Heretofore, it is known that the functions of numerous hormones and neurotransmitters are expressed by an increase in the concentration of adenosine 3xe2x80x2,5xe2x80x2-cyclic monophosphate (cAMP) or guanosine 3xe2x80x2,5xe2x80x2-cyclic monophosphate (cGMP), both of which are the secondary messengers in cells. The cellular concentrations of cAMP and cGMP are controlled by the generation and decomposition thereof, and their decomposition is carried out by phosphodiesterase (PDE). Therefore, when PDE is inhibited, the concentrations of these secondary cellular messengers increase. Up to the present, 8 kinds of PDE isozymes have been found, and the isozyme-selective PDE inhibitors are expected to exhibit pharmaceutical effect based on their physiological significance and distribution in vivo [TiPS, 11, 150 (1990), ibid., 12, 19 (1991), and Biochemical and Biophysical Research Communications, 250, 751 (1998)].
It is known that the activation of inflammatory leukocytes can be suppressed by increasing the concentration of the cellular CAMP. The extraordinary activation of leukocytes causes secretion of inflammatory cytokines such as tumor necrosis factor (TNF), and expression of the cellular adhesion molecules such as intercellular adhesion molecules (ICAM), followed by cellular infiltration [J. Mol. Cell. Cardiol., 12 (Suppl. II), S61 (1989)].
It is known that the contraction of a respiratory smooth muscle can be suppressed by increasing the concentration of the cellular cAMP (T. J. Torphy in Directions for New Anti-Asthma Drugs, eds S. R. O""Donell and C. G. A. Persson, 1988, 37, Birkhauser-Verlag). The extraordinary contraction of a respiratory smooth muscle is a main symptom of bronchial asthma. Infiltration of inflammatory-leukocytes such as neutrophils is observed in lesions of organopathy associated with ischemia-reperfusion such as myocardial ischemia. It has been found that the type IV PDE (PDE IV) mainly participates in the decomposition of cAMP in these inflammatory cells and tracheal smooth muscle cells. Therefore, the inhibitors selective for PDE IV are expected to have therapeutic and/or preventive effect on inflammatory diseases, respiratory obstructive diseases, and ischemic diseases.
The PDE IV inhibitors are expected to prevent the progress and spread of the inflammatory reaction transmitted by inflammatory cytokines such as TNFxcex1 and interleukin (IL)-8, because the PDE IV inhibitors suppress the secretion of these cytokines by increasing the concentration of cAMP. For example, TNFxcex1 is reported to be a factor of insulin-resistant diabetes because it declines the phosphorylating mechanism of insulin receptors in muscle and fat cells [J. Clin. Invest., 94, 1543 (1994)]. Similarly, it is suggested that the PDE IV inhibitors may be useful for autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, and Crohn""s disease because TNFxcex1 participates in the onset and progress of these diseases [Nature Medicine, 1, 211 (1995) and ibid., 1, 244 (1995)].
Further, participation of TNFxcex1 in the fatigued feeling after dialysis and that of patients suffering from cancer has been also reported [International Journal of Artificial Organs, 21, 83 (1998) and Oncology Nursing Forum, 19, 419 (1992)]. Accordingly, a PDE IV inhibitor can be expected to be effective for improvement in fatigue, malaise, and the like.
It has been reported that a drug which increases cAMP promotes the healing of wounds [The 68th Annual Meeting of Japan Pharmacological Society (in Nagoya), Presentation P3-116 (1995)].
PDE-IV inhibitors exhibit a therapeutic effect to carcinomatous osteopenia model, sciatic nerve excision model and ovariectomic model which are animal models for osteoporosis and their possibility as a therapeutic agent for osteoporosis is suggested [Jpn. J. Pharmacol., 79, 477 (1999)].
Relaxation of ureter has been known to promote the excretion of calculus while a PDE IV inhibitor suppresses the vermicular movement of ureter, and therefore, there is a suggestion for the probability that it is effective for the therapy and/or prevention of urinary calculus [J. Urol., 160, 920 (1998)].
Japanese Published Unexamined Patent Application Nos. 95/242543 and 95/242655 disclose 1,4-benzodioxane derivatives as a therapeutic agent for hepatic diseases. WO 92/10494 discloses 1,4-benzodioxane derivatives having an antagonistic action to serotonin (5HT)3 receptors.
In U.S. Pat. No. 5,166,367, 1,4-benzodioxane derivatives having an anti-hallucination action are disclosed.
In Japanese Published Unexamined Patent Application No. 88/179868, 1,4-benzodioxane derivatives having a vasodilating action are disclosed.
AU 521225 discloses 1,4-benzodioxane derivatives as intermediates for the synthesis of cinnamoylpiperazine.
WO 98/22455 discloses 1,4-benzodioxane derivatives having PDE IV inhibitory activity.
The present invention relates to oxygen-containing heterocyclic compounds which have phosphodiesterase (PDE) IV inhibitory activity and which are useful as a therapeutic agent for inflammatory allergic diseases such as bronchial asthma, allergic rhinitis, atopic dermatitis and nephritis; autoimmune diseases such as chronic obstructive pulmonary disease, rheumatism, multiple sclerosis, Crohn""s disease, psoriasis and systemic lupus erythematosus; diseases of the central nervous system such as depression, amnesia and dementia; organopathy associated with ischemia-reperfusion caused by cardiac failure, shock and cerebrovascular disease, and the like; insulin-resistant diabetes; wounds; AIDS; osteoporosis; urinary calculus; urinary incontinence and the like; and as a recuperative agent for fatigue, malaise and the like.
Novel and useful PDE IV inhibitors are expected to have a preventive or therapeutic effect to diseases of a broad range. An object of the present invention is to provide novel oxygen-containing heterocyclic compounds having a bronchodilating or an anti-inflammatory action due to the presence of a PDE IV-selective inhibiting action so that CAMP concentrations in cells are increased.
