EP1210340A1 - Derives de piperazine substitues, leur fabrication et leur utilisation comme medicaments - Google Patents

Derives de piperazine substitues, leur fabrication et leur utilisation comme medicaments

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Publication number
EP1210340A1
EP1210340A1 EP00962322A EP00962322A EP1210340A1 EP 1210340 A1 EP1210340 A1 EP 1210340A1 EP 00962322 A EP00962322 A EP 00962322A EP 00962322 A EP00962322 A EP 00962322A EP 1210340 A1 EP1210340 A1 EP 1210340A1
Authority
EP
European Patent Office
Prior art keywords
group
phenyl
piperazin
methyl
alkyl
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Withdrawn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
EP00962322A
Other languages
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
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from DE1999139516 external-priority patent/DE19939516A1/de
Priority claimed from DE1999139745 external-priority patent/DE19939745A1/de
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1210340A1 publication Critical patent/EP1210340A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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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    • 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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    • C07D213/02—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
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    • 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
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
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    • 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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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07—ORGANIC CHEMISTRY
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having 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
    • C07D241/20—Nitrogen atoms
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    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—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
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    • 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
    • C07D295/15—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 to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C07D317/66—Nitrogen atoms not forming part of a nitro radical
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    • 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
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    • 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

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 3, 4 or 5
  • R a is a phenyl group substituted by the radicals R x and R 2 , where
  • R- L is a hydrogen, fluorine, chlorine or bromine atom, a 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 _ 4 alkoxy, Phenyl-C- 3- alkoxy-, carboxy-, C 1 _ 3 -alkoxycarbonyl-, aminocarbonyl-, C ⁇ - j -Alkylaminocarbonyl-, N, N-Di- (C._ 3- alkyl) -aminocarbonyl - (. 1 C 3 alkyl), nitro, amino, c._ 3 alkylamino, di- -amino-, phenyl-C 1.
  • R 2 is a hydrogen, fluorine, chlorine or bromine atom, a C ⁇ j alkyl group or
  • R x and R 2 together represent a methylenedioxy group
  • a monocyclic heteroaryl or phenyl group each of which is substituted by a phenyl or monocyclic heteroaryl group
  • the above-mentioned phenyl parts each having a fluorine, chlorine or bromine atom
  • the above-mentioned phenyl parts and heteroaryl groups each having a C 1 -3 alkyl group , in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, by a hydroxy, C 1 _ 3 alkoxy, carboxy, C- L. j -alkoxycarbonyl, aminocarbonyl, C 1 _ 3 -alkylaminocarbonyl or N, N-di- (C ⁇ -alkyl) -aminocarbonyl group may be substituted,
  • R b represents a hydrogen atom or a C 1-4 alkyl group
  • R c is a hydrogen atom
  • R d one optionally by a fluorine, chlorine or bromine atom, by a C 1 _ 3 alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, by a hydroxy, C x .
  • R e is a carboxy group, a C .. 6 alkoxycarbonyl or C 3 _ 7 cycloalkoxycarbonyl group, the carbon atom of the alkoxycarbonyl group linked to the oxygen atom being a primary or secondary carbon atom and the alkyl or cycloalkyl part of both groups in each case from position 2 based on the oxygen atom can be substituted by a C ..
  • heteroaryl groups mentioned above are 6-membered heteroaryl groups containing one, two or three nitrogen atoms and 5-membered heteroaryl groups containing an imino group optionally substituted by a C. 3 alkyl group, an oxygen or sulfur atom or an optionally substituted by a C. 1 _ 3 alkyl group substituted imino group and an oxygen or sulfur atom or one or two nitrogen atoms.
  • R e is defined as mentioned at the beginning
  • n is the number 3, 4 or 5
  • R a is a phenyl group which is substituted by the radicals R 2 and R 2 , where
  • R ⁇ is a hydrogen, chlorine or bromine atom, a C ⁇ alkyl, C 1 _ 3 alkoxy, benzyloxy, carboxy, C ⁇ alkyloxycarbonyl, nitro, amino, acetamino or methanesulfonylamino group and
  • R 2 is a hydrogen, chlorine or bromine atom or a methyl group or
  • R x and R 2 together represent a methylenedioxy group
  • biphenyl group which can be substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy or trifluoromethyl group,
  • R b is a hydrogen atom
  • R c a ⁇ . 2 alkyl or phenyl group
  • R d represents a phenyl group which is optionally substituted by a fluorine or chlorine atom, a methyl or methoxy group,
