JPH0616557A - Improver for cerebral cerebral function disorder - Google Patents

Abstract

PURPOSE:To obtain a medicine useful as an improver for higher function disorder of brain such as memory disturbance caused by presenile dementia and sequela of encephalopathy, comprising a [2,3-d]thienopyrimidine derivative as an active ingredient. CONSTITUTION:A medicine comprises a compound of formula I [R<1> and R<2> are H, halogen or 1-6C alkyl; R<3> and R<4> are H or 1-6C alkyl; R<5> is H, 1-6C alkyl, group of formula II (X is halogen; m is 1-3), etc.; Ar is phenyl; n is 2 or 3] or its salt such as 6-methyl-4-phenyl-2-piperazinyl-[2, 3-d]thienopyrimidine as an active ingredient. The compound shows effective action especially on central nervous system. Namely the compound strongly antagonizes body temperature dropping action by reserpine and has improving action on reduction in passive avoidance reaction, as a model of memory disturbance, by electric shock.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a brain function improving agent containing a [2,3-d] thienopyrimidine derivative or a salt thereof as an active ingredient.

[0002]

OBJECTS OF THE INVENTION The present inventors have conducted various studies to find compounds having a psychotropic action, and have a piperazinyl group or a homopiperazinyl group at the 2-position and a phenyl group at the 4-position [2,3-d The inventors have found that a thienopyrimidine derivative has a cerebral dysfunction-improving action, and have reached the present invention.

That is, the gist of the present invention is the following general formula (I):

[0004]

[Chemical 3]

[In the above general formula (I), R ¹ and R ²
Represents a hydrogen atom, a halogen atom (fluorine, chlorine, bromine, iodine, etc.) or a C ₁ -C ₆ (preferably C ₁ -C ₄ ) alkyl group (methyl, ethyl, propyl, butyl, etc.), R ³ and R ⁴ is a hydrogen atom or a C _{1 to} C ₆ (preferably C _{1 to} C ₄ ) alkyl group (methyl, ethyl,
Propyl, butyl, etc.).

R ⁵ is a hydrogen atom or a C _{1 to} C ₆ (preferably C _{1 to} C ₄ ) alkyl group (methyl, ethyl,
Propyl, butyl, etc.),

[0007]

[Chemical 4]

Represents Ar represents a phenyl group which may have a substituent. n represents an integer of 2 or 3. ] [2,3-d] thienopyrimidine derivative or a salt thereof represented by the formula [2] as an active ingredient.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The [2,3-d] thienopyrimidine derivative according to the present invention is represented by the above general formula (I) and has R ^{1 to} R ^1
5 , n and Ar are as defined above, but Ar
When is a substituted phenyl group, the substituent is
For example, a halogen atom such as fluorine, chlorine, bromine and iodine; a C _{1 to} C ₆ alkyl group such as methyl, ethyl, propyl, butyl and hexyl; a C _{1 to} C ₆ alkoxy such as methoxy, ethoxy, propoxy and butoxy. Group; hydroxyl group; nitro group; amino group; cyano group; and alkyl-substituted amino groups such as methylamino, ethylamino, dimethylamino, diethylamino and the like.

The [2,3-d] thienopyrimidine derivative according to the present invention can be produced, for example, by the method represented by the following formula.

(A)

[Chemical 5]

(In the above reaction formula, R¹~ R^Five, Ar and
n is as defined above, Y is a halogen atom, R
⁷Represents an amino-protecting group. ) That is, the general formula
The compound represented by (II) and the general formula (III) or (IV)
Reacts with the indicated amines and is represented by the general formula (IV)
When using amines that
The target compound (I) is obtained by removing. R ⁷
As specific examples of, for example, benzyl group, formyl
Group, acetyl group, benzyloxycarbonyl group, etc.
To be

In the reaction with amines (III) or (IV), one equivalent of amines is used for elimination of hydrogen halide formed, so it is advisable to add at least two equivalents of amines. Although preferred, it is often preferred to use the amines in excess, often in amounts up to 20 equivalents, to accelerate the reaction. When carrying out the reaction with 1 equivalent of amines, tertiary amines or potassium carbonate or sodium carbonate are added as acid binders. When the amines are used in excess, the reaction is possible without a solvent, but when a solvent is used, an inert organic solvent such as C ₁ -C is used.
₈ alcohols, tetrahydrofuran, dioxane,
Single or mixed solvents such as benzene, alkyl-substituted benzene, halogen-substituted benzene, chloroform, di- or trichloroethylene, acetonitrile, dimethylformamide, dimethylsulfoxide, etc. are used. The reaction is generally 20 ° C to 200 ° C, preferably 50 ° C to 100 ° C.
It is performed in the range of ° C.

