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Definitions

• the present invention relates to pyridinylpyrazolopyrimidinone compounds, pharmaceutically acceptable salts and solvates thereof, having selective PDE 7 (phosphodiesterase VII) inhibiting effect. These compounds are effective compounds for treating various kinds of disease such as allergic disease, inflammatory disease and immunologic disease.
• the PDE 7 selectively decomposes CAMP, and is characterized as an enzyme not decomposed by rolipram.
• Rolipram is a selective inhibitor of PDE 4 which decomposes CAMP.
• PDE 7 plays an important role for activating T cells (Beavo, et al., Science, 283, 848 (1999)), and well known that activating of T-cell is concerned with the exacerbation of allergic disease, inflammatory disease or immunologic disease.
• bronchial asthma chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, hepatitis, pancreatitis, encephalomyelitis, septicemia, Crohn's disease, rejection for organ transplantation, graft versus host disease (GVH disease), and restenosis after angioplasty.
• bronchial asthma chronic bronchitis, chronic obstructive pulmonary disease
• allergic rhinitis psoriasis
• atopic dermatitis conjunctivitis
• osteoarthritis osteoarthritis
• rheumatoid arthritis multiple sclerosis
• systemic lupus erythematosus inflammatory bowel disease
• a compound having PDE 7 inhibiting effect is useful for treating various kinds of disease such as allergic disease, inflammatory disease or immunologic disease concerned with T cells.
• the purpose of the present invention is to provide novel compounds having PDE 7 inhibiting effect, and PDE 7 inhibiting composition containing the same as an active ingredient.
• the compounds of the present invention inhibit PDE 7 selectively, and therefore, enhance cellular cAMP level. Consequently, the compounds of the present invention are useful for treating various kinds of disease such as allergic disease, inflammatory disease or immunologic disease.
• the compounds of the present invention are useful for treating or preventing the diseases such as bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, atopicdermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, hepatitis, pancreatitis, encephalomyelitis, septicemia, Crohn's disease, rejection for organ transplantation, GVH disease, restenosis after angioplasty.
• diseases such as bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, ps
• pyridinylpyrazolopyrimidinone compounds represented by the following formula (IA) or (IB): wherein:
• R 1 is substituted or unsubsituted C 3 -C 8 cycloalkyl group or tert-butyl group;
• R 2 is a hydrogen atom or C 1 -C 3 alkyl group
• R 4 is a hydrogen atom or C 1 -C 3 alkoxy group which is unsubstututed or substituted by one or more fluorine atom(s);
• R 5 and R 6 are, same or different from each other, a hydrogen atom, substituted or unsubsituted C 1 -C 6 alkyl group, substituted or unsubsituted acyl group, substituted or unsubsituted heterocycloalkyl group, and substituted or unsubsituted heterocycloalkyl ring is formed with nitrogen atom which is binding R 5 and R 6 ;
• R 7 is a group: —OR 9 or —NR 5 R 6 ;
• R 8 is a hydrogen atom, a halogen atom, a group: —NR 5 R 6 , substituted or unsubsituted C 1 -C 6 alkyl group, or substituted or unsubsituted aryl group;
• R 9 is a hydrogen atom or substituted or unsubsituted C 1 -C 6 alkyl group
• C 1 -C 3 alkyl group of the present invention includes a straight or branched-chained alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl and propyl group
• C 1 -C 6 alkyl group of the present invention means a straight or branched-chained alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl and hexyl group.
• C 3 -C 8 cycloalkyl group of the present invention includes a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl.
• heterocycloalkyl group is 3 to 7 membered heterocyclic group containing the same or different 1 to 4 hetero atom(s) such as oxygen, nitrogen or sulfur atom(s), and examples may include pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl and azetidinyl.
• C 1 -C 3 alkoxy group means alkoxy group having 1 to 3 carbon atoms and examples include methoxy, ethoxy and propoxy.
• acyl group means acyl group having 1 to 8 carbon atoms, and examples include formyl, acetyl, propionyl, butanoyl, pentanoyl, benzoylandtoluoyl.
