EP1259492A1 - Substituierte piperazinderivate als inhibitoren des mtp - Google Patents
Substituierte piperazinderivate als inhibitoren des mtpInfo
- Publication number
- EP1259492A1 EP1259492A1 EP00987409A EP00987409A EP1259492A1 EP 1259492 A1 EP1259492 A1 EP 1259492A1 EP 00987409 A EP00987409 A EP 00987409A EP 00987409 A EP00987409 A EP 00987409A EP 1259492 A1 EP1259492 A1 EP 1259492A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- alkyl
- phenyl
- butyl
- carboxylic acid
- 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- Withdrawn
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- 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
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
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- C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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- C07D295/22—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 hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
- C07D311/84—Xanthenes 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 in position 9
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- 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
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07C2601/14—The ring being saturated
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- C07C2602/00—Systems containing two condensed rings
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- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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- 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 pipazine derivatives of the general formula
- the compounds of the general formula I above are valuable inhibitors of the microsomal triglyceride transfer protein (MTP) and are therefore suitable for lowering the plasma levels of the atherogenic lipoproteins.
- MTP microsomal triglyceride transfer protein
- n is the number 2, 3, 4 or 5
- X is a carbon-carbon bond, an oxygen atom, a methylene, ethylene, imino or N- (C ⁇ -alkyl) -imino group
- Y a is a carbonyl or sulfonyl group
- Y b is the group - (CH 2 ) m - / where m is the number 2 or 3 and in which a hydrogen tom can be replaced by a C 3 alkyl group or a methylene group linked to a nitrogen atom by a carbonyl group,
- R a is a C X - 6 alkoxy, phenyl -C 3 alkoxy or amino group, where the amino group can be mono- or disubstituted by C ⁇ 3 alkyl, phenyl C 4 alkyl or phenyl groups and the substituents can be the same or different,
- a phenyl, naphthyl, tetrahydronaphthyl, phenoxy or heteroaryl group one optionally by a hydroxy, Ci- 3 -alko y-, C 1 . 4 -alkoxycarbonyl or C 1 - 4 alkyl-substituted carbo- nyloxy distr C ⁇ _ 9 alkyl group which 3. in the alkyl moiety by a C - 3 -AIkyl distr by one or two phenyl groups, by a naphthyl, fluorenyl, phenoxy , Heteroaryl or C 3 . 7 cycloalkyl group may be substituted, or a substituted by a phenyl C 3-7 cycloalkyl group,
- R a all of the phenyl, naphthyl and heteroaryl parts mentioned above under R a can each be substituted by the radicals R x and R 2 , where Ri is a hydrogen, fluorine, chlorine or bromine atom, a cyano, C ⁇ _ 3 alkyl, C 2 - 4 alkenyl, phenyl, hydroxy, C ⁇ 4 alkoxy, phenyl C 3 alkoxy -, Carboxy-, C ⁇ _ 3 -alkoxycarbonyl-, aminocarbonyl-, C- 3 -alkylaminocarbonyl-, N, N-di- (C ⁇ - 3 -alkyl) -aminocarbonyl-, nitro-, amino-, C ⁇ _ 3 -alkylamines - no-, di- (C ⁇ -3-alkyl) -amino-, phenyl-C ⁇ _ 3 -alkylamino-, N- (C ⁇ - 3 -alkyl)
