WO2003095435A1 - Derives d'amides - Google Patents

Derives d'amides Download PDF

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Publication number
WO2003095435A1
WO2003095435A1 PCT/JP2003/005756 JP0305756W WO03095435A1 WO 2003095435 A1 WO2003095435 A1 WO 2003095435A1 JP 0305756 W JP0305756 W JP 0305756W WO 03095435 A1 WO03095435 A1 WO 03095435A1
Authority
WO
WIPO (PCT)
Prior art keywords
salt
phenyl
methyl
compound
aminothiazol
Prior art date
Application number
PCT/JP2003/005756
Other languages
English (en)
Japanese (ja)
Inventor
Toru Kontani
Junji Miyata
Wataru Hamaguchi
Yoji Miyazaki
Osamu Yamamoto
Hiroshi Suzuki
Kenji Sudo
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
Rational Drug Design Laboratories
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 Yamanouchi Pharmaceutical Co., Ltd., Rational Drug Design Laboratories filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Priority to AU2003235889A priority Critical patent/AU2003235889A1/en
Publication of WO2003095435A1 publication Critical patent/WO2003095435A1/fr

Links

Classifications

    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
    • 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

  • R is hydrogen, lower alkyl, amino, lower alkylamino, etc.
  • R 2 is hydrogen or lower alkyl
  • Q is absent or methylene
  • R 3 is hydrogen, lower alkyl, etc.
  • R 4 is unsubstituted or substituted.
  • the novel compound combining the specific substituents shown in the table below shows good antiviral activity even at low dose oral administration, and The present invention has been completed by finding that it can be a useful drug.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or a salt thereof and a pharmaceutically acceptable carrier, and an anti-herpesvirus agent, particularly an anti-VZV agent.
  • an anti-herpesvirus agent particularly an anti-VZV agent.
  • the compound of the present invention includes compounds having isomers, and the present invention includes a mixture of these isomers and an isolated isomer.
  • the present invention further includes various hydrates, solvates and polymorphs of the compound of the present invention or a salt thereof.
  • the compounds of the present invention also include all compounds that are metabolized in vivo and converted to the compounds of the present invention or salts thereof, so-called prodrugs.
  • the group forming the prodrug of the present invention is described in Prog. Med. 5: 2157-2161 (1985). Groups that have been used.
  • the acid is reacted with a condensing agent (such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), 1,1'-l-pyrrolbis-1H-imidazole (CDI), etc.)
  • a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), 1,1'-l-pyrrolbis-1H-imidazole (CDI), etc.
  • WSC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • CDI 1,1'-l-pyrrolbis-1H-imidazole
  • HOBt 1-hydroxybenzotriazole
  • the reaction temperature can be appropriately selected depending on the starting compound.
  • Active solvents for example, aromatic hydrocarbon solvents such as benzene and toluene, ether solvents such as tetrahydrofuran (THF) and 1,4-dioxane, halogenated hydrocarbon solvents such as dichloromethane and chloroform, N, N Examples include amide solvents such as N-dimethylformamide (DMF) and N, N-dimethylacetamide, and basic solvents such as pyridine, etc.
  • the solvent is appropriately selected according to the type of the starting compound, etc., and may be used alone or in combination of two These are used as a mixture. Second manufacturing method
  • an alkyl ester such as ethyl ester is treated with a base such as aqueous sodium hydroxide, and an aralkyl ester such as benzyl ester is treated with palladium monocarbon (Pd-C) under a hydrogen atmosphere. It can be done by reducing with.
  • the reaction can be performed according to the method described in the above-mentioned Protective Groups in Organic Synthesis, 3rd edition.
  • the compound of the present invention thus produced can be isolated or purified as it is or by subjecting it to a salt-forming treatment by a conventional method. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various types of chromatography.
  • the various isomers can be isolated by a conventional method utilizing the difference in the physicochemical properties between the isomers, and can be separated by, for example, fractional crystallization or chromatography. Further, by using an appropriate starting compound, only one isomer can be produced. Industrial applicability
  • the one or more active substances include at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, It is mixed with magnesium metasilicate and aluminate.
  • the composition may contain an inert additive such as a lubricant such as magnesium stearate or a disintegrating agent such as carboxymethyl starch sodium. And a solubilizing agent. If necessary, tablets or pills may be coated with sugar coating or gastric or enteric coating agent.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert solvents such as purified water, ethanol and the like. including.
  • the composition may contain, in addition to the inert solvent, auxiliaries such as solubilizing agents, wetting agents, and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.
  • Reference Example 1 Potassium carbonate and ethyl bromoacetate were added to a DMF solution of aniline, and the mixture was heated and stirred. After water and ethyl acetate were added to the reaction mixture, the organic layer was separated, washed and dried, and the solvent was distilled off under reduced pressure to obtain a crude product. This was dissolved in chloroform and TEA, 4-fluorobenzoyl chloride and dimethylaminopyridine (DMAP) were added and stirred. 1 M hydrochloric acid was added to the reaction solution, the organic layer was separated, washed and dried, and the solvent was distilled off under reduced pressure.
  • DMAP dimethylaminopyridine

