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  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/20—Oxygen atoms
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  • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
  • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
  • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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  • C07C255/00—Carboxylic acid nitriles
  • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
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  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/62—Oxygen or sulfur atoms
  • C07D213/63—One oxygen atom
  • C07D213/64—One oxygen atom attached in position 2 or 6
  • C07D213/643—2-Phenoxypyridines; Derivatives thereof
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/62—Oxygen or sulfur atoms
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  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

• the invention is directed to novel anthranilic acid derivatives of the formula (I) and pharmaceutically acceptable salts and pharmaceutically acceptable esters thereof.
• the invention is directed to a process for the manufacture of the above compounds, pharmaceutical preparations which contain such compounds as well as the use of these compounds for the production of pharmaceutical preparations.
• Coronary heart disease remains the leading cause of death in Western countries. In the United States 13.2 million or 4.85% of the population is affected, with 1.2 million new or recurrent attacks and around 500 thousand deaths per year (American Heart Association, Statistics for 2001). The disease is influenced by several well-established risk factors, such as age, sex, blood lipids, blood pressure, smoking, diabetes, and body mass index (BMI) as an indicator of overweight and obesity.
• the National Cholesterol Education Program (NCEP) Adult Treatment Panel III defines elevated plasma levels of low density lipoprotein (LDL) cholesterol (LDL-C ⁇ 160 mg/dL), and low levels of high density lipoprotein (HDL) cholesterol (HDL-C ⁇ 40 mg/dL) as independent risk factors for CHD.
• LDL low density lipoprotein
• HDL-C ⁇ 40 mg/dL high density lipoprotein
• Many prospective epidemiological studies have indicated that a decreased HDL-C level is a significant independent risk factor for heart disease, while increased HDL-C levels ⁇ 60 mg/dL ( ⁇
• Nicotinic acid (Niacin), a vitamin of the B complex, is used for almost 40 years as a lipid-lowering drug with a favorable profile for all lipoprotein classes. Numerous clinical studies have shown the beneficial effects of niacin, demonstrating a reduction of coronary artery disease and overall mortality. Niacin is the most potent agent currently available to raise HDL. It has been proposed than niacin's main mode of action is through inhibition of lipolysis in the adipose tissue having as a result the reduction of free fatty acids (FFA) in plasma and liver and consequently the decreased production of very low density lipoproteins (VLDL), accounting for the reduction of total cholesterol (TC), triglycerides (TGs), and LDL-C.
• FFA free fatty acids
• VLDL very low density lipoproteins
• LPAI-HDL lipoprotein AI-HDL
• Niacin also has anti-diabetic, anti-thrombotic and anti-inflammatory properties that contribute to the overall cardioprotective effects.
• niacin reduces thrombosis, such as the reduction of lipoprotein (a) (Lp(a)) which is a potent inhibitor of fibrinolytic activity, and it is the only currently approved drug that effectively reduces the serum levels of Lp(a) (Carlson et al J Intern Med 1989, 17, 2020-8).
• Inflammation is a critical component of atherosclerosis, leading to recruitment of macrophages which both promote plaque development and decrease plaque stability thus increasing cardiovascular risk.
• Niacin has been suggested to have anti-inflammatory properties, such as the reduction of C-reactive protein (CRP) levels (Grundy et al Arch Intern Med 2002, 162, 1568-76).
• CRP C-reactive protein
• HM74A/HM74 a G-protein coupled receptor (GPCR)
• GPCR G-protein coupled receptor
• composition comprising a therapeutically effecitve amount of a compound according to formula (I) or a compound selected from the group consisting of:
• HM74A agonists comprising the step of administering a therapeutically effective amount of a compound according to formula (I) or a compound selected from the group consisting of:
• novel compounds of the present invention exceed the compounds known in the art, inasmuch as they bind to and activate HM74A.
• the compounds of the present invention are selective for HM74A by which is meant that they show greater affinity for HM74A than for HM74.
• the compounds of the present invention are expected to have an enhanced therapeutic potential and exhibit reduced side effects compared to nicotinic acid.
• the compounds of the present invention can be used as medicaments for the treatment and/or prevention of diseases which are modulated by HM74A agonists.
• diseases are increased lipid and cholesterol levels, particularly dyslipidemia, low HDL-cholesterol, atherosclerotic diseases, hypertriglyceridemia, thrombosis, angina pectoris, peripheral vascular disease, stroke, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, Alzheimer's disease, Parkinson's disease, schizophrenia, sepsis, inflammatory diseases (such as e.g. colitis, pancreatitis, cholestasis/fibrosis of the liver, and diseases that have an inflammatory component such as e.g. Alzheimer's disease or impaired/improvable cognitive function).
