EP1301464A1 - Amides d'acide diphenylcarboxylique, leur preparation et leur utilisation en tant que produits pharmaceutiques - Google Patents

Amides d'acide diphenylcarboxylique, leur preparation et leur utilisation en tant que produits pharmaceutiques

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Publication number
EP1301464A1
EP1301464A1 EP01945336A EP01945336A EP1301464A1 EP 1301464 A1 EP1301464 A1 EP 1301464A1 EP 01945336 A EP01945336 A EP 01945336A EP 01945336 A EP01945336 A EP 01945336A EP 1301464 A1 EP1301464 A1 EP 1301464A1
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EP
European Patent Office
Prior art keywords
alkyl
group
phenyl
carbonylamino
aminocarbonyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01945336A
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German (de)
English (en)
Inventor
Henning Priepke
Norbert Hauel
Leo Thomas
Michael Mark
Georg Dahmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
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Application filed by Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1301464A1 publication Critical patent/EP1301464A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07C311/21—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 six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D295/12—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 singly or doubly bound nitrogen atoms
    • C07D295/135—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 singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D295/16—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 acylated on ring nitrogen atoms
    • C07D295/18—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 acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D295/16—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 acylated on ring nitrogen atoms
    • C07D295/20—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 acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • the present invention relates to biphenylcarboxamides of the general formula
  • the compounds of the general formula I above are valuable inhibitors of the microsomal triglyceride transfer protein (MTP) and are therefore suitable for lowering the plasma levels of the atherogenic lipoproteins.
  • MTP microsomal triglyceride transfer protein
  • R 1 , R 2 and R 3 which may be the same or different, are each a hydrogen, fluorine, chlorine or bromine atom, a straight-chain or branched C 1 . 3 -alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, a hydroxy, C 1 . 3- alkoxy, amino, C 1 _ 3 -alkylamino or di- (C 1 _ 3 -alkyl) -amino group, where R 1 and R 2 in the ortho, ortho 'position of the biphenyl radical of the formula I together can also represent a carbonyl group,
  • R 4 represents a hydrogen atom or a C 1 _ 3 alkyl group
  • R 5 represents a hydrogen atom or a straight-chain or branched one
  • 3- alkyl-carbonyl-, benzoyl-, phenyl- (C ⁇ -alkyl) -carbonyl-, C 1 _ 3 -alkyl-aminocarbonyl-, di- (C 1. 3 -alkyl) -aminocarbonyl-, phenylaminocarbonyl- or N - (C 1-4 alkyl) phenylaminocarbonyl substituted imino group can be replaced,
  • the two hydrogen atoms of the methylene group in the 3-position of a cyclopentyl group or in the 3- or -position of a cyclohexyl or cycloheptyl group by an n-butylene, n-pentylene, n-hexylene, 1,2-ethylenedioxy or 1,3 -Propylenedioxy distr can be replaced or
  • one or two single bonds separated from one another by at least one bond and from position 1 can each be condensed with a phenyl radical
  • heteroaryl radical which is condensed via two adjacent carbon atoms or, in the case of a 5-membered heteroaryl radical, also via an imino nitrogen atom and an adjacent carbon atom with an aryl or heteroaryl radical,
  • methylene group in the 4-position of a 6- or 7-membered ring by an oxygen or sulfur atom or by an optionally by a oxy-carbonyl-, benzoyl-, phenyl- (Cj__ 3- alkyl-carbonyl) -, C ⁇ -alkyl-aminocarbonyl-, di- (C 1-3 -alkyl) -aminocarbonyl-, phenylaminocarbonyl- or N- (C 1 _ 3- alkyl) -phenylaminocarbonyl-substituted imino group can be replaced, or by a phenylaminosulfonyl or phenylsulfonylamino group
  • a phenylcarbonylamino-aryl phenylaminocarbonyl-aryl, N- (C 1, 3- alkyl) -phenylcarbonylamino-aryl or N- (C ⁇ -alkyl) -phenylaminocarbonyl-aryl group,
  • heteroarylcarbonylamino-aryl by a heteroarylcarbonylamino-aryl, heteroarylaminocarbonyl-aryl, heteroarylcarbonyl-N- (C x _ 3 -alkyl) -amino-aryl or heteroaryl-N- (C _ 2 -alkyl) -aminocarbonyl-aryl group,
  • aryl-aminocarbonylamino-aryl group in which one or both amino hydrogen atoms can each be replaced by a C 1 _ 3 -alkyl group
  • R 5 and R 6 together with the enclosed nitrogen atom are a 4- to 7-membered cycloalkyleneimino group in which the cycloalkylene part can be fused with a phenyl ring, R 7 is a hydrogen, fluorine, chlorine, bromine or iodine atom, a Cj__ 3 alkyl, C 1 . 3 -alkoxy, nitro or amino group,
  • aryl radical mentioned above means a phenyl, 1-naphthyl or 2-naphthyl radical
  • a 1, 4-butadienylene group can be added to the 5-membered heteroaromatic rings mentioned above via two adjacent carbon atoms or via an imino nitrogen atom and an adjacent carbon atom and also to the 6-membered heteroaromatic rings via two adjacent carbon atoms, and that bicyclic heteroaromatic rings formed in this way can also be bonded via a carbon atom of the 1,4-butadienylene group,
  • a hydrogen atom bonded to a nitrogen atom of the abovementioned 5-membered monocyclic or condensed heteroaryl radicals by a C x _ 3 alkyl, phenyl or phenyl C 1 . 3 -alkyl, C 1 _ 3 -alkylcarbonyl, phenylcarbonyl or phenyl-C ⁇ -alkylcarbonyl group can be replaced,
  • the methylene group in position 4 of a 6- or 7-membered cycloalkyleneimino group through an oxygen or sulfur atom, through a sulfinyl or sulfonyl group or through an optionally by a G ⁇ alkyl, phenyl, G ⁇ alkyl carbonyl, G ⁇ alkoxycarbonyl, C x _ 3 alkyl aminocarbonyl or di (G ⁇ alkyl) aminocarbonyl group substituted imino group can be replaced,
  • 3- alkyl, trifluoromethyl, G ⁇ - j -alkoxy, hydroxy and amino also disubsti- can be tuiert, where two adjacent hydrogen atoms in a phenyl group or a phenyl part contained in the groups defined above can also be replaced by a methylenedioxy or 1,2-ethylenedioxy group, or by three substituents selected from fluorine, chlorine and bromine atoms and C _ 3 -alkyl groups can also be trisubstituted, where the substituents can be the same or different and the above-mentioned phenyl groups or phenyl parts in turn can each be substituted by a fluorine, chlorine or bromine atom, by a methyl, trifluoromethyl or methoxy group,
  • the cycloalkylene part can be condensed with a phenyl ring or
  • one or two hydrogen atoms can each be replaced by a C x _ 3 alkyl group or / and
  • the hydrogen atoms in the G 1-4 alkyl and alkoxy groups mentioned in the definition of the abovementioned radicals can be partially or completely replaced by fluorine atoms, additionally a carboxy, amino or imino group present in the abovementioned radicals can be substituted by a radical which can be split off in vivo and can thus be present in the form of a prodrug radical,
  • a imino or amino group in vivo "releasable group such as a hydroxy group, an acyl group, such as the benzoyl or pyridinoyl group or a C 1 _ 16 alkanoyl group such as formyl, acetyl, propionyl, butyl tanoyl -, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a ⁇ such as methoxy carbonyl, ethoxycarbonyl, propoxycarbonyl, bonyl- Isopropoxycar-, butoxycarbonyl, tert .Butoxycarbonyl-, nyl- Pentoxycarbo-, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, Undecyloxycarbonyl-, dodecyloxycarbonyl or Hexadec
  • R e a C 5 _ 7 cycloalkyl, phenyl or phenyl G ⁇ alkyl group
  • R f is a hydrogen atom, a G ⁇ alkyl, C 5 . 7- cycloalkyl or phenyl group and
  • R g is a hydrogen atom, a C 1 . 3 alkyl or
  • R e represents C0-0- (R f CR g ) -O group in which R e to R g are defined as mentioned above,
  • ester residues can also be used as a group which can be converted into a carboxy group in vivo.
  • definition of the above and below-mentioned saturated alkyl and alkoxy parts which contain more than 2 carbon atoms also include their branched isomers, such as the isopropyl, tert-butyl, isobutyl group etc., unless stated otherwise ,
  • R 1 is a hydrogen, fluorine, chlorine or bromine atom or a C ⁇ _ 3 alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms,
  • R 2 is a hydrogen atom or a G ⁇ alkyl group or
  • R 3 , R 4 and R s which may be the same or different, each represent a hydrogen atom or a C 1-4 alkyl group
  • R 6 is a straight-chain or branched C 1 . 4 -alkyl group
  • each the methylene group in the 4-position of the cyclohexyl radical through an oxygen or sulfur atom or through one optionally through a C 1 . 3 alkyl, phenyl, C 1 . 3 alkyl carbonyl, , Benzoyl, C x .
  • 3- alkyl-aminocarbonyl, di- (G ⁇ -alkyl) aminocarbonyl, phenylaminocarbonyl or N- (G ⁇ -alkyl) -phenylaminocarbonyl group substituted imino group can be replaced, a phenylamino, 1-naphthylamino or 2-naphthylamino group optionally substituted on the nitrogen atom by a C 1 _ 3 -alkyl group,
  • the two hydrogen atoms of the methylene group in the 3-position of a cyclopentyl group or in the 4-position of a cyclohexyl group can be replaced by an n-butylene, n-pentylene, 1, 2-ethylenedioxy or 1, 3-propylenedioxy group or
  • a fluorine, chlorine, bromine or iodine atom by an optionally by a fluorine, chlorine, bromine or iodine atom, a straight-chain or branched C 1-4 alkyl group, a trifluoromethyl, hydroxy, C 1 . 3 -alkoxy-, difluoromethoxy-, benzyloxy-, amiomethyl-, amino-,, ⁇ - alkylamino-, di- ( ⁇ -alkyl) -amino-, phenylamino-, N- (C ⁇ -alkyl) -phenylamino-, Acetylamino, acetyl, propionyl, benzoyl, hydroxycarbonyl, C ⁇ alkoxycarbonyl, aminocarbonyl, G ⁇ alkylamino carbonyl, di (G ⁇ alkyl) amino carbonyl, 2nd , 2, 2-trifluoroethylaminocarbonyl,
  • a phenyl-C ⁇ C or phenyl-CH CH radical, each in the phenyl part by a fluorine, chlorine, bromine or iodine atom, by a straight-chain or branched C - ⁇ - alkyl or C 1 _ 3 Alkoxy group, can be substituted by a trifluoromethyl, dimethylamino, phenyl or cyano group, by an indolyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl or quinazolinyl group bonded via a carbon atom or, in the case of the first two groups, also via a nitrogen atom,
  • a phenyl group by a carbon atom, optionally by a fluorine, chlorine, bromine or iodine atom, by a straight-chain or branched C 1-4 alkyl group, by a C 3 . 7- cycloalkyl, trifluoromethyl, phenyl or cyano group substituted heteroaryl group is substituted,
  • C 3 _ 7 cycloalkyl radical where each the methylene group in the 4-position of the cyclohexyl radical through an oxygen or sulfur atom or through one optionally through a C 1 .
  • aminocarbonyl by an aminocarbonyl, C ⁇ _ 3 alkyl aminocarbonyl, benzyl aminocarbonyl, di (C ⁇ alkyl) aminocarbonyl, aminocarbonyl G L. 3 -alkyl aminocarbonyl or C x . 3 alkoxy carbonyl C. ⁇ 3 alkyl aminocarbonyl group
  • R s and R 6 together with the enclosed nitrogen atom represent a pyrrolidino or piperidino group
  • R 7 represents a hydrogen, fluorine, chlorine or bromine atom, a G ⁇ alkyl group, a nitro or amino group,
  • one of the abovementioned heteroaryl groups is optionally in the carbon skeleton by up to three C 1 .
  • 3- alkyl groups substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl , 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 1-imidazolyl, 2-imidazolyl, 4- Imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, [1, 2, 3] thiadia zol-4-yl, benzimidazol-2-yl, benzimidazol-5-yl, or imidazo [1, 2-a]
  • phenyl groups, heteroaryl groups, aromatic or heteroaromatic molecular parts in the carbon skeleton can optionally be additionally substituted by a fluorine, chlorine or bromine atom, by a cyano group or by a straight-chain or branched G ⁇ alkyl or trifluoromethyl group,
  • R 1 is a hydrogen, fluorine, chlorine or bromine atom, a G ⁇ alkyl or trifluoromethyl group,
  • R 2 is a hydrogen atom or a G ⁇ alkyl group or
  • R 3 and R 4 each represent a hydrogen atom
  • R 5 is a hydrogen atom or a C 1 . 3 -alkyl group
  • R ⁇ is a straight-chain or branched C - ⁇ - alkyl group
  • a phenyl, biphenyl or phenyl-C 1 _ 3 -alkylphenyl group a in the 1-position, optionally substituted by a cyclopropyl group or a C 1 _ 3 -alkyl group, a straight-chain C 1 -C 4 -alkyl group, the terminal
  • a phenyl or biphenyl group each by a fluorine, chlorine or bromine atom, by a straight-chain or branched C 1 . 4 -alkyl group, can be substituted by a trifluoromethyl, hydroxy, phenylamino or N- (G ⁇ -alkyl) phenylamino group,
  • a phenyl group which is replaced by a 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4 -Pyridazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl , 2-thiazolyl-, 4-thiazolyl-, 5-thiazolyl-, [1, 2, 3] -thiadiazol-4-yl-, benzimidazol-2-yl- or imidazo- [1, 2-a] pyridin-2 -yl group is substituted, wherein the heteroaromatic groups mentioned in the carbon skeleton by a fluorine, chlorine or bromine atom, by a phenyl, C - ⁇
  • a phenyl group which is substituted by a pyrrolidino or piperidino group which may be condensed with a phenyl group
  • a phenyl-C ⁇ C radical in the phenyl part by a fluorine, chlorine or bromine atom, by a straight-chain or branched C 1 . 4 alkyl or C 1 . 3 -alkoxy group, can be substituted by a trifluoromethyl or phenyl group, by a on the nitrogen atom, optionally by a C _ 3 alkyl, C x _ 3 alkyl carbonyl, benzoyl.
  • G alkyl aminocarbonyl, di (C 1 _ 3 alkyl) aminocarbonyl, Phenylaminocarbonyl or N- (C 1-4 alkyl) phenylaminocarbonyl group substituted 4-piperidinyl group,
  • heteroaryl-carbonylamino-phenyl or N- (C x _ 3 -alkyl) heteroaryl-carbonylamino-phenyl group the heteroaryl part being selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, 2- Pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl and [1, 2, 3] thiadiazol-4-yl, a hydrogen atom bonded to a nitrogen atom of a heteroaromatic radical and / or a hydrogen atom bonded to a carbon atom
  • R 7 represents a hydrogen, fluorine, chlorine or bromine atom, a G ⁇ alkyl group or an amino group
  • phenyl groups, heteroaryl groups, aromatic or heteroaromatic molecular parts in the carbon skeleton if appropriate additionally by a fluorine, chlorine or bromine atom, by a straight-chain or branched C 1 . 3 alkyl group, can be substituted by a cyano or a trifluoromethyl group, their tautomers, their diastereomers, their enantiomers, their mixtures and their salts.
  • the new compounds are obtained by processes known from the literature, for example by the following processes:
  • R 1 to R 4 and R 7 are defined as mentioned at the outset, and Z is one
  • R 5 and R 6 are defined as mentioned at the beginning.
  • reaction is advantageously carried out with a corresponding halide or anhydride of the general formula III in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulfolane, optionally in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C, carried out.
  • a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulfolane
  • an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C, carried out.
  • this can also be carried out with the free acid, if appropriate in
  • R 1 to R 3 are defined as mentioned at the outset, and Z is one
  • R 4 and R 7 are defined as mentioned at the beginning.
  • reaction can be carried out in accordance with the conditions mentioned above in process (a).
  • a compound of the general formula I which contains an amino, alkylamino or imino group, this can be converted into a corresponding acyl or sulfonyl compound of the general formula I by means of acylation or sulfonylation or
  • the subsequent acylation or sulfonylation is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene zol, tetrahydrofuran, benzene / tetrahydrofuran or dioxane with a corresponding acyl or sulfonyl derivative, optionally in the presence of a tertiary organic base or in the presence of an inorganic base or in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, sulfuric acid, Methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, M, N '-dicyclohexylcarbodiimide, N, N * -dicyclohexylcarbodiimi
  • the subsequent alkylation is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane with an alkylating agent such as a corresponding halide or sulfonic acid ester, e.g. with methyl iodide, ethyl bromide, dimethyl sulfate or benzyl chloride, optionally in the presence of a tertiary organic base or in the presence of an inorganic base, conveniently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C.
  • a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or di
  • the subsequent reductive alkylation is advantageously carried out with a corresponding carbonyl compound such as formaldehyde, acetaldehyde, propionaldehyde, acetone or butyraldehyde in the presence of a complex metal hydride such as sodium borohydride, lithium borohydride or sodium cyanoborohydride at a pH of 6-7 and at room temperature or in the presence of a hydrogenation catalyst, for example with hydrogen in the presence of palladium / carbon, at a hydrogen pressure of 1 to 5 bar.
  • a complex metal hydride such as sodium borohydride, lithium borohydride or sodium cyanoborohydride
  • a hydrogenation catalyst for example with hydrogen in the presence of palladium / carbon, at a hydrogen pressure of 1 to 5 bar.
  • the methylation is preferably increased in the presence of formic acid as a reducing agent Temperatures, for example at temperatures between 60 and 120 ° C, carried out.
  • the subsequent esterification is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane or particularly advantageously in a corresponding alcohol, optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent .Means, e.g.
  • the subsequent amidation is carried out by reacting an appropriate reactive carboxylic acid derivative with an appropriate amine, if appropriate in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, and the amine used can simultaneously serve as a solvent , optionally in the presence of a tertiary organic base or in the presence of an inorganic base or with a corresponding carboxylic acid in the presence of a dehydrating agent, for example: in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, O- (benzotriazol-1-yl) -N, N, N '
  • any reactive groups present such as hydroxyl, carboxy, amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups which are split off again after the reaction.
  • the trimethylsilyl, tert.butyldimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, trityl, benzyl or tetrahydropyryl group comes as a protective radical for a hydroxyl group
  • an amino, alkylamino or imino group the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group in addition consider the phthalyl group.
  • the subsequent subsequent splitting off of a protective radical used is carried out, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide or aprotic, for example in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.
  • an aqueous solvent for example in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as
  • a silyl group can also be split off using tetrabutylammonium fluoride as described above.
  • a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, for example using hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
  • a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • cleavage of a tert-butyl or tert. -Butyloxycarbonyl- rest is preferably carried out by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • an acid such as trifluoroacetic acid or hydrochloric acid
  • iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • a trifluoroacetyl radical is preferably split off by treatment with an acid such as hydrochloric acid, if appropriate in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C. or by treatment with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ° C.
  • a phthalyl radical is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.
  • the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
  • cis / trans mixtures can be converted into their ice and trans iso- mers, and compounds with at least one optically active carbon atom are separated into their enantiomers.
  • the cis / trans mixtures obtained can be chromatographed into their eis and trans isomers, the compounds of general formula I obtained which occur in racemates, according to methods known per se (see Allinger .NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of the general formula I with at least 2 asymmetric carbon atoms on the basis of their physicochemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, into their diastereomers, which, if they occur in racemic form, can subsequently be separated into the -enantiomers as mentioned above.
  • the separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives such as esters or amides, in particular acids and their activated derivatives or alcohols, with the racemic compound. and separating the diastereomeric salt mixture or derivative obtained in this way, for example on the basis of different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
  • optically active acids are, for example, the D and L forms of tartaric acid or dibenzoyl acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.
  • suitable optically active alcohols are (+) or (-) menthol and optically active acyl radicals in amides are, for example, (+) or (-) menthyloxycarbonyl.
  • the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids.
  • suitable acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the new compounds of formula I obtained in this way if they contain an acidic group such as a carboxy group, can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts.
  • bases which can be used here are sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • a compound of the general formula II is obtained, for example, by reacting a compound of the general formula
  • R 1 to R 3 are defined as mentioned at the outset and Z 1 represents a carboxy group or a reactive derivative of a carboxy group, with an amine of the general formula
  • R 4 to R 7 are defined as mentioned at the outset and Z 2 represents a protective group for a carboxy group, and subsequent cleavage of the protective group.
  • the amines of the general formula III in which R s represents a heteroaryl-aryl radical or a heteroaryl-aryl-C 1-6 alkyl group can, for example, by building up the heteroaromatic ring from suitably substituted aryl- or aryl-C 1-6 -alkyl- Educts, for example by condensation reactions with suitable dicarbonyl compounds.
  • biphenyl-2-carboxylic acids according to general formula IV are known from the literature or can be prepared from corresponding biphenyl starting materials by processes known from the literature.
  • 3-amino-benzoic acid amides according to the general formula VI are also known from the literature or can be prepared in a simple manner from optionally substituted 3-aminobenzoic acids by reaction with the corresponding amines.
  • the compounds of the general formula I and their physiologically tolerable salts have valuable pharmacological properties. These are particularly valuable inhibitors of the microsomal triglyceride transfer protein (MTP) and are therefore suitable for lowering the plasma levels of the atherogenic lipoproteins.
  • MTP microsomal triglyceride transfer protein
  • MTP inhibitors were identified by a cell-free MTP activity test. Solubilized liver microsomes from different species (eg rat, pig) can be used as an MTP source.
  • MTP source e.g rat, pig
  • To produce donor and acceptor vesicles lipids dissolved in organic solvents were mixed in a suitable ratio and applied to a glass vessel wall as a thin layer by blowing the solvent in a stream of nitrogen.
  • the solution used to prepare donor vesicles contained 400 ⁇ M phosphatidylcholine, 75 ⁇ M cardiolipin and 10 ⁇ M [ 14 C] -triolein (68.8 ⁇ Ci / mg).
  • a solution of 1.2 mM phosphatidylcholine, 5 ⁇ M triolein and 15 ⁇ M [ 3 H] -dipalmitoylphosphatidylcholine (108 mCi / mg) was used to produce acceptor vesicles. Vesicles are formed by wetting the dried lipids with test buffer and subsequent sonication. Vesicle populations of uniform size were obtained by gel filtration of the ultrasound-exposed lipids.
  • the MTP activity test contains donor vesicles, acceptor vesicles and the MTP source in test buffer. Substances were added from concentrated DMSO-containing stock solutions, the final concentration of DMSO in the test was 0.1%. The reaction was started by adding MTP.
  • the transfer process was stopped by adding 500 ⁇ l of a SOURCE 30Q anion exchange suspension (Pharmacia Biotech). The mixture was shaken for 5 minutes and the donor vesicles bound to the anion exchange material were separated by centrifugation. The radioactivity of [3H] and [14C] in the supernatant was determined by liquid scintillation measurement and from this the recovery of the acceptor vesicles and the triglyceride transfer rate were calculated. In the test described, the compounds of the general formula I show IC 5Q values ⁇ 100 ⁇ m.
  • the compounds of the general formula I and their physiologically tolerable salts are particularly suitable for lowering the plasma concentration of atherogenic apolipoprotein B.
  • apoB atherogenic apolipoprotein B.
  • VLDL very low density lipoproteins
  • LDL low density lipoproteins
  • Lp (a) lipoprotein
  • the daily dose required to achieve a corresponding effect in adults is between 0.5 and 500 mg, advantageously between 1 and 350 mg, but preferably between 5 and 200 mg.
  • the compounds of the formula I prepared according to the invention optionally in combination with other active substances such as other lipid-lowering agents, for example with HMG-CoA reductase inhibitors, cholesterol biosynthesis inhibitors such as squalene synthase inhibitors and squalene cyclase inhibitors, bile acid-binding resins, fibrates, Cholesterol absorption inhibitors, niacin, probucol, CETP inhibitors and ACAT inhibitors together with one or more inert customary carriers and / or diluents, for example with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / - sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fat-containing substances such as hard fat incorporate their suitable
  • N- (4-Benzoylamino-phenylmethyl) -3- (4'-trifluoromethylbiphenyl-2-carbonylamino) benzoic acid amide Prepared analogously to Example 7 from 3- (4'-trifluoromethylbiphenyl-2-carbonylamino) benzoic acid and 4-benzoylamino-phenylmethylamine in dichloromethane with the addition of propanephosphonic acid cycloanhydride and N-methylmorpholine. Yield: 30% of theory
  • N-phenyl-3- (biphenyl - -carbonylamino) -benzoic acid amide Prepared analogously to Example 34 from 3- (biphenyl-2-carbonylamino) -benzoic acid, aniline, TBTU and N-ethyldiisopropylamine in dirnethylformamide.
  • Example 36 N-tert. Butyl-3- (b-henyl-2-carbonylamino) -benzoic acid amide Prepared analogously to Example 34 from 3- (biphenyl-2-carbonylamino) -benzoic acid, tert-butylamine, TBTU and N-ethyldiisopropylamine in dimethylformamide.
  • N-Hydroxyethyl-3- (biphenyl-2-carbonylamino) -benzoic acid ami Prepared analogously to Example 34 from 3- (biphenyl-2-carbonylamino) -benzoic acid, 2-aminoethanol, TBTU and N-ethyl-diisopropylamine in dimethylformamide.
  • N- (4-isopropylphenylmethyl) -3- (4'-trifluoromethylbiphenyl-2-carbonylamino) benzoic acid amide Prepared analogously to Example 7 from 3- (4'-trifluoromethylbiphenyl-2-carbonylamino) benzoic acid and 4-isopropylbenzylamine in dichloromethane with the addition of propanephosphonic acid cycloanhydride and N-methylmorpholine. Yield: 58% of theory
  • Example 74 N- [4- (Pyridin-3 -yl-carbonylamino) -phenylmethyl] -3- (4'-trifluoromethyl.biphenyl-2-carbonylamino) -benzoic acid amide Prepared analogously to Example lf from N- (4-aminophenylmethyl) -3 - (4'-Trifluoromethylbiphenyl-2-carbonylamino) -benzoic acid amide and nicotinic acid chloride in tetrahydrofuran with the addition of triethylamine.
  • N- [4- (pyridin-4-yl-carbonylamino) phenylmethyl] -3- (4 '- trifluoromethylbiphenyl-2-carbonylamino) benzoic acid ami Prepared analogously to Example lf from N- (4-aminophenylmethyl) -3- ( 4'-trifluoromethylbiphenyl-2-carbonylamino) benzoic acid amide and isonicotinoyl chloride in tetrahydrofuran with the addition of triethylami.
  • N- [4- (2-methylphenylcarbonylamino) phenylmethyl] -3- (4 '- trifluoromethyl biphenyl-2-carbonylamino) benzoic acid amide Prepared analogously to Example lf from N- (4-aminophenylmethyl) -3- (4' - trifluoromethylbiphenyl -2-carbonylamino) benzoic acid amide and 2-tolyl chloride in tetrahydrofuran with the addition of triethylamine.
  • N- [4- (4-Methylphenylcarbonylamino) phenylmethyl] -3- (4 '- trifluoromethylbiphenyl-2-carbonylamino) benzoic acid amide Prepared analogously to Example lf from N- (4-aminophenylmethyl) -3- (4' -trifluoromethylbiphenyl -2-carbonylamino) -benzoic acid amide and 4-tolyl acid chloride in tetrahydrofuran with the addition of triethylamine.
  • N- [4- (5-Methylpyrazin-2-yl-carbonylamino] phenylmethyl-3- (4 '- trifluoromethylbiphenyl- carbonylamino) benzoic acid ami Prepared analogously to Example 7 from N- (4-aminophenylmethyl) -3- ( 4'-trifluoromethylbiphenyl-2-carbonylamino) benzoic acid amide and 5-methylpyrazine-2-carboxylic acid in dichloromethane with the addition of propanephosphonic acid cycloanhydride and N-methylmorpholine.
  • N- (9-fluorenyl) -3- (4'-trifluoromethylbiphenyl-2-carbonylamino) benzoic acid amide Prepared analogously to Example 34 from 3- (4 '-trifluoromethylbiphenyl-2-carbonylamino) benzoic acid, 9-aminofluorene hydrochloride, TBTU and N-ethyldiisopropylamine in dimethylformamide.
  • the active ingredient is mixed for 15 minutes together with lactose monohydrate, microcrystalline cellulose and carboxymethyl cellulose sodium in a suitable diffusion mixer. Magnesium stearate is added and mixed with the other substances for a further 3 minutes.
  • the finished mixture is compressed on a tablet press into round, flat tablets with a facet. Tablet diameter: 7 mm. Weight of one tablet: 120 mg
  • composition Active ingredient 50.0 mg
  • a starch paste is made by swelling part of the corn starch with an appropriate amount of hot water. The paste is then allowed to cool to room temperature.
  • the active ingredient is premixed in a suitable mixer with lactose monohydrate and corn starch for 15 minutes.
  • the starch paste is added and sufficient water is added to the mixture to obtain a homogeneous moist mass.
  • the moist mass is passed through a sieve with a mesh size of 1.6 mm.
  • the sieved granules are dried on trays at about 55 ° C for 12 hours.
  • the dried granulate is then passed through sieves with mesh sizes of 1.2 and 0.8 mm. Highly disperse silicon is mixed with the granules in a suitable mixer in 3 minutes. Then magnesium stearate is added and mixed for a further 3 minutes.
  • the finished mixture is filled into empty capsule shells made of size 1 hard gelatin using a capsule filling machine.
  • HPMC HPMC is dispersed in hot water. After cooling, the mixture gives a clear solution.
  • the active ingredient is premixed in a suitable mixer for 5 minutes with lactose monohydrate and microcrystalline cellulose.
  • the HPMC solution is added and mixing continued until a homogeneous moist mass is obtained.
  • the moist mass is passed through a sieve with a mesh size of 1.6 mm.
  • the sieved granules are dried on trays at about 55 ° C for 12 hours.
  • the dried granules are then passed through sieves with a mesh size of 1.2 and 0.8 mm.
  • Poly-l-vinyl-2-pyrrolidone is mixed with the granules in a suitable mixer for 3 minutes.
  • magnesium stearate is added and mixed for a further 3 minutes.
  • the finished mixture is compressed on a tablet press to oblong tablets (16.2 x 7.9 mm). Weight of one tablet: 480 mg

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Abstract

La présente invention concerne des dérivés de pipérazine substitués de formule générale (I) dans laquelle R1 à R7 sont tels que définis dans la revendication 1, leurs isomères et leurs sels, notamment leurs sels acceptables d'un point de vue physiologique, qui sont de bons inhibiteurs de la protéine microsomale de transfert de triglycéride (MTP). Cette invention concerne également des produits pharmaceutiques contenant ces composés, et leur utilisation ainsi que leur préparation.
EP01945336A 2000-07-08 2001-07-04 Amides d'acide diphenylcarboxylique, leur preparation et leur utilisation en tant que produits pharmaceutiques Withdrawn EP1301464A1 (fr)

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DE10033337 2000-07-08
DE10033337A DE10033337A1 (de) 2000-07-08 2000-07-08 Biphenylcarbonsäureamide, ihre Herstellung und ihre Verwendung als Arzneimittel
PCT/EP2001/007627 WO2002004403A1 (fr) 2000-07-08 2001-07-04 Amides d'acide diphenylcarboxylique, leur preparation et leur utilisation en tant que produits pharmaceutiques

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GB0000079D0 (en) 2000-01-05 2000-02-23 Ferring Bv Novel antidiuretic agents
WO2002062778A2 (fr) * 2001-02-02 2002-08-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Composes antithrombotiques, leur preparation et leur utilisation comme produits pharmaceutiques
IL158516A0 (en) 2001-06-28 2004-05-12 Pfizer Prod Inc Triamide-substituted indoles, benzofuranes and benzothiophenes as inhibitors of microsomal triglyceride transfer protein (mtp) and/or apolipoprotein b (apo b) secretion
DE10132686A1 (de) * 2001-07-05 2003-01-16 Boehringer Ingelheim Pharma Heteroarylcarbonsäureamide, ihre Herstellung und ihre Verwendung als Arzneimittel
EP1465613A2 (fr) * 2002-01-10 2004-10-13 Boehringer Ingelheim Pharma GmbH & Co. KG Combinaison d'inhibiteurs de mtp ou d'inhibiteurs de secretions apob avec des fibrates en vue d'une utilisation comme medicament
MXPA04002602A (es) 2002-02-28 2004-08-11 Japan Tobacco Inc Compuestos de ester y sus usos medicos.
BR0317323A (pt) * 2002-12-20 2005-11-16 Pfizer Prod Inc Inibidores de proteìna de transferência de triglicerìdeos microssomal
EP1669345A4 (fr) 2003-08-29 2008-02-20 Japan Tobacco Inc Derive d'ester et utilisation medicale de celui-ci
JP2007008816A (ja) * 2003-10-15 2007-01-18 Ube Ind Ltd 新規イソキノリン誘導体
FR2871463B1 (fr) * 2004-06-11 2006-09-22 Merck Sante Soc Par Actions Si Derives a structure aroyl-o-piperidine, leurs procedes de preparation, les compositions pharmaceutiques qui les contiennent et leurs applications en therapeutique
EP1632494A1 (fr) 2004-08-24 2006-03-08 Ferring B.V. Antagonistes de la v1a vasopressine
US8101774B2 (en) 2004-10-18 2012-01-24 Japan Tobacco Inc. Ester derivatives and medicinal use thereof
EP1911751A4 (fr) 2005-06-21 2010-10-20 Mitsui Chemicals Agro Inc Derive d'amide et pesticide contenant un tel compose
GB0607899D0 (en) * 2006-04-03 2006-05-31 Glaxo Group Ltd Process for preparing heterocyclic derivatives
US9353046B2 (en) 2012-04-03 2016-05-31 Mitsui Chemicals Agro, Inc. Method for producing alkylated aromatic amide derivative
UY37806A (es) 2017-07-11 2020-01-31 Vertex Pharma Carboxamidas como moduladores de los canales de sodio

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EP0832069B1 (fr) * 1995-06-07 2003-03-05 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)
US5968950A (en) * 1997-06-23 1999-10-19 Pfizer Inc Apo B-secretion/MTP inhibitor hydrochloride salt
EP1085846A2 (fr) * 1998-06-08 2001-03-28 Advanced Medicine, Inc. Inhibiteurs multiliaison de proteine triglyceride transferase microsomique
CA2325358C (fr) * 1999-11-10 2005-08-02 Pfizer Products Inc. Amides de l'acide 7-¬(4'-trifluoromethylbiphenyl-2-carbonyl)amino|-quinoleine-3-carboxylique et methodes pour inhiber la secretion d'apolipoproteine b

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