JP2001192384A - Pyrazolopyridine compound and pharmaceutical use thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an adenosine antagonist useful for prophylaxis and/or therapy of depression, dementia (e.g. Alzheimer's disease, the cerebrovascular dementia, and the dementia accompanied with Parkinson's disease), the Parkinson's disease, anxiety, pain, cerebrovascular disease (e.g. apoplexy), cardiac failure or the like. SOLUTION: This pyrazolopyridine compound is a compound represented by formula (I), wherein, R is a lower alkenyl or a lower alkyl substituted with an aryl wherein the lower alkyl can be intercepted by an oxygen atom, or a group represented by the formula A-R1, wherein, R1 is an oxadiazolyl, thiazolyl, oxazolyl or imidazolyl each of which has one or more proper substituents selected from a group of a lower alkyl, an acyl, an aryl, a pyridyl and a trihalomethyl; and A is a lower alkylene), or a salt thereof. The pyrazolopyridine compound and the salt thereof are adenosine antagonists.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel pyrazolopyridine compound useful as a medicine and a salt thereof.

[0002]

2. Description of the Related Art Some pyrazolopyridine compounds are known to be useful as psychostimulants, remedies for renal failure, etc. (for example, EP-0299209, EP-03).
No. 79979, EP-0467248, EP
-0516941, etc.).

[0003]

DISCLOSURE OF THE INVENTION The present invention relates to a novel pyrazolopyridine compound and a pharmaceutically acceptable salt thereof, which are useful as a medicine; a method for producing the pyrazolopyridine compound and a salt thereof; and a pyrazolopyridine compound or a salt thereof as an active ingredient. A pharmaceutical composition containing a pharmaceutically acceptable salt; use of the pyrazolopyridine compound or a pharmaceutically acceptable salt thereof as a medicament; and, in a human or animal, the pyrazolopyridine compound or a pharmaceutically acceptable salt thereof. Using the pyrazolopyridine compound or a pharmaceutically acceptable salt thereof for therapeutic purposes, comprising administering a salt.

[0004] Pyrazolopyridine compounds and salts thereof are
Adenosine antagonists (particularly A ₁ receptor and A ₂ (particularly A _2a ) receptor dual antagonists), which have an anti-catalepsy effect, a cognition-enhancing effect, an analgesic effect, a locomotor activity increasing effect,
Antidepressant action, diuretic action, cardioprotective action, cardiotonic action, vasodilatory action (for example, cerebral vasodilatory action, etc.), renal blood flow increasing action, renal protective action, renal function improving action, lipolysis enhancing action,
It has various pharmacological effects such as an anaphylactic bronchoconstriction inhibitory effect, an insulin secretion promoting effect, an erythropoietin production increasing effect, and a platelet aggregation suppressing effect.

These include cognition enhancers, anxiolytics, anti-dementia drugs, psychostimulants, analgesics, cardioprotectants, antidepressants, cerebral circulation improvers, tranquilizers, drugs for heart failure, inotropic drugs,
Antihypertensive, renal failure drug, nephrotoxicity drug, renal protective agent, renal function improving drug, diuretic, edema drug, antiobesity drug, antiasthmatic drug, bronchodilator, apnea drug, gout drug , Drugs for hyperuricemia, drugs for sudden infant death syndrome (SIDS),
Improves immunosuppressive effects of adenosine, antidiabetic drugs,
Drugs for ulcers, drugs for pancreatitis, drugs for Meniere's syndrome, drugs for anemia; drugs for thrombosis, drugs for myocardial infarction, drugs for obstruction, drugs for obstructive arteriosclerosis, drugs for thrombophlebitis, drugs for cerebral infarction It is useful as a transient ischemic agent, a drug for angina, etc., and depression, dementia (eg, Alzheimer's disease, cerebrovascular dementia, dementia associated with Parkinson's disease, etc.),
Parkinson's disease, anxiety, pain, cerebrovascular disease (eg, stroke), heart failure; hypertension (eg, essential hypertension, nephrogenic hypertension, etc.); eg, ischemia / reperfusion injury (eg, myocardial ischemia /
Circulatory failure (acute circulatory failure) induced by reperfusion injury, cerebral ischemia / reperfusion injury, peripheral ischemia / reperfusion injury, etc., shock (eg, endotoxin shock, hemorrhagic shock, etc.), surgical treatment, etc .; Systolic dysfunction after resuscitation; bradyarrhythmia; electro-mechanical disso
ciation); hemodynamic collaps
e); SIRS (systemic inflammatory response synd)
rome); multiple organ failure; renal failure (such as acute renal failure);
Nephrotoxicity [eg cisplatin, gentamicin, FR-
900506 (disclosed in EP-0184162), cyclosporin (eg cyclosporin A) and the like;
Nephrotoxicity induced by drugs such as glycerol], nephrosis, nephritis, edema (eg, cardiac edema, renal edema,
(Hepatic edema, idiopathic edema, drug-induced edema, acute vascular neuroedema, hereditary vascular neuroedema, cancerous ascites, pregnancy edema, etc.); obesity, bronchial asthma, gout, hyperuricemia, sudden infant Ulcers such as death syndrome, immunosuppression, diabetes, peptic ulcer (eg, gastric ulcer, duodenal ulcer, etc.), pancreatitis, Meniere's syndrome, anemia, dialysis-induced hypotension, constipation, ischemic bowel disease, ileus (eg, mechanical Myocardial infarction, thrombosis (eg, arterial thrombosis, cerebral thrombosis, etc.), obstruction, obstructive arteriosclerosis, thrombophlebitis, cerebral infarction, transient ischemic attack, narrowing It is useful for prevention and / or treatment of heart disease and the like.

The novel pyrazolopyridine compound of the present invention has the following formula (I)

[0007]

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Wherein R is lower alkenyl; lower alkyl substituted by aryl, wherein the lower alkyl may be interrupted by an oxygen atom;

[0009]

Embedded image -A-R ¹ (wherein, R ¹ is oxadiazolyl, thiazolyl, oxazolyl or imidazolyl, each of lower alkyl, acyl, aryl, one selected from the group consisting of pyridyl and trihalomethyl or A is a group having a further suitable substituent and A is lower alkylene). Or a salt thereof.

The target compound (I) of the present invention and a salt thereof are produced by the following steps. Step 1

[0011]

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Step 2

[0013]

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[0014]

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[0015]

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Step 3

[0017]

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[0018]

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Step 4

[0020]

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Step 5

[0022]

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[0023]

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Step 6

[0025]

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Step 7

[0027]

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[0028]

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Step 8

[0030]

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[0031]

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[0032]

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Step 9

[0034]

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Wherein R ² is lower alkyl; R ³ is hydrogen, lower alkyl, acyl or phenyl;
⁴ is lower alkyl, acyl, aryl, pyridyl or trihalomethyl; R ⁵ is lower alkyl or phenyl; R ⁷ is phenyl; R ⁹ is lower alkyl substituted with lower alkenyl, aryl; Lower alkyl is lower alkyl substituted with an oxadiazole optionally interrupted by an oxygen atom or optionally having lower alkyl; R ¹⁰ is a protected carboxy; R ¹¹ and R ¹² are each Hydrogen, lower alkyl, di (lower) alkylamino (lower) alkyl or aryl, which may form a ring therebetween; R ¹³ is lower alkyl or phenyl; R ¹⁴ is lower alkyl; Is a lower alkylene, and X ¹ , X ² , X ³ ,
X ⁴ , X ⁵ and X ⁶ are each a leaving group. In addition to the above-described steps, the target compound (I) and a salt thereof can be produced, for example, according to the procedures described in Production Examples or Examples of the present specification or by a method similar thereto.

The starting compound can be produced according to a conventional method.

The desired compound (I) and a salt thereof can be produced according to the methods shown in Production Examples or Examples or by the same method.

The target compound (I) may include a geometric isomer based on a double bond and / or a stereoisomer based on an asymmetric carbon atom. In this regard, one isomer,
It can be converted to another isomer according to conventional methods in this technical field.

The solvated forms (eg hydrates) of compound (I) and any crystalline forms of compound (I) are included within the scope of the present invention.

Suitable salts of the target compound (I) are conventional pharmaceutically acceptable salts, and include alkali metal salts (eg, sodium salt, potassium salt, etc.) and alkaline earth metal salts (eg, calcium salt, magnesium salt). Metal salts, ammonium salts, organic base salts (eg, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, etc.), and organic acid salts (eg, acetic acid) Salt, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), inorganic acid salt (for example, hydrochloride, hydrobromic acid) Salts, hydroiodide, sulfate, phosphate, etc.), amino acids (eg, arginine, aspartic acid,
Glutamic acid and the like).

Preferred examples and explanations of the various definitions included within the scope of the present invention and found herein above and below are described in detail below.

The term "lower" is used unless otherwise noted.
Means 1 to 6 carbon atoms.

Preferred "lower alkyl" are straight or branched ones such as methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl,
Hexyl and the like, preferably (C ₁ -C ₄ ) alkyl, more preferably methyl, ethyl, propyl and tertiary butyl.

Suitable "lower alkenyl" includes linear or branched ones, for example, vinyl, propenyl, isopropenyl, butenyl, pentenyl and the like, preferably (C ₂ -C ₅ ) alkenyl, more preferably Is allyl.

Preferred "aryl" include phenyl,
Examples include naphthyl, indenyl, anthryl and the like, preferably (C ₆ -C ₁₀ ) aryl, more preferably phenyl.

