EP0706522A1 - Derives tetrazoliques a activite antihistaminique et antiallergique - Google Patents

Derives tetrazoliques a activite antihistaminique et antiallergique

Info

Publication number
EP0706522A1
EP0706522A1 EP94918560A EP94918560A EP0706522A1 EP 0706522 A1 EP0706522 A1 EP 0706522A1 EP 94918560 A EP94918560 A EP 94918560A EP 94918560 A EP94918560 A EP 94918560A EP 0706522 A1 EP0706522 A1 EP 0706522A1
Authority
EP
European Patent Office
Prior art keywords
atom
compound
tetrazol
piperidine
bond
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP94918560A
Other languages
German (de)
English (en)
Inventor
Masatoshi Sumitomo Metal Industries Ltd. HAYASHI
Masaya Sumitomo Metal Industries Ltd. KATO
Yusuke Sumitomo Metal Industries Ltd. SAKAI
Kazuhiko Sumitomo Metal Industries Ltd. MITSUI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Steel Corp
Original Assignee
Sumitomo Metal Industries 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 Sumitomo Metal Industries Ltd filed Critical Sumitomo Metal Industries Ltd
Publication of EP0706522A1 publication Critical patent/EP0706522A1/fr
Withdrawn legal-status Critical Current

Links

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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D405/14—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 three or more hetero rings
    • 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

  • This invention relates to novel tetrazole derivatives or salts thereof, as well as antihistamines, antiallergic agents and asthma treating agents that contain the novel tetrazole derivatives or salts thereof and which exhibit satisfactory antihistaminic and antiallergic actions while causing less central nervous system depressing effects.
  • the compounds of the invention are also effective in the treatment of rhinitis, nephritis, atopic dermatitis and psoriasis.
  • An object, therefore, of the present invention is to provide compounds that exhibit more satisfactory antiallergic and antihistaminic actions, that are effective against both early- and late-phase reaction in asthma and which yet are highly safe in use.
  • the present inventors synthesized many tetrazole derivatives and reviewed their antihistaminic, antiallergic and central nervous system depressing actions. Surprisingly enough, they found that tetrazole derivatives of the general formula (1) to be defined below or salts thereof exhibited satisfactory antihistaminic and antiallergic actions and that, in addition, those derivatives or salts thereof were as effective as steroids in suppressing the late-phase reaction in asthma, while causing only weak central nervous system depressing effects. The present invention has been accomplished on the basis of this finding.
  • the present invention in its first aspect, provides tetrazole derivatives of the general formula(l):
  • X and Y each independently represents an alkoxy group, a halogen atom or a hydrogen atom;
  • W represents a bond, Z represents a carbon atom or methine, and B either forms a bond together with Z or represents a hydroxyl group, or
  • W, Z and B represent a bond, a nitrogen atom and a hydrogen atom, respectively, or
  • W, Z and B represent an oxygen atom, methine and a hydrogen atom, respectively;
  • p represents an integer of 2 or 3; and
  • n represents an integer of 1 - 6) or pharmacologically acceptable salts thereof.
  • the invention provides an antihistamine, an antiallergic agent and an asthma treating agent that contain those tetrazole derivatives or pharmacologically acceptable salts thereof as effective ingredients.
  • Salts of the compounds of the invention are any medicinally acceptable salts that are exemplified by, but in no way limited to, addition salts of acids including hydrochloric acid, nitric acid, sulfuric acid, maleic acid, fumaric acid, oxalic acid, citric acid, hydrobromic acid, tartaric acid, succinic acid, sulfamic acid, mandelic acid, malonic acid and phosphoric acid, as well as basic salts including sodium salts, potassium salts, lithium salts, calcium salts and zinc salts.
  • Compounds (1) of the invention may be produced by the following reaction scheme 1) :
  • Exemplary solvents include:water; esters such as methyl acetate and ethyl acetate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; ketones such as acetone and methyl ethyl ketone; halogenated hydrocarbons such as dichloromethane and chloroform; aromatic hydrocarbons such as benzene, toluene and xylene; others such as acetonitrile, dimethyl sulfoxide and dimethylformamide. These solvents may be used either independently or in combination.
  • the reaction temperature varies with the starting materials to be used but the range from 0 to 200*C may typically be adopted.
  • Base catalysts are generally effective for but by no means indispensable to the progress of the reaction.
  • Preferred bases include potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, triethyla ine, pyridine and tributylammonium hydroxide.
  • Compounds of the general formula (3) may further be reacted with trialkyltin azide or trialkylsilye azide; alternatively, the compounds may be reacted with metal salts of hydrogen azide such as sodium azide or potassium azide in the presence of ammonium salts.
  • This reaction is preferably carried out in inert solvents such as xylene, toluene, benzene, tetrahydrofuran, dioxane, dimethylfor- mamide and N-methylpyrrolidone, which may be used either independently or in combination.
  • inert solvents such as xylene, toluene, benzene, tetrahydrofuran, dioxane, dimethylfor- mamide and N-methylpyrrolidone, which may be used either independently or in combination.
  • the reaction temperature varies with the starting materials to be used but the range from 0 to 200 °C may typically be adopted.
  • Conversion from (5) to (6) can be accomplished by causing a substituted phenyl magnesium halide or substituted phenyl lithium to act on (5).
  • Conversion from (6) to (7) can be accomplished by causing a catalyst (e.g. platinum oxide, palladium on carbon, or palladium) to act In hydrogen at either atmospheric or superatmospheric pressure.
  • Conversion from (7) to (2a) can readily be accomplished either under acidic conditions (e.g. acetic acid-sulfurlc acid) or under ordinary dehydrative reactive conditions (e.g. toluenesulfonlc acid-benzene). )
  • Conversion from (9) to (10) can be accomplished by using titanium in a lower oxidation state.
  • Any inert solvents may be used and preferred examples are ethereal solvents such as dioxane, tetrahydrofuran, dimethoxyethane and ether. 4)
