JPH0753557A - Condensed ring pyridine derivative - Google Patents

Abstract

PURPOSE:To provide a new compound having excellent anti-inflammatory action, immunomodulating action, analgestic action, etc., and useful as an immunomodulative agent and anti-inflammatory, analgestic and antipyretic agent for the treatment and prevention of chronic articular rheumatoism, nephtitis, proriasis, systemic erythematodes, etc. CONSTITUTION:A compound of formula I [R<1> is H or a lower alkyl; R<2> and R<3> are lower alkyls; R<4> is H or a lower alkanoyl; X is S or N-R<5> (R<5> is a lower alkyl); Y is CH or N], e.g. 3-amino-5-ethyl-1-methyl-1H-pyrazolo[3,4-d]pyridin-4-(5 H)-one. The compound can be produced, e.g. by successively acetylating and alkylating a compound of formula II (R is a lower alkyl), cyclizing the product with potassium ethoxide, etc., subjecting the resultant compound of formula III to Vilsmeier reaction, reacting with hydroxylamine, dehydrating the reactional prouct and reacting the produced compound of formula IV with a hydrazine derivative of the formula R<3>-NH-NH2.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel condensed ring pyridine derivative.

[0002]

The condensed ring pyridine derivative of the present invention is a novel compound which has not been published in the literature.

[0003]

DISCLOSURE OF THE INVENTION The present invention aims to provide a compound useful as a pharmaceutical as described below.

[0004]

According to the present invention, a condensed ring pyridine derivative represented by the following general formula (1) is provided.

[0005]

[Chemical 2]

[Wherein R ¹ is a hydrogen atom or a lower alkyl group, R ² and R ³ are the same or different and each is a lower alkyl group, and R ⁴ is a hydrogen atom or a lower alkanoyl group,
X represents a sulfur atom or a group N—R ⁵ (R ⁵ represents a lower alkyl group), and Y represents a CH or nitrogen atom. ]
Specific examples of the respective groups in the general formula (1) include the following respective groups. That is, as the lower alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl,
Examples thereof include linear or branched lower alkyl groups such as isobutyl, tert-butyl, pentyl and hexyl groups.

Examples of the lower alkanoyl group include acetyl, propionyl, butyryl, valeryl, pivaloyl, hexanoyl and heptanoyl groups.

The condensed fused pyridine derivative of the present invention represented by the above general formula (1) has excellent anti-inflammatory action, immunoregulatory action, analgesic action, antipyretic action and the like.
As an anti-inflammatory / analgesic / antipyretic, for example rheumatoid arthritis,
It is useful for the treatment and prevention of nephritis, psoriasis, systemic lupus erythematosus, back pain and the like.

The method for producing the condensed ring pyridine derivative of the present invention will be described in detail below. The compound can be produced by various methods. Specific examples thereof are shown in the following reaction process formulas.

[0010]

[Chemical 3]

[0011]

[Chemical 4]

[In each formula, R ¹ , R ² , R ³ , X and Y are the same as defined above. R represents a lower alkyl group and R ^4a represents a lower alkanoyl group. ] Compound (2) shown in Reaction Process Formula-1
The acetylation reaction of is carried out in acetic anhydride at a temperature condition of about 80 ° C. to reflux temperature for about 1 to 30 hours. In this reaction, acetic anhydride also serves as a solvent, so that no other solvent is particularly required, but tertiary amines such as pyridine and triethylamine can be used if necessary.

Acetamide derivative (3) obtained above
Can then be converted to compound (4) by subjecting it to an alkylation reaction. This alkylation reaction is
For example, in an inert solvent such as N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), or tetrahydrofuran (TFH), in the presence of about 1 to 5 equivalents, preferably about 1 to 2 equivalents of a base, It can be carried out using about 3 equivalents of alkyl halide. Examples of the alkyl halide include methyl iodide, methyl bromide, ethyl iodide and the like. Examples of the base include sodium hydride, sodium ethoxide,
Potassium carbonate, sodium carbonate, etc. can be used. The reaction is completed at about 0 ° C to reflux temperature for about 1 to 48 hours.

The ring closure reaction of the resulting compound (4) is carried out in an aromatic hydrocarbon-based inert solvent such as xylene or toluene.
It is carried out by treating compound (4) with a base. As the base, for example, an alkali metal alkoxide such as potassium t-butoxide or potassium ethoxide is suitable, and it is usually preferable to use about 2 to 3 equivalents of the compound (4). As the reaction conditions, a temperature condition of 80 ° C. to reflux temperature and a time of about 1 to 24 hours can be adopted.

