WO1993013068A1 - Tricyclic compound and medicine containing the same - Google Patents

Tricyclic compound and medicine containing the same 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
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Prior art keywords
compound
ylidene
group
same
ethoxy
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PCT/JP1992/001640
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French (fr)
Japanese (ja)
Inventor
Kazuhiro Kumagai
Masaaki Nagasawa
Hidenori Takahashi
Tooru Abe
Takeshi Omata
Yoshihide Segawa
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Zeria Pharmaceutical Co., Ltd.
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Publication of WO1993013068A1 publication Critical patent/WO1993013068A1/en

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    • 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.

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  • 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

A tricyclic compound represented by general (I), a salt thereof, and an antihistaminic and an antiallergic containing the same as the active ingredient wherein R represents hydrogen or halogen; X represents -CH2CH2-, -CH=CH- or -CH2-CO-; A represents benzene, thiophene or pyridine; B represents hydroxy, lower alkoxy or (α); and m represents an integer of 2 to 5. The compound has a potent antihistaminic activity and a high safety, and is hence useful for treating various allergic diseases including inflammation, nephritis, hepatitis, pancreatitis, etc., for preventing and/or treating respiratory system diseases, and as an antiasthmatic.

Description

明 細 書  Specification
三環系化合物及びこれを含有する医薬 技術分野  Tricyclic compounds and pharmaceuticals containing them
本発明は、 強い抗ヒスタミン作用を示し、 かつ安全性も高い新規な三環系化合 物並びにこれを含有する抗喘息薬等の抗アレルギー剤及び抗ヒス夕ミン剤に関す る。 背景  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. Background
«、 数多くの Ξ環系化^ lが合成され、 それらの抗喘息作用等の抗アレルギ ~f乍用及び抗ヒスタミン作用などが検討されているが、 充分な効果を有し、 かつ 安全性の高い化^は知られていない。  «Many Ξ-rings have been synthesized, and their anti-allergic and anti-histamine actions such as anti-asthmatic action have been studied, but they have sufficient effects and safety. The rise is not known.
例えば、 特表平 2-503909号公報、 特開平 3-128354号公報、 特表平 3-504012号公 報などに抗アレルギ ~f乍用、 抗ヒス夕ミン作用などを有する化^が開示されて いるが、 それらの化合物は未だ安全性と有効性の両者を十分に満足するものでは ない。  For example, 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.
そこで、 本発明者らは、 より優れた抗喘息作用等の抗アレルギ~ 用及び抗ヒ ス夕ミン作用を併せ持ち、 かつ安全性の高い化合物を創製すべく鋭意研究を行い、 本発明を完成するに至った。 発明の開示  Therefore, the present inventors have conducted intensive studies to create a compound that has both an anti-allergic effect such as an anti-asthmatic effect and an anti-histamine effect and is highly safe, and completes the present invention. Reached. Disclosure of the invention
本発明は、 一般式 ( I )  The present invention provides a compound represented by the general formula (I):
Figure imgf000003_0001
Figure imgf000003_0001
(式中、 Rは水素原子又はハロゲン原子を示し、 Xは基一 CH2CH2—, 一 CH=CH—又は一 CH2— CO—を示し、 Aはベンゼン環、 チォフェン 環又はビリジン環を示し、 Bはヒドロキシル基、 低級アルコキシル基又は 基 -NH , を示し、 mは 2〜5の整数を示す。 ) (Wherein, R represents a hydrogen atom or a halogen atom, and 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. )
H H
で表される三環系化^/及びその塩並びにこれを有効成分とする抗ヒス夕ミン剤 並びに抗ァレノレギ Uに係るものである。 And a salt thereof, and an anti-histamine compound containing the tricyclic compound as an active ingredient and anti-arenoregi U.
本発明化 は）は、優れた抗喘息作用等の抗ヒスタミン作用、 抗アレルギー 作用を有し、 かつ安全性も高いので、各種アレルギ 疾患の治療剤、例えば抗 炎 腎炎、 肝炎及び膝炎の治療剤、 呼吸 患の予防及び/又は治 及び 抗喘息薬として有用である。 発明を するための最良の形態  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. BEST MODE FOR CARRYING OUT THE INVENTION
式（I)において、 Bの低級アルコキシル基としては、 炭素数 1〜4の麵 又は分 ¾1臭のアルコキシル基が挙げられ、 メトキシル、 エトキシル、 プロボキシ ル、 ブトキシル基及びその異性体が好ましい。 また、 Rのハロゲン原子としては、 m, フッ素及びヨウ素原子が挙げられる。  In the formula (I), 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.
