WO2000005201A1 - Derives n-benzocycloalkyl-amide et leur utilisation comme medicaments - Google Patents

Derives n-benzocycloalkyl-amide et leur utilisation comme medicaments Download PDF

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Publication number
WO2000005201A1
WO2000005201A1 PCT/EP1999/005131 EP9905131W WO0005201A1 WO 2000005201 A1 WO2000005201 A1 WO 2000005201A1 EP 9905131 W EP9905131 W EP 9905131W WO 0005201 A1 WO0005201 A1 WO 0005201A1
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Prior art keywords
alkyl
amino
aryl
trifluoromethyl
substituted
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PCT/EP1999/005131
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English (en)
Inventor
Cynthia Anne Fink
Gary Michael Ksander
Paivi Jaana Kukkola
Eli Melville Wallace
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Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft Mbh
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Priority to CA002338198A priority Critical patent/CA2338198A1/fr
Priority to EP99936567A priority patent/EP1097129A1/fr
Priority to AU51613/99A priority patent/AU5161399A/en
Priority to JP2000561158A priority patent/JP2002521360A/ja
Publication of WO2000005201A1 publication Critical patent/WO2000005201A1/fr

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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/80—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino 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
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    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
    • C07C235/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/56—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C307/00—Amides of sulfuric acids, i.e. compounds having singly-bound oxygen atoms of sulfate groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C307/04—Diamides of sulfuric acids
    • C07C307/08—Diamides of sulfuric acids having nitrogen atoms of the sulfamide groups bound to carbon atoms of rings other than six-membered aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/07—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/20—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/14—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • 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
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    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/12—One of the condensed rings being a six-membered aromatic ring the other ring being at least seven-membered

Definitions

  • the invention relates to the compounds of formula
  • R 2 -C, R 3 -C, R -C or R 5 -C may be replaced by N; and wherein n is 1 , 2 or 3;
  • R is aryl, cycloalkyl or heterocyclyl
  • R 2 , R 3 , R 4 and R 5 are independently hydrogen, optionally substituted alkyl, halo, amino, substituted amino, trifluoromethyl, cyano, carboxyl, alkoxycarbonyl, aralkoxycarbonyl, (alkyl, aryl or aralkyl)-thio, (alkyl, aryl or aralkyl)-oxy, acyloxy, (alkyl, aryl or aralkyl)-aminocarbonyloxy; or any two of R 2 , R 3 , R 4 and R 5 at adjacent positions are alkylenedioxy;
  • R 6 is hydrogen, optionally substituted alkyl, amino, substituted amino, acylamino,
  • R a is hydrogen or optionally substituted alkyl
  • R b and R c are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; or R b and R c together represent lower alkylene or lower alkylene interrupted by
  • R d is optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl
  • R ⁇ is optionally substituted alkyl, aryl, heterocyclyl, cycloalkyl, amino or substituted amino; and pharmaceutically acceptable salts thereof; and enantiomers thereof.
  • MTP microsomal triglyceride transfer protein
  • ApoB apolipoprotein B
  • a particular embodiment of the invention relates to the compounds of formula I'
  • R 2 -C, R 3 -C, R 4 -C or R 5 -C may be replaced by N; and wherein n, and RrR 6 have meaning as defined above; pharmaceutically acceptable salts thereof; and enantiomers thereof.
  • X is R -C or N; and n, and RrR 6 have meaning as defined above.
  • Ri represents heterocyclyl, in particular aromatic heterocyclyl (heteroaryl);
  • R 6 is amino, substituted amino or acyiamino; (g) R 6 is
  • n 1 ; R ⁇ , is monocyciic aryl or heteroaryl; X is R 2 -C or N; R 2 , R 3l R 4 and R 5 are independently hydrogen, lower alkyl, halo, trifluoromethyl, lower alkoxy or amino; and R 6 is amino, substituted amino, acylamino,
  • R a is hydrogen
  • R and R c are independently hydrogen, lower alkyl, aralkyl, aryl, heteroaryl or heteroaralkyl; or R b and R c together with the nitrogen represent piperidino, morpholino, pyrrolidino, or N-lower alkylpiperazino
  • R d and R e are lower alkyl, aralkyl, aryl, heteroaryl or heteroaralkyl; and pharmaceutically acceptable salts thereof.
  • Preferred are the compounds of formula I, I' or la wherein R 6 is located on the 5-, 6- or 7- membered saturated ring (n 1 , 2, or 3) at a position not directly adjacent to the ring junction (non-benzylic position).
  • R 2 -C, R 3 -C, R 4 -C or R 5 -C may be replaced by N; wherein n is 1 , 2 or 3;
  • Ri is phenyl or thienyl which in each case is unsubstituted or substituted by a substituent selected from the group consisting of lower alkyl, lower alkoxy, halo, trifluoromethyl, cyano, and trifluoromethoxy;
  • R 2 , R 3 , R 4 and R 5 are independently hydrogen, lower alkyl, lower alkoxy, halo, trifluoromethyl, amino, lower alkyiamino, di-lower aikyl amino, or lower alkanoyl-amino;
  • R 6 is amino, phenyl-lower alkyl-amino, lower alkanoyl-amino, lower alkanoyl-amino in which the alkyl group of the alkanoyl group is substituted by phenyl, by lower alkoxy, by phenoxy, by lower alkylthio, by phenylthio, by di-lower aI.kylamino, by morpholino, by thiomo ⁇ holino, by piperazino, or by 4-lower alkyl-piperazino, or is N-methyl-N'-lower alkanoyl-amino, benzoyl-amino, or isoxazolylcarbonyl-amino in which isoxazoyl is unsubstituted or substituted by lower alkyl, or is
  • R a is hydrogen or alkyl
  • R and R c are independently hydrogen, lower alkyl, 5- to 7-membered cycloalkyl, or phenyl; or R and R c together are morpholino, thiomo ⁇ hoiino or lower alkylene;
  • R d is lower alkyl, lower alkyl substituted by lower alkoxy, by lower alkoxy-lower alkoxy, by mo ⁇ holino, by thiomo ⁇ holino, by 2-oxo-1 -pyrrolidino, by pyridyl, by phenyl, or by phenyl which is substituted by a substituent selected from halo, trifluoromethyl, lower alkyl, and lower alkoxy, or is phenyl, phenyl substituted by substituent selected from halo, trifluoromethyl, lower alkyl, and lower alkoxy, or is 5- to 7-membered cycloalkyl, or pyranyl; and
  • R ⁇ is lower alkyl, phenyl-lower alkyl, phenyl which is unsubstituted or substituted by a group selected from lower alkyl, lower alkoxy, halo, trifluoromethyl, and lower alkane- sulphonyl, or is naphthyl, thienyl, furyl, isoxazolyl, imidazolyi or quinolinyl each of which is unsubstituted or substituted by a group selected from lower alkyl, halo and trifluoromethyl, or is lower alkyl-amino, di-lower alkyl-amino or 5- to 7-membered cycloalkyl-amino; and pharmaceutically acceptable salts thereof; and enantiomers thereof.
  • a particular aspect of the invention relates to the indane derivatives of formula lb
  • Ar is monocyclic aryl or heteroaryl;
  • X is R 2 -C or N;
  • R 2 , R 3 , R 4 and R 5 are independently hydrogen, lower alkyl, halo, trifluoromethyl, cyano, or lower alkoxy; and R 6 has meaning as defined above in each case.
  • R 2 , R 3 and R are independently hydrogen, CrC 4 -alkyl, CrC 4 alkoxy, trifluoromethyl, chloro or fluoro; R 7 is trifluoromethyl, chloro or cyano; and R 6 is
  • R d is C ⁇ -C 4 -alkyl
  • R e is C ⁇ -C 4 -alkyl, monocyclic carbocyclic aryl or heterocyclic aryl.
  • a particular embodiment relates to the compounds of formula ic wherein R 2 is methyl; R 3 is hydrogen; R 4 is hydrogen or methyl; R 6 is -NHSO 2 R ⁇ wherein R ⁇ is methyl or thienyl; and R 7 is trifluoromethyl.
  • Another embodiment relates to the compounds of formula Ic wherein R 2 is methyl; R 3 is hydrogen; R 4 is hydrogen or methyl; R 6 is
  • R d is methyl; and R7 is trifluoromethyl.
  • optionally substituted alkyl refers to unsubstituted or substituted straight or branched chain hydrocarbon groups having 1 to 20 carbon atoms, preferably lower alkyl of 1 to 7 carbon atoms.
  • exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like.
  • substituted alkyl refers to alkyl groups substituted by one or more of the following groups: halo (such as CCI 3 or CF 3 ), hydroxy, alkoxy, alkoxyalkoxy, aryloxy, cyclo- Ikyl, alkanoyl, alkanoyloxy, amino, substituted amino, alkanoylamino, thiol, alkylthio, arylthio, alkylthiono, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, nitro, cyano, carboxy, carbamyl, alkoxycarbonyl, aryl, aralkoxy, guanidino, heterocyclyl ⁇ e.g., indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimididyl,
  • lower alkyl refers to those alkyl groups as described above having 1 to 7, preferably 1 to 4 carbon atoms.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • haloalkyl refers to alkyl which mono- or poiysubstituted by halo, such as trifluoromethoxy.
  • alkylene refers to a straight chain bridge of 1 to 6 carbon atoms connected by single bonds (e.g., -(CH 2 ) ⁇ - wherein x is 1 to 6) which may be substituted with 1 to 3 lower alkyl groups.
  • alkylene interrupted by O, S, N-(H, alkyl or aralkyl refers to a straight chain of 2 to 6 carbon atoms which is interrupted by O, S, N-(H, alkyl or aralkyl), such as (m)ethyleneoxy(m)ethylene, (m)ethylenethio(m)ethylene, or (m)ethyieneimino(m)ethylene.
  • cycloalkyl refers to cyclic hydrocarbon groups of 3 to 8 carbon atoms such as cyclopentyl, cyclohexyl or cycloheptyi.
  • alkoxy or "alkyloxy” refers to alkyl-O-.
  • alkanoyl refers to alkyl-C(O)-.
  • alkanoyloxy refers to alkyl-C(O)-O-.
  • alkylamino and “dialkylamino” refer to (alkyl)NH- and (alkyl)2N-, respectively.
  • alkanoylamino refers to alkyl-C(O)-NH-.
  • alkylthio refers to alkyl-S-.
  • alkylt iono refers to alkyl-S(O)-.
  • alkylsulfonyl refers to al yl-S(0) 2 -.
  • carboxylate refers to -C(O)-amino or -C(O)-substituted am o.
  • alkoxycarbonyl refers to alkyl-O-C(O)-.
  • acyl refers to alkanoyl, aroyl, heteroaryol, aryl-alkanoyl, heteroarylalkanoyl, and the like.
  • aryl refers to monocyciic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ⁇ ng portion, such as phenyl, naphthyl, tetrahydronaphthyl, and biphenyl groups, each of which may optionally be substituted by one to four substituents such as alkyl, halo, trifluoromethyl, hydroxy, alkoxy, halo-alkyl, alkanoyl, alkanoyloxy, ammo, substituted amino, alkanoylamino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, alkylsulfonyl, aminosulfonyl, heterocyclyl and the like.
  • aralkyl refers to an aryl group linked to an alkyl group, such as benzyl.
  • aralkoxy refers to an aryl group linked to an alkoxy group, such as locozyloxy.
  • arylsulfonyl refers to aryl-SO 2 -.
  • aroyl refers to aryl-CO-.
  • heterocyclyl refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyciic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyciic 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 atom.
  • Exemplary monocyciic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazoiidinyl, oxazolyl, oxazoiidinyl, isoxazohnyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazoiidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, pipendinyl, piperaz yl, 2-oxop ⁇ peraz ⁇ nyl, 2-oxop ⁇ pe ⁇ d ⁇ nyl, 2-oxopyrrolod ⁇ nyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, pyr
  • bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, couma ⁇ nyl, benzopyranyl, cinnolinyl, quinoxaiinyl, indazolyl, pyrrolopyndyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyndinyl), dihydroisoindolyl, dihydroqumazolinyl (such as 3,4-dihydro-4-oxo-qu ⁇ nazolinyl) and the like.
  • Exemplary tricyciic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, ac ⁇ dinyl, phenanthridinyl, xanthenyl and the like.
  • heterocyclyl also includes substituted heterocyclic groups.
  • Substituted heterocyclic groups refer to heterocyclic groups substituted with 1 , 2 or 3 of the following:
  • (l) alkoxycarbonyl such as unsubstituted lower alkoxycarbonyl
  • (x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, ammo, alkylammo, dialkylamino or halo.
  • heterocyclic group denotes a heterocyclic group bonded through an oxygen bridge.
  • heteroaryl refers to an aromatic heterocycle, for example monocyciic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl, and the like, optionally substituted by e.g., lower alkyl, lower alkoxy or halo.
  • heteroarylsulfonyl refers to heteroaryl-SO 2 -.
  • heteroaroyl refers to heteroaryl-CO-.
  • acylamino refer to acyl-NH-.
  • substituted amino refers to amino mono- or, independently, disubstituted by alkyl, aralkyl, aryl, heteroaryl, cycloalkyl, cycloalkylaikyl, heteroaralkyl, or disubstituted by lower alkylene or lower alkylene interrupted by O, S, N-(H, alkyl, aralkyl) and the like.
  • salts of any acidic compounds of the invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyiammonium, diethylammonium, and tris-(hydroxymethyl)- methylammonium salts.
  • bases namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethyiammonium, diethylammonium, and tris-(hydroxymethyl)- methylammonium salts.
  • acid addition salts such as of mineral acids, organic carboxylic, and organic sulfonic acids e.g., hydrochloric acid, methanesulfonic acid, maieic acid, are possible provided a basic group, such as amino or pyridyl, constitutes part of the structure.
  • BOC is the protecting group t-butoxycarbonyl, with e.g, an activated carboxyl derivative, e.g. a compound of formula III
  • R R 5 and X have meaning as defined above, in the presence of a base such as N-methylmo ⁇ holine, diisopropylethylamine or pyridine to provide compounds of the formula IV
  • Compounds of formula V are then treated with an electrophile corresponding to the amino substituent in R 6 , such as an appropriately substituted sulfonyl chloride (e.g., phenylsulfonyl chloride), a chloroformate (e.g., methyl chloroformate), an acid chloride (e.g., acetyl chloride), an isocyanate (e.g., phenyl isocyanate), an isothiocyanate (e.g., phenyl isothiocyanate) and the like, optionally in the presence of a base such as sodium hydroxide or triethylamine to form compounds of formula la.
  • an electrophile corresponding to the amino substituent in R 6 such as an appropriately substituted sulfonyl chloride (e.g., phenylsulfonyl chloride), a chloroformate (e.g., methyl chloroformate), an acid chloride (e.g.,
  • Compounds of formula V may be N- alkylated according to methods well known in the art prior to treatment with an electrophile.
  • Compounds of formula II are prepared by acid hydrolysis of e.g., N-(5-nitro-indan-2- yl)acetamide followed by protection of the resulting amine with BOC-anhydride and subsequent reduction, e.g., by catalytic hydrogenation, of the nitro group.
  • amines of formula II are acylated with compounds of formula IX in the presence of a base such as N- methylmo ⁇ holine, diisopropylethylamine or pyridine to give compounds of the formula X.
  • a base such as N- methylmo ⁇ holine, diisopropylethylamine or pyridine
  • Palladium catalyzed aryl-aryl coupling of aryl boronic acids of formula (R B(OH)2) with aryl bromides of the formula X (or iodides or triflates) gives compounds of formula IV.
  • Acid, e.g., formic acid, treatment readily deprotects the nitrogen to give compounds of formula V.
  • Chiral compounds of the invention can be prepared as follows:
  • chiral compounds of the invention can be prepared e.g., by acylating a protected amine of e.g., formula XVI
  • Amines of formula V are then treated with an electrophile as previously described to form other N-substituted chiral compounds of formula la.
  • protecting groups are to protect the functional groups from undesired reactions with reaction components under the conditions used for carrying out a desired chemical transformation.
  • the need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (hydroxy group, amino group, etc.), the structure and stability of the molecule of which the substituent is a part and the reaction conditions.
  • reactive functional derivatives of carboxylic acids represent, for example, anhydrides (especially mixed anhydrides), acid halides, acid azides, lower alkyl esters, and activated esters thereof.
  • Mixed anhydrides are preferably such from pivalic acid, or a lower alkyl (ethyl, isobutyl) hemiester of carbonic acid; acid halides are for exampie chlorides or bromides; activated esters for example succinimido, phthalimido or 4- nitrophenyi esters; lower alkyl esters are for example the methyl or ethyl esters.
  • the new compounds may be in the form of one of the possible isomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, optical isomers (antipodes), racemates, or mixtures thereof.
  • the aforesaid possible isomers or mixtures thereof are within the purview of this invention.
  • Any resulting mixtures of isomers can be separated on the basis of the physico- chemical differences of the constituents, into the pure geometric or optical isomers, diastereoisomers, racemates, for example by chromatography and/or fractional crystallization.
  • any resulting racemates of intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereoisomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
  • the amine intermediates can thus be resolved into their optical antipodes e.g., by fractional crystallization of salts of d- or l-carboxylic acids (e.g., d-or l-tartaric acid).
  • Racemic products can also be resolved by chiral chromatography, e.g., high-pressure liquid chromatography using a chiral adsorbent.
  • Acidic compounds of the invention may be converted into salts with pharmaceutically acceptable bases, e.g., an aqueous alkali metal hydroxide, advantageously in the presence of an ethereal or alcoholic solvent, such as a lower alkanol. From the solutions of the latter, the salts may be precipitated with ethers, e.g., diethyl ether. Resulting salts may be converted into the free compounds by treatment with acids. These or other salts can also be used for purification of the compounds obtained.
  • Compounds of the invention having basic groups can be converted into acid addition salts, especially pharmaceutically acceptable salts.
  • inorganic acids such as mineral acids, for example sulfuric acid, a phosphoric or hydrohalic acid
  • organic carboxylic acids such as (C ⁇ -C 4 )-alkanecarboxyiic acids which, for example, are unsubstituted or substituted by halogen
  • acetic acid such as saturated or unsaturated dicarboxylic acids, for example oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylic acids, for example glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid
  • organic sulfonic acids such as (C C 4 )-alkylsulfonic acids (for example methanesulfonic acid) or arylsulfonic acids which are unsubstituted or substituted (for example by halogen).
  • the compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
  • compositions according to the invention are those suitable for enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including man, e.g. to inhibit microsomal triglyceride transfer protein (MTP) and apolipoprotein B (Apo B) secretion, and e.g. for the treatment of disorders responsive thereto, comprising an effective amount of a pharmacologically active compound of the invention, alone or in combination, with one or more pharmaceutically acceptable carriers.
  • MTP microsomal triglyceride transfer protein
  • Apo B apolipoprotein B secretion
  • the pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application.
  • Preferred are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyv ylpyrrolidone; if desired d) dis tegrants, e.g., starches, agar, alginic acid or its sodium salt,
  • compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
  • Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1% to 100%, especially about 0.1 to75%, preferably about 1 to 50%, of the active ingredient.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the
  • Suitable formulations for topical application are preferably aqueous solutions, ointments, creams or gels well known in the art.
  • the pharmaceutical formulations contain an inhibiting amount of a compound of the invention as defined above, either alone or in combination with another therapeutic agent, e.g., each at an effective therapeutic dose as reported in the art.
  • therapeutic agents are well known in the art.
  • a compound of the invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation.
  • the dosage of active compound administered is dependent on the species of warmblooded animal (mammal), the body weight, age and individual condition, and on the form of administration.
  • a unit dosage for oral administration to a mammal of about 50 to 70 kg may contain between about 10 and 1000 mg, advantageously between about 25 and 500 mg of the active ingredient.
  • the present invention also relates to methods of using the compounds of the invention and their pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in mammals for the prevention or treatment of elevated levels of MTP and of Apo B and conditions related thereto.
  • the present invention also relates to the use of a compound according to the instant invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of diseases or conditions associated with elevated levels of MTP and of Apo B.
  • the compounds of the invention are inhibitors of microsomal t ⁇ glyce ⁇ de transfer protein (MTP) and of apolipoprotein B (Apo B) secretion and are thus useful for lowering serum lipid levels, including serum triglyceride and serum cholesterol levels.
  • MTP microsomal t ⁇ glyce ⁇ de transfer protein
  • Apo B apolipoprotein B
  • Such compounds are therefore useful for the treatment and prevention of hyperlipedemia, hypercholesterolemia and hypertriglyce ⁇ demia and diseases associated therewith, e.g., cardiovascular diseases including cardiac ischemia, atherosclerosis and its clinical sequelae, as well as obesity, pancreatitis and diabetes.
  • the dosage in vivo may range, depending on the route of administration, between about 1 and 100 mg/kg
  • the tests are generally known in the art
  • the compounds are generally administered as a solution or suspension, e.g., as a suspension in 3% cornstarch
  • the activity of a compound according to the invention can be assessed by the following methods:
  • Hep G2 ceils are maintained in T-75 culture flasks (Corning) in Dulbecco's modified Eagles Medium (DMEM; Gibco-BRL) supplemented with 10% fetal calf serum Gibco-BRL) in a humidified atmosphere containing 5% carbon dioxide until they are confluent.
  • DMEM Dulbecco's modified Eagles Medium
  • Gibco-BRL Dulbecco's modified Eagles Medium
  • fetal calf serum Gibco-BRL 10% fetal calf serum
  • Test compound is dissolved at 1 mg/ml (w/v;1-5 mM) in dimethyl sulfoxide DMSO; Sigma) as stock solution.
  • the stock solution of compound Prior to use, the stock solution of compound is diluted to 133 ⁇ M with DMSO and diluted further with growth medium (DMEM containing 10% fetal calf serum) to obtain 1 ⁇ M of compound in 100 ⁇ l of growth medium.
  • growth medium DMEM containing 10% fetal calf serum
  • 100 ⁇ l of growth medium containing the test compound is added to separate wells of a 96-well culture plate containing Hep G2 cells.
  • a stock solution of test compound in DMSO is made at 665 ⁇ M and various dilutions from this solution are made in growth medium to obtain range of concentration of compound from 0.01 ⁇ M to 5 ⁇ M in 100 ⁇ l of growth medium.
  • ⁇ l of the growth medium containing different concentrations of test compound is added to separate wells containing Hep G2 cells. Twenty-four hours later, growth medium is collected and assayed by specific ELISA for apolipoprotein B (Apo B). At the same time Hep G2 cells from wells are assayed for protein (BioRad ; cat# 500-0006 ) and / or cell viability (Promega; CellTiter 96 Aqueous, cat # G3581 ). Inhibitors are identified as compounds that decrease Apo B secretion into the medium without decreasing the total cellular protein and/or cell viability. For performing Apo B ELISA, an antisera for human Apo B is made by immunizing rabbit with purified human Apo B.
  • Apo B apolipoprotein B
  • the antisera is further purified by using an affinity column (CNBr activated Sepharose 4B, Pharmacia) with human LDL as ligand and used as primary antibody for human Apo B.
  • a secondary antibody for Apo B is prepared by conjugating the human Apo B antibody with alkaline phosphatase (Sigma).
  • the ELISA for Apo B is performed as follows. 15 ⁇ l of primary antibody solution prepared against Apo B is diluted to a final volume of 10 ml with coating buffer (containing 15 mM sodium carbonate, 35 mM sodium bicarbonate, 3 mM sodium azide, pH 9.6). 200 ⁇ l of diluted antibody solution is added to each well of a 96 well plate (Maxisorb, Nunc , cat # 439454).
  • the antibody solution is removed.
  • Nonspecific sites on the plastic well are blocked by adding 300 ⁇ l of blocking solution containing phosphate buffered saline (PBS) , 1% (w/v) bovine serum albumin (Sigma), pH 7.4) and incubated for 45 minutes at room temperature.
  • 200 ⁇ l of dilution buffer containing PBS/ 0.05% Tween 20 / 5 mM decyl sodium sulfate (Acros Organics) / 2% BSA, pH 7.4 containing 20 ⁇ l of growth medium from Hep G2 cells or 1 - 30 ng of Apo B standards (prepared in dilution buffer) is added to each well.
  • washing buffer containing PBS and 0.05% Tween 20, pH 7.4.
  • 200 ⁇ l of diluted conjugated secondary antibody for Apo B (15 ⁇ l diluted to a final volume of 10 ml in dilution buffer) is added to each well.
  • p-nitrophenyl phosphate disodium hexahydrate solution (Sigma, cat # 104-0) is prepared in substrate buffer (containing 0.95M diethanoiamine / 0.5mM MgCI2 / 3 mM sodium azide, pH 9.5) at a concentration of 1 mg/ml and 200 ⁇ l of substrate solution is added to each well and incubated for 45-60 minutes. Absorbance of each well is read at 405 nm using a Beckman Biomek workstation. Apo B concentration is calculated from a standard curve generated from purified LDL standards that are run in parallel in the same assay. Secreted Apo B values are normalized with the total cellular protein assay and/or cell viability assay.
  • the inhibition of MTP is measured as follows:
  • Inhibition of the lipid transfer activity of MTP can be quantitated by measuring the inhibition of transfer of radiolabeled triglyceride from donor vesicles to acceptor vesicles in presence of soluble rat MTP.
  • the procedure for preparing MTP is based on the method of Wetterau and Zilversmit (Biochim. Biophys. Acta (1986) 875:610). Briefly rats are decapitated under ether anesthesia. The liver is placed in ice cold sucrose buffer (contains 0.25M sucrose, 50 mM Tris Hcl, 1 mM EDTA, 0.02% sodium azide, pH 7.4) rinsed several times with the sucrose buffer.
  • a 57% homogenate (120g/210 ml) of rat liver in 0.25M sucrose buffer is prepared by using a Potter-Elvehjem homogenizer. The homogenate is then centrifuged at 4°C for 30 min at 13,000 x g to remove large cellular organells. The supernatant is then centrifuged for 90 min at 105,000 x g to pellet the microsomes. The pellet is resuspended in 10mM Tris-HCI buffer pH 8.6. and centrifuged for 90 min at 105,000 x g. The washed pellet is then resuspended in 1mM Tris buffer (pH 8.6) and centrifuged for 2 hrs.
  • the pellet is resuspended in 28.5 ml of 0.25M sucrose solution and 1 ml aliquotes containing 4.2 g of liver are stored frozen at -80 ° C until needed. Prior to performing the assay, the thawed pellet is suspended in 12 ml of cold Tris-HCI, 50 mM KCI, 5 mM MgCI, pH 7.4 and 1.2 ml of a 0.54% deoxycholate solution (pH 7.4) is added slowly with gentle mixing. The suspension is kept on ice for 30 min and then centrifuged at 105,000g for 75 min.
  • the supernatant containing soluble MTP is dialyzed against assay buffer (150 mM Tris-HCI, 40 mM NaCI, 1 mM EDTA, 0.02% Na N3, pH 7.4).
  • assay buffer 150 mM Tris-HCI, 40 mM NaCI, 1 mM EDTA, 0.02% Na N3, pH 7.4
  • the protein content is measured using the Sigma Lowry micro total protein method and reagents (Sigma Cat # 690A).
  • the rat MTP is diluted with assay buffer to contain 15 ⁇ g protein per 50 ⁇ l and stored at 4°C.
  • Donor and acceptor liposomes are prepared as follows. For preparation of donor vesicles, 12.4 mgs of egg phosphatidylcholine (Sigma, cat# P-3556), 5.2 mgs of cardiolipin (Sigma, Cat# C-0563) and 8 mgs of hydroxybutylate toluene are dissolved in 4 ml of chloroform. To this solution, 34.8 ⁇ l of 3 H labeled Triolein (Amersham, Cat# TRA 191 , glycerol tri[1 ,9- 3 H]oleate) is added and mixed. 200 ⁇ l of this mixture is transferred into a screw cap glass vial, dried under nitrogen and reconstituted in 2 ml of assay buffer.
  • Triolein Amersham, Cat# TRA 191 , glycerol tri[1 ,9- 3 H]oleate
  • the lipid suspension is sonicated for 30 min at 1.5 setting with pulse at 75 using Branson 450 sonifier in a water bath with ice.
  • 18 mgs of egg phophatidylcholine and 4 mgs of hydroxybutylated toluene is added in 1 ml of chloroform.
  • a 200 ⁇ l aliquot from this mixture is transferred into a screw cap glass vial.
  • MTP activity is measured using a MTP transfer assay.
  • donor and acceptor vesicles are mixed together with soluble MTP and test compound to measure the transfer of triglycerides from donor vesicles to acceptor vesicles.
  • 50 ⁇ l of donor vesicles, 50 ⁇ l of acceptor vesicles, 20 ⁇ l of bovine serum albumin (10% w/v) and 50 ⁇ l of MTP (15 ⁇ g protein) are added along with various concentrations of test compound in a final volume 450 ⁇ l of assay buffer.
  • the triglyceride transfer was terminated by addition of 300 ⁇ l of DEAE cellulose suspension (50%, w/v). After 4 min of vortexing, the donor vesicles bound to the DEAE cellulose are separated from acceptor vesicles by centrifuging at 14,00 ⁇ m for 7 min. 250 ⁇ l of supernatant containing acceptor vesicles are counted using 5.5 ml of Ready safe scintillation solution (Beckman, cat# 158735). The 14 C and 3 H counts are used to calculate the percent recovery of acceptor liposomes and the percent of triglyceride transfer using first order kinetics. Inhibition of triglyceride transfer by test compound is calculated by measuring the decrease in 3 H label of triglyceride present in the acceptor vesicles as compared to controls where no test compound is present.
  • the compound of example 13b demonstrates an IC 50 of about 1.8 nM in the Apo B assay and an IC 5 0 of about 60 nM in the MTP assay.
  • the compound of example 13(i) demonstrates an IC 50 of about 0.7nM in the Apo B assay and an IC50 of about 70nM in the MTP assay.
  • the compound of example 13(al) demonstrates an IC 50 of about 3 nM in the Apo B assay.
  • the compound of example 13(ey) demonstrates an IC 50 of about 1 nM in the Apo B assay.
  • the in vivo serum triglyceride lowering effect of the compounds of the invention can be determined by measuring their effect on triglyceride levels in mice, rats or dogs according to methodology well known in the art, e.g., in a model of pre-established hypertriglyceridemia in fructose fed rats or in normoiipidemic rats.
  • the in vivo serum cholesterol lowering effect of the compounds of the invention can be determined by measuring their effect on cholesterol levels in mice, rats or dogs according to methodology well known in the art, e.g., in normoiipidemic rats.
  • the compound of example 13(i) lowers both plasma triglycerides and cholesterol at a dose of 10 mg/kg. p.o.
  • the organic layer is washed with 8% NaHC ⁇ 3 solution until the aqueous layer remains basic at which point a precipitate forms in the organic layer.
  • the precipitate is collected by filtration to give 4'- trifluoromethylbiphenyl-2-carboxylic acid (2-amino-indan-5-yl)-amide.
  • the organic layer of the filtrate is dried (MgSO4) and concentrated under reduced pressure to give a solid. Trituation of the soiid with diethyl ether yields additional 4'-trifluoromethylbiphenyl-2- carboxylic acid (2-amino-indan-5-yl)-amide.
  • Example 1 The following compounds are prepared similarly to Example 1 using the title F compound of Example 1 (4'-trifluoromethylbiphenyl-2-carboxylic acid (2-amino-indan-5-yl)- amide and the appropriate N-derivatizing agent (e.g., a sulfonyl chloride, an acid chloride, an isocyanate, a sulfamoyl chloride).
  • N-derivatizing agent e.g., a sulfonyl chloride, an acid chloride, an isocyanate, a sulfamoyl chloride.
  • N-(5-nitro-indan-2-yl)-acetamide (Bigge, C.F.; Retz, D. M. WO 9617832 A1 ) (0.37 g, 1.68 mmol) in ethanol (10 mL) is degassed and 10% palladium on carbon added (0.05 g). The reaction mixture is evacuated and placed under 1 atm H2(g) for 2h. Fitration of the reaction mixture through Celite is followed by concentration of the filtrate under reduced pressure to give N-(5-amino-indan-2-yl)-acetamide as a white solid which is used directly without further purification.
  • 2-Bromobenzoyl Chloride 2-Bromobenzoyl chloride is prepared as described for 4-trifluoromethyl-2-biphenyl- carboxylic acid chloride (the title D compound of Example 1 ) and used as is without purification.
  • the title compound is prepared as described for ⁇ 5-[(4'-trifluoromethylbiphenyl-2- carbonyl)-amino]-indan-2-yl ⁇ -carbamic acid tert-butyl ester (the title E compound of Example 1) using N-(5-amino-indan-2-yl)-acetamide (the title A compound; 1.05 g, 5.50 mmol) and 2- bromo-benzoyl chloride (the title B compound; 1.21 g, 5.50 mmol) to give the product, mp 216-217 °C. MS (ES+), m/z 373 (M+H), 375 (M+H).
  • Example 4 The following compounds are prepared similarly to Examples 1 or 3.
  • N-(lndan-5-yl)-5-nitro-2-(thiophen-2-yl)-benzamide is prepared similarly to the title compound of Example 3 using the title B compound, 2-bromo-N-(indan-5-yl)-5-nitro- benzamide (0.137 g, 0.380 mmol) and 2-thiopheneboronic acid (0.073 g, 0.570 mmol).
  • the title compound is prepared in a manner similar to that described for the title E compound of Example 1 using 2-(4-trifluoromethyl-phenyl)-nicotinoyl chloride (2.228 mmol) and 5-aminoindan (0.296 g, 2.228 mmol) to give the product as the free base.
  • the hydrochloride salt is prepared by bubbling HCI(g) through an ethyl acetate solution of the free base and trituation of the salt with diethyl ether; mp 190-205 °C. MS (ES+) m/z 383 (M+1 ).
  • the precipitate is vacuum filtered and the filtrate extracted into 1 N HCI.
  • the acid solution is washed with fresh Et 2 O, then basified with cold 1 N NaOH.
  • the cloudy mixture is extracted with Et 2 O, washed with saturated brine, dried over Na 2 SO , is filtered and concentrated to an oil.
  • (R)-(5-aminoindan-2-yl)-carbamic acid methyl ester is similarly prepared from (1- acetyloxyindan-2-yl)-carbamic acid methyl ester (1 R-trans), starting with D-phenylalanine instead of L-phenylaianine.
  • the product is purified by crystallisation from ethyl acetate / hexanes to yield 6-methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid melting at 202-203°C. MS m/z 279 (M -1 ).
  • step B The compound from step B is treated with methyl chloroformate, nitrated, reduced, and acylated with 6-methyl-4'-trifluoromethylbiphenyl-2-carboxylic acid chloride according to procedure described in example 12 to give the title compound; m.p. 190-193°C.
  • Example 16 The compound of example 15 is treated with trimethylsilyl iodide and the resulting amine is then reacted with the appropriate N-derivatizing agent (as described in previous examples) to yield the following compounds of the formula
  • Hard gelatin capsules comprising 100 mg active substance, for example 4'-trifluoromethylbiphenyl-2-carboxylic acid (2-benzenesulfonylamino-indan-5-yl)- amide, can be prepared for example as follows:
  • Composition for 1000 capsules
  • the sodium lauryl sulfate is added to the lyophilized active ingredient via a sieve with a mesh size of 0.2 mm. Both components are intimately mixed. Then first the lactose is added via a sieve with a mesh size of 0.6 mm and then the microcrystalline cellulose via a sieve with a mesh size of 0.9 mm. Thereupon these components are intimately mixed for a further 10 minutes. Finally the magnesium stearate is added via a sieve with a mesh size of 0.8 mm. After 3 minutes of further mixing, 390 mg each of the formulation obtained are filled into hard gelatin capsules of size 0.

Abstract

L'invention concerne un composé de formule (I), ou un sel pharmaceutiquement acceptable de celui-ci, ou un énantiomère de celui-ci. Les composés de formule (I) sont utilisés pour inhiber la sécrétion de la protéine de transfert des triglycérides microsomique (MTP) et de l'apolipoprotéine B (ApoB), et donc pour prévenir et traiter les états dépendant de MTP et de ApoB.
PCT/EP1999/005131 1998-07-21 1999-07-19 Derives n-benzocycloalkyl-amide et leur utilisation comme medicaments WO2000005201A1 (fr)

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CA002338198A CA2338198A1 (fr) 1998-07-21 1999-07-19 Derives n-benzocycloalkyl-amide et leur utilisation comme medicaments
EP99936567A EP1097129A1 (fr) 1998-07-21 1999-07-19 Derives n-benzocycloalkyl-amide et leur utilisation comme medicaments
AU51613/99A AU5161399A (en) 1998-07-21 1999-07-19 N-benzocycloalkyl-amide derivatives and their use as medicaments
JP2000561158A JP2002521360A (ja) 1998-07-21 1999-07-19 Ｎ−ベンゾシクロアルキルアミド誘導体およびその医薬としての使用

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001005767A1 (fr) * 1999-07-20 2001-01-25 Novartis Ag Composes organiques
WO2001053260A1 (fr) * 2000-01-18 2001-07-26 Novartis Ag Carboxamides utilises comme inhibiteurs de proteine de transfert triglyceridique microsomique et de la secretion d'apolipoproteine b
WO2002046141A2 (fr) * 2000-12-07 2002-06-13 Cv Therapeutics, Inc. Composes developpant abca-1
WO2002098872A1 (fr) * 2001-06-01 2002-12-12 Tanabe Seiyaku Co., Ltd. Isoindolines et procede d'elaboration
WO2003002533A1 (fr) * 2001-06-28 2003-01-09 Pfizer Products Inc. Indoles substitues par triamide, benzofuranes et benzothiophenes utiles comme inhibiteurs de la proteine de transfert triglyceride microsomale (mtp) et/ou de la secretion de l'apolipoproteine b (apo b)
WO2003103651A1 (fr) * 2002-06-04 2003-12-18 Cv Therapeutics, Inc. Composes de formule r1-x-y-z-nr2r3 utilises en tant qu'agents permettant d'augmenter le niveau d'expression du gene abca-1 contre les coronaropathies (cad) et l'artheriosclerose
WO2004039795A2 (fr) * 2002-10-29 2004-05-13 Fujisawa Pharmaceutical Co., Ltd. Composes amide
US6762199B2 (en) * 2000-02-28 2004-07-13 Aventis Pharma Limited Indane derivatives
WO2005080373A1 (fr) 2004-02-04 2005-09-01 Pfizer Products Inc. Composes de quinoline substitues
WO2007120827A2 (fr) * 2006-04-14 2007-10-25 Novartis Ag Utilisation de biarylcarboxamides dans le traitement de troubles associés à la voie hedgehog
WO2008090198A1 (fr) * 2007-01-25 2008-07-31 Janssen Pharmaceutica Nv Utilisation d'inhibiteurs de la mtp pour augmenter les taux d'hormones de satiété
US7432392B2 (en) 2003-08-29 2008-10-07 Japan Tobacco Inc. Ester derivatives and medical use thereof
US7625948B2 (en) 2002-02-28 2009-12-01 Japan Tobacco Inc. Ester compound and medicinal use thereof
US8101774B2 (en) 2004-10-18 2012-01-24 Japan Tobacco Inc. Ester derivatives and medicinal use thereof
EP3023097A1 (fr) 2008-10-01 2016-05-25 Novartis AG Antagonisme lissé pour le traitement de troubles liés à la voie hedgehog
CN111116604A (zh) * 2019-12-24 2020-05-08 苏州百灵威超精细材料有限公司 一种制备荧光胺的工艺方法
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors

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WO2008066900A1 (fr) * 2006-11-28 2008-06-05 Valeant Pharmaceuticals International Analogues de 1,4-diamino rétigabine bicycliques en tant que modulateurs de canaux potassiques

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Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001005767A1 (fr) * 1999-07-20 2001-01-25 Novartis Ag Composes organiques
WO2001053260A1 (fr) * 2000-01-18 2001-07-26 Novartis Ag Carboxamides utilises comme inhibiteurs de proteine de transfert triglyceridique microsomique et de la secretion d'apolipoproteine b
US6878707B2 (en) 2000-01-18 2005-04-12 Novartis Ag Carboxamides useful as inhibitors of microsomal triglyceride transfer protein and of apolipoprotein b secretion
US6762199B2 (en) * 2000-02-28 2004-07-13 Aventis Pharma Limited Indane derivatives
WO2002046181A3 (fr) * 2000-12-07 2002-12-27 Cv Therapeutics Inc Composes elevant abca-1
WO2002046141A2 (fr) * 2000-12-07 2002-06-13 Cv Therapeutics, Inc. Composes developpant abca-1
WO2002046141A3 (fr) * 2000-12-07 2003-02-06 Cv Therapeutics Inc Composes developpant abca-1
US6548548B2 (en) 2000-12-07 2003-04-15 Cv Therapeutics, Inc. ABCA-1 elevating compounds
WO2002046181A2 (fr) * 2000-12-07 2002-06-13 Cv Therapeutics, Inc. Composes elevant abca-1
US6713650B2 (en) 2000-12-07 2004-03-30 Prabha N. Ibrahim ABCA-1 elevating compounds
WO2002098872A1 (fr) * 2001-06-01 2002-12-12 Tanabe Seiyaku Co., Ltd. Isoindolines et procede d'elaboration
US6720351B2 (en) 2001-06-28 2004-04-13 Pfizer Inc. Triamide-substituted heterobicyclic compounds
CN1880304B (zh) * 2001-06-28 2010-11-24 辉瑞产品公司 三酰胺取代的吲哚、苯并呋喃及苯并噻吩
US7348355B2 (en) 2001-06-28 2008-03-25 Pfizer Inc. Triamide-substituted heterobicyclic compounds
CN1522246B (zh) * 2001-06-28 2010-04-21 辉瑞产品公司 三酰胺取代的吲哚、苯并呋喃及苯并噻吩
HRP20031051B1 (en) * 2001-06-28 2012-01-31 Pfizer Products Inc. Triamide-substituted indoles, benzofuranes and benzothiophenes as inhibitors of microsomal triglyceride transfer protein (mtp) and/or apolipoprotein b (apo b) secretion
WO2003002533A1 (fr) * 2001-06-28 2003-01-09 Pfizer Products Inc. Indoles substitues par triamide, benzofuranes et benzothiophenes utiles comme inhibiteurs de la proteine de transfert triglyceride microsomale (mtp) et/ou de la secretion de l'apolipoproteine b (apo b)
US6949572B2 (en) 2001-06-28 2005-09-27 Pfizer Inc. Triamide-substituted heterobicyclic compounds
US6979692B2 (en) 2001-06-28 2005-12-27 Pfizer Inc. Triamide-substituted heterobicyclic compounds
US7482368B2 (en) 2001-06-28 2009-01-27 Pfizer Inc Triamide-substituted heterobicyclic compounds
US7625948B2 (en) 2002-02-28 2009-12-01 Japan Tobacco Inc. Ester compound and medicinal use thereof
WO2003103651A1 (fr) * 2002-06-04 2003-12-18 Cv Therapeutics, Inc. Composes de formule r1-x-y-z-nr2r3 utilises en tant qu'agents permettant d'augmenter le niveau d'expression du gene abca-1 contre les coronaropathies (cad) et l'artheriosclerose
WO2004039795A3 (fr) * 2002-10-29 2005-03-24 Fujisawa Pharmaceutical Co Composes amide
WO2004039795A2 (fr) * 2002-10-29 2004-05-13 Fujisawa Pharmaceutical Co., Ltd. Composes amide
US7432392B2 (en) 2003-08-29 2008-10-07 Japan Tobacco Inc. Ester derivatives and medical use thereof
US7468378B2 (en) 2004-02-04 2008-12-23 Pfizer Inc. Substituted quinoline compounds
WO2005080373A1 (fr) 2004-02-04 2005-09-01 Pfizer Products Inc. Composes de quinoline substitues
US7368573B2 (en) 2004-02-04 2008-05-06 Pfizer Inc. Triamide-substituted heterobicyclic compounds
US8101774B2 (en) 2004-10-18 2012-01-24 Japan Tobacco Inc. Ester derivatives and medicinal use thereof
WO2007120827A2 (fr) * 2006-04-14 2007-10-25 Novartis Ag Utilisation de biarylcarboxamides dans le traitement de troubles associés à la voie hedgehog
WO2007120827A3 (fr) * 2006-04-14 2007-12-13 Novartis Ag Utilisation de biarylcarboxamides dans le traitement de troubles associés à la voie hedgehog
WO2008090198A1 (fr) * 2007-01-25 2008-07-31 Janssen Pharmaceutica Nv Utilisation d'inhibiteurs de la mtp pour augmenter les taux d'hormones de satiété
EP3023097A1 (fr) 2008-10-01 2016-05-25 Novartis AG Antagonisme lissé pour le traitement de troubles liés à la voie hedgehog
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
CN111116604A (zh) * 2019-12-24 2020-05-08 苏州百灵威超精细材料有限公司 一种制备荧光胺的工艺方法
CN111116604B (zh) * 2019-12-24 2021-10-08 苏州百灵威超精细材料有限公司 一种制备荧光胺的工艺方法

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PE20001091A1 (es) 2000-10-24
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CO5090829A1 (es) 2001-10-30
JP2002521360A (ja) 2002-07-16
AR029447A1 (es) 2003-07-02
AU5161399A (en) 2000-02-14

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