The present invention relates to oxygen-containing heterocyclic compounds represented by the following formula (I): 
wherein m represents an integer of 0 to 4;
R1, R2, R3 and R4 independently represent a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, polycycloalkyl, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted lower alkanoyloxy, cyano, hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted lower alkenyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic hetecyclic group, substituted or unsubstituted aralkyl, or xe2x80x94CONR7R8 (wherein R7 and R8 independently represent a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted aralkyl, or R7 and R8 are combined to represent a substituted or unsubstituted heterocyclic group together with the adjacent nitrogen atom); two groups present on the same carbon atom among R1, R2, R3and R4 are combined to represent a saturated Spiro carbon ring together with the said carbon atom; two groups present on the adjacent carbon atoms among R1, R2, R3 and R4 are combined to represent a saturated carbon ring together with the said adjacent two carbon atoms; two groups present on the adjacent carbon atoms among R1, R2, R3 and R4are combined to represent a single bond (forming a double bond together with the already-existing bond)
R5 represents hydroxy, or substituted or unsubstituted lower alkoxy;
R6 represents a hydrogen atom or halogen;
Y represents the following formula (II): 
wherein R9 represents cyano, ethynyl or carbamoyl, and R10 represents a hydrogen atom, or R9 and R10 are combined to represent a single bond (forming a double bond together with the already-existing bond), R11 represents hydroxy, formyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted tetrazolyl, xe2x80x94NR13R14 (wherein R13 and R14 independently represent a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted aralkyl, or R13 and R14 are combined to represent a substituted or unsubstituted heterocyclic group together with the adjacent nitrogen atom), xe2x80x94COOR15 (wherein R15 represents a hydrogen atom, or substituted or unsubstituted lower alkyl), xe2x80x94CONR16R17 (wherein R16 and R17 independently represent a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, or substituted or unsubstituted aralkyl, or R16 and R17 are combined to represent a substituted or unsubstituted heterocyclic group together with the adjacent nitrogen atom), or xe2x80x94CH2COOR18 (wherein R18 represents a hydrogen atom or substituted or unsubstituted lower alkyl), R12 represents a hydrogen atom, or substituted or unsubstituted lower alkoxy, or R11 and R12 are combined together to represent xe2x80x94OCH2(CH2)pOxe2x80x94 (wherein p represents an integer of 1 to 3), xe2x80x94CR19R20Oxe2x80x94 (wherein R19 and R20 independently represent a hydrogen atom or cyano), xe2x95x90CHOR21 (wherein R21 represents substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, or substituted or unsubstituted aralkyl), xe2x95x90CHCOOR22 (wherein R22 represents a hydrogen atom, or substituted or unsubstituted lower alkyl) or xe2x95x90O; the following formula (III): 
wherein n represents an integer of 0 to 4, X represents CH2, NR23 (wherein R23 represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group, or substituted or unsubstituted aralkyl) or O; the following formula (IV): 
wherein Z1xe2x80x94Z2xe2x80x94Z3 represents Oxe2x80x94Nxe2x95x90CH, Sxe2x80x94Nxe2x95x90CH, Oxe2x80x94CHxe2x95x90CH, Sxe2x80x94CHxe2x95x90CH, Nxe2x95x90CHxe2x80x94S, Nxe2x95x90CHxe2x80x94O, C(xe2x95x90O)xe2x80x94NHxe2x80x94NH, C(xe2x95x90O)xe2x80x94Nxe2x95x90N, C(xe2x95x90O)xe2x80x94CH2xe2x80x94C(xe2x95x90O), C(xe2x95x90O)xe2x80x94NRaxe2x80x94C(xe2x95x90O) (wherein Ra represents a hydrogen atom, substituted or unsubstituted lower alkyl, or substituted or unsubstituted aralkyl) or CH2xe2x80x94NRbxe2x80x94C(xe2x95x90O) (wherein Rb represents a hydrogen atom, substituted or unsubstituted lower alkyl, or substituted or unsubstituted aryl); 2,1,3-benzothiadiazolyl; or 2,1,3-benzofurazanyl; or
pharmaceutically acceptable salts thereof.
The present invention relates to oxygen-containing heterocyclic compounds wherein Y in the formula (I) is the formula (II) or pharmaceutically acceptable salts thereof. Among the above, oxygen-containing heterocyclic compounds wherein R9 is cyano or pharmaceutically acceptable salts thereof are preferred.
In the present invention, oxygen-containing heterocyclic compounds wherein m is 0 to 2 in the formula (I) or pharmaceutically acceptable salts thereof, oxygen-containing heterocyclic compounds wherein all of R1, R2, R3 and R4 are hydrogen atoms or pharmaceutically acceptable salts thereof and oxygen-containing heterocyclic compounds wherein one group among R1, R2, R3 and R4 is substituted or unsubstituted lower alkyl while other three groups are hydrogen atoms or pharmaceutically acceptable salts thereof are preferred examples as well.
Further, in the above-mentioned compounds group, oxygen-containing heterocyclic compounds wherein R11 represents carboxy or hydroxy, or R11 and R12 are combined together to represent xe2x95x90O or pharmaceutically acceptable salts thereof are preferred as well.
Furthermore, oxygen-containing heterocyclic compounds wherein Y in the formula (I) is the formula (III) or pharmaceutically acceptable salts thereof are preferred as well. Still further, among the above, oxygen-containing heterocyclic compounds wherein n is 1 or pharmaceutically acceptable salts thereof and oxygen-containing heterocyclic compounds wherein X is CH2 or pharmaceutically acceptable salts thereof are preferred.
The present invention further relates to a pharmaceutical composition comprising an effective amount of at least one oxygen-containing heterocyclic compound represented by the formula (I) together with a pharmaceutically acceptable carrier or diluent.
The present invention furthermore relates to a method of inhibiting phosphodiesterase (PDE) IV, which comprises administering an effective dose of at least one oxygen-containing heterocyclic compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
Hereinafter, the compounds represented by the formula (I) are referred to as a compound (I). The same applies to the compounds of other formula numbers.
