+

WO2002034711A1 - Biaryl compounds as serine protease inhibitors - Google Patents

Biaryl compounds as serine protease inhibitors Download PDF

Info

Publication number
WO2002034711A1
WO2002034711A1 PCT/US2001/032582 US0132582W WO0234711A1 WO 2002034711 A1 WO2002034711 A1 WO 2002034711A1 US 0132582 W US0132582 W US 0132582W WO 0234711 A1 WO0234711 A1 WO 0234711A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
alkyl
prodrugs
acceptable salts
Prior art date
Application number
PCT/US2001/032582
Other languages
French (fr)
Inventor
Yarlagadda S. Babu
Scott R. Rowland
Pooran Chand
Pravin L. Kotian
Yahya El-Kattan
Shri Niwas
Original Assignee
Biocryst Pharmaceuticals, 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
Priority to EP01981772A priority Critical patent/EP1383731B1/en
Priority to AT01981772T priority patent/ATE438615T1/en
Priority to IL15520201A priority patent/IL155202A0/en
Priority to DK01981772T priority patent/DK1383731T3/en
Priority to AU2002213393A priority patent/AU2002213393B2/en
Priority to AU1339302A priority patent/AU1339302A/en
Priority to JP2002537705A priority patent/JP4342178B2/en
Priority to CA2426430A priority patent/CA2426430C/en
Priority to MXPA03009130A priority patent/MXPA03009130A/en
Application filed by Biocryst Pharmaceuticals, Inc. filed Critical Biocryst Pharmaceuticals, Inc.
Priority to DE60139510T priority patent/DE60139510D1/en
Priority to NZ526003A priority patent/NZ526003A/en
Priority to US10/127,460 priority patent/US6699994B1/en
Publication of WO2002034711A1 publication Critical patent/WO2002034711A1/en
Priority to IL155202A priority patent/IL155202A/en
Priority to US10/738,027 priority patent/US6936719B2/en
Priority to HK04105585.6A priority patent/HK1062676A1/en
Priority to IL222773A priority patent/IL222773B/en

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
    • 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
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to 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
    • 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
    • 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
    • C07C259/20—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 with at least one nitrogen atom of hydroxamidine groups bound to another nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/62—Compounds containing any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylcarbamates
    • C07C271/64—Y being a hydrogen or a carbon atom, e.g. benzoylcarbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • 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
    • C07D207/33—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 ring carbon atoms
    • C07D207/337—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
    • 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
    • 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
    • C07D213/54—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
    • C07D213/60—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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon 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
    • C07D213/60—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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • 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
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters 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
    • C07D213/04—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
    • 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
    • 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
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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
    • 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
    • C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • 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
    • C07D235/14—Radicals substituted by nitrogen 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
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • 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
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C07D235/32—Benzimidazole-2-carbamic acids, unsubstituted or substituted; Esters thereof; Thio-analogues thereof
    • 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
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/12—Nitrogen atoms not forming part of a nitro radical
    • C07D239/14—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to said nitrogen 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
    • 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
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • 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
    • C07D277/22—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—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
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—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
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • 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
    • 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
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C07D317/68—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
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—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
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered

Definitions

  • the present invention relates to the identification, through synthesis and testing, of heretofore unreported compounds which, in appropriate pharmaceutical compositions, exert a therapeutic effect through reversible inhibition of serine proteases.
  • Serine proteases make up the largest and most extensively studied group of proteolytic enzymes. Their critical roles in physiological processes extend over such diverse areas as blood coagulation, fibrinolysis, complement activation, reproduction, digestion, and the release of physiologically active peptides. Many of these vital processes begin with cleavage of a single peptide bond or a few peptide bonds in precursor protein or peptides. Sequential limited proteolytic reactions or cascades are involved in blood clotting, fibrinolysis, and complement activation. The biological signals to start these cascades can be controlled and amplified as well. Similarly, controlled proteolysis can shut down or inactivate proteins or peptides through single bond cleavages.
  • hile serine proteases are physiologically vital, they also can be hazardous. Their proteolytic action, if uncontrolled, can destroy cells and tissues through degradation of proteins. As a natural safeguard in normal plasma, 10% of the protein matter is composed of protease inhibitors.
  • the major natural plasma inhibitors are specific for serine proteinases. Diseases (associated protease given in the parentheses) such as pulmonary emphysema (cathepsin G), adult respiratory distress syndrome (chymases), and pancreatitis (trypsin, chymotrypsin, and others) are characterized by uncontrolled serine proteases. Other proteases appear to be involved in tumor invasion (plasmin, plasminogen activator), viral transformation, and inflammation (kallikrein). Thus the design and synthesis of specific inhibitors for this class of proteinases could offer major therapeutic benefits.
  • Thrombus formation that is blood coagulation, is normally initiated by tissue injury; its normal purpose is to slow or prevent blood loss and facilitate wound healing.
  • tissue injury There are other conditions, however, not directly connected with tissue injury that may promote the coagulation process and lead instead to harmful consequences; examples of such conditions are atherosclerosis and inflammation.
  • Blood coagulation or the coagulation cascade, is viewed mechanistically as two pathways, the extrinsic and the intrinsic (Fig. 1). Each pathway proceeds through a sequence of the Roman-numeral-designated factors until they converge at the activation of factor X after merger of the pathways.
  • Thrombin generation proceeds stepwise through a common pathway. Thrombin then acts on the solution plasma protein, fibrinogen, to convert it to stable insoluble fibrin clots, thus completing the coagulation cascade.
  • the extrinsic pathway is vital to the initiation phase of blood coagulation while the intrinsic pathway provides necessary factors in the maintenance and growth of fibrin.
  • the initiation of the coagulation cascade involves the release of tissue factor (TF) from injured vessel endothelial cells and subendothelium. TF then acts upon factor VII to form the TF/FVIIa complex (where Vila designates the activated factor rather than the zymogen form).
  • TF tissue factor
  • TF tissue factor
  • factor VII acts upon factor VII to form the TF/FVIIa complex (where Vila designates the activated factor rather than the zymogen form).
  • This complex initiates coagulation by activating factors IX and X.
  • the resulting factor Xa forms a prothrombinase complex that activates prothrombin to produce the thrombin that converts fibrinogen to insoluble fibrin.
  • the intrinsic system is activated in vivo when certain coagulation proteins contact subendotheUal connective tissue.
  • contact factors XII and XI are activated.
  • the resulting factor XIa activates factor LX; then factor LXa activates factor X thereby intersecting with the extrinsic pathway.
  • TFPI tissue factor pathway inhibitor
  • Kunitz-type protease inhibitor protein which, when complexed with factor Xa, can inhibit the proteolytic activity of TF/FVIIa. If the extrinsic system is inhibited, additional factor Xa is produced through the thrombin-mediated action in the intrinsic pathway. Thrombin, therefore, exerts a dual catalytic role in (a) the conversion of fibrinogen to fibrin and (b) mediating its own production.
  • the autocatalytic aspect of thrombin production affords an important safeguard against excessive blood loss, and, assuming presence of a threshold level of prothrombinase, ensures that the blood coagulation process will go to completion.
  • Heparin and certain derivatives thereof are the most commonly used anti-clotting agents. These substances exert their effects mainly through inactivation of thrombin, which is inactivated 100 times faster than factor Xa. Two other thrombin-specific anticoagulants, hirudin and hirulog, are in clinical trials (as of September 1999). However, bleeding complications are associated with these agents.
  • a specific inhibitor of factor Vila would provide clinicians with a valuable and needed agent that would be safe and effective in situations where the present drags of choice, heparin and related sulfated polysaccharides, are no better than marginally effective.
  • An aspect of the present invention relates to compounds represented by the formula:
  • Each E ! and L individually is a 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic saturated or unsaturated carbon ring, bicyclic saturated or unsaturated hetero ring, or 1-8 hydrocarbon chain which maybe substituted with one or more hetero groups selected from N, O, S, S(O), and S(O 2 ) which may be saturated or unsaturated.
  • the bicyclic rings typically contain 7-13 atoms in the ring.
  • R 1 is H, -R, -NO 2 , -CN, -halo, -N 3 , -C ⁇ _ 8 alkyl, -(CH 2 ) complicatCO 2 R 2 , -C 2 . 8 alkenyl-CO 2 R 2 , -O(CH 2 ) n CO 2 R 2 , -C(O)NR 2 R 3 , -P(O)(OR 2 ) 2 , alkyl substituted tetrazol-5-yl, -(CH 2 ) n O(CH 2 ) n aryl, -NR 2 R 3 , -(CH 2 ) n OR 2 , -(CH 2 ) n SR 2 , -N(R 2 )C(O)R 3 , -S(O 2 )NR 2 R 3 , -N(R )S(O 2 )R 3 , -(CHR 2 ) n NR 2 R 3 , -C(
  • m is 1 except that when E l is a cyclic ring of more than 5 atoms, then m is 1 or higher, depending upon the size of the ring.
  • R 2 is H, -halo, -alkyl, -haloalkyl, -(CH 2 ) n -phenyl, -(CH 2 ) ⁇ _ 3 -biphenyl, -(CH 2 ) -Ph- N(SO 2 -Ci. 2 -alkyl) 2 , -CO(CHR 1 ) n -OR 1 , -(CHR 5 ) n -heterocycle, -(CHR ⁇ -NH-CO-R 1 , -(CHR 1 )n-NH-SO 2 R 1 , -(CHR 1 ) n -Ph-N(SO -C,.
  • R 3 is H, -OH, -CN, substituted alkyl, -C 2 . 8 alkenyl, substituted or unsubstituted cycloalkyl, -N(R ! )R 2 , or 5-6 membered saturated substituted or unsubstituted hetero ring.
  • -NR 2 R 3 may form a ring system having 4 to 7 atoms or may be bicyclic ring.
  • the ring system may be of carbon or hetero atoms and further it may saturated or unsaturated and also may be substituted or unsubstituted.
  • E 2 is 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, C ⁇ _ 8 alkyl, C 2 . 8 alkenyl, C 2 . 8 alkynyl, alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino.
  • each X individually is a direct bond, substituted or unsubstituted C ⁇ methylene chain; O, S, NR 2 , S(O), S(O 2 ), or N(O) containing one or two C M substituted or unsubstituted methylene chains.
  • X at different places may be same or different.
  • B 1 is selected from B; B 1 and B may be same or different.
  • E there may be more than one similar or different R groups present on E , when E is a cyclic group of more than 5 atoms.
  • p is 1 except that when E 2 is a cyclic ring of more than 5 atoms, p is 1 or higher depending upon the size of the ring.
  • n 0-4
  • A is selected from R . o is 1 except that when L is a cyclic ring of more than 5 atoms, o is 1 or higher depending upon the size of the ring.
  • Each V and V 1 individually is selected from R 1 and N-alkyl substituted carboxamidyl (- CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic; N,N- disubstituted carboxamidyl (-CONR 1 R 2 where Ri and R 2 may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (SO 2 NHR or -SO 2 NR1R2); and methylene- or polymethylene chain- extended variants thereof.
  • - CONHR N-alkyl substituted carboxamidyl
  • -CONR 1 R 2 where Ri and R 2 may be substituted or unsubstituted alkyl or aryl and may be the same or different
  • mono- or disubstituted sulfonamides SO 2 NHR or -SO 2 NR1R2
  • Each R 4 and R 5 individually is H, -(CH 2 ) n OH, -C(O)OR 6 , -C(O)SR 6 , -(CH 2 ) objection C(O)NR 7 R 8 , -O-C(O)-O-R 7 , an amino acid or a dpeptide,
  • Each R 6 is H, R 7 , -C(R 7 )(R 8 )-(CH 2 ) n -O-C(O)-R 9 , -(CH 2 ) n -C(R 7 )(R 8 )-O-C(O)R 9 , -(CH 2 ) n - C(R 7 )(R 8 )-O-C(O)-O-R 9 , or -C(R 7 )(R 8 )-(CH 2 ) n -O-C(O)-O-R 9 ,
  • Each R 7 , R s and R 9 individually is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or CH 2 CO 2 alkyl.
  • the present invention also relates to pharmaceutical compositions containing at least one of the above disclosed compounds and their prodrugs.
  • a further aspect of the present invention relates to a method for inhibiting trypsin- like serine protease enzymes, such as thrombin, factor Xa, factor Vila, TF/VIIa, and trypsin in a patient which comprises administering to the patient an effective serine protease inhibiting amount of at least one of the above disclosed compounds.
  • An aspect of the present invention relates to compounds represented by the formula: R B 1
  • Each E 1 and L individually is a 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic saturated or unsaturated carbon ring, bicyclic saturated or unsaturated hetero ring, or 1-8 hydrocarbon chain which may be substituted with one or more hetero groups selected from N, O, S, S(O), and S(O 2 ) which maybe saturated or unsaturated.
  • these R, R 1 , R 2 , or R 3 do not include -(C 2 .
  • R 1 is H, -R, -NO 2 , -CN, -halo, -N 3 , -C ⁇ . 8 alkyl, -(CH 2 ) n CO 2 R 2 , -C 2 . 8 alkenyl-CO 2 R 2 , -O(CH 2 ) n CO 2 R 2 , -C(O)NR 2 R 3 , -P(O)(OR 2 ) 2 , alkyl substituted tetrazol-5-yl,
  • n is 1 except that when E 1 is a cyclic ring of more than 5 atoms, then m is 1 or higher, depending upon the size of the ring. For instance if the ring is 6 atoms, m can be 1 or 2.
  • R 2 is H, -halo, -alkyl, -haloalkyl, -(CH 2 ) réelle -phenyl, -(CH 2 ) ⁇ - 3 -biphenyl, -(CH ⁇ M -Ph- N(SO 2 -C ⁇ .
  • R 3 is H, -OH, -CN, substituted alkyl, -C 2 . 8 alkenyl, substituted or unsubstituted cycloalkyl, -N R ⁇ R 2 , or 5-6 membered saturated substituted or unsubstituted hetero ring.
  • -NR R may form a nng system having 4 to 7 atoms or may be bicyclic ring.
  • the ring system may be of carbon or hetero atoms and further it may saturated or unsaturated and also may be substituted or unsubstituted.
  • E 2 is 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, Ci-g alkyl, C 2 - 8 alkenyl, C 2 . 8 alkynyl, alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino.
  • each X individually is a direct bond, substituted or unsubstituted C methylene chain; O, S, NR 2 , S(O), S(O 2 ), orN(O) containing one or two C M substituted or unsubstituted methylene chains.
  • X at different places may be same or different.
  • B 1 is selected from B; B 1 and B may be same or different.
  • There may be more than one similar or different R 2 groups present on E 2 when E 2 is a cyclic system of more than 5 atoms, p is 1 or higher if E 2 is a cyclic ring of more than 5 atoms. For example, if the ring is 6 atoms, p can be 1 or 2.
  • n 0-4
  • A is selected from R 1 .
  • o is 1 except that when L is a cyclic ring of more than 5 atoms, o is 1 or higher depending upon the size of the ring. For instance, if the ring is 6 atoms, o can be 1 or 2.
  • Each N and N ! individually is selected from R 1 and ⁇ -alkyl substituted carboxamidyl (- CO ⁇ HR) where the alkyl group may be straight, branched, cyclic, or bicyclic; ⁇ , ⁇ - disubstituted carboxamidyl (-CONR ⁇ R 2 where Ri and R2 may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (SO 2 NHR or -SO 2 NR1R 2 ); and methylene- or polymethylene chain- extended variants thereof.
  • Each R 4 and R 5 individually is H, -(CH 2 ) n OH, -C(O)OR 6 , -C(O)SR 6 , -(CH 2 ) n C(O)NR 7 R 8 , -O-C(O)-O-R 7 , an amino acid or a dipeptide,
  • Each R 6 is H, R 7 , -C(R 7 )(R 8 )-(CH 2 ) n -O-C(O)-R 9 , -(CH 2 ) n -C(R 7 )(R 8 )-O-C(O)R 9 , -(CH 2 ) n - C(R 7 )(R 8 )-O-C(O)-O-R 9 , or -C(R 7 )(R 8 )-(CH 2 ) n -O-C(O)-O-R 9 ,
  • Each R 7 , R 8- and R 9 individually is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or CH 2 CO 2 alkyl.
  • R substituent groups employed pursuant to the present invention contribute to significantly enhanced activity of the compounds of the present invention.
  • alkyl refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms.
  • lower alkyl refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
  • alkenyl and alkynyl refer to straight or branched chain unsubstituted hydrocarbon groups typically having 2 to 8 carbon atoms.
  • substituted alkyl refers to an alkyl, alkenyl or alkynyl group substituted by, for example, one to four substituents, such as halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamine, aroylamino, aralkanoylamino, substituted alkanolamino, substituted arylamino, substituted aralkanoylamino, thiol
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.
  • aralkyl or “alkylaryl” refers to an aryl group bonded directly through an alkyl group, such as benzyl or phenethyl.
  • substituted aryl or “substituted alkylaryl” refers to an aryl group or alkylaryl group substituted by, for example, one to four substituents such as alkyl; substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, azido, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, hydroxyalkyl, aminoalkyl, azidoalkyl, alkenyl, alkynyl, allenyl, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl
  • the substituent may be further substituted by halo, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.
  • substituted benzyl refers to a benzyl group substituted by, for example, any of the groups listed above for substituted aryl.
  • cycloalkyl refers to optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C -C carbocyclic ring.
  • exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and adamantyl.
  • substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
  • cycloalkenyl refers to optionally substituted, unsaturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3-7 carbons per ring.
  • exemplary groups include cyclopentenyl and cyclohexenyl.
  • heterocycle refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized.
  • the heterocyclic group may be attached at any heteroatom or carbon atoms.
  • Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazoUdinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, thiophenyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, dihydropyrid
  • bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, cournarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolapridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,l-b]pyridinyl, or furo[2,3-b]pyridinyl), dihydroisoindolyl, diyhydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl,
  • Exemplary substituents include one or more alkyl groups as described above or one or more groups described above as alkyl substituents.
  • Preferred alkyl groups are lower alkyl groups containing 1 to about 8 carbon, and more preferably 1 to about 5 carbon atoms, and can be straight, branched-chain or cyclic saturated aliphatic hydrocarbon groups.
  • suitable alkyl groups include methyl, ethyl and propyl.
  • Examples of branched alkyl groups include isopropyl and t-butyl.
  • An example of a suitable alkylaryl group is phenethyl.
  • suitable cycloalkyl groups typically contain 3-8 carbon atoms and include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the aromatic or aryl groups are preferably phenyl or alkyl substituted aromatic groups (aralkyl) such as phenyl C 1 - 3 alkyl such as benzyl.
  • the N-heterocyclic rings preferably contain 3-7 atoms in the ring and a heteroatom such as N, S or O in the ring.
  • suitable prefe ⁇ ed heterocyclic groups are pyrrolidino, azetidino, piperidino, 3,4-didehydropiperidino, 2- methylpiperidino and 2-ethylpiperidino.
  • the above substitutions can include halo such as F, CI, Br, lower alkyl, lower alkoxy and halo substituted lower alkoxy.
  • Prodrug forms of the compounds bearing various nitrogen functions may include the following types of derivatives where each R group individually may be hydrogen, substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, heterocycle, alkylaryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, or cycloalkenyl groups as defined beginning on page 7.
  • prodrug derivatives are discussed in various literature sources (examples are: Alexander et al, J. Med. Chem. 1988, 31, 318; Aligas-Martin et al, PCT WO pp/41531, p. 30).
  • the nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the invention.
  • Prodrug forms of carboxyl-bearing compounds of the invention include esters (-CO 2 R) where the R group corresponds to any alcohol whose release in the body through enzymatic or hydrolytic processes would be at pharmaceutically acceptable levels.
  • Another prodrug derived from a carboxylic acid form of the invention may be a quaternary salt type
  • Pharmaceutically acceptable salts of the compounds of the present invention include those derived from pharmaceutically acceptable, inorganic and organic acids and bases.
  • suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycoUic, lactic, salicyclic, succinic, toluene-p- sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic, trifluoroacetic and benzenesulphonic acids.
  • Salts derived from appropriate bases include alkali such as sodium and ammonia.
  • the reduction of the formyl group of 24ab, 24ae, 24ae, and 24ad was accomplished with NaBH 4 to give corresponding alcohols 24ab-i, 24ac-i, 24ae-i, and 24ad-i, respectively. Later, the MEM group was removed under acidic conditions to give 25ab, 25ac, 25ae, and 25af, respectively.
  • the vinyl compound 24ah was oxidized with Os0 to give diol 24ah-i, followed by acidic hydrolysis of the MEM group to produce 25ah.
  • the vinyl compound 24ah on dihydroxylation with Os0 gave diol 24ah-i.
  • Oxidative cleavage of the diol with NaI0 4 produced aldehyde 24ah-ii.
  • the aldehyde on reduction gave alcohol 24ah-iii, which on further reaction with methane sulfonyl chloride yielded mesylate 24ah-iv.
  • the mesylate on further reaction with sodium azide gave the corresponding azide 24ah-v, which on acidic hydrolysis produced 25ai.
  • Aldehyde 29g was converted to alcohol 29g-i by reduction with NaBH 4) followed by the reaction of methanesulfonyl chloride to give mesylate 29g-ii.
  • the mesyl group was displaced with azide to give 29g- iii and finally, the MEM group was removed under acidic conditions to give 30g.
  • DME 1,2-Dimethoxyethane
  • DMAP 4-(Dimethylamino)pyridine Boc anhydride: Di-tert-butyl dicarbonate
  • TIPS Triisopropylsilyl
  • MEM Methoxyethoxyrnethyl
  • Bn Phenylmethyl or Benzyl
  • the organic extracts were dried over sodium sulfate or magnesium sulfate.
  • reaction mixture was concentrated in vacuo to remove acetonitrile, diluted with water (10 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, washed with water, brine, dried and concentrated in vacuo to furnish crude acid. Purification was achieved, if needed, by crystallization or using flash column chromatography to obtain pure acid.
  • the reaction mixture was cooled to -40 °C and tributyl borate (5.6 mmol) in ether (20 mL) was added to the reaction and stirred at 4 °C for 12 h.
  • the reaction mixture was allowed to warm to 0 °C and quenched with 2 M HCl (3 mmol) and heated at reflux for 2 h and added to ice water (25 mL).
  • the aqueous layer was separated and the organic layer extracted twice with IN NaOH (2 X 10 mL). The basic extracts were combined and washed with ether (10 mL).
  • the basic layer was acidified to pH 3 using 6 N HCl and the solid that separated out was collected by filtration, washed with water and hexane and dried in vacuo to furnish boronic acid as a solid. If no solid product was obtained, then the basic layer was extracted with ether (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo to furnish boronic acid.
  • the basic extracts were combined and washed with ether (10 mL).
  • the basic layer was acidified to pH 4 using 6 N HCl and the solid that separated out was collected by filtration, washed with water and hexane and dried in vacuo to furnish boronic acid as a solid. If no solid ' product was obtained then the mixture was extracted with ether (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo to furnish boronic acid.
  • pyridine hydrochloride (lOg) was heated in an oil bath at 180 °C. After the entire solid had melted, the corresponding aryl methyl ether (1 mmol) was added in small portions over a period of 20 min. The reaction mixture was heated at 180 °C for 4 h, cooled and quenched with water (100 mL). The reaction mixture was extracted with ethyl acetate (3 X lOmL). The combined organic layers were washed with brine, dried over MgSO , concentrated to give phenol. This can be further purified if needed by crystallization or column chromatography.
  • a solution of methanolic HCl or ethanolic HCl was prepared by the addition of acetyl chloride (1 mL) to methanol/ethanol (9 mL) at 0 °C and stirred for 30 mins. To the solution of anhydrous methanolic HCl was added acid (1 mmol) and stirred at room temperature (or reflux if needed) overnight. The reaction mixture was concentrated to dryness in vacuo and the residue was purified by column chromatography or crystallization to furnish the desired ester.
  • the water layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO ) and evaporated to yield a solid.
  • the solid was washed with hexane and dried in vacuo to furnish the desired amide.
  • the mixture was diluted with water (15 mL) and washed with ether (2 x 10 mL).
  • the aqueous layer was acidified to pH 2 using 6 N HCl and the solid that separated out was collected by filtration, washed with ether, dried in vacuo to furnish product, which was purified by flash column chromatography, if needed.
  • the mixture was diluted with water (15 L) and washed with ether (2 X 10 mL).
  • the aqueous layer was filtered and solid obtained was kept aside (mainly product).
  • the aqueous layer was acidified to pH 2 using 6 N HCl and the solid that separated out was collected by filtration.
  • the combined solid materials were purified, if needed, by flash column chromatography.
  • the filtrate was concentrated in vacuo to give a second crop of the cmde desired aldehyde (60 g) as a dark brown solid.
  • the above solids were combined and dissolved in glacial acetic acid (360 mL) by heating. Water (840 mL) was added and the solution was filtered hot. The solution was allowed to attain room temperature and kept in a refrigerator overnight. The crystals obtained were collected by filtration and washed with water, dried overnight in vacuo to furnish (60 g, 37%) of the desired product as a purplish brown crystalline solid, mp: 135 °C.
  • AK Conversion of aryl triflates or halides to boronate ester
  • the examples of the compounds prepared are given in the following tables.
  • the tables describe the compounds, their method of preparation, the starting material, and the analytical data. In some cases, where analytical data have not been given, those compounds were characterized at the later step in the synthesis.
  • TF/FNIIa an amidolytic assay based upon the absorbance of p- ⁇ itroanalide (p ⁇ A) at OD 405 was utilized.
  • the IC 50 of the test compounds was determined by using KC4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Nmax values.
  • TF/FNIIa assay reactions were performed in a 200 ⁇ L mixture containing 4 nM FNIIa, 10 nM lipidated tissue factor, in an assay buffer containing 100 mM Tris, pH 7.2, 150 mM ⁇ aCl, 5 mM calcium chloride, 0.1 % bovine serum albumin (BSA), and 10% dimethyl sulfoxide (DMSO).
  • TF and FVIIa were allowed to equilibrate at room temperature for 15 minutes.
  • Test compounds dissolved in DMSO were incubated at varied concentrations with TF/FNIIa for 10 minutes, followed by addition of 500 DM substrate Spectrozyme-FNIIa. Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD 4 o 5 mn for 10 minutes at 21 second intervals with a Powerwave x (Bio-Tek Instruments) microplate reader.
  • IC50 of the test compounds was determined by using KC4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Nmax values.
  • Thrombin assay reactions were performed in a 200 ⁇ L mixture containing human thrombin at (1 U/mL) in an assay buffer containing 100 mM HEPES, 10 mM calcium chloride, and 10 % DMSO, pH 7.5. Test compounds dissolved in DMSO were added to thrombin enzyme reactions at varied concentrations, followed by the addition of substrate N ⁇ -Benzoyl-Phe-Nal-Arg p- ⁇ itroanilide at a final concentration of 1 mM. Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD 05 nm for 10 minutes at 21 second intervals with a Powerwave (Bio-Tek Instruments) microplate reader.
  • Powerwave Bio-Tek Instruments
  • IC 5 o of the test compounds was determined by using KC4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Nmax values.
  • Trypsin assay reactions were performed in a 200 ⁇ L mixture containing human pancreatic trypsin at 1 ⁇ g/mL in an assay buffer containing 200 mM triethanolamine (TEA), 10 mM calcium chloride, 10 % DMSO, pH 7.8.
  • Test compounds dissolved in DMSO were added to trypsin enzyme reactions at varied concentrations, followed by the addition of substrate ⁇ -Benzoyl-L-Arginine p- ⁇ itroanilide (L-BAP ⁇ A) at a final concentration of (0.25 mg/mL). Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD 4 os nm for 10 minutes at 21 second intervals with a Powerwave x (Bio-Tek Instruments) microplate reader.
  • IC 50 values + means >1 ⁇ M; ++ means >100 nM; +++ means ⁇ 100 nM
  • Compounds of the present invention are useful as inhibitors of trypsin-like serine protease enzymes such as thrombin, factor Vila, TF/FNIIa, and trypsin.
  • These compounds may be employed to inhibit the coagulation cascade and prevent or limit coagulation.
  • These compounds may be used to inhibit the formation of emboli or thromboli in blood vessels.
  • These compounds may be used to treat thrombolymphangitis, thrombosinusitis, thromboendocarditis, thromboangitis, and thrornboarteritis.
  • These compounds may be used to inhibit thrombus formation following angioplasty. These may be used in combination with other antithrombolytic agents such as tissue plasminogen activators and their derivatives, streptokinase and its derivatives, or urokinase and its derivatives to prevent arterial occlusion following thrombolytic therapy.
  • tissue plasminogen activators and their derivatives such as tissue plasminogen activators and their derivatives, streptokinase and its derivatives, or urokinase and its derivatives to prevent arterial occlusion following thrombolytic therapy.
  • These compounds may also be used in matastatic diseases, or for any disease where inhibition of coagulation is indicated.
  • These compounds may be used as diagnostic reagents in vitro for inhibiting clotting of blood in the tubes.
  • These compounds may be used alone or in combination with other compounds such as heparin, aspirin, or warfarin and any other anticoagulant agents. These compounds may be used as anti-inflammatory agents.
  • compounds may be employed in preventing ex vivo coagulation such as that encountered in the extracorporeal perfusion of blood through for example artificial valves, prothesis, stents or catheters.
  • the extracorporeal device may be coated with the compositions of the invention resulting in a lower risk of clot formation due to extrinsic pathway activation.
  • the compounds of this invention can be administered by any means that produces contact of the active agent's site of action with factor Vila and other serine proteases in the body of a human, mammal, bird, or other animal. They can be administered by any conventional means, such as oral, topical, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. Parenteral infusion includes intramuscular, intravenous, and intraarterial. They can be administered alone, but generally administered with a pharmaceutical carrier elected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • the dosage administered will, or course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms, the kind of concurrent treatment; the frequency of treatment; and the effect desired.
  • a daily dosage of active ingredient can be expected to be about 0.0001 to 1000 milligram (mg) per kilogram (kg) of body weight, with the preferred dose being 0.1 to about 30 mg/kg.
  • Dosage forms contain from about mg to about 500 mg of compound per unit. In these pharmaceutical compositions, the compound of the present invention will ordinarily be present in an amount of about 0.5- 95% by weight based on the total weight of the composition.
  • the daily dose of the compounds of the invention that is to be administered can be a single daily dose or can be divided into several, for example, two, three or four, part administrations.
  • the pharmaceutical compositions or medicaments of the invention can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures.
  • Administration can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or percutaneously or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.
  • Gelatin capsules contain a compound of the present invention and powdered carriers, such as lactose, starch, cellulose derivatives, biocompatible polymers, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated to mask by unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • powdered carriers such as lactose, starch, cellulose derivatives, biocompatible polymers, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated to mask by unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. They may also contain buffering agents, surfactants and preservatives. Liquid oral products can be developed to have sustained-release properties. They may also contain cyclodextrin derivatives to enhance the solubility of the active ingredient and to promote its oral uptake.
  • parenteral solutions In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and, if necessary, buffering agents.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical
  • Useful pharmaceutical dosage forms for administration of the compounds according to the present invention can be illustrated as follows:
  • a large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered 1500 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.
  • Soft Gelatin Capsules 100 mg of powdered 1500 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.
  • a mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient.
  • the capsules are washed and dried.
  • the prodrug can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
  • a large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcystalline cellulose, 11 mg of starch, and 9.98 mg of lactose.
  • Appropriate aqueous and non-aqueous coatings may be applied to increase palatability improve elegance and stability or delay absorption.
  • the drug is mixed containing ingredient such as sugar, gelatin, pectin, and sweeteners.
  • ingredient such as sugar, gelatin, pectin, and sweeteners.
  • These liquids are solidified into solid tablets or caplets by freeze drying and solid thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
  • the compounds of the present invention can be administered in the form of nose drops, metered dose nasal or buccal inhalers.
  • the drug is delivered from a nasal solution as a fine mist or from a powder as an aerosol.
  • a compound of the invention can be used in an assay to identify the presence of factor Vila and other serine protease or to isolate , factor Vila and other serine protease in a substantially purified form.
  • the compound of the invention can be labeled with, for example, a radioisotope, and the labeled compound is detected using a routine method useful for detecting the particular label.
  • a compound the invention can be used advantageously as a probe to detect the location or amount of factor Vila and other serine protease activity in vivo, in vitro or ex vivo.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Compounds of formula (I) are useful as inhibitors of trypsin like serine protease enzymes such as thrombin, factor VIIa, factor Xa, TF/FVIIa, and trypsin. These compounds could be useful to treat and/or prevent clotting disorders, and as anticoagulating agents.

