JPS63188677A - 4h-quinolizin-4-one derivative - Google Patents

Abstract

NEW MATERIAL:A 4H-quinolizin-4-one derivative expressed by formula I (R<1> is saturated or unsaturated monocyclic or polycyclic and alicyclic group which may have a substituent group; R<2> is lower alkyl; R<3> is H or lower alkyl). EXAMPLE:Cyclopentyl 3-cyano-2-methylthio-4H-quinolizin-4-one carboxylate. USE:Capable of exhibiting inhibitory action on production of immunoglobulin E antibody and useful as a remedy for diseases caused by immunoglobulin E, e.g. certain kinds of bronchial asthma, rhinitis, dermatitis, anaphylaxia, etc., and having excellent sustained action properties. PREPARATION:2-Pyridylacetic acid derivative expressed by formula II is reacted with a compound expressed by formula III to provide the compound expressed by formula I. Furthermore, the compound expressed by formula II partially includes novel compounds and is synthesized by reacting a compound expressed by formula IV with an alcohol derivative compound formula V.

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 novel 4H-quinolidin-4-one derivatives that can be used as therapeutic agents 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 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 Igε antibody producers during the immune response induction period has been observed, and there is no sustained effect on rgE antibody production over a long period of time. Regarding m85, it is not mentioned [Japanese Patent Publication Publication No. 1984-13]
No. 0516, No. 62-76, etc.].

A compound represented by the general formula (R in the formula is a methyl group or an ethyl group) is already known as a 4H-quinolidin-4-one transparent conductor as in the present invention (Yakugaku Zasshi, Vol. 89, 2, pp. 203-208, 1969). However, these compounds were synthesized solely out of synthetic interest, and their pharmacological actions are not disclosed at all.

In addition, it has been reported that the compound represented by the formula shows antitumor activity, but no other effects, especially Igε antibody production suppressing activity, have been reported (Pharmaceutical Journal Vol. 97, No. 9, I
039-1045, 1977).

Furthermore, the general formula (wherein R1+ is a carboxy group, amidated carboxy group, cyano 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, R13 is hydrogen, hydroxy group, lower alkyl group, lower alkoxy group, lower alkenyloxy group, aryl group which may have an appropriate substituent, arylthio group, aroyl group, a(lower) alkyl group, 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 - CI-12CI
(2C1(,-,-CH=C)1- or -C)1=c
The compound represented by ll-['')I=C)l- has an inhibitory effect on water immersion restraint stress ulcer experiments and passive cutaneous anaphylactic reactions using rats. has been reported, but Ig
The effect on B antibody production is not disclosed at all (Japanese Patent Publication No. 1982-222482).

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 IgE antibodies against specific antigens.

Therefore, an IgE antibody production inhibitor used for the treatment of IgH-induced diseases 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.

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

Since it was revealed that IgE antibodies cause certain types of bronchial asthma, rhinitis, dermatitis, hypersensitivity, etc.
Many studies have been conducted on gE antibody production inhibitors, but all of the compounds that have been reported to suppress l1jE antibody production have been administered before, during, or immediately after immunization to inhibit IgE production during the immune response induction period. It has only been confirmed that it suppresses antibody production, but no effect on sustained IglE antibody production has been confirmed. Also, IgF!
In most cases, the selectivity between the effect on antibody production and the effect on other [g antibody production] is low.

The purpose of the present invention is to provide a selection method that, unlike conventional Igε antibody production inhibitors, does not significantly affect the production of gG antibodies, etc., which are important for infection prevention, etc., and also acts on persistent IgB antibody production. It has the effect of suppressing IgE antibody production, and
Novel 4H useful as a therapeutic agent for various diseases caused by E.
- quinolidin-4-one derivatives.

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 g The present invention has been accomplished.

That is, the present invention is based on the general formula (in which R1 is a saturated or unsaturated monocyclic or polycyclic alicyclic group that may have a substituent, R2 is a lower alkyl group, and R3 is a hydrogen atom). or a lower alkyl group).

The compound represented by the general formula (I) 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 (R1 right and R3 in the formula have the same meanings as above) and a 2-pyridyl acetate derivative represented by the general formula (R2 in the formula has the same meanings as above). It can be produced by reacting with a compound.

General formula (
Some of the compounds of I[) include new compounds, but 2-
It can be produced by reacting a pyridylacetic acid permeable conductor and an alcohol derivative represented by the general formula 3 (%) (in which R' has the same meaning as above) according to a conventional method [ Compendium of Organic Synthetic Methods
ium of Organic SyntheticM
methods; FJd, by I, T, Harr
ison and S, Harrison.

