JPS59110674A - Pyridine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A piridine derivative shown by the formula I (R<1> is H, or lower alkyloxy; R<2> is H, OH carboxyl, or lower alkyloxycarbonyl; n is 1-20). EXAMPLE:2-n-Decyloxymethyl-4-hydroxy-5-methoxypyridine. USE:A drug for circulatory system. Having hypotensive action and inhibitory action on blood platelet aggregation. PROCESS:For example, 2-hydro-5-methoxy-4H-pyran-4-one shown by the formulaII is reacted with a compound shown by the formula X-(CH2)n-H(X is halogen) to give a novel compound shown by the formula III (R<3> is H or OH), which is reacted with NH3 such as strong ammonia water, ammonia gas, etc. preferably in a sealed tube at 100-110 deg.C to give a compound shown by the formula I where R<1> is H and R<2> is H or OH.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel pyridine derivative and a method for producing the same.
More specifically, the following general formula (1) (where tt' represents a hydrogen atom or a lower alkyloxy group, R2 represents a hydrogen atom, a hydroxyl group, a carboxyl group, or a lower acetyloxycarbonyl group, and n represents 1 to 20) and a method for producing the same.

The present inventors synthesized various compounds and examined their pharmacological effects, and found that the compound represented by formula (I) has antihypertensive and platelet aggregation inhibitory effects and is useful as a drug for the cardiovascular system. They found that this is the case, and completed the present invention.

The compound (1) of the present invention can be easily produced, for example, by any of the following methods.

Method 1! 2-Linear alkyloxymethyl-5-methoxy-4)(
- React bilan-4 ion (If) with ammonia.

(Ia) (at r°C, RA represents a hydrogen atom or a hydroxyl group, n is the previous 1
This reaction is preferably carried out in a sealed tube, and the reaction temperature is preferably 100 to 110°C.

- Also, as the ammonia, strong ammonia water, ammonia gas, etc. are not used.

Method 2: 4-benzyloxy-5,6-simethoxy-2-pyridine methanol (lit) is reacted with a non-rogenated alkyl or ω-no-rogen-substituted linear carbonyl lower alkyl ester (IV) and an alkali hydride. Then, the resulting reaction product is subjected to a debenzylation reaction using a hydrogenation catalyst.

(1) H (Ib) (In the formula, n and The reaction between compound (I) and compound 1, which is the step of step 2, is preferably carried out in the presence of a solvent.

Examples of the solvent used include dimethylformamide, dimethylsulfate, tetrahydrofuran, dimethyl ether, and the like. Moreover, the compound (I
V (large) -C is preferably one in which the ) rogen atom is a wood or iodine, and as the alkali hydride, sodium hydride, potassium hydride, calcium hydride, etc. are used.

The second step, the debenzylation reaction, is carried out in the presence of a solvent, and preferred solvents include ethanol, methanol, ethyl acetate, and the like.

In addition, the hydrogenation catalyst used is palladium-
Examples include carbon and palladium black, and debenzylation is carried out by catalytic reduction using a conventional method in the presence of hydrogen gas.

Method 3: 2-Lower alkyloxycarbonyl linear alkyloxymethyl-4-hydroxydi-5,6-simethoxypyridine (IC) is hydrolyzed in a mixed solvent of water and lower alcohol under reflux by adding alkali hydroxide. .

(Ic) H (Id) (In the formula, it' and R5 each represent a lower "r-alkyl group, and n has the meaning described above.) The alkali hydroxide used in this reaction includes sodium hydroxide and potassium hydroxide. Examples of the water-lower alcohol mixed solvent include methanol or a mixed solvent of ethanol and water.

Compound (II), which is the starting material for Method 1, is a new compound, but it is different from the known compound 2-hydroxy-
It can be easily obtained from 5-methoxy-4H-bilan-4-one (7) as follows.

The following margins (in the formula, n has the above-mentioned meaning, , is prepared from the known compound 6-promu-5-methoxy-2-hydroxymethyl-4H-bilan-4-one (2) as follows.

