JPS62294654A - Isatin derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R is halogen, alkyl, alkoxy, amino, acylamino or alkoxycarbonyl; n is 0 or 1; R<1> is H, alkyl, aryl, aralkyl or cycloalkyl; Y is 2-4C alkylene; R<2> and R<3> are H, 1-5C alkyl, alkenyl, aralkyl or cycloalkyl; R<2> and R<3> may together with N form pyrrolidinyl, piperidino, piperazinyl or tetrahydroisoquinolyl) and its acid addition salt. EXAMPLE:(E)-5-bromo-1-[2-(2,2,6,6-tetramethylpiperidino)ethyl]isatin-3 -semicarba zone. USE:A remedy for gastric and duodenal ulcer free from strong central suppressing activity. PREPARATION:The compound of formula I can be produced by reacting the compound of formula II with a semicarbazide derivative of formula III. The starting compound of formula II is obtained e.g. by the reaction of the compound of formula IV with an aminoalkyl derivative of formula V (X is acid residue).

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel isatin derivative useful as a pharmaceutical. More specifically, 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. It is something.

[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 H2-receptor antagonists, etc., and these drugs mainly treat gastric and duodenal ulcers by inactivating or suppressing the secretion of gastric digestive juices, including gastric acid. It is something to treat.

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 defense mechanisms in the stomach and duodenum are disrupted.

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 it 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 Levi: s-(Ch
em, Rev, ) J, Volume 44, Page 393; Column; See Volume 77, Column 15212211 of the same magazine
It is also known that 3-thiosemicarbazone derivatives of 1-aminoalkylisatin have antiviral, antibacterial, antifungal, and bactericidal effects.

For example, isatin=3-thiosemicarbazone derivatives represented by the general formula % (in which Alk is an alkylene group having 1 to 5 carbon atoms and Z is an amino group) have antiviral and antibacterial effects. It is known to exhibit central stimulating action, antihistamine action, analgesic action, etc., and is useful as a medicine such as a therapeutic agent for viral diseases (US Pat. No. 3,374,234).

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 isatin 3-thiosemicarbazone derivative described above is specific; for example, this compound exhibits anti-vaccine virus activity, whereas the 3-semicarbazone derivative, which has a very similar chemical structure, has a specific pharmacological action. [[Chemical Abstraf';/(Chem, Absts,) j Vol. 47, No. 5542f] is known to exhibit no activity at all. View].

[Problem that the invention seeks to solve]

The object of the present invention is to provide a drug that, when used as an ulcer treatment agent, can be used in conventional antacids, antipepsin agents, anticholinergic agents,
- To provide a novel compound that does not require concomitant use of tranquilizers and does not exhibit side effects due to strong central depressant action, such as receptor antagonists, in the treatment of stress-induced gastric and duodenal ulcers. It is.

[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 isatin derivative. , we have achieved the present invention.

That is, the present invention is based on the general formula (wherein R is a halogen atom, a lower alkyl group, a lower alkoxy group, an amino group, an acylamino group, or an alkoxycarbonyl group, n is 0 or 1, and R1 is a hydrogen atom, a lower alkyl group, an aryl group) group, aralkyl group or cycloalkyl group, Y is a straight chain or branched alkylene group having 2 to 4 carbon atoms, R2 and R3 may be the same or different, hydrogen atom, straight chain having 1 to 5 carbon atoms alkyl group, lower alkenyl group, aralkyl group or cycloalkyl group, or R2 and R3 together with the nitrogen atom form a pyrrolidinyl group, piperidino group, piperazinyl group or tetrahydroisoquinolyl group which may have a substituent. ) and acid addition salts thereof.

The isatin derivative of the present invention represented by the general formula N) 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 above general formula (r) is a novel compound that has not been described in any literature, for example, represented by the general formula (R5R2, R3, Y and n in the formula have the same meanings as above). isatin derivatives and the general formula % formula % [
) (R' in the formula has the same meaning as above) or an acid addition salt thereof.

In this case, some of the compounds of general formula (II) 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] Book, “Zientia Pharmacoitic Power” (Sci.

Pharm, ) J Vol. 38, page 98].

That is, isatin derivatives represented by the general formula (R and n in the formula have the same meanings as above) and general formulas (wherein X is an acid residue and R2, R3 and Y have the same meanings as above) or an aminoalkyl derivative represented by the formula (having the same meaning as above), or an aminoalkyl derivative represented by the general formula (RSX, Y and n have the same meanings as above).
It can be produced by reacting the isatin derivative represented by at least an equimolar amount of the amine derivative represented by the general formula (in which R2 and R3 have the same meanings as above) according to a conventional method. can.

When producing a compound represented by the general formula (I[) in which either 82 or R3 is a hydrogen atom by the first method, the compound of the general formula (V) is prepared in advance with a protective group such as an acyl group. It is better to protect and react with That is, a compound of the general formula (TV) and a compound of the general formula (in the formula, Acyl is an acyl group, R6 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) to form a compound represented by the general formula (Acyl SRSR8, Y and n have the same meanings as above). The protecting group is removed by a conventional method to obtain the desired compound.

General formula (I) used in these methods, (r'
Most of the compounds represented by /), (V), (v'), (Vl), and (■) are known compounds, and can be obtained as commercially available products or manually prepared according to known methods. can also be easily obtained by referring to methods for producing known compounds having similar structures.

In order to suitably produce the compound of the present invention, the general formula (II
) is dissolved or suspended in an inert organic solvent such as aqueous alcohol, and then an equimolar to slightly excess molar amount of the general formula (
The semicarbazide derivative of III) or its acid addition salt is added, and if necessary, sodium acetate, acetic acid or hydrochloric acid is added, and the mixture is reacted 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, recrystallized using a solvent to obtain the desired general formula (I
) is obtained.

The isatin derivative represented by the general formula (I) 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 a slightly excess molar amount of methanol, and then adding diethyl ether after concentration, filtering out the precipitated crystals, and recrystallizing them from a suitable solvent. In addition to the above hydrochlorides, acid addition salts include hydrobromide, hydroiodide, sulfate, acetate, oxalate, 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.

Isatin induction and 3 represented by general formula (I) of the present invention
- Regarding the isomers of thiosemicarbazone derivatives, most of the 3-thiosemicarbazone derivatives of isatin and 1-methylisatin exist in two forms, whereas the corresponding 3-
Semicarbazone derivatives mainly exist in the E form, and this E
2 by heat-treating the body or acid-treating the body.
[Chemical Abstracts (Chem,^bsts,) J Vol. 79, No. 41.782, Column f, same volume, No. 91459b and the same magazine, Vol. 81, No. 37145z] , the compounds of the present invention similarly exist mainly in the E form, and can be converted into 2 by treatment such as heating.
Convert to body.

The isatin derivative represented by the general formula (I) of the present invention exhibits an antiulcer effect in either the E-form or the 2-form structure, and can be used as a pharmaceutical.

In actual treatment, the isatin derivative represented by the general formula (I) of the present invention can be used alone or in a pharmaceutical composition mixed with appropriate pharmaceutical additives in various dosage forms, such as powders, fine granules, tablets, etc. It is used as capsules, syrups, liquids, injections, etc.

When the pharmaceutical composition containing the isatin derivative represented by the general formula (I) and its acid addition salt is used for treatment, the dosage is adjusted as appropriate depending on the patient's age, sex, weight, severity of symptoms, etc. However, in the case of oral administration, it is generally 10 mg to 5000 mg per day for adults.

For parenteral administration, lll1g to 100 per day for adults.
Administered within the range of 0 mg.

〔Effect of the invention〕

The isatin derivatives represented by the general formula (1) of the present invention and their acid addition salts can be used in experimental studies using animals, such as stress 73! Shows remarkable inhibitory effect on tumors. For example, in a water immersion restraint stress ulcer experiment using Wistar male rats (8 weeks old), oral administration of 1 oomg/kg body weight shows approximately 30-95% suppressive effect.

The isatin derivatives represented by the general formula (I) of the present invention and their acid addition salts are effective against the increase in gastric acid secretion caused by the administration of histamine or pentagastrin.
The isatin derivatives represented by and their acid addition salts do not exhibit the side effects such as sleep prolongation that are seen in common central nervous system depressants.

As described above, the isatin derivatives represented by the bifurcated formula (I) of the present invention and their acid addition salts have centrally acting anti-ulcer effects, particularly suppressive effects on stress ulcers, and are similar to tranquilizers. Since it does not exhibit hypnotic and motor-suppressing effects, it is useful as a therapeutic agent for gastric and duodenal ulcers in 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 2.26 g of 5-bromoisatin and 2.40 g of 1-(2-chloroethyl)-2,2.2.6.6-titramethylbiveridine hydrochloride/60rn1 of dried N,N-dimethylformamide ．． After soaking and stirring under water cooling, 0.80 g of 60% sodium hydride (oil-based) was added, and the mixture was reacted at room temperature for 30 minutes and further 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 from beef sanitation to give 5-bromo-
2.76 g of 1-(2-(2,2,6,6-titramethylbiperidino)ethylcoisatin was obtained.

Elemental analysis value' (as C+5HzsBrN202)
0% 8% N% Calculated value 5f1.02 6.41 7.12
Actual value 58.20 6.53 6.80I
R (Br): νco 1730 cm-
'NMR (CDCl2) δ: 1.10 (12) 1. s), 1.35-1.
6 (6H, m).

2.6-2.7 (2H, m), 3.55-3.7 (2
H, m>.

6.80 (IH, d, J=8.8Hz), 7.65
~7.75 (2H.

m) Reference Example 2 5-Methoxyisatin and 2-dibutylaminoethyl chloride hydrochloride were reacted in substantially the same manner as in Reference Example 1, and then subjected to silica gel flash column chromatography (
Elution solvent: chloroform) to produce the following compound.

1-(2-dibutylaminoethyl)-5-methoxyisaf> Melting point: 32-34℃ Yield: 79.3% Elemental analysis value' (as C+5H2aN2L) 0%
8% N% Calculated value 68.65 8.49 8.43 Actual value 68.89 8.79 8.411R
(KBr): L'CO1715Cm-'NMR (
CDC13) δ: 0.86 (6H, t, J=7.1)1z),
1.15-1.45 (8 days.

m), 2.45 (4H, t, J=7.1Hz),
2.68 (2H.

t, J=6.6Hz), 3.75(2)1. t,
J=6.6Hz).

3.80(3)1. s), 6.8-6.9(1)1
．． m), 7.1 to 7.2 (2H, m) Reference Example 3 Using 5-fluoroisatin and 2-dibutylaminoethyl chloride hydrochloride, react in almost the same manner as in Reference Example 1, and then perform silica gel column chromatography. Graphy (elution solvent:
chloroform) to produce the following compound.

1-(2-dibutylaminoethyl)-5-fluoroisatin Melting point: 52-54°C Yield: 61.0% Elemental analysis value' (as C+aHzsFNz02)
6% 8% N% Calculated value 67.48 7.86 8.74 Actual value 67.65 8.02 8.69IR
(KBr): L”CO1730Cm-'NMR(
CDCI3) δ: 0.85 (6H, t, J=7.1Hz), 1
．． 1-1.4 (8H.

m), 2.44 (41(,t, J=7.1)12)
, 2.69 (2H.

t, J=6.6Hz), 3.78(2H,t, J
= 6.6Hz).

6, 85~? , 0 (1)1. m), 7.25
~7.4 (2)1. m) Reference Example 4 Using 5-chloroisatin and 2-dibutylaminoethyl chloride hydrochloride, the reaction was carried out in substantially the same manner as in Reference Example 1, and then purified by silica gel column chromatography (elution solvent: chloroform) to obtain the following compound. Manufactured.

5-Chloro-1-(2-dibutylaminoethyl)isachi Melting point: 35-36°C Yield: 51.5% Elemental analysis value' (as C+5LsCINzO2)6
% 8% N% Calculated value 64.18 ? , 48 8.32
Actual value 64.31? , 69 8.55
IR (KBr): I) co 1725
Cm-'NMR (CDCI,) δ: 0°86 (6H, t, J=7.1H2), 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 (LH, 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) to obtain the following A compound was prepared.

5-bromo-1-(2-dibutylaminoethyl)isachi Melting point: 38-40°C Yield: 46.9% Elemental analysis: (as c18H25BrN307)
6% 8% N% Calculated value 56.70 6.61 7.35 Actual value 56.38 6.85 7.59IR
(KBr): ν. o 1730 cm-'
N! , IR(CDCI,) δ: 0.86 (6H,t, J=7.IHz), 1
．． 1~1.4 (811゜m), 2.44 (4H, t
, J=7.1Hz), 2.68 (2H.

t, J=6.6flz), 3.77(2H,t,
J=6.6Hz).

