EP0846116A1 - Derives de 1-benzoyl-2-(indolyl-3-alkyl)-piperazine utilises comme antagonistes du recepteur de la neurokinine - Google Patents

Derives de 1-benzoyl-2-(indolyl-3-alkyl)-piperazine utilises comme antagonistes du recepteur de la neurokinine

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Publication number
EP0846116A1
EP0846116A1 EP96915200A EP96915200A EP0846116A1 EP 0846116 A1 EP0846116 A1 EP 0846116A1 EP 96915200 A EP96915200 A EP 96915200A EP 96915200 A EP96915200 A EP 96915200A EP 0846116 A1 EP0846116 A1 EP 0846116A1
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EP
European Patent Office
Prior art keywords
compound
salt
alkyl
formula
acid
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.)
Ceased
Application number
EP96915200A
Other languages
German (de)
English (en)
Inventor
Masaaki Matsuo
Daijiro Hagiwara
Takashi Manabe
Nobukiyo Konishi
Shinji Shigenaga
Kenji Murano
Hiroshi Matsuda
Hiroshi Miyake
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.)
Fujisawa Pharmaceutical Co Ltd
Original Assignee
Fujisawa Pharmaceutical Co Ltd
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Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Publication of EP0846116A1 publication Critical patent/EP0846116A1/fr
Ceased legal-status Critical Current

