Pyrido [2,3-D] pyrimidine derivatives and pharmaceutical compositions thereof

专利摘要:
The present invention has the effect of inhibiting the activity of type IV phosphodiesterase and is useful as a medicament, particularly as a phosphodiesterase inhibitor of type IV, or as a medicament for the prevention of diseases associated with promotion of antinastiant type IV PDE activity, particularly respiratory diseases such as bronchial asthma And a compound of formula (I) or a pharmaceutically acceptable salt thereof useful as a therapeutic agent. Formula I In this formula, X is oxygen or sulfur, R <1> is lower alkyl, cycloalkyl (lower alkyl) or cycloalkyl, R 2 is hydrogen, halogeno, lower alkyl, halo (lower alkyl), hydroxy (lower alkyl), mercapto (lower alkyl), (lower alkoxy) (lower alkyl), (lower alkylthio) (Lower alkyl), (lower alkanoylthio) (lower alkyl), (lower alkanoyl) (lower alkyl), hydroxyimino (lower alkyl), (lower alkoxyimino) Cycloalkyl, aryl or lower alkanoyl, R &lt; 3 &gt; is hydrogen, halogeno or lower alkyl, R &lt; 4 &gt; is hydrogen or lower alkyl, R 5 is cycloalkyl which may be substituted with the same group of R 6 ; Naphthyl optionally substituted with the same group of R &lt; 6 & gt ;; A 5- or 6-membered monocyclic heterocycle optionally substituted with the same group of R &lt; 6 &gt; and having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, optionally fused with a benzene ring; Or &lt; Lt; / RTI &gt; R 6 is halogeno, lower alkyl, halo (lower alkyl), hydroxy, lower alkoxy, cyano or nitro a furnace.
公开号:KR19990071520A
申请号:KR1019980703792
申请日:1996-11-20
公开日:1999-09-27
发明作者:가즈히사 다카야마；히로유키 히사미치；마사히로 이와타；히데키 구보타；모토노리 아오키
申请人:오노다 마사요시；야마노우치세이야쿠 가부시키가이샤；
IPC主号:

专利说明:

Pyrido [2,3-D] pyrimidine derivatives and pharmaceutical compositions thereof
Asthma is a respiratory disease that recurs stridor and seizures due to airway constriction. The number of asthmatic patients is steadily increasing and is expected to increase further in the future.
The major pathological manifestations of asthma are a) inflammatory responses caused by the sudden contraction of the airway smooth muscle and b) activation of respiratory tract invasive cells, including the lungs. Thus, inhibition of airway smooth muscle contraction and inhibition or prevention of invasive cell activation may be an effective means of treating asthma symptoms.
For the treatment of asthma, β-stimulants such as aminophylline, theophylline xanthine derivatives and procaterol are currently used as medicines to alleviate asthma symptoms by expanding the bronchi. The mechanism of action of these compounds is to increase the concentration of cyclic adenosine 3 ', 5'-monophosphate (cAMP) in airway smooth muscle cells to inhibit the contraction of the airway smooth muscle. This is due to activation of the cAMP production enzyme adenylate cyclase Or inhibition of phosphodiesterase (PDE), the cAMP hydrolase [Thorax, 46, 512-523 (1991)].
However, xanthine derivatives cause systemic adverse effects such as blood pressure reduction and cardiac activity [J. Cyclic Nucleotide and Protein Phosphorylation Res., 10, 551-564 (1985)], and thus its plasma concentration needs to be measured to prevent such systemic side effects. Additionally, with respect to the infiltration of inflammatory cells, xanthine derivatives do not have a clear effect on asthma.
On the other hand, when increasing the dose due to the tendency to induce desensitization, the beta -stimulants cause side effects such as tremor, palpitation and the like.
Subsequent studies have revealed that the PDE, an enzyme that hydrolyzes cAMP, is subdivided into four or more different types, I to IV, with different distribution and function [Pharmacological Therapy, 51, 13-33 (1991)]. In particular, type IV PDE does not act on cyclic guanosine 3 ', 5'-monophosphate (cGMP) in nucleotides and hydrolyses cAMP in a specific manner, its presence being found in both airway smooth muscle and invasive cells.
Incidentally, PDEV is known as an enzyme that degrades cGMP.
The concentration of cAMP in the cell is determined by the balance between cAMP production by adenylate cyclase and cAMP hydrolysis by PDE. As a result, intracellular cAMP levels can be increased by stimulating adenylate cyclase or inhibiting PDE. Increased intracellular cAMP concentration leads to 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)].
In addition, the IV type PDE inhibitor inhibits eosinophil infiltration by antigen and platelet activating factor in guinea pig [Eur. J. Phamacol., 255, 253-256 (1994)] have been reported to inhibit the secretion of cytotoxic proteins (MBP, ECP) from eosinophils [Br. J. Pharmacol., 115, 39-47 (1995)]. In addition, type IV PDE inhibitors inhibit airway smooth muscle contraction by shrinking substances (histamine, LTD ₄ , methacholine) and [Br. J. Pharmacol., 113, 1423-1431 (1994)] inhibits the production of IL-4, a cytokine member believed to be closely associated with asthma [J. Invest. Dermatol., 100, 681-684 (1993)], inhibiting the acceleration of vascular permeability in airways [Fundam. Clin. Pharmacol., 6, 247-249 (1992)] exhibit activity to suppress airway hyperreactivity [Eur. J. Pharmacol., 275, 75-82 (1995)].
As a result, a drug having excellent activity for inhibiting type IV PDE is expected as an anti-asthma medicament that can effectively alleviate or prevent asthma symptoms without causing side effects.
Compounds having a quinazolin-2-one structure have PDE inhibitory activity that is not limited to type IV (International Patent Publication 94/12499), the structure of which is similar to that of the pyrimidine Lt; RTI ID = 0.0 &gt; [2,3-d] pyrimidine &lt; / RTI &gt;
On the other hand, a compound having a 4-phenylpyrido [2,3-d] pyrimidin-2-one structure is disclosed in G. E. Hardman et al., In U.S. Pat. Patent 3,758,475. In this patent publication, a compound having anti-inflammatory activity, which is recognized by the carrageenin-induced edema inhibition test, is represented by the following general formula:

The or ego,
In this formula,
R is hydrogen or lower alkyl of 1 to 5 carbon atoms, such as methyl;
R 'is lower alkyl of 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, tert-butyl and the like; Allyl; Methallyl; Propargyl; Or cycloalkyl of 3 to 6 carbon atoms, for example, cyclopropyl;
R &quot; is phenyl or substituted phenyl of the formula;

Y is an atomic weight of 19 to 80; Lower alkyl of 1 to 4 carbon atoms; Lower alkoxy of 1 to 4 carbon atoms;
Y 'is hydrogen, halo, lower alkyl or lower alkoxy (all are as defined for Y).
Similar anti-inflammatory compounds are also described in G. E. Hardman et al., In J. Med. Chem. (Vol. 17, No. 16, 636-639, 1974).
Also disclosed is a method of inhibiting platelet aggregation by administering a compound analogous to the above-mentioned compound, 1-substituted-4-arylpyrido [2,3-d] pyrimidin- unexamined published Japanese patent application (kokai) No. 53-94040.
Some of the compounds provided in the present invention are included in the general formulas shown in the above-mentioned U.S. Patents in which R is a lower alkyl group, R 'is a lower alkyl group or a C _3-6 cycloalkyl group and R Is a phenyl group having a halogen atom, a lower alkyl group or a lower alkoxy group.
However, in the examples and other parts of the above-mentioned U.S. patents, only those compounds having a halogen atom or a lower alkyl group at only the meta position of the phenyl group and having a lower alkyl group at the 7-position of the pyrido [2,3-d] pyrimidine There is no illustration of a compound. Additionally, the above-mentioned U.S. patents only describe anti-inflammatory activity and do not describe or suggest inhibitory and anti-asthmatic activity against type IV PDE.
The present invention relates to novel pyrido [2,3-d] pyrimidine derivatives and their pharmaceutically acceptable salts, their pharmaceutical compositions, their use for the production of medicaments, and their use as medicaments, in particular as a type IV phosphodiesterase inhibitor, In an effective amount.
The inventors of the present invention conducted intensive studies on compounds showing inhibitory activity against the type IV PDE, and achieved the present invention based on the discovery that the compound represented by the following formula (I) has excellent IV type PDE inhibitory activity.
Accordingly, in accordance with the present invention there is provided a pyrido [2,3-d] pyrimidine derivative of the general formula (I), or a pharmaceutically acceptable salt thereof,
[Wherein each symbol has the following meaning;
X is an oxygen atom or a sulfur atom,
R ^{1 is a} lower alkyl group, a cycloalkyl-lower alkyl group or a cycloalkyl group,
R ^{2 represents a} hydrogen atom, a halogen atom, a lower alkyl group, a halogeno-lower alkyl group, a hydroxy-lower alkyl group, a mercapto-lower alkyl group, a lower alkoxy- Lower alkanoylthio-lower alkyl, lower alkanoyl-lower alkyl group, hydroxyimino-lower alkyl group, lower alkoxyimino-lower alkyl group, cycloalkyl group, aryl group or lower alkanoyl-lower alkyl group, Group,
R ^{3 is a} hydrogen atom, a halogen atom or a lower alkyl group,
R ^{4 is a} hydrogen atom or a lower alkyl group,
R ⁵ : a cycloalkyl group which may be substituted with the same group of R ⁶ ; A naphthyl group which may be substituted with the same group of R ⁶ ; A 5- or 6-membered monocyclic heterocyclic group having 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom which may be substituted with the same group of R &lt; ⁶ &gt; and which may be condensed with a benzene ring; Or &lt; Lt; / RTI &gt;
R ^{6 is a} halogen atom, a lower alkyl group, a halogen-lower alkyl group, a hydroxy group, a lower alkoxy group, a cyano group or a nitro group,
Provided that R &lt; ^{5 &} R ⁶ is a halogen atom, a lower alkyl group or a lower alkoxy group, R ¹ is a lower alkyl group or a cycloalkyl group, and R ³ and R ⁴ are both a hydrogen atom and X is an oxygen atom, R ² Is a group other than a hydrogen atom.]
In the compound represented by formula I, wherein X is an oxygen atom, R ¹ is a lower alkyl group or cycloalkyl group, R ² is a lower alkyl group, R ³ and R ⁴ are both hydrogen atoms, R ⁵ has the formula And R &lt; ⁶ &gt; is a halogen atom, a lower alkyl group or a lower alkoxy group is included in the formulas of the above-mentioned U.S. Patent.
However, the compounds of the present invention are useful for the preparation of compounds of formula (I) wherein the halogen atom, the lower alkyl group or the lower alkoxy group is replaced only at the meta position of the 1-substituted 4-phenylpyrido [2,3-d] pyrimidin- Position 3), and is characterized in terms of the chemical structure in which the alkyl group is introduced at position 7.
Such compounds having specific substituents at particular sites are novel as they have not been exemplified in the above-mentioned U. S. patents.
In addition, these compounds have pharmacological properties that exhibit a very excellent effect in terms of the type IV PDE inhibitory activity not described or suggested in the above-mentioned U. S. patents.
In particular, pyrido [2,3-d] pyrimidine derivatives represented by the following formula (II) and pharmaceutically acceptable salts thereof are more effective than the potential effects of similar compounds described in the above-mentioned U.S. patents, And exhibits a very excellent effect.
[In the above formula,
R ⁷ represents a methyl, ethyl, propyl or isopropyl group,
R ⁸ represents a methyl, ethyl, propyl or isopropyl group,
R ⁹ represents chlorine or bromine or methyl group.
On the other hand, pyrido [2,3-d] pyrimidine derivatives represented by the formula (III) below and the pharmaceutically acceptable salts thereof, excluding the compounds included in the formulas of the above-mentioned United States patents, Are novel compounds which have not been described in the prior art.
[In the above formula,
X, R ¹ , R ³ , R ⁴ and R ⁵ are defined as above,
R ¹⁰ represents a hydrogen atom, a halogen atom, a lower alkyl group, a halogeno-lower alkyl group, a hydroxy-lower alkyl group, a mercapto-lower alkyl group, a lower alkoxy-lower alkyl group, Lower alkanoylthio-lower alkyl group, lower alkanoyl-lower alkyl group, hydroxyimino-lower alkyl group, lower alkoxyimino-lower alkyl group, cycloalkyl group, aryl group or lower alkanoyl-lower alkyl group, Noile group,
Provided that R &lt; ^{5 &} R ⁶ is a halogen atom, a lower alkyl group or a lower alkoxy group, R ¹ is a lower alkyl group or a cycloalkyl group, and R ³ and R ⁴ are both hydrogen atoms and X is an oxygen atom, R ¹⁰ Is a group other than a hydrogen atom.]
The compound of formula (III) or a pharmaceutically acceptable salt thereof of the present invention is characterized in that the pyrido [2,3-d] pyrimidine skeleton has a specific alkyl group at position 1 and an oxo or thioxo group at position 2 Having chemical structural properties with specific substituents at positions 5, 6, and 7, having a specific ring group at position 4, and having pharmacological properties that have selective inhibitory activity against type IV PDE.
In particular, the compound of formula III of the present invention is characterized in that the compound having a pyrido [2,3-d] pyrimidine structure is first provided as a type IV PDE inhibitor.
Especially preferred among the compounds of the present invention are the compounds represented by the general formulas (II) and (III) and pharmaceutically acceptable salts thereof. Especially preferred among the compounds of formula (II) are those wherein R ⁸ is methyl or ethyl, more preferably R ⁸ is the above group and R ⁷ is ethyl or propyl.
Illustrative examples of the most preferred compounds are as follows.
Diethylpyrido [2,3-d] pyrimidin-2- (1H) -one, 4- (3-bromophenyl) 2,3-d] pyrimidin-2 (1 H) -one, 4- (3-chlorophenyl) -7-methylpyrido [2,3-d] pyrimidin-2 (1H) -one, 2,3-d] pyrimidin-2 (1H) -one and 1,7-diethyl-4- (3-methylphenyl) pyrido [ (1H) -one.
Particularly preferred among the compounds of formula III are those wherein R ¹⁰ is a hydrogen atom, a lower alkyl group, a halogeno-lower alkyl group, a hydroxy-lower alkyl group, a mercapto-lower alkyl group, a lower alkoxy- -lower alkyl group, a lower alkanoyloxy-lower alkyl group, lower alkanoyl alkylthio-lower alkyl group, a hydroxyimino-lower alkyl group, cycloalkyl group, an aryl group or a lower alkanoyl group, more preferred is R ¹⁰ A lower alkanoyloxy-lower alkyl group, a lower alkanoylthio-lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy-alkyl group, a lower alkanoyloxy- An alkyl group, a cycloalkyl group, an aryl group or a lower alkanoyl group. More particularly, R &lt; ¹⁰ &gt; is a group as described above; R ⁴ is a hydrogen atom; R ⁵ is a 5- or 6-membered heterocyclic group having 1 to 4 heteroatoms selected from (1) a cycloalkyl group which may be substituted with lower alkyl, (2) a naphthyl group, (3) a nitrogen, A monocyclic heterocyclic group or (4) &Lt; / RTI &gt; R ⁶ is a halogen atom, a lower alkyl group, a halogeno-and lower alkyl group, lower alkoxy group, a cyano preferably no group or a nitro group in the compound, R ¹ is lower alkyl group or a cycloalkyl-lower alkyl group, R ¹⁰ is lower alkyl groups, halogeno-lower alkyl group, hydroxy-lower alkyl group, lower alkanoyl alkylthio-lower alkyl group, a hydroxyimino-lower alkyl group, cycloalkyl group or lower alkanoyl group, R ³ and R ⁴ Is a hydrogen atom, R &lt; ⁵ &gt; is a cycloalkyl group which may be substituted with a lower alkyl group, Lt; / RTI &gt; R ⁶ is preferably a halogen atom, a lower alkyl group or a nitro group.
Illustrative examples of the most preferred compounds are as follows.
7-methylpyrido [2,3-d] pyrimidin-2 (1H) -one and 4- (3-chlorophenyl) (3-chlorophenyl) -7-cyclopropyl-ethylpyrido [2,3-d] pyrimidin-2 (1 H) -one, 1, 7-diethyl-4 (3-methylcyclohexyl) pyrido [ - (3-methylcyclohexyl) pyrido [2,3-d] pyrimidin-2 (1H) -one and 4- (3- chlorophenyl) pyrido [2,3-d] pyrimidin-2 (1 H) -one, 4-methyl- -7-diethylpyrido [2,3-d] pyrimidin-2 (1H) -one, 4- (3- chlorophenyl) 2,3-d] pyrimidin-2-one [0215] To a solution of 2- (lH- 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 a compound of formula I or a pharmaceutically acceptable salt thereof, preferably a compound of formula (III) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. An embodiment of the medicinal composition is a composition comprising a compound of formula I, preferably a compound of formula III, or a pharmaceutically acceptable salt thereof, more particularly a formulation for use in the prevention or treatment of respiratory diseases, particularly bronchial asthma, IV type PDE inhibitors.
The present invention also includes a Type IV PDE inhibitor comprising a compound of Formula II or a pharmaceutically acceptable salt thereof, more particularly a medicament for use in the prevention and treatment of respiratory diseases, particularly bronchial asthma, in which type IV PDE is associated.
The present invention also relates to a compound of formula (I), preferably a compound of formula (II) or a compound of formula (III) for the manufacture of a medicament for use in the prevention or treatment of diseases related to the promotion of type IV PDE, particularly respiratory diseases, more particularly bronchial asthma , Or a pharmaceutically acceptable salt thereof, or a method of preventing or treating the above-mentioned disease by administering an effective amount of the compound to a patient having or susceptible to the disease.
The compounds of the present invention are described in more detail below.
Unless otherwise indicated, the term " lower " as used in the definition of the formulas of the present invention means a straight or branched chain carbon chain having 1 to 6 carbon atoms.
Illustrative examples of a "lower alkyl group" include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, isopentyl, neopentyl, Butyl, 2-methylbutyl, 1,2-dimethylbutyl, 1,2-dimethylbutyl, 1,2-dimethylbutyl, Dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2- ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethyl profile, comprises a straight chain or branched chain C _1-6 alkyl group such as 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl. Among these groups, C _1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl and the like are preferable, and C _1-3 alkyl groups such as methyl, ethyl, propyl, isopropyl and the like are particularly preferable.
C _2-3 alkyl groups are particularly preferred, and C _1-3 alkyl groups, especially methyl and ethyl groups, are preferred as R ² lower alkyl groups.
Illustrative examples of a "lower alkoxy group" include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert- Includes straight chain or branched chain C _1-6 alkoxy groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, , A double-methoxy group and an ethoxy group are preferable.
As used herein, the term " lower alkylthio group " means a group wherein the hydrogen atom of the thiol group is substituted with a lower alkyl group as mentioned above, examples of which include methylthio, ethylthio, propylthio, isopropylthio Butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, tert-pentylthio, 2-methylbutylthio, , 1-ethyl propyl thio, and includes a straight-chain or branched C _1-6 alkylthio group such as hexylthio, the methylthio and ethylthio groups are preferred to the double.
Illustrative examples of a "lower alkanoyl group" include straight or branched chain C _1-6 alkanoyl groups such as formyl, acetyl, propionyl, butyl, isobutyl, valeryl, isobaryl, Of these, formyl, acetyl and propionyl groups are preferred.
A "lower alkanoyloxy group" is a group resulting from the esterification of an alcohol and a lower carboxylic acid, illustrative examples of which include formyloxy, acetoxy, propionyloxy, butylyloxy, isobutyryloxy, valeryloxy includes a straight chain or branched chain C _1-6 alkanoyloxy group such as pivaloyl-yloxy.
A "lower alkanoylthio group" is a group resulting from the thioesterification of a thiol and a lower carboxylic acid, illustrative examples of which include formylthio, acetylthio, propionylthio, butylilithio, isobutyrylthio, valeryl A straight chain or branched chain C _1-6 alkanoylthio group such as thio, pivaloylthio, and the like.
Illustrative examples of " cycloalkyl groups " have 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cyclopropyl group is particularly preferred as the cycloalkyl group of the "cycloalkyl-lower alkyl group" of R ¹ and R ² . Also, the cyclohexyl group is particularly preferred as the cycloalkyl group of the " cycloalkyl group which may be substituted " of R &lt; ⁵ &gt;.
The term " aryl group " preferably refers to an aromatic hydrocarbon group having from 6 to 14 carbon atoms. Preferred illustrative examples thereof include phenyl, tolyl, xylyl, biphenyl, naphthyl, indenyl, anthryl and phenanthryl groups, more preferably comprising phenyl and naphthyl groups, .
Examples of " halogen atoms " include fluorine, chlorine, bromine and iodine atoms, chlorine and bromine being particularly preferred as substituents in the ring system, and fluorine, chlorine and bromine atoms being preferred as substituents of the alkyl chain.
Substituted "lower alkyl groups" of R ¹ , R ² , R ⁶ and R ¹⁰ , especially R ² or R ¹⁰ , as mentioned above, may be substituted with 1 to 4 (especially 1 to 3) Illustrative examples of each substituent group include a halogeno group, a hydroxyl group, a mercapto group, a lower alkoxy group, a lower alkylthio group, a lower alkanoyloxy group, a lower alkanoylthio group, a lower alkanoyl group, a hydroxyimino group, Lower alkoxyimino groups and cycloalkyl groups. In this case, illustrative examples of the halogen atoms constituting the "halogeno group" and lower alkoxy, lower alkylthio, lower alkanoyloxy, lower alkanoylthio, lower alkanoyl and cycloalkyl groups include those described in the prior art do.
Illustrative examples of a " lower alkoxyimino group " include straight chain or branched chain groups such as methoxyimino, ethoxyimino, propoxyimino, isopropoxyimino, butoxyimino, isobutoxyimino, tertiary-butoxyimino and the like C _1-6 alkoxyimino group.
As a result, preferred illustrative examples of each of the substituted alkyl groups include:
Such as trifluoromethyl, chloromethyl, bromomethyl, 2-chloroethyl, 1-chloroethyl, 2-bromoethyl, 1-bromoethyl and "halogeno-lower alkyl groups"; Hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and analogues thereof such as " hydroxy-lower alkyl group "; Mercaptomethyl, 2-mercaptoethyl, 1-mercaptoethyl and the like, such as a "mercapto-lower alkyl group"; Methoxymethyl, ethoxymethyl, 2-methoxyethyl, 1-methoxyethyl, dimethoxyethyl and similar analogs such as a "lower alkoxy-lower alkyl group"; Such as methylthiomethyl, ethylthiomethyl, 2-methylthioethyl, 1-methylthioethyl and the "lower alkylthio-lower alkyl group"; Acetoxymethyl, 2-acetoxyethyl, 1-acetoxyethyl and the like, such as " lower alkanoyloxy-lower alkyl group "; Acetylthioethyl, 2-acetylthioethyl, 1-acetylthioethyl and the like, such as a "lower alkanoylthio-lower alkyl group"; Formylmethyl, acetonyl, 2-oxobutyl and the like, such as " lower alkanoyl-lower alkyl group "; Hydroxyiminomethyl, 2-hydroxyiminoethyl, 1-hydroxyiminoethyl and analogues thereof such as a "hydroxyimino-lower alkyl group"; Methoxyiminomethyl, ethoxyiminomethyl and analogues thereof such as a " lower alkoxyimino-lower alkyl group "; And analogs thereof such as cyclopropylmethyl, cyclohexylmethyl, 2-cyclopropylethyl and " cycloalkyl-lower alkyl groups ".
The "5- or 6-membered monocyclic heterocyclic group having 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom which can be condensed with a benzene ring" includes furyl, thienyl, A pyrrolyl group, a pyrrolyl group, a pyrrolyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, a triazolyl group, an oxadiazolyl group, a thiadiazolyl group, a tetrazolyl group, These monocyclic heterocyclic groups, together with the benzene ring, are selected from the group consisting of indolyl, indazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isoindolyl, isoquinolyl, To form a condensed ring such as, for example, phenyl, naphthyl, quinolyl, quinolyl, quinolyl, quinazolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, benzoxadiazolyl, phthalazinyl, quinoxalinyl, . The bond of these condensed rings at the 4-position of the pyrido [2,3-d] pyrimidine ring may be formed through any carbon and nitrogen atom of the heterocycle or through the carbon atom of the benzene ring. Among these monocyclic heterocyclic rings, furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl groups are preferable, and thienyl, thiazolyl and pyridyl More preferable.
When R ⁵ is a cycloalkyl group, a naphthyl group or a heterocyclic group, the number of substituents to be substituted is not limited to one, and is more preferably one to three.
The compounds of the present invention can form salts. Examples of such salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and the like. And organic acids such as formic acid, acetic acid, valeric acid, isovaleric acid, pivalic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, citric acid, malic acid, tartaric acid, , Glutamic acid, aspartic acid, and the like).
The compounds of the present invention are present in the form of tautomers based on the presence of cyclic urea or thiourea having a double bond. Depending on the type of substituent, it can also exist in optical isomers based on the presence of asymmetric carbons and can exist in the form of other isomers based on the presence of cyclic rings, hydroxyimino groups and lower alkoxyimino groups. All these isomers and their mixtures in their individual forms are included in the present invention.
In addition, the compounds of the present invention can be separated into a variety of crystal forms, such as solutes using hydrates, ethanol, and the like, or polymorphs, depending on their physicochemical properties or manufacturing conditions. Both hydrates, solutes using ethanol and the like, and materials having various crystal forms are also included in the present invention.
(Manufacturing method)
The compounds of the present invention and their salts can be prepared by using various synthetic methods, using the characteristics of the basic structure thereof and the type of substituent. The following describes a typical production process thereof.
In this regard, the starting compounds or compounds of the invention may be introduced into the synthesis reaction after protecting the functional groups using appropriate protecting groups. Examples of such protecting groups can be found in, for example, " Protective Groups in Organic Synthesis " 2nd edition, edited by Greene and Wuts, and these groups may be optionally used according to the respective reaction conditions.
Additionally, all aldehyde compounds can be obtained via reactions using the corresponding acetyl compounds and subsequent conversion to aldehydes.
The first production method (cyclization reaction)

(Wherein,
R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above,
And Y &lt; ^{1 &gt;} and Z represent a leaving group favorable to the present reaction.
Compound Ia, which is one of the compounds of the present invention wherein X is an oxo group, can be produced by reacting a 2-aminopyridyl ketone derivative IV with an isocyanate represented by the formula Va or with a carbamate derivative represented by the formula Vb to effect a cyclization reaction Can be produced.
Examples of the leaving group represented by Y ¹ include a halogen-substituted sulfonyl group such as a chlorosulfonyl group and the like and a tri-substituted silyl group such as a trimethylsilyl group and the like.
Examples of the leaving group represented by Z include an alkoxy group (e.g., methoxy and ethoxy) and a phenoxy group.
The reaction in which the isocyanate is used is carried out at a temperature of from -78 to 0 캜 under cooling, at a cooling to a room temperature or in some cases at an elevated temperature and at room temperature, for example, a halogenated hydrocarbon (for example, dichloromethane, dichloroethane, chloroform and the like Which is inert to the reaction and which is selected from hydrocarbons (e.g. water), aromatic hydrocarbons (e.g. benzene, toluene, xylene and the like) and ethers (e.g. diethyl ether, tetrahydrofuran, dioxane and the like) Lt; / RTI &gt;
The reaction is carried out using equimolar amounts of compound IV and isocyanate Va, or one excess of ether is used, and the reaction is carried out in the presence of a base such as triethylamine, diisopropylethylamine, N-methylmorpholine, N, For example, in the presence of a base such as 4- (N, N-dimethylamino) pyridine, picoline, lutidine or the like, which is advantageous for smoothly carrying out the reaction if desired.
When a carbamate derivative represented by the formula Vb is used in place of the isocyanate Va, it is advantageous to carry out the reaction in the presence of a Lewis acid such as zinc chloride, tin chloride, titanium tetrachloride, boron trichloride-ethyl ether or the like.
From this viewpoint, compounds having a halogen at the 6-position are often obtained as a by-product of this process.
The above-mentioned starting compound IV can be easily obtained by synthesizing it by the process for producing the following reaction formula described in Reference Example or a modified method thereof.

(Wherein,
R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above,
Other symbols indicate the following;
R ^{2 '} : in the same group as R ² , which may be protected,
R ^{3 '} : the same group as R ³ except for a halogen atom,
Y ² , Y ³ and Y ⁴ are the same or different from each other and each represents a halogen atom,
Z ² and Z ³ : are leaving groups favorable for the pyrimidine synthesis reaction,
Ts: p-toluenesulfonyl group.)
That is, when 3-acyl-2-halopyridine derivative 7 is used as a starting material, starting material IV can be prepared by often using an N-alkylation reaction, which is described hereinafter, Reacted with the R &lt; ¹ &gt; -substituted amine 8, and subsequently deprotected if necessary. It is possible to apply the first production method without removing the protective group. In addition, when 3-acyl-2- (p-toluenesulfonyloxy) pyridine derivative 13 is used as the starting material, the starting material IV can often be prepared by introducing an N-alkylation reaction, , The derivative is reacted with the R &lt; ¹ &gt; -substituted amine 8 in the same manner as described above. Additionally, when 2-substituted aminopyridine carbonitrile 14 is used as the starting material, starting material IV is prepared by reacting starting material 14 with a Grignard reagent derived from the halide of R &lt; ⁵ & Can be prepared by introducing a general method for ketone synthesis from nitrile.
In this respect, Intermediate 7 can be prepared by introducing a method of using the corresponding nitrile 1 or carbonate 3 as a starting material and reacting with the above-mentioned Grignard Formation 2, or by reacting the aldehyde 5 of R ⁵ in position 3 Halo-3-substituted hydroxymethylpyridine derivative obtained by reacting a 2-halopyridine derivative 4 having high reactivity with a 2-halo-3-substituted hydroxymethylpyridine derivative.
Intermediate compound 13 is obtained by reacting ketone 9 (e.g., 1,1-diethoxypentane source) with acylacetamide and reacting the resulting product, 2-oxopyridyl ketone, with a tosyl halide.
The preparation of these starting compounds can be carried out by choosing an appropriate method depending on the difference in substituents such as R ² , R ³ and R ⁴ of the compound of interest. Further, the substituent can be introduced at any stage, for example, by nitration or the like method.
Second Manufacturing Method (Mutual Conversion of Substituent)
The compounds of the present invention may be derived from other substituent-containing compounds of the present invention. The method of switching a mutual substituent can be achieved by introducing a general method. The following describes typical examples thereof.
(a) Thionation

(Wherein,
R ¹ , R ² , R ³ , R ⁴ and R ⁵ are defined as above.
Among the compounds of the present invention, compounds Ib in which X is a sulfur atom can be obtained by reacting another compound Ia of the present invention wherein X is an oxygen atom with phosphorus pentachloride or Lawesson reagent.
This reaction can be carried out in an organic solvent inert to the reaction such as benzene, toluene, tetrahydrofuran, ether, dioxane, methylene chloride using equimolar amounts of compound Ia and phosphorus pentosulfide, Or by heating in some cases.
(b) Reduction

(Wherein,
R ¹ , R ³ , R ⁴ , R ⁵ and X are as defined above,
R ¹¹ represents a hydrogen atom or a C _1-5 alkyl group
A ¹ represents a single bond or a C _1-5 alkylene group.)
The hydroxy-lower alkyl compound Id can be prepared by reducing the corresponding carbonyl compound Ic thereof.
Reduction is carried out by introducing a general reduction method of synthesizing an alcohol compound from a carbonyl compound. (E.g., lithium aluminum hydride or the like) in an inert solvent such as ether, tetrahydrofuran, or the like under cooling conditions, or using sodium hydrogenborhydride in a proton solvent such as ethanol, . &Lt; / RTI &gt;
(c) C-alkylation

(Wherein,
R ¹ , R ³ , R ⁴ , R ⁵ , X and Y ³ are as defined above,
R ¹² represents a C _1-5 alkyl group.)
The 2- (1-hydroxy-lower alkyl) -substituted compound If can be prepared by a conventional method of reacting the corresponding aldehyde with a Grignard preparation VI derived from a lower alkyl halide and magnesium.
This reaction is generally advantageously carried out under cooling conditions in an inert solvent such as tetrahydrofuran, ether or the like.
(d) oxidation

(Wherein,
R ¹ , R ³ , R ⁴ , R ⁵ , and A ¹ are as defined above.
Unlike method (b), oxidation of the hydroxyl compound Id produces its corresponding carbonyl compound Ic.
Oxidation is accomplished by introducing a common method of oxidizing the corresponding hydroxy compound to produce a carbonyl compound, which can be accomplished by heating the material and the oxidizing agent under reflux in an inert solvent such as benzene, toluene or the like Is generally performed. As the oxidizing agent, manganese dioxide, pyridinium chlorochromate or the like is preferably used.
(e) Halogenation
i) 1 halogenation of the side chain

(Wherein,
R ¹ , R ³ , R ⁴ , R ⁵ , X, R ¹¹ , Y ² and A ¹ are as defined above.
The halogeno-lower alkyl compounds Ig are prepared in a conventional manner by treating the corresponding hydroxy compound Id with a suitable halogenating agent. The reaction may be carried out in a solvent inert to the reaction, such as benzene, carbon tetrachloride or the like, or may be carried out in the absence of a solvent such as thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, hydrochloric acid, hydrobromic acid or the like It is advantageous to carry out by heating under reflux, optionally using a halogenating agent.
ii) 2-halogenation of the side chain (2)

(Wherein,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ¹¹ and Y ² are as defined above,
R ¹² represents a hydrogen atom or a C _1-5 alkyl group having a substituent.
The halogeno-lower alkyl compound Ii is prepared by treating the corresponding alkyl compound Ih with a suitable halogenating agent.
This reaction can be carried out by heating the mixture under reflux using a halogenating agent such as chlorine gas, bromine, N-bromosuccinimide or the like in a reaction inert to the reaction, such as carbon tetrachloride or the like, 2'-azobisisobutyronitrile, 2'-azobisisobutyronitrile, benzoyl peroxide or the like.
iii) halogenation of the ring
It is preferred to carry out the ring halogenation in the starting compound stage. The method described in the reference examples can be preferably used, in which phosphorus oxychloride, phosphorus trichloride, phosphorus tin, bromine or the like is used.
(f) Acylation

(Wherein,
R ¹ , R ³ , R ⁴ , R ⁵ , X, R ¹¹ and A ¹ are as defined above,
Y &lt; ⁵ &gt; is a halogen atom or a hydroxyl group
And R ¹³ represents a C _1-5 alkanoyl group.
The lower alkanoyloxy-lower alkyl compounds Ik can be readily synthesized by the esterification method of reacting a corresponding carboxylic acid VII or a reactive derivative thereof, such as an ester, acid anhydride or the like, with the corresponding hydroxy compound or halide Ij. Often the esterification process can be applied to this reaction.
In this respect, lower alkanoylthio-lower alkyl compounds can also be prepared by analogous esterification methods. Additionally, a lower alkanoyloxy-lower alkyl compound can also be obtained by reacting a corresponding halogeno-lower alkyl compound with an alkali metal salt of the corresponding carboxylic acid.
(g) saponification reaction

(Wherein,
R ¹ , R ³ , R ⁴ , R ⁵ , X, R ¹¹ , R ¹³ and A ¹ are as defined above.
In contrast to preparation process (f), the corresponding hydroxyl compound Id can be synthesized using ester compound Ik as a starting material. This can be prepared by a commonly used method of treating the starting material with a base such as sodium hydroxide or the like.
(h) oxime formation
Compounds of the present invention having a hydroxylimino group or a lower alkoxyimino group can be prepared by reacting the corresponding aldehyde or ketone compound with a hydroxylamine or a lower alkoxyamine.
The reaction can be carried out in a conventional manner, for example, using an equimolar amount or an excess amount of an aldehyde or ketone compound and a hydroxylamine or a lower alkoxyamine or a salt thereof in an organic solvent inert to the reaction (e.g., methanol and ethanol In the presence of a base (for example, sodium carbonate and sodium acetate) under cooling, at room temperature or at a reflux temperature.
Third Manufacturing Method (N-alkylation)

(Wherein,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ and X are as defined above,
Y ⁶ represents a leaving group favorable for this reaction.)
In the present preparation method, Compound I of the present invention is prepared by reacting Compound VIII with Compound IX.
Illustrative examples of leaving groups represented by Y ⁶ include halogen atoms such as iodine, bromine, chlorine and the like, organic (e.g., Sulfonyloxy groups (e.g., benzenesulfonyloxy, toluene (especially p-toluene) sulfonyloxy and the like).
This reaction can be carried out in a reaction such as benzene, toluene, diethyl ether, tetrahydrofuran, dioxane dimethylformamide, dimethylsulfoxide or the like, using equimolar amounts of Compound VIII and Compound IX, In an inert organic solvent, in the presence of a base, at a cooling temperature of -78 to 0 캜, or at room temperature, or optionally with heating. Illustrative examples of the base used include sodium hydride, potassium hydride, diisopropylamide lithium, hexamethyldisilazide lithium, tert-butoxy potassium, sodium methoxide and the like. The reaction may also be carried out using a base such as sodium alcoholate, alcoholate potassium, sodium hydroxide, potassium hydroxide or the like in an alcoholic solvent such as methanol, ethanol or the like.
In this respect, the starting compound VIII can be introduced into the reaction without using a base when the position 1 thereof is substituted with an alkali metal.
The compound of the present invention thus prepared is isolated and purified in three forms or as a salt thereof by introducing into a commonly used salt formation reaction. Separation and purification are carried out by introducing general chemical treatments such as extraction, concentration, evaporation, crystallization, filtration, recrystallization and various types of chromatography.
Various forms of isomers can be separated by conventional methods using differences in physicochemical properties between isomers. For example, a racemic compound can be introduced into a stereochemically pure isomer by a common racemate method (e. G., A method in which an optical assay is accomplished by incorporation into a diastereomer with a common optically active acid such as tartaric acid) . In addition, the diastereomeric mixtures can be separated by commonly used fraction crystallization, chromatography or the like.
Additionally, optically active compounds can be prepared by using suitable optically active substances.
The starting materials of the present invention include novel compounds. The preparation 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 g, 0.24 mol) and phosphorus oxychloride (250 ml) was heated under reflux for 2 hours. The reaction solution is concentrated under reduced pressure, and the resulting residue is mixed with toluene and concentrated under reduced pressure. The resulting residue is diluted with chloroform and washed with 1N aqueous sodium hydroxide solution. The aqueous layer was extracted with chloroform, and the chloroform layer was mixed and dried over anhydrous magnesium sulfate. After removing magnesium sulfate through filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2-chloro-3-cyano-6-ethylpyridine 19.6 g, 49%).
Reference Example 2
Magnesium (2.72 g, 112 mmol) was added to a solution of 3-bromochlorobenzene (22.1 g, 115 mmol) in tetrahydrofuran (200 ml) and the mixture was stirred at room temperature. Since a spontaneous exothermic reaction occurs, stirring is continued until the heat generation ceases. The reaction solution was cooled to -20 占 폚, and 2-chloro-3-cyano-6-ethylpyridine (9.33 g, 56 mmol) was mixed and stirred at room temperature for 16 hours. The reaction solution was mixed with saturated ammonium chloride aqueous solution, stirred at room temperature for 30 minutes, mixed with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, the magnesium sulfate is removed through filtration, and the filtrate is concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2.48 g (22%) of 2-chloro-3- (3- chlorobenzoyl) -6-ethylpyrimidine as a pale yellow oily substance .
Reference Example 3
The following compounds are obtained in the same manner as described in Reference Example 2:
3- (3-Bromobenzoyl) -2-chloro-6-ethylpyrimidine
Reference Example 4
Magnesium (4.8 g, 200 mmol) was added to a solution of 3-bromochlorobenzene (38 g, 200 mmol) in tetrahydrofuran (400 ml) and the mixture was stirred at room temperature. Since it is a spontaneous exothermic reaction, it is stirred until the heat generation is stopped. The reaction solution is cooled to -40 DEG C and 2-chloro-6-methylnicotinic acid (9.2 g, 53 mmol) is mixed and stirred at room temperature overnight. The reaction solution is mixed with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, the magnesium sulfate is removed by filtration, and the filtrate is concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (chloroform) to obtain 2-chloro-3- (3-chlorobenzoyl) -6-methylpyrimidine (6.25 g, 44%) as an oily substance.
Reference Example 5
The following compounds are obtained in the same manner as described in Reference Example 4.
3- (Bromobenzoyl) -2-chloro-6-methylpyrimidine
Reference Example 6
A mixture of 2-chloro-3- (3-chlorobenzoyl) -6-ethylpyrimidine (3.4 g, 12 mmol) and 70% ethylamine aqueous solution (15 ml) was placed in a test tube and stirred at 100 ° C for 4 hours. The reaction solution is cooled to room temperature and transferred to a separatory funnel. 1N hydrochloric acid was added thereto to make it acidic and vigorously stirred, followed by addition of an aqueous 1N sodium hydroxide solution to alkalize it. The solution is extracted with chloroform and the resulting organic layer is dried over anhydrous magnesium sulfate, the magnesium sulfate is removed by filtration and the filtrate is concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3- (3-chlorobenzoyl) -6-ethyl-2- ethylaminopyrimidine (2.6 g, 76% .
The compounds of Examples 7 to 9, which are given below, are obtained in the same manner as described in Reference Example 6.
Reference Example 7
3- (3-Bromobenzoyl) -6-ethyl-2-ethylaminopyrimidine
Reference Example 8
3- (3-Chlorobenzoyl) -2-ethylamino-6-methylpyrimidine
Reference Example 9
3- (3-Bromobenzoyl) -2-ethylamino-6-methylpyrimidine
Reference Example 10
Magnesium (4.82 g, 200 mmol) was added to a solution of 3-bromotoluene (35.1 g, 200 mmol) in tetrahydrofuran (300 ml) and the mixture was stirred at room temperature. Since a spontaneous exothermic reaction occurs, stirring is continued until the exothermic reaction is stopped. The reaction solution is cooled to -40 占 폚, mixed with 2-chloro-6-methylnicotinic acid (11.6 g, 68 mmol) and stirred at room temperature for 16 hours. The reaction solution is mixed with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, the magnesium sulfate is removed by filtration, and the filtrate is concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2.70 g (52%) of 2-chloro-6-methyl-3- (3- methylbenzoyl) pyrimidine as a pale yellow oily substance .
Reference Example 11
3-Bromotoluene (12.5 g, 73.1 mmol) was added to a solution of magnesium (1.70 g, 70.0 mmol) in tetrahydrofuran (200 ml) and the mixture was stirred until the magnesium fractions disappeared. The reaction solution was cooled to -20 占 폚, and 2-chloro-3-cyano-6-ethylpyrimidine (10.6 g, 63.6 mmol) was mixed and stirred at room temperature for 17 hours. The reaction solution is mixed with saturated aqueous ammonium chloride solution and 1N hydrochloric acid, and the mixture is stirred at room temperature for 2 hours and then extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, the magnesium sulfate is removed by filtration, and the filtrate is concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2-chloro-6-ethyl-3- (3-methylbenzoyl) pyrimidine (9.19 g, 56% .
Reference Example 12
A mixture of 2-chloro-6-methyl-3- (3-methylbenzoyl) pyrimidine (2.45 g, 10 mmol) and 70% ethylamine aqueous solution (10 ml) was placed in a test tube and stirred at 100 ° C for 4 hours. The reaction solution is cooled to room temperature and transferred to a separatory funnel. It is adjusted to pH 1 with 1N hydrochloric acid, stirred vigorously, adjusted to pH 10 with 1N aqueous sodium hydroxide solution, and then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure.
Thereafter, the resulting residue was purified by a silica gel column (hexane-ethyl acetate) to obtain 2-ethylamino-6-methyl-3- (3- methylbenzoyl) pyrimidine (2.10 g, 83%) as a yellow oily substance do.
Reference Example 13
The following compounds are obtained in the same manner as described in reference example 12.
Ethylamino-6-ethyl-3- (3-methylbenzoyl) pyrimidine
Reference Example 14
Diisopropylamine (23 ml, 175 mmol) was added to a tetrahydrofuran (500 ml) solution of a 1.6 M solution of hexane in n-butyllithium (100 ml, 160 mmol) at -65 DEG C or lower and the mixture was warmed to -40 . The reaction solution is mixed with 2-chloropyrimidine (17 g, 150 mmol) at -70 占 폚 or lower and stirred at -70 占 폚 or lower for 1.5 hours. The reaction solution is mixed with cyclohexanecarbaldehyde (17 g, 151 mmol) at -70 占 폚 or lower and stirred at -70 占 폚 or lower for 2 hours. The reaction solution is mixed with water, heated to room temperature and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (chloroform) to obtain 2-chloro-a-cyclohexyl-3-pyrimidine methanol (17 g, 50%).
Reference Example 15
Under an argon atmosphere, a 1.6 M solution of hexane (30 ml) in n-butyllithium was added dropwise to a solution of diisopropylamine (5.52 g, 54.7 mmol) in tetrahydrofuran (200 ml) cooled to -78 ° C, And stirred for a minute. 2-Chloropyridine (5.71 g, 50.3 mmol) was added dropwise to the reaction solution and stirred for 90 minutes. 2-thiophenecarbaldehyde (6.01 g, 53.7 mmol) was added dropwise to the reaction solution and stirred for 30 minutes. The reaction solution is mixed with brine and extracted with chloroform. The organic layer is washed with brine and dried over anhydrous sodium sulfate. After removal of 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 α- (2-chloropyridin-3-yl) -2-thiophenemethanol (6.66 g, 27.5 mmol, 59%).
The following compounds of Reference Examples 16 to 20 were obtained in the same manner as described in Reference Example 15.
Reference Example 16
alpha - (2-Chloropyridin-3-yl) -thiophene Methanol
Reference Example 17
- (2-Chloropyridin-3-yl) -2-thiazollemethanol
Reference Example 18
- (2-Chloropyridin-3-yl) -2-pyridne Methanol
Reference Example 19
- (2-Chloropyridin-3-yl) -3-pyridinemethanol
Reference Example 20
- (2-Chloropyridin-3-yl) -4-pyridne Methanol
Reference Example 21
A solution of 2-chloro-6-methylnicotinic acid (3.43 g, 20 mmol) in tetrahydrofuran (30 ml) was cooled to -40 C and mixed with a solution of 2.0 M cyclohexylmagnesium chloride in ether (30 ml) . The reaction solution is poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer is washed with brine and dried over anhydrous sodium 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 , 14%) as a brown oily substance.
Reference Example 22
(20.0 g, 93 mmol) was added to a dichloromethane (200 ml) solution of 2-chloro-a cyclohexyl-3-pyridinemethanol (17.0 g, 75 mmol) Lt; / RTI &gt; The reaction solution was mixed with pyrrolidinium chlorochromate (10.0 g, 46 mmol) and stirred at room temperature for 2 hours, then ether was added to the reaction solution and the insoluble matter was removed by filtration. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 2-chloro-3-cyclohexylcarbonylpyridine (14.9 g, 88%) as an oily substance.
Reference Example 23
85% manganese dioxide (25 g, 245 mmol) was added to a toluene (100 ml) solution of a- (2-chloropyridin-3- yl) -2-thiophenemethanol (6.14 g, 27.2 mmol) Heat it. The reaction solution is filtered through celite and the resulting filtrate is concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 2-chloro-3- (2-thiophenecarbonyl) pyridine (5.32 g, 23.8 mmol, 87%).
The following compounds of Reference Examples 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-thiazolecarbonyl) pyridine
Reference Example 26
2-Chloro-3- (2-pyridinedecarbonyl) pyridine
Reference Example 27
2-Chloro-3- (3-pyridinedecarbonyl) 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-pyridinedecarbonyl) pyridine
Reference Example 35
2-ethylamino-3- (3-pyridinedecarbonyl) pyridine
Reference Example 36
2-ethylamino-3- (4-pyridinecarbonyl) pyridine
The following compounds of Reference Examples 37 to 38 are obtained in the same manner as described in Reference Example 15.
Reference Example 37
2-Chloro - - (3-chlorophenyl) -6-trifluoromethyl-3-pyridinemethanol
Reference Example 38
alpha - (3-bromophenyl) -2-chloro-6-trifluoromethyl-3-pyridinemethanol
The following compounds of Reference Examples 39 to 40 were obtained in the same manner as described in Reference Example 23. &lt; Desc /
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 to 42 were obtained in the same manner as described in Reference Example 6. &lt; tb &gt; &lt; TABLE &gt;
Reference Example 41
3- (3-Chlorobenzoyl) -2-ethylamino-6-trifluoromethylpyridine
Reference Example 42
3- (3-Bromobenzoyl) -2-ethylamino-6-trifluoromethylpyridine
Reference Example 43
2-Amino-3-cyano-6-dimethoxymethylpyridine (39.6 g, 0.2 mol) and 12 mL (0.2 mol) of acetaldehyde were dissolved in 400 mL of acetic acid and the resulting solution was treated with 45.5 g of sodium triacetoxyborohydride (0.2 mol) and stirred at room temperature for 2.5 hours. The reaction solution is concentrated under reduced pressure, diluted with chloroform, and washed with 1N aqueous sodium hydroxide solution. The organic layer is dried over anhydrous magnesium sulfate, the magnesium sulfate is removed by filtration, and the filtrate is concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 33.9 g of 3-cyano-2-ethylamino-6-dimethoxymethylpyridine as an oily substance. The yield is 77%.
Reference Example 44
Magnesium (18.6 g, 0.76 mol) was added to 500 ml of tetrahydrofuran in which 146.7 g (0.77 mol) of 3-bromochlorobenzene was dissolved, and the mixture was stirred at room temperature. Since it is an exothermic reaction, stirring is continued until the heat generation is stopped. The reaction solution is cooled to -20 占 폚, mixed with 33.9 g (0.15 mol) of 3-cyano-2-ethylamino-6-dimethoxymethylpyridine and then heated under reflux overnight. The reaction solution is mixed with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer is washed with water and dried over anhydrous magnesium sulfate. After removing the magnesium sulfate by filtration, the solvent was evaporated under reduced pressure to obtain crude 3- (3-chlorobenzoyl) -2-ethylamino-6-dimethoxymethylpyridine.
3- (3-Chlorobenzoyl) -2-ethylamino-6-dimethoxymethylpyridine is diluted with 500 ml of tetrahydrofuran, mixed with 6N hydrochloric acid, and stirred at room temperature for 6 hours. The reaction mixture is adjusted to pH 10 with aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, the magnesium sulfate is removed by filtration, and the resulting filtrate is concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography (hexane-ethyl acetate) to give 3- (3-chlorobenzoyl) -2-ethylaminopyrimidine-6-carbaldehyde.
Reference Example 45
(19.76 g, 0.1 mole) was dissolved in 250 ml of ethanol, and the solution was mixed with 19.15 g (0.11 mole) of 1,1-diethoxy-3-pentanone, Lt; / RTI &gt; After cooling to room temperature, the reaction solution is poured into ice water and extracted with chloroform. The organic layer was washed with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate, and the magnesium sulfate was removed by filtration and the resulting filtrate was concentrated under reduced pressure. Thereafter, the resulting residue was mixed with diethyl ether. The crystals formed were collected by filtration and washed with diethyl ether to obtain 18.50 g of 3- (3-chlorobenzoyl) -6-ethyl-2-pyridone as a crystalline form . The yield is 71%.
The following compounds of Reference Examples 46 and 47 are 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
6-Ethyl-2-pyridone (95.8 g, 366 mmol) was dissolved in 1000 ml of dichloroethane, and 56.4 ml (403 mmol) of triethylamine and 4.52 g 366 mmol) and 76.7 g (403 mmol) of p-toluenesulfonyl chloride were added, followed by stirring at room temperature for 1 hour. The reaction solution is washed with water, 1N hydrochloric acid-brine and dried over anhydrous magnesium sulfate.
The magnesium sulfate is removed by filtration and the resulting filtrate is concentrated under reduced pressure. The resulting residue was then recrystallized from ethyl acetate-hexane to give 139.90 g of 3- (3-chlorobenzoyl) -6-ethyl-2-pyridyl p-toluenesulfonate in crystalline form. The yield is 91.9%.
Reference Example 49
3- (3-Chlorobenzoyl) -6-phenyl-2-pyridyl p-toluenesulfonate
Reference Example 50
3- (3-Chlorobenzoyl) -6-cyclopropyl-2-pyridyl p-toluenesulfonate
Reference Example 51
A solution of 3- (3-chlorobenzoyl) -6-ethyl-2-pyridyl p-toluenesulfonate (26.20 g, 63 mmol) in 400 ml of toluene was mixed with 70% Lt; / RTI &gt; After cooling to room temperature, the reaction solution is concentrated under reduced pressure, diluted with diethyl ether, and washed with water and a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, and magnesium sulfate was removed by filtration, and then the solvent was evaporated under reduced pressure to obtain 19.50 g of 3- (3-chlorobenzoyl) -6-ethyl-2-ethylaminopyridine as an oily substance . The yield is 100%.
The following compounds 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 are 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
(4.16 g, 17.9 mmol) was dissolved in 100 ml of 1,2-dichloroethane and the solution was treated with 6.0 ml (43 mmol) of triethylamine ), 600 mg (492 mmol) of 4-dimethylaminopyridine and 6.00 g (31.6 mmol) of p-toluenesulfonyl chloride and stirred at an oil temperature of 70 ° C for 2 hours. After cooling to room temperature, it is mixed with water and extracted with chloroform. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine, dried over anhydrous magnesium sulfate, and the magnesium sulfate was removed by filtration and then concentrated under reduced pressure to obtain partially purified 6-ethyl- -Methylcyclohexyl) carbonyl] -2-pyridyl p-toluenesulfonate. This partially purified product is dissolved in 100 ml of toluene and the solution is mixed with 20 ml of 70% ethylamine aqueous solution and heated under reflux for 8 hours. Thereafter, 20 ml of 70% ethylamine aqueous solution is added and the mixture is heated under reflux overnight. After cooling to room temperature, 1N hydrochloric acid was added to adjust the pH to 1, and the mixture was stirred for 15 minutes. It is neutralized with 1N aqueous sodium hydroxide solution and then extracted with chloroform. The organic layer is washed with brine, dried over anhydrous sodium sulfate, filtered off to remove sodium sulfate, and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography (ethyl acetate-hexane) to obtain 2.60 g of 6-ethyl-2-ethylamino-3 - [(3-methylcyclohexyl) carbonyl] pyrimidine. The yield is 56%.
Reference Example 57
The following compounds are obtained in the same manner as described in reference example 56. &lt; Desc /
Methyl-2-ethylamino-4 - [(3-methylcyclohexyl) carbonyl] pyrimidine
The following compounds of Reference Examples 58 and 59 were obtained in the same manner as described in Reference Example 4. &lt; tb &gt; &lt; TABLE &gt;
Reference Example 58
2-Chloro-3- (3-chlorobenzoyl) -6-methylpyridine
Reference Example 59
2-Chloro-6-methyl-3- (3-methylbenzoyl) 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) pyridine
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 compounds are obtained in the same manner as described in Reference Example 4. [
3-Benzoyl-2-chloro-6-methylpyridine
Reference Example 65
3-Benzoyl-2-chloro-6-methylpyridine (3.00 g, 12.9 mmol) dissolved in 1.0 ml of concentrated sulfuric acid was cooled to 5 캜 and 1.0 ml of fuming nitric acid was slowly added dropwise and stirred for 30 minutes. The reaction solution is poured into ice water, neutralized with aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer is 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-diisopropyl ether to give 1.81 g of 2-chloro-6-methyl-3- (3-nitrobenzoyl) do.
Reference Example 66
The following compounds are obtained in the same manner as described in Reference Example 6. &lt; tb &gt; &lt; TABLE &gt;
2-ethylamino-6-methyl-3- (3-nitrobenzoyl) pyridine
Reference Example 67
The following compounds are obtained in the same manner as described in reference example 45. &lt; Desc /
6-methyl-3- (1-naphthylcarbonyl) -2-pyridone
Reference Example 68
The following compounds are obtained in the same manner as described in reference example 48:
6-methyl-3- (1-naphthylcarbonyl) -2-pyridyl p-toluenesulfonate
Reference Example 69
The following compounds are obtained in the same manner as described in reference example 51. &lt; Desc /
2-ethylamino-6-methyl-3- (1-naphthylcarbonyl) pyridine
Example 1
(0.8 ml, 9 mmol) was added to a solution of 3- (3-chlorobenzoyl) -6-ethyl-2-ethylaminopyridine (2.6 g, 9 mmol) in tetrahydrofuran (50 ml) under ice- , And the mixture is stirred under ice-cooling for 1 hour. To the reaction solution were added water and a saturated aqueous sodium bicarbonate solution in this order, and the mixture was stirred at room temperature for 30 minutes. The pH is adjusted to 10 with 1N aqueous sodium hydroxide solution and extracted with chloroform. After 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. The resulting residue was then purified by silica gel column chromatography (hexane-ethyl acetate) to give 4- (3-chlorophenyl) -1,7-diethylpyrido [2,3- d] pyrimidin- ) -One (1.7 g, 60%) in crystalline form.
The following compounds of Examples 2 to 8 were obtained in the same manner as described in Example 1. &lt; tb &gt; &lt; TABLE &gt;
Example 2
Diethylpyrido [2,3-d] pyrimidin-2 (lH) -one To a solution of 4- (3-bromophenyl)
Example 3
Methylpyrido [2,3-d] pyrimidin-2 (1H) -one
Example 4
Methyl-pyrido [2,3-d] pyrimidin-2 (1H) -one
Example 5
Methyl-4- (3-methylphenyl) -pyrido [2,3-d] pyrimidin-2 (1H)
Example 6
(3-methylphenyl) pyrido [2,3-d] pyridin-2 (1H) -one
Example 7
7-methylpyrido [2,3-d] pyrimidin-2 (1H) -one
Example 8
L-ethylpyrido [2,3-d] pyrimidin-2 (1H) -one
Example 9
Chlorosulfonyl isocyanate (0.5 ml, 5.6 mmol) was added to a solution of 2-ethylamino-3- (2-thiophenecarbonyl) pyridine (1.01 g, 4.35 mmol) in tetrahydrofuran (50 ml) Stir for 30 minutes. The reaction solution is mixed with water and extracted with chloroform. The organic layer is washed with brine and dried over anhydrous sodium sulfate. After filtering off the sodium sulfate, the resulting filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform-ethyl acetate) and recrystallized from ethyl acetate to give 1-ethyl-4- (2-thienyl ) Pyrido [2,3-d] pyrimidin-2 (1H) -one (613 mg, 2.38 mmol, 55%).
The following compounds of Examples 10 to 16 were obtained in the same manner as described in Example 9. [
Example 10
Pyrido [2,3-d] pyrimidin-2 (1H) -one
Example 11
Pyrido [2,3-d] pyrimidin-2 (1H) -one
Example 12
Pyridyl) pyrido [2,3-d] pyrimidin-2 (1H) -one
Example 13
Pyridyl) pyrido [2,3-d] pyrimidin-2 (1H) -one
Example 14
Pyridyl) pyrido [2,3-d] pyrimidin-2 (1H) -one
Example 15
7-Trifluoromethylpyrido [2,3-d] pyrimidin-2 (1H) -one Synthesis of 4- (3-chlorophenyl)
Example 16
Trifluoromethylpyrido [2,3-d] pyrimidin-2 (1H) -one To a solution of 4- (3-bromophenyl)
Example 17
The following compounds are obtained in the same manner as described in Example 1. &lt; RTI ID = 0.0 &gt;
4- (3-Chlorophenyl) -1-ethyl-2-oxo-1,2-dihydropyrido [2,3- d] pyrimidine- 7- carbaldehyde
Example 18
Sodium borohydride (35 mg, 0.9 mmol) was added to a solution of 1.16 g of 4- (3-chlorophenyl) -1- ethylpyrido [2,3- d] pyrimidin-2 (1H) 3.7 mmol) and ethanol (20 ml), and the mixture was stirred under ice-cooling for 30 minutes. The reaction solution is mixed with acetone and concentrated under reduced pressure, the resulting residue is mixed with water and extracted with chloroform. The chloroform layer is dried over anhydrous magnesium sulfate, the magnesium sulfate is filtered off and the resulting filtrate is concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography (hexane-ethyl acetate-chloroform) and further recrystallized from acetonitrile-ethanol to give 4- (3-chlorophenyl) -1-ethyl-7- Pyrido [2,3-d] pyrimidin-2 (1H) -one. The yield is 23%.
Example 19
(3-chlorophenyl) -1-ethylpyrido [2,3-d] pyrimidin-2 (1H) -one-7 -Carbaldehyde (4.4 g, 14 mmol) and stirred for 30 minutes under ice-cooling. Thereafter, 7 ml (7 mmol) of 1 M bromomethyl magnesium was added and the mixture was stirred under ice-cooling for 30 minutes. Thereafter, a saturated ammonium chloride aqueous solution is added and extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate, the magnesium sulfate is filtered off and the resulting filtrate is concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate-chloroform) to give 4- (3-chlorophenyl) -1-ethyl-7- (1- hydroxyethyl) pyrido [ -d] pyrimidin-2 (lH) -one. &lt; / RTI &gt; The yield is 30%.
Example 20
2,3-d] pyrimidin-2 (1 H) -quinolinone (1.00 g) was added to a solution of 4- (3-chlorophenyl) -One, and the mixture is heated under reflux for 1 hour. The reaction solution is mixed with 1.00 g of manganese dioxide, heated under reflux for 1 hour, mixed again with 500 mg of manganese dioxide and heated under reflux for 1 hour. The insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate-chloroform) to obtain 7-acetyl-4- (3- chlorophenyl) Pyrido [2,3-d] pyrimidin-2 (1H) -one. The yield is 84%.
The following compounds of Examples 21 and 22 were obtained in the same manner as described in Example 1. &lt; tb &gt; &lt; TABLE &gt;
Example 21
7-phenylpyrido [2,3-d] pyrimidin-2 (1H) -one
Example 22
Preparation of 4- (3-chlorophenyl) -7-cyclopropyl-1-ethylpyrido [2,3- d] pyrimidin-
Example 23
200 mg of N-bromosuccinimide (8.94 g, 50.2 mmol) and 2,2'-azobis (isobutyronitrile) were added to a solution of 4- (3-chlorophenyl) -1,7- Is added to a solution of 15.0 g (47.8 mmol) of [2,3-d] pyrimidin-2 (1H) -one and heated under reflux for 3 hours. The reaction solution was mixed again with 1.28 g (7.17 mmol) of N-bromosuccinimide and 100 mg of 2,2'-azobis (isobutyronitrile) and heated under reflux for 1 hour. After cooling to room temperature, the insoluble material is removed by filtration, and the resulting filtrate is mixed with water and extracted with carbon tetrachloride. The organic layer is washed with brine and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 7- (bromoethyl) -4- (3-chlorophenyl) -1 -Ethylpyrido [2,3-d] pyrimidin-2 (1H) -one in crystalline form. The yield is 61%.
Example 24
10 mg of N-bromosuccinimide (590 mg, 3.3 mmol) and 2,2'-azobis (isobutyronitrile) were added to a solution of 4- (3-chlorophenyl) -1,7-diethylpyrido (3 mmol) of [2,3-d] pyrimidin-2 (1H) -one and heated under reflux for 5 hours. The reaction solution is again mixed with 210 mg (1.2 mmol) of N-bromosuccinimide and heated under reflux overnight.
The insoluble matter is removed by filtration, the resulting filtrate is mixed with water and extracted with carbon tetrachloride. The organic layer is washed with brine, dried over anhydrous magnesium sulfate, the magnesium sulfate is removed by filtration, and the resulting filtrate is concentrated under reduced pressure. The thus obtained residue is mixed with 10 ml of methanol and 300 mg of sodium acetate and heated under reflux overnight. The reaction solution is 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 the resulting filtrate was concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography (hexane-ethyl acetate) to give 7- (1-acetoxyethyl) -4- (3-chlorophenyl) -1-ethylpyrido [2,3- d ] Pyrimidin-2 (1H) -one in crystalline form. The yield is 47%.
Example 25
2,3-d] pyrimidin-2 (1H) - pyrimidin-3-ylmethyl) -piperidine- Was added to 6.78 g (18.2 mmol) of N, N-dimethylformamide, and the mixture was stirred at room temperature for 20 minutes. The reaction solution is neutralized with 1N hydrochloric acid and extracted with chloroform. The organic layer is washed with brine, dried over anhydrous magnesium sulfate, the magnesium sulfate is filtered off and the resulting filtrate is concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (chloroform) to give 4- (3-chlorophenyl) -1-ethyl-7- (1-hydroxyethyl) pyrido [2,3-d] pyrimidine -2 (1H) -one &lt; / RTI &gt; in crystalline form. The yield is 75%.
The following compounds of Examples 26 and 27 were obtained in the same manner as described in Example 1. &lt; tb &gt; &lt; TABLE &gt;
Example 26
Methyl-4- (3-methylcyclohexyl) -pyrido [2,3-d] pyrimidin-2 (1H)
Example 27
(3-methylcyclohexyl) -pyrido [2,3-d] pyrimidin-2 (1H) -one
Example 28
(3.00 g, 13.5 mmol) was added dropwise to a suspension of 2.00 g (0.60 mmol) of 4- (3-chlorophenyl) -1-ethyl-7-methylpyrido [ 6.60 mmol) and heated at reflux for 6 hours. The reaction solution is cooled to room temperature, mixed with saturated sodium bicarbonate and extracted with chloroform. The organic layer is washed with brine, dried over anhydrous magnesium sulfate, the magnesium sulfate is filtered off and the resulting filtrate is concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography (hexane-chloroform) and further recrystallized from ethyl acetate-diisopropyl ether to give 4- (3-chlorophenyl) -1-ethyl- [2,3-d] pyrimidin-2 (1H) -thione was obtained. The yield is 54%.
The following compounds of Examples 29-34 were obtained in the same manner as described in Example 1. &lt; Desc /
Example 29
Dimethyl-1-ethylpyrido [2,3-d] pyrimidin-2 (1H) -one
Example 30
Methyl-1-propylpyrido [2,3-d] pyrimidin-2 (1H) -one
Example 31
7-methylpyrido [2,3-d] pyrimidin-2 (1H) -one
Example 32
Methyl-4- (3-methylphenyl) -1-propylpyrido [2,3-d] pyrimidin-2 (1H)
Example 33
Methyl-4- (3-methylphenyl) pyrido [2,3-d] pyrimidin-2 (1H)
Example 34
Cyclohexyl-1,7-diethylpyrido [2,3-d] pyrimidin-2 (1H) -one
Example 35
The following compound is obtained as a by-product of Example 5.
Methyl-4- (3-methylphenyl) pyrido [2,3-d] pyrimidin-2 (1H)
Example 36
2,3-d] pyrimidine-7-carbaldehyde (900 mg, 2.9 mmol) was dissolved in 10 ml of methanol. To this solution was added dropwise a solution of 4- (3-chlorophenyl) , 420 mg (6.0 mmol) of hydroxyamine hydrochloride and 550 mg (6.7 mmol) of sodium acetate are added, and the mixture is stirred at room temperature overnight. The insoluble material was washed with water and chloroform and recrystallized from dimethylformamide-acetonitrile to obtain 4- (3-chlorophenyl) -1-ethyl-7-hydroxyiminomethylpyrido [2,3-d] pyrimidine- 2 (1H) -one.
Example 37
The following compounds are obtained in the same manner as described in Example 1. &lt; Desc /
Methyl-4- (3-nitrophenyl) -pyrido [2,3-d] pyrimidin-2 (1H)
Example 38
The following compounds are obtained in the same manner as described in Example 23. &lt; RTI ID = 0.0 &gt;
7- (3-chlorophenyl) -1-ethylpyrido [2,3-d] pyrimidin-2 (1H)
Example 39
The following compounds are obtained as by-products of Example 1.
6-chloro-4 (3-chlorophenyl) -1,7-diethylpyrido [2,3- d] pyrimidin-
Example 40
Potassium thioacetate (.54 g, 48 mmol) was added to a solution of 7- (1-bromoethyl) -4- (3-chlorophenyl) -1-ethylpyrido [2,3- Methyl-1H-indol-2 (1H) -one (1.57 g, 40 mmol) and stirred at room temperature for 2 hours. The reaction solution is mixed with ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulfate. Magnesium sulfate is removed by filtration and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 7- (1-acetylthioethyl) -4- (3-chlorophenyl) -1-ethylpyrido [2,3- d] pyrimidin- (LH) -one (1.13 g, 73%).
Example 41
The following compounds are obtained in the same manner as described in example 28. &lt; Desc /
(3-chlorophenyl) -1,7-diethylpyrido [2,3-d] pyrimidin-2 (1H)
Example 42
The following compounds are obtained in the same manner as described in Example 1. &lt; Desc /
Methyl-4- (1-naphthyl) pyrido [2,3-d] pyrimidin-2 (1H)
Example 43
(1.62 g, 495 mmol) and methyl orthoformate (30 ml) were added to a solution of 30 ml of methanol , A catalytically effective amount of DOWEX-50W-X4 was added, and the mixture was heated under reflux overnight. After cooling to room temperature, the insoluble material is removed by filtration and the solvent is evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (toluene-ethyl acetate) and recrystallized from diisopropyl ether to give 4- (3-chlorophenyl) -1-ethyl-7- (1,1-dimethoxyethyl) (69%) of [2,3-d] pyrimidin-2 (1H) -one.
The physical properties of the compounds obtained in the Reference Examples and Examples are shown in Tables 3 and 4. [
In the table,
Rex. No. means a reference number;
Ex. No. means an embodiment number;
NMR was measured at 400 MHz at room temperature using TMS as the internal standard and DMSO-d ₆ (reference examples 45 to 47) or CSCl ₃ (all examples and reference examples excluding 45 to 47) as NMR solvent Nuclear magnetic resonance spectrum;
mp means melting point;
Anal. Refers to ingredient analysis data;
calcd. means the calculated value,
found means experimental data;
Et means ethyl group;
Ac means acetyl group;
iPr means isopropyl group;
dec. means decomposition.






In Tables 5, 6 and 7 below, the chemical structures of the compounds obtained in the Examples are tabulated and presented with the classification according to the type of compound.
In the table,
Ex., No., iPr, and Ac are as described above,
Me means a methyl group,
nPr means the normal profile group,
cPr means cyclopropyl group,
cHex means a cyclohexyl group,
Ph means a phenyl group,
Naph means a naphthyl group,
Py means pyridyl group.
Example No.R ¹ R ² R ⁶OneMeatMeatCl 2MeatMeatBr 3MeatMeCl 4MeatMeBr 5MeatMeMe 6MeatMeatMe 30nPrMeCl 32nPrMeMe
Example No.R ¹ R ² R ³ R ⁴ R ⁶ X 15Meat-CF ₃ HHClO 16Meat-CF ₃ HHBrO 17Meat-CHOHHClO 18Meat-CH ₂ OHHHClO 19Meat-CH (OH) CH ₃ HHClO 20MeatAcHHClO 21MeatPhHHClO 22MeatcPrHHClO 23Meat-CHBrCH ₃ HHClO 24Meat-CH (OAc) CH ₃ HHClO 25Meat-CH (OH) CH ₃ HHClO 28MeatMeHHClS 29MeatMeMeHBrO 31-CH ₂ -cPrMeHHClO 33-CH ₂ -cPrMeHHMeO 35MeatMeClHMeO 36Meat-CH = N-OHHHClO 37MeatMeHHNO ₂ O 38Meat-CH ₂ BrHHClO 39MeatMeatClHClO 40Meat-CH (SAc) CH ₃ HHClO 41MeatMeatHHClS 43Meat-C (OMe) ₂ CH ₃ HHClO
Example No.R ¹ R ² R ³ R ⁴ R ⁵ X 7MeatMeHHcHexO 8MeatHHHcHexO 9MeatHHH2-thienylO 10MeatHHH3-thienylO 11MeatHHH2-thiazolylO 12MeatHHH2-PyO 13MeatHHH3-PyO 14MeatHHH4-PyO 26MeatMeHH3-Me-cHexO 27MeatMeatHH3-Me-cHexO 34MeatMeatHHcHexO 42MeatMeHH1-NaphO
In addition to the compounds of the examples described above, other compounds of the invention are shown in Tables 8 and 9. These compounds can be synthesized according to any of the methods described in the above-described preparation methods, preparation methods and examples, and modified methods known to those skilled in the art without special experimentation.
Some of the compounds shown in Table 8 exist in various isomeric forms. All of the mixtures or isomers in the free form are included in the present invention.
In the table,
Me, Et, nPr, iPr, cPr, Ac, Ph, Naph and Py are as defined above,
Respectively, Compnd. No. denotes a compound number,
cBu means cyclobutyl group,
cPe means a cyclopentyl group,
cHep means a cycloheptyl group.
Compound No.R ¹ R ² R ³ R ⁴ R ⁵ X OneMeatMeatHHCF ₃ O 2MeatMeHHCF ₃ O 3MeatMeatHHOHO 4MeatMeHHOHO 5MeatMeatHHOMeO 6MeatMeHHOMeO 7MeatMeatHHCNO 8MeatMeHHCNO 9MeatMeatHHNO ₂ O 10MeatMeatHHFS 11MeatMeHHFS 12MeatMeatHHBrS 13MeatMeHHBrS 14MeatMeatHHMeS 15MeatMeHHMeS 16MeatMeatHHCF ₃ S 17MeatMeHHCF ₃ S 18MeatMeatHHOHS 19MeatMeHHOHS 20MeatMeatHHOMeS 21MeatMeHHOMeS 22MeatMeatHHCNS 23MeatMeHHCNS
24MeatMeatHHNO ₂ S 25MeatMeHHNO ₂ S 26MeatFHHClO 27MeatFHHClS 28MeatClHHClO 29MeatClHHClS 30MeatBrHHClO 31MeatBrHHClS 32nPrcPrHHClO 33nPrcPrHHClS 34MeatcPrHHClS 35MeatcPrHHBrO 36MeatcPrHHBrS 37MeatcPrHHMeO 38MeatcPrHHMeS 39MeatcBuHHClO 40MeatcBuHHClS 41MeatcPeHHClO 42MeatcPeHHClS 43MeatcHexHHClO 44MeatcHexHHClS 45MeatcHepHHClO 46MeatcHepHHClS 47Meat-CHFCH ₃ HHClO 48Meat-CHFCH ₃ HHClS 49Meat-CHClCH ₃ HHClO 50Meat-CHClCH ₃ HHClS 51Meat-CH (OH) CH ₃ HHClS 52Meat-CH (OH) CH ₃ HHBrO 53Meat-CH (OH) CH ₃ HHBrS
54Meat-CH (OH) CH ₃ HHMeO 55Meat-CH (OH) CH ₃ HHMeS 56Meat-CH ₂ OAcHHClO 57Meat-CH ₂ OAcHHClS 58Meat-CH (SAc) CH ₃ HHClS 59Meat-CH (SAc) CH ₃ HHBrO 60Meat-CH (SAc) CH ₃ HHBrS 61Meat-CH = N-OHHHClS 62Meat-CH = N-OHHHBrO 63Meat-CH = N-OHHHBrS 64Meat-CH = N-OHHHMeO 65Meat-CH = N-OHHHMeS 66Meat-CH = N - OMeHHClO 67Meat-CH = N - OMeHHClS
Compound No.R ¹ R ² R ³ R ⁴ R ⁶ X 68MeatcPrHHcHexO 69MeatcPrHHcHexS 70MeatCF ₃ HHcHexO 71MeatCF ₃ HHcHexS 72Meat-CHBrCH ₃ HHcHexO 73Meat-CHBrCH ₃ HHcHexS 74Meat-CH (OH) CH ₃ HHcHexO 75Meat-CH (OH) CH ₃ HHcHexS 76Meat-CH (SAc) CH ₃ HHcHexO 77Meat-CH (SAc) CH ₃ HHcHexS 78Meat-CH = N-OHHHcHexO 79Meat-CH = N-OHHHcHexS 80MeatcPrHH3-Me-cHexO 81MeatcPrHH3-Me-cHexS 82MeatCF ₃ HH3-Me-cHexO 83MeatCF ₃ HH3-Me-cHexS 84Meat-CHBrCH ₃ HH3-Me-cHexO 85Meat-CHBrCH ₃ HH3-Me-cHexS 86Meat-CH (OH) CH ₃ HH3-Me-cHexO 87Meat-CH (OH) CH ₃ HH3-Me-cHexS 88Meat-CH (SAc) CH ₃ HH3-Me-cHexO 89Meat-CH (SAc) CH ₃ HH3-Me-cHexS 90Meat-CH = N-OHHH3-Me-cHexO 91Meat-CH = N-OHHH3-Me-cHexS 92MeatMeatHH3-Cl-cHexO
93MeatMeatHH3-Cl-cHexS 94MeatMeatHH3-Br-cHexO 95MeatMeatHH3-Br-cHexS 96MeatMeatHH5-Cl-2-thienylO 97MeatMeHH5-Cl-2-thienylO 98MeatMeatHH5-Br-2-thienylO 99MeatMeHH5-Br-2-thienylO 100MeatMeatHH5-Me-2-thienylO 101MeatMeHH5-Me-2-thienylO 102MeatMeatHH4-Cl-2-thiazolylO 103MeatMeHH4-Cl-2-thiazolylO 104MeatMeatHH4-Br-2-thiazolylO 105MeatMeHH4-Br-2-thiazolylO 106MeatMeatHH4-Me-2-thiazolylO 107MeatMeHH4-Me-2-thiazolylO 108MeatMeatHH6-Cl-2-PyO 109MeatMeHH6-Cl-2-PyO 110MeatMeatHH6-Br-2-PyO 111MeatMeHH6-Br-2-PyO 112MeatMeatHH6-Me-2-PyO 113MeatMeHH6-Me-2-PyO 114MeatMeatHH2-Cl-6-pyrimidinylO 115MeatMeHH2-Cl-6-pyrimidinylO 116MeatMeatHH2-Br-6-pyrimidinylO 117MeatMeHH2-Br-6-pyrimidinylO 118MeatMeatHH2-Me-6-pyrimidinylO 119MeatMeHH2-Me-6-pyrimidinylO 120MeatMeatHH4-benzofurylO 121MeatMeHH4-benzofurylO 122MeatMeatHH4-benzothienylO 123MeatMeHH4-benzothienylO 124MeatMeatHH4-benzoxazolylO 125MeatMeHH4-benzoxazolylO
126MeatMeatHH4-benzothiazolylO 127MeatMeHH4-benzothiazolylO 128MeatMeatHH5-quinolylO 129MeatMeHH5-quinolylO
The compound of the present invention represented by the formula (I) or a pharmaceutically acceptable salt thereof has excellent activity for inhibiting the type IV PDE, and this activity is useful as a medicine since it is selective for the type IV PDE.
As a result, the compounds of the present invention can be used for the prevention and treatment of various diseases involving type IV PDE. The following is an illustration of the type of this disease.
· Respiratory diseases [eg, bronchial asthma (including hypersensitive asthma), chronic bronchitis, pneumonia, adult respiratory distress syndrome (ARDS)
· Inflammatory diseases (eg, atopic dermatitis, conjunctivitis, urticaria, AIDS, keloid formation, rhinitis, iridocylitis, ), Gingivitis, peridontitis, alveolar pyorrhea, gastritis, ulcerative colitis, Crohn disease, gastrointestinal ulcer, esophagitis, Myositis, encephalitis, myasthenia gravis, mutiple sclerosis, and neuritis), hepatitis, cicatrization, proliferative (e. G. Nephritis, peritonitis, pleuritis, scleritis, scleroderma, burns and the like diseases, including proliferative nephritis,
Systemic or localized arthropathy [e.g., osteoarthrosis, gouty arthritis, chronic rheumatoid arthritis, rheumatoid arthritis, psoriatic arthritis and the like]
Proliferative diseases (for example, malignant tumors, leukemia, proliferative dermatoses (keratosis and various types of dermatitis), collagen diseases and the like diseases]
Learning, memory and cognitive disorders associated with neurodegeneration such as Alzheimer's disease, Parkinson's disease and its like disorders, multiple lateral sclerosis, acute demyelinating neuritis ), Muscular dystrophy and similar diseases]
Manic-depressive psychosis, schizoid, anxiety, panic disorder and the like), psychotic dysfunction (for example, manic-depressive psychosis, schizoid,
· Inflammation due to organ transplantation and the like [eg, reperfusion injury, graft versus host reaction and the like]
For example, cardiac arrest, spinal cord injury, intermittent claudication, isochemic disease, such as angina pectoris, and the like. Myocardial infarction, stroke, cerebral anomalies and the like) and similar diseases]
· Disorders related to urination (eg, diabetes insipidus, urethritis, urinary incontinence, cystitis, irritable bladder, neuropsychiatric bladder, uremia, tubular disorder, urinary incontinence polloakiuria, urinary retention and similar diseases]
Diabetic nephropathy, diabetic neuropathy, amyloidosis, pancreatitis, thyroiditis, obesity, prostatic hypertrophy, and the like diseases, including diabetic retinopathy, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, ],
(Eg, psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, sepsis) associated with tumor necrosis factor (TNF) and other cytokines (IL-1, IL-6 and the like) ), Septic shock, endotoxic shock, gram negative bacillary sepsis, toxic shock symptoms, nephritis, hepatitis, (bacterial and viral) infections, heart failure, arteriosclerosis, myocardial infarction infarction, seizures) and similar diseases]
In the case of autoimmune diseases (eg systemic lupus, erythematosus, atrophic gastritis, thyroid disease, glomerulonephritis, orchitis, adrenal disease, hemolytic anemia, oophoritis oophoritis and similar diseases],
Cardiovascular diseases (for example, hypertension, angina pectoris, heart failure, myocarditis, epicarditis, endocarditis, valvulitis and the like)
[0003] In the case of vasculopathy and vascular diseases (for example, angitis, aneurysm, vascular endothelial damage, thrombosis, granuloma, cerebrovascular inflammation, arteriosclerosis, peripheral vascular inflammation, leukopenia, Thrombocytopenia, sarcoidosis, and the like)
(Eg, contact dermatitis, seropositivity, drug allergy, Goodpasture syndrome, lymphomatosis, rheumatic fever, AIDS, anaphylactic shock) and diseases associated with immune allergic reactions ,
· Other diseases [glaucoma, spastic paralysis, impotence, pain disorders (eg bruises, headaches and the like), cervico-omo-branchial syndrome, kidney disease, Kidney failure, liver failure and obesity].
The compounds I of the present invention are particularly
Respiratory diseases [e.g., bronchial asthma (including hypersensitive asthma), chronic bronchitis, pneumonia, ARDS and similar diseases]
Inflammatory diseases such as hypersensitivity dermatitis, conjunctivitis, urticaria, AIDS, seaweed formation, rhinitis, iridocyclitis, gingivitis, dichromatitis, dental pyoderma, gastritis, ulcerative colitis, Crohn's disease, gastric ulcer, esophagitis , Nephritis, peritonitis, pleurisy, scleritis, scleritis, burns and the like, including myositis, encephalitis (gastric paralytic myasthenia gravis, multiple sclerosis and neuritis), hepatitis, scarring, proliferative nephritis, and
(Such as psoriasis, rheumatoid arthritis, ulcerative colitis, Crohn &apos; s disease, septicemia, septic shock, intestinal metaplasia (TNF) and other cytokines (IL-1, IL-6 and the like) (Heart failure, atherosclerosis, myocardial infarction, seizure), and the like), and the like, which are caused by a variety of diseases such as asthma, chronic obstructive pulmonary disease, and the like.
More particularly, the compounds of the present invention are useful as excellent preventive and therapeutic agents for respiratory diseases such as bronchial asthma and the like.
In addition, the compounds of the present invention exhibit an extremely weak vomiting action as compared to the prior phosphodystearase inhibitors, and are therefore particularly useful for the treatment or prevention of diseases in patients requiring systemic administration.
The activity of the compounds of the present invention to inhibit Type IV and Forms I, II, III, and V phosphodystearases is demonstrated by the following tests.
Phosphodiesterase inhibitory activity measurement test (in vitro)
(1) Method for measuring IV inhibitory activity of phosphodiesterase
The following assay is used to evaluate the ability of the compounds of the invention to inhibit type IV phosphodiesterase inhibition.
1) Physiological saline supplemented with dextran (3%) (200 ml) is added to 500 ml of healthy human peripheral blood supplemented with heparin and incubated at 37 ° C for 40 minutes to precipitate red blood cells. After erythrocyte precipitation, the supernatant was collected and centrifuged once, and the resulting precipitate was suspended in buffer A (140 ml of NaCl, 5 mM of KCl, 5 mM of glucose and 10 mM of HEPES, pH 7.4), and the solution for concentration gradient centrifugation Ficoll solution) and centrifuged at 450 xg for 40 minutes at room temperature to isolate mononuclear and granulocyte fractions. The granulocyte fraction was rinsed once with buffer B (NaCl 140 mM, KCl 5 mM, CaCl ₂ 1 mM, MgCl ₂ 1 mM, glucose 5 mM and HEPES 10 mM, pH 7.4) and incubated with protease inhibitor (phenyl- methylsulfonyl- (Bis-Tris 20 mM, dithioerythritol 5 mM, EGTA 2 mM and sodium acetate 50 mM, pH 6.5) containing 5 uM of peptatin A, 40 uM of rupeptin, 20 uM of aprotinin or 2 mM of benjaminidine, The cells are pulverized using a polytron and an ultrasonic sonicator and ultracentrifuged (4 ° C., 100,000 × g, 60 minutes) to obtain a solution fraction.
2) The resulting solution fraction is applied to a 1.6 x 10 cm column filled with Q Sepharose equilibrated with Buffer C. Next, the column is washed with 300 ml of Buffer C to remove non-adsorbed proteins. Sodium acetic acid Phosphodiesterase was eluted using 200 ml of Buffer C with a linear gradient of 0.05-1.25 M to obtain 40 fractions each containing 5.0 ml eluate. For each fraction, cAMP- and cGMP-metabolizing activity is investigated. The fraction lacking the cGMP-metabolizing activity but having the cAMP-metabolic activity and disappearing the metabolic activity by 10 uM of rolipram (IV type phosphodiesterase selective inhibitor) was collected and tested for inhibitory activity of the IV type phosphodiesterase As stock solution.
3) Each of the predetermined amounts of each compound to be tested was incubated at 30 占 폚 with Tris-HCl 40 mM (pH 8.0), MgCl2 5 mM, ₂ mM mercaptoethanol 4 mM, cilostamide (type III phosphodiesterase 0.0 &gt; uM, &lt; / RTI &gt; cAMP 1 uM, ³ H-cAMP 10 nM, and IV phosphodiesterase mother liquor. The reaction solution is heated at 90 占 폚 for 1 minute, cooled in an ice bath, mixed with a first unit of 5'-nucleotide, reacted at 30 占 폚 for 10 minutes, and 1 ml of methanol is added to terminate the reaction. The reaction solution is applied to a Dowex 1 x 8 column to adsorb the non-hydrolyzed material and measure the radioactivity.
4) The concentration of each compound to be tested, which inhibits 50% of metabolic activity of type IV phosphodiesterase, is measured and expressed as IC ₅₀ .
Test Results: The results of measuring the activity of the compounds of the present invention to inhibit type IV PDE are shown in Tables 1 and 2 together with the results of the exemplifying compounds described in the above-mentioned U.S. patents and similar comparative compounds individually synthesized .
compound Type IV PDE inhibitory activity IC ₅₀ (nM) Example 19 8.08 Example 22 7.80 Example 33 6.19 Example 34 1.47 Example 36 0.93 Example 37 4.75 Example 40 5.79 Example 41 0.85
Test compound Type IV PDE inhibitory activity IC ₅₀ (nM) R ¹ R ² R Example 1 -CH ₂ CH ₃ -CH ₂ CH ₃ m-Cl 0.81 Example 2 -CH ₂ CH ₃ -CH ₂ CH ₃ m-Br 1.15 Example 3 -CH ₂ CH ₃ -CH ₃ m-Cl 2.32 Example 4 -CH ₂ CH ₃ -CH ₃ m-Br 1.45 Example 5 -CH ₂ CH ₃ -CH ₃ m-Ch ₃ 3.50 Example 6 -CH ₂ CH ₃ -CH ₂ CH ₃ m-CH ₃ 3.70 Comparative compound 1 -CH ₂ CH ₃ -H o-Cl 2842 Comparative compound 2 -CH (CH _{3) 2} -H p-Cl > 3000 Comparative compound 3 -CH ₂ CH ₃ -H p-Cl > 3000 Comparative compound 4 -CH (CH _{3) 2} -H m, p-diCl > 3000 Comparative compound 5 -CH ₂ CH ₃ -H m, p-diCl > 3000 Comparative compound 6 -CH (CH _{3) 2} -H m-Cl 803 Comparative Compound 7 -CH ₂ CH ₃ -H m-Cl 308 Comparative compound 8 -CH ₂ CH ₃ -H m-CH ₃ 612
Comparative Compound 1: 4- (2-chlorophenyl) -1-ethylpyrido [2,3-d] pyrimidin-2 (1H) -one; Mp 134-135 [deg.] C (AcOEt-hexane)
Comparative Compound 2: The compound of Example 5f
Comparative Compound 3: 4- (4-chlorophenyl) -1-ethylpyrido [2,3-d] pyrimidin-2 (1H) -one; Melting point, 221-222 [deg.] C (AcOEt-hexane)
Comparative Compound 4: The compound of Example 5e
Comparative Compound 5: 4- (3,4-dichlorophenyl) -1-ethylpyrido [2,3-d] pyrimidin-2 (1H) -one; Melting _{point, 236-239 ℃ (AcOEt-iPr 2} O)
Comparative Compound 6: 4- (3-chlorophenyl) -1-isopropylpyrido [2,3-d] pyrimidin-2 (1H) -one; Melting _{point, 169-171 ℃ (AcOEt-iPr 2} O)
Comparative Compound 7: 4- (3-chlorophenyl) -1-ethylpyrido [2,3-d] pyrimidin-2 (1H) -one; Melting point, 154-156 &lt; 0 &gt; C (AcOEt-hexane)
Comparative Compound 8: 4- (3-methylphenyl) -1-ethylpyrido [2,3-d] pyrimidin-2 (1H) -one; Melting point, 148-149 [deg.] C (AcOEt-hexane)
As is apparent from the test results, the compounds of the present invention have remarkably high type IV PDE inhibitory activity.
In particular, compounds having a substituent of the phenyl group at the 4-position in the ortho or para position in the 4- (substituted phenyl) -1 -substituted pyrido [2,3-d] pyrimidin- The compounds have extremely low IV type PDE inhibitory activity. This can be referred to as a di-substituted compound at para and meta positions. Conversely, compounds having substituents only at the meta position (comparison compounds) have a one-fold higher activity than ortho-, para- or di-substituted compounds. Additionally, the compounds of the present invention wherein the 4-position phenyl group only has a substituent at the meta position and the lower alkyl group is introduced at the 7-position are useful for the inhibition of type IV PDE It is remarkable.
As a result, 4- (substituted phenyl) -1 -substituted pyrido [2,3-d] pyrimidines in which the 4-position phenyl group is only substituted at the meta position and a lower alkyl- Among the compounds of the present invention, especially those compounds shown in Table 2 [including compound II of the present invention], which are comparable to the potential effects of the compounds exemplified in the aforementioned US patents, , It has superior IV type PDE inhibitory activity.
(2) a method for measuring the activity of inhibiting various phosphodiesterase (isozyme)
[A] In order to evaluate the selectivity of the compound of the present invention for the IV type phosphodiesterase, the I, II, III and V type phosphodiesterase isozymes are isolated by the following method.
1) A solution containing various phosphodiesterase (types I, II, and III) is isolated from mouse myocardial cells in the following manner. Under ether anesthesia, a Wistar mouse is chest incised to excise the heart. After perfusion with physiological saline supplemented with heparin (1 unit / ml) to remove blood, scissors are used to cut the heart finely. This was diluted with Buffer A (Bis-Tris 20 mM, dithioerythritol) containing a protease inhibitor (50 uM phenyl-methyl-sulfonyl-fluoride, 5 uM Pepstatin A, 40 uM Ruepeptin, 20 uM aprotinin or 2 mM Benjaminidine) 5 mM, EGTA 2 mM and sodium acetate 50 mM, pH 6.5), the cells are pulverized using a polytron and an ultrasonic mill and subjected to ultracentrifugation (4 ° C., 100,000 × g, 60 minutes) to obtain a solution fraction.
2) A solution containing various phosphodiesterase isozymes is obtained from the resulting solution aliquots by the following method. The resulting aliquot of the solution is applied to a 1.6 x 10.0 cm column packed with Q Sepharose equilibrated with Buffer A. Next, the column is washed with 300 ml of Buffer A to remove non-adsorbed proteins. Phosphodiesterase was eluted with 200 ml of buffer A having a linear concentration gradient of 0.05 to 1.25 M sodium acetate to obtain 40 fractions each containing 5.0 ml of eluate. The cAMP- and cGMP-metabolic phosphodiesterase activity is investigated for each fraction. Of these fractions, the fraction having only the cAMP-metabolic activity and disappearing the metabolic activity by 0.1 uM of cilostamide (type III phosphodiesterase selectivity inhibitor) is used as the III type phosphodiesterase. In addition, a fraction showing an increase in cAMP metabolism activity in addition to 2 uM of cGMP is used as type II phosphodiesterase. Additionally, a fraction that does not show a change in cAMP metabolism activity with the addition of cGMP but has an increased cAMP metabolism activity with the addition of ₂ mM CaCl ₂ is used as the I-form phosphodiesterase. These fractions are collected separately and used as phosphodiesterase stock solutions (type I, II and III) for the selectivity test.
3) A solution containing V-form phosphodiesterase is prepared from the peripheral blood vessels of healthy persons in the following manner. 200 ml of physiological saline supplemented with dextran (3%) is added to 500 ml of peripheral blood supplemented with heparin and incubated at 37 ° C for 40 minutes to precipitate red blood cells. After erythrocyte precipitation, the supernatant was obtained and centrifuged once, and the precipitate was suspended in buffer B (NaCl 140 ml, KCl 5 mM, glucose 5 mM and HEPES 10 mM, pH 7.4), added to the density gradient centrifugation solution and 450 xg For 40 minutes to separate the mononuclear cell fraction and granulocyte fraction, respectively. The granulocyte fraction was washed once with buffer C (NaCl 140 mM, KCl 5 mM, 1 mM CaCl _2, 1 mM MgCl _2, 1 mM MgCl ₂ , 5 mM glucose and 10 mM HEPES, pH 7.4) and incubated with protease inhibitors (lupepatin 40 uM, Pepstatin A 5 uM, aprotinin Suspended in buffer D (Bis-Tris 20 mM <dithioerythritol 5 mM, EGTA 2 mM and sodium acetate 50 mM, pH 6.5) containing 20 uM, phenyl-methyl-sulfonyl-fluoride 50 uM or benzamidine 2 mM) And an ultrasonic disintegrator, and the cells were pulverized and ultracentrifuged (4 ° C., 100,000 × g, 60 minutes) to obtain a solution fraction.
4) The resulting solution aliquot is applied to a 1.6 x 10 cm column filled with Q Sepharose equilibrated with Buffer D. The column is then washed with 120 ml of Buffer D to remove non-adsorbed proteins.
Phosphodiesterase is eluted with 300 ml of Buffer D with a linear gradient of 0.05-1.25 M sodium acetate to obtain fractions each having 5.0 ml eluate. The cAMP- and cGMP-metabolic phosphodiesterase activity is investigated for each fraction. The fraction having only cGMP metabolism activity is collected and used as a V-form phosphodiesterase mother liquor.
[B] The inhibitory activity is measured using the various phosphodiesterase isoenzymes obtained as a result.
1) Each of the predetermined amounts of each compound to be tested was diluted with 40 mM Tris-HCl (pH 8.0), 5 mM MgCl ₂ , 4 mM 2-mercaptoethanol, 10 μM Rorifurem (IV type phosphodiesterase selective inhibitor) , ³ H-cAMP 10 nM (in the case of V-form phosphodiesterase, 1 uM cAMP and 10 nM ³ H-cAMP are replaced by 1 uM cGMP and 100 nM ³ H-cGMP) and a homogeneous enzyme The reaction is carried out at 30 DEG C for 10 minutes. After termination of the reaction, the reaction mixture is heated at 90 占 폚 for 1 minute, cooled in an ice bath, mixed with the first unit of 5'-nucleotide, maintained at 30 占 폚 for 1 minute, and 1 ml of methanol is added to terminate the reaction. The reaction solution is applied to a Dowex 1 x 8 cm column to adsorb non-metabolized cAMP or cGMP and the radioactivity of the eluate is then measured with a scintillation counter.
2) The IC ₅₀ value of each compound to be tested is measured as the concentration of the compound that inhibits 50% of the metabolic activity of each of the isozyme enzymes, and the selectivity of the inhibitory activity (IC ₅₀ ) is evaluated.
Test results: The above measurement results demonstrate that most compounds of the present invention are superior in selectively inhibiting type IV PDE activity compared to other PDE isozymes.
For example, in Examples 1, 3, 4, and 19, the selectivity of the inhibitory activity against type IV PDE is demonstrated to be 1000-fold higher than for other types of PDE.
(3) inhibition of antigen-induced airway inflammatory cell infiltration
1) Eagle albumin (5 ug) and aluminum hydroxide gel (100 mg) are subjected to abdominal treatment (three times at intervals of once a week) to activate sensitization, and then male Hartley guinea pigs are used. Airway inflammation is induced by intravenous injection of the H ₁ -histamine antagonist, pyrilamine (2 mg / kg), followed by inhalation exposure to 0.5% egg albumin for 30 minutes.
2) Each compound to be tested is suspended in purified water containing 0.5% methylcellulose and orally administered 30 minutes before or 3 hours after exposure to egg albumin. As a control, a solvent (0.5% methylcellulose purified water, 3 ml / kg) is administered in the same manner. 24 hours after exposure to egg albumin, anesthetize with urethane (2 g / kg, intraperitoneal injection) to release blood from the abdominal aorta and sacrifice and clean alveoli with physiological saline (10 ml x 3 times).
3) The total number of leukocyte cells in the alveolar cleansing solution is measured using a cell counter (Celltac-α, Nippon Koden). In addition, since the ratio of each leukocyte (eosinophil, monocyte, lymphocyte, and neutrophil) appears as cloudy phase on the slide glass, it is stained with DifQuick (The Green Cross Corporation), and the leukocyte cells in the alveolar cleansing solution are microscopically Obtained by observation, and the number of airway invasion of each leukocyte cell is calculated on the basis of the following formula.
[Number of leukocytes (eosinophils, monocytes, lymphocytes and neutrophils)] = [total number of leukocytes] x [ratio of leukocytes (eosinophils, monocytes, lymphocytes and neutrophils)
4) The ED ₅₀ value is calculated from the inhalation ratio of the total infiltrating leukocyte cell population to the individual dose of each compound to be tested, based on the sum of the control group. Additionally, the inhalation effect on the number of leukocytes (eosinophils, monocytes, lymphocytes and neutrophils) was judged by a significant difference (p <0.05) in the Dunnett's test.
Test results: The above measurement results demonstrate that the compounds of the present invention have an excellent effect in inhibiting the infiltration of airway inflammatory cells and thus can be used as excellent bronchial asthma-treating agents.
Pharmaceutical preparations containing one or more compounds of the present invention or a salt thereof as an active ingredient are prepared using carriers, excipients and other additives commonly used in pharmaceutical preparations.
(For example, intravenous injection, intramuscular injection and the like) in the form of tablets, pills, capsules, granules, powders, solutions and the like, suppositories, transdermal preparations, inhalants and the like &Lt; / RTI &gt; parenteral administration or by intravesical injection. The dose is arbitrarily determined depending on the situation in consideration of each patient's symptoms, age, sex, and the like, and is generally about 0.001 mg / kg to about 100 mg / kg per adult per day in the case of oral administration, Once or two to four times a day. When administered by intravenous injection according to the symptoms, it can be administered in the range of 0.001 mg / kg to 10 mg / kg per adult once a day or several times a day. In addition, in the case of inhalation, it is generally administered in the range of 0.0001 mg / kg to 1 mg / kg per adult once a day or several times a day, or, in the case of application, generally 0.0001 mg / 1 mg / kg once a day or several times.
Tablets, powders, granules and the like are used as the solid composition of the present invention for oral administration. Among these solid compositions, the one or more active substances are mixed with one or more inert diluents such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or aluminum magnesium silicate. The composition may additionally contain a lubricant (e.g., magnesium stearate or the like), a disintegrant (e.g., calcium cellulose glycolate or the like), a stabilizer (e.g., lactose or Analogs), and solubilizers (e.g., glutamic acid, aspartic acid, or the like). Optionally, the tablet or pill can be coated with a film of stomach or intestinal material, such as sugar or sucrose, gelatin, hydroxypropylcellulose or hydroxypropylmethylcellulose phthalate.
Liquid compositions for oral administration contain pharmaceutically acceptable emulsions, solvents, suspensions, syrups, elixirs and the like, and contain commonly used inert diluents, such as purified water or ethanol. In addition to inert diluents, such compositions may also contain adjuvants such as wetting agents, suspending agents and the like, sweeteners, flavoring agents, fragrances, and preservatives.
Injections for parenteral administration include preservative or non-aqueous solvents, suspensions, and emulsions. Distilled water, physiological saline, and the like are used as aqueous solvents and suspensions. Propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), alcohols (e. G., Ethanol), polysorbate 80 and the like are used as non-aqueous solvents and suspensions. These compositions also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizers (for example, lactose) and solubilizing agents (for example, glutamic acid and aspartic acid). These compositions are sterilized, for example, by filtration through a bacterial correction filter, in combination with a bactericide or irradiation.
In addition, the compositions may be prepared as a preservative solid composition for use in sterile water or sterile solvents prior to use.
BEST MODE FOR CARRYING OUT THE INVENTION
The following describes the invention in further detail with reference to the examples. Of course, the present invention is not limited to the description of the embodiments.

权利要求:
Claims (28)
[1" claim-type="Currently amended] Pyrido [2,3-d] pyrimidine derivatives of formula (I) or pharmaceutically acceptable salts thereof:
Formula I

In this formula,
X is an oxygen atom or a sulfur atom,
R ¹ is a lower alkyl group, a cycloalkyl-lower alkyl group or a cycloalkyl group,
R ² represents a hydrogen atom, a halogen atom, a lower alkyl group, a halogeno-lower alkyl group, a hydroxy-lower alkyl group, a mercapto-lower alkyl group, a lower alkoxy- Lower alkanoylthio-lower alkyl group, lower alkanoyl-lower alkyl group, hydroxyimino-lower alkyl group, lower alkoxyimino-lower alkyl group, cycloalkyl group, aryl group or lower alkanoyl-lower alkyl group, Noile group,
R ³ is a hydrogen atom, a halogen atom or a lower alkyl group,
R ⁴ is a hydrogen atom or a lower alkyl group,
R ⁵ is a cycloalkyl group which may be substituted with the same group of R ⁶ ; A naphthyl group which may be substituted with the same group of R ⁶ ; A 5- or 6-membered monocyclic heterocyclic group having 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom which may be substituted with the same group of R &lt; ⁶ &gt; and which may be condensed with a benzene ring; Or &lt; Lt; / RTI &gt;
R ⁶ is a halogen atom, a lower alkyl group, a halogeno-lower alkyl group, a hydroxy group, a lower alkoxy group, a cyano group or a nitro group;
Provided that R &lt; ^{5 &} Lt; / RTI &gt; R ⁶ is a halogen atom, a lower alkyl group or a lower alkoxy group, R ¹ is a lower alkyl group or a cycloalkyl group, R ³ and R ⁴ are both hydrogen atoms, and X is an oxygen atom,
R ² is a group other than a hydrogen atom.
[2" claim-type="Currently amended] The compound according to claim 1, which is a pyrido [2,3-d] pyrimidine derivative of the formula (II) or a pharmaceutically acceptable salt thereof:
(II)

