EP1438285A1 - Essigsäurederivate - Google Patents

Essigsäurederivate

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Publication number
EP1438285A1
EP1438285A1 EP02777295A EP02777295A EP1438285A1 EP 1438285 A1 EP1438285 A1 EP 1438285A1 EP 02777295 A EP02777295 A EP 02777295A EP 02777295 A EP02777295 A EP 02777295A EP 1438285 A1 EP1438285 A1 EP 1438285A1
Authority
EP
European Patent Office
Prior art keywords
hydrogen
compounds
methyl
alkyl
general formula
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Withdrawn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
EP02777295A
Other languages
German (de)
English (en)
French (fr)
Inventor
Hilmar Bischoff
Elke Dittrich-Wengenroth
Heike Heckroth
Andrea Vaupel
Michael Woltering
Stefan Weigand
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.)
Bayer AG
Original Assignee
Bayer Healthcare AG
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Filing date
Publication date
Application filed by Bayer Healthcare AG filed Critical Bayer Healthcare AG
Publication of EP1438285A1 publication Critical patent/EP1438285A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered

Definitions

  • the present application relates to novel substituted acetic acid derivatives, to processes for their preparation and to their use in medicaments, in particular as potent PPAR-delta activating compounds for the prophylaxis and / or treatment of cardiovascular diseases, in particular of dyslipidaemias and coronary heart diseases.
  • Fibrates are now the only form of therapy for patients in these risk groups. They act as weak agonists of the peroxisome proliferator-activated receptor (PPAR) -alpha (Nature 1990, 347, 645-50). A disadvantage of previously approved fibrates is their poor interaction with the receptor, which leads to high daily doses and significant side effects.
  • PPAR peroxisome proliferator-activated receptor
  • WO 00/23407 describes PPAR modulators for the treatment of obesity, atherosclerosis and / or diabetes.
  • the object of the present invention was to provide novel compounds which can be used as PPAR delta modulators.
  • X is O, S or CH 2 ,
  • R 1 , R 2 and R 3 are identical or different and independently of one another represent hydrogen, (-CC 6 ) -alkyl, (C 3 -C 7 ) -cycloalkyl, hydroxy, (CC 6 ) -alkoxy, ino, mono or di- (C 1 -C 6 ) -A] -alkylamino, halogen, trifluoromethyl,
  • R 4 is hydrogen or (CC) -alkyl
  • R 5 and R 6 are hydrogen or together with the carbon atom to which they are attached form a carbonyl group
  • R 7 is hydrogen or (CC 4 ) -alkyl
  • R 8 is straight-chain (C 5 -C 10) -alkyl or a group of the formula - (CH 2 ) n -E, in which for (C3-Ci2) cycloalkyl, up to four times by identical or different substituents from (C ⁇ -C6) alkyl, TrifTuormethyl, hydroxy, (C ⁇ -C6) alkoxy, carboxyl or (C ⁇ -C6 ) Alkoxycarbonyl, or for 4- to 8-membered heterocyclyl having up to two heteroatoms of O and / or S, which may be substituted up to two times, identically or differently, by (C * -C 6 ) -alkyl , stands,
  • n is the number 0, 1 or 2
  • R 9 and R 10 are identical or different and independently of one another represent hydrogen, (C 1 -C 6 ) -alkyl, (C 1 -C 6 ) -alkoxy, trifluoromethyl or halogen,
  • R ⁇ and R 12 are identical or different and are independently hydrogen or (C, -C 4) are alkyl
  • R 13 is hydrogen or a hydrolyzable group which can be degraded to the corresponding carboxylic acid
  • a hydrolyzable group means a group which, in particular in the body, converts the
  • OR 13 grouping into the corresponding carboxylic acid (R 13 hydrogen) leads.
  • Such groups are, for example and preferably: benzyl, (. C-C6) alkyl or (C 3 - C 8) cycloalkyl which is optionally mono- or polysubstituted in each case, identical or different, by halogen, hydroxy, amino, (C ⁇ -C 6) 6) alkoxy, carboxyl, (C ⁇ -C - alkoxycarbonyl, (CrC 6) alkoxycarbonylamino or (C ⁇ -C6) alkanoyloxy tuiert are substitutable, or, especially, (C -C 4) -alkyl.
