EP1228053A1 - Derives de piperazine substitues, fabrication et utilisation en tant qu'agents pharmaceutiques - Google Patents

Derives de piperazine substitues, fabrication et utilisation en tant qu'agents pharmaceutiques

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Publication number
EP1228053A1
EP1228053A1 EP00969264A EP00969264A EP1228053A1 EP 1228053 A1 EP1228053 A1 EP 1228053A1 EP 00969264 A EP00969264 A EP 00969264A EP 00969264 A EP00969264 A EP 00969264A EP 1228053 A1 EP1228053 A1 EP 1228053A1
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EP
European Patent Office
Prior art keywords
group
alkyl
phenyl
atoms
replaced
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.)
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Application number
EP00969264A
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German (de)
English (en)
Inventor
Thorsten Lehmann-Lintz
Armin Heckel
Leo Thomas
Michael Mark
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
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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 EP1228053A1 publication Critical patent/EP1228053A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
    • 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
    • C07D295/14—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms
    • 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 substituted piperazine derivatives of the general formula
  • the compounds of the general formula I above are valuable inhibitors of microsomal triglyceride transfer protein (MTP) and are therefore suitable for lowering the plasma levels of the atherogenic lipoproteins.
  • MTP microsomal triglyceride transfer protein
  • n is the number 1, 2, 3, 4 or 5
  • n 1 or 2
  • X is a carbon-carbon bond, an oxygen atom, a methylene, ethylene, imino or N (C 3 alkyl) mmo group
  • R a is a phenyl group or heteroaryl group substituted by the radicals R 1 and R 2 , where
  • Ri is a hydrogen, fluorine, chlorine or bromine atom, a C ⁇ - 3 alkyl group, m the hydrogen atoms can be replaced in whole or in part by fluorine atoms, a hydroxy group, a C ⁇ - 4 alkoxy group, m the hydrogen atoms entirely or can be partially replaced by fluorine atoms, a phenoxy, heteroaryloxy, phenyl -C 3 alkoxy, carboxy, C 3 alkoxycarbonyl, ammocarbonyl, C 3 alkyl ammocarbonyl, N, N-di (C ⁇ _ 3 -alkyl) -ammocarbonyl-, nitro-, amino, C ⁇ - 3 -alkylammo-, di- (C ⁇ _ 3 -alkyl) -ammo-, phenyl- C ⁇ - 3 -alkylamino, N- (C ⁇ - 3 -Alkyl) -phenyl-C ⁇ - 3 -al
  • R 2 is a hydrogen, fluorine, chlorine or bromine atom, a C ⁇ - 3 alkyl group, m the hydrogen atoms can be replaced in whole or in part by fluorine atoms, or a C ⁇ - 4 alkoxy group, m which the hydrogen atoms in whole or in part Fluorine atoms can be replaced, or Ri and R 2 together represent a methylenedioxy group,
  • Ra is a monocyclic heteroaryl or phenyl group, each of which is substituted by a phenyl or monocyclic heteroaryl group, the above-mentioned phenyl groups and heteroaryl groups in each case by a fluorine, chlorine or bromine atom, a C 3 alkyl group in which all or part of the hydrogen atoms can be replaced by fluorine atoms, by a hydroxy, C 3 alkoxy, carboxy, C 3 alkoxycarbonyl, ammocarbonyl, C 3 alkylammocarbonyl or N, N-di - (C ⁇ _ 3 alkyl) - ammocarbonyl group can be substituted,
  • R b and R c independently of one another are a hydrogen atom or a C 3 alkyl group and
  • R f and R g which may be the same or different, hydrogen atoms, C ⁇ - 6 alkyl groups, to which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, C 3 _-- cycloalkyl groups, phenyl, heteroaryl, phenyl C ⁇ _ 3rd -alkyl- or heteroaryl-C ⁇ _ 3 -alkyl groups, the above-mentioned phenyl groups and heteroaryl groups in each case by one to three fluorine, chlorine or bromine atoms, by one to three C ⁇ _ 3 alkyl groups in which the hydrogen atoms are completely or partially replaced by fluorine atoms can be by one to three hydroxy, one to three C ⁇ - 3 alkoxy groups, where the hydrogen atoms can be replaced in whole or in part by fluorine atoms, or by a carboxy, C ⁇ _ 3 alkoxycarbonyl, ammocarbonyl, C ⁇ - 3rd -Alkyl
  • n of the above-mentioned general formula I can be mono- or disubstituted by fluorine or chlorine atoms, by methyl or methoxy groups and the substituents can be the same or different.
  • heteroaryl groups are understood to mean a 6-membered heteroaryl group containing one, two or three nitrogen atoms, or a 5-membered heteroaryl group which may contain one to four heteroatoms such as nitrogen, oxygen and sulfur, with nitrogen bound hydrogen atoms can optionally be replaced by C 3 alkyl groups.
  • Preferred compounds of the general formula I above are those which m
  • n is the number 3, 4 or 5
  • X is a carbon-carbon bond, an oxygen atom, a methylene, ethylene, immo- or N- (C ⁇ _ 3 alkyl) -Immogrup-, R a is a phenyl group or heteroaryl group substituted by the radicals R 1 and R 2 , where
  • Ri is a hydrogen, fluorine, chlorine or bromine atom, a C ⁇ - 3 alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, a hydroxy group, a C ⁇ - 4 alkoxy group in which the hydrogen atoms are whole or can be partially replaced by fluorine atoms, a phenoxy, heteroaryloxy, phenyl -C 3 alkoxy, carboxy, C 3 alkoxycarbonyl, ammocarbonyl, C 3 alkylammocarbonyl, N, N-di (C ⁇ - 3 -alkyl) -ammocarbonyl-, nitro-, amino-, C ⁇ - 3 -alkylam ⁇ no-, di- (C ⁇ - 3 -alkyl) -amino-, phenyl-C ⁇ - 3 -alkyl-amino-, N- (C ⁇ - 3 -alkyl) -phenyl-C ⁇ _ 3
  • R 2 is a hydrogen, fluorine, chlorine or bromine atom, a C ⁇ - 3 alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, or a C ⁇ - 4 alkoxy group in which the hydrogen atoms can be replaced in whole or in part by Fluorine atoms can be replaced, or
  • Ri and R 2 together represent a methylenedioxy group, or R a e a monocyclic heteroaryl or phenyl group, each of which is substituted by a phenyl or monocyclic heteroaryl group, the above-mentioned phenyl groups and heteroaryl groups each having a fluorine, chlorine or bromine atom, a C 3 alkyl group, in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, can be substituted by a hydroxy or C 3 alkoxy group,
  • R b and R c independently of one another em hydrogen atom or a C ⁇ - 3 alkyl group and
  • R f and R g which can be the same or different, hydrogen atoms, C ⁇ _ 6 alkyl groups in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, C 3 _ 7 cycloalkyl groups, phenyl, heteroaryl, phenyl C ⁇ _ 3rd -alkyl- or heteroaryl-C ⁇ - 3 alkyl groups, the above-mentioned phenyl groups and heteroaryl groups in each case by em to three fluorine, chlorine or bromine atoms, by e to three C ⁇ - 3 alkyl groups, in which the hydrogen atoms are wholly or partly by Fluorine atoms can be replaced by one to three hydroxy, em to three C ⁇ _ 3 alkoxy groups, in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, or by a carboxy, C ⁇ - 3 alkoxycarbonyl, ammocarbonyl, C ⁇ - 3 -
  • R f and R g together with the intervening nitrogen atom form a 3- to 7-membered cycloalkylene immunogroup
  • n is the number 3, 4 or 5
  • n 2 or 3
  • X represents a carbon-carbon bond or an oxygen atom
  • R a is as defined above, and
  • R b and R c independently of one another em hydrogen atom or a methyl group
  • the new compounds are obtained by processes known from the literature, for example by the following processes:
  • R a , R b and R are defined as mentioned at the beginning, with a
  • n, R f , R g and the tricyclic system are defined as mentioned at the beginning and
  • Zi is a nucleofugic leaving group such as a halogen atom, e.g. is a chlorine, bromine or iodine atom.
  • the reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, acetone / water, dimethylformamide or dimethyl sulfoxide, optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium tert. butylate or N-ethyl-diisopropylamine at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 60 ° C.
  • a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, acetone / water, dimethylformamide or dimethyl sulfoxide
  • a base such as sodium hydride, potassium carbonate, potassium tert. butylate or N-ethyl-diisopropylamine at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 60 ° C.
