JPH0533947B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to an intermediate for producing isatin=3-semicarbazone derivatives useful as therapeutic agents for gastric and duodenal ulcers caused by stress and the like.

[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 their application as ulcer therapeutic agents is being considered.

However, few ulcer therapeutic agents 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 currently used as agents for gastric and duodenal ulcers include antacids, antipepsin agents, anticholinergic agents, and histamine H ₂ -receptor antagonists.
All of these attempts to treat ulcers by neutralizing, inactivating, or suppressing secretion of digestive juices.

On the other hand, according to clinical findings, patients with gastric and duodenal ulcers are not necessarily in a hyperacid state, but rather have been reported to have a hypoacid state.

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 some conventional peptic ulcer treatments are effective against stress-induced stomach and duodenal ulcers. There are almost no For this reason, in actual treatment, a method is commonly used in which ordinary ulcer treatment agents are used in combination with anxiolytics or tranquilizers. 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 inventors of the present invention have conducted extensive research to find a compound effective in treating gastric and duodenal ulcers caused by stress, and have discovered that the purpose can be achieved with isisan=3-semicarbazone derivatives.

The present invention is an intermediate for producing this isisane=3-semicarbazone derivative, which has the general formula (X in the formula is a lower alkyl group, lower alkoxy group, amino group, acylamino group, or alkoxycarbonyl group, n is 1 or 2, and Y
is a linear or branched alkylene chain having 2 to 4 carbon atoms, and R ¹ is a linear or branched alkyl group having 3 to 5 carbon atoms or a linear or branched alkyl group having 3 to 6 carbon atoms.
is a cycloalkyl group, and R ² has 1 to 5 carbon atoms.
straight-chain or branched alkyl group)
The present invention provides isatin derivatives represented by: and acid addition salts thereof.

The isatin derivative represented by the general formula () of the present invention and the general formula H ₂ NNHCONHR ³ () (R ³ in the formula is a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group or a cycloalkyl group) The general formula is easily useful as a therapeutic agent for peptic ulcers by reacting with the semicarbazide derivative represented by the formula or its acid addition salt. (In the formula, X, Y, n, R ¹ , R ² and R ³ have the same meanings as above).

Itisane=3-semicarbazone derivatives of the general formula () and their pharmacologically acceptable acid addition salts have shown excellent anti-ulcer properties in experimental ulcers, such as water immersion restraint stress ulcer experiments using male Wistar rats. It is useful as a therapeutic agent for gastric and duodenal ulcers in mammals including humans.

The compound represented by the general formula () of the present invention is a new compound, for example, the compound represented by the general formula (X and n in the formula have the same meanings as above) and an isatin derivative represented by the general formula (In the formula, Z is an acid residue, and R ¹ , R ² and Y have the same meanings as above) or an acid addition salt thereof, and the Reaction in the presence of a base or general formula (In the formula, n, X, Y and Z have the same meanings as above) and an equimolar or excess molar amount of the general formula (R ¹ and R ² in the formula have the same meanings as above)
amine derivative represented by benzene, N,N-
It can be produced by reaction in an inert solvent such as dimethylformamide in the presence or absence of a base such as potassium carbonate.

Although some of the compounds represented by the general formulas (), (), (), and () used as starting materials in this production method are new compounds, they are available as commercially available products or by known methods or similar methods. Therefore, it can be easily obtained by manufacturing.

In order to suitably carry out the production method of the present invention, the compound of the general formula () and the compound of the general formula () or an acid addition salt thereof in an equimolar to slightly excess molar amount are mixed in an inert solvent, for example, N, Dissolve or suspend in N-diethylformamide or its mixed solvent with toluene, add the necessary amount of sodium hydroxide under ice cooling, react at room temperature or under heating for 1 to 20 hours, and treat according to a conventional method. to obtain the desired object.

Further, 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 the isatin derivative represented by the general formula () An amine derivative represented by is reacted with an inert solvent such as benzene or N,N-dimethylformamide at 60 to 120°C for 1 to 70 hours in the presence or absence of a base such as potassium carbonate and sodium iodide. let The target product is obtained by processing in a conventional manner and purifying by an appropriate method.

When using a compound of general formula () or () in which the nuclear substituent X is an amino group in this reaction,
Prior to the reaction, it is better to protect the amino group with an acetyl group or the like. After the reaction, the protecting group is removed according to a conventional method.

The compound represented by the general formula () derived from the compound of the general formula () of the present invention can treat peptic ulcers,
Its suitability as a therapeutic agent for stress-induced gastric and duodenal ulcers is confirmed by its anti-ulcer effect on experimental ulcers. For example, in a water immersion restraint stress ulcer experiment using male Wistar rats,
The compound of general formula () is 100 mg per 1 kg of body weight.
Oral administration shows an inhibitory effect of about 40% to 95%. Especially (E)-1-(2-diisopropylaminoethyl)
Itisan=3-semicarbazone shows an inhibitory effect of about 50% even when administered orally at a dose of 10 mg/kg body weight.

Furthermore, the fact that the compound represented by the general formula (
Although this compound is confirmed to have a suppressive effect on increased gastric acid secretion caused by administration of D-glucose, this compound hardly exhibits the sleep prolonging and movement suppressing effects seen in anxiolytics and tranquilizers.

As described above, the isisane 3-semicarbazone derivative () derived from the compound represented by the general formula () of the present invention is suitable as a therapeutic agent for peptic ulcers, particularly gastric and duodenal ulcers caused by stress or the like.

