JPS5970675A - Benzoxazine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula 1 [R<1> is H, lower alkyl or phenyl (lower alkyl); R<2> is lower alkyl, lower alkoxy or halogen; A is lower alkylene; z is O or S; n is 0, 1, 2 or 3] and its salt. EXAMPLE:7-{ 3-[4-(3-Chlorophenyl)-1-piperazinyl]propoxy }-2H-1, 4-benzothiazine- 3(4H). USE:Analgesic, sedative, tranquillizer, antipyretic, antispasmodic, antihistaminic, hypotensor, etc. PROCESS:The compound of formula 1 can be obtained, e.g. by reacting the compound of formula 2 (X is halogen, lower alkanesulfonyloxy, arylsulfonyloxy, or aralkylsulfonyloxy) with the compound of formula 3 in the absence of a solvent or in a conventional inert solvent at 60-120 deg.C for several -24hr.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel beshizosujin derivatives and salts thereof.

The beshizoozin derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (1).

1 [In the formula, R1 is a hydrogen atom, a lower alkyl group or a phenyl lower alkyl group, R2 is a lower alkyl group, a lower alkyl group, or a halogen atom, A is a lower alkyl group, Z
represents an oxygen atom or a sulfur atom, and ru represents 0 or an integer of 1 to 3, respectively. ] The compound of the present invention represented by the above general formula (1) and its salt have a central nervous system depressing effect, an antistasis effect, an antihypertensive effect, etc., such as an analgesic, a sedative,
It is useful as a tranquilizer, antipyretic, anticonvulsant, antispasmodic, antihypertensive, etc.

More specifically, the groups represented by R1, R2 and A in the above general formula (1) include the following.

Lower alkyl group: an alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isodurobyl, butyl, tert-butyl, pesityl, and hexyl group.

Phenyl lower alkyl group - besidyl, 2-phenylethyl, l-phenylethyl, 3-phenyldropyl,
・Niphenylbutyl, 1,1-dimethyl-2-phenylethyl, 5-phenylethyl, 6-phenyl+sil, 2-methyl-3-phenyl+0hir group, etc. with 1 or more carbon atoms
A phenylalyl group having 6 alkyl moieties.

Lower alkoxy groups: methoxy, etoxy, zurobo, iso-5[]po+shi, zutojushi, t art-zutojushi, peshichiruojushi, heshishiruo+shi Number of carbon atoms in group: 1
~6 alkoxy groups.

Heroge, 7g, child...Fluorine, chlorine, bromine and iodine atoms.

Lower alkyl + resin group -methylene resin, ethylene resin, trimethylene resin, 2-methyl trimethylene resin, 2,2-dimethyl trimethylene resin, l-methyl trimethylene resin, methyl methylene, ethyl methylene, tetramethylene, pentamethylene resin, hetosu Mechi! , 7.7 groups and the like having 1 to 6 carbon atoms.

In addition, the group represented by e(R2)rL in the above general formula (1) is specifically phenyl, 2-chlorophenyl, 3-O-ruphenyl, 4-D-ruphenyl, 2-fluorophenyl, 3- Fluorophenyl, 4-fluorophenyl, 2-dromphenyl, 3-dromphenyl,
4-D-mphenyl, 2-iodophenyl, 4-B-dophenyl, 3,5-dichlorophenyl, 2,6-;
dichlorophenyl, 3.4-dichlorophenyl, 3.4
', ;Fluorophenyl, 3,5-didiromphenyl,
3,4.5-1-Dichlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 3-isodurobylphenyl, 4- + sylphenyl, 3-4-; methylphenyl, 2,5-dimethylphenyl, 2,3-dimethylphenyl, 3. ．． 4.5-)
Dimethylphenyl, 2-methoxydiphenyl, 3-methoxydiphenyl, 4-methoxydiphenyl, 2-ethoxydiphenyl, 3-ethoxydiphenyl, 4-ethoxydiphenyl,
4-isopropyl diphenyl, 4-to+silo-deca diphenyl, 3,4-dichlorophenyl, 3.4-diphenyl in shed, 2.5-;methodeca diphenyl, 3.4.5
- t-rimetox diphenyl, 3-methyl-4-ri00
Examples include phenyl, 2-chloro-6-methylphenyl, and 2-methoxyphenyl.

The compound of the present invention can be produced by various methods, for example, by the method shown in the following reaction scheme.

