MXPA98004050A - Derivatives of pirido (2,3-d) pyrimidine and pharmaceutical compositions of mis - Google Patents

Abstract

This invention relates to the compounds (I) or pharmaceutically acceptable salts thereof, which have a function to inhibit type IV phosphodiesterase (PDE) and which are useful as medicaments, specifically as phosphodiesterase type IV inhibitors, or as preventive or anti-inflammatory agents. therapeutic diseases in which the acceleration of the activity of type IV phosphodiesterase is compromised, particularly respiratory diseases such as bronchial asthma as well as the pharmaceutical compositions thereof. [X: an oxygen atom or a sulfur atom, R1: a lower alkyl group, a lower cycloalkylalkyl group or a cycloalkyl group, R2: a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a hydroxy-lower alkyl group, a mercapto-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkyl-lower alkylthio group, a lower alkanoyloxy-lower alkyl group, a lower alkylthioalkanoyl group, a lower alkanoyl-alkyl group lower, a hydroxy-imino-lower alkyl group, a lower alkoxy-imino-lower alkyl group, a cycloalkyl group, an aryl group or a lower alkanoyl group, R3: a hydrogen atom, a halogen atom or a lower alkyl group, R4: a hydrogen atom or a lower alkyl group, R5: a cycloalkyl group which may be substituted with the same group of R6, a naphthyl group which may be substituted with the same group of R6; five- or six-membered monocyclic hetero ring having from 1 to 4 selected heteroatoms of nitrogen atom, oxygen atom and sulfur atom, which can be substituted with the same group of R6 and which can be condensed with benzene ring; by the formula (II), and R6: a halogen atom, a lower alkyl group, lower alkoxy, a cyano group or a nit group

Description

DERIVADOS DE PIRIDO 12 .3 -Di PYRIMIDINE AND PHARMACEUTICAL COMPOSITIONS THEREOF Technical Field This invention relates to novel derivatives of pyrido [2,3-d] pyrimidine useful as medicaments, particularly as phosphodiesterase inhibitors of type IV, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, the use of same for the production of drugs and a method of prevention or treatment in which an effective amount thereof is administered. Prior art Asthma is a respiratory disease which repeats the stridor and the attack due to the contraction of the respiratory tract. The number of asthma patients has increased steadily and it is considered that it will increase more in the future. The main morbid states of asthma are a) sudden contraction of the smooth muscle surrounding the airway and b) inflammatory reaction caused by the activation of infiltrating cells in the respiratory organs that include the lungs. Therefore, inhibition of airway smooth muscle contraction and inhibition or prevention of infiltrating cell activation is considered an effective means of treating asthma symptoms. For the treatment of asthma, currently used mainly xanthine derivatives such as aminophylline, theophylline and ß-stimulants such as procaterol, as drugs that remit the symptoms of asthma by dilating the bronchi. The mechanism of action of these compounds is that they inhibit smooth muscle contraction of the airway by increasing the concentration of 3 ', 5' - cyclic adenosine monophosphate (cAMP) in the smooth muscle cells of the respiratory tract , which is effected by the activation of adenylate cyclase as an enzyme that produces cAMP or by inhibiting phosphodiesterase (PDE) as a hydrolyzing enzyme of cAMP [Thorax, 46, 512-523 (1991)]. However, xanthine derivatives generate systemic side effects such as lowering of blood pressure, cardiotonic action and the like [J. Cyclic Nucleotide and Protein Phosphorylation Res. , 10, 551-564 (1985)] and, therefore, it is necessary to monitor its concentration in the blood in order to avoid these systemic side effects. In addition, xanthine derivatives do not exert clear effects against asthma when it involves infiltration of inflammatory cells. On the other hand, it is known that β-stimulators generate side effects, such as trembling fingers, palpitation and the like, when the dose increases due to its ability to generate desensitization. Subsequently conducted studies have revealed that phosphodiesterase, an enzyme that hydrolyzes cAMP, is divided into at least four different types from I to IV that have different distributions and functions [Pharmachological Therapy, 51, 13-33 (1991)]. Particularly type IV phosphodiesterase hydrolyzes cAMP in a specific manner without acting on the 3 *, 5'-cyclic guanosine monophosphate (cGMP) between nucleotides, and its presence is found both in the smooth muscle of the airways and in the cells infiltrants Incidentally, phosphodiesterase V is known as an enzyme that degrades cGMP. The concentration of cAMP in the cells is established by the balance of the production rate of cAMP by adenylate cyclase and the rate of hydrolysis of cAMP by phosphodiesterase. Consequently, the concentration of intracellular cAMP can be increased by stimulating adenylate cyclase or inhibiting phosphodiesterase. The increase in intracellular cAMP concentration induces inhibition of airway smooth muscle contraction and inhibition of inflammatory cell activation [Clin. Exp. Allergy, 22, 337-344 (1992), Drugs of the Future, 17, 799-807 (1992)]. It has also been reported that a type IV phosphodiesterase inhibitor shows an action to inhibit the infiltration of eosinophils by an antigen and platelet activation factor in guinea pigs [Eur. J. Pharmacol., 255, 253-256 (1994)] and inhibits the release of cytotoxic proteins (BP, ECP) from eosinophils [Br. J. Pharmacol. , 115, 39-47 (1995)]. It has also been reported to show an action to inhibit contraction of smooth muscle of the airways caused by contractile substances (histamine, LTD4, methacholine) [Br. J. Pharmacol. , 113, 1423-1431 (1994)], inhibits the production of interleukin 4, which is a member of the cytokine that is considered to be deeply involved in asthma [J ". Invest. Dermatol., 100, 681-684 (1993)], expresses an action to inhibit the acceleration of vascular permeability in the respiratory tract [Fundam Clin Clin Pharmacol, 6, 247-249 (1992)] and shows an action to inhibit airway hyperreactivity [ Eur. J. Pharmacol., 275, 75-82 (1995).] Accordingly, an agent that has excellent activity to inhibit phosphodiesterase type IV is expected to be an anti-asthma drug which hardly generates side effects and can repress or to effectively prevent asthmatic symptoms It is known that a compound having a quinazolin-2-one structure has phosphodiesterase inhibition activity, which is not limited to type IV (cf. International Patent Publication 94/12499), but its structure is different e of that of the pyrido [2,3-d] pyrimidine compound provided by the present invention. On the other hand, a compound having a structure of 4-phenylpyrido [2,3-d] pyrimidin-2-one has been reported by G.E. Hardtmann et al. In U.S. Patent Number: 3,758, 475. In this patent, a compound having anti-inflammatory activity is shown, which can be recognized by a suppression test of carrageenan-induced edema, by The general formula: wherein R is hydrogen or lower alkyl of 1 to 5 carbon atoms, for example, methyl; R 'is lower alkyl of 1 to 6 carbon atoms, for example methyl, ethyl, propyl, isopropyl, tertiary butyl, etc.; allyl; metalyl; propargyl; or cycloalkyl of 3 to 6 carbon atoms, for example cyclopropyl; and R "is phenyl or substituted phenyl of the formula: and Y represents halogen of atomic weight from 19 to 80; lower alkyl of 1 to 4 carbon atoms; or lower alkoxy of 1 to 4 carbon atoms; and Y1 represents hydrogen, halogen, lower alkyl or lower alkoxy (all as defined for Y). A similar anti-inflammatory compound has also been reported by G.E. Hardtmann et al. In J. Med. Chem. (Vol. 17, No. 16, 636-639, 1974). A method for the inhibition of platelet agglutination has also been reported in which 1-substituted-4-arylpyrido [2,3-d] pyrimidin-2-one, a compound similar to the compound mentioned above, is administered [see an application Japanese Unexamined Patent Document (Kokai) No. 53-94040]. Some of the compounds provided by the present invention are included in the general formula shown in the aforementioned United States of America patent, because they correspond to the compound of the formula in which R is a lower alkyl group, R 'is a group lower alkyl or a cycloalkyl group of 3 to 6 carbon atoms and R "is a phenyl group having a halogen atom, a lower alkyl group or a lower alkoxy group in its meta position. However, there are no illustrative descriptions in the Examples and elsewhere in the U.S. Patent about a compound having a halogen atom or a lower alkyl group only in the meta position of the phenyl group and also having a lower alkyl group in the 7-position of the pyrido [2,3-d] pyrimidine In addition, the aforementioned US Patent describes only the anti-inflammatory activity and does not describe its The inhibitory action against type IV phosphodiesterase and the ani-asthma reaction is observed. DESCRIPTION OF THE INVENTION The inventors of the present invention have carried out intensive studies on compounds showing inhibitory activity against type IV phosphodiesterase and performed the present invention based on the finding that the compounds represented by the following general formula (I) have excellent inhibitory activity of type IV phosphodiesterase. Thus, according to the present invention, there is provided a pyrido [2,3-d] pyrimidine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof: [Each symbol in the formula represents the following meaning; X: an oxygen atom or a sulfur atom, R1: a lower alkyl group, a lower cycloalkylalkyl group or a cycloalkyl group, R: a hydrogen atom, a halogen atom, a lower alkyl group, a haloalkyl group lower, a hydroxy-lower alkyl group, a mercapto-lower alkyl group, a lower alkoxy-lower alkyl group, a lower-thioalkyl-lower alkyl group, a lower alkanoyloxy-lower alkyl group, a lower alkylthio-lower alkoyl group, an alkanoyl group lower - lower alkyl, a lower hydroxy iminoalkyl group, a lower alkoxy imino lower alkyl group, a cycloalkyl group, an aryl group or a lower alkanoyl group, R: a hydrogen atom, a halogen atom or an alkyl group lower, R: a hydrogen atom or a lower alkyl group, R5: a cycloalkyl group which may be substituted with the same group of R6; a naphthyl group which may be substituted with the same group of R6; a six-membered monocyclic hetero ring group having from 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, which can be substituted with the same group of R "and which can be condensed with benzene ring; or a group represented by the formula and R6: a halogen atom, a lower alkyl group, a halo-lower alkyl group, a hydroxyl group, a lower alkoxy group, a cyano group or a nitro group, with the proviso that R2 is a group other than an hydrogen and R5 is a group represented by the formula R6 is a halogen atom, a lower alkyl group or a lower alkoxy group, R1 is a lower alkyl group or a cycloalkyl group, R3 and R4 are both a hydrogen atom and X is an oxygen atom. ] Among the compounds represented by the general formula (I), those in which X is an oxygen atom, R is a lower alkyl group or a cycloalkyl group, R is a lower alkyl group, R3 and R4 are both an hydrogen, R5 is a group represented by the formula and R is a halogen atom, a lower alkyl group or a lower alkoxy group are included in the general formula shown in the aforementioned United States of America patent. However, these compounds of the present invention are characterized in terms of the chemical structure in which a halogen atom, a lower alkyl group or a lower alkoxy group are introduced only in the meta position (3-position) of the phenyl group of the position 4 of the structure of the l-substituted-4-phenylpyrido [2,3-d] pyrimidin-2 (lH) -one, and in which an alkyl group is introduced in the 7-position. These compounds having specific substituents in positions specific are novel, because they are not described illustratively in the aforementioned United States Patent. Also, these compounds have a pharmacological characteristic in that they exert markedly excellent action in terms of the inhibitory activity of type IV phosphodiesterase which is neither described nor suggested in the aforementioned US Patent. Particularly, it has been confirmed that a pyrido [2, 3-d] pyrimidine derivative represented by the following general formula (II) or a pharmaceutically acceptable salt thereof exerts markedly excellent action on TV-type phosphodiesterase compared to the inherent effect of compounds similarities described in the aforementioned United States Patent.

[In the above formula, R represents a methyl, ethyl, or propyl or isopropyl group, R represents a methyl, ethyl, propyl or isopropyl group, and R "represents a chlorine or bromine atom or a methyl group.] On the other side, a pyrido [2, 3-d] pyrimidine derivative represented by the following general formula (III), which results from the exclusion of the compounds included in the general formula of the aforementioned United States Patent of the compound ( I) of the present invention, or a pharmaceutically acceptable salt thereof is a novel compound that is not described in the prior art references.

