WO1996019454A1

WO1996019454A1 - Pyridylalkyl phenyl sulfone derivatives and medicinal preparation containing the same

Info

Publication number: WO1996019454A1
Application number: PCT/JP1995/002590
Authority: WO
Inventors: Hiroyuki Ohnishi; Katsumi Morimoto; Harue Kitamura; Hiroaki Kasukawa
Original assignee: Terumo Kabushiki Kaisha
Priority date: 1994-12-20
Filing date: 1995-12-18
Publication date: 1996-06-27
Also published as: AU4189296A

Abstract

A pyridylalkyl phenyl sulfone derivative which has thromboxane A2 and prostaglandin H2 antagonisms and the effect of inhibiting the synthesis of thromboxane A2, is useful as an antithrombotic agent and an antiallergic agent, and is represented by general formula (1), wherein X represents hydrogen, halogeno, lower alkyl, lower alkoxy, hydroxy, nitro, cyano or trifluoromethyl; R represents -O-(CH2)a-CO2-R1, -(CH2)a-CO2-R1, -CR2=CR3-CO2-R1 or -CR2R3-CR4R5-CO2-R1 (wherein R1, R2, R3, R4, and R5 represent each hydrogen or lower alkyl; and a represents an integer of 0 to 5); and 1, m and n represent each an integer of 0 to 5.

Description

Specification

"Title of Invention"

(Pyridylalkyl) (phenylsulfone) derivatives and pharmaceutical preparations containing them

The present invention relates to a novel (pyridylalkyl) (Fuwenirusuruhon) derivatives and thromboxane A ₂ synthesis inhibitors containing the same, thromboxane A ₂ antagonists, prosulfuron evening Grandin H ₂ antagonists, antithrombotic and anti Arerugi one-component It is about.

"Background technology"

Thrombosis such as myocardial infarction and cerebral infarction has been steadily increasing in recent years, and the emergence of antithrombotic drugs that effectively prevent them is strongly desired. One of the causes of these diseases is tonomboxan A ₂ (TXA ₂ ), which is produced by cells such as platelets and has a strong platelet aggregating action, and plays an important role. It is known to be an effective means of preventing thrombus formation. Also, allergies and asthma, TXA ₂ and leukotriene 0 _₄ (LTD ₄₎ Chemical Medei d Isseki one of Do and 'are known to be involved, late is possible to suppress the effect of TXA ₂ onset This is one of the effective tools for treating sexual asthma.

Synthesis inhibitors and TXA ₂ antagonist and the like are already known L inhibiting the production of TXA _2, Ru, both of which contain the problem. For example, biosynthesis inhibitors such as dazoxiben (Da zox i ben) and ozagreil (Oz agre 1) inhibit thromboxane synthase, and conversely, prostaglandin H ₂ (PGH ₂ ), a substrate of this enzyme, is used. Will accumulate. PGH ₂ itself has a platelet aggregation effect and smooth muscle contraction effect similarly to TXA _2, and prostaglandins such as PGE ₂ generated from PGH ₂ also have a similar effect. Thus, despite the inhibition of TXA ₂ production, alternative coagulants and contractiles are produced, halving the effectiveness of the actual drug. On the other hand, S-145 and Dart Robin (D a 1 troban) TXA ₂ antagonists such as TX A ₂ Resebuta order to antagonize, shows effective inhibitory effect in antagonizing this when the amount of TX A ₂ is small but, TXA Excessive production of ₂ diminishes its effectiveness. Therefore, in such a case, it is necessary to inhibit the generation of TXA ₂ itself.

"Disclosure of the invention"

The present invention has been made in view of the above problems, and an object thereof is to provide compounds and pharmaceutical formulations containing it having TXA ₂ antagonism with TXA ₂ synthesis inhibiting action. The present inventors have synthesized novel (pyridylalkyl) (phenylsulfone) derivatives, and have studied diligently on their pharmacological activities. As a result, the specific derivatives have both TXA ₂ synthesis inhibitory activity and TXA ₂ antagonistic activity. Found to have. As a result, it was found that the problems of the above-mentioned synthesis inhibitors and antagonists could be solved, and the present invention was completed.

The present invention is a (pyridylalkyl) (funyursulfone) derivative represented by the following general formula 1.