The "aryl" is a halogen (fluorine,
Lower alkyl as described above; lower alkoxy (for example, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like, preferably (C _1-
C ₄₎ alkoxy, more preferably methoxy);
It may have one or more (preferably 1 to 3) substituents selected from the group consisting of hydroxy; nitro and the like.

Suitable "lower alkylene" includes straight or branched ones, for example, methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, and preferably (C ₁
—C ₄ ) alkylene, more preferably methylene.

Suitable "acyl" includes lower alkanoyl (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl and the like),
Carboxy, protected carboxy and the like.

Suitable "protected carboxy" includes: (1) esterified carboxy, and specific examples include:
Lower alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, 1-cyclopropylethoxycarbonyl, etc.) and the like. (2) amidated carboxy, specifically carbamoyl; N- (lower) alkylcarbamoyl (eg, N-methylcarbamoyl, N-ethylcarbamoyl,
N-isopropylcarbamoyl, N-butylcarbamoyl, N-pentylcarbamoyl, N-hexylcarbamoyl, etc.); two lower alkyl groups may be bonded to each other to form a 3- to 6-membered ring. Di (low grade)
Alkylcarbamoyl (for example, N, N-dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl, N, N
-Diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N-di (tert-butyl) carbamoyl, N-
Pentyl-N-hexylcarbamoyl, 1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, etc.);
Arylcarbamoyl (eg, N-phenylcarbamoyl, N-3,4,5-trimethoxyphenylcarbamoyl, etc.); N-lower alkylamino (lower) alkylcarbamoyl (eg, N-methylaminomethylcarbamoyl, N-methyl (2-amino Ethyl) carbamoyl, N
-Methyl (3-aminopropyl) carbamoyl, N-ethylaminomethylcarbamoyl, N-ethyl (2-aminoethyl) carbamoyl, N-propylaminomethylcarbamoyl, N-propyl (2-aminoethyl) carbamoyl, etc.); Di (lower) alkylamino (lower) alkylcarbamoyl (for example, N-dimethylaminomethylcarbamoyl, N-dimethyl (2-aminoethyl) carbamoyl, N-dimethyl (3-aminopropyl) carbamoyl, N- (N-methyl-N -Ethylaminomethyl)
Carbamoyl, N-diethylaminomethylcarbamoyl, N-diethyl (2-aminoethyl) carbamoyl, etc.).

Preferred "trihalomethyl" are trifluoromethyl, trichloromethyl, tribromomethyl,
Triiodomethyl. Suitable "leaving groups" include acyloxy such as halogen (fluorine, chlorine, bromine, iodine), hydroxy, alkanoyloxy (eg, acetoxy, propionyloxy, etc.) and sulfonyloxy (eg, mesyloxy, tosyloxy, etc.).

R is a formula

[0052]

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(Wherein R ² is lower alkyl and A is lower alkylene) The desired pyrazolopyridine compound (I) or a salt thereof, which is an oxadiazolyl group represented by the following formula: Examples thereof include a compound (I) wherein R ² is (C ₁ -C ₄ ) alkyl and A is (C ₁ -C ₄ ) alkylene, or a salt thereof. (2) More preferably, compound (I) wherein R ² is methyl; ethyl; propyl or tertiary butyl, and A is methylene, or a salt thereof.

R is a formula

[0055]

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(Wherein at least one of R ³ and R ⁴ is lower alkyl, acyl, aryl, pyridyl or trihalomethyl and A is lower alkylene), the desired pyrazolo group represented by thiazolyl group In the pyridine compound (I) or a salt thereof, (1) R ³ is preferably hydrogen; lower alkyl; acyl; or phenyl; R ⁴ is lower alkyl; acyl; aryl; pyridyl;
Is a lower alkylene, or a compound (I) or a salt thereof. (2) More preferably, R ³ is hydrogen; (C _1-
(C ₄ ) alkyl; (C ₁ -C ₄ ) alkanoyl; or phenyl, wherein R ⁴ is (C ₁ -C ₄ ) alkyl; carboxy; lower alkoxycarbonyl; amidated carboxy;
A compound (I) in which one or more (preferably 1 to 3) phenyl optionally having a substituent; pyridyl; or trihalomethyl, wherein A is (C ₁ -C ₄ ) alkylene; Or a salt thereof. (3) Most preferably, R ³ is hydrogen; methyl; acetyl; or phenyl; R ⁴ is methyl; ethyl; carboxy; (C ₁ -C ₄ ) alkoxycarbonyl;
N, N-di (lower) alkylcarbamoyl wherein the alkyl group may form a 3- to 6-membered ring;
-Di (lower) alkylamino (lower) alkylcarbamoyl; N-phenylcarbamoyl wherein phenyl optionally has one or more (preferably 1 to 3) methoxy; phenyl; one or more ( (Preferably 1 to 3) phenyl having methoxy; phenyl having lower alkyl; phenyl having halogen; phenyl having nitro; pyridyl; or trihalomethyl, compound (I) wherein A is methylene, or a salt thereof. Can be (4) Most preferably, R ³ is hydrogen; methyl; acetyl; or phenyl; R ⁴ is methyl; ethyl; carboxy; ethoxycarbonyl;
N, N-dimethylcarbamoyl; piperidinocarbonyl; N-dimethylaminoethylcarbamoyl; N-trimethoxyphenylcarbamoyl; phenyl; methoxyphenyl; dimethoxyphenyl; trimethoxyphenyl;
Compound (I) or a salt thereof, wherein methylphenyl; chlorophenyl; nitrophenyl; pyridyl; or trifluoromethyl, wherein A is methylene.

R is a formula

[0058]

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(Wherein R ⁵ is lower alkyl or phenyl, R ⁶ is hydrogen; lower alkyl or phenyl, and A is lower alkylene) The desired pyrazolopyridine compound (I) which is an oxazolyl group represented by the formula: Or a salt thereof: (1) Preferred are those in which R ⁵ is (C ₁ -C ₄ ) alkyl or phenyl, R ⁶ is hydrogen, (C ₁ -C ₄ ) alkyl or phenyl, and A is (C ₁ -C ₄ ) ₄ ) Alkylene, compound (I) or a salt thereof. (2) More preferably, R ⁵ is methyl or phenyl, R ⁶
Is hydrogen, methyl or phenyl, and A is methylene, and the compound (I) or a salt thereof.

R is a formula

[0061]

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Wherein R ⁷ is phenyl, R ⁸ is hydrogen or lower alkyl, and A is lower alkylene. The target pyrazolopyridine compound (I), which is an imidazolyl group represented by the formula: (1) Preferred are the compounds (I) wherein R ⁷ is phenyl, R ⁸ is hydrogen or (C ₁ -C ₄ ) alkyl, and A is (C ₁ -C ₄ ) alkylene, or a salt thereof. . (2) More preferably, the compound (I) wherein R ⁷ is phenyl, R ⁸ is hydrogen or methyl, and A is methylene, or a salt thereof. Desired pyrazolopyridine compound (I)
The process of manufacturing is described in detail below. Step 1 Compound (Ia) or a salt thereof can be produced by reacting compound (II) or a salt thereof with compound (III) or a salt thereof.

Suitable salts of the compounds (II) and (III) include those exemplified for the compound (I).

This reaction is carried out using water, a phosphate buffer, acetone,
Solvents such as chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chloride, formamide, N, N-dimethylformamide, methanol, ethanol, secondary butanol, amyl alcohol, diethyl ether, dioxane, tetrahydrofuran, dimethyl sulfoxide, or adversely affect the reaction The reaction is carried out in another organic solvent which does not affect the reaction, preferably in a solvent having strong polarity. Among the above solvents, a hydrophilic solvent may be used by mixing with water. When compound (III) is a liquid, it can also be used as a solvent. The reaction is preferably performed in the presence of a base, for example, an inorganic base such as an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, or an alkali metal hydride, or an organic base such as a trialkylamine.

The reaction temperature is not particularly limited.
It is carried out at room temperature, under heating or under heating.

In this reaction, alkali metal halides (eg, sodium iodide, potassium iodide, etc.), alkali metal thiocyanates (eg, sodium thiocyanate, potassium thiocyanate, etc.), di (lower) alkyl azodicarboxylates (eg, Diethyl azodicarboxylate,
It is preferably carried out in the presence of diisopropyl azodicarboxylate or the like.

When X is -OH, activation of OH with triphenylphosphine or the like may be necessary. Step 2 The reaction in this step can be carried out by the method disclosed in Production Example 1 and Example 4 described below, or a conventional method similar thereto. Step 3 Compound (Ic) or a salt thereof can be produced by reacting compound (VII) or a salt thereof with compound (VIII) or a salt thereof.

Suitable salts of the compounds (VII) and (VIII) include those exemplified for the compound (I).

This reaction is usually carried out by using ethyl acetate, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, dioxane, water, alcohol (eg, methanol, ethanol, etc.), acetic acid , Formic acid, etc., in a conventional solvent that does not adversely affect the reaction, or a mixture thereof.

The reaction temperature is not particularly limited.
It is performed under cooling or heating. Step 4 Compound (Ie) or a salt thereof can be produced by subjecting compound (Id) or a salt thereof to an elimination reaction of a carboxy protecting group.

Suitable salts of the compounds (Id) and (Ie) include those exemplified for the compound (I).