6.86(11(,d, J=8.8Hz), ?,6
5-7.75 (28°) 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 value' (as C2oLsN30s) 6%
8% N% Calculated value 66.83 8.13 11.69 Actual value 66.56 8.00 11.511R
(KBr): ν111+ 3340 cm
-'νco 1740. 1710. 1670
cm-'NMR (d6-DMSO) δ: 0.78 (6H, t, J=7.1flz),
1.05-1.35 (8) 1゜m), 2.04
(3H, s), 2.37 (4H, t, J=
7.1Hz), 2.60 (2fl, t, J=6.
6Hz), 3.70(2)1. t, J=6.6H
z), 7.13 (LH, d, J=8.2tlZ),
7.72 (Ill, dd, J=2.2 and8
．． 2Hz), 7.84(1)l, d, J=2.2
Hz>, 10.04 (IH,S) Reference Example 7 Using methyl tisatincarboxylate and 2-dibutylaminoethyl chloride hydrochloride, the reaction was performed in substantially the same manner as in Reference Example 1, and then silica gel column chromatography (elution solvent :chloroform) to produce the following compound.

Properties: Oil Yield: 91.7% Elemental analysis: (C2°H28N204・0.07CHC
1°) 0% 8% N% Calculated value 65.36 7.67 7.60 Actual value 65.1111 7.87 7.70
IR (neat): VCO 1720 cm
-'NMR (CDC13) δ: 0.79 (68, t, J=7.1Hz), 1
．． 0-1.2 (8H.

m), 2.30 (4H, t, J=7.1)1z),
2.46 (2tl.

t, J=6.6Hz), 3.97(3H,s),
4.10 (2Lt, J=6.6t(z), 7.
14(LH, t+'J=7.7Hz>.

7.74 (IH, dd, J=1.7 and 7
．． 7) 1z), 7.88 (LH, dd, J=1
．． 7 and 7.7Hz) Reference Example 8 Using isatin and 2-dibenzylaminoethyl chloride hydrochloride, the reaction was carried out in substantially the same manner as in Reference Example 1, and then subjected to silica gel flash column chromatography (elution solvent:
benzene) to produce the following compound.

■-(2-Dibenzylaminoethyl)isatin Properties: Oily Yield: 85.9% Elemental analysis: (as C24H22N20□) 0%
8% N% Calculated value 77.81 5.99 7.56 Actual value? 7.63 5.81 7.511R
(neat): ”Co 1725 cm-'N
MR(CDC1,) δ: 2.71(2)! , t, J=6,0Hz),
3.62 (4H, s).

3.74 (2H, t, J=6.0Hz), 6.36
(IH, Tun J=7.7Hz), 7.01(1)1.
t, J=7.7Hz), 7.1~7.4(
IIH, m), 7.52 (II(, dd, J=
1.1 and7.7Hz) Reference example 9 5-methoxyisatin and 1-(2-chloroethyl)-2
゜2, using 6.67 tetramethylpiveridine hydrochloride,
The following compound was produced in substantially the same manner as in Reference Example 1.

(Benzene-hexane) Yield: 72.7% Elemental analysis value: (as C2°H2aN20z) 0%
8% N% Calculated value 69.74 8.19 8.13 Actual value 69.78 8,38 8.011R
(KBr): νGo 1720 Cm-'
NMR (CDC13) δ: 1. IH12H,S), 1.4-1.6(
6H, m).

2.65-2.75 (2H, m), 3.55-3.
65(2)1゜m), 3.80(3H,s),
6.75-6.85 (IH, m).

7.1-7.2 (2H, m) Reference example 10 5-fluoroisatin and 1-(2-chloroethyl)-2
The following compound was produced in substantially the same manner as Reference 2/Example 1 using ゜-2,6,6-titramethylpiperidine hydrochloride.

Melting point = 143-144℃ (benzene) Yield:
65.6% Elemental analysis value' (as CI!1H25FN202) 0% 8% N% Calculated value 68.65 7.58 8.43 Actual value 68.64 7.73 8.62IR
(KBr): L' co 172b cm
-'NMR (CDC1,) δ: 1.1H12)1. s), 1.4-1
．． 65(6)1. m).

2, 6-2.75 (2H, m), 3.55-3
．． 7 (2H, m).

6.85 (LH, dd, J=3.8 ancl
8.8Hz).

7.25-7.4 (2H, m) Reference example 11 5-chloroethinto 1-(2-chloroethyl)-2,2
゜Using 6.6-titramethylpiperidine hydrochloride, reference melting point: 162-163℃ (benzene-hexane) Yield: 67.5% Elemental analysis value' (as C+5H2sCIN20z)
0% 8% N% Calculated value 65.41? , 22 8.03
Actual value 65.32 7.30 7.811
R(KBr)' vco 1730 c+yr
'NMR (CDCI,) 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(1)1. d, , J=8.8t(z)
, 7.5-7.6 (2tl.

m) Reference example 12 5-acetamidoisatin and 1-(2-chloroethyl)
Using -2,2,6,6-titramethylpiperidine hydrochloride, melting point = 295-297℃ (decomposition) (ethanol-ethyl acetate) Yield: 55.2% Elemental analysis value' (as Cz + LsN30*) 0 %
8% N% Calculated value 67.90 7.87 11.31 Actual value 68.01 8.01 11.12IR
(KBr) + I/Mll 3360 cm-
'νCo 1725. 1685 Cm-'NMR
(d, -DMSO) δ: 1.07 (12H, s), 1.3 to 1.5
5 (6ft, m).

2.04 (3H, s), 2.55-2.7 (2) 1
．． m).

3, 45-3.6 (2H, m), 6.94 (
IH, d, J=8.2fiz), 7.71(L
H, dd, J=2.2 and 8.2Hz).

7.85 (ill, d, J=2.2Hz),
10.05 (LH, s), the reaction was carried out in substantially the same manner as in Reference Example 1, and after treatment 1, the product was purified by silica gel column chromatography (elution solvent: chloroform) to produce the following compound.

Melting point = 39-40℃ Yield: 90.2% Elemental analysis value: (as C21H28N204) 0%
8% N% Calculated value 67.72 7.58 7.52 Actual value 67.41 7.82 7.42IR
(KBr): I/co 1740cm
-'NMR (CDCI, ) δ: 1.02 (12H, s>, 1.35-1.6 (
6H, m).

2.45-2.6 (2) 1. m), 3.94(3)
1. s).

3.95-4.05 (2H, m), 7.14 (1N,
t, J=7.7Hz), 7.73(LH, dd,
J=1.7 and 7.7Hz).

7.87 (IH, dcl, J=1.7 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 purified by silica gel column chromatography (elution solvent 1X: chloroform/methanol = 10/1). , produced the following compounds.

1-(3-diethylaminopropyl)isatin Properties: Oil Yield: 82.1% Elemental analysis: (C,5)12ON202-0.03
As CHCIff) 6% 8% N% Calculated value 68.40? , 65 10.61
Actual value 68.35 7.83 10.711
R (neat): I/co 1720 cm-
'NMR (CDC13) δ: 1.00 (6H, t, J=7.1H2), 1
．． 85 (2H, quint.

J=7.1flz), 2.51(2N, t, J=
Near, 1) 1z), 2.53 (4) 1. q, J=
7.1)1z), 3.78(2H,t, J=7.1
)1z), 6.99(IH,d, J=7.1JIz
), 7.11 (LH.

t, J=7.1Hz＞, 7.58(IH, t, J
=7.1Hz).

7.59 (LH, d, J = 7.1 Hz) Reference Example 15 Using isatin and 3-dibutylaminopropyl chloride hydrochloride, the reaction was performed in substantially the same manner as in Reference Example I, and then silica gel flash column chromatography (elution solvent:
The following compound was produced by purification using chloroform/ethanol = 100/1).

1-(3-dibutylaminoprobyl) isatin oil Yield: 83.7% Elemental analysis value (as CI9828N20□) 6%
8% N% Calculated value 72.12 8.92 8.85 Actual value 72.09 9.11 8.771R
(neatton: νCO1730cm-'NM
R (CDC1, > δ: 0.90 (6H, t, J=7.1Hz), 1
．． 2-1.5 (8H.

m), 1.83 (2H, quint, J=7.1H
z), 2.39(4)1. t, J=7,1tlz
), 2.49(2)1. t, J=7.1Hz＞,
3.77 (2H,t, J=7,1)1z), 6.
96 (LH.

d, J=7.7Hz), 7.10(IH, t, J
=7.7Hz>.

7.58 (LH, t, J=7.7)lz), 7.6
0 (lft, d, J=7,7Hz) Reference example 16 1- (2-(2,2,6,6-titramethylpiperidino)ethyl coisatin 24.4 g of isatin and 1-(2-chloroethyl )-2,
2,6゜6-titramethylpiperidine hydrochloride 40.0g
was suspended in a mixture of 250 d of dry N,N-dimethylformamide and 250 d of dry toluene, and while stirring under water cooling, 60% sodium hydride (3.3 g of oily N) was added, and the solution was stirred at room temperature for 30 minutes, and further at 70°C. The reaction was allowed to proceed for 16 hours.The solvent was distilled off under reduced pressure, and the residue was dissolved in hydrogen carbonate.
45.6 g of 1-(2-(2,2,6,6-titramethylpiperidino)ethylcoisatin) at 71-173°C was obtained.

Elemental analysis value' (as C1sLaLL) 6%
8% N% Calculated value 72.58 -8.33 8.91 Actual value 72.44 8.37 g, 96r
R(KBr): L'CO1720cm-'NMR
(COCIs) δ: 1.11 (12)1. s>, 1.4~
1゜65(6)1. m＞.

2.65~2.75 (2H, m), 3°6~3.7
(2H, m).

6.89 (LH, d, J=7.78'z), 7
．． 09 (IH, t, J=7.7Hz>, 7.55~
7.65 (2)l, [+1) Reference Example 1 A compound of physatin and 2-diallylaminoethyl chloride salt was produced.

1-(2-diallylaminoethyl)isatin Properties
2 Oil yield 2 61.1% Elemental analysis value (as CIBH1llN20□)6
% 8% N% Calculated value? 1.09 6.71 40.36 Actual value 70.75 6.93 10.19JR
(neat): νca 1730 cm-'N
MR (CDCI: +) δ: 2.74 (2) 1. t, J=6.6H
z), 3.15(4)1. d, J=6,6
Hz), 3.81 (2H, t, J=6.6Hz
), 5.11 (2H, dd, J=1.7 a
nd 9.9Hz), 5.16 (2H.

dd, J=1.7 and 17.0Hz),
5.75 (2H, ddt.

J=9.9. 17.0. and 6.6Hz>
, 6.91 (IH, d.

J=7.7Hz>, 7.13(IH,t, J=
7.7Hz), 7.57(lft, t, J
=7.7Hz), 7.60(IH,d, J=7
．． Reference Example 18 Using isatin and 2-dibutylaminoethyl chloride hydrochloride, the reaction was carried out in substantially the same manner as in Reference Example 16, and silica gel flash column chromatography (elution solvent:
After purification with chloroform/methanol=100/1), the following compound was produced by recrystallizing from hexane.

1-(2-dibutylaminoethyl)isatin melting point
: 40-42℃ Yield: 79.3% Elemental analysis value: (as CIB826N20□) 0%
8% N% Calculated value 71.49 8.67 9.26 Actual value 71.48 B, 79 9.16I
R(KBr): I'CO1720cm-'NMR
(CDC13) δ: 0.86 (6H, t, J=7.1Hz), 1
．． 15-1.45 (8H.

m), 2.45 (4H, t, J=7. IHz),
2.69 (2H.

t, J=6.6Hz), 3.78(2H,t, J
= 6.6Hz).

6.93 (IH, d, J=7.7Hz), 7.10
(IH, t, J・7.7Hz), 7.58 (IH,
t, J=7.7Hz), 7.60(IH, d, J
= 7.7 Hz> Reference Example 19 Using 5-methylisatin and 2-dibutylaminoethyl chloride hydrochloride, the reaction was performed in substantially the same manner as in Reference Example 16, and then subjected to silica gel flash column chromatography (
Elution solvent: chloroform) to produce the following compound.

