WO1999024424A1

WO1999024424A1 - Pyrazole compounds and medicinal use thereof

Info

Publication number: WO1999024424A1
Application number: PCT/JP1998/004892
Authority: WO
Inventors: Atsushi Akahane; Satoru Kuroda; Hiromichi Itani
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1997-11-07
Filing date: 1998-10-28
Publication date: 1999-05-20

Abstract

Pyrazole compounds represented by general formula (I) or salts thereof, exhibiting an intensive antagonism against both of A1 and A2 receptors, thus serving as preventives and/or remedies for ischemic heart diseases such as angina pectoris, peripheral vascular diseases such as claudication, cerebral ischemia, migraine, diabetes, melancholia, Parkinson's disease, etc. wherein R?1 and R2¿ may be the same or different and each represents optionally substituted aryl; R3 represents hydrogen, lower alkyl, or optionally substituted ar(lower)alkyl; and R4 represents either a group of formula (A) (wherein R5 represents optionally substituted ar(lower)alkyl or lower alkanoyl(lower)alkyl) or a group of formula (B) (wherein R6 represents optionally protected carboxyl).

Description

Specification

Birazol compounds and their pharmaceutical uses

Technical field

The present invention relates to a novel pyrazole compound useful as a medicament, a salt thereof, and a use thereof. More specifically, the present invention relates to the prevention of ischemic heart disease (eg, angina), peripheral vascular disease (eg, claudication), cerebral ischemia, migraine, diabetes, depression, Parkinson's disease, etc. And z or a novel pyrazole compound useful for treatment and a salt thereof, and a use thereof.

Background art

Adenosine receptors to date (hereinafter, A, receptor) antagonists or adenosine emissions A ₂ receptor (hereinafter, A ₂ receptor) Various compounds have been proposed as antagonists. However, the compounds proposed to date have not always been effective enough.

An object of the present invention is to provide a novel pyrazole compound useful as an adenosine antagonist and a salt thereof.

Another object of the present invention is to provide a medicament comprising the pyrazole compound or a salt thereof.o

Disclosure of the invention

The present inventors have result of intensive studies, the general formula (I) novel pyrazole represented by - strength have antagonism against both receptors Le compound or a salt thereof receptors and A ₂ receptors Yes In addition, the compound of the present invention can be used as a preventive and / or therapeutic agent for ischemic heart disease such as angina, peripheral vascular disease such as claudication, cerebral ischemia, migraine, diabetes, depression, Parkinson's disease, and the like. And completed the present invention.

The pyrazole compound of the present invention or a salt thereof is novel and represented by the following general formula (I). General formula (I)

[Wherein, R ¹ and R ² may be the same or different and each is an aryl group which may have a substituent, and R ³ may have a hydrogen, a lower alkyl group or a substituent An ar (lower) alkyl group, and R ⁴ has the formula:

0

N—R ⁵

I

; N

(Wherein, R ⁵ represents an ar (lower) alkyl group which may have a substituent, or a lower alkanoyl (lower) alkyl group), or a formula:

0

(Wherein, R ⁶ represents a carboxy group which may be protected), respectively, wherein R ⁶ represents a carboxy group which may be protected.

The birazol compound of the present invention or a salt thereof can be produced as follows.

Manufacturing method 1

(Ila) (la)-or its salt or its salt Production method 2

(lb) (Ic)

Or its salt or its salt Production method 3

(Id) (Ie)

Or its salt or its salt

Manufacturing method 5

(If) (Ig) or its salt or its salt

Wherein R ¹ , R ² , R ³ and R ⁵ are as defined above, X is a leaving group, R ^3a is an ar (lower) alkyl group, R ^3b is a lower alkyl group and R ^6a is protected. Means a carboxyl group)

The reactions of the above Production Methods 1 to 5 can be carried out according to the methods described in Examples of the present specification or conventional methods in this technical field. The pyrazole compound (I) may include a geometric isomer based on a double bond and a stereoisomer based on Z or an asymmetric carbon atom. Here, the isomer can be converted into another isomer by a conventional method in this technical field.

Examples of the salt of the pyrazole compound (I) include, for example, metal salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.) and alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), and ammonium salts. Salts, organic base salts (eg, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N, dibenzylethylenediamine salt, etc.), organic acid salts (eg, acetate, trifluoroacetic acid) Salt, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc., inorganic acid salts (eg, hydrochloride, hydrobromide, iodide) Hydrochloride, sulfate, phosphate, etc.), amino acid (alginic acid, aspartic acid, glutamic acid, etc.) Salts of Ru and the like. Among these, non-toxic salts are preferably used as pharmaceutically acceptable salts of the pyrazole compounds (I).

The various definitions falling within the scope of the invention as used in the above and below description of the specification are set forth, and suitable examples are set forth in detail.

"Lower" means 1 to 6 carbon atoms unless otherwise noted.

“Aryl” includes, for example, phenyl, naphthyl, indenyl, anthryl and the like, preferably phenyl, naphthyl and more preferably phenyl.