Description

BIARYL COMPOUNDS AS SERINE PROTEASE INHIBITORS
DESCRIPTION
Cross-Reference to Related Applications
This application is a continuation-in-part of copending U. S. applications S.N.
60/241,848 filed October 20, 2000 and entitled "Inhibitors for Activated Blood
Coagulation Factor Vila (FVHa)" and S.N. 60/281,735 filed April 6, 2001 and entitled "Biaryl Compounds as Serine Protease Inhibitors"
Technical Field
The present invention relates to the identification, through synthesis and testing, of heretofore unreported compounds which, in appropriate pharmaceutical compositions, exert a therapeutic effect through reversible inhibition of serine proteases.
Background of Invention
Serine proteases make up the largest and most extensively studied group of proteolytic enzymes. Their critical roles in physiological processes extend over such diverse areas as blood coagulation, fibrinolysis, complement activation, reproduction, digestion, and the release of physiologically active peptides. Many of these vital processes begin with cleavage of a single peptide bond or a few peptide bonds in precursor protein or peptides. Sequential limited proteolytic reactions or cascades are involved in blood clotting, fibrinolysis, and complement activation. The biological signals to start these cascades can be controlled and amplified as well. Similarly, controlled proteolysis can shut down or inactivate proteins or peptides through single bond cleavages. hile serine proteases are physiologically vital, they also can be hazardous. Their proteolytic action, if uncontrolled, can destroy cells and tissues through degradation of proteins. As a natural safeguard in normal plasma, 10% of the protein matter is composed of protease inhibitors. The major natural plasma inhibitors are specific for serine proteinases. Diseases (associated protease given in the parentheses) such as pulmonary emphysema (cathepsin G), adult respiratory distress syndrome (chymases), and pancreatitis (trypsin, chymotrypsin, and others) are characterized by uncontrolled serine proteases. Other proteases appear to be involved in tumor invasion (plasmin, plasminogen activator), viral transformation, and inflammation (kallikrein). Thus the design and synthesis of specific inhibitors for this class of proteinases could offer major therapeutic benefits.
Thrombus formation, that is blood coagulation, is normally initiated by tissue injury; its normal purpose is to slow or prevent blood loss and facilitate wound healing. There are other conditions, however, not directly connected with tissue injury that may promote the coagulation process and lead instead to harmful consequences; examples of such conditions are atherosclerosis and inflammation.
The complex pathways of blood coagulation involve a series of enzyme reactions in which plasma coagulation factors, actually enzyme precursors or zymogens, are sequentially activated by limited proteolysis. Blood coagulation, or the coagulation cascade, is viewed mechanistically as two pathways, the extrinsic and the intrinsic (Fig. 1). Each pathway proceeds through a sequence of the Roman-numeral-designated factors until they converge at the activation of factor X after merger of the pathways. Thrombin generation proceeds stepwise through a common pathway. Thrombin then acts on the solution plasma protein, fibrinogen, to convert it to stable insoluble fibrin clots, thus completing the coagulation cascade. The extrinsic pathway is vital to the initiation phase of blood coagulation while the intrinsic pathway provides necessary factors in the maintenance and growth of fibrin. The initiation of the coagulation cascade involves the release of tissue factor (TF) from injured vessel endothelial cells and subendothelium. TF then acts upon factor VII to form the TF/FVIIa complex (where Vila designates the activated factor rather than the zymogen form). This complex initiates coagulation by activating factors IX and X. The resulting factor Xa forms a prothrombinase complex that activates prothrombin to produce the thrombin that converts fibrinogen to insoluble fibrin. In contrast, the intrinsic system is activated in vivo when certain coagulation proteins contact subendotheUal connective tissue. In the sequence that follows, contact factors XII and XI are activated. The resulting factor XIa activates factor LX; then factor LXa activates factor X thereby intersecting with the extrinsic pathway.
With time, the TF FVIIIa complex (of the extrinsic pathway) loses activity due to the action of tissue factor pathway inhibitor (TFPI), a Kunitz-type protease inhibitor protein which, when complexed with factor Xa, can inhibit the proteolytic activity of TF/FVIIa. If the extrinsic system is inhibited, additional factor Xa is produced through the thrombin-mediated action in the intrinsic pathway. Thrombin, therefore, exerts a dual catalytic role in (a) the conversion of fibrinogen to fibrin and (b) mediating its own production. The autocatalytic aspect of thrombin production affords an important safeguard against excessive blood loss, and, assuming presence of a threshold level of prothrombinase, ensures that the blood coagulation process will go to completion.
While the ability to form blood clots is vital to survival, there are disease states wherein the formation of blood clots within the circulatory system can cause death. When patients are afflicted with such disease states, it is not desirable to completely inhibit the clotting system because life-threatening hemorrhage would follow. Thus, it is highly desirable to develop agents that inhibit coagulation by inhibition of factor Vila without directly inhibiting thrombin. Need for the prevention of intravascular blood clots or for anti-coagulant treatment in many clinical situations is well known. Drugs in use today are often not satisfactory. A high percentage of patients who suffer internal injuries or undergo certain surgical procedures develop intravascular blood clots which, if unchecked, cause death. In total hip replacement surgery, for example, it is reported that 50% of the patients develop deep vein thrombosis (DVT). Current approved therapies involve administration of heparin in various forms, but results are not entirely satisfactory; 10-20% of patients suffer DVT and 5-10% have bleeding complications. Along these lines, see International Publication No. WO 00/15658.
Other examples of clinical situations for which better anticoagulants would be of great value are when patients undergo transluminal coronary angioplasty and treatment for myocardial infarction or crescendo angina. The present therapy for these conditions is administration of heparin and aspirin, but this treatment is associated with a 6-8% abrupt vessel closure rate within 24 hours of the procedure. Transfusion therapy due to bleeding complications is required in approximately 7% of cases following the use of heparin. Occurrences of delayed vessel closures are also significant, but administration of heparin after termination of the procedure affords little beneficial effect and can be detrimental.
Heparin and certain derivatives thereof are the most commonly used anti-clotting agents. These substances exert their effects mainly through inactivation of thrombin, which is inactivated 100 times faster than factor Xa. Two other thrombin-specific anticoagulants, hirudin and hirulog, are in clinical trials (as of September 1999). However, bleeding complications are associated with these agents.
In preclinical studies in baboons and dogs, the targeting of enzymes involved in earlier stages of the coagulation cascade, such as factor Vila or factor Xa, prevents clot formation and does not produce bleeding side effects observed with direct thrombin inhibitors.
Several preclinical studies reveal that inhibition of TF FVIIa offers the widest window of therapeutic effectiveness and safety with respect to bleeding risk of any anticoagulant approach tested including thrombin, platelet, and factor Xa inhibition.
A specific inhibitor of factor Vila would provide clinicians with a valuable and needed agent that would be safe and effective in situations where the present drags of choice, heparin and related sulfated polysaccharides, are no better than marginally effective.
There exists a need for a low molecular weight specific serine protease inhibitors specific toward various enzymes, particularly for factor Vila that does not cause unwanted side effects.
Figure 1. Pathways of Coagulation
Extrinsic Pathway Intrinsic Pathway Release of TF Release of Contact Factors XII and XI
Figure imgf000006_0001
Common Pathway Prothrombin - Thrombin - Fibrinogen Fibrin The figure illustrates the extrinsic and intrinsic pathways of blood coagulation.
Summary of Invention
An aspect of the present invention relates to compounds represented by the formula:
R B1
(R1) m- E1- W E2- B
X (R2L ; pharmaceutically acceptable salts thereof; v- -v and prodrugs thereof.
X
(I)
( A)
Each E! and L individually is a 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic saturated or unsaturated carbon ring, bicyclic saturated or unsaturated hetero ring, or 1-8 hydrocarbon chain which maybe substituted with one or more hetero groups selected from N, O, S, S(O), and S(O2) which may be saturated or unsaturated. The bicyclic rings typically contain 7-13 atoms in the ring.
R is -CH=CH:R2, -C≡C-R2, -C(R2)=CH2, -C(R2)=C(R3), -CH-NR2, -C(R2)=N-R3 , 4-7 membered saturated or unsaturated carbon ring system with or without substitution, 4-7 membered saturated or unsaturated hetero ring system with or without substitution, or chain of 2 to 8 carbon atoms having 1 to 5 double or triple bonds with substitutions selected from R1, R2, or R3. R1 is H, -R, -NO2, -CN, -halo, -N3, -C ι_8 alkyl, -(CH2)„CO2R2, -C2.8 alkenyl-CO2R2, -O(CH2)nCO2R2, -C(O)NR2R3, -P(O)(OR2)2, alkyl substituted tetrazol-5-yl, -(CH2)nO(CH2)n aryl, -NR2R3, -(CH2)n OR2, -(CH2)n SR2, -N(R2)C(O)R3, -S(O2)NR2R3, -N(R )S(O2)R3, -(CHR2)n NR2R3, -C(O)R3, (CH2)n N(R3)C(O)R3, -N(R2)CR2R3 substituted or unsubstituted (CH2)n-cyclo alkyl, substituted or unsubstituted (CH2)n- • phenyl, or substituted or unsubstituted (CH2)n-heterocycle which may be saturated or unsaturated.
m is 1 except that when El is a cyclic ring of more than 5 atoms, then m is 1 or higher, depending upon the size of the ring.
R2 is H, -halo, -alkyl, -haloalkyl, -(CH2)n -phenyl, -(CH2)ι_3-biphenyl, -(CH2) -Ph- N(SO2-Ci.2-alkyl)2, -CO(CHR1)n-OR1, -(CHR5)n-heterocycle, -(CHR^-NH-CO-R1, -(CHR1)n-NH-SO2R1, -(CHR1)n-Ph-N(SO -C,.2-alkyl)2, -(CHR1)n-C(O)(CHR1)-NHR1, -(CHR1)n-C(S)(CHR1)-NHR1, -(CH2)nO(CH2)nCH3, -CF3, -C2.5 acyl, -(CHR^OH, -(CHR^nCOzR1, -(CHR^n-O-alkyl, -(CHR1)n-O-(CH2)n-O-alkyl, -(CHR'^-S-alkyl,
Figure imgf000008_0001
-(CHR3)n-N3, -(CHR3)nNHR4 ; 2 to 8 carbon atom alkene chain having 1 to 5 double bonds, 2 to 8 carbon atom alkyne chain having 1 to 5 triple bonds, substituted or unsubstituted- (CHR3)n heterocycle, or substituted or unsubstituted-(CHR3)n cycloalkyl which may be saturated or unsaturated. When n is more than 1, the substitutions R1 and R3 may be same or different.
R3 is H, -OH, -CN, substituted alkyl, -C2.8 alkenyl, substituted or unsubstituted cycloalkyl, -N(R!)R2, or 5-6 membered saturated substituted or unsubstituted hetero ring.
-NR2R3 may form a ring system having 4 to 7 atoms or may be bicyclic ring. The ring system may be of carbon or hetero atoms and further it may saturated or unsaturated and also may be substituted or unsubstituted. W is a direct bond, -CHR -, -CH=CR2-, -CR2=CH-, -CR2= R2-, -C≡C-, -O-CHR2-, -CHR2-O-, -N(R2)-C(O)-, -C(O)-N(R2)-, -N(R2)-CH-(R3)-, -CH2-N(R2)-, -CH(Rl)-N(R2)-, -S-CHR2-, -CHR2-S-, -S(O2)-N(R2)-, -C(O)N(R2)-(CHR2)n-, -C(R1R2)n-NR2-, -N(R2)-S(O2)-, -R2C(O)NR2-, -R2NC(O)NR2-, -CONR2CO-, - C(=NR2)NR2-, -NR2C(=NR2)NR2-, -NR O-, -N=NCHR2-, or -C(O)NR SO2-.
E2 is 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, Cι_8 alkyl, C2.8 alkenyl, C2.8 alkynyl, alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino.
each X individually is a direct bond, substituted or unsubstituted Cμ methylene chain; O, S, NR2 , S(O), S(O2), or N(O) containing one or two CM substituted or unsubstituted methylene chains. X at different places may be same or different.
B is H, -halo, -CN, -NH2, -(CH2)n-C(=NR4)NHR5, -(CH2)n-NHR4, - (CH2)nNHC(=NR4) R5, -(CH2)n-OR4, Cι.8 substituted or unsubstituted alkyl, substituted or unsubstituted ring system having 4 to 7 carbon or hetero atoms which may be saturated or unsaturated.
B1 is selected from B; B1 and B may be same or different.
There may be more than one similar or different R groups present on E , when E is a cyclic group of more than 5 atoms. In particular, p is 1 except that when E2 is a cyclic ring of more than 5 atoms, p is 1 or higher depending upon the size of the ring.
n is 0-4
A is selected from R . o is 1 except that when L is a cyclic ring of more than 5 atoms, o is 1 or higher depending upon the size of the ring.
Each V and V1 individually is selected from R1 and N-alkyl substituted carboxamidyl (- CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic; N,N- disubstituted carboxamidyl (-CONR1R2 where Ri and R2 may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (SO2NHR or -SO2NR1R2); and methylene- or polymethylene chain- extended variants thereof.
Each R4 and R5 individually is H, -(CH2)nOH, -C(O)OR6, -C(O)SR6, -(CH2)„ C(O)NR7R8, -O-C(O)-O-R7, an amino acid or a dpeptide,
Each R6 is H, R7, -C(R7)(R8)-(CH2)n-O-C(O)-R9, -(CH2)n-C(R7)(R8)-O-C(O)R9, -(CH2)n- C(R7)(R8)-O-C(O)-O-R9, or -C(R7)(R8)-(CH2)n-O-C(O)-O-R9,
Each R7, Rs and R9 individually is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or CH2CO2alkyl.
The present invention also relates to pharmaceutical compositions containing at least one of the above disclosed compounds and their prodrugs.
A further aspect of the present invention relates to a method for inhibiting trypsin- like serine protease enzymes, such as thrombin, factor Xa, factor Vila, TF/VIIa, and trypsin in a patient which comprises administering to the patient an effective serine protease inhibiting amount of at least one of the above disclosed compounds. Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described preferred embodiments of the invention, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from the invention. Accordingly, the description is to be regarded as illustrative in nature and not as restrictive.
Best and Various Modes for Carrying Out Invention
An aspect of the present invention relates to compounds represented by the formula: R B1
(R1) m- :1 - w E2- B
X /D2-) ; pharmaceutically acceptable salts thereof;
Ψ- -V and prodrugs thereof.
X
(I)
( A)
Each E1 and L individually is a 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic saturated or unsaturated carbon ring, bicyclic saturated or unsaturated hetero ring, or 1-8 hydrocarbon chain which may be substituted with one or more hetero groups selected from N, O, S, S(O), and S(O2) which maybe saturated or unsaturated. R is -CH=CH-R2, -C≡C-R2, -C(R2)=CH2, -C(R2)=C(R3), -CH=NR2, -C(R2)=N-R3, 4-7 membered saturated or unsaturated carbon ring system with or without substitution, 4-7 membered saturated or unsaturated hetero ring system with or without substitution, or chain of 2 to 8 carbon atoms having 1 to 5 double or triple bonds with substitutions selected from R1 , R2, or R3. Preferably, these R, R1 , R2, or R3 do not include -(C2.4 alkenyl)-CO2-Cι-8 alkyl, -(C2.4 alkenyl)-CO2-Cι.8 alkyl-phenyl, and-(C2. alkenyl)-CO2- d-8 alkyl-O-Ci-4 alkyl.
R1 is H, -R, -NO2, -CN, -halo, -N3, -C ι.8 alkyl, -(CH2)nCO2R2, -C2.8 alkenyl-CO2R2, -O(CH2)nCO2R2, -C(O)NR2R3, -P(O)(OR2)2, alkyl substituted tetrazol-5-yl,
-(CH2)nO(CH2)n aryl, -NR2R3, -(CH2)n OR2, -(CH2)n SR2, -N(R2)C(O)R3, -S(O2)NR2R3, -N(R2)S(O2)R3, -(CHR2)n NR2R3, -C(O)R3, (CH2)n N(R3)C(O)R3, -N(R2)CR2R3 substituted or unsubstituted (CH2)n-cycloalkyl, substituted or unsubstituted (CH2)π- phenyl, or substituted or unsubstituted (CH2)n-heterocycle which may be saturated or unsaturated.
m is 1 except that when E1 is a cyclic ring of more than 5 atoms, then m is 1 or higher, depending upon the size of the ring. For instance if the ring is 6 atoms, m can be 1 or 2.
R2 is H, -halo, -alkyl, -haloalkyl, -(CH2)„ -phenyl, -(CH2)ι-3-biphenyl, -(CH^M-Ph- N(SO2-Cι.2-alkyl)2, -CO(CHR1)n-OR1, -(CHRVheterocycle, -(CHR^-NH-CO-R1, -(CHR^n-NH-SOzR^ ^CHR^n-Ph-^SOa-Ci^-alkyl^^^HR^n-C^^HR^-NHR1, -(CHR1)n-C(S)(CHR1)-NHR1, -(CH2)nO(CH2)nCH3, -CF3, -C2.5 acyl, -(CHR^OH,
Figure imgf000012_0001
-(CHR1)n-S(O)-alkyl, -(CHR1)n-S(O2)-alkyl, -(CHR1)n-S(O2)-NHR3, -(CHR3)n-N3, -(CHR3)nNHR4 2 to 8 carbon atom alkene chain having 1 to 5 double bonds, 2 to 8 carbon atom alkyne chain having 1 to 5 triple bonds, substituted or unsubstituted- (CHR3)n heterocycle, or substituted or unsubstituted-(CHR3)n cycloalkyl which may be saturated or unsaturated. When n is more than 1, the substitutions R1 and R3 may be same or different.
R3 is H, -OH, -CN, substituted alkyl, -C2.8 alkenyl, substituted or unsubstituted cycloalkyl, -N R^R2, or 5-6 membered saturated substituted or unsubstituted hetero ring.
-NR R may form a nng system having 4 to 7 atoms or may be bicyclic ring. The ring system may be of carbon or hetero atoms and further it may saturated or unsaturated and also may be substituted or unsubstituted.
W is a direct bond, -CHR2-, -CH=CR2-, -CR2=CH-, -CR2=CR2-, -C≡C-, -O-CHR2-, -CHR2-O-, -N(R2)-C(O)-, -C(O)-N(R2)-, -N(R2)-CH-(R3)-, -CH2-N(R2)-,
Figure imgf000013_0001
-S-CHR2-, -CHR2-S-, -S(O2)-N(R2)-, -C(O)N(R2)-(CHR2)n-, -C(R1R2)n-NR2-, -N(R2)-S(O2)-, -R2C(O)NR2-, -R2NC(O) R2-, -CONR2CO-, - C(=NR2) R2-, -NR2C(= R2)NR2-, -NR2O-, -N=NCHR2-, or -C(O)NR2SO2-.
E2 is 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, Ci-g alkyl, C2-8 alkenyl, C2.8 alkynyl, alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino.
each X individually is a direct bond, substituted or unsubstituted C methylene chain; O, S, NR2 , S(O), S(O2), orN(O) containing one or two CM substituted or unsubstituted methylene chains. X at different places may be same or different.
B is H, -halo, -CN, -NH2, -(CH2)n-C(=NR4)NHR5, -(CH2)n-NHR4, - (CH2)nNHC(=NR4)NR5, -(CH2)n-OR4, Cι-8 substituted or .unsubstituted alkyl, substituted or unsubstituted ring system having 4 to 7 carbon or hetero atoms which may be saturated or unsaturated.
B1 is selected from B; B1 and B may be same or different. There may be more than one similar or different R2 groups present on E2, when E2 is a cyclic system of more than 5 atoms, p is 1 or higher if E2 is a cyclic ring of more than 5 atoms. For example, if the ring is 6 atoms, p can be 1 or 2.
n is 0-4
A is selected from R1. o is 1 except that when L is a cyclic ring of more than 5 atoms, o is 1 or higher depending upon the size of the ring. For instance, if the ring is 6 atoms, o can be 1 or 2.
Each N and N! individually is selected from R1 and Ν-alkyl substituted carboxamidyl (- COΝHR) where the alkyl group may be straight, branched, cyclic, or bicyclic; Ν,Ν- disubstituted carboxamidyl (-CONRιR2 where Ri and R2 may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (SO2NHR or -SO2NR1R2); and methylene- or polymethylene chain- extended variants thereof.
Each R4 and R5 individually is H, -(CH2)nOH, -C(O)OR6, -C(O)SR6, -(CH2)n C(O)NR7R8, -O-C(O)-O-R7, an amino acid or a dipeptide,
Each R6is H, R7, -C(R7)(R8)-(CH2)n-O-C(O)-R9, -(CH2)n-C(R7)(R8)-O-C(O)R9, -(CH2)n- C(R7)(R8)-O-C(O)-O-R9, or -C(R7)(R8)-(CH2)n-O-C(O)-O-R9,
Each R7, R8- and R9 individually is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or CH2CO2alkyl. R substituent groups employed pursuant to the present invention contribute to significantly enhanced activity of the compounds of the present invention.
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term "alkyl" refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms. The expression "lower alkyl" refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
The terms "alkenyl" and "alkynyl" refer to straight or branched chain unsubstituted hydrocarbon groups typically having 2 to 8 carbon atoms.
The terms "substituted alkyl", "substituted alkenyl" or substituted alkynyl" refer to an alkyl, alkenyl or alkynyl group substituted by, for example, one to four substituents, such as halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamine, aroylamino, aralkanoylamino, substituted alkanolamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO2NH2), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. CONH2), substituted carbamyl (e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where noted above where the substituent is further substituted it will be with halogen, alkyl, alkoxy, aryl or aralkyl.
The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.
The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.
The term "aralkyl" or "alkylaryl" refers to an aryl group bonded directly through an alkyl group, such as benzyl or phenethyl.
The term "substituted aryl" or "substituted alkylaryl" refers to an aryl group or alkylaryl group substituted by, for example, one to four substituents such as alkyl; substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, azido, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, hydroxyalkyl, aminoalkyl, azidoalkyl, alkenyl, alkynyl, allenyl, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy and the like. The substituent may be further substituted by halo, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl. "Substituted benzyl" refers to a benzyl group substituted by, for example, any of the groups listed above for substituted aryl.
The term "cycloalkyl" refers to optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C -C carbocyclic ring. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and adamantyl. Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
The term "cycloalkenyl" refers to optionally substituted, unsaturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3-7 carbons per ring. Exemplary groups include cyclopentenyl and cyclohexenyl.
The terms "heterocycle", "heterocyclic" and "heterocyclo" refer to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atoms.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazoUdinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, thiophenyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, dihydropyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3- dixolane and tetrahydro-1, 1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl and triazolyl and the like. Exemplary bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, cournarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolapridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,l-b]pyridinyl, or furo[2,3-b]pyridinyl), dihydroisoindolyl, diyhydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzorurazanyl, benzothiopyranyl, benzothrasolyl, benzpyrasolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, theinofuryl, thienopyridyl, thienothienyl, and the like.
Exemplary substituents include one or more alkyl groups as described above or one or more groups described above as alkyl substituents.
Within the above-described definitions, certain embodiments are preferred. Preferred alkyl groups are lower alkyl groups containing 1 to about 8 carbon, and more preferably 1 to about 5 carbon atoms, and can be straight, branched-chain or cyclic saturated aliphatic hydrocarbon groups.
Examples of suitable alkyl groups include methyl, ethyl and propyl. Examples of branched alkyl groups include isopropyl and t-butyl. An example of a suitable alkylaryl group is phenethyl. Examples of suitable cycloalkyl groups typically contain 3-8 carbon atoms and include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The aromatic or aryl groups are preferably phenyl or alkyl substituted aromatic groups (aralkyl) such as phenyl C1-3 alkyl such as benzyl.
The N-heterocyclic rings preferably contain 3-7 atoms in the ring and a heteroatom such as N, S or O in the ring. Examples of suitable prefeπed heterocyclic groups are pyrrolidino, azetidino, piperidino, 3,4-didehydropiperidino, 2- methylpiperidino and 2-ethylpiperidino. In addition, the above substitutions can include halo such as F, CI, Br, lower alkyl, lower alkoxy and halo substituted lower alkoxy.
Examples of some preferred B groups include
Figure imgf000019_0001
NH2, various N-substituted variants, and assorted prodrug derivatives.
Prodrug forms of the compounds bearing various nitrogen functions (amino, hydroxyamino, hydrazino, guanidino, amidino, amide, etc.) may include the following types of derivatives where each R group individually may be hydrogen, substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, heterocycle, alkylaryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, or cycloalkenyl groups as defined beginning on page 7.
(a) Carboxamides, -NHC(O)R
(b) Carbamates, -NHC(O)OR
(c) (Acyloxy)alkyl carbamates, -NHC(O)OROC(O)R
(d) Enamines, -NHCR(=CHCRO2R) or -NHCR(=CHCRONR2)
(e) Schiff bases, -N=CR2
(f) Mannich bases (from carboximide compounds), RCONHCH2NR2
Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al, J. Med. Chem. 1988, 31, 318; Aligas-Martin et al, PCT WO pp/41531, p. 30). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the invention. Prodrug forms of carboxyl-bearing compounds of the invention include esters (-CO2R) where the R group corresponds to any alcohol whose release in the body through enzymatic or hydrolytic processes would be at pharmaceutically acceptable levels. Another prodrug derived from a carboxylic acid form of the invention may be a quaternary salt type
Figure imgf000020_0001
of structure described by Boder et al, J. Med. Chem. 1980, 23, 469. Examples of some prefeπed groups for W are -CH2CH2-, -CH=CH-, -C≡C-, -
CH2CH2CH2-, -CH2CH=CH-, -CH2C≡C-, -CONH, -CH2CONH-, -NHCONH-, -CONHCO-, -CONHCH2-, -C(=NH)NH-, -CH2C(=NH)NH-, -NHC(=NH)NH-, -NHNH-, -NHO-, -CONHSO2-, -SO2NH-, -NHSO2CH2-, -SO2NHCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-, -CH2NH-, -CH2CH2NH-, -CH2NHCH2-, -CH2S-, -SCH2CH2, -CH2SCH2-, - CH2SO2CH2-, -CH2SOCH2-, -CH(CO2H)O and -CH(CO2H)OCH2.
Examples of some preferred groups for V and V1 are N-alkyl substituted carboxamidyl (-CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic, and typically containing up to ten carbons; N,N-disubstituted carboxamidyl (- CONR1R2 where Ri and R2 may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (SO2NHR or -SO2NRiR2); methylene- or polymethylene chain- extended variants thereof such as -(CH )πCONHRι, -(CH2)nCONR,R2, -(CH2)nSO2NHRι, -(CH2)nSO2NRi 2 (where n = 1-4), -NHC(O)R, N(Rι)C(O)R2, NHSO2R, CH2NHR, CH2NRιR2. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from pharmaceutically acceptable, inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycoUic, lactic, salicyclic, succinic, toluene-p- sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic, trifluoroacetic and benzenesulphonic acids.
Salts derived from appropriate bases include alkali such as sodium and ammonia.
It is of course understood that the compounds of the present invention relate to all optical isomers and stereo-isomers at the various possible atoms of the molecule.
The synthetic routes leading to the compounds in formula (I) are described in the following schemes.
Scheme 1
Figure imgf000022_0001
Figure imgf000022_0002
Scheme 2
Figure imgf000023_0001
Scheme 3
Figure imgf000024_0001
Scheme 4
Figure imgf000025_0001
Scheme 5
Figure imgf000026_0001
Figure imgf000026_0002
4, R = (continued)
Figure imgf000027_0001
Figure imgf000027_0002
Figure imgf000028_0001
n, CH, °. / \ CH, S. ^N CH,
OH
H3C
Figure imgf000028_0002
27, R = (continued)
Figure imgf000029_0001
Conversion of 24ab ■ *» 25ab
24ac K' M » 2Sac
24ae K' H > 25ae
24ad K' " > 25af The reduction of the formyl group of 24ab, 24ae, 24ae, and 24ad was accomplished with NaBH4 to give corresponding alcohols 24ab-i, 24ac-i, 24ae-i, and 24ad-i, respectively. Later, the MEM group was removed under acidic conditions to give 25ab, 25ac, 25ae, and 25af, respectively.
E, H, 1-1 Conversion of 24ad - 25ad The aldehyde 24ad was oxidized to acid 24ad-i which was protected as benzyl ester to give 24ad-ii. MEM deprotection under acidic conditions produced 25ad.
Conversion of 24ah — '■ ■" ■ 25ah
The vinyl compound 24ah was oxidized with Os0 to give diol 24ah-i, followed by acidic hydrolysis of the MEM group to produce 25ah.
L, M, K, N, 0, 1-1 Conversion of 24ah *- 25ai
The vinyl compound 24ah on dihydroxylation with Os0 gave diol 24ah-i. Oxidative cleavage of the diol with NaI04 produced aldehyde 24ah-ii. The aldehyde on reduction gave alcohol 24ah-iii, which on further reaction with methane sulfonyl chloride yielded mesylate 24ah-iv. The mesylate on further reaction with sodium azide gave the corresponding azide 24ah-v, which on acidic hydrolysis produced 25ai.
Conversion of 24 — >■ 25w Scheme 6
Figure imgf000030_0001
29, R =
Figure imgf000030_0002
Figure imgf000031_0001
31, R =
Figure imgf000031_0002
32, R =
Figure imgf000031_0003
K, N, 0, 1-1 Conversion of 29g *- 30g
Aldehyde 29g was converted to alcohol 29g-i by reduction with NaBH4) followed by the reaction of methanesulfonyl chloride to give mesylate 29g-ii. The mesyl group was displaced with azide to give 29g- iii and finally, the MEM group was removed under acidic conditions to give 30g.
K, I-1 Conversion of 29h *- 30h
K, I-1 29i ». 30j
The reduction of the formyl group of 29h and 29i was accomplished with NaBH4 to give corresponding alcohols 29h-i and 29i-i, respectively. Later, the MEM group was removed under acidic conditions to give 30h and 30i, respectively.
Compounds of the type 23 and 28, where X = -Sn(Bu)3) are prepared using the methods AG-1 or AG-2 Scheme 7
Figure imgf000032_0001
Scheme 8A
Figure imgf000033_0001
Figure imgf000033_0002
Figure imgf000033_0003
Scheme 8B
Scheme 8C
Figure imgf000034_0001
Scheme 8D
Figure imgf000034_0002
Scheme 8E zon G 27aj (R =
32f - G
- 27ak(R = - CH3)
G
26ai — ^ 27aI(R = . NH„ G 27am (R=.
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000037_0002
Figure imgf000038_0001
Figure imgf000038_0003
Figure imgf000038_0002
Figure imgf000038_0004
Figure imgf000038_0005
Figure imgf000039_0001
,NHBoc s,
Figure imgf000039_0002
x, - XH3
-OH
Figure imgf000040_0001
Scheme 11
Figure imgf000041_0001
77a, 78a, 79a, 80a, R = C= :CH2;R' = CH3
H
78b, 79b, R = OSO,CF,; R' = Bn; 80b, R = OH
77b, 78c, 79c, R = -0-CH2C02C2H5; R' = Bn; 80c, R= -0-CH2CQ2H
77c, 78d, 79d, 80d, R = -0-CH2CONH2; R' = Bn
77d,78e,79e,80e,R = R' = Bn
Figure imgf000042_0001
77e, 78f, 79f ',,80f,R = — o- XX ;R' = Bn
E
74 ■78g- ■79g- 1-2
80g
78g, 79g, 80g, R = OCH3, R' = CH3
.0.
77f,78h,79h,80h,R = - CH3;R' = Bn
77g,78i,79i,80i,R =
Figure imgf000042_0002
;R' = Bn
Figure imgf000042_0003
77i, 78k, 79k, R = OCH,-CH,-OAc; R' = Bn; 80k, R = -0-CH2-CH2-OH
Scheme 12
Figure imgf000043_0001
86a,R=CH(0H)CH20H 86b,R=CH,OH 86c, R=C02H Scheme 13
Figure imgf000044_0001
98b __H — *.98c, R = -OH Scheme 14
Figure imgf000045_0001
Figure imgf000045_0002
Figure imgf000045_0004
Figure imgf000045_0003
Scheme IS
Figure imgf000046_0001
111 112
Scheme 16
Figure imgf000047_0001
O
114a, 115a, 116a, R = CH3; 114b, 115b, 116b, R= C2H5; 114c, 115c, 116c, R = -CH(CH3)2; 115d, R= C C(CH3)3
Figure imgf000048_0001
117f~125f,R = CH3; R' =
117g--125g,R = CH3;R' = CF,
117h"125h,R=CH3;R' =
Figure imgf000048_0002
117k- 125k, R = CH3;R' = -CH,
Figure imgf000048_0003
117m - 124m, R 125m, R = H; R' =
Figure imgf000048_0004
Figure imgf000048_0005
Scheme 16a
Figure imgf000049_0001
Scheme 16b
Figure imgf000049_0002
Scheme 17
Figure imgf000050_0001
Figure imgf000050_0003
Figure imgf000050_0002
Figure imgf000050_0004
Figure imgf000050_0005
133, 134, R= (continued)
Figure imgf000051_0001
Scheme 17a
Figure imgf000051_0002
35, 136, R =
Figure imgf000051_0003
Scheme 18
Figure imgf000052_0001
146a- 149a, R = f 146b- 149b, R = ΓΛ 146c- 149c, R = -CH=CH, Scheme 19
Figure imgf000053_0001
Scheme 19a
Figure imgf000054_0001
Scheme 20
Figure imgf000055_0001
162b,R = -C2H5
160e, 161e,R = -CH2-CCl3
Figure imgf000055_0002
162d,R = -C(CH3)3
Figure imgf000055_0003
Scheme 21
Figure imgf000056_0001
167
Scheme 22
ffi
Figure imgf000057_0001
Figure imgf000057_0002
168 169 170
AA
Figure imgf000057_0003
Figure imgf000057_0004
Scheme 23
Figure imgf000058_0001
177 178 R
Figure imgf000058_0002
179
Figure imgf000058_0003
183 182
Scheme 24
Figure imgf000059_0001
3f, 184b, 185b, 186b, 187b, 188b, R= CH2CF3
3i, 184c, I85c, 186c, 187c, 188c, R = CH2CH3
Figure imgf000059_0002
Scheme 25
Figure imgf000060_0001
189a, 189b, 189c, 189d
AE-4, 1-2
74. 189a
184a. AE-3
■ 189b- -189c
189a,X = H,y = OCH3
189b,X = OCH2C6H5,Y = H
189c,X=OH,Y = H
AE-3
131 -189d
(Prepared by method AJ-1, AJ-2, or AJ-3)
Figure imgf000060_0002
Scheme 26
Figure imgf000061_0001
190a, 192a- 195a, R = H
190b, 192b- 195b, R=CH3 Scheme 27
Figure imgf000062_0001
Scheme 28
Figure imgf000063_0001
Scheme 29
Figure imgf000064_0001
209a, R = H
209b -211b, R = ^^-
Scheme 30
Figure imgf000065_0001
Scheme 31
Figure imgf000066_0001
Scheme 32
Figure imgf000067_0001
231a, 232a, 233a, 234a, 235a, R = H
231b,R=C02CH3
232b, 233b, 234b, R = C02H Scheme 33
Figure imgf000068_0001
Scheme 34
Figure imgf000069_0001
Figure imgf000069_0002
Figure imgf000069_0003
Figure imgf000069_0004
Scheme 35
Figure imgf000070_0001
Scheme 36
Figure imgf000071_0001
256
1-2, S
Figure imgf000071_0002
General Methods of Preparation
The following abbreviations have been used:
THF: Tetrahydrofuran; DMF: Dimethylformamide
DME: 1,2-Dimethoxyethane; DMAP: 4-(Dimethylamino)pyridine Boc anhydride: Di-tert-butyl dicarbonate; TIPS: Triisopropylsilyl MEM: Methoxyethoxyrnethyl; Bn: Phenylmethyl or Benzyl
The organic extracts were dried over sodium sulfate or magnesium sulfate.
The general methods for the preparation of the compounds of formula (I) are given below:
A-l: Conversion of acid to amide
To derivative (1 mmol), was added thionyl chloride (12.6 mmol) and a few drops of DMF. The reaction mixture was refluxed for 2 h and concentrated in vacuo to obtain an oily residue. The residue was dissolved in dichloromethane (3 mL); cooled with ice water and amine (5 mmol) was added. The reaction mixture was stirred at room temperature overnight, washed with IN HC1, saturated sodium hydrogen carbonate, water, brine, dried and concentrated in vacuo. The product obtained was purified by crystallization or flash column chromatography to furnish the desired amide.
A-2: Conversion of acid to amide
To a solution of acid derivative (1 mmol) in dichloromethane (10 mL) at 0 °C was added triethylamine (3 mmol) and ethyl chloroformate (3 mmol). The reaction mixture was stirred at the same temperature for 30 min and the corresponding amine (6 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched with IN HC1. The organic layer was separated, washed with water, brine, dried and concentrated in vacuo. The product obtained was purified by crystallization or flash column chromatography to furnish the desired amide.
A-3: Conversion of acid to amide
To a solution of acid (1 mmol) in dichloromethane (5 mL) was added 2M oxalyl chloride in dichloromethane (2.5 mmol), followed by a drop of DMF. The reaction mixture was stirred for 2h at room temperature and concentrated in vacuo. The residue was co-evaporated once with dichloromethane (5 mL) and then dried in vacuo. To the residue in dichloromethane (10 mL) were further added triethylamine (3 mmol) and the corresponding amine (1.2 mmol). The reaction mixture was stirred for 16 h and washed with water, brine, dried and concentrated in vacuo. The product obtained was purified by crystallization or flash column chromatography to furnish the desired amide.
A-4: Conversion of acid to amide
To a solution of acid (1 mmol) in dichloromethane or THF (10 mL) cooled with an ice bath was added triemylamine (1.2 mmol) and ethyl chloroformate or isobutyl chloroformate (1.2 mmol). The reaction mixture was stirred at 0°C for 30 min and the corresponding amine (2.5 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched with IN HC1. The organic layer was separated, washed with water, brine, dried and concentrated in vacuo. The product obtained was purified by crystallization or flash column chromatography to furnish the desired amide.
A-5: Conversion of acid to amide
A mixture of carboxylic acid (1 mmol), amine (1.1 mmol), 1- hydroxybenzotriazole (1 mmol) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (1.1 mmol) in pyridine (10 mL) was stirred overnight at room temperature and was concentrated in vacuo to dryness. The residue obtained was purified by column chromatography or used as such for the next step.
A-6: Reduction of acid to alcohol
To a solution of acid (1 mmol) in dichloromethane or THF (10 mL) at 0 °C was added triethylamine (1.2 mmol) and ethyl chloroformate or isobutyl chloroformate (1.2 mmol). The reaction mixture was stirred at 0 °C for 30 min and sodium borohydride (1.25 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched with IN HCl. The reaction mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried and concentrated in vacuo to furnish the desired alcohol. This can be purified further, if needed, by crystallization or column chromatography.
A-7: Conversion of acid to amide
A mixture of carboxylic acid (1 mmol), amine (1 mmol), and 4- dimethylaminopyridie (0.12 mmol) in xylene (10 mL) was stirred at 80 °C for 10 min. Phosphorus trichloride (1 mmol) was added and the reaction mixture was heated with stirring at 150 °C for 2 hr. After cooling, the product was extracted with EtOAc. The organic layers were combined, washed with water, brine, dried and concentrated in vacuo. The product obtained was purified by flash column chromatography to furnish the desired amide. B-l : Conversion of phenolic hydroxyl to triflate
To a phenol (1 mmol) in dichloromethane (2.5 mL) was added pyridine (5 mmol) under a nitrogen atmosphere and cooled to -10 C. To the cold reaction mixture was added dropwise triflic anhydride (2 mmol) in dichloromethane (2.5 mL) over a period of 10 mins and allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution and the organic layer was separated. The organic layer was washed with IN HCl, saturated sodium hydrogen carbonate, water, brine, dried and concentrated in vacuo. The product obtained was purified by crystallization or flash column chromatography to furnish the desired triflate.
B-2: Conversion of phenolic hydroxyl to triflate
To a solution of substituted phenol (1 mmol) in DMF (10 mL) was added N- phenylbis(trifluoromethanesulphonimide) (1.1 mmol), and triethylamine (2 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with ice water and extracted twice with ether. The organic layers were combined, washed with brine, dried and concentrated in vacuo to furnish the desired triflate.
C: Conversion of acid to MEM ester
To a solution of acid derivative (1 mmol) in DMF (10 mL) was added sodium bicarbonate (1.05 mmol), and MEM-C1 (1.05 mmol) and was stirred at room temperature for 24 h. The reaction mixture was quenched with ice water and extracted twice with ether. The organic layers were combined, washed with brine, dried and concentrated in vacuo to furnish crude product. Purification by flash column chromatography or crystallization gave the desired MEM ester. D-1: Coupling of boronic acid with triflate
A mixture of triflate (1 mmol), aryl boronic acid (1.5 mmol), potassium phosphate (3 mmol), potassium bromide (2.4 mmol) and tetra is(triphenylphosphine)ρalladium (0.05 mmol) in dioxane (10 mL) was heated at reflux overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water and was extracted with ethyl acetate. The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product.
D-2: Coupling of boronic acid with triflate
A mixture of triflate (1 mmol), aryl boronic acid (2 mmol), sodium hydrogen carbonate (3 mmol) and tetrakis(triphenylphosphine)palladium (0.05 mmol) or bis(triphenylphosphine)palladium(II)chloride (0.05 mmol) in DME/water (9:1, 10 mL) was heated at reflux overnight. The reaction mixture was cooled, quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product.
D-3: Coupling of tributyltin derivative with triflate
A mixture of triflate (1 mmol), tributyltin derivative (3 mmol), tetraethylammonium chloride (6 mmol), and bis(triphenylphosphine)palladium(II)- chloride (0.05 mmol) in DMF (10 mL) was heated at 70 °C overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water (20 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product. D-4: Coupling of trimethyltin derivative with triflate
A mixture of triflate (1 mmol), trimethyltin derivative (3 mmol), and bis(triphenylphosphine)palladium(π)chloride (0.05 mmol) in THF (10 mL) was heated at 70 °C overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water and extracted with ethyl acetate (2 X 10 L). The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product.
D-5: Coupling of alkyne with triflate
A mixture of triflate (1 mmol), triethylamine (4.5 mmol), substituted alkyne (3.5 mmol), and bis(triphenylphosphine)palladium(II)chloride (0.05 mmol) in DMF (10 mL) was heated at 70 °C overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water (20 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product.
D-6: Coupling of boronate ester with aryl bromides
A mixture of boronate ester (2 mmol),' aryl bromide (1 mmol), potassium phosphate (3 mmol) and bis(diphenylphosphinoferrocene)palladium(II)chloride (0.05 mmol) in DMF (10 mL) was heated at 100 °C for overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water (20 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the desired product. D-7: Coupling of boronate ester with aryl bromides
A mixture of boronate ester (2 mmol), aryl bromide (1 mmol), sodium hydrogen carbonate (3 mmol) and bis(diphenylphosphinoferrocene)palladium(II)chloride (0.05 mmol) in DME/water (9:1, 10 mL) was heated at 50-70 °C for overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water (20 mL) and was extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product.
D-8: Coupling of phenol with boronic acid
A mixture of phenol (1 mmol), aryl boronic acid (3 mmol), molecular sieves (4A°), pyridine (5 mmol), copper(II)acetate (1 mmol) and bis(triphenylphosphine)- palladium(II)chloride (0.05 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight under an argon atmosphere. The reaction mixture was cooled, filtered through a pad of Celite and concentrated in vacuo. Purification of the crude by flash column chromatography gave the coupled aryl ether.
D-9: Coupling of trimethyltin derivative with triflate
To a solution of triflate (1 mmol), LiCl (4 mmol), PPh3 (0.15 mmol), CuBr (0.2 mmol), andbis(triphenylphosphine)palladium(π)chloride (0.07 g) in DMF (10 mL) under an atmosphere of argon was added trimethylstannyl compound (0.8 mmol) and a crystal of 2,6-di-t-butyl-4-methylphenol. After the mixture was stirred at 90 °C for 3 h, a second portion of aryl-trimethylstannyl compound (0.5 mmol) was added. The reaction mixture was stirred at 90 °C overnight. Water was added and extracted with ethyl acetate. The organic layer was dried (MgSO ), concentrated and purified by flash column chromatography or crystallization to furnish the desired coupled product. D-10: Coupling of amine with triflate
A mixture of triflate (0J5 mmol), amine (0.9 mmol), potassium phosphate (1.1 mmol), 2-(di-t-butylphosphino)biphenyl (0.015 mmol) and tris(dibenzylideneacetone) dipalladium(O) (10 mg) in DME (10 L) was heated at reflux overnight under an argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography to furnish the desired coupled product.
D-11 : Conversion of triflate to cyano compound
To a solution of triflate (0.84 mmol), zinc cyanide (0.54 mmol), Palladium acetate (0.016 mmol), 2-(di-tert-butylphosphine)biphenyl ( 0.016 mmol) and N-methyl pyrrolidine (10 mL) was heated under argon at 160 °C for 48 h. The reaction mixture was cooled to room temperature and quenched with water (50 mL). The reaction mixture was extracted with ethyl acetate (2 X 25 mL). The organic layers were combined, dried, filtered and concentrated in vacuo. The residue obtained was purified by flash column chromatography to furnish the desired cyano compound.
D-12: Coupling of tetravinyltin with triflate or halide
To a solution of aryl triflate or bromide (1 mmol) in DMF (5 mL) were added LiCl (5 mmol), tetravinyltin (2 mol), and dichlorbis(triphenylphosphine)ρalladium (II) (0.01 mmol). The reaction mixture was stirred at 70 °C under nitrogen for 5 h and then diluted with ethyl acetate and filtered. The organic layer was washed with water and brine and dried (MgSO4). After evaporating the solvent in vacuo, the compound was purified by flash-column chromatography to give the desired product. E: Oxidation of aryl aldehyde to acid
A mixture of aldehyde (1 mmol), tert-butanol (5 mL), water (2 mL) and acetonitrile (1 mL, additional amount may be added until the reaction mixture was homogenous) was stirred at room temperature. The solution was cooled in ice-bath and 2-methyl-2-butene (1 mL), sodium chlorite (6 mmol) and sodium dihydrogenphosphate (1.6 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. If the solid separated out, the mixture was filtered to collect the solid, the desired product. If no solid separated out, then the reaction mixture was concentrated in vacuo to remove acetonitrile, diluted with water (10 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, washed with water, brine, dried and concentrated in vacuo to furnish crude acid. Purification was achieved, if needed, by crystallization or using flash column chromatography to obtain pure acid.
E-2: Oxidation of vinyl compound to acid
To a solution of vinyl compound (1 mmol) in acetone (5 mL) was added MnO4 (4 mmol). The reaction mixture was stirred for 3 h (the reaction is exothermic, and refluxed on its own during the addition of MnO4). The reaction mixture was diluted with methanol and water and filtered. The organic solvents were evaporated in vacuo and the aqueous layer was acidified to pH 1 and extracted several times with ethyl acetate/DME. The combined organic layers were dried (MgSO4) to furnish the desired acid.
F: Conversion of aromatic acid to MEM ester
To a solution of aromatic acid (1 mmol) in THF (10 mL) was added diisopropyle ylainine (2 mmol) and 2-methoxyethoxymethylchloride (1.1 mmol). The reaction mixture was stirred a room temperature for 3 h and diluted with ether (25 mL). The reaction mixture was washed with water (10 mL), brine (10 mL), dried and concentrated in vacuo to obtain product as colorless oil. The product was purified by flash column chromatography to furnish desired product.
G: Conversion of aromatic benzyl ether to aromatic phenol, benzyl ester to acid, benzyl carbamate to amine, alkene to alkane, azide to amine, nitro to amine, and oxime to amine
To a solution of appropriate substrate (1 mmol) in ethanol (10 mL) was added 10% palladium on carbon (10-wt%). The reaction mixture was hydrogenated at 50 psi for 2 to 24 h (until all starting material disappeared as confirmed by MS and TLC analysis). The catalyst was removed by filtration through a pad of Celite under nitrogen. The filtrate was concentrated in vacuo to furnish the product, which was purified by flash column chromatography or crystallization.
H: Conversion of aromatic acid to benzyl ester
To a solution of aromatic acid (1 mmol) in DMF (10 mL) was added sodium bicarbonate (1.05 mmol), and benzyl bromide (1.05 mmol) and stirred at room temperature for 24 h. The reaction mixture was quenched with ice water and extracted twice with ethyl acetate. The organic layers were combined, washed with water and brine, dried and concentrated in vacuo to furnish crude product. Purification by crystallization or flash column chromatography gave the desired ester.
1-1 : Hydrolysis of MEM ester to acid
To a solution of MEM ester (1 mmol) in DME (8 mL) was added 6 N HCl (2 mL) and stirred at room temperature overnight. The reaction mixture was neutralized with solid sodium hydrogen carbonate (18 mmol) and concentrated in vacuo. The reaction mixture was acidified with 0.5 N HCl (20 mL) and extracted with ethyl acetate (2 X 20 mL). The organic layers were combined, washed with brine (20 mL), dried and concentrated in vacuo to furnish crude product. Purification of the crude by flash column chromatography gave the product. Alternatively the crude reaction mixture was diluted with water (10 L) and concentrated in vacuo to remove DME. The solid obtained was collected by filtration and dried in vacuo to furnish pure acid.
1-2: Hydrolysis of ester to acid
To a solution of ester (1 mmol) in MeOH (10 mL) was added 1 N NaOH (10 mmol). The reaction mixture was stirred at room temperature for 2-3 h, filtered through a plug of cotton, and concentrated in vacuo to remove MeOH. The pH of the aqueous layer was adjusted to below 7. The solid that separated, was collected by filtration, washed with water and dried in vacuo to furnish the desired acid.
J: Coupling of acid with amino compounds
To a solution of acid (1 mmol) in DMF (5 mL) was added corresponding amine (1.1 mmol) and stirred at room temperature until homogenous. Pyridine (5 mL) was added to the reaction mixture followed by 1,3-dicyclohexylcarbodiimide (1.2 mmol) and stirred overnight at room temperature. The mixture was quenched with 6 N HCl (10 mL), diluted with ice cold water (10 mL) and extracted with chloroform (2 X 10 mL). The organic layers were combined washed with brine (10 L), dried and filtered. Purification of the crude by flash column chromatography gave the product as a solid. If the product was soluble in water, then the reaction mixture was concentrated in vacuo to remove pyridine and DMF and purified by flash column chromatography. K: Reduction of aldehyde to alcohol
To a solution of aldehyde (1 mmol) in THF (10 mL) was added sodium borohydride (0.4 mmol). The reaction mixture was stirred for 30 mins and quenched with glacial acetic acid (0.3 mL). The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 X 10 mL).. The organic layers were combined and washed with brine (10 mL), dried, filtered and concentrated in vacuo to obtain crude product which was purified by flash column chromatography.
L: Conversion of vinyl group to diol
To a solution of vinyl compound (1 mmol) in THF/tert-butanol (1:1, 10 mL) and water (2 mL) was added 4-methylmorpholine N-oxide (2.5 mmol) and osmium tetraoxide (1 mL, 2.5 wt% in tert-butanol, 0.1 mmol). The reaction mixture was stirred at room temperature for 2 h and quenched with saturated aqueous solution of sodium sulfite (5 mL). The reaction was stirred at room temperature for 30 mins and diluted with brine (10 mL) and ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (10 L). The organic layers were combined and washed with brine (10 mL), dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography to furnish the desired diol.
M: Conversion of diol to aldehyde
To a solution of diol (1 mmol) in DME/water (9:1, 10 L) was added sodium metaperiodate (3 mmol) and stirred at room temperature for 30 min. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined and washed with brine (10 mL), dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography to furnish the desired aldehyde. N: Conversion of alcohol to mesylate
To a solution of alcohol (1 mmol) in DME (10 mL) was added dimethylaminopyridme (0.1 mmol), methane sulfonyl chloride (3 mmol) and diisopropylethylamine or triethylamine (5 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 X 10 mL). The combined organic layers were washed with brine, dried, filtered and concentrated in vacuo. The residue obtained, was purified by column chromatography to furnish the desired mesylate.
O: Conversion of mesylate to azide
To a solution of mesylate (1 mmol) in DMSO (10 mL) was added sodium azide (25 mmol) and heated at 100 °C overnight. The reaction mixture was cooled and diluted with cold water (25 mL). The reaction mixture was extracted with ethyl acetate (2 X 15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried, filtered and concentrated in vacuo The residue obtained was purified by column chromatography to furnish the desired azido compound.
P: Protection of amine as benzyl carbamate
A mixture of amino compound (1 mmol), benzyl chloroformate (2 mmol) and triethylamine (10 mL) in pyridine (10 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to remove organic solvents and diluted with 0.1 N HCl (10 mL). The product was extracted with chloroform (2 X 10 mL), dried, filtered and concentrated in vacuo. The residue obtained was purified by column chromatography to furnish the desired carbamate. Q: Conversion of silyl protected amine to amine
A mixture of silyl protected amine (1 mmol), tetrabutylammonium fluoride (1.0 M in THF, 2 mmol) in THF (10 mL) was stirred at room temperature for 1.5 h. The reaction mixture was concentrated in vacuo and purified by column chromatography to obtain the desired product.
R: Protection of amine as tert-butyl carbamate
To a solution of amino compound (1 mmol) in acetonitrile (5 mL) was added triethylamine (2 mmol) and BOC anhydride (1.2 mmol). The reaction mixture was stirred for 2 h and concentrated in vacuo. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and the solvent was evaporated in vacuo to furnish tert-butyl carbamate. If needed, the product was purified by crystallization or column chromatography.
S: Conversion of tert-butyl carbamate to amine
To a solution of tert-butyl carbamate (1 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL). The solution was stirred at room temperature for 4 h and concentrated in vacuo. The residue was purified by column chromatography or crystallization to give the desired amine.
S-2: Conversion of tert-butyl carbamate to amine
To a solution of tert-butyl carbamate (1 mmol) in methanol (13 mL) was added 6 N HCl (8.75 mL, 52 mmol) and water (4.25 mL). The reaction mixture was stirred at room temperature for 2 days. The pH was adjusted to 7 using cone, ammonium hydroxide and the solid that separated out, was collected by filtration, washed with ether, dried in vacuo to furnish the desired product. If no solid separated out, the product was isolated by extraction with chloroform and evaporating the organic layer.
T: Protection of aldehyde as acetal
To a solution of aldehyde (1 mmol) in ethanol (5 mL) was added triethyl orthoformate (1.4 mmol), ammonium nitrate (0.2 mmol) and stirred at room temperature overnight (if reaction was not complete by TLC and NMR analysis of an aliquot, the reaction mixture was heated at 50 °C until complete). After completion of the reaction, the mixture was quenched with triethylamine (0.2 mmol) and concentrated in vacuo to remove ethanol. The residue was dissolved in ether, filtered to remove any insoluble inorganic impurities, and evaporated to dryness. The product obtained was used as such without further purification.
U-l: Conversion of bromide to boronic acid
To a mixture of bromo compound (1 mmol) in ether (10 mL), cooled to -78 °C, n- butyl lithium (1.2 mmol) was added dropwise and the reaction mixture was stirred for 30 mins after the addition was completed. Tributyl borate (1.3 mmol) in ether (10 mL) was added to the reaction and stirred at -78 °C for 2 h. The reaction mixture was allowed to warm to 0 °C and quenched with 2 M HCl (10 mL). The reaction mixture was stirred at room temperature for lh and cooled with ice. The aqueous layer was separated and the organic layer was extracted twice with IN NaOH (2 X 10 mL). The basic extracts were combined and washed with ether (10 mL). The basic layer was acidified to pH 4 using 6 N HCl and the solid that separated out was collected by filtration, washed with water and hexane and dried in vacuo to furnish boronic acid as a solid. If no solid product is obtained then the basic layer was extracted with ether (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo to furnish boronic acid. U-2: Synthesis of boronic acid by ortho lithiation of aryl aldehyde
To a solution of N,N,N'-trimethylethylenediamine (1 mmol) in THF/ether (10 mL, 1:1) cooled to -20 °C was added dropwise, over a period of 15 mins, n-butyl lithium (1 mmol) and stirred at -20 °C for 15 mins. Aldehyde (1 mmol) at -20 °C was added dropwise over a period of 10 mins to this mixture. The reaction mixture was further stirred for 15 mins at -20 °C followed by the addition of n-butyl lithium (2.8 mmol) dropwise over a period of 15 mins and stirred at 4 °C overnight. The reaction mixture was cooled to -40 °C and tributyl borate (5.6 mmol) in ether (20 mL) was added to the reaction and stirred at 4 °C for 12 h. The reaction mixture was allowed to warm to 0 °C and quenched with 2 M HCl (3 mmol) and heated at reflux for 2 h and added to ice water (25 mL). The aqueous layer was separated and the organic layer extracted twice with IN NaOH (2 X 10 mL). The basic extracts were combined and washed with ether (10 mL). The basic layer was acidified to pH 3 using 6 N HCl and the solid that separated out was collected by filtration, washed with water and hexane and dried in vacuo to furnish boronic acid as a solid. If no solid product was obtained, then the basic layer was extracted with ether (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo to furnish boronic acid.
U-3: Synthesis of boronic acid by ortho lithiation of aryl acetal
To a solution of aryl acetal compound (1 mmol) in ether (10 mL) at -78 °C, tert- butyl lithium (1.1 mmol) was added dropwise and the reaction mixture was stirred for 3 h at -20 °C after the addition was completed. Tributyl borate (1.2 mmol) in ether (10 mL) was added to the reaction and stirred at -20 °C for 1 h. The reaction mixture was allowed to warm to 0 °C and quenched with 2 M HCl (10 mL). The reaction mixture was stirred at room temperature for lh. The aqueous layer was separated and the organic layer was extracted twice with IN NaOH (2 X 10 mL). The basic extracts were combined and washed with ether (10 mL). The basic layer was acidified to pH 4 using 6 N HCl and the solid that separated out was collected by filtration, washed with water and hexane and dried in vacuo to furnish boronic acid as a solid. If no solid' product was obtained then the mixture was extracted with ether (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo to furnish boronic acid.
N-l: Demethylation of aryl methyl ether to phenol
In a round bottom flask (50 mL), pyridine hydrochloride (lOg) was heated in an oil bath at 180 °C. After the entire solid had melted, the corresponding aryl methyl ether (1 mmol) was added in small portions over a period of 20 min. The reaction mixture was heated at 180 °C for 4 h, cooled and quenched with water (100 mL). The reaction mixture was extracted with ethyl acetate (3 X lOmL). The combined organic layers were washed with brine, dried over MgSO , concentrated to give phenol. This can be further purified if needed by crystallization or column chromatography.
V-2: Demethylation of aryl methyl ether to phenol
To a solution of aryl ether (1 mmol) in dichloromethane (10 mL) cooled to -78 °C was added boron tribromide (3 mmol). The reaction mixture was allowed to warm to room temperature overnight and quenched with water (10 mL). The solid obtained was collected by filtration to give the desired product. More product was obtained after evaporation of the organic layer and washing the residue with water. Alternatively, if a homogenous biphasic mixture was obtained on addition of water, the organic layer was separated, washed with brine, dried over MgSO4, and concentrated to give the desired phenol. This can be further purified if needed by crystallization or column chromatography. V-3: Demethylation of aryl methyl ether to phenol
To a solution of aryl methyl ether (1 mmol) in dichloromethane (5 mL) was added A1C13 (8.5 mmol). The reaction mixture was heated to reflux for 12 h under nitrogen. To this mixture was added 12 mL of 1 N HCl slowly and the organic layer was separated. The aqueous layer was re-extracted several times with ethyl acetate/DME. The combined organic layers were washed with brine, dried (MgSO ), and evaporated in vacuo to furnish the desired phenol, which was purified by column chromatography.
V-4: Demethylation of aryl methyl ether to phenol
To a stirred slurry of NaH (2 mmol) in anhydrous toluene (5 mL) under nitrogen atmosphere was added para-thiocresol (2 mmol) dissolved in toluene (40 mL). The mixture was stirred at room temperature for 30 min and hexamethylphosphoric triamide (2 mmol) in toluene (5 mL) was added dropwise over a period of 30 min. A solution of aryl ether (1 mmol) in toluene (5 mL) was added in one portion. The reaction mixture was stirred at reflux for 9.5 h, cooled to room temperature and diluted with ethyl acetate (40 mL). The organic layer was extracted with 1 N aqueous NaOH solution (2 X 20 mL). The basic layer was acidified to pH 5 and extracted with ethyl acetate (2 X 20 mL). The organic layers were combined, washed with water, dried (MgSO ) and concentrated in vacuo. The residue obtained was purified by flash column chromatography to afford the desired phenol compound.
: Conversion of acid to methyl ester
A mixture of acid (1 mmol), cone. H2SO or cone HCl (0.5 mL) and methanol (10 mL) was heated at reflux for 16 h. The mixture was concentrated to half of its volume and the residue poured into a saturated sodium bicarbonate solution. The precipitate was collected by filtration, washed with water and dried to give the desired ester. If the ester did not come as solid, it was extracted with ethyl acetate. The organic layer was dried, filtered and concentrated to give the desired ester.
W-2: Conversion of acid to ester
A solution of methanolic HCl or ethanolic HCl was prepared by the addition of acetyl chloride (1 mL) to methanol/ethanol (9 mL) at 0 °C and stirred for 30 mins. To the solution of anhydrous methanolic HCl was added acid (1 mmol) and stirred at room temperature (or reflux if needed) overnight. The reaction mixture was concentrated to dryness in vacuo and the residue was purified by column chromatography or crystallization to furnish the desired ester.
X: Conversion of phenol to alkyl aryl ethers or alkylation of amines
To a solution phenol or amine (1 mmol) in DMF (10 mL) was added cesium carbonate (1.25 mmol) and corresponding bromide (1.1 mmol). The reaction mixture was stirred at room temperature overnight and quenched with water (25 mL). The product was extracted with ether (2 X 25 mL), the organic layers were combined and washed with water (25 mL), brine (25 mL), dried and concentrated in vacuo to furnish crude product. The crude was purified by crystallization or flash column chromatography.
Y: Conversion of nitrile to hydroxycarbamimidoyl
To a solution of nitrile compound (1 mmol) in ethyl alcohol (10 mL) was added hydroxylamine (50% aqueous solution, 5 mmol). The mixture was stirred at reflux for 2- 5 h. The reaction mixture was concentrated in vacuo to furnish the desired hydroxycarbamimidoyl compound. Z: Opening of aromatic methylene dioxy compound with alcohol
A solution of potassium tert-butoxide (2.25 mmol) in DMSO (1.25 mL) was heated at 50 °C for 30 min. Methanol (1.25 mL) was added to it and continued heating at 50 °C for 30 min. To the reaction mixture was added 1,2-methylenedioxy aromatic compound (1 mmol) and continued heating at 50 °C for 30 min. The reaction mixture was cooled to room temperature and quenched with water (10 mL) and 1 N sodium hydroxide (16 mL). The reaction m mixture was washed with ether (2 X 10 mL) and acidified to pH 4 using cone HCl. The solid obtained was collected by filtration to furnish the desired product.
Z-l: Opening of aromatic methylene dioxy compound with alcohol
To a mixture of methylene dioxy compound (1 mmol) in HMPA (2.5 mL) were added sodium methoxide (2.5 mmol) and heated with stirring at 150 °C for 12 min. The mixture was cooled and poured into ice water (20 mL), NaOH (30 mg) and stirred for 10 min. It was then extracted with ether and the aqueous layer was acidified to pH 4 with HCl and extracted with ether. The later ethereal extracts were combined, dried and concentrated. The residue was purified by crystallization or column chromatography.
AA: Conversion of amine to amide in the presence of a phenol
To a solution of amino compound (1 mmol) in pyridine (5 mL) was added, dropwise, acid chloride (2 mmol) at 0 °C under N . The mixture was stirred for 45 min and was then poured into ice water and acidified with 1 N HCl. The precipitated solid was collected by filtration, washed with IN HCl, hexane, and then dried in vacuo to give crude product. The crude product was added to freshly prepared sodium methoxide solution (0.1 M, 10 mL) and stirred for 30 min at room temperature. The reaction mixture was quenched with acetic acid (1 mmol) and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The water layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO ) and evaporated to yield a solid. The solid was washed with hexane and dried in vacuo to furnish the desired amide.
AB-1: Conversion of amino of amidine to amino carbamate
To amidine compound (1 mmol) was added 0.1N NaOH (10 mL) and stirred at room temperature for 5 min. The reaction mixture was concentrated in vacuo and to the residue was added alkyl or aryl 4-nitrophenyl carbonate (2 mmol) in 20 mL of hexamethylphosphoramide and stirred at 45 C for 24 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (2 X 100 mL). The combined extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue obtained was purified by flash column chromatography to furnish the desired product.
AB-2: Conversion of amino of amidine to amino carbamate
To a solution of amidine compound (1 mmol) in acetonitrile (25 mL) was added triethylamine (5 mL) and aryl/alkyl chloroformate (2 mmol) or dialkyl/aryl carbonate. The reaction mixture was stirred at room temperature for 16 h and quenched with water (100 mL). The reaction mixture was extracted with ethyl acetate (2 X 100 mL). The combined extracts were washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue obtained was purified by flash column chromatography to furnish the desired product. AC: Conversion of aldehyde to oxime
To a stirred solution of aldehyde (1 mmol) in ethanol (10 mL) was added pyridine (10 mL) and hydroxylamine hydrochloride (1.25 mmol). The reaction mixture was stirred overnight at room temperature under nitrogen and then concentrated in vacuo to one third of its original volume. Water (10 mL) was added and the precipitated solid was collected by filtration and dried in vacuo. The product was used as such for next step without further purification.
AD: Debenzylation in the presence of aldehyde
To a solution of phenyl methoxyaryl aldehyde (1 mmol) in dichloromethane (10 L) cooled to -78 °C was added dropwise under a nitrogen atmosphere boron tribromide (IM solution in dichloromethane, 1.2 mmol). The reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was quenched with water (10 mL) and the layers were separated. The aqueous layer was extracted with chloroform (10 mL). The organic layers were combined, washed with brine (10 mL), dried, filtered and concentrated in vacuo to furnish crude product. Purification of the crude by flash column chromatography furnished the desired phenolic aldehyde
AE-1: Reductive amination of aldehyde
To a stirred solution of aldehyde (1 mmol) in methanol (40 mL) was added amine (3.3 mmol) followed by the addition of glacial acetic acid (0.3 mL). The reaction mixture was stirred for 30 min under nitrogen at room temperature, and then sodium cyanoborohydride (1.5 mmol) was added. After stirring for 20 min, the solvent was evaporated in vacuo, and the residue was taken in ethyl acetate. The organic layer was washed with water, and the insoluble material was removed from the organic layer by filtration. The pH of the aqueous phase was adjusted to 7 with IN NaOH and was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). The solvent was evaporated in vacuo to furnish crude product. The crude product was purified by crystallization or flash column chromatography.
AE-2: Reductive amination of aldehyde
To a mixture of aminoarylamidine (1.2 mmol), 4A° molecular sieves, and sodium hydroxide (1 N solution in anhydrous methanol, 1.2 mL, 1.2 mmol) in methanol (10 mL) was added a solution of aldehyde (1 mmol) in THF (10 mL). The reaction mixture was heated for 15 mins at reflux temperature and was cooled to room temperature. Acetic acid (1 %) and sodium cyanoborohydride (1 M solution in THF, 5 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was quenched with 1 N NaOH (30 mmol) and stirred for additional 2 h and concentrated in vacuo to remove methanol. The mixture was diluted with water (15 mL) and washed with ether (2 x 10 mL). The aqueous layer was acidified to pH 2 using 6 N HCl and the solid that separated out was collected by filtration, washed with ether, dried in vacuo to furnish product, which was purified by flash column chromatography, if needed.
AE-3: Reductive amination of aldehyde
A mixture of aminoarylamidine (2 mmol), 4A° molecular sieves, pyridine (6 mL) in methanol (9 mL) was heated at 50 °C for one hour. A solution of aldehyde (1 mmol) in methanol (7.5 mL) containing acetic acid (1 %) was added and continued heating for 4 h to 12 h. The reaction mixture was cooled and sodium cyanoborohydride (1 M solution in THF, 5 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was quenched with 5 N NaOH (30 mmol) and stirred for additional 2 h. The reaction mixture was filtered through Celite (to remove molecular sieves) and concentrated to remove methanol. The mixture was diluted with water (15 L) and washed with ether (2 X 10 mL). The aqueous layer was filtered and solid obtained was kept aside (mainly product). The aqueous layer was acidified to pH 2 using 6 N HCl and the solid that separated out was collected by filtration. The combined solid materials were purified, if needed, by flash column chromatography.
AE-4: Reductive amination of aldehyde
To a mixture of aldehyde (1 mmol) and aminoarylamidine (1.1 mmol) in MeOH at room temperature was added triethyl amine (2.75 mmol), sodium cyanoborohydride (0.83 mmol) and zinc chloride (0.9 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to remove methanol. The reaction mixture was quenched with 1 N NaOH (10 mL), diluted with water (10 mL), and extracted with EtOAc (5 X 20 mL). The combined organic extracts were washed with brine (15 mL), dried (MgSO4), filtered through Celite and concentrated to give the product. Purification of the crude by flash column chromatography gave the desired product.
AE-5: Reductive amination of aldehyde
To a solution of a ine (1.2 mmol) in MeOH (10 L) was added aldehyde (1 mmol) in THF (10 mL) containing acetic acid (0.1 mL) drop-wise. The mixture was stirred at 50 °C for 4-12 h and then cooled to room temperature. Sodium cyanoborohydride (1.5 mmol) was added to the reaction mixture and stirred at room temperature overnight. Water was added and pH of the solution was adjusted to 7. The solution was extracted with ethyl acetate. The organic layer was dried (MgSO4) and evaporated in vacuo. The residue was purifeid by flash column chromatography to furnish the desired amine. AF-1: Synthesis of amidine from nitrile
Acetyl chloride (5 mL) was added to methanol (5 mL) at 0 °C drop-wise and stirred at room temperature for 15 mins. To this solution of methanolic HCl was added nitrile compound (1 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and dried. The residue obtained of the resulting methyl imidate was dissolved in methanol (10 mL). Dry ammonia gas was bubbled into the reaction mixture at reflux temperature for 5 h. The reaction mixture was concentrated to furnish the required amidine.
AG: Addition of Grignard reagent to aryl aldehyde
To a solution of aryl aldehyde (1 mmol) in THF (15 mL) cooled to -78 °C was added drop wise under a nitrogen atmosphere, vinyl magnesium bromide (1 M solution in THF, 5 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 48 h. The reaction was quenched carefully with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, washed with brine (10 mL), dried and concentrated in vacuo. The residue obtained was purified by flash column chromatography to obtain the desired addition product.
AG-1: Synthesis of tributylvinyltin compounds from vinyl bromide containing hydroxyl
To a solution of vinyl bromide with hydroxyl (1 mmol) in dichloromethane (20 mL) was added tert-butyldimethylsilyl chloride (1.5 mmol) and DMAP (1.5 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with water (20 mL) and the aqueous layer separated. The organic layer was washed with 0.1 N aqueous HCl (10 mL), brine (20 mL), dried and concentrated in vacuo to furnish corresponding tert-butyldimethylsilyloxy compound as an oil which was used as such for the next step.
To a solution of the above oily residue (1 mmol) in diethyl ether (20 mL) cooled to -78 °C was added dropwise tert-butyllithium (1 J M in pentane, 2 mmol) over a period of 15 mins. The reaction mixture was stirred at -78 °C for 3 h and quenched at -78 °C with 2 N aqueous sulfuric acid (2 mL) and water (18 L). The reaction mixture was neutralized using 2 N NaOH and the organic layer was separated. The organic layer was washed with water (20 mL), brine (20 mL), dried and concentrated in vacuo. Purification of the crude residue obtained by flash column chromatography furnished the desired tributyltin compound.
AG-2: Synthesis of tributylmethyltin compounds from arylmethyl bromides or allyl bromides
To lithium clippings (10 mmol) in THF (10 mL) cooled to -40 °C was added dropwise tributyltin chloride (0.27 mL, 1 mmol) in THF (5 mL) over a period of 15 min. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was filtered through glass wool to remove insoluble impurities and cooled to -40 °C. A freshly prepared solution of arylmethyl bromide or allyl bromide (1 mmol) was added dropwise over a period of 10 mins and stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ether (2 X 10 mL). The organic layers were combined, washed with brine (1 mL), dried, filtered and concentrated in vacuo to furnish desired tributyltinalkyl and was used as such without further purification. AG-3: 4-Bromo-5-formyl-benzo[l,3]dioxole-2-carboxylic acid methyl ester
To a mixture of 2-bromo-3,4-dihydroxy-benzaldehyde (2.17 g, 10.0 mmol) and K2CO3 (5.56 g, 40.2 mmol) in «-propanol (25 mL) was added dibromoacetic acid (2.18, 10.0 mmol) and the mixture was heated at reflux temperature for 24 h. After cooling to room temperature, another portion of dibromoacetic acid (1.75 g, 8.0 mmol) was added. The mixture was stirred at reflux for 46 h. w-Propanol was evaporated and water (30 mL) was added. The resulting aqueous solution was acidified to pH 2 by adding 1 N HCl and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were dried (MgSO ) and evaporated in vacuo to afford crude 4-bromo-5-formyl-benzo[l,3]dioxole- 2-carboxylic acid (1.34 g) as a brownish solid. This crude product was dissolved in anhydrous methanol (50 mL) and cone. H2SO (5 mL) was added drop by drop. The resulting mixture was refluxed overnight and cooled to room temperature. Water (50 mL) was added and the resulting aqueous solution was extracted with ethyl acetate (100 mL X 3). The combined organic layers were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (ethyl acetate:hexane = 5:95) to furnish 4-bromo-5-formyl-benzo[l,3]dioxole-2-carboxylic acid methyl ester as a white solid.
AH: Synthesis of tert-butyl ester of phenol
To a solution of phenol (1 mmol) in pyridine (10 mL) was added 2,2-dimethyl- propionyl chloride (1.2 mmol) dropwise. The mixture was stirred at room temperature for overnight and diluted with water (100 mL). The reaction mixture was extracted with ethyl acetate (3 X 50 mL). The organic layers were combined and washed with aqueous 0.5 N HCl (100 mL), water, brine, dried (MgSO ) and concentrated in vacuo. The cmde residue was purified by flash column chromatography to furnish the desired ester. Al: Preparation of 2-bromo-5-hydroxy benzaldehyde
To a solution 3-hydroxybenzaldehyde (Aldrich, 101.39 g, 805 mmol) in chloroform (1000 mL), was added bromine (45 mL, 845 mmol) in chloroform (200 mL) drop wise over a period of 2 h at room temperature. The reaction mixture was stirred at room temperature overnight and filtered to collect crude 2-bromo-5 -hydroxy benzaldehyde (32 g) as a dark brown solid. The filtrate was concentrated to 200 mL, filtered through a pad of Celite and silica gel (40 g) and washed with ether (1000 mL). The filtrate was concentrated in vacuo to give a second crop of the cmde desired aldehyde (60 g) as a dark brown solid. The above solids were combined and dissolved in glacial acetic acid (360 mL) by heating. Water (840 mL) was added and the solution was filtered hot. The solution was allowed to attain room temperature and kept in a refrigerator overnight. The crystals obtained were collected by filtration and washed with water, dried overnight in vacuo to furnish (60 g, 37%) of the desired product as a purplish brown crystalline solid, mp: 135 °C.
AJ-1: Amidine from nitrile
A mixture of nitrile (1 mmol) and hydroxylamine (aqueous 50%, 1.8 mL) in EtOH (15 mL) was refluxed for 3 h and concentrated in vacuo. To the residue obtained was added EtOH (20 mL), acetic acid (2 mL) and a small amount of Raney nickel. The reaction mixture was hydrogenated (50 psi) for 14-24 h, filtered and concentrated in vacuo. The residue obtained, was purified by flash column chromatography to obtain the corresponding amidine.
AJ-2: Amidine from nitrile
A mixture of nitrile (1 mmol) and saturated methanolic HCl solution (freshly prepared by bubbling HCl gas or prepared in-situ by premixing methanol and acetyl chloride at ice cold temperature) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to furnish methyl imidate. To the residue of methyl imidate was added MeOH (40 mL) and ammonia gas was bubbled at reflux temperature for 16 h or till the reaction was complete. The reaction mixture was concentrated in vacuo and dried to furnish the desired amidine. Alternatively, the methyl imidate was dissolved in methanol and ammonium acetate (10 mmol) was added. The reaction mixture was concentrated in vacuo and purified by flash column chromatography to obtain the corresponding amidine.
AJ-3: Amidine from nitrile
To a solution of nitrile (1 mmol) dissolved in methanol (5 mL) was added N- acetyl cystein (0.1 or 1 mmol) and ammonium acetate (5 mmol) and heated at reflux till the reaction was complete. The reaction mixture was concentrated in vacuo and purified by flash column chromatography to obtain the corresponding amidine,
AK: Conversion of aryl triflates or halides to boronate ester
To dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium (II) dichloro- methane adduct (0.75 mmol) under argon in dioxane (100 mL) was added aryl triflate (25 mmol), pinacolborane (31.5 mmol) arid triethylamine (75 mmol). The reaction mixture was heated under argon at 100 °C for 3h or until complete as evidenced from TLC analysis. The reaction mixture was concentrated in vacuo. The residue obtained was purified by flash column chromatography to furnish the desired boronate ester. Alternatively, the following method can be used.
To dichloro[l, -bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.03 mmol), l, -bis(diphenylphosphino)ferrocene (0.03 mmol) under argon in dioxane (100 mL) was added aryl triflate (1 mmol), bis(pinacolata)diboron (1.1 mmol) and potassium acetate (3 mmol). The reaction mixture was heated under argon at 100 °C for 3h or until complete as evidenced from TLC analysis. The reaction mixture was concentrated in vacuo. The residue obtained was purified by flash column chromatography to furnish the desired boronate ester.
The examples of the compounds prepared are given in the following tables. The tables describe the compounds, their method of preparation, the starting material, and the analytical data. In some cases, where analytical data have not been given, those compounds were characterized at the later step in the synthesis.
Figure imgf000102_0002
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000104_0002
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000106_0002
Figure imgf000107_0001
Figure imgf000107_0002
Figure imgf000108_0001
o
~4
Figure imgf000108_0002
©
90
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000110_0002
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000112_0002
Figure imgf000113_0001
Figure imgf000113_0002
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
©
Figure imgf000121_0002
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Ul
Figure imgf000126_0002
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Ul
©
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000133_0002
Figure imgf000134_0001
Figure imgf000134_0002
Figure imgf000134_0003
Figure imgf000135_0001
Ul Ul
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000137_0002
Figure imgf000138_0002
Figure imgf000138_0001
Ul
90
Figure imgf000139_0001
Ul
KO
Figure imgf000140_0001
4-
©
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000145_0002
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Ul
©
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000152_0002
Figure imgf000153_0001
Figure imgf000153_0002
Figure imgf000154_0001
n i
Figure imgf000155_0001
Figure imgf000155_0003
Figure imgf000155_0002
Figure imgf000156_0001
Ul Ul
Figure imgf000156_0002
en
Figure imgf000157_0001
Figure imgf000158_0002
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000159_0002
en κo
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000161_0002
Figure imgf000162_0001
Figure imgf000163_0001
oκ
Figure imgf000163_0002
Ul
Figure imgf000164_0001
Figure imgf000165_0001
oκ en
Figure imgf000166_0001
Figure imgf000167_0001
Cpd. Starting Method
-R -R' Analytical Data
No. From Used
62m -CH, CH, 61 A-4 MS (ES4): 597.3
62n -CH3 61 A-4 MS (ES4): 639.4
Figure imgf000168_0001
62o -CH3 61 A-4 MS (ES+): 695.4 (M+Na)+
62p -CH3 XF, 61 A-4 MS (ES"): 665.4
~4
62q -CH3 61 A-4 MS (ES4): 653.4
62r -CH3 61 A-4 MS (ES4): 567.3
62s -CH3 61 A-4 MS (ES+): 667.5
Figure imgf000168_0002
62t -CH3 OH 61 A-4 MS (ES+): 641.3
62u -CH3 Η 61 A-4 MS (ES+): 655.3
oκ
90
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000171_0002
Figure imgf000172_0001
-4
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000176_0002
Figure imgf000177_0001
Figure imgf000177_0002
Figure imgf000178_0001
-4 -4
Figure imgf000178_0002
Figure imgf000179_0001
-4
90
Figure imgf000180_0001
Figure imgf000180_0002
Cpd. Starting Method
-R -R' Analytical Data
No. From Used F,
68g -CH3 67 A-4 MS (ES4): 625.2
68h -CH3 67 A-4 MS (ES4): 619.2
Figure imgf000181_0001
68i -CH3 67 A-4 MS (ES4): 615.3
68j -CH3 67 A-4 MS (ES4): 597.3
90 © 68k -CH3 CH, 67 A-4 MS (ES4): 557.3
681 -CH3 XH, 67 A-4 MS (ES4): 571.4
68m -CH3 67 A-4 MS (ES+): 639.4
Figure imgf000181_0002
.CH,
68n -CH3 67 A-4 Characterized in the next step
68o -CH3 XH, 67 A-4 MS (ES4): 613.5
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000183_0002
90 Ul
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000186_0002
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000188_0002
Figure imgf000189_0001
Figure imgf000189_0002
Figure imgf000190_0001
©
Figure imgf000191_0002
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000195_0002
en
Figure imgf000196_0001
Figure imgf000197_0001
KO -4
Figure imgf000198_0001
90
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000201_0003
15
Figure imgf000201_0002
Figure imgf000202_0001
©
Figure imgf000202_0002
Figure imgf000203_0001
©
Figure imgf000204_0001
15
©
Ul
Figure imgf000204_0002
Figure imgf000205_0001
Figure imgf000205_0002
© en
Figure imgf000206_0001
©
Figure imgf000207_0002
Figure imgf000207_0001
©
-4
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000209_0002
©
Figure imgf000210_0001
—
©
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0002
Ul
Figure imgf000214_0001
Figure imgf000215_0002
Figure imgf000215_0001
I) en
Figure imgf000216_0001
Figure imgf000217_0001
-4
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000221_0002
Figure imgf000222_0001
Figure imgf000223_0001
Ul
Figure imgf000224_0001
Figure imgf000225_0002
Figure imgf000225_0001
en
Figure imgf000226_0001
O
Figure imgf000227_0001
-4
Figure imgf000228_0001
90
Figure imgf000229_0002
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Ul
©
Figure imgf000231_0002
Figure imgf000232_0001
Figure imgf000232_0002
Figure imgf000233_0001
Figure imgf000233_0002
Ul Ul
Figure imgf000234_0001
Figure imgf000235_0001
Ul en
Figure imgf000236_0001
Ul
Figure imgf000237_0001
Ul -4
Figure imgf000238_0001
Ul
90
Figure imgf000239_0001
Ul
KO
Figure imgf000240_0001
4-
©
Figure imgf000241_0001
Figure imgf000242_0001
-
Figure imgf000243_0001
- i
Figure imgf000244_0001
Figure imgf000245_0001
4- en
Figure imgf000246_0001
Figure imgf000247_0001
-
Figure imgf000248_0001
Figure imgf000248_0002
Figure imgf000248_0003
Figure imgf000249_0001
Figure imgf000249_0002
Figure imgf000250_0001
- O
en
©
Figure imgf000251_0001
Figure imgf000251_0002
en
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000253_0002
en ui
Figure imgf000255_0001
Figure imgf000255_0002
en en
Figure imgf000256_0002
Figure imgf000256_0001
en
Figure imgf000257_0001
Figure imgf000257_0002
10
en
-4
Figure imgf000258_0001
Figure imgf000258_0002
Figure imgf000259_0001
Figure imgf000260_0002
Figure imgf000260_0001
Figure imgf000261_0001
©
Figure imgf000262_0001
Figure imgf000262_0002
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000264_0002
Figure imgf000265_0001
Figure imgf000265_0002
Figure imgf000266_0002
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000268_0002
-4
Figure imgf000269_0001
Figure imgf000269_0002
Figure imgf000270_0001
-4
©
Figure imgf000271_0001
Figure imgf000271_0002
Figure imgf000272_0001
Figure imgf000272_0002
-4
The following non-limiting examples are presented to further illustrate the present invention.
2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4- [(isobutylamino)carbonyl]-4'-thien-2-yl-l,l'-biphenyl-2-carboxylic acid
2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4- [(isobutylamino)carbonyl]-4'-thien-3-yl-l,r-biphenyl-2-carboxylic acid
2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4- [(isobutylamino)carbonylj- 1 , 1 ':4', 1 "-terphenyl-2-carboxylic acid
2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4'-(3-furyl)-4- [(isobutylamino)carbonyl] -1,1 '-biphenyl-2-carboxylic acid
2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4- [(isobutylamino)carbonyl]-4'-pyridin-4-yl- 1 , 1 '-biphenyl-2 -carboxylic acid
2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4- [(isobutylamino)carbonyl]-4'-(lH-pyrrol-2-yl)-l,r-biphenyl-2-carboxylic acid
2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4'-[2-(hydroxymethyl)thien- 3-yl]-4-[(isobutylamino)carbonyl]- 1 , 1 '-biphenyl-2-carboxylic acid
2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4'-[3-(hydroxymethyl)thien- 2-yl]-4-[(isobutylamino)carbonyl]- 1 , 1 '-biphenyl-2-carboxylic acid
2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4- [(isobutylamino)carbonyl] -4'- vinyl- l,l'-biphenyl-2 -carboxylic acid 4'-AUyl-2'-[( {4-[amino(imino)methyl]phenyl} amino)carbonyl]-4- [(isobutylamino)carbonyl]- 1 , 1 '-biphenyl-2-carboxylate
2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4- [(isobutylamino)carbonyl]-4'-(l,3-thiazol-2-yl)-l,r-biphenyl-2-carboxylic acid
2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4'-[3-(hydroxymethyl)-2- furyl] -4- [(isobutylamino)carbonyl] -1,1 '-biphenyl-2-carboxylic acid
2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4- [(isobutyIamino)carbonyl]-4'-prop- 1 -ynyl- 1 , 1 '-biphenyl-2-carboxylic acid
2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4'-(3-hydroxy-3-methylbut- 1 -ynyl)-4-[(isobutylamino)carbonyl]- 1 , 1 '-biphenyl-2-carboxylic acid
2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(3- methylbutanoyl)amino] -4'-vinyl- 1 , 1 '-biphenyl-2-carboxylic acid
2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4'-(4-hydroxybut- 1 -ynyl)-4- [(isobutylamino)carbonyl]-l,r-biphenyl-2-carboxylic acid
2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4- [(isobutylamino)carbonyl]-4'-[(lE)-3-methylbuta-l,3-dienyl]-l,r-biphenyl-2- carboxylic acid
2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4'-(3-hydroxyprop-l-ynyl)- 4-[(isobutylamino)carbonyl] -1,1 '-biphenyl-2-carboxylic acid 2,~[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4'-(2-furyl)-4- [(propylamino)carbonyl]- 1 , 1 '-biphenyl-2-carboxylic acid
2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(sec- butylamino)carbonyl]-4'-(2-furyl)- 1 , 1 '-biphenyl-2-carboxylic acid
2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4'-(2-furyl)-4-{[(2,2,2- trifluoroethyl)amino]carbonyl}-l, -biphenyl-2-carboxylic acid
2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4'-(2-furyl)-4- {[(4- hydroxybutyl)amino]carbonyl} -1,1 '-biphenyl-2-carboxylic acid
2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4-[(ethylamino)carbonyl]-4'- (2-furyl)- 1 , 1 '-biρhenyl-2-carboxylic acid
2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4- [(isobutylamino)carbonyl]-5'-methoxy-4'-vinyl-l,r-biphenyl-2-carboxylic acid
2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4- [(isobutylamino)carbonyl]-4'-(thien-2-ylmethyl)- 1 , 1 '-biphenyl-2-carboxylic acid
2-{3-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]pyridin-4-yl}-5- [(isobutylamino)carbonyl]benzoic acid
2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4- [(cyclopentylamino)carbonyl]-4'-vinyl-l,r-biphenyl-2-carboxylic cid 2"-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-5'-ethoxy-4- [(isobutylamino)carbonyl]-4'- vinyl- 1 , 1 -biphenyl-2-carboxylic acid
Methyl 2'-[({4-[({[(acetyloxy)methoxy]carbonyl}amino)(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'- vinyl- 1 , 1 '-biphenyl-2-carboxylate
Methyl 2'-[({4-[{[(benzyloxy)carbonyl]amino}(imino)methyl]phenyl}amino) carbonyl]-4-[(isobutylamino)carbonyl]-4'- vinyl- 1 , 1 '-biphenyl-2-carboxylate
N'-{4-[Amino(imino)methyl]phenyl}-N8-isobutyl-6-oxo-6H-benzo[c]chromene- 1,8-dicarboxamide
2'-[({4-[Amino(imino)methyl]phenyl}amino)methyl]-4-[(isobutylamino)carbonyl]- 4'-vinyl- 1 , 1 '-biphenyl-2-carboxylic acid
2'-( { [4-(4, 5-Dihydro- 1 H-imidazol-2-yl)phenyl] amino } carbonyl)-4- [(isobutylamino)carbonyl]-l,l'-biphenyl-2 -carboxylic acid
2'-[( {4-[Atnino(imino)methyl]phenyl} amino)carbonyl]-4- [(isobutylamino)carbonyl]-5'-thien-2-yl-l,r-biphenyl-2-carboxylic acid
2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-5'-(2-amino-2-oxoethoxy)-4- [(isobutylamino)carbonyl]- 1 , 1 '-biphenyl-2-carboxylic acid
2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4'-ethoxy-4- [(isobutylamino)carbonyl] -1,1 '-biphenyl-2-carboxylic acid 2- {5-[( {4-[Amino(imino)methyl]phenyl}ammo)carbonyl]- 1 ,3-benzodioxol-4-yl} -5- [(isobutylamino)carbonyl]benzoic acid
2'-[l-({4-[Amino(imino)methyl]phenyl}amino)ethyl]-4-[(isobutylamino)carbonyl]- l,l'-biphenyl-2-carboxylic acid
3-[2-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4-(benzyloxy)phenyl]-6- [(isobutylamino)carbonyl]pyridine-2-carboxylic acid
3-[2-(4-Carbamimidoyl-ρhenylcarbamoyl)-4-vinyl-phenyl]-6-isobutylcarbamoyl- pyridine-2-carboxylic acid
2'-[(5-Carbarnimidoyl-pyridin-2-ylamino)-methyl]-4-isobutylcarbamoyl-4'-vinyl- biphenyl-2 -carboxylic acid
2'-{[4-(N-Hydroxycarbamimidoyl)-phenylamino]-methyl}-4-isobutylcarbamoyl-4'- vinyl-biphenyl-2-carboxylic acid
2'-{[4-(N-Hydroxycarbamimidoyl)-phenylamino]-methyl}-4-isobutylcarbamoyl-4'- vinyl-biphenyl-2-carboxylic acid methyl ester
3- {2-[(4-Carbamimidoyl-phenylamino)-methyl]-4-vinyl-phenyl} -6- isobutylcarbamoyl-pyridine-2-carboxylic acid Biological Assay Methods
In Vitro Assay for Inhibition of TF/FVIIa
To assess the inhibition of the test compounds against the target enzyme, TF/FNIIa, an amidolytic assay based upon the absorbance of p-Νitroanalide (pΝA) at OD405 was utilized. The IC50 of the test compounds was determined by using KC4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Nmax values.
TF/FNIIa assay reactions were performed in a 200 μL mixture containing 4 nM FNIIa, 10 nM lipidated tissue factor, in an assay buffer containing 100 mM Tris, pH 7.2, 150 mM ΝaCl, 5 mM calcium chloride, 0.1 % bovine serum albumin (BSA), and 10% dimethyl sulfoxide (DMSO). TF and FVIIa were allowed to equilibrate at room temperature for 15 minutes. Test compounds dissolved in DMSO were incubated at varied concentrations with TF/FNIIa for 10 minutes, followed by addition of 500 DM substrate Spectrozyme-FNIIa. Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD4o5 mn for 10 minutes at 21 second intervals with a Powerwave x (Bio-Tek Instruments) microplate reader.
In Vitro Assay for Human Thrombin
This colorimetric assay was used to assess the ability of the test compounds to inhibit the human thrombin enzyme. IC50 of the test compounds was determined by using KC4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Nmax values.
Thrombin assay reactions were performed in a 200 μL mixture containing human thrombin at (1 U/mL) in an assay buffer containing 100 mM HEPES, 10 mM calcium chloride, and 10 % DMSO, pH 7.5. Test compounds dissolved in DMSO were added to thrombin enzyme reactions at varied concentrations, followed by the addition of substrate Nα-Benzoyl-Phe-Nal-Arg p-Νitroanilide at a final concentration of 1 mM. Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD 05 nm for 10 minutes at 21 second intervals with a Powerwave (Bio-Tek Instruments) microplate reader.
In Vitro Assay for Human Trypsin
This enzymatic assay was employed to evaluate the ability of the test compounds to inhibit human pancreatic trypsin. IC5o of the test compounds was determined by using KC4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Nmax values.
Trypsin assay reactions were performed in a 200 μL mixture containing human pancreatic trypsin at 1 μg/mL in an assay buffer containing 200 mM triethanolamine (TEA), 10 mM calcium chloride, 10 % DMSO, pH 7.8. Test compounds dissolved in DMSO were added to trypsin enzyme reactions at varied concentrations, followed by the addition of substrate Να-Benzoyl-L-Arginine p-Νitroanilide (L-BAPΝA) at a final concentration of (0.25 mg/mL). Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD4os nm for 10 minutes at 21 second intervals with a Powerwave x (Bio-Tek Instruments) microplate reader.
Biological Data
IC50 Values of Some Selected Compounds on Different Serine Protease Enzymes
Figure imgf000280_0001
Figure imgf000280_0002
Figure imgf000281_0001
IC50 values: + means >1 μM; ++ means >100 nM; +++ means <100 nM
A comparison of Examples with R group and without R group illustrates the greatly-enhanced activity achieved pursuant to the present invention.
Compounds of the present invention are useful as inhibitors of trypsin-like serine protease enzymes such as thrombin, factor Vila, TF/FNIIa, and trypsin.
These compounds may be employed to inhibit the coagulation cascade and prevent or limit coagulation.
These compounds may be used to inhibit the formation of emboli or thromboli in blood vessels.
These compounds may be used to treat thrombolymphangitis, thrombosinusitis, thromboendocarditis, thromboangitis, and thrornboarteritis.
These compounds may be used to inhibit thrombus formation following angioplasty. These may be used in combination with other antithrombolytic agents such as tissue plasminogen activators and their derivatives, streptokinase and its derivatives, or urokinase and its derivatives to prevent arterial occlusion following thrombolytic therapy.
These compounds may also be used in matastatic diseases, or for any disease where inhibition of coagulation is indicated.
These compounds may be used as diagnostic reagents in vitro for inhibiting clotting of blood in the tubes.
These compounds may be used alone or in combination with other compounds such as heparin, aspirin, or warfarin and any other anticoagulant agents. These compounds may be used as anti-inflammatory agents.
According to a further aspect of the invention, compounds may be employed in preventing ex vivo coagulation such as that encountered in the extracorporeal perfusion of blood through for example artificial valves, prothesis, stents or catheters. According to this aspect of the invention the extracorporeal device may be coated with the compositions of the invention resulting in a lower risk of clot formation due to extrinsic pathway activation.
Dosage and Formulation
The compounds of this invention can be administered by any means that produces contact of the active agent's site of action with factor Vila and other serine proteases in the body of a human, mammal, bird, or other animal. They can be administered by any conventional means, such as oral, topical, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. Parenteral infusion includes intramuscular, intravenous, and intraarterial. They can be administered alone, but generally administered with a pharmaceutical carrier elected on the basis of the chosen route of administration and standard pharmaceutical practice.
The dosage administered will, or course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms, the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.0001 to 1000 milligram (mg) per kilogram (kg) of body weight, with the preferred dose being 0.1 to about 30 mg/kg. Dosage forms (compositions suitable for administration) contain from about mg to about 500 mg of compound per unit. In these pharmaceutical compositions, the compound of the present invention will ordinarily be present in an amount of about 0.5- 95% by weight based on the total weight of the composition.
The daily dose of the compounds of the invention that is to be administered can be a single daily dose or can be divided into several, for example, two, three or four, part administrations. The pharmaceutical compositions or medicaments of the invention can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or percutaneously or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.
Gelatin capsules contain a compound of the present invention and powdered carriers, such as lactose, starch, cellulose derivatives, biocompatible polymers, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated to mask by unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. They may also contain buffering agents, surfactants and preservatives. Liquid oral products can be developed to have sustained-release properties. They may also contain cyclodextrin derivatives to enhance the solubility of the active ingredient and to promote its oral uptake.
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and, if necessary, buffering agents. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical
Sciences, Mack Publishing Company and in the Handbook of Pharmaceuticals Excipients, American Pharmaceutical Association, both standard reference texts in this field.
Useful pharmaceutical dosage forms for administration of the compounds according to the present invention can be illustrated as follows:
Hard Shell Capsules
A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered 1500 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate. Soft Gelatin Capsules
A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The prodrug can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
Tablets
' A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcystalline cellulose, 11 mg of starch, and 9.98 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability improve elegance and stability or delay absorption.
Immediate Release Tablets/Capsules
These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The drug is mixed containing ingredient such as sugar, gelatin, pectin, and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
Moreover, the compounds of the present invention can be administered in the form of nose drops, metered dose nasal or buccal inhalers. The drug is delivered from a nasal solution as a fine mist or from a powder as an aerosol. In another embodiment of the invention, a compound of the invention can be used in an assay to identify the presence of factor Vila and other serine protease or to isolate , factor Vila and other serine protease in a substantially purified form. For example, the compound of the invention can be labeled with, for example, a radioisotope, and the labeled compound is detected using a routine method useful for detecting the particular label. In addition, a compound the invention can be used advantageously as a probe to detect the location or amount of factor Vila and other serine protease activity in vivo, in vitro or ex vivo.
Various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.
The foregoing disclosure includes all the information deemed essential to enable those skilled in the art to practice the claimed invention. The foregoing description of the invention illustrates and describes the present invention. Additionally, the disclosure shows and describes only the preferred embodiments of the invention but, as mentioned above, it is to be understood that the invention is capable of use in various other combinations, modifications, and environments and is capable of changes or modifications within the scope of the inventive concept as expressed herein, commensurate with the above teachings and/or the skill or knowledge of the relevant art. The embodiments described hereinabove are further intended to explain best modes known of practicing the invention and to enable others skilled in the art to utilize the invention in such, or other, embodiments and with the various modifications required by the particular applications or uses of the invention. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended that the appended claims be construed to include alternative embodiments.

Claims

What is claimed is
Compound having the structure (I) shown below:
R B1
(R1) m- E1- W E2- B
; pharmaceutically
X (R2), P acceptable salts thereof; and prodrugs thereof;
V1- L V
X
(I)
( A )
Each E1 and L individually is a 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic saturated or unsaturated carbon ring, bicyclic saturated or unsaturated hetero ring, or 1-8 hydrocarbon chain which may be substituted with one or more hetero groups selected from N, O, S, S(O), and S(O2) which may be saturated or unsaturated;
R is -CH=CH-R2, -C≡C-R2, -C(R2)=CH2, -C(R2)=C(R3), -CH=NR2, -C(R2)=N-R3, 4-7 membered saturated or unsaturated carbon ring system with or without substitution, 4-7 membered saturated or unsaturated hetero ring system with or without substitution, or chain of 2 to 8 carbon atoms having 1 to 5 double or triple bonds with substitutions selected from R1 , R2, or R3. Preferably, these R, R1 , R2, or R3 do not include -(C2.4 alkenyl)-CO2-Cι-8 alkyl, -(C2.4 alkenyl)-CO2-Cι.8 alkyl-phenyl, and -(C2.4 a!kenyl)-CO2- Cι-8 alkyl-O-Cι.4 alkyl;
R1 is H, -R, -NO2, -CN, -halo, -N3, -C ,.8 alkyl, -(CH2)nCO2R2, -C2.8 alkenyl-CO2R2, -O(CH2)nCO2R2, -C(O)NR2R3, -P(O)(OR2)2, alkyl substituted tetrazol-5-yl, -(CH2)nO(CH2)n aryl, -NR2R3, -(CH2)π OR2, -(CH2)„ SR2, -N(R2)C(O)R3, -S(O2)NR2R3, -N(R2)S(O2)R3, -(CHR2)n NR2R3, -C(O)R3, (CH2)n N(R3)C(O)R3, -N(R2)CR2R3 substituted or unsubstituted (CH2)n-cycloalkyl, substituted or unsubstituted (CH2)n- phenyl, or substituted or unsubstituted (CH2)n-heterocycle which may be saturated or unsaturated;
m is 1 except that when E1 is a cyclic ring of more than 5 atoms, then m is 1 or higher, depending upon the size of the ring;
R2 is H, -halo, -alkyl, -haloalkyl, -(CH2)n -phenyl, -(CH2)ι.3-biphenyl, -(CH2) -Ph- N(SO2-Cι.2-alkyl)2, -CO(CHR1)n-OR1, -(CHR^-heterocycle, -(CHR^-NH-CO-R1, -(CHR1)n-NH-SO2R1, -(CHR1)n-Ph-N(SO2-C,.2-alkyl)2, -(CHR1)π-C(O)(CHR1)-NHR1, -(CHR1)n-C(S)(CHR1)-NHR1, -(CH2)nO(CH2)nCH3, -CF3, -C2.5 acyl, -(CHR')nOH, -(CHR^COzR1, -(CHR^n-O-alkyl, -(CHR')n-O-(CH2)n-O-alkyl, -(CHR')n-S-alkyl, -(CHR1)n-S(O)-alkyl, -(CHR!)n-S(O2)-alkyl, -(CHR!)n-S(O2)-NHR3, -(CHR3)n-N3, -(CHR3)nNHR4 j 2 to 8 carbon atom alkene chain having 1 to 5 double bonds, 2 to 8 carbon atom alkyne chain having 1 to 5 triple bonds, substituted or unsubstituted- (CHR )n heterocycle, or substituted or unsubstituted-(CHR )n cycloalkyl which may be saturated or unsaturated; When n is more than 1 , the substitutions R1 and R3 may be same or different;
R3 is H, -OH, -CN, substituted alkyl, -C2.8 alkenyl, substituted or unsubstituted cycloalkyl, -N(R')R2, or 5-6 membered saturated substituted or unsubstituted hetero ring;
-NR2R3 may form a ring system having 4 to 7 atoms or may be bicyclic ring; wherein said ring system comprises carbon or hetero atoms and further it may saturated or unsaturated and also may be substituted or unsubstituted; W is a direct bond, -CHR2-, -CH=CR2-, -CR2=CH-, -CR2=CR2-, -C≡C-, -O-CHR2-, -CHR2-O-, -N(R2)-C(O)-, -C(O)-N(R2)-, -N(R2)-CH-(R3)-, -CH2-N(R2)-, -CH(R1)-N(R2)-, -S-CHR2-, -CHR2-S-, -S(O2)-N(R2)-, -C(O)N(R2)-(CHR2)n-, -C(R1R2)n-NR2-, -N(R2)-S(O2)-, -R2C(O)NR2-, -R2NC(O)NR2-, -CONR2CO-, -C(=NR2)NR2-, -NR2C(=NR2)NR2-, -NR2O-, -N=NCHR2-, or -C(O)NR2SO2-;
E2 is 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, Cι-8 alkyl, C2.8 alkenyl, C2.8 alkynyl, alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino;
each X individually is a direct bond, substituted or unsubstituted CM methylene chain, O, S, NR2 , S(O), S(O2), or N(O) containing one or two Cι.4 substituted or unsubstituted methylene chains; X at different places may be same or different;
B is H, -halo, -CN, -NH2, -(CH2)n-C(=NR4)NHR5, -(CH2)n-NHR4, - (CH2)nNHC(=NR4)NR5, -(CH2)n-OR4, Cι-8 substituted or unsubstituted alkyl, substituted or unsubstituted ring system having 4 to 7 carbon or hetero atoms which may be saturated or unsaturated;
B1 is selected from B; B1 and B may be same or different;
There may be more than one similar or different R2 groups present on E2, when E2 is a cyclic group of more than 5 atoms; p is 1 except that when E2 is a cyclic ring of more than 5 atoms, p is 1 or higher depending upon the size of the ring;
n is 0-4;
A is selected from R1; o is 1 except that when L is a cyclic ring of more than 5 atoms, o is 1 or higher depending upon the size of the ring; Each V and N individually is selected from R and Ν-alkyl substituted carboxamidyl (- COΝHR) where the alkyl group may be straight, branched, cyclic, or bicyclic; Ν,Ν- disubstituted carboxamidyl of the formula -CONRιR2 where Ri and R2 may be substituted or unsubstituted alkyl or aryl and may be the same or different; mono- or disubstituted sulfonamides of the formula SO2NHR or -SO2NRιR2; and methylene- or polymethylene chain-extended variants thereof;
Each R4 and R5 individually is H, -(CH2)nOH, -C(O)OR6, -C(O)SR6, -(CH2)n C(O)NR7R8, -O-C(O)-O-R7, an amino acid or a dipeptide;
Each R6is H, R7, -C(R7)(R8)-(CH2)n-O-C(O)-R9, -(CH2)n-C(R7)(R8)-O-C(O)R9, -(CH2)n- C(R7)(R8)-O-C(O)-O-R9, or -C(R7)(R8)-(CH2)n-O-C(O)-O-R9; and
Each R7, R8 and R9 individually is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or CH2CO2alkyl.
2. The compound of claim 1 represented by the structure
Figure imgf000292_0001
wherein R is selected from the group consisting of
Figure imgf000292_0002
and R' is selected from the group consisting of
Figure imgf000292_0003
pharmaceutically acceptable salts thereof; and prodrugs thereof. The compound of claim 1 represented by the structure
Figure imgf000293_0001
wherein R is selected from the group consisting of
-OBn, -OH, -OSO2CF3,
Figure imgf000293_0002
Figure imgf000293_0003
Figure imgf000293_0004
-OCH3; and R' is selected from the group consisting of -CHO, -CO H, and -CO2MEM; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
4. The compound of claim 1 represented by the structure
Figure imgf000294_0001
wherein R is -OSO2CF3; and R' is selected from the group consisting of
-CHO, -CO2H, ; and pharmaceutically acceptable salts thereof;
Figure imgf000294_0002
and prodrugs thereof.
The compound of claim 1 represented by the structure
Figure imgf000295_0001
Figure imgf000295_0002
and R' is selected from the group consisting of -CHO, -CO2H, and -CO2MEM; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
6. The compound of claim 1 represented by the structure
Figure imgf000297_0001
Figure imgf000297_0002
Figure imgf000298_0001
Figure imgf000298_0002
and ^ N3 ; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
The compound of claim 1 represented by the structure
Figure imgf000299_0001
wherein R is selected from the group consisting of
Figure imgf000299_0002
Figure imgf000300_0001
Figure imgf000300_0002
Figure imgf000300_0003
and R' is selected from the group consisting of
Figure imgf000300_0004
Figure imgf000301_0001
Figure imgf000301_0002
Figure imgf000301_0003
Figure imgf000301_0004
and pharmaceutically acceptable salts thereof; and prodrugs thereof.
The compound of claim 1 represented by the structure
Figure imgf000302_0001
wherein R is selected from the group consisting of
Figure imgf000302_0002
-OBn, -OCH3, and aceutically acceptable salts thereof; and prodrugs thereof.
The compound of claim 1 represented by the structure
Figure imgf000303_0001
wherein R is selected from the group consisting of
Figure imgf000303_0002
and R' is -H or ; and pharmaceutically acceptable salts thereof; and prodrugs
Figure imgf000303_0003
thereof.
10. The compound of claim 1 represented by the structure
Figure imgf000304_0001
wherein R is selected from the group consisting of
-OBn, -OH, -OSO2CF3, -CH=CH2, and -H;
Figure imgf000304_0002
R' is selected from the group consisting of -CHO, -CO2H, and -CO2MEM;
and R" is selected from the group consisting of
Figure imgf000304_0003
and pharmaceutically acceptable salts thereof; and prodrugs thereof
11. The compound of claim 1 represented by the structure
Figure imgf000305_0001
wherein R is selected from the group consisting of
-OBn, -OH, -OSO2CF3, X~ > -CH=CH2;
O
R' is -H or -Boc; and R" is -CO2MEM or -CO2H; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
12. The compound of claim 1 represented by the structure
Figure imgf000306_0001
wherein R is -CH3 and R' is selected from the group consisting of
Figure imgf000306_0002
Figure imgf000307_0001
or NHR' = N ) , or NHR' = N -CH,
and pharmaceutically acceptable salts thereof; and prodrugs thereof.
13. The compound of claim 1 represented by the structure
Figure imgf000308_0001
wherein R is y P ; and R' is selected from the group consisting of
Figure imgf000308_0002
Figure imgf000308_0003
Figure imgf000309_0001
and pharmaceutically acceptable salts thereof; and prodrugs thereof.
14. The compound of claim 1 represented by the structure
Figure imgf000310_0001
and -CH=CH2 and R' is selected from the group consisting of
Figure imgf000310_0002
Figure imgf000310_0003
and pharmaceutically acceptable salts thereof; and prodrugs thereof.
15. The compound of claim 1 represented by the structure
Figure imgf000311_0001
wherein R is -CH3 and R' is selected from the group consisting of
Figure imgf000311_0002
Figure imgf000311_0003
Figure imgf000311_0004
and pharmaceutically acceptable salts thereof; and prodrugs thereof.
16. The compound
Figure imgf000312_0001
wherein at least one R is selected from the group consisting of -OCH3, -OH, -OSO2CF3, -CH=CH2, -OCH2CO2C2H5,
Figure imgf000312_0002
.OAc , \ / \ , -OBn , -OH, -OSO2CF3,
0 v ° OAc
Figure imgf000312_0003
R' is selected from the group consisting of
Figure imgf000312_0004
Figure imgf000313_0001
Figure imgf000314_0001
and R" is selected from the group consisting of-H, -CH and -Bn; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
17. The compound of claim 1 represented by the structure
Figure imgf000315_0001
wherein at least one R is selected from the group consisting of -CH=CH2, -OSO2CF3, -OCH2CO2C2H5, -OCH2CONH2,
Figure imgf000315_0002
.CH, o "CH, 0 ,-O-CH2-CH2-OAc, -OH,
CH,
-OCH2CO2H, -O-CH2-CH2-OH, -CH(OH)CH2OH, -CH2OH, -CO2H,
-OBn, -OH, -OCH3, -OBn, -OH, -OC2H5,
Figure imgf000315_0003
-OBn, -OCH3, and -CH(OH)CH3; and R' is selected from the group consisting of -CH3, -CH2C6H5, -Bn, -H; and pharmaceutically acceptable salts thereof; and prodrugs thereof
18. The compound of claim 1 represented by the structure
Figure imgf000316_0001
wherein at least one R is selected from the group consisting of -CH=CH2, -CH(OH)CH2OH, -CH=O, -CH2OH, -CO2H, -OCH3, -CH=CH2; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
19. The compound of claim 1 represented by the structure
Figure imgf000317_0001
wherein R is selected from the group consisting of halo and -B(OH)2; Rl is selected from the group consisting of -H, -OCH , -OBn; R2 is selected from the group consisting of
-H, -OCH3, -OC2H5, -OCH(CH3)2, and
Figure imgf000317_0002
R3 is selected from the group consisting of-H, -OH, -OBn; and R4 is -OBn or -H; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
20. The compound of claim 19 wherein said halo is -Br.
21. The compound of claim 1 represented by the structare
Figure imgf000318_0001
and pharmaceutically acceptable salts thereof; and prodrugs thereof.
22. The compound of claim 1 represented by the structure
Figure imgf000319_0001
wherein R is selected from the group consisting of
-CH3, -C2H5, -CH(CH3)2,
Figure imgf000319_0002
R' is selected from the group consisting of -OBn, -OH, -OSO2CF3, and -CH=CH2;
R" is selected from the group consisting of -CO2H, -CO2MEM, or -CHO;
and R"' is selected from the group consisting of
Figure imgf000319_0003
Figure imgf000319_0004
, and ;and pharmaceutically acceptable salts thereof;
Figure imgf000319_0005
Figure imgf000319_0006
and prodrugs thereof.
23. The compound of claim 1 represented by the structure
Figure imgf000320_0001
wherein R is selected from the group consisting of
-CH3, -C2H5, -CH(CH3)2, , and -H;
Figure imgf000320_0002
R' is -H or alkyl; and R" is selected from the group consisting of
Figure imgf000320_0003
thereof; and prodrugs thereof.
24. The compound of claim 23 wherein said alkyl is -CH3.
25. The compound of claim 1 represented by the structure
Figure imgf000321_0001
wherein R is selected from the group consisting of
Figure imgf000321_0002
Figure imgf000321_0003
Figure imgf000321_0004
Figure imgf000322_0001
Figure imgf000322_0002
Figure imgf000322_0003
Figure imgf000323_0001
Figure imgf000323_0002
R' is -H,
Figure imgf000323_0003
and R" is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
26. The compound of claim 25 wherein said alkyl is -CH3.
27. The compound of claim 1 represented by the structure
Figure imgf000324_0001
wherein R is selected from the group consisting of
Jl , XL^ , -CH=CH2, and -H; R' is -H or alkyl; and R" is selected o s
from the group consisting of
Figure imgf000324_0002
; and pharmaceutically acceptable salts thereof; and prodrugs
Figure imgf000324_0003
28. The compound of claim 27 wherein said alkyl is -CH3.
29. The compound of claim 1 represented by the structure
Figure imgf000325_0001
wherein N is located at position 3 or 4 in the phenyl ring; R is selected from the group consisting of -CHO, -CO2H, and
Figure imgf000325_0002
and R' is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
30. The compound of claim 29 wherein said alkyl is -CH3.
31. The compound of claim 1 represented by the structure
Figure imgf000326_0001
wherein R is selected from the group consisting of
-CH3, -C2H5, -CH2C6H5, -C(CH )3, -CH2-CC13, γj~
Figure imgf000326_0002
Figure imgf000326_0003
and R' is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
32. The compound of claim 31 wherein alkyl is CH3.
33. The compound of claim 1 represented by the structure
Figure imgf000327_0001
wherein R is selected from the group consisting of
-CHO, ; and R' is -H or alkyl; and
Figure imgf000327_0002
pharmaceutically acceptable salts thereof; and prodrugs thereof.
34. The compound of claim 33 wherein said alkyl is -CH3.
35. The compound of claim 1 represented by the structure
Figure imgf000328_0001
wherein at least one R is selected from the group consisting of -CH=CH2, -OCH3, -OBn, -OH, and -H; R' is
Figure imgf000328_0002
R" is selected from the group consisting of
, > and and R'" is -H; and pharmaceutically
Figure imgf000328_0003
acceptable salts thereof; and prodrugs thereof.
36. The compound of claim 1 represented by the structure
wherein R is -CH2O
Figure imgf000329_0001
and R' is -Boc, or -H; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
37. The compound of claim 1 represented by the structure
Figure imgf000330_0001
wherein R is -OCH3, -OH, -OSO2CF3, -C(=NH)NH2, and -H;
Figure imgf000330_0002
and R" is halo, -CH=CH2, -CO2CH3, and
Figure imgf000330_0003
and pharmaceutically acceptable salts thereof; and prodrugs thereof.
38. The compound of claim 37 wherein said halo is -Br.
39. The compound of claim 1 represented by the structure
Figure imgf000331_0001
wherein R is selected from the group consisting of -CHO, -CO2H, -CO2MEM,
Figure imgf000331_0002
R' is selected from the group consisting of -OBn, -OH, -OSO2CF3, and -CH=CH2;
and R" is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
40. The compound of claim 39 wherein said alkyl is -CH3.
41. The compound of claim 1 represented by the structare
Figure imgf000332_0001
wherein R is -CO2CH3; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
42. The compound of claim 1 represented by the structure
Figure imgf000333_0001
wherein R is -H or -CO2H;
R' is selected from the group consisting of -CHO, -CO2H, and
Figure imgf000333_0002
and R" is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
43. The compound of claim 42 wherein said alkyl is -CH3.
44. The compound of claim 1 represented by the structare
Figure imgf000334_0001
wherein R is selected from the group consisting of -CH(OH)-CH2OH, -CHO, and -CH(OH)-CH=CH2;
R' is -Boc or -H; and R" is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
45. The compound of claim 44 wherein said alkyl is -CH3.
46. The compound of claim 1 represented by the structure
Figure imgf000335_0001
wherein R is
Figure imgf000335_0002
and pharmaceutically acceptable salts thereof; and prodrugs thereof.
47. A pharmaceutical composition containing at least one compound according to claim 1.
48. A method for inhibiting serine protease in a patient which comprises administering to the patient an effective serine protease inhibiting amount of at least one compound according to claim 1.
49. A method for inhibiting the coagulation cascade and preventing or limiting coagulation by administering to a patient an effective amount of at least one compound according to claim 1.
50. A method for inhibiting the formation of emboli or thromboli in blood vessels by administering to a patient an effective amount of at least one compound according to claim 1.
51. A method for treating at least one condition selected from the group consisting of thrombolymphangitis, thrombosinusitis, thromboendocarditis, thromboangitis, and thromboarteritis which comprises administering to a patient an effective amount of at least one compound according to claim 1.
52. A method for inhibiting thrombus formation following angioplasty which comprises administering to a patient an effective amount of at least one compound according to claim 1.
53. A method for preventing arteria occlusion following thrombolytic therapy which comprises administering to a patient an effective amount of at least one compound according to claim 1 and an effective amount of at least another antithrombolytic agent.
54. The method of claim 53 wherein said other antithrombolytic agent is selected from the group consisting of tissue plasminogen activators, streptokinase and urokinase, and functional derivatives thereof.
55. A method for treating metastatic diseases which comprises administering to a patient an effective amount of at least one compound according to claim 1.
56. A method of claim 49 which further comprises administering a further anticoagulant agent to said patient.
57. t The method of claim 56 wherein said further anticoagulant agent is selected from the group consisting of heparin, aspirin, and warfarin.
58. A methof for treating a patient in need of an anti-inflammatory agent which comprises administering to said patient an effective amount of at least one of the compounds according to claim 1.
59. A method for inhibiting in vitro clotting of blood which comprises contacting said blood with at least one compound according to claim 1.
60. The method of claim 59 which comprises inhibiting said blood in tabes.
61. An extraarpereal device having a coating therein which comprises a compound according to claim 1.
62. A method for detecting future presence of a serine protease which comprises contacting a sample with a compound according to claim 1.
63. The compound of claim 1 represented by the structure
Figure imgf000337_0001
wherein R is alkyl and R' is selected from the group consisting of
Figure imgf000337_0002
Figure imgf000337_0003
Figure imgf000338_0001
and pharmaceutically acceptable salts thereof; and prodrugs thereof.
PCT/US2001/032582 2000-10-20 2001-10-22 Biaryl compounds as serine protease inhibitors WO2002034711A1 (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
MXPA03009130A MXPA03009130A (en) 2000-10-20 2001-10-22 Biaryl compounds as serine protease inhibitors.
IL15520201A IL155202A0 (en) 2000-10-20 2001-10-22 Biaryl compounds as serine protease inhibitors
DK01981772T DK1383731T3 (en) 2000-10-20 2001-10-22 Biaryl compounds as serine protease inhibitors
AU2002213393A AU2002213393B2 (en) 2000-10-20 2001-10-22 Biaryl compounds as serine protease inhibitors
AU1339302A AU1339302A (en) 2000-10-20 2001-10-22 Biaryl compounds as serine protease inhibitors
JP2002537705A JP4342178B2 (en) 2001-04-06 2001-10-22 Biaryl compounds as serine protease inhibitors
CA2426430A CA2426430C (en) 2000-10-20 2001-10-22 Biaryl compounds as serine protease inhibitors
EP01981772A EP1383731B1 (en) 2001-04-06 2001-10-22 Biaryl compounds as serine protease inhibitors
DE60139510T DE60139510D1 (en) 2001-04-06 2001-10-22 BIARYL COMPOUNDS AS SERINE PROTEASE INHIBITORS
AT01981772T ATE438615T1 (en) 2001-04-06 2001-10-22 BIARYL COMPOUNDS AS SERINE PROTEASE INHIBITORS
NZ526003A NZ526003A (en) 2000-10-20 2001-10-22 Biaryl compounds as serine protease inhibitors
US10/127,460 US6699994B1 (en) 2001-04-06 2002-04-23 Biaryl compounds as serine protease inhibitors
IL155202A IL155202A (en) 2001-04-06 2003-04-02 Biaryl compounds as serine protease inhibitors
US10/738,027 US6936719B2 (en) 2001-04-06 2003-12-18 Biaryl compounds as serine protease inhibitors
HK04105585.6A HK1062676A1 (en) 2000-10-20 2004-07-28 Biaryl compounds as serine protease inhibitors
IL222773A IL222773B (en) 2001-04-06 2012-10-30 Biaryl compounds, pharmaceutical compositions comprising the same, use of such compounds in the manufacture of medicaments and in vitro methods and devices using such compounds

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US24184800P 2000-10-20 2000-10-20
US60/241,848 2000-10-20
US28173501P 2001-04-06 2001-04-06
US60/281,735 2001-04-06

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US10/127,460 Continuation-In-Part US6699994B1 (en) 2001-04-06 2002-04-23 Biaryl compounds as serine protease inhibitors

Publications (1)

Publication Number Publication Date
WO2002034711A1 true WO2002034711A1 (en) 2002-05-02

Family

ID=26934639

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2001/032582 WO2002034711A1 (en) 2000-10-20 2001-10-22 Biaryl compounds as serine protease inhibitors

Country Status (8)

Country Link
AU (2) AU1339302A (en)
CA (1) CA2426430C (en)
DK (1) DK1383731T3 (en)
HK (1) HK1062676A1 (en)
IL (1) IL155202A0 (en)
MX (1) MXPA03009130A (en)
NZ (1) NZ526003A (en)
WO (1) WO2002034711A1 (en)

Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002037937A2 (en) * 2000-11-07 2002-05-16 Bristol-Myers Squibb Company Acid derivatives useful as serine protease inhibitors
WO2002042273A2 (en) * 2000-11-07 2002-05-30 Bristol-Myers Squibb Company Acid derivatives useful as serine protease inhibitors
WO2003011858A1 (en) * 2001-07-30 2003-02-13 Bayer Healthcare Ag Substituted isoindoles and e use thereof
EP1388341A1 (en) * 2002-08-07 2004-02-11 Aventis Pharma Deutschland GmbH Acylamino-substituted heteroaromatic compounds and their use as pharmaceuticals
EP1394147A1 (en) * 2001-06-04 2004-03-03 Eisai Co., Ltd. Carboxylic acid derivative and medicine comprising salt or ester of the same
WO2004048335A2 (en) * 2002-11-25 2004-06-10 F. Hoffmann-La Roche Ag Mandelic acid derivatives
US6818787B2 (en) 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US6833140B2 (en) * 2001-06-11 2004-12-21 Xenoport, Inc. Orally administered dosage forms of GABA analog prodrugs having reduced toxicity
US6906192B2 (en) 2000-11-07 2005-06-14 Bristol Myers Squibb Company Processes for the preparation of acid derivatives useful as serine protease inhibitors
FR2871157A1 (en) * 2004-06-04 2005-12-09 Aventis Pharma Sa BIARYL AROMATIC PRODUCTS, COMPOSITIONS CONTAINING SAME AND USE THEREOF
US7122559B2 (en) 2003-02-11 2006-10-17 Bristol-Myers Squibb Company Phenylglycine derivatives useful as serine protease inhibitors
US7144895B2 (en) 2003-02-11 2006-12-05 Bristol-Myers Squibb Co. Benzene acetamide compounds useful as serine protease inhibitors
US7148230B2 (en) 2003-07-29 2006-12-12 Astrazeneca Ab Quinazoline derivatives
US7163952B2 (en) 2001-12-03 2007-01-16 Japan Tobacco Inc. Azole compound and medicinal use thereof
US7186855B2 (en) 2001-06-11 2007-03-06 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7232924B2 (en) 2001-06-11 2007-06-19 Xenoport, Inc. Methods for synthesis of acyloxyalkyl derivatives of GABA analogs
JP2007523935A (en) * 2004-02-28 2007-08-23 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Novel carboxamides for use as XA inhibitors
US7338956B2 (en) 2002-08-07 2008-03-04 Sanofi-Aventis Deutschland Gmbh Acylamino-substituted heteroaromatic compounds and their use as pharmaceuticals
US7348353B2 (en) 2001-12-04 2008-03-25 Novartis Ag Acetylene derivatives having mGluR 5 antagonistic activity
US7459468B2 (en) 2004-10-28 2008-12-02 Medicure International, Inc. Aryl sulfonic pyridoxines as antiplatelet agents
US7544835B2 (en) 2001-04-20 2009-06-09 Eisai R&D Management Co., Ltd. Carboxylic acid derivative and salt thereof
US7622585B2 (en) 2005-01-10 2009-11-24 Bristol-Myers Squibb Company Phenylglycinamide derivatives useful as anticoagulants
US7754717B2 (en) 2005-08-15 2010-07-13 Amgen Inc. Bis-aryl amide compounds and methods of use
US7816391B2 (en) 2007-02-12 2010-10-19 Astrazeneca Ab Chemical compounds
US7910731B2 (en) 2002-03-30 2011-03-22 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
US7964618B2 (en) 2006-11-03 2011-06-21 Astrazeneca Ab Chemical compounds
US7998949B2 (en) 2007-02-06 2011-08-16 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof
US8048917B2 (en) 2005-04-06 2011-11-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US8084614B2 (en) 2007-04-06 2011-12-27 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8088782B2 (en) 2008-05-13 2012-01-03 Astrazeneca Ab Crystalline 4-(3-chloro-2-fluoroanilino)-7 methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline difumarate form A
US8263588B2 (en) 2007-04-06 2012-09-11 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8399461B2 (en) 2006-11-10 2013-03-19 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for production of same
US8497369B2 (en) 2008-02-07 2013-07-30 Boehringer Ingelheim International Gmbh Spirocyclic heterocycles medicaments containing said compounds, use thereof and method for their production
US8623871B2 (en) 2006-01-25 2014-01-07 Synta Pharmaceuticals Corp. Substituted biaryl compounds for inflammation and immune-related uses
US8648191B2 (en) 2008-08-08 2014-02-11 Boehringer Ingelheim International Gmbh Cyclohexyloxy substituted heterocycles, pharmaceutical compositions containing these compounds and processes for preparing them
US8673889B2 (en) * 2004-04-26 2014-03-18 Ono Pharmaceutical Co., Ltd. BLT2-mediated disease, BLT2 binding agent and the compound
US8673974B2 (en) 2010-11-16 2014-03-18 Novartis Ag Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors
US8795725B2 (en) 2004-11-04 2014-08-05 Xenoport, Inc. GABA analog prodrug sustained release oral dosage forms
WO2016029214A1 (en) * 2014-08-22 2016-02-25 Biocryst Pharmaceuticals, Inc. Compositions and uses of amidine derivatives
US9925174B2 (en) 2002-03-07 2018-03-27 Boehringer Ingelheim International Gmbh Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof
WO2018081513A1 (en) * 2016-10-31 2018-05-03 Biocryst Pharmaceuticals, Inc. Prodrugs of kallikrein inhibitors
US10647661B2 (en) 2017-07-11 2020-05-12 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
US12030903B2 (en) 2020-02-18 2024-07-09 Gilead Sciences, Inc. Antiviral compounds
US12054507B2 (en) 2020-02-18 2024-08-06 Gilead Sciences, Inc. Antiviral compounds
US12116380B2 (en) 2021-08-18 2024-10-15 Gilead Sciences, Inc. Phospholipid compounds and methods of making and using the same

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4551279A (en) * 1984-01-09 1985-11-05 G. D. Searle & Co. Protease inhibitors
WO1999041231A1 (en) * 1998-02-17 1999-08-19 Ono Pharmaceutical Co., Ltd. Amidino derivatives and drugs containing the same as the active ingredient
WO2000015658A1 (en) 1998-09-15 2000-03-23 Aventis Pharma Deutschland Gmbh FACTOR VIIa INHIBITORS
WO2000041531A2 (en) 1999-01-13 2000-07-20 Genentech, Inc. Serine protease inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4551279A (en) * 1984-01-09 1985-11-05 G. D. Searle & Co. Protease inhibitors
WO1999041231A1 (en) * 1998-02-17 1999-08-19 Ono Pharmaceutical Co., Ltd. Amidino derivatives and drugs containing the same as the active ingredient
WO2000015658A1 (en) 1998-09-15 2000-03-23 Aventis Pharma Deutschland Gmbh FACTOR VIIa INHIBITORS
WO2000041531A2 (en) 1999-01-13 2000-07-20 Genentech, Inc. Serine protease inhibitors

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ALEXANDER ET AL., J. MED. CHEM., vol. 31, 1988, pages 318
BODER ET AL., J. MED. CHEM, vol. 23, 1980, pages 469
PRYOR K.E. ET AL.: "The activated core approach to combinatorial chemistry: A selection of new core molecules", TETRAHEDRON, vol. 54, 1998, pages 4107 - 4124, XP004162184 *
See also references of EP1383731A4

Cited By (85)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002042273A2 (en) * 2000-11-07 2002-05-30 Bristol-Myers Squibb Company Acid derivatives useful as serine protease inhibitors
WO2002042273A3 (en) * 2000-11-07 2002-08-29 Bristol Myers Squibb Co Acid derivatives useful as serine protease inhibitors
WO2002037937A3 (en) * 2000-11-07 2002-08-29 Bristol Myers Squibb Co Acid derivatives useful as serine protease inhibitors
US6642252B2 (en) 2000-11-07 2003-11-04 Bristol-Myers Squibb Company Acid derivatives useful as serine protease inhibitors
WO2002037937A2 (en) * 2000-11-07 2002-05-16 Bristol-Myers Squibb Company Acid derivatives useful as serine protease inhibitors
US6713467B2 (en) 2000-11-07 2004-03-30 Bristol-Myers Squibb Company Acid derivatives useful as serine protease inhibitors
US6906192B2 (en) 2000-11-07 2005-06-14 Bristol Myers Squibb Company Processes for the preparation of acid derivatives useful as serine protease inhibitors
US7544835B2 (en) 2001-04-20 2009-06-09 Eisai R&D Management Co., Ltd. Carboxylic acid derivative and salt thereof
EP1394147A4 (en) * 2001-06-04 2007-10-24 Eisai R&D Man Co Ltd Carboxylic acid derivative and medicine comprising salt or ester of the same
US7687664B2 (en) 2001-06-04 2010-03-30 Eisai R&D Management Co., Ltd. Carboxylic acid derivative, a salt thereof or an ester of them, and medicament comprising it
EP1394147A1 (en) * 2001-06-04 2004-03-03 Eisai Co., Ltd. Carboxylic acid derivative and medicine comprising salt or ester of the same
US6818787B2 (en) 2001-06-11 2004-11-16 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7423169B2 (en) 2001-06-11 2008-09-09 Xenoport, Inc. Methods for synthesis of acyloxyalkyl derivatives of GABA analogs
US6833140B2 (en) * 2001-06-11 2004-12-21 Xenoport, Inc. Orally administered dosage forms of GABA analog prodrugs having reduced toxicity
US7790708B2 (en) 2001-06-11 2010-09-07 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US6972341B2 (en) 2001-06-11 2005-12-06 Xeno Port, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7232924B2 (en) 2001-06-11 2007-06-19 Xenoport, Inc. Methods for synthesis of acyloxyalkyl derivatives of GABA analogs
US8168623B2 (en) 2001-06-11 2012-05-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US9238616B2 (en) 2001-06-11 2016-01-19 Xenoport, Inc. Prodrugs of gaba analogs, compositions and uses thereof
US7186855B2 (en) 2001-06-11 2007-03-06 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
WO2003011858A1 (en) * 2001-07-30 2003-02-13 Bayer Healthcare Ag Substituted isoindoles and e use thereof
US7482472B2 (en) 2001-07-30 2009-01-27 Bayer Healthcare Ag Substituted isoindoles and their use
US7189738B2 (en) 2001-07-30 2007-03-13 Bayer Healthcare Ag Substituted isoindoles and their use thereof
US7163952B2 (en) 2001-12-03 2007-01-16 Japan Tobacco Inc. Azole compound and medicinal use thereof
US8536229B2 (en) 2001-12-04 2013-09-17 Novartis Ag Acetylene derivatives having MGluR 5 antagonistic activity
US7348353B2 (en) 2001-12-04 2008-03-25 Novartis Ag Acetylene derivatives having mGluR 5 antagonistic activity
US9925174B2 (en) 2002-03-07 2018-03-27 Boehringer Ingelheim International Gmbh Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof
US8343982B2 (en) 2002-03-30 2013-01-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocyclic compounds pharmaceutical compositions containing these compounds, their use and process for preparing the same
US7910731B2 (en) 2002-03-30 2011-03-22 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
EP1388341A1 (en) * 2002-08-07 2004-02-11 Aventis Pharma Deutschland GmbH Acylamino-substituted heteroaromatic compounds and their use as pharmaceuticals
JP4778230B2 (en) * 2002-08-07 2011-09-21 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Acylamino-substituted heteroaromatic compounds and their use as medicaments
US7338956B2 (en) 2002-08-07 2008-03-04 Sanofi-Aventis Deutschland Gmbh Acylamino-substituted heteroaromatic compounds and their use as pharmaceuticals
JP2005538123A (en) * 2002-08-07 2005-12-15 アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング Acylamino-substituted heteroaromatic compounds and their use as medicaments
WO2004014369A1 (en) * 2002-08-07 2004-02-19 Aventis Pharma Deutschland Gmbh Acylamino-substituted heteroaromatic compounds and their use as pharmaceuticals
WO2004048335A2 (en) * 2002-11-25 2004-06-10 F. Hoffmann-La Roche Ag Mandelic acid derivatives
WO2004048335A3 (en) * 2002-11-25 2004-08-19 Hoffmann La Roche Mandelic acid derivatives
US7144895B2 (en) 2003-02-11 2006-12-05 Bristol-Myers Squibb Co. Benzene acetamide compounds useful as serine protease inhibitors
US7122559B2 (en) 2003-02-11 2006-10-17 Bristol-Myers Squibb Company Phenylglycine derivatives useful as serine protease inhibitors
US7148230B2 (en) 2003-07-29 2006-12-12 Astrazeneca Ab Quinazoline derivatives
JP4657282B2 (en) * 2004-02-28 2011-03-23 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Novel carboxamides for use as XA inhibitors
US8791103B2 (en) 2004-02-28 2014-07-29 Boehringer Ingelheim International Gmbh Carboxylic acid amides, the preparation thereof and their use as medicaments
JP2007523935A (en) * 2004-02-28 2007-08-23 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Novel carboxamides for use as XA inhibitors
US8673889B2 (en) * 2004-04-26 2014-03-18 Ono Pharmaceutical Co., Ltd. BLT2-mediated disease, BLT2 binding agent and the compound
FR2871157A1 (en) * 2004-06-04 2005-12-09 Aventis Pharma Sa BIARYL AROMATIC PRODUCTS, COMPOSITIONS CONTAINING SAME AND USE THEREOF
US7459468B2 (en) 2004-10-28 2008-12-02 Medicure International, Inc. Aryl sulfonic pyridoxines as antiplatelet agents
US8795725B2 (en) 2004-11-04 2014-08-05 Xenoport, Inc. GABA analog prodrug sustained release oral dosage forms
US8906412B2 (en) 2004-11-04 2014-12-09 Xenoport, Inc. GABA analog prodrug sustained release oral dosage forms
US7622585B2 (en) 2005-01-10 2009-11-24 Bristol-Myers Squibb Company Phenylglycinamide derivatives useful as anticoagulants
US8048917B2 (en) 2005-04-06 2011-11-01 Xenoport, Inc. Prodrugs of GABA analogs, compositions and uses thereof
US7754717B2 (en) 2005-08-15 2010-07-13 Amgen Inc. Bis-aryl amide compounds and methods of use
US8492404B2 (en) 2005-08-15 2013-07-23 Amgen Inc. Bis-aryl amide compounds and methods of use
US8623871B2 (en) 2006-01-25 2014-01-07 Synta Pharmaceuticals Corp. Substituted biaryl compounds for inflammation and immune-related uses
US8673938B2 (en) 2006-11-03 2014-03-18 Astrazeneca Ab Chemical compounds
US7964618B2 (en) 2006-11-03 2011-06-21 Astrazeneca Ab Chemical compounds
US8399461B2 (en) 2006-11-10 2013-03-19 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, medicaments containing said compounds, use thereof, and method for production of same
US7998949B2 (en) 2007-02-06 2011-08-16 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, drugs containing said compounds, use thereof, and method for production thereof
US8344016B2 (en) 2007-02-12 2013-01-01 Astrazeneca Ab Pyrazole derivatives as 11-beta-HSD1 inhibitors
US7816391B2 (en) 2007-02-12 2010-10-19 Astrazeneca Ab Chemical compounds
US8507536B2 (en) 2007-04-06 2013-08-13 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8481738B2 (en) 2007-04-06 2013-07-09 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US10336769B2 (en) 2007-04-06 2019-07-02 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US11713324B2 (en) 2007-04-06 2023-08-01 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8263588B2 (en) 2007-04-06 2012-09-11 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US10941159B2 (en) 2007-04-06 2021-03-09 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8084614B2 (en) 2007-04-06 2011-12-27 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8952161B2 (en) 2007-04-06 2015-02-10 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US9422310B2 (en) 2007-04-06 2016-08-23 Neurocrine Biosciences, Inc. Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
US8497369B2 (en) 2008-02-07 2013-07-30 Boehringer Ingelheim International Gmbh Spirocyclic heterocycles medicaments containing said compounds, use thereof and method for their production
US8772298B2 (en) 2008-02-07 2014-07-08 Boehringer Ingelheim International Gmbh Spirocyclic heterocycles medicaments containing said compounds, use thereof and method for their production
US8088782B2 (en) 2008-05-13 2012-01-03 Astrazeneca Ab Crystalline 4-(3-chloro-2-fluoroanilino)-7 methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline difumarate form A
US8648191B2 (en) 2008-08-08 2014-02-11 Boehringer Ingelheim International Gmbh Cyclohexyloxy substituted heterocycles, pharmaceutical compositions containing these compounds and processes for preparing them
US8673974B2 (en) 2010-11-16 2014-03-18 Novartis Ag Substituted amino bisphenyl pentanoic acid derivatives as NEP inhibitors
WO2016029214A1 (en) * 2014-08-22 2016-02-25 Biocryst Pharmaceuticals, Inc. Compositions and uses of amidine derivatives
US10905683B2 (en) 2014-08-22 2021-02-02 Biocryst Pharmaceuticals, Inc. Compositions and uses of amidine derivatives
US10759759B2 (en) 2016-10-31 2020-09-01 Biocryst Pharmaceuticals, Inc. Prodrugs of kallikrein inhibitors
US11618731B2 (en) 2016-10-31 2023-04-04 Biocryst Pharmaceuticals, Inc. Prodrugs of kallikrein inhibitors
WO2018081513A1 (en) * 2016-10-31 2018-05-03 Biocryst Pharmaceuticals, Inc. Prodrugs of kallikrein inhibitors
US10647661B2 (en) 2017-07-11 2020-05-12 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US11603351B2 (en) 2017-07-11 2023-03-14 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
US12030903B2 (en) 2020-02-18 2024-07-09 Gilead Sciences, Inc. Antiviral compounds
US12054507B2 (en) 2020-02-18 2024-08-06 Gilead Sciences, Inc. Antiviral compounds
US12264173B2 (en) 2020-02-18 2025-04-01 Gilead Sciences, Inc. Antiviral compounds
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
US12116380B2 (en) 2021-08-18 2024-10-15 Gilead Sciences, Inc. Phospholipid compounds and methods of making and using the same

Also Published As

Publication number Publication date
CA2426430A1 (en) 2002-05-02
NZ526003A (en) 2005-09-30
AU1339302A (en) 2002-05-06
IL155202A0 (en) 2003-11-23
CA2426430C (en) 2014-10-07
DK1383731T3 (en) 2009-12-07
AU2002213393B2 (en) 2007-02-15
HK1062676A1 (en) 2004-11-19
MXPA03009130A (en) 2004-02-26

Similar Documents

Publication Publication Date Title
WO2002034711A1 (en) Biaryl compounds as serine protease inhibitors
EP1383731A1 (en) Biaryl compounds as serine protease inhibitors
AU2002213393A1 (en) Biaryl compounds as serine protease inhibitors
US6916813B2 (en) (1-phenyl-2-heteoaryl)ethyl-guanidine compounds as inhibitors of mitochondrial F1F0 ATP hydrolase
TWI443088B (en) Novel pharmaceutical salts and polymorphs of a factor xa inhibitor
JP2013121919A (en) Plasma kallikrein inhibitor
US20020040144A1 (en) 1-amino-7-isoquinoline derivatives as serine protease inhibitors
US20070129361A1 (en) LACTAM-CONTAINING DIAMINOALKYL, Beta-AMINOACIDS, Alpha-AMINOACIDS AND DERIVATIVES THEREOF AS FACTOR XA INHIBITORS
JP2003500385A (en) Factor Xa inhibitor
CA2362375A1 (en) Alkenyl and alkynyl compounds as inhibitors of factor xa
AU2001295507B2 (en) Novel compounds inhibiting factor Xa activity
JP2002538136A (en) Alkenyl and alkynyl containing metalloprotease inhibitors
GB2372740A (en) Diketopiperazines
US6846836B2 (en) N-substituted phenylurea inhibitors of mitochondrial F1F0 ATP hydrolase
KR101909910B1 (en) Pharmaceutical composition comprising pyridinol derivative or a pharmaceutically acceptable salt
CZ2003835A3 (en) Method for efficient preparation of Xa factor inhibitor
US20080051388A1 (en) Novel Compounds That Inhibit Factor Xa Activity
US20240336638A1 (en) Imidazole compound, and intermediate and application thereof
CN109721613B (en) Macrocyclic amide compound containing quaternary ammonium ions, and pharmaceutical composition and application thereof
US20060058389A1 (en) Novel compounds that inhibit factor xa activity
KR100441635B1 (en) Selective Thrombin Inhibitors for Oral Administration
KR100373373B1 (en) Selective thrombin inhibitor
KR100242264B1 (en) Novel Thrombin Inhibitors with N-alkyl-N-alkoxyamine Structures
KR19980076024A (en) Selective thrombin inhibitors for oral administration
MXPA01003408A (en) Benzamide derivatives as thrombin inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1-2003-500984

Country of ref document: PH

WWE Wipo information: entry into national phase

Ref document number: 155202

Country of ref document: IL

Ref document number: 2002213393

Country of ref document: AU

Ref document number: 392/KOLNP/2003

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2003/02645

Country of ref document: ZA

Ref document number: 200302645

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 2426430

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 526003

Country of ref document: NZ

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWE Wipo information: entry into national phase

Ref document number: PA/a/2003/009130

Country of ref document: MX

Ref document number: 2002537705

Country of ref document: JP

Ref document number: 1020037013075

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 2001981772

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2003132706

Country of ref document: RU

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2001981772

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 526003

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 526003

Country of ref document: NZ

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载