HK1219099B - Pyrazole derivative - Google Patents

Description

Pyrazole derivatives

Technical Field

The present invention relates to a novel compound having xanthine oxidase inhibitory activity, a process for producing the same, and a xanthine oxidase inhibitor containing the compound as an active ingredient. In particular, the present invention relates to a pyrazole derivative (pyrazolederivative) which is effective as a therapeutic or prophylactic agent for a disease involving xanthine oxidase such as gout, hyperuricemia, tumor lysis syndrome, urethral calculus, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and cardiac insufficiency, renal diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease and autoimmune diseases.

Background

Xanthine oxidase is an enzyme that catalyzes the conversion of hypoxanthine into xanthine and then into uric acid in nucleic acid metabolism.

In response to the action of xanthine oxidase, xanthine oxidase inhibitors lower the level of uric acid in blood by inhibiting the synthesis of uric acid. That is, xanthine oxidase inhibitors are effective for the treatment of hyperuricemia and various diseases caused by hyperuricemia. On the other hand, hyperuricemia continues to cause urate crystals to be deposited, and as a result, gouty arthritis called gout and gout nodules are caused as pathological conditions. In addition, hyperuricemia has also been highlighted as a factor of lifestyle-related diseases or metabolic syndrome associated with obesity, hypertension, dyslipidemia, diabetes, and the like, and it has recently been clarified by epidemiological investigation: hyperuricemia is a risk factor for renal damage, urinary calculi, cardiovascular diseases (hyperuricemia, the 2 nd edition of therapeutic guidelines for gout and seeds). Further, xanthine oxidase inhibitors are expected to be effective in the treatment of diseases in which active oxygen clusters are involved, for example, in the treatment of cardiovascular diseases based on the effect of improving vascular function, because of their active oxygen species inhibitory activity (circulation 2006; 114: 2508) -2516).

Allopurinol and febuxostat have been clinically used as a therapeutic agent for hyperuricemia, but allopurinol has been reported to have side effects such as Stevens-Johnson syndrome, toxic epidermal necrosis, liver damage, renal function damage and the like (nippon rinsho, 2003; 61, suppul.1: 197-.

Examples of compounds having xanthine oxidase inhibitory activity include pyrazole derivatives having a benzene ring in the central aromatic ring, such as phenylpyrazole derivatives (patent documents 1 to 3) and triarylcarboxylic acid derivatives (patent documents 4 to 7). Further, pyrazole derivatives having a central bicyclic heterocycle, such as 6-indolpyrazole derivatives (patent document 8), have been reported.

In non-patent document 1 and non-patent document 2, pyrazolecarboxylic acid derivatives having a pyridine ring at the center are reported.

Documents of the prior art

Patent document

Patent document 1: japanese patent laid-open publication No. 59-95272;

patent document 2: international publication No. 98/18765;

patent document 3: japanese patent application laid-open No. 10-310578;

patent document 4: international publication No. 2007/043457;

patent document 5: international publication No. 2007/097403;

patent document 6: international publication No. 2008/126770;

patent document 7: international publication No. 2008/126772;

patent document 8: international publication No. 2011/043568;

non-patent document

Non-patent document 1: bioorganic Medicinal Chemistry Letters, 2006, volume 16 (21), page 5616-;

non-patent document 2: bioorganic Medicinal Chemistry Letters, 2006, volume 16 (21), page 5687-5690.

Disclosure of Invention

Problems to be solved by the invention

The present invention addresses the problem of providing a novel compound having xanthine oxidase inhibitory activity. Further, an object of the present invention is to provide a compound having an excellent uric acid lowering effect. Another object of the present invention is to provide a compound effective as a therapeutic or prophylactic agent for diseases involving xanthine oxidase, such as gout, hyperuricemia, tumor lysis syndrome, urethral calculus, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and cardiac insufficiency, renal diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease and autoimmune diseases.

Means for solving the problems

The inventors have conducted intensive studies on compounds having xanthine oxidase inhibitory activity, and as a result, found that: the following formula (I)

The compound represented by the formula (i) is a tricyclic triaryl structure, and a pyrazole derivative having a pyridine ring substituted with a cyano group having one nitrogen atom in the central ring has xanthine oxidase inhibitory activity, has novel xanthine oxidase inhibitory activity accompanied by excellent uric acid lowering action, and has sustained xanthine oxidase inhibitory activity capable of realizing particularly excellent uric acid lowering action for a long period of time, and thus the present invention has been completed. And found that: the pyrazole derivative can be used as a good therapeutic or prophylactic agent for gout, hyperuricemia, tumor lysis syndrome, urethral calculus, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and cardiac insufficiency, renal diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease, autoimmune diseases, and the like, and the present invention has been completed.

The present invention relates to a compound represented by the following formula (I):

in the formula (I), the compound is shown in the specification,

a represents an aryl or heteroaryl group having 6 to 10 carbon atoms, wherein the aryl or heteroaryl groups are unsubstituted or the same or different from each other and may be substituted by a halogen atom, -CN, -NO₂Alkyl group having 1 to 6 carbon atoms, cycloalkyl group having 3 to 7 carbon atoms, haloalkyl group having 1 to 6 carbon atoms, phenyl group, -CH₂-O-R²、-O-R²-O-a C1-6 haloalkyl group, -O-benzyl, -O-phenyl, -O-CO-R²、-NR³R⁴、-NH-CO-R²、-CO₂-R²、-CO-R²、-CO-NR³R⁴、-NH-SO₂-R²-CO-aryl, -S-R²、-SO₂An alkyl group having 1 to 6 carbon atoms, and-SO₂1 to 3 groups Q of phenyl,

x, Y and Z denotes CR⁵Or a nitrogen atom, wherein 1 of X, Y and Z represents a nitrogen atom, and the remaining 2 represent CR⁵，

R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R¹represents a hydrogen atom, an amino group or an alkyl group having 1 to 6 carbon atoms,

R²represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R³and R⁴The same or different from each other, is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, wherein R³And R⁴Are integrated and can form a monocyclic nitrogen-containing saturated heterocyclic ring together with the nitrogen atom to which they are bonded,

R⁵represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms.

Furthermore, the present invention relates to a pharmaceutical composition comprising the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention also relates to a xanthine oxidase inhibitor containing the compound represented by the above formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also relates to a therapeutic or prophylactic agent for a disease involving xanthine oxidase, such as gout, hyperuricemia, tumor lysis syndrome, urinary calculus, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and cardiac insufficiency, renal diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease and autoimmune diseases, which contains the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

Also, the present invention relates to a compound represented by the following formula (II) useful as a production intermediate of the compound represented by the above formula (I):

in the formula (I), the compound is shown in the specification,

a represents an aryl or heteroaryl group having 6 to 10 carbon atoms, wherein the aryl or heteroaryl groups are unsubstituted or the same or different from each other and may be substituted by a halogen atom, -CN, -NO₂Alkyl group having 1 to 6 carbon atoms, cycloalkyl group having 3 to 7 carbon atoms, haloalkyl group having 1 to 6 carbon atoms, phenyl group, -CH₂-O-R²、-O-R²-O-a C1-6 haloalkyl group, -O-benzyl, -O-phenyl, -O-CO-R²、-NR³R⁴、-NH-CO-R²、-CO₂-R²、-CO-R²、-CO-NR³R⁴、-NH-SO₂-R²-CO-aryl, -S-R²、-SO₂An alkyl group having 1 to 6 carbon atoms, and-SO₂1 to 3 groups Q of phenyl,

x, Y and Z denotes CR⁵Or a nitrogen atom, wherein 1 of X, Y and Z represents a nitrogen atom, and the remaining 2 represent CR⁵，

R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R¹represents a hydrogen atom, an amino group or an alkyl group having 1 to 6 carbon atoms,

R²represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R³and R⁴The same or different from each other, is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, wherein R³And R⁴Are integrated and can form a monocyclic nitrogen-containing heterocycle together with the nitrogen atom to which they are bonded,

R⁵represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms,

R⁶represents a protecting group for a carboxyl group,

w represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group or a cyano group.

Also, the present invention relates to a compound represented by the following formula (III) useful as a production intermediate of the compound represented by the above formula (I):

in the formula (I), the compound is shown in the specification,

x, Y and Z denotes CR⁵Or a nitrogen atom, wherein 1 of X, Y and Z represents a nitrogen atom, and the remaining 2 represent CR⁵，

R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R¹represents a hydrogen atom, an amino group or an alkyl group having 1 to 6 carbon atoms,

R⁵represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms,

R⁶represents a protecting group for a carboxyl group,

v represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, a hydroxyl group or a benzyloxy group,

w represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group or a cyano group.

Also, the present invention relates to a compound represented by the following formula (IV) useful as a production intermediate of the compound represented by the above formula (I):

in the formula (I), the compound is shown in the specification,

a represents an aryl or heteroaryl group having 6 to 10 carbon atoms, wherein the aryl or heteroaryl groups are unsubstituted or the same or different from each other and may be substituted by a halogen atom, -CN, -NO₂Alkyl group having 1 to 6 carbon atoms, cycloalkyl group having 3 to 7 carbon atoms, haloalkyl group having 1 to 6 carbon atoms, benzeneradical-CH₂-O-R²、-O-R²-O-a C1-6 haloalkyl group, -O-benzyl, -O-phenyl, -O-CO-R²、-NR³R⁴、-NH-CO-R²、-CO₂-R²、-CO-R²、-CO-NR³R⁴、-NH-SO₂-R²-CO-aryl, -S-R²、-SO₂An alkyl group having 1 to 6 carbon atoms, and-SO₂1 to 3 groups Q of phenyl,

x, Y and Z denotes CR⁵Or a nitrogen atom, wherein 1 of X, Y and Z represents a nitrogen atom, and the remaining 2 represent CR⁵，

R²Represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R³and R⁴The same or different from each other, is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, wherein R³And R⁴Are integrated and can form a monocyclic nitrogen-containing saturated heterocyclic ring together with the nitrogen atom to which they are bonded,

R⁵represents a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms,

X²represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group.

Effects of the invention

The present invention provides a novel compound having a high xanthine oxidase inhibitory activity and a process for producing the same. The compound of the present invention is particularly effective as a therapeutic or prophylactic agent for diseases involving xanthine oxidase, such as gout, hyperuricemia, tumor lysis syndrome, urinary calculi, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and cardiac insufficiency, renal diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease and autoimmune diseases.

