WO1995001350A1 - Tetrazole derivatives having antihistaminic and antiallergic activity - Google Patents

Tetrazole derivatives having antihistaminic and antiallergic activity Download PDF

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Publication number
WO1995001350A1
WO1995001350A1 PCT/JP1994/001010 JP9401010W WO9501350A1 WO 1995001350 A1 WO1995001350 A1 WO 1995001350A1 JP 9401010 W JP9401010 W JP 9401010W WO 9501350 A1 WO9501350 A1 WO 9501350A1
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Prior art keywords
atom
compound
tetrazol
piperidine
bond
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PCT/JP1994/001010
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French (fr)
Inventor
Masatoshi Hayashi
Masaya Kato
Yusuke Sakai
Kazuhiko Mitsui
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Sumitomo Metal Industries, Ltd.
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Priority to KR1019950705952A priority Critical patent/KR960703405A/en
Priority to EP94918560A priority patent/EP0706522A1/en
Priority to AU69830/94A priority patent/AU673754B2/en
Publication of WO1995001350A1 publication Critical patent/WO1995001350A1/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
    • C07D401/06—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%).

Abstract

A tetrazole derivative of general formula (1), where A represents -CH=CH-, -CH2-CH2-, -CH2O-, an oxygen atom or a sulfur atom or, in the case where A does not interconnect the adjacent aromatic rings, it represents two hydrogen atoms each bonded to the adjacent aromatic ring; V represents -CH=CH- or a sulfur atom; X and Y each independently represents an alkoxy group, a halogen atom or a hydrogen atom; (a) 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 (b) W, Z and B represent a bond, a nitrogen atom and a hydrogen atom, respectively, or (c) 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 a pharmacologically acceptable salt thereof, or an antihistamine, an anti-allergic agent or an asthma treating agent containing the same.

Description

DESCRIPTION
TETRAZOLE DERIVATIVES HAVING ANTIHISTAMINIC AND ANTIALLERGIC ACTIVITY BACKGROUND OF THE INVENTION:
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.
A number of benzhydryl derivatives have heretofore been synthesized and their various pharmacological actions including antiallergic action are under review. European Patent No. 82-870006 and Japanese Patent Public Disclosure (Kokai) No. Hei 3-246287 teach certain kinds of carboxylic acid derivatives, and WO 93/02062 teaches certain kinds of tetrazole derivatives. Japanese Patent Public Disclosure (Kokai) Nos. Hei 4-234359 and 4-234387 teach piperazine derivatives. However, these compounds have been unsatisfactory in that their efficacy is insufficient or that they cause central nervous system depressing effects such as sleepiness and sedation. It should also be mentioned that the prior art compounds are capable of suppressing the early-phase reaction in asthma but their ability to suppress the late-phase reaction has been insufficient. Under the circumstances, steroids are currently used in the treatment of asthma of the late-phase reaction type but steroids have their own problems, namely, those of side effects. Conventional antihistamines also have had defects, one of which is that they have anticholinergic actions causing side effects such as thirst and ydriasis. With a view to solving these problems, various studies have so far been conducted but the results have not been completely satisfactory. SUMMARY OF THE INVENTION:
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.
Under the circumstances described above in connection with the prior art, 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):
Figure imgf000004_0001
(where A represents -CH=CH- , -CH2-CH2-, -CH20-, and oxygen atom or a sulfur atom or in the case where A does not interconnect the adjacent aromatic rings, it represents two hydrogen atoms each bonded to the adjacent aromatic ring; V represents -CH=CH- or a sulfur atom; X and Y each independently represents an alkoxy group, a halogen atom or a hydrogen atom; (a) 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 (b) W, Z and B represent a bond, a nitrogen atom and a hydrogen atom, respectively, or (c) 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.
In its second aspect, 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. DETAILED DESCRIPTION OF THE INVENTION:
Some of the compounds of the present invention have optical isomers and in that case the invention encompasses all applicable isomers.
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) :
Figure imgf000006_0001
Figure imgf000006_0002
(where V, W, X, Y, Z, p, n, A and B have the same meanings as defined above, and L represents a halogen atom). In this step, the compounds represented by the general formula (2) are reacted with compounds of the general formula (4) in the presence of bases to prepare compounds represented by the general formula (3). The reaction is preferably carried out in inert solvents. 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. The reaction temperature varies with the starting materials to be used but the range from 0 to 200 °C may typically be adopted.
Compounds represented by the structural formula (2) are either known or synthesizable by reaction in accordance with one of the following schemes 2) , 3) or 4) : 2)
Figure imgf000007_0001
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). )
Figure imgf000008_0001
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)
Figure imgf000008_0002
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.