The “aryl” is a halogen (eg, fluoro, chloro, bromo, halide)-a lower alkyl, as described below, a lower alkoxy, a hydroxy group, a tri (lower) alkylsilyloxy (eg, trimethylsilyloxy, t-methyl). Butyldimethylsilyloxy, etc.), phenyl (lower) alkoxy (for example, phenylmethoxy, phenylethoxy, phenylpropoxy, fuunylbutoxy, phenylpentyloxy, phenylhexyloxy, etc.), and halo (lower) alkyl. Phenyl (eg, trifluoromethylphenyl), heterocyclic (lower) alkoxy And one or more (preferably 1 to 3) suitable substituents selected from the above.

Examples of the heterocyclic ring in the “heterocyclic (lower) alkoxy” include a saturated or unsaturated monocyclic or polycyclic heterocyclic ring.

Unsaturated 3- to 8-membered (more preferably 5- to 7-membered) complex monocyclic group containing 1 to 4 nitrogen atoms, such as azepinyl (eg, 1 H-azepinyl etc.), pyrrolyl, pyrrolinyl, imidazolyl, Birazolyl, pyridyl and its N-oxides, dihydric pyridyl, pyrimidinyl, virazinyl, pyridazinyl, triazolyl (eg, 4H-1, 2,4,1-triazolyl, 1H-1,2,3—triazolyl, 2H-1, 2,3_triazolyl), tetrazolyl (for example, 1H-tetrazolyl, 2H-tetrazolyl, etc.);

Saturated 3 to 8 membered (more preferably 5 to 7 membered) heterocyclic group containing 1 to 4 nitrogen atoms, for example perhydroazepinyl (for example, perhydro-1H-azepinyl etc.), pyrrolidinyl, imidazolidinyl, Piperidyl, piperazinyl, etc .;

Unsaturated fused heterocyclic groups containing 1 to 4 nitrogen atoms, such as indolyl, isoindolyl, indolizinyl, benzoimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, quinoxalinyl, imidazopyridyl (for example, Imidazo [4, 5-c] pyridyl, etc.), tetrahydroimidazo pyridyl (for example, 4, 5, 6, 7-tetrahydro [4, 5-c] pyridyl, etc.);

A saturated condensed heterocyclic group containing 1 to 4 nitrogen atoms, for example, 7-azabicyclo [2.2.1] heptyl, 3-azabicyclo [3.2.2] nonanyl, and the like;

Unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing one or two oxygen atoms and one to three nitrogen atoms, such as oxazolyl, isoxazolyl, oxaziazolyl (eg, 1, 2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.);

Saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing one or two oxygen atoms and one to three nitrogen atoms, such as morpholinyl (2-morpholinyl) Nil, 3-morpholinyl), morpholino, sydnoyl, etc .;

Unsaturated condensed heterocyclic groups containing one or two oxygen atoms and one to three nitrogen atoms, such as benzoxazolyl, benzoxodiazolyl and the like;

Unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heterocyclic monocyclic groups containing one or two sulfur atoms and one to three nitrogen atoms, such as thiazolyl, isothiazolyl, thiadiazolyl (eg, 2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc .;

A saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl;

Unsaturated fused heterocyclic groups containing one or two sulfur atoms and one to three nitrogen atoms, such as benzothiazolyl, benzothiaziazolyl, and the like;

An unsaturated 3- to 8-membered (more preferably 5- or 6-membered) complex monocyclic group containing one oxygen atom, such as furyl;

An unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heterocyclic monocyclic group containing one oxygen atom and one or two sulfur atoms, such as dihydrooxathiinyl;

Unsaturated condensed heterocyclic groups containing one or two sulfur atoms, such as benzodienyl, benzodithiynyl and the like;

Unsaturated condensed heterocyclic groups containing one oxygen atom and one or two sulfur atoms, such as benzoxoxathiinyl;

In the “heterocyclic group”, an unsaturated 3 to 8-membered heteromonocyclic group containing one oxygen atom is preferable, and more preferably furyl.

Examples of the alkoxy in the “heterocycle (lower) alkoxy” include methoxy, ethoxy, propoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, neopentyloxy, t_pentyloxy, hexyloxy and the like. .

“Lower alkyl” includes straight-chain or branched alkyl such as methyl, ethyl Propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl and the like. Preferably it is (d—C ₅ ) alkyl, more preferably methyl, ethyl, isobutyl or pentyl.

Examples of the “lower alkoxy” include the alkoxy in the above-mentioned heterocyclic (lower) alkoxy.

Examples of the “alk (lower) alkyl” include, for example, phenyl (lower) alkyl (specifically, benzyl, phenethyl, benzhydryl, trityl, 2-phenylpropyl, 3,4-diphenylbutyl, 2-phenylpentyl). , 6-phenylhexyl and the like).

The “ar (lower) alkyl” may have one or more (preferably 1 to 3) suitable substituents, for example, lower alkyl, lower alkoxy, nitro group and the like as described above. .

Examples of the lower alkanoyl in the “lower alkanoyl (lower) alkyl” include acetyl, propanoyl, butanol, isobutanol, pentanoyl, hexanoyl and the like.

Examples of the lower alkyl in the “lower alkanoyl (lower) alkyl” include the same as those described above.

The “optionally protected carboxy group” is a carboxy group or a protected carboxy group. Examples of the protected carboxy group include an esterified carboxy group and an amidated carboxy group. No. Examples of the esterified carboxy group include lower alkyl esters (eg, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, etc.). However, these may have at least one substituent.