The compound of the general formula (II), which is the starting material of the above-mentioned method (a), is prepared according to Chem. Pharm. Bul
l. , 28 (11), 3172 (1980). The general formula (I
When the compound represented by V) is used, after the reaction is completed,
Further, the protecting group of the amino group is removed. For example, when R ⁷ is a benzyl group or a benzyloxycarbonyl group, R ⁷ is a formyl group or an acetyl group by catalytic hydrogenation using palladium carbon as a catalyst. When it is a group, R ⁷ can be removed by acid hydrolysis.

(B)

[Chemical 6]

(In the above reaction formula, R¹~ R^Five, N and A
r is as defined above and Z is a halogen atom.
You R^Five'Is the above R^FiveIs the same as defined in or
R ⁶Is the R^FiveAs defined above. ) You
That is, the compound (V) obtained by the method (a) and the general formula (V
I) or (VII) by reacting with a compound
Thus, the target compound (I) can be obtained.

The reaction with the compound represented by the general formula (VI) can be carried out in a solvent such as acetone, methylethylketone, dimethylformamide or dimethylsulfoxide, using potassium carbonate or sodium carbonate as an acid binder. . The reaction with the alkyl isocyanate represented by the general formula (VII) is carried out at room temperature in a solvent such as dichloromethane or chloroform.

(C) The compound represented by the general formula (I) obtained by the above method (a) or (b) has the general formula (I) by further converting the substituent Ar or R ⁵ into another substituent. Other compounds of formula I) can be prepared. For example, as conversion of the substituent on the substituent Ar,
Examples include conversion of a nitro group into an amino group by iron powder-acetic acid, conversion of a bromo group into cyano group by cuprous cyanide in dimethylformamide, and conversion of the substituent R ⁵ includes parafluorophena. Examples include conversion of a sil group into a 2- (4-fluorophenyl) -2-hydroxyethyl group with sodium borohydride.

The compounds suitable as the [2,3-d] thienopyrimidine derivative according to the present invention, which are produced by the above-mentioned method, are exemplified below. 6-methyl-4-phenyl-2-piperazinyl- [2,
3-d] thienopyrimidine 5,6-dimethyl-4-phenyl-2-piperazinyl-
[2,3-d] thienopyrimidine 5-methyl-4-phenyl-2-piperazinyl- [2,2
3-d] thienopyrimidine 6-chloro-4-phenyl-2-piperazinyl- [2,2
3-d] thienopyrimidine 4- (2-fluorophenyl) -6-methyl-2-piperazinyl- [2,3-d] thienopyrimidine 4- (2-bromophenyl) -6-methyl-2-piperazinyl- [ 2,3-d] thienopyrimidine 6-methyl-4- (2-methylphenyl) -2-piperazinyl- [2,3-d] thienopyrimidine 4- (2-cyanophenyl) -6-methyl-2-piperazinyl -[2,3-d] Thienopyrimidine Further, a pharmaceutically acceptable acid addition salt of the [2,3-d] thienopyrimidine derivative represented by the general formula (I) is also included in the scope of the present invention. Examples of the acid addition salt include salts with inorganic acids such as hydrochloric acid, phosphoric acid and sulfuric acid and organic acids such as acetic acid, formic acid, citric acid and paratoluenesulfonic acid.

The [2,3-d] thienopyrimidine derivative according to the present invention has a therapeutically useful activity, and particularly exhibits a useful action on the central nervous system. In other words, it strongly antagonizes the hypothermic effect of reserpine and improves the decline of passive avoidance reaction due to electric shock, which is a memory impairment model. Due to their activity, the compounds according to the invention are
It is useful as a drug that can be used to improve intellectual dysfunction.

When the compound of the present invention is used as a therapeutic agent, it is administered alone or in combination with a pharmaceutically acceptable carrier. Its composition is determined by the solubility, chemical properties, administration route, administration schedule, etc. of the compound. For example, when the compound is parenterally administered by intramuscular injection, intravenous injection or subcutaneous injection, it is used as a sterile solution to which other solutes such as salt or glucose are added to make the solution isotonic. The compound is also orally administered in the form of tablets, capsules or granules containing a suitable excipient such as starch, lactose, sucrose and the like. Further, sugar, corn syrup, fragrance, dye, etc. are added to the compound, and the mixture is dehydrated and solidified to be used as lozenges or lozenges. When administered orally as a solution, coloring agents and fragrances are added.

The dose is determined by the doctor according to the administration method, the kind of compound and the condition of the patient. The therapeutic dose is generally 0.1 to 50 mg / kg per day for parenteral administration and 0.5 to 500 mg / kg for 1 day by oral administration.