In the definitions of the groups in the formula (I), the lower alkyl and the lower alkyl moiety of the lower alkoxy, the lower alkanoyl, the lower alkanoyloxy and the lower alkoxycarbonyl include straight-chain or branched alkyl groups having 1 to 8 carbon atom(s) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl; the cycloalkyl includes cycloalkyl groups having 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl; and the polycycloalkyl includes polycycloalkyl groups having 5 to 12 carbon atoms such as bicyclo[3.2.1]octyl, bicyclo[4.3.2]undecyl, adamantyl and noradamantyl. The lower alkenyl includes straight-chain or branched alkenyl groups having 2 to 8 carbon atoms such as vinyl, 1-propenyl, allyl, methacryl, 1-butenyl, crotyl, pentenyl, isoprenyl, hexenyl, heptenyl and octenyl; and the cycloalkenyl includes cycloalkenyl groups having 4 to 10 carbon atoms such as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl and cyclodecenyl. The aryl includes phenyl and naphthyl for example; and the aralkyl includes aralkyl groups having 7 to 15 carbon atoms such as benzyl, phenethyl, benzhydryl and naphthylmethyl. The aromatic heterocyclic group includes 5- or 6-membered monocyclic aromatic heterocyclic groups having 1 to 2 oxygen atom(s), 5- or 6-membered monocyclic aromatic heterocyclic groups having 1 to 2 sulfur atom(s), 5- or 6-membered monocyclic aromatic heterocyclic groups having 1 to 4 nitrogen atom(s), condensed bicyclic aromatic heterocyclic groups consisting of 5- and 6-membered rings and condensed bicyclic aromatic heterocyclic groups consisting of 6- and 6-membered rings, where oxygen, sulfur and nitrogen may be mixedly present therein. Specific examples thereof include furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthylidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl and purinyl.
The heterocyclic group which is formed together with the adjacent nitrogen atom includes 5-, 6- or 7-membered monocyclic heterocyclic groups and condensed heterocyclic groups consisting of 6- and 6-membered rings, such as pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, homopiperidino, homopiperazinyl, tetrahydropyridyl, tetrahydroquinolyl and tetrahydroisoquinolyl.
The saturated spiro carbon ring which is formed by two groups present on the same carbon atom together with the said carbon atom and the saturated carbon ring which is formed by two groups present on the adjacent carbon atoms together with the said two carbon atoms include those having 3 to 10 carbon atoms such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane and cyclodecane. Halogen includes fluorine, chlorine, bromine and iodine atoms.
The substituents in the substituted lower alkyl, the substituted lower alkoxy, the substituted lower alkoxycarbonyl, the substituted lower alkanoyl, the substituted lower alkanoyloxy, the substituted lower alkenyl, the substituted cycloalkyl and the substituted cycloalkenyl are the same or different 1 to 3 substituent(s), such as lower alkyl, lower alkenyl, cyano, cycloalkyl, cycloalkenyl, hydroxy, lower alkoxy, carboxy and halogen where the lower alkyl, the lower alkenyl, the cycloalkyl, the cycloalkenyl, the lower alkoxy and the halogen each have the same meanings as defined above.
The substituents in the substituted aryl, the substituted tetrazolyl, the substituted aromatic heterocyclic group, the substituted heterocyclic group which is formed together with the adjacent nitrogen atom and the substituted aralkyl are the same or different 1 to 3 substituent(s), such as substituted or unsubstituted lower alkyl, hydroxy, lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, carboxy, carbamoyl, trifluoromethyl, amino, mono- or di-lower alkyl-substituted amino, cyano, nitro and halogen. The lower alkyl, the lower alkyl moiety of the lower alkoxy, the lower alkanoyl, the lower alkoxycarbonyl and the mono- or di-lower alkyl-substituted amino and the halogen each have the same meanings as defined above where the substituent(s) in the substituted lower alkyl has/have the same meaning(s) as defined above.
The pharmaceutically acceptable salts of the compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, and organic amine addition salts.
The pharmaceutically acceptable acid addition salts of the compound (I) include inorganic acid addition salts such as a hydrochloride, a sulfate, a nitrate, and a phosphate, and organic acid addition salts such as an acetate, a maleate, a fumarate, and a citrate; the pharmaceutically acceptable metal salts include alkali metal salts such as a sodium salt and a potassium salt, alkaline earth metal salts such as a magnesium salt and a calcium salt, an aluminium salt, and a zinc salt; the pharmaceutically acceptable ammonium salts include ammonium and tetramethylammonium; and the pharmaceutically acceptable organic amine addition salts include an addition salt with morpholine or piperidine.
Processes for preparing the compound (I) are described below.
Producing method: The compound (I) can be obtained according to the following process.
Process 1 
(In the formulae, m, R1, R2, R3, R4, R5 and R6 have the same meanings as defined above.)
The starting compound (V) can be obtained by a known method [Khimiya Geterotsiklicheskikh Soedinenii, 12, 1614 (1982), etc.] or by a method similar thereto.
After the formyl group of the compound (V) is directly converted to the corresponding halogenated methyl derivative or after the formyl group of the compound (V) is reduced and the resulting hydroxymethyl derivative is converted to the corresponding halide or sulfonate derivative, it is reacted with a metal cyanide whereupon the compound (VI) can be obtained.
The compound (V) is reacted with one equivalent to a large excess of trialkylsilyl halide or triarylsilane halide, or with one equivalent to a large excess of a halogenated salt and one equivalent to a large excess of trimethylsilyl chloride in an inert solvent at the temperature between xe2x88x9250xc2x0 C. and the boiling point of the used solvent for 5 minutes to 5 hours, followed by treatment with one equivalent to a large excess of a reducing agent at the temperature between xe2x88x9250xc2x0 C. and the boiling point of the used solvent for 5 minutes to 48 hours, whereupon the corresponding halide can be obtained.
Alternatively, the compound (V) is treated with one equivalent to a large excess of a reducing agent in an inert solvent at the temperature between xe2x88x9250xc2x0 C. and the boiling point of the used solvent for 5 minutes to 48 hours whereby the corresponding hydroxylmethyl derivative is obtained. The resulting hydroxylmethyl derivative is reacted with one equivalent to a large excess of a halogenating agent in an inert solvent at the temperature between xe2x88x9230xc2x0 C. and the boiling point of the used solvent for 5 minutes to 120 hours to give the corresponding halide.
Alternatively, the resulting hydroxymethyl derivative is treated with one equivalent to a large excess of an alkylsulfonyl chloride or an arylsulfonyl chloride in the presence of one equivalent to a large excess of a base in an inert solvent at the temperature between xe2x88x9230xc2x0 C. and the boiling point of the used solvent for 5 minutes to 120 hours whereby the corresponding sulfonate derivative is obtained.
The resulting halide or sulfonate derivative is treated with one equivalent to a large excess of a metal cyanide in an insert solvent at the temperature between xe2x88x9230xc2x0 C. and the boiling point of the used solvent for 5 minutes to 120 hours whereupon the compound (VI) can be obtained.
Examples of the trialkylsilyl halide or the triarylsilyl halide are trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, triethylsilyl chloride, dimethylethylsilyl chloride and triphenylsilyl chloride.
Examples of the halogenated salt are lithium bromide, sodium bromide, potassium bromide, lithium chloride, sodium chloride, potassium chloride, lithium iodide, sodium iodide and potassium iodide.
Examples of the reducing agent are 1,1,3,3-tetramethyldisiloxane, triethylsilane, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and lithium aluminum hydride.
Examples of the halogenating agent are hydrochloric acid, hydrogen bromide, hydrogen iodide, thionyl chloride, phosphorus oxychloride and phosphorus tribromide.
Examples of the base are triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene (hereinafter, abbreviated as DBU), potassium carbonate and sodium hydride.
Examples of the alkylsulfonyl chloride or arylsulfonyl chloride are methanesulfonyl chloride, p-toluenesulfonyl chloride and benzenesulfonyl chloride.
Examples of the metal cyanide are sodium cyanide, potassium cyanide and copper cyanide.
Examples of the inert solvent are tetrahydrofuran (hereinafter, abbreviated as THF), dioxane, 1,2-dimethoxyethane, diethyl ether, acetonitrile, dimethylformamide (hereinafter, abbreviated as DMF), dimethyl sulfoxide (hereinafter, abbreviated as DMSO), methanol, ethanol, propanol, dichloromethane, chloroform, benzene, toluene, pyridine and ethyl acetate.
Process 2 
(In the formulae, m, R1, R2, R3, R4, R5 and R6 have the same meanings as defined above and R24 stands for the lower alkyl having the same meaning as defined above.)
The compound (VIII) can be obtained by the following method.
The compound (VI) is treated with the compound (VII) in an inert solvent in the presence of a catalytic amount to a large excess amount of a base at the temperature between 0xc2x0 C. and the boiling point of the used solvent for 5 minutes to 48 hours whereby the compound (VIII) can be obtained.
Examples of the base are benzyltrimethylammonium hydroxide (Triton B), sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium methoxide, lithium diisopropylamide (hereinafter, abbreviated as LDA), pyridine, potassium tert-butoxide, DBU, triethylamine and diisopropylethylamine.
Examples of the inert solvent are THF, dioxane, diethyl ether, methanol, ethanol, 1-propanol, 2-propanol, n-butanol, tert-butyl alcohol, pyridine, acetonitrile, DMF, DMSO, 1,2-dimethoxyethane, diethylene glycol methyl ether, dichloromethane, chloroform, benzene and toluene.
Process 3 
(In the formulae, m, R1, R2, R3, R4, R5, R6 and R24 have the same meanings as defined above.)
The compound (IX) can be obtained by the following method from the compound (VIII).
The compound (VIII) is treated in an inert solvent in the presence of one equivalent to a large excess of a base at the temperature between 0xc2x0 C. and the boiling point of the used solvent for 5 minutes to 48 hours whereupon the compound (IX) can be obtained.
Examples of the base are sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, LDA, pyridine, potassium tert-butoxide, DBU, triethylamine and diisopropylethylamine.
Examples of the inert solvent are THF, dioxane, pyridine, diethyl ether, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, tert-butyl alcohol, acetonitrile, DMF, DMSO, 1,2-dimethoxyethane, diethylene glycol methyl ether, dichloromethane, chloroform, benzene and toluene.
Process 4 
(In the formulae, m, R1, R2, R3, R4, R5, R6 and R24 have the same meanings as defined above.)
The compound (Ia) can be obtained according to the following reaction step.
The compound (IX) is treated in an inert solvent in the presence of one equivalent to a large excess of water at the temperature between 60xc2x0 C. and the boiling point of the used solvent for 5 minutes to 120 hours whereupon the compound (Ia) can be obtained. If necessary, a catalytic amount to an excess amount of a salt such as sodium chloride, lithium chloride, sodium iodide, lithium iodide or sodium cyanide may be added thereto.
Examples of the inert solvent are dioxane, toluene, DMF, DMSO, tert-butyl alcohol, acetonitrile, 1,2-dimethoxyethane, diethylene glycol methyl ether, ethylene glycol, triethylene glycol and water.
Process 5 
(In the formulae, m, R1, R2, R3, R4, R5 and R6 have the same meanings as defined above.)
The compound (X) can be obtained according to the following reaction step.
2-Trimethylsilyl-1,3-dithiane is treated with a base in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and 0xc2x0 C., followed by reaction with the compound (Ia) at the temperature between xe2x88x92100xc2x0 C. and 30xc2x0 C. for 1 minute to 12 hours whereupon the compound (X) can be obtained.
Examples of the base are sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium methoxide, butyl lithium, LDA, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, potassium tert-butoxide, DBU, triethylamine, diisopropylethylamine and ethyl magnesium bromide.
Examples of the inert solvent are THF, dioxane, diethyl ether, 1,2-dimethoxyethane and diisopropyl ether.
Process 6 
(In the formulae, m, R1, R2, R3, R4, R5 and R6 have the same meanings as defined above and R25 represents the same lower alkyl as defined above.)
The compound (Ib) can be obtained according to the following reaction step.
The compound (X) is treated in a solvent [with regard to the said solvent, a lower alcohol which will be mentioned later may be used solely or as a mixed solvent containing the lower alcohol (dioxane/lower alcohol, THF/lower alcohol, and the like); and the said lower alcohol also acts as a reagent for esterifying the carboxyl group which is obtained by the reaction] in the presence of one equivalent to an excess amount of a divalent mercury salt and an acid at the temperature between 0xc2x0 C. and the boiling point of the used solvent for 5 minutes to 48 hours whereupon the compound (Ib) can be obtained.
Examples of the divalent mercury salt are mercury chloride (HgCl2) and mercury acetate [Hg(OCOCH3)2]. Examples of the acid are perchloric acid, sulfuric acid, hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid and boron trifluoride.
Examples of the solvent are lower alcohols (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-methyl-1-propanol, 2-butanol, tert-butyl alcohol, 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol, and the like), a mixed solvent of dioxane/a lower alcohol (wherein the lower alcohol has the same meaning as defined above) and a mixed solvent of THF/a lower alcohol (wherein the lower alcohol has the same meaning as defined above).
Process 7 
(In the formulae, m, R1, R2, R3, R4, R5, R6 and R25 have the same meanings as defined above.)
The compound (Ic) can be obtained according to the following reaction step.
The compound (Ib) is treated with an aqueous solution of an alkali in an inert solvent at the temperature between 0xc2x0 C. and the boiling point of the used solvent for 5 minutes to 48 hours whereupon the compound (Ic) can be obtained.
Examples of the aqueous solution of an alkali are aqueous solutions of sodium hydroxide, potassium hydroxide and lithium hydroxide while examples of the inert solvent are ethanol, dioxane, methanol, THF, a mixed solvent of ethanol/THF, a mixed solvent of methanol/THF, and DMSO.
Process 8 
(In the formulae, m, R1, R2, R3, R4, R5 and R6 have the same meanings as defined above.)
The compound (Id) can be obtained according to the following reaction step.
One equivalent to an excess amount of methoxymethyl-triphenylphosphonium chloride is treated with one equivalent to an excess amount of a base in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the used solvent, followed by reaction with the compound (Ia) at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the used solvent for 5 minutes to 12 hours whereupon the compound (Id) can be obtained.
Examples of the base are sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium methoxide, butyl lithium, LDA, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, potassium tert-butoxide, DBU, sodium amide and sodium ethoxide.
Examples of the inert solvent are THF, dioxane, diethyl ether, 1,2-dimethoxyethane, DMF and diisopropyl ether.
Process 9 
(In the formulae, m, R1, R2, R3, R4, R5 and R6 have the same meanings as defined above.)
The compound (Ie) can be obtained according to the following reaction step.
The compound (Id) is treated with a catalytic amount to an excess amount of an acid in the absence of a solvent or in an inert solvent at the temperature between 0xc2x0 C. and the boiling point of the used solvent for 5 minutes to 48 hours whereupon the compound (Ie) can be obtained.
Examples of the acid are hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, 10-camphorsulfonic acid, boron trifluoride and aluminum chloride.
Examples of the inert solvent are THF, acetone, acetonitrile, methanol, ethanol, dioxane and a mixed solvent of such an inert solvent with water.
Process 10 
(In the formulae, m, R1, R2, R3, R4, R5 and R6 have the same meanings as defined above.)
The compound (If) can be obtained according to the following reaction step.
The compound (Ia) is treated with one equivalent to a large excess of trimethylsulfoxonium iodide or trimethylsulfonium iodide in the presence of one equivalent to a large excess of a base in an inert solvent at the temperature between xe2x88x9230xc2x0 C. and the boiling point of the used solvent for 5 minutes to 48 hours whereupon the compound (If) can be obtained.
Examples of the base are sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium methoxide, butyl lithium, LDA, lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide, potassium tert-butoxide, DBU, sodium amide and sodium ethoxide.
Examples of the inert solvent are THF, dioxane, diethyl ether, 1,2-dimethoxyethane, DMF and diisopropyl ether.
Process 11 
(In the formulae, m, R1, R2, R3, R4, R5 and R6 have the same meanings as defined above.)
The compound (Ie) can be obtained according to the following reaction step.
The compound (If) is treated with one equivalent to an excess amount of an acid in the absence of a solvent or in an inert solvent at the temperature between 0xc2x0 C. and the boiling point of the used solvent for 5 minutes to 48 hours whereupon the compound (Ie) can be obtained.
Examples of the acid are hydrochloric acid, sulfuric acid, hydrogen bromide, magnesium chloride, magnesium bromide, lithium bromide, trifluoroacetic acid, lithium perchlorate, p-toluenesulfonic acid, methanesulfonic acid, 10-camphorsulfonic acid, boron trifluoride, aluminum chloride and silica gel.
Examples of the inert solvent are THF, acetone, acetonitrile, methanol, ethanol and dioxane.
Process 12 
(In the formulae, m, R1, R2, R3, R4, R5 and R6 have the same meanings as defined above.)
The compound (Ic) can be obtained according to the following reaction step.
The compound (Ie) is treated with one equivalent to an excess amount of an oxidizing agent in an inert solvent at the temperature between 0xc2x0 C. and the boiling point of the used solvent for 5 minutes to 48 hours whereupon the compound (Ic) can be obtained.
Examples of the oxidizing agent are sodium chlorite, potassium permanganate and hydrogen peroxide.
When sodium chlorite is used as an oxidizing agent, one equivalent to an excess amount of 2-methyl-2-butene, sulfamic acid, DMSO, an aqueous solution of hydrogen peroxide, or the like may be added if necessary, or further, one equivalent to an excess amount of sodium dihydrogen phophate may be added thereto.
Examples of the inert solvent are tert-butyl alcohol, acetic acid, DMSO, acetone and acetonitrile.
Process 13 
(In the formulae, m, R1, R2, R3, R4, R5 and R6 have the same meanings as defined above.)
The compound (Ig) can be obtained according to the following reaction step.
The compound (Ia) is treated with one equivalent to a large excess of chloroacetonitrile in the presence of one equivalent to a large excess of a base in an inert solvent at the temperature between xe2x88x9210xc2x0 C. and the boiling point of the used solvent for 5 minutes to 48 hours whereupon the compound (Ig) can be obtained. If necessary, a catalytic amount to an excess amount of a salt such as benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium bromide, tetraethylammonium chloride or triethylmethylammonium bromide may be added thereto.
Examples of the base are potassium carbonate, sodium carbonate, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium methoxide, butyl lithium, potassium tert-butoxide, DBU and sodium ethoxide.
Examples of the inert solvent are methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, ethyl acetate, toluene, THF, 1,2-dimethoxyethane, DMF, DMSO and diisopropyl ether.
Process 14 
(In the formulae, m, R1, R2, R3, R4, R5 and R6 have the same meanings as defined above.)
The compound (Ic) can be obtained according to the following reaction step.
The compound (Ig) is treated with one equivalent to an excess amount of magnesium bromide or lithium bromide in the absence of a solvent or in an inert solvent in the presence of one equivalent to an excess amount of water at the temperature between 0xc2x0 C. and the boiling point of the used solvent for 5 minutes to 48 hours whereupon the compound (Ic) can be obtained.
Examples of the inert solvent are THF, DMF, acetone, acetonitrile, methanol, ethanol, dioxane and a mixed solvent of DMF/acetonitrile.
Process 15 
(In the formulae, m, R1, R2, R3, R4, R5, R6, R11 and R12 each have the same meanings as defined above and L1 represents chlorine, bromine or iodine.)
The compound (XIII) can be obtained according to the following reaction step.
The starting compound (XI) can be obtained according to a known method (WO 98/22455) or a method similar thereto. A commercially available compound can be used as the compound (XII).
The compound (XI) is treated with one equivalent to an excess amount of a base in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and room temperature for 5 minutes to 10 hours, followed by reaction with one equivalent to an excess amount of the compound (XII) at the temperature between xe2x88x92100xc2x0 C. and room temperature for 5 minutes to 30 hours whereupon the compound (XIII) can be obtained. If necessary, tetramethylethylenediamine, cerium chloride, or the like may be added thereto.
Examples of the base are lithium, magnesium, methyl lithium, methyl magnesium bromide, ethyl magnesium bromide and butyl lithium.
Examples of the inert solvent are THF, dioxane, diethyl ether, 1, 2-dimethoxyethane, diethylene glycol dimethyl ether, benzene, toluene and hexane.
Process 16 
(In the formulae, m, R1, R2, R3, R4, R5, R6, R11 and R12 have the same meanings as defined above.)
The compound (Ih) can be obtained according to the following reaction step.
The compound (XIII) is treated with one equivalent to an excess amount of an acid in the absence of a solvent or in an inert solvent at the temperature between 0xc2x0 C. and the boiling point of the used solvent for 5 minutes to 48 hours whereupon the compound (Ih) can be obtained. If necessary, water may be added thereto.
Examples of the acid are hydrochloric acid, sulfuric acid, 10-camphorsulfonic acid, acetic acid, formic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, boron trifluoride and aluminum chloride.
Examples of the inert solvent are THF, acetone, acetonitrile, toluene, xylene, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butyl alcohol, 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol and dioxane.
Process 17 
(In the formulae, m, R1, R2, R3, R4, R5, R6, R11 and R12 have the same meanings as defined above.)
The compound (Ii) can be obtained according to the following reaction step.
The compound (XIII) is treated with one equivalent to an excess amount of a cyanide in the presence of one equivalent to an excess amount of an acid in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the used solvent for 5 minutes to 48 hours whereupon the compound (Ii) can be obtained.
Examples of the acid are hydrochloric acid, sulfuric acid, 10-camphorsulfonic acid, acetic acid, formic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, titanium tetrachloride, boron trifluoride and aluminum chloride.
Examples of the cyanide are trimethylsilyl cyanide, sodium cyanide and potassium cyanide.
Examples of the inert solvent are THF, dioxane, diethyl ether, 1,2-dimethoxyethane, methanol, ethanol, acetonitrile, dichloromethane, 1, 2-dichloroethane, chloroform and toluene.
Process 18 
(In the formulae, m, p, R1, R2, R3, R4, R5 and R6 have the same meanings as defined above.)
The compound (Ia) can be obtained according to the following reaction step.
The starting compound (Iia) can be synthesized in such a manner that a compound (XIII) wherein R11 and R12 have a ketal structure is obtained using a compound (XII) wherein R11 and R12 have a ketal structure as a starting material in Process 15 and a method mentioned in Process 17 is applied using the compound (XIII) wherein R11 and R12 have a ketal structure as a starting material.
The compound (Iia) is treated with one equivalent to an excess amount of an acid in the absence of a solvent or in an inert solvent at the temperature between 0xc2x0 C. and the boiling point of the used solvent for 5 minutes to 48 hours whereupon the compound (Ia) can be obtained.
Examples of the acid are hydrochloric acid, sulfuric acid, 10-camphorsulfonic acid, acetic acid, formic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, boron trifluoride and aluminum chloride.
Examples of the inert solvent are THF, acetone, acetonitrile, toluene, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butyl alcohol, 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol, dioxane and a mixed solvent of such an insert solvent with water.
Process 19 
(In the formulae, m, R1, R2, R3, R4, R5 and R6 have the same meanings as defined above.)
The compound (Ij) can be obtained according to the following reaction step.
The compound (Ia) is treated with one equivalent to an excess amount of a reducing agent in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the used solvent for 5 minutes to 48 hours whereupon the compound (Ij) can be obtained.
Examples of the reducing agent are 1,1,3,3-tetramethyldisiloxane, triethylsilane, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and lithium aluminum hydride.
Examples of the inert solvent are methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butyl alcohol, 1-pentanol, 1-hexanol, 1-heptanol, 1-octanol and dioxane.
Process 20 
(In the formulae, m, n, R1, R2, R3, R4, R5, R6, L1 and X each have the same meanings as defined above, and L2 represents chlorine, bromine, iodine or a trifluoromethanesulfonate group.)
The compound (Ik) can be obtained according to the following reaction step.
With regard to the compound (XIV), the commercially available one may be used or it may be obtained according to a known method [Tetrahedron Lett., 30, 5499 (1992)].
After the compound (XI) is treated with a base in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and room temperature for 5 minutes to 10 hours, the resulting compound is treated with a metal halide or a boron compound at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the used solvent for 5 minutes to 30 hours, followed by further reaction with the compound (XIV) in an inert solvent in the presence of a catalytic amount to an excess amount of a palladium complex at the temperature between room temperature and the boiling point of the used solvent for 5 minutes to 30 hours whereupon the compound (Ik) can be obtained. Incidentally, in the above reaction which is carried out in the presence of a catalytic amount to an excess amount of a palladium complex, a salt such as lithium chloride or silver oxide may be added, if necessary.
Examples of the base are lithium, magnesium, methyl lithium, methyl magnesium bromide, ethyl magnesium bromide and butyl lithium.
Examples of the metal halide are halogenated alkyl tin derivatives such as chlorotributyltin and chlorotrimethyltin and halogenated zinc derivatives such as zinc chloride, zinc bromide and zinc iodide while examples of the boron compound are trimethyl borate, triisopropyl borate, tributyl borate, triethyl borate and borane.
Examples of the palladium complex are tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, dichlorobis(acetonitrile)palladium, [1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloropalladium and palladium acetate.
Examples of the inert solvent used in the reaction with a metal halide or a boron compound are THF, dioxane, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, benzene, toluene and hexane.
Examples of the inert solvent used in the reaction in the presence of a palladium complex are THF, dioxane, diethyl ether, ethylene glycol, triethylene glycol, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, methanol, ethanol, 1-butanol, 2-propanol, dichloromethane, chloroform, acetonitrile, benzene, toluene, dimethylacetamide, DMF and DMSO.
Process 21 
(In the formulae, m, R1, R2, R3, R4, R5, R6, L1 and Z1xe2x80x94Z2xe2x80x94Z3 each have the same meanings as defined above, Z4 represents an oxygen atom or a sulfur atom, and L3 and L4 represent chlorine, bromine, iodine or a trifluoromethanesulfoxy group.)
The compound (Im) and the compound (In) can be obtained according to the following reaction step.
With regard to the compound (XV) and the compound (XVI), the commercially available ones may be used or they may be obtained according to known methods [J. Chem. Soc., Perkin Trans. 1, 1954 (1973); J. Org. Chem., 60(7), 1936 (1995); Tetrahedron Lett., 30(42), 7719 (1994); Chem. Pharm. Bull., 40(10), 2597 (1992); J. Heterocyclic Chem., 7, 815 (1970); J. Chem. Soc. Chem. Comm., 1183 (1985); etc.]
The compound (XI) is treated with a base in an inert solvent at the temperature between xe2x88x92100xc2x0 C. and room temperature for 5 minutes to 10 hours, followed by reaction with a metal halide or a boron compound at the temperature between xe2x88x92100xc2x0 C. and the boiling point of the used solvent for 5 minutes to 30 hours. The resulting compound is treated with the compound (XV) in an inert solvent in the presence of a catalytic amount to an excess amount of a palladium complex or a nickel complex at the temperature between room temperature and the boiling point of the used solvent for 5 minutes to 30 hours whereby the compound (Im) can be obtained. Incidentally, when the compound (XVI) is used instead of the compound (XV) and the same reaction as in the case of the compound (XV) is carried out, the compound (In) is obtained.
In the above-mentioned reaction carried out in the presence of a catalytic amount to an excess amount of a palladium complex or a nickel complex, a salt such as lithium chloride or silver oxide may be added thereto, if necessary.
Examples of the base are lithium, magnesium, methyl lithium, methyl magnesium bromide, ethyl magnesium bromide and butyl lithium.
Examples of the metal halide are halogenated alkyl tin derivatives such as chlorotributyltin and chlorotrimethyltin and halogenated zinc derivatives such as zinc chloride, zinc bromide and zinc iodide while examples of the boron compound are trimethyl borate, triisopropyl borate, tributyl borate, triethyl borate and borane.
Examples of the palladium complex are tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, dichlorobis(acetonitrile)palladium, [1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloropalladium and palladium acetate.
Examples of the nickel complex are [1,1xe2x80x2-bis(diphenylphosphino)ferrocene]dichloronickel and dichlorobis(triphenylphosphine)nickel.
Examples of the inert solvent used in the reaction with a metal halide or a boron compound are THF, dioxane, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, benzene, toluene and hexane.
Examples of the inert solvent used in the reaction in the presence of a palladium complex or a nickel catalyst are THF, dioxane, diethyl ether, ethylene glycol, triethylene glycol, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, methanol, ethanol, 1-butanol, 2-propanol, dichloromethane, chloroform, acetonitrile, benzene, toluene, dimethylacetamide, DMF and DMSO.
The compound (Ima) which is the compound (Im) wherein Z1xe2x80x94Z2xe2x80x94Z3 is C(xe2x95x90O)xe2x80x94NHxe2x80x94C(xe2x95x90O) can also be obtained in such a way that a reaction similar to that mentioned in Process 21 is carried out using the compound (XI) and a diethyl 4-halogenated phthalate such as diethyl 4-bromophthalate followed by hydrolysis and the product obtained thereby is treated with urea.
The compound (I) wherein R9 is carbamoyl can be obtained using the compound (I) wherein R9 is cyano according to a known method [xe2x80x9cJikken Kagaku Koza (Handbook of Experimental Chemistry)xe2x80x9d, fourth edition, edited by the Chemical Society of Japan, 22, 151-154 (1992)] or a method similar thereto.
