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WO2001077077A1 - Derives d'(hetero)aryl-carboxamide en tant qu'inhibiteurs de la proteine microsomale de transfert des triglycerides (mtp) et de la secretion d'apolipoproteine b (apo b) - Google Patents

Derives d'(hetero)aryl-carboxamide en tant qu'inhibiteurs de la proteine microsomale de transfert des triglycerides (mtp) et de la secretion d'apolipoproteine b (apo b) Download PDF

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Publication number
WO2001077077A1
WO2001077077A1 PCT/EP2001/004052 EP0104052W WO0177077A1 WO 2001077077 A1 WO2001077077 A1 WO 2001077077A1 EP 0104052 W EP0104052 W EP 0104052W WO 0177077 A1 WO0177077 A1 WO 0177077A1
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Prior art keywords
aryl
lower alkyl
heteroaryl
hydrogen
direct bond
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PCT/EP2001/004052
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English (en)
Inventor
Robert E. Ii Damon
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Novartis Pharma GmbH Austria
Novartis AG
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Novartis Erfindungen Verwaltungs GmbH
Novartis AG
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Priority to AU2001262185A priority Critical patent/AU2001262185A1/en
Publication of WO2001077077A1 publication Critical patent/WO2001077077A1/fr
Anticipated expiration legal-status Critical
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    • 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
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    • 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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    • C07C311/17—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 hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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    • 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
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
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    • 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
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Definitions

  • the present invention relates to the amide derivatives described herein which are particularly useful as inhibitors of microsomal triglyceride transfer protein (MTP) and of apolipoprotein B (apo B) secretion, methods for preparation thereof, pharmaceutical compositions comprising said compounds, a method of inhibiting MTP and apo B secretion and of treating conditions in mammals which are responsive to MTP inhibition or inhibition of apo B secretion using said compounds or pharmaceutical compositions comprising said compounds of the invention.
  • MTP microsomal triglyceride transfer protein
  • apo B apolipoprotein B
  • the invention relates to the compounds of formula I
  • Ri is aryl, cycloalkyl, heterocyclyl, aryl-lower alkoxy or aryl-lower alkylthio; provided that Ri is not carboxyphenyl when both V and W are O or when one of V and W is O and the other is a direct bond, and when Z is aryl or heteroaryl;
  • L and L' are arylene or heteroarylene
  • V and W are independently O, S(O) m , NR 0 or a direct bond, provided that only one of V and may be a direct bond;
  • Z is aryl or heteroaryl; or when W is NR 0 , Z is also
  • heteroaryl-lower alkyl —- COR a ,-CON , — COOR d , or — SO 2 R ⁇ in which
  • R a , R d and R e are independently optionally substituted lower alkyl, cycloalkyl, adamantyl, aryl, heteroaryl or (aryl or heteroaryl)-lower alkyl; and Rb and R c are independently hydrogen, cycloalkyl, optionally substituted lower alkyl, aryl, heteroaryl or (aryl or heteroaryl)-lower alkyl; or R and R 0 together represent lower alkylene or lower-alkylene interrupted by O, S or N-(H, lower alkyl, acyl or aralkyl); R 0 is hydrogen, lower alkyl or aryl-lower alkyl; m is zero, 1 or 2; and alk is lower alkylene; and pharmaceutically acceptable salts thereof.
  • the invention relates to compounds of formula I wherein R ⁇ is monocyclic . (aryl, heteroaryl, or aryl-lower alkoxy); and L and L' are monocyclic (arylene or heteroarylene).
  • R is hydrogen, lower alkyl, lower alkoxy, halo or trifluoromethyl
  • Ri is aryl, cycloalkyl, heterocyclyl, aryl-lower alkoxy or aryl-lower alkylthio; provided that R t is not carboxyphenyl when V and W are O or when one of V and W is O and the other is a direct bond, and when Z is aryl or heteroaryl;
  • L is arylene or heteroarylene
  • Y is CH or N
  • V and W are independently O, S(O) m , NR 0 or a direct bond, provided that only one of V and W may be a direct bond;
  • Z is aryl or heteroaryl; or when W is NR 0 , Z is also
  • R a » R and R ⁇ are independently optionally substituted lower alkyl, cycloalkyl, adamantyl, heteroaryl or (aryl or heteroaryl)-lower alkyl; and R b and R 0 are independently hydrogen, cycloalkyl, optionally substituted lower alkyl, aryl, heteroaryl or (aryl or heteroaryl)-lower alkyl; or R b and R 0 together represent lower alkylene or lower-alkylene interrupted by O, S or N-(H, lower alkyl, acyl or aralkyl);
  • R 0 is hydrogen, lower alkyl or aryl-lower alkyl; m is zero, 1 or 2; and n is an integer from 1-4 provided that either V or W is a direct bond when n is 1 ; and pharmaceutically acceptable salts thereof.
  • X is N or CR 2 ;
  • Y is N or CH
  • V and W are independently O, S(O) m , NR 0 or a direct bond, provided that only one of V and W may be a direct bond;
  • R is hydrogen, lower alkyl, lower alkoxy, halo or trifluoromethyl
  • R 0 is hydrogen or lower alkyl
  • Ri is aryl, cycloalkyl, heteroaryl, aryl-lower alkoxy or aryl-lower alkylthio; provided that Ri is not carboxyphenyl when both V and W are O or when one of V and W is O and the other is a direct bond;
  • Ar is monocyclic aryl or heteroaryl
  • R 2 , R 3 , R4, 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 or R 2 , R3, R and R 5 at adjacent positions are alkylenedioxy; n is 2 or 3; m is zero; and pharmaceutically acceptable salts thereof.
  • V is O, S(O) m or NR 0 , and W is a direct bond; and pharmaceutically acceptable salts thereof.
  • Ri is phenyl or phenyl-lower alkoxy, each optionally substituted on phenyl by lower alkyl, lower alkoxy, halo, trifluoromethyl or cyano
  • X is CR 2 ;
  • R, R 2 , R3, R4 and R 5 are independently hydrogen, lower alkyl, lower alkoxy, halo or trifluoromethyl;
  • Y is CH or N;
  • V is NH, N-CH 3 or O; n is 1 , 2 or 3; W is a direct bond;
  • Ar is phenyl or phenyl substituted by lower alkyl, halo, trifluoromethyl, lower alkoxy or cyano; or
  • Ar is thienyl, pyridyl, indolyl or pyrimidyl optionally substituted by lower alkyl; and pharmaceutically acceptable salts thereof.
  • Ri is trifluoromethylphenyl or benzyloxy
  • Y is CH or N
  • X is CR 2
  • R 2 is methyl
  • R is hydrogen, methyl, or chloro
  • R 3 , R 4 and R 5 are hydrogen
  • V is NH
  • n is 2 or 3
  • W is a direct bond
  • Ar is phenyl or 2-pyridyl; and pharmaceutically acceptable salts thereof.
  • X is N or CR 2 ;
  • Y is N or CH
  • V is O, S(O) m , NR 0 or a direct bond
  • R is hydrogen, lower alkyl, lower alkoxy, halo or trifluoromethyl
  • R 0 is hydrogen or lower alkyl
  • R ! is aryl, cycloalkyl, heteroaryl, aryl-lower alkoxy or aryl-lower alkylthio;
  • R 2 , R 3 , R 4 , and R 5 are independently hydrogen, lower alkyl, halo, trifluoromethyl, cyano, (lower alkyl, aryl, or aralkyl)-thio, (lower alkyl, aryl, or aralkyl)-oxy, acyloxy, (alkyl, aryl or aralkyl)-aminocarbonyloxy; or any two or R 2 , R 3 , R 4 and R 5 at adjacent positions are alkylenedioxy;
  • Z is heteroaryl-lower alkyl, — COR a ,-CON ' , — COOR d , or — SO 2 R e in which
  • R a , R d and R e are independently optionally substituted lower alkyl, cycloalkyl, adamantyl, aryl, heteroaryl or (aryl or heteroaryl)-lower alkyl; and R and R c are independently hydrogen, cycloalkyl, optionally substituted lower alkyl, aryl, heteroaryl or (aryl or heteroaryl)-lower alkyl; or R and R c together represent lower alkylene or lower-alkylene interrupted by O, S or N-(H, lower alkyl, acyl or aralkyl); m is zero, 1 or 2; and n is an integer from 1-4; and pharmaceutically acceptable salts thereof.
  • Ri is phenyl or phenyl -lower alkoxy, each optionally substituted on phenyl by lower alkyl, lower alkoxy, halo, trifluoromethyl or cyano;
  • X is CR 2 ;
  • Y is CH or N;
  • R, R 2 , R 3 , R 4 and R 5 are independently hydrogen, lower alkyl, lower alkoxy, halo or trifluoromethyl;
  • R 0 is hydrogen;
  • V is a direct bond, NH, N-CH 3 or O;
  • n is 2 or 3;
  • Z is heteroaryl-
  • R b and R c are lower alkyl; or R and R c together represent lower alkylene or lower alkylene interrupted by O, S, N-(H, lower alkyl or aralkyl);
  • R d is lower alkyl or aryl -lower alkyl
  • R is hydrogen, methyl or chloro
  • Ri is trifluoromethylphenyl
  • X is CR 2
  • Y is CH or N
  • R 2 is methyl
  • R 3 , FU and R 5 are hydrogen
  • Ro is hydrogen
  • V is NH, O, or a direct bond
  • n is 2 or 3
  • Z is -COOR d wherein R d is lower alkyl; and pharmaceutically acceptable salts thereof.
  • lower referred to herein in connection with organic radicals or compounds respectively generally defines, if not defined differently, such with up to and including 7, preferably up and including 4 and advantageously one or two carbon atoms. Such may be straight chain or branched.
  • optionally substituted lower alkyl refers to unsubstituted or substituted straight or branched chain hydrocarbon groups having 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, and the like.
  • substituted lower 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, cycloalkyl, alkanoyl, alkanoyloxy, amino, substituted amino, alkanoylamino, thiol, alkylthio, arylthio, alkylthiono, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl, nitro, cyano, carboxy, carbamyl, alkoxycarbonyl, aryl, aralkoxy, heterocyclyl (e.g., indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl), fluoren
  • 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, preferably
  • lower alkylene refers to a straight chain bridge of 1 to 7 carbon atoms connected by single bonds (e.g., -(CH 2 ) ⁇ - wherein x is 1 to 7) which may be substituted with 1 to 3 lower alkyl groups.
  • lower alkylene interrupted by O, S, N-(H, alkyl, acyl or aralkyl) refers to a straight chain of 2 to 6 carbon atoms which is interrupted by O, S, N-(H, alkyl, acyl or aralkyl), such as (m)ethyleneoxy(m)ethylene, (m)ethylenethio(m)ethylene, or (m)ethyleneimino(m)ethylene.
  • cycloalkyl refers to cyclic hydrocarbon groups of 3 to 8 carbon atoms such as cyclopentyl, cyclohexyl or cycloheptyl.
  • alkoxy or "alkyloxy” refers to alkyl-O-.
  • alkanoyl refers to alkyl-C(O)-.
  • alkylamino and “dialkylamino” refer to (alkyl)NH- and (alkyl)2N-, respectively.
  • alkanoylamino refers to alkyl-C(O)-NH-.
  • alkylthio refers to alkyl-S-.
  • alkoxycarbonyl refers to alkyl-O-C(O)-.
  • acyl refers to alkanoyl, aroyl, heteroaroyl, aryl-alkanoyl, heteroarylalkanoyl, and the like.
  • aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring 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, amino, substituted amino, alkanoylamino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, alkylsulfonyl, aminosulfonyl, heterocyclyl and the like.
  • aralkoxy refers to an aryl group linked to an alkoxy group, such as benzyloxy.
  • 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 monocyclic, 7 to 11 membered bicyclic 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.
  • the heterocyclic group may be attached at any heteroatom or carbon atom.
  • Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, fury!, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyri
  • bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl) and the like.
  • heterocyclyl also includes substituted heterocyclic groups.
  • Substituted heterocyclic groups refer to heterocyclic groups substituted independently with 1 , 2 or 3 of e.g. the following:
  • heteroaryl refers to an aromatic heterocycle, for example monocyclic 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.
  • the point of attachment of the heteroaryl group is at any of the available carbon positions.
  • pyridyl refers to 2-,3- or 4-pyridyl.
  • 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, cycloalkylalkyl, heteroaralkyl, or disubstituted by lower alkylene or lower alkylene interrupted by O, S, N-(H, alkyl, acyl or aralkyl), and the like.
  • heteroarylene for "L” refers to a monocyclic or bicyclic heteroaryl linking group preferably pyridylene, thienylene, furanylene, each optionally substituted by lower alkyl, lower alkoxy, halo or cyano with the points of attachment of the two groups in formula I attached thereto being preferably at adjacent carbon atoms, such as 2,3-pyridylene, 2,3- thienylene or 2,3-furanylene.
  • arylene for the linking group L refers to a monocyclic or bicyclic aryl linking group, preferably phenylene, advantageously ortho-phenylene optionally substituted by 1 to 4 substituents independently selected from lower alkyl, lower alkoxy, halo, trifluoromethyl and cyano, or arylene preferably refers to phenylene optionally substituted at adjacent positions by alkylenedioxy.
  • heteroarylene for "L* " refers to a monocyclic or bicyclic heteroaryl linking group preferably pyridylene, thienylene, furanylene, each optionally substituted by e.g. lower alkyl, lower alkoxy, halo or cyano, with the points of attachment of the two groups in formula I attached thereto being preferably at non-adjacent carbon atoms, such as pyridylene, preferably 2,4- or 2,5-pyridylene.
  • arylene for the linking group L' refers preferably to phenylene, advantageously para-phenylene optionally substituted by 1 to 4 substituents independently selected from lower alkyl, lower alkoxy, halo, trifluoromethyl or cyano, or arylene refers to phenylene optionally substituted at adjacent positions by alkylenedioxy.
  • Pharmaceutically acceptable salts are primarily acid addition salts, such as of mineral acids, organic carboxylic, and organic sulfonic acids e.g., hydrochloric acid, methanesulfonic acid, maleic acid, provided a basic group, such as amino or pyridyl, constitutes part of the structure.
  • acid addition salts such as of mineral acids, organic carboxylic, and organic sulfonic acids e.g., hydrochloric acid, methanesulfonic acid, maleic acid, provided a basic group, such as amino or pyridyl, constitutes part of the structure.
  • 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, trimethylammonium, 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, trimethylammonium, diethylammonium, and tris-(hydroxymethyl)- methylammonium salts.
  • the compounds of the invention depending on the nature of the substituents, may possess one or more asymmetric carbon atoms, and therefore may exist as racemates and the (R) and (S) enantiomers thereof. All are within the scope of the invention.
  • the compounds of the invention of formula I are prepared by condensing a compound of the formula
  • L', V, alk, W and Z have meaning as defined hereinabove.
  • the condensation using a carboxylic acid, is carried out under conditions well known in the art for the preparation of amides, and as illustrated in the examples, in the presence of condensing agents such as 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (EDCI) optionally in combination with 1 -hydroxy-7-azabenzotriazole (HOAt).
  • EDCI 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride
  • HOAt 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride
  • HOAt 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride
  • HOAt 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride
  • HOAt
  • the substituted aryl carboxylic acids of formula V are prepared as follows.
  • Ri represents aryl or heteroaryl and L is arylene or heteroarylene
  • L is arylene or heteroarylene
  • acids of formula VII wherein Ri is aryl or heteroaryl and R 2 - R 5 have meaning as defined above for compounds of formula III are prepared as exemplified in the scheme below by palladium catalyzed coupling of aryl boronic acids of formula VIII with bromo-, iodo- or trifluromethanesulfonoxy- substituted arylcarboxylic acid esters e.g., of formula IX. Subsequent hydrolysis of the ester group of resulting compounds of formula X gives the carboxylic acids of formula VII.
  • Reactive derivatives of the carboxylic acids are prepared by reaction with a chlorinating agent, such as oxalyl chloride.
  • a chlorinating agent such as oxalyl chloride.
  • the carboxylic acids of formula V wherein Ri represents aryl-lower alkoxy or aryl-lower alkylthio are prepared from the appropriate phenols or thiophenols by reaction with e.g. an aryl-lower alkyl halide e.g. as illustrated below.
  • the amine starting materials of formula VI are prepared according to general methods known in the art, e.g. as illustrated below and in the example herein.
  • Nitro intermediates of formula XII e.g. those wherein V is NR 0 and W is a direct bond are prepared by condensing a reactive aromatic nitro derivative of formula XIII
  • amine of formula XIV in the presence of a base, e.g. a tertiary amine such as triethylamine, in a polar solvent such as ethanol or dimethylsulfoxide.
  • a base e.g. a tertiary amine such as triethylamine
  • a polar solvent such as ethanol or dimethylsulfoxide.
  • nitro intermediates of formula XII wherein V is O or S are prepared by condensing e.g. a compound of formula XIII with the appropriate alcohol or thiol in the presence of a base, such as sodium hydride, in a solvent, such as dimethylformamide.
  • a base such as sodium hydride
  • Nitro intermediates of formula XII wherein V is O and W is a direct bond can also be prepared by condensing a nitro compound of formula XV with the appropriate alcohol in the presence
  • nitro compounds of formula XVII are in turn prepared by condensation of a reactive aromatic nitro derivative, e.g. of formula XIII, with a compound of formula XVIII
  • V is O, S or NR 0 ,
  • Z is e.g.— COR a , — COORd or — SO 2 R e as defined above.
  • the condensation is carried out in the presence of a base.
  • V is NR 0
  • the condensation is preferably carried ' oT.tlrrth ⁇ TB ⁇ Ti ⁇ e ⁇ gT ⁇ triethylamine, or sodium acetate, using a polar solvent such as ethanol.
  • V is O or S
  • the condensation is preferably carried out using a strong base, such as sodium hydride, in a solvent such as dimethylformanide.
  • V is O
  • intermediates of formula XVII can also be prepared by condensation of a nitro compound of formula XV with an alcohol of formula XVIII (V being O) in the presence of triphenylphosphine and diethyl azodicarboxylate.
  • nitro intermediates of formula XVII can be prepared by treating an amine of the formula
  • amine intermediates of formula XIX may be prepared by condensation of starting materials of formula XIII or XV with an appropriate compound of the formula HV- (CH 2 ) n NHR 0 .
  • the amines of formula XIX can be prepared by N-deprotection of compounds of formula XVII wherein Z is t-butoxycarbonyl under conditions well known in the art for the removal of a t-butoxycarbonyl group, e.g. with trifluoroacetic acid in methylene chloride.
  • compounds of the invention represented by formula IV can be prepared from compounds of formula IV wherein Z is t-butoxycarbonyl, prepared as described herein. Removal of the t-butoxycarbonyl, e.g. with trifluoroacetic acid in methylene chloride give amines of formula
  • R, R 0 , Ri, R 3 -R 5 , X, Y, V and n have meaning as previously described.
  • Compounds of formula IV wherein Z is heteroaryl-lower alkyl can be prepared similarly to previously described methods using e.g. an heteroaryl-alkyl halide, such as an heteroaryl- alkyl bromide.
  • Compounds of the invention of formula IV wherein V is a direct bond are prepared from either an intermediate of formula IVa or XVI wherein V is a direct bond according to processes previously described.
  • the starting materials of formula XVII wherein V is a direct bond can be prepared starting from the corresponding nitro-substituted (aryl or heteroaryl)-alkyl-carboxylic acids esters or alcohols according to methods well known in the art for the conversion of esters and alcohols to amines and substituted amines.
  • the starting materials of formula IVa may also be similarly prepared starting e.g. from the corresponding carboxylic acid derivatives which are prepared by acylation of an appropriate amino-substituted (aryl or heteroaryl)-alkylcarboxylic acid ester with an acid of e.g. formula VII.
  • the starting materials of formula IVa wherein V is a direct bond may also be prepared by deprotection of an intermediate of formula XVI wherein Z is t-butoxycarbonyl amino and V is a direct bond.
  • Such intermediate of formula XVI may be prepared by condensation of a nitro-substituted aryl or heteroaryl bromide with e.g. 3-(t-butoxycarbonylamino)-propyne in the presence of e.g. C ⁇ l, Pd (PPh 3 )CI 2 and triethylamine, followed by catalytic hydrogenation.
  • Compounds of the invention may be converted to other compounds of the invention.
  • a compound of formula IV wherein R 0 is hydrogen and Z is -SO 2 R ⁇ may be converted to the corresponding compound wherein R 0 is methyl, by treatment with e.g. methyl iodide in the presence of sodium hydride in dimethylformamide.
  • 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 example chlorides or bromides; activated esters for example succinimido, phthalimido or 4- nitrophenyl 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, or resolved by enzymatic resolution.
  • 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 or d- or I- camphorsulfonic acid).
  • Racemic products can also be resolved by chiral chromatography, e.g., high-pressure liquid chromatography using a chiral absorbent.
  • -especialJy-pharmaceutically ⁇ cceptaW inorganic acids such as mineral acids, for example sulfuric acid, a phosphoric or hydrohalic acid, or with organic carboxylic acids, such as (C ⁇ -C 4 )-alkanecarboxylic acids which, for example, are unsubstituted or substituted by halogen, for example 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, or with organic sulfonic acids, such as (CrC 4 )-alkylsulfonic acids (for example methanesulfonic acid) or arylsulfonic acids which are unsubstituted or substituted (for example by halogen).
  • organic carboxylic acids such as (C
  • 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, to inhibit microsomal triglyceride transfer protein (MTP) and apolipoprotein B (apo B) secretion, and 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.
  • enteral such as oral or rectal, transdermal and parenteral administration to mammals, including man, to inhibit microsomal triglyceride transfer protein (MTP) and apolipoprotein B (apo B) secretion, and 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.especially 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 polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or e
  • 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 to75%, preferably about 1 to 50%, of the active ingredient.
  • Suitable formulations for transdermal application include an effective amount of a compound of the invention with carrier.
  • transdermal devices include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • 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 skin.
  • Suitable formulations for topical application are preferably aqueous solutions, ointments, creams or gels well known in the art.
  • the pharmaceutical formulations contain an effective therapeutic amount of a compound of the invention as defined above, either alone or in combination with another therapeutic agent, at an effective therapeutic dose as reported in the art.
  • Such 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.
  • 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 treatment of elevated levels of MTP and of apo B and conditions related thereto.
  • the compounds of the invention are inhibitors of microsomal triglyceride 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 triglyceride transfer protein
  • apo B apolipoprotein B
  • Such compounds are therefore useful for the treatment and prevention of hyperlipidemia, hypercholesterolemia and hypertriglyceridemia and diseases associated therewith, e.g., cardiovascular diseases including cardiac ischemia, atherosclerosis and its clinical sequelae, as well as obesity, pancreatitis and diabetes.
  • the above-cited properties are demonstrable in vitro and in vivo tests using advantageously mammals, e.g., rats, hamsters, mice, dogs, monkeys, and isolated cells or enzyme preparations.
  • Said compounds can be applied in vitro in the form of solutions, e.g., aqueous solutions, and in vivo advantageously orally, topically or parenterally, e.g., intravenously.
  • the dosage in vitro may range from about 10 '5 to 10 '9 molar concentrations.
  • 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.
  • Hep G2 cells are maintained in T-75 culture flasks (Corning) in Dulbecco's modified Eagles
  • DMEM fetal calf serum Gibco-BRL
  • Hep G2 cells from the T-75 maintenance flasks are harvested and seeded in
  • Test compound is dissolved at 1 mg/mL (w/v;1-5 mM) in dimethyl sulfoxide DMSO; Sigma) as stock solution. 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. 100 ⁇ L of growth medium containing the test compound is added to separate wells of a 96-well culture plate containing Hep G2 cells.
  • DMEM fetal calf serum
  • 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.
  • 100 ⁇ 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.
  • Inhibitors are identified as compounds that decrease apo B secretion into the medium without decreasing the total cellular protein and/or cell viability.
  • an antisera for human apo B is made by immunizing rabbit with purified human apo 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). After an overnight incubation at 4 ° C, 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.
  • PBS phosphate buffered saline
  • SB % (w/v) bovine serum albumin
  • dilution buffer containing PBS/ 0.05% Tween 20 / 5 mM decyl sodium sulfate (Acros Organics) / 2% BSA, pH 7.4
  • 20 ⁇ L of growth medium from Hep G2 cells or 1 - 30 ng of apo B standards prepared in dilution buffer
  • 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 diethanolamine / 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 HCI, 1 mM EDTA, 0.02% sodium azide, pH 7.4) rinsed several times with the sucrose buffer.
  • a 57% homogenate (120 g/210 mL) of rat liver in 0.25M sucrose buffer is prepared by using a Potter-Elvehjem homogenizer. The homogenate is then centrif uged 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 10 mM Tris-HCI buffer pH 8.6. and centrifuged for 90 min at 105,000 x g. The washed pellet is then resuspended in 1 mM 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 ⁇ lowly-with ⁇ entle-mixing ⁇ The ⁇ uspension-is-kept ⁇ n ice-for-30-inin-and hen centrifuged at 105,000 g 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% NaN 3 , pH 7.4).
  • assay buffer 150 mM Tris-HCI, 40 mM NaCI, 1 mM EDTA, 0.02% NaN 3 , 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 mg of egg phosphatidylcholine (Sigma, cat. # P-3556), 5.2 mgs of cardiolipin (Sigma, Cat. # C-0563) and 8 mg 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 is 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 14,000 rpm 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 1 demonstrates an IC 50 of about 1nM in the apo B assay and an IC 50 of about 90 nM in the MTP 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 normolipidemic 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 normolipidemic rats.
  • the compound of example 1 lowers both plasma triglycerides and cholesterol at a dose of 5 mg/kg. p.o. in the rat.
  • 6-methyl-4'-trifluoromethyl-1,1'-biphenyl-2-carboxylic acid can be prepared as follows:
  • 3-Methylsalicylic acid is esterified to methyl 3-methylsalicylate by reaction under reflux for about 48 hours with methanol in the presence of trimethyl orthoformate (4.0 moles) and concentrated sulfuric acid (1.1 moles) while removing by distillation the generated methyl formate and replacing the methanol which is lost by distillation.
  • the reaction mixture is then evaporated to dryness at 40 9 under vacuum and toluene is added.
  • the toluene solution is washed with water, then 20% aqueous potassium bicarbonate solution and saturated sodium chloride solution.
  • the toluene solution is filtered through neutral activated aluminum oxide and evaporated to dryness to yield methyl 3-methylsalicylate as a liquid.
  • a solution of 155 g of methyl 3-methyl-2-trifluoromethylmethanesulfonyloxybenzoate, 107.8 g of potassium carbonate in 467.5 mL of THF and 935 g of deionized water is stirred under nitrogen for 20 minutes.
  • 15.0 g of Tetrakis(triphenylphosphine)palladium (0) and -1610 mL of boronate solution from step above are added and the reaction mixture is heated under gentle reflux ( ⁇ 64 9 C) for 16 hours.
  • the reaction mixture is cooled to room temperature and filtered through a pad of 40 g of the filter agent Celite ® 521.
  • the filter cake is washed with 100 mL of THF and the total filtrate is partially evaporated under reduced pressure (110-120 mbar/40 9 C) to remove about 1500 mL of distillate and obtain a three phase mixture (about 1250 mL).
  • 500 mL of f-Butyl methyl ether and 200 mL of 2% sodium chloride solution are added.
  • the mixture is stirred for 5 minutes and filtered through a pad of 40 g of Filter agent, Celite ® 521 and the filter cake is washed with 100 mL of f-butyl methyl ether.
  • the top organic layer (1100 mL) is separated from the bottom aqueous layer (950 mL).
  • the bottom aqueous layer (950 mL) is extracted with 300 mL of f-butyl methyl ether.
  • the combined upper organic phases are washed with 300 mL of 2% sodium chloride solution and evaporated under reduced pressure (28 mbar/40 9 C) to obtain methyl 6-methyl-4'- trifluoromethyl-1 ,1 '-biphenyl-2-carboxylate.
  • the organic layer is separated and the aqueous layer is washed with 250 mL of heptane.
  • the aqueous layer is acidified with 500 mL of 4N hydrochloric acid and extracted with ethyl acetate.
  • the ethyl acetate extract is washed with water and filtered through the filter agent Celite ® 521.
  • the ethyl acetate solution (ca.1000 mL) is evaporated under reduced pressure (110-120 mbar/40 9 C) to a volume of 600 mL to which is added heptane (3125 mL).
  • 2-(4-Trifluoromethyl-phenyl)-nicotinic acid methyl ester is prepared by palladium [PdCI 2 (dppf)] catalyzed coupling of 2-chloronicotinic acid methyl ester (1.45 g, 8.45 mmol) and 4- trifluoromethylbenzeneboronic acid (2.41 g, 12.68 mmol) to give an oil: 1 H NMR (CDCI 3 , 300 MHz): ⁇ 8.80 (1H, dd), 8.19 (1H, dd), 7.67 (4H, q), 7.40 (1H, dd), 3.70 (3H, s). MS (ES+) m/z 282 (M+1).
  • Step B ⁇ / 1 -[2-(2-Pyridinyl)ethyl]-1,4-benzenediamine
  • Step A A mixture of the product from Step A (1.98 g, 8.14 mmol) and 10% Pd/C (0.47g) in ethanol (80 mL) is shaken under 40 psi of hydrogen for 3 hours. The solution is filtered and concentrated under vacuum to give desired product as a pink solid.
  • Step C 6- ethyl- ⁇ -[4-[[2-(2-pyridinyl)ethyl]amino]phenyl]-4'-(trif luoromethyl)-[1 ,1 '- biphenyl]-2-carboxamide
  • triphenylphosphine (2.07 g, 7.89 mmol) in 20 mL of THF at room temperature is added diethyl azodicarboxylate (DEAD), (1.37 g, 7.89 mmol) dropwise with stirring. After 30 minutes, 2-(4-nitrophenyl) ethyl alcohol and 2-hydroxypyridine are added separately. The mixture is stirred at room temperature for 24 hours.
  • DEAD diethyl azodicarboxylate
  • Step C 6-Methyl-/V-[4-[2-(2-pyridinyloxy)ethyl]phenyl]-4'-(trifluoromethyl)-[1 ,1 '- biphenyl]-2-carboxamide
  • Step B /v-[4-[2-[(Phenylsulfonyl)amino]ethyl]phenyl]-4'-(trifluoromethyl)-[1 ,1 '- biphenyl]-2-carboxamide
  • Step A ⁇ . 1 -(4-Nitrophenyl)-1,2-ethanediamine
  • Step B [2-[(4-Nitrophenyl)amino]ethyl]-carbamic acid, methyl ester
  • Methyl chloroformate (261 mg, 2.76 mmol) is added to a solution of the diamine derivative from Step A (500 mg, 2.76 mmol) in 10 mL of DMF containing triethylamine (559 mg, 5.52 mmol) at 0 9 C. The mixture is allowed to warm to room temperature and is stirred overnight after which it is partitioned between water and ethyl acetate. The organic solution is washed with brine, dried over sodium sulfate, filtered, and concentrated to give the desired compound as a yellow solid; MS: 240 (M + 1).
  • Step D [2-[[4-[[[6-Methyl-4'-(trifluoromethyl)-[1 ,1 '-biphenyl]-2-yl]carbonyl]amino]- phenyl]amino]ethyl]-carbamic acid, methyl ester
  • Step B [2-(4-Aminophenoxy)ethyl]-carbamic acid, t-butyl ester
  • Step A The nitrobenzene derivative from Step A (590 mg) is shaken under 40 psi of hydrogen gas in ethanol with 60 mg of 10% palladium on carbon at room temperature overnight. The reaction is then filtered and concentrated to give the desired aniline derivative as an oil. MS: 253 (M + 1).
  • Step C 2-[[4-[[6-Methyl-4'-(trif luoromethyl)-[1 , 1 '-biphenyl]-2-yl]carbonyl]amino]- phenoxy]ethyl]-carbamic acid, t-butyl ester
  • Step D ⁇ /-[4-(2-Aminoethoxy)phenyl]-6-methyl-4'-(trifluoromethyl)-[1 ,1 '-biphenyl]-2- carboxamide
  • Trifluoroacetic acid (1.55 g, 13.6 mmol) is added to a solution of the BOC derivative from Step C (700 mg, 1.36 mmol) in methylene chloride at 0 9 C. The mixture is allowed to warm to room temperature and stirred overnight after which it is concentrated. The residue is partitioned between 1 N HCI and ethyl acetate. The aqueous layer is basified with 6N sodium hydroxide to pH 12 and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered, and concentrated to give the desired product as a yellow foam. MS: 415 (M + 1). Step E.
  • Step A [2-[(5-Nitro-2-pyridinyl)amino]ethyl]-carbamic acid, t-butyl ester
  • Step B [2-[(5-Amino-2-pyridinyl)amlno]ethyl]- carbamic acid, t-butyl ester
  • Step C [2-[[5-[[[4'-(Trifluoromethyl)-[1 ,1 '-biphenyl]-2-yl]carbonyl]amino]-2-pyridinyl]- amino]ethyl]-carbamic acid, t-butyl ester
  • Trifluoroacetic acid (4.39 g, 38.5 mmol) is added to a suspension of the t-BOC derivative from Step C (1.93 g, 3.85 mmol) in methylene chloride at room temperature.
  • the reaction mixture is stirred 24 h, then concentrated under vacuum.
  • Toluene (4 mL) is added to the residue and the mixture is again concentrated under vacuum. Toluene addition and concentration is repeated twice more, and the residue is taken up in a small amount of water.
  • Sodium carbonate (3 g in 20 mL of water) is added with stirring, and the mixture is extracted with ethyl acetate and MTBE. The organic solution is washed with brine, dried over magnesium sulfate, and concentrated to give desired product as an off-white foam.
  • MS 401.1 (M + 1).
  • Step E [2-[[5-[[[4'-(Trif luoromethyl)-[1 ,1 '-biphenyl]-2-yl]carbonyl]amino]-2- pyridinyl]amino]ethyl]-carbamic acid, methyl ester
  • Hard gelatin capsules comprising 50 mg active substance can be prepared for example as follows:
  • composition for 1000 capsules
  • Active ingredient 50.0 g
  • the sodium lauryl sulfate is added to the active ingredient. Both components are intimately mixed. Then first the lactose is added and then the microcrystalline cellulose. Thereupon these components are intimately mixed for a further 10 minutes. Finally the magnesium stearate is added. After 3 minutes of further mixing, the formulation is filled into hard gelatin capsules of size 0 (340 mg each).

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Abstract

L'invention concerne des composés représentés par la formule (I), dans laquelle, R1, L, L', alk, W et Z ont les significations décrites, ainsi que les sels pharmaceutiquement acceptables de ces composés. Ces composés et sels sont utiles en tant qu'inhibiteurs de la protéine microsomale de transfert des triglycérides (MTP) et de la sécrétion de l'apolipoprotéine B (apo B).
PCT/EP2001/004052 2000-04-10 2001-04-09 Derives d'(hetero)aryl-carboxamide en tant qu'inhibiteurs de la proteine microsomale de transfert des triglycerides (mtp) et de la secretion d'apolipoproteine b (apo b) Ceased WO2001077077A1 (fr)

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AU2001262185A AU2001262185A1 (en) 2000-04-10 2001-04-09 Substituted (hetero)aryl carboxamide derivatives as microsomal triglyceride transfer protein (mtp) and apolipoprotein b (apo b) secretion

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US09/545,620 2000-04-10

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Cited By (13)

* Cited by examiner, † Cited by third party
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WO2002028835A1 (fr) * 2000-10-05 2002-04-11 Fujisawa Pharmaceutical Co., Ltd. Composés à base de benzamide, inhibiteurs des sécrétions d'apolipoprotéine b
WO2002042271A3 (fr) * 2000-11-21 2002-11-21 Janssen Pharmaceutica Nv Biphenylcarboxamides utiles comme hypolipidemiants
WO2002098839A1 (fr) * 2001-06-01 2002-12-12 Tanabe Seiyaku Co., Ltd. Biphenylcarboxamides et procede de preparation de ceux-ci
US6720351B2 (en) 2001-06-28 2004-04-13 Pfizer Inc. Triamide-substituted heterobicyclic compounds
WO2004056775A1 (fr) * 2002-12-20 2004-07-08 Pfizer Products Inc. Inhibiteurs de proteine de transfert de triglyceride microsomale
US7169796B2 (en) 2000-09-04 2007-01-30 Janssen Pharmaceutica N.V. Polyarylcarboxamides useful as lipid lowering agents
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
US8980915B2 (en) 2005-04-19 2015-03-17 Surface Logix, Inc. Inhibitors of microsomal triglyceride transfer protein and apo-B secretion
US10196359B2 (en) * 2014-08-24 2019-02-05 Fudan University 2-alkyloxy benzene formyl arylamine compound and pharmaceutical use thereof
US12344597B2 (en) 2018-06-07 2025-07-01 Idorsia Pharmaceuticals Ltd Alkoxy-substituted pyridinyl derivatives as LPA1 receptor antagonists and their use in the treatment of fibrosis
US12479820B2 (en) 2019-06-18 2025-11-25 Idorsia Pharmaceuticals Ltd Pyridin-3-yl derivatives

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WO1996040640A1 (fr) * 1995-06-07 1996-12-19 Pfizer Inc. DERIVES DE BIPHENYL-2-ACIDE CARBOXYLIQUE-TETRAHYDRO-ISOQUINOLEINE-6-YL AMIDES, PREPARATION DE CES AMIDES ET UTILISATION EN TANT QU'INHIBITEURS DE LA PROTEINE DE TRANSFERT DE TRIGLYCERIDE MICROSOMAL ET/OU DE LA SECRETION D'APOLIPOPROTEINES B (Apo B)
WO1998023593A1 (fr) * 1996-11-27 1998-06-04 Pfizer Inc. AMIDES INHIBANT LA SECRETION D'Apo B ET/OU LA PROTEINE MTP
WO1998027979A1 (fr) * 1996-12-20 1998-07-02 Bristol-Myers Squibb Company Inhibiteurs heterocycliques de la proteine de transfert des triglycerides microsomiques et methode associee
EP0887345A1 (fr) * 1997-06-23 1998-12-30 Pfizer Inc. Chlorhydrate de 4'-trifluoromethyl-[2-(2-acéthylaminoéthyl)-1,2,3,4-tétrahydroisoquinoléine-6-yl]-2-carboxamide comme inhibiteurs de sécrétion d'apo B et de MTP

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EP0643057A1 (fr) * 1993-09-03 1995-03-15 Bristol-Myers Squibb Company Inhibiteurs de la protéine microsomale de transfert des triglycerides
WO1996040640A1 (fr) * 1995-06-07 1996-12-19 Pfizer Inc. DERIVES DE BIPHENYL-2-ACIDE CARBOXYLIQUE-TETRAHYDRO-ISOQUINOLEINE-6-YL AMIDES, PREPARATION DE CES AMIDES ET UTILISATION EN TANT QU'INHIBITEURS DE LA PROTEINE DE TRANSFERT DE TRIGLYCERIDE MICROSOMAL ET/OU DE LA SECRETION D'APOLIPOPROTEINES B (Apo B)
WO1998023593A1 (fr) * 1996-11-27 1998-06-04 Pfizer Inc. AMIDES INHIBANT LA SECRETION D'Apo B ET/OU LA PROTEINE MTP
WO1998027979A1 (fr) * 1996-12-20 1998-07-02 Bristol-Myers Squibb Company Inhibiteurs heterocycliques de la proteine de transfert des triglycerides microsomiques et methode associee
EP0887345A1 (fr) * 1997-06-23 1998-12-30 Pfizer Inc. Chlorhydrate de 4'-trifluoromethyl-[2-(2-acéthylaminoéthyl)-1,2,3,4-tétrahydroisoquinoléine-6-yl]-2-carboxamide comme inhibiteurs de sécrétion d'apo B et de MTP

Cited By (26)

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Publication number Priority date Publication date Assignee Title
US8354402B2 (en) 2000-09-04 2013-01-15 Janssen Pharmaceutica N.V. Polyarylcarboxamides useful as lipid lowering agents
US7528154B2 (en) 2000-09-04 2009-05-05 Janssen Pharmaceutical N.V. Polyarylcarboxamides useful as lipid lowering agents
US7169796B2 (en) 2000-09-04 2007-01-30 Janssen Pharmaceutica N.V. Polyarylcarboxamides useful as lipid lowering agents
US7253157B2 (en) 2000-09-04 2007-08-07 Janssen Pharmaceutica N.V. Polyarylcarboxamides useful as lipid lowering agents
WO2002028835A1 (fr) * 2000-10-05 2002-04-11 Fujisawa Pharmaceutical Co., Ltd. Composés à base de benzamide, inhibiteurs des sécrétions d'apolipoprotéine b
WO2002042271A3 (fr) * 2000-11-21 2002-11-21 Janssen Pharmaceutica Nv Biphenylcarboxamides utiles comme hypolipidemiants
US7538124B2 (en) 2000-11-21 2009-05-26 Janssen Pharmaceutica N.V. Biphenylcarboxamides useful as lipid lowering agents
US7405307B2 (en) 2000-11-21 2008-07-29 Janssen Pharmaceutica N.V. Biphenylcarboxamides useful as lipid lowering agents
US7135586B2 (en) 2000-11-21 2006-11-14 Janssen Pharmaceutica, Nv Biphenylcarboxamides useful as lipid lowering agents
US7244848B2 (en) 2000-11-21 2007-07-17 Janssen Pharmaceutica N.V. Biphenylcarboxamides useful as lipid lowering agents
US7304167B2 (en) 2000-11-21 2007-12-04 Janssen Pharmaceutica N.V. Biphenylcarboxamides useful as lipid lowering agents
WO2002098839A1 (fr) * 2001-06-01 2002-12-12 Tanabe Seiyaku Co., Ltd. Biphenylcarboxamides et procede de preparation de ceux-ci
US7348355B2 (en) 2001-06-28 2008-03-25 Pfizer Inc. Triamide-substituted heterobicyclic compounds
US6720351B2 (en) 2001-06-28 2004-04-13 Pfizer Inc. Triamide-substituted heterobicyclic compounds
US7482368B2 (en) 2001-06-28 2009-01-27 Pfizer Inc Triamide-substituted heterobicyclic compounds
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
US7625948B2 (en) 2002-02-28 2009-12-01 Japan Tobacco Inc. Ester compound and medicinal use thereof
WO2004056775A1 (fr) * 2002-12-20 2004-07-08 Pfizer Products Inc. Inhibiteurs de proteine de transfert de triglyceride microsomale
US7432392B2 (en) 2003-08-29 2008-10-07 Japan Tobacco Inc. Ester derivatives and medical use thereof
US8101774B2 (en) 2004-10-18 2012-01-24 Japan Tobacco Inc. Ester derivatives and medicinal use thereof
US8980915B2 (en) 2005-04-19 2015-03-17 Surface Logix, Inc. Inhibitors of microsomal triglyceride transfer protein and apo-B secretion
US9656960B2 (en) 2005-04-19 2017-05-23 Surface Logix, Inc. Inhibitors of microsomal triglyceride transfer protein and apo-B secretion
US10196359B2 (en) * 2014-08-24 2019-02-05 Fudan University 2-alkyloxy benzene formyl arylamine compound and pharmaceutical use thereof
US12344597B2 (en) 2018-06-07 2025-07-01 Idorsia Pharmaceuticals Ltd Alkoxy-substituted pyridinyl derivatives as LPA1 receptor antagonists and their use in the treatment of fibrosis
US12479820B2 (en) 2019-06-18 2025-11-25 Idorsia Pharmaceuticals Ltd Pyridin-3-yl derivatives

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