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux dérivés d'amides caractérisés en ce que dans un dérivé de N-({[4-(thiozolyl-4-l substitué) phényl]carbamoyl}méthyl)amide, l'atome N du groupe amide est directement substitué par un groupe noyau aromatique (un groupe aryle ou hétéroaryle). Ayant une excellente activité anti-virus herpétique, ces dérivés d'amide sont utiles comme médicaments et agents antiviraux, notamment pour prévenir ou remédier aux différentes maladies telles que l'infection due à des virus appartenant à l'herpes-virus, notamment, les infections au virus herpétique telles que la varicelle de l'infection au virus varicelle-zona, zona de l'infection récurrente par le virus varicelle-zona, l'herpès de la lèvre et l'encéphalite herpétique de l'infection HSV-1 et l'herpès génital de l'infection HSV-2.
PCT/JP2003/005756 2002-05-09 2003-05-08 Derives d'amides WO2003095435A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003235889A AU2003235889A1 (en) 2002-05-09 2003-05-08 Amide derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2002-133416 2002-05-09
JP2002133416 2002-05-09

Publications (1)

Publication Number Publication Date
WO2003095435A1 true WO2003095435A1 (fr) 2003-11-20

Family

ID=29416669

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2003/005756 WO2003095435A1 (fr) 2002-05-09 2003-05-08 Derives d'amides

Country Status (2)

Country Link
AU (1) AU2003235889A1 (fr)
WO (1) WO2003095435A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6903125B2 (en) 2003-08-08 2005-06-07 Yamanouchi Pharmaceutical Co., Ltd. Tetrahydro-2H-thiopyran-4-carboxamide derivative
WO2006082822A1 (fr) * 2005-02-02 2006-08-10 Astellas Pharma Inc. Agent destine a la prevention/au traitement d'une maladie causee par un virus de l'herpes acyclovir-resistant
WO2006082821A1 (fr) * 2005-02-02 2006-08-10 Astellas Pharma Inc. Agent preventif ou therapeutique contre une maladie liee au virus de l'herpes
WO2006082820A1 (fr) * 2005-02-02 2006-08-10 Astellas Pharma Inc. Agent thérapeutique pour le traitement de l'herpès génital
JP2006241144A (ja) * 2005-02-03 2006-09-14 Astellas Pharma Inc テトラヒドロ−２ｈ−チオピラン−４−カルボキサミド誘導体を含有する医薬組成物
WO2010047295A1 (fr) 2008-10-20 2010-04-29 アステラス製薬株式会社 Médicament destiné à la prévention ou au traitement de la douleur associée à un zona

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997024343A1 (fr) * 1995-12-29 1997-07-10 Boehringer Ingelheim Pharmaceuticals, Inc. Derives de phenylthiazole dotes de proprietes anti virus de l'herpes
WO1999042455A1 (fr) * 1998-02-19 1999-08-26 Tularik Inc. Agents antiviraux
WO2000029399A1 (fr) * 1998-11-12 2000-05-25 Boehringer Ingelheim (Canada) Ltd. Composes antiherpes
WO2002038554A1 (fr) * 2000-11-10 2002-05-16 Yamanouchi Pharmaceutical Co., Ltd. Derives amides

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997024343A1 (fr) * 1995-12-29 1997-07-10 Boehringer Ingelheim Pharmaceuticals, Inc. Derives de phenylthiazole dotes de proprietes anti virus de l'herpes
WO1999042455A1 (fr) * 1998-02-19 1999-08-26 Tularik Inc. Agents antiviraux
WO2000029399A1 (fr) * 1998-11-12 2000-05-25 Boehringer Ingelheim (Canada) Ltd. Composes antiherpes
WO2002038554A1 (fr) * 2000-11-10 2002-05-16 Yamanouchi Pharmaceutical Co., Ltd. Derives amides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CRUTE J.J.: "Herpes simplex virus helicase-primase inhibitors are active in animal models of human disease", NAT. MED., vol. 8, no. 4, 2002, pages 386 - 391, XP002969973 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6903125B2 (en) 2003-08-08 2005-06-07 Yamanouchi Pharmaceutical Co., Ltd. Tetrahydro-2H-thiopyran-4-carboxamide derivative
US7465748B2 (en) 2003-08-08 2008-12-16 Astellas Pharma Inc. Amide derivative
WO2006082822A1 (fr) * 2005-02-02 2006-08-10 Astellas Pharma Inc. Agent destine a la prevention/au traitement d'une maladie causee par un virus de l'herpes acyclovir-resistant
WO2006082821A1 (fr) * 2005-02-02 2006-08-10 Astellas Pharma Inc. Agent preventif ou therapeutique contre une maladie liee au virus de l'herpes
WO2006082820A1 (fr) * 2005-02-02 2006-08-10 Astellas Pharma Inc. Agent thérapeutique pour le traitement de l'herpès génital
JP2006241144A (ja) * 2005-02-03 2006-09-14 Astellas Pharma Inc テトラヒドロ−２ｈ−チオピラン−４−カルボキサミド誘導体を含有する医薬組成物
WO2010047295A1 (fr) 2008-10-20 2010-04-29 アステラス製薬株式会社 Médicament destiné à la prévention ou au traitement de la douleur associée à un zona

Also Published As

Publication number Publication date
AU2003235889A8 (en) 2003-11-11
AU2003235889A1 (en) 2003-11-11

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