■-(2-dibutylaminoethyl)-5-methylisatin Melting point 2 33-35℃ Yield: 62.2% Elemental analysis value' (as CI9828N202) 0%
8% N% Calculated value 72.12 8.92 8.85 Actual value 72.00 9.13 8.79m)
, 2.33 (3ft, s), 2.45 (4H, t
, J=7.1Hz), 2.68(2H,t, J=
6.6 flz), 3.76 (2N.

t, J=6.6tlz), 6.82(ltl, d
, J=7.7Hz).

7.38 (IH, d, J=7.7Hz), 7.39
(1N, s) Reference example 20 Isatin and 2-zinchlorohexylamine ethylc 01J
Hydrochloride, the reaction was carried out in the same manner as in Reference Example 16, and silica gel flash column chromatography (
After purification using chloroform (elution solvent), the product was recrystallized from chloroform-hexane to produce the following compound.

1-(2-Dicyclohexylaminoethyl) isachii Melting point: 98-100°C Yield: 55.1% Elemental analysis value (as C22H3ON202) 0%
8% N% Calculated value 74.54 8.53 7.90 Actual value 74.46 8.76 7.89IR
(KBr): I'CQ 1725 cm-'
NMR (CDCI,) δ: 0.95-1.85 (20H, m), 2.
45-2.6 (2H, m).

2.80(2)1. t, J=6.6Hz), 3.
67(2H,t, J=6,6)1z), 6.90(
1M, d, J=7.7tlz), 7.08(LH
, t, J=7.7Hz), 7.5~7.7 (2
H, m> Reference example 21 5-methylisatinto 1-(2-chloroethyl)-2,
The following compound was produced in substantially the same manner as in Reference Example 16 using 2°6.6-titramethylbiperidine hydrochloride.

Melting point: 157-159℃ (hexane) Yield:
81.5% Elemental analysis value = (as C3゜828N202) 0%
8% N% Calculated value 73.1.4 g, 59 8.5
3 Actual measurement value 72.87 8.67 8.49
IR (KBr): νco 1725 cm
-'NMR (C'DCIs) δ: 1.11 (121 (; s), 1.4-1.6
(6tl, m), 2J3 (3H, s), 2.65
~2.75 (2) 1. m), 3.55-3,7 (
2H, m), 6.79 (IH, d, J=8.2
)1z).

7, 38(1)l, d, J=8.2)1z), 7
．． 40(IH,s) Reference example 22 1-C2-(1-pyrrolidinyl)ethylcoisatin 2-
3.5 g of (1-pyrrolidinyl)ethyl chloride hydrochloride and 3.0 g of isatin were dissolved in 50 ml of dry ethylene glycol dimethyl ether, and while stirring under ice cooling, 2.0 g of 60% sodium hydride (oil-based) was added. Thereafter, the reaction was continued at room temperature for 30 minutes and then at 70°C for 16 hours.

After concentrating the reaction solution under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue and acetic acid solution (elution solvent: chloroform/
After purification with methanol = 100/1), it was recrystallized from ethyl acetate-hexane to give 1-(2-(
0.8 g of 1-pyrrolidinyl)ethyl coisatin was obtained.

Elemental analysis value' (as CI4H16820□) 0%
8% N% Calculated value 68.83 6゜60 11.47 Actual value 68.78 6.74 11.40IR
(Br): I'CO1720(m-1HMR(
CDC13) δ: 1.7-1.85 (4) 1. m), 2.55
~2.7 (48, m).

2.78 (2H, t, J=7.1Hz), 3.
89 (2H, t, J=7.1Hz), 6.97
(ltl, d, J=7.7Hz), 7.1
1 (LH, t, J=7.7Hz), 7.58 (
IH, dt, J=1.1 and 7.7Hz),
7゜61 [IH, dd, J=1.1 and
7.7Hz) 5-acetamido-1-[2-(2,2,6,6-titramethylpiperidino)ethylcoisatin 1.1Og
It was dissolved in 60af2 of normal 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 distilling off the solvent under reduced pressure, the residue was dissolved in ethanol,
After treatment with activated carbon, recrystallization from chloroform-hexane yielded 5-amino-1-[2-
0.87 g of (2,2,6,6-titramethylbiperidino)ethylcoisatin was obtained.

Elemental analysis value' (as C+5Hz7Nj02) 0%
8% N% Calculated value 69.27 g, 26 12.76
Actual value 69.33 8.26 12.511
R (Br): ! 'KM 3445.3410
．． 3345 (m-1νco 1705 cm-
' NMR (d@-0M5O) δ: 1.06 (12) 1. s), IJ ~1.6
(6H, m).

2, 55-2.65 (2H, m), 3.4-3.
55 (2H, m).

5, 14 (2tl, s), 6. To(1)1.
d, J=8.2flz).

6.78 (IL d, J=2.2Hz), 6.89
(lft, dd.

J=2.2 and 8.2Hz) Reference example 24 5-acetamido-1-(2-dibutylaminoethyl)
The following compound was produced in substantially the same manner as in Reference Example 23 using isatin.

5-Amino-1-(2-dibutylaminoethyl)isachi Melting point: 134-135°C (ethyl acetate-hexane) Yield: 85.3% Elemental analysis value: (C, 8) 12. N, 0. Close) 0
% 8% N% Calculated value 68.11 8.57 13.24 Actual value 68.09 8.66 13.13IR
(KBr): I/111 3450.3350
cm-'νco 1715 cm-' NMR (d, -DMSO) δ: 0.79 (6) 1. t, J=7.1Hz＞,
1.05-1. j(IE.

m>, 2J6 (4H, t, J=7.1Hz), 2
．． 58 (2H.

t, J=6.6Hz),' 3.63(2H,t,
J=6.6)1z).

5.13 (2H, s), 6.76 (1) 1. s),
6.87(2H,s) Reference example 25 1-(2-dipropylaminoethyl)isatin 1-(2
-bromoethyl)isatin, 1.37 mj2 of dipropylamine, 1.38 g of anhydrous potassium carbonate and 1.50 g of sodium iodide in 100 m of dry benzene.
j2 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-dipropylamine ethyl) isatin as a solid with a melting point of 30°C or less, calculated value 69.14.
8.12 10.08 Actual value 69.26 8
．． 23 9.911R (KBr): V c
o 1730 Cm NMR (CDCIs) δ: 0.83 (6 days, t, J=7.IHz),
1.40 (4H, 5ext.

J=7.1Hz), 2.43(4JI, t, J=
7.1Hz), 2.70(2H,t, J=6.6H
2), 3.79 (2H, t, J=6.6)1z),
6.94(1)1. d, J=7.7Hz>, 7
．． 09 (LH.

t, J=7.7Hz), 7.58 (LH,t,
J=7.7Hz).

7.59 (LH, d, J = 7.7Hz) Reference example 26 1-C2-(4-methyl-1-piperazinyl)ethylcoisatin -(2-bromoethyl)isatin 2.54 g, N-methylpiperazine 1.5 mA , ) ethylamine 1.
7d and 1.66 g of potassium iodide were dissolved in 30In1 of dry N,N-dimethylformamide and heated at 70°C.
Stir again for an hour. After concentrating the reaction solution under reduced pressure, a 17-figure thorium hydrogen carbonate aqueous 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) and recrystallized from methanol-hexane to give 1- (2-(4-
Methyl-1-piperazinyl)ethylcoisatin 1.57
I got g.

Elemental analysis value' (CISH19N302・0.311
．． (as 0) 0% 8% N% Kotojukan no Nao 64.64 7.09
15.0? Actual value 64.63 7
,04 14.811R (Br): +'c
o 1740.1720 cm-'NOR(CDC
13) δ: 2.29(3)1. s), 2.35~
2.65(8)1. m).

2.65 (2H, t, J=6.6Hz), 3.85
(2H, t, J=6.6)1z), 6.93(LH, d
, J=7.7)1z), 7.11-(2-bromoethyl)isatin and N-benzylpiperazine were used to produce the following compound in substantially the same manner as in Reference Example 26.

1-(2-(4-benzyl-1-piperazinyl)ethyl goisatin Melting point = 119-121℃ (ethyl acetate-diethyl ether) Yield: 68.6% Elemental analysis value' (C2+) as 12aN*02) C
% 896 N% Calculated value 72.1g 8.63 12.03
Actual value 7L92 6.84 11.87IR
(KBr): νco 1735 cm-INM
R (CDC13) δ: 2.35 to 2.65 (8H, m), 2.6
5 (2H, t, J=6.6Hz), 3.50 (2H
, br-s), 3.85 (2H, t, J=6.6Hz)
, 6.93 (IH, d, J=7.7Hz),
7.11 (LH, t, J=7.1Hz), 7
．． 2-7.4 (5H, m).

7, 5-7.65 (2)1. m) Reference example 28 4.59 g of isatin and 1-(2-chloropropyl)-2
,2゜6.6-titramethylpiperidine hydrochloride 7.93
Dissolve g in 80 mA of dry N,N-dimethylformamide and add 60% sodium hydride (
After adding 2.52g of oil-based), leave for another 30 minutes at room temperature.
The reaction was carried out at 00°C for 16 hours. The solvent was distilled off under reduced pressure,
Water was added to the residue, extracted with chloroform, washed with water, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: chloroform), hexane was added, and the crystals were collected by filtration. The obtained crystals were recrystallized from ethyl acetate to give 1-(2-(2,2
,6,6-tetramethylpiperidino)propylcoisatin 4.06g was obtained.

Elemental analysis value' (as CzoLeN20z) 0%
8% N% Calculated value 73.14 8.59 8.53 Actual value 73.28 8.54 8.63IR
(KBr): I/'Co 1720 Cm-
'HR (CDC1,) δ: 1.0~1.8 (21B, m), 3.55~
3.8 (2H, m).

3.9-4.05 (1) 1. m), 6.92(lt
l, d, J=7.7Hz>, 7. H(LH,t,
J=7.7Hz), 7.5-7.65 (2H, m) On the other hand, the hexane filtrate was concentrated, the residue was recrystallized from hexane, and 1-[1- Methyl-2
-(2,2,6,6-tetramethylpiperidino)ethylcoisatin 2.00 g was obtained.

Elemental analysis value: (as C2゜HzNJl) 0%
8% N% Calculated value 73.14. 8.59 8.53
Actual value 73.23 8.81 8.45I
R (KBr): νco 1720 cm-
'NMR (CDCl2) δ: 0.8-1.6 (21H, m>, 2.811H
, dd, J=4.9 and 15°7Hz),
3.06 (IH, dd, J=7.0and
15.7Hz), 4.15~4.35 (LH, m
).

7.00 (IH, d, J=7.7Hz), 7.06
(LH, t, J=7, 7Hz), 7.5~? ,'
65 (2) I, m) Reference example 29 1-(2-chloroethyl)-2,2,6,6-titramethylbiperidine hydrochloride 10.00 g and sodium cyanide 6.40 g Wot+Ia dimethyl sulfonate The mixture was soaked in 100 volumes of water 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 9.13 g of oily 3-(2,2,6,6-tetramethylpiperidino)propionitrile.

IR (neat): I/cN 2250 cm
-'NMR (CDC1a) δ: 1.04 (12) 1. s), 1.35~
1.6(6)l, m), 2.3~2.45(2
H, m), 2.75 to 2.9 (2H, m). The solvent was distilled off under reduced pressure, and an aqueous sodium bicarbonate solution was added to the residue, extracted with chloroform, washed with water, and then dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure to obtain an oily 3-(2,2,6,6
,-tetramethylpiperidino)ethyl propionate9.
06g was obtained.

IR (neat): v co 1720 C
m"'NMR(CDCl2> δ: 1.03 (12H, s), 1.26 (3H,
t, J=7. Ll(z).

1.35-1.6 (6H, m), 2.35-2.5 (
2H, m).

2.7-2.85 (21 (, m), 4.11 (21
(, q, J = 7.1 Hz) 9.00 g of ethyl 3-(2,2□6.6-titramethylpiberidino)propionate was mixed with 200 d of diethyl ether.
The solution was added dropwise to a suspension of 3.80 g of lithium aluminum hydride in 300-diethyl ether while stirring under water cooling, and then heated under reflux for 16 hours. Add water dropwise (2, 2, 6,
6-Titramethylbiperidino)-1-propatool6.
68g was obtained.

IR(neat)+va! (3300cn+-'N
MR (CDCI3) δ: 1.11 (12) 1. s>, 1.4~1
．． 65 (6H, m).

