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
  • C07—ORGANIC CHEMISTRY
  • 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 invention 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.
• a further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said urea derivatives and pharmaceutically acceptable salt thereof.
• 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.
• ACAT 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.), cerebrovascular disturbance (e.g. cerebral infarction, cerebral apoplexy, etc.), arterial aneurism, peripheral vascular disease, xantho as, restenosis after percutaneous transluminal coronary angioplasty, or the like.
• cardiac insufficiency e.g. angina pectoris, myocardial infarction, etc.
• cerebrovascular disturbance e.g. cerebral infarction, cerebral apoplexy, etc.
• arterial aneurism e.g. cerebral infarction, cerebral apoplexy, etc.
• peripheral vascular disease xantho as, restenosis after percutaneous transluminal coronary angioplasty, or the like.
• 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
• 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 heterocyclic group which may have suitable substituent (s)
• n is 0 or I.
• the object compound (I) of the present invention can be prepared by the following processes. - 4 -
• R 1-, R9, R'-. and n are each as defined above,
• R ⁇ is pyridyl having two lower alkylthio and lower alkyl
• Rg is pyridyl having two lower alkylsulfonyl and lower alkyl
• pyridyl having lower alkylsulfonyl, lower alkylsulfinyl and lower alkyl are pyridyl having two lower alkylthio and lower alkyl
• Rg is pyridyl having two lower alkylsulfonyl and lower alkyl
• pyridyl having two lower alkylsulfinyl and lower alkyl or pyridyl having lower alkylsulfonyl, lower alkylsulfinyl and lower alkyl.
• the starting compound can be prepared by tne following processes .
• R , R , and R are each as defined above, R is lower alkoxy, R° is lower alkyl, R is aryl which may have suitable substituent (s) , and X is a leaving group.
• - 11 - 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, 5 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, ethanolamine salt, triethanolamine salt, dicyclohexylamine o salt, N,N'-dibenzylethylenediamine salt, etc.); 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
• 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” may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, 5 propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyi, pentyl, tert-pentyl, hexyl, and the like, and in which more preferable example may be C ⁇ -C ⁇ alkyl.
• Suitable "lower alkylene” may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethyiene, methvlmethylene, ethylethylene, propylene, and the like, in which more preferable example may be C -C 4 alkylene and the most preferable one may be methylene.
• Suitable "lower alkoxy” and “lower alkoxy oiety" 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 (C3-C7) alkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.) and the like.
• Suitable "aryl” and “aryl moiety” in the term “ar (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 exemplified above, and the like.
• Suitable "heterocylic group” and “heterocyclic moiety” in the term “heterocyclic (lower) alkyl” may include unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocvclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyi, i idazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyi, pyridazinyl, triazolyl (e.g., 1H-1, 2, -triazolyi, 4K-1,2,4- triazolyl, 1H-1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl, etc.), tetrazolyl (e.g., IH-tetrazolyl, 2H-tetrazolyl, etc.), etc.
• Suitable "protected amino” may include acylamino or an a ino 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, t ⁇ tyi, etc. ) or the like .
• protected hydroxy may include acyl, mono (or di or tri) phenyl (lower) alkyl which may have one or more suitable substituent (s) (e.g., benzyl, 4-methoxybenzyl, trityi, etc.) , trisubstituted silyl [e.g., tri (lower) alkylsilyl (e.g., trimethylsilyl, t-butyldimethylsilyl, etc.), et: substituted (lower) alkyl (e.g., methoxymethyl, ethoxymethyl, etc.) , tetrahydropyranyl and the like.
• suitable substituent e.g., benzyl, 4-methoxybenzyl, trityi, etc.
• silyl e.g., tri (lower) alkylsilyl (e.g., trimethylsilyl, t-butyldimethylsilyl, etc.),
• acylamino may include Carbamoyl; Thiocarbamoyl;
• A.liphatic 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, pentadecanoyi, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyi, icosanoyl, etc.
• alkanoyl e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropano
• lower or higher alkoxycarbonyl e.g., methoxycarbonyl, ethoxycarbcnyl, t-butoxycarbonyi, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.
• lower or higher alkylsulfonyl e.g., methylsulfonyl, ethylsulfonyl, etc.
• lower or higher alkoxysulfonyl e.g., methoxysulfonyl, ethoxysulfonyl, etc.
• cyclo (lower) alkylcarbonyl e.g., cyclopentylcarbonyl, cyclohexylcarbonyl, etc.
• Aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyi, etc.); ar (lower) alkanoyl [e.g., phenyl (lower)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl (lower)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.]; ar (lower)alkenoyl [e.g., phenyl (lower) alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phen
• Suitable "substituent” in the terms "aryl which may have suitable substituent (s) " and “ar (lower) lkyl 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 carboxy(lower) alkyl,
• Suitable “substituent” the term “heterocyclic group whic 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 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, as exemplified above, 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) alky
• Suitable "substituent" in the term “thiazolyl, imidazolyl, pyrazolyl, pyridyl, thienyl, furyl or isoxazolyl, each of which may have suitable substituen (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, haloaryl wherein halogen moiety and aryl moiety are each as exemplified above, arylthio wherein aryl moiety is as exemplified above, heterocycl
• 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, -dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ⁇ thylene 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, -dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ⁇ thylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
• reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
• the starting compound is 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, etc.], a combination of carbon monoxide and catalysts such as palladium chloride, etc., or the like.
• 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 carbon
• 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., trimethylamine, triethylamine, diisopropylethylamine, etc. ) , or the like.
• organic base such as tri (lower)alkylamine (e.g., 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 (e.g., perbenzoic acid, -chloroperbenzoic acid, etc.), and the like.
• the reaction is usually carried out in 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 .
• 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 disclosed in Preparation 2 or similar manners thereto.
• 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 disclosed in Preparation 20 or similar manners thereto.
• the compound (X) or a salt thereof can oe prepare:: r_. 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 m cne ⁇ ucal reduction and hydrides (e.g., hydrogen iodide, hydrogen s ⁇ lfide, lithium aluminum nydride, sodium borohyd ⁇ e, sodium cyanoborohyd ⁇ de, ⁇ iisooutylalummum hydride, etc.;, a metal (e.g., tin, zinc, iron, etc. ) or metallic compounc (e.g., chromium chloride, chromium acetate, etc.), ana t e like.
• a metal e.g., tin, zinc, iron, etc.
• metallic compounc e.g., chromium chloride, chromium acetate, etc.
• Suitable catalysts to be used 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, palla
• the reduction is usually carried out in the conventional solvent such as water, alcohol (e.g., methanol, ethanol, propanol, etc.), tetrahydrofuran, toluene, dichloromethane, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or any other solvents which do not adversely affect the reaction, or a mixture thereof.
• 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, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc. ) .
• an organic acid or an inorganic acid e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.
• 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 disclosed in Preparation 48 or similar manners thereto.
• 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 - 22 - 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.
• 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, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.
• 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.
• 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.
• 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, palla
• the reduction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, propanol, etc.), tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N, -dimethylacetamide or any other solvents which do not adversely affect the reaction, or a mixture thereof.
• a conventional solvent such as water, alcohol (e.g., methanol, ethanol, propanol, etc.), tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N, -dimethylacetamide or any other solvents which do not adversely affect the reaction, or a mixture thereof.
• Processes (l)-(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 asymmetric carbon atom(s) and double bond(s), and all of such isomers and mixture thereof are included within the scope of this invention.
• Preferred embodiments of the object compound (I) are as follows.
• R 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; most preferably lower alkylsulfonylamino) , cyano, heterocyclic group (more preferably tetrazolyl) which may have mono (or di or tri) ar (lower) lkyl
• suitable substituent (s) (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; pyridyl having halogen, lower alkyl and lower 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; pyridyl having two lower alkylsulfonyl and lower alkyl; pyridyl having lower alkylthio, lower alkoxy and lower alkyl
• the object compounds (I) and pharmaceutically 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) inhibitory activity
• 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 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 [ C]oleoyl-CoA and endogenous cholesterol as follows. [ C]Oleoyl-CoA and microsome were incubated with test compound at 37°C for 5 minutes. The reaction was stopped by the addition of chloroform-methanol (2:1, V/V) . 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 (topical) administration, wherein more preferable one is oral administration.
• a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external (topical) administration, wherein more preferable one is oral administration.
• the pharmaceutical preparations 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 emulsifying 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. Ir general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
• the resicue was crystallized from hexane and ethyl acetate (5:1), and the crystal was collected by filtration to give ethyl 4- (benzoylammo - benzoate (5.14 g) .
• 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.
• IR (Film) 3025, 2905, 2850, 1510 cm "1
• N-benzyl-3- (l-tritylpyrazol-3- yl) benzylamine 8.60 g
• anisole 17.2 ml
• trifluoroacetic acid 34.4 ml
• 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 ( rifluoroacetate) (7.35 g) .
• N,N-dimethylformamide (30 ml) was added sodium hydride (60% oil suspension, 950 mg) at 0-5°C. After stirring for 30 minutes, to the mixture was added a solution of 4-bromomethylbenzonitrile (4.0 g) in N,N-dimethylformamide (10 ml) dropwise under ice cooling, and the mixture was stirred for two hours at room temperature. The reaction mixture was diluted with ethyl acetate (240 ml), washed with water and brine, dried over magnesium sulfate, evaporated in vacuo. The residue was chromatographed on silica gel (100 g, eluting with n-hexane - ethyl acetate
• N-cycloheptyl-4-formylbenzylamine (18.26 g) in ethanol (200 ml) were added thiazolidin 2,4- dione (9.25 g) and piperidine (6.72 g) , and the mixture was refluxed for 17 hours.
• the mixture was cooled to 5°C and the precipitates were collected by filtration, washed with ethanol and diisopropyl ether and dried in vacuo to give N-cycloheptyl-4-[ (2, -dioxothiazolidin-5-ylidene)methyl]- benzylamine (9.61 g) as a yellow crystal.
• the filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel to give the second crop (4.13 g ) •
• N-cycloheptyl-4- [ (2, 4- dioxothiazolin-5-ylidene)methyl]benzylamine 13.61 g
• tetrahydrofuran 300 ml
• methanol 300 ml
• 5 ' sodium-amalgam 56.8 g
• the insoluble materials were removed by filtration on celite and the filtrate was evaporated in vacuo.
• the residue was purified by column chromatography on silica gel to give N-cycloheptyl-4- [ (2, 4- dioxothiazolidin-5-yl)methyl]benzylamine (5.84 g) as a yellow solid.

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• 1995
  • 1995-09-29 EP EP95932934A patent/EP0784612A1/en not_active Withdrawn
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