In this formula,
R ⁷ is a methyl group, an ethyl group, a propyl group or an isopropyl group,
R ⁸ is a methyl group, an ethyl group, a propyl group or an isopropyl group,
R ⁹ is a chlorine atom, a bromine atom or a methyl group.
[3" claim-type="Currently amended] 3. The compound according to claim 2, wherein R &lt; ⁸ &gt; is a methyl group or an ethyl group.
[4" claim-type="Currently amended] The compound according to claim 3, wherein R ⁷ is an ethyl group or a propyl group and R ⁸ is a group described in claim 3.
[5" claim-type="Currently amended] 5. The compound according to claim 4, which is 4- (3-chlorophenyl) -1,7-diethylpyrido [2,3-d] pyrimidin- Diethylpyrido [2,3-d] pyrimidin-2 (1H) -one, 4- (3-chlorophenyl) Pyrimidin-2 (1H) -one, 1-ethyl-7- methylpyrido [2,3- Pyrido [2,3-d] pyrimidin-2 (1H) -one or 1,7-diethyl-4- (3-methylphenyl) pyrido [2,3 lt; / RTI &gt; d] pyrimidin-2 (1H) -one.
[6" claim-type="Currently amended] A compound according to claim 1, which is a pyrido [2,3-d] pyrimidine derivative of formula (III) or a pharmaceutically acceptable salt thereof:
(III)

In this formula,
X, R ¹ , R ³ , R ⁴ and R ⁵ are as defined in claim 1,
R ¹⁰ represents a hydrogen atom, a halogen atom, a lower alkyl group, a halogeno-lower alkyl group, a hydroxy-lower alkyl group, a mercapto-lower alkyl group, a lower alkoxy-lower alkyl group, Lower alkanoylthio-lower alkyl group, lower alkanoyl-lower alkyl group, hydroxyimino-lower alkyl group, lower alkoxyimino-lower alkyl group, cycloalkyl group, aryl group or lower alkanoyl-lower alkyl group, Noile group,
Provided that R &lt; ^{5 &} R ⁶ is a halogen atom, a lower alkyl group or a lower alkoxy group, R ¹ is a lower alkyl group or a cycloalkyl group, R ³ and R ⁴ are both hydrogen atoms, and X is an oxygen atom,
R ¹⁰ is a group other than a hydrogen atom and a lower alkyl group.
[7" claim-type="Currently amended] 7. The compound of claim 6 wherein R &lt; ¹⁰ &gt; is hydrogen, lower alkyl, halogeno-lower alkyl, hydroxy- Group, a lower alkanoyloxy-lower alkyl group, a lower alkanoylthio-lower alkyl group, a hydroxyimino-lower alkyl group, a cycloalkyl group, an aryl group or a lower alkanoyl group.
[8" claim-type="Currently amended] 8. The compound of claim 7, wherein R &lt; ¹⁰ &gt; is hydrogen, lower alkyl, halogeno-lower alkyl, hydroxy- A lower alkyl group, a hydroxyimino-lower alkyl group, a cycloalkyl group, an aryl group or a lower alkanoyl group.
[9" claim-type="Currently amended] 9. The method of claim 8,
R ¹⁰ is as defined in claim 8;
R ⁴ is a hydrogen atom;
R ⁵ is a group selected from the group consisting of (1) a cycloalkyl group which may be substituted with a lower alkyl group, (2) a naphthyl group, (3) a heterocyclic group having 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, 5- or 6-membered monocyclic heterocyclic group or (4) Lt; / RTI &gt;
R ⁶ is a halogen atom, a lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a cyano group or a nitro group.
[10" claim-type="Currently amended] 10. The method of claim 9,
R &lt; ¹ &gt; is a lower alkyl group or a cycloalkyl-lower alkyl group,
R ¹⁰ is a lower alkyl group, a halogeno-lower alkyl group, a hydroxy-lower alkyl group, a lower alkanoylthio-lower alkyl group, a hydroxyimino-lower alkyl group, a cycloalkyl group or a lower alkanoyl group,
R ³ and R ⁴ are both hydrogen atoms,
R ⁵ is a cycloalkyl group which may be substituted with a lower alkyl group, Lt; / RTI &gt;
R ⁶ is a halogen atom, a lower alkyl group or a nitro group.
[11" claim-type="Currently amended] 11. A compound according to claim 10, which is 4-cyclohexyl-1-ethyl-7-methylpyrido [2,3- d] pyrimidin- Pyrimido-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] pyrimidin-2 (1H) -one, 4- (3-chlorophenyl) -1-ethyl-7- Methylpyrido [2,3-d] pyrimidin-2 (1H) -thione, 1-cyclopropylmethyl- 2 (1H) -one, 4- (3-Chlorophenyl) -l-ethyl-pyrimidin- 7-hydroxyiminopyrido [2,3-d] pyrimidin-2 (1H) -one and 7- (1-acetylthioethyl) -4- (3- chlorophenyl) 2,3-d] pyrimidin-2 (1H) -one or 1,7-diethyl-4- (3- chlorophenyl) pyrido [ Compound.
[12" claim-type="Currently amended] A pharmaceutical composition comprising a pyrido [2,3-d] pyrimidine derivative according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[13" claim-type="Currently amended] 13. The pharmaceutical composition according to claim 12, which is a type IV phosphodiesterase inhibitor.
[14" claim-type="Currently amended] 14. The pharmaceutical composition according to claim 13, which is a preparation for the prevention or treatment of type IV phosphodiesterase-related respiratory diseases.
[15" claim-type="Currently amended] The pharmaceutical composition according to claim 14, which is a preparation for preventing or treating bronchial asthma.
[16" claim-type="Currently amended] The pharmaceutical composition according to claim 12, which comprises a pyrido [2,3-d] pyrimidine derivative according to any one of claims 6 to 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier .
[17" claim-type="Currently amended] 17. The pharmaceutical composition according to claim 16, which is a type IV phosphodiesterase inhibitor.
[18" claim-type="Currently amended] 18. The pharmaceutical composition according to claim 17, which is a preparation for the prevention or treatment of type IV phosphodiesterase-related respiratory diseases.
[19" claim-type="Currently amended] The pharmaceutical composition according to claim 18, which is a preparation for preventing or treating bronchial asthma.
[20" claim-type="Currently amended] A phosphodiesterase IV inhibitor comprising a pyrido [2,3-d] pyrimidine derivative according to any one of claims 2 to 5 or a pharmaceutically acceptable salt thereof.
[21" claim-type="Currently amended] 21. The medicament according to claim 20, which is an agent for the prevention or treatment of type IV phosphodiesterase-related respiratory diseases.
[22" claim-type="Currently amended] 22. The medicament according to claim 21, which is an agent for preventing or treating bronchial asthma.
[23" claim-type="Currently amended] The pyrido [2,3-d] pyrimidine compound according to any one of claims 1 to 11 for the preparation of a type IV phosphodiesterase inhibitor for the prevention or treatment of diseases associated with the promotion of type IV phosphodiesterase activity. ] Pyrimidine derivative or a pharmaceutically acceptable salt thereof.
[24" claim-type="Currently amended] 24. The use according to claim 23, wherein the disease associated with the promotion of type IV phosphodiesterase activity is a respiratory disease.
[25" claim-type="Currently amended] 25. Use according to claim 24, wherein the disease associated with the promotion of type IV phosphodiesterase activity is bronchial asthma.
[26" claim-type="Currently amended] An effective amount of a pyrido [2,3-d] pyrimidine derivative according to any one of claims 1 to 11 for the prophylaxis or treatment of a disease associated with the promotion of type IV phosphodiesterase activity or a pharmaceutically acceptable salt thereof. Or a salt thereof, to a patient suffering from or susceptible to the disease. &Lt; Desc / Clms Page number 19 &gt;
[27" claim-type="Currently amended] 27. The method of claim 26, wherein the disease associated with promoting activity of type IV phosphodiesterase is a respiratory disease.
[28" claim-type="Currently amended] 28. The method of claim 27 wherein the disease associated with promoting activity of type IV phosphodiesterase is bronchial asthma.

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同族专利:

---

公开号 | 公开日

---

CA2236683A1|1997-05-29|

---

WO1997019078A1|1997-05-29|

---

HU9900607A3|1999-11-29|

---

AU705039B2|1999-05-13|

---

JP3110765B2|2000-11-20|

---

TW377352B|1999-12-21|

---

EP0885894A1|1998-12-23|

---

HU9900607A2|1999-06-28|

---

AU7588696A|1997-06-11|

---

US6136810A|2000-10-24|

---

EP0885894A4|2000-01-19|

---

CN1202171A|1998-12-16|

---

NZ322197A|1999-02-25|

---

BR9611628A|1999-06-01|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1995-11-21|Priority to JP30306595

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1995-11-21|Priority to JP95-303065

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1996-01-19|Priority to JP772596

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1996-01-19|Priority to JP96-007725

---

1996-02-29|Priority to JP4385396

---

1996-02-29|Priority to JP96-043853

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1996-06-04|Priority to JP96-141868

---

1996-06-04|Priority to JP14186896

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1996-11-20|Application filed by 오노다 마사요시, 야마노우치세이야쿠 가부시키가이샤

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1996-11-20|Priority to PCT/JP1996/003389

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1999-09-27|Publication of KR19990071520A

优先权:

---

申请号 | 申请日 | 专利标题

---

JP30306595|1995-11-21|

---

JP95-303065|1995-11-21|

---

JP772596|1996-01-19|

---

JP96-007725|1996-01-19|

---

JP96-043853|1996-02-29|

---

JP4385396|1996-02-29|

---

JP96-141868|1996-06-04|

---

JP14186896|1996-06-04|

---

PCT/JP1996/003389|WO1997019078A1|1995-11-21|1996-11-20|Pyrido[2, 3-d] pyrimidine derivatives and medicinal compositions thereof|