JPS6270360A - Pyridine derivative and pharmaceutical composition containing said compound - Google Patents

Abstract

NEW MATERIAL:A pyridine derivative expressed by formula I (Z is -CH2-CH2- or -CH=CH-) or a salt thereof. EXAMPLE:5-(3-Carboxypropyl)-2-pyridinepropanoic acid. USE: A medicine and remedy for hypertension having more powerful hypotensive action than fusaric acid expressed by formula II. PREPARATION:For example, a pyrdinealdehyde expressed by formula III (R is lower alkyl) is condensed with malonic acid in a solvent, e.g. pyridine, while heating to carry out decarbonation and form a pyridinepropanoic acid expressed by formula IV, which is then hydrolyzed with an alkali, etc., to afford the compound expressed by formula I (Z is -CH=CH-). The resultant compound is catalytically reduced in the presence of a catalyst, e.g. Pd/C, in an alcoholic solvent,e.g. ethanol, at room temperature -100 deg.C under normal or higher pressure to give the compound expressed by formula I (Z is -CH2-CH2-).

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel pyridine derivative useful in the pharmaceutical field and having a blood pressure lowering effect.

BACKGROUND OF THE INVENTION There have been many research reports regarding the blood pressure lowering effect of pyridine derivatives, most of which relate to fusaric acid, which is a pyridine derivative represented by the following structural formula, and its derivatives. (For example, chemical and
Farmashtail Bulletin Volume 17 2377~
2380 ache 1969, JP-A-48-5'74.

JP-A No. 48'-39481, JP-A-50-893'i
'3 etc.).

The antihypertensive effect of fusaric acid and its derivatives is relatively weak, and large doses are required for prevention and treatment of hypertension. Performing large needle administration in this way
This is not preferable because it increases the risk of side effects. The purpose of the present invention is to solve these problems.

Means to Solve All Problems This is the result of intensive research aimed at improving the relatively weak hypotensive effect of fusaric acid and its derivatives.

The present inventors have discovered that the novel compound of the present invention has a 2-carboxyethyl group or 2-carboxyvinyl group at the 2-position of the pyridine ring, and a 3-carboxypropyl group at the 5-position. <Unsurprisingly, we found that it has a stronger antihypertensive effect than fusaric acid. In other words, one aspect of the present invention is.

General formula (in the formula, Z is -01 (2-0H2-, or -〇) (=O
The present invention relates to a pyridine derivative represented by (H-) or a pharmaceutically usable non-toxic salt thereof, and a therapeutic agent for hypertension containing the compound as an active ingredient. In other words, the present invention is based on the following structural formula (I-a
), (I-b) and C: [-c) or a pharmaceutically usable non-toxic salt thereof, and a therapeutic agent for hypertension containing the compound as an active ingredient and 1 to 1. .

Next, a method for producing one of the compounds of the present invention will be explained below.

The compound of the present invention is obtained by the reaction of pyridine aldehyde (I[) represented by the general formula (wherein the formula shows a lower alkyl group) with malonic acid (wherein the formula has the above-mentioned meaning). It can be produced by hydrolyzing pyridinepropenoic acid (ffl) represented by

The reaction between pyridine aldehyde (II) and malonic acid is usually carried out under heating using a solvent such as pyridine.

This dehydration condensation reaction proceeds satisfactorily with decarboxylation.

The condensation product of this reaction is easily hydrolyzed by commonly used methods such as alkaline hydrolysis.

In addition, 9 compounds of the present invention include pyridine aldehyde [, II
) and triphenylphosphine carbalkoxymethylene [■] represented by the general formula % formula % () (wherein R1 represents a lower alkyl group) (wherein R and 几1 are It can also be produced by hydrolyzing pyridine propenoic acid ester (V) represented by (having the above meaning). The reaction between pyridine aldehyde (II) and triphenylphosphinecarbalkoxymethylene [■] is usually carried out using a solvent that does not participate in the reaction, but preferred solvents include chloroform, methylene chloride, benzene, dimethylformamide, etc. can be mentioned. that time.

The reaction temperature is within the range of OC to the boiling point of the solvent, and the reaction time is usually α5 to 10 hours.

Further, the ester group of the condensation product (V) is easily decomposed by a conventional method such as an alkaline aqueous solution. The product can easily be prepared by crystallization methods.

Sweet. General formula [■] (7) Z car 0H2-0H
The compound of the present invention 2-f can be produced by catalytic reduction of the compound of the present invention having a double bond obtained by the above method. This catalytic reduction reaction is carried out using a known suitable solvent in the presence of a catalyst such as palladium-carbon, platinum, or Raney nickel. Suitable solvents include:
alcohol.

Examples include water, dioxins, acetic acid, and mixtures thereof. The reaction is carried out at normal pressure, in a box, or under pressure, and the reaction temperature is usually room temperature to 100C. However, if necessary.

It can also be carried out at higher temperatures. The product thus obtained can be purified by recrystallization, chromatography, etc.

The compound of the present invention can also be produced by catalytically reducing the compound represented by the general formula [1] or the compound represented by the general formula [■], and then hydrolyzing the ester group thereof.

The catalytic reduction reaction at this time can also be easily carried out under the above-mentioned conditions, and the hydrolysis can be carried out by a conventional method using an acid or alkaline aqueous solution.

Depending on the reaction conditions or post-treatment of the reaction, the compounds of the present invention represented by the general formula CI) can be obtained in the form of free or non-toxic salts which can be used as pharmaceuticals. If obtained in the form of a salt, it can be converted into the free form using a suitable acid or ion exchange resin. On the other hand, the free form of the compound of the invention can be converted into the salt form using a suitable acid or base.

9. Non-toxic salts of the compounds of the present invention that can be used as pharmaceuticals include inorganic acid salts such as hydrochloride, sulfate, and nitrate, acetate, oxalate, maleate, malate, salicylate, and benzoate. acid salt.

Organic acid salts such as methanesulfonate, ethanesulfone di, P-toluenesulfonic acid, naphthalene-2-sulfonic acid, sodium salt, potassium salt, lithium salt, magnesium salt, calcium salt, aluminum salt, barium salt, ammonium salt , inorganic or organic base salts such as triethylamine salts.

The active ingredient according to the present invention can be used in combination or formulation with a suitable carrier for oral or parenteral administration of its pharmaceutically effective properties. Tablets and gelatin capsules are preferred as pharmaceutical formulations, which contain the active ingredient in diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, and lubricants such as silica, talc.

Contains stearic acid, together with hydrogenated oil or its magnesium or calcium salts and/or polyethylene glycol. The tablets also contain binders magnesium aluminum silicate, starch, gelatin, tragacanth,
Methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone.

If desired, leavening agents such as starch, agar, alginic acid or its sodium salt, enzymes or foaming agent mixtures of these binders, and/or adsorbent 1 colorants, flavors, etc. are also included. Injectable formulations are preferably isotonic aqueous solutions or mixtures, and suppositories are advantageously fatty emulsions or suspensions. They can be sterilized and (!) contain auxiliary agents such as preservatives, stabilizers, wetting agents or emulsifiers, solubilizers, osmotic salts and (!) buffers. Furthermore, they can also contain other substances of therapeutic value. The formulation is prepared by conventional mixing;
It shall be manufactured by granulation or coating methods and contain about 01-75% of active ingredient, preferably about 1-50%.

The dosage of the compound of the present invention is adjusted as appropriate depending on the purpose, symptoms, etc., and cannot necessarily be strictly regulated, but for example, for adults, oral administration is 1 to 200 tn9, intravenous injection, etc. is 01 to 5 m921 times per day. It is used in parts.

Effect The antihypertensive effect of the compound of the present invention was measured by the following pharmacological test method.

(Test compound) Compound A Nidorans 5-(3-carboxypropyl)
-2-H+)Zinpropenoic acid compound B: 5-(3-carboxypropyl)-2-pyridinepropanoic acid (Test method) Spontaneous hypertensive rats (20-25 Blood pressure was measured in awake, unrestrained animals (male, 2 weeks old). The test compound was dissolved in distilled water and adjusted to pH 5 to 0 with αIN sodium hydroxide to a final concentration of 5 m97 ml, and intravenously injected via a cannula inserted into the femoral vein. Blood pressure was measured using a blood pressure transducer (5t) using a cannula inserted into the aorta.
at, ham: P231D).

Table 1 As shown in Table 1, the nine compounds of the present invention exhibited a stronger antihypertensive effect than fusaric acid.

Example The present invention will be explained below with reference to Examples.

Example 1 5-(3-ethoxycarbonylprobyl)-2-pyridinecarboxaldehyde g, 9.9 and malonic acid ao
Dissolve g in lOd of pyridine.

When one drop of piperidine is added and heated to 10-'f5C, carbon dioxide gas is generated, the reaction proceeds, and is completed in about 2 hours.

The solvent is distilled off from the reaction solution, the residue is diluted with water, and the target product is extracted with chloroform. After drying with chloroform and sodium sulfate, the residue was concentrated to dryness under reduced pressure and reconsolidated with water-containing methanol to give 55 g of trans-5-(3-ethoxycarbonylpropyl)-2-pyridinepropenoic acid.
(yield 47%) is obtained as crystals with a melting point of 101-103C.

IJL I/K"'p-" :2920,2440
,2330,1720°ax 1640,14B0.1200.1145°980,
Bo.

NMR (ODOI3) δ: 134 (3H,t),
L'70-420 (aH.

m), 4.20 (2H, q), a8tsu (LH, d
).

t4o-tso (2H, m), t86 (LH.

d), a67 (IH, 8) 1N hydroxylation of 2.6 g of the above trans-3-(3-ethoxycarbonylprobyl)-2-pyridinepropenoic acid)
Add to 4011 Ll of IJum and stir at room temperature for 2 hours. The reaction solution was adjusted to volume 3 with acetic acid.

After cooling, the crystals are separated. This crystal contains 15 g of water (
(yield: 6%) as crystals with a melting point of 193-6C (decomposition) (compound A).

The starting material 5-(3-ethoxycarbonylprobyl)-2-pyridinecarboxaldehyde can be obtained by the following method.

Dissolve 108 g of 5-(3-ethoxycarbonylprobyl)-2-pyridine methanol in 140 M of dioxane,
Add selenium dioxide zsg.

Heat and stir at 80-85C for 3 hours.

After removing the precipitated selenium, the P solution was distilled under reduced pressure to obtain 3-(ethoxycarbonylprobyl)-2-pyridinecarboxaldehyde q9.9 (yield 93%) with a boiling point of 127-9C/
Obtained as an oil of 1 tran Hg.

1 liter ν cm: 29 tb, 2t1o, x
I7z5,1ylo'.

ax 1590.13B0,1200,1030°5O NMR (0014) δ: Yu, 35 (3H,
t), ]JO~2.50 (4H9m), 2
75' (2H, t), 4.06 (2H, qri.

'250-aoo (2H, m), a55 (IH, s).

Q91(IH,S) Example 2 trans-5-(3-carboxypropyl)-2-hy+)
Dissolve 1.5 g of synpropenoic acid in 60 ml of ethanol, add 03 g of 10% palladium-carbon, and pressurize at room temperature (
3 Kv/ctI) for 20 hours. After removing the catalyst, the liquid was concentrated under reduced pressure and the residue was recrystallized from a mixture of methanol and impropyl ether to give 5-(
3-carboxypropyl)-2-pyridinepropanoic acid L
5 g (yield 95%) are obtained as crystals with a melting point of 146C (compound B).

■几 KB', -': 3040, 2920, 246
0,2100°ax 1'700.1610.1400.1205°995.
860 nyl<cyo,),,so)δ: L50-a30
(m, l0H), '21'7 (d, IH),
t53 (dd, IH), aso (d, LH)
.

QIO (br, 2H) Example 3 24 g of 5-(3-methoxycarbonylpropyl)-2-pyridine rpoxyfuldehyde
Dissolve ml IIC, add 4.5.9 ml of triphenylphosphinecarboethoxymethylene, and stir at room temperature for 3 hours. The solvent was distilled off from the reaction solution.

Add a mixture of benzene and luhexane to the residue. The precipitated triphenylphosphine oxide crystals were removed, the solvent was distilled off, and the residue was purified using a silica gel column to obtain trans-5-(3-methoxycarbonylpropyl)-2-pyridinepropenoic acid ethyl ester 27
9 (yield 84%) is obtained as crystals with a melting point of 64-5c. Also, a mixture of cis and trans isomers C15j;l
(yield 16%) is obtained.

IRVKB' c, n-': 1"45,1710,1
650, 1305° aX 1210, 1165° NMR (ODOI3) δ: L30 (t, 3H),
hso-290 (m.

bH), a60 (3i(,s), 420 (
q.

2H), aE30 (d, IH), '220-1
'25 (m, 3H), a4o (d, LH) 08 g of the above trans-5-(3-methoxycarbonylpropyl)-2-pyridinepropenoic acid ethyl ester
Add to a mixture of 5 N sodium hydroxide and 5 m of dioxane, and stir at room temperature for 3 hours. P! the reaction solution! 13 and cooled crystal tP. When this crystal is recrystallized from aqueous methanol, trans-5-(3-carboxypropyl)-2-7' lobenic acid Q52.!i+ (yield 7-/%) is obtained. ) was obtained as a crystal with a melting point of 193-5C (decomposition).The IR, NMR and melting point of this crystal were consistent with the compound obtained in Example 1.

Example 4 Trans-5-(3-methoxycarbonylpropyl)-2
- Dissolve 2.2 g of pyridine propenoic acid ethyl ester in 22 mJ of ethanol, and dissolve 02 g of 10% palladium-carbon.
was added and hydrogenated at room temperature and normal pressure for 10 hours. After removing the catalyst, liquid F was concentrated under reduced pressure and the residue was purified using a silica gel column to obtain 3-(3-methoxycarbonylpropyl)-2-pyridinepropanoic acid ethyl ester L4.
, 9 (yield 63%) is obtained as an oil.

IRvoe"cm': 2970.1745.1
505.1450°ax 13B5.1265.1220.1185NMI'l,
(ODOI3) δ: L20 (t, 3H), L80-4
10 (m.

10H), a6o (S, 3H), 405 (
q.

2H), Tsuoo (d, xH), 720~+250(
m, LH), a20 (d, IH) above 5-(
1-0 g of 3-methoxycarbonylpropyl)-2-pyridinepropanoic acid ethyl ester was dissolved in 1 ml of IN hydrochloric acid, heated under reflux for 6 hours, the reaction solution was dried under reduced pressure, and the residue was re-purified from a mixture of methanol and ether. When it crystallizes.

08 g (yield 81%) of 5-(3-carboxypropyl)-2-pyridinepropanoic acid base salt had a melting point of 66-9C (
obtained as crystals (decomposition).

IRVKBrcm-” :3050.1'725,14
10,1195°ax 118O NMR (D20) δ: 180-2.60 (m, l0
H),'z90(d.

LH), a35-a70 (m, 2H) Example 5 Capsule 5-(3-carboxypropyl-2-pyridinepropanoic acid 25η lactose)
80 rv Calcium hydrogen phosphate 50 m 9 Calcium carboxymethyl cellulose 10 m 9 Sucrose fatty acid ester 2 m 9 Total 170 The above components were mixed uniformly and filled into hard capsules.

Effects of the Invention As is clear from the above, the compounds of the present invention can be expected to have a more powerful hypotensive effect than fusaric acid.

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [ I ] (In the formula, Z is -CH_2-CH_2-, or -CH=C
A pyridine derivative represented by H-) or a pharmaceutically usable non-toxic salt thereof. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [ I ] (In the formula, Z is -CH_2-CH_2-, or -OH=O
A therapeutic agent for hypertension containing a pyridine derivative represented by H- or a pharmaceutically usable non-toxic salt thereof as an active ingredient.