JPH0670036B2 - 4H-quinolidin-4-one derivative - Google Patents

Description

TECHNICAL FIELD OF THE INVENTION The present invention has an inhibitory action on immunoglobulin E (hereinafter referred to as IgE) antibody production, and diseases caused by IgE, such as certain bronchial asthma, rhinitis, dermatitis, and hypersensitivity. The present invention relates to a novel 4H-quinolizin-4-one derivative useful as a therapeutic agent for diseases and the like.

2. Description of the Related Art Immunoglobulin (hereinafter referred to as Ig) is well known as a protein that controls the immune response of the living body. Recently, it is one of this immunoglobulin class. Since it was revealed that IgE is the causative agent of various diseases such as bronchial asthma, rhinitis, dermatitis, and hypersensitivity, compounds that suppress IgE antibody production have been used as causative therapeutic agents for those diseases. Its appearance is expected as being useful as a therapeutic agent.

So far, several compounds have been found and reported as compounds that suppress IgE antibody production. However, all of them were administered before or during immunization or immediately after immunization, and only an inhibitory effect on IgE antibody production during the immune response induction period was observed. Has not been confirmed [Japanese Patent Publication No. 54-130516, No. 62-76, etc.].

The 4H-quinolizin-4-one derivative of the present invention has the general formula A compound represented by the formula (R in the formula is a methyl group or an ethyl group) is already known (Pharmaceutical Journal, Vol. 89, No. 2,
203-208, 1969). However, these compounds are merely synthesized from synthetic interests, and their pharmacological actions are not disclosed at all.

Also, the formula It has been reported that the compound represented by the formula (1) shows antitumor activity, but no other action, particularly the action of suppressing IgE antibody production is disclosed (Pharmaceutical Journal, Vol. 97, No. 9, 1039-).
1045, 1977).

Furthermore, the general formula (In the formula, R ¹¹ is a carboxy group, amidated carboxy group, cyano group, thiocarbamoyl group or tetrazolyl group, R ¹⁷ is hydrogen or an aryl group, R ¹² is hydrogen, a hydroxy group, a lower alkyl group or a lower alkoxy group. , R ¹³
Is hydrogen, hydroxy group, lower alkyl group, lower alkoxy group, lower alkenyloxy group, optionally substituted aryl group, arylthio group, aroyl group,
Ar (lower) alkyl group, arenesulfonyl group, arylamino group which may have an appropriate substituent or aryloxy group, respectively, and R ¹² and R ¹³ may be located at any position of the quinolidinone ring. And bonded to each other, -CH ₂ CH ₂ CH _2- , -CH = CH- or -CH = CH
-CH = CH- can be formed), but it is reported that the compound has a suppressive effect on a water immersion restraint stress ulcer experiment using rats and a passive cutaneous anaphylactic reaction, respectively. No effect on IgE antibody production is disclosed (Japanese Patent Publication No. Sho 60-222482).

Problems to be Solved by the Invention It has been confirmed in animal experiments that IgE induces its production by antigen sensitization under certain conditions, and that its production continues for a long period of time thereafter [immunology (Immunolog
y), vol. 21, pp. 11-15, 1971].

It has been reported clinically that in patients with diseases such as bronchial asthma, continuous production of IgE antibody against a specific antigen is observed in many cases.

Therefore, the IgE antibody production inhibitor used for the treatment of diseases caused by IgE is not limited to IgE antibody production in the immune response induction period,
It should suppress the subsequent persistent IgE antibody production.

In addition, there are various globulins in addition to IgE in the immunoglobulin class, and most of these play an important role in biological protection. For example, immunoglobulin G, which is the most abundant immunoglobulin produced,
It is well known that (IgG) plays an important role in infection control.

When suppressing IgE antibody production, it is also necessary not to affect the antibody production of such other immunoglobulins.