  • R e is defined as mentioned at the beginning
  • n is the number 3 or 4
  • R a is a phenyl group which is substituted by the radicals R x and R 2 , where
  • R x is a hydrogen, chlorine or bromine atom, a C ⁇ alkyl, C 1 _ 3 alkoxy or benzyloxy group and
  • R 2 represents a hydrogen, chlorine or bromine atom or a methyl group
  • biphenyl group which can be substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy or trifluoromethyl group,
  • a pyridyl, pyrimidyl, pyrazinyl, pyridazinyl or thienyl group which is optionally substituted by a phenyl group or a phenyl group substituted by a thienyl, thiazolyl, pyrrolyl, imidazolyl, pyridyl or benzimidazolyl group,
  • R b is a hydrogen atom
  • R c is a C - ⁇ - alkyl group
  • R d represents a phenyl group which is optionally substituted by a fluorine atom
  • the new compounds are obtained by processes known from the literature, for example by the following processes:
  • R a and R b are defined as mentioned above, with a compound of the general formula
  • n and R c to R e are defined as mentioned at the beginning and
  • Z- L means a nucleofugic leaving group such as a halogen atom, for example 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-butoxide or N-ethyl-diisopropylamine at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 60 ° C, performed.
  • 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-butoxide or N-ethyl-diisopropylamine at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 60 ° C, performed.
  • R a to R d are defined as mentioned above, or their reactive derivatives with an alcohol of the general formula
  • R- 1 is a C._ 6 alkoxy or C 3 _ 7 cycloalkoxy group, in which the alkyl or cycloalkyl part in each case from position 2, based on the oxygen atom, is replaced by a C 1-4 alkoxy, amino, C 1-4 alkyl group.
  • amino or di- (C ⁇ alkyl) amino group may be substituted, alkoxy, a phenyl-C 3 _-or heteroaryl-C ⁇ - j alkoxy, wherein the heteroaryl moiety is defined as mentioned above means, or Preparation of a tert-butyl ester, including 2, 2-dimethyl-ethene in the presence of an acid.
  • the reaction is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, but preferably in an excess of the alcohol of the general formula V used as solvent, optionally in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetic acid, 2, 2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus trichloride, phosphorus trichloride, phosphorus trichloride, phosphorus trichloride, phosphorus trichloride, phosphorus
  • reaction of a corresponding reactive compound of the general formula IV, such as its esters, imidazolides or halides, with an alcohol of the general formula V is preferably carried out in a corresponding alcohol as solvent, if appropriate in the presence of a further solvent such as methylene chloride or ether and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C.
  • the tert. Butyl ester formation with 2, 2-dimethyl-ethene is preferably in a solvent such as diethyl ether, dioxane, methylene chloride or tert-butanol in the presence of an acid such as sulfuric acid, hydrochloric acid or boron fluoride diethyl etherate at temperatures between -20 and 150 ° C, preferably at temperatures between 0 and 100 ° C.
  • a solvent such as diethyl ether, dioxane, methylene chloride or tert-butanol
  • an acid such as sulfuric acid, hydrochloric acid or boron fluoride diethyl etherate at temperatures between -20 and 150 ° C, preferably at temperatures between 0 and 100 ° C.
  • n and R a to R d are defined as mentioned at the beginning and
  • R e represents a group which can be converted into a carboxy group, into a compound of the general formula I, in which R e is a
  • a group which can be converted into a carboxy group is, for example, a carboxyl group protected by a protective radical, such as its functional derivatives, e.g. B. their unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or imino esters, which are expediently converted into a carboxyl group by means of hydrolysis,
  • esters with tertiary alcohols e.g. the tert. Butyl esters which are expediently converted into a carboxyl group by treatment with an acid or thermolysis, and
  • esters with aralkanols e.g. the benzyl ester, which are expediently converted into a carboxyl group by means of hydrogenolysis.
  • the hydrolysis is expediently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, water / ethanol, Water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane at temperatures between -10 and 120 ° C, for example at temperatures between room temperature and the boiling point of the reaction mixture.
  • an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof
  • a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide
  • a suitable solvent such as water, water / methanol, water
  • R e "in a compound of the formula VI is, for example, the tert-butyloxycarbonyl group
  • this can also be obtained by treatment with an acid such as trifluoroacetic acid, formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid, optionally in an inert solvent such as methylene chloride, chloroform , Benzene, toluene, diethyl ether, tetrahydrofuran or dioxane preferably at temperatures between -10 and 120 ° C, for example at temperatures between 0 and 60 ° C, or also thermally, if appropriate, in an inert solvent such as methylene chloride, chloroform, benzene, Toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfur
  • R e "in a compound of the formula VI is, for example, the benzyloxycarbonyl group
  • this can preferably also be hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide at temperatures between 0 and 50 ° C, for example at room temperature, and a hydrogen pressure of 1 to 5 bar.
  • a hydrogenation catalyst such as palladium / carbon
  • a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide
  • the subsequent reduction of a nitro group is expediently hydrogenolytic, for example 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) chloride , Sodium sulfide, sodium hydrogen sulfite 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.
  • a catalyst such as platinum
  • the trimethylsilyl, tert.butyldimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, trityl, benzyl or tetrahyropyryl group comes as a protective radical for a hydroxyl group
  • a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. 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, e.g. 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, 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 separated into their ice and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.
  • the cis / trans mixtures obtained can be broken down into their ice and trans isomers by chromatography, 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) into 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, to separate them into their diastereomers which, if they occur in racemic form, then subsequently, as mentioned above, into the antiomers can be separated.
  • 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 a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols, and separation of the diastereomeric salt mixture or derivative thus obtained, e.g. due to 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.
  • a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols
  • the D and L forms of tartaric acid or dibenzoyl tartaric 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 in their physiologically tolerable salts with inorganic or organic acids.
  • acids for this are hydrochloric acid, hydrobromic acid, sulfur Feic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the new compounds of formula I thus obtained 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.
  • 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
  • Inhibitors of MTP were identified using a commercially available MTP activity kit (WAK-Chemie Medical GmbH, Sulzbacherstrasse 15-21, D-65812 Bad Soden, Germany). This test kit contains donor and acceptor particles.
  • the donor particles contain fluorescence-labeled triglycerides in one Concentration that is so high that the fluorescence is self-quenched.
  • fluorescence-labeled triglycerides were transferred from the donor to the acceptor particles. This led to an increase in the fluorescence in the sample.
  • Solubilized liver microsomes from different species eg rat
  • Inhibitors of MTP were identified as those substances which reduced the transfer of fluorescence-labeled triglycerides compared to a control batch without an inhibitor.
  • 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) -containing lipoproteins such as chylomicrons and / or very low density lipoproteins (VLDL) and their remains, such as low-density lipoproteins (LDL) and / or lipoprotein (a) (Lp (a)), for the treatment of hyperlipidemia, for the prevention and treatment of atherosclerosis and its clinical consequences, and for the prevention and treatment of related diseases such as diabetes mellitus, obesity and pancreatitis, with oral administration being preferred.
  • apoB apolipoprotein B
  • VLDL very low density lipoproteins
  • LDL low-density lipoproteins
  • Lp (a) lipoprotein
  • related diseases such as diabetes mellitus, obesity and pancreatitis
  • 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, e.g.
  • 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
  • the present invention further relates to the intermediates of the general formula
  • R a and R b are defined as mentioned above, and their salts
  • the compounds of the general formula VII are obtained by processes known from the literature, for example by reacting a compound of the general formula
  • Z 2 is a protective group for an amino group, for example the tert. -Butoxycarbonyl- or benzyloxycarbonyl group, and R a ', 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 catalyst such as palladium acetate
  • a base such as potassium tert.
  • the protective group is split off using processes known from the literature and leads to a compound of the general formula VII.
  • 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 tert-butoxide in 40 ml of toluene is brought to 80 ° C. under nitrogen heated. Then 0.01 g (0.011 mmol) of tris (dibenzylideneactone) dipalladium (O) and 0.02 g (0.032 mmol) of 2,2'-bis (diphenylphosphino) -1, 1'-binaphthyl are added, Heated to 86 for 7 hours and stirred at room temperature for 14 hours.
  • Example 2a Prepared analogously to Example 2a from 1- (3 '-trifluoromethyl-biphenyl-3-yl) piperazine, 5-bromo-2-ethyl-2-phenyl-pentanecarboxylic acid methyl ester and dimethylformamide.
  • the reaction mixture was concentrated. The residue is filtered off and washed with water.
  • 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 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.
  • Example 40 The finished mixture is filled into empty capsule shells made of size 1 hard gelatin using a capsule filling machine.
  • Example 40
  • 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

Abstract

L'invention concerne des dérivés de pipérazine substitués de formule générale (I) dans laquelle Ra à Re et n sont définis comme dans la revendication 1. L'invention concerne également leurs isomères et leurs sels, en particulier leurs sels physiologiquement tolérables qui constituent des inhibiteurs précieux de la protéine de transfert de triglycéride microsomale (MTP). L'invention concerne enfin les médicaments contenant ces composés, leur utilisation et leur fabrication.
EP00962322A 1999-08-20 2000-08-16 Derives de piperazine substitues, leur fabrication et leur utilisation comme medicaments Withdrawn EP1210340A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE1999139516 DE19939516A1 (de) 1999-08-20 1999-08-20 Substituierte Piperazinderivate, ihre Herstellung und ihre Verwendung als Arzneimittel
DE19939516 1999-08-20
DE19939745 1999-08-21
DE1999139745 DE19939745A1 (de) 1999-08-21 1999-08-21 Substituierte Piperazinderivate, ihre Herstellung und ihre Verwendung als Arzneimittel
PCT/EP2000/007976 WO2001014355A1 (fr) 1999-08-20 2000-08-16 Derives de piperazine substitues, leur fabrication et leur utilisation comme medicaments

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EP1210340A1 true EP1210340A1 (fr) 2002-06-05

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JP (1) JP2003507463A (fr)
AU (1) AU7409300A (fr)
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US20100004287A1 (en) * 2006-05-22 2010-01-07 Merck Frosst Canada Ltd. Cyclic Derivatives as Inhibitors of Stearoyl-Coenzyme a Delta-9 Desaturase
KR101052620B1 (ko) * 2008-08-28 2011-07-29 한국과학기술연구원 신규 페닐아세테이트 유도체 또는 이의 약학적으로 허용가능한 염, 이의 제조방법 및 이를 유효성분으로 함유하는 ｔ-형 칼슘 이온 채널의 활성에 의해 유발되는 질환의 예방 또는 치료용 조성물

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BE642084A (fr) *
US4397855A (en) * 1981-06-26 1983-08-09 Warner-Lambert Company 4-(Substituted)-α, α-dimethyl-1-piperazine pentanoic acids and derivatives as anti-arteriosclerotic agents and method
US5700801A (en) * 1994-12-23 1997-12-23 Karl Thomae, Gmbh Piperazine derivatives, pharmaceutical compositions containing these compounds, their use and processes for preparing them

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