JPS63198681A - 4h-quinolizin-4-one derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [the group of formula II is (substituted)alicyclic amino; R<1> is lower alkyl or aralkyl; R<2> is H or lower alkyl]. EXAMPLE:3-Cyano-2-methylthio-1-( 4-phenyl-piperidino-carbonyl )-4H-quinolizin-4- one. USE:Medicine. It has an activity to suppress the formation of antibody of immunoglobulin E (IgE) and is useful as a remedy for diseases caused by IgE, e.g. bronchial asthma, rhinitis, dermatitis, anaphylaxis, etc. PREPARATION:The compound of formula I can be produced by reacting 2- pyridylacetic acid with an amine derivative of formula III and reacting the resultant 2-pyridylacetamide derivative of formula IV (including novel compounds) with equimolar amount of a compound of formula V in an inert solvent or in the absence of solvent by heating at 100-120 deg.C for 2-10hr. The compound of formula V can be produced by the reaction of methyl cyanoacetate, CS2 and a compound of formula R<2>-X (X is acid residue).

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention has the effect of suppressing immunoglobulin (hereinafter referred to as gE) antibody production, and is useful for diseases caused by IgB, such as certain types of bronchial asthma, rhinitis, dermatitis, etc. The present invention relates to a novel 4H-quinolidin-4-one derivative useful as a therapeutic agent for hypersensitivity and the like.

BACKGROUND OF THE INVENTION Immunoglobulin (hereinafter referred to as 1g) is well known as a protein that controls the immune response of living organisms. In recent years, it has become clear that IgB, one of the immunoglobulin classes, is the causative agent of various diseases, such as certain types of bronchial asthma, rhinitis, dermatitis, and hypersensitivity. The emergence of compounds that do this is expected to be useful as therapeutic agents for the causation of these diseases.

To date, several compounds have been discovered and reported as compounds that suppress IgB antibody production.

However, when administered before, during, or immediately after immunization, only a suppressive effect on Ig[i antibody production during the immune response induction period has been observed; The effect has not been confirmed [Japanese Patent Publication No. 1983-130]
No. 516, Kaimei No. 62-76, etc.].

As the 4H-quinolidin-4-one derivatives of the present invention, compounds represented by the general formula (R in the formula is a methyl group or an ethyl group) are already known (Pharmaceutical Journal, Vol. 89, 2 No. 203-208, 1969). However, these compounds were synthesized solely for synthetic interest, and their pharmacological actions have not been fully disclosed.

Furthermore, although it has been reported that the compound represented by the formula exhibits antitumor activity, there is no disclosure of other effects, especially [gB antibody production suppressing effect (Pharmaceutical Journal Vol. 97, No. 9, No. 1).
039-1045, 1977).

Further, the general formula (wherein R11 is a carboxy group, amidated carboxy group, cyan group, thiocarbamoyl group, or tetrazolyl group, R17 is hydrogen or an aryl group, R12 is hydrogen, a hydroxy group, a lower alkyl group, or a lower alkoxy group, RI3 is hydrogen, a hydroxy group, a lower alkyl group, a lower alkoxy group, a lower alkenyloxy group, an aryl group which may have an appropriate substituent, an arylthio group, an aroyl group, an ar(lower) alkyl group, an arene. Each represents a sulfonyl group, an arylamino group which may have an appropriate substituent, or an aryloxy group, and R12 and R13 can be located at any position on the quinolidinone ring, and are bonded to each other, and - C) 12CLC
) I2-, -C11"CH- or -C') I-Cll
It has been reported that the compound represented by -C1 (capable of forming =C)l- has inhibitory effects on water immersion restraint stress ulcer experiments and passive cutaneous anaphylactic reactions in rats. However, the effect on IgE antibody production is not disclosed at all (Japanese Patent Publication No. 60-222482).

Problems to be Solved by the Invention It has been confirmed in animal experiments that the production of IgB is induced by antigen sensitization under certain conditions, and that the production continues for a long period of time.
21, pages 11-15, 1971
Year〕.

Clinically, it has been reported that patients with diseases such as bronchial asthma often exhibit sustained production of IgE antibodies against specific antigens.

Therefore, an IgB antibody production inhibitor used in the treatment of IgE-induced diseases must suppress not only rgB antibody production during the immune response induction period, but also subsequent sustained IgE antibody production.

In addition to 1g8, there are various other globulins in the immunoglobulin class, and most of these play an important role in biological defense.

For example, it is well known that immunoglobulin G (IgG), which is produced in the largest amount among immunoglobulins, plays an important role in preventing infection.

When suppressing Ig[, antibody production], it is also necessary that antibody production of such other immunoglobulins is not affected.

Since it was revealed that IgB antibodies cause certain types of bronchial asthma, rhinitis, dermatitis, hypersensitivity, etc.
Many studies have been conducted on gB antibody production inhibitors, but all compounds that have been reported to suppress IgB antibody production have been administered before, during, or immediately after immunization to suppress IgB antibody production during the immune response induction period. It has only been confirmed that it suppresses antibody production, but no effect on sustained IgE antibody production has been confirmed. In addition, most of them have low selectivity between the effect on IgB antibody production and the effect on other Ig antibody production.

The purpose of the present invention is to provide a selective drug that does not significantly affect the production of IgG antibodies, etc., which are important for infection prevention, and that acts on the sustained production of Ig8 antibodies, unlike conventional IgB antibody production inhibitors. It has the effect of suppressing the production of antibodies against Ig.
Novel 4H useful as a therapeutic agent for various diseases caused by B.
- quinolidine-4=one derivatives.

Means for Solving the Problems The present inventors have developed an IgB antibody that has a selective IgB antibody production suppressing effect.
As a result of extensive research to find compounds useful as therapeutic agents for diseases caused by gB, it was discovered that certain 4H-quinolidin-4-one derivatives gave good results and that the objective could be achieved, and the present invention We have achieved this.

That is, the present invention provides a 4H-quinolidin-4-one derivative represented by the general formula: aralkyl group, R2 is a hydrogen atom or a lower alkyl group.

In the present invention, a lower alkyl group means a straight or branched alkyl group having 1 to 6 carbon atoms, and a lower acyloxy group means an acyloxy group having 2 to 6 carbon atoms.

Furthermore, an aryl group refers to an aromatic hydrocarbon group that may have a suitable substituent on the ring, such as a phenyl group or a naphthyl group, and an aralkyl group refers to a lower alkyl group having at least one aryl group. means.

Furthermore, the alicyclic amino group refers to a monocyclic or polycyclic alicyclic amino group, such as a piperidino group, a piperazinyl group, 1.
2.3.4-tetrahydro-2-isoquinolyl group, 1.
2.3. It means a 4-tetrahydro-1-quinolyl group, a perhydro-1-indolyl group, a perhydro-1-quinolyl group, etc.

The compound represented by the general formula (1) of the present invention is a new compound, and can be produced by the following method.

That is, it can be produced by reacting with a compound represented by the general formula (R1 in the formula has the same meaning as above).

General formula (
Although some of the compounds in II) include new compounds, they can be produced by combining 2-pyridylacetic acid with the general formula [Peptite'
(Peptides; Ed, by
B, 5coffone, North-Hol
land Pub, Co,, Amsterdam
), page 17, 1969].

In addition, the general formula (I
For the compound H), methyl cyanoacetate, carbon disulfide, and a compound represented by the general formula % (in which R1 has the same meaning as above and X is an acid residue) were used, and It can be produced according to the method described or a method similar thereto [Chem, Ber, vol. 95, 28
61-2870, 1962].

The production method of the present invention is a known method and can be easily carried out according to the method described in the literature (Pharmaceutical Journal, 89
Vol. 2, pp. 203-208, 1969).

In order to suitably carry out the production method of the present invention, the general formula (II
) and an equimolar amount of the compound of general formula (III) in an inert organic solvent or without a solvent at 100 to 120
The mixture is heated at ℃ for 2 to 10 hours, treated and purified according to conventional methods to obtain the desired product.

The compound of general formula (I) of the present invention has an adaptive secondary response to dinitrophenylated Ascaris protein (DNP-As).
BA showing condary response)
In vitro (in vitro) using tile cells of LB/c mice
1g production measurement test in vitro (Cellular immunology)
, Vol. 53, pp. 188-201, 1981] shows a remarkable IgE antibody production suppressing effect.

When the compound of general formula (I) of the present invention is used for actual treatment, suitable pharmaceutical excipients such as excipients, binders, lubricants, disintegrants, solubilizing agents, stabilizers, etc. are added. Various dosage forms such as powders, tablets, capsules, syrups, and injections are prepared according to conventional methods and administered orally or parenterally.