1.72 (2H, quint, , h6.9H2),
2.75 (2H.

t, J=6.9Hz>, 3.80(2)1.
t, J=6.9)1z).

4,70 (l)l, br-s) 3- (2,2,6,6-titramethylpiperidino)-
1- Propatool 6.60g chloroform 20m/!
30d of thionyl chloride while stirring under ice-cooling.
After dropping into the solution, the solution was heated under reflux for 2 hours. The solvent was distilled off under reduced pressure, and diethyl ether was added to the remaining crystals, which was then recrystallized from ethanol-diethyl ether to give a melting point of 1.
1-(3-chloropropyl)-2,2 at 80-189°C
, 7.40 g of 6,6-titramethylbiperidine hydrochloride was obtained.

Elemental analysis value' (CI282SCIN・0.LH2
0% 8% N% Calculated value 56.29 9.92 5.47 Actual value 56.07 10.22 5.33HM
R(d,-DMSO) δ: IJI(6H,s), 1.47(6)1. s
), 1.5-2.4 (8H, m), 3.15-3J
(2H, m), 3.77 (2H.

t, J=6.3)1z), 9.22(1)1. s
) isatin and 1-(3-chloropropyl)-2,2,6
, 6-titramethylbiperidine hydrochloride, Reference Example I
I-(3-(2,2,6,6-titramethylbiperidino)propylquisatin) was produced in substantially the same manner as above.

Melting point: 105-107℃ (hexane) Yield:
72.8% Elemental analysis value: (as C2°LsLL) 0% 8%
N% Calculated value 73.14 8.59 8.53 Actual value 72.98 8.81 8.42rR
(KBr): vco 1720 cm-'N
MR (CDCI,) δ: 0.98 (12H, s), IJ ~ 1.6 (6B
, m), 1.75-1.9 (2H, m), 2.4
5-2.55 (2H, m).

3.67 (2tl, t, J=7.2Hz), 6.
89 (LH, d, J=7.7Hz), 7. '1l(
IH,t,'J=7.7flz), 7.55~7,
65 (28, m) Reference example 30 Isatin and 2-(N-methylbutylamino)ethylc C
The reaction was carried out in substantially the same manner as in Reference Example 1 using IJ dehydrochloride, and the mixture was purified by gel flash column chromatography (elution solvent: chloroform) to produce the following compound.

1- [2-(N-methylbutylamino)ethylquisatin Properties: 2 Oily Yield: 83.5% Elemental analysis value (as CISH2ON202) 0%
8% N% Calculated value 69.21? , 74 10.76
Actual value 69.10? , 94 10.67
IR (neat): vca 1720 cm-
'NMR (CDCI3) δ: 0.84 (3H, t, J・7.1Hz), 1
．． 15-1.45 (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(If(,d,
J=7.7)(z).

7.10 (LH, t, J=7.7Hz), 7.58
(LH, t, J=7, 711z), 7.60 (IH
, d, J=7.7Hz>Reference example 31 1-(2-cyclohexylaminoethyl)isatin 1-
2.00 g of (2-bromoethyl)isatin and 3.90 g of cyclohexylamine were dissolved in 20 mA of dry N,N-dimethylformamide and stirred at 80°C for 1 hour.

The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 10% hydrochloric acid, washed with diethyl ether, neutralized with sodium bicarbonate, and 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 chromatographed on a silica gel flash column (gracylaminoethyl) isatin 1.32
I got g.

Elemental analysis value' (as CisHzoN20z) 0%
8% N% Calculated value 70.56 7.40 10.29 Actual value 70.46 7.51 10.24IR
(KBr): ”)Ill 3400 cm-
'C co1720 c++r' NMR (CDCI3) δ2 0.9~1.4 (6H, m), 1.5~
1.9 (51 (, m).

2.4-2.55 (IH, m), 2.96 (2H,
t, J=6.6Hz>, 3.82 (2H, t, J=
6.6Hz>, 6.98 (IH.

d, J=7.7Hz), 7.11[LH,t,
J=7.7Hz).

7.58 (LH, t, J=7.7Hz), 7.
60 (LH, d, J = 7, 7Hz) Reference Example 32 Dissolved in 100 d of lformamide and stirred at 95°C for 1 hour. The solvent was distilled off under reduced pressure, and the residue was dissolved in 2N hydrochloric acid 5
After dissolving in 0ml, the solution was washed with ethyl acetate, neutralized with an aqueous sodium bicarbonate solution, and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by 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-mefcyclohexylamino)ethylquisatin) with a melting point of 58 to 60°C (7).

Elemental analysis value' (as CI71422N202) 0
% 8% N% Calculated value 71.30 7.74 9.78 Actual value 71.17 7.79 9.65IR
(KBr): l'co 1725 cm-'
NMR (CDCI δ: 0.95-1.3 (5H, m), 1.5-1.
8 (5L m>.

2.25-2.4 (4ft, m), 2.71 (2H,
t, J=6.6Hz), 3.80(2H, t, J
・6.6Hz), 6.95(ltl.

d, J=7.1)1z), 7.09(LH,t,
J = 7.1Hz).

7.57 (ltl, t, J=7.1Hz), 7.
59 (LH, d, J = 7, 1 Hz) Reference Example 33 Using 1-(2-bromoethyl)isatin and N-methylbenzylamine, reaction was performed in substantially the same manner as in Reference Example 26, and then silica gel flash column chromatography (
Elution solvent: chloroform) to produce the following compound.

1-(2-(N-Methylbenzylamino)ethylquisatin Properties: Oily Yield ￥A: 39.0% Elemental analysis value: (C,811,8N, as 0□)0
% 8% N% Calculated value 73.45 6.16 9.52 Actual value 73.17 6.37 9.33IR
(neat): L/GO1730cm-'NM
R (CDCI3) δ: 2.37 (3fi, s), 2.64 (2H,
t, J=6.6Hz).

3,53 (2tl, s), 3.81 (2H,t,
J=6.6Hz).

6.67 (IH, d, J=7.7)1z), 7.0
6(lft, t, J=7.7)1z), 7.16
(5ft, s), 7.44(Ift, dt, J
=1.1 and 7.7Hz), 7.58(LH,
dd, J=1.1and 7.7Hz) Reference example 34 1- "2- (1,2,3,4-tetrahydro-2-
quinolyl)ethylquisatin 5.00 g, potassium iodide 3.27 g, ) ethylquisatin 1-(2-:l'cromotyl)isatin, ) ethylamine 1.
99 g and 2.62 g of 1,2.3.4-tetrahydroisoquinoline in 50 g of dry N,N-dimethylformamide.
mN 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 ethyl acetate,
The organic layer was dried over decahydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 1.39 g.

Elemental analysis value' (as C+sH+eJO□) 0%
8% N% Calculated value? 4.49 5.92 9.14 Actual value? 4.72 5.83 9.111R
(KBr): νCO1725cm-'NMR (C
[lC1 δ: 2.75-2.9 (68, m), 3. ．． 7
3(2H,s), 3.96(2)1. t,
J=6.6Hz), 6.98(IH,d, J=
7.7)1z), 6.99(1)1. t,
J=7.7Hz), 7.05~7.15(4H, m
), 7.56 (18, dt, J=l, la
nd7.7Hz), 7°59(1)1. dd,
J=1.1 and 7.7Hz) Reference example 35 Sun 100 m7! In addition, while stirring under water cooling,
A 20d solution of benzoyl chloride 4.7- in dry dioxane was added dropwise, and the mixture 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 9.7 g of oily N-butyl-N-(2-tetraloethyl)benzamide.

IR (neat): v co 1620 C
m'''isatintoN-' Thiru N-(2-chloroethyl)benzamide was reacted in substantially the same manner as in Reference Example 16, and then recrystallized from diethyl ether to give 1-C2
-(N-benzoylbutylamino)ethylquisatin was obtained.

Melting point: 125-127℃ Yield: 80.9% Elemental analysis value: (as C21H2□N2O3) 0%
8% N% Calculated value 71.98 6.33 7.99 Actual measurement ? 1.77 6.35 7.88IR
(KBr): vco 1730 cm-'
NMR (CDCl2) δ: 0.77 (3H, t, J=7.1Hz),
1.05-1.2 (2H.

m), 1.4-1.6<2tl, m), 3.2
6(2)! , t, J=7.1)1z), 3.7
4 (2H, t, J=6.6Hz), 4.08 (2H
, t, J=6.6Hz), 7.13(ltl, t
, J=7.1Hz), 7.25-7.45 (6H,
m), 7,61 (2N, d.

J=7.1)1z) 1- [2.60 g of 2-(N-benzoylbutylamino)ethylquisatin was dissolved in a mixture of 20 farts of ethanol and 60 farts of 20% hydrochloric acid, and the mixture was 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 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-butylamino/ethyl)isatin.

Elemental analysis value' (Cz)I+@N20z・0, O4
As CMCl3) 0% 8% N% Calculated value 67.16 7.24 11.16 Actual value 67.13 7.01 1! , 22IR
(neat): vco 1730 Cm-'
NMR (CDCI*) δ: 0.89 (38, t, J=7.1Hz),
1.15-1.6 (5H.

LT+), 2.65 (2H, t, J=6.6Hz)
, 2.95 (2H.

t, J=6.6)1z), 3.85(28,t,
J=6.6Hz).

6.98 (IH, d, J・7.7Hz), 7.11
(LH, t, J=7.7)1z), 7.58(1)
1. dt, J=1.7 and 7.7Hz),
7.60 (IH, dd, J=1.7 and 7.7
Hz) Example 1 After adding 1.00 g of - and 5-bromo-1C2-(2,2,6,6-titramethylbiveridino)ethylcoisatin and semicarbazi solution, it was extracted with chloroform, and after washing with water, anhydrous magnesium sulfate was added. It was dried. After distilling off the solvent under reduced pressure, the residue was recrystallized from methanol-water to give a melting point of 21.
(ε)-5-bromo-1-(2-(2,
0.93 g of 2,6,6-titramethylpiperidino)ethyl]isatin=3-semicarbazone was obtained.

Elemental analysis value' (C2oHzBrNsOt・0.4
(as H20) 0% 8% N% Calculated value 52.50 6.34 15.30 Actual value 52.49 6.47 15.011R
(KBr): L'NI+ 3400 Cm
−'ν. . 1695 cm” NMR (d6-DMSO) δ: 1.06 (12M, s), IJ~1.6 (
6H, m).

2.5-2.65 (2H, m), 3.55-3.
7 (2H, m).

6, 92 (1) 1. d, J=8.2)+2),
8.93(2)1. br-s).

7, 63 (IH, d, J=8.2Hz),
8.42 (IH,s).

10, 59 (1)1. s) Example 2 l-(2-diallylaminoethyl)isatin 1.00g
and semicarbazide hydrochloride 0.50g in 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 then recrystallized from ethanol.
1.058 of (sn)-1-(2-diallylaminoethyl)isatin-3-semicarbazone was obtained at ~182°C.

Elemental analysis value' (as C+J2+NsL) 0%
8% N% Calculated value 62.37 6.47 21.39 Actual value 62.47 6.45 21.25IR
(KBr): l'1l11 3380.3320
．． 3180 C11-'νco 1725.168
OCTI+-'NMR (d,, -DMSD>δ: 2.63 (2N, t, J=6.6H2),
3.09(4)1.6. J=6.6Hz), 3.8
0(28,,t, J=6.6Hz), 5.05(2
tl, dd, J=1.7 and 9.9Hz),
5.12 (2H.

dd, J=1,7 and 1? ,0)1z),5
．． 69(2)1. ddt.

J=9.9.17.0. and 6.6Hz), 6
．． 85 (2H, br-s>, 7.08 (IH, t,
J=7.7Hz), 7.09 (1N.

d, J=7.7Hz), 7.41(LH,t, J
=7.7Hz).

8.09 (IH, d, J=7.7)1z), 10.
22(1)1. s) Example 3 The following compound was produced in substantially the same manner as in Example 1 using l-(2-dibutylaminoethyl)-5-methoxyisatin and semicarbazide hydrochloride.