  • (C 1 -C 6 ) -alkyl, (CC 4 ) -alkyl and (CC 3 ) -alkyl are in the context of the invention a straight-chain or branched alkyl radical having 1 to 6, 1 to 4 or 1 to 3 carbon atoms.
  • Preferred is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms.
  • (C 5 -C 1 o) alkyl in the context of the invention a straight-chain alkyl having 5 to 10 carbon atoms. Preference is given to a straight-chain alkyl radical having 5 to 7 carbon atoms. Examples which may be mentioned are: n-pentyl, n-hexyl and n-heptyl.
  • Examples which may be mentioned by way of example include cyclobutyl, cyclopentyl and cyclohexyl.
  • (C ⁇ -C6) alkoxy, (C.-C 4) -alkoxy and (C, -C 3) are in the context of the invention a straight-chain or branched alkoxy radical having from 1 to 6, 1 to 4 or 1 up to 3 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.
  • (C 1 -C 6 ) -alkoxycarbonyl in the context of the invention is a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms which is linked via a carbonyl group. Preference is given to a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl.
  • (C.-C6) alkoxycarbonylamino is in the context of the invention for an amino group having a straight-chain or branched alkoxycarbonyl substituent which has in the alkoxy radical and from 1 to 6 carbon atoms is linked via the carbonyl group.
  • Preferred is a Alkoxycaibonylamino radical having 1 to 4 carbon atoms.
  • memoxycarbonylamino, emoxycarbonylamino, n-propoxycarbonylamino and t-butoxycarbonylamino are examples of: memoxycarbonylamino, emoxycarbonylamino, n-propoxycarbonylamino and t-butoxycarbonylamino.
  • (C t -C 6 ) -Alkanoyloxy in the context of the invention is a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, which carries a doubly bonded oxygen atom in the 1-position and linked in the 1-position via another oxygen atom is.
  • Examples which may be mentioned by way of example include: acetoxy, propionoxy, n-butyroxy, i-butyroxy, pivaloyloxy, n-hexanoyloxy.
  • Mono (C 1 -C 6 ) -alkylamino in the context of the invention represents an amino group having a straight-chain or branched alkyl substituent which has 1 to 6 carbon atoms. Preference is given to a straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms.
  • Pentylamino and n-hexylamino are Pentylamino and n-hexylamino.
  • Di (C 1 -C 6 ) -alkylamino and di (C 1 -C 4 ) -alkylamino in the context of the invention are an amino group having two identical or different straight-chain or branched alkyl substituents, each of which has 1 to 6 or 1 have up to 4 carbon atoms.
  • Straight-chain or branched dialkylamino radicals are preferred each 1 to 4 carbon atoms.
  • N N-dimethylamino
  • N N-dimethylamino
  • N-enyl-N-memylamino N-methyl-N-propylamino
  • N-isopropyl-Nn-propylamino N-butyl-N-memylamino
  • N-ethyl N-penlylamino Nn-hexyl-N-memylamino.
  • Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
  • Heterocycle linked via a ring carbon atom Preference is given to a 5- to 6-membered saturated heterocycle having an oxygen atom as heteroatom.
  • tetrahydrofuran-3-yl, tetrahydropyran-3-yl and tetrahydropyran-4-yl By way of example and by way of preference: tetrahydrofuran-3-yl, tetrahydropyran-3-yl and tetrahydropyran-4-yl.
  • the compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers) or which do not behave as image and mirror image (diastereomers).
  • the invention relates to both the enantiomers or diastereomers as well as their respective mixtures.
  • the racemic forms can be separated as well as the diastereomers in a known manner in the stereoisomerically uniform components.
  • the compounds according to the invention can also be present as salts.
  • physiologically acceptable salts are preferred.
  • Pharmaceutically acceptable salts may be salts of the compounds of the invention with inorganic or organic acids. Preference is given to salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic caffeic or sulfonic acids such as, for example, acetic acid, propylene acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid , Ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.
  • 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, for example ethylamine, di- or trie ylamine, ethylsilylamine, monoemanolamine, di-methylamine.