Reaction Scheme-1 1 (1) [In the formula, R1, R2, A, Z and L are the same as above. X represents a halogen atom, a lower alkacysulfonyl group, an arylsulfonyl group, or an aral + sulfonyl group. ] That is, the compound of the present invention is produced by reacting a compound represented by general formula (2) with a known phenylpiperazine derivative represented by general formula (3).

The above reaction can be carried out without solvent or in a common inert solvent at room temperature to
The process is completed in several hours to about 24 hours at a temperature of 200°C, preferably 60 to 120°C.

Examples of inert solvents include Geo + Sun, Tetra Shido O, etc.
Fura':, t(THF), ethers such as ethylenecylicol and dimethyl ether, aromatic hydrocarbons such as beshizeshi, tornidi, and beef shireshi, methanol, ethanol,
Lower alcohols such as isodurobanol, dimethylformamide (DMF), dimethylsulfocytosite (DMSO)
), acetol, acetonitrile, N-methyl dihydride (NMP), hesyl methyl lysic acid triamide (xxpA
) can be used. The above reaction is preferably carried out using a basic compound as a deoxidizing agent. Examples of the basic compound include potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide, sodium hydride, 1,8-diazapicic O
Examples include tertiary amici such as [5,4,0:l-7-butylene (DBU), triethyl amici, trizuo pyrua sanshi, hiri, ;shi, +norishi, and the like. The above reaction may be carried out by adding an alkali metal iodide compound such as potassium iodide or sodium iodide as a reaction promoter, if necessary.

The ratio of the compound represented by the general formula (2) and the compound represented by the general formula (3) in the above reaction is usually 7 to an excess of the former, preferably 1 to 5.
It is preferably 1 to 1.2 times the mole amount.

In the compound represented by the general formula (2) used as a starting material, the lower alkanesulfonyl group represented by X is specifically metacissulfonyl group,
ethacysulfonyl, isoduropathic, sulfonyl, tert-sulfonyl, pentanesulfonyl, pentansulfonyl, Examples include sulfonyl groups, and examples of arylsulfonyl groups include phenylsulfonyl groups, 4-methylphenylsulfonyl groups, 2-methylphenylsulfonyl groups,
Substituted or unsubstituted arylsulfonylonoxy groups such as 4-nitrophenylsulfonyloxy, 4-meth+cyphenylsulfonyloxy, 3-Oluphenylsulfonyloxy, and α-naphthylsulfonyloxy groups Examples of the aral + sulfonyl group include besidylsulfonyl, 2-phenylethylsulfonyl, 1-phenylsulfonyl, 4
-Methylbesidylsulfonyl, 2-methylbesidylsulfonyl, 4-nitrobesidylsulfonyl, 4-methoxybesidylsulfonyl, 3-ri0 rubesidylsulfonyl Examples include substituted or unsubstituted aral sulfonyl groups such as α-naphthylmethylsulfonyl groups. The compound of general formula (2) having such group X is produced, for example, by the method shown in Reaction Scheme-2 below.

Reaction Scheme-2 (41(2) [In the formula, R1, A, Z and X are the same as above. In other words, by reacting the compound represented by the general formula (4) with the compound represented by the general formula (5), the general formula (2
) is produced. The reaction conditions in the above method may be the same as those in the reaction of reaction scheme-1 described above.

The compound of the present invention can also be produced by the methods shown in Reaction Schemes -3 and -4 below.

Reactivity η Formula-3 1 (1 [In the formula, R1, R2, A%, Z and X are the same as above.]
Compound of general formula (4) and general formula (6) in the above method
The reaction conditions with the compound may be the same as those in the reaction scheme-1 described above.

Reaction Scheme-4 (1,z) (IA) [In the formula, R2, A, Z and L are the same as above. R1' represents a lower alkyl group or a phenyl lower alkyl group.

X2 represents an atom. ] According to Reaction Scheme-4, by converting a compound of the present invention in which R is a hydrogen atom [compound of general formula (1α)] into alkyl, the corresponding R1 is a lower alkyl group or This can lead to a compound showing a phenyl lower alkyl group [compound of general formula (1h)].

