JPS62427A - Antidepressant and agent for ameliorating cerebral function disorder - Google Patents

Abstract

PURPOSE:To provide an antidepressant and an agent for ameliorating cerebral function disorder, containing a [2,3-d]thienopyrimidine derivative or its salt. CONSTITUTION:The objective agent contains the compound of formula I [R<1> and R<2> are H, halogen or 1-6C alkyl; R<1> and R<2> may together form a 5-6- membered alkylene ring; R<3> and R<4> are H or 1-6C alkyl; R<5> is H or 1-6C alkyl or group of formula II, formula III (m is 1-3; X is halogen) or formula IV 9R<6> is 1-6C alkyl); Ar is phenyl or 2- or 3-thienyl which may have substituent group; n is 2-3] or its salt. The compound of formula I is e.g. 6-methyl-4- phenyl-2-piperazinyl-[2,3-d]thienopyrimidine, etc. Preferable dose is 0.1-5mg/kg daily for parenteral administration and 0.5-500mg/kg daily for oral administration.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to an antidepressant agent 1 and a brain function improving agent containing (2, J-a) a cenobi9 midine derivative or its carrier as an active ingredient.

(Object of the invention) The present inventors have discovered a compound that has psychoactive effects (
We conducted various studies and found that the 2nd position has a piperazinyl group or homopiperazinyl group, and the 4th position has a phenyl group or chenyl group [co,,? The present invention has been achieved by discovering that -alchenobinone derivatives have antidepressant effects and ameliorating effects on brain dysfunction.

That is, the gist of the present invention is the following general formula (1): [In the above general formula (1), R1 and Hl /fi hydrogen atom, halogen atom (fluorine, chlorine, bromine, iodine, etc.)
Or it represents an alkyl group (methyl, ethyl, propyl, butyl, etc.) of 01 to C, - (preferably 01 to C4), and RL and R'' may be combined to form an alkylene group of RL members. .

R1 and R4 represent a hydrogen atom or an alkyl group (methyl, ethyl, propyl, butyl'4) of #-tO+ to's (preferably C1 to C6).

R11Fi■ Hydrogen atom or C3~0. (preferably 0, to C4) alkyl group (methyl, ethyl, propyl, butyl, etc.), H (m is an integer of 1 to 3, and X represents a halogen atom (fluorine, chlorine, bromine, iodine, etc.).

or ■-0-NH-R1(R' ij O, ~Os(
Preferable device 0〈kec,,a, ) alkyl group (methyl,
Represents ethyl, propyl, butyl, etc.).

Ay represents a phenyl group, co- or 3-chenyl group which may have a substituent.

n 2tfc represents an integer of J. ] An antidepressant and a brain function enhancer containing a [λ, J-a] chenopyrimidine derivative or the like as an active ingredient.

(Structure of the Invention) The [λ, J-a] chenopyrimidine nine-fold complex according to the present invention is represented by the general formula (1) above, and R1, , Ha, n and ArII′i are defined above. However, when Ar is a phenyl group, examples of substituents include halogen atoms such as fluorine, salt, bromine, and iodine, and C8 to dimethyl, ethyl, propyl, butyl, and hexyl.
C6 alkyl group; ethoxy, ethoxy, propoxy,
Examples thereof include C9-06 alkoxy groups such as butoxy; hydroxyl groups; nitro groups; amino groups; diano groups; and alkylrjIL-converted amino groups such as methylamino, ethylamino, dimethylamino, and diethylamino.

The [λ, , 7-d] chenopyridine derivative according to the present invention can be produced, for example, by a method as shown in the following formula.

at RI RI hal (In the above reaction formula, H1 to R6, ar and n are as defined above, and %xB halogen atom R? represents a protecting group for an amino group.) That is, as shown in general formula (11) Compound and general formula (
Reacting with the amines represented by II) or (IV),
When using amines represented by the general formula (IV), the target compound@
(1) is obtained. As a specific example of R7, for example,
Examples include benzyl group, formyl group, acetyl group, and benzyloxycarbonyl group.

In the reaction with amines (1) and rfi (4V), 7 equivalent amines are used to eliminate the generated hydrogen halide, so it is recommended to add at least λ equivalent of amine a. It is preferred, however, to use an excess of amines, often up to -000 to accelerate the reaction.

l When conducting a reaction using our amines, Fi, tertiary
amines or potassium carbonate, add sodium carbonate as an acid binding agent.

If an excess of amines is used, the reaction can be carried out without a solvent, but if a bath medium is used, an inert organic solvent such as 01-C6 alcohols, tetrahydrofuran, dioxane, benzene, Single or mixed columns η of alkyl-substituted benzene, halogen-substituted benzene, chloroform, di- or di- or di-trichloroethylene, acetonitrile, dimethylformamide, dimethyl sulfoxide, etc. are used. The reaction is generally 200~. It is carried out at 20θ°C, preferably in the range of 5θ0 to 1θθ°C.

Compounds are % Ohem-Pharnn, Bull-+
It can be synthesized according to the method of 2g ('l)hiko, 7/7ko (/?go).

When a compound represented by the general formula (1v) is used as an amine, the amino group is further removed after the reaction is completed.For example, when R7 is a penzyl group or a benzyloxycarbonyl group, case rc i
-t, by contact water treatment using palladium carbon as a catalyst, or by acid hydrolysis when R7 is a formyl group or an acetyl group. can be removed.

(V) (%R1, , R11, n and Ar in the above reaction formula)
u is as defined above, and 2 represents a) Rodan atom. R5' ti has the same meaning as defined in the above RI O■matter■, and all is as defined in the above R1+. ) That is, (compound (V) obtained by the al method and the general formula (
The target compound (1) can be obtained by reacting with a compound represented by Vl) or (■).

-pH The reaction with the compound represented by the formula (■) is carried out in a solvent such as acetone, methyl ethyl ketone, dimethyl formamide, dimethyl sulfoxide, or the like.

Potassium carbonate or sodium carbonate can be used as the acid binder.

-M < (The reaction with the alkyl isocyanate represented by 1.i is carried out in a solvent such as dichloromethane or chloroform at room temperature). The compound represented by formula (1) has a substituent a
Another compound represented by the general formula (J) can be prepared by converting r or ♂ into a radical.

For example, as a conversion of the a substituent on the substituent Ar, a nitro group is converted to an amino group by iron powder-acetic acid. Examples include conversion of a bromo group to a cyano group with cupric cyanide in dimethylformamide, and conversion of a parafluorophenacyl group to a cyano group with cupric cyanide in dimethylformamide. &-fluorophenyl)-2-hydroxydiethyl group, etc.

7, (s,
, ya) Compounds suitable as chenopyrimidine derivatives are illustrated below.

6-) f-ru-phenyl-cobipelaginyl [ko,
, 7-a) Chenopyrimidine s, b-dimethyl-q-phenyl-co-biperazinyl [co, J-a) Chenopyrimidine j-methyl-q-phenyl-co-biperazinyl-(2,, y-a) ) Chenopyrimidine 6-chloro-q-phenyl-hiberacinyl-[ko,,? -a) Chenopyrimidine g-(nifluorophenyl)-b-methyl-
1-Piperazinyl-[co,,y-a)chenopyrimidine 4-(2-bromophenyl)-6-methyl-piverazinyl-(2,3-a)chenopyrimidine 6-methyl-Hiro-( -monomethylphenyl) -λ-piperazinyl [yu...? -43 Chenopyrimidine 4=-(Nicyanophenyl)-6-Methyl=Cobiverazinyl[Co,, 7-a) Chenopyrimidine Also represented by the general formula (21.7 a) Chenopyrimidine Pharmaceutically acceptable acid addition salts of the pyrimidine derivatives are also within the scope of this invention. The acid addition salt includes hydrochloric acid,
Salts with inorganic acids such as phosphoric acid and (#L acid) and organic acids such as acetic acid, formic acid, citric acid, and para-toluenesulfonic acid are excluded.

The (x, J-(1) thienopyrimidine derivative of the present invention has therapeutically useful activity, and particularly shows a useful effect on the central nervous system. Namely, it lowers body temperature by reserpine. It strongly antagonizes the effects and is a model for memory impairment.'I
Correct the decrease in passive avoidance response caused by IC Qi shock. Because of these activities, the compounds according to the present invention are useful as pharmaceuticals that can be used to improve depressive conditions as well as intellectual dysfunction.

When a compound according to the invention is used as a therapeutic agent, it is administered singly or in combination with a pharmaceutically acceptable carrier. Its composition is determined by the compound's solubility, chemical properties, route of administration, regimen, etc.

For example, injecting the compound parenterally and intramuscularly.

When administered by intravenous or subcutaneous injection, other bath substances such as salt or glucose may be added to make the bath solution isotonic.
It is used once as a sterile solution.

The compounds may also be administered orally in the form of tablets, capsules or granules with suitable excipients such as starch, lactose, sucrose and the like. In addition, the compound is added with sugar, corn syrup, flavor, color, etc., dehydrated, molded, solidified, and used as a lozenge such as a troche or lozenge. In addition, when orally administered as a solution, an N coloring agent and flavoring agent are added.

The dosage will be determined by the physician depending on the method of administration, the type of compound used, and the condition of the patient.

Therapeutic doses are generally administered parenterally at 0. / -, tOri/
Oral administration: 9/kg/day.

(-^ [Example 02 Li)] Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to the following Examples unless the gist thereof is exceeded.

