WO1996019454A1 - Derives de pyridylalkyle-phenyl-sulfone et preparation medicinale les contenant - Google Patents

Derives de pyridylalkyle-phenyl-sulfone et preparation medicinale les contenant Download PDF

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Publication number
WO1996019454A1
WO1996019454A1 PCT/JP1995/002590 JP9502590W WO9619454A1 WO 1996019454 A1 WO1996019454 A1 WO 1996019454A1 JP 9502590 W JP9502590 W JP 9502590W WO 9619454 A1 WO9619454 A1 WO 9619454A1
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WO
WIPO (PCT)
Prior art keywords
pyridylalkyl
pyridyl
ethyl
acid
butyl
Prior art date
Application number
PCT/JP1995/002590
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English (en)
Japanese (ja)
Inventor
Hiroyuki Ohnishi
Katsumi Morimoto
Harue Kitamura
Hiroaki Kasukawa
Original Assignee
Terumo Kabushiki Kaisha
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Terumo Kabushiki Kaisha filed Critical Terumo Kabushiki Kaisha
Priority to AU41892/96A priority Critical patent/AU4189296A/en
Publication of WO1996019454A1 publication Critical patent/WO1996019454A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
    • C07D213/34—Sulfur atoms to which a second hetero atom is attached

Definitions

  • 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.
  • TXA 2 tonomboxan A 2
  • TXA 2 tonomboxan A 2
  • 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.
  • 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.
  • PGH 2 itself has a platelet aggregation effect and smooth muscle contraction effect similarly to TXA 2
  • prostaglandins such as PGE 2 generated from PGH 2 also have a similar effect.
  • TXA 2 Despite the inhibition of TXA 2 production, alternative coagulants and contractiles are produced, halving the effectiveness of the actual drug.
  • 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.
  • 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.
  • 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
  • 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).
  • the present invention is a prostaglandin H 2 antagonist comprising the (pyridylalkyl) (fuunyl sulfone) derivative according to the above (1).
  • 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).
  • 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.
  • 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.
  • 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
  • the terephthalaldehyde monogetyl acetal and the corresponding organic metal compound 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.
  • 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).
  • an inert solvent preferably N, N-dimethylformamide
  • palladium acetate at room temperature to reflux temperature (preferably 100 to 140 ° C).
  • a suitable catalyst including Raney nickel, Raney cobalt, platinum oxide, palladium monocarbon, etc.
  • 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.
  • an inert organic solvent preferably DMF, THF, etc.
  • E, Z forms of ethyl carboxylate is obtained, and a mixture of E, Z forms of ⁇ , ⁇ -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.
  • a subsequent acid treatment preferably, dilute hydrochloric acid, dilute sulfuric acid, etc.
  • the compound and a suitable base preferably LDA, sodium hydride, n-butyllithium. Sodium ethkind, potassium tert-butoxide
  • an inert solvent preferably THF, DMF, etc.
  • 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).
  • 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
  • DMF inert solvent
  • 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).
  • a suitable base such as lithium hydroxide, potassium hydroxide, or sodium hydroxide
  • 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.).
  • a salt thereof can be obtained by treating with an equivalent amount of a base or an acid.
  • 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.
  • 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.
  • the salt can be obtained by treating with an equivalent amount of a base or an acid.
  • Toronbokisa down A 2 antagonists can be used as an agent and a therapeutic agent.
  • 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
  • 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%).
  • Example 1 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.
  • 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.
  • the (pyridylalkyl) (phenylsulfone) derivative of the present invention exhibited an excellent inhibitory effect on toxanboxane synthase.
  • 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"
  • a novel (pyridylalkyl) (phenylsulfone) ⁇ 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un dérivé de pyridylalkyl-phényl-sulfone qui présente un antagonisme entre la thromboxane A2 et la prostaglandine H2, ainsi qu'un effet inhibiteur de la synthèse de la thromboxane A2, et est utile comme agent antithrombotique et antiallergique, et sa formule générale (1), dans laquelle X représente l'hydrogène, un halogèno, un alkyle inférieur, un alcoxy, hydroxy, nitro, cyano ou trifluorométhyle inférieur; R représente -O-(CH2)a-CO2-R1, -(CH2)a-CO2-R1, -CR2=CR3-CO2-R1 or -CR2R3-CR4R5-CO2-R1 (où R1, R2, R3, R4, et R5 représentent chacun l'hydrogène ou un alkyle inférieur, et a représente un nombre entier de 0 à 5); et 1, m et n représentent chacun un nombre entier de 0 à 5.
PCT/JP1995/002590 1994-12-20 1995-12-18 Derives de pyridylalkyle-phenyl-sulfone et preparation medicinale les contenant WO1996019454A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU41892/96A AU4189296A (en) 1994-12-20 1995-12-18 Pyridylalkyl phenyl sulfone derivatives and medicinal preparation containing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP6/316279 1994-12-20
JP31627994 1994-12-20

Publications (1)

Publication Number Publication Date
WO1996019454A1 true WO1996019454A1 (fr) 1996-06-27

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ID=18075342

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Application Number Title Priority Date Filing Date
PCT/JP1995/002590 WO1996019454A1 (fr) 1994-12-20 1995-12-18 Derives de pyridylalkyle-phenyl-sulfone et preparation medicinale les contenant

Country Status (2)

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AU (1) AU4189296A (fr)
WO (1) WO1996019454A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5062979A (fr) * 1973-10-04 1975-05-29

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5062979A (fr) * 1973-10-04 1975-05-29

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEM. BER., Vol. 116, No. 9, (1983), ANDERS E. et al., pages 3192-3204. *
CHEM. BER., Vol. 122, No. 1, (1989), ANDERS E. et al., pages 105-111. *

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Publication number Publication date
AU4189296A (en) 1996-07-10

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