Detailed Description

Hereinafter, terms used alone or in combination in the present specification will be described. Unless otherwise specified, the description of each substituent is common to each site. When any variable is present in any component, its definition is independent in each component. In addition, with respect to combinations of substituents and variables, such combinations are permissible only if they result in chemically stable compounds.

"xanthine oxidase" is generally used in the "broad sense" which means an enzyme that catalyzes an oxidation reaction in which hypoxanthine is converted into xanthine and then converted into uric acid, and in the "narrow sense" which means an oxidase-type xanthine oxidoreductase that is one of enzymes that catalyze the same reaction, but in the present invention, unless otherwise specified, "xanthine oxidase" is a generic term for an enzyme that catalyzes an oxidation reaction in which hypoxanthine is converted into xanthine and then converted into uric acid. In the xanthine oxidoreductase responsible for this reaction, there are two types, an oxidase type and a dehydrogenase type, both of which are included in the xanthine oxidase of the present invention. In the terms of "xanthine oxidase inhibitory activity", "xanthine oxidase inhibitor" and the like, "xanthine oxidase" has the same meaning as defined above unless otherwise specified.

In the present invention, "aryl group" means a group produced by leaving 1 hydrogen atom bonded to a ring of an aromatic hydrocarbon. Examples of the aryl group having 6 to 10 carbon atoms include: phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, azulenyl, and the like.

In the present invention, the term "heteroaryl" refers to an aromatic heterocyclic ring system having 3 to 10-membered monocyclic or bicyclic ring system containing 1 to 5 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom. The "3-to 10-membered monocyclic or bicyclic aromatic heterocyclic ring system" refers to a 1-valent group obtained by removing a hydrogen atom from a 3-to 10-membered monocyclic or bicyclic aromatic heterocyclic ring having 1-5 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom. In the case of a bicyclic heteroaryl group, if one ring is an aromatic ring or an aromatic heterocyclic ring, the other ring may not be an aromatic ring structure. The number of each hetero atom in the heteroaryl group or a combination thereof is not particularly limited as long as the hetero atom can form a ring having a predetermined number of elements and can be chemically stably present. Examples of the heteroaryl group include: pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl, pyrazolyl, 1, 3-dioxaindanyl, isoxazolyl, isothiazolyl, benzofuryl, isobenzofuryl, benzothienyl, indolyl, isoindolyl, chromanyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, pyranyl, imidazolyl, oxazolyl, thiazolyl, triazinyl, triazolyl, furazanyl, thiadiazolyl, dihydrobenzofuryl, dihydroisobenzofuryl, dihydroquinolinyl, dihydroisoquinolinyl, dihydrobenzoxazolyl, dihydropteridinyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, benzotriazolyl, pteridinyl, purinyl, quinoxalinyl, quinazolinyl, cinnolinyl, and tetrazolyl, and the like.

In the present invention, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

In the present invention, "alkyl" refers to a saturated straight-chain or branched-chain aliphatic hydrocarbon group having a valence of 1. Examples of the alkyl group having 1 to 6 carbon atoms include: methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, tert-pentyl, isohexyl and the like.

In the present invention, the "alkylene group" refers to a 2-valent saturated linear or branched aliphatic hydrocarbon group having 1 to 6 carbon atoms. Examples of the alkylene group having 1 to 6 carbon atoms include: methylene, ethylene, n-propylene, isopropylene, n-pentylene, n-hexylene, and the like.

In the present invention, "cycloalkyl" refers to a cyclic saturated hydrocarbon group. Examples of the cycloalkyl group having 3 to 7 carbon atoms include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

In the present invention, "haloalkyl" means an alkyl group substituted with 1 or more halogens. Examples of the haloalkyl group having 1 to 6 carbon atoms include: trifluoromethyl, difluoromethyl, and the like.

In the present invention, the "monocyclic nitrogen-containing saturated heterocyclic ring" refers to a 5 to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1 nitrogen atom and containing 1 hetero atom consisting of a nitrogen atom, a sulfur atom and an oxygen atom, and examples thereof include: pyrrolidine, piperidine, piperazine, azepane, diazepane, azocane, morpholine, thiomorpholine, tetrahydropyridine rings, and the like.

In the above-mentioned "monocyclic nitrogen-containing saturated heterocyclic ring", a sulfur atom as a ring atom may be oxidized to form an oxide or a dioxide, or a nitrogen atom may be oxidized to form an oxide.

In the present invention, the "protecting group for carboxyl group" refers to, for example, a protecting group in organic synthesis, third edition, a common protecting group for carboxyl group described in John Wiley & Sons, Inc., and examples thereof include: methyl, ethyl, isopropyl, heptyl, tert-butyl, methoxymethyl, methylthiomethyl, methoxyethoxymethyl, methoxyethyl, benzyl, tert-butyldimethylsilyl and the like.

In the formula (I), A represents aryl or heteroaryl with 6-10 carbon atoms, wherein the aryl or heteroaryl is unsubstituted or the same and can be selected from halogen atoms, -CN, -NO₂Alkyl group having 1 to 6 carbon atoms, cycloalkyl group having 3 to 7 carbon atoms, haloalkyl group having 1 to 6 carbon atoms, phenyl group, -CH₂-O-R²、-O-R²-O-a C1-6 haloalkyl group, -O-benzyl, -O-phenyl, -O-CO-R²、-NR³R⁴、-NH-CO-R²、-CO₂-R²、-CO-R²、-CO-NR³R⁴、-NH-SO₂-R²-CO-aryl, -S-R²、-SO₂An alkyl group having 1 to 6 carbon atoms, and-SO₂-1 to 3 groups Q of phenyl.

Specific examples of "aryl" and "heteroaryl" are as defined above, and as preferred "aryl" or "heteroaryl" for a, mention may be made of: phenyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, thienyl, isoxazolyl, isothiazolyl, benzofuryl, benzothienyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, pyranyl, imidazolyl, oxazolyl, thiazolyl, triazinyl, triazolyl, benzoxazolyl, benzisoxazolyl, and the like, and more preferably phenyl and thienyl.

A is unsubstituted or, identical or different from each other, may be chosen from halogen atoms, -CN, -NO₂Alkyl group having 1 to 6 carbon atoms, cycloalkyl group having 3 to 7 carbon atoms, haloalkyl group having 1 to 6 carbon atoms, phenyl group, -CH₂-O-R²、-O-R²-O-a C1-6 haloalkyl group, -O-benzyl, -O-phenyl, -O-CO-R²、-NR³R⁴、-NH-CO-R²、-CO₂-R²、-CO-R²、-CO-NR³R⁴、-NH-SO₂-R²-CO-aryl, -S-R²、-SO₂An alkyl group having 1 to 6 carbon atoms, and-SO₂-1 to 3 groups Q of phenyl. When A is substituted by Q, the number of Q is preferably 1 or 2. A is preferably unsubstituted or substituted by a halogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a phenyl group, -O-R²and-O-a halogenated alkyl group having 1 to 6 carbon atoms. More preferably, A is unsubstituted or substituted by a group Q selected from a halogen atom, a methyl group and a methoxy group. The halogen atom is preferablyA fluorine atom.

A is particularly preferably represented by the following structural formula.

In the formula (I), R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. Specific examples of the "alkyl group having 1 to 6 carbon atoms" are as defined above, and preferable examples of the "alkyl group having 1 to 6 carbon atoms" include: methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, tert-pentyl, isohexyl and the like, R is more preferably a hydrogen atom or a methyl group, particularly preferably a hydrogen atom.

In the above formula (I), R¹Represents a hydrogen atom, an amino group or an alkyl group having 1 to 6 carbon atoms. Specific examples of the "alkyl group having 1 to 6 carbon atoms" are as defined above, and preferable "alkyl group having 1 to 6 carbon atoms" include: methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, tert-pentyl, and isohexyl, etc., R, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-¹More preferred is a hydrogen atom, an amino group or a methyl group, and particularly preferred is a hydrogen atom.

In the above formula (I), R²Represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. Specific examples of the "alkyl group having 1 to 6 carbon atoms" areAs defined above, preferable "alkyl group having 1 to 6 carbon atoms" includes: methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, tert-pentyl, and isohexyl, etc., R, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-²More preferred is a hydrogen atom or a methyl group, and particularly preferred is a methyl group.

In the above formula (I), R³And R⁴The same or different from each other, is a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, wherein R³And R⁴Are integrated and can form a monocyclic nitrogen-containing saturated heterocyclic ring together with the nitrogen atom to which they are bonded. Specific examples of the "alkyl group having 1 to 6 carbon atoms" and the "monocyclic nitrogen-containing saturated heterocycle" are as defined above, and preferable "alkyl group having 1 to 6 carbon atoms" include: methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, tert-pentyl, isohexyl and the like, preferred "monocyclic nitrogen-containing saturated heterocyclic ring" includes: pyrrolidine, piperidine, piperazine, azepane, diazepane, azocane, morpholine, thiomorpholine, tetrahydropyridine rings, and the like. R³、R⁴And the "monocyclic nitrogen-containing saturated heterocycle" is more preferably a hydrogen atom, a methyl group, pyrrolidine, piperidine, piperazine, and morpholine, and particularly preferably a hydrogen atom, a methyl group, and morpholine.

In the above formula (I), X, Y and Z represent CR⁵Or a nitrogen atom, wherein 1 of X, Y and Z represents a nitrogen atom, and the remaining 2 are shown in the tableShow CR⁵. X, Y, Z are each 3 examples of a nitrogen atom and can be represented by the following structural formula. Among them, Y is preferably a nitrogen atom.

As R⁵Examples thereof include: a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms, preferably a hydrogen atom.

In the above formula (I), as A, Q, R, R¹、R²、R³、R⁴、R⁵X, Y and Z, the preferred groups mentioned above are preferably combined with each other, more preferably with more preferred groups, for each combination. A, R of the structure of formula (I) obtained by combining more preferable groups is particularly preferable¹Combinations with substitution as a particularly preferred group.

The compound of the present invention is a compound showing an excellent xanthine oxidase inhibitory activity. Moreover, the compounds of the present invention have excellent uric acid lowering action. Further, the compound of the present invention has a long-lasting uric acid lowering effect.

Specific examples of preferable compounds include the following compounds.

Among more preferred compounds are compounds 1,2, 5,6, 7, 10, 13, 14, 15, 16, 19, 20, 21, 22, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 42, 43, 44, 47, 48, 50, 51, 52, 53, 54, 55, 57, 59, 61, 63, 64, 65, 66, 68, 69, 70, 71, 73, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106 and 107, and further preferred are compounds 1,5, 10, 14, 19, 21, 33, 97 and 98.