Examples of the substituted lower alkyl ester include lower alkanoyloxy (lower) alkyl esters [eg, acetyloxymethyl ester, propionyloxy) Cimethyl ester, Butyryloxymethyl ester, Valeryloxymethyl ester, Bivaloyloxymethyl ester, Hexanoyloxymethyl ester,

1— (or 2 _) acetoxityl ester, 1— (or 2—or 3—) acetooxypropyl ester, 1 (or 2—or 3—or 4—) acetoxybutyl ester, 1 _ (Or 2—) propionyloxyxethyl ester, 1 (or 2 — or 3—) propionyloxypropyl ester, 1 (or 2—) ptyriloxyxethyl ester, 1 (or 2—) Isobutyryloxyshethyl ester, 1_ (or 2—) Bivaloyloxyl ester, 1 (or 2—) Hexanoyloxyxethyl ester, Isobutyryloxymethyl ester, 2— Tylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1- (or 2 _) pentanoyloxethyl ester, etc.], lower alkane sulfoni (Lower) alkyl ester (e.g., 2-main sill ester), mono (or di or tri) halo (lower) alkyl ester

(Eg, 2-hydroxyethyl ester, 2,2,2-trichloroethyl ester, etc.), lower alkoxycarbonyloxy (lower) alkyl ester [eg, methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl Ester, propoxycarbonyloxymethyl ester, tert-butoxycarbonyloxymethyl ester, one (or two) methoxycarboxyloxyethyl ester, one (or two _) ethoxycarbonyloxyethyl ester, one (Or 2-) isopropoxycarbonyl oxethyl ester, etc.].

Examples of the amidated carboxy group include a carbazole group, a carbamoyl group, and an N-lower alkylcarbamoyl group.

Examples of the leaving group include the above-mentioned halogen and sulfoxy, such as sulfonyloxy (eg, mesiloxy, tosiloxy, etc.).

In the above-mentioned pyrazole compound (I) or a salt thereof, preferably, R ¹ and R ² are the same or different and each represents a hydroxy group or a tri (lower) alkyl group. An aryl group optionally having 1 to 3 substituents selected from the group consisting of a lyloxy group and a heterocyclic (lower) alkoxy group, wherein R ³ is hydrogen, a lower alkyl group, or 1 to 3 lower alkoxy groups may have ar (lower) alkyl group, and R ⁴ has the formula:

0

N

I

: N

(Wherein, R ⁵ is an ar (lower) alkyl group optionally having 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group and a nitro group, or a lower alkanol ( Lower) which means an alkyl group) or a group represented by the formula:

(Wherein, R ⁶ represents a carboxy group or an amidated carboxy group) or a salt thereof.

Among them, R ¹ and R ² are the same or different and each have 1 to 3 substituents selected from the group consisting of a hydroxy group, a tri (lower) alkylsilyloxy group and a morpholino (lower) alkoxy group. An optionally substituted phenyl group, R ³ is hydrogen, a lower alkyl group or a phenyl (lower) alkyl group optionally having 1-3 lower alkoxy groups, and R ⁴ is a group represented by the formula:

(In the formula, R ⁵ is a group consisting of a lower alkyl group, a lower alkoxy group, and a nitro group. A phenyl (lower) alkyl group optionally having 1 to 3 substituents or a lower alkanol (lower) alkyl group, or a group represented by the formula:

(Wherein, R ⁶ represents a carboxy group or a carbazolyl group) or a salt thereof.

Among them, R ¹ and R ² are the same or different and each have 1 to 3 substituents selected from the group consisting of a hydroxy group, a tri (lower) alkylsilyloxy group and a morpholino (lower) alkoxy group. A phenyl group (optionally), R ³ is hydrogen, a lower alkyl group or a phenyl (lower) alkyl group optionally having 1 to 3 lower alkoxy groups, and R ⁴ is a group represented by the formula:

0

(Wherein, R ⁵ is a phenyl (lower) alkyl group optionally having 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group and a nitro group, or a lower alkanol (lower group) A) a compound or a salt thereof, which is a group represented by

R ¹ and R ² may be the same or different and each have 1 to 3 substituents selected from the group consisting of a hydroxy group, a tri (lower) alkylsilyloxy group and a morpholino (lower) alkoxy group A good phenyl group, R ³ is hydrogen, a lower alkyl group or a phenyl (lower) alkyl group optionally having 1 to 3 lower alkoxy groups, and R ⁴ is a group represented by the formula:

(Wherein R ⁶ represents a carboxy group) or a salt thereof.

Pyrazole Ichiru compounds for (I), the receptor, by binding experiments using A ₂ receptor, their adenosine antagonism is confirmed.

Pyrazole Ichiru Compound (I) or a salt thereof of the present invention, adenosine and / or are useful as A ₂ antagonists, cognition-enhancing effects, analgesia, motor activity increasing effect, antidepressant activity, diuretic, cardiac Protective action, cardiotonic action, vasodilatory action (eg, cerebral vasodilatory action), renal blood flow increasing action, renal protective action, renal function improving action, fat degradation increasing action, anti-asthmatic action, insulin secretion promoting action, erythropoietin It has various pharmacological effects, such as production enhancement and platelet aggregation inhibitory effects.It has cognitive enhancers, anti-dementia drugs, psychostimulants, analgesics, cardioprotective drugs, antidepressants, cerebral circulation improvers, and tranquilizers. Therapeutic drugs for heart failure, inotropic drugs, antihypertensive drugs, renal failure drugs, nephrotoxic drugs, renal protective drugs, renal function improvers, diuretics, edema drugs, antiobesity drugs, antiasthmatic drugs, bronchodilators Antipyretic, Gout, Hyperuricemia, Sudden Infant Death Syndrome (SIDS), Immunosuppressive Adenosine, Antidiabetic, Antiulcer, Knee, Meniere Syndrome, anti-anemic, thrombosis, myocardial infarction, embolism, obstructive atherosclerosis, thrombophlebitis, cerebral infarction, transient ischemic therapy It is useful as a remedy, a drug for treating angina, etc., depression, dementia (eg, Alzheimer's disease, cerebrovascular dementia, dementia associated with Parkinson's disease, etc.), Parkinson's disease, anxiety, pain, cerebrovascular disease (eg, essential Hypertension, renal hypertension, etc.), ischemia / reperfusion injury (for example, myocardial ischemia / Z reperfusion injury, cerebral blood / reperfusion injury, peripheral ischemia / reportation injury, etc.), shock (Eg endotoxin shock, bleeding Circulatory insufficiency (acute circulatory insufficiency) due to surgical treatment, systolic dysfunction after resuscitation, bradyarrhythmia, Electro-mechanical dissociation, hemodynamic collapse; ヽ SIRS (systemic inflammatory response syndrome), multiple organ failure, renal failure (eg, acute renal failure, etc.), nephrotoxicity [eg, cisplatines Gentamicin, FR-900506 (disclosed in EP-0184162), cyclosporine (eg, cyclosporin A), etc., nephrotoxicity caused by drugs such as glycerol, nephrotic syndrome, nephritis, edema (eg, cardiac edema, renal edema, Hepatic edema, idiopathic edema, drug-induced edema, acute vascular edema, hereditary vascular edema, cancerous ascites, gestational adenoma, etc.), obesity, bronchial asthma, gout, hyperuricemia, Ulcers such as sudden infant death syndrome, immunosuppression, diabetes mellitus, peptic ulcers (eg gastric ulcer, duodenal ulcer, etc.), inflammation, Meniere's syndrome, anemia, myocardial infarction , Thrombosis (eg, arterial thrombosis, cerebral thrombosis, etc.), embolism, obstructive arteriosclerosis, thrombophlebitis, cerebral infarction, transient ischemic attack, ischemic heart disease (eg, angina, etc.) It is useful for prevention and Z or treatment of peripheral vascular diseases (eg, claudication, etc.), cerebral ischemia, migraine, diabetes and the like.

The medicament of the present invention comprises, as an active ingredient, a pyrazole compound (I) or a salt thereof, for rectal administration, pulmonary inhalation (nasal inhalation or oral mucosal inhalation), nasal instillation, ophthalmic instillation, topical administration (topical administration), oral or non-oral administration. Pharmaceutically acceptable carriers (excipients, binders, disintegrants, flavoring agents, flavoring agents, emulsifiers, diluents, dissolutions, suitable for oral (including subcutaneous, intravenous and intramuscular) administration or infusion Adjuvants). For example, it can be used as a solid, semi-solid or liquid form of a pharmaceutical preparation.

Such active ingredients include, for example, tablets, granules, troches, capsules, suppositories, creams, ointments, aerosols, powders for inhalation, solutions, emulsions, suspensions and any other suitable for use. In combination with the usual pharmaceutically acceptable carriers for the form. And, if necessary, some of the auxiliaries, stabilizers, thickeners, coloring agents and fragrances may be further used.

The medicament of the present invention can be produced by a conventional method in this technical field. If necessary, a drug bioavailability improvement technique commonly used in this technical field can be applied. Intravenous (including intravenous)-intramuscular, pulmonary or oral administration, or inhalation or insufflation of aerosol from a metered dose inhaler, nebulizer or dry powder inhaler when applying the drug to humans or animals It is preferably applied by

The therapeutically effective amount of the Pyrazol Compound (I) can vary depending on the age and condition of each individual treated patient. In general, for intravenous administration, the daily dose of pyrazole compound (I) is 0.01 to 100 mg per kg body weight of human or animal, and for intramuscular administration, human or animal kg The daily dose of the pyrazole compound (I) per body weight is 0.1 to 10 O mg; in the case of oral administration, the daily dose of the pyrazole compound (I) is 0.5 to 10 per kg body weight of human or animal. O mg is commonly given for prevention and Z or treatment of the disease.

