JPH0374663B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a novel pyridine derivative, and more particularly to a novel pyridine derivative useful for circulatory system diseases. [Prior Art] In connection with the prevention of circulatory disorders, the phenomenon of platelet aggregation has attracted attention, and pharmaceuticals that have an inhibitory effect on platelet aggregation have been actively researched. [Problems to be Solved by the Invention] Under these circumstances, it has been desired to develop a new drug for circulatory system diseases. [Means for solving the problem] The present inventor synthesized various pyridine derivatives,
While exploring its pharmacological effects, we discovered that pyridine derivatives with specific substituents have strong platelet aggregation inhibitory effects and are useful for cardiovascular diseases accompanied by thrombus formation. Completed the invention. That is, the present invention provides the following general formula () (In the formula, R ₁ is a hydrogen atom or a lower alkoxy group, R ₂ is a hydrogen atom, a benzyl group, a linear or branched lower alkyl group, or an alkyl group having a carboxyl group, lower alkoxycarbonyl group, or carbamoyl group at the end) group, R ₃ is a hydrogen atom,
Represents a benzyl group or a lower alkyl group, and A is 1-
This invention provides pyridine derivatives represented by the following (representing an imidazolyl group or a 1-pyrazolyl group) and acid addition salts thereof. The compound represented by formula () of the present invention can be produced, for example, by the following method. Method 1: Compound (Ia) is obtained by reacting a γ-pyran derivative () with aqueous ammonia. (In the formula, R ₄ is a benzyl group, a straight chain or branched lower alkyl group, or an alkyl group having a lower alkoxyl carbonyl group at the end, and R ₅ is a benzyl group, a straight chain or branched lower alkyl group, or a carbamoyl group at the end) (A represents an alkyl group having the above meaning) This reaction proceeds easily by stirring at 20 to 80°C for 1 to 5 hours, and R ₄ in the formula () is a lower alkoxycarbonyl group at the terminal. In the case of an alkyl group bearing a group, the product is converted into an alkyl group having a terminal carbamoyl group. In addition, the γ-pyran derivative (), which is the expression fee,
is a new compound, but for example, according to the following formula, 2
It is produced by reacting a -halomethyl-4H-pyran-4-one derivative () with an alkali metal salt of imidazole or pyrazole (). (In _the formula, It is carried out by stirring a certain known compound () in a solvent such as dimethylformamide or dimethyl sulfoxide at room temperature for 1 to 5 hours. Also compound ()
is preferably one in which the halogen atom is chlorine, bromine or iodine. Method 2: Compound (Ib) is obtained by reacting a 2-halomethylpyridine derivative () with an alkali metal salt of imidazole or pyrazole (). (In the formula, R ₆ represents a benzyl group or a lower alkyl group, and R ₁ , R ₄ , A, M and The method is carried out by stirring the prepared compound () and the known compound () as a starting material in a solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc. at room temperature for 1 to 5 hours. Further, the compound () preferably has a halogen atom of chlorine, bromine or iodine. Method 3: Pyridine derivative (Ic) is subjected to a debenzylation reaction using a hydrogenation catalyst to obtain compound (Id). (In the formula, R ₇ and R ₈ are the same or different and represent a hydrogen atom or a lower alkyl group, and R ₁ , R ₃ ,
R ₆ and A have the meanings given above) This reaction is carried out in the presence of a solvent, and preferred solvents include ethanol, methanol, acetic acid, ethyl acetate, dioxane and the like. Catalysts used include palladium-carbon, palladium black, etc., and catalytic reduction is carried out in the presence of hydrogen gas by a conventional method. Method 4: Pyridine derivative (Ie) is hydrolyzed in water or a water-lower alcohol mixed solvent under reflux by adding alkali hydroxide to obtain compound (If). (In the formula, R ₉ represents a lower alkoxy group or an amino group, n represents a number from 1 to 5, and R ₁ , R ₃ and A have the meanings described above.) The alkali hydroxide used in this reaction is water Examples include sodium oxide and potassium hydroxide, and the water-lower alcohol mixed solvent is preferably methanol or a mixture of ethanol and water. The pyridine derivative () of the present invention thus obtained can be further treated with a hydrochloride, a hydrochloride, or
It can be an inorganic salt such as hydrobromide or sulfate, or an organic acid salt such as methanesulfonate or p-toluenesulfonate. [Effect] The results of testing the platelet aggregation inhibitory effect of the compound of the present invention are as follows. Platelet aggregation inhibitory effect: Citrated blood is collected from a male rabbit (weight 3 kg) and centrifuged appropriately to produce platelet-rich plasma (PRP).
and platelet poor plasma (PPP) were obtained, and ADP (3μM) and arachidonic acid (1mM) were added according to the following standard method.
The inhibitory effect on aggregation was investigated. The test compound (compound numbers are shown in the examples) was dissolved in physiological saline and added to the PRP 2 minutes before each flocculant addition. The results are shown in Table 1.

