JPH03151323A - Substituted phenylalkanoylamine derivative and use thereof - Google Patents

Abstract

PURPOSE:To obtain a cerebral circulation, cerebral metabolism and anamnesis improving agent having excellent anti-low oxygen action with high safety containing a substituted phenylalkanoylamine derivative. CONSTITUTION:A compound expressed by the formula (A is 1,3-thiazolidin-3-yl, 1,2,3,6-tetrahydropyridin-1-yl, thiomorpholin-4-yl or 3-pyrrolin-1-yl; R is lower alkyl-substituted amino, pyrrolidin-1-yl, piperidino or guanidino; n is 2-6) or salt of said compound, e.g. 3-{4-[4-(N,N-dimethylamino)phenyl]butanoyl}-1,3- thiazolidine, is contained in the aimed agent as active ingredient. Administration dose of said agent is suitably in a range of 1-2000mg/day, preferably 10-200mg/ day at 1-3 times per day in a case of oral administration.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel substituted phenylalkanoylamine derivative and its use as a pharmaceutical agent for improving cerebral circulation, cerebral metabolism, and memory.

[Prior art and problems to be solved by the invention] With the advent of an aging society, various adult diseases, especially diseases caused by brain dysfunction such as cerebrovascular disorders, cerebral circulation disorders, cerebral metabolic disorders, and memory disorders, are increasing. It has increased. In response to this, many brain 'tiEjs improving agents, brain metabolism improving agents, etc. are widely used clinically.

However, these conventional cerebral circulation improving agents and cerebral metabolism improving agents are still not fully satisfactory in the treatment of diseases such as sequelae of cerebrovascular disorders.

By the way, mammalian brain tissue mainly relies on the aerobic jt'J'll system as an energy source to maintain its functions. For this purpose, large amounts of oxygen and glucose must be constantly supplied. Clinically, when the amount of oxygen supplied to the brain tissue decreases due to circulatory disorders, the function of brain cells is extremely reduced, and if the supply is stopped (for more than a few minutes) ) It is known that if continued, the physiological function will be lost and irreversible organic damage will occur. From this point of view, pharmacological tests using the low y1 loading method have been experimentally conducted for a long time. In recent years, the issue of cerebral ischemia has attracted attention, and biochemical studies have been conducted to investigate changes in brain function and the mechanisms of tissue damage caused by lack of oxygen.
The usefulness of this hypoxia test method has also been proven from a hemodynamic and electrophysiological perspective. And, this drug that protects the brain from hypoxic stress shows superior effects on improving cerebral circulation, cerebral metabolism, and memory compared to conventional cerebral circulation improving agents.
It's bug-eyed.

[Means for Solving the Problems] In view of the above circumstances, the present inventors have conducted intensive studies to develop even better cerebral circulation, brain metabolism, and memory improving agents, and have found that they are expressed by the following general formula (1). The present invention has been completed based on the discovery that substituted phenylalkanoyl adenyl derivatives have excellent antihypoxic effects and are useful as pharmaceuticals.

That is, the present invention relates to the following general formula (where A is], 3-thiazolidin-3-yl group, 1.
2. 3. G-tetrahydropyridin-1-yl group, morpholinok thiomorpholin-4-yl group or 3
-pyrrolidin-1-ylno, t, and R is a lower alkyl-substituted amino group, a pyrrolidin-1-yl group, piperi'dino2. Indicates guanidino or guanidino group.

(2) indicates the order τ of 2 to G. Substituted phenylalkanoylamine L1 conductor and its salt, which is 11ゎ.

and i? expressed by general formula (1)? ! The present invention provides a memory modifying agent for improving cerebral circulation and brain function, which contains a converted phenylalkanoylamine conductor as an active ingredient.

In the compound (1) of the present invention, the lower alkyl-substituted amino group represented by R is an 11-chain or branched chain having 1 to 6 carbon atoms such as a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a diisopropylamino group, etc. Examples include lower alkyl-substituted amine groups on the chain. In addition, the salts of the wood compound (f) include physiologically acceptable salts, such as inorganic salts such as @ acid salts, sulfur salts, and nitrate salts;
Acetate.

Examples include organic acid salts such as oxalate, tartrate, citric W1@, and maleate.

The following compounds are exemplified as representative compounds of the present invention (1).

