Classifications

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  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
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  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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  • A61P3/00—Drugs for disorders of the metabolism
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  • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
  • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
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  • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
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  • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
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  • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C275/38—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by doubly-bound oxygen atoms
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  • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C275/40—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
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  • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
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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
  • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
  • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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  • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
  • C07C311/47—Y being a hetero atom
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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
  • C07C323/23—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 nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
  • C07C323/39—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 nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
  • C07C323/43—Y being a hetero atom
  • C07C323/44—X or Y being nitrogen atoms
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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
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—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
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—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
  • C07D213/72—Nitrogen atoms
  • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
  • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
  • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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

• This invention relates to new urea derivatives and pharmaceutically acceptable salts thereof which are useful as a medicament.
• acyl-CoA cholesterol acyltransferase enzyme (hereinafter, ACAT) inhibitors, for example, in U.S. Patent Nos. 4,473,579 and 4,623,662, EP Patent Application Publication Nos. 0354994, 0399422 and 0512570 and PCT International Publication Nos. WO 91/13871, WO 93/24458 and WO 94/26738.
• ACAT cholesterol acyltransferase enzyme
• This inventios relates to new urea derivatives and pharmaceutically acceptable sales thereof which have an inhibitory activity against ACAT and an advantage of good absorption into blood on oral administration, to processes for the preparation thereof, to a pharmaceutical
• composition comprising the same and to a method for the prevention and/or treatment of hypercholesterolemia, hyperlipidemia, atherosclerosis or diseases caused thereby.
• One object of this invention is to provide new and useful urea derivatives and pharmaceutically acceptable salts which possess an inhibitory activity against ACAT.
• Another object of this invention is to provide
• a further object of this invention is to provide a pharmaceutical composition comprising, as an active
• Still further object of this invention is to provide a therapeutic method for the prevention and/or treatment of hypercholesterolemia, hyperlipidemia, atherosclerosis or diseases caused thereby in human beings or animals, using said urea derivatives and pharmaceutically acceptable salts thereof.
• inhibitors are useful for the prevention and/or treatment of hypercholesterolemia, hyperlipidemia, atherosclerosis of diseases caused thereby such as cardiac insufficiency (e.g. angina pectoris, myocardial infarction, etc.),
• cardiac insufficiency e.g. angina pectoris, myocardial infarction, etc.
• the object urea derivatives of this invention are new and can be represented by the following general formula (I):
• R 1 is a group of the formula :
• R 4 is aryl which may have suitable substituent (s), or heterocyclic group which may have suitable substituent (s), and
• Y is bond, lower alkylene, H
• R 2 is lower alkyl, lower alkoxy (lower) alkyl, cycloalkyl, ar (lower) alkyl which may have suitable substituent (s), heterocyclic group or heterocyclic (lower) alkyl,
• R 3 is aryl which may have suitable substituent (s) or
• n 0 or 1.
• the object compound (I) of the present invention can be prepared by the following processes.
• R 1 , R 9 , R 3 and n are each as defined above,
• the starting compound can be prepared by tne following processes.
• R 1 , R 2 , and R 4 are each as defined above,
• R 5 is lower alkoxy
• R 6 is lower alkyl
• X is a leaving group
• Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt,
• a salt with an inorganic base for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt
• a salt with an organic base for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt,
• an inorganic acid addition salt e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.
• an organic carboxylic or sulfonic acid addition salt e.g., formate, acetate, trifluoroacetate, maieate, tartrate, fumarate, citrate, methanesulfonate, benzenesulfonate,
• toluenesulfonate etc.
• a salt with a basic or acidic amino acid e.g., arginine, aspartic acid, glutamic acid, etc.
• lower is used to intend a group having 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise provided.
• Suitable “lower alkyl” and “lower alkyl moiety” in the terms “ar (lower) alkyl”, “lower alkoxy (lower) alkyl” and “heterocyclic (lower) alkyl” may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, and the like, and in which more preferable example may be C 1 -C 4 alkyl.
• Suitable "lower alkylene” may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,
• methvlmethylene, ethylethylene, propylene, and the like in which more preferable example may be C 1 -C 4 alkylene and the most preferable one may be methylene.
• Suitable "lower alkoxy” and “lower alkoxy moiety" in the term “lower alkoxy (lower) alkyl” may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.
• Suitable "cycloalkyl” may include cyclo (C 3 -C 7 ) alkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.) and the like.
• aromatic (lower) alkyl may include phenyl, naphthyl and the like.
• Suitable "halogen” may include fluorine, bromine, chlorine and iodine.
• Suitable “leaving group” may include acid residue, and the like.
• Suitable "acid residue” may include halogen as
• Suitable "heterocylic group” and “heterocyclic moiety” in the term “heterocyclic (lower) alkyl” may include
• thiazolyl isothiazolyl, thiadiazolyl (e.g., 1,2,3- thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,
• benzothiazolyl benzothiadiazolyl, etc.
• Suitable "protected amino” may include acylamino or an amino group substituted by a conventional protecting group such as mono (or di or tri i aryl (lower ) alkyl, for example, mono (or di or tri ) phenyl ( lower ) alkyl (e.g., benzyl, trityl, etc.) or the like.
• a conventional protecting group such as mono (or di or tri i aryl (lower ) alkyl, for example, mono (or di or tri ) phenyl ( lower ) alkyl (e.g., benzyl, trityl, etc.) or the like.
• protected hydroxy may include acyl, mono (or di or
• phenyl ( lower) alkyl which may have one or more suitable substituent (s) (e.g., benzyl, 4-methoxybenzyl, trityl, etc.), trisubstituted silyl [e.g., tri (lower) alkylsilyl (e.g., trimethylsilyl, t-butyldimethylsilyl, etc.), et:c.], substituted (lower) alkyl (e.g., methoxymethyl,
• acylamino may include Carbamoyl; Thiocarbamoyl;
• Aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2, 2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.);
• alkanoyl e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2, 2-dimethylpropanoy
• alkoxycarbonyl e.g., methoxycarbonyl, ethoxycarbcnyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.
• alkylsulfonyl e.g., methylsulfonyl, ethylsulfonyl, etc.
• lower or higher alkoxysulfonyl e.g., methoxysulfonyl, ethoxysulfonyl, etc.
• cyclo (lower) alkylcarbonyl e.g., cyclopentylcarbonyl, cyclohexylcarbonyl, etc.
• alkoxysulfonyl e.g., methoxysulfonyl, ethoxysulfonyl, etc.
• cyclo (lower) alkylcarbonyl e.g., cyclopentylcarbonyl, cyclohexylcarbonyl, etc.
• Aromatic acyl such as
• aroyl e.g., benzoyl, toluoyl, naphthoyl, etc.
• ar (lower) alkanoyl e.g., phenyl (lower) alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl,
• phenylisobutanoyl phenylpentanoyl, phenylhexanoyl, etc.
• naphthyl (lower) alkanoyl e.g., naphthylacetyl
• ar (lower) alkenoyl e.g., phenyl (lower) alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.),
• naphthyl (lower) alkenoyl e.g., naphthylpropenoyl
• ar (lower) alkoxycarbonyl e.g., phenyl (lower) alkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), etc.];
• aryloxycarbonyl e.g., phenoxycarbonyl
• aryloxy (lower) alkanoyl e.g., phenoxyacetyl
• arylglyoxyloyl e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.
• arylsulfonyl e.g., phenylsulfonyl, p-tolylsulfonyl, etc.; or the like.
• Suitable "substituent” in the terms "aryl which may have suitable substituent (s) " and “ar (lower) alkyl which may have suitable substituent (s) " may include lower alkyl as exemplified above, lower alkoxy as exemplified above, lower alkenyl, lower alkynyl, mono (or di or tri) halo (lower) alkyl wherein halogen moiety and lower alkyl moiety are each as exemplified above, cyclo (lower) alkyl, cyclo ( lower) alkenyl, halogen as exemplified above, carboxy, protected carboxy, hydroxy, protected hydroxy, aryl as exemplified above, ar (lower) alkyl wherein aryl moiety and lower alkyl moiety are each as exemplified above, carboxy (lower) alkyl wherein lower alkyl moiety as exemplified above, protected
• Suitable "substituent” m the term “heterocyclic group whicn may have suitable suostituent (s)” may include lower alkyl as exemplified above, lower alkoxy as exemplified above, lower alkenyl, lower alkynyl, mono (or ⁇ i or
• halogen moiety and lower alkyl moiety are each as exemplified above, cyclo (lower) alkyl, cyclo (lower) alkenyl, halogen as exemplified above, carboxy, protected carboxy, hydroxy, protected hydroxy, as
• aryl as exemplified above, mono (or di or tri) ar (lower) alkyl wherein aryl moiety and lower alkyl moiety are each as exemplified above, carboxy (lower) alkyl wherein lower alkyl moiety as exemplified above, protected carboxy (lower) alkyl, nitro, amino, protected amino,
• di (lower) alkylamino wherein lower alkyl moiety is as exemplified above, amino (lower) alkyl wherein lower alkyl moiety is as exemplified above, protected amino (lower)- alkyl, hydroxy (lower) alkyl wherein lower alkyl moiety is as exemplified above, protected hydroxy (lower) alkyl, cyanc, sulfo, sulfamoyl, carbamoyloxy, mercapto, lower alkylthio wherein lower alkyl moiety is as exemplified above, lower alkylsulfinyl wherein lower alkyl moiety is as exemplified above, acyl as exemplified above, oxo, imino, and the like.
• isoxazolyl each of which may have suitable substituent (s)" may include lower alkyl as exemplified above, lower alkoxy as exemplified above, lower alkenyl, lower alkynyl, mono (or di or tri) halo (lower) alkyl wherein halogen moiety and lower alkyl moiety are each as exemplified above,
• arylthio wherein aryl moiety is as exemplified above, heterocyclic group as exemplified above, ar (lower) alkyl wherein aryl moiety and lower alkyl moiety are each as exemplified above, carboxy (lower) alkyl wherein lower alkyl moiety as exemplified above, protected
• the compound (I) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) or a salt thereof.
• This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
• a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
• the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
• the starting compound when in liquid, it can be used also as a solvent.
• the compound (I) or a salt thereof can be prepared by subjecting the compound (II) or a salt thereof and the compound (IV) or a salt thereof to formation reaction of ureido group.
• This reaction is carried out in the presence of reagent which introduces carbonyl group such as phosgene [e.g. , triphosgene, etc.], haloformate compound [e.g. ethyl chloroformate, trichloromethyl chloroformate, phenyl chloroformate, etc.], N,N'-carbonyldiimidazole, metal carbonyl compounds [a.g. cobalt carbonyl, manganese
• carbonyl group such as phosgene [e.g. , triphosgene, etc.]
• haloformate compound e.g. ethyl chloroformate, trichloromethyl chloroformate, phenyl chloroformate, etc.
• N,N'-carbonyldiimidazole a.g. cobalt carbonyl, manganese
• carbonyl etc.
• catalysts such as palladium chloride, etc., or the like.
• This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N, N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which ⁇ o not adversely affect the reaction, or the mixture thereof.
• a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N, N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which ⁇ o not adversely affect the reaction, or the mixture thereof.
• the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
• the reaction is usually carried out in the presence of an organic base such as tri (lower) alkylamine (e.g., tri (lower) alkylamine (e.g., tri (lower) alkylamine (e.g., tri (lower) alkylamine (e.g., tri (lower) alkylamine (e.g., tri (lower) alkylamine (e.g., tri (lower) alkylamine (e.g., tri (lower) alkylamine
• trimethylamine triethylamine, diisopropylethylamine, etc.), or the like.
• the compound (lb) or a salt thereof can be prepared by subjecting the compound (la) or a salt thereof to oxidation reaction.
• Oxidation is carried out in a conventional manner, which is capable or oxidizing a sulfur atom to an oxidized sulfur atom
• suitable oxidizing reagent may be oxygen acid such as periodate (e.g. sodium periodate, potassium periodate, etc.), peroxy acid such as perbenzoic acid
• the reaction is usually carried out in a conventional solvent such as water, alcohol, (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane,
• a conventional solvent such as water, alcohol, (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane,
• dichloromethane ethylene dichloride, chloroform, N,N- dimethylformamide, N, N-dimethylacetamide, or any other organic solvent which does not adversely affect the reaction .
• hydrophilic solvents may be used in a mixture with water.
• the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
• the compound (VII) or a salt thereof can be prepared by reacting the compound (V; with the compound (VI;.
• the reaction can be carried out m the manner
• the compound (IXa) or a salt thereof can be prepared DV reacting the compound (VII) or a salt thereof with the compound (VIII) or a salt thereof.
• reaction can oe carried out m the manner
• the compound (X) or a salt thereof can oe prepared by subjecting the compoun ⁇ (IX) or a salt thereof to reduction reaction.
• Reduction is carried out m a conventional manner, including chemical re ⁇ uction and catalytic reduction.
• Suitable reducing reagents to be used in cnemical reduction and hydrides e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum nydride, sodium borohydride, sodium cyanoborohydride, ⁇ iisooutylaluminum hydride, etc.
• a metal e.g., tin, zinc, iron, etc.
• metallic compounc e.g., chromium chloride, chromium acetate, etc.
• Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g., platinum plate, spongy platinum, platinum blac ⁇ , colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc.), nickel catalysts (e.g., reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g., reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g., reduced iron, Raney iron, Ullman iron, etc.), and the like.
• platinum catalysts e.g., platinum plate, spongy platinum, platinum blac ⁇ , colloidal platinum, platinum oxide, platinum wire, etc.
• palladium catalysts e.g., spongy palladium, pal
• the reduction is usually carried out in the
• the reduction is usually carried out in the presence of an organic acid or an inorganic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid,
• an organic acid or an inorganic acid e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid,
• the compound (Xa) or a salt thereof can be prepared by reacting the compound (XI) or a salt thereof with the compound (XII) or a salt thereof.
• the reaction can be carried out in the manner
• the compound (Xb) or a salt thereof can be prepared by reacting the compound (XIII) or a salt thereof with the compound (XII) or a salt thereof.
• the reaction can be carried out in the manner disclosed in Preparation 38 or similar manners thereto.
• the compound (Ila) or a salt thereof can be prepared by reacting the compound (X) or a salt thereof with the compound (XIV) or a salt thereof and then by subjecting the resultant compound to reduction reaction.
• Reduction is carried out in a conventional manner, including chemical reduction and catalytic reduction.
• Suitable reducing reagent to be used in chemical reduction are hydrides (e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.) or a combination of a metal (e.g., tin, zinc, iron, etc.) or metallic compound (e.g., chromium chloride, chromium acetate, etc.) and an organic acid or an inorganic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid,
• hydrides e.g., hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, etc.
• a metal e.g., tin, zinc, iron, etc.
• metallic compound e.g., chromium chloride, chromium acetate, etc.
• Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g., spongy palladium, palladium black,
• palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc. nickel catalysts (e.g., reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g., reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g., reduced iron, Raney iron, Ullman iron, etc.), and the like.
• nickel catalysts e.g., reduced nickel, nickel oxide, Raney nickel, etc.
• cobalt catalysts e.g., reduced cobalt, Raney cobalt, etc.
• iron catalysts e.g., reduced iron, Raney iron, Ullman iron, etc.
• the reduction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, propanol, etc.), tetrahydrofuran, toluene, dioxane,
• a conventional solvent such as water, alcohol (e.g., methanol, ethanol, propanol, etc.), tetrahydrofuran, toluene, dioxane,
• Processes (1)-(3) and (A) - (E) can be referred to the ones as exemplified for the compound (I).
• the compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, or the like.
• the compound (I) and the other compounds may include one or more stereoisomer (s) such as optical isomer(s) and geometrical isomer(s) due to
• Preferred embodiments of the object compound (I) are as follows.
• R 1 is a group of the formula
• R 4 is phenyl which may have 1 to 3 suitable
• substituent (s) (more preferably substituent selected from the group consisting of halogen, lower alkyl, di (lower) alkylamino, protected amino (more preferably acylamino;
• alkoxy (lower) alkoxy; and mono (or di or
• tetrazolylphenyl (triphenyl (lower)- alkyltetrazolyl) phenyl, trihalo (lower)- alkylphenyl, phenyl having two lower alkyl and hydroxy, or phenyl having two lower alkyl and lower alkoxy (lower) alkoxy]; or heterocyclic group
• triphenyl (lower alkyl) and oxo) [more preferably thienyl; pyrazolyl which may have lower alkyl or triphenyl (lower) alkyl; imidazolyl;
• triazolyl which may have one or two
• substituent (s) selected from the group consisting of lower alkyl and phenyl (lower) alkyl; pyridyl; pyrrolyl; tetrazolyl which may have lower alkyl or triphenyl (lower) alkyl; oxazolyl;
• Y is bond, lower alkylene
• acyloxy preferably acyloxy
• R 2 is lower alkyl, lower alkoxy (lower) alkyl,
• cyclo (C 3 -C 7 ) alkyl (more preferably cyclopentyl, cyclohexyl or cycloheptyl), phenyl (lower) alkyl which may nave 1 to 3 (more preferably one or two;
• substituent (s) (more preferably substituent (s) selected from the group consisting of halogen, lower alkoxy and di (lower alkyl) ammo) [more preferably phenyl (lower) alkyl, halophenyl (lower) alkyl, lower alkoxyphenyl (lower) alkyl or ci (lower alkyl) ammophenyl (lower) alkyl],
• R 3 is phenyl which may have 1 to 3 (more preferably two or three) suitable substituent (s) (more preferably substituent selected from the group consisting of lower alkyl and halogen) [more preferably di (or tri) (lower alkyl)phenyl or trihalcphenyl];
• each of whicn may nave 1 to 3 (more preferably two or three) suitable substituent (s) (more preferably substituent selected from the group consisting of lower alkyl, lower alkylthio, halogen, lower alkoxy, lower alkylsulfinyl and lower
• alkylsulfonyl [more preferably pyridyl having two lower alkylthio and lower alkyl;
• alkylthio tri (lower alkyl) pyridyl; pyridyl having two (lower) alkoxy and lower alkyl; pyridyl having lower alkoxy, lower alkylthio and lower alkyl; pyridyl having two lower alkylsulfinyl and lower alkyl;
• n 0 or 1.
• acceptable salts thereof possess a strong inhibitory activity against ACAT, and are useful for the prevention and/or treatment of hypercholesterolemia, hyperlipidemia, atherosclerosis or diseases caused thereby.
• Test compound (a) is :
• Acyl-CoA cholesterol acyltransferase (ACAT)
• ACAT activity was measured by the method of Heider et al. described in Journal of Lipid Research, Vol. 24, page 1127 (1983).
• the enzyme ACAT was prepared from the mucosal microsome fraction of the small intestine of male, 18-week old Japanese white rabbits which had been fed diet
• test compound containing 2% cholesterol for 8 weeks.
• the inhibitory activity of test compound was calculated by measuring the amount of the labeled cholesterol ester produced from
• Cholesterol ester fraction in the chloroform-methanol extracts was isolated by thin-layer chromatographv and was counted their label.
