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WO2004111053A1 - Imidazotriazinone derivatives as pde 7 (phosphodiesterase 7) inhibitors - Google Patents

Imidazotriazinone derivatives as pde 7 (phosphodiesterase 7) inhibitors Download PDF

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WO2004111053A1
WO2004111053A1 PCT/JP2004/008642 JP2004008642W WO2004111053A1 WO 2004111053 A1 WO2004111053 A1 WO 2004111053A1 JP 2004008642 W JP2004008642 W JP 2004008642W WO 2004111053 A1 WO2004111053 A1 WO 2004111053A1
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group
substituted
compound
unsubstituted
cyclohexyl
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PCT/JP2004/008642
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French (fr)
Inventor
Hidekazu Inoue
Hidenobu Murafuji
Yasuharu Hayashi
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Daiichi Asubio Pharma Co.,Ltd.
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Priority to JP2006516843A priority Critical patent/JP2008501617A/en
Priority to US10/560,503 priority patent/US7713972B2/en
Priority to EP04736703A priority patent/EP1636234A1/en
Publication of WO2004111053A1 publication Critical patent/WO2004111053A1/en

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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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Definitions

  • the present invention relates to imidazotriazinone compounds, pharmaceutically acceptable salts and solvates thereof, having PDE 7
  • a cyclic AMP (cAMP) or cyclic GMP (cGMP) which is an intracellular second messenger substance, is decomposed and inactivated by phosphodiesterase (PDE 1 to PDE 11) .
  • the PDE 7 selectively decomposes cAMP, andis characterizedasanenzymenotdecomposedbyrolipram.
  • 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 ofT-cell is concernedwiththe exacerbation ofallergicdisease, 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.
  • GVH disease graft versus host 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, 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,
  • imidazotriazinone compounds represented by the following formula (IA) or (IB) : wherein:
  • A is N or CR 4 ;
  • R 1 is substituted or unsubstituted C 3 -C 8 cycloalkyl group or tert-butyl group;
  • R 2 is a hydrogen atom or C 1 -C 6 alkyl group
  • R 3 is a hydrogen atom; nitro group; cyano group; a halogen atom; heteroaryl group; substituted or unsubstituted Ci-Cg alkyl group; substituted or unsubstituted C 2 -C 6 alkenyl group; saturated or unsaturated heterocycloalkyl group which is substituted or unsubstituted; a group:
  • R 4 is a hydrogen atom or C 3. -C 3 alkoxy group which is unsubstituted 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 unsubstituted Ci-C 6 alkyl group; substituted or unsubstitutedacyl group; or substitutedorunsubstitutedheterocycloalkyl group;
  • R 7 is a hydrogen atom; substituted or unsubstituted Ci-C 6 alkyl group; substituted or unsubstituted heterocycloalkyl group; OH; -OR 8 or -NR 5 R 6 ;
  • R 8 is a hydrogen atom, substituted or unsubstituted Ci-C 6 alkyl group; or substituted or unsubstituted heterocycloalkyl group; or pharmaceutically acceptable salts or solvates thereof.
  • Ci-C 5 alkyl group of the present invention includes a straight or branched-chained alkyl group having 1 to 6 carbon atoms
  • C 2 -C 6 alkenyl group of the present invention means a straight or branched-chained alkenyl group having 2 to 6 carbon atoms
  • cycloalkyl group of the present invention includes a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 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 piperidinyl, pyrrolidinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, azetidinyl, and homopiperazinyl.
  • heteroarylgroup is 5to7memberedmonocyclicorpolycyclic group thereof containing 2 to 8 carbon atoms and the same or different 1 to 4 hetero atom(s) such as oxygen, nitrogen or sulfur atom(s) .
  • the examples includepyrrole, furyl, thienyl, imidazolyl, thiazolyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, tetrazolyl, pyridinyl, pyrazolyl, pyridazinyl, and pyrimidinyl.
  • the "halogen atom” includes fluorine, chlorine, bromine and iodine.
  • substituted or unsubstituted Ci-C ⁇ alkyl group examples include a straight or branched-chained, or substituted or unsubstituted alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, substituted or unsubstituted cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; hydroxyl group; cyano group; alkoxy group such as methoxy and ethoxy
  • R 1 is cyclopentyl, cyclohexyl or cycloheptyl group;
  • R 2 is methyl group;
  • R 3 is hydrogen atom, halogen atom, heteroaryl group, Ci-C 6 alky1 groupwhich is substitutedor unsubstituted;
  • C 2 -C 6 alkenyl group which is substituted or unsubstituted, saturated or unsaturated heterocycloalkyl group which is substituted or unsubstituted;
  • A is CR 4 in which R 4 is methoxy or ethoxy group; and B is CH, are preferable out of the compounds represented by the formula (IA) or (IB) .
  • 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 radiolabelled compounds of the formula (IA) and (IB) shall be included within the scope of the compounds of the present invention.
  • the compounds of thepresent invention contain one ormore asymmetric carbon atom and therefore, the compounds of the present invention exist as optical isomer of (R) -form or (S) -form, racemic form, as well as diastereomers . Further, the compounds of the present invention 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 isomersperseas well as the isomericmixtures thereof.
  • the compounds of the present invention may form acid additional salt thereof with various acids .
  • the acid additional salt include the saltswith inorganic acid such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; 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, glutamic acid and the like.
  • 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, calcium salt and the like. 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 imidazotriazinone compounds of the formula (IA) or (IB) of the present invention.
  • the compound of the formula (IA) of the present invention can be synthesized by the following methods. wherein, A, B, R 1 , R 2 and R 3 have same meaning mentioned above; L is C 1 -C 3 alkyl, Y is hydroxyl or a halogen atom, preferably chlorine atom, and Z is a halogen atom, preferably iodine atom.
  • thecompound (V) is obtained fromthe compound (VII) in accordance with the knownmethod.
  • This method can be conducted by the reaction of the amine compound (VII) with carboxylic acid derivatives (VIII) to obtain the corresponding acid amide compound (V) by the various methods.
  • the reaction can be conducted by reacting the compound (VII) with 1.0 to 1.5 equivalent, preferably 1.2 equivalent of the compound (VIII) in the presence of 1 to 5 equivalent, preferably 1.5 equivalent of tertiary amine such as triethylamine, based on the compound (VII) , and if necessary in the presence of the catalyst such as 4-dimethylaminopyridine.
  • the reaction can be conducted by reacting the compound (VII) with 1.0 to 1.5 equivalent, preferably 1.2 equivalent of the compound (VIII) in the presence of 1 to 5 equivalent, preferably 1.2 equivalent of the condensingagent suchas l-ethyl-3- (3-dimethyl-aminopropyl) carbodiimide, based on the compound (VII) , and if necessary in the presence of the catalyst such as 4-dimethylaminopyridine.
  • the condensingagent suchas l-ethyl-3- (3-dimethyl-aminopropyl) carbodiimide
  • the reaction mixture is diluted with the 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 (V) .
  • This compound can be purified by column chromatography, if necessary.
  • the compound (VII) to be used in this reaction can be commercially available or known compound and the compound (VIII) to be used in this reaction can also be commercially available or known compound.
  • the reaction can be conducted by reacting thecompound (V) withthe compound (VI) inthepresenceof 1 to 1.5 equivalent, preferably 1.0 equivalent of metal alkoxide such as sodium ethoxide or sodium methoxide, based on the compound (V) .
  • the reaction can be carried out in alcohols solvent such as methanol or ethanol at 0 0 C to the reflux temperature of the solvent .
  • the reaction mixture is acidified with inorganic acid such as hydrochloric acid, and the mixture is extracted with the organic solvent, which is nonmiscible solvent with water, and the extract is washed sequentially with water and saturated saline solution.
  • the reaction canbe conductedbyreacting the compound (III) with 0.3 to 2.0 equivalent, preferably 0.5 equivalent of the compound (IV) in alcohols solvent such as methanol or ethanol, at room temperature to the reflux temperature of the solvent.
  • alcohols solvent such as methanol or ethanol
  • water is added to the reaction mixture and the mixture is extracted with the organic solvent, which is nonmiscible solvent with water.
