JP2000290246A - Cycloalkyl derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having strongly inhibiting action on acyl- CoA: cholesterol acyltransferase and useful for therapeutic agents for hyperlipemia and arteriosclerosis, or the therapy and prophylaxis of arteriosclerosis-related diseases. SOLUTION: This new compound is a cycloalkyl compound expressed by formula I [wherein, Y1 and Y2 are each a (substituted) aryl or the like; Y3 is a (substituted) aryl or the like; (n) is 1 or 2] or its prodrug, or its pharmaceutically permissible salt, and is e.g. N-[2,2-bis)4-hydroxyphenyl)cyclopropyl]-N'-(2,6- diisopropylphenyl)urea. The compound of formula I is obtained by reacting a compound (e.g. 2,2-diphenylcyclopropanoic acid) of formula II (wherein, Y11 and Y21 are respectively Y1 and Y2 in which reactive groups are protected) with an azidation agent in the presence of a base to obtain a compound of formula III and then by reacting it with a compound of the formula Y31-NH2 (wherein, Y31 is Y3 in which reactive group is protected) in a solvent at a temperature preferably from room temperature to 120 deg.C and, at need, by the deprotection of the reaction product.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an acyl-CoA:
Cholesterol acyltransferase (ACAT)
A cycloalkyl derivative or a prodrug thereof or a pharmaceutically acceptable salt thereof which has an inhibitory effect and is useful as a therapeutic agent for hyperlipidemia and a therapeutic agent for arteriosclerosis (hereinafter, referred to as “
It may be abbreviated as the compound of the present invention. ) And their uses.

[0002]

2. Description of the Related Art Cerebrovascular disorders such as stroke, myocardial infarction and the like, which are the leading causes of death in developed countries, all develop arteriosclerosis as a basic disease. Epidemiological studies indicate that hypercholesterolemia is one of the risk factors for arteriosclerosis.Prevention and treatment of this disease are currently mainly antihyperlipidemic drugs that lower blood cholesterol. Is used, but there is no definitive effect. In recent years, it has been observed that macrophage-derived cells accumulate cholesterol esters as lipid droplets in cells in the lesions of arteriosclerosis and foam, indicating that they are deeply involved in the development of lesions (Arteriosclerosis
10,164-177, 1990). In addition, it has been reported that the ACAT activity of the blood vessel wall at the site of atherosclerotic lesion is high, and cholesterol ester is accumulated in the blood vessel wall (Bi).
ochem. Biophys. Acta 617, 458-471, 1980). Therefore, an inhibitor of ACAT, which is a cholesterol esterifying enzyme, can suppress the formation or progression of atherosclerotic lesions by suppressing foaming of macrophages and suppressing accumulation of cholesterol ester at the lesion site. . On the other hand, cholesterol in food is absorbed in free form in intestinal epithelial cells, then esterified by ACAT and released into the blood in the form of chylomicron. Thus, inhibitors of ACAT inhibit intestinal absorption of dietary cholesterol, and also inhibit reabsorption of cholesterol released into the intestinal tract, lowering blood cholesterol (J. Lipid. Research, 34, 279-). 294, 1993). Published Patent Gazette 1991 No. 181465, Published Patent Gazette 1991
No. 223254 and Published Patent Publication No.
Japanese Patent Publication No. 1993-32666 discloses a certain quinoline derivative having CAT inhibitory activity, a certain thienopyridine derivative having ACAT-inhibiting activity, and Japanese Patent Publication No. Although certain active naphthyridine derivatives are disclosed, they all differ in chemical structure from the compounds of the present invention.

[0003]

The object of the present invention is to provide an AC
An object of the present invention is to provide a compound having AT inhibitory activity and useful as a therapeutic drug for hyperlipidemia and a therapeutic drug for arteriosclerosis.

[0004]

Means for Solving the Problems The present inventors have intensively studied to solve the above-mentioned problems, and have obtained a cycloalkyl derivative represented by the following general formula (1), a prodrug thereof, or a pharmaceutically acceptable drug thereof. The present inventors have found that salts have a strong ACAT inhibitory action, and have completed the present invention. The compound of the present invention is a novel compound having a different structure from the known compounds disclosed above.

That is, the present invention provides: [1] General formula (1)

Embedded image(Where Y¹And Y²Are each independently cycloalkyl
Kill group, aryl group, heterocyclic group, substituted cycloalkyl
Represents a group, a substituted aryl group, or a substituted heterocyclic group. This
Where Y¹And Y²Is the same carbon on the cycloalkyl ring
The above may be substituted. Y³Is an alkyl group, alkenyl
Group, alkynyl group, cycloalkyl group, cycloalkenyl
Group, cycloalkylalkyl group, cycloalkenyl group
Alkyl group, aryl group, aralkyl group, heteroaryl
Alkyl group, heterocyclic group, substituted alkyl group, substituted alk
Nil group, substituted alkynyl group, substituted cycloalkyl group,
Substituted cycloalkenyl group, substituted cycloalkylalkyl
Group, substituted cycloalkenylalkyl group, substituted aryl
Group, substituted aralkyl group, substituted heteroarylalkyl
Represents a group or a substituted heterocyclic group. n represents 1 or 2
You. ) Or a cycloalkyl derivative represented by the formula
Lodrugs or their pharmaceutically acceptable salts. [2] Y¹, Y²And Y³1 to 3 are allies
Group, heterocyclic group, substituted aryl group, or substituted hetero group
The cycloalkyl derivative according to [1], which is a cyclic group or
Its prodrugs or their pharmaceutically acceptable
salt. [3] Y³Is an aryl group, a heterocyclic group, a substituted aryl
Or a substituted heterocyclic group [1] or [2]
Cycloalkyl derivatives or their prodrugs
Or a pharmaceutically acceptable salt thereof. [4] Y¹, Y²And Y³1 to 3 are replaced
A substituted cycloalkyl group, a substituted aryl group, or
A substituted heterocyclic group, wherein at least one of said substituents
One is the formula -M¹−EQ [M¹Is a bond, oxygen atom, sulfur
Yellow atom or formula -NR¹− (R¹Is a hydrogen atom or low
Represents a lower alkyl group. ) Wherein E contains an unsaturated bond
Divalent aliphatic hydrocarbons having 1 to 15 carbon atoms which may be
Represents a hydrogen atom or a phenylene group, and Q represents a hydrogen atom, water
Acid group, carboxyl group, lower alkoxycarbonyl group,
Benzyloxycarbonyl group, halogen atom, cyano
Group, benzyloxy group, lower alkoxy group, lower alk
Noyloxy group, lower alkylthio group, lower alkyls
Rufinyl group, lower alkylsulfonyl group, alkyl group
Substituted or unsubstituted benzenesulfonyloxy group, lower
Alkanoylamino group, lower alkoxycarbonylamido
Group, lower alkylsulfonamide group, phthalimide
Group, cycloalkyl group, cycloalkenyl group, aryl
Group, aralkyl group, heteroarylalkyl group, hetero
Ring group, substituted aryl group, substituted heterocyclic group, formula -NR^TwoR^Three
｛R^TwoAnd R^ThreeAre each independently a hydrogen atom, an alkyl
Group, alkenyl group, alkynyl group, di-lower alkylamido
置換 -substituted lower alkyl, lower alkoxy-substituted lower alkyl
Kill group, cycloalkyl group, lower alkoxycarbonyl
Group, heteroarylmethyl group, or aralkyl group
Represents or R ^TwoAnd R^ThreeAre connected to each other,
Together with a nitrogen atom to which^Four−
(R^FourIs a hydrogen atom, lower alkyl group, phenyl group, lower
Represents an alkoxycarbonyl group or a benzyl group. )
Or a ring which may contain one oxygen atom
Represents a saturated cyclic amino group having 4 to 8 carbon atoms.
You. ｝ Or the formula -C (= O) NR^TwoR^Three(R^Twoand
R^ThreeRepresents the above-mentioned meaning. ). In the group represented by
The cycloal according to any one of [1] to [3].
Kill derivatives or their prodrugs or their physicians
Pharmaceutically acceptable salts. [5] Y¹, Y²And Y³1 to 3 are replaced
And the cycloalkyl derivative according to [4],
As the body or its prodrugs or their medicaments
Acceptable salt. [6] Y¹And Y²Is a phenyl group substituted with
[5] The cycloalkyl derivative according to [5] or a cycloalkyl derivative thereof
Prodrugs or their pharmaceutically acceptable salts. [7] M¹Is an oxygen atom, any of [4] to [6]
Or the cycloalkyl derivative or its pro-
Drugs or their pharmaceutically acceptable salts. [8] Q is hydrogen atom, hydroxyl group, carboxyl group, lower
Alkoxycarbonyl group, benzyloxycarbonyl
Group, benzyloxy group, lower alkoxy group, lower alk
Noyloxy group, lower alkanoylamino group, heterocycle
Group, substituted heterocyclic group, or formula -NR^TwoR^ThreeIs
[4] The cycloalkyl according to any one of [7].
Derivatives or their prodrugs or their medicaments
Acceptable salts.

[9] E is alkylene having 1 to 4 carbon atoms, and Q
There are acceptable substituted or unsubstituted pyridyl group, 1,2,4-triazol-1-yl group or a cycloalkyl derivative or a prodrug thereof or a pharmaceutical which is formula -NR ² R ³ [8], Salt. [10] The cycloalkyl derivative or prodrug thereof or the pharmaceutically acceptable salt thereof according to any one of [4] to [6], wherein M ¹ is a bond. [11] Q is a hydrogen atom, a hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group, a benzyloxycarbonyl group, a benzyloxy group, a lower alkoxy group, a lower alkanoyloxy group, a lower alkanoylamino group, a heterocyclic group, a substituted heterocyclic group, Or a formula of —NR ² R ³ [1
[0] The cycloalkyl derivative or a prodrug thereof or a pharmaceutically acceptable salt thereof according to [1]. [12] The cycloalkyl derivative according to any one of [1] to [11], wherein Y ¹ and Y ² are both substituted on the same carbon on the cycloalkyl ring, or a prodrug thereof, or a medicament thereof. Acceptable salt. [13] any one of [1] to [12], wherein n is 1
Or a prodrug thereof or a pharmaceutically acceptable salt thereof. [14] A pharmaceutical comprising the cycloalkyl derivative according to any one of [1] to [13], a prodrug thereof, or a pharmaceutically acceptable salt thereof. [15] Inhibition of acyl CoA: cholesterol acyltransferase (ACAT) containing, as an active ingredient, the cycloalkyl derivative according to any one of [1] to [13], a prodrug thereof, or a pharmaceutically acceptable salt thereof. Agent. [16] A therapeutic agent for hyperlipidemia or arteriosclerosis, comprising, as an active ingredient, the cycloalkyl derivative according to any one of [1] to [13], a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION Various groups in the present invention will be described below. The following description includes the case where each group is a part of another substituent unless otherwise specified. As the alkyl group or the alkyl group portion of the substituted alkyl group,
For example, methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 3-pentyl, hexyl, 3-hexyl, heptyl, octyl, undecyl, dodecyl,
Straight-chain or branched carbon atoms having 1 to 20 carbon atoms such as hexadecyl, 2,2-dimethyldodecyl and 2-tetradodecyl
Alkyl groups. Examples of the alkenyl group or the alkenyl group moiety of the substituted alkenyl group include vinyl, allyl, 2-propenyl, 2-methyl-2-propenyl, 2-butenyl, 3-butenyl, and 3-methyl-2.
Linear or branched alkenyl groups having 2 to 15 carbon atoms such as -butenyl, 4-pentenyl, 3-hexenyl, 3-ethyl-2-pentenyl, 4-ethyl-3-hexenyl and the like. Examples of the alkynyl group or the alkynyl group part of the substituted alkynyl group include ethynyl,
2-propynyl, 3-butynyl, 4-pentynyl, 3-
A straight-chain or branched alkynyl group having 2 to 15 carbon atoms such as hexynyl, 5-methyl-2-hexynyl, 2-heptynyl and 6-methyl-4-heptynyl is exemplified. Examples of the cycloalkyl group or the cycloalkyl group portion of the substituted cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Cycloheptyl, cyclooctyl, cis-decalin-1
And cycloalkyl groups having 3 to 12 carbon atoms, such as -yl, cis-decalin-2-yl and trans-decalin-1-yl. Examples of the cycloalkylalkyl group or the cycloalkylalkyl group portion of the substituted cycloalkylalkyl group include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, 1-cyclopropylethyl, -Cyclopropylethyl, 1-cyclobutylethyl, 2-cyclobutylethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclohexylethyl, 1-cycloheptylethyl, 2-cycloheptylethyl, 1 And cycloalkylalkyl groups having 4 to 14 carbon atoms such as -cyclooctylethyl and 2-cyclooctylethyl.

Examples of the cycloalkenyl group or the cycloalkenyl group part of the substituted cycloalkenyl group include 1-cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3
3-1 carbon atoms such as cycloheptenyl, 4-cycloheptenyl, 1-cyclooctenyl, 2-cyclooctenyl, 3-cyclooctenyl and 4-cyclooctenyl;
Four cycloalkenyl groups are mentioned. Examples of the cycloalkenylalkyl group or the cycloalkenylalkyl group portion of the substituted cycloalkenylalkyl group include 1-cyclobutenylmethyl, 1-cyclopentenylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, 1-cyclohexenyl Methyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, 1-cycloheptenylmethyl, 2-cycloheptenylmethyl,
3-cycloheptenylmethyl, 4-cycloheptenylmethyl, 1-cyclooctenylmethyl, 2-cyclooctenylmethyl, 3-cyclooctenylmethyl, 4-cyclooctenylmethyl, 1- (1-cyclobutenyl) ethyl 2- (1-cyclobutenyl) ethyl, 1- (1-cyclopentenyl) ethyl, 2- (1-cyclopentenyl) ethyl, 1- (2-cyclopentenyl) ethyl,
-(2-cyclopentenyl) ethyl, 1- (3-cyclopentenyl) ethyl, 2- (3-cyclopentenyl) ethyl, 1- (1-cyclohexenyl) ethyl, 2- (1
-Cyclohexenyl) ethyl, 1- (2-cyclohexenyl) ethyl, 2- (2-cyclohexenyl) ethyl,
1- (3-cyclohexenyl) ethyl, 2- (3-cyclohexenyl) ethyl, 1- (1-cycloheptenyl)
Ethyl, 2- (1-cycloheptenyl) ethyl, 1-
(2-cycloheptenyl) ethyl, 2- (2-cycloheptenyl) ethyl, 1- (3-cycloheptenyl) ethyl, 2- (3-cycloheptenyl) ethyl, 1- (4-
Cycloheptenyl) ethyl, 2- (4-cycloheptenyl) ethyl, 1- (1-cyclooctenyl) ethyl, 2
-(1-cyclooctenyl) ethyl, 1- (2-cyclooctenyl) ethyl, 2- (2-cyclooctenyl) ethyl, 1- (3-cyclooctenyl) ethyl, 2- (3
And cycloalkenylalkyl groups having 4 to 14 carbon atoms such as -cyclooctenyl) ethyl, 1- (4-cyclooctenyl) ethyl, and 2- (4-cyclooctenyl) ethyl. Examples of the aryl group or the aryl group portion of the substituted aryl group include aryl groups having 10 or less carbon atoms, such as phenyl and naphthyl.

The aralkyl group or the aralkyl group part of the substituted aralkyl group includes, for example, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl,
-Phenylbutyl, 3-phenylbutyl, 2-phenylbutyl, 1-phenylbutyl, 1-naphthylmethyl, 2
-Naphthylmethyl, 2- (1-naphthyl) -ethyl, 2
-(2-naphthyl) -ethyl, 3- (1-naphthyl)-
Propyl, 2- (2-naphthyl) -propyl, 4- (1
And aralkyl groups having 14 or less carbon atoms such as -naphthyl) -butyl and 3- (2-naphthyl) -butyl. The heterocyclic group or the heterocyclic group portion of the substituted heterocyclic group is a heteroaryl group or a 5- to 6-membered member composed of 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms and carbon atoms. A ring unsaturated heterocyclic group or a saturated heterocyclic group is exemplified. Examples of the saturated heterocyclic group include 2-pyrrolidinyl, 2-piperidyl, 2-piperazinyl, 2-morpholinyl, 3-morpholinyl and the like. As the unsaturated heterocyclic group, 2-imidazolin-4-yl, 4,5
-Dihydrothiazol-2-yl, 3-pyrroline-2-
And the like. Examples of the heteroaryl group include a 5- to 6-membered ring group containing 1 to 4 nitrogen atoms, and a 5- to 6-membered ring containing 1 to 2 nitrogen atoms and one oxygen atom or one sulfur atom. Examples include a group, a 5- to 6-membered ring group containing one oxygen atom or one sulfur atom, or a group in which the above groups are condensed with each other or the above group and an aryl group are condensed. Specifically, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-imidazolyl, 1,2,4-triazole-
1-yl, tetrazolyl, 1-pyrazolyl, 2-pyrrolyl, 2-thiazolyl, 3-isothiazolyl, 2-oxazolyl, 3-isoxazolyl, 2-benzo [b] furyl, 2-benzo [b] thienyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 2-indolyl, 1H-indazol-3-yl, 8-purinyl, 2-quinazolinyl,
3-cinnolinyl, 1,8-naphthyridin-2-yl and the like.

Examples of the heteroarylalkyl group include a linear or branched alkyl group having 1 to 8 carbon atoms, a 5- to 6-membered ring group having 1 to 4 nitrogen atoms, and a nitrogen atom having 1 to 4 nitrogen atoms. A group in which a group such as a 5- to 6-membered ring containing two and one oxygen atom or one sulfur atom, and a 5- or 6-membered ring containing one oxygen atom or one sulfur atom are bonded. Can be Specifically, 2-pyridylmethyl, 1- (2-
Pyridyl) ethyl, 2- (2-pyridyl) ethyl, 3-
Pyridylmethyl, 1- (3-pyridyl) ethyl, 2-
(3-pyridyl) ethyl, 1- (3-pyridyl) propyl, 2- (3-pyridyl) propyl, 3- (3-pyridyl) propyl, 4-pyridylmethyl, 2-thienylmethyl, 3- (2-thienyl ) -2-Methylpropyl, 3-
Thienylmethyl, 4- (2-thienyl) -3-methylbutyl, 1- (2-furyl) ethyl, 2- (2-furyl)
Ethyl, 1- (2-furyl) pentyl, 2- (2-furyl) pentyl, 3- (2-furyl) pentyl, 4- (2
-Furyl) pentyl, 5- (2-furyl) pentyl, 3
-Furylmethyl, 5- (3-furyl) -3-methylpentyl, 2-imidazolylmethyl, 2- (1,2,4-triazol-1-yl) ethyl, tetrazolylmethyl,
3- (1-pyrazolyl) propyl, 3- (3-pyrazolyl) -propyl, 1-pyrrolylmethyl, 3- (1-pyrrolyl) -butyl, 2-pyrrolylmethyl, 2-thiazolylmethyl, 4- (2-thiazolyl) pentyl, 3-isothiazolylmethyl, 3- (2-oxazolyl) pentyl,
3-Isoxazolylmethyl and the like. Examples of the halogen atom include fluorine, chlorine, bromine and iodine atoms.

Substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, substituted cycloalkylalkyl, substituted cycloalkenylalkyl, substituted aryl, substituted aralkyl, substituted heteroarylalkyl Or the substituents in the substituted heterocyclic group may be the same or different
Or two or more, for example, a halogen atom,
Cyano group, trifluoromethyl group, nitro group, hydroxyl group,
Methylenedioxy group, alkyl group, alkenyl group, alkynyl group, lower alkoxy group, benzyloxy group, lower alkanoyloxy group, amino group, mono-lower alkylamino group, di-lower alkylamino group, carbamoyl group, lower alkylaminocarbonyl group Di-lower alkylaminocarbonyl group, carboxyl group, lower alkoxycarbonyl group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkanoylamino group, lower alkylsulfonamide group or formula -M ¹
—EQ [M ¹ represents a bond, an oxygen atom, a sulfur atom or a formula —NR ¹ — (R ¹ represents a hydrogen atom or a lower alkyl group), and E may contain an unsaturated bond. It represents a divalent aliphatic hydrocarbon group having 1 to 15 carbon atoms or a phenylene group, and Q represents a hydrogen atom, a hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group, a benzyloxycarbonyl group, a halogen atom, a cyano group, or a benzyl group. Oxy group, lower alkoxy group, lower alkanoyloxy group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, alkyl-substituted or unsubstituted benzenesulfonyloxy group, lower alkanoylamino group, lower alkoxycarbonylamino group, lower alkyl Sulfonamide group, phthalimide group, cycloalkyl group, cycloalkyl A kenyl group, an aryl group, an aralkyl group, a heteroarylalkyl group, a heterocyclic group, a substituted aryl group, a substituted heterocyclic group, a formula —NR ² R ³ ｛R ² and R ³ each independently represent a hydrogen atom, an alkyl group Represents an alkenyl group, an alkynyl group, a di-lower alkylamino-substituted lower alkyl group, a lower alkoxy group-substituted lower alkyl group, a cycloalkyl group, a lower alkoxycarbonyl group, a heteroarylmethyl group, or an aralkyl group, or R ² and R ³ are bonded to each other, together with the nitrogen atom to which they are attached, further -NR in the ring ⁴ - (R ⁴ is a hydrogen atom, a lower alkyl group, a phenyl group, a lower alkoxycarbonyl group or a benzyl group.) the A saturated cyclic amino group having from 4 to 8 carbon atoms constituting a ring, which may contain one or one oxygen atom; Represent. } Or the formula -C (= O) NR ² R ³ (R ² and R ³ represent the same meaning as above). ] The group shown by these is mentioned.

