JPH02243658A - Nitrogen-containing hydroxy ethers and improver for cerebral function containing the same as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [X<1> to X<4> and Y<1> to Y<4> are H or X<1> and Y<1>, X<2> and Y<2>, X<3> and Y<3> and X<4> and Y<4> together represent single bond; A is H or methyl; Z is O or S; R<1> and R<2> are H, lower alkyl, aryl, 4-piperidyl, etc., or, together with N to which both are linked, represent 5- to 6-membered heterocyclic ring; n is 0-2; m, l and k are 0-1], ester or salt thereof. EXAMPLE:1-Amino-3-[(3,7-dimethyloctyl)oxy]-2-propanol. USE:An improver for cerebral function capable of exhibiting excellent antianoxic action with low toxicity. PREPARATION:An epoxy compound expressed by formula II is reacted with a nitrogen-containing compound expressed by formula III while being heated according to the reaction formula to afford the compound expressed by formula I. The reaction is normally carried out at about 80-200 deg.C temperature in the presence or absence of a solvent, such as methyl alcohol.

Description

[Detailed description of the invention] 1 degree 1 "Lq 泗" Shimaru! The present invention provides novel nitrogen-containing hydroxy ethers or pharmacologically acceptable esters or ammonium esters thereof useful as pharmaceuticals.
, and a brain function improving agent containing the same as an active ingredient.

Brain function improving agents are drugs for treating acute or chronic cerebral ischemia, cerebral hypoxia, improving cerebral circulation, cerebral metabolism, and anti-epileptic disease. submembranous hemorrhage,
Cerebral ischemia caused by transient ischemic attacks, cerebrovascular disorders such as hypertensive encephalopathy, cerebral edema, US trauma, etc.
It improves or slows down the progression of brain tissue/function damage caused by cerebral hypoxia, and improves the prognosis of chronic cerebral circulation/metabolic disorders or senile dementia.

BACKGROUND OF THE INVENTION In recent years, as society has become more stressful, patients suffering from hypertension, stroke, diabetes, etc., which were traditionally considered diseases of the elderly, have been decreasing in age to middle-aged and young people, even to N1 children. Moreover, as the population continues to age, the number of patients suffering from these diseases is expected to increase further in the future. Among these, meclofenoxate hydrochloride, CD
P-choline, calcium fobantenate, gamma-aminobutyric acid, nicardipine hydrochloride, idabenone hydrochloride, etc. are used clinically.

The present inventors have also synthesized various compounds, discovered amino alcohols that have excellent brain function improving effects, and have applied for a vertical writing ζ patent (JP-A No. 63-60925; 179850). In addition, 2-acyloxypropylamine derivatives have been disclosed as therapeutic agents for heart and circulatory system diseases (Japanese Patent Application Laid-Open No. 63-48250).
.

Problems to be Solved by the Invention The effects of clinically used cerebral circulation/metabolism improving drugs are not necessarily pronounced, and some have problems in terms of toxicity. Currently, there is a desire to develop a drug that has the same properties and is highly safe.

Furthermore, the compound described in JP-A No. 63-48250 does not have a brain function improving effect, as is clear from the test examples described below.

Therefore, one object of the present invention is to improve brain function.
The object of the present invention is to provide a novel compound that has various pharmacological effects and is highly safe. Another object of the present invention is to provide a brain function improving agent containing such a novel compound as an active ingredient.

Ninth Means for Solving the Problem The present inventors have synthesized various compounds using the intermediate raw materials for amino alcohols described in the above-mentioned JP-A-63-60925 and JP-A-63-179850. As a result of nine evaluations, we discovered nitrogen-containing and droxyethers that have an excellent effect on improving brain function, leading to the present invention.

According to the present invention, the above object can be achieved by (1) the general formula [where xl
and Yl each represent a hydrogen atom or take together to form a single bond; r and Yl each represent a hydrogen atom or take together to form a single bond; K and each represent hydrogen; X4 or p each represents a hydrogen atom or together form a single bond; 6A represents a hydrogen atom or methyl; 2 represents an oxygen atom or a sulfur atom, R1 and R1 are the same or different hydrogen atoms, an optionally substituted lower alkyl group, an optionally afl-substituted aryl group, an optionally substituted 4 −
represents a piperidyl group, pyridyl group, pyridylcarbonyl group or isoquinolyl group, or together with the cell atom to which they are bonded, t! La- is 5 or 6
form a 1M elementary ring, and 1 to 3 groups selected from this group are
R3 represents a hydrogen atom, and each lower alkyl which may be substituted represents O or an integer of 1.

