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  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—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
  • C07D295/182—Radicals derived from carboxylic acids
  • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
  • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/64—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 sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
  • C07C323/67—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 sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfonamide groups, bound to the carbon skeleton
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  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
  • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
• • C—CHEMISTRY; METALLURGY
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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
  • C07D295/182—Radicals derived from carboxylic acids
  • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/22—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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  • 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

Definitions

• the present invention relates to novel compounds of formula
• W is O, S, S(O) or S(O) 2 ;
• X is -SR4, -S(O)R4, -S(O) 2 R4, or -S(O) 2 NR5R6; or X is -C(O)NR5R6 provided that -C(O)NR5R6 is located at the 3'-, 4'- or 5'-position;
• Y is O or H 2 ;
• Z is hydrogen, halogen, hydroxy, optionally substituted alkoxy, aralkoxy, acyloxy or alkoxycarbonyloxy;
• R is hydrogen, halogen, trifluoromethyl, lower alkyl or cycloalkyl
• R1 is hydroxy, optionally substituted alkoxy, aryloxy, heteroaryloxy, aralkoxy, cycloalkoxy, heteroaralkoxy or -NR5R6;
• R2 is hydrogen, halogen or alkyl
• R3 is halogen or alkyl
• R4 is optionally substituted alkyl, aryl, aralkyl, heteroaralkyl or heteroaryl;
• R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R5 and R6 combined are alkylene optionally interrupted by O, S, S(O), S(O) 2 or NR7 which together with the nitrogen atom to which they are attached form a 5- to 7- membered ring; n represents zero or an integer from 1 to 4; and pharmaceutically acceptable salts thereof.
• the compounds of the invention are thyromimetic agents which can be used to prevent and/or treat diseases associated with an imbalance of thyroid hormones, such as hypo- and hyper-thyroidism, obesity, osteoporosis and depression.
• the compounds of the invention are, in particular, hypoiipedemic agents which enhance the clearance of cholesterol from circulation, particularly the clearance of cholesterol in the form of low density lipoproteins (LDL). They, inter alia, upregulate hepatic LDL receptor function in mammals. Thus, they are useful for reducing total cholesterol plasma levels in mammals, in particular for reducing levels of LDL-cholesterol. Furthermore, such compounds also lower elevated lipoprotein (a) [Lp(a)] levels, an independent cardiovascular risk factor, in mammals.
• the compounds of the invention can therefore be used for the prevention and/or treatment of occlusive cardiovascular conditions in which hyperlipidemia and hyperlipoproteinemia are implicated, such as atherosclerosis and coronary heart disease in mammals.
• the present invention provides for compounds of formula I, pharmaceutical compositions comprising such compounds and for methods of using such compounds.
• optionally substituted alkyl refers to unsubstituted or substituted straight or branched chain hydrocarbon groups having 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms.
• exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, f-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpenthyl, octyl and the like.
• Substituted alkyl groups include, but are not limited to, alkyl groups substituted by one or more (e.g.
• halo lower alkenyl, hydroxy, cycloalkyl, alkanoyl, alkoxy, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, dialkylaminocarbonyl, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfonamido, nitro, cyano, carboxy, alkoxycarbonyl, aryl, aralkyl, aralkoxy, guanidino, heterocyclyl including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl, morpholinyl and the like.
• Preferred substituents of substituted alkyl are lower alkyl, cycloalkyl, lower alkenyl, benzyl, mono or disubstituted lower alkyl, e.g. ⁇ - (amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl, c-(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl, such as pivaloyloxy-methyl.
• lower alkyl refers to those alkyl groups as described above having 1 to 7, preferably 1 to 4 carbon atoms.
• halogen refers to fluorine, chlorine, bromine and iodine.
• alkenyl refers to any of the above alkyl groups having at least 2 carbon atoms and further containing at least one carbon to carbon double bond. Groups having two to four carbon atoms are preferred.
• alkylene refers to a straight chain bridge of 1 to 6 carbon atoms connected by single bonds (e.g., -(CH 2 ) X - wherein x is 1 to 6), which may be substituted with 1 to 3 lower alkyl groups.
• cycloalkyl refers to cyclic hydrocarbon groups of 3 to 8 carbon atoms.
