JPH049791B2 - - Google Patents

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention exhibits a remarkable anti-ulcer effect in experimental ulcers, particularly in water immersion restraint stress ulcer experiments using rats, and has been shown to have a significant anti-ulcer effect on the stomach and duodenum of mammals including humans. The present invention provides isatin derivatives and pharmacologically acceptable acid addition salts thereof useful as ulcer therapeutic agents.

[Conventional technology]

Traditionally, drugs used to treat gastric and duodenal ulcers include (1) antacids and anti-pepsin agents that neutralize and deactivate gastric acid or digestive juices in the stomach, (2) acetylcholine, a chemical mediator involved in the secretion of gastric acid, etc. Histamine, an anticholinergic drug that suppresses the secretion of gastric acid, etc. by antagonizing histamine.
H ₂ -Receptor Antagonist (3) Many drugs have been developed and used to protect and repair damaged gastric mucosa, such as gastric mucus secretion enhancers, local circulation improvers, and tissue repair agents.

In addition, prostaglandins, which are physiologically active substances in vivo, have recently attracted attention for their gastric acid secretion suppressing effects and cell protective effects, and the application of their derivatives to ulcer therapeutic agents is being considered.

However, few therapeutic agents for peptic ulcers have been developed that are effective for stomach and duodenal ulcers caused by stress, which have been on the rise in recent years.

[Problem that the invention seeks to solve]

Currently, the drugs used to treat gastric and duodenal ulcers are mainly antacids, antipepsin agents, anticholinergic agents, and histamine _H2 -receptor antagonists, all of which reduce secretion. It attempts to treat ulcers by neutralizing, inactivating, or suppressing secretion.

On the other hand, clinical findings suggest that patients with gastric and duodenal ulcers do not necessarily exhibit hyperacidity;
In fact, there have been many reports of cases showing hypoacidity.

It is said that there are many cases of gastric and duodenal ulcers caused by stress, which have been on the rise in recent years, but among the conventional ulcer treatments, none are effective for stomach and duodenal ulcers caused by stress. rare. For this reason, in actual treatment, a method is commonly used in which ordinary ulcer treatment agents are used in combination with anxiolytics, tranquilizers, and the like.

However, these drugs have a strong central depressing effect and often cause side effects such as hypnosis and motor inhibition.

[Means for solving problems]

The present inventors have conducted repeated research to find a compound effective for treating stress-induced gastric and duodenal ulcers, and as a result, they have discovered that the purpose can be achieved with a certain isatin derivative, and have accomplished the present invention.

That is, the present invention provides a general formula that exhibits a remarkable inhibitory effect on experimental ulcers, particularly in water immersion stress ulcer experiments using rats, and is useful as a therapeutic agent for gastric and duodenal ulcers in mammals including humans. (X in the formula is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group, an acylamino group, or an alkoxycarbonyl group, and Y
is a linear or branched alkylene chain having 2 to 5 carbon atoms) and pharmacologically acceptable acid addition salts thereof.

The compound represented by the general formula () of the present invention is a novel compound that has not been described in any literature, and can be produced as follows. That is, the general formula An isatin derivative represented by (X in the formula has the same meaning as above) and an equimolar or slightly excess molar amount of the general formula (in the formula, Z is an acid residue and Y has the same meaning as above) or an acid addition salt thereof, and the necessary amount of chlorination, such as sodium hydride, sodium amide, potassium tert- The reaction is carried out in the presence of butoxide or potassium carbonate, etc., in an inert solvent such as benzene, toluene, xylene, dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, etc., or a mixed solvent thereof, or the general formula (In the formula, X, Y and Z have the same meanings as above) and an equimolar to excess molar amount of 2,2,6,6-tetramethylpiperidine are mixed with a small amount of sodium iodide. and an inert solvent such as xylene, in the presence of the required amount of a base such as sodium carbonate or potassium carbonate, etc.
The desired product is obtained by reacting in a solvent such as N,N-dimethylformamide or without a solvent.

