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WO1999016766A1 - Derives de benzodioxole - Google Patents

Derives de benzodioxole Download PDF

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Publication number
WO1999016766A1
WO1999016766A1 PCT/JP1998/004431 JP9804431W WO9916766A1 WO 1999016766 A1 WO1999016766 A1 WO 1999016766A1 JP 9804431 W JP9804431 W JP 9804431W WO 9916766 A1 WO9916766 A1 WO 9916766A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
lower alkyl
acceptable salt
benzodioxol
pharmacologically acceptable
Prior art date
Application number
PCT/JP1998/004431
Other languages
English (en)
Japanese (ja)
Inventor
Etsuo Ohshima
Hoshisuke Nakasato
Koji Yanagawa
Haruhiko Manabe
Original Assignee
Kyowa Hakko Kogyo Co., Ltd.
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 Kyowa Hakko Kogyo Co., Ltd. filed Critical Kyowa Hakko Kogyo Co., Ltd.
Priority to AU92812/98A priority Critical patent/AU9281298A/en
Publication of WO1999016766A1 publication Critical patent/WO1999016766A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/64—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention has a phosphodiesterase (PDE) IV inhibitory effect, and has an inflammatory and allergic disease such as bronchial asthma, allergic rhinitis and nephritis, rheumatism, multiple sclerosis, Crohn's disease, psoriasis, and systemic lupus erythematosus.
  • Central nervous system diseases such as immune diseases, depression, amnesia, and dementia; organ damage due to ischemia reperfusion caused by heart failure, shock, cerebrovascular disorders, etc., diabetes due to insulin resistance, wounds, AIDS, etc.
  • the present invention relates to benzofuran derivatives useful as therapeutic agents.
  • cAMP adenosine 3,5'-cyclic monophosphate
  • guanosine 3,5,5 monocyclic monophosphate adenosine 3,5'-cyclic monophosphate
  • cGMP guanosine 3,5,5 monocyclic monophosphate
  • TNF tumor necrosis factor
  • IAM intercellular adhesion molecule
  • PDE IV has been shown to be involved in cAMP degradation. Therefore, PDE IV selective inhibitors can be expected to have therapeutic and / or preventive effects on inflammatory diseases, airway obstructive diseases, and ischemic diseases.
  • PDE IV inhibitors suppress the secretion of inflammatory cytokines such as TNF and inulin-leukin (IL) -8 by increasing cAMP, and are further transmitted by these cytokines. Is expected to prevent the development and prolongation of the inflammatory response. For example, it has been reported that TNF reduces phosphorylation of insulin receptors in muscle and fat cells and contributes to insulin-resistant diabetes. 'Instique, J. Clin. Invest., 94, 1543 (1994)]. Similarly, TNF is involved in the development and progression of autoimmune diseases such as rheumatism, multiple sclerosis, and Crohn's disease, suggesting that PDE IV inhibitors may be effective in those diseases. [Nature Medicine, 1, 211 (1995) and Ibid, 1, 244 (1995)].
  • WO97 / 20833 discloses a benzofurancarboxamide derivative having a PDE IV inhibitory action.
  • W096 / 36624 discloses a compound having a biphenyl ring having PDE IV inhibitory activity.
  • PDE IV inhibitors are expected to have prophylactic or therapeutic effects on a wide range of diseases.
  • An object of the present invention is to provide a benzodioxole derivative which has excellent anti-inflammatory activity and does not show vomiting.
  • the present invention provides a compound represented by the general formula (I):
  • R 1 and R 2 are the same or different and each represents hydrogen or lower alkyl or joined together to represent cycloalkyl, R 3 represents lower alkyl, R 4 represents lower alkyl, nitro, Represents cyano, carbamoyl, formyl, lower alkoxycarbonyl or carboxy; X and Y are the same or different and represent N or CR 5 , wherein R 5 represents hydrogen, lower alkyl, hydroxy or halogen. Or a pharmacologically acceptable salt thereof.
  • compound (I) the compound represented by the general formula (I).
  • compound (I) the compound represented by the general formula (I).
  • the present invention also relates to a therapeutic agent for inflammatory allergic diseases comprising Compound (I) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention relates to a method for treating an inflammatory allergic disease, which comprises administering an effective amount of compound (I) or a pharmacologically acceptable salt thereof.
  • the present invention also relates to the use of compound (I) or a pharmacologically acceptable salt thereof for producing a pharmacological composition useful for treating an inflammatory allergic disease.
  • Pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts and the like.
  • Pharmaceutically acceptable acid addition salts of compound (I) include inorganic acids such as hydrochloride, sulfate, nitrate and phosphate, acetate, maleate, fumarate, citrate and the like.
  • Pharmacologically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc.
  • Examples of the pharmacologically acceptable ammonium salts include salts of ammonium and tetramethylammonium, and examples of the pharmacologically acceptable organic amine addition salts include morpholine and pyridine. And addition salts such as azine.
  • the lower alkyl moiety of lower alkyl and lower alkoxycarbonyl represents a straight-chain or branched alkyl having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like.
  • cycloalkyl examples include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Halogen represents each atom of fluorine, chlorine, bromine and iodine.
  • R 1 and R 2 together represent cycloalkyl, R 4 represents carboxy or lower alkyl, X represents CH, and Y represents N, or R 1 and R 2 Preferred are compounds in which R 2 is the same or different and represents lower alkyl, R 4 represents carboxy, and X and Y represent CH.
  • R 3 is alkyl having 1 to 4 carbon atoms. Some are preferred Among them, methyl is more preferable.
  • Production method Compound (I) can be produced by the following production method.
  • R 6 represents lower alkyl
  • L 1 represents chlorine, bromine or iodine
  • L 2 represents chlorine, bromine or iodine. Or a trifluoromethanesulfonate group.
  • the lower alkyl represented by R 6 has the same meaning as the definition of the lower alkyl described above.
  • Compound (I) is obtained by treating compound (II) with a base in an inert solvent at a temperature between 110 ° C and room temperature for 5 minutes to 10 hours, and then reacting 1 equivalent to an excess of halogenated compound.
  • the metal or boron compound is allowed to react at a temperature between 100 ° C and the boiling point of the solvent used for 5 minutes to 30 hours, and then the compound (Ilia) is added in an inert solvent in excess of the catalyst amount.
  • the reaction can be carried out in the presence of an amount of the palladium complex at a temperature between room temperature and the boiling point of the solvent used for 5 minutes to 30 hours.
  • a salt such as lithium chloride or silver oxide may be added in excess of the amount of the catalyst.
  • Bases include sodium hydroxide, potassium hydroxide, sodium methoxide, potassium ethoxide, sodium hydride, potassium hydride, butyllithium, lithium diisopropylamide (hereinafter abbreviated as LDA), potassium tert-butoxide, triethylamine, Examples include diisopropylethylamine, triptylamine, dicyclohexylmethylamine, N-methylmorpholine, N-methylbiveridine, 1,8-diazabicyclo [5.4.0] 7-indene (hereinafter abbreviated as DBU), and the like.
  • LDA lithium diisopropylamide
  • DBU 1,8-diazabicyclo [5.4.0] 7-indene
  • metal halide examples include alkyltin compounds such as chlorotributyltin and chlorotrimethyltin, and zinc halides such as zinc chloride, zinc bromide, and zinc iodide.
  • alkyltin compounds such as chlorotributyltin and chlorotrimethyltin
  • zinc halides such as zinc chloride, zinc bromide, and zinc iodide.
  • boron compound examples include trimethoxy boron. Phenylboric acid, boric acid and the like.
  • Examples of the palladium complex include tetrakistriphenylphosphine palladium, dichlorobistriphenylphosphine palladium, dichlorobisacetonitrile palladium, diphenylphosphinophene phenyl palladium, palladium acetate and the like.
  • Inert solvents used in the reaction with metal halides or boron compounds include tetrahydrofuran (hereinafter abbreviated as THF), dioxane, dimethyl ether, 1,2-dimethyloxetane, diethylene glycol dimethyl ether, benzene, Examples include toluene and hexane.
  • THF tetrahydrofuran
  • dioxane dimethyl ether
  • 1,2-dimethyloxetane diethylene glycol dimethyl ether
  • benzene examples include toluene and hexane.
  • Examples of the inert solvent used in the reaction in the presence of the palladium complex include THF, dioxane, dimethyl ether, ethylene glycol, triethylene glycol, 1,2-dimethoxetane, diethylene glycol dimethyl ether, and methanol. , Ethanol, butanol, isopropanol, dichloromethane, dichloromethane, benzene, toluene, dimethylacetamide (hereinafter abbreviated as DMA), dimethylformamide (hereinafter abbreviated as DMF), dimethylsulfoxide (hereinafter abbreviated as DMSO) Abbreviations) and the like.
  • DMA dimethylacetamide
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • Compound (II) can be synthesized according to the method described in Synthesis, 122 (1986).
  • the compound (Ilia) can be synthesized according to the method described in Tetrahedron Lett., 36, 5319 (1995).
  • Compound (I) wherein R 4 is carboxy may be produced by the following steps 2 and 3.
  • Compound (la) can be obtained by reacting compound (II) with compound (Ilb) according to step 1.
  • the compound (Illb) can be obtained by purchasing a commercial product or synthesizing it according to the method described in WO95 / 06640 or Falman,-(Pharmazie), 38, 591 (1983).
  • Compound (lb) is prepared by converting compound (la) in the presence of a catalytic amount to a large excess of a base in an inert solvent containing water at a temperature between room temperature and the boiling point of the solvent used for 0.1 to 48 hours. It can be obtained by processing.
  • Bases include sodium hydroxide, potassium hydroxide, sodium methoxide, potassium ethoxide, sodium hydride, potassium hydride, butyllithium, LDA, potassium tert-butoxide, triethylamine, disopropylethylamine, tributylamine, dicyclohexyl.
  • Methylamine, N-methyl Examples include morpholine, N-methylbiperidine, DBU and the like.
  • Inert solvents include THF, dioxane, getyl ether, ethylene glycol, triethylene glycol, 1,2-dimethoxetane, diethylene glycol dimethyl ether, methanol, ethanol, butanol, isopropanol, dichloromethane, Black form, benzene, toluene, DMA, DMF,
  • Compound (Ic) is prepared by converting compound (la) in a solvent-free or inert solvent from 1 equivalent to an excess amount of ammonia or ammonia dissolved in an inert solvent at a temperature between 150 ° C and the boiling point of the solvent used. It can be obtained by reacting at temperature for 5 minutes to 168 hours. Wear. If necessary, a catalytic amount to an excessive amount of ammonium chloride, sodium amide, sodium methoxide and the like may be added.
  • inert solvents examples include THF, dioxane, geethylether, ethylene glycol, triethylene glycol, 1,2-dimethoxetane, diethylene glycol dimethyl ether, methanol, ethanol, butanol, isopropanol, acetonitrile, water, Examples include acetone, DMA, DMF, and DMSO.
  • Compound (Ic) can be prepared by using compound (lb) in a solvent-free or inert solvent using 1 equivalent to excess amount of inorganic halide, if necessary in the presence of an excess base from a catalytic amount, at ⁇ 50 ° C. After treating for 5 minutes to 24 hours at a temperature between the boiling points of the solvent and the corresponding acid halide, 1 equivalent to an excess amount of ammonia or inert, either as is or in an inert solvent It can be obtained by reacting with ammonia dissolved in a solvent at a temperature between ⁇ 50 ° C. and the boiling point of the used solvent for 5 minutes to 48 hours in the presence of a catalytic amount and an excess of a base if necessary.
  • inorganic halide examples include thionyl chloride, phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride, and phosphorus tribromide.
  • Examples of the base include triethylamine, diisopropylethylamine, triptylamine, pyridine and the like.
  • Examples of the inert solvent used for introducing the acid halide include dichloromethane, dichloroethane, chloroform, benzene, toluene, trifluoromethylbenzene, pyridine, DMA, DMF, and DMSO.
  • Examples of the inert solvent used in the reaction with ammonia or ammonia dissolved in an inert solvent include dichloromethane, THF, pyridine, dioxane, dimethyl ether, ethylene glycol, triethylene glycol, 1,2-dimethoxyethane, and diethylene glycol.
  • Dimethyl ether, methanol, ethanol, Examples include butanol, isopropanol, acetonitrile, water, acetone, DMA, DMF, and DMSO.
  • the intermediates and target compounds in each of the above production methods are isolated and purified by separation and purification methods commonly used in synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various chromatographies, etc. can do. Further, the intermediate can be subjected to the next reaction without purification.
  • compound (I) when compound (I) is obtained in the form of a salt, purification may be carried out as it is. When compound (I) is obtained in a free form, compound (I) may be appropriately purified. What is necessary is just to dissolve or suspend in a solvent, add an acid or a base, and isolate and purify.
  • Compound (I) and its pharmacologically acceptable salts may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.
  • compound (I) may have various stereoisomers such as enantiomers and diastereoisomers, and the present invention includes these and further includes mixtures thereof.
  • Table 1 shows specific examples of the compound (I) obtained by the present invention.
  • Test Example 1 Inhibition of TNF production in LPS-induced mouse sepsis model
  • the solution was dissolved in physiological saline, and administered to the tail vein at a dose of 200 veins per 20 g of body weight.
  • the test compound was dissolved or suspended in a 0.5% methylcellulose solution to a final concentration of 1 mg / ml, and administered orally at 200 1 per 20 g body weight 90 minutes before LPS administration.
  • Serum TNF concentration measured by enzyme-linked immunosorbent assay It was measured by the ELISA method.
  • the inhibition rate of TNF production by the test compound was determined by the following equation.
  • control TNF concentration was determined in the absence of the test compound (0.5% methylcell mouth).
  • Compound A was used as a comparative compound.
  • the compounds 1 to 3 of the present invention suppressed the production of TNF tx which activates inflammatory leukocyte cells. Also, the compounds of the present invention are superior to compound A in reducing vomiting, a common side effect of PDE IV inhibitors.
  • Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations. The pharmaceutical preparations are used for animals and humans.
  • the pharmaceutical preparation according to the present invention can contain Compound (I) or a pharmacologically acceptable salt thereof alone or as a mixture with any other active ingredient for treatment as an active ingredient.
  • these pharmaceutical preparations are produced by mixing the active ingredient with one or more pharmacologically acceptable carriers and by any method well known in the technical field of pharmaceuticals.
  • the route of administration is preferably the one that is most effective in the treatment, and may be oral or non-oral, for example, oral, respiratory, rectal, subcutaneous, intramuscular, and intravenous .
  • Dosage forms include sprays, capsules, tablets, granules, syrups, emulsions, Suppositories, injections, ointments, tapes, etc.
  • Liquid preparations suitable for oral administration include water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive oil, soybean oil. Oils such as, for example, preservatives such as p-hydroxybenzoic acid esters, and flavors such as peridotium flavor and peppermint.
  • Capsules, tablets, powders, granules, etc. are excipients such as lactose, glucose, sucrose, mannitol, disintegrants such as starch and sodium alginate, and lubricants such as magnesium stearate and sugar. It can be produced using a binder such as polyvinyl alcohol, hydroxypropylcellulose, and gelatin, a surfactant such as a fatty acid ester, and a plasticizer such as glycerin.
  • Formulations suitable for parenteral administration comprise a sterile aqueous preparation containing the active compound, which is preferably isotonic with the blood of the recipient.
  • a solution for injection is prepared using a carrier comprising a salt solution, a glucose solution, or a mixture of saline and a pudose solution.
  • Formulations for enteral administration are prepared using carriers such as, for example, cocoa butter, hydrogenated fats or hydrogenated carboxylic acids, and are provided as suppositories.
  • Sprays are prepared using a carrier which does not irritate the active compound itself or the oral and respiratory mucosa of the recipient and which disperses the active compound as fine particles to facilitate absorption.
  • lactose, glycerin and the like are exemplified.
  • Formulations such as aerosols and dry powders are possible depending on the nature of the active compound and the carrier used.
  • auxiliary components can also be added.
  • the effective amount and frequency of administration of compound (I) or a pharmaceutically acceptable salt thereof will vary depending on the mode of administration, the age and weight of the patient, and the nature or severity of the condition to be treated. However, the usual dosage is 0.01 mg to 1 g, preferably 0.05 to 50 mg, per adult once or several times a day when administered orally. In the case of parenteral administration such as intravenous administration, 0.001 to 100 mg, preferably 0.01 to 100 mg per adult is administered once to several times a day. These dosages vary depending on the various conditions described above. Hereinafter, preparation examples of the compound of the present invention are shown.
  • a tablet consisting of the following composition is prepared by a conventional method.
  • a powder having the following composition is prepared by a conventional method.
  • a capsule having the following composition is prepared by a conventional method.
  • Example 2 Compound 1 (100 mg ) obtained in Example 1 was dissolved in dichloromethane (1 ml), and thionyl chloride (1 ml) was added, followed by heating under reflux for 10 minutes. After removing the solvent, a saturated ammonia ethanol solution was added, and the mixture was stirred for 2 hours. The precipitated crystals were collected by filtration and washed with ethanol to obtain Compound 8 (35 mg, 35%) as pale yellow crystals.
  • Step A 4-Methoxy-7-triptylsylnylspiro [1,3-benzodioxo-2,1'-cyclopentane] (Compound aa) Under an argon atmosphere, a THF solution (100 1111) of 7-bromo-1-methoxyspiro [1,3-benzodioxo-l-2, -cyclopentene] (5.5 g) was cooled to -78 ° ( A butyllithium hexane solution (1.6 M) (15 ml) was added dropwise, and the mixture was stirred at the same temperature for 1 hour, and then a drop-port triptyltin (6.3 ml) was added dropwise and stirred for 1 hour. Ether was added, and the organic layer was extracted, washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude target product, which was used directly in the next step without purification.
  • Example 3 Using the compound aa (3.4 g) obtained in the step A, methyl 5-iodopyridine-12-carboxylate (1.2 g), and palladium diphenylphosphinophane (0.2 g), Example 3 was used. Compound a (0.78 g, 50%) was obtained as colorless crystals by a similar method.
  • step B Using the compound ea, 4-ethyl-2-ethyl benzoate (0.88 g), palladium acetate (0.043 g), sodium carbonate (0.71 g) and DMF (6.5 ml), in the same manner as in Reference Example 3, step B As a result, compound f (0.18 g, 17%) was obtained as colorless crystals.
  • Step B 7-Acetyl-1-4-methoxyspiro [1,3-benzodioxo- 1,2,1,1-cyclopentane] (Compound gb)
  • the present invention has a PDE IV inhibitory effect, and has asthma, allergy, rheumatism, psoriasis, myocardial infarction, depression, amnesia, multiple sclerosis, Crohn's disease, systemic lupus erythematosus, diabetes, wound, AIDS
  • An oxygen-containing heterocyclic compound useful as a therapeutic agent can be provided.

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

Abstract

Dérivés de benzodioxole de formule générale (I), ou sels acceptables sur le plan pharmacologique desdits dérivés, dans laquelle R1 et R2 sont identiques ou différents et chacun représente hydrogène ou alkyle inférieur, ou bien R1 et R2 en combinaison représentent cycloalkyle, R3 représente alkyle inférieur, R4 représente alkyle inférieur, nitro, cyano, carbamoyl, formyle, alcoxycarbonyle inférieur ou carboxy, et X et Y sont identiques ou différents et chacun représente N ou CR5 (dans laquelle R5 représente hydrogène, alkyle inférieur, hydroxy ou halogéno).
PCT/JP1998/004431 1997-10-01 1998-10-01 Derives de benzodioxole WO1999016766A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU92812/98A AU9281298A (en) 1997-10-01 1998-10-01 Benzodioxole derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/268400 1997-10-01
JP26840097 1997-10-01

Publications (1)

Publication Number Publication Date
WO1999016766A1 true WO1999016766A1 (fr) 1999-04-08

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AU (1) AU9281298A (fr)
WO (1) WO1999016766A1 (fr)

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