JPS5854141B2 - Method for producing isocarbostyryl derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 2-amino-3-phenylisocarbostyryl derivatives represented by general formula (n), which are characterized by acylating 2-amino-3-phenylisocarbostyryl derivatives represented by general formula (I). The present invention relates to a method for producing an acylamino-3-phenylisocarbostyryl derivative.

[However, in the general formulas (I) and (n), R1 represents a hydrogen atom, a nitro group, an amino group, a hydroxyl group, a lower alkoxyl group, and a norogen atom, and R2 represents a hydrogen atom, a halogen atom, a lower alkyl group, It represents a lower alkoxyl group, and R3 represents a hydrogen atom or a methyl group.

Note that cases where R1 and R2 are both hydrogen atoms and R3 is a methyl group are excluded.

The 2-acylamino-3-phenylisocarbostyryl derivative provided by the present invention is a new compound and is useful as a medicine for anticonvulsants, tranquilizers, analgesics, antipyretics, central depression, and the like.

]★ In carrying out the present invention, the 2-amino-3-phenylisocarbostyryl derivative (I), which is a starting compound, is produced by reacting the corresponding isocoumarin with hydrazine, and then carrying out a rearrangement reaction with hydrochloric acid. I can do it.

(L. Legrand, N. Lezach, B.
ull, Soc, Chim, Fr, 2237-223
(p. 9, 1970) In this case, the substituents R1 and R2 are selected from the groups shown in the general formula (I) above.

The lower alkyl group and the lower alkoxyl group include an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, n-7'lopyl, 1so-furovyl, n-butyl, tert-butyl, 1so-butyl, and 8ee-butyl. represent.

Halogen atoms represent chlorine, fluorine, bromine and iodine.

The acylating agent used in the acylation of the 2-amino-3-phenylisocarbostyryl derivative is acetic acid, acetic anhydride, acetyl halide, etc. when R3 is a methyl group; In the case of hydrogen atoms, concentrated formic acid or the like is used.

Their selection is appropriately selected depending on the reactivity of the amino group to be acylated and the reactivity of the substituents of R1 and R2.

The molar ratio of the acylating agent to the raw material is 2 to 50 times by molar.

The reaction temperature is appropriately determined depending on the acylating agent used, the reactivity of the amino group to be acylated, and the reactivity of the substituents of R1 and R2, but it is in the range of 00 to 150 ° C.
Reflux temperatures are particularly suitable.

However, if the acylating agent is acetyl...
It is carried out at a low temperature of 0-5°C.

The reaction time is determined by the acylating agent and reaction temperature selected, but it is preferable to monitor the progress of the reaction by thin layer chromatography to check for disappearance of the starting compounds.

This is usually carried out under reflux conditions for 2 to 4 hours.

When acetyl halide is used as the acylating agent, about 10 seconds is sufficient.

In acylation, when the acylating agent is other than acetyl halide, the acylating agent itself often serves as a solvent, so there is no need to add it.

When using acetyl halide, bases such as pyridine and triethylamine are effective as acid acceptors.

It is also effective to add dimethylformamide and an alkali metal carbonate.

Other solvents may be added as long as they do not interfere with the reaction.

Next, the pharmacological action of the compound obtained according to the present invention will be explained.

1. Hypnotic effect When the compound obtained in each of the Examples (excluding Example 7) (hereinafter referred to as the present compound) is dissolved in propylene glycol and administered intraperitoneally to mice, it exhibits a hypnotic effect;
That ED.

The value is 20-60rII9/kI! Met.

2. Anti-spasmodic effect a: A 1% solution of metrazol was injected into the tail vein at a rate of 0.33 ml/m using a microinjector into spastic mice caused by the compound, and the time until tonic spasticity occurred was determined. Observed.

The compound was dissolved in propylene glycol and administered intraperitoneally 20 minutes before metrazole injection.

As a result, it showed a strong anticonvulsant effect against tonic convulsions, with an ED5o value of 1.5 to 15 mm/kg.

On the other hand, it showed no inhibitory effect on electric shock caused by strychnine.

b. Electrical stimulation (Woodbury method) This compound was dissolved in propylene glycol and administered intraperitoneally to mice, followed by electrical stimulation (50 mA, 750 V, 0.1 s).
ec, 50 cps) to cause an electric shock attack, and the resulting tonic extensor electric shock (tonic e
xtension convulsion) and the time of onset of death as markers, the presence or absence of a delaying or suppressive effect of the present compound on both markers was observed.

For both markers, this compound has a 5-20 ■Dosage of 2/- significantly delayed or suppressed the effect.