• alkoxy refers to alkyl-O-.
• acyl refers to alkanoyl, aroyl, heteroaroyl, arylalkanoyl or heteroarylalkanoyl.
• alkanoyl refers to alkyl-C(O)-.
• alkanoyloxy refers to alkyl-C(O)-O-.
• alkylamino and dialkylamino refer to (alkyl)NH- and (alkyl) 2 N-, respectively.
• alkanoylamino refers to alkyl-C(O)-NH-.
• alkylthio refers to alkyl-S-.
• alkylthiono refers to alkyl-S(O)-.
• alkylsulfonyl refers to alkyl-S(O) 2 -.
• alkoxycarbonyl refers to alkyl-O-C(O)-.
• alkoxycarbonyloxy refers to alkyl-O-C(O)O-.
• alkyl as referred to in the above definitions relates to optionally substituted alkyl as defined above.
• aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, tetrahydronaphthyl, and biphenyl groups, each of which may optionally be substituted by one to four substituents such as alkyl, halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoyl-amino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, alkylthiono, alkyl-sulfonyl, sulfonamido, heterocyclyl and the like.
• monocyclic aryl refers to optionally substituted phenyl as described under aryl.
• aralkyl refers to an aryl group bonded directly through an alkyl group, such as benzyl.
• alkoxy refers to an aryl group bonded through an alkoxy group.
• arylsulfonyl refers to aryl-S(O) 2 -.
• heterocyclyl refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring.
• Each ring of the heterocyclic group containing a heteroatom may have 1 , 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized.
• the heterocyclic group may be attached at a heteroatom or carbon atom.
• Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl, 2- pyridone, N-lower alkyl-pyridon
• N-lower alkyl-2-pyridone pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, S-oxo-thiamorpholinyl S,S- dioxo-thiamorpholinyl, 1,3-dioxolane and tetrahydro-1 ,1-dioxothienyl, and the like.
• bicyclic heterocyclic groups include indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, tetrahydroisoquinoiinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyI, furo[3,2-b]- pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro- 4-oxo-quinazolinyl) and the like.
• Exemplary tricyclic heterocyclic groups include carbazolyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
• heterocyclyl includes substituted heterocyclic groups.
• Substituted heterocyclic groups refer to heterocyclic groups substituted with 1 , 2 or 3 of the following:
• alkoxycarbonyl such as unsubstituted lower alkoxycarbonyl
• heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge.
• heteroaryl refers to an aromatic heterocycle, for example monocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl, and the like, optionally substituted by one or more substitutents as described in connection with substituted aryl, e.g. by lower alkyl, lower alkoxy or halo.
• heteroaryloxy refers to heteroaryl-O-.
• heteroarylsulfonyl refers to heteroaryl-S(O) 2 -.
• heteroaroyl refers to heteroaryl-C(O)-.
• heteroarylkyl refer to a heteroaryl group bonded through an alkyl group.
• prodrug derivatives e.g., any pharmaceutically acceptable prodrug ester derivatives of the carboxylic acids of the invention (COR1 being carboxy) which are convertible by solvolysis or under physiological conditions to the free carboxylic acids.
• carboxylic acid esters include esters defined by COR 1 , and are preferably lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono or disubstituted lower alkyl esters, e.g. the o (amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters, the ⁇ -(lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxy-methyl ester, and the like conventionally used in the art.
• esters defined by COR 1 are preferably lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, mono or disubstituted lower alkyl esters, e.g. the o (amino, mono- or
• R are hydrogen or lower alkyl
• R1 are hydroxy, lower alkoxy or aryioxy.
• R2 are hydrogen, halogen or lower alkyl.
• R3 are halogen or lower alkyl.
• R4 are phenyl or phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluoromethyl.
• R5 is hydrogen.
• Preferred meanings of R6 are phenyl or phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluoromethyl.
• Preferred W is O.
• Preferred X is -S(O) 2 R4 or -S(O) 2 NR5R6
• Preferred Y is O.
• Preferred Z is hydrogen or hydroxy.
• n preferably is zero, 1 or 2.
• the compounds of the invention depending on the nature of the substituents, may possess one or more asymmetric centers.