11i1ey-1interscience New Y
Ork) Volume 1, pages 272-279, 1971].

In addition, the general formula (I
The compound II) uses cyanoacetic acid methyl ester, hydrogen sulfide, and a compound represented by the general formula (% formula %) (in which R2 has the same meaning as above and X is an acid residue), and is described in the literature. It can be produced according to the method or similar method ["Mikkus Berichte (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 the general formula (I [I) in an inert organic solvent or without a solvent, at a concentration of 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 exhibits an adoptive secondary response to dinitrophenylated Ascaris protein (DNP-As).
BA showing condary response)
In vitro (in vitro) using lung cells of LB/c mice
1g production measurement test in vitro (Cellular immunology)
ogy), volume 58, pages 188-201, 1981
2009] shows a remarkable inhibitory effect on IgB antibody production.

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 for parenteral administration
~5■/kg.

Effect of the invention 4H-quinolidine-4 represented by general formula (1) of the present invention
-one derivatives are adaptive to DNP-As
In an rg production measurement test using lung cells of BALB/c mice showing secondary response, at a concentration of 10-8 to 10-' g/-, approximately 40 to
It exhibits an approximately 80% 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 Cyclopentyl 2-pyridyl acetate 2-pyridylacetic acid hydrochloride 417 mg, cyclopentanol (436
d), 1,3-dicyclohexylcarbodiimide (6
45 mg> is stirred in dry pyridine (5rn1) at room temperature for 40 hours. The precipitated crystals were filtered off, the solvent was distilled off under reduced pressure, and the residue was dissolved in 1N hydrochloric acid (20 mt) and washed twice with diethyl ether (25 mN). A 2N aqueous caustic soda solution is added to the hydrochloric acid solution to adjust the pH to 11, and the precipitated oil is extracted with methylene chloride (50rR1). After drying the methylene chloride solution over anhydrous sodium sulfate, the solvent was distilled off to give cyclopentyl 2-pyridyl acetate (46
4 mg) as an oil.

NMR (CDCI, ) δ: 1.2-1.95 (m, 8H), 3.81 (
s, 2H), 5.21 (m, IH), 7.18
(dd, IH), 7.28(d, 1)I).

8.56 (d, 1N) Reference example 2 The following compound is obtained in the same manner as in Reference Example 1.

(1) Cyclobutyl 2-pyridyl acetate NM
R (CDC13) δ: 1.10-2.41 (m, 6H), 3.85
(s, 2N), 5.03 (m, LH), 7
．． 18(dd, 1)1), 7.29(d,
1)1).

7.65 (dt, 18), 8.56 (d,
IH) (2) Cyclohexyl 2-pyridyl acetate NMR (CDC1a) δ: 1.19-1.90 (m, 10) 1), 3.
84 (s, 2) 1).

4.81 (m, IH), 7.18 (dd, 1
)1), 7.30 (d.

LH), 7.66(dt, LH>, 8.56(d
, IH) (3) 2'-cyclohexenyl 2-
Pyridyl aceter] NMR (CDCl2>δ: 1.60-2.18 (m, 6H), 3.85
(s, 2H), 5.33 (m, IH), 5.7
2(m, LH), 5.94(m, 1)1).

7.18 (dd, IH), 7.30 (d, IH)
, 7.65 (dt.

IH), 8.56(d, IH) NMR (CDC
l2) δ: 1.2:3-1.58 (m, 58),
1.80-2.06 (m.

4ft), 3.71 (m, IH), 3.8
3 (s, 2H), 4.81 (m, IH),
7.19 (dd, IH), 7.29 (d,
IH).

7.66 (dt, IH), 8.55 (d,
IH) (5) 2°-Methylcyclohexyl 2-pyridyl acetate NMR (CDCIs) δ: 0.79 and 0.83 (d, 311),
0.95-2.05 (m.

9H), 3.84 and 3.86(s, 211
), 4.45 and 4.96 (m, IH),
7.18 (dd, IH), 7.31 (d.

IH), 7.65 (m, IH), 8.56
(d, IH) (6) Cyclohexyl 4-methyl-2-pyridyl acetate NMR (CDC13) δ: 1.17-1.90 (m, 10H), 2.
34(s, 3H).

3.78 (s, 2H), 4.81 (m, IH
), 7.00 (d.