(In the formula 1, X represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, a nitro group, a cyano group, or a trifluoromethyl group, and R represents a formula 10— (CH ₂ ) a -C0 ₂ -Ri, one (CH ₂ ) a— C0 ₂ — R CR ₁ = CR ₃ — C0 ₂ — or one CR ₂ R ₃ — CR ₄ R ₅ — C0 ₂ — (R _{1 (} R ₂ , R ₃ , R 4 and R ₅ represent a hydrogen atom or a lower alkyl group), and a represents an integer of 0 to 5. 1), m, and n are integers from 0 to 5)

The present invention also provides a pharmaceutical preparation containing the (pyridylalkyl) (fuunyl sulfone) derivative according to the above (1).

The present invention is a thromboxane A ₂ synthesis inhibitors containing (pyridylalkyl) (Fuwenirusuruhon I) derivative according to the above (1).

The present invention is also a thromboxane A ₂ antagonist comprising the (pyridylalkyl) (phenylsulfone) derivative according to the above (1).

Further, the present invention is a prostaglandin H ₂ antagonist comprising the (pyridylalkyl) (fuunyl sulfone) derivative according to the above (1).

Further, the present invention is an antithrombotic agent comprising the (pyridylalkyl) (phenylsulfone) derivative according to the above (1).

The present invention also provides an antiallergic agent comprising the (pyridylalkyl) (phenylsulfone) derivative according to (1).

(Pyridylalkyl) (phenylpropyl sulfone) derivatives of the present invention causes增large production of PGH ₂ described above with inhibiting the production of fit TX A ₂ having the Toronbokisa emissions synthesis inhibitory action. However, since this compound also has a TXA ₂ antagonistic effect, it inhibits the action of PGH ₂ at the receptor site similarly to TXA ₂ . Therefore, the compound can be an effective antithrombotic and antiallergic agent. PGH ₂ is further accumulated in platelets in such is converted into PG I ₂ in the vessel wall, which because it causes inhibition of the thrombus formation, (pyridylalkyl) (Fuwenirusuruhon) derivatives of the present invention can be a more effective prophylactic. Further, it is effective as a therapeutic or preventive agent for various pathological conditions TXA ₂ is involved.

The (pyridylalkyl) (phenylsulfone) derivative of the present invention may be a pharmaceutically acceptable salt thereof. Examples of such a salt include alkali metal salts such as sodium salt and potassium salt, calcium salt and the like. Al such as magnesium salt Potassium earth metal salts, ammonium salts, salts with organic bases, for example, triethylamine salt, pyridine salts, tromethamine salts, dicyclohexylamine salts, etc., and salts with organic or inorganic acids, for example, acetate, tartaric acid Salts, methanesulfonate, formate, toluenesulfonate, trifluoroacetate, hydrochloride, sulfate, nitrate, etc., and amino acid salts such as arginine, lysine, aspartic acid, etc. are included. Further, the (pyridylalkyl) (funinylsulfone) derivative of the present invention may be an optical isomer or a pharmaceutically acceptable salt thereof.

The (pyridylalkyl) (phenylsulfone) derivative of the present invention can be synthesized by the following method. The terephthalaldehyde monogetyl acetal and the corresponding organic metal compound (preferably alkenylmagnesium bromide or alkenyllithium) are mixed at a temperature of from 78 ° C to 30 ° C (preferably from 178 ° C). (0 ° C) Reaction in an inert organic solvent (preferably getyl ether, tetrahydrofuran, etc.) to give alcohol. The compound and 3-bromopyridine are added in an inert solvent (preferably N, N-dimethylformamide) in the presence of palladium acetate at room temperature to reflux temperature (preferably 100 to 140 ° C). By Heck reaction, it becomes an adduct of a mixture of E and Z.

Then, in a suitable catalyst (including Raney nickel, Raney cobalt, platinum oxide, palladium monocarbon, etc.) and a suitable solvent (including various alcohols, acetic acid and its ester, dioxane, etc.), hydrogenate and saturate. Alcohol. The compound is oxidized with an oxidizing agent (including various oxidizing agents, and preferably, a method of stirring with active manganese dioxide in room-mouth form at room temperature to reflux temperature) to obtain a ketone. The compound and a suitable base (preferably JL DA, sodium hydride, n-butyllithium, sodium ethoxide, potassium tert-butoxide, etc.) and an inert organic solvent (preferably DMF, THF, etc.) Α, ^ and α, unsaturated when the Horner-Wittig reaction with a suitable Horner reagent A mixture of E, Z forms of ethyl carboxylate is obtained, and a mixture of E, Z forms of β, α-unsaturated ethyl carboxylate is reduced in the same manner as in the above-mentioned hydrogenation to obtain a saturated carboxylate ester form.

The compound was subjected to LAH reduction in an inert organic solvent (preferably getyl ether or THF) at a temperature of 1 78 ° C to room temperature (preferably 130 ° C to 0 ° C) to give an alcohol form. After that, a subsequent acid treatment (preferably, dilute hydrochloric acid, dilute sulfuric acid, etc.) is performed to obtain a deacetal form. The compound and a suitable base (preferably LDA, sodium hydride, n-butyllithium. Sodium ethkind, potassium tert-butoxide) and an appropriate base in an inert solvent (preferably THF, DMF, etc.) Reaction with Horner-Wittig with rner reagent gives cinnamate. If necessary, a saturated product can be obtained by hydrogenation under the same conditions as described above.

These alcohols are halogenated with a suitable halogenating agent (such as phosphorus oxychloride, thionyl chloride, phosphorus tribromide, and mesyl chloride lithium chloride, preferably thionyl chloride). Sodium benzenesulfinate having X of Formula 1 is reacted with an inert solvent (preferably DMF) at a temperature of 0 ° C to reflux (preferably 120 ° C to 140 ° C) to obtain a (pyridylalkyl) (phenylsulfone) derivative Derivatives can be obtained. If necessary, the compound may be added to a suitable base (such as lithium hydroxide, potassium hydroxide, or sodium hydroxide) in a water-soluble solvent (such as alcohol or ethylene glycol). (Pyridylalkyl) (fuunyl sulfone) derivative can be obtained by hydrolysis with an aqueous solution of sodium chloride or an appropriate acid (dilute hydrochloric acid, dilute sulfuric acid, aqueous solution of trifluoroacetic acid, etc.). Furthermore, a salt thereof can be obtained by treating with an equivalent amount of a base or an acid. Alternatively, the reaction can be carried out in the same manner as described above from the hydroxy protected form of p-hydroxybenzaldehyde, deprotected, and then obtained by substitution with a halo-substituted alkyl alkanoate. Can be. If necessary, the compound can be hydrolyzed with a suitable aqueous base solution or a suitable acid in a water-soluble solvent to obtain a (pyridylalkyl) (fuunyl sulfone) derivative. Further, the salt can be obtained by treating with an equivalent amount of a base or an acid.

(Pyridylalkyl) (Fuwenirusuruhon) derivatives of the present invention, Toronbokisa down A ₂ antagonists, prostaglandin H ₂ antagonists, thromboxane A ₂ synthesis inhibitors, and diseases effective prevention which is caused by thromboxane A ₂ It can be used as an agent and a therapeutic agent.For example, it is used as an antithrombotic agent, a platelet aggregation inhibitor, or an antiallergic agent.The dosage varies depending on the condition, but is generally 0.1 to 600 mg / day for adults, preferably It is 1 to 20 mg, and it is recommended to administer it in 1 to 3 divided doses as needed according to symptoms. The administration method can be in any form suitable for administration. In particular, oral administration is preferable, but intravenous injection is also possible.

The (pyridylalkyl) (funinylsulfone) derivative of the present invention may be used as a tablet, powder, capsule, granule, syrup, or the like as an active ingredient or one of the active ingredients either alone or together with a pharmaceutical carrier by a known formulation technique. Any formulation suitable for administration such as solutions, suspensions, injections, eye drops, or suppositories can be used. Specific pharmaceutical carriers include starch, sucrose, lactose, methylcellulose, carboxymethylcellulose, crystalline cellulose, sodium alginate, calcium hydrogenphosphate, magnesium metasilicate, magnesium aluminate, and maleic anhydride. Excipients such as aluminum; binders such as hydroxypropylcellulose, hydroquinpropylmethylcellulose, gelatin and polyvinylpyrrolidone; carboquin methylcellulose calcium, carboxymethylcellulose sodium and crosslinked polyvinylpyrrolidone Disintegrants, lubricants such as magnesium stearate and talc, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, methacrylic acid and methacrylic acid Methyl luate Control agents such as polymers, dissolution aids such as polyethylene glycol, sodium lauryl sulfate, lecithin, sorbitan monooleate, polyoxyethylene cetyl ether, sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil and glyceryl Examples include emulsifiers such as monostearate, chelating agents such as EDTA, buffers, humectants, preservatives, bases such as cacao butter and Witebsol W35.

"Best mode for carrying out the invention"

Next, the present invention will be described more specifically with reference to examples and test examples, but the present invention is not limited to these examples.

(Example 11 (1))

3 -— (4- {1- [2- (4-chlorophenylsulfonyl) ethyl) -1-41- (3-pyridyl) butyl} phenyl) Synthesis of propionic acid

i) In a nitrogen stream, a fragment of iodine was added to a suspension of 2.33 g of magnesium in 5 ml of anhydrous ether, followed by stirring. 14 mL of a 2 Oml ether solution in which 11.62 g of arylpromide was dissolved was added dropwise, 100 ml of anhydrous ether was added, and the remaining ether solution of aryl bromide was added dropwise so as to return slowly. The obtained Grignard reagent was cooled to 0 ° C., and a 5 Oml ether solution of 20.00 g of terephthalaldehyde monogetyl acetal was added dropwise. Stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 ° C, water was added, the aqueous layer was separated, extracted with ethyl acetate, the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. I left. The obtained residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl hexane monoacetate (1: 9 v / v), 4.87 g of 4- (1-hydroxy-3-butenyl) benzaldehyde getylacetal was obtained. (37%).

ii) 4- (1-hydroxy-3-butenyl) benzaldehyde getylua cetal 8.87 g, 3-bromopyridine 6.03 g, potassium carbonate 5.05 g, And 0.43 g of palladium acetate were suspended in 10 Oml of N, N-dimethylformamide (hereinafter abbreviated as DMF) and heated at 130 to 135 ° C for 10 hours. Water was added to the reaction mixture, extracted with ethyl acetate, washed thoroughly with water, further washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography. From the fraction eluted with hexane monoethyl acetate (1: 1 v / v), 4- [1-hydroxy-1-41- (3-pyridyl) -1-3- Butenyl] benzylaldehyde 7.89 g (61%) was obtained.

iii) 4— [1-Hydroxy-1- (3-pyridyl) -1-3-butenyl] benzaldehyde getylacetal 7.89 g and 10% palladium-carbon 2.00 g are suspended in 100 ml of ethanol. After hydrogenation at normal temperature and normal pressure for 3.5 hours, the mixture was filtered, and the solvent was distilled off from the filtrate under reduced pressure to obtain 4- [1-hydroxy41- (3-pyridyl) butyl] benzaldehyde getylacetal 7.69 g (97 %).

iv) 4- [1-Hydroxy-1- (3-pyridyl) butyl] 2.90 g of benzaldehyde getylacetal and 17.40 g of active manganese dioxide are refluxed in 100 ml of a form-mouthed form for 3 hours, filtered and filtrated. The solvent was distilled off under reduced pressure to obtain 2.87 g (quantitative) of 4- [1-oxo-41- (3-pyridyl) butyl] benzaldehyde getylase.

V) Under a nitrogen atmosphere, 1.80 g of 60% sodium hydride in mineral oil was washed with hexane and suspended in 20 ml of DMF. In C, a solution of 10.08 g of getyl phosphonoacetate in 20 ml of DMF was added dropwise, and the mixture was stirred at room temperature for 15 minutes. 4- [1-oxo-41- (3-pyridyl) butyl] benzaldehyde getylacetal 7.36 g of DMF in 10 ml was added, and the mixture was stirred at 140 ° C for 1 hour. Water was added to the reaction mixture, extracted with ethyl acetate, washed thoroughly with water, further washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The respective E, Z mixtures of the seven unsaturated carboxylic esters were obtained. This was subjected to Silica gel gel column chromatography. From the fractions eluted with hexane monoethyl acetate (1: 1 v / v), E and Z-4-1 [1-ethoxycarbonylmethyl-4-1- (3-pyridyl) 1) Butenyl] Benzaldehyde getylacetal 4.30 g (48%) was obtained.

vi) E and Z—4— [1-Ethoxycarbonylmethyl-4-1 (3-pyridyl) -11-butenyl) benzaldehyde 1.20 g of getyl acetal and 10% palladium / carbon are suspended in 3 ml of ethyl acetate. The mixture was hydrogenated at normal temperature and normal pressure for 9 hours. The reaction mixture was filtered, and the solvent was distilled off from the filtrate under reduced pressure to obtain 1.16 g (91%) of 4- [1-ethoxycarbonylmethyl-41- (3-pyridyl) butyl] benzaldehyde dimethyl lacetal.

vii) Under a nitrogen atmosphere, 4- [1-Ethoxycarbonylmethyl-41- (3-pyridyl) butyl] benzaldehyde getylacetal 3.38 g to 0. At C, 0.24 g of lithium aluminum hydride was added, and the mixture was stirred at 0 ° C for 1.'5 hours. To the reaction mixture was added 2N-hydrochloric acid to make the liquid acidic, and the mixture was stirred for 30 minutes. A 2N aqueous solution of sodium hydroxide was added to the reaction mixture to make the solution alkaline, then the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers are thoroughly washed with water, further washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure to give 4- [1- (2-hydroxyxethyl) 4- 4- (3-pyridyl). [Butyl] benzaldehyde 2.19 g (quantitative) was obtained.

viii) Under a nitrogen atmosphere, 0.13 g of 60% sodium hydride in mineral oil was washed with hexane, suspended in THF l Oml, and at 0 ° C, a solution of 0.59 g of ethylphosphonoacetate in 5 ml of THF was added dropwise. The mixture was stirred at 0 ° C for 30 minutes. 4- (1- (2-Hydroxitytyl) -14- (3-pyridyl) butyl) A solution of 0.75 g of benzaldehyde in 5 ml of THF was added at 0 C, and the mixture was stirred at room temperature for 3.5 hours. Saturated reaction mixture Brine was added to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate, 4- [1- (2-hydroxyxethyl) -14- (3-pyridyl) butyl] ethyl cinnamate 0.35 g (3 7%).

ix) 4- [1- (2-hydroxyl) -4-1 (3-pyridyl) butyl] Ethyl cinnamate 0.35 g and 10% palladium-carbon are suspended in 20 ml of 1,4-dioxane 20 ml. It became cloudy and was hydrogenated at normal temperature and normal pressure for 11.5 hours. The reaction mixture was filtered, and the solvent was distilled off from the filtrate under reduced pressure. 3- {4- [1- (2-Hydroxyshetyl) -14- (3-pyridyl) butyl] phenyl} ethyl propionate 0.36 g ( Quantitative) was obtained.

X) 3— {4— [1— (2-Hydroxityl) 1-4— (3-pyridyl) butyl] phenyl} 0.95 g of ethyl propionate and 5 ml of thionyl chloride are stirred for 1 hour with 45 g did. Excess thionyl chloride was distilled off under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to make the liquid alkaline. After extraction with ethyl acetate, washing with saturated saline and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.

[1- (2-Chloroethyl) _4- (3-pyridyl) butyl] phenyl} 0.89 g (88%) of ethyl propionate was obtained.

xi) 3—14- [1- (2-chloroethyl) 1-141- (3-pyridyl) butyl] phenyl} ethyl propionate 0.89 g and sodium perfluorobenzenesulfonate 0.59 g DMF 8 The ml solution was stirred at 130 ° C for 1 hour. Water was added to the reaction mixture, extracted with ethyl acetate, washed thoroughly with water, further washed with saturated saline, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography, and hexane monoacetate (1: 1 v / v) was eluted. From the fraction, 3— (4— {1— [2 — (4-phenylphenylsulfonyl) ethyl] 0.64 g (54%) of ethyl 4- (3-pyridyl) butyl} phenyl) propionate was obtained.

xii) 3- (4- {1- [1- [4- (4-chlorophenylsulfonyl) ethyl] 1-41- (3-pyridyl) butyl} phenyl) ethyl ethyl brobionate 0.57 g in 2 ml ethanol 2 N—water Sodium oxide 2. Q ml was added and heated at 60 for 30 minutes. After the reaction mixture was neutralized with 2 N hydrochloric acid, the solvent was distilled off under reduced pressure, and the aqueous layer was extracted with methanol-methylene chloride (5:95 v / v), washed with saturated saline, and then sulfuric anhydride. After drying with magnesium and distilling off the solvent under reduced pressure, 3- (4- {1- [1- [4- (4-chlorophenylphenylsulfonyl) ethyl] -14- (3-pyridyl) butyl} phenyl represented by the following formula 2 is obtained. ) 0.5 g (95%) of propionic acid was obtained as colorless prisms (recrystallized from ether methylene chloride). Its spectroscopic data supports the structure of Equation 2 below.

^{_{J H NMR (CDC 1 s)}} (5:. 1.31 - 1.72 (4 H. m) 1.81 - 1. 95 (lH, m), 2.01- 2.13 (lH.m), 2.40- 3.00 (9H, m), 6.90 (2H, d, J = 7.7Hz), 7.13 (2H, d, J = 7.7Hz), 7.2 4-7.34 (lH, m) .7.44-7.54 (1H, m), 7.50 (2H, d, J = 8.6Hz), 7.74 (2H, d, J = 8.6Hz), 8.19 (lH.br), 8.42 (lH.br)

I R (KB r) cm- 2940, 2925, 1720, 1584, 131 2, 1152, 1092

Melting point: 101.5-103.8V

(Example 11 (2))

Synthesis of 3- (4- {1- [2- (4-chlorophenylsulfonyl) ethyl] 1-41- (3-pyridyl) butyl} phenyl) sodium bropionate

3— (4- {1-1-1 [2 -— (4-chlorophenylsulfonyl) ethyl] -4-1- (3-pyridyl) butyl} phenyl) ppionic acid 600.8 mg of 5N Oml in a 5 Oml ethanol solution After adding 0.614 ml of aqueous sodium oxide solution (factor 1.006) and evaporating the solvent under reduced pressure, 3- (4- {1- [1- (2- (4-chlorophenyl) sulfonyl) ethyl] 1-41 ( 628 mg (stationary) of sodium 3-pyridyl) butyl} phenyl) propionate were obtained as a white amorphous. Its spectroscopic data supports the structure of Equation 3 below.

NMR (CDC ") 5: 1.15-1.55 (4H, m), 1.74-1.90 (2H, m), 2.20-2.49 (5H, m), 2.67-2.83 (3H, m), 2.84-2.97 (lH .m), 6.77 (2H, d, J = 8.OHz), 6.90 (2H, d, J = 8.0Hz), 7.02 (lH.dd, J = 7.0.4.9Hz), 7.26 (1H, brd , J = 7.7Hz), 7.40 (2H, d, J = 8.8Bz), 7.70 (2H, d, J = 8.8Hz), 8.11 C1H, d, J = 1.6Hz), 8.26 (1H, dd, (J = 4.9, 1.6 Hz)

IR (KBr) cm " ¹ : 3600-2800, 1580, 1408. 131 6, 1152, 1090

(Example 2) Synthesis of 3- (4- {1-1- [2 -— (4-chlorophenylsulfonyl) ethyl] -1-5- (3-pyridyl) pentyl} phenyl) propionic acid

The reaction was carried out in the same manner as in Example 1 using 3-butenyl bromide as a starting material, and 3- (4- {1- [1- [4- (4-chlorophenylsulfonyl) ethyl] -15- (3- Pyridyl) pentyl} fuunil) 46.8 mg of propionic acid was obtained as a colorless oil. Its spectroscopic data supports the structure of equation 4 below.

_{lH NMR (CDC 1 3) δ} : 1.00-1.20 (2H, m), 1.38- 1. 69 (4H, m), 1.81-1.95 (lH.m), 1.98 - 2.12 (lH'm), 2.42-3.00 (9H, m) .6.90 (2Η, d, J = 8.1 Hz) .7.13 (2 H, d.J = 8.1 Hz), 7.18-7.30 (lH.m), 7.44-7.54 (1 H, m), 7.50 (2H, d, J = 8.8Hz), 7.74 (2H, d, J = 8.8Hz), 8.19 (1H, br), 8.40 (lH.br)

IR (KB r) cm " ¹ : 2930. 1720, 1582, 1318, 115 4, 1090

(Example 3)

Synthesis of 3- (4- {1- [2- (4-cyclophenylphenylsulfonyl) ethyl] -16- (3-pyridyl) hexyl} phenyl) propionic acid

4 The reaction was carried out in the same manner as in Example 1 using 1-pentenyl bromide as a starting material. 3- (4- {1- [2- (4-chlorophenylsulfonyl) ethyl] -1 6- (3-Pyridyl) hexyl} phenyl) 22.3 mg of propionic acid were obtained as a colorless oil. Its spectroscopic data supports the structure of equation 5 below. ^{_{J H NMR (CDC 1 s)}} (5:. 0.80- 1.62 (8H, m), 1.80-1 93 (lH.m), 1.98-2.11 (lH, m), 2.40- 3.00 (9H, m), 6.90 (2H, d, J = 7.9Hz), 7.14 (2H.d, J = 7.9Hz), 7.18-7.30 (lH, m), 7.46-7.54 (lH, m), 7.50 (1H, d, J = 8.6Hz) .1.1 (1H, d, J = 8.6flz), 8.21 (lH.br), 8.4 0 (1H, br)

I R (KB r) cm '2960. 1718, 1318, 1152. 109

0

(Example 4)

Synthesis of 3- (4- {1- [2- (phenylsulfonyl) ethyl] —4- (3-pyridyl) butyl} phenylpropionic acid

The reaction was carried out in the same manner as in Example 1 using the compound of Example 1 (X) and sodium phenylsulfinate as starting materials, to give 3- (4- {1- [2- (phenylsulfonyl) 1) 4- (3-Pyridyl) butyl} phenylpropionic acid (21.2 mg) was obtained as a white amorphous material, whose spectroscopic data supports the structure of Formula 6 below.

lU NMR (CDC ") 5: 1.30-1.69 (4H.m), 1.83.-1.95 (lH, m), 2.02-2.14 (lH.m), 2.42-3.00 (9H, m), 6.89 (2H , D, J = 8.1 Hz), 7.12 (2H, d, J = 8.1 Hz) .7.22 (1 H. dd, J = 7.7, 4.9 Hz), 7.44 (1 H, dd, 5 = 7.7 Hz), 7. 53 (2H, dd, J = 7.9, 7.9Hz), 7.63 (1H, dd, J = 7.9.7.9Hz), 7.82 (2H, d.J = 7.9Hz), 8.21 (lH.br), 8.39 ( 1 H, br)

IR (KB r) cm ' ¹ : 2935. 1718, 1584. 1450, 131 0.1152, 1088

(Example 5)

Synthesis of 3- (4- {1- [2 -— (p-toluenesulfonyl) ethyl] 1-41- (3-pyridyl) butyl} phenylpropionic acid

The compound of Example 1) was reacted with sodium p-toluenesulfinate in the same manner as in Example 1 to obtain 3- (4- {1- [2- [p- Toluenesulfonyl) ethyl] 1- (3-pyridyl) butyl} phenylpropionic acid (19.7 mg) was obtained as a white amorphous material, whose spectroscopic data supports the structure of Formula 7 below.

_{! H NMR (CDC 1 3)} <5: 1.32 - 1.70 (4 H, m), 1.81- 1. 95 (lH.m), 2.01-2.13 (lH, m), 2.44 (3Η, s), 2.4 0 -2.98 (9H, m), 6.99 (2Η, d, J = 8.OHz), 7.12 (2H.d, J = 8.0Hz), 7.21 (1 H, dd, J = 7.6.5.2Hz), 7.32 ( 2H, d, J = 8.4Hz), 7.43 (1H, d, J = 7.6Hz), 7.69 (2H, d, J = 8.4Hz), 8.16 (lH.br). 8.38 (1H, br)

IR (KB r) cm ' ¹ : 2935. 1722, 1600, 1426, 130 4, 50, 1088

(Test Example 1) Platelet aggregation inhibitory action

After sodium human forearm 3.8% 1Z10 volume than section Kuen acid blood collection, the blood was centrifuged, and platelet rich plasma (PRP: platelet count 2 XI 0 ⁵ or 1) was obtained. The P RP200 // 1 and Tris-buffered saline (25mil Tr is- HC 1, 13 OmH N a C 1, 1 On C a C 1 2, pH7.4 ( hereinafter referred to as TBS)) queue the 24 l Put it in a bet and set it on the aggregometer. C for 2 minutes, add a solution of the (pyridylalkyl) (fXnylsulfone) derivative of the present invention in dimethyl sulfoxide (DMSO) 11 and incubate for 3 minutes, then add a stable derivative of PGG ₂ ZH ₂ U-46619 (Cayman Chemcal Cam p.), Which has a strong platelet aggregation-inducing action, was added to the platelet to measure the platelet aggregation [Hematracer VI: Nikko Bio Science Co., Ltd.]. Table 1 shows the 50% inhibitory concentrations for platelet aggregation induced by U-46619 (1 M).

Table 1 TXA ₂ antagonism

As shown in Table 1, the (pyridylalkyl) (phenylsulfone) derivatives of the present invention The body showed significant antiplatelet aggregation activity. The 50% inhibitory concentration in Table 1 means the (pyridylalkyl) of the present invention when the platelet agglutinating ability without adding the (pyridylalkyl) (fuunylsulfone) derivative of the present invention is 100%. (Funyl sulfone) means the concentration of the (pyridylalkyl) (Funyl sulfone) derivative solution of the present invention required to suppress the platelet aggregation ability to 50% by introducing the derivative.

(Test Example 2) Thromboxane synthase inhibitory action

After human forearm than 1/1 0 vol 3. Sodium 8% Kuen acid blood collection, the blood was centrifuged, and platelet rich plasma (PRP: platelet count 2 X 1 0 ⁵ cells / 1) to obtain a. The PP2001 and TBS24 / l were placed in a cuvette, set in an agglomerator, and kept at 37 ° C for 2 minutes to obtain DMSO of the (pyridylalkyl) (fuunylsulfone) derivative of the present invention. After adding 1/1 of the solution and incubating for 3 minutes, 2 OU / ml of a thrombin solution was added to induce platelet aggregation. It was fractionated plasma after coagulation, by the addition of acetic acid Echiru the generated thromboxane B ₂ 'is extracted and quantified by RIA method (using Amersham m Co. kit). Table 2 shows the results.

Table ₂ TX A 2 TaiNaru inhibitory action

As shown in Table 2, the (pyridylalkyl) (phenylsulfone) derivative of the present invention exhibited an excellent inhibitory effect on toxanboxane synthase.

(Acute toxicity)

Acute toxicity tests were performed by oral administration using male ICR mice (5 weeks old). The LD50 values of the compounds of the present invention were all 30 OmgZkg or more, and high safety was confirmed. "Industrial applications"

According to the present invention, a novel (pyridylalkyl) (phenylsulfone) 锈 conductor is provided. Novel (pyridylalkyl) (Fuwenirusuruhon) derivatives of the present invention, anti-platelet aggregation action, because it has a thromboxane A ₂ and prostaglandin H ₂ antagonism and thromboxane A ₂ synthesis inhibiting activity, thromboxane A ₂ is caused It is effective as a prophylactic and therapeutic agent for diseases caused by the disease. It is particularly effective as an antithrombotic and antiallergy agent.

Claims

"The scope of the claims"

(1) A (pyridylalkyl) (phenylsulfone) derivative represented by the following general formula 1.

)

(In the formula 1, X represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, a nitro group, a cyano group, or a trifluoromethyl group, and R represents a formula 10— (CH ₂ ) a -COZ-Rj, one _{_{(CH 2) a-C0 2}} -Ri -CR 2 = CR s -. C0 2 - R or a _{_{CR 2 R 3, - CR <}} R 5 - C0 2 - Ri (R 1 (R ₂ , R ₃ , R 4, and R ₅ represent a hydrogen atom or a lower alkyl group), a represents an integer of 0 to 5), and n represents an integer of 0 to 5)

(2) A pharmaceutical preparation comprising the (pyridylalkyl) (phenylsulfone) derivative according to claim 1.