Examples will be given to explain the present invention in more detail. The starting compounds used in the following examples are compounds produced according to WO97 / 01551. Example

3,5-Diphenyl-2- (4-Methoxybenzyl) -1-4- [2- (3-Methoxybenzyl) -1-3-Oxo-1,2,3-dihydropyridazine-1 6-yl] pyrazol ( A solution of 1.15 g), anisol (2.3 ml) and trifluoroacetic acid (5.8 ml) in 1,2-dichloroethane (12 ml) was refluxed with stirring for 7 hours. The mixture was concentrated in vacuo and the residue was chromatographed on silica gel (50 ml) using a mixture of ethyl acetate and n-hexane (1: 2.5). The desired fractions were collected and concentrated in vacuo. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 3,5-diphenyl-14- [2- (3-methoxybenzyl) -13-oxo-1-2,3-dihydropyridazine-6— Birazol (0.54 g) was obtained. Melting point: 142-144 ° C

IR (Nujol): 1640, 1605, 1575 cm- ¹ NMR (DMSO-de, δ): 3.70 (3H, s), 5.21 (2H, s),

6.68 (1H, d, J = 7.6Hz), 6.80—6.94 (3H, m), 7.14-7.44 (13H, m), 13.62 (1H, s)

Calculated value for C ₂₇ H ₂₂ N ₄ 0 ₂ · 1 / 4H ₂ 0:

C 73.87, H 5.16, N 12.76

Found: C 73.90, H 5.17, N 12.70

(+)-APCI / MS: 435 (M + H) ^{+ The} following compound (Example 2) was obtained in the same manner as in Example 1.

Example 2

4-(2-benzyl-3-oxo-2,3-dihydropyridazin-1-yl) — 3,5-divinylpyrazole Melting point: 177-178 ° C (AcOEt: n-hexane)

IR (Nujol): 3200, 1660, 1590 cnT ¹

_{NMR (DMS0-d 6, <} 5): 5.22 (2H, s), 6.91 (1H, d, J = 9.5Hz),

7.11-7.20 (2H, m), 7.22 (1H, d, J = 9.5Hz), 7.27-7.44 (13H, m), 13.60 (1H, s)

C ₂₆ H _2. Calculated value for N ₄₀ · 1 / 4H ₂₀ :

C 76.36, H 5.05, N 13.70

Found: C 76.56, H 4.85, N 13.69

(+)-APCI / MS: 405 (M + H) ⁺ Example 3

3,5-diphenyl 1-1 (4-methoxybenzyl) 1-41 (3-oxo-1,3-dihydropyridazine-1-6-yl) villazol (0.50 g). Potassium tert-butoxide (0.14 g) and 18-crown-16 (30 mg) in anhydrous tetrahydrofura (10 ml) was added with 2-methylbenzyl bromide (0.16 ml) at room temperature. After stirring at room temperature for 2 hours, the mixture was partitioned between ethyl acetate and water, and the separated organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. A solution of 1,2-dichloroethane (4.4 ml) in trifluoroacetic acid (2.2 ml) and trifluoroacetic acid (2.2 ml) was added to the residue, and the mixture was refluxed for 8 hours. The mixture was concentrated in vacuo. The residue was chromatographed on silica gel (30 ml) using a mixture of ethyl acetate and n-hexane (1: 1). The desired fractions were collected and concentrated in vacuo. The residue was recrystallized from a mixture of chloroform and methanol to give 3,5-diphenyl-4- [2- (2-methylbenzyl) -13-oxo-1 2,3-dipyridazine-6. —Vil] (0.24 g) was obtained. Melting point: 243-245 ° C

IR (Nujol): 3220, 1640, 1580 cm- ¹

NMR (DMSO-de, <5): 2.24 (3H, s), 5.23 (2H, s),

6.84 (1H, d, J = 7.4Hz), 6.94 (1H, d, J = 9.5Hz),

7. 02-7. 43 (wind m), 13.59 (1H, s)

_{_{_{C 27 H 22 N 4 0 -}}} 0. 4-CHCls Calcd:

C 70.58, H 4.84, 12.02

Found: C 70. 06, H 4.87, N 11. 84

(+)-APCI / MS: 419 (M + H) ^{+ The} following compound (Example 4) was obtained in the same manner as in Example 3.

Example 4

3,5-Diphenyl-1-4- [2- (3-Nitrobenzyl) -1-3-oxo-2,3-Dihydropyridazin-1-yl] birazol Melting point: 182-184 ° C (AcOEt: n- Hexane) IR (Nujol): 3200, 1645, 1575, 1525 cm— ¹

NMR (DMSO-de, δ): 5.36 (2H, s), 6.96 (1H, d, J = 9.6Hz),

7.18 (1H, d, J = 9.6Hz), 7.30-7.63 (12H, m), 8.05 (1H, s),

8.12-8.18 (1H, m), 13.60 (1H, s)

C ₂₆ H ₁₉ N ₅ 0 ₃ Analysis Calculated:

C 69.48, H 4.26, N 15.58

Found: C 69.47, H 4.20, N 15.22

(+)-APCI / MS: 450 (M + H) ⁺ Example 5

3,5-diphenyl 1- (4-methoxybenzyl) 1-41 (3-oxo2,3-dihydroxypyridazine-1-6-yl) virazole (1.0 g), 18-crown-1 6 (61 mg ) And potassium tert-butoxide (0.28 g) in anhydrous tetrahydrofuran (20 ml) was added with 3-methoxybenzyl chloride (0.35 ml) at room temperature. After stirring at room temperature for 24 hours, the mixture was partitioned between ethyl acetate and water, and the separated organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 3,5- Diphenyl 1 _ (4-Methoxybenzyl) 1 4 1 [2-(3-Methoxybenzyl) 1-3-oxo-1,2,3-dihydroxypyridazine-6-yl] pyrazol (1.18 g) Was obtained as an oil.

IR (film): 1660, 1590 , 1510 cm one ¹

NMR (CDCls, <5): 3.74 (3H, s), 3.77 (3H, s), 5.09 (2H, s),

5.21 (2H, s), 6.63-7.54 (20H, m)

(+)-APCI / MS: 555 (M + H) ^{+ The} following compound (Example 6) was obtained in the same manner as in Example 5.

Example 6 4- (2-benzyl-1-3-oxo-1,2,3-dihydroxypyridazine-16-yl) -1,3,5-diphenyl-1- (4-methoxybenzyl) pyrazole

IR (film): 1660, 1590 , 1500 cm one ¹

Corrupt (CDCls, δ): 3.77 (3Η, s), 5.11 (2H, s), 5.21 (2H, s),

6.64 (1H, d, J = 9.6Hz), 6.76-6.83 (3H, m), 7.01-7.51 (17H, m)

(+)-APCI / MS: 525 (M + H) + Example 7

3,5-diphenyl-4-1- [2- (3-Methoxybenzyl) -1-3-oxo-2,3-dihydropyridazine-1-yl] -11-pyrazol (0.38 g) and anhydrous N, N To a mixture of dimethylformamide (4 ml) was added 60% sodium hydride (38 mg) with stirring under a nitrogen atmosphere below 10 ° C. After stirring under the same conditions for 1 hour, methyl iodide (0.06 ml) was added to the mixture, and the mixture was stirred at room temperature for 3.5 hours. The mixture was poured into water, and the resulting solid was collected by filtration and recrystallized from ethyl acetate to give 3,5-diphenyl-4_ [2- (3-methoxybenzyl)-3-oxo1-2, [3-Dihydropyridazine-1-yl] -1-methylvirazole (0.35 g) was obtained. Melting point: 161-162 ° C (AcOEt)

IR (Nujol): 1650, 1580 cm— ¹

NMR (DMSO-de, 5): 3.70 (3H, s), 3.81 (3H, s), 5.10 (2H, s),

6.52 (1H, d, J = 7.6Hz), 6.73 (1H, s), 6.80—6.85 (1H, m),

6.81 (1H, d, J = 9.5Hz), 7.05 (1H, d, J = 9.5Hz),

7.17 (1H, t, J = 7.9Hz), 7.30-7.50 (10H, m)

Calculated value for C ₂₈ H ₂₄ N ₄ 0 ₂ · 1 / 2H ₂ 0:

C 73.51, H 5.51, N 12.25

Found: C 73.13, H 5.39, N 12.04 (+)-APCI / MS: 449 (M + H) ⁺ Example 8

3,5-diphenyl-1-methyl-41- (3-oxo-1,2,3-dihydropyridazin-1-yl) pyrazol (0.33 g), 18-crown-16 (26 mg) and potassium tert To a mixture of 1-butoxide (123 mg) and anhydrous tetrahydrofuran (14 ml) was added acetone (0.087 ml) at room temperature. After stirring at room temperature for 3 days, the mixture was concentrated in vacuo, the residue was partitioned between ethyl acetate and water, and the separated ethyl acetate layer was concentrated in vacuo. The residue was chromatographed on silica gel (20 ml) using a mixture of dichloromethane and methanol (50: 1). The desired fractions are collected and concentrated in vacuo, and the residue is recrystallized from a mixture of ethyl acetate and hexane to give 3,5-diphenyl-1-1methyl-4-1 [3-oxo-2- (2-oxopropyl). ) 1,2,3-Dihydroxypyridazine-16-yl] pyrazole (0.20 g) was obtained. Melting point: 154-156 ° C

IR (Nujol): 1730, 1660, 1590 cm- ¹

NMR (DMSO-de, δ): 2.07 (3H, s), 3.82 (3H, s), 4.87 (2H, s),

6.82 (1H, d, J = 9.6Hz), 7.04 (1H, d, J = 9.6Hz), 7.31-7.55 ( wind m) C ₂₃ H _2. N ₄ 0 ₂ Analysis Calculated:

C 71.86, H 5.24, N 14.57

Obtained values: C 71.42, H 5.17, N 14.43

(+)-APCI / MS: 385 (+ H) ⁺ Example 9

3- [3- (tert-butyldimethylsilyloxy) phenyl] — 4- (3-oxo-1,2,3-dihydropyridazine-1-yl) -5-phenylvinylazole Is reacted with 4-methoxybenzyl alcohol, triphenylphosphine and getyl azodicarboxylate in tetrahydrofuran to give 3- [3- (tert-butyldimethylsilyloxy) phenyl] 111 (4- (Methoxybenzyl)-4- [2- (4-Methoxybenzyl) -13-oxo-1,2,3-dihydroxypyridazine-6-yl] -5-phenylpyrazole and 5- [3- ( tert-butyldimethylsilyloxy) phenyl] 1-1_ (4-methoxybenzyl) 141

2- (4-Methoxybenzyl) -1-3-oxo-2,3-dihydroxypyridazine-1-yl] —3-phenylvinylazole was obtained.

IR (film): 1660, 1600 , 1580, 1500 cm one ¹

NMR (DMSO-de, 5): 0.05, 0.72 (total 6H, each s),

0.85, 0.87 (total 9H, each s), 3.72, 3.73 (total 6H, each s), 4.99 (2H, s), 5.22, 5.25 (total 2H, each s), 6.58-7.39 (19H, m)

(+)-APCI / S: 685 (M + H) ⁺ Example 10

1 M tetrabutylammonium fluoride-tetrahydrofuran solution (2.6 ml)

3- [3- (tert-Butyldimethylsilyloxy) phenyl] 1-11 (4-methoxybenzyl) 1-41 [2- (4-Methoxybenzyl) 1-3-oxo-1 2,3-dihydro Pyridazine-1-yl] —5-phenylvinylazolyl and 5- [3- (tert-butyldimethylsilyloxy) phenyl] 1-1— (4-methoxybenzyl) 14-1—2- (4-methyl Toxibenzyl) -1,3-oxo-2,3-dihydropyridazine-16-yl] _3-Fenylvirazole (1.5 g) was added dropwise to a solution of anhydrous tetrahydrofuran (15 ml) under ice cooling with stirring. . After stirring for 20 minutes, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, concentrated in vacuo, and the residue was subjected to silica gel (100 ml) chromatography using a mixture of ethyl acetate and hexane to give 3- (3-hydroxyphenyl) -1- ( 4-Methoxybenzyl) 1-41 [2- (4-Methoxybenzyl) 1-3-oxo-1,2,3-dihydroxypyridazine-1-6-yl] — 5-phenylpyrazole and 5- (3 —Hydroxyphenyl) 1 1— (4-Methoxybenzyl) 1 4— [2- (4-Methoxybenzyl) 1 3-oxo-1 2,3—Dihydroxypyridazine-1 6-yl] Nilvirazole (0.85 was obtained.

IR (Nujol): 1640, 1600 , 1575, 1500 cm one ¹

_{NMR (MS0 - d 6, 5} ): 3.70, 3.71 (total 3H, each s), 3.73 (3H, s),

5.00 (2H, s), 5.21 (2H, s), 6.71-7.46 (17H, m)

9.45, 9.71 (total 1H, each s)

(+)-APCI / MS: 571 (M + H) ⁺ Example 1 1

3_ (3-Hydroxyphenyl) —11- (4-methoxybenzyl) 1-41 obtained in Example 10 [2- (4-Methoxybenzyl) -13-oxo-1 2,3- Dihydroxypyridazine-1-6-yl] — 5-phenylpyrazole and 5- (3-hydroxyphenyl) 1-1- (4-methoxybenzyl) 1-14-1 [2- (4-methoxybenzyl) A) reacting a mixture of 13-oxo-1,2,3-dihydropyridazine-16-yl] -13-phenylpyrazole with 2-morpholinoethanol, triphenylphosphine and getylazodicarboxylate 1- (4-Methoxybenzyl) _4- [2-(4-Methoxybenzyl) -13-oxo-1,2,3 dihydropyridazin-1 6_yl] 1 3— {3-[2- (Morpholino) ethoxy] phenyl} 1-5-phenylvirazole and 1— (4— Methoxybenzyl) 1 4- 1 [2- (4-Methoxybenzyl) 1-3-oxo-1 2,3-dihydropyridazine 16-yl] 1-5— {3- [2- (morpholino) ethoxy] phenyl} — 3-phenylphenylazole was obtained. IR (film): 1645, 1570 cm one ¹

NMR (CDCls, δ): 2.48-2.57 (4H, m), 2.69-2.79 (2H, m),

3.67-3.74 (4H, m), 3.77, 3.78 (total 6H, each s),

3.92 (1H, t, J = 5.7Hz), 4.05 (1H, t, J = 5.7Hz),

5.03, 5.04 (total 2H, each s), 5.20, 5.21 (total 2H, each s), 6.61-7.51 (19H, m)

(+)-APCI / MS: 684 (M + H) ^{+ The} following compound (Example 12) was obtained in the same manner as in Example 1.

Example 1 2

4- [2- (4-Methoxybenzyl) -1-3-oxo-1,2,3-dihydropyridazin-1-yl] — 3— {3- [2- (Morpholino) ethoxy] phenyl} 1— Furnylpyrazol hydrochloride Melting point: 186-188 ° C (EtOH)

IR (Nujol): 1625, 1600, 1560 cm— ¹

NMR (DMSO-de, δ): 3.10-3.35 (2H, m), 3.40-3.65 (4H, m),

3.74 (3H, s), 3.76-4.10 (4H, m), 4.40-4.55 (2H, m),

5.14 (2H, s), 6.79-7.46 (15H, m), 11.56 (1H, bs)

(+)-APCI / MS: 564 (M + H) + Example 13

A mixture of 4-acetyl-3,5-diphenyl-1-methylvirazole (2.0 g) and getyl ketomalonate (1.63 ml) was heated for 3 days at 100 to 105 ° C with stirring. . 80% hydrazine monohydrate (3.8 ml) was added to the mixture, and the mixture was heated with stirring at 130 ° C for 2 hours. Ethanol was added to the mixture, and the resulting solid was collected by filtration. This solid is recovered from a mixture of ethanol and black form. By crystallization, 41- (l-l-zobazolu 3- 3-oxo-l, 3-dihydropyridazin-l-l-yl) -l, 5-diphenyl-l-methylpyrazole (0.17 g) was obtained as yellow crystals. Was. Melting point: 262-264 ° C

IR (Nujol): 3450, 3270, 1680, 1630, 1590, 1500 cm— ¹

_{NMR (MS0 - d 6, δ} :. 3. 83 (3Η, s), 4. 78 (2H, s), 7. 32-7 47 ( wind m),

7.58 (1H, s), 10.35 (1H, s), 13.76 (1H, s)

Calculated value for C2 i H ₁₈ N ₆₀ ₂ · 1 / 4H ₂₀ :

C 64.52, H 4.77, N 21.50

Obtained values: C 64.27, H 4.56, N 21.33

(+)-APCI / MS: 387 (M + H) + Example 14

4- (4-carbazolyl 3-oxo-1,2,3-dihydropyridazine-16-yl) —3,5-diphenyl-1-methylpyrazol (1.0 g), sulfuric acid (1.95 ml) and A mixture of water (20 ml) was refluxed for 30 hours with stirring. A 1N aqueous solution of sodium hydroxide (6 ml) was added to the mixture, and the mixture was washed with a black hole form. The mixture was acidified with 1 N hydrochloric acid (9 ml). The resulting solid was collected by filtration and recrystallized from ethanol and chloroform to give 4- (4-carboxy-3-oxo-2,3-dihydropyridazine-16-yl) -1,3-diphenyl-2-yl. 1-Methylvirazole (0.78 g) was obtained. Melting point: 226-228 ° C

IR (Nujol): 1750, 1635, 1585 cm— ¹

NMR (DMSO-de, δ: 3.83 (3H, s), 7.34-7.62 (11H, s),

13.98 (1H, bs) _{_{_{C 2 1 H 1 6 N 4}}} 0 3 Analysis Calculated:

C 67. 73, H 4.33, N 15.05

Found: C 67.28, H 4.28, N 15.13

(+)-APCI / MS: 373 (M + H) ⁺ industrial availability

Pyrazole Ichiru compound or a salt thereof of the present invention has a strong antagonistic action against both receptors receptors and A ₂ receptor, ischemic heart diseases such as angina pectoris, peripheral vascular diseases claudication, etc. And prophylactic and / or therapeutic agents for cerebral ischemia, migraine, diabetes, depression, Parkinson's disease and the like. This application is based on Japanese Patent Application No. 3061671 filed in Japan, the contents of which are incorporated in full herein.

Claims

The scope of the claims

1. General formula (I):

0

(Wherein, R ⁶ represents a carboxy group which may be protected), respectively, or a salt thereof.

2. R ¹ and R ² are the same or different and each have 1 to 3 substituents selected from the group consisting of a hydroxy group, a tri (lower) alkylsilyloxy group and a heterocyclic (lower) alkoxy group An aryl group, R ³ is hydrogen, a lower alkyl group or an alkyl (lower) alkyl group optionally having 1 to 3 lower alkoxy groups, and R ⁴ is a group represented by the formula: NR ⁵

N

(Wherein R ⁶ represents a carboxy group or an amidated carboxy group). The biazole compound or a salt thereof according to claim 1, which is a group represented by the formula:

3. R ¹ and R ² are the same or different and each have 1 to 3 substituents selected from the group consisting of a hydroxy group, a tri (lower) alkylsilyloxy group and a morpholino (lower) alkoxy group. which may be Fuweniru group, R ³ is hydrogen, which may have a lower § alkyl group or 1 to 3 lower alkoxy groups Fuweniru (lower) alkyl, and R ⁴ has the formula:

(Wherein, R ⁵ is a fuunyl (lower) alkyl group optionally having 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group and a nitro group, or a lower alkanol (lower group) Or a group represented by the formula: NH

I

; N

The pyrazole compound or a salt thereof according to claim 2, wherein R ⁶ is a carboxy group or a carbazolyl group.

4. R ¹ and R ² are the same or different and each have 1 to 3 substituents selected from the group consisting of a hydroxy group, a tri (lower) alkylsilyloxy group and a morpholino (lower) alkoxy group. which may be Fuweniru group, R ³ is hydrogen, which may have a lower § alkyl group or from 1 to 3 lower alkoxy groups Fuweniru (lower) alkyl, and R ⁴ has the formula:

0

NR ⁵

I

N

(Wherein, R ⁵ is a fuunyl (lower) alkyl group optionally having 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkoxy group and a nitro group, or a lower alkanol (lower group) 4. The virazole compound or a salt thereof according to claim 3, which is a group represented by the following formula:

5. R ¹ and R ² are the same or different and each have 1 to 3 substituents selected from the group consisting of a hydroxy group, a tri (lower) alkylsilyloxy group and a morpholino (lower) alkoxy group. which may be Fuweniru group, R ³ is hydrogen, which may have a lower § alkyl group or from 1 to 3 lower alkoxy groups Fuweniru (lower) alkyl, and R ⁴ has the formula:

4. The pyrazole compound or a salt thereof according to claim 3, wherein R ⁶ is a carboxy group.

6. A medicament comprising the biazole compound according to claim 1 or a salt thereof.