- R 2 is a hydrogen, fluorine, chlorine or bromine atom, a C 3 alkyl, hydroxy or C 4 alkoxy group, the hydrogen atoms in the abovementioned alkyl and alkoxy parts of the radicals R 1 and R 2 each being completely or can be partially replaced by fluorine atoms, or
- Ri and R 2 together represent a methylenedioxy group
- R b is a carboxy, C ⁇ S alkoxycarbonyl, C ⁇ . 6 -alkoxycarbonyl-C- 3 -alkylcarbonyl, C 3 - 7 -cycloalkoxycarbonyl or phenyl - C ⁇ - 3 -alkoxycarbonyl group or an R 3 NR 4 -CO group in which
- R 3 and R 4 which may be the same or different, hydrogen atoms, Ci-g-alkyl groups in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms and the C ⁇ _ 3 alkyl part of a C ⁇ - 3 alkylamino group by one Carboxy or C ⁇ - 3 alkoxycarbonyl group or in the 2- or 3-position can also be substituted by an amino, C ⁇ - 3 alkylamino or di- (C ⁇ - 3 alkyl) amino group, C 3 _ 7 -Cy - Cloalkyl, pyridyl, pyridinyl-C ⁇ _ 3 alkyl, phenyl, naphthyl or phenyl-C ⁇ - 3 alkyl groups, the above-mentioned phenyl groups in each case by a fluorine, chlorine or bromine atom, by a C ⁇ _ 3 alkyl group, in which the hydrogen atoms can be replaced in whole or in part by fluorine atom
- R 3 and R 4 together with the intervening nitrogen atom form a 3- to 7-membered cycloalkyleneimino group, the methylene group in position 4 in a 6- or 7-membered cycloalkyleneimino group additionally being provided by an oxygen or sulfur atom, by a sulfinyl , Sulfonyl, imino or N- (-C 3 alkyl) -imino group can be replaced,
- R c is a hydrogen atom or a C 3 alkyl group
- tricyclic group in the above-mentioned general formula I can additionally be mono- or disubstituted by fluorine or chlorine atoms, by methyl or methoxy groups and the substituents can be identical or different,
- a 6-membered heteroaryl group containing one, two or three nitrogen atoms or a 5-membered heteroaryl group containing an imino group optionally substituted by a C ⁇ - 3 alkyl group, an oxygen or sulfur atom or
- carboxy group mentioned in the definition of the above-mentioned radicals can also be replaced by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions.
- a group which can be converted into a carboxy group in vivo is, for example, a hydroxmethyl group, a carboxy group esterified with an alcohol, in which the alcoholic part is preferably a C 1 -C. 6 -alkanol, a phenyl -C 3 alkanol, a C 3 -. 9 -cycloalkanol, where a C 5 _ 8 -cycloalkanol can additionally be substituted by one or two C ⁇ - 3 alkyl groups, a C 5 - 8 -cycloalkanol in which a methylene group in the 3- or 4-position by an oxygen atom or by an optionally by a C ⁇ _ 3 alkyl, phenyl-C !
- R a is a C 8 alkyl, C 5 _ 7 cycloalkyl, phenyl or phenyl
- R b is a hydrogen atom, a -C 3 alkyl, C 5 _ 7 cycloalkyl or phenyl group and
- R c represents a hydrogen atom or a C ⁇ - 3 alkyl group
- saturated alkyl and alkoxy parts which contain more than 2 carbon atoms also include their branched isomers such as the isopropyl, tert-butyl, isobutyl group etc.
- X, Y a , Y b and R a to R c are as defined above and n is 3, 4 or 5,
- n is the number 3 or 4
- X is a carbon-carbon bond or an oxygen atom
- Y a is a carbonyl or sulfonyl group
- Y b is the group - (CH 2 ) m -, where m is the number 2 or 3 and in which a hydrogen atom can be replaced by a C ⁇ - 3 alkyl group or a methylene group linked to a nitrogen atom by a carbonyl group,
- R a is a C 4 alkoxy or phenyl C alkoxy group, a by a C ⁇ _ 3 alkyl, phenyl-alkyl or C ⁇ - 3 monosubstitiutechnisch phenyl or alkyl by a C ⁇ _ 3 alkyl and a phenyl C ⁇ _ 3 or phenyl disubstituted amino, wherein the alkyl moieties may be straight chain or branched .