IH), 7.11(s, IH), 8.40
(d, IH) (7) Cycloheptyl 2-pyridyl acetate NMR (CDCl2) δ: 1.20-1.95 (m, 12H), 3.8
0(s, 28).

4.98 (m, IH), 7.18 (dd, IH)
, 7JO (d.

LH), 7.65 (dt, IH), 8.55 (d
, 1) 1) (8) Cyclooctyl 2-pyridyl acetate N iAR (CDC1s) δ: 1.25-1.88 (m, 14H), 3.8
0s, 2H).

4.99 (m, IH), 7.18 (dd, IH)
, 7.29 (d.

IH), 7.65 (dt, LH), 8.56 (d
, 1ll) (9) 2'-adamantyl 2-pyridyl acetate NMR (CDC13) δ: 1.45-2.03 (m, 14B), 3.8
9(s, 2H).

4,97 (m-, IH), 7.19 (dt, IH)
, 7.32 (d.

IH), 7.66 (dt, IH), 8.56 (d
, IH) NMR (CDCl2) δ: 1.67-2.06 (m, 4H), 2
．． 66-2.91 (m.

21(), 3.87(s, 2H), 6.0
5 (t, IH), 7.09~? JHm, 6
H), 7.64 (dt, IH), 8.56
(d.

IH) Reference Example 3 Methyl 2-cyano-3,3-dimethylthioacrylate methyl cyanoacetate 9.0-, sodium methoxide (synthesized from 4.20 g of Na and 53 ml of anhydrous methanol) and carbon disulfide ( 5.3mN) at a temperature of 18℃
Gradually drip while keeping the amount below. After the addition, the mixture was stirred for 30 minutes under water cooling, dimethyl sulfuric acid (16.5 ml) was added over 30 minutes, and the mixture was stirred at room temperature for 1 hour. Water 125- was added to the reaction solution, the precipitated crystals were collected by filtration, and recrystallized from methanol to obtain methyl 2-cyano-3,3-dimethylthioacrylate (13.0 g).

Melting point: 85-86°C NλIR (CDCl2) δ: 2.61 (s, 3H), 2.78 (s
, 3H), 3.84 (s.

3H) Example 1 Cyclopentyl 2-pyridyl aceter) (,464
mg) and methyl 2-cyano-3,3-dimethylthioacrylate (459 mg) at 120°C.
Heat for an hour. The reaction solution was subjected to silica gel column chromatography, and methylene chloride and diethyl ether (l:
By elution with 1), cyclopentyl 3-cyano-
2-Methylthio-4H-quinolizin-4-one-1-carboxylar) (294 mg) is obtained as pale yellow crystals.

Melting point: 149-151°C IR (KBr): 2210.1700.1660.
1620 cm-'NMR (CIICI3) δ: 1.60-2.10 (m, 8H), 2.75
(s, 3!(), 5.50(m, IH),
7.31 (m, LH), 7.78 (n+,
2H).

9.26 (d, IH) Elemental analysis value: (as C+J+5N20zS) 0
% 8% N% Calculated value 62.18 4.91 8.53 Actual value 61.83 4.93 7.93 Example 2 The following compound is obtained in the same manner as in Example 1.

Melting point: 111-112°C IR (KBr): 2210.1700.1660.
1615 cm-'NMR (CDCL,) δ:1°6:3-. 2.60 (m, 6H), 2.7
5(s, 3H), 5.30(m, 11(), 7
．． 30 (m, LH), '7.71! (+n, 21(
).

9.26 (d, IH) Elemental analysis value (as C16) 114N203S) 0% 8% N% Calculated value 61.13 4.49 8.91 Actual value 61.02 4.44 8.24
Point: 145-146°C IR (KBr): 2220. 1705. 166
0. 1615 cm-'NMR (CDC1,) δ: 1.23-2.13 (m, 10B),
2.75 (s, 3H).

5.12 (m, IH), 7.29 (m, L
H), 7.65 (n+.

2H); 9.26 (Tun 1) 1) Elemental analysis value: (C+sl (+J2GsS))
0% 8% N% Calculated value 63,14 5.30 8.18 Actual value 62.95 5Jl 8.00F
Point:' 143.5 ~ 145℃ IR (KBr):
2210. 1690.1660. 1620
cm-'NMR (CDCl2) δ: 1.65-2.21 (m, 6) 1),
2.75 (s, 3H), 5.59 (m, 1
)1), 5.92(m, 1)1), 6.0
6(m, 1)1).