] or a pharmacologically acceptable ester or salt thereof [hereinafter, these compounds may be collectively referred to as nitrogen-containing hydroxyethers (I)], and ■ the nitrogen-containing hydroxy ether This can be achieved by providing a brain function improving agent containing as an active ingredient.

In the above general formula (I), the optionally substituted lower alkyl group represented by R1 and W is a lower alkyl group such as a methyl group, an ethyl group, a propyl group, a butyl group, or a hydroxyl group, a morpholino group, a phenyl group, Examples of the lower alkyl group having a substituent such as a pyridyl group include a phenyl group, a 4-hydroxyphenyl group, a 2-methoxyphenyl group, and an optionally substituted aryl group. Examples include rimethoxyphenyl group and naphthyl group, and examples of optionally substituted 4-piperidyl group include 4-piperidyl group and N-methyl-4-
Examples include piperidyl group, N-benzyl-4-piperidyl group, etc. 6 Also, as a heterocycle in which the number of members formed by R1 and R1 together with the base atom to which they are bonded is 5 or 6. and so on. The optionally substituted alkyl group represented by R1 includes methyl group, ethyl group, propyl group, butyl group, diphenylmethyl group, 2-methoxypendino νi, 3,4.5-)rimethoxypenzyl Examples of the aryl group which may be substituted include phenyl group, 4-poxyphenyl group, 2-methoxyphenyl group, 3゜4.5-
Examples include trimethoxyphenyl group and naphthyl group.

The following are representative examples of the nitrogen-containing and droxyether represented by the general formula (I).

1-Amino-3-((3,?-dimethyloctyl)oxy)-2-10panol [Compound (I)) 1-((3
,7-dimethyloctyl)oxy]-3-(methylamino)-2-propatol [Compound (2)] 1-(diethylamino)-3-((3,7-dimethyloctyl)oxy)-2- 10 panol [compound-(phenylamino)-z-10 panol [compound 1-[(3,7-
[dimethyloctyl)oxy]-3-(2-pyridinylamino)-2-propatur1-((3,7-dimethyloctyl)oxy]-3-(N-methyl-N-nicotinoylamino)-2] -(diethylamino)-3-((3,
7-dimethyloctyl)oxy]-2-propatool[
Compound (3)] ]-((3,7-dimethyloctyl)oxy]-3-(
1-pyrrolidinyl)-2-propatol [compound (14) ] l H-1.2.4 triazole-]-yl) 2-probanol [compound mark] 4-methylbiperazine-1-inole)-2-7'H-imidazole-1 monoyl)-2 [3.7 monodimethyloctyl )oxy]-3 Globanol [Compound (16)) 4-diphenylmethylpiverazin-1-yl)oxy]
-3-(1H-imidazol-1-yl-2-propanol [compound α] Globanol [Compound Q3] cy)-3-( IH-imidazol-1 -yl) l [3.7-dimethyl-2.6-octadienyl)[5,9.13-}limethyltetradecyl)oxy]- 3-(zH-imidazol-l-yl)-3-(H-imidazol-l-yl)-2 Probanol [Compound @] l[6.10-dimethyl-3. 5. 9-Undecatrici)-3-(IH-imidazol-1-yl)en-2-yl)oxy]-3-(1H-imidazol-1-yl)-2-probanol [Compound M] [6.10-! / Methinole-2-Undecynole) Oquine]
-3-biperidino-2-globanol [compound [3.7-dimethyl-2.6-octadienyl (Inc.)] thio] -3-(lH-imidazole-1 monoyl) -2-probanol [compound ■] [2 ,6.10-trimethynoleundecinole)oxy]l H-imidazol-1-yl)-2-tetra and draw2H-1,4-thiazin-4yl)-2-
Probanol [Compound α] [4,8.12-trimethyltridecyl)oxy] IH imidazoleyl)-2-pro1,4-dihydro-2-methyl-4-oxoquinol-1-yl)-2-globanol [ Compound ■] Pharmacologically acceptable esters of nitrogen-containing and droxyether represented by general formula (1) include, for example, esters of lower fatty acids such as acetic acid, propionic acid, butyric acid; valmitic acid, linoleic acid, These include esters of higher fatty acids such as oleic acid and stearic acid, esters such as minicotinic acid, benzoic acid, phosphoric acid, monomannosyl honuphaate, etc., and pharmacologically acceptable salts include hydrochloric acid, sulfuric acid, etc. Salts of mineral acids; salts of organic sulfonic acids such as methanesulfonic acid, P-)luenesulfonic acid; organic carboxylic acids such as acetic acid, propionic acid, succinic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, etc. Examples include acids.