- Ri is a hydrogen, fluorine, chlorine or bromine atom, a cyano, C 3. -. 3- alkyl-, C 3 _ 4 -alkenyl-, phenyl-, hydroxy-, C ⁇ - 3 -alkoxy-, nitro-, amino-, C ⁇ _ 3 -alkylamino-, di- (- 3 -alkyl) -amino-, C ⁇ - 3 -alkylcarbonylamino- or N- (C ⁇ _ 3 -alkyl) - C ⁇ - 3rd -alkylcarbonylamino group and
- R 2 is a hydrogen, fluorine, chlorine or bromine atom, a C 3 alkyl, hydroxyl or C 3 alkoxy group, the hydrogen atoms in the abovementioned alkyl and alkoxy parts of the radicals R 1 and R 2 each being completely or can be partially replaced by fluorine atoms, or
- Ri and R 2 together represent a methylenedioxy group
- R is a C 3 -C 3 -alkoxycarbonyl-, C 1 _ 3 -alkoxy carbonyl-C 3 C alkylcarbonyl or an R 3 NR4-CO group in which
- R 3 is a hydrogen atom or a C ⁇ - 3 alkyl group
- R is a C 6 alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, a C 3 _ 7 cycloalkyl, phenyl, naphthyl, pyridyl, C 3 _ 7 cycloalkyl C 1 - 3 alkyl, phenyl-3 C ⁇ _ alkyl, or pyridinyl C 1 - 3 alkyl group,
- R c represents a hydrogen atom or a C ⁇ _ 3 alkyl group
- the tricyclic group in the above-mentioned general formula I can additionally be substituted by a fluorine or chlorine atom, by a methyl or methoxy group,
- X is a carbon-carbon bond
- Y a is a carbonyl group
- R a is a phenyl-C 3 alkylamino group
- Ri is a hydrogen, fluorine, chlorine or bromine atom, a cyano or C x - 3 alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, and
- R 2 is a hydrogen, fluorine, chlorine or bromine atom
- R b is an R 3 NR 4 -CO group in which
- R 3 is a hydrogen atom and R is a C ⁇ - 3 alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, or a phenyl-C ⁇ _ 3 alkyl group,
- R c represents a hydrogen atom or a C 3 alkyl group
- the new compounds are obtained by processes known from the literature, for example by the following processes:
- R b , R c , X, Y b and n are defined as mentioned at the outset, with a compound of the general formula
- R a and Y a are defined as mentioned at the outset and Z- L is a hydroxyl group, a nucleofugic leaving group such as a halogen atom, for example a chlorine, bromine or iodine atom, or, if Y a is a carbonyl group, together with the hydrogen atom of an adjacent one NH group of the radical R a means a further carbon-nitrogen bond.
- a nucleofugic leaving group such as a halogen atom, for example a chlorine, bromine or iodine atom, or, if Y a is a carbonyl group, together with the hydrogen atom of an adjacent one NH group of the radical R a means a further carbon-nitrogen bond.
- 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, if appropriate in the presence of an inorganic or organic base and if appropriate in the presence of a dehydrating agent, advantageously at temperatures between -50 and 150 ° C., preferably at temperatures between -20 and 80 ° C.
- a solvent or solvent mixture such as methylene chloride, dimethylformamide, Benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane
- 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 in the presence of a tertiary organic base such as triethylamine, pyridine or 2-dimethylaminopyridine, in the presence of N-ethyl-diisopropylamine (Hünig base), these organic bases can also serve as solvents at the same time, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate or Sodium hydroxide solution expediently carried out at temperatures between -50 and 150 ° C, preferably at temperatures between -20 and 80 ° C.
- a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene
- the reaction is preferably carried out in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, hexamethyl disilazane, N, N '- Dicyclohexylcarbodiimide, O- (benzotriazol-1-yl) -N, NN ', N' -tetraethyluroniumtetrafluoroborat, N, N '-di- cyclohexylcarbodiimide / N-hydroxysuccinimide or 1-hydroxy-benzotriazole and optionally additionally in the presence of 4 -Dimethylamino-pyridine, N, N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachlor
- Nem solvent such as methylene chloride, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethyl sulfoxide, ethylene glycol diethyl ether or sulfolane and optionally in the presence of a reaction accelerator such as 4-dimethylaminopyridine at temperatures between -50 and 150 ° C, but preferably at temperatures between -20 and 80 ° C.
- a reaction accelerator such as 4-dimethylaminopyridine at temperatures between -50 and 150 ° C, but preferably at temperatures between -20 and 80 ° C.
- R is a Ci- 6 alkoxycarbonyl, C 3-7 -Cycloalkoxycarbonyl- or phenyl -ci- 3 alkoxycarbonyl group or an R 3 NR 4 -CO group, in which R 3 and R 4 are defined as mentioned at the beginning:
- R a , R c . X. Y a / Yb and n are defined as mentioned above, with a compound of the general formula
- reaction is advantageously carried out with 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, optionally in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.
- a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulfolane
- an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.
- this can also be done with the free acid, optionally in the presence of an acid activating agent
- a compound of the general formula I which contains an amino or alkylamino group, this can be converted into a corresponding acyl compound by means of acylation, or
- a compound of the general formula I which contains a nitro group this can be converted into a corresponding amino compound by reduction.
- the subsequent acylation is advantageously carried out with a corresponding halide, anhydride or isocyanate in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulfolane, optionally in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.
- this can also be carried out with the free acid, if appropriate in the presence of an acid-activating agent or a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N.
- an acid-activating agent or a dehydrating agent for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N.
- 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 a Acid such as hydrochloric acid and at a hydrogen pressure of 1 to 7 bar, but preferably 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 temperature temperatures between 0 and 100 ° C, but preferably at temperatures between 20 and 60 ° C.
- a catalyst such as
- 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
- an amino, alkylamino or imino group the formyl, 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.
- the compounds of general formula I obtained can be converted into their enantiomeric ren and / or diastereomers are separated.
- 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 chromatographed into their eis and trans isomers, the compounds of general formula I obtained which occur in racemates, according to methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of 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, into their diastereomers, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.
- the enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols, and Separation of the diastereomeric salt mixture or derivative obtained in this way, for example on the basis of different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
- an optically active substance which forms salts or derivatives, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols
- optically active acids are, for example, 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 into their physiologically tolerable salts with inorganic or organic acids.
- suitable acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
- the new compounds of formula I 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.
- a compound of the general formula II is obtained, for example, by reacting a compound of the general formula in the
- R b , X and n are defined as mentioned at the outset and Z 2 represents a nucleofugic leaving group such as a chlorine or bromine atom, with a corresponding piperazine or homopiperazine, in which an imino group can conveniently be protected by a customary protective radical, for example by a tert.
- Butoxycarbonyl or benzyloxycarbonyl group in the melt or in a solvent such as ethanol, dioxane, tetrahydrofuran, acetonitrile or dimethylformamide in the presence of a base such as triethylamine or potassium carbonate and at temperatures between 0 and 130 ° C, but preferably at temperatures between 20 and 80 ° C.
- a base such as triethylamine or potassium carbonate
- a compound of the general formula IV is obtained, for example, analogously to process a) by reacting an appropriately substituted carboxylic acid derivative with a compound of the general formula III and, if appropriate, subsequently splitting off a protective radical used to protect the carboxy group.
- the compounds of the general formula I and their physiologically tolerable salts have valuable pharmacological properties. These are particularly valuable inhibitors of the microsomal triglycer rid transfer protein (MTP) and are therefore suitable for lowering the plasma levels of atherogenic lipoproteins.
- MTP microsomal triglycer rid transfer protein
- MTP inhibitors were identified by a cell-free MTP activity test. Solubilized liver microsomes from various species (eg rats, pigs) can be used as MTP sources.
- lipids dissolved in organic solvents were mixed in a suitable ratio and applied to a glass vessel wall as a thin layer by blowing the solvent in a stream of nitrogen.
- the solution used to prepare donor vesicles contained 400 ⁇ M phosphatidylcholine, 75 ⁇ M cardiolipin and 10 ⁇ M [ 1 C] triolein
- [ 3 H] dipalmitoylphosphatidylcholine (108 mCi / mg) was used. Vesicles are formed by wetting the dried lipids with test buffer and subsequent sonication. Vesicle populations of uniform size were obtained by gel filtration of the ultrasound-exposed lipids.