本発明の化合物は薬理学的に許容される塩として用いることができ、 このよう な塩としては、 例えば繊塩、硝酸塩、纖塩、酢酸塩、 マレイン酸塩、 フマル ^, シユウ酸塩、 クェン酸塩、 臭化水素酸塩、 コハク酸塩、 スフレファミン酸塩、 マンデル酸塩、 マロン酸塩、 リン酸塩等の酸付加塩、 又はナトリウム塩、 力リウ ム塩、 リチウム塩、 カルシウム塩等の塩 s½塩を挙げることができる。  The compound of the present invention can be used as a pharmacologically acceptable salt. Examples of such 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 s½ salt.
本発明の化合物（ I )は、例えば以下に示す方法に従つて^ tすることができる。
Figure imgf000005_0001
Compound (I) of the present invention can be prepared, for example, according to the following method.
Figure imgf000005_0001
(式中、 R、 X、 A及び mは前記と同意義を有し、 B1は低級アルキル基を示し、 Zはハロゲン原子を示す。 ） (Wherein, 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.)
すなわち、 一般式 (II)で表されるピペリジン誘導体と一般式 (ffl)で表されるサ リチル酸誘導体を塩基の存在下で反応させることにより、 一般式 ( I )において B が低級アルコキシル基であるエステル誘導体 (la)が される。  That is, by reacting a piperidine derivative represented by the general formula (II) with a salicylic acid derivative represented by the general formula (ffl) in the presence of a base, B in the general formula (I) is a lower alkoxyl group. An ester derivative (la) is synthesized.
上記の 芯は、 反応に影響を及ぼさない溶媒中で行うことが好ましい。 このよ うな溶媒としては、 例えば酢酸メチル、 酢酸ェチル等のエステル類；ジェチルェ 一テル、 ジイソプロビルエーテル、 テトラヒドロフラン、 ジォキサン等のエーテ ル類；アセトン、 メチルェチルケトン等のケトン類；ァセトニトリル、 ジメチル スルホキシド、 ジメチルホルムアミド等；ジクロロメタン、 クロ口ホルム等のハ ロゲン化炭化水素；ベンゼン、 トルエン、 キシレン等の芳香 匕水素などが挙 げられる。 これらは単独で又は混合して使用することができる。  The above-mentioned core is preferably carried out in a solvent that does not affect the reaction. Examples of such 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.
继は使用する原料化^)に応じて変化させればよく、 通常は常圧下、 0 °Cないし還流温度の範囲で選ぶのが有利である。  继 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.
としては、 例えば炭酸カリウム、 炭酸ナトリウム、 炭^素ナトリウム、 炭酸水素力リゥム等の炭酸塩又はトリェチルァミン、 ジイソプロビルァミン、 1, 8-ジァザビシクロ [5. 4. 0] -7-ゥンデセン（DBU)等の有^ 基類が挙げられる。 次に、下阪応式に示すように、 I3 によって生成されるエステル誘導体 (la)を通常用いられる加水分解 に付することによつて対応するカルボン酸誘 導体 (lb)が得ら さらに、 このカルボン酸誘導体 (lb)を 5-ァミノ- 1H-テトラゾ ールと縮合させることにより、 一般式（ I )において Bが 5-1H-テトラゾリルァミ ノ基である本発明化^ ¾ (Ic)に導くことができる。 For example, 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). Next, as shown in the Shimosaka O formula, the corresponding carboxylic acid derivative (lb) was obtained by subjecting the ester derivative (la) generated by I3 to hydrolysis that is usually used. The condensation of the carboxylic acid derivative (lb) with 5-amino-1H-tetrazole leads to the present invention (Ic) in which B in the general formula (I) is a 5-1H-tetrazolylamino group. Can be.
Figure imgf000006_0001
Figure imgf000006_0001
(式中、 R、 X、 A及び mは前記と同意義を有する。 )  (Wherein, R, X, A and m have the same meaning as described above.)
この縮合反応は公知の方法に準じ、反応に影響を及ぼさない 中で行うこと が好ましい。 このような溶媒としては、例えば酢酸メチル、酢酸ェチル等のエス テル類；ジメチルホルムアミド、 ジェチルホルムアミド等のアミド類；ジェチル エーテル、 ジイソプロビルエーテリレ、 テトラヒドロフラン、 ジォキサン等のエー テル類；ァセトニトリル、 ジメチルスルホキシド等；ジクロロメタン、 クロロホ ルム等のハロゲン化炭化水素；ベンゼン、 トルエス キシレン等の芳香族炭化水 素などが挙げられる。 これらは ?虫で又は混合して使用することができる。 This condensation reaction is preferably carried out according to a known method without affecting the reaction. Such 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.
縮合剤としては、 N, N' -ジシクロへキシルカルボジィミド、 1， Γ -カルボニルジ イミダゾール等のカルポジィミド誘導体などが挙げられる。  Examples of the condensing agent include carbodiimide derivatives such as N, N'-dicyclohexylcarbodiimide and 1, Γ-carbonyldiimidazole.
は、 使用する原料化^/に応じて変ィ匕させればよく、 通常は常圧下、 0でないし還流温度の範囲で選ぶのが有利である。  May be changed according to the raw material used, and it is usually advantageous to select under normal pressure a value other than 0 or a reflux temperature.
