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WO1993013068A1 - Compose tricyclique et medicament renfermant ce compose - Google Patents

Compose tricyclique et medicament renfermant ce compose Download PDF

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Publication number
WO1993013068A1
WO1993013068A1 PCT/JP1992/001640 JP9201640W WO9313068A1 WO 1993013068 A1 WO1993013068 A1 WO 1993013068A1 JP 9201640 W JP9201640 W JP 9201640W WO 9313068 A1 WO9313068 A1 WO 9313068A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
ylidene
group
same
ethoxy
Prior art date
Application number
PCT/JP1992/001640
Other languages
English (en)
Japanese (ja)
Inventor
Kazuhiro Kumagai
Masaaki Nagasawa
Hidenori Takahashi
Tooru Abe
Takeshi Omata
Yoshihide Segawa
Original Assignee
Zeria 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
Application filed by Zeria Pharmaceutical Co., Ltd. filed Critical Zeria Pharmaceutical Co., Ltd.
Publication of WO1993013068A1 publication Critical patent/WO1993013068A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • Tricyclic compounds and pharmaceuticals containing them Tricyclic compounds and pharmaceuticals containing them
  • the present invention relates to a novel tricyclic compound exhibiting strong antihistamine action and having high safety, and an antiallergic agent such as an antiasthmatic drug and an antihistamine containing the same.
  • Japanese Unexamined Patent Publication No. 2-503909, Japanese Unexamined Patent Publication No. 3-128354, and Japanese Unexamined Patent Publication No. 3-504012 disclose compounds having antiallergic activity, antihistamine effect, etc. However, these compounds do not yet fully satisfy both safety and efficacy.
  • the present invention provides a compound represented by the general formula (I):
  • R represents a hydrogen atom or a halogen atom
  • X represents a group CH 2 CH 2 —
  • One CH CH- or a single CH 2 - CO- indicates
  • A is a benzene ring, indicates Chiofen ring or Pyridine ring
  • B is a hydroxyl group, a lower alkoxyl group or a group - indicates
  • NH m is 2-5 Indicates an integer.
  • the present invention has excellent antihistamine action such as anti-asthma action, anti-allergic action, etc. and high safety. Therefore, it is a therapeutic agent for various allergic diseases, for example, treatment for anti-inflammatory nephritis, hepatitis and knee inflammation. And preventive and / or cure of respiratory diseases and antiasthmatics.
  • examples of the lower alkoxyl group represented by B include alkoxyl groups having 1 to 4 carbon atoms or 1 or 2 odors, and methoxyl, ethoxyl, propoxyl, butoxyl and isomers thereof are preferable.
  • examples of the halogen atom for R include m, fluorine and iodine atoms.
  • the compound of the present invention can be used as a pharmacologically acceptable salt.
  • a salt include a fiber salt, a nitrate, a fiber salt, an acetate, a maleate, a fumarate, a oxalate, and a quinate.
  • Acid addition salts such as acid salts, hydrobromides, succinates, sfflefamates, mandelates, malonates, phosphates, etc., or sodium salts, potassium salts, lithium salts, calcium salts, etc. Salt s1 ⁇ 2 salt.
  • Compound (I) of the present invention can be prepared, for example, according to the following method.
  • R, X, A and m have the same meaning as described above, B 1 represents a lower alkyl group, and Z represents a halogen atom.
  • the above-mentioned core is preferably carried out in a solvent that does not affect the reaction.
  • a solvent include esters such as methyl acetate and ethyl acetate; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran and dioxane; ketones such as acetone and methyl ethyl ketone; acetonitrile and dimethyl Sulfoxide, dimethylformamide and the like; halogenated hydrocarbons such as dichloromethane and chloroform; and aromatic hydrogen such as benzene, toluene and xylene. These can be used alone or as a mixture.
  • ⁇ may be changed according to the raw material used ⁇ ), and it is usually advantageous to select from 0 ° C to reflux temperature under normal pressure.
  • potassium carbonate, sodium carbonate, sodium carbonate examples thereof include carbonates such as hydrogen carbonate and the like, and organic groups such as triethylamine, diisopropylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU).
  • DBU 1,8-diazabicyclo [5.4.0] -7-undecene
  • This condensation reaction is preferably carried out according to a known method without affecting the reaction.
  • solvents include, for example, esters such as methyl acetate and ethyl acetate; amides such as dimethylformamide and getylformamide; ethers such as getyl ether, diisopropyl ether, tetrahydrofuran and dioxane; acetonitrile; Dimethyl sulfoxide, etc .; dichloromethane, chloropho Halogenated hydrocarbons such as lume; aromatic hydrocarbons such as benzene and tolues xylene; These can be used in insects or mixed.
  • condensing agent examples include carbodiimide derivatives such as N, N'-dicyclohexylcarbodiimide and 1, ⁇ -carbonyldiimidazole.
  • the thus-obtained compound (I) of the present invention can be formulated into a preparation for oral administration or a preparation for parenteral administration by combining a pharmaceutically acceptable auxiliary.
  • Formulations for oral administration include the above compounds in suitable additives, for example, excipients such as mannitol, corn starch, crystalline cellulose; binders such as cellulose-derived gum arabic and gelatin; disintegration of carboxymethylcellulose calcium and the like.
  • Agents Powders, powders, granules, and capsules can be prepared by combining them with lubricants such as talc and magnesium stearate appropriately. Further, these solid preparations are made enteric-soluble by using a coating base such as hydroxypropyl methylcellulose phthalate, hydroxybutyl propylmethylcellulose acetate succinate, cellulose acetate phthalate, and methacrylate copolymer.
  • a coating base such as hydroxypropyl methylcellulose phthalate, hydroxybutyl propylmethylcellulose acetate succinate, cellulose acetate phthalate, and methacrylate copolymer.
  • Liquid preparations for oral administration include emulsions, solutions, suspensions, syrup U, elixirs, etc., and commonly used inert diluents such as purified M, ethanol, etc. be able to.
  • This omega-substance may contain, in addition to the inert diluent, adjuvants such as wetting agents and emollients, sweetening agents, flavoring agents, fragrances, preservatives and the like.
  • adjuvants such as wetting agents and emollients, sweetening agents, flavoring agents, fragrances, preservatives and the like.
  • it can also be an aerosol formulated by a known method.
  • a liquid preparation can be prepared by combining, for example, water, ethanol, glycerin, a conventional surfactant and the like.
  • it can be an inhalant, a topical solution, an eye drop, a nasal drop, or a coating such as an ointment formulated by a known method.
  • the dose of the compound (I) of the present invention varies depending on age, body weight, symptom, therapeutic effect, administration method and administration period, but is usually 1 to 500 ⁇ ⁇ days, preferably 5 to 50ag / day.
  • Administer orally 1 to 3 times a day or parenteral once to several times a day in the range of 0.1 to 500 ng Administer. ⁇
  • the ileum was removed from male Hartley guinea pigs (body weight 300-600 g) and suspended in a Magnus bath (30.C, under aeration) filled with lOmfl Tyrode's solution at an initial load of 0.5 g.
  • Anti-BP0-BGG serum diluted 20-fold with a physiological diet was administered at a rate of 1 / kg to the hind limb vein of 4 guinea pigs per group to passively sensitize.
  • PSA was induced by intravenously administering 0.5 ng / BP0-BGG at a rate of lmfl / kg.
  • the compound obtained in Example 5 was orally administered to guinea pigs fasted on the previous day at a rate of 4 ng / kg one hour before the antigen administration.
  • the general symptoms of guinea pigs were observed, and the best response was determined from the mortality rate. As a result, the highest expression level was 1.0 ng / kg.
  • mice Four to five-week-old ICR mice (Charles Lipper) were used as 10 mice per group. After the compound obtained in each Example became cloudy with 5% gum arabic, each compound was orally administered at a dose of 1000 mg / kg, and observation was performed for 7 days. As a result, no deaths due to the toxicity of the compound of the present invention were observed. Difficult case
  • Example 4 The compounds of Examples 4 to 15 shown in Tables 3 to 5 were obtained according to the methods of mi to 3. Each chemical name is as follows. In the table, A, B, R, m and X represent symbols in the compound (I) of the present invention. In addition, in the column of the X group in the table, it represents a bond with the A ring. ⁇ Example 4
  • the above components are mixed uniformly, and a 200% aqueous solution of 7.5% hydroxypropylcellulose is added, and the mixture is granulated by an extrusion granulator using a screen with a diameter of 0.5, immediately rounded with a marmellaizer, and dried to obtain granules. did.
  • the dry granules were coated with 1.9 kg of the following film coating solution using a fluidized bed machine to obtain enteric coated granules.
  • the tablet was spray-coated with a coating solution having the following composition to give a coating of 100 ng per tablet, thereby obtaining an enteric film coating ⁇ 0.
  • the aerosol was prepared by the usual method.
  • the compound of the present invention exhibits strong antihistamine activity and high safety. It is useful as a prophylactic and / or curative drug and as an anti-asthmatic drug.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé tricyclique représenté par la formule générale (I), celle dérivée de ce composé est antihistaminique et antiallergique renfermant ce composé en tant qu'ingrédient actif dans laquelle R représente l'hydrogène ou un halogène; X représente -CH2CH2-, -CH=CH- ou -CH2-CO-; A représente le benzène, le thiophène ou le pyridine; B représente hydroxy ou un alcoxy inférieur (α); et m représente un entier de 2 à 5. Ce composé est un antihistaminique puissant qui présente une grande sécurité et qui est donc très utile pour traiter diverses maladies allergiques avec inflammation, les néphrites, les hépatites, les pancréatites, etc., pour prévenir et/ou traiter les maladies du système respiratoire et comme antiasthmatique.
PCT/JP1992/001640 1991-12-25 1992-12-16 Compose tricyclique et medicament renfermant ce compose WO1993013068A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP3/356615 1991-12-25
JP35661591 1991-12-25

Publications (1)

Publication Number Publication Date
WO1993013068A1 true WO1993013068A1 (fr) 1993-07-08

Family

ID=18449913

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1992/001640 WO1993013068A1 (fr) 1991-12-25 1992-12-16 Compose tricyclique et medicament renfermant ce compose

Country Status (2)

Country Link
AU (1) AU3170793A (fr)
WO (1) WO1993013068A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014526438A (ja) * 2011-06-28 2014-10-06 フジアン・ミンドン・レジュヴネイション・ファーマスーティカル・カンパニー・リミテッド 抗アレルギ性ベンゾシクロヘプタチオフェン誘導体
CN107602534A (zh) * 2017-09-05 2018-01-19 合肥医工医药有限公司 具有抗组胺和抗炎活性的化合物及其制备方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989012443A1 (fr) * 1988-06-17 1989-12-28 Fisons Corporation Nouvelles amines dibenzo-cycloheptenyle, dibenzo-cycloheptyle et dibenzo-oxepinyle presentant des proprietes antihistaminiques
JPH0347168A (ja) * 1988-11-30 1991-02-28 Ajinomoto Co Inc ピペリジン誘導体
JPH0363263A (ja) * 1989-05-19 1991-03-19 Hoechst Roussel Pharmaceut Inc Ｎ―（アリールオキシアルキル）ヘテロアリールピペリジンおよびｎ―（アリールオキシアルキル）ヘテロアリールピペラジン

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989012443A1 (fr) * 1988-06-17 1989-12-28 Fisons Corporation Nouvelles amines dibenzo-cycloheptenyle, dibenzo-cycloheptyle et dibenzo-oxepinyle presentant des proprietes antihistaminiques
JPH0347168A (ja) * 1988-11-30 1991-02-28 Ajinomoto Co Inc ピペリジン誘導体
JPH0363263A (ja) * 1989-05-19 1991-03-19 Hoechst Roussel Pharmaceut Inc Ｎ―（アリールオキシアルキル）ヘテロアリールピペリジンおよびｎ―（アリールオキシアルキル）ヘテロアリールピペラジン

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014526438A (ja) * 2011-06-28 2014-10-06 フジアン・ミンドン・レジュヴネイション・ファーマスーティカル・カンパニー・リミテッド 抗アレルギ性ベンゾシクロヘプタチオフェン誘導体
CN107602534A (zh) * 2017-09-05 2018-01-19 合肥医工医药有限公司 具有抗组胺和抗炎活性的化合物及其制备方法和应用
CN107602534B (zh) * 2017-09-05 2020-04-24 合肥医工医药股份有限公司 具有抗组胺和抗炎活性的化合物及其制备方法和应用

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AU3170793A (en) 1993-07-28

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