The dosage or therapeutically effective amount of the compound of general formula (I) of the present invention varies depending on the age, sex, degree of disease, treatment conditions, etc. of the target patient, but when used for the treatment of large animals or animals. In the case of oral administration, the daily dose is approximately 0.
1 to 10 mg/kg, approximately 0.02 in the case of parenteral administration
~5 ll1g/kg.

Effect of the invention 4H-quinolidine-4 represented by general formula (1) of the present invention
-one derivatives are adaptive to DNP-As
B showing secondary response
In an Ig production measurement test using tile cells of ALB/c mice, 10-8 to 10-'g/+++1. At a concentration of about 4
It shows an inhibitory effect on IgB antibody production of about 0 to 80%.

EXAMPLES The content of the present invention will be explained in further detail using the following reference examples and examples. Note that the melting points of the compounds in each Reference Example and Examples are all uncorrected.

Reference Example 1 Dry pyridine solution (5 mL
1,3-dicyclohexylcarbodiimide (61
7) and stirred at room temperature for 14 hours. The precipitated crystals were filtered off, the solvent was distilled off under reduced pressure, and the residue was diluted with 1N hydrochloric acid (20 m
Add N) and dissolve. After washing this hydrochloric acid aqueous solution twice with diethyl ether (25 ml), 2N caustic soda aqueous solution was added to adjust the pH to 11, the precipitated oil was extracted with methylene chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. to obtain 4-phenyl-1-(2-pyridylacetyl)piperidine (590II1 g) as an oil.

NMR (CDCI,) δ: 1.50-1.95 (m, 4H), 2.58
~2.80 (m.

2H), 3.11 (m, LH), 3.98 (s
, 2H), 4.23 (m, IH), 4.7
9 (m, IH), 7.10-7.37 (m.

6)1), 7.39(d, 1)1), 7.6
6(dt, II(), 8.53(d, 1)1
) Reference Example 2 The following compound was obtained in the same manner as in Reference Example 1.

(1) 1-(2-pyridylacetyl)piperidine N
MR, (CDC1,) δ: 1.35-1.65 (m, 6H), 3.48
~3.60 (m.

4)1), 3.93(s, 2)1), 7.16(
dd, 1)1), 7.36(d, 1)1), 7
．． 64(dt, LH), 8.52(d, IH)N
MR (CDCI3) δ: 1.86 (m, LH), 1.90 (s, 3
H), 2.06 (m.

IH), 2.27-2.32 (m, 2H),
3.16 (m.

1ft), 3.33(m, LH>, 3.8
2 (dt, IH), 3.92 (s, 211
), 4.20 (dt, IH), 7.17 (
dd, 1fl).

7.23~7.40<m, 6H), 7.64(
dt, LH).

8.51 (d, IH) (3) 4-benzyl-1-(2-pyridylacetyl)piperidine NMR (CDCI3) δ: 0.88-1.26 (m, 2) 1),
1.57-1.80 (m.

3H), 2.50(d, 2H), 2.51
(m, LH), 2.92 (dt, III)
, 3゜93(s, 2H), 4.06(m,
1ft).

4.61 (in, IH), 7.08-7.36
(+n, 7H).

7.64 (dt, III), 8.53 (d,
LH) NMR (CDC13) δ: L, 47-1.95 (m, 48), 2
．． 37 (s, 3H), 2.71 (m, 2f
t), 3.14 (dt, LH), 3.98
(s, 2H).

4.23 (m, LH), 4.81 (m, I
H), 7.09 (dd.

IH), 7.16-7.35 (m, 6H),
7.47 (d.

1) 1), 8.38 (d, IH) (5) 1
-(2-pyridylacetyl) barhydroindone NMR (CDC13) δ: 1.05-2.40 (m, IIH), 3.4
5-4.12 (m.

3H), 3.82 and 3.90(s, 2H)
, 7.17 (dd.

LH), 7.37 and 7.42 (d, IH)
, 7.64 (t.

LH), 8.51 (d, 11 () (6) 1-(2-pyridylacetyl) perhydroquinolite NMR (CDC13) δ: 1.05-1°85 (m, 13tl), 2.6
1 and 2.98 (dt, IH), 3.84
and 4.02 (m, 18), 3.92 and
3.95 (s and d, 2H), 4.50 a
nd 4.66 (m, IH), 7.16 (dt,
1N), 7.36 (t, 18).