Among the compounds represented by the above formula (II) which can be used as intermediates for the production of the above compound represented by the above formula (I) of the present invention, A, Q, R, R¹、R²、R³、R⁴、R⁵X, Y and Z are as defined above for formula (I). W represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group or a cyano group. W is more preferably a halogen atom or a cyano group, and particularly preferably a cyano group. R⁶Represents a protecting group for a carboxyl group. The protecting group for carboxyl group is defined as above, and is preferably methyl, ethyl or benzyl.

R, R among the compounds represented by the above formula (III) which are useful as intermediates for the production of the compounds represented by the above formula (I) of the present invention¹、R⁵X, Y and Z are as defined above for formula (I). V represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, a hydroxyl group or a benzyloxy group. V is preferably a halogen atom, a trifluoromethanesulfonyloxy group, a hydroxyl group or a benzyloxy group. W represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group or a cyano group. W is more preferably a halogen atom or a cyano group,cyano is particularly preferred. R⁶Represents a protecting group for a carboxyl group. The protecting group for carboxyl group is defined as above, and is preferably methyl, ethyl or benzyl.

Among the compounds represented by the above formula (IV) which are useful as intermediates for the production of the above compound represented by the above formula (I) of the present invention, A, Q, R²、R³、R⁴、R⁵X, Y and Z are as defined above for formula (I). X²Represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group. Preferably a halogen atom.

< general Synthesis method >

The compound of formula (I) and the intermediate of the present invention can be synthesized, for example, by any of the following synthetic methods. In each of the formulae, A, R, R¹Q, X, Y and Z are as defined for formula (I). The reagents, solvents, and the like described in the chemical formulae as conditions are merely examples as described herein. Each substituent may be protected with an appropriate protecting group as necessary, or may be deprotected at an appropriate stage. Suitable protecting groups and methods for removing the protecting groups can be those commonly used in the art, and known methods, for example, are described in protection of ORGANIC group in ORGANIC SYNTHESIS, third edition, John Wiley & Sons, inc.

Also, when abbreviations are used herein or in the tables for substituents, reagents and solvents, respectively, they are as follows:

DMF: n, N-dimethylformamide

THF: tetrahydrofuran (THF)

Ph: phenyl radical

TFA: trifluoroacetic acid

Synthesis method (A)

Synthesis of Compound (A-2)

(in the formula, X¹And X²Represents a leaving group. ) As X¹And X²Examples of the leaving group include: halogen atom, methylsulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group and the like. This reaction is a method of synthesizing the compound (A-2) by lithiating or sodium-treating the pyridine position 4 in the compound (A-1) with a base and then formylating with a formylating agent. Examples of the base include: lithium Diisopropylamide (LDA) prepared from diisopropylamine and n-butyllithium, and the like. Examples of the formylating agent include: n, N-Dimethylformamide (DMF), N-formylmorpholine, and the like. The reaction is carried out by reacting the compound (A-1) with an equal or slight excess of a base in a solvent inert to the reaction at-78 ℃ to 0 ℃ and then adding an equal or excess amount of a formylating agent to the reaction mixture for usually 0.5 to 5 hours. The reaction is preferably carried out under an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, and examples thereof include: ethers such as diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane, 1, 2-dimethoxyethane, and 1, 2-diethoxyethane; or a mixed solvent thereof.

Synthesis of Compound (A-4)

(in the formula, X¹And X²Represents a leaving group, Y¹represents-B (OH)₂OR-B (OR)⁷)OR⁸. Herein, R is⁷And R⁸The same or different from each other, represent an alkyl group having 1 to 6 carbon atoms, or R⁷And R⁸The alkylene group has 1 to 6 carbon atoms. ) This reaction is a method for synthesizing the compound (A-4) by coupling the compound (A-2) with the compound (A-3). As X¹And X²Examples of the leaving group include: a halogen atom,Methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy and the like. The reaction is carried out by using an equal amount or an excess of the compounds (A-2) and (A-3) and reacting the reaction mixture in a solvent inert to the reaction in the presence of a base and a palladium catalyst at room temperature to reflux under heating for usually 0.5 to 2 days. The reaction is preferably carried out under an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, and examples thereof include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane, 1, 2-dimethoxyethane, and 1, 2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; n, N-Dimethylformamide (DMF), N-methylpyrrolidone, Dimethylsulfoxide (DMSO); water or a mixed solvent thereof, and the like. Examples of the base include: inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and potassium phosphate; metal alcoholates such as sodium ethoxide and sodium methoxide; or a solution obtained by diluting these bases with water or the like. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1, 1' -bis (diphenylphosphino) ferrocene, and the like are preferable.

Synthesis of Compound (A-5)

(in the formula, X²Represents a leaving group. ) As X²Examples of the leaving group include: halogen atom, methylsulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group and the like. The reaction is carried out by reacting an aromatic aldehyde derivative represented by the above formula (A-4) with hydroxylamine. As the hydroxylamine, other salts such as hydrochloride thereof can be used, and in this case, an appropriate alkali substance is preferably added. Furthermore, 1.0 to 3.0 equivalents of acetic anhydride, acetyl chloride, trichloroacetyl chloride, and the like may be added to accelerate the reaction. The amount of hydroxylamine or a salt thereof used in these reactions is usually 1 equivalent or more, preferably 1 equivalent or moreIs 1.0 to 2.0 equivalents. When the alkaline substance is used, the amount of the alkaline substance is 1.0 to 3.0 equivalents based on the salt of hydroxylamine. As the basic substance used, there can be used: formates such as sodium formate, potassium formate, sodium acetate and the like; carbonates such as potassium carbonate, sodium carbonate, and sodium hydrogen carbonate; organic amine salts such as triethylamine, pyridine, and 4-aminopyridine. The reaction is carried out in an inert solvent in the presence of a base, at room temperature to under heating reflux for usually 0.5 hours to 3 days. The reaction is preferably carried out under an inert gas atmosphere such as nitrogen. Examples of the solvent used in these reactions include: solvents such as acetic acid, formic acid, toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, 1, 2-diethoxyethane, N-Dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), methanol, ethanol, and 2-propanol.

Synthesis of Compound (A-7)

(in the formula, R⁶Represents a protecting group for a carboxyl group. And, X²Represents a leaving group. ) As X²Examples of the leaving group include: halogen atom, methylsulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group and the like. This reaction is carried out by using an equal amount or an excess of the compounds (A-5) and (A-6) and reacting the reaction mixture in a solvent inert to the reaction in the presence of a base at room temperature to under reflux with heating for usually 0.5 hour to 3 days. The reaction is preferably carried out under an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, and examples thereof include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane, 1, 2-dimethoxyethane, and 1, 2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane, and chloroform; n, N-Dimethylformamide (DMF), N-methylpyrrolidone, Dimethylsulfoxide (DMSO); or a mixed solvent thereof. As a base, it is possible to use,there may be mentioned: inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate; metal alcoholates such as sodium ethoxide and sodium methoxide; triethylamine, N-ethyl-N, N-Diisopropylamine (DIPEA), 1, 8-diazabicyclo [5.4.0 ]]-7-undecene (DBU), and the like.

Synthesis of Compound (A-8)

(in the formula, R⁶Represents a protecting group for a carboxyl group. ) The synthesis method is to make the protecting group R of the compound (A-7) by using acid or alkali⁶Deprotection to synthesize the compound (A-8) of the present invention.

The reaction is carried out by reacting the compound (A-7) with an equivalent or excess amount of an acid or base in a solvent inert to the reaction at room temperature to under reflux with heating for usually 0.5 to 5 days. Here, the solvent is not particularly limited, and examples thereof include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane, 1, 2-dimethoxyethane, and 1, 2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; n, N-Dimethylformamide (DMF), N-methylpyrrolidone, Dimethylsulfoxide (DMSO); water or a mixed solvent thereof, and the like. Examples of the acid include: inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, and the like; or a solution obtained by diluting these acids with water or an organic solvent. Examples of the base include: inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, and potassium carbonate; metal alcoholates such as sodium ethoxide and sodium methoxide; or a solution obtained by diluting these bases with water or the like.

Further, the compound (a-7) can be synthesized, for example, according to the synthesis method (B) described below.

Synthesis method (B)

Synthesis of Compound (B-1)

(in the formula, X¹And X²Represents a leaving group. And, R⁹And R¹⁰The same or different from each other, represent an alkyl group having 1 to 6 carbon atoms, or R⁹And R¹⁰The alkylene group has 1 to 6 carbon atoms. ) As X¹And X²Examples of the leaving group include: halogen atom, methylsulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group and the like. The reaction is carried out by reacting the compound (A-2) with an equal amount or an excess of an alcohol or trialkyl orthoformate in a solvent inert to the reaction in the presence of an acid at room temperature to under reflux with heating for usually 0.5 to 2 days. Here, as the acid, there can be used: bronsted acids such as hydrogen chloride, trifluoroacetic acid, p-toluenesulfonylsulfonic acid and camphorsulfonic acid; lewis acids such as trimethylsilyl trifluoromethanesulfonic acid and boron trifluoride. Examples of the solvent used in these reactions include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane, 1, 2-dimethoxyethane, and 1, 2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, etc.; alcohols such as methanol, ethanol, and 2-propanol; or a mixed solvent thereof.

Synthesis of Compound (B-2)

(in the formula, R⁶Represents a protecting group of a carboxyl group, X¹And X²Represents a leaving group. And, R⁹And R¹⁰The same or different from each other, represent an alkyl group having 1 to 6 carbon atoms, or R⁹And R¹⁰The alkylene group has 1 to 6 carbon atoms. ) As X¹And X²Examples of the leaving group include: halogen atom, methylsulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group and the like. This reaction is carried out by using an equal amount or an excess of the compounds (B-1) and (A-6) and reacting the reaction mixture in a solvent inert to the reaction in the presence of a base at room temperature to under reflux with heating for usually 0.5 hours to 3 days. The reaction is preferably carried out under an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, and examples thereof include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane, 1, 2-dimethoxyethane, and 1, 2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane, and chloroform; n, N-Dimethylformamide (DMF), N-methylpyrrolidone, Dimethylsulfoxide (DMSO); or a mixed solvent thereof. Examples of the base include: inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride; metal alcoholates such as sodium ethoxide and sodium methoxide; triethylamine, N-ethyl-N, N-Diisopropylamine (DIPEA), 1, 8-diazabicyclo [5.4.0 ]]-7-undecene (DBU), and the like.