7.29 (m, 1ft), 7.76 (m,
2) 1), 9.25 (d.

IH) Elemental analysis value (as CIllH16N203S) 0% 8% N% Calculated value 63.51 4.74 8.23 Actual value 63.86 4. ．． 75 7.76 Melting point: 169-170°C IR (Br): 2210.1700.1640.
1615 cm-'NMR (CDC13) δ: 1.40-1.75 (m, 58), 1.98
~2.28 (m.

4H), 2.75(s, 3H), 3.80(m,
IH), 5.12 (m, LH), 7.31
(m, IIl, 7.76 (m, 2H).

9.26 (d, 18) Elemental analysis value: (as C, 8H, 8N204S)
6% 8% N% Calculated value 60.32 5.06 7.82 Actual value 60.37 5.03 7.85 Lard melting point: 105-108°C IR (KBr): 2205. 1720. 166
5. 1620 cm-'NMR (CDCl2) δ: 1.99 and 1.03 (d, 3
H),' 1.10-2.37 (m.

98>, 2.75 (s, 3H), 4.78
and 5.31 (m.

LH), 7.31 (dd, 1ff), 7.
75 (m, 2H), 9.26 (d, IH) Elemental analysis value: (C19)+2°N, 0. S) 6% 8% N% Calculated value 64.02 5.66 7.86 Actual value 63.97 5.68 7.74 Lard melting point: 179-180°C IR (KBr): 2200. 1?20. 167
0. 1630 cm-'NMR (CDCl2) δ: 1.23-2.15 (m, 10 fl),
2.52 (brs, 3)1).

2.72 (s, 3) 1), 5. ．． 13 (m,
11(), 7.13(dd.

IH), 7.26 (brs, 1ft), 9
．． 16(d, -IH) Elemental analysis value: (C1゜H2゜N2
0. S) 6%, 8% N% Calculated value 64.02 5.66 7.86 Actual value 64.06 5.60 7.76 (7
) cycloheptyl 3-cyano-2-methylthio-
4H-quinolidin-4-one-1-carboxilade Melting point: 130-131°C IR (KBr):
2210.1700. 1660.1620 c
m-'NMR (CDC13) δ: 1.50-2.20 (m, 12N>,
2.75 (s, 3tl).

5.30 (m, 18), 7.30 (m, 1
N), 7.76(i+.

21 (), 9.25 (m, 1) 1) Elemental analysis value: (as C19)12ON203S) 6%
8% N% Calculated value 64.02 5.66 7.86 Actual value 63.93 5.66 7.63
Point: 121.5 ~ 122.5℃ IR (KBr
): 2205.1700.1660.1620 c
m-'NMR (CDC13) δ: 1.45-2.10 (+++, 14H), 2
．． 75 (s, 3) 1).

5.28 (m, IH), 7.30 (m, 1)1)
, 7.74 (m.

28), 9.25 (d, IH) Elemental analysis value' (as C2oHzJzOsS)6
% 8% N% Calculated value 64.84 5.99 7.56 Actual value 64.41 5.95 7.54
Point: 177-178°C IR (KBr): 2205. 1705. 167
0. 1615 c+c'~MR (CDC13) δ: 1.58~2.28 (m, 14H),
2.75 (s, 3N).

5.32 (m, IH), 7.30 (m, 1
8), 7.75 (m.

211), 9.26 (d, IH) elemental analysis value'
(as C22H22N203S) 6% 8
% N% Calculated value 66.98 5.62 7.10 Actual value 67.54 5.68 6.32 Amorphous powder IR (KBr): 2205.1715.1670.
1620 cm-'NMR (CDCI,) δ: 1. ．． 70-2.40 (m, 4H), 2.7
0(s, 3H), 2.71.

~2.95(m, 21(), 6.37(t, 1)
1), 7.08-7.32 (m, 4N>, 7.4
6 (m, 1N), 7.70 (m.

21(), 9.24(d, IH) Elemental analysis value: (as C*dl+aN20+S)
6% 8% N%

Claims (3)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^1 in the formula is a saturated or unsaturated monocyclic or polycyclic alicyclic group that may have a substituent, and R^ 2 is a lower alkyl group, and R^3 is a hydrogen atom or a lower alkyl group. (2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (R^1 in the formula is a saturated or unsaturated monocyclic or polycyclic alicyclic group that may have a substituent) 4H-quinolidine-4 according to claim 1
-one derivative. (3) 4H-quinolidin-4-one derivative according to claim 2, which is represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼.