JPH085884B2 - 5H-Pyrazolo [4,3-a] quinolidin-5-one derivatives - Google Patents

Description

TECHNICAL FIELD The present invention has 5H-pyrazolo [4, which has an antiallergic effect and is useful as a therapeutic agent for allergic diseases such as bronchial asthma, rhinitis, dermatitis, and hypersensitivity. 3-a] quinolidine-
It relates to a 5-one derivative.

BACKGROUND ART Various compounds have been used as therapeutic agents for diseases caused by allergies, and among them, chemical mediator release inhibitors have been conventionally known as causative therapeutic drugs.

In recent years, it has been revealed that immunoglobulin E (hereinafter referred to as IgE), which is one of the immunoglobulins (hereinafter referred to as Ig) known as proteins that control the immune response of the body, acts as a causative agent of allergic diseases. Since then, IgE
The drug that suppresses the production of is attracting attention as a causative drug for these allergic diseases, and several compounds have been found so far [Japanese Patent Publication No. 54-130516, the same. 62-76].

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

Problems to be Solved by the Invention Ig is a protein that controls the immune reaction of a living body, and among them, immunoglobulin G (hereinafter referred to as IgG) plays an important role especially in infection prevention and the like.

Therefore, Ig used as a therapeutic agent for allergic diseases
It is important that the E production inhibitor does not significantly affect the production of Ig other than IgE.

An object of the present invention is to provide a 5H-pyrazolo [4,3-a] quinolidin-5-one derivative having such selective IgE production inhibitory activity and useful as a therapeutic agent for allergic diseases.

Means for Solving the Problems The present inventors have conducted intensive studies to find a compound having a selective IgE production inhibitory action and useful as a therapeutic agent for allergic diseases, and as a result, a certain 5H-pyrazolo (4 , 3-a]
The inventors have found that good results were obtained with the quinolidin-5-one derivative, and that the object could be achieved, and completed the present invention.

That is, the present invention has the general formula (Wherein R ¹ is a lower alkyl group, an aryl group or an aralkyl group, and R ² is a hydrogen atom, a lower alkyl group or an aryl group) and is represented by 5H-pyrazolo [4,3-a].
A quinolidin-5-one derivative is provided.

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

The aryl group means an aromatic carbon hydrogen group which may have an appropriate substituent on the ring, for example, a phenyl group or a naphthyl group, and the aralkyl group means a lower alkyl group having the aryl group as a substituent as described above. Means

The compound represented by the general formula (I) of the present invention is a novel compound and can be produced by the following method.

That is, the general formula (R ¹ in the formula has the same meaning as described above) and a 4H-quinolizin-4-one derivative represented by the general formula R ² —NHNH ₂ (III) (wherein R ² has the same meaning as described above) It can be produced by reacting with a hydrazine derivative represented by

The compound of the general formula (II) used as a starting material in the present production method is as described in Pharmaceutical Journal, Vol. 89, No. 2, 203-2.
It can be produced by a reaction similar to the method described on page 08, 1969.

That is, the general formula (Wherein R ¹ has the same meaning as described above), It can be produced by reacting with methyl 2-cyano-3,3-dimethylthioacrylate represented by

The compound represented by the general formula (IV) used as a starting material in the production of the compound of the general formula (II) is
Helvetica Himika Acta (Helv.Chim.Acta), 45
Vol., P.729-737, 1962.

Further, the compound of the formula (V) can be produced by the method described in Hemisch Berichte (Chem. Ber.), Vol. 95, pages 281-2870, 1962.

In order to preferably carry out the production method of the present invention, the general formula (I
The compound of I) is dissolved in a suitable organic solvent such as dimethylsulfoxide, and an excess of the hydrazine derivative (II
I) is added, and the mixture is stirred at room temperature or slightly warmed for 1 to several hours. Cold water was added to the reaction mixture, and the precipitated crystals were collected by filtration,
Wash with water and a suitable organic solvent, and dry to obtain the desired product.

The inhibitory effect of the compound represented by the general formula (I) of the present invention on IgE production is as follows.
unology), vol. 58, pp. 188-201, 1981, that is, for the dinitrophenylated Ascaris protein (hereinafter referred to as DNP-As), an adaptive secondary immune response (adoptive seconda).
It can be confirmed by an Ig production measurement test using BALB / c mouse splenocytes exhibiting ry immune response.

