JPH01290676A - 5h-pyrazolo(4,3-a)quinolizin-5-one derivative - Google Patents

Abstract

NEW MATERIAL:A 5H-pyrazolo [4, 3-a] quinolizin-5-one derivative shown by formula I (R<1> is lower alkyl, aryl or aralkyl; K<2> is H, lower alkyl or aryl). EXAMPLE:4-Cyano-1-propyl-5H-pyrazolo [4, 3-a] quinolizin-5-one. USE:Having antiallergic action and useful as a remedy for allergic diseases such as bronchial asthama, rhinitis, dermatitis, hypersensitiveness, etc. PREPARATION:A 4H-quinolizin-4-one derivative shown by formula II is reacted with a hydrazine derivative shown by formula III in a solvent such as dimethyl sulfoxide at room temperature or under a little heating to give a compound shown by formula I. The compound shown by formula II is synthesized by reacting a ketone derivative shown by formula IV with methyl 2-cyano-3, 3- dimethylthioacrylate shown by formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention has an anti-allergic effect,
The present invention relates to 5-pyrazolo(4,3-a)quinolidin-5-one derivatives useful as therapeutic agents for, for example, bronchial asthma, rhinitis, dermatitis, hypersensitivity, and the like.

BACKGROUND OF THE INVENTION Various compounds have been used as therapeutic agents for diseases caused by allergies, and among them, chemical mediator release inhibitors have been known as agents for treating the cause.

In recent years, it has become clear that immunoglobulin E (hereinafter referred to as 1gB), which is one of the immunoglobulins (hereinafter referred to as 1g) known as a protein that controls the immune response of the living body, acts as a causative agent of allergic diseases. Since then, I
Drugs that suppress the production of gε have come to attract attention as therapeutic agents for these allergic diseases.
Several compounds have been discovered so far [Japanese Patent Publications No. 130516/1980 and No. 62-76].

However, these compounds have not yet been put to practical use.

The problem 1g that the invention seeks to solve is the protein that governs the immune response of the living body, and among these proteins, immunoglobulin G (hereinafter referred to as ``gG'') plays an especially important role in preventing infection.

Therefore, 1g used as a therapeutic agent for allergic diseases
It is important that the daily production inhibitor does not have much effect on the production of Ig other than IgE.

The object of the present invention is to provide 5-pyrazoloC4,3-a) quinolidin-5-one derivatives which have such a selective IgE production inhibiting effect and are useful as therapeutic agents for allergic diseases.

Means for Solving the Problems The present inventors have conducted extensive research to find a compound that has a selective 1g1E production inhibiting effect and is useful as a therapeutic agent for allergic diseases. As a result, a certain type of 5H-pyrazoloC4, 3
-a) Good results were obtained with quinolidin-5-one derivatives, and it was discovered that the object could be achieved, and the present invention was completed.

That is, the present invention provides a 5-pyrazo-C group represented by the general formula (in which R1 is a lower alkyl group, an aryl group, or an aralkyl group, and 1112 is a hydrogen atom, a lower alkyl group, or an aryl group).
4,3-a) Quinolidin-5-one derivatives are provided.

In the present invention, a lower alkyl group means a straight-chain or branched alkyl group having 1 to 10 carbon atoms.

An aryl group means an aromatic hydrocarbon group which may have a suitable substituent on the ring, such as a phenyl group or a naphthyl group, and an aralkyl group means a lower alkyl group having an aryl group as a substituent as described above. means.

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, 4■ expressed by the general formula (R1 in the formula has the same meaning as above)
-quinolidin-4-one derivative and the general formula (R2 in the formula
has the same meaning as above)).

The compound of general formula (II) used as a starting material in this production method is described in Pharmaceutical Journal, Volume 89, No. 2, 20
It can be produced by a reaction similar to the method described on pages 3-208, 1969.

That is, produced by reacting a ketone derivative represented by the general formula (R1 in the formula has the same meaning as above) and methyl 2-cyano-3,3-dimethylthioacrylate represented by the formula. can do.

The compound represented by the above-mentioned -Momona (IV) used as a starting material in the production of the compound of the above-mentioned -Momona (II) has Helveti force, Himi force, Acta (Helv, Ch
im, ^member a), volume 45, pages 729-737, 1
It can be prepared according to a reaction similar to that described in 1996.

Further, the compound of formula (V) is
(Chem, 8er,), vol. 95, 2861-28
It can be produced by the method described on page 70, 1962.