Specific examples of the compounds of the present invention are listed below. Compound 1: 4-Dibenzo[a,d]cyclohepten-5-ylidene-l-[3-(lH-tetrazole-5- yl)propyl]piperidine Compound 2: 4-Dibenzo[a,d]cyclohepten-5-ylidene-l-(lH-tetrazol-5- ylmethyl)piperidine
Compound 3: 4-Dibenzo[a,d]cyclohepten-5-ylidene-l-[4-(lH-tetrazol-5-yl)- butyl]piperidine Compound 4:
4-(10,ll-Dihydrodibenzo[a,d]cyclohepten-5-ylidene)-1-[3-(1H- tetrazol-5-yl)propyl]piperidine
Compound 5: 4-(6H-Dibenzo[b,e]oxepin-ll-ylidene)-l-[3-(lH-tetrazol-5- yl)-propyl]piperidine Compound 6: 4-[Bis(4-fluorophenyl)methylene]-l-[3-(lH-tetrazol-5- yDpropyl]piperidine Compound 7: 4-(phenyl-2-thienylmethylene)-l-[3-(lH-tetrazol-5- yl)propyl]piperidine
Compound 8: 4-Benzhydrylylidene-l-[3-(lH-tetrazol-5-yl)propyl]piperidine
Compound 9: 4-Benzhydrylylidene-l-[5-(III-tetrazol-5-yl)pentyl]piperidine
Compound 10: α,α-Dlphenyl-N-[3-(lH-te razol-5-yl)propyl]piperidin-4- ylmethanol Compound 11: 4-[Bis(4-methoxyphenyl)methylene]-l-[4-(lH-tetrazol-5- yl)butyl]piperidine
Compound 12: 4-Dibenzo[a,d]cyclohepten-5-ylidene-l-[5-(lH-tetrazol-5- yl)pentyl]piperidine
Compound 13: 4-Xanthen-9-ylidene-l-[3-(lH-tetrazol-5-yl)propyl]piperidine
Compound 14: 4-Thioxanthen-9-ylidene-l-[3-(lH-tetrazol-5- yDpropyl]piperidine
Compound 15: l-Benzhydryl-4-[3-(lH-tetrazol-5-yl)propyl]piperazine
Compound 16: l-Benzhydryl-4-[3-(lH-tetrazol-5-yl)propyl]-[1,4]diazepan
Compound 17: l-Benzhydryl-4-(lH-tetrazol-5-ylmethyl)piperazine
Compound 18: l-Benzhydryl-4-[4-(lH-tetrazol-5-yl)butyl]piperazine Compound 19:
1-[ (4-chlorophenyl)phenylmethyl]-4-[3-(lH-tetrazol-5- yl)propyl]piperazine
Compound 20: l-[Bis(4-fluorophenyl)methyl]-4-[3-(lH-tetrazol-5- yl)propyl]piperazine
Compound 21: 4-Benzhydryloxy-l-[3-(lH-tetrazol-5-yl)propyl]-piperidine
Compound 22: 4-[ (4-chlorophenyl)phenylmethoxy]-l-[3-(lH-tetrazol-5- yl)propyl]piperidine
Compound 23: 4-[Bis(4-fluorophenyl)methoxy]-l-[3-(III-tetrazol-5- yDpropyl]piperidine
Compound 24: 4-[ (4-chlorophenyl)phenylmethoxy]-l-[4-(lH-tetrazol-5- yl)butyl]piperidine Compound 25: 4-(Phenyl-p-chlorophenylmethylene)-1-[3-(lH-tetrazol-5- yDpropyl]piperidine Compound 26: 4-(10,ll-Dihydrodibenzo[a,d]cycloheptan-5-yl)-l-[3-(lH- tetrazol-5-yl)propyl]piperazine
Compound 27: 4-(10,11-Dihydrodibenzo[a,d]cycloheptan-5-yl)-1-[4-(1H- tetrazol-5-yl)butyl]piperazine Compound 28:
4-(6H-Dibenzo[b,e]oxepin-ll-yl)-1-[3-(lH-tetrazol-5- yl)propyl]piperazine
Compound 29: 4-(Dibenzo[a,d]cyclohepten-5-yl)-l-[3-(lH-tetrazol-5- yl)propyl]piperidine Compound 30: 4-(Dibenzo[a,d]cyclohepten-5-yl)-l-[4-(lH-tetrazol-5- yl)butyl]piperidine Compound 31: 4-(6H-Dibenzo[b,e]oxepin-ll-yl)-1-[4-(lH-tetrazol-5- yl)butyl]piperazine
Compound 32: 4-[ (4-Chlorophenyl)phenylmethylene]-l-[4-(lH-tetrazol-5- yl)butyl]piperidine Compound 33:
4-[ (4-Chlorophenyl)phenylmethylene]-1-[3-(1H-tetrazol-5- yDpropyl]piperidine
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). If desired, these solid preparations may be formulated as enteric drugs by coating with bases such as hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate phthalate and methacrylate copolymer. 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. In addition to inert diluents, the resulting compositions may contain adjuvants (e.g. wetting agents or suspending agents), sweeteners, flavoring agents, fragrances and antiseptics. Other applicable dosage forms are aerosols that can be produced by known methods.
Pharmaceutical preparations 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. Typically, the compounds are administered perorally one to three times a day at doses of 1 - 500 mg, preferably 5 - 50 mg. Alternatively, they may be administered parenterally one to several times a day at doses of 0.1 - 500 mg.
The pharmacological actions of representative examples of the compound (1) and salts thereof are described below. Test 1: Histamine Hi-receptor antagonism in vitro
Trachea were removed from Male Hartley guinea-pigs (300 - 600g) and cut into strips. The tissues were suspended in 20-ml jacketed organ baths containing Tyrode physiological solution, aerated with 95% 02 : 5% C02 and maintained at 37°C. Changes in isometric tension were measured with a force-displacement transducer and recorded on a polygraph. The preparations were placed under 1 g of passive tension and allowed to equilibrate for 30 - 60 min. The efficacy of test compounds on histamine(10"5 M)-induced constriction was calculated and expressed as Inhibitory concentration of 50% (IC50). The data obtained are shown in Table 1.
Cetirizine (see Japanese Patent Public Disclosure No. Sho 57-149282) used as a control had an IC5o of 2.40 μM.
Table 1
Compounds ICso (μM) compound 1 0.08 compound 5 0.04 compound 15 0.07 compound 20 0.08 compound 21 0.01 oxatomide 0.13 diphenhydramin 0.3 ketotlfene 0.08
Test 2: Antiallergic effect(s)
Passive cutaneous anaphylaxis (PCA) 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 μg of DNP-As and 5 μg 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) .
Table 2
Compounds Inhibition(%) compound 1 99 compound 7 99 compound 19 70 compound 20 81 compound 21 80 compound 22 79 compound 25 71 ketotifene 99 oxatomide 53
Test 3: Acute toxicity
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.
Each of the test compounds was suspended in 0.5% methyl cellulose solution and administered orally at a dose of 25 mg/Kg. One hour later, 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) .
Table 3
Compounds Increase in Sleep Time (%)
Terfenadine + 44
Compound 3 - 9
Compound 6 + 4
Compound 20 - 31
Thus, the invention compounds were verified to have a smaller central nervous system depressing action. 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. Twenty four hours later, 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;
Inhibition (%)
(cells in treated animals) (cells in non-challenged animals (cells in non-treated animals) (cells in non-challenged animals) x 100
In these series of experiments, the compounds tested showed the efficacy to inhibiting the recruitment of leukocytes into bronchoalveolar fluid; showing the ability to employ to allergic late phase reactions. In contrast, oxatomide, ketotifene and diphenyldramin showed no inhibitory effects on this experiment. Cetirizine had weak effects as noted below.
Table 4
Inhibition (%)
Compounds Eosinophils ophils Monocyte compound 22 69 46 14 compound 19 53 67 63 compound 21 60 20 25 compound 26 29 73 84 compound 6 28 70 79 compound 20 52 67 0 cetirizine 15 10 8 Test 6: Anti-Anaphylactic Bronchoconstriction
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) . The animals were artificially ventilated at 60 strokes per minute (stroke volume of 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.
The 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;
Increase in V (control group) - Increase in V (test group) Increase in V (control group) x 100
where V means "Bronchoconstriction represented as peak hight or AUC" Table 5
Inhibition (peak height, %) Inhibition (AUC, %) compound 22 35 52 compound 21 53 59 centilizine 20 19
Example 62 18 16 (WO 93/02062)
The results of 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. It should particularly be noted that 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. In view of these pharmacological effects they have, the compounds of the invention are also useful for the treatment of rhinitis, nephritis, atopic dermatitis and psoriasis.
The following examples are provided for the purpose of further illustrating the present invention but are in no way to be taken as limiting.
Example 1
4-Dibenzo[a,d]cyclohepten-5-ylidene-l-[3-(lH-tetrazol-5- yl)propyl]piperidine:
Figure imgf000018_0001
4-Dibenzo[a,d]cyclohepten-5-ylidenepiperidine (5 g, 18.3 mmol), bromobutyronitrile (2.7 g, 18.3 mol) and potassium carbonate (10 g) were suspended in DMF and stirred at 100 βC for 3 h. The reaction solution was poured into water, subjected to extraction with ether, dried and concentrated under vacuum to yield an oil of 4-(4-di-benzo[a,d]cyclohepten-5-ylidenepiperidin-l- yl)butyronitrile. IR(nujol): cm"1: 2250, 1490, 1435, 1135
Without further purification, sodium azide (5.9 g, 0.92 mmol) and ammonium chloride (4.9 g, 0.92 mmol) were added to the compound and the mixture was stirred overnight at 110βC. The stirred reaction mixture was poured into water, adjusted to a pH of 6, subjected to extraction with chloroform, dried and concentrated under vacuum to an approximate volume of 30 ml. The concentrate was left to stand and the precipitating crystals were collected to yield the titled compound as a powder, m.p. (with decomposition): 134 - 139βC Elemental analysis for C2 H25Ns•2H20
C H N
Cal ' d 68.71 6.97 16.69
Found 69.08 7.21 16.85 MS(m/z): 384 (M+H) , (SIMS)
IR(nujol): cm"1: 1300, 1160, 1080, 990, 960, 950, 880 NMR(DMS0-d6) δppm: 7.37: (4H,m) , 7.28 (2H,d,J=7.3) , 6.96 (2H.s), 2,85 (2H,t,J=7.2) , 2.66 (2H,t,J=7.2) , 2.46 (2H,m), 2,27 (4H,m), 2.01 (2H,m), 1.86 (2H,m)
Example 2
4-Dibenzo [ a , d ] cyclohepten-5-ylidene-l ( lH-tetrazol-5- ylmethyD piperidine :
Figure imgf000019_0001
4-Dibenzo[a,d]cyclohepten-5-ylidenepiperidine (3.8 g. 14 mmol), bromoacetonitrile (1.68 g, 14 mmol) and potassium carbonate (5.5 g) were suspended in DMF and stirred at 100 βC for 3 h. The reaction solution was poured into water, subjected to extraction with ether, dried and concentrated under vacuum to yield an oil of 4-(4-dibenzo[a,d]cyclohepten-5-ylidenepiperidin-l-yl)- acetonitrile. Without further refining, sodium azide (2.99 g, 40.2 mmol) and triethylammonium chloride (2,77 g, 20.1 mmol) were added to the compound and the mixture was stirred in methylpyrrolidone (50 ml) for 3 h at 150 °C. The stirred reaction mixture was poured into water and adjusted to a pH of 6, subjected to extraction with chloroform, dried and concentrated under vacuum. The residue was subjected to silica gel chromatography and crystallized from ethyl acetate, yielding the titled compound in an amount of 3.19 g (62%). m.p. : 231 - 233βC MS(m/z): 356(M+H), 277, 185 IR(nujol): cm"1: 1630, 1305, 1270, 1160, 1025, 950
Similar procedures were taken in Examples 3 to 14 to synthesize the titled compounds.