The nitrogen-containing hydroxyether represented by the general formula (I) can be produced, for example, by the following method.

(n) (III) (In the above formula, Xl, yt, door, yt, X", Y",
X4, Y4, A, ZlRl, W, and l, m, and n are as defined above. ) This method involves reacting an epoxy compound represented by the general formula (n) with a nitrogen-containing compound represented by the general formula (III) under heating, or reacting a nitrogen-containing metal compound represented by the general formula (III). Alkali metals such as lithium, sodium, potassium; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; methyllithium,
After conversion to the corresponding metal nitrogen-containing compound by reaction with an organolithium such as copyllithium or phenyllithium; or a Grignard reagent such as methylmagnesium chlophyte, methylmagnesium chlophyte, ethylmagnesium chloride, or ethylmagnesium chloride. , the metal nitrogen-containing compound and general formula (II)
This is carried out by reacting an epoxy compound shown in The reaction between the epoxy compound represented by general formula (II) and the nitrogen-containing compound represented by general formula (III) is carried out in the presence of an inert solvent such as methyl alcohol, ethyl alcohol, tetrahydrofuran, dioxane, toluene, dimethylformamide, etc. Or normally 80-200 in the absence
Perform at a temperature of °C. The amount of the nitrogen-containing compound used is about 1 to 5 moles per mole of the epoxy compound. When the boiling point of the nitrogen-containing compound used is lower than the reaction temperature, it is preferable to carry out the reaction under pressure. Further, the nitrogen-containing metal material can be used even in a state containing water. The reaction time varies depending on the reaction temperature, but is usually about 1 to 24 hours. A reaction line for converting a nitrogen-containing compound represented by the general formula (In) into a corresponding metal nitrogen-containing compound, and converting the nitrogen-containing compound into an equimolar amount of an alkali metal hydroxide, alkali metal, organolithium or Grignard reagent according to a conventional method. (by reacting with). The reaction between the obtained metal nitrogen-containing compound and the epoxy compound represented by the general formula (II) is the reaction between the epoxy compound represented by the general formula (II) and the nitrogen-containing metal compound represented by the general formula (III). Approximately 0 to 100℃ as reaction temperature
The same procedure can be performed except that the temperature of .

The epoxy compound represented by the general formula (II) used as a raw material can be produced, for example, by a method similar to that described in JP-A-64-115307. This method is based on the general formula (in the above formula, Xl, Yl, Xl, Y snow, Xl, Yl,
X4, Y4, Z, A, and lSm and n are as defined above. ) to sodium hydride, potassium hydride, sodium amide, LD
Add an alkali metallizing agent such as A (lithium diisopropylamide) to alcoholade or thiolate,
By reacting this with shrimp chlorohydrin or shrimp bromohydrin, an epoxy compound represented by general formula 0 can be produced.

The compound can be separated from the reaction mixture containing the nitrogen-containing formula (I) and droxyether obtained by the above method, for example, by pouring the reaction mixture into water, saturated saline, etc., and adding diethyl ether to the reaction mixture. , dichloromethane, etc., and the extract is washed with water, sodium bicarbonate, etc., dried over anhydrous magnesium sulfate, etc., the f8 peak is distilled off, and the residue is subjected to vacuum distillation or column chromatography. can be done.

Next, test examples regarding the pharmacological properties of nitrogen-containing hydroxyethers (I) will be shown.

Test Example KN Nosiddy male mice (5 to 6 weeks old, 10 mice per group) were used. A predetermined amount of the test compound was orally administered to the mice.
After 0 minutes, 3.1 y/y of potassium chloride was administered intravenously. Mice that did not stop breathing even after 180 seconds or more had passed after the end of potassium cyanide administration were counted as survivors, and the survival rate was determined. As a comparative compound, JP-A-63
(±)-1-octadecyloxy-3-biperidino-2-globyl acetate and dolochloride described in Example 1a of Publication No. 48250 were used. The results are shown in Table 1.

