NOVEL ANTIALLERGIC AGENTS AND PROCESS FOR THEIR PREPARATION

Abstract: The present invention is concerned with certain novel an­ tiallergic agents and process for their preparation.

Description: The present invention is concerned with novel compounds having an antiallergic activity and their manufacturing methods. Certain types of cells, for example, mast cells release the chemical mediators which mediate the allergic reaction in response to antigen-antibody reactions. As the chemical mediators participating in the immediate allergic reaction, histamines and SRS-A (slow reacting substance of anaphylaxis) are looked upon as important, but the latter plays the most important role particularly in the bronchial asthma. SRS-A is the mixture of leukotriene C₄ (LTC₄) , leukotriene D₄ (LTD₄) and leukotriene E₄ (LTE₄) , which is metabolites of arachidonic acid by 5-lipoxy-genase pathway. In general, the study of the medicinal drugs to prevent, improve and remove the symptoms of allergic reaction has been directed to the development of those inhibit the release of chemical mediator or antagonize to the action of it. As a result, antihistaminics (for example, diphenhydramine, chlorpheniramine, etc.), SRS-A release inhibitors (disodium cromoglycate) and the like are on the market. However, the effect of the former against the bronchial asthma is unreliable, and the latter has the only preventive activity and has no effects when used internally. Therefore it is expected from the drugs which antagonize to the action of SRS-A to be useful as antiallergic agents. At this time, only a few drugs are known to have such an activity, but none of them are known to have such an activity when used internally. The EP-A-O 181 779 falling under Art. 54(3) EPC is directed to 5- or 6- membered heterocyclic compounds having 1 to 3 hetero atoms selected from the groups containing an oxygen atom, a sulfur atom, and a nitrogen atom, for example isothiazole ring, pyrazole ring, and a pyrimidine ring, etc. including optical isomers based on the existence of an asymmetric carbon atom which are useful for the prophylaxis and treatment of various allergic diseases for examples bronchial asthma, allergic rhinitis, urticaria, etc. and ischemic heart diseases. The object of the present invention is to provide compounds having the general formula (I) [wherein Ar represents a pyrazolo[1,5-alpyridine-3-yl ring with or without a substituent like a straight or a branched alkyl group having 1 to 4 carbon atoms or a benzimidazole-2-yl ring, and n means an integer of 0 to 2]; and their salts thereof, with the exclusion of 4-[3-(2-benzimidazolylthio)-propoxy]-2-hydroxy-3-propylacetophenone. A further object of the present invention is a process for the preparation of compounds of the general formula (I), [wherein Ar is as defined as in claim 1, and n means 0 with the exclusion of 4-[3-(2-benzimidazolylthio]-propoxy]-2-hydroxy-3-propylacetophenone which com prises reacting compounds of the general formula (II), with phenoxyalkyl derivatives of the general formula (III), [wherein X is a halogen atom]. A further object of the present invention is a process for the preparation of compounds of the general formula (I), [wherein Ar is as defined as in claim 1, and n means 0], which comprises converting the thiocyano group in a compound having the general formula (IV) to a mercapto group, and then reacting the converted compound with phenoxyalkyl derivatives of the general formula (III), [wherein X is a halogen atom]. A further object of the present invention is a process for the preparation of compounds of the general formula (I), [wherein Ar is as defined as in claim 1, and n means 1 or 2], which comprises oxidizing compounds wherein n means 0 in the general formula (I). As a result of the extensive investigation on the compounds having an antiallergic action, the present inventors have found that novel compounds shown by a formula (I) have an excellent anitallergic action, in particular, extremely powerful inhibitory action on the anaphylaxis, which may be caused by SRS-A, even when used internally, wherein Ar represents a pyrazolo[1,5-alpyridine-3-yl ring with or without a substituent like a straight a branched alkyl group having 1 to 4 carbon atoms or a benzimidazole-2-yl group, and n means an integer of 0 to 2 with the exclusion of 4-[3-(2-benzimidazolylthio)-propoxy]-2-hydroxy-3-propylacetophenone. According to the present, invention the compounds shown by the general formula (I) can be manufactured through various pathways. (I) The compounds wherein n means 0 in the general formula (I) with the exclusion of 4-[3-(2-benzimidazolylthio)-propoxy]-2-hydroxy-3-propylacetophenone, can be manufactured through allowing the compounds of the general formula (II) to react with phenoxyalkyl derivatives of the general formula (III). Typically, they can be manufactured through allowing the compounds of the general formula (II) to react with phenoxyalkyl derivatives of the general formula (III) in a suitable solvent, for example, methanol, ethanol, tetrahydrofuran or the like, and in the presence or absence of the base, for example, potassium hydroxide, sodium hydride or the like, [wherein Ar is as defined as described above]. [wherein X is halogen atom]. (2) The compounds wherein n means 0 in the general formula (I) can also be manufactured after converting the compounds of a general formula (IV) to the compounds of the general formula (II), which are then reacted with the compounds of the general formula (III) by the same method as (1). Typically, the compounds of the general formula (IV) are converted to the compounds of the general formula (II) by a suitable reagent, for example, zinc-hydrochloric acid, sodium borohydride, potassium hydroxide or the like, in a suitable solvent, for example, methanol, ethanol or the like. [wherein Ar stands for same as described above]. (3) The compounds wherein n means 1 in the general formula (I) can be manufactured through allowing the compounds wherein n means 0 in the general formula (I) to react with oxidizing reagents. Typically, they can be manufactured through allowing the compounds wherein n means 0 in the general formula (I) to react with one or more molar equivalents mild oxidizing reagents, for example, hydrogen peroxide in methanol, m-chloroperbenzoic acid in dichloromethane or the like. (4) The compounds wherein n means 2 in the general formula (I) can also be manufactured through allowing the compounds wherein n means 0 in the general formula (I) to react with oxidizing reagents in the same manner as (3). Typically, they can be manufactured through allowing the compounds wherein n means 0 in the general formula (I) to react with two or more molar equivalents mild oxidizing reagents in the same manner as (3). In following, the present invention will be explained by using concrete examples. But the invention is not confined to them. Referential example 1 Manufacture of 2-isopropyl-3-thiocyanopyrazolo[1,5-a]pyridine To a solution of 3 g of 2-isopropylpyrazolo[1,5-a]pyridine in 56 ml of methanol was added 5.74 g of potassium thiocyanate and stirred at room temperature. 3.3 g of bromine was dissolved in 13 ml of methanol saturated with potassium bromide and added dropwise to the previous solution. Then, the mixture was stirred at room temperature for an hour, poured into 130 ml of water and resulting precipitate was filtered and dried. This crude pre cipitate was recrystallized from methanol to give 3.53 g (yield 87 %) of the aimed compound as pale yellow prismatic crystals. mp 91-92.5 °C. Referential example 2 Manufacture of 2-methyl-3-thiocyanopyrazolo[1,5-a]pyridine This compounds was synthesized by the same method as referential example 1 using 2-methylpyrazolo[1,5-a]pyridine instead of 2-isopropylpyrazolo[1,5-a]pyridine. Pale yellow powder (yield 50 %). mp 111-113 °C. Example 2 Manufacture of 3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio]-2-isopropylpyrazolo[1,5-a]pyridine To a suspension of 1 g of 2-isopropyl-3-thiocyanopyrazolo[1,5-a]pyridine (described in referential example 1) in 25 ml of methanol was added 2.6 ml of concentrated hydrochloric acid and stirred at room temperature. To this solution was added 1.3 g of zinc powder little by little, then stirred at room temperature for an hour. This solution was diluted with 40 ml of water and extracted with dichloromethane twice, then organic layer was combined, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was reacted with the same method as example 1, the crude products were purified by flash column chromatography (dichloromethane:benzene = 2:1) and then recrystallized from n-hexane to give 750 mg (yield 38 %) of the aimed compound as colorless needles. mp 95-95.5 °C. Analysis (%) for C₂₄H₃₀N₂0₃S: Calcd. (Found); C, 67.58 (67.70); H, 7.09 (7.19); N, 6.57 (6.43). Example 3 Manufacture of 