JPH0670042B2 - 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. In recent years, since it has been revealed that IgE, which is one of the immunoglobulin classes, is the causative agent of various diseases such as bronchial asthma, rhinitis, dermatitis, and hypersensitivity, it suppresses IgE antibody production. Compounds are expected to be useful as therapeutic agents for causative therapy of these diseases.

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 were synthesized solely 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. can be, and combined with each _{other, -CH 2 CH 2 CH 2 -} , - CH = CH- or -C
H = CH-CH = CH- can be formed) and it has been reported that it has an inhibitory effect on a water immersion restraint stress ulcer experiment using rats and a passive cutaneous anaphylactic reaction. However, there is no disclosure about the effect on IgE antibody production (Japanese Patent Publication No. 60-222482).

Problems to be solved by the invention IgE is induced by antigen sensitization under certain conditions, and its production is confirmed to be sustained for a long period of time afterwards in animal experiments (Immunology,
21: 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 (hereinafter, referred to as IgG) and the like play an important role in preventing infection.

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 Ig 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 (In the formula, R ¹ is a cycloalkyl group, an aryl group or a lower alkyl group which may have a heterocyclic group, R ² is a lower alkyl group, and R ³ is a hydrogen atom or a lower alkyl group.) The present invention provides a 4H-quinolidin-4-one derivative represented by:

In the present invention, the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, and the cycloalkyl group means a monocyclic or polycyclic alicyclic group having 3 to 10 carbon atoms. To do.

The aryl group means an aromatic hydrocarbon group which may have a suitable substituent on the ring, and the heterocyclic group means a saturated or unsaturated 5- to 7-membered ring having at least one hetero atom. It means a saturated cyclic group.

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 and R ³ have the same meaning as described above), and a compound 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 some novel compounds. An α-picoline derivative represented by the formula (R ³ has the same meaning as described above) and a general formula R ¹ —CN (V) (wherein R ¹ has the same meaning as described above) Can be synthesized according to the method described in the literature or a method similar thereto [Helvetica Himika Actor].
(Helv. Chim. Acta) Vol. 45, pages 729-737, 1962].

In addition, the general formula (II
The compound of I) is methyl cyanoacetate, carbon disulfide and a compound represented by the general formula R ² —X (VI) (wherein R ² has the same meaning as described above and X is an acid residue). It can be produced according to the method described in the literature or a method similar thereto (Hemisch Berichte (Chem. Ber.) 95, 2861 to 2870,
1962].

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 preferably carry out the production method of the present invention, the compound represented by the general formula (II)
The compound of formula (III) and the compound of formula (III) equimolar thereto are heated in an inert organic solvent or without solvent at 100 to 120 ° C. for 2 to 10 hours, treated and purified according to a conventional method to give the desired product. obtain.

The compound of the general formula (I) of the present invention has an adaptive secondary response to dinitrophenylated Ascaris protein (DNP-As).
e) showing the production of IgB in vitro using BALB / c mouse splenocytes (Cellular Immunology, 58, 188-201, 1981) Shows a remarkable IgE antibody production inhibitory effect.

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 resp for DNP-As
In the Ig production measurement test using splenocytes of BALB / c mouse showing onse, it shows about 40-80% inhibition of IgE antibody production at a concentration of 10 ^-8 -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 Methyl 2-pyridylmethyl ketone Under a stream of Algol, α-picoline (1480 μl) was added dropwise to a diethyl ether solution of n-butyllithium (960 mg) at 0 ° C., and the mixture was stirred at 0 ° C. for 10 minutes, and further acetonitrile (782 μm
l) is added. After stirring at room temperature for 3 hours, 1.5N sulfuric acid (30 ml) was added to the reaction solution for extraction, and this acidic aqueous solution was washed with diethyl ether (25 ml). The acidic aqueous solution was adjusted to pH 11 with 2N caustic soda aqueous solution, the precipitated oily substance was extracted with methylene chloride, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residual oily substance was distilled under reduced pressure to obtain methyl 2-pyridylmethyl ketone (700 mg). ) As an oil.

Boiling point: 140 ~ 145 ℃ / 15 mmHg NMR (CDCl ₃ ) δ: 2.24 (s, 3H), 3.93 (s.2H), 7.17 ~ 7.25 (m, 2H), 7.67
(dt, 1H), 8.58 (d, 1H) Reference Example 2 In the same manner as in Reference Example 1, the following compound is obtained.

(1) Propyl 2-pyridyl methyl ketone NMR (CDCl ₃ ) δ: 0.90 (t, 3H), 1.63 (m, 2H), 2.53 (t, 2H), 3.90 (s, 2
H), 7.17 to 7.29 (m, 2H), 7.66 (dt, 1H), 8.56 (d, 1H) (2) cyclohexylmethyl 2-pyridylmethyl ketone NMR (CDCl ₃ ) δ: 0.80 to 1.96 (m, 11H) , 2.41 (d, 2H), 3.89 (s, 2H), 7.1
5 to 7.25 (m, 2H), 7.65 (dt, 1H), 8.56 (d. 1H) (3) benzyl 2-pyridylmethyl ketone NMR (CDCl ₃ ) δ: 3.83 (s, 2H), 3.95 (s, 2H) ), 7.13〜7.38 (m, 7H), 7.63
(dt, 1H), 8.57 ( d, 1H) (4) 4- chlorobenzyl 2-pyridylmethyl ketone _{NMR (CDCl 3) δ: 3.80} (s, 2H), 3.95 (s, 2H), 7.06~7.31 (m , 6H), 7.64
(dt, 1H), 8.57 (d, 1H) (5) 3-methylbenzyl 2-pyridylmethylketone NMR (CDCl ₃ ) δ: 2.32 (s, 3H), 3.78 (s, 2H), 3.94 (s, 2H ), 6.97 to 7.23
(m, 6H), 7.63 ( dt, 1H), 8.56 (d, 1H) (6) 2- methylbenzyl 2-pyridylmethyl ketone _{NMR (CDCl 3) δ: 2.18} (s, 3H), 3.84 (s, 2H ), 3.93 (s, 2H), 7.09 ~ 7.20
(m, 6H), 7.64 (dt, 1H), 8.57 (d, 1H) (7) 4-methylbenzyl 2-pyridylmethylketone NMR (CDCl ₃ ) δ: 2.32 (s, 3H), 3.78 (s, 2H ), 3.93 (s, 2H), 7.06〜7.23
(m, 6H), 7.63 (dt, 1H), 8.56 (d, 1H) (8) 2,4-dimethylbenzyl 2-pyridylmethyl
Ketone NMR (CDCl ₃ ) δ: 2.14 (s, 3H), 2.28 (s, 3H), 3.80 (s, 2H), 3.92 (s, 2
H), 6.96-7.21 (m, 5H), 7.64 (dt, 1H), 8.56 (d, 1H) (9) 3,4-Dimethylbenzyl 2-pyridylmethyl
Ketone NMR (CDCl ₃ ) δ: 2.22 (s, 6H), 3.76 (s, 2H), 3.94 (s, 2H), 6.92 to 7.21
(m, 3H), 7.63 (dt, 1H), 8.57 (d, 1H) (10) 4-methoxybenzyl 2-pyridylmethylketone NMR (CDCl ₃ ) δ: 3.76 (s, 2H), 3.79 (s, 3H ), 3.94 (s, 2H), 6.86 (d, 2
H), 7.10 (d, 2H), 7.10 ~ 7.25 (m, 2H), 7.63 (dt, 1H), 8.56 (d,
1H) (11) 1-naphthylmethyl 2-pyridylmethyl ketone NMR (CDCl ₃ ) δ: 3.93 (s, 2H), 4.28 (s, 2H), 7.05 to 7.88 (m, 10H), 8.5
6 (d, 1H) (12) 2-phenylethyl 2-pyridylmethyl ketone NMR (CDCl ₃ ) δ: 2.89 (m, 4H), 3.90 (s, 2H), 7.13 to 7.30 (m, 7H), 7.63
(dt, 1H), 8.55 (d, 1H) (13) 3-phenylpropyl 2-pyridylmethyl ketone NMR (CDCl ₃ ) δ: 1.92 (m, 2H), 2.57 (m, 4H), 3.87 (s, 2H ), 7.11 ~ 7.30
(m, 7H), 7.65 (dt, 1H), 8.56 (d, 1H) (14) 2-pyridylmethyl 3-thienylpropyl ketone NMR (CDCl ₃ ) δ: 1.97 (m, 2H), 2.60 (t, 2H ), 2.82 (t, 2H), 3.89 (s, 2
H), 6.74 (d, 1H), 6.90 (t, 1H), 7.11 (d, 1H), 7.15 ~ 7.25 (m, 2
H), 7.66 (dt, 1H), 8.56 (d, 1H) (15) 4-phenylbutyl 2-pyridylmethylketone NMR (CDCl ₃ ) δ: 1.51 to 1.69 (m, 4H), 2.51 to 2.69 (m, 4H), 3.89 (s, 2
H), 7.12~7.30 (m, 7H ), 7.64 (dt, 1H), 8.55 (d, 1H) (16) 4- methyl-2-pyridylmethyl 4-phenylbutyl ketone NMR (CDCl ₃₎ δ: 1.52~ 1.70 (m, 4H), 2.33 (s, 3H), 2.48 ~ 2.63 (m, 4
H), 3.84 (s, 2H), 6.97 to 7.30 (m, 7H), 8.39 (d, 1H) (17) 1-phenyl-4-piperidylmethyl 2-pyridylmethylketone NMR (CDCl ₃ ) δ: 1.56 ~ 2.05 (m, 5H), 2.45 (d, 2H), 2.81 (d, 2H), 3.47
(s, 2H), 3.88 (s, 2H), 7.14 to 7.33 (m, 7H), 7.65 (m, 2H), 8.55
(d, 1H) Reference Example 3 Methyl 2-cyano-3,3-dimethylthioacrylate 9.0 ml of methyl cyanoacetate was added with sodium methoxide (Na 4.
20 g and 53 ml of anhydrous methanol) and carbon disulfide
(5.3 ml) is gradually added dropwise while keeping the temperature below 18 ° C. After completion of dropping, the mixture is stirred for 30 minutes under ice cooling, 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 mixture, 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 to 86 ° C NMR (CDCl ₃ ) δ: 2.61 (s, 3H), 2.78 (s, 3H), 3.84 (s, 3H) Example 1 1-Acetyl-3-cyano-2-methylthio-4H −
Quinolidin-4-one methyl 2-pyridylmethyl ketone (153 mg) and methyl 2-cyano-3,3-dimethylthioacrylate (230 m
The mixture of g) is heated at 120 ° C. for 10 hours. The reaction solution was subjected to silica gel column chromatography, and methylene chloride-
By eluting with diethyl ether (1: 1), 1-
Acetyl-3-cyano-2-methylthio-4H-quinolidin-4-one (85 mg) is obtained as pale yellow crystals.

Melting point: 177.5 to 178 ° C IR (KBr): 2210,1690,1650,1615 cm ^-1 NMR (CDCl ₃ ) δ: 2.69 (s, 3H), 2.74 (s, 3H), 7.34 (dt, 1H), 7.64 (d, 1
H), 7.78 (dt, 1H), 9.31 (d, 1H) Elemental analysis value: (as C ₁₃ H ₁₀ N ₂ O ₂ S) C% H% N% Calculated value 60.45 3.90 10.85 Measured value 60.41 3.91 10.69 Example 2 The following compound is obtained in the same manner as in Example 1.

(1) 1-Butyryl-3-cyano-2-methylthio-4H-quinolizin-4-one Melting point: 142-144 ° C IR (KBr): 2205,1695,1660,1620 cm ^-1 NMR (CDCl ₃ ) δ : 1.04 (t, 3H), 1.80 (m, 2H), 2.73 (s, 3H), 2.91 (t, 2
H), 7.33 (dd, 1H), 7.53 (d, 1H), 7.76 (dt, 1H), 9.30 (d, 1H) Elemental analysis value: (as C ₁₅ H ₁₄ N ₂ O ₂ S) C% H% N% Calculated 62.92 4.93 9.78 Found 62.55 4.88 9.62 (2) 3-Cyano-1-cyclohexylacetyl-
2-Methylthio-4H-quinolizin-4-one Melting point: 159 to 160 ° C IR (KBr): 2205, 1695, 1660, 1620 cm ^-1 NMR (CDCl ₃ ) δ: 0.96 to 2.11 (m, 11H), 2.72 (s, 3H), 2.83 (d, 2H), 7.3
2 (dt, 1H), 7.53 (d, 1H), 7.76 (dt, 1H), 9.30 (d, 1H) Elemental analysis value: (as C ₁₉ H ₂₀ N ₂ O ₂ S) C% H% N% Calculation Value 67.03 5.92 8.23 Actual value 68.18 5.97 8.00 (3) 3-Cyano-2-methylthio-1-phenylacetyl-4H-quinolizin-4-one Melting point: 165 to 168 ° C IR (KBr): 2210,1705,1675, 1620 cm ^-1 NMR (CDCl ₃ ) δ: 2.75 (s, 3H), 4.26 (s, 2H), 7.14 to 7.33 (m, 7H), 7.56
(dt, 1H), 9.24 (d, 1H) Elemental analysis value: (as C ₁₉ H ₁₄ N ₂ O ₂ S) C% H% N% Calculated value 68.24 4.22 8.38 Measured value 67.68 4.08 8.20 (4) 1- ( 4-chlorophenylacetyl) -3-cyano-2-methylthio-4H-quinolizin-4-one Melting point: 168 to 171 ° C IR (KBr): 2210,1700,1660,1620 cm ^-1 NMR (CDCl ₃ ) δ: 2.76 (s, 3H), 4.23 (s, 2H), 7.18 (d, 2H), 7.27 ~ 7.33
(m, 4H), 7.65 (dt, 1H), 9.27 (d, 1H) Elemental analysis value: (as C ₁₉ H ₁₃ N ₂ O ₂ SCl) C% H% N% Calculated value 61.87 3.55 7.59 Measured value 61.97 3.56 7.13 (5) 3-cyano-1- (3-methyl-phenylacetyl) -2-methylthio -4H- quinolizine-4-one melting point: 150~152 ℃ IR (KBr): 2210,1700,1660,1620 cm - ¹ NMR (CDCl ₃ ) δ: 2.29 (s, 3H), 2.77 (s, 3H), 4.22 (s, 2H), 6.95 to 7.29
(m, 6H), 7.57 ( dt, 1H), 9.24 (d, 1H) Elemental _{analysis: (C 20 H 16 N 2} O as _{2 S) C% H% N} % Calculated 68.94 4.63 8.04 Found 68.76 4.46 7.61 (6) 3-cyano-1- (2-methyl-phenylacetyl) -2-methylthio -4H- quinolizine-4-one melting point: 154~156 ℃ IR (KBr): 2205,1700,1660,1615 cm - ¹ NMR (CDCl ₃ ) δ: 2.32 (s, 3H), 2.75 (s, 3H), 4.30 (s, 2H), 7.05 to 7.16