[In the above formula, X, R1, R3, R4 and R5 are as defined in the above, and R represents a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a group hydroxy-lower alkyl, a lower mercaptoalkyl group, a lower alkoxy-lower alkyl group, a lower alkylthio-lower alkyl group, a lower alkanoyloxy-lower alkyl group, a lower thioalkanoyl-lower alkyl group, a lower alkanoyl-lower alkyl group, a hydroxy imino-lower alkyl group, a lower alkoxy-imino-lower alkyl group, a cycloalkyl group, an aryl group or a lower alkanoyl group, with the proviso that R is a group other than a hydrogen atom and a group lower alkyl when R5 is a group represented by the formula R "is a halogen atom, a lower alkyl group or a lower alkoxy group, R is a lower alkyl group or a cycloalkyl group, R3 or R are both a hydrogen atom and X is an oxygen atom.] The compound ( III) of the present invention or a pharmaceutically acceptable salt thereof has a structural chemical characteristic in that the skeleton of pyrido [2], 3-d] irimidine has a group based on alkyl specified in its 1-position, an oxo or thioxo group in its 2-position, a ring-based group specified in its 4-position and substituents specified in its 5, 6 and 7 positions and a pharmacological characteristic in that it has a selective inhibition activity against type IV phosphodiesterase. Particularly, the invention of the compound (III) is characterized in that a compound having a pyrido [2,3-d] pyrimidine structure is first provided as an inhibitor of type IV phosphodiesterase. Particularly preferred among the compounds of the present invention are the compounds represented by the general formulas (II) and (III) and the pharmaceutically acceptable salts thereof. Among the compounds of (II), those in which R is methyl or ethyl or more preferably those in which R is the mentioned group and R is ethyl or propyl are particularly preferred. Illustrative examples of the most preferred compounds are those that follow. 4- (3-chlorophenyl) -1,7-diethylpyrido [2,3-d] pyrimidin-2 (1H) -one 4- (3-bromo-phenyl) -1,7-diethylpyrido [2,3-d] pyrimidine -2 (1H) -one, 4- (3-chlorophenyl) -l-ethyl-7-methylpyrido [2,3-d] pyrimidin-2 (1H) -one, 4 - (3-bromo-enyl) -1- et il-7-methylpyrido [2,3-d] pyrimidin-2 (1H) -one, l-ethyl-7-methyl-4- (3-methylphenyl) pyrido [2,3-d] pyrimidin-2 (1H) ) -one and 1, 7, diethyl-4- (3-methylphenyl) pyrido [2,3-d] pyrimidin-2 (1H) -one. Among the compounds of (III), particularly preferred are those in which R is a hydrogen atom, a lower alkyl group, a halo-lower alkyl group, a hydroxy-lower alkyl group, a lower mercaptoalkyl group, a lower alkoxy group - lower alkyl, a lower alkylthio group-lower alkyl, a lower alkanoyloxy-lower alkyl group, a lower thioalkanoyl-lower alkyl group, a hydroxy-imino-lower alkyl group, a cycloalkyl group, an aryl group or a lower alkanoyl group, more preferably those in which R is a hydrogen atom, a lower alkyl group, a halo-lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkanoyloxy-lower alkyl group, a thioalkanoyl group lower-lower alkyl, a hydroxy-imino-lower alkyl group, a cycloalkyl group, an aryl group or a lower alkanoyl group. More particularly, those in which R is the group just described; R4 is a hydrogen atom, -R5 is (1) a cycloalkyl group which may be substituted with a lower alkyl group, (2) a naphthyl group, (3) a five or six member monocyclic hetero ring group having from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms or (4) a group represented by the formula and R6 is a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a cyano group or a nitro group are preferred, and those in which R1 is a lower alkyl group or a cycloalkyl group -lower alkyl, R10 is a lower alkyl group, a halo-lower alkyl group, a hydroxy-lower alkyl group, a thioalkanoyl-lower alkyl group, a hydroxy imino-lower alkyl group, a cycloalkyl group or an alkanoyl group, R and R are both a hydrogen atom, R5 is a cycloalkyl group which can be substituted with a lower alkyl group or a group represented by the formula and R6 is a halogen atom, a lower alkyl group or a nitro group are more preferred. Illustrative examples of the most preferred compounds are the following. 4-cyclohexyl-1-ethyl-7-methylpyrido [2, 3-d] pyrimidin-2 (1H) -one, 4- (3-chlorophenyl) -l-ethyl-7- (1-hydroxyethyl) pyrido [2, 3-d] pyrimidin-2 (1H) -one, 4- (3-chlorophenyl) -7-cyclopropyl-1-ethylpyrido [2, 3-d] pyrimidin-2 (1H) -one, 1-ethyl-7- methyl-4- (3-methylcyclohexyl) pyrido [2,3-d] pyridimidin-2 (lH) ona, i, 7-diethyl-4- (3-methylcyclohexyl) pyrido [2,3-d] pyrimidin-2 ( ÍH) -one, 4- (3-chlorophenyl) -l-ethyl-7-methylpyrido [2,3-d] pyrimidin-2 (1H) -thione, 1- (1-methylpropylmethyl) -7-methyl-4- (3-methylphenyl) ) pyrido [2, 3-d] pyrimidin-2 (lH) -one, 4-cyclohexyl-l, 7-diethylpyrido [2,3-d] pyrimidin-2 (lH) -one, 4- (3-chlorophenyl) -l-ethyl-7-hydroxy-iminopyrido [2,3-d] pyrimidin-2 (1H) -one, 7- (1-thioacetylethyl) -4- (3-chlorophenyl) -1-ethylpyrido [2, 3 d] pyrimidin-2 (1H) -one and 1,7-diethyl-4- (3-chlorophenyl) pyrido [2, 3-d] pyrimidin-2 (1H) -thione. The present invention also includes a pharmaceutical composition comprising the compound (I) or a pharmaceutically acceptable salt thereof, preferably the compound (III) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Modes of the pharmaceutical composition include a type IV phosphodiesterase inhibitor containing the compound (I), preferably the compound (III), or a pharmaceutically acceptable salt thereof, more particularly an agent for use in the prevention or treatment of respiratory diseases in which type IV phosphodiesterase is involved, especially bronchial asthma. Also included in the present invention is the type IV phosphodiesterase inhibitor containing the compound (II) or a pharmaceutically acceptable salt thereof, more particularly an agent for use in the prevention or treatment of respiratory diseases to which phosphodiesterase concerns. type IV, especially bronchial asthma. Also included in the present invention is the use of the compound (I), preferably Compound (II) or (III), or a pharmaceutically acceptable salt thereof for the production of an agent for use in the prevention or treatment of diseases to the which concerns the acceleration of type IV phosphodiesterase, especially respiratory diseases more especially bronchial asthma, or a method for the prevention and treatment of that disease which is that an effective amount of said compound is administered to patients who have contracted or have a possibility of contract that disease. The following describes the compound of the present invention in greater detail. Unless otherwise indicated, the term "lower" as used in the general formulas of the present invention means a straight or branched carbon chain having from 1 to 6 carbon atoms. Illustrative examples of the "lower alkyl group" include straight or branched alkyl groups of 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, -methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylutyl, 3,3-dimethylutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 2 -trimethylpropyl, 1,2,2-tri-ethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and the like. Of these groups, alkyl groups of 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl and the like are preferred, and alkyl groups of 1 to 3 carbon atoms such as methyl, ethyl, propyl, isopropyl and similar are particularly preferred. As the lower alkyl group of R, alkyl groups of 1 to 6 carbon atoms, particularly alkyl groups of 2 to 3 carbon atoms, are preferred, and alkyl groups of 1 to 3 carbon atoms, especially methyl groups and ethyl, are preferred as the lower alkyl groups of R. Illustrative examples of the "lower alkoxy group" include straight or branched alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentyloxy (amyloxy), isopentyloxy, pentyloxy. tertiary, neopentyloxy, 2-methylbutoxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy and the like, of which methoxy and ethoxy groups are preferred. The term "lower thioalkyl group" as used herein means a group in which the hydrogen atom of the thiol group is substituted with the lower alkyl group mentioned above, and its illustrative examples include straight or branched thioalkyl groups of 1 to 6 carbon atoms such as thiomethyl, thioethyl, thiopropyl, isothiopropyl, thiobutyl, isothiobutyl, secondary thiobutyl, tertiary thiobutyl, thiopentyl, isothiopentyl, neothiopentyl, tertiary thiopentyl, 2-methylthiobutyl, 1,2-dimethylthiopropyl, 1-ethylthiopropyl, thiohexyl and the like , of which thiomethyl and thioethyl groups are preferred. Illustrative examples of "lower alkanoyl group" include straight or branched alkanoyl groups of 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyl, isobutyl, valeryl, isovaleryl, pivaloyl and the like, of which formyl, acetyl groups are preferred. and propionyl. The "lower alkanoyloxy group" is a group that results from the esterification of an alcohol and a lower carboxylic acid, and its illustrative examples include straight or branched alkanoyloxy groups of 1 to 6 carbon atoms such as formyloxy, acetoxy, propionyloxy, butyloxy, isobutyloxy , Varyloxy, Pivaloyloxy and the like. The "lower thioalkanoyl group" is a group that results from the thioesterification of a thiol and a lower carboxylic acid, and its illustrative examples include straight or branched thioalkanoyl groups of 1 to 6 carbon atoms such as thioformyl, thioacetyl, thiopropionyl, thiobutyl, isothiobutyl , thiovaleryl, tiopivaloyl and the like. Illustrative examples of "cycloalkyl group" include those having from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. A cyclopropyl group is particularly preferred as the cycloalkyl group of "a cycloalkyl-lower alkyl group of R1 and that of R2. Also a cyclohexyl group is particularly preferred as the cycloalkyl group of" a cycloalkyl group which can be substituted "of R5. The term "aryl group" means an aromatic hydrocarbon group preferably having from 6 to 14 carbon atoms, examples of which include phenyl, tolyl, xylyl, biphenyl, naphthyl, indenyl, anthryl and phenanthryl groups, more preferably phenyl and naphthyl groups, most preferably a phenyl group Examples of the "halogen atom" include fluorine, chlorine, bromine and iodine atoms, and the chlorine and bromine atoms are particularly preferred as the substituent for the ring systems, and the fluorine and chlorine and bromine as a substituent for alkyl chain The "substituted lower alkyl group" mentioned before R1, R2, R6 or R10, particularly of R2 or R10, may be substituted with from one to four (particularly one to three) various substituents and the illustrative examples of those substituents respectively include a halogen group, a hydroxyl group, a mercapto group , a lower alkoxy group, a lower thioalkyl group, a lower alkanoyloxy group, a lower thioalkanoyl group, a lower alkanoyl group, a hydroxy imino group, an alkoxy imino group and a cycloalkyl group. In this case, illustrative examples of the halogen atom constituting the "halogen group" and the lower alkoxy, lower thioalkyl, lower alkanoyloyl, lower thioalkanoyl, lower alkanoyl and cycloalkyl groups include those described above. Illustrative examples of the "lower alkoxy imino group" include straight or branched alkoxy imino groups of 1 to 6 carbon atoms, such as methoxy imino, ethoxy imino, propoxy imino, isopropoxy imino, butoxy imino, tertiary-imino butoxy and the like. Accordingly, preferred illustrative examples of substituted lower alkyl groups respectively include: trifluoromethyl, chloromethyl, bromomethyl, 2-chloroethyl, 1-chloroethyl, 2-bromoethyl, 1-bromoethyl, and the like as the "halo-lower alkyl group"; hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and similarly as the "hydroxy-lower alkyl group"; mercaptomethyl, 2-mercaptoethyl, 1-mercaptoethyl and the like as the "mercapto-lower alkyl group"; methoxymethyl, ethoxymethyl, 2-methoxyethyl, 1-methoxyethyl, dimethoxyethyl and the like as the "lower alkoxy-lower alkyl group"; thiomethylmethyl, thioethylmethyl, 2-thiomethylethyl, 1-thiomethylethyl and the like as the "lower thioalkyl-lower alkyl group"; acetoxymethyl, 2-acetoxyethyl, 1-acetoxyethyl and the like "lower alkanoyloxy-lower alkyl, thioacetylmethyl, 2-thioacetylethyl, 1-thioacetylethyl group and the like" lower thioalkanoyl group-lower alkyl "; formyl ethyl, acetonyl, 2- oxobutyl and the like as the "lower alkanoyl-lower alkyl group"; hydroxy-iminomethyl, 2-hydroxy-iminoethyl, 1-hydroxy-iminoethyl and the like as the "hydroxy-imino-lower alkyl group"; methoxy-iminomethyl, ethoxy-iminomethyl and similar as the "lower alkoxy imino-lower alkyl group" and cyclopropylmethyl, cyclohexylmethyl, 2-cyclopropylethyl and the like as the "cycloalkyl-lower alkyl group." Illustrative examples of the "five or six member monocyclic hetero ring group" from 1 to 4 heteroatoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom, which can be condensed with benzene ring "includes monocyclic hetero rings such as furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxasolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and the like, and these monocyclic hetero ring groups, together with benzene ring can form condensed rings such as indolyl, indazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isoindolyl, isoquinyl, chromenyl, quinolyl, quinazolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, benzoxadiazolyl, phthalazinyl, quinoxalinyl, cinolinyl and the like. The binding of these fused rings to the 4-position of the pyrido [2,3-d] pyrimidine ring can be formed through any of the carbon and nitrogen atoms in the hetero ring or carbon atoms in the benzene ring. Of these monocyclic hetero rings, furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl groups are preferred, and thienyl, thiazolyl and pyridyl are more preferred. When R is a cycloalkyl group, a naphthyl group or a hetero ring group, the number of substituents to be substituted is not limited to one, more preferably from one to three. The compounds of the present invention can form salts. Pharmaceutically acceptable salts of the compound (I), particularly the compounds (II) and (III), are included in the present invention, and examples of those salts include acid addition salts with inorganic acid (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like) and with organic acids (eg, formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, acid oxalic, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, citric acid, malic acid, tartaric acid, carbonic acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid, aspartic acid and the like). The compounds of the present invention exist in tautomeric forms based on the presence of cyclic urea or thiourea having conjugated double bond. Also, depending on the type of substituents, it may exist in forms of optical isomers based on the presence of asymmetric carbons and other forms of isomers based on the presence of a cyclic ring, a hydroxy imino group and a lower alkoxy-invino group. All of these isomers separately or mixtures thereof are included in the present invention. In addition, the compounds of the present invention can be isolated in the form of hydrates, solvates with ethanol and the like or suetances having various crystalline forms having polymorphism, depending on their physicochemical properties or production conditions. All estoe hydrate, solvates with ethanol and the like and substances having various crystalline forms are also included in the present invention.

(Production Methods) The compounds of the present invention and salts of the eemoe ee can be produced using various synthetic methods, making use of the characteristics of their basic structure and types of substituents. The following describes your typical production methods. In this regard, the initiate compounds or compounds of the present invention can be subjected to synthetic reactions after protecting their functional groups with appropriate protecting groups. Examples of such protecting groups can be found, for example, in "Protective Groups in Organic Synthesis" 2a. edition, edited by Greene and Wuts, and these groups can be used optionally depending on each reaction condition. In addition, an aldehyde compound can be obtained by the reaction using a corresponding acetal compound and the subsequent conversion to the aldehyde.