• halogen atom includes fluorine, chlorine, bromine and iodine.
• aryl group is phenyl, naphthyl, biphenyl group which is consisted by 6 to 12 carbon atoms, and the term “heteroaryl group” is 5 to 7 membered monocyclic or polycyclic group thereof containing 2 to 8 carbon atoms and the same or different 1 to 4 hetero atom(s) such as oxygen, nitrogen, sulfuratom(s).
• the examples includepyrrole, furyl, thienyl, imidazolyl, thiazolyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, tetrazolyl, pyridinyl, pyrazolyl pyridazinyl and pyrimidinyl.
• Examples of suitable substituent of “substituted or unsubstituted C 1 -C 6 alkyl group” include hydroxyl group and halogen atom
• examples of suitable substituent of “substituted or unsubstituted acyl group” include halogen atom and nitro group.
• examples of suitable substituent of “substituted or unsubstituted aryl group” include C 1 -C 3 alkyl, halogenatom, amino group, acylgroup, amidegroup, hydroxyl group, acylamino group, carboxyl group and sulfonyl group.
• Examples of suitable substituent of “substituted or unsubstituted C 3 -C8 cycloalkyl group” is C 1 -C 3 alkyl, hydroxyl group and oxo group
• suitable substituent of “substituted or unsubstituted heterocycloalkyl group” may include carboxy group, acyl group, alkoxy group, amino group, alkylamino group, acylamino group, hydroxyl group, oxo group, ethylenedioxy group, ethyl group, ethyl group and hydroxyethyl group.
• Preferable compounds of the formula (IA) and (IB) of the present invention include the compounds wherein R 1 is cyclohexyl group or cycloheptyl group; R 2 is methyl group; R 3 is the group —NR 5 R 6 or —S(O) 0-2 R 8 ; and R 4 is methoxy or ethoxy group.
• the compounds of the formula (IA) and (IB) of the present invention may exist in the tautomeric mixtures, the tautomeric isomers per se, and the mixture thereof. Furthermore, the radio labelled compounds of the formula (IA) and (IB) shall be included within the scope of the compounds of the present invention.
• the compounds of the present invention may contain one or more asymmetric carbon atom and therefore, the compounds of the present invention may exist as optically isomer of (R)-form or (S)-form, racemic forms, as well as diastereomers. Further, the compounds of the present invention may exist as geometrical isomer such as (Z)-form or (E)-form due to the double bond in the substituent. Therefore, the compounds of the present invention should include these isomers per se as well as the isomeric mixtures thereof.
• the compounds of the present invention may form acid additional salt thereof with various acids.
• the acid additional salt include the salts with inorganic acid such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid and phosphoric acid; salts with organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, benzoic acid, picric acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, trichloroacetic acid, trifluoroacetic acid, asparaginic acid and glutamic acid.
• inorganic acid such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid and phosphoric acid
• organic acid such as formic acid, acetic acid, propionic
• the compounds of the present invention may form pharmaceutically acceptable metal salts by treating with various kinds of metal, especially alkali metal or alkali earth metal. These salts may include sodium salt, potassium salt and calcium salt. Further, the compounds of the present invention may include hydrate or solvate with water, ethanol or isopropanol, and polymorphisms thereof.
• the following compounds are preferable pyridinylpyrazolo-pyrimidinone compounds of the formula (IA) or (IB).
• the compound of the formula (IA) of the present invention can be synthesized by the following methods. (wherein, R 1 , R 2 , R 4 , R 5 , R 6 and R 8 have same meaning mentioned above; L is C 1 -C 3 lower alkyl, and Y is hydroxyl group or halogen atom, preferably chlorine atom)
• R′NHNH 2 or salt thereof in accordance with the known method. Namely, the compound (X) is reacted with 1 to 2 equivalent, preferably about 1 equivalent of R 1 NHNH 2 or salt thereof in the solvent or absent of the solvent at room temperature to 120° C.
• the solvent to be used in the reaction is inorganic acid aqueous solution such as hydrochloric acid or sulfuric acid; aromatic carbon hydrate such as benzene or toluene; organic acid such as acetic acid; alcohols such as methanol or ethanol; or the mixture solvent there of.
• inorganic base aqueous solution such as sodium hydroxide aqueous solution is added to the reaction mixture and the mixture is extracted wit an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution. Then, the compound (IX) can be obtained by removal of the solvent. This compound (IX) can be purified by recrystallization, if necessary.
• the compound (X) to be used in this reaction can be commercially available or can be easily prepared from known compounds by using common methods. Further, the compound represent by the formula R 1 NHNH 2 or salt thereof can also be commercially available or can be easily prepared from known compounds by using common methods (For example: J. Org. Chem., 1981, 46, 5414-5415).
• the compound (IX) is converted to the compound (VIII) in accordance with the common method.
• the reaction can be conducted by reacting the compound (IX) with 1 to 5 equivalent of halogenate reagent such as phosphorus oxychloride or thionyl chloride in aromatic hydrocarbon solvent such as benzene or toluene, or the absence of the solvent, at room temperature to refluxing temperature of the solvent.
• halogenate reagent such as phosphorus oxychloride or thionyl chloride
• aromatic hydrocarbon solvent such as benzene or toluene
• the obtained compound (VIII) is converted, without further purification, to the compound (VII) by nitration in accordance with the common method.
• the nitration can be conducted by using nitric acid with sulfuric acid or acetic anhydride at the temperature from ⁇ 20° to room temperature. After the reaction is completed, the reaction mixture is poured into ice and the resulting precipitate is collected to obtain the purpose compound (VII).
• This compound (VII) can be purified by recrystallization, if necessary.
• the obtained compound (VII) is converted to the compound (VI) in accordance with the common method.
• the reaction can be conducted by reacting the compound (VII) with 1 to 3 equivalent metal cyanide such as potassium cyanide or sodium cyanide in a polar solvent such as N,N-dimethylformamide at room temperature to 120° C.
• a polar solvent such as N,N-dimethylformamide
• water is added to the reaction mixture and the mixture is extracted with an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution.
• the compound (VI) can be obtained by removal of the solvent.
• This compound (VI) can be purified by chromatography, if necessary.
• the obtained compound (VI) is converted to the compound (V) in accordance with the common method.
• This reaction is hydrolysis reaction of nitrile group converting to the corresponding acid amide group, and various methods are applied.
• the reaction can be conducted by reacting the compound (VI) with hydrogen peroxide in the presence of base such as sodium hydroxide or potassium carbonate in a solvent at 0° C. to the room temperature.
• the solvent to be used is water, alcohols such as methanol or ethanol, ethers such as 1,4-dioxane or tetrahydrofuran, or the mixture thereof.
• the reaction mixture is extracted with an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution. Then, the compound (V) can be obtained by removal of the solvent. This compound (V) can be purified by recrystallization, if necessary.
• the obtained compound (V) is converted to the compound (III) in accordance with the common method.
• This reaction is reduction of nitro group converting to the corresponding amino group, and various methods are applied.
• the reaction can be conducted by reacting the compound (V) with 2 to 10 equivalent of tin(II) chloride in the presence of inorganic acid such as hydrochloric acid at 0° C. to the refluxing temperature.
• inorganic acid such as hydrochloric acid
• the reaction mixture is neutralized by inorganic base such as sodium hydroxide, and filtrate by Celite®.
• the obtained filtrate is extracted with an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution.
• the compound (III) can be obtained by removal of the solvent.
• This compound (III) can be purified by chromatography, if necessary.
• the obtained compound (III) is, then, converted to the compound (II) in accordance with the common method.
• This reaction can be conducted by the reaction of the amine compound (III) with carboxylic compound (IV) to obtain the corresponding acid amide compound (II), and various methods are applied.
• the reaction can be conducted by reacting the compound (III) with 1.0 to 1.5 equivalent, preferably 1.2 equivalent of the compound (IV) in the presence of 1 to 5 equivalent, preferably 2.5 equivalent of tertiary amine such as triethylamine, based on the compound (III), and if necessary in the presence of the catalyst such as 4-dimethylaminopyridine.
• the reaction can be carried out in the presence of inert solvent such as dichloromethane at 0° C. to the room temperature.
• the reaction can be conducted by reacting the compound (III) with 1.0 to 1.5 equivalent, preferably 1.2 equivalent of the compound (IV) 15 in the presence of 1 to 5 equivalent, preferably 1.2 equivalent of the condensing agent such as 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride, based on the compound (III), and if necessary in the presence of the catalyst such as 4-dimethylaminopyridine in the inert solvent such as dichloromethane.
• the condensing agent such as 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydrochloride
• the reaction mixture is diluted with an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution, then, the solvent is removed to give the purpose compound (II).
• This compound can be purified by column chromatography, if necessary.
• the obtained compound (II) is converted to the compound (IA′) by pyrimidine ring formation reaction.
• This ring formation reaction can be carried out by heating the compound (II) with base such as sodium hydroxide, potassium t-butoxide or potassium carbonate in ethanol/water in the seal tube at 120 to 140° C. Further, the reaction can be carried out in high boiling solvent such as methoxyethanol in the presence of base such as potassium t-butoxide at 120 to 140° C.
• the reaction mixture is diluted with an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution.
• the compound (IA′) can be obtained by removal of the solvent.
• This compound (IA′) can be purified by chromatography or recrystallization, if necessary.
• the compound (IA′′) can be obtained from the obtained compound (IA′) by the function group converting reaction with per acid such as m-chloroperbenzoic acid or magnesium mono-peroxyphthalate in chloroform or dichloromethane or chloroform at ° C. to the room temperature.
• per acid such as m-chloroperbenzoic acid or magnesium mono-peroxyphthalate in chloroform or dichloromethane or chloroform at ° C. to the room temperature.
• the compound (IA′′′) can be obtained by reacting the compound (IA′′) with lithium amide, which is obtained by reacting the amine compound with n-butyllithium.
• lithium amide which is obtained by reacting the amine compound with n-butyllithium.
• ethers such as 1,4-dioxan or tertahydrofuran
• the compound (IA′′) is added to this mixture of lithium amide solution to obtain the compound (IA′′′).
• the carboxylic compound (IV) to be used in the above reaction can be obtained by the following reaction scheme. (wherein, L, Y, R 4 and R 6 have same meaning mentioned above; and X is a halogen atom)
• the compound (XII) is obtained from the compound (XIII) in accordance with the known method (e.g., Chem. Pharm. Bull., 48(12), 1847-1853 (2000)).
• the reaction can be conducted by reacting the compound (XIII) with about 1 equivalent thiol compound such as ethanethiol or benzenethiol in the presence of base such as potassium t-butoxide, in polar solvent such as N,N-dimethylformamide at the room temperature to ⁇ 30° C., preferably ⁇ 30° C.
• compound (XII) is converted to the compound (XI) in accordance with common method.
• the reaction is conducted by reacting the compound (XII) with small excess of metal alcoholate such as sodium methylate in ethers solvent such as 1,4-dioxan or tetrahydrofuran at the room temperature to refluxing temperature.
• metal alcoholate such as sodium methylate
• ethers solvent such as 1,4-dioxan or tetrahydrofuran
• water is added to the reaction mixture and the mixture is extracted with an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution.
• the compound (XI) can be obtained by removal of the solvent.
• This compound (XI) can be purified by recrystallization, if necessary.
• the obtained compound (XI) is converted to the compound (IV) in accordance with common method.
• This reaction is hydrolysis reaction of ester compound and various methods are applied.
• the reaction is conducted by reacting the compound (XI) with base such as sodium hydroxide in the alcohol solvent such as methanol or water, as well as a mixture thereof at the room temperature to refluxing temperature. After the reaction is completed, the reaction mixture is condensed and the residue is neutralized to give the compound (IV).
• the compound of the formula (IB) of the present invention may be synthesized by the following methods. (wherein, R 1 , R 2 , R 3 and R 4 have same meaning mentioned above; and Y is hydroxyl group or halogen atom, preferably chlorine atom)
• the compound (XIX) is obtained from the compound (XX) in accordance with the known method (e.g., J. Chem. Soc, Perkin Trans. I, 1996, 1545-1552).
• This method can be conducted by the reaction of the compound (XX) with 1 to 1.5 equivalent of the compound (XXI) based on the compound (XX), in the presence of the 2 to 2.5 equivalent of alkali metal hydride such as sodium hydride and potassium hydride, or tertiary amine such as triethlyamine based on the compound (XX).
• the reaction can be carried out in an appropriate solvent and these are halogenated hydrocarbons such as dichloromethane; aromatic hydrocarbon such as toluene and benzene; ethers solvent such as diethyl ether tetrahydrofuran; or a mixture of solvent thereof.
• the reaction temperature is a range from 0° C. to the room temperature.
• the reaction mixture is diluted with an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution. Then, the compound (XIX) can be obtained by removal of the solvent. This compound (XIX) can be purified by chromatography, if necessary.
• the obtained compound (XIX) is converted to the compound (XVIII) in accordance with the common method (e.g., J. Chem. Soc, Perkin Trans. I , 1996, 1545-1552).
• the reaction can be carried out by the reacting the compound (XIX) with 5 to 10 equivalent of the methylation reagent such as dimethyl sulfate in an appropriate solvent.
• the solvent to be used in this reaction may include halogenated hydrocarbons such as dichloromethane; aromatic hydrocarbon such as toluene and benzene; ethers solvent such as diethyl ether tetrahydrofuran; or a mixture of solvent thereof, and the reaction temperature is from the room temperature to the refluxing temperature of the solvent.
• the reaction mixture is diluted with an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution. Then, the compound (XVIII) can be obtained by removal of the solvent. This compound (XVIII) can be purified by chromatography, if necessary.
• the obtained compound (XVIII) is converted to the compound (XVI) in accordance with the common method (e.g., J. Chem. Soc, Perkin Trans. I, 1996, 1545-1552).
• the reaction can be carried out by the reacting the compound (XVIII) with 1 to 1.5 equivalent of the compound XVII) based on the compound (XVIII) in an appropriate solvent.
• the solvent to be used in this reaction may include halogenated hydrocarbons such as dichloromethane; aromatic hydrocarbon such as toluene and benzene; ethers solvent such as diethyl ether tetrahydrofuran; or a mixture solvent thereof, and the reaction temperature is from the room temperature to the refluxing temperature of the solvent.
• the solvent is removed to give the compound (XVI).
• This compound (XVI) can be purified by chromatography, if necessary.
• the obtained compound (XVI) is converted to the compound (XV) in accordance with the common method.
• This reaction is hydrolysis reaction of nitrile group converting to the corresponding acid amide group, and various methods are applied.
• the reaction can be conducted by treating the compound (XVI) with catalyst such as sulfuric acid or hydrochloric acid in an appropriate solvent at the room temperature to 100° C.
• the solvent to be used is water, alcohols such as methanol or ethanol, ethers such as diethyl ether, tetrahydrofuran or dioxane, or the mixture thereof.
• reaction mixture After the reaction is completed, the pH of reaction mixture is adjusted to alkali side, and the reaction mixture is extracted with an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution. Then, the compound (XV) can be obtained by removal of the solvent. This compound (XV) can be purified by recrystallization, if necessary.
• the obtained compound (XV) is, then, converted to the compound (XIV) in accordance with the common method.
• This reaction can be conducted by the reaction of the compound (XV) with compound (IV) to obtain the corresponding acid amide compound (XIV).
• the reaction can be conducted by reacting the compound (XV) with 1.0 to 2.0 equivalent, preferably about 1.4 equivalent of the compound (IV) in the presence of 1 to 5 equivalent, preferably 2.5 equivalent of tertiary amine such as triethylamine, based on the compound (XV), and if necessary in the presence of the catalyst such as 4-dimethylaminopyridine.
• the reaction can be carried out in the presence of inert solvent such as dichloromethane at 0° C. to the room temperature.
• the reaction can be conducted by reacting the compound (XV) with 1.0 to 1.5 equivalent, preferably about 1.2 equivalent of the compound (IV) in the presence of 1 to 5 equivalent, preferably about 1.2 equivalent of the condensing agent such as 1-ethyl-3-(3-dimethyl-aminopropyl)-carbodiimide hydrochloride, based on the compound (XV), and if necessary in the presence of the catalyst such as 4-dimethylaminopyridine in the inert solvent such as dichloromethane.
• the condensing agent such as 1-ethyl-3-(3-dimethyl-aminopropyl)-carbodiimide hydrochloride
• the reaction mixture is diluted with an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution, then, the solvent is removed to give the purpose compound (XIV).
• the obtained compound (XIV) is used for the next reaction without further purification, and is converted to the compound (IB) by pyrimidine ring formation reaction by mean of the known method (e.g., J. Med. Chem., 39 1635-1644 (1996)).
• This ring formation reaction can be carried out by heating the compound (XIV) with base such as sodium hydroxide, potassium t-butoxide or potassium carbonate in ethanol/water in the seal tube at 120 to 140° C. Further, the reaction can be carried out in high boiling solvent such as methoxyethanol in the presence of base such as potassium t-butoxide at 120 to 140° C.
• the reaction mixture is diluted with an organic solvent, which is nonmiscible solvent with water, and the organic layer is washed sequentially with water and saturated saline solution. Then, the compound (IB) can be obtained by removal of the solvent. This compound (IB) can be purified by chromatography or recrystallization, if necessary.
• PDE 7 phosphodiesterase VII
• the PDE 7 (phosphodiesterase VII) inhibiting effect of the compounds of the present invention was performed by the following method, which was modified assay method described in Biochemical. Pharmacol. 48(6), 1219-1223 (1994).
• the compounds of the present invention showed significant PDE 7 inhibiting effect.
• the compounds of the present invention selectively inhibit PDE 7 and their selectivities are more than 10 times compared to PDE 4 (phosphodiesterase IV), which is similar to the PDE 7. Therefore, it is expected that the side effect of the compounds of the present invention caused by PDE 4 to be less.
• the selectivity against PDE 4 (phosphodiesterase IV) of the compounds of the present invention was affirmed by means of the following Biological Test.
• the PDE 4 (phosphodiesterase IV) inhibiting effect of the compounds of the present invention was performed by the following method, which was modified assay method described in Biochemical. Pharmacol. 48(6), 1219-1223 (1994).
• the IC 50 of the compounds of the present invention was more than 10 times weaker than that of PDE 7 inhibiting effect.
• the compounds of the present invention inhibit PDE 7 selectively, and therefore, enhance cellular cAMP level. Consequently, the compounds of the present invention are useful for treating various kinds of disease such as allergic disease, inflammatory disease or immunologic disease.
• the compounds of the present invention are useful for treating or preventing the diseases such as bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, hepatitis, pancreatitis, encephalomyelitis, septicemia, CrohnIs disease, rejection for organ transplantation, GVH disease, and restenosis after angioplasty.
• diseases such as bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis,
• the compounds of the present invention can be used for preparation of the pharmaceutical composition or PDE 7 inhibitor.
• one or more compounds may be administered in the appropriated formulation.
• the formulation for oral administration may include for example, capsules, granules, fine granules, syrups, dry syrups or the like;
• the formulation for parenteral administration may include, for example injectable solution, suppository formulation such as rectal suppository or vaginal suppository, nasal administration such as sprays, or percutaneous absorption formulation such as ointment and tapes, and the like.
• the administration dose may vary depending on the various kinds of factors. These factors may be the condition of the patients, the severity of the disease, ages, existence of a complication, as well as formulation.
• a usual recommended daily dose for oral administration is within the range of 0.1-1,000 mg/day/adult, preferably 0.1-500 mg/day/adult, and more preferably1-100 mg/day/adult.
• a usual recommended daily dose is within the range of 1/1000 to 1 ⁇ 2 based on dose of oral administration. These doses can be adjusted depending on age, as well as the patient's condition.
• the toxicological properties of the compounds of the present invention is low, therefore, the compounds of the present invention is expected to have high safety margin.
• the obtained crude crystalline was further purified by recrystallization (hexane-ethyl acetate) to give 20.7 g (39%) of the title compound.
• the obtained amide compound was suspended in 50 mL of methoxyethanol and to this suspension was added 2.30 g (20.4 mmol) of potassium t-butoxide, then the mixture was stirred for 2 hours at 140° C. After the reaction mixture was cooled to the-room temperature, the mixture was condensed under reduced pressure and water was added to the residue. Further added 21 mL of 1N-HCl to the mixture, the mixture was extracted with chloroform. The organic layer was washed with water and saturated saline solution, and dried over anhydrous sodium sulfate.
• the title compound 1.02 g (87%) was obtained in a manner similar to the Example 9 by using the compound obtained in the Example 14, instead of the compound obtained in the Example 8.
• the title compound 16 mg (12%) was obtained in a manner similar to the Example 16 by using N-methyl-homopiperazine, instead of N-methylpiperazine.
• the title compound 58 mg (45%) was obtained in a manner similar to the Example 16 using morpholine and the compound obtained in the Example 15, instead of N-methylpiperazine and the compound obtained in the Example 9, respectively.
• the title compound 255 mg (50%) was obtained in a manner similar to the Example 24 using the compound obtained in the Example 30 instead of the compound obtained in the Example 23.
• the title compound 68 mg (55%) was obtained in a manner similar to the Example 26 using the compound obtained in the Example 31 instead of the compound obtained in the Example 24.
• the title compound 102 mg (94%) was obtained in a manner similar to the Example 26 using the compound obtained in the Example 31 and dimethylamine instead of the compound obtained in the Example 24 and methylamine, respectively.
• the title compound 733 mg (60%) was obtained in a manner similar to the Example 25 using the compound obtained in the Example 31 instead of the compound obtained in the Example 24.
• the title compound 131 mg (98%) was obtained in a manner similar to the Example 16 using the compound obtained in the Example 42 instead of the compound obtained in the Example 9.
• the title compound 128 mg (93%) was obtained in a manner similar to the Example 16 using N-methylhomopiperazine and the compound obtained in the Example 42, instead of N-methylpiperazine and the compound obtained in the Example 9, respectively.
• the title compound 791 mg (97%) was obtained in a manner similar to the Example 24 using the compound obtained in the Example 45 instead of the compound obtained in the Example 23.
• the title compound 122 mg (86%) was obtained in a manner similar to the Example 26 using dimethylamine and the compound obtained in the Example4 6, instead of methylamine and the compound obtained in the Example 24, respectively.
• the title compound 103 mg (83%) was obtained in a manner similar to the Example 26 by using the compound obtained in the Example 46 instead of the compound obtained in the Example 24.
• the title compound 92 mg (76%) was obtained in a manner similar to the Example 25 using the compound obtained in the Example 46 instead of the compound obtained in the Example 24.
• the compounds of the present invention inhibit PDE 7 selectively, and therefore, enhance cellular CAMP level. Consequently, the compounds of the present invention are useful for treating various kinds of disease such as allergic disease, inflammatory disease or immunologic disease.
• the compounds of the present invention are useful for treating or preventing the diseases such as bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, hepatitis, pancreatitis, encephalomyelitis, septicemia, Crohn's disease, rejection for organ transplantation, GVH disease, and restenosis after angioplasty.
• diseases such as bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus,

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