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WO1996037489A1 - 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 Download PDF

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Publication number
WO1996037489A1
WO1996037489A1 PCT/JP1996/001335 JP9601335W WO9637489A1 WO 1996037489 A1 WO1996037489 A1 WO 1996037489A1 JP 9601335 W JP9601335 W JP 9601335W WO 9637489 A1 WO9637489 A1 WO 9637489A1
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WIPO (PCT)
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
PCT/JP1996/001335
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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
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co Ltd filed Critical Fujisawa Pharmaceutical Co Ltd
Priority to AU57031/96A priority Critical patent/AU706021B2/en
Priority to EA199700425A priority patent/EA000669B1/ru
Priority to NZ307625A priority patent/NZ307625A/xx
Priority to MX9709079A priority patent/MX9709079A/es
Priority to EP96915200A priority patent/EP0846116A1/fr
Priority to JP8535553A priority patent/JP3071829B2/ja
Publication of WO1996037489A1 publication Critical patent/WO1996037489A1/fr
Anticipated expiration legal-status Critical
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
  • 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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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
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  • Pulmonology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Neurosurgery (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Cardiology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)

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.
PCT/JP1996/001335 1995-05-25 1996-05-21 Derives de 1-benzoyl-2-(indolyl-3-alkyl)-piperazine utilises comme antagonistes du recepteur de la neurokinine Ceased WO1996037489A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AU57031/96A AU706021B2 (en) 1995-05-25 1996-05-21 Piperazine derivatives
EA199700425A EA000669B1 (ru) 1995-05-25 1996-05-21 Производные пиперазина
NZ307625A NZ307625A (en) 1995-05-25 1996-05-21 1-benzoyl-2-(indolyl-3-alkyl)-piperazine derivatives as neurokinin receptor antagonists
MX9709079A MX9709079A (es) 1996-05-21 1996-05-21 Derivados de 1-benzol-2-(indolil-3-alquil) piperazina como antagonistas del receptor de neuroquinina.
EP96915200A EP0846116A1 (fr) 1995-05-25 1996-05-21 Derives de 1-benzoyl-2-(indolyl-3-alkyl)-piperazine utilises comme antagonistes du recepteur de la neurokinine
JP8535553A JP3071829B2 (ja) 1995-05-25 1996-05-21 ニューロキニン受容体拮抗剤としての１−ベンゾイル−２−（インドリル−３−アルキル）−ピペラジン誘導体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US45017695A 1995-05-25 1995-05-25
US08/450,176 1995-05-25

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WO1996037489A1 true WO1996037489A1 (fr) 1996-11-28

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PCT/JP1996/001335 Ceased 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

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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)

Cited By (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997022597A1 (fr) * 1995-12-18 1997-06-26 Fujisawa Pharmaceutical Co., Ltd. Derives de la piperazine antagonistes de la tachykinine
WO1998057954A1 (fr) * 1997-06-17 1998-12-23 Fujisawa Pharmaceutical Co., Ltd. Derives d'aroyle-piperazine, leur preparation et leur utilisation en tant qu'antagonistes de tachykinine
EP0899270A1 (fr) * 1997-08-27 1999-03-03 Solvay Pharmaceuticals GmbH Indolylmethyl-N,N'-bisacylpipérazines comme antagonistes des récepteurs de neurokinine
EP0773026A3 (fr) * 1995-11-06 1999-11-17 Pfizer Inc. Antagonistes des récepteurs NK-1 pour traiter le cancer
US6001833A (en) * 1997-08-27 1999-12-14 Solvay Pharmaceuticals Gmbh Urea derivatives
WO2003006459A1 (fr) * 2001-07-09 2003-01-23 Solvay Pharmaceuticals B.V. Derives oximes de piperazine presentant une activite antagoniste du recepteur de nk-1
WO2003084955A1 (fr) 2002-04-04 2003-10-16 Solvay Pharmaceuticals B.V. Derives de diazabicyclo-alcane uniques presentant une activite antagoniste contre nk1
US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US7084152B2 (en) 2000-07-11 2006-08-01 Amr Technology, Inc. 4-phenyl substituted tetrahydroisoquinolines therapeutic use thereof
WO2006123182A2 (fr) 2005-05-17 2006-11-23 Merck Sharp & Dohme Limited Sulfones de cyclohexyle pour le traitement du cancer
US7163949B1 (en) 1999-11-03 2007-01-16 Amr Technology, Inc. 4-phenyl substituted tetrahydroisoquinolines and use thereof
WO2007011820A2 (fr) 2005-07-15 2007-01-25 Amr Technology, Inc. Tetrahydrobenzazepines substituees par aryle et heteroaryle, et leur utilisation pour bloquer la reabsorption de la noradrenaline, de la dopamine, et de la serotonine
WO2007041052A2 (fr) 2005-09-29 2007-04-12 Merck & Co., Inc. Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4
WO2007093827A1 (fr) 2006-02-15 2007-08-23 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Dérivés de trifluoroéthanone substitués par thiophène et thiazole en tant qu'inhibiteurs d'histone désacétylase (hdac)
US7265116B2 (en) 1999-11-03 2007-09-04 Arm Technology, Inc. Aryl and heteroaryl substituted tetrahydroisoquinolines and use thereof
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques
WO2008120653A1 (fr) 2007-04-02 2008-10-09 Banyu Pharmaceutical Co., Ltd. Dérivé d'indoledione
WO2009002495A1 (fr) 2007-06-27 2008-12-31 Merck & Co., Inc. Dérivés de 4-carboxybenzylamino utilisés en tant qu'inhibiteurs de l'histone désacétylase
US7541357B2 (en) 2004-07-15 2009-06-02 Amr Technology, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
WO2008147864A3 (fr) * 2007-05-22 2009-07-09 Xenon Pharmaceuticals Inc Procédés d'utilisaton de composés pipérazine dans le traitement de maladies ou états médiés par le canal sodium
WO2009111354A2 (fr) 2008-03-03 2009-09-11 Tiger Pharmatech Inhibiteurs de la tyrosine kinase
WO2010114780A1 (fr) 2009-04-01 2010-10-07 Merck Sharp & Dohme Corp. Inhibiteurs de l'activité akt
WO2010132442A1 (fr) 2009-05-12 2010-11-18 Albany Molecular Reserch, Inc. 7-([1,2, 4,]triazolo[1,5,-a]pyridine-6-yl)-4-(3,4-dichlorophényl)-1,2,3,4- tétrahydroisoquinoline et son utilisation
WO2010132487A1 (fr) 2009-05-12 2010-11-18 Bristol-Myers Squibb Company Formes cristallines de (s)-7-([1,2,4]triazolo[1,5-a] pyridin -6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline et leurs utilisations