[0023]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to the following examples as long as the gist thereof is not exceeded. Reference Example 1 <6-Methyl-4-phenyl-2-piperazinyl- [2,3-d] thienopyrimidine> [(a) method] 2-chloro-dissolved in 40 ml of warm chloroform.
15.64 g of 6-methyl-4-phenyl- [2,3-d] thienopyrimidine was dropped into a solution of 62 g of anhydrous piperazine in 100 ml of ethanol by heating under reflux, and the mixture was further heated under reflux for 1 hour. . Chloroform and ethanol were distilled off under reduced pressure, and chloroform (300 ml) and water (30 ml) were added.
0 ml is added and the product is extracted into the chloroform layer. The chloroform layer is further washed twice with 200 ml of water, washed with saturated saline and then dried over anhydrous sodium sulfate. Chloroform is concentrated and crystallized from chloroform-cyclohexane to give the desired product of the free base, mp 186-187 ° C. 17.17 g. This was dissolved in 60 ml of chloroform by heating, 1.1 equivalent of 20% hydrogen chloride ethanol solution was added, and further 350 m of ethanol was added.
After the addition of l, 100 ml was distilled off under reduced pressure and allowed to cool to precipitate crystals, which were collected by filtration to obtain 18.20 g of 1-hydrochloride. Melting point 270 ° C-280 ° C (decomposition).

In the same manner, the compounds shown in Table 1 below were
It is synthesized from the corresponding 2-chloro- [2,3-d] thienopyrimidines and piperazines or homopiperazines.

[0025]

[Table 1]

[0026]

[Table 2]

[0027]

[Table 3]

[0028]

[Table 4]

Reference Example 22 <6-methyl-2- (2-methylpiperazinyl) -4-phenyl- [2,3-d] thienopyrimidine> [(a) method (a method for removing a protective group from an amino group)] ] 2-Chloro-6-methyl-4-phenyl [2,3-d]
Thienopyrimidine (3 g), 1-benzyl-3-methylpiperazine (2.2 g) and sodium carbonate (1.1 g) are mixed with dimethylformamide (4 ml), and the mixture is reacted under heating under reflux for 3 hours. After cooling, 80 ml of benzene and 80 ml of water are added for liquid separation, and the benzene layer is washed twice with 100 ml of water. Further, it is washed with saturated saline and dried over anhydrous sodium sulfate. Benzene was distilled off, and the residue was purified by silica gel chromatography (silica gel 180 g, n-hexane-ethyl acetate (10: 1)) to give oily 2- (4-benzyl-2-methylpiperazinyl) -6-methyl-. 4-
4.3 g of phenyl- [2,3-d] thienopyrimidine
can get. This was dissolved in 90 ml of acetic acid and 10 ml of concentrated hydrochloric acid, and 7 g of palladium black was used as a catalyst.
Contact hydrogenation is carried out at 0 ° C. for 4 hours at 1 atm. After filtering off the catalyst,
Acetic acid and hydrochloric acid were distilled off under reduced pressure, and 150 ml of ethyl acetate and 100 ml of 10% aqueous potassium carbonate solution were added to separate the layers. The ethyl acetate layer is washed with water, washed with saturated brine, and dried over anhydrous sodium sulfate. When ethyl acetate was distilled off and the residue was recrystallized from chloroform-n-hexane, it was 1.85.
g object is obtained. Melting point 168 ° C-170 ° C

Reference Example 23 <2- [4- (4-Fluorophenacyl) -piperazinyl] -6-methyl-4-phenyl [2,3-d] thienopyrimidine> [(b) Method] 6-methyl- 4-phenyl-2-piperazinyl- [2,
2.03 g of 3-d] thienopyrimidine, 1.25 g of 4-fluorophenacyl chloride and 0.73 g of triethylamine are reacted in 6 ml of methyl ethyl ketone with heating under reflux for 5 hours. After cooling, 70 ml of chloroform is added, washed twice with 100 ml of water, washed with saturated saline, and then dried over anhydrous sodium sulfate. After distilling off chloroform, crystallization from diethyl ether-methanol gives 2.68 g of the desired product. Melting point 141-142
℃

Reference Example 24 <2- [4- {2- (4-fluorophenyl) -2-hydroxyethyl} -piperazinyl] -6-methyl-4-phenyl- [2,3-d] thienopyrimidine> [ Method (c) (Conversion of R ⁵ )] 2- [4- (4-Fluorophenacyl) -piperazinyl] -6-methyl-4-phenyl- [2,3-d] thienopyrimidine (1.34 g) in chloroform (10 ml). And dissolved in 10 ml of ethanol, 0.2 sodium borohydride
Add 3 g at room temperature and react for 1 hour. Chloroform (60 ml) and water (100 ml) are added for liquid separation, and the chloroform layer is washed with water (100 ml), saturated brine and dried over anhydrous sodium sulfate. Chloroform was distilled off and the product was crystallized from methanol.
g is obtained. Melting point 180-181.5 ° C

Reference Example 25 <4- (2-aminophenyl)
-6-Methyl-2-piperazinyl- [2,3-d] thienopyrimidine> [(c) method (conversion of substituent of Ar group)] 6-methyl-4- (2-nitrophenyl) -2-piperazinyl -1.25 g of [2,3-d] thienopyrimidine is dissolved in 8 ml of ethanol, 3.5 ml of water and 4 ml of acetic acid, and 1.5 g of iron powder is added little by little at 90 ° C over 1 hour. After reacting at 90 ° C for another 20 minutes, ethanol 2
5 ml and 6 ml of water are added and the reaction is filtered through a layer of Celite. Celite is washed with hot ethanol, and the washings are combined with the filtrate and evaporated under reduced pressure. The residue is treated with 20 ml of 10% aqueous sodium carbonate solution and 80 ml of chloroform,
After filtration through a Celite layer, the chloroform layer is separated. After drying over anhydrous sodium sulfate, the chloroform is concentrated and crystallized from chloroform-cyclohexane to give 0.93 g of the desired product. Melting point 232-236 ° C

Example A Antagonism of the hypothermic action of reserpine In the test, 6 ddY male mice (22-25) were grouped per group.
g) is used. Intraperitoneal administration of 5 mg / kg of reserpine reduces the body temperature of mice from about 38 ° C. before administration to about 8 ° C. after 4 hours on average. At this time, the test compound was
It is orally administered at the same time as reserpine, and the extent to which the hypothermic action of reserpine is antagonized is examined. This test has traditionally been used as an evaluation method for antidepressant effects.
The most widely used one. When the hypothermic effect of reserpine is completely suppressed, antagonism is 100
%, The dose of each test compound was variously changed, and the antagonism at that time was calculated as%. In addition, a 50% antagonizing dose of each test compound was administered to Litchfield-Wi.
lcoxon method (J. Pharmacol. Exp. T.
her. , 96 , 99, 1949), and calculated as an ED ₅₀ value.

Among the [2,3-d] thienopyrimidine derivatives according to the present invention, the activity of eight representative compounds is shown in Table-2. As a control, the activity of amitriptyline, which is an existing antidepressant, is shown. In addition, the acute toxicity value (L
D ₅₀₎ indicating the (male mice).

[0035]

[Table 5]

B Passive avoidance reaction disorder model due to electric shock (memory disorder model) As a memory disorder model, Susan J. et al. Sara's method (Psychopharmacology, 68 , 2
35-241, 1980) was used. The test equipment is Two
Compartment Avidance Bo
Called x, it consists of a black, bright, lighted box, followed by a dark box with a conductive grid floor. When a Wistar male rat (170 to 220 g) is placed in a large box, the animal has a property of quickly entering a small box. However, when entering the small box, closing the entrance and passing a current (3 mA, 5 seconds) through the floor grid, after 3 hours or more, when the same rat was put into the large box again, until the small box entered The time is significantly extended. This reaction is called "passive avoidance reaction". However, when a small box was entered and current was passed through the floor grid, electrodes were placed on both ears of the rat, and an electric shock (60 mA, 200 Hz, 0.8 seconds) was applied, the "passive avoidance reaction" was impaired. It That is, the time (Latency) from the large box to the small box is shortened. This is a phenomenon that occurs when the rat forgets the electric current stimulation received from the floor lattice by electric shock.
The reduced length of y is used as an index of lost memory. The memory-improving effect was obtained by a test after oral administration of a test compound for 3 hours or more after giving an electric shock,
It is indicated by the extent to which Latency is extended (% improvement rate).

Among the [2,3-d] thienopyrimidine derivatives according to the present invention, the activity of three typical compounds is shown in Table-3. Nootropic drug (Noo
Pirac known as tropic Agent)
Compared with etam, the compounds according to the present invention have comparable activity.

[0038]

[Table 6]

[0039]

The compound of the present invention is useful as a remedy for higher functional dysfunction of the brain such as presenile dementia and memory disorder due to sequelae of encephalopathy.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Sansei Egawa Sanyo Kasei Co., Ltd., Research Institute, Sanyo Kasei Co., Ltd. 1000 No. 1000 Kamoshida-cho, Midori-ku, Yokohama-shi, Kanagawa Prefecture Address Sanryo Kasei Co., Ltd.

Claims (1)

[Claims] 1. The following general formula (I): [In the general formula (I), R ¹ and R ² are hydrogen atoms,
Represents a halogen atom or a C ₁ -C ₆ alkyl group,
R ³ and R ⁴ represent a hydrogen atom or a C _{1 to} C ₆ alkyl group. R ⁵ is a hydrogen atom or a C ₁ -C ₆ alkyl group, Represents Ar represents a phenyl group which may have a substituent. n represents an integer of 2 or 3. ] [2,3-d] thienopyrimidine derivative or a salt thereof as an active ingredient.