3. Analgesic effect a, acetic acid Writhing method Inject 0.1ml of 0.7% acetic acid solution into the abdominal cavity of mice.
? It was administered in proportion to body weight, and the number of writtings that occurred was measured.

This compound was dissolved in propylene glycol and acetic acid was administered 3 times.
Injected subcutaneously 0 minutes ago.

The compounds of the present invention have an ED of 10 to 50 μ/kg.

Writhi■ was suppressed by the value.

b, Randall-8elitto method Ugo,
Analgesimeter manufactured by Ba5i1 was used to measure the pain threshold when applying pressure to the rat's hind limbs.

This compound was dissolved in 50% propylene glycol and administered intraperitoneally.

In this test, the compounds of the present invention were 2 to 10 times more effective than aminopyrine, which was used as a control drug.

4. Body temperature lowering effect This compound was administered intraperitoneally and orally to mice.

For intraperitoneal administration, it was dissolved in 85% propylene glycol, and for oral administration, it was suspended in 1% gum tragacanth solution.

When body temperature was measured from 30 minutes to 4 hours after administration, it showed a hypothermia effect, and its strength was 2 to 15 times that of aspirin and aminopyrine.

5. Using the locomotor-suppressing mouse, an Animex activity meter was used.
).

This compound was suspended in 0.5% CMC and administered intraperitoneally.

Locomotor activity decreased with administration of 2■/- or more, and 3 to 10■
It showed an ED5o value of /-.

6. Conditioned avoidance inhibition effect Measured using male Wistar rats and an escape/avoidance learning experimental device manufactured by Takei Instruments.

This compound was dissolved in propylene glycol and administered intraperitoneally.

2 seconds of illumination and 3 seconds of buzzer were used as conditioned stimuli, and 3 seconds of electric shock was used as unconditioned stimulus.

Administration of this compound at doses of 15 μ/- or more strongly inhibited conditioned avoidance over a period of 30 minutes to 4 hours.

7. Effect on brain waves Using a cat or rabbit with chronically implanted electrodes, this compound was dissolved in propylene glycol and intravenously injected at a rate of 0.5 In9/kg, and the brain waves were observed using a Sanei Sokki ■ electroencephalograph. Immediately after the injection, high-amplitude slow wave patterns mixed with the solution appeared in the neocortex, paleocortex, and old cortex;
It lasted for 2 hours and then recovered.

8. Acute toxicity The acute toxicity of this compound to mice is LD59 (intraperitoneal administration): 400 to 1000 μ/9, L
D59 (oral administration) is extremely low at 9 in 1000-2000 cm/.

Due to the above pharmacological properties, the compounds of the present invention are useful as medicines such as anticonvulsants, tranquilizers, analgesics, antipyretics, and central depressants.

When using this compound as a pharmaceutical, the dosage is appropriately selected depending on the route of administration, purpose of administration, etc. For example, when used orally as a tranquilizer,
It is advisable to give between 5 and 500 pounds per person.

The present compound can be administered in an appropriate dosage form, such as tablets, powders, capsules, granules, crude drugs, solutions, injections, and the like.

Administration routes include oral, rectal, and intravenous administration; oral and rectal administration are also suitable.

For the above administration, the compound of the present invention may be used alone, but it may also be administered in a composition containing pharmacologically acceptable adjuvants, excipients, granulating agents, lubricants, suspending agents, wetting agents, and the like.

Next, the present invention will be specifically illustrated with examples, but the present invention is not limited thereto.

Reference example 1 2,3-dihydro-4-(p-chlorophenyl)-IH
-2,3-penzodiacehin-1-one 3-(p-chlorophenyl)inkma') 70.51 and a small excess of hydrazine hydride are refluxed in ethanol 20 for 1 hour.

The solvent was distilled off under reduced pressure and the residue was recrystallized from ethanol to obtain 0.4S' white needle crystals.

Yield 90% Melting point 222° to 225°C UV λ meta / /L' (log, )Tanegi Calculated value as C;
66.55%, H; 4.10%, N; 10.35% Actual value C; 66.73%, H: 4.10%, N; 10
．． 05% Reference Example 2 2-amino-3-(p-chlorophenyl)isocarbostyryl 2,3-dihydro-4-(p-chlorophenyl)-IH
0.4y of -2,3-benzodiazepin-1-one is heated under reflux for 1 hour in a mixture of 2rILl of concentrated hydrochloric acid and 20rILl of ethanol.

After concentrating the solvent, it is made alkaline by adding a 10% aqueous sodium carbonate solution and extracted with benzene.

After drying with Glauber's salt, the solvent was distilled off and the residue was recrystallized from ethanol to obtain white needle-like crystals of 0.36F.

Yield 90% Melting point 161’C UV λmethanol (logε) aX 232mμ (4,53) 303mμ (4,21) 330mμ(4,16)S.

IRvcrtt-13300 (NH) 3200 (NH) 1650 (CO) Elemental analysis value C□, calculated value as H1□0N2C1 C;
66.55%, H; 4.1 0%, N; 10.35% Actual value C; 66.55%, H; 4.09%, N; 10
．． 21% Example 1 2-Acetylamino-3-(p-chlorphenyl)isocarbostyryl 0.51 of 2-amino-3-(p-chlorphenyl)incarbostyryl was mixed with acetic anhydride 207711 on a boiling water bath.
After heating for a period of time, ice water is added and the precipitated crystals are collected by suction filtration.

Recrystallization is performed with ethyl acetate to obtain white needle-like crystals of 0.49P.

Yield 85% Melting point 240°C UV λmethanol” (logε) ax 231 mμ (4,13) 290 mμ (3,85) 330 mμ (3,61) IRvcIIL' 3200 (NH) 1690 (C
o) 1658 (CO) Calculated value C as elemental analysis value C17H1302N2C1
; 65.28%, H; 4.18%, N; 8.95% Actual value C; 65.44%, H; 4.19%, N; 8.
83% Example 2 2-acetylamino-3-(p-tolyl)isocarbostyryl 2-amino-3-(p-tolyl)incarbostyryl 0
．． After heating 51 with 20 ml of acetic anhydride on a boiling water bath for 2 hours,
It is treated in the same manner as in Example 1 to obtain 0.41P white needle-like crystals.

(Recrystallization solvent, ethyl acetate) Yield 70% Melting point 197°C UV λ meta/ - meta/ (logε) aX 233 mμ (4,38) 290 mμ (4,14) 330 mμ (3,85) IRvcrrL' 3200 (NH) 1680(
CO) 1660 (CO) Elemental analysis value c18 HI3 Calculated value as o2N2 C
; 73.95%, H; 5.52%, N; 9.58% Actual value C; 73.79%, H; 5.53%, N; 9.
54% Example 3 2-Acetylamino-3-(p-methoxyphenyl)incarbostyryl 0.51 of 2-amino-3-(p-methoxyphenyl)incarbostyryl was heated with 20rrLl of acetic anhydride on a boiling water bath for 2 hours. Thereafter, it is treated in the same manner as in Example 1 to obtain colorless acicular crystals of 0.40P.

(Recrystallization solvent, ethanol) Yield 69% Melting point 196°C UV λ meta/-/l/ (logε)ax 231 mμ (4,27) 291 mμ (4,09) 330 mμ (3,81) IRvCrfL' 3200 (NH) 1690(C
O) 1660 (Co) Calculated value based on elemental analysis value Cl8H1603N2 C: 70.11%, H: 5.23%, N: 9.
09% Actual value C: 70.06%, H: 5.24%, N: 9.
23% Example 4 0.51 of 2-acetylamino-7-nitro-3-phenylisocarbostyryl 2-7mi/-7-nitro-3-phenylisocarbostyryl was heated under reflux in 30 rnl of acetic acid for 4 hours. do.

After concentrating the reaction solution, ice water is added and the precipitated crystals are collected by suction filtration.

Recrystallized from ethanol, 0.37? yellow needle-like crystals are obtained.

Yield 65% Melting point 218℃ Uv λmethanol” (log e) aX 235mμ(4,35)S.

IRvCrIL-13230(NH) 1680(Co) 1660(CO) 1328(NO2) Elemental analysis value Calculated value as C1□H13o4N3 C; 63.15%, H; 4.05%, N; 13
．． 00% Actual value C; 62.72%, H; 4.05%, N; 13
．． 02% Example 5 2-formylamino-3-phenylisocarbostyryl 0.5t
The mixture was heated under reflux for 1 hour in 20 ml of 99% formic acid.

After concentrating the reaction solution, ice water is added and the precipitated crystals are collected by suction filtration.

Recrystallize from ethanol to obtain scaly crystals of 0.482.

Yield 86% Melting point 202℃ UV λ meta/-/L/ (logε)ax 233mμ(4,41) 289mμ(4,13) 331mμ(3,64) IRvca' 3200(NH) 1697(CO) 1640(CO ) Calculated value as elemental analysis value C16H1202N2 C: 72.71%, H: 4.58%, N: 10
．． 60% Actual value C; 72.60%, H; 4.59%, N; 1
0.69% Example 6 2-formylamino-3-(p-chlorphenyl)incarbostyryl 0.51 of 2-amino-3-(p-chlorphenyl)isocarbostyryl in 20 ml of 99% formic acid for 1 hour The crystals were heated to reflux and treated in the same manner as in Example 5, and the obtained crystals were recrystallized using an inproper tool to obtain white granular crystals of 0.41'.

Yield 80% Melting point 198℃ UV λ meta7-7L' (logε) ax 233mμ (4,42) 291rrLμ (4,15) 330mμ (3,90) IRvcrIL' 3100 (NH) 1690 (C
O) 1665(Co) Calculated value as elemental analysis value C16H1,02N2C1 C
; 64.33%, H; 3.72%, N; 9.38% Actual value C; 64.31%, H; 3.65%, N; 9.
39% Example 7 2-formylamino-7-nitro-3-(p-chlorphenyl)incarbostyryl 2-amino-7-nitro-3-(p-chlorphenyl)
0.5y of incarbostyril was heated under reflux in 20ml of 99% formic acid for 1 hour, and the crystals obtained by treatment in the same manner as in Example 5 were recrystallized from ethanol to obtain 0.38y pale yellow needle crystals. .

Yield 70% Melting point 245℃ UV λ meta/-/l/ (logε)aX 235mμ(4,37)S.

IRvca' 3230 (NH) 169o (CO) 1666 (co) 1340 (NO2) Calculated value as elemental analysis value C16H1oO4N3Cl C
: 55.91%, H; 2.94%, N; 12.23% Actual value C; 55.87%, H; 2.80%, N; 12
．． 43% Example 8 2-acetylamino-7-amino-3-phenylisocarbostyryl 2,7-diami2-3-phenylisocarbostyryl.
Hydrobromide 0.51 and acetyl chloride 79.5P (
1 mol) is stirred for io seconds in 20 ml of pyridine at a temperature of 0-5°C.

Add ice water to the reaction solution, and collect the precipitated crystals by suction filtration.

Recrystallized from ethanol, 0.30? Obtain white scaly crystals.

Yield 68% Melting point 232℃ UV λ meta/-/L/ (logε)aX 231rrLμ(4,50) 307mμ(4,31) IRνcfrL' 3245(NH) 3220(NH) 3175(NH) 1660(CO) Element Calculated value as analytical value C17H1502N3 C: 69.61%, H: 5.15%, N: 14
．． 33% Actual value C: 69.86%, H: 5.17%, N: 14
．． 32% Example 9 Synthesis of 2-acetylamino-3-phenyl-7-chloroincarbostyryl 0.31 of 2-amino-3-phenyl-7-chloroisocarbostyryl was dissolved in 15-acetic anhydride at 80°C on a water bath. At 2
After heating and cooling for an hour, ice water was added to make it alkaline with NaHCO3, and the precipitated crystals were taken out by suction and recrystallized from benzene, with a melting point of 2.
Crystals at 05° C. were obtained in a yield of 85%.

Elemental analysis calculated value C; 65.28 H; 4.18 N; 8.95 Actual value C; 65.31 H; 4.19 N; 8.98 Infrared absorption (4 pairs) 3400 (NH) 1678, 165
0 (, > O) eOH Ultraviolet absorption (λ) aX 296 nm (log ε: 4.24) 340 nm (logg: 3.80) Example 10 Synthesis of 2-acetylamino-3-(p-fromophenyl)incarbostyryl 2 -amino-3-(P-7''romophenyl)incarbostyryl 0.31 in 15 ml of acetic anhydride on a water bath at 80°C.
After cooling for 2 hours, the mixture was made alkaline with NaHCO3 by adding ice water and the precipitate was recrystallized from ethyl acetate under suction F to obtain crystals with a melting point of 228°C in a yield of 80%.

elemental analysis Calculated value C; 57.16 H; 3.68N; 7.84 Minoru [K Nao] C ;57.62 H: 3.72 Nni A, 70 V λMeOH aX 233nmc1ogε:4.42) 272nm (logε: 4.15) 330nm (logε: 3.93)

Claims (1)

[Scope of Claims] 1. A compound of the general formula (II) characterized by acylating a 2-amino-3-phenylisocarbostyryl derivative represented by the general formula (I)
) A method for producing a 2-acylamino-3-phenylisocarbostyryl derivative. [However, in general formulas (I) and (II), R1 represents a hydrogen atom, a nitro group, an amino group, or a halogen atom, and R2 represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxyl group. , R3 is a hydrogen atom,
Indicates a methyl group. In addition, if R1 and R2 are both hydrogen atoms and R3 is a methyl group, this is excluded (.).