Melting point: 157-160°C (benzene-diethyl ether) Yield: 61.0% Elemental analysis: (as C2°H31NSO3) 0%
8% N% Calculated value 61.67 8.02 17.9.3
Actual value 61.82 8.23 1? ,90I
R(KE!r): νNM 3450.3400
．． 3250 cm-'ν. . 1715.1680
cm-1 NMR (d, -DMSD) δ: 0.79 (68,t, J=7,1)Iz),
1.05-1.35 (8H.

m), 2.38 (4H, t, J=7.1Hz),
2.58 (2tl.

t, J・6.6flz), 3.73(2H,t,
J・6.6! lz).

3,79(3H,s), 6.87(2H,br-s)
, 7.00 (2H, s), 7.77 (lft, s
), 10.42 (IH, s) Example 4 ■ The following compound was produced in substantially the same manner as in Example 1 using -(2-dibutylaminoethyl)-5-fluoroisatin and semicarbazide hydrochloride.

S゛ (chloroform-hexane) collection
Rate: 65.4% Elemental analysis value' (as C+5HzsFNsOz)
6% 8% N% Calculated value 60.46 7.48 18.55 Actual value 60. ．． 12 7,73 18.32I
R (KBr): L'1l11 3475.340
0.3300 Cm-'W. . 1720.1690
cm-'NMR (d, -DMSO) δ: 0.89 (6) 1. t, J=7.1Hz),
1.15-1.45 (8n.

m), 2.48 (4N, t, J=6.6t(
z), 2.70 (28°t, J=6.1Hz)
, 3.88 (2t(,t, J=6.1Hz).

7, DO(2)l, br-s), 7.22 (
IH, dd, J=4.4and 8.8Hz>,
7.39 (IH, dt, J=2.2 and8
．． 8Hz), 8.23(it(, dd, J=2
．． 2 and8, 8H2), 10.52 (IH
, br-s) Example 5 Melting point: 146-150°C (chloroform-hexane) Yield: 59.8% Elemental analysis value: (C+5LaCINs [as 12)
6% 8% N% Calculated value 57.93 7.16 17.78 Actual value 57.66 7.30 17.49IR
(KBr): νNH3450, 3400, 32
60cm-'Wc-1720, 1675cm-' NMR (d, l-DMSO) δ: 0.77 (6H, t, J=7.1Hz),
1.0-1.4 (8H.

rn'), 2.37 (4H, t, J=7.1H
z), 2.59 (2H.

t, J=6.1Hz), 3.77(2tl,
t, J=6.1tlz).

6.90<28. br-s), ? , 13(1)
1. d, J=8.8Hz).

7.46 (IH, dd, J=2.2 and
8.8Hz>, 8.29(lft, d, J
=2.2)1z), 10.49(LH,br-s)
Example 6 The following compound was produced in substantially the same manner as in Example 1 using 5-bromo-1-(2-dibutylaminoethyl)isatin and semicarbazide hydrochloride.

Melting point: 156-159℃ (chloroform-hexane) Yield: 92.3% Elemental analysis value' (C+, as HzBrNs02)
6% 8% N% Calculated value 52. Q6 6.44 15.98 Actual value 51.80 6.44 15.68IR
(KBr): 11011 3400. 3250
cm-'Vco, 1720. 1690c
m-'NMR (dll-DIJSO) δ: 0. ．． 78 (6H, t, J=7.1tlz)
, 1.05-1.35 (81(.

m), 2.36(4)1. t, J=7.1
)1z), 2.58(2)1°t, J=6.0
tlz), 3.76 (2H,t, J=6.01
(z).

6.88 (2H, br-s), 7.08 (IH, d
, J=8.2H2).

7.58 (IH, d, J=8.2Hz), 8.
40 (LH, s).

10, 53 (1)1. br-s) Example 7 The following compound was produced in substantially the same manner as in Example 1 using 5-amino-1-(2-dibutylaminoethyl)isatin and semicarbazide hydrochloride.

Melting point: 199-201℃ (chloroform-methanol) Yield: 84.3% Elemental analysis value' (as C+9LoN602) 6%
8% N% Calculated value 60.94 8,07 22.44 Actual value 60.92 8.18 22.20IR
(Br): νNH3350,3290cm-'
νco 1690.1670 cm-'NMR(d
s-DMSO) δ2 0.81 (6H, t, J=7.1Hz),
1.1-1.35 (8t(.

m), 2.38 (4H, t, J=7.1Hz),
2.56 (2H.

t, J=6.6Hz), 3.66 (2)1.
t, J=6.6flz).

4,85 (2H,br-s), 6.65 (1)1
．． dd, J=1.7and 8.2Hz), 6.
78 (IH, d, J=8.2Hz).

6.80 (2H, br-s), 7.35 (IH, d,
J=1.7Hz).

9,78 (ltl, s) Example 8 5-acetamido-1-(2-dibutylaminoethyl)
The following compound was produced in substantially the same manner as in Example 1 using isatin and semicarbazide hydrochloride.

Melting point: 150-152℃ (methanol-water) yield
Rate: 26.9% Elemental analysis value: (as Cz+LJsL・0.711,0) 6% 8% N% Calculated value 58.78 7.85 19.58 Actual value 58.71 8.02 19.59IR
(KBr): I')Ill 3400.326
0 cm-'νco 1705.1640 cm
-1HMR (ds-DMSO) δ: 0.79 (6H, t, J=7.IHz), 1
．． 05-1.35 (8H.

m), 2.03(3)1. s), 2.39 (4f
l, t, J=7.1Hz), , 2.55-2.6
5 (2H, 1Tl), 3.65-3.8 (2H,
m), 6.87 (2tl, br-s), 7.03
(lft, d.

J=8.8Hz>, 7.62(ltl, d, J=
8.8Hz), 8.09(18,s), 9.89(
IH, S), 10.06 (LH, s) Example 9 Using methyl l-(2-dibutylaminoethyl)-7-isatincarboxylate and semicarbazide hydrochloride, Example 1
The following compounds were produced in substantially the same manner as above.

Yield: 23.7% Elemental analysis value: (Cz+Hs1CO<・0.5CsL
4 (as hexane)) 6% 8% N% Calculated value 62.58 g, 32 15.20
Actual value 62.49 8.23 15.34I
R (KBr): l/N14 3450.3225
cm-'L'-61710. 1690 cm-
'NMR (d6-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(38,s
), 4.05 (2H, t, J=6.0Hz),
7.05 (2H, br-s), 7.30 (18, t
.

J=7.7Hz), 7.75(IH,d, J=
7.71 (z), 8.42 (IH, d, J=7
．． 7) 1z), 10.59 (IH, br-s) Example 10 Melting point: 182-185°C (ethanol) Yield
: 52.7% Elemental analysis value: (as C20H31NSO2) 6%
8% N% Calculated value 64.32 8.37 18.75 Actual value 64.38 8.36 18.711R
(KBr): l/N11 3440.
3325. 3220 cm-'ν. . 17
00 cm-'NMR(d6-D!,lSO)δ: 0
．． 85 (6H, t, J=7.1Hz>, 1.15
~1.4 (811゜m), 1.69 (2H, qu
int, 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 (IH, t, J=7.7
)1z), 7.12(IH,d, J=7.7H
z), 7.42 (IH, t, J=7.7) 1z
), 8.12(01,d, J=7.7)1z)
, III), 24(1)1°br-s) Example 11 Performed using 5-methoxy-1-(2-(2,2,6,6-titramethylpiperidino)ethylshiisatin and semicarbazide hydrochloride) The following compounds were produced in substantially the same manner as in Example 1.

Synthetic melting point: 176-178℃ (chloroform-ethanol) Yield: 71.6% Elemental analysis value' (C21) 131N503・C2H6
0 (ethanol)) 0% 8% N% Calculated value 61.72 8.33 15.65 Actual value 61.92 8.49 15.68JI
I(KBr): νNl! 3350 cm-
'ν. . 1690 cm NMR (d, -DMSO) δ: 1.06 (12H, s), 1.35-1.6
(68, m).

2.5-2.65 (2L m), 3.5-3.65 (
2H, m).

3.80(3)1. s), 6.86 (IH, d,
J=8.8Hz).

6.88 (2H, br-s>, 7.05 (LH, dd
, J=2.7and 8.8)1z), 7.80(
LH, d, , b2.7Hz).

10,48 (IH,s) Example 12 The procedure was carried out almost in the same manner as in Example 1 using 5-fluoro-1-[2-(2,2,6,6-titramethylbiperidino)ethylshiisatin and semicarbazide hydrochloride. The following compound was produced.

(E)zu-fluoro-1-[:2- (2,2,6,6
-Titramethison Melting point: 204-207℃ (methanol-water) yield
Rate: 73.696 Elemental analysis'M: (C20H211FNSO2' 0
．． 4H20) 0% 8% N% Calculated value 60.56 7.32 17.65 Actual value 60.61 7.52 17.49IR
(KBr): νNl+ 3490. 3370
cm-'shi co1725.1595 cm-'N
,',! R(d6-D!JSO>δ:
1.06 (12tl, s), 1.3-1.55 (6
H, m).

2,5-2.65 (2)1. m), 3.55~
3.7 (2t(,m).

6.90 (2H, br-s), 6.94 (IH, dd
, J=4.4and 8.8Hz), 7.3
1 (LH, dt, J=2.2 and8.8H
z), 8.14 (IH, dd, J=2.2and
8.8Hz), 10.48 (ltl, br-s) Example 13 Example 1 using 5-chloro-1(2-(2,2,6,6-titramethylbiperrJdino)ethylshiisatin and semicarbazide hydrochloride) The following compounds were produced in substantially the same manner as above.

Melting point: 197-202℃ (chloroform-hexane) Yield: 87.6% Elemental analysis value'(C2QH28CINSO2'0,0
5CHC1) 0% 8% N% Calculated value 58,47 6.86 17.00 Actual value 58.28 6.94 16.92IR
(Kart: L'NH3500, 3375cm-
'ν. o 1725. 1695 cm-'Nul
l (d, -oyso) δ: 1.06 (12H, s), 1.3-1.6 (
6H, m).

2.5-2.65 (2H, m), 3.55-3.6
5(2)1. m).

6.90 (2H, br-s), 6.96 (18, d
, J=8.8Hz).

7.50 (18, dd, J=1.6 and 8.
8Hz), 8.31 (LH, d, J=1.6H
z), 10.57 (1N, s) Example 14 Rubazone melting point: 172-174°C (methanol-water) Yield
Rate: 55.4% Elemental analysis value: (as C2□H32NsOs・It, 0) 0% 8% N% Calculated value 59.17 7.67 18.82 Actual value 59.31 ? , 71 18.86I
R (KBr): ”NH3350,3200cm-
'νco 1715. 1695 cm-'NMR
(dll-DMSO) δ: 1.07 (12H, s), IJ ~1.6
(6H, m>, 2.04 (311, s), 2.
5-2.65 (2H, m), 3.5-3.65 (2
tl, m), 6.85(2)1. br-s
), 6.89 (IH, d.

J=8.2Hz), 7.63(1)1. d,
J=8.2Hz), 8.13(IH,s),
9.91(IH,s>, 10.14(11(,s)
Example 15 The following compound was produced in substantially the same manner as in Example 1 using 5-amino-1-(2-(2,2,6,6-tetramethylpiperidino)ethylcoisatin and semicarbazide hydrochloride.

- and melting point: 211-216℃ (chloroform-hexane) Yield: 43.1% Elemental analysis value: (Czo113oNsOz'0.2C
) as ICIs) 0% 8% N% Calculated value 59.12 7.42 2 (1,48
Actual value 59.19 7.61 20.16I
R (KBr): v Nil 3320 c
m-'νco 1690 cm-' NMR (ds-DMSO>δ: 1.06 (12H, s), 1.3-1.6
(6H, m>.

2,45~2.6 (28,m), 3.45~3
．． 6 (28, m).

4,85 (2)1. br-s), 6.67
(2ft, s), 6.80 (2tl,
br-s>, 7.38 (11(,s), 9.8
5(LH,S) Example 16 1 Using methyl [2-(2,2,6,6-titramethylpiberidino)ethyl]-7-isatinecarboxylate and semicarbazide hydrochloride, almost the same as Example 1. The following compounds were produced in the same manner.

Melting point: 214-218°C (methanol-hexane) Yield: 53.7% Elemental analysis: (C2Js+N5On・0.2C1i
H1* (as hexane) 0% 8% N
% Calculated value 62,37 7.63 15.68 Actual value 62.27 ? , 54 15.52r
R(KBr): νNH3460,3250cm-
'νco 1720.1685 Cm-'NMR(
ds-DMSCI) δ: 0.98 (12H, s), 1.3-1.55 (
611, m).