The isatin derivatives of general formula () and general formula () used as starting materials in this production method are both known compounds and can be easily obtained as commercial products or by manufacturing according to known methods. . [J.prak.Chem.]
Volume 315, Page 339, 1973, JP-A No. 55-62064] In addition, some of the compounds of general formula () used as starting materials in this production method are new compounds, but they can be prepared by the following method. It can be manufactured by For example, 2,2,6,6-tetramethylpiperidine and the general formula (R ¹ , R ² , R ³ and R ⁴ in the formula may be the same or different and each has a hydrogen atom or a carbon number of 1 to 1.
The alkyl group of 3) is reacted with the oxirane derivative represented by the general formula A 1-piperidine ethanol derivative represented by the formula (R ¹ , R ² , R ³ and R ⁴ have the same meanings as above) is prepared, and then a halogenating agent such as thionyl chloride or p-toluene is added to the derivative. By reacting with a sulfonylating agent such as sulfonyl chloride, benzenesulfonyl chloride, etc., the general formula ()
A compound in which the straight chain portion of Y has 2 carbon atoms can be produced using the compound. [Journal of Medicinal Chemistry (J.Med.Chem.) 6
Vol. 381, 1963, Chemical Abstracts Vol. 62, 9099b, 1965] Next, using this compound, a compound of the general formula () was obtained by carrying out a commonly used carburizing reaction. Compounds in which Y has three or more linear moieties can be produced.

The compound of general formula () used as a starting material in this production method is a known compound and can be obtained as a commercially available product or can be easily produced according to a known method.

In order to suitably carry out the first method of the method for producing a compound of the general formula () of the present invention, the isatin derivative represented by the general formula () and the isatin derivative represented by the general formula () and an equimolar to slightly excess molar amount of the general formula ( ) or an acid addition salt thereof is dissolved or suspended in a mixture with an inert solvent, such as dry N,N-dimethylformamide or dry toluene, and a necessary amount of a base, such as hydrogenation, is added under ice cooling. Add sodium, stir briefly at room temperature, and react for 1 to 20 hours with further heating. After the reaction is complete, the solvent is distilled off under reduced pressure, water is added to the residue, and extracted with a suitable solvent such as ethyl acetate or benzene.
After washing with water and drying, the solvent is distilled off under reduced pressure, and the residue is purified by an appropriate method to obtain the desired product.

In addition, in order to suitably carry out the second method for producing the compound of the general formula () of the present invention, the isatin derivative represented by the general formula () and an equimolar to excess molar amount of 2,2,6 , 6-tetramethylpiperidine, a small amount of sodium iodide, and the required amount of a base, such as potassium carbonate, at 100 to 160°C without solvent or in a solvent such as xylene for 30 minutes.
Allow to react for minutes to 3 hours. After the reaction is completed, if necessary, a solvent such as chloroform is added to the reaction mixture, washed with water, dried, and the solvent is distilled off under reduced pressure. The residue is purified by an appropriate method to obtain the desired product.

In the above reaction, when using a compound having an amino group as the nuclear substituent X in the compound of general formula () or (), it is better to protect the amino group with an acetyl group or the like prior to the reaction.
After the reaction is complete, the protecting group is removed according to a conventional method.

The isatin derivative represented by the general formula () thus produced can be converted into an acid addition salt according to a conventional method. For example, 1 N hydrochloric acid in a molar equivalent to a slight excess molar amount of ethanol is added, the solvent is distilled off under reduced pressure, and the remaining crystals are recrystallized from an appropriate solvent to obtain a hydrochloride. In addition to the above-mentioned hydrochlorides, examples of acid addition salts include hydrobromides, hydroiodides, sulfates, acetates, cyudates, malates, tartrates, citrates, mandates, Mention may be made of addition salts of inorganic or organic acids such as fumarates, maleates, benzenesulfonates, p-toluenesulfonates, and the like.

The isatin derivatives of the present invention represented by the above general formula () or their pharmacologically acceptable acid addition salts can be used in ordinary preparations as they are or after being mixed with appropriate pharmaceutical excipients. The drug is prepared into various dosage forms such as powders, granules, fine granules, tablets, capsules, syrups, liquids, and injections by various techniques, and then administered orally or parenterally.

When the isatin derivatives of the present invention represented by the general formula () or their pharmacologically acceptable acid addition salts are used for treatment, the dosage is determined by the age of the patient,
It is determined appropriately depending on gender, body weight, severity of symptoms, etc., but in general, for oral administration, 10 mg per day for adults.
~5000 mg, 1 per adult day for parenteral administration
Administered in the range of mg to 1000 mg.