Suitable methods for the elimination reaction include conventional methods such as hydrolysis and reduction. (1) Hydrolysis The hydrolysis is preferably carried out in the presence of a base or an acid such as a Lewis acid.

Suitable bases include inorganic and organic bases, such as alkali metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, magnesium, calcium, etc.), hydroxides or carbonates or bicarbonates thereof, Trialkylamines (eg, trimethylamine, triethylamine, etc.), hydrazine, picoline, 1,5-
Diazabicyclo [4.3.0] non-5-ene, 1,4
-Diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene, and the like.

Suitable acids include organic acids (eg, formic acid,
Acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.) and inorganic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid,
Hydrogen chloride, hydrogen bromide, etc.).

The elimination using a Lewis acid (eg, aluminum chloride, titanium trichloride, tin tetrachloride, etc.) is preferably performed in the presence of a cation scavenger (eg, anisole, phenol, etc.).

The reaction is usually carried out with water, alcohol (eg, methanol, ethanol, isopropyl alcohol, etc.),
In a solvent such as tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N, N-dimethylformamide, N, N-dimethylacetamide, or another organic solvent that does not adversely influence the reaction, or a mixture thereof. Done.

[0077] Liquid bases or acids can also be used as solvents. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating. (2) Reduction Reduction is performed by a conventional method such as chemical reduction and catalytic reduction.

Suitable reducing agents used for chemical reduction include hydrides (eg, hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.) or metals (eg, tin,
Zinc or iron) or a metal compound (eg, chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (eg, formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.) And a combination with

Suitable catalysts used for catalytic reduction include conventional catalysts such as platinum catalysts (for example, platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.).
Palladium catalyst (for example, palladium sponge, palladium black, palladium oxide, palladium charcoal, palladium hydroxide charcoal, colloidal palladium, palladium-barium sulfate,
Palladium-barium carbonate, etc.), nickel catalysts (eg, reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (eg, reduced cobalt, Raney cobalt, etc.), iron catalysts (eg, reduced iron, Raney iron, Ullman iron, etc.), etc. be able to.

The reaction is usually carried out with water, alcohol (eg, methanol, ethanol, isopropyl alcohol, etc.),
Conventional solvents such as tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N, N-dimethylformamide, N, N-dimethylacetamide, or other organic solvents that do not adversely influence the reaction, or mixtures thereof Done in

Furthermore, when the acids used for chemical reduction are liquid, they can also be used as solvents.

The reaction temperature for this reduction is not particularly limited, and the reaction is usually carried out under cooling or heating. Step 5: Compound (If) or a salt thereof is produced by reacting compound (Ie) or a reactive derivative thereof at a carboxy group or a salt thereof with compound (IX) or a reactive derivative thereof at an amino group or a salt thereof. Can be.

Suitable reactive derivatives of compound (IX) include Schiff base imino or tautomeric enamine isomer thereof formed by reacting compound (IX) with a carbonyl compound such as aldehyde or ketone; And silyl compounds such as O-bis (trimethylsilyl) acetamide and N-trimethylsilylacetamide; and derivatives formed by reacting compound (IX) with phosphorus trichloride or phosgene.

Suitable reactive derivatives of compound (Ie) include acid halides, acid anhydrides and active esters. Preferred examples include acid chlorides; acid azides; substituted phosphoric acids (eg, dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid,
Alkanesulfonic acid (eg, methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkyl carbonate, aliphatic carboxylic acid (eg, pivalic acid, pentanoic acid, isopentanoic acid,
Mixed anhydrides with acids such as -ethylbutyric acid, trichloroacetic acid, etc.); aromatic carboxylic acids (eg, benzoic acid, etc.); symmetric acid anhydrides; activity with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole Amides; active esters (eg, cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N ⁺ = CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester , Trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester,
Phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.); or N-hydroxy compounds (for example, N, N-dimethylhydroxylamine) , 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide,
-Hydroxy-6-chloro-1H-benzotriazole). These reactive derivatives can be arbitrarily selected depending on the type of the compound (Ie) used.

The reaction is usually carried out with water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N
In a conventional solvent such as dimethylformamide, pyridine or other organic solvents which do not adversely influence the reaction, or in mixtures thereof.

When the compound (Ie) is used in the form of a free acid or a salt thereof in this reaction, the reaction is preferably carried out in the presence of a conventional condensing agent. Examples of the condensing agent include N, N '-Dicyclohexylcarbodiimide; N
-Cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide; N, N'-diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide; N N-carbonyl-bis (2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; Phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5 hydroxide
-(M-sulfophenyl) isoxazolium inner salt;
1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; the so-called Vilsmeier reagent prepared by reacting N, N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride and the like. Can be.

The reaction is carried out in the presence of an organic or inorganic base such as alkali metal bicarbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine and the like. But it is possible.

The reaction temperature is not particularly limited.
It is performed under cooling or heating. Step 6 The reaction of this step can be carried out by the method disclosed in Example 17 below, or a conventional method analogous thereto. Step 7 The reaction of this step can be carried out by the method disclosed in Production Example 2 and Example 34 described below, or a conventional method similar thereto. Step 8 The reaction of this step can be carried out by the method disclosed in Production Example 4 and Example 34 described later, or a conventional method similar thereto. Step 9 The reaction of this step can be carried out by the method disclosed in Example 37 below, or a conventional method analogous thereto.

The target compound (I) of the present invention is an adenosine antagonist and has various pharmacological actions as described above.

In order to show the usefulness of the compound (I) of the present invention, the results of pharmacological tests of representative compounds of the present invention are shown below. Test 1: Adenosine antagonist activity [I] Test method The adenosine antagonist activity [Ki (nM)] of the test compound was
The human A ₁ receptor 8-cyclopentyl-1,3
-Dipropylxanthine [dipropyl-2,3- ³ H
(N)] ([ ³ H] DPCPX, 4.5 nM), human A
_{For the 2a} receptor, [ ³ H] CGS21680 (20 n
M) was tested by a radioligand binding method. [II] Test compound 3- (2-allyl-3-oxo-2,3-dihydropyridazin-6-yl) -2-phenylpyrazolo [1,5-
a] Pyridine (Example 1) 3- [3-oxo-2-[(5-methyl-1,2,4-
Oxadiazol-3-yl) methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5-a] pyridine (Example 4) 3- [3-oxo-2- [(4-methylthiazole-2
-Yl) methyl] -2,3-dihydropyridazine-6-
Yl] -2-phenylpyrazolo [1,5-a] pyridine (Example 5) [III] Test results

[0091]

[Table 1]

Test 2: Anti-cataleptic activity in mice [I] Test method Test compounds (3.2 mg / kg) were administered to ddY mice (n =
7) was orally administered. 30 minutes after administration of the compound,
Haloperidol (0.32 mg / kg) was injected intraperitoneally. Thirty minutes after the injection, the catalepsy reaction of the mice was measured. The forelimb of each mouse was placed on a horizontal bar having a height of 3 cm and a width of 3 mm, and the duration of the catalepsy posture was measured for up to 30 seconds. [II] Test compound Same compound as used in Test 1. [III] Test results

[0093]

[Table 2]

The pyrazolopyridine compound (I) of the present invention and a salt thereof are useful as adenosine antagonists (particularly A ₁ receptor and A ₂ (particularly A _2a ) receptor dual antagonists), (Eg, Alzheimer's disease, cerebrovascular dementia, dementia associated with Parkinson's disease, etc.), Parkinson's disease, anxiety, pain, cerebrovascular disease, heart failure, hypertension, circulatory failure, contractile dysfunction after resuscitation, bradyarrhythmia, electromechanical Dysfunction (electro-mechanical dissociation), cardiac hemodynamic collapse (hemodynamic collapse), SIRS (syst
emic inflammatory response syndrome), multiple organ failure, renal failure, nephrotoxicity, nephrosis, nephritis, edema, obesity, bronchial asthma, gout, hyperuricemia, sudden infant death syndrome, immunosuppression, diabetes, ulcer, pancreatitis, meniere Syndrome, anemia, dialysis-induced hypotension, constipation, ischemic bowel disease, ileus, myocardial infarction, thrombosis, obstruction, obstructive arteriosclerosis, thrombophlebitis, cerebral infarction, transient ischemic It is useful for prevention and / or treatment of seizures, angina, etc.

The pharmaceutical composition of the present invention may be administered rectally, pulmonary (nasally or buccal inhalation), nasal drops, eye drops, topical (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) or It contains the pyrazolopyridine compound (I) or a pharmaceutically acceptable salt thereof as the active ingredient in the form of a mixture with an organic or inorganic carrier or excipient suitable for inhalation, for example as a solid, semi-solid or liquid It can be used in the form of a pharmaceutical preparation. Such active ingredients include, for example, tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for inhalation, solutions, emulsions, suspensions,
It can be mixed with usual non-toxic pharmaceutically acceptable carriers for any other dosage forms suitable for other uses. If necessary, auxiliary agents, stabilizers, thickeners, coloring agents and fragrances may be used. The pyrazolopyridine compound (I) or a pharmaceutically acceptable salt thereof is contained in the pharmaceutical composition in an amount sufficient to exert the above-mentioned desired pharmaceutical effect on the process or condition of the disease.