・3-(4-(4-(N,N-dimethylamino)phenyl]butanoyl)-1,3-thiazolidine・3-(
4-(4-(N,N-dimethylamino)phenyl]butanoyl)-1,3-thiazolidine@acid acid 3-(5-(4-guanidinophenyl)pentanoyl]-1,3-thiazolidine 3-( 6-(4-(N,N-dimethylamino)phenyl]hexanoyl)-1,3-thiazolidi-3- (
4-(4-(N,N-diethylamino)phenyl]butanoyl)-1,3-thiazolidine hydrochloride 3-(4-[4-(N,N-diisopropylamino)phenyl]butanoyl)-1,3- Thiazolidine 3-(4-(4-piperidinophenyl)butanoyl)-1,3-thiazolidine 3-(4-(4-(1-pyrrolidinyl)phenyl)
butanoyl)-1,3-thiazolidine 3-(4-(4
-guanidinophenyl)butanoyl)-1,3-thiazolidine・3- C4-(4-guanidinophenyl)butanoyl)-1,3-thiazolidine hydrochloride・3-(4-(4-guanidinophenyl)butanoyl)-1, 3-thiazolidine sulfate/l-(4-r,4-<N,N-dimethylamino)phenyl]butanoyl)-1,2,3,8-tetrahydropyridine/1-(4-(4-guanidinophenyl) butanoyl)
-1,2,3,8-tetrahydropyridine 4- (
3-(4-(N,N-dimethylamino)phenyl]propanoyl)morpholine・4-(5-(4-guanidinophenyl)pentanoyl1morpholine・4-(6-(4-(N,N-dimethylamino) Phenyl]hexanoyl)thiomorpholine 4- (6-(
4-(N-ethyl-N-methylamino)phenylhexanoyl)thiomorpholine, 4-(3-(4-guanidinophenyl)propanoylcothiomorpholine, 1-(4-(4-(N,N-dimethyl) Amino)phenyl]butanoyl)-3-pyrroline 1-(6-(4
-guanidinophenyl)hexanoyl-3-pyrroline The compound of the present invention having the general formula (1) has excellent antihypoxic properties and is highly safe, so it is useful as an agent for improving cerebral circulation, cerebral metabolism, and memory. . The compound (I) of the present invention may be blended alone or in combination with other pharmaceutically active ingredients in the cerebral circulation/brain metabolism/memory improving agent of the present invention, and may also contain pharmaceutically acceptable adjuvants. It can be made into oral or parenteral preparations.

For formulations for oral administration, the above compounds are combined with suitable excipients such as lactose, mannitol, corn starch,
Excipients such as crystalline cellulose, cellulose derivatives, binders such as gum arabic and gelatin.

By appropriately combining with a disintegrant such as carboxymethyl cellulose calcium, a lubricant such as talc, magnesium stearate, etc., it can be made into tablets, powders, granules, and capsules. Further, these solid preparations can be made into enteric-coated preparations by using a coating base such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate, or methacrylate copolymer. In addition, medium chain fina! It can also be dissolved in triglyceride, safflower oil, soybean oil, polyethylene glycol 400, etc. to form soft capsules. As preparations for parenteral administration, for example, solutions for injection can be prepared by combining water, ethanol, glycerin, conventional surfactants, etc., and suppositories can be prepared using a base for suppositories.

The dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, and administration period, but usually 1 to 2 doses are administered orally.
000 mg/day, preferably 10 to 200 mg/day, and is suitably administered once to three times a day.

The present invention will be explained in more detail with reference to Examples below.
The present invention is not limited to these Examples.

Example 1 3-(4-(4-(N,N-dimethylamino)phenyl]butanoyl)-1,3-thiazolidine (blank below) a): e "U t'l! 20 ml and ethanol 20 +++ 1, 3-(4-(4-nitrophenyl)butanoyl)-1,3-thiazolidine 2
．． Dissolve 70 g of iron powder, add 1.68 μl of iron powder little by little at room temperature, and stir for 3 hours. After the reaction is complete, remove the iron powder by filtration, and add 50 ml of ethyl acetate and water to the υ wave. In addition,
After neutralization with sodium carbonate, the liquid was separated and the water M was extracted with ethyl acetate. All organic layers are washed with hot water at RL? After drying with sodium, r8 soot was distilled off under reduced pressure, and the resulting refined residue was washed with ether.
3-(4-(4-aminophenyl)p!t-noyl)-1,3-thiazolidine 1. ．． 94g (81%)
1+3.

mp 80-82℃ IR (Kn r) cut-electricity: 3
4 2 5. 3 3 r) O.

2950, 1635. 1610. 1515. 1
420. 1370. 1285. 1175. 81
ONMR (CDCl3) δ: 1.86-2.04
(2H, m), 2.22-2.37 (2H
, m), 2.57 (2H,t, Jl=7H
z), 2.90-3.10 (2H, m), 3.
14-3.73 (2H, br).

3.62 (IH, t, J=5Hz), 3.
83, (IH-t, J = 6 Hz) p 4
-37 (IH*s) -4,57(IH,
s), 6.81 (2H, d, J=8Hz)
, 6.97 (2H, d, J=8Hz) 3-(4-(4-aminophenyl)butanoyl)-
20 ml of saturated alcoholic hydrochloric acid was added to 920 mg of 4,3-thiazolidine, and after stirring for 30 minutes, the solvent was distilled off under reduced pressure. The resulting crystalline residue was washed with ether to obtain colorless crystals of 3-(4-( 4-aminophenyl)butanoyl)-
1.03 g (92%) of 1,3-thiazolidine hydrochloride was obtained.

mp 166-169°C b): 300 mg of 3-(4-(4-aminophenyl)butanoyl)-1,3-thiazolidine obtained in a) and 280 mg of trimethyl phosphate were gradually heated under an argon atmosphere and heated to 180°C. The mixture was stirred for 2 hours. After cooling, 2 ml of 15% aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours.

The reaction solution was extracted with methylene chloride, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain colorless crystals.
- (4-(4-(N,N-dimethylamino)phenyl]butanoyl)-1,3-thiazolidine 93 mg (1
7%).

mp 54-55℃ IR (KBr) am-': 2920, 1635゜1
520, 1425. 1335 HMR (CDCa) δ: 1.91-2.20 (2H
, m), 2.27-2.34 (2H, m), 2.59
(2)(, t, J=8!(z), 2.91 (6H,
s), 2°90-3.06 (2T-L m), 3.
61~3°86 (2H, m), 4.38 (11(,
s), 4.58 (LH, s), 6.70 (2H, d
, J=8Hz), 7.06 (2H,d, J=8)(Z
) Example 2 3-(4-(4-guanidinophenyl)yl)-1,
3-thiazolidine salt a-salt butano 3-(4-(4-aminophenyl)butanoyl)-1,3-thiazolidine cap 11'' obtained in Example 1.8)!
287 mg and 42 mg of cyanamide were dissolved in 5 ml of hot water ethanol, and the reaction solution was heated and stirred at 70°C for 4 hours. The resulting crystalline residue was recrystallized from ethanol-ether to give colorless crystals of 3-(4-(
210 mg (6456) of 4-guanidinophenyl)butanoyl)-1,3-thiazolidine@0 salt was obtained.

mp 140-148℃ (decomposition) IR (KBr) cm-': 2830, 2520゜1
605, 1510. 145O NMR (DMSO-da) δ: 1.75
~1.83 (2H, m), 2.30-2.38
(2H, m)2.61 (2H,t, J=7Hz
), 2.94-3.09 (2F!, m),
3.61-3.68 (2H, m).

4.43 (IH,s), 4.50 (IH,
s), 7.27 (4H, s), 8.45~
8.72 (5H, br) <Anti-hypoxic production> A group of 10 male TCR mice (Charles River), 4 to 5 weeks old, were incubated after fasting for 24 rI. A transparent synthetic resin with two cocks on the top and bottom to replace the air inside! Ensu container (diameter 19cm, IF 30cm)
4%02+96%N2 from the upper cock.
The mixed gas was flowed in at a flow rate of 10 Q/min. The time from the start of inflow of the mixed gas until each mouse stopped breathing was determined, and the time was determined to be open when the mouse was alive.

The test compound is 10% gum arabic solution! Cloudy.

It was administered into the M cavity 30 minutes before the start of the inflow of the mixed gas.

In addition, mice to which only 10% gum arabic solution was intraperitoneally administered were used as controls.

What are the experimental results?

Calculated from the formula below, Shown in the table.

Antihypoxic effect (%) Survival time table of control group <Toxicity test> - Peritoneal administration 4-5 week old appropriate age CR mice were used, 10 mice per group. The compounds of Examples 1 and 2 were each suspended in a 10% gum arabic solution and administered intraperitoneally at a dose of 300 mg/kg, followed by observation for 7 days. As a result, no deaths were observed in any of the cases.

- Oral administration 6 Male Fischer 344 rats of suitable age were used as 1r #5 rats. The compounds of Examples 1 and 2 were suspended in 10% gum arabic and then heated at 2°O, 400, and 800°C, respectively.
Dose i: mg/kg was orally administered for 14 consecutive days. As a result, no cases of death due to the toxicity of the compound of the present invention were observed.

Formulation Example 1 Compound of Example 9111 20g Lactose 315g Corn Starch 125g Crystalline Cellulose
7. Mix 25g of the above ingredients uniformly.
200 ml of a 5% hydroxypropylcellulose aqueous solution was added, and the mixture was made into granules using an extrusion granulator using a 0.5 mm diameter screen, immediately rolled into balls using a marmerizer, and then dried. 1.9 kg of a film coating liquid of the following composition was applied to the dried granules using a fluidized granulator.

It was coated and made into enteric-coated granules.

Coating liquid composition: Hydroxyprobyl methyl cellulose phthalate) 5.0 (w/w)% stearic acid 0.25 (w/w)% methylene chloride 50.0 (w/w)% ethanol 44.75 (w/w) W)% Formulation Example 2 Compound of Example 1 20g milk! 10
0 g Corn starch 36 g Microcrystalline cellulose 30 g Calcium carboxymethyl cellulose 10 g Magnesium stearate 4 g The components of the above composition were mixed uniformly and made into tablets of 200 mg each with a diameter of 7.5 mm using a single-shot tablet machine. Next, the tablets were spray coated with a coating liquid having the following composition,
Each tablet was coated with 10 mg to form an enteric film coated tablet.

Coating liquid composition: Mybaset 0.4 (W/W)% Methylene chloride 50.0 (W/W)% White beeswax 0.1 (W/W)% Isopropanol 41.5 (W/W)% formulation Example 3 Compound of Example 2 200 g Polysorbate 80 20 g Panacet 81
0 1780g After mixing the components of the above composition and completely dissolving them, use a soft capsule layer formation liquid consisting of 100 parts of gelatin, 30 parts of glycerin, 0.4 parts of ethylparaben, and 0.2 parts of propylparaben. Soft capsules containing 200 mg of drug solution per capsule were prepared using the rotary method.

Formulation Example 4 Compound of Example 1 100mg*Sodium acid 2mg Vinegar m (PH5
,814! ! Jl) Appropriate water for injection Remaining amount 10 ml/vial The above formulation was prepared as an injection by a conventional method.

〔Effect of the invention〕

As mentioned above, the compounds of the present invention exhibit strong antihypoxic effects and are highly safe, resulting in excellent cerebral circulation, cerebral metabolism, and
Useful as a memory improver. Therefore, the compounds of the present invention can be used to treat cerebral hemorrhage sequelae, cerebral infarction sequelae, cerebral arteriosclerosis, subarachnoid hemorrhage sequelae, head trauma sequelae, brain surgery sequelae, and cerebrovascular dementia.

Parkinson's disease, Alzheimer's disease, Pick's disease.

Treatment of aftereffects of hypoxic poisoning, alcohol encephalopathy, etc.! 11 It is useful as a medicine.

Claims (2)

[Claims] (1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, A is 1,3-thiazolidin-3-yl group, 1,
2,3,6-tetrahydropyridin-1-yl group, morpholino group, thiomorpholin-4-yl group or 3-pyrrolin-1-yl group, R is a lower alkyl-substituted amino group, pyrrolidin-1-yl group , represents a piperidino group or a guanidino group, and n represents an integer of 2 to 6. ) Substituted phenylalkanoylamine derivatives and salts thereof. (2) A cerebral circulation/brain metabolism/memory improving agent containing the substituted phenylalkanoylamine derivative or its salt according to claim (1) as an active ingredient.