Synthesis of Compound (B-3)

(in the formula, R⁶Represents a protecting group of a carboxyl group, X¹Represents a leaving group. And, R⁹And R¹⁰The same or different from each other, represent an alkyl group having 1 to 6 carbon atoms, or R⁹And R¹⁰The alkylene group has 1 to 6 carbon atoms. ) This synthesis method is a method for synthesizing the compound (B-3) by cyanating the compound (B-2). As X¹Examples of the leaving group include: halogen atom, methylsulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group and the like. This reaction is carried out by converting an aromatic dialkoxyacetal derivative represented by the above formula (B-2) into an aldehyde derivative by a deprotection reaction, and then reacting it with hydroxylamineAnd (4) cyaniding. As the hydroxylamine, other salts such as hydrochloride thereof can be used, and in this case, an appropriate alkali substance is preferably added. The amount of hydroxylamine or a salt thereof used in these reactions is usually 1 equivalent or more, and preferably 1.0 to 2.0 equivalents. When the alkaline substance is used, the amount of the alkaline substance is 1.0 to 3.0 equivalents based on the salt of hydroxylamine. As the basic substance used, there can be used: formates such as sodium formate, potassium formate and sodium acetate, carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate; organic amine salts such as triethylamine, pyridine, and 4-aminopyridine. The reaction is carried out in an inert solvent in the presence of a base, at room temperature to under heating reflux for usually 0.5 hours to 3 days. The reaction is preferably carried out under an inert gas atmosphere such as nitrogen. Examples of the solvent used in these reactions include: acetic acid, formic acid, toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane, 1, 2-dimethoxyethane, 1, 2-diethoxyethane, N-Dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), methanol, ethanol, 2-propanol, or a mixed solvent thereof, and the like.

Synthesis of Compound (A-7)

(in the formula, R⁶Represents a protecting group of a carboxyl group, X¹Represents a leaving group, Y¹represents-B (OH)₂OR-B (OR)⁷)OR⁸. Herein, R is⁷And R⁸The same or different from each other, represent an alkyl group having 1 to 6 carbon atoms, or R⁷And R⁸The alkylene group has 1 to 6 carbon atoms. ) The present synthesis method is a method for synthesizing the compound (A-7) by coupling the compound (B-3) with the compound (A-3). As X¹Examples of the leaving group include: halogen atom, methylsulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group and the like. In this reaction, compounds (B-3) and (A-3) are used in the same amount or in excessThe reaction is carried out in an inert solvent in the presence of alkali and a palladium catalyst at room temperature to under heating reflux for 0.5 to 2 days. The reaction is preferably carried out under an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, and examples thereof include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane, 1, 2-dimethoxyethane, and 1, 2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; n, N-Dimethylformamide (DMF), N-methylpyrrolidone, Dimethylsulfoxide (DMSO); water or a mixed solvent thereof, and the like. Examples of the base include: inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and potassium phosphate; metal alcoholates such as sodium ethoxide and sodium methoxide; or a solution obtained by diluting these bases with water or the like. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1, 1' -bis (diphenylphosphino) ferrocene, and the like are preferable.

Synthesis method (C)

Synthesis of Compound (C-2)

(in the formula, R⁶A protecting group representing a carboxyl group, X¹、X²And X³Represents a leaving group. ) As X¹、X²And X³Examples of the leaving group include: halogen atom, methylsulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group and the like. This reaction is carried out by using an equal amount or an excess of the compounds (C-1) and (A-6) and reacting the reaction mixture in a solvent inert to the reaction in the presence of a base at room temperature to under reflux with heating for usually 0.5 hours to 3 days. The reaction is preferably carried out under an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, and examples thereof include: aromatic hydrocarbons such as benzene, toluene, and xylene; diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxanEthers such as alkane, 1, 2-dimethoxyethane and 1, 2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane, and chloroform; n, N-Dimethylformamide (DMF), N-methylpyrrolidone, Dimethylsulfoxide (DMSO); or a mixed solvent thereof. Examples of the base include: inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium hydride; metal alcoholates such as sodium ethoxide and sodium methoxide; triethylamine, N-ethyl-N, N-Diisopropylamine (DIPEA), 1, 8-diazabicyclo [5.4.0 ]]-7-undecene (DBU), and the like.

Synthesis of Compound (C-3)

(in the formula, R⁶A protecting group representing a carboxyl group, X¹And X³Represents a leaving group, Y¹represents-B (OH)₂OR-B (OR)⁷)OR⁸. Herein, R is⁷And R⁸The same or different from each other, represent an alkyl group having 1 to 6 carbon atoms, or R⁷And R⁸The alkylene group has 1 to 6 carbon atoms. ) The present synthesis method is a method for synthesizing the compound (C-3) by coupling the compound (C-2) with the compound (A-3). As X¹And X³Examples of the leaving group include: halogen atom, methylsulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group and the like. The reaction is carried out by using an equal amount or an excess of the compounds (C-2) and (A-3) and reacting the reaction mixture in a solvent inert to the reaction in the presence of a base and a palladium catalyst at room temperature to reflux under heating for usually 0.5 to 2 days. The reaction is preferably carried out under an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, and examples thereof include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane, 1, 2-dimethoxyethane, and 1, 2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; n, N-Dimethylformamide (DMF), N-methylpyrroleAlkanones, dimethyl sulfoxide (DMSO); water or a mixed solvent thereof, and the like. Examples of the base include: inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and potassium phosphate; metal alcoholates such as sodium ethoxide and sodium methoxide; or a solution obtained by diluting these bases with water or the like. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1, 1' -bis (diphenylphosphino) ferrocene, and the like are preferable.

Synthesis of Compound (C-4)

(in the formula, R⁶Represents a protecting group of a carboxyl group, X³Represents a leaving group. ) The present synthesis method is a method of cyanating compound (C-3) to synthesize compound (C-4). As X³Examples of the leaving group include a halogen atom. The reaction is carried out by substituting a leaving group X with a cyano group³The reaction of (4) is carried out by reacting the above formula (C-3) with a cyanating reagent. The reaction is carried out by using an equal or one excess of the compound (C-3) and a cyanating reagent, and reacting the mixture in a solvent inert to the reaction, optionally in the presence of a base and a palladium or copper catalyst, usually at room temperature to under reflux with heating for 0.5 hours to 2 days. The reaction is preferably carried out under an inert gas atmosphere such as nitrogen. As cyanating agents used, there may be used: cyaniding agents such as potassium cyanide, sodium cyanide, copper cyanide, zinc cyanide, and the like. The amount of the cyanating agent is usually 1 equivalent or more, preferably 1.0 to 2.0 equivalents. When a basic substance is used, 1.0 to 3.0 equivalents are used relative to the compound (C-3). As the basic substance used, there can be used: formates such as sodium formate, potassium formate, sodium acetate and the like; carbonates such as potassium carbonate, sodium carbonate, and sodium hydrogen carbonate; organic amine salts such as triethylamine, pyridine, and 4-aminopyridine. Examples of the solvent used in these reactions include: acetic acid, formic acid, toluene, benzene, pyridine, ethyl acetate, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, diethyl etherEther, Tetrahydrofuran (THF), 1, 4-dioxane, 1, 2-dimethoxyethane, 1, 2-diethoxyethane, N-Dimethylformamide (DMF), N-methylpyrrolidone, Dimethylsulfoxide (DMSO), or a mixed solvent thereof. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1, 1' -bis (diphenylphosphino) ferrocene, and the like are preferable. As the copper catalyst, copper iodide or the like is preferable.

Synthesis of Compound (C-5)

(in the formula, R⁶Represents a protecting group for a carboxyl group. ) The synthesis method is to make the protecting group R of the compound (C-4) by using acid or alkali⁶Deprotection to synthesize the compound (C-5) of the present invention.

The reaction is carried out by reacting the compound (C-4) with an equivalent or excess amount of an acid or base in a solvent inert to the reaction at room temperature to under reflux with heating for usually 0.5 to 5 days. Here, the solvent is not particularly limited, and examples thereof include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane, 1, 2-dimethoxyethane, and 1, 2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; n, N-Dimethylformamide (DMF), N-methylpyrrolidone, Dimethylsulfoxide (DMSO); water or a mixed solvent thereof, and the like. Examples of the acid include: inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, and the like; or a solution obtained by diluting these acids with water or an organic solvent. Examples of the base include: inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, and potassium carbonate; metal alcoholates such as sodium ethoxide and sodium methoxide; or a solution obtained by diluting these bases with water or the like.

Synthesis method (D)

Synthesis of Compound (D-2)

(in the formula, X⁴Represents a leaving group. ) The present synthesis method is a method for synthesizing the compound (D-2) by halogenating the compound (D-1). As X⁴Examples of the leaving group include: iodine atom, bromine atom, chlorine atom. The reaction is carried out by reacting the compound (D-1) with an equal amount or an excess of a halogenating agent in a solvent inert to the reaction, usually at 0 ℃ to reflux under heating for 0.5 hours to 3 days. The reaction is preferably carried out under an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, and examples thereof include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane, 1, 2-dimethoxyethane, and 1, 2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane, and chloroform; ethyl acetate; water or a mixed solvent thereof, and the like. Examples of the halogenating agent include: chlorine, bromine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, water, or a mixed solvent thereof.

Synthesis of Compound (D-4)

(in the formula, X⁴And Y²Represents a leaving group. ) The present synthesis method is a method for synthesizing the compound (D-4) by reacting the compound (D-2) with the compound (D-3). As X⁴Examples of the leaving group include: iodine atom, bromine atom, chlorine atom. As Y²Examples of the leaving group include: halogen atom, methylsulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group and the like. The reaction is carried out by using an equal amount or an excess of the compounds (D-2) and (D-3) in a solvent inert to the reaction in the presence of a base at room temperature to reflux under heatingThe reaction is carried out for 0.5 hour to 3 days. The reaction is preferably carried out under an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, and examples thereof include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane, 1, 2-dimethoxyethane, and 1, 2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane, and chloroform; n, N-Dimethylformamide (DMF), N-methylpyrrolidone (cpmp), dimethyl sulfoxide (DMSO), pyridine, ethyl acetate; or a mixed solvent thereof; examples of the base include: inorganic salts such as sodium hydride, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate; metal alcoholates such as sodium ethoxide and sodium methoxide; triethylamine, N-ethyl-N, N-Diisopropylamine (DIPEA), 1, 8-diazabicyclo [5.4.0 ]]-7-undecene (DBU), pyridine and the like.

Synthesis of Compound (D-5)

(in the formula, X⁴Represents a leaving group, R⁶Represents a protecting group for a carboxyl group. ) The present synthesis method is a method for synthesizing compound (D-5) by coupling compound (D-4) with compound (A-6). As X⁴Examples of the leaving group include: iodine atom, bromine atom, chlorine atom. The reaction is carried out by using an equal amount or an excess of the compounds (D-4) and (A-6) and reacting the reaction mixture in a solvent inert to the reaction in the presence of a base, a copper catalyst and a ligand at room temperature to under reflux with heating for usually 0.5 hours to 3 days. The reaction is preferably carried out under an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, and examples thereof include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane, 1, 2-dimethoxyethane, and 1, 2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane, and chloroform; n, N-Dimethylformamide (DMF), N-methylpyrrolidone (cpmp), dimethyl sulfoxide (DMSO), ethyl acetate; or a mixed solvent thereof. As the base, there may be mentionedTo cite: inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and cesium carbonate; metal alcoholates such as sodium ethoxide and sodium methoxide; triethylamine, N-ethyl-N, N-Diisopropylamine (DIPEA), 1, 8-diazabicyclo [5.4.0 ]]-7-undecene (DBU), and the like. Examples of the copper catalyst include: cupric chloride, cupric bromide, cupric iodide, cupric oxide, etc. Examples of the ligand include: proline, trans-N, N' -dimethylcyclohexane-1, 2-diamine, N-dimethylaminoacetic acid, 1, 10-phenanthroline, and the like.

Synthesis of Compound (D-6)

(in the formula, R⁶Represents a protecting group for a carboxyl group. ) The present synthesis method is a method for synthesizing the compound (D-6) by debenzylation of the compound (D-5). The reaction is carried out by reacting the compound (D-5) in a solvent inert to the reaction in the presence of a palladium catalyst under a hydrogen atmosphere at room temperature to under heating reflux for usually 0.5 to 2 days. Here, the solvent is not particularly limited, and examples thereof include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane, 1, 2-dimethoxyethane, and 1, 2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; n, N-Dimethylformamide (DMF), N-methylpyrrolidone (cpmp), dimethyl sulfoxide (DMSO), ethyl acetate; or a mixed solvent thereof. The palladium catalyst is preferably palladium-carbon, palladium hydroxide, palladium black, or the like.

Synthesis of Compound (D-8)

(in the formula, R⁶Represents a protecting group for a carboxyl group. And, R¹¹Represents an unsubstituted or substituted alkylsulfonyl group having 1 to 9 carbon atoms or an unsubstituted or substituted phenylsulfonyl group. And, Z¹Represents a leaving group. ) The present synthesis method is a method for synthesizing the compound (D-8) by sulfonylesterifying the phenolic hydroxyl group of the compound (D-6). As R¹¹Examples of the sulfonyl group include: methylsulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, and the like. As Z¹Examples of the leaving group include: halogen atom, methylsulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group and the like. The reaction is carried out by using an equal amount or an excess of the compounds (D-6) and (D-7) and reacting the reaction mixture in a solvent inert to the reaction in the presence of a base at 0 ℃ to reflux with heating for usually 0.5 hours to 3 days. The reaction is preferably carried out under an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, and examples thereof include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane, 1, 2-dimethoxyethane, and 1, 2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane, and chloroform; n, N-Dimethylformamide (DMF), N-methylpyrrolidone (cpmp), dimethyl sulfoxide (DMSO), pyridine, ethyl acetate; or a mixed solvent thereof. The reaction is preferably carried out under an inert gas atmosphere. Examples of the base include: inorganic salts such as sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate; triethylamine, N-ethyl-N, N-Diisopropylamine (DIPEA), 1, 8-diazabicyclo [5.4.0 ]]-7-undecene (DBU), pyridine and the like.

Synthesis of Compound (D-9)

(in the formula, R⁶Represents a protecting group for a carboxyl group. And, R¹¹Represents an unsubstituted or substituted alkylsulfonyl group having 1 to 9 carbon atoms or an unsubstituted or substituted phenylsulfonyl group. And, Y¹represents-B (OH)₂OR-B (OR)⁷)OR⁸. Herein, R is⁷And R⁸The same or different from each other, represent an alkyl group having 1 to 6 carbon atoms, or R⁷And R⁸The alkylene group has 1 to 6 carbon atoms. ) The present synthesis method is a method for synthesizing compound (D-9) by coupling compound (D-8) with (A-3). As R¹¹Examples of the sulfonyl group include: methylsulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, and the like. The reaction is carried out by using an equal amount or an excess of the compounds (D-8) and (A-3) and reacting the reaction mixture in a solvent inert to the reaction in the presence of a base and a palladium catalyst at room temperature to reflux under heating for usually 0.5 to 2 days. The reaction is preferably carried out under an inert gas atmosphere such as nitrogen. Here, the solvent is not particularly limited, and examples thereof include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane, 1, 2-dimethoxyethane, and 1, 2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; n, N-Dimethylformamide (DMF), N-methylpyrrolidone, Dimethylsulfoxide (DMSO); water or a mixed solvent thereof, and the like. Examples of the base include: inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and potassium phosphate; metal alcoholates such as sodium ethoxide and sodium methoxide; or a solution obtained by diluting these bases with water or the like. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, palladium chloride-1, 1' -bis (diphenylphosphino) ferrocene, and the like are preferable.

Synthesis of Compound (D-10)

(in the formula, R⁶Represents a protecting group for a carboxyl group. ) The synthesis method is to make the protecting group R of the compound (D-9) by using an acid, a base or the like⁶Deprotection to synthesize the compound (D-10) of the present invention. The reaction is carried out by reacting the compound (D-9) with an equivalent or excess of an acid or base in a manner inert to the reactionThe reaction is carried out in a solvent at room temperature to under heating reflux for 0.5 to 5 days. Here, the solvent is not particularly limited, and examples thereof include: aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, Tetrahydrofuran (THF), 1, 4-dioxane, 1, 2-dimethoxyethane, and 1, 2-diethoxyethane; halogenated hydrocarbons such as dichloromethane, 1, 2-dichloroethane, and chloroform; alcohols such as methanol, ethanol, 2-propanol, and butanol; n, N-Dimethylformamide (DMF), N-methylpyrrolidone, Dimethylsulfoxide (DMSO); water or a mixed solvent thereof, and the like. Examples of the acid include: inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, and the like; or a solution obtained by diluting these acids with water or an organic solvent. Examples of the base include: inorganic salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, and potassium carbonate; metal alcoholates such as sodium ethoxide and sodium methoxide; or a solution obtained by diluting these bases with water or the like.

Among the compounds represented by the above formula (I), preferred compounds and pharmaceutically acceptable salts thereof are not particularly limited as long as they are pharmaceutically acceptable salts, and examples of the salts include: salts with inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; salts with organic acids such as maleic acid, fumaric acid, citric acid, malic acid, tartaric acid, lactic acid, succinic acid, benzoic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, formic acid, etc.; salts with amino acids such as glycine, lysine, arginine, histidine, ornithine, glutamic acid, and aspartic acid; salts with alkali metals such as sodium, potassium, and lithium; salts with alkaline earth metals such as calcium and magnesium; salts with metals such as aluminum, zinc, and iron; salts with organic onium such as tetramethylammonium and choline; and salts with organic bases such as ammonia, propylenediamine, pyrrolidine, piperidine, pyridine, ethanolamine, N-dimethylethanolamine, 4-hydroxypiperidine, tert-octylamine, dibenzylamine, morpholine, glucosamine, phenylglycylalkyl ester (フェニルグリシルアルキルエステル), ethylenediamine, N-methylglucamine, guanidine, diethylamine, triethylamine, dicyclohexylamine, N' -dibenzylethylenediamine, chloroprocaine, procaine, diethanolamine, N-benzylphenylamine, piperazine, tris (hydroxymethyl) aminomethane.

The compound represented by the formula (I) and a salt thereof include various hydrates or solvates.

The above-mentioned various pharmaceutically acceptable salts of the compound represented by the formula (I) can be appropriately prepared according to the basic knowledge in the art.

The compounds of the present invention also include stereoisomers, racemates, and all possible optically active forms of the compounds represented by formula (I).

The compound represented by the formula (I) and the pharmaceutically acceptable salt thereof of the present invention have particularly excellent xanthine oxidase inhibitory activity. The compound represented by the formula (I) and the pharmaceutically acceptable salts thereof of the present invention are effective as xanthine oxidase inhibitors due to their excellent xanthine oxidase inhibitory activity.

The compound represented by the formula (I) and a pharmaceutically acceptable salt thereof of the present invention can be used as a drug which can be clinically used as a xanthine oxidase inhibitor and is useful for treating or preventing gout, hyperuricemia, tumor lysis syndrome, urinary calculi, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and cardiac insufficiency, renal diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease, and diseases in which xanthine oxidase is involved, such as autoimmune diseases, and the like.

The compound represented by the above formula (I) and pharmaceutically acceptable salts thereof may be combined with a pharmaceutically acceptable carrier and/or diluent to form a pharmaceutical composition. The pharmaceutical composition can be formed into various dosage forms for oral or parenteral administration. Examples of parenteral administration include: intravenous, subcutaneous, intramuscular, transdermal or intrarectal administration.

A preparation containing one or more of the compounds represented by the formula (I) or salts thereof of the present invention as an active ingredient is prepared using a carrier or excipient or other additives usually used for the preparation of preparations. The carrier or excipient for the pharmaceutical preparation may be either solid or liquid, and examples thereof include: lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cacao butter, ethylene glycol, etc. or other commonly used substances. The administration may be any form of oral administration such as tablets, pills, capsules, granules, powders, and liquid preparations, or parenteral administration such as injections such as intravenous injection and intramuscular injection, suppositories, and transdermal injection.

The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof varies depending on the kind of disease, the route of administration, the symptoms, age, sex, body weight, and the like of a patient, and can be administered usually in 1 or several times per day in an amount ranging from 0.01 to 1000mg for an adult. However, since the dose varies depending on various conditions, it may be sufficient to administer a smaller amount than the above dose, and it may be necessary to administer an amount exceeding the above range.

Examples

The present invention will be described below with reference to specific examples. However, the present invention is not limited to these examples.

The isolated novel compounds have the structure¹H NMR and/or mass analysis (mass spectrometry) using a single quadrupole device (single quadrupole ionization) with an electrospray source, or other suitable analysis methods.