The reaction between the compound of general formula (1α) and the compound of general formula (7) is preferably carried out, for example, in the presence of a basic compound in a suitable solvent. Examples of the basic compound include sodium hydride, potassium, sodium, sodium amide, potassium amide, and the like. Examples of solvents include ethers such as diosaccharide, diethyl ether, 7talicol, and dimethyl ether; aromatic hydrocarbons such as toluene and dimethyl silicate; dimethylformamide, dimethylforpho+cyto, and hesyl methyl lysic acid triamide. . The ratio of the compound of general formula (lα) and the compound of general formula (7) to be used is not particularly limited and may be appropriately selected within a wide range. Generally, the latter is preferably used in an amount of at least about 7 moles or more, preferably about 1 to 2 times the mole of the former. The reaction is usually carried out at about -50 to 70°C, preferably from about 0°C to room temperature, and is generally completed in about 0.5 to 12 hours.

The compounds of general formula (4) used as starting materials in the reaction schemes -2 and -3 include some new compounds. Such a compound can be produced, for example, by the method shown in Reaction Scheme-5 below.

Reaction Scheme-5 (91(4b) [In the formula, R1' and A compound of the general formula (4α) is obtained by subjecting it to a chemical reaction.The reaction is carried out using hydrogen halide, such as hydrogen bromide. Among them, it is preferable to use water as a solvent in the form of hydrohalic acid. For example, in the case of hydrogen bromide, it is usually 10 to 50
H. It is preferably used after preparing an aqueous solution of about 47%. In the above reaction, the amount of hydrogen 80) fυ hydride used is usually an equivalent to a large excess relative to the compound of general formula (8), and a large excess is preferably used.

Moreover, the reaction is usually 10~! In some examples, the compound of the general formula (8) is reacted with the compound of the general formula (7) under heating at 50°C, preferably under heating reflux for about 5 to 20 hours. A raw material compound represented by general formula (4b) is obtained by subjecting the compound 9) to a deallulation reaction. The reaction between the compound of general formula (8) and the compound of general formula (7) is carried out in the same manner as the reaction between the compound of general formula (lα) and the compound of general formula (7). The deallylation reaction of the compound of general formula (9) is also carried out under the same conditions as the deallylation reaction of the compound of general formula (8).

The pendio+sazine derivative represented by the general formula (11) of the present invention can be easily converted into an acid addition salt by reacting with a pharmaceutically acceptable acid.

Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, and organic acids such as oxalic acid, maleic acid, fumaric acid, ricinic acid, tartaric acid, citric acid, and benzoic acid. can.

The target compounds obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, and thin layer chromatography.

Incidentally, the present invention naturally also includes optical isomers.

When the compound of general formula (1) and its salts are used as antihistamines, antihypertensives, and central nervous system depressants, they are usually put into the form of a pharmaceutical composition together with a pharmaceutical carrier. As a partner, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc., which are commonly used to prepare drugs according to the usage form. can be used.

As the dosage unit form of the antistaminic agent, antihypertensive agent, and central nervous system depressant, various forms can be selected depending on the therapeutic purpose. Typical examples include tablets, pills, powders, solutions, suspensions, emulsions, granules, forceps, suppositories, and injections (
(solutions, suspensions, etc.), ointments, etc. When molding into tablet form, carriers such as lactose, sucrose,
Sodium salt, sugar solution, urea, excipients such as calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, Panor L, bamboo syrup, etc. Dose sugar, decimal solution, gelatin solution, carboxydimethylcellulose, shellac, methiphrecel 0-su,
Binders such as potassium phosphate, polyvinyl 01 nodone,
Dry starch, sodium alkosinate, agar powder, laminaria powder, sodium hydrogen carbonate, calcium carbonate, twin, sodium sulfate, stearic acid [
Nocriceride, Dec'5. ．． 7. Disintegrants such as lactose, disintegration inhibitors such as sucrose, stearone, cocoa butter, hydrogenated oil, etc., absorption enhancers such as quaternary ammonium bases, sodium lauryl sulfate, silicerin, de:/'5, etc. 11. Before moisturizing, adsorbents such as desiccant, lactose, kaolin, bentonite, colloidal silicic acid, and lubricants such as purified talc, stearate, boric acid powder, macrodur, solid polyethylene resin, etc. You can use a brightener etc. When forming into a pill form, carriers such as excipients such as glucose, lactose, ginseng, cacao butter, hydrogenated vegetable oil, kaorishi, and talc, gum arabic powder, toratoshito powder, gelatin, and ethanol are used. A binder, a disintegrant such as laminaria, or kashten, etc. can be used. Furthermore, the tablets can be made into conventionally coated tablets, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated ink tablets, double tablets, or multilayer tablets, if necessary. When forming into a suppository, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin y1 semi-synthetic glyceride, etc. can be used as carriers. Solutions, emulsions, suspensions, etc. prepared as injections are usually sterilized and preferably isotonic with blood. When molding these liquid preparations, use diluents such as water, ethyl alcohol, propylene glycol, isostearyl alcohol, polio + isostearyl alcohol, polio and isostearyl silicide, solvita υ Esters etc. can be used. In this case, the preparation may contain a sufficient amount of salt, glucose or chrycerin to prepare an isotonic solution. The pharmaceutical compositions in the various forms described above may contain conventional solubilizing agents, buffering agents, soothing agents, preservatives, etc., as well as coloring agents, preservatives, fragrances, flavoring agents, sweeteners, etc., as necessary. It is possible to add and blend other pharmaceutical products. When forming pastes, creams, and gels, diluents such as white wax,
Paraphyte, chrycerin, cellulose derivatives, polyethylene glycol, silicoυ, bethonite, etc. can be used.

The amount of the compound of general formula (1) or a salt thereof to be contained in antihistamic agents, antihypertensive agents, and central nervous system depressants is not particularly limited and can be appropriately selected within a wide range, but usually 1 to 70% of the total composition. It is preferable to express it in weight %.

The above-mentioned antihypertensive drugs, antihypertensive drugs, and central nervous system depressants are administered in various ways depending on their form.

For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are administered orally; injections are administered alone or (
It is administered intravenously mixed with normal replacement fluids such as glucose and amino acids, or administered alone intramuscularly, subcutaneously, subcutaneously, or intraperitoneally; suppositories are administered rectally, and softeners are applied. .

The dosage of the compounds of the present invention and their salts as antistatic agents, antihypertensive agents, and central nervous system depressants is appropriately selected depending on the purpose of use, symptoms, and the like. Usually, a pharmaceutical composition containing about 40 μ2 to 10 μg/kg of the compound of general formula it) or a salt thereof per day may be administered in 3 to 4 divided doses.

Hereinafter, production examples of the raw material compounds used for producing the compounds of the present invention will be listed as reference examples, and then production examples of the compounds of the present invention will be listed as examples, but the present invention is not limited thereto.

Reference example 1 ■ Ethanol 20ml with 1.25F sodium hydroxide
4. Add 2-amino-5-meth+Cibe'J centiol to the solution. l' and 3.57 methyl chloroacetate,
Reflux for 3 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with chloroform. 100 ml of a 47% hydrobromic acid aqueous solution was added to the residue after chloroform was distilled off, and after refluxing for 3 hours, the solvent was distilled off, and the resulting residue was recrystallized from ethanol.
- Shidoro Beef Sea 211-1.4-Benzithiazine-3 (
4ff)-on 1.51 is obtained.

Colorless powder melting point 240-242℃ (decomposed) Elemental analysis value (as C3H, 02NS) HN Calculated value (chi) 53.02 3.89 7.73 Analysis value (%) 53.14j, 80 7.69 NMR (d
6-DMSO) δpp7n= 3.3C2H, 4.5-6.3(]
J7. hs), TSP 6.46CIH, dd, 7Hz, 2Hz), 6.59
(IH, c!, 2H2), 6.73 (Iff, d
.

7 #z), 10.12 (III, J-) JR (KEr) ν” = +642.3220 mαX ■ 6-Med 10 Sea 211-1.4-Pen Soti Aji Sea
3 (4H) - 47% hydrobromic acid aqueous solution IQQmA at J2.09! After refluxing for 3 hours, the solvent was distilled off, and the resulting residue was recrystallized from ethanol. NMR and I
Confirmed from R, 1.42 of 6-B-2H-1,4-B-3(4H)-O2 is obtained.

Colorless powder elemental analysis value (as C3H702NS) CHN Calculated value (%) 53.02 3.89 7.73
Analysis value (%) 52.98 3.92 7.69
Reference example 2 ■ 7-Hydroxy2H-1,4-besidithiazine-
3(4H)-Sai 1.52, DBUl, 5ml and 1.
1.77 ml of 3-dichloropropane was dissolved in 30 ml of isopropanol, and after stirring under reflux for 3 hours, it was dried under reduced pressure. It was recrystallized from 7-(3-zu0nanazuropogyushi)-2H-1 of about 3/10 by NMR.
, 7-( containing 4-besidithiazin-3(4H)-one)
1.22 of 3-chloro-2B'-1,4-besisothiadicy-3(IM)-one is obtained.

