AP861A - Substituted N-({Aminoiminomethyl or aminomethyl} phenyl] propyl amides. - Google Patents

Substituted N-({Aminoiminomethyl or aminomethyl} phenyl] propyl amides. Download PDF

Info

Publication number
AP861A
AP861A APAP/P/1998/001288A AP9801288A AP861A AP 861 A AP861 A AP 861A AP 9801288 A AP9801288 A AP 9801288A AP 861 A AP861 A AP 861A
Authority
AP
ARIPO
Prior art keywords
group
alkyl
formula
exemplary
substituted
Prior art date
Application number
APAP/P/1998/001288A
Other versions
AP9801288A0 (en
Inventor
Kevin R Guertin
Scott I Klein
Alfred P Spada
Original Assignee
Aventis Pharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=21737952&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=AP861(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Aventis Pharma Inc filed Critical Aventis Pharma Inc
Publication of AP9801288A0 publication Critical patent/AP9801288A0/en
Application granted granted Critical
Publication of AP861A publication Critical patent/AP861A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C07D207/327—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
    • C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • 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
    • 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
    • C07D213/24—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
    • C07D213/56—Amides
    • 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
    • C07D213/57—Nitriles
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • 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
    • C07D213/82—Amides; Imides in position 3
    • 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
    • C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or 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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)
  • Indole Compounds (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

The compounds according to the invention are substituted N-[ (aminoiminomethyl or aminomethyl) phenyl]propyl amides of formula (I) herein which exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More especially, they are Factor Xa inhibitors. The present invention is directed to compounds of formula (I), compositions containing compounds of formula (I), methods for their preparation and their use, which are for treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of Factor"' Xa.

Description

SUBSTITUTED N-ffAMINQIMlNOMETHYL OR AMINOMETHYUPHENYL1PROPYL AMIDES
Field of the Invention
The compounds ot formula I exhibit useful pharmacological activity and accordingly are incorporated into pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. More especially, they are Factor Xa inhibitors. The present invention is directed to compounds of formula 1, compositions containing compounds of fo/mula I, and their use, which are for treating a patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of Factor Xa.
Factor Xa is the penultimate enzyme in the coagulation cascade. Both free"factor Xa and factor Xa assembled in the protnrombinase complex (Factor Xa, Factor Va, calcium and phospholipid) are inhibited by compounds of formuia I. Factor Xa inhibition is obtained by direct complex formation between the inhibitor and the enzyme and is therefore independent of the plasma cofactor antithrombin 111. Effective factor Xa inhibition is achieved by administering the compounds either by oral administration, continuous intravenous infusion, bolus intravenous administration or any other parenteral route such that it achieves the desired effect of preventing the factor Xa induced formation of thrombin from prothrombin. >
Anticoagulant-therapy is indicated for the treatment and prophylaxis of a variety of thrombotic conditions of both the venous and arterial vasculature. In the arterial system, abnormal thrombus formation is primarily associated with aneries of the coronary, cerebral and peripheral vasculature. The diseases associated with thrombotic occlusion of these vessels principally include acute myocardial infarction (AMI), unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous .transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke, intermittent claudication and bypass grafting of the coronary (CABG) or peripheral arteries. Chronic anticoagulant therapy may also be beneficial in preventing the vessel luminal narrowing (restenosis) that often occurs following PTCA and CABG, and in the maintenance of vascular access patency in long-term hemodialysis patients. With respect to the venous vasculature, pathologic thrombus formation frequently occurs in the veins of the lower extremities following abdominal, knee and hip surgery (deep vein thrombosis, DVT). DVT further predisposes the patient to a higher risk of pulmonary thromboembolism. A systemic, disseminated intravascular coagulopathy (DiC) commonly occurs in both vascular systems during septic shock, certain viral infections and cancer. This condition is characterized by a rapid consumption of coagulation factors and their plasma inhibitors resuiting in the formation of life-threatening clots throughout the microvasculature of several organ systems. Tne indications discussed above include some, but not all, of the possible clinical situations where anticoagulant therapy*is warranted. Those experienced in this field aO well aware of the circumstances requiring either acute or chronic prophylactic anticoagulant therapy.
SUMMARY OF THE INVENTION • This invention is directed to the pharmaceutical use of a compound of formula i below to inhibit the production or physiological effects of Factor Xa in the treatment of a patient suffering from a disease state associated with a physiologically detrimental excess of Factor Xa, where formula I is as follows:
R-| and R2 are hydrogen or taken together are =NRg; R3 is -CO2R6, -C(O)Rg, -CONRgRg, -CH2OR7 or -CH2SR7; R4 is a group of formula
or R4 is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl; R5 is alkyl, alkenyl, optionally substituted aryl or optionally substituted heteroaryl; R6 is hydrogen or lower alkyl;
Ry is hydrogen, lower alkyl, lower acyl, aroyl or heteroaryl;
Rg is hydrogen*or lower alkyl;
Rg is wherein Rg is RiqO2C-, R10O-, HO-, cyano, R10CO-, HCO-, lower alkyl, nitro, or Y 1Y^N- , where R-jq is optionally substituted alkyl, optionally substituted aralkyl, or optionally substituted heteroaralkyl, and where Y and 2 Y 'are independently hydrogen or alkyl; A and B are hydrogen or taken together are a bond;
Ar is optionally substituted aryl or optionally substituted heteroaryl; and n is 0, 1 or 2; or a pharmaceutically acceptable,salt thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof. ‘
DETAILED DESCRIPTION OF THE INVENTION
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
Definitions
"Patient" includes both human and other mammals. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 15 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. “Lower alkyl" means about 1 to about 6 carbon atoms in the chain which may be straight or branched. The alkyl group may be substituted by one or more halo, cycloalkyi or cycloalkenyl. Exemplary alkyl groups include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, π-propyl, /-propyl, n-butyl, f-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl. “Alkenyl" means an aliphatic hydrocarbon group containing a carbon-carbon double bond and whictn may be straight or branched having about about 15 carbon atoms in the chain. 'Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. “Lower alkenyl" means about 2 to about 4 carbon atoms in the chain which may be straight or branched. The alkenyl group may be substituted by one or more halo. Exemplary alkenyl groups include ethenyl, propenyi, n-butenyl, /-butenyl, 3-methylbut-2-enyl, n-pentenyi, heptenyi, octenyl and decenyl. "Cycloalkyi" means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkyi rings include cyclopentyl, fluorocyclopentyl, cyclohexyl and cycloheptyl. The y cycloalkyi group may be substituted by one or more halo, methylene (H2C=por alkyl. Exemplary .multicyclic cycloalkyi rings include 1-decalin, adamant-{1- or 2-)yl and norbornyl. "Cycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system containing a carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyi or cycloheptenyi. An exemplary.multicyclic cycloalkenyl ring is norbornylenyl. The cycloalkenyl group may be substituted by one or more halo, methylene (H2C=) or alkyl. "Heterocylyl" means a non-aromatic monocyclic or muiticyclic ring system of about 3 to about 10 ring atoms. Preferred rings include about 5 to about 6 ring atoms wherein one of the ring atoms is oxygen, nitrogen or sulfur. The heterocyclyi may be optionally substituted by one or more halo. Preferred monocyclic heterocyclyi rings include pyrrole, tetranydrothiophenyl and tetrahydrothiopyranyl. The thio or nitrogen moiety of the hetercyclyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. “Aryl’1 means aromatic carbocyciic radical containing about 6 to about 10 carbon atoms. Exemplary aryl include phenyl or naphthyl optionally substituted with one or more aryl group substituents which may be the same or different, where “aryl group substituent" includes hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryi, aralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, carboxy, acyl, aroyi, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryioxycarbonyl, aralkoxycarbonyl, acylamino, aroylamino, alkylsulfonyl, arylsuifohyl, alkylsulfinyl, aryisulfinyl, alkylthio, arylthio, aralkyithio, Y1 Υ2Ν-, Υ1Υ2Ν-, Y1 Y2N-alkyl-, CO- or y1y2NSO2-, where Y1 and Y2 are independently hydrogen, alkyl, aryl, and aralkyl. Preferred aryl group substituents include hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, acyl, aroyi, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, Υ"'Υ2Ν-, Y^ Y2NCO- or Y"· Y2NSO2-, where Y-' and Y2 are independently hydrogen and alkyl. ’Heteroaryi" means about a 5- to about a 10- membered aromatic monocyclic or muiticyclic hydrocarbon ring system in which one or more of the carbon atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. The "heteroaryi’ may also be substituted by one or more aryf group substituents. Exemplary heteroaryi groups include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, quinolinyl, indolyl, and isoquinolinyl. "Aralkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls contain a lower alkyl moiety. Exemplary aralkyl groups include benzyl, 2-p'nenethyl and naphthlenemethyl. “Hydroxyalkyl” means a HO-alkyl- group in which alky! is as previously defined. Preferred hydroxyaikyis contain lower alkyl. Exemplary hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. nAcyl“ means an H-CO- or alkyl-CO- group in which the alkyl group is as previously described. Preferred acyis contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methyipropanoyl, butanoyl and palmitoyl. "Aroyl" means an aryl-CO- group in which the alkyl group is as previously described. Exemplary groups include benzoyl and 1- and 2-naphthoyl. "Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Exemplary alkoxy groups include methoxy, ethoxy, © n-propoxy, /-propoxy, n-butoxy and heptoxy. "Aryloxy" means an aryl-O- group in which the aryl group is as previously I described. Exemplary aryloxy groups include phenoxy and naphthoxy. "Aralkyloxy" means an aralkyl-O- group in which the aralkyl groups is as previously described. Exemplary aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. "Alkylthio" means an alkyi-S- group in which the alkyl group is as previously described. Exemplary alkylthio groups include methylthio, ethylthio, Apropylthio and heptylthio. Ay ) "Arylthio" means an aryi-S- group in which the aryl group is as previously described. Exemplary arylthio groups include phenylthio and naphthylthio. "Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as 5 previously described. An exemplary aralkylthio group is benzyithio. «γ1γ2Ν-“ means a substituted or unsubstituted amino group, wherein Y1 and Y2 are as previously described. Exemplary groups include amino (H2N-), methylamino, ethyimethylamino, dimethyiamino and diethylamino. "Aikoxycarbonyl" means an aikyl-O-CO- group. Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl. "Aryloxycarbonyr means an aryl-O-CO- group. Exemplary aryloxycarbonyl groups include phenoxy- and naphthoxycarbonyl. "Aralkoxycarbonyl" means an aralkyl-O-CO- group. An exemplary aralkoxycarbonyi group is benzyloxycarbonyl. nY1Y2NCO-° means a substituted or unsubstituted carbamoyl group, wherein Y1 and Y2 are as previously described. Exemplary groups are 'carbamoyl (H2NCO-) and dimethyiaminocarbamoyl (Me2NC0-). γ1γ2Ν502-" means a substituted or unsubstituted sulfamoyl group, wherein Y"1 and Y2 are as previously described. Exemplary groups are aminosulfamoyl (H2NSO2-) and dimethylaminosuifamoyl (Me2NSO2-). "Acylamino" is an acyl-NH- group wherein acyl is as defined herein. ‘‘Aroylamino" is an aroyl-NH- group wherein aroyl is as defined herein. "Alkylsuifonyl" means an alkyl-SO2- group. Preferred groups are those in which the alkyl group is lower alkyl. "Alkylsulfinyl" means an alkyi-SO- group.. Preferred groups are those in > which the aikyl group is lower alkyl. "Arylsuifonyl" means an aryl-SC>2- group. "Arylsulfinyl" means an aryl-SO- group. "Halo" means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro or bromo, and more preferred are fluoro or chloro. "Pro-drug" means a compound which may or may not itself be biologically active but which may, by metabolic, solvolytic, or other physiological means be converted to a biologically active chemical entity.
Preferred Embodiments A preferred embodiment of the invention is a method for treating a disease state capable of being modulated by inhibiting production of Factor Xa to a patient suffering from said disease state an effective amount of the compound of formuia I . A preferred compound aspect of the invention is the compound of formula 1 wherein R-j and Rg taken together are =NH.
Another preferred compound aspect of the invention is the compound'! formula I wherein Rg is -COgRg, -CHgORy or-CHgSR7;
Another preferred compound aspect of the invention is the compound of formula I wherein n is 1.
Another preferred compound aspect of the invention is the compound of formula I wherein Rg is -COgRg and Rg is lower alkyl.
Another preferred compound aspect of the invention is the compound of formula I wherein Rg is -CHgORy or -CHgSRy and Ry is hydrogen or lower alkyl. <··
Another preferred compound aspect of the invention is the compound of formula I wherein R-] and Rg taken together are =NH and form an aminoiminomethyl on the phenyl moiety that is in the meta position to the position of attachment of the phenyl moiety to the propyl moiety.
Another preferred compound aspect of the invention is the compound of formula I wherein Ar is optionally substituted aryl.
Another preferred compound aspect of the invention is the compound of formula I wherein Ar is phenyl.
Another preferred compound aspect of the invention is the compound of formula I wherein R5 is optionally substituted phenyl, optionally substituted biphenyl, optionally substituted naphthyl, or optionally substituted heterobiphenyl.
Another preferred compound aspect of the invention is the compound of formula 1 wherein R10 is lower alkyl.
Included within the scope of formula I are compounds wherein R-j and R2 taken together are =NRg, wherein Rg is R-j^O2C-, R-jqO-, cyano, R-jqCO-, optionally substituted lower alkyl, nitro, or Y Y N-. Such derivatives may themselves comprise the biologically active compound useful for treating a * disease state capable of being modulated by inhibiting production of Factor Xa to a patient suffering from said disease state, or may act as pro-drugs to such biologically active compounds which are formed therefrom under physiological conditions.
Species according to the invention are selected from the following:

Claims (1)

  1. Original document published without claims.
APAP/P/1998/001288A 1996-01-02 1996-12-23 Substituted N-({Aminoiminomethyl or aminomethyl} phenyl] propyl amides. AP861A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US948596P 1996-01-02 1996-01-02
PCT/US1996/020770 WO1997024118A1 (en) 1996-01-02 1996-12-23 Substituted n-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides

Publications (2)

Publication Number Publication Date
AP9801288A0 AP9801288A0 (en) 1998-09-30
AP861A true AP861A (en) 2000-08-01

Family

ID=21737952

Family Applications (1)

Application Number Title Priority Date Filing Date
APAP/P/1998/001288A AP861A (en) 1996-01-02 1996-12-23 Substituted N-({Aminoiminomethyl or aminomethyl} phenyl] propyl amides.

Country Status (28)

Country Link
US (1) US6140504A (en)
EP (1) EP0906094B1 (en)
JP (1) JP4053597B2 (en)
KR (1) KR100348338B1 (en)
CN (1) CN1273128C (en)
AP (1) AP861A (en)
AT (1) ATE243512T1 (en)
AU (1) AU723338B2 (en)
BG (1) BG64143B1 (en)
BR (1) BR9612423B1 (en)
CA (1) CA2241904C (en)
CL (1) CL2004000376A1 (en)
CZ (1) CZ297544B6 (en)
DE (1) DE69628856T2 (en)
DK (1) DK0906094T3 (en)
EA (2) EA001932B1 (en)
ES (1) ES2197257T3 (en)
HU (1) HU228355B1 (en)
IL (1) IL125163A0 (en)
NO (1) NO310719B1 (en)
OA (1) OA10804A (en)
PL (1) PL185460B1 (en)
PT (1) PT906094E (en)
RO (1) RO117913B1 (en)
SI (2) SI9620136B (en)
SK (1) SK284507B6 (en)
UA (1) UA46821C2 (en)
WO (1) WO1997024118A1 (en)

Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AP861A (en) * 1996-01-02 2000-08-01 Aventis Pharma Inc Substituted N-({Aminoiminomethyl or aminomethyl} phenyl] propyl amides.
US6080767A (en) * 1996-01-02 2000-06-27 Aventis Pharmaceuticals Products Inc. Substituted n-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides
TW542822B (en) * 1997-01-17 2003-07-21 Ajinomoto Kk Benzamidine derivatives
WO1999010317A1 (en) * 1997-08-26 1999-03-04 Kumiai Chemical Industry Co., Ltd. Biarylalkylenecarbamic acid derivatives and bacteriocides for agricultural and horticultural use
US6740682B2 (en) 1997-08-29 2004-05-25 Tularik Limited Meta-benzamidine derivatives as serine protease inhibitors
CN1297440A (en) * 1998-03-23 2001-05-30 阿温蒂斯药物制品公司 Piperidinyl and N-amidinopiperidinyl derivatives
EP1086946A4 (en) * 1998-06-08 2003-03-05 Ajinomoto Kk Benzamidine derivative
US6610704B1 (en) 1998-12-23 2003-08-26 Eli Lilly And Company Antithrombotic amides
EP1140862A4 (en) 1998-12-23 2004-07-28 Bristol Myers Squibb Pharma Co THROMBIN OR FACTOR Xa INHIBITORS
IL143906A0 (en) 1998-12-24 2002-04-21 Aventis Pharmaceuticals Produs Substituted (aminoiminomethyl or aminomethyl) benzoheteroaryl compounds as factor xa inhibitors
IL144095A0 (en) * 1999-01-02 2002-05-23 Aventis Pharma Gmbh Arylalkanoyl derivatives, processes for their preparation, their use and pharmaceutical compositions containing them
EP1022268A1 (en) * 1999-01-02 2000-07-26 Aventis Pharma Deutschland GmbH Arylalkanoyl derivatives, processes for their preparation, their use and pharmaceutical compositions containing them
US6794412B1 (en) * 1999-03-11 2004-09-21 Bristol-Myers Squibb Pharma Company Treatment of thrombosis by combined use of a factor Xa inhibitor and aspirin
CA2375920A1 (en) 1999-06-14 2000-12-21 Eli Lilly And Company Compounds
MXPA02004218A (en) * 1999-10-28 2002-10-17 Sankyo Co Benzamidine derivatives.
IL149398A0 (en) 1999-11-02 2002-11-10 Aventis Pharma Gmbh USE OF RUSSELL'S VIPER VENOM-INDUCED PLASMA FACTOR Xa ACTIVITY TO MONITOR THE ACTIVITY OF FACTOR Xa INHIBITORS
DE10006601A1 (en) 2000-02-15 2001-08-16 Clariant Gmbh Process for the preparation of 4- (4'-carboxyphenyl) pyridine
GB0108903D0 (en) * 2000-10-05 2001-05-30 Aventis Pharm Prod Inc Novel crystalline forms of a factor Xa inhibitor
PT1569912E (en) 2002-12-03 2015-09-15 Pharmacyclics Llc 2-(2-hydroxybiphenyl-3-yl)-1h-benzoimidazole-5-carboxamidine derivatives as factor viia inhibitors
DE102006048300A1 (en) * 2006-01-26 2007-08-02 Hellstern, Peter, Prof. Dr.med. New amidinobenzylamino-peptide derivatives, useful as anticoagulant in ex vivo systems, are inhibitors of activated factor X and other enzymes involved in coagulation
KR20120006059A (en) * 2009-04-17 2012-01-17 메르츠 파마 게엠베하 운트 코. 카가아 Synthesis of 1-amino-1,3,3,5,5-pentamethylcyclohexane mesylate
US9492437B2 (en) * 2009-07-29 2016-11-15 Sanofi Otamixaban for treatment of elderly and renal impaired non-ST elevation myocardial infarction patients
GB0919194D0 (en) 2009-11-02 2009-12-16 Lytix Biopharma As Compounds
MX2013011266A (en) * 2011-03-29 2014-03-27 Sanofi Sa Benzoic acid salt of otamixaban.
SG193932A1 (en) 2011-03-29 2013-11-29 Sanofi Sa Otamixaban formulations with improved stability
WO2013042782A1 (en) 2011-09-22 2013-03-28 武田薬品工業株式会社 Condensed heterocyclic compound
MX2015002646A (en) 2012-08-31 2015-05-20 Sanofi Sa Otamixaban for use in the treatment of non-st elevation acute coronary syndrome in patients planned to undergo coronary artery bypass grafting.
DE102014108210A1 (en) 2014-06-11 2015-12-17 Dietrich Gulba rodenticide
US10351750B2 (en) 2017-02-03 2019-07-16 Saudi Arabian Oil Company Drilling fluid compositions with enhanced rheology and methods of using same
EP4070658A1 (en) 2021-04-06 2022-10-12 BIORoxx GmbH Use of anticoagulant active compounds as rodenticide

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5424334A (en) * 1991-12-19 1995-06-13 G. D. Searle & Co. Peptide mimetic compounds useful as platelet aggregation inhibitors

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AP861A (en) * 1996-01-02 2000-08-01 Aventis Pharma Inc Substituted N-({Aminoiminomethyl or aminomethyl} phenyl] propyl amides.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5424334A (en) * 1991-12-19 1995-06-13 G. D. Searle & Co. Peptide mimetic compounds useful as platelet aggregation inhibitors

Also Published As

Publication number Publication date
CN1273128C (en) 2006-09-06
SK89798A3 (en) 2000-08-14
SI0906094T1 (en) 2003-12-31
BR9612423B1 (en) 2010-11-30
EP0906094A4 (en) 2000-05-17
BG64143B1 (en) 2004-02-27
EA001280B1 (en) 2000-12-25
OA10804A (en) 2001-03-07
SI9620136B (en) 2005-08-31
KR100348338B1 (en) 2003-06-02
CA2241904C (en) 2004-12-21
HUP9900930A3 (en) 2001-11-28
NO310719B1 (en) 2001-08-20
CL2004000376A1 (en) 2005-06-03
AU723338B2 (en) 2000-08-24
NO983039D0 (en) 1998-06-30
EA001932B1 (en) 2001-10-22
PT906094E (en) 2003-11-28
EA199900669A1 (en) 2000-06-26
AP9801288A0 (en) 1998-09-30
EP0906094B1 (en) 2003-06-25
SK284507B6 (en) 2005-05-05
BR9612423A (en) 1999-12-28
RO117913B1 (en) 2002-09-30
CZ297544B6 (en) 2007-02-07
HK1017613A1 (en) 1999-11-26
JP2000502710A (en) 2000-03-07
CN1208347A (en) 1999-02-17
DE69628856T2 (en) 2004-05-06
JP4053597B2 (en) 2008-02-27
IL125163A0 (en) 1999-01-26
DE69628856D1 (en) 2003-07-31
NO983039L (en) 1998-09-02
PL327633A1 (en) 1998-12-21
US6140504A (en) 2000-10-31
UA46821C2 (en) 2002-06-17
ES2197257T3 (en) 2004-01-01
WO1997024118A1 (en) 1997-07-10
HUP9900930A2 (en) 1999-08-30
HU228355B1 (en) 2013-03-28
SI9620136A (en) 1999-04-30
EA199800620A1 (en) 1999-02-25
ATE243512T1 (en) 2003-07-15
AU1520797A (en) 1997-07-28
PL185460B1 (en) 2003-05-30
EP0906094A1 (en) 1999-04-07
KR19990076965A (en) 1999-10-25
CA2241904A1 (en) 1997-07-10
CZ9802010A3 (en) 1999-09-15
DK0906094T3 (en) 2003-10-20
BG102619A (en) 1999-04-30

Similar Documents

Publication Publication Date Title
AP861A (en) Substituted N-({Aminoiminomethyl or aminomethyl} phenyl] propyl amides.
AP800A (en) Substituted sulfonic acid n-[{aminoiminomethyl)phenylalkyl] -azaheterocyclamide compounds.
AP799A (en) Substituted (sulfinic acid, sulfonic acid, sulfonylamino or sulfinylamino) N-[(aminoiminomethyl) phenylalkyl]-azaheterocyclylamide compounds.
AP1032A (en) Sulfonic acid or sulfonylamino n-(Heterorlkyl)-zheterocyclylmie compounds.
US5698586A (en) Angiogenesis inhibitory agent
AP1061A (en) Substituted N-[(Aminoiminomethyl or aminomethyl) Phenyl] Propyl amides.
US6831082B2 (en) Method of using soluble epoxide hydrolase inhibitors
WO2013134660A1 (en) 4 -hydroxy- isoquinoline compounds as hif hydroxylase inhibitors
DE69719344T2 (en) 4-SUBSTITUTED-3- (2-AMINO-2-CYCLOALKYLMETHYL) -ACETAMIDO-AZETIDINE-2-ON DERIVATIVES AS CYSTEIN PROTEINAS REGULATORS
RU94034115A (en) Condensed cyclic compounds and squalene-synthetase inhibitors
JPH08502974A (en) Farnesyl-protein transferase inhibitors
AU2014237198A1 (en) Anti-PCSK9 compounds and methods for the treatment and/or prevention of cardiovascular diseases
CN101583352A (en) Preparation and use of biphenyl amino acid derivatives for the treatment of obesity
KR20050026568A (en) Pyrrolidinedione substituted piperidine-phthalazones as pde4 inhibitors
IL143142A (en) Protease inhibitors
IL155333A0 (en) Sulfanilide derivatives for use in medicine, certain such new derivatives and their preparation
JPH01156957A (en) Novel prolinal derivative, production thereof and antiamnesia containing said derivative
CZ126899A3 (en) Piperidethoxycarbonyl derivatives, their use and therapeutic agent
IE49356B1 (en) New pleuromutilin derivatives,their production use and pharmaceutical compositions containing them
MY103348A (en) Heteroaryl 3-0x0-propanenitrile derivatives and process for their preparation
HUP0101482A2 (en) Piperidinyl and n-amidinopiperidinyl derivatives, use of them for producing pharmaceutical compositions and pharmaceutical compositions containing the same
CN101421242B (en) Dicarboxamide derivatives
US5710174A (en) Factor XIIIA inhibitor
US5527801A (en) Ameliorant for blood lipid metabolism
EP4532512A2 (en) Cilagicin compounds and methods of use thereof