Since the IgE antibody was revealed to be an antibody that induces certain types of bronchial asthma, rhinitis, dermatitis, hypersensitivity, etc.
Although many studies have been conducted on antibody production inhibitors, all compounds that have been reported to suppress IgE antibody production until now are administered before, during or immediately after immunization, and the IgE antibody in the immune response induction period is used. It has only been confirmed that production is suppressed, but no effect on persistent IgE antibody production has been confirmed. In addition, most of them have low selectivity between the action on IgE antibody production and the action on other IgE antibody production.

The purpose of the present invention, unlike conventional IgE antibody production inhibitors, does not significantly affect the production of IgG antibodies and the like which are important for protection against infection, etc., and still selectively acts on persistent IgE antibody production. Another object of the present invention is to provide a novel 4H-quinolizin-4-one derivative having a strong IgE antibody production inhibitory action and useful as a therapeutic agent for various diseases caused by IgE.

Means for Solving the Problems The present inventors have a selective IgE antibody production inhibitory action, and as a result of repeated studies to find a compound useful as a therapeutic agent for diseases caused by IgE, a certain 4H- The inventors have found that good results were obtained with the quinolidin-4-one derivative, and that the object could be achieved, and completed the present invention.

That is, the present invention has the general formula (Wherein R ¹ is a halogen atom, a hydroxyl group, a lower alkoxy group or a lower alkyl group which may have a cycloalkyl, a lower alkenyl group or a lower alkynyl group,
R ² is a lower alkyl group, a lower alkenyl group or an aralkyl group. Provided that R ¹ is a methyl group or an ethyl group and R ² is a methyl group) 4H
A quinolidin-4-one derivative.

In the present invention, the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, and the lower alkenyl group means a linear or branched alkenyl group having 3 to 6 carbon atoms, a lower alkynyl group. Means a linear or branched alkynyl group having 3 to 6 carbon atoms, respectively.

The aralkyl group means an aromatic hydrocarbon group which may have an appropriate substituent on the ring, for example, a lower alkyl group having a phenyl group, a naphthyl group and the like.

Further, the halogen atom means chlorine, bromine, iodine and fluorine, and the cycloalkyl group means a monocyclic or polycyclic alicyclic group having 3 to 10 carbon atoms.

The compound represented by formula (I) of the present invention is a novel compound and can be produced by the following method.
That is, the general formula (Wherein R ¹ has the same meaning as described above), and a 2-pyridyl acetic acid ester derivative represented by the general formula It can be produced by reacting with a compound represented by the formula (R ² in the formula has the same meaning as described above).

The compound of the general formula (II) used as a starting material in the production method of the present invention includes a part of a novel compound, but 2-pyridylacetic acid and the general formula R ¹ -OH (IV) (wherein R ² is It has the same meaning as above), and can be produced by reacting it according to a conventional method [Compendium of Organic Synthetic Method (Compendium of Or
ganic Synthetic Methods; Ed. by ITHarrison and SH
arrison, Wiley-Interscience New York) Volume 1, 272-
279, 1971].

In addition, the general formula (II
The compound of I) is cyanoacetic acid methyl ester, hydrogen sulfide and a compound represented by the general formula R ² -X (V) (wherein R ² has the same meaning as described above and X is an acid residue). It can be used according to the method described in the literature or a method similar thereto [Hemisch Berichte (Chem. Ber.) 95, 2861 to 2870, 1
962].

The production method of the present invention is a known method, and can be easily performed according to the method described in the literature (Pharmaceutical Journal, 89
Vol. 2, No. 203-208, 1969).

In order to suitably carry out the production method of the present invention, the compound of the general (II) and the compound of the general formula (III) equimolar thereto are mixed with an inert organic solvent or without a solvent at 100 to 120 ° C. for 2 to 2 It is heated for 10 hours, treated and purified according to a conventional method to obtain the desired product.

The compounds of general formula (I) of the present invention are applicable to dinitrophenylated alkaline proteins (DNP-As).
Secondary response (adoptive secondary respo
nse) showing BALB / c mouse splenocytes,
In vitro Ig production measurement test [Cellular Immunology, Volume 58, 188-
201, 1981] shows a remarkable suppression of IgE antibody production.