7.64 (dt, 1) 1), 8.52 (m, 18
)(7) 2-(2-pyridylacetyl)-1,2,
3,4-tetrahy NMR (CDC13) δ: 2.75 and 2.86 (t, 2H),
3.84 (m, 2H).

4.01(s, 21(), 4.87(m, 2H)
, 7.03-7.22 (m, 5H), 7.36 (
t, 1N), 7.62 (q, 18).

8.53 (t, LH) NMR (CDCI, ) δ: 1.94 (m, 2) 1), 2.70 (m,
2H), 3.87 (m.

2H), 4.08(s, 2H), 7.05-7.
35 (m, 6H).

7.62(t, III), 8.53(6,11()
(9) 1-biperonyl-4-(2-pyridylacetyl)hyherazine NMR (CDCI, ) δ: 2.2 g (t, 2H), 2.37 (t
, 2H), 3.38 (s.

2) 1), 3.57 (t, 2 days), 3.65 (t
, 2H), 3.93(s, 2H), 5.9
5 (s, 2H), 6.73 (m, 2H).

6.83 (s, IH), 7.18 (dd,
IH), 7.34 (d.

IH), 7.65 (dt, IH), 8.5
1(d, 1) 1) α11-benzyl-4-(2-pyridylacetyl)pipera oligomer N9iR (CDCL) δ: 2.31 (t, 2H), 2.40 (t, 2
H), 3.48 (s.

2H), 3.59(t, 2H), 3.66(t
, 2H), 3.93(s, 2H), 7.17(
dt, IH), 7.22-7.37 (m, 6H
), 7.64 (dt, IH), 8.52 (d,
LH)0υ 1-phenyl-4-(2-pyridylacetyl)piveraeZ NMR (CDC13) δ: 3.04 (t, 2H), 3.12 (t, 2
fl), 3.79 (m.

4H), 3.98 (s, 2H), 6.85-6.
95 (m, 31().

7.16-7.40 (m, 4H), 7.66 (dt
, IH).

8.53(d, IH) Reference Example 3 Methyl 2-cyano-3,3-dimethylthioacrylate methyl cyanoacetate9. Sodium methoxide (synthesized with 4.20 g of Na and 53 ml of anhydrous methanol) and carbon disulfide (5.3 mg) are gradually added dropwise to Omj2 while keeping the temperature below 18°C. After dropping, cool with water for 30 minutes.
After stirring for 1 minute, dimethyl sulfate (16.5d) was added over 30 minutes, and the mixture was stirred at room temperature for 1 hour. 12 parts of water to the reaction solution
5- was added, the precipitated crystals were collected by filtration, and recrystallized from methanol to obtain methyl 2-cyano-3,3-dimethylthioacrylate (13.0 g).

Melting point 2 85-86℃ NMR (CDC1,) δ: 2.6Hs, 3H), 2.78(s, 3H
), 3.84 (s.

Example 1 A mixture of 4-phenyl-1-(2-pyridylacetyl)piperidine (590 mg) and methyl 2-cyano-3,3-dimethylthioacrylate (400 mg) was added to 120 mg of
Heat at ℃ for 10 hours. The reaction mixture was subjected to silica gel column chromatography and eluted with methylene chloride-diethyl ether-methanol (1:1:0.1) to obtain 3-cyano-2-methylthio-1-(4-phenylpiperidinocarbonyl). )-4H-quinolidine-4
-one (250 mg) is obtained as pale yellow crystals.

IR(KBr): 2205.1665.1620
cm -' Elemental analysis value: (as C23H2IN, 02S) 0% 8% N% Calculated value 68.46 5.25 10.41 Actual value 6g, 435.22 10.08 This is a mixture of two isomers. Isomers 1 and 2 were isolated by silica gel column chromatography (elution solvent: methylene chloride-diethyl ether-methanol = 1:1:0.1).
Separate.

Isomer 1 Melting point: 187.5 to 190°C NMR (CD
CI3) δ: 1.40 (m, LH), 1.77 (m, 1
)1), 1.87 (m.

IH), 2.14 (m, IH), 2.78 (s,
3H), 2.83(dt, LH>, 3.00(
dt, IH), 3.30 (dt.

IH), 3.58 (dt, IH), 5.02 (d
t, 11().

7.15-7.35 (m, 6tl), 7.67 (d
, 18), 7.78(dt, 1B>, 9.26
(d, IH) isomer 2 Melting point: 196.5 to 198°C NMR (CD
CI, ) δ: 1.80-2.10 (m, 48), 2.78
(dt, 01).

2.83 (s, 3H), 2.97 (dt, IH)
, 3.15 (dt.

IH), 3.62 (dt, 1N), 5.06 (d
t, IH).

7.20-7.35 (m, 6H), 7.5Hd,
1j (), 7.74 (dt, IH), 9.26 (
d, 18) Example 2 The following compound is obtained in the same manner as in Example 1.

Melting point: 199-200°C IR (KBr): 2210.1660.1615
cm-'NMR (DMSO-d8) δ: 1.35-1.80 (m, 6H), 2.77
(s, ]I), 3.27-3.56 (m, 2H)
, 3.69 (m, IH), 3.95 (m.

IH), 7.67 (t, IH), 7.69 (d,
III), 8.15(dt, III), 9.2
9(d, LH) Elemental analysis value' (CIJ1J30□
S) 0% 8% N% Calculated value 62J6 5.23 12.83 Actual value 62J3 - 5.25 12.58 N-4-
Melting point: 99-103°C IR (KBr): 2210. 1700. 16
70. 1625 cm-'NMR (CDCI3) δ: 1.77 (m, IH), 1.97 (s, 3H),
2.20m.

E), 2.48 (m, IH), 2.64 (
m, 18), 2.79 (s, 3H),
3.28-3.58 (m, 3H), 4.39 (
m.

LH), 7.21-7.44 (m, 6H),
7.47 (d.

LH), 7.67 (dt, 1) 1), 9.
22(d, IH) - Elemental analysis value: (
C25H23N30'4S) 0% 8%
N% Calculated value 65.06 5.02 9.10 Actual value 65.21 5.26 9.314-
On IR (KBr): 2210. 1675. 162
5 cm - 'Elemental analysis value' (CzJzJJzS
) 0% 8% N% Calculated value 69.04 5.55 10.06 Actual value 69.37 5.70 9.74 This is a mixture of two isomers, and silica gel column chromatography (elution solvent: Isomers 1 and 2 are separated using methylene chloride-diethyl ether-methanol (1:1:0.1).

Isomer 1 Melting point: 227-229°C NMR (MSO-d6) δ: 1.56-2.12 (m, 4) 1), 2.6
1(s, 3H), 2.78(s, 3)1), 2
．． 87-3J5 (m, 3H), 3.89 (m.

1.8), 4.85 (m, IH), 7.30-7
．． 48 (m, 5H).

7.66 (t, IH), 8.08 (d, LH),
9J7 (d.

IH) Isomer 2 Melting point: 183-186°C NMR (DMSO-d,) δ: 1.73-2.08 (+m, 4H), 2.5
7 (s, 3H), 2.82 (s, 3H), 2.
87-3.20 (m, 3H), 3.73 (m.

1) 1), 4.86 (m, IH), 7.29~7
．． 47 (m, 5H).

7.63 (t, IH), 8.08 (d, L
H), 9.36 (d.

IH) IR (KBr): 2210. 1665. 16
25 c+++-'elemental analysis value'(C2<H23
(as N30□S) 0% 8% N% Calculated value 69.04 5.55 10.06 Actual value 68.71 5.40 9.65 This is a mixture of two isomers, and silica gel column chromatography ( Elution solvent: methylene chloride-diethyl ether-methanol-1:1:0.1) to separate isomers 1 and 2.

Isomer 1 Melting point: 106-109°C NMR (CDC13) δ: 0.97 (m, IH), 1.28 (m, L
H), 1.65 (m.

IH), 1.73-1.94 (m, 2H), 2.
57 (d.

2) 1), 2.64 (s, 3H), 2.8
3(dt, 1)1), 3.10(dt, I
H), 3.43 (m, IH), 4.84 (
m, 1)I).

7.08~7JO(m, 6)1), 7.57(
d, 1tl), 7.72(dt, LH),
9.23 (d, 1B) isomer 2 Melting point: 147-150°C NMR (CDC13) δ: 1.10-1.94 (m, 5H), 2.62
(d, 2H), 2.79 (s, 3H), 2.7
5-3.00 (m, 2) 1), 3.45 (m.

IH), 4.86 (m, IH), 7.68-7.
34 (m, 6H).