The Vilsmeier reaction of the compound (5) following the above is carried out using chloroform, dichloromethane, 1,2-
It is carried out using an N, N-disubstituted formamide and an oxide halide in an inert solvent such as dichloroethane, toluene, benzene and the like. Examples of the N, N-disubstituted formamide include DMF, N, N-diethylformamide and the like, and examples of the oxide halide include phosphorus oxychloride and the like. It is preferred that these are usually used in an amount of about 1 to 10 times, preferably about 3 to 4 times the molar amount of the compound (5). The reaction is generally -20
It is completed in about 8 to 20 hours under a temperature condition of about to 150 ° C.

The aldehyde (6) obtained above is used in a solvent such as water, methanol, ethanol, propanol or the like in an amount of 1 to 10 equivalents of hydroxylamine (usually a mineral acid salt such as hydrochloride is used). It can be converted into an oxime derivative (7) by reacting with. The temperature condition of this reaction is about 0 to 100 ° C., preferably 20 to
A temperature of about 50 ° C. is adopted, and the reaction is usually completed in about 0.5 to 5 hours, preferably about 0.5 to 1 hour.

In the subsequent dehydration reaction of the oxime derivative (7), phosphorus oxychloride, phosphorus oxybromide and the like are used as dehydrating agents in an inert solvent such as diethyl ether, THF, dioxane, benzene and toluene to obtain the oxime derivative (7). It is carried out by treating with 1 to 10 times the molar amount of 7) at about 0 to 100 ° C, preferably about 0 to 50 ° C for about 1 to 8 hours, preferably about 1 to 3 hours.

The compound (1a) of the present invention can be obtained by reacting the cyano derivative (8) thus obtained with the hydrazine derivative (9). This reaction is performed with methanol, ethanol, propanol, DMF, N, N-
In an inert solvent such as dimethylacetamide (DMA),
Further, if necessary, a deoxidizing agent such as triethylamine, pyridine, sodium hydrogen carbonate, potassium carbonate or the like is added to carry out. The hydrazine derivative (9) is generally used in an amount of about 1 to 5 equivalents based on the cyano derivative (8). When the deoxidizing agent is added and used, the amount thereof is preferably about 1 to 5 times the molar amount of the cyano derivative (8).
The reaction is carried out at about 20 to 100 ° C. for about 1 to 72 hours.

Further, the compound (1b) of the present invention can be obtained by alkanoylating the compound (1a). The reaction is solvent-free or pyridine, lutidine, DMF, DMA
Performed using an alkanoylating agent in an inert solvent such as. Examples of the alkanoylating agent include acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride, hexanoic acid, acid anhydrides such as anhydrous heptanoic acid or acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride, hexanoyl chloride, Acid halides such as heptanoyl chloride can be used. Usually, it is preferable to use 1 to 10 equivalents. The reaction is completed at about 20 to 100 ° C. in about 1 to 10 hours.

The target compound in each of the above steps can be easily isolated and purified by a conventional separation means. Examples of such means include adsorption chromatography, preparative thin layer chromatography, solvent extraction, recrystallization and the like.

The compound of the present invention can be easily converted into a pharmaceutically acceptable acid addition salt by subjecting the compound of the present invention to an addition reaction with a suitable acidic compound according to a conventional method. The acid addition salt is in a free form. It has the same pharmacological activity as the compound of the present invention, and the present invention also includes such an acid addition salt. Examples of the acidic compound capable of forming the acid addition salt include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, and maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid and benzesulfonic acid. Examples thereof include organic acids.

[0022]

EXAMPLES In order to explain the present invention in more detail, production examples of the compounds of the present invention will be given below as Examples.

[0023]

Example 1 3-Amino-5-ethyl-1-methyl-1
Production of H-pyrazolo [3,4-d] thieno [3,2-b] pyridin-4 (5H) -one (Step 1) 75 g of methyl 3-amino-2-thiophenecarboxylate was dissolved in 300 ml of acetic anhydride, 10
Heated at 0 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, and the precipitated crystals were collected by filtration, washed successively with n-hexane and isopropyl ether, and methyl-3-acetylamino-2-
86 g of thiophene carboxylate was obtained.

