JPS6042792B2 - Pyridoxine derivatives, their production methods, and pharmaceutical compositions - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel pyridoxine derivative, a process for its preparation and its application in human and veterinary medicine.

The novel compound of the present invention has the following general formula (1) to form an isopropylidene group, and R3 and R4 represent a lower alkyl group, or together with the nitrogen atom to which they are bonded, a 4-membered or form an 8-membered saturated heterocyclic group which optionally contains a sulfur, oxygen or nitrogen atom as second heteroatom, which nitrogen atom is optionally an organic group, in particular an unsubstituted phenyl group or may be substituted with a phenyl group substituted with a halogen, trifluoromethyl, lower alkyl or lower alkoxy substituent, n represents 2 or 3]. Alkyl and alkoxy groups have up to 12 carbon atoms, preferably up to 6 carbon atoms;
Particular preference is given to up to 4 lower groups. Advantageously, the halogen is chlorine or bromine. Preferred heterocyclic groups are morpholino, piperazino, pyrrolidino and peridino. The present invention also encompasses physiologically acceptable acid addition salts of compounds of general formula (1) with inorganic or organic acids and quaternary ammonium derivatives.

The present invention also provides pyridoxine derivatives of the formula (■) and [wherein x represents a halogen, for example chlorine,
and n represents the above-mentioned compound] to produce a compound of general formula (1a), which is then treated with an acid to convert it into a compound of general formula (Ib) below. It also relates to a method for producing a compound of general formula (1); the compound of formula (■) is a known compound and is described in W. K.O.
rytnik and W. A method for its production has been reported by J. Chem. SOc., 19
62, “2531).

The haloalkylamine of the general formula (■) is a known compound and is available from DOumlasC. Kriesel and 01eGis
v01d (J. Pharrrl. Sci., 1967,
56, p. 327) and J. Bourdais (Bull
．． SOc. Chim. Fr. l968, (8), 324
6) using the method reported by.

The condensation giving compound (1a) is carried out in the presence of a concentrated aqueous solution of a hydroxide, especially an alkali metal hydroxide, such as sodium hydroxide, in a concentration of 10 to 6% by weight, preferably 5% by weight. Advantageously, the reactants of formulas (■) and (■) are used in stoichiometric amounts in this reaction;
It is also possible to use an excess of one of the reactants.

It is advantageous to maintain the temperature of the reaction medium between 50 and 100°C. This manufacturing method uses an original reaction in a heterogeneous medium using a phase transfer catalyst.

The catalytic action is caused by the quaternary ammonium salt of the formula: resulting from the dimerization and intramolecular ring closure of the haloalkylamine of the general formula (■), respectively.

The conversion of the compound of general formula (1a) to the compound of general formula (Ib) is carried out at 20 to 100°C in an aqueous or anhydrous medium.
This is carried out by treatment with an inorganic or organic acid at a temperature of .

Next, a method for producing the compound of the present invention will be explained based on Examples.

Example 1 5-[(β-morpholinoethoxy)-methyl]-2●2
●8-trimethyl-4H-1●3-dioxolo[4・5
-c]-Production of pyridine (derivative number 1); R1+R2
=isopropylidene, -NR2R4=morpholino, n=
2.N-(2
-chloroethyl) morpholine and 5-hydroxymethyl-2,2,8-trimethyl-1,3-dioxolo(
A mixture of 20 f of 4.5-c)-pyridine hydrochloride is heated to 100° C. for 5 hours with vigorous stirring.

The mixture is then diluted with water and extracted with ether. The ether extract was washed with water, dried over sodium sulfate,
Evaporate to dryness. The residue is dissolved in chloroform and the resulting solution is filtered over a bed of silica and concentrated in vacuo. The resulting oil is converted into dihydrochloride hydrate.