Example 3
4-Dibenzo[a,d]cyclohepten-5-ylidene-l-[4-(lH-tetrazol-5- yl)butyl]piperidine:
Figure imgf000020_0001
Foam
MS ( m/z ) : 398 ( M+H ) , 286 , 185 ( SIMS )
IR(nujol): cm"1: 1650, 1550, 1300, 1250, 950, 800, 760
NMR(DMS0-d6) δppm: 7.49 (4H,m), 7.40 (2H,m), 7.31
(2H,d,J=8.3) , 7.08 (2H,s), 2.95 (2H,t,J=7.2) , 2.71
(2H,t,J=7.2) , 2.49 (2H,t,J=6.9) , 2.37 (4H,m), 2.12 (2H,m),
1.77 (2H,m) , 1.58 (2H,m)
Example 4
4-(10,ll-Dihydrodibenzo[a,d]cyclohepten-5-ylidene)-l-[3-(lH- tetrazol-5-yl)propyl]piperidine:
Figure imgf000021_0001
Foam
MS(m/z): 386 (M+H) . (SIMS)
IR(nujol): cm"1: 1640, 1295, 950, 750
NMR(DMSO-de) δppm: 7.0 - 7.4 (8H,m), 4.03 (lH.s) 3,89
(2H,m), 2,85 (2H,t,J=7), 2.72 (2H,m), 2.44 (4H,m) 1,84
(2H,quintet,J=7)
Example 5
4-(6H-Dibenzo[b,e]oxepin-ll-ylidene)-l-[3-(lH-tetrazol-5- yDpropyl]piperidine:
Figure imgf000021_0002
1350
-20- m.p. (with decomposition): 192 - 196 βC
MS(m/z): 388 (M+H) , 290 (SIMS)
IR(nujol): cm"1: 2700, 1550, 1290, 1220, 760
NMR(DMS0-d6) δppm: 7.50 (lH,d,J=6), 7.35 (2H,m), 7.0-7.3
(3H,m), 6,84 (lH,t,J=7), 6.73 (lH,d,J=7), 3.1-3.6 (6H,m)
2.99 (4H,m), 2.88 (2H,m) , 2.79 (2H,m), 2.13 (2H, quintet,
J=7)
Example 6
4-[Bis(4-fluorophenyl)methylene]-l-[3-(lH-tetrazol-5- yDpropyl)piperidine:
Figure imgf000022_0001
Colorless powder m.p.: 185 - 187βC (from ethyl acetate)
MS(m/z): 396(M+H) . 298, 106 (SIMS)
IR(nujol): cm"1: 1600, 1500, 1450, 1410, 1220, 1160, 840
NMR(DMS0-d6) δppm: 7.21 (8H,m), 2.96 (2H, t ,J=7.3) , 2.68
(4H,t,J=5.3) , 2.59 (4H,t,J=2.0) , 2.35 (2H, t,J=5.3) , 1.98
(2H,m)
Example 7
4-(Phenyl-2-thienylmethylene)-l-[3-(lH-tetrazol-5- yl)propyl]piperidine:
Figure imgf000022_0002
m . p . : 215 - 219 °C
MS (m/z ) : 366 (M+H) , 268 ( SIMS )
IR(nujol): cπr : 1405, 1340, 1080, 970, 830, 705
NMR(DMS0-d6) δppm: 7.57 (IH,dd,J=l.0,5.3) , 7.43 (3H,m),
7.26 (2H,m), 7.12 (IH,dd,J=4.9,3.3) , 6.97 (lH.m), 3.00
(2H,t.J=7.2) , 2.62 (8H,m), 2.35 (2H,t,J=5.3) , 2.00 (2H,m)
Example 8
4-Benzhydrylylidene-l-[3-(lH-tetrazol-5- yl)proρyl]piperidine:
Figure imgf000023_0001
Colorless powder m.p.: 223 - 226 °C (from ethyl acetate)
MS(m/z): 360(M+H), 262, (SIMS)
IR(nujol): cm"1: 1600. 1500, 1450, 1410, 1220, 1160, 840
NMR(DMS0-d6) δppm: 7.21 (lOH.m), 2.96 (2H,t,J=7.3) ,
2.68(4H,t,J=5.3) , 2.59 (4H,t,J=2.0) , 2.35 (2H,t,J=5.3) , 1.98
(2H,m)
Example 9
4-Benzhydrylylidene-l-[5-(lH-tetrazol-5- yDpentyl]piperidine:
Figure imgf000023_0002
Foam
MS ( m/z ) : 388 ( M+H ) , ( SIMS )
IR(nujol): cffl-»: 1600, 1500, 1450, 1410, 1220, 1160, 840
NMR(DMSO-de) δppm: 7.2-7.6 (lOH.m), 3.01 (2H,t,J=7), 2,81
(4H,t,J=7), 2.64(4H,m), 2.48 (2H,m), 1.86 (2H,quintet,J=7) ,
1.66 (2H,quintet,J=7) , 1.48 (2H,quintet,J=7)
Example 10 α,α-Diphenyl-N-[3-(lH-tetrazol-5-yl)propyl]piperidin-4-yl- methanol:
Figure imgf000024_0001
m.p. (with decomposition ) ≥ 250 °C
MS(m/z): 378(M+H) , 133, 105
IR(nujol): cm"1: 1660, 1170, 1100, 1060
NMR(DMS0-d6) δppm: 7.51 (4H,d,J=7.6) , 7.27 (4H, t,J=6.9) ,
7.14 (2H,dd,J=7.6,6.9) , 3.20 (2H,d,J=ll .2) , 2.79 (4H,m),
2.50 (8H,m) , 1.92 (2H,m), 1.63 (lH.m) , 1.35 (2H,d,J=12.6)
Example 11
4-[Bis(4-methoxyphenyl)methylene]-l-[4-(lH-tetrazol-5- yl)butyl]-piperidine:
H
Figure imgf000024_0002
m.p. : 120 - 123 °C
MS(m/z): 434(M+H), 322, 121
NMR(DMS0-d6) δppra: 6.95 (4H, d, J=8.6) , 6.85 (4H, d, J=8.6) ,
3.72 (6H,s), 2.84 ( 2H, t , J=7.2) , 2.55 (4H,brs) , 2.50
(4H,brs), 2.30 (2.50,m), 1.69 (2H,m), 1.50 (2H,m)
Example 12
4-Dibenzo[a,d]cyclohepten-5-ylidene-l-[5-(lH-tetrazol-5- yDpentyl] piper idine:
Figure imgf000025_0001