In order to suitably carry out the manufacturing method of the present invention, - Monka (II)
) is dissolved in a suitable organic solvent such as dimethyl sulfoxide, an excess of hydrazine derivative (I) is added thereto, and the mixture is stirred at room temperature to slightly warmed for 1 to several hours. Cold water is added to the reaction mixture, and the precipitated crystals are collected by filtration, washed with water and a suitable organic solvent, and dried to obtain the desired product.

IglE of the compound represented by the above-Momona (1) of the present invention
The production suppressing effect is caused by cellular immunology (Cellu
lar Immunology), Volume 58, 188~
p. 201, 1981, i.e. dinitrophenylated Ascaris protein (hereinafter DN
(referred to as P-As)
Immune Response (adaptive 5eco
1 using a LB/c strain mouse capsule to B showing
This can be confirmed by g production measurement test.

Furthermore, the antiallergic effect of the compound of the above-mentioned Monana (I) of the present invention was demonstrated by homologous passive anaphylaxis (R) using rats.
at Homologous Pa5sive Cut
Aneous, Anaphylaxis (hereinafter referred to as PC8) reactions can also be confirmed.

Among the compounds of general formula (1) of the present invention, preferred are compounds in which R2 is a hydrogen atom and R' is a lower alkyl group, particularly a straight or branched lower alkyl group having 1 to 4 carbon atoms. Preferred examples of R1 include groups such as ethyl group, n-propyl group, isopropyl group, lobutyl group, secondary butyl group, tertiary butyl group, and isobutyl group.

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; The daily dose is approximately 0.1-10 mg/kg for oral administration, and for parenteral administration,
It is approximately 0.02-5 mg/kg.

Effect of the invention The 5H-pyrazolo (4,
3-a) Quinolidine-5~Neon conductor is DNP-As
adaptive to 5esecondary im
BALB/c showing mune response
In a 1g production measurement test using mouse lung cells, 10
At a concentration of -8 to 10-5 g/ml, it exhibits an IgE production inhibitory effect of about 40 to 80%.

Furthermore, in the PCA reaction using Wistar rats, oral administration of 1 to 50 mg/kg shows an inhibitory activity of about 30 to 100%.

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 Propyl 2-pyridylmethyl ketone (56.1g>
, methyl 2-cyano-3,3-dimethylthioacrylate) (70.0 g) was heated and stirred at 120° C. for about 16 hours. The reaction mixture was subjected to silica gel column chromatography using methylene chloride-diethyl ether (
5:1. 1-butyryl-3-noano-2-methylthio-4H-quinolidine-
4-one (50.3 g) is obtained as pale yellow crystals.

') I NMR (CDCl2) δ: 1.04 (t, 3H), 1.80 (m, 2
H), 2.73 (s.

311), 2.91 (t, 2H), 7.33 (d
t, IH), 7.53 (d, 1N), 7.76
(dt, IH), 9.30 (d, IH) reference example
2-17 The following compounds were obtained in the same manner as in Reference Example 1.

Example 1 ■-Butyryl-3-cyano-2-methylthio-4H-quinolidin-4-one (212 g, Reference Example 1) in dimethyl sulfoxide (OMSOll, 51) was added with hydrazine hydrate (74 mL), and the mixture was heated to room temperature. Stir for 1 hour.

Add 2 portions of cold water to the reaction solution! The crystals that precipitate are filtered and treated with water (1, Oj') and ethyl alcohol (0,51').
, diethyl ether (0,5A), and 4-
Cyano-1-propyl-5d-pyrazolo[:4.3-
a] Quinolidin-5-one 144 g) is obtained as pale yellow crystals.

Melting point: 298-300°C +R (Br): 2205.1670. 1625.
1605 cm-''HNMR (DMSO-66) δ: 1.12 (t, 3H), 1.89 (m,
2H), 3.17 (t.

21(), 7.78(t, 11(), translation 3
8 (m, 2H), 9.50 (d, 1ll),
13.46 (br, IH) Elemental analysis value' (C1
4H12N40) 0% 8%
N% Theoretical value 66.65 4.79 22.21 Measured value 66.78 4.81 22.21 Examples 2-25 The following compounds were obtained in the same manner as in Example I.

Claims (3)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 is a lower alkyl group, aryl group, or aralkyl group, and R^2 is a hydrogen atom, lower alkyl group, or aryl group. ) 5H-pyrazolo [
4,3-a] Quinolidin-5-one derivative. (2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (R^3 in the formula is a linear or branched alkyl group having 1 to 4 carbon atoms) 5H-pyrazolo [4
, 3-a] quinolidin-5-one derivative. (3) 5H-pyrazolo[4,3-a]quinolidine- expressed by the formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼
5-one derivative.