2.4~2.55 (2H, m>, 3.8~3゜95
(5N, 171).

7.23 (IH, t, J□7.4Hz), 7.25
(2H, br-s).

7.64(It(,d, J=7.4Hz), 7.8
8<IJ(,d, J=7.4Hz), 11.68(
LH,s) Example 17 1-C2-(2,2,6,6-titramethylpiperidi/
) The following compound was produced in substantially the same manner as in Example 1 using ethylcoisatin and 4-benzylsemicarbazide hydrochloride.

Melting point: 167-168℃ (ethanol) Yield
: 82.3% Elemental analysis value' (as Cz7LsNsL) 0%
8% N% Calculated value 70.25 7.64 15.17 Actual value 70.27 7.86 15.00IR
(KBr): νNH33g0.3220 cm
-'shico1710.1680 c+c'NMR(d
, -DMSO) δ: 1.0? (12H, s), IJ ~16 (68
, m).

2.5-2.65 (2H,, m), 3.55-3.7
(2H, m).

4.42 (2H, d, J=6.0Hz), 6.96
(1N, d, J=7.7)1z), ? ,09(1
)1. t, J-T, IHz>, 7.2~7.4 (
5H, m), 7.45 (LH, t, J=7.7Hz
).

7.79 (IH, t, J=6,0Hz), 8.12
(LH, d, J=7.7Hz), 10.43(LH
，! ,) Example 18 The following compound was produced in substantially the same manner as in Example 1 using 1-[1-methyl-2-(2,2,6,6-titramethylpiveridino)ethylcoisatin and semicarbazide hydrochloride. did.

Melting point: 180-183°C (chloroform-methanol) Yield: 64.8% Elemental analysis value: (C21831NSO□0.7CII
40 (as methanol) 0% 8% N
% Calculated value 63.89 135 17.17 Actual value 63.97 8.64 1? ,04IR(
KBr): ν+u+ 3400. 3200
cm-'1'co1690 cm-' NMR (d, -DMSO) δ: 0.85 (6H, br-s), 1.04 (6H
,br-s).

1.2-1.6 (9H, m>, 2.76 (LH, dd
, J=4.7and 15.7Hz), 3.01(
1N, dd, J=7.2 and15.7Hz),
4.2-4.4 (IH, m), 6.84 (2H.

br-s), 7.06 (IH, t, J=7.7Hz),
7.15 (18°d, J=7.7)1z), 7
．． 4HLH,t, J=7.7Hz).

8.09(1)1. d, J=7.7Hz),
10.23 (IH,s>Example 19 ゛l C2-(2,2,6,6-titramethylbiperidino)p1-0 Melting point: 193-195°C (Chloroform-methanol) Yield: 53 .7% Elemental analysis value' (as C21H31NSO2) 0%
8% N% Calculated value 65.43 8.10 18.17 Actual value 65.40 8.34 17.99IR
(Or): l'wn 3410.3225
cm-'νco 1680 cm-' +111R(d, -Dj4SO) δ: 1. O~1.7 (21H, m), 3.55
~3.75 (28, Il+).

3.8-4.0 (Ift, m), 6.85 (2
H, br-s).

7.01 (LH, d, J=7.7Hz), 7.
08(1)1. t.

J=7.7Hz), 7.43(L)! , t,
J=7.7Hz), 8.11(LH,d, J
= 7.7 Hz), 10.25 (1N, s)゛4 Example 20', "l-(3-(2,2,6,6-titramethylpiberidino)pta.

Melting point: 208-211°C (chloroform-methanol) Yield: 63.9% Elemental analysis value + (as cz + Hz + NsO□) 0%
8% N% Calculated value 65.43 8.10 18.17 Actual value 65.35 8.31 17.94IR
(KBr)+L'+Ill:3:3! lo,
3300.3175 Cm-'shi co1680
cm-Tsuta NMR (ds-DMSO) δ: 0.92 (12H, s), 1.2-1.55 (
6H, m>, 1.6 to 1.8 (2H, m), 2.3
5-2.5 (2) 1. m), 3.67(2H,t,
J=6.6Hz), 6.86 (2H,br-s
>.

7.09(LH,t, J=7.7t(z), 7.1
2 (LH, d, 7.7) 1z), 7.43 (LH
,t, J=7.7Hz), 8.11(LH,d,
J=7.7Hz), 10.24(ill, br-s
) Example 21 1-[2-(4-Methyl-1-piperazinyl)ethylcoisatin and semicarbazide hydrochloride were used to produce the following compound in substantially the same manner as in Example 1.

(8)-1-C2-(4-methyl-1-piperazinyl)
Ethylquisatin-3-semicarbazone Melting point: 173-176°C (decomposition) (ethanol) Yield: 67.8% Elemental analysis: <C+5H2zNs02・0.4H2
0% 8% N% Calculated value 56,92 6.81 24.89 Actual value 57.02 6.77 24.80IR
(KBr): L/NI (3400, 3310, 3
180cm-'ν. . 1680 cm-' NMR (d8-DMSO) δ: 2°12(3)1. s), 2.15-2.6(
IOH, m), 3.82 (2H, t, J=6.6H
z), 6.66 (2H, br-s).

? , 03 (IL t, J=7.7Hz), 7.
07 (1N, d, J=7,7)1z), 7.32
(IH, t, J=7.7flz), 8.11(LH
, d, J=7,7tlz), 10.24(Il
l, br-s) Example 22 Using 1-C2-(4-benzyl-1-piperazinyl)ethylcoisatin and semicarbazide hydrochloride, Example 1
The following compounds were produced in substantially the same manner as above.

(E)-1-(2-(4-penzyl-nipiperazinyl)) Melting point 2 194-196°C (ethanol-water)
Yield: 70.1% Elemental analysis value = (C2□H211NS (]□) 0%
8% N% Calculated value 65.01 6.45 20.67 Actual value 64.90 6.54 20.70IR
(KBr)'l'NII 3375.3300
．． 3175 cm - 'νco' 1680 cm
-' NMR (d6-DMSO) δ: 2.25 to 2.7 (10 tl, m), 3.4
6 (2H, s), 3.86 (2H, t, J=6.6
Hz>, 6.90(2)i, ,br-s).

7.12 (ltl, t, J=7.7Hz), 7.
16 (IH, d, J=7.7Hz), 7.2-7.
5 (6H, m), 8.13 (LH.

d, J=7.7Hz), 10.26 (1
)l, 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.

Melting point: 169-171°C (chloroform-diethyl ether) Yield: 81.0% Elemental analysis: (as C2°827NSO2) 0%
8% N% Calculated value 67.15 6.92 17.80 Actual value 66.98 6.84 (7,80I
R (Or): νNH3260cm-'shico1
690 cm-'NMR(d6-DMSO)δ: 0.8
7 (6H, t, J=7.IHz), 2.48 (4H
, q, J=7, 1Hz), 2.60 (2tl,
t, J=6.6Hz), 3.77 (2tl.

t, J=6.6)1z), 4.42(2N, d,
J = 6.0 Hz).

7.07 (IH, t, J=7.7Hz), 7.12
(LH, d, J=7.7Hz>, 7.2~7.4<
58. m), 7.42 (LH, t.

J=7.7Hz), 7.81<18. t, J=6
．． 0Hz), 110(It(,d, J=7.7Hz
), 10.36 (Iff, s) Example 24 1 (2-(2,2,6,6-titramethylpiperidino)ethyl]isatin 1.50 g, semicarbazide hydrochloride 0.64 g and sodium acetate 0. 47 g was suspended in 90% of ethanol-water (2:1) and stirred at room temperature for 16 hours.The reaction solution was concentrated under reduced pressure, and the residue was diluted with hydrogen carbonate.) An aqueous solution of IJ was added and the crystals were filtered out using a filter. Water semicarbazone 1.20. I got g.

Elemental analysis value'(C2o)1zsNsOz'0.9H
20) 6% 8% N% Calculated value 61.96 8.01 18.06 Actual value 62.10 7.97 17.96IR
(KBr): L'llll+ 3440. 32
50 cm-'νco 1690 cm-heavy NMR (d6-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 (LH, d, J
=7.7Hz).

7.08 (LH, t, J=7.7Hz), 7.
45 (LH, t, J=7.7)1z), 8.1
1 (LH, d, J=7.7Hz), 10.28
(18,8) Example 25 The following compound was produced in substantially the same manner as in Example 24 using 1-(2-dipropylaminoethyl)isatin and semicarbazide hydrochloride.

Melting point: 180-182℃ (ethanol-water) yield
Rate: 35.9% Elemental analysis value: (as C+JzsNsO□) 6%
8% N% Calculated value 61.61 7.60 21.13 Actual value 61.28 7.81 21.00IR
(KBr): l')Ill 3380. 331
0. 3175 cm-'1'co 1685
cm-' NMR (d, -DMSO) δ: 0.75 (6H,t, J=7.1)1z)
, 1.30 (4H, 5ext.

J=7.1Hz), 2.36(4H,t, J=
7.1Hz), 2.61(2H,t, J・6.
6Hz), 3.77 (2H, t, J=6.6H
z), 6.84 (2H, br-s), 7.07
(1)1. t, J=7, 7)1z), 7.
10 (18, d, J=7.7Hz), 7.42
(III, t, J・7.7Hz),
8.09 (LH, d, J・7.7flz),
10.21 (IH, s) Example 26 The following compound was produced in substantially the same manner as in Example 24 using -(2-dibutylaminoethyl)isatin and semicarbazide hydrochloride.

Melting point: 176-178℃ (methanol-water) yield
Rate: 39.4% Elemental analysis value' (C19H29NSO2・0.411
20) 6% 8% N% Calculated value 62.26 8.14 19.12 Actual value 62.45 8.13 19.05IR
(KBr): ν) Ill 3440. 331
0. 3250 Cm-'νco 1690 c
m-' NMR (d, -DMSO) δ: 0.78 (6H, t, J=7.1Hz>,
t, i ~ 1.35 (811°m), 2.38 (
4t(,t, J=7.1Hz), 2.60(2
H.

t, J=6.6Hz), 3.76 (2H, t, J=6.
6Hz).

6.85 (2H, br-s), 7.07 (11 (,
t, J=7.7Hz>.

7.10 (IH, d, J=7.7)1z), 7
．． 42 (LH, t, J=7.71(z), 8.
09 (ltl, d, J=7.7Hz), 1
0.22(1)1. S) Example 27 The following compound was produced in substantially the same manner as in Example 24 using 1-(2-dibutylaminoethyl)-5-methylisatin and semicarbazide hydrochloride.

Melting point: 158-160°C (chloroform-hexane) Yield: 71.3% Elemental analysis value: (as C20H31N502) 0%
8% N% Calculated value 64.32 8.37 18.75 Actual value 64.11 8.46 18.46IR
(KBr): l'N11 3460.3390.
3250 am-'C. 1715. [90cm-
'NMR (d8-DMSO) δ: 0.79 (6H, t, J=7.1)1z),
1.05-IJ5 (8H.

m), 2.31 (3H, s), 2.38 (4N,
t, J=7,1)1z), 2.58(2)1. t
, J・6.6t(z), '3.73 (2H.

t, J=6.6Hz), 6.83 (2H,br-
s), 6.98 (LH, d, J=8.2Hz),
7.23 (IH, d, J=8.2Hz), 7.9
9 (LH, s), 10.16 (1N, s) Example
28 The following compound was produced in substantially the same manner as in Example 24 using 1-(2-dicyclohexylaminoethyl)isatin and semicarbazide hydrochloride.

Melting point: 199-202℃ (methanol-water) yield
Rate: 56.0% Elemental analysis value' (CzJ3Js02・0.lH2O
)0% 8% N% Calculated value 66.83 8.10 16.94 Actual value 67.0? 8.12 16.62I
R (Br): vwn 3400.3320.
3200 cm-'1'c. 1725.1685
cm-'NMR (d, -0M5O) δ: 0. Ri-1,75 (20H, m), 2.4-2
．． 6 (2H, m>.

2.71 (2H, t, J=6.6Hz>, 3.65
(2H, t, J=6, fliHz), 6.85(
2H,br-s), 7.06(iH,d.

J=7.7Hz), 7.07(IL t, J=7.
7Hz), 7.42 (LH, t, J=7.7Hz)
, 8.09 (LH, d, J・7.7Hz), 10
．． 21 (lfl, 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.

Melting point: 177-180℃ (ethanol) Yield
: 73.8% Elemental analysis value' (as C2SH2SNSO2) 0%
8% N% Calculated value 70.24 5.89 16.38 Actual value 70.40 5.97 16.13IR
(KBr): ”IIH3400,3275,32
25°3175 cm-' ν. . 1680 cm-' N! JR (d6-DMSO) δ: 2.60 (2H, t, J=6.01(z),
3.59 (4H, s).

3.86 (2ft, t, J=6.0Hz), 6.
80 (LH, Tun J = 7.7Hz), 6.86 (2H
,br-s), 7.04 (LH,t.

J=7.711z), 7.1~7.3(IIH,m)
, 8.09 (18,d, J=7.7Hz),
10.25 (ltl, s) Example 30 i The following compound was produced in substantially the same manner as in Example 24 using C2-(1-pyrrolidinyl)ethyl]isatin and semicarbazide hydrochloride.

Melting point: 184-186℃ (methanol-water) yield
Rate: 29.9% Elemental analysis value' (C2SH2SNSO2・0.2H2
0) 0% 8% N% Calculated value 59.08 6.41 22.97 Actual value 59.18 6.33 23.02IR
(KBr): “NO3380, 3310, 317
5cm-'νco 1725.1680 cm-'
Nl,! R(d6-D!JSO)δ:
1.5-1.75 (4H, m), 2.4-2.6 (4
tl, m).

2.65 (2H, t, J=6.6Hz), 3.34
(2H, t, J=6.6Hz), 6. a8 (2H,
br-s), 7.09 (IH, t.

J=7.7Hz), 7.13(Hf, d,
J=7.7Hz), 7.42(18,t, J=
7.7Hz>, 8.09 (LH, d, J=7.
7Hz), 10.25 (IH, 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.

Melting point: 181-183℃ (methanol-water) yield
Rate: 50.4% Elemental analysis value: (as C, 18H21N50□) 0%
8% N% Calculated value 60.94 6.71 22.21 Actual value 61.09 6.64 22.06JR
(KBr): ! '11 3370.3300.3
175 cm-'νco 1685 c+rr' NMR (ds-DMSO) δ2 1.25-1.55 (6N, m),
2.3-2.45 (4N, m).

2.48(2)1. t, , J=6.6Hz),
3.82(2)f, t, J=6.6Hz)
, 6.87 (2H, br-s), 7.08 (L
H,t.

J=7.1Hz), 7.12(ltl, d,
J=7.1flz), 7.41(IH,t,
J=7.1Hz), 8.09(1N, d,
J=7.1)1z), io, 25(LH,br-
s) Example 32 5-Methyl-1-C2-(2,2',6.6-titramethylbipey Melting point: 192-195°C (ethanol-water) Yield
';4: 69.9% Element molecule? Value' (C2J3+N5112・0.1)
120) 0% 8% N%
Calculated value 65.12 8.12 18.08 Actual value 65,34 8.25 17.75IR
(KBr): ν,, 3490. 3370
cm-'ν. . 1720. 1695 cnr'
, NMR (d, -Dλ1sO) δ: 1.06 (12) 1. s), 1.35
~1.6(6)1. m), 2.32(3H,s
), 2.5-2.65 (2t(,m), 3.5
5-3, 65 (2L m), 6.84 (01, d
, J=8.2FIz).

6,85 (2H,br-s), 7.26 (l
tl, d, J=8.2H2), 8.02(
LH, s), 10.23 (IH, 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.

Melting point: 184-187℃ (decomposition) (chloroform-methanol) Yield: 57.9% Elemental analysis 1st round: (as C,, H,, N, O) 0
% 8% N% Calculated value 58.12 6.62 24.20 Actual value 57.96 6.69 24.09IR
(KBr): I/B 3340. 3125
cm-'ν. . 1695. 1680 cm-'
NMR (d, -DMSO) δ: 1.71 (2H, quint, J=7.1Hz
), 2.11 (6H.

s), 2.23(2H,t, J=7.L)lz
), 3.74(2f(.

t, J=7. IHz>, 6.88 (28, br-s>,
7.09 (Ill, t, J=7.7Hz), 7
．． 14 (LH, d, J=7.7Hz), 7.4
1 (IH, t, J=7,7tlz), 8.11
(IH, d, J=7.7Hz), 10.25(
LH, br) Example 34 The following compound was produced in substantially the same manner as in Example 24 using 1-(3-diethylaminoprobyl)isatin and semicarbazide hydrochloride.

Melting point = 178-180℃ (decomposition) (chloroform-methanol) Yield: 33.9% Elemental analysis value' (C+J2Js02・0.03CHC
1) 6% 8% N% Calculated value 59.99 7.23 21.82 Actual value 59.73 7.17 21.811R
(KBr): I')I)+3400. 33
10. 3175 cm - 1680 cm
-' NMR (ds-DMSO) δ: 0.92 (6H, t, J=7.1Hz),
1.69 (21L quint.

J=7.1flz), 2.42(2tl,
t, J=7.1flz), 2.43(4H
,q, J=7.1Hz>, 3.74(2H,t,
J=7.1Hz), 6.89(2H,br-s),
7.09 (ltl, t, J=7, 4Hz), 7.
13 (IH, d, J=7.4Hz), 7.42 (L
H, t, J=7.4) (z), 8.11 (LH, d
, J=7.4Hz), 10.25 (LH, br) Example 35 ■-(2-dibutylaminoethyl)isatin i, oog
and 4-cyclohexyl semicarbazide 0.63g ethanol lQ+nj! To the mixture was added 4 mA of 1N hydrochloric acid, and the mixture was stirred at room temperature for 5 hours. After concentrating the reaction solution under reduced pressure and adding an aqueous sodium hydrogen carbonate solution to the residue,
It was extracted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from ethanol to give (巳)-1(2) with a melting point of 139-140°C.
-Dibutylaminoethyltin=3-(4-cyclohexylsemicarbazone) 0.82 g was obtained.

Elemental analysis value' (C2SH39NS02・0.2C2
(as H60 (ethanol)) 6% 8% N% Calculated value 67, 67 8.99 15.5
3 Actual value 67, 49 9.09 15.
42IR (KBr): νN) + 346
0.338(), 3200 cm-'ν. . 169
0. 1670 cm-'NMR (d,-DM
SO) δ: 0.78 (6H, t, J=7.1Hz
), 1.0 to 1.9 (18H.

m), 2.38 (4H, t, , J=7.1
Hz), 2.59 (21(.

t, J=6.0Hz), 3.5 to 3.65(
LH, m), 3.76 (2H, t, J
=6.0Hz), 6.95 ~7.15(3)1,
m).

7, 41 (1M, t, J=7.7Hz),
8.08 (LH, d, J=7, 7Hz),
10. 20 (LH, s) Example 36 The following compound was produced in substantially the same manner as in Example 35 using 1-(2-diethylamineethyl)isatin and 4-cyclohexyl semicarbazide.

Melting point: 166-168℃ (chloroform-hexane) Yield: 87.5% Elemental analysis value' (C21H31NSO2・0, 03
CHC1) 6% 8% N% Calculated value 64.92 8.04 18.0
0 Actual value 64.94 8.11 18.
03IR (KBr): νlII+ 32
00 0m-'νco 1690 cm-' NMR (d6-DMSO) δ: 0.87 (6H, t, J=7.1Hz
), 1.1-1. 95 (10H.

m>, 2.49 (4H, q, J=7.11
(z), 2.60 (2H.

t, J=6.6Hz>, 3.5 ~ 3.7
(18, m), 3.77 (2H, t,
J = 6.6Hz>, 7.0 ~ 7.2 (3H,
m).

7, 42 (LH, t, J・7.7Hz),
8. 08 (LH, d, J=7, 7Hz
), 10.22 (IH, 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 to 145.5°C (benzene-diethyl ether) Yield 2 43.8% Elemental analysis value: (as C2゜H,, N, O□) 0%
8% N% Calculated value 64J2 g, 37 18.75 Actual value 64.24 8,41 18.811R
(KBr): "Mll 3280 cm-'
1'-8,1700. 1685 cm-'NMR (
d, -DMSO) δ: 0.7g (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
(ill, t, J=7.7Hz), 7.09(1
)1. d, J=7.7Hz), 7.19(1)l
, [1, J=4.4)1z), 7.41 (IH,
t, J=7.7flz), 8.10(LH,d,
J=7.7Hz), 10.30<1)1°S) Example 38 Example 38 Using 1-C2-(2,2,6,6-titramethylpiperidino)ethylcoisatin and 4-methylsemicarbazide The following compound was produced in substantially the same manner as No. 35.

Melting point: 221-223℃ (chloroform-ethanol) Yield: 83.8% Elemental analysis value' (C2+Hff+N502・C2)1
．． 0 (as ethanol)) 0% 8% N% Calculated value 64.01 8.64 16.23 Actual value 63.83 g, 74 16.33I
R(KBr): Ll) IH3360cm-'ν.

. 1685 cm-' NMR (d6-DMSO) δ: 1.07 (12H, s), 1.3-1.6 (
6H, m).

2.5-2.65 (2tl, m>, 2.77 (3H
, d, J=4.4Hz), 3.55~3.7(2
H, m), 6.96 (IH, d.

J=7.7Hz), 7.09(IH,t, J=
7.7Hz), 7.19(Ill, q, J
・4.4Hz), 7.44(II(,t, J=
7.7Hz), 8.11 (1N, d, J=
7.7Hz), 10.37 (IH.

S) Example 39 1 The following compound was prepared in substantially the same manner as in Example 35 using C2-(2,2,6,6-titramethylpiveridino)ethylcoisatin and 4-cyclohexyl semicarbazide. Manufactured.

(C2sHsJsOz・C2H,0(
(as ethanol) 0% 8% N% Calculated value 67.30 9.08 14.02 Actual value 67.21 9.35 13.93IR
(KBr)+1'+Il! 3380. 3
220 cm-'νc. 1705. 1670
cm-'NMR (ds-DMSO) δ: 1,07 (12H,s>, 1.1-1.9
5 (16H, m>.

2.5-2.65 (2tl, m), 3.5-3
．． 7 (3H, m).

6.96 (LH, d, J=7.7Hz), 7.
01 (LH, d, J=7, 7Hz), 7.0
9 (LH, t, J=7.7Hz), 7.45
(IH, t, J=7.7Hz), 8.10(L
H, rJ, J=7.7Hz), 10.29(L
H, s) Example 40 i The following compound was produced in substantially the same manner as in Example 35 using C2-(2,2,6,6-titramethylbiperidino)ethylcoisatin and 4-phenylsemicarbazide.

Melting point: 174-175.5℃ (ethanol) yield
Rate: 80.4% Elemental analysis value: (CzsL*NsO□・0.7C2H
,0 (ethanol)) 0% 8% N% Calculated value 68.59 7.81 14.60 Actual value 68.46 7.94 14.411R
(KBr): ”IIH3330,3220cm-
'ν. . 1680 cm-' NλiR (ds-DMSO) δ: 1.08 (12H, s), 1.35-1.6
(6H, m).

2.55-2.65 (2H, m), 3.6-3.7 (
2)1. m).

6.99 (IH, d; J=7.7Hz), 7.07
(1N, t, J=7.7Hz), 7.15 (IH
, t, J=7.7Hz), 7.35(2fl, t
, J=7.7Hz), 7.49(1N, t, J
=7.7)1z), 7.60(2H,d, J・7.
7tlz), 8.16 (LH.

d, J=7.7Hz), 9.48(Ift, s)
, 10.51(II(.

S) Example 41 1-(2-diethylaminoethyl)isatin 1.00g
and 0.50 g of semicarbazide hydrochloride were stirred in 30 ff Li2 of N,N-dimethylformamide at 120°C for 1 hour. Concentrate the reaction solution under reduced pressure and add hydrogen carbonate to the residue)
After adding IJum aqueous solution, extraction with ethyl acetate,
After washing with water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from benzene-hexane.
(Z)-1-(2-diethylaminoethyl)isatin = 0.74 g of 3-semicarbazone with a melting point of 170-173°C
I got it.

Elemental analysis value' (as CIS821NSO2) 0%
8% N% Calculated value 59.39 6.98 23.09 Actual value 59.44 7.07 22.811R
(KBr): vwH3450,3180cm-'
νco 1705.1670 cm-'NMR(d
s-DMSO) δ: 0.85 (68,t, J=7.IHz),
2.47 (4H, (], J=7.1Hz),
2.63 (2H, t, J=6.6Hz), 3
．． 80 (2H, t, J=6.6) (z), 7
゜12(1)1. t, , J=7.7)1z),
7.14 (IH, d, J=7.7)1z),
7.18 (2H.

s), 7.39 (LH, t, J=7.7Hz)
, 7.64 (LH.

d, J=7.7Hz), 11.71 (IN, s) Example 42 The following compound was produced in substantially the same manner as Example 41 using 1-(3-dimethylaminopropyl)isatin and semicarbazide hydrochloride. did.

Melting point: 137-139℃ (benzene) Yield:
69.3% Elemental analysis value: (as C,, H, 9N, 0□) 0%
8% N% Calculated value 58.12 6.62 24.20 Actual value 58.24 6.61 24.23IR
(KBr): vw, I 3350 cm-'
νC01665Cm-' NMR (ds-DMSO) δ: 1.74<2H, quint, J=7.
1flz), 2.1H6H.

S), 2.24 (2H, t, J=7.1Hz), 3.7
7 (2H.

t, J=7.1Hz), 7.1~7.25
(4H, m), ? , 40(1)1. t,
J=7,7tlz), 7.65(IH,d,
J・7,7Hz), 11゜68(IH,s) Example 43 1-(2-dibutylaminoethyl)isatin 1.14g
and semicarbazide hydrochloride 0.49g with N,N-dimethylformamide 2Off+7! and stirred at 100°C for 4 hours. 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 purified by silica gel flash column chromatography (elution solvent: chloroform/ethanol = 50/1), recrystallized from ethanol-hexane, and purified with a melting point of 80-81°C ( Z)-1-(2-dibutylaminoethyl)isatin-3-semicarbazone 0
．． 73g is 4.

Elemental analysis value' (C+5thsNsL・0.411,
0) 6% 8% N% Calculated value 62.24 8.19 19.10 Actual value 62.27 8.03 19.03IR
(KBr): L'llll! 3450.320
0 cm-'νco 1710. 1670C
m-'NMR (ds-DMSO) δ: 0.76 (6H, t, J=7.1Hz>,
1.05-1.3 (8H.

m), 2.36(4)i, t, J=7.1Hz
), 2.64(2)1°t, J=6.6Hz),
3.80 (2H, t, J=6.6)1z).

7.05-7.2 (4H, m), 7.39 (IH, t
, J=7.7tlz), 7.64(LH,d, J
=7.7Hz), 11.72(LH.

S) Example 44 (2)-1-C2-(2,2,6,6-titramethylbiperidino)ethyl]isatin=3-semicarbazone (ε
)-1-C2-(2,2,6,6-titramethylpiperidino)ethyl]isatin=3-semicarbazone 1.06
g was suspended in 40 mN of dry N,N-dimethylformamide and stirred at 100°C for 2 hours. The reaction solution was concentrated under reduced pressure, and the remaining crystals were mixed with water and then recrystallized from benzene to give (Z)-1[2-(2) with a melting point of 225-227°C.
, 2°6.6-titramethylpiveridino)ethylcoisatin/3-semicarbazone 0.85 g was obtained.

Elemental analysis value = (C2°)129NSO2) 6%
8% N% Calculated value 64.67 7.87 18.85 Actual value 64.76 8.02 19.0? IR
(KBr): ”1111 3460.3200
cm-'shico1710.1670 cm-'NM
R(d,-DMSO) δ: 1.08 (12tl, s), 1.35-1.
6 (6 fl, m).

2.55-2.7 (2H, m), 3.55-3.7 (
2N, m).

6.99 (III, d, J・7.7Hz), 7.
13 (IH, t, J-7, 7Hz), 7.15 (2
H, br-s), 7.43 (IH, t.

J=7.7)1z), 7.64(1B, d,
J=7.7Hz).

11.73 (ILs) Example 45 The following compound was produced in substantially the same manner as in Example 1 using ■-(2-butylaminoethyl)isatin and semicarbazide hydrochloride.

Melting point: 161-163℃ (di-tetraloform diethyl ether) Yield: 27.4% Elemental analysis: (CISH21NSO□・0,05C
As HCI3) 6% 8% N% Calculated value 58.44 6,86 22.64 Actual value 58.73 6.94 22.38IR
(Kerb: vs+43390.3275.31
75 cm-'co1680 cm-' NMR (d7-DMF) δ: 0.85 (3H, t, J=7.1Hz),
1.2~1.45 (4) 1゜m), 2.59
(2H, t, J=7.1Hz), 2.87(2
H.

t, J=6.6Hz), 3.89 (2ft
, t, J=6.6Hz).

7.02 (2H, s), 7. L3(LH,t,
J=7,1tlz).

7.22 (IH, d, J=7.1Hz), 7.
45 (IH, t, J=7.1Hz), 8.28 (L
H, d, J・7.1 Hz) Example 46 The following compound was produced in substantially the same manner as in Example 2 using 1-C2-(N-methylbutylamino)ethylcoisatin and semicarbazide hydrochloride.

Melting point: 186-188℃ (ethanol) Yield
: 80.5% Elemental analysis value' (CI6823NS [as l□)6
% 8% N% Calculated value 60.55 7.30 22.07 Actual value 60.46 7.38 21.93IR
(Kart: v■ 3400, 3300.318
0 cm-'νco 1680 cm-' NMR (d, -DMSO) δ: 0.75 (3H, t, J=7.1) 1z)
, 1.05-1.35 (4H.

m), 2.20 (3H, s), 2.29 (2N
, t, J=7.1Hz), 2.53(2N,
t, J=6.6Hz), 3.81 (2H.

t, J=6.6Hz), 6.87 (2H, br-s),
7.08 (LH, t, J=7.7Hz), 7.
12 (IH, d, J=7.7fiz), 7.4
1 (Ift, t, J=7.7)1z), 8
．． 10 (LH.

d, J=7.7Hz, ), 10.24(LH,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.

Melting point: 174-176℃ (ethanol) Yield
: 60.7% Elemental analysis value: (C,) as 123N502) 0%
8% N% Calculated value 61.99 7.04 21.26 Actual value 61.96 7.03 20.93IR
(KBr): ν111 3380.3300.3
175 cm-'νco 1680 c+c' NMR (dji DMSO) δ: 0.85-1.3 (5H, m), 1.45
~1.85 (5H, m>.

2.3-2.45 (IH, Tl+), 2.76 (2
)1. t, J=6.6Hz>, 3.76(2
tl, t, J=6.6)1z), 6.84(21
(.

br-s), 7.07 (LH, t, J=7.7
Hz), 7.14 (IH, d, J=7.7)1
z), 7.40(it(,t, J=7.7)1
z), 8.10 (LH, d, J=7.7Hz)
Example 48 1-C2-(N-methylcyclohexylamino)ethylquisatin 1.61 g and semicarbazide hydrochloride 0.7
4 g was dissolved in 60 mN of ethanol-water (2:1) and stirred at room temperature for 1 hour. After concentrating the reaction solution under reduced pressure, 6.8 d of a 1N aqueous sodium hydroxide solution was added, and the crystals were filtered and washed with water. The obtained crystals were recrystallized from ethanol to give (E)-1-C2-(N
-methylcyclohexylamino)ethylcoisatin-3
- 1.15 g of semicarbazone was obtained.

Elemental analysis value' (as C+aHzsNsO2) 0%
8% N% Calculated value 62.95 7□34 20.39 Actual measurement residue 62.80 7.34 20.39IR
(Br): NH3400, 3320, 31
80cm-'νCo 1680 Cm-'R(ds-D!JSO) δ: 0.9-1.25 (5H, m), 1.45-1
．． 75(5)l.

m), 2.15-2.35 (4ft, m), 2.
60 (2H, t.

J=6.6Hz), 3.76 (2)l, t,
J=6.6)1z), 6.84(2H,br-s)
, 7.07(IH,t, J=7.71(z).

7.10 (IH, d, J=7.7tlz), 7.4
1 (LH, t, J=7.7Hz), 8.09 (lt
l, d, J=7.7Hz), 10.21(LH,
s) Example 49 The following compound was produced in substantially the same manner as in Example 1 using 1-(2-(N-methylbenzylamino)ethylquisatin and semicarbazide hydrochloride.

Melting point: 175-178℃ (ethanol-water) yield
Rate: 57.9% Elemental analysis value: (as CI91121NSO2) 0
% 8% N% Calculated value 64.94 6.02 19.93 Actual value 64.91 6.01 19.63IR
(KBr): ν) Il+ 3380. 330
0. 3170 cm-'ν. . 1680 cm-
'NMR (d8-DMS'O) δ: 2.23 (3fl, s>, 2.55 (2H,
t, J=6.0Hz).

3,49 (2H,s), 3.86 (2H,t,
J=6.0Hz>.

6.86 (2H, br-s), 6.99 (1N,
d, J=7.7)1z), 7.05-7.
2(6)1. m), 7.34(1)1.
t.

J=7.7Hz), 8.11(ltl, d, J・
7.7Hz).

10, 25 (LH,s) Example 50 The following compound was prepared in substantially the same manner as in Example 1 using 1-[2-(1,2,3,4-tetrahydro-2-isoquinolyl)ethylcoisatin and semicarbazide hydrochloride. was manufactured.

Melting point: 176-179℃ (ethanol) Yield
: 72.5% Elemental analysis value' (as C20H21NSO2) 0%
8% N% Calculated value 66.10 5.82 19.27 Actual value 66.01 5.77 19.08IR
(KBr>+ νNil 3400.3300.
3180 cm-'νCo 1685 Cm-' NMR (d, -DMSO) δ: 2.65-2.8 (6H, m), 3.63 (2
H, s), 3.95 (2H, t, J=6.6Hz)
, 6.85 (2L br-s).

6.95-7.15 (5H, m), 7.19 (LH
, d, J=7.7)1z), 7.42(1)1
．． t, J=7.7Hz), 8.09(LH
.

Claims (19)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (R in the formula is a halogen atom, 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 are the same or different; may also be 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 where R^2 and R^3 may have a substituent together with a nitrogen atom. , a piperidino group, a piperazinyl group or a tetrahydroisoquinolyl group) and acid addition salts thereof. (2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (R in the formula is a halogen atom, 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 are the same or different; isatin derivatives according to claim 1, which are hydrogen atoms, linear alkyl groups having 1 to 5 carbon atoms, lower alkenyl groups, aralkyl groups, or cycloalkyl groups, and their acids. Added salt. (3) R^4 and R^5 may be the same or different, and are a linear alkyl group having 1 to 5 carbon atoms or a linear alkyl group having 3 to 5 carbon atoms.
6 cycloalkyl group, provided that when R^4 and R^5 are both linear alkyl groups, at least one of them has 3 or more carbon atoms, and the isatin derivatives according to claim 2, and those Acid addition salts of. (4) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (R in the formula is a halogen atom, 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, ▲There are mathematical formulas, chemical formulas, tables, etc.▼
isatin derivatives and acid addition salts thereof according to claim 1, wherein isatin derivatives are represented by pyrrolidinyl group, piperidino group, piperazinyl group or tetrahydroisoquinolyl group which may have a substituent. (5) General formula▲ Numerical formula, chemical formula, table, etc.▼ (R in the formula is a halogen atom, 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, and Y is a linear or branched alkylene group having 2 to 4 carbon atoms. The described isatin derivatives and acid addition salts thereof. (6) The isatin derivative and acid addition salt thereof according to claim 3, which are represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼. (7) The isatin derivative and acid addition salt thereof according to claim 3, which are represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼. (8) The isatin derivative and acid addition salt thereof according to claim 3, represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. (9) The isatin derivative and its acid addition salt according to claim 3, which are represented by the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼. (10) The isatin derivative and acid addition salt thereof according to claim 3, represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. (11) The isatin derivative and its acid addition salt according to claim 3, which are represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. (12) The isatin derivative and acid addition salt thereof according to claim 5, represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. (13) The isatin derivative and acid addition salt thereof according to claim 5, represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. (14) The isatin derivative and acid addition salt thereof according to claim 5, represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. (15) The isatin derivative and its acid addition salt according to claim 5, which are represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. (16) The isatin derivative and acid addition salt thereof according to claim 5, represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. (17) The isatin derivative and acid addition salt thereof according to claim 5, represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. (18) The isatin derivative and acid addition salt thereof according to claim 5, represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. (19) The isatin derivative and acid addition salt thereof according to claim 5, represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼.