WO2001044203A1 - Composes de n-(1-phenylethyl)-5-phenyl-imidazole-2-amine, leurs compositions et utilisations - Google Patents

Composes de n-(1-phenylethyl)-5-phenyl-imidazole-2-amine, leurs compositions et utilisations Download PDF

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Publication number
WO2001044203A1
WO2001044203A1 PCT/US2000/033820 US0033820W WO0144203A1 WO 2001044203 A1 WO2001044203 A1 WO 2001044203A1 US 0033820 W US0033820 W US 0033820W WO 0144203 A1 WO0144203 A1 WO 0144203A1
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Prior art keywords
alkyl
hydrogen
aryl
phenyl
heterocycle
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PCT/US2000/033820
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English (en)
Inventor
Song Liu
Benjamin Eric Blass
David Edward Portlock
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The Procter & Gamble Company
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Priority to EP00984333A priority Critical patent/EP1237876A1/fr
Priority to US10/149,880 priority patent/US6596739B2/en
Priority to IL14974900A priority patent/IL149749A0/xx
Priority to CA002394570A priority patent/CA2394570A1/fr
Priority to HU0204144A priority patent/HUP0204144A3/hu
Priority to BR0016463-1A priority patent/BR0016463A/pt
Application filed by The Procter & Gamble Company filed Critical The Procter & Gamble Company
Priority to KR1020027007608A priority patent/KR20020062339A/ko
Priority to AU20969/01A priority patent/AU2096901A/en
Priority to JP2001544693A priority patent/JP2003516972A/ja
Priority to MXPA02005957A priority patent/MXPA02005957A/es
Publication of WO2001044203A1 publication Critical patent/WO2001044203A1/fr
Priority to NO20022844A priority patent/NO20022844L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D233/66—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 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
    • C07D233/68—Halogen 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
    • C07D233/66—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 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
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • 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
    • C07D233/66—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 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
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the subject invention relates to novel imidazo-containing compounds, pharmaceutical compositions containing them, and their therapeutic or preventative use in the areas of cardiovascular, oncology, infectious and inflammatory diseases.
  • Rl is selected from alkyl, aryl, and heterocycle
  • R2 is selected from hydrogen, alkyl, aryl, and heterocycle
  • each R3 is independently selected from hydrogen, halo, alkyl, aryl, heterocycle, nitro, cyano, and unsubstituted or alkyl- or aryl- or heterocycle- substituted hydroxy, thio, amino, amide, formyl (acyl), carboxy, and carboxamide; two R3's on adjacent carbons may optionally together be alkylene or heteroalkylene, thereby forming a fused ring with the phenyl to which they are attached;
  • R4 is selected from hydrogen, halo, alkyl, aryl, heterocycle, and carboxy and its alkyl and aryl esters and amides;
  • R7 is selected from hydrogen, alkyl, aryl, and heterocycle
  • R8 is selected from hydrogen, alkyl, alkylacyl, arylacyl, alkylsulfonyl, and arylsulfonyl;
  • A is aryl or heterocycle; and an optical isomer, diestereomer or enantiomer thereof; a pharmaceutically acceptable salt, hydrate, or biohydrolyzable ester, amide or imide thereof.
  • the subject invention also includes compositions comprising a subject compound and a pharmaceutically-acceptable excipient; and methods for treating or preventing diseases or disorders by administering to a human or lower animal in need thereof, a safe and effective amount of a subject compound.
  • alkyl means a hydrocarbon chain which is branched, linear or cyclic, saturated or unsaturated (but not aromatic), substituted or unsubstituted.
  • alkyl may be used alone or as part of another word where it may be shortened to "alk” (e.g., in alkoxy, alkylacyl).
  • Preferred linear alkyl have from one to about twenty carbon atoms, more preferably from one to about ten carbon atoms, more preferably still from one to about six carbon atoms, still more preferably from one to about four carbon atoms; most preferred are methyl or ethyl.
  • Preferred cyclic and branched alkyl have from three to about twenty carbon atoms, more preferably from three to about ten carbon atoms, more preferably still from three to about seven carbon atoms, still more preferably from three to about five carbon atoms.
  • Preferred cyclic alkyl have one hydrocarbon ring, but may have two, three, or more, fused hydrocarbon rings.
  • Preferred alkyl are unsaturated with from one to about three double or triple bonds, preferably double bonds; more preferably they are mono- unsaturated with one double bond. Still more preferred alkyl are saturated. Saturated alkyl are referred to herein as "alkanyl".
  • alkyl unsaturated only with one or more double bonds (no triple bonds) are referred to herein as "alkenyl”.
  • Preferred substituents of alkyl include halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl and aryl esters and amides, nitro, and cyano. Also, unsubstituted alkyl are preferred.
  • heteroatom means a nitrogen, oxygen, or sulfur atom.
  • alkyl ⁇ ne means an alkyl which connects two other moieties
  • heteroalkylene means an alkylene having one or more heteroatoms in the connecting chain.
  • aryl means an aromatic hydrocarbon ring (or fused rings) which is substituted or unsubstituted.
  • aryl may be used alone or as part of another word (e.g., in aryloxy, arylacyl).
  • Preferred aryl have from six to about fourteen, preferably to about ten, carbon atoms in the aromatic ring(s), and a total of from about six to about twenty, preferably to about twelve, carbon atoms.
  • Preferred aryl is phenyl or naphthyl; most preferred is phenyl.
  • Preferred substituents of aryl include halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl and aryl esters and amides, nitro, and cyano. Also, unsubstituted aryl are preferred.
  • heterocycle means a saturated, unsaturated or aromatic cyclic hydrocarbon ring (or fused rings) with one or more heteroatoms in the hydrocarbon ring(s).
  • Preferred heterocycles have from one to about six heteroatoms in the ring(s), more preferably one or two or three heteroatoms in the ring(s).
  • Preferred heterocycles have from three to about fourteen, preferably to about ten, carbon plus heteroatoms in the ring(s), more preferably from three to about seven, more preferably still five or six, carbon plus heteroatoms in the rings(s); and a total of from three to about twenty carbon plus heteroatoms, more preferably from three to about ten, more preferably still five or six, carbon plus heteroatoms.
  • Preferred heterocycles have one ring, but may have two, three, or more, fused rings. More preferred heterocycle rings include those which are one ring with 5 or 6 carbon plus heteroatoms in the ring with no more than three ring heteroatoms, no more than two of which are O and S. Still more preferred are such 5- or 6-ring atom heterocycles with one or two ring atoms being O or S and the others being C; or with one, two or three ring atoms being N and the others being C. Such preferred 5- or 6-ring atom heterocycles are preferably saturated, unsaturated with one or two double bonds, or aromatic.
  • Such preferred 5- or 6-ring atom heterocycles are preferably a single ring; or fused with a 3- to 6-ring atom hydrocarbon ring which is saturated, unsaturated with one double bond, or aromatic (phenyl); or fused with another such 5- or 6-ring atom heterocyclic ring.
  • Heterocycles are unsubstituted or substituted.
  • Preferred heterocycle substituents are the same as for alkyl.
  • Rl is selected from alkyl, aryl, and heterocycle.
  • Preferred Rl includes linear alkanyl having from 1 to about 6 carbon atoms, linear alkenyl having from 2 to about 6 carbon atoms, and branched and cyclic alkanyl and alkenyl having from 3 to about 6 carbon atoms, such alkenyl preferably having 1 double bond.
  • Such preferred alkanyl and alkenyl are preferably unsubstituted or substituted; if substituted, preferably with aryl, heterocycle, amino, hydroxy, cyano, carboxy and its esters and amides; more preferably with phenyl, heterocycle having 5 or 6 ring atoms, carboxy and its Cj-Cg alkyl and phenyl esters, or cyano. More preferably such alkanyl and alkenyl have up to about 5 carbon atoms, more preferably still up to 4 carbon atoms. More preferred Rl is methyl, ethyl or isopropyl. Most preferred Rl is unsubstituted methyl.
  • R2 is selected from hydrogen, alkyl, aryl, and heterocycle.
  • Preferred R2 includes hydrogen, linear alkanyl having from 1 to about 6 carbon atoms, linear alkenyl having from 2 to about 6 carbon atoms, and branched and cyclic alkanyl and alkenyl having from 3 to about 6 carbon atoms, such alkenyl preferably having 1 double bond.
  • Such preferred alkanyl and alkenyl are preferably unsubstituted or substituted; if substituted, preferably with aryl, heterocycle, amino, hydroxy, cyano, carboxy and its esters and amides; more preferably with phenyl, heterocycle having 5 or 6 ring atoms, carboxy and its Ci -Cg alkyl and phenyl esters, or cyano. More preferably such alkanyl and alkenyl have up to about 5 carbon atoms, more preferably still up to 4 carbon atoms. More preferred Rl is methyl, ethyl or isopropyl. Most preferred Rl is hydrogen.
  • each R3 is each independently selected from hydrogen, halo, alkyl, aryl, heterocycle, nitro and cyano; also from hydroxy, thio, amino, amide, formyl (acyl), carboxy, and carboxamide which are unsubstituted or substituted, preferably with alkyl or aryl or heterocycle; or two R3 together are alkylene or heteroalkylene attached to adjacent carbon atoms of the phenyl ring, thereby forming a cycloalkyl or aryl or heterocycle ring which is fused to the phenyl ring.
  • Preferred R3 are independently selected from hydrogen, halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl or aryl esters and amides; more preferably from hydrogen, halo, C1 -C4 alkyl, thio, C1-C4 alkylthio, C1-C4 mono-or dialkylamino, and C1-C4 alkylacyl.
  • R3's being halo, the others being hydrogen. Also more preferred is for from one to three R3's being methyl or ethyl, the others being hydrogen. Also preferred is one R3 being dialkylamino, the alkyls having from 1 to about 6 carbon atoms, preferably from about 1 to about 4 carbon atoms, and the others being hydrogen, such R3 preferably being attached to the 4' carbon. More preferred still is for from one to three R3's being independently selected from F, Cl and Br, the others being hydrogen; still more preferred, when two or three R3's are F, Cl or Br, they are the same. Also more preferred is from one to three R3's being unsubstituted methyl, the others being hydrogen. Also more preferred is one or two R3's being trifluoromethyl, the others being hydrogen.
  • R3's which are attached to adjacent carbon atoms of the phenyl ring, together being a saturated or unsaturated alkylene or heteroalkylene having from 1 to about 6 carbon atoms and from 0 to about 3 heteroatoms, thus forming a ring fused to the phenyl, such ring having from about 5 to about 8 ring atoms.
  • Such ring fused to the phenyl preferably has from about 5 to about 6 ring atoms of which from 0 to 2, more preferably 0 or 1, are heteroatoms.
  • Preferred fused rings include naphthyl, indolyl, benzimidazoyl, benzofuryl, benzopyranyl.
  • R3's When two R3's form a ring fused with the phenyl, other R3's are preferably H.
  • R4 is selected from hydrogen, halo, alkyl, aryl, heterocycle, carboxy and its alkyl esters and amides.
  • Preferred R4 is selected from hydrogen, halo, Ci -C4 alkyl, phenyl. More preferred R4 is selected from hydrogen and unsubstituted and substitituted phenyl; substituents on such phenyl are preferably selected from hydroxy, alkoxy, thio and alkylthio. Most preferred R4 is hydrogen.
  • R7 is selected from hydrogen, alkyl, aryl, and heterocycle.
  • Non- hydrogen R7 are preferably phenyl, or alkyl having from 1 to about 4 carbon atoms, preferably 1 or 2 carbon atoms. Such non-hydrogen R7 are preferably unsubstituted.
  • Alkyl R7 are preferably saturated. More preferably R7 is hydrogen.
  • R8 is selected from hydrogen, alkyl, alkylacyl, arylacyl, alkylsulfonyl, and arylsulfonyl.
  • Preferred R8 is selected from hydrogen; C1 -Cg alkyl, such alkyl being saturated or unsaturated with one double bond and unsubstituted or substituted with phenyl; C1 -C alkylacyl, the alkyl being saturated or unsaturated with one double bond; and phenylacyl. More preferred is the alkyl portions of the aforementioned moieties being C1-C4 and saturated. More preferred still is R8 being methyl. Most preferred R8 is hydrogen.
  • A is aryl or heterocycle.
  • Preferred A includes phenyl, naphthyl, furyl, pyridinyl, pyrrolyl, thienyl, thiazolyl, and imidazolyl; more preferred are phenyl and naphthyl.
  • phenyl fused with a heterocycle preferred heterocycles fused with phenyl include furyl, thienyl, dioxanyl, thiazolyl, imidazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, and piperidinyl.
  • A is phenyl fused with another ring
  • A is preferably attached to the remainder of structure 1 at a carbon of the phenyl, and the heterocycle ring is preferably fused at any other two adjacent carbon atoms of the phenyl, more preferably at carbons 3-4 of the phenyl.
  • Each ring carbon of A is unsubstituted or substituted; preferably no more than three ring carbons of A are substituted; more preferably no more than one ring carbon of A is substituted.
  • Preferred substituents of A when A is phenyl or naphthyl, are selected from halo, alkyl, aryl, heterocycle, cyano and nitro; also from hydroxy, thio, amino, amide, amido, formyl (acyl), carboxy, carboxamide, and sulfonamide which are unsubstituted or substituted, preferably with alkyl or aryl or heterocycle.
  • substituents of phenyl and naphthyl A are selected from halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, sulfonamide, alkylsulfonamide, arylsulfonamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl and aryl esters and amides; more preferred still from halo, hydroxy, C1-C4 alkoxy, thio, C1-C4 alkylthio, C1 -C4 alkyl esters and amides of carboxy, phenyl, and heterocycle having 5 or 6 ring atoms 1-3 of which are heteroatoms.
  • Preferred substituents of A when A is heterocycle are selected from alkyl, aryl, alkoxy, and aryloxy. More preferred substituents of heterocycle A are selected from C1-C4 alkyl or C1 -C4 alkoxy.
  • the subject invention includes optical isomers, diastereomers, and enantiomers of the compounds of structure 1.
  • the subject invention includes pharmaceutically-acceptable salts, hydrates, and biohydrolizable esters, amides and imides of such compounds.
  • a “pharmaceutically-acceptable salt” is a cationic salt formed at any acidic group (e.g., carboxy group), or an anionic salt formed at any basic group (e.g., amino group) on a compound of structure 1.
  • Preferred cationic salts include the alkali metal salts, such as sodium and potassium, alkaline earth metal salts, such as magnesium and calcium, and organic salts, such as ammonium.
  • Preferred anionic salts include halides, sulfonates, carboxolates, phosphates, and the like. Salts of addition may provide an optical center where once there was none.
  • the compounds of the subject invention, and salts thereof, may have one or more chiral centers.
  • the invention includes all optical isomers of the compounds of structure 1 and salts thereof, including diastereomers and enanteomers
  • the subject invention includes and contemplates each optical isomer, diastereomer or enanteomer thereof, in purified form, substantially purified form, and mixtures, including racemic mixtures.
  • Preferred compounds of the subject invention include those having structure 2:
  • Rl, R2, R3's, R7, and A are as described hereinabove.
  • Rl is preferably selected from linear alkanyl having from one to four carbon atoms, linear alkenyl having one double bond and from two to four carbon atoms, branched and cyclic alkanyl having from three to five carbon atoms, and branched and cyclic alkenyl having one double bond and from three to five carbon atoms.
  • Such preferred Rl is unsubstituted or substituted with one phenyl, more preferably is unsubstituted.
  • Rl is selected from methyl, ethyl, ethenyl, n-propyl, i-propyl, n-propenyl, i- propenyl, s-butyl, cyclopropyl, cyclobutyl, and cyclopentyl. More preferred still Rl is selected from methyl, ethyl, ethenyl, i-propyl, and n-propenyl. Still more preferred Rl is methyl.
  • R2 is preferably hydrogen or includes the same preferences of moieties as stated for Rl in the immediately preceding paragraph, R2 being independent of Rl . More preferred R2 is hydrogen or the same as Rl . Most preferred R2 is hydrogen.
  • the R3's are preferably selected from all hydrogen; mono-, di-, or trihalo, preferably selected from fluoro, chloro and bromo, preferably in one or more of the 2', 3', 4' and 5' positions; mono- di-, and trimethyl, preferably in one or more of the 2', 3', 4' and 6' positions; and mono- or di-trifluoromethyl, preferably in one or both of the 3' and 5' positions.
  • one R3 being diakylamino, preferably in the 4' position, the two alkyls preferably being the same and preferably having from 1 to 4 carbon atoms, and the other R3's being hydrogen.
  • R3's are selected from 4'- fluoro, 4'-chloro, 4'-bromo, 2',4'-difluoro, 2',4'-dichloro, 2',4'-dibromo, 2',4',5'-trifluoro, 2',4',5'-trichloro, 3',4'-difluoro, 3',4'-dichloro, 3',4'-dibromo, 4'-methyl.
  • R3 combinations are selected from 2',4'-dihalo and 3',4'-dihalo, where one halo is selected from fluoro, chloro, and bromo, and the other halo is a different one of those three; more preferably one of such halo is fluoro, all other R3's having hydrogen. Most preferred R3 combinations are selected from 4'-chloro, 4'-bromo, and 2',4'-dichloro, all other R3's being hydrogen.
  • R7 is preferably hydrogen or methyl.
  • A is preferably unsubstituted or substituted phenyl, naphthyl, or pyridyl; more preferably substituted phenyl, or unsubstituted naphthyl, or unsubstituted 2- pyridyl.
  • Non-limiting examples of compounds of the subject invention include those of structure 2 wherein R2 is H and Rl, R3's, R7, and A are as indicated in the following table (R3's not specified are all hydrogen):
  • the order of synthetic steps may be varied to increase yield of desired product.
  • the skilled artisan will recognize that the judicious choice of reactants, solvents, and temperatures is important in successful synthesis.
  • the starting materials used in preparing the subject compounds are known, made by known methods, or are commercially available.
  • Pd(PPh3)4 (0.0177g, 0.015 mmol) is added to a solution of stannylimidazole D (0.51 g, 0.80 mmol), 4,5-dimethoxy-2-(2-hydroxyethyl)phenyl bromide E (0.33 g, 1.1 mmol), and LiCl (0.087 g, 2.1 mmol) in anhydrous dioxane (4.0 mL) at room temperature.
  • the resulting solution is then extracted with EtOAc (2 x 100 ml) and methylene chloride (2 x 100 ml), and the combined organic layers are dried over MgS0 4 , filtered and stripped to a pale yellow solid which is used without further purification (8.3 g).
  • the solid is dissolved in 150 ml methylene chloride and 11.64 g (52.6 mmol) of MCPBA (80% by weight) is added.
  • the reaction is stirred at room temperature for 14 h, and then diluted with 450 ml methylene chloride.
  • the resulting solution is washed with Na 2 C0 3 (aq., 2 x 450 ml), and the water is back extracted with methylene chloride (450 ml).
  • the combined organic layers are then dried over MgS0 4 , filtered and stripped to yield 7.76 g (83%) of the desired product (B) as a pale yellow solid.
  • N-bromosuccinimide (NBS) solid (98 mg, 0.26 mmol) is added to a solution of compound F (0.5 mmol) in 15 mL of CCI4. Radical initiator benzoyl peroxide (2 mol %) is subsequently added. The flask is placed into a 90 °C oil bath. After 10 min stirring, the reaction is complete. Filtration of the mixture through a celite pad, and evaporation of the filtrate gives a residue. Purification by chromatography (EtOAc:hexane, 1:3 to 1:1) affords compound K.
  • the filtrate is treated with 3 mL of 30% aqueous KF at room temperature for 2h.
  • the solid is filtered off.
  • the filtrate is diluted with CH2CI2 and washed with water, 30% aqueous NH4OH (3X), brine, extracted with EtOAc, dried (Na2S04), and concentrated in vacuo to yield crude product. Chromatography purification (silica gel, EtOAc :hexane, 1 :1 to 1 :0) yields compound L.
  • compositions of the invention comprises: a) a safe and effective amount of a compound of the invention; and b) a pharmaceutically-acceptable excipient.
  • such composition comprises several excipients. It may also optionally comprise other active compounds which do not substantially interfere with the activity of the subject invention compound.
  • compositions of the subject invention may be in any of a variety of forms, suitable (for example) for oral, rectal, topical or parenteral administration.
  • Compositions of the subject invention are preferably provided in unit dosage form.
  • a "unit dosage form" is a composition containing an amount of a subject compound that is suitable for administration to a human or lower animal subject, in a single dose, according to good medical practice.
  • a "safe and effective amount" of a subject compound is an amount large enough to significantly induce a positive modification in the symptoms and/or condition to be treated in a host, but small enough to avoid serious adverse side effects in the host (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio.
  • the safe and effective amount will vary with such factors as the particular condition being treated, the age and physical condition of the patient, the duration of treatment, the nature of concurrent therapy (if any), the specific dosage form to be used, and the dosage regimen employed.
  • pharmaceutically-acceptable excipient includes physiologically inert, pharmacologically inactive substances which are compatible with the physical and chemical characteristics of the subject invention compound used, and which are of sufficiently high purity and sufficiently low toxicity to be suitable for administration to a human or lower animal.
  • compatible means that the excipients of the subject composition are capable of being commingled with the subject invention compound, and with each other in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the compound, under ordinary use situations.
  • Excipients include, but are not limited to, polymers, resins, plasticizers, fillers, binders, lubricants, glidants, disintegrants, solvents, co-solvents, buffer systems, surfactants, preservatives, sweetening agents, flavoring agents, and dyes or pigments.
  • the amount of excipients employed in conjunction with the subject compound is sufficient to provide a practical quantity of material for administration per unit dose of the subject compound.
  • substances which can serve as pharmaceutically-acceptable excipients are sugars, such as lactose, dextrose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose and its derivatives, such as methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylcellulose and cellulose acetate; polymers, such as povidone and carbomers; powdered tragacanth; gums, such as xanthan, guar and acacia; malt; solid lubricants, such as stearic acid, magnesium stearate, and talc; inorganic fillers, such as calcium phosphates and calcium sulfate; disintigrants, such as sodium starch glycolate, crospovidone, croscarmelose sodium, and microcrystalline cellulose; encapsulating and coating materials, such as gelatins, waxes, and cellulose derivatives; vegetable oils, such as peanut oil.
  • sugars such as lactose,
  • cottonseed oil, sesame oil, olive oil, corn oil and oil of the obroma polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol
  • alginic acid such as the Tweens®, alkyl sulfate salts, salts of fatty acids, sucrose esters; ethyl oleate; coloring agents; flavoring agents; tableting agents; stabilizers; antioxidants; preservatives
  • solvents such as ethanol, pyrogen-free water; isotonic saline; and buffer solutions, such as phosphoric, tartaric, citric, and acetic acids, and their sodium, potassium, and ammonium salts.
  • compositions of the subject invention are oral dosage forms.
  • oral dosage form means any pharmaceutical composition intended to be systemically administered to an individual by delivering the composition via the mouth to the gastrointestinal tract of an individual.
  • oral unit dosage forms such as tablets, coated or non-coated, and capsules, hard or soft gel.
  • Subject oral unit dosage form compositions comprise preferably at least about 4 mg, more preferably at least about 20 mg, more preferably still at least about 100 mg, and preferably at most about 1000 mg, more preferably at most about 500 mg, more preferably still at most about 250 mg. of a subject compound.
  • Subject oral dosage form compositions comprise preferably at least about 1%, more preferably at least about 10%, and preferably at most about 70%, more preferably at most about 40%, of a subject compound; and comprise preferably at least about 30%, more preferably at least about 60%, and preferably at most about 99%, more preferably at most about 90%, pharmaceutically-acceptable excipients.
  • Parenteral dosage forms are also preferred subject invention compositions.
  • the term "parenteral dosage form", as used herein, means any pharmaceutical composition intended to be systemically administered to a human or lower animal via delivery of a solution or emulsion containing the active ingredient, by puncturing the skin of the individual, in order to deliver the solution or emulsion to the circulatory system of the individual either by intravenous, intramuscular, intraperitoneal or subcutaneous injection.
  • Subject parenteral unit dosage form compositions comprise preferably at least about 1 mg, more preferably at least about 6 mg, more preferably still at least about 30 mg, and preferably at most about 400 mg, more preferably at most about 100 mg, more preferably still at most about 40 mg, of a subject compound.
  • Subject parenteral dosage form compositions comprise preferably at least about 1%, more preferably at least about 5%, and preferably at most about 20%, more preferably at most about 10%, of a subject compound; and comprises preferably at least about 80%, more preferably at least about 90%, and preferably at most about 99%, more preferably at most about 95%, pharmaceutically- acceptable excipients.
  • dosages for injection may be prepared in dried or lyophilized form. Such forms can be reconstituted with water, saline solution, or a buffer solution, depending on the preparation of the dosage form. Such forms may be packaged as individual dosages or multiple dosages for easier handling. Where lyophilized or dried dosages are used, the reconstituted dosage form is preferably isotonic, and at a physiologically compatible pH, and comprises the subject compound and excipients in the amounts and percentages indicated previously in this paragraph.
  • Subject invention compounds have demonstrated pharmacological activity in processes known to be associated with one or more of cardiovascular activity, inflammatory mechanisms, oncology, and regulation of protein transport from cells.
  • the subject invention includes methods of using the above compounds of the subject invention for therapeutic or preventative treatment of one or more of the following diseases or disorders: congestive heart failure, arrhythmia, hypotension, cardiac reperfusion injury, arteriosclerosis, restenosis, vascular tone, bacterial infection, cancer, Kaposi's sarcoma, psoriasis, migraine, nasal congestion, allergic responses, rheumatoid arthritis, and osteoporosis.
  • Such methods comprise administering to a human or lower animal in need of such treatment or prevention a safe and effective amount of a subject invention compound.
  • a subject compound is administered to a human or lower animal, preferably at least about 1 time, more preferably at least about 2 times, and preferably at most about 4 times, more preferably at most about 2 times, daily.
  • Treatment duration using such oral daily dosages is dependent on the disease or disorder being treated; it is preferably at least about 1 day, more preferably at least about 3 days, more preferably still at least 7 days, and preferably at most about 5 years, more preferably at most about 60 days, more preferably still at most about 15 days.
  • a subject compound is administered to a human or lower animal, preferably at least about 1 time, more preferably at least about 2 times, and preferably at most about 4 times, more preferably at most about 2 times, daily.
  • Treatment duration using such parenteral daily dosages is dependent on the disease or disorder being treated; it is preferably at least about 1 day, more preferably at least about 3 days, more preferably still at least 7 days, and preferably at most about 60 days, more preferably at most about 20 days, more preferably still at most about 5 days.

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Abstract

L'invention concerne des composés ayant la structure (1) dans laquelle chaque R1 représente indépendamment alkyle, aryle ou un hétérocycle; chaque R2, R4, R7 et R8 représente indépendamment hydrogène ou un autre substituant; A représente aryle ou un hétérocycle; et leurs formes pharmaceutiquement acceptables. La présente invention concerne également des compositions pharmaceutiques contenant ces composés, ainsi que des méthodes de traitement ou de prévention de maladies ou de troubles à l'aide de ces composés.
PCT/US2000/033820 1999-12-17 2000-12-14 Composes de n-(1-phenylethyl)-5-phenyl-imidazole-2-amine, leurs compositions et utilisations WO2001044203A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
US10/149,880 US6596739B2 (en) 2000-03-29 2000-12-14 N-(1-phenylethyl)-5-phenyl-imidazole-2-amine compounds, their compositions and uses
IL14974900A IL149749A0 (en) 1999-12-17 2000-12-14 N-(1-phenylethyl)-5-phenylimidazole-2-amine compounds, their compositions and uses
CA002394570A CA2394570A1 (fr) 1999-12-17 2000-12-14 Composes de n-(1-phenylethyl)-5-phenyl-imidazole-2-amine, leurs compositions et utilisations
HU0204144A HUP0204144A3 (en) 1999-12-17 2000-12-14 N-(1-phenylethyl)-5-phenyl-imidazole-2-amine compounds, their compositions and uses
BR0016463-1A BR0016463A (pt) 1999-12-17 2000-12-14 Compostos de n-(1-feniletil)-5-fenil-imidazol-2-amina, suas composições e usos
EP00984333A EP1237876A1 (fr) 1999-12-17 2000-12-14 Composes de n-(1-phenylethyl)-5-phenyl-imidazole-2-amine, leurs compositions et utilisations
KR1020027007608A KR20020062339A (ko) 1999-12-17 2000-12-14 Ｎ-(1-페닐에틸)-5-페닐-이미다졸-2-아민 화합물, 이의조성물 및 그의 용도
AU20969/01A AU2096901A (en) 1999-12-17 2000-12-14 N-(1-phenylethyl)-5-phenyl-imidazole-2-amine compounds, their compositions and uses
JP2001544693A JP2003516972A (ja) 1999-12-17 2000-12-14 Ｎ−（１−フェニルエチル）−５−フェニル−イミダゾール−２−アミン化合物と、その組成物及び使用
MXPA02005957A MXPA02005957A (es) 1999-12-17 2000-12-14 Compuestos de n-(feniletil)-5-feni-imidazol-2-amina, sus composiciones y usos.
NO20022844A NO20022844L (no) 1999-12-17 2002-06-14 N-(1-fenyletyl)-5-fenyl-imidazol-2-aminforbindelser, deres sammensetninger og anvendelser

Applications Claiming Priority (4)

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US17270999P 1999-12-17 1999-12-17
US60/172,709 1999-12-17
US19281100P 2000-03-29 2000-03-29
US60/192,811 2000-03-29

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7678810B2 (en) 2004-03-05 2010-03-16 Taisho Pharmaceutical Co., Ltd Thiazole derivative
US8906915B2 (en) 2009-12-17 2014-12-09 Katholieke Universiteit Leuven, K.U.Leuven R&D Compounds, compositions, and methods for controlling biofilms

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FR1508888A (fr) * 1966-01-25 1968-01-05 Geigy Ag J R Dérivés de l'imidazole et leur préparation
DD135724A1 (de) * 1978-04-14 1979-05-23 Annemarie Hetzheim Verfahren zur herstellung von 2-amino-3-phenacyl-benzoxazoliumhalogeniden und 2-amino-1-o-hydroxyphenyl-4-aryl-imidazolen
JPS54112864A (en) * 1978-02-22 1979-09-04 Teijin Ltd Novel imidazole derivative, its mineral acid salt, and their preparation
EP0044486A1 (fr) * 1980-07-21 1982-01-27 E.I. Du Pont De Nemours And Company 4,5-Diaryl-alpha-polyfluoroalkyl-1H-imidazole-2-méthanamines anti-inflammatoires
JPS6310767A (ja) * 1986-07-02 1988-01-18 Yoshitomi Pharmaceut Ind Ltd イミダゾ−ルカルボキサミド誘導体
WO2000069860A1 (fr) * 1999-05-19 2000-11-23 The Procter & Gamble Company Composes heterocycliques a contenu imidazo, preparations en etant faites, et leurs utilisations

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Publication number Priority date Publication date Assignee Title
FR1508888A (fr) * 1966-01-25 1968-01-05 Geigy Ag J R Dérivés de l'imidazole et leur préparation
JPS54112864A (en) * 1978-02-22 1979-09-04 Teijin Ltd Novel imidazole derivative, its mineral acid salt, and their preparation
DD135724A1 (de) * 1978-04-14 1979-05-23 Annemarie Hetzheim Verfahren zur herstellung von 2-amino-3-phenacyl-benzoxazoliumhalogeniden und 2-amino-1-o-hydroxyphenyl-4-aryl-imidazolen
EP0044486A1 (fr) * 1980-07-21 1982-01-27 E.I. Du Pont De Nemours And Company 4,5-Diaryl-alpha-polyfluoroalkyl-1H-imidazole-2-méthanamines anti-inflammatoires
JPS6310767A (ja) * 1986-07-02 1988-01-18 Yoshitomi Pharmaceut Ind Ltd イミダゾ−ルカルボキサミド誘導体
WO2000069860A1 (fr) * 1999-05-19 2000-11-23 The Procter & Gamble Company Composes heterocycliques a contenu imidazo, preparations en etant faites, et leurs utilisations

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Title
BLASS B E ET AL: "Parallel synthesis and evaluation of N-(1-phenylethyl)-5-phenyl-imida zole-2-amines as Na/KATPase inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,OXFORD,GB, vol. 10, no. 14, 17 July 2000 (2000-07-17), pages 1543 - 1545, XP004209698, ISSN: 0960-894X *
PATENT ABSTRACTS OF JAPAN vol. 003, no. 133 (C - 063) 7 November 1979 (1979-11-07) *
PATENT ABSTRACTS OF JAPAN vol. 012, no. 213 (C - 505) 17 June 1988 (1988-06-17) *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7678810B2 (en) 2004-03-05 2010-03-16 Taisho Pharmaceutical Co., Ltd Thiazole derivative
US8906915B2 (en) 2009-12-17 2014-12-09 Katholieke Universiteit Leuven, K.U.Leuven R&D Compounds, compositions, and methods for controlling biofilms

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CZ20021834A3 (cs) 2002-10-16
HUP0204144A2 (en) 2003-05-28
EP1237876A1 (fr) 2002-09-11
AU2096901A (en) 2001-06-25
CN1411449A (zh) 2003-04-16
PL356172A1 (en) 2004-06-14
BR0016463A (pt) 2002-08-27
KR20020062339A (ko) 2002-07-25
CA2394570A1 (fr) 2001-06-21
JP2003516972A (ja) 2003-05-20
HUP0204144A3 (en) 2003-07-28
NO20022844D0 (no) 2002-06-14
NO20022844L (no) 2002-08-19
CO5261516A1 (es) 2003-03-31
PE20010928A1 (es) 2001-09-12
IL149749A0 (en) 2002-11-10

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