Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—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
• 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
• 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
• Still further object of the present invention is to provide a use of said piperazine derivatives or a
• Substance P 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.
• inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like
• pains or aches e.g., migraine, headache, toothache cancerous pain, back pain, etc.
• 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 2 is trihalo (lower) alkyl
• R 3 is indolyl (lower) alkyl
• R 5 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,
• the object compounds can be prepared by processes which are illustrated in the following schemes. wherein R 1 , R 2 , R 3 and R 4 are each as defined above;
• -A 1 - is -CH 2 -;
• 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.
• a salt with an amino acid e.g.
• arginine aspartic acid, glutamic acid, etc.
• a metal salt such as an alkali metal salt (e.g. sodium salt,
• potassium salt, etc. and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), or the like.
• alkaline earth metal salt e.g. calcium salt, magnesium salt, etc.
• an ammonium salt e.g. calcium salt, magnesium 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
• alkoxy (lower) alkanoyl may include methoxy, ethoxy,
• 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.
• cyclo (lower) alkylcarbonyl may include cyclopropyl
• 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.
• Process 1 for preparing the object compounds of the present invention are explained in detail in the following.
• the object compound (I) or a salt thereof can be
• 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.
• 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,
• 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
• the reaction is usually carried out in a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, 2-butanone, dioxane, acetonitrile,
• a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, 2-butanone, dioxane, acetonitrile,
• 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,N'-diethylcarbodiimide N,N'-diisopropylcarbodiimide
• phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride;
• triphenylphosphine 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H- benzotriazole; 1-hydroxybenzotriazole; so-called Mukaiyama reagent such as 2-chloro-1-methylpyridinium iodide;
• the reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal
• 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,
• a conventional solvent such as water, alcohol [e.g. methanol, ethanol, etc.], acetone, 2-butanone, dioxane, acetonitrile,
• 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
• 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.]
• the base to be used in liquid it can also be used as a solvent.
• the reaction temperature is not critical, and the reaction can be carried out under cooling, at room
• 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,
• Substance P-mediated diseases for example, respiratory diseases such as asthma, bronchitis (e.g. chronic bronchitis, acute bronchitis and diffuse panbronchiolitis, etc.), rhinitis, cough, expectoration, and the like;
• respiratory diseases such as asthma, bronchitis (e.g. chronic bronchitis, acute bronchitis and diffuse panbronchiolitis, etc.), rhinitis, cough, expectoration, and the like;
• ophthalmic diseases such as conjunctivitis, vernal
• cutaneous diseases such as contact dermatitis, atopic
• dermatitis 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.; and the like.
• 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
• 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; hemodialysis-associated itching; lichen planus; laryngopharyngitis; bronchiectasis; coniosis; whooping cough; pulmonary tuberculosis; cystic fibrosis; emesis; mental diseases, particularly anxiety, depression, dysthymic disorders and schizophrenia;
• demyelinating diseases such as multiple sclerosis and
• amyotrophic lateral sclerosis amyotrophic lateral sclerosis; attenuation of morphine withdrawal; oedema, such as oedema caused by thermal injury; small cell carcinomas, particularly small cell lung cancer (SCLC); hypersensitivity disorders such as poison ivy;
• fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; reflex sympathetic dystrophy such as shoulder/hand syndrome; addiction disorders such as alcoholism; stress related somatic disorders; rheumatic diseases such as fibrositis; and the like.
• 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
• 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
• the pharmaceutical preparations may be solid, semi-solid or solutions such as capsules, tablets, pellets, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections,
• aerosols suspension, emulsion, or the like. If desired, there may be included in these preparations, 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
• kits 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.
• Example 2 1 25 I-BH-Substance P Binding to h-NK 1 Receptors Test Method : 125 I-BH-Substance P Binding to h-NK 1 Receptors
• 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 mM Tris-HCl pH 7.4, 10 mM MgCl 2 ,
• buffer 25 mM Tris-HCl pH 7.4, 10 mM MgCl 2 , 1 mM EDTA, 5 ⁇ g/ml p-APMSF
• buffer 25 mM Tris-HCl pH 7.4, 10 mM MgCl 2 , 1 mM EDTA, 5 ⁇ g/ml p-APMSF
• the object compound of the present invention is also superior in stability and the like.
• IR (CCCl 3 ) 3430, 3300, 3000, 2910, 2800,

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• Pyridine Compounds (AREA)

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Citations (2)

• 1996
  • 1996-05-21 JP JP8535553A patent/JP3071829B2/ja not_active Expired - Fee Related
  • 1996-05-21 WO PCT/JP1996/001335 patent/WO1996037489A1/en not_active Application Discontinuation
  • 1996-05-21 AU AU57031/96A patent/AU706021B2/en not_active Ceased
  • 1996-05-21 CN CN96195744A patent/CN1072220C/zh not_active Expired - Fee Related
  • 1996-05-21 HU HU9900822A patent/HUP9900822A3/hu unknown
  • 1996-05-21 NZ NZ307625A patent/NZ307625A/xx unknown
  • 1996-05-21 EP EP96915200A patent/EP0846116A1/en not_active Ceased
  • 1996-05-21 KR KR1019970708331A patent/KR19990021857A/ko not_active Application Discontinuation
  • 1996-05-21 CA CA002222041A patent/CA2222041A1/en not_active Abandoned
  • 1996-05-21 EA EA199700425A patent/EA000669B1/ru not_active IP Right Cessation
  • 1996-05-22 ZA ZA964101A patent/ZA964101B/xx unknown
  • 1996-05-22 IL IL11836996A patent/IL118369A/xx active IP Right Grant
  • 1996-05-23 TW TW085106105A patent/TW391960B/zh not_active IP Right Cessation
  • 1996-05-24 TR TR96/00438A patent/TR199600438A2/xx unknown

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