JPH0670044B2 - 4H-quinolizin-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 glasses, is the causative agent of various diseases such as certain 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.].

As a 4H-quinolizin-4-one derivative as in the present invention, a compound of the formula The compound represented by
No. 2, pp. 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. It can be, and combined with each _{other, -CH 2 CH 2 CH 2 -} , - CH = CH- or -CH = CH-CH = CH-
And a general formula (In the formula, R ²¹ is a carboxy group, a tetrazolylcarbamoyl group or a triazolylcarbamoyl group having an amino group, R ²² is hydrogen or a lower alkoxy group, R ²³ is hydrogen, an aroyl group, an aryl group, a carboxy group or a protected group. A carboxy group and R ²⁴ each represent hydrogen or a hydroxy group, provided that (i) when R ²³ is hydrogen, R ²⁴ is a hydroxy group, and (ii) when R ²³ is an aryl group, R ²¹ is an amino group. a triazolyl group having, (iii) if R ²³ is aroyl group, R ²² is a compound represented by means a lower alkoxy group), a water immersion restraint stress ulcers experiments and passive cutaneous anaphylaxis reaction in rats Although it has been reported to have an inhibitory action against the above, there is no disclosure about the action on IgE antibody production (Japanese Patent Publication Nos. 60-222482 and 62-7738). No. 5).

Problems to be solved by the invention IgE is induced by antigen sensitization under certain conditions, and its production has been confirmed to be sustained for a long period of time 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 must also 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 (I
It is well known that gG) plays an important role in infection control.

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 Ig 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 (R in the formula is an alkyl group having 1 to 6 carbon atoms which may have a phenyl group as a substituent, and Y is 1 to 6 carbon atoms.
Is a linear or branched alkylene group, B is a single bond or -NH-, and Het is a 5- or 6-membered aromatic heterocyclic group which may have a substituent). Be done
A 4H-quinolizin-4-one derivative is provided.

In the present invention, the 5- or 6-membered aromatic heterocyclic group is the same or different from, for example, pyrrole, furan, thiophene, imidazole, triazole, oxazole, oxadiazole, thiazole, thiadiazole, pyridine, pyrimidine, pyridazine, pyrazine. It means an aromatic heterocyclic group having 1 to 3 heteroatoms. The heterocyclic group may have 1 or 2 substituents such as an alkyl group having 1 to 3 carbon atoms, an amino group and a nitro group as a nuclear substituent.

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 A 2-pyridyl acetic acid ester derivative represented by the formula (wherein R has the same meaning as described above); The compound represented by the general formula (Wherein R has the same meaning as described above), a 2-methylthio-4H-quinolizin-4-one derivative represented by the formula H ₂ NYB-Het (V) (Y in the formula , B and Het have the same meanings as described above).

The compound of general formula (II) used as a starting material in the production method of the present invention is represented by 2-pyridylacetic acid and general formula R-OH (VI) (wherein R has the same meaning as described above). It can be produced by reacting with an alcohol derivative according to a conventional method (Compendium of Organic Method).
anic Synthetic Methods; Ed. by IT Harrison and S.
Harrison, Wiley-Interscience New York) Volume 1, 272-
279, 1971].

In addition, the formula (III) used as the other starting material
Can be prepared according to the method described in the literature using methyl cyanoacetate, carbon disulfide and dimethylsulfate [Chem. Ber., Chem. Ber., Vol. 95, 286].
1-2870, 1962].

In order to preferably carry out the production method of the present invention, the compound represented by the general formula (II)
And a compound of formula (III) in equimolar amounts with them are reacted in an inert solvent or without solvent at 100 to 120 ° C. for 2 to 10 hours and treated according to a conventional method to give a compound of general formula (IV). obtain. Then an equimolar or excess molar amount of the general formula (V)
Compound in an inert organic solvent or without solvent,
The compound of the general formula (I) is obtained by reacting at room temperature to 140 ° C. for 2 to 48 hours and treating according to a conventional method.

The compound of the general formula (I) of the present invention is an adaptive secondary immune response to dinitrophenylated Ascaris protein (DNP-As).
In vitro measurement of Ig production using spleen cells of BALB / c mouse showing dary immune response (Cellular Immunolog
y), 58, 188-201, 1981].
E Shows an 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 of the compound of general formula (I) of the present invention is determined according to the age, sex, degree of disease and treatment condition of the subject patient. The daily dose is generally 0 for oral administration.
The dose is 1 to 50 mg / kg, and generally 0.01 to 5 mg / kg for parenteral administration.

EFFECT OF THE INVENTION 4H-quinolizine-4-represented by the general formula (I) of the present invention
On-derivative is an adaptive secondary immun for DNP-As
In the Ig production measurement test using splenocytes of BALB / c mice showing e response, it was about 40 ~ at a concentration of 10 ^-8 ~ 10 ^-5 g / ml.
It exhibits an IgE antibody production inhibitory effect of about 90%.

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 3-Cyano-1-ethoxycarbonyl-2-methylthio-4H-quinolizin-4-one ethyl 2-pyridylacetate (1.42 g), methyl 2-cyano-
A mixture of 3,3-dimethylthioacrylate (1.75 g) was added to 120
Heat at ℃ for 10 hours. Methanol (8 ml) was added to the reaction solution, and the precipitated crystals were collected by filtration and recrystallized from methanol to give 3-
Cyano-1-ethoxycarbonyl-2-methylthio-4H
-Quinolidin-4-one (1.19g) is obtained as pale yellow crystals.

Melting point: 128-129 ° C IR (KBr): 2200,1695,1665cm ^-1 NMR (CDCl ₃ ) δ: 1.44 (t, 3H), 2.76 (s, 3H), 4.48 (q, 2H), 7.30
(M, 1H), 7.80 ( m, 2H), 9.27 (d, 1H) Elemental _{analysis: (C 14 H 12 N 2} O 3 S as) C% H% N% Calculated 58.32 4.20 9.72 Found 57.79 4.22 9.82 Reference Example 2 In the same manner as in Reference Example 1, the following compound was obtained.

3-Cyano-2-methylthio-1- (3-phenylpropoxycarbonyl) -4H-quinolizin-4-one Melting point: 80-81 ° C IR (KBr): 2200,1700,1665,1620cm ^-1 NMR (CDCl ₃ ) δ: 2.13 (m, 2H), 2.75 (s, 3H), 2.78 (t, 2H), 4.43
(T, 2H), 7.18 to 7.36 (m, 6H), 7.77 (m, 2H), 9.26 (d, 1
H) Elemental analysis value: (as C ₂₁ H ₁₈ N ₂ O 3 _S ) C% H% N% Calculated value 66.65 4.79 7.40 Measured value 66.93 4.72 6.92 Example 1 3-Cyano-1-ethoxycarbonyl-2- (2- Pyridylmethylamino) -4H-quinolizin-4-one 3-cyano-1-ethoxycarbonyl-2-methylthio-4H-quinolidin-4-one (1.53g) was added with 2-aminomethylpyridine (4.93g) at room temperature. Stir for 17 hours. The precipitated crystals were collected by filtration and recrystallized from methanol to give 3-cyano-1-ethoxycarbonyl-2-
(2-Pyridylmethylamino) -4H-quinolizine-4-
Get on (1.68g).

Melting point: 176.5 to 177 ° C IR (KBr): 2200,1695,1655,1630cm ^-1 NMR (CDCl ₃ ) δ: 1.46 (t, 3H), 4.51 (q, 2H), 5.22 (d, 2H), 6.92
(T, 1H), 7.27 (t, 1H), 7.34 (d, 1H), 7.51 (dt, 1H),
7.72 (dt, 1H), 8.25 (d, 1H), 8.62 (d, 1H), 9.06 (d, 1
H), 9.62 (br, 1H) Elemental analysis value: (as C ₁₉ H ₁₆ O ₃ N ₄ ) C% H% N% Calculated value 65.51 4.63 16.08 Measured value 65.44 4.68 15.69 Examples 2-21 Corresponding general formula ( IV) and the compound of general formula (V) were reacted in the same manner as in Example 1 to obtain the following compound.

Example 22 3-Cyano-1-methoxycarbonyl-2- (2-pyridylmethylamino) -4H-quinolizin-4-one 3-cyano-1-ethoxycarbonyl-2- (2-pyridylmethylamino) -4H- Quinolidin-4-one (3.00
g) is dissolved in dry methanol (1.0 L), NaH (40 mg) is added, and the mixture is heated under reflux for 3 hours. After cooling, the precipitated crystals are collected by filtration and dried to give 3-cyano-1-methoxycarbonyl-2- (2-pyridylmethylamino) -4H-quinolidin-4-one (2.56g).

Melting point: 231 ° C (decomposition) IR (KBr): 2200,1690,1650,1620cm ^-1 NMR (DMSO-d ₆ ) δ: 4.03 (s, 3H), 5.37 (d, 2H), 7.33 (t, 1H ), 7.85 ~
7.96 (m, 3H), 8.24 (d, 1H), 8.44 (d, 1H), 8.87 ~ 8.97
(M, 2H), 9.05 ( d, 1H) Elemental _{analysis: (C 18 H 14 O 3} N 4 as a) C% H% N% Calculated 64.67 4.22 16.76 Found 64.74 4.21 16.53 Example 23 3-cyano - 1-Methoxycarbonyl-2- (2-pyridylmethylamino) -4H-quinolizin-4-one hydrochloride 3-Cyano-1-methoxycarbonyl-2- (2-pyridylmethylamino) -4H-quinolidin-4-one (1.00
g) was dissolved in 3 ml of concentrated hydrochloric acid, excess hydrochloric acid was distilled off under reduced pressure, ether (50 ml) was added to the residue, and the precipitated crystals were collected by filtration to give 3-cyano-1-methoxycarbonyl-2- ( Two
-Pyridylmethylamino) -4H-quinolidin-4-one hydrochloride (1.01g) is obtained.

Melting point: 220 ° C (decomposition) IR (KBr): 2200,1680,1645,1615cm ^-1 NMR (DMSO-d ₆ ) δ: 4.04 (s, 3H), 5.28 (d, 2H), 7.31 (t, 1H ), 7.69〜
7.80 (m, 3H), 7.95 (dt, 1H), 8.20 ~ 8.30 (m, 2H), 8.86
(D, 1H), 9.05 ( d, 2H) Elemental _{analysis: (C 18 H 15 O 3} N 4 as Cl) C% H% N% Calculated 58.31 4.08 15.51 Found 58.35 4.04 15.59

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location A61K 31/495 ACD 7431-4C 31/505 7431-4C

Claims (6)

[Claims] 1. A general formula (R in the formula is an alkyl group having 1 to 6 carbon atoms which may have a phenyl group as a substituent, and Y is 1 to 6 carbon atoms.
Is a linear or branched alkylene group, B is a single bond or -NH-, and Het is a 5- or 6-membered aromatic heterocyclic group which may have a substituent). Be done
4H-quinolizin-4-one derivatives and pharmaceutically acceptable salts. 2. General formula (In the formula, R ¹ is an alkyl group having 1 to 3 carbon atoms, and n is 0
The 4H-quinolizin-4-one derivative according to claim 1, wherein R, Y and B have the same meanings as described above. 3. A formula The 4H-quinolizin-4-one derivative according to claim 1, which is represented by: 4. A formula The 4H-quinolizin-4-one derivative according to claim 1, which is represented by: 5. A formula The 4H-quinolizin-4-one derivative according to claim 1, which is represented by: 6. A formula The 4H-quinolizin-4-one derivative according to claim 1, which is represented by: