JPS6222718A - Antagonist for blood platelet-activating factor - Google Patents

Abstract

PURPOSE:An antagonist for blood platelet-activating factor effective for anti- inflammatory diseases, asthma, etc., having strongly antagonizing action on blood platelet-activating factor, containing at least one of a 5-membered heterocy clic condensed thienodiazepine compound and its acid addition salt as an active ingredient. CONSTITUTION:An antagonist containing a compound shown by the formula [R is halogen, phenyl, etc.,; R<1> is H, lower alkyl, etc.,; R<2> is H or lower alkyl; R<3> is H, halogen, etc.,; R<2> and R<3> are mutually condensed to form trimethylene, etc.; A is =C(R<4>)- or N; N<4> is H or lower alkyl] or its acid addition salt as an active ingredient. The compound shown by the formula shows antagonizing action on aggregation of blood platelet activated factor (PAF for short) induction using blood platelet of rabbit and on bronchial muscle contraction induced by PAF of guinea pig. Namely, the compound shown by the formula can remedy various diseases such as anti-inflammatory diseases, diseases of cardiac muscle, asthma, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a platelet activating factor antagonist characterized by containing at least one type of 5-membered heterocyclic fused chenodiazepine compound as an active ingredient. More specifically, the present invention relates to a therapeutic drug for various diseases derived from platelet activating factors, which is characterized by containing at least seven types of triazolochenodiazepine compounds or imidazochenodiazepine compounds as active ingredients.

[Conventional technology]

As a compound having anxiolytic or anticonvulsant activity, S~triazolo(3,4-c)cheno(2,3-e)
(R4) Diazepine compound
Publication No. 8, Publication No. 50-10875, Publication No. 57-507
Publication No. 94, Publication No. 58-33234, Publication No. 59 = 3
0''713 or 6 (1-15634), and imidazo [2,'1-a) Cheno (2,3-e
) [l, 4) Diazepine compounds were approved by Special Publication No. 51300.
It is described in Publication No. 79.

[Problem that the invention seeks to solve]

In 1972, Benveniste et al. discovered a factor that strongly aggregates platelets (platelet-activating factor) from rabbit basophils.
ng factor, hereinafter sometimes abbreviated as PAP.

) was discovered, and in 1980, Hanahan et al. discovered that it was an alkyl ether-type phosphoglyceride with an acetyl group at the 2-position (i.e., 1-0-hexadecyl or octadecyl-2-acetyl-5n-glyceryl-3-phosphorylcholine). ) was identified.

Since then, the physiological roles of PAF have been increasingly elucidated, including platelet aggregation, immediate allergic reactions, smooth muscle contraction, inflammation, pain, edema, and modulation of the respiratory, cardiovascular, and venous systems in vivo. It has been known that it is a factor in various physiological reactions.

Therefore, when P,AF operates beyond the normal physiological response, it induces many inflammatory diseases, anaphylaxis, myocardial system diseases, asthma, pulmonary edema, and adult respiratory system diseases. Therefore, drugs that have PAF antagonistic or inhibitory activity are considered to be extremely useful in treating such diseases.

[Means to solve the problem]

In view of the above points, the present inventors conducted intensive research with the aim of developing a compound having PAF antagonistic activity, and as a result,
It was unexpectedly discovered that the above five-membered heterocyclic fused chenodiazepine compound has a strong PAF antagonistic effect, and the present invention was completed. That is, the present invention is based on the general formula [wherein R is phenyl or pyridyl which may be substituted with halogen, lower alkyl or lower alkoxy, R1 is hydrogen, lower alkyl, cycloalkyl or phenitite, and R2 is hydrogen or lower alkyl, R
3 represents hydrogen, halogen, lower alkyl, lower alkanoyl or 1-hydroxyethyl, or represents a group in which R2 and R3 are linked to each other to form trimethylene or tetramethylene. A represents -C(R4)- (here, R4 represents hydrogen or lower alkyl) or a nitrogen atom. ] The present invention relates to a platelet activating factor antagonist characterized by containing as an active ingredient at least one of a 5-membered heterocyclic fused chenodiazepine compound represented by =5- or a pharmaceutically acceptable acid addition salt thereof.

In the definitions of each symbol above, halogen refers to chlorine, bromine, fluorine, and iodine, and lower alkyl refers to alkyl having 1 to 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tertiary. Butyl, etc., lower alkoxy refers to alkoxy having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, etc., and lower alkanoyl refers to alkoxy having 2 to 5 carbon atoms. Alkanoyl, such as acetyl, propionyl, butyryl, pivaloyl,
Cycloalkyl refers to cycloalkyl having 3 to 7 carbon atoms, and refers to cyclopropyl, cyclobutyl, cyclobentylmicyclohexyl, and cycloheptyl, and pyridyl refers to 2-pyridyl, 3-bilidyl, and 4-pyridyl.

-6~ Pharmaceutically acceptable acid addition salts of the compound of general formula (1) include salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and nitric acid, or salts with inorganic acids such as maleic acid, fumaric acid, and malic acid. acid,
Examples include salts with organic acids such as tartaric acid, succinic acid, acetic acid, lactic acid, methanesulfonic acid, paratoluenesulfonic acid, and pamoic acid.

Examples of compounds of general formula N) used in the present invention include:
In addition to the compounds described in the above-mentioned patent specifications, mention may be made of all related compounds encompassed by the present invention.

The PAF antagonist of the present invention comprises a therapeutically effective amount of the compound of general formula (1) or a pharmaceutically acceptable acid addition salt thereof and, as appropriate,
It can be safely used orally or parenterally by mixing with excipients, fillers, diluents, solubilizing agents, and other pharmaceutical additives to make tablets, gunpowders, powders, capsules, granules, liquids, or injections. It can be administered to The dosage varies depending on the compound selected, the severity of the disease, age, etc., but usually 1 to 50 ml per day for adults can be administered once or divided into several doses.

Diseases that can be treated with the PAF antagonist of the present invention include:
Various diseases derived from PAF include inflammatory diseases, anaphylaxis, myocardial diseases, asthma, pulmonary edema, and adult respiratory diseases.

[Action and effect of the invention]

As is clear from the following experimental examples, the compounds of the present invention are useful as PAF antagonists due to PAF-induced aggregation using rabbit platelets.

〔Example〕

Next, the present invention will be specifically explained using experimental examples and formulation examples. The test compounds used therein are as follows.

Compound 1: 6-(o-chlorophenyl)-8-ethyl-
1-Methyl-4H-s-triazolo (3,4-,C)cheno (2,3-8)(1,
4) Diazepine compound j: 6-. (o-chlorophenyl)-1J8-dimethyl-4H-s-)riazolo[3,4-c)cheno(2,3-e)[1,4]diazepine compound 3:6-(o-chlorophenyl)-1, 7°8-
Trimethyl-4H-s-)riazolo(,3,4-C)chenol;,3-e](3,4)diazepine compound@4: 8-acetyl-6-(o-chlorophenyl)-1-methyl- 4H-s-tri, Azolo(3,4-c)cheno[2,3-e), (
1,,,4) Diazepine compound 5:6-,,(,,o-chlorophenyl)-1
-Methyl-4H-s-triazolo[3,4 7c]thieno (2,,3-e) (1,4) diazepine compound 6: 6-(o-chlorophenyl) = 1.8-
Diethyl-4H7s-triazolo[3,4-c)cheno (2,3-8) (1.4] diazepine compound'?: 6-(0-chlorophenyl) -8-(1
-Hydrokibiethyl)-1-methyl-4H”s-)riazolo (3,47,c)cheno (
2','3''e)(1,4)sia,zepine compound 8:8-ethyl-1-methyl-6-phenyl-4
H-s-triazolo(3,4- C]cheno (2,37e) (1,4) diazepine compound 9:'3-4thi-1-methyl-6-(3-pyridyl)-4H-s-)riazolo [3,4-C)cheno (2,3-e)(1,4]diazepine compound 10j6-(0-chlorophenyl)-8-ethyl-4H-s-)riazolo[3,4-c)cheno (2 ,:je) (1,4)Diazepine compound 11:8-chloro-6-(0-chloropheni=1
0-ru)-1-methyl-4H-s-triazolo(3,4-c)cheno C2,3-8) (1,4)
Diazepine compound 12: 6-(0-bromophenyl)-8-ethyl-1-methyl-4H-s-)riazolo(3,4-C)chenoC2,3-e)(1,4)
Diazepine compound 13:6-(Q-chlorophenyl)-7,8゜9
．． 10-tetrahydro-4H-s- triazolo(3,4-C)(1)benzocheno(2,3-e)(1,4)diazepine compound 14:6-(0-chlorophenyl)-8-ethyl-4H- imidazo(2,1-C)cheno(2,3-e)(1,4)diazepine compound 15:8-ethyl-6-(0-fluorophenyl)-1-methyl-4H-s-1-riazolo( 3,4-C
) Cheno [2,3 -1) (1,4) Diazepine Experimental Example 1 Inhibitory effect on rabbit platelet aggregation 1710 volumes of blood to which 3.8% sodium citrate solution was added was collected from rabbits and centrifuged at 200xg for 10 minutes. Then, platelet-rich plasma (hereinafter referred to as PPP) was prepared. Furthermore, the platelet-poor plasma (hereinafter referred to as PPP) was prepared by centrifugation at 1100Ox for 10 minutes.

Measurement of aggregation ability is described in J. Physiology, Vol. 168, 1.
BORN, described on page 78 (1963).

Measurements were made with a 6-channel NKK Hematotracer 1 (FAT"-6A) according to the turbidity measurement method of G, V, R,). Light transmission was adjusted from 0 to 100% with PPP and PPP. Stirred at 11000 rpm. While PRPo
, add 3 μl of test compound solution or solvent to 3 ml,
After holding at 7℃ for 2 minutes, synthesized platelet activating factor 3μ
Add l to give a final concentration of 8 x 10-'M,
Light transmission was recorded for 5 minutes.

The inhibition rate of platelet aggregation by the test compound was determined by the maximum light transmittance in the presence and absence of the test compound, as shown in the following formula.

From this % inhibition vs. dose curve, the IC5o value (μg/l
, 50% inhibitory concentration) were determined, and the results are summarized in Table 1.

Table 1 Experimental Example 2 Effect experiments on guinea pig bronchoconstriction were carried out using the method of Vargaf jig et al.
r, J, Pharmacol, Vol. 65, p. 185 (
(1980)]. Bronchoconstriction is measured using the Konzett and Racecy method (Konzett and R.
Ossler method, Naunyn SchIIliede
bergs^rch, t! xp, Pathol.

Pharmak, Vol. 195, page 71 (1940)
[Goto et al., Japan, J., PharmaCO
1, Vol. 30, p. 537 (1980)] as an increase in airway resistance.

Three to six female guinea pigs weighing 350 to 450 g were used in each group. After the animal was anesthetized by intraperitoneal administration of 1.5 g/kg of urethane, the back was fixed, the trachea was incised, and a cannula was inserted. Artificial respiration was performed under positive pressure at a rate of 50 strokes/min, and the airway pressure was recorded via a pressure transducer (Nihon Kohden, MFP-1) connected to the tracheal cannula. After the baseline was stabilized, platelet activating factor (Serdary Research Lab,) 0
．． 3 μg/kg was administered at 1 ml/kg through the common jugular vein to induce bronchoconstriction, and the rate of increase was determined when the maximum constriction was taken as 100%.

The test compound was administered at 0 min 2 minutes before intravenous administration of platelet activating factor.
．． 1/kg was administered intravenously.

The results were expressed as a suppression rate relative to the average rate of increase in airway resistance in the control group, and are summarized in Table 2 below.

Table 2 Experimental Example 3 Acute Toxicity 5 male mice weighing 30-45 g were given 100 doses of the test compound.
．． When &- was orally administered to 300 and 1000 ■/kg and observed for 5 days, each test compound showed 1000 ■/kg.
There were no cases of death following administration of the drug.

In addition, LDS of compound 1. The values are shown in Table 3.

Table 3 Formulation Example 1 1 part of Tablet Compound 1, 30 parts of lactose, 40 parts of crystalline cellulose and 5 parts of cornstarch were thoroughly mixed, and then thoroughly kneaded with a binder prepared from 2 parts of cornstarch. This mixture was sieved through a 16-mesh sieve, dried in an oven at 50°C,
It was passed through a 24 sieve sieve. After thoroughly mixing the obtained kneaded powder with 10 parts of cornstarch, 13 parts of crystalline cellulose, and 9 parts of talc, the mixture was compressed into tablets, and each tablet weighed 110 parts.
■ Tablets were obtained.

Formulation Example 21% Powder 1 part of Compound 1 and 90 parts of lactose are thoroughly mixed, and the mixture is thoroughly kneaded with an appropriate amount of a binder made of methylcellulose. This was sieved through a 16-mesh screen and dried at 50°C during opening. The dried granules were pressure sieved through a 32-mesh filter and thoroughly mixed with an appropriate amount of silicon dioxide to obtain a 1% powder.

Although the present invention has been fully described in the above specification and the examples contained therein, various changes and modifications may be made thereto without departing from the spirit and scope of the present invention.

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R is phenyl or pyridyl which may be substituted with halogen, lower alkyl or lower alkoxy, R^1 is hydrogen, lower alkyl, cycloalkyl or phenyl, R^2 is hydrogen or lower alkyl, R
^3 represents hydrogen, halogen, lower alkyl, lower alkanoyl or 1-hydroxyethyl, or R^2 and R^
3 represents a group in which 3 and 3 are linked to each other to form trimethylene or tetramethylene. A represents =C(R^4)- (here, R^4 represents hydrogen or lower alkyl) or a nitrogen atom. ] A platelet activating factor antagonist characterized by containing as an active ingredient at least one of the five-membered heterocyclic fused thienodiazepine compound represented by the following formula or a pharmaceutically acceptable acid addition salt thereof.