JPH0482147B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel isatin derivative useful as a pharmaceutical. In more detail,
The present invention relates to novel isatin derivatives and acid addition salts thereof, which exhibit remarkable anti-ulcer effects in experimental ulcers, such as stress ulcers, and are useful as therapeutic agents for gastric and duodenal ulcers in mammals including humans.

[Conventional technology]

Up to now, various therapeutic agents for gastric and duodenal ulcers have been known. For example, there are antacids, antipepsin drugs, anticholinergic drugs, histamine H ₂ -receptor antagonists, etc., and these drugs mainly treat the stomach by inactivating or suppressing the secretion of gastric digestive juices, including gastric acid. It is used to treat duodenal ulcers.

According to the clinical findings of gastric and duodenal ulcers, not only cases of hyperacidity symptoms but also cases of hypoacidity symptoms have been reported, but the factor behind ulcer development in such cases is hypersecretion. Rather, it is thought that the internal defense mechanism for gastric and duodenal ulcers is broken.

Stress-induced gastric and duodenal ulcers, which have been on the rise in recent years, have many cases in which this protective mechanism has failed, and this drug has an effective central inhibitory effect on such stress-induced gastric and duodenal ulcers. There are almost no therapeutic agents for ulcers, and in actual treatment, anti-anxiety agents, tranquilizers, etc. are used in combination.

On the other hand, many 3-semicarbazone derivatives of isatin compounds such as isatin, 1-methylisatin, and 1-benzylisatin are also known [Chemical
"Chem. Rev.", Volume 34, Page 393; "Chem.
Absts.), Vol. 43, Column 8979g; Vol. 45, No.
Column 8005g; Volume 47 of the same magazine, Column 5542f; Volume 73 of the same magazine,
Column 76977b; see volume 77 of the same magazine, column 152122u]
It is also known that 3-thiosemicarbazone derivatives of 1-aminoalkylisatin have antiviral, antibacterial, antifungal, and bactericidal effects.

For example, the general formula (Alk in the formula is an alkylene group having 1 to 5 carbon atoms,
Z is an amino group) isatin = 3
- Thiosemicarbazone derivatives exhibit antiviral, antibacterial, central stimulatory, antihistamine, and analgesic effects, and are known to be useful as medicines for the treatment of viral diseases (U.S. Patent No. 3374234 specification).

As described above, some isatin = 3-semicarbazone derivatives or 3-thiosemicarbazone derivatives are already known, and 3-thiosemicarbazone derivatives have various pharmacological actions as described above. However, it was not known at all that it had an anti-ulcer effect. Moreover, the pharmacological action of the above-mentioned isatin=3-thiosemicarbazone derivative is specific;
For example, this compound shows anti-vaccine virus activity, while 3-
It is known that semicarbazone derivatives exhibit no activity at all [Chem.Absts., Vol. 47, Column 5542f].

[Problem that the invention seeks to solve]

The object of the present invention is to treat conventional antacids, antipepsin agents, anticholinergic agents,
New compounds, such as histamine _H2 -receptor antagonists, do not require concomitant use of tranquilizers and do not exhibit side effects due to strong central depressant effects when treating stress-induced gastric or duodenal ulcers. It is to provide.

[Means for solving problems]

The present inventors investigated the development of a therapeutic agent for gastric and duodenal ulcers that exhibits a therapeutic effect on stress ulcers and does not have a strong central depressant effect, and as a result, they discovered that this objective could be achieved with a certain type of isatin derivative. , we have achieved the present invention.

That is, the present invention is based on the general formula (R in the formula is a halogen atom, a lower alkyl group,
lower alkoxy group, amino group, acylamino group or alkoxycarbonyl group, n is 0 or 1,
R ¹ is a hydrogen atom, a lower alkyl group, an aryl group,
an aralkyl group or a cycloalkyl group, Y is a linear or branched alkylene group having 2 to 4 carbon atoms, R ² and R ³ may be the same or different,
A hydrogen atom, a linear alkyl group having 1 to 5 carbon atoms, a lower alkenyl group, an aralkyl group or a cycloalkyl group, or a pyrrolidinyl group, piperidino group, piperazinyl in which R ² and R ³ may have a substituent together with a nitrogen atom An object of the present invention is to provide isatin derivatives represented by the following formula (forming a tetrahydroisoquinolyl group or a tetrahydroisoquinolyl group) and acid addition salts thereof.

The isatin derivative of the present invention represented by the general formula () exhibits a remarkable suppressive effect on water immersion stress ulcers in rats, and is useful as a therapeutic agent for gastric and duodenal ulcers in mammals including humans. .

The isatin derivative of the present invention represented by the general formula () is a new compound that has not been described in any literature, for example,
general formula (R, R ² , R ³ , Y and n in the formula have the same meanings as above) and the general formula H ₂ NNHCONHR ¹ () (R ¹ in the formula has the same meanings as above). It can be obtained by reacting with a semicarbazide derivative represented by (having) or an acid addition salt thereof.

In this case, some of the compounds of the general formula () used as starting materials are known compounds, but they can be produced according to methods described in literature or methods analogous thereto [U.S. Pat. No. 3,374,234, " Sci. falmacoiteica (Sci.
Pharm.) Volume 38, page 98].

That is, the general formula (wherein R and n have the same meanings as above) and an isatin derivative represented by the general formula (X in the formula is an acid residue, R ² , R ³ and Y
has the same meaning as above) or an acid addition salt thereof according to a conventional method, or the general formula (R, X, Y and n in the formula have the same meanings as above) and at least equimolar amount of the isatin derivative of the general formula (R ² and R ³ in the formula have the same meanings as above)
It can be produced by reacting with an amine derivative represented by the following in accordance with a conventional method.

R ² or R ³ in a compound represented by the general formula ()
When producing a compound having any one of hydrogen atoms by the first method, it is better to protect the compound of general formula () with a protecting group such as an acyl group in advance and react it. That is, a compound of general formula () and a compound of general formula (In the formula, Acyl is an acyl group, R ⁶ is a hydrogen atom, a linear alkyl group having 1 to 5 carbon atoms, a lower alkenyl group, an aralkyl group, or a cycloalkyl group, and X and Y have the same meanings as above. by reacting with an acylaminoalkyl derivative represented by A compound represented by the formula (Acyl, R, R ⁶ , Y and n have the same meanings as above) is obtained, and the protecting group is removed by a conventional method to obtain the desired object.

General formula () used in these methods,
Most of the compounds (), (), ('), (), and () are known compounds and can be obtained as commercial products or according to known methods, and new compounds are also available. It can be easily obtained by referring to methods for producing known compounds having this structure.

In order to suitably produce the compound of the present invention, the isatin derivative of the general formula () is mixed with an inert organic solvent,
For example, it is dissolved or suspended in hydrous alcohol, then an equimolar to slightly excess molar amount of the semicarbazide derivative of the general formula () or its acid addition salt is added to the isatin derivative, and if necessary, sodium acetate, acetic acid, or hydrochloric acid is added. and react at a temperature of 0 to 80°C for 1 to 40 hours. After the reaction is completed, the reaction solution is concentrated, and if necessary, a base such as an aqueous sodium hydrogen carbonate solution or an aqueous sodium hydroxide solution is added, and the precipitated crystals are collected by filtration or extracted with an appropriate solvent.
By crystallizing using a suitable solvent, the desired isatin derivative of the general formula () can be obtained.

The isatin derivative represented by the general formula () can be converted into an acid addition salt by a conventional method, if desired. For example, the hydrochloride salt can be obtained by adding 1N hydrochloric acid in a molar equivalent to slightly excess molar amount of methanol, adding diethyl ether after concentration, filtering the precipitated crystals, and recrystallizing them from a suitable solvent. In addition to the above-mentioned hydrochlorides, examples of acid addition salts include hydrobromide, hydroiodide, sulfate, acetate, oxuate, malate, tartrate, citrate, mandelate, Mention may be made of addition salts of inorganic or organic acids such as fumarates, maleates, benzenesulfonates, p-toluenesulfonates, and the like. Such acid addition salts also exhibit significant inhibitory effects on stress ulcers.

The isatin derivative represented by the general formula () of the present invention has two geometric isomers, E form and Z form, due to its steric structure.

Until now, regarding the isomers of isatin = 3-semicarbazone derivatives and 3-thiosemicarbazone derivatives, the 3
- Thiosemicarbazone derivatives mostly exist in the Z form, whereas the corresponding 3-semicarbazone derivatives mainly exist in the E form, and this E form can be converted to the Z form by heat treatment or acid treatment. [Chem.Absts.] Vol. 79, No.
Column 41782f, Column 91459b of the same volume, and Vol. 81, No.
37145z column], the compounds of the present invention similarly exist mainly in the E form, and are converted to the Z form by treatment such as heating.

The isatin derivative represented by the general formula () of the present invention exhibits an anti-ulcer effect in both E-form and Z-form, and can be used as a pharmaceutical.

In actual treatment, the isatin derivative represented by the general formula () of the present invention can be used alone or in pharmaceutical compositions mixed with appropriate pharmaceutical excipients in various dosage forms, such as powders, fine granules, etc. tablets, capsules,
Used as syrup, liquid, injection, etc.
When a pharmaceutical composition containing an isatin derivative represented by the general formula () and its acid addition salt is used for treatment, the dosage should be adjusted as appropriate depending on the patient's age, sex, weight, severity of symptoms, etc. However, in general, when administered orally, the daily dose for adults is 10mg to 5000.
mg, per adult per day for parenteral administration, 1 mg/day
Administered within the range of 100mg.

〔Effect of the invention〕

The isatin derivatives represented by the general formula () and their acid addition salts of the present invention exhibit remarkable suppressive effects on experimental ulcers in animals, such as stress ulcers. For example, male Wistar rats (8 weeks old)
In a water immersion restraint stress ulcer experiment using , oral administration of 100 mg/kg body weight showed approximately 30 to 95% suppressive effect.

The isatin derivatives represented by the general formula () and their acid addition salts of the present invention do not show an inhibitory effect on the increase in gastric acid secretion caused by administration of histamine or pentagastrin, and do not show any suppressive effect on the increase in gastric acid secretion caused by administration of 2-deoxy-D-glucose. Shows a remarkable suppressive effect on secretion secretion.

The isatin derivatives represented by the general formula () and their acid addition salts of the present invention do not exhibit the side effects such as sleep prolongation that are observed in common central nervous system depressants.

As described above, the isatin derivatives represented by the general formula () and their acid addition salts of the present invention have centrally acting anti-ulcer effects, particularly suppressive effects on stress ulcers, and are also found in tranquilizers, etc. Since it does not exhibit hypnotic or motor-suppressing effects, it is useful as a therapeutic agent for the stomach and duodenum of mammals including humans.

〔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 5-bromo-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin 2.26 g of 5-bromoisatin and 1-(2-chloroethyl)-2,2,6, Suspend 2.40 g of 6-tetramethylpiperidine hydrochloride in 60 ml of dry N,N-dimethylformamide, add 0.80 g of 60% sodium hydride (oil-based) while stirring under ice cooling, and stir at room temperature for 30 minutes. The reaction was carried out 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 (H, m),
6.80 (1H, d, J = 8.8Hz), 7.65-7.75
(2H, m) Reference Example 2 Using 5-methoxyisatin and 2-dibutylaminoethyl chloride hydrochloride, the reaction was carried out in the same manner as in Reference Example 1, followed by silica gel flash column chromatography (elution solvent: chloroform).
The following compound was produced.

1-(2-dibutylaminoethyl)-5-methoxyisatin Melting point: 32-34℃ 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, t, 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 to 7.2 (2H, m) Reference Example 3 Using 5-fluoroisatin and 2-dibutylaminoethyl chloride hydrochloride, react in the same manner as in Reference Example 1, and then perform silica gel column chromatography (elution Solvent: Chloroform)
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, t, 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), 6.85~7.0 (1H, m), 7.25~
7.4 (2H, m) Reference Example 4 Using 5-chloroisatin and 2-dibutylaminoethyl chloride hydrochloride, the reaction was carried out in the same manner as in Reference Example 1, and then purified by silica gel column chromatography (elution solvent: chloroform). , produced the following compounds.

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, t, 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), 6.85~6.95 (1H, m), 7.5~
7.6 (2H, m) Reference Example 5 Using 5-bromoisatin and 2-dibutylaminoethyl chloride hydrochloride, the reaction was carried out in the same manner as in Reference Example 1, and then purified by silica gel column chromatography (elution solvent: chloroform). , produced the following compounds.

