JPH051067A - Triazoloquinazolinone derivative and its pharmaceutical use - Google Patents

Abstract

PURPOSE:To provide the subject new compound having antihistaminic action, etc., and useful as antiinflammatory agent, antiallergic agent and anti-PAF agent. CONSTITUTION:The compound of formula I [R1 is lower alkyl; (m) is 2-4; (n) is 2 or 3; Ar<1> and Ar<2> are (substituted)aryl], e.g. 5,6-dihydro-3-me thyl-6-{3-[4-(4- chlorophenyl-phenylmethyl)-piperazin-1-yl]propyl}-[1,2,4]riazolo[4,3-c ]quinazolin-5(6 H)-one. The compound of formula I can be produced by reacting a compound of formula II with a compound of formula III in an inert solvent (e.g. xylene) at a temperature between 50 deg.C and the refluxing temperature of the solvent for 30min to 6hr.

Description

Detailed Description of the Invention

[0001]

The present invention relates to an anti-inflammatory agent, an anti-allergic agent and an anti-P agent which antagonize the action of PAF (platelet activating factor; hereinafter referred to as PAF) and also have an antihistamine action.
The present invention relates to a novel triazoloquinazolinone derivative useful as an AF agent.

[0002]

2. Description of the Related Art Platelet activating factor (PAF-Platelet A)
ctivating Factor-hereinafter referred to as PAF) has received a great deal of attention in recent years, and recently, its relevance to various diseases is becoming clear. That is, inflammation, allergic disease, anaphylactic shock, pulmonary shock, D
IC, endotoxin shock, cardiomyopathy, asthma,
It is presumed to be involved in pulmonary edema, gastrointestinal ulcer, nephritis, hepatitis and rejection at the time of organ transplantation. [See Hyundai Kagaku Special Issue 17, Platelet Activating Factors-Biochemistry, Physiology, Pathology, edited by Keizo Waku, Keizo Inoue, Tokyo Kagaku Dojin, 1989].
Therefore, compounds that antagonize the action of PAF are expected to have therapeutic effect in blocking or treating the above-mentioned diseases, or other diseases where it is desirable to antagonize PAF.

[0003] In fact, administration of a PAF antagonist suppressed the Alsace reaction in mice, which is a model of inflammatory reaction, indicating that PAF is involved in the inflammatory reaction (Jpn. J. Pharmacol. , 46 , 55P (1988)). on the other hand,
Among allergic diseases involved in PAF, it is known that, in addition to PAF, chemical mediators such as histamine and leukotriene are released from various cells as a result of antigen-antibody reaction. Therefore PAF
PAF is a compound that has both antagonistic and antihistamine effects
It can be expected to have a more effective antiallergic effect than the antagonist alone and the antihistamine alone.

At present, thienotriazolo-1,4-diazepine compounds are known as anti-PAF agents. (JP-A-61-176591, JP-A-2-256681, JP-A-2-256682) As a compound having both an antihistamine action and a PAF antagonistic action, only a benzocycloheptapyridine compound is known. Is. (EP 270818) On the other hand, the following compounds are known as triazoloquinazolinone compounds. (Chem.Ber. 108 , 3799 (1975))

[0005]

[Chemical 2]

However, there are no reports on the antiallergic action and the anti-PAF action of this compound.

[0007]

[PROBLEMS TO BE SOLVED BY THE INVENTION] New and useful anti-PA
Agent F is expected and required to have preventive and therapeutic effects on a wide range of diseases. Further, an antiallergic drug having an antihistamine action in addition to an antiPAF action is expected and required for prevention and treatment of allergic and inflammatory diseases.

The present invention provides a novel triazoloquinazolinone derivative having a PAF antagonistic action and an antihistamine action and a pharmacologically acceptable salt thereof, and an anti-inflammatory agent and an antiallergic agent containing the derivative as an active ingredient. , To provide an anti-PAF agent.

[0009]

The present invention provides formula (I)

[0010]

[Chemical 3]

(Wherein R ¹ represents lower alkyl, m represents 2 to 4, n represents 2 or 3, and Ar ¹ and Ar ²
Are the same or different and are substituted or unsubstituted ari-
And a pharmacologically acceptable salt thereof and an anti-inflammatory agent, anti-allergic agent and anti-PAF agent containing the compound as an active ingredient.

In the definition of formula (I), aryl represented by Ar ¹ and Ar ² has 6 carbon atoms such as phenyl and naphthyl.
~ 10 aryl and heteroaromatic rings such as 2-pyridyl. The substituent in each group is the same or different and means a substituent on the aromatic ring having 1 to 3 substituents, and represents lower alkyl or halogen.

The lower alkyl in the definition of each group of the formula (I) means a linear or branched alkyl having 1 to 3 carbon atoms, and examples thereof include methyl, ethyl, propyl and isopropyl. Further, halogen means each atom of fluorine, chlorine, bromine and iodine.

The pharmacologically acceptable salts of the compound represented by the formula (I) include inorganic acid salts such as hydrochloride and sulfate, and organic salts such as acetate, maleate, fumarate and tartrate. Amino acid addition salts such as acid salts, lysine, glycine, phenylalanine and the like can be mentioned.

When the compound of the present invention has an asymmetric carbon atom, racemates and individual optical isomers may exist, but the present invention includes all of them.

The method for producing the compound represented by the formula (I) will be described below. However, the production method is not limited thereto, and in various production methods, the reaction conditions are appropriately selected from those described below.

The compound represented by the formula (I) of the present invention has the formula (II)

[0018]

[Chemical 4]

(Wherein Ar ¹ , Ar ² , m and n have the same meanings as defined above), a compound of the formula (III) R ¹ CONHNH ₂ (III) (wherein R ¹ is as defined above) Synonyms), in a solvent inert to the reaction (xylene, butanol, hexanole, cyclohexanol, etc.) from 50 ℃ at the reflux temperature of the solvent used for 30 minutes to 6 hours It can be obtained by reacting. At this time, in order to increase the reaction rate, the reaction can be carried out in the presence of an organic acid (acetic acid, propionic acid, etc.), an inorganic acid (hydrochloric acid, sulfuric acid, etc.) or silica gel. The compound of formula (I) thus obtained can be separated and purified from the reaction mixture by a method known per se such as recrystallization or chromatography.

The compound represented by the formula (I) can be converted into the above-mentioned pharmacologically acceptable salt by treating it with an inorganic acid or an organic acid by a conventional method.

When the compound of the present invention has an asymmetric carbon atom, it is usually obtained as a racemate. The racemate can be resolved into optical isomers by a conventional method. Such optical isomers can also be produced by using an optically active compound as a starting material.

The compound represented by the formula (II) is disclosed in
It can be synthesized according to the method of No. 60-8274.

[0023]

[Chemical 5]

That is, a compound represented by the formula (IV) (in the formula, m has the same meaning as above, and X represents halogen), and a compound represented by the formula (V)
(Wherein Ar ¹ , Ar ² and n have the same meanings as described above) or an acid addition salt thereof is added to a solvent inert to the reaction (acetone, chloroform, dioxane, 2-butanone, ethanol- , Dimethylformamide, etc.)
The compound represented by the formula (VI) is obtained by reacting from room temperature to the boiling point of the solvent used for 5 minutes to 24 hours. At this time, the reaction is carried out in the coexistence of a base such as sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or triethylamine as a deoxidizing agent.

Next, phosphorus pentasulfide and a thionation reagent such as Lawesson's reagent (registered trademark) were added to a reaction inert solvent (pyridine, toluene, carbon disulfide, diglyme, acetonitrile, etc.) for 5 minutes to 24 hours at room temperature. By reacting at the boiling point of the solvent used, the compound represented by the formula (II) can be obtained.

The compounds represented by the formula (I) and salts thereof of the present invention show excellent PAF antagonistic activity and antihistamine activity, and are caused by inflammatory, allergic diseases (bronchial asthma, psoriasis, etc.) and PAF. Circulation of diseases (e.g. thrombosis, stroke, myocardial infarction, angina, thrombophlebitis, nephritis, diabetic nephropathy, endotoxin shock, endovascular coagulation syndrome caused by endotoxin, anaphylactic shock, hemorrhagic shock, etc. Disorders, gastrointestinal disorders such as gastric ulcers, pneumonia, rejection due to increased PAF production during organ transplantation, organ failure during organ surgery, etc., and diseases for which PAF antagonists are effective (such as hyperendothelinosis) , Useful as a therapeutic agent.

Since the compound represented by the formula (I) and its acid addition salt have low toxicity, they can be orally or parenterally administered to mammals as a powder or as a pharmaceutical composition in a suitable dosage form. Can be administered to.

Specific examples of the dosage form for oral administration include tablets, pills, powders, capsules, granules, syrups, emulsions and suspensions. Such a dosage form is produced by a method known per se and contains a carrier or an excipient that is usually used in the field of formulation. For example, carriers and excipients for tablets include lactose, starch, sucrose, magnesium stearate and the like.

Examples of dosage forms for parenteral administration include ointments, injections, poultices, coatings, inhalants, suppositories,
Examples include transdermal inhalants. The injection is prepared by a method known per se, for example, by dissolving, suspending or emulsifying the compound represented by the formula (I) or a salt thereof in a sterile aqueous or oily liquid usually used for injection. Examples of the aqueous solution for injection include physiological saline and glucose solution, and examples of the oily liquid include sesame oil and soybean oil, which may be used together with a solubilizing agent. The suppository used for enteral administration is prepared by a method known per se, for example, by mixing the compound represented by the formula (I) or a salt thereof with an ordinary suppository base and molding the mixture.

The effective dose and frequency of administration of the compound represented by formula (I) or a pharmacologically acceptable salt thereof depend on the administration form, the age and weight of the patient, the nature or severity of symptoms to be treated. , But usually 0 per adult per day.
1-1000 mg, preferably 1-200 mg, can be administered once or in several divided doses.

Each of the above-mentioned preparations may contain other therapeutically active ingredients as long as the compound of the formula (I) or a salt thereof does not cause an unfavorable interaction. For example, steroid drug, non-steroid anti-inflammatory drug, lipoxygenase inhibitor, leukotriene antagonist,
Phospholipase A ₂ inhibitor, interleukin 1 production inhibitor, bronchodilator, thromboxane synthesis inhibitor, thromboxane antagonist, histamine release inhibitor, cerebral circulation improver, brain protector, liver protector, anti Platelet agents, serotonin antagonists, adenosine receptor antagonists, adrenergic β receptor antagonists, immunomodulators, immunosuppressants, immunostimulants and the like can be mentioned.

The compositional examples of tablets using the compound of the present invention are shown below. Formulation Example Tablet A tablet having the following composition is prepared by a conventional method . Compound of Example 4 20 mg Lactose 80 mg Corn starch 30 mg Polyvinyl alcohol 2 mg Magnesium stearate 1 mg Tar dye Trace amount

[0033]

EXAMPLES The present invention will be specifically described below with reference to examples. The present invention is not limited to these.

Reference Example 1 1- {3- [4- (4-chlorophenyl-phenylmethyl) -piperazin-1-yl] -propyl} -2,4- (1H, 3H) -quinazolinedione (1)

[0035]

[Chemical 6]

1- (3-bromopropyl) -2,4- (1H, 3H)-
20 ml of dimethylformamide is added to 3.3 g of quinazolinedione, 3.3 g of 1- (4-chlorophenyl-phenylmethyl) -piperazine and 4.4 g of potassium carbonate, and the mixture is stirred at 70 ° C for 4.8 hours. The solvent is evaporated, water is added, the crystals are filtered and washed with ethyl acetate to give 2.6 g of the title compound.

IR (KBr) cm ^-1 : 2816,1688,1487,758 ¹ NMR (DMSO-d6) δ: 11.33 (1H, brs), 8.00 (1H, dd, J = 7.8,1.
2), 7.72-7.16 (12H, m), 4.29 (1H, s), 4.06 (2H, m), 2.31 (10
H, brs), 1.74 (2H, brs)

Reference Example 2 1- {3- [4- (4-chlorophenyl-phenylmethyl) -piperazin-1-yl] -propyl} -4-thioxo-3,4-dihydro-2 (1H) -quinazolinone ( 2)

[0039]

[Chemical 7]

2.6 g of the compound of Example 1 and 2.4 g of phosphorus pentasulfide
Add 50 ml of pyridine to the mixture and stir at 100 ° C for 7.4 hours. The solvent was distilled off, chloroform and water were added, extracted, washed with water,
dry. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform-2% methanol),
2.0 g of the title compound is obtained.

IR (KBr) cm ^-1 : 1698,1607,1584,1491,756 ¹ NMR (CDCl3) δ: 8.66-8.55 (1H, m), 7.81-7.14 (12H, m), 4.
28-4.12 (2H, m), 4.20 (1H, s), 2.7-2.3 (10H, m), 2.10-1.79
(2H, m) MS: 504 (M ⁺ )

Example 1 5,6-dihydro-3-methyl-6- {3- [4- (4-chlorophenyl-phenylmethyl) -piperazin-1-yl] -propyl}-[1,2,4] Triazolo [4,3-c] quinazoline-5 (6H) -one (3)

[0043]

[Chemical 8]

2.0 g of the compound of Example 2 and acetohydrazide
2 ml of n-butanol was added to 0.61 g, and the mixture was stirred at 150 ° C for 30 minutes while distilling off the solvent. Silica gel column chromatography (chloroform: methanol = 100: 4 to 100: 6)
Purify with to give 1.4 g of the title compound.

IR (KBr) cm ^-1 : 2942,2814,1717,1489,1350,
754 ¹ NMR (CDCl3) δ: 8.42 (1H, dd, J = 7.8,1.5), 7.58-7.17 (12
H, m), 4.31 (2H, t, J = 7.3), 4.15 (1H, s), 2.93 (3H, s), 2.52 (2
H, t, J = 6.4), 2.6-2.2 (8H, m), 1.96 (2H, t, J = 6.8) MS: 527 (M + H ⁺ )

Example 2 5,6-Dihydro-3-methyl-6- {3- [4- (4-chlorophenyl-phenylmethyl) -piperazin-1-yl] -propyl}-[1,2,4] Triazolo [4,3-c] quinazoline-5 (6H) -one.hydrochloride (4) 0.31 g of the compound of Example 3 was dissolved in methanol, acidified by adding concentrated hydrochloric acid, and then concentrated. Recrystallized from water to give 0.15 g of the title compound.

Mp: 186 ° C. (decomposition) Elemental analysis: calculated as C30H31N6Cl.HCl: C; 63.94, H; 5.72, N; 14.91 Found: C; 63.75, H; 5.72, N; 14.51 IR (KBr) cm ^-1 : 3398,2410,1717,1489,1352,754

Example 3 Next, the PAF antagonistic action and antiallergic action of the compound represented by the formula (I) will be explained. 1. Antiallergic action test (rat PCA reaction) The antiallergic action was examined according to the passive cutaneous anaphylaxis (PCA) test using rats. As an experimental animal, weigh 150-
200 g of Wister male rats were used.

A physiological saline containing an anti-dinitrophenyl group (DNP) mouse IgE monoclonal antibody (Seikagaku Corporation) was injected into the dorsal skin of the rat. 23 hours and 40 minutes later, the test compound was intravenously administered at a dose of 1 mg / kg.
Minutes later, 2 mg / ml DNPylated ovalbumin and 1% Evans blue
0.5 ml of physiological saline containing was administered through the hip vein. After 30 minutes, the carotid artery was cut to cause exsanguination, the skin was peeled off, the blue-stained portion was cut out and finely cut in 4 ml of formamide, and then the dye was extracted at 60 ° C. for 48 hours. 620 nm of the supernatant after removing the finely cut skin by centrifugation (1500 × g, 10 min)
Absorbance was measured and the amount of dye leaked locally was quantified from a calibration curve prepared in advance. The dye amount when the olive oil was administered was taken as the control, and the dye amount relative to the control when the test compound was administered was shown as the inhibition rate (n number = 4). The results are shown in Table 1.

2. Histamine antagonism 1. A test compound was intravenously administered to the same rats as the above at a dose of 1 mg / kg. 20 minutes after that, physiological saline containing 1% Evans blue was intravenously administered at a dose of 3 ml / kg, and immediately thereafter.
A 900 μM histamine solution (50 μl) was intradermally administered to the rat. After 30 minutes, the dye in the blue-stained part of the obtained skin was extracted and quantified according to the method described above. The dye amount when the olive oil was administered was taken as the control, and the dye amount relative to the control when the test compound was administered was shown as the inhibition rate (n number = 4). The results are shown in Table 1.

[0051]

[Table 1]

As is apparent from the above test results, the compound represented by the formula (I) or a salt thereof has excellent antihistamine action and antiallergic action.

3. In Vitro Platelet Aggregation Inhibition Test In order to measure the platelet activating factor (PAF) antagonism of this compound, PAF of rabbit platelets in vitro was measured.
Use induced aggregation. Venous blood is drawn from the rabbit ear vein into a plastic centrifuge tube containing 1.0% sodium citrate solution to obtain platelet-rich plasma (PRP). The ratio of sodium citrate solution to blood is 1:10
Is. The citrated blood thus obtained was allowed to stand at room temperature at 70 × g (62
Centrifuge at 5 rpm for 20 minutes and collect the upper PRP in another plastic tube. The remaining lower layer is 1500 ×
Centrifuge at g (2800 rpm) for 10 minutes to collect upper platelet-poor plasma (PPP). Platelet aggregation is measured using an aglycometer manufactured by Nikko Bioscience. PRP was dispensed into a measuring cuvette and immediately aspirin, creatinine phosphate and creatinine phosphokinase were added to a final concentration of 0.1 mM, 7 mM and
Add 45 U / ml. Subsequently, the test drug solution was added and stirred at 37 ° C for 2 minutes, and then PAF (final concentration 10
ng / ml) to induce platelet aggregation. The platelet aggregation rate is calculated from the maximum value of the aggregation curve, where the PPP permeability is the maximum aggregation (100% aggregation). The aggregation rate with the addition of physiological saline was used as the control, and the aggregation rate with the addition of each test compound was calculated as the inhibition rate for the control, and the IC ₅₀ value was determined by interpolation from the figure.

The results are shown in Table 2.

[0055]

[Table 2]

As is clear from the above test results, the compound represented by the formula (I) or a salt thereof has excellent PA.
It has an F antagonism.

4. Binding test using [ ³ H] -PAF (PAF receptor binding test) A cell membrane fraction of rabbit platelets was prepared according to the method of Hwang et al. (Biochemistry; 22 ; 4756, (1983)). This membrane fraction (50 mg) was suspended in 10 mM Tris buffer containing 0.25% bovine serum albumin, and tritium-labeled PAF was suspended therein.
([ ³ H] -PAF; 0.4 nM) and test compound were added. After keeping the temperature at 25 ° C. for 60 minutes, it was filtered through a glass fiber filter paper.
The filter paper was washed 3 times with cold Tris buffer, transferred to a vial, a scintillator was added, and the radioactivity was measured with a liquid scintillation counter. The inhibition rate (binding ability) of the test compound was calculated according to the following formula, and the IC ₅₀ value was determined by interpolating from the figure.

[0058]

[Equation 1]

The total binding amount is the amount of [ ³ H] -PAF binding radioactivity in the absence of the test compound, and the non-specific binding amount is the amount of [ ³ H] -PAF in the presence of 1 μM PAF. It is the amount of bound radioactivity. The results are shown in Table 3. WEB 2086 (Patent Document 1) disclosed as a PAF antagonist as a control drug
65-176591) was used.

[0060]

[Table 3]

As is apparent from the above test results, the compound represented by the formula (I) or a salt thereof has excellent PA.
It has an F receptor antagonistic action.

[0062]

INDUSTRIAL APPLICABILITY According to the present invention, the compound represented by the formula (I) and the pharmacologically acceptable salt thereof have both an antihistamine action and a PAF antagonistic action, and when histamine and PAF are involved. It is expected to have preventive and therapeutic effects on various possible diseases. In particular, it can be used as an anti-asthma agent, an anti-allergic agent, an anti-inflammatory agent, an agent for relieving shock symptoms, a therapeutic agent for thrombosis and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display area A61K 31/505 ACD ACL

Claims (4)

[Claims] 1. Formula (I): (In the formula, R ¹ represents lower alkyl, m represents 2 to 4, n represents 2 or 3, and Ar ¹ and Ar ² are the same or different and represent a substituted or unsubstituted aryl.)
The triazoloquinazolinone derivative represented by or a pharmacologically acceptable salt thereof. 2. An anti-inflammatory agent comprising the derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 3. An anti-allergic agent comprising the derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 4. An anti-PAF agent comprising the derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.