  • Tri- e anolamine dicyclohexylamine, Dime ylaminoethanol, dibenzylamine, N-methyl-mo ⁇ holin, dihydroabietylamine, 1-ephenamine, methylpiperidine, arginine, lysine, Emylen & amine or 2-phenylemylamine.
  • the compounds according to the invention can also be present in the form of their solvates, in particular in the form of their hydrates.
  • A is a -CH 2 - or -CH 2 CH 2 group
  • R 1 and R 2 are identical or different and independently of one another are hydrogen, (C 1 -C 4 ) -alkyl, di- (C 1 -C 4 ) -alkylamino, chlorine, fluorine, trifluoromethyl, trifluoromethoxy, nitro or cyano,
  • R> 3 J is hydrogen
  • R is hydrogen or methyl
  • R 5 and R 6 are hydrogen or together with the carbon atom to which they are attached form a carbonyl group
  • R 7 is hydrogen
  • R 8 is (C 3 -C 8 ) -cycloalkyl which is up to four times, identical or different, by (C 1 -C 4 ) -alkyl, trifluoromethyl, (C 1 -C 4 ) -alkoxy, carboxyl or (CC 4 ) -
  • R 9 is hydrogen, (C.-C 3 ) -alkyl, (-CC 3 ) -alkoxy, trifluoromethyl, fluorine or
  • R 10 is hydrogen
  • R 11 and R 12 are the same or different and independently of one another represent hydrogen or methyl
  • R 13 is hydrogen or a hydrolyzable group which can be degraded to the corresponding carboxylic acid, and their pharmaceutically acceptable salts, hydrates and solvates.
  • A is a -CH 2 group
  • R 1 is hydrogen, methyl, trifluoromethyl, chlorine, fluorine, nitro or cyano,
  • R 2 is methyl, trifluoromethyl, chlorine, fluorine, nitro or cyano
  • R 3 is hydrogen
  • R 4 is hydrogen
  • R 7 is hydrogen
  • R 8 represents cyclopentyl or cyclohexyl, which may each be substituted by methoxy, ethoxy or up to four times by methyl, or 3-tetrahydrofuranyl, 3-tetrahydropyranyl or 4-tetrahydropyranyl, which may be substituted one to two times by methyl, stands,
  • R 9 is methyl
  • R 10 is hydrogen
  • R 11 and R 12 are both hydrogen or methyl
  • R 13 is a hydrolyzable group which can be degraded to the corresponding carboxylic acid, or in particular represents hydrogen,
  • radical definitions given in detail in the respective combinations or preferred combinations of radicals are also replaced by radical definitions of other combinations, irrespective of the particular combinations of the radicals indicated.
  • R 1 and R 2 are the same or different and are each independently methyl
  • A, X, R 8 , R 9 , R 10 , R 11 and R 12 are each as defined above.
  • T is benzyl, (C 1 -C 6 ) -alkyl or a polymeric carrier suitable for solid-phase synthesis,
  • R 1 , R 2 , R 3 and R 4 have the abovementioned meaning
  • A, X, T, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have the abovementioned meaning
  • A, X, T, R 8 , R 9 , R 10 , R 11 and R 12 are as defined above,
  • Q is a suitable leaving group such as halogen
  • Mesylate or tosylate preferably bromine or iodine
  • A, X, T, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 have the abovementioned meaning
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are those indicated above
  • R 13 has the meaning given above
  • Z is a suitable leaving group such as halogen, mesylate or
  • Tosylate or is a hydroxy group
  • the process of the invention is generally carried out at atmospheric pressure. However, it is also possible to carry out the process at overpressure or under reduced pressure (for example in a range from 0.5 to 5 bar).
  • Suitable solvents for the process are customary organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or halohydrocarbons, such as dichloromethane, trichloromethane, tetrachloromethane, dichloroethylene, trichlorethylene or Chlorobenzene, or ethyl acetate, pyridine, D methylsulf- oxide, dimethylformamide, N, N'-dimemylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), acetonitrile, acetone or nitromethane.
  • ethers such as diethyl ether, dioxane, tetrahydro
  • Preferred solvents for process step (JI) + (JE) - (Ia) are dichloromethane, dimethylformamide and dimethylformamide in combination with pyridine.
  • process step (TV) + (V) - (Ia) dimethylformamide is preferred.
  • the inventive Nerfahrens Colour (IT) + (rfl) - (la) is generally carried out in a temperature range of 0 ° C to + 100 ° C, preferably from 0 ° C to + 40 ° C.
  • the process step (TV) + (V) - (la) is generally carried out in a temperature range from 0 ° C to + 120 ° C, preferably from + 50 ° C to + 100 ° C.
  • auxiliaries for amide formation in process step (H) + (JE) - »(la) preference is given to using customary condensation agents, such as carbodiimides, for example ⁇ , ⁇ -diethyl, N, N'-dipropyl, N, N-diisopropyl , N, N'-Dicyclohexylcarbo ⁇ umid (DCC), N- (3-Dimethylanunoisopropyl) -N-ethylcarbom 'imide hydrochloride (EDC), or carbonyl compounds such as carbonyldiimidazole, or 1,2-Oxazoüumtagenen as 2-ethyl-5-phenyl- l, 2-oxazohum-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dyrodroquinoline, or propanephosphonic an
  • EDC EDC
  • N-methylmorpholine N-methylmorpholine
  • 1-hydroxybenzotriazole EDC
  • triethylamine and 1-hydroxybenzotriazole HATU and diisopropylethylamine, as well as HATU and pyridine.
  • Suitable bases for the reaction (TV) + (N) - »(Ia) are the customary inorganic bases such as alkali metal hydroxides, such as, for example, lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium, potassium, calcium or Cesium carbonate or sodium or potassium bicarbonate, or organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine or diisopropylemylamine. Preference is given to sodium bicarbonate.
  • alkali metal hydroxides such as, for example, lithium, sodium or potassium hydroxide
  • alkali metal or alkaline earth metal carbonates such as sodium, potassium, calcium or Cesium carbonate or sodium or potassium bicarbonate
  • organic bases such as trialkylamines, for example triethylamine, N-methylmorpholine, N-methylpiperidine or diisopropylemylamine. Preference is given to sodium bicarbonate.
  • the hydrolysis of the carboxylic acid esters in the Nerfahrens Colour (la) or (Tb) ⁇ (Ic) is carried out by conventional methods by treating the esters in inert solvents with bases, wherein the initially formed salts are converted by treatment with acid in the free carboxylic acids.
  • the hydrolysis is preferably carried out with acids.
  • Suitable solvents for the hydrolysis of the carboxylic acid esters are water or the organic solvents customary for ester cleavage. These are preferred
  • Alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, dimethylformamide, dichloromethane or dimethyl sulfoxide. It is also possible to use mixtures of said solvents. Preference is given to water / tetrahydrofuran and, in the case of the reaction with trifluoroacetic acid, dichloromethane and, in the case of hydrogen chloride, tetrahydrofuran,
  • Suitable bases for the hydrolysis are the customary inorganic bases. These include preferably alkali metal hydroxides or alkaline earth metal hydroxides such as sodium hydroxide, lithium hydroxide, potassium hydroxide or barium hydroxide, or
  • Alkalicarbonates such as sodium or potassium carbonate or sodium bicarbonate. Particular preference is given to using sodium hydroxide or lithium hydroxide.
  • Trifluoroacetic acid sulfuric acid, chlorine-hydrogen, hydrogen bromide and acetic acid or mixtures thereof are suitable as acids in general with the addition of water.
  • Hydrogen chloride or trifluoroacetic acid are preferred in the case of the tert-butyl esters and hydrochloric acid in the case of the methyl esters.
  • the base or the acid is generally used in an amount of 1 to 100 mol, preferably 1.5 to 40 mol based on 1 mol of the ester.
  • the hydrolysis is generally carried out in a temperature range from 0 ° C to + 100 ° C, preferably from 0 ° C to + 50 ° C.
  • the compounds of general formula (TJ) are novel and can be prepared by first
  • B is a bond or a methylene group
  • R [a-1] has the meaning of R given above
  • [a-2] is a group of the formula wherein
  • R 7 has the meaning given above
  • R 15 is (C 1 -C 4 ) -alkyl or trimethylsilyl
  • R 7 and R 15 have the abovementioned meaning
  • Y is a suitable leaving group such as, for example, halogen, mesylate or tosylate, preferably bromine or iodine, to compounds of the general formula (XI)
  • A, X, T, R 9, R 1, R 7, R 11, and R 12 have the abovementioned meaning, in the presence of a suitable reducing agent with compounds of the general formula (XTU)
  • R 17 is straight-chain (C 4 -C 9 ) -alkyl or a group of the formula - (CH 2 ) m -E, in which
  • n is the number 0 or 1
  • A, X, T, R 9 , R 10 , R ⁇ , R 12 and R 17 are as defined above,
  • R 7 , R 15 and Y have the abovementioned meaning
  • the entire process can also be carried out as a solid-phase synthesis.