Reference J example/ <t,-methyl-4-phenyl-cobiverazinyl [7-a) chenopyrimidine> (
(a) Method] Coke claw 6-methyl-q-phenyl- [co,, 7-a) Chenopyrimidine ts, bllfs dissolved in chloroform qθ- at 0 temperature by heating m water piperazine & 211fl in ethanol toomt During melting, the mixture was refluxed for a few hours, and then heated under reflux for 1 hour. Distill chloroform and ethanol under reduced pressure, chloroform, ? 00
14 Add 300 ml of water and drain the product into the chloroform layer.

The chloroform layer was further washed twice with water and then with saturated saline, and then dried with anhydrous sulfuric acid and IJum.

When chloroform is reformed and crystallized from chloroform-cyclohexane, the melting point is 4-7°C, /? /
Play! ! ? ! The target product of the base is obtained. Dissolve this in 60 grams of chloroform by heating, and add 10% of this to
Add hydrogen chloride ethanol solution and add 3 ml of ethanol.
After SO- is removed by DO, 100 wt is distilled off under reduced pressure and allowed to cool to precipitate crystals, and when P is removed, 2 og of l-hydrochloride is obtained. Melting point: 2700-2gθ°C (decomposed).

In a similar manner, the compound shown in 4-/ below was converted to the corresponding sul λ-
Chloro-(X, 3-a) chenopyrimidines and piperazines or homopiperazine reference examples, 22 <6-methyl-2-(2-methylpiperazinyl)-4-phenyl-[co, J-a] Chenopyrimidine> (Method (a) (Amino group removal method)) Coke claw 6-methyl-q-phenyl (2'lJ
a ] Chenopyrimidine, ty, i-benzyl-3-methylpiperazi72.217 and sodium R acid
was mixed with 1 mt of dimethylformamide and heated under reflux for 3
Allow time to react. After cooling, add benzene gOd and water to Q
Rinse and wash benzene N twice with water ioθ-.

Furthermore, it is washed with saturated saline and dried over anhydrous sodium sulfate. Benzene was distilled off and purified with silica gel/109°n-hexane-ethyl acetate (lo:)) to give an oily 2-(Hiro-penzyl-comethylpiperazinyl)- 6-
Methyl-terphenyl-[coIJ-a)chenopyrimidine is converted into 4'-7Ni. This was dissolved in 9Q-acetic acid and 10 mt of carbonic acid, and catalytically hydrogenated at 0°C for 4 hours at 7 atm using palladium black θ, sl as a catalyst.

After removing the catalyst, acetic acid and hydrochloric acid were distilled off under reduced pressure, and ethyl acetate/diO- and 10% potassium carbonate aqueous solution Q/00
am! t-Add and separate. The ethyl acetate layer is washed with water, then with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Ethyl acetate is distilled off and the desired product of sult, t, tr s g is obtained by recrystallization from chloroform-n-hexane. Melting point / A f' ~ /90 °C Reference example: iJ <co(==-(4=-fluorophenacyl)-piperazinyl]-6 monomethyl-derphenyl [co, J -a)chenopyrimidine> [(b ) method] 6-methyl-q-7enyl-2-piperazinyl-[co,
j-a) Chenopyrimida, 0Jli.

Hiro - Fluorophenacyl chloride hecoSI and triethylamine o,? j, 17 as methyl ethyl ketone 6
The reaction was allowed to proceed for 7 J [S hours under reflux. After cooling, add a chloroform layer Omt, wash once with 100 ml of water, wash with saturated brine, and dry over anhydrous sodium sulfate. After distilling off chloroform, crystallization from diethyl ether-methanol yielded the desired product, 2.4ff, 975
! can get. Melting point IU/ ~ / Da λ ℃ Reference example Koq Kuko [q-(Co(-monofluorophenyl)-Cohydroxyethyl)-piperazinyl]-6 Monomethyl-q-phenyl[λ, J-4)chenopyrimidine 〉 Ctcl method (f exchange of R5)] 2 [dar(4=-fluoro7enacyl]-pyheracinyl]-6-methyl-q-7enyl[x, J-a]chenopyrimidine 8 to ait chloroform/Or4 ( !
: Ethanol iotst F (8% L, sodium borohydride θ, 23 g was added at room temperature.

Allow to react for 1 hour. The chloroform layer was washed with 100 ml of water and then with saturated saline.