The compound (I) wherein R9 is cyano is converted to the compound wherein the moiety corresponding to R9 is an aldehyde according to a known method [xe2x80x9cJikken Kagaku Koza (Handbook of Experimental Chemistry)xe2x80x9d, fourth edition, edited by the Chemical Society of Japan, 21, 89-94 (1992)] or a method similarly thereto, and then the compound (I) wherein R9 is ethynyl can be obtained according to a known method [xe2x80x9cJikken Kagaku Koza (Handbook of Experimental Chemistry)xe2x80x9d, fourth edition, edited by the Chemical Society of Japan, 19, 306-307 (1992)] or a method similar thereto.
The intermediates and the desired compounds in each of the above-mentioned process can be isolated and purified by separation and purification methods conventionally used in synthetic organic chemistry such as filtration, extraction, washing, drying, concentration, recrystallization and various kinds of chromatography. The intermediates may be subjected to the subsequent reaction without particular purification.
When it is desired to obtain a salt of the compound (I), the compound (I) is dissolved or suspended in a suitable solvent, then an acid or a base is added thereto, and the resulting salt may be isolated and purified.
Further, the compound (I) and pharmaceutically acceptable salts thereof can also exist in the form of adducts with water or various solvents, which are also within the scope of the present invention.
Specific examples of the compound (I) obtained according to the present invention are shown in Table 1.
The pharmacological activities of the representative the compounds (I) are described in more detail by Test Examples.
Human phosphodiesterase cDNA (HSPDE4A) was isolated from testicles. Its predicted amino acid sequence is identical with the sequence (HSPDE4A5) reported by Bolger, G. et al. (Mol. Cell. Biol., 6558 (1993)) except that 223 amino acids have been deleted from the N-terminal thereof. This recombinant protein was expressed by an E. coli expression plasmid and then purified. The PDE activity was measured in the following 2-step process according to the method of Kincaid, R. and Manganiello, V. [Method. Enzymol., 159, 457 (1988)]. The substrate used was [3H]cAMP (final concentration: 1 xcexcmol/L), and the reaction was performed in a standard mixture containing N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (50 mmol/L, pH 7.2), MgCl2 (1 mmol/L) and soybean trypsin inhibitor (0.1 mg/ml). The reaction was initiated by adding the enzyme thereto, and the mixture was incubated at 30xc2x0 C. for 10 to 30 minutes. The reaction was quenched by hydrochloric acid, and the formed 5xe2x80x2-AMP was completely decomposed with 5xe2x80x2-nucleosidase. This sample was subjected to chromatography on DEAE-Sephadex A-25, and the eluted [3H]adenosine was counted 15 with a scintillation counter. The test compound was added after dissolved (concentration: 1.7%) in DMSO.
In this study, Compound 5 showed enzyme inhibitory activity of over 87% at a drug concentration of 1 mol/L.
Although the compound (I) or pharmaceutically acceptable salts thereof can also be administered as such, it is usually desirable to provide them in the form of various pharmaceutical preparations. Such pharmaceutical preparations may be used for animals and humans.
The pharmaceutical preparations according to the present invention may contain the compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient, alone or as a mixture with other therapeutically effective components. Further, such pharmaceutical preparations are obtained by any means which are well-known in the technical field of pharmaceutics after mixing the active ingredient with one or more pharmaceutically acceptable carriers.
Examples of the effective ingredient to be mixed therewith are a serotonin (5HT)3 receptor antagonist, a serotonin (5HT)4 receptor agonist, a serotonin (5HT)1A receptor agonist, a dopamine (D)2receptor antagonist, a histamine (H)1 receptor antagonist, a muscarine receptor antagonist, a neurokinin (NK)1 receptor antagonist and an endothelin (ET)A receptor antagonist.
It is desired to use the administration route which is the most effective in therapy such as oral administration and parenteral administration which includes intrabuccal, intratracheal, intrarectal, subcutaneous, intramuscular and intravenous administration.
The administration form includes sprays, capsules, tablets, granules, syrups, emulsions, suppositories, injections, ointments and tapes.
Liquid preparations such as emulsions and syrups which are suitable for oral administration can be obtained using water, sugars such as sucrose, sorbitol and fructose, glycols such as polyethylene glycol and propylene glycol, oils such as sesame oil, olive oil and soybean oil, preservatives such as p-hydroxybenzoate and flavors such as strawberry flavor and peppermint. Capsules, tablets, powder and granules can be obtained using excipients such as lactose, glucose, sucrose and mannitol, disintegrators such as starch and sodium alginate, lubricants such as magnesium stearate and talc, binders such as polyvinyl alcohol, hydroxypropyl cellulose and gelatin, surfactants such as fatty acid esters, and plasticizers such as glycerin.
Preparations suitable for parenteral administration comprise a sterilized aqueous agent containing the active compound, which is preferably isotonic to the blood of a patient. For example, a solution for injection is prepared using a carrier such as a salt solution, a glucose solution or a mixture of a saline solution and a glucose solution. Preparations for intrarectal administration are prepared using a carrier such as cacao fat, hydrogenated fat and hydrogenated carboxylic acid, and provided as suppositories. Sprays are prepared using an active compound itself or an active compound with a carrier which can disperse the active compound as fine particles to facilitate absorption without stimulating oral or respiratory mucosa. Examples of such carriers are lactose and glycerin. Preparations such as aerosol and dry powder can be used depending on the properties of the active compound and carriers used.
These parenteral preparations may also contain one or more auxiliary components selected from diluents, flavors, preservatives, excipients, disintegrators, lubricants, binders, surfactants, and plasticizers, all of which are mentioned in the above oral preparations.
The effective dose and administration schedule of the compound (I) or a pharmaceutically acceptable salt thereof may vary depending on the form of administration, the age and body weight of a patient, and the type or degree of the disease to be treated, but usually, in the case of oral administration, the compound (I) or a pharmaceutically acceptable salt thereof is administered in a dose of 0.01 mg to 1 g/adult/day, preferably 0.05 to 50 mg/adult/day, at one time or in several parts. In the case of parenteral administration such as intravenous administration, the compound (I).or a pharmaceutically acceptable salt thereof is administered in a dose of 0.001 to 100 mg/adult/day, preferably 0.01 to 10 mg/adult/day, at one time or in several parts. However, these doses vary depending on the various conditions described above.