JPH04503516A - Dihydropyrimidine antiallergic agent - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Dihydropyrimidine antiallergic agent The present invention relates to particular 1,4-dihydropyrimidines. These compounds are and blood cells with clinical utility in the treatment of allergies and inflammation in animals. It is a potent and selective antagonist of plate activator.

Platelet activating factor (PAF), 1-0-alkyl-2-acetyl-5n-g Lyceryl-3-phosphorylcholine is an ether phospholipid whose structure is 197 It was first revealed in 1999. This blows many inflammatory cells, platelets and kidneys 1 produced, released, and interacting with potent platelet aggregation activity. In addition, PAF can be used directly or with other strong mediator substances such as thrombocytopenia. broad-spectrum induced via release of xane-At or leukotrienes. Showing biological activity, in vitro, PAF inhibits neutrophil migration and aggregation and stimulates the release of tissue-damaging enzymes and oxygen radicals. These activities are in vivo This is important in inflammatory and allergic reactions. Consistent with the fact that PAF in the skin plays a role in the associated pain, It was found to cause an inflammatory response accompanied by accumulation of inflammatory cells and increased vascular permeability. , which is comparable to an allergic skin reaction after exposure to an allergen. similarly , acute bronchoconstriction and chronic inflammatory response caused by allergens in asthma. Both can be simulated by intratracheal administration of PAF. Therefore P antagonize the effects of AF and consequently inhibit the release of mediator substances by PAF. Drugs that prevent secretion are used to treat various allergic, inflammatory and hypersecretory disorders such as asthma, joint May have clinical utility in the treatment of rhinitis, rhinitis, bronchitis and urticaria. cormorant.

In addition to the above, PAF has been implicated in many other medical conditions. Ru. i.e., characterized by systemic hypotension, pulmonary hypertension and increased pulmonary vascular permeability In circulatory system shock, symptoms can be simulated by injecting PAF. . In conjunction with evidence showing that PAF levels in the blood are increased by endotoxin injection; This suggests that PAF is the most important mediator in certain forms of shock. At a dose of 20-200 pmol kg-'min-I to the runt, showing that Intravenous infusion of PAF resulted in the formation of extensive hemorrhagic erosions in the gastric mucosa; Therefore, PAF may contribute to the MW of some types of gastric ulcer due to its release in the body. is the strongest gastric ulcer-inducing substance that has already been described. Dry skin causes skin lesions It is a characteristically inflammatory and diffuse disease. PAF is pro-inflammatory and is associated with xerosis. This supports the possibility of an analgesic role for patients. In other words, recent research on patients with angina pectoris Research has shown that PAF is released during the atrium's pacing. To the pig Intracoronal injection of PAF in the brain results in a prolonged decrease in coronary blood flow and PAF causes focal shunting and ischemia in the guinea pig heart. Both externally administered and internally released mesenteric artery markers Known to initiate blood clot formation. More recently, PAF It is known to play an important role in cerebral ischemia induced in medium animal models. ing.

That is, the compounds of the present invention have the ability to antagonize the action of PAF, and therefore are effective in treating the above-mentioned symptoms. It is useful for

According to the invention, the following formula: (In the formula, Ar is (a) optionally a nitro group, a halogen atom, a trifluoromethyl group, Alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, fluoro- (alkoxy having 1 to 4 atoms) group, alkylthio group having 1 to 4 carbon atoms, carbon each from an alkylsulfonyl group having 1 to 4 atoms, a hydroxy group, and a cyano group; a phenyl group optionally substituted with 1 to 3 independently selected substituents; (b) is either a methylenedioxyphenyl group or a benzothenyl group. the law of nature; R1 is an alkyl group having 1 to 4 carbon atoms; R2 is a hydroxy group; number of carbon atoms 1-4 alkoxy group; alkylthio group having 1-4 carbon atoms; 1-4 carbon atoms an alkyl group; optionally substituted with one or two halogen substituents; phenyl group: or a group represented by -NR3R', in which R3 and R4 are each independently H or an alkyl group having 1 to 4 carbon atoms; and “He Bi has one or more nitrogen atoms and optionally one oxygen or sulfur in the ring. atoms, optionally containing one or more nitrogen atoms or one nitrogen atom in the benzene ring or rings. yet another 5- or 6-membered aromatic heterocyclic ring containing an oxygen or sulfur atom; A 5- or 6-membered aromatic heterocyclic group that may be fused, and One or both are optionally an alkyl group having 1 to 4 carbon atoms, and 1 to 4 carbon atoms. from an alkoxy group, a halogen atom, a trifluoromethyl group, and a cyano group, respectively. optionally substituted with up to three independently selected substituents) Provided are compounds represented by and pharmaceutically acceptable salts thereof.

As defined herein, the term halogen atom refers to fluorine, chlorine, bromine or means an iodine atom. Alkyl and alkoxy groups with 3 or more carbon atoms are directly It may be a chain or a branched chain.

'Het' is preferably imidazolyl, thiazolyl, oxacylyl, triazolyl pyridyl, benzimidazolyl, imidazopyridyl or imidazothiazolyl and all these groups are optionally defined as for formula (1). may be replaced with

A typical example of “Het” is 2-methylimidazo(4,5-c)pyrid-1-yl , 2-trifluoromethylimidazo(4,5-c)pyrid-1-yl, 2-ni Butyl-imidazo[4,5-c)pyrid-1-yl, 3,5-dimethyl-1゜2 , 4-triazol-4-yl, 2-methylimidazo(4,5-b)pyrido- 1-yl, 2-methylimidazo(1,2-a]pyrid-3-yl, 2-methylbenzene dimethylimidazol-1-yl, 2,4.5-)dimethylimidazol-1-yl , 2,4-dimethylthiazol-5-yl, 2,4-dimethyloxazole-5 -yl, 2,6-dimethylpyridol-3-yl and 2-methylimidazo(1,2 -b]thiazol-3-yl group.

When R8 is -OH, the following tautomers are possible, both tautomers and Also within the scope of this invention: Similarly, when R3 or R゛ is H, the following tautomers are possible, where However, both tautomers are within the scope of the invention: Ar has (i) one or two halide Phenyl group substituted with rogene substituent, (11) methylenedioxyphenyl and (iii) a benzothenyl group, where Ar is 2- Most preferred is a chlorophenyl group.

R1 is preferably a methyl group or an ethyl group.

Ro is preferably hydroxy, methoxy, methylthio, amino, methylamino, Dimethylamino, methyl or phenyl group.

“Het” is preferably a 2-methylimidazo(4,5-c)pyrid-1-yl group It is.

The compound represented by formula (1) has at least one asymmetric center and one or more pairs of enamel. Exists as anti-thiomers. Such paired or individual isomers can be isolated by physical methods. can be separated, e.g. decomposed compounds or their suitable salts or derivatives can be separated. This invention can be separated by separate crystallization or chromatography. Includes all enantiomers whether separated or not.

Pharmaceutically acceptable acid addition of a compound represented by formula (1) to form such a salt Salts are those formed from acids that form non-toxic acid addition salts, such as hydrochloride, odorous Hydrohydrides, sulfates or hydrogen sulfates, phosphates or acid phosphates, acetic acid salt, citrate, fumarate, gluconate, lactate, maleate, succinate salts and tartrates.

The compound represented by the formula ■ can be obtained according to the following reaction formula: (wherein, Ar, R ', R'' and Het are as defined above, provided that R1 is -OH. ) In a typical procedure, the ketoester cap) and formula (II) a compound represented by, optionally in the presence of a base such as sodium bicarbonate, in a suitable organic solvent such as ethanol or dimethylformamide for several hours. For example, heat together at 60-80°C. Then the product represented by formula (1) isolated and purified by conventional methods, e.g. by partitioning, recrystallization or chromatography. can be done.

Some of the compounds represented by formula (1) can be conveniently prepared using simple chemical transformation reactions. In formula (1), R2 is preferably an alkoxy group having 1 to 4 carbon atoms. or a methoxy group can undergo conventional dealkylation reactions, e.g. Using hydrochloric acid in a suitable organic solvent at about room temperature, the corresponding It becomes a compound.

The ketoester represented by formula (Ill) is a known compound or can be prepared as described below. It can be prepared by methods identical to those of the prior art, such as those described in the Preparation Examples.

The activity of the compound represented by formula (1) is the platelet aggregation activity of PAF in vitro. This is indicated by the ability to prevent The test is performed as follows: blood sample The sample was taken from either a rabbit or a human and 0.1 volume of ethylenediamine was added. platelet enrichment by centrifuging the sample for 15 minutes. Obtain wealth plasma. Furthermore, the plasma is centrifuged to form a platelet pellet, which is Buffer (4mWKHzPO, 6mM NatHPO, 10r)mMNacI, Wash with 0.1% glucose and 0.1% bovine serum albumin, pH 7.25) and finally resuspended in buffer solution to a concentration of 2 x 10" platelets/d. (0,5d) in vehicle alone or in a vehicle containing the particular compound under test. Both of them were stirred for 2 minutes at 37°C in a Pa-ton flocculation company. Play invest. Maximum agglutination reaction is obtained in the absence of test compound Add PAF at a sufficient concentration (10-” to 10-9 molar) to inhibit platelet aggregation from the solution. Measured by tracking the increase in light transmission. of a test compound over a range of concentrations. Repeat the experiment in the presence of the amount necessary to reduce the reaction by 50% of its maximum value. The compound concentration is IC. Record as a value.

The activity of the compound represented by formula (1) is also shown in mice due to the lethal effect of PAF injection. It is also demonstrated in vivo by its ability to protect 0.9%-/V sodium chloride A mixture of medium PAF (50μ/kg) and DL-propranolol (5μ/kg), Inject mice via tail vein (0.2 d). The compound under test is PAF/ Inject into the tail vein immediately before propranolol injection or gavage 2 hours earlier administered orally. Administration of several doses of compound to groups of 5 mice each PDs are tested and the dose that reduces the mortality rate by 50%. Record as a value.

The compound also inhibited PAF-induced tracheal damage in anesthetized guinea pigs. The ability to reduce twitch contractions is also tested. In this test, airway resistance Measure bronchoconstriction. Test compound administered 1 hour after first dose of PAF Compounds that reduce the bronchoconstrictor effect of PAF, causing repeated attacks by PAF Calculate the ability as a ratio.

For therapeutic use, compounds of formula (1) are generally administered according to the intended route of administration and and a pharmaceutical carrier selected in accordance with standard pharmaceutical practice. It will be done. For example, tablet forms containing starch or lactose as excipients, or even alone or capsules or pellets mixed with excipients, or flavorings or colorings. It can be administered orally in the form of an elixir or suspension. These are also For example, it can be parenterally injected by intravenous, intramuscular or subcutaneous injection. parenteral administration In some cases, these may include other substances, such as sufficient salt or It is best used in the form of a sterile aqueous solution containing glucose or glucose.

Administration to humans in the treatment or prophylaxis of allergic bronchial diseases and arthritis When used, the oral dosage of the compound is generally 2 times a day for an average adult patient (70 kg). It is in the range of ~1000■. i.e. for a typical adult patient, individual tablets or Capsules contain the active substances 1 to 1 in a suitable pharmaceutically acceptable vehicle or carrier. Doses for intravenous administration, including 500 μl, are generally given in single doses as needed. It is in the range of 1 to 10 cm. For the treatment of allergic and tracheal traffic reactivity symptoms For patients, inhalation via nebulizer or aerosol is the preferred method of drug administration. It is the root. Dosage levels by this route may be 0.000. It is within the range of 1 to 50 ■. In reality, the doctor will determine the most suitable for the individual patient. Determine the practical dose, which will vary depending on the age, weight, and response of the particular patient. The above dosages are illustrative of the average case, and of course higher or lower dosages may be used. There may be individual cases where dosage ranges may be advantageous and such are also within the scope of the invention. Ru.

Therefore, in another aspect, the present invention relates to a compound represented by formula (+) or its Pharmaceutical composition comprising a pharmaceutically acceptable salt and a pharmaceutically acceptable diluent or carrier It provides:

The present invention also has applications in medicine, particularly in humans for allergy, inflammation and A compound represented by (1) or its compound for use in the treatment of hypersecretion Contains pharmaceutically acceptable salts.

The preparation of the compound represented by formula (1) will be further explained according to the following examples. .

Actual journey worker 4-2-chlorophenyl-14-dihydro-5-ethoxycarbonyl-2-methane Toxi-6-4-2-methylimizo 45-c bi-1 do-1-yl Egoto Y tanship and 2z 1-one (200 m, see Example 1 of Class J), 0-methylisourea hydrogen sulfate (155 ■) and sodium bicarbonate (240 ■) in dimethylformamide ( DMF) (5 m) at 70°C for 16 hours. The cooled mixture was diluted with water (25 -) and extracted with ethyl acetate (3X25m). Wash the collected organic layer with water, Dry (MgSOJ), filter, evaporate, and chromatograph the residue on silica. Roughly eluted with methylene chloride/methanol. The product containing fluxicon Upon collection and evaporation, the title compound (105,) was obtained, m, p, 22B-23 2°C9 analysis% knee Actual measurement value: C, 63,48; H, 4,87; N, 13.95; Calculated value Cz, HtaCINsOs・+Au, o: C, 63, 47, H, 4, 93; N, 13.71 disaster relief efforts The following compounds were prepared using the appropriate 3-(aryl-substituted)propenoester by the method of Example 1. and O-methylisourea or S-methylthiourea or substituted Made using guanidine.

1 Analysis of 574H20; Analysis of umbrella H,0 Disaster relief efforts The following compound is 3-(2-chlorophenyl)-2-ethoxycarbonyl-'1- C4-(2-methylimidazoC4,5-c)pyrid-1-yl)phenyl]pro The method of Example 1 was followed using boo-2-en-1-one and the appropriate amidine hydrochloride. Made by.

Implementation■Yu 4-2-chlorophenyl-14-dihydro-5-oxycarbonyl-6-4 -2-methylimizo 45-Cpi1bi-1-yl phenyl pyuenyl Two masters 4-(2-chlorophenyl)-1,4-dihydro-5-ethoxycarbonyl-2 -methoxy-6-(4-(2-methylimidazo(4,5-c)pyrid-1-yl ) phenyl) pyridine (100) in methanol/tetrahydrofuran 1:1. solution (10ati) and then dry the organic layer (MgSOa). , filtered and evaporated. The residue was chromatographed on silica and ethyl acetate / diethylamine, the product-containing components were collected and evaporated to give the title compound (7 5■) was obtained, m, P, >300''C.

analysis%: Actual value: C, 60,43; H, 4,64; N, 13.21; Theoretical value (C zJbzCINsOs/1!4LO): C, 60, 64; H, 4, 89; N, 13.6 The following Preparation Examples provide the new starting materials used in the previous Examples. Explaining the preparation: Hand-made example 2-chlorobenzaldehyde (2.8 g), ethyl 4'-(2-methylimida Zo(4,5-c)pyrid-1-yl)benzoyl acetate (6,4g - Preparation example 2) and piperidine (100 pf) in acetonitrile (30 pf). ) at room temperature for 48 hours. The mixture was evaporated to dryness and the residue was chromatographed on silica. The product-containing fraction was eluted with ethyl acetate/methanol (5:1). The fractions were collected and evaporated to give the title compound (5.3 g).

N, cr, (COCl, x + 300 MHz), δ = 1.35 (311, t, J 8Hz, C%CHt); 2.53 (38,5,CP,-”:); 4.27 (2H, d, J 8Hz, CHsCHz); 7-9.1 (12H , m) Preparation spots 2 trillion or more The following compound was produced by the method of Preparation Example 1 using a suitable aromatic aldehyde. .

Made of clay ■Soil Ethyl 4'-2-methylimizo 45-c bi-1dol-l-yl benzo substance Wai Kishi (Y, K15hi), Nis M Haninck (S, M, Han) nick), J. Or, Che-01983, 48, 3833.

Zinc powder (894 μ, 13.7 mmol) was dried in tetrahydrofuran under nitrogen. (3 m) and sonicated for 10 min at room temperature. Ethyl bromoacetate ( 2 drops) were added and the mixture was refluxed for 5 minutes. in dry tetrahydrofuran (6d) 1-(4-cyanophenyl)-2-methylimidazoC4,5-c)pyridine(6 A solution of 40 μm, 2.74 mmol) was added, and the mixture was refluxed for 5 minutes.

Ethyl bromoacetate) (1,822 g) in dry tetrahydrofuran C2d) , 10.94 mmol) was added dropwise under reflux over 1 hour. After an additional 10 minutes, the mixture was allowed to cool to room temperature. 50% potassium carbonate aqueous solution (Ld) was added and the mixture was stirred at room temperature for 45 minutes, then Arbocel Filter through filter aid and wash with THF. The filtrate was concentrated under reduced pressure to give a yellow gum. I got something like that. This material was stirred at room temperature for 15 minutes in a 20% aqueous trifluoroacetic acid solution (10% m) and dichloromethane (50d). Add the mixture to saturated bicarbonate Neutralize by addition of aqueous thorium solution and then extract with dichloromethane (2X30d). I put it out. The collected extracts were dried (MgSOJL, concentrated under reduced pressure, and the crude product was filtered. Rush chromatography (eluted with 10-20% methanol solution in ethyl acetate) ) to produce ethyl 4'-(2-methylimidazo(4,5-c)pi (rid-1-yl)benzoyl acetate (480 ■.

54%) was obtained as a yellow gum.

The material obtained with method A was a white solid after recrystallization from ethyl acetate; ■, p , 111. -112'C.

'H-NMR (300MH2, CDCl5) 1.32 (3Lt, J6H z), 2.61 (3H, s), 4.09 (2H, s), S. 28 (21 (, q, J 6Hz), 7.16 (LH, d, J 6Hz), 7 ．． 55 (2H, d, J 9) 1z), 8.23 (28, пA J 9 Hz), 8.46 (1B, d, J 6Hz), 9.09 (1B, s) method (a) l: 121j tylphenyl amino-3-nido-1 Kore 1 and Otsuka Sakeeta 4-chloro-3-nitropyridine hydrochloride (9.75 g, 5 0 mmol) dissolved in ethanol (p-aminoacetate in 2HM solution). Add to the slurry of phenone (6.76 g, 50 ae) and stir the mixture overnight at room temperature. did.

The mixture was quenched in water, the yellow solid was filtered off and dried under reduced pressure. Yield 10 ．． 1g (69%), ■, p197-200°C0'H-NMR (300MH2, DMSO-da) 2.61 (3H, s), 7.19 (1,) 1. d, J 7Hz), 7.53 (2k d.

J 8H2), 8.07 (211, d, J 8Hz), 8.33 (IL d, J711z), 9.36 (IH, s), 10. V4 (LH, 5) (b) Q-acetylphenyl amino-3-aminobidine 4-(4-acetyl phenyl)amino-3-nitropyridine hydrochloride (2.0 g.

71.8 mmol) was partitioned between aqueous sodium hydroxide and dichloromethane. (3x20d), the combined organic layer was washed with water (20m) and concentrated under reduced pressure to a solid. I got a body. Add ethanol (20d) and dilute the solution to 50p, s, i, (34 Hydrogenated on 5% palladium-supported charcoal (0.2 g) for 3.5 h at 5 kPa) . The catalyst was filtered off and the solvent was removed under reduced pressure to give a brown solid (1.8 g), which This was used directly in the next reaction without further purification: wound p, 165-166 °C (after recrystallization from ethanol).

'H-NMR (300MHz, DMSO-d,) 2.47 (3H, s), 5.00 (2H, br, s), 7.04 (3H, mL7.70 (18, br , s), 7.83 (2H, d, J 8Hz), 7.98 (IH, br, s ), 8.12(1)1. s) Acetic acid (204m) and acetic anhydride (204m ) in 4-(4-acetylphenyl)amino-3-aminopyridine (68.0 g , 0.3 mmol) dissolved in the solution was heated to 95°C for 1.5 hours and then Cooled and concentrated under reduced pressure. Dissolve the residue in water (500-) and add saturated ammonia water. was added to make it basic. The product was filtered off and washed with water (2X100d) I under reduced pressure. Upon drying to give the title compound (61.0 g, 81%) as a brown solid; m, p, 155 156°C (after recrystallization from water).

'II-NMR (300Mtlz, CDCl5), 2.59 (3[1,s) , 2.72 (3B, s), 7.12 (IH, d, J@5H2).

7.53 (211, d, J 88K), 8.22 (2M, d, J 8H z), 8.40 (1B, d, J 5) 1z), 9. O4 (IO, 5) (d) Ethyl・4'-2-)5-tv4亙'bu　4　5-c　e')'-1 2(/L, 1-(4-acetyl)fluoride in L dry tetrahydrofuran (175 m). phenyl-2-methylimidazo(4,5-c)pyridine (17.5g, 69.7 (mmol) dissolved in the solution was heated under reflux with stirring for 45 minutes, of trahydrofuran (35d) and diethyl carbonate (24.7g, 209 mmol) Addition of sodium hydride (3,68 g, 153 mmol) to the slurry in the mixture did. After another hour, the mixture was cooled, hexane (200d) was added, and The resulting precipitate was filtered off and washed with hexane (2×100d). The solid was dissolved in acetic acid. It was suspended in chill (200m) and acetic acid (io, 2g) was added. After stirring for 15 minutes , water (200 d) was added and the ai was separated. The aqueous layer was diluted with ethyl acetate (100m). Extract and wash the collected organic solution with water (200-) and dry (gate gsO4) L, f i'1M gave a gum (17.3 g, 77%). This substance is desired Flash chromatography (eluted with ethyl acetate:methanol-7:1) Further purification gave the title compound as a white solid.

1-(4-cyanophenyl)-2-methylimida in absolute ethanol (55d) Zo[4,5-c)pyridine (12.0 g, 51.3 mmol) and 40% water A mixture of aqueous sodium oxide (55d) was heated to reflux for IA hours. Remove solvent under vacuum The brown residue was dissolved in water. Reduce the solution to O'C by adding ice. It was rapidly cooled.

Glacial acetic acid (approximately 33 m) was added slowly. Filter off the precipitated pale yellow solid and wash with water. and dried at 70°C under reduced pressure. Yield 9.14g (70%).

'H-N? IR (300MHz, DMSO-dJ 2.49 (3B, s), 7.25 (1B, d, J 6Hz), 7.72 (2g, d.

J 682), 8.17 (2H, d, J 6H2), 8.30 (IH, d , J 6H2), 8.92 (IH, s) oxalyl chloride (17,0m, 18 4 mmol) in dry dichloromethane (200 m) under nitrogen with ice cooling. 4-(2-methylimidazoC4,,5-c)pyrid-1-yl)benzoic acid (11 , 64 g, 46 mmol) and dry dimethylformamide (0.2 m). added. At the end of the addition, the mixture was sonicated for 1 hour at room temperature and then concentrated under reduced pressure. and resuspended in dry dichloroethane (200aN).

In a separate flask, add isopropylmagnesium chloride (2 Mi solution (137 yd, 274 mmol) was added to ethylmalonic acid at 0°C for 20 minutes. (18.14 g, 137 mmol) was dissolved in dry dichloromethane (100 d). The solution was added to the solution. After a further 20 minutes, the solution was brought to room temperature to form the acid chloride produced above. was added to the suspension. The red mixture was sonicated for 30 minutes at room temperature and then treated with 4N hydrochloric acid ( 250 m) was cooled in water. The mixture was stirred at room temperature for 10 minutes and diluted. Diluted with lolomethane (200m) and separated the layers. Saturate the aqueous layer with sodium bicarbonate. Neutralized with aqueous solution and extracted with dichloromethane (3×200d). The collected extract Dry (MgSO,) L, concentrate under reduced pressure to obtain a yellow gum, which is It crystallized slowly on standing. Yield: 12.10g (80%).

weekly kimono i -4-cyanophenyl-2-methylimizo 45-c pyridine (a) N- 4-Cyanophenyl-4-aminol 3-nitrobi1dine J, C, S, Per kin Trans, 1. 1979. By the method of 135, P-cyano Aniline (6,894 g, 58.4 mmol) in ethanol (200 d) 4-chloro-3-nitroviridine (9.26 g, 58.4 mmol) was dissolved in The mixture was stirred at room temperature for 18 hours. The resulting yellow suspension was The mixture was poured into water-cooled dilute ammonia (500 g) and filtered. Boil solid ethanol 15 0 m, cooled in water, and filtered to give N. 12.15 g of amino-3-nitropyridine was obtained as a light yellow powder; m, p , 210 211°C0'H-NMR (CDCh, 300MHz): 7. 15 (II (, d, J 6flz), 7.45 (2H, d, J 9Hz) , V. 79 (2H.

d, J 9Hz), 8.43 (IH, d, J 6Hz), 9.36 (I H, s), 9.80 (18, br, 5) (b) 3-amino-4-4'-sia Nophenyl-aminopyridine Phar-1Helν, Acta, 1975, By a modified method of 50, 188, tin dichloride hydrate (56.4 g, 250 mi rimole) in a 2N aqueous hydrochloric acid solution (35IR1), water (150ae) and ethanol. N-(4-cyanophenyl)-4-amino-3-nitropyridine in (75m) (12.0 g, 50 mmol) was added to the suspension, and the resulting mixture was The mixture was heated under reflux for 10 minutes. Cool the mixture in water and add water-cooled 2N sodium hydroxide. The mixture was poured into aqueous solution (400d) and filtered. 2N hydroxide of cream-colored solid It was washed with an aqueous sodium solution and water, and then dried in a vacuum desiccator. product , 3-amino-4-(4'-cyanophenyl)aminopyridine, 9.31g is , gradually turns reddish-brown on exposure to light and air.

'H-NMR (CDCIs, 300MHz) 3.52 (2H, br, s), 6.04 (IH, br s), 7.03 (2B, d, @J 9 Hz), 7.59 (28, d, J 91 (z), 8.07 (18, m), 8.2 0(1B,5)3-amino-4-(4'-cyanophenyl)aminopyridine(9 , 31 g, 44.3 mmol), triethyl-orthoacetate (40d) or A mixture of and acetic anhydride (30d) was heated to reflux under nitrogen for 2 hours, cooled and then The mixture was concentrated under reduced pressure. The brown residue was dissolved in 1M hydrochloric acid and ethyl acetate (200id ). The aqueous layer was made basic with saturated aqueous ammonia, dichloromethane (3X2 00m). The collected extracts were washed with water, dried (MgSOJ), and concentrated. and 1-(4-cyanophenyl)-2-methylimidazoC4,5-c)pyridine , 6.5 g were obtained as a brown solid.

'H-NMR (CDCIs, 300MHz): 2.61 (3H, s), 7.13 (Ill, d, J 6Hz), 7.58 (2P, d, J 9 Hz), 7.98 (2H, d, J 9Hz), 8.45 (1B, d, J 6Hz), 9.11 (IH, s) From the above explanation, the scope of the claims of the present invention It will be clear that it includes the following:

(1) Compounds represented by formula (1) and pharmaceutically acceptable salts thereof; (2) The methods described herein for preparing compounds of formula (1) and their salts Method; (3) A compound represented by formula (1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt thereof a pharmaceutical composition comprising an acceptable diluent or carrier; (4) for medical use, especially for allergy Compounds of formula (1) for use in the treatment of inflammation and inflammation or a pharmaceutically acceptable salt thereof; (5) for the treatment of allergies and inflammatory symptoms; Formula (1) for manufacturing pharmaceuticals (attached sheet) The scope of claims is amended as follows.

r10th order formula (I): Ar is (a) optionally a nitro group, a halogen atom, a trifluoromethyl group, a carbon Alkyl group having 1 to 4 atoms, alkoxy group having 1 to 4 carbon atoms, fluoro-( alkoxy) group having 1 to 4 carbon atoms, alkylthio group having 1 to 4 carbon atoms, carbon each independently from an alkylsulfonyl group having 1 to 4 atoms, a hydroxy group, and a cyano group; a phenyl group optionally substituted with 1 to 3 independently selected substituents, or (b) methylenedioxyphenyl group or benzothenyl group; R1 is an alkyl group having 1 to 4 carbon atoms; R2 is a hydroxy group; number of carbon atoms 1-4 alkoxy group; alkylthio group having 1-4 carbon atoms; 1-4 carbon atoms an alkyl group; optionally substituted with one or two halogen substituents; phenyl group; or a group represented by -NR"R', in which R3 and R4 are each independently H or an alkyl group having 1 to 4 carbon atoms; and “Het” means one or more nitrogen atoms and optionally one oxygen or ion in the ring. optionally one or more nitrogen atoms or one in the benzene ring or ring yet another 5- or 6-membered aromatic heterocyclic ring containing an oxygen or sulfur atom a 5- or 6-membered aromatic heterocyclic group which may be fused with One or both of the above may optionally be an alkyl group having 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms. Each of the alkoxy groups, halogen atoms, trifluoromethyl groups and cyano groups of 4 each may be substituted with up to three independently selected substituents) *’I+-mu”jJI’1-Ji+tノ>pl+r’filow) Substituted phase Nyl group, (II) methylenedioxyphenyl group and (I[I) benzochenyl group selected from the group pyridol-1-yl, 2-trifluoromethylimidazo(4,5-c) Pyrid-1-yl, 2-nibutyl-imidazo[4,5-c:lpyrid-1- yl, Ar is (a) optionally a nitro group, a halogen atom, trifluoromethyl group, alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, fluorocarbon group, Rho-(alkoxy having 1 to 4 carbon atoms) group, alkylthio group having 1 to 4 carbon atoms , an alkylsulfonyl group having 1 to 4 carbon atoms, a hydroxy group, and a cyano group A phenyl group optionally substituted with 1 to 3 substituents each independently selected from , or (b) a methylenedioxyphenyl group or a benzothenyl group; R1 is an alkyl group having 1 to 4 carbon atoms; R2 is a hydroxy group; number of carbon atoms 1-4 alkoxy group; alkylthio group having 1-4 carbon atoms; 1-4 carbon atoms an alkyl group; optionally substituted with one or two halogen substituents; phenyl group; or a group represented by -NR"R', in which R3 and R4 are each independently H or an alkyl group having 1 to 4 carbon atoms; and “Het” means one or more nitrogen atoms and optionally one oxygen or ion in the ring. optionally one or more nitrogen atoms or one in the benzene ring or ring yet another 5- or 6-membered aromatic heterocyclic ring containing an oxygen or sulfur atom a 5- or 6-membered aromatic heterocyclic group which may be fused with One or both of the above may optionally be an alkyl group having 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms. Each of the alkoxy groups, halogen atoms, trifluoromethyl groups and cyano groups of 4 each may be substituted with up to three independently selected substituents) A method for producing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, the method comprising: I) and (I[[) (wherein Ar, R'', R'' and Het are as defined above However, R2 is not -OH. ) react together with the compounds represented by let me, The resulting compound is optionally dealkylated to form a compound of formula (1) in which R2 is -OH. ) of the compound represented by formula (1). Production method.

Mi, compound (II) and (I[[) in an organic solvent as described in the claims Method.

The method described in section.

M, Ar is (■) a phenyl group substituted with one or two halogen substituents , (n) methylenedioxyphenyl group and (Ill) benzochenyl group@! , Claim 1 wherein Ar is a 2-chlorophenyl group The claimed '?' in which n and R' are methyl or ethyl groups. +3 The method according to any one of the ranges 4 to 4.

God, R” is hydroxy, methoxy, methylthio, 1 now The method according to any one of paragraph 1.

! 6 God, imidazolyl, thiazolyl, oxasily with optional substitution of “Het” triazolyl, triazolyl, pyridyl, benzimidazolyl, imidazopyridyl or Claim 't15 which is a midazothiazolyl group The method according to any one of Items 0 to Sakaki.

"Bet" is 2-methylimidazo(4,5-c)pyrid-1-yl, 2 -trifluoromethylimidazoC4,5-'c)pyrid-1-yl,2-ni Butyl-imidazo(4,5-c)pyrid-1-yl,2-methylimidazo (4,5-b)]Pyridol-1-yl2-methylimidazo(L2-a) Rid-3-yl, 2-methylbenzimidazol-1-yl, 2,4.5-) Dimethylimidazol-1-yl, 2,4-dimethylthiazol-5-yl, 2 ゜4-dimethyloxazol-5-yl, 2,6-dimethylpyridol-3-yl or 2-methylimidazo[1,2-b　)thiazol-3-yl group, 1? Jp;1. "Het" is 2-methylimidazoC4,5-c).

A therapeutic agent for allergic or inflammatory symptoms, containing the compound described in .

λ01 Azusa, blood cells containing the compound according to any one of claims 1 to 8. Pharmaceutical compositions for antagonizing plate activators. j international search report

Claims (21)

[Claims] 1. The following formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (in the formula, Ar is (a) optionally a nitro group, a halogen atom, a trifluoromethyl group, a carbon Alkyl group having 1 to 4 atoms, alkoxy group having 1 to 4 carbon atoms, fluoro-( alkoxy) group having 1 to 4 carbon atoms, alkylthio group having 1 to 4 carbon atoms, carbon each independently from an alkylsulfonyl group having 1 to 4 atoms, a hydroxy group, and a cyano group; a phenyl group optionally substituted with 1 to 3 independently selected substituents, or (b) a methylenedioxyphenyl group or a benzothienyl group; R1 is an alkyl group having 1 to 4 carbon atoms; R2 is a hydroxy group; number of carbon atoms 1-4 alkoxy group; alkylthio group having 1-4 carbon atoms; 1-4 carbon atoms an alkyl group; optionally substituted with one or two halogen substituents; phenyl group; or a group represented by -NR3R4, in which R3 and R4 are each independently H or an alkyl group having 1 to 4 carbon atoms; and “Het” means one or more nitrogen atoms and optionally one oxygen or ion in the ring. optionally one or more nitrogen atoms or one in the benzene ring or ring yet another 5- or 6-membered aromatic heterocyclic ring containing an oxygen or sulfur atom a 5- or 6-membered aromatic heterocyclic group which may be fused with One or both of the above may optionally be an alkyl group having 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms. Each of the alkoxy groups, halogen atoms, trifluoromethyl groups and cyano groups of 4 each may be substituted with up to three independently selected substituents) A compound represented by or a pharmaceutically acceptable salt thereof. 2. Ar is (I) or a phenyl group substituted with two halogen substituents, (II ) methylatedioxyphenyl group and (III) benzothienyl group. A compound according to claim 1. 3. 3. The compound according to claim 2, wherein Ar is a 2-chlorophenyl group. 4. Any one of claims 1 to 3, wherein R1 is a methyl or ethyl group. Compound according to item 1. 5. R2 is hydroxy, methoxy, methylthio, amino, methylamino, dimethy Any one of claims 1 to 4, which is a ruamino, methyl or phenyl group. The compound according to item 1. 6. “Het” may be optionally substituted imidazolyl, thiazolyl, oxy Sazolyl, triazolyl, pyridyl, benzimidazolyl, imidazopyridyl or imidazothiazolyl group, according to any one of claims 1 to 5. Compounds described. 7. “Het” is 2-methylimidazo[4,5-c]pyrid-1-yl, 2-t Lifluoromethylimidazo[4,5-c]pyrid-1-yl, 2-n-butyl imidazo[4,5-c]pyrid-1-yl, 3,5-dimethyl-1,2,4-to Riazol-4-yl, 2-methylimidazo[4,5-b]pyrid-1-yl, 2-methylimidazo[1,2-a]pyrid-3-yl, 2-methylbenzimida Zol-1-yl, 2,4,5-trimethylimidazol-1-yl, 2,4- Dimethylthiazol-5-yl, 2,4-dimethyloxazol-5-yl, 2 , 6-dimethylpyrid-3-yl or 2-methylimidazo[1,2-b]thia 7. The compound according to claim 6, which is a zol-3-yl group. 8. “Het” is 2-methylimidazo[4,5-c]pyrid-1-yl group , a compound according to claim 7. 9. The method according to any one of claims 1 to 8 for medical use. A compound or a pharmaceutically acceptable salt thereof. 10. Claim 1 for producing a drug for antagonizing platelet activating factor Use of a compound according to any one of Items 8 to 8. 11. The following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (in the formula, Ar is (a) optionally a nitro group, a halogen atom, a trifluoromethyl group, a carbon Alkyl group having 1 to 4 atoms, alkoxy group having 1 to 4 carbon atoms, fluoro( alkoxy) group having 1 to 4 carbon atoms, alkylthio group having 1 to 4 carbon atoms, carbon each independently from an alkylsulfonyl group having 1 to 4 atoms, a hydroxy group, and a cyano group; a phenyl group optionally substituted with 1 to 3 independently selected substituents, or (b) a methylenedioxyphenyl group or a benzothenyl group; R1 is an alkyl group having 1 to 4 carbon atoms; R2 is a hydroxy group; number of carbon atoms 1-4 alkoxy group; alkylthio group having 1-4 carbon atoms; 1-4 carbon atoms an alkyl group; optionally substituted with one or two halogen substituents; phenyl group; or a group represented by -NR3R4, in which R3 and R4 are each independently H or an alkyl group having 1 to 4 carbon atoms; and “Het” means one or more nitrogen atoms and optionally one oxygen or ion in the ring. optionally one or more nitrogen atoms or one in the benzene ring or ring yet another 5- or 6-membered aromatic heterocyclic ring containing an oxygen or sulfur atom a 5- or 6-membered aromatic heterocyclic group which may be fused with One or both of the above may optionally be an alkyl group having 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms. Each of the alkoxy groups, halogen atoms, trifluoromethyl groups and cyano groups of 4 each may be substituted with up to three independently selected substituents) A method for producing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, the method comprising: I) and (III) (wherein Ar, R1, R2 and Het are as defined above) However, R2 is not -OH. ) are reacted together. , ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II)▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) Optionally, the obtained compound is dealkylated so that R2 is -OH in the formula comprising preparing a compound represented by formula (I), A method for producing a compound. 12. Compounds (II) and (III) in an organic solvent, optionally in the presence of a base. 12. The method according to claim 11, wherein the components are heated together. 13. Claims wherein the resulting compound is dealkylated by treatment with an acid The method according to item 11 or 12. 14. Ar is (I) a phenyl group substituted with 1 or 2 halogen substituents , (II) methylenedioxyphenyl group and (III) benzothenyl group 14. The method of claim 11, 12 or 13, wherein the method is selected. 15. 15. The method according to claim 14, wherein Ar is a 2-chlorophenyl group. 16. Claims 11 to 15, wherein R1 is a methyl or ethyl group The method described in any one of the above. 17. R2 is hydroxy, methoxy, methylthio, amino, methylamino, dimethyl Claims 11 to 16 which are thylamino, methyl or phenyl groups The method according to any one of the above. 18. “Het” is optionally substituted imidazolyl, thiazolyl, oxazo Lyle, triazolyl, pyridyl, benzimidazolyl, imidazopyridyl or In any one of claims 11 to 17, which is an imidazothiazolyl group. Method described. 19. "Het" is 2-methylimidazo[4,5-c]pyrid-1-yl, 2 -trifluoromethylimidazo[4,5-c]pyrid-1-yl, 2-n-buty Rouimidazo[4,5-c]pyrid-1-yl, 3,5-dimethyl-1,2,4 -triazol-4-yl, 2-methylimidazo[4,5-b]pyrid-1-y 2-methylimidazo[1,2-a]pyrid-3-yl, 2-methylbenziyl midazol-1-yl, 2,4,5-trimethylimidazol-1-yl, 2, 4-dimethylthiazol-5-yl, 2,4-dimethyloxazol-5-yl , 2,6-dimethylpyrid-3-yl or 2-methylimidazo[1,2-b] 19. The method according to claim 18, which is a thiazol-3-yl group. 20. “Het” is a 2-methylimidazo[4,5-c]pyrid-1-yl group 20. The method of claim 19, wherein: 21. The compound according to any one of claims 1 to 8 is administered to a patient. A method of treating allergic or inflammatory conditions comprising: