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WO1992002513A1 - Heterocyclic compounds - Google Patents

Heterocyclic compounds 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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WO
WIPO (PCT)
Prior art keywords
alkyl
compound
group
formula
salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1991/001042
Other languages
French (fr)
Inventor
Hisashi Takasugi
Hiroyoshi Sakai
Akito Tanaka
Takatoshi Ishikawa
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fujisawa Pharmaceutical Co Ltd
Original Assignee
Fujisawa Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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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/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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
    • C07D213/36—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
    • 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
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • 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
    • C07D213/44—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
    • 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
    • C07D213/54—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
    • 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
    • C07D213/79—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

Heterocyclic compounds of formula (I), wherein R?1 and R2¿ are each lower alkoxy, R3 is substituted amino, etc., Y is CH or N and Z is CH or N, and pharmaceutically acceptable salts thereof which are useful as a medicament.

Description

DESCRIPTION HETEROCYCLIC COMPOUNDS
TECHNICAL FIELD
This invention relates to new heterocyclic compounds and pharmaceutically acceptable salts thereof which are useful as a medicament.
BACKGROUND ART
Some heterocyclic compounds have been known as described, for example, in U.S. Patent 3,979,516, U.S. Patent 4,021,553, U.S. Patent 4,190,725 and U.S. Patent 4,318,911.
DISCLOSURE OF INVENTION
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.
Accordingly, 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
inflammation, particularly thrombosis, in human being and animals.
The object heterocyclic compounds of the present invention are novel and can be represented by the
following general formula (I) :
Figure imgf000004_0001
wherein R1 and R2 are each lower alkoxy,
R3 is heterocyclic group selected from the group consisting of pyridyl, tetrahydropyridyl, piperidyl, piperazinyl and morpholinyl, which may have suitable substituent(s);
substituted amino; carboxy(lower)alkenyl; carboxy( lower) alkyl; hydroxy( lower)alkyl; amino( lower) alkyl which may have suitable substituent(s);
a group of the formula :
Figure imgf000004_0002
(in which R4 is hydrogen, ethoxy,
mono(or di) lower alkylamino, di( lower)alkylamino- ( lower)- alkylamino, heterocyclicamino which may have suitable
substituent(s), or
heterocyclic group which may have suitable substituent(s)); or a group of the formula :
Figure imgf000005_0001
(in which R5 is lower alkyl or
ar(lower)alkyl
which may have suitable
substituent(s), and
X1 is an acid residue),
Y is CH or N and
z is CH or N,
with proviso that
when R3 is pyridyl; piperidyl which may have hydroxy
group; 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
amino substituted with two substituents selected from the group consisting of lower alkyl and hydroxy(lower)alkyl, and Y is N,
then Z is CH.
The object compound (I) of the present invention can be prepared by the following processes.
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
wherein R1, R2, R3, R5, Y, Z and X1 are each as defined above, is mono(or di) lower alkylamino.
Figure imgf000016_0001
di( lower)alkylamino-(lower)alkylamino, heterocyclicamino which may have suitable substituent(s), or heterocyclic group containing at least one nitrogen atom which may have suitable substituent(s),
Ra 3 is protected amino( lower)alkyl,
Ra 3 is amino( lower)alkyl,
Rc 3 is acylamino( lower)alkyl,
Rd 3 is carboxy or protected carboxy,
R 6 and R7 are each lower alkyl,
R 8 and R9 are each hydrogen, lower alkyl,
cyclo( lower) alkyl, ar( lower)alkyl,
heterocyclic group which may have suitable substituent ( s ) , or
R 8 and R9 are linked together with the attached nitrogen atom to form heterocyclic group which may have suitable substituent(s), X2 is a leaving group,
R10 is hydrogen or lower alkyl and
R11 is lower alkyl or 1-amino-1-iminomethyl, or
R10 and R11 are linked together with the attached nitrogen atom to form heterocyclic group which may have suitable substituent(s), R 12 and R13 are each lower alkyl,
R3 is carboxy( lower)alken ,
Rf 3 is carboxy( lower) alkyl- ==== in Process (6) means a single or double bond, R3 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);
a group of the formula :
Figure imgf000017_0001
(in which R4 is hydrogen, ethoxy, mono(or di) lower alkylamino,
di( lower)alkylamino- ( lower)- alkylamino, heterocyclicamino which may have suitable substituent(s), or
heterocyclic group which may have suitable substituent(s); or a group of the formula :
Figure imgf000017_0002
(in which R5 is lower alkyl or
ar( lower) alkyl which may have suitable substituent(s), and X is an acid residue).
Y1 is CH or N and
Z1 is CH or N.
The starting compound (III) or a salt thereof can be prepared by the following Processes. Process (a)
Figure imgf000018_0001
wherein R3 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. 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.
arginine, aspartic acid, glutamic acid, etc.), and the like.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention include within the scope thereof are explained in detail as follows. The term "lower" is intended to mean 1 to 6 carbon atom(s), preferably one having 1 to 4 carbon atom(s), unless otherwise indicated.
Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy,
pentyloxy, t-pentyloxy, hexyloxy and the like.
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
substituent such as halogen [e.g. fluorine, chlorine, bromine or iodine], and the like.
Suitable "lower alkenyl" in the terms
"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;
lower alkylguanidino; cyclo( lower)alkylguanidino;
ar( lower)alkylguanidino; heterocyclicguanidino which may be substituted with suitable substituent(s) such as ar( lower)alkyl or the like;
(1-heterocyclic-l-iminomethyl)amino which may have
suitable substituent(s) such as lower alkyl,
ar ( lower)alkyl, aryl which may have suitable
substituent( s) such as lower alkoxy or the like, or the like; di( lower)alkylamino; and the like.
Suitable "lower alkyl" and "lower alkyl moiety" in the terms "carboxy(lower)alkyl", "hydroxy( lower)alkyl". " amino ( lower ) alkyl" , "di ( lower ) alkylamino( lower)alkylamino", "acylamino( lower)alkyl", "protected amino( lower) alkyl", "di ( lower)alkylamino",
"di( lower) alkylguanidino", "lower alkylguanidino",
"ar( lower)alkyl", "hydroxy(lower)alkylamino", "mono(or di) lower alkylamino", "halophenyl(lower)alkylamino" and "ar{ lower)alkylguanidino 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).
Suitable "protected amino moiety" in the term
"protected amino(lower)alkyl" may include acylamino and the like.
Suitable "protected carboxy" may include esterified carboxy and the like.
Suitable example of the 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
example, lower alkanoyloxy( lower)alkyl ester [e.g.
acetoxymethyl ester, propionyloxymethyl ester,
butyryloxymethyl ester, valeryloxymethyl 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
2)-propionyloxyethyl ester, 1(or 2 or
3)-propionyloxypropyl ester, 1(or 2)-butyryloxyethyl ester, 1(or 2)-isobutyryloxyethyl ester, l(or
2)-pivaloyloxyethyl ester, 1(or 2)-hexanoyloxyethtl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1(or 2 ) -pentanoy oxyethyl ester, etc.], lower alkanesulfonyl(lower) alkyl ester (e.g. 2-mesylethyl ester, etc.), mono(or di or tri)-halo( lower)alkyl ester (e.g. 2-iodoethyl ester,
2,2,2-trichloroethyl ester, etc.), lower
alkoxycarbonyloxy( lower)alkyl ester (e.g. methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester, 1-isopropoxycarbonyloxyethyl ester, etc.),
phthalidylidene( lower)alkyl ester, or (5-lower alkyl
2-oxo-1,3-dioxol-4-yl) (lower)alkyl ester [e.g.
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,
(5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester,
( 5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl 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,
3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester, etc.);
aryl ester which may have at least one suitable
substituent(s) (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.);
phthalidyl ester; and the like.
Suitable "acyl" in the terms "acylamino" and
"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.
Suitable example of said 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.);
lower or higher alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.);
lower alkylcarbamoyl (e.g. methylcarbamoyl,
ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, etc.), lower or higher alkanesulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.);
lower or higher 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,
phenylisobutylyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl(lower) alkanoyl (e.g. naphthylacety1,
naphthylpropanoyl, naphthylbutanoyl, etc.), etc.];
ar( lower)alkenoyl [e.g. phenyl(lower)alkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.),
naphthyl( lower)alkenoyl (e.g. naphthylpropenoyl,
naphthyIbutenoyl, naphthylpentenoyl, etc.), etc.];
ar ( lower)alkoxycarbonyl [e.g. phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.), etc.];
aryloxycarbonyl (e.g. phenoxycarbonyl,
naphthyloxycarbonyl, etc.);
aryloxy(lower)alkanoyl (e.g. phenoxyacetyl,
phenoxypropionyl, etc.); 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
heterocycliccarbonyl;
heterocyclic (lower)alkanoyl (e.g. thienylacetyl,
thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl, tetrazolylacetyl, etc.);
heterocyclic(lower)alkenoyl (e.g. heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl,
heterocyclichexenoyl, etc.);
heterocyclicglyoxyloyl (e.g. thiazolylglyoxyloyl,
thienylglyoxyloyl, etc.); or the like; 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
unsaturated 3 to 8-membered more preferably 5 or 6-membered heteromonycyclic group containing 1 to
4-nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide,
dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl,
tetrahydropyridazmyl ( e. g. 2 , 3 , 4 , 5-tetrahydropyridazinyl, etc . ) , triazolyl (e.g. 4H-1,2,4-triazolyl,
1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
saturated 3 to 8-membered (more prlferably 5 or 6- membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl,
isoquinolyl, indazolyl, benzotriazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example,
oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.;
saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example,
morpholinyl, sydnonyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atorn(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or
6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,
thiazolyl, isothiazolyl, thiadiazolyl (e.g.
1,2,3-thiadiazolyl, 1, 2 4-thiadiazolyl,
1,3, 4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.),
dihydrothiazinyl, etc.;
saturated 3 to 8-membered (more preferably 5 or
6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or
6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl,
dihydrodithionyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 to
6-membered) heteromonocyclic group containing an oxygen atom, for example, furyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or
6-membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom( s), for example,
dihydrooxathiinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc.;
unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, benzoxathiinyl, etc. and the like. The 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 "heterocyclic group" in the terms
"heterocyclic group which may have suitable
substituent( s) ", " ( 1-heterocyclic-l-iminomethyl)amino" "heterocyclicguanidino" and "heterocyclicamino which may have suitable substituent(s)" can be referred to the ones as mentioned above.
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.)
ar( lower) alkyl, hydroxy( lower)alkyl and the like.
8
Suitable "heterocyclic group" in the definitions "R and R9 are linked together with .the attached nitrogen atom to form heterocyclic group which may have suitable
substituent(s)", "R10 and R11 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
8-membered (more preferably 5 or 6-membered)
heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.;
saturated 3 to 8-membered (more preferably 5 or
6-membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, etc. and the like.
Suitable "substituent" in the term "heteroσyclicamino which may have suitable substituent(s)" may include ar( lower)alkyl, and the like.
Suitable "substituent" in the definitions "R 8 and R9 are linked together with the attached nitrogen atom to form heterocyclic group which may have suitable
substituent(s)" and "R10 and R11 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.
Suitable "substituent" in the definition
"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.
Suitable "aryl" and "aryl moiety" in the terms
"ar(lower)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.
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.
R1 is lower alkoxy,
R2 is lower alkoxy,
R3 is heterocyclic group selected from the group
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;
most 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, phenyl{ lower)alkyl and halophenyl(lower)alkyl]; cyanoamino; imidazolinylamino; guanidino;
di ( lower) alkylguanidino; lower alkylguanidino;
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 one to three (more preferably one) suitable
substituent(s) [more preferably
(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
{morpholinyl(imino)methyl}amino,
{piperidyl(imino)methyl}amino which may have
phenyl(lower) alkyl, or
{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];
a group of the formula :
Figure imgf000029_0001
(in which R4 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
[more preferably saturated 5 or
6-membered heteromonocyclicamino in which heteromonocyclic group contains
1 to 3 nitrogen atom( s), which may have one or two substituent(s)
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
2 oxygen atom(s) and 1 to 3 nitrogen atom(s), which may have one or two substituent(s) selected from the group consisting of lower alkyl, lower
alkoxy, halogen, phenyl(lower)alkyl and hydroxy(lower)alkyl, or saturated 5 or 6-membered heteromonocyclic group containing 1 to 3 nitrogen atom(s), which may have one or two
substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, halogen, phenyl(lower)alkyl and hydroxy(lower)alkyl; most
preferably morpholinyl, or piperazinyl which may have lower alkyl,
hydroxy(lower) alkyl or
phenyl(lower)alkyl];
or a group of the formula :
Figure imgf000030_0001
(in which R5 is lower alkyl, or ar(lower)alkyl
which may have one to three (more preferably one or two)substituent(s) selected from the group consisting of halogen, lower alkyl and lower alkoxy [more preferably phenyl(lower)alkyl which may have one or two
substituent(s) selected from the group consisting of halogen, lower alkyl and lower alkoxy; most preferably
phenyl(lower) alkyl which may have halogen], and
X is an acid residue [more preferably halogen]),
Y is CH or N and Z is CH or N,
with proviso that
when R3 is pyridyl; piperidyl which may have hydroxy
group; 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,
then Z is CH.
The processes for preparing the object and starting compounds are explained in detail in the following. Process (1)
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,
N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction. Among these solvents, 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.
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,
dimethylaminopyridine, etc.), N-(lower)alkylmorpholine, N,N-di (lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like. When the base, the acid and/or the starting compound are in liquid, they can be used also as a
solvent.
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 ).
Process ( 2)
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.
As suitable said reactive derivatives at the carboxy group, there may be mentioned acid halides, acid
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,
2,4-dinitrophenyl ester, pentachlorophenyl ester. phenylazophenyl ester, carboxymethylthio ester, and
N-hydroxysuccinimide ester.
The reaction is usually carried out in a conventional solvent, such as methylene chloride, chloroform, alcohol [e.g. methanol, ethanol, etc.], benzene, toluene,
pyridine, diethyl ether, dioxane, tetrahydrofuran, acetone, acetonitrile, ethyl acetate,
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.
triethylamine, pyridine, N,N-dimethylaniline, etc.], 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.] and the like. In case that the base is liquid, 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
compound (I).
Process (3)
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 Ra 3.
Suitable method of this reaction may include conventional one such as hydrolysis, reduction and the like. (i) For Hydrolysis :
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
bicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[ 4.3.0]-non-5-ene, 1,4-diazabicyclo[2.2.2]octane,
l,8-diazabicyclo[5.4.0]undec-7-ene, or the like.
Suitable acid may include an organic acid [e.g.
formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.]. The
elimination using 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.].
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.
(ii) For 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 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.).
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
carbonate, etc.), 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.) and the like. The reduction is usually carried out in a
conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol,
N,N-dimethylformamide, tetrahydrofuran, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent.
The 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).
Process (4)
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
reaction.
Suitable acylating agent to be used in the present acylation reaction may include the compound of the
formula : R14 - 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
activated amide, an activated ester, isoσyanate, and the like. 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,
dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, sulfurous acid,
thiosulfuric acid, alkanesulfonic acid (e.g.
methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid,
2-ethylbutyric acid or trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g. benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g.
cyanomethyl ester, methoxymethyl ester,
dimethyliminomethyl [ (CH3 ) 2N=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl
thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.), or an ester with a N-hydroxy compound (e.g. N,N-dimethylhydroxylamine, l-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide,
N-hydroxybenzotriazole, N-hydroxyphthalimide,
l-hydroxy-6-chloro-1H-benzotriazole, etc.);
substituted or unsubstituted aryl isocyanate;
substituted or unsubstituted aryl isothiocyanate, and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound (XXII) to be used.
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride,
tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which do not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.
When the compound (XXII) is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;
N-cyclohexyl-N'-morpholinoethylcarbodiimide;
N-cyclohexyl-N'-(4-diethylaminoσyclohexyl)carbodiimide; N,N' -diethylcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;
N,N-carbonylbis-(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene ; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride;
triphenylphosphine; 2-ethyl-7-hydroxybenzisoxasolium salt; 2-ethyl-5-(m-sulfophenyl) isoxazolium hydroxide
intra-molecular salt; 1-(p-chlorobenzenesulfonyloxy)- 6-chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride, etc.; or the like.
The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine,
N-(lower) 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. Process (5)
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,
N,N-dimethylformamide or any other organic solvent which does not adversely influence the reaction. Among these solvents, 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.
Suitable salts of the compounds (XVIII) and (If) can be referred to the ones as exemplified for the compound (I). Process ( 6 )
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,
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
carbonate, etc.), 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.) and the like.
The reduction is usually carried out in a solvent such as water, alcohol (e.g. methanol, ethanol, etc.),
N,N-dimethylformamide, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely affect the reaction.
Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent.
The 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) .
Process (7)
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).
Suitable salts of the compounds (Ii) and (Ij) can be referred to the ones as exemplified for the compound ( I ). Process ( 8)
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.
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 ).
Process (9)
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.),
N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like. When 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).
Suitable salts of the compounds (IX) and (IS.) can be referred to the ones as exemplified for the compound (I) . Process (10)
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,
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
carbonate, etc.), 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.) and the like. The reduction is usually carried out in a
conventional solvent which does not adversely influence the reaction such as methanol, ethanol, propanol,
N,N-dimethylformamide, tetrahydrofuran, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to heating.
Suitable salts of the compound (Im) can be referred to the ones as exemplified for the compound (I). Process (11)
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, and 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. Among these solvents, 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).
Process (12)
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.),
N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like. When 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). Process ( 13 )
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.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating. In case that 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).
Process (14)
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.
The reaction temperature is not critical and the reaction is usually carried out under cooling to heating. In case that 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).
Process (15)
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).
Process (16)
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.
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.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.). When 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).
Process (17)
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).
Suitable salts of the compounds (Iw) and (Iv) can be referred to the ones as exemplified for the compound (I). Process (a)
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
(I).
suitable salts of the compounds (XIX) and (III) can be referred to the ones as exemplified for the compound
(I).
The new heterocyclic compounds (I) and a
pharmaceutically acceptable salt thereof of the present invention possess strong antithrombotic activity
inhibiting the activities against cyclooxygenase,
thrombin, phosphodiesterase and the like, and/or
inhibiting aggregation of platelet; vasodilating activity; and anti-inflammatory activity; particularly
antithrombotic activity, and therefore are useful as antithrombotic agent, vasodilating agent, and
anti-inflammatory agent, particularly anti-thrombotic agent.
Accordingly, the new heterocyclic compounds (I) and a pharmaceutically acceptable salt thereof can be used for prophylactic and thrapeutic treatment of cerebral
thrombosis, atrophic thrombosis; coronary thrombosis;
creeping thrombosis; dilation thrombosis; jumping
thrombosis; mural 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
infarction; reocclusion after percutaneous transluminal coronary angioplasty or percutaneous transluminal coronary recanalization; arteriosclerosis; cerebiral vasospam;
disseminated intravascular coagulopathy; hypertension such as pulmonary hypertension; psoriasis; arthritis;
nephritis; inflammatory bowel diseases; septic shock;
dysmnesia; senile dementia; endotoxin shock; and the like.
And, these compounds are also useful for inhibition of thrombosis during extracorporeal circulation such as dialysis.
Further, 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.
The heterocyclic compounds (I) and a pharmaceutically acceptable salt thereof scarcely have side effect exerting a bad influence upon patients.
In order to show the utilities of the heterocyclic compounds (I) and a pharmaceutically acceptable salt thereof of the present invention, pharmacological test data of the representative compound of the heterocyclic compounds (I) are illustrated in the following.
The expressions of "Example 1-(1)", "Example 2-(l)" and "Example 7-(3)" "Example 17- (2)", "Example 21-(1)" and "Example 24- (1)" in the following tests mean the compounds prepared in Example 1-(1), 2-(l), 7-(3), 17-(2), 21-(1) and 24- (1) respectively. Platelet aggregation ex vivo
1. Test method
Male Hartley guinea-pigs weighing about 300 g were used after 24 hours fasting. Six hours after oral administration of the test compound or vehicle of test compound (control), blood was collected into a tube containing 0.1 vol. of 3.8% sodium citrate and platelet rich plasma (PRP) was prepared.
To the 250 ul of PRP, 5 μl of arachidonic acid (final 50 μM) was added as an aggregation inducer. Aggregation was measured by using an aggregometer (NKK HEMA-TRACER 1). The following result shows the relationship between the dose of the test compound and the percentage (%) of its inhibitory activity against the platelet aggregation responses.
Figure imgf000048_0001
Relaxation effect on isolated rat aorta
1. Test method
Helical strip of rat thoracic aorta was suspended in the organ bath containing Tyrode
solution gassed with 95%O2 - 5% CO2 at 37°C under 0.5 g load. Contraction was induced by addition of
KCS, solution (final concentration was 30 mM) . After the tonus reached plateau, drug solution (dissolved in dimethyl sulfoxide) was, added cumulatively and finally 10 -4M of papaverine was added to get maximum relaxation. Activities of the test compound were expressed as ED50 values i.e. doses required to relax the isolated rat aorta by 50%.
Figure imgf000049_0001
Effect on ma londi aldehyde (MDA) production in rabbit
platelets
1. Test method
Washed rabbit PRP (990 μl) was preincubated with drug solution (dissolved in dimethyl sulfoxide) (10 μl) at 37°C for 5 minutes. Then, 2.5 mM arachidonic acid solution (20 μl) was added to the reaction mixture. After 3 minutes, thiobarbiturate reagent (1000 μl) was added, and the reaction mixture was heated in a boiled water for 10 minutes. After centrifugation at 1500 g for 10 minutes, the
absorbance of suparnatant was measured at 532 nm. This test was carried out to see inhibitory activity of the test compound against the activity of
cyclooxygenase.
Figure imgf000049_0002
For therapeutic administration, the object compounds (I) of the present invention and pharmaceutically
acceptable salts thereof are used in a form of the
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. However, the above dosage may be increased or decreased according to age, weight and conditions of the patient or the
administering method.
The following preparations and examples are given only for the purpose of illustrating the present invention in more detail.
Preparation 1
To a solution of anisil (25 g) and sodium hydroxide (21.62 g) in methanol (1.5 ℓ) was added
2,3-diaminopropanoic acid hydrobromide (36.52 g). The mixture was refluxed for 1 hour, and the cooled mixture was filtered. The filtrate was concentrated to a volume of 200 ml under reduced pressure and insolble material was collected by filtration. A mixture of this precipitate, water (100 ml) and ethyl acetate (50 ml) was adjusted to pH 10.5 with 3N-sodium hydroxide aqueous solution and the resultant mixture was acidified to pH 4.0 with
4N-hydrochloric acid. The precipitate was collected and washed with water to give 2,3-bis(4-methoxyphenyl)-pyrazine-5-carboxylic acid.
mp : 233°C (dec.)
IR (Nujol) : 1690, 1600, 1510 cm-1
NMR (DMSO-d6 , δ ) : 2.80 ( 6H, s ) , 6. 97 , 7.46 ( 8H,
ABq, J=9Hz), 9.13 (1H, s)
MASS (m/z) : 336 (M+)
Preparation 2
A mixture of 2,3-bis(4-methoxyphenyl)pyrazine-5-carboxylic acid (0.5 g), 3-methyl-1-p-tolyltriazine (0.44 g) in tetrahydrofuran (15 ml) was stirred at 40°C for 1 hour. The reaction mixture was poured into a mixture of ethyl acetate and water and adjusted to pH =2 with
6N-hydrochloric acid. The separated organic layer was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the resulting precipitate was washed with isopropyl ether to give 5-methoxycarbonyl-2,3-bis(4-methoxyphenyl)pyrazine (0.36 g).
IR (Nujol) : 1720, 1600, 1505 cm-1
NMR (CDCl3, δ) : 3.82 ( 3H, s), 3.83 ( 3H, s),
4.04 (3H, s), 6.85 (4H, d, J=9Hz), 7. 47 (2H, d. J=9Hz) , 7. 48 ( 2H, d, J=9Hz ) , 9.18 ( 1H, s)
Mass (m/z ) : 350 (M+)
Example 1
(1) To a mixture of 2-acetylamino-1-thioxoethylamine
(0.50 g) and ethanol was added hydrazine monohydrate (0.18 ml) at -70°C and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture containing 2-acetylamino-1-hydrazonoethylamine was added p-anisil (1.02 g) at -20°C, and an ethanol solution of hydrogen chloride (3 drops) was added thereto. The reaction mixture was stirred and refluxed for 20 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 saturated aqueous sodium bicarboante, 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 (50 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 isopropyl ether to give 3-(acetylaminomethyl)-5,6-bis(4-methoxyphenyl)-1,2,4-triazine (0.20 g).
mp : 44-55°C
IR (Nujol) : 1650, 1600, 1490 cm-1
NMR (CDCl3, δ) : 2.13 (3H, s), 3.83 (3H, s),
3.85 (3H, s), 4.90 (2H, d, J=5Hz),
6.8-7.1 (5H, m), 7.55 (2H, d, J=9Hz), 7.58 (2H, d, J=9Hz)
MASS (m/z) : 364 (M+)
The following compounds were obtained according to a similar manner to that of Example 1-(1). ( 2 ) 3-Ethoxycarbonyl-5,6-bis(4-methoxyphenyl)-1,2,4- triazine
mp : 120-122°C
IR (Nujol) : 1740, 1650, 1595, 1570 cm-1
NMR (CDCl3, δ) : 1.50 (3H, t, J=7Hz), 3.84 (3H, s),
3.86 (3H, s), 4.6 (2H, q, J=7Hz), 6.88 (2H, d, J=9Hz), 6.96 (2H, d, J=9Hz), 7.62 (2H, d,
J=9Hz), 7.69 (2H, d, J=9Hz)
MASS (m/z) : 365 (M+)
( 3 ) 3-(2-tert-Butyloxycarbonylaminoethyl)-5,6- bis(4-methoxyphenyl)-1,2,4-triazine
mp : 102-105°C
IR (Nujol) : 3320, 1680, 1610, 1490, 1250 cm-1
NMR (DMSO-d6, δ) : 1.33 (9H, s), 3.18 (2H, t, J=6Hz),
3.48 (2H, q, J=6Hz), 3.78 (3H, s), 3.80 (3H, s), 6.95 (2H, d, J=9Hz), 6.99 (2H, d, J=9Hz),
7.43 (2H, d, J=9Hz), 7.52 (2H, d, J=9Hz)
MASS (m/z) : 436 (M+)
( 4 ) 3-(1-tert-Butyloxycarbonylamino-1-methylethyl)-5,6- bis(4-methoxyphenyl)-1,2,4-triazine
mp : 140°C
IR (Nujol) : 3250, 1700, 1600, 1490, 1300, 1250 cm-1 NMR (DMSO-d6, δ) : 1.31 (9H, s), 1.68 (6H, s),
3.79 (3H, s), 3.80 (3H, s), 6.97 (2H, d, J=9Hz), 7.01 (2H, d, J=9Hz), 7.46 (2H, d, J=9Hz),
7.51 (2H, d, J=9Hz)
MASS (m/z) : 450 (M+)
( 5 ) 3-(N,N-Dimethylaminomethyl)-5,6-bis(4-methoxyphenyl)- 1,2,4-triazine
IR (Neat) : 2820, 1600, 1480, 1250 cm-1
NMR (DMSO-d6, δ) : 2.33 (6H, s), 3.79 (3H, s), 3.80 (3H, s), 3.87 (2H, s), 6.95 (2H, d, J=8Hz), 6.99 ( 2H, d, J=8Hz ) , 7 . 45 ( 2H , d, J=8Hz ) , 7 . 52 ( 2H, d, J=8Hz )
MASS (m/z ) : 350 (M+) (6) 5,6-Bis(4-methoxyphenyl)-3-{(4-methylpiperazin-1-yl)- carbonyl}-1,2,4-triazine hydrochloride
mp : 252-254°C
IR (Nujol) : 3400, 2400, 1645, 1600, 1575 cm-1 Example 2
(1) A mixture of 3-ethoxycarbonyl-5,6-bis(4-methoxyphenyl)-1,2,4-triazine (1.00g) and
N-methγlpiperazine (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
5,6-bis(4-methoxyphenyl)-3-{(4-methylpiperazin-1-yl)-carbonyl}-1,2,4-triazine hydrochloride (0.76 g).
mp : 252-254°C
IR (Nujol) : 3400, 2400, 1645, 1600, 1575 cm-1
NMR (DMSO-d6, δ) : 2.81 (3H, s), 2.80-4.80 (8H, m) , 3.80 (3H, s), 3.81 (3H, s), 6.98 (2H, d, J=9Hz), 7.03 (2H, d, J=9Hz), 7.53 (4H, d, J=9Hz)
MASS (m/z) : 418 [M+ (419) of free compound-1]
The following compounds were obtained according to a similar manner to that of Example 2-(1). ( 2 ) 3-{ (4-(2-Hydroxyethyl)piperazin-l-yl)carbonyl}-5,6- bis(4-methoxyphenyl)-1,2,4-triazine hydrochloride mp : 141-147°C
IR (Nujol) : 1650, 1610 cm-1
NMR (DMSO-d6, δ) : 2.8-4.8 (12H, m) , 3.80 (3H, s),
3.81 (3H, s), 6.98 (2H, d, J=9Hz),
7.03 (2H, d, J=9Hz), 7.53 (4H, d, J=9Hz)
MASS (m/z) : 449 (M of free compound) (3) 3-(Morpholmocarbonyl) -5, 6-bis(4-methoxyphenyl)- 1,2,4-triazine
mp : 65-70°C
IR (Nujol) : 1650, 1600, 1580 cm-1
NMR (DMSO-d6, δ) : 3.4-3.8 (8H, m) , 3.79 (3H, s), 3.81 (3H, s), 6.96 (2H, d, J=9Hz),
7.03 (2H, d, J=9Hz), 7.53 (4H, d, J=9Hz)
MASS (m/z) : 406 (M+)
(4) 3-(N,N-Dimethylaminocarbonyl)-5,6-bis(4-methoxyphenyl)-1,2,4-triazine
mp : 50-60°C
IR (Nujol) : 1650, 1600 cm-1
NMR (DMSO-d6, δ) : 2.98 ( 3H, s), 3.10 (3H, s),
3.79 (3H, s), 3.81 (3H, s), 6.96 (2H, d, J=9Hz), 7.01 (2H, d, J=9Hz), 7.53 (4H, d, J=9Hz)
MASS (m/z) : 364 (M+)
(5) 3- [{2-(N,N-Dimethylamino)ethyl}carbamoyl]-5,6- bis(4-methoxyphenyl)-1,2,4-triazine
mp : 137-140°C
IR (Nujol) : 1690, 1600, 1250 cm-1
NMR (DMSO-d6, δ) : 2.21 (6H, s), 2.48 (2H, t,
J=6Hz), 3.46 (2H, q, J=6Hz), 3.80 (3H, s), 3.81 (3H, s), 6.98 (2H, d, J=8Hz), 7.02 (2H, d,
J=8Hz), 7.53 (2H, d, J=8Hz), 7.61 (2H, d. J=8Hz ) , 9. 06 ( 1H, t , J=6Hz )
MASS (m/z ) : 407 (M+)
(6) 3-[(4-Benzylpiperazin-1-yl)carbonyl]-5,6-bis(4- methoxyphenyl)-1,2,4-triazine
mp : 126-129°C
IR (Nujol) : 1630 ,1600, 1480 cm-1
NMR (CDCl3, δ) : 2.4-2.7 (4H, m), 3.57 (2H, s),
3.7-4.0 (4H, m), 3.83 (3H, s), 3.85 (3H, s), 6.84 (2H, d, J=8.9Hz), 6.92 (2H, d, J=8.9Hz),
7.2-7.45 (5H, m), 7.56 (2H, d, J=8.9Hz), 7.66
(2H, d, J=8.9Hz)
(7) 3-[(1-Benzylpiperidin-4-yl)carbamoyl]-5,6-bis(4- methoxyphenyl)-1,2,4-triazine
mp : 132-136°C
IR (Nujol) : 3380, 1690, 1600, 1520, 1490 cm-1
NMR (CDCl3, δ) : 1.55-2.4 (6H, m), 2.75-3.0 (2H, m),
3.54 (2H, s), 3.84 (3H, s), 3.86 (3H, s),
4.03-4.18 (1H, m), 6.86 (2H, d, J=8.9Hz), 6.93
(2H, d, J=8.9Hz), 7.18-7.5 (5H, m) , 7.59 (2H, d,
J=8.9Hz), 7.69 (2H, d, J=8.9Hz), 8.01 (1H, d,
J=8.2Hz )
MASS (m/z) : 509 (M*)
Example 3
A mixture of 3-(acetylaminomethyl)-5,6-bis(4-methoxyphenyl)-1,2,4-triazine (0.79 g) and concentrated
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. To the resulting mixture was added diethyl ether and it was triturated to give powder of 3-(aminomethyl)-5,6-bis(4-methoxyphenyl)-1,2,4-triazine hydrochloride (0.18 g).
mp : 163-173°C (decomp.)
IR (Nujol) : 1600, 1580, 1520 cm-1
NMR (DMSO-d6, δ) : 3.80 ( 3H, s), 3.81 (3H, s),
4.52 (2H, br s), 6.98 (2H, d, J=9Hz),
7.03 (2H, d, J=9Hz), 7.49 (2H, d, J=9Hz),
7.63 (2H, d, J=9Hz), 9.00 (3H, br s) MASS (m/z) : 322 (M+ of free compound) Example 4
A mixture of 3-(aminomethyl)-5,6-bis(4-methoxyphenyl)-1,2,4-triazine hydrochloride (1.00 g), chloroform and an aqueous solution of sodium
bicarbonate was stirred at ambient temperature for 30 minutes, and the separated organic layer was dried over magnesium sulfate and treated with active carbon. After filtration, the filtrate was evaporated in vacuo. The resulting matter was dissolved with N,N-dimethylformamide (10 ml), and to the mixture were added 6-carboxyl-3-oxo-2,3,4,5-tetrahydropyridazine (0.40 g),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (0.53 g) and triethylamine (0.39 ml). The resulting mixture was stirred at 100°C for 15 hours.
After allowing to cool to room temperature, the mixture was poured into water, and extracted with ethyl acetate.
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
5, 6-bis ( 4-methoxyphenyl)-3-{(3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)carbonylaminomethyl}-1,2,4-triazine (0.07 g).
mp : 183-187°C
IR (Nujol) : 3400, 1700, 1670, 1660, 1640, 1610,
1580 cm-1
NMR (DMSO-d6, δ) : 2.47 (2H, t, J=8.2Hz), 2.78 (2H, t, J=8.2Hz), 3.78 (3H, s), 3.80 (3H, s),
4.78 (2H, d, J=5.8Hz), 6.95 (2H, d, J=8.3Hz), 7.00 (2H, d, J=8.3Hz), 7.45 (2H, d, J=8.3Hz),
7.49 (2H, d, J=8.3Hz), 8.75 (1H, t, J=5.8Hz) MASS (m/z) : 446 (M+)
Example 5
(1) A mixture of 5,6-bis(4-methoxyphenyl)-3-[2-(tert- butyloxycarbonylamino)ethyl]-1,2,4-triazine (1.00 g) and dichloromethane (10 ml) was stirred at 2°C. To the reaction mixture was added 4N-hydrogen
chloride-1,4-dioxane (10 ml), and the mixture was stirred at ambient temperature for 1 hour. The resulting matter was evaporated in vacuo. To the residue was added
isopropyl ether (50 ml) and it was stirred at 2°C for 3 hours. The resulting precipitate was collected by
filtration and washed with isopropyl ether to give
3-(2-aminoethyl)-5,6-bis(4-methoxyphenyl)-1,2,4-triazine hydrochloride (0.73 g).
mp : 98°C (decomp.)
IR (Nujol) : 3500-3300, 1600, 1510, 1310, 1260 cm-1 NMR (DMSO-d6, δ) : 3.17-3.70 (4H, m), 3.79 (3H, s), 3.80 (3H, s), 6.97 (3H, d, J=9Hz), 7.01 (3H, d, J=9Hz), 7.46 (3H, d, J=9Hz), 7. 53 (3H, d, J=9Hz), 8.01 (2H, br s) MASS : m/z 336 (M of free compound) The following compound was obtained according to a similar manner to that of Example 5-(l).
( 2 ) 3-(1-Amino-1-methylethyl)-5,6-bis(4-methoxyphenyl)-1,2,4-triazine hydrochloride
mp : 245-247°C
IR (Nujol) : 3600-3300, 1600, 1490, 1300 cm-1 NMR (DMSO-d6, δ): 1.79 (6H, s), 3.80 (3H, s),
3.81 (3H, s), 6.99 (2H, d, J=9Hz),
7.03 (2H, d, J=9Hz), 7.50 (2H, d, J=9Hz), 7.65 (2H, d, J=9Hz), 8.93 (3H, br s)
MASS (m/z) : 350 (M+)
Example 6
(1) To a solution of 3-(1-amino-1-methylethyl)-5,6- bis(4-methoxyphenyl)-l,2,4-triazme hydrochloride (1.30 g), 3-oxo-6-carboxy-2,3,4,5-tetrahydropyridazine (0.48 g) and 1-hydroxybenzotriazole hydrate (0.52 g) in
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. The resulting precipitate was collected by filtration, and washed with diethyl ether to give 5,6-bis(4-methoxyphenyl)-3-[1-{(3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)carbonylamino}-1-methylethyl]-1,2,4-triazine (1.33 g). mp : 221-222°C
IR (Nujol) : 3350, 3250, 1700, 1660, 1600, 1500,
1250 cm-1
NMR (DMSO-d6, δ) : 1.83 (6H, s), 2.42 (2H, t, J=8Hz), 2.72 (2H, t, J=8Hz), 3.79 (3H, s), 3.80 (3H, s), 6.97 (2H, d, J=9Hz), 7.02 (2H, d, J=9Hz),
7.48 (2H, d, J=9Hz), 7.53 (2H, d, J=9Hz),
8.72 (1H, s), 11.20 (1H, s)
MASS (m/z) : 474 (M+)
The following compound was obtained according to a similar manner to that of Example 6-(1).
(2) 5,6-Bis(4-methoxyphenyl)-3-[2-{(3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)carbonylamino}ethyl]-1,2,4-triazine
mp : 85°C (decomp.)
IR (Nujol) : 3500-3200, 1660, 1600, 1250 cm-1
NMR (DMSO-d6, δ) : 2.36 (2H, t, J=8Hz),
2.70 (2H, t, J=8Hz), 3.30-3.36 (2H, m),
3.78 (3H, s), 3.80 (3H, s), 6.91 (2H, d, J=9Hz), 7.00 (2H, d, J=9Hz), 7.45 (2H, d, J=9Hz),
7.50 (2H, d, J=9Hz), 8.33 (1H, t, J=6Hz),
11.10 (1H, s)
MASS (m/z) : 460 (M+)
Example 7
(1) A mixture of 3-(aminomethyl)-5,6-bis(4-methoxyphenyl)-1,2,4-triazine hydrochloride (0.80 g), chloroform and an aqueous solution of sodium
bicarbonate was stirred at ambient temperature for 30 minutes, and the separated organic layer was dried over magnesium sulfate and treated with active carbon. After filtration, the filtrate was evaporated in vacuo. To the resulting matter was added a mixture of tetrahydrofuran (20 ml) and methanol (7 ml), and to the mixture was added isopropyl isocyanate (0.26 ml). The reaction mixture was stirred at ambient temperature for 3 hours and 50 minutes. The mixture was evaporated in vacuo, and the resulting matter was triturated with isopropyl ether and diethyl ether to give 3-(N'-isopropylureidomethyl)-5,6-bis(4-methoxyphenyl)-1,2,4-triazine (0.75 g).
mp : 80-83°C
IR (Nujol) : 3300, 1630, 1600, 1560, 1490 cm-1
NMR (DMSO-d6, δ) : 1.06 (6H, d, J=6.5Hz),
3.70 (1H, m), 3.78 (3H, s), 3.80 (3H, s),
4.64 (2H, d, J=5.8Hz), 6.14 (1H, d, J=7.7Hz), 6.45 (1H, t, J=5.8Hz), 6.95 (2H, d, J=8.8Hz), 7.00 (2H, d, J=8.8Hz), 7.45 (2H, d, J=8.8Hz), 7.52 (2H, d, J=8.8Hz)
MASS (m/z) : 407 (M+)
The following compounds were obtained according to a similar manner to that of Example 7-(l).
( 2 ) 3-(N'-Ethylureidomethyl)-5,6-bis(4-methoxyphenyl)- 1,2,4-triazine
mp : 69-74°C
IR (Nujol) : 3300, 1640, 1600, 1560 cm-1
NMR (DMSO-d6, δ) : 1.03 (3H, t, J=7Hz),
3.05 (2H, q, J=7Hz), 3.78 (3H, s), 3.80 (3H, s), 4.64 (2H, d, J=5.9Hz), 6.23 (1H, t, J=5.5Hz), 6.56 (1H, t, J=5.5Hz), 6.95 (2H, d, J=9Hz), 7.00 (2H, d, J=9Hz), 7.45 (2H, d, J=9Hz),
7.52 (2H, d, J=9Hz)
MASS (m/z) : 393 (M+)
(3) 3-[2-(N'-Isopropylureido)ethyl]-5,6-bis(4- methoxyphenyl)-1,2,4-triazine
mp : 157-160°C IR (Nujol) : 3400-3200, 1640, 1620, 1570, 1180 cm-1 NMR (DMSO-d6, δ) : 0.98 (6H, d, J=6.5Hz), 3.20 (2H, t, J=7Hz), 3.51-3.72 (3H, m) , 3.79 (3H, s), 3.80 (3H, s), 5.73 (1H, d, J=7.5Hz), 5.85 (1H, t, J=6Hz), 6.96 (2H, d, J=9Hz),
6.99 (2H, d, J=9Hz), 7.45 (2H, d, J=9Hz),
7.52 (2H, d, J=9Hz)
MASS (m/z) : 421 (M+) Example 8
(1) A solution of 5 ,6-bis(4-methoxyphenyl)-3-(pyridin-4-yl)-l,2,4-triazine (0.50 g) and methyl iodide (0.75 ml) in a mixture of chloroform and methanol (9:1) (20 ml) was allowed to stand at ambient temperature for 1 day. The reaction mixture containing 4-[5,6-bis(4-methoxyphenyl)-triazin-3-yl]-1-methylpyridinium iodide was evaporated in vacuo and the residue was dissolved in a mixture of methanol (30 ml) and water (10 ml). To the resultant solution was added portionwise sodium borohydride (0.10 g) under stirring at 5 to 10°C. The reaction mixture was stirred for 2.5 hours at the same temperature. Water (100 ml) was added to the reaction mixture and the resulting precipitate was collected by filtration. The precipitate was dissolved in chloroform, washed with brine and dried over magnesium sulfate. The separated organic layer was evaporated in vacuo, and the residue was washed with diethyl ether to give 5, 6-bis(4-methoxyphenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1,2,4-triazine (0.32 g).
mp : 163-165°C
IR (Nujol) : 1600, 1300, 1250 cm-1
NMR (DMSO-d6, δ) : 2.33 (3H, s), 2.64 (2H, m),
2.76 (2H, m), 3.17 (2H, m), 3.78 (3H, s),
3.80 (3H, s), 6.95 (2H, d, J=9Hz),
7.00 (2H, d, J=9Hz), 7.33 (1H, m), 7 . 47 ( 2H, d, J=9Hz ) , 7 . 54 ( 2H, d, J=9Hz )
MASS (m/z ) : 388 (M+)
The following compound was obtained according to a similar manner to that of Example 8-(1).
( 2 ) 5,6-Bis(4-methoxyphenyl)-3-[1-(4-fluorobenzyl)- 1,2,3,6-tetrahydropyridin-4-yl]-1, 2 ,4-triazine mp : 137-138°C
IR (Nujol) : 1645, 1600, 1570, 1505 cm-1
NMR (DMSO-d6, δ) : 2.70 (4H, br s), 3.21 (2H, br s), 3.63 (2H, s), 3.78 (3H, s), 3.79 (3H, s),
6.91-7.00 (4H, m), 7.12-7.20 (2H, m) , 7.20-7.55 (7H, m)
MASS (m/z) : 482 (M+)
Example 9
(1) A mixture of 3-ethoxycarbonyl-5,6-bis(4-methoxyphenyl)-1,2,4-triazine (10 g) and 2,5-norbornadiene
(5.55 g) in the xylene (400 ml) was refluxed under
stirring for 24 hours. The reaction mixture was
evaporated in vacuo, and the resulting precipitate was washed with diethyl ether to give
6-ethoxycarbonyl-2,3-bis(4-methoxyphenyl)pyridine
(6.47 g).
mp : 108-109°C
IR (Nujol) : 1700, 1600, 1505 cm-1
NMR ( CDCl3, δ ) : 1. 45 ( 3H, t, J=7Hz ) , 3.79 ( 3H, s ) , 3.81 (3H, s), 4.48 (2H, q, J=7Hz), 6.78 (2H, d, J=8Hz), 6.84 (2H, d, J=8Hz), 7.12 (2H, d,
J=8Hz), 7.37 (2H, d, J=8Hz), 7.78 (1H, d,
J=8Hz), 8.05 (1H, d, J=8Hz)
MASS (m/z) : 363 (M+) The following compounds were obtained according to a similar manner to that of Example 9-(l).
( 2) 6-Acetylaminomethyl-2,3-bis ( 4-methoxyphenyl)pyridine
IR (Film) : 1720 cm-1
NMR (CDCl3, δ) : 2.08 (3H, s), 3.80 (3H, s),
3.81 (3H, s), 4.63 (2H, d, J=5Hz),
6.7-7.0 (5H, m), 7.07 (2H, d, J=8Hz), 7.2-7.4 (3H, m), 7.64 (1H, d, J=8Hz)
MASS (m/z) : 362 (M+)
( 3 ) 6-(Pyridin-4-yl)-2,3-bis(4-methoxyphenyl)pyridine
mp : 175-178°C
IR (Nujol) : 1610, 1600, 1510, 1250 cm-1
NMR (DMSO-d6, δ) : 3.77 (6H, s), 6.90 (2H, d, J=8Hz), 6.94 (2H, d, J=8Hz), 7.19 (2H, d, J=8Hz),
7.37 (2H, d, J=8Hz), 7.93 (1H, br s), 8.15 (1H, br s), 8.74 (2H, br s)
MASS (m/z) : 368 (M+) (4) 2,3-Bis(4-methoxyphenyl)-6-(N,N-dimethylaminomethyl)- pyridine
mp : 103-108°C (dec.)
IR (Nujol) : 1610, 1510, 1250 cm-1
NMR (DMSO-d6, δ) : 2.82 (3H, s), 2.83 (3H, s), 3.74 (3H, s), 3.76 (3H, s), 4.46 (2H, s), 6.84 (2H, d, J=8Hz), 6.90 (2H, d, J=8Hz), 7.13 (2H, , J=8Hz), 7.32 (2H, d, J=8Hz), 7.63 (1H, d,
J=8Hz), 7.85 (2H, d, J=8Hz) Example 10
(1) A mixture of 6-ethoxycarbonyl-2,3-bis(4-methoxyphenyl)pyridine (1.03 g) and
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.
After filtration, the filtrate was evaporated in vacuo, and the resulting residue was dissolved with diethyl ether, and to it was added an ethanol solution of hydrogen chloride. The resulting precipitate was
collected by filtration and washed with ethanol and diethyl ether to give 2,3-bis(4-methoxyphenyl)-6-[(4-methyl-piperazin-1-yl)carbonyl]pyridine dihydrochloride (0.25 g).
mp : 213-216°C
IR (Nujol) : 3400 (br), 2400 (br), 1980 (br),
1650, 1610, 1510 cm-1
NMR (DMSO-d6, δ) : 2.77 (3H, s), 2.8-4.8 (8H, m) ,
3.75 (3H, s), 3.76 (3H,s), 6.85 (2H, d, J=9Hz), 6.91 (2H, d, J=9Hz), 7.15 (2H, d, J=9Hz),
7.26 (2H, d, J=9Hz), 7.68 (1H, d, J=9Hz),
7.92 (1H, d, J=9HZ)
MASS (m/z) : 415 [M+(417) of free compound -2]
The following cαrpounds were obtained according to a similar manner to that of Example 10-(1).
(2) 2,3-Bis(4-methoxyphenyl)-6-[{2-(N,N-dimethylamino)- ethyl}carbamoyl]pyridine dihydrochloride
mp : 68-71°C
IR (Nujol) : 1600, 1510, 1300, 1250 cm-1
NMR (DMSO-d6, δ) : 2.80 (3H, s), 2.83 (3H, s),
3.28 (2H, q, J=6Hz), 3.73 (2H, t, J=6Hz),
3.75 (3H, s), 3.76 (3H, s), 6.86 (2H, d, J=8Hz), 6.91 (2H, d, J=8Hz), .7.15 (2H, d, J=8Hz),
7.42 (2H, d, J=8Hz), 7.92 (2H, d, J=8Hz),
8.00 (2H, d, J=8Hz), 9.02 (1H, t, J=6Hz), 10.58 (1H, m)
MASS (m/z) : 405 (M of free compound)
(3) 2 ,3-Bis (4-methoxyphenyl)-6-[(4-benzylpiperazin-1-yl)- carbamoyl]pyridine
mp : 126-132°C
IR (Nujol) : 1610, 1500 cm-1
NMR (CDCl3, δ) : 2.4-2.7 (4H, m), 3.56 (2H, s),
3.7-3.95 (4H, m) , 3.79 (3H, s), 3.81 (3H, s), 6.77 (2H, d, J=8.9Hz), 6.83 (2H, d, J=8.9Hz),
7.11 (2H, d, J=8.9Hz), 7.2-7.45 (7H, m),
7.63 (1H, d, J=7.9Hz), 7.75 (1H, d, J=7.9Hz) MASS (m/z) : 493 (M+) Example 11
(1) To a mixture of lithium aluminum hydride (0.24 g) and tetrahydrofuran (20 ml) was added a solution of
6-ethoxycarbonyl-2,3-bis(4-methoxyphenyl)pyridine (2.1 g) in tetrahydrofuran (2.1 ml) with stirring and ice-cooling, and the mixture was stirred for 1 hour at the same
temperature. To the reaction mixture were added ethyl acetate (20 ml) and water (20 ml) very carefully. The organic layer was washed with brine and dried over
magnesium sulfate. After filtration, the filtrate was evaporated in. vacuo to give 6-hydroxymethyl-2,3-bis(4-methoxyphenyl)pyridine (2.04 g) .
NMR (CDCl3, δ) : 3.79 (3H, s), 3.81 (3H, s),
4.82 (2H, s), 6.79 (2H, d, J=9Hz),
6.84 (2H, d, J=9Hz), 7.0-7.4 (5H, m), 7.67 (1H, d, J=8Hz)
Mass (m/z) : 321 (M+)
(2) A mixture of 6-hydroxymethyl-2,3-bis(4-methoxyphenyl)pyridine (2 g) and activated
manganese dioxide (6 g) in the chloroform (20 ml) was stirred at ambient temperature for 5.5 hours. After filtration, the filtrate was evaporated in vacuo, and the resulting precipitate was washed with isopropyl ether to give 2,3-bis(4-methoxyphenyl)-6-pyridinecarbaldehyde (1.61 g).
MMR (CDCl3, δ) : 3.81 (3H, s), 3.82 (3H, s),
6.81 (2H, d, J=9Hz), 6.84 (2H, d, J=9Hz),
7.12 (2H, d, J=9HZ), 7.37 (2H, d, J=9Hz),
7.81 (1H, d, J=8Hz), 7. 95 (1H, d, J=8Hz)
MASS (m/z) : 319 (M+)
Example 12
The following compound was obtained by reacting 5-methoxycarbonyl-2,3-bis(4-methoxyphenyl)pyrazine according to a similar manner to that of Example 11.
2,3-Bis(4-methoxyphenyl)-6-pyrazinecarbaldehyde IR (Nujol) : 1700, 1600, 1505 cm-1
NMR (CDCl3, δ) : 3.83 (3H, s), 3.84 (3H, s),
6.8-7.0 (4H, m) , 7.44-7.6 (4H, m) ,
9.07 (1H, s), 10.22 (1H, s)
MASS (m/z) : 320 (M+)
Example 13
(1) A mixture of 2,3-bis(4-methoxyphenyl)-6-pyridinecarbaldehyde (0.6 g), malonic acid (0.98 g), piperidine (0.1 ml) and pyridine (6 ml) was refluxed under stirring for 1 hour and 20 minutes. After allowing to cool to room temperature, the mixture was poured into water and ethyl acetate, and adjusted to pH =10.5 with an aqueous solution of 4N sodium hydroxide. The separated aqueous layer was washed with ethyl acetate, and the aqueous layer was adjusted to pH =A with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo to give 3-[2,3-bis(4-methoxyphenyl)pyridin-6-yl]-(E)-propenoic acid (0.35 g).
mp : 160-170°C
IR (Nujol) : 1680, 1630, 1600, 1500 cm-1
NMR (DMSO-d6, δ) : 3.75 (6H, s), 6.75-6.97 (4H, m), 6.85 (1H, d, J=15.6Hz), 6.99-7.35 (4H, m), 7.67 (1H, d, J=16Hz), 7.69 (1H, d, J=8Hz), 7.8 (1H, d, J=8Hz)
MASS (m/z) : 361 (M+)
The following compound was obtained according to a similar manner to that of Example 13-(1). (2) 3-[2,3-Bis(4-methoxyphenyl)pyrazin-5-yl]-(E)- propenoic acid
mp : 238-240°C
IR (Nujol) : 1680, 1630, 1600, 1500 cm-1
NMR (CDCl3 + DMSO-d6, δ) : 3.82 (3H, s), 3.83 (3H, s)
6.85-6.93 (4H, m), 7.07 (1H, d, J=15.6Hz), 7.35-7.54 (4H, m), 7.75 (1H, d, J=15.6Hz), 8.56 (1H, s)
MASS (m/z) : 362 (M+)
Example 14
(1) A mixture of 3-[2,3-bis(4-methoxyphenyl)pyridin-6-yl]-(E)-propenoic acid (0.8 g) and 10% palladium-carbon (0.16 g) in methanol (8 ml) was stirred under hydrogen at low pressure at ambient temperature for 5 hours. The insoluble material was filtered and washed with a mixture of chloroform and methanol, and the filtrate was
evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate and water and the resultant solution was adjusted to pH =4 with 6N-hydrochloric acid. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (10:1). The eluted solution was evaporated in vacuo and the resulting precipitate was washed with diethyl ether to give 3-[2,3-bis(4-methoxyphenyl)pyridin- 6-yl]propanoic acid (495 mg).
mp : 146-147°C
IR (Nujol) : 1710, 1600, 1510 cm-1
NMR (CDCl3, δ) : 2.8-2.95 (2H, m), 3.15-3.29 (2H, m) ,
3.8 (3H, s), 3.81 (3H, s), 6.75-7.33 (9H, m) , 7.76 (1H, d, J=8Hz)
MASS (m/z) : 363 (M+) The following compound was obtained according to a similar manner to that of Example 14-(1).
(2) 3-[2,3-Bis(4-methoxyphenyl)pyrazin-5-y1]propanoic
acid
mp : 120-128°C
IR (Nujol) : 1700, 1600, 1570, 1500 cm-1
NMR (CDCl3, δ) : 2.8-3.0 (2H, m), 3.1-3.3 (2H, m), 3.8 (3H, s), 3.81 (3H, s), 6.83 (2H, d, J=9Hz), 6.84 (2H, d, J=9Hz), 7.37 (2H, d, J=9Hz),
7.38 (2H, d, J=9Hz), 8.46 (1H, s)
MASS (m/z) : 364 (M+)
Example 15
(1) A mixture of 6-acetylaminomethyl-2,3-bis(4-methoxyphenyl)pyridine (1.64 g) and concentrated
hydrochloric acid (3.3 ml) was stirred and refluxed for 1.5 hours. The reaction mixture was poured into a mixture of ethyl acetate and ice-water and adjusted to pH =10 with 4N-sodium hydroxide. The separated organic layer was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the resulting residue was dissolved in ethanol and to it was added an ethanol solution of hydrogen chloride. To the resulting mixture was added diethyl ether and it was triturated to give 6-aminomethyl-2,3-bis(4-methoxyphenyl)pyridine dihydrochloride (1.13 g).
mp : 150°C (dec.)
IR (Nujol) : 3400 (br), lξOO, 1500 cm-1
NMR (CDCl3, δ) : 3.71 (3H, s), 3.76 (3H, s),
5.2 (2H, br s), 6.75 (2H, d, J=9Hz),
6.81 (2H, d, J=9Hz), 7.01 (2H, d, J=9Hz),
7.45 (2H, d, J=9Hz), 8.31 (1H, d, J=8Hz),
8.54 (1H, d, J=8Hz), 9.49 (2H, br s) MASS (m/z) : 320 (M+ of free compound)
The following compound was obtained according to a similar manner to that of Example 15-(1).
( 2) 2-Aminomethyl-4,5-bis(4-methoxyphenyl)pyrimidine
hydrochloride
IR (Nujol) : 1605, 1585, 1570, 1510 cm-1
NMR (DMSO-d6, δ) : 3.78 (6H, s),
4.33 (2H, d,-J=6Hz), 4.82 (2H, s),
6.90 (2H, d, J=9Hz), 6.98 (2H, d, J=9Hz),
7.21 (2H, d, J=9Hz), 7.50 (2H, d, J=9Hz),
8.76 (1H, s)
Example 16
(1) A mixture of 6-aminomethyl-2 ,3-bis(4-methoxyphenyl)-pyridine dihydrochloride (0.2 g), 6-carboxy-3-oxo-2,3,4,5-tetrahydropyridazine (72 mg), N-hydroxybenzotriazole (69 mg) , 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
hydrochloride (97 mg) and triethylamine (0.15 g) in tetrahydrofuran (4 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into water and the resulting precipitate was washed with water and tetrahydrofuran to give 2, 3-bis(4-methoxyphenyl)-6- [(3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-carbonylaminomethyl]pyridine (126 mg) .
mp : 234-235°C
IR (Nujol) : 3380, 1670, 1655, 1620, 1500 cm-1
NMR (CDCl3, δ) : 2.55 (2H, t, J=8Hz),
2.98 (2H, t, J=8Hz), 3.80 (3H, s), 3.81 (3H, s), 4.70 (2H, d, J=5Hz), 6.73-6.87 (4H, m) , 7.08 (2H, d, J=9Hz), 7.2-7.36 (4H, m) ,
7.64 (1H, d, J=8Hz), 8.1 (1H, br s), 8.63 (1H, s)
MASS (m/z) : 444 (M+) The following compound was obtained according to a similar manner to that of Example 16- (1)
(2) 2,3-Bis-(4-methoxyphenyl)-6-[2-[(3-oxo-2,3,4,5- tetrahydropyridazin-6-yl)carbonylamino]ethyl]pyridine mp : 148-151°C
IR (Nujol) : 1685, 1650, 1600, 1510, 1240 cm-1
NMR (DMSO-d6, δ) : 2.38 (2H, t, J=8Hz), 2.73 (2H, t, J=8Hz), 3.00 (2H, t, J=6HZ), 3.58 (2H, q,
J=6Hz), 3.73 (3H, s), 3.74 (3H, s), 6.82 (2H, d, J=8Hz), 6.87 (2H, d, J=8Hz), 7.08 (2H, d,
J=8Hz), 7.24 (2H, d, J=8Hz), 7.48 (2H, d,
J=8Hz), 7.65 (2H, d, J=8Hz), 8.26 (1H, t,
J=6Hz), 11.09 (1H, s)
MASS (m/z) : 458 (M+)
Example 17
(1) A mixture of 6-aminomethyl-2,3-bis(4-methoxyphenyl)-pyridine dihydrochloride (0.3 g), dichloromethane and an aqueous solution of sodium hydrogencarbonate was stirred at ambient temperature for 30 minutes, and the separated organic layer was dried over magnesium sulfate. After filtration the filtrate was evaporated in vacuo. To the resulting residue was added a mixture of tetrahydrofuran (6 ml) and methanol (2 ml), and then added isopropyl isocyanate (0.1 ml). The reaction mixture was stirred at ambient temperature for 14 hours. The mixture was
evaporated in vacuo, and the resulting residue was
triturated with isopropyl ether to give
6-(3-isopropylureidomethyl)-2,3-bis(4-methoxyphenyl)-pyridine (0.24 g).
mp : 120°C (dec.)
IR (Nujol) : 3300, 1610, 1565, 1500 cm-1
NMR (CDCl3, δ) : 1.13 (6H, d, J=6.5Hz), 3.80 (3H, s), 3.81 (3H, s), 3.90 (1H, m) , 4.52 (2H, d, J=5Hz), 4.71 (1H, br), 5.54 (1H, br), 6.73-6.86 (4H, m) ,
7.0-7.4 (7H, m), 7.64 (1H, d, J=8Hz)
MASS (m/z) : 405 (M+)
The following compound was obtained according to a similar manner to that of Example 17- (1).
( 2) 4,5-Bis(4-methoxyphenyl)-2-(3-isopropylureidomethyl)-pyrimidine
NMR (DMSO-d6, δ) : 1.05 (6H, d, J=7Hz), 3.69 (1H, m) , 3.72 (6H, s), 4.45 (2H, d, J=6Hz), 6.15 (1H, d,
J=8Hz), 6.28 (1H, t, J=6Hz), 6.88 (2H, d,
J=9Hz), 6.91 (2H, d, J=9Hz), 7.18 (2H, d,
J=9Hz), 7.40 (2H, d, J=9Hz), 8.64 (1H, s)
MASS (m/z) : 406 (M+)
Example 18
(1) A mixture of 1,2-bis(4-methoxyphenyl)-3-dimethylamino-2-propen-1-one (3.1 g) , dicyandiamide (1.68 g) and 28% sodium methylate-methanol solution (4 ml) in ethanol (50 ml) was refluxed for 5 hours under stirring. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and water. The resultant solution was adjusted to pH 7.0 with 10% hydrochloric acid. The separated organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol ( 97 : 3 ) . The eluted solution was evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 4,5-bis(4-methoxyphenyl)-2-cyanoaminopyrimidine (2.0 g).
mp : 208°C (dec.)
IR (Nujol) : 2220, 2100, 1610, 1580 cm-1
NMR (DMSO-d6, δ) : 3.80 (6H, s), 6.91 (2H, d,
J=9Hz), 6.93 (2H, d, J=9Hz), 7.20 (2H, d,
J=9Hz), 7.40 (2H, d, J=9Hz), 8.48 (1H, s)
MASS (m/z) : 332 (M+) The following compounds were obtained according to a similar manner to that of Example 18-(1).
( 2 ) 2-Acetylaminomethyl-4,5-bis(4-methoxyphenyl)- pyrimidine
NMR (DMSO-d6, δ) : 1.95 (3H, s) , 3.64 (3H, s),
3.67 (3H, s), 4.50 (2H, d, J=6Hz), 6.83 (2H, d, J=9Hz), 6.90 (2H, d, J=9Hz), 7.15 (2H, d,
J=9Hz), 7.38 (2H, d, J=9Hz), 8.45 (1H, m) , 8.60 (1H, s)
( 3 ) 4,5-Bis(4-methoxyphenyl)-2-(1-methyl-1,2,3,6- tetrahydropyridin-4-yl)pyrimidine
mp : 131-132.5°C
IR (Nujol) : 1650, 1605, 1580, 1560, 1500 cm-1 Example 19
(1) A mixture of 1,2-bis(4-methoxyphenyl)-3-dimethylamino-2-propen-1-one (3.1 g), 4-amidino-morpholine hydrobromide (4.2 g) and 28% sodium methylate-methanol solution (4 ml) in ethanol (30 ml) was refluxed for 7 hours under stirring. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and 10% hydrochloric acid. The
separated-aqueous layer was adjusted to pH 8.0 with 20% aqueous potassium carbonate and evaporated 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 diisopropyl ether to give 4,5-bis(4-methoxyphenyl)-2-morpholino pyrimidine (0.47 g).
mp : 147-150°C
IR (Nujol) : 1605, 1585, 1570, 1525 cm-1
NMR (DMSO-d6, δ) : 3.73 (6H, s) , 3.73 (8H, s),
6.80 (2H, d, J=8Hz), 6.85 (2H, d, J=9Hz),
7.05 (2H, d, J=9Hz), 7.32 (2H, d, J=9Hz),
8.26 (1H, s)
Elemental Analysis Calcd. for C22H23N3O3 :
C 70.01, H 6.14, N 11.13 Found : C 70.25, H 6.26, N 11.25
The following compounds were obtained according to a similar manner to that of Example 19-(1). (2) 4,5-Bis(4-methoxyphenyl)-2-(pyridin-4-yl)pyrimidine mp : 175-177°C
IR (Nujol) : 1600, 1590, 1565, 1550, 1500 cm-1
NMR (DMSO-d6, δ) : 3.80 (6H, s) , 6.90 (2H, d, J=9Hz), 6.95 (2H, d, J=9Hz), 7.25 (2H, d, J=9Hz), 7 . 50 ( 2H , d, J=9Hz ) , 8 . 30 ( 2H, dd, J=2 , 5Hz ) , 8 .78 ( 2H, dd, J=2 , 5Hz ) , 8 . 83 ( 1H, s ) MASS (m/z ) : 370 (M++1 ) (3) 4,5-Bis(4-methoxyphenyl)-2-(2,6-dimethylmorpholino)- pyrimidine
mp : 138-140°C
IR (Nujol) : 1610, 1590, 1570, 1500 cm-1
NMR (DMSO-d6, δ) : 1.17 (6H, d, J=6Hz),
2.30-2.70 (2H, m) , 3.35-3.80 (2H, m) , 3.73 (6H, s), 4.40-4.72 (2H, m) , 8.78 (2H, d, J=9Hz), 6.82 (2H, d, J=9Hz), 7.03 (2H, d, J=9Hz),
7.32 (2H, d, J=9Hz), 8.32 (1H, s)
MASS (m/z) : 405 (M+)
Elemental Analysis Calcd. for C24H27N3O3 :
C 71.09, H 6.71, N 10.36 Found : C 70.82, H 6.69, N 10.30
Example 20
A solution of 4,5-bis(4-methoxyphenyl)-2-(pyridin-4-yl)pyrimidine (2.6 g) and 3-fluorobenzyl iodide (2.36 g) in a mixture of chloroform and methanol (2:4) (30 ml) was allowed to stand at ambient temperature for 2 days. The reaction mixture was evaporated in vacuo and the residue containing 4-[4,5-bis(4-methoxyphenyl)pyrimidin-2-yl]-1-(3-fluorobenzyl)pyridinium iodide was dissolved in a mixture of methanol (40 ml), chloroform (10 ml) and water (10 ml). To the resulting solution was added portionwise sodium borohydride (0.54 g) with stirring at 5 to 10°C. The reaction mixture was stirred for one hour at the same temperature. The reaction mixture was evaporated in vacuo. The residue was dissolved in chloroform and washed with brine and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo and the residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and acetone (19:1). The eluted solution was concentrated in vacuo and the crystalline residue was collected by filtration and dried in vacuo to give 4,5-bis(4-methoxyphenyl)-2-[1-(3-fluorobenzyl)-1,2,3,6-tetrahydropyridin-4-yl]pyrimidine (1.33 g).
mp : 130-132°C
IR (Nujol) : 1660, 1615, 1560, 1505 cm-1
NMR (DMSO-d6, δ) : 2.55-2.77 (4H, m) , 3.03-3.27 (2H, m), 3.60 (2H, s), 3.71 (3H, s), 3.77 (3H, s),
6.77 (2H, d, J=9Hz), 6.85 (2H, d, J=9Hz),
7.10 (2H, d, J=9Hz), 7.31 (2H, d, J=9Hz),
6.70-7.40 (5H, m) , 8.53 (1H, s) Example 21
(1). A solution of 4,5-bis(4-methoxyphenyl)-2-(pyridin-4-yl)pyrimidine (3.7 g) and methyl iodide (4 ml) in a mixture of chloroform and methanol (9:1) (30 ml) was allowed to stand at ambient temperature for 2 days. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of methanol (50 ml) and water (10 ml). To the resultant solution was added portionwise sodium borohydride (0.76 g) under stirring at 5 to 10°C. The reaction mixture was stirred for one hour at the same temperature. Water ( 16 ml) was added to the reaction mixture and the precipitate was collected by filtration. The precipitate was dissolved in chloroform and washed with brine and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the residue was recrystallized from an aqueous methanol to give 4 , 5-bis(4-methoxyphenyl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine (1.7 g) .
mp : 131-132.5°C
IR (Nujol) : 1650, 1605, 1580, 1560, 1500 cm-1
NMR (DMSO-d6, δ) : 2.30 (3H, s), 2.40-2.80 (4H, m) , 3.00-3.20 (2H, m), 3.75 (3H, s), 3.77 (3H, s), 6.83 (2H, d, J=9Hz), 6.89 (2H, d, J=9Hz),
7.13 (2H, d, J=7Hz), 7.18 (IH, s), 7.37 (2H, d, J=9Hz), 8.58 (IH, s)
( 2 ) 4 , 5-Bis ( 4-methoxyphenyl)-2-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine was obtained according to a similar manner to that of Example 21- (1). The product obtained above was dissolved in a solution of hydrochloric acid-ethanol and the resultant solution was evaporated in vacuo. The residue was recrystallized from a mixture of ethanol and ether to give
4, 5-bis(4-methoxyphenyl)-2-(1-ethyl-1,2,3,6-tetrahydro pyridin-4-yl)pyrimidine hydrochloride.
mp : 183-186°C (dec.)
IR (Nujol) : 1660, 1610, 1590, 1565, 1510 cm-1 NMR (DMSO-d6, δ) : 1.35 (3H, t, J=7Hz),
3.05-4.13 (6H, m) , 3.04 (2H, m) ,
3.52-4.18 (2H, m) , 6.90 (2H, d, J=9Hz), 6.96 (2H, d, J=9Hz), 7.18 (1H, s),
7.20 (2H, d, J=9Hz), 7.42 (2H, d, J=9Hz),
8.72 (1H, s)
The following compounds were obtained according to a similar manner to that of Example 21- (1).
( 3 ) 2 ,3-Bis(4-methoxyphenyl)-6-[1-(4-fluorobenzyl)- 1,2,3,6-tetrahydropyridin-4-yl]pyridine
mp : 115-117°C
IR (Nujol) : 1600, 1580, 1545, 1500 cm-1
NMR (DMSO-d6, δ) : 2.64 (4H, br s), 3.12 (2H, br s), 3.59 (2H, s), 3.73 (3H, s), 3.74 (3H, s),
6.72-7.07 (5H, m) , 7.11-7.42 (8H, m) , 7.47 (1H, d, J=8Hz), 7.67 (1H, d, J=8Hz)
MASS (m/z) : 481 (M+) ( 4) 4 ,5-Bis(4-methoxyphenyl)-2-[1-(4-fluorobenzyl)- 1,2,3,6-tetrahydropyridin-4-yl]pyrimidine
mp : 118-120°C
IR (Nujol) : 1645, 1600, 1570, 1500 cm-1
NMR (DMSO-d6, δ) : 2.67 (4H, br s), 3.17 (2H, br s),
3.61 (2H, s), 3.75 (3H, s), 3.77 (3H, s), 6.87 (2H, d, J=9Hz), 6.94 (2H, d, J=9Hz), 7.11-7.20 (3H, m), 7.13 (2H, d, J=9Hz), 7.33 (2H, d,
J=9Hz), 7.20-7.42 (2H, m) , 8.64 (1H, s)
( 5) 4,5-Bis(4-methoxyphenyl)-2-[1-(2-phenylethyl)- 1,2,3,6-tetrahydropyridin-4-yl]pyrimidine
mp : 135-136°C
IR (Nujol) : 1600, 1560, 1500 cm-1
NMR (DMSO-d6, δ) : 2.70-2.85 (8H, m) , 3.27-3.35 (2H, m), 3.76 (6H, s), 6.87 (2H, d, J=9Hz), 6.94 (2H, d, J=9Hz), 7.16-7.33 (6H, m) , 7.46 (2H, d,
J=9Hz), 8.65 (1H, s)
MASS (m/z) : 477 (M+)
( 6) 4,5-Bis(4-methoxyphenyl)-2-[1-(2-fluorobenzyl)- 1,2,3,6-tetrahydropyridin-4-yl]pyrimidine
mp : 96-99°C
IR (Nujol) : 1650, 1600, 1570, 1550 cm-1
NMR (DMSO-d6, δ) : 2.69 (4H, br s), 3.23 (2H, br s) ,
3.68 (2H, s), 3.75 (3H, s), 3.77 (3H, s), 6.86 (2H, d, J=9Hz), 6.93 (2H, d, J=9Hz) , 7.18 (2H, d, J=9Hz), 7.13-7.47 (5H, m) , 7.39 (2H, d,
J=9Hz), 8.67 (1H, s)
MASS (m/z) : 481 (M+)
(7) 4, 5-Bis(4-methoxyphenyl)-2-[1-benzyl-1,2,3,6- tetrahydropyridin-4-yl]pyrimidine
mp : 128-130°C
IR (Nujol) : 1645, 1600, 1570, 1545 cm-1 NMR (DMSO-d6, δ) : 2.50 (4H, br s), 3.20 (2H, br s), 3.63 (2H, s), 3.75 (3H, s), 3.77 (3H, s), 6.87 (2H, d, J=9Hz), 6.93 (2H, d, J=9Hz), 7.17 (2H, d, J=9Hz), 7.16-7.42 (5H, m) , 7.25 (1H, s), 7.39 (2H, d, J=9Hz), 8.64 (1H, s)
MASS (m/z) : 463 (M+)
Example 22
( 1) A mixture of 4,5-bis ( 4-methoxyphenyl)-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine (2.10 g) , 10% palladium-carbon (0.6 g) and ammonium formate (1.71 g) in acetic acid (40 ml) was stirred at 100 to 110°C for 2 hours. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate, tetrahydrofuran and water and the resulting mixture was adjusted to pH 8.0 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo and the residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (8:2). The eluted solution was evaporated in vacuo and the oily residue was dissolved in a solution of hydrochloric acid-ethanol and the resultant solution was evaporated in vacuo and the residue was recrystallized from a mixture of ethanol and ether to give 4,5-bis(4-methoxyphenyl)-2-(1-methylpiperidin-4-yl)pyrimidine dihydrochloride (0.34 g) .
mp : 227-230°C (dec.)
IR (Nujol) : 1590, 1510 cm-1
NMR (DMSO-d6, δ) : 2.02-2.20 (4H, m) , 2.72 (3H, s) , 2.96-3.64 (6H, m) , 3.77 (5H, s), 6.90 (2H, d, J=9Hz), 6.96 (2H, d, J=9Hz), 7.21 (2H, d,
J=9Hz), 7.42 (2H, d, J=9Hz), 8.72 (1H, s) The following compound was obtained according to a similar manner to that of Example 22- (1).
4, 5-Bis(4-methoxyphenyl)-2-[1-(3-fluorobenzyl)-piperidin-4-yl]pyrimidine hydrochloride
mp : 207-211°C (dec.)
IR (Nujol) : 1595, 1510 cm-1
NMR (DMSO-d6, δ) : 2.16-2.22 (4H, m) , 3.00-3.54 (5H, m), 3.77 (2H, s), 4.39 (2H, d, J=5Hz), 6.85 (2H, d, J=9Hz), 6.96 (2H, d, J=9Hz),
7.20 (2H, d, J=9Hz), 7.41 (2H, d, J=9Hz),
7.27-7.75 (4H, m) , 8.70 (1H, s)
Example 23
(1) A solution of 4,5-bis(4-methoxyphenyl)-2- cyanoaminopyrimidine (1.0 g) and morpholine (1.3 g) in ethanol (10 ml) was refluxed for one hour under stirring. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 8.0 with 20% aqueous potassium carbonate and extracted with a mixture of ethyl acetate and
tetrahydrofuran. The organic layer 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 ether to give 4,5-bis(4-methoxyphenyl)-2-[(4-morpholinecarboximidoyl)amino]pyrimidine (0.72 g).
mp : 176-178°C
IR {Nujol) : 3270. 3150, 1610, 1590 cm-1
NMR (DMSO-d6, δ) : 3.33 (4H, s), 3.60 (4H, s),
3.75 (6H, s), 6.83 (2H, d, J=9Hz),
6.85 (2H, d, J=9Hz),.7.08 (2H, d, J=7Hz),
7.28 (2H, d, J=9Hz), 8.36 (1H, s), 8.37 (2H, s) MASS (m/z) : 419 (M+) Elemental Analysis Calcd. for C23H25N5O3 :
C 65.85, H 6.01, N 16.70 Found : C 65.60, H 6.07, N 16.67
The following compounds were obtained according to a similar manner to that of example 23- (1).
(2) 4,5-Bis(4-methoxyphenyl)-2-[(4-methyl-1- piperazinecarboximidoyl)amino]pyrimidine
mp : 138-140°C (dec.)
IR (Nujol) : 3280, 3130, 1610, 1590, 1510 cm-1
NMR (DMSO-d6, δ) : 2.19 (3H, s), 2.00-2.43 (4H, m),
3.40-3.70 (4H, m) , 3.73 (6H, s), 6.84 (2H, d,
J=9Hz), 6.86 (2H, d, J=9Hz), 7.06 (2H, d,
J=9Hz), 7.27 (2H, d, J=9Hz), 8.33 (1H, s) , 8.10-8.66 (2H, m)
MASS (m/z) : 432 (M+)
(3) 4,5-Bis(4-methoxyphenyl)-2-[(4-benzyl-l-piperazinecarboximidoyl) amino]pyrimidine
mp : 175-177°C
IR (Nujol) : 3300, 3150, 1605, 1580, 1505 cm-1
NMR (DMSO-d6, δ)-: 2.40 ( 4H, br s) , 3.31-3.60 (6H, m), 3.74 (6H, s), 6.78-7.05 (4H, m) ,
7.13 (2H, d, J=9Hz) ,7.23-7.38 (8H, m) ,
8.35 (1H, s), 8.35-8.43 (2H, m)
MASS (m/z) : 508 (M+)
( 4) 4,5-Bis(4-methoxyphenyl)-2-[3-(l-benzylpiperidin-4- y1)guanidino]pyrimidine
mp : 157-159°C (dec.)
IR (Nujol) : 3150, 3300, 1640 (sch), 1605, 1580 cm-1 NMR (DMSO-d6, δ) : 1.17-1.52 (2H, m) , 1.81-2.28 (4H, m), 2.67-2.73 (2H, m) , 3.44 (2H, s), 3.75 (6H, s), 3.64-3.89 (1H, m) , 6.82 (2H, d, J=9Hz), 6 . 91 ( 2H, d, J=9Hz ) , 7 .11 ( 2H, d, J=9Hz) ,
7.19-7 . 40 ( 8H, m) , 8.48 ( 1H, s)
MASS (m/z ) : 522 (M+) (5) 4,5-Bis(4-methoxyphenyl)-2-[(4-benzyl-1-piperidinecarboximidoyl)amino]pyrimidine
mp : 160°C (dec.)
IR (Nujol) : 3300, 3150, 1600, 1580, 1520 cm-1
NMR (DMSO-d6, δ) : 1.02-1.15 (2H, m) , 1.57-1.78 (3H, m) , 2.70-2.82 (2H, m) , 3.22-3.86 (2H, m) , 3.75
(6H, s), 4.33-4.40 (2H, m) , 6.83-6.90 (4H, m) , 7.07 (2H, d, J=9Hz), 7.10-7.31 (8H, m) , 8.33 (1H, s), 8.37 (2H, br s)
MASS (m/z) : 507 (M+)
(6.) 4, 5-Bis(4-methoxyphenyl)-2-[{4-(2-methoxyphenyl)-1- piperazinecarboximidoyl}amino]pyrimidine
mp : 199-200°C
IR (Nujol) : 3320, 3180, 1605, 1570, 1515 cm-1
NMR (DMSO-d6, δ) : 3.00 (4H, br s), 3.75 (9H, s ) ,
3.82(4H, br s), 6.84-7.07 (8H, m), 7.15 (2H, d, J=9Hz), 7.31 (2H, d, J=9Hz), 8.38 (1H, s), 8.49 (2H, br s)
Example 24
(1) A solution of 4,5-bis(4-methoxyphenyl)-2-cyanoamino pyrimidine (1.0 g) and piperidine (1.1 g) in methyl cellosolve (5 ml) was stirred at 120 to 125°C for 3 hours.
The 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
diisopropyl ether to give 4,5-bis(4-methoxyphenyl)- 2-[(1-piperidinecarboximidoyl)amino]pyrimidine (0.65 g). mp : 185-187°C
IR (Nujol) : 3330, 3170, 1610, 1590, 1565, 1525 cm-1 NMR (DMSO-d6, δ) : 1.30-1.70 (6H, m) , 3.40-3.70 (4H, m), 3.73 (6H, s), 6.81 (2H, d, J=9Hz), 6.83 (2H, d, J=9Hz), 7.05 (2H, d, J=9Hz) , 7.27 (2H, d, J=9Hz), 8.30 (1H, s), 8.32 (2H, m)
The following compounds were obtained according to a similar manner to that of Example 24- (1).
( 2 ) 4 , 5-Bis ( 4-methoxyphenyl)-2-(3-cyclohexylguanidino)- pyrimidine
mp : 203-205°C
IR (Nujol) : 3310, 3205, 1595, 1510 cm-1
NMR (DMSO-d6, δ) : 0.86-2.03 (11H, m) , 3.75 (6H, s),
6.85 (2H, d, J=9Hz), 6.88 (2H, d, J=9Hz),
7.10 (2H, d, J=9Hz), 7.30 (2H, d, J=9Hz),
8.47 (1H, s)
MASS (m/z) : 431 (M+)
( 3 ) 4,5-Bis(4-methoxyphenyl)-2-[(2-imidazolin-2-yl)- amino]pyrimidine
mp : 190-192°C
IR (Nujol) : 3460, 3320, 3200, 1640, 1610, 1585,
1575, 15105 cm-1
NMR (DMSO-d6, δ) : 3.10-3.45 (4H, m) , 3.73 (6H, s) , 6.60 (2H, s), 6.80 (2H, d, J=9Hz), 6.83 (2H, d, J=9Hz), 7.03 (2H, d, J=9Hz), 7.28 (2H, d,
J=9Hz), 8.15 (1H, s)
( 4) 4 ,5-Bis(4-methoxyphenyl)-2-(3-isopropylguanidino)- pyrimidine
mp : 167-169°C (dec.)
IR (Nujol) : 3350, 3170, 1680, 1640, 1610, 1580,
1530 cm-1 NMR (DMSO-dg , δ ) : 1.18 ( 6H, d, J=5Hz) , 3 . 40-4.00 ( 1H, m) , 3 .75 ( 6H, s) , 6. 60-7 . 50 ( 8H, m) , 8. 46 ( 1H, s)
MASS (m/z) : 391 (M+)
( 5) 4, 5-Bis(4-methoxyphenyl)-2-(3-benzylguanidino)- pyrimidine
mp : 204-206°C
IR (Nujol) : 3460, 1630, 1610, 1560 cm-1
NMR (DMSO-d6, δ) : 3.80 (6H, s) , 4.62 (2H, s),
6.92 (2H, d, J=9Hz), 6.97 (2H, d, J=9Hz),
7.20 (2H, d, J=9Hz), 7.38 (2H, d, J=9Hz),
7.43 (5H, s), 8.43 (1H, s) Example 25
A solution of 4, 5-bis(4-methoxyphenyl)-2-cyanoamino pyrimidine (0.67 g) and dimethylamine hydrochloride (0.4 g) in ethanol (20 ml) was refluxed for 10 hours under stirring. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 8.0 with 20% aqueous pctassium carbonate 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 oily residue was dissolved in a hydrochloric acid ethanol solution. The resultant mixture was evaporated in vacuo and the residue was recrystallized from a mixture of ethanol and ether to give 4,5-bis(4-methoxyphenyl)-2-(3,3- dimethylguanidino)pyrimidine hydrochloride (0.28 g) .
mp : 238-239°C
IR (Nujol) : 3130, 1640, 1605, 1580 cm-1
NMR (DMSO-d6, δ) : 3.20 (6H, s) , 3.78 (6H, s),
6.88 (2H, d, J=7Hz), 6.95 (2H, d, J=9Hz),
7.17 (2H, d, J=9Hz), 7.39 (2H, d, J=9Hz), 8.62 (1H, s), 9.22 (2H, m)
MASS (m/z) : 377 (M+)
Elemental Analysis Calcd. for C21H23N5O2 :
C 60.94, H 5.84, N 16.92, Cl 8.57 Found : C 60.90, H 5.64, N 16.78, Cl 8.64
Example 26
A mixture of 2, 3-bis(4-methoxyphenyl)pyrazine5-carboxylic acid (1.01 g), 1-hydroxybenzotriazole (446 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (573 mg) in N,N-dimethylformamide (20 ml) was stirred for 1 hour at ambient temperature. N-methyl piperazine (500 mg) was added thereto, and the mixture was stirred for 2 hours. After the solvent was removed, to the residue were added chloroform (30 ml) and water (20 ml) , and the mixture was adjusted to pH 9 with a saturated aqueous solution of potassium carbonate. The separated organic layer was washed with water (20 ml), dried over magnesium sulfate and concentrated. The residue was dissolved with ethyl acetate (20 ml) and crystallized with a diethyl ether solution saturated with hydrogen chloride and the precipitate was collected and washed with ethyl acetate to give 2,3-bis(4-methoxyphenyl)-5-[(4-methylpiperazin-1-yl)carbonyl}pyrazine hydrochloride.
mp : 90-93°C
IR (Nujol) : 1630, 1600, 1505 cm-1
NMR (D2O, δ) : 3.23 (3H, s) , 3.70 (6H, s),
3.1-4.3 (8H, m), 6.6-7.1 (4H, m) , 7.2-7.7 (4H, m), 9.03 (1H, s)
MASS (m/z) : 418 (M+ of free compound)
Example 27
(1) A mixture of 2 ,3-bis(4-methoxyphenyl)pyrazine-5-carboxylic acid (1.03 g), 1-hydroxybenzotriazole (446 mg) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (573 mg) in N,N-dimethylformamide (20 ml) was stirred for 1 hour at ambient temperature.
30% Methylamine-methanol solution (5 ml) was added thereto, and the mixture was stirred for 3 hours. After the solvent was removed, to the residue were added chloroform (30 ml) and water (20 ml), and the mixture was adjusted to pH 9 with a saturated aqueous solution of potassium carbonate. The separated organic layer was dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (50 g) and eluted with 15% solution of methanol in chloroform. The fractions containing the desired compoun were collected and concentrated. The residue was
crystallized with a diethyl ether solution saturated with hydrogen-chloride to give 2,3-bis(4-methoxyphenyl)-5-(methylcarbamoyl)pyrazine hydrochloride.
mp : 125-127°C
IR (Nujol) : 1680, 1600, 1520, 1510 cm-1
NMR (DMSO-d6, δ) : 2.87 (3H, d, J=5Hz), 3.77 (6H, s), 6.93 (4H, d, J=10Hz), 7.3-7.6 (4H, m),
8.72 (1H, d, J=5Hz), 9.03 (1H, s)
MASS (m/z) : 349 (M of free compound)
The following compound was obtained according to a similar manner to that of Example 27-(1).
(2) 2,3-Bis(4-methoxyphenyl)-5-[(1-benzylpiperidin-4-yl)- carbamoyl]pyrazine
mp : 157-159°C
IR (Nujol) : 3400, 1655, 1600, 1500 cm-1
NMR (CDCl3, δ) : 1.5-2.33 (6H, m) , 2.77-3.0 (2H, m), 3.53 (2H, s), 3.82 (3H, s) , 3.85 (3H, s),
3.95-4.2 (1H, m), 6.8-7.02 (4H, m), 7.15-7.53 (10H, m), 7.76 (1H, d, J=8.5Hz), 9.28 (1H, s) MASS (m/z) : 508 (M+) Example 28
A mixture of 5-chloro-2,3-(4-methoxyphenyl)pyrazine (653 mg) and guanidine carbonate (900 mg) in N,N-dimethyl formamide (5 ml) was heated at 140°C for 15 hours. After the solvent was removed under reduced pressure, to the residue were added water (15 ml) and 5% methanol in chloroform (30 ml). The separated organic layer was washed with saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was removed and the residue was subjected to column chromatography on silica gel (50 g) and eluted with 10% solution of methanol in chloroform, the fractions containing the desired compound were collected and concentrated. The residue was pulverized with diethyl ether to give
5-(N,N-dimethylamino)-2,3-bis(4-methoxyphenyl)pyrazine. mp : 161-163°C
IR (Nujol) : 1605, 1555, 1490 cm-1
NMR (DMSO-d6, δ) : 3.10 (6H, s), 3.68 (6H, s),
6.80 (2H, d, J=10Hz), 6.82 (2H, d, J=10Hz), 7.20 (2H, d, J=10Hz), 7.30 (2H, d, J=10Hz),
8.07 (1H, s)
MASS (m/z) : 335 (M+)
Example 29
A mixture of 5-chloro-2,3-bis(4-methoxyphenyl)-pyrazine (980 mg) and guanidine (1.8 g) and
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
chromatography on silica gel (50 g) and eluted with 15% solution of methanol in chloroform. The fractions
containing the desired compound were collected and
concentrated. The residue was dissolved in ethyl acetate (20 ml) and crystallized with an ethanol solution saturated with hydrogen chloride. The precipitate was collected and washed with ethyl acetate to give 5-guanidino-2,3-bis(4-methoxyphenyl)pyrazine hydrochloride.
mp : 246-269°C (dec.)
IR (Nujol) : 3250, 1680, 1620, 1600, 1510 cm-1 NMR (DMSO-d6, δ) : 3.74 (6H, s) , 6.7-7.0 (4H, m),
7.2-7.5 (4H, m), 8.38 (5H, s) MASS (m/z) : 349 (M+)
Example 30
A mixture of morpholine (3 ml) and
5-chloro-2,3-bis(4-methoxyphenyl)pyrazine (980 mg) was stirred at 100°C for 3 hours. The solvent was removed under reduced pressure and the residue was crystallized with ether to give 2,3-bis(4-methoxyphenyl)-5- (morpholin-4-yl)-pyrazine.
. mp : 138-139°C
IR (Nujol) : 1603, 1573, 1545, 1505 cm-1
NMR (CDCl3, δ) : 3.5-4.0 (8H, m), 3.76 (6H, s),
6.89 (4H, d, J=10Hz), 7.2-7.5 (4H, m), 8.03 (1H, s)
MASS (m/z) : 377 (M+)
Example 31
A mixture of piperazine (5 g) and 5-chloro2,3-bis(4-methoxyphenyl)pyrazine (980 mg) in ethanol (10 ml) was refluxed for 3 hours. After the solvent was removed, to the residue were added ethyl acetate (20 ml) and water (30 ml). The separated organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After the solvent was removed, the residue was crystallized with ether to give 2,3-bis(4-methoxyphenyl)-5-(piperazin-1-yl)pyrazine.
mp : 128-129°C
IR (Nujol) : 3400, 1605, 1570, 1545, 1510 cm-1
NMR (DMSO-d6, δ) : 2.6-2.9 (4H, m) , 3.4-3.6 (4H, m) , 3.73 (6H, s), 6.82 (4H, d, J=9Hz),
7.12-7.43 (4H, m) , 8.12 (1H, s)
MASS (m/z) : 376 (M+) Example 32
A mixture of 5-chloro-2,3-bis(4-methoxyphenyl)pyrazine (980 mg) and N-methylpiperazine (3 ml) was stirred at 60°C for 3 hours and at 100°C for 2 hours. After the solvent was removed under reduced pressure, the residue was
dissolved in diethyl ether (30 ml) and crystallized with an ether solution saturated with hydrogen chloride. The precipitate was collected and washed with ether to give 2 ,3-bis(4-methoxyphenyl)-5-(4-methylpiperazin-1-yl)-pirazine dihydrochloride.
mp : 187-189°C
IR (Nujol) : 1600, 1570, 1510, 1490 cm-1
NMR (DMSO-d6, δ) : 2.79 (3H, d, J=5Hz), 2.9-4.7 (8H, m), 3.74 (6H, s) , 6.8-7.4 (10H, m), 8.36 (1H, s) MASS (m/z) : 390 (M of free compound)
Example 33
A mixture of 2,3-bis(4-methoxyphenyl)-5-methyl
pyrazine (1.07 g), dimethylamine hydrochloride (346 mg) and paraformaldehyde (126 mg) in acetic acid (3 ml) was stirred for 10 days at ambient temperature. After the solvent was removed, to the residue were added water (10 ml) and 5% solution of methanol in chloroform (20 ml), and the mixture was adjusted to pH 9 with a saturated aqueous solution of potassium carbonate. The separated organic layer was dried over magnesium sulfate. The solvent was removed and the residue was subjected to column
chromatography on silica gel (50 g) and eluted with 10% solution of methanol in chloroform. The fractions
containing the desired compound were collected and
concentrated. The residue was dissolved in ethyl acetate (30 ml) and crystallized with a solution of hydrogen chloride in ether to give 5-[2-(N,N-dimethylamino)ethyl]-2,3-bis(4-methoxyphenyl)pyrazine hydrochloride.
mp : 203-207°C (dec.)
IR (Nujol) : 3350, 2600, 1600, 1520 cm-1
NMR (D2O, δ) : 2.8-3.2 (2H, m) , 3.0 (6H, s),
3.6-4.0 (2H, m) , 3.85 (6H, s) , 6.8-7.6 (8H, m), 8.83 (1H, s)
MASS (m/z) : 363 (M+)
Example 34
A mixture of 3-(2-t-butoxycarbonylaminoethyl)-5,6-bis(4-methoxyphenyl)-1,2,4-triazine (5.00 g) and
2.5-norbornadiene (12.0 ml) in xylene (200 ml) was refluxed under stirring for 3 days. The reaction mixture was evaporated in vacuo. To the residue was added
4N-1,4-dioxane solution of hydrogen chloride and the mixture was stirred at 0°C for 2 hours. The reaction mixture was evaporated in vacuo. The resulting
precipitate was washed with diethyl ether and dried to give 6-(2-aminoethyl)-2,3-bis(4-methoxyphenyl)pyridine hydrochloride (5.35 g).
IR (Nujol) : 1610, 1510, 1300, 1250 cm-1
NMR (DMSO-d6, δ) : 3.33-3.43 (4H, m) , 3.75 (3H, s), 3.78 (3H, s), 6.91 (2H, d, J=7Hz) , 6.94 (2H, d,
J=7Hz), 7.11 (2H, d, J=7Hz), 7.34 (2H, d,
J=7Hz), 7.76 (1H, d, J=8Hz) , 8.19 (1H, d,
J=8Hz), 8.44 (3H, br s)
MASS (m/z) : 334 (M of free compound)
Example 35
(i) A mixture of 3-{N,N-dimethylaminomethyl}-5,6-bis(4-methoxyphenyl)-1,2,4-triazine (0.60 g) and an ethanol solution of hydrogen chloride (15 ml) was stirred at the ambient temperature for 3 hours. The reaction mixture was evaporated in vacuo and the residue was washed with diethyl ether to give 3-{N,N-dimethylaminomethyl}-5,6-bis(4-methoxyphenyl)-1,2,4-triazine hydrochloride (0.58 g).
mp : 215-218°C
IR (Nujol) : 1600, 1300, 1250 cm-1
NMR (DMSO-d6, δ) : 2.97 (3H, s), 2.99 (3H, s), 3.80 (3H, s), 3.81 (3H, s), 4.85 (2H, d, J=6Hz), 6.98 (2H, d, J=8Hz), 7.03 (2H, d, J=8Hz), 7.50 (2H, d, J=8Hz), 7.63 (2H, d, J=8Hz)
Mass (m/z) : 350 (M of free compound)
The following compound was obtained according to a similar manner to that of Example 35-(1)
( 2) 2,3-Bis(4-methoxyphenyl)-6-(N,N-dimethylaminomethyl)- pyridine dihydrochloride
mp : 80°C-82°C (dec.)
IR (Nujol) : 1600, 1510, 1300, 1250 cm-1
NMR (DMSO-d6, δ) : 2.86 (6H, s), 3.75 (3H, s), 3.76
(3H, s), 4.54 (2H, s), 6.85 (2H, d, J=8Hz), 6.91 (2H, d, J=8Hz), 7.13 (2H, d, J=8Hz), 7.34 (2H, d, J=8Hz), 7.72 (1H, d, J=8Hz), 7.90 (1H, d, J=8Hz)

Claims

C L A I M S
A compound of the formula :
Figure imgf000092_0001
wherein R1 and R2 are each lower alkoxy,
R3 is heterocyclic group selected from the group consisting of pyridyl,
tetrahydropyridyl, piperidyl,
piperazinyl and morpholinyl, which may have suitable substituent(s);
substituted amino;
carboxy(lower)alkenyl;
carboxy(lower)alkyl;
hydroxy(lower)alkyl;
amino ( lower) alkyl which may have suitable substituent(s);
a group of the formula :
Figure imgf000092_0002
(in which R4 is hydrogen, ethoxy,
mono(or di) lower
alkylamino, di(lower)- alkylamino-(lower)- alkylamino,
heterocyclicamino
which may have suitable substituent(s), or heterocyclic group which may have suitable
substituent(s));
or a group of the formula :
Figure imgf000093_0001
(in which R5 is lower alkyl or
ar(lower)alkyl
which may have suitable substituent(s), and
X1 is an acid residue), Y is CH or N and
Z is CH or N,
with proviso that
when R3 is pyridyl; piperidyl which may have hydroxy group; 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,
then Z is CH,
and a pharmaceutically acceptable salt thereof.
2. A compound of claim 1, wherein
R3 is heterocyclic group selected from the group consisting of pyridyl, tetrahydropyridyl, piperidyl, piperazinyl and morpholinyl, which may have one to three suitable substituent(s); cyanoamino; imidazolinylamino; guanidino;
di(lower)alkylguanidino; lower alkylguanidino; cyclo(lower)alkylguanidino;
ar( lower)alkylguanidino; heterocyclicguanidino which may be substituted with one to three suitable substituent(s);
(1-heterocyclic-1-iminomethyl)amino which may have one to three suitable substituent(s);
di(lower)alkylamino; hydroxy(lower)alkyl;
carboxy(lower)alkyl; carboxy(lower)alkenyl; amino(lower)alkyl which may have one to three substituent(s) selected from the group consisting of lower alkyl and acyl;
a group of the formula :
Figure imgf000094_0001
(in which R4 is hydrogen; ethoxy; mono(or
di)lower alkylamino; di(lower)- alkylamino-(lower)alkylamino;
heterocyclicamino which may have one to three substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, halogen and ar(lower)alkyl; or heterocyclic group which may have one to three substituent(s) selected from the group consisting of lower alkyl, lower alkoxy. halogen, ar(lower)alkyl and
hydroxy(lower)alkyl);
or a group of the formula :
Figure imgf000095_0001
(in which R5 is lower alkyl, or ar( lower)alkyl which may have one to three substituent(s) selected from the group consisting of halogen, lower alkyl and lower alkoxy; and X1 is an acid residue).
3. A compound of claim 2, wherein
R3 is 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; cyanoamino; imidazolinylamino; guanidino; di ( lower)alkylguanidino; lower
alkylguanidino; cyclo(lower)alkylguanidino;
phenyl( lower)alkylguanidino;
heterocyclicguanidino which may have
ar( lower)alkyl; ( 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; di(lower)alkylamino;
hydroxy(lower)alkyl; carboxy(lower)alkyl;
carboxy(lower)alkenyl; 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); a group of the formula :
Figure imgf000096_0001
(in which R4 is hydrogen; ethoxy; mono(or
di) lower alkylamino;
di(lower)alkylamino-(lower)- alkylamino; saturated 5 or
6-membered heteromonocyclicamino in which heteromonocyclic group contains 1 to 3 nitrogen
atom(s), which may have one or two substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, halogen and phenyl(lower)alkyl;
saturated 5 or 6-membered heteromonocyclic group
containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) which may have one or two substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, halogen,
phenyl(lower)alkyl and
hydroxy(lower) alkyl; or
saturated 5 or 6-membered heteromonocyclic group
containing 1 to 3 nitrogen atom(s), which may have one or two substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, halogen, phenyl(lower)alkyl and
hydroxy(lower)alkyl);
or a group of the formula :
Figure imgf000097_0001
(in which R5 is lower alkyl, or
phenyl(lower) alkyl which may have one or two substituent(s) selected from the group
consisting of halogen, lower alkyl and lower alkoxy; and X1 is halogen).
4. A compound of claim 3, wherein
R 3 is 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;
di( lower) alkylguanidino; lower alkylguanidino; cyclo(lower)alkylguanidino;
phenyl(lower)alkylguanidino;
phenyl(lower)alkylpiperidylguanidino;
{morpholinyl(imino)methyl}amino;
{piperidyl(imino)methyl}amino which may have phenyl(lower)alkyl;
{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 or two substituent(s) selected from the group consisting of lower alkyl, lower alkanoyl, lower alkylcarbamoyl, lower
alkoxycarbonyl and tetrahydropyridazmylcarbonyl which may have oxb group;
a group of the formula :
Figure imgf000098_0001
(in which R4 is hydrogen, ethoxy ,mono(or
di) lower alkylamino, di(lower)alkylamino- ( lower)alkylamino, phenyl( lower)alkylpiperidylamino, morpholinyl, or piperazinyl which may have lower alkyl,
hydroxy(lower) alkyl or
phenyl(lower)alkyl);
or a group of the formula :
Figure imgf000098_0002
(in which R5 is lower alkyl, or
phenyl(lower) alkyl which may have halogen, and
X1 is halogen).
5. A compound of claim 4, wherein
R3 is a group of the formula :
Figure imgf000099_0002
(in which R4 is lower alkylpiperazinyl),
Y is N and
Z is N. 6. A compound of claim 5, which is 5,
6-Bis(4-methoxyphenyl)-3-{(4-methylpiperazin-1-yl)carbonyl}-1,2,4- triazine hydrochloride.
7. A compound of claim 4, wherein
R3 is lower alkyltetrahydropyridyl,
Y is CH and
Z is N.
8. A compound of claim 7, which is
4,5-Bis(4-methoxyphenyl)-2-(1-methyl-1,2,3,6- tetrahydropyridine-4-yl)pyrimidine.
9. A process for preparing a compound of the formula
Figure imgf000099_0001
wherein R 1 and R2 are each lower alkoxy,
R3 is heterocyclic group selected from the group consisting of pyridyl,
tetrahydropyridyl, piperidyl, piperazinyl and morpholinyl, which may have suitable substituent(s);
substituted amino;
carboxy(lower) alkenyl;
carboxy(lower)alkyl;
hydroxy(lower)alkyl;
amino(lower)alkyl which may have suitable substituent(s);
a group of the formula :
Figure imgf000100_0001
(in which R4 is hydrogen, ethoxy,
mono(or di)loweralkylamino, di(lower)- alkylamino- ( lower)- alkylamino, heterocyclicamino
which may have suitable substituent(s), or heterocyclic group which may have suitable
substituent(s));
or a group of the formula :
Figure imgf000100_0002
(m which R5 is lower alkyl or
ar(lower)alkyl which may have suitable substituent(s), and X1 is an acid residue), Y is CH or N and
Z is CH or N,
with proviso that
when R 3 is pyridyl; piperidyl which may have hydroxy group; 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,
then Z is CH,
or a salt thereof,
which comprises
(1) reacting a compound of the formula
Figure imgf000101_0001
wherein R 1 and R2 are each as defined above,
with a compound of the formula :
Figure imgf000102_0001
wherein R3 is as defined above,
or a salt thereof to give a compound of the formula
Figure imgf000102_0002
wherein R 1 , R2 and R3 are each as defined above, or a salt thereof, or
(2) reacting a compound of the formula :
Figure imgf000102_0003
wherein R 1, R2, Y and Z are each as defined above, or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula :
Figure imgf000102_0005
wherein is mono(or di)lower alkylamino.
Figure imgf000102_0004
di(lower)alkylamino-(lower)alkylamino, heterocyclicamino which may have suitable substituent(s), or heterocyclic group containing at least one nitrogen atom which may have suitable substituent(s), or a salt thereof to give a compound of the formula
Figure imgf000103_0001
wherein R 1 , R2 , Y, Z and are each as defined above,
Figure imgf000103_0002
or a salt thereof, or
(3) subjecting a compound of the formula
Figure imgf000103_0003
wherein R 1 , R2, Y and Z are each as defined above and
Rb 3 is protected amino(lower)alkyl, or a salt thereof to elimination reaction of the amino-protective group to give a compound of the formula :
Figure imgf000103_0004
wherein R1, R2, Y and Z are each as defined
above and
R3 b is amino(lower) alkyl,
or a salt thereof,
or
(4) subjecting a compound of the formula :
Figure imgf000104_0001
wherein R 1, R2, Rb 3 , Y and Z are each as defined
above,
or its reactive derivative at the amino group or a salt thereof to acylation reaction to give a compound of the formula :
Figure imgf000104_0002
wherein R 1, R2,Y and Z are each as defined above and
Rc 3 is acylamino(lower)alkyl.
or a salt thereof,
or (5) reacting a compound of the formula
Figure imgf000105_0001
wherein R 1 and R2 are each as defined above,
Y1 is CH or N and
Z1 is CH or N,
or a salt thereof with a compound of the formula
1 5
X -R~ wherein R5 and X are each as defined above,
to give a compound of the formula :
Figure imgf000105_0002
wherein R1, R2, R5 , Y , Z and X are each as defined above,
or a salt thereof,
or
(6) subjecting a compound of the formula
Figure imgf000106_0001
wherein R 1, R2, R5, Y, Z and X1 are each as defined above,
or a salt thereof to reduction reaction to give a compound of the formula :
Figure imgf000106_0002
wherein R 1, R2, R5, Y and Z are each as defined above and
==== means a single or double bond,
or a salt thereof, or subjecting a compound of the formula
Figure imgf000106_0003
wherein R1, R2 , R5, Y and Z are each as defined above,
or a salt thereof to reduction reaction to give a compound of the formula :
Figure imgf000107_0001
wherein R 1 , R2 , R5 , Y and Z are each as defined
above,
or a salt thereof, or
(8) reacting a compound of the formula
Figure imgf000107_0002
wherein R 1 and R2 are each as defined above and
R3 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(lower) alkenyl; carboxy(lower)alkyl;
hydroxy(lower)alkyl; amino( lower)alkyl which may have suitable substituent(s); a group of the formula :
Figure imgf000108_0001
(in which R4 is hydrogen, ethoxy,
mono(or di)lower
alkylamino,
di (lower)alkylamino(lower)- alkylamino,
heterocyclicamino which may have suitable
substituent(s), or
heterocyclic group which may have suitable
substituent(s));
or a group of the formula :
Figure imgf000108_0002
(in which R5 is lower alkyl or
ar(lower)alkyl which may have suitable
substituent(s), and
X1 is an acid residue), or a salt thereof with a compound of the formula :
Figure imgf000108_0003
to give a compound of the formula
Figure imgf000109_0001
wherein R 1 , R2 and R3 are each as defined above, or a salt thereof, or (9) reacting a compound of the formula :
Figure imgf000109_0002
wherein R 1 and R2 are each as defined above, and
R6 and R7 are each lower alkyl,
or a salt thereof with a compound of the formula :
Figure imgf000109_0003
wherein R3 is as defined above,
or a salt thereof to give a compound of the formula :
Figure imgf000110_0001
wherein R 1, R2 and R3 are each as defined above, or a salt thereof, or
(10) subjecting a compound of the formula
Figure imgf000110_0002
wherein R 1 , R2 , Y and Z are each as defined above and
R3 d is carboxy or protected carboxy,
or a salt thereof to reduction reaction to give a compound of the formula :
Figure imgf000110_0003
wherein R 1, R2 , Y and Z are each as defined above. or a salt thereof, or
(11) subjecting a compound of the formula :
Figure imgf000111_0001
wherein R 1, R2, Y and Z are each as defined above, or a salt thereof to oxidation reaction to give a compound of the formula :
Figure imgf000111_0002
wherein R 1, R2, Y and Z are each as defined above, or a salt thereof, or
(12) reacting a compound of the formula
Figure imgf000111_0003
wherein R1 , R2 , Y and Z are each as defined above, or a salt thereof with a compound of the formula :
Figure imgf000112_0001
or a salt thereof to give a compound of the formula
Figure imgf000112_0002
wherein R 1 , R2, Y and Z are each as defined above, or a salt thereof, or
(13) reacting a compound of the formula
Figure imgf000112_0003
wherein R 1, R2, Y and Z are each as defined above, or a salt thereof with a compound of the formula :
Figure imgf000112_0004
wherein R8 and R9 are each hydrogen, lower alkyl, cyclo(lower) alkyl, ar( lower) alkyl, heterocyclic group which may have suitable substituent(s), or
R 8 and R9 are linked together with the
attached nitrogen atom to form heterocyclic group which may have suitable substituent(s),
or a salt thereof to give a compound of the formula
Figure imgf000113_0001
wherein R1, R2, R8 , R9, Y and Z are each as defined above,
or a salt thereof, or (14) reacting a compound of the formula :
Figure imgf000113_0002
wherein R 1, R2, Y and Z are each as defined above, or a salt thereof with a compound of the formula :
Figure imgf000114_0001
or a salt thereof to give a compound of the formula :
Figure imgf000114_0002
wherein R 1 , R2, Y and Z are each as defined above, or a salt thereof, or
(15) reacting a compound of the formula
Figure imgf000114_0003
wherein R 1, R2, Y and Z are each as defined above and
X2 is a leaving group,
or a salt thereof with a compound of the formula :
Figure imgf000114_0004
wherein R10 is hydrogen or lower alkyl and
R11 is lower alkyl or 1-amino-l-iminomethyl, or
R10 and R11 are linked together with the
attached nitrogen atom to form heterocyclic group which may have suitable substituent(s),
or a salt thereof to give a compound of the formula
Figure imgf000115_0001
wherein R1, R2, R10, R11, Y and Z are each as defined above,
or a salt thereof, or
(16) reacting a compound of the formula
Figure imgf000115_0002
wherein R 1 , R2, Y and Z are each as defined above, or a salt thereof with a compound of the formula :
HCHO and a compound of the formula
Figure imgf000116_0001
wherein R 12 and R13 are each lower alkyl,
or a salt thereof to give a compound of the formula
Figure imgf000116_0002
wherein R 1, R2, R12, R13 , Y and Z are each as defined above,
or a salt thereof, or
(17) subjecting a compound of the formula
Figure imgf000116_0003
wherein R 1, R2, Y and Z are each as defined above and
Re 3 is carboxy(lower)alkenyl,
or a salt thereof to reduction reaction to give a compound of the formula :
Figure imgf000117_0001
wherein R1 , R2 Y and Z are each as defined above and
Rf 3 is carboxy(lower)alkyl,
or a salt thereof.
10. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers.
11. A use of a compound of claim 1 or a pharmaceutically acceptable salt thereof as antithrombotic,
vasodilating or anti-inflammatory agent.
12. A method for the prophylactic or therapeutic
treatment of thrombosis, hypertension, cardiovascular or cerebrovascular diseases, or inflammation which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to human or animals.
13. A process for preparing a pharmaceutical composition which comprises admixing a compound of claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.
PCT/JP1991/001042 1990-08-06 1991-08-05 Heterocyclic compounds Ceased WO1992002513A1 (en)

Applications Claiming Priority (4)

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