Colorless powder
MS(m/z): 412(M+H), (SIMS)
IR(nujol): cm-1: 1650, 1550, 1300, 1250, 950, 800, 760
NMR(DMS0-d6) δppm: 7.51 (4H,m), 7.43 (2H,m), 7.33
(2H,d,J=8.3) , 7.10 (2H,s), 2.94 (2H,t,J=7.2) ,2.75
(2H,t.J=7.2) , 2.40 (4H,t,J=6.9) , 2.16 (4H,m), 1.80 (2H,m),
1.59 (2H,m). 1.44 (2H,m)
Example 13
4-Xanthen-9-ylidene-l-[3-(lH-tetrazol-5- yDpropyl)piperidine:
Figure imgf000025_0002
m.p. ≥ 250 °C (from ethyl acetate)
MS(m/z): 374(M+H), (SIMS)
IR(nujol): cm"1: 2450, 1590, 1550, 1250, 1200, 1150,
1100, 1060, 1050,
NMR(DMSO-dε) δppm: 7.2-7.7 (8H,m), 2.8-3.6 (12H,m),
2.25 (2H,quintet,J=7)
Example 14
4-Thioxanthen-9-ylidene-l-[3-(lH-tetrazol-5- yDpropyl]piperidine:
Figure imgf000026_0001
m.p ≥ 250 °C
MS(m/z): 390 (SIMS)
NMR(DMS0-d6) δppm: 7.2-7.7 (8H,m), 2.8-3.6 (12H,m),
2.26 (2H,quintet,J=7)
Example 15 l-Benzhydryl-4-[3-(lH-tetrazol-5-yl)propyl]-piperazine
Figure imgf000026_0002
Benzhydrylpiperazine (10.62 g,42 mmol), 4- broraobutyronitrile (6.23 g, 42 mmol) and potassium carbonate(11.6 g, 84 mmol) were suspended in acetonitrile (200ml) and stirred overnight at 60 βC. The reaction solution was cooled and, thereafter, the inorganic matter was filtered off and the acetonitrile was concentrated under vacuum to yield an oil of 4-(4-benzhydrylpiperazin- l-yl)butyronitrile (13.4 g, 99%). MS (m/z) SI-MS,Pos: 319(M+H) IR (Neat), cm-1: 2250 (nitrile), 1490, 1445 Without further purification, 4-(4- benzhydrylpiperazin-l-yl)-butyronitrile was dissolved in DMF (150 ml) and ammonium chloride (6.74 g) and sodium azide (8.19 g) were added to the solution, followed by stirring at 90°C for 48 h. The reaction mixture was poured into water (300 ml) , extracted with ethyl acetate (200 ml) and the extract was removed.
Then, the aqueous layer was extracted twice with chloroform (200 ml). The chloroform layer was combined, dried with magnesium sulfate and concentrated under vacuum to reduce the volume of the solution to approximately 30 ml. Upon leaving the solution to stand, crystals precipitated and recovered by filtration to yield the titled compound
(5.5 g).
Decomposition point: 218 βC
MS (ra/z) SI-MS,Pos: 363 (M+H)
Elemental analysis for C2iH26N6
C H N Cal'd 69.58 7.23 23.19 found 69.70 7.32 23.10
IR(nujol) cm"1: 1405, 1310, 1192, 1087
1H-NMR(DMS0-d6) δppm: 50 βC , 1.84 (2H,m), 2.2-3.7 (lOH.m) .
2.85 (2H,m) , 4.27 (lH.s) , 5.60 (211 ,brs , H20) , 7.0-7.4 (lOH.m)
13C-NMR(DMS0-d6) δppm: 50°C, 156.07, 142.48, 128.16,
127.35. 126.54, 95.29, 74.83, 56.41, 52.42. 50.95. 23.80,
20.87 Exa ple 16 l-Benzhydryl-4-[3-(lH-tetrazol-5-yl)propyl]-[1,4]diazepan:
Figure imgf000028_0001
The titled compound was synthesized via an intermediate nitrile form as in Example 1. m.p. 172 - 175 °C (from ethyl acetate) MS (m/z) SI-MS : 377(M+H) Elemental analysis for C22H28N6 •1/2H20
C H N
Cal ' d 68 . 54 7 . 58 21 . 80 found 68.60 7.45 21.85
IR(nujol) cm-1: 1600, 1495, 1405, 1330, 1320 1H-NMR(DMS0-d6) δppm: 21.8°C, 1.81 (2H,m), 1.94 (2H,m), 2.4-2.7 (lOH.m), 3.13 (2H,m), 4.71 (lH,s), 7.0-7.4 (lOH.m)
Example 17 l-Benzhydryl-4-(lH-tetrazol-5-ylmethyl)piperazine:
Figure imgf000028_0002
m.p. 179 - 182°C (from ethyl acetate) MS(m/z) SI-MS,Pos : 335(M+H) Elemental analysis for Cι9H22N6
C H N
Cal'd 68.24 6.63 25.13 found 68.10 6.54 25.10
IR(nujol) cm"1: 2450, 1600, 1490, 1410, 1340, 1190, 1080, 1040, 970, 750, 710
Example 18 l-Benzhydryl-4-[4-(lH-tetrazol-5-yl)butyl]-piperazine
Figure imgf000029_0001
m.p. 67 - 68°C
Elemental analysis for C22H28N6 c H N Cal'd 70.18 7.50 22.30 found 70.10 7.40 22.35 MS (m/z) SI-MS,Pos: 377(M+H)