Further, the antiallergic action of the compound of the general formula (I) of the present invention can be confirmed also in a rat homologous anaphylaxis (Rat Homologous Passive Cutaneous Anaphylaxis, hereinafter referred to as PCA) reaction using rats.

Preferred compounds of the general formula (I) of the present invention are those in which R ² is a hydrogen atom, R ¹ is a lower alkyl group, and especially C 1
To 4 straight chain or branched lower alkyl group compounds. Preferred R ¹ includes groups such as ethyl group, n-propyl group, isopropyl group, n-butyl group, secondary butyl group, tertiary butyl group and isobutyl group.

When the compound of general formula (I) of the present invention is used for the actual treatment, suitable pharmaceutical additives such as excipients, binders,
Add various agents such as powders, tablets, capsules, syrups, and injections by adding lubricants, disintegrants, solubilizers, stabilizers, etc. according to a conventional method, and then orally or parenterally. Administered to.

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 one day when used for treatment of humans or animals The dose is generally 0 for oral administration.
The dose is 1 to 10 mg / kg, and generally 0.02 to 5 mg / kg for parenteral administration.

EFFECT OF THE INVENTION 5H-pyrazolo [4,3] represented by the general formula (I) of the present invention
-A] quinolidin-5-one derivative is ad
BALB / c showing optive secondary immune response
In a test for measuring Ig production using splenocytes of mouse strains, 10 ^-8 ~
It exhibits an inhibitory effect on IgE production of about 40-80% at a concentration of 10 ^-5 g / ml.

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

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 1-butyryl-3-cyano-2-methylthio-4H-quinolizin-4-one propyl 2-pyridylmethyl ketone (56.1 g),
A mixture of methyl 2-cyano-3,3-dimethylthioacrylate (70.0 g) is heated with stirring at 120 ° C for about 16 hours. The reaction mixture was subjected to silica gel column chromatography, and eluted with methylene chloride-diethyl ether (5: 1, v / v) to give 1-butyryl-3-cyano-2-methylthio-4H-quinolidin-4-one. (50.3g) is obtained as pale yellow crystals. ¹ H NMR (CDCl ₃ ) δ: 1.04 (t, 3H), 1.80 (m, 2H), 2.73 (s, 3H), 2.91 (t,
2H), 7.33 (dt, 1H), 7.53 (d, 1H), 7.76 (dt, 1H), 9.30
(D, 1H) Reference Examples 2 to 17 In the same manner as in Reference Example 1, the following compounds were obtained.

Example 1 4-Cyano-1-propyl-5H-pyrazolo [4,3-
a] quinolizin-5-one 1-butyryl-3-cyano-2-methylthio-4H-quinolidin-4-one (212 g, Reference Example 1) in dimethyl sulfoxide (DMSO, 1.5 l) was added to a solution of hydrazine monohydrate. (74 ml) is added, and the mixture is stirred at room temperature for 1 hour. Cold water in the reaction solution
2 l was added and the precipitated crystals were collected by filtration, and the crystals were washed with water (1.0 l),
Ethyl alcohol (0.5l), diethyl ether (0.5l)
Then, 4-cyano-1-propyl-5H-pyrazolo [4,3-a] quinolidin-5-one (144 g) is obtained as pale yellow crystals.

Mp: 298~300 ℃ IR (KBr): 2205,1670,1625,1605cm -1 1 H NMR (DMSO-d 6) δ: 1.12 (t, 3H), 1.89 (m, 2H), 3.17 (t, 2H ), 7.78 (t,
1H), 8.38 (m, 2H), 9.50 (d, 1H), 13.46 (br, 1H) Elemental analysis value: (as C ₁₄ H ₁₂ N ₄ O) C% H% N% Theoretical value 66.65 4.79 22.21 Measured value 66.78 4.81 22.21 Examples 2 to 25 The following compounds were obtained in the same manner as in Example 1.

Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location A61K 31/435 ADA

Claims (3)

[Claims] 1. A general formula (Wherein R ¹ is a lower alkyl group, an aryl group or an aralkyl group, and R ² is a hydrogen atom, a lower alkyl group or an aryl group) and is represented by 5H-pyrazolo [4,3-a].
A quinolidin-5-one derivative. 2. General formula (Wherein R ³ is a linear or branched alkyl group having 1 to 4 carbon atoms) represented by 5H-pyrazolo [4,3-
a] Quinolidin-5-one derivative. 3. A formula 5H-pyrazolo [4,3-a] quinolizin-5 represented by
On derivative.