  • R and R g are defined as mentioned above, or with their reactive derivatives.
  • reaction is expediently carried out using a corresponding halide or anhydride of the general formula IV in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulfolane, if appropriate 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.
  • a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulfolane, if appropriate 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.
  • the subsequent reduction of a nitro group is expediently carried out by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as platinum, palladium / carbon or Raney nickel in a suitable solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, dimethylformamide or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid and at a hydrogen pressure of 1 to 7 bar, but preferably from 1 to 5 bar, with metals such as iron, tin or zinc in the presence of an acid such as acetic acid or hydrochloric acid, with salts such as iron (II) sulfate, tin (II) chlo ⁇ d, sodium sulfide, sodium bisulfite or sodium dithionite , or with hydrazine in the presence of Raney nickel at temperatures between 0 and 100 ° C, but preferably at temperatures between 20 and 60 ° C.
  • the subsequent alkylation is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane, dimethyl sulfoxide or sulfolane with an alkylating agent such as a corresponding halide or sulfonic acid ester, for example with methyl iodide, ethyl, methyl bromide, or ethyl bromide, such as methyl iodide, ethyl Benzylchloride, optionally in the presence of a tertiary organic base or in the presence of an inorganic base, expediently 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, tol
  • 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 comes as a protective residue for a hydroxyl group.
  • Butyl, trityl, benzyl or tetrahyropyranyl group
  • protective residues for an amino, alkylamino or imino group the for yl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert. - Butoxycarbonyl-, Benzyloxycarbonyl-, Benzyl-, Methoxybenzyl- or 2, 4-Dimethoxybenzyl distr and for the amino group additionally 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.
  • 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, e.g. with 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.
  • the splitting off 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, ethylamm or n-butylamm, 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 separated into their ice and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.
  • the c ⁇ s- / trans mixtures obtained can be chromatographed into their ice 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 m "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms due to their physicochemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, m separate their diastereomers which, if they occur in racemic form, can then 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, for example, esters or amides, in particular acids and their activated derivatives or with the racemic compound Alcohols, and separation of the diastereomeric salt mixture or derivative obtained in this way, for example on the basis of different solubilities, the pure diastereomeric salts or Derivatives that can be released by the action of suitable agents.
  • an optically active substance which forms salts or derivatives such as, for example, esters or amides, in particular acids and their activated derivatives or with the racemic compound Alcohols
  • optically active acids are, for example, the D and L forms of tartaric acid or dibenzoylwemic acid, di-o-tolylwemic acid, malic acid, almond acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.
  • Suitable optically active alcohols are, for example, (+) - or (-) menthol, and optically active acyl radicals in amides are, for example, (+) - or (-) menthyloxycarbonyl m.
  • the compounds of formula I obtained, their salts, in particular for pharmaceutical use can be converted into their physiologically acceptable salts with inorganic or organic acids.
  • suitable acids for this 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 the formula I obtained in this way contain an acidic group such as a carboxy group, if desired, they can subsequently be converted into their salts with inorganic or organic bases, in particular for pharmaceutical use in their physiologically acceptable salts.
  • Suitable bases are, for example, sodium hydroxide, potassium hydroxide, arginine, cyclohexylam, ethanolamine, diethanolamm and tnethanolamm.
  • the compounds of general formulas II to VI used as starting materials are known from the literature or are obtained by processes known from the literature or are described in the examples.
  • the compounds of the general formula II are obtained, for example, by reacting a compound of the general formula
  • Z 2 represents a protective group for an amino group, for example the tert-butoxycarbonyl or benzyloxycarbonyl group
  • R a ' is, for example, a phenyl or monocyclic heteroaryl group substituted by a bromine or iodine atom means with a trifluoromethyl-substituted monocyclic aryl or heteroaryl group, which is additionally substituted by a boric acid residue, in the presence of a catalyst such as palladium acetate, a base such as potassium tert.
  • a compound of general formula III is obtained, for example, by reacting a corresponding disubstituted carboxylic acid with an ⁇ , ⁇ -dihaloalkane in the presence of a strong base such as lithium diisopropylamide, sodium amide or sodium hydride and then reacting the carboxylic acid with an appropriate amine.
  • a strong base such as lithium diisopropylamide, sodium amide or sodium hydride
  • the compounds of the general formula I and their physiologically acceptable salts have valuable pharmacological properties. These are particularly valuable inhibitors of the microsomal triglyceride transfer protease (MTP) and are therefore suitable for lowering the plasma levels of the atherogenic lipoprotems.
  • MTP microsomal triglyceride transfer protease
  • 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.
  • Solubilized liver microsomes from different species eg rat, pig
  • 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 as a thin layer to a glass vessel wall by blowing the solvent in a stream of nitrogen.
  • the solution used for the preparation of donor vesicles contained 400 ⁇ M phosphatidylcholine, 75 ⁇ M cardiolipin and 10 ⁇ M [ 1 C] tri-ol (68.8 ⁇ Ci / mg).
  • a solution of 1.2 mM phosphatidylcholm, 5 ⁇ M t ⁇ olein and 15 ⁇ M [ 3 H] -dipalmitoylphosphatidylcholm (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 lipids.
  • the MTP activity test contains donor vesicles, acceptor vesicles and the MTP source in the 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 compounds of the general formula I and their physiologically acceptable salts are particularly suitable for lowering the plasma concentration of atherogenic apolipoprotem B (apoB) -containing lipoproteins such as chylomicrons and / or very low density lipoproteins (VLDL) and their remains, such as low-density lipoprotems (LDL) and / or lipoproteins (a) (Lp (a)), for the treatment of hyperlipidamias, for the prevention and treatment of atherosclerosis and their clinical consequences, and for the prevention and treatment of related diseases such as diabetes mellitus, obesity and pancreatitis, with oral administration being preferred.
  • apoB apolipoprotem B
  • VLDL very low density lipoproteins
  • LDL low-density lipoprotems
  • a) lipoproteins
  • 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 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 inhibitors, Resins, fibrates, cholesterol absorption inhibitors, niacin, probucol, CETP inhibitors and ACAT inhibitors together with one or more inert conventional carriers and / or diluents, e.g.
  • a suspension of 1 g (4.29 mmol) of 3-bromobiphenyl, 2.2 g (25.54 mmol) of piperazine and 2.499 g (26 mmol) of sodium tertiary butoxide in 40 ml of toluene is heated to 80 under nitrogen. Then 0.01 g (0.011 mmol) of tris (dibenzylidene acetone) dipalladium (0) and 0.02 g (0.032 mmol) of BINAP are added, the mixture is heated to 86 for 7 hours and stirred at room temperature for 14 hours. Water and ethyl acetate are added in succession, the organic phase is separated off, dried over sodium sulfate and concentrated.
  • Example 2 b Prepared analogously to Example 2 b from 1- (4-fluorophenyl) piperazine and 9- (4-bromo-butyl) -9H-fluorene-9-carboxylic acid (2, 2, 2-t ⁇ fluoro-ethyl) -amide.
  • Example 2 b Prepared analogously to Example 2 b from 1- (2-methoxyphenyl) piperazine and 9- (4-bromo-butyl) -9H-fluorene-9-carboxylic acid (2, 2, 2-trifluoro-ethyl) -amide.
  • Example 2 b Prepared analogously to Example 2 b from l-pyridin-2-yl-piperazine and 9- (4-bromo-butyl) -9H-fluorene-9-carboxylic acid (2,2,2-trifluoroethyl) amide.
  • Example 2 b Prepared analogously to Example 2 b from 1- (6-methoxy-pyridin-2-yl) piperazine and 9- (4-bromo-butyl) -9H-fluorene-9-carboxylic acid-4-fluorobenzyl amide.
  • Example 2 b Prepared analogously to Example 2 b from 1- (6-methoxy-pyridin-2-yl) piperazine and 9- (4-bromo-butyl) -9H-fluorene-9-carboxylic acid.
  • Example 2 b Prepared analogously to Example 2 b from 1- (6-methyl-pyridin-2-yl) piperazine and 9- (4-bromo-butyl) -9H-fluorene-9-carboxylic acid.
  • Example 2 b Prepared analogously to Example 2 b from 1- (3-phenyl- [1, 2,] thia-diazol-5-yl) piperazine and 9- (4-bromo-butyl) -9H-fluorene-9-carbonic acid. (2,2,2-trifluoro-ethyl) amide.
  • 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
  • a starch paste is made by swelling part of the corn starch with a suitable 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 granulate in a suitable mixer for 3 minutes mixed. Then magnesium stearate is added and mixed for a further 3 minutes.
  • the finished mixture is filled into empty capsule shells made of hard gelatin size 1 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-1-vinyl-2-pyrrolidone is mixed with the granules in a suitable mixer for 3 minutes mixed. Then 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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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

La présente invention concerne des dérivés de pipérazine substitués, de formule générale (I), dans laquelle Ra, Rb, Rc, Rf, Rg, ainsi que m, n et X possèdent la signification de la revendication 1, les isomères et les sels de ces dérivés, en particulier leurs sels physiologiquement acceptables, représentant des inhibiteurs précieux de la protéine de transfert de triglycérides microsomale (MTP), des produits pharmaceutiques contenant ces composés, leur utilisation, ainsi que leur fabrication.
EP00969264A 1999-09-23 2000-09-19 Derives de piperazine substitues, fabrication et utilisation en tant qu'agents pharmaceutiques Withdrawn EP1228053A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19945594 1999-09-23
DE19945594A DE19945594A1 (de) 1999-09-23 1999-09-23 Substituierte Piperazinderivate, ihre Herstellung und ihre Verwendung als Arzneimittel
PCT/EP2000/009146 WO2001021604A1 (fr) 1999-09-23 2000-09-19 Derives de piperazine substitues, fabrication et utilisation en tant qu'agents pharmaceutiques

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DE19963234A1 (de) 1999-12-27 2002-01-24 Boehringer Ingelheim Pharma Substituierte Piperazinderivate, ihre Herstellung und ihre Verwendung als Arzneimittel
CN1522246B (zh) 2001-06-28 2010-04-21 辉瑞产品公司 三酰胺取代的吲哚、苯并呋喃及苯并噻吩
NZ531890A (en) 2002-02-28 2006-02-24 Japan Tobacco Inc Ester compound and medicinal use thereof
EP1669345A4 (fr) * 2003-08-29 2008-02-20 Japan Tobacco Inc Derive d'ester et utilisation medicale de celui-ci
US20060030623A1 (en) * 2004-07-16 2006-02-09 Noboru Furukawa Agent for the treatment or prevention of diabetes, obesity or arteriosclerosis
US8101774B2 (en) 2004-10-18 2012-01-24 Japan Tobacco Inc. Ester derivatives and medicinal use thereof
JP4782695B2 (ja) * 2004-10-25 2011-09-28 日本たばこ産業株式会社 溶解性及び安定性の改善された固形製剤及びその製造方法
KR20070072888A (ko) * 2004-10-25 2007-07-06 니뽄 다바코 산교 가부시키가이샤 용해성 및 안정성이 개선된 고형 제제 및 그의 제조 방법
EP2513057B1 (fr) * 2009-12-14 2013-09-04 Merck Patent GmbH Inhibiteurs de la sphingosine kinase
US9260400B2 (en) 2011-05-24 2016-02-16 Universita' Degli Studi Di Bari “Aldo Moro” I-arylpiperazinic ligands of 5-HT7 receptor and use thereof
US20150359798A1 (en) * 2011-09-06 2015-12-17 Jansfat Biotechnology Co., Ltd. Piperazinyl derivative reduces high-fat diet-induced accumulation of fat in the livers, therapeutically

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US2838509A (en) * 1956-10-02 1958-06-10 Searle & Co 9-aminoalkyl-9-xanthenecarboxamides
US5739135A (en) * 1993-09-03 1998-04-14 Bristol-Myers Squibb Company Inhibitors of microsomal triglyceride transfer protein and method
PL328094A1 (en) * 1996-01-16 1999-01-04 Bristol Myers Squibb Co Conformingly restricted aromatic inhibitors triglycerides carrying chromosome protein and method of obtaining such inhibitors
AU779550B2 (en) * 1999-04-09 2005-01-27 Meiji Seika Kaisha Ltd. Nitrogen-containing heterocyclic compounds and benamide compounds and drugs containing the same

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CA2388759A1 (fr) 2001-03-29
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WO2001021604A1 (fr) 2001-03-29
CA2388759C (fr) 2008-04-22
JP2003509505A (ja) 2003-03-11
MXPA02002838A (es) 2003-07-21
US6818644B1 (en) 2004-11-16
AU7904600A (en) 2001-04-24
WO2001021604A8 (fr) 2001-07-12

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