• dyslipidemia particularly dyslipidemia, low HDL-cholesterol, atherosclerotic diseases, hypertriglyceridemia, thrombosis, angina pectoris, peripheral vascular disease, stroke, diabetes, particularly non-insulin dependent diabetes mellitus, metabolic syndrome, Alzheimer's disease, Parkinson's disease, schizophrenia, sepsis, inflammatory diseases (such as e.g. colitis,
• lower is used to mean a group consisting of one to seven, preferably of one to four carbon atom(s).
• halogen refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.
• alkyl refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms. Lower-alkyl groups as described below also are preferred alkyl groups.
• lower-alkyl refers to a branched or straight-chain monovalent alkyl radical of one to seven carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
• Lower-alkyl groups can optionally be substituted, e.g. by hydroxy or cyano. Such substituted lower-alkyl-groups are referred to as “hydroxy-lower-alkyl” or “cyano-lower-alkyl”. Unsubstituted lower-alkyl groups are preferred
• fluoro-lower-alkyl refers to lower-alkyl groups which are mono- or multiply substituted with fluorine.
• fluoro-lower-alkyl groups are e.g. CFH 2 , CF 2 H, CF 3 , CF 3 CH 2 , CF 3 (CH 2 ) 2 , (CF 3 ) 2 CH and CF 2 H—CF 2 .
• alkenyl stands for a straight-chain or branched hydrocarbon residue comprising an olefinic bond and up to 20, preferably up to 16 carbon atoms.
• lower-alkenyl refers to a straight-chain or branched hydrocarbon residue comprising an olefinic bond and up to 7, preferably up to 4 carbon atoms, such as e.g. 2-propenyl.
• alkinyl stands for a straight-chain or branched hydrocarbon residue comprising a triple bond and up to 20, preferably up to 16 carbon atoms.
• lower-alkinyl refers to a straight-chain or branched hydrocarbon residue comprising a triple bond and up to 7, preferably up to 4 carbon atoms, such as e.g. 2-propinyl.
• amino signifies a primary, secondary or tertiary amino group bonded via the nitrogen atom, with the secondary amino group carrying an alkyl or cycloalkyl substituent and the tertiary amino group carrying two similar or different alkyl or cycloalkyl substituents or the two nitrogen substitutents together forming a ring, such as, for example, —NH 2 , methylamino, ethylamino, dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl or piperidino etc., preferably primary amino, dimethylamino and diethylamino and particularly dimethylamino.
• cycloalkyl refers to a monovalent carbocyclic radical of 3 to 10 carbon atoms, preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
• alkoxy refers to the group R′—O—, wherein R′ is an alkyl.
• lower-alkoxy refers to the group R′—O—, wherein R′ is a lower-alkyl.
• fluoro-lower-alkoxy refers to the group R′′—O—, wherein R′′ is fluoro-lower-alkyl.
• fluoro-lower-alkoxy groups are e.g. CFH 2 —O, CF 2 H—O, CF 3 —O, CF 3 CH 2 —O, CF 3 (CH 2 ) 2 —O, (CF 3 ) 2 CH—O, and CF 2 H—CF 2 —O.
• aryl alone or in combination, relates to the phenyl or naphthyl group, preferably the phenyl group, which can optionally be substituted by 1 to 5, preferably 1 to 3, substituents independently selected from the group consisting of halogen, lower-alkyl, hydroxy-lower-alkyl, lower-alkoxy, carboxy, carboxy-lower-alkyl, lower-alkoxy-carbonyl, lower-alkoxy-carbonyl-lower-alkyl, H 2 NC(O), (H,lower-alkyl)NC(O), (lower-alkyl) 2 NC(O), H 2 NC(O)-lower-alkyl, (H,lower-alkyl)NC(O)-lower-alkyl, (lower-alkyl) 2 NC(O)-lower-alkyl, fluoro-lower-alkyl, H 2 N-lower-alkyl, (H,lower-alkyl)N-lower
• substituents are e.g. hydroxy, amino, NO 2 , dioxo-lower-alkylene (forming e.g. a benzodioxyl group), lower-alkylcarbonyl, lower-alkylcarbonyloxy, lower-alkylcarbonyl-NH, cycloalkyl, phenyl and phenyloxy.
• Preferred substituents are halogen, lower-alkyl, fluoro-lower-alkyl, lower-alkoxy and fluoro-lower-alkoxy.
• aryl groups can be substituted as described in the description below.
• heteroaryl refers to an aromatic 5 to 6 membered monocyclic ring or 9 to 10 membered bicyclic ring which can comprise 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulphur, such as furyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzoimidazolyl, indolyl, indazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl and quinolinyl.
• Preferred heteroaryl groups are pyridinyl and quinolinyl.
• a heteroaryl group may be unsubstituted or optionally have a substitution pattern as described earlier in connection with the term “aryl”.
• a heteroaryl group may be substituted as described in the specification below and in the claims.
• protecting group refers to groups such as e.g. acyl, alkoxycarbonyl, aryloxycarbonyl, silyl, or imine-derivatives, which are used to temporarily block the reactivity of functional groups.
• protecting groups are e.g. t-butyloxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl or diphenylmethylene which can be used for the protection of amino groups, or lower-alkyl-, ⁇ -trimethylsilylethyl- and ⁇ -trichloroethyl-esters, which can be used for the protection of carboxy groups.
• esters embraces derivatives of the compounds of formula (I), in which a carboxy group has been converted to an ester.
• esters are preferred esters.
• the methyl and ethyl esters are especially preferred.
• pharmaceutically acceptable esters furthermore embraces compounds of formula (I) in which hydroxy groups have been converted to the corresponding esters with inorganic or organic acids such as, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non toxic to living organisms.
• Compounds of formula (I) in which a COOH group is present can form salts with bases.
• Examples of such salts are alkaline, earth-alkaline and ammonium salts such as e.g. Na—, K—, Ca—, Mg— and trimethylammonium-salt.
• the compounds of formula (I) can also be solvated, e.g. hydrated. The solvation can be effected in the course of the manufacturing process or can take place e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of formula (I) (hydration).
• the term pharmaceutically acceptable salts also includes pharmaceutically acceptable solvates.
• the compounds of formula (I) can have one or more asymmetric C atoms and can therefore exist as an enantiomeric mixture, diastereomeric mixture or as optically pure compounds.
• Preferred compounds of formula (I) as described above are those, wherein R 1 is hydrogen. In compounds wherein R 1 is lower-alkyl, R 1 preferably is C 2-7 -alkyl.
• Other preferred compounds of formula (I) as described above are those wherein R 2 , R 3 , R 4 and R 5 , independently from each other, are hydrogen, halogen or fluoro-lower-alkyl, with the proviso that R 4 is not bromine.
• R 2 , R 3 , R 4 and R 5 independently from each other, are hydrogen or halogen, with the proviso that R 4 is not bromine.
• R 2 is hydrogen or fluorine.
• Other preferred compounds are those, wherein R 3 is hydrogen.
• Still other preferred compounds are those, wherein R 4 is hydrogen or fluorine.
• Compounds, wherein R 5 is hydrogen are also preferred.
• R 6 , R 7 , R 8 and R 9 independently from each other, are hydrogen, lower-alkyl or lower-alkoxy.
• R 6 preferably is hydrogen, methyl or methoxy.
• Other preferred compounds are those, wherein R 7 is hydrogen or methyl.
• Compounds wherein R 8 is hydrogen are also preferred.
• Further preferred compounds are those, wherein R 9 is hydrogen.
• R 14 is pyridinyl, quinolinyl or phenyl which is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, lower-alkyl, lower-alkoxy, lower-alkyl-SO 2 , lower-alkoxy-carbonyl, cyano, fluoro-lower-alkyl, R 15 R 16 NC(O) and triazolyl, wherein R 15 and R 16 independently from each other are hydrogen or lower-alkyl.
• R 14 is phenyl, 2-methyl-phenyl, 2-fluoro-phenyl, 2-chloro-phenyl, 3-fluoro-phenyl, 3-methyl-phenyl, quinolin-8-yl, 4-[1,2,4]-triazol-1-yl-phenyl, 2,4-difluoro-phenyl, pyridin-2-yl or 2,5-difluoro-phenyl.
• n is 0 or 1 and R 12 and R 13 are hydrogen are also preferred, particularly those, wherein n is 0.
• preferred compounds are the compounds of formula (I) described in the examples as individual compounds as well as pharmaceutically acceptable salts as well as pharmaceutically acceptable esters thereof.
• Preferred compounds of formula (I) are those selected from the group consisting of:
• Particularly preferred compounds of formula (I) are those selected from the group consisting of
• the compounds of general formula (I) in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.
• the invention further relates to a process for the manufacture of compounds of formula (I) as defined above, which process comprises
• R 17 is a carboxylic acid moiety, it is preferably pivaloylic acid, p-nitrobenzoic acid, p-trifluoromethylbenzoic acid, 2,4,6-trichloro benzoic acid, acetic acid, trifluoroacetic acid, carbonic acid monoisobutyl ester, diphenyl phosphinic acid or benzene sulfonic acid to form an asymmetric anhydride, or it is the remainder of a second moiety of formula (III) bound via an oxygen atom to form a symmetric anhydride.
• R 17 is Cl.
• reaction of a compound of formula (II) with a compound of formula (III) or the reaction of a compound of formula (Ia) can be performed under reaction conditions well known to the person skilled in the art. Such reactions can conveniently be carried out for amide bond formation (process a)) with compounds of formula (III) (R 17 ⁇ Cl, Br) or with mixed or symmetric anhydrides (III), wherein R 17 is a carboxylic acid moiety such as e.g.
• pivaloylic acid pivaloylic acid, p-nitrobenzoic acid, p-trifluoromethylbenzoic acid, 2,4,6-trichloro benzoic acid, acetic acid, trifluoroacetic acid, carbonic acid monoisobutyl ester, diphenyl phosphinic acid or benzene sulfonic acid or the remainder of a second moiety of formula (III) bound via an oxygen atom to form a symmetric anhydride, in a solvent such as dichloromethane, in the presence of a base such as triethylamine, ethyl-diisopropyl-amine or N-ethylmorpholine at temperatures between 0° C.
• a base such as triethylamine, ethyl-diisopropyl-amine or N-ethylmorpholine at temperatures between 0° C.
• an alkali hydroxide like LiOH or NaOH in a polar solvent such as tetrahydrofuran, methanol, ethanol or water or mixtures thereof.
• a polar solvent such as tetrahydrofuran, methanol, ethanol or water or mixtures thereof.
• appropriate protecting groups as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 2 nd Ed., 1991, Wiley N.Y.
• Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.
• the present invention also relates to compounds of formula (I) as defined above, when prepared by a process as described above.
• the compounds of formula (I) can be prepared by methods known in the art or as described below in schemes 1 to 4. All starting materials are either commercially available, described in the literature or can be prepared by methods well known in the art. Unless otherwise indicated, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , m and n are as described above
• R 17 is equal to chlorine or bromine such an amide bond formation can be performed in a solvent such as dichloromethane, in the presence of a base such as triethylamine, ethyl-diisopropyl-amine or N-ethylmorpholine at temperatures between 0° C. and ambient temperature.
• compounds of formula Ia or Ib may be prepared by treatment of anilines II with carboxylic acid anhydrides III in a solvent such as dichloromethane, in the presence of a base such as triethylamine, ethyl-diisopropyl-amine or N-ethylmorpholine at temperatures between 0° C. and ambient temperature.
• condensations of amines II with carboxylic acids III can be performed using well known procedures for amide formation, such as the use of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide-hydrochloride or BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophoshate) in the presence of a base such as ethyl-diisopropyl-amine, triethylamine, N-methylmorpholine optionally in the presence of 4-dimethylamino-pyridine or HOBt (1-hydroxybenzo-triazole) in solvents such as dichloromethane, DMF, DMA or dioxane at temperatures between 0° C. and ambient temperature.
• BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophoshate
• one of the starting materials II or III contains one or more functional groups which are not stable or are reactive under the conditions of the amide bond formation
• appropriate protecting groups as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 2 nd Ed., 1991, Wiley N.Y.
• Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.
• Compounds of the general formula Ia and Ib can contain one or more stereocenters and can optionally be separated into optically pure enantiomers or diastereomers by methods well known in the art, e. g. by HPLC chromatography, chromatography on a chiral HPLC column, chromatography with a chiral eluant or by derivatization of compound Ib with an optically pure alcohol to form esters, which can be separated by conventional HPLC chromatography and then converted back to the enantiomerically pure acids Ib (R 1 ⁇ H).
• racemic compounds Ib can be separated into their antipodes via diastereomeric salts by crystallization with optically pure amines such as e. g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine or quinidine.
• step a The preparation of compounds of formula Ib with R 1 ⁇ H from compounds of formula Ia with R 1 not H is described in scheme 2 (step a).
• These hydrolysis reactions can be performed according to standard procedures, e. g. by treatment with an alkali hydroxide like LiOH or NaOH in a polar solvent such as tetrahydrofuran, methanol, ethanol or water or mixtures thereof to give carboxylic acids Ib.
• R 1 is equal to tert-butyl
• treatment with e. g. trifluoroacetic acid optionally in the presence of anisole in a solvent like dichloromethane or dichloroethane between room temperature and the reflux temperature of the solvents yields carboxylic acids Ib.
• ester Ia contains one or more functional groups which are not stable under the hydrolysis conditions
• appropriate protecting groups as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 2 nd Ed., 1991, Wiley N.Y.
• Subsequent hydrolysis and removal of the protecting group(s) provides carboxylic acid Ib.
• Compounds of the general formula Ib can contain one or more stereocenters and can optionally be separated into optically pure enantiomers or diastereomers by methods well known in the art, e. g. by HPLC chromatography, chromatography on a chiral HPLC column, chromatography with a chiral eluant or by derivatization of compound Ib with an optically pure alcohol to form esters, which can be separated by conventional HPLC chromatography and then converted back to the enantiomerically pure acids Ib.
• racemic compounds Ib can be separated into their antipodes via diastereomeric salts by crystallization with optically pure amines such as e. g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine or quinidine.
• R 17 is equal to chlorine, bromine or for the carboxylic acid anhydrides the reaction could be performed in a solvent such as dichloromethane, in the presence of a base such as triethylamine, ethyl-diisopropyl-amine or N-ethylmorpholine at temperatures between 0° C. and ambient temperature (step a). If R 17 is equal to OH activating reagents like e. g.
• BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophoshate
• a base such as ethyl-diisopropyl-amine, triethylamine, N-methylmorpholine optionally in the presence of 4-dimethylamino-pyridine or HOBt (1-hydroxybenzo-triazole) in solvents such as dichloromethane, DMF, DMA or dioxane at temperatures between 0° C. and ambient temperature could be used.
• Halides V (R 18 ⁇ Cl, Br, I), phenols V (R 18 ⁇ OH) or triflates V (R 18 ⁇ OTf) can be reacted with alcohols VI to give ethers Ic using methods well known in the art (step b).
• Phenols V (R 18 ⁇ OH) may be generated from the protected phenols V (R 18 ⁇ OPG) prior to use by methods well known to the person skilled in the art (as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M.
• ethers Ic or Id can be synthesized applying e. g. the procedure from Larock et al. (R. C. Larock et al., Organic Letters, 6, 99; 2004) using CsF in acetonitrile at ambient temperature.
• transition metal mediated procedures for the formation of aryl ethers are reported in the literature (see e. g. J. F. Hartwig et al., J. Am. Chem. Soc., 121, 3224; 1999).
• phenols V may be treated with alcohols VI using Mitsunobu (e.g. O. Mitsunobu, Synthesis 1981,1.) conditions to yield compounds Ic.
• Mitsunobu e.g. O. Mitsunobu, Synthesis 1981,1.
• This transformation is preferably carried out with triphenylphosphine and di-tert-butyl-, diisopropyl- or diethyl-azodicarboxylate as reagents, in a solvent like toluene, dichloromethane or tetrahydrofuran at 0° C. to ambient temperature.
• compounds Ic and Id may be prepared from phenol V (R 18 ⁇ OH) by alkylation with compounds VII (R 19 ⁇ Br, Cl, I, MsO, TsO, TfO) in solvents such as acetone, acetonitrile, DMF, DMA or THF in the presence of bases such as K 2 CO 3 , Cs 2 CO 3 or ethyl-diisopropyl-amine at ambient temperature to reflux (step c).
• Aryl ethers Ic with an ester group (R 1 ⁇ H) can be hydrolyzed according to standard procedures, e. g. by treatment with an alkali hydroxide like LiOH or NaOH in a polar solvent mixture like tetrahydrofurane/ethanol/water to give carboxylic acids of formula Id (R 1 ⁇ H) (step d).
• R 1 is equal to tert-butyl
• treatment with e. g. trifluoroacetic acid optionally in the presence of anisole in a solvent like dichloromethane or dichloroethane between room temperature and the reflux temperature of the solvents yields carboxylic acids Id (step d).
• one of the starting materials II, IV, V, VI, or VII contains one or more functional groups which are not stable or are reactive under the conditions of the amide bond formation
• appropriate protecting groups as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 2 nd Ed., 1991, Wiley N.Y.
• Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.
• Compounds of the general formula Ic and Id can contain one or more stereocenters and can optionally be separated into optically pure enantiomers or diastereomers by methods well known in the art, e. g. by HPLC chromatography, chromatography on a chiral HPLC column, chromatography with a chiral eluant or by derivatization of compounds Id with an optically pure alcohol to form esters, which can be separated by conventional HPLC chromatography and then converted back to the enantiomerically pure acids Id.
• racemic compounds Id can be separated into their antipodes via diastereomeric salts by crystallization with optically pure amines such as e. g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine or quinidine.
• R 17 is equal to chlorine or bromine or for the carboxylic acid anhydrides the reaction could be performed in a solvent such as dichloromethane, in the presence of a base such as triethylamine, ethyl-diisopropyl-amine or N-ethylmorpholine at temperatures between 0° C. and ambient temperature (step a). If R 17 is equal to OH activating reagents like e. g.
• BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophoshate
• a base such as ethyl-diisopropyl-amine, triethylamine, N-methylmorpholine optionally in the presence of 4-dimethylamino-pyridine or HOBt (1-hydroxybenzo-triazole) in solvents such as dichloromethane, DMF, DMA or dioxane at temperatures between 0° C. and ambient temperature could be used.
• Alcohols V (R 20 ⁇ OH) can be reacted with alcohols VI to give ethers Ic using methods well known in the art (step b).
• Alcohols V may be generated from the protected alcohols V (R 20 ⁇ OPG) prior to use by methods well known to the person skilled in the art (as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 2 nd Ed., 1991, Wiley N.Y.).
• the alcohols VI are either commercially available, described in the literature or can be prepared by methods well known to a person skilled in the art.
• Mitsunobu conditions may be used to give compounds Ic.
• This transformation is preferably carried out with triphenylphosphine and di-tert-butyl-, diisopropyl- or diethyl-azodicarboxylate as reagents, in a solvent like toluene, dichloromethane or tetrahydrofuran at 0° C. to ambient temperature.
• alcohol V may be converted to the corresponding mesylate or tosylate V (R 20 ⁇ OMs, OTs) by treatment with methanesulfonyl chloride or para-toluenesulfonyl chloride, respectively, in CH 2 Cl 2 in the presence of a base such as pyridine or ethyl-diisopropyl-amine optionally in the presence of DMAP at temperatures between 0° C. to ambient temperature (step c).
• the corresponding triflates V (R 20 ⁇ OTf) may be prepared in pyridine with trifluoromethanesulfonic anhydride at 0° C. to ambient temperature.
• compounds Ic and Id may be prepared from alcohol V (R 20 ⁇ OH) by alkylation with compounds VII (R 21 ⁇ Br, Cl, I, MsO, TsO, TfO) in the presence of sodium hydride in solvents such as DMF or THF at temperatures between 0° C. to reflux of the solvent (step e).
• Aryl ethers Ic with an ester group (R 1 ⁇ H) can be hydrolyzed according to standard procedures, e. g. by treatment with an alkali hydroxide like LiOH or NaOH in a polar solvent mixture like tetrahydrofurane/ethanol/water to give carboxylic acids of formula Id (R 1 ⁇ H) (step f).
• R 1 is equal to tert-butyl
• treatment with e. g. trifluoroacetic acid optionally in the presence of anisole in a solvent like dichloromethane or dichloroethane between room temperature and the reflux temperature of the solvents yields carboxylic acids Id (step d).
• one of the starting materials II, IV, V, VI, or VII contains one or more functional groups which are not stable or are reactive under the conditions of the amide bond formation
• appropriate protecting groups as described e.g. in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 2 nd Ed., 1991, Wiley N.Y.
• Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.
• Compounds of the general formula Ic and Id can contain one or more stereocenters and can optionally be separated into optically pure enantiomers or diastereomers by methods well known in the art, e. g. by HPLC chromatography, chromatography on a chiral HPLC column, chromatography with a chiral eluant or by derivatization of acids Id with an optically pure alcohol to form esters, which can be separated by conventional HPLC chromatography and then converted back to the enantiomerically pure acids Id.
• racemic compounds Id can be separated into their antipodes via diastereomeric salts by crystallization with optically pure amines such as e. g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine or quinidine.
• Compounds of the general formula Ic/Id can contain one or more stereocenters and can optionally be separated into optically pure enantiomers or diastereomers by methods well known in the art, e. g. by HPLC chromatography, chromatography on a chiral HPLC column, chromatography with a chiral eluant or by derivatization with an optically pure alcohol to form esters, which can be separated by conventional HPLC chromatography and then converted back to the enantiomerically pure acids Id.
• racemic compounds can be separated into their antipodes via diastereomeric salts by crystallization with optically pure amines such as e. g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine or quinidine.
• a compound of formula (I) into a pharmaceutically acceptable salt can be carried out by treatment of such a compound with physiologically compatible bases.
• such salts are alkaline, earth-alkaline and ammonium salts such as e.g. Na—, K—, Ca— and trimethylammonium-salt.
• a suitable solvent e.g. ethanol, ethanol-water mixture, tetrahydrofurane-water mixture
• the conversion of compounds of formula (I) into pharmaceutically acceptable esters can be carried out e.g. by treatment of a suitable carboxy group present in the molecule with a suitable alcohol using e.g. a condensating reagent such as benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), N,N-dicylohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCl) or O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N,N-tetra-methyluronium-tetrafluorborate (TPTU).
• a condensating reagent such as benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP
• the invention therefore also relates to pharmaceutical compositions comprising a compound as described above or a compound selected from the group consisting of:
• the invention relates to a method for the treatment and/or prevention of diseases which are modulated by HM74A agonists, particularly for the treatment and/or prevention of increased lipid levels, increased cholesterol levels, atherosclerotic diseases, dyslipidemia, low HDL-cholesterol, hypertriglyceridemia, thrombosis, angina pectoris, peripheral vascular disease, stroke, diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome, Alzheimer's disease, Parkinson's disease, schizophrenia, impaired or improvable cognitive function, sepsis, inflammatory diseases, colitis, pancreatitis and cholestasisfibrosis of the liver, which method comprises administering a compound as described above or a compound selected from the group consisting of:
• the invention further relates to the use of compounds as defined above or compounds selected from the group consisting of:
• the invention relates to the use of compounds as described above or compounds selected from the group consisting of:
• HM74A agonists for the preparation of medicaments for the treatment and/or prevention of diseases which are modulated by HM74A agonists, particularly for the treatment and/or prevention of increased lipid levels, increased cholesterol levels, atherosclerotic diseases, dyslipidemia, low HDL-cholesterol, hypertriglyceridemia, thrombosis, angina pectoris, peripheral vascular disease, stroke, diabetes, non-insulin dependent diabetes mellitus, metabolic syndrome, Alzheimer's disease, Parkinson's disease, schizophrenia, impaired or improvable cognitive function, sepsis, inflammatory diseases, colitis, pancreatitis and cholestasisfibrosis of the liver.
• Such medicaments comprise a compound as described above.
• Nicotinic acid binding assays were performed with membrane preparations.
• Nuclei and unbroken cells were removed by centrifugation for 5 min at 1,000 ⁇ g after the addition of 1 ml of tonicity restoration buffer (10 mM Tris pH 7.6, 0.5 mM MgCl 2 , 600 mM NaCl). The homogenate was centrifuged at 60,000 ⁇ g for 30 min and pellets were resuspended in Tris buffer (50 mM Tris pH 7.4, containing protease inhibitors).
• Binding reactions contained 20 ⁇ g membranes as determined by BCA protein assay (Pierce), 50 nM [ 3 H]-nicotinic acid (Amersham) with or without compound addition in 250 ⁇ l of binding buffer (50 mM Tris pH 7.4, 2 mM MgCl 2 , 0.02 % CHAPS). Incubations were carried out at room temperature for 2 hrs and terminated by filtration using a Filtermate Harvester (PerkinElmer) onto GF/C filter plates (Millipore). Bound [ 3 H]-nicotinic acid was determined by scintillation counting using Top Count NXT (PerkinElmer).
• the compounds of the present invention exhibit IC 50 values in a range of about 0.001 ⁇ M to about 100 ⁇ M in the binding assay.
• the compounds of the present invention have IC 50 values in a range of about 0.001 ⁇ M to about 10.0 ⁇ M, more preferably about 0.001 ⁇ M to about 1 ⁇ M.
• FLIPR Fluorescent Calcium Indicator Assay
• HEK-293 cells were grown in tissue culture medium (DMEM/Nut mix F12 Medium with Glutamax I (Invitrogen), containing 10% FBS) at 37° C. in a 5% CO 2 atmosphere. These cells were cultured in 6-well dishes at 3 ⁇ 10 5 cells/well and double transfected with DNA vectors (pcDNA3.1, Invitrogen) expressing either HM74A or HM74 and the chimeric G protein Gqi9. Two days after transfection the wells were combined and plated in 150 cm 2 flasks, in the presence of 50 ⁇ g/ml Hygromycin (Invitrogen) and 500 ⁇ g/ml Geneticin (Gibco).
• tissue culture medium DMEM/Nut mix F12 Medium with Glutamax I (Invitrogen)
• FBS fetal bovine serum
• HEK-293 cells expressing either HM74A or HM74 and the chimeric G protein Gqi9 were plated at 50,000 cells/well in black 96-well plates with clear bottom (Costar) and cultured to confluency overnight in growth media (DMEM/Nut mix F12 Medium with Glutamax I (Invitrogen), containing 10% FBS) at 37° C. in a humidified cell incubator containing 5% CO 2 .
• the compounds of the present invention exhibit EC 50 values in a range of about 0.001 ⁇ M about 100 ⁇ M in the FLIPR assay.
• the compounds of the present invention have EC 50 values in a range of about 0.001 ⁇ M to about 10.0 ⁇ M; more preferably about 0.001 ⁇ M to about 1 ⁇ M.
• the compounds of formula I and/or their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or suspensions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils. Oral administration is preferred.
• the production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula I and/or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
• Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials.
• lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragées and hard gelatine capsules.
• Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers might, however, be required in the case of soft gelatine capsules).
• Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like.
• Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils.
• Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.
• Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.
• Usual stabilizers preservatives, wetting and emulsifying agents, consistency-improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
• the dosage of the compounds of formula I can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case.
• the compound could be administered with one or several daily dosage units, e.g. in 1 to 3 dosage units.
• the pharmaceutical preparations conveniently contain about 1-1000 mg, preferably 1-300 mg, more preferably 1-100 mg, of a compound of formula I.
• This compound was prepared in analogy to the method of Herzig et al. ( Synlett 2005, 3107): Under an atmosphere of Nitrogen, a solution of n-butyl lithium in hexane (1.6N, 3.72 ml) was added dropwise at a temperature of ⁇ 78° C. to a solution of N,N-di-tert-butyloxycarbonyl-2-bromo-5-chloro-4-fluoro-aniline (2.3 g) in THF (10 ml). After 30 min, the mixture was allowed to warm to r.t., then quenched with satd. NH 4 Cl, and extracted with ethyl acetate. The extract was dried (Na 2 SO 4 ) and evaporated.
• Film coated tablets containing the following ingredients can be manufactured in a conventional manner: Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg Film Coat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide (yellow) 0.8 mg 1.6 mg Titanium dioxide 0.8 mg 1.6 mg
• the active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidon in water.
• the granulate is mixed with sodium starch glycolate and magesiumstearate and compressed to yield kernels of 120 or 350 mg respectively.
• the kernels are lacquered with an aqueous solution/suspension of the above mentioned film coat.
• Capsules containing the following ingredients can be manufactured in a conventional manner: Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc 5.0 mg
• the components are sieved and mixed and filled into capsules of size 2.
• Injection solutions can have the following composition: Compound of formula (I) 3.0 mg Polyethylene Glycol 400 150.0 mg Acetic Acid q.s. ad pH 5.0 Water for injection solutions ad 1.0 ml
• the active ingredient is dissolved in a mixture of Polyethylene Glycol 400 and water for injection (part).
• the pH is adjusted to 5.0 by Acetic Acid.
• the volume is adjusted to 1.0 ml by addition of the residual amount of water.
• the solution is filtered, filled into vials using an appropriate overage and sterilized.
• Soft gelatin capsules containing the following ingredients can be manufactured in a conventional manner: Capsule contents Compound of formula (I) 5.0 mg Yellow wax 8.0 mg Hydrogenated Soya bean oil 8.0 mg Partially hydrogenated plant oils 34.0 mg Soya bean oil 110.0 mg Weight of capsule contents 165.0 mg Gelatin capsule mg Gelatin 75.0 Glycerol 85% 32.0 mg Karion 83 8.0 mg (dry matter) Titanium dioxide 0.4 mg Iron oxide yellow 1.1 mg
• the active ingredient is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size.
• the filled soft gelatin capsules are treated according to the usual procedures.
• Sachets containing the following ingredients can be manufactured in a conventional manner: Compound of formula (I) 50.0 mg Lactose, fine powder 1015.0 mg Microcrystalline cellulose (AVICEL PH 102) 1400.0 mg Sodium carboxymethyl cellulose 14.0 mg Polyvinylpyrrolidon K 30 10.0 mg Magnesium stearate 10.0 mg Flavoring additives 1.0 mg
• the active ingredient is mixed with lactose, microcristalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water.
• the granulate is mixed with magnesium stearate and the flavoring additives and filled into sachets.

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