IR(nujol) era"1: 1655, 1600, 1310. 1280, 1080, 970, 750, 710 1H-NMR(DMS0-d6) δppm: 1.56 (2H,m), 1.78 (2H,m) , 2.49 (2H,m), 2.60 (8H,s), 2.95 (2H,t,J=7.2) , 4.38 (lH.s), 7.28 (2H,t,J=7.0) , 7.39 (2H,t,J=7.2) , 7.52 (2H,d,J=7.6) 01350
-28 -
Example 19 l-[ (4-Chlorophenyl)phenylmethyl]-4-[3-(lH-tetrazol-5- yl)propyl]piperazine dihydrochloride:
Figure imgf000030_0001
m.p. 198 - 203°C
MS(m/z) SI-MS, Pos: 397(M+H), 201, 166 Elemental analysis for C2ιH27 6Cl3
C H N
Cal ' d 53. 68 5 . 79 17 . 89 found 53.65 5.90 17.91
IR(nujol) cm"1: 1550, 1095, 1020, 760, 730
1H-NMR(DMS0-d6) tfppm: 2.13 (2H,m), 2.98 (2H,t,J=7.0) , 3.35
(4H,m), 3.63 (4H,m), 5.53 (lH.brs), 7.2-8.1 (9H,m)
Example 20
1-[Bis(4-fluorophenyl)methyl]-4-[3-(lH-tetrazol-5- yl)propyl]piperazine:
Figure imgf000030_0002
m.p. 170 - 172°C
MS (m/z) SI-MS: 399(M+H),203 Elemental analysis for C2ιH24F2Nβ
C H N Cal'd 63.30 6.07 21.09 Found 63.25 6.10 21.21
IR(nujol) cm"1: 2100, 1600, 1500, 1400, 1300, 1225, 1090,
970, 870, 830, 725 iH-NMRtDMSO-de) δppm: 1.85 (2H,m), 2.50 (lOH.m), 2.86
(2H,t,J=7.3) ,4.36 (lH.s), 7.12 (4H,t,J=8.9) , 7.43
(4H,dd,J=8.2,5.9)
Example 21
4-Benzhydryloxy-l-[3-(lH-tetrazol-5-yl)propyl]piperidine:
Figure imgf000031_0001
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 βC 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 - 217βC
MS (m/z) SI-MS. Pos: 378(M+H) ,167,133 Elemental analysis for C22H27Ns0
C H N
Cal'd 70.00 7.21 18.55
Found 70.31 7.30 18.70
IR(nujol) cm-1 1500, 1400, 1300, 1260, 1220, 1110, 1060, 960, 745, 705 iH-NMR (DMSO-de) δppm: 1.47 (2H,m), 1.96 (4H,m), 2.49 (2H,t,J=9.5) , 2.68 (2H,t,J=6.7) , 2.93 (4H,m), 5.73 (lH,s), 7.31 (2H,t,J=6.1Hz) , 7.43 (8H,m)
Example 22
4-[ (4-Chlorophenyl)phenylmethoxy]-l-[3-(lH-tetrazol-5- yDpropyl]piperidine:
Figure imgf000032_0001
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 βC 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
MS (m/z) SI-MS: 412(M+H), 201, 165 Elemental analysis for C22H26C1N50
C H N
Cal'd 64.15 6.36 17.00
Found 64.13 6.50 17.20
IR(nujol) cm"1: 1495, 1400, 1300, 1090, 1055, 750, 710 lH-NMR(DMSO-de) δppm: 1.75 (2H,m), 1.99 (4H,m), 2.61 (2H,m), 2.76 (2H,t,J=6.9) , 2.93 (2H,t,J=7.3) , 3.01 (2H,m), 5.73 (lH.s) , 7.44 (9H.m) Exa p l e 23
4[Bis(4-fluorophenyl)methoxy]-l-[3-(lH-tetrazol-5- yDpropyl]-piperidine:
Figure imgf000033_0001
Colorless powder
MS (m/z) SI-MS,Pos: 414(M+H), 203 Elemental analysis for C22H2sN502F2
C H N
Cal'd 63.91 6.09 16.94
Found 63.81 6.20 16.90
Hydrochloride
IR(nujol) cm"1: 1500, 1400, 1260, 1120, 970, 830, 725 1H-NMR(DMSO-d6) δppm: 1.95 (2H,m), 2.16 (4H.m), 2.92 (8H,m), 3.52 (lH.m), 5.70 (lH.s), 7.15 (4H,m), 7.40 (4H,m)
Example 24
4-[ (4-chlorophenyl)phenylmethoxy]-1-[4-(lH-tetrazol-5- yl)butyl]piperidine:
Figure imgf000033_0002
Colorless powder
FAB-MS (m/z) 425(M+H), 278, 202, 187
IR(nujol) cm"1: 1500, 1400, 1260, 1120, 970, 830, 725
1H-NMR(DMS0-d6) δppm: 7.2-7.4 (9H.m), 5.62 (lH.s), 3.38
(lH.m), 2.84 (2H,t,J=6), 2.73 (2H,m), 2.37 (2H,t,J=6), 2.16
(2H,m), 1.4-2.0 (8H,m)
Example 25
4-[(4-Chlorophenyl)phenylmethylene]-l-[3-(lH-tetrazol-5- yl)propyl]piperidine:
Figure imgf000034_0001
Colorless powder
MS (m/z) SI-MS,Pos: 393(M+H), 360, 296. 140 Elemental analysis for C22H23N5 •1.5H20
C H N
Cal ' d 62 . 93 6 . 23 16 . 68
Found 63.15 5.90 17.09
IR (KBr) cm"1: 3435. 2565, 1487, 1089. 1031, 964, 825, 763, 703, 509 H-NMR (CDC13) δppm: 7.32 (5H,m), 7.18 (4H,m), 3.20 (4H,m), 3.09 (4H,m), 2.87 (4H,m), 2.23 (2H,t,J=6) Example 26
4-(Dibenzo[a,d]cycloheptan-5-yl)-l-[3-(lH-tetrazol-5- yl)propyl]piperazine dihydrochloride:
Figure imgf000035_0001
White amorphous
MS (m/z) SI-MS, Pos: 389(M+H), 194. 178, 114 Elemental analysis for C24H30N62HC1 -H20
C H N
Cal ' d 57 . 62 6 . 30 17 . 53
Found 57.73 6.78 17.43
IR (KBr) cm"1: 2997, 2725, 2584, 1635, 1560, 1442, 1419,
1076, 906, 630 iH-NMR (CDC13) δppm: 7.35 (8H,m), 5.21 (lH.brs), 3.90
(2H.m). 3.37 (2H,brt), 3.27 (2H,t,J=6), 3.08 (4H,m), 2.31
(2H,m)
Example 27
4-(Dibenzo[a,d]cycloheptan-5-yl)-l-[4-(lH-tetrazol-5- yl)butyl]piperazine dihydrochloride :
Figure imgf000035_0002
White amorphous
MS (m/z) SI-MS. Pos 403(M+H), 193 Elemental analysis for C24H30N6 •2HC1•0.5H20
C H N
Cal'd 59.50 6.44 17.35
Found 59.41 7.03 16.91
IR (KBr) cm-1: 2960, 1564, 1446, 1396, 1058, 773. 744 iH-NMR(CDCls) δppra: 7.38 (4H.m) . 7.27 (4H,m) , 5.21 (IH.brs). 3.91 (2H,m) , 3.39 (2H,m), 3.22 (6H,m), 3.01 (4H,m), 1.87(4H,m)
Example 28
4-(6H-Dibenzo[b,e]-oxepin-ll-yl)-l-[3-(lH-tetrazol-5- yl)propyl]piperazine:
Figure imgf000036_0001
White amorphous
MS (m/z) FAB-MS, Pos: 391(M+H), 195
IR(KBr) cm"1: 3389, 2869, 1606, 1574, 1478, 1456, 1255,
1228, 1109, 1004, 761, 725, 638
1H-NMR(CDC13) δppm: 7.30 (4H,m), 7.15 (2H,t,J=7.5) , 6.82
(2H,t,J=7.5) , 6.72 (IH,d,J=ll.5) , 4.73 (IH,d,J=ll.9) , 4.03
(lH.s), 3.09 (2H,m), 2.73 (8H,m),
1.9-2.1 (2H,m) Exa ple 29
4-(Dibenzo[a,d]cyclohepten-5-yl)-l-[3-(lH-tetrazol-5- yDpropyl] piper idine:
Figure imgf000037_0001
White amorphous
MS (m/z) FAB-MS, Pos: 387 (M+H) . 191
IR(KBr) cm"1 : 3392. 1654, 1436. 1402. 1276, 1103. 973. 796.
763, 730, 628, 493 1H-NMR(CDC13) δppm: 7.37 (8H,m), 6.94 (2H,s), 4.48 (lH.s), 3.18 (2H,t-like) 2.73 (2H,t-like), 2.69 (4H,m), 2.29 (4H,m). 1.95 (2H,m)
Example 30
4-(Dibenzo[a,d]cyclohepten-5-yl)-l-[4-(lH-tetrazol-5- yl)butyl]piperidine :
Figure imgf000037_0002
White amorphous
MS (m/z) FAB-MS, Pos: 401(M+H), 191
IR(KBr) cm"1 : 3045, 2871, 1635, 1436, 1402, 1247, 1103,
997. 798, 763. 730, 464 iH-NMRtCDCla) δppm: 7.31 (8H,m) , 6.94 (2H, S) , 4.40 (lH.s).
2.92 (2H,t,J=6.0) , 2.64 (6H,m), 2.28 (4H, t ,J=4.6) , 1.78
(2H,m), 1.63 (2H,m) Exa ple 31
4-(6H-Dibenzo[b,e]oxepin-ll-yl)-l-[4-(lH-tetrazol-5- yl)butyl]-piperazine:
Figure imgf000038_0001
White amorphous
MS (m/z) FAB-MS,Pos: 405(M+H). 195
IR(KBr) cm"1: 3485, 1487, 1446, 1255, 1228, 1109, 1004, 765 iH-NMR CDCls) δppm: 7.29 (6H,m), 6.82 (2H,m), 6.69
(lH,d,J=11.5) , 4.72 (IH,d,J=ll.5) , 4.00 (lH.s), 3.00
(2H,t,J=5.6) , 2.5-2.9 (lOH.m), 1,87 (2H.m) , 1.71 (2H.m)
Example 32
4-[ (4-Chlorophenyl)phenylmethylene]-1-[4-(lH-tetrazol-5- yl)butyl]piperidine:
Figure imgf000038_0002
White amorphous
MS (m/z) FAB-MS,Pos: 408(M+H), 296
IR(KBr) cm"1: 3438, 3099, 2763, 2650, 1487, 1442, 1398,
1087, 1014, 829, 763, 703 lH-NMR(CDCl3) δppm: 7.26 (5H,m), 7.04 (4H,m), 3.00 (4H,t- like), 2.87 (2H,t-like), 2.70 (4H,t-like), 1.83 (4H.m) Example 33
4-[ (4-Chlorophenyl)phenylmethylene]-l-[3-(lH-tetrazol-5- yl)propyl)piperidine:
Figure imgf000039_0001
White amorphous
MS (m/z) FAB-MS. Pos: 393(M+H) , 296
IR(KBr) cm"1: 3436, 2565, 1487, 1089, 1031, 825, 763, 703
1H-NMR(CDC13) δppm: 7.32 (5H,m), 7.08 (4H,m), 3.15 (6H,m),
2.87 (2H,t-like), 2.30 (2H,m)
Example 34
4-[Bis(4-methoxyphenyl)methylene]-1-(ethoxycarbonyl)- piperidine:
Figure imgf000040_0001
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 -10βC 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 0βC 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 βC 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%).
