JPH04270222A - Brain function improver - Google Patents

Abstract

PURPOSE:To obtain a drain function improver having excellent brain function improving action and effective as a preventive and therapeutis agent for mental disorders, nerve disorders, etc., including demential disorders caused by brain- degenerative diseases such as apoplexia cerebri, head injury or Altzheimer syndrome. CONSTITUTION:A brain function improver containing a xanthine derivative expressed by formula I (R<1> to R<3> are H or lower alkyl; X<1> and X<2> are O or S; Q is formula II to formula III; Y is single bond or alkylene; (n) is 0 or 1) or pharmacologically permissible salt thereof, e.g. 8-(noradamantan-3-yl)-1,3- dipropylaxanthine as an active constituent. The active constituent can be administered orally or parenterally as an injection and the improver is ordinarily administered by dividing into three or four portions at a daily dosage of 1-50mg/kg.

Description

[Detailed description of the invention]

0001

TECHNICAL FIELD The present invention relates to a brain function improving agent.

0002

[Prior Art] The present application shows that a compound represented by the general formula (I) described below selectively shows an antagonistic effect on the A1 receptor of the adenosine receptor, and has a diuretic effect, a nephroprotective effect, and a bronchodilator effect. The application has been filed by a person (
Patent Application No. 2-228941). However, it is not known that this compound has a brain function improving effect. Also,
In relation to general formula (I), 8-(1-adamantyl)-
1,3,7-trimethylxanthine is Tetrahe
drone Lett. , 27, 6337 (198
6), but its pharmacological action is unknown.

[0003] Furthermore, in the general formula (I) described below, R3
is the formula (c)

0004

[C4]

or formula (d)

[0006]

[C5]

It is known that the xanthine derivative represented by
247180).

[0008]

SUMMARY OF THE INVENTION An object of the present invention is to provide an excellent brain function improving agent.

[0009]

[Means for Solving the Problems] The present invention provides general formula (I)

0010

[C6]

[In the formula, R1, R2 and R3 are the same or different and represent hydrogen or lower alkyl,
X1 and X2 are the same or different and represent oxygen or sulfur atoms, and Q is represented by formula (a)

0012

[C7]

(wherein Y represents a single bond or alkylene) or formula (b)

[0014]

[Chemical formula 8]

A xanthine derivative represented by the following formula (in which n means 0 or 1 and Y has the same meaning as above) [hereinafter referred to as compound (I)]. The same applies to compounds of other formula numbers] or a pharmacologically acceptable salt thereof as an active ingredient. Compound (I
), lower alkyl is a linear or branched group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -
Butyl, tert-butyl, pentyl, neopentyl,
Including hexyl and the like. Alkylene is a linear or branched carbon atom having 1 to 4 carbon atoms, such as methylene, ethylene,
Includes trimethylene, tetramethylene, methylmethylene, propylene, ethylethylene and the like.

The pharmacologically acceptable salts of compound (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like. Compound(
Pharmaceutically acceptable acid addition salts of I) include inorganic acid salts such as hydrochloride, sulfate, phosphate, acetate, maleate,
Examples include organic acid salts such as fumarate, tartrate, and citrate, and pharmacologically acceptable metal salts include sodium salt,
In addition to alkali metal salts such as potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts and zinc salts are also mentioned, and ammonium salts include salts such as ammonium and tetramethylammonium.
Examples of pharmacologically acceptable organic amine addition salts include addition salts such as morpholine and piperidine, and pharmacologically acceptable amino acid addition salts include addition salts such as lysine, glycine, and phenylalanine.

Next, the method for producing compound (I) will be explained. Compound (I-1) in which R3 is hydrogen can be obtained according to the following reaction scheme (A).

[0018]

[Chemical formula 9]

(In the formula, Hal represents a halogen atom such as chlorine, bromine, or iodine, and R1, R2, X1, X2
and Q have the same meanings as above) Step 1: Known method (for example, JP-A-59-42383
Compound (IV) can be obtained by reacting uracil derivative (II) obtained according to the method disclosed in Japanese Patent Application Publication No. 2003-100002 with carboxylic acid (III) or a reactive derivative thereof. Step 2: Compound (I-1) can be obtained by ring-closing compound (IV) by treatment with a dehydrating agent or heating in the presence of a base. Step 3: Schiff base (VI) can be obtained by reacting compound (II) and aldehyde (V). Step 4: Compound (I-1) can be obtained by subjecting compound (VI) to an oxidative cyclization reaction. Step 5: Compound (
IX) can be obtained. Step 6: Compound (I-1) can be obtained by reacting compound (IX) with a nitrous acid derivative such as sodium nitrite or isoamyl nitrite as a nitrosating agent.

Compound (I-2) in which R3 is lower alkyl in compound (I) can be obtained according to the following reaction scheme (B).

[0021]

[Chemical formula 10]

(In the formula, R1, R2, X1, X2
and Q have the same meanings as above, R3a represents lower alkyl in the definition of R3) Step 7: That is, obtained by the above production method (I-1
) and an alkylating agent in the presence of a base if necessary to obtain compound (I-2).

Compound (I-4) in which X2 is sulfur can be obtained according to the following reaction scheme (C).

[0024]

[Chemical formula 11]

(In the formula, R1, R2, R3, X1
and Q have the same meanings as above) Step 8: By reacting (I-3) [a compound in which X2 is oxygen in compound (I)] obtained by the above production method with an appropriate thiolating agent, Compound (I-4) can be obtained.

The intermediate and compound (I) in the above-mentioned production method are purified by purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. Can be separated and purified. Further, the intermediate can also be subjected to the next reaction without being particularly purified. When you want to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, you can simply purify it as it is, or if it is obtained in a free form, you can obtain the salt by a conventional method. Just let it form.

Preferred compounds as the brain function improving agent of the present invention include those shown in Table 1 below.

[0028]

[Table 1]

[0029]

[Table 2]

Table 2 shows the physical properties of the compounds in Table 1.

[0031]

[Table 3]

Compound (I) has a brain function-improving effect and is effective as a preventive or therapeutic agent for psychiatric symptoms and neurological symptoms, including dementia symptoms caused by stroke, head trauma, or brain degenerative diseases such as Alzheimer's disease. be. Compound(
I) or a pharmacologically acceptable salt thereof can be used as it is or in various pharmaceutical forms. The pharmaceutical composition of the present invention can be prepared by uniformly mixing an effective amount of Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient with a pharmaceutically acceptable carrier. These pharmaceutical compositions are desirably in unit dosage form suitable for administration orally or by injection.

[0033] Any useful pharmaceutically acceptable carrier can be used in preparing the compositions in oral dosage forms. Oral liquid preparations, such as suspensions and syrups, can be prepared using water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive oil, etc.
It can be manufactured using oils such as soybean oil, preservatives such as p-hydroxybenzoic acid esters, and flavors such as strawberry flavor and peppermint. powder,
Pills, capsules and tablets contain excipients such as lactose, glucose, sucrose and mannitol, starch, disintegrants such as sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl alcohol, hydroxypropyl cellulose, It can be manufactured using a binder such as gelatin, a surfactant such as fatty acid ester, a plasticizer such as glycerin, etc. Tablets and capsules are the most useful oral dosage units because of their ease of administration. Solid pharmaceutical carriers are used in the manufacture of tablets and capsules.

Injectables can also be prepared using a carrier consisting of distilled water, saline solution, glucose solution, or a mixture of saline and glucose solution. At this time, it is prepared as a solution, suspension or dispersion using a suitable auxiliary agent according to a conventional method. Compound (I) or a pharmacologically acceptable salt thereof can be administered orally in the above pharmaceutical form or parenterally as an injection, and its effective dose and frequency of administration are determined depending on the dosage form and the age of the patient. Although it varies depending on body weight, symptoms, etc., the dose is usually 1 to 50 mg/kg per day, divided into 3 to 4 doses.

The following test examples will explain the pharmacological action of compound (I). Test Example 1 Yawning behavior expression effect It is known that central muscarinic receptor stimulation causes a yawning response [Nature, 267,
261-262 (1977), Pharmaco
l. Biochem, Behav. , 21 ,
297-300 (1984)]. Test method Wistar rats (male, weight 250-300 g,
(supplied by Charles River) in wire mesh cages (2
After intraperitoneal administration of the test compound (dose: 1.0 ml/kg), the number of yawn responses was measured for 60 minutes.

Furthermore, as a control, the number of yawning reactions was measured in the same manner as above, except that physiological saline was used instead of the test compound. The results are shown in Table 3.

[0037]

[Table 4]

[0038] The number of yawning reactions in Table 3 is expressed as the average number of yawning reactions per rat in which yawning reactions appeared for 60 minutes. According to the test results, compound (I)
Since it exhibits a yawning behavior-inducing effect, it is useful as a brain function improving agent based on its activation of central cholinergic nerves.

Test Example 2 Acute toxicity test weight 20±
The test compound was administered orally (po; 300 mg/kg) to 1 g of DD male mice (3 mice per group). Observe the mortality status 7 days after administration and determine the minimum lethal dose (MLD).
I found the value. Compounds A, C~F, H, K~N and P~
For U, the MLD is >300 mg/kg, and it has low toxicity and can be safely used over a wide dose range.

Examples and reference examples of the present invention are shown below.

[0041]

[Examples] Example 1 Tablets Tablets having the following composition were prepared by a conventional method. Compound D 40g,
286.8 g lactose and 60 g potato starch
120 g of a 10% aqueous solution of hydroxypropylcellulose was added. This mixture was kneaded in a conventional manner, granulated, dried, and then sized to form granules for tabletting. Add 1.2 g of magnesium stearate to this, mix, and use a tablet machine (RT-15 manufactured by Kikusuisha Co., Ltd.) equipped with a punch with a diameter of 8 mm.
Tablets (20ml of active ingredient per tablet)
g) was obtained.

Formulation Compound D
20mg
lactose
143.4mg Potato starch 30mg
hydroxypropyl cellulose
6 mg Magnesium stearate 0.6 mg

200 mg Example 2
Fine granules A fine granule having the following composition was prepared by a conventional method.

Compound D 20g, lactose 655g
and 285 g of corn starch were mixed, and 400 g of a 10% aqueous solution of hydroxypropylcellulose was added. This mixture is kneaded in a conventional manner, granulated and dried to produce fine granules (2 active ingredients per 1,000 mg of fine granules).
(containing 0 mg) was obtained. Example 3 Capsules Capsules having the following composition were prepared by a conventional method.

Compound D 200g, Avicel 995g
and 5 g of magnesium stearate were mixed in a conventional manner. This mixture was filled into hard capsules No. 4 (120 mg capacity per capsule) using a capsule filling machine (manufactured by Zanasi, model LZ-64), and the capsules (1
(containing 50 mg of active ingredient per capsule). Prescription Compound D
20mg
Avisel
99.5mg Magnesium stearate 0.5mg

120 mg Example 4 Injection An injection having the following composition was prepared by a conventional method.

[0045] 1 g of compound D was added to 100 g of refined soybean oil.
12 g of purified egg yolk lecithin and 25 g of glycerin for injection were added. This mixture was kneaded and emulsified to 1000 ml with distilled water for injection in a conventional manner. The resulting dispersion was sterile filtered using a 0.2 μm disposable membrane filter, and then placed in a 2 m glass vial.
Each vial was filled aseptically to obtain an injection (containing 2 mg of active ingredient per vial).

Reference Example 8 - Process for producing (noradamantan-3-yl)-1,3-dipropylxanthine (compound D) 1.62 g (9.74 g) of 3-noradamantanecarboxylic acid
mmol) was dissolved in 30 ml of pyridine, and 0.78 ml (10.7 mmol) of thionyl chloride was slowly added at 0°C. After stirring at room temperature for 30 minutes, 2.00 g (8.8
5 mmol) was added slowly at 0°C. 3 at 0℃
After stirring for 0 minutes, the mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate was added, and the mixture was extracted three times with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Pyridine was removed by azeotroping with toluene, and the resulting crude product was subjected to silica gel column chromatography (
Elution solvent: 1% methanol/chloroform), 6
-Amino-5-(noradamantane-3-carbonylamino)-1,3-dipropyluracil 3.55 g (quantitative yield) was obtained as an irregularly shaped substance.

NMR (90MHz; CDCl 3 )
δ (ppm): 7.38 (brs, 1H),
5.62 (brs, 2H), 4.00 ~ 3.70 (
m, 4H), 2.90-2.60 (m, 1H), 2
．． 40-1.30 (m, 16H), 1.10-0.
80 (m, 6H) 2.90 g of the above compound (7.55
mmol) was heated under reflux for 30 minutes in 100 ml of phosphorus oxychloride. After concentration under reduced pressure, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: 20% ethyl acetate/hexane) and then recrystallized from isopropanol-water to obtain 509 mg of compound D (yield 14%).
was obtained as white needles.

Melting point: 190.0 to 191.0°C (
Heptane) Elemental analysis value: C20H28N4O
2 Calculated value (%): C 67.39, H 7.
92, N 15.72 Actual value (%): C 67
．． 41, H 7.62, N 15.78IR (
KBr) νmax (cm-1): 1699, 1
651, 1499NMR (DMSO-d6) δ
(ppm): 12.97 (s, 1H), 3.9
5 (t, 2H), 3.85 (t, 2H), 2.70
~2.60 (m, 1H), 2.35 ~ 2.26 (m,
2H), 2.20-2.10 (m, 2H), 1.9
5-1.82 (m, 4H), 1.80-1.50 (m
, 8H), 0.95 ~ 0.80 (m, 6H) 13
C-NMR (DMSO-d 6 ) δ (ppm)
: 159.9, 153.9, 150.7, 14
7.6, 106.6, 48.8, 48.2, 45
．． 1, 44.2, 43.2, 41.9, 36.
9, 34.1, 20.8, 11.1, 10.9

[0049]

[Effects of the Invention] The present invention provides an excellent brain function improving agent.

Claims (1)

[Claims] Claim 1: General formula (I) [In the formula, R1, R2 and R3 are the same or different and represent hydrogen or lower alkyl, and X1 and X2 are the same or different and represent an oxygen or sulfur atom; and Q is represented by the formula (a) [Chemical formula 2] (wherein, Y represents a single bond or alkylene) or the formula (b) [Chemical formula 3] (wherein, n means 0 or 1, and Y is A brain function improving agent containing a xanthine derivative or a pharmacologically acceptable salt thereof as an active ingredient.