WO2011046771A1 (fr) 2009-10-14 2011-04-21 Schering Corporation Pipéridines substituées qui accroissent l'activité de p53, et utilisations de ces composés
EP2336120A1 (fr) 2007-01-10 2011-06-22 Istituto di ricerche di Biologia Molecolare P. Angeletti S.R.L. Combinaisons contenant indazoles à substitution amide utilisés comme inhibiteurs de la poly(ADP-ribose)polymérase (PARP)
WO2011163330A1 (fr) 2010-06-24 2011-12-29 Merck Sharp & Dohme Corp. Nouveaux composés hétérocycliques utilisés comme inhibiteurs de erk
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WO2012027236A1 (fr) 2010-08-23 2012-03-01 Schering Corporation Nouveaux dérivés de pyrazolo[1,5-a]pyrimidine utilisés comme inhibiteurs de mtor
WO2012030685A2 (fr) 2010-09-01 2012-03-08 Schering Corporation Dérivés d'indazole utilisables en tant qu'inhibiteurs de la voie erk
WO2012036997A1 (fr) 2010-09-16 2012-03-22 Schering Corporation Dérivés condensés de pyrazole utilisés comme nouveaux inhibiteurs erk
WO2012087772A1 (fr) 2010-12-21 2012-06-28 Schering Corporation Dérivés d'indazole utiles en tant qu'inhibiteurs de erk
WO2012145471A1 (fr) 2011-04-21 2012-10-26 Merck Sharp & Dohme Corp. Inhibiteurs du récepteur du facteur de croissance 1 analogue à l'insuline
WO2013063214A1 (fr) 2011-10-27 2013-05-02 Merck Sharp & Dohme Corp. Nouveaux composés qui sont des inhibiteurs d'erk
WO2013165816A2 (fr) 2012-05-02 2013-11-07 Merck Sharp & Dohme Corp. Compositions de petit acide nucléique interférent (sina)
EP2698157A1 (fr) 2006-09-22 2014-02-19 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de synthèse d'acide gras
WO2014052563A2 (fr) 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Nouveaux composés inhibiteurs de erk
WO2014085216A1 (fr) 2012-11-28 2014-06-05 Merck Sharp & Dohme Corp. Compositions et procédés pour traiter le cancer
WO2014100065A1 (fr) 2012-12-20 2014-06-26 Merck Sharp & Dohme Corp. Imidazopyridines substituées en tant qu'inhibiteurs de hdm2
WO2014120748A1 (fr) 2013-01-30 2014-08-07 Merck Sharp & Dohme Corp. Purines 2,6,7,8-substituées utilisées en tant qu'inhibiteurs de hdm2
WO2015034925A1 (fr) 2013-09-03 2015-03-12 Moderna Therapeutics, Inc. Polynucléotides circulaires
US9034899B2 (en) 2009-05-12 2015-05-19 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
US9156812B2 (en) 2008-06-04 2015-10-13 Bristol-Myers Squibb Company Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
WO2018071283A1 (fr) 2016-10-12 2018-04-19 Merck Sharp & Dohme Corp. Inhibiteurs de kdm5
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US11096950B2 (en) 2006-11-01 2021-08-24 Barbara Brooke Jennings Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development
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Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10036818A1 (de) * 2000-07-28 2002-02-07 Solvay Pharm Gmbh Neue N-Triazolylmethyl-Piperazinderivate als Neurokininrezeptor-Antagonisten
RU2396270C2 (ru) * 2005-01-07 2010-08-10 Ф.Хоффманн-Ля Рош Аг Производные [4-(гетероарил)пиперазин-1-ил]-(2,5-замещенный фенил)метанона в качестве ингибиторов переносчика глицина-1 (glyt-1) для лечения неврологических и психоневрологических заболеваний

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0411150A1 (fr) * 1989-02-10 1991-02-06 Otsuka Pharmaceutical Co., Ltd. Derives d'indole, leur preparation et medicament les contenant destine a la prevention et au traitement de la nephrite
EP0655442A1 (fr) * 1993-11-29 1995-05-31 Fujisawa Pharmaceutical Co., Ltd. Dérivés de pipérazine en tant qu'antagonistes de Tachykinine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0411150A1 (fr) * 1989-02-10 1991-02-06 Otsuka Pharmaceutical Co., Ltd. Derives d'indole, leur preparation et medicament les contenant destine a la prevention et au traitement de la nephrite
EP0655442A1 (fr) * 1993-11-29 1995-05-31 Fujisawa Pharmaceutical Co., Ltd. Dérivés de pipérazine en tant qu'antagonistes de Tachykinine

Cited By (73)

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EP0773026A3 (fr) * 1995-11-06 1999-11-17 Pfizer Inc. Antagonistes des récepteurs NK-1 pour traiter le cancer
WO1997022597A1 (fr) * 1995-12-18 1997-06-26 Fujisawa Pharmaceutical Co., Ltd. Derives de la piperazine antagonistes de la tachykinine
US6924278B2 (en) 1997-06-17 2005-08-02 Fujisawa Pharmaceutical Co., Ltd. Aroyl-piperazine derivatives, their preparation and their use as tachykinin antagonists
WO1998057954A1 (fr) * 1997-06-17 1998-12-23 Fujisawa Pharmaceutical Co., Ltd. Derives d'aroyle-piperazine, leur preparation et leur utilisation en tant qu'antagonistes de tachykinine
RU2198883C2 (ru) * 1997-08-27 2003-02-20 Солвей Фармасьютикалс Гмбх Производные мочевины, способ их получения (варианты) и лекарственное средство
CN1108290C (zh) * 1997-08-27 2003-05-14 索尔瓦药物有限公司 新的尿素衍生物
US6001833A (en) * 1997-08-27 1999-12-14 Solvay Pharmaceuticals Gmbh Urea derivatives
EP0899270A1 (fr) * 1997-08-27 1999-03-03 Solvay Pharmaceuticals GmbH Indolylmethyl-N,N'-bisacylpipérazines comme antagonistes des récepteurs de neurokinine
US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
US7612090B2 (en) 1999-11-03 2009-11-03 Albany Molecular Research, Inc. Aryl and heteroaryl substituted tetrahydroisoquinolines and use thereof
US7163949B1 (en) 1999-11-03 2007-01-16 Amr Technology, Inc. 4-phenyl substituted tetrahydroisoquinolines and use thereof
US7265116B2 (en) 1999-11-03 2007-09-04 Arm Technology, Inc. Aryl and heteroaryl substituted tetrahydroisoquinolines and use thereof
US7419985B2 (en) 2000-07-11 2008-09-02 Amr Technology, Inc. 4-Phenyl substituted tetrahydroisoquinolines and therapeutic use thereof
US7084152B2 (en) 2000-07-11 2006-08-01 Amr Technology, Inc. 4-phenyl substituted tetrahydroisoquinolines therapeutic use thereof
US7309789B2 (en) 2000-07-11 2007-12-18 Amr Technology, Inc. 4-phenyl substituted tetrahydroisoquinolines and therapeutic use thereof
US7094779B2 (en) 2001-07-09 2006-08-22 Solvay Pharmaceuticals B.V. Piperazine oxime dervatives having NK-1 receptor antagonistic activity
AU2002333229B2 (en) * 2001-07-09 2006-11-30 Solvay Pharmaceuticals B.V. Piperazine oxime derivatives having NK-1 receptor antagonistic activity
WO2003006459A1 (fr) * 2001-07-09 2003-01-23 Solvay Pharmaceuticals B.V. Derives oximes de piperazine presentant une activite antagoniste du recepteur de nk-1
US7202238B2 (en) 2002-04-04 2007-04-10 Solvay Pharmaceuticals B.V. Diazabicyclo alkane derivatives with NK1 antagonistic activity
WO2003084955A1 (fr) 2002-04-04 2003-10-16 Solvay Pharmaceuticals B.V. Derives de diazabicyclo-alcane uniques presentant une activite antagoniste contre nk1
US9085531B2 (en) 2004-07-15 2015-07-21 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US7541357B2 (en) 2004-07-15 2009-06-02 Amr Technology, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
US9499531B2 (en) 2004-07-15 2016-11-22 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
WO2006123182A2 (fr) 2005-05-17 2006-11-23 Merck Sharp & Dohme Limited Sulfones de cyclohexyle pour le traitement du cancer
WO2007011820A2 (fr) 2005-07-15 2007-01-25 Amr Technology, Inc. Tetrahydrobenzazepines substituees par aryle et heteroaryle, et leur utilisation pour bloquer la reabsorption de la noradrenaline, de la dopamine, et de la serotonine
US9403776B2 (en) 2005-07-15 2016-08-02 Albany Molecular Research, Inc. Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin
WO2007041052A2 (fr) 2005-09-29 2007-04-12 Merck & Co., Inc. Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4
WO2007093827A1 (fr) 2006-02-15 2007-08-23 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Dérivés de trifluoroéthanone substitués par thiophène et thiazole en tant qu'inhibiteurs d'histone désacétylase (hdac)
EP2946778A1 (fr) 2006-09-22 2015-11-25 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de la synthèse d'acides gras
EP2698157A1 (fr) 2006-09-22 2014-02-19 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de synthèse d'acide gras
US11096950B2 (en) 2006-11-01 2021-08-24 Barbara Brooke Jennings Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development
EP2336120A1 (fr) 2007-01-10 2011-06-22 Istituto di ricerche di Biologia Molecolare P. Angeletti S.R.L. Combinaisons contenant indazoles à substitution amide utilisés comme inhibiteurs de la poly(ADP-ribose)polymérase (PARP)
EP2805945A1 (fr) 2007-01-10 2014-11-26 MSD Italia S.r.l. Indazoles substitués d'amide en tant qu'inhibiteurs PARP de poly(ADP-ribose)polymérase
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques
WO2008120653A1 (fr) 2007-04-02 2008-10-09 Banyu Pharmaceutical Co., Ltd. Dérivé d'indoledione
WO2008147864A3 (fr) * 2007-05-22 2009-07-09 Xenon Pharmaceuticals Inc Procédés d'utilisaton de composés pipérazine dans le traitement de maladies ou états médiés par le canal sodium
WO2009002495A1 (fr) 2007-06-27 2008-12-31 Merck & Co., Inc. Dérivés de 4-carboxybenzylamino utilisés en tant qu'inhibiteurs de l'histone désacétylase
EP3103791A1 (fr) 2007-06-27 2016-12-14 Merck Sharp & Dohme Corp. Dérivés de4-carboxybenzylamino utilisés comme inhibiteurs de l'histone désacétylase
WO2009111354A2 (fr) 2008-03-03 2009-09-11 Tiger Pharmatech Inhibiteurs de la tyrosine kinase
US9156812B2 (en) 2008-06-04 2015-10-13 Bristol-Myers Squibb Company Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
US9498476B2 (en) 2008-06-04 2016-11-22 Albany Molecular Research, Inc. Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine
WO2010114780A1 (fr) 2009-04-01 2010-10-07 Merck Sharp & Dohme Corp. Inhibiteurs de l'activité akt
US9604960B2 (en) 2009-05-12 2017-03-28 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
WO2010132442A1 (fr) 2009-05-12 2010-11-18 Albany Molecular Reserch, Inc. 7-([1,2, 4,]triazolo[1,5,-a]pyridine-6-yl)-4-(3,4-dichlorophényl)-1,2,3,4- tétrahydroisoquinoline et son utilisation
WO2010132487A1 (fr) 2009-05-12 2010-11-18 Bristol-Myers Squibb Company Formes cristallines de (s)-7-([1,2,4]triazolo[1,5-a] pyridin -6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline et leurs utilisations
US9173879B2 (en) 2009-05-12 2015-11-03 Bristol-Myers Squibb Company Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a ]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof
US9034899B2 (en) 2009-05-12 2015-05-19 Albany Molecular Research, Inc. Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof
WO2011046771A1 (fr) 2009-10-14 2011-04-21 Schering Corporation Pipéridines substituées qui accroissent l'activité de p53, et utilisations de ces composés
WO2011163330A1 (fr) 2010-06-24 2011-12-29 Merck Sharp & Dohme Corp. Nouveaux composés hétérocycliques utilisés comme inhibiteurs de erk