Control compound (8) Compound (9) Compound (lO) Compound (11) Compound (14) Compound (16) Compound (19) Compound (20) Compound (21) Compound (24) Compound (25) Compound (26) Compound (27) 1*1 table 0/10 3/10 6/10 3/10 3/]0 7/10 5/10 8/10 5/10 4/10 4/10 8/10 4/10 6/10 30.0 60.0*Book 30.0 30.0 ? 0.0 * Shin 50.0 * Umbrella 80.0 * Jail 50.0 Umbrella * 40.0 * 40.0 Kushi SO, O ** 40.0 * aO, O * Fuku x P < 0.05 Umbrella fist P (0,01 As is clear from Table 1, the compounds of the present invention exhibit excellent anti-anoxia effects.

Thus, the nitrogen-containing hydroxyethers (I) have nine excellent properties as a brain function improving agent.

It was confirmed in toxicity tests that nitrogen-containing hydroxyethers (I) have low toxicity. For example, compound (1)
Acute toxicity value (LDio (ddy mouse,
Body fi 20 to 30], - group 10 animals, oral administration)] were all 2000 ■/# or more. 1+, the toxicity was low even when administered intravenously, and the hepatotoxicity after short-term continuous administration was also low.

Based on the above test results, nitrogen-containing hydroxyethers (
I) can be used as a drug for the prevention and/or treatment of various brain dysfunctions associated with abnormal regulation of coordination in the brain, that is, as a brain function improving agent.

For example, numbness and blurred vision caused by head trauma, brain surgery, cerebrovascular disorder, etc.; hyper- or hypothyroidism, parathyroid disease, Wilson's disease, liver disease, hyperlipidemia, hypoglycemia, hypercalcemia. Dementia and blurriness caused by endocrine and agglomerative diseases such as hypocalcemia, Cushing's syndrome, hypopituitarism and urinary toxicity; Dementia caused by hypoxia such as cardiopulmonary disease and anemia; Pocket: Dementia caused by infectious diseases such as cerebral membrane tumors, bacterial meningitis, tuberculous meningitis, syphilis, and brain parasitic diseases. It exhibits excellent therapeutic effects when used to prevent and/or treat dementia, blurred vision, etc. caused by widespread parenchymal lesions in the central nervous system.

When using nitrogen-containing hydroxyethers (I) for the prevention and/or treatment of brain dysfunction as described above, the effective dosage depends on the purpose of administration, the method of administration, and the symptoms, body weight, and age of the patient to whom it is administered. Although it can be varied widely depending on gender, the judgment of the treating physician, etc., in the case of humans, it can generally be in the range of 30 to 2000 mg per day, preferably in the range of 50 to 600 + a97 days,
This dosage can be administered once a day or in divided doses.

The method of administration may be either oral or parenteral, and examples of parenteral administration include intravenous administration, intravascular administration such as intraarterial administration, intramuscular administration, intraperitoneal administration, intramedullary administration, and rectal administration. The following method can be used.

Therefore, when administering nitrogen-containing hydroxyether M (1)', nitrogen-containing hydroxyether (I)
together with a suitable pharmacologically acceptable diluent or carrier, and in a dosage form suitable for the method of administration, such as tablets, granules, powders, coated tablets, hard capsules, soft capsules, syrups. It can be formulated into a form suitable for oral administration in the form of a tablet or the like. Furthermore, they can be formulated into suitable formulations (injections, drops) for injection or infusion administration, for example suspensions, solutions, oil-based or aqueous emulsions.

Pharmacologically acceptable liquid or solid diluents or carriers that can be used to prepare such dosage forms include those commonly used in formulating the above-mentioned types of drugs. Examples include syrup, gum arabic, gelatin, sorbitol, towgacanth, polyvinylpyrrolidone, magnesium stearate, tartar, polyethylene glycol-I
Examples include silica, lactose, sugar, corn starch, calcium phosphate, glycine, potato starch, calcium carboxymethylcellulose, sodium furyl sulfate, water, ethanol, glycerin, mannitol, and phosphate buffer.

In addition to the pharmacologically acceptable diluent or carrier as exemplified above, the drug containing nitrogen and droxyethers (I) may optionally contain other auxiliary agents commonly used in the pharmaceutical field, such as colorants. Other adjuvants such as agents, flavoring agents, flavoring agents, preservatives, solubilizing agents, suspending agents, dispersing agents, etc. may further be included.