- the MTP activity test contains donor vesicles, acceptor vesicles and the MTP source in test buffer. Substances were added from concentrated DMSO-containing stock solutions, the final concentration of DMSO in the test was 0.1%. The reaction was started by adding MTP. After an appropriate incubation period, the transfer process was stopped by adding 500 ⁇ l of a SOURCE 30Q anion exchange suspension (Pharmacia ' Biotech).
- 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 formula I prepared according to the invention optionally in combination with other active substances such as other lipid-lowering agents, for example with HMG-CoA reductase inhibitors, cholesterol biosynthesis inhibitors such as squalene synthase inhibitors and squalene cyclase inhibitors, bile acid-binding resins, fibrates, Cholesterol absorption inhibitors, niacin, probucol, CETP inhibitors and ACAT inhibitors together with one or more inert customary carriers and / or diluents, for example with Corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / - sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fat-containing substances such as hard fat suitable mixtures,
- the aqueous phase is acidified with 150 ml IN hydrochloric acid and extracted three times with 250 ml dichloromethane. The combined organic phases are dried over sodium sulfate and the solvent is removed. Yield: 18.5 g (53.6% of theory), melting point: 123 ° C
- Example 12 3.5 g of methyl 9- [3- (4-phenylacetylpiperazino) propyl] -9H-fluorene-9-carboxylate (Example 12) are taken up in 80 ml of methanol / dioxane (1: 1) and with 38 ml Stirred in sodium hydroxide solution at 50 ° C. for 2 hours. Then it is acidified and with
- Methyl 9- (4- ⁇ 4-phenyl-acetyl] piperazin-2-one-l-yl ⁇ -butyl) -9H-fluorene-9-carboxylate is saponified analogously to Example VI and then to 9- (4- ⁇ 4-phenyl-acetyl] -piperazin-2-one-1-yl ⁇ -butyl) -9H-fluorene-9-carboxylic acid chloride reacted analogously to Example II.
- the active ingredient is mixed with lactose monohydrate, microcrystalline cellulose and carboxymethyl cellulose sodium in a suitable diffusion mixer for 15 minutes. 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.
- the finished mixture is filled into empty capsule shells made of size 1 hard gelatin using a capsule filling machine.
- HPMC HPMC is dispersed in hot water. After cooling, the mixture gives a clear solution.
- the active ingredient is premixed in a suitable mixer for 5 minutes with lactose monohydrate and microcrystalline cellulose.
- the HPMC solution is added and mixing continued until a homogeneous moist mass is obtained.
- the moist mass is passed through a sieve with a mesh size of 1.6 mm.
- the sieved granules are dried on trays at about 55 ° C for 12 hours.
- the dried granules are then passed through sieves with a mesh size of 1.2 and 0.8 mm.
- Poly-l-vinyl-2-pyrrolidone is mixed with the granules in a suitable mixer for 3 minutes.
- magnesium stearate is added and mixed for a further 3 minutes.
