ethanol (40mL). After hydrazine hydrate (3.64mL, 72.7mmol) was added dropwise thereto, the solution was stirred at room temperature for 10 hours. The reaction solution was distilled under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride:methanol (20:1) as eluent. The fractions containing the product were combined and evaporated to give a milky solid (1.24g, 61%)
Η-NMR(CDC13); δ = 7.9(d, 1H), 7.29(s, 1H), 7.2 l(s, 1H), 6.6 l(m, 1H), 6.20- 6.11(m, 1H), 5.03(d, 2H), 3.40-3.34(ss, 3H), 3.25(m, 1H), 2.30-1.30(m, 9H). f) Synthesis of l-amino-6-(4-hydroxy-cyclohexyl)-4-imidazole-l-yl-lH-pyridine- 2-one (Compound 34)
1 -Amino-4-imidazole- 1 -yl-6-(4-methoxy-cyclohexyl)- 1 H-pyridine-2-one ( 150mg, 0.52mmol) was dissolved in MC (1.3mL), and a solution of Nal (1.17g, 7.8mmol) and 15- crown-5 (617μL, 3.12mmol) diluted with MC (lOmL) was slowly added dropwise thereto. The solution was cooled down to -30 °C followed by the addition of BBr3 (391mg, 1.56mmol). The resulting solution was stirred at the same temperature for 3 hours, and then the reaction temperature was slowly elevated to room temperature. After the reaction was quenched by adding NaHCO3 aqueous solution (0.5mL), the residue was purified by column chromatography on silica gel using MC:MeOH (10:1) as eluent. The fractions containing the product were combined and evaporated to give a yellow solid (94mg, 66%).
'H-NMR (CDClj); 5 = 7.91 (s, 1H), 7.27(s, 1H), 7.20(s, 1H), 6.5 l(d, 1H), 6.13(d, 1H), 5.01(s, 2H), 3.49(s, 3H), 3.25(m, 1H), 2.05-0.5(m, 9H).
MS (ESI); 275(M++1). EXAMPLE 34
Synthesis of 4-(l -amino-2-oxo-6-phenyl-l ,2-dihydro-pyridine-4-yl)-benzoic acid a) Synthesis of 4-(2-oxo-6-phenyl-2H-pyrane-4-yl)-benzonitrile
4-Bromo-6-phenyl-pyrane-2-one (lOOOmg, 3.98mmol) was dissolved in a dried THF (25mL). After Pd(PPh3)4 (lOOmg) was added thereto, a 0.5M solution of 4- cyanophenyl zinc bromide (16mL, 7.96 mmol) was added dropwise. After an hour, ammonium chloride aqueous solution (20mL) was added thereto, and then the solution was extracted twice with ethyl acetate (lOOmL). The extract was dried over anhydrous MgSO4, filtered, and distilled under reduced pressure. The residue was purified by column chromatography on silica gel using n-hexane/ethylacetate (5:1) as eluent. The fractions containing the product were combined and evaporated to give a white solid(591mg, 54%). 'H-NMR (CDC13); δ = 8.17(d, 2H), 8.03(m, 4H), 7.54(m, 4H), 6.80(d, 1H).
MS (ESI); 274(M++1). b) Synthesis of 4-(l-amino-2-oxo-6-phenyl-l,2-dihydro-pyridine-4-yl)- benzonitrile (Compound 35)
4-(2-Oxo-6-phenyl-2H-pyrane-4-yl)-benzonitrile (150mg, 0.549mmol) was dissolved in ethanol (2mL) and MC (2mL). After hydrazine hydrate (137mg,
2.745mmol) was added dropwise thereto, the solution was stirred at 60 °C for 6 hours.
After 3 hours, the reaction solution was distilled under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (20:1) as eluent. The fractions containing the product were combined and evaporated to give a white solid (lOlmg, 64%).
Η-NMR(CDC13); δ = 7.82-7.41(m, 9H), 6.88(d, 1H), 6.42(d, 1H).
MS(ESI); 288(M++1). c) Synthesis of 4-(l-amino-2-oxo-6-phenyl-l,2-dihydro-pyridine-4-yl)-benzoic acid (Compound 36)
4-(l-Amino-2-oxo-6-phenyl-l,2-dihydro-pyridine-4-yl)-benzonitrile (6.0mg,
0.0208mmol) was dissolved in a cone. HC1 (4mL) and then heated up to 80 °C. After 12 hours, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (10:1) as eluent. The fractions containing the product were combined and evaporated to give a white solid (4.8mg, 75%).
'H-NMR (CDC13); δ = 8.25(d, 2H), 7.92(d, 2H), 7.78(m, 2H), 7.61(m, 3H), 7.03(d, 1H), 6.82(d, 1H). MS (ESI); 307(M++1).
EXAMPLE 35 Synthesis of 4-( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydro-pyridine-4-yl)-benzamide a) Synthesis of 4-(l-amino-6-cyclohexyl-2-oxo-l,2-dihydro-pyridine-4-yl)- benzonitrile (Compound 37) The compound of 4-(6-cyclohexyl-2-oxo-2H-pyrane-4-yl)-benzonitrile (206mg,
90%) was obtained by reacting 4-bromo-6-cyclohexyl-pyrane-2-one (219mg, 0.817mmol) in the same manner as in Example 1 (d). Then, 200mg of the title compound was reacted in the same manner as in Example 1 (e) to obtain the title compound of 4-(l-amino-6- cyclohexyl-2-oxo-l ,2-dihydro-pyridine-4-yl)-benzonitrile (78mg, 37%).
Η-NMR(CDC13); δ = 7.75(d, 2H), 7.65(d, 2H), 6.69(d, 1H), 6.35(d, 1H), 5.13(s, 2H), 3.26(m, 1H), 2.08-1.72(m, 5H), 1.60-1.20(m, 5H).
MS (ESI); 294(M++1). b) Synthesis of 4-(l-amino-6-cyclohexyl-2-oxo-l,2-dihydro-pyridine-4-yl)- benzoic acid (Compound 38)
4-( 1 - Amino-6-cyclohexyl-2-oxo- 1 ,2-dihydro-pyridine-4-yl)-benzonitrile (23mg,
0.078mmol) was dissolved in a cone. HC1 (lOmL) and heated to 110°C . After 3 hours, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (20:1) as eluent. The fractions containing the product were combined and evaporated to give a white solid (18mg, 74%).
Η-NMR(CDC13); δ = 8.2(d, 2H), 7.88(d, 2H), 6.88(d, 1H), 6.73(d, 1H), 2.3-1.5(m, 11H).
MS(ESI); 313(M++1). c) Synthesis of 4-(l-amino-6-cyclohexyl-2-oxo-l,2-dihydro-pyridine-4-yl)- benzamide (Compound 39)
4-( 1 -Amino-6-cyclohexyl-2-oxo- 1 ,2-dihydro-pyridine-4-yl)-benzonitrile (400mg,
1.364mmol) was dissolved in a cone. HC1 (35mL) and heated at 70 °C . After 4 hours, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (30:1) as eluent. The fractions containing the product were combined and evaporated to give a white solid (1 lOmg, 26%).