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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
    • C07D401/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to new piperazine derivatives and a pharmaceutically acceptable salt thereof.
  • new piperazine derivatives and a pharmaceutically acceptable salt thereof which have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism, Neurokinin B antagonism, and the like, to a process for preparation thereof, to a pharmaceutical composition comprising the same, and to a use of the same as a medicament.
  • one object of the present invention is to provide new and useful piperazine derivatives and a pharmaceutically acceptable salt thereof which have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism, Neurokinin B antagonism, and the like.
  • Another object of the present invention is to provide a process for the preparation of said piperazine derivatives ⁇ and a salt thereof.
  • a further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said piperazine derivatives and a pharmaceutically acceptable salt thereof.
  • Still further object of the present invention is to provide a use of said piperazine derivatives or a pharmaceutically acceptable salt thereof as Tachykinin antagonist, especially Substance P antagonist, Neurokinin A antagonist or Neurokinin B antagonist, useful for treating or preventing Tachykinin-mediated diseases, for example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, expectoration, and the like; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like; inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like; pains or aches (e.g., migraine, headache, toothache cancerous pain, back pain, etc.); and the like in human being or animals.
  • respiratory diseases such as asthma, bronchitis, rhinitis, cough, expectoration
  • the object compound of the present invention is the compound of the following formula (I) :
  • the other object compound of the present invention can be represented by the following general formula (Ig) :
  • R 1 is trihalo (lower)alkyl
  • R ⁇ is trihalo (lower)alkyl
  • R J is mdolyl(lower)alkyl
  • -A- is -CH' or - -flC-*CH 2 - and
  • R is hydrogen or lower alkoxycarbonyl
  • R 6 is hydrogen or lower alkanoyl
  • R 7 is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl, lower alkoxy(lower)alkanoyl, cyclo(lower)alkylcarbonyl, aroyl or lower alkylsulfonyl, or its pharmaceutically acceptable salt.
  • the object compounds can be prepared by processes which are illustrated in the following schemes. - t -
  • Suitable salts and pharmaceutically acceptable salts of the starting and object compounds are conventional non-toxic salt and include an acid addition salt such as an organic acid salt (e.g. acetate, trifluoroacetate, fumarate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), or a salt with an amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.), or a metal salt such as an alkali metal salt (e.g.
  • an organic acid salt e.g. acetate, trifluoroacetate, fumarate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate
  • an alkaline earth metal salt e.g. calcium salt, magnesium salt, etc.
  • an ammonium salt e.g. sodium salt, potassium salt, etc.
  • an organic base salt e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.
  • an organic base salt e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.
  • Suitable "lower alkyl” and “lower alkyl moiety" in the terms “indolyl(lower)alkyl” and “lower alkylsulfonyl” is straight or branched one having 1 to 6 carbon atom(s) and may include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like.
  • Suitable “trihalo (lower) alkyl” may include trichloromethyl, tribromomethyl, trifluoromethyl and the like.
  • Suitable "lower alkoxy” and “lower alkoxy moiety" in the terms “lower alkoxycarbonyl” and “lower alkoxy(lower)alkanoyl” may include methoxy, ethoxy, isopropyloxy, butoxy and the like.
  • Suitable "lower alkanoyl” and “lower alkanoyl moiety" in the term “lower alkoxy(lower)alkanoyl” may include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl, pivaloyl and the like.
  • Suitable "cyclo (lower)alkyl moiety" in the term “cyclo(lower) alkylcarbonyl” may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • Suitable “aroyl” may include benzoyl, toluoyl, naphthoyl and the like.
  • Suitable “leaving group” may include hydroxy, reactive group derived from hydroxy and the like.
  • Suitable “reactive group derived from hydroxy” may include acid residue and the like.
  • Suitable “acid residue” may include halogen (e.g. fluoro, chloro, bromo, iodo) , acyloxy (e.g. acetoxy, tosyloxy, mesyloxy, etc.) and the like.
  • halogen e.g. fluoro, chloro, bromo, iodo
  • acyloxy e.g. acetoxy, tosyloxy, mesyloxy, etc.
  • the object compound (I) or a salt thereof can be prepared by reacting a compound (II) or its reactive derivative at the carboxy group or a salt thereof with a compound (III) or its reactive derivative at the amino group or a salt thereof.
  • Suitable reactive derivative at the carboxy group of the compound (II) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
  • Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid [e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid,
  • substituted phosphoric acid e.g. dialkylphosphoric
  • cvanomethyl ester methoxymethyl ester, dimethyliminomethyl [ ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.], or an ester with a N-hydroxy compound [e.g.
  • Suitable reactive derivative at the amino group of the compound (III) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (III) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (III) with a silyl compound such as bis (trimethylsilyl)acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl)urea or the like; a derivative formed by reaction of the compound (III) with phosphorus trichloride or phosgene and the like.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, 2-butanone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction, or the mixture thereof.
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, 2-butanone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction, or the mixture thereof.
  • the reaction when the compound (II) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'- (4-diethylaminocyclohexyl) carbodiimide; N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide; N-ethyl-N'- (3-dimethylaminopropyl)carbodiimide; pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl poly
  • the reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri (lower)alkylamine, pyridine, N-(lower) alkylmorpholine, N,N-di (lower)alkylbenzylamine, or the like.
  • an inorganic or organic base such as an alkali metal bicarbonate, tri (lower)alkylamine, pyridine, N-(lower) alkylmorpholine, N,N-di (lower)alkylbenzylamine, or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
  • the object compound (If) can be prepared by reacting the compound (I) or a salt thereof other than fumaric acid salt thereof with fumaric acid.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, 2-butanone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction, or the mixture thereof.
  • a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, 2-butanone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction, or the mixture thereof.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.
  • the object compound (Ig') or a salt thereof can be prepared by reacting the compound (IV) or its reactive derivative at the imino group or a salt thereof with the compound (V) or a salt thereof.
  • Suitable reactive derivative at the imino group of the compound (IV) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (IV) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (IV) with a silyl compound such as bis (trimethylsilyl) acetamide, mono(trimethylsilyl)acetamide. bis (trimethylsilyl)urea or the like; a derivative formed by reaction of the compound (IV) with phosphorus trichloride or phosgene and the like.
  • This reaction is usually carried out in a solvent such as alcohol [e.g. methanol, ethanol, etc.], dichloromethane, benzene, N,N-dimethylformamide, tetrahydrofuran, diethyl ether or any other solvent which does not adversely affect the reaction.
  • a solvent such as alcohol [e.g. methanol, ethanol, etc.], dichloromethane, benzene, N,N-dimethylformamide, tetrahydrofuran, diethyl ether or any other solvent which does not adversely affect the reaction.
  • the raction may be carried out in the presence of an inorganic or an organic base such as an alkali metal hydroxide [e.g. sodium hydroxide, potassium hydroxide, etc.], an alkali metal carbonate [e.g. sodium carbonate, potassium carbonate, etc.], an alkali metal bicarbonate [e.g. sodium bicarbonate, potassium bicarbonate, etc.], alkali metal hydride [e.g. sodium hydride, potassium hydride, etc.], tri (lower) alkylamine [e.g. trimethylamine, triethylamine, diisopropylethylamine, etc.], pyridine or its derivative [e.g. picoline, lutidine, 4-dimethylaminopyridine, etc.], or the like.
  • an alkali metal hydroxide e.g. sodium hydroxide, potassium hydroxide, etc.
  • an alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
  • the reaction temperature is not critical, and the reaction can be carried out under cooling, at room temperature or under warming or heating.
  • the compound (Ig") or a salt thereof can be prepared by reacting a compound (IV) or its reactive derivative at the imino group or a salt thereof with a compound (VI) or its reactive derivative at the carboxy group or a salt thereof.
  • the reaction can be carried out in the manner disclosed in Preparation 10 or similar manners thereto.
  • the object compounds of the present invention have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism or Neurokinin B antagonism, and therefore are useful for treating or preventing Tachykinin-mediated diseases, particularly Substance P-mediated diseases, for example, respiratory diseases such as asthma, bronchitis (e.g.
  • ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like
  • cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like
  • inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like
  • pains or aches e.g. migraine, headache, cluster headache, toothache, cancerous pain, back pain, neuralgia, etc.
  • the object compounds of the present invention are useful for treating or preventing ophthalmic diseases such as glaucoma, uveitis, and the like; gastrointestinal diseases such as ulcer, ulcerative colitis, irritable bowel syndrome, food allergy, and the like; inflammatory diseases such as nephritis, and the like, circulatory diseases such as hypertension, angina pectoris, cardiac failure, thrombosis, Raynaud's disease, and the like; epilepsy; spastic paralysis; pollakiuria; cystitis; bladder detrusor hyperreflexia; urinary incontinence; Parkinson- diseases; dementia; AIDS related dementia; Alzheimer's diseases; Down's syndrome; Huntington's chorea; carcinoid syndrome; disorders related to immune enhancement or suppression; disorders caused by Helicobacter pylori or another spiral urease-positive gram-negative bacterium; sunburn; angiogenesis or diseases caused by angiogenesis; and the like.
  • ophthalmic diseases such as glaucoma,
  • the object compounds of the present invention are useful for treating or preventing chronic obstructive pulmonary diseases, particularly chronic pulmonary emphysema; blinkis; proliferative vitreoretinopathy; psoriasis; inflammatory intestinal diseases, particularly Crohn's diseases; hepatitis; superficial pain on congelation, burn, herpes zoster or diabetic neuropathy; tenalgia attended to hyperlipidemia; postoperative neuroma, particularly of mastectomy; vulvar vestibulitis; he odialysis-associated itching; lichen planus; laryngopharyngitis; bronchiectasis; coniosis; whooping cough; pulmonary tuberculosis; cystic fibrosis; e esis; mental diseases, particularly anxiety, depression, dysthymic disorders and schizophrenia; demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis; attenuation of morphine withdrawal; oe
  • the object compounds of the present invention can be used in a form of pharmaceutical preparation containing one of said compound, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral, external including topical, enteral, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal or transocular administration.
  • a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral, external including topical, enteral, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal or transocular administration.
  • the pharmaceutical preparations may be solid, semi-solid or solutions such as capsules, tablets, pellets, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solution, syrups, aerosols, suspension, emulsion, or the like.
  • auxiliary substances stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
  • an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the object compounds may be effective for treating Tachykinin-mediated diseases such as asthma and the like.
  • amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
  • CHO cells permanently expressing h-NK-, receptors were harvested and homogenized with a Dounce homogenizer at 4°C in a buffer (0.25 M sucrose, 25 M Tris-HCl pH 7.4, 10 mM MgCl 2 ,
  • Cell membranes (6 ⁇ g/ml) were incubated with 12 ⁇ I-BH- Substance P (0.1 nM) with or without test compounds in 0.25 ml of Medium 2 (50 mM Tris-HCl pH 7.4, 5 mM MnCl 2 , 20 ⁇ g/ml chvmostatin, 40 ⁇ g/ml bacitracin, 4 ⁇ g/ml leupeptin, 5 ⁇ g/ml p-APMSF, 200 ⁇ g/ml BSA) at 22°C for 90 minutes. At the end of the incubation period, the content was quickly filtered over a Wahtman GF/C glass filter (pretreated with 0.1% polyethylene imine for 3 hours prior to use) under aspiration.
  • Medium 2 50 mM Tris-HCl pH 7.4, 5 mM MnCl 2 , 20 ⁇ g/ml chvmostatin, 40 ⁇ g/ml bacitracin, 4 ⁇ g/ml le
  • the object compound of the present invention is also superior in stability and the like.
  • Example 5 The following piperazine derivatives (Table 1) were prepared by the similar manner to that of the each Example