- the finished mixture is compressed on a tablet press to oblong tablets (16.2 x 7.9 mm). Weight of one tablet: 480 mg
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19963235A DE19963235A1 (de) | 1999-12-27 | 1999-12-27 | Substituierte Piperazinderivate, ihre Herstellung und ihre Verwendung als Arzneimittel |
DE19963235 | 1999-12-27 | ||
PCT/EP2000/012842 WO2001047899A1 (de) | 1999-12-27 | 2000-12-16 | Substituierte piperazinderivateals inhibitoren des mtp |
Publications (1)
Publication Number | Publication Date |
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EP1259492A1 true EP1259492A1 (de) | 2002-11-27 |
Family
ID=7934665
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP00987409A Withdrawn EP1259492A1 (de) | 1999-12-27 | 2000-12-16 | Substituierte piperazinderivate als inhibitoren des mtp |
Country Status (26)
Country | Link |
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US (1) | US20030114442A1 (ru) |
EP (1) | EP1259492A1 (ru) |
JP (1) | JP2003519131A (ru) |
KR (1) | KR20020065916A (ru) |
CN (1) | CN1414956A (ru) |
AR (1) | AR027112A1 (ru) |
AU (1) | AU2366001A (ru) |
BG (1) | BG106847A (ru) |
BR (1) | BR0016780A (ru) |
CA (1) | CA2394644A1 (ru) |
CO (1) | CO5251384A1 (ru) |
CZ (1) | CZ20022281A3 (ru) |
DE (1) | DE19963235A1 (ru) |
EA (1) | EA200200650A1 (ru) |
EE (1) | EE200200364A (ru) |
HU (1) | HUP0203855A3 (ru) |
IL (1) | IL150357A0 (ru) |
MX (1) | MXPA02006510A (ru) |
NO (1) | NO20023001D0 (ru) |
PL (1) | PL355394A1 (ru) |
SK (1) | SK9272002A3 (ru) |
TR (1) | TR200201669T2 (ru) |
UY (1) | UY26501A1 (ru) |
WO (1) | WO2001047899A1 (ru) |
YU (1) | YU49902A (ru) |
ZA (1) | ZA200205012B (ru) |
Families Citing this family (13)
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KR100575944B1 (ko) | 2001-06-28 | 2006-05-02 | 화이자 프로덕츠 인코포레이티드 | 미소체 트리글리세라이드 전달 단백질(mtp) 및/또는아포지방단백질 b(apo b)분비의 억제제로서의트리아미드-치환된 인돌, 벤조푸란 및 벤조티오펜 |
DE10200633A1 (de) * | 2002-01-10 | 2003-07-24 | Boehringer Ingelheim Pharma | Kombination von MTP Inhibitoren oder apoB-Sekretions-Inhibitoren mit Fibraten zur Verwendung als Arzneimittel |
CN1943786A (zh) * | 2002-02-28 | 2007-04-11 | 日本烟草产业株式会社 | 酯化合物及其医药用途 |
WO2005021486A1 (ja) * | 2003-08-29 | 2005-03-10 | Japan Tobacco Inc. | エステル誘導体及びその医薬用途 |
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 |
CA2582767C (en) * | 2004-10-25 | 2011-05-24 | Japan Tobacco Inc. | Solid formulation with improved solubility and stability and method for producing said formulation |
MX2009004387A (es) * | 2006-10-24 | 2009-05-08 | Janssen Pharmaceutica Nv | Derivados de acido tetrahidro-naftalen-1-carboxilico inhibidores de proteina de transferencia de trigliceridos microsomales. |
JO2653B1 (en) * | 2006-10-24 | 2012-06-17 | شركة جانسين فارماسوتيكا ان. في | Tetrahydroflavin 1-carboxylic acid substituted with pyridine or pyrazine inhibit MTB |
US8190707B2 (en) * | 2007-10-20 | 2012-05-29 | Citrix Systems, Inc. | System and method for transferring data among computing environments |
CA2710039C (en) | 2007-12-26 | 2018-07-03 | Critical Outcome Technologies, Inc. | Semicarbazones, thiosemicarbazones and related compounds and methods for treatment of cancer |
EP3023426A1 (en) | 2008-07-17 | 2016-05-25 | Critical Outcome Technologies, Inc. | Thiosemicarbazone inhibitor compounds and cancer treatment methods |
CA2999435A1 (en) | 2010-04-01 | 2011-10-06 | Critical Outcome Technologies Inc. | Compounds and method for treatment of hiv |
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US5739135A (en) * | 1993-09-03 | 1998-04-14 | Bristol-Myers Squibb Company | Inhibitors of microsomal triglyceride transfer protein and method |
US5885983A (en) * | 1996-05-10 | 1999-03-23 | Bristol-Myers Squibb Company | Inhibitors of microsomal triglyceride transfer protein and method |
WO1998027979A1 (en) * | 1996-12-20 | 1998-07-02 | Bristol-Myers Squibb Company | Heterocyclic inhibitors of microsomal triglyceride transfer protein and method |
-
1999
- 1999-12-27 DE DE19963235A patent/DE19963235A1/de not_active Withdrawn
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2000
- 2000-12-16 EA EA200200650A patent/EA200200650A1/ru unknown
- 2000-12-16 BR BR0016780-0A patent/BR0016780A/pt active Pending
- 2000-12-16 US US10/168,926 patent/US20030114442A1/en not_active Abandoned
- 2000-12-16 CZ CZ20022281A patent/CZ20022281A3/cs unknown
- 2000-12-16 EP EP00987409A patent/EP1259492A1/de not_active Withdrawn
- 2000-12-16 JP JP2001549371A patent/JP2003519131A/ja active Pending
- 2000-12-16 CA CA002394644A patent/CA2394644A1/en not_active Abandoned
- 2000-12-16 PL PL00355394A patent/PL355394A1/xx not_active Application Discontinuation
- 2000-12-16 KR KR1020027008320A patent/KR20020065916A/ko not_active Application Discontinuation
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- 2000-12-16 AU AU23660/01A patent/AU2366001A/en not_active Abandoned
- 2000-12-16 CN CN00817889A patent/CN1414956A/zh active Pending
- 2000-12-16 IL IL15035700A patent/IL150357A0/xx unknown
- 2000-12-16 HU HU0203855A patent/HUP0203855A3/hu unknown
- 2000-12-16 WO PCT/EP2000/012842 patent/WO2001047899A1/de not_active Application Discontinuation
- 2000-12-16 SK SK927-2002A patent/SK9272002A3/sk unknown
- 2000-12-16 YU YU49902A patent/YU49902A/sh unknown
- 2000-12-16 TR TR2002/01669T patent/TR200201669T2/xx unknown
- 2000-12-16 EE EEP200200364A patent/EE200200364A/xx unknown
- 2000-12-22 UY UY26501A patent/UY26501A1/es not_active Application Discontinuation
- 2000-12-26 CO CO00097654A patent/CO5251384A1/es not_active Application Discontinuation
- 2000-12-27 AR ARP000106940A patent/AR027112A1/es not_active Suspension/Interruption
-
2002
- 2002-06-20 BG BG106847A patent/BG106847A/xx active Pending
- 2002-06-21 ZA ZA200205012A patent/ZA200205012B/en unknown
- 2002-06-21 NO NO20023001A patent/NO20023001D0/no not_active Application Discontinuation
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See references of WO0147899A1 * |
Also Published As
Publication number | Publication date |
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EA200200650A1 (ru) | 2002-12-26 |
MXPA02006510A (es) | 2002-11-29 |
CZ20022281A3 (cs) | 2002-10-16 |
NO20023001L (no) | 2002-06-21 |
BR0016780A (pt) | 2002-08-27 |
JP2003519131A (ja) | 2003-06-17 |
DE19963235A1 (de) | 2001-07-05 |
YU49902A (sh) | 2005-03-15 |
SK9272002A3 (en) | 2002-11-06 |
CO5251384A1 (es) | 2003-02-28 |
TR200201669T2 (tr) | 2002-10-21 |
BG106847A (en) | 2003-02-28 |
AU2366001A (en) | 2001-07-09 |
UY26501A1 (es) | 2001-07-31 |
HUP0203855A2 (hu) | 2003-03-28 |
AR027112A1 (es) | 2003-03-12 |
WO2001047899A1 (de) | 2001-07-05 |
KR20020065916A (ko) | 2002-08-14 |
NO20023001D0 (no) | 2002-06-21 |
CN1414956A (zh) | 2003-04-30 |
US20030114442A1 (en) | 2003-06-19 |
CA2394644A1 (en) | 2001-07-05 |
ZA200205012B (en) | 2003-01-16 |
IL150357A0 (en) | 2002-12-01 |
EE200200364A (et) | 2003-10-15 |
HUP0203855A3 (en) | 2004-07-28 |
PL355394A1 (en) | 2004-04-19 |
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