WO1992002513A1 - Composes heterocycliques - Google Patents

Composes heterocycliques Download PDF

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Publication number
WO1992002513A1
WO1992002513A1 PCT/JP1991/001042 JP9101042W WO9202513A1 WO 1992002513 A1 WO1992002513 A1 WO 1992002513A1 JP 9101042 W JP9101042 W JP 9101042W WO 9202513 A1 WO9202513 A1 WO 9202513A1
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WIPO (PCT)
Prior art keywords
alkyl
compound
group
formula
salt
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PCT/JP1991/001042
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English (en)
Inventor
Hisashi Takasugi
Hiroyoshi Sakai
Akito Tanaka
Takatoshi Ishikawa
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Fujisawa Pharmaceutical Co., Ltd.
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Priority claimed from GB909017183A external-priority patent/GB9017183D0/en
Priority claimed from GB909020345A external-priority patent/GB9020345D0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Publication of WO1992002513A1 publication Critical patent/WO1992002513A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A61P9/08—Vasodilators for multiple indications
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/48—Aldehydo radicals
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having 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
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having 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
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/12—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 chain containing hetero atoms as chain links

Definitions

  • This invention relates to new heterocyclic compounds and pharmaceutically acceptable salts thereof which are useful as a medicament.
  • This invention relates to new heterocyclic compounds. More particularly, this invention relates to new
  • heterocyclic compounds and pharmaceutically acceptable salts thereof which have pharmacological activities, processes for preparation thereof, a pharmaceutical composition comprising the same and a use of the same.
  • one object of this invention is to provide the new and useful heterocyclic compounds and pharmaceutically acceptable salts thereof which possess antithrombotic , vasodilating, and anti-inflammatory activities.
  • Another object of this invention is to provide processes for preparation of the heterocyclic compounds and salts thereof.
  • a further object of this invention is to provide a pharmaceutical composition comprising said heterocyclic compounds or a pharmaceutically acceptable salt thereof.
  • Still further object of this invention is to provide a use of said heterocyclic compound or a pharmaceutically acceptable salt thereof as a medicament for prophylactic and therapeutic treatment of thrombosis, hypertension, cardiovascular or cerebrovascular diseases and
  • the object heterocyclic compounds of the present invention are novel and can be represented by the
  • R 1 and R 2 are each lower alkoxy
  • R 3 is heterocyclic group selected from the group consisting of pyridyl, tetrahydropyridyl, piperidyl, piperazinyl and morpholinyl, which may have suitable substituent(s);
  • heterocyclic group which may have suitable substituent(s)); or a group of the formula :
  • R 5 is lower alkyl
  • X 1 is an acid residue
  • Y is CH or N
  • z is CH or N
  • R 3 is pyridyl; piperidyl which may have hydroxy
  • piperazinyl which has lower alkyl group or hydroxy(lower)alkyl group; morpholinyl; lower alkenylamino; hydroxy(lower)alkylamino; phenylamino which may have lower alkoxy group or halogen on the benzene ring;
  • halophenyl(lower)alkylamino phenylsulfonylamino which has nitro group, amino group or halogen on th benzene ring; or
  • the object compound (I) of the present invention can be prepared by the following processes.
  • R 1 , R 2 , R 3 , R 5 , Y, Z and X 1 are each as defined above, is mono(or di) lower alkylamino.
  • R a 3 is protected amino( lower)alkyl
  • R a 3 is amino( lower)alkyl
  • R c 3 is acylamino( lower)alkyl
  • R d 3 is carboxy or protected carboxy
  • R 6 and R 7 are each lower alkyl
  • R 8 and R 9 are each hydrogen, lower alkyl
  • heterocyclic group which may have suitable substituent ( s ) , or
  • R 8 and R 9 are linked together with the attached nitrogen atom to form heterocyclic group which may have suitable substituent(s), X 2 is a leaving group,
  • R 10 is hydrogen or lower alkyl
  • R 11 is lower alkyl or 1-amino-1-iminomethyl, or
  • R 10 and R 11 are linked together with the attached nitrogen atom to form heterocyclic group which may have suitable substituent(s), R 12 and R 13 are each lower alkyl,
  • R 3 is carboxy( lower)alken
  • R 3 g is heterocyclic group selected from the group consisting of pyridyl, tetrahydropyridyl, piperidyl, piperazinyl and morpholinyl, which may have suitable substituent(s); substituted amino; carboxy(lowerlalkenyl; carboxy(lower) alkyl; hydroxy(lower)alkyl; amino( lower)alkyl which may have suitable substituent(s);
  • R 4 is hydrogen, ethoxy, mono(or di) lower alkylamino
  • heterocyclic group which may have suitable substituent(s); or a group of the formula :
  • R 5 is lower alkyl
  • Y 1 is CH or N
  • Z 1 is CH or N.
  • the starting compound (III) or a salt thereof can be prepared by the following Processes.
  • R 3 is as defined above.
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include 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' -dibenzylethylenediamme salt, etc.), an organic acid salt (e.g.
  • 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' -d
  • acetate maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, etc.
  • an inorganic acid salt e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.
  • a salt with an amino acid e.g.
  • Suitable "lower alkoxy” may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy,
  • Suitable "substituent” in the term “heterocyclic group selected from the group consisting of pyridyl, tetrahydropyridyl, piperidyl, piperazinyl and morpholinyl, which may have suitable substituent( s) " may include lower alkyl, ar( lower)alkyl which may have a suitable
  • halogen e.g. fluorine, chlorine, bromine or iodine
  • Carboxy( lower)alkenyl and “lower alkenylamino” may include straight or branched one having 2 to 6 carbon atom(s), such as vinyl, propenyl, butenyl, isobutenyl or the like, preferably one having 2 to 4 carbon atom(s).
  • Suitable "substituted amino” may include cyanoamino; imidazolinylamino; guanidino; di(lower)alkylguanidino;
  • ar( lower)alkylguanidino heterocyclicguanidino which may be substituted with suitable substituent(s) such as ar( lower)alkyl or the like;
  • substituent( s) such as lower alkoxy or the like, or the like; di( lower)alkylamino; and the like.
  • aromatic( lower)alkyl may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl or the like, preferably one having 1 to 4 carbon atom(s).
  • protected amino(lower)alkyl may include acylamino and the like.
  • Suitable "protected carboxy” may include esterified carboxy and the like.
  • ester moiety of an esterified carboxy may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.) which may have at least one suitable substituent(s), for
  • lower alkanoyloxy( lower)alkyl ester e.g.
  • pivaloyloxymethyl ester pivaloyloxymethyl ester, hexanoyloxymethyl ester, l(or 2)-acetoxyethyl ester, 1(or 2 or 3 )-acetoxypropyl ester, 1(or 2 or 3 or 4)-acetoxybutyl ester, l(or
  • alkoxycarbonyloxy( lower)alkyl ester e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl ester, etc.
  • lower alkenyl ester e.g. vinyl ester, allyl ester, etc.
  • lower alkynyl ester e.g. ethynyl ester, propynyl ester, etc.
  • ar( lower)alkyl ester which may have at least one suitable substituent( s) such as mono(or di or tri) -phenyl(lower)-alkyl ester which may have at least one suitable
  • substituent(s) e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl)methyl ester,
  • substituent(s) e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.
  • substituent(s) e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.
  • acylamino(lower)alkyl may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring which is referred to as heterocyclic acyl.
  • acyl may be illustrated as follows :- Carbamoyl
  • Alliphatic acyl such as lower or higher alkanoyl (e.g. formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.);
  • alkanoyl e.g. formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl
  • alkoxycarbonyl e.g. methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.
  • lower alkylcarbamoyl e.g. methylcarbamoyl
  • ethylcarbamoyl ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, etc.
  • lower or higher alkanesulfonyl e.g. methanesulfonyl, ethanesulfonyl, etc.
  • alkanesulfonyl e.g. methanesulfonyl, ethanesulfonyl, etc.
  • alkoxysulfonyl e.g. methoxysulfonyl, ethoxysulfonyl, etc.; or the like;
  • Aromatic acyl such as
  • aroyl e.g. benzoyl, toluoyl, naphthoyl, etc.
  • ar( lower)alkanoyl e.g. phenyl( lower) alkanoyl (e.g. phenylacetyl, phenylpropanoyl, phenylbutanoyl,
  • ar( lower)alkenoyl e.g. phenyl(lower)alkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.),
  • naphthyl( lower)alkenoyl e.g. naphthylpropenoyl
  • ar ( lower)alkoxycarbonyl e.g. phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.), etc.];
  • aryloxycarbonyl e.g. phenoxycarbonyl
  • aryloxy(lower)alkanoyl e.g. phenoxyacetyl
  • arylcarbamoyl e.g. phenylcarbamoyl, etc.
  • arylthiocarbamoyl e.g. phenylthiocarbamoyl, etc.
  • arylglyoxyloyl e.g. phenylglyoxyloyl, naphthylglyoxyloyl, etc.
  • arenesulfonyl e.g. benzenesulfonyl, p-toluenesulfonyl, etc.; or the like;
  • Heterocyclic acyl such as
  • heterocyclic (lower)alkanoyl e.g. thienylacetyl
  • heterocyclic(lower)alkenoyl e.g. heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl,
  • heterocyclicglyoxyloyl e.g. thiazolylglyoxyloyl
  • heterocycliccarbonyl in which suitable hetetocyclic moiety in the terms "hetetocycliccarbonyl", heterocyclic( lower)alkanoyl", heterocyclic( lower)alkenoyl and “heterocyclicglyoxyloyl” as mentioned above means, in more detail, saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like. And, especially preferable heterocyclic group may be heterocyclic group such as
  • 4-nitrogen atom(s) for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide,
  • tetrahydropyridazmyl e. g. 2 , 3 , 4 , 5-tetrahydropyridazinyl, etc .
  • triazolyl e.g. 4H-1,2,4-triazolyl
  • oxazolyl isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.;
  • thiazolyl isothiazolyl, thiadiazolyl (e.g.
  • 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.;
  • 6-membered) heteromonocyclic group containing an oxygen atom for example, furyl, etc.
  • acyl moiety as stated above may have one to ten, same or different, suitable substituent( s ) such as halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, nitro, oxo, lower alkyl (e.g. methyl, ethyl propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.) or the like.
  • suitable substituent( s ) such as halogen (e.g. fluorine, chlorine, bromine or iodine), hydroxy, nitro, oxo, lower alkyl (e.g. methyl, ethyl propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, etc.) or the like.
  • heterocyclic group which may have suitable
  • Suitable "substituent" in the term “heterocyclic group which may have suitable substituent(s)” may include lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl, etc.)
  • heterocyclic group in the definitions "R and R 9 are linked together with .the attached nitrogen atom to form heterocyclic group which may have suitable
  • substituent(s) "R 10 and R 11 are linked together with the attached nitrogen atom to form heterocyclic group which may have suitable substituent(s)" and "heterocyclic group containing at least one nitrogen atom which may have suitable substituent(s)” may include saturated 3 to
  • Suitable "substituent" in the term “hetero ⁇ yclicamino which may have suitable substituent(s)” may include ar( lower)alkyl, and the like.
  • substituent(s)" and “R 10 and R 11 are linked together with the attached nitrogen atom to form heterocyclic group which may have suitable substituent(s)" may include lower alkyl, ar( lower)alkyl, aryl having lower alkoxy, and the like.
  • heterocyclic group containing at least one nitrogen atom which may have suitable substituent(s) may include lower alkyl, ar( lower)alkyl, hydroxy(lower)alkyl, and the like.
  • Suitable "cyclo(lower)alkyl” and “cyclo(lower)alkyl moiety" in the term “cyclo( lower) alkylguanidino” may include 3 to 8-membered cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
  • cyclooctyl and the like, preferably one having 5 to 7 carbon atoms.
  • Suitable "substituent" in the term “amino(lower)alkyl which may have suitable substituent(s)” may include lower lkyl, acyl as exemplified above, and the like.
  • Suitable " acid residue” may include halogen as exemplified above.
  • Suitable “leaving group” may include an acid residue as exemplified above, and the like.
  • aromatic alkyl and “ar( lower)alkylguanidino” may include phenyl, naphthyl and the like.
  • Suitable "substituent" in the term "ar(lower)alkyl which may have suitable substituent(s)” may include halogen as exemplified above, and the like.
  • halophenyl(lower)alkylamino Suitable "halogen” and “halogen moiety” in the term “halophenyl(lower)alkylamino” is as exemplified above.
  • Preferred embodiments of the object compound (I) are as follows.
  • R 1 is lower alkoxy
  • R 2 is lower alkoxy
  • R 3 is heterocyclic group selected from the group
  • pyridyl consisting of pyridyl, tetrahydropyridyl, piperidyl, piperazinyl and morpholinyl, which may have one to three (more preferably one or two) suitable
  • substituent(s) [more preferably heterocyclic group selected from the group consisting of pyridyl, tetrahydropyridyl, piperidyl, piperazinyl and
  • morpholinyl which may have one or two substituent(s) selected from the group consisting of lower alkyl and ar( lower)alkyl which may have one or two halogen;
  • heterocyclic group selected from the group consisting of pyridyl, tetrahydropyridyl, piperidyl, piperazinyl and morpholinyl, which may have one or two substituent(s) selected from the group consisting of lower alkyl, phenyl ⁇ lower)alkyl and halophenyl(lower)alkyl]; cyanoamino; imidazolinylamino; guanidino;
  • cyclo(lower)alkylguan "Ino; ar(lower)alkylguanidino [more preferably phenyl(lower)alkylguanidino];
  • heterocyclicguanidino which may be substituted with one to three (more preferably one) suitable
  • substituent( s) [more preferably heterocyclicguanidino which may have ar(lower) alkyl; most preferably phenyl(lower)alkylpiperidylguanidino];
  • (1-heterocyclic-1-iminomethyl)amino which may have substituent selected from the group consisting of lower alkyl, ar( lower)alkyl and aryl which may have lower alkoxy; most preferably
  • ⁇ piperazinyl(imino)methyl>amino which may have substituent selected from the group consisting of lower alkyl, phenyl( lower)alkyl and lower alkoxy phenyl]; di(lower)alkylamino; hydroxy(lower)alkyl; carboxy(lower)alkyl; carboxy( lower)alkenyl;
  • amino(lower) alkyl which may have one to three (more preferably one or two) substituent(s) selected from the group consisting of lower alkyl and acyl [more preferably amino(lower)alkyl which may have one or two substituent(s) selected from the group consisting of lower alkyl, lower alkanoyl, lower alkylcarbamoyl, lower alkoxycarbonyl and heterocycliccarbonyl which may have one to three suitable substituent(s); most preferably amino(lower)alkyl which may have one or two substituent(s) selected from the group consisting of lower alkyl, lower alkanoyl, lower alkylcarbamoyl. lower alkoxycarbonyl and tetrahydropyridazinyl- carbonyl which may have oxo group];
  • R 4 is hydrogen, ethoxy, mono(or di)lower alkylamino
  • di( lower)alkylamino-(lower) alkylamino, heterocyclicamino which. may have one to three (more preferably one or two) substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, halogen and ar(lower)alkyl
  • phenyl(lower)alkyl selected from the group consisting of lower alkyl, lower alkoxy halogen and phenyl(lower)alkyl; most preferably phenyl(lower) alkylpiperidylamino] or heterocyclic group which may have one to three (more preferably one or two) substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, halogen, ar( lower)alkyl and hydroxy(lower)alkyl [more preferably saturated 5 or 6-membered heteromonocyclic group containing 1 to
  • substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, halogen, phenyl(lower)alkyl and hydroxy(lower)alkyl; most
  • morpholinyl or piperazinyl which may have lower alkyl
  • R 5 is lower alkyl, or ar(lower)alkyl
  • substituent(s) selected from the group consisting of halogen, lower alkyl and lower alkoxy; most preferably
  • X is an acid residue [more preferably halogen]
  • Y is CH or N and Z is CH or N
  • R 3 is pyridyl; piperidyl which may have hydroxy
  • piperazinyl which has lower alkyl group or hydroxy(lower)alkyl group; morpholinyl; lower alkenylamino; hydroxy( lower)alkylamino; phenylamino which may have lower alkoxy group or halogen on the benzene ring;
  • halophenyl(lower)alkylamino phenylsulfonylamino which has nitro group, amino group or halogen on the benzene ring; or amino substituted with two substituents selected from the group consisting of lower alkyl and hydroxy( lower) alkyl, and Y is N,
  • the compound (la) or a salt thereof can be prepared by reacting the compound (II) with the compound (III) or a salt thereof.
  • the reaction is usually carried out in a conventional solvent such as water, alcohols (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide,
  • a conventional solvent such as water, alcohols (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide,
  • hydrophilic solvents may be used in a mixture with water.
  • This reaction is preferably carried out in the presence of an inorganic or an organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), an organic acid (e.g. formic acid, acetic acid. trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), and the like.
  • an organic acid e.g. formic acid, acetic acid. trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • the reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal hydroxide, an alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal acetate, tri(lower)alkylamine, pyridine (e.g. pyridine, lutidine, picoline,
  • an inorganic or an organic base such as an alkali metal hydroxide, an alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal acetate, tri(lower)alkylamine, pyridine (e.g. pyridine, lutidine, picoline,
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • Suitable salts of the compounds (III) and (la) can be referred to the ones as exemplified for the compound (I ).
  • the compound (lb) or a salt thereof can be prepared by reacting a compound (IV) or its reactive derivative at the carboxy group or a salt thereof with a compound (V) or a salt thereof.
  • anhydrides active amides and esters.
  • Suitable examples are acid halides such as acid chloride and acid bromide, mixed acid anhydrides with various acids [e.g. substituted phosphoric acid such as dialkyl phosphoric acid, sulfuric acid, aliphatic carboxylie acid, aromatic carboxylic acid, etc.], symmetric acid anhydrides, active amides with various imidazoles, and esters such as lower alkyl ester [e.g. methyl ester, ethyl ester, etc.], cyanomethyl ester, methoxymethyl ester, p-nitrophenyl ester,
  • acid halides such as acid chloride and acid bromide
  • mixed acid anhydrides with various acids e.g. substituted phosphoric acid such as dialkyl phosphoric acid, sulfuric acid, aliphatic carboxylie acid, aromatic carboxylic acid, etc.
  • symmetric acid anhydrides active amides with various imidazoles
  • esters such as lower alkyl este
  • the reaction is usually carried out in a conventional solvent, such as methylene chloride, chloroform, alcohol [e.g. methanol, ethanol, etc.], benzene, toluene,
  • a conventional solvent such as methylene chloride, chloroform, alcohol [e.g. methanol, ethanol, etc.], benzene, toluene,
  • N,N-dimethylformamide or any other organic solvent which does not adversely affect the reaction In case that the compound (V) is 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 ambient temperature, or under heating.
  • This reaction can typically be conducted in the presence or absence of an accelerator such as base.
  • Suitable base may include a tertiary amine [e.g.
  • an alkali metal hydroxide e.g. sodium hydroxide, potassium hydroxide, etc.
  • an alkali metal carbonate e.g. sodium carbonate, potassium carbonate, etc.
  • alkali metal bicarbonate e.g. sodium bicarbonate, etc.
  • a salt of an organic acid e.g. sodium acetate, etc.
  • the base can be used as a solvent.
  • Suitable salts of the compounds (IV), (V) and (lb) can be referred to the ones as exemplified for the
  • the compound (Id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereof to elimination reaction of the ammo-protective group on R a 3 .
  • Suitable method of this reaction may include conventional one such as hydrolysis, reduction and the like.
  • the hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
  • Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. sodium, potassium, etc.], the hydroxide or carbonate or
  • trialkylamine e.g. trimethylamine, triethylamine, etc.
  • picoline 1,5-diazabicyclo[ 4.3.0]-non-5-ene
  • 1,4-diazabicyclo[2.2.2]octane 1,4-diazabicyclo[2.2.2]octane
  • Suitable acid may include an organic acid [e.g.
  • Lewis acid such as trihaloacetic acid [e.g. trichloroacetic acid, trifluoroacetic acid, etc.] or the like is preferably carried out in the presence of cation trapping agents [e.g. anisole, phenol, etc.].
  • cation trapping agents e.g. anisole, phenol, etc.
  • the reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
  • Suitable reducing agents to be used in chemical reduction are a combination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound (e.g. chromium chloride, chromium acetate, etc. ) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid. trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).
  • a metal e.g. tin, zinc, iron, etc.
  • metallic compound e.g. chromium chloride, chromium acetate, etc.
  • organic or inorganic acid e.g. formic acid, acetic acid, propionic acid. trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.
  • Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium palladium on barium sulfate, palladium on barium
  • platinum catalysts e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • palladium catalysts e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium palladium on barium sulfate, palladium on barium
  • nickel catalysts e.g. reduced nickel, nickel oxide, Raney nickel, etc.
  • cobalt catalysts e.g. reduced cobalt, Raney cobalt, etc.
  • iron catalysts e.g. reduced iron, Raney iron, etc.
  • copper catalysts e.g. reduced copper, Raney copper, Ullman copper, etc.
  • the reduction is usually carried out in a
  • N,N-dimethylformamide, tetrahydrofuran, or a mixture thereof are in liquid, they can also be used as a solvent.
  • reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
  • Suitable salts of the compounds (Ic) and (Id) can be referred to the ones as exemplified for the compound (I).
  • the compound (Ie) or a salt thereof can be prepared by subjecting the compound (Id) or its reactive derivative at the amino group or a salt thereof to acylation
  • Suitable acylating agent to be used in the present acylation reaction may include the compound of the
  • R 14 - OH ( XXII ) (wherein R 14 is acyl) or its reactive derivative or a salt thereof.
  • Suitable reactive derivative at the amino group of the compound (Id) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (Id) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (Id) with a silyl compound such as N,O-bis(trimethylsilyl)acetamide,
  • N-trimethylsilylacetamide or the like a derivative formed by the reaction of the compound (Id) with phosphorus trichloride or phosgene, and the like.
  • Suitable salts of the compound (Id) and (Ie) can be referred to the ones as exemplified for the compound (I) .
  • Suitable reactive derivative of the compound (XXII) may include an acid halide, an acid anhydride, an
  • the suitable example 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,
  • substituted phosphoric acid e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,
  • dibenzylphosphoric acid dibenzylphosphoric acid, halogenated phosphoric acid, etc.
  • dialkylphosphorous acid dialkylphosphorous acid
  • sulfurous acid dialkylphosphorous acid
  • methanesulfonic acid ethanesulfonic acid, etc.
  • sulfuric acid alkylcarbonic acid
  • aliphatic carboxylic acid e.g. pivalic acid, pentanoic acid, isopentanoic acid
  • aromatic carboxylic acid e.g. benzoic acid, etc.
  • aromatic carboxylic acid e.g. benzoic acid, etc.
  • a symmetrical acid anhydride an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole
  • an activated ester e.g.
  • N-hydroxy compound e.g. N,N-dimethylhydroxylamine, l-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide,
  • the reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride,
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;
  • N-cyclohexyl-N'-(4-diethylamino ⁇ yclohexyl)carbodiimide N,N' -diethylcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
  • triphenylphosphine 2-ethyl-7-hydroxybenzisoxasolium salt
  • 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) alkylmorphorine N,N-di(lower)alkylbenzylamine, or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the compound (If) or a salt thereof can be prepared by reacting the compound (XVIII) or a salt thereof with the compound (VI).
  • the reaction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide,
  • a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide,
  • hydrophilic solvents may be used in a mixture with water.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (Ih) or a salt thereof can be prepared by subjecting the compound (Ig) or a salt thereof to reduction.
  • Reduction is carried out in a conventional manner including chemical reduction and catalytic reduction.
  • Suitable reducing agents to be used in chemical reduction are hydrides (e.g. hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, etc.) or a combination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound (e.g. chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid,
  • hydrides e.g. hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, etc.
  • a metal e.g. tin, zinc, iron, etc.
  • metallic compound e.g. chromium chloride, chromium acetate, etc.
  • organic or inorganic acid e.g. formic acid, acetic acid, propionic acid
  • Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium
  • platinum catalysts e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • palladium catalysts e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium
  • nickel catalysts e.g. reduced nickel, nickel oxide, Raney nickel, etc.
  • cobalt catalysts e.g. reduced cobalt, Raney cobalt, etc.
  • iron catalysts e.g. reduced iron, Raney iron, etc.
  • copper catalysts e.g. reduced copper, Raney copper, Ullman copper, etc.
  • the reduction is usually carried out in a solvent such as water, alcohol (e.g. methanol, ethanol, etc.),
  • reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to heating.
  • Suitable salts of the compounds (Ig) and (Ih) can be referred to the ones as exemplified for the compound (I) .
  • the compound (Ij) or a salt thereof can be prepared by subjecting the compound (Ii) or a salt thereof to reduction as explained in Process ( 6).
  • the compound (Ik) or a salt thereof can be prepared by reacting the compound (XXI) or a salt thereof with the compound (VII).
  • the reaction is usually carried out in a conventional solvent such as water, alcohols (e.g., methanol, ethanol, isopropyl alcohcl, etc.), tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide, xylene, 2-methoxyethanol, N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, alcohols (e.g., methanol, ethanol, isopropyl alcohcl, etc.), tetrahydrofuran, dioxane, chloroform, methylene chloride, dimethyl acetamide, xylene, 2-methoxyethanol, N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • Suitable salts of the compounds (Ik) and (XXI) can be referred to the ones as exemplified for the compound ( I ).
  • the compound (IS,) or a salt thereof can be prepared by reacting the compound (VIII).or a salt thereof with the compound (IX) or a salt thereof.
  • This reaction is usually carried out in a conventional solvent as exemplified in Process (8).
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the reaction is usually carried out in the presence of an inorganic or an organic base such as an alkali metal hydroxide, an alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal acetate, tri(lower)alkylamine, alkali metal methoxide, pyridine (e.g. pyridine, lutidine, picoline, dimethylaminopyridine, etc.),
  • an inorganic or an organic base such as an alkali metal hydroxide, an alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal acetate, tri(lower)alkylamine, alkali metal methoxide, pyridine (e.g. pyridine, lutidine, picoline, dimethylaminopyridine, etc.),
  • the base and/or the starting compound are in liquid, they can be used also as a solvent.
  • Suitable salts of the compound (VIII) can be referred to the acid addition salts as exemplified for the compound (I).
  • the compound (In) or a salt thereof can be prepared by subjecting the compound (Im) or a salt thereof to reduction.
  • Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
  • Suitable reducing agents to be used in chemical reduction are hydrides (e.g. hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, etc.), or a combination of a metal (e.g. tin, zinc, iron, etc.) or metallic compound (e.g. chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g. formic acid, acetic acid, propionic acid,
  • hydrides e.g. hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, etc.
  • a metal e.g. tin, zinc, iron, etc.
  • metallic compound e.g. chromium chloride, chromium acetate, etc.
  • organic or inorganic acid e.g. formic acid, acetic acid, propionic acid
  • Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium palladium on barium sulfate, palladium on barium
  • platinum catalysts e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
  • palladium catalysts e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium palladium on barium sulfate, palladium on barium
  • nickel catalysts e.g. reduced nickel, nickel oxide, Raney nickel, etc.
  • cobalt catalysts e.g. reduced cobalt, Raney cobalt, etc.
  • iron catalysts e.g. reduced iron, Raney iron, etc.
  • copper catalysts e.g. reduced copper, Raney copper, Ullman copper, etc.
  • the reduction is usually carried out in a
  • N,N-dimethylformamide, tetrahydrofuran, or a mixture thereof are in liquid, they can also be used as a solvent.
  • reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (Io) or a salt thereof can be prepared by subjecting the compound (In) or a salt thereof to oxidation reaction.
  • Oxidation is carried out in a conventional manner, which is capable of oxidizing a hydroxymethyl group to a formyl group
  • suitable oxidizing reagent may be oxygen acid such as periodate (e.g. sodium periodate, etc.), peroxy acid such as peroxybenzoic acid (e.g. peroxybenzoic acid, m-chloroperoxybenzoic acid, etc.), magnese dioxide, and the like.
  • the reaction is usually carried out in a conventional solvent as exemplified in Process ( 8 ) , or any other organic solvent which does not adversely influence the reaction.
  • hydrophilic solvents may be used in a mixture with water.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • Suitable salts of the compounds (In) and (Io) can be referred to the acid addition salts as exemplified for the compound (I).
  • the compound (lp) or a salt thereof can be prepared by reacting the compound (Io) or a salt thereof with the compound (X) or a salt thereof.
  • the reaction is usually carried out in a conventional solvent as exemplified in Process ( 8 ), or any other organic solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the reaction is usually carried out in the presence of an inorganic or an organic base such as an alkali metal hydroxide, an alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal acetate, tri( lower)alkylamine, piperidine, piperazine, pyridine (e.g. pyridine, lutidine, picoline, dimethylaminopyridine, etc.),
  • an inorganic or an organic base such as an alkali metal hydroxide, an alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal acetate, tri( lower)alkylamine, piperidine, piperazine, pyridine (e.g. pyridine, lutidine, picoline, dimethylaminopyridine, etc.),
  • the base and/or the starting compound are in liquid, they can be used also as a solvent.
  • Suitable salts of the compound (X) can be referred to the base salts as exemplified for the compound (I).
  • Suitable salts of the compound (lp) can be referred to the ones as exemplified for the compound (I).
  • the compound (Ir) or a salt thereof can be prepared by reacting the compound (Iq) or a salt thereof with the compound (XI) or a salt thereof.
  • the reaction is usually carried out in a conventional solvent as exemplified in Process ( 8), or any other organic solvent which does not adversely influence the reaction.
  • reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (XI) is liquid, it can be used as a solvent.
  • Suitable salts of the compounds (Ir) and (XI) can be referred to the ones as exemplified for the compound (I).
  • the compound (Is) or a salt thereof can be prepared by reacting the compound (Iq) or a salt thereof with the compound (XII) or a salt thereof.
  • the reaction is usually carried out in a conventional solvent as exemplified in Process (8), or any other organic solvent which does not adversely influence the reaction.
  • reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (XII) is liquid, it can be used as a solvent.
  • Suitable salts of the compound (Iq), (Is) and (XII) can be referred to the acid addition salts as exemplified for the compound (I).
  • the compound (It) or a salt thereof can be prepared by reacting the compound (XIII) or a salt thereof with the compound (XIV) or a salt thereof.
  • the reaction is usually carried out in a conventional solvent as exemplified in Process ( 8), or any other organic solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
  • Suitable salts of the compounds (XIII), (XIV) and (It) can be referred to the ones as exemplified for the compound (I).
  • the compound (Iu) or a salt thereof can be prepared by reacting the compound (XV) or a salt thereof with the compound (XVI) and the compound (XVII) or a salt thereof.
  • the reaction is usually carried out in a conventional solvent such as alcohols (e.g. methanol, ethanol, ethylene glycol, etc.), chloroform, ether, tetrahydrofuran, benzene or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as alcohols (e.g. methanol, ethanol, ethylene glycol, etc.), chloroform, ether, tetrahydrofuran, benzene or any other organic solvent which does not adversely influence the reaction.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
  • the reaction is usually carried out in the presence of an acid.
  • Suitable acid may include an organic acid (e.g.
  • formic acid acetic acid, propionic acid, etc.
  • an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
  • the acid is liquid, it can be used also as a solvent.
  • Suitable salts of the compounds (XV) (XVII) and (Iu) can be referred to the acid addition salts as exemplified for the compound (I).
  • the compound (Iw) or a salt thereof can be prepared by subjecting the compound (Iv) or a salt thereof to reduction as explained in Process (10).
  • the compound (III) or a salt thereof can be prepared by the compound (XIX) or a salt thereof with the compound (XX) or a salt thereof.
  • This reaction can be carried out in the presence or absence of a conventional solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling or at ambient temperature.
  • Suitable salts of the compound (XX) can be referred to the acid addition salts as exemplified for the compound
  • thrombin thrombin, phosphodiesterase and the like, and/or
  • antithrombotic activity and therefore are useful as antithrombotic agent, vasodilating agent, and
  • anti-inflammatory agent particularly anti-thrombotic agent.
  • the new heterocyclic compounds (I) and a pharmaceutically acceptable salt thereof can be used for prophylactic and thrapeutic treatment of cerebral
  • thrombosis thrombosis, atrophic thrombosis; coronary thrombosis;
  • thrombosis thrombosis
  • mural thrombosis thrombosis
  • placental thrombosis platelet thrombosis
  • posttraumatic arterial thrombosis thrombostasis
  • compression thrombosis peripheral vascular disorders such as chronic arterial occlusion; transient ischemic attack; myocardial infarction; cerebral vascular disorders such as chronic arterial occlusion; transient ischemic attack; myocardial infarction; cerebral
  • disseminated intravascular coagulopathy disseminated intravascular coagulopathy; hypertension such as pulmonary hypertension; psoriasis; arthritis;
  • dysmnesia senile dementia
  • endotoxin shock a substance that causes a wide range of diseases and conditions.
  • these compounds are also useful for inhibition of thrombosis during extracorporeal circulation such as dialysis.
  • these compounds are also expected to have antipyretic activity, analgesic activity, antiviral activity, antifungal activity, anti-allergic activity, 5-lipoxygenase inhibitory activity and the like.
  • heterocyclic compounds (I) and a pharmaceutically acceptable salt thereof scarcely have side effect exerting a bad influence upon patients.
  • Example 1-(1) means the compounds prepared in Example 1-(1), 2-(l), 7-(3), 17-(2), 21-(1) and 24- (1) respectively.
  • Platelet aggregation ex vivo means the compounds prepared in Example 1-(1), 2-(l), 7-(3), 17-(2), 21-(1) and 24- (1) respectively.
  • Washed rabbit PRP (990 ⁇ l) was preincubated with drug solution (dissolved in dimethyl sulfoxide) (10 ⁇ l) at 37°C for 5 minutes. Then, 2.5 mM arachidonic acid solution (20 ⁇ l) was added to the reaction mixture. After 3 minutes, thiobarbiturate reagent (1000 ⁇ l) was added, and the reaction mixture was heated in a boiled water for 10 minutes. After centrifugation at 1500 g for 10 minutes, the
  • a conventional pharmaceutical preparation in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration.
  • the pharmaceutical preparation may be compounded in a solid form such as granule, capsule, tablet, dragee or suppository, or in a liquid form such as solution, suspension or emulsion for injection, ingestion, eye drops, etc. If needed, there may be included in the above preparation auxiliary substance such as stabilizing agent, wetting or emulsifying agent, buffer or any other commonly used additives.
  • the effective ingredient may usually be administered with a unit dose of 0.001 mg/kg to 500 mg/kg, preferably 0.01 mg/kg to 10 mg/kg, 1 to 4 times a day.
  • the above dosage may be increased or decreased according to age, weight and conditions of the patient or the
  • N-meth ⁇ lpiperazine (1.82 ml) was heated at 80-90°C for 4 hours and 40 minutes. After allowing to cool to room temperature, the mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and treated with active carbon. After filtration, the filtrate was evaporated in vacuo, and the resulting matter was dissolved with diethyl ether, and to it was added an ethanol solution of hydrogen chloride. The resulting precipitate was collected by filtration, washed with ethanol and diethyl ether, and dried to give
  • hydrochloric acid (5 ml) was stirred and refluxed for 2 hours. After allowing to cool to room temperature, the mixture was poured into water. Then, an aqueous solution of sodium bicarbonate was added thereto to adjust to pH 10, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and treated with active carbon. After filtration. the filtrate was evaporated in vacuo, and the resulting matter was dissolved with ethanol and to it was added an ethanol solution of hydrogen chloride.
  • the separated organic layer was washed with water, diluted aqueous hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, water and brine, dried over magnesium sulfate and treated with active carbon. After filtration, the filtrate was evaporated in vacuo, the residue was subjected to column chromatography on silica gel (25 g) and eluted with a mixture of chloroform and methanol. The fractions containing the object compound were combined and evaporated in vacuo, and the residue was triturated with ethanol and diethyl ether to give
  • N,N-dimethylformamide (30 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.62 ml) under stirring at ambient temperature and the resulting mixture was stirred for one hour at same condition.
  • the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, water and brine and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo.
  • N-methylpiperazine (1.87 ml) was stirred and refluxed for 26.5 hours. After allowing to cool to room temperature, the reaction mixture was poured into water and ethyl acetate. The separated organic layer was washed with water, saturated aqueous sodium bicarbonate, water and brine, and dried over magnesium sulfate and treated with active carbon.
  • Example 21- (1) The following compounds were obtained according to a similar manner to that of Example 21- (1).
  • reaction mixture was poured into water and extracted with ethyl acetate.
  • the extract was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and
  • Example 24- (1) The following compounds were obtained according to a similar manner to that of Example 24- (1).
  • N,N-dimethylformamide (1.0 ml) was heated at 150°C for 8 hours. After the solvent was removed under reduced pressure, the residue was subjected to column

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Abstract

Les composés hétérocycliques répondant à la formule (I), dans laquelle R1 et R2 représentent chacun alcoxy inférieur; R3 représente amino substitué, etc.; Y représente CH ou N; et Z représente CH ou N; et leurs sels pharmaceutiquement acceptables, sont utiles en tant que médicament.
PCT/JP1991/001042 1990-08-06 1991-08-05 Composes heterocycliques WO1992002513A1 (fr)

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GB909017183A GB9017183D0 (en) 1990-08-06 1990-08-06 Triazine compounds,processes for the preparation thereof and pharmaceutical composition comprising the same
GB9017183.6 1990-08-06
GB9020345.6 1990-09-18
GB909020345A GB9020345D0 (en) 1990-09-18 1990-09-18 Heteromonocyclic compounds,processes for the preparation thereof and pharmaceutical composition comprising the same

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Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0591767A1 (fr) * 1992-10-05 1994-04-13 Bayer Ag Triazinecarboxamides sulfonylés
US5591746A (en) * 1988-12-07 1997-01-07 Glaxo Wellcome Inc Treatment of damage from a stroke using 4-amino(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidine
EP0761225A1 (fr) * 1994-06-02 1997-03-12 Teijin Limited Composition pharmaceutique pour le traitement de troubles du systeme circulatoire peripherique
WO1999032448A1 (fr) * 1997-12-19 1999-07-01 Amgen Inc. Compose de pyridine et de pyridazine substituees et leurs utilisations pharmaceutiques
US6096753A (en) * 1996-12-05 2000-08-01 Amgen Inc. Substituted pyrimidinone and pyridone compounds and methods of use
US6174901B1 (en) 1998-12-18 2001-01-16 Amgen Inc. Substituted pyridine and pyridazine compounds and methods of use
WO2001036387A1 (fr) * 1999-11-15 2001-05-25 Sankio Chemical Co., Ltd. Nouveaux derives bipyridyles
WO2001096314A1 (fr) * 2000-06-13 2001-12-20 Basf Aktiengesellschaft 2-(cyanoamino)pyrimidines 5-phenyl-substituees a action fongicide
US6410729B1 (en) 1996-12-05 2002-06-25 Amgen Inc. Substituted pyrimidine compounds and methods of use
WO2002055502A1 (fr) * 2001-01-02 2002-07-18 Fujisawa Pharmaceutical Co., Ltd. Derives de pyridine utiles en tant qu'inhibiteurs de cyclo-oxygenase
WO2002088084A1 (fr) * 2001-04-26 2002-11-07 Nippon Shinyaku Co., Ltd. Derives de composes heterocycliques et medicaments
WO2003051850A1 (fr) * 2001-12-19 2003-06-26 Astrazeneca Ab Composes de la pyrazine et compositions pharmaceutiques les contenant
WO2003051851A1 (fr) * 2001-12-19 2003-06-26 Astrazeneca Ab Derives de 5, 6-diaryl-pyrazine-2-amide comme antagonistes de cb1
WO2003084930A1 (fr) * 2002-04-11 2003-10-16 Sanofi-Synthelabo Derives de diphenylpyridine, leur preparation, les compositions pharmaceutiques en contenant
WO2004009560A1 (fr) 2002-07-22 2004-01-29 Orchid Chemicals & Pharmaceuticals Ltd Nouvelles molecules bioactives
WO2004069277A1 (fr) * 2003-02-06 2004-08-19 Astrazeneca Ab Dispersion stable de particules solides comprenant un compose pyrazine insoluble dans l'eau
WO2004111034A1 (fr) * 2003-06-18 2004-12-23 Astrazeneca Ab Derives de 2-carboxamide et 2-sulfonamide-5,6-diaryl-pyrazine substitues en 3, utilises comme modulateurs de cb1
WO2004111033A1 (fr) * 2003-06-18 2004-12-23 Astrazeneca Ab Agents therapeutiques
WO2004111038A1 (fr) * 2003-06-18 2004-12-23 Astrazeneca Ab 5,6-bis (4-chlorophenyl)-n-piperidin1-yl-3-(piperidin-1-yl-carbonyl)pyrazine-2-carboxamide
WO2004111039A1 (fr) * 2003-06-19 2004-12-23 Astrazeneca Ab Utilisation de derives de 5,6-diaryl-pyrazine 2,3-substituee comme modulateurs du recepteur cannabinoide 1
EP1492784A2 (fr) * 2002-03-28 2005-01-05 Merck & Co., Inc. 2,3-diphenyl-pyridines substituees
EP1546115A2 (fr) * 2002-09-27 2005-06-29 Merck & Co., Inc. Pyrimidines substituees
WO2005123680A1 (fr) * 2004-06-15 2005-12-29 Bristol-Myers Squibb Company Heterocycles a six chainons convenant comme inhibiteurs des serine proteases
FR2888237A1 (fr) * 2005-07-08 2007-01-12 Sanofi Aventis Sa Derives de n-[(4,5-diphenylpyrimidin-2-yl)methyl] amine, leur preparation et leur application en therapeutique
US7517900B2 (en) 2003-10-10 2009-04-14 Bristol-Myers Squibb Company Pyrazole derivatives as cannabinoid receptor modulators
WO2011095625A1 (fr) 2010-02-05 2011-08-11 Heptares Therapeutics Limited Dérivés de 1,2,4-triazine-4-amine
US20110230458A1 (en) * 2010-02-18 2011-09-22 Transtech Pharma, Inc. Phenyl-heteroaryl derivatives and methods of use thereof
WO2011143332A1 (fr) 2010-05-14 2011-11-17 Allergan, Inc. Composés aromatiques ayant une activité de récepteur de sphingosine-1-phosphonate (s1p)
US20120225846A1 (en) * 2011-03-02 2012-09-06 Bioenergenix Heterocyclic compounds for the inhibition of pask
US8513220B2 (en) 2010-05-14 2013-08-20 Allergan, Inc. Aromatic compounds having sphingosine-1-phosphonate (S1P) receptor activity
US9133178B2 (en) 2010-10-27 2015-09-15 Proximagen Limited Alpha-7 nicotinic receptor modulators for the treatment of pain, a psychotic disorder, cognitive impairment or alzheimer'S disease
US9296697B2 (en) 2005-08-24 2016-03-29 Abbott Laboratories Hetaryl-substituted guanidine compounds and use thereof as binding partners for 5-HT5-receptors

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6664256B1 (en) * 2000-07-10 2003-12-16 Kowa Co., Ltd. Phenylpyridazine compounds and medicines containing the same
EP1679309A4 (fr) * 2003-10-24 2007-03-28 Ono Pharmaceutical Co Medicament antistress et usage medical correspondant
JP2010504286A (ja) * 2006-09-07 2010-02-12 アラーガン インコーポレイテッド スフィンゴシン−１−リン酸（ｓ１ｐ）受容体アゴニスト及び／又はアンタゴニスト生物活性を有するヘテロ芳香族化合物

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2173868A1 (en) * 1972-03-24 1973-10-12 Mac Neil Lab In Pyrazine-acetic acid, acetates and acetamides - useful as uv absorber in sunscreening materials plastics, and resins
US3979516A (en) * 1974-01-31 1976-09-07 Eli Lilly And Company Anti-inflammatory 3-amino-5,6-diaryl-1,2,4-triazines
US4021553A (en) * 1976-03-10 1977-05-03 Eli Lilly And Company 5,6-Diaryl-1,2,4-triazines as topically-active anti-inflammatory agents
US4318911A (en) * 1980-12-29 1982-03-09 Eli Lilly And Company 5,6-Diaryl-1,2,4-triazines as topical antithrombotic agents
EP0088593A2 (fr) * 1982-03-05 1983-09-14 Eli Lilly And Company Dérivés de 1,2,4-triazine et de pyrazine
WO1989004308A1 (fr) * 1987-11-12 1989-05-18 Terumo Kabushiki Kaisha Derives de pyrazine et preparation medicinale les contenant

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2173868A1 (en) * 1972-03-24 1973-10-12 Mac Neil Lab In Pyrazine-acetic acid, acetates and acetamides - useful as uv absorber in sunscreening materials plastics, and resins
US3979516A (en) * 1974-01-31 1976-09-07 Eli Lilly And Company Anti-inflammatory 3-amino-5,6-diaryl-1,2,4-triazines
US4021553A (en) * 1976-03-10 1977-05-03 Eli Lilly And Company 5,6-Diaryl-1,2,4-triazines as topically-active anti-inflammatory agents
US4318911A (en) * 1980-12-29 1982-03-09 Eli Lilly And Company 5,6-Diaryl-1,2,4-triazines as topical antithrombotic agents
EP0088593A2 (fr) * 1982-03-05 1983-09-14 Eli Lilly And Company Dérivés de 1,2,4-triazine et de pyrazine
WO1989004308A1 (fr) * 1987-11-12 1989-05-18 Terumo Kabushiki Kaisha Derives de pyrazine et preparation medicinale les contenant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 104, No. 1, 6 January 1986, (Columbus, Ohio, US), PITET G. et al., "Synthesis and Pharmacological Profile of New Diaryl-as-triazines", page 18, Abstract 228w; & BULL. CHIM. FARM., 1985, 124(6), 271-278. *

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US5591746A (en) * 1988-12-07 1997-01-07 Glaxo Wellcome Inc Treatment of damage from a stroke using 4-amino(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidine
US5597827A (en) * 1988-12-07 1997-01-28 Glaxo Wellcome Inc Treatment of injury of the spinal cord or brain using 4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidine
US5684005A (en) * 1988-12-07 1997-11-04 Glaxo Wellcome Inc. Pharmacologically active CNS compounds
US5712276A (en) * 1988-12-07 1998-01-27 Glaxo Wellcome Inc. 2-(n-alkylpiperazino or morpholino)-4-amino-5-aryl-pyrimidines
EP0591767A1 (fr) * 1992-10-05 1994-04-13 Bayer Ag Triazinecarboxamides sulfonylés
EP0761225A4 (fr) * 1994-06-02 2002-07-24 Teijin Ltd Composition pharmaceutique pour le traitement de troubles du systeme circulatoire peripherique
EP0761225A1 (fr) * 1994-06-02 1997-03-12 Teijin Limited Composition pharmaceutique pour le traitement de troubles du systeme circulatoire peripherique
US6096753A (en) * 1996-12-05 2000-08-01 Amgen Inc. Substituted pyrimidinone and pyridone compounds and methods of use
US6610698B2 (en) 1996-12-05 2003-08-26 Amgen, Inc. Substituted pyrimidine compounds and methods of use
US6410729B1 (en) 1996-12-05 2002-06-25 Amgen Inc. Substituted pyrimidine compounds and methods of use
US6420385B1 (en) 1996-12-05 2002-07-16 Amgen Inc. Substituted pyrimidinone and pyridone compounds and methods of use
US6649604B2 (en) 1996-12-05 2003-11-18 Amgen Inc. Substituted pyridone compounds and methods of use
WO1999032448A1 (fr) * 1997-12-19 1999-07-01 Amgen Inc. Compose de pyridine et de pyridazine substituees et leurs utilisations pharmaceutiques
AU755421B2 (en) * 1997-12-19 2002-12-12 Amgen, Inc. Substituted pyridine and pyridazine compounds and their pharmaceutical use
US6174901B1 (en) 1998-12-18 2001-01-16 Amgen Inc. Substituted pyridine and pyridazine compounds and methods of use
WO2001036387A1 (fr) * 1999-11-15 2001-05-25 Sankio Chemical Co., Ltd. Nouveaux derives bipyridyles
US6603007B1 (en) * 1999-11-15 2003-08-05 Sankio Chemical Co., Ltd. Bipyridyl derivatives
WO2001096314A1 (fr) * 2000-06-13 2001-12-20 Basf Aktiengesellschaft 2-(cyanoamino)pyrimidines 5-phenyl-substituees a action fongicide
US6943252B2 (en) 2000-06-13 2005-09-13 Basf Aktiengesellschaft Fungicidal 5-phenyl substituted 2-(cyanoamino) pyrimidines
US7230104B2 (en) 2000-06-13 2007-06-12 Basf Aktiengesellschaft Fungicidal 5-phenyl substituted 2-(cyanoamino) pyrimidines
WO2002055502A1 (fr) * 2001-01-02 2002-07-18 Fujisawa Pharmaceutical Co., Ltd. Derives de pyridine utiles en tant qu'inhibiteurs de cyclo-oxygenase
US7205302B2 (en) 2001-04-26 2007-04-17 Nippon Shinyaku Co., Ltd. Heterocyclic compound derivatives and medicines
WO2002088084A1 (fr) * 2001-04-26 2002-11-07 Nippon Shinyaku Co., Ltd. Derives de composes heterocycliques et medicaments
WO2003051851A1 (fr) * 2001-12-19 2003-06-26 Astrazeneca Ab Derives de 5, 6-diaryl-pyrazine-2-amide comme antagonistes de cb1
US7342019B2 (en) 2001-12-19 2008-03-11 Astrazeneca Ab 5, 6-diaryl-pyrazine-2-amide derivatives as CB1 antagonists
WO2003051850A1 (fr) * 2001-12-19 2003-06-26 Astrazeneca Ab Composes de la pyrazine et compositions pharmaceutiques les contenant
US7271266B2 (en) 2002-03-28 2007-09-18 Merck & Co., Inc. Substituted 2,3-diphenyl pyridines
EP1492784A4 (fr) * 2002-03-28 2006-03-29 Merck & Co Inc 2,3-diphenyl-pyridines substituees
EP1492784A2 (fr) * 2002-03-28 2005-01-05 Merck & Co., Inc. 2,3-diphenyl-pyridines substituees
WO2003084930A1 (fr) * 2002-04-11 2003-10-16 Sanofi-Synthelabo Derives de diphenylpyridine, leur preparation, les compositions pharmaceutiques en contenant
FR2838438A1 (fr) * 2002-04-11 2003-10-17 Sanofi Synthelabo Derives de diphenylpyridine,leur preparation, les compositions pharmaceutiques en contenant
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US7317014B2 (en) * 2002-07-22 2008-01-08 Orchid Research Laboratories, Ltd. Bio-active pyrimidine molecules
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EP1546115A4 (fr) * 2002-09-27 2010-08-04 Merck Sharp & Dohme Pyrimidines substituees
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WO2004069277A1 (fr) * 2003-02-06 2004-08-19 Astrazeneca Ab Dispersion stable de particules solides comprenant un compose pyrazine insoluble dans l'eau
US7473693B2 (en) 2003-02-06 2009-01-06 Astrazeneca Ab Stable dispersion of solid particles comprising a water-insoluble pyrazine compound
WO2004111034A1 (fr) * 2003-06-18 2004-12-23 Astrazeneca Ab Derives de 2-carboxamide et 2-sulfonamide-5,6-diaryl-pyrazine substitues en 3, utilises comme modulateurs de cb1
WO2004111033A1 (fr) * 2003-06-18 2004-12-23 Astrazeneca Ab Agents therapeutiques
WO2004111038A1 (fr) * 2003-06-18 2004-12-23 Astrazeneca Ab 5,6-bis (4-chlorophenyl)-n-piperidin1-yl-3-(piperidin-1-yl-carbonyl)pyrazine-2-carboxamide
AU2004247615B2 (en) * 2003-06-18 2008-02-21 Astrazeneca Ab 2-substituted 5,6-diaryl-pyrazine derivatives as CB1 modulators
AU2004247614B2 (en) * 2003-06-19 2008-02-28 Astrazeneca Ab 2,3-substituted 5,6-diaryl-pyrazine derivatives as CB1 modulators
WO2004111039A1 (fr) * 2003-06-19 2004-12-23 Astrazeneca Ab Utilisation de derives de 5,6-diaryl-pyrazine 2,3-substituee comme modulateurs du recepteur cannabinoide 1
US7517900B2 (en) 2003-10-10 2009-04-14 Bristol-Myers Squibb Company Pyrazole derivatives as cannabinoid receptor modulators
WO2005123680A1 (fr) * 2004-06-15 2005-12-29 Bristol-Myers Squibb Company Heterocycles a six chainons convenant comme inhibiteurs des serine proteases
US7429604B2 (en) 2004-06-15 2008-09-30 Bristol Myers Squibb Company Six-membered heterocycles useful as serine protease inhibitors
WO2007006928A1 (fr) * 2005-07-08 2007-01-18 Sanofi-Aventis Derives de n-[(4,5-diphenylpyrimidin-2-yl)methyl] amine, leur preparation et leur application en therapeutique
JP2009500381A (ja) * 2005-07-08 2009-01-08 サノフイ−アベンテイス Ｎ−［（４，５−ジフェニルピリミジン−２−イル）メチル］アミン誘導体、その調製及びそれらの治療上の使用
US7541361B2 (en) 2005-07-08 2009-06-02 Sanofi-Aventis N-[4,5-diphenylpyrimidin-2-yl)methyl]amine derivatives, the preparation thereof and their therapeutic use
FR2888237A1 (fr) * 2005-07-08 2007-01-12 Sanofi Aventis Sa Derives de n-[(4,5-diphenylpyrimidin-2-yl)methyl] amine, leur preparation et leur application en therapeutique
US9296697B2 (en) 2005-08-24 2016-03-29 Abbott Laboratories Hetaryl-substituted guanidine compounds and use thereof as binding partners for 5-HT5-receptors
US10988455B2 (en) 2010-02-05 2021-04-27 Heptares Therapeutics Limited 1,2,4-triazine-4-amine derivatives
US12054472B2 (en) 2010-02-05 2024-08-06 Nxera Pharma Uk Limited 1,2,4-triazine-4-amine derivatives
WO2011095625A1 (fr) 2010-02-05 2011-08-11 Heptares Therapeutics Limited Dérivés de 1,2,4-triazine-4-amine
US10112923B2 (en) 2010-02-05 2018-10-30 Heptares Therapeutics Limited 1,2,4-triazine-4-amine derivatives
US9249130B2 (en) 2010-02-05 2016-02-02 Heptares Therapeutics Limited 1,2,4-triazine-4-amine derivatives
US8809525B2 (en) 2010-02-05 2014-08-19 Heptares Therapeutics Limited 1,2,4-triazine-4-amine derivatives
US8741900B2 (en) 2010-02-18 2014-06-03 Transtech Pharma, Llc Phenyl-heteroaryl derivatives and methods of use thereof
US9045461B2 (en) 2010-02-18 2015-06-02 Transtech Pharma, Llc Phenyl-heteroaryl derivatives and methods of use thereof
US20130197007A1 (en) * 2010-02-18 2013-08-01 Transtech Pharma, Inc. Phenyl-Heteroaryl Derivatives and Methods of Use Thereof
US8431575B2 (en) * 2010-02-18 2013-04-30 Transtech Pharma, Inc. Phenyl-heteroaryl derivatives and methods of use thereof
US20110230458A1 (en) * 2010-02-18 2011-09-22 Transtech Pharma, Inc. Phenyl-heteroaryl derivatives and methods of use thereof
US8513220B2 (en) 2010-05-14 2013-08-20 Allergan, Inc. Aromatic compounds having sphingosine-1-phosphonate (S1P) receptor activity
WO2011143332A1 (fr) 2010-05-14 2011-11-17 Allergan, Inc. Composés aromatiques ayant une activité de récepteur de sphingosine-1-phosphonate (s1p)
US9133178B2 (en) 2010-10-27 2015-09-15 Proximagen Limited Alpha-7 nicotinic receptor modulators for the treatment of pain, a psychotic disorder, cognitive impairment or alzheimer'S disease
US9012637B2 (en) 2011-03-02 2015-04-21 Bioenergenix, Llc Substituted pyrazinyl acrylic acid compounds for the inhibition of pask
US9675584B2 (en) 2011-03-02 2017-06-13 Bioenergenix, Llc Substituted indoles for the inhibition of PASK
US20120225846A1 (en) * 2011-03-02 2012-09-06 Bioenergenix Heterocyclic compounds for the inhibition of pask

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