Abstract

La présente invention concerne des composés représentés par la formule générale (Ig) ou certains de leurs sels pharmaceutiquement acceptables, un procédé de préparation de ces composés, une composition pharmaceutique comprenant ces composés et l'utilisation de ces composés comme médicament. Dans la formule générale (Ig), R1 est trihalo alkyle (inférieur), R2 est trihalo alkyle (inférieur), R3 est indolyl alkyle (inférieur), -A- est un radical -CH¿2?- ou un radical représenté par les formules spécifiques (a), et -R?4¿ est représenté par les formules spécifiques (b, c ou d). Dans ces formules spécifiques (b, c ou d), R5 est hydrogène ou alcoxycarbonyle inférieur, R6 est hydrogène ou alcanoyle inférieur, R7 est hydrogène, alkyle inférieur, alcanoyle inférieur, alcoxycarboyle inférieur, alcoxy inférieur alcanoyle (inférieur), cyclo alkyl carbonyle (inférieur), aroyle ou alkylsylfonyle inférieur.
EP96915200A 1995-05-25 1996-05-21 Derives de 1-benzoyl-2-(indolyl-3-alkyl)-piperazine utilises comme antagonistes du recepteur de la neurokinine Ceased EP0846116A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US45017695A 1995-05-25 1995-05-25
US450176 1995-05-25
PCT/JP1996/001335 WO1996037489A1 (fr) 1995-05-25 1996-05-21 Derives de 1-benzoyl-2-(indolyl-3-alkyl)-piperazine utilises comme antagonistes du recepteur de la neurokinine

Publications (1)

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EP0846116A1 true EP0846116A1 (fr) 1998-06-10

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Country Status (14)

Country Link
EP (1) EP0846116A1 (fr)
JP (1) JP3071829B2 (fr)
KR (1) KR19990021857A (fr)
CN (1) CN1072220C (fr)
AU (1) AU706021B2 (fr)
CA (1) CA2222041A1 (fr)
EA (1) EA000669B1 (fr)
HU (1) HUP9900822A3 (fr)
IL (1) IL118369A (fr)
NZ (1) NZ307625A (fr)
TR (1) TR199600438A2 (fr)
TW (1) TW391960B (fr)
WO (1) WO1996037489A1 (fr)
ZA (1) ZA964101B (fr)

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CA2189501A1 (fr) * 1995-11-06 1997-05-07 Harry R. Howard Antagonistes des recepteurs de nk-1 pour le traitement du cancer
US6087357A (en) * 1995-12-18 2000-07-11 Fujisawa Pharmaceutical Co., Ltd. Piperazine derivatives as tachykinin antagonists
AUPO735997A0 (en) 1997-06-17 1997-07-10 Fujisawa Pharmaceutical Co., Ltd. Piperazine derivatives
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CN1191533A (zh) 1998-08-26
AU706021B2 (en) 1999-06-03
TW391960B (en) 2000-06-01
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TR199600438A2 (tr) 1996-12-21
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CN1072220C (zh) 2001-10-03
EA199700425A1 (ru) 1998-12-24
AU5703196A (en) 1996-12-11
WO1996037489A1 (fr) 1996-11-28
JP3071829B2 (ja) 2000-07-31
CA2222041A1 (fr) 1996-11-28
ZA964101B (en) 1996-07-29
HUP9900822A3 (en) 1999-11-29
KR19990021857A (ko) 1999-03-25

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