CN105111126A - Isatin derivative 6-bromo-2,3-dioxoindolin-N-halogen substituted phenylacetamide, and preparation method and application thereof - Google Patents

Abstract

The present invention relates to a kind of antidepressant, anticonvulsant novel compound and its druggable salt, it is isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen represented by formula (I) Substituted phenylacetamides: The isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen substituted phenylacetamide method has the characteristics of flexible reaction time, high yield, easy operation and wide application range, and is suitable for industrialization Production. The neurotoxicity is very low, and the new compound synthesized by the present invention shows that its antidepressant activity is similar to that of the contrast drug fluoxetine in the pharmacological experiment results of forced swimming in mice, and the neurotoxicity is very low (TD ₅₀ >1000mg/kg) , is very safe, and in the anticonvulsant experiment, isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen substituted phenylacetamide can show anti-convulsant effects induced by the chemical substance pentylenetetrazole. It is a good antidepressant and antiepileptic compound.

Description

Isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen substituted phenylacetamide and its preparation method and application

technical field

The invention relates to a class of medicinal compounds and a preparation method thereof, in particular to a isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen substituted phenylethyl ether used as antidepressant and antiepileptic Amide, preparation method and application in preparation of antidepressant and antiepileptic drugs.

Background technique

Depression is a psychosomatic disease characterized by abnormal behavior and low mood as the main symptoms. Depression can affect people's digestion, immunity, nervous system and other functions, and even cause damage, and the disease has the characteristics of high morbidity, refractory cure and high recurrence rate. Epilepsy is a collective term used to describe a group of chronic convulsive disorders that are characterized by transient seizures accompanied by loss or disturbance of consciousness. Relevant studies have shown that epilepsy and anxiety and depression may have a common neurobiological pathogenesis. The study believes that the structural abnormalities of the frontal and temporal lobes and the secretion of neurotransmitters (r-aminobutyric acid, 5-hydroxytryptamine, norepinephrine and dopamine) in the brain Reductions are jointly involved in the occurrence of epilepsy and anxiety-depression. Many areas of the brain that cause seizures are involved in the expression of fear, and the amygdala is thought to play a key role in this, and anxiety and depression are thought to be based on amygdala-based conditioned emotional associations.

In clinical application, a variety of drugs have been used alone for antidepressant patients, such as amitepine, clomipramine, moclobemide, fluoxetine, paroxetine, sertraline, citalopram, etc.; There are also many kinds of antiepileptic drugs that can be used alone in clinical application, such as phenytoin, phenobarbital, valproic acid, carbamazepine, lamotrigine, etc.; but doctors will not choose it for patients with epilepsy and depression. Antidepressant drugs, as a result, can make the patient's depression worse. Some drugs, including epilepsy drugs, can also cause depression. Some antiepileptic drugs are closely related to behavior changes and depression. Other antiepileptic drugs can reduce the level of folic acid in the body. It can also lead to depression.

For this reason, a novel compound with completely new structural features and a new mechanism of action is needed for patients with coexistence of epilepsy, anxiety and depression.

Contents of the invention

A technical problem to be solved by the present invention is to provide a novel isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen substituted benzene that can be used as antidepressant and antiepileptic. acetamide.

Another technical problem to be solved by the present invention is to provide a preparation method comprising the above-mentioned compound in view of the current state of the art.

Another technical problem to be solved by the present invention is to provide a kind of isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen substituted phenylacetamide for the present situation of the prior art in the preparation of antidepressant, Use of antiepileptic drugs.

The technical solution adopted by the present invention to solve the above-mentioned technical problems is: a kind of isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen substituted phenylacetamide represented by formula (I):

In the formula, R is a halogen or a halogen-substituted alkyl at any substitution position and any substitution number of the benzene ring.

In formula (I), R is 2-F, 3-F, 3-Cl, 2-Br, 3-Br, 3-CF ₃ .

The following compound represented by the general formula I of the present invention is preferably: 6-bromo-2,3-dioxoindoline-N-halogen substituted phenylacetamide.

The present invention also includes a pharmaceutical composition comprising as an active ingredient the isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen substituted phenylacetamide according to claim 1 or 2 And one or more inert, non-toxic pharmaceutically acceptable carriers.

The pharmaceutically acceptable excipients are inert and non-toxic excipients. Among the pharmaceutical compositions according to the invention, mention may especially be made of those tablets or sugar-coated tablets, sublingual tablets, gelatin capsules, suppositories, Cream, ointment, dermal gel, injectable formulation or drinkable suspension.

The present invention also provides a method for preparing a compound represented by general formula I, which method is based on general formula II as a starting material:

Compound II reacts with substituted phenyl chloroacetamide through nucleophilic substitution reaction, and the product obtained is obtained by general formula I through recrystallization.

The concrete steps of described nucleophilic substitution reaction are:

Add 30mL DMF to a 50mL round bottom flask, add 3.4mmol compound II (6-bromo-2,3-indoledione) in batches under ice-cooling, stir and dissolve, then add 3.4mmol K ₂ CO ₃ 0.3g in one go, Stir to room temperature and continue to stir for 1 h; add 0.53 g of 3.4 mmol substituted phenyl chloroacetamide and 0.5 g of potassium iodide 6 mmol, raise the temperature to 80°C for 2-24 h, monitor the reaction by TLC until the reaction is complete, cool to room temperature, and add about 6 times distilled water to the volume of the reaction solution, dilute hydrochloric acid was added dropwise to adjust the pH value of the solution to 3-4, stirred for 10 minutes, suction filtered, dried, and the crude product was recrystallized with ethanol to obtain the product.

Application of the above-mentioned isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen substituted phenylacetamide and the pharmaceutical composition in the preparation of antidepressant and antiepileptic drugs.

Compared with the prior art, the present invention has the following advantages: the compounds of the present invention have antidepressant and anticonvulsant properties, so that they can be used as antidepressant and antiepileptic compounds. The results of pharmacological experiments of swimming showed that its antidepressant activity was similar to that of the control drug fluoxetine, and its neurotoxicity was very low (TD ₅₀ >1000mg/kg), and its safety was very high. In the anticonvulsant experiment, isatin derivative 6 -Bromo-2,3-dioxoindoline-N-halogen-substituted phenylacetamides can be shown to protect against convulsions induced by the chemical substance pentylenetetrazole, the compound I (6-bromo-2,3-di Oxoindoline-N-halogen substituted phenylacetamide) has the biggest advantages of rapid onset at low doses, relatively low toxic and side effects, and good safety, and the toxic and side effects of compound I of the present invention are better than those of clinical fluoxetine In addition, the preparation of the present invention, the isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen substituted phenylacetamide method has the advantages of flexible reaction time, high yield and easy operation , the characteristics of a wide range of applications, suitable for industrial production.

Detailed ways

The present invention will be further described below through embodiment.

Embodiment 16-Bromo-2,3-dioxoindoline-N-halogen substituted phenylacetamide derivative physical constant

(a) Preparation of 6-bromo-dioxoindoline-1-yl-N-(2-fluorophenyl)acetamide

Add 30mL DMF into a 50mL round bottom flask, add 3.4mmol compound II (6-bromo-2,3-indoledione) 0.5g in batches under ice bath, stir and dissolve, then add 3.4mmol K ₂ CO ₃ 0.3 g, stirred at room temperature for 1h. Add 0.42 g of 3.4 mmol of 2-fluorophenyl chloroacetamide and 0.5 g of potassium iodide 6 mmol, raise the temperature to 80° C. for 8 h, and monitor the reaction by TLC until the reaction is complete. Cool to room temperature, add distilled water about 6 times the volume of the reaction solution, add dropwise dilute hydrochloric acid to adjust the pH value of the solution to 3-4, stir for 10 min, filter with suction, dry, and recrystallize the crude product with ethanol to obtain product a. The spectral data of the compound are as follows: IR(KBr)cm ^-1 : 3495, 1732, 1651, 1251. ¹ H-NMR (CDCl ₃ , 300MHz): δ10.10(1H, s, -NH), 7.10-7.47(4H ,m,-C ₆ H ₄ ),7.51-7.84(3H,m,-C ₆ H ₃ ),4.73(2H,s,-CH ₂ ). ¹³ C-NMR(CDCl ₃ ,75MHz):138.36,170.03 , 162.57, 157.37, 149.29, 143.61, 132.85, 130.75, 129.52, 129.22, 124.98, 121.45, 120.57, 120.30, 114.96, 48.08. MSm/z: 378 (M+1).

(b) Preparation of 6-bromo-dioxoindolin-1-yl-N-(3-fluorophenyl)acetamide

Add 30mL DMF into a 50mL round bottom flask, add 3.4mmol compound II (6-bromo-2,3-indoledione) 0.5g in batches under ice bath, stir and dissolve, then add 3.4mmol K ₂ CO ₃ 0.3 g, continue to stir for 1 h after room temperature. 0.42 g of 3.4 mmol of 3-fluorophenyl chloroacetamide and 0.5 g of potassium iodide 6 mmol were added, and the temperature was raised to 80° C. for 10 h. The reaction was monitored by TLC until the reaction was complete. Cool to room temperature, add distilled water about 6 times the volume of the reaction solution, add dropwise dilute hydrochloric acid to adjust the pH of the solution to 3-4, stir for 10 min, filter with suction, dry, and recrystallize the crude product with ethanol to obtain product b. IR(KBr)cm ^－1 :3500,1733,1648,1253. ¹ H-NMR(CDCl ₃ ,300MHz):δ10.01(1H,s,-NH),6.90-7.41(4H,m,-C ₆ H ₄ ),7.43-7.7.74(3H,m,-C ₆ H ₃ ),4.57(2H,s,-CH2). ¹³ C-NMR(CDCl ₃ ,75MHz):138.43,169.34,162.43,156.64, 149.17, 143.17, 133.31, 129.52, 124.98, 121.45, 120.38, 115.62, 114.12, 112.60, 112.25, 48.29. MS m/z: 378 (M+1).

(c) Preparation of 6-bromo-dioxoindolin-1-yl-N-(3-chlorophenyl)acetamide

Add 30mL DMF into a 50mL round bottom flask, add 3.4mmol compound II (6-bromo-2,3-indoledione) 0.5g in batches under ice bath, stir and dissolve, then add 3.4mmol K ₂ CO ₃ 0.3 g, stirred to room temperature and continued to stir for 1h. Add 0.45 g of 3.4 mmol of 3-chlorophenyl chloroacetamide and 0.5 g of potassium iodide 6 mmol, raise the temperature to 80° C. for 2-24 h, and monitor the reaction by TLC until the reaction is complete. Cool to room temperature, add distilled water about 6 times the volume of the reaction solution, add dropwise dilute hydrochloric acid to adjust the pH value of the solution to 3-4, stir for 10 min, filter with suction, dry, and recrystallize the crude product with ethanol to obtain product c. IR(KBr)cm ^－1 :3497,1731,1649,1252. ¹ H-NMR(CDCl ₃ ,300MHz):δ10.11(1H,s,-NH),6.97-7.46(4H,m,-C ₆ H ₄ ),7.58-7.78(3H,m,-C ₆ H ₃ ),4.76(2H,s,-CH2). ¹³ C-NMR(CDCl ₃ ,75MHz):138.45,169.51,162.61,157.20,148.85, 143.24, 138.79, 132.76, 129.60, 126.54, 124.87, 121.32, 120.25, 117.78, 114.56, 48.27. MS m/z: 394 (M+1).

(d) Preparation of 6-bromo-dioxoindolin-1-yl-N-(2-bromophenyl)acetamide

Add 30mL DMF into a 50mL round bottom flask, add 3.4mmol compound II (6-bromo-2,3-indoledione) 0.5g in batches under ice bath, stir and dissolve, then add 3.4mmol K ₂ CO ₃ 0.3 g, stirred to room temperature and continued to stir for 1h. Add 0.55 g of 3.4 mmol of 2-bromophenyl chloroacetamide and 0.5 g of 6 mmol of potassium iodide, raise the temperature to 80° C. for 8 h, and monitor the reaction by TLC until the reaction is complete. Cool to room temperature, add distilled water about 6 times the volume of the reaction solution, add dilute hydrochloric acid dropwise to adjust the pH value of the solution to 3-4, stir for 10 min, filter with suction, cold water, dry, and recrystallize the crude product with ethanol to obtain product d. IR(KBr)cm ^－1 :3501,1733,1649,1253. ¹ H-NMR(CDCl ₃ ,300MHz):δ9.78(1H,s,-NH),7.02-7.57(4H,m,-C6H4) ,7.60-7.72(3H,m,-C ₆ H ₃ ),4.86(2H,s,-CH ₂ ). ¹³ C-NMR(CDCl ₃ ,75MHz):138.37,169.11,165.32,156.34,152.01,143.32, 138.47, 135.38, 132.38, 128.37, 128.01, 127.64, 127.42, 120.49, 109.88, 43.27. MS m/z: 439 (M+1).

(e) 6-bromo-dioxoindolin-1-yl-N-(3-bromophenyl)acetamide

Add 30mL DMF into a 50mL round bottom flask, add 3.4mmol compound II (6-bromo-2,3-indoledione) 0.5g in batches under ice bath, stir and dissolve, then add 3.4mmol K ₂ CO ₃ 0.3 g, stirred to room temperature and continued to stir for 1h. Add 0.55 g of 3.4 mmol of 3-bromophenyl chloroacetamide and 0.5 g of 6 mmol of potassium iodide, raise the temperature to 80° C. for 2-24 h, and monitor the reaction by TLC until the reaction is complete. Cool to room temperature, add distilled water about 6 times the volume of the reaction solution, add dilute hydrochloric acid dropwise to adjust the pH value of the solution to 3-4, stir for 10 min, filter with suction, dry, and recrystallize the crude product with ethanol to obtain product e. IR(KBr)cm ^－1 :3497,1731,1648,1252. ¹ H-NMR(CDCl ₃ ,300MHz):δ10.13(1H,s,-NH),6.94-7.41(4H,m,-C ₆ H ₄ ),7.45-7.81(3H,m,-C ₆ H ₃ ),4.52(2H,s,-CH ₂ ). ¹³ C-NMR(CDCl ₃ ,75MHz):138.46,169.58,165.24,156.28,152.13 , 143.34, 138.53, 135.39, 132.27, 128.53, 128.15, 127.48, 127.33, 120.50, 111.32, 44.35. MS m/z: 439 (M+1).

(f) 6-bromo-dioxoindolin-1-yl-N-(3-fluoromethylphenyl)acetamide

Add 30mL DMF into a 50mL round bottom flask, add 3.4mmol compound II (6-bromo-2,3-indoledione) 0.5g in batches under ice bath, stir and dissolve, then add 3.4mmol K ₂ CO ₃ 0.3 g, stirred to room temperature and continued to stir for 1h. Add 0.53 g of 3.4 mmol of 3-fluoromethylphenyl chloroacetamide and 0.5 g of potassium iodide 6 mmol, raise the temperature to 80° C. for 2-24 h, and monitor the reaction by TLC until the reaction is complete. Cool to room temperature, add distilled water about 6 times the volume of the reaction solution, add dropwise dilute hydrochloric acid to adjust the pH of the solution to 3-4, stir for 10 min, filter with suction, dry, and recrystallize the crude product with ethanol to obtain product f. IR(KBr)cm ^－1 :3497,1731,1650,1253. ¹ H-NMR(CDCl _3, 300MHz):δ10.32(1H,s,-NH),6.95-7.50(4H,m,-C ₆ H ₄ ),7.67-7.81(3H,m,-C ₆ H ₃ ),4.56(2H,s,-CH ₂ ). ¹³ C-NMR(CDCl ₃ ,75MHz):185.14,169.29,165.48,159.41,149.05 , 143.34, 138.61, 134.41, 132.31, 128.28, 125.38, 123.67, 121.54, 120.54, 112.14, 109.43, 48.28. MS m/z: 428 (M+1).

Embodiment 2 anticonvulsant pharmacological experiment and neurotoxicity experiment

The forced swimming test is the most commonly used experiment for the study of depressants and antidepressants. The sum of the time for mice to give up swimming and struggling in the water is called the immobility time, which reflects the symptoms of helplessness in mice, while the forced swimming test The prolongation of the immobility time in the middle showed depression-like symptoms. The compound provided by the invention is screened by the mouse forced swimming test to evaluate its antidepressant efficacy and safety.

(1) Mice forced swimming test:

a method: see (PorsoltRDetal, ArchIntPharmaeodynTher, 1997) and other reported methods, after intraperitoneal injection for 30 minutes, put the mouse into the XSC-mouse constant temperature swimming instrument (in a bucket with a water depth of 10cm and a diameter of 34cm, the water temperature is 25 ± 2°C), observe the swimming situation of the mouse within 6 minutes, and count the accumulated immobility time of the mouse within 4 minutes after swimming (immobility means that the mouse stops struggling or the mouse is in a floating state, and the mouse limbs have slight movements to keep the head on the water).

Group b: ① vehicle blank group: intraperitoneal injection of 100mg/kg (0.1ml/20g) dimethyl sulfoxide (DMSO);

② Compound Ⅰ group: intraperitoneal injection of 100mg/kg each derivative 0.1ml/20g;

③ Fluoxetine positive control group: intraperitoneal injection of 100mg/kg fluoxetine 0.1ml/20g; record the accumulated immobility time of the mice in the 3 groups, and the experiment was repeated three times.

c results: each derivative induced immobility time under the dose of intraperitoneal injection of 100mg/kg (Control=112.6±12.3s; a=61.2±14.9s; b=68±27s; c=50.8±18.5s; d =76.2±9.1s; e=62.4±12.6s; f=66±16s; FLU=58.5±9.3s), compared with the model group there were significant differences (p<0.05, p<0.01, p<0.001), Can draw to show certain antidepressant activity, its antidepressant activity is similar to contrast drug fluoxetine, and neurotoxicity is very low (TD ₅₀ >1000mg/kg), safety is very high.

(2) Rotating Rod Toxicity Test

Method: 30 minutes after administration, the mice were placed on a rotarod instrument with an engraved diameter of 30 mm at a speed of 6 rpm, and the number of falls within 2 minutes was recorded to indicate their motor coordination ability. Each mouse was measured 3 times with an interval of 30 min, and the average value of the 3 measurements was taken. SPSS13.0 statistical software was used for one-way analysis of variance.

Where: ^a TD ₅₀ : half the toxic dose mg/kg;

It can be seen from the above table that the neurotoxicity of compound I is very low (TD ₅₀ >1000mg/kg), and the safety is very high.

Convulsion experiment induced by embodiment 3 pentylenetetrazole

The invention provides a basis for studying the therapeutic effect of the isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen substituted phenylacetamide on a mouse convulsion model induced by pentylenetetrazole.

a Model establishment: The convulsion mouse model was injected intraperitoneally with 90 mg/kg pentylenetetrazole, and the occurrence of convulsions in mice was observed within 30 minutes after intraperitoneal injection of pentylenetetrazole. Convulsions were diagnosed according to the Racine standard, and the acute convulsion model was successfully established if the mice had seizures of grade 4 or above.

b Observation indicators: observe the number of mice with convulsions in each group, calculate the percentage of convulsions, compare the difference between the administration group and the control group, and determine whether there is anticonvulsant activity. Index of convulsions: within 5-15 minutes after the administration of the mouse, clonic convulsions or excitatory jumps appeared, followed by bending of the forelimbs, rigidity of the hind limbs, and opisthotonus. These symptoms of rigidity of the hind limbs were sign.

c Grouping: Experimental mice (18-22g) are randomly selected, in groups of 3, both male and female. 30 minutes after the previous administration, the experimental mice were intraperitoneally injected with 90 mg/kg of pentylenetetrazole;

The experimental control group was given carbamazepine 100mg/kg, the number of mice with convulsions in each group was observed within 30 minutes, the percentage of convulsions was calculated, and the difference between the administration group and the control group was compared to determine whether there was anticonvulsant activity.

statistical processing

SPSS13.0 statistical software was used for processing, and the data was t test was used for comparison between groups. p<0.05 is statistically significant.

result

In the anticonvulsant experiment, except compound b, the other four compounds all showed anticonvulsion induced by the chemical substance pentylenetetrazol, among which compounds e and f had good anticonvulsant activity (see Table 1).

Table 1 Antiepileptic activity of compounds a-f in pentylenetetrazol-induced convulsion model

PTZ: subcutaneous pentylenetetrazole convulsion model; 5/5 (tonic seizures): no activity at the administered dose; 0/5-4/5 (tonic seizures): significant activity at the administered dose.

Claims (7)

1. A isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen substituted phenylacetamide represented by formula (I): In the formula, R is a halogen or a halogen-substituted alkyl at any substitution position and any substitution number of the benzene ring. 2. isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen substituted phenylacetamide according to claim 1, is characterized in that described R is 2-F, 3- F, 3-Cl, 2-Br, 3-Br, 3- _CF3 . 3. A pharmaceutical composition comprising as an active ingredient the isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen substituted phenylacetamide according to claim 1 or 2 and one or A variety of inert, non-toxic pharmaceutically acceptable carriers. 4. A preparation of isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen substituted phenylacetamide as claimed in claim 1 or 2, characterized in that: With general formula II as starting material: Compound II reacts with substituted phenyl chloroacetamide through nucleophilic substitution reaction, and the product obtained is obtained by general formula I through recrystallization. 5. the preparation method of isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen substituted phenylacetamide according to claim 4 is characterized in that: the nucleophilic substitution reaction The specific steps are: Add 30mL DMF into a 50mL round bottom flask, add 3.4mmol compound II (6-bromo-2,3-indoledione) 0.5g in batches under ice bath, stir and dissolve, then add 3.4mmol K ₂ CO ₃ 0.3 g, stirred to room temperature and continued to stir for 1 h; added 0.53 g of 3.4 mmol substituted phenyl chloroacetamide and 0.5 g of 6 mmol potassium iodide, raised the temperature to 80°C for 2-24 h, monitored the reaction by TLC until the reaction was complete, cooled to room temperature, and added about 6 times the volume of the reaction solution in distilled water, drop dilute hydrochloric acid to adjust the pH of the solution to 3-4, stir for 10 minutes, filter with suction, dry, and recrystallize the crude product with ethanol to obtain the product. 6. The application of isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen substituted phenylacetamide according to claim 1 or 2 in the preparation of antidepressant and antiepileptic drugs . 7. a kind of isatin derivative 6-bromo-2,3-dioxoindoline-N-halogen substituted phenylacetamide pharmaceutical composition according to claim 3 in the preparation antidepressant, antiepileptic drug application.