Recrystallization from a mixture of ethanol and ethyl acetate gives
6.20 Da (65.6% yield) of white crystals are produced. Its melting point is 216° C., determined on a block of Kefler (K6flOr). Example 2 5-([3-(4-p-chlorophenyl-1-piperazinyl)-propoxy]-methyl)-2●2●8-trimethyl-4H-1.3-dioxoro[4.5-c]pyridine Manufacture of (derivative number 2); R1+R2=isopropylidene, NR3R4=4-p-k-ch lefuenyl-piperazinyl, n=3.50% sodium hydroxide solution 50ml
5-hydroxymethyl-2,2,8-trimethyl-shinichi 1,3-dioxolo(4,5-c)pyridine hydrochloride 10q and 1-(3-kuyama lepropyl)-4-p-chlorphene The mixture of nilupiperazine 14.1y is heated to 100'C for 6 hours with thorough stirring.

Against. The reaction mixture is diluted with water and extracted with chloroform.
The chloroform extract is dried over sodium sulfate and filtered over a silica bed. After evaporating the solvent in vacuo, the oily product 14f obtained is converted into the dihydrochloride hydrate. Recrystallized from ethanol to give white crystals 12y (yield 56%)
). Melting point: 188℃ (measured with Kefler Prok)
. Example 3 Preparation of 3-hydroxy-4-hydroxymethyl-2-methyl-5-[(β-morpholinoethoxy)--methyl]-pyridine (derivative number 3); R1=R2=H. ,NR
3R4=Morpholy8n=2.9% formic acid aqueous solution 500mL
5-[(β-morpholinoethoxy)-methyl]-2
・2,8-trimethyl-1●3-dioxolo(4●
5-c) A solution of 11.4 Da of pyridine is heated to 100° C. for 3 hours.

After cooling and evaporating to dryness, the residue is taken up in a saturated aqueous solution of sodium chloride and made basic by adding sodium carbonate.
Extract with chloroform. The chloroform extract is dried over sodium sulfate, filtered over a bed of silica, and evaporated to dryness. The solid product obtained is recrystallized from ethyl acetate to give white crystals 5.5y (yield: 56%). The melting point is 98°C, measured on a Keffler proc. Example 4 5-([3-(4-p-chlorophenyl-1-piperazinyl)-propoxy]-methyl)-3-hydroxy-4
-Production of hydroxymethyl-2-methyl-pyridine (derivative number 4); R1=R2=HlNR3R4=4-p-
Chlorphenyl-piperazinyl, n=3.70% acetic acid 1
5-([3-(4-p-chlorophenyl-1-piperazinyl)-propoxy]-methyl)-2.2 in 00 mL
・8-trimethyl-4H-1,3-dioxolo(4,5
-c) A solution of pyridine dihydrochloride hydrate 6y for 6 hours 90
Heat to ℃.

Evaporation of the solvent in vacuo resulted in a solid residue, which was
Recrystallization from 0.00 ethanol gives 2.60 Da (yield: 50%) of white crystals of dihydrochloride hydrate (melting point 1
86℃). Derivative number 5 5-[(β-dimethylaminoethoxy)-methyl]-2
・2,8-trimethyl-4H-1,3-dioxolo(4
・5-c) Pyridine; R10R2=isopropylidene;
R3=R4=methyl, n=2.2 hydrochloride hydrate; white crystals, melting point 192°C (ethanol), prepared as in Example 1; yield 20%.

Derivative number 65-[(β-diethylaminoethoxy)-
methyl] mono-1,3-dioxoro(4,51c)pyridine R1+R2=isopropylidene; R3=R4=
Ethyl; n=2.2 Hydrochloride: White crystals, melting point 200'C
(Ethyl acetate/ethanol) Prepared as in Example 1: Yield 6
2%.

Derivative number 75-[2-(1-pyrrolidinyl)monoethoxy]-methyl-2●2,8-trimethyl-4H-13-
Dioxo(4.5-c)pyridine; R1+R2=isopropylidene NR3R4=pyrrolidinyl, n=2.2 Hydrochloride hydrate: white crystals, melting point 170°C (isopropanol), prepared similarly to Example 1; yield 65% , derivative number 85
-[(β-piperidinoethoxy)-methyl]-2.2.
8-trimethylated-1,3-dioxolo(4●5-c
) Pyridine; R1+R2=isopropylidene; NR,R
4=piperidino, n=2.2 hydrochloride hydrate; white crystals,
Melting point 143°C (ethanol), prepared as in Example 1; yield 25%.