The application of the composition to humans or animals is
It is preferably applied by intravenous, intramuscular, pulmonary or oral administration, or by inhalation. The therapeutically effective amount of the pyrazolopyridine compound (I) will vary with the age and condition of each individual patient to be treated, but for intravenous administration,
0.01-100m / kg body weight of human or animal
g of pyrazolopyridine compound (I) as a daily dose, and in the case of intramuscular administration, 0.1 to 100 mg of pyrazolopyridine compound (I) per kg of human or animal body weight
In the case of oral administration, in the case of oral administration, 0.5 to 100 mg of pyrazolopyridine compound (I) per kg of human or animal body weight per day, for preventing and / or treating the above-mentioned diseases. Administer.

[0097]

The following production examples and examples are provided to explain the present invention in more detail.

Production Example 1 2-[[2,3-dihydro-3-oxo-6- (2-phenylpyrazolo [1,5-a] pyridin-3-yl) pyridazin] -2-yl] acetonitrile ( 300m
g) A mixture of hydroxylamine hydrochloride (260 mg) and potassium carbonate (260 mg) in a mixture of methanol (9 ml) and water (1.5 ml) was heated to reflux for 40 minutes. The reaction mixture was diluted with water, and the resulting solid was collected by filtration. The crude product was recrystallized from a mixture of ethanol and dichloromethane to give 0.28 g of 2-[[2,3-dihydro-3-oxo-6- (2-phenylpyrazolo [1,5-a] pyridine- 3-yl) pyridazine] -2
-Yl] acetamidooxime was obtained. Melting point: 231-232 ° C IR (Nujol): 3400, 3310, 1660, 1640, 1565 cm ^-1 NMR (DMSO-d ₆ , δ): 4.74 (2H, s), 5.55 (2H, s), 6.88
(1H, d, J = 9.7Hz), 7.04 (1H, d, J = 9.7Hz), 7.04-7.1
2 (1H, m), 7.38-7.53 (4H, m), 7.61-7.66 (2H, m), 8.
04 (1H, d, J = 8.9Hz), 8.82 (1H, d, J = 6.9Hz), 9.31
(1H, s) APCI / MS: 361 [M + H] ⁺

Production Example 2 3- (3-oxo-2-carboxymethyl-2,3-dihydropyridazin-6-yl) -2-phenylpyrazolo [1,5-a] pyridine (669 mg), 1- ( 3-dimethylaminopropyl) -3-ethylcarbodiimide
Hydrochloride (408 mg), 4-dimethylaminopyridine (259 mg), 3-hydroxy-2-butanone (18
A mixture of 7 mg) and dichloromethane (13 ml) was stirred at room temperature for 23 hours. A saturated saline solution was added to the reaction solution, and the mixture was extracted twice with chloroform. The extract was washed with saturated saline, dried over magnesium sulfate, and the solvent was concentrated to dryness under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (eluted with a mixture of normal hexane and ethyl acetate 2: 1) to give 3- [3-oxo-2-[(3-oxo-2-butoxy) carbonylmethyl] -2. , 3-Dihydropyridazin-6-yl] -2-
Phenylpyrazolo [1,5-a] pyridine (232 m
g) was obtained as an amorphous substance. APCI / MS: 417 [M + H] ⁺ NMR (DMSO-d6, d): 1.39 (3H, d, J = 7.0 Hz), 2.16 (3H,
s), 5.10-5.24 (3H, m), 6.95 (1H, d, J = 9.7 Hz), 7.06-
7.14 (2H, m), 7.39-7.51 (4H, m), 7.59-7.62 (2H, m),
7.97 (1H, d, J = 8.9 Hz), 8.83 (1H, d, J = 6.9 Hz)

Production Example 3 3- [3-oxo-2-[(3-oxo-1,2-diphenylethoxy) carbonylmethyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [ [1,5-a] pyridine was obtained in the same manner as in Production Example 2. NMR (DMSO-d6, d): 5.16 (1H, d, J = 16.9 Hz), 5.28 (1H,
d, J = 16.9 Hz), 6.93 (1H, d, J = 9.7 Hz), 7.05-7.13
(2H, m), 7.33-7.67 (14H, m), 8.00 (1H, d, J = 8.9Hz),
8.10 (2H, d, J = 7.2 Hz), 8.83 (1H, d, J = 6.9 Hz)

Production Example 4 3- (3-oxo-2-carboxymethyl-2,3-dihydropyridazin-6-yl) -2-phenylpyrazolo [1,5-a] pyridine (460 mg), phenacyl bromide (398 mg), potassium carbonate (367 mg)
And a mixture of N, N-dimethylformamide (9 ml) was stirred at room temperature for 2 hours and 40 minutes. The reaction solution was poured into ice water and extracted twice with ethyl acetate. The extract was washed with water and saturated saline, dried over magnesium sulfate, and the solvent was concentrated to dryness under reduced pressure to obtain a crude product. This was subjected to silica gel column chromatography (chloroform and ethyl acetate 1).
(Eluted with a 0: 1 mixture)) and purified by 3- [3-oxo-2-[(2-oxo-2-phenylethoxy) carbonylmethyl] -2,3-dihydropyridazin-6-yl]- 2-phenylpyrazolo [1,5-a] pyridine was obtained. APCI / MS: 465 [M + H] ⁺ NMR (DMSO-d6, d): 5.19 (2H, s), 5.68 (2h, S), 6.95 (1
H, d, J = 9.7 Hz), 7.08-7.13 (2H, m), 7.41-7.75 (9H,
m), 7.99-8.07 (3H, m), 8.84 (1H, d, J = 6.9 Hz)

Example 1 3- (3-oxo-2,3-dihydropyridazine-6-
Yl) -2-phenylpyrazolo [1,5-a] pyridine (2.88 g) and sodium hydride (60% dispersion in mineral oil, 560 mg) in N, N-dimethylformamide (5
0 ml) was added to allyl bromide (1.21 ml) and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. Water (300 ml) was added to the reaction mixture, and the insoluble solid was collected by filtration and purified by silica gel column chromatography (n-hexane-ethyl acetate, 2: 1, 1: 1, 1: 2 and ethyl acetate). . Recrystallized from 95% ethanol, 3
-(2-allyl-3-oxo-2,3-dihydropyridazin-6-yl) -2-phenylpyrazolo [1,5-
a] Pyridine (2.04 g) was obtained as a pale yellow solid. Melting point: 148.5-149.0 ° C (95% ethanol) FT-IR (KBr): 1670.0, 1594.8, 1531.2, 1496.5, 1467.
6, 1446.4, 1411.6 cm ^-1 NMR (CDCl ₃ , δ): 4.89 (2H, d
t, J = 6.0, 1.3Hz), 5.31-5.41 (2H, m), 6.05-6.25 (1
H, m), 6.78 (1H, d, J = 9.7Hz), 6.91 (1H, td, J = 6.9,
1.4Hz), 7.02 (1H, d, J = 9.7Hz), 7.25-7.35 (1H, m),
7.43-7.49 (3H, m), 7.59-7.65 (2H, m), 8.00 (1H, d
t, J = 8.9, 1.2Hz) , 8.52 (1H, dt, J = 6.9, 1.0Hz) APCI / MS: 329 [M + H] + Elemental analysis: C ₂₀ H ₁₆ N ₄ O Calculated: C, 73.15 ; H, 4.91; N, 17.06 Found: C, 73.04; H, 4.89; N, 17.03

Example 2 3- (2-benzyl-3-oxo-2,3-dihydropyridazin-6-yl) -2-phenylpyrazolo [1,5
-A] Pyridine was obtained in the same manner as in Example 1. Melting point: 185.0-186.0 ° C (95% ethanol) FT-IR (KBr): 1664.3, 1631.5, 1591.0, 1525.4, 1488.
8, 1467.6, 1417.4 cm ^-1 NMR (CDCl ₃ , δ): 5.44 (2H,
s), 6.78 (1H, d, J = 9.6Hz), 6.87 (1H, t, J = 6.9Hz),
6.98 (1H, d, J = 9.6Hz), 7.13-7.22 (1H, m), 7.34-7.6
3 (11H, m), 8.49 (1H, d, J = 6.8Hz) APCI / MS: 379 [M + H] ⁺ Elemental analysis: C ₂₄ H ₁₈ N ₄ O ・ 0.2H ₂ O Calculated: C, 75.45 ; H, 4.85; N, 14.67 Found: C, 75.62; H, 4.75; N, 14.66

Example 3 3- [2- (3-benzyloxypropyl) -3-oxo-2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5-a] pyridine was carried out. Obtained in the same manner as in Example 1. Melting point: 105.5-106.5 ° C (95% ethanol) FT-IR (KBr): 1656.6, 1587.1, 1527.3, 1500.3, 1463.
7, 1415.5 cm ^{-1 1} H NMR (CDCl ₃ , δ): 2.26 (2H, p, J = 6.8 Hz), 3.64 (2H,
t, J = 6.1Hz), 4.42 (2H, t, J = 7.0Hz), 4.51 (2H, s),
6.74 (1H, d, J = 9.6Hz), 6.89 (1H, td, J = 6.9,1.3H
z), 7.00 (1H, d, J = 9.6Hz), 7.17-7.35 (6H, m), 7.43
-7.47 (3H, m), 7.58-7.63 (2H, m), 8.01 (1H, d, J =
8.9Hz), 8.52 (1H, d , J = 6.9Hz) APCI / MS: 437 [M + H] + Elemental _{analysis: C 27 H 24 N 4 O} 2 Calculated: C, 74.29; H, 5.54 ; N, 12.84 Found: C, 73.94; H, 5.49; N, 12.69

Example 4 2-[[2,3-dihydro-3-oxo-6- (2-phenylpyrazolo [1,5-a] pyridin-3-yl) pyridazin] -2-yl] acetamidooxime (0.5
To a suspension of 0 g) in pyridine (5 ml) was added acetyl chloride (0.11 ml) at room temperature. Mix the mixture at room temperature for 2 hours.
After stirring for hours, it was heated at 130 ° C. for 0.5 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of ethyl acetate and n-hexane (1: 1) to give 3- [3-oxo-2-.
[(5-methyl-1,2,4-oxadiazole-3-
Yl) methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5-a] pyridine (40 mg) was obtained. Melting point: 199-200 ° C (ethyl acetate) IR (Nujol): 1660, 1620, 1580 cm ^-1 NMR (DMSO-d ₆ , δ): 2.62 (3H, s), 5.49 (2H, s), 6.94
(1H, d, J = 9.7Hz), 7.11 (1H, d, J = 9.7Hz), 7.04-7.1
1 (1H, m), 7.38-7.50 (4H, m), 7.59-7.64 (2H, m), 7.
91 (1H, d, J = 8.9Hz), 8.82 (1H, d, J = 6.9Hz) APCI / MS: 385 [M + H] ⁺

Example 5 3- (3-oxo-2-thiocarbamoylmethyl-2,
3-Dihydropyridazin-6-yl) -2-phenylpyrazolo [1,5-a] pyridine (0.5 g) and chloroacetone (0.17 ml) in chloroform (2.5 m
The mixture in a mixture of 1) and methanol (2.5 ml) was refluxed for 8 hours. After evaporation of the solvent, the residue was chromatographed on silica gel (40 ml) using a mixture of chloroform and ethyl acetate (20: 1). The desired fraction was collected and the solvent was distilled off in vacuo. The residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 3- [3-oxo-2-[(4-methylthiazol-2-yl) methyl] -2,3-dihydropyridazin-6-yl. ] -2-
Phenylpyrazolo [1,5-a] pyridine (0.27
g) was obtained as a solid. Melting point: 172-173 ° C IR (Nujol): 1650, 1620, 1585, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 2.38 (3H, s), 5.60 (2H, s), 6.94
(1H, d, J = 9.7Hz), 7.05-7.12 (2H, m), 7.28 (1H,
s), 7.37-7.63 (7H, m), 7.92-7.97 (1H, m), 8.80-8.8
4 (1H, m) APCI / MS: 400 [M + H] ⁺

Example 6 3- [3-oxo-2-[(5-acetyl-4-methylthiazol-2-yl) methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5
-A] Pyridine was obtained in the same manner as in Example 5. Melting point: 192-193 ° C (ethanol) IR (Nujol): 1660, 1650, 1625, 1590, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 2.52 (3H, s), 2.66 (3H, s), 5.63
(2H, s), 6.97 (1H, d, J = 9.7Hz), 7.04-7.12 (1H, m),
7.14 (1H, d, J = 9.7Hz), 7.37-7.64 (6H, m), 7.93-7.9
8 (1H, m), 8.80-8.83 (1H, m) APCI / MS: 442 [M + H] ⁺ Elemental analysis: C ₂₄ H ₁₉ N ₅ O ₂ S Calculated: C, 65.29; H, 4.34; N , 15.86 Found: C, 65.06; H, 4.13; N, 15.73.

Example 7 3- [3-oxo-2-[(4-phenylthiazole-
2-yl) methyl] -2,3-dihydro-pyridazine-
6-yl] -2-phenylpyrazolo [1,5-a] pyridine was obtained in the same manner as in Example 5. Melting point: 166-167 ° C (ethanol) IR (Nujol): 1655, 1625, 1580, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 5.73 (2H, s), 6.95-7.13 (3H, m),
7.25-7.64 (9H, m), 7.94-8.01 (3H, m), 8.14 (1H,
s), 8.80-8.83 (1H, m) APCI / MS: 462 [M + H] ⁺

Example 8 3- [3-oxo-2-[(3,4,5-trimethoxyphenylthiazol-2-yl) methyl] -2,3-dihydropyridazin-6-yl] -2-phenyl Pyrazolo [1,5-a] pyridine was obtained in the same manner as in Example 5. Melting point: 220-221 ° C (ethanol-chloroform) IR (Nujol): 1660, 1610, 1585, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 3.69 (3H, s), 3.83 (6H, s), 5.73
(2H, s), 6.96-7.16 (3H, m), 7.25-7.33 (3H, m), 7.
45-7.62 (5H, m), 7.91-7.96 (1H, m), 8.15 (1H, s),
8.80-8.84 (1H, m) APCI / MS: 552 [M + H] ⁺ Elemental analysis: C ₂₆ H ₂₅ N ₇ O ₂ S Calculated: C, 65.32; H, 4.57; N, 12.70 Found: C, 65.05; H, 4.55; N, 12.64

Example 9 3- [3-oxo-2-[(4-ethoxycarbonylthiazol-2-yl) methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1, 5-
a] Pyridine was obtained in the same manner as in Example 5. Melting point: 200-201 ° C (ethanol) IR (Nujol): 1705, 1670, 1630, 1590, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 1.30 (3H, t, J = 7.1Hz), 4.32 ( 2H,
q, J = 7.1Hz), 5.70 (2H, s), 6.98 (1H, d, J = 9.7Hz),
7.13 (2H, m), 7.36-7.64 (6H, m), 7.97-8.01 (1H,
m), 8.54 (1H, s), 8.81-8.85 (1H, m) APCI / MS: 458 [M + H] ⁺ Elemental analysis: C ₂₄ H ₁₉ N ₅ O ₃ S Calculated: C, 63.00; H, 4.19; N, 15.31 Found: C, 63.35; H, 4.05; N, 15.33.

Example 10 3- [3-oxo-2-[(4,5-dimethylthiazol-2-yl) methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1 [5-a] pyridine was obtained in the same manner as in Example 5. Melting point: 151-152 ° C (ethyl acetate-N-hexane) IR (Nujol): 1670, 1630, 1625, 1590, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 2.26 (3H, s), 2.31 ( 3H, s), 5.51
(2H, s), 6.92 (1H, d, J = 9.7Hz), 7.04-7.11 (2H, m),
7.37-7.63 (6H, m), 7.93-7.98 (1H, m), 8.80-8.83
(1H, m) APCI / MS: 414 [M + H] ⁺

Example 11 3- [3-oxo-2-[(4-ethoxycarbonylthiazol-2-yl) methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1, 5-
a] A mixture of pyridine (0.24 g) and 1 N sodium hydroxide solution (0.57 ml) in methanol (7 ml) was stirred at room temperature for 7 days. After evaporation of the solvent, the residue was dissolved in water. The solution was made basic with a 1N hydrogen chloride solution. The resulting precipitate was collected by filtration. The obtained paste was recrystallized from ethanol to give 3- [3-oxo-2-[(4-carboxythiazol-2-yl) methyl] -2,3-dihydropyridazin-6-yl] -2. -Phenylpyrazolo [1,5-a] pyridine (0.19 g) was obtained as a solid. Melting point: 232-234 ° C (ethanol) IR (Nujol): 1720, 1640, 1575, 1530 cm ^-1 NMR (DMSO-d ₆ , δ): 5.69 (2H, s), 6.97 (1H, d, J = 9.7)
Hz), 7.05-7.14 (2H, m), 7.36-7.64 (6H, m), 7.99-8.
03 (1H, m), 8.47 (1H, s), 8.81-8.85 (1H, m), 7.25
7.33 (3H, m), 7.45-7.62 (5H, m), 7.91-7.96 (1H,
m), 8.15 (1H, s), 8.80-8.84 (1H, m) APCI / MS: 430 [M + H] ⁺

Example 12 3- [3-oxo-2-[(4-carboxythiazol-2-yl) methyl] -2,3-dihydropyridazine-
6-yl] -2-phenylpyrazolo [1,5-a] pyridine (0.30 g), piperidine (0.067 ml),
A mixture of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.14 ml) and 1-hydroxybenzotriazole (0.104 g) in N, N-dimethylformamide (6 ml) was stirred at room temperature for 18 hours. . The reaction mixture was poured into water, and the resulting precipitate was collected by filtration.
The obtained paste was recrystallized from a mixture of ethanol and water to give 3- [3-oxo-2-[[(4-piperidinocarbonyl) thiazol-2-yl] methyl] -2,2.
3-Dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5-a] pyridine (0.27 g) was obtained as a solid. Melting point: 202-204 ° C IR (Nujol): 1660, 1610, 1585, 1520 cm ^-1 NMR (DMSO-d ₆ , δ): 1.20-1.70 (6H, m), 3.40-3.70 (4
H, m), 5.69 (2H, s), 6.94-7.14 (3H, m), 7.34-7.63
(6H, m), 7.85-7.90 (1H, m), 8.05 (1H, s), 8.80-8.8
3 (1H, m) APCI / MS: 497 [M + H] ⁺

Example 13 3- [3-oxo-2-[[4- (3,4,5-trimethoxyanilinocarbonyl) thiazol-2-yl] methyl] -2,3-dihydropyridazine-6- Il] -2
Example 1 using -phenylpyrazolo [1,5-a] pyridine
Obtained in the same manner as 2. Melting point: 148-150 ℃ (Ethanol) IR (Nujol): 3380, 1670, 1595, 1540, 1535, 151
0 cm ^-1 NMR (DMSO-d ₆ , δ): 3.64 (3H, s), 3.76 (6H, s), 5.76
(2H, s), 6.98-7.11 (3H, m), 7.32-7.62 (8H, m), 7.
89-7.94 (1H, m), 8.43 (1H, s), 8.80-8.84 (1H, m), 1
0.16 (1H, s) APCI / MS: 595 [M + H] ⁺

Example 14 3- [3-oxo-2-[[4- (dimethylaminocarbonyl) thiazol-2-yl] methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5-a] pyridine was obtained in the same manner as in Example 12. Melting point: 160-162 ° C (ethanol-water) IR (Nujol): 1670, 1625, 1595 cm ^-1 NMR (DMSO-d ₆ , δ): 2.98 (3H, s), 3.08 (3H, s), 5.69
(2H, s), 6.94-7.13 (3H, m), 7.35-7.61 (6H, m), 7.
86-7.91 (1H, m), 8.08 (1H, s), 8.80-8.84 (1H, m) APCI / MS: 457 [M + H] ⁺ Elemental analysis: C ₂₄ H ₂₀ N ₆ O ₂ S Calculated: C, 63.14; H, 4.42; N, 18.41 Found: C, 62.84; H, 4.38; N, 18.28

Example 15 3- [3-oxo-2-[[4-[(2-dimethylaminoethyl) aminocarbonyl] thiazol-2-yl]
Methyl] -2,3-dihydropyridazin-6-yl]-
2-Phenylpyrazolo [1,5-a] pyridine was obtained in the same manner as in Example 12. Melting point: 173-176 ° C (ethanol-water) IR (Nujol): 3420, 1655, 1590 cm ^-1 NMR (DMSO-d ₆ , δ): 2.12 (6H, s), 2.37 (2H, t, J = 6.4
Hz), 3.32-3.37 (2H, m), 5.69 (2H, s), 6.96-7.16 (3
H, m), 7.35-7.61 (6H, m), 7.85-7.89 (1H, m), 8.26
(1H, s), 8.80-8.84 (1H, m) APCI / MS: 500 [M + H] ⁺ Elemental analysis: C ₂₆ H ₂₅ N ₇ O ₂ S Calculated: C, 62.51; H, 5.04; N, 19.63 Found: C, 62.19; H, 4.99; N, 19.43

Example 16 3- [3-oxo-2-[(4-carboxythiazol-2-yl) methyl] -2,3-dihydropyridazine-
6-yl] -2-phenylpyrazolo [1,5-a] pyridine (0.30 g) and N-methylmorpholine (0.14 g)
To a solution of (5 ml) in tetrahydrofuran (10 ml) was added dropwise isobutyl chloroformate (0.15 ml) at -25 to -15 ° C under a nitrogen atmosphere. After stirring for 0.25 hours under the same conditions, 28% ammonia solution (1 ml)
Was added to the reaction mixture. The mixture was stirred at room temperature for 10 minutes. After evaporation of the solvent, the residue was suspended in 1N sodium hydroxide solution. The resulting precipitate was collected by filtration. The obtained paste was recrystallized from ethanol to give 3- [3-oxo-
2-[(4-carbamoylthiazol-2-yl) methyl] -2,3-dihydropyridazin-6-yl] -2-
Phenylpyrazolo [1,5-a] pyridine (0.27
g) was obtained as a solid. Melting point: 232-234 ° C IR (Nujol): 3420, 3310, 1655, 1585 cm ^-1 NMR (DMSO-d ₆ , δ): 5.69 (2H, s), 6.96-7.15 (3H, m),
7.35-7.92 (9H, m), 8.27 (1H, s), 8.80-8.84 (1H,
m) APCI / MS: 429 [M + H] ⁺

Example 17 3- [3-oxo-2-[(4-ethoxycarbonylthiazol-2-yl) methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1, 5-
a] pyridine, tetrahydrofuran and ethanol (4:
Trimethyl boronate (34.8 mg) and lithium borohydride (292 m) were added to a mixture of the mixture (76 ml) of 1).
g) was added at room temperature. The reaction solution was stirred at room temperature for 2 hours, cooled in an ice-water bath, and 1N hydrochloric acid was added. The solvent was concentrated under reduced pressure, and then separated with water-chloroform. The chloroform extract was washed with brine, dried over magnesium sulfate, and the solvent was concentrated to dryness under reduced pressure to obtain a crude product. This was subjected to silica gel column chromatography, and eluted with a mixed solution of chloroform and ethyl acetate (10: 1-3: 1-2: 1).
-[3-oxo-2-[(4-hydroxymethylthiazol-2-yl) methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5-a]
Pyridine (925 mg) was obtained. Melting point: 193-194 ° C (ethanol) APCI / MS: 416 [M + H] ⁺ NMR (DMSO-d6, d): 4.58 (2H, d, J = 5.7 Hz), 5.36 (1H,
t, J = 5.7 Hz), 5.63 (2H, s), 6.95 (1H, d, J = 9.7 Hz),
7.07-7.12 (2H, m), 7.38-7.50 (5H, m), 7.59-7.64 (2H, m
m), 7.94 (1H, d, J = 8.9 Hz), 8.82 (1H, d, J = 6.9Hz)

Example 18 3- [3-oxo-2-[[4- (4-methoxyphenyl) thiazol-2-yl] methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyra Zolo [1,5-a] pyridine was obtained in the same manner as in Example 5. Melting point: 215-216 ° C (95% ethanol) APCI / MS: 492 [M + H] ⁺ NMR (DMSO-d6, d): 3.80 (3H, s), 5.71 (2H, s), 6.95-
7.13 (5H, m), 7.26-7.35 (1H, m), 7.46-7.49 (3H, m),
7.61-7.62 (2H, m), 7.90-7.97 (4H, m), 8.82 (1H, d, J =
(6.9Hz)

Example 19 3- [3-oxo-2-[[4- (2-methoxyphenyl) thiazol-2-yl] methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyra Zolo [1,5-a] pyridine was obtained in the same manner as in Example 5. Melting point: 190-191 ° C (95% ethanol) APCI / MS: 492 [M + H] ⁺ NMR (DMSO-d6, d): 3.93 (3H, s), 5.72 (2H, s), 6.95-
7.18 (5H, m), 7.25-7.36 (2H, m), 7.46-7.49 (3H, m),
7.60-7.62 (2H, m), 7.96 (1H, d, J = 8.7 Hz), 8.10 (1H, m
s), 8.18 (1H, d, J = 7.8 Hz), 8.82 (1H, d, J = 6.8Hz)

Example 20 3- [3-oxo-2-[[4- (3-methoxyphenyl) thiazol-2-yl] methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyra Zolo [1,5-a] pyridine was obtained in the same manner as in Example 5. Melting point: 165-166 ° C (95% ethanol) APCI / MS: 492 [M + H] ⁺ NMR (DMSO-d6, d): 3.81 (3H, s), 5.73 (2H, s), 6.92-
7.14 (4H, m), 7.27-7.63 (9H, m), 7.97 (1H, d, J = 8.7 H
z), 8.18 (1H, s), 8.82 (1H, d, J = 6.9Hz)

Example 21 3- [3-oxo-2-[[4- (2,5-dimethoxyphenyl) thiazol-2-yl] methyl] -2,3-
Dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5-a] pyridine was obtained in the same manner as in Example 5. Melting point: 199-200 ° C (95% ethanol) APCI / MS: 522 [M + H] ⁺ NMR (DMSO-d6, d): 3.74 (3H, s), 3.87 (3H, s), 5.72 (2
H, s), 6.90-7.14 (5H, m), 7.25-7.32 (1H, m), 7.44-7.
50 (3H, m), 7.57-7.63 (2H, m), 7.74 (1H, d, J = 3.1 H
z), 7.96 (1H, d, J = 8.9 Hz), 8.13 (1H, s), 8.82 (1H,
d, J = 6.6 Hz)

Example 22 3- [3-oxo-2-[[4- (3-pyridyl) thiazol-2-yl] methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5-
a] Pyridine was obtained in the same manner as in Example 5. Melting point: 209-210 ° C (95% ethanol) APCI / MS: 463 [M + H] ⁺ NMR (DMSO-d6, d): 5.75 (2H, s), 6.96-7.15 (3H, m),
7.25-7.32 (1H, m), 7.32 (1H, t, J = 7.6 Hz), 7.46-7.30
(4H, m), 7.61-7.62 (2H, m), 7.97 (1H, d, J = 8.8Hz),
8.33 (2H, m), 8.57 (1H, d, J = 3.3 Hz), 8.82 (1H, d, J =
6.9 Hz), 9.20 (1H, d, J = 3.5 Hz)

Example 23 3- [3-oxo-2-[[4- (4-nitrophenyl) thiazol-2-yl] methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyra Zolo [1,5-a] pyridine was obtained in the same manner as in Example 5. Melting point: 254-255 ° C (methanol-dioxane) APCI / MS: 507 [M + H] ⁺ NMR (DMSO-d6, d): 5.75 (2H, s), 6.97-7.16 (3H, m),
7.32 (1H, t, J = 7.6 Hz), 7.44-7.49 (3H, m), 7.60-7.64
(2H, m), 7.96 (1H, d, J = 8.7 Hz), 8.26 (2H, d, J = 8.9
Hz), 8.34 (2H, d, J = 8.9 Hz), 8.51 (1H, s), 8.82 (1H,
d, J = 6.8 Hz)

Example 24 3- [3-oxo-2-[(4-ethylthiazole-2)
-Yl) methyl] -2,3-dihydropyridazine-6-
[Ill] -2-phenylpyrazolo [1,5-a] pyridine was obtained in the same manner as in Example 5. Melting point: 155-156 ° C (95% ethanol) APCI / MS: 414 [M + H] ⁺ NMR (DMSO-d6, d): 1.24 (3H, t, J = 7.5 Hz), 2.74 (2H,
q, J = 7.5 Hz), 5.62 (2H, s), 6.92-7.11 (3H, m), 7.29 (1
H, s), 7.35 (1H, t, J = 7.9 Hz), 7.47-7.50 (3H, m), 7.
59-7.62 (2H, m), 7.93 (1H, d, J = 8.9 Hz), 8.82 (1H,
d, J = 6.9 Hz)

Example 25 3- [3-oxo-2-[[4- (4-methylphenyl) thiazol-2-yl] methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyra Zolo [1,5-a] pyridine was obtained in the same manner as in Example 5. Melting point: 195-196 ° C (95% ethanol) APCI / MS: 476 [M + H] ⁺ NMR (DMSO-d6, d): 2.34 (3H, s), 5.71 (2H, s), 6.95-
7.31 (3H, m), 7.25-7.35 (2H, m), 7.46-7.49 (3H, m),
7.60-7.62 (2H, m), 7.88 (2H, d, J = 8.1 Hz), 7.97 (1H,
d, J = 8.9 Hz), 8.06 (1H, s), 8.82 (1H, d, J = 6.8 Hz)

Example 26 3- [3-oxo-2-[[4- (4-chlorophenyl) thiazol-2-yl] methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5-a] pyridine was obtained in the same manner as in Example 5. Melting point: 221-222 ° C. (95% ethanol) APCI / MS: 496 [M + H] ⁺ NMR (DMSO-d6, d): 5.72 (2H, s), 6.95-7.14 (3H, m),
7.32 (1H, t, J = 7.8 Hz), 7.46-7.62 (7H, m), 7.93-8.03
(3H, m), 8.21 (1H, s), 8.82 (1H, d, J = 6.9 Hz)

Example 27 3- [3-oxo-2-[[4- (2,4-dimethoxyphenyl) thiazol-2-yl] methyl] -2,3-
Dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5-a] pyridine was obtained in the same manner as in Example 5. Melting point: 188-189 ° C (95% ethanol) APCI / MS: 522 [M + H] ⁺ NMR (DMSO-d6, d): 3.82 (3H, s), 3.92 (3H, s), 5.70 (2
H, s), 6.64-6.69 (2H, s), 6.97 (1H, d, J = 9.7 Hz), 7.
03-7.13 (2H, m), 7.30 (1H, t, J = 7.8 Hz), 7.46-7.49 (3
H, m), 7.60-7.62 (2H, m), 7.93 (1H, s), 7.95 (1H, d,
J = 9.2 Hz), 8.08 (1H, d, J = 8.5 Hz), 8.81 (1H, d, J = 6.
9 Hz)

Example 28 3- [3-oxo-2-[(4,5-diphenylthiazol-2-yl) methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1 , 5-a]
Pyridine was obtained as in Example 5. Melting point: 162-163 ° C. (95% ethanol) (+)-APCI / MS: 538 [M + H] + NMR (DMSO-d6, d): 5.72 (2H, s), 6.96-7.16 (3H, m) ,
7.23-7.47 (14H, m), 7.60-7.63 (2H, m), 8.00 (1H, d, J
= 8.9 Hz), 8.82 (1H, d, J = 6.9 Hz)

Example 29 3- [3-oxo-2-[(4-trifluoromethylthiazol-2-yl) methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1 , 5-
a] Pyridine was obtained in the same manner as in Example 5. Melting point: 162-163 ° C (ethanol) (+)-ESI / MS: 476 [M + Na] + NMR (DMSO-d6, d): 5.74 (2H, s), 6.99 (1H, d, J = 9.7 H)
z), 7.05-7.15 (2H, m), 7.38 (1H, t, J = 7.5 Hz), 7.46-
7.50 (3H, m), 7.59-7.64 (2H, m), 7.94 (1H, d, J = 8.9 H
z), 8.54 (1H, d, J = 0.8 Hz), 8.83 (1H, d, J = 6.9 Hz)

Example 30 3- [3-oxo-2-[(4-methyl-5-phenylthiazol-2-yl) methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5
-A] Pyridine was obtained in the same manner as in Example 5. Melting point: 165-166 ° C (ethanol) APCI / MS: 476 [M + H] ⁺ NMR (DMSO-d6, d): 2.55 (3H, s), 5.63 (2H, s), 6.96 (1
H, d, J = 9.7 Hz), 7.05-7.13 (2H, m), 7.42 (1H, t, J =
7.2 Hz), 7.47-7.52 (6H, m), 7.59-7.71 (4H, m), 7.97 (1
H, d, J = 8.9 Hz), 8.82 (1H, d, J = 6.9 Hz)

Example 31 3- [3-oxo-2-[(5-propyl-1,2,4
-Oxadiazol-3-yl) methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5-a] pyridine was obtained in the same manner as in Example 4. Melting point: 159-160 ° C (ethyl acetate-diisopropyl ether) APCI / MS: 413 [M + H] ⁺ NMR (DMSO-d6, d): 0.94 (3H, t, J = 7.4 Hz), 1.76 (2H,
6-plet, J = 7.4 Hz), 2.94 (2H, t, J = 7.4 Hz), 5.51 (2H,
s), 6.94 (1H, d, J = 9.7 Hz), 7.00-7.12 (2H, m), 7.40
(1H, t, J = 7.9 Hz), 7.47-7.50 (3H, m), 7.59-7.64 (2H,
m), 7.90 (1H, d, J = 8.9 Hz), 8.82 (1H, d, J = 6.9 Hz)

Example 32 3- [3-oxo-2-[(5-ethyl-1,2,4-
Oxadiazol-3-yl) methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5-a] pyridine was obtained in the same manner as in Example 4. Melting point: 161-162 ° C (ethyl acetate) APCI / MS: 399 [M + H] ⁺ NMR (DMSO-d6, d): 1.29 (3H, t, J = 7.5 Hz), 2.98 (2H,
q, J = 7.5 Hz), 5.50 (2H, s), 6.94 (1H, d, J = 9.7 Hz),
7.04-7.12 (2H, m), 7.37-7.50 (4H, m), 7.59-7.64 (2H, m
m), 7.91 (1H, d, J = 8.9 Hz), 8.82 (1H, d, J = 6.9 Hz)

Example 33 3- [3-oxo-2-[(5-tert-butyl-1,2,2,
4-oxadiazol-3-yl) methyl] -2,3-
Dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5-a] pyridine was obtained in the same manner as in Example 1. Melting point: 155-156 ° C (ethanol) APCI / MS: 427 [M + H] ⁺ NMR (DMSO-d6, d): 1.40 (9H, s), 5.51 (2H, s), 6.94 (1
H, d, J = 9.7 Hz), 7.05-7.12 (2H, m), 7.38 (1H, t, J =
7.5 Hz), 7.47-7.50 (3H, m), 7.59-7.62 (2H, m), 7.89 (1
H, d, J = 8.9 Hz), 8.82 (1H, d, J = 6.9 Hz)

Example 34 3- [3-oxo-2-[(3-oxo-2-butoxy) carbonylmethyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5 -A] pyridine (205 mg), ammonium acetate (380 m
g) and acetic acid (2.1 ml) were heated at reflux for 3.5 hours. The reaction solution was poured into a mixture of a 1 N aqueous sodium hydroxide solution and ice, and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over magnesium sulfate, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluted with a mixture of chloroform and ethyl acetate 10: 1) to give 3- [3-oxo-2- [2-
(4,5-dimethyloxazolyl) methyl] -2,3-
Dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5-a] pyridine (189 mg) was obtained. Melting point: 171-172 ° C (95% ethanol) APCI / MS: 398 [M + H] ⁺ NMR (DMSO-d6, d): 2.04 (3H, s), 2.24 (3H, s), 5.39 (2
H, s), 6.92 (1H, d, J = 9.7 Hz), 7.05-7.11 (2H, m), 7.
59-7.64 (2H, m), 7.59-7.62 (2H, m), 7.86 (1H, d, J = 8.9
Hz), 8.82 (1H, d, J = 6.9 Hz)

Example 35 3- [3-oxo-2- [2- (4,5-diphenyloxazolyl) methyl] -2,3-dihydropyridazine-
6-yl] -2-phenylpyrazolo [1,5-a] pyridine was obtained in the same manner as in Example 34. Melting point: 183-184 ° C (ethyl acetate) APCI / MS: 522 [M + H] ⁺ NMR (DMSO-d6, d): 5.63 (2H, s), 7.00-7.12 (4H, m),
7.41-7.63 (15H, m), 7.88 (1H, d, J = 8.2 Hz), 8.80 (1H,
d, J = 6.9 Hz)

Example 36 The following two compounds were obtained in the same manner as in Example 34.

3- [3-oxo-2- [2- (4-phenyloxazolyl) methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5-
a] Pyridine Melting point: 198-199 ° C (95% ethanol) APCI / MS: 446 [M + H] ⁺ NMR (DMSO-d6, d): 5.58 (2H, s), 6.94-7.24 (4H, m),
7.30-7.50 (6H, m), 7.60-7.63 (2H, m), 7.79-7.89 (3H, m
m), 8.68 (1H, s), 8.80 (1H, d, J = 6.9 Hz) and 3- [3-oxo-2- [2- (4-phenylimidazolyl) methyl] -2,3-dihydropyridazine- 6-yl] -2-phenylpyrazolo [1,5-a] pyridine Melting point: 231-232 ° C. (95% ethanol) APCI / MS: 445 [M + H] ⁺ NMR (DMSO-d6, d): 5.42 (2H, s), 6.90-7.24 (5H, m),
7.37 (1H, t, J = 7.5 Hz),), 7.47-7.50 (3H, m), 7.78-7.
87 (3H, m), 8.77 (1H, d, J = 6.8 Hz)

Example 37 3- [3-oxo-2- [2- (4-phenylimidazolyl) methyl] -2,3-dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5-a ] Pyridine (208 mg) in N, N-dimethylformamide (2 m
Cool the mixture of l) in an ice-water bath. After adding 60% sodium hydride (20 mg) and stirring for 10 minutes, 41.8 μl of methyl iodide is added dropwise. After stirring for 2 hours under cooling in an ice water bath and for 5 hours and 20 minutes at room temperature, the reaction solution is poured into ice water and extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to dryness to obtain a crude product. This was subjected to silica gel column chromatography, and chloroform and ethyl acetate (2: 1) were used.
And eluted with a mixture of 3- [3-oxo-2- [2- (3-
Methyl-4-phenylimidazolyl) methyl] -2,3
-Dihydropyridazin-6-yl] -2-phenylpyrazolo [1,5-a] pyridine was obtained. Melting point: 202-203 ° C (95% ethanol) APCI / MS: 459 [M + H] ⁺ NMR (DMSO-d6, d): 3.71 (3H, s), 5.47 (2H, s), 6.89-
7.24 (5H, m), 7.34-7.41 (2H, m), 7.47-7.50 (3H, m),
7.59-7.62 (2H, m), 7.69 (1H, s), 7.77-7.85 (3H, m),
8.77 (1H, d, J = 6.5Hz)

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 3/10 A61P 3/10 7/02 7/02 7/06 7/06 7/10 7/10 9 / 00 9/00 9/04 9/04 9/06 9/06 9/10 9/10 101 101 9/12 9/12 11/08 11/08 13/12 13/12 17/02 17/02 17 / 10 17/10 19/06 19/06 25/16 25/16 25/22 25/22 25/24 25/24 25/28 25/28 27/16 27/16 29/00 29/00 37/04 37/04 43/00 111 43/00 111

Claims (11)

[Claims] 1. A compound represented by the following formula (I): Wherein R is lower alkenyl; lower alkyl substituted with aryl, wherein the lower alkyl may be interrupted by an oxygen atom; or a compound represented by the formula: -A-R ^{1 wherein} R ¹ Is oxadiazolyl, thiazolyl, oxazolyl or imidazolyl, each of which has one or more suitable substituents selected from the group consisting of lower alkyl, acyl, aryl, pyridyl and trihalomethyl; Is a group represented by: Or a salt thereof. 2. R is allyl; lower alkyl substituted by phenyl, which lower alkyl may be interrupted by an oxygen atom; Wherein R ² is lower alkyl. A group represented by the formula:
Formula Wherein R ³ is hydrogen, lower alkyl, acyl or phenyl; R ⁴ is lower alkyl, acyl, aryl,
Pyridyl or trihalomethyl. A group represented by the formula: Wherein, R ⁵ is lower alkyl or phenyl, R ⁶
Is hydrogen, lower alkyl or phenyl. Or a group represented by the formula: Wherein R ⁷ is phenyl and R ⁸ is hydrogen or lower alkyl. The compound according to claim 1, which is a group represented by the formula: 3. The method for producing a pyrazolopyridine compound or a salt thereof according to claim 1, wherein (1) a compound represented by the formula (II): X ¹ -R ⁹ (III) wherein R ⁹ is lower alkenyl; lower alkyl substituted with aryl, and the lower alkyl is Lower alkyl optionally substituted with an oxadiazole optionally interrupted by an oxygen atom; or X
¹ is a leaving group. ) Or a salt thereof to give a compound of the formula (Ia) (Wherein R ⁹ is as defined above) or a salt thereof, (2) Formula (IV) (Wherein A is as defined in claim 1) or a salt thereof is represented by the formula (V): R ² —COX ² (V) (wherein R ² is And X ² is a leaving group.) Or a salt thereof to give a compound of the formula (Ib) (Wherein R ² and A are as defined above) or a salt thereof, and (3) a compound represented by the formula (V
I) (Wherein, A is as defined above.) And a compound represented by or a salt thereof with the formula (VII) embedded image ^{R 3 -CHX 3 CO-R 4} (VII) ( wherein, R ³ Is hydrogen, lower alkyl, acyl or phenyl; R ⁴ is lower alkyl, acyl, aryl,
Pyridyl or trihalomethyl; X ³ is a leaving group. ) Or a salt thereof,
Formula (Ic) (In the formula, R ³ , R ⁴ and A are as defined above.)
(4) obtaining a compound represented by the formula: or a salt thereof; (Wherein R ¹⁰ is protected carboxy and A is as defined above) or a salt thereof is subjected to an elimination reaction of a carboxy-protecting group to give a compound of the formula (Ie) Embedded image Wherein A is as defined above, or a salt thereof, and (5) converting the compound represented by the formula (Ie) into a compound represented by the formula (VIII): (Wherein R ¹¹ and R ¹² are hydrogen, lower alkyl which may form a ring therebetween, di (lower) alkylamino (lower) alkyl or aryl) or a salt thereof. And an amidation reaction with the compound of formula (If) (Wherein R ¹¹ , R ¹² and A are as defined above) or a salt thereof,
(6) Formula (Id) (Wherein R ¹⁰ and A are as defined above) or a salt thereof is subjected to an elimination and reduction reaction of a carboxy-protecting group to give a compound of the formula (Ig) (Wherein A is as defined above) or a salt thereof, (7) Formula (Ih) A compound represented by the formula (IX): R ¹³ -CHX ⁴ CO-R ⁵ (IX) wherein R ⁵ is lower alkyl or phenyl;
¹³ is lower alkyl or phenyl; X ⁴ is a leaving group. ) Or a salt thereof to give a compound of the formula (Ii) (Wherein R ⁵ , R ¹³ and A are as defined above) or a salt thereof,
(8) Formula (Ii) (Wherein R ⁵ , R ¹³ and A are as defined above) or a salt thereof is reacted with a mixture of ammonium acetate and acetic acid to give a compound of the formula (Ij) (Wherein R ⁵ , R ¹³ and A are as defined above) or a salt thereof,
(9) Formula (Ih) A compound represented by the formula or a salt thereof is converted to a compound represented by the formula (X): CH ₂ X ⁵ CO—R ⁷ (X) (wherein R ⁷ is phenyl and X ⁵ is a leaving group)
And a salt thereof, to react with a compound represented by the formula (I
k) (Wherein R ⁷ and A are as defined above) or a salt thereof, (10) a compound represented by the formula (I)
k) (Wherein R ⁷ and A are as defined above) or a salt thereof with a mixture of ammonium acetate and acetic acid to give a compound of formula (Il) (Wherein R ⁷ and A are as defined above), or a salt thereof, and / or a compound of the formula (Im) (Wherein R ⁷ and A are as defined above) or a salt thereof, (11) Formula (I)
m) embedded image (Wherein R ⁷ and A are the same as defined above) or a salt thereof, represented by the formula (XI): R ¹⁴ -X ⁶ (XI) (where R ¹⁴ is Is a lower alkyl, and X ⁶ is a leaving group.) Or a salt thereof to obtain a compound of the formula (In) Wherein R ⁷ , R ¹⁴ and A are as defined above, or a salt thereof. 4. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier. 5. Depression, dementia, Parkinson's disease, anxiety, pain, cerebrovascular disease, cerebrovascular disease, heart failure, hypertension, circulating, comprising administering the compound of claim 1 or a pharmaceutically acceptable salt thereof to a human or animal. Insufficiency, systolic failure after resuscitation, bradyarrhythmia, electromechanical dysfunction (electro-mechanical
dissociation, cardiac hemodynamic dysfunction (hemodynamic colla)
pse), SIRS (systemic inflammatory response sy)
ndrome), multiple organ failure, renal failure, nephrotoxicity, nephrosis,
Nephritis, edema, obesity, bronchial asthma, gout, hyperuricemia,
Sudden infant death syndrome, immunosuppression, diabetes, ulcers, pancreatitis,
Meniere's syndrome, anemia, dialysis-induced hypotension, constipation, ischemic bowel disease, ileus, myocardial infarction, thrombosis, obstruction, obstructive atherosclerosis, thrombophlebitis, cerebral infarction, transient ischemia A method for preventing or treating a disease selected from the group consisting of bloody attacks and angina. 6. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof as a medicament. 7. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof as an adenosine antagonist. 8. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof as an A ₁ receptor and A ₂ receptor dual antagonist. 9. A method for producing a pharmaceutical composition, comprising mixing the compound of claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier. 10. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of a disease for which an adenosine antagonist is therapeutically effective. 11. A method for evaluating adenosine antagonism, comprising using the compound of claim 1 or a pharmaceutically acceptable salt thereof.