• the compound (I) of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external
• compositions may be capsules, tablets, dragees, granules, suppositories, solution, lotion, suspension, emulsion, ointment, gel, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifylng agents, buffers and other commonly used additives.
• the dosage of the compound (I) will vary depending upon the age and condition of the patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating the above-mentioned diseases. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
• the following Preparations and Examples are given for the purpose of illustrating the present invention in more detail.
• dichlorometha.ne (1 ( ⁇ and anhydrous sodium carbonate (206.8 g) was added a solution of 1-methylpyrazole (80 g) in dichloromethane u00 ml) at 0-5°C. After stirring for one hour under ice-cooling, the mixture was stirred for further one hour at room temperature, then cooled. To the reaction mixture water (1 l) was added thereto. The dichloromethane layer was separated and aqueous layer was extracted twice with dichloromethane. The combined organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was distilled in vacuo to afford 4-bromo-1-methylpyrazole
• IR (Film) 3515, 3265, 3060, 2935, 2875, 1705, 1650, 1615, 1515 cm -1
• N-bromosuccmimide (5.29 gi m tetrachlorometnane (150 ml) was added benzoyl peroxide (144 mg) and the mixture was refluxed for 6 hours. The mixture was cooled, and the insoluble materials were filtered off. The filtrate was evaporated m vacuo and the residue was purified by column chromatography on silica gel to give crude 3-bromomethyl bipnenyl (6.59 g) as a yellow oil.
• IR (Film) 3360, 3075, 2835, 2740, 1695, 1600,
• dichloromethane (30 ml) was added a solution of dimethyl sulfoxide (1.83 ml) in dichloromethane (4 ml) keeping the temperature below -60°C.
• 4-(oxazol-5- yDbenzyl alcohol 2.5 g
• dichloromethane 25 ml
• dimethyl sulfoxide 2 ml
• triethylamine 8 ml
• triphenylchloromethane (1.76 g) at 0-5°C. The mixture was stirred for 4 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with dil.
• IR (Film) 3265, 3150, 3070, 2925, 2850, 1645,
• N-cycloheptyl-4-(4- benzoyl) benzylamine (1.87 g) in ethylene glycol (10 ml) were added potassium hydroxide (511 mg) and hydrazine monohydrate (1.95 g), and the mixture was stirred at 150°C for 5 hours and at 200°C for 4 hours.
• the mixture was poured into a mixture of dichloromethane and ice water, and the separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo.
• the residue was purified by column chromatography on silica gel to give N-cycloheptyl-4-(4-benzyl) benzylamine (1.29 g) as an orange oil.
• N-benzyl-3-(1-tritylpyrazol-3- yl) benzylamine (8.60 g) in anisole (17.2 ml) was added trifluoroacetic acid (34.4 ml) at room temperature and the mixture was stirred at 80°C for 3.5 hours. The mixture was concentrated in vacuo and the residue was pulverized with diisopropyl ether. The powder was collected by filtration, washed with diisopropyl ether and dried in vacuo to give N- benzyl-3-(pyrazol-3-yl) benzylamine bis ( trifluoroacetate) (7.35 g).

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• 1995
  • 1995-09-29 EP EP95932934A patent/EP0784612A1/en not_active Withdrawn
  • 1995-09-29 CA CA002200981A patent/CA2200981A1/en not_active Abandoned
  • 1995-09-29 AU AU35779/95A patent/AU3577995A/en not_active Abandoned
  • 1995-09-29 KR KR1019970702138A patent/KR970706242A/ko not_active Application Discontinuation
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  • 1995-09-29 WO PCT/JP1995/001982 patent/WO1996010559A1/en not_active Application Discontinuation
  • 1995-10-02 IL IL11548395A patent/IL115483A0/xx unknown
  • 1995-10-03 TR TR95/01209A patent/TR199501209A2/tr unknown

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