JPH0175A - Peripheral circulation disorder treatment agent - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a therapeutic agent for peripheral circulation disorders. More specifically, the present invention is based on the following general formula [wherein R1 is a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group, R2 is a hydrogen atom or a lower alkyl group, and A is a hydrogen atom or a lower alkyl group, phenyl group or styryl group which may have a substituent). ] A therapeutic agent for peripheral circulation disorder containing a compound represented by the following and salts thereof as active ingredients.

The compound of the present invention represented by formula [I] directly above the foreskin was previously synthesized by the present inventors, and has been reported to have a lipid and lipid peroxide lowering effect, a hypoglycemic effect, a platelet aggregation suppressing effect, etc.
-168180), and has been found to have a memory-enhancing effect (Japanese Unexamined Patent Publication No. 144319/1983), making it a useful compound as a medicine.

■ I ゛. ´ Many of the conventional therapeutic agents for cerebral circulation disorders have a rapid rate of disappearance from the blood and a short duration of action. The compound of the present invention is
In the case of oral administration, the absorption is extremely good and the rate of disappearance from the blood is slow, so the blood concentration after administration remains stable for a relatively long period of time.

The increase in local cerebral blood flow reached its maximum 30 minutes after administration, and the effect was observed for over 4 hours thereafter, indicating excellent persistence. Furthermore, the present inventors have also found that intravenous administration has a similar persistence of action and is useful for the treatment of cerebral circulation disorders, as well as other peripheral circulation disorders, thereby completing the present invention. reached.

When examining the pharmacological effects of conventional therapeutic agents for cerebral circulation disorders, the effects are often observed in animals under anesthesia or under artificial respiration through galamin immobilization. , it cannot necessarily be said that it reflects the physiological state.

Therefore, the present inventors used a hydrogen clearance method to place platinum electrodes in advance in the posterior sigmoid gyrus (Posterior sigmoid gyrus) of the cerebral cortex.
t, Sigmoid G,).

nG, ) and the deep hippocampal (Hil) po.
campus) t Jii gdala (AmYgdala),
The compound of the present invention No.
, 1 and No. 2 are regional cerebral blood flow (r-CBF; re
gional Cerebral Blood
Flow) was investigated. Also,
In particular, by implanting catheters in the femoral artery and vein, blood pressure, PH1 blood gas components, and blood sugar levels were also analyzed.

Furthermore, the femoral artery blood volume was measured using anesthetized cats, and the effects of compounds Nos. 3 and 4 of the present invention were investigated.

By the above method, the compound of the present invention has an excellent effect of increasing peripheral blood flow, and is therefore useful as a therapeutic agent for peripheral circulation disorders. In particular, based on the following diseases (improvement of various symptoms, i.e. after-effects of cerebral infarction, after-effects of cerebral hemorrhage, after-effects of stroke, encephalomalacia, cerebral floaters, Bersher's disease, Raynaud's syndrome 1 intermittent limpetia, acute peripheral arterial embolism, and elderly) Suitable for treatment of sexual hearing loss, etc.

When the peripheral circulatory disorder therapeutic agent of the present invention is orally administered to adults, the daily dose is 0.05 to 10 g, preferably 0.
．． It is used in the range of 2 to 3.0 g, and in the case of intravenous injection, it is preferably 0.01 to 2.0 g per day.
It is used in a range of 5 to 0.5 g.

For application, it is formulated by means commonly used for oral administration and injections.

That is, in the case of oral preparations, carriers for preparation include, for example, lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, cellulose derivatives, or gelatin (depending on the auxiliary agent used, and at the same time stearic acid). Magnesium is added as a lubricant. In some cases, a lubricant such as carbowax or polyethylene glycol can be added. The above mixture can be made into granules, tablets, capsules, etc. by a conventional method. .