〔Effect of the invention〕

Itisan=3-semicarbazone derivatives () useful as pharmaceuticals can be produced very easily from the compound of the general formula () of the present invention.

This itisan=3-semicarbazone derivative exhibits a remarkable anti-ulcer effect in experimental ulcers using animals, and is useful as a therapeutic agent for peptic ulcers in mammals including humans, especially gastric and duodenal ulcers caused by stress, etc.

〔Example〕

The content of the present invention will be explained in more detail with reference to 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 7Bromo-5-methylisatin Suspend 8.0g of 5-methylisatin in 200ml of acetic acid and add 3.3ml of bromine and acetic acid while stirring at room temperature.
After dropping 50 ml of the solution, the mixture was reacted at 50°C for 16 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from methanol-hexane to give 7-
11.4 g of bromo-5-methylisatin was obtained.

Elemental analysis value: (as C ₉ H ₆ BrNO ₂ ) C% H% N% Calculated value 45.03 2.52 5.83 Actual value 45.05 2.46 5.50 IR (KBr): ν _CO 1730cm ^-1 NMR (d ₆ -DMSO) δ: 2.27 ( 3H, s), 7.35 (1H, s), 7.64 (1H,
s), 11.22 (1H, s) Reference example 2 2-(N-isopropylcyclohexylamino)
Ethyl chloride hydrochloride N-isopropylcyclohexylamine 5.0g
4.3 g of triethylamine were dissolved in 100 ml of dry methylene chloride, and 5.8 g of acetoxyacetyl chloride was added dropwise while stirring under ice cooling.
Stir at room temperature for 16 hours. The reaction solution was washed with an aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure,
Oily 2-acetoxy-N-cyclohexyl-N
- 8.5 g of isopropylacetamide was obtained.

IR (neat): ν _CO 1735, 1650 cm ^-1 NMR (CDCl ₃ ) δ: 1.05 (16H, m), 2.18 (3H, s), 2.3-2.5
(1H, m), 3.1~3.15 (1H, m), 4.67 (2H,
s) 4.1 g of lithium aluminum hydride was suspended in 500 ml of diethyl ether, 2.9 ml of concentrated sulfuric acid was added dropwise while stirring under ice cooling, and the mixture was stirred for 1 hour. Add 2-acetoxy-N-cyclohexyl-N-isopropylacetamide to this reaction solution.
A solution of 8.4 g in 150 ml of diethyl ether was added dropwise while stirring under ice cooling, and the mixture was heated under reflux for 16 hours. After cooling, an aqueous sodium hydroxide solution and water were added dropwise to the reaction solution while stirring under ice cooling, and after drying over anhydrous magnesium sulfate, insoluble matter was filtered off. The solvent was distilled off under reduced pressure to obtain oily 2-(N-isopropylcyclohexylamino)ethanol.
6.1g was obtained.

IR (neat): ν _CO 3375cm ^-1 NMR (CDCl ₃ ) δ: 1.03 (6H, d, J = 6.6Hz), 1.15 to 1.85
(10H, m), 2.45-2.6 (1H, m), 2.68 (2H,
t, J = 5.5Hz), 3.07 (1H, sept, J = 6.6
Hz), 3.25 (1H, br-s), 3.45 (2H, t, J
=5.5Hz) 2-(N-isopropylcyclohexylamino)
Dissolve 6.0g of ethanol in 100ml of dry benzene,
After adding 3.2 ml of thionyl chloride dropwise at room temperature with stirring, the mixture was heated under reflux for 4 hours. The solvent was distilled off under reduced pressure, and diethyl ether was added to the residue for crystallization, which was collected by filtration to obtain 7.4 g of 2-(N-isopropylcyclohexylamino)ethyl chloride hydrochloride having a melting point of 99-103°C.

Elemental analysis value: ( _{as C11H23Cl2N} ) C% H% N _% Calculated value 55.00 9.65 5.83 Actual value 54.82 10.00 5.73 NMR ( _CDCl3 ) δ: 1.15-2.4 (16H, m), 3.15-3.3 ( 3H, m),
3.65-3.85 (1H, m), 4.05-4.25 (2H, m),
11.90 (1H, br-s) Example 1 1-(2-Diisopropylaminoethyl)isatin A mixture of 2.94 g of isatin and 4.00 g of 2-diisopropylaminoethyl chloride hydrochloride in 50 ml of dry toluene and 10 ml of dry N,N-dimethylformamide. Add 1.60 g of 60% sodium hydride (oil-based) to the Nikkendakushi while stirring under ice-cooling, and then stir at room temperature.
The reaction was continued 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 hexane to obtain 4.62 g of 1-(2-diisopropylaminoethyl)isatin having a melting point of 60 to 61°C.

Elemental analysis value: (as C ₁₆ H ₂₂ N ₂ O ₂ ) C% H% N% Calculated value 70.04 8.08 10.21 Actual value 69.99 8.29 10.06 IR (KBr): ν _CO 1725cm ^-1 NMR (CDCl ₃ ) δ: 0.98 ( 12H, d, J = 6.6Hz), 2.70 (2H,
t, J = 6.9Hz), 3.04 (2H, sept, J = 6.6
Hz), 3.69 (2H, t, J = 6.9Hz), 6.91 (1H,
d, J = 7.2Hz), 7.09 (1H, t, J = 7.2Hz),
7.57 (1H, t, J = 7.2Hz), 7.59 (1H, d,
J = 7.2 Hz) Example 2 1-(2-diisopropylaminoethyl) isatin 2.94 g of isatin, 4.20 g of 2-diisopropylaminoethyl chloride hydrochloride and 3.17 g of anhydrous potassium carbonate were suspended in 50 ml of toluene, and the
Stirred for an hour. After cooling, the reaction solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from hexane to give 1-(2-
4.93 g of isatin (diisopropylaminoethyl) was obtained. The physical properties of this product were the same as those of the compound obtained in Example 1.

Example 3 Isatin and 3-diisopropylaminopropyl chloride hydrochloride were reacted and treated in substantially the same manner as in Example 1, and subjected to silica gel column chromatography (elution solvent: chloroform/methanol =
50/1) and then recrystallized from hexane to produce the following compound.

1-(3-diisopropylaminopropyl) isatin Melting point: 49-50℃ Yield: 72.9% Elemental analysis: (as C ₁₇ H ₂₄ N ₂ O ₂ ) C% H% N% Calculated value 70.80 8.39 9.71 Actual value 70.98 8.35 9.41 IR (KBr): ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 1.20 (12H, d, J = 6.6Hz), 1.79 (2H,
quint, J = 6.6Hz), 2.55 (2H, t, J = 6.6
Hz), 3.04 (2H, sept, J=6.6Hz), 3.76 (2H,
t, J = 6.6Hz), 6.93 (1H, d, J = 7.7Hz),
7.10 (1H, t, J=7.7Hz), 7.58 (1H, t,
J = 7.7Hz), 7.60 (1H, d, J = 7.7Hz) Example 4 1-(2-diisopropylaminopropyl)isatin and 1-(2-diisopropylamino-1-methylthyl)isatin 4.16 g of isatin and 2- Diisopropylamino
Dissolve 6.06 g of 1-methylethyl chloride hydrochloride in 80 ml of dry N,N-diethylformamide, add 2.28 g of 60% sodium hydride (oil-based) while stirring under ice cooling, and then incubate at room temperature for 30 minutes at 90°C.
The mixture was allowed to react 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. The solvent was distilled off under reduced pressure, hexane was added to the residue, the crystals were collected by filtration, and then recrystallized from benzene-hexane.
4.48 g of 1-(2-diisopropylaminopropyl)isatin having a melting point of 111-112°C was obtained.

Elemental analysis value: (as C ₁₇ H ₂₄ N ₂ O ₂ ) C% H% N% Calculated value 70.80 8.39 9.71 Actual value 70.86 8.59 9.65 IR (KBr): ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 0.89 ( 6H, d, J = 6.6Hz), 1.01 (6H, d,
J = 6.6Hz), 1.12 (3H, d, J = 6.6Hz), 3.16
(2H, sept, J=6.6Hz), 3.3~3.45 (1H,
m), 3.46 (1H, dd, J=6.6and13.7Hz),
3.71 (1H, dd, J=7.7 and 13.7Hz), 6.87
(1H, d, J = 7.7Hz), 7.09 (1H, t, J =
7.7Hz), 7.55-7.65 (2H, m) Meanwhile, the hexane filtrate was concentrated and the residue was subjected to silica gel column chromatography (elution solvent:
After purification with chloroform), recrystallized from hexane,
0.83 g of 1-(2-diisopropylamino-1-methylethyl)isatin having a melting point of 70-71°C was obtained.

Elemental analysis value: (as C ₁₇ H ₂₄ N ₂ O ₂ ) C% H% N% Calculated value 70.80 8.39 9.71 Actual value 70.81 8.60 9.57 IR (KBr): ν _CO 1730cm ^-1 NMR (CDCl ₃ ) δ: 0.82 ( 6H, d, J = 6.6Hz), 0.96 (6H, d,
J = 6.6Hz), 1.50 (3H, d, J = 7.2Hz), 2.68
(1H, dd, J=5.3and14.0Hz), 2.9~3.05
(3H, m), 4.25-4.45 (1H, m), 6.98 (1H,
d, J = 7.7Hz), 7.06 (1H, t, J = 7.7Hz),
7.53 (1H, dt, J=1.1and7.7Hz), 7.58 (1H,
dd, J=1.1and7.7Hz) Example 5 The following compound was produced in substantially the same manner as in Example 1 using 5-methylisatin and 2-diisopropylaminoethyl chloride hydrochloride.

1-(2-diisopropylaminoethyl)-5-methylisatin Melting point: 65-67°C (hexane) Yield: 82.0% Elemental analysis: (as C ₁₇ H ₂₄ N ₂ O ₂ ) C% H% N% Calculated value 70.80 8.39 9.71 Actual value 70.58 8.34 9.44 IR (KBr): ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 0.97 (12H, d, J = 6.6Hz), 2.33 (3H,
s), 2.68 (2H, t, J=6.6Hz), 3.03 (2H,
sept, J = 6.6Hz), 3.67 (2H, t, J = 6.6
Hz), 6.80 (1H, d, J=7, 7Hz), 7.38
(1H, d, J=7.7Hz), 7.39 (1H, s) Example 6 The following compound was produced in substantially the same manner as in Example 1 using 7-methylisatin and 2-diisopropylaminoethyl chloride hydrochloride.

1-(2-diisopropylaminoethyl)-7-methylisatin Melting point: 92-93°C (hexane) Yield: 65.2% Elemental analysis: (as C ₁₇ H ₂₄ N ₂ O ₂ ) C% H% N% Calculated value 70.80 8.39 9.71 Actual value 70.62 8.49 9.66 IR (KBr): ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 0.93 (12H, d, J = 6.6Hz), 2.53 (3H,
s), 2.68 (2H, t, J=6.6Hz), 3.03 (2H,
sept, J = 6.6Hz), 3.96 (2H, t, J = 6.6
Hz), 6.99 (1H, t., J=7, 1Hz), 7.33
(1H, d, J = 7.1Hz), 7.47 (1H, d, J =
7.1Hz) Example 7 1-(2-diisopropylaminoethyl)-5-
Fluoroisatin 3.30 g of 5-fluoroisatin and 4.00 g of 2-diisopropylaminoethyl chloride hydrochloride were suspended in 75 ml of dry N,N-diethylformamide, and while stirring under ice-cooling, 60% sodium hydride (oil-based) was added. After adding 1.60 g, the mixture was reacted at room temperature for 30 minutes and then at 80°C for 17 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 hexane-petroleum benzine to give 1-(2-
4.97 g of (diisopropylaminoethyl)-5-fluoroisatin was obtained.

Elemental analysis value: (as C ₁₆ H ₂₁ FN ₂ O ₂ ) C% H% N% Calculated value 65.73 7.24 9.58 Actual value 65.64 7.52 9.59 IR (KBr): ν _CO 1725cm ^-1 NMR (CDCl ₃ ) δ: 0.97 ( 12H, d, J = 6.6Hz), 2.70 (2H,
t, J=6.6Hz), 3.03(2H, sept, J=6.6
Hz), 3.96 (2H, t, J = 6.6Hz), 6.85-6.95
(1H, m), 7.25-7.4 (2H, m) Example 8 The following compound was produced in substantially the same manner as in Example 7 using 5-chloroisatin and 2-diisopropylaminoethyl chloride hydrochloride.

5-Chloro-1-(2-diisopropylaminoethyl)isatin Melting point: 99-101°C (hexane) Yield: 70.0% Elemental analysis: (as C ₁₆ H ₂₁ ClN ₂ O ₂ ) C% H% N% Calculation Value 62.23 6.85 9.07 Actual value 61.99 6.87 8.99 IR (KBr): ν _CO 1730cm ^-1 NMR (CDCl ₃ ) δ: 0.96 (12H, d, J = 6.6Hz), 2.69 (2H,
t, J = 6.6Hz), 3.02 (2H, sept, J = 6.6
Hz), 3.69 (2H, t, J = 6.6Hz), 6.89 (1H,
d, J=8.8Hz), 7.5-7.6 (2H, m) Example 9 The following compound was produced in substantially the same manner as in Example 1 using 6-chloroisatin and 2-diisopropylaminoethyl chloride hydrochloride.

6-Chloro-1-(2-diisopropylaminoethyl)isatin Melting point: 78-79°C (hexane) Yield: 86.2% Elemental analysis: (as C ₁₆ H ₂₁ N ₂ O ₂ ) C% H% N% Calculation Value 62.23 6.85 9.07 Actual value 61.98 6.97 9.00 IR (KBr): ν _CO 1730cm ^-1 NMR (CDCl ₃ ) δ: 0.96 (12H, d, J = 6.6Hz), 2.71 (2H,
t, J=6.6Hz), 3.03(2H, sept, J=6.6
Hz), 3.68 (2H, t, J=6.6Hz), 6.95 (1H,
d, J=1.7Hz), 7.06(1H, dd, J=
1.7 and 8.2 Hz), 7.52 (1H, d, J = 8.2 Hz) Example 10 The following compound was produced in substantially the same manner as in Example 7 using 5-bromoisatin and 2-diisopropylaminoethyl chloride hydrochloride.

5-Bromo-1-(2-diisopropylaminoethyl)isatin Melting point: 91-93℃ (hexane-petroleum benzine) Yield: 82.9% Elemental analysis: (C ₁₆ H ₂₁ BrN ₂ O ₂・0.1C ₆ H ₁₄ (as hexane) C% H% N% Calculated value 55.10 6.24 7.74 Actual value 55.25 6.32 7.70 IR (KBr): ν _cp 1725cm ^-1 NMR (CDCl ₃ ) δ: 0.96 (12H, d, J = 6.6Hz), 2.69 (2H,
t, J = 6.6Hz), 3.02 (2H, sept, J = 6.6
Hz), 3.68 (2H, t, J = 6.6Hz), 6.8-6.85
(1H, m), 7.65-7.7 (2H, m) Example 11 Using 5-acetamidoisatin and 2-diisopropylaminoethyl chloride hydrochloride, Example 7
The following compounds were produced in substantially the same manner as above.

-Toamide-1-(2-diisopropylaminoethyl)isatin Melting point: 187-190°C (ethyl acetate-hexane) Yield: 77.0% Elemental analysis: (as C ₁₈ H ₂₅ N ₃ O ₃ ) C% H% N % Calculated value 65.24 7.60 12.68 Actual value 65.07 7.61 12.38 IR (KBr): ν _NH 3300cm ^-1 ν _CO 1720, 1660cm ^-1 NMR (d ₆ −DMSO) δ: 0.88 (12H, d, J = 6.6Hz), 2.04 (3H,
s), 2.62 (2H, t, J=6.6Hz), 2.99 (2H,
sept, J = 6.6Hz), 3.62 (2H, t, J = 6.6
Hz), 7.10 (1H, d, J = 7.5Hz), 7.72 (1H,
dd, J=2.2and7.5Hz), 7.84(1H, d, J=
2.2Hz), 10.05 (1H, s) Example 12 5-amino-1-(2-diisopropylaminoethyl)isatin 2.07g of 5-acetamido-1-(2-diisopropylaminoethyl)isatin was dissolved in 6N hydrochloric acid 150
ml and heated under reflux for 1.5 hours. The reaction solution was concentrated 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, and the residue was dissolved in ethyl acetate, treated with activated carbon, and then the solvent was distilled off under reduced pressure. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 1.45 g of 5-amino-1-(2-diisopropylaminoethyl)isachi having a melting point of 166-167°C.

Elemental analysis value: (as C ₁₆ H ₂₃ N ₃ O ₂ ) C% H% N% Calculated value 66.41 8.01 14.52 Actual value 66.16 8.05 14.24 IR (KBr): ν _NH 3420, 3320cm ^-1 ν _CO 1715cm ^-1 NMR ( d ₆ −DMSO) δ: 0.88 (12H, d, J = 6.6Hz), 2.59 (2H,
t, J = 6.6Hz), 2.98 (2H, sept, J = 6.6
Hz), 3.55 (2H, t, J = 6.6Hz), 5.13 (2H,
s), 6.76 (1H, d, J=2.2Hz), 6.84 (1H,
d, J=8.2Hz), 6.89(1H, dd, J=
2.2 and 8.2 Hz) Example 13 The following compound was produced in substantially the same manner as in Example 7 using methyl 7-isatincarboxylate and 2-diisopropylaminoethyl chloride hydrochloride.

Methyl 1-(2-diisopropylaminoethyl)-7-isatincarboxylate Properties: Oil Yield: 94.6% IR (neat): ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 0.80 (12H, d, J= 6.6Hz), 2.51(2H,
t, J = 6.6Hz), 2.95 (2H, sept, J = 6.6
Hz), 3.98 (3H, s), 4.04 (2H, t, J=6.6
Hz), 7.13 (1H, t, J = 7.7Hz), 7.72 (1H,
dd, J=1.7and7.7Hz), 7.86(1H, dd, J=
1.7and7.7Hz) Example 14 1-(2-diisopropylaminoethyl)-5-
Methoxyisatin Dissolve 3.00 g of 5-methoxyisatin and 3.38 g of 2-diisopropylaminoethyl chloride hydrochloride in 50 ml of dry N,N-dimethylformamide, and add 1.36 g of 60% sodium hydride (oil-based) while stirring under ice cooling. 80°C for another 1 hour at room temperature.
The reaction was carried out at ℃ for 13 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, and the residue was purified by silica gel flash column chromatography (elution solvent: chloroform) and then recrystallized from hexane to give a melting point of 81~
1-(2-diisopropylaminoethyl) at 82.5℃
3.33 g of -5-methoxyisatin was obtained.

Elemental analysis value: (as C ₁₇ H ₂₄ N ₂ O ₃ ) C% H% N% Calculated value 67.08 7.95 9.20 Actual value 67.35 8.11 9.19 IR (KBr): ν _CO 1715cm ^-1 NMR (CDCl ₃ ) δ: 0.97 ( 12H, d, J = 6.6Hz), 2.68 (2H,
t, J=6.6Hz), 3.03(2H, sept, J=6.6
Hz), 3.66 (2H, t, J=6.6Hz), 3.80 (3H,
s), 6.8-6.9 (1H, m), 7.1-7.2 (2H, m) Example 15 In almost the same manner as in Example 1 using 7-bromo-5-methylisatin and 2-diisopropylaminoethyl chloride hydrochloride. The following compounds were prepared.

7-bromo-1-(2-diisopropylaminoethyl)-5-methylisatin Melting point: 94-97°C (hexane) Yield: 13.1% Elemental analysis: (as C ₁₇ H ₂₃ BrN ₂ O ₂ )
C% H% N% Calculated value 55.59 6.31 7.63 Actual value 55.35 6.29 7.53 IR (KBr): ν _CO 1730cm ^-1 NMR (CDCl ₃ ) δ: 0.90 (12H, d, J = 6.6Hz), 2.30 (3H,
s), 2.73 (2H, t, J=6.6Hz), 3.03 (2H,
sept, J = 6.6Hz), 4.17 (2H, t, J = 6.6
Hz), 7.37 (1H, d, J = 1.1Hz), 7.52 (1H,
d, J=1.1Hz) Example 16 The following compound was produced in substantially the same manner as in Example 1 using 5-methylisatin and 3-diisopropylaminopropyl chloride hydrochloride.

1-(3-diisopropylaminopropyl)-5-
Methylisatin Melting point: 87-89℃ (hexane) Yield: 53.3% Elemental analysis: (as C ₁₈ H ₂₆ N ₂ O ₂ ) C% H% N% Calculated value 71.49 8.67 9.26 Actual value 71.61 8.86 9.24 IR (KBr) :ν _CO 1730cm ^-1 NMR (CDCl ₃ ) δ: 1.01 (12H, d, J = 6.6Hz), 1.7 to 1.85
(2H, m), 2.33 (3H, s), 2.45~2.6 (2H,
m), 2.95-3.1 (2H, m). 3.73 (2H, t, J
= 7.1Hz), 6.81 (1H, d, J = 7.7Hz), 7.38
(1H, d, J = 7.7Hz), 7.40 (1H, s) Example 17 Using 5-methoxyisatin and 2-dibutylaminoethyl chloride hydrochloride, after treatment in almost the same manner as in Example 7, silica gel Flash column chromatography (elution solvent: chloroform)
The following compound was produced.

1-(2-dibutylaminoethyl)-5-methoxyisatin Melting point: 32-34°C Yield: 79.3% Elemental analysis: (as C ₁₉ H ₂₈ N ₂ O ₃ ) C% H% N% Calculated value 68.65 8.49 8.43 Actual value 68.89 8.79 8.41 IR (KBr): ν _CO 1715cm ^-1 NMR (CDCl ₃ ) δ: 0.86 (6H, d, J = 7.1Hz), 1.15 to 1.45
(8H, m), 2.45 (4H, t, J=7.1Hz), 2.68
(2H, t, J=6.6Hz), 3.75 (2H, t, J=
6.6Hz). 3.80 (3H, s), 6.8~6.9 (1H, m),
7.1-7.2 (2H, m) Example 18 Using 5-fluoroisatin and 2-dibutylaminoethyl chloride hydrochloride, react in almost the same manner as in Example 7, and then perform silica gel column chromatography (elution solvent: chloroform) Refined with
The following compounds were prepared.

1-(2-dibutylaminoethyl)-5-fluoroisatin Melting point: 52-54℃ Yield: 61.0% Elemental analysis: (as C ₁₈ H ₂₅ FN ₂ O ₂ ) C% H% N% Calculated value 67.48 7.86 8.74 Actual value 67.65 8.02 8.69 IR (KBr): ν _CO 1730cm ^-1 NMR (CDCl ₃ ) δ: 0.85 (6H, d, J = 7.1Hz), 1.1 to 1.4 (8H,
m), 2.44 (4H, t, J=7.1Hz), 2.69 (2H,
t, J = 6.6Hz), 3.78 (2H, t, J = 6.6Hz),
6.58 to 7.0 (1H, m), 7.25 to 7.4 (2H, m) Example 19 Using 5-chloroisatin and 2-dibutylaminoethylethyl chloride hydrochloride, react in almost the same manner as in Example 7, and then apply it to a silica gel column. It was purified by chromatography (elution solvent: chloroform) to produce the following compound.

5-chloro-1-(2-dibutylaminoethyl)
Isatin Melting point: 35-36℃ Yield: 51.5% Elemental analysis: (as C ₁₈ H ₂₅ ClN ₂ O ₂ ) C% H% N% Calculated value 64.18 7.48 8.32 Actual value 64.31 7.69 8.55 IR (KBr): ν _CO 1725cm ^-1 NMR (CDCl ₃ ) δ: 0.86 (6H, d, J = 7.1Hz), 1.1-1.4 (8H,
m), 2.44 (4H, t, J=7.1Hz), 2.68 (2H,
t, J = 6.6Hz), 3.78 (2H, t, J = 6.6Hz),
6.85 to 7.95 (1H, m), 7.5 to 7.6 (2H, m) Example 20 Using 5-bromoisatin and 2-dibutylaminoethyl chloride hydrochloride, react in almost the same manner as in Example 7, and then perform silica gel column chromatography. It was purified by graphie (elution solvent: chloroform) to produce the following compound.

5-Bromo-1-(2-dibutylaminoethyl)
Isatin Melting point: 38-40℃ Yield: 46.9% Elemental analysis value: (as C ₁₈ H ₂₅ BrN ₂ O ₂ ) C% H% N% Calculated value 56.70 6.61 7.35 Actual value 56.38 6.85 7.59 IR (KBr): ν _CO 1730cm ^-1 NMR (CDCl ₃ ) δ: 0.86 (6H, d, J = 7.1Hz), 1.1-1.4 (8H,
m), 2.44 (4H, t, J=7.1Hz), 2.68 (2H,
t, J = 6.6Hz), 3.77 (2H, t, J = 6.6Hz),
6.86 (1H, d, J = 8.8Hz), 7.65~7.75 (2H,
m) Example 21 The following compound was produced in substantially the same manner as in Example 7 using 5-acetamidoisatin and 2-dibutylaminoethyl chloride hydrochloride.

5-acetamido-1-(2-dibutylaminoethyl)isatin Melting point: 157-159°C (ethyl acetate) Yield: 63.3% Elemental analysis: (as C ₂₀ H ₂₉ N ₃ O ₃ ) C% H% N% Calculated value 66.83 8.13 11.69 Actual value 66.56 8.00 11.51 IR (KBr): ν _NH 3340cm ^-1 ν _CO 1740, 1710, 1670cm ^-1 NMR (d ₆ −DMSO) δ: 0.78 (6H, t, J = 7.1Hz), 1.05~1.35
(8H, m), 2.04 (3H, s), 2.37 (4H, t,
J=7.1Hz), 2.60 (2H, t, J=6.6Hz), 3.70
(2H, d, J = 6.6Hz), 7.13 (1H, d, J =
8.2Hz), 7.72 (1H, dd, J=2.2and8.2Hz),
7.84 (1H, d, J = 2.2Hz), 10.04 (1H, s) Example 22 Using methyl 7-isatincarboxylate and 2-dibutylaminoethyl chloride hydrochloride, react and treat in almost the same manner as in Example 7. Thereafter, the product was purified by silica gel column chromatography (elution solvent: chloroform) to produce the following compound.

Methyl 1-(2-dibutylaminoethyl)-7-isatincarboxylate Properties: _{Oil Yield} : 91.7% _Elemental analysis: (as _C20H28N2O4・_0.07CHCl3 ) C% H% N% Calculated value 65.36 7.67 7.60 Actual value 65.18 7.87 7.70 IR (neat): ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 0.79 (6H, t, J = 7.1Hz), 1.0 to 1.2 (8H,
m), 2.30 (4H, t, J=7.1Hz), 2.46 (2H,
t, J=6.6Hz), 3.97 (3H, s), 4.10 (2H,
t, J = 6.6Hz), 7.14 (1H, t, J = 7.7Hz),
7.74 (1H, dd, J=1.7and7.7Hz), 7.88 (1H,
dd, J = 1.7 and 7.7 Hz) Example 23 Using isatin and 3-dibutylaminopropyl chloride hydrochloride, they were reacted in the same manner as in Example 7, and then subjected to silica gel flash column chromatography (elution solvent: chloroform/ The following compound was produced by purification using ethanol (100/1).

1-(3-dibutylaminopropyl)isatin Properties: Oil Yield: 83.7% Elemental analysis: (as C ₁₉ H ₂₈ N ₂ O ₂ ) C% H% N% Calculated value 72.12 8.92 8.85 Actual value 72.09 9.11 8.77 IR (neat): ν _CO 1730cm ^-1 NMR (CDCl ₃ ) δ: 0.90 (6H, t, J = 7.1Hz), 1.2-1.5 (8H,
m), 1.83 (2H, quint, J=7.1Hz), 2.39
(4H, t, 7.1Hz), 2.49 (2H, t, J=7.1
Hz), 3.77 (2H, t, J=7.1Hz), 6.96 (1H,
d, J = 7.7Hz), 7.10 (1H, t, J = 7.7Hz),
7.58 (1H, t, J = 7.7Hz), 7.60 (1H, d,
J = 7.7Hz) Example 24 Using isatin and 2-dibutylaminoethyl chloride hydrochloride, the reaction was carried out in almost the same manner as in Example 1, and silica gel flash column chromatography (elution solvent: chloroform/mtanol =
100/1) and recrystallized from hexane to produce the following compound.

1-(2-dibutylaminoethyl)isatin Melting point: 40-42℃ Yield: 79.3% Elemental analysis: (as C ₁₈ H ₂₆ N ₂ O ₂ ) C% H% N% Calculated value 71.49 8.67 9.26 Actual value 71.48 8.79 9.16 IR (KBr): ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 0.86 (6H, t, J = 7.1Hz), 1.15 to 1.45
(8H, m), 2.45 (4H, t, J=7.1Hz), 2.69
(2H, t, J=6.6Hz), 3.78 (2H, t, J=
6.6Hz), 6.93 (1H, d, J = 7.7Hz), 7.10
(1H, t, J=7.7Hz), 7.58 (1H, t, J=
7.7Hz), 7.60 (1H, d, J = 7.7Hz) Example 25 Using 5-methylisatin and 2-dibutylaminoethyl chloride hydrochloride, the reaction was performed in substantially the same manner as in Example 1, and then subjected to silica gel flash column chromatography. Purification was performed using Graphi (elution solvent: chloroform) to produce the following compound.

1-(2-dibutylaminoethyl)-5-methylisatin Melting point: 33-35°C Yield: 62.2% Elemental analysis: (as C ₁₉ H ₂₈ N ₂ O ₂ ) C% H% N% Calculated value 72.12 8.92 8.85 Actual value 72.00 9.13 8.79 IR (KBr): ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 0.86 (6H, t, J = 7.1Hz), 1.15 to 1.45
(8H, m), 2.33 (3H, s), 2.45 (4H, t,
J=7.1Hz), 2.68 (2H, t, J=6.6Hz), 3.76
(2H, t, J = 6.6Hz), 6.82 (1H, d, J =
7.7Hz), 7.38 (1H, d, J = 7.7Hz), 7.39
(1H, s) Example 26 The following compound was produced in substantially the same manner as in Example 1 using 5-acetamido-1-(2-dibutylaminoethyl)isatin.

5-amino-1-(2-dibutylaminoethyl)
Isatin Melting point: 134-135℃ Yield: 85.3% Elemental analysis: (as C ₁₈ H ₂₇ N ₃ O ₂ ) C% H% N% Calculated value 68.11 8.57 13.24 Actual value 68.09 8.66 13.13 IR (KBr): ν _NH 3450, 3350cm ^-1 ν _CO 1715cm ^-1 NMR ( _d6 -DMSO) δ: 0.79 (6H, t, J = 7.1Hz), 1.05-1.3 (8H,
m), 2.36 (4H, t, J=7.1Hz), 2.58 (2H,
t, J = 6.6Hz), 3.63 (2H, t, J = 6.6Hz),
5.13 (2H, s), 6.76 (1H, s), 6.87 (2H,
s) Example 27 Isatin and 2-(N-methylbutylamino)ethyl chloride hydrochloride were reacted in substantially the same manner as in Example 7, followed by silica gel flash column chromatography (elution solvent: chloroform).
The following compound was produced.

1-[2-(N-methylbutylamino)ethyl]isatin] Properties: Oil Yield: 83.5% Elemental analysis: (as C ₁₅ H ₂₀ N ₂ O ₂ ) C% H% N% Calculated value 69.21 7.74 10.76 Actual value 69.10 7.94 10.67 IR (neat): ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 0.84 (3H, t, J = 7.1Hz), 1.15 to 1.45
(4H, m), 2.30 (3H, s), 2.38 (2H, t,
J = 7.1Hz), 2.64 (2H, t, J = 6.6Hz), 3.83
(2H, t, J = 6.6Hz), 6.94 (1H, d, J =
7.7Hz), 7.10 (1H, t, J = 7.7Hz), 7.10
(1H, t, J=7.7Hz), 7.58 (1H, t, J=
7.7Hz), 7.60 (1H, d, J = 7.7Hz) Example 28 The following compound was produced in substantially the same manner as in Example 1 using isatin and 2-(N-isopropylcyclohexylamino)ethyl chloride hydrochloride. .

1-[2-(N-isopropylcyclohexylamino)ethyl]isatin Melting point: 103-106°C (ethyl acetate-hexane) Yield: 75.5% Elemental analysis: (as C ₁₉ H ₂₆ N ₂ O ₂ ) C% H% N% Calculated value 72.58 8.33 8.91 Actual value 72.37 8.48 8.99 IR (KBr): ν _CO 1725cm ^-1 NMR (CDCl ₃ ) δ: 0.96 (6H, d, J = 6.6Hz), 1.0 to 1.8 (10H,
m), 2.45-2.6 (2H, m), 2.75 (2H, t, J
= 6.6Hz), 3.06 (1H, sept, J = 6.6Hz), 3.68
(2H, t, J = 6.6Hz), 6.91 (1H, d, J =
7.7Hz), 7.08 (1H, t, J = 7.7Hz), 7.57
(1H, t, J = 7.7Hz), 7.58 (1H, d, J =
7.7Hz) Example 29 1-(2-dipropylaminoethyl) isatin 2.50 g of 1-(2-bromoethyl) isatin, 1.37 ml of dipropylamine, 1.38 g of anhydrous potassium carbonate
and 1.50 g of sodium iodide in dry benzene
The mixture was added to 100 ml and heated under reflux for 72 hours. After cooling, the reaction solution was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (elution solvent: chloroform) to obtain 1-(2-dipropylaminoethyl) as a solid with a melting point of 30°C or lower.
1.82 g of isatin was obtained.

Elemental analysis value: (as C ₁₆ H ₂₂ N ₂ O ₂・0.2H ₂ O) C% H% N% Calculated value 69.14 8.12 10.08 Actual value 69.26 8.23 9.91 IR (KBr): ν _CO 1730cm ^-1 NMR (CDCl ₃ ) δ: 0.83 (6H, t, J=7.1Hz), 1.40 (4H,
sexn, J = 7.1Hz), 2.43 (4H, t, J = 7.1
Hz), 2.70 (2H, t, J = 6.6Hz), 3.79 (2H,
t, J = 6.6Hz), 6.94 (1H, d, J = 7.7Hz),
7.09 (1H, t, J = 7.7Hz), 7.58 (1H, t,
J=7.7Hz), 7.59 (1H, d, J=7.7Hz) Example 30 1-[2-N-methylcyclohexylamino)
Ethyl] isatin 1-(2-bromoethyl) isatin 4.00g and N
- Dry 3.58 g of methylsilohexylamine with N,N
-Dissolved in 100ml of diethylformamide and stirred at 95°C for 1 hour. The solvent was distilled off under reduced pressure, and the residue was dissolved in 50 ml of 2N hydrochloric acid, washed with ethyl acetate, neutralized with an aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The residue was subjected to silica gel column chromatography (elution solvent: chloroform/methanol = 10/1)
After purification, the product was recrystallized from benzene-hexane to obtain 2.44 g of 1-[2-(N-methylcyclohexylamino)ethyl]isatin having a melting point of 58 to 60°C.

Elemental analysis value: (as C ₁₇ H ₂₂ N ₂ O ₂ ) C% H% N% Calculated value 71.30 7.74 9.78 Actual value 71.17 7.79 9.65 IR (KBr): ν _CO 1725 cm ^-1 NMR (CDCl ₃ ) δ: 0.95 ~ 1.3 (5H, m), 1.5-1.8 (5H, m),
2.25-2.4 (2H, m), 2.71 (2H, t, J = 6.6
Hz), 3.80 (2H, t, J=6.6Hz), 6.95 (1H,
d, J = 7.1Hz), 7.09 (1H, t, J = 7.1Hz),
7.57 (1H, t, J = 7.1Hz), 7.59 (1H, d,
J=7.1Hz)

Claims (1)

[Claims] 1. General formula (X in the formula is a lower alkyl group, lower alkoxy group, amino group, acylamino group, or alkoxycarbonyl group, n is 1 or 2, and Y
is a linear or branched alkylene chain having 2 to 4 carbon atoms, and R ¹ is a linear or branched alkyl group having 3 to 5 carbon atoms or a linear or branched alkyl group having 3 to 6 carbon atoms.
is a cycloalkyl group, and R ² has 1 to 5 carbon atoms.
straight-chain or branched alkyl group)
Isatin derivatives represented by and acid addition salts thereof.