Dry with anhydrous sodium sulfate. Chloroform? When distilled off and crystallized from methanol, the target product has a rich body. Melting point 1go-1ti, z"c referencejHF'1J2
j<der(neeaminophenyl)-6-methyl-cobiperazinyl-C2,3-a) chenopyrimidine> [(C) Method (A
(Conversion of substituent of r group)]]]]]]]]]]]]]][6-Methyl-q-2-nitrophenyl)-cobiperazinyl-(x,, y-a) chenopyryl-di-no-box-sy to ethanol fm/, water, ? ,j
- and 8 acids 4 are bath-dissolved in -, and sg is added to iron powder at 9g℃,
Gain DΩ little by little over an hour. Another λθ minute? θ℃
Then, add 2 ji of ethanol and 6 liters of water to the reaction wave, and drain 1 g of reaction through a layer of celite. Wash the Celite with hot ethanol, mix the wash with the doorboard, and remove the seeds from the pressure. The residue was treated with 70% sodium carbonate solution and chloroform, filtered through 7 m of Celite, and the chloroform layer was separated. Dry sickle with anhydrous sodium sulfate.

Chloroform′! When crystallized from chloroform-cyclohexa7, the target product 0.9 j ,
9 is obtained. Melting point: 3~6°C Example A An antagonistic effect (2-~-sg) to the body temperature lowering effect of reserpine is used. Reserpine, ttW/ /
Intraperitoneal administration of cg lowers the body temperature of mice from about 3 t<0>C before administration to an average of -g[deg.] C. after administration.

At this time, the test compound is orally administered at the same time as reserpine, and the extent to which it antagonizes the body temperature lowering effect of reserpine is examined. This exam is the same as before.

It is the most commonly used method for evaluating antidepressant effects. The case where the body temperature lowering effect of reserpine was completely inhibited was defined as 100% antagonism, and the dosage of each test compound was varied to calculate the antagonism in %.

(J, Pnarmacol jijxp, T
her,, 9b, 9q, /9a de) K, ED5
Calculated as a ° value.

Among the (, -r, 3-a) chenopyrimidine drug conductors according to the present invention, two examples of t compounds are shown in Table 2. As a control, existing antidepressant fields. Shows the activity of γmitributyrin.

In addition, acute toxicity value (LD, □) (male mouse)
shows.

Awe -2 Due to BvIL ki shock. Passive avoidance response disorder model (memory disorder model) As a memory disorder model Duaan J, 5ara method (Psychopha:r; aacalcgy, 6
g, 2Js-2 (I/.

iqgo)k use-h, test = installation a is TWOOompa
It consists of a bright, ventilated large box with RT-painting, and a dark φ box with a lattice floor that can be used for counterfeiting or bending the flow. Wlstar male rat (170
When you put ~2 kg) into a large bowl, it quickly enters the small box λf:; When an electric current (JmA for 1j seconds) is passed through the wire, the same rat is placed in the large box again for more than 3 hours, and the time it takes to enter the small box is significantly prolonged.This reaction is called a ``passive avoidance response.'' However, it is true.

After passing the PM flow through the grid on the floor, electrodes were placed on both ears of the rat, and an electric shock (bOmAS 20t) was applied.
) Hz, 0.1 seconds) wo is given.

The "passive avoidance response" is impaired. In other words, the time (Latθncy) it takes for the large hakama to enter the small box is calculated.

This shows that when rats receive electric current stimulation from a grid on the floor,
This is a phenomenon that occurs when people forget due to FFC shock.
The memory-improving effect of the length of Laten = 7, which is used as an index of memory, is to give a shock to 'i, , 111: reading ratio compound with water volume of approximately administered to,
How much DateΩc did you get in a nine-hour test that lasted more than three hours?
It is shown as whether y is extended (% improvement rate).

The activity of three representative examples of the chenopyrimidine derivatives according to the present invention (3-a) is as follows:
As shown in J.

It has comparable activity.

Table J (Effects of the Invention) The compounds according to the present invention can improve various depressive symptoms including psychosomatic disorders and t+ depression. ! It is useful as an R agent and as a remedial agent for higher-order brain disorders such as presenile dementia and memory impairment due to the after-effects of Ronjin V.

Claims (1)

[Claims] (1) The following general formula (1) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (1) [In the above general formula (1), R^1 and R^2 are hydrogen atoms, halogen atoms, or C_1 to C_6 It represents an alkyl group, and R^1 and R^2 may be combined to form a 5- or 6-membered alkylene ring. R^3 and R^4 represent a hydrogen atom or a C_1 to C_6 alkyl group. R^5 is (1) a hydrogen atom or an alkyl group of C_1 to C_6, ▲ there is a mathematical formula, chemical formula, table, etc. ▼ (m is an integer from 1 to 3, X represents a halogen atom) or (3) ▲ mathematical formula, There are chemical formulas, tables, etc.▼(R^
6 represents an alkyl group of C_1 to C_6. ) represents. Ar is a phenyl group which may have a substituent or 2-
Or it represents a 3-thienyl group. n represents an integer of 2 or 3. ] denoted by [2,3
-d] Antidepressant and brain dysfunction improving agent containing a thienopyrimidine derivative or its salt as an active ingredient