Examples of the divalent aliphatic hydrocarbon group having 1 to 15 carbon atoms which may contain an unsaturated bond include carbon atoms such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene. Number 1
To 6, preferably 1 to 4 alkylene chains, alkenylene chains such as propenylene and butenylene, and alkynylene chains such as ethinylene, propynylene and butynylene. The substituents of the substituted aryl group in Q may be the same or different, and may be one or more. For example, a halogen atom, a cyano group, a trifluoromethyl group, a nitro group, a hydroxyl group, a methylenedioxy group, an alkyl group , Alkenyl, alkynyl, lower alkoxy, benzyloxy, lower alkanoyloxy, amino, mono-lower alkylamino, di-lower alkylamino, carbamoyl, lower alkylaminocarbonyl, di-lower alkylaminocarbonyl Carboxyl group, lower alkoxycarbonyl group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkanoylamino group, and lower alkylsulfonamide group. The substituents of the substituted heterocyclic group for Q may be the same or different and may be one or more, and examples thereof include an alkyl group, an alkenyl group, an alkynyl group, a lower alkoxy group and a halogen atom.

The saturated cyclic amino group formed by NR ² R ³ includes, for example, 4-lower alkyl-1-piperazinyl,
-Phenyl-1-piperazinyl, 4-benzyl-1-piperazinyl and the like

Embedded image (R ⁴⁰ represents a hydrogen atom, a lower alkyl group, a phenyl group, a lower alkoxycarbonyl group, or a benzyl group.)
Or a monocyclic group such as 1-pyrrolidinyl, 1-piperidyl, 1-homopiperidyl, morpholino, or a bicyclic group such as 3-azabicyclo [3,2,2] nonane. Can be Examples of the phenylene group include o-phenylene, m-phenylene, and p-phenylene.
The lower in the present invention means that the alkyl portion of the group is a lower alkyl group. Examples of such a lower alkyl group include carbon atoms such as methyl, ethyl, propyl, 2-propyl, butyl, pentyl and hexyl. Examples thereof include a lower alkyl group having 1 to 6 numbers. Examples of the lower alkanoyl group include those in which the above lower alkyl group is bonded to a carbonyl group.

The "prodrug" includes one that is easily hydrolyzed in vivo to regenerate the cycloalkyl derivative of the formula (1). Examples of the compound include a compound that has become a group, a compound that has become an alkylthiocarbonyl group, and a compound that has become an alkylaminocarbonyl group. Further, for example, a compound having an amino group, a compound in which the amino group is substituted with an alkanoyl group to become an alkanoylamino group, a compound in which the amino group is substituted with an alkoxycarbonyl group to become an alkoxycarbonylamino group, and an acyloxymethylamino group. Or a compound that has become hydroxylamine. In addition, for example, in the case of a compound having a hydroxyl group, a compound in which the hydroxyl group has been substituted with the acyl group to form an acyloxy group, a compound in which a phosphoric ester has been formed, or a compound in which the hydroxyl group has become an acyloxymethyloxy group can be mentioned. Examples of the alkyl moiety of the group used for these prodrugs include the aforementioned alkyl groups, and the alkyl group may be substituted (for example, by an alkoxy group having 1 to 6 carbon atoms). Preferable examples include, for example, a compound in which a carboxyl group is an alkoxycarbonyl group, for example, lower (for example, having 1 to 6 carbon atoms) alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, methoxymethoxycarbonyl, ethoxymethoxycarbonyl, -Methoxyethoxycarbonyl,
Lower (for example, 1 to 6 carbon atoms) alkoxycarbonyl substituted by an alkoxy group such as 2-methoxyethoxymethoxycarbonyl and pivaloyloxymethoxycarbonyl is exemplified.

Preferred examples of Y ¹ and Y ² include a phenyl group and a pyridyl group which may have a substituent. The substituents may be the same or different and may be one or more. Preferred examples of the substituent include a halogen atom such as fluorine and chlorine, a cyano group, a trifluoromethyl group, a nitro group, a hydroxyl group, a methylenedioxy group. Group, lower alkyl group, lower alkoxy group,
Lower alkanoyloxy group, amino group, mono-lower alkylamino group, di-lower alkylamino group, carbamoyl group, lower alkylaminocarbonyl group, di-lower alkylaminocarbonyl group, carboxyl group, lower alkoxycarbonyl group, lower alkylthio group, lower alkyl Examples thereof include a sulfinyl group, a lower alkylsulfonyl group, a lower alkanoylamino group, a lower alkylsulfonamide group, and a group represented by the formula -M ¹ -EQ (M ¹ , E and Q have the same meanings as described above).

A preferred group for E is a carbon atom
A linear alkylene chain, alkenylene chain,
And a quinylene chain, more preferably a carbon atom number.
1-3 linear alkylene chains and alkynylene chains are mentioned.
Can be Preferred groups for Q include a hydroxyl group, a halo
Gen atom, cyano group, lower alkoxy group, lower alkano
Yloxy group, lower alkylthio group, lower alkyl sulf
Finyl group, lower alkylsulfonyl group, lower alkano
Ylamino group, lower alkylsulfonamide group, hetero
Ring group, formula -NR^TwoR^Three(R^Two, R^ThreeRepresents the above meaning)
The groups shown are mentioned. More preferably, 2-pyridyl
, 3-pyridyl, 2-methylpyridin-3-yl, 4
-Pyridyl, 1-imidazolyl, 1,2,4-triazo
Substituted or unsubstituted heteroaryl such as -1-yl
Or a group of formula -NR^TwoR^Three(R ^Two, R^ThreeHas the above meaning
Represents a group represented by: Formula -NR^TwoR
^Three(R^Two, R^ThreeRepresents the above-mentioned meaning)
As the group, for example, dimethylamino, diethylamino,
Diisopropylamino, 1-pyrrolidinyl, piperidi
No, morpholino, 4-methylpiperazin-1-yl and the like
No.

Further, preferred groups represented by -M ¹ -EQ include 2-pyridylmethoxy, 3-pyridylmethoxy, 4-pyridylmethoxy, (2-methylpyridin-3-yl) methoxy, (2,4-dimethylpyridine
-3-yl) methoxy, 2-hydroxyethoxy, 2-acetoxyethoxy, 2- (2-pyridyl) ethoxy,
-(3-pyridyl) ethoxy, 2- (4-pyridyl) ethoxy, 2- (diethylamino) ethoxy, 2- (dimethylamino) ethoxy, 2- (piperidino) ethoxy,
2- (1-pyrrolidinyl) ethoxy, 2- (morpholino) ethoxy, 2- (1,2,4-triazole-1-
Il) ethoxy, 3-hydroxypropoxy, 3-acetoxypropoxy, 3- (2-pyridyl) propoxy,
3- (3-pyridyl) propoxy, 3- (4-pyridyl) propoxy, 3- (diethylamino) propoxy,
3- (dimethylamino) propoxy, 3- (piperidino) propoxy, 3- (1-pyrrolidinyl) propoxy, 3- (morpholino) propoxy, 2- (1,2,4
-Triazol-1-yl) propoxy, 3-dimethylamino-1-propynyl, 3-diethylamino-1-propynyl, 3- (1-pyrrolidinyl) -1-propynyl, 3- (N-methyl-N- (3- Pyridylmethyl) amino) -1-propynyl, 2- (diethylamino) ethylthio, N-methyl-N- (3-pyridylmethyl) amino, 3- (diethylamino) propyl and the like.

Preferred examples of Y ³ include a phenyl group and a heteroaryl group which may have a substituent. More preferred groups include, for example, a halogen atom such as fluorine and chlorine, a lower alkyl group, a phenyl group or a pyridyl group substituted with 1 to 3 lower alkoxy groups or lower alkylthio groups, or a lower alkyl group having the formula -M ¹ -E -Q (M ^1, E and Q. representing the meaning of the) include phenyl group substituted by a group represented by. Preferred groups for E include a linear alkylene chain having 1 to 6 carbon atoms, an alkenylene chain,
An alkynylene chain is mentioned, and a linear alkylene chain having 1 to 3 carbon atoms and an alkynylene chain are more preferable. Preferred groups for Q include a hydroxyl group, a heteroaryl group, and a group represented by the formula —NR ² R ³ (R ² and R ³ represent the same meaning as described above). More preferably,
2-pyridyl, 3-pyridyl, 2-methylpyridine-3
-Yl, 4-pyridyl, 1-imidazolyl, 2-isopropyl-1-imidazolyl, 1-pyrazolyl, 1,2,2
Examples thereof include a substituted or unsubstituted heteroaryl group such as 4-triazol-1-yl or a group represented by the formula —NR ² R ³ (R ² and R ³ represent the same meaning as described above). Formula -N
Preferred groups represented by R ² R ³ (R ² and R ³ represent the above-mentioned meanings) include, for example, dimethylamino, diethylamino, diisopropylamino, 1-pyrrolidinyl, piperidino, morpholino, 4-methylpiperazin-1-yl And the like.

Specific examples of preferred groups for Y ³ include, for example, 2,6-diisopropylphenyl, 2,4,6-
Trimethylphenyl, 2,4,6-trimethoxyphenyl, 2,4-difluorophenyl, (3-amino-2,
6-diisopropyl) phenyl, (4-amino-2,6
-Diisopropyl) phenyl, (3-aminomethyl-
2,6-diisopropyl) phenyl, (4-aminomethyl-2,6-diisopropyl) phenyl, 2,4,6-
Trifluorophenyl, 2-tert-butyl-5-
(Morpholinomethyl) phenyl, 2-tert-butyl-5- (1-imidazolylmethyl) phenyl, 2-te
rt-butyl-5- (2-isopropyl-1-imidazolyl) phenyl, 2-isopropyl-5- (1-imidazolylmethyl) phenyl, 2-tert-butyl-5-
(1-pyrazolyl) phenyl, 2-tert-butyl-
5- {N-methyl-N- (2-pyridylmethyl) aminomethyl} phenyl, 2-tert-butyl-5- {N-
Methyl-N- (3-pyridylmethyl) aminomethyl} phenyl, 2-tert-butyl-5- {N-methyl-N
-(4-pyridylmethyl) aminomethyldiphenyl,
2,4-bis (methylthio) pyridin-3-yl, 2-
tert-butyl-5- {N-ethyl-N- (3-pyridylmethyl) aminomethyl} phenyl, 2,4-bis (methylthio) -6-methylpyridin-3-yl and the like.

Pharmaceutically acceptable salts formed by the cycloalkyl derivatives or prodrugs thereof of the present invention include acid addition salts such as hydrochloride, hydrobromide,
Inorganic acid salts such as hydroiodide, nitrate, sulfate, phosphate, and formate, acetate, oxalate, citrate, malate, tartrate, fumarate, maleate, Methanesulfonate, benzenesulfonate, p-
Organic acid salts such as toluenesulfonate and the like, and alkali addition salts include, for example, ammonium salt, lithium salt, potassium salt, sodium salt, calcium salt, magnesium salt and the like. The cycloalkyl derivative of the present invention or a prodrug thereof or a pharmaceutically acceptable salt thereof may have an asymmetric carbon atom and may have a stereoisomer. In such a case, the compound of the present invention includes a mixture of each isomer and an isolated one. The cycloalkyl derivative of the present invention or a prodrug thereof or a pharmaceutically acceptable salt thereof may be a solvate such as an anhydride or a hydrate thereof.

The cycloalkyl derivative of the present invention represented by the general formula (1), a prodrug thereof or a pharmaceutically acceptable salt thereof is used parenterally or orally when using it as the above-mentioned drug. Can be administered. That is, solutions in the form of solutions, emulsions, suspensions, and the like can be administered as injections, and buffers, solubilizing agents, isotonic agents, and the like can be added as necessary. It can also be administered rectally in the form of suppositories. Also,
It can be orally administered in the form of commonly used dosage forms such as tablets, capsules, syrups, suspensions and the like. Such a dosage form can be manufactured according to a general method by mixing an active ingredient with a usual carrier, excipient, binder, stabilizer and the like. The dose and frequency of administration of the compound of the present invention vary depending on symptoms, age, body weight, dosage form, and the like. However, in the case of oral administration, it is usually about 1 to 500 mg per adult per day.
It can be administered in four divided doses.

The cycloalkyl derivative or prodrug thereof or pharmaceutically acceptable salt thereof as an active ingredient of the present invention can be synthesized by the following method.

Embedded image (Wherein, Y ¹ , Y ² , Y ³ and n represent the above-mentioned meanings, and R