3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio]-2-isopropylpyrazolo[1,5-a]pyridine-S-oxide To a solution of 800 mg of 3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylthio]-2-isopropylpyrazolo[1,5-a]pyridine (described in example 2) in 25 ml of dichloromethane, cooled with ice-salt-water bath below 0 °C, was added 405 mg of m-chloroper benzoic acid and stirred at 0 °C for 15 minutes. To the reacting mixture was added 4 g of calcium hydroxide and stirred at room temperature for 10 minutes, then precipitate of suspension was filtered off with Celite. The filtrate was further washed with 5 % aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The crystalline residue was recrystallized from dichloromethane-n-hexane to give 770 mg (yield 93 %) of the aimed compound as colorless powder. mp 145-146 °C. Analysis (%) for C₂₄H₃₀N₂0₄S: Calcd. (Found); C, 65.13 (65.17); H, 6.83 (6.79); N, 6,33 (6.23). Example 4 Manufacture of 3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylsulfonyl]-2-isopropylpyrazolo[1,5-a]pyridine To a solution of 2 g of 3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxy)propylthio]-2-isopropylpyrazolo[1,5-a]pyridine (described in example 2) in 50 ml of dichloromethane, cooled with water bath below 15 °C, was added 2.22 g of m-chloroperbenzoic acid and stirred at room temperature for 2 hours. The purification procedure was same as described in example 3. The resulting residue was further recrystallized from dichloromethane-n-hexane to give 1.98 g (yield 92 %) of the aimed compound as pale yellow powder. mp 169.5-170.5 °C. Analysis (%) for C₂₄H₃₀N₂0₅S: Calcd. (Found); C, 62.86 (62.70); H, 6.59 (6.66); N, 6.11 (6.01). Using the procedure described in examle 1 to 4, compounds shown in Table 1 were synthesized. The compounds presented here have shown the potent antagonizing effect on LTD₄ -induced contraction of the isolated guinea-pig ileum. Noticeably, all the compounds are orally effective in the experimental model of bronchial asthma. Inhalation of aerosolized antigen to actively sensitized guinea-pigs treated beforehand with indomethacin and tripelennamine induces anaphylactic bronchoconstriction, in which endogenously released SRS-A may play a predominant role. The compounds of the present invention strongly inhibited this anaphylactic broncho-constriction at the oral dose of 20 mg/kg (Table 2). FPL55712, sodium 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate, a well known SRS-A antagonist, is reported to be orally inactive (P. Sheard et al.: Monogr. Allergy, pp. 244-248. S. Karger, 1977). Thus, the compounds of the present invention are promising anti-allergic agents possessing the potent anti-SRS-A (leukotriene) activities. These compounds are considered to be of a prophylactic and/or therapeutic value in allergic diseases, such as bronchial asthma, allergic rhinitis and urticaria.

Claims: Compounds having the general formula (I) [wherein Ar represents a pyrazolo[1,5-alpyridine-3-yl ring with or without a substituent like a straight or a branched alkyl group having 1 to 4 carbon atoms or a benzimidazole-2-yl ring, and n means an integer of 0 to 2]; and their salts thereof with the exclusion of 4-[3-(2-benzimidazolylthio)-propoxy]-2-hydroxy-3-propylacetophenone. A process for the preparation of compounds of the general formula (I), [wherein Ar is as defined as in claim 1, and n means 0 with the exclusion of 4-[3-(2-benzimidazolylthio)-propoxy]-2-hydroxy-3-propylacetophenone, which comprises reacting compounds of the general formula (II), with phenoxyalkyl derivatives of the general formula (III), [wherein X is a halogen atom]. A process for the preparation of compounds of the general formula (I), [wherein Ar is as defined as in claim 1, and n means 0], which comprises converting a thiocyano group in a compound having the general formula (IV) to a mercapto group, and then reacting the converted compound with phenoxyalkyl derivatives of the general formula (III), [wherein X is a halogen atom]. A process for the preparation of compounds of the general formula (I), [wherein Ar is as defined as in claim 1, and n means 1 or 2], which comprises oxidizing compounds wherein n means 0 in the general formula (I),

Inventors: IKEDA, TOSHIYA, IRIKURA, TSUTOMU, NISHINO, KEIGO, OKAMURA, KYUYA
Applicants: KYORIN PHARMACEUTICAL CO., LTD.
Application year: 1986
Main classification: C07D471
IPC codes: C07D471, A61K31, A61P43, A61P11, A61P27, A61P37, C07D235