• the resulting diastereoisomers, enantiomers and geometric isomers are encompassed by the instant invention.
• W is O or S
• X is -S(O) 2 R4; R4 being lower alkyl, phenyl or phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluoromethyl; or is -S(O) 2 NR5R6 or is -C(O)NR5R6; R5, in each case, being hydrogen or lower alkyl and R6, in each case, being hydrogen, lower alkyl, lower alkyl substituted by NR5R6, 3- to 7-membered cycloalkyl, phenyl, phenyl substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen and trifluoromethyl; pyridyl or N-lower alkyl-2-pyridone; or
• R5 and R6 combined, in each case, being alkylene or alkylene interrupted by O or S(O) 2 which together with the nitrogen atom to which they are attached form a 5- to 7- membered ring;
• Y is O or H 2 ;
• Z is hydrogen or hydroxy
• R is hydrogen;
• R1 is hydroxy, lower alkoxy or NR5R6;
• R5 being hydrogen or lower alkyl and
• R6 being hydrogen, lower alkyl, lower alkoxy or R5 and R6 combined being alkylene or alkylene interrupted by O which together with the nitrogen atom to which they are attached form a 5- to 7- membered ring ;
• R2 is hydrogen, halogen or lower alkyl
• R3 is halogen or lower alkyl; n represents zero, 1 or 2; and pharmaceutically acceptable salts thereof.
• W is O or S
• X is -SR4, -S(O)R4, -S(O) 2 R4, -S(O) 2 NR5R6 or -C(O)NR5R6;
• Y is O or H 2 ;
• Z is hydrogen, halogen, hydroxy, alkoxy, aralkoxy, acyloxy or alkoxycarbonyloxy;
• R1 is hydroxy, lower alkoxy or aryloxy
• R2 is hydrogen, halogen or lower alkyl
• R3 is halogen or lower alkyl
• R4 is optionally substituted alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl;
• R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R5 and R6 combined are alkylene optionally interrupted by O, S, S(O), S(O) 2 or NR7 which together with the nitrogen atom to which they are attached form a 5- to 7- membered ring; n represents zero, 1 or 2; and pharmaceutically acceptable salts thereof. Further preferred are the compounds of formula IB
• X is -S(O) 2 R4, -S(O) 2 NR5R6 or -C(O)NR5R6;
• Z is hydroxy, lower alkanoyloxy or lower alkoxy
• R1 is hydroxy or lower alkoxy
• R2 and R3 are lower alkyl
• R4 is aryl
• R5, R6 and R7 are independently hydrogen, optionally substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R5 and R6 combined are alkylene optionally interrupted by O, S, S(O), S(O) 2 or NR7 which together with the nitrogen atom to which they are attached form a 5- to 7- membered ring; and pharmaceutically acceptable salts thereof.
• X is -S(O) 2 R4 or -S(O) 2 NR5R6;
• R4 is monocyclic aryl
• R5, R6 and R7 are independently hydrogen, optionally substituted alkyl or aryl; or R5 and R6 combined are CH 2 CH 2 -Q-CH2CH 2 wherein Q is CH 2 , O, NR7, S, S(O) or S(O) 2 which together with the nitrogen atom to which they are attached from a 6-membered ring; pharmaceutically acceptable prodrug esters thereof; and pharmaceutically acceptable salts thereof.
• X is S(O) 2 R4 and R4 is phenyl optionally substituted by lower alkyl, halo, lower alkoxy or trifluoromethyl; pharmaceutically acceptable salts thereof; and prodrug derivatives thereof.
• salts of any acidic compounds of the invention are salts formed with bases, namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tris-(hydroxymethyl)-methyl- ammonium salts.
• bases namely cationic salts such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tris-(hydroxymethyl)-methyl- ammonium salts.
• acid addition salts such as of mineral acids, organic carboxylic, and organic sulfonic acids e.g. hydrochloric acid, methanesulfonic acid, maleic acid, are possible provided a basic group, such as pyridyl, constitutes part of the structure.
• R2 and R3 have meaning as defined herein and W is oxygen (prepared according to methods well-known in the literature) by first converting such to e.g. a trifluoromethylsulfonyl ester, and treating the latter with lithium chloride in an inert solvent such as N-methyl-pyrrolidone, N,N-dimethylformamide or dimethylsulfoxide to form compounds of formula III
• HW ⁇ t/ ( ) z
• R has meaning as defined herein
• X' and Z' represent X and Z as defined herein, or X' and Z' are groups convertible to X and Z respectively, in the presence of a base such as sodium hydride or potassium carbonate in an inert solvent such as N-methylpyrrolidone, N,N-dimethylformamide or dimethylsulfoxide at ambient or elevated temperature.
• a base such as sodium hydride or potassium carbonate
• an inert solvent such as N-methylpyrrolidone, N,N-dimethylformamide or dimethylsulfoxide at ambient or elevated temperature.
• compounds of formula IV can be obtained by condensing bis-aryl iodonium tetrafluoroborates of formula VI
• R, X' and Z' are as defined above, with phenols or thiophenols of formula II wherein W is oxygen or sulfur as described in the art, e.g, in the presence of a copper catalyst and a base such as triethylamine in an inert solvent such as dichloromethane.
• Compounds of formula IV wherein 71 is alkoxy or aralkoxy can be converted to compounds of formula IV wherein Z' is hydroxy according to methods well-known in the art, e.g. using acid such as hydrobromic acid or a boron trihalide, such as boron trichloride or boron tribromide when 71 is in particular a methoxy group or using hydrogen in the presence of a catalyst such as palladium on carbon when 71 is in particular a benzyloxy group.
• acid such as hydrobromic acid or a boron trihalide, such as boron trichloride or boron tribromide when 71 is in particular a methoxy group or using hydrogen in the presence of a catalyst such as palladium on carbon when 71 is in particular a benzyloxy group.
• Compounds of the invention wherein X is S(O) 2 NR5R6 may be prepared by, for example, first treating compounds of formula IV, wherein R and X' are hydrogen and X' is located at the 3' position, and 71 is hydroxy, alkoxy or aralkoxy and Z' is located at the 4' position, with chlorosulfonic acid in an organic solvent such as dichloromethane to produce compounds of formula VII
• 71 is as defined above by reaction with a chlorinating agent such as oxalyl chloride orthionyl chloride in an inert solvent such as dichloromethane or tetrahydrofuran in the presence of a catalytic amount of N,N-dimethylformamide.
• a chlorinating agent such as oxalyl chloride orthionyl chloride in an inert solvent such as dichloromethane or tetrahydrofuran in the presence of a catalytic amount of N,N-dimethylformamide.
• Any resulting amines for example those of formula X, can be treated with acylating agents such as ethyl oxalyl chloride, ethyl malonyl chloride, ethyl succinyl chloride or ethyl bromoacetate in the presence of a base such as N-methylmorpholine or triethylamine in an organic solvent such as dichloromethane, tetrahydrofuran or N,N-dimethylformamide to form compounds of formula I, e.g. those of formula XI
• acylating agents such as ethyl oxalyl chloride, ethyl malonyl chloride, ethyl succinyl chloride or ethyl bromoacetate
• a base such as N-methylmorpholine or triethylamine
• organic solvent such as dichloromethane, tetrahydrofuran or N,N-dimethylformamide
• R1 is alkoxy
• Y is oxygen or H 2
• 71 represents Z as defined herein or 71 is a group convertible to Z
• n represents an integer from zero to four.
• Compounds of formula I wherein R1 is alkoxy can also be prepared by condensing e.g. compounds of formula X with acylating agents such as dimethyl or diethyl oxalate at elevated temperature using the acylating agent both as a reagent and a solvent.
• protecting groups are to protect the functional groups from undesired reactions with reaction components under the conditions used for carrying out a desired chemical transformation.
• the need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (hydroxy group, amino group, etc.), the structure and stability of the molecule of which the substituent is a part and the reaction conditions.
• reactive functional derivatives of carboxylic acids represent, for example, anhydrides (especially mixed anhydrides), acid halides, acid azides, lower alkyl esters, and activated esters thereof.
• Mixed anhydrides are preferably such from pivalic acid, or a lower alkyl (ethyl, isobutyl) hemiester of carbonic acid; acid halides are for example chlorides or bromides; activated esters for example succinimido, phthalimido or 4- nitrophenyl esters; lower alkyl esters are for example the methyl or ethyl esters.
• the above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluent, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures (preferably at or near the boiling point of the solvents used), and at atmospheric or super-atmospheric pressure.
• diluent preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low temperatures, room temperature or elevated temperatures (preferably at or near the boiling point of the solvents used), and at atmospheric or super-atmospheric pressure.
• the invention further includes any variant of the present processes, in which an intermediate product obtainable at any stage thereof is used as starting material and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure antipodes.
• the new compounds may be in the form of one of the possible isomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, optical isomers (antipodes), racemates, or mixtures thereof.
• the aforesaid possible isomers or mixtures thereof are within the purview of this invention.
• Any resulting mixtures of isomers can be separated on the basis of the physico- chemical differences of the constituents, into the pure geometric or optical isomers, diastereoisomers, racemates, for example by chromatography and/or fractional crystallization.
• Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g. by separation of the diastereoisomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound.
• the carboxylic acid intermediates can thus be resolved into their optical antipodes e.g. by fractional crystallization of d- or l-(alpha-methylbenzylamine, cinchonidine, cinchonine, quinine, quinidine, ephedrine, dehydroabietylamine, brucine or strychnine)-salts.
• Racemic products can also be resolved by chiral chromatography, e.g. high pressure liquid chromatography using a chiral adsorbent.
• Acidic compounds of the invention may be converted into salts with pharmaceutically acceptable bases, e.g. an aqueous alkali metal hydroxide, advantageously in the presence of an ethereal or alcoholic solvent, such as a lower alkanol. From the solutions of the latter, the salts may be precipitated with ethers, e.g. diethyl ether. Resulting salts may be converted into the free compounds by treatment with acids. These or other salts can also be used for purification of the compounds obtained.
• Compounds of the invention having basic groups can be converted into acid addition salts, especially pharmaceutically acceptable salts.
• the compounds, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.
• compositions according to the invention are those suitable for enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including man, for the treatment of diseases associated with an imbalance of thyroid hormones, such as hypo- and hyperthyroidism, obesity, osteoporosis, depression, and in particular for the treatment and/or pre-vention of occulsive cardiovascular conditions in which hyperlipidimia and hyperlipoproteinemia are implicated, comprising an effective amount of a pharmacologically active compound of the inventon, alone or in combination with one or more pharmaceutically acceptable carriers.
• enteral such as oral or rectal, transdermal and parenteral administration to mammals, including man
• diseases associated with an imbalance of thyroid hormones such as hypo- and hyperthyroidism, obesity, osteoporosis, depression
• occulsive cardiovascular conditions in which hyperlipidimia and hyperlipoproteinemia are implicated
• a pharmacologically active compound of the inventon alone or in combination with one or more pharmaceutically acceptable carriers.
• the pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application.
• Preferred are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders e.g.
• Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions.
• compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
• adjuvants such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers.
• Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, preferably about 1 to 50%, of the active ingredient.
• transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
• a unit dosage for a mammal of about 50 to 70 kg may contain between about 0.01 mg and 10 mg of the active ingredient.
• the dosage of active compound is dependent on the species of warm-blooded aninial (mammal), the body weight, age and individual condition, on the form of administration, and on the compound involved.
• the problem solved by the present invention is to provide pharmacologically potent hypolipidemic agents which reduce plasma cholesterol levels in mammals.
• the compounds of the invention demonstrate potent binding to the triiodothyronine (T ) nuclear receptor which is indicative of upregulation of LDL receptor activity and enhancement of the clearance of LDL-cholesterol from the circulation.
• T triiodothyronine
• the compounds of the invention are thus particularly useful in mammals as hypocholesteremic agents for the treatment and prevention of occlusive cardio-vascular conditions in which hypercholesteremia is implicated, by reducing plasma levels of total and LDL-cholesterol.
• the invention furthermore relates to the use of the compounds according to the invention for the preparation of medicaments, in particular of medicaments useful for the treatment and prevention of occlusive cardiovascular conditions in which hypercholestermia is implicated, by reducing plasma levels of total and LDL-cholesterol.
• Compounds of the invention also reduce lipoprotein (a) levels and are thus useful for the treatment and prevention of occlusive cardiovascular conditions in which Lp(a) is implicated.
• thyromimetic hypolipidemic agents of the invention which are substantially free of undesirable cardiac side effects associated with thyroid hormones are preferred.
• the above-cited properties are demonstrable in vitro and in vivo tests, using advantageously mammals, e.g. mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
• Said compounds can be applied in vitro in the form of solutions, e.g. preferably aqueous solutions, and in vivo either enterally, parenteraliy, advantageously intravenously, e.g. as a suspension or in aqueous solution.
• the dosage in vitro may range between about 10 molar and 10 molar concentrations.
• the dosage in vivo may range depending on the route of administraton, between about 0. 1 and 1000 micrograms/kg, preferably between about 0.5 and 300 micrograms/kg, advantageously between about 1 and 100 micrograms/kg.
• the compounds of the invention bind to the triodoethyronine (T 3 ) receptor and are thus useful as thyroid hormone agonists in mammals.
• Rat liver nuclei and plasma membrane preparations are obtained from Sprague- Dawley (CD) rats (Charles River Labs.) by differential centrifugation as described by Emmelot at al (Methods in Enzymology 31 :75, Part A, 1974) with minor modif icatons.
• the nuclear fraction obtained from the 275 x g pellet is further purified as generally described by Spindler et al (J. Biol. Chem.250:4118, 1975).
• the novel test compounds are assayed for binding to the nuclei by the method of Spindler et al (J. Biol. Chem. 250:4118, 1975).
• the nuclei are incubated at 22°C with 0.3
• the amount of [ l]-L-T 3 specifically bound is determined by subtracting the amount nonspecifically bound (radioactivity contained in the nuclear pellet following incubation with excess (3 ⁇ M) non-radioactive L-T 3 .
• Cholesterol lowering activity is determined in the rat as follows: Male Sprague-Dawley rats (230-250 g) (Taconic Farms) are maintained ad libitum on water and a high cholesterol diet (1.5% cholesterol and 0.5% cholic acid) for two weeks prior to and during the 7-day treatment period. Groups of animals are treated orally by gavage with the vehicle alone or with test compound for 7 consecutive days. After the last dose, animals are fasted for 18 hours and blood is collected. Blood samples are centrifuged at 2500 ⁇ m for 10 minutes to prepare plasma for total cholesterol determination as well as LDL and HDL cholesterol concentrations. HDL values are determined after LDL/VLDL precipitation (Warnick and Albers, 1978).
• LDL/VLDL fractions are precipitated in the following manner: 0.35 mL of plasma is aliquoted into Eppendorf tubes to which 12 ⁇ L of 2M manganese chloride, 11.2 ⁇ L of sodium heparin (Porcine Intestinal, 5000 units/mL), and 8.3 ⁇ L of normal saline are added. The samples are vortexed and are placed on ice for 15 minutes, then centrifuged at 4°C for 10 minutes at 1300 ⁇ m and the supernatant is enzymatically analyzed for cholesterol. The HDL cholesterol concentration is adjusted for dilution by multiplying the supernatant cholesterol value by 1.09. LDL/VLDL cholesterol values are obtained by subtracting HDL cholesterol from total cholesterol.
• Cholesterol lowering activity can also be evaluated in normocholesterolemic dogs fed regular chow following the procedure described above, by administration of test compound orally for 5 days.
• Cholesterol and Lp(a) lowering activity can be determined in the normolipemic cynomolgus monkey as follows:
• Plasma samples are divided into aliquots and stored at -70 °C until analyzed.
• Plasma concentrations of total cholesterol (TC) and triglycerides (TG) are determined by enzymatic methods using commercial kits (Sigma Diagnostics).
• High-density lipoprotein cholesterol (HDL-C) concentration is measured after precipitation of apoB-containing iipoproteins. Since the fasting plasma of cynomolgus monkeys on a chow diet contains negligible amounts of cholesterol in very low-density lipoprotein, the low-density lipoprotein cholesterol (LDL-C) concentration is calculated by subtracting HDL-C from TC.
• HDL-C low-density lipoprotein cholesterol
• the assays are performed in 96-well microtiter plates, which are read in a microplate spectrophotometer (Dynatech MR 5000). Plasma concentrations of Lp(a) are determined by a commercial Lp(a) ELISA (Perlmmune, Inc.) using the kit controls and reference Lp(a) standard.
• the Lp(a) ELISA employs a monoclonal antibody against apolipoprotein(a) for capture and a polyclonal antibody against apolipoprotein B for detection.
• the assay is specific for Lp(a) and does not measure free apo(a), apoB or plasminogen. Quantification of Lp(a) is not affected by apo(a) size.
• the Lp(a) plasma concentration is reported as milligrams of total Lp(a) mass. Samples from each study are assayed in a single run. lllustrative of the invention, the compound of example 26 demonstrates an IC 50 of about 0.17 nM, the compound of example 28 demonstrates an IC 50 of about 0.13 nM, the compound of example 35 demonstrates an IC 50 of about 1.00 nM and the compound of example 39 demonstrates an IC 50 of about 0.04 nM in the T 3 nuclear receptor binding assay. Furthermore, said compound of example 26 significantly lowers serum cholesterol at a daily dose of about 20 micrograms ( ⁇ g)/kg p.o. in the rat and about 10 ⁇ g/kg p.o. in the dog. Furthermore, Lp(a) levels in the normoiipemic cynomolgus monkeys are lowered by about 40% after 4 week treatment with the said compound of example 26 at a daily oral dose of 75 ⁇ g/kg.
• a suspension of sodium hydride (NaH; 60% dispersion in mineral oil; 64.11 g, 1.603 mol) in 350 mL of N-methyipyrroiidone (NMP) is cooled to 0°C and treated with a solution of 4-methoxyphenol (208.4 g, 1.679 mol) over 30 min.
• the mixture is warmed to room temperature (RT) and after 30 min, 4-chloro-3,5-dimethylnitrobenzene ( 283.2 g, 1.526 mol; prepared by the method described by Yokoyama et. al. in EP580550) is added in one portion and the reaction is heated at 120°C for 2 h.
• the reaction is cooled to room temperature (RT) and quenched with water (1500 mL).
• the suspension is cooled to 0°C, stirred for 30 min, then filtered and the filtercake is washed with water and dried in vacuo.
• the crude product, ethyl acetate (EtOAc; 2100 mL) and charcoal (42.6 g) were heated to reflux and the solids were removed by filtration through celite while hot.
• the filtrate is concentrated under reduced pressure to ca. 800 mL and the resulting suspension is cooled to 0°C and stirred for 30 min.
• a suspension of sodium NaH (60% dispersion in mineral oil; 1.32 g, 33 mmol) in 50 mL of NMP is cooled to 0°C and 2,5-dihydroxybenzoic acid (1.54 g, 10 mmol) is added in one portion.
• the mixture is warmed to room temperature, and after 30 min, 4-chloro-3,5- dimethyl-nitrobenzene ( 2.41 g, 13 mmol) is added in one portion and the reaction is heated at 120°C for 3 h.
• the reaction is cooled to RT and 2-methoxyethoxymethyl chloride (2.85 mL, 25 mmol) is added. After stirring for 30 min, the mixture is poured onto water and the product is taken up in Et 2 O.
• Example 51 The title compound is prepared similarly to Example 46: ESI-MS 458 [M+1] + .
• Example 51
• Hard gelatin capsules comprising 100 mg active substance, for example, N- ⁇ 4-[3-(4-fiuorobenzenesulfonyl)-4-hydroxyphenoxy]-3,5-dimethylphenyl ⁇ oxamic acid, can be prepared for example as follows:
• Composition for 1000 capsules
• the sodium lauryl sulfate is added to the lyophilized active ingredient via a sieve with a mesh size of 0.2 mm. Both components are intimately mixed. Then first the lactose is added via a sieve with a mesh size of 0.6 mm and then the microcrystalline cellulose via a sieve with a mesh size of 0.9 mm. Thereupon these components are intimately mixed for a further 10 minutes. Finally the magnesium stearate is added via a sieve with a mesh size of 0.8 mm. After 3 minutes of further mixing, 390 mg each of the formulation obtained are filled into hard gelatin capsules of size 0.

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