JPH01149783A - 4h-quinolidin-4-one derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R is phenyl or (OH substituted) 1-6C alkyl; formula II is a 5--6-membered heterocyclic ring optionally having 1-2 hetero atoms other than the linked N atom; the heterocyclic ring may have 1-3C alkyl, phenyl(alkyl), formyl, etc., as a substituent group]. EXAMPLE:3-Cyano-1-ethoxycarbonyl-2-piperidino-4H-quinolidin-4-one. USE:A remedy having inhibitory action on production of immunoglobulin E antibodies and useful for diseases, e.g., bronchial asthma, rhinitis, dermatitis or anaphylaxis, caused by immunoglobulin E. PREPARATION:A 2-pyridylacetic acid ester derivative expressed by formula III is reacted with a compound expressed by formula IV to provide a 2- methylthio-4H-quinolidin-4-one derivative expressed by formula V, which is then reacted with cyclic amines expressed by formula VI.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention has the effect of suppressing immunoglobulin E (hereinafter referred to as 1gB) antibody production, and is effective against diseases caused by IgE, such as certain types of bronchial asthma, rhinitis, dermatitis, and hypersensitivity. The present invention relates to a novel 4H-quinolidin-4-one derivative useful as a therapeutic agent for diseases such as diseases.

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 IgE, 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 IgE antibody production during the immune response induction period has been observed, and the effects on long-term sustained IgB antibody production thereafter have only been confirmed. is not m51 [Japanese Patent Publication Publication No. 1983-13]
No. 0516, No. 62-76 of the same town].

A compound represented by the formula has already been synthesized as a 4H-quinolidin-4-one derivative as used in the present invention. Although this compound has been reported to exhibit antitumor activity, other effects,
In particular, there is no disclosure whatsoever regarding the inhibitory effect on Ig[E antibody production (Pharmaceutical Journal Vol. 97, No. 9, 1039-1045)
Page, 1977).

Furthermore, the general formula (wherein R11 is a carboxy group, amidated carboxy group, cyano group, thiocarbamoyl group, or tetrazolyl group, R17 is hydrogen or an aryl group, and RIiJ is hydrogen, a hydroxy group, a lower alkyl group, or a lower alkoxy group, 1li13 is hydrogen, a hydroxy group, a lower alkyl group, a lower alkoxy group, a lower alkenyloxy group, a 71J-l group which may have an appropriate substituent, an arylthio group, an aroyl group, an alkyl (low 1) group. group, arenesulfonyl group, arylamino group which may have an appropriate substituent, or aryloxy group, respectively.
R+2 and R13 can be located at any position on the quinolidinone ring and are bonded to each other to form -C11
2CH2CH2-, -C)I=C'H- or -CH=
CH-CH=CH- can be formed) and (in the formula, R2+ is a carboxy group, a tetrazolylcarbamoyl group, or a triazolylcarbamoyl group having an amino group, R22 is hydrogen or a lower alkoxy group, R23 means hydrogen, an aroyl group, an aryl group, a carboxy group or a protected carboxy group, and R24 means hydrogen or a hydroxy group, provided that (j) R
When 23 is hydrogen, R24 is a hydroxy group, (ii)
When R'' is an aryl group, R21 is a triazolyl group having an amino group, and (ut) When R2'' is an aroyl group, R22 is a lower alkoxy group. It has been reported that it has a suppressive effect on immersion restraint stress ulcer experiments and passive skin anaphylactic reactions, but there is no disclosure of its effect on IgB antibody production (Japanese Patent Publication No. 60-222482, the same town). 62-77385).

Problems to be Solved by the Invention It has been confirmed in animal experiments that production of IgB is induced by antigen sensitization under certain conditions, and that 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 Igε antibodies against specific antigens.

Therefore, gE antibody production inhibitors used in the treatment of diseases caused by IgH must suppress not only IgE antibody production during the immune response induction period, but also subsequent sustained IgE antibody production.

In addition to IgE, the immunoglobulin class includes various other globulins, 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.

Since it was revealed that IglE antibodies are the triggering antibodies for certain types of bronchial asthma, rhinitis, dermatitis, hypersensitivity, etc.
Many studies have been conducted on IgE antibody production inhibitors, but all of the compounds that have been reported to suppress Igε antibody production have been administered before, during, or immediately after immunization, and have been administered during the immune response induction period. It has only been confirmed that it suppresses gB 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 rgε antibody production and the effect on other Ig antibody production.

The purpose of the present invention is to provide a selective agent that does not significantly affect the production of 100 antibodies, etc., which are important for infection prevention, and that acts on persistent IgB antibody production, unlike conventional l1iB antibody production inhibitors. An object of the present invention is to provide a novel 4-quinolizin-4-one derivative that has an inhibitory effect on Il([E antibody production) and is useful as a therapeutic agent for various diseases caused by IgE.

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

That is, the present invention is based on the general formula (R in the formula (in the formula, R is a C1-C6 alkyl layer atom which may have a phenyl group or a hydroxyl group as a substituent)
It is a 5- to 6-membered heterocyclic group that may have two members. The heterocyclic group has as a substituent an alkyl group having 1 to 3 carbon atoms,
4 which may have a group selected from phenyl group, phenylalkyl group, hydroxyalkyl group, morpholinocarbonylalkyl group and formyl group)
11-quinolidine-4-one transparent conductor.

The 5- to 6-membered heterocyclic group in the present invention is a saturated or unsaturated heterocyclic group that may have a substitutable nitrogen atom and other heteroatoms. Examples include saturated heterocyclic groups such as pyrrolidine, piperidine, morpholine, piperazine, thiomorpholine, etc., and unsaturated heterocyclic groups such as imidazole, triazole, etc.

Further, when the heterocyclic group has a substituent, the substituent may be substituted on either a carbon atom of the ring or a bondable nitrogen atom.

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, a 2-pyridyl acetate derivative represented by the general formula (R in the formula has the same meaning as above) is reacted with a compound represented by the formula, have the same meaning)
It can be produced by obtaining a 2-methylthio-4H-quinolidin-4-one derivative represented by and reacting this compound with a cyclic amine of the general formula.

General formula (
Compound n) can be produced by reacting 2-pyridylacetic acid and an alcohol derivative represented by the general formula % (in which R has the same meaning as above) according to a conventional method. [Compendium of Organic Synthetic Methods]
um of Organic SyntheticMe
thods; Bd, by I, T, Harriso
n and S, Harrison.

Wiley-1ntersc+ence New Yo
rk) Volume 1, pages 272-279, 1971].

In addition, the formula (III
) can be prepared using methyl cyanoacetate, carbon disulfide and dimethyl sulfate according to the method described in the literature [Chem, Berichte, et al.
r, ), volume 95, pages 2861-2870, 1962
Year〕.

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 formula (III) in an inert solvent or without solvent at 100 to 120°C for 2 to 30 minutes.
The reaction was carried out for 10 hours and treated according to a conventional method to obtain the general formula (IV
) is obtained. Next, an equimolar or excess molar amount of the compound of general formula (V) is added, and the inert compound is reacted in an organic solvent or without a solvent at room temperature to 140°C for 2 to 48 hours, and treated according to a conventional method to obtain a general compound. A compound of formula (I) is obtained.

The compound of general formula (I) of the present invention exhibits an atobutybacterial secondary immune response (adap) to dinitrophenylated ascaris protein (DNP-AS).
tive 5econdary immune res
An in vitro 1g production measurement test using lung cells of BALB/c mice showing
r Immunology), Volume 5g, 188-20
1, p. 1, 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 of the compound of general formula (1) of the present invention is determined depending on the age, sex, degree of disease, treatment conditions, etc. of the subject patient. The daily dose is approximately 0 in the case of oral administration.
．． 1-50 mg/kg, approximately 0.0 mg/kg for parenteral administration. O1-5 mg/kg.

Effect of the invention 4H-quinolidine-4 represented by general formula (I) of the present invention
-one derivatives are adOptive to DNP-As
secondary immune response
1 using lung cells of BALB/c mice showing
In the g production measurement test, 10-8 to 10-5 g/+nj2
At a concentration of about 40-90%, it exhibits an inhibitory effect on IgE antibody production.

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 Ethyl 2-pyridylacetate (1,42g), methyl 2-cyano-3,3-dimethylthioacrylic [1,75g]
Heat the mixture at 120° C. for 10 hours. Methanol (8d) 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-quinolizin-4-one (1,1
9 g) as pale yellow crystals.

Melting point: 128-129°C IR (KBr): 2200. 1695. 16
65 cm-'NMR (CDCI, ) δ: 1.44 (t, 3H), 2.76 (s, 3
H), 4.48 (q.

28), 7.30 (m, IH), , 7.80 (m
, 2H), 9.27 (d, IH) Elemental analysis value' (as CI4812N203S)
0% 8% N% Calculated value 58.32 4.20 9.72 Actual value 57.79 4.22 9.82 Reference Example 2 The following compound was obtained in the same manner as in Reference Example 1.

3-cyano-2-methylthio-1-(3-phenylpropo) Melting point: 80-81°C IR (KBr): 2200.1700.16
65. 1620 cm-'NMR (CDCl2) δ: 2.13 (m, 2), 2.75 (s, 3
) 1), 2.78 (t.

2H), 4.43(t, 2tl), 7.18-7
．． 36 (m, 6N).

7.77 (m, 2H), 9.26 (d, IH) Elemental analysis value: (as C,,H,8N203S) 0
% N% N% Calculated value 66.65 4.79 7.40 Actual value 66.93 4.72 6.92 Example 1 3-cyano-1-ethoxycarbonyl-2-methylthio-4H-quinolidin-4-one (1,44g) and piperidine (5,0ml) in acetonitrile (10rR1)
The solution is heated to reflux for 10 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography.
By elution with a mixed solvent of ethyl acetate-hexane (2:1), 3-cyano-1-ethoxycarbonyl-2
-piperidino-4H-quinolizin-4-one (0,95
g) is obtained.

Melting point: 143-144°C IR (KBr): 2200.1710.1665.
1630 c+tr'NMR (CDCl2) δ: 1.38 (t, 3H), 1.60-1.82
(m, 6H).

3.33-3.46 (m, 4H), 4.39 (q,
2) 1), 6.99'(t, IH),
7.53 (dt, 1N), 7.95 (d, IH)
.

9.06 (d, LH) Elemental analysis value' (as C+aLsOJ3) 0%
N% N% Calculated value 66.45 5.89 12.91 Actual value 66.47 5.95 13.17 Examples 2 to 22 Performed using the corresponding compounds of general formula (VI) and general formula (V) The reaction was carried out in the same manner as in Example 1 to obtain the following compound.

Example 23 3-cyano-1-ethoxycarbonyl-2-piperidino-48-quinolidin-4-one (Example 1 1.10 g
) to an ethylene glycol (30 mN) solution was added 60% hydrogenated) IJium (150 mg), and the mixture was heated at 100°C for 14
Stir for an hour. 3-cyano-1-(2-hydroxyethyl Oxycarbonyl>-2-piperidino-4H-quinolidin-4-one (180 mg) is obtained.

Melting point: 140-141°C IR (KBr): 3375.2210.1710.
1675.1640°1630 c+yr' N! , I R (CD C13) δ: 1.62-1.82 (m, 7H), 3.47
(m, 4H), 3.99 (m, 2H), 4.4
7 (m, 2) 1), 7.00 (t, IH).

7.55 (dt, 18), 8.02 (d, LH)
, 9.07 (d.

IH) Elemental analysis value: (as C, aLsOJs) 6%
N% N%

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R is an alkyl group having 1 to 6 carbon atoms that may have a phenyl group or a hydroxyl group as a substituent, There are chemical formulas, tables, etc. ▼ is a 5- to 6-membered heterocyclic group that may have 1 to 2 heteroatoms in addition to the bonded nitrogen atom.The heterocyclic group can be used as a substituent. , alkyl group having 1 to 3 carbon atoms, phenyl group, phenylalkyl group, hydroxyalkyl group, morpholinocarbonylalkyl group, and formyl group) 4H-quinolidine- 4-one derivative.