  • the extracted 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 compound (IA) of the present invention can be obtained from the compound (II) by imidazotriazinone ring formation reaction.
  • the reaction can be conducted in accordance with the known methods (e.g., J. Org. Chem. , 1981, 46, 3681-3685). Specifically, to pyridine solution of the compound (II) is added 1 to 5 equivalent, preferably 3 equivalent chlorotrimethylsilane and themixture is stirred. Then, 1 to 5 equivalent, preferably 3 equivalent of hexamethyldisilazane is added to the reaction mixture, and reaction is continued at the room temperature to the reflux temperature of the solvent .
  • the compound of the formula (IB) of the present invention may be synthesized by the following methods.
  • A, B, R 1 , R 2 and R 3 have same meaning mentioned above;
  • L is C 4 -C 3 lower alkyl, and
  • Z' is halogen atom, preferably chlorine atom.
  • the compound (IB) of the present invention can be obtained in accordance with the known method (e.g., Japanese Patent Publication No. 2001-522851) . That is, the compound (X) is obtained by the reaction of the compound (XI) with the compound (XIV) . This reaction can be conducted in ethers solvent such as tetrahydrofuran, in the presence of organic base such as pyridine or triethylamin, and catalyst such as 4-dimethylaminopyridine, at O 0 C to reflux temperature.
  • the compound (XII) is obtained from the compound (XIII) by reacting hydrazine hydrate in alcohols solvent at 0 0 C to reflux temperature.
  • the compound (IX) is obtained by reacting the above compound (X) with the compound (XII) in alcohols solvent such as ethanol at room temperature to reflux temperature.
  • the purpose compound (IB) is obtainedby the reaction ofthe compound (IX) withphosphorus oxychloride in a halogenated hydrocarbon such as 1,2-dichloromethane or chloroform.
  • the solvent is neutralizedbyadding inorganic base aqueous solution such as sodium hydrogen carbonate aqueous solution, and the mixture is extracted with the organic solvent, which is nonmiscible solvent with water.
  • the extracted organic layer is washed sequentially with water and saturated saline solution, then, the solvent is removed to give the purpose compound (IB) .
  • the compounds (XI) , (XIV) and (XIII) to be used in this reaction can be commercially available or known compounds. Further, the compound (XIII) to be used in this reaction can also be prepared in accordance with the knownmethod (e.g., Japanese Patent Publication No.2001-522851) .
  • the present invention is illustrated in more detail by way of the following Biological Test and Examples, but it is to be noted that the present invention is not limited by those Examples in any way.
  • the synthesis of the compounds of the present invention and intermediate compounds to be used in the synthesis are illustrated in the Example mentioned later. Further, the physicochemical data and chemical structure of the compounds and intermediate compounds obtained by the Examples are summarized in the Tables mentions later. The compound numbers in the Examples are identical to those in the Tables .
  • 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).
  • MOLT-4 obtained from ATCC as ATCC No. CRL-1582
  • MOLT-4 was incubated in RPMIl640 culture medium containing 10% fetal bovine serum to obtain 5 X 10 8 MOLT-4 cells.
  • the cells were collected by centrifugation and suspended with 1OmL of buffer solution A [25mM of tris-HCl, 5mM of 2-mercaptoethnol, 2mM of benzamidine, 2mM of EDTA, 0.ImM of 4- (2-aminoethyl)benzensulfonyl hydrochloride; pH 7.5] , then homogenized by Polytron® homogenizer.
  • the homogenate were centrifuged under 25,000 X G for 10 minutes at 4 0 C.
  • the supernatant was separated and thus obtained supernatant was further centrifuged under 100,000 X G for 60 minutes at 4 0 C, and then filtrated with 0.2 ⁇ m filter to obtain the soluble fraction.
  • IC 50 was calculated as 50% inhibiting concentration of the metabolic activities of phosphodiesterase VII of the tested compound.
  • 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 causedbyPDE 4 tobeless.
  • the selectivityagainst 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 active fraction of PDE 4 (phosphodiesterase IV) was obtained. That is, the livers obtained from three Balb/c mice (male, 12 weeks: obtainable fromCLEAJapan, Inc. ) weresuspendedwith3OmLofbuffersolution B [2OmM of bis-tris, 5mM of 2-mercaptoethnol, 2mM of benzamidine, 2mM of EDTA, O.lmM of 4- (2-aminoethyl)benzensulfonyl hydrochloride, 5OmM of sodium acetate; pH 6.5] , then homogenized by Polytron® homogenizer. The homogenate were centrifuged under 25,000 X G for 10 minutes at 4 0 C. The supernatant was separated and thus obtained supernatant was further centrifuged under 100,000 X G for 60 minutes at 4°C, and then filtrated with 0.2um filter to obtain the soluble fraction.
  • PDE 4 phosphodiesterase IV
  • IC 50 was calculated as 50% inhibiting concentration of the metabolic activities of phosphodiesterase IV of the tested compound.
  • 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, Crohn's disease, rejection for organ transplantation, graft versus host disease (GVH disease), and restenosis after angioplasty.
  • diseases such as bronchial asthma, chronic bronchitis, chronic obstructive pulmonary disease, allergic
  • 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 factorsmaybe the conditionofthepatients, 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 - l,000mg/day/adult, preferably 0.1 - 500mg/day/adult, and more preferably 1 - lOOmg/day/adult .
  • a usual recommended daily dose is within the range of 1/1000 tol/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.
  • Sodium ethoxide was prepared from 2.3g (102mmol) of sodium and 15OmL of ethanol, and to this mixture was added a suspension of 24.2g (102mmol) of the compound obtained in the Manufacturing Example 5 in 15OmL of ethanol at 0 0 C, andthen, themixturewas stirredthroughthe suspensionwasperfectly dissolved. Then, 6.32mL (102mmol) ofmethyliodidewas addedtothe reaction mixture after stirring 4 hours at room temperature, the reaction mixture was acidified with IM-HCl, then, the solvent was removed under reduced pressure. Water was added to the residue and the mixture was extracted with dichloromethane.
  • Sodium ethoxide was prepared from 117mg (5.10mmol) of sodium and l ⁇ mL of ethanol, and to this mixture was added 8 ⁇ 5mg (4.64mmol) of 2-methoxybenzamidine hydrochloride, then, the mixture was stirred for 45 minutes at room temperature. The unsolved substance was removed off by filtration and 2.34g (9.27mmol) of the compound obtained in the Manufacturing Example ⁇ in 25mL of methanol solution was added to the filtrate, and the mixture was refluxed for 20 hours. After the reaction mixture was cooled to the room temperature, appeared precipitate was collected by the filtration. The filtrate was removed under reduced pressure andwater was added to the residue, then, the mixture was extracted withdichloromethane .
  • Theorganiclayer waswashedwithwaterandsaturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was combined with above obtained precipitate, then, recrystallized from ethanol to give the solid.
  • a suspension of 320mg (0.90mmol) of the compound obtained in the Manufacturing Example 7 in 15mL of pyridine was added 0.34mL (2.7mmol) of chlorotrimethylsilane, and the mixture was stirred for 30 minutes at room temperature. Then, 0.57mL (2.7mmol) of hexar ⁇ ethyldisilazane was added to the reaction mixture and the mixture was refluxed for 5 hours.
  • the title compound 439mg (9%) was obtained in a manner similar to the Manufacturing Example 7 by using the compound obtained in the Manufacturing Example 3 instead of 2-methoxybenzamidine hydrochloride.
  • the title compound 14mg (3%) was obtained in a manner similar to the Example 1 by using the compound obtained in the Manufacturing Example 9 instead of the compound obtained in the Manufacturing Example 7.
  • 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 preventing or treating 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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Abstract

The present invention provides the compounds inhibiting PDE 7 selectively, and therefore, enhances cellular cAMP level. Consequently, the compound is useful for treating various kinds of disease such as allergic disease, inflammatory disease or immunologic disease. The compound is imidazotirazinone compound represented by the following formula (IA) or (IB): especially, R1 is cyclohexyl group, R2 is methyl group; R3 is a hydrogen atom; nitro group; cyano group; a halogen atom; heteroaryl group; substituted or unsubstituted C1-C6 alkyl group; substituted or unsubstituted C2-C6 alkenyl group; saturated or unsaturated heterocycloalkyl group which is substituted or unsubstituted; a group: -NR5R6, -C(O)R7, -SO2R7, -OR8, -NR8COR7, -NR8SO2R7; A is CR4; and B is CH.

Description

DESCRIPTION
IMIDAZOTRIAZINONE DERIVATIVES AS PDE 7 (PHOSPHODIESTERASE 7) INHIBITORS
Technical Field
The present invention relates to imidazotriazinone compounds, pharmaceutically acceptable salts and solvates thereof, having 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.
Background Art
A cyclic AMP (cAMP) or cyclic GMP (cGMP) , which is an intracellular second messenger substance, is decomposed and inactivated by phosphodiesterase (PDE 1 to PDE 11) . The PDE 7 selectively decomposes cAMP, andis characterizedasanenzymenotdecomposedbyrolipram. Rolipram is a selective inhibitor of PDE 4 which decomposes cAMP.
It is suggested that PDE 7 plays an important role for activating T cells (Beavo, et al., Science, 283, 848 (1999)), and well known that activating ofT-cell is concernedwiththe exacerbation ofallergicdisease, inflammatory disease or immunologic disease. These diseases are for example, 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. [J. Allergy Clin. Immunol. , 2000 Nov; 106(5 Suppl.) : S221-6; Am. J. Respir. Crit. CareMed. , 1996 Feb; 153(2) : 629-32; Am. J. Respir. Crit. CareMed., 1999 Nov; 160(5 Pt 2): S33-7; Clin. Exp. Allergy, 2000 Feb; 30(2): 242-54; Hosp. Med., 1998 JuI; 59(7): 530-3; Int. Arch. Allergy Immunol. , 1998 Mar; 115(3): 179-90; J. Immunol., 1991 Feb 15; 146(4) : 1169-74; Osteoarthritis Cartilage, 1999 JuI; 7(4) : 401-2; Rheum. Dis. Clin. North Am. , 2001 May; 27(2): 317-34; J. Autoimmun. , 2001 May; 16(3): 187-92; Curr. Rheumatol. Rep., 2000 Feb; 2(1): 24-31; Trends Immunol., 2001 Jan; 22(1): 21-6; Curr. Opin. Immunol., 2000 Aug; 12(4): 403-8; Diabetes Care, 2001 Sep; 24(9): 1661-7; J. Neuroimmunol . , 2000 Novl; 111(1-2) : 224-8; Curr. Opin. Immunol., 1997 Dec; 9(6) : 793-9; JSMA, 1999 Sep 15; 282(11) : 1076-82; Semin. Cancer Biol., 1996 Apr; 7(2) : 57-64; J. Interferon Cytokine Res., 2001 Apr; 21(4): 219-21].
Therefore, it is considered that 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.
There has been proposed many compounds selectively inhibit PDE 7. These are for example, imidazopyridine derivatives (International Patent PublicationWO 01/34601) , dihydropurine derivatives (International Patent Publication WO 00/68203), pyrrole derivatives (International Patent Publication WO 01/32618), benzothiopyranoimidazolone derivatives (DE Patent 19950647), heterocyclic compounds (International Patent Publications WO 02/88080; 02/87513) , quinazoline and pyridopyrimidine derivatives (International Patent Publication WO 02/102315) , spiro tricyclic compounds (International Patent Publication WO 02/74754) , thiazole and oxathiazole derivatives (International Patent Publication WO 02/28847), sulfonamide derivatives (International Patent Publication WO 01/98274) , heterobiarylsulfonamide derivatives (International Patent Publication WO 01/74786) , dihydroisoquinoline derivatives (International Patent Publication WO 02/40450) , guanine derivatives (Bioorg. Med. Chem. Lett., 11(2001), 1081), benzothiadiazine derivatives (J. Med. Chem., 43(2000), 683) andbenzothienothiadiazine derivatives (Eur. J.Med. Chem., 36(2001), 333) . However, no curative medicines having PDE 7 inhibiting effect as main pharmacological mechanism have developed up to now.
Though some imidazotriazinone derivatives have been known (For examples: International Patent Publications WO 01/47928; WO 02/98880; WO02/98879;WO02/98873; WO02/79203; WO02/74774; WO02/68423; WO02/64593; WO 02/50078; WO 01/64677; WO 99/67244; WO 99/24433; and EP 1092719), the compounds represented by the general formula of the present application in which R1 is cycloalkyl group or tert-butyl group have never been proposed and there is no suggestions that these compounds have. PDE 7 inhibiting effect .
Therefore, 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. For example, 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.
Disclosure of Invention
Through extensive investigations of researching compounds having the capabilities of inhibiting PDE I1 the present inventors discovered that the compounds having imidazotriazinone skeleton in the molecular represented by the formula (IA) or (IB) mentioned below' possess potent and selective PDE 7 inhibiting effect, and therefore, completed the present invention.
Accordingly, as one aspect of the present invention, it is provided imidazotriazinone compounds represented by the following formula (IA) or (IB) :
Figure imgf000005_0001
wherein:
A is N or CR4;
B is N or CH; R1 is substituted or unsubstituted C3-C8 cycloalkyl group or tert-butyl group;
R2 is a hydrogen atom or C1-C6 alkyl group;
R3 is a hydrogen atom; nitro group; cyano group; a halogen atom; heteroaryl group; substituted or unsubstituted Ci-Cg alkyl group; substituted or unsubstituted C2-C6 alkenyl group; saturated or unsaturated heterocycloalkyl group which is substituted or unsubstituted; a group:
-NR5R6, -C(O)R7, -SO2R7, -OR8, -NR8COR7, -NR8SO2R7;
R4 is a hydrogen atom or C3.-C3 alkoxy group which is unsubstituted or substituted by one or more fluorine atom(s) ; R5 and R6 are, same or different from each other, a hydrogen atom; substituted or unsubstituted Ci-C6 alkyl group; substituted or unsubstitutedacyl group; or substitutedorunsubstitutedheterocycloalkyl group;
R7 is a hydrogen atom; substituted or unsubstituted Ci-C6 alkyl group; substituted or unsubstituted heterocycloalkyl group; OH; -OR8 or -NR5R6;
R8 is a hydrogen atom, substituted or unsubstituted Ci-C6 alkyl group; or substituted or unsubstituted heterocycloalkyl group; or pharmaceutically acceptable salts or solvates thereof.
Still another aspect of the present invention, it is provided PDE 7 inhibiting composition containing the imidazotriazinone compounds mentioned above, or pharmaceutically acceptable salts or solvates thereof as an active ingredient.
Best Mode for Carrying Out the Invention- The present invention will now be explained more specifically as following.
The term "Ci-C5 alkyl group" of the present invention includes a straight or branched-chained alkyl group having 1 to 6 carbon atoms, and the term "C2-C6 alkenyl group" of the present invention means a straight or branched-chained alkenyl group having 2 to 6 carbon atoms. The term "cycloalkyl group" of the present invention includes a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The term "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 piperidinyl, pyrrolidinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, azetidinyl, and homopiperazinyl.
Theterm"heteroarylgroup" is 5to7memberedmonocyclicorpolycyclic group thereof containing 2 to 8 carbon atoms and the same or different 1 to 4 hetero atom(s) such as oxygen, nitrogen or sulfur atom(s) . The examples includepyrrole, furyl, thienyl, imidazolyl, thiazolyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, tetrazolyl, pyridinyl, pyrazolyl, pyridazinyl, and pyrimidinyl. The "halogen atom" includes fluorine, chlorine, bromine and iodine.
Examples of the suitable substitiuent of "substituted or unsubstituted Ci-Cβ alkyl group", "substituted or unsubstituted C3-C8 cycloalkyl group", "substituted or unsubstituted alkenyl group", " substituted or unsubstituted heterocycloalkyl group" and " substituted or unsubstituted acyl group" include a straight or branched-chained, or substituted or unsubstituted alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, substituted or unsubstituted cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; hydroxyl group; cyano group; alkoxy group such as methoxy and ethoxy; substituted or unsubstituted amino group such as amino, methylamino, ethylamino, and dimethylamino; substituted or unsubstituted acyl group such as acetyl, and propionyl; substituted or unsubstituted aryl group; substituted or unsubstituted heteroaryl group; saturated or unsaturated heterocycloalkyl group which is substituted or unsubstituted; substitutedorunsubstitutedcarbamoyl group; substitutedorunsubstituted amide group; halogen atom; nitro group; substituted or unsubstituted sulfone group; oxo group; urea group; a straight or branched-chained, or cyclic alkenyl group which is substituted or unsubstituted such as ethenyl, propenyl, cyclohexenyl and the like.
The compounds wherein R1 is cyclopentyl, cyclohexyl or cycloheptyl group; R2 is methyl group; R3 is hydrogen atom, halogen atom, heteroaryl group, Ci-C6 alky1 groupwhich is substitutedor unsubstituted; C2-C6alkenyl group which is substituted or unsubstituted, saturated or unsaturated heterocycloalkyl group which is substituted or unsubstituted; group -NR5R6 in which R5R6 is heterocycloalkyl group which is substituted or unsubstituted; A is CR4 in which R4 is methoxy or ethoxy group; and B is CH, are preferable out of the compounds represented by the formula (IA) or (IB) .
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 radiolabelled compounds of the formula (IA) and (IB) shall be included within the scope of the compounds of the present invention.
The compounds of thepresent invention contain one ormore asymmetric carbon atom and therefore, the compounds of the present invention exist as optical isomer of (R) -form or (S) -form, racemic form, as well as diastereomers . Further, the compounds of the present invention 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 isomersperseas well as the isomericmixtures thereof.
The compounds of the present invention may form acid additional salt thereof with various acids . Examples of the acid additional salt include the saltswith inorganic acidsuch as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; 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, glutamic acid and the like. 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, calcium salt and the like. 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 imidazotriazinone compounds of the formula (IA) or (IB) of the present invention.
6-cyclohexyl-2- (2-methoxyphenyl) -8-methylimidazo[l, 5-a] [1, 3,5] - triazin-4 (3H) -one; β-cyclohexyl-2- [2-methoxy-4~ (1-piperazinyl) phenyl] -8-methylimidazo-
[1, 5-a] [1, 3, 5] triazin-4 (3H) -one; β-cyclohexyl-2- [2-methoxy-4- (4-methyl-l-piperazinyl) phenyl] -8- methylimidazo [1, 5-a] [1,3,5] triazin-4 (3H) -one;
2- [4- (4-amino-l-piperidinyl) -2-methoxyphenyl] -6-cyclohexyl-8~ methylimidazo[l, 5-a] [1, 3, 5] triazin-4 (3H) -one; β-cyclohexyl-2-{2-methoxy-4- [4- (methylamino) -1-piperidinyl]phenyl }-
8-methylimidazo[l,5-a] [1, 3, 5] triazin-4 (3H) -one; β-cyclohexyl-2-{4- [4- (dimethylamino) -1-piperidinyl] -2-methoxy- phenyl}-8-methylimidazo[l,5-a] [1, 3,5] triazin-4 (3H) -one; β-cyclohexyl-2- [4- (1, 4-diazepan-l-yl) -2-methoxyphenyl] -8~ methylimidazo[l,5-a] [1, 3, 5] triazin-4 (3H) -one; β-cyclohexyl-2- [2-methoxy-4- (4-methyl-l, 4-diazepan-l-yl) phenyl] -8- methylimidazo[l,5-a] [1, 3,5] triazin-4 (3H) -one;
6-cyclohexyl-2- [4- (4-hydroxy-l-piperidinyl) -2-methoxyphenyl] -8- methylimidazo [1, 5-a] [1,3,5] triazin-4 (3H) -one;
6-cyclohexyl-2-{4- [ (4-hydroxy-l-piperidinyl) sulfonyl]-2- methoxyphenyl}-8-methylimidazo [1, 5-a] [1, 3, 5] triazin-4 (3H) -one;
6-cyclohexyl-2-[2-methoxy-4-(l-piperazinylsulfonyl) phenyl] -8- methylimidazo [1, 5-a] [1, 3, 5] triazin-4 (3H) -one; β-cyclohexyl-2-{2-methoxy-4- [ (4-methyl-1-piperazinyl) sulfonyl] - phenyl}-8-rαethylimidazo[l,5-a] [1,3,5] triazin-4 (3H) -one; β-cyclohexyl-2- [4- (1, 4-diazepan-l-ylsulfonyl) -2-methoxyphenyl] -8- methylimidazo [1, 5-a] [1,3,5] triazin-4 (3H) -one; β-cyclohexyl-2-{2-methoxy-4- [ (4-methyl-l, 4-diazepam-l-yl) sulfonyl] - phenyl}-8-methylimidazo[l,5-a] [1, 3,5] triazin-4 (3H) -one;
5-cyclohexyl-2- (2-methoxyphenyl) -7-methylimidazo [5, 1-f] [1,2,4]- triazin-4 (3H) -one; 5-cyclohexyl-2- [2-methoxy-4- (4-methyl-l-piperazinyl) phenyl] -7- methylimidazo[5,l-f] [1, 2, 4] triazin-4 (3H) -one;
5-cyclohexyl-2- [2-methoxy-4- (1-piperazinyl) phenyl] -7-methylimidazo-
[5, 1-f] [1,2, 4] triazin-4 (3H) -one;
2- [4- (4-amino-l-piperidinyl) -2-methoxyphenyl] -5-cyclohexyl-7- methylimidazo [5, 1-f] [1,2, 4] triazin-4 (3H) -one;
5-cyclohexyl-2-{2-methoxy-4- [4- (methylamino) -1-piperidinyl]phenyl}-
7-methylimidazo [5, 1-f] [1,2,4] triazin-4 (3H) -one;
5-cyclohexyl-2-{ 4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl}-7-methylimidazo [5, 1-f] [1,2, 4] triazin-4 (3H) -one; 5-cyclohexyl-2- [4- (1, 4-diazepan-l-yl) -2-methoxyphenyl] -7- methylimidazo[5,l-f] [1,2, 4] triazin-4 (3H) -one;
5-cyclohexyl-2- [2-methoxy-4- (4-methyl-l, 4-diazepan-l-yl) phenyl] -7- methylimidazo[5,l-f] [1,2, 4] triazin-4 (3H) -one;
5-cyclohexyl-2- [4- (4-hydroxy-l-piperidinyl) -2-methoxyphenyl] -7- methylimidazo [5, 1-f] [1,2, 4] triazin-4 (3H) -one;
5-cyclohexyl-2-{ 4- [ (4-hydroxy-l-piperidinyl) sulfonyl] -2-methoxyphenyl} -7-methylimidazo [5, 1-f] [1,2, 4]triazin-4 (3H) -one;
5-cyclohexyl-2-[2-methoxy-4- (1-piperazinylsulfonyl) phenyl] -7- methylimidazo[5,l-f] [1,2, 4] triazin-4 (3H) -one; ] 5-cyclohexyl-2-{2-methoxy-4- [ (4-methyl-l-piperazinyl) sulfonyl] - phenyl}-7-methylimidazo[5,l-f] [1,2, 4] triazin-4 (3H) -one;
5-cyclohexyl-2- [4- (1, 4-diazepan-l-ylsulfonyl) -2-methoxyphenyl] -7- methylimidazo [5, 1-f] [1, 2, 4] triazin-4 (3H) -one; 5-cyclohexyl-2-{2-methoxy-4- [ (4-methyl-1, 4-diazepan-l-yl) sulfonyl] - phenyl}-7-methylimidazo [5, 1-f] [1, 2, 4] triazin-4 (3H) -one; 6-cyclohexyl-2- (2-ethoxyphenyl) -8-methylimidazo [1, 5-a] [1,3, 5] - triazin-4 (3H) -one; 6-cyclohexyl-2- [2-ethoxy-4- (1-piperazinyl) phenyl] -8-methylimidazo- [1,5-a] [1,3, 5] triazin-4 (3H) -one;
6-cyclohexyl-2- [2-ethoxy-4- (4-methyl-1-piperazinyl) phenyl] -8- methylimidazo[l, 5-a] [1, 3, 5] triazin-4 (3H) -one; 2- [4- (4-amino-l-piperidinyl) -2-ethoxyphenyl] -6-cyclohexyl-8- methylimidazo [1, 5-a] [1,3, 5] triazin-4 (3H) -one;
6-cyclohexyl-2-{2-ethoxy [4- (methylamino) -1-piperidinyl] phenyl}-8- methylimidazo [1, 5-a] [1, 3, 5] triazin-4 (3H) -one; 6-cyclohexyl-2-{4- [4- (dimethylamino) -1-piperidinyl] -2-ethoxyphenyl}-8-methylimidazo [1, 5-a] [1, 3, 5] triazin-4 (3H) -one; β-cyclohexyl-2- [4- (1, 4-diazepan-l-yl) -2-ethoxyphenyl] -8-methylimidazo [1, 5-a] [1, 3, 5] triazin-4 (3H) -one;
6-cyclohexyl-2- [2-ethoxy-4- (4-methyl-l, 4-diazepan-l-yl) phenyl] -8- methylimidazo[l,5-a] [1, 3, 5] triazin-4 (3H) -one; β-cyclohexyl-2- [4- (4-hydroxy-l-piperidinyl) -2-ethoxyphenyl] -8- methylimidazo [1, 5-a] [1, 3, 5] triazin-4 (3H) -one;
6-cyclohexyl-2-{4- [ (4-hydroxy-l-piperidinyl) sulfonyl] -2-ethoxyphenyl}-8-methylimidazo [1, 5-a] [1,3, 5] triazin-4 (3H) -one; β-cyclohexyl-2-[2-ethoxy-4- (1-piperazinylsulfonyl) phenyl] -8- methylimidazo[l,5-a] [1, 3, 5] triazin-4 (3H) -one; 6-cyclohexyl-2-{2-ethoxy-4- [ (4-methyl-l-piperazinyl) sulfonyl] - phenyl}-8-methylimidazo [1, 5-a] [1, 3, 5] triazin-4 (3H) -one; β-cyclohexyl-2- [4- (1, 4-diazepan-l-ylsulfonyl) -2-ethoxyphenyl] -8- methylimidazo[l,5~a] [1,3, 5] triazin-4 (3H) -one; 6-cyclohexyl-2-{2-ethoxy-4- [ (4-methyl-l, 4-diazepan-l-yl) sulfonyl] - phenyl}-8-methylimidazo [1, 5-a] [1, 3, 5] triazin-4 (3H) -one;
5-cyclohexyl-2- (2-ethoxyphenyl) -7-methylimidazo [5, 1-f] [1,2,4]- triazin-4 (3H) -one;
5-cyclohexyl-2- [2-ethoxy-4- (4-methyl-l-piperazinyl) phenyl] -7- methylimidazo[5,l-f] [1,2, 4] triazin-4 (3H) -one; 5-cyclohexyl-2- [2-ethoxy-4- (1-piperazinyl) phenyl] -7-methylimidazo [5, 1-f] [I12, 4] triazin-4 (3H) -one;
2- [4- (4-amino-l-ρiperidinyl) -2-ethoxyphenyl] -5-cyclohexyl-7- methylimidazo[5,l-f] [1,2, 4] triazin-4 (3H) -one;
5-cyclohexyl-2-{2-ethoxy-4- [4- (methylamino) -1-piperidinyl] phenyl}- 7-methylimidazo [5, 1-f] [1, 2, 4] triazin-4 (3H) -one; 5-cyclohexyl-2-{4~ [4- (dimethylamino) -1-piperidinyl] -2-ethoxyphenyl}-7-methylimidazo [5, 1-f] [1,2,4] triazin-4 (3H) -one; 5-cyclohexyl-2- [4- (1, 4-diazepan-l-yl) -2-ethoxyphenyl] -7-methylimidazo [5, 1-f] [1,2, 4] triazin-4 (3H) -one;
5-cyclohexyl-2-[2-ethoxy-4-(4-methyl-l, 4-diazepan-l-yl) phenyl] -7- methylimidazo[5,l-f] [1,2, 4] triazin-4 (3H) -one; 5-cyclohexyl-2- [4- (4-hydroxy-l-piperidinyl) -2-ethoxyphenyl] -7- methylimidazo[5,l-f] [1,2, 4] triazin-4 (3H) -one;
5-cyclohexyl-2-{4- [ (4-hydroxy-l-piperidinyl) sulfonyl] -2-ethoxyphenyl}-7-methylimidazo [5, 1-f] [1,2, 4] triazin-4 (3H) -one; 5-cyclohexyl-2-[2-ethoxy-4- (1-piperazinylsulfonyl) phenyl] -7- methylimidazo[5,l-f] [1,2, 4] triazin-4 (3H) -one; 5-cyclohexyl-2-{2-ethoxy-4- [ (4-methyl-l-piperazinyl) sulfonyl] - phenyl}-7-methylimidazo [5, 1-f] [1, 2, 4] triazin-4 (3H) -one; 5-cyclohexyl-2- [4- (1, 4-diazepan-l-ylsulfonyl) -2-ethoxyphenyl] -7- methylimidazo[5,l-f] [1,2, 4] triazin-4 (3H) -one; 5-cyclohexyl-2-{2-ethoxy-4- [ (4-methyl-l, 4-diazepan-l-yl) sulfonyl] - phenyl}-7-methylimidazo[5,l-f] [1,2, 4] triazin-4 (3H) -one.
The compound of the formula (IA) of the present invention can be synthesized by the following methods.
Figure imgf000012_0001
wherein, A, B, R1, R2 and R3 have same meaning mentioned above; L is C1-C3 alkyl, Y is hydroxyl or a halogen atom, preferably chlorine atom, and Z is a halogen atom, preferably iodine atom.
At thebeginning, tocarryoutthemethoddescribedabove, thecompound (V) is obtained fromthe compound (VII) in accordance with the knownmethod. This method can be conducted by the reaction of the amine compound (VII) with carboxylic acid derivatives (VIII) to obtain the corresponding acid amide compound (V) by the various methods. For example, in the case of the compound (VIII) in which Y is halogen atom, preferably chlorine atom, the reaction can be conducted by reacting the compound (VII) with 1.0 to 1.5 equivalent, preferably 1.2 equivalent of the compound (VIII) in the presence of 1 to 5 equivalent, preferably 1.5 equivalent of tertiary amine such as triethylamine, based on the compound (VII) , and if necessary in the presence of the catalyst such as 4-dimethylaminopyridine.
Furthermore, in the case of the compound (VIII) in which Y is hydroxyl group, the reaction can be conducted by reacting the compound (VII) with 1.0 to 1.5 equivalent, preferably 1.2 equivalent of the compound (VIII) in the presence of 1 to 5 equivalent, preferably 1.2 equivalent of the condensingagent suchas l-ethyl-3- (3-dimethyl-aminopropyl) carbodiimide, based on the compound (VII) , and if necessary in the presence of the catalyst such as 4-dimethylaminopyridine.
After the reaction is completed, the reaction mixture is diluted with the 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 (V) .
This compound can be purified by column chromatography, if necessary.
The compound (VII) to be used in this reaction can be commercially available or known compound and the compound (VIII) to be used in this reaction can also be commercially available or known compound.
Then, thecompound (V) is convertedtothecompound (III) inaccordance with the known reaction method. The reaction can be conducted by reacting thecompound (V) withthe compound (VI) inthepresenceof 1 to 1.5 equivalent, preferably 1.0 equivalent of metal alkoxide such as sodium ethoxide or sodium methoxide, based on the compound (V) . The reaction can be carried out in alcohols solvent such as methanol or ethanol at 00C to the reflux temperature of the solvent . After the reaction is completed, the reaction mixture is acidified with inorganic acid such as hydrochloric acid, and the mixture is extracted with the organic solvent, which is nonmiscible solvent with water, and the extract is washed sequentially with water and saturated saline solution. Then, the solvent is removed to give the purpose compound (III) . This compound can be purified by column chromatography, if necessary. The obtained compound (III) is converted to the compound (II) in accordance withthe knownmethod. The reaction canbe conductedbyreacting the compound (III) with 0.3 to 2.0 equivalent, preferably 0.5 equivalent of the compound (IV) in alcohols solvent such as methanol or ethanol, at room temperature to the reflux temperature of the solvent. After the reaction is completed, water is added to the reaction mixture and the mixture is extracted with the organic solvent, which is nonmiscible solvent with water. The extracted 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.
Next, the compound (IA) of the present invention can be obtained from the compound (II) by imidazotriazinone ring formation reaction. The reaction can be conducted in accordance with the known methods (e.g., J. Org. Chem. , 1981, 46, 3681-3685). Specifically, to pyridine solution of the compound (II) is added 1 to 5 equivalent, preferably 3 equivalent chlorotrimethylsilane and themixture is stirred. Then, 1 to 5 equivalent, preferably 3 equivalent of hexamethyldisilazane is added to the reaction mixture, and reaction is continued at the room temperature to the reflux temperature of the solvent . After the reaction is completed, the solvent is removed and alcohols solvent such as methanol or ethanol is added to the residue and the solvent is stirred and removed. Water is added to the residue and the mixture is extracted with the organic solvent, which is nonmiscible solvent with water. The extracted organic layer is washed sequentially with water and saturated saline solution, then, the solvent is removed to give the purpose compound (IA) . This compound can be purified by column chromatography, if necessary.
All reaction mentioned above are well known, and the reagents to be used or the reaction conditions to be applied can be easily established in accordance with the standard text book and the examples mentioned later. Therefore, the othermethods ormodifiedmethods for obtaining the compound (IA) of the present invention can be easily selected by the person skilled in this field.
The compound of the formula (IB) of the present invention may be synthesized by the following methods.
Figure imgf000014_0001
wherein, A, B, R1, R2 and R3 have same meaning mentioned above; L is C4-C3 lower alkyl, and Z' is halogen atom, preferably chlorine atom.
The compound (IB) of the present invention can be obtained in accordance with the known method (e.g., Japanese Patent Publication No. 2001-522851) . That is, the compound (X) is obtained by the reaction of the compound (XI) with the compound (XIV) . This reaction can be conducted in ethers solvent such as tetrahydrofuran, in the presence of organic base such as pyridine or triethylamin, and catalyst such as 4-dimethylaminopyridine, at O0C to reflux temperature. Separately, the compound (XII) is obtained from the compound (XIII) by reacting hydrazine hydrate in alcohols solvent at 00C to reflux temperature.
Then, the compound (IX) is obtained by reacting the above compound (X) with the compound (XII) in alcohols solvent such as ethanol at room temperature to reflux temperature. Finally, the purpose compound (IB) is obtainedby the reaction ofthe compound (IX) withphosphorus oxychloride in a halogenated hydrocarbon such as 1,2-dichloromethane or chloroform.
After the reaction is completed, the solvent is neutralizedbyadding inorganic base aqueous solution such as sodium hydrogen carbonate aqueous solution, and the mixture is extracted with the organic solvent, which is nonmiscible solvent with water. The extracted organic layer is washed sequentially with water and saturated saline solution, then, the solvent is removed to give the purpose compound (IB) .
The compounds (XI) , (XIV) and (XIII) to be used in this reaction can be commercially available or known compounds. Further, the compound (XIII) to be used in this reaction can also be prepared in accordance with the knownmethod (e.g., Japanese Patent Publication No.2001-522851) .
All reaction mentioned above are well known, and the reagents to be used or the reaction conditions to be applied can be easily established in accordance with the standard text book and the examples mentioned later. Therefore, the othermethods ormodifiedmethods for obtaining the compound (IB) of the present invention can be easily selected by the person skilled in the art in this field. Examples :
The present invention is illustrated in more detail by way of the following Biological Test and Examples, but it is to be noted that the present invention is not limited by those Examples in any way. The synthesis of the compounds of the present invention and intermediate compounds to be used in the synthesis are illustrated in the Example mentioned later. Further, the physicochemical data and chemical structure of the compounds and intermediate compounds obtained by the Examples are summarized in the Tables mentions later. The compound numbers in the Examples are identical to those in the Tables .
The PDE 7 (phosphodiesterase VII) inhibiting effect of the compounds of the present invention obtained in the later mentioned Examples was evaluated by mean of the following Biological Tests.
Biological Test 1:
Methods for evaluating the PDE 7 inhibiting effect
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).
(1) The active fraction of PDE 7 (phosphodiesterase VII) was obtained. That is, MOLT-4 (obtainable from ATCC as ATCC No. CRL-1582) , which was cell line of human acute lymphoblastic lymphoma T cells, was incubated in RPMIl640 culture medium containing 10% fetal bovine serum to obtain 5 X 108 MOLT-4 cells. The cells were collected by centrifugation and suspended with 1OmL of buffer solution A [25mM of tris-HCl, 5mM of 2-mercaptoethnol, 2mM of benzamidine, 2mM of EDTA, 0.ImM of 4- (2-aminoethyl)benzensulfonyl hydrochloride; pH 7.5] , then homogenized by Polytron® homogenizer. The homogenate were centrifuged under 25,000 X G for 10 minutes at 40C. The supernatant was separated and thus obtained supernatant was further centrifuged under 100,000 X G for 60 minutes at 40C, and then filtrated with 0.2μm filter to obtain the soluble fraction.
(2) The obtained soluble fraction was filled in equilibrium HiTrap Q column (5mL X 2) with buffer solution A, and phosphodiesterase fractions were eluted by 30OmL of buffer solution A with linear gradient from 0 to 0.8 M NaCl concentration. 5 ml each of 60 eluents were collected, and each eluents were examined for cyclic AMP metabolic activities of phosphodiesterase. The fraction eluting with about 35OmM NaCl concentration parts, where metabolic activities were not inactivated by lOμM of rolipram (selective inhibitor for phosphodiesterase IV) and lOμM of milrinone (selective inhibitor for phosphodiesterase III) , were collected as storage solution for using to test PDE 7 inhibiting effect.
(3) The tested compound having desired concentration was reacted in the solution of 2OmMtris-HCl (pH7.5), ImMOfMgCl2, lOOμMofEDTA, 330μg/mL of bovine serum albumin, 4μg/mL of 5 ' -nucleotidase, O.lμCi of 3H-CAMP (0.064μM of cAMP) , lOμM of rolipram in storage solution of PDE 7 for 2 hours at 25°C. After the reaction, suspension of Sephadex®-QAE in 1OmM of HEPES-Na (pH 7.0) was added to the reaction mixture, and the mixture was left at rest for 5 minutes. Further, Sephadex®-QAE was added to the obtained supernatant and the mixture was leaved at rest for 5 minutes, then, the radioactivity of the solution was measured.
(4) IC50 was calculated as 50% inhibiting concentration of the metabolic activities of phosphodiesterase VII of the tested compound.
The followingarePDE7 inhibitingactivities ofthetestedcompounds .
Compound 8: IC50 = 0.34μM; Compound 11: IC50 = 0.055μM;
Compound 12: IC50 = 0.49μM:
As described above, 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 causedbyPDE 4 tobeless. The selectivityagainst PDE 4 (phosphodiesterase IV) of the compounds of the present invention was affirmed by means of the following Biological Test.
Biological Test 2:
Methods for evaluating the PDE 4 inhibiting effect
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) .
(1) The active fraction of PDE 4 (phosphodiesterase IV) was obtained. That is, the livers obtained from three Balb/c mice (male, 12 weeks: obtainable fromCLEAJapan, Inc. ) weresuspendedwith3OmLofbuffersolution B [2OmM of bis-tris, 5mM of 2-mercaptoethnol, 2mM of benzamidine, 2mM of EDTA, O.lmM of 4- (2-aminoethyl)benzensulfonyl hydrochloride, 5OmM of sodium acetate; pH 6.5] , then homogenized by Polytron® homogenizer. The homogenate were centrifuged under 25,000 X G for 10 minutes at 40C. The supernatant was separated and thus obtained supernatant was further centrifuged under 100,000 X G for 60 minutes at 4°C, and then filtrated with 0.2um filter to obtain the soluble fraction.
(2) The obtained soluble fraction was filled in equilibrium DEAE sepharose column (1 X 10cm) with buffer solution B, andphosphodiesterase fractions were eluted by 12OmL of buffer solution B with linear gradient from 0.05 to IM sodium acetate concentration. 5 ml each of 24 eluents were collected, and each eluents were examined for cyclic AMP metabolic activities of phosphodiesterase. The fraction eluting with about 62OmM of sosdium acetate concentration parts, where metabolic activities were inactivatedby 30μMof rolipram (selective inhibitor forphosphodiesterase IV) , were collected as storage solution to test PDE 4 inhibiting effect. (3) The tested compound having desired concentration was reacted in the solution of 2OmM tris-HCl (pH7.5), ImMOfMgCl2, lOOμMofEDTA, 330μg/mL of bovine serum albumin, 4μg/mL of 5' -nucleotidase, 0. lμCi of 3H-CAMP (0.064μM of cAMP) , and storage solution of PDE 4 for 2 hours at 25°C. After the reaction, suspension of Seρhadex®-QAE in 1OmM of HEPES-Na (pH 7.0) was added to the reaction mixture, and the mixture was left at rest for 5minutes . Further, Sephadex®-QAEwas addedtotheobtainedsupernatant and the mixture was left at rest for 5 minutes, then, the radioactivity of the solution was measured.
(4) IC50 was calculated as 50% inhibiting concentration of the metabolic activities of phosphodiesterase IV of the tested compound.
As the results of the mentioned above Biological Test 2, the IC50 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. For example, 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, graft versus host disease (GVH disease), and restenosis after angioplasty.
The compounds of the present invention can be used for preparation of the pharmaceutical composition or PDE 7 inhibitor. As an active ingredient, 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 factorsmaybe the conditionofthepatients, 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 - l,000mg/day/adult, preferably 0.1 - 500mg/day/adult, and more preferably 1 - lOOmg/day/adult . In the case of parenteral administration, a usual recommended daily dose is within the range of 1/1000 tol/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.
Manufacturing Examples and Examples:
The synthesis of the compounds of the present invention and intermediate compounds to be used in the synthesis are illustrated in the following Manufacturing Examples and Examples .
The physicochemical data and chemical structure of the compounds are summarized in the Tables mentions later. The compound numbers in the
Examples are identical to those in the Tables.
Manufacturing Example 1 (Compound 1) :
4-Bromo-2-methoxybenzamide
To a suspension of 12.59g (54.5mmol) of 4-bromo-2-methoxybenzamide in 7OmL of 1, 2-dichloroethane was added 11.9mL (163.5mmol) of thionyl chloride, and themixture was refluxed for 2 hours . The solvent was removed under reduced pressure to obtain the corresponding acid chloride. Then, to 125mL of 28% ammonia solution was added dripping solution of above acid chloride in 8OmL of acetone at 00C, and the resulting precipitate was collected to give 9.22g (74%) of the title compound.
Manufacturing Example 2 (Compound 2) :
4-Bromo-2-methoxybexzonitrile
To a solution of 9.22g (40.1mmol) of the compound obtained in the Manufacturing Example 1 in 20OmL of anhydrous dichloromethane were added 11.17mL (80.2mmol) of triethyamine and 8.09mL of anhydrous trifluoroitiethanesulfonic acid at 00C, and the mixture was stirred for 30 minutes at the same temperature and for 1 hour at room temperature. Then, water was added to the reactionmixture and the mixture was extracted with dichloromethane. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: chloroform) to give 7.84g (92%) of the title compound.
Manufacturing Example 3 (Compound 3) :
4-Bromo-2-methoxybenzamidine hydrochloride
To a suspension of 5.349g (lOOmmol) of ammonium chloride in 20OmL of toluene was dropped 10OmL (lOOmmol) of lM-triethylaluminum/hexane, and the mixture was stirred for 1.5 hours at room temperature. Then, to this mixture was added 8.48g (40mmol) of the compound obtained in the
Manufacturing Example 2, and the mixture was stirred for 24 hours at 80° .
After the reaction mixture was cooled with ice water, 3Og of silica gel and 30OmL of chloroform were added to the mixture and the mixture was stirredfor 30minutesundertheroomtemperature. Themixturewas filtrated with Celite®and the residue was washedwith 40OmL of methanol. The organic layer was concentrated and 20OmL of chloroform/methanol (9/1) solution was added to the residue. The mixture was filtrated and the filtrate was concentrated and the residue was washed sequentially with ether to give
3.47g (33%) of the title compound.
Manufacturing Example 4 (Compound 4) :
(R) - (Acetylamino) (cyclohexyl) acetic acid
To a solution of 15g of (R) - (acetylamino) (1, 4-cyclohexadiene-l- yl) acetic acid in 50OmL of methanol was added 500mg of platinum oxide, and the mixture was stirred for 4 hours under hydrogen gas atmosphere.
Then, the reaction mixture was filtrated and the filtrate was condensed.
The residue was recrystallized from ethanol to give 11.4g (75%) of the title compound. Manufacturing Example 5 (Compound 5) :
Ethyl cyano [ (cyclohexylcarbonyl) amino] acetate
To a solution of 18.3g (143mmol) of ethyl amino (cyano) acetate in 50OmL of anhydrous dichloromethane were added 3OmL (214mmol) of triethylamine and 23mL (171mmol) of cyclohexanecarbonyl chloride, and themixture was stirred for 3 hours at 00C. Then, saturated sodiumhydrogen carbonate aqueous solutionwas addedto the reactionmixture and themixture was extracted with dichloromethane. The organic layer was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with ethyl acetate to give the solid substance . The obtained solid substance was collected and the filtrate was removed under reduced pressure. The obtained residue was treated with ethyl acetate to give solid substance. This treatment was further repeated. The filtrate was purified by silica gel column chromatography (eluent: dichloromethane/ methanol = 50/1) to give crude crystalline. The obtained crude crystalline was washed with ether and combined with the above all solid products to give 24.3g (71%) of the title compound.
Manufacturing Example 6 (Compound 6) :
Ethyl 2-cyano-2- [ (cyclohexylcarbonyl) amino] propanoate
Sodium ethoxide was prepared from 2.3g (102mmol) of sodium and 15OmL of ethanol, and to this mixture was added a suspension of 24.2g (102mmol) of the compound obtained in the Manufacturing Example 5 in 15OmL of ethanol at 00C, andthen, themixturewas stirredthroughthe suspensionwasperfectly dissolved. Then, 6.32mL (102mmol) ofmethyliodidewas addedtothe reaction mixture after stirring 4 hours at room temperature, the reaction mixture was acidified with IM-HCl, then, the solvent was removed under reduced pressure. Water was added to the residue and the mixture was extracted with dichloromethane. Then the organic layer was washed with saturated saline solution and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with a mixture solvent of ethyl acetate/hexane (1/1) to give the solid substance. Theobtainedsolidsubstancewas collectedbythe filtrationandthe filtrate was removed under reduced pressure. The residue was further treated with amixture solvent of ethyl acetate/hexane (1/1) to give the solid substance. Theobtainedsolidsubstancewas collectedbythe filtrationandthe filtrate was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 2/1) , and the obtained solid substance was combined with the above solid substances to give 22.8g (88%) of the title compound.
Manufacturing Example 7 (Compound 7) : N- [6-Amino~2- (2-methoxyphenyl) -5-rαethyl-4-oxo-4, 5-dihydro-5- pyrimidinyl] cyclohexanecarboxamide
Sodium ethoxide was prepared from 117mg (5.10mmol) of sodium and lβmL of ethanol, and to this mixture was added 8β5mg (4.64mmol) of 2-methoxybenzamidine hydrochloride, then, the mixture was stirred for 45 minutes at room temperature. The unsolved substance was removed off by filtration and 2.34g (9.27mmol) of the compound obtained in the Manufacturing Example β in 25mL of methanol solution was added to the filtrate, and the mixture was refluxed for 20 hours. After the reaction mixture was cooled to the room temperature, appeared precipitate was collected by the filtration. The filtrate was removed under reduced pressure andwater was added to the residue, then, the mixture was extracted withdichloromethane . Theorganiclayerwaswashedwithwaterandsaturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was combined with above obtained precipitate, then, recrystallized from ethanol to give the solid. The filtrate was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 20/1 to 10/1) to give the solid substance, and this solid substance was combined with above obtained solid substance to give 343mg (21%) of the title compound.
Example 1 (Compound 8) :
6-Cyclohexyl-2~ (2-methoxyphenyl) -8-methylimidazo [1, 5-a] [1,3,5] - triazin-4 (3H) -one To a suspension of 320mg (0.90mmol) of the compound obtained in the Manufacturing Example 7 in 15mL of pyridine was added 0.34mL (2.7mmol) of chlorotrimethylsilane, and the mixture was stirred for 30 minutes at room temperature. Then, 0.57mL (2.7mmol) of hexarαethyldisilazane was added to the reaction mixture and the mixture was refluxed for 5 hours. After the reaction mixture was cooled to the room temperature, the solvent was removed under reduced pressure and methanol was added to the residue, then, the mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 1/1) to give 20mg (7%) of the title compound.
Manufacturing Example 8 (Compound 9) :
N- [6-Amino-2- (4~bromo-2-methoxyphenyl) -5-methyl-4-oxo-4, 5-dihydro- 5-pyrimidinyl] cyclohexanecarboxamide
The title compound 439mg (9%) was obtained in a manner similar to the Manufacturing Example 7 by using the compound obtained in the Manufacturing Example 3 instead of 2-methoxybenzamidine hydrochloride.
Example 2 (Compound 10) :
2- (4-Bromo~2-methoxyphenyl) -β-cyclohexyl-δ-methylimidazo-
[1, 5-a] [1,3,5] triazin-4 (3H) -one
The title compound 14mg (3%) was obtained in a manner similar to the Example 1 by using the compound obtained in the Manufacturing Example 9 instead of the compound obtained in the Manufacturing Example 7.
Example 3 (Compound 11) :
6-Cyclohexyl-2- [2-methoxy-4- (4-methyl-l-piperadinyl) phenyl] -8- methylimidazo[l,5-a] [1, 3, 5] triazin-4 (3H) -one To a solution of 12mg (0.029mmol) of the compound obtained in the Example 2 in 2mL of toluene were added 5.5mg (0.058mmol) of sodium tert-butoxide, O.δmg (0.0029mmol) of tri-tert-butylphosphine and 0.3mg (0.0014mmol) of palladium(II) acetate under argon gas atmosphere, and the mixture was stirred for 4 hours at 1100C. After the reaction mixture was cooled to the room temperature, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution, and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 30/1 to 10/1) to give 3mg (24%) of the title compound.
Example 4 (Compound 12) :
5-Cyclohexyl-2- (2-methoxyphenyl) -7-methylimidazo- [5, 1-f] [1, 2, 4] triazin-4 (3H) -one
To a solution of 1.5g (7.52mmol) of the compound obtained in the Manufacturing Example 4 in 5mL of pyridine was added ca. 5mg of DMAP, and the mixture was refluxed. Then, 1.68mL (15. Oβmmol) of ethyl oxalyl chloride was added by dripping to this mixture and the mixture was refluxed for 3 hours. The reaction mixture was poured into ice water and extracted withethylacetate. Theextractwas driedoverwithanhydrous sodiumsulfate and removed under reduced pressure. The residue was dissolved in 5mL of ethanol and the mixture was refluxed for 2.5 hours with sodium hydrogen carbonate, then, filtrated after cooling to give ethanol filtrate. Next, 365μL (7.52mmol) of hydrazine hydrate was added by dripping to a solution of 1.41g (7.32mmol) of 2-methoxybenzamideinehydrocholide in 8mL of ethanol, and the mixture was stirred for 10 minutes at the room temperature. Then, to this mixture was added above obtained ethanol filtrate, and the mixture was stirred for 4 hours at 70°C. After the reaction, the mixture was filtrated and the filtrate was diluted with dichloromethane. The organic layer was washed with water and dried over with anhydrous sodium sulfate. The solvent was removedunder reducedpressure and the residue was dissolved into 1OmL of 1,2-dichloromethane, then, 1.25mL of phosphorus oxychloride was added. After the mixture was refluxed for 2 hours, the reactionmixture was cooled to the room temperature, and diluted with dichloromethane, then neutralized with saturated sodiumhydrogen carbonate and solid sodium hydrogen carbonate. The organic layer was separated and dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give 5mg (0.2%) of the title compound.
Physicochemical data and chemical structure of the compounds obtained by the above-mentioned examples are summarized in the following Tables.
cr
(D
J 1
to
Figure imgf000027_0001
OJ
CD ND
to
Figure imgf000028_0001
Figure imgf000029_0001
Industrial Applicability
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.
That is, the compounds of the present invention are useful for preventing or treating 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.

Claims

1. An imidazotriazinone compound represented by the following formula (IA) or (IB) :
Figure imgf000031_0001
wherein
A is N or CR4;
B is N or CH;
R1 is substituted or unsubstituted cycloalkyl group or tert-butyl group;
R2 is a hydrogen atom or Ci-Ce alkyl group;
R3 is a hydrogen atom; nitro group; cyano group; a halogen atom; heteroaryl group; substituted or unsubstituted Ci-C6 alkyl group; substituted or unsubstituted C2-C5 alkenyl group; saturated or unsaturated heterocycloalkyl group which is substituted or unsubstituted; a group:
-NR5R6, -C(O)R7, -SO2R7, -OR8, -NR8COR7, -NR8SO2R7;
R4 is a hydrogen atom or C1-C3 alkoxy group which is unsubstituted or substituted by one or more fluorine atom(s);
R5 and R6 are, same or different from each other, a hydrogen atom; substituted or unsubstituted Ci-C6 alkyl group; substituted or unsubstitutedacyl group; or substitutedorunsubstitutedheterocycloalkyl group;
R7 is a hydrogen atom; substituted or unsubstitutedCi-C6 alkyl group; substituted or unsubstituted heterocycloalkyl group; OH; -OR8 or -NR5R6; R8 is a hydrogen atom, substitutedor unsubstitutedCx-C6 alkyl group; or substituted or unsubstituted heterocycloalkyl group; or pharmaceutically acceptable salts or solvates thereof.
2. The compound represented by the formula (IA) according to claim 1.
3. The compound represented by the formula (IB) according to claim 1.
4. The compound according to claim 1, 2 or 3, in which Rl is substituted or unsubstituted C3-Cs cycloalkyl group.
5. The compound according to claim 4, in which R1 is selected from the group consisting of cyclopentyl, cyclohexyl and cycloheptyl .
6. The compound according to any one of claims 1 to 5, in which A is CR4 wherein R4 is methoxy or ethoxy group.
7. The compound according to any one of claims 1 to 6, in which B is CH.
8 The compound according to any one of claims 1 to 7, in which R2 is methyl group.
9. The compound according to any one of claims 1 to 8, in which R3 is a haydrogen atom; a halogen atom; saturated or unsaturated heterocycloalkyl group; group selected fromthe -NR5R6, -C(O)R7, and-SC^R7, wherein R7 is OH, -OR8, -NR5R5 and substituted or unsubstituted heterocycloalkyl group.
10. Apharmaceutical composition containing a compound according to any one of claims 1 to 9, or pharmaceutically acceptable salts or solvates thereof as active ingredient.
11. A PDE 7 inhibitor containing a compound according to any one of claims 1 to 9, or pharmaceutically acceptable salts or solvates thereof as active ingredient.
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US8637528B2 (en) 2007-03-27 2014-01-28 Omeros Corporation Use of PDE7 inhibitors for the treatment of movement disorders
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