About measuring¹H NMR Spectroscopy (400MHz, DMSO-d)₆Or CDCl₃) The compound of (1), showing its chemical shift (: ppm) and coupling constant (J: hz). As to the results of the mass analysis, in terms of M⁺+ H, i.e. addition of a proton (H) to the molecular mass (M) of the compound⁺) The form of the value of (a) shows the observed measured value. The following abbreviations respectively have the following meanings.

s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet.

The compounds synthesized according to the following examples were further analyzed by High Performance Liquid Chromatography (HPLC) analysis and mass analysis using a Time Of Flight mass spectrometer (TOF-MS) equipped with an electrospray ion source.

The retention time (unit: min) of the compound in the HPLC analysis under the following analytical conditions is shown as the HPLC retention time.

HPLC measurement conditions

A measuring device: Hewlett-Packard 1100HPLC

Column Imtakt Cadenza CD-Cl 8100 mm × 4.6.6 mm 3μm

UV: PDA detection (254nm)

Column temperature: 40 degree

Gradient conditions:

solvent: a: h₂O/acetonitrile =95/5

0.05% TFA (trifluoroacetic acid)

B：H₂O/acetonitrile =5/95

0.05% TFA (trifluoroacetic acid)

Flow rate: 1.0 mL/min

Gradient: 0-1 minute, solvent B: 2% solvent a: 98 percent of

1-14 minutes, solvent B: 2% → 100% solvent a: 98% → 0%

14-17 minutes, solvent B: 100% of solvent A: 0 percent of

17-19 minutes, solvent B: 100% → 2% solvent a: 0% → 98%

In addition, as to the results of the mass analysis,"M" observed by the following apparatus and analysis conditions is displayed⁺The value of + H "(Obs. Mass: addition of a proton (H) to the molecular Mass (M) of the compound⁺) Measured value of), "M⁺The calculated value of + H (Pred. Mass) and the measured value of "M" are also shown⁺The value of + H "is calculated as a composition formula (chemical formula).

TOF-MS measurement conditions

A mass spectrometer comprises: shimadzu corporation LCMS-IT-TOF

LC：Prominence

Column Phenomenex Synergi Hydro-RP 4.0mm × 20mm 2.5 mmμm

UV: PDA detection (254nm)

Flow rate: 0.6 mL/min

Column temperature: 40 degree

Detecting voltage: 1.63kV

Gradient condition

Solvent: a: h₂O/acetonitrile =95/5

0.1% HCOOH

B：H₂O/acetonitrile =5/95

0.1% HCOOH

Flow rate: 0.5 mL/min

Gradient: 0-0.2 min, solvent B: 2% solvent a: 98 percent of

0.2-2.5 minutes, solvent B: 2% → 100% solvent a: 98% → 0%

2.5-3.8 minutes, solvent B: 100% of solvent A: 0 percent of

3.8-4.0 minutes, solvent B: 100% → 2% solvent a: 0% → 98%

4.0-5.0 minutes, solvent B: 2% solvent a: 98 percent of

[ reference example ] Synthesis of 5-bromo-2-chloropyridine-4-carbaldehyde (reference example Compound)

10.6mL of diisopropylamine was dissolved in =100mL of THF, and after cooling to-78 deg.C, 22.7mL of n-butyllithium was slowly added dropwise thereto. After the reaction solution was stirred for 1 hour, a solution of 9.7g of 5-bromo-2-chloropyridine dissolved in 50mL of THF was slowly added dropwise thereto, and the reaction solution was further stirred for 1 hour. Thereafter, 10ml of N-Dimethylformamide (DMF) was added dropwise thereto. After the mixed solution was stirred at-78 ℃ for 1 hour, 30mL of a 2M aqueous hydrochloric acid solution was added, the temperature was gradually raised to room temperature, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure. 10mL of methylene chloride was added to the residue to obtain 3.23g of 5-bromo-2-chloropyridine-4-carbaldehyde. Then, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate ═ 9: 1), whereby 6.34g of 5-bromo-2-chloropyridine-4-carbaldehyde was obtained.

[ example 1]1- (4-cyano-5-phenylpyridin-2-yl) -1H-pyrazole-4-carboxylic acid (Compound number)1) (Synthesis method (A))

(1) 8.80g of 5-bromo-2-chloropyridine-4-carbaldehyde, 5.36g of phenylboronic acid and 11.06g of potassium carbonate were suspended in 100mL of a mixed solution of 4-dioxane/water 4/1, and 924mg of tetrakis (triphenylphosphine) palladium was added and heated at 80 ℃ for 5 hours under nitrogen atmosphere. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain 10.80g of 2-chloro-5-phenylpyridine-4-carbaldehyde.

(2) 10.80g of 2-chloro-5-phenylpyridine-4-carbaldehyde, 5.56g of hydroxylamine seed 1 hydrochloride and 5.44g of sodium formate were suspended in 100mL of formic acid, and 12.2g of acetic anhydride was added thereto, followed by heating at 100 ℃ for 2 hours in a nitrogen atmosphere. 100mL of water was added and purification was carried out by a conventional method to obtain 6.34g of 2-chloro-5-phenylpyridine-4-carbonitrile.

(3) 3.22g of 2-chloro-5-phenylpyridine-4-carbonitrile, 2.31g of ethyl 1H-pyrazole-4-carboxylate, and 3.11g of potassium carbonate were suspended in 40mL of dimethyl sulfoxide, and the mixture was heated at 120 ℃ for 2.5 hours under a nitrogen atmosphere. 50mL of water was added and purification was carried out by a conventional method to obtain 3.97g of ethyl 1- (4-cyano-5-phenylpyridin-2-yl) -1H-pyrazole-4-carboxylate.

(4) 3.97g of ethyl 1- (4-cyano-5-phenylpyridin-2-yl) -1H-pyrazole-4-carboxylate was dissolved in 30mL of a mixed solution of tetrahydrofuran/methanol (1/1), 30mL of a 6M aqueous hydrochloric acid solution was added, and the mixture was heated at 80 ℃ for 48 hours. Purification was carried out by a conventional method to obtain 3.71g of 1- (4-cyano-5-phenylpyridin-2-yl) -1H-pyrazole-4-carboxylic acid.

HPLC retention time: 10.48 minutes

Obs Mass (M⁺+H)：291.0880

Pred Mass (M⁺+H)：291.0877

Formula (M): c₁₆H₁₀N₄O₂

[ examples 2 to 70]

Compounds nos. 2 to 70 were synthesized in the same manner as in example 1 using the compounds of the above reference examples as starting materials.

[ example 71]1- (4-cyano-5- (3-methylsulfonylphenyl) pyridin-2-yl) -1H-pyrazole-4-carboxylic acid (Compound number)71) (Synthesis method (B))

(1) 5.51g of 5-bromo-2-chloropyridine-4-carbaldehyde, 26.5g of trimethyl orthoformate and 4.75g of p-toluenesulfonic acid monohydrate were suspended in 50mL of methanol, and the suspension was heated at 70 ℃ for 4 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and brine, and then dried and concentrated under reduced pressure to obtain 5.48g of 5-bromo-2-chloro-4- (dimethoxymethyl) -pyridine.

(2) 5.33g of 5-bromo-2-chloro-4- (dimethoxymethyl) -pyridine, 2.33g of ethyl 1H-pyrazole-4-carboxylate and 4.14g of potassium carbonate were suspended in 50mL of dimethylformamide and heated at 90 ℃ for 7 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain a crude product of ethyl 1- (5-bromo-4- (dimethoxymethyl) pyridin-2-yl) -1H-pyrazole-4-carboxylate.

The crude product obtained above was suspended in 25mL of formic acid, 2.78g of hydroxylamine seed 1 hydrochloride was added, and the mixture was heated at 70 ℃ for 30 minutes in a nitrogen atmosphere. After the formation of oxime was confirmed, 2.72g of sodium formate and 10.2g of acetic anhydride were added, and the mixture was heated at 110 ℃ for 15 hours. After the reaction mixture was cooled to room temperature, 25mL of water was added and the mixture was washed with 100mL of water to obtain 2.26g of 1- (5-bromo-4-cyanopyridin-2-yl) -1H-pyrazole-4-carboxylic acid ethyl ester.

(3) 80.3mg of ethyl 1- (5-bromo-4-cyanopyridin-2-yl) -1H-pyrazole-4-carboxylate, 75.0mg of 3- (methylsulfonyl) benzeneboronic acid, 10.2mg of palladium chloride-1, 1' -bis (diphenylphosphino) ferrocene and 106.1mg of potassium phosphate were suspended in 0.8mL of a mixed solvent of 1, 4-dioxane/water 3/1 and heated at 90 ℃ for 15 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, 2mL of water and 4mL of ethyl acetate were added to the reaction mixture, followed by stirring, and the organic phase was concentrated and dried under reduced pressure to obtain a crude product of ethyl 1- (4-cyano-5- (3-methylsulfonylphenyl) pyridin-2-yl) -1H-pyrazole-4-carboxylate.

The crude product obtained above was dissolved in 0.8mL of 4M hydrochloric acid 1, 4-dioxane solution, 0.2mL of 6M aqueous hydrochloric acid solution was added, and heated at 100 ℃ for 14 hours. The reaction mixture was cooled to room temperature, and then concentrated to obtain a crude product of 1- (4-cyano-5- (3-methylsulfonylphenyl) pyridin-2-yl) -1H-pyrazole-4-carboxylic acid. This was purified by reverse phase HPLC to obtain 18.1mg of 1- (4-cyano-5- (3-methylsulfonylphenyl) pyridin-2-yl) -1H-pyrazole-4-carboxylic acid.

HPLC retention time: 8.60 minutes

Obs Mass(M⁺+H)：369.0645

Pred Mass(M⁺+H)：369.0652

Formula (M): c₁₇H₁₂N₄O₄S

[ examples 72 to 74]

Compounds No. 72 to 74 were synthesized in the same manner as in example 71 using the compounds of the above-mentioned reference examples as starting materials.

EXAMPLE 75]1- (5-cyano-6-phenylpyridin-3-yl) -1H-pyrazole-4-carboxylic acid (Compound number)75) (Synthesis method (C))

(1) 255mg of 2, 3-dibromo-5-fluoropyridine, 168mg of 1H-pyrazole-4-carboxylic acid ethyl ester and 207mg of potassium carbonate were suspended in 2mL of dimethyl sulfoxide, and the mixture was heated at 120 ℃ for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, brine, and then dried and concentrated under reduced pressure to obtain a crude product of ethyl 1- (5, 6-dibromopyridine-1H-pyrazole-4-carboxylate, which was purified by column chromatography (hexane/ethyl acetate ═ 9/1), thereby obtaining 164mg of ethyl 1- (5, 6-dibromopyridine-1H-pyrazole-4-carboxylate.