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

The dose or therapeutically effective amount of the compound of the general formula (I) of the present invention varies depending on the age, sex, degree of disease and treatment condition of the target patient, but when used for treatment of humans or animals, The daily dose is approximately 0.1 for oral administration.
-10 mg / kg, and for parenteral administration, it is generally 0.02-5 mg / kg.

EFFECT OF THE INVENTION 4H-quinolizine-4-represented by the general formula (I) of the present invention
On-derivative is an adaptive secondary respo for DNP-As
In the Ig production measurement test using splenocytes of BALB / c mouse showing nse, it shows about 40 to 80% suppression of IgE antibody production at a concentration of 10 ^-8 to 10 ^-5 g / ml. .

EXAMPLES The contents of the present invention will be described in more detail with reference to the following reference examples and examples. The melting points of the compounds in Reference Examples and Examples are all uncorrected.

Reference Example 1 cyclohexylmethyl 2-pyridyl acetate 2-pyridyl acetic acid / hydrochloride (422 mg) and cyclohexylmethanol (596 μl) in a dry pyridine (5 ml) solution
3-dicyclohexylcarbodiimide (651 mg) was added,
Stir at room temperature for 10 hours. After filtering off the precipitated crystals, the solvent is distilled off under reduced pressure. The residue is dissolved in 1N hydrochloric acid (20 ml), this solution is washed twice with diethyl ether (25 ml), and 2N caustic soda aqueous solution is added to adjust the pH to 11.
The precipitated oily substance was extracted with methylene chloride (50 ml), the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to give cyclohexylmethyl 2-pyridyl acetate (525 m
g) is obtained as an oil.

NMR (CDCl ₃ ) δ: 0.85 to 1.80 (m, 11H), 3.85 (s, 2H), 3.93 (d, 2H),
7.19 (dd, 1H), 7.29 (d, 1H), 7.66 (dt, 1H), 8.56 (d, 1
H) Reference Example 2 In the same manner as in Reference Example 1, the following compound is obtained.

(1) Cyclopropylmethyl 2-pyridyl acetate NMR (CDCl ₃ ) δ: 0.29 (m, 2H), 0.55 (m, 2H), 1.13 (m, 1H), 3.88 (s,
2H), 3.96 (d, 2H), 7.21 (dd, 1H), 7.32 (d, 1H), 7.67
(Dt, 1H), 8.56 ( d, 1H) (2) 2 ', 2', 2'- trichloroethyl 2-pyridyl acetate _{NMR (CDCl 3) δ: 4.00} (s, 2H), 4.79 (s, 2H ), 7.22 (dd, 1H), 7.34
(D, 1H), 7.68 (dt, 1H), 8.58 (d, 1H) (3) Isopentyl 2-pyridyl acetate NMR (CDCl ₃ ) δ: 0.89 (d, 6H), 1.51 (q, 2H), 1.63 (M, 1H), 3.84 (s,
2H), 4.16 (t, 2H), 7.18 (dd, 1H), 7.29 (d, 1H), 7.65
(Dt, 1H), 8.56 (d, 1H) (4) 2′-propynyl 2-pyridyl acetate NMR (CDCl ₃ ) δ: 2.47 (t, 1H), 3.91 (s, 2H), 4.74 (d, 2H) ), 7.20 (d
d, 1H), 7.31 (d, 1H), 7.68 (dt, 1H), 8.57 (d, 1H) (5) 2'-propenyl 2-pyridylacetate NMR (CDCl ₃ ) δ: 3.88 (s, 2H) , 4.63 (m, 2H), 5.20 ~ 5.34 (m, 2H), 5.
85 ~ 6.00 (m, 1H), 7.21 (dd, 1H), 7.30 (d, 1H), 7.66
(Dt, 1H), 8.57 (d, 1H) (6) 3′-cyclohexylpropyl 2-pyridylacetate NMR (CDCl ₃ ) δ: 0.75 to 2.75 (m, 15H), 3.84 (s, 2H), 4.11 ( t, 2H),
7.19 (dd, 1H), 7.30 (d, 1H), 7.64 (dt, 1H), 8.56 (d, 1
H) Reference Example 3 Isopropyl 2-pyridylacetate 2-pyridylacetic acid hydrochloride (355 mg) in 2-propanol (5 ml) was poured into a solution of hydrogen chloride under ice cooling until saturated, and then stirred at room temperature for 10 hours. . The reaction mixture is made basic with sodium hydrogen carbonate and extracted with diethyl ether (50 ml). The ether layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give isopropyl 2-pyridyl acetate (305 mg) as an oil.

NMR (CDCl ₃ ) δ: 1.24 (d, 6H), 3.82 (s, 2H), 5.06 (m, 1H), 7.19 (d
t, 1H), 7.30 (d, 1H), 7.66 (dt, 1H), 8.56 (d, 1H) Reference Example 4 In the same manner as in Reference Example 3, the following compound is obtained.

(1) Propyl 2-pyridyl acetate NMR (CDCl ₃ ) δ: 0.90 (t, 3H), 1.65 (m, 2H), 3.86 (s, 2H), 4.09 (t,
2H), 7.19 (dt, 1H), 7.30 (d, 1H), 7.66 (dt, 1H), 8.56
(D, 1H) (2) Butyl 2-pyridyl acetate NMR (CDCl ₃ ) δ: 0.90 (t, 3H), 1.34 (m, 2H), 1.63 (m, 2H), 3.85 (s,
2H), 4.13 (t, 2H), 7.19 (dd, 1H), 7.30 (d, 1H), 7.66
(Dt, 1H), 8.56 ( d, 1H) (3) 1'- methylpropyl pyridylmethyl acetate _{NMR (CDCl 3) δ: 0.85} (t, 3H), 1.21 (d, 3H), 1.43~1.70 ( m, 2H), 3.
84 (s, 2H), 4.90 (m, 1H), 7.20 (dd, 1H), 7.31 (d, 1
H), 7.67 (dt, 1H), 8.55 (d, 1H) Reference Example 5 Methyl 2-cyano-3,3-dimethylthioacrylate Methyl cyanoacetate 9.0 ml sodium methoxide (Na 4.20 g and 53 ml anhydrous) Synthesized from methanol) and carbon disulfide (5.3 ml) are gradually added dropwise while keeping the temperature below 18 ° C. After completion of dropping, the mixture is stirred under ice cooling for 30 minutes, dimethylsulfate (16.5 ml) is added over 30 minutes, and the mixture is stirred at room temperature for 1 hour. 125 ml of water was added to the reaction solution, and the precipitated crystals were collected by filtration and recrystallized from methanol to give methyl 2-
Cyano-3,3-dimethylthioacrylate (13.0 g) is obtained.

Melting point: 85-86 ° C NMR (CDCl ₃ ) δ: 2.61 (s, 3H), 2.78 (s, 3H), 3.84 (s, 3H) Reference Example 6 The following compound was obtained in the same manner as in Reference Example 5.

(1) Methyl 2-cyano-3,3-dibenzylthioacrylate Melting point: 98 to 99 ° C NMR (CDCl ₃ ) δ: 3.83 (s, 3H), 4.21 (s, 2H), 4.83 (s, 2H) , 7.20 ~ 7.
40 (m, 10H) (2 ) Methyl 2-cyano-3,3-dibutyl acrylate _{NMR (CDCl 3) δ: 0.94} (t, 6H), 1.46 (m, 4H), 1.69 (m, 4H), 3.13 (t,
2H), 3.23 (t, 2H), 3.83 (s, 3H) (3) Methyl 2-cyano-3,3-diisopropylthioacrylate NMR (CDCl ₃ ) δ: 1.39 (d, 12H), 3.83 (s, 3H), 3.85 to 4.05 (m, 2H) (4) Methyl 2-cyano-3,3-dimethallylthioacrylate NMR (CDCl ₃ ) δ: 1.81 (brs, 6H), 3.51 (q, 4H), 3.84 (S, 3H), 4.90 ~
5.16 (m, 4H) Example 1 Cyclohexylmethyl 3-cyano-2-methylthio-
4H-quinolizin-4-one-1-carboxylate cyclohexylmethyl 2-pyridyl acetate (500m
A mixture of g) and methyl 2-cyano-3,3-dimethylthioacrylate (436 mg) is heated at 120 ° C for 10 hours. This mixture was subjected to silica gel column chromatography,
Elution with methylene chloride and diethyl ether (1: 1) gave cyclohexylmethyl 3-cyano-2-methylthio-4H-quinolidin-4-one-1-carboxylate (460 mg) as pale yellow crystals.

Melting point: 130 to 133 ° C IR (KBr): 2210, 1705, 1665, 1620 cm ^-1 NMR (CDCl ₃ ) δ: 1.00 to 1.85 (m, 11H), 2.74 (s, 3H), 4.21 (d, 2H),
7.29 (m, 1H), 7.77 (m, 2H), 9.26 (d, 1H) Elemental analysis value: (as C ₁₉ H ₂₀ N ₂ O ₃ S) C% H% N% Calculated value 64.02 5.66 7.86 Measured value 64.09 5.70 7.15 Example 2 In the same manner as in Example 1, the following compound is obtained.

(1) Cyclopropylmethyl 3-cyano-2-methylthio-4H-quinolidin-4-one-1-carboxylate Melting point: 148 to 149 ° C IR (KBr): 2225,1720,1660,1620cm ^-1 NMR (CDCl ₃ ) Δ: 0.40 (m, 2H), 0.67 (m, 2H), 1.29 (m, 1H), 2.76 (s,
3H), 4.25 (d, 2H), 7.30 (m, 1H), 7.74 to 7.88 (m, 2H),
9.27 (d, 1H) Elemental analysis value: (as C ₁₆ H ₁₄ N ₂ O ₃ S) C% H% N% Calculated value 61.13 4.49 8.91 Found value 60.68 4.63 8.64 (2) 3'-Cyclohexylpropyl 3-cyano- Two
-Methylthio-4H-quinolidin-4-one-1-carboxylate Melting point: 82-83 ° C IR (KBr): 2205,1700,1662,1620cm ^-1 NMR (CDCl ₃ ) δ: 0.80-1.86 (m, 15H) , 2.75 (s, 3H), 4.38 (t, 2H),
7.30 (m, 1H), 7.77 (m, 2H), 9.26 (d, 1H) Elemental analysis value: (as C ₂₁ H ₂₄ N ₂ O ₃ S) C% H% N% Calculated value 65.60 6.29 7.29 Measured value 65.42 6.30 7.02 (3) 2 ', 2', 2'-trichloroethyl 3-cyano-
2-Methylthio-4H-quinolidin-4-one-1-carboxylate Melting point: 138-140 ° C IR (KBr): 2205,1730,1675,1625cm ^-1 NMR (CDCl ₃ ) δ: 2.77 (s, 3H), 5.06 (s, 2H), 7.33 (m, 1H), 7.83 (m,
1H), 7.93 (d, 1H), 9,30 (d, 1H) Elemental analysis value: (as C ₁₄ H ₉ O ₃ N ₂ SCl ₃ ) C% H% N% Calculated value 42.93 2.32 7.15 Measured value 42.82 2.42 7.25 (4) 2'-propenyl 3-cyano-2-methylthio-4H-quinolidin-4-one-1-carboxylate Melting point: 70 to 72 ° C IR (KBr): 2210,1700,1660,1615cm ^-1 NMR ( CDCl ₃ ) δ: 2.75 (s, 3H), 4.91 (dt, 2H), 5.36 (dd, 1H), 5.47
(M, 1H), 6.0 to 6.15 (m, 1H), 7.30 (m, 1H), 7,80 (m, 2
H), 9.27 (d, 1H) Elemental analysis value: (as C ₁₅ H ₁₂ N ₂ O ₃ S) C% H% N% Calculated value 59.99 4.03 9.33 Measured value 59.92 4.04 9.04 (5) 2'-propynyl 3- Cyano-2-methylthio-4H-quinolidin-4-one-1-carboxylate Melting point: 153-155 ° C IR (KBr): 2225,1715,1660,1620cm ^-1 NMR (CDCl ₃ ) δ: 2.60 (t, 1H ), 2.76 (s, 3H), 5.00 (d, 2H), 7.32 (m,
1H), 7.81 (m, 2H), 9.27 (d, 1H) Elemental analysis value: (as C ₁₅ H ₁₀ N ₂ O ₃ S) C% H% N% Calculated value 60.39 3.38 9.39 Measured value 60.01 3.31 9.02 (6 ) Propyl 3-cyano-2-methylthio-4H-quinolidin-4-one-1-carboxylate Melting point: 71.5 to 72.5 ° C IR (KBr): 2210, 1710, 1665, 1620 cm ^-1 NMR (CDCl ₃ ) δ: 1.04 (T, 3H), 1.83 (m, 2H), 2.75 (s, 3H), 4.37 (t,
2H), 7.30 (m, 1H), 7.79 (m, 2H), 9.26 (d, 1H) Elemental analysis value: (as C ₁₅ H ₁₄ N ₂ O ₃ S) C% H% N% Calculated value 59.59 4.67 9.27 Found 59.37 4.74 9.01 (7) Isopropyl 3-cyano-2-methylthio-4H
-Quinolidin-4-one-1-carboxylate Melting point: 126.5 to 128 ° C IR (KBr): 2210,1700,1660,1615cm ^-1 NMR (CDCl ₃ ) δ: 1.43 (d, 6H), 2.75 (s, 3H ), 5.35 (m, 1H), 7.29 (m,
1H), 7.75 (m, 2H), 9.25 (d, 1H) Elemental analysis value: (as C ₁₅ H ₁₄ N ₂ O ₃ S) C% H% N% Calculated value 59.59 4.67 9.27 Measured value 59.56 4.60 8.75 (8 ) Butyl 3-cyano-2-methylthio-4H-quinolidin-4-one-1-carboxylate Melting point: 67 to 68 ° C IR (KBr): 2220,1700,1660,1615cm ^-1 NMR (CDCl ₃ ) δ: 0.98 (T, 3H), 1.48 (m, 2H), 1.77 (m, 2H), 2.75 (s,
3H), 4.41 (t, 2H), 7.30 (m, 1H), 7.78 (m, 2H), 9.26
(D, 1H) Elemental analysis value: (as C ₁₆ H ₁₆ N ₂ O ₃ S) C% H% N% Calculated value 60.74 5.10 8.85 Measured value 60.92 5.05 8.36 (9) 1'-Methylpropyl 3-cyano-2 -Methylthio-4H-quinolidin-4-one-1-carboxylate Melting point: 75-76 ° C IR (KBr): 2210,1710,1660,1615cm ^-1 NMR (CDCl ₃ ) δ: 0.98 (t, 3H), 1.43 (D, 3H), 1.76 (m, 2H), 2.75 (s,
3H), 5.19 (m, 1H), 7.30 (m, 1H), 7.74 (m, 2H), 9.26
(D, 1H) Elemental analysis value: (as C ₁₆ H ₁₆ N ₂ O ₃ S) C% H% N% Calculated value 60.74 5.10 8.85 Measured value 60.93 5.05 8.12 (10) Isopentyl 3-cyano-2-methylthio-4H
-Quinolidin-4-one-1-carboxylate Melting point: 65 to 67 ° C IR (KBr): 2210, 1695, 1655, 1615 cm ^-1 NMR (CDCl ₃ ) δ: 0.98 (d, 6H), 1.68 (m, 2H ), 1.78 (m, 1H), 2.75 (s,
3H), 4.44 (t, 2H), 7.30 (m, 1H), 7.78 (m, 2H), 9.25
(D, IH) Elemental _{analysis: (C 17 H 18 N 2} O 3 S as) C% H% N% Calculated 61.80 5.49 8.48 Found 61.74 5.44 8.19 (11) Ethyl 3-cyano-2-methylthio--4H -Quinolidin-4-one-1-carboxylate Melting point: 90 to 92 ° C IR (KBr): 2210,1720,1670,1620cm ^-1 NMR (CDCl ₃ ) δ: 1.44 (t, 3H), 1.81 (brs, 3H ), 3.87 (brs, 2H), 4.48
(Q, 2H), 4.81 (m, 1H), 4.91 (m, 1H), 7.31 (m, 1H), 7.
76 (m, 2H), 9.27 (d, 1H) Elemental analysis value: (as C ₁₇ H ₁₆ N ₂ O ₃ S) C% H% N% Calculated value 62.19 4.91 8.53 Measured value 62.30 5.12 8.49 (12) Ethyl 3 -Cyano-2-isopropylthio-4H
-Quinolidin-4-one-1-carboxylate Melting point: 103 to 105 ° C IR (KBr): 2210,1720,1660,1620cm ^-1 NMR (CDCl ₃ ) δ: 1.34 (d, 6H), 1.44 (t, 3H ), 4.06 (m, 1H), 4.80 (q,
2H), 7.32 (m, 1H), 7.70 to 7.85 (m, 2H), 9.28 (d, 1H) Elemental analysis value: (as C ₁₆ H ₁₆ N ₂ O ₃ S) C% H% N% Calculated value 60.75 5.10 8.86 Found 60.70 5.12 8.83 (13) ethyl 3-cyano-2-butylthio -4H- quinolizin-4-one-1-carboxylate mp: 58~61 ℃ IR (KBr): 2225,1715,1660,1620cm - ¹ NMR (CDCl ₃ ) δ: 0.90 (t, 3H), 1.43 (m, 5H), 1.59 (m, 2H), 3.25 (t,
2H), 4.48 (q, 2H), 7.31 (m, 1H), 7.75 (m, 2H), 9.26
(D, 1H) Elemental analysis value: (as C ₁₇ H ₁₈ N ₂ O ₃ S) C% H% N% Calculated value 61.81 5.49 8.48 Measured value 61.75 5.53 8.42 (14) Ethyl 3-cyano-2-benzylthio-4H -Quinolidin-4-one-1-carboxylate Melting point: 143-144 ° C IR (KBr): 2215,1720,1670,1620cm ^-1 NMR (CDCl ₃ ) δ: 1.40 (t, 3H), 4.44 (q, 2H ), 4.45 (brs, 2H), 7.18 ~
7.39 (m, 6H), 7.75 (m, 2H), 9.26 (d, 1H) Elemental analysis value: (as C ₂₀ H ₁₆ N ₂ O ₃ S) C% H% N% Calculated value 65.60 6.29 7.29 Measured value 65.42 6.30 7.02

Claims (6)

[Claims] 1. A general formula (In the formula, R ¹ is a halogen atom, a hydroxyl group, a lower alkoxy group or a lower alkyl group which may have a cycloalkyl group, a lower alkenyl group or a lower alkynyl group, and R ² is a lower alkyl group, a lower alkenyl group or an aralkyl group. A group, provided that R ¹ is a methyl group or an ethyl group, and R ² is a methyl group). 2. General formula (R ³ in the formula is a lower alkyl group having 3 or more carbon atoms, a lower alkenyl group or a lower alkynyl group, or a lower alkyl group having at least one halogen atom, a hydroxyl group, a lower alkoxy group or a cycloalkyl group. Wherein R ⁴ is a lower alkyl group), and the 4H-quinolizin-4-one derivative according to claim 1. 3. A formula The 4H-quinolizin-4-one derivative according to claim 2, which is represented by 4. A formula The 4H-quinolizin-4-one derivative according to claim 2, which is represented by 5. A formula The 4H-quinolizin-4-one derivative according to claim 2, which is represented by 6. A formula The 4H-quinolizin-4-one derivative according to claim 2, which is represented by