In the case of injections, the carrier for the preparation is, for example, in the case of an aqueous preparation, an effective amount of the active ingredient is dissolved in distilled water for injection, and if necessary, an isotonic agent, a stabilizer, a local anesthetic, a preservative, etc. are added. After addition and complete dissolution, an injection can be prepared by filtration, filling, sealing, and steam sterilization in a conventional manner. In addition, when formulating as a lyophilized preparation, an aqueous solution of crude drugs dissolved in distilled water for injection may be lyophilized in a conventional manner;
If necessary, sugars or sugar alcohols such as mannitol, inositol, lactose, maltose, sucrose, or glycine can be added as excipients that facilitate freeze-drying, and freeze-drying can be carried out in a conventional manner.

Examples are shown below, but the present invention is not limited thereto.

One month before the start of the experiment on the supracuspid, platinum electrodes were applied to four locations in the cerebral cortex of the jam cat (female and male): the posterior sigmoid gyrus, the posterior sylvian gyrus, the mediolateral sylvian gyrus, and the superior sylvian gyrus, as well as the deep hippocampus and amygdala. Compound No. 1 of the present invention was implanted in three locations in the hypothalamus and exposed to a certain amount of hydrogen gas in a box without anesthesia or restraint.
The effects of Compound No. 2 on regional cerebral blood flow (r-CBF) were also investigated.

Each drug was administered orally (1), o, ) after encapsulating a predetermined amount in a gelatin capsule. Intravenous injection (i, v
, ), the compound of the present invention is dissolved in an amount equivalent to 0.2 mg/kg or 1 mg/kg in physiological saline equivalent to 1 ml/kg body weight, and the entire amount is added to the cannula inserted into the femoral vein for 10 minutes. The injection was more continuous. Vinpocetine is 1 mg/kg or 5 mg/kg equivalent to 1 m
It was dissolved in 10% ascorbic acid corresponding to l/kg body weight, and the entire amount was similarly injected over 10 minutes through the cannula of the femoral vein.

At the same time, catheters were implanted in the femoral arteries and veins to analyze blood pressure, pH 9 blood gas components in blood flow, and blood sugar levels. All r-CBF values were calculated by semi-logarithmically converting the clearance curve obtained using a computer (Signal Processor 7T17; manufactured by NEC Corporation, Saneisha) and using the initial slope method. In addition, data with a correlation coefficient of 0.9 or more in the regression line were used, and the significance was determined using the absolute value. Using the pre-administration value as a control, Pa1red- was determined by a test.
Significance relative to the control group was tested by time series analysis of variance. The above results are shown in Table 1.

Table 1 Vinpocetine P, 0.
2G 12.3 5
．． 2 (+IP, 0.10 1
2.9 14.4) 4P, 0. 2
0 1 layer, 8 11.0
) 4P, 0. 50 +4.6 10.0
> 42P, O, Otori 00.999.1ku2 P, 0. 20 13.8 19.8) 4P,
0. 50 28.9 22.4) 4 pin 4t
Chin 1. v,
1 1.0 -2.3
-1,v, -5-0,98,3
11 (Na salt) 1. v, 0.2 9
．． 'B 13J <41, v, 1.
013.3 F4.7 > 42 (Na salt)
1. v, 0.2 +2.1 21
．． 0 > 41, v, 1.0 B, 1 1
0.0>4 At this time, no noticeable changes in blood pressure, blood pH, blood gas components, or blood sugar levels were observed with the compound of the present invention.

Example 119-2 = Acute toxicity The compound of the present invention was orally administered to male CD-1 (ICR) mice (5 weeks old), and LD5G (g/kg) was determined by a conventional method. The results are shown in Table 2.

Table 2 Compound No. LD50 (g/kg) No. 1! (
Formulation example) a) Granules 1000 g of main ingredient, 3450 g of lactose, 500 g of carboxymethyl cellulose were mixed well in a kneader, then 10%
500 g of corn starch mucilage was added and kneaded. The mixture was granulated using a cylindrical granulator with a diameter of 0.7 mm, and then dried at 60° C. for 3 hours in a box dryer. After drying, the powder was sieved through a 14-mesh sieve.

b) Capsule 1000g of crude drug, 2000g of lactose, 75% of crystalline cellulose
0 g, carboxymethyl cellulose calcium 2
After adding 00 g of talc, 30 g of talc, and 20 g of magnesium stearate to the V-type mixer, the mixture was mixed for 15 minutes. The mixture was filled into size 1 capsules using a capsule filling machine so that the content of each capsule was 400 mg.

C) Tablet main ingredient 1000g, lactose 540g, crystalline cellulose 70g
After putting 0 g of corn starch, 250 g of corn starch, and 10 g of calcium stearate into a V-type mixer, they were mixed for 15 minutes. The mixture was directly compressed into tablets on a rotary tablet press. The mortar is 8mmφdeep concave.
The weight of one tablet was 250 mg.

d) For aqueous injection preparations: 5g of the main drug (Na salt) and the required amount of Nac.
1 to a total volume of 11 (specific osmotic pressure 1 to 3). Filter by conventional method and fill ampoules with 10 ml of the filtrate.

This is sterilized in an autoclave at 9100° C. for 40 minutes to obtain an injection solution. For freeze-dried preparations: Dissolve 5 g of the main drug (Na salt) in distilled water for injection, and add 5 g of mannitol to this.
Dissolve 0g to make a total amount of 11. Sterile filtration is performed using a conventional method, and 10 ml of the filtrate is filled into a vial. After that, freeze-dry it using the usual method, put a rubber stopper on it, and seal it with an aluminum cap. If necessary, dissolve in physiological saline and use.

Fruit 11u1 Using jam cats (female and male), animals were treated with galamin (gal).
The animals were immobilized (lamins) and maintained under urethane anesthesia by artificial respiration.

Femoral artery blood flow was measured using an electromagnetic blood flow meter, and drugs were administered by cannulating a side branch of the femoral artery.

The above results are shown in Table 3.

Table 3 FBF: Femoral (artery) Blood
Flow (Femoral artery blood flow) 1° above (Synthesis example) 11-Methyl-3-methoxydibenzo[b,fco[1,
Dissolve 1 g of ethyl 4-cooxazepine-8-carboxylate in 10 ml of methanol, and add 1 ml of IN sodium hydroxide to this.
Add 0ml and reflux for 1 hour. After cooling, it was neutralized with dilute hydrochloric acid, and the precipitated crystals were collected by filtration and recrystallized from methanol to give 11-methyl-3-methoxydibenzo[),fco[1,4]oxazepine-8-carboxylic acid. (Compound N
o, 1) Obtain 0.84 g. Yield 92%, melting point 247°C
(Decomposition) Elemental analysis value Molecular formula C+bH1CONO4HN Theoretical value (%) 87.84 4. Ei3 4.94 Actual value (%) 67.82 4,61 4.90 This compound N0
01 was dissolved in an aqueous sodium hydroxide solution and 11-methyl-3-methoxydibenzo[: b, f
The sodium salt of l[1,4]oxazepine-8-carboxylic acid was prepared.

Set of 2 2゜By the same method as in Reference Example 1, 11-ethyl-3-methoxydibenzo[:b,fl[1,4-cooxazepine-
8-carboxylic acid (compound No. 2) is obtained. Melting point 248
~250℃ Elemental analysis value Molecular formula C++H+5NO4HN Theoretical value (%) C38,685,094,71 Actual value (%
) 68.59 5.05 4.7B This compound No. 2
to 11-ethyl-3-methoxydibenzo[b, fl[1,4]oxazepine-8 in the same manner as in Reference Example 1.
- The sodium salt of a carboxylic acid was prepared.

3-methoxy-11-methyldibenzo cb, r co[1,
4] Oxazepine-8-carboxylic acid (compound No. -1
) 10.0g with 150ml of 47% hydrogen bromide water and 15ml of acetic acid
The mixture was added to 0 ml of a mixed solvent and heated under reflux for 3 days. After the reaction, the solvent was removed under reduced pressure, the suspension was suspended in water, and the pH was adjusted to 10 by adding a 10% aqueous sodium hydroxide solution. After treating this solution with activated carbon, 10% hydrochloric acid was added to adjust the pH to 5 to 6, and the resulting solid was collected by filtration, dried, and 3-hydroxy-1
4.39 g of 1-methyldibenzo[b,fl[1,4-cooxazepine-8-carboxylic acid (compound No. 3)] was obtained as a pale yellow powder.

Yield 52%.

Elemental analysis value Molecular formula Cps H11NO4HN Theoretical value (%) 54.02 3.32 4.20 Actual value (
%) 53.9B 3.02 4.311 (肚1 3-Methoxy-11-methyldibenzo[b, fl[1,
4-cooxazepine-8-carboxylic acid (compound No. 1)
5.0 g was dissolved in 200 ml of methanol, 1.34 g of sodium borohydroxide was added, and the mixture was heated under reflux for 30 minutes. After the reaction, two-thirds of the solvent was distilled off under reduced pressure, and water
After adding m1 and separating the solid produced by filtration, 10% hydrochloric acid was added to adjust the mother liquor to pH 7. The produced solid was collected by filtration and dried to give to, tt-sibaido-3-methoxy-11-methyldibenzo[b,fl[1,4]oxazepine-
8-Carboxylic acid (compound No. 4) 4.4E! g was obtained as a colorless powder.

Yield 89% Melting point 195-198°C.

Elemental analysis value Molecular formula C1b Has N 04HN ゛Theoretical value (%) 54.98 4,33 4.01 Actual value (%) 54.77 4.52 4.20 Compound No. 3 to 4 obtained by the above method can be converted into sodium salts by dissolving them in an aqueous sodium hydroxide solution and following conventional methods.

hair skin blood elutriation 1

Claims (1)

[Claims] 1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 is a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group, and R_2 is a hydrogen atom or a lower alkyl group, A is a group▲There are mathematical formulas, chemical formulas, tables, etc.▼or a group▲mathematical formula,
There are chemical formulas, tables, etc. ▼ (R_3 represents a hydrogen atom, a lower alkyl group, a phenyl group that may have a substituent, or a styryl group). ] A therapeutic agent for peripheral circulation disorder containing a compound represented by the following and salts thereof as active ingredients. 2) The therapeutic agent for peripheral circulation disorder according to claim 1, wherein the peripheral circulation disorder is a cerebral circulation disorder. 3) The therapeutic agent for peripheral circulation disorder according to claim 2, wherein the cerebral circulation disorder is aftereffects of cerebral infarction, aftereffects of cerebral hemorrhage, aftereffects of stroke, encephalomalacia, or cerebral edema. 4) Peripheral circulation disorder is caused by Buerger's disease, Raynaud's syndrome,
2. The therapeutic agent for peripheral circulation disorder according to claim 1, which is intermittent claudication, acute peripheral arterial embolism, or presbycusis. 5) 3-methoxy-11-methyldibenzo[b,f][
1,4] A therapeutic agent for peripheral circulation disorder containing oxazepine-8-carboxylic acid and its salts as an active ingredient. 6) 3-hydroxy-11-methyldibenzo[b,f]
[1,4] A therapeutic agent for peripheral circulation disorder containing oxazepine-8-carboxylic acid and its salts as an active ingredient. 7) 10,11-dihydro-3-methoxy-11-methyldibenzo[b,f][1,4]oxazepine-8-
A therapeutic agent for peripheral circulation disorder containing carboxylic acid and its salts as active ingredients. 8) 3-hydroxy-11-methyldibenzo[b,f]
[1,4]Oxazepine-8-carboxylic acid and its salts. 9) 10,11-dihydro-3-methoxy-11-methyldibenzo[b,f][1,4]oxazepine-8-
Carboxylic acids and their salts.