Η-NMR(CDC13); δ = 7.99(d, 2H), 7.70(d, 2H), 6.73(d, 1H), 6.53(d, 1H), 2.17- 1.40(m, 11H). MS(ESI); 312(M++1). EXAMPLE 36
Synthesis of 1 -amino-6-cyclohexyl-4-(4-trifluoromethyl-imidazole-l -yl)- 1 H-pyridine-2- one (Compound 40) a) Synthesis of 6-cyclohexyl-4-(4-trifluoromethyl-imidazole- 1 -yl)-pyrane-2-one
4-Bromo-6-cyclohexyl-pyrane-2-one (257mg, l.OOmmol) and 4-trifluoromethyl- lH-imidazole (204mg, 1.50mmol) were dissolved in acetonitrile (50mL) in a lOOmL flask, and K2CO3 (414mg, 3.00mmol) and KI (25mg, 10%w/w) were added thereto. The reaction solution was heated under reflux. After 15 hours, the reaction solution was cooled down to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using MC:MeOH (20:1) as eluent. The fractions containing the product were combined and evaporated to give a white solid (298mg, 96%).
Η-NMR(CDC13); δ = 7.99(s, 1H), 7.64(s, 1H), 6.17(dd, 2H), 2.53(m, 1H), 2.1- 1.2(m, 10H). b) Synthesis of l-amino-6-cyclohexyl-4-(4-trifluoromethyl-imidazole-l-yl)-lH- pyridine-2-one
6-Cyclohexyl-4-(4-trifluoromethyl-imidazole- 1 -yl)-pyrane-2-one (290mg,
0.929mmol) was dissolved in ethanol (lOmL) and MC (5mL). Hydrazine hydrate (465mg, 9.29mmol) was added dropwise, and the solution was then stirred at 60 °C for 6 hours. After 3 hours, the reaction solution was distilled under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (20:1) as eluent. The fractions containing the product were combined and evaporated to give a white solid (126mg, 38.7%).
Η-NMR(CDC13); δ = 7.70(s, 1H), 7.43(s, 1H), 6.64(d, 1H, J=9Hz), 6.43(d, 1H, J=9Hz), 2.07-1.26(m, 11 H). EXAMPLE 37 Synthesis of 1 -( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydro-pyridine-4-yl)- 1 H-imidazole-4- carboxylic acid amide a) Synthesis of l-(6-cyclohexyl-2-oxo-2H-pyrane-4-yl)-lH-imidazole-4- carbonitrile
4-Bromo-6-cyclohexyl-pyrane-2-one (915mg, 3.56mmol) and lH-imidazole-4- carbonitrile (276mg, 2.96mmol) were dissolved in acetonitrile (20mL) in a lOOmL flask. After K2CO3 (1.23g, 8.88mmol) and KI (91mg, 10%w/w) were added thereto, the reaction solution was heated under reflux. After 4 hours, the reaction solution was cooled down to room temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using MC:MeOH (20:1) as eluent. The fractions containing the product were combined and evaporated to give a white solid (271mg, 34%).
Η-NMR(CDC13); δ = 7.99(s, 1H), 7.86(s, 1H), 7.68(d, 1H), 7.63(d, 1H), 2.55(m, 1H), 2.1-I.2(m, 10H).
MS(ESI); 270(M++1). b) Synthesis of l-(l-amino-6-cyclohexyl-2-oxo-l,2-dihydro-pyridine-4-yl)-lH- imidazole-4-carbonitrile (Compound 41).
1 -(6-cyclohexyl-2-oxo-2H-pyrane-4-yl)- 1 H-imidazole-4-carbonitrile (270g,
1.003mmol) was dissolved in ethanol (20mL). After hydrazine hydrate (502mg, 10.03mmol) was added dropwise thereto, the reaction solution was stirred at room temperature for 4 hours. The reaction solution was distilled under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (30:1) as eluent. The fractions containing the product were combined and evaporated to give a milky solid (170mg, 60%).
Η-NMR(CDC13); δ = 8.49(s, 1H), 8.43(s, 1H), 6.70(d, 1H), 6.55(d, 1H), 2.3- 1.2(m, 11H).
MS(ESI); 284(M++1). c) Synthesis of l-(l-amino-6-cyclohexyl-2-oxo-l,2-dihydro-pyridine-4-yl)-lH- imidazole-4-carboxlic acid amide (Compound 42)
1 -(1 -Amino-6-cyclohexyl-2-oxo- 1 ,2-dihydro-pyridine-4-yl)- 1 H-imidazole-4- carbonitrile (17mg, 0.06mmol) was dissolved in a cone. HC1 (15mL) and then heated at 70 °C . After 4 hours, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (20:1) as eluent. The fractions containing the product were combined and evaporated to give a white solid (12mg, 66%).
Η-NMR(CDC13); δ = 9.2 l(s, 1H), 8.55(s, 1H), 6.73(d, 1H), 6.53(d, 1H), 2.21- 0.72(m, 11H).
MS(ESI); 302(M++1). EXAMPLE 38
Synthesis of (6-cyclohexyl-4-imidazole-l-yl-2-oxo-2H-pyridine-l-yl)-carbamic acid methyl ester (Compound 43)
1 -Amino-6-cyclohexyl-4-imidazole- 1 -yl- 1 H-pyridine-2-one ( 1 OOmg, 0.387mmol) was dissolved in MC (20mL). After triethylamine (108μL, 0.774mmol) and methylchloroformate (30.8 μL, 0.387mmol) were added thereto, the reaction solution was stirred at room temperature. After 14 hours, the solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (30:1) as eluent. The fractions containing the product were combined and evaporated to give a pale yellow solid (32mg, 26%).
