WO2002090344A1 - Derives d'amido-diphenyle - Google Patents

Derives d'amido-diphenyle Download PDF

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Publication number
WO2002090344A1
WO2002090344A1 PCT/EP2002/004622 EP0204622W WO02090344A1 WO 2002090344 A1 WO2002090344 A1 WO 2002090344A1 EP 0204622 W EP0204622 W EP 0204622W WO 02090344 A1 WO02090344 A1 WO 02090344A1
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alkyl
substituted
different
alkoxy
phenyl
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PCT/EP2002/004622
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German (de)
English (en)
Inventor
Helmut Haning
Michael Woltering
Gunter Schmidt
Christiane Faeste
Hilmar Bischoff
Axel Kretschmer
Verena Vöhringer
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Bayer Aktiengesellschaft
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Publication of WO2002090344A1 publication Critical patent/WO2002090344A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/22—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton

Definitions

  • the invention relates to new amido-diphenyl derivatives, processes for their preparation and their use in medicaments.
  • EP-A-580 550 describes oxamic acid derivatives which have cholesterol-lowering properties in mammals.
  • Cholesterol-lowering effects are also described in EP-A-188 351 for certain diphenyl ethers with thyroid hormone-like effects.
  • Diphenyl ethers as thyroid receptor ligands are also disclosed in WO 99/00353 and WO 00/39077. Further diphenyl derivatives with thyroid hormone-like properties are described in the applications WO 98/57919, WO 99/26966, WO
  • the object of the present invention is to provide new compounds with improved, in particular pharmaceutical, effects.
  • X represents O, S, SO, SO 2 , CH 2 , CHF, CF 2 or NR 8 , in which R 8 is hydrogen or (Cj-C) -alkyl,
  • R 1 and R 2 are the same or different and represent hydrogen or (QC ⁇ alkyl
  • R 3 and R 4 are the same or different and represent hydrogen, halogen, cyano, (C r C 6 ) alkyl, CF 3 , CHF 2 , CH 2 F, vinyl or (C 3 -C 7 ) cycloalkyl, where at least one of the two substituents is not hydrogen,
  • R > 5 represents hydrogen, (C t -C ⁇ alkyl or halogen
  • R 6 represents a group of the formula -SR 9 , -S (O) n -R 10 , -NR u -C (O) -R 12 , -CH 2 -R 13 or -MR 14 , in which
  • n the number 1 or 2
  • R 15 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 and R 28 are the same or different and each represents hydrogen, phenyl, benzyl, or (C -C 8 ) -cycloalkyl, which in turn are optionally one or more, identical or different, by halogen, hydroxy, amino, carboxyl, (dG -alkoxy, (-C ⁇ -alkoxycarbonyl, (-C ⁇ -alkoxycarbonylamino , (- C 5 ) -alkanoyloxy, a heterocycle or, in turn, optionally substituted by halogen or hydroxy-substituted phenyl,
  • R 16 and R 17 are identical or different and, independently of one another, represent hydrogen, straight-chain or branched (-C-Cö) alkyl, which one or more times, identical or different, by mono- (C r C 6 ) -alkylamino, di- (C r C 6 ) alkylamino, (C r C4) alkoxy, (C ⁇ -C 6 ) alkoxycarbonyl, carboxyl, pyridyl or (C 6 - C 10 ) aryl, the latter in turn optionally being substituted by halogen, trifluoromethyl, or (C r C 6 ) alkoxy is substituted, for (C 6 -C 10 ) aryl, which is optionally substituted by halogen, trifluoromethyl, (Cj-C 6 ) alkyl or (Ci-Cg ⁇ alkoxy), or for (C ß -Cgj-cycloalkyl or a 5- bis 7-membered heterocycle containing one
  • R and R together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated, optionally benzo-fused heterocycle, which may be up to two more
  • Heteroatoms from the series N, O and / or S contain and by amino, (C ⁇ -Cg) alkyl, (Ci-C ⁇ alkoxycarbonyl, (C j -
  • R 11 represents hydrogen, straight-chain or branched (C 1 -C 6 ) -alkyl, which one or more times, identically or differently, by mono- (C r C 6 ) -alkylamino, di- (C r C 6 ) -alkylamino, (C r C 4 ) alkoxy, (C r
  • Cö) alkoxycarbonyl, carboxyl, pyridyl or (C * 5 -C ⁇ o) aryl may be substituted, the latter in turn optionally substituted by halogen, trifluoromethyl, (C 1 -Cö) alkyl or (C 1 -C 6 ) alkoxy is (C 3 -Cg) cycloalkyl or a 5- to 7-membered heterocycle containing one to two nitrogen atoms, where
  • R 12 is straight-chain or branched (C j -C ⁇ alkyl, which can be substituted by (C 3 -Cg) cycloalkyl, (Cj-C 4 ) alkoxy, phenyl, phenoxy or benzyloxy, the aromatics mentioned in each case up to three times the same or different can be substituted by halogen, (C ⁇ C ⁇ ⁇ alkyl or (Ci-C ⁇ alkoxy,
  • (C6-C ⁇ o) aryl which can be substituted up to three times the same or different by (Ci-C ⁇ alkyl, (C 1 -C 6 ) alkoxy, halogen, cyano, amino, trifluoromethyl or phenyl,
  • R 29 stands for straight-chain or branched (-CC6) -alkyl
  • R 30 and R 31 are the same or different and independent of each other
  • R 32 and R 33 are identical or different and independently of one another represent hydrogen, (C 1 -C 6 ) alkyl, phenyl or (C6-C ⁇ o) arylsulfonyl,
  • R 30 and R 31 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle which contains up to two further heteroatoms from the series, N, O and / or S and are replaced by amino, ( C j -Cg ⁇ alkyl, (C ⁇ - C4) alkanoyl, aminocarbonyl, (C 1 -C) alkoxycarbonyl, (Ci
  • R represents a saturated, partially unsaturated or aromatic 5- to 10-membered heterocycle with up to three identical or different heteroatoms from the series N, O and / or S, which is optionally selected from one, two or three identical or different substituents the group (-G -alkyl, hydroxy, oxo, (CrC ⁇ -alkoxy, halogen, cyano, carboxyl and (CrC 4 ) - alkoxycarbonyl,
  • R 1 ⁇ stands for the group -NR J4 R J:> , in which
  • R 34 and R 35 are identical or different and represent hydrogen, (Ci).
  • M represents CO, CH (OH), CHF or CF 2 ,
  • R 14 has the meaning of R 10 given above,
  • R 7 represents hydrogen, (dC 4 ) -alkyl or (dC 4 ) -alkanoyl
  • R 36 represents hydrogen or (CC 4 ) -alkyl
  • a means the number 0 or 1
  • d denotes the number 0 or 1, with the proviso that the sum (a + d) is not equal to the number 0,
  • a stands for SO 2 or C O
  • D represents a straight-chain (dC 4 ) alkylene group, which, if appropriate. is substituted one or more times, identically or differently, by (dC 3 ) -alkyl, hydroxy, amino or fluorine,
  • R 37 represents OR 38 or NR 39 R 40 , wherein
  • R 38 , R 39 and R 40 are the same or different and each represents hydrogen, phenyl, benzyl, (dC 6 ) alkyl or (C 3 -C 8 ) cycloalkyl, which in turn may be one or more, identical or different , by halogen, hydroxy, amino, carboxyl,
  • R 9 , R 10 or R 13 The following may preferably be mentioned as heterocycles in the definition of R 9 , R 10 or R 13 :
  • Examples include: tetrahydro colryl, pyrrolidinyl, pyrrolinyl, piperidinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, piperazinyl, morpholinyl, azepinyl, 1,4-diazepinyl, furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, Triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,
  • pyridyl pyrimidinyl
  • pyridazinyl pyrimidinonyl
  • pyridazinonyl pyridazinonyl
  • alkyl represents a straight-chain or branched alkyl radical having preferably 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 3 carbon atoms.
  • a straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. Examples and preferably are:
  • alkenyl represents a straight-chain or branched alkenyl radical having preferably 2 to 6 or 2 to 4 carbon atoms.
  • a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms is preferred.
  • the following may be mentioned by way of example and preferably: vinyl, allyl, isopropenyl and n-but-2-en-1-yi.
  • aryl stands for an aromatic radical having preferably 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • Cycloalkyl in the context of the invention represents a cycloalkyl group with preferably 3 to 8, 3 to 7 or 3 to 6 carbon atoms. Examples and preferably mentioned are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • alkoxy preferably represents a straight-chain or branched alkoxy radical having 1 to 6, 1 to 4 or 1 to 3 carbon atoms.
  • a straight-chain or branched alkoxy radical having 1 to 3 carbon atoms is preferred.
  • Alkoxycarbonyl in the context of the invention preferably represents a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms, which is linked via a carbonyl group.
  • a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms is preferred.
  • the following may be mentioned as examples and preferably: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.
  • Alkanoyl in the context of the invention preferably represents a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms, which carries a double-bonded oxygen atom in the 1 position and is linked via the 1 position.
  • a straight-chain or branched alkanoyloxy radical having 1 to 4 carbon atoms is preferred. The following may be mentioned as examples and preferably: formyl, acetyl, propionyl, n-butyryl, i-butyryl, pivaloyl and n-hexanoyl.
  • Alkanoyloxy in the context of the invention preferably represents a straight-chain or branched alkyl radical having 1 to 6, 1 to 5 or 1 to 3 carbon atoms, which bears a double-bonded oxygen atom in the 1-position and which is linked via a further oxygen atom in the 1-position is.
  • a straight-chain or branched alkanoyloxy radical having 1 to 3 carbon atoms is preferred. Examples and preferably mentioned are: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy and n-hexanoyloxy.
  • monoalkylamino represents an amino group with a straight-chain or branched alkyl substituent which preferably has 1 to 6, 1 to 4 or 1 to 2 carbon atoms.
  • dialkylamino stands for an amino group with two identical or different straight-chain or branched alkyl substituents which preferably each have 1 to 6, 1 to 4 or 1 to 2 carbon atoms.
  • Straight-chain or branched dialkylamino radicals each having 1 to 4 carbon atoms are preferred. The following may be mentioned by way of example and preferably: NN-dimethylamino, NN-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-
  • mono- or dialkylaminocarbonyl represents an amino group which is linked via a carbonyl group and which has a straight-chain or branched or two identical or different straight-chain or branched alkyl substituents, each preferably having 1 to 4 or 1 to 2 carbon atoms ,
  • the following may be mentioned by way of example and preferably: methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, t-butylaminocarbonyl, NN-dimethylaminocarbonyl, NN-diethylarninocarbonyl, N-ethyl-N-methylaminocarbonyl and N-t-
  • monoacylamino represents an amino group with a straight-chain or branched alkanoyl substituent which preferably has 1 to 6, 1 to 4 or 1 to 2 carbon atoms and is linked via the carbonyl group.
  • a monoacylamino radical having 1 to 2 carbon atoms is preferred. The following may be mentioned as examples and preferably: formamido, acetamido, propionamido, n-butyramido and pivaloylamido.
  • alkoxycarbonylamino represents an amino group with a straight-chain or branched alkoxycarbonyl substituent, the preferred has 1 to 6 or 1 to 4 carbon atoms in the alkoxy radical and is linked via the carbonyl group.
  • An alkoxycarbonylamino radical having 1 to 4 carbon atoms is preferred. Examples that may be mentioned are: methoxycarbonyl-a ino, ethoxycarbonylamino, n-propoxycarbonylamino and t-butoxycarbonylamino.
  • 5- to 6-membered heteroaryl with up to 3 identical or different heteroatoms from the series S, N and / or O preferably stands for an aromatic heterocycle in the context of the invention which is via a ring carbon atom of the heteroaromatic, optionally also via a ring nitrogen atom of the heteroaromatic is linked.
  • aromatic heterocycle in the context of the invention which is via a ring carbon atom of the heteroaromatic, optionally also via a ring nitrogen atom of the heteroaromatic is linked.
  • Examples include: furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl,
  • Imidazolyl triazolyl, pyridyl, pyrimidinyl, pyridazinyl. Pyridyl, pyrimidinyl, pyridazinyl, furyl and thiazolyl are preferred.
  • S, N and / or O in the context of the invention preferably represents a heterocycle which can contain one or two double bonds and which is linked via a ring carbon atom or a ring nitrogen atom.
  • a 5- to 7-membered saturated heterocycle with up to 2 identical or different heteroatoms from the S, N and / or O series is preferred. Examples include: tetrahydrofur-2-yl,
  • Piperidinyl, piperazinyl, morpholinyl and pyrrolidinyl are preferred.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Fluorine, chlorine or bromine are preferred.
  • the compounds according to the invention can be expressed in stereoisomeric forms which are either like images and mirror images
  • the invention relates both to the enantiomers or diastereomers and to their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
  • the compounds according to the invention can also be present as salts.
  • Physiologically acceptable salts are preferred in the context of the invention.
  • Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids.
  • Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carbon or sulfonic acids such as acetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid are preferred , Benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.
  • Physiologically acceptable salts can also be salts of the compounds according to the invention with bases, such as, for example, metal or ammonium salts.
  • bases such as, for example, metal or ammonium salts.
  • alkali metal salts for example sodium or potassium salts
  • alkaline earth salts for example magnesium or calcium salts
  • ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, ethyldiisopropylamine, monoethanolamine, Di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, dibenzylamine, N-methylmorpholine, dihydroabietylamine, 1-ephenamine, methylpiperidine, arginine, lysine, ethylenediamine or 2-phenylethylamine.
  • the compounds according to the invention can also be present in the form of their solvates, in particular in the form of their
  • prodrugs refer to those derivatives of the compounds of the general formula (I) which themselves may be less biologically active or also inactive but which, after application under physiological conditions, are converted into the corresponding biologically active form (for example metabolically, solvolytically or on other way).
  • X represents O, S, CH 2 or CF 2 ,
  • R 1 and R 2 are the same or different and represent hydrogen or methyl
  • R 3 and R 4 are identical or different and represent hydrogen, halogen, (C 1 -C 4 ) alkyl, CF 3 , CHF 2 , CH 2 F, vinyl or (C 3 -C 5 ) cycloalkyl, at least one of the two substituents is not hydrogen,
  • R 5 represents hydrogen, (d -C 3 ) -alkyl, fluorine, chlorine or bromine,
  • R 6 for a group of the formula -S (O) 2 -R 10 , -NR ⁇ -C (O) -R 12 , -CH 2 -R 13 or
  • R 22 , R 23 , R 24 , R 25 , R 26 , R 27 and R 28 are the same or different and each represents hydrogen, phenyl, benzyl, (dC ⁇ alkyl or (C 5 -C 7 ) cycloalkyl, which in turn, if appropriate, one or more times, identically or differently, by halogen, hydroxy, amino, carboxyl, (dC 4 ) alkoxy, (dC-alkoxycarbonyl, (dC 4 ) alkoxycarbonylamino or (d-Cs) -
  • R 16 and R 17 are the same or different and independently of one another are hydrogen, straight-chain or branched (Cj-Cg) alkyl, which one or more times, the same or different, by (-C-C) alkoxy, (C1-C4) Alkoxycarbonyl, carboxyl, pyridyl or phenyl can be substituted, the latter in turn optionally being substituted by halogen, trifluoromethyl, (C 1 -C 4 -alkyl or (C 1 -C 4) -alkoxy),
  • (C1-C4) alkyl or (C j -d alkoxy) is substituted, or for (C 5 -C 7 ) cycloalkyl or a 5- to 7-membered one or two
  • R 16 and R 17 together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle which contains up to two further heteroatoms from the series N, O and / or S and are replaced by amino, (C1 -C4) - alkyl, (C ⁇ - C4) - alkoxycarbonyl, (C ⁇ -C4) alkoxycarbonylamino or
  • R ⁇ represents hydrogen, straight-chain or branched (C1-C4) alkyl, benzyl, (C 3 -C 7 ) cycloalkyl or a 5- to 7-membered heterocycle containing one to two nitrogen atoms, cycloalkyl and heterocycle optionally are substituted by (C1-C4) alkyl,
  • R 12 for straight-chain or branched (-C-Cg) alkyl which by (C -C 7 ) - cycloalkyl, Phenyl, phenoxy or benzyloxy can be substituted, the aromatics mentioned in turn each being substituted up to three times in the same or different manner by halogen, (C1-C4) alkyl or (C ⁇ -C4) alkoxy,
  • R 29 represents straight-chain or branched (C1-C4) alkyl
  • R 30 and R 31 are the same or different and independent of each other
  • C j -Cg alkyl for hydrogen, straight-chain or branched (C j -Cg) alkyl, which may be substituted by phenyl, which in turn may be up to two times the same or different
  • Amino may be substituted
  • R 30 and R 31 together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated heterocycle, which contain up to two further heteroatoms from the series, N, O and / or S and are replaced by amino, (C 1 -C4) - alkyl, (Cj- C4) - alkanoyl, aminocarbonyl, (C1-C4) - alkoxycarbonyl, ( C ⁇ ⁇ C4) alkoxycarbonylamino or phenyl may be substituted,
  • R 13 for a saturated, partially unsaturated or aromatic 5- to 6-membered heterocycle with up to three identical or different
  • Heteroatoms from the series N, O and / or S which is optionally selected from the group (-C-C 4 ) alkyl, hydroxy, oxo, (dC 4 ) by one, two or three identical or different substituents -
  • R 34 and R 5 are identical or different and for hydrogen, (Cj-C 6 ) alkyl, which may be substituted by phenyl, for (Cs-C) - cycloalkyl, phenyl or for 5- to 6-membered heteroaryl with bis stand for three identical or different heteroatoms from the series N, O and / or S, phenyl and heteroaryl in turn optionally, in each case once or twice, identically or differently, by hydroxyl, amino, cyano, halogen, (d-C 4 ) - Alkyl, trifluoromethyl, (dC 4 ) alkoxy, carboxyl or (d-
  • R 14 has the meaning of R 10 given above,
  • R 7 represents hydrogen, methyl or acetyl
  • a means the number 0 or 1
  • d denotes the number 0 or 1, with the proviso that the sum (a + d) is not equal to the number 0,
  • D represents a straight-chain (dC 4 ) alkylene group which is optionally substituted one or more times, identically or differently, by (dC 3 ) alkyl, hydroxy, amino or fluorine,
  • R 37 represents OR 38 or NR 39 R 40 , wherein R 38 represents hydrogen, phenyl, benzyl, (-CC 6 ) alkyl or (C 3 -C 7 ) - cycloalkyl, which in turn may be one or more, identical or different, by halogen, hydroxy, amino, carboxyl, (dC 4 ) alkoxy, (dC 4 ) alkoxycarbonyl, (dC ⁇ alkoxycarbonylamino, (C 1 -Cs) alkanoyloxy or a heterocycle are substituted,
  • R 39 and R 40 are the same or different and each represents hydrogen
  • (dC 6 ) -alkyl or (C 3 -C 7 ) -cycloalkyl which in turn are optionally one or more, identical or different, by halogen, hydroxy, amino, carboxyl, (dC 4 ) -alkoxy, (dC 4 ) -Alkoxycarbonyl, (dC 4 ) -alkoxycarbonylamino, (d- C 5 ) -alkanoyloxy, a heterocycle or, in turn, optionally substituted by halogen or hydroxy-substituted phenyl,
  • X represents O, S or CH 2 ,
  • R and R represent hydrogen
  • R and R 4 are the same or different and are methyl, ethyl, propyl, isopropyl,
  • R 6 for a group of the formula -S (O) 2 -R 10 , -NH-C (O) -R 12 , -CH 2 -R 13 , -C (O) -R 14 or -CH (OH) - R 41 is what
  • R 10 stands for phenyl or for 5- to 6-membered heteroaryl with up to three identical or different heteroatoms from the series N, O and / or S, which may be mono- or discrete, identical or different, by fluorine, chlorine, bromine , Hydroxy, cyano, trifluoromethyl, (dC 4 ) -alkyl, (dC 4 ) -alkoxy, carboxyl or (dC 4 > alkoxycarbonyl) are substituted,
  • R 16 and R 17 together with the nitrogen atom to which they are attached form a 5- to 6-membered saturated heterocycle, which contain a further hetero atom from the series N, O or S and substituted by (C 1 -C 4) -alkyl can be,
  • R 12 stands for straight-chain or branched (C C 1-4 alkyl which is optionally substituted by phenoxy or benzyloxy,
  • R 13 for 5- to 6-membered heteroaryl with up to three identical or different heteroatoms from the series N, O and / or S, which is optionally selected from the group (dC 4 ) -alkyl by one or two identical or different substituents, Hydroxy, (dC 4 ) -alkoxy, fluorine, chlorine, bromine, cyano, carboxyl and (dC) -alkoxycarbonyl is substituted, or stands for the group -NR 34 R 35 , wherein R, 3'4 4 represents (dC 6 ) alkyl or (C 5 -C 7 ) cycloalkyl,
  • R 35 stands for benzyl which is optionally substituted in the phenyl ring by hydroxy, (dC 4 ) alkoxy, (dC 4 ) alkyl, trifluoromethyl, fluorine, chlorine or cyano,
  • R 14 represents a group of the formula -NR 42 R 43 , wherein
  • R 42 represents hydrogen, (dC 6 ) -alkyl or (C 5 -C 7 ) -cycloalkyl
  • R 43 represents hydrogen or (dC 4 ) -alkyl, which can be substituted by phenyl,
  • R and R together with the nitrogen atom to which they are attached form a 5- to 6-membered saturated heterocycle which contain a further heteroatom from the series N, O or S and which are substituted by (C j -dt) - alkyl can
  • R 41 represents phenyl which is optionally mono- or disubstituted, identical or different, by fluorine, chlorine, bromine, (dC) -alkyl, (dC) -alkoxy, cyano, trifluoromethyl or (CC 4 ) -alkoxycarbonyl,
  • R 37 is hydroxy or the radical -SO 2 -R 37 or -C (O) -R 37 has the meanings of R 37 given above for a group which, in the sense of a prodrug to the sulfonic acid -SO 2 - OH or to the carboxylic acid -C (O) -OH or their salts can be degraded,
  • X represents CH 2 or in particular oxygen
  • R and R represent hydrogen
  • R 3 and R 4 are identical or different and represent methyl, ethyl, propyl, isopropyl, cyclopropyl, trifluoromethyl, chlorine or bromine, R 5 represents hydrogen,
  • R 6 represents a group of the formula -S (O) 2 -R 10 , -CH 2 -R 13 or -C (O) -R 14 , in which
  • R 10 stands for phenyl, pyridyl, pyrimidinyl or pyridazinyl, which may be mono- or bivalent, identical or different, by fluorine, chlorine, bromine, hydroxy, cyano, trifluoromethyl, (dC 4 ) - alkyl, (d- C 4 ) - Alkoxy, carboxyl or (dC 4 ) - alkoxycarbonyl are substituted,
  • R 13 is pyridyl, pyrimidinyl or pyridazinyl, optionally substituted by one or two identical or different substituents selected from the group (dC 4) - alkyl, hydroxy, (dC 4) -alkoxy, fluorine, chlorine,
  • -RT represents (dC 4 ) alkyl or (C 5 -C 7 ) cycloalkyl
  • R 35 represents benzyl, which is optionally substituted in the phenyl ring by hydroxy, (dC 4 ) alkoxy, (dC 4 alkyl, trifluoromethyl, fluorine, chlorine or cyano,
  • R 14 represents a group of the formula -NR 42 R 43 , wherein
  • R 42 represents hydrogen, (d -C 4 ) alkyl or (C 5 -C 7 ) cycloalkyl
  • R 43 represents hydrogen or (dC) - alkyl, which can be substituted by phenyl,
  • R represents hydrogen
  • R 38 is hydrogen, (CC 4 ) -alkyl or (C 4 -C 6 ) -cycloalkyl, and their pharmaceutically acceptable salts, solvates, hydrates and hydrates of the salts.
  • radical definitions specified in detail in the respective combinations or preferred combinations of radicals are also replaced by radical definitions of other combinations, regardless of the respectively specified combinations of the radicals.
  • R 38 is hydrogen, methyl or ethyl.
  • R 6 represents a group of formula -S (O) 2 -R 10
  • R 10 stands for phenyl or for 5- to 6-membered heteroaryl with up to two identical or different heteroatoms from the series N, O and / or S, which may be mono- or discrete, identical or different, by fluorine, chlorine, bromine , Hydroxy, cyano, trifluoromethyl, (dC) - alkyl, (dC 4 ) - alkoxy, carboxyl or (dC) -alkoxycarbonyl are substituted,
  • R 16 and R 17 together with the nitrogen atom to which they are attached form a 5- to 6-membered saturated heterocycle, which contain a further hetero atom from the series N, O or S and substituted by (C 1 -C 4) -alkyl can be.
  • X represents CH 2 or O
  • R 3 and R 4 are identical or different and represent bromine, trifluoromethyl, ethyl, cyclopropyl and in particular methyl or chlorine,
  • R is a group of formula -S (O) 2 - 10, wherein
  • R, 10 represents phenyl or pyridyl, which are optionally substituted once or twice, identically or differently, by fluorine, chlorine, cyano, trifluoromethyl, methyl, hydroxy or methoxy.
  • the compounds of the general formula (I) according to the invention can be prepared by reacting one of the following process variants [A], [B] or [C] with reactive phenol derivatives of the general formulas (Ila-c) with reactive phenyl derivatives of the general If necessary, formulas (IIla-c) are reacted in the presence of inert solvents and catalysts and, if appropriate, with isolation of the intermediates of the general formulas (IV), (IVa), (IVb) or (IVc) or to give compounds of the formula (I), where the substituents R 1 , R 2 , R 3 , R 4 , R 5 and R 6 and X and Z each have the meanings given above,
  • Z ' has the meaning given for Z or represents a nitro, amino, acetamido, benzyloxycarbonylamino or tert-butoxycarbonylamino group
  • PG stands for a suitable protective group.
  • Coupling catalysts such as Pd, Rh and / or Cu compounds may be mentioned as examples of catalysts.
  • Examples of the reactive groups V and W may be mentioned: halogen, hydroxy, CH2Br, mercapto, amino, CHO, Li, or magnesium, tin, boron, copper, cerium or zinc derivatives.
  • the phenol derivatives of the general formulas (Ila-c) which can be used according to the invention are known or can be prepared by known methods [compare e.g. Ogata et al., Tetrahedron 26: 731-736 (1970); Borsche et al., Justus Liebigs Ann. Chem. 450, 82 (1926); Pickholz, J. Chem. Soc, 685 (1946); Truce, J. Amer. Chem.
  • the phenyl derivatives of the general formulas (IIIa-c) are also known or can be prepared by known methods [compare, for example, van de Bunt, Recl. Trav. Chim. Pays-Bas 48, 131 (1929); Valkanas, J. Chem. Soc, 5554 (1963); Thea et al., J. Org. Chem. 50, 1867-1872 (1985); Baker et al., J. Chem. Soc, 2303-2306 (1948); Miller et al., J. Med. Chem. 23 (10), 1083-1087 (1980)].
  • reaction of the starting compounds (Ila-c) with (Illa-c) generally takes place under normal pressure. However, it can also be carried out under increased or reduced pressure.
  • the reaction can be carried out in a temperature range from -100 ° C to + 200 ° C, preferably between -78 ° C and + 150 ° C in the presence of inert solvents.
  • inert solvents dimethyl sulfoxide (DMSO), dimethylformamide (DMF), N-methyl-2-pyrrolidinone (NMP), tetrahydrofuran (THF), diethyl ether, dichloromethane etc.
  • Registration understood such groups in starting materials and / or intermediates that present functional groups such as Protect carboxyl, amino, mercapto or hydroxy groups and which are common in preparative organic chemistry.
  • the groups protected in this way can then be converted into free functional groups in a simple manner under known conditions.
  • the compounds of formula (I) according to the invention show a surprising and valuable spectrum of pharmacological activity and can therefore be used as versatile medicaments.
  • they can be used for all indications that can be treated with natural thyroid hormones, such as, for example and preferably, depression, goiter or thyroid cancer.
  • Arteriosclerosis, hypercholesterolemia and dyslipidemia can preferably be treated with the compounds of formula (I) according to the invention.
  • obesity and heart failure can be treated and a postprandial reduction in triglycerides can be achieved.
  • the compounds are also suitable for the treatment of certain respiratory diseases, in particular pulmonary emphysema and for the medicinal promotion of pulmonary maturation.
  • the compounds are also suitable for the treatment of pain and migraines, for neuronal repair (remyelination) and for the treatment of Alzheimer's disease.
  • the compounds are also suitable for the treatment of osteoporosis, cardiac arrhythmias, hypothyroidisms and skin diseases.
  • the compounds can also be used to promote and regenerate hair growth and to treat diabetes.
  • the active compounds according to the invention open up a further treatment alternative and represent an enrichment of the pharmaceutical industry.
  • the compounds according to the invention show an improved spectrum of activity. They are preferably characterized by great specificity, good tolerance and fewer side effects, especially in the cardiovascular area.
  • the activity of the compounds according to the invention can e.g. Test in vitro using the T3 promoter assay cell test described below:
  • the test is carried out with a stably transfected human HepG2 hepatocarcinoma cell which expresses a luciferase gene under the control of a thyroid hormone-regulated promoter.
  • the vector used for transfection carries a minimal thymidine kinase promoter with a thyroid hormone responsive element (TRE), which consists of two inverted palindromes of 12 bp each and an 8 bp spacer, in front of the luciferase gene.
  • TRE thyroid hormone responsive element
  • the cell cultures are sown in 96-well plates in Eagle's Minimal Essential Medium with the following additives: glutamine, tricine [N- (tris (hydroxymethyl) methyl) glycine], sodium pyruvate, non-essential amino acids (L- Ala, L-Asn, L-Asp, L-Pro, L-Ser, L-Glu, Gly), insulin, selenium and transferrin.
  • glutamine glutamine
  • sodium pyruvate sodium pyruvate
  • non-essential amino acids L- Ala, L-Asn, L-Asp, L-Pro, L-Ser, L-Glu, Gly
  • insulin selenium and transferrin.
  • test substance or reference compound T3, T4
  • costimulator retinoic acid costimulator retinoic acid
  • the cells are then made luciferase by adding a Triton and Luci ferine-containing buffers (from Promega) lysed and immediately measured luminometrically.
  • the EC50 values of each connection are calculated.
  • the substances that are to be tested for their serum cholesterol-lowering effect in vivo are administered orally to male mice with a body weight between 25 and 35 g.
  • the substances are administered orally once a day for 7 days.
  • the test substances are, for example, in a solution made from Solutol HS 15 +
  • the dissolved substances are applied in a volume of 10 ml / kg body weight with a gavage. Animals that are treated in the same way but only receive the solvent (10 ml / kg body weight) without test substance serve as a control group.
  • the effect of the test substances on the serum cholesterol concentration is determined by subtracting the cholesterol value of the 1st blood sample (previous value) from the cholesterol value of the 2nd blood sample (after treatment). The differences of all cholesterol values in a group are averaged and compared with the mean value of the differences in the control group.
  • Substances that reduce the serum cholesterol of the treated animals statistically significantly (p ⁇ 0.05) by at least 10% compared to that of the control group are considered to be pharmacologically active.
  • the animals are weighed and killed after the blood is drawn.
  • the hearts are removed and weighed.
  • An effect on the cardiovascular system can be determined by a significant increase in heart weight.
  • a change in body weight can be used as a further parameter for the substance effect.
  • Another in vivo test in which the compounds according to the invention show surprisingly advantageous properties is the animal model of the cholesterol-fed rat [A. Taylor et al., Molecular Pharmacology 52, 542-547 (1997); Z. Stephan et al., Atherosclerosis 126, 53-63 (1996)]. Furthermore, the cholesterol-lowering effect of the compounds according to the invention can also be checked in normocholesterolemic dogs by oral administration of the test substances for 5-7 days.
  • Influence of substances can be used, inter alia, to determine the expression of the mRNA of the "HCN2" ion channel ("hyperpolarization-activated cyclic nucleotide-gated channel”) in mouse or rat hearts [cf. also: Trost et al., Endocrinology 141 (9), 3057-3064 (2000); Gloss et al., Endocrinology 142 (2), 544-550 (2001); Pachuki et al., Circulation Research 85, 498-503 (1999)]:
  • mRNA of the "hyperpolarization-activated cyclic nucleotide-gated" cation channel (HCN2) in rat hearts was determined using real-time PCR
  • RNA is isolated using RNaesy columns (Qiagen), digested with DNase and then rewritten into cDNA (SUPERS CRTPT-II RT cDNA synthesis kit, Gibco).
  • the HCN2 mRNA determination is carried out on an ABI Prism 7700 device (from Applied Biosystems).
  • FAM fluorescent 6-carboxyfluorescein
  • TAMRA quencher 6-carboxytetramethylrhodamine
  • Taq polymerase cleaved the fluorescent dye FAM and thereby obtained the previously quenched fluorescence signal.
  • the number of cycles at which the fluorescence intensity was 10 standard deviations above the background fluorescence is recorded as the so-called “threshold cyle” (Ct value).
  • the relative expression of the HCN2 mRNA calculated in this way is then based on the expression of the ribosomal
  • Protein L32 standardized. This assay can also be carried out in an analogous manner with mouse hearts.
  • the sequence of the "forward” and “reverse” primer in this case was 5'-CGAGGTGCTGGAGGAATACC-3 'and 5'-CTAGCCGGTCAATAGCCACAG-3', that of the fluorescent sample 5'-6FAM-CATGATGCGGCGTGCCTTTGAG-
  • all customary application forms come into consideration, i.e. i.e. oral, parenteral, inhalative, nasal, sublingual, buccal, rectal or external, e.g. transdermally, particularly preferably orally or parenterally.
  • parenteral administration intravenous, intramuscular, subcutaneous administration should be mentioned in particular, e.g. as a subcutaneous depot.
  • Oral application is very particularly preferred.
  • the active ingredients can be administered alone or in the form of preparations.
  • suitable preparations include Tablets, capsules, pellets, dragees, pills, granules, solid and liquid aerosols, syrups, emulsions, suspensions and solutions.
  • the active ingredient must be present in such an amount that a therapeutic effect is achieved.
  • the active ingredient can be present in a concentration of 0.1 to 100% by weight, in particular 0.5 to 90% by weight, preferably 5 to 80% by weight.
  • the concentration of the active ingredient should be 0.5-90% by weight, i.e. the active substance should be present in amounts sufficient to achieve the dosage range indicated.
  • the active ingredients can be converted into the customary preparations in a manner known per se. This is done using inert, non-toxic, pharmaceutically suitable carriers, auxiliaries, solvents, vehicles, emulsifiers and / or dispersants.
  • auxiliaries include: water, non-toxic organic solvents such as paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerol), glycols (e.g. polyethylene glycol), solid carriers such as natural or synthetic rock powder (e.g. talc or silicates), Sugar (e.g. milk sugar), emulsifiers, dispersants (e.g. polyvinylpyrrolidone) and lubricants (e.g. magnesium sulfate).
  • non-toxic organic solvents such as paraffins, vegetable oils (e.g. sesame oil), alcohols (e.g. ethanol, glycerol), glycols (e.g. polyethylene glycol), solid carriers such as
  • tablets can of course also contain additives such as sodium citrate together with additives such as starch, gelatin and the like.
  • additives such as sodium citrate together with additives such as starch, gelatin and the like.
  • Aqueous preparations for oral administration can also be mixed with flavor enhancers or colorants.
  • doses of 0.001 to 5 mg / kg, preferably 0.001 to 3 mg / kg of body weight are preferably administered per 24 hours.
  • the new active substances can be used alone and, if necessary, also in combination with other active substances, preferably from the group CETP inhibitors, antidiabetics, antioxidants, cytostatics, calcium antagonists, antihypertensive agents, thyroid hormones, inhibitors of HMG-CoA reductase, inhibitors of HMG-CoA reductase Gene expression, squalene synthesis inhibitors, ACAT inhibitors, circulatory agents, platelet aggregation inhibitors, anticoagulants, angiotensin II receptor antagonists, cholesterol absorption inhibitors, MTP inhibitors, aldose reductase inhibitors, fibrates, niacin, niacin Inhibitors and PPAR agonists are administered.
  • active substances preferably from the group CETP inhibitors, antidiabetics, antioxidants, cytostatics, calcium antagonists, antihypertensive agents, thyroid hormones, inhibitors of HMG-CoA reductase, inhibitors of HMG-CoA reductase Gene

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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Abstract

La présente invention concerne des dérivés d'amido-diphényle de formule (I) dans laquelle les variables X, Z et R1-R7 correspondent aux éléments indiqués dans la revendication 1, un procédé permettant leur préparation et leur utilisation en tant que produits pharmaceutiques.
PCT/EP2002/004622 2001-05-09 2002-04-26 Derives d'amido-diphenyle WO2002090344A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10122443.5 2001-05-09
DE2001122443 DE10122443A1 (de) 2001-05-09 2001-05-09 Amido-Diphenyl-Derivate

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WO2002090344A1 true WO2002090344A1 (fr) 2002-11-14

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7342127B2 (en) 2003-01-24 2008-03-11 Bristol-Myers Squibb Company Substituted anilide ligands for the thyroid receptor

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000039077A2 (fr) * 1998-12-24 2000-07-06 Karo Bio Ab Nouveaux ligands de recepteurs thyroidiens et procede ii
WO2000051971A1 (fr) * 1999-03-01 2000-09-08 Pfizer Products Inc. Acides oxamiques et derives utilises en tant que ligands du recepteur des hormones thyroidiennes
WO2000058279A1 (fr) * 1999-03-29 2000-10-05 Novartis Ag Derives diaryle et utilisations de ceux-ci comme medicaments

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000039077A2 (fr) * 1998-12-24 2000-07-06 Karo Bio Ab Nouveaux ligands de recepteurs thyroidiens et procede ii
WO2000051971A1 (fr) * 1999-03-01 2000-09-08 Pfizer Products Inc. Acides oxamiques et derives utilises en tant que ligands du recepteur des hormones thyroidiennes
WO2000058279A1 (fr) * 1999-03-29 2000-10-05 Novartis Ag Derives diaryle et utilisations de ceux-ci comme medicaments

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GREENIDGE, P.A. ET AL.: "Pharmacophores incorporating numerous excluded volumes defined by X-ray crystallographic structure in three-dimensional database searching: application to the thyroid hormone receptor", J. MED. CHEM., vol. 41, no. 14, 1998, pages 2503 - 2512, XP002212857 *
YOKOYAMA N: "Synthesis and structure-activity relationships of oxamic acid and acetic acid derivatives related to L-thyronine", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 38, 1995, pages 695 - 707, XP002080908, ISSN: 0022-2623 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7342127B2 (en) 2003-01-24 2008-03-11 Bristol-Myers Squibb Company Substituted anilide ligands for the thyroid receptor

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