The following blank space (in the formula, Examples of the stabilizer include methylene chloride, chloroform, etc. If the solvent contains alcohol as a stabilizer, it is preferable to remove this before use. Further, the subsequent reaction proceeds even if it is not carried out in a sealed tube, and by heating at 90 to 1()0°C, the raw materials completely disappear i~ and the reaction is completed.

In the reaction to obtain compound 1 from compound (VID),
It is preferable to react the compound (Vll) and the benzyl halide in an equimolar amount at room temperature in the presence of a solvent.

...If the benzyl monomer is used in excess, the resulting product becomes complex and the yield decreases. Preferred benzyl halides used in this reaction are:
Examples include benzyl bromide and benzyl iodide, and preferred bases include potassium carbonate and sodium carbonate. Furthermore, examples of the solvent used in this reaction include solvents that can dissolve the compound (V well, such as dimethylformamide, dimethyl sulfoxide, etc.).

Among the reactions for obtaining compound (1) from compound Hata, examples of dilute acids used in the first step include hydrochloric acid and acetic acid, and examples of preferable solvents include lower alcohols such as methanol and ethanol.

Moreover, it is preferable to use the lower alcohol as a solvent also in the latter step.

In the reaction where the diagonal compound is also produced from 1 to compound (@), in addition to compound (1), the following compound represented by 20K)C1 is also produced as a by-product. The production ratio of compound (1) and compound (2) is approximately 51% when using the method described above.
+44, but when using the following method, the amount of the female compound ■ produced is about 12180, which is large.

The pharmacological effects of the compound of the present invention obtained as described above were investigated and the results are as follows.

(1) Blood pressure lowering effect After anesthetizing male Wistar rats weighing 200 to 300 F with urethane 1 t/kg"i, p, the trachea, femoral vein (
Place the cannulae on the mulberry (4th river) and carotid artery (for blood pressure measurement), and move to the 1st floor transducer.
4. Blood pressure was measured through 2 tubes. After dissolving in IN sodium hydroxide, it was diluted with physiological saline and administered intravenously.

The results are shown in Table 1.

As shown in Table 1, compound number 1 is 3.0. η/kgi
, v.

So 2 I)! It showed a blood pressure lowering effect of 6 or more.

(2) Menoplate l raccoon action (1) l) Prepared weight of RP and P P P 2-3 kg
3.8 1/10 concentration of sodium citrate was added to blood collected from a male rabbit.

This blood was separated at 62 Orpm for 20 minutes to obtain platelet-rich plasma (PRP). Further lower layer 3.0+1
Centrifuge for 15 minutes and collect platelet-poor plasma (P i
) P) was obtained. In the implementation, 4i and lj were prepared with PPP so that the number of platelets in PRP was 300,000/silk 3.

(11) Measurement: Add 20μ of the test compound or control solvent to 250 ppρ of PRP, incubate for 2 minutes, and add flocculant 2.
Add 0 μp and measure the change in absorbance due to aggregation using a platelet agglutination meter.

As flocculants, ADP 3 μM and Arachidon r (A
A) 1 mM solution was used/46 bodies were dissolved in a small amount of dimethyl sulfoxide (DMSO') and then diluted with physiological to saline solution.

The results are shown in Table 2.

As shown in Table 2, the compound of the present invention exhibits a clear platelet N inhibition effect.1. Ta.

Next, the present invention will be described with reference to Reference Examples and Examples.

[Yes] Example I 6-bromo-5-methoyac-2-hydroxymethyl-4
II-Biran-4on 23.5 Ft (100m+n
og ) and 2,3-dihydro-4H-pilaf 12,6W
(150mtno13) Jiku DA/Meta y400r
After stirring at room temperature, a catalytic amount of p-)luenesulfonic acid was added, followed by stirring at room temperature for 2 hours. The reaction solution was washed successively with a saturated aqueous hexathorium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. Dichloromethane was distilled off under reduced pressure, and 4001 nl of strong aqueous ammonia was added to the residue to give a 90-100%
The mixture was heated and stirred at ℃ for 1 hour. 200% stronger ammonia water
After adding m and heating under the same conditions for 1 hour, ml of the reaction solution was dried under reduced pressure. The residue was extracted with hot acetone, and the extract was concentrated under reduced pressure to obtain yellow crystals. Recrystallized from acetone,
14.07 crystals (yield: 54.9) of 3-methoxy-4-hydroxy-6-(2-tetrahydro-4H-pyranyl)oxymethyl-2(IH)-pyridinone were obtained.

NMR691m in DMSOd-65,77 (S,
IH), 4.56 (t, IH), 4.18 (d, d
, 2H).

3.57 (s, 3H), 3゜90-3.40 (m
, 2H), 1.85-1.35 (+n, 610 θ Example 2 Compound 10.20SF obtained in Reference Example 1 (40 mmot3
) 11e Dissolved in 140 ml of water dimethylformamide,
About 151 liters of potassium carbonate was added to benzene bromide dissolved in 30 ml of anhydrous dimethylborumamide under stirring at room temperature.
6.84 S' (40 mmol) was added dropwise over about 1 hour. After stirring at room temperature for 6 hours, the reaction solution was poured into ice water for 40 hours.
0 ml and extracted 3 times with 30 liters of ethyl acetate.
The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. Concentrating ethyl acetate under reduced pressure gave pale orange crystals, which were recrystallized from acetone to give 3-methoxy-4-benzyloxy-6-(2-tetrahydro-4-pyranyl).
7.84 P (yield: 56.8 P) of colorless needle-like crystals of oxymethyl-2(I It )-pyridinone were obtained.

NMRδ ppm in CDCAs7.29 (br
, s, 5H), 6.00 (s, IH), 5.10 (s,
2)().

4.60 (t, IH), 4.41 (d, d, 2t (),
3.78(s, 3t().

3.90-3.30 (m, 2H), 1.90-1.35
(m, 6) () Reference Example 3 Compound 10.35'/(30m m
og) in methanol 60ON, 6N hydrochloric acid H□m
1 was added thereto, and the mixture was stirred at room temperature for 5 hours. The reaction solution was dried under reduced pressure, and a slightly excess amount of diazomethane-ether solution was added to form a residual methanol solution of 5 mol and 1 mol.
I had a time requirement. The reaction solution was distilled off under reduced pressure, and the residual liquid was recrystallized from acetone to give 1-methyl-3-methoxy-4-benzyloxy-6-hydroxymethyl-2(IH)-pyridinone as colorless needle crystals, 3,607 (yield 43.6%). In addition, when the recrystallization mother liquor was purified by silica gel column chromatography using benzene-acetone as a developing solvent, 4-benzyloxy-5.6-simethoxy-2-pyridinemethanol was obtained as a colorless oil. 20t
(yield: 50.9 cm).

@1-methyl-3-methoxy-4-benzyloxy-6
-Hydroxymethyl-2(IH)-biIJ dione: Button NMRδ pp+n in CD30D7.32 (1
), s, 5H), 6.75(s, 11(), 5.
24(s, 2) [).

4.55 (s, 2) (), 3.75 (s, 3H),
3.60(s,3H)-4-benzyloxy-5,6
-Simethoxy 2-pyridine methanol; (1) NMR δppm in CD (J3 7.30 (h, s, 5f (), 6.48 (s, IH)
, 5.12(s, 2H) 4.52(s, 2H), 3
．． 96 (s, 3H), 3.81 (s, 3M) Reference Example 4 Compound a obtained in Reference Example 2 10.35. ii' (30 mmo
, 6) and methyl iodide 12.781i' (90 mmol
) in acetone 600 and about 12 g of potassium carbonate.
- was added and heated under reflux for 6 hours. After cooling, inorganic substances were removed by filtration, and the filtrate was distilled off under reduced pressure. Dichloromethane was added to the residue to form a solution, washed with water, and dried over anhydrous sodium sulfate. Dichloromethane was distilled off under reduced pressure, and the residue was dissolved in methanol 2
00 Inl, 5 d of 6N salt was added, and the mixture was stirred for 15 hours at Muronishiki. The reaction solution was dried under reduced pressure, and the residue was recrystallized from acetone to give 1-methyl-3-methoxy-4-benzyloxy-6. -Hydroquinemethyl-2(IH)-pyridinone was obtained as colorless needle crystals at 6.5sP (yield 79.8%). In addition, the recrystallization mother liquor was purified by silica gel column chromatography using 7 tons of benzene as a developing solvent.
-benzyloxy-5,6-simethoxy-2-pyridine methanol as a colorless oil from 0.991 (yield: 12
, 6ch) obtained.

Example 5 2-Hydroxymethyl-5-methoxy-4H-pyran-
4-off 4.68 y-(30+n mol3) and 1-bromine 76.44? (36m mo, g
) was dissolved in 100 ml of anhydrous dimethylformamide, 1,201 (:30 m + nog) of sodium 60 thihydride was added little by little under stirring at room temperature in nitrogen gas γAf, and the mixture was then stirred for 1W at room temperature for 15 hours. Pour the reaction solution into ice water at 200mA! Pour into the mouth and add ethyl acetate! (extracted three times with water, washed the ethyl acetate layer with water, and dissolved in anhydrous sulfuric acid)
It was dried with IJum.

Ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography using chloroform-methanol as a developing solvent, yielding a pale yellow color with a crystallinity of 1%. Recrystallization from isopropyl ether gave 2-n-hebutyloxymethyl-5-methoxy-4H-pyraf-4-one as colorless needle crystals at 3.48 Sl' (yield: $45.7).

mp, 61-62'C llLu l<Br cm-' 1 6 50ax NMRδ ppm in CDCe37.50 (s,
IH), 6.37 (s, IH), 4.23 (s, 2
H).

3.70 (s, 3H), 3.48 (t, 2t(), 1.
90-1.00 (m.

101(), 0.89(t, 3)I) Example 1 2-n-decyl t-oxymethyl-5-methoxy-4H-vilan-4-one obtained in Reference Example 5 1.485' (5 m m
Add 30 mJ of strong ammonia water to
Heated at 00-110°C for 2 hours. The reaction solution was dried under reduced pressure to obtain yellow crystals, which were recrystallized from acetone to obtain colorless needle-shaped crystals of 2-n-decyloxymethyl-4-hydroquine-5-methoxypyridine (Compound No. 5). 32
P (yield 89.2%) was obtained.

Example 2 4-benzyloxy-5,6-simethoxy-2-pyridinemethanol obtained in Reference Example 3 1.38P (5m mo,
Q) and io-”+-ethyl dodecanoate #1.96fF
(6m moA) in anhydrous dimethylformamide 25a
60% sodium hydride O1''24S' (6 mmol) was added little by little under stirring at room temperature in a nitrogen gas stream, and the mixture was stirred at room temperature for 15 hours. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was extracted with silica gel using benzene-acetone as a developing solvent. Purification by column chromatography gave a pale yellow oil.This oil was diluted with ethanol t'
Dissolved in o o ml, 10 tipalladium carbon 0.3!
After stirring at room temperature for 2 hours while introducing hydrogen gas using F as a catalyst, the mixture was filtered once and the r liquid was concentrated under reduced pressure to obtain colorless crystals.

Recrystallization from isopropyl ether gave ethyl 1O-(4-hydroxy-5,6-simethoxy-2-pyridinyl)methyloxydecanoate (Compound No. 14) as colorless needle crystals of 1.151/- (yield 60.1). h) Obtained.

Example 3 Ethyl 10-(4-hydroxy-5,6-simethoxy-2-pyridinyl)methyloxydecanoate (Compound No. 1
4) o, 3g! ? (1mmoA) in methanol 2r)r
nl, IN-aqueous sodium hydroxide solution 3 rn
After heating under reflux for 2 hours with UfE, the reaction solution was cooled on ice.
The residue was made weakly acidic by adding 3.3 d of IN hydrochloric acid and dried under reduced pressure. The residue was extracted with hot acetone, and the extract was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using chloroform-methanol as the developing solvent. Colorless crystals were obtained.

Recrystallized from acetone-inopropyl ether to give 1O-
(4-Hydroxy-5,6-simethoxy-2-pyridinyl)methyloxydecanoic acid (Compound No. 27) was obtained as colorless crystals at a yield of 0.31!1I- (yield: 87.3I).

Example 4 The following compound was obtained in the same manner as in Examples 1 to 3. In addition, the compounds obtained in Examples 1 to 3 are also listed in the table.

The following margin procedural amendment (voluntary) March 14, 1981 1 t'l'Ii' 1. <Kanwakasugi Kazuo J Kotoi'
Table of Contents I 1982 Patent Application No. 220884 2 Name of the invention Pyridine derivatives and process for producing the same 3 Relationship with the case of the person making the amendment
Number 4 Name Name Nisnis Pharmaceutical Co., Ltd. Representative Yasumichi Nookata 4th representative Brother \,)°;.

6. Column 7 of "Detailed Description of the Invention" of the specification to be amended, contents of the amendment (1) "4-benzyloxy-5,6-simethoxy 2" in the fifth line from the bottom of page 5 of the specification The statement has been corrected to "4-benzyloxy-5-methoxy-6-alkyloxy-2."

(2) Same, page 7, lines 13-14 r --------5,6-cymethoxypyridine (1,)
Correct J to r-=--5-methoxy-6-alkyloxypyridine (1-) J.

(3) Same, page 9, in the reaction formula for compounds ω to (Ilb), [alkali hydride] is corrected to read DMTJ ``alkali hydride.''

DMF J (4) Same! Page ¥10, in the reaction formula from compound (Vl) to 1), in the third row, ``Diazomethane'' ``Diazoalkyl 1--------------□2> (Corrected as 11).

Ether-Lower Alcohol" (5), page 12, lines 1 to 6 from the bottom, correct the statement, "Also, the amount of 11111 in the latter part will increase." as in the first sentence.

"In addition, the diazoalkyl used in the later process is extracted with diazomethane, diazoethane, cyasibushihan, etc.
It is selected depending on the target compound. As the solvent, lower alcohols such as methanol, ethanol, and the like are preferably used.

In the reaction for producing compound Ql) from the vaporized compound (Vl), a compound represented by # or the following formula (IX)4 of compound (lI) is also produced as a by-product. The production ratio of this compound Δ) and compound (IX) is about 51:44 when using the method described above, using diazomethane as the diazoalkyl, lower alcohol, and methanol, but using the following method, using acetone Δ methanol. When the time is about 12:80, the amount of compound (IX) produced increases. (6) Same, page 13, Table 1 is amended as follows.

(7) Same, No. 13, negative, second line from the bottom, ``Platelet aggregation effect'' is corrected to ``Platelet aggregation inhibitory effect.''

(8) Same, page 20, lines 4-5 It says "acetone 60o", “Corrected as acetone 60 (ldJ).

(9) Same, page 27, footnote to table 3 CD30
Correct the text D3 J to r CD30D J.

Claims (1)

[Claims] ■ General formula (I) (wherein, R1 is a hydrogen atom or a lower alkyloxy group,
(1t2 represents a hydrogen atom, a hydroxyl group, a carboxyl group, or a lower alkyloxycarbonyl group, and n represents a number from 1 to 20). 2. General formula (11) () (wherein, R3 represents a hydrogen atom or a hydroxyl group, and n is 1 to 2
A method for producing a pyridine derivative represented by the general formula (Ia) (in which R8 and n have the above-mentioned meanings), which comprises reacting ammonia with a compound represented by the formula (indicating the number of 0). 3. To the compound represented by the general formula (1) (wherein R4 represents a lower alkyl group), a compound represented by the general formula 0v) atom or lower alkyloxycarbonyl group, n is a number from 1 to 20) and an alkali hydride, and then subjecting the obtained reaction product to a debenzylation reaction. Preparation and removal of a pyridine derivative having a 4ψ Wasanae with the general formula (Ib) (wherein R', A and n have the meanings described above). 4. General formula (Ic) (wherein R4 and R11 each represent a lower alkyl group, and n represents a number from 1 to 20. has the above-mentioned meaning).