このようにして得られた本発明の化合物（ I )は、 ¾上許容される補助剤を配 合して、 経口投与用製剤又は非経口投与用製剤とすることができる。  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.
経口投与用の製剤としては、 上記化合物を適当な添加剤、 例えば 、 マンニ ヅト、 トウモロコシデンプン、 結晶セルロース等の賦形剤；セルロース誘導 アラビアゴム、 ゼラチン等の結合剤、 カルボキシメチルセルロースカルシウム等 の崩壊剤；タルク、 ステアリン酸マグネシウム等の滑沢剤等々と適当に組み合せ ることにより餘剤、 散剤、 顆粒剤、 カプセル剤とすることができる。 また、 これ らの固型製剤をヒドロキシプロビルメチルセルロースフタレート、 ヒドロキシブ 口ピルメチルセルロースアセテートサクシネート、 セルロースアセテートフタレ ート、 メタァクリレートコーポリマーなどの被覆用基剤を用いて腸溶性 とす ることができる。  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. Can be
絰ロ投与用の液剤としては、 乳濁剤、 溶液剤、 懸濁剤、 シロヅ U、 エリキシ ル剤等を含み、 一般的に用いられる不活性な希!^、 例えば精 M、 エタノール 等を含むことができる。 この ω物は不活性な希釈剤以外に湿潤剤、 想濁剤のよ うな補助剤、 甘味剤、 風味剤、 芳香剤、 防腐剤等を含有していてもよい。 その他、 公知の方法により処方されるエアゾール剤とすることもできる。  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. In addition, it can also be an aerosol formulated by a known method.
非経口投与用の製剤としては、 例えば水、 エタノール、 グリセリン、 慣用の界 面活性剤等を組み合せることにより ¾*ί用液剤とすることができる。 さらに、 公 知の方法により処方される吸入剤、 外用液剤、 点眼剤、 点鼻剤、 軟膏のような塗 布剤等とすることができる。  As a preparation for parenteral administration, a liquid preparation can be prepared by combining, for example, water, ethanol, glycerin, a conventional surfactant and the like. In addition, 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.
本発明の化合物 ( I )の投与量は、 年齢、 体重、 症状、 治療効果、 投与方法、 投 与期間により異なるが、 通常、 1〜500π^日、 好ましくは 5〜50ag/日の範囲 で 1日 1〜3回経口投与するか、 又は 0. l〜500ngの範囲で 1日 1回〜数回非経口 投与する。 舰 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 500π ^ 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.舰
〈抗ヒスタミン ί乍用〉  <For antihistamines>
雄性 Hartley系モルモヅト （体重 300〜600g) より回腸を摘出し、 lOmflの Tyrode 液を満たしたマグヌス槽（30。C、通気下）中に初期負荷 0. 5gで懸垂した。試験化 合物をヒスタミン （3 X10-7モル）添加前 3分間処置し、 ヒスタミンによる摘出 回腸の の抑制作用を、 腿力変化の測定により検討し、抗ヒスタミ ン作用 （50%抑制濃度： IC50値） を求めた。 この結果を表 1に示す。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. The test of compound treated histamine (3 X10- 7 mol) added before 3 minutes, the inhibitory effect of the isolated ileum by histamine was examined by measurement of the thigh force change, antihistamine down effect (50% inhibitory concentration: IC 50 values). Table 1 shows the results.
: 1 抗ヒスタミン作用  : 1 Antihistamine action
Figure imgf000008_0001
Figure imgf000008_0001
〈抗アレルギー作用〉  <Anti-allergic action>
雄性 SD系ラヅト （体重 150〜250g) の背部を予め毛刈し、生理:^及び生理 ^ lで適当な濃度に希釈した抗 DNP-As (Dinitrophenyl conjugated Ascaris) IgE血清 O. lmflを背部皮内に注射し、 受動的に感作した。 48時間後に 2. 5ng の DNP-BSA (Dinitrophenyl conjugated Bovine Serum Albumin) を ^ fO. 5%Evans Blue生理食^ K lmfiを静脈内投与した。 30分後に ¾«C死せしめ背部皮膚の青斑 部位を皮革用パンチにて打ち抜き、 原田らの方法（アレルギー， 15， 1-7, (1966) ) に従い漏出色素量を測定した。 受動感作皮痏アナフィラキシー (PCA) による漏 出色素量は、 PCA部位の漏出色素量から生理:^ *投与部位の漏出色素量を差し 引いて求めた。試験化合物は 5 %アラビアゴム又は 0. 5%メチルセルロースに想 濁し、 lOmg/4 / kgを娜投与 1時間前に経口投与した。纖化^/の効力は漏 出色素量の抑制率（抗アレルギ" ·{乍用） で判定した。 この結果を表 2に示す。 表 2 抗アレルギー作用 The back of a male SD rat (body weight 150-250g) was shaved beforehand, and anti-DNP-As (Dinitrophenyl conjugated Ascaris) IgE serum O. lmfl diluted to appropriate concentrations with physiology: ^ and physiology ^ l intradermally into the back And sensitized passively. Forty-eight hours later, 2.5 ng of DNP-BSA (Dinitrophenyl conjugated Bovine Serum Albumin) was administered intravenously with ^ fO. 5% Evans Blue physiological diet ^ K lmfi. After 30 minutes, the blue spots on the back skin were punched out with a punch for leather, and the amount of leaked pigment was measured according to the method of Harada et al. (Allergy, 15, 1-7, (1966)). The amount of pigment leaked by passive sensitization skin anaphylaxis (PCA) was calculated by subtracting the amount of pigment leaked at the site of administration: ^ * from the amount of pigment leaked at the PCA site. The test compound was suspended in 5% gum arabic or 0.5% methylcellulose and orally administered lOmg / 4 / kg 1 hour before administration of Na. The efficacy of fiberized ^ / was determined by the rate of suppression of the amount of leaked dye (anti-allergic) .The results are shown in Table 2. Table 2 Antiallergic effects
Figure imgf000009_0001
Figure imgf000009_0001
〈抗喘息作用〉  <Anti-asthmatic effect>
生理食 ί¾を用いて 20倍に希釈した抗 BP0-BGG血清を、 1 /kgの割合で 1群 4 匹のモルモヅトの後肢静脈に投与し、 受動的に感作した。 48時間後に 0. 5ng / の BP0-BGGを l mfl/kgの割合で静脈内投与して PSAを惹起した。実施例 5で得られた 化合物を前日に絶食としたモルモヅトに抗原投与の 1時間前に 4ng/kgの割合で 経口投与した。 モルモットの一般症状を観察し、 死亡率から最 効発 ¾1を求 めた。 この結果、 最«¾発現量は 1. 0ng/kgであった。  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. After 48 hours, 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.
〈毒性難〉  <Toxic difficulty>
4〜5週齢の ICR系マウス （チヤ一ルス ·リパー社） を 1群 10匹として用いた。 各実施例で得られた化合物を 5 %アラビアゴムに懇濁した後、 それそれ 1000 mg/kgの用量にて経口投与し、 7日間にわたり観察を行った。その結果、 本発明 の化合物の毒性に起因した死亡例は認められなかった。 難例  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
以下、 »例により本発明をさらに具体的に説明するが、 本発明はこれらによ り限定されるものではない。  Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited thereto.
贿例 1  贿 Example 1
2- [2- [4- (5H-ジベンゾ [a, d]シクロヘプテン- 5-ィリデン ) -1-ビペリジニル]ェ トキシ]ベンゾィヅクァシヅドメチルエステル
Figure imgf000010_0001
2- [2- [4- (5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-biperidinyl] ethoxy] benzodiacid methyl ester
Figure imgf000010_0001
4- (5H-ジベンゾ [a，d]シクロへブテン- 5-イリデン）ピぺリジン 2.73g (10廳 ol) をアセトン 50υώに溶かし、 2- (2-ブロモエトキシ)ベンゾィヅクァシヅドメチル エステル 3. Ig (12腿 ol)及び炭酸カリウム 1.66g (12薩 ol) を加え、 3時間加熱 »した。 ίδ液を永水中にあけ酢酸ェチルにて抽出し、 I ^食 ¾で洗浄後、 «c硫酸マグネシウムにて した。霞留去後、 得られた残留物をシリカゲル カラムクロマトグラフィー（群酸ェチル： n-へキサン = 1： 1) にて精製し、 標
Figure imgf000010_0002
収率 87%。 Dissolve 2.73 g (10 cafe ol) of 4- (5H-dibenzo [a, d] cycloheptene-5-ylidene) piperidine in 50 ml of acetone and give 2- (2-bromoethoxy) benzodiacid methyl. Ester 3. Ig (12 t ol) and potassium carbonate 1.66 g (12 t ol) were added and heated for 3 hours. The ίδ solution was poured into permanent water, extracted with ethyl acetate, washed with I ^ diet, and washed with magnesium sulfate. After evaporation of the haze, the obtained residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1),
Figure imgf000010_0002
87% yield.
(分解点） ： 144〜U5。C (フマール酸塩）  (Decomposition point): 144 to U5. C (Fumarate)
MS (i/z) ： 451 (M  MS (i / z): 451 (M
IRfn joDcni-1 : 1720, 1690 IRfn joDcni- 1 : 1720, 1690
腿 (DMSO-de) δ： (フマール艦） L 99-2.05 (2Η, ι)， 2.30-2.50 (4H, m) ,  Thigh (DMSO-de) δ: (Humal) L 99-2.05 (2Η, ι), 2.30-2.50 (4H, m),
2.70-2.90 (2H,m), 2.76 (2H, t) , 3.72(3H,s), 4.16(2H，t), 6.61(2H，s), 6.97(2H,s), 7.00-7.63 (12H, m)  2.70-2.90 (2H, m), 2.76 (2H, t), 3.72 (3H, s), 4.16 (2H, t), 6.61 (2H, s), 6.97 (2H, s), 7.00-7.63 (12H, m)
2- [2- [4- (5H-ジベンゾ [a， d]シクロへブテン- 5-ィリデン) -卜ピペリジニル〗ェ トキシ]ペンゾィックァシッド 2- [2- [4- (5H-dibenzo [a, d] cycloheptene-5-ylidene) -topiperidinylethoxy] penzoic acid
Figure imgf000010_0003
mm 1で得られた 2- [2- [4- (SH-ジベンゾ [a， d]シクロヘプテン- 5-ィリデン) -
Figure imgf000010_0003
2- [2- [4- (SH-dibenzo [a, d] cycloheptene-5-ylidene) obtained in mm 1
1-ピぺリジニル]ェトキシ]ベンゾィヅクァシヅドメチルエステル ·フマール酸塩 l.Og (1.76匪 ol) をエタノール 10mlに溶解し、 水酸化カリウム 0.5gを加えて、 70でで 2時間撹拌した。冷後、 水を加え、 さらに酢酸を加えて pH6とし、 酢酸ェ チルにて抽出、 S¾食駄で洗浄後、 無水碰マグネシウムにて乾燥した。職 留去後、 得られた残留物をシリカゲルカラムクロマトグラフィー（クロ口ホルム ：メタノール =20 : 1)にて精製し、標記化^ 640mgを得た。収率 83%。 Dissolve 1-piridinyl] ethoxy] benzodiacid methyl ester fumarate l.Og (1.76 marl) in 10 ml of ethanol, add 0.5 g of potassium hydroxide and stir at 70 for 2 hours did. After cooling, water was added, and acetic acid was further added to adjust the pH to 6, and the mixture was extracted with ethyl acetate, washed with S¾ waste, and dried over anhydrous magnesium. After evaporation, the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 640640 mg of the title. Yield 83%.
アモルファス  Amorphous
MS (m/z) ： 437 (M+)  MS (m / z): 437 (M +)
IR(nujol) ci"1： 1711 IR (nujol) ci " 1 : 1711
腿 (CDCls) 6： 2.06-2.15 (2H, m)， 2.20-2.30 (2H, m) , 2.45-2.56 (2Η, m) ,  Thigh (CDCls) 6: 2.06-2.15 (2H, m), 2.20-2.30 (2H, m), 2.45-2.56 (2Η, m),
2.68 (2H, t), 2.66-2.76 (2Η,ι), 4.32 (2H, t), 5.95(lH,br)， 6.89 (2H, s) , 6.99-7.47 (llH,m)， 7.94-7.97 (1H, m)  2.68 (2H, t), 2.66-2.76 (2Η, ι), 4.32 (2H, t), 5.95 (lH, br), 6.89 (2H, s), 6.99-7.47 (llH, m), 7.94-7.97 ( 1H, m)
«例 3  «Example 3
2- [2- [4- (5H-ジベンゾ [a, d]シクロヘプテン- 5-ィリデン) -1-ビペリジニル]ェ トキシ] -N-(1H-テトラゾール -5-ィル)ベンズアミド  2- [2- [4- (5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-biperidinyl] ethoxy] -N- (1H-tetrazol-5-yl) benzamide
Figure imgf000011_0001
Figure imgf000011_0001
例 2で得た 2-[2-[4-(5H-ジベンゾ [a， d]シクロヘプテン- 5-ィリデン )-1-ピ ペリジニル]エトキシ]ベンゾィヅクァシヅド 200mg (0.46腿 ol) を無 ジメチル ホルムァミト' 5mlに溶解し、 Ι, -カルポジイミダゾール 185mg (1.14腿 ol) を 加えて、 80。Cで 2時間 した。冷後、 5-アミノテトラゾール 142mg (1.37匪 ol) を加えて、 80でで 2時間撹拌した。 冷後、 液に水を加えて析出した結晶をろ 取し、標記化合物 167mgを得た。収率 73%。 ァモノレファス 200 mg (0.46 tmol) of 2- [2- [4- (5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-piperidinyl] ethoxy] benzodiacid obtained in Example 2 was used. Dissolve in 5 ml of dimethylformamide, add 185, -carpoimidazole 185 mg (1.14 t ol), and add 80. C for 2 hours. After cooling, 142 mg (1.37 marl) of 5-aminotetrazole was added, and the mixture was stirred at 80 for 2 hours. After cooling, water was added to the solution, and the precipitated crystals were collected by filtration to obtain 167 mg of the title compound. 73% yield. Amonorefass
MS i /z) ： 504 (M+) MS i / z): 504 (M + )
IR (nujol) cm-1： 1670 IR (nujol) cm -1 : 1670
麵 (CDCla) δ ： 2. 13-2. 20 (2Η, m)， 2. 27-2. 45 (4H, m)， 2. 75-2. 85 (2H, m) ,  CD (CDCla) δ: 2.13-2.20 (2Η, m), 2.27-2.45 (4H, m), 2.75-2.85 (2H, m),
2. 89 (2H, t) , 3. 00-3. 60 (2H, br) , 4. 37 (2H, t) , 6. 89 (2H, s) , 7. 02 - 7. 36 (10H, m) , 7. 52-7. 59 (1H, m) , 8. 14 (1¾ dd)  2.89 (2H, t), 3.00-3.60 (2H, br), 4.37 (2H, t), 6.89 (2H, s), 7.02-7.36 (10H, m), 7.52-7.59 (1H, m), 8.14 (1¾ dd)
鋪例 4〜15 Shop example 4-15
m i〜 3の方法に準拠して表 3〜 5に示す実施例 4〜 15の化合物を得た。 各々の化 名は以下の通りである。表中、 A、 B、 R、 m及び Xは本発明化合 物（I)中の記号を表す。なお、 表中 X基の欄において は A環との結合を表す。 麵例 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.麵 Example 4
2- [2- [4- (10-ォキソ -9， 10-ジヒドロ- 4H-ベンゾ [4， 5]シクロへブタ [1, 2-b]チォ フェン- II-ィリデン) -1-ピペリジニル]エトキシ]ペンゾィヅクァシヅドメチルェ ステル  2- [2- [4- (10-oxo-9,10-dihydro-4H-benzo [4,5] cyclohepta [1,2-b] thiophene-II-ylidene) -1-piperidinyl] ethoxy ] Penzoic methyl ester
例 5  Example 5
2- [2- [4- (10-ォキソ -9， 10-ジヒドロ- 4H-ペンゾ [4， 5]シクロへプタ [1, 2-b]チォ フェン- 11-ィリデン) -1-ビペリジニル]エトキシ]ペンゾィヅクァシヅド  2- [2- [4- (10-oxo-9,10-dihydro-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-11-ylidene) -1-biperidinyl] ethoxy ] Penzoic Quasid
mmm 6  mmm 6
2- [2- [4- (10-ォキソ -9， 10-ジヒド口- 4H-ペンゾ [4， 5]シクロへブタ [1, 2-b]チォ フェン -11-ィリデン） -1-ビぺリジニル]ェトキシ] -N- (1H-テトラゾール -5-ィル） ペンズアミド  2- [2- [4- (10-oxo-9,10-dihydropent-4H-benzo [4,5] cyclohepta [1,2-b] thiophen-11-ylidene) -1-bi ぺLysinyl] ethoxy] -N- (1H-tetrazol-5-yl) penzamide
雄例 7  Male example 7
2- [3- [4- (10-ォキソ -9， 10-ジヒドロ- 4H-ベンゾ [4, 5]シク口ヘプ夕 [1, 2-b]チォ フェン- 11-イリデン) -1-ビペリジニル]プロボキシ]ペンゾィヅクァシヅドメチル エステル  2- [3- [4- (10-oxo-9,10-dihydro-4H-benzo [4,5] cyclohexyl [1,2-b] thiophen-11-ylidene) -1-biperidinyl] Proboxy] benzoic acid methyl ester
魏例 8  Wei example 8
2- [3- [4- (10-ォキゾ -9, 10-ジヒドロ- 4K-ベンゾ [4, 5]シクロヘプ夕 [1， 2-b]チォ フェン- 11-イリデン) -1-ビペリジニル]プロボキシ]ペンゾィヅクァシヅド  2- [3- [4- (10-oxo-9,10-dihydro-4K-benzo [4,5] cyclohepno [1,2-b] thiophen-11-ylidene) -1-biperidinyl] propoxy] Penzo Quasid
麵例 9 2- [3- [4- (10-ォキソ -9, 10-ジヒド口- 4H-ベンゾ [4, 5]シクロヘプ夕 [1, 2-b]チォ フェン- 1卜ィリデン) -1-ビペリジニル]プロポキシ] -N- (1H-テトラゾール -5-ィル) ベンズアミド 麵 Example 9 2- [3- [4- (10-oxo-9,10-dihydropent-4H-benzo [4,5] cyclohepno [1,2-b] thiophen-1 trilidene) -1-biperidinyl] propoxy ] -N- (1H-tetrazol-5-yl) benzamide
2- [2- [4- (8-クロ口 -5, 6-ジヒドロ- 11H-ベンゾ [5, 6]シクロヘプ夕 [1, 2-b]ビリ ジン- 11-ィリデン ) -1-ピペリジニル]エトキシ]ベンゾイツクァシヅドメチルエス テル 2- [2- [4- (8-Chloro-5,6-dihydro-11H-benzo [5,6] cycloheptane [1,2-b] Vyridin-11-ylidene) -1-piperidinyl] ethoxy ] Benzoic acid methyl ester
魏例 11  Wei example 11
2 - [2- [4- (8-クロ口 -5, 6-ジヒドロ- 11H-ベンゾ [5, 6]シク口へブ夕 [1, 2-b]ビリ ジン- U-ィリデン） -卜ビペリジニル]エトキシ]ベンゾィヅクァシヅド  2- [2- [4- (8-chloro-5,6-dihydro-11H-benzo [5,6] cyclohexyl [1,2-b] viridine-U-ylidene) -toviperidinyl ] Ethoxy] benzoic acid
餓例 12  Hunger 12
2- [2- [4- (8-クロ口- 5, 6-ジヒドロ- 11H-ベンゾ [5, 6]シク口へブタ [1, 2-b]ビリ ジン- 1卜ィリデン） -卜ビベリジニル]エトキシ] -N- (1H-テトラゾール -5-ィル)ベ ンズァミド  2- [2- [4- (8-chloro-5,6-dihydro-11H-benzo [5,6] cyclobuta] [1,2-b] Biridine-1 trilidene) -toviberidinyl] Ethoxy] -N- (1H-tetrazol-5-yl) benzamide
鋪例 13  Shop example 13
2- [2- [4- (10, 11-ジヒド口 -5H-ジベンゾ [a, d]シク口ヘプテン- 5-ィリデン) -1- ビペリジニル]エトキシ]ベンゾィヅクァシヅドメチルエステル  2- [2- [4- (10,11-dihydroxy-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-biperidinyl] ethoxy] benzodiacid methyl ester
赚例 14  赚 Example 14
2- [2- [4- (10, 11-ジヒドロ- 5H-ジベンゾ [a, d]シクロヘプテン- 5-ィリデン）-1- 謹例 15  2- [2- [4- (10,11-Dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1- Discreet Example 15
2- [2- [4- (10, 11-ジヒドロ- 5H-ジベンゾ [a, d]シクロヘプテン- 5-ィリデン）-1- ピペリジニル]エトキシ] -N- (1H-テトラゾール -5-ィル)ベンズアミド
Figure imgf000014_0001
表 4 2- [2- [4- (10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-piperidinyl] ethoxy] -N- (1H-tetrazol-5-yl) benzamide
Figure imgf000014_0001
Table 4
Figure imgf000015_0001
Figure imgf000015_0001
Figure imgf000016_0001
製剤例 1
Figure imgf000016_0001
Formulation Example 1
»例 1の化^/ 50g  »Example 1 ^ / 50g
315g  315g
トウモロコシデンプン 125g  125g corn starch
結晶セルロース 25g  25g crystalline cellulose
上記成分を均一に混合し、 7. 5%ヒドロキシプロピルセルロース水溶液 200 を加え、 押出し造粒機により、 直径 0. 5 スクリーンを用いて顆粒とし、 直ちに マルメライザ一により丸めた後、 乾燥し顆粒剤とした。  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.
この乾^^粒剤に下記 のフィルムコ一ティング液 1. 9kgを流動層 機を 用いてコーティングし、 腸溶 ½^粒剤とした。  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.
コーティング  Coating
ヒドロキシプロビルメチルセルロースフタレート 5. 0 ( /w) %  Hydroxypropyl methylcellulose phthalate 5.0 (/ w)%
ステアリン酸 0. 25 (w/w) %  Stearic acid 0.25 (w / w)%
塩ィ匕メチレン 50. 0 (w/w) %  Shiodii Methylene 50.0 (w / w)%
エタノール 44. 75 (w/w) % 製剤例 2  Ethanol 44.75 (w / w)% Formulation Example 2
«例 5の化^/ 20g  «Example 5: ^ / 20g
乳糖 100g  Lactose 100g
トウモロコシデンプン 36g  36g corn starch
結晶セルロース 30g  30g crystalline cellulose
カルボキシメチルセルロースカルシウム 10g  Carboxymethylcellulose calcium 10g
ステアリン酸マグネシウム 4g  Magnesium stearate 4g
上記ま！ ^の成分を均一に混合し、 単発打 I»にて直径 7. 5nmの杵で 1錠 200ngの ,とした。  Above! The components of ^ were uniformly mixed and made into 200 ng per tablet with a single punch I »with a 7.5 nm diameter punch.
次いで、 この錠剤に下記組成のコーティング液をスプレーコーティングして 1 錠当り lOngの被覆を施し、 腸溶性フィルムコーティング^ 0とした。  Next, 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.