Oil
IR(nujol) cm"1: 1735, 1605, 1578, 1490, 1390, 1130
XH-NMR(DMSO-de) δppm: 7.01 (4H,d,J=9), 6.82 (4H,d,J=9),
4.15 (2H,q,J=7), 3.78 (6H,s), 3.49 (4H,m), 2.35 (4H,m), 1.25
(3H,t,J=7) Exa ple 35
4-[Bis(4-methoxyphenyl)methylene]piperidine:
Figure imgf000041_0001
4-[Bis(4-methoxyphenyl)methylene]-l- (ethoxycarbonyl)piperidine (35 g) was dissolved in ethanol (300 ml) and potassium hydroxide (120 g) was added to the solution, which was then stirred over-night. Ethanol was concentrated, mixed with water (500 ml), subjected to extraction with chloroform (200 ml) , dried and concentrated under vacuum. The residue was recrystallized from ethyl acetate-hexane to yield the end compound (20 g) .
*H-NMR (CDC13) δppm: 7.01 (4H,d,J=9), 6.82 (4H,d,J=9), 3.78 (6H,s), 2.90 (4H,m) , 2.32 (4H,m)

Claims

CLAIMS 1. A tetrazole derivative of the general formula (1):
Figure imgf000042_0001
(where A represents -CH=CH-, -CH2-CH2-, -CH20-, an oxygen atom or a sulfur atom or, in the case where A does not interconnect the adjacent aromatic rings, it represents two hydrogen atoms each bonded to the adjacent aromatic ring; V represents -CH=CH- or a sulfur atom; X and Y each independently represents an alkoxy group, a halogen atom or a hydrogen atom; (a) 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 (b) W, Z and B represent a bond, a nitrogen atom and a hydrogen atom, respectively, or (c) 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 a pharmacologically acceptable salt thereof. 2. An antihistamine, an antiallergic agent or an asthma treating agent that contain as an active ingredient a tetrazole derivative of the general formula (1):
Figure imgf000042_0002
(where A represents -CH=CH-, -CH2-CH2-, -CH20-, an oxygen atom or a sulfur atom or, in the case where A does not interconnect the adjacent aromatic rings, it represents two hydrogen atoms each bonded to the adjacent aromatic ring, V represents -CH=CH- or a sulfur atom; X and Y each independently represents an alkoxy group, a halogen atom or a hydrogen atom; (a) 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 (b) W, Z and B represent a bond, a nitrogen atom and a hydrogen atom, respectively, or (c) 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 and integer of 1 - 6) or a pharmacologically acceptable salt thereof.
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WO2005102335A2 (en) * 2004-04-23 2005-11-03 Hypnion, Inc. Methods of treating sleep disorders
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US7189757B2 (en) 2001-10-16 2007-03-13 Hypnion, Inc. Treatment of sleep disorders using CNS target modulators
JP2007534696A (en) * 2004-04-23 2007-11-29 ヒプニオン， インコーポレイテッド Treatment using CNS target modulator or CNS diagnosis
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US7326721B2 (en) 2003-12-10 2008-02-05 Hypnion, Inc. Doxepin analogs and methods of use thereof
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US7482460B2 (en) 2003-12-10 2009-01-27 Hypnion, Inc. Doxepin analogs and methods of use thereof
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EP0739881A2 (en) * 1995-04-24 1996-10-30 Kowa Co. Ltd. Piperidine derivatives
EP0739881A3 (en) * 1995-04-24 1999-02-03 Kowa Co. Ltd. Piperidine derivatives
WO1998004554A1 (en) * 1996-07-29 1998-02-05 Banyu Pharmaceutical Co., Ltd. Chemokine receptor antagonists
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WO2002036589A1 (en) * 2000-10-31 2002-05-10 Almirall Prodesfarma S.A. Indolylpiperidine derivatives as antihistaminic and antiallergic agents
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US7355042B2 (en) 2001-10-16 2008-04-08 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
US7560471B2 (en) 2002-05-29 2009-07-14 Laboratorios Almirall S.A. Indolylpiperidine derivatives as potent antihistaminic and antiallergic agents
US7326721B2 (en) 2003-12-10 2008-02-05 Hypnion, Inc. Doxepin analogs and methods of use thereof
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
JP2007534696A (en) * 2004-04-23 2007-11-29 ヒプニオン， インコーポレイテッド Treatment using CNS target modulator or CNS diagnosis
WO2005102335A3 (en) * 2004-04-23 2006-04-06 Hypnion Inc Methods of treating sleep disorders
US7524864B2 (en) 2004-04-23 2009-04-28 Hypnion, Inc. Methods of treating sleep disorders
WO2005102335A2 (en) * 2004-04-23 2005-11-03 Hypnion, Inc. Methods of treating sleep disorders
WO2007018460A1 (en) * 2005-08-08 2007-02-15 Astrazeneca Ab Therapeutic agents
WO2019203296A1 (en) 2018-04-19 2019-10-24 国立大学法人東京農工大学 Preventative and therapeutic agents for sarcopenia
US11883410B2 (en) 2018-04-19 2024-01-30 National University Corporation Tokyo University Of Agriculture And Technolgy Preventative and therapeutic agents for sarcopenia
CN113880808A (en) * 2020-07-03 2022-01-04 合肥医工医药股份有限公司 Triazole compounds, preparation method and medical application thereof

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