7.43(d, 11(), 7.70(dt, IH
), 9.24 (d.

IH) IR(KBr): 2210.1670.1625
cm-'Elemental analysis value' (C29H25N302S
) 0% 8% N% Calculated value 72.63 5.25 8.76 Actual value 72.58 5.11 8.95 This is a mixture of two isomers, and silica gel column chromatography (elution solvent; Isomers 1 and 2 are separated using methylene chloride-diethyl ether-methanol (1:0.1).

Isomer 1 Melting point: 190-192°C NMR (CDCl2) δ: 1.27 (m, IH), 1.56 (m, L)
H), 1.80 (m.

1tl), 1.93(m, 1N), 2.70~2
．． 95 (m, 3H).

3.48 (m, Itl), 4.40 (d, IH)
, 4.47 (d.

1tl), 4.78(m, IH), 7.18~7
．． 38 (m.

10H), 7.60 (dt, LH), 7.79 (
d, LH>.

8.10 (dt, LH), 9.20 (d, LH)
Isomer 2 Melting point: 108-110°C NMR (CDC13) δ: 1.60-2.00 (m, 4H), 2
．． 80m, LH), 2.95~3.15(m,
2H), 3.60 (m, LH), 4.
46 (d.

LH>, 4.54(d, 1)1), 4.7
8 (m, IH), 7.13-7.40 (m,
10H), 7.55-7.65 (m, 2H)
.

8.06 (dt, LH), 9.19 (d, LH
)IR(KBr): 2210.1670,162
0 cnr'elemental analysis value' (C3oLJ302S
) 0% 8% N% Calculated value 73.00 5.51 B', 5
1 Actual value 72.92 5.32 7.94
This is a mixture of two isomers, and isomers 1 and 2 are separated by silica gel column chromatography (elution solvent: methylene chloride-diethyl ether-methanol = 1:1:0.1).

Isomer 1 Melting point: 138-140t NMR (DMSO-66) δ: 0.85 (+n, IH), 1.20-1.
75(m, 51().

2,73 (t, 2H), 3.33 (m,
21), 4.37 (d.

LH), 4.4Hd, LH), 4.60(
m, LH), 7.12~7.37 (m,
l0H), 7.53-7.67 (m, 2H)
.

8.06 (dt, 18), 9.19 (d,
1) 1) Isomer 2 Melting point: 109-111°C NMR (DMSO-dB) δ: 1.10-1.80 (m, 5H), 2.72
(m, LH), 2.88 (m, 2H), 3.2
0-3.47 (m, 2H), 4.46 (d.

2H), 4.56(m, LH), 7.1:3-
7', 40 (m.

10H), 7.52-7.66 (m, 2H), 8
．． 01(dt.

18), 9.16 (Tun IH) (7) 3-cyano-2-methylthio-1-(perhydroindol-1-ylcarbonyl)-48-quinolidin-4-one JR (KBr): 2205. 1665.162
0 cm-'Elemental analysis value' (CzoHz+N5O
zS) 0% 8% N% Calculated value 65J7 5.76 11.43 Actual value 65.25 5. '71 11.24 This is a mixture of two isomers, and isomers 1 and 2 are separated by silica gel column chromatography (elution solvent: methylene chloride-diethyl ether-methanol = 1:1:0.1). .

Isomer 1 Melting point: 156-158°C NMR (CI) C13) δ: 1.18-2.48 (m, 11) 1), 2.
78 (s, 3) 1).

3, 10 (t, IH), 3.37 (m, IH),
4.34 (m.

It(), 7.26(t, 1ft), 7.54(
d, 1)I), 7.73 (clt, 1N), 9
．． 23(d, IH) isomer 2 Melting point: 144-146°C NMR (CDC1,) δ: 0.90-2.18 (m, 10)l), 2
．． 47<m, 1)1).

2.76(s, 3)1), 3.44(m,
1) 1), 3.78 (m.

2H), 7.26(t, 1)1), 7.62
(d, 1)1), 7.70 (dt, 1)1)
, 9.22(6,1)1)IR(KBr): 22
10.1670.1620 cm-'Elemental analysis value:
(C21H23N302S) 0% 8%
N% Calculated value 66.12 6.08 11. (11
Actual value 66.07 6.13 10.56 Melting point = 209°C TR (KBr): 2200.1670. 162
5 cm-'NMR (CDCI, ) δ: 2.63 and 2.78 (S, 3) 1),
2.70~3.16 (t71°2H), 3.57
and 4.12 (m and t, 2
)1).

4.37. 4.55. 4.88 and 5.
19(d, 2) 1).

6.88~7J3(m, 5)1), 7.54(
m, IH), 7.70 (m, LH),
9.25 (d, IH) elemental analysis value' (C2+t
(as +tNs02S) 0% 8% N% Calculated value 67.18 4.56 11.19 Actual value 67.34 4.50 11.00
Point: 214-215.5℃ IR (KBr):
2210.1670.1630 cm-'NMR (
CDC13) δ: 1.85-2.49 (m, 2H), 2.25
and 2.82 (s.

3H), 2.87 (m, 2H), 3.60
and 4.61 (m.

2H), 6.24-8.26 (m, 7H),
9.30 (d, LH > elemental analysis value' (Ca+
(as LJJ□S) 0% 8% N% Calculated value 67.18 4.56 11.19 Actual value 66.84 4.45 10.56 On Melting point: 198-200°C IR (KBr): 2205. 1670.152
5 cm-'NMR (CDCI3) δ: 2.14 (+y+, LH),
2.52 (m, 2H), 2.66 (m.

1) 1), 2.77 (S, 3H), 3.2
5 (m, IH), 3.36 (m, 1tl),
3.45 (s, 2H), 3.83 (m,
E).

3.97 (m, IH), 5.95 (S, 2
H), 6.74 (t.

2t(), 6.84(s, 1N),
7.28 (dd, 18), 7.53 (d,
1)1), 7.74(dt, 1)1),
9.23 (d, IH) elemental analysis value: (C24
)lzJ4(]<S as)0% 8%
N% Calculated value 62.32 4.79 12.11 Actual value 62.11 4.62 11.82
Point: 149-151°C IR (KBr): 2220. 1680. 16
25 cm-'NMR (C[lCI,) δ: 2.26 (m, IH), 2.54 (m
, 2H), 2.69 (rn.

18), 2.78 (s, 3tl), 3.2
6 (o+, IH), 3.37 (m, 1) 1
), 3.56 (s, 2H), 3.85 (m
, 1tl).

3.97 (m, LH), 7.24-7J7 (m, 6H)
.

7.54 (d, IH), 7.73 (dt,
1 Old, 9.24 (d.

Elemental analysis value: (as C2382□N, 0.S)
0% 8% N% Calculated value 6'6. Ol 5.30 13J9
Actual value 65.98 5.03 13.25 side 3-cyano-2-methylthio-1-4-phenyl-
1-E Melting point = 255-256°C IR (KBr): 2200. 1670. 162
5 cm-'NMR (CDCI, ) δ: 2.79 (s, 3H), 3.00 (m,
LH), 3.21-3.57 (m, 5H), 4.
02 (+n, LH), 4.12 (m, IH).

6.90-6.99 (m, 3H), , 7.26-7
．． 34 (m.

3H), 7.56 (d, IH), 7.75 (dt
, IH), 9.25 (d, III) Elemental analysis value' (as C22H2ON402S)
0% 8% N%

Claims (8)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, -▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ is an alicyclic amino group that may have a substituent, and R^1 is a lower 4H-quinolidin-4-one derivatives represented by the following formula: an alkyl group or an aralkyl group, and R^2 is a hydrogen atom or a lower alkyl group. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 is a lower alkyl group or an aralkyl group, R^2 is a hydrogen atom or a lower alkyl group,
R^3 is a hydrogen atom or a lower acyloxy group, and R
4H-quinolidin-4-one derivative according to claim 1, wherein ^4 is a hydrogen atom, an aryl group, or an aralkyl group. (3) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is a lower alkyl group or an aralkyl group, R^2 is a hydrogen atom or a lower alkyl group,
R^3 is a hydrogen atom or a lower acyloxy group, and R
4H-quinolidin-4-one derivative according to claim 2, wherein ^4 is a hydrogen atom, an aryl group, or an aralkyl group. (4) 4H-quinolidin-4-one derivative according to claim 3, which is represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. (5) 4H-quinolidin-4-one derivative according to claim 3, which is represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. (6) 4H-quinolidin-4-one derivative according to claim 3, which is represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. (7) 4H-quinolidin-4-one derivative according to claim 3, which is represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼. (8) 4H-quinolidin-4-one derivative according to claim 3, which is represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼.