WO1992009561A1 - New amide derivatives - Google Patents

New amide derivatives Download PDF

Info

Publication number
WO1992009561A1
WO1992009561A1 PCT/JP1991/001556 JP9101556W WO9209561A1 WO 1992009561 A1 WO1992009561 A1 WO 1992009561A1 JP 9101556 W JP9101556 W JP 9101556W WO 9209561 A1 WO9209561 A1 WO 9209561A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
nmr
cdc1
acid
rac
Prior art date
Application number
PCT/JP1991/001556
Other languages
French (fr)
Inventor
Yoshikuni Itoh
Takumi Yatabe
Kazuhiko Ohne
Hirokazu Tanaka
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP3518018A priority Critical patent/JPH06504521A/en
Publication of WO1992009561A1 publication Critical patent/WO1992009561A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/11—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C07C235/46—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 atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton

Definitions

  • This invention relates to new amide derivatives which are useful as a medicament.
  • Some amide derivatives have been known as useful cholesterol-lowering agents, for example, in U.S. Patent Nos. 3,784,577 and 3,995,059, and EP Patent Application Publication No. 0025569.
  • This invention relates to new amide derivatives. More particularly, it relates to new amide derivatives which have an inhibitory activity against acyl-CoA : cholesterol acyltransferase enzyme (hereinafter, ACAT) , 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.
  • ACAT cholesterol acyltransferase enzyme
  • One object of this invention is to provide new and useful amide derivatives which possess an inhibitory activity against ACAT.
  • Another object of this invention is to provide processes for preparation of said amide derivatives.
  • a further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said amide derivatives.
  • Still further object of this invention is to provide a therapeutical method for the prevention and/or treatment of hypercholesterolemia, hyperlipidemia, atherosclerosis or diseases caused thereby in human beings or animals, using said amide derivatives.
  • ACAT inhibitors are useful for the prevention and/or treatment of hypercholesterolemia, hyperlipidemia, atherosclerosis or 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, xanthomas, 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.
  • R is ar(lower)alkyl
  • R is aryl
  • R is alkyl or alkenyl
  • A is a single bond, lower alkylene or lower alkenylene, and X is 0, S or a single bond.
  • the object compound (I) can be prepared by processes s illustrated in the following reaction schemes.
  • R 1, R2, R3, A and X are each as defined above,
  • A is lower alkenylene, and'
  • lower is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
  • lower alkenylene and “lower alkenyl” is intended to mean a group having 2 to 6 carbon atoms.
  • alkyl may include lower alkyl, higher alkyl and the like.
  • alkenyl may include lower alkenyl, higher alkenyl and the like.
  • Suitable “lower alkyl” may be a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, or the like, in which preferable one is one having 2 to 6 carbon atoms and the most preferable one is butyl or hexyl.
  • Suitable “lower alkenyl” may be a straight or branched one such as vinyl, propenyl, butenyl, pentenyl, hexenyl, isopropenyl, or the like.
  • Suitable "higher alkyl” may be a straight or branched one such as heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, methylheptyl, methyloctyl, methylnonyl, methyldecyl, ethylheptyl, ethyloctyl, ethylnonyl, ethyldecyl or the like, in which preferable one is one having 7 to 12 carbon atoms and the most preferable one is heptyl, octyl, nonyl, decyl, undecyl or dodecyl.
  • Suitable "higher alkenyl” may be a straight or branched one. such as heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, methylheptenyl, methyloctenyl, methylnonenyl, methyldecenyl, ethylheptenyl, ethyloctenyl, ethylnonenyl, ethyldecenyl, or the like, in which preferable one is octenyl, nonenyl or undecenyl.
  • Suitable "aryl” may be phenyl, naphthyl, phenyl substituted with lower alkyl [e.g. tolyl, xylyl, mesityl, cumenyl, etc.], and the like, in which preferable one is phenyl.
  • Suitable "ar(lower)alkyl” may be phenyl(lower)alkyl [e.g. benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, etc.], tolyl(lower) lkyl [e.g. tolylmethyl, tolylethyl, etc.
  • xylylmethyl mesitylmethyl, cumenylmethyl, and the like, in which preferable one is phenyl(lower)alkyl or tolyl(lower)alkyl and the most preferable one is benzyl or tolylmethyl.
  • Suitable "lower alkylene” may be a straight or branched one such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene , ethylethylene, or the like, in which preferable one is methylene, ethylene or trimethylene.
  • Suitable "lower alkenylene” may be a straight or branched one such as vinylene, propenylene, butenylene, pentenylene, hexenylene, isopropenylene, or the like, in which preferable one is vinylene.
  • Preferable compound (I) is one which has ar(lower)alkyl (more preferably phenyl(lower)alkyl) for
  • R 1 aryl (more preferably phenyl) for R2, higher alkyl
  • R 3 (more preferably one having 7 to 12 carbon atoms) for R , lower alkylene for A, and 0 for X.
  • More preferable compound (I) is one which has benzyl or tolylmethyl for R 1, phenyl for R2, heptyl, octyl,
  • the object compound (I) can be prepared by reacting a compound (II) or its salt with compound (III) or its reactive derivative at the carboxy group.
  • Suitable salt of the compound (II) may be an acid addition salt such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc. ], or the like.
  • Suitable reactive derivative of the compound (III) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
  • the suitable example may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid etc.), dialkylphosphorus acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (e.g. methanesulfonic acid, etc.), alkylcarbonic acid, aliphatic carb ⁇ xylic acid (e.g.
  • substituted phosphoric acid e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid etc.
  • dialkylphosphorus acid e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric
  • pivalic acid pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid, etc.
  • aromatic carboxylic acid e.g. benzoic acid, etc.
  • a symmetrical acid anhydride an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g.
  • These reactive derivatives can optionally be selected from them according to the kind of the compound (III) to be used.
  • the reaction is usually carried out in a conventional solvent such as water, alcohol (e.g.
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; N,N'-dieth ⁇ lcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide; N,N-carbonylbis-(2-methylimidazole) ; pentamethyleneketene- N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-l-chloroethylene
  • reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, N, -di(lower)alkylbenzylamine, or the like.
  • an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, N, -di(lower)alkylbenzylamine, or the like.
  • the reaction temperature is not critical, and the reaction is preferably carried out under cooling or at ambient temperature.
  • the object compound (lb) can be prepared by subjecting a compound (la) to reduction.
  • the present reduction is carried out by chemical reduction, catalytic reduction, or the like.
  • Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc. ] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].
  • Suitable catalysts to be used in catalytic reduction are conventional ones such- as platinum catalyst [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalyst [e.g.
  • nickel catalyst e.g. reduced nickel, nickel oxide, Raney nickel, etc.
  • cobalt catalyst e.g. reduced cobalt, Raney cobalt, etc.
  • iron catalyst e.g. reduced iron, Raney iron, etc.
  • copper catalyst e.g. reduced copper, Raney copper, Ullman copper, etc.
  • the reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, an alcohol [e.g. methanol, ethanol, propanol, etc.], N,N-dimethylformamide, or a mixture thereof.
  • a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent and other conventional solvent such as diethyl ether, methylene chloride, dioxane, tetrahydrofuran, etc., or a mixture thereof.
  • reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to heating.
  • the compound (lb) having alkyl for R may be obtained according to reaction conditions. This case is included within the scope of the present reaction.
  • the compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chr ⁇ matography, reprecipitation, or the like.
  • the compound (I) and the other compounds may include one or more stereoisomers due to asymmetric carbon atom(s), and all of such isomers and mixture thereof are included within the scope of this invention.
  • the object compounds (I) possess an strong inhibitory activity against ACAT, and are useful for the prevention and/or treatment of hypercholesterolemia, hyperlipidemia, atherosclerosis or diseases caused thereby.
  • the pharmacological test data of some representative compounds of the compound (I) are shown in the following.
  • 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 feeded diet containing 2% cholesterol for 8 weeks.
  • the inhibitory activity of compounds were calculated by measuring the amount of the labeled cholesterol ester produced from [ 14C]oleoyl-CoA and endogenous cholesterol as follows. [ 14C]oleoyl-CoA and microsome were incubated with test compounds at 37°C for 5 minutes. The reaction was stopped by the addition of chloroform-methanol (2:1,
  • 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.
  • a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external (topical) 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. In general, amounts between 0.1 mg/body and about 1,000 mg/bod ⁇ may be administered per day.
  • Example 1 A mixture of 4-butoxyphenylacetic acid (470 mg) and thionyl chloride (2 ml) was stirred at 100°C for 30 minutes. After cooling excess thionyl chloride was evaporated and removed azeotropically with benzene under reduced pressure to give 4-butoxyphenylacetyl chloride (490 mg) . To a stirred solution of rac-l,2-diphen ⁇ lethylamine (460 mg) and triethylamine (0.4 ml) in chloroform (15 ml) was added a solution of 4-butoxyphenylacetyl chloride (490 mg) in chloroform (5 ml) dropwise at 0°C and the mixture was stirred at 0°C for 30 minutes.
  • Example 2-1 The following compounds (Examples 2-1) to 2-37)) were obtained according to a similar manner to that of Example 1.
  • Examples 4-1) to 4-5 were obtained according to a similar manner to that of Example 3 .
  • Example 6 The following compounds (Examples 6-1) to 6-12)) were obtained according to a similar manner to that of Example

Abstract

This invention relates to new amide derivatives having an inhibitory activity against acyl-CoA: cholesterol acyltransferase enzyme and represented by general formula (I), wherein R1 is ar(lower)alkyl, R2 is aryl, R3 is alkyl or alkenyl, A is a single bond, lower alkylene or lower alkenylene, and X is O, S or a single bond, to processes for the preparation thereof and to a pharmaceutical composition comprising the same.

Description

DESCRIPTION
NEW AMIDE DERIVATIVES
TECHNICAL FIELD
This invention relates to new amide derivatives which are useful as a medicament.
BACKGROUND ART Some amide derivatives have been known as useful cholesterol-lowering agents, for example, in U.S. Patent Nos. 3,784,577 and 3,995,059, and EP Patent Application Publication No. 0025569.
DISCLOSURE OF INVENTION
This invention relates to new amide derivatives. More particularly, it relates to new amide derivatives which have an inhibitory activity against acyl-CoA : cholesterol acyltransferase enzyme (hereinafter, ACAT) , 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 amide derivatives which possess an inhibitory activity against ACAT.
Another object of this invention is to provide processes for preparation of said amide derivatives. A further object of this invention is to provide a pharmaceutical composition comprising, as an active ingredient, said amide derivatives.
Still further object of this invention is to provide a therapeutical method for the prevention and/or treatment of hypercholesterolemia, hyperlipidemia, atherosclerosis or diseases caused thereby in human beings or animals, using said amide derivatives.
High levels of blood cholesterol and blood lipids are conditions which are involved in the onset of atherosclerosis.
It is well known that inhibition of ACAT-catalyzed cholesterol esterification could lead to diminish intestinal absorption of cholesterol as well as a decrease in the intracellular accumulation of cholesterol esters in the intima of the arterial wall. Therefore, ACAT inhibitors are useful for the prevention and/or treatment of hypercholesterolemia, hyperlipidemia, atherosclerosis or 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, xanthomas, restenosis after percutaneous transluminal coronary angioplasty, or the like.
The object amide derivatives of this invention are new and can be represented by the following general formula (I) :
Figure imgf000004_0001
wherein R is ar(lower)alkyl,
R is aryl,
R is alkyl or alkenyl,
A is a single bond, lower alkylene or lower alkenylene, and X is 0, S or a single bond.
The object compound (I) can be prepared by processes s illustrated in the following reaction schemes. Process 1
Figure imgf000005_0001
(ID (III) or its salt or its reactive derivative at the carboxy group
Figure imgf000005_0002
(I)
Process 2
Figure imgf000005_0003
(la) (lb)
wherein R 1, R2, R3, A and X are each as defined above,
A is lower alkenylene, and'
2 A is lower alkylene.
In the above and subsequent description of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in detail in the following.
The term "lower" is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
The lower moiety in the terms "lower alkenylene" and "lower alkenyl" is intended to mean a group having 2 to 6 carbon atoms.
The term "alkyl" may include lower alkyl, higher alkyl and the like.
The term "alkenyl" may include lower alkenyl, higher alkenyl and the like.
Suitable "lower alkyl" may be a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, or the like, in which preferable one is one having 2 to 6 carbon atoms and the most preferable one is butyl or hexyl.
Suitable "lower alkenyl" may be a straight or branched one such as vinyl, propenyl, butenyl, pentenyl, hexenyl, isopropenyl, or the like.
The term "higher" is intended to mean 7 to 20 carbon atoms, unless otherwise provided.
Suitable "higher alkyl" may be a straight or branched one such as heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, methylheptyl, methyloctyl, methylnonyl, methyldecyl, ethylheptyl, ethyloctyl, ethylnonyl, ethyldecyl or the like, in which preferable one is one having 7 to 12 carbon atoms and the most preferable one is heptyl, octyl, nonyl, decyl, undecyl or dodecyl. Suitable "higher alkenyl" may be a straight or branched one. such as heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, methylheptenyl, methyloctenyl, methylnonenyl, methyldecenyl, ethylheptenyl, ethyloctenyl, ethylnonenyl, ethyldecenyl, or the like, in which preferable one is octenyl, nonenyl or undecenyl.
Suitable "aryl" may be phenyl, naphthyl, phenyl substituted with lower alkyl [e.g. tolyl, xylyl, mesityl, cumenyl, etc.], and the like, in which preferable one is phenyl. Suitable "ar(lower)alkyl" may be phenyl(lower)alkyl [e.g. benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, etc.], tolyl(lower) lkyl [e.g. tolylmethyl, tolylethyl, etc. ] , xylylmethyl, mesitylmethyl, cumenylmethyl, and the like, in which preferable one is phenyl(lower)alkyl or tolyl(lower)alkyl and the most preferable one is benzyl or tolylmethyl.
Suitable "lower alkylene" may be a straight or branched one such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene , ethylethylene, or the like, in which preferable one is methylene, ethylene or trimethylene.
Suitable "lower alkenylene" may be a straight or branched one such as vinylene, propenylene, butenylene, pentenylene, hexenylene, isopropenylene, or the like, in which preferable one is vinylene.
Preferable compound (I) is one which has ar(lower)alkyl (more preferably phenyl(lower)alkyl) for
R 1, aryl (more preferably phenyl) for R2, higher alkyl
3 (more preferably one having 7 to 12 carbon atoms) for R , lower alkylene for A, and 0 for X.
More preferable compound (I) is one which has benzyl or tolylmethyl for R 1, phenyl for R2, heptyl, octyl,
3 nonyl, decyl, undecyl or dodecyl for R , methylene, ethylene or trimethylene for A, and' O for X.
The processes for preparing the object compound (I) are explained in detail in the following.
Process 1 The object compound (I) can be prepared by reacting a compound (II) or its salt with compound (III) or its reactive derivative at the carboxy group.
Suitable salt of the compound (II) may be an acid addition salt such as an inorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], an organic acid addition salt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc. ], or the like. Suitable reactive derivative of the compound (III) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. The suitable example may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid etc.), dialkylphosphorus acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (e.g. methanesulfonic acid, etc.), alkylcarbonic acid, aliphatic carbσxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g. benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester (e.g. cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH-)2N=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.), or an ester with a N-hydroxy compound (e.g. N,N-dimethylhydroxylamine, l-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-lH-benzotriazole, l-hydroxy-6-chloro-lH-benzotriazole, etc.) and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound (III) to be used. The reaction is usually carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofura , ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvent may also be used in a mixture with water.
When the compound (III) is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; N,N'-diethγlcarbodiimide, N,N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide; N,N-carbonylbis-(2-methylimidazole) ; pentamethyleneketene- N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-l-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phohsphorus trichloride; thionyl chloride; oxalyl chloride; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intra-molecular salt; l-(p-chlorobehzenesulfonyloxy)-6- chloro-lH-benzotriazole; so-called Vilsmeier reagent prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc. ; or the like. The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine, N, -di(lower)alkylbenzylamine, or the like. The reaction temperature is not critical, and the reaction is preferably carried out under cooling or at ambient temperature.
Process 2
The object compound (lb) can be prepared by subjecting a compound (la) to reduction.
The present reduction is carried out by chemical reduction, catalytic reduction, or the like.
Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc.] or metallic compound [e.g. chromium chloride, chromium acetate, etc. ] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.]. Suitable catalysts to be used in catalytic reduction are conventional ones such- as platinum catalyst [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalyst [e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium _ - carbonate, etc.], nickel catalyst [e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalyst [e.g. reduced cobalt, Raney cobalt, etc.], iron catalyst [e.g. reduced iron, Raney iron, etc.], copper catalyst [e.g. reduced copper, Raney copper, Ullman copper, etc.] or the like.
The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, an alcohol [e.g. methanol, ethanol, propanol, etc.], N,N-dimethylformamide, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent and other conventional solvent such as diethyl ether, methylene chloride, dioxane, tetrahydrofuran, etc., or a mixture thereof.
The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to heating.
In this reaction, in case that the compound (la)
3 having alkenyl for R is used as a starting compound, the compound (lb) having alkyl for R may be obtained according to reaction conditions. This case is included within the scope of the present reaction.
The compounds obtained by the above processes can be isolated and purified by a conventional method such as pulverization, recrystallization, column chrσmatography, reprecipitation, or the like.
It is to be noted that the compound (I) and the other compounds may include one or more stereoisomers due to asymmetric carbon atom(s), and all of such isomers and mixture thereof are included within the scope of this invention.
The object compounds (I) possess an strong inhibitory activity against ACAT, and are useful for the prevention and/or treatment of hypercholesterolemia, hyperlipidemia, atherosclerosis or diseases caused thereby. in order to illustrate the usefulness of the object compound (I) , the pharmacological test data of some representative compounds of the compound (I) are shown in the following.
Test compounds :
(a) rac-N-(1,2-Diphenγlethγl)-3-(2-heptyloxyρhenyl)- propionamide
(b) rac-N-(1,2-Diphenylethyl)-3-(4-heptyloxyρhenyl)- propionamide (c) rac-N-(l,2-Diphenylethγl)-2-octγloxyphenylacetamide - 10 -
(d) rac-N-[2-(4-Methylphenγl)-1-phenylethyl]-2-octyloxy- phenylacetamide
(e) rac-N-[2-(4-Methylphenγl)-1-phenylethyl]-2-nonyloxy- phenylacetamide (f) rac-N-(1,2-Diphenylethyl)-2-decyloxyphenylacetamide (g) rac-(E)-N-[2-(4-Methγlphenyl)-1-phenylethyl]-2-(2- octenyloxy)phenylacet mide
Test : Acyl-CoA : cholesterol acyltransferase (ACAT) inhibitory activity
Method :
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 feeded diet containing 2% cholesterol for 8 weeks. The inhibitory activity of compounds were calculated by measuring the amount of the labeled cholesterol ester produced from [ 14C]oleoyl-CoA and endogenous cholesterol as follows. [ 14C]oleoyl-CoA and microsome were incubated with test compounds 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 chromatography and was counted their label. Results
Figure imgf000013_0001
For therapeutic purpose, 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. 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.
While 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/bodγ may be administered per day.
The following Preparations and Examples are given for the purpose of -illustrating this invention.
Preparation 1 To a stirred mixture of 3-hydroxyphenylacetic acid (1.52 g) and aqueous 10% sodium hydroxide solution (8 ml) in dimethyl sulfoxide (30 ml) was added a solution of 1-iodooctane (2.40 g) in dimethyl sulfoxide (10 ml) dropwise at 80°C and the mixture was stirred at 80°C for 2 hours. After cooling the reaction mixture was poured into 3% hydrochloric acid and extracted with diethyl ether. The ethereal extract was washed with brine, dried and evaporated. Recrystallization from n-hexane gave 3-octyloxyphenylacetic acid (1.93 g) . mp : 76-77°C
IR (Nujol) : 3100, 1680, 1590, 1490, 1400, 1260,
870, 770, 700 cm"1 NMR (CDC13, δ) : 0.88 (3H, t, J=7Hz) ,
1.22-1.50 (10H, m), 1.70-1.83 (2H, m) , 3.58 (2H, s), 3.93 (2H, t, J=7Hz),
6.75-6.85 (3H, m) , 7.18-7.28 (1H, m)
The following compounds (Preparations 2-1) to 2-25)) were obtained according to a similar manner to that of Preparation 1.
Preparation 2
1) 3-Heptyloxycinnamic acid mp : 84-86°C IR (Nujol) : 3400, 1680, 1620, 1570, 1370, 1300, 1260, 1040 cm-1 NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz) , 1.20-1.48 (8H, ), 1.72-1.88 (2H, m) , 3.95 (2H, t, J=7Hz), 6.43 (IH, d, J=15Hz), 6.93 (IH, d, J=7Hz), 7.07-7.19 (2H, m) , 7.32 (IH, t, J=8Hz),
7.75 (IH, d, J=15Hz)
2) 4-Octyloxγphenylacetic acid mp : 76-78°C IR (Nujol) : 3100, 1680, 1600, 1400, 1300, 1240,
1040, 620 cm"1 NMR (CDC13, δ) : 0.85 (3H, t, J=7Hz),
1.23-1.47 (10H, m) , 1.70-1.85 (2H, m) , 3.55 (2H, s), 3.92 (2H, t, J=7Hz), 6.85 (2H, d, J=10Hz), 7.18 (2H, d, J=10Hz)
3) 2-Octγloxγphenylacetic acid
IR (Neat) : 3030, 2930, 1700, 1600, 1500, 1455, 1240, 745 cm"1
NMR (CDC13, δ) : 0.88 (3H, t, J=7Hz),
1.20-1.48 (10H, m) , 1.78 (2H, t, J=7Hz), 3.63 (2H, s), 3.98 (2H, t, J=7Hz), 6.81-6.95 (2H, m) , 7.17-7.30 (2H, m)
4) 4-Nonyloxybenzoic acid mp : 90-92°C IR (Nujol) : 1670, 1600, 1300, 1250, 840, 760 cm -1 NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz),
1.20-1.52 (12H, m) , 1.81 (2H, t, J=7Hz), 4.03 (2H, t, J=7Hz), 6.93 (2H, d, J=8Hz),
8.05 (2H, d, J=8Hz)
5) 4-Decyloxyphenylacetic acid mp : 75-76°C IR (Nujol) : 3050, 1680, 1520, 1400, 1300, 1250, 1180, 1030, 900, 830, 790, 720 cm"1 NMR (CDC13, δ) : 0.88 (3H, t, J=7Hz),
1.22-1.48 (14H, m) , 1.70-1.82 (2H, m) , 3.59 (2H, s), 3.95 (2H, t, J=7Hz), 6.85 (2H, d, J=8Hz), 7.18 (2H, d, J=8Hz)
6) 2-Heptyloxγcinnamic acid
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.33 (8H, m) , 1.88 (2H, q, J=7Hz), 4.05 (2H, t, J=7Hz), 6.57 (IH, d, J=15Hz), 6.89-7.00 (2H, m) , 7.36 (IH, ddd, J=9, 9, 2Hz), 7.53 (IH, dd, J=9, 2Hz), 8.10 (IH, d, J=15Hz)
7) 4-Heptγloxycinnamic acid NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.30 (8H, m) ,
1.80 (2H, q, J=7Hz), 4.00 (2H, t, J=7Hz),
6.35 (IH, d, J=15Hz), 6.90 (2H, d, J=9Hz), 7.50 (2H, d, J=9Hz), 7.75 (IH, d, J=15Hz)
8) 2-Deσyloxycinnamic acid
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.33 (14H, m) , 1.90 (2H, q, J=7Hz), 4.04 (2H, t, J=7Hz), 6.59 (IH, d, J=15Hz), 6.90-7.00 (2H, m) ,
7.36 (IH, ddd, J=9, 9, 2Hz), 7.55 (IH, dd, J=9, 2Hz), 8.10 (IH, d, J=15Hz')
9) 4-Decyloxycinnamic acid
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.30 (14H, m) ,
1.80 (2H, q, J=7Hz), 4.00 (2H, t, J=7Hz), 6.30 (IH, d, J=15Hz), 6.90 (2H, d, J=9Hz),
7.50 (2H, d, J=9Hz), 7.70 (IH, d, J=15Hz)
10) 2-Butoxycinnamic acid
NMR (CDC13, δ) : 1.00 (3Hr t, J=7Hz), 1.55 (2H, m) , 1.87 (2H, q, J=7Hz), 4.05 (2H, t, J=7Hz), -
6 . 60 ( IH, d , J=15Hz ) , 6. 90-7. 00 ( 2H , m) , 7. 46 ( IH, ddd , J=9 , 9 , 2Hz ) , 7. 55 ( IH, dd, J=9 , 2Hz ) , 8.10 ( IH, d, J=15Hz )
11) 2-Butoxγphenylacetic acid
NMR (CDC13, δ) : 0.96 (3H, t, J=7Hz), 1.39-1.56 (2H, m), 1.78 (2H, q, J=7Hz), 3.67 (2H, s), 4.00 (2H, t, J=7Hz), 6.83-6.94 (2H, m) , 7.15-7.30 (2H, m)
12) 2-Hexyloxyphenylacetic acid
NMR (CDC13, δ) : 0.94 (3H, t, J=7Hz), 1.35 (6H, br s), 1.80 (2H, q, J=7Hz), 3.69 (2H, s), 4.00 (2H, t, J=7Hz), 6.83-6.94 (2H, m) , 7.16-7.30 (2H, m)
13) 2-Heptyloxyphenylacetic acid
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.30 (8H, br s), 1.79 (2H, q, J=7Hz), 3.65 (2H, s), 3.99 (2H, t, J=7Hz), 6.82-6.94 (2H, m) , 7.17-7.40 (2H, m)
14) 4-(4-Heptyloxγphenyl)butyric acid
NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz), 1.31 (10H, br s), 1.90-1.99 (2H, m) , 2.36 (2H, t, J=7Hz), 2.62 (2H, t, J=7Hz), 3.92 (2H, t, J=7Hz) , 6.92 (2H, d, J=9Hz), 7.08 (2H, d, J=9Hz)
15) 2-Octyloxyphenylacetic acid
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.30 (10H, br s), 1.78 (2H, q, J=7Hz), 3.68 (2H, s), 3.98 (2H, t, J=7Hz), 6.84-6.94 (2H, m) , 7.18-7.30 (2H, m)
16) 4-Octyloxycinnamic acid
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.30 (10H, br s), 1.78 (2H, ui, J=7Hz), 4.00 (2H, t, J=7Hz), 6.32 (IH, d, J=15Hz), 6.91 (2H, d, J=9Hz), 7.51 (2H, d, J=9Hz), 7.75 (IH, d, J=15Hz) 17) 2-Octyloxycinnamic acid
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.35 (10H, br s), 1.87 (2H, q, J=7Hz), 4.05 (2H, t, J=7Hz), 6.57 (IH, d, J=15Hz), 6.89-7.00 (2H, m) , 7.30-7.40 (IH, m) , 7.53 (IH, dd, J=9, 2Hz),
8.11 (IH, d, J=15Hz)
18) 2-Dodecyloxyphenylacetic acid
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.30 (18H, br s), 1.80 (2H, q, J=7Hz), 3.68 (2H, s), 4.00 (2H, t, J=7Hz), 6.84-6.96 (2H, m) , 7.15-7.30 (2H, m)
19) (E)-2-(2-Octenyloxy)phenγlacetic acid
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.32 (6H, br s), 2.02-2.12 (2H, m) , 3.70 (2H, s), 4.52 (2H, dd, J=7, 2Hz), 5.59-5.90 (2H, m) , 6.88-6.98 (2H, m), 7.18-7.29 (2H, m)
20) 2-Nonyloxyphenylacetic acid NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.29 (12H, br s), 1.79 (2H, q, J=7Hz), 3.65 (2H, s), 4.00 (2H, t, J=7Hz), 6.85-6.96 (2H, m) , 7.17-7.30 (2H, m)
21) 2-Decyloxyphenylacetic acid NMR (CDC13, δ) : 0.88 (3H, t,' J=7Hz), 1.27-1.47
(14H, m), 1.76 (2H, q, J=7Hz), 3.66 (2H, s) , 3.96 (2H, t, J=7Hz), 6.84-6.93 (2H, m) , 7.15-7.29 (2H, m)
22) 2-Heptyloxycinnamic acid
NMR (CDC13, δ) : 0.91 (3H, t, J=7Hz), 1.30-1.56 (8H, m), 1.85 (2H, q, J=7Hz) , 4.03 (2H, t, J=7Hz), 6.58 (IH, d, J=16Hz), 6.90-7.00 (2H, m) , 7.35 (IH, ddd, J=8, 8, 2Hz), 7.53 (IH, dd, J=8, 2Hz), 8.12 (IH, d, J=16Hz) 23) 2-Hexyloxyphenylacetic acid
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.27-1.48 (6H, m), 1.77 (2H, q, J=7Hz), 3.66 (2H, s), 3.97 (2H, t, J=7Hz), 6.83-6.95 (2H, m) , 7.17-7.30 (2H, m)
24) 2-Hexyloxγcinnamic acid
NMR (CDC13, δ) : 0.92 (3H, t, J=7Hz), 1.32-1.53 (6H, m), 1.86 (2H, q, J=7Hz), 4.03 (2H, t, J=7Hz), 6.58 (IH, d, J=16Hz), 6.89-6.99 (2H, m) , 7.33 (IH, ddd, J=1.5, 8, 8Hz), 7.52 (IH, dd, J=1.5,
8Hz), 8.12 (IH, d, J=16Hz)
25) 4-Hexγloxycinnamic acid
NMR (CDC13, δ) : 0.91 (3H, t, J=7Hz), 1.30-1.49 (6H, m), 1.78 (2H, q, J=7Hz), 3.99 (2H, t, J=7Hz),
6.32 (IH, d, J=16Hz), 6.91 (2H, d, J=8Hz), 7.49 (2H, d, J=8Hz), 7.75 (IH, d, J=16Hz)
Preparation 3 A solution of 2-hexyloxycinnamic acid (3.74 g) in tetrahydrofuran (50 ml) was hydrogenated over 10% palladium on carbon (0.5 g) at ambient temperature at 1 at for 4 hours. The catalyst was filtered off and washed with tetrahydrofuran. The filtrate and washings were concentrated under the reduced pressure to leave 3-(2-hexyloxypheny1)propionic acid (3.4 g) .
NMR (CDC13, δ) : 0.91 (3H, t, J=7Hz), 1.30-1.54 (6H, m), 1.81 (2H, q, J=7Hz), 2.66 (2H, t, J=7Hz) , 2.95 (2H, t, J=7Hz), 3.95 (2H, t, J=7Hz), 6.80-6.90 (2H, m) , 7.12-7.22 (2H, m)
The following compound (Preparation 4) was obtained according to a similar manner to that of Preparation 3. Preparation 4
3-(4-Hexyloxyphenyl)propionic acid
NMR (CDCl.,, δ) : 0.91 (3H, t, J=7Hz), 1.29-1.47 (6H, m), 1.77 (2H, q, J=7Hz), 2.62 (2H, t, J=7Hz) , 2.97 (2H, t, J=7Hz), 3.91 (2H, t, J=7Hz), 6.82
(2H, d, J=8Hz), 7.10 (2H, d, J=8Hz)
Preparation 5
To a stirred solution of decyltriphenylphosphonium bromide (12.9 g) in tetrahydrofuran (25 ml) was added potassium tert-butoxide (2.7 g) at 0°C and the mixture was stirred at 0°C for 30 minutes. To this mixture was added a solution of methyl 3-(4-formylphenyl)propionate (2.6 g) in tetrahydrofuran (20 ml) at 0°C and the mixture was refluxed for 3 hours. After cooling the reaction mixture was poured into aqueous saturated ammonium chloride and extracted with diethyl ether. The extract was washed with water and dried. Evaporation of solvent gave an oily residue which was chromatographed on silica gel. Elution with ethyl acetate-n-hexane (1:10) afforded methyl
(Z)-3-[4-(l-undecenyl)phenyl]propionate (741 mg). _ -
NMR (CDC13, δ) : 0.88 (3H, t, J=7Hz), 1.24 (14H, br s), 2.30 (2H,'m), 2.63 (2H, t, J=7Hz), 2.95 (2H, t, J=7Hz), 3.69 (3H, s), 5.58-5.7 (IH, m) , 6.37 (IH, d, J=llHz), 7.10-7.25 (4H, m)
The following compounds (Preparations 6-1) and 6-2)) were obtained according to a similar manner to that of Preparation 5.
Preparation 6
1) Methyl (Z)-3-[4-(l-octenyl)phenyl]propionate
NMR (CDC13, δ) : 0.88 (3H, t, J=7Hz) , 1.28 (8H, br s), 2.18-2.38 (2H, m) , 2.63 (2H, t, J=7Hz), 2.96 (2H, t, J=7Hz), 3.69 (3H, s) . 5.63 (IH, dt, J=ll, 7Hz), 6.37 (IH, d, J=llHz), 7.09-7.24 (4H, m)
2) Methyl (Z)-3-[4-(1-nonenyl)phenyl]propionate
NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz) , 1.29 (10H, br s), 2.27-2.38 (2H, m) , 2.63 (2H, t, J=7Hz), 2.95 (2H, t, J=7Hz), 3.70 (3H, s), 5.63 (IH, dt, J=ll, 7Hz), 6.36 (IH, d, J=llHz), 7.09-7.29 (4H, )
Preparation 7
A mixture of methyl (Z)-3-[4-(l-octenyl)phenyl]- propionate (2.385 g) and IN sodium hydroxide (17.4 ml) in methanol (30 ml) was stirred at ambient temperature for 4 hours. Methanol was evaporated to leave a residue which was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give (Z)-3-[4-(1-octenyl)phenyl]- propionic acid (2.025 g). NMR (CDC13, δ) : 0.88 (3H, t, J=7Hz), 1.28 (8H, br s), 2.15-2.48 (2H, m) , 2.71 (2H, t, J=7Hz), 2.98 (2H, t, J=7Hz), 5.64 (IH, dt, J=ll, 7Hz), 6.87 (IH, d, J=llHz), 7.10-7.30 (4H, m)
The following compounds (Preparation 8-1) and 8-2)) were obtained according to a similar manner to that of Preparation 7.
Preparation 8 1) (Z)-3-[4-(l-Undecenγl)phenγl]propionic acid
2) (Z)-3-[4-(l-Nonenyl)phenyl]propionic acid
Example 1 A mixture of 4-butoxyphenylacetic acid (470 mg) and thionyl chloride (2 ml) was stirred at 100°C for 30 minutes. After cooling excess thionyl chloride was evaporated and removed azeotropically with benzene under reduced pressure to give 4-butoxyphenylacetyl chloride (490 mg) . To a stirred solution of rac-l,2-diphenγlethylamine (460 mg) and triethylamine (0.4 ml) in chloroform (15 ml) was added a solution of 4-butoxyphenylacetyl chloride (490 mg) in chloroform (5 ml) dropwise at 0°C and the mixture was stirred at 0°C for 30 minutes. The reaction mixture was washed with dilute hydrochloric acid, dilute sodium bicarbonate solution and water, and dried. Evaporation of solvent gave an oily residue which was chromatographed on silica gel. Elution with chloroform gave rac-N-(l,2-diphenγlethγl)-4- butoxyphenylacetamide as a crystal (700 mg) . mp : 148°C
NMR (CDC13, δ) : 1.00 (3H, t, J=7Hz), 1.52 (2H, tq, J=7, 7Hz), 1.80 (2H, tt, J=7, 7Hz), 2.85 (IH, dd, J=7, 14Hz), 3.03 (IH, dd, J=7, 14Hz), 3.44 (2H, s), 3.99 (2H, t, J=7Hz), 5.25 (IH, dt, J=7,
7Hz), 5.68 (IH, d, J=7Hz), 6.83-7.24 (14H, m)
The following compounds (Examples 2-1) to 2-37)) were obtained according to a similar manner to that of Example 1.
Example 2
1) rac-N-(l,2-Diphenylethyl)-2-heptyloxycinnamamide mp : 105-107°C NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.30 (8H, m) ,
1.84 (2H, q, J=7Hz), 3.20 (2H, d, J=7Hz), 4.00 (2H, t, J=7Hz), 5.41 (IH, dt, J=7, 9Hz), 5.83 (IH, d, J=9Hz), 6.48 (IH, d, J=15Hz), 6.90 (2H, ddd, J=9, 9, 2Hz), 7.05-7.30 (11H, m) , 7.45 (IH, d, J=9Hz), 7.89 (IH, d, J=15Hz) ) rac-N-(1,2-Diphenylethyl)-4-heptyloxycinnamamide mp : 142-144°C
NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz), 1.30 (8H, m) , 1.80 (2H, q, J=7Hz), 3.20 (2H, d, J=7Hz), 3.98 (2H, t, J=7Hz), 5.41 (IH, dt, J=9, 7Hz), 5.82 (IH, d, J=9Hz), 6.20 (IH, d, J=15Hz), 6.85 (2H, d, J=9Hz), 7.07-7.10 (2H, m) , 7.20-7.30 (8H, m) , 7.40 (2H, d, J=9Hz), 7.52 (IH, d, J=15Hz)
) rac-N-(1,2-Diphenylethyl)-4-decyloxycinnamamide
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.35 (14H, m) , 1.80 (2H, q, J=7Hz), 3.20 (2H, d, J=7Hz), 4.00 (2H, t, J=7Hz), 5.45 (IH, dt, J=9, 7Hz), 5.95 (IH, d, J=9Hz), 6.00 (IH, d, J=15Hz),
6.90 (2H, d, J=9Hz), 7.10-7.35 (10H, m) , 7.40 (2H, d, J=9HZ), 7.55 (IH, d, J=15Hz)
) rac-N-(1,2-Diphenylethyl)-2-decyloxycinnamamide mp : 85-87.5°C
NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz), 1.30 (L4H, m) ,
1.85 (2H, q, J=7Hz), 3.20 (2H, d, J=7Hz),
4.00 (2H, t, J=7Hz), 5.40 (IH, dt, J=9, 7Hz),
5.85 (IH, d, J=9Hz), 6.50 (IH, d, J=15Hz), 6.90 (2H, t, J=9Hz), 7.iσ-7.33 (11H, m) ,
7.45 (IH, dd, J=9, 2Hz), 7.89 (IH, d, J=15Hz)
) rac-N-(1,2-Diphenylethyl)-2-butoxycinnamamide mp : 163-164.5°C NMR (CDC13, δ) : 0.97 (3H, t, J=7Hz) , 1.50 (2H, m) ,
1.82 (2H, q, J=7Hz) , 3.19 (2H, d, J=7Hz) ,
4.00 (2H, t, J=7Hz), 5.40 (IH, dt, J=9, 7Hz),
5.85 (IH, d, J=9Hz), 6.48 (IH, d, J=15Hz),
6.89 (IH, d, J=9Hz), 7.05-7.40 (12H, m) , 7.43 (IH, d, J=9Hz), 7.90 (IH, d, J=15Hz) ) rac-N-[2-(4-Methylphenyl)-1-phenylethyl]-4- hep yloxycinnamamide mp : 155-158°C
NMR (CDC13, δ) : 0.88 (3H, t, J=7Hz), 1.27 (8H, m) , 1.80 (2H, q, J=7Hz) , 2.29 (3H, s) ,
3.15 (2H, d, J=7Hz), 3.97 (2H, t, J=7Hz) , 5.40 (IH, dt, J=9, 7Hz), 5.82 (IH, d, J=9Hz), 6.20 (IH, d, J=15Hz), 6.88 (2H, d, J=9Hz), 7.00 (4H, m), 7.20-7.40 (5H, m) , 7.39 (2H, d, J=9Hz), 7.54 (IH, d, J=15Hz)
) rac-N-(1,2-Diphenγlethγl)-2-butoxγphenγlacetamide mp : 139-141°C
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.30-1.49 (2H, m), 1.57-1.70 (2H, m) , 2.84-3.05 (2H, m) , 3.55
(2H, m), 3.87 (2H, t, J=7Hz), 5.22 (IH, dt, J=9, 7Hz), 6.13 (IH, d, J=9Hz), 6.75-7.32 (14H, m)
) rac-N-(1,2-Diphenylethyl)-2-hexyloxγphenylacetamide mp : 111-113.5°C
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.30 (6H, br s), 1.55-1.68 (2H, m) , 2.85-3.07 (2H, m) , 3.55 (2H, m), 3.87 (2H, t, J=7Hz), 5.23 (IH, dt, J=9, 7Hz), 6.17 (IH, d, J=9Hz), 6.73-7.32 (14H, m)
) rac-N-(1,2-Diphenylethγl)-2-heptγloxyphenylacetamide mp : 110.5-111.5°C
NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz), 1.28 (10H, br s), 2.95 (2H, m), 3.56 (2H, m) , 3.88 (2H, t, J=7Hz), 5.23 (IH, dt, J=9, 7Hz), 6.15 (IH, d,
J=9Hz), 6.75-7.30 (14H, m)
) rac-N-[2-(4-Methylphenyl)-1-phenylethγl]-2- heptyloxyphenylacetamide mp : 102-104°C NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz) , 1.30 (8H, br s), 1.58-1.73 (2H, m) , 2.26 (3H, s), 2.80-3.01 (2H, m), 3.47 (IH, d, J=15Hz), 3.62 (IH, d, J=15Hz), 3.88 (2H, t, J=7Hz) , 5.20 (IH, dt, J=9, 7Hz), 6.14 (IH, d, J=9Hz), 6.68 (2H, d, J=9Hz),
6.82-6.98 (4H, m) , 7.02-7.33 (7H, m)
11) rac-N-(1,2-Diphenylethyl)-4-(4-heptyloxyphenyl)- butyramide mp : 110.5-111.5°C
NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz), 1.30 (8H, br s), 1.69-1.91 (4H, m), 2.13 (2H, t, J=7Hz), 2.48 (2H, t, J=7HZ), 3.10 (2H, d, J=7Hz), 4.00 (2H, t, J=7Hz), 5.30 (IH, dt, J=9, 7Hz), 5.68 (IH, d, J=9Hz), 6.76-7.35 (14H, m)
12) rac-N-[2-(4-Methylphenyl)-1-phenylethyl]-2- octyloxyphenylacetamide mp : 97-99.5°C NMR (CDC13, δ) : 0.88 (3H, t, J=7Hz) , 1.29 (10H, br s), 1.59-1.72 (2H, m) , 2.29 (3H, s), 2.79-3.00 (2H, m), 3.47 (IH, d, J=15Hz), 3.62 (IH, d, J=15Hz), 3.88 (2H, t, J=7Hz), 5.20 (IH, dt, J=9, 7Hz), 6.17 (IH, d, J=9Hz), 6.67 (2H, d, J=9Hz), 6.90 (4H, q, J=9Hz), 7.02-7.31 (7H, m)
13) rac-N-(1,2-Diphenylethγl)-4-octyloxycinnamamide
NMR (CDC13, δ) : 0.88 (3H, t, J=7Hz) , 1.28 (10H, br s), 1.65-1.85 (2H, m) , 3.19 (2H, d, J=7Hz), 3.98 (2H, t, J=7Hz), 5.42 (IH, dt, J=9, 7Hz), 5.89
(IH, d, J=9Hz), 6.23 (IH, d, J=15Hz), 6.80-6.90 (3H, m), 7.04-7.43 (11H, m) , 7.54 (IH, d, J=15Hz)
14) rac-N-[2-(4-Methylρhenyl)-l-phenγlethyl]-4- octyloxycinnamamide
NMR (CDC13, δ) : 0.90 (3H, s), 1.31 (10H, br s) , 1.73-1.85 (2H, m) , 2.30 (3H, s), 3.15 (2H, d, J=7Hz), 3.98 (2H, t, J=7Hz), 5.40 (IH, dt, J=9, 7Hz), 5.84 (IH, d, J=9Hz), 6.22 (IH, d, J=15Hz),
6.86 (2H, d, J=9Hz), 7.00 (4H, q, J=9Hz), 7.23-7.30 (5H, m) , 7.40 (2H, d, J=9Hz), 7.55 (IH, d, J=15Hz)
15) rac-N-(1,2-Diphenylethyl)-2-octyloxycinnamamide
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.30 (10H, br s), 1.78-1.90 (2H, m), 3.20 (2H, dd, J=7, 2Hz), 4.00 (2H, t, J=7Hz), 5.40 (IH, dt, J=9, 7Hz) ,
5.87 (IH, d, J=9Hz), 6.48 (IH, d, J=15Hz), 6.88 (2H, t, J=9Hz), 7.05-7.30 (11H, m) , 7.45 (IH, dd, J=9, 2Hz), 7.89 (IH, d, J=15Hz)
16) rac-N-[2-(4-Methylphenyl)-1-phenylethyl) ]-2- octyloxycinnamamide
NMR (CDC13, δ) : 0.88 (3H, t, J=7Hz) , 1.29 (10H, br s), 1.76-1.90 (2H, m) , 2.28 (3H, s), 3.25 (2H, d, J=7Hz), 3.99 (2H, t, J=7Hz) , 5.39 (IH, dt, J=9, 7Hz), 5.84 (IH, d, J=9Hz), 6.48 (IH, d, J=15Hz), 6.84-7.07 (7H, m) , 7.20-7.35 (5H, m) , 7.45 (IH, dd, J=9, 2Hz)/ 7.89 (IH, d, J=15Hz)
17) rac-N-(1,2-Diphenylethyl)-2-dodecyloxyphenylacetamide mp : 103-105°C
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.29 (18H, br s), 1.53-1.68 (2H, m) , 2.84-3.07 (2H, m) , 3.62 (IH, d, J=15Hz), 3.47 (IH, d, J=15Hz), 3.87 (2H, t, J=7Hz), 5.23 (IH, dt, J=9, 7Hz), 6.16 (IH, d, J=9Hz), 6.73-7.24 (14H, m)
18) rac-N-[2-(4-MethyIpheny1)-1-phenylethyl]-2- dodecyloxyphenylacetamide mp : 105-107.5°C
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz) , 1.28 (18H, br s), 1.60-1.80 (2H, m), 2.27 (3H, s), 2.79-3.00 (2H, m), 3.47 (IH, d, J=15Hz), 3.62 (IH, d,
J=15Hz), 3.88 (2H, t, J=7Hz), 5.20 (IH, dt, J=9, 7Hz), 6.15 (IH, d, J=9Hz), 6.68 (2H, d, J=9Hz), 6.90 (4H, q, J=9Hz) , 7.04-7.32 (7H, m)
19) rac-(E)-N-(l,2-Diphenγlethyl)-2-(2-octenyloxy)- phenylacetamide mp : 108-110°C
NMR (CDC13, δ) : 0.88 (3H, t, J=7Hz), 1.30 (6H, br s), 1.98-2.10 (2H, m) , 2.84-3.05 (2H, m) , 3.47 (IH, d, J=15Hz), 3.62 (IH, d, J=15Hz), 4.40 (2H, d, J=7Hz), 5.22 (IH, dt, J=9, 7Hz), 5.50-5.85 (2H, m), 6.30 (IH, d, J=9Hz), 6.77-7.30 (14H, m)
20) rac-(E)-N-[2-(4-MethyIpheny1)-1-phenylethyl -2-(2- octenyloxy)phenylacetamide mp : 108-108.5°C
NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz), 1.30 (6H, br s), 2.00-2.10 (2H, m), 2.29 (3H, s), 2.79-3.01 (2H, m), 3.47 (IH, d, J=15Hz), 3.62 (IH, d, J=15Hz), 4.40 (2H, d, J=7Hz), 5.20 (IH, dt, J=9,
7Hz), 5.48-5.87 (2H, m) , 6.26 (IH, d, J=9Hz), 6.69 (2H, d, J=7Hz), 6.85-7.30 (11H, m)
1) rac-N-(1,2-Diphenylethyl)-2-nonyloxyphenylacetamide mp : 104-105°C
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.29 (14H, s), 2.83-3.04 (2H, m) , 3.47 (IH, d, J=15Hz), 3.62 (IH, d, J=15Hz), 3.88 (2H, t, J=7Hz), 5.23 (IH, dt, J=9, 7Hz), 6.17 (IH, d, J=9Hz), 6.75-6.97 (4H, m), 7.02-7.25 (10H, m) 22) rac-N-[2-(4-Methylphenyl)-1-phenylethyl]-2- nonyloxyphenylacetamide mp : 106.5-108.5°C
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.29 (14H, br s), 2.25 (3H, s), 2.80-3.02 (2H, m) , 3.47 (IH, d, J=15Hz), 3.62 (IH, d, J=15Hz), 3.87 (2H, d, J=7Hz), 5.20 (IH, dt, J=9, 7Hz), 6.15 (IH, d, J=9Hz), 6.67 (2H, d, J=7Hz), 6.82-6.97 (4H, m) , 7.03-7.25 (7H, m)
23) rac-N-[2-(4-Methylphenyl)-1-phenylethyl]-2- decyloxyphenylacetamide mp : 111°C
NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz), 1.38 (14H, s) , 1.64 (2H, q, J=7Hz), 2.26 (3H, s) , 2.84 (IH, dd,
J=7, 15Hz), 2.96 (IH, dd, J=7, 15Hz), 3.47 (IH, d, J=15Hz), 3.62 (IH, d, J=15Hz), 3.87 (2H, t, J=7Hz), 5.20 (IH, dt, J=7, 8Hz), 6.14 (IH, d, J=8Hz), 6.66 (2H, d, J=8Hz), 6.83-6.96 (4H, m) , 7.03-7.32 (7H, m)
24) rac-N-(1,2-Diphenylethyl)-2-decyloxyphenylacetamide mp : 105-106.5°C
NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz), 1.26 (14H, m) , 1.63 (2H, m), 2.90 (IH, dd, J=7, 15Hz), 3.00
(IH, dd, J=7, 15Hz), 3.47 (IH, d, J=15Hz), 3.62 (IH, d, J=15Hz), 3.87 (2H, t, J=7Hz), 5.22 (IH, dt, J=7, 8Hz), 6.15 (IH, d, J=8Hz), 6.74-6.80 (2H, m) , 6.85 (IH, d, J=8Hz), 6.94 (IH, d, J=8Hz), 7.02-7.32 (10H, m)
25) rac-N-[2-(4-Methylphenyl)-1-phenylethyl]-2- heptyloxycinnama ide mp : 166-167°C NMR (DMSO-dg, δ) : 0.85 (3H, t, J=7Hz) , 1.22-1.44 (8H, ), 1.76 (2H, m) , 2.23 (3H, s), 2.97 (2H, d, J=8Hz), 4.01 (2H, t, J=7Hz), 5.13 (IH, dt, J=8, 8Hz), 6.64 (IH, d, J=16Hz), 6.92-7.52 (13H, m), 7.62 (IH, d, J=16Hz), 8.59 (IH, d, J=8Hz)
26) rac-N-[2-(4-Methylphenyl)-1-phenylethyl]-2- hexyloxyphenylacetamide mp : 88°C
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.25-1.41 (6H, m), 1.64 (2H, m) , 2.27 (3H, s), 2.84 (IH, dd,
J=7, 14Hz), 2.96 (IH, dd, J=7, 14Hz), 3.46 (IH, d, J=15Hz), 3.62 (IH, d, J=15Hz), 3.87 (2H, t, J=7Hz), 5.21 (IH, dt, J=7, 8Hz), 6.13 (IH, d, J=8Hz), 6.67 (2H, d, J=8Hz) , 6.84-7.32 (11H, m)
27) rac-N-[2-(4-Methylphenyl)-1-phenylethyl]-3-(2- hexyloxypheny1)propionamide mp : 98°C
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.28-1.51 (6H, m), 1.76 (2H, q, J=7Hz) , 2.27 (3H, s) , 2.46 (2H, t, J=7Hz), 2.90 (2H, t, J=7Hz), 2.95 (2H, d, J=7Hz), 3.93 (2H, t, J=7Hz), 5.22 (IH, dt, J=7, 7Hz), 5.70 (IH, d, J=7Hz), 6.80-6.86 (4H, m) , 6.97-7.31 (9H, m)
28) rac-N-(1,2-Diphenylethyl)-3-(2-hexyloxγphenyl)- propionamide mp : 96°C
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.29-1.52 (6H, m), 1.76 (2H, q, J=7Hz), 2.46 (2H, t, J=7Hz) ,
2.89 (2H, t, J=7Hz), 3.02 (2H, d, J=7Hz), 3.93 (2H, t, J=7Hz), 5.25 (IH, dt, J=7, 8Hz), 5.69 (IH, d, J=8Hz), 6.80-7.29 (14H, m)
29) rac-N-(l,2-Diphenylethyl)-3-(4-hexyloxyphenyl)- propionamide p : 107.5°C
NMR (CDC13, δ) : 0.91 (3H, t, J=7Hz), 1.30-1.52 (6H, m), 1.75 (2H, q, J=7Hz), 2.41 (2H, t, J=7Hz), 2.82 (2H, t, J=7Hz), 3.03 (2H, d, J=7Hz), 3.90 (2H, t, J=7Hz), 5.25 (IH, dt,
J=7, 7Hz), 5.63 (IH, d, J=7Hz), 6.77 (2H, d, J=8Hz), 6.93-7.31 (12H, m)
30) rac-N-[2-(4-Methylphenyl)-1-phenylethyl]-3-(4- hexyloxyphenyl)propionamide mp : 130.5°C
NMR (CDC13, δ) : 0.91 (3H, t, J=7Hz), 1.29-1.48 (6H, m), 1.76 (2H, q, J=7Hz), 2.29 (3H, s), 2.40 (2H, t, J=7Hz), 2.82 (2H, t, J=7Hz), 2.99 (2H, d, J=7Hz), 3.92 (2H, t, J=7Hz) , 5.23 (IH, dt, J=7,
7Hz), 5.63 (IH, d, J=7Hz), 6.75-6.85 (4H, m) , 6.99-7.10 (6H, m) , 7.22-7.31 (3H, m)
31) rac-(Z)-N-(l,2-Diphenγlethγl)-3-[4-(l-undecenyl) phenyl]propionamide mp : 90-91.5°C
NMR (CDC13, δ) : 0.87 (3H, t, J=7Hz), 1.26 (14H, br s), 2.30 (2H, m), 2.43 (2H, t, J=7Hz), 2.87 (2H, t, J=7Hz), 3.05 (2H, d, J=7Hz), 5.28 (IH, dt, J=9, 7Hz), 5.64 (2H, m) , 5.38 (IH, d, J=llHz),
6.92-7.25 (14H, m)
32) rac-(Z)-N-[2-(4-Methylphenyl)-1-phenylethyl]-3-[4-(1- undecenyl)phenyl]propionamide mp : 87-89°C
NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz), 1.29 (14H, br s), 2.25-2.38 (2H, m) , 2.30 (3H, s), 2.44 (2H, t, J=7Hz), 2.99 (2H, t, J=7Hz) , 3.00 (2H, d, J=7Hz), 5.24 (IH, dt, J=9, 7Hz), 5.58-5.72 (2H, m), 6.37 (IH, d, J=llHz), 6.82-7.28 (13H, m) 33) rac-(Z)-N-(1,2-Diphenylethyl)-3-[4-(1-octenyl)- phenyl]propionamide mp : 89-91°C
NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz), 1.30 (8H, br s), 2.18-2.38 (2H, m) , 2.47 (2Hf t, J=7Hz), 2.89
(2H, t, J=7Hz), 3.07 (2H, d, J=7Hz), 5.28 (IH, dt, J=9, 7Hz), 5.57-5.70 (2H, m) , 6.36 (IH, d, J=llHz), 6.95-7.27 (14H, m)
34) rac-(Z)-N-[2-(4-Methγlphenyl)-l-phenylethyl]-3-[4- (1-octenyl)phenyl]propionamide mp : 92-94°C
NMR (CDC13, δ) : 0.88 (3H, t, J=7Hz), 1.28 (8H, br s), 2.30 (3H, s), 2.15-2.39 (2H, m) , 2.44 (2H, t, J=7Hz), 2.90 (2H, t, J=7Hz), 3.00 (2H, d,
J=7Hz), 5.25 (IH, dt, J=9, 7Hz), 5.59-5.72 (2H, m), 6.36 (IH, d, J=llHz), 6.85 (2H, d, J=9Hz), 6.98-7.25 (11H, m)
35) rac-(Z)-N-(1,2-Diphenylethyl)-3-[4-(l-nonenyD- phenyl]propionamide mp : 95-98°C
NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz) , 1.29 (10H, br s), 2.27-2.38 (2H, m) , 2.44 (2H, t, J=7Hz), 2.90 (2H, t, J=7Hz), 3.04 (2H d, J=7Hz), 5.20-5.32
(IH, dt, J=9, 7Hz), 5.57-5.70 (2H, m) , 6.37 (IH, d, J=llHz), 6.94-7.30 (14H, m)
6) rac-(Z)-N-[2-(4-Methylphenyl)-1-phenylethyl]-3-[4-(1- nonenyl)phenyl]propionamide mp : 72-74°C
NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz), 1.29 (10H, br s), 2.29 (3H, s), 2.18-2.38 (2H, m) , 2.42 (2H, t, J=7Hz), 2.89 (2H, t, J=7Hz), 2.99 (2H, d, J=7Hz), 5.23 (IH, dt, J=9, 7Hz), 5.58-5.70 (2H, m) , 6. 36 ( IH, d, J=llHz ) , 6. 85 ( 2H, d, J=9Hz ) , 6. 98-7. 29 ( 11H, m)
37) rac-N-(1,2-Diphenylethyl)-3-(4-decylthiophenyl)- propionamide mp : 96-97°C
NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz), 1.28 (16H, br s), 2.43 (2H, t, J=7Hz), 2.82-2.95 (4H, m) , 3.05 (2H, d, J=7Hz), 5.27 (IH, dt, J=9, 7Hz), 5.65 (IH, d, J=9Hz), 6.96-7.24 (14H, m)
MASS (m/z) : 502 (M+ + 1)
Example 3
To a stirred solution of 3-octyloxyphenylacetic acid (528 mg) in methylene chloride (15 ml) was added 1-hydroxybenzotriazole (270 mg) and N,N'-dicγclohexylcarbodiimide (412 mg) at ambient temperature and the mixture was stirred for 20 minutes at the same temperature. To this mixture was added a solution of rac-l,2-diphenylethylamine (396 mg) in methylene chloride (5 ml) dropwise at ambient temperature and the mixture was stirred for 1 hour at the same temperature. The resulting N,N'-dicyclohexylurea was removed by filtration. The filtrate was washed with 3% hydrochloric acid, saturated sodium* bicarbonate solution and brine, and dried. Evaporation of solvent gave a residue which was recrystallized from n-hexane-ethyl acetate to give rac-N-(1,2-diphenylethyl)-3-octyloxyphenyl- acetamide (512 mg) . mp : 91-92°C
IR (Nujol) : 3300, 1640, 1580, 1520, 1260, 1150,
940, 750, 700 cm"1 NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz),
1.25-1.51 (10H, m), 1.71-1.88 (2H, m) , 2.80-3.07 (2H, m) , 3.50 (2H, s), 3.91 (2H, t, J=7Hz ) , 5 . 21 ( IH , q, J=7Hz ) , 5 . 72 ( IH, d, J=7Hz ) , 6. 68-7. 32 ( 14H, m )
The following compounds (Examples 4-1) to 4-5)) were obtained according to a similar manner to that of Example 3 .
Example 4
1) rac-N-(1,2-Diphenylethyl)-3-heptyloxycinnamamide mp : 104-105°C
IR (Nujol) : 3320, 1655, 1615, 1520, 1250, 970,
760, 700 cm"1 NMR (CDC13, δ) : 0.88 (3H, t, J=7Hz) ,
1.28-1.50 (8H, m), 1.70-1.82 (2H, m) , 3.19 (2H, d, J=7Hz), 3.93 (2H, t, J=7Hz), 5.40 (IH, q,
J=7Hz), 5.92 (IH, d, J=7Hz), 6.32 (IH, d, J=15Hz), 6.83-7.37 (14H, m) , 7.53 (IH, d, J=15Hz)
2) rac-N-(l,2-Diphenγlethγl)-4-octyloxyphenylacetamide mp : 146-147°C IR (Nujol) : 3300, 1640, 1605, 1505, 1300, 1240,
1175, 750, 700 cm"1 NMR (CDC13, δ) : 0.85 (3H, t, J=7Hz), 1.30-1.52 (10H, m) , 1.73-1.90 (2H, m) ,
2.80-3.08 (2H, m) , 3.46 (2H, s), 3.98 (2H, t, J=7Hz), 5.21 (IH, q, J=7Hz), 5.67 (IH, d, J=7Hz), 6.90-7.30 (14H, m)
3) rac-N-(l,2-Diphenγlethγl)-2-octyloxγphenylacetamide mp : 107-108°C
IR (Nujol) : 3300, 1640, 1530, 1240, 1110, 1040, 740, 700 cm"1
NMR (CDC13, δ) : 0.88 (3H, t, J=7Hz) , 1.12-1.45 (10H, m) , 1.65 (2H, t, J=7Hz), 2.83-3.05 (2H, m) , 3.45 (IH, d, J=15Hz), 3.63 (IH, d, J=15Hz), 3.88 (2H, t, J=7Hz),
5.21 (IH, q, J=7Hz), 6.12 (IH, d, J=7Hz), 6.75-7.37 (14H, m)
4) rac-N-(1,2-Diphenylethyl)-4-nonyloxybenzamide mp : 117-119°C
IR (Nujol) : 3340, 1625, 1605, 1530, 1500, 1305, 1240, 740, 700 cm'1 NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz),
1.07-1.48 (1QH, m) , 1.65-1.98 (4H, m) ,
3.22 (2H, d, J=7Hz), 3.97 (2H, t, J=7Hz), 5.45 (IH, q, J=7Hz), 6.32 (IH, d, J=7Hz), 6.85 (2H, d, J=8Hz), 7.07-7.35 (10H, m) , 7.63 (2H, d, J=8Hz)
5) rac-N-(1,2-Diphenylethyl)-4-decyloxγphenylacetamide mp : 136-138°C
IR (Nujol) : 3300, 1640, 1530, 1510, 1240, 1180, 750, 700 cm"1
NMR (CDC13, δ) : 0.87 (3H, t, J=7Hz) ,
1.20-1.53 (12H, m) , 1.72-1.97 (4H, m) , 2.80-3.08 (2H, m) , 3.45 (2H, s), 3.95 (2H, t, J=7Hz), 5.27 (IH, q, J=7Hz), 5.70 (IH, d, J=7Hz), 6.85-7.28 (14H, m)
Example 5
A mixture of rac-N-(1,2-diphenylethyl)-3-heptyloxy- cinnamamide (200 mg) and 10% palladium on carbon (30 mg) in methanol (30 ml) was hydrogenated at ambient temperature at 1 atmospheric pressure for 5 hours. The catalyst was filtered and washed with methanol. The filtrate was evaporated. The residue was recrystallized from ethanol to give rac-N-(1,2-diphenylethyl)-3-(3- heptyloxyphenyl)propionamide (74 mg) . mp : 94-96 °C
IR (Nujol) : 3320, 1640, 1600, 1530, 1250, 1170,
750, 700 cm'1 NMR (CDC13, δ): 0.89 (3H, t, J=7Hz) , 1.22-1.50 (8H, m), 1.68-1.81 (2H, m) , 2.40 (2H, t, J=7Hz),
2.90 (2H, t, J=7Hz), 3.02 (2H, d, J=7Hz), 3.90 (2H, t, J=7Hz), 5.26 (IH, q, J=7Hz) , 5.60 (IH, d, J=7Hz), 6.70-7.32 (14H, m)
The following compounds (Examples 6-1) to 6-12)) were obtained according to a similar manner to that of Example
5_.
Example 6 1) rac-N-(l,2-Diphenylethyl)-3-(2-heptyloxyphenyl)- propionamide mp : 93.5-94.5°C
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz) , 1.30 (8H, m) , 1.80 (2H, q, J=7Hz), 2.46 (2H, t, J=7Hz), 2.90 (2H, t, J=7Hz), 3.04 (2H, d, J=7Hz),
3.95 (2H, t, J=7Hz), 5.26 (IH, dt, J=9, 7Hz), 5.68 (IH, d, J=9Hz), 6.80-7.23 (14H, m)
2) rac-N-(1,2-Diphenylethyl)-3-(4-heptyloxyphenyl)- propionamide mp : 98-100°C
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz) , 1.30 (8H, m), 1.79 (2H, q, J=7Hz), 2.38 (2H, t, J=7Hz), 2.80 (2H, t, J=7Hz) , 3.05 (2H, d, J=7Hz), 3.90 (2H, t, J=7Hz),
5.27 (IH, dt, J=9, 7Hz), 5.60 (IH, d, J=9Hz), 6.77 (2H, d, J=9Hz), 6.94-7.10 (8H, m) , 7.13-7.25 (4H, m)
3) rac-N-(l,2-Diphenylethyl)-3-(4-decγloxyphenyl)- propionamide NMR (CDC13, δ) : 0.99 (3H, t, J=7Hz) , 1.30 (14H, m) ,
1.78 (2H, q, J=7Hz), 2.40 (2H, t, J=7Hz),
2.85 (2H, t, J=7Hz), 3.05 (2H, d, J=7Hz),
3.90 (2H, t, J=7Hz), 5.25 (IH, dt, J=9 , 7Hz), 5.60 (IH, d, J=9Hz), 6.80 (2H, d, J=9Hz),
6.95-7.30 (12H, m)
4) rac-N-(1,2-Diphenylethyl)-3-(2-decyloxγphenγl)- propionamide mp : 93-95°C
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.28 (14H, m) ,
1.77 (2H, q, J=7Hz), 2.48 (2H, t, J=7Hz) , 2.90 (2H, t, J=7Hz), 3.02 (2H, d, J=9Hz) , 3.93 (2H, t, J=7Hz), 5.35 (IH, dt, J=9, 7Hz) , 5.68 (IH, d, J=9Hz), 6.80-7.24 (14H, m)
5) rac-N-(1,2-Diphenγlethγl)-3-(2-butoxyphenyl)- propionamide mp : 129-130°C NMR (CDC13, δ) : 1.00 (3H, t, J=7Hz), 1.50 (2H, m) ,
1.78 (2H, q, J=7Hz), 2.48 (2H, t, J=7Hz), 2.90 (2H, t, J=7Hz), 3.04 (2H, d, J=7Hz), 3.96 (2H, t, J=7Hz), 5.25 (IH, dt, J=7, 9Hz), 5.59 (IH, d, J=9Hz), 6.79-6.88 (2H, m) , 6.91-6.98 (2H, m) , 7.05-7.25 (10H, m)
) rac-N-[2-(4-Methylphenyl)-1-phenγlethyl]-3-(4- heptyloxyphenyl)propionamide mp : 119-122°C NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz), 1.30 (8H, m) ,
1.78 (2H, q, J=7Hz), 2.30 (3H, s), 2.40 (2H, t, J=7Hz), 2.83 (2H, t, J=7Hz), 3.00 (2H, d, J=7Hz), 3.93 (2H, t, J=7Hz), 5.25 (IH, dt, J=9, 7Hz), 5.60 (IH, d, J=9Hz), 6.75-6.88 (4H, m) , 6.98-7.10 (6H, m) , 7.00-7.25 (3H, m) 7) rac-N-(1,2-Diphenylethyl)-3-(4-octyloxyphenyl)- propionamide mp : 79-81°C
NMR (CDC13, δ) : 0.90 (3H, t, J=7Hz) , 1.30 (10H, br s), 1.68-1.84 (2H, m) , 2.40 (2H, t, J=7Hz), 2.82
(2H, t, J=7Hz), 3.03 (2H, d, J=7Hz), 3.90 (2H, t, J=7Hz), 5.26 (IH, dt, J=9, 7Hz), 5.67 (IH, d, J=9Hz), 6.74-7.28 (14H, m)
8) rac-N-[2-(4-Methylphenyl)-l-phenylethγl]-3-(4- octyloxyphenyl)propionamide mp : 113-114.5°C
NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz), 1.30 (10H, br s), 1.70-1.83 (2H, m) , 2.92 (3H, s), 2.40 (2H, t, J=7Hz), 2.85 (2H, t, J=7Hz) , 2.99 (2H, d,
J=7Hz), 3.92 (2H, t, J=7Hz), 5.24 (IH, dt, J=9, 7Hz), 5.61 (IH, d, J=9Hz), 6.75-7.22 (13H, m)
9) rac-N-(1,2-Diphenylethyl)-3-(2-octyloxyphenγl)- propionamide mp : 77-79°C
NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz), 1.30 (10H, br s), 1.71-1.85 (2H, m), 2.48 (2H, t, J=7Hz) , 2.90 (2H, t, J=7Hz), 3.02 (2H, d, J=7Hz), 3.94 (2H, t, J=7Hz), 5.25 (IH, dt, \J=9, 7Hz), 5.72 (IH, d,
J=9Hz), 6.80-7.30 (14H, m)
0) rac-N-[2-(4-Methylphenyl)-1-phenylethyl]-3-(2- octyloxyphenyl)propionamide mp : 103.5-106°C
NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz) , 1.29 (10H, br s), 1.72-1.85 (2H, m) , 2.28 (3H, s), 2.46 (2H, t, J=7Hz), 2.90 (2H, t, J=7Hz), 2.98 (2H, d, J=7Hz), 3.95 (2H, t, J=7Hz), 5.23 (IH, dt, J=9, 7Hz), 5.68 (IH, d, J=9Hz) , 6.81-7.34 (11H, m) 11) rac-N-[2-(4-Methylphenyl)-1-phenylethyl]-3-(2- heptyloxyphenyl)propionamide mp : 67-68.5°C
NMR (CDC13, δ) : 0.89 (3H, t, J=7Hz), 1.31-1.47 (8H, m), 1.78 (2H, m) , 2.28 (3H, s), 2.46 (2H, t,
J=7Hz), 2.90 (2H, t, J=7Hz), 2.97 (2H, t, J=7Hz), 3.93 (2H, t, J=7Hz), 5.22 (IH, dt, J=7, 7Hz), 5.67 (IH, d, J=7Hz), 6.80-7.27 (13H, m)
12) rac-N-(l,2-Diphenγlethyl)-3-(4-undecylphenyl)- propionamide mp : 101-102°C
NMR (CDC13, δ) : 0.88 (3H, t, J=7Hz) , 1.25 (18H, br s), 2.44 (2H, t, J=7Hz), 2.58 (2H, t, J=7Hz), 2.87 (2H, t, J=7Hz), 3.05 (2H, d, J=7Hz), 5.26
(IH, dt, J=9, 7Hz), 5.60 (IH, d, J=9Hz), 6.93-7.25 (14H, m)

Claims

1. A compound of the formula :
Figure imgf000039_0001
wherein R is ar(lower)alkyl,
R is aryl.
R is alkyl or alkenyl,
A is a single bond, lower alkylene or lower alkenylene, and X is O, S or a single bond.
2. A compound according to claim 1,
3 wherein R is higher alkyl,
A is lower alkylene, and
X is O.
3. A compound according to claim 2 , wherein R is benzyl or tolylmethyl,
2 R is phenyl,
3 R is heptyl, octyl, nonyl, decyl, undecyl or dodecyl, and
A is methylene or ethylene.
4. A compound of claim 3, which is rac-N-(1,2-diphenylethyl)-2-octyloxyphenylacetamide.
5. A process for preparing a compound of the formula :
(I)
Figure imgf000039_0002
wherein R is ar(lower)alkyl,
R is aryl,
3 R is alkyl or alkenyl,
A is a single bond, lower alkylene or lower alkenylene , and
X is 0, S or a single bond, which comprises,
a) reacting a compound of the formula :
Figure imgf000040_0001
or its salt with a compound of the formula :
Figure imgf000040_0002
or its reactive derivative at the carboxy group to provide a compound of the formula :
Figure imgf000040_0003
in the above formulas, R 1, R2, R3, A and X are each as defined above, or
) subjecting a compound of the formula :
Figure imgf000040_0004
to reduction to provide a compound of the formula :
Figure imgf000041_0001
in the above formulas, R 1, R2, R3 and X are each as defined above, A 1 is lower alkenylene, and A2 is lower alkylene.
6. A pharmaceutical composition comprising a compound of claim 1, as an active ingredient, in association with a pharmaceutically acceptable, substantially non-toxic carrier or excipient.
7. A compound of claim 1 for use as a medicament.
8. A method for therapeutic treatment of hypercholesterolemia, hyperlipidemia, atherosclerosis or diseases caused thereby which comprises administering an effective amount of a compound of claim 1 to hu a'n beings or animals.
9. Use of a compound of claim 1 for the manufacture of a medicament for treating hypercholesterolemia, hyperlipidemia, atherosclerosis or diseases caused thereby.
PCT/JP1991/001556 1990-11-23 1991-11-14 New amide derivatives WO1992009561A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP3518018A JPH06504521A (en) 1990-11-23 1991-11-14 New amide derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9025509.2 1990-11-23
GB909025509A GB9025509D0 (en) 1990-11-23 1990-11-23 New amide derivatives,processes for the preparation thereof and pharmaceutical composition comprising the same

Publications (1)

Publication Number Publication Date
WO1992009561A1 true WO1992009561A1 (en) 1992-06-11

Family

ID=10685878

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1991/001556 WO1992009561A1 (en) 1990-11-23 1991-11-14 New amide derivatives

Country Status (3)

Country Link
JP (1) JPH06504521A (en)
GB (1) GB9025509D0 (en)
WO (1) WO1992009561A1 (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994019330A1 (en) * 1993-02-18 1994-09-01 Warner-Lambert Company Heterocyclic-substituted alkyl amide acat inhibitors
EP0716082A1 (en) * 1994-12-09 1996-06-12 Bayer Ag Oxy-phenyl-(phenyl)glycinolamides substituted with a heterocycle having antiatherosclerotic activity
WO2000072833A2 (en) * 1999-05-26 2000-12-07 Universität Heidelberg Pharmaceutical preparations for inhibiting sphingomyelinase
WO2003020315A1 (en) * 2001-08-28 2003-03-13 Sankyo Company, Limited Medicinal compositions containing angiotensin ii receptor antagonist
US6852708B2 (en) 1991-07-03 2005-02-08 Jagotec Ag Use of hyaluronic acid and forms to prevent the narrowing of the vascular walls
WO2006128056A2 (en) 2005-05-26 2006-11-30 Metabasis Therapeutics, Inc. Novel phosphinic acid-containing thyromimetics
WO2010093601A1 (en) 2009-02-10 2010-08-19 Metabasis Therapeutics, Inc. Novel sulfonic acid-containing thyromimetics, and methods for their use
US7923573B2 (en) 2004-10-27 2011-04-12 Daiichi Sankyo Company, Limited Benzene compound having 2 or more substituents
EP2428516A1 (en) 2003-11-19 2012-03-14 Metabasis Therapeutics, Inc. Novel phosphorus-containing thyromimetics

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUE033642T2 (en) * 2011-06-02 2017-12-28 Chinoin Zrt Novel processes for the preparation of prostaglandin amides

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3784577A (en) * 1971-10-26 1974-01-08 Sumitomo Chemical Co Fatty acid amide derivatives
US4603145A (en) * 1983-05-06 1986-07-29 American Cyanamid Company Antiatherosclerotic diphenyl alkanamides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3784577A (en) * 1971-10-26 1974-01-08 Sumitomo Chemical Co Fatty acid amide derivatives
US4603145A (en) * 1983-05-06 1986-07-29 American Cyanamid Company Antiatherosclerotic diphenyl alkanamides

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 105, no. 21, 24 November 1996, Columbus, Ohio, US; abstract no. 190968D, 'TRISUBSTITUTED 3-(4-TOLYL)-1,2,3,4-TETRAHYDROISOQUINOLINES AND THEIR SALTS' page 718 ; *
CHEMICAL ABSTRACTS, vol. 96, no. 9, 1 March 1982, Columbus, Ohio, US; abstract no. 68196F, 'STEREOCHEMICAL STUDIES.LII.CHIRAL AMIDES OF O-HYDROXY- AND O-METHOXY-SUBSTITUTED BENZOIC ACIDS' page 543 ; *
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY vol. 34, no. 3, 3 July 1989, pages 255 - 276; G.A.WHITE: 'SUBSTITUTED 2-METHYLBENZANILIDES AND STRUCTURALLY RELATED CARBOXAMIDES: INHIBITION OF COMPLEX II ACTIVITY IN MITOCHONDRIA FROM A WILD-TYPE STRAIN AND A CARBOXIN-RESISTANT MUTANT STRAIN OF USTILAGO MAIDIS' *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6852708B2 (en) 1991-07-03 2005-02-08 Jagotec Ag Use of hyaluronic acid and forms to prevent the narrowing of the vascular walls
WO1994019330A1 (en) * 1993-02-18 1994-09-01 Warner-Lambert Company Heterocyclic-substituted alkyl amide acat inhibitors
EP1203767A1 (en) * 1993-02-18 2002-05-08 Warner-Lambert Company Heterocyclic-substituted alkylamide acat inhibitors
EP0716082A1 (en) * 1994-12-09 1996-06-12 Bayer Ag Oxy-phenyl-(phenyl)glycinolamides substituted with a heterocycle having antiatherosclerotic activity
US5646162A (en) * 1994-12-09 1997-07-08 Bayer Aktiengesellschaft Oxy-phenyl-(phenyl)glycinolamides with heterocyclic substituents
WO2000072833A2 (en) * 1999-05-26 2000-12-07 Universität Heidelberg Pharmaceutical preparations for inhibiting sphingomyelinase
WO2000072833A3 (en) * 1999-05-26 2001-05-25 Univ Heidelberg Pharmaceutical preparations for inhibiting sphingomyelinase
WO2003020315A1 (en) * 2001-08-28 2003-03-13 Sankyo Company, Limited Medicinal compositions containing angiotensin ii receptor antagonist
EP2428516A1 (en) 2003-11-19 2012-03-14 Metabasis Therapeutics, Inc. Novel phosphorus-containing thyromimetics
US7923573B2 (en) 2004-10-27 2011-04-12 Daiichi Sankyo Company, Limited Benzene compound having 2 or more substituents
WO2006128056A2 (en) 2005-05-26 2006-11-30 Metabasis Therapeutics, Inc. Novel phosphinic acid-containing thyromimetics
WO2010093601A1 (en) 2009-02-10 2010-08-19 Metabasis Therapeutics, Inc. Novel sulfonic acid-containing thyromimetics, and methods for their use

Also Published As

Publication number Publication date
GB9025509D0 (en) 1991-01-09
JPH06504521A (en) 1994-05-26

Similar Documents

Publication Publication Date Title
EP0512570B1 (en) Urea derivatives, processes for the preparation thereof and pharmaceutical composition comprising the same
US5597926A (en) Retroviral protease inhibiting compounds
JP3569240B2 (en) Retrovirus inhibitory compounds
AU705439B2 (en) Matrix metalloprotease inhibitors
JP4456312B2 (en) Novel aminodicarboxylic acid derivatives having pharmaceutical properties
US8071618B2 (en) Caspase inhibitors and uses thereof
WO1994026738A1 (en) N'-heterocyclyl-n-benzofuranyl urea derivatives and their analogs as acat inhibitors
SK12892001A3 (en) N-cyanomethyl amides as protease inhibitors
JPH11139969A (en) Pharmaceutical composition
WO1996010559A1 (en) Urea derivatives and their use as acat-inhibitors
JPH0660144B2 (en) Cycloalkyl-substituted glutaramide antihypertensive agent
EP0686625A1 (en) Anthranilic acid derivative
JP2001508811A (en) Anthranilic acid derivatives as cGMP-phosphodiesterase inhibitors
WO1992009561A1 (en) New amide derivatives
US4935432A (en) Indolylpiperidine compounds, processes for the preparation thereof and pharmaceutical composition comprising the same
EP0854863B1 (en) Esters and amides as pla2 inhibitors
EP0419676B1 (en) Thionaphthalene derivatives, method of producing the same, and antiallergic agent containing the same
EP0185079B1 (en) N-substituted butyramide derivatives
EP0378991A1 (en) Certain pyrrolylphenyl-substituted hydroxamic acid derivatives
JPH09328469A (en) New substituted acetamide compound
JPH10195037A (en) Phenol derivative
US5149709A (en) Inhibitors of acyl-coenzyme A: cholesterol acyl transferase
WO2008080268A1 (en) Derivates of substituted tartaric aicd and usage for preparating beta secretase inhibitors
KR100292070B1 (en) Thiourea derivatives capable of inhibiting the growth of ras mutant and nontoxic salt thereof
JP2003533506A5 (en) N-substituted peptidyl nitriles as cysteine cathepsin inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU NL SE

122 Ep: pct application non-entry in european phase