〔Example〕

Next, the present invention will be explained with reference to Examples and Reference Examples. Reference example 1 1.75 g (10 mmol) of 2-chloromethyl-5-methoxy-4H-pyran-4-one and imidazole
0.82g (12mmol) in anhydrous dimethylformamide
Dissolve in 20 ml and stir in a nitrogen gas stream at room temperature for 60 min.
After adding 0.48 g (12 mmol) of % sodium hydride little by little, the mixture was stirred at room temperature for 1 hour. The reaction solution,
The mixture was poured into 80 ml of ice-cooled 10% ammonium chloride aqueous solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, filtered,
The liquid was dried under reduced pressure. The residue was purified by silica gel column chromatography and 5% (v/v)
The crystals obtained from the methanol-chloroform mixture elution fraction were recrystallized from ethyl acetate to give 1.29 g of colorless needle-like crystals of 2-(1-imidazolyl)methyl-5-methoxy-4H-pyran-4-one (yield: 62.6%)
I got it. Melting point: 127-128℃ IRν ^KBr _nax cm ^-1 : 1650 ¹ H−NMRδppm (CDCl ₃ ): 7.50 (s, 1H), 7.45 (br.s, 1H), 6.95 (br.s,
1H), 6.90 (br.s, 1H), 6.10 (s, 1H), 4.95
(s, 2H), 3.65 (s, 3H) Reference example 2 (2-chloromethyl-4H-pyran-4-one-5-yl)oxyacetic acid methyl ester 2.33 g
(10 mmol) and pyrazole 0.82 g (12 mmol) were dissolved in 20 ml of anhydrous dimethylformamide, and in the same manner as in Reference Example 1, [2-(1-pyrazolyl)methyl-4H-pyran-4-one-5-yl] 1.18 g of colorless needle-like crystals of methyl oxyacetate (yield
44.7%). Melting point: 101-105℃ IRν ^KBr _nax cm ^-1 : 1760, 1660 ¹ H−NMRδppm (CDCl ₃ ): 7.81 (s, 1H), 7.50 (m, 2H), 6.29 (b,
t, 1H), 6.07 (s, 1H), 5.16 (s, 2H),
4.65 (s, 2H), 3.17 (s, 3H) Example 1 2-4(1-imidazolyl)methyl-5-methoxy-4H-pyran-4-one 1.03g (5mmol)
30 ml of strong ammonia water was added to the mixture and heated at 80°C for 2 hours. The reaction solution was dried under reduced pressure to obtain yellow crystals, which were recrystallized from ethanol to give 2-(1-
imidazolyl)methyl-4-hydroxy-5-
Methoxypyridine [() in the formula, R ₁ = H, R ₂ = -
CH ₃ , R ₃ =H,

0.94 g (yield: 91.3%) of colorless needle-like crystals of the formula (Compound 1) was obtained. Melting point: 163-164℃ IRν ^KBr _nax cm ^-1 : 1625 ¹ H−NMRδppm (CD ₃ OD): 7.67 (b, s, 1H), 7.50 (s, 1H), 7.06
(b, s, 1H), 6.95 (bs, 1H), 6.30 (s,
1H), 5.13 (s, 2H), 3.75 (s, 3H) Example 2 [2-(1-pyrazolyl)methyl-4H-pyran-4-one-5-yl]oxyacetic acid methyl ester 0.53 g (2 mmol) 10 ml of strong ammonia water was added to the mixture, and the mixture was stirred at room temperature for 5 hours. The reaction solution was dried under reduced pressure and the obtained crystals were recrystallized from methanol [2
-(1-pyrazolyl)methyl-4-hydroxy-5-pyridinyl]oxyacetic acid amide [(in the formula, R ₁ = H, R ₂ = -CH ₂ CONH ₂ , R ₃ = H,

0.46 g (yield: 92.0%) of colorless crystals of [Formula] (Compound 2) was obtained. Melting point: 243-245℃ (decomposition) IRν ^KBr _nax cm ^-1 : 1680 ¹ H−NMRδppm (CD ₃ OD): 7.71 (bd, 1H), 7.61 (s, 1H), 7.53 (bd,
1H), 6.35 (bt, 1H), 6.22 (s, 1H), 5.32
(s, 2H), 4.42 (s, 2H) Example 3 0.34 g of imidazole was added to 10 ml of anhydrous dimethylformamide suspension containing 0.28 g (7 mmol) of 60% sodium hydride under stirring at room temperature in a nitrogen gas stream.
(5 mmol) was added little by little. After 10 minutes, the reaction mixture was diluted with
-chloromethyl-4-benzyloxy-5,6-
1.17 g (4 mmol) of dimethoxypyridine was added dropwise over about 30 minutes, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into 60 ml of ice-cooled 10% ammonium chloride aqueous solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, filtered,
The liquid was dried under reduced pressure. The residue was purified by silica gel column chromatography and 1% (v/v)
From the methanol-chloroform mixture elution fraction, 2-
(1-imidazolyl)methyl-4-benzyloxy-5,6-dimethoxypyridine [() in the formula,
R ₁ = -OCH ₃ , R ₂ = -CH ₃ , R ₃ = -CH ₂ Ph,

1.18 g (yield: 90.8%) of a colorless oil of the formula (Compound 3) was obtained. IRν ^neat _nax cm ^-1 : 1605 ¹ H−NMR δppm (CDCl ₃ ): 7.56 (bs, 1H), 7.34 (s, 5H), 7.08 (bs,
1H), 6.92 (bs, 1H), 6.21 (s, 1H), 5.06
(s, 2H), 4.99 (s, 2H), 3.94 (s, 3H),
3.83 (s, 3H) Example 4 0.98 g (3 mmol) of 2-(1-imidazolyl)methyl-4-benzyloxy-5,6-dimethoxypyridine (compound 3) was dissolved in 30 ml of ethanol. Next, using 0.10 g of palladium black as a catalyst, the mixture was stirred at room temperature for 2 hours while introducing hydrogen gas. Next, the palladium black was removed, the liquid was concentrated under reduced pressure, and the obtained crystals were recrystallized from ethanol to obtain 2-(1-imidazolyl)methyl-4-hydroxy-5,6-dimethoxypyridine [()
In the formula, R ₁ = -OCH ₃ , R ₂ = -CH ₃ , R ₃ = H,

0.69 g (yield: 97.2%) of colorless needle crystals of the formula (Compound 4) were obtained. Melting point: 205-206℃ IRν ^KBr _nax cm ^-1 : 1625 ¹ H−NMRδppm (CDCl ₃ − CD ₃ OD): 7.62 (bs, 1H), 7.03 (bs, 1H), 7.02 (bs,
1H), 6.20 (s, 1H), 5.00 (s, 2H), 3.93
(s, 3H), 3.81 (s, 3H) Example 5 2-(1-imidazolyl)methyl-4-hydroxy-5-benzyloxypyridine (second
0.79 g (2.8 mmol) of compound 10 in the table was dissolved in 30 ml of acetic acid. Next, using 0.10 g of palladium black as a catalyst, the mixture was stirred at room temperature for 5 hours while introducing hydrogen gas. Next, remove the palladium black,
The crystals obtained by drying the liquid under reduced pressure were recrystallized from methanol to obtain 2-(1-imidazolyl)methyl-4,
5-dihydroxypyridine [(in the formula, R ₁ =
H, R ₂ = H, R ₃ = H,

0.50 g (yield: 94.3%) of colorless needle crystals of [Formula] (Compound 5) was obtained. Melting point: 249-250℃ (decomposition) IRν ^KBr _nax cm ^-1 : 1625 ¹ H−NMRδppm (DMSO _d-6 : 7.73 (s, 1H), 7.58 (bs, 1H), 7, 19 (bs,
1H), 6.93 (bs, 1H), 6.23 (s, 1H), 5.07
(s, 2H) Example 6 Add 1N to 0.25 g (1 mmol) of [2-(1-imidazolyl)methyl-4-hydroxy-5-pyridinyl]oxyacetic acid amide (compound 15 in Table 2 below)
4 ml of aqueous sodium hydroxide solution was added, and the mixture was heated under reflux for 4 hours. The reaction solution was cooled with ice, made acidic by adding 1N hydrochloric acid, and dried under reduced pressure. The residue was extracted with anhydrous methanol and directly recrystallized from methanol.
[2-(1-imidazolyl)methyl-4-hydroxy-5-pyridinyl]oxyacetic acid [() in the formula,
R ₁ = H, R ₂ = -CH ₂ COOH, R ₃ = H,

0.19 g (yield: 67.9%) of colorless crystals was obtained as the hydrochloride of [Formula] (Compound 6)]. Melting point: 233-235℃ IRν ^KBr _nax cm ^-1 : 1710, 1625 ¹ H−NMRδppm (DMSO _d-6 −CD ₃ OD): 9.26 (bs, 1H), 8.28 (s, 1H), 7.79 (bs,
1H), 7.66 (bs, 1H), 7.14 (s, 1H), 5.65
(s, 2H), 4.93 (s, 2H) Example 7 [2-(1-imidazolyl)methyl-4-methoxy-5-pyridinyl]oxyacetic acid methyl ester (compound 14 in Table 2 below) 0.55 g (2 mmol) ) was dissolved in 20 ml of methanol, 3 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was heated under reflux for 2 hours. The reaction solution was cooled with ice, made acidic by adding 1N hydrochloric acid, and dried under reduced pressure. The residue was extracted with anhydrous methanol and directly recrystallized from methanol to obtain [2-(1-imidazolyl)methyl-4-methoxy-5-pyridinyl].
Oxyacetic acid [() in the formula, R ₁ = H, R ₂ = -
_CH2COOH , _R3 = _-CH3 ,

0.50 g (yield: 83.3%) of colorless crystals was obtained as the hydrochloride of [Formula] (Compound 7). Melting point: 189-190℃ IRν ^KBr _nax cm ^-1 : 1720 ¹ H−NMRδppm (DMSO _d-6 : 9.44 (bs, 1H), 8.27 (s, 1H), 7.92 (bs,
1H), 7.73 (s, 1H), 7.67 (bs, 1H), 5.66
(s, 2H), 4.84 (s, 2H), 4.00 (s, 3H) Examples 8-19 The compounds shown in Table 2 were obtained in the same manner as in Examples 1-7.

【table】

【table】

Claims (1)

[Claims] First-order general formula () (In the formula, R ₁ is a hydrogen atom or a lower alkoxy group, and R ₂ is a hydrogen atom, a benzyl group, a linear or branched lower alkyl group, or an alkyl group having a carboxyl group, lower alkoxycarbonyl group, or carbamoyl group at the end) , R ₃ is a hydrogen atom,
Represents a benzyl group or a lower alkyl group, and A is 1-
A pyridine derivative represented by the following (representing an imidazolyl group or a 1-pyrazolyl group) and its acid addition salt.