5-Bromo-1-(2-dibutylaminoethyl)
Isatin Melting point: 38-40℃ Yield: 46.9% Elemental analysis: (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, t, 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) Reference Example 6 The following compound was produced in substantially the same manner as in Reference Example 1 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, t, J = 6.6Hz), 7.13 (1H, d,
J = 8.2Hz), 7.72 (1H, dd, J = 2.2and8.2
Hz), 7.84 (1H, d, J = 2.2Hz), 10.04
(1H, s) Reference Example 7 Using methyl 7-isatincarboxylate and 2-dibutylaminoethyl chloride hydrochloride, the reaction was carried out in the same manner as in Reference Example 1, followed by silica gel column chromatography (elution solvent: chloroform). The following compound was produced.

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), 410 (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) Reference Example 8 Using isatin and 2-dibutylaminoethyl chloride hydrochloride, the reaction was carried out in the same manner as in Reference Example 1, and then purified by silica gel flash column chromatography (elution solvent: benzene). The following compounds were prepared.

1-(2-Dibenzylaminoethyl)isatin Properties: Oil Yield: 85.9% Elemental analysis: (as C ₂₄ H ₂₂ N ₂ O ₂ ) C% H% N% Calculated value 77.81 5.99 7.56 Actual value 77.63 5.81 7.51 IR (neat): ν _CO 1725cm ^-1 NMR (CDCl ₃ ) δ: 2.71 (2H, t, J = 6.0Hz), 3.62 (4H,
s), 3.74 (2H, t, J = 6.0Hz), 6.36
(1H, d, J = 7.7Hz), 7.01 (1H, t, J
=7.7Hz), 7.1~7.4 (11H, m), 7.52 (1H,
dd, J = 1.1 and 7.7 Hz Reference Example 9 Using 5-methoxyisatin and 1-(2-chloromethyl)-2,2,6,6-tetramethylpiperidine hydrochloride, in almost the same manner as Reference Example 1. The following compounds were prepared.

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 to 7.2 (2H, m) Reference Example 10 Almost the same as Reference Example 1 using 5-fluoroisatin and 1-(2-chloroethyl)-2,2,6,6-tetramethylpiperidine hydrochloride The following compound was produced.

5-Fluoro-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin Melting point: 143-144℃ (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 to 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) Reference example 11 5-chloroisatin and 1-(2-chloroethyl)
The following compound was produced in substantially the same manner as in Reference Example 1 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 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=88Hz), 7.5~7.6 (2H,
m) Reference Example 12 The following compound was produced in substantially the same manner as in Reference Example 1 using 5-acetamidoisatin and 1-(2-chloroethyl)-2,2,6,6-tetramethylpiperidine hydrochloride.

5-acetamido-1-[2-(2,2,6,6
-tetramethylpiperidino)ethyl]isatin Melting point: 295-297℃ (decomposition) (ethanol-ethyl acetate) Yield: 55.2% Elemental analysis: (as C ₂₁ H ₂₉ N ₂ 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 = 8.2
Hz), 7.71 (1H, dd, J=2.2and8.2Hz),
7.85 (1H, d, J = 2.2Hz), 10.05 (1H,
s) Reference Example 13 Using methyl 7-isatincarboxylate and 1-(2-chloroethyl)-2,2,6,6-tetramethylpiperidine hydrochloride, the reaction was performed in substantially the same manner as in Reference Example 1, and then silica gel It was purified by column chromatography (elution solvent: chloroform) to produce the following compound.

Methyl 1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]-7-isatinecarboxylate Melting point: 39-40℃ Yield: 90.2% Elemental analysis: (C ₂₁ H ₂₈ 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), 1.35-1.6 (6H, m),
2.45-2.6 (2H, m), 3.94 (3H, s), 3.95
~4.05 (2H, m), 7.14 (1H, t, J = 7.7
Hz), 7.73 (1H, dd, J=1.7and7.7Hz),
7.87 (1H, dd, J = 17 and 7.7Hz) Reference Example 14 Using isatin and 3-diethylaminopropyl chloride hydrochloride, the reaction was carried out in the same manner as in Reference Example 1, and then subjected to silica gel column chromatography (elution solvent: chloroform/ methanol = 10/1)
The following compound was produced.

1-(3-diethylaminopropyl)isatin Properties: Oil Yield: 82.1% Elemental analysis: (as C ₁₅ H ₂₀ N ₂ O ₂・0.03 CHCl ₃ ) C% H% N% Calculated value 68.40 7.65 10.61 Actual measurement Value 68.35 7.83 10.71 IR (neat): ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 1.00 (6H, t, J = 7.1Hz), 1.85 (2H,
quint, J=7.1Hz), 2.51(2H,t,J=
7.1Hz), 2.53 (4H, q, J = 7.1Hz), 3.78
(2H, t, J = 7.1Hz), 6.99 (1H, d, J
= 7.1Hz), 7.11 (1H, t, J = 7.1Hz), 7.58
(1H, t, J = 7.1Hz), 7.59 (1H, d, J
= 7.1 Hz) Reference Example 15 Using isatin and 3-dibutylaminopropyl chloride hydrochloride, the reaction was carried out in the same manner as in Reference Example 1, followed by silica gel flash column chromatography (elution solvent: chloroform/ethanol = 100/1). ) to produce the following compound.

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 to 1.5
(8H, m), 1.83 (2H, quint, J=7.1Hz),
2.39 (4H, t, J = 7.1Hz), 2.49 (2H, t,
J = 7.1Hz), 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) Reference example 16 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
Knead 250ml and 250ml of dry toluene,
Add 13.3g of 60% sodium hydride (oil-based) while stirring under ice-cooling, and 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) Reference Example 17 Using isatin and 2-diallylaminoethyl chloride hydrochloride, the reaction was carried out in the same manner as in Reference Example 16, and then silica gel flash column chromatography ( Elution solvent: chloroform) to produce the following compound.

1-(2-diallylaminoethyl)isatin Properties: Oil Yield: 61.1% Elemental analysis: (as C ₁₆ H ₁₈ N ₂ O ₂ ) C% H% N% Calculated value 71.09 6.71 10.36 Actual value 70.75 6.93 10.19 IR (neat): ν _CO 1730cm ^-1 NMR (CDCl ₃ ) δ: 2.74 (2H, t, J = 6.6Hz), 3.15 (4H,
d, J = 6.6Hz), 3.81 (2H, t, J = 6.6
Hz), 5.11 (2H, dd, J=1.7and9.9Hz),
5.16 (2H, dd, J=1.7and17.0Hz), 5.75
(2H, ddt, J=9.9, 17.0, and6.6Hz),
6.91 (1H, d, J = 7.7Hz), 7.13 (1H, t,
J = 7.7Hz), 7.57 (1H, t, J = 7.7Hz),
7.60 (1H, d, J = 7.7Hz) Reference Example 18 Using isatin and 2-dibutylaminoethyl chloride hydrochloride, the reaction was carried out in the same manner as in Reference Example 16, and silica gel flash column chromatography (elution solvent: Chloroform/methanol =
After purification with 100/1), the following compound was produced by recrystallization from hexane.

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 14.5
(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 = 7.1Hz), 7.60 (1H, d, J = 7.7Hz) Reference Example 19 Using 5-methylisatin and 2-dibutylaminoethyl chloride hydrochloride, react in almost the same manner as in Reference Example 16, and then silica gel flash. It was purified by column chromatography (elution solvent: chloroform) to produce the following compound.

1-(2-Dibutylaminoethyl)-5-methylisatin Melting point: 33-35℃ 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) Reference Example 20 Using isatin and 2-dicyclohexylaminoethyl chloride hydrochloride, react and treat in almost the same manner as Reference Example 16, and after purification by silica gel flash column chromatography (elution solvent: chloroform). , was recrystallized from chloroform-hexane to produce the following compound.

1-(2-dicyclohexylaminoethyl)isatin Melting point: 98-100℃ Yield: 55.1% Elemental analysis: (as C ₂₂ H ₃₀ N ₂ O ₂ ) C% H% N% Calculated value 74.54 8.53 7.90 Actual value 74.46 8.76 7.89 IR (KBr): ν _CO 1725cm ^-1 NMR (CDCl ₃ ) δ: 0.95 to 1.85 (20H, m), 2.45 to 2.6 (2H,
m), 2.80 (2H, t, J = 6.6Hz), 3.67
(2H, t, J = 6.6Hz), 6.90 (1H, d, J
= 7.7Hz), 7.08 (1H, t, J = 7.7Hz), 7.5
~7.7 (2H, m) Reference example 21 5-methylisatin and 1-(2-chloroethyl)
The following compound was produced in substantially the same manner as in Reference Example 16 using -2,2,6,6-tetramethylpiperidine hydrochloride.

5-Methyl-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin Melting point: 157-159℃ (hexane) Yield: 81.5% Elemental analysis: (C ₂₀ H ₂₈ 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 (2H, s), 1.4 to 1.6 (6H, m), 2.33
(3H, s), 2.65~2.2.75 (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) Reference example 22 1-[2-(1-pyrrolidinyl)ethyl]isatin 3.5 g of 2-(1-pyrrolidinyl)ethyl chloride hydrochloride and 3.0 g of isatin Suspend g in 50 ml of dry ethylene glycol dimethyl ether, stir while cooling on ice, and add 60% sodium hydride (oil-based).
After adding 2.0g, heat at room temperature for 30 minutes and then at 70℃ for 16 minutes.
Allowed time to react. After the reaction solution was concentrated under reduced pressure, an aqueous sodium bicarbonate solution was added to the residue, extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel flash column chromatography (elution solvent: chloroform/methanol =
100/1) and recrystallized from ethyl acetate-hexane to obtain 0.8 g of 1-[2-(1-pyrrolidinyl)ethyl]isatin having a melting point of 59-61°C.

Elemental analysis value: (as C ₁₄ H ₁₆ N ₂ O ₂ ) C% H% N% Calculated value 68.83 6.60 11.47 Actual value 68.78 6.74 11.40 IR (KBr): ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 1.7 ~ 1.85 (4H, m), 2.55~2.7 (4H,
m), 2.78 (2H, t, J = 7.1Hz), 3.89
(2H, t, J = 7.1Hz), 6.97 (1H, d, J
= 7.7Hz), 7.11 (1H, t, J = 7.7Hz), 7.58
(1H, dt, J=1.1and7.7Hz), 7.61 (1H,
dd, J=1.1and7.7Hz) Reference example 23 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 = 8.2
Hz), 6.78 (1H, d, J = 2.2Hz), 6.79
(1H, dd, J=2.2 and 8.2 Hz) Reference Example 24 The following compound was produced in substantially the same manner as Reference Example 23 using 5-acetamido-1-(2-dibutylaminoethyl)isatin.

5-amino-1-(2-dibutylaminoethyl)
Isatin Melting point: 134-135℃ (ethyl acetate-hexane) 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, 3350 cm ^-1 ν _CO 1715 cm ^-1 NMR (d ₆ −DMSO) δ: 0.79 (6H, t, J = 7.1 Hz), 1.05 to 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) Reference example 25 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), and the melting point was 30°C.
1.82 g of 1-(2-dipropylaminoethyl) isatin was obtained as the following solid.

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, = 7.1Hz), 1.40 (4H, sext,
J = 7.1Hz), 2.43 (4H, t, J = 7.1Hz),
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) Reference example 26 1-[2-(4-methyl-1-piperazinyl)ethyl]isatin 1-(2-bromoethyl)isatin 2.54g, N
-Methylpiperazine 1.5ml, triethylamine
1.7 ml and 1.66 g of Calicum iodide were dried N,N
-Dissolved in 30 ml of dimethylformamide and heated to 70℃ for 4 hours.
Stirred for an hour. After concentrating the reaction solution under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, extracted with chloroform, and dried over anhydrous magnesium sulfate.
After distilling off the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (elution solvent: chloroform/ethanol = 10/1), recrystallized from methanol-hexane, and the melting point
1.57 g of 1-[2-(4-methyl-1-piperazinyl)ethyl]isatin at 109-112°C was obtained.