Η-NMR(CDC13); δ = 7.16(s, 1H), 6.96(s, 1H), 6.87(s, 1H), 6.30(d, 1H), 6.12(s, 1H), 5.68(bs, 1H), 3.75(s, 3H), 3.23(m, 1H), 2.04-1.29(m, 10H). MS(ESI); 317(M++1). EXAMPLE 39
Synthesis of 4-(l -amino-4-imidazole- 1 -yl-6-oxo- 1 ,6-dihydro-pyridine-2-yl)-cyclohexane carbonitrile (Compound 44) a) Synthesis of 4-(4-hydrxy-6-oxo-6H-pyrane-2-yl)-cyclohexane carbonitrile
A flask was installed with the reflux equipment. Into the flask, NaH (9.08g, 0.227mol) was introduced and then diluted with dimethoxy ethane (DME: 80mL). The reaction solution was heated to 100C under reflux. After an hour, a solution of 4- cyanocyclohexane carboxylic acid methyl ester (11.5g, 0.0688mol) and 3-oxo-butyric acid ethyl ester (9.4g, 0.0722mol) diluted with DME (lOOmL) was slowly added thereto over 30 minutes and refluxed for 8 hours. The reaction solution was cooled down to room temperature. The solvent was distilled off under reduced pressure followed by adding water (200mL). Then, the solution was stirred at room temperature for 2 hours. The reaction solution was acidified with a 2N HC1 aqueous solution and was extracted twice with ethyl acetate (200mL). The extract was dried over anhydrous MgSO4 and filtered. The filtrate was distilled under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (30:1) as eluent. The fractions containing the product were combined and evaporated to obtain yellowish oil. The resulting yellowish oil was dissolved in ether (lOOmL). The solution was cooled down to 0°C, and then trifluoroacetic anhydride[(TFA) 2O): 13mL, 0.092mol] was slowly added dropwise thereto over 30 minutes. After 2 hours, the reaction solution was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (30:1) as eluent. The fractions containing the product were combined and evaporated to give a light brown solid (5.58g, 37%). Η-NMR(CDC13); δ =5.80(d, 1H), 5.35(d, 1H), 2.50-2.40(m, 3H), 2.28-2.20(m,
3H), 1.76-1.45(m, 4H). b) Synthesis of 4-(4-bromo-6-oxo-6H-pyrane-2-yl)-cyclohexane carbonitrile Into a flask, DMF (80mL) was introduced and cooled down to -10°C . Then, a solution of PBr3 (9.59mL, 0.102mol) diluted with ether (80mL) was slowly added dropwise thereto over 10 minutes. After 10 minutes, a solution of 4-(4-hydroxy-6-oxo- 6H-pyrane-2-yl)-cyclohexane carbonitrile (5.58g, 0.0255mol) dissolved in DMF (80mL) was slowly added dropwise thereto over 30 minutes. The reaction temperature was elevated to 60 °C , and the reaction solution was heated at the same temperature for 10 hours. The reaction solution was then cooled down to room temperature followed by adding water. The resulting solution was extracted with ethyl acetate. The extract was dried over anhydrous MgSO4 and filtered. The filtrate was distilled under reduced pressure. The residue was purified by column chromatography on silica gel using n-hexane/ethylacetate (4:1) as eluent. The fractions containing the product were combined and evaporated to give a light yellow solid (4.73g, 66%).
Η-NMR(CDC13); δ = 6.50(d, 1H), 6.15(d, 1H), 2.50-2.42(m, 2H), 2.28-2.22(m, 2H), 2.12-2.05(m, 2H), 1.75-1.42(m, 4H). c) Synthesis of 4-(4-imidazole-l-yl-6-oxo-6H-pyrane-2-yl)-cyclohexane carbonitrile
4-(4-Bromo-6-oxo-6H-pyrane-2-yl)-cyclohexane carbonitrile (3.09g, 0.01 lmol) and imidazole (1.50g, 0.022mol) were dissolved in acetonitrile (25mL) in a flask, and then K2CO3 (3.04g, 0.022mol) and KI (365mg, 0.0022mol) were added. The resulting solution was heated under reflux. After 8 hours, the reaction solution was cooled down to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using MC:MeOH (50:1) as eluent. The fractions containing the product were combined and evaporated to give a light yellow solid (2.2g, 75%).
Η-NMR(CDC13); δ = 7.98(m, 1H), 7.28-7.24(m, 2H), 6.18(d, 1H), 6.12(d, 1H), 2.60-2.48(m, 2H), 2.32-2.12(m, 4H), 1.78-1.52(m, 4H). d) Synthesis of 4-(l-amino-4-imidazole-l-yl-6-oxo-l,6-dihydro-pyridine-2-yl)- cyclohexane carbonitrile
4-(4-Imidazole- 1 -yl-6-oxo-6H-pyrane-2-yl)-cyclohexane carbonitrile (2.13g, 7.91 mmol) was dissolved in a mixed solvent of ethanol (lOmL) and MC (5mL). After hydrazine hydrate (4.3mL, 79.1 mmol) was added dropwise thereto, the resulting solution was stirred at room temperature for 24 hours. The reaction solution was distilled under reduced pressure. The residue was purified by column chromatography on silica gel using MC.'MeOH (30:1) as eluent. The fractions containing the product were combined and evaporated to give a light yellow solid (1.44g, 64%).
Η-NMR(CDC13); δ =7.90(s, IH), 7.22(s, IH), 7.12(s, IH), 6.52(d, IH), 6.18(d, IH), 4.92(s, 2H), 3.36-3.28(m, IH), 2.58-2.48(m, IH), 2.36-2.30(m, 2H), 2.20-2.14(m, 2H), 1.90-1.76(m, 2H), 1.50-1.38(m, 2H). MS(ESI); 284(M++1).
EXAMPLE 40
Synthesis of 4-( 1 -amino-4-imidazole- 1 -yl-6-oxo- 1 ,6-dihydro-pyridine-2-yl)-cyclohexane carboxylic acid (Compound 45) a) 4-( 1 -amino-4-imidazole- 1 -yl-6-oxo- 1 ,6-dihydro-pyridine-2-yl)-cy clohexane carboxylic acid
4-( 1 - Amino-4-imidazole- 1 -yl-6-oxo- 1 ,6-dihydro-pyridine-2-yl)-cyclohexane carbonitrile (lOOmg, 0.353mmol) was dissolved in a cone. HC1 (2mL) in a flask. The reaction solution was heated to 30 °C and stirred for 18 hours. Then, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (5:1) as eluent. The fractions containing the product were combined and evaporated to give a light yellow solid (60mg, 56%).
Η-NMR(MeOH-d4); δ =9.45(s, IH), 8.16(s, IH), 7.68(s, IH), 6.82(d, IH), 6.68(d, IH), 3.46-3.38(m, IH), 2.40-2.32(m, IH), 2.20-2.14(m, 2H), 2.08-2.00(m, 2H), 1.76- 1.54(m, 4H). MS(ESI); 303(M++1).
EXAMPLE 41 Synthesis of r-amino-6'-cyclohexyl-lΗ-[2,4']-bipyridinyl-2'-one (Compound 46) a) Synthesis of 6-cyclohexyl-4-pyridine-2-yl-pyrane-2-one 4-Bromo-6-cyclohexyl-pyrane-2-one (lOOmg, 0.389mmol) was dissolved in a dried THF (4mL). Pd(PPh3)4 (23mg, 0.0195mmol) was added, and then a 0.5M solution of 2-pyridyl zinc chloride (1.6mL, 0.778mmol) was added dropwise. After' the reaction solution was stirred at room temperature for 24 hours, an aqueous ammonium chloride solution (lOmL) was added thereto, and then the solution was extracted with ethyl acetate (50mL). The extract was dried over anhydrous MgSO4, filtered, and distilled under reduced pressure. The residue was purified by column chromatography on silica gel using n-hexane/ethylacetate (3:1) as eluent. The fractions containing the product were combined and evaporated to give a light yellow solid (80mg, 81%). Η-NMR(CDC13); δ = 8.76-8.72(m, IH), 7.84-7.72(m, 2H), 7.40-7.36(m, IH),
6.80(d, IH), 6.65(d, IH), 2.56-2.46(m, IH), 2.08-1.82(m, 4H), 1.55-1.20(m, 6H). b) Synthesis of -amino-6'-cyclohexyl-rH-[2,4']-bipyridinyl-2-one
6-Cyclohexyl-4-pyridine-2-yl-pyrane-2-one (75mg, 0.294mmol) was dissolved in a mixed solvent of ethanol (3mL) and MC (0.5mL). After hydrazine hydrate (0.32mL, 5.88mmol) was added dropwise thereto, the resulting solution was stirred at room temperature for 36 hours. Then, the reaction solution was distilled under reduced pressure and then purified by column chromatography on silica gel using MC:MeOH (30:1) as eluent. The fractions containing the product were combined and evaporated to give a light yellow solid (49mg, 62%). Η-NMR(CDC13); δ = 8.74-8.70(m, IH), 7.82-7.70(m, 2H), 7.34-7.30(m, IH),
7.02(d, IH), 6.90(d, IH), 5.16(s, 2H), 3.28-3.18(m, IH), 2.05-1.86(m, 4H), 1.55-1.22(m, 6H).
MS(ESI); 270(M++1). EXAMPLE 42
Synthesis of N-[3-(l-amino-6-cyclohexyl-2-oxo-l,2-dihydro-pyridine-4-yl)-phenyl]- acetamide (Compound 47) a) Synthesis of 6-cyclohexyl-4-(3-nitro-phenyl)-pyrane-2-one 4-Bromo-6-cyclohexyl-pyrane-2-one (500mg, 1.95mmol) was dissolved in dimethyl acetamide (DMA: 5mL). Then, 3-Nitrophenyl boric acid (490mg, 2.92mmol), Pd(OAc)2 (22mg, 0.098mmol), K3PO4 (830mg, 3.90mmol) and tetrabutylammonium bromide (130mg, 0.390mmol) were added thereto in order. The reaction solution was heated to 130°C and stirred for 3 hours. Then, the reaction solution was cooled down to room temperature followed by adding water (lOmL), and then extracted twice with ethyl acetate (50mL). The organic layer was washed with a saturated NaCl solution, dried over anhydrous MgSO4, filtered, and then distilled under reduced pressure. The residue was purified by column chromatography on silica gel using n-hexane/ethylacetate (3:1) as eluent. The fractions containing the product were combined and evaporated to give a light yellow solid (500mg, 86%).
Η-NMR(CDC13); δ = 8.42-8.34(m, 2H), 7.92-7.88(m, IH), 7.72-7.68(m, IH), 6.38(d, IH), 6.24(d, IH), 2.56-2.46(m, IH), 2.08-1.82(m, 4H), 1.56-1.22(m, 6H). b) Synthesis of 4-(3-amino-phenyl)-6-cyclohexyl-pyrane-2-one 6-Cyclohexyl-4-(3-nitro-phenyl)-pyrane-2-one (300mg, 1.002mmol) was dissolved in a mixed solvent of ethanol (lOmL) and ethyl acetate (5mL), and then 10%- Pd/C (15mg) was added thereto. The reaction mixture was stirred at room temperature under hydrogen stream for 3 hours. The resulting precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using n-hexane:ethylacetate (3:1) as eluent. The fractions containing the product were combined and evaporated to give a yellow solid (200mg, 74%).
Η-NMR(CDC13); δ = 7.24-7.20(m, IH), 6.96-6.92(m, IH), 6.84-6.76(m, 2H),
6.28(d, IH), 6.22(d, IH), 3.80(s, 2H), 2.50-2.42(m, IH), 2.05-1.82(m, 4H), 1.50-1.25(m, 6H). c) Synthesis of N-[3-(6-cyclohexyl-2-oxo-2H-pyrane-4-yl)-phenyl]-acetamide
4-(3-Amino-phenyl)-6-cyclohexyl-pyrane-2-one (30mg, O.ll lmmol) was dissolved in MC (2mL), and then N-methyl morpholine (0.025mL, 0.223mmol) was added thereto. The reaction solution was cooled down to 5 °C , and then acetyl chloride (O.OlmL, 0.134mmol) was slowly added dropwise. Then, the reaction solution was stirred at room temperature for 18 hours. Then, there was added water to the reaction solution followed by extraction with MC (20mL). The organic layer was dried over anhydrous MgSO4, filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using n-hexane:ethylacetate (1 :1) as eluent. The fractions containing the product were combined and evaporated to give light yellow solid
(21mg, 61%).
Η-NMR(CDC13); δ = 7.84(s, IH), 7.56-7.52(m, IH), 7.46-7.42(m, IH), 7.34- 7.28(m, 2H), 6.32(d, IH), 6.25(d, IH), 2.52-2.42(m, IH), 2.22(s, 3H), 2.05-1.82(m, 4H), 1.50-1.25(m, 6H). d) Synthesis of N-[3-(l-amino-6-cyclohexyl-2-oxo-l,2-dihydro-pyridine-4-yl)- phenyl]-acetamide
A light yellow solid (13mg, 59%) was obtained by reacting N-[3-6-cyclohexyl-2- oxo-2H-pyrane-4-yl)-phenyl]-acetamide (21mg, 0.0674mmol) in the same manner as in Example 1 (e).
Η-NMR(CDC13); δ = 7.72(s, IH), 7.58-7.54(m, IH), 7.42-7.28(m, 3H), 6.68(d, IH), 6.30(d, IH), 5.12(S, 2H), 3.26-3.18(m, IH), 2.20(s, 3H), 2.02-1.86(m, 4H), 1.50- 1.25(m, 6H). MS(ESI); 326(M++1).
EXAMPLE 43
Synthesis of 1 '-amino-6'-cyclohexyl-2'-oxo- 1 ',2'-dihydro-[2,4']-bipyridinyl-5-carbonitrile (Compound 48) a) Synthesis of 6-(6-cyclohexyl-2-oxo-2H-pyrane-4-yl)-nicotinonitrile 4-Bromo-6-cyclohexyl-pyrane-2-one (495mg, 1.925mmol) was dissolved in 1,4- dioxane (5mL), and then 6-bromo-nicotinonitrile (352mg, 1.925mmol), hexamethylditin (631mg, 1.925mmol) and Pd(PPh3) 4 (140mg, 0.122mmol) were added thereto in order. The reaction solution was heated to the reflux temperature and stirred for 18 hours. The solution was cooled down to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using n- hexane:ethylacetate (5:1) as eluent. The fractions containing the product were combined and evaporated to give a pale yellow solid (340mg, 63%).
Η-NMR(CDC13); δ = 8.98(d, IH), 8.08(dd, IH), 7.85(dd, IH), 6.76(d, IH), 6.72(d, IH), 2.56-2.46(m, IH), 2.08-2.02(m, 2H), 1.88-1.74(m, 3H), 1.50-1.22(m, 5H). b) Synthesis of -amino-6'-cyclohexyl-2'-oxo- ,2'-dihydro-[2',4']-bipyridinyl-5- carbonitrile
A light yellow solid (98mg, 55%) was obtained by reacting 6-(6-cyclohexyl-2- oxo-2H-pyrane-4-yl)-nicotinonitrile (170mg, 0.606mmol) in the same manner as in Example 1 (e).
Η-NMR(CDC13); δ = 8.98(d, IH), 8.04(dd, IH), 7.84(dd, IH), 7.06(d, IH), 6.86(d, IH), 5.20(s, 2H), 3.28-3.20(m, IH), 2.05-1.80(m, 5H), 1.50-1.22(m, 5H).
MS(ESI); 295(M++1). EXAMPLE 44
Synthesis of -amino-6'-cyclohexyl-2'-oxo-r,2'-dihydro-[2,4']-bipyridinyl-5-carboxlic acid amide (Compound 49) a) Synthesis of -amino-6'-cyclohexyl-2'-oxo-r,2'-dihydro-[2,4']-bipyridinyl-5- carboxlic acid amide -Amino-6'-cyclohexyl-2I-oxo- ,2,-dihydro-[2,4']-bipyridinyl-5-carbonitrile
(40mg, 0.136mmol) was dissolved in a cone. HC1 (lmL), and the solution was heated to 60 °C and stirred for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (20:1) as eluent. The fractions containing the product were combined and evaporated to give a light yellow solid (2 lmg, 49%).
Η-NMR(MeOH-d4); δ = 9.12(d, IH), 8.30(dd, IH), 7.84(dd, IH), 7.06(d, IH), 6.88(d, IH), 5.20(s, 2H), 3.28-3.20(m, IH), 2.05-1.80(m, 5H), 1.50-1.25(m, 5H).
MS(ESI); 313(M++1). EXAMPLE 45 Synthesis of 1 -( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydro-pyridine-4-yl)- 1 H-imidazole-4- carboxlic acid (Compound 50)
1 -( 1 -Amino-6-cyclohexyl-2-oxo- 1 ,2-dihydro-pyridine-4-yl)- 1 H-imidazole-4- carboxlic acid methyl ester (8.5mg, 0.027mmol) and a magnetic bar were introduced into a 10mL flask, and then the flask was filled with nitrogen gas. After the reactant was dissolved in methanol (0.5mL), a IN KOH (0.04mL, 0.04mmol) was added thereto, and then the resulting solution was stirred at room temperature for 2 hours. Then, the solvent was distilled under reduced pressure, and the residue was purified by HLPC. The fractions containing the product were combined and evaporated to give a white solid (4.2mg, 51%).
Η-NMR(CD3OD); δ =8.10(1H, m), 7.92(1H, m), 6.56(1H, m), 6.46(1H, m), 3.20(lH, m), 1.6(10H, m). EXAMPLE 46 Synthesis of 1 -( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydro-pyridine-4-yl)- 1 H-imidazole-4- carboxlic acid methyl ester (Compound 51) a) Synthesis of l-(6-cyclohexyl-2-oxo-2H-pyrane-4-yl)-lH-imidazole-4-carboxlic acid methyl ester lH-Imidazole-4-carboxlic acid methyl ester (293.8mg, 2.33mmol), 4-bromo-6- cyclohexyl-pyrane-2-one (300mg, 1.17mmol) and potassium carbonate (483.8mg, 3.50mmol) were introduced into a 50mL flask, and the flask was then filled with nitrogen gas. After acetonitrile (lOmL) was added thereto, the reaction solution was refluxed for 2 hours and then cooled down to room temperature. The precipitate was filtered off, and the filtrate was distilled under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (20:1) as eluent. The fractions containing the product were combined and evaporated to give a white solid (290mg, 82.2%).
Η-NMR(CDC13); δ =7.99(2H, m), 6.19(2H, m), 3.98(3H, s), 2.52(1H, m), 1.99(5H, m), 1.40(5H, m). b) Synthesis of l-(l-amino-6-cyclohexyl-2-oxo-l,2-dihydro-pyridine-4-yl)-lH- imidazole-4-carboxlic acid methyl ester
Into a lOmL flask, l-(6-cyclohexyl-2-oxo-2H-pyrane-4-yι)-lH-imidazole-4- carboxlic acid methyl ester (lOOmg, 0.333mmol) and a magnetic bar were introduced, and then the flask was filled with nitrogen gas. After the reactant was dissolved in dichloromethane (3mL) and ethanol (lmL), hydrazine hydrate (0.036mL) was added, and then the reaction solution was stirred at room temperature for 30 hours. The reaction solution was purified by column chromatography on silica gel using MC:MeOH (20:1) as eluent. The fractions containing the product were combined and evaporated to give a white solid (56mg, 53.0%).
Η-NMR(CDC13); δ =7.99(1H, m), 7.89(1H, m), 6.58(1H, m), 6.19(1H, m), 5.10(2H, s), 3.99(3H, s), 3.30(1H, m), 1.6(10H, m). EXAMPLE 47
Synthesis of 4-(l-amino-6-oxo-4-phenyl-l,6-dihydro-pyridine-2-yl)-benzoic acid (Compound 52)
Into a 50mL flask, 4-(l-amino-6-oxo-4-phenyl-l,6-dihydro-pyridine-2-yl)- benzonitrile (78mg, 0.27mmol) and a magnetic bar were introduced, and then the flask was filled with nitrogen gas. After a cone. HC1 was added thereto, the reaction solution was refluxed for 4 hours. Then, HC1 was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (10:1) as eluent. The fractions containing the product were combined and evaporated to give a white solid (47.4mg, 57%).
Η-NMR(CD3OD); δ =8.10(2H, m), 7.70(4H, m), 7.45(3H, m), 6.85(1 H, d, J=2.289), 6.68(1H, d, J=2.289). EXAMPLE 48
Synthesis of 4-(l-amino-6-oxo-4-phenyl-l,6-dihydro-pyridine-2-yl)-benzonitrile
(Compound 53) a) Synthesis of 4-(4-hydroxy-6-oxo-6H-pyrane-2-yl)-benzonitrile
The title compound of 4-(4-hydroxy-6-oxo-6H-pyrane-2-yl)-benzonitrile(26.5g, 95.7%) was produced by reacting 5-(4-cyano-phenyl)-3,5-dioxo-pentanoic acid (30g, 0.13mmol) in the same manner as in Example 1 (b).
'H-NMR(DMSO); δ =8.01(4H, m), 6.99(1H, d, J=1.907), 5.55(1H, d, J=1.907). b) Synthesis of 4-(4-bromo-6-oxo-6H-pyrane-2-yl)-benzonitrile
4-(4-hydroxy-6-oxo-6H-pyrane-2-yl)-benzonitrile (lOg, 23.4mmol), phosphorous pentaoxide (30.6g, 107.6mmol) and tetrabutylammonium bromide (16.6g, 51.4mmol) were introduced into a lOOOmL flask, and then toluene (300mL) was added thereto. The reaction solution was refluxed for 15 hours. After the solution was filtered over filter paper, a saturated NaHCO3 solution (lOOmL) was added thereto. The organic layer was washed once with brine (lOOmL). After the organic layer was filtered under reduced pressure, the residue was purified by column chromatography on silica gel using EA:Hex:MC (1:2:2) as eluent. The fractions containing the product were combined and evaporated to give a brown solid (8.67g, 67%). 'H-NMR(DMSO); δ =8.11(2H, m), 8.01(2H, m), 7.61(1H, d, J=1.526), 6.92(1H, d,
J=1.526). c) Synthesis of 4-(6-oxo-4-phenyl-6H-pyrane-2-yl)-benzonitrile
4-(4-Bromo-6-oxo-6H-pyrane-2-yl)-benzonitrile (2g, 7.24mmol), tributylphenyltin (2.36mL, 7.24mmol) and Pd(PPh3)4 (419mg, 0.05mmol) were introduced into a lOOmL flask. After DMF (40mL) was added thereto, the reaction solution was stirred at 110 °C for 12 hours, and then the solvent was distilled off under reduced pressure followed by adding water. The resulting solution was extracted with ethyl acetate. After the extract was dried over anhydrous MgSO4 and filtered, the filtrate was distilled under reduced pressure. The residue was purified by column chromatography on silica gel using E A/Hex (1:10) as eluent. The fractions containing the product were combined and evaporated to give a white solid (1.49g, 75.4%).
Η-NMR(CDC13); δ =8.01(2H, m), 7.79(2H, m), 7.64(2H, m), 7.54(3H, m), 7.05(1H, d, J=1.526), 6.56(1H, d, J=1.526). d) Synthesis of 4-(l-amino-6-oxo-4-phenyl-l,6-dihydro-pyridine-2-yl)- benzonitrile
Into a 50mL flask, 4-(6-oxo-4-phenyl-6H-pyrane-2-yl)-benzonitrile (lg, 3.66mmol) and a magnetic bar were introduced, and then the flask was filled with nitrogen gas, and then ethanol (lOmL) was added thereto. After hydrazine hydrate (3.57mL, 7.32mmol) was added, the reaction solution was stirred at 60 °C for 12 hours. The solution was distilled under reduced pressure. The residue was purified by column chromatography on silica gel using EA Hex MC (1 :5:5) as eluent. The fractions containing the product were combined and evaporated, and then was recrystallized from ethyl acetate/n-hexane to give a white solid (571mg, 51%).
Η-NMR(CDC13); δ =7.79(lH,m), 7.77(1H, m), 7.72(1H, m), 7.69(1H, m), 7.58(2H, m), 7.45(3H, m), 6.91(1H, d, J=1.907), 6.44(1H, d, J=1.907). EXAMPLE 49 Synthesis of 3-(l-amino-6-cyclohexyl-2-oxo-l,2-dihydro-pyridine-4-yl)-benzoic acid
(Compound 54)
Into a 50mL flask, 3-(l-amino-6-cyclohexyl-2-oxo-l,2-dihydro-pyridine-4-yl)- benzonitrile (200mg, 0.68mmol) and a magnetic bar were introduced, and then the flask was filled with nitrogen gas. After a cone. HCl (lOmL) was added thereto, the solution was refluxed for 4 hours. Then, HCl was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (10:1) as eluent. The fractions containing the product were combined and evaporated to give a white solid (164mg, 56%). 'H-NMR(DMSO); δ =8.15(t, IH), 7.96(m, 2H), 7.61(t, IH), 6.62(d, IH, J=2.289),
6.39(d, IH, J=2.289), 5.95(s, 2H), 1.99(m, 2H), 1.74(m, 3H), 1.36(m, 5H).
EXAMPLE 50
Synthesis of 3-( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydro-pyridine-4-yl)-benzonitrile
(Compound 55) The title compound of 3-(l-amino-6-cyclohexyl-2-oxo-l,2-dihydro-pyridine-4- yl)-benzonitrile(641mg, 61%) was obtained by reacting 3-(6-cyclohexyl-2-oxo-2H-pyrane-
4-yl)-benzonitrile (lg, 3.58mmol) in the same manner as in Example 1 (e).
'H-NMR(DMSO); δ =8.27(1H, t, J=1.526), 8.07(1H, m), 7.90(1H, m), 7.67(1H, t,
J=8.011), 6.73(1H, d, J=2.289), 6.49(1H, d, J=2.289), 5.99(1H, s), 5.97(1H, s), 3.20(1H, m), 1.99(2H, m), 1.79(3H, m), 1.39(5H, m).
EXAMPLE 51
Synthesis of 1 -amino-6-cyclohexyl-4-[4-(5H-tetτazol-5-yl)-phenyl]- 1 H-pyridine-2-one
(Compound 56) 4-(l-Amino-6-cyclohexyl-2-oxo-l,2-dihydro-pyridine-4-yl)-benzonitrile (290mg, 0.989mmol) was dissolved in DMF (20mL). After NaN3 (192mg, 2.967mmol) and NH4CI (159mg, 2.967mmol) were added, the reaction solution was heated to 110°C . After 4 hours, the reaction solution was distilled under reduced pressure. The residue was purified by column chromatography on silica gel using MC:MeOH (4:1) as eluent. The fractions containing the product were combined and evaporated to give a white solid (128mg, 39%).
Η-NMR(CDC13); d =8.57(d, 2H), 7.81(s, IH), 7.65(s, IH), 6.76(d, IH, J=2.4Hz), 6.54(d, IH, J=2.1Hz), 3.28(m, IH), 2.2-1.4(m, 10H). MS(ESI); 337(^+1).
EXPERIMENTAL EXAMPLE 1 LPDE4 Inhibition Activity (Low Affinity for Rolipram)
Lungs of a rat (male, 200-300g) was extracted and immediately placed into the buffer solution [50mM TRIS HCl (pH 6.5), 2mM EDTA, 5mM 2-mercaptoethanol, 2mM benzamidine and lOμM Leupeptin]. The extracted lungs were first cut into fine pieces with scissors and then homogenized by a polytron. The homogenized lungs prepared as above were centrifuged by 35,000g for an hour. The resulting supernatant was collected and then applied to diethylaminoethyl(DEAE)-sepharose column and PDE4 enzymes were eluted with a linearly increasing salt gradient running from 50mM to lOOOmM sodium acetate (Flow rate : 3mL/min., volume of the fractional distillation: 5mL). To each fraction prepared as above was added bovine serum albumin to the final concentration of 0.1 % and fractions showing PDE4 activity were collected and stored until use.
The buffer solution for analysis was prepared [50mM TRIS HCl (pH 6.5), 5mM MgCl2, 4mM 2-mercaptoethanol and 0.15mg/mL bovine serum albumin (BSA)], and all the analyses were carried out in the presence of cGMP in order to inhibit any remaining, if any, PDE3 activity. The final reaction volume was lOOμL and 0.25μM [3H]cAMP was added as a substrate. The reaction was carried out at 30 °C for 30 minutes and was terminated by placing the sample in boiling water bath for 1 min followed by a immediate transfer onto an ice bath. Then, 1 OμL (5mg/mL) of snake toxin was added into each well and the samples were further incubated for 20min at 30 °C . Subsequently, [3H]adenosin was separated from the reaction solution by addition of AG1-X8 resin and the radioactivity of the resulting sample was determined by liquid-scintillation counting. The inhibitory effects of the PDE4 inhibitors according to the present invention was expressed as the percent of inhibition at each concentration and the concentration of the compound at which it shows 50% inhibition activity (IC50) was also calculated.
The inhibitory effects on LPDE4 of the compounds according to the present invention is given in Table 1. EXPERIMENTAL EXAMPLE 2
HPDE4 Inhibition Activity (High Affinity for Rolipram)
Brain of a rat (male, 200-300g) was extracted and immediately placed into the buffer solution [50mM TRIS HCl (pH 8.0), 2mM MgCl2, O.lmM DTT and lOμM Leupeptin]. The brains were first cut into fine pieces with scissors and then homogenized by a polytron. The homogenized brains prepared as above were centrifuged by 45,000g for an hour. The resulting pellets were collected and resuspended in buffer solution [50mM TRIS HCl (pH 8.0), 2mM MgCl2] and aliquoted and stored at -20 °C until use.
The buffer solution for analysis was prepared [50mM TRIS HCl (pH 8.0), 5mM MgCl2 and 0.05mM 5'-AMP] and the reactions were carried out in the final volume of 200μL and 200μg of homogenized brains was added to each well. Finally, [3H]-(± ) Rolipram was added to the final concentration of 3nM thereto and the samples were incubated at 30 °C for an hour. Subsequently the bound Rolipram was removed by passing the resulting solution through the filter by centrifugation (3000 rpm, 3minutes). The non-specific bindings were determined in the presence of lOμM RP73401. The radioactivity was then determined by liquid-scintillation counting. The decrease in the amount of radioactivity caused by the compounds according to the present invention was expressed in the percent of reduction at each concentration and the concentration of the compound at which it shows 50% inhibition (IC50) was also calculated.
The inhibitory effects on HPDE4 of the compounds according to the present invention is given in Table 1. [Table 1]
Figure imgf000079_0001
Figure imgf000080_0001
EFFECT OF THE INVENTION
The compounds of the present invention exhibit potent PDE4 inhibition activity, and furthermore, they do not show any side effects such as nausea and emesis in the therapeutic dosage range. Therefore, the compounds according to the present invention can be useful for preventing the acute deterioration of lung function associated with COPD through the direct functional activities of bronchodilation and anti -inflammation as well as for curing the gradual deterioration of lung function associated with disease and thus improving the quality of life of the patients.

Claims

WHAT IS CLAIMED IS:
1. A compound of formula (1)
Figure imgf000082_0001
in which
R, is selected from the group consisting of C6-CI2 aryl, C3-C8 cycloalkyl, and saturated or unsaturated C2-CH mono- or poly-heterocyclyl containing 1 to 3 heteroatoms, which may be substituted by one or two R7's;
R2 is selected from the group consisting of C6-C12 aryl, C3-C8 cycloalkyl, and saturated or unsaturated C2-Cπ mono- or poly-heterocyclyl containing 1 to 3 heteroatoms, which may be substituted by one or two Rg's;
R3 and R4, which may be identical or different, are selected from the group consisting of hydrogen, C,-C6 alkyl, and C2-C7 alkylcarbonyl;
R5 and R6, which may be identical or different, are selected from the group consisting of hydrogen, C,-C6 alkyl, C2-C7 alkylcarbonyl, and C2-C7 alkoxycarbonyl;
R7 is selected from the group consisting of hydrogen, C,-C6 alkyl, C,-C6 alkoxy, C2-C7 alkoxycarbonyl, C6-C12 aryl, C C5 heteroaryl containing 1 to 4 heteroatoms, halogen, CN, CF3, CO2H, CONH2, CONHNH2, and NHCOCH3; R8 is selected from the group consisting of hydrogen, C,-C6 alkyl, C,-C6 alkoxy, hydroxy, halogen, CN, and CO2H; R, and R4 may be selectively linked to form an aromatic ring; or pharmaceutically acceptable salts thereof.
2. The compound according to claim 1 , in which:
R, is selected from the group consisting of phenyl, C5-C6 cycloalkyl, and C2-C5 heterocyclyl containing 1 to 2 heteroatoms, which may be substituted by one or two R7's;
R2 is selected from the group consisting of phenyl, C5-C6 cycloalkyl, and C2-C5 heterocyclyl containing 1 to 2 heteroatoms, which may be substituted by one or two R8's;
R3 and R4, which may be identical or different, are selected from the group consisting of hydrogen, C,-C6 alkyl, and C2-C7 alkylcarbonyl; R5 and R6, which may be identical or different, are selected from the group consisting of hydrogen, C,-C6 alkyl, C2-C7 alkylcarbonyl, and C2-C7 alkoxycarbonyl; R7 is selected from the group consisting of hydrogen, C,-C6 alkyl, C,-C6 alkoxy, C2-C7 alkoxycarbonyl, C6-C12 aryl, CrC3 heteroaryl containing 1 to 4 heteroatoms, halogen, CN, CF3, CO2H, CONH2, CONHNH2, and NHCOCH3; R8 is selected from the group consisting of hydrogen, C,-C6 alkyl, C,-C6 alkoxy, hydroxy, halogen, CN, and CO2H; R, and R4 may be selectively linked to form an aromatic ring.
3. The compound according to claim 1, in which the C3-C8 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
4. The compound according to claim 1, in which C2-Cπ mono- or poly- heterocyclyl is thienyl, thiazolyl, imidazolyl, benzoimidazolyl, triazolyl, tetrahydropyranyl, pyridinyl, furanyl, pyranyl, pyrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, isothiazolyl, isooxazolyl, pyridazinyl, isobenzopyranyl, chromenyl, indolyl, indazolyl, quinolinyl, purinyl, pyrolinyl, chromanyl, pyrazolidinyl, piperidinyl, or piperazinyl.
5. The compound according to claim 1, which is selected from the group consisting of: l-amino-6-cyclohexyl-4-phenyl-lH-pyridine-2-one (Compound 1); 1 -amino-4,6-bis(cyclohexyl)- 1 H-pyridine-2-one (Compound 2);
1 -amino-6-cyclohexyl-5-methyl-4-phenyl- 1 H-pyridine-2-one (Compound 3);
1 -amino-6-cyclohexyl-3-methyl-4-phenyl- 1 H-pyridine-2-one (Compound 4); l-amino-6-(2-methoxyphenyl)-4-phenyl-lH-pyridine-2-one (Compound 5);
1 -amino-6-(3-methoxyphenyl)-4-phenyl- 1 H-pyridine-2-one (Compound 6); l-amino-6-(4-fluorophenyl)-4-phenyl-lH-pyridine-2-one (Compound 7);
1 -amino-6-(3 ,4-dimethoxyphenyl)-4-phenyl- 1 H-pyridine-2-one (Compound 8); l-amino-4-phenyl-6-o-toyl-lH-pyridine-2-one (Compound 9); l-amino-6-cyclopropyl-4-phenyl-lH-pyridine-2-one (Compound 10); l-amino-6-cyclopentyl-4-phenyl-lH-pyridine-2-one (Compound 11); l-amino-4-phenyl-6-(tetrahydropyran-4-yl)-lH-pyridine-2-one (Compound 12);
1 -amino-6-(4-methoxyphenyl)-4-phenyl- 1 H-pyridine-2-one (Compound 13);
1 -amino-6-cycloheptyl-4-imidazole- 1 -yl- 1 H-pyridine-2-one (Compound 14);
1 -amino-4-(4-fluorophenyl)-6-phenyl- 1 H-pyridine-2-one (Compound 15); l-amino-4-cyclopentyl-6-phenyl-lH-pyridine-2-one (Compound 16);
1 -amino-6-cyclohexyl-4-naphthalene-l -yl- 1 H-pyridine-2-one (Compound 17); l-methylamino-4,6-diphenyl-lH-pyridine-2-one (Compound 18);
1 -amino-6-cyclohexyl-4-imidazole- 1 -yl- 1 H-pyridine-2-one (Compound 19); l-amino-6-cyclohexyl-4-[l,2,3]triazol-l-yl-lH-pyridine-2-one (Compound 20);