Derivative number 95-([2-(4-phenyl-1-piperazinyl)monoethoxy]-methyl)-2●2,8-trimethyl-4H-1,3-dioxolo(4,5-c)pyridine R1+R2=isopropylidene, NR3R4=4-
Phenyl-piperazinyl, n=2.2 hydrochloride hydrate; white crystals, melting point 206°C (ethanol), prepared as in Example 2; yield 42%.

Derivative number 105-([2-(4-0-chlorophenyl-1-piperazinyl)monoethoxy]-methyl)-2.
2,8-trimethyl-4H-1,3-dioxolo(4.
5-c) Pyridine, R1+R2=isopropylidene, N
R3R4=4-0-chlorophenyl-piperazinyl; n
=2.゜Dihydrochloride hydrate; white crystals, melting point 190°C (ethanol), produced in the same manner as Example 2; yield 36%, derivative number 115-([2-(4-m-chlorophenyl-1-piperazinyl)- ethoxy]-methyl)-2●2●8-trimethyl-4H-1,3-dioxolo(4,5-c)-
Pyridine; R1+R2=isopropylidene, NR3R4
=4-m-chlorophenyl-piperazinyl; n=2.2
Hydrochloride hydrate; white crystals, melting point 208°C (ethanol)
, prepared as in Example 2; yield 57.5%.

Derivative number 125-([2-(4-p-chlorophenyl-1-piperazinyl)monoethoxy]-methyl)-2.2
・8-trimethyl-bile-1,3-dioxolo(4,5-
c)-pyridine; R1+R2=isopropylidene, NR
3R4=4-p-chlorophenyl-piperazinyl; n=
2.2 Hydrochloride hydrate: white crystals, melting point 214°C (ethanol), prepared similarly to Example 2; yield 52% Derivative No. 13 5-([2-(4-m-trifluoromethylphenyl-1- piperazinyl)-monoethoxy]-methyl)-2.2.
8-trimethyl-13-dioxolo(4.5-c)
Pyridine, R1=R2=H, . NR3R4 = 4-m-trifluoromethylphenylpiperazinyl; n = 2.2 Hydrochloride hydrate: white crystals, melting point 168°C (ethyl acetate/ethanol), prepared similarly to Example 2, yield 31%, Derivative No. 14 5-([2-(4-p-trily-1-piperazinyl)monoethoxy]-methyl)-2,2,8-trimethyl-center-
1,3-dioxolo(4,5-c)pyridine; R1+R
2=isopropylidene; NR3R4=4-p-tolylupiperazinyl; n=2.2 hydrochloride hydrate; white crystals, melting point 177°C (ethanol), prepared similarly to Example 2, yield 4
4%.

Derivative number 155-([2-(4-0-methoxyphenyl-1-piperazinyl)monoethoxy]-methyl)-2.
2●8-trimethyl-4H-1.3-dioxolo(4.
5-c) Pyridine; R1+R2=isopropylidene, N
R3R4=4-0-methoxyphenylpiperazinyl, n
=2.2 Hydrochloride hydrate; white crystals, melting point 216°C (ethanol), produced in the same manner as Example 2, yield 16%, derivative number 165-[(1-dimethylaminomethylethoxy)-methyl]-2. 2,8-trimethyl-4H-1,3-dioxolo(4,5-c)pyridine and 5-[(2-dimethylanopropoxy)-methyl]-2,2,8-trimethyl-■-13-dioxolo(4, 5-c) Mixture with pyridine. Dihydrochloride: white crystals (ethyl acetate/ethanol), prepared similarly to Example 1, yield 38%, derivative number 17 5-[(3-dimethylaminopropoxy)-methyl]
-22,8-trimethyl-Kuichi 1●3-dioxolo(4
・5-c) Pyridine; R1+R2=isopropylidene,
R3=R4=methyl, n=3.2 hydrochloride hydrate; white crystals, melting point 208°C (isopropanol), prepared as in Example 1, yield 29%.

Derivative number 185-[(β-dimethylaminoethoxy)
-methyl]-3-hydroxy-4-hydroxymethyl-2-methyl-pyridine; R1=R2=H. ．． R3=R4
= methyl, n = 2.2 hydrochloride hemihydrate; pale yellow crystals,
Melting point: 170° C. (ethanol), prepared as in Example 4, yield 75%.

Derivative No. 193-Hydroxy-4-hydroxymethyl-2-methyl-5-([2-(1-pyrrolidinyl)-ethoxy]-methyl)-pyrylidine; R1=R2=H,.
NR3R4=pyrrolidinyl, n=2.2 hydrochloride hydrate;
Ivory crystal, melting point 157! 'C (isopropanol),
Manufactured in the same manner as Example 4, yield 40%.

Derivative number 20 3-hydroxy-4-hydroxymethyl-2-methyl-5-[(β-piperidinoethoxy)-methyl]-pyridine; R1=R2=H1-NR3R4=piperidino, n=
2. Beige crystals, melting point 76°C (ethyl ether/methanol), prepared as in Example 3, yield 50%.

Derivative number 213-Hydroxy-4-hydroxymethyl-2-methyl-5-([2-(4-phenyl-1-piperazinyl)monoethoxy]-methyl)-pyridine; R1=
R2=H. ．． NR3R4=4-phenyl-piperazinyl, n=2.2 hydrochloride hydrate; white crystals, melting point 169°C (
Ethanol): Produced in the same manner as Example 4, yield 35%.

Derivative number 225-([2-(4-0-chlorophenyl-1-piperazinyl)monoethoxy]-methyl)-3-hydroxy-4-hydroxymethyl-2-methyl-pyridine; R1=R2=H. ．． NR3R4=4-0-Chlorphenylpiperazinyl, n=2.2 Hydrochloride hydrate: white crystals, melting point 176°C (954 ethanol), prepared as in Example 4, yield 40%.

Derivative No. 235-([2-(4-m-chlorophenyl-1-piperazinyl)monoethoxy]-methyl)-3-hydroxy-4-hydroxymethyl-2-methylpyrrolidine)R1=R2=H. sNR3R4=4-m-chlorophenyl-piperazinyl, n=2. Pale cream crystals, melting point 110°C (isopropyl ether/ethyl acetate), prepared as in Example 3, yield 69%.

Derivative number 24 5-([2-(4-p-chlorophenyl-1-piperazinyl)monoethoxy]-methyl)-3-hydroxy-4-
Hydroxymethyl-2-methyl-pyridine; R1=R2
=H. ．． NR3R4=4-P-chlorophenyl-piperazinyl, n=2.2 hydrochloride hydrate; white crystals, melting point 18
Prepared as in Example 4 at 6°C (ethanol), yield 65%.

Derivative number 253-Hydroxy-4-hydroxymethyl-2-methyl-5-([2-(4-m-trifluoromethyl-phenyl-1-piperazinyl)monoethoxy]-methyl)-pyridinyR1=R2=HlNR3R4=4-
m-trifluoromethylphenyl-piperazinyl, n=
2.2 Hydrochloride hydrate; white crystals, melting point 198°C (95% ethanol), prepared in the same manner as Example 4, yield 76%.

Derivative number 263-Hydroxy-4-hydroxymethyl-2-methyl-5-([2-(4-p-tri-1-piperazinyl)monoethoxy]-methyl)-pyridine; R1
=R2=H,. NR3R4=4-p-tolylupiperazinyl, n=2.2 hydrochloride hydrate; white crystals, melting point 156
C (ethanol), prepared as in Example 4, yield 60%.

Derivative No. 273-Hydroxy-4-hydroxymethyl-5-([2-(4-0-methoxyphenyl-1-piperazinyl)monoethoxy]-methyl)-2-methyl-lupyridine; R1=R2=H, . NR3R4 = 4-0-methoxyphenyl-piperazinyl, n = 2.2 hydrochloride hydrate) White crystals, melting point 188°C (ethanol), prepared as in Example 4, yield 45%.

Derivative number 285-[(1-dimethylaminomethyl-ethoxy)-methyl]-3-hydroxy-4-hydroxymethyl-2-methyl-pyridine and 5-[(2-dimethylaminopropoxy)-methyl]-3-hydroxy- 4
-Mixture with hydroxymethyl-2-methyl-pyridine; dihydrochloride hemihydrate; white crystals (isopropanol)
, prepared as in Example 3, yield 61%.

The results of the toxicity and pharmacology tests presented below demonstrate the interesting activities of compounds of the invention D, in particular their sedative and peripheral vasodilatory effects.

Therefore, the present invention is characterized in that it contains a compound of general formula (1) or a physiologically acceptable acid sized salt thereof or a quaternary ammonium derivative as an active ingredient. To provide a medicine having the following.

I Toxicity Test The compounds of the invention are very well tolerated and have low toxicity.

By intravenous injection, the method of Miller and Tainter! The animal LD5O/241 Terama/K9 measured in mice was 250 mg for derivative number 1, 38 m9 for derivative number 2, 310 m9 for derivative number 3, 115 m9 for derivative number 4, 74 mg for derivative number 5, Derivative number 6 is 89 mg, derivative number 7 is 79 mg, derivative number 8 is 70 mg, derivative number 9 is 42 m9, derivative number 10 is 43 m9, derivative number 11 is 61 mg, derivative number 12 is 55 mg, derivative number 13 is 49 mg, 65 mg for derivative number 14, 74 m9 for derivative number 15, 86 m9 for derivative number 16,
78mg for derivative number 17, 3003 for derivative number 18
mg, 125 mg for derivative number 19, 160 mg for derivative number 20, 120 m9 for derivative number 21, 69 mg for derivative number 22, 31 m9 for derivative number 23, 63 m9 for derivative number 24, 74 m9 for derivative number 25, 87 m9 for derivative number 26, Derivative number 27 is 55 m9, and derivative number 28 is 2663 mg.

1 Pharmacological Test This test shows the activity of the compound which is the active ingredient of the medicament of the present invention.

1 Sedative effect 4 (a) Behavioral test Samuel Irvin
The study was conducted using the method of Win) (Animal and Clinical Pharmacy Techniques in PhDl Drug Evaluation).

[161] The derivative of the present invention was administered once at a dose of 30m91k9 via the gastrointestinal tract to mice that had been fasted for V.

Tests of mouse behavior and various physiological parameters (body temperature, heart rate and respiratory rate) show that these derivatives have a pronounced sedative and muscle relaxant effect.

In fact, from the 5th minute onwards, a marked decrease in locomotor activity, a decrease in muscle tone and alertness, a decrease in breathing and a decrease in response to sound and the environment are observed in all animals.

(b) Activity with respect to hypnotic agents The compound of the invention is administered 3 times prior to intraperitoneal injection of a mild hypnotic dose of pentobarbital sodium.
At 0 min, different groups of mice are dosed orally with a dose of 30m91k9.

The number of animals falling asleep, the time required to fall asleep and the duration of sleep were determined.

The results summarized in Table 1 below show that the test compounds have a clear synergistic effect compared to control animals.

(c) 4-plate test (BOissier,.SimO
n and ArOn. sEurOpJ. OfPharmac
Ol. 4, 1968, 145-151) A mouse placed in an area containing four charged plates is given an electric shock, but the mouse runs irregularly, moving from one plate to the other each time.

After n electric shocks, the mouse does not move. I'm tired.

The degree of sedation obtained is considered to be proportional to the number of electric shocks n given before the treated mouse becomes immobile in a corner.

In this manner, it was found that when administered orally at a dose of 30 m91 kg, the derivative of the present invention increases the number of shocks n by a considerable percentage after 1, 4 and 9 doses.

The results are summarized in Table ■.

, using two methods of vasodilatory action,
This effect was tested.

(a) Activity against gangrene induced by ergotamine.

Administration of large doses of ergomine causes sustained vasospasm of arteriolar limbs by acting directly on vascular smooth muscle;
Subsequently, arteritis obliterans and tissue asphyxia occur, which is mainly seen in the less well-supplied extremities (rat tails) and takes the form of a more or less severe cyanosis, followed by cell destruction and sedation. It can even cause pox.

Administration of a test substance that has a vasodilatory effect can counteract or suppress the vasoconstrictive effect caused by ergotamine.

Beagle Bock Method (Arc
h. Exp. Path. PharmOcOl. l962
, 217, 430): Control animals are injected with ergotamine-adrenaline at the base of the tail daily for 11E].

The treated group received 30 m9 of the test derivative intramuscularly for 12 days.
Also administer 1 kg. The animals are observed daily and the changes caused by the action of ergotamine are evaluated; mild cyanosis (C1), moderate cyanosis (Cm), strong cyanosis (Ci) and gangrene (G).

The results are summarized in the table below, which shows the percentage of movements exhibiting the various symptoms described above as a function of time.

(b) Irrigation of the posterior half of the rat's body The study is carried out on rats anesthetized with an intraperitoneal injection of 1 fI kg of ethyl urethane.

Irrigation of Ringer's solution is performed by the gravity of the animal's abdominal aorta. Collect fluid from the inferior vena cava. The increase in blood flow is measured by collecting a drop using a load, placing it on a record needle, and recording it as a graph.

The test substance was administered intraperitoneally at a dose of 30Tn91k9.
to be administered.

The results are summarized in the table below, which shows, for each tested derivative, the vasodilation rate achieved and the duration of the vasodilatory effect produced.

The above toxicity and pharmacology tests show that the compound Z of the invention has low toxicity with high tolerance and has significant sedative and vasodilatory effects.

The medicament of the invention may be in the form of tablets, dragees, capsules, drops or syrups for oral administration.

For rectal administration, it may be in the form of suppositories, and for parenteral administration, it may be in the form of an injection solution.0.19 to 5 q.
One dosage unit of 0.010y to 0.25y of active ingredient
Advantageously, the daily dose contains 0.010y to 1y of the active ingredient.

Some prescriptions for the medicament of the present invention are listed below, but the prescriptions are not limited thereto. Examples A to F A dragee core Derivative number 60.075g Sugar, lactose, talc, magnesium stearate, kaolin, starch, coating Sierra tac, pine resin, starch, gelatin, sucrose, tartrazine yellow, B tablet derivative number 90.050y Excipient Agents: Starch, dextrin, hydrated silica, pharmacopoeial gelatin, magnesium stearate, C Capsule derivative number 110.100y Excipients: Talc, lactose, magnesium stearate D Syrup derivative number 210.500f Excipients: Sweetness and add flavoring.

Appropriate amount 100mt
E Suppository Derivative No. 150.100f Excipient; Semi-synthetic Triglyceride F Injection Solution Derivative No. 260.050 Da Isotonic Solution Appropriate Amount 5ml The pharmaceutical of the present invention is suitable for human and veterinary use due to its important sedative and vasodilatory effects. Can be used in medicine.

The medicament is advantageously administered as a sedative to relieve emotional tension as a regular drug.

The drug exhibits a sedative effect and promotes physiological sleep.

Claims (1)

[Claims] 1. General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, R
_1 and R_2 represent hydrogen or together form an isopropylidene group, R_3 and R_4 are the same or different and represent a lower alkyl group or together with the nitrogen atom to which they are bonded; form a 4- to 5-membered saturated heterocyclic group, which heterocyclic group optionally contains a sulfur, oxygen or nitrogen atom as a second heteroatom, and the nitrogen atom is optionally an unsubstituted phenyl group or a halogen atom. , which may be substituted with a phenyl group substituted with a trifluoromethyl, lower alkyl or lower alkoxy substituent, and n represents 2 or 3] and physiologically acceptable salts thereof. 2 Claim 1 in which the halogen is chlorine or bromine
Pyridoxine derivatives described in Section. 3. The pyridoxine derivative according to claim 1 or 2, wherein the heterocyclic group is a morpholino group, a piperazino group, a pyrrolidino group, or a piperidino group. 4 5-[(β-morpholino-ethoxy)-methyl]-
2,2,8-trimethyl-4H-1,3-dioxolo(
4.5-c) Pyridine and its salts, 5-{[3-(4-
p-chlorophenyl-1-piperazinyl)-propoxy]-methyl}-2,2,8-trimethyl-4H-1,3
-dioxolo(4.5-c)-pyridine and its salts,
3-hydroxy-4-hydroxymethyl-2-methyl-
5-[(β-morpholino-ethoxy)-methyl]-pyridine and its salts, 5-{[3-(4-p-chlorophenyl-1-piperazinyl)-propoxy]-methyl}-3
-Hydroxy-4-hydroxymethyl-2-methylpyridine and its salts, 5-[(β-dimethylamino-ethoxy)-methyl]-2,2,8-trimethyl-4H-1.
3-Dioxolo(4.5-c)pyridine and its salts, 5
-[(β-dimethylamino-ethoxy)-methyl]-4
H-1,3-dioxolo(4,5-c)pyridine and its salts, 5-([2-(1-pyrrolidinyl)-ethoxy]
-methyl)-2,2,8-trimethyl-4H-1,3-
Dioxolo-(4.5-c)pyridine and its salts, 5-
[(β-piperidino-ethoxy)-methyl]-2.2.
8-trimethyl-4H-1,3-dioxolo(4,5-
c) Pyridine and its salts, 5-{[2-(4-phenyl-1-piperazinyl)-ethoxy]-methyl}-2.2
・8-trimethyl-4H-1,3-dioxolo(4,5
-c) Pyridine and its salts, 5-{[2-(4-o-chlorophenyl-1-piperazinyl)-ethoxy]-methyl}-2,2,8-trimethyl-4H-1,3-dioxolo(4, 5-c)-Pyridine and its salts, 5-{[2
-(4-m-chlorophenyl-1-piperazinyl)-ethoxy]-methyl}-2,2,8-trimethyl-4H-
1,3-dioxolo-(4,5-c)-pyridine and its salts, 5-{[2-(4-p-chlorophenyl-1-piperazinyl)-ethoxy]-methyl}-2,2,8-trimethyl -4H-1,3-dioxolo-(4,5-c)
-Pyridine and its salts, 5-{[2-(4-m-trifluoromethylphenyl-1-piperazinyl)-ethoxy]-methyl}-2,2,8-trimethyl-4H-1,3
-dioxolo(4.5-c)-pyridine and its salts, 5
-{[2-(4-p-tolyl-1-piperazinyl)-ethoxyl]-methyl}-2,2,8-trimethyl-4H
-1,3-dioxolo(4,5-c)-pyridine and its salts, 5-{[2-(4-o-methoxyphenyl-1-
piperazinyl)-ethoxy]-methyl}-2,2,8-
Trimethyl-4H-1,3-dioxolo-(4,5-c
)-pyridine and its salts, 5-[(1-dimethylaminomethyl-ethoxy)-methyl]-2,2,8-trimethyl-4H-1,3-dioxolo(4,5-c)-pyridine and its salts , 5-[(2-dimethylamino-propoxy)-methyl]-2,2,8-trimethyl-4H-1.
3-dioxolo-(4.5-c)-pyridine and its salts, 5-[(3-dimethylamino-propoxy)-methyl]-2.2.8-trimethyl-4H-1.3-dioxolo(4. 5-c)-Pyridine and its salts, 5-[(β-
dimethylamino-ethoxy)-methyl]-3-hydroxy-4-hydroxymethyl-2-methyl-pyridine and its salts, 3-hydroxy-4-hydroxymethyl-2-
Methyl-5-{[2-(1-pyrrolidinyl)-ethoxy]-methyl}-pyridine and its salts, 3-hydroxy-
4-hydroxymethyl-2-methyl-5-[(β-piperidino-ethoxy)-methyl]-pyridine and its salts,
3-hydroxy-4-hydroxymethyl-2-methyl-
5-{[2-(4-phenyl-1-piperazinyl)-ethoxy]-methyl}-pyridine and its salts, 5-{[2
-(4-o-chlorophenyl-1-piperazinyl)-ethoxy]-methyl}-3-hydroxy-4-hydroxymethyl-2-methylpyridine and its salts, 5-{[2-
(4-m-chlorophenyl-1-piperazinyl)-ethoxy]-methyl}-3-hydroxy-4-hydroxymethyl-2-methyl-pyridine and its salts, 5-{[2-
(4-p-chlorophenyl-1-piperazinyl)-ethoxy]-methyl}-3-hydroxy-4-hydroxymethyl-2-methyl-pyridine and its salts, 3-hydroxy-4-hydroxymethyl-2-methyl-5 -{[2-
(4-m-trifluoromethylphenyl-1-piperazinyl)-ethoxy]-methyl}-pyridine and its salts,
3-hydroxy-4-hydroxymethyl-2-methyl-
5-{[2-(4-p-tolyl-1-piperazinyl)-
ethoxy]-methyl}-pyridine and its salts, 3-hydroxy-4-hydroxymethyl-5-{[2-(4-o
-methoxyphenyl-1-piperidinyl)-ethoxy]
-methyl}-2-methyl-pyridine and its salts, 5-[
(1-dimethylaminomethyl-ethoxy)-methyl]-
3-hydroxy-4-hydroxymethyl-2-methyl-
Pyridine and its salts or 5-[(2-dimethylamino-
The pyridoxine derivative according to claim 1, which is propoxy)-methyl]-3-hydroxy-4-hydroxymethyl-2-methyl-pyridine and a salt thereof. 5 General formula (I): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 and R_2 represent hydrogen or together form an isopropylidene group, R_3 and R_4
are the same or different and represent a lower alkyl group, or together with the nitrogen atom to which they are bonded, represent a 4- to 8-membered
forming a saturated heterocyclic group with a member of , which may be substituted with a phenyl group substituted with a lower alkyl or lower alkoxy substituent, and n represents 2 or 3] and physiologically acceptable salts thereof; , chemical formulas, tables, etc. ▼ Pyridoxine derivatives with the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ Condensation of haloalkylamines [in the formula, to form a compound of the general formula (I) in which R_1 and R_2 together represent an isopropylidene group, and when it is desired to obtain a compound in which R_1 and R_2 represent hydrogen, the compound is characterized by treatment with an acid. Method for producing pyridoxine derivatives. 6. The method for producing a pyridoxine derivative according to claim 5, wherein the condensation is carried out in the presence of a concentrated aqueous solution of an alkali metal hydroxide. 7. The method for producing a pyridoxine derivative according to claim 6, wherein the condensation is carried out at 50 to 100°C. 8. The method for producing a pyridoxine derivative according to any one of claims 5 to 7, wherein the treatment with an acid is carried out at 20 to 100°C. 9. Together with physiologically acceptable excipients, the general formula (I
); ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, R_1 and R_2 represent hydrogen or together form an isopropylidene group, and R_3 and R_4 are the same or different and are lower alkyl groups. or together with the nitrogen atom to which they are attached, form a 4- to 8-membered saturated heterocyclic group, which optionally contains sulfur or oxygen as the second heteroatom. or containing a nitrogen atom, which nitrogen atom may be optionally substituted with an unsubstituted phenyl group or a phenyl group substituted with a halogen, trifluoromethyl, lower alkyl or lower alkoxy substituent, and n represents 2 or 3. A sedative, hypnotic and vasodilator agent characterized by containing a pyridoxine derivative and a physiologically acceptable salt thereof.