(m, 5H), 7.25 ( dt, 1H), 7.56 (dt, 1H), 9.24 (d, 1H) Elemental _{analysis: (C 20 H 16 N 2} O as _{2 S) C% H% N} % Calculated 68.94 4.63 8.04 Found 69.22 4.56 7.77 (7) 3-Cyano-1- (4-methylphenylacetyl) -2-methylthio-4H-quinolizin-4-one Melting point: 169-171 ° C IR (KBr): 2205, 1690, 1665, 1620 cm ^-1 NMR (CDCl ₃ ) δ: 2.30 (s, 3H), 2.74 (s, 3H), 4.23 (s, 2H), 7.09 (brs, 4
H), 7.18~7.28 (m, 2H ), 7.56 (dt, 1H), 9.24 (d, 1H) Elemental analysis: (as _{C 20 H 16 N 2 O 2} S) C% H% N% Calculated 68.94 4.63 8.04 Measured value 68.43 4.48 7.97 (8) 3-Cyano-1- (2,4-dimethylphenylacetyl) -2-methylthio-4H-quinolizin-4-one Melting point: 148 to 151 ° C IR (KBr): 2205 , 1700,1660,1625 cm ^-1 NMR (CDCl ₃ ) δ: 2.27 (s, 6H), 2.75 (s, 3H), 4.26 (s, 2H), 6.87-7.28
(m, 5H), 7.57 (dt, 1H), 9.25 (d, 1H) Elemental analysis value: (as C ₂₁ H ₁₈ N ₂ O ₂ S) C% H% N% Calculated value 69.59 5.01 7.73 Measured value 68.81 4.98 7.54 (9) 3-Cyano-1- (3,4-dimethylphenylacetyl) -2-methylthio-4H-quinolizin-4-one Melting point: 161-164 ° C IR (KBr): 2205,1695,1665,1620 cm ^-1 NMR (CDCl ₃ ) δ: 2.19 (s, 3H), 2.20 (s, 3H), 2.74 (s, 3H), 4.17 (s, 2
H), 6.87 to 7.28 (m, 5H), 7.58 (dt, 1H), 9.24 (d, 1H) Elemental analysis value: (as C ₂₁ H ₁₈ N ₂ O ₂ S) C% H% N% Calculated value 69.59 5.01 7.73 Actual value 69.25 5.07 7.64 (10) 3-Cyano-1- (4-methoxyphenylacetyl) -2-methylthio-4H-quinolizin-4-one Melting point: 165 to 168 ° C IR (KBr): 2210,1705 , 1660,1625 cm ^-1 NMR (CDCl ₃ ) δ: 2.74 (s, 3H), 3.77 (s, 3H), 4.19 (s, 2H), 6.79 (d, 2
H), 7.11 (d, 2H), 7.20 (d, 1H), 7.27 (m, 1H), 7.58 (dt, 1H), 9.
24 (d, 1H) Elemental analysis value: (as C ₂₀ H ₁₆ N ₂ O ₃ S) C% H% N% Calculated value 65.92 4.43 7.69 Measured value 66.05 4.32 7.25 (11) 3-Cyano-2-methylthio-1 -(1-naphthylacetyl) -4H-quinolizin-4-one Melting point: 210 to 212 ° C IR (KBr): 2200,1705,1650,1620 cm ^-1 NMR (CDCl ₃ ) δ: 2.28 (s, 3H) , 4.76 (s, 2H), 6.83 (d, 1H), 7.11 (dt, 1
H), 7.12 ~ 7.54 (m, 6H), 7.72 (d, 1H), 7.80 (d, 1H), 9.13 (d, 1
H) Elemental analysis value: (as C ₂₃ H ₁₆ N ₂ O ₂ S) C% H% N% Calculated value 71.86 4.19 7.29 Measured value 71.48 4.04 7.07 (12) 3-Cyano-2-methylthio-1- (3- Phenylpropionyl) -4H-quinolizin-4-one Melting point: 112-114 ° C IR (KBr): 2205,1695,1670,1620 cm ^-1 NMR (CDCl ₃ ) δ: 2.68 (s, 3H), 3.13 (t , 2H), 3.27 (t, 2H), 7.16 to 7.33
(m, 7H), 7.59 ( dt, 1H), 9.26 (d, 1H) Elemental _{analysis: (C 20 H 16 N 2} O as _{2 S) C% H% N} % Calculated 68.94 4.63 8.04 Found 69.10 4.60 7.66 (13) 3-Cyano-2-methylthio-1- (4-phenylbityryl) -4H-quinolizin-4-one Melting point: 64-66 ° C IR (KBr): 2210,1700,1665,1625 cm ^-1 NMR (CDCl ₃ ) δ: 2.13 (m, 2H), 2.62 (s, 3H), 2.76 (t, 2H), 2.89 (t, 2
H), 7.15 ~ 7.35 (m, 6H), 7.47 (d, 1H), 7.72 (dt, 1H), 9.28 (d,
1H) Elemental analysis value: (as C ₂₁ H ₁₈ N ₂ O ₂ S) C% H% N% Calculated value 69.59 5.01 7.73 Measured value 69.59 4.93 7.63 (14) 3-Cyano-2-methylthio-1- [4- Thienylbutyryl] -4H-quinolizin-4-one Melting point: 93 to 95 ° C IR (KBr): 2210,1690,1670,1630 cm ^-1 NMR (CDCl ₃ ) δ: 2.17 (m, 2H), 2.66 (s, 3H), 2.95 (t, 2H), 2.98 (t, 2
H), 6.81 (d, 1H), 6.93 (t, 1H), 7.14 (d, 1H), 7.32 (dt, 1H), 7.
48 (d, 1H), 7.73 (dt, 1H), 9.28 (d, 1H) Elemental analysis value: (as C ₁₉ H ₁₆ N ₂ O ₂ S ₂ ) C% H% N% Calculated value 61.93 4.38 7.60 Measured value 61.94 4.29 7.46 (15) 3-Cyano-2-methylthio-1- (5-phenylvaleryl) -4H-quinolizin-4-one Melting point: 89-91 ° C IR (KBr): 2200,1695,1660,1620 cm ^-1 NMR (CDCl ₃ ) δ: 1.68 to 1.88 (m, 4H), 2.67 (t, 2H), 2.70 (s, 3H), 2.94
(t, 2H), 7.14 to 7.33 (m, 6H), 7.48 (d, 1H), 7.73 (dt, 1H), 9.2
9 (d, 1H) Elemental analysis value: (as C ₂₂ H ₂₀ N ₂ O ₂ S) C% H% N% Calculated value 70.19 5.35 7.44 Measured value 70.53 5.38 7.43 (16) 3-Cyano-8-methyl-2 -Methylthio-
1- (5-phenylvaleryl) -4H-quinolidine-4
-On melting point: 111 to 113 ° C IR (KBr): 2200,1695,1660,1635 cm ^-1 NMR (CDCl ₃ ) δ: 1.68 to 1.89 (m, 4H), 2.49 (s, 3H), 2.67 (t , 2H), 2.68
(s, 3H), 2.93 ( t, 2H), 7.12~7.32 (m, 7H), 9.19 (d, 1H) Elemental analysis: (as _{C 23 H 22 N 2 O 2} S) C% H% N% Calculated 70.74 5.68 7.17 Found 70.91 5.64 7.27 (17) 3-Cyano-2-methylthio-1- (1-phenyl-4-piperidylacetyl) -4H-quinolidine
-4-ON Melting point: 150-151 ° C IR (KBr): 2210,1690,1675,1630 cm ^-1 NMR (CDCl ₃ ) δ: 1.38 (m, 2H), 1.82 (brd, 2H), 2.06 (m , 3H), 2.73 (s, 3
H), 2.86 (d, 2H), 2.89 (brd, 2H), 7.20 ~ 7.36 (m, 6H), 7.50
(d, 1H), 7.76 (dt, 1H), 9.29 (d, 1H) Elemental analysis value: (as C ₂₄ H ₂₃ N ₃ O ₂ S) C% H% N% Calculated value 69.04 5.55 10.06 Measured value 69.29 5.73 10.01

Claims (5)

[Claims] 1. A general formula (In the formula, R ¹ is a cycloalkyl group, an aryl group or a lower alkyl group which may have a heterocyclic group, R ² is a lower alkyl group, and R ³ is a hydrogen atom or a lower alkyl group.) A 4H-quinolidin-4-one derivative represented by: 2. General formula (In the formula, R ⁴ is at least one cycloalkyl group, aryl group or lower alkyl group having a heterocyclic group)
The 4H-quinolizin-4-one derivative according to claim 1, which is represented by: 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