  • Conversion from (8) to (12) can be accomplished by known methods. Conversion from (12) to (13) can readily be accomplished either under acidic conditions (e.g. acetic acid-sulfuric acid) or under ordinary dehydrative reaction conditions (e.g. toluenesulfonic acid-benzene). Conversion from (13) to (2b) can be accomplished by first causing an alkyl chloroformate to act on (13) to form a carbamate and then hydrolyzing it with an alkali.
  • acidic conditions e.g. acetic acid-sulfuric acid
  • ordinary dehydrative reaction conditions e.g. toluenesulfonic acid-benzene
  • the compounds of the invention or pharmacologically acceptable salts thereof may be formulated for peroral or parenteral administration by mixing them with adjuvants that are acceptable in pharmaceutical formulation procedures.
  • Solid pharmaceutical formulations for peroral administration include tablets, powders, granules and capsules and these can be produced by combining the compound (1) of the invention with suitable additives such as exciplents (e.g. lactose, mannitol, corn starch and crystalline cellulose), binders (e.g. cellulose derivatives, gum arable and gelatin), disintegrators (e.g. carboxymethyl cellulose calcium), and lubricants (e.g. talc and magnesium stearate).
  • exciplents e.g. lactose, mannitol, corn starch and crystalline cellulose
  • binders e.g. cellulose derivatives, gum arable and gelatin
  • disintegrators e.g. carboxymethyl cellulose calcium
  • lubricants e.g. talc and magnesium stearate
  • these solid preparations may be formulated as enteric drugs by coating with bases such as hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose
  • Liquids for peroral administration may be exemplified by emulsions, solutions, suspensions, syrups and elixirs and these can be produced by combining the compound (1) of the invention with commonly employed inert diluents such as purified water and ethanol.
  • inert diluents such as purified water and ethanol.
  • the resulting compositions may contain adjuvants (e.g. wetting agents or suspending agents), sweeteners, flavoring agents, fragrances and antiseptics.
  • adjuvants e.g. wetting agents or suspending agents
  • sweeteners e.g. sweeteners, flavoring agents, fragrances and antiseptics.
  • Other applicable dosage forms are aerosols that can be produced by known methods.
  • compositions for parenteral administration include liquids for injection and they can be produced by combining the compound (1) of the invention with water, ethanol, glycerin, common surfactants, etc.
  • Other parenteral dosage forms include inhalers, liquids for external application, eye drops, nasal solutions and liniments such as ointments.
  • the dosage of the compound (1) of the invention depends on various factors including age, body weight, the severity of the disease, the efficacy in treatment, the method of administration and the period of administra ⁇ tion.
  • the compounds are administered perorally one to three times a day at doses of 1 - 500 mg, preferably 5 - 50 mg.
  • they may be administered parenterally one to several times a day at doses of 0.1 - 500 mg.
  • Test 1 Histamine Hi-receptor antagonism in vitro
  • Cetirizine (see Japanese Patent Public Disclosure No. Sho 57-149282) used as a control had an IC 5 o of 2.40 ⁇ M.
  • PCA Passive cutaneous anaphylaxis in rats: Male SD rats were sensitized intradermally on their shaved backs with 0.1 ml of appropriately diluted homologous anti-serum containing anti-dinitrophenyl conjugated Ascaris (DNP-As). Forty eight hours later, the rats were challenged with 1 ml of saline containing 300 ⁇ g of DNP-As and 5 ⁇ g of Evans blue. Thirty minutes after the challenge, the rats were killed, and the skin of the back was removed. The severity of PCA was assessed by measuring the dye exudate Into the skin according to the method of Harada (Japanese Journal of Allergology, 15,1). Test compounds were suspended in 0.5% methyl cellulose in saline and administered (p.o.) before 60 min. of the challenge. The data of inhibiting PCA was expressed by the amount of dye exudate on the site (Table 2) .
  • Test 3 Acute toxicity
  • mice Groups of 4 - 5 wk-old ICR mice were used, each group consisting of 5 animals. Each compound was suspended in 0.5% methyl cellulose in saline and administered 100 mg/Kg (i.p.). Observation was made for 7 days. No animals administered the test compounds were dead at this dosage, but diphenhydramin was lethal at 100 mg/Kg. Test 4: Effect on Pentobarbital Induced Sleep Groups of 4 or 5 wk-old ICR mice were used, each group consisting of 10 animals.
  • test compounds were suspended in 0.5% methyl cellulose solution and administered orally at a dose of 25 mg/Kg.
  • pentobarbital was injected intraperitoneally at a dose of 40 mg/Kg to induce coma.
  • the moment the animal lost the righting reflex to lie on the back was regarded the start of coma and the moment it recovered the righting reflex was regarded as the end of coma.
  • Terfenadine was used as a control compound, which is a known antiallergic agent that is not a strong sleep inducer.
  • the data obtained are shown in Table 3 as the percent increase in sleep time compared to the negative control group (given no compounds) .
  • Test 5 Inhibitory effects on leukocytes recruited into Guinea-pig broncoalveolar lavage fluid This experiment was conducted according to the methods described in America Review of Respiratory Disease, 1990,142,680-685. Male Hartley Guinea-pig (5 weeks old) was passively sensitized with injection of 0.25 ml of anti-ovalbumin (raised in rabbit). Forty eight hours later the animals were treated with mepyramin (an Hi- receptor antagonist, i.p.) in order to avoid anaphylactic death, then applied to plastic exposure-chamber connected with ultrasonic nebulizer, where 0.25% ovalbumin in saline was inhalated for 10 in.
  • mepyramin an Hi- receptor antagonist, i.p.
  • the treated guinea-pigs were administered overdose of pentobarbital, and lung were lavaged with 25 ml of phosphate buffered saline (pH 7.4) through a polyethylene tube introduced through tracheostomy.
  • Total cells in the lavage fluid were counted by Coulter Counter, and differential cell counts were determined from cytospun preparations and stained by May-Gruenwald Giemza stain. Cells were identified as macrophage , neutrophils, eosinophils and lymphocytes by standard morphology, and absolute number of each cell type were calculated.
  • Each compound suspended in 0.5% methyl cellulose containing 0.05% Tween 80 was administered (30 mg/Kg, p.o.) two times (1 hour before and 6 hours after ovalbumin-challenge) Inhibition of recruitment of leukocytes into lavage fluid were expressed;
  • Bronchoconstriction was measured by the overflow technique of Konzett and Roessler.
  • Male guinea-pigs (5 weeks, 300-350 g) were passively sensitized by an injection with anti-ovalbumin rabbit serum (0.1 ml/animal, i.v.). Two days later, the animals were anesthetized with urethane (1.5 g/Kg; i.p.). The trachea was canulated . for artificial ventilation. The right jagular vein was canulated for administration of test compound and antigen. Spontaneous respiration was abolished by gallamine triethiodide (5 mg/Kg) .
  • mice were artificially ventilated at 60 strokes per minute (stroke volume of 10 ml/Kg) .
  • stroke volume 10 ml/Kg
  • Bronchoconstriction was measured as the volume of inspiration overflow using a Ugo Bassile 7020 bronchospasm transducer.
  • the compounds (1 mg/Kg) were administered intravenously 15 min. before antigen challenge In control group, vehicle alone was administered instead of the compounds.
  • guinea-pigs were challenged with intravenous administration of ovalbumin (0.1 mg/Kg), then changes in the overflow volume were recorded for 30 min.
  • Bronchoconstriction was represented as, (1) the peak height and (2) the area under the curve (AUC) of each trace. Percent inhibition of bronchoconstriction Is then calculated in terms of the peak height or the AUC as follows;
  • Tests 1 - 6 show that the compounds of the invention had satisfactory antihistaminic and antiallergic effects and proved to be significantly effective against both late- and early-phase reactions in asthma.
  • compounds 21 and 22 at the most preferred since they are potent suppressors of not only bronchoconstriction which occurs at the early phase of asthma but also the recruitment of leukocytes into bronchoalveolar fluid which occurs at the late stage of asthma.
  • the compounds of the invention are also useful for the treatment of rhinitis, nephritis, atopic dermatitis and psoriasis.
  • IR(nujol) cm" 1 2450, 1600, 1490, 1410, 1340, 1190, 1080, 1040, 970, 750, 710
  • IR(nujol) cm 1 : 2100, 1600, 1500, 1400, 1300, 1225, 1090,
  • Example 20 The procedure of Example 20 was repeated to synthesize 4-(4-benzhydryloxypiperidin-l-yl)butyronitrile (2g, 5.3 mmol). This compound, as well as tributyltin azide (3.35 g, 10.6 mmol) were stirred in dimethoxyethane (DME) at 90 ⁇ C for 48 h. Water was added to the reaction solution, followed by the addition of ethyl acetate (20 ml) and hexane (100 ml). The precipitating crystals were recovered by filtration and recrystallized from chloroform-ether to produce the titled compound (1.8 g) in a yield of 80%. m.p. 216 - 217 ⁇ C
  • Example 2 The procedure of Example 1 was repeated to synthesize 4- ⁇ 4-[ (4-chlorophenyl)phenylmethoxy]piperidin- l-yl ⁇ butyronitrile (1.7 g, 4.6 mmol).
  • This compound, as well as tributyltin azide (2.87 g, 9.2 mmol) were stirred in dimethoxyethane (DME) at 90 ⁇ C for 48 h.
  • Acetonitrile (10 ml) was added to the reaction solution, which was further stirred for 6 h at 90 °C. Water was added to the reaction solution and the precipitating crystals were recovered by filtration. Upon recrystallization from chloroform-ether, the titled compound was obtained (1.3 g) in a yield of 69%. m.p. 210 - 213°C
  • IR(nujol) cm" 1 1500, 1400, 1260, 1120, 970, 830, 725
  • a zinc powder (40.5 g, 0.62 mmol) was suspended in dry THF (500 ml) and titanium tetrachloride (34 ml, 0.30 mol) was added dropwlse to the suspension at -10 ⁇ C or below.
  • the mixture was dried for 0.5 h and thereafter heated at 80 °C for 1 h.
  • the reaction solution was cooled again to 0 ⁇ C and both 4,4'-dimethoxy-benzophenone (25 g, 0.103 mol) and 1-ethoxycarbonylpiperidone (18 g, 0.103 mol) as dissolved in THF (100 ml) were added.
  • the reaction mixture was transferred to an oil bath, where it was heated under reflux at 80 ⁇ C for 2 h.
  • the reaction solution was cooled and poured into an aqueous solution of potassium carbonate.
  • the THF layer was recovered and subjected to extraction with ethylacetate.
  • the extracts were combined, dried and concentrated.
  • the concentrate was subjected to silica gel chromatography and eluted with ethyl acetate- hexane (2:8) to yield the end product (34 g, 94%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