First production method (cyclization) (In the above formulas, R1, R2, R3, R and R are as defined in the foregoing, and Z repreend outgoing groups which are suitable for this reaction.) A compound (a) as one of the compounds herein invention in which X is an oxo group can be produced by allowing a 2-aminopyridyl ketone derivative (IV) reacting with an isocyanate represented by a general formula (Va) or a carbamate derivative represented by a general formula (Vb), thereby effecting cyclization. Examples of the leaving group represented by Y1 include halo-eulphonyl groups as a chlorosulfonyl group and similaree and tri-suetituidoe silyl groups as a trimethylylyl group and the like. Examples of the leaving group represented by Z include alkoxy groups (for example, methoxy and ethoxy) and a phenoxy group. The reaction in which an isocyanate is used is carried out in an inert solvent for the reaction which is selected, for example, from halogenated hydrocarbons (for example, dichloromethane, dichloroethane, chloroform and the like), aromatic hydrocarbons (for example, benzene) , toluene, xylene and the like) and ethers (for example diethyl ether, tetrahydrofuran, dioxane and the like) at a cooling temperature of -78 ° C to 0 ° C, at room temperature to room temperature, or at room temperature. it requires it, at room temperature to heating. In order to carry out the reaction, the compound (IV) and the isocyanate (Va) are used in molar amounts equivalent to either one being used in an excessive amount, and the reaction can be done in the presence of a base such as triethyl amine , di-isopropylethyl amine, N-methyl morpholine, N, N-dimethyl aniline, pyridine, 4- (N, N-dimethylamino) pyridine, picoline, lutidine or the like, it is sometimes convenient to carry out the reaction smoothly. When the carbamate derivative represented by the general formula (Vb) is used in place of the isocyanate (Va), it is convenient to carry out the reaction in the presence of a Lewis acid such as zinc chloride, tin chloride, titanium tetrachloride, boron trifluoride-ethyl ether or the like. In this sense, a compound having a halogen atom in position 6 is sometimes obtained as a by-product of this method. The above mentioned starting compound (IV) can be easily obtained by synthesizing it by the production method of the following reaction scheme described in the Reference Examples or a modified method thereof. (14) (IV) (In the formulas above, R1, R2, R3, R4 and R are as defined in the above, and other symbols represent the following: R2: the same group of R2, which can be protected, P R3 ° ': the same group of R, excluding halogen atoms, Y2, Y3 and Y4: the same or different from each other, and each represents a halogen atom, Z2 and Z3: suitable leaving groups for the reaction of synthesis of pyridine, and Ts: a p-toluene-sulfonyl group. ) That is, when the 3-acyl-2-halopyridine derivative (7) is used as the starting material, the starting compound(IV) can be produced using a common N-alkylation reaction, which will be described later, in which the above derivative is allowed to react with a substituted R-amine (8), subeequently removing the protective group when the occasion requires it. It is possible to apply it to the first production method without removing the protection group. Also, when a derivative of 3-acyl-2- (p-toluene sulfonyloxy pyridine is used (13) As the starting material, the starting compound (IV) can be produced using a common N-alkylation reaction, which will be described later, in which the above derivative is allowed to react with the substituted-R amine (8) ) in the same way as described above. In addition, when a 2-substituted aminopyridinecarbonitrile (14) is used as the starting material, the starting compound (IV) can be produced using a general method for the synthesis of ketones from nitrile in which the starting material (14) it is allowed to react with a Grignard reagent (2) derived from the halide of R5. In this regard, the intermediate (7) can be produced using a method in which the corresponding nitrile (1) or carbonic acid (3) is used as the starting material and allowed to react with the aforementioned Grignard reagent (2) , or by oxidizing, in the general method, a substituted 2-halogeno-3-pyridine hydroxymethyl derivative (6) which is obtained by leaving the aldehyde (5) of R5 to react with a 2-halopyridine derivative (4) having high reactivity in position 3. Intermediate (13) is obtained by reacting a ketone (9) (eg, 1, 1-diethoxypentanone) with an acylacetamide (10) and reacting the resulting 2-oxopyridyl ketone with a tosyl halide . The production of these initial compounds can be carried out optionally by selecting appropriate method depending on the difference in substituents such as R, R, R, of the compound of interest. Also, a substituent may be introduced in an optional step, for example, by nitration or the like. Second production method (mutual conversion of substituents). The compound of the present invention can be derived from another compound containing a substituent of the present invention. The method of mutual conversion of substituents can be carried out using general methods. What follows describes typical examples (a) Tsionation (the) (Ib) (In the above formulas, R1, R2, R3, R4, and R5, are as defined in the foregoing.) Among the compounds of the present invention, a compound (Ib) in which X is a sulfur atom can be obtaining leaving another compound (Ia) of the present invention, in which X is an oxygen atom, reacting with phosphorus pentasulfide or Lawesson's reagent. This reaction may be carried out in an inert organic solvent for the reaction such as benzene, toluene, tetrahydrofuran, ether, dioxane, methylene chloride, using the compound and phosphorus pentasulfide or Lawesson's reagent in equivalent molar amounts, or either one in an excessive amount, at room temperature or with heating, as the occasion requires. (b) Reduction (In the above formulas, R1, R3, R4, R5 and X, are as defined above, R11 represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms and A1 represents a single bond or a group alkylene of 1 to 5 carbon atoms.) A hydroxy-lower alkyl compound (Id) can be produced by reducing its corresponding carbonyl compound (le). The reduction is carried out using a general reduction method in which an alcohol compound is synthesized from a carbonyl compound. It is convenient to carry out the reduction using sodium borohydride in a protic solvent such as ethanol or the like or by treating it with a metal hydride (for example, lithium aluminum hydride or the like) in an inert solvent such as ether, tetrahydrofuran or the like, usually under cooling condition. (c) C-Alkylation (In the above formulas, R1, R3, R4, R5 and X, and Y3, are as defined above, and R represents an alkyl group of 1 to 5 carbon atoms). A compound substituted with 2-1- (hydroxy-lower alkyl) (If) can be produced by a general method in which its corresponding aldehyde is allowed to react with the Grignard reagent (VI) derived from a lower alkyl halide and magnesium .

It is convenient to carry out the reaction in an inert solvent such as tetrahydrofuran, ether or the like, generally under the condition of cooling. (d) Oxidation (In the above formulas, R1, R3, R4, R5, X, R11 and A1, are as defined above.) In contrast to Method (b), the oxidation of a hydroxyl compound (Id) results in its corresponding carbonyl compound (le). Oxidation is effected using a general method in which a carbonyl compound is produced by oxidizing its corresponding hydroxyl compound, which is generally carried out by heating the material and an oxidizing agent under reflux in an inert solvent such as benzene, toluene or the like. As an oxidizing agent, manganese dioxide, pyridinium chlorochromate or the like are advantageously used. (e) Halogenation i) Halogenation of the side chain (1) (In the above formulas, R1, R3, R4, R5, X, R11, Y2, and A1 are as defined above.) A halo-lower alkyl compound (Ig) is produced by treating its corresponding hydroxyl compound (Id. ) with an appropriate halogenation agent in the general method. It is convenient to carry out the reaction in an inert solvent for the reaction such as benzene, carbon tetrachloride or the like, or in the absence of solvent, using a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus trichloride, pentachloride of phosphorus, hydrochloric acid, hydrobromic acid or the like, if necessary by heating under reflux. ii) Side chain halogenation (2) (In the above formula, R1, R2, R3, R4, R5, R11 and Y2 are as defined above and R represents a hydrogen atom or an alkyl group of 1 to 5 carbon atoms which may have a substituent. ) A halogeno-lower alkyl compound (Ii) is produced by treating its corresponding alkyl compound (Ih) with a suitable halogenating agent. It is convenient to carry out the reaction in an inert solvent for the reaction such as carbon tetrachloride or the like using a halogenating agent such as chlorine gas, bromine, N-bromosuccinimide or the like and to heat the mixture under reflux, if necessary, in presence of a catalyst such as 2, 2'-azobisisobutyronitrile, benzoyl peroxide or the like. When N-bromosuccinimide is used, the reaction can also be carried out under light irradiation in the presence of a catalyst such as 2-2'-azobisisobutyronitrile, benzoyl peroxide or the like. iii) Ring Halogenation It is convenient to carry out ring halogenation in the initial compound step. The method described in the Reference Example can be used advantageously, in which phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, bromine or the like are used. f) Acylation (In the above formulas, R1, R3, R4, R5, X, R11 and A1 are as defined above, Y5 represents a halogen atom or a hydroxyl group and R represents an alkanoyl group of 1 to 5 carbon atoms .) A lower alkanoyloxy-lower alkyl compound (Ik) can be easily synthesized by an esterification method in which its corresponding carboxylic acid (VII) or a reactive derivative thereof such as ester, acid anhydride or the like is left react with a corresponding hydroxyl compound or halide (Ij). The common esterification method can be applied to this reaction. In this regard, a lower alkanoylthio-lower alkyl compound can also be produced by a similar esterification method. In addition, the lower alkanoyloxy-lower alkyl compound can also be obtained by a method in which its corresponding halo-lower alkyl compound is allowed to react with an alkali metal salt of the corresponding carboxylic acid. (g) Saponification (In the above formulas, R1, R3, R4, R5, X, R11, R13 and A1 are as defined above.) Contrary to the production method (f), the corresponding hydroxyl compound (Id) can be synthesized using an ester compound (Ik) as the raw material. It can be produced by a commonly used method in which the initial material is treated with a base such as sodium hydroxide or the like. (h) Oxime Formation The compound of the present invention having a hydroxylimino group or a lower alkoxy imino group can be produced by reacting the corresponding aldehyde or ketone compound with hydroxyl amine or a lower alkoxyamine. The reaction can be carried out using a general method, for example, by reacting the aldehyde or ketone compound and hydroxyl amine or a lower alkoxyamine or a salt thereof in equivalent molar amounts or either one in a slightly excessive amount , in an organic solvent inert to the reaction (eg, methanol and ethanol) and, if desired, in the presence of a base (eg, sodium carbonate and sodium acetate), under cooling, at room temperature, or under reflux temperature. Third production method (N-Alkylation) (In the above formulas, R1, R, R3, R, R5, and X are as defined above and Y6 represents a leaving group which is convenient for this reaction.) In this production method, the compound (I) of the present invention is produced by leaving a compound (VIII) to react with a compound (IX). Illustrative examples of the leaving group represented by Y6 include halogen atoms such as iodine, bromine, chlorine and the like, and organic sulfonic acid residues such as alkylsulfonyloxy groups (eg, methanesulfonyloxy, ethanesulfonyloxy and the like) and arylsulfonyloxy groups (eg. example, benzenesulfonyloxy, toluene- (particularly p-toluene) sulfonyloxy, and the like). This reaction is carried out using the compound (Vlll) and the compound (IX) in equivalent molar amounts, or one of them in an excessive amount, in an organic solvent inert to the reaction such as benzene, toluene, diethyl ether, tetrahydrofuran , dioxane, dimethyl formamide, dimethyl sulfoxide or the like, in the presence of a base, and at a cooling temperature of -78 ° C to 0 ° C, at room temperature or, as the occasion demands, with heating. Illustrative examples of the base to be used include sodium hydride, potassium hydride, lithium diisopropyl amide, lithium hexamethyldisilazide, potassium tertiary butoxy, sodium methoxide and the like. This reaction can also be carried out using a base such as sodium alcolate, potassium alcolate, sodium hydroxide, potassium hydroxide and the like in an alcohol solvent such as methanol, ethanol or the like. In this regard, the initial compound (VIII) can be subjected to the reaction without using a base, when its 1-position is replaced with an alkali metal. The compound thus produced of the present invention is isolated and purified in a free form or as a salt thereof by subjecting it to a commonly used salt formation reaction. The isolation and purification are carried out using usual chemical treatments such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various types of chromatography. Various types of isomers can be isolated in the usual way making use of the differences in the physicochemical properties between the isomers. For example, a racemic compound can be introduced into stereochemically pure isomers by a general racemic resolution method (e.g., a method in which optical resolution is effected by introducing into a diastereomeric salt with an optically general active acid such as tartaric acid. ). Also a diastereomeric mixture ee can be separated by commonly used means such as fractional crystallization, chromatography or the like. In addition, an optically active compound can be produced using an appropriate optically active material.

Industrial Applicability The compounds of the present invention represented by the general formula (I) or the pharmaceutically acceptable salts thereof are useful as medicines, because they have an excellent activity to inhibit type IV foefodieeterae, and the activity is selective for the phosphodiesterase type. IV. Accordingly, the compounds of the present invention can be used for the prevention or treatment of various diseases in which type IV phosphodiesterase is involved. What follows exemplifies this type of disease. Respiratory diseases [e.g., bronchial asthma (including atopic asthma), chronic bronchitis, pneumonia, adult respiratory distress syndrome (ARDS) and the like], Inflammatory diseases [e.g., atopic dermatitis, conjunctivitis, urticaria, acquired immunodeficiency syndrome ( AIDS), keloid formation, rhinitis, iridocilitis, gingivitis, periodontitis, alveolar pyorrhea, gastritis, ulcerative colitis, Crohn's disease, gastrointestinal ulcer, esophagitis, myositis, encephalitis (myasthenia gravis, multiple sclerosis and neuritis), hepatitis, scarring, nephritis (including proliferative nephritis), peritonitis, pleuritis, scleritis, scleroderma, wounding by burn and the like], systemic or local arthropathy (eg, osteoarthrosis, gouty arthritis, arthritis chronic rheumatoid, malignant rheumatoid, psoriatic arthritis and the like • proliferative diseases [malignant tumor, leukemia, proliferative dermatopathy (keratosis and various types of dermatitis), collagen and eimilar disease], diseases related to abnormality of nervous function (for example, alterations) learning, memory and cognition related to nerve degeneration such as Alzheimer's disease, Parkinson's disease and the like, lateral multiple sclerosis, senile dementia, lateral amyotrophic sclerosis, acute demyelinating neuritis, muscular dystrophy and eimilar), • diseases with abnormality of function mental (for example eg, manic-depressive, schizoid, anxiety, panic and the like), inflammation due to organ transplantation and similaree (eg, reperfusion injury, graft-versus-host reaction and the like), diseases requiring protection of nerves and cells [ example, cardiac arrest, spinal cord injury, intermittent lameness, ischemic diseases (eg, angina pectoris, myocardial infarction, stroke, head injuries and the like) and similaree], micturition-related diseases (eg, ineffective diabetes, urethritis, urinary incontinence, cystitis, irritable bladder, neurogenic bladder, uremia, tubular alterations, frequency, urinary retention and the like), endocrine disease including diabetee mellitus (for example, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, amyloidosis, pancreatitis) , thyroiditis, obesity, prostatic hypertrophy and the like), • diseases in which the tumor necrosis factor (TNF) and another cytokine (IL-1, IL-6 and the like) are involved [eg, psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, sepsis, septic shock, endotoxic shock , sepsis due to gram negative bacillus, toxic shock syndrome, nephritis, hepatitis, infection (bacterial and viral), circulatory failure (heart failure), arteriesclerosis, myocardial infarction, stroke) and similar], autoimmune diseases (for example, lupus erythematosus) systemic, atrophic gastritis, thyroid gland disease, glomerulonephritis, orchitis, adrenal disease, hemolytic anemia, ovaritis and the like), diseases of the circulatory system (for example, hypertension, angina pectoris, heart failure, myocarditis, epicarditis, endocarditis, valvulitis and similar), diseases of the vascular and blood system (for example, angitis, aneurysm, vascular endothelial injury, inflammation due to thrombosis, granuloma, cerebrovascular inflammation, arteriosclerosis, perivaecular inflammation, leukopenia, thrombocytopenia, earcoidoeie and eimilares), diseases in which immunoallergic reactions are involved (for example, contact dermatitis, serum sickness, drug allergy, Goodpasture syndrome, lymphomatosis, rheumatic fever, AIDS, anaphylactic shock and the like), and other diseases [glaucoma, spastic paralysis, impotence, diseases with pain (for example, contusion, headache and similar.) cervico-omo-gill syndrome, neuropathy, renal failure, Hepatic insufficiency and obesity]. The compound (I) of the present invention is particularly useful for the prevention or treatment of respiratory diseases [eg, bronchial asthma (including atopic asthma), chronic bronchitis, pneumonia, adult respiratory distress syndrome (ARDS) and the like], inflammatory diseases [eg, atopic dermatitis, conjunctivitis, urticaria, acquired immunodeficiency syndrome (AIDS), keloid formation, rhinitis, iridocilitis, gingivitis, periodontitis, alveolar pyorrhea, gastritis, ulcerative colitis, Crohn's disease, gastrointestinal ulcer, esophagitis, miositis , encephalitis (myasthenia gravis, multiple sclerosis and neuritis), hepatitis, scarring, nephritis (including proliferative nephritis), peritonitis, pleuritis, scleritis, scleroderma, burn injuries and the like], and diseases in which tumor necrosis factor (TNF) ) and another cytokine (IL-1, IL-6 and the like) are involved [eg, psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, eepeiae, septic shock, endotoxic shock, sepsis due to gram-negative bacillus, toxic shock syndrome, nephritis, hepatitis, infection (bacterial and viral), circulatory failure (heart failure), arteriosclerosis, infarction to the myocardium, apoplexy) and similar]. More particularly, the components of the present invention are useful as excellent agents for preventing and treating respiratory diseases such as bronchial asthma and the like. Also, since the compounds of the present invention exhibit an extremely weak emetic action compared to the above phosphodiesterase inhibitors, they are particularly useful for the treatment or prevention of diseases in patients requiring systemic administration. The activities of the compounds of the present invention to inhibit phosphodiesterase, type IV and types I, II, III and V, were confirmed by the following tests. Phosphodiesterase Inhibition Activity Measurement Test (± n vitro) (I) Method to measure the inhibition activity of type IV phosphodiesterase. The following assay was used for the evaluation of the ability of the compounds of the present invention to inhibit type IV phosphodiesterase. 1) Physiological saline (200 milliliters) supplemented with dextran (3 percent) was added to 500 milliliter of heparinized peripheral blood from a healthy person and incubated at 37 ° C for 40 minutes to effect the precipitation of erythrocytes. The supernatant after the red cell precipitation was recovered and centrifuged once, and the resulting precipitate was suspended in regulator A (140 mM NaCl, 5 mM KCl, 5 mM glucose and 10 mM HEPES, pH 7.4), extended on a solution for the use of density gradient centrifugation (Ficoll solution) and then centrifuged at room temperature for 40 minutes at 450 xg, separating the monocyte fraction and the granulocyte fraction. The granulocyte fraction was washed once with regulator B (140 mM NaCl, 5 mM KCl, lmM CaCl 2, lmM MgCl 2, 5 mM glucose and 10 mM HEPES, pH 7.4), and was suspended in regulator C (20 mM Bis- Trie, 5 mM dithioerythritol, 2 mM EGTA and 50 mM eodium acetate, pH 6.5) containing a protease inhibitor (50 μM phenyl fluoride-methyl-sulfonyl, 5 μM pepstatin A, 40 μM of leupeptin, 20 of aprotinin or 2 mM of benzamidine) and then the cells were disrupted using polytron and sonicator and they were subjected to ultracentrifugation (4 ° C, 100,000 x g, 60 minutes) to give a soluble fraction. 2) The soluble fraction thus obtained was applied to a column of 1.6 x 10 centimeters packed with Q Sepharose which was equilibrated with the regulator C. Next, the column was washed with 300 milliliter of regulator C to remove the non-absorbed protein. The phosphodiesterase was eluted with 200 milliliters of buffer C having 0.05 to 1.25 linear gradient of sodium acetate to collect 40 fractions each containing 5.0 milliliters of eluate. Each fraction was verified to determine the activities of the foefodieeteraea by metabolizing cAMP and cGMP. Fractions that have no cGMP metabolizing activity but cCAMP and that show disappearance of metabolisation activity by 10 μM rolipram (a type of selective inhibitor of phosphodiesterase type IV) were collected for use as a base solution for the examination of the inhibition activity of type IV phosphodiesterase. 3) A pre-determined amount of each compound to be examined was subjected to 10 minutes of reaction at 30 ° C in a reaction mixture containing 40 mM Tris-HCl (pH 8.0), 5 mM MgCl2, 4 mM 2-mercaptoethanol, 0.3 mM cilostamide (a selective inhibitor of phosphodiesterase type III), 1 μM cAMP, 10 Nm 3 H-cAMP, and the phosphodiesterase type IV control solution. The reaction solution was boiled at 90 ° C for 1 minute, cooled in an ice bath, mixed with 1 unit of 5 'nucleotidase and then subjected to 10 minutes of reaction at 30 ° C, and the solution of the reaction was passed through a Dowex column of 1 x 8 to adsorb the non-hydrolyzed material and then the radioactivity was measured. 4) The concentration of each compound to be examined that inhibits 50 percent of the metabolic activity of type IV phosphodiesterase was calculated and expressed as IC5u. Test results: The results of the measurement of the activity of the compounds of the present invention to inhibit type IV phosphodiesterase are shown in Tables 1 and 2, together with the results of the compounds described illustratively in the State Patent. United States of America mentioned above and similar comparative compounds were synthesized separately.