(2) 82.0mg of ethyl 1- (5, 6-dibromopyridine-1H-pyrazole-4-carboxylate, 29.3g of phenylboronic acid and 60.5mg of potassium carbonate were suspended in 1.5mL of a mixed solution of 1, 4-dioxane/water-4/1, 12.6mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was heated at 80 ℃ for 7 hours under nitrogen, water was added to the reaction mixture, extraction was performed with ethyl acetate, the organic layer was washed with brine, and then dried and concentrated under reduced pressure to obtain a crude product of ethyl 1- (5-bromo-6-phenylpyridin-3-yl) -1H-pyrazole-4-carboxylate, which was purified by column chromatography (hexane/ethyl acetate-3/1), whereby 82.2mg of 1- (5-bromo-6-phenylpyridin-3-yl) was obtained 1H-pyrazole-4-carboxylic acid ethyl ester.

(3) 82.2mg of ethyl 1- (5-bromo-6-phenylpyridin-3-yl) -1H-pyrazole-4-carboxylate and 31.3mg of copper (I) cyanide were suspended in 1.5mL of dimethylformamide and heated at 160 ℃ for 6 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then, the insoluble matter was removed by celite filtration, and water was added to the filtrate to conduct extraction with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain a crude product of ethyl 1- (5-cyano-6-phenylpyridin-3-yl) -1H-pyrazole-4-carboxylate. This was purified by column chromatography (hexane/ethyl acetate ═ 3/1), whereby 54.2mg of 1- (5-cyano-6-phenylpyridin-3-yl) -1H-pyrazole-4-carboxylic acid ethyl ester was obtained.

(4) 54.2mg of 1- (5-cyano-6-phenylpyridin-3-yl) -1H-pyrazole-4-carboxylic acid ethyl ester was suspended in 1.0mL of a mixed solution of tetrahydrofuran/methanol (1/1), 0.2mL of a 2M aqueous sodium hydroxide solution was added, and the mixture was heated at 50 ℃ for 2 hours under a nitrogen atmosphere. To the reaction mixture was added 0.2mL of a 2M aqueous hydrochloric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain a crude product of 1- (5-cyano-6-phenylpyridin-3-yl) -1H-pyrazole-4-carboxylic acid. This was purified by reverse phase HPLC, whereby 6.35mg of 1- (5-cyano-6-phenylpyridin-3-yl) -1H-pyrazole-4-carboxylic acid was obtained.

HPLC retention time: 9.76 minutes

Obs Mass(M⁺+H)：291.0875

Pred Mass(M⁺+H)：291.0877

Formula (M): c₁₆H₁₀N₄O₂

[ examples 76 to 84]

Compounds No. 76 to 84 were synthesized in the same manner as in example 75 using the above ethyl 1- (5, 6-dibromopyridine-1H-pyrazole-4-carboxylate as a starting material.

Example 85]1- (6-cyano-5-phenylpyridin-2-yl) -1H-pyrazole-4-carboxylic acid (Compound number)85) (Synthesis method (D))

(1) 2.73g of 2-cyano-3-hydroxypyridine was suspended in 60mL of a mixed solution of acetonitrile/water (5/1), cooled to 0 ℃, and then 4.85g N-bromosuccinimide was added slowly, and the reaction solution was stirred under nitrogen atmosphere for 2 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with brine, and then dried and concentrated under reduced pressure, whereby 5.39g of a crude product of 6-bromo-2-cyano-3-hydroxypyridine was obtained.

(2) 5.39g of 6-bromo-2-cyano-3-hydroxypyridine and 4.71g of potassium carbonate were suspended in 60mL of dimethylformamide, and 4.66g of benzyl bromide was added thereto and the mixture was heated at 60 ℃ for 12 hours. After the reaction mixture was cooled to room temperature, 60mL of water was added and purification was carried out by a conventional method to obtain 4.73g of 3-benzyloxy-6-bromo-2-cyanopyridine.

(3) 2.64g of 3-benzyloxy-6-bromo-2-cyanopyridine, 1.44g of ethyl 1H-pyrazole-4-carboxylate, 98mg of copper iodide and 2.29g of potassium carbonate were suspended in 20mL of toluene, and 236mg of trans-N, N' -dimethylcyclohexane-1, 2-diamine was added and the mixture was heated at 100 ℃ for 12 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water was added thereto, and extraction was performed with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained crude product was isolated and purified by means of a silica gel column chromatography, whereby 1.30g of 1- (5-benzyloxy) -6-cyanopyridin-2-yl) -1H-pyrazole-4-carboxylic acid ethyl ester was obtained.

(4) 1.39g of 1- (5-benzyloxy) -6-cyanopyridin-2-yl) -1H-pyrazole-4-carboxylic acid ethyl ester was suspended in 30mL of a mixed solution of tetrahydrofuran/ethanol (1/1), and after 409mg of palladium/carbon (10% by weight) was added, the mixture was stirred under hydrogen atmosphere at room temperature for 14 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, whereby 1.02g of ethyl 1- (6-cyano-5-hydroxypyridin-2-yl) -1H-pyrazole-4-carboxylate was obtained.

(5) 46mg of ethyl 1- (6-cyano-5-hydroxypyridin-2-yl) -1H-pyrazole-4-carboxylate was suspended in 1mL of dichloromethane, 35mg of N, N-diisopropylethylamine was added thereto, and after cooling to 0 ℃, 76mg of trifluoromethanesulfonic anhydride was added and the mixture was stirred at room temperature for 4 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The obtained crude product was isolated and purified by means of a silica gel column chromatography, whereby 45.3mg of 1- (6-cyano-5- ((trifluoromethyl) sulfonyloxy) pyridin-2-yl) -1H-pyrazole-2-carboxylic acid ethyl ester was obtained.

(6) 46.8mg of ethyl 1- (6-cyano-5- ((trifluoromethyl) sulfonyloxy) pyridin-2-yl) -1H-pyrazole-2-carboxylate, 17.6mg of phenylboronic acid and 7.8mg of palladium chloride-1, 1' -bis (diphenylphosphino) ferrocene-dichloromethane complex were suspended in 1.0mL of 1, 2-dimethoxyethane, 0.12mL of 1M aqueous potassium carbonate solution was added, and the mixture was heated at 80 ℃ for 3 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure to obtain a crude product of ethyl 1- (6-cyano-5-phenylpyridin-2-yl) -1H-pyrazole-4-carboxylate.

The crude product was suspended in 1.5mL of a mixed solution of tetrahydrofuran/methanol (2/1), 0.24mL of a 2M aqueous sodium hydroxide solution was added, and the mixture was heated at 50 ℃ for 4 hours. After the reaction mixture was cooled to room temperature, 0.24mL and 2mL of 2M hydrochloric acid were added, and extraction was performed with ethyl acetate and concentration under reduced pressure was performed. The obtained crude product was purified by reverse phase HPLC, whereby 18.8mg of 1- (6-cyano-5-phenylpyridin-2-yl) -1H-pyrazole-4-carboxylic acid was obtained.

HPLC retention time: 10.40 minutes

Obs Mass(M⁺+H)：291.0874

Pred Mass(M⁺+H)：291.0877

Formula (M): c₁₆H₁₀N₄O₂

[ examples 86 to 96]

Using ethyl 1- (6-cyano-5- ((trifluoromethyl) sulfonyloxy) pyridin-2-yl) -1H-pyrazole-2-carboxylate obtained in (5) of example 85 as a starting material, compounds nos. 86 to 96 were synthesized in the same manner as in example 85.

[ examples 97 to 107]

Compounds No. 97 to 107 were synthesized in the same manner as in example 1 using the compounds of the above reference examples as starting materials.

[ example 108]

For the compounds synthesized according to the methods of the above examples, xanthine oxidase inhibitory activities were measured.

(1) Preparation of test Compound

The test compound was dissolved in DMSO (manufactured by Sigma) to a concentration of 20mM, and then adjusted to a target concentration for use.

(2) Measurement method

The xanthine oxidase inhibitory activity of the compounds of the present invention was evaluated by partially modifying the Method described in the literature (Method enzymic Analysis, 1,521-522, 1974). This evaluation was carried out by measuring the oxidase-type xanthine oxidoreductase activity. That is, a xanthine (manufactured by Sigma Co.) solution prepared in advance with a 20mM sodium hydroxide solution to 10mM was prepared with a 100mM phosphate buffer to 30 mMμM, at 75μL/well add in 96-well plate. At 1.5μEach test compound diluted to 100 times the final concentration in DMSO was added to the well at L ratio, and mixed using a microplate reader SPECTRA maxPlus384(Molecular analyzer)Manufactured by Devices corporation) was measured for absorbance at 290 nm. Next, the oxidase type xanthine oxidoreductase (manufactured by Calbiochem corporation, buttermilk) was adjusted to 30.6mU/mL using 100mM phosphate buffer solution, and the concentration was adjusted to 73.5 mU/mLμL/well was added. The absorbance change at 290nm was measured immediately after mixing for 5 minutes. The inhibition ratio of the test compound was calculated by using the enzyme activity when DMSO was added instead of the test compound solution as 100%, and the 50% inhibition concentration of the oxidase-type xanthine oxidoreductase was calculated by fitting to a dose response curve.

The results are shown in the following table. Wherein the symbols (+, ++, +++) in the table indicate the inhibitory activity values as follows:

10.0nM≤IC₅₀：+

5.0nM≤IC₅₀＜10.0nM：++

1.0nM≤IC₅₀＜5.0nM：+++

。

[ example 109]

Uric acid lowering action in blood (Normal rat)

A test compound suspended in a 0.5% methyl cellulose solution was forcibly administered to 7-8 week-old male Crlj: CD 1-line rats (Charles river, Japan) using a feeding needle (feeding needle). Blood was collected from the heart at 6 hours, 16 hours, and 24 hours after administration, and then serum was isolated. Uric acid reduction rate was determined by the following equation by measuring uric acid value in blood using a uric acid enzyme method using a uric acid measurement kit (オートセラ SUA: メディカル) and an absorbance meter (Hitachi automatic analyzer 7180).