コーティング γ¾ίΜ：  Coating γ¾ίΜ:
ヒドロキシプロビルメチルセルロースフタレート 8. 0 (w/w) %  Hydroxypropyl methylcellulose phthalate 8.0 (w / w)%
グリセリン脂肪酸エステル 0. 4 (w/w) % 塩化メチレン 50. 0 (w/w) % Glycerin fatty acid ester 0.4 (w / w)% Methylene chloride 50.0 (w / w)%
サラシミヅロウ 0. 1 (w/w) %  Sara Shimizu wax 0.1 (w / w)%
ィソブロピルアルコール 41. 5 ( /w) %  Isopropropyl alcohol 41.5 (/ w)%
觀例 3 Observation example 3
贿例 15の化^ i 0. 1 (w/ff) %  化 Example 15: ^ i 0.1 (w / ff)%
エタノール 20. 0 ( /w) %  Ethanol 20.0 (/ w)%
液化ガス （プロペラント 114) 49. 2 (w/w) %  Liquefied gas (propellant 114) 49.2 (w / w)%
液化ガス （プロペラント 12) 30. 7 (w/w) %  Liquefied gas (Propellant 12) 30.7 (w / w)%
上 ,方で常法によりエアゾール剤とした。  Above, the aerosol was prepared by the usual method.
：の利用可難 : Difficult to use
J¾±のように、本発明の化^/は強い抗ヒスタミン作用を示し、 かつ安全性も 高いことから、 各種アレルギ H¾患、 例えば抗炎症剤、 腎炎、肝炎、脬炎等の mk 呼吸器疾患の予防及び/又は治 並びに抗喘息薬として有用である。  As shown in J¾ ±, 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.

Claims

請求の範囲 The scope of the claims
. 一般式（I ) General formula (I)
Figure imgf000019_0001
Figure imgf000019_0001
(式中、 Rは水素原子又はハロゲン原子を示し、 Xは基—CH2CH2—、 一 CH=CH—又は一 CH2— CO—を示し、 Aはベンゼン環、 チォフェン 環又はピリジン環を示し、 Bはヒドロキシル基、 低級アルコキシル基又は 基 を示し、 mは 2〜5の整数を示す。 ）(In the formula, R represents a hydrogen atom or a halogen atom, X represents a group —CH 2 CH 2 —, one CH = CH— or one CH 2 —CO—, and A represents a benzene ring, a thiophene ring, or a pyridine ring. And B represents a hydroxyl group, a lower alkoxyl group or a group, and m represents an integer of 2 to 5.)
Figure imgf000019_0002
Figure imgf000019_0002
で表される三 TO化 0 Three TOs represented by 0
2. 請求項 1記載のジフエニルメトキシピペリジン誘導体を有効成分とする抗ヒ スタミン剤。  2. An antihistamine comprising the diphenylmethoxypiperidine derivative according to claim 1 as an active ingredient.
3. 請求項 1記載のジフエニルメトキシビペリジン誘導体を有効成分とする抗ァ レルギ一剤。  3. An anti-allergic agent comprising the diphenylmethoxybiperidine derivative according to claim 1 as an active ingredient.
4. 抗喘息薬である請求項 3記載の抗アレルギ U。  4. The anti-allergic U according to claim 3, which is an anti-asthmatic drug.
PCT/JP1992/001640 1991-12-25 1992-12-16 Tricyclic compound and medicine containing the same WO1993013068A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014526438A (en) * 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 Anti-allergic benzocycloheptathiophene derivatives
CN107602534A (en) * 2017-09-05 2018-01-19 合肥医工医药有限公司 Compound with antihistamine and anti-inflammatory activity and its preparation method and application

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989012443A1 (en) * 1988-06-17 1989-12-28 Fisons Corporation Novel dibenzo-cycloheptenyl, -cycloheptyl and -oxepinyl amines having antihistaminic properties
JPH0347168A (en) * 1988-11-30 1991-02-28 Ajinomoto Co Inc Piperidine derivative and hypotensor containing same derivative
JPH0363263A (en) * 1989-05-19 1991-03-19 Hoechst Roussel Pharmaceut Inc N-(aryloxyalkyl)heteroaryl piperidine and n- (aryloxyalkyl) heteroaryl piperazine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989012443A1 (en) * 1988-06-17 1989-12-28 Fisons Corporation Novel dibenzo-cycloheptenyl, -cycloheptyl and -oxepinyl amines having antihistaminic properties
JPH0347168A (en) * 1988-11-30 1991-02-28 Ajinomoto Co Inc Piperidine derivative and hypotensor containing same derivative
JPH0363263A (en) * 1989-05-19 1991-03-19 Hoechst Roussel Pharmaceut Inc N-(aryloxyalkyl)heteroaryl piperidine and n- (aryloxyalkyl) heteroaryl piperazine

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014526438A (en) * 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 Anti-allergic benzocycloheptathiophene derivatives
CN107602534A (en) * 2017-09-05 2018-01-19 合肥医工医药有限公司 Compound with antihistamine and anti-inflammatory activity and its preparation method and application
CN107602534B (en) * 2017-09-05 2020-04-24 合肥医工医药股份有限公司 Compound with anti-histamine and anti-inflammatory activity and preparation method and application thereof

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