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WO1990012004A1 - Nouveaux composes de naphthalene et leur procede de production - Google Patents

Nouveaux composes de naphthalene et leur procede de production Download PDF

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Publication number
WO1990012004A1
WO1990012004A1 PCT/JP1990/000466 JP9000466W WO9012004A1 WO 1990012004 A1 WO1990012004 A1 WO 1990012004A1 JP 9000466 W JP9000466 W JP 9000466W WO 9012004 A1 WO9012004 A1 WO 9012004A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
salt
hydrogen
formula
Prior art date
Application number
PCT/JP1990/000466
Other languages
English (en)
Japanese (ja)
Inventor
Takayuki Namiki
Akira Katayama
Keiji Hemmi
Masashi Hashimoto
Original Assignee
Fujisawa Pharmaceutical 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
Priority claimed from GB898907868A external-priority patent/GB8907868D0/en
Priority claimed from GB898919410A external-priority patent/GB8919410D0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Publication of WO1990012004A1 publication Critical patent/WO1990012004A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel naphthalene compound and a salt acceptable as a medicament thereof, and is useful in the field of medicine. Background technology
  • one object of the present invention is to provide a naphthalene compound which is a phospholipase II inhibitor and a salt thereof which is pharmaceutically acceptable. That is.
  • a further object of the present invention is to provide a method for preventing inflammation, which comprises administering the naphthalene compound to a human or animal and / or preventing inflammation. Or to provide treatment.
  • the naphthalene compound as the object of this invention is novel and can be represented by the following general formula [I].
  • R 1 is hydrogen, a lower alkyl group or an amino protecting group
  • R 2 and R 3 represent hydrogen or halogen, respectively, and A represents a lower alkylene group).
  • the group A is bonded to the 2- or 3-position of the pyrrolidine ring.
  • the target naphthalene compound [I] or a salt thereof can be produced according to the following reaction formula. Manufacturing method
  • R a is an amino protecting group
  • R t is a lower alkyl group
  • X represents an acid residue.
  • Some of the raw material compounds [ ⁇ ] are novel, and may be prepared by the production method disclosed in the production described later or by a similar production method. It can be manufactured more.
  • Suitable pharmaceutically acceptable salts of compound [I] are conventional non-toxic salts, for example, acetate, trifluoric acid, etc.
  • Organic acids such as salt, maleate, tartrate, methansulfonate, benzenesulfonate, formate, and toluenesulfonate
  • Inorganic acid addition salts such as addition salts, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc., or for example, aspartic acid, glue
  • An acid addition salt such as a salt with an acidic amino acid such as tamic acid is exemplified.
  • “Lower” shall mean 1 to 6 carbon atoms unless otherwise indicated.
  • lower alkyl groups j include methyl, ethyl, propyl, isopropyl, butyr, tertiary butyl, pentyl, and the like. Examples thereof include a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms such as xyl, and among these, preferred are Among them, a -C 4 ) alkyl group is mentioned, and the most preferable one is a methyl group.
  • Suitable "lower alkylene radicals j include methylene, ethylene, trimethylene, propylene, tetramethylene,
  • Suitable “nologogens” include black mouth, bromo, iodine and fluorine mouth.
  • Suitable “amino protecting groups” include, for example, benzyl, phenyl, 11-phenylene, benzylhydryl, trityl and the like. Mono or di- or triphenyl (lower) alkyl groups such as lower alkyl groups; and acyl groups as described below. It is possible.
  • Suitable acyl groups include aliphatic acyl groups and aromatic acyl groups derived from carboxylic acid, carbonic acid, carboxylic acid, sulfonic acid and the like. Groups, aryl aliphatic groups and heteroaliphatic acyl groups.
  • acyl group in this meaning include, for example, holmil, acetyl, propionyl, hexanol, and biyl.
  • a lower alkoxy group such as valoyl, for example, mono (or di or tri) such as chloroacetyl, trifluoroacetyl, etc. ) No.
  • ⁇ (lower) alkoxy radicals such as methoxycarbonyl, ethoxycarbonyl, tertiary butoxycarbonyl, Lower alcoholic carbonyl groups such as tertiary pentoxycarboxylic carbonyls, hexylcarboxylic carbonyls, for example, chlorome Mono (or di or tox) such as toxylbonyl, dichloroethoxy, or tricyclodexile Li) c (Lower) Alkoxy carbonyl group, for example, Benzoyl, Toluoiru, Kishikoiru, naphthoyl, etc., for example, If you want to buy Al (lower) alkanol groups such as vinyl (lower) alkanol groups such as nirubovyonil, for example, phenolic Aryloxy carbonyl groups such as bonyl and naphthoxy carbonyl, for example phenoxy acetyl and phenoxy pro Aryloxy (lower
  • Phenyl (lower) alkylsulphonyl groups such as benzylsulphonyl, phenethylsulphonyl, benzylhydrylsulphonyl, etc.
  • Alkyl (lower) alkyl sulfonyl groups and the like are examples of alkyl (lower) alkyl sulfonyl groups and the like.
  • Alkoxycarbonyl groups most preferred are tertiary butoxycarbonyl groups and benzylol And a carbonyl group.
  • Pen Lower alkoxy groups such as tanyloxy and hexanoyloxy, for example, slurries such as mesyloxy and tosiloxy
  • An acyloxy group such as a polyoxyl group; for example, a halogen such as a black mouth, bromo, iodine, and fluoro. It is possible.
  • the method for producing the naphthalene compound [I] of the present invention will be described in detail.
  • the naphthalene compound [I] or a salt thereof can be produced by reacting a compound [ ⁇ ] with the compound [H] or a salt thereof. And can be done.
  • Suitable salts of compound [IE] include those as exemplified for compound [I].
  • This reaction is carried out, for example, in a hydrogen hydride Alkali metal hydrides such as sodium iodide, alkali metal halides such as sodium iodide, etc., for example, sodium carbonate, carbonate Alkali metal carbonates such as potassium, for example, in the presence of bases such as sodium hydroxide, alkali metal hydroxides such as hydroxylated lime You may go to
  • This reaction is usually carried out in water, black mouth, alcohols such as methanol, ethanol, etc., N, N-dimethylformamide
  • the reaction can be carried out in any conventional solvent such as described above, but the reaction can be carried out in any other solvent that does not adversely affect the reaction.
  • the reaction may be performed in a mixture of these solvents.
  • the reaction temperature is not particularly limited, but this reaction is usually carried out at room temperature, under heating or under heating.
  • Compound [Ib] or a salt thereof can be produced by subjecting a ligate compound [Ia] or a salt thereof to an elimination reaction of an amino protecting group. it can .
  • Suitable salts of the compounds [Ia] and [Ib] include those as exemplified for the compound [I].
  • This reaction is performed according to a conventional method such as hydrolysis, reduction and the like.
  • the hydrolysis is preferably performed in the presence of a base or an acid, including Lewis acid.
  • Suitable bases include, for example, alkaline metals such as sodium and potassium, and magnesium salts such as magnesium and calcium. Earth metals, hydroxides or carbonates or bicarbonates of those metals, for example, trimethylamine, triethylamine, etc. Kiramin, picolin, 1,5-diazabicyclo [4.3.0] non-1 5-diene, 1,4-diazabicyclo [2 . 2.2] octane, 1, 8 — diaza bicyclo
  • Suitable acids include, for example, organic acids such as formic acid, acetic acid, bupiionic acid, trichloroacetic acid, trifluoroacetic acid and the like, for example, hydrochloric acid, hydrogen bromide Inorganic acids such as acid, sulfuric acid, hydrogen chloride, hydrogen bromide and the like can be mentioned.
  • desorption using a luciferic acid such as trichloroacetic acid, trichloroacetic acid, etc. can be carried out using, for example, anisol, It is desirable to carry out the reaction in the presence of a positive ion scavenger such as phenol.
  • the reaction is usually carried out with water, for example, alcohols such as methanol, ethanol, etc., ethyl acetate, salted methylene, tetrahydrofuran.
  • the reaction is carried out in such a solvent or a mixture thereof, but the reaction can be carried out in any other solvent that does not adversely affect the reaction.
  • Liquid bases or acids can also be used as solvents.
  • the reaction temperature is not particularly limited, but the reaction is usually carried out without cooling or heating.
  • Reduction methods applicable to the elimination reaction include chemical reduction and catalytic reduction.
  • Suitable reducing agents used for chemical reduction include metals such as, for example, tin, zinc, iron or metal compounds such as, for example, chromium chloride, chromium acetate, and for example, formic acid,
  • metals such as, for example, tin, zinc, iron or metal compounds such as, for example, chromium chloride, chromium acetate, and for example, formic acid
  • organic or inorganic acids such as acetic acid, propionic acid, trifluorosulfonic acid, p-toluenesulfonic acid, hydrochloric acid and hydrobromic acid
  • Suitable catalysts used for the catalytic reduction are, for example, platinum catalysts such as platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc., for example, palladium sponge, Radium black, acid paradium, paradium-carbon, colloid, radium, no, radium monosulfate, parium Palladium catalysts such as radium monocarbonate, for example, nickel catalysts such as reduced nickel, nickel oxide, and Raney nickel, for example
  • cobalt catalysts such as reduced cobalt and Raney cobalt
  • iron catalysts such as reduced iron and Raney iron, for example, reduced copper, Raney copper, and urethane It is a commonly used material such as a copper catalyst such as man copper.
  • Reduction usually does not adversely affect reactions such as water, methanol, ethanol, propanol, N, N-dimethylformamide. It is carried out in common solvents or their mixtures.
  • acids used for chemical reduction are liquid, they can also be used as solvents.
  • suitable solvents used for the catalytic reduction include the above-mentioned solvents and other ethyl ethers, dioxans, tetrahydrofurans and the like.
  • a common solvent, such as Mixtures thereof are mentioned.
  • the reaction temperature of this reduction is not particularly limited, but the reaction is usually carried out without cooling or heating.
  • Compound [Ic] or a salt thereof can be produced by reacting compound [Ib] or a salt thereof with a lower alkylating agent. .
  • Suitable salts of the compound [Ic] include those as exemplified for the compound [I].
  • Suitable "lower alkylating agents j" include, for example, methyl iodide, iodide methyl, propyl bromide, tertiary butyl chloride,
  • Lower alkylenyl halides such as 3-pentyl iodide and 2-hexyl chloride; di (lower) alkyl sulphates such as dimethyl sulphate and dimethyl sulphate;
  • di (lower) alkyl sulphates such as dimethyl sulphate and dimethyl sulphate;
  • lower aldehydes such as home aldehyde, ethanal, blopanal, butanal, 2, 2 —dimethyl propanal, hexanal Canal and reducing agents, for example, hydrogenated boron compounds such as sodium borohydride, hydrogenated cyanoborohydride, etc.
  • This reaction is usually carried out in water, for example in alcohols such as methanol, ethanol, etc., N, N-dimethylformamide, dimethylsul It is carried out in a common solvent such as oxide, Any other solvent that does not adversely affect the reaction can be used for the reaction.
  • the reaction temperature is not particularly limited, but the reaction is usually performed without cooling or heating.
  • the naphthalene compound [I] obtained by these production methods is in a free form, it can be converted to its salt form according to a conventional method. Wear . It is also possible to change from one salt form to another according to the usual law.
  • the target compound [I] may include a stereoisomer based on an asymmetric carbon atom, and this isomer is also included in the scope of the present invention.
  • the naphthalene compound [I] of this mushroom and its pharmaceutically acceptable salts are hospholipase A. Suppresses the action of inflammation and is therefore useful for the prevention and treatment of inflammation, especially organ inflammation (eg, mastitis, etc.).
  • Test 1 [ 14 C] one from rabbit platelets by collagen stimulation
  • Platelets were washed once with the same buffer and resuspended in an initial volume of Tyrode's solution.
  • Labeled platelets 400 parts fin queue based preparative 3 minutes with the test compound and 37 e C, then stimulated for 3 minutes at by Ri 37'C to co La chromatography gain down (final concentration 10 € ⁇ ⁇ ) .
  • the lipid fraction was extracted by adding 3 ⁇ of acid acid and shaking for 5 minutes. 2500 rpm, 4 e C After centrifugation for 1 minute, the Ke I acid 50mg in acetic acid E chill on eyebrows 2 Po, and mixed for 15 seconds Ri by the Pol Te Tsu click scan mixer.
  • the 50% inhibitory concentration (IC 5 () value) was as follows
  • mice All mice were maintained on standard laboratory chow prior to the experiment.
  • mice were randomly assigned to different treatment groups.
  • test compound was administered intraperitoneally (orally) twice a day (about 6 hours apart) for 4 days from the start of the experiment (8 injections per animal in total). Mortality was monitored for one week after the start of the experiment.
  • the 50% effective dose (ED 5 fl value :) was as follows.
  • the naphthalene compound [I] of the present invention is useful for prevention and treatment of mastitis.
  • the compound [I] and the pharmaceutically acceptable salts of this compound of the present invention are orally administered.
  • a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for parenteral, parenteral and topical administration; It is used as a usual pharmaceutical preparation containing the compound as an active ingredient.
  • Pharmaceutical preparations include tablets, granules, powders, solids such as capsules, or solutions, suspensions, syrups, emalegions, and lemonade. Such as liquids.
  • the dosage of the active ingredient of compound [I] will depend on various factors, such as the weight and age of the patient and the condition of the disease, as well as on the type of administration route. Depending on the dose, it is generally 0.5 mg or 2000 mg daily, preferably 1 mg or less, via oral administration or injection. OOO mg is administered.
  • An effective single dose should be selected from the range of 0.1 mg / k or 40 mg / kg, preferably 0.05 mgZ kg or 20 mg / kg per patient weight. I can do it.
  • Example 1 Example 1
  • Example 9 In the same manner as in Example 8, the following compound (Example 9 or 11) is obtained.
  • Example 9 In the same manner as in Example 8, the following compound (Example 9 or 11) is obtained.
  • Example 23 The following compounds (Examples 23 and 24) are obtained in the same manner as in Example 22.
  • Hydrogen shampoo sodium boron (94.3 mg) was taken as a 4-1 mouth [2-((2S) -pyrrolidine 1-2-yl ⁇ ethoxy) [Na] phthalene hydrochloride (312.2 mg) and a 37% aqueous solution of formaldehyde (0.132 M :) in anhydrous methanol (9.0 ⁇ ) at room temperature in a nitrogen atmosphere
  • the reaction mixture is stirred at room temperature for 60 minutes, the solvent is distilled off under reduced pressure, the residue is extracted with ethyl acetate (20 mfi :) and the aqueous solution of saturated sodium hydrogen carbonate (20 mfi :) is added.
  • Example 31 and 1 ⁇ The following compounds (Example 31 and 1 ⁇ ) are obtained in the same manner as in Example 30.
  • Example 33 to Example 33 are obtained in the same manner as in Example 1.
  • Example 44 The following compound (Example 44) was obtained in the same manner as in Example 25.

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

Abstract

L'invention concerne des composés de naphthalène représentés par la formule générale (I), ainsi que leurs sels pharmaceutiquement acceptables, utiles en tant qu'inhibiteur de phospholipase A2, ainsi qu'en tant qu'agent anti-inflammatoire, dans laquelle R1 représente hydrogène, un groupe alcoyle inférieur ou amino-protecteur; R2 et R3 représentent chacun hydrogène ou halogène; et A représente alkylène inférieur. L'invention concerne en outre un procédé de production de ces composés, des préparations pharmaceutiques les contenant en tant qu'ingrédient actif et un procédé de prévention et/ou de traitement de maladies inflammatoires affectant l'homme et l'animal.
PCT/JP1990/000466 1989-04-07 1990-04-06 Nouveaux composes de naphthalene et leur procede de production WO1990012004A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB898907868A GB8907868D0 (en) 1989-04-07 1989-04-07 A novel naphthalene compound and a process for preparation thereof
GB8907868.7 1989-04-07
GB898919410A GB8919410D0 (en) 1989-08-25 1989-08-25 A novel naphthalene compound and a process for preparation thereof
GB8919410.4 1989-08-25

Publications (1)

Publication Number Publication Date
WO1990012004A1 true WO1990012004A1 (fr) 1990-10-18

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Application Number Title Priority Date Filing Date
PCT/JP1990/000466 WO1990012004A1 (fr) 1989-04-07 1990-04-06 Nouveaux composes de naphthalene et leur procede de production

Country Status (2)

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AU (1) AU5358490A (fr)
WO (1) WO1990012004A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001253A3 (fr) * 1994-07-01 1996-07-18 Warner Lambert Co Inhibiteurs de pla2 et leur utilisation pour l'inhibition de l'absorption intestinale du cholesterol

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS495963A (fr) * 1972-03-30 1974-01-19
JPS5639065A (en) * 1979-07-06 1981-04-14 Ile De France Novel phenoxy heterocyclic amine* its manufacture and local narcotic as active component thereof
JPS60163861A (ja) * 1984-02-03 1985-08-26 エイ・エツチ・ロビンス・カンパニー・インコーポレーテツド 抗抑うつ、抗不整脈あるいは血圧降下作用を有するアリールオキシメチルピロリジノール類およびピペリジノール類

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS495963A (fr) * 1972-03-30 1974-01-19
JPS5639065A (en) * 1979-07-06 1981-04-14 Ile De France Novel phenoxy heterocyclic amine* its manufacture and local narcotic as active component thereof
JPS60163861A (ja) * 1984-02-03 1985-08-26 エイ・エツチ・ロビンス・カンパニー・インコーポレーテツド 抗抑うつ、抗不整脈あるいは血圧降下作用を有するアリールオキシメチルピロリジノール類およびピペリジノール類

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001253A3 (fr) * 1994-07-01 1996-07-18 Warner Lambert Co Inhibiteurs de pla2 et leur utilisation pour l'inhibition de l'absorption intestinale du cholesterol
US5968963A (en) * 1994-07-01 1999-10-19 Warner-Lambert Company PLA2 inhibitors and their use for inhibition of intestinal cholesterol absorption

Also Published As

Publication number Publication date
AU5358490A (en) 1990-11-05

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