〔Effect of the invention〕

The isatin derivatives represented by the general formula () and their pharmacologically acceptable acid addition salts of the present invention exhibit remarkable suppressive effects on experimental ulcers in animals, particularly stress ulcers. For example, in a water immersion restraint stress ulcer experiment using Wester male rats (8 weeks old), oral administration of 100 mg/kg of body weight shows an inhibitory effect of about 40% to 95%.

Furthermore, the isatin derivatives represented by the general formula () and their pharmacologically acceptable acid addition salts of the present invention have few side effects and low toxicity.

As described above, the isatin derivatives represented by the general formula () and their pharmacologically acceptable acid addition salts of the present invention exhibit strong anti-ulcer effects and have low toxicity, so they are suitable for use in mammals including humans. It is useful as a therapeutic agent for gastric and duodenal ulcers.

〔Example〕

The content of the present invention will be explained in further detail using the following reference examples and examples.

Note that the melting points of the compounds in each Reference Example and Examples are all uncorrected.

Reference example 1-(3-chloropropyl)-2,2,6,6-
Tetramethylpiperidine hydrochloride 10.00 g of 1-(2-chloroethyl)-2,2,6,6-tetramethylpiperidine hydrochloride and 6.40 g of sodium cyanide were suspended in 100 ml of dry dimethyl sulfoxide and stirred at 100°C for 5 hours. Ta. Water was added to the reaction solution, extracted with chloroform, washed with water, and then dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure to obtain an oily 3-(2,2,6,
6-tetramethylpiperidino)propionitrile
9.13g was obtained.

IR (neat): ν _CN 2250cm ^-1 NMR (CDCl ₃ ) δ: 1.04 (12H, s), 1.35~1.6 (6H, m), 2.3~
2.45 (2H, m), 2.75-2.9 (2H, m) 9.10 g of this nitrile was dissolved in 300 ml of ethanol, hydrogen chloride was introduced under ice cooling, and the mixture was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and an aqueous sodium bicarbonate solution was added to the residue, extracted with chloroform, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an oily 3-(2,
9.06 g of ethyl 2,6,6-tetramethylpiperidino)propionate was obtained.

IR (neat): ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 1.03 (12H, m), 1.26 (3H, t, J = 7.1Hz),
1.35-1.6 (3H, m), 2.35-2.5 (2H, m), 2.7
~2.85 (2H, m), 4.11 (2H, q, J = 7.1Hz) 9.00g of this ester and 200ml of diethyl ether
Dissolve 3.80 g of lithium aluminum hydride in 300 ml of diethyl ether while stirring under ice cooling.
The mixture was added dropwise to the suspension and heated under reflux for 16 hours. Water was added dropwise to the reaction solution while stirring under ice-cooling, and the insoluble matter was filtered off, and the filtrate was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain oily 3-(2,2,6,6-tetramethylpiperidino).
6.68 g of -1-propanol was obtained.

IR (neat): ν _OH 3300cm ^-1 NMR (CDCl ₃ ) δ: 1.11 (12H, s), 1.4-1.65 (6H, m), 1.72
(2H, quint, J=6.9Hz), 2.75 (2H, t, J=
6.9Hz), 3.80 (2H, t, J = 6.9Hz), 4.70 (1H,
br-s) Dissolve 6.60 g of this alcohol in 20 ml of chloroform and add 30 ml of thionyl chloride while stirring under ice cooling.
After dropping into the solution, the solution was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, diethyl ether was added to the remaining crystals, the crystals were collected by filtration, and then recrystallized from ethanol-diethyl ether to give 1-(3-chloropropyl)-2,2,6, with a melting point of 180-189°C. 7.40 g of 6-tetramethylpiperidine hydrochloride was obtained.

Elemental analysis value: (as _C12H25ClN・_0.1H2O ) C% H% N% Calculated value 56.29 9.92 _5.47 Actual value 56.07 10.22 5.33 NMR ( _d6 -DMSO) δ: 1.31 (6H, s), 1.47 (6H, s), 1.5-2.4
(8H, m), 3.15-3.3 (2H, m), 3.77 (2H, t,
J=6.3Hz), 9.22 (1H, s) Example 1 1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin 24.4 g of isatin and 1-(2-chloroethyl)-
2,2,6,6-tetramethylpiperidine hydrochloride
40.0g of dry N,N-dimethylformamide
Dissolve in a mixture of 250ml and 250ml of dry toluene,
Add 13.3g of 60% sodium hydride (oil) while stirring under ice-cooling, then leave at room temperature for another 30 minutes.
The reaction was carried out at 70°C for 16 hours. The solvent was distilled off under reduced pressure, and an aqueous sodium hydrogen carbonate solution was added to the residue, extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the residue, the crystals were collected by filtration, and recrystallized from ethyl acetate-hexane.
45.6 g of -[2-2,2,6,6-tetramethylpiperidino)ethyl]isatin was obtained.

Elemental analysis value: (as C ₁₉ H ₂₆ N ₂ O ₂ ) C% H% N% Calculated value 72.58 8.33 8.91 Actual value 72.44 8.37 8.96 IR (KBr): ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 1.11 ( 12H, s), 1.4~1.65 (6H, m), 2.65~
2.75 (2H, m), 3.6-3.7 (2H, m), 6.89 (1H,
d, J = 7.7Hz), 7.09 (1H, t, J = 7.7Hz),
7.55-7.65 (2H, m) Example 2 1-[2-(2,2,6,6-tetramethylpiperidino)propyl]isatin and 1-[1-
Methyl-2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin 4.59 g of isatin and 1-(2-chloropropyl)-
2,2,6,6-tetramethylpiperidine hydrochloride
7.93g dried N,N-dimethylformamide 80ml
After adding 2.52 g of 60% sodium hydride (oil-based) while stirring under ice-cooling,
The mixture was further reacted at 100°C for 16 hours. The solvent was distilled off under reduced pressure, water was added to the residue, extracted with chloroform, washed with water, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: chloroform), hexane was added, and the crystals were collected by filtration. The obtained crystals were recrystallized from ethyl acetate to give 1-[2-(2,2,
4.06 g of 6,6-tetramethylpiperidino)propyl]isatin was obtained.

Elemental analysis value: (as C ₂₀ H ₂₈ N ₂ O ₂ ) C% H% N% Calculated value 73.14 8.59 8.53 Actual value 73.28 8.54 8.63 IR (KBr): ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 1.0 ~ 1.8 (21H, m), 3.55-3.8 (2H, m),
3.9-4.05 (1H, m), 6.92 (1H, d, J = 7.7
Hz), 7.08 (1H, t, J = 7.7Hz), 7.5-7.65
(2H, m) Meanwhile, the hexane filtrate was concentrated, the residue was recrystallized from hexane, and the 1-[1-
2.00 g of methyl-2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin was obtained.

Elemental analysis value: (as C ₂₀ H ₂₈ N ₂ O ₂ ) C% H% N% Calculated value 73.14 8.59 8.53 Actual value 73.23 8.81 8.45 IR (KBr): ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 0.8~ 1.6 (21H, m), 2.81 (1H, dd, J=
4.9and15.7Hz), 3.06 (1H, dd, J=7.0and15.7
Hz), 4.15-4.35 (1H, m), 7.00 (1H, d, J
= 7.7Hz), 7.06 (1H, t, J = 7.7Hz), 7.5~
7.65 (2H, m) Example 3 1-[3-(2,2,6,6-tetramethylpiperidino)propyl]isatin 3.94 g of isatin and 1-(3-chloropropyl)-
2,2,6,6-tetramethylpiperidine hydrochloride
6.80g dry N,N-dimethylformamide 100
ml, add 2.16 g of 60% sodium hydride (oil-based) while stirring under ice-cooling, and then cool at room temperature.
The reaction was continued for 30 minutes and then at 80°C for 16 hours. The solvent was distilled off under reduced pressure, water was added to the residue, extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the residue, the crystals were collected by filtration, and then recrystallized from hexane.
1-[3-(2,2,6,6-tetramethylpiperidino)propyl]isatin 6.41 with melting point 105-107°C
I got g.

Elemental analysis value: (as C ₂₀ H ₂₈ N ₂ O ₂ ) C% H% N% Calculated value 73.14 8.59 8.53 Actual value 72.98 8.81 8.42 IR (KBr): ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 0.98 ( 12H, s), 1.3~1.6 (6H, m), 1.75~
1.9 (2H, m), 2.45-2.55 (2H, m), 3.67 (2H,
t, J = 7.2Hz), 6.89 (1H, d, J = 7.7Hz),
7.11 (1H, t, J = 7.7Hz), 7.55-7.65 (2H,
m) Example 4 1-[4-(2,2,6,6-tetramethylpiperidino)butyl]isatin 1-(4-bromobutyl)isatin 11.0 g, 2,
A mixture of 15.6 g of 2,6,6-tetramethylpiperidine, 5.4 g of potassium carbonate and 4.7 g of sodium iodide was reacted at 150°C for 50 minutes. Chloroform was added to the reaction mixture, washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent:
After purification with chloroform/methanol = 10/1),
Recrystallized from benzene-hexane, melting point 98-99℃
4.1 g of 1-[4-(2,2,6,6-tetramerpiperidino)butyl]isatin was obtained.

Elemental analysis value: (as C ₂₁ H ₃₀ N ₂ O ₂ ) C% H% N% Calculated value 73.65 8.83 8.18 Actual value 73.53 8.98 8.10 IR (KBr): ν _CO 1725cm ^-1 NMR (CDCl ₃ ) δ: 1.00 ( 12H, s), 1.35-1.7 (10H, m), 2.35
~2.45 (2H, m), 3.65 ~ 3.75 (2H, m), 6.90
(1H, d, J = 7.7Hz), 7.11 (1H, t, J = 7.7
Hz), 7.55-7.65 (2H, m) Example 5 5-bromo-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin 2.26 g of 5-bromoisatin and 1-( Suspend 2.40 g of 2-chloroethyl)-2,2,6,6-tetramethylpiperidine hydrochloride in 60 ml of dry N,N-dimethylformamide, and while stirring under ice cooling, add 0.80 g of 60% sodium hydride (oil-based). After adding g, the mixture was reacted at room temperature for 30 minutes and then at 80°C for 19 hours. The solvent was distilled off under reduced pressure, water was added to the residue, extracted with benzene, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from benzene-hexane.
5-Bromo-1-[2-(2,2,6,6
-tetramethylpiperidino)ethyl]isatin
2.76g was obtained.

Elemental analysis value: (as C ₁₉ H ₂₅ BrN ₂ O ₂ ) C% H% N% Calculated value 58.02 6.41 7.12 Actual value 58.20 6.53 6.80 IR (KBr): ν _CO 1730cm ^-1 NMR (CDCl ₃ ) δ: 1.10 ( 12H, s), 1.35~1.6 (6H, m), 2.6~
2.7 (2H, m), 3.55-3.7 (2H, m), 6.80 (1H,
d, J=8.8Hz), 7.65-7.75 (2H, m) Example 6 5-bromo-1-[2-(2,2,6,6-tetramethylpiperidino)propyl]isatin and 5-bromo -1-[1-methyl-2-(2,
2,6,6-tetramethylpiperidino)ethyl]isatin 7.68 g of 5-bromoisatin and 8.63 g of 1-(2-chloropropyl)-2,2,6,6-tetramethylpiperidine hydrochloride were dried with N,N - Dissolved in 150 ml of dimethylformamide, added 2.72 g of 60% sodium hydride (oil-based) while stirring under ice-cooling, and reacted at room temperature for 1 hour and further at 90°C for 15 hours. The solvent was distilled off under reduced pressure, water was added to the residue, extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (eluent: benzene/chloroform = 3/2), 200 ml of hexane was added, and the crystals were collected by filtration. The obtained crystals were recrystallized from benzene-hexane to give 5-bromo-
3.85 g of 1-[2-(2,2,6,6-tetramethylpiperidino)propyl]isatin was obtained.

Elemental analysis value: (as C ₂₀ H ₂₇ BrN ₂ O ₂ ) C% H% N% Calculated value 58.97 6.68 6.88 Actual value 59.11 6.83 6.72 IR (KBr): ν _CO 1725cm ^-1 NMR (CDCl ₃ ) δ: 1.0 ~ 1.8 (21H, m), 3.55-3.75 (2H, m),
3.96 (1H, dd, J=11.5and14.8Hz), 6.84 (1H,
d, J=9.3Hz), 7.65-7.75 (2H, m) On the other hand, after concentrating the hexane filtrate under reduced pressure, the residue was recrystallized from hexane, and the melting point was 132.5-134°C.
5-bromo-1-[1-methyl-2-(2,2,
1.31 g of 6,6-tetramethylpiperidino)ethyl]isatin was obtained.

Elemental analysis value: (as C ₂₀ H ₂₇ BrN ₂ O ₂ ) C% H% N% Calculated value 58.97 6.68 6.88 Actual value 58.82 6.79 6.78 IR (KBr): ν _CO 1725cm ^-1 NMR (CDCl ₃ ) δ: 0.8~ 1.6 (21H, m), 2.77 (1H, dd, J=
4.4and15.9Hz), 3.06 (1H, dd, J=7.1and15.9
Hz), 4.1-4.3 (1H, m), 6.91 (1H, d, J=
9.3Hz), 7.6-7.7 (2H, m) Example 7 Using 5-methoxyisatin and 1-(2-chloroethyl)-2,2,6,6-tetramethylpiperidine hydrochloride, approximately the same as Example 5. The following compounds were produced in the same manner.

5-methoxy-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin Melting point: 159-161℃ (benzene-hexane) Yield: 72.7% Elemental analysis value: (C ₂₀ H ₂₈ N ₂ O ₃ ) C% H% N% Calculated value 69.74 8.19 8.13 Actual value 69.78 8.38 8.01 IR (KBr): ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 1.11 (12H, s), 1.4~ 1.6 (6H, m), 2.65~
2.75 (2H, m), 3.55-3.65 (2H, m), 3.80
(3H, s), 6.75-6.85 (1H, m), 7.1-7.2
(2H, m) Example 8 The following compound was prepared in substantially the same manner as in Example 5 using 5-fluoroisatin and 1-(2-chloroethyl)-2,2,6,6-tetramethylpiperidine hydrochloride. Manufactured.

5-fluoro-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin Melting point: 143-144°C (benzene) Yield: 65.6% Elemental analysis: (C ₁₉ H ₂₅ As FN ₂ O ₂ ) C% H% N% Calculated value 68.65 7.58 8.43 Actual value 68.64 7.73 8.62 IR (KBr): ν _CO 1725cm ^-1 NMR (CDCl ₃ ) δ: 1.11 (12H, s), 1.4~1.65 ( 6H, m), 2.6~
2.75 (2H, m), 3.55-3.7 (2H, m), 6.85 (1H,
dd, J=3.8and8.8Hz), 7.25-7.4 (2H, m) Example 9 5-chloroisatin and 1-(2-chloroethyl)
The following compound was produced in substantially the same manner as in Example 5 using -2,2,6,6-tetramethylpiperidine hydrochloride.

5-chloro-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin Melting point: 162-163℃ (benzene-hexane) Yield: 67.5% Elemental analysis value: (C ₁₉ As H ₂₅ ClN ₂ O ₂ ) C% H% N% Calculated value 65.41 7.22 8.03 Actual value 65.32 7.30 7.81 IR (KBr): ν _CO 1730cm ^-1 NMR (CDCl ₃ ) δ: 1.10 (12H, s), 1.4~ 1.6 (6H, m), 2.6~
2.75 (2H, m), 3.55-3.7 (2H, m), 6.85 (1H,
d, J = 8.8Hz), 7.5-7.6 (2H, m) Example 10 Performed using 5-acetamidoisatin and 1-(2-chloroethyl)-2,2,6,6-tetramethylpiperidine hydrochloride The following compound was produced in substantially the same manner as in Example 5.

5-acetamido-1-[2-(2,2,6,6
-tetramethylpiperidino)ethyl]isatin Melting point: 295-297°C (decomposition) (ethanol-ethyl acetate) Yield: 55.2% Elemental analysis: (as C ₂₁ H ₂₉ N ₃ O ₃ ) C% H% N % Calculated value 67.90 7.87 11.31 Actual value 68.01 8.01 11.12 IR (KBr): ν _NH 3360cm ^-1 ν _CO 1725, 1685cm ^-1 NMR (d ₆ −DMSO) δ: 1.07 (12H, s), 1.3 to 1.55 (6H, m), 2.04
(3H, s), 2.55-2.7 (2H, m), 3.45-3.6
(2H, m), 6.94 (1H, d, J=8.2Hz), 7.71
(1H, dd, J=2.2and8.2Hz), 7.85 (1H, d,
J = 2.2Hz), 10.05 (1H, s) Example 11 Example 5 using methyl 7-isatincarboxylate and 1-(2-chloroethyl)-2,2,6,6-tetramethylpiperidine hydrochloride After reacting and treating in the same manner as above, the product was purified by silicage column chromatography (elution solvent: chloroform) to produce the following compound.

Methyl 1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]-7-isatincarboxylate Melting point: 39-40°C Yield: 90.2% Elemental analysis: (C ₂₁ H ₂₈ As N ₂ O ₄ ) C% H% N% Calculated value 67.72 7.58 7.52 Actual value 67.41 7.82 7.42 IR (KBr): ν _CO 1740cm ^-1 NMR (CDCl ₃ ) δ: 1.02 (12H, s), 1.35 to 1.6 ( 6H, m), 2.45~
2.6 (2H, m), 3.94 (3H, s), 3.95~4.05 (2H,
m), 7.14 (1H, t, J = 7.7Hz), 7.73 (1H,
dd, J=1.7and7.7Hz), 7.87(1H, dd, J=
1.7and7.7Hz) Example 12 5-methylisatin and 1-(2-chloroethyl)
The following compound was produced in substantially the same manner as in Example 1 using -2,2,6,6-tetramethylpiperidine hydrochloride.

5-Methyl-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin Melting point: 157-159°C (hexane) Yield: 81.5% Elemental analysis: (C ₂₀ H ₂₈ As N ₂ O ₂ ) C% H% N% Calculated value 73.14 8.59 8.53 Actual value 72.87 8.67 8.49 IR (KBr): ν _CO 1725cm ^-1 NMR (CDCl ₃ ) δ: 1.11 (12H, s), 1.4-1.6 ( 6H, m), 2.33
(3H, s), 2.65-2.75 (2H, m), 3.55-3.7
(2H, m), 6.79 (1H, d, J=8.2Hz), 7.38
(1H, d, J = 8.2Hz), 7.40 (1H, s) Example 13 Performed using 5-methylisatin and 1-(3-chloropropyl)-2,2,6,6-tetramethylpiperidine hydrochloride The following compound was produced in substantially the same manner as in Example 5.

5-Methyl-1-[3-(2,2,6,6-tetramethylpiperidino)propyl]isatin Melting point: 125-127°C (ethyl acetate-hexyl) Yield: 75.5% Elemental analysis value: (C ₂₁ H ₃₀ N ₂ O ₂ ) C% H% N% Calculated value 73.65 8.83 8.18 Actual value 73.35 9.01 7.97 IR (KBr): ν _CO 1715cm ^-1 NMR (CDCl ₃ ) δ: 0.98 (12H, s), 1.3 ~1.6 (6H, m), 1.75~
1.92H, m), 2.33 (3H, s), 2.45~2.55 (2H,
m), 3.65 (2H, t, J=7.1Hz), 6.78 (1H,
d, J=7.7Hz), 7.38 (1H, d, J=7.7Hz),
7.41 (1H, s) Example 14 5-amino-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin 5-acetamido-1-[2-(2,2, 6,6
-tetramethylpiperidino)ethyl]isatin
1.10 g was dissolved in 60 ml of 6N hydrochloric acid and heated under reflux for 5 hours. After the reaction solution was concentrated under reduced pressure, an aqueous sodium bicarbonate solution was added to the residue, extracted with chloroform, washed with water, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was dissolved in ethanol, treated with activated carbon, and recrystallized from chloroform-hexane to give 5-amino-1-[2-(2,2,6 , 6-tetramethylpiperidino)ethyl]isatin (0.87 g) was obtained.

Elemental analysis value: (as C ₁₉ H ₂₇ N ₃ O ₂ ) C% H% N% Calculated value 69.27 8.26 12.76 Actual value 69.33 8.26 12.51 IR (KBr): ν _NH 3445, 3410, 3345cm ^-1 ν _CO 1705cm ^-1 NMR ( _d6 -DMSO) δ: 1.06 (12H, s), 1.3~1.6 (6H, m), 2.55~
2.65 (2H, m), 3.4-3.55 (2H, m), 5.14 (2H,
s), 6.70 (1H, d, J=8.2Hz), 6.78 (1H,
d, J=2.2Hz) 6.89 (1H, dd, J=2.2and8.2
Hz)

Claims (1)

[Claims] 1. General formula (X in the formula is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group, an acylamino group, or an alkoxycarbonyl group, and Y
is a linear or branched alkylene chain having 2 to 5 carbon atoms) and pharmacologically acceptable acid addition salts thereof.