Uric acid reduction Rate (%)

(uric acid number of control animal-uric acid number of animal to which test compound was administered). times.100/uric acid number of control animal

In this test, it was confirmed that: the excellent blood uric acid lowering effect of the compound of the present invention. For example, compounds No. 1,5, 10, 14, 19, 21 and 33 showed a 70% or more uric acid lowering rate after oral administration for 6 hours at an amount of 1 mg/kg.

The above results show that: the compound has a powerful blood uric acid reducing effect.

[ example 110]

Uric acid lowering action in blood (Normal rat)

The test compound suspended in a 0.5% methyl cellulose solution was forcibly administered to 8-9 weeks old male rats of Sprague-Dawley line (Charles River, Japan) using a feeding needle (feeding needle). Blood was collected from the tail vein at 6 hours, 24 hours after administration, after which plasma was separated. The uric acid reduction rate was determined by the following formula by measuring the uric acid level in blood using a uric acid measurement kit (L type Wako UA, seed and seed F: and pure chemical industries) according to the uric acid enzymatic method using an absorbance meter.

Uric acid reduction Rate (%)

(uric acid number of control animal-uric acid number of animal to which test compound was administered). times.100/uric acid number of control animal

Compound No. 1 compound showed a 70% or more uric acid lowering rate at an amount of 1mg/kg at 6 hours and 24 hours after administration. Further, the compounds of compound nos. 97 and 98 showed a uric acid lowering rate of 50% or more at an amount of 10mg/kg at 6 hours and 24 hours after the administration. The results show that: the compound has a powerful and continuous blood uric acid reduction effect.

[ example 111]

Uric acid lowering action in blood (Setarian monkey (フサオマキザル))

Test compounds suspended in 0.5% methylcellulose solution were forcibly administered into the stomach from the nasal cavity of a cynomolgus monkey using a disposable catheter and syringe. Blood was collected from the saphenous vein at 4 hours, 24 hours after administration, after which plasma was isolated. The uric acid reduction rate was determined by the following formula by measuring the uric acid level in blood using a uric acid measurement kit (L type Wako UA, seed and seed F: and pure chemical industries) according to the uric acid enzymatic method using an absorbance meter.

Uric acid reduction Rate (%)

(uric acid number of control animal-uric acid number of animal to which test compound was administered). times.100/uric acid number of control animal

Compound No. 1 compound showed a uric acid lowering rate of 50% or more at an amount of 1mg/kg at 4 hours and 24 hours after administration.

The results show that: even for cynomolgus monkeys, the compounds of the present invention have potent and sustained uric acid lowering effects in blood.

[ example 112]

Uric acid lowering action in blood (beagle dog)

With respect to compound No. 1, a uric acid lowering effect in blood of beagle dogs was confirmed. Beagle dogs (northern mountain labes) were orally and forcibly administered test compounds suspended in a 0.5% methylcellulose solution. Blood was collected from the radial cutaneous vein 24 hours after administration, after which plasma was isolated. The uric acid level in blood was measured by the LC-MS/MS method, and the uric acid lowering rate was determined by the following equation.

Uric acid reduction Rate (%)

(uric acid number of control animal-uric acid number of animal to which test compound was administered). times.100/uric acid number of control animal

Compound No. 1 showed a uric acid lowering rate of 50% or more at an amount of 3mg/kg at 24 hours after administration.

The results show that: the compounds of the invention have a sustained blood uric acid lowering effect in dogs.

From the above results, it is expected that: the compound of the present invention exerts a potent uric acid lowering effect even when administered 1 time or more per 1 day. In addition, in clinical practice, it is important to continuously decrease the uric acid level for the treatment or prevention of hyperuricemia and various diseases caused by hyperuricemia, particularly chronic diseases, and it is expected that: the present invention exerts an excellent effect on the diseases.

Industrial applicability

The compound represented by the formula (I) and a pharmaceutically acceptable salt thereof of the present invention have xanthine oxidase inhibitory activity and are useful as therapeutic or prophylactic agents for diseases in which xanthine oxidase is involved, particularly gout, hyperuricemia, tumor lysis syndrome, urinary calculus, hypertension, dyslipidemia, diabetes, cardiovascular diseases such as arteriosclerosis and cardiac insufficiency, renal diseases such as diabetic nephropathy, respiratory diseases such as chronic obstructive pulmonary disease, inflammatory bowel disease, autoimmune diseases, and the like, which are clinically applicable as xanthine oxidase inhibitors.

Claims (9)

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

in the formula (I), the compound is shown in the specification,

a represents a phenyl group, wherein the phenyl groups are unsubstituted, the same or different from each other, and may be selected from the group consisting of a halogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a phenyl group, and a-O-R group²and-O-a halogenated alkyl group having 1 to 6 carbon atoms, wherein 1 to 3 groups of the group Q are substituted,

x, and Z represent CH, and Y represents a nitrogen atom,

r represents a hydrogen atom, and R represents a hydrogen atom,

R¹represents a hydrogen atom, and

R²represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a is unsubstituted.

3. The compound according to claim 1 or 2, wherein A is the same or different from each other, and may be substituted with 1 to 3 groups Q selected from a halogen atom, a methyl group and a methoxy group, or a pharmaceutically acceptable salt thereof.

4. A compound selected from any one of the following (1) to (46) or a pharmaceutically acceptable salt thereof:

(1) 1- (4-cyano-5-phenylpyridin-2-yl) -1H-pyrazole-4-carboxylic acid,

(2) 1- [ 4-cyano-5- (4-methoxyphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(3) 1- [ 4-cyano-5- (2-ethoxyphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(4) 1- [ 4-cyano-5- (2-methylphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(5) 1- [ 4-cyano-5- (2-fluorophenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(6) 1- [ 4-cyano-5- (2-chlorophenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(7) 1- [ 4-cyano-5- (2-methoxyphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(8) 1- { 4-cyano-5- [2- (trifluoromethyl) phenyl ] pyridin-2-yl } -1H-pyrazole-4-carboxylic acid,

(9) 1- { 4-cyano-5- [2- (trifluoromethoxy) phenyl ] pyridin-2-yl } -1H-pyrazole-4-carboxylic acid,

(10) 1- [ 4-cyano-5- (3-methylphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(11) 1- [ 4-cyano-5- (3-fluorophenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(12) 1- [ 4-cyano-5- (3-chlorophenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(13) 1- [ 4-cyano-5- (3-methoxyphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(14) 1- [ 4-cyano-5- (4-methylphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(15) 1- [ 4-cyano-5- (4-chlorophenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(16) 1- [ 4-cyano-5- (4-hydroxyphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(17) 1- [ 4-cyano-5- (2-ethoxy-6-fluorophenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(18) 1- [ 4-cyano-5- (2-fluoro-6-methoxyphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(19) 1- [ 4-cyano-5- (2-fluoro-3-methoxyphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(20) 1- [ 4-cyano-5- (2, 3-difluorophenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(21) 1- [ 4-cyano-5- (4-fluorophenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(22) 1- [ 4-cyano-5- (3-ethoxyphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(23) 1- [ 4-cyano-5- (3-propoxyphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(24) 1- [ 4-cyano-5- (2, 4-difluorophenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(25) 1- [ 4-cyano-5- (2-fluoro-4-methylphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(26) 1- [ 4-cyano-5- (2-fluoro-5-methylphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(27) 1- [ 4-cyano-5- (2, 5-difluorophenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(28) 1- [ 4-cyano-5- (2-fluoro-3-methylphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(29) 1- [ 4-cyano-5- (4-fluoro-3-methylphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(30) 1- [ 4-cyano-5- (2, 3-dimethylphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(31) 1- [ 4-cyano-5- (3-fluoro-4-methylphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(32) 1- [ 4-cyano-5- (3-chloro-4-fluorophenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(33) 1- { 4-cyano-5- [4- (trifluoromethyl) phenyl ] pyridin-2-yl } -1H-pyrazole-4-carboxylic acid,

(34) 1- { 4-cyano-5- [4- (trifluoromethoxy) phenyl ] pyridin-2-yl } -1H-pyrazole-4-carboxylic acid,

(35) 1- { 4-cyano-5- [3- (trifluoromethyl) phenyl ] pyridin-2-yl } -1H-pyrazole-4-carboxylic acid,

(36) 1- { 4-cyano-5- [3- (difluoromethoxy) phenyl ] pyridin-2-yl } -1H-pyrazole-4-carboxylic acid,

(37) 1- { 4-cyano-5- [4- (propan-2-yl) phenyl ] pyridin-2-yl } -1H-pyrazole-4-carboxylic acid,

(38) 1- { 4-cyano-5- [3- (propan-2-yl) phenyl ] pyridin-2-yl } -1H-pyrazole-4-carboxylic acid,

(39) 1- [ 4-cyano-5- (4-fluoro-2-methylphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(40) 1- [ 4-cyano-5- (4-fluoro-2-methoxyphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(41) 1- [ 4-cyano-5- (4-chloro-3-methylphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(42) 1- [ 4-cyano-5- (4-propan-2-yloxy) phenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(43) 1- [5- (4-tert-butylphenyl) -4-cyanopyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(44) 1- [ 4-cyano-5- (4-phenoxyphenyl) pyridin-2-yl ] -1H-pyrazole-4-carboxylic acid,

(45) 1- { 4-cyano-5- [4- (methoxymethyl) phenyl ] pyridin-2-yl } -1H-pyrazole-4-carboxylic acid, and

(46) 1- { 4-cyano-5- [3- (2-methylpropoxy) phenyl ] pyridin-2-yl } -1H-pyrazole-4-carboxylic acid.

5. A pharmaceutical composition comprising a compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. A xanthine oxidase inhibitor comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient.

7. A therapeutic or prophylactic agent for gout, hyperuricemia, tumor lysis syndrome, urinary calculi, hypertension, dyslipidemia, diabetes, cardiovascular disease, renal disease, respiratory disease, inflammatory bowel disease, or autoimmune disease, which comprises the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient.

8. A therapeutic or prophylactic agent for gout or hyperuricemia, which comprises the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient.

9. A compound represented by the formula (II):

in the formula (I), the compound is shown in the specification,

a represents a phenyl group, wherein the phenyl groups are unsubstituted, the same or different from each other, and may be selected from the group consisting of a halogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a phenyl group, and a-O-R group²and-O-a halogenated alkyl group having 1 to 6 carbon atoms, wherein 1 to 3 groups of the group Q are substituted,

x, and Z represent CH, and Y represents a nitrogen atom,

r represents a hydrogen atom, and R represents a hydrogen atom,

R¹represents a hydrogen atom, and is represented by,

R²represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,

R⁶a protecting group representing a carboxyl group, and

w represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group or a cyano group.