Elemental analysis value: (as C ₁₅ H ₁₉ N ₃ O ₂・0.3H ₂ O) C% H% N% Calculated value 64.64 7.09 15.07 Actual value 64.63 7.04 14.81 IR (KBr): ν _CO 1740, 1720cm ^-1 NMR ( CDCl ₃ ) δ: 2.29 (3H, s), 2.35 to 2.65 (8H, m),
2.65 (2H, t, J = 6.6Hz), 3.85 (2H, t,
J = 6.6Hz), 6.93 (1H, d, J = 7.7Hz),
7.11 (1H, t, J = 7.7Hz), 7.55-7.65
(2H, m) Reference Example 27 The following compound was produced in substantially the same manner as Reference Example 26 using 1-(2-bromoethyl)isatin and N-benzylpiperazine.

1-[2-(4-benzyl-1-piperazinyl)
Ethyl isatin Melting point: 119-121℃ (ethyl acetate-diethyl ether) Yield: 68.6% Elemental analysis: (as C ₂₁ H ₂₃ N ₃ O ₂ ) C% H% N% Calculated value 72.18 6.63 12.03 Actual value 71.92 6.84 11.87 IR (KBr): ν _CO 1735cm ^-1 NMR (CDCl ₃ ) δ: 2.35 to 2.65 (8H, m), 2.65 (2H, t, J
= 6.6Hz), 3.50 (2H, br-s), 3.85 (2H,
t, J = 6.6Hz), 6.93 (1H, d, J = 7.7
Hz), 7.11 (1H, t, J = 7.7Hz), 7.2-7.4
(5H, m), 7.5-7.65 (2H, m) Reference example 28 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 crystallized from ethyl acetate to give 1-[2-(2,2,6,
4.06 g of 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 = 7.7Hz), 7.08 (1H, t, J = 7.7Hz),
7.5-7.65 (2H, m) Meanwhile, the hexane filtrate was concentrated, and the residue was recrystallized from hexane to give 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=
7.0and15.7Hz), 4.15~4.35 (1H, m), 7.00
(1H, d, J = 7.7Hz), 7.06 (1Ht, J = 7.7
Hz), 7.5-7.65 (2H, m) Reference example 29 1-[3-(2,2,6,6-tetramethylpiperidino)propyl]isatin 1-(2-chloroethyl)-2,2,6 , 10.00 g of 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. 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 to 2.45 (2H, m), 2.75 to 2.9 (2H, m) 9.10 g of 3-(2,2,6,6-tetramethylpiperidino)propionitrile to 300 ml of ethanol
After hydrogen chloride was introduced under cooling, 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 and the oily 3-
9.06 g of ethyl (2,2,6,6-tetramethylpiperidino)propionate was obtained.

IR (neat): ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 1.03 (12H, s), 1.26 (3H, t, J = 7.1
Hz), 1.35-1.6 (6H, m), 2.35-2.5 (2H,
m), 2.7-2.85 (2H, m), 4.11 (2H, q,
J=7.1Hz) Dissolve 9.00 g of ethyl 3-(2,2,6,6-tetramethylpiperidino)propionate in 200 ml of diethyl ether, and while stirring under ice cooling, dissolve 3.80 g of lithium aluminum hydride in 300 ml of diethyl ether. 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 6.68 g of oily 3-(2,2,6,6-tetramethylpiperidino)-1-propanol.

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 = 6.9
Hz), 4.70 (1H, br-s) 6.60 g of 3-(2,2,6,6-tetramethylpiperidino)-1-propanol was dissolved in chloroform 20
ml, added dropwise to 30 ml of thionyl chloride while stirring under ice cooling, and then 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
7.40 g of -chloropropyl)-2,2,6,6-tetramethylpiperidine hydrochloride was obtained.

Elemental analysis value: (as _C12H25Cl2N・_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) Isatin and 1-(3-chloropropyl)-2,
1-[3-(2,
2,6,6-tetramethylpiperidino)propyl]isatin was produced.

Melting point: 105-107℃ (hexane) Yield: 72.8% 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) Reference Example 30 Using isatin and 2-(N-methylbutylamino)ethyl chloride hydrochloride, react in the same manner as in Reference Example 1, and then perform 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),
7.58 (1H, t, J = 7.7Hz), 7.60 (1H, d,
J=7.7Hz) Reference Example 31 1-(2-Cyclohexylaminoethyl)isatin 2.00g of 1-(2-bromoethyl)isatin and 3.90g of cyclohexylamine were dissolved in 20ml of dry N,N-dimethylformamide and heated at 80°C for 1 hour. Stirred. Concentrate the reaction solution under reduced pressure to reduce the residue to 10%.
After dissolving in hydrochloric acid, wash with diethyl ether,
After neutralizing with sodium hydrogen carbonate, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, 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/ethanol = 100/1), and then recrystallized from diethyl ether-hexane to give 1-
(2-cyclohexylaminoethyl)isatin
1.32g was obtained.

Elemental analysis value: (as C ₁₆ H ₂₀ N ₂ O ₂ ) C% H% N% Calculated value 70.56 7.40 10.29 Actual value 70.46 7.51 10.24 IR (KBr): ν _NH 3400cm ^-1 ν _CO 1720cm ^-1 NMR (CDCl ₃ ) δ: 0.9~1.4 (6H, m), 1.5~1.9 (5H, m),
2.4-2.55 (1H, m), 2.96 (2H, t, J=
6.6Hz), 3.82 (2H, t, J = 6.6Hz), 6.98
(1H, d, J = 7.7Hz), 7.11 (1H, t, J
= 7.7Hz), 7.58 (1H, t, J = 7.7Hz), 7.60
(1H, d, J = 7.7Hz) Reference example 32 1-[2-(N-methylcyclohexylamino)
Ethyl] isatin 1-(2-bromoethyl) isatin 4.00g and N
- 3.58 g of methylcyclohexylamine was dried with N,
Dissolve in 100ml of N-dimethylformamide and heat to 95°C.
Stir 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, and neutralized with an aqueous sodium hydrogen carbonate solution.
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/
After purification in step 1), 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 (4H, m), 2.71 (2H, t, J=
6.6Hz), 3.80 (2H, t, J = 6.6Hz), 6.95
(1H, d, J = 7.1Hz), 7.09 (1H, t, J
= 7.7Hz), 7.57 (1H, t, J = 7.1Hz), 7.59
(1H, d, J = 7.1 Hz) Reference Example 33 Using 1-(2-bromoethyl)isatin and N-methylbenzylamine, the reaction was carried out in the same manner as in Reference Example 26, followed by silica gel flash column chromatography (elution). Solvent: chloroform) to produce the following compound.

1-[2-(N-methylbenzylamino)ethyl]isatin Properties: Oil Yield: 39.0% Elemental analysis: (as C ₁₈ H ₁₈ N ₂ O ₂ ) C% H% N% Calculated value 73.45 6.16 9.52 Actual value 73.17 6.37 9.33 IR (neat): ν _CO 1730cm ^-1 NMR (CDCl ₃ ) δ: 2.37 (3H, s), 2.64 (2H, t, J = 6.6
Hz), 3.53 (2H, s), 3.81 (2H, t, J=
6.6Hz), 6.67 (1H, d, J = 7.7Hz), 7.06
(1H, t, J=7.7Hz), 7.16 (5H, s),
7.44 (1H, dt, J=1.1and7.7Hz), 7.58
(1H, dd, J=1.1and7.7Hz) Reference example 34 1-[2-(1,2,3,4-tetrahydro-2
-isoquinolyl)ethyl]isatin 5.00 g of 1-(2-bromoethyl) isatin, 3.27 g of potassium iodide, 1.99 g of triethylamine and 1,2,3,4-tetrahydroisoquinoline
2.62g in 50ml of dry N,N-dimethylformamide
and stirred at 70°C for 2 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and after extraction with acetic acid,
The organic layer was extracted with 10% hydrochloric acid. The hydrochloric acid layer was neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was dissolved in benzene.
Recrystallized from hexane, 1-
1.39 g of [2-(1,2,3,4-tetrahydro-2-isoquinolyl)ethyl]isatin was obtained.

Elemental analysis value: (as C ₁₉ H ₁₈ N ₂ O ₂ ) C% H% N% Calculated value 74.49 5.92 9.14 Actual value 74.72 5.83 9.11 IR (KBr): ν _CO 1725 cm ^-1 NMR (CDCl ₃ ) δ: 2.75 ~ 2.9 (6H, m), 3.73 (2H, s),
3.96 (2H, t, J = 6.6Hz), 6.98 (1H, d,
J = 7.7Hz), 6.99 (1H, t, J = 7.7Hz),
7.05-7.15 (4H, m), 7.56 (1H, dt, J=
1.1and7.7Hz), 7.59(1H, dd, J=
1.1and7.7Hz) Reference example 35 1-(2-butylaminoethyl)isatin 2-butylaminoethyl chloride hydrochloride 7.0g
Add 10.3 g of sodium hydrogen carbonate to 100 ml of 50% hydrated dioxane, and stir while cooling on ice.
4.7ml benzoyl chloride 20ml dry dioxane
After dropping the solution, it was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure, extracted with diethyl ether, washed with water, and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure to obtain an oily N-butyl-N-
9.7 g of (2-chloroethyl)benzamide was obtained.

IR (neat): ν _CO 1620cm ^-1 Using isatin and N-butyl-N-(2-chloroethyl)benzamide, the reaction was performed in almost the same manner as in Reference Example 16, and then recrystallized from diethyl ether to give 1-[2 -(N-benzoylbutylamino)ethyl]isatin was obtained.

Melting point: 125-127℃ Yield: 80.9% Elemental analysis: (as C ₂₁ H ₂₂ N ₂ O ₃ ) C% H% N% Calculated value 71.98 6.33 7.99 Actual value 71.77 6.35 7.88 IR (KBr): ν _CO 1730cm ^-1 NMR (CDCl ₃ ) δ: 0.77 (3H, t, J = 7.1Hz), 1.05 to 1.2
(2H, m), 1.4-1.6 (2H, m), 3.26 (2H,
t, J = 7.1Hz), 3.74 (2H, t, J = 6.6
Hz), 4.08 (2H, t, J = 6.6Hz), 7.13
(1H, t, J = 7.1Hz), 7.25~7.45 (6H,
m), 7.61 (2H, d, J = 7.1 Hz) 2.60 g of 1-[2-(N-benzoylbutylamino)ethyl]isatin was added to 20 ml of ethanol and 20% hydrochloric acid.
The mixture was dissolved in 60 ml of mixed liquid and heated under reflux for 48 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was washed with ethyl acetate. The aqueous layer was neutralized with sodium hydrogen carbonate, extracted with chloroform, and washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1.24 g of oily 1-(2-butylaminoethyl)isatin.

Elemental analysis value: (as C ₁₄ H ₁₈ N ₂ O ₂・0.04CHCl ₃ ) C% H% N% Calculated value 67.16 7.24 11.16 Actual value 67.13 7.01 11.22 IR (neat): ν _CO 1730cm ^-1 NMR (CDCl ₃ ) δ: 0.89 (3H, t, J=7.1Hz), 1.15~1.6
(5H, m), 2.65 (2H, t, J=6.6Hz),
2.95 (2H, t, J = 6.6Hz), 3.85 (2H, t,
J = 6.6Hz), 6.98 (1H, d, J = 7.7Hz),
7.11 (1H, t, J = 7.7Hz), 7.58 (1H, dt,
J=1.7and7.7Hz), 7.60(1H, dd, J=
1.7and7.7Hz) Example 1 (E)-5-bromo-1-[2-(2,2,6,6-
Tetramethylpiperidino)ethyl]isatin=
Dissolve 1.00 g of 3-semicarbazone 5-bromo-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin and 0.43 g of semicarbazide hydrochloride in 90 ml of ethanol-water (2:1). , stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and an aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction with chloroform, washing with water, and drying over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from methanol-water to give (E)- with a melting point of 210-213°C.
0.93 g of 5-bromo-1-[2-(2,2,6,6,-tetramethylpiperidino)ethyl]isatin-3-semicarbazone was obtained.

Elemental analysis value: (as C ₂₀ H ₂₈ BrN ₅ O ₂・0.4H ₂ O) C% H% N% Calculated value 52.50 6.34 15.30 Actual value 52.49 6.47 15.01 IR (KBr): ν _NH 3400cm ^-1 ν _CO 1695cm ^{- 1} NMR ( _d6 -DMSO) δ: 1.06 (12H, s), 1.3-1.6 (6H, m), 2.5
~2.65 (2H, m), 3.55 ~ 3.7 (2H, m),
6.92 (1H, d, J = 8.2Hz), 6.93 (2H, br
−s), 7.63 (1H, d, J=8.2Hz), 8.42
(1H, s), 10.59 (1H, s) Example 2 (E)-1-(2-diallylaminoethyl)isatin = 3-semicarbazone 1-(2-diallylaminoethyl)isatin
1.00 g and semicarbazide hydrochloride 0.50 g were dissolved in 15 ml of ethanol-water (2:1) and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, an aqueous sodium bicarbonate solution was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The crystals were collected by filtration, washed with water, and recrystallized from ethanol. 1.05 g of -1-(2-diallylaminoethyl)]isatin-3-semicarbazone was obtained.

Elemental analysis value: (as C ₁₇ H ₂₁ N ₅ O ₂ ) C% H% N% Calculated value 62.37 6.47 21.39 Actual value 62.47 6.45 21.25 IR (KBr): ν _NH 3380, 3320, 3180cm ^-1 ν _CO 1725, 1680cm ^-1 NMR (d ₆ -DMSO) δ: 2.63 (2H, t, J = 6.6Hz), 3.09 (4H,
d, J = 6.6Hz), 3.80 (2H, t, J = 6.6
Hz), 5.05 (2H, dd, J=1.7and9.9Hz),
5.12 (2H, dd, J=1.7and17.0Hz), 5.69
(2H, ddt, J=9.9, 17.0, and6.6Hz),
6.85 (2H, br-s), 7.08 (1H, t, J=
7.7Hz), 7.09 (1H, d, J = 7.7Hz), 7.41
(1H, t, J = 7.7Hz), 8.09 (1H, d, J
=7.7Hz), 10.22 (1H, s) Example 3 The following compound was produced in substantially the same manner as in Example 1 using 1-(2-dibutylaminoethyl)-5-methoxyisatin and semicarbazide hydrochloride. .

(E)-1-(2-dibutylaminoethyl)-5-methoxyisatin = 3-semicarbazone Melting point: 157-160℃ (benzene-diethyl ether) Yield: 61.0% Elemental analysis: (C ₂₀ H ₃₁ As N ₅ O ₃ ) C% H% N% Calculated value 61.67 8.02 17.98 Actual value 61.82 8.23 17.90 IR (KBr): ν _NH 3450, 3400, 3250cm ^-1 ν _CO 1715, 1680cm ^-1 NMR (d ₆ -DMSO) δ: 0.79 (6H, t, J=7.1Hz), 1.05-1.35
(8H, m), 2.38 (4H, t, J=7.1Hz),
2.58 (2H, t, J = 6.6Hz), 3.73 (2H, t,
J = 6.6Hz), 3.79 (3H, s), 6.87 (2H, br
-s), 7.00 (2H, s), 7.77 (1H, s),
10.42 (1H, s) Example 4 The following compound was produced in substantially the same manner as in Example 1 using 1-(2-dibutylaminoethyl)-5-fluoroisatin and semicarbazide hydrochloride.

(E)-1-(2-dibutylaminoethyl)-5-fluoroisatin = 3-semicarbazone Melting point: 141-143℃ (chloroform-hexane) Yield: 65.4% Elemental analysis: (C ₁₉ H ₂₈ FN ₅ O ₂ ) C% H% N% Calculated value 60.46 7.48 18.55 Actual value 60.12 7.73 18.32 IR (KBr): ν _NH 3475, 3400, 3300 cm ^-1 ν _CO 1720, 1690 cm ^-1 NMR (d ₆ -DMSO) δ :0.89 (6H, t, J=7.1Hz), 1.15~1.45
(8H, m), 2.48 (4H, t, J=6.6Hz),
2.70 (2H, t, J = 6.1Hz), 3.88 (2H, t,
J = 6.1Hz), 7.00 (2H, br-s), 7.22
(1H, dd, J=4.4and8.8Hz), 7.39 (1H,
dt, J=2.2and8.8Hz), 8.23(1H, dd, J
=2.2and8.8Hz), 10.52 (1H, br-s) Example 5 5-chloro-1-(2-dibutylaminoethyl)
The following compound was produced in substantially the same manner as in Example 1 using isatin and semicarbazide hydrochloride.

(E)-5-chloro-1-(2-dibutylaminoethyl)isatin = 3-semicarbazone Melting point: 146-150℃ (chloroform-hexane) Yield: 59.8% Elemental analysis: (C ₁₉ H ₂₈ ClN ₅ (as O ₂ ) C% H% N% Calculated value 57.93 7.16 17.78 Actual value 57.66 7.30 17.49 IR (KBr): ν _NH 3450, 3400, 3260 cm ^-1 ν _CO 1720, 1675 cm ^-1 NMR (d ₆ -DMSO) δ: 0.77 (6H, t, J=7.1Hz), 1.0~1.4
(8H, m), 2.37 (4H, t, J=7.1Hz),
2.59 (2H, t, J = 6.1Hz), 3.77 (2H, t,
J = 6.1Hz), 6.90 (2H, br-s), 7.13
(1H, d, J = 8.8Hz), 7.46 (1H, dd, J
= 2.2 and 8.8Hz), 8.29 (1H, d, J = 2.2
Hz), 10.49 (1H, br-s) Example 6 5-bromo-1-(2-dibutylaminoethyl)
The following compound was produced in substantially the same manner as in Example 1 using isatin and semicarbazide hydrochloride.

(E)-5-Bromo-1-(2-dibutylaminoethyl)isatin = 3-semicarbazone Melting point: 156-159℃ (chloroform-hexane) Yield: 92.3% Elemental analysis: (C ₁₉ H ₂₈ BrN ₅ (as O ₂ ) C% H% N% Calculated value 52.06 6.44 15.98 Actual value 51.80 6.44 15.68 IR (KBr): ν _NH 3400, 3250 cm ^-1 ν _CO 1720, 1690 cm ^-1 NMR (d ₆ −DMSO) δ: 0.78 ( 6H, t, J=7.1Hz), 1.05~1.35
(8H, m), 2.36 (4H, t, J=7.1Hz),
2.58 (2H, t, J = 6.0Hz), 3.76 (2H, t,
J = 6.0Hz), 6.88 (2H, br-s), 7.08
(1H, d, J = 8.2Hz), 7.58 (1H, d, J
= 8.2Hz), 8.40 (1H, s), 10.53 (1H, br
-s) Example 7 5-amino-1-(2-dibutylaminoethyl)
The following compound was produced in substantially the same manner as in Example 1 using isatin and semicarbazide hydrochloride.

(E)-5-amino-1-(2-dibutylaminoethyl)isatin = 3-semicarbazone Melting point: 199-201°C (chloroform-methanol) Yield: 84.3% Elemental analysis: (C ₁₉ H ₃₀ N ₆ (as O ₂ ) C% H% N% Calculated value 60.94 8.07 22.44 Actual value 60.92 8.18 22.20 IR (KBr): ν _NH 3350, 3290 cm ^-1 ν _CO 1690, 1670 cm ^-1 NMR (d ₆ -DMSO) δ: 0.81 ( 6H, t, J=7.1Hz), 1.1~1.35
(8H, m), 2.38 (4H, t, J=7.1Hz),
2.56 (2H, t, J = 6.6Hz), 3.66 (2H, t,
J = 6.6Hz), 4.85 (2H, br-s), 6.65
(1H, dd, J=1.7and8.2Hz), 6.78 (1H,
d, J=8.2Hz), 6.80 (2H, br-s), 7.35
(1H, d, J = 1.7Hz), 9.78 (1H, s) Example 8 The following procedure was carried out in the same manner as in Example 1 using 5-acetamido-1-(2-dibutylaminoethyl)isatin and semicarbazide hydrochloride. The compound was prepared.

(E)-5-acetamido-1-(2-dibutylaminoethyl)isatin = 3-semicarbazone Melting point: 150-152℃ (methanol-water) Yield: 26.9% Elemental analysis: (C ₂₁ H ₃₂ N ₆ O ₃・0.7H ₂ O) C% H% N% Calculated value 58.78 7.85 19.58 Actual value 58.71 8.02 19.59 IR (KBr): ν _NH 3400, 3260cm ^-1 ν _CO 1705, 1640cm ^-1 NMR (d ₆ -DMSO ) δ: 0.79 (6H, t, J = 7.1Hz), 1.05 to 1.35
(8H, m), 2.03 (3H, s), 2.39 (4H, t,
J=7.1Hz), 2.55~2.65 (2H, m), 3.65~
3.8 (2H, m), 6.87 (2H, br-s), 7.03
(1H, d, J = 8.8Hz), 7.62 (1H, d, J
=8.8Hz), 8.09 (1H, s), 9.89 (1H, s),
10.06 (1H, s) Example 9 The following compound was produced in substantially the same manner as in Example 1 using methyl 1-(2-dibutylaminoethyl)-7-isatincarboxylate and semicarbazide hydrochloride.

(E)-1-(2-dibutylaminoethyl)-7-methoxycycarbonyl isatin = 3-semicarbazone Melting point: 158-160℃ (methanol-hexane) Yield: 23.7% Elemental analysis: (C ₂₁ H ₃₁ N ₅ O ₄・0.5C ₆ H ₁₄ (Hexane)
) C% H% N% Calculated value 62.58 8.32 15.20 Actual value 62.49 8.23 15.34 IR (KBr): ν _NH 3450, 3225 cm ^-1 ν _CO 1710, 1690 cm ^-1 NMR (d ₆ −DMSO) δ: 0.87 (6H, t, J=7.1Hz), 1.1~1.35
(8H, m), 2.25-2.4 (4H, m), 2.50 (2H,
t, J=6.0Hz), 4.02 (3H, s), 4.05
(2H, t, J = 6.0Hz), 7.05 (2H, br−
s), 7.30 (1H, t, J = 7.7Hz), 7.75
(1H, d, J = 7.7Hz), 8.42 (1H, d, J
=7.7Hz), 10.59 (1H, br-s) Example 10 The following compound was produced in substantially the same manner as in Example 1 using 1-(3-dibutylaminopropyl)isatin and semicarbazide hydrochloride.

(E)-1-(3-dibutylaminopropyl)isatin = 3-semicarbazone Melting point: 182-185℃ (ethanol) Yield: 52.7% Elemental analysis value: (as C ₂₀ H ₃₁ N ₅ O ₂ ) C% H% N% Calculated value 64.32 8.37 18.75 Actual value 64.38 8.36 18.71 IR (KBr): ν _NH 3440, 3325, 3220 cm ^-1 ν _CO 1700 cm ^-1 NMR (d ₆ −DMSO) δ: 0.85 (6H, t, J= 7.1Hz), 1.15~1.4
(8H, m), 1.69 (2H, quint, J=7.1Hz),
2.32 (4H, t, J = 7.1Hz), 2.40 (2H, t,
J = 7.1Hz), 3.73 (2H, t, J = 7.1Hz),
6.86 (2H, br-s), 7.09 (1H, t, J=
7.7Hz), 7.12 (1H, d, J = 7.7Hz), 7.42
(1H, t, J = 7.7Hz), 8.12 (1H, d, J
=7.7Hz), 10.24 (1H, br-s) Example 11 Using 5-methoxy-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin and semicarbazide hydrochloride, The following compounds were produced in substantially the same manner as in Example 1.

(E)-5-methoxy-1-[2-(2,2,6,6
-tetramethylpiperidino)ethyl]isatin = 3-semicarbazone Melting point: 176-178℃ (chloroform-ethanol) Yield: 71.6% Elemental analysis: (C ₂₁ H ₃₁ N ₅ O ₃・C ₂ H ₆ O (as ethanol) C% H% N% Calculated value 61.72 8.33 15.65 Actual value 61.92 8.49 15.68 IR (KBr): ν _NH 3350cm ^-1 ν _CO 1690cm ^-1 NMR (d ₆ -DMSO) δ: 1.06 (12H, s ), 1.35~1.6 (6H, m),
2.5-2.65 (2H, m), 3.5-3.65 (2H, m),
3.80 (3H, s), 6.86 (1H, d, J = 8.8
Hz), 6.88 (2H, br-s), 7.05 (1H, dd,
J = 2.7 and 8.8Hz), 7.80 (1H, d, J = 2.7
Hz), 10.48 (1H, s) Example 12 Using 5-fluoro-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin and semicarbazide hydrochloride, Example 1 and The following compounds were produced in substantially the same manner.

(E)-5-fluoro-1-[2-(2,2,6,6
-tetramethylpiperidino)ethyl]isatin = 3-semicarbazone Melting point: 204-207℃ (methanol-water) Yield: 73.6% Elemental analysis: (as C ₂₀ H ₂₈ FN ₅ O ₂・0.4H ₂ O ) C% H% N% Calculated value 60.56 7.32 17.65 Actual value 60.61 7.52 17.49 IR (KBr): ν _NH 3490, 3370cm ^-1 ν _CO 1725, 1695cm ^-1 NMR (d ₆ -DMSO) δ: 1.06 (12H, s ), 1.35~1.55 (6H, m),
2.5~2.65 (2H, m), 3.55~3.7 (2H, m),
6.90 (2H, br-s), 6.94 (1H, dd, J=
4.4and8.8Hz), 7.31 (1H, dt, J=
2.2and8.8Hz), 8.14(1H, dd, J=
2.2and8.8Hz), 10.48 (1H, br-s) Example 13 Using 5-chloro-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin and semicarbazide hydrochloride The following compound was produced in substantially the same manner as in Example 1.

(E)-5-chloro-1-[2-(2,2,6,6-
Tetramethylpiperidino)ethyl]isatin =
3-Semicarbazone Melting point: 197-202℃ (chloroform-hexane) Yield: 87.6% Elemental analysis value: (as C ₂₀ H ₂₈ ClN ₅ O ₂・0.05 CHCl ₃ ) C% H% N% Calculated value 58.47 6.86 17.00 Actual value 58.28 6.94 16.92 IR (KBr): ν _NH 3500, 3375 cm ^-1 ν _CO 1725, 1695 cm ^-1 NMR (d ₆ -DMSO) δ: 1.06 (12H, s), 1.3 to 1.6 (6H, m), 2.5
~2.65 (2H, m), 3.55 ~ 3.65 (2H, m),
6.90 (2H, br-s), 6.96 (1H, d, J=
8.8Hz), 7.50 (1H, dd, J=1.6and8.8Hz),
8.31 (1H, d, J = 1.6Hz), 10.57 (1H,
s) Example 14 5-acetamido-1-[2-(2,2,6,6
-tetramethylpiperidino)ethyl] The following compound was produced in substantially the same manner as in Example 1 using isatin and semicarbazide hydrochloride.

(E)-5-acetamido-1-[2-(2,2,
6,6-tetramethylpiperidino)ethyl]isatin = 3-semicarbazone Melting point: 172-174℃ (methanol-water) Yield: 55.4% Elemental analysis: (C ₂₂ H ₃₂ N ₆ O ₃・H ₂ (as O) C% H% N% Calculated value 59.17 7.67 18.82 Actual value 59.31 7.71 18.86 IR (KBr): ν _NH 3350, 3200 cm ^-1 ν _CO 1715, 1695 cm ^-1 NMR (d ₆ −DMSO) δ: 1.07 (12H , s), 1.3-1.6 (6H, m),
2.04 (3H, s), 2.5~2.65 (2H, m), 3.5~
3.65 (2H, m), 6.85 (2H, br-s), 6.89
(1H, d, J = 8.2Hz), 7.63 (1H, d, J
=8.2Hz), 8.13 (1H, s), 9.91 (1H, s),
10.14 (1H, s) Example 15 5-Amino-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin and semicarbazide hydrochloride were used in the same manner as in Example 1. The following compound was produced.

(E)-5-amino-1-[2-(2,2,6,6-
Tetramethylpiperidino)ethyl]isatin =
3-Semicarbazone Melting point: 211-216℃ (chloroform-hexane) Yield: 43.1% Elemental analysis value: (as C ₂₀ H ₃₀ N ₆ O ₂・0.2CHCl ₃ ) C% H% N% Calculated value 59.12 7.42 20.48 Actual value 59.19 7.61 20.16 IR (KBr): ν _NH 3320cm ^-1 ν _CO 1690cm ^-1 NMR (d ₆ -DMSO) δ: 1.06 (12H, s), 1.3 to 1.6 (6H, m),
2.45~2.6 (2H, m), 3.45~3.6 (2H, m),
4.85 (2H, br-s), 6.67 (2H, s), 6.80
(2H, br-s), 7.38 (1H, s), 9.85 (1H,
s) Example 16 In almost the same manner as in Example 1, using methyl 1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]-7-isatinecarboxylate and semicarbazide hydrochloride. The following compounds were prepared.

(Z)-7-methoxycarbonyl-1-[2-(2,
2,6,6-tetramethylpiperidino)ethyl]isatin = 3-semicarbazone Melting point: 214-218℃ (methanol-hexane) Yield: 53.7% Elemental analysis: (C ₂₂ H ₃₁ N ₅ O ₄・0.2C ₆ H ₁₄ (as hexane)) C% H% N% Calculated value 62.37 7.63 15.68 Actual value 62.27 7.54 15.52 IR (KBr): ν _NH 3460, 3250 cm ^-1 ν _CO 1720, 1685 cm ^-1 NMR (d ₆ − DMSO) δ: 0.98 (12H, s), 1.3 to 1.55 (6H, m),
2.4~2.55 (2H, m), 3.8~3.95 (5H, m),
7.23 (1H, t, J = 7.4Hz), 7.25 (2H, br
-s), 7.64 (1H, d, J = 7.4Hz), 7.88
(1H, d, J = 7.4Hz), 11.68 (1H, s) Example 17 1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin and 4-benzylsemicarbazide hydrochloride The following compound was produced in substantially the same manner as in Example 1.

(E)-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin = 3-(4-benzylsemicarbazone) Melting point: 167-168℃ (ethanol) Yield :82.3% Elemental analysis value: (as C ₂₇ H ₃₅ N ₅ O ₂ ) C% H% N% Calculated value 70.25 7.64 15.17 Actual value 70.27 7.86 15.00 IR (KBr): ν _NH 3380, 3220cm ^-1 ν _CO 1710, 1680cm ^-1 NMR (d ₆ -DMSO) δ: 1.07 (12H, s), 1.3-1.6 (6H, m), 2.5
~2.65 (2H, m), 3.55 ~ 3.7 (2H, m),
4.42 (2H, d, J = 6.0Hz), 6.96 (1H, d,
J = 7.7Hz), 7.09 (1H, t, J = 7.7Hz),
7.2-7.4 (5H, m), 7.45 (1H, t, J = 7.7
Hz), 7.79 (1H, t, J = 6.0Hz), 8.12
(1H, d, J = 7.7Hz), 10.43 (1H, s) Example 18 1-[1-methyl-2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin and semicarbazide hydrochloride The following compound was produced in substantially the same manner as in Example 1 using the salt.

(E)-1-[1-methyl-2-(2,2,6,6-
Tetramethylpiperidino)ethyl]isatin =
3-Semicarbazone Melting point: 180-183℃ (chloroform-methanol) Yield: 64.8% Elemental analysis: (as C ₂₁ H ₃₁ N ₅ O ₂ 0.7 CH ₄ O (methanol)) C% H% N% Calculated value 63.89 8.35 17.17 Actual value 63.97 8.64 17.04 IR (KBr): ν _NH 3400, 3200cm ^-1 ν _CO 1690cm ^-1 NMR (d ₆ -DMSO) δ: 0.85 (6H, br-s), 1.04 (6H, br-s ),
1.2-1.6 (9H, m), 2.76 (1H, dd, J=
4.7and15.7Hz), 3.01(1H, dd, J=
7.2and15.7Hz), 4.2~4.4 (1H, m), 6.84
(2H, br−s), 7.06 (1H, t, J=7.7
Hz), 7.15 (1H, d, J = 7.7Hz), 7.41
(1H, t, J = 7.7Hz), 8.09 (1H, d, J
=7.7Hz), 10.23(1H,s) Example 19 Almost the same as Example 1 using 1-[2-(2,2,6,6-tetramethylpiperidino)propyl]isatin and semicarbazide hydrochloride. The following compound was produced.

(E)-1-[2-(2,2,6,6-tetramethylpiperidino)propyl]isatin = 3-semicarbazone Melting point: 193-195℃ (Chloroform-methanol) Yield: 53.7% Elemental analysis Value: (as C ₂₁ H ₃₁ N ₅ O ₂ ) C% H% N% Calculated value 65.43 8.10 18.17 Actual value 65.40 8.34 17.99 IR (KBr): ν _NH 3410, 3225cm ^-1 ν _CO 1680cm ^-1 NMR (d ₆ −DMSO) δ: 1.0 to 1.7 (21H, m), 3.55 to 3.75 (2H,
m), 3.8-4.0 (1H, m), 6.85 (2H, br-
s), 7.01 (1H, d, J = 7.7Hz), 7.08
(1H, t, J = 7.7Hz), 7.43 (1H, t, J
= 7.7Hz), 8.11 (1H, d, J = 7.7Hz),
10.25 (1H, s) Example 20 The following compound was prepared in substantially the same manner as in Example 1 using 1-[3-(2,2,6,6-tetramethylpiperidino)propyl]isatin and semicarbazide hydrochloride. was manufactured.

(E)-1-[3-(2,2,6,6-tetramethylpiperidino)propyl]isatin = 3-semicarbazone Melting point: 208-211℃ (Chloroform-methanol) Yield: 63.9% Elemental analysis Value: (as C ₂₁ H ₃₁ N ₅ O ₂ ) C% H% N% Calculated value 65.43 8.10 18.17 Actual value 65.35 8.31 17.94 IR (KBr): ν _NH 3390, 3300, 3175cm ^-1 ν _CO 1680cm ^-1 NMR ( _d6 -DMSO) δ: 0.92 (12H, s), 1.2-1.55 (6H, m),
1.6~1.8 (2H, m), 2.35~2.5 (2H, m),
3.67 (2H, t, J = 6.6Hz), 6.86 (2H, br
-s), 7.09 (1H, t, J=7.7Hz), 7.12
(1H, d, J = 7.7Hz), 7.43 (1H, t, J
= 7.7Hz), 8.11 (1H, d, J = 7.7Hz),
10.24 (1H, br-s) Example 21 Using 1-[2-(4-methyl-1-piperazinyl)ethyl]isatin and semicarbazide hydrochloride,
The following compounds were produced in substantially the same manner as in Example 1.

(E)-1-[2-(4-Methyl-1-piperazinyl)ethyl]isatin = 3-semicarbazone Melting point: 173-176℃ (decomposition) (ethanol) Yield: 67.8% Elemental analysis value: (C ₁₆ H ₂₂ N ₆ O ₂・0.4H ₂ O) C% H% N% Calculated value 56.92 6.81 24.89 Actual value 57.02 6.77 24.80 IR (KBr): ν _NH 3400, 3310, 3180cm ^-1 ν _CO 1680cm ^-1 NMR ( _d6 -DMSO) δ: 2.12 (3H, s), 2.15-2.6 (10H, m),
3.82 (2H, t, J = 6.6Hz), 6.66 (2H, br
−s), 7.03 (1H, t, J=7.7Hz), 7.07
(1H, d, J = 7.7Hz), 7.32 (1H, t, J
= 7.7Hz), 8.11 (1H, d, J = 7.7Hz),
10.24(1H,br-s) Example 22 1-[2-(4-benzyl-1-piperazinyl)
The following compound was produced in substantially the same manner as in Example 1 using ethyl isatin and semicarbazide hydrochloride.

(E)-1-[2-(4-benzyl-1-piperazinyl)ethyl]isatin = 3-semicarbazone Melting point: 194-196℃ (ethanol-water) Yield: 70.1% Elemental analysis: (C ₂₂ H ₂₆ N ₆ O ₂ ) C% H% N% Calculated value 65.01 6.45 20.67 Actual value 64.90 6.54 20.70 IR (KBr): ν _NH 3375, 3300, 3175 cm ^-1 ν _CO 1680 cm ^-1 NMR (d ₆ −DMSO) δ :2.25~2.7 (10H, m), 3.46 (2H, s),
3.86 (2H, t, J = 6.6Hz), 6.90 (2H, br
-s), 7.12 (1H, t, J=7.7Hz), 7.16
(1H, d, J = 7.7Hz), 7.2~7.5 (6H,
m), 8.13 (1H, d, J = 7.7Hz), 10.26
(1H,s) Example 23 The following compound was produced in substantially the same manner as in Example 1 using 1-(2-diethylaminoethyl)isatin and 4-benzylsemicarbazide hydrochloride.

(E)-1-(2-diethylaminoethyl)isatin = 3-(4-benzyl semicarbazone Melting point: 169-171℃ (Chloroform-diethyl ether) Yield: 81.0% Elemental analysis: (C ₂₂ H ₂₇ As N ₅ O ₂ ) C% H% N% Calculated value 67.15 6.92 17.80 Actual value 66.98 6.84 17.80 IR (KBr): ν _NH 3260cm ^-1 ν _CO 1690cm ^-1 NMR (d ₆ −DMSO) δ: 0.87 (6H, t, J = 7.1Hz), 2.48 (4H,
q, J = 7.1Hz), 2.60 (2H, t, J = 6.6
Hz), 3.77 (2H, t, J=6.6Hz), 4.42
(2H, d, J = 6.0Hz), 7.07 (1H, t, J
= 7.7Hz), 7.12 (1H, d, J = 7.7Hz), 7.2
~7.4 (5H, m), 7.42 (1H, t, J = 7.7
Hz), 7.81 (1H, t, J = 6.0Hz), 8.10
(1H, d, J = 7.7Hz), 10.36 (1H, s) Example 24 (E)-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin = 3- Semicarbazone 1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin 1.50 g, semicarbazide hydrochloride 0.64 g and sodium acetate 0.47 g were suspended in 90 ml of ethanol-water (2:1). and stirred at room temperature for 16 hours. Concentrate the reaction solution under reduced pressure,
An aqueous sodium hydrogen carbonate solution was added to the residue, and the crystals were collected by filtration and washed with water. The obtained crystals were recrystallized from ethanol-water to give (E)-1-[2-
1.20 g of (2,2,6,6-tetramethylpiperidino)ethyl]isatin=3-semicarbazone was obtained.

Elemental analysis value: (as C ₂₀ H ₂₉ N ₅ O ₂・0.9H ₂ O) C% H% N% Calculated value 61.96 8.01 18.06 Actual value 62.10 7.97 17.96 IR (KBr): ν _NH 3440, 3250cm ^-1 ν _CO 1690cm ^-1 NMR (d ₆ -DMSO) δ: 1.07 (12H, s), 1.3-1.6 (6H, m), 2.5
~2.65 (2H, m), 3.55 ~ 3.7 (2H, m),
6.85 (2H, br-s), 6.96 (1H, d, J=
7.7Hz), 7.08 (1H, t, J = 7.7Hz), 7.45
(1H, t, J = 7.7Hz), 8.11 (1H, d, J
=7.7Hz), 10.28 (1H, s) Example 25 The following compound was produced in substantially the same manner as in Example 24 using 1-(2-dipropylaminoethyl)isatin and semicarbazide hydrochloride.

(E)-1-[2-dipropylaminoethyl)isatin = 3-semicarbazone Melting point: 180-182℃ (ethanol-water) Yield: 35.9% Elemental analysis: (as C ₁₇ H ₂₅ N ₅ O ₂ ) C% H% N% Calculated value 61.61 7.60 21.13 Actual value 61.28 7.81 21.00 IR (KBr): ν _NH 3380, 3310, 3175 cm ^-1 ν _CO 1685 cm ^-1 NMR (d ₆ -DMSO) δ: 0.75 (6H, t , J=7.1Hz), 1.30(4H,
sext, J = 7.1Hz), 2.36 (4H, t, J = 7.1
Hz), 2.61 (2H, t, J=6.6Hz), 3.77
(2H, t, J = 6.6Hz), 6.84 (2H, br−
s), 7.07 (1H, t, J = 7.7Hz), 7.10
(1H, d, J = 7.7Hz), 7.42 (1H, t, J
= 7.7Hz), 8.09 (1H, d, J = 7.7Hz),
10.21 (1H, s) Example 26 The following compound was produced in substantially the same manner as in Example 24 using 1-(2-dibutylaminoethyl)isatin and semicarbazide hydrochloride.

(E)-1-(2-dibutylaminoethyl)isatin = 3-semicarbazone Melting point: 176-178℃ (methanol-water) Yield: 39.4% Elemental analysis: (C ₁₉ H ₂₉ N ₅ O ₂・0.4 (as H ₂ O) C% H% N% Calculated value 62.64 8.19 19.10 Actual value 62.45 8.13 19.05 IR (KBr): ν _NH 3440, 3310, 3250 cm ^-1 ν _CO 1690 cm ^-1 NMR (d ₆ -DMSO) δ: 0.78 (6H, t, J=7.1Hz), 1.1~1.35
(8H, m), 2.38 (4H, t, J=7.1Hz),
2.60 (2H, t, J = 6.6Hz), 3.76 (2H, t,
J=6.6Hz), 6.85 (2H, br-s), 7.07
(1H, t, J = 7.7Hz), 7.10 (1H, d, J
= 7.7Hz), 7.42 (1H, t, J = 7.7Hz), 8.09
(1H, d, J = 7.7Hz), 10.22 (1H, s) Example 27 Example using 1-(2-dibutylaminoethyl)-5-methylisatin and semicarbazide hydrochloride.
The following compound was produced in substantially the same manner as 24.

(E)-1-(2-Dibutylaminoethyl)-5-methylisatin = 3-semicarbazone Melting point: 158-160℃ (chloroform-hexane) Yield: 71.3% Elemental analysis: (C ₂₀ H ₃₁ N ₅ O ₂ ) C% H% N% Calculated value 64.32 8.37 18.75 Actual value 64.11 8.46 18.46 IR (KBr): ν _NH 3460, 3390, 3250 cm ^-1 ν _CO 1715, 1690 cm ^-1 NMR (d ₆ −DMSO) δ: 0.79 (6H, t, J=7.1Hz), 1.05~1.35
(8H, m), 2.31 (3H, s), 2.38 (4H, t,
J = 7.1Hz), 2.58 (2H, t, J = 6.6Hz),
3.73 (2H, t, J = 6.6Hz), 6.83 (2H, br
−s), 6.98 (1H, d, J=8.2Hz), 7.23
(1H, d, J=8.2Hz), 7.99 (1H, s),
10.16 (1H, s) Example 28 Using 1-(2-dicyclohexylaminoethyl)isatin and semicarbazide hydrochloride, Example 24
The following compounds were produced in substantially the same manner as above.

(E)-1-(2-dicyclohexylaminoethyl)
Isatin = 3 _- semicarbazone _Melting point: 199-202℃ ( _methanol -water) Yield: 56.0% Elemental analysis: (as _C23H33N5O2・_0.1H2O ) C% H% N% Calculated value 66.83 8.10 16.94 Actual value 67.07 8.12 16.62 IR (KBr): ν _NH 3400, 3320, 3200cm ^-1 ν _CO 1725, 1685cm ^-1 NMR (d ₆ −DMSO) δ: 0.9 to 1.75 (20H, m), 2.4 to 2.6 (2H,
m), 2.71 (2H, t, J = 6.6Hz), 3.65
(2H, t, J = 6.6Hz), 6.85 (2H, br−
s), 7.06 (1H, d, J = 7.7Hz), 7.07
(1H, t, J = 7.7Hz), 7.42 (1H, t, J
= 7.7Hz), 8.09 (1H, d, J = 7.7Hz),
10.21 (1H, s) Example 29 The following compound was produced in substantially the same manner as in Example 24 using 1-(2-dibenzylaminoethyl)isatin and semicarbazide hydrochloride.

(E)-1-(2-dibenzylaminoethyl)isatin = 3-semicarbazone Melting point: 177-180℃ (ethanol) Yield: 73.8% Elemental analysis value: (as C ₂₅ H ₂₅ N ₅ O ₂ ) C % H% N% Calculated value 70.24 5.89 16.38 Actual value 70.40 5.97 16.13 IR (KBr): ν _NH 3400, 3275, 3225, 3175 cm ^-1 ν _CO 1680 cm ^-1 NMR (d ₆ -DMSO) δ: 2.60 (2H, t , J=6.0Hz), 3.59(4H,
s), 3.86 (2H, t, J=6.0Hz), 6.80
(1H, d, J = 7.7Hz), 6.86 (2H, br−
s), 7.04 (1H, t, J = 7.7Hz), 7.1~7.3
(11H, m), 8.09 (1H, d, J=7.7Hz),
10.25 (1H, s) Example 30 The following compound was produced in substantially the same manner as in Example 24 using 1-[2-(1-pyrrolidinyl)ethyl]isatin and semicarbazide hydrochloride.

(E)-1-[2-(1-pyrrolidinyl)ethyl]isatin = 3-semicarbazone Melting point: 184-186℃ (methanol-water) Yield: 29.9% Elemental analysis: (C ₁₅ H ₁₉ N ₅ O ₂・0.2H ₂ O) C% H% N% Calculated value 59.08 6.41 22.97 Actual value 59.18 6.33 23.02 IR (KBr): ν _NH 3380, 3310, 3175cm ^-1 ν _CO 1725, 1680cm ^-1 NMR (d ₆ − DMSO) δ: 1.5 to 1.75 (4H, m), 2.4 to 2.6 (4H, m),
2.65 (2H, t, J = 6.6Hz), 3.84 (2H, t,
J = 6.6Hz), 6.88 (2H, br-s), 7.09
(1H, t, J = 7.7Hz), 7.13 (1H, d, J
= 7.7Hz), 7.42 (1H, t, J = 7.7Hz), 8.09
(1H, d, J = 7.7Hz), 10.25 (1H, br−
s) Example 31 The following compound was produced in substantially the same manner as in Example 24 using 1-(2-piperidinoethyl)isatin and semicarbazide hydrochloride.

(E)-1-(2-piperidinoethyl)isatin =
3-Semicarbazone Melting point: 181-183℃ (methanol-water) Yield: 50.4% Elemental analysis: (as C ₁₆ H ₂₁ N ₅ O ₂ ) C% H% N% Calculated value 60.94 6.71 22.21 Actual value 61.09 6.64 22.06 IR (KBr): ν _NH 3370, 3300, 3175 cm ^-1 ν _CO 1685 cm ^-1 NMR (d ₆ −DMSO) δ: 1.25 to 1.55 (6H, m), 2.3 to 2.45 (4H,
m), 2.48 (2H, t, J = 6.6Hz), 3.82
(2H, t, J = 6.6Hz), 6.87 (2H, br−
s), 7.08 (1H, t, J = 7.7Hz), 7.12
(1H, d, J = 7.1Hz), 7.41 (1H, t, J
= 7.1Hz), 8.09 (1H, d, J = 7.1Hz),
10.25 (1H, br-s) Example 32 Using 5-methyl-1-[2-(2,2,6,6,-tetramethylpiperidino)ethyl]isatin and semicarbazide hydrochloride, Example 24 and The following compounds were produced in substantially the same manner.

(E)-5-methyl-1-[2-(2,2,6,6-
Tetramethylpiperidino)ethyl]isatin =
3-Semicarbazone Melting point: 192-195℃ ( _ethanol -water) Yield: 69.9% Elemental analysis value: (as _C21H31N5O2・_0.1H2O ) C% _H % N% _Calculated value 65.12 8.12 18.08 Actual value 65.34 8.25 17.75 IR (KBr): ν _NH 3490, 3370cm ^-1 ν _CO 1720, 1695cm ^-1 NMR (d ₆ -DMSO) δ: 1.06 (12H, s), 1.35-1.6 (6H, m),
2.32 (3H, s), 2.5-2.65 (2H, m), 3.55
~3.65 (2H, m), 6.84 (1H, d, J = 8.2
Hz), 6.85 (2H, br-3), 7.26 (1H, d,
J = 8.2Hz), 8.02 (1H, s), 10.23 (1H,
s) Example 33 The following compound was produced in substantially the same manner as in Example 24 using 1-(3-dimethylaminopropyl)isatin and semicarbazide hydrochloride.

(E)-1-(3-dimethylaminopropyl)isatin = 3-semicarbazone Melting point: 184-187℃ (decomposition) (chloroform-methanol) Yield: 57.9% Elemental analysis: (C ₁₄ H ₁₉ N ₅ O ₂ ) C% H% N% Calculated value 58.12 6.62 24.20 Actual value 57.96 6.69 24.09 IR (KBr): ν _NH 3340, 3125 cm ^-1 ν _CO 1695, 1680 cm ^-1 NMR (d ₆ -DMSO) δ: 1.71 (2H , quint, J=7.1Hz), 2.11(6H,
s), 2.23 (2H, t, J=7.1Hz), 3.74
(2H, t, J = 7.1Hz), 6.88 (2H, br−
s), 7.09 (1H, t, J = 7.7Hz), 7.14
(1H, d, J = 7.7Hz), 7.41 (1H, t, J
= 7.7Hz), 8.11 (1H, d, J = 7.7Hz),
10.25 (1H, br) Example 34 The following compound was produced in substantially the same manner as in Example 24 using 1-(3-diethylaminopropyl)isatin and semicarbazide hydrochloride.

(E)-1-(3-diethylaminopropyl)isatin = 3-semicarbazone Melting point: 178-180℃ (decomposition) (chloroform-methanol) Yield: 33.9% Elemental analysis: (C ₁₆ H ₂₃ N ₅ O ₂・0.03CHCl ₃ ) C% H% N% Calculated value 59.99 7.23 21.82 Actual value 59.73 7.17 21.81 IR (KBr): ν _NH 3400, 3310, 3175 cm ^-1 ν _CO 1680 cm ^-1 NMR (d ₆ -DMSO) δ: 0.92 (6H, t, J=7.1Hz), 1.69 (2H,
quint, J = 7.1Hz), 2.42 (2H, t, J =
7.1Hz), 2.43 (4H, q, J = 7.1Hz), 3.74
(2H, t, J = 7.1Hz), 6.89 (2H, br−
s), 7.09 (1H, t, J = 7.4Hz), 7.13
(1H, d, J = 7.4Hz), 7.42 (1H, t, J
= 7.4Hz), 8.11 (1H, d, J = 7.4Hz),
10.25 (1H, br) Example 35 (E)-1-(2-dibutylaminoethyl)isatin = 3-(4-cyclohexylsemicarbazone) 1-(2-dibutylaminoethyl)isatin
1.00g and 4-cyclohexyl semicarbazide 0.63
Dissolve g in 10 ml of ethanol and add 4 ml of 1N hydrochloric acid.
ml and stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and an aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction with chloroform, washing with water, and drying over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from ethanol to give (E)-1-(2-dibutylaminoethyl)isatin = 3-(4-cyclohexylsemicarbazone) 0.82 with a melting point of 139-140°C. I got g.

Elemental analysis value: (as C ₂₅ H ₃₉ N ₅ O ₂・0.2C ₂ H ₆ O (ethanol)) C% H% N% Calculated value 67.67 8.99 15.53 Actual value 67.49 9.09 15.42 IR (KBr): ν _NH 3460, 3380, 3200cm ^-1 ν _CO 1690, 1670cm ^-1 NMR (d ₆ -DMSO) δ: 0.78 (6H, t, J = 7.1Hz), 1.0 to 1.9
(18H, m), 2.38 (4H, t, J=7.1Hz),
2.59 (2H, t, J=6.0Hz), 3.5~3.65 (1H,
m), 3.76 (2H, t, J = 6.0Hz), 6.95~
7.15 (3H, m), 7.41 (1H, t, J = 7.7
Hz), 8.08 (1H, d, J = 7.7Hz), 10.20
(1H,s) Example 36 The following compound was produced in substantially the same manner as in Example 35 using 1-(2-diethylaminoethyl)isatin and 4-cyclohexyl semicarbazide.

(E)-1-(2-diethylaminoethyl)isatin = 3-(4-cyclohexylsemicarbazone) Melting point: 166-168℃ (chloroform-hexane) Yield: 87.5% Elemental analysis: (C ₂₁ H ₃₁ As _N5O2・_0.03CHCl3 ) C% H% N% Calculated value 64.92 8.04 18.00 Actual value 64.94 8.11 18.03 IR (KBr): ν _NH 3200cm ^-1 ν _CO 1690cm ^-1 _NMR (d ₆ −DMSO) δ: 0.87 (6H, t, J=7.1Hz), 1.1~1.95
(10H, m), 2.49 (4H, q, J = 7.1Hz),
2.60 (2H, t, J=6.6Hz), 3.5~3.7 (1H,
m), 3.77 (2H, t, J = 6.6Hz), 7.0~7.2
(3H, m), 7.42 (1H, t, J=7.7Hz),
8.08 (1H, d, J = 7.7Hz), 10.22 (1H, br
-s) Example 37 The following compound was produced in substantially the same manner as in Example 35 using 1-(2-dibutylaminoethyl)isatin and 4-methylsemicarbazide.

(E)-1-(2-dibutylaminoethyl)isatin = 3-(4-methylsemicarbazone) Melting point: 143.5-145.5℃ (benzene-diethyl ether) Yield: 43.8% Elemental analysis: (C ₂₀ H ₃₁ N ₅ O ₂ ) C% H% N% Calculated value 64.32 8.37 18.75 Actual value 64.24 8.41 18.81 IR (KBr): ν _NH 3280cm ^-1 ν _CO 1700, 1685cm ^-1 NMR (d ₆ −DMSO) δ: 0.78 (6H, t, J=7.1Hz), 1.05~1.35
(8H, m), 2.38 (4H, t, J=7.1Hz),
2.60 (2H, t, J = 6.6Hz), 2.77 (3H, d,
J = 4.4Hz), 3.76 (2H, t, J = 6.6Hz),
7.07 (1H, t, J = 7.7Hz), 7.09 (1H, d,
J = 7.7Hz), 7.19 (1H, q, J = 4.4Hz),
7.41 (1H, t, J = 7.7Hz), 8.10 (1H, d,
J = 7.7Hz), 10.30 (1H, s) Example 38 Using 1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin and 4-methylsemicarbazide, Example 35 and The following compounds were produced in substantially the same manner.

(E)-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin = 3-(4-methylsemicarbazone) Melting point: 221-223℃ (Chloroform-ethanol) Yield: 83.8% Elemental analysis value: (as C ₂₁ H ₃₁ N ₅ O ₂・C ₂ H ₆ O (ethanol)) C% H% N% Calculated value 64.01 8.64 16.23 Actual value 63.83 8.74 16.33 IR (KBr): ν _NH 3360cm ^-1 ν _CO 1685cm ^-1 NMR (d ₆ -DMSO) δ: 1.07 (12H, s), 1.3 to 1.6 (6H, m), 2.5
~2.65 (2H, m), 2.77 (3H, d, J = 4.4
Hz), 3.55-3.7 (2H, m), 6.96 (1H, d,
J = 7.7Hz), 7.09 (1H, t, J = 7.7Hz),
7.19 (1H, q, J = 4.4Hz), 7.44 (1H, t,
J = 7.7Hz), 8.11 (1H, d, J = 7.7Hz),
10.37 (1H, s) Example 39 The following procedure was carried out in substantially the same manner as in Example 35 using 1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin and 4-cyclohexyl semicarbazide. A compound was prepared.

(E)-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin = 3-(4-cyclohexylsemicarbazone) Melting point: 172-173℃ (Chloroform-ethanol) Yield: 76.8% Elemental analysis: (as _{C26H39N5O2 ・ C2H6O} ( _ethanol ) ₎ C% H% N% Calculated value 67.30 _9.08 14.02 Actual value 67.21 9.35 13.93 IR (KBr): ν _NH 3380, 3220cm ^-1 ν _CO 1705, 1670cm ^-1 NMR (d ₆ -DMSO) δ: 1.07 (12H, s), 1.1 to 1.95 (16H, m),
2.5-2.65 (2H, m), 3.5-3.7 (3H, m),
6.96 (1H, d, J = 7.7Hz), 7.01 (1H, d,
J = 7.7Hz), 7.09 (1H, t, J = 7.7Hz),
7.45 (1H, t, J = 7.7Hz), 8.10 (1H, d,
J = 7.7Hz), 10.29 (1H, s) Example 40 Using 1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin and 4-phenyl semicarbazide, Example 35 The following compounds were produced in substantially the same manner as above.

(E)-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin = 3-(4-phenylsemicarbazone) Melting point: 174-175.5℃ (ethanol) Yield Rate: 80.4% Elemental analysis value: (as C ₂₆ H ₃₃ N ₅ O ₂・0.7C ₂ H ₆ O (ethanol)) C% H% N% Calculated value 68.59 7.81 14.60 Actual value 68.46 7.94 14.41 IR (KBr): ν _NH 3330, 3220cm ^-1 ν _CO 1680cm ^-1 NMR (d ₆ -DMSO) δ: 1.08 (12H, s), 1.35-1.6 (16H, m),
2.55~2.65 (2H, m), 3.6~3.7 (2H, m),
6.99 (1H, d, J = 7.7Hz), 7.07 (1H, t,
J = 7.7Hz), 7.15 (1H, t, J = 7.7Hz),
7.35 (2H, t, J = 7.7Hz), 7.49 (1H, t,
J = 7.7Hz), 7.60 (2H, d, J = 7.7Hz),
8.16 (1H, d, J=7.7Hz), 948 (1H, s),
10.51 (1H, s) Example 41 (Z)-1-(2-diethylaminoethyl)isatin = 3-semicarbazone 1-(2-diethylaminoethyl)isatin
1.00g and semicarbazide hydrochloride 0.50g N,N-
The mixture was stirred in 30 ml of dimethylformamide at 120° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and an aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction with ethyl acetate, washing with water, and drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in benzene.
(Z)-1 recrystallized from hexane with a melting point of 170-173℃
-(2-diethylaminoethyl)isatin = 3-
0.74 g of semicarbazone was obtained.

Elemental analysis value: (as C ₁₅ H ₂₁ N ₅ O ₂ ) C% H% N% Calculated value 59.39 6.98 23.09 Actual value 59.44 7.07 22.81 IR (KBr): ν _NH 3450, 3180cm ^-1 ν _CO 1705, 1670cm ^-1 NMR ( _d6 -DMSO) δ: 0.85 (6H, t, J=7.1Hz), 2.47 (4H,
q, J = 7.1Hz), 2.63 (2H, t, J = 6.6
Hz), 3.80 (2H, t, J = 6.6Hz), 7.12
(1H, t, J = 7.7Hz), 7.14 (1H, d, J
=7.7Hz), 7.18 (2H, s), 7.39 (1H, t,
J = 7.7Hz), 7.64 (1H, d, J = 7.7Hz),
11.71 (1H, s) Example 42 The following compound was produced in substantially the same manner as in Example 41 using 1-(3-dimethylaminopropyl)isatin and semicarbazide hydrochloride.

(Z)-1-(3-dimethylaminopropyl)isatin = 3-semicarbazone Melting point: 137-139℃ (benzene) Yield: 69.3% Elemental analysis: (as C ₁₄ H ₁₉ N ₅ O ₂ ) C% H% N% Calculated value 58.12 6.62 24.20 Actual value 58.24 6.61 24.23 IR (KBr): ν _NH 3350cm ^-1 ν _CO 1665cm ^-1 NMR (d ₆ -DMSO) δ: 1.74 (2H, quint, J = 7.1Hz) ,2.11
(6H, s), 2.24 (2H, t, J=7.1Hz),
3.77 (2H, t, J = 7.1Hz), 7.1~7.25 (4H,
m), 7.40 (1H, t, J = 7.7Hz), 7.65
(1H, d, J = 7.7Hz), 11.68 (1H, s) Example 43 (Z)-1-(2-dibutylaminoethyl)isatin = 3-semicarbazone 1-(2-dibutylaminoethyl)isatin
1.14g and semicarbazide hydrochloride 0.49g N,N-
Melt in 20ml of dimethylformamide and heat at 100℃ for 4 hours.
Stirred for an hour. The reaction solution was concentrated under reduced pressure, and an aqueous sodium bicarbonate solution was added to the residue, followed by extraction with chloroform, washing with water, and drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel flash column chromatography (elution solvent: chloroform/ethanol = 50/1).
After purification, it was recrystallized from ethanol-hexane,
0.73 g of (Z)-1-(2-dibutylaminoethyl)isatin=3-semicarbazone having a melting point of 80-81°C was obtained.

Elemental analysis value: (as C ₁₉ H ₂₉ N ₅ O ₂・0.4H ₂ O) C% H% N% Calculated value 62.24 8.19 19.10 Actual value 62.27 8.03 19.03 IR (KBr): ν _NH 3450, 3200cm ^-1 ν _CO 1710, 1670cm ^-1 NMR (d ₆ -DMSO) δ: 0.76 (6H, t, J = 7.1Hz), 1.05-1.3
(8H, m), 2.36 (4H, t, J=7.1Hz),
2.64 (2H, t, J = 6.6Hz), 3.80 (2H, t,
J=6.6Hz), 7.05~7.2 (4H, m), 7.39
(1H, t, J = 7.7Hz), 7.64 (1H, d, J
=7.7Hz), 11.72 (1H, s) Example 44 (Z)-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin = 3-semicarbazone (E)-1 - [2-(2,2,6,6,-tetramethylpiperidino)ethyl]isatin = 1.06 g of 3-semicarbazone was suspended in 40 ml of dry N,N-dimethylformamide and stirred at 100°C for 2 hours. .
The reaction solution was concentrated under reduced pressure, water was added to the remaining crystals, the mixture was collected by filtration, and then recrystallized from benzene to obtain a crystal with a melting point of 225-227°C.
0.85 g of (Z)-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin=3-semicarbazone was obtained.

Elemental analysis value: (as C ₂₀ H ₂₉ N ₅ O ₂ ) C% H% N% Calculated value 64.67 7.87 18.85 Actual value 64.76 8.02 19.07 IR (KBr): ν _NH 3460, 3200cm ^-1 ν _CO 1710, 1670cm ^-1 NMR ( _d6 -DMSO) δ: 1.08 (12H, s), 1.35-1.6 (6H, m),
2.55-2.7 (2H, m), 3.55-3.7 (2H, m),
6.99 (1H, d, J = 7.7Hz), 7.13 (1H, t,
J=7.7Hz), 7.15 (2H, br-s), 7.43
(1H, t, J = 7.7Hz), 7.64 (1H, d, J
=7.7Hz), 11.73 (1H, s) Example 45 The following compound was produced in substantially the same manner as in Example 1 using 1-(2-butylaminoethyl)isatin and semicarbazide hydrochloride.

(E)-1-(2-Butylaminoethyl)isatin = 3-semicarbazone Melting point: 161-163℃ (chloroform-diethyl ether) Yield: 27.4% Elemental analysis: (C ₁₆ H ₂₁ N ₅ O ₂ (as 0.05CHCl ₃ ) C% H% N% Calculated value 58.44 6.86 22.64 Actual value 58.73 6.94 22.38 IR (KBr): ν _NH 3390, 3275, 3175 cm ^-1 ν _CO 1680 cm ^-1 NMR (d ₇ −DMF) δ: 0.85 (3H, t, J=7.1Hz), 1.2~1.45
(4H, m), 2.59 (2H, t, J=7.1Hz),
2.87 (2H, t, J = 6.6Hz), 3.89 (2H, t,
J=6.6Hz), 7.02 (2H, s), 7.13 (1H,
t, J = 7.1Hz), 7.22 (1H, d, J = 7.1
Hz), 7.45 (1H, t, J = 7.1Hz), 8.28
(1H, d, J=7.1Hz) Example 46 1-[2-(N-methylbutylamino)ethyl]
The following compound was produced in substantially the same manner as in Example 2 using isatin and semicarbazide hydrochloride.

(E)-1-[2-(N-methylbutylamino)ethyl]isatin = 3-semicarbazone) Melting point: 186-188℃ (ethanol) Yield: 80.5% Elemental analysis: (C ₁₆ H ₂₃ N ₅ (as O ₂ ) C% H% N% Calculated value 60.55 7.30 22.07 Actual value 60.46 7.38 21.93 IR (KBr): ν _NH 3400, 3300, 3180 cm ^-1 ν _CO 1680 cm ^-1 NMR (d ₆ -DMSO) δ: 0.75 ( 3H, t, J=7.1Hz), 1.05~1.35
(4H, m), 2.20 (3H, s), 2.29 (2H, t,
J = 7.1Hz), 2.53 (2H, t, J = 6.6Hz),
3.81 (2H, t, J = 6.6Hz), 6.87 (2H, br
-s), 7.08 (1H, t, J=7.7Hz), 7.12
(1H, d, J = 7.7Hz), 7.41 (1H, t, J
= 7.7Hz), 8.10 (1H, d, J = 7.7Hz),
10.24 (1H, s) Example 47 The following compound was produced in substantially the same manner as in Example 1 using 1-(2-cyclohexylaminoethyl)isatin and semicarbazide hydrochloride.

(E)-1-(2-cyclohexylaminoethyl)
Isatin = 3-semicarbazone Melting point: 174-176℃ (ethanol) Yield: 60.7% Elemental analysis: (as C ₁₇ H ₂₃ N ₅ O ₂ ) C% H% N% Calculated value 61.99 7.04 21.26 Actual value 61.96 7.03 20.93 IR (KBr): ν _NH 3380, 3300, 3175 cm ^-1 ν _CO 1680 cm ^-1 NMR (d ₆ −DMSO) δ: 0.85 to 1.3 (5H, m), 1.45 to 1.85 (5H,
m), 2.3-2.45 (1H, m), 2.76 (2H, t,
J = 6.6Hz), 3.76 (2H, t, J = 6.6Hz),
6.84 (2H, br-s), 7.07 (1H, t, J=
7.7Hz), 7.14 (1H, d, J = 7.7Hz), 7.40
(1H, t, J = 7.7Hz), 8.10 (1H, d, J
=7.7Hz) Example 48 (E)-1-[2-N-methylcyclohexylamino)ethyl]isatin = 3-semicarbazone 1-[2-(N-methylcyclohexylamino)
Ethyl] isatin 1.61g and semicarbazide hydrochloride
0.74 g was dissolved in 60 ml of ethanol-water (2:1) and stirred at room temperature for 1 hour. After concentrating the reaction solution under reduced pressure, 6.8 ml of 1N aqueous sodium hydroxide solution was added, and the crystals were collected by filtration and washed with water. The obtained crystals were recrystallized from ethanol, and the melting point was 181-183℃ (decomposition).
(E)-1-[2-(N-methylcyclohexylamino)ethyl]isatin = 3-semicarbazone 1.15
I got g.

Elemental analysis value: (as C ₁₈ H ₂₅ N ₅ O ₂ ) C% H% N% Calculated value 62.95 7.34 20.39 Actual value 62.80 7.34 20.39 IR (KBr): ν _NH 3400, 3320, 3180cm ^-1 ν _CO 1680cm ^-1 NMR ( _d6 -DMSO) δ: 0.9-1.25 (5H, m), 1.45-1.75 (5H,
m), 2.15-2.35 (4H, m), 2.60 (2H, t,
J = 6.6Hz), 3.76 (2H, t, J = 6.6Hz),
6.84 (2H, br-s), 7.07 (1H, t, J=
7.7Hz), 7.10 (1H, d, J = 7.7Hz), 7.41
(1H, t, J = 7.7Hz), 8.09 (1H, d, J
=7.7Hz), 10.21 (1H, s) Example 49 The following compound was produced in substantially the same manner as in Example 1 using 1-[2-(N-methylbenzylamino)ethyl]isatin and semicarbazide hydrochloride. .

(E)-1-[2-(N-methylbenzylamino)ethyl]isatin = 3-semicarbazone) Melting point: 175-178℃ (ethanol-water) Yield: 57.9% Elemental analysis: (C ₁₉ H ₂₁ As N ₅ O ₂ ) C% H% N% Calculated value 64.94 6.02 19.93 Actual value 64.91 6.01 19.63 IR (KBr): ν _NH 3380, 3300, 3175 cm ^-1 ν _CO 1680 cm ^-1 NMR (d ₆ -DMSO) δ: 2.23 (3H, s), 2.55 (2H, t, J = 6.0
Hz), 3.49 (2H, s), 3.86 (2H, t, J=
6.0Hz), 6.86 (2H, br-s), 6.99 (1H,
d, J=7.7Hz), 7.05-7.2 (6H, m), 7.34
(1H, t, J = 7.7Hz), 8.11 (1H, d, J
=7.7Hz), 10.25 (1H, s) Example 50 1-[2-(1,2,3,4-tetrahydro-2
-isoquinolyl)ethyl] The following compound was produced in substantially the same manner as in Example 1 using isatin and semicarbazide hydrochloride.

(E)-1-[2-(1,2,3,4-tetrahydro-2-isoquinolyl)ethyl]isatin = 3-
Semicarbazone Melting point: 176-179℃ (ethanol) Yield: 72.5% Elemental analysis: (as C ₂₀ H ₂₁ N ₅ O ₂ ) C% H% N% Calculated value 66.10 5.82 19.27 Actual value 66.01 5.77 19.08 IR (KBr ): ν _NH 3400, 3300, 3180 cm ^-1 ν _CO 1685 cm ^-1 NMR (d ₆ -DMSO) δ: 2.65-2.8 (6H, m), 3.63 (2H, s),
3.95 (2H, t, J = 6.6Hz), 6.85 (2H, br
-s), 6.95-7.15 (5H, m), 7.19 (1H,
d, J = 7.7Hz), 7.42 (1H, t, J = 7.7
Hz), 8.09 (1H, d, J = 7.7Hz), 10.22
(1H, s)

Claims (1)

[Claims] 1. General formula (R in the formula is a halogen atom, a lower alkyl group,
lower alkoxy group, amino group, acylamino group or alkoxycarbonyl group, n is 0 or 1,
R ¹ is a hydrogen atom, a lower alkyl group, an aryl group,
an aralkyl group or a cycloalkyl group, Y is a linear or branched alkylene group having 2 to 4 carbon atoms, R ² and R ³ may be the same or different,
A hydrogen atom, a linear alkyl group having 1 to 5 carbon atoms, a lower alkenyl group, an aralkyl group or a cycloalkyl group, or a pyrrolidinyl group, piperidino group, piperazinyl in which R ² and R ³ may have a substituent together with a nitrogen atom or tetrahydroisoquinolyl group) and acid addition salts thereof. 2 General formula (R in the formula is a halogen atom, a lower alkyl group,
lower alkoxy group, amino group, acylamino group or alkoxycarbonyl group, n is 0 or 1,
R ¹ is a hydrogen atom, a lower alkyl group, an aryl group,
an aralkyl group or a cycloalkyl group, Y is a linear or branched alkylene group having 2 to 4 carbon atoms, R ⁴ and R ⁵ may be the same or different,
The isatin derivative according to claim 1, which is a hydrogen atom, a linear alkyl group having 1 to 5 carbon atoms, a lower alkenyl group, an aralkyl group, or a cycloalkyl group, and acid addition salts thereof. 3 R ⁴ and R ⁵ may be the same or different,
Straight chain alkyl group having 1 to 5 carbon atoms or 3 carbon atoms
to 6 cycloalkyl groups, provided that when both R ⁴ and R ⁵ are linear alkyl groups, at least one of them has 3 or more carbon atoms, and isatin derivatives according to claim 2, and their Acid addition salts. 4 General formula (R in the formula is a halogen atom, a lower alkyl group,
lower alkoxy group, amino group, acylamino group or alkoxycarbonyl group, n is 0 or 1,
R ¹ is a hydrogen atom, a lower alkyl group, an aryl group,
Aralkyl group or cycloalkyl group, Y is a linear or branched alkylene group having 2 to 4 carbon atoms, [Formula] is a pyrrolidinyl group, piperidino group, piperazinyl group or tetrahydroisoquinoline group which may have a substituent. ) and acid addition salts thereof according to claim 1. 5 General formula (R in the formula is a halogen atom, a lower alkyl group,
lower alkoxy group, amino group, acylamino group or alkoxycarbonyl group, n is 0 or 1,
R ¹ is a hydrogen atom, a lower alkyl group, an aryl group,
The isatin derivatives and acid addition salts thereof according to claim 4, which are represented by an aralkyl group or a cycloalkyl group, Y is a linear or branched alkylene group having 2 to 4 carbon atoms. 6 formula The isatin derivative according to claim 3, which is represented by: and its acid addition salt. 7 formula The isatin derivative according to claim 3, which is represented by: and its acid addition salt. 8 formula The isatin derivative according to claim 3, which is represented by: and its acid addition salt. 9 formula The isatin derivative according to claim 3, which is represented by: and its acid addition salt. 10 formula The isatin derivative according to claim 3, which is represented by: and its acid addition salt. 11 formula The isatin derivative according to claim 3, which is represented by: and its acid addition salt. 12 formula The isatin derivative and acid addition salt thereof according to claim 5, which are represented by: 13 formula The isatin derivative and acid addition salt thereof according to claim 5, which are represented by: 14 formula The isatin derivative and acid addition salt thereof according to claim 5, which are represented by: 15 formula The isatin derivative and acid addition salt thereof according to claim 5, which are represented by: 16 formula The isatin derivative according to claim 5, which is represented by: and its acid addition salt. 17 formula The isatin derivative according to claim 5, which is represented by: and its acid addition salt. 18 formula The isatin derivative according to claim 5, which is represented by: and its acid addition salt. 19 formula The isatin derivative according to claim 5, which is represented by: and its acid addition salt.