Drugs containing nitrogen-containing hydroxyethers (I) can be prepared in the form of fixed melon dosage forms such as tablets, tablets, coated tablets, ampoules, etc. as exemplified above, or in multi-dose containers. It can be housed in a good shape.

Depending on the form of the drug, the nitrogen-containing hydroxyether (I) is generally 0.01 to 5011196,
It can be contained preferably in a concentration of 0.1 to 20% by weight.

EXAMPLES The present invention will be explained below using examples. Note that the present invention is not limited to these Examples.

Reference examples 1 to 10 for margin under varnish 200ynA with stirrer, cooler and thermometer! After purging the volumetric flask with nitrogen, add 1.5 ml of sodium hydride.
2 g L 38rrunol) and dry'lHF 1
00 trd and keep the internal temperature at 0℃ 3,
7-dimethyl-octyl-1-ol 5 g (31,
6 mmol IJ was added dropwise, and the mixture was stirred for 1 hour while keeping the internal temperature at 0°C. After stirring, add 5.21 g of shrimp bromohydrin (38
mmol) was added dropwise over 30 minutes, and the mixture was stirred for 2 hours, followed by reaction. After the reaction, one reaction solution was poured into ice water, transferred to separation liquid a-), and extracted with diethyl ale. The extract was washed three times with 2 equivalents of water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain 1-(tz, a-
Epoxypropylene) -3,7-dimethyloctane 4.0 s g t? It's G.

Yield 60% FD-Mass Spectrum/z): 2
14iAl”) UIJCI 3.

'fl-NMli spectrum (90Mtiz) δ
11M8'0.84 (d, J=711z 9H)
%0.93-1.70 (rn, 1oii).

2.37 (dd, J = 311z and 611
z, ILL), 2.5 to 2.65 trt1.11i,
2.8~3.0 (tn, Ikln, 3.15~3.6
(m.

In the above method, 3,7-dimethyl-octyl-1
- Terpene alcohols shown in Table 2 (I
Epoxy compound (II) shown in Table 2 was obtained by performing the same reaction and pongee-making operation using V). The yield and physical properties of the product are shown in Table 3.

Lower margin of construction section 3 Table Example 1 [Compound u41] 3.87 g of imidazole (56.9H track 01
) and 5 orall of toluene were weighed out and one reactor was heated to reflux the toluene. Into this, 4.06 g of 1-((2゜3-epoxypropyl)oxy)-3,7 dimethyloctane (19wrnoN was added to toluene in a total amount of 20rI).
The solution was diluted with Le and added dropwise over 20 minutes. More tFR after completion of dripping? The reaction was stirred for a while, and after one reaction was completed, the reaction solution was allowed to cool and was poured into 100 ml of water, etc.
Extracted twice with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue from the pot is subjected to silica gel column chromatography.
-((3,7dimethyloctyl]oxy)-3-(lk
4 l-imidazol-2-purpanol [compound 0 gradient]
．． 29j (15,2nllllO)-Mass spectrum (n/z): 80% yield.
282-(M)t3L)C13゜'li-NMil spectrum (90Mfiz)
811M8 ”0.80 (d, J=6.6Hz, 9H
), 0.92-1.88 (m, 10113.3.05-
3.58 (m, 411), 3.72-4.22 (m, 3
kir, 4.52~5.05 (broad, im)
, 0.85 (s, 111).

6.88 (8,111 J, 7.38 (8,1) Example 2 [Compound (3)] A stirrer, a condenser and a thermometer were attached. 1-((2,3-epoxy provil)oxy)
-3,7 dimethyloctane 1.0 g (4,67ro
mol) and 10rrLl of isopropyl alcohol. Dimethylamine 0.64 g L 7.01 mmol while maintaining the internal temperature of the reactor between 5°C and 15°C
5096 aqueous solution) was slowly added dropwise. After the dropwise addition was completed, the reaction was continued by stirring for an additional hour while maintaining the same temperature. After distilling off the solvent, the reaction solution was added to water and ThR
The extract was extracted three times with 30 ml of diethyl ether, and the organic 7 layer was washed three times with 1 equivalent of... and dried over anhydrous magnesium sulfate. After drying, the solvent was distilled off, the residue was subjected to silica gel column chromatography, and then distilled on a Kugelrohr to obtain 1-(dimethylamino)-3-(3,7-dimeloctyl]oxy]-2- 0.50 g of Propatool [Compound t31] was obtained. Yield 41% b, ρ, 130'O to 150°C 10.2 degrees Ml (distilled on Kugelrohr) FLJ-Mass spectrum Lm/z): 259
(M+)(31J013゜'H-NMfi spectrum (90Mllz)δn
M8 '0.80 (d, J=611z, 9M), 0.
95-1.72 (rn, l0H), 2.2 (s, fiH
L 2.23(+n, 21(), 2.5~3.I L
broad.

1) 1), 3.3~3.55jm, 4kl), 3.6~
3.9 Lm, 1k:i) Examples 3 to 5 The epoxy compound (It) shown in Table 4 and the nitrogen-containing compound Lm) were reacted in the same manner as in Example 2, and then treated in a silica gel column. By subjecting them to purification by chromatography, the corresponding nitrogen-containing terpene alcohols represented by the general formula (I) were obtained. The yield and physical properties of the product are shown in Table 5.

Example 6 [Compound 06] A stirrer, a condenser and a thermometer were attached. 1.05 g of imidazole (15,4
mrrto, 1-(t2.3-epoxybrobyrin-o)-3,7,11 trimethifredododecane 1.1
g (4,82i 0 mouths and 30rrLl of toluene were weighed out, one reactor was heated, and the reaction was carried out for 2 hours under toluene reflux.

After the reaction was completed, the reaction solution was allowed to cool, poured into 100-100 ml of water, and poured twice with an equal amount of diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography and roughy, and then distilled using a Kugelrohr MW to obtain 1-((
3,7,11-trimethyldodecyl)oxy)-3-(
III-imidazol-1-yl)-2-propatol [compound αQ] 1.05 g (2,98 mrno obtained. Yield 6296 m, p 200-250°C 10.21
skig tkugelrohr bath temperature'l)-Mass
Spectrum (m/z): 352 (M”) (j
DOls.

In-NMk spectrum (90Mfiz) δnM8
'0.82 (d, J=6Hz, l 211
), 0.93-1.78 (m, 17H), 2.
95-3.55 (m, 4M), 3.65-4.
25 L m, 31i), 4.4-4.9 L
broad, l1l), 6.8(s, IR
J.

6.87L8. ILi), 7.3t8. ll1) Examples 7 to 27 After the reactions were carried out, the separation operations shown in Table 6 were carried out to obtain the corresponding nitrogen-containing terpene alcohols represented by the general formula (I). Table 7 shows the product yield, physical properties, and separation operations.

The epoxy compound LII) and the nitrogen-containing compound (III) shown in Table 6 below were prepared in the same manner as in Example 3. 2.74 g of shrimp bromohydrin (20mm01
) and 20 ml of ethyl alcohol, and while keeping the internal temperature at 0°C to 10°C under water cooling, add 3.0 g of 3.7-dimethyl-2.6-octarenine-1-thiol.
L 17.6 mtno order, sodium hydroxide 0.78
A mixed solution of 10 ml of ethyl alcohol and 10 ml of 7IC was slowly added dropwise to No. 9 (No. 19, 4) to cause a reaction.

After the dropwise addition was completed, stirring was continued for 1 hour at the same temperature, and then ethyl alcohol was distilled off under reduced pressure. Pour the remainder of the pot into 20mJ of water and 30rrL of diethyl ether! Extract 3 times with...
did. After washing the organic layer twice with 1 equivalent amount of water,
It was dried over anhydrous magnesium sulfate, and the solvent was distilled off.

The residue from the pot (1.0 g) contains 0.779 piperidine (8,
The mixture was weighed into a 50 mJ eggplant flask equipped with a condenser and 20 ml of toluene, and reacted for 3.5 hours under toluene reflux. The reaction solution was poured into cooled condensate water, transferred to a separating funnel, and added with 30 ml of diethyl ether.
The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography and then distilled on a Kugelrohr to obtain 1-(3,7-dimethyl-2,6-octagenyl λthio)-3-(xH-imidazol.l-yl).
0.91 g of -2-propatool [compound] was obtained. Yield 66%b, p-170℃~180℃/0.1 rr
rmklg (Kugerrohr kettle temperature) k' 1)-M a s s spectrum (m/z
) : 31 t (M+) CDCI.

'1i-shti+ spectrum (90MJllZ)
δJ=LM8'1.17~1.77 Lrn,
1511no, 1.9~2.1 (to, 411
), 1.9-2.7 (m, 711re 2.47 (
d, J=4.5flZ, 2M), 3.21 (
d, J = 7.511z, 2ti), 3.5~
3.9 (ru, IM).

4.9-5.4 (m, 2H) Example 29, which shows a formulation example containing compound (9) as an active ingredient Capsule Compound f91 5 g Microcrystalline cellulose 80 g Corn starch 20 g Lactose
22Q total 'm
130 g The above ingredients were granulated by a conventional method and filled into 1,000 capsules of hard gelatin capsules. One capsule contains 915 mg of compound.

Example 30 Powder compound (9150Q microcrystalline cells 400g corn starch 550g total 1k
1.000g compound (9
) was dissolved in rough seven tons, then adsorbed onto microcrystalline cellulose, and then dried. Mix this with corn starch and prepare the compound (9) as a powder by a conventional method.
A 20x powder was prepared.

Example 31 Tablet Compound (9) 5 y
corn starch tog milk
Sugar 2OQ carboxymethylcellulose calcium
10g is crystalline cellulose
409 Polyvinylpyrrolidone
5g total amount 10
0 Q Compound (9) was dissolved in 77 tons, and then this w
After being adsorbed onto th-bound A cellulose, it was dried. Corn starch, milk eg, and carboxymethyl cellulose calcium were mixed with this, and then an aqueous solution of polyvinylpyrrolidone was added as a binder to form granules in a conventional manner. After adding Merck as a lubricant and mixing it,
Each tablet was compressed into 100 mg tablets. Compound I in one tablet
9) Contains 5H.

Example 32 Injectable compound (9110Q Nikkol 1ieu-60 (Nikkol Chemical Co., Ltd. product name) 37 g Sesame oil
2g sodium chloride 9g propylene glycol
401J phosphate buffer (0.1M, p
f16.0) 100 g Distilled water Total amount 1,000 g Compound (9), 1 U of N1kko (J-60, sesame oil and half the amount of propylene glycol were mixed and dissolved by heating at about 80°C, and phosphoric acid was added to this mixture. Distilled water in which a buffer solution, sodium chloride, and propylene glycol had been dissolved in advance was heated to about 80° C. and added to form an aqueous solution with a total volume of 1.000 ynJ.

This aqueous solution was dispensed into 2 ml ampoules, which were sealed and then heat sterilized.

One tube contains 9120 mg of compound.

Effects of the Invention According to the present invention, novel nitrogen-containing hydroxyethers (Il), which are useful as medicines, are provided. It has excellent properties as a improving agent.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, X^1 and Y^1 each represent a hydrogen atom or together form a single bond, ^2 and Y^
2 each represents a hydrogen atom or together form a single bond; X^3 and Y^3 each represent a hydrogen atom or together form a single bond; X^4 and Y^4 each represents a hydrogen atom or together form a single bond; A represents a hydrogen atom or a methyl group; Z represents an oxygen atom or a sulfur atom; R^1 and R
^2 may be the same or different, and each represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted 4-piperidyl group, a pyridyl group, a pyridylcarbonyl group, or an isoquinolyl group. or together with the nitrogen atom to which they are bonded, form a heterocycle having 5 or 6 members,
Here, the heterocycle is -O-, -S-, ▲ has a mathematical formula, chemical formula, table, etc. ▼, ▲ has a mathematical formula, chemical formula, table, etc. ▼, -CH_2CH_2-, ▲ mathematical formula, chemical formula, table, etc. It may have 1 to 3 groups selected from the group consisting of ▼, -CH=N-, and ▲Mathematical formulas, chemical formulas, tables, etc.▼, and R^3 is a hydrogen atom, unsubstituted represents an optionally substituted lower alkyl group or an optionally substituted aryl group; m represents an integer of 0 to 2; m, l and k each represent an integer of 0 or 1; ] A nitrogen-containing hydroxyether or a pharmacologically acceptable ester or salt thereof. 2. A brain function improving agent comprising the nitrogen-containing hydroxyether according to claim 1 or a pharmacologically acceptable ester or salt thereof as an active ingredient.