(Step 2) 3.9 g of 60% sodium hydride was suspended in 100 ml of DMF, and 15 g of the crystals obtained above were added under stirring at 0 ° C. Subsequently, 18 g of ethyl iodide was added, and the mixture was stirred at room temperature for 2 hours. Water was poured into the reaction mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude methyl 3- (N-acetyl-N-ethylamino) -2.
15.8 g of thiophenecarboxylate were obtained.

(Step 3) 15 g of the compound obtained in Step 2
Is dissolved in 250 ml of m-xylene, and potassium-
18 g of t-butoxide was added, and the mixture was heated with stirring at 130 ° C. for 1 hour. The reaction mixture was allowed to cool, 150 ml of water was added and the mixture was transferred to a separatory funnel, the aqueous layer was separated, and an aqueous citric acid solution was added to adjust the pH to 5. The precipitated crystals were collected by filtration, washed with water and air-dried to give 4-ethyl-7-hydroxythieno [3,2-
b] 10.5 g of crystals of pyridin-5 (4H) -one were obtained.

(Step 4) Crystal 10.5 obtained in Step 3
g was dissolved in 20 ml of DMF, 150 ml of chloroform and 21 m of phosphorus oxychloride were added thereto while cooling to -5 ° C with stirring.
1 was added sequentially and the mixture was heated to reflux overnight. Water was added to the reaction mixture and extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate. Crystals obtained by concentration under reduced pressure were collected by filtration, washed with diisopropyl ether, and 9.8 g of 7-chloro-4-ethyl-6-formylthieno [3,2-b] pyridin-5 (4H) -one.
Got

(Step 5) 9.5 g of the crystal obtained in Step 4
Was dissolved in 50 ml of ethanol, to which 8.2 g of hydroxylamine hydrochloride was added, and the mixture was stirred at 80 ° C. for 30 minutes. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration and washed with methanol to give 7-chloro-4-ethylthieno [3,3.
2-b] Pyridine-5 (4H) -one-6-carbaldehyde oxime crystals (9.8 g) were obtained.

(Step 6) 9.5 g of the crystal obtained in Step 5
Was dissolved in 70 ml of THF, cooled to 0 ° C., 17 g of phosphorus oxychloride was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration and washed with water to obtain 8.3 g of 7-chloro-4-ethyl-6-cyanothieno [3,2-b] pyridin-5 (4H) -one. It was

(Step 7) 2 g of the crystal obtained in Step 6 was dissolved in 10 ml of methanol to give 1.1 g of methylhydrazine.
Was added and stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the precipitated crystals were collected by filtration and washed successively with water and diisopropyl ether to give 1.6 g of the title target compound.
Structure and physical properties of the obtained compound (melting point (° C) and 1 H-
NMR (δ: ppm)) is shown in Table 1.

[0030]

Examples 2 to 7 In the same manner as in Example 1, each compound shown in Table 1 was produced. The structure and physical properties of each compound are also shown in Table 1.

[0031]

Example 8 3-Acetylamino-5-ethyl-1-methyl-1H-pyrazolo [3,4-d] thieno [3,2-
b] Production of pyridin 4 (5H) -one 600 mg of the compound obtained in Example 1 was added to 10 m of acetic anhydride.
It was dissolved in 1 and heated at 60 ° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration and washed with diisopropyl ether to give the title object compound (670 mg). Table 1 shows the structure and physical properties of the obtained compound.

[0032]

Examples 9 to 13 In the same manner as in Example 8, each compound shown in Table 1 was produced. The structure and physical properties of the obtained compound are also shown in Table 1.

[0033]

[Table 1]

[0034]

[Table 2]

[0035]

[Table 3]

[0036]

[Table 4]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/435 ABB ABE 9454-4C ABG ADA (C07D 471/14 207: 00 221: 00 231: 00 ) (C07D 471/14 221: 00 231: 00 233: 00) (C07D 513/14 221: 00 231: 00 277: 00)

Claims (1)

[Claims] 1. A general formula: [Wherein R ¹ is a hydrogen atom or a lower alkyl group, R ² and R ³ are the same or different and each is a lower alkyl group, R 2
⁴ is a hydrogen atom or a lower alkanoyl group, X is a sulfur atom or a group N—R ⁵ (R ⁵ is a lower alkyl group), Y
Represents CH or a nitrogen atom, respectively. ] A condensed ring pyridine derivative represented by the following formula.