Dérivé tétrazolique répondant à la formule générale (1), dans laquelle A représente -CH=CH-, -CH2-CH2-, -CH2O-, un atome d'oxygène ou un atome de soufre, ou, au cas où A ne relierait pas entre eux les cycles aromatiques voisins, A représente deux atomes d'hydrogène dont chacun est lié au cycle aromatique voisin; V représente -CH=CH-, ou un atome de soufre; X et Y, indépendamment l'un de l'autre, représentent un groupe alcoxy, un atome d'halogène ou un atome d'hydrogène; (a) W représente une liaison, Z représente un atome de carbone ou méthine, et B forme une liaison conjointement avec Z ou représente un groupe hydroxyle, ou (b) W, Z et B représentent respectivement une liaison, un atome d'azote et un atome d'hydrogène, ou (c) W, Z et B représentent respectivement un atome d'oxygène, méthine et un atome d'hydrogène; p est 2 ou 3; et n est un nombre entier compris entre 1 et 6; ou son sel pharmacologiquement acceptable; et agent antihistaminique, agent antiallergique ou agent de traitement de l'asthme le contenant.
EP94918560A 1993-06-29 1994-06-23 Derives tetrazoliques a activite antihistaminique et antiallergique Withdrawn EP0706522A1 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
JP158745/93 1993-06-29
JP15874193 1993-06-29
JP158741/93 1993-06-29
JP15874593 1993-06-29
JP13875694A JP3338913B2 (ja) 1993-06-29 1994-06-21 テトラゾール誘導体
JP138756/94 1994-06-21
PCT/JP1994/001010 WO1995001350A1 (fr) 1993-06-29 1994-06-23 Derives tetrazoliques a activite antihistaminique et antiallergique

Publications (1)

Publication Number Publication Date
EP0706522A1 true EP0706522A1 (fr) 1996-04-17

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Application Number Title Priority Date Filing Date
EP94918560A Withdrawn EP0706522A1 (fr) 1993-06-29 1994-06-23 Derives tetrazoliques a activite antihistaminique et antiallergique

Country Status (8)

Country Link
EP (1) EP0706522A1 (fr)
JP (1) JP3338913B2 (fr)
KR (1) KR960703405A (fr)
AU (1) AU673754B2 (fr)
CA (1) CA2165792A1 (fr)
IL (1) IL110144A0 (fr)
TW (1) TW281677B (fr)
WO (1) WO1995001350A1 (fr)

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JP3779349B2 (ja) * 1995-04-24 2006-05-24 興和株式会社 ピペリジン誘導体
CA2261633A1 (fr) * 1996-07-29 1998-02-05 Banyu Pharmaceutical Co., Ltd. Antagonistes de recepteurs de chemokines
ES2172436B1 (es) * 2000-10-31 2004-01-16 Almirall Prodesfarma Sa Derivados de indolilpiperidina como agentes antihistaminicos y antialergicos.
AU2002347906A2 (en) 2001-10-16 2003-04-28 Hypnion, Inc. Treatment of CNS disorders using CNS target modulators
US7189757B2 (en) 2001-10-16 2007-03-13 Hypnion, Inc. Treatment of sleep disorders using CNS target modulators
US7355042B2 (en) 2001-10-16 2008-04-08 Hypnion, Inc. Treatment of CNS disorders using CNS target modulators
ES2201907B1 (es) 2002-05-29 2005-06-01 Almirall Prodesfarma, S.A. Nuevos derivados de indolilpiperidina como potentes agentes antihistaminicos y antialergicos.
CN100384421C (zh) * 2002-12-18 2008-04-30 拜尔农科股份公司 N-(取代的芳基甲基)-4-(二取代的甲基)哌啶和吡啶
US7411069B2 (en) 2003-12-10 2008-08-12 Hypnion, Inc. Doxepin analogs and methods of use thereof
US7482460B2 (en) 2003-12-10 2009-01-27 Hypnion, Inc. Doxepin analogs and methods of use thereof
US7326721B2 (en) 2003-12-10 2008-02-05 Hypnion, Inc. Doxepin analogs and methods of use thereof
US7524864B2 (en) 2004-04-23 2009-04-28 Hypnion, Inc. Methods of treating sleep disorders
WO2007018460A1 (fr) * 2005-08-08 2007-02-15 Astrazeneca Ab Agents thérapeutiques
TWI457341B (zh) * 2008-08-01 2014-10-21 Nippon Zoki Pharmaceutical Co 胺基亞丙基衍生物
CN110869200B (zh) * 2017-06-30 2022-05-10 株式会社尼康 制造光学器件的方法及相应的系统
US11883410B2 (en) 2018-04-19 2024-01-30 National University Corporation Tokyo University Of Agriculture And Technolgy Preventative and therapeutic agents for sarcopenia
CN113880808A (zh) * 2020-07-03 2022-01-04 合肥医工医药股份有限公司 一类三唑类化合物、制备方法及其医药用途

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NO155805C (no) * 1981-02-06 1987-06-10 Ucb Sa Analogifremgangsmaate for fremstilling av terapeutisk virksomme 2-(4-(difenylmethyl)-1-piperazinyl)-eddiksyrer og deres amider og ikke-toksiske salter.
JPH03246287A (ja) * 1990-02-22 1991-11-01 Hokuriku Seiyaku Co Ltd ピペラジン誘導体
FR2665161B1 (fr) * 1990-07-26 1992-11-27 Esteve Labor Dr Nouveaux derives de benzimidazole, leur preparation et leur application en tant que medicaments.
FR2665160A1 (fr) * 1990-07-26 1992-01-31 Esteve Labor Dr Nouveaux derives de 1-diphenylmethylpiperazine, leur preparation et leur application en tant que medicaments.

Non-Patent Citations (1)

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Title
See references of WO9501350A1 *

Also Published As

Publication number Publication date
JPH0770112A (ja) 1995-03-14
TW281677B (fr) 1996-07-21
CA2165792A1 (fr) 1995-01-12
WO1995001350A1 (fr) 1995-01-12
KR960703405A (ko) 1996-08-17
AU673754B2 (en) 1996-11-21
AU6983094A (en) 1995-01-24
JP3338913B2 (ja) 2002-10-28
IL110144A0 (en) 1994-10-07

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