JPS58124776A - Novel piperazine derivative, its preparation and ameliorant for cerebral circulation containing the same - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI(R is H or lower alkyl) and a salt thereof. EXAMPLE:2-(4-Diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)ethanol. USE:An ameliorant for the cerebral circulation. PROCESS:A compound of formula II is reduced by any one of the general methods, e.g. reduction with a metallic hydride complex compound, catalytic reduction or reduction with a metal and an alkali, to give the aimed compound of formulaI. The reaction temperature is within the range of 0 deg.C- the boiling point of a solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel mold perazine derivative, a method for producing the same, and a circulation improving agent containing the same as an active ingredient.

A must for the activity of troublesome cells! Glucose and oxygen, which are major energy sources, are mainly supplied by the blood. Even if cerebral blood flow is interrupted for a few seconds, it can cause functional disorders, such as blood clots forming in cerebral blood vessels, and blood flow can decrease, causing vaginal stroke. It is also known that platelet aggregation reactions are involved in the process of thrombus formation.

Therefore, in order to prevent or treat septal circulation disorders, it is desired to develop a drug that has both an effect of increasing blood flow and an effect of inhibiting platelet aggregation.

Therefore, the present inventor conducted Eikura research for the purpose of developing such a drug, and as a result, it was expressed by the following general formula (I), (wherein 1 represents a hydrogen atom or a lower alkyl group). It was discovered that piperazine derivatives specifically dilate peripheral blood vessels, particularly vertebral arteries, to increase blood flow and have a platelet aggregation reaction.

As a compound structurally similar to the piperazine derivative (I) of the present invention, 2-(4-diphenylmethylpiperazinyl)- represented by the following formula (in the formula, R1 represents a hydrogen atom or a methyl group) 1-
Phenylethanol [1vJlk@l*vasm, Fl
@rimsTr, Nmm@km*1mm1@4゜Kkl
m, -Farm, lm5t, *8 a 89-100
(1972)) and 2-(4-diphenylmethylpiperazinyl)-1-methyl-1-phenylethanol [D 1 mlamd@8. Mu,, Get, Offam, 411
1.776) is known.

However, the above-mentioned literature does not report at all that these compounds have a secret circulation concentration-improving effect, and tests conducted by the present inventors have shown that the peripheral vasodilatory effect was extremely low, as described below. That is, in the compound (1) of the present invention, the presence of a hydroxyl group at the 4-position of the benzene nucleus of the phenylethyl group is important for the expression of the 111 effect.
The present invention was completed based on the surprising fact that even if it exists at the 2nd position, the effect is extremely small.

Accordingly, one object of the present invention is to provide novel intermediate piperazine derivatives and salts thereof useful as pharmaceuticals.

Another object is to provide a ninth novel method for producing wrinkle compounds.

Still another object is to provide a drug for improving collusion, which contains a piperazine derivative of formula (I) or a salt thereof as an active ingredient.

A piperazine derivative represented by the formula (1) [jiP,
! Examples of the lower alkyl group represented by include a methyl group, an ethyl group, and a gouvil group.

The compounds of the present invention are produced, for example, by reducing a carbonyl compound (group) according to the following reaction formula.

(In the formula, R has the same meaning as above) Raw materials of the present invention (
For example, the set is 4 to 1-diphenylmethylpiperaziy@
- produced by reacting human-xyacetophenone derivative surfaces.

Hereinafter, F margin (1') (In the formula, Xli represents an 84-hen atom, and 凰 has the same meaning as above.) In this reaction, the hydroxyl group of the compound of formula 0 is a commonly used protecting group such as a benzyl group. You can keep it for a while.

Moreover, the reaction can be carried out in the presence of a basic catalyst.

The reduction in the method of the present invention includes reduction with metal hydride complexes represented by sodium borohydride, aluminum lithium hydride, zinc borohydride, and aluminum borohydride; copper, cobalt, nickel; Catalytic reduction using , badge cum, palladium on carbon, platinum, platinum oxide, chloride, etc. in a hydrogen atmosphere under normal pressure or under pressure of several to tens of atmospheres: iron and acetic acid, zinc and hydrochloric acid, formic acid, Reduction with metal and acid using acetic acid etc.; Reduction with metal and alkali using cold zinc and sodium hydroxide; Meerv@
l+a -P@m1ll 纏srf) Reduction: For K, a reduction method commonly used to convert a carbonyl group to an alcohol, such as reduction with an alcohol, a metal such as sodium, and an alcohol, is employed.

The reaction solvent may be any solvent as long as it does not interfere with the raw materials and the reduction reaction, for example, nato9 human stomach furan, diethyl ether-based O ether*.

Alcohols such as methanol and ethanol; mixed solvents such as acetic acid and hydrochloric acid: water or molasses can be used. The reaction is carried out within the temperature range from super to °C to the boiling point of the solvent used, and the reaction time varies depending on the type of reduction method, but
#′ within hours! ! ends.

(The piperazine derivative of formula 13 can be converted into its salt by a conventional method.The salt may be any pharmaceutically acceptable salt, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, sulfuric acid, etc.) Acid, citric acid, fumaric acid, maleic acid ml,
Examples include salts such as 111 acid, di-toluenesulfone, and so on. (9) When R in formula (1) is a lower alkyl group, erythroid and threo stereoisomers exist, and the compounds of the present invention include both of these isomers.

Next, the results of testing the peripheral vasodilating effect, platelet aggregation inhibiting effect, and toxicity of the compound (1) of the present invention are shown.

The following compounds of the present invention and comparative compounds were used in the test.

Invention compound 1: 2-(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)ethanol-hydrochloride Invention compound 2: at-Elis E! -2-(4-diphenylmethylpiperazinyl)-1-(4-diphenylmethylpiperazinyl)propatool 1/21i petrate Invention compound 3: at-threo-2-(4-diphenylmethylviperazinyl) -1-(4-human axyphenyl) propatool/tartrate comparison compound 1: 2-(4-diphenylmethylpiperazinyl'l-1-(2-human xyphenyl)propertool/-hydrochloride comparison compound 2: 2- < 4.-diphenylmethylpiperazinyl)-1-phenylethanol dihydrochloride comparison Compound 3: 2-(4-diphenylmethylpiperazinyl)-1-methyl-1-phenylethanol dihydrochloride comparison Compound 4: Bendiclane fumarate (commercially available as a cerebral circulation improving agent) Comparative compound 5: Cinnarizine (commercially available as a cerebral circulation improving agent) Experiment 1 Peripheral vasodilatory effect Male and female dogs weighing around 2:10 was used. Anesthetized with bentoparbital sodium (35 wq/KSE, 1,000 m), the patient was fixed in the dorsal position, and under artificial ventilation (blood pressure and heart rate were measured) blood flow in the vertebral, femoral, and common carotid arteries was measured electromagnetically using an internal probe. It was measured with a flow rate needle (Nihon Kohden MF-27). The drug solution was administered 9 times to 18117 through a polyethylene cannier inserted into the brachial vein.

The results are shown in Table 1.

Table 1: Physiological saline solution, 1 distilled aqueous solution, and 10% tartaric acid aqueous solution.

Experiment 2 Platelet aggregation inhibitory effect on male Wistar rats weighing around 3,009 lbs.
0 W/Ni was orally administered, and 3 hours after administration, the animals were anesthetized with ether and blood was collected from the abdominal vena cava (using 3.8% sodium citrate as an anticoagulant). 100 Or of blood
P1at@l*t Rleh by centrifugation at pm for 10 minutes.
Plasmm (PRP), further 1 at 300 Orpm
Centrifuge for 0 min and P1at@l@t Peer Plam
mm (PPP) was collected.

ADP or collagen was added to the pap obtained above to induce aggregation, and plate red aggregation tracer (
Platelet aggregation was measured by nephelometry using FAT-4, a binary instrument), and the aggregation inhibition rate was determined by the following formula.

M: Maximum aggregation rate when the drug is administered B: Maximum aggregation rate when physiological saline is administered. The results are shown in Table 2.

Table 2 Experiment 3 Acute Toxicity Compounds 1 and 2 of the present invention were orally administered to male and female 8D rats weighing 150-200P and observed for 7 days. As a result, the LDsotf of both rats was 2000 capes/q or more. .

As is clear from the above experiments, the compound of the present invention has both peripheral vasodilating action and platelet aggregation inhibiting action, and exhibits superior effects compared to existing cerebral circulation improving agents.

The compounds of the present invention (11) can be administered either orally or parenterally, and dosage forms for oral administration include, for example, tablets, capsules, powders, granules, and tablets. The dosage form for use is an injection.

The usual excipients, disintegrants, binders, lubricants, dyes, diluents, etc. are used in the preparation of zeta straw.

Excipients include glucose, lactose, etc. Disintegrants include starch, sodium alginate, etc. Lubricants include magnesium stearate, paraffin sulfate, talc, etc. Binders include dimethyl cellulose, gelatin, etc. Polyvinylpyrrolidone and the like are used.

The dosage is usually 50w to 400w per day for adults, but it can be increased or decreased depending on the age and symptoms.

Next, examples and reference examples will be given and explained.

Reference example 1 2-(4-diphenylmethylpiperazinyl)-1-(4
-hydroxyphenyl)ethanone 2.52 t (10 mmol) of 1-diphenylmethylbiperazine and 1.11 t of triethylamine? (11 mmol) Improper Tools 30 IIl! 1, and add 2.15% of α-bromo-hydroxyacetophenone to this. (10 mmol) was dissolved and a solution of 9 isopropanol (20 m) was added. After leaving it at room temperature overnight, filter out the precipitated crystals.
By sequentially washing with Improper Tool, water, and Improper Tool, and drying, 3.271 g of crude crystals of 2-(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)ethanone were collected. 84.6%) was obtained.

1680an-' Nuclear magnetic resonance spectrum (CDCjs) a: 3.7
3 (2H, s, C horse C-0) 4.18 (IIIs @, pJCH-) 6.7-7.9
(14H, Peng, aromatic water*) 8.17 (IH, s, -Misaki-) Reference example 2 a) l-(4-benzyloxyphenyl)-2-(4-
diphenylmethylpiperazinyl) ethanone 1-Schiff x nylmethylbiperazine 7.56 ft (30 mmol) and triethyl aquine 3.339 (33 mmol) in ethyl acetate 90 sd .15SF (30 mmol) was added and stirred at room temperature for 45 minutes. Ice water 100-
was added and stirred for about 10 minutes. The precipitated crystals were collected by filtration, washed sequentially with water, ethanol, and ethyl acetate, and dried.
-(4-benzyloxyphenyl)-2-(4-diphenylmethylpiperazinyl)ethanone 12.5 P (yield -87, 4%) was obtained.

Theory p (148-151℃) lr Infrared absorption spectrum ν: 16855-1tmax Nuclear magnetic resonance spectrum (CNcz,) δ: 3.71 (2
H,s,CH鵞-C=O)4-23 (i Hp I
#phficI()5.0 7 (2H, s,
pbckl goose-〇-) 6.8~8.1 (19H, m
, aromatic water purple) b) 2-(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)ethanone 1
-(4-benzyloxyphenyl)-2-(4-diphenylmethylpiperazinyl)ethanone 12.5t (26 mmol) and anisole 2.1F (26 mmol) were mixed with acetic acid 37.5-47% hydrobromic acid. 126s-mixture-
The mixture was dissolved in water and heated under reflux for 1 hour. From now on, by washing the reaction mixture with ethers 200- and 50-
Remove acetic acid! Neutralized with 2N aqueous sodium hydroxide solution.

The separated organic matter was extracted with 120 d of ethyl acetate and washed with saturated brine. 13
After drying with aluminum, it was concentrated. When the residue is dissolved in Improper Tool 60- and left at room temperature, 2- (4-
The crude crystals of diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)ethanone were 6.28F (yield: 62
%) obtained.

In addition, this crude crystal was dissolved in ethanol 25-, and 01 g
If concentrated hydrochloric acid is added and left to stand, monohydrochloride crystals will precipitate. After reconverting the monohydrochloride of the kidney to the free base, the same operation was repeated again. 4.737 was obtained.

Reference example 3 2-(4-diphenylmethylpiperazinyl)-1-(4
-Hydroxyphenyl)propanone A solution of 12.69 (50 mmol) of 1-diphenylmethylbiperazine and 5.62 mmol of triethylamine in chloroform was heated under reflux.
B-tetramo p-hydro-U xyproofhenone 12.7F (
55z remol) glue proform solution in 2 hours,
The mixture was heated under reflux for 1 hour. Afterwards, the reaction mixture was concentrated and ether 200- was added to the residue. This was washed with water and saturated brine, and dried with anhydrous sulfuric acid (1) rum.

Chloroform:methanol concentration 100:1) to give crude 2-(4-diphenylmethylpiperazinyl) as a colorless oil.
-1-(4-hydroxyphenyl)propanone12. I
P (yield 60%) was obtained.

166551-' Nuclear magnetic resonance spectrum (CDC1,) δ: 1.2 e
(3H, a, J=6H1, C)l-CH,)3.9
9 (IH, q, x=6■, , c!!-cH,
)4.14 (IH,s, phlcH)6.43
(Ill, s, 0K) 6.7-8.1 (14H-ms aromatic water 11) Reference example 4 a) 1-(4-benzyloxyphenyl)-2-(4-
diphenylmethylpiperazinyl) propanone 1-diphenylmethylbiperazine 116F (50 mmol), -penzyloxy-alpha-mopribiofuenone 16.0y (50 mmol) and triethylamine 5.569 (55i I) mol ) Chloroform 10
Heat to reflux in Osd for 2 hours. The chloroform solution was then washed with water and saturated brine, and dried over anhydrous sodium sulfate. 11. Re-crystallize the crude crystals obtained by concentrating the chloroform solution from methanol. C11-(4-benzyloxyphenyl)-2-(4-diphenylmethylpiperazinyl)-vpanone 20.3P (collection vehicle 83X) was obtained.

mp 106-107℃ Nuclear magnetic resonance spectrum (CDCtI) J: 1.24
(3II, d, 1w7Hs -C1i-CHI
) 3.97 (IH, q, J=7Hz, 0K-CH))
4-18 (1i[,s*pJCTI)5-1
0 (2H-s I? h-CH goose-0-)6
．． 97-8.11 (19H, m, aromatic hydrogen) b) 2-
(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)propanone Hot acetic acid 27-[x-(4-benzyloxyphenyl)-
Dissolve 9.0f (18 mmol) of 2-(4-diphenylmethylpiperazinyl)propanone, and add 1 ml of concentrated hydrochloric acid to the solution.
3- was added. The reaction mixture was heated under reflux for 2.5 hours and then cooled to room temperature. Add ether 50- to this mixture, filter out the precipitated crystals, and wash thoroughly with ether. Crude crystals of the dihydrochloride of 8.6 were obtained. The crystals were oxidized with 30 m of 17 um aqueous solution and 100 m of ethyl acetate.
The mixture was stirred thoroughly, and then a saturated aqueous sodium hydrogen carbonate solution was added with an alkaline solution and stirring was continued. The ethyl acetate layer was separated, washed with water and saturated brine, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure to obtain crude 2-(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)propanone 6, IP (yield: 85%) as a colorless oil.

Example 1 2-(4-diphenylmethylpiperazinyl)-1-(4
-hydroxyphenyl)ethanol 2-(4-diphenylmethylpiperazinyl)-1-(4
-Hydroxyphenyl)ethanone 3.0F (7.8 mmol) was dissolved in methanol 501, and sodium borohydride 3.0F (79 tmol) was gradually added under cooling in an oven.9.

Thereafter, the mixture was stirred overnight in room IIFK, and methanol was distilled off under reduced pressure. Ether 100- was added to the residue, washed with water and saturated brine, and dried over anhydrous sodium sulfate.

The ether solution was concentrated, and the residue was purified by silica gel column chromatography (silica gel 90t, chloroform:methanol-100:1) to give 2-(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl). 2.4 t of ethanol (yield 79%) was obtained. When recrystallized from ethyl acetate-hexane, the melting point is 153-1.
White crystals with a temperature of 54.5° C. are obtained.

3400.2820.1620,160G.

1510.1450.1250.1150°1005.
830,750.710cPR-' Nuclear magnetic resonance spectrum (CDczl) J: 4.18 (IH,m,
pbBCdan) 4.59 (in, t, J 7H wealth, C
l-0R) & 50 (21Lbr@ad, *, 0HX2)
6-5 to 7-5 (141 [e wa - aromatic water purple) Elemental analysis calculated value % Analysis value % Carbon 77.29 77.09 Water 7.26 7.13 Nitrogen 7.21 7.22 Examples 2 2-(4-diphenylmethylpiperazinyl)-1-(4
-hydroxyphenyl)clopanol 2-(4-diphenylmethylpiperazinyl)-1-(4
-Hydroxyphenyl)propanone 4.8 F (12 mmol) was dissolved in methanol 50-, and sodium borohydride 5.0 F (132 mmol) was added to the solution under water cooling.

After the reaction was completed, 100 d of water was added to the reaction mixture, and the mixture was extracted with ether. The ether extract was washed with water and saturated brine, and dried over 17 um of anhydrous sulfuric acid. The ether solution was concentrated, and the residue was subjected to silica gel Kamura chromatography (silica gel 130?, μroform:methanol: 1:1) to give dt-threo-2-(4-diphenylmethylpiperazinyl)-1. -(4-Hydroxyphenyl) tetrahanol 1.44F (yield 36% d4-eryth--2-(4-diphenylmethylpiperazinyl)-
1-(4-human xyphenyl)furopanol 1.42
Obtain f (35% pickup). When recrystallized from benzene:n-hexane, the melting point of the threolyte is 179-180°C.
The erythro form is a white crystal with a melting point of 116-118°C.

Below'Ii White Example 3 2-(4-diphenylmethylpiperazinyl)-1-(4
-hydroxyphenyl)ethanol monohydrochloride 2-(4-diphenylmethylpiperazinyl)-1-(4
-hydroxyphenyl)ethanol 21.8P (56,
2 mmol) was added to the mixture in 112x1K of IN hydrochloric acid, and the mixture was vigorously stirred at room temperature for 2 hours, and a white solid was collected by filtration and washed with water. This white solid was suspended in 80° C. of water and heated and stirred at 75 to 80° C. for 40 minutes. The suspended white powder when heated was collected by filtration, washed with water, and dried to give 2-(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)ethanol monohydrochloride 22.0f! I got it.

mP 213-214°C (decomposition) Example 4 At-erythro-2-(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)panol 1/2 Tartrate was mixed with monoerythro τ -(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)propanol 9.8F (24(1-vol)
A hot solution of 3 o- of acetone was dissolved in tartaric acid 1.9
A 1N solution of F (13 mmol) dissolved in acetone 30- while hot! and gradually returned to room temperature. By filtering and drying the precipitated white crystals, Hashi was made into Erisida-2-(
4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)propanol 1/2 tartrate 8.8
I got an F.

rap　200~201℃(decomposition) Example 5 Formulation example (tablet) One tablet (220 capes) contains the following ingredients.

Active Ingredients 50 Lactoy, 10011F Starch 50y Magnesium Stearate 511F Hydroxypropyl Cellulose 15119
Example 6 Formulation Example (Capsule) One hard gelatin capsule contains the following ingredients (350 gq).

Active ingredient 4011F lactose
200w starch
7o Misaki Polyvinylpyrrolidone 5wII Crystalline Cellulose 35mg@17 Formulation Example (Granule) Granule 19 contains the following ingredients.

Active ingredient 200 Misaki Lacto-y,
450iIF corn starch
30 (lv Hydroxygprol cellulose 50v or more Procedural amendment (voluntary) November 2, 1982: Japan Patent Office Lξ Official permission Mr. Kazuo Sugi 1 Indication of π 1982 Patent Application No. 8028 2 Invention Name: New hyperazine derivative and its manufacturing method, and cerebral circulation concentration-altering agent containing the same 3 Relationship with the case of the person making the amendment Applicant's address: 2-2-3 Iwamoto-cho, Chiyoda-ku, Tokyo Name:
Nippon Chemifa Co., Ltd. Representative Akira Yamaguchi 4 Representative Director 6, 111 positive burning elephant #3 #l1 tatami mat "@Kiri no Hyōsei Keimon-" -7, II positive contents (1) Details of expenses , $4 page, line 8, "platelet aggregation effect" is corrected to "platelet aggregation inhibitory effect."

(2) m', 8th Jij%jiiT line "Aluminum borohydride" is corrected to "Lithium borohydride" (aIim, 10'jj, 3rd line from the bottom "Oxalic acid,
” and delete Ai.

(41ml, 15th jif, 2nd shot Correct rlOXJ stop to "5 islands".

(5) Same, page 32, line 11 [(yield a 6X) J stop [(yield 3 GX)
Correct it with J.

(6) r”s No. 32jj, second row 1 from the bottom (yield 35%
)" should be corrected to "(yield 295%) J.

(7) rl'rl, page III & 36, line 6
-” and corrected.

Claims (1)

[Claims] 1. A piperazine derivative represented by the following general formula (1) (in the formula, a wing represents a hydrogen atom or a lower alkyl group) and a salt thereof. 2. General formula (11) characterized in that it reduces a compound represented by general formula (I) (wherein, the trap represents a hydrogen atom or a lower alkyl group) 3. A method for producing a piperazine derivative represented by the following general formula (1), (wherein the wing contains a hydrogen atom or a lower alkyl group as an active ingredient) or a salt thereof. A characteristic cerebral circulation improving agent.