NMR (DMSO) δpp″l = 2.12 (2H, m), :3.34 (
2H, -? ), TSP 3.55 (2H,t, 6ffz), 3.69 (2
B'.

t=6Hz), 3.97 (2H,t, 6Hz
), 6.6-6.9C3H,yn), 10-28 (
IH, s) ■ 8-Hydroshishi 2H-1.4-Beshijioshi Sajin-3 (44)-years old, 718.3f, 3-
zu0'f.

-1-ri OJbzuDpa: /20m1 and DBU20m
1 is added to isodurobanol 400711J, and the mixture is refluxed for 885 hours under a stream of argon. After distilling off the solvent, water from the large bones is added to the residue and stirred. The precipitated crystals were collected, recrystallized with ethanol, and NMR showed 115 8-(3-zu0muzurobo+shi)-2H-1,4-be, 7rioshisagyshi3
(4H)-8-(3-riOruzu0bogyushi)-2H-1,4-pen9saiji4jji,1/
-3(4H)-one 5.749 is obtained.

colorless needle crystals Melting point: 179-180℃ ■ The following compound is obtained in the same manner as in the above ■.

03-ZromzuOpogyoshi substitution product at NMR at 215
Contains 7-(3-riol)-2H-1,4-pensoogyushi-3(4H)-on colorless powder (ethanol) Contains 6-(3-riol"jOboshi) -211-1,4
- Heshisoujisaiji 3 (4H) - Oshi Colorless Powder (Ethanol) Melting Point 123-124℃ 07- (4-Drombut + Shi) -2H-1,4-Benzoi J-3<411) - Oshi Colorless Needle crystals (ethanol-L) Melting point 143-147°C Example 1 7-(3-ri0ro'JJOpo+shi)- obtained in the above reference example
2H-1,4-besizothiadicy-3(4H)-oxyI,
22 and sodium iodide 1.52 in acetonitrile 2
After refluxing for 3 hours, 0.96F of 4-(3-D-lophenyl)piperazine and 1.0% of triethylamine were added.
After adding 0 Tnl and refluxing for 2 hours, the mixture was dried under reduced pressure. After separation using silica gel ((1'-200) glue and 1 column column, it was recrystallized from ethanol and 7-C3-(4-(3-
riDrophenyl)-1-piperazinyl)zuropogyushi)-
2H-1,4-pendithiadiυ-3(4H)0.61F
get.

Colorless acicular crystals Melting point 145-146°C Example 2 8-(3-Chloropo+shi)-2H obtained in the above reference example
-1,4-Besidio Beef Sujin-3(4H)-OshilOP
and sodium iodide 12.1 to acetonitrile 200
m1 and reflux for 4 hours. 4-(3-methylphenyl)hyperazide 8.76F and triethylamine 8.66ml were added to the reaction solution. and reflux for 4 hours. After evaporating the solvent, chloroform and an aqueous sodium bicarbonate solution are added to the residue for extraction.

The organic layer was dried over magnesium sulfate and evaporated, and the resulting residue was recrystallized from ethanol to give 8-[:3-(+-C3-
methylphenyl)-1-piperazinyl)zu0po+shi)-
2H-1,4-Benziobeef tendon-J-3(4J7)-one 7.12 is obtained.

Colorless flakes Melting point: 184-185.5°C Examples 3-20 In the same manner as in Examples 1 and 2, the following compounds of Examples 3-20 are obtained.

Example 3 6-(3-(4-phenyl-I-piperazinyl)Dpo+shi)-24-1,4-benzisythc 3 (44)
-White colorless plate crystals (ethanol-water) Melting point 174-175°C Example 4 4-Methyl-6-(3-(4-phenyl-l-piperazinyl)-2H-1,4- Benzionitris 3(17)-one I hydrochloride colorless platelet crystals (ethanol) Melting point 229-230°C Example 5 6-[3-(4-(2,3-dimethylphenyl)-1
-piperazinyl)dO+S]-2H-1,4=Pendio-Sazi,/-3(4H)-O2 Colorless plate crystals (ethanol) Melting point 147-148°C Example 6 6-C3-(4- (3-Methylphenyl)-1-biperazinyl) 50bo + C':l -2H-1,4-vesidio-beef horseradish'J-3(4H)-Osicolorless phosphorus flake crystals (Iso-panol) Melting point 142 ~143°C Example 7 6-C3-(+-(3-chlorophenyl)-1-piperazinyl)-JO-2H-1,4-benzione-3(4H)-Saiυ Colorless Needle-like crystals (ethanol) Melting point 157-157.5°C Example 8 7-(3-(4-phenyl-1-piperazinyl)propo+cy)-2H-1,4-hesidiosudine-3(4H)
-Osi colorless prismatic crystals (ethanol) Melting point 181-183°C Example 9 7-C3-(4-C3-chlorophenyl)-1-piperazinyl)duro+shi]-2H-1.4-benzoosadi, 17-3(4H)-one·l hydrochloride colorless prismatic crystals (methanol) Melting point 256-259°C (min wf) Example IO “t-[: 3-(4-(2,3--;methylphenyl) )-1-perazinil) -2H-1
,4-bendios,;C3(44)-oxy-l hydrochloride colorless prismatic crystals (methanol) Melting point 272-277°C (decomposed) Example 11 7-C3-(4-(2-ethyl diphenyl) )-1-Piperazinyl)-2, H-j, 4-be, 7-dihydric 3(4H)-1-water fD colorless prismatic crystals (ethanol) Melting point 149-151°C Example 12 7-C3-(4-(3-methylphenyl)-1-piperazinyl)J-2H-1,4-benzinyl 3(4H)-oxycolorless plate crystals (ethanol) Melting point: 191-192°C Example 13 7-C3-(4-(4-methylphenyl)-1-piperazinyl)-2H-I, 4-benzyl-3(4H)-oyl colorless plate Crystal (ethanol) Melting point 167-169°C Example 14 4-Methyl-7-C3-(+-(3-methylphenyl)
-1-perazinil)-2H-I, 4-be'J-dihydrochloride colorless needle crystals (ethanol) Melting point 192-197°C Example 15 4 -be, 7. , ;R7-[:3-(4-(3-methylphenyl)-1-piperazinyl)zuropo+shi]-2H-
1.4-C4-(4H)-one dihydrochloride colorless powder (ethanol) Melting point 174-179°C Example 16 7-C4-(+-(3-methylphenyl)-1-piperazinyl) Shishi': J-2H-1.4-beshizuojusajishi 3(4H)-oshi colorless lishi flakes (ethanol) Melting point 123-124°C Example 17 8-1:3-(4-(3-chloro) phenyl)-1-[:
Perazinil)DPo+Si]-2H-1,4-bendios,;-J-3(4H)-one Colorless lisi flakes (ethanol) Melting point 183°C Example 18 8-C3-(4- (2,3-”:;methylphenyl)-
1-Piperazinyl)-2H-1,4-vesidiolysine-3(4H)-O colorless flakes (methanol), melting point 197.5-205°C NMR (DMSO) p, 7; −+, r−2, o(2x, m), 2.1
(3H,, r), 2.15 (3E', E > 2.3-2.6 (6H, m), 2.6-2.8 (4H
.

771), 3.95 (2H,t, 6Hz), 4.
45 (2H.

S), 6.3-6.9 (6H, m), 10.5 (I
H*bs) IR (KBr) Example 19 4-Methyl-8-43-(Imaichi (3-methylphenyl)
-1-piperazinyl)zu Robogyushi] -2H-1.4-Beshisooshi Sajishi 3 (4H) -Oshi! Hydrochloride colorless needle crystals (isodpanol-water) Melting point 214-215°C Example 20 6-C3-(4-(3-methylphenyl)-1-piperazinyl)'-2B-1 , 4-Hydroxysilyl 2H-1.4-Pendiolysine-3
C4H)-oxy16.5y, 3-1:4-(3-O-lophenyl)-1-piperazinyl]-1-d'ezuloba, J131.8F and DBUI5. 0 ml to 100 ml of isodurobanol and refluxed under a stream of alkaline air for 12 hours. After evaporating the solvent, a 5% aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with chloroform. The extract was concentrated under reduced pressure, purified using silica gel (C-200) column chromatography, and recrystallized from ethanol to yield 8-(3-[4-(3-chlorophenyl)-1-piperazinyl]zu0bo+shi). -2
H-1,4-hesidio medium sagyshi 3 (IM)-oshi8.
Get 21.

Colorless flaky crystals Melting point: 183°C Example 22 In the same manner as Example 21, Examples 1 to 16 and 18 were prepared.
~20 each compound is obtained.

Example 23 8-[3-(4-(3-methylphenyl)-1-piperazinyl)zurobo+shi]-2H-1,4-beshizo+sajiJ-3(4H)-oy 4.9 f 617 ml of 60% sodium hydride was added to 5 Qml of dimethylbormamide solution, and the mixture was stirred for 1 hour while cooling with water.

812 μt of methyl iodide was added dropwise to the reaction solution, and after stirring overnight, the solvent was distilled off under reduced pressure. Oloborum and water are added to the residue for extraction, and the chloroform layer is washed with water several times and then distilled off to obtain a red oil. A solution of 1.5 ml of #hydrochloric acid in methanol 25% was added to 2.5 ml of red oil purified by column chromatography, and the solvent was distilled off to obtain a white solid hydrochloride salt, which was recrystallized from isobasanol-water. 4-methyl-8-[3-(4-(3-methylphenyl)-1-piperazinyl)-50po+cy]-2H-1,4-pendio±
1.3 El of Sajin-3 (44)-one I hydrochloride is obtained.

Melting point of hot colored needles 214-215°C Example 24 In the same manner as in Example 21, Examples 4.14 and 15 were prepared.
Each compound is obtained.

Examples of pharmacological tests for the compounds of the present invention are listed below.

<Pharmacological test example 1> Suppressive effect on dithesy pink behavior in mice induced by methamphetamine and L-dopa - Group of 6 d and dy male and female mice weighing 17-251 days and night fasted)
7. The test compound was orally administered, and 40 minutes later, 74 μ/Kp was administered intraperitoneally. Further, 15 minutes after the administration of methamphetamine, 400 μl/~ of L-dopa was administered intraperitoneally. The number of hiccups of the mouse for 60 minutes after administration of L-dopa is measured. Mice were placed one by one in a 2-ton glass beaker and measured after L-dopa administration! Jisei of time: If the number of times of J-bini or I is 10 or less, it is considered to be suppression positive, and if it is more than 10 times, it is considered to be negative.

The effective dose (ED5o value) of the test compound that can cause 3 out of 6 animals in a group to be positive is calculated.

In addition, the number of repetitions per hour for the physiological saline administration group was 150 to 200 times. [H0Lαl, F,
C, colpagrat and P, La, daro.
nEuropactn J.

Pharm, 30.113-I 16 (1975
)] As a test compound? -C3-(4-(3-methylphenyl)-1-piperazinyl) proponate 2H
As a result of the above test using -1,4-Beshizoo and Bovine Sagyshi 3(4H)-Oshi, the ED3° value of the compound was 4.0~/
It was Ky.

Pharmacology Test Example 2 Mouse Epinephrine Antagonism - The test compound is orally administered to DDY male mice (10 mice per group) weighing 17 to 2 hours, fasted day and night, and 1 hour later, 40 my/Ky of epinephrine is administered intraperitoneally. . The number of surviving and dead mice is measured for 24 hours after administration of epinephrine, and the ED5o value is calculated from the number of survivors.

In the control group administered with physiological saline, all 10 mice died within several minutes of administration of ehinephrine. [Loeuy, E.

R, and Ihcetich A, J, Pha.
rmctcol, Exp, Ther.

93.434-443 (19+8) and E.
A11erL.

H, C, Ftrgtbson, and R, H, Car.
, Jr., Artn, trtm-Forsch (Dr.
wyl Rgs, ), 24,917-922 (
1974)] As a test compound, 7-(3-(4-(3-methylphenyl)-1-piperazinyl)-2H-1,4
As a result of the above test using dicy-3(44)-oxy in -benzi, the EI)5 value of the compound was 5.03wy/9f6.

Examples of formulations using the compounds of the present invention are listed below.

Formulation example l Cocystarch 132 ■ Macnesium stearate I 8 vy lactose 45 g total
Tablets of the above composition in one iron are prepared by a conventional method.

(that's all)

Claims (1)

[Scope of Claims] ■ General formula [In the formula, R1 is a hydrogen atom, a lower alkyl group, or a nyl-lower arunal group, R2 is a lower alkyl group, a lower alkyl group, or a halogen atom, and A is a A lower alkali group, Z
represents an oxygen atom or a sulfur atom, and ru represents 0 or an integer of 1 to 3, respectively. ] and its salts.