JPH07215974A - Arylethenylpyrazolopyridine derivative and method for producting the same - Google Patents

Abstract

PURPOSE:To provide a new arylethenylpyrazolopyridine derivative exhibiting an excellent neutrophil migration-inhibiting action in a low concentration and useful as a therapeutic medicine for diseases relating to inflamatory cells for glomerular nephritis, colitis ulcerosa, asthma and allergic rhinitis. CONSTITUTION:A compound of formula I [R<1> is H, lower alkyl, cycloalky, lower alkoxy(carbonyl); R<2>, R<3> are H, halogen, lower alkyl, lower alkoxy; Ar is (substituted) aromatic ring, (substituted) heteroaromatic ring], a salt thereof. For example, (E)-2-isopropyl-[2-(3,4,5-trimethoxyphenyl) ethenyl]pyrozolo[1,5- a]pyridine. The compound of formula I is obtained by reacting a compound of formula II (Ph is phenyl) with a compound of formula: Ar-CHO in the presence of a base.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to novel arylethenylpyrazolopyridine derivatives, and more particularly to novel arylethenylpyrazolopyridine derivatives useful for the treatment of diseases involving inflammatory cells and their preparation. The present invention relates to methods and therapeutic agents containing them.

[0002]

2. Description of the Related Art As a pyrazolopyridine derivative having an action on inflammatory cells, the applicant of the present invention disclosed in JP-A-59-167.
The compound described in Japanese Patent No. 516 is known, and its structure is such that the 3-position substituent of the pyrazolopyridine skeleton is an acyl derivative.

As a silver halide photographic emulsion for direct positive use, compounds having pyrazolopyridine derivatives described in JP-A-55-7703 and JP-A-3-274546 are known, but the compounds of the present invention act. And the 3-position substituent of the pyrazolopyridine skeleton is a quaternary salt derivative of a bicyclic compound such as benzothiazole or 1,8-naphthyridine, and is structurally different.

[0004]

Many diseases associated with inflammatory cells are known, and there is a strong demand for an effective drug having a superior neutrophil migration inhibitory effect.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies on drugs that act on inflammatory cells, and as a result, the novel arylethenylpyrazolopyridine derivative represented by the following general formula (1) was excellent. The present invention has been completed by discovering that it has a neutrophil migration inhibitory effect. [Wherein R ¹ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkoxy group or a lower alkoxycarbonyl group, and R ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group or Represents a lower alkoxy group, and Ar represents an aromatic ring or heteroaromatic ring which may have a substituent]

In the general formula (1) of the present invention, examples of the "lower alkyl group" include linear or branched ones having 1 to 6 carbon atoms such as methyl, ethyl, propyl and isopropyl. Include linear or branched ones having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, etc., "cycloalkyl group" means one having 3 to 6 carbon atoms, and "lower alkoxycarbonyl group" means 2 carbon atoms such as methoxycarbonyl and ethoxycarbonyl
~ 5 are mentioned. Examples of the “halogen atom” include fluorine, chlorine, bromine and iodine. Further, the “aromatic ring which may have a substituent” includes a benzene ring, a naphthalene ring and the like, and as the substituent, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl (wherein lower alkyl is methyl, ethyl , Straight-chain or branched ones having 1 to 4 carbon atoms such as propyl),
Alkoxy (linear or branched ones such as methoxy, ethoxy and propoxy having 1 to 4 carbon atoms, benzyloxy and the like), lower alkoxycarbonyl (straight or branched carbon atoms such as methoxycarbonyl and ethoxycarbonyl) 2 to 5), nitro, cyano, formyl, carboxy, tetrazolyl,
Amino, acetyl, etc. are mentioned, and those in which 2 to 3 of these substituents are simultaneously substituted are also included. Furthermore, as the "heteroaromatic ring which may have a substituent",
Examples thereof include a pyridine ring and quinoline ring, and examples of the substituent include lower alkyl such as methyl, ethyl and propyl, and halogen atoms such as fluorine, chlorine, bromine and iodine. Further, in the general formula (5), X = P (= O) (O
Examples of the “lower alkyl group” of R ′) ₂ include linear or branched ones having 1 to 4 carbon atoms such as methyl, ethyl and propyl.

According to the present invention, the compound of the general formula (1) can be produced by the route described below.

1) The compound of the general formula (1) is a compound of the general formula (2) [Wherein R ¹ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkoxy group or a lower alkoxycarbonyl group, and R ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group or A lower alkoxy group] can be produced by reacting the compound represented by the general formula (3) in the presence of a base. Ar-CHO (3) [in the formula, Ar represents an aromatic ring or a heteroaromatic ring which may have a substituent]

Similarly, the compound represented by the general formula (1) is the same as the compound represented by the general formula (5) and ArCH X (5) (R 'represents a lower alkyl group)] General formula (4)
It can be produced by reacting with a compound represented by [Wherein R ¹ , R ² and R ³ are as described above]

The reaction is preferably carried out in an organic solvent such as methanol, ethanol or tetrahydrofuran in the presence of a base such as sodium alkoxide, sodium hydride or butyllithium at a reaction temperature of -60 ° C to solvent reflux temperature.

2) The compound of the general formula (2) is novel,
It can be produced by reducing the compound of the general formula (4) to an alcohol compound, and then reacting it with triphenylphosphine and carbon tetrachloride. [Wherein R ¹ , R ² and R ³ are as described above] [Wherein R ¹ , R ² and R ³ are as described above]

For the reduction reaction, sodium borohydride is preferable, for example, in methanol or ethanol, and the reaction temperature is preferably room temperature to reflux temperature. The reaction temperature with triphenylphosphine and carbon tetrachloride is then preferably at reflux temperature.

The compound of the present invention has a strong neutrophil migration inhibitory effect and is a disease involving inflammatory cells, such as glomerulonephritis, ulcerative colitis, Crohn's disease, Behcet's disease, chronic granulomatosis, asthma, Adult respiratory distress syndrome, emphysema, idiopathic pulmonary fibrosis, pulmonary infection, acquired hemolytic anemia, agranulocytosis,
Gutpasture syndrome, serum sickness, hypersensitivity pneumonitis, allergic rhinitis, atopic dermatitis, myocardial infarction, ulcer wound,
It is useful for the treatment of duodenal ulcer, various thrombosis and peripheral circulatory failure.

In the compound (1) of the present invention, the compound containing a nitrogen atom in the Ar group can be converted to a pharmaceutically acceptable non-toxic salt thereof, if necessary. Examples of such salts include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, tartaric acid, citric acid, glycolic acid, gluconic acid, succinic acid, malic acid, glutamic acid, aspartic acid, methane. Examples thereof include salts with organic acids such as sulfonic acid.

The compound of the present invention can be used in the form of a pharmaceutical preparation suitable for parenteral administration, oral administration or external administration. Pharmaceutical preparations include injections, syrups, liquids such as emulsions, solids such as tablets, capsules and granules, and ointments,
Examples include external preparations such as suppositories.

[0016]

EXAMPLES The present invention will now be described with reference to specific examples, but the present invention is not limited thereto.

Reference Example 1 (2-Isopropylpyrazolo [1,5-a] pyridine-
3-ylmethyl) triphenylphosphonium chloride

3-Formyl-2-isopropylpyrazolo [1,5-a] pyridine (30.1 g), methanol 200 ml
Sodium borohydride (6.35g) to the mixed solution of 10-15 ℃
The mixture was gradually added at a temperature of 3 with stirring and stirred for 15 minutes. After returning to room temperature and stirring, the mixture was poured into ice water and extracted with benzene. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Add a mixture of the residue (28.9g), triphenylphosphine (79.7g), carbon tetrachloride (60ml) and benzene (100ml) to 4.5.
Heated to reflux for hours. After cooling, the precipitate was collected by filtration, washed with benzene and then with ether, and dried under reduced pressure to obtain 71.2 g of the desired product as pale yellow crystals.

Example 1 (E) -2-Isopropyl-3- [2- (3,4,5-
Trimethoxyphenyl) ethenyl] pyrazolo [1,5-
a] pyridine

Methanol (25 ml) and metallic sodium (0.
73 g) in a methanol solution of sodium methoxide adjusted with 3,4,5-trimethoxybenzaldehyde (2.08 g) and (2-isopropylpyrazolo [1,5-a] pyridin-3-ylmethyl under stirring in an ice-water bath. ) Triphenylphosphonium chloride (5.00 g) was added. After stirring at room temperature for 5 minutes, the mixture was heated under reflux for 5 hours. After cooling
The yellow crystals were collected by filtration, washed with cold methanol and water, and dried. Purified by silica gel column chromatography (methylene chloride), 2.30 g (62
%) Was obtained. Melting point: 163-165 ° C

Elemental analysis value (%) As C ₂₁ H ₂₄ N ₂ O ₃

(Examples 2 to 12) In the same manner as in Example 1, the compounds shown in Tables 1 and 2 were obtained.

[0023]

[Table 1]

[0024]

[Table 2]

Example 13 (E) -2-Isopropyl-3- [2- [4- (methylsulfinyl) phenyl] ethenyl] pyrazolo [1,5
-A] pyridine

The compound of Example 3 (1.61 g) was dissolved in methylene chloride (30 ml), and m-chloroperbenzoic acid (1.28 g) was added little by little while stirring in an ice-water bath. After stirring at room temperature for 10 minutes, the reaction solution was cooled. It was washed with an aqueous potassium carbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from ethyl acetate-hexane to give 1.22 g of the desired product as yellow crystals.
(72%) was obtained. Melting point: 145-147 ° C

Elemental analysis value (%) As C ₁₉ H ₂₀ N ₂ OS

Example 14 (E) -2-Isopropyl-3- [2- [4- (methylsulfonyl) phenyl] ethenyl] pyrazolo [1,5-
a] pyridine

The compound of Example 3 (1.50 g) was dissolved in methylene chloride (100 ml), and m-chloroperbenzoic acid (2.39 g) was added little by little with stirring in an ice-water bath. After stirring at room temperature for 30 minutes, the reaction solution was cooled. It was washed successively with aqueous potassium carbonate solution, water and brine, and dried over anhydrous sodium sulfate.
The solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (benzene: ethyl acetate = 7: 3), and recrystallized from ethyl acetate-hexane to give 0.92 g (56%) of the desired product as yellow crystals. Got Melting point: 177-178 ° C

Elemental analysis value (%) As C ₁₉ H ₂₀ N ₂ O ₂ S

Example 15 (E) -2-Methyl-3- [2- [4- (methylsulfinyl) phenyl] ethenyl] pyrazolo [1,5-a]
Pyridine

In the same manner as in Example 13, the target product was obtained with a yield of 87%. Melting point: 131-134 ℃

Elemental analysis value (%) As C ₁₇ H ₁₆ N ₂ OS

(Example 16) (E) -3- [2- (2-isopropylpyrazolo [1,
5-a] pyridin-2-yl) ethenyl] benzoic acid

In the same manner as in Example 1, 3-formylbenzoic acid (1.97 g) was used as a yellow oil to give a crude (E)-
3- [2- (2-isopropylpyrazolo [1,5-a]
Pyridin-2-yl) ethenyl] methyl benzoate (3.90
g) was obtained. This ester (3.90g) was added to ethanol (10
ml), sodium hydroxide (0.96 g) in water (5 ml)
The solution dissolved in was added and heated on a water bath for 10 minutes. Ice water was added to the reaction solution, which was washed with ether. The aqueous layer was acidified by adding concentrated hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was recrystallized from ethanol-ethyl acetate to obtain 1.53 g (42%) of the desired product as yellow crystals. Melting point: 208-210 ℃

Elemental analysis value (%) As C ₁₉ H ₁₈ N ₂ O ₂

Example 17 (E) -3- [2- (2-isopropylpyrazolo [1,
5-a] pyridin-3-yl) ethenyl] benzaldehyde

A mixture of the compound of Example 7 (1.20 g), Raney nickel (1.20 g) and 75% formic acid (18 ml) was stirred under reflux for 1 hour. After cooling, Lalur nickel was filtered off, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (benzene: ethyl acetate = 9: 1), and recrystallized from benzene-hexane to obtain 0.37 g (31%) of the desired product as yellow crystals. It was Melting point: 89-91 ° C

Elemental analysis value (%) As C ₁₉ H ₁₈ N ₂ O

Example 18 (E) -2-Isopropyl-3- [2- [3 (1H-tetrazol-5-yl) phenyl] ethenyl] pyrazolo [1,5-a] pyridine

A mixture of the compound of Example 7 (2.00 g), sodium azide (1.13 g), ammonium chloride (0.93 g) and dimethylformamide (15 ml) was heated (outer bath temperature).
It stirred at 130 degreeC for 2 hours. Ice water and concentrated sulfuric acid were added to the reaction solution to make it acidic, and the precipitated crystals were collected by filtration and washed with water. The product was purified by silica gel column chromatography (methylene chloride: ethanol = 100: 4), and the obtained crystals were washed with benzene to give 1.01 g (44 g) of the desired product as yellow crystals.
%) Was obtained. Melting point: 235 ~ 237 ℃

Elemental analysis value (%) As C ₁₉ H ₁₈ N ₆

Example 19 (E) -2-Isopropyl-3- [2- (2-naphthyl) ethenyl] pyrazolo [1,5-a] pyridine

Methanol (20 ml) and sodium metal (0.
2-naphthylaldehyde (2.08 g) in a methanol solution of sodium methoxide prepared from
g) and (2-isopropylpyrazolo [1,5-a] pyridin-3-ylmethyl) triphenylphosphonium
Chloride (5.00 g) was added. The reaction mixture was stirred under reflux, 4 hours later, a phosphonium salt (3 g) was further added, and the mixture was heated under reflux for 7 hours in total. Concentrate the solvent under reduced pressure,
Ice water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (benzene) and recrystallized from hexane to obtain 1.83 g (55%) of the desired product as yellow crystals. Melting point: 124-1
26 ° C

Elemental analysis value (%) As C ₂₂ H ₂₀ N ₂

Example 20 (E) -2-Isopropyl-3- [2- (3-quinolyl) ethenyl] pyrazolo [1,5-a] pyridine

In the same manner as in Example 19, the target product was obtained with a yield of 30%. Melting point: ~ 210 ℃

Elemental analysis value (%) C ₂₁ H ₁₉ N ₃ .HCl
・ As 1 / 4H ₂ O

Experimental Example 1 Rabbit Peripheral Blood Inhibition Test on Neutrophil Migration Ability Rabbits were fixed in the dorsal position without anesthesia, and blood was collected from the femoral artery using citric acid. After adding dextran to the blood to sediment the red blood cells, distilled water was added to the supernatant, and the mixed red blood cells were subjected to a hypotonic treatment to hemolyze. Ny the obtained white blood cells
Overlaid with coPrep (registered trademark), lymphocytes and neutrophils were separated, and the neutrophils were suspended in RPMI1640 medium. Neutrophil migration was measured using a blind well chemotaxis chamber. As the chemotaxis membrane, a membrane having a pore size of 2 μm was used. F for neutrophil stimulation
MLP and LTB ₄ were used. The compound of the present invention exhibited a neutrophil migration inhibitory action at a low concentration.

Claims (5)

[Claims] 1. The general formula (1) [Wherein R ¹ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkoxy group or a lower alkoxycarbonyl group, and R ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group or A lower alkoxy group, and Ar represents an aromatic ring or a heteroaromatic ring which may have a substituent], and an arylethenylpyrazolopyridine derivative and a pharmaceutically acceptable salt thereof. salt. 2. The general formula (2) [Wherein R ¹ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkoxy group or a lower alkoxycarbonyl group, and R ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group or A compound represented by a lower alkoxy group] and a compound represented by the general formula (3) Ar-CHO (3) [wherein Ar represents an aromatic ring or a heteroaromatic ring which may have a substituent] General formula (1), characterized in that and are reacted in the presence of a base. [Wherein R ¹ , R ² , R ³ and Ar are as described above]. 3. The general formula (4) [Wherein R ¹ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkoxy group or a lower alkoxycarbonyl group, and R ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group or A compound represented by a lower alkoxy group] and a compound represented by the general formula (5) ArCH ₂ X (5) [wherein Ar represents an aromatic ring or a heteroaromatic ring which may have a substituent, X is General formula (1), characterized in that [Wherein R ¹ , R ² , R ³ and Ar are as described above]. 4. The general formula (4) [Wherein R ¹ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkoxy group or a lower alkoxycarbonyl group, and R ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group or A lower alkoxy group] is reduced to an alcohol compound, and then triphenylphosphine and carbon tetrachloride are allowed to act on the compound of the general formula (2). A method for producing a compound represented by the formula: wherein R ¹ , R ² and R ³ are as described above. 5. The general formula (1) [Wherein R ¹ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a lower alkoxy group or a lower alkoxycarbonyl group, and R ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group or A lower alkoxy group, and Ar represents an aromatic ring or a heteroaromatic ring which may have a substituent], and at least one of the arylethenylpyrazolopyridine derivative or an acid salt thereof
A therapeutic agent for diseases involving inflammatory cells, which comprises one or more species as active ingredients.