  • the compounds of the general formula (VH) or (XU) are attached as a carboxylic ester to a suitable carrier resin, the further reactions are carried out on solid phase and the target compound is finally cleaved from the resin.
  • Solid phase synthesis as well as attachment and cleavage from the resin are common standard techniques.
  • Linkers for Solid Phase Organic Synthesis van W. James, Tetrahedron 55, 4855-4946 (1999).
  • reaction (Nile) + (VJE) ⁇ (LX) or (XU) + (XJ) ⁇ (XIN) is carried out in the usual for a reductive amination, under the reaction conditions inert solvents, optionally in the presence of an acid.
  • solvents include, for example, water, dimethylformamide, tetrahydrofuran, dichloromethane, dichloroethane or alcohols such as methanol, ethanol, propanol, isopropanol or butanol; It is also possible to use mixtures of the solvents mentioned. Preference is given to methanol and ethanol in each case with the addition of acetic acid.
  • Suitable reducing agents for the reaction are complex aluminum or borohydrides, such as diisobutylaluminum hydride, ⁇ atriumborhydrid, ⁇ atriumtriacetoxyborhydrid, ⁇ atriumcyanoborhydrid or tetiabutylammonium borohydride, or also the catalytic hydrogenation in the presence of transition metal catalysts such as palladium, platinum, rhodium or Raney- ⁇ ickel.
  • Preferred reducing agents are sodium cyanoborohydride, sodium triacetoxyborohydride and tetrabutylammonium borohydride.
  • reaction (VE) + (VTJJ) ⁇ (LX) or (XU) + (Xffl) - »(XTV) is generally carried out in a temperature range from 0 ° C to + 40 ° C.
  • Suitable bases for the reaction (LX) + (X) ⁇ (XI) or (XTV) + (XV) ⁇ (XVI) are the customary inorganic or organic bases. Preferred is triethylamine.
  • the reaction (LX) + (X) ⁇ (XI) or (XIV) + (XV) ⁇ (XVI) is generally carried out in a temperature range from 0 ° C to + 100 ° C.
  • Hydrolysis these are preferably tetrahydrofuran, dioxane and alcohols such as methanol and ethanol each in admixture with water.
  • tetrahydrofuran dioxane
  • alcohols such as methanol and ethanol each in admixture with water.
  • silyl ester Spal ung preferably dioxane or tetrahydrofuran is used.
  • reaction (XI) - (U) or (XVI) -> (U) is generally carried out in one
  • Temperature range from 0 ° C to + 100 ° C.
  • the compounds of the general formula (TV) correspond to the compounds of the general formula (LX) or (XIV) and can be prepared as described above.
  • the Neritatien invention of formula (I) show a surprising and valuable pharmacological W ⁇ kungsspektrum and can therefore be used as versatile drugs.
  • they are suitable for the treatment of coronary heart disease, for myocardial infarction prophylaxis and for the treatment of restenosis after coronary angioplasty or stenting.
  • the Neritatien of formula (I) according to the invention are preferably suitable for the treatment of arteriosclerosis and hypercholesterolemia, to increase pathologically low HDL levels and to lower elevated triglyceride and LDL levels.
  • they can be used to treat obesity, diabetes, metabolic syndrome (glucose intolerance, hyperinsulinemia, dyslipidemia and hypertension due to insulin resistance), liver fibrosis and cancer.
  • the new active compounds may be used alone or as required in combination with other active substances, preferably from the group consisting of CETP inhibitors, antidiabetic agents, antioxidants, cytostatic agents, calcium antagonists, antihypertensives, thyroid hormones and / or thyroid mimetics, inhibitors of HMG-CoA reductase,
  • the activity of the compounds of the invention can be e.g. in vitro by the transactivation assay described in the Examples section.
  • the efficacy of the compounds of the invention in vivo can be e.g. Check by the tests described in the example section.
  • all customary forms of administration come into consideration, ie, oral, parenteral, inhalative, nasal, sublingual, rectal, external, such as transdermal, or local, such as implants or stents.
  • parenteral administration intravenous, intramuscular or subcutaneous administration, for example as a subcutaneous depot, should be mentioned in particular.
  • the active ingredients can be administered alone or in the form of preparations. Suitable preparations for oral administration include tablets, capsules, pellets, dragees, pills, granules, solid and liquid aerosols, syrups, emulsions, suspensions and solutions.
  • the active ingredient must be kept in such an amount that a therapeutic effect is achieved.
  • the active compound may be present in a concentration of from 0.1 to 100% by weight, in particular from 0.5 to 90% by weight, preferably from 5 to 80% by weight.
  • the concentration of the active ingredient should be 0.5-90% by weight, ie the active ingredient should be present in amounts sufficient to achieve the stated dosage margin.
  • the active compounds can be converted in a conventional manner into the usual preparations. This is done using inert, non-toxic, pharmaceutically suitable excipients, adjuvants, solvents, vehicles, emulsifiers and / or dispersants.
  • adjuvants may be mentioned, for example: water, non-toxic organic solvents such. Paraffins, vegetable oils (e.g., sesame oil), alcohols (e.g., ethanol, glycerin), glycols (e.g., polyethylene glycol), solid carriers such as natural or synthetic minerals (e.g., talc or silicates), sugars (e.g.
  • Lactose Lactose
  • emulsifying agents e.g., polyvinyl pyrrolidone
  • dispersing agents e.g., polyvinyl pyrrolidone
  • lubricants e.g., magnesium sulfate
  • tablets may also contain additives such as sodium citrate together with adjuvants such as starch, gelatin and the like.
  • adjuvants such as starch, gelatin and the like.
  • Aqueous preparations for oral administration may further be treated with flavor enhancers or colorants.
  • dosages of 0.001 to 5 mg / kg, preferably 0.005 to 3 mg / kg of body weight per 24 hours are preferably applied.
  • the following exemplary embodiments illustrate the invention The invention is not limited to the examples.
  • reaction mixture is concentrated and purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate, gradient 95: 5-> 70:30). 0.909 g (56% of theory) of the desired product are obtained.
  • Potassium carbonate are introduced into 45 ml of dimethylformamide and stirred at 50 ° C for 30 min. Then 10.0 g (51.4 mmol) of tert-butyl 2-bromoacetate are added at 50.degree. After 1 h at 50 ° C is stirred overnight at room temperature. The solvent is removed in vacuo. It is taken up in ethyl acetate and washed twice with water, twice with saturated aqueous sodium bicarbonate.
  • reaction is stopped by adding 1 ml of 1 N hydrochloric acid, the reaction mixture is concentrated and taken up in ethyl acetate. It is shaken out with saturated sodium bicarbonate solution and with saturated sodium chloride solution and dried over magnesium sulfate. Chromatographic purification on silica gel (eluent: dichloromethane) gives 0.55 g (65% of theory) of the desired product as an oil.
  • Pol polymeric carrier resin; Reaction conditions: a) diisopropylcarbodiimide, DMAP, triethylamine, dichloromethane, room temperature, 20 h; b) cesium carbonate, dioxane / isopropanol 1: 1, 60 ° C, 24 h; c) trimethyl orthoformate / dimethylformamide 1: 1, room temperature, 20 h; Tetrabutylammonium borohydride, acetic acid, dimethylformamide, room temperature, 20 h; d) triethylamine, dioxane, 60 ° C, 20 h; Tetiabutylammonium fluoride, dioxane,
  • Resin (from Rapp Polymere, Order No. H 1011) are suspended in 200 ml of dichloromethane. After the addition of 12.9 g (84.6 mmol) of 2-bromopropanoic acid, 17.8 g (141 mmol) of diisopropylcarbodiimide and 5.17 g (42.3 mmol) of DMAP, the mixture is shaken at room temperature for 20 h. The mixture is then filtered, the resin with dimethylformamide and alternately with methanol and
  • the resin is suspended in 50 ml of dioxane and admixed with 3.8 ml (3.8 mmol) of a 1 M solution of tetrabutylammonium fluoride in THF. The mixture is shaken for 1-2 h at room temperature and then filtered. Subsequently, the resin is washed with dimethylformamide, methanol and dichloromethane. The resin 6d thus obtained is further reacted directly.
  • Pol polymeric carrier resin
  • Reaction conditions a) trimethyl orthoformate / dimethylformamide 1: 1, room temperature, 12-20 h; Tetiabutylammonium borohydride, acetic acid, dimethylformamide, room temperature, 20 h; b) triethylamine, dioxane, 60 ° C, 12-20 h; Tetrabutylammonium fluoride, dioxane, room temperature, 1-2 h; c) HATU, pyridine / dimethylamine formamide 2: 1, room temperature, 20 h; d) trifluoroacetic acid, dichloromethane, room temperature, 30 min.
  • Pol polymeric carrier resin
  • Reaction conditions a) potassium carbonate, dimethylformamide, 50-100 ° C, 20 h; b) trifluoroacetic acid, dichloromethane, room temperature, 2 h; c) N, N-Diisopropylcarbodiimide, DMAP, dichloromethane, room temperature, 20 h.
  • the resin is suspended in pyridine / dimethylformamide (2: 1) and the aniline derivative (5-10 eq.) And HATU (3 eq.) Are added. The mixture is shaken for 20 h at room temperature and then filtered. For complete implementation, this process must be partially repeated. It is then washed with 30% acetic acid, water, dimethylformamide, methanol, dichloromethane,
  • the reactors are cut open at the bottom and treated in Flex-Chem blocks four times with 500 ⁇ l each dichloromethane / trifluoroacetic acid (1: 1). After concentration in vacuo to obtain the respective product.
  • reaction scheme 2 The separated reaction vessels with the resins JE obtained according to method 1 (reaction scheme 2) are initially charged in dimethylformamide and admixed with sodium bicarbonate (3 eq.) And the bromoacetic acid anilide from example 1 / step 1c), via or VIb (3 eq.). The mixture is stirred for 3 h at 90 ° C. Subsequently, with
  • B: LiChrospher 100 RP 18, 5 ⁇ m, 40 ° C; 2.5 ml min; Laufinittel A acetonitrile +
  • PAR-delta Peroxisome proliferator-activated receptor delta
  • PPAR ⁇ receptor is fused to the DNA binding domain of the yeast transcription factor GAL4.
  • the resulting GAI ⁇ -PPAR ⁇ chimera is co-transfected into CHO cells with a reporter construct and stably expressed.
  • the GAI PPAR ⁇ expression construct contains the ligand binding domain of PPAR ⁇ (amino acids 414-1326), which is PCR amplified and cloned into the vector pcDNA3.1. This vector already contains the GAL4 DNA binding domain (amino acids 1-147) of the vector pFC2-dbd (Stratagene).
  • the reporter construct containing five copies of the GAL4 binding site upstream of a tymine kinase promoter, expresses the firefly luciferase (Photinus pyralis) upon activation and binding of GAL4-PPAR ⁇ .
  • Transactivation assay luciferase reporter: CHO (Chinese hamster ovary) cells are grown in CHO-A-SFM medium (GIBCO) supplemented with 2.5% fetal calf serum and 1% penicillin streptomycin (GIBCO) at a cell density of 2 x 10 3 cells per well seeded in a 384 well plate (Greiner). After culturing for 48 h at 37 ° C, the cells are stimulated. For this purpose, the substances to be tested are taken up in the above-mentioned medium and added to the cells. After a stimulation time of 24
  • luciferase activity is measured with the help of a video camera.
  • the measured relative light units result in a sigmoidal stimulation curve as a function of the substance concentration.
  • the ECso values are calculated using the compute program GraphPad PRISM (version 3.02).
  • HDL-C HDL-cholesterol
  • the substances to be tested for their HDL-C increasing activity in vivo are orally administered to male transgenic hApoAl mice.
  • the substances are administered orally once a day for 7 days.
  • the test substances are dissolved in a solution of Solutol HS 15 + ethanol + saline (0.9%) in the ratio 1 + 1 + 8 or in a solution of Solutol HS 15 + saline (0.9%) in the ratio 2 + 8.
  • the application of the dissolved substances takes place in a volume of 10 ml / kg body weight with a gavage.
  • the controls are animals treated in the same way but only the solvent
  • each mouse is used to determine ApoAl
  • the non-HDL-C fraction is precipitated with 20% PEG 8000 in 0.2 M glycine buffer pH 10. From the supernatant, the cholesterol in a
  • the human mouse ApoAl is determined by a sandwich ELISA method using a polyclonal anti-human Apo AI and a monoclonal anti-human ApoAl antibody (Biodesign International, USA). The quantification is carried out by UV photometry (BIO-TEK Instruments, USA) with peroxidase-coupled anti-mouse IgG antibodies (KPL, USA) and peroxidase substrate (KPL, USA).
  • the effect of the test substances on the HDL-C concentration is determined by subtracting the measured value of the 1st blood sample (pre-value) from the measured value of the 2nd blood sample (after treatment).
  • the differences of all HDL-C values of a group are averaged and compared with the mean of the differences of the control group.
  • mice with insulin resistance and elevated blood glucose levels are used.
  • C57B1 / 6J Lep ⁇ ob> mice are treated according to the same protocol as the transgenic ApoAl mice.
  • the serum lipids are determined as described above.
  • serum glucose is determined as a parameter for blood glucose in these animals.
  • the serum glucose is enzymatically added to an EPOS
  • a blood glucose-lowering effect of the test substances is determined by subtracting the measured value of the first blood sample of an animal (pre-value) from the measured value of the 2.
  • Substances which reduce the serum glucose concentration of the treated animals statistically significantly (p ⁇ 0.05) by at least 10% compared to those of the control group are considered to be pharmacologically active.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP02777295A 2001-10-18 2002-10-09 Essigsäurederivate Withdrawn EP1438285A1 (de)

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DE10337839A1 (de) * 2003-08-18 2005-03-17 Bayer Healthcare Ag Indolin-Derivate
EP1661890B1 (en) * 2003-09-03 2011-01-05 Kowa Co., Ltd. Ppar-activating compound and pharmaceutical composition containing same
DE602005024384D1 (de) 2004-05-05 2010-12-09 High Point Pharmaceuticals Llc Neue verbindungen, ihre herstellung und verwendung
EP1745014B1 (en) 2004-05-05 2011-07-06 High Point Pharmaceuticals, LLC Novel compounds, their preparation and use
WO2007003581A1 (en) 2005-06-30 2007-01-11 Novo Nordisk A/S Phenoxy acetic acids as ppar delta activators
AU2006327003B2 (en) 2005-12-22 2011-10-06 Vtv Therapeutics Llc Phenoxy acetic acids as PPAR delta activators
WO2007101864A2 (en) 2006-03-09 2007-09-13 High Point Pharmaceuticals, Llc Compounds that modulate ppar activity, their preparation and use
WO2010047982A1 (en) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
EP2362731B1 (en) 2008-10-31 2016-04-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
EP2538784B1 (en) 2010-02-25 2015-09-09 Merck Sharp & Dohme Corp. Benzimidazole derivatives useful anti-diabetic agents
CA2826649C (en) 2011-02-25 2016-07-26 Merck Sharp & Dohme Corp. Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents
CA2880901A1 (en) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
CN104994848A (zh) 2013-02-22 2015-10-21 默沙东公司 抗糖尿病二环化合物
WO2014139388A1 (en) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Novel indole derivatives useful as anti-diabetic agents
ES2811087T3 (es) 2013-09-09 2021-03-10 Vtv Therapeutics Llc Uso de agonistas de PPAR-delta para tratar la atrofia muscular
WO2015051496A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
WO2018106518A1 (en) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Antidiabetic heterocyclic compounds
EP3558298A4 (en) 2016-12-20 2020-08-05 Merck Sharp & Dohme Corp. ANTIDIABETIC SPIROCHROMAN COMPOUNDS
WO2023147309A1 (en) 2022-01-25 2023-08-03 Reneo Pharmaceuticals, Inc. Use of ppar-delta agonists in the treatment of disease

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US20050154061A1 (en) 2005-07-14
SV2004001294A (es) 2004-02-24
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