Table 1 Table 2 Comparative compound 1: 4- (2-chlorophenyl) -1-ethylpyrido [2,3-d] pyrimidin-2 (1H) -one; mp 134-135 ° C (AcOEt-hexane) Comparative Compound 2: Compound of Example 5f in the Patent of the States United States of America mentioned above. Comparative compound 3: 4- (4-chlorophenyl) -1-ethylpyrido [2,3-d] pyrimidin-2 (1H) -one; mp 221-222 ° C (AcOEt-hexane) Comparative Compound 4: Compound of Example 5e in the aforementioned United States Patent. Comparative compound 5: 4- (3,4-dichlorophenyl) -1-ethylpyrido [2,3-d] pyrimidin-2 (lH) -one; pf. , 236-239 ° C (AcOEt-iPr20) Comparative compound 6: 4- (3-chlorophenyl) -l-isopropyl-pyrido [2,3-d] pyrimidin-2 (lH) -one; mp 169-171 ° C (AcOEt-iPr20) Comparative compound 7: 4- (3-chlorophenyl) -l-ethylpyrido [2,3-d] pyrimidin-2 (lH) -one; mp 154-156 ° C (AcOEt-hexane) Comparative compound 8: 4- (3-methylphenyl) -1-ethylpyrido [2,3-d] pyrimidin-2 (1H) -one; pf. 148-149 ° C (AcOEt-hexane) As is evident from the above test results, the compounds of the present invention have a markedly high activity to inhibit type IV phosphodiesterase. Particularly, in compounds of the type compounds 4- (substituted phenyl) -1-pyrido [2,3-d] pyrimidine substituted-2 (1H) -one having the substituent of the phenyl group of the 4-position in the ortho or para position they have extremely low type IV phosphodiesterase inhibition activity. The same can be said of the compounds that are di-substituted in the para and meta positions. In contrast, compounds having the substituent only in the meta position (comparative compounds) have a higher order activity than those having ortho-, para- or di-suetituidoe compounds. In addition, the compounds of the present invention in which the phenyl group in the 4 position has a substituent only in its meta position and a lower alkyl group is introduced in the 7th section is remarkably excellent in its inhibition activity of phosphodiesterase type IV in comparison with compounds that have only one substituent in the meta position. Accordingly, among compounds of the compound type are 4- (substituted phenyl) -1-pyrido [2,3-d] pyrimidine substituted-2 (1H) -one of the present invention in which the phenyl group at position 4 has a substituent only in its meta position and a substituent based on lower alkyl is introduced at the 7-position, particularly the compounds shown in Table 2 [included in the compote (II) of the present invention], have markedly excellent activity to inhibit phosphodiesterase type IV, even in comparison with the inherent effect of the compounds described illustratively in the aforementioned United States Patent. (2) Method for measuring activity to inhibit various phosphodiesterase isozymes [A] In order to selectively evaluate the compounds of the present invention for type IV phosphodiesterase, isozymes of phosphodiesterase type I, II, III and V were purified as follows. 1) Solutions containing several phosphodiesterase isozymes (types I, II and III) were purified from rat heart muscle cells in the following manner. Under anesthesia with ether, a Wistar rat underwent a thoracotomy to cut the heart. After removing the blood by perfusion with physiological saline solution supplemented with heparin (1 unit / milliliter), the heart was finely chopped with scissors. This was suspended in saline A (20 mM Bis-Tris, 5 mM dithioerythritol, 2 mM EGTA and 50 mM sodium acetate, pH 6.5) containing a protease inhibitor (50 μM phenyl fluoride-methyl-sulfonyl, 5 μM of pepstatin A, 40 μM of leupeptin, 20 μM of aprotinin or 2 mM of benzamidine) and then the cells are broken using polytron and sonicator and subjected to ultracentrifugation (4 ° C, 100,000 xg, 60 minutes) to give a soluble fraction. 2) Solutions containing several isozymes of phosphodiesteraea ee obtained from the soluble fraction obtained in the following manner. The soluble fraction thus obtained was applied to a column of 1.6 x 10.0 centimeters packed with Q Sepharose that had been equilibrated with regulator A. Next, said column was washed with 300 milliliters of regulator A to remove non-absorbed protein. The phosphodiesterase was eluted with 200 milliliters of regulator A having from 0.05 to 1.25 M linear gradient of sodium acetate to collect approximately 40 fractions each containing 5.0 milliliters of eluate. Each fraction was verified to determine phosphodiesterase activities that metabolize cAMP and cGMP. Of these fractions, a fraction that only has the activity of metabolizing cAMP and which stops the metabolizing activity from 0.1 μM of ciloetamide (an eelective inhibitor of type III phosphodiesterase) was used as type III phosphodiesterase. Also a fraction that showed enhanced cAMP metabolizing activity by the addition of 2 μM cGMP was used as the phosphodiesterase type II. In addition, a fraction that showed no change in the metabolizing activity of cAMP by the addition of cGMP and the metabolizing activity of cAMP was increased by the addition of 2 mM CaCl2 was used as the phosphodiesterase type I. These fractions were collected separately for be used as a solution for the supply of phosphodiesterase (type I, II and III) for the selectivity test. 3) A solution containing type V phosphodiesterase was prepared from the peripheral blood of a healthy person in the following manner. A 200 milliliter portion of physiological saline supplemented with dextran (3 percent) was added to 500 milliliters of heparinized peripheral blood and incubated at 37 ° C for 40 minutes to effect red cell precipitation. The erobanadante fluid after the erythrocyte precipitation was recovered and centrifuged once, and the resulting precipitate was suede in regulator B (140 mM NaCl, 5 mM KCl, 5 mM glucoea and 10 mM HEPES, pH 7.4 ), superimposed on a solution for the use of density gradient centrifugation (Ficoll solution) and then centrifuged at room temperature for 40 minutes at 450 xg, whereby the monocyte fraction and the granulocyte fraction are separated. The granulocyte fraction was washed once with regulator C (140 mM NaCl, 5 mM KCl, 1 mM CaCl 2, 1 mM MgCl 2, 45 mM glucose and 10 mM HEPES, pH 7.4) and suspended in buffer D (20 mM Bis-Tris, 5 mM dithioerythritol, 2 mM EGTA and 50 mM sodium acetate, pH 6.5) containing a protease inhibitor (40 μM leupeptin, 5 μM pepstatin A, 20 μM aprotinin, 50 μM phenyl fluoride-methyl-sulfonyl or 2-mM benzamidine) and then the cells were disrupted using polytron and eonicator and subjected to ultracentrifugation (4 ° C, 1000,000 xg, 60 minutes) to give an eoluble fraction. 4) The soluble fraction thus obtained was applied to a column of 1.6 x 10 centimeters packed with Sepharose Q which had been equilibrated with regulator D. Next, the column was washed with 120 milliliters of regulator D to remove the non-absorbed protein. The phosphodiesterase was eluted with 300 milliliters of regulator D having 0.05 to 1.25 linear gradient of sodium acetate to collect fractions each containing 5.0 milliliters of eluate. Each fraction was checked for phosphodiesterase activities that metabolize cAMP and cGMP. Fractions that only had cGMP metabolising activity were collected to be used as the supply solution of type V-type phosphodiesterase. [B] Inhibitory activities were measured using the delivery solutions thus obtained from various phosphodiesterase isozymes. 1) A pre-determined amount of each compound to be tested was subjected to 10 minutes of reaction at 30 ° C in a reaction mixture containing 40 mM Tris-HCl (pH 8.0), 5 mM MgCl2, 4 mM 2-mercaptoethanol, 10 μM rolipram (a selective inhibitor of phosphodiesterase type IV), 1 μM cAMP, 10 nM 3 H-cAMP (in the case of phosphodiesterase type V, 1 μM cAMP and 10 nM 3H -cAMP are replaced by 1 μM of cGMP and 100 nM 3H-cGMP) and each of the isozyme delivery solutions. After completion of the reaction, the reaction mixture was boiled at 90 ° C for 1 minute, cooled in an ice bath, mixed with a 5 '-nucleus idase unit and then subjected to 10 minutes of reaction to 30 ° C, and the reaction was stopped by adding 1 milliliter of methanol. The reaction was passed through a Dowex 1 x 8 column to effect adsorption of unmetabolized cAMP or cGMP and then the radioactivity in the eluate was measured using a scintillation counter. 2) The IC5 value? of each compound to be tested was calculated as a concentration of the compound which inhibits 50 percent of the metabolic activity of each of the isozymes, and the selectivity of the inhibition activity (IC5?) was evaluated. Test results: The results of the above measurement confirmed that most of the compounds of the present invention are excellent for selectively inhibiting the activity of phosphodieteraterae type IV compared to other isozymes of phosphodiesterase. For example, with respect to the compounds of Examples 1, 3, 4 and 19, it was confirmed that the selectivity in the inhibition activity against the phosphodiesterase type IV was 1000 times or higher than against the other types of phosphodiesterase. (3) Inhibition of infiltration of inflammatory airway cells induced by antigen 1) Hartley male guinea pigs were used after their active eensibilization by peritoneal cavity treatment (three times with a one week interval) with egg albumin (5). μg) and aluminum hydroxide gel (100 mg). Inflammation of the respiratory tract was induced by exposure to inhalation for 30 minutes of 0.5 percent egg albumin under intravenous treatment with a hietamine antagonist Hj, pyrilamine (2 mg / kg). 2) Each test item was removed in purified water containing 0.5 percent methyl cellulose and orally administered 30 minutes before or 3 hours after exposure to egg albumin. In the control group, the solvent (0.5 percent methyl cellulose in purified water, 3 milliliters / kg) was administered in the same manner. After 24 hours of exposure to egg albumin, the animals were sacrificed by releasing blood from the abdominal aorta under anesthesia with urethane (2 g / kg, intraperitoneal injection) and underwent alveolar lavage with physiological saline (10 ml x 3 times). 3) The total number of white blood cells in the cell wash solution was counted using a blood cell counter (Celltac-a, Nippon Koden). Also, the proportion of lae repective white blood cells (eosinophils, monocytes, lymphocytes and neutrophils) was obtained by microscopically observing the white blood cells in the alveolar lavage solution, which had been rubbed on a slide and stained with DifQuick (The Green Cross Corporation), and the number of respective airway infiltrations of white blood cells was calculated based on the following formula. [The number of respective sangree cells blancae (eosinophils, monocytes, lymphocytes and neutrophils)] = [total white blood cell count] x [proportion of respective sanguinee white cells (eosinophil, monocyte, lymphocyte and neutrophil)] 4) The ED50 ee value was calculated from the ratio of inhibition of the white blood cell count -3 total infiltration in each dose of each compound to be tested based on the count in the control group.In addition, the action of inhibition on the number of white blood cells respective ( eosinophils, monocytes, lymphocytes and neutrophils) was judged by the significant difference (p <0.05) of the Dunnett test. Results of the test: The results of the previous measurement confirmed that the compounds of the present invention have excellent action for inhibit the infiltration of inflammatory airway cells and therefore it is expected that they will be used as an excellent treatment agent for Bronchial asthma A pharmaceutical preparation containing one or a plurality of the compounds of the present invention or salts thereof as an active ingredient is prepared using vehicles, excipients, and other additive agents generally used in the preparation of medicament. They may be administered by oral administration in the form of doses of tablets, pills, capsules, granules, powders, solutions and the like or by parenteral administration in the form of injections (eg, intravenous injection, intramuscular injection, and the like), supra-items, transdermal, inhalant and similar preparations or by intravesical injection. Its dosage is optionally decided on a case-by-case basis taking into consideration the symptoms, age, sex and the like of each patient, and can generally be from about 0.001 mg / kg to about 100 mg / kg per day per adult in case of oral administration, and The daily dose can be used once a day or divided into 2 to 4 doses per day. When administered by intravenous injection due to symptoms, it may be administered once a day or a plurality of doses per day in the range of from 0.001 mg / kg to 10 mg / kg per adult. Also, in the case of inhalation, it may be administered once a day or a plurality of doses per day generally within the range of from 0.0001 mg / kg to 1 mg / kg per adult, or, in the case of application, may be administered. administer once a day or a plurality of doses per day generally within the range of from 0.0001 mg / kg to 1 mg / kg per adult. Tablets, powders, granules, and the like are used as the solid composition of the present invention for oral administration use. In these solid compositions, one or more of the active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone or aluminum magnesium silicate. According to the usual manner, the composition may further contain other additive agents than the inert diluent, such as lubricants (eg, magnesium stearate or the like), disintegrants (eg, calcium cellulose glycolate or similar), stabilizer (eg example, lactoea or the like) and solubilizing agents (for example, glutamic acid, aspartic acid or eimilaree). As required by the invention, the tablets or pills may be coated with sugar or films of a gastric or enteric substance such as sucrose, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate. The liquid composition for oral administration use includes emulsions, solutions, suspensions, syrups, elixirs and pharmaceutically acceptable similar, and generally contains inert diluent used as purified water or ethanol. In addition to the inert diluent, this composition may also contain auxiliary agents such as wetting agents, suspeneion and eimilaree agents., sweeteners, flavorings, aromatics and antiseptics. Injections for the use of parenteral administration include aqueous solutions, aqueous or non-aqueous, suspensions and emulsification. Distilled water for injection use, physiological saline and the like are used in aqueous solutions and suspensions. Propylene glycol, polyethylene glycol, vegetable oils (for example, olive oil), alcohole (for example, ethanol), polysorbate 80 and the like are in non-aqueous solutions and suspensions. These compositions may also contain auxiliary agents such as antiseptic, moisturizing agent, emulsifying agent, dieting agent, stabilizing agent (for example, lactose) and solubilizing agent (for example, glutamic acid and aspartic acid). These compositions are sterilized, for example, by filtration through a filter that retains bacteria, mixtures of a germicide or irradiation. Also, these compositions can be produced as aseptic solid compositions which are used by dissolving in sterile water or a sterile solvent for injection use before use. BEST MODE FOR CARRYING OUT THE INVENTION The following describes the present invention more in detail with reference to examples. In fact, the present invention should not be limited to the description of the Examples. The initial compounds of the present invention include compound noveldoe. The production method of the starting materials is shown in the Reference Examples. Reference Example 1 A mixture of 3-cyano-6-ethyl-2 (1H) -pyridone (36.2 grams, 0.24 mol) and phosphorus oxychloride (250 milliliters) was heated at reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was mixed with toluene and concentrated under reduced pressure. The residue thus obtained was diluted with chloroform and washed with 1N aqueous sodium hydroxide solution. The aqueous layer was extracted with chloroform and the chloroform layers were combined and dried over anhydrous magnesium eulfate. After removal of the magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-chor-3-cyano-6 -ethylpyridine (19.6 grams, 49 percent) as an oily material. Reference Example 2 Magnesium (2.72 grams, 112 mmol) was added to a solution of 3-bromochlorobenzene (22.1 g, 115 mmol) in tetrahydrofuran (200 milliliter), and the mixture was stirred at room temperature. Since the spontaneous exothermic reaction occurred, stirring was continued until exothermicity ceased. The reaction solution was cooled to -20 ° C, mixed with 2-chloro-3-cyano-6-ethylpyridine (9.33 grams, 56 mmol) and then stirred for 16 h at room temperature. The reaction solution was mixed with saturated aqueous ammonium chloride solution and stirred for 30 minutes at room temperature and then mixed with IN hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration and then the filtrate was concentrated under reduced pressure. After which, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-chloro-3- (3-chlorobenzoyl) -6-ethylpyridine (3.48 gram, 22 percent) as a pale yellow oily material. Reference Example 3 The following compound was obtained in the same manner as described in Reference Example 2: 3- (3-bromobenzoyl) -2-chloro-6-ethylpyridine. Reference Example 4 Magnesium (4.8 grams, 200 mmol) was added to a solution of 3-bromochlorobenzene (38 grams, 200 mmol) in tetrahydrofuran (400 milliliters), and the mixture was stirred at room temperature. Since the spontaneous exothermic reaction was presented, stirring was continued until the exothermicity ceased. The reaction solution was cooled to -40 ° C, mixed with 2-chloro-6-methylnicotinic acid (9.2 grams, 53 mmol) and then stirred overnight at room temperature. The reaction solution was mixed with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration and then the filtrate was concentrated under reduced pressure. After which, the resulting residue was purified by silica gel column chromatography (chloroform) to give 2-chloro-3- (3-chlorobenzoyl) -6-methylpyridine (6.25 grams, 44 percent) as an oily material . Reference Example 5 The following compound was obtained in the same manner as that described in Reference Example 4. 3- (bromobenzoyl) -2-chloro-6-methylpyridine. Reference Example 6 A mixture of 2-chloro-3 (3-chlorobenzoyl) -6-ethylpyridine (3.4 grams, 12 mmol) and a 70 percent aqueous solution of ethyl amine (15 milliliters) was sealed in a tube and stirred at 100 ° C for 4 hours. The reaction solution was cooled to room temperature and then transferred to a separatory funnel. This was acidified by adding IN hydrochloric acid, stirred vigorously and then made alkaline by adding an aqueous solution of sodium hydroxide IN. This was extracted with chloroform, the resulting organic layer was dried over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration and then the filtrate was concentrated under reduced pressure. After this, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- (3-chlorobenzoyl) -6-ethyl-2-ethylaminopyridine (2.6 grams, 76 percent) as a oily yellow material. The following compounds of Reference Examples 7 to 9 were obtained in the same manner as that described in Reference Example 6. Reference Example 7 3- (3-bromobenzoyl) -6-ethyl-2-ethylaminopyridine Reference Example 8 3- (3-Chlorobenzoyl) 2-ethylamino-6-methylpyridine Reference example 9 3- (3-bromobenzoyl) -2-ethylamino-6-methylpyridine Reference example 10 Magnesium (4.82 grams, 200 mmol) was added to a solution of 3-bromo-toluene (35.1 grams, 200 mmol) in tetrahydrofuran (300 milliliters), and the mixture was stirred at room temperature. Since the spontaneous exothermic reaction occurred, the agitation continued until the exothermicity ceased. The reaction solution was cooled to -40 ° C, mixed with 2-chloro-6-methylnicotinic acid (11.6 grams, 68 mmol) and then stirred for 16 hours at room temperature. The reaction solution was mixed with an aqueous solution of saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration and then the filtrate was concentrated under reduced pressure. After this, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-chloro-6-methyl-3- (3-methylbenzoyl) pyridine (8.70 grams, 52 percent) as a pale yellow oily material. Reference Example 11 3-Bromotoluene (12.5 grams, 73.1 mmol) was added to a solution of magnesium (1.70 grams, 70.0 mmol) in tetrahydrofuran (200 milliliters), and the mixture was stirred until the magnesium pieces disappeared. The reaction solution was cooled to -20 ° C, mixed with 2-chloro-3-cyano-6-ethylpyridine (10.6 grams, 63.6 mmol) and then stirred for 17 hours at room temperature. The reaction solution was mixed with an aqueous solution of saturated ammonium chloride and IN hydrochloric acid, and the mixture was stirred for 2 hours at room temperature and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the anhydrous magnesium sulfate was removed by filtration and then the filtrate was concentrated under reduced pressure. After that, the re-emerging residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-chloro-6-ethyl-3- (3-methylbenzoyl) pyridine (9.19 grams, 56 percent) as a material oily yellow Reference Example 12 A mixture of 2-chloro-6-methyl-3- (3-methylbenzoyl) _ pyridine (2.45 grams, 10 mmol) and a 70 percent aqueous solution of ethyl amine (10 milliliters) was sealed in a tube and stirred for 4 hours at 100 ° C. The reaction solution was cooled to room temperature and transferred to a separatory funnel. This was adjusted to pH 1 with IN hydrochloric acid, vigorously stirred, adjusted to pH 10 by adding an aqueous solution of IN sodium hydroxide and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration and then the filtrate was concentrated under reduced pressure. After that, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-ethylamino-6-methyl-3- (3-methylbenzoyl) pyridine (2.10 grams, 83 percent) as a yellow oily material. Reference Example 13 The following compound was obtained in the same manner as described in Reference Example 12. 2-ethylamino-6-ethyl-3- (3-methylbenzoyl) pyridine Reference example 14 Di-isopropyl amine (23 milliliters, 175 mmol) was added to a solution of normal-lithium butyl in a solution of 1.6 M hexane (100 milliliter, 160 mmol) in tetrahydrofuran (500 milliliter) at -65 ° C or less, and the mixture was heated to -40 ° C. The reaction solution was mixed with 2-chloropyridine (17 grams, 150 mmol) at -70 ° C or less and stirred for 1.5 hour at -70 ° C or less. The reaction solution was mixed with cyclohexanecarbaldehyde (17 grams, 151 mmol) at -70 ° C or less and stirred for 2 hours at -70 ° C or less. The reaction solution was mixed with water, warmed to room temperature and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After this, the resulting residue was purified by silica gel column chromatography (chloroform) to give 2-chloro-α-cyclohexyl-3-pyridinemethanol (17 grams, 50 percent). Reference Example 15 Under an argon atmosphere, a solution of normal-lithium butyl in 1.6 M hexane (30 milliliters) was added dropwise to a solution of di-isopropyl amine (5.52 grams, 54.7 mmol in tetrahydrofuran (200 milliliters) which was cooled to -78 ° C, and the mixture was stirred for 30 minutes, 2-chloropyridine (5.71 grams, 50.3 mmol) was added dropwise to the reaction solution, followed by 90 minutes of stirring. 2-thiophenecarbaldehyde (6.01 grams, 53.7 mmol) was added to the reaction solution, followed by 30 minutes of stirring The reaction solution was mixed with the brine and extracted with chloroform.The organic layer was washed with brine and dried over sulfate. Anhydrous sodium After removing sodium sulfate by filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform) to give o; - (2-chloropyr din-3-yl) -2-thiophenemethanol (6.66 grams 27.5 mmol, 59 percent). The following compounds of Reference Examples 16 to 20 were obtained in the same manner as described in Reference Example 15. Reference Example 16 o¿- (2-chloropyridin-3-yl) -3-thiophenemethanol Reference Example 17 o ~ - (2-chloropyridin-3-yl) -2-thiazolemethanol Reference example 18 o? - (2-chloropyridin-3-yl) -2-pyridinemethanol Reference example 19 or; - (2-chloropyridin-3 -yl) -3-pyridinemethanol Reference example 20 or; - (2-chloropyridin-3-yl) -4-pyridinemethanol Reference example 21 A solution of 2-chloro-6-methylnicotinic acid (3.43 grams, 20 mmol) in tetrahydrofuran (30 milliliters) was cooled to -40 ° C, mixed with a 2.0 M solution of cyclohexyl magnesium chloride in ether (30 milliliters) and stirred overnight at room temperature. The reaction solution was poured into an aqueous solution of saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removal of the magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-chloro-3-cyclohexylcarbonyl-6. -methylpyridine (650 milligrams, 14 percent) as a brown oily material. Reference Example 22 Pyridinium chlorochromate (20.0 grams, 93 mmol) was added to a solution of 2-chloro-α-cyclohexyl-3-pyridinemethanol (17.0 gram, 75 mmol) in dichloromethane (200 milliliter), and the mixture was stirred at room temperature for 4 hours. The reaction solution was mixed with pyridinium chlorochromate (10.0 grams, 46 mmol) was stirred for 2 hours at room temperature, and then ether was added to the reaction solution to remove insoluble matter by filtration. The solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-chloroform) to give 2-chloroX-cyclohexylcarbonylpyridine (14.9 grams)., 88 percent) as an oily material. Reference Example 23 To a solution of a- (2-chloropyridin-3-yl) -2-thiophenemethanol (6.14 grams, 27.2 mmol) in toluene (100 ml) was added 85 percent manganese dioxide (25 grams, 245 mmol), followed by 2 hours of heating under reflux. The reaction solution was passed through "celite" and the resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-chloroform) to give 2-chloro-3- (2-thiophenecarbonyl) pyridine (5.32 grams, 23.8 mmol, 87 percent). The following compounds of the Examples of Reference 24 to 28 were obtained in the same manner as described in Reference Example 23. Reference example 24 2-chloro-3- (3-thiophenecarbonyl) pyridine Reference example 25 2-chloro-3- (2 - thiazolcarbonyl) pyridine Reference example 26 2-chloro-3- (2-pyridincarbonyl) pyridine Reference example 27 2-chloro-3- (3-pyridincarbonyl) pyridine Reference example 28 2-chloro-3- (4-pyridinecarbonyl) pyridine The following compounds of Reference Examples 29 to 36 were obtained in the same manner as described in Reference Example 6. Reference Example 29 3-Cyclohexylcarbonyl-2-ethylamino-6-methylpyridine Reference Example 30 3-Cyclohexylcarbonyl -2-ethylaminopyridine Reference example 31 2-ethylamino-3- (2-thiophenecarbonyl) pyridine Reference example 32 2-ethylamino-3- (3-thiophenecarbonyl) pyridine Reference example 33 2-ethylamino-3- (2-thiazolecarbonyl) ) pyridine Reference example 34 2-ethylamino-3- (2-pyridinecarbon) il) pyridine Reference Example 35 2-ethylamino-3- (3-pyridinecarbonyl) pyridine Reference Example 36 2-ethylamino-3- (4-pyridinecarbonyl) pyridine The following compounds of Reference Examples 37 and 38 were obtained from the same as described in Reference Example 15. Reference Example 37 2-chloro-a- (3-chlorophenyl) 6-trifluoromethyl-3-pyridinemethanol Reference example 38 or; - (3-bromo-phenyl) -2-chloro - 6 - trifluoromethyl-3-pyridinemethanol The following compounds of Reference Examples 39 and 40 were obtained in the same manner as described in Reference Example 23. Reference example 39 2-chloro-3- (3-chlorobenzoyl) ) -6-trifluoromethylpyridine Reference Example 40 3- (3-bromobenzoyl) 2-chloro-6-trifluoromethylpyridine The following compounds of Reference Examples 41 and 42 were obtained in the same manner as described in Reference Example 6. Reference Example 41 3 - (3-chlorobenzoii) -2-ethylamino-6-trifluoromethyl-pyridine Reference example 42 3- (3-bromobenzoyl) -2-ethylamino-6-trifluoromethyl-pyridine Reference example 43 2-amino-3-cyano-6-dimethoxymethylpyridine (39.6 grams, 0. 2 mol) and 12 ml (0.2 mol) of acetaldehyde were dissolved in 400 milliliters of acetic acid, and the resulting solution was mixed with 45.5 grams (0.2 mol) of sodium triacetoxyborohydride and stirred for 2.5 hours at room temperature. The reaction solution was concentrated under reduced pressure, diluted with chloroform and then washed with an aqueous solution of iodomodium hydroxide. The organic layer was dried over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration and then the filtrate was concentrated under reduced pressure. After that, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 33.9 grams of 3-cyano-2-ethylamino-6-dimethoxymethylpyridine as an oily material. The yield was 77 percent. Reference Example 44 Magnesium (18.6 grams, 0.76 mol) was added to 500 milliliters of tetrahydrofuran in which 3-bromochlorobenzene (146.7 grams, 0.77 mol) had been dissolved, followed by stirring at room temperature. Since the exothermic reaction occurred, the agitation continued until the exothermicity ceased. The reaction solution was cooled to -20 ° C, mixed with 33.9 grams (0.15 mol) of 3-cyano-2-ethylamino-6-dimethoxymethylpyridine and then heated overnight under reflux. The reaction solution was mixed with an aqueous solution of saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After removing Magneeium eulfate by filtration, the solvent was evaporated under reduced pressure to give crude 3- (3-chlorobenzoyl) -2-ethylamino-6-dimethoxymethylpyridine. The crude 3- (3-chlorobenzoyl) -2-ethylamino-6-dimethoxymethylpyridine was diluted with 500 milliliters of tetrahydrofuran, it was mixed with 6N hydrochloric acid and then stirred at room temperature for 6 hours. The reaction mixture was adjusted to pH 10 with an aqueous solution of sodium hydroxide and extracted with ethyl acetate. The organic layer was washed over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration and then the resulting filtrate was concentrated under reduced pressure. After that, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- (3-chlorobenzoyl) -2-ethylaminopyridine-6-carbaldehyde. Reference Example 45 a- (3-chlorobenzoyl) acetamide (19.76 grams, 0.1 mol) was dissolved in 250 milliliters of ethanol, and the solution was mixed with 19.15 grams (0.11) mol of 1, l-diethoxy-3-pentanone and heated under reflux for 40 hours. After cooling to room temperature, the reaction solution was poured into ice water and extracted with chloroform. The organic layer was washed with IN hydrochloric acid, brine and dried over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration and then the resulting filtrate was concentrated under reduced pressure. After which, the resulting residue was mixed with diethyl ether and the crystals thus formed were collected by filtration and washed with diethyl ether to give 18.50 grams of 3- (3-chlorobenzoyl) -6-ethyl-2-pyridone in the form of crystals. The yield was 71 percent. The following compounds of Reference Examples 46 and 47 were obtained in the same manner as described in Reference Example 45. Reference Example 46 3- (3-chlorobenzoyl) -6-phenyl-2-pyridone Reference Example 47 3- (3-chlorobenzoyl) -6-cyclopropyl-2-pyridone Reference example 48 3- (3-chlorobenzoyl) -6-ethyl-2-pyridone (95.8 grams, 366 mmol) was dissolved in 1,000 milliliters of dichloroethane, 56.4 milliliters (403 mmol) of triethyl amine, 4.52 grams (366 mmol) of 4-dimethylaminopyridine and 76.7 grams (403 mmol) of p-toluenesulfonyl chloride were added thereto, followed by stirring at room temperature for 1 hour. The reaction solution was washed with water, 1 N hydrochloric acid-brine and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration and then the resulting filtrate was concentrated under reduced pressure. After this, the resulting residue was recrystallized from ethyl acetate-hexane to give 139.90 grams of 3- (3-chlorobenzoyl) -6-ethyl-2-pyridyl p-toluene sulfonate in the crystal form. The yield was 91.9 percent. The following compounds of Reference Examples 49 and 50 were obtained in the same manner as described in Reference Example 48. Reference Example 49 p-Toluene sulfonate 3- (3-chlorobenzoyl) -6-phenyl- 2-pyridyl Reference example 50 3- (3-chlorobenzoyl) -6-cyclopropyl-2-pyridyl p-toluene sulfonate Reference example 51 p-Toluene sulfonate 3- (3-chlorobenzoyl) -6-ethyl- 2-pyridyl (26.20 grams, 63 mmol) was dissolved in 400 milliliters of toluene, and the solution was mixed with 50 milliliters of aqueous 70% ethyl amine solution and heated under reflux for 4 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, diluted with diethyl ether and then washed with water and saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration and then the solvent was evaporated under reduced pressure to give 19.50 grams of 3- (3-chlorobenzoyl) -6-ethyl-2-ethylaminopyridine as an oily material The yield was 100 percent. The following comets of Reference Examples 52 and 53 were obtained in the same manner as described in Reference Example 51. Reference Example 52 3- (3-chlorobenzoyl) -2-ethylamino-6-phenylpyridine Reference Example 53 3- (3-chlorobenzoyl) -6-cyclopropyl-2-ethylaminopyridine The following compounds of Reference Examples 54 and 55 were obtained in the same manner as described in Reference Example 45. Reference Example 54 6- ethyl-3- [(3-methylcyclohexyl) carbonyl] -2-pyridone Reference example 55 6-methyl-3- [(3-methylcyclohexyl) carbonyl] -2-pyridone Reference Example 56 6-Ethyl-3- [(3-methylcyclohexyl) carbonyl] -2-pyridone (4.16 grams, 17.9 mmol) was dissolved in 100 milliliters of 1,2-dichloroethane, and the solution was mixed with 6.0 milliliters (43 mmol) of triethyl amine, 600 milligrams (492 mmol) of 4-dimethylaminopyridine and 6.00 grams (31.6 mmol). mmol) of p-toluene-eulphonyl chloride and stirred for 2 hours at an oil temperature of 70 ° C. After cooling to room temperature, this was mixed with water and extracted with chloroform. The organic layer was washed with IN hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine in that order, dried over anhydrous magnesium sulfate and, after removal of the magnesium sulfate by filtration, concentrated under reduced pressure to give 7.80 grams of 6-ethyl-3- [(3-methylcyclohexyl) carbonyl] -2-pyridyl p-toluene sulfonate. The partially purified product was thus dissolved in 100 milliliters of toluene, and the solution was mixed with 20 milliliters of 70% ethyl amine aqueous solution and heated under reflux for 8 hours. Then, 20 milliliters of aqueous solution of 70% ethyl amine was added, followed by heating overnight under reflux. After cooling to room temperature, this was adjusted to pH 1 by adding IN hydrochloric acid and stirring for 15 minutes. This was neutralized with aqueous IN sodium hydroxide solution and then extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and then, after removal of sodium sulfate by filtration, concentrated under reduced pressure. After that, the resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give 2.60 grams of 6-ethyl-2-ethylamino-3- [(3-methylcyclohexyl) carbonyl] pyridine. The yield was 56 percent. Reference Example 57 The following compound was obtained in the same manner as described in Reference Example 56. 6-methyl-2-ethylamino-3- [(3-methylcyclohexyl) carbonyl] _ pyridine. The following compounds of Reference Examples 58 and 59 were obtained in the same manner as described in Reference Example 4. Reference Example 58 2-Chloro-3- (3-methylbenzoyl) -6-methylpyridine Reference Example 59 2-Chloro-6-methyl-3- (3-chlorobenzoyl) pyridine The following compounds of Reference Examples 60 to 63 were obtained in the same manner as described in Reference Example 6. Reference Example 60 3 - (3-chlorobenzoyl) -6-methyl-2- (propylamino) iridine Reference example 61 3- (3-chlorobenzoyl) -2- (cyclopropylmethylamino) -6-methylpyridine Reference example 62 6-methyl-2- (propylamino ) -3- (3-methylbenzoyl) pyridine Reference Example 63 2- (Cyclopropylmethylamino) -6-methyl-3- (3-methylbenzoyl) pyridine Reference Example 64 The following compound was obtained in the same manner as described in Reference example 4. 3 - . 3-benzoyl-2-chloro-6-methylpyridine Reference example 65 3-benzoyl-2-chloro-6-methylpyridine (3.00 grams, 12.9 mmol) dissolved in 40 milliliters of concentrated sulfuric acid was cooled to 5 ° C or less, 1.0 milliliter of fuming nitric acid was slowly added dropwise thereto, followed by stirring for 30 minutes. The reaction solution was poured into ice water, neutralized with aqueous solution of eodium hydroxide and then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removal of the magnesium sulfate by filtration, the solvent was evaporated under reduced pressure and the resulting residue was recrystallized from ethyl acetate-di-isopropyl ether to give 1.81 grams (51 percent) of 2-chloro-6 -methyl-3- (3-nitrobenzoyl) pyridine. Reference Example 66 The following example was obtained in the same manner as described in Reference Example 6. 2-ethylamino-6-methyl-3- (3-Nitrobenzoyl) pyridine Reference example 67 The following compound was obtained in the same manner as described in reference example 45. 6-methyl-3- (l-naphthylcarbonyl) -2-pyridone Reference example 68 The following The compound was obtained in the same manner as described in Reference Example 48. 6-methyl-3- (l-naphthylcarbonyl) -2-pyridyl p-toluene sulfonate Reference example 69 The following compound was obtained therefrom as described in Reference Example 51. 2-ethylamino-6-methyl-3- (l-naphthylcarbonyl) pyridine Example 1 Chlorosulfonyl isocyanate (0.8 milliliter, 9 mmol) to a solution in tetrahydrofuran (50 milliliter of 3- (3-chlorobenzoyl) -6-ethyl-2-ethylaminopyridine (2.6 gram, 9 mmol) under cooling on ice, followed by stirring for 1 hour under ice-cooling. To the reaction solution was added water and aqueous solution of saturated sodium bicarbonate in that order, followed by 30 minutes of stirring at room temperature. This was adjusted to pH 10 with aqueous sodium hydroxide solution IN and extracted with chloroform. After drying the organic layer over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration and the resulting filtrate was concentrated under reduced pressure. After that, the resulting refidue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4- (3-chlorophenyl) -1,7-diethylpyrido [2,3-d] pyridimidin-2 (1H) -one (1.7 grams, 60 percent) as crystals.

The following compounds of Examples 2 to 8 were obtained in the same manner as described in Example 1. Example 2 4- (3-Bromofenyl) -1,7-diethylpyrido [2,3-d] pyrimidin-2 ( lH) -one Example 3 4- (3-chlorophenyl) -l-ethyl-7-methylpyrido [2,3-d] pyrimidin-2 (1H) -one Example 4 4 - (3-bromo-phenyl) -l-ethyl 7-methylpyrido [2,3-d] pyrimidin-2 (1H) -one Example 5 l-ethyl-7-methyl-4- (3-methylphenyl) -pyrido [2,3-d] pyrimidin-2 ( ÍH) -one Example 6 1, 7-Diethyl-4- (3-methylphenyl) pyrido [2,3-d] pyrimidin-2 (1H) -one Example 7 4-cyclohexyl-l-ethyl-7-methylpyrido [ 2, 3-d] pyrimidin-2 (lH) -one Example 8 4-cyclohexyl-l-ethylpyrido [2,3-d] pyrimidin-2 (1H) -one Example 9 Chlorosulfonyl isocyanate (80.5 milliliters, 5.6 mmol) it was added to a solution of 2-ethylamino-3- (2-thiophenecarbonyl) pyridine (1.01 grams, 4.34 mmol) in tetrahydrofuran (50 milliliters) under ice-cooling, followed by stirring for 30 minutes. The reaction solution was mixed with water and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium eulfate. After removing the sodium sulfate by filtration, the resulting filtrate was concentrated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform-ethyl acetate) and recrystallized from ethyl acetate give l-ethyl-4- (2-thienyl) pyrido [2,3-d] pyrimidin-2 (1H) -one (613 milligrams, 2.38 mmol, 55 percent). The following compounds of Examples 10 to 16 were obtained in the same manner as described in Example 9. Example 10 l-Ethyl-4- (3-thienyl) pyrido [2,3-d] pyrimidine-2 (1H) -one Example 11 l-ethyl-4- (2-thiazolyl) pyrido [2,3-d] pyrimidin-2 (1H) -one Example 12 l-ethyl-4- (2-pyridyl) pyrido [2, 3 d] pyrimidin-2 (IH) -one Example 13 l-ethyl-4- (3-pyridyl) pyrido [2,3-d] pyrimidin-2 (1H) -one Example 14 l-ethyl-4- (4-pyridyl) pyrido [2, 3-d] pyrimidin-2 (HH) -one Example 15 4- (3-Chlorophenyl) -l-ethyl-7-trifluoromethyl-pyrido [2,3-d] pyrimidin-2 (HH) -one Example 16 4- (3-bromophenyl) - l-ethyl-7-trifluoromethylpyrido [2,3-d] pyrimidin-2 (1H) -one Example 17 The following compound is obtained in the same manner as described in Example 1. 4- (3-chlorophenyl) -l -ethyl-2-oxo-l, 2-dihydropyrido [2,3-d] pyrimidine-7-carbaldehyde Example 18 Sodium borohydride (35 milligrams, 0.9 mmol) was added to a mixture of 1.16 grams (3.7 mmol) of 4- (3-chlorophenyl) -l-ethylpyrido [2,3-d] pyrimidin-2 (1H) -one- 7 -carbaldehyde and 20 milliliter of ethanol under cooling with ice, followed by stirring for 30 minutes under ice-cooling . The reaction solution was mixed with acetone and concentrated under reduced pressure, and the resulting residue was mixed with water and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration and the resulting filtrate was concentrated under reduced pressure. After which, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate-chloroform) and then recrystallized from acetonitrile-ethanol to give 271 milligrams of 4- (3-chlorophenyl) - l-ethyl-7-hydroxymethylpyrido [2, 3-d] pyrimidin-2 (1H) -one. The yield was 23 percent. Example 19 Methylmagnesium bromide 1M (14 milliliters, 14 mmol) was added to a solution of 4.4 grams (14 mmol) of 4- (3-chlorophenyl) -1-ethylpyrido [2,3-d] pyrimidine -2 (1H) -one- 7-carbaldehyde in 50 milliliters of tetrahydrofuran under cooling with ice, followed by stirring for 30 minutes under ice-cooling. Then, 7 milliliters (7 mmol) of 1M methylmagnesium bromide were added and the mixture was stirred for 30 minutes under ice-cooling. Then, the aqueous solution of saturated ammonium chloride was added, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration and the resulting filtrate was concentrated under reduced pressure. After which, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate-chloroform) to give 1.4 grams of 4- (3-chlorophenyl) -l-ethyl-7- (1-hydroxyethyl) ) pyrido [2,3-d] pyrimidin-2 (HH) -one. The yield was 30 percent. Example 20 Manganese dioxide (1.00 gram) was added to a solution of 366 milligrams (1.1 mmol) of 4- (3-chlorophenyl) -1-ethyl-7- (l-hydroxyethyl) pyrido [2,3-d] pyrimidine. -2 (1H) -one dissolved in 20 milliliters of chloroform, and the mixture was heated under reflux for 1 hour. The reaction solution was mixed with 1.00 grams of manganese dioxide and heated under reflux for 1 hour and then again mixed with 500 milligrams of manganese dioxide and heated under reflux for 1 hour. After removing insoluble matter by filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate-chloroform) to give 303 milligrams of 7-acetyl-4- (3-chlorophenyl) -1-ethylpyrido [2,3-d] pyrimidin-2 (1H) -one. The yield was 84 percent. The following compounds of Examples 21 and 22 were obtained in the same manner as described in example 1. Example 21 4- (3-chlorophenyl) -l-ethyl-7-f-enylpyrido [2,3-d] pyrimidine- 2 (1H) -one Example 22 4- (3-Chlorophenyl) -7-cyclopropyl-1-ethylpyrido [2,3-d] pyrimidin-2 (1H) -one Example 23 N-bromosuccinimide (8.94 grams, 50.2 mmol) and 200 milligrams of 2, 2'-azobis (ieobutyronitrile) were added to a solution of 15.0 'grams (47.8 mmol) of 4- (3-chlorophenyl) -1,7-diethylpyrido [2,3-d] pyrimidin-2. (H H) -one in 150 milliliters of carbon tetrachloride, followed by heating under reflux for 3 hours. The reaction solution was mixed again with 1.28 grams (7.17 mmol) of N-bromosuccinimide and 100 milligram of 2, 2'-azobis (isobutyronitrile), followed by heating under reflux for 1 hour. After cooling to room temperature, the insoluble matter was removed by filtration, and the resulting filtrate was mixed with water and extracted with carbon tetrachloride. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removing the magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 11.5 grams of 7- (1-bromoethyl) ) -4- (3-chlorophenyl) -1-ethylpyrido [2,3-d] pyrimidin-2 (lH) -one in the form of crystals. The yield was 61 percent. Example 24 N-bromosuccinimide (590 milligrams 3.3 mmol) and 10 milligrams of 2, 2'-azobie (ieobutyronitrile) were added to a solution of 940 milligrams (3 mmol) of 4- (3-chlorophenyl) -1,7-diethylpyride [2, 3-d] pyrimidin-2 (1H) -one in 20 milliliters of carbon tetrachloride, followed by heating under reflux for 5 hours. The reaction solution was mixed again with 210 milligrams (1.2 mmol) of N-bromosuccinimide and heated overnight under reflux. Insoluble matter was removed by filtration, and the resulting filtrate was mixed with water and extracted with carbon tetrachloride. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, the magnesium eulfate was removed by filtration, and the resulting filtrate was concentrated under reduced pressure. The residue obtained was mixed with 10 milliliters of methanol and 300 milligrams of sodium acetate and heated overnight under reflux. The reaction solution was diluted with chloroform and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration, and then the resulting filtrate was concentrated under a reduced pressure. After that, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 520 milligrams of 7- (1-acetoxyethyl) -4- (3-chlorophenyl) -1-ethylpyrido [2 , 3-d] pyrimidin-2 (1H) -one in the form of crystals. The yield was 47 percent. Example 25 Methanol (30 milliliters) and 30 milliliters of IN sodium hydroxide solution were added to 6.78 grams (18.2 mmol) of 7- (1-acetoxyethyl) -4- (3-chlorophenyl) -1-ethylpyrido [2,3 -d] pyrimidin-2 (1H) -one, followed by stirring for 20 minutes at room temperature. The reaction solution was neutralized by adding IN hydrochloric acid and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration and the resulting filtrate was concentrated under reduced pressure. After that, the resulting residue was purified by silica gel column chromatography (chloroform) to give 4.50 grams of 4- (3-chlorophenyl) -l-ethyl-7- (1-hydroxyethyl) pyrido [2, 3- d] pyrimidin-2 (1H) -one in the form of crystals. The yield was 75 percent. The following compounds of Examples 26 and 27 were obtained in the same manner as described in Example 1. Example 26 1- ethyl -7-methyl-4- (3-methylcyclohexyl) -pyrido [2,3-d] pyrimidine -2 (1H) -one Example 27 1, 7-Diethyl-4- (3-methylcyclohexyl) -pyrido [2,3-d] pyrimidin-2 (1H) -one Example 28 Diphosphorus pentasulfide (3.00 gram, 13.5 mmol ) was added to a solution of 2.00 grams (6.69 mmol) of 4- (3-chlorophenyl) -l-ethyl-7-methylpyrido [2,3-d] pyrimidine in 100 milliliters of 1,2-dichloroethane, followed by heating under reflux for 6 hours. The reaction solution was cooled to room temperature, mixed with saturated sodium bicarbonate and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, the magnesium sulfate was removed by filtration and the resulting filtrate was concentrated under reduced pressure. After that, the resulting residue was purified by silica gel column chromatography (hexane-chloroform) and then recrystallized from ethyl acetate-di-isopropyl ether to give 1.14 grams of 4- (3-chlorophenyl) - l-ethyl-7-methylpyrido [2,3-d] pyrimidin-2 (1H) -thione. The yield was 54 percent. The following compounds of Examples 29 to 34 were obtained in the same manner as described in Example 1. Example 29 4- (3-bromo phenyl) -6,7-dimethyl-1-ethylpyrido [2,3-d] pyrimidin-2 (1H) -one Example 30 4- (3-chlorophenyl) -7-methyl-1-propylpyrido [2,3-d] pyrimidin-2 (1H) -one Example 31 4- (3-chlorophenyl) - 1-cyclopropylmethyl-7-methylpyrido [2,3-d] pyrimidin-2 (1H) -one Example 32 7 -methyl-4- (3-methylphenyl) -1-propylpiido [2,3-d] pyrimidin-2 (1H) -one Example 33 l-cycl op r opylmethyl-7-methyl-4 - (3-methylphenyl) irido [2,3-d] pyrimidin-2 (1H) -one Example 34 4- ( cyclohexyl) -1,7-diethylpyrido [2,3-d] pyrimidin-2 (1H) -one Example 35 The following compound was obtained as a by-product of Example 5. 6-Chloro-1-ethyl-7-methyl-4 - (3-methylphenyl) pyrido [2,3-d] pyrimidin-2 (1H) -one Example 36 4- (3-chlorophenyl) -l-ethyl-2-oxo-l, 2-dihydropyrido [2, 3-d] pyrimidine-7-carbaldehyde (900 milligrams 2.9 mmol) was dissolved in 10 milliliters of methanol, 420 milligrams (6.0 mmol) of hydroxyl amine hydrochloride and 550 milligrams (6.7 mmol) of sodium acetate were added thereto. , followed by stirring overnight at room temperature. The insoluble material was washed with water and chloroform and recrystallized from dimethyl-acetonitrile formamide to give 171 milligram (18 percent) of 4- (3-chlorophenyl) -l-ethyl-7-hydroxy-iminomethyl-pyrido [2, 3 -d] pyrimidin-2 (HH) -one. Example 37 The following compound was obtained in the same manner as described in Example 1. l-ethyl-7- methyl-4- (3-nitrophenyl) -pyrido [2,3-d] pyrimidin-2 (1H) -one Example 38 The following compound was obtained in the same manner as described in Example 23. 7-Bromomethyl-4- (3-chlorophenyl) -l-ethylpyrido [2,3-d] pyrimidin-2 (1H) - Example 39 The following compound was obtained as a by-product of Example 1. 6-chloro-4- (3-chlorophenyl) -1,7-diethylpyrido [2,3-d] pyrimidin-2 (1H) -one Example 40 Thioacetate of potassium (0.54 grams, 48 mmol) was added to 7- (1-bromoethyl) -4- (3-chlorophenyl) -1-ethylpyrido [2,3-d] pyrimidin-2 (1H) -one (1.57 grams, 40 mmol) dissolved in dimethyl formamide (16 milliliters), followed by stirring at room temperature for 2 hours. The reaction solution was mixed with ethyl acetate, washed with water and with brine, and dried with anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 7- (1-thioacetylethyl) -4- (3-chlorophenyl) -1-ethylpyrido [2,3-d] pyrimidin-2 (ÍH) -one (1.13 grams, 73 percent). Example 41 The following compound was obtained in the same manner as described in Example 28. 4- (3-chlorophenyl) -1,7-diethylpyrido [2,3-d] pyrimidin-2 (1H) -thione. Example 42 The following compound was obtained in the same manner as described in Example 1. 1-ethyl-7-methyl-4- (l-naphthyl) pyrido [2,3-d] pyrimidine-2 (H) -one . Example 43 7-Acetyl-4- (3-chlorophenyl) -1-ethylpyrido [2,3-d] pyrimidin-2 (1H) -one (1.62 grams, 495 mmol) and 30 milliliters of methyl orthoformate were dissolved in 30 ml. milliliters of methanol, a catalytically effective amount of Dowex-50W-X4 was added thereto, followed by heating overnight under reflux. After cooling to room temperature, the insoluble matter was removed by filtration and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (toluene-ethyl acetate) and recrystallized from di-isopropyl ether to give 1.27 gram (69 percent) of 4- (3-chlorophenyl) -l ethyl-7- (1,1-dimethoxyethyl) pyrido [2,3-d] pyrimidin-2 (1H) -one. The physical properties of the compounds obtained in the Reference examples and the Examples are shown in Tables 3 and 4. In the tables, Ex R No. means Reference number; Ex. No. means Example number; NMR means nuclear magnetic resonance spectrum measured at 400 MHz and at room temperature using TMS as the internal standard and using DMSO-dg (Reference Examples 45 to 47) or CDC13 (all Examples and Reference examples other than Reference Examples) 45 to 47) as a solvent for nuclear magnetic resonance; pf. means melting point, - and anal, means elemental analysis data; caled, means the calculated value, encon. eignifies the value found experimentally; Et means an ethyl group; Ac means an acetyl group; iPr means an isopropyl group; and dec. it means decomposition.

Table 3 Table 4 - In the following Tables 5, 6, and 7, the chemical structures of the compounds obtained in the examples are shown using tables and with classification depending on the types of the compounds. In the tablae, Ex. No., Et, iPr, and Ac are as described above, and Me means a methyl group, nPr means a normal propyl group, cPr means a cyclopropyl group, cHex means a cyclohexyl group, Ph means a phenyl group, Naf means a naphthyl group, and Pi means a pyridyl group.

Table 5 Table 7 In addition to the compounds described above of the examples, other compounds of the present invention will be shown in the following Table 8 and 9. These compounds can be synthesized, without particular experiments, according to any of the preparation paths described above and described processes. in Production Methods and examples and modified process thereof known to technicians with ordinary experience in the field. Some compounds shown in Table 8 as various types of isomers. All these isomers as mixtures or isolated forms are included in the present invention. In the Tables, Me, Et, nPr, iPr, cPr, cHex, Ac, Ph, Naf, and Pi are as described above and Comp. No. means Compound number, cBu means a cyclobutyl group, cPe means a cyclopentyl group, and cHep means a cycloheptyl group, respectively.

Table 8 Table 9

Claims (28)

1. A pyrido [2, 3-d] pyrimidine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof: [Each symbol in the formula represents the following meaning; X: an oxygen atom or a sulfur atom, R: a lower alkyl group, a cycloalkyl lower alkyl group or a cycloalkyl group, R: a hydrogen atom, a halogen atom, a lower alkyl group, a halo group -low alkyl, a hydroxy-lower alkyl group, a mercapto-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkyl-lower alkyl group, a lower alkanoyloxy-lower alkyl group, a lower-thioalkanoyl group-lower alkyl, a lower alkanoyl-lower alkyl group, a hydroxy imino-lower alkyl group, a lower alkoxy-imino-lower alkyl group, a cycloalkyl group, an aryl group or a lower alkanoyl group, R3: a hydrogen atom, a halogen atom or a lower alkyl group, R: a hydrogen atom or a lower alkyl group, R5: a cycloalkyl group which may be substituted with the same group of R, - a naphthyl group which may be substituted with the same g R rupo; a six-membered monocyclic hetero ring group having from 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, which can be substituted with the same group of R6 and which can be condensed with benzene ring; or a group represented by the formula and R6: a halogen atom, a lower alkyl group, a halo-lower alkyl group, a hydroxyl group, a lower alkoxy group, a cyano group or a nitro group, with the proviso that R2 is a difit hydrogen and when R5 is a group represented by the formula R6 is a halogen atom, a lower alkyl group or a lower alkoxy group, R1 is a lower alkyl group or a cycloalkyl group, R and R are both a hydrogen atom and X is an oxygen atom.]

2. The compound , according to claim 1, which is a pyrido [2,3-d] pyrimidine derivative represented by the following general formula (II) or a pharmaceutically acceptable salt thereof: [Each symbol in the formula represents the following meaning: R7 represents a methyl, ethyl, propyl or isopropyl group, R represents a methyl, ethyl, propyl or isopropyl group, and R9 represents a chlorine atom or bromine a methyl group.

3. The compound according to claim 2, wherein R8 is a methyl group or an ethyl group.

The compound according to claim 3, wherein R 7 is an ethyl group or a propyl group and RR is the group described in claim 3.

The compound according to claim 4 which is 4- ( 3-chlorophenyl) -1,7-diethylpyrido [2,3-d] irimidin-2 (1H) -one, 4- (3-bromo-phenyl) -1,7-diethylpyrido [2, 3-d] pyrimidin-2 ( 1 H) -one, 4- (3-chlorophenyl) -l-ethyl-7-methylpyrido [2,3-d] pyrimidin-2 (1H) -one, 4- (3-bromo-phenyl) -l-ethyl-7- methylpyrido [2, 3-d] pyrimidin-2 (HH) -one, l-ethyl-7-methyl-4- (3-methylphenyl) pyrido [2,3-d] pyrimidin-2 (HH) -onaol, 7, diethyl-4- (3-methylphenyl) pyrido [2,3-d] pyrimidin-2 (1H) -one.

6. The compound according to claim 1, which is a pyrido [2,3-d] pyrimidine derivative represented by the following general formula (III) or a pharmaceutically acceptable salt thereof: (III) [In the above formula, X, R1, R3, R4 and R5 are as defined in the above, and R10 represents a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a group hydroxy-lower alkyl, a mercapto-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkyl-lower alkyl group, a lower alkanoyloxy-lower alkyl group, a lower-thioalkanoyl group-lower alkyl, a lower alkanoyl-alkyl group lower, a hydroxy-imino-lower alkyl group, a lower alkoxy-imino-lower alkyl group, a cycloalkyl group, an aryl group or a lower alkanoyl group, with the proviso that R10 is a group other than a hydrogen atom and a lower alkyl group when R5 is a group represented by the formula R6 is a halogen atom, a lower alkyl group or a lower alkoxy group, R1 is a lower alkyl group or a cycloalkyl group, R3 or R are both a hydrogen atom and X is an oxygen atom.

7. The compound according to claim 6, wherein R10 is a hydrogen atom, a lower alkyl group, a halo-lower alkyl group, a hydroxyalkyl lower group, a mercapts-lower alkyl group, a lower alkoxy group- lower alkyl, a lower alkylthioalkyl-lower alkyl group, a lower alkanoyloxy group-lower alkyl, a lower thioalkanoyl group-lower alkyl, a hydroxy imino-lower alkyl group, a cycloalkyl group, an aryl group or a lower alkanoyl group.

The compound according to claim 7, wherein R 10 is a hydrogen atom, a lower alkyl group, a halo-lower alkyl group, a lower hydroxyalkyl group, a lower alkoxy-lower alkyl group, a lower alkanoyloxy group- lower alkyl, a lower thioalkanoyl group-lower alkyl, a hydroxy imino-lower alkyl group, a cycloalkyl group, an aryl group or a lower alkanoyl group.

9. The compound according to claim 8, wherein R10 is the group of claim 8; R4 is a hydrogen atom; R is (1) a cycloalkyl group that can be substituted with a lower alkyl group, (2) a naphthyl group, (3) a monocyclic heteroaryl group of five or six members having from 1 to 4 heteroatom ee selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom or (4) a group represented by the formula and R6 is a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a cyano group or a nitro group.

10. The composition according to claim 9, wherein R is a lower alkyl group or a cycloalkyl-lower alkyl group, R ° is a lower alkyl group, a halo-lower alkyl group, a hydroxy-lower alkyl group, a lower thioalkanoyl group-lower alkyl, a hydroxy imino-lower alkyl group, a cycloalkyl group or a lower alkanoyl group, R3 and R4 are both a hydrogen atom, R5 is a cycloalkyl group that can be substituted with a lower alkyl group, or a group represented by the formula and R is a halogen atom, a lower alkyl group or a nitro group.

11. The compound according to claim 10, which is 4-cyclohexyl-1-ethyl-7-methylpyrido [2,3-d] pyrimidin-2 (1H) -one, 4- (3-chlorofenyl) -l- ethyl-7- (1-hydroxyethyl) pyrido [2,3-d] pyrimidine-2 (H) -one, 4- (3-chlorophenyl) -7-cyclopropyl-l-ethylpyrido [2,3-d] pyrimidine- 2 (1H) -one, l-ethyl-7-methyl-4- (3-methylcyclohexyl) pyrido [2,3-d] pyridimidin-2 (1H) -one, 1,7-diethyl-4- (3- methylcyclohexyl) irido [2,3-d] pyrimidin-2 (1H) -one, 4- (3-chlorophenyl) -l-ethyl-7-met-ilpyrido [2,3-d] pyrimidin-2 (1H) -thione , l-cyclopropylmethyl-7-methyl-4- (3-methylphenyl) pyrido [2,3-d] pyrimidin-2 (1H) -one, 4-cyclohexyl-1,7-diethylpyrido [2, 3-d] pyrimidin-2 (HH) -one, 4- (3-chlorophenyl) -1-ethyl-7-hydroxy-iminopyrido [2,3-d] pyrimidin-2 (HH) -one, 7- (1-thioacetylethyl) - 4- (3-chlorophenyl) -1-ethylpyrido [2,3-d] pyrimidin-2 (lH) -one, or 1, 7-diethyl-4- (3-chlorofenyl) pyrido [2, 3-d] pyrimidin-2 (1H) -thione.

12. A pharmaceutical composition which comprises a pyrido [2,3-d] pyrimidine derivative claimed in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition according to claim 12, which is a type IV phosphodiesterase inhibitor.

14. The pharmaceutical composition according to claim 13, which is an agent for the prevention or treatment of respiratory diseases related to type IV phosphodiesterase.

15. The pharmaceutical composition according to claim 14, which is an agent for the prevention or treatment of bronchial asthma.

16. The pharmaceutical composition according to claim 12, wherein it comprises the pyrido [2,3-d] pyrimidine derivative claimed in any of claims 6 to 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition according to claim 16, which is a type IV phosphodiesterase inhibitor.

18. The pharmaceutical composition according to claim 17, which is an agent for the prevention or treatment of respiratory diseases related to type IV phosphodiesterase.

19. The pharmaceutical composition according to claim 18, which is an agent for the prevention or treatment of bronchial asthma.

20. An inhibitor of type IV phosphodiesterase, which comprises the pyrido [2,3-d] pyrimidine derivative claimed in any of claims 2 to 5 or a pharmaceutically acceptable salt thereof.

21. The drug according to claim 20, which is an agent for the prevention or treatment of respiratory diseases related to phosphodiesterase.

22. The drug according to claim 21, which is an agent for the prevention or treatment of bronchial asthma.

23. The use of a pyrido [2,3-d] pyridine derivative claimed in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for the production of a type IV foefodiesterase inhibitor for the prevention or treatment of a disease in which the acceleration of the activity of type IV phosphodiesterase is compromised.

24. The use, according to claim 23, wherein the disease in which the acceleration of the activity of phosphodiesteraea type IV is compromised is a respiratory disease.

25. The use according to claim 24, wherein the disease in which the acceleration of the activity of phosphodiesterase type IV is compromised is bronchial asthma.

26. A method for preventing or treating a disease in which the acceleration of the activity of type IV phosphodiesterase is compromised, which comprises administering a pyrido [2,3-d] pyrimidine derivative claimed in any of claim 1 to 11, or a pharmaceutically acceptable salt thereof, in an amount effective to prevent or treat said disease in which the acceleration of the activity of type IV phosphodiesterase is compromised, to a patient suffering from or having a possibility of having said disease.

27. The method according to claim 26, wherein the disease in which the acceleration of the activity of type IV phosphodiesteraea is compromised is a respiratory disease. The method, according to claim 27, wherein the disease in which the acceleration of type IV phosphodiesterase activity is compromised is bronchial asthma. SUMMARY This invention relates to the compounds (I) or pharmaceutically acceptable salts thereof, which has a function to inhibit phosphodiesterase (PDE) type IV and which are useful as medicaments, especially as inhibitors of phosphodiesterase type IV, or as preventive agents or therapeutic diseases in which the acceleration of the activity of phosphodiesterase type IV is compromised, particularly respiratory diseases such as bronchial asthma as well as the pharmaceutical compositions thereof. [X: an oxygen atom or a sulfur atom, R1: a lower alkyl group, a lower cycloalkylalkyl group or a cycloalkyl group, R2: a hydrogen atom, a halogen atom, a lower alkyl group, a halo- lower alkyl, a hydroxy-lower alkyl group, a mercapto-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkyl thioalkyl-lower alkyl group, a lower alkanoyloxy-lower alkyl group, a lower alkyl lower alkyl thioalkanoyl group, a lower alkyl group lower alkanoyl-lower alkyl, a hydroxy-imino-lower alkyl group, a lower alkoxy-imino-lower alkyl group, a cycloalkyl group, an aryl group or a lower alkanoyl group, R3: a hydrogen atom, a halogen atom or a lower alkyl group, R 4: a hydrogen atom or a lower alkyl group, R 5: a cycloalkyl group which may be substituted with the same group of R, - a naphthyl group which may be substituted with the moiety g R rupo; a five or six membered monocyclic hetero ring group having from 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, which can be substituted with the group moiety of R6 and which can be condensed with ring of benzene; or a group represented by the formula and R: a halogen atom, a lower alkyl group, a halo-lower alkyl group, a hydroxyl group, a lower alkoxy group, a cyano group or a nitro group. • k ie -k k -k