1 -amino-6-cyclopentyl-4-(imidazole)- 1 -yl- 1 H-pyridine-2-one (Compound 21);
1 -amino-6-cyclohexyl-4-( 1 ,2,4-triazol)- 1 -yl-1 H-pyridine-2-one (Compound 22);
1 -amino-6-cyclohexyl-4-[3-(methyl)pyrol]- 1 -yl- 1 H-pyridine-2-one (Compound 23); l-amino-6-cyclohexyl-4-(4-methylimidazole)-l-yl-lH-pyridine-2-one
(Compound 24);
1 -amino-6-cyclohexyl-4-(4-phenylimidazole)- 1 -yl- 1 H-pyridine-2-one (Compound 25); l-amino-6-cyclohexyl-4-pyrazol-l-yl-lH-pyridine-2-one (Compound 26); 1 -amino-6-cyclohexyl-4-(2-methylimidazole-l -yl)-l H-pyridine-2-one
(Compound 27);
1 -amino-6-cyclohexyl-4-(2-ethylimidazole- 1 -yl)- 1 H-pyridine-2-one (Compound 28);
1 -(amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)- 1 H-imidazole-4- carboxylic acid hydrazide (Compound 29);
1 -amino-4-benzimidazole- 1 -yl-6-cyclohexyl- 1 H-pyridine-2-one (Compound 30);
2-amino-3-phenyl-2H-isoquinoline-l-one (Compound 31);
4-acetyl-2-amino-3-phenyl-2H-isoquinoline-l-one (Compound 32); 1 -amino-4-imidazole- 1 -yl-6-(4-methoxycyclohexyl)- 1 H-pyridine-2-one (Compound 33);
1 -amino-6-(4-hydroxycyclohexyl)-4-imidazole- 1 -yl- 1 H-pyridine-2-one (Compound 34); 4-( 1 -amino-2-oxo-6-phenyl- 1 ,2-dihydropyridine-4-yl)-benzonitrile (Compound
35);
4-( 1 -amino-2-oxo-6-phenyl- 1 ,2-dihydropyridine-4-yl)-benzoic acid (Compound 36);
4-( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)-benzonitrile (Compound 37);
4-( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)-benzoic acid
(Compound 38);
4-( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)-benzaimde (Compound 39); 1 -amino-6-cyclohexyl-4-(4-trifluoromethylimidazole- 1 -yl)- 1 H-pyridine-2-one
(Compound 40);
1 -( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)- 1 H-imidazole-4- carbonitrile (Compound 41);
1 -( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)- 1 H-imidazole-4- carboxylic acid amide (Compound 42);
(6-cyclohexyl-4-imidazole- 1 -yl-2-oxo-2H-pyridine- 1 -yl)-carbamic acid methyl ester (Compound 43);
4-( 1 -amino-4-imidazole- 1 -yl-6-oxo- 1 ,6-dihydropyridine-2-yl)-cyclohexane- carbonitrile (Compound 44);
4-( 1 -amino-4-imidazole- 1 -yl-6-oxo- 1 ,6-dihydropyridine-2-yl)-cyclohexane- carboxylic acid (Compound 45); -amino-6'-cyclohexyl-lΗ-[2,4']bipyridinyl-2'-one (Compound 46); N- [3 -( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)-phenyl] -acetamide
(Compound 47); -amino-6'-cyclohexyl-2'-oxo- ,2'-dihydro-[2,4']bipyridinyl-5-carbonitrile (Compound 48);
1 '-amino-6'-cyclohexyl-2'-oxo-l l,2'-dihydro-[2,4']bipyridinyl-5-carboxylic acid amide (Compound 49);
1 -( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)- 1 H-imidazole-4- carboxylic acid (Compound 50);
1 -( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)- 1 H-imidazole-4- carboxylic acid methyl ester (Compound 51); 4-(l-amino-6-oxo-4-phenyl-l,6-dihydropyridine-2-yl)-benzoic acid (Compound
52);
4-( 1 -amino-6-oxo-4-phenyl- 1 ,6-dihydropyridine-2-yl)-benzonitrile (Compound 53);
3-( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)-benzoic acid (Compound 54);
3-( 1 -amino-6-cyclohexyl-2-oxo- 1 ,2-dihydropyridine-4-yl)-benzonitrile (Compound 55); and l-amino-6-cyclohexyl-4-[4-(5H-tetτazol-5-yl)-phenyl]-lH-pyridine-2-one (Compound 56).
6. A method for preparing a compound of formula (1) or pharmaceutically acceptable salts thereof, comprising the steps of:
Figure imgf000088_0001
(1) a) subjecting a compound of formula (9) to a condensation reaction
Figure imgf000088_0002
(9) with a compound of formula (8)
Figure imgf000088_0003
(8) to obtain a compound of formula (7),
Figure imgf000088_0004
(7) b) conducting a cyclization reaction of the compound of formula (7) to obtain a compound of formula (6),
Figure imgf000089_0001
(6) c) halogenating the compound of formula (6) to obtain a compound of formula (5),
Figure imgf000089_0002
(5) d) coupling the compound of formula (5) with a compound of formula (4)
R,-H
(4) to obtain a substituted compound of formula (3), and
Figure imgf000089_0003
(3) e) substituting the compound of formula (3) with a compound of formula (2)
R5R6N-NH2
(2) to obtain a compound of formula (1), : R, is selected from the group consisting of C6-CI2 aryl, C3-C8 cycloalkyl, and saturated or unsaturated C2-C„ mono- or poly-heterocyclyl containing 1 to 3 heteroatoms, which can be substituted with one or two R7's;
R2 is selected from the group consisting of C6-C12 aryl, C3-C8 cycloalkyl, and saturated or unsaturated C2-Cπ mono- or poly-heterocyclyl containing 1 to 3 heteroatoms , which can be substituted with one or two R8's;
R3 and R4, which may be identical or different, are selected from the group consisting of hydrogen, CrC6 alkyl, and C2-C7 alkylcarbonyl;
R5 and R6, which may be identical or different, are selected from the group consisting of hydrogen, C,-C6 alkyl, C2-C7 alkylcarbonyl, and C2-C7 alkoxycarbonyl;
R7 is selected from the group consisting of hydrogen, C,-C6 alkyl, C,-C6 alkoxy, C2-C7 alkoxycarbonyl, C6-C12 aryl, C,-C3 heteroaryl containing 1 to 4 heteroatoms, halogen, CN, CF3, CO2H, CONH2, CONHNH2, and NHCOCH3;
R8 is selected from the group consisting of hydrogen, C,-C6 alkyl, C,-C6 alkoxy, hydroxy, halogen, CN, and CO2H;
R, and R4 may be selectively linked to form an aromatic ring;
X represents a reactive leaving group such as hydroxy or halogen.
7. A PDE4 (phosphodiesterase 4) inhibitor composition, which comprises the effective amount of a compound of formula (1) according to any one of claims 1 to 5, pharmaceutically acceptable salts or stereochemical isomers thereof as an active component, and a pharmaceutically acceptable carrier.
8. The PDE4 inhibitor composition according to claim 7, which is used as a medicament for the treatment of chronic obstructive pulmonary disease (COPD).
9. The PDE4 inhibitor composition according to claim 7 or 8, which is formulated as an orally adminisfrable medicament.
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JP2006509786A (en) 2006-03-23

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