WO2012018754A2 (fr) 2010-08-02 2012-02-09 Merck Sharp & Dohme Corp. Inhibition à médiation par interférence arn de caténine (protéine associée à cadhérine), expression du gène bêta 1 (ctnnb1) à l'aide de petit acide nucléique interférent (sian)
EP3330377A1 (fr) 2010-08-02 2018-06-06 Sirna Therapeutics, Inc. Inhibition à médiation par interférence arn de caténine (protéine associée à cadhérine), expression du gène bêta 1 (ctnnb1) à l'aide de petit acide nucléique interférent (sian)
EP4079856A1 (fr) 2010-08-17 2022-10-26 Sirna Therapeutics, Inc. Inhibition médiée par des arn interférents de l'expression génique du virus de l'hépatite b (vhb) à l'aide de petits acides nucléiques interférents (pani)
WO2012027236A1 (fr) 2010-08-23 2012-03-01 Schering Corporation Nouveaux dérivés de pyrazolo[1,5-a]pyrimidine utilisés comme inhibiteurs de mtor
WO2012030685A2 (fr) 2010-09-01 2012-03-08 Schering Corporation Dérivés d'indazole utilisables en tant qu'inhibiteurs de la voie erk
WO2012036997A1 (fr) 2010-09-16 2012-03-22 Schering Corporation Dérivés condensés de pyrazole utilisés comme nouveaux inhibiteurs erk
EP3766975A1 (fr) 2010-10-29 2021-01-20 Sirna Therapeutics, Inc. Inhibition au moyen d'interférence arn d'une expression de gène utilisant des acides nucléiques à petit interférent (sina)
EP3327125A1 (fr) 2010-10-29 2018-05-30 Sirna Therapeutics, Inc. Inhibition au moyen d'interférence arn d'une expression de gène utilisant des acides nucléiques à petit interférent (sina)
WO2012087772A1 (fr) 2010-12-21 2012-06-28 Schering Corporation Dérivés d'indazole utiles en tant qu'inhibiteurs de erk
WO2012145471A1 (fr) 2011-04-21 2012-10-26 Merck Sharp & Dohme Corp. Inhibiteurs du récepteur du facteur de croissance 1 analogue à l'insuline
WO2013063214A1 (fr) 2011-10-27 2013-05-02 Merck Sharp & Dohme Corp. Nouveaux composés qui sont des inhibiteurs d'erk
WO2013165816A2 (fr) 2012-05-02 2013-11-07 Merck Sharp & Dohme Corp. Compositions de petit acide nucléique interférent (sina)
EP3919620A1 (fr) 2012-05-02 2021-12-08 Sirna Therapeutics, Inc. Compositions d'acide nucléique interférent court (sina)
WO2014052563A2 (fr) 2012-09-28 2014-04-03 Merck Sharp & Dohme Corp. Nouveaux composés inhibiteurs de erk
WO2014085216A1 (fr) 2012-11-28 2014-06-05 Merck Sharp & Dohme Corp. Compositions et procédés pour traiter le cancer
WO2014100065A1 (fr) 2012-12-20 2014-06-26 Merck Sharp & Dohme Corp. Imidazopyridines substituées en tant qu'inhibiteurs de hdm2
WO2014120748A1 (fr) 2013-01-30 2014-08-07 Merck Sharp & Dohme Corp. Purines 2,6,7,8-substituées utilisées en tant qu'inhibiteurs de hdm2
WO2015034925A1 (fr) 2013-09-03 2015-03-12 Moderna Therapeutics, Inc. Polynucléotides circulaires
WO2018071283A1 (fr) 2016-10-12 2018-04-19 Merck Sharp & Dohme Corp. Inhibiteurs de kdm5
WO2019094312A1 (fr) 2017-11-08 2019-05-16 Merck Sharp & Dohme Corp. Inhibiteurs de prmt5
WO2019094311A1 (fr) 2017-11-08 2019-05-16 Merck Sharp & Dohme Corp. Inhibiteurs de prmt5
WO2020033288A1 (fr) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Inhibiteurs de prmt5
WO2020033282A1 (fr) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Inhibiteurs de prmt5
WO2020033284A1 (fr) 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Inhibiteurs de prmt5

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TW391960B (en) 2000-06-01
JP3071829B2 (ja) 2000-07-31
AU5703196A (en) 1996-12-11
CN1191533A (zh) 1998-08-26
AU706021B2 (en) 1999-06-03
JPH11505830A (ja) 1999-05-25
NZ307625A (en) 1999-02-25
HUP9900822A3 (en) 1999-11-29
TR199600438A2 (tr) 1996-12-21
EP0846116A1 (fr) 1998-06-10
EA000669B1 (ru) 2000-02-28
IL118369A0 (en) 1996-09-12
HUP9900822A2 (hu) 1999-06-28
ZA964101B (en) 1996-07-29
CA2222041A1 (fr) 1996-11-28
KR19990021857A (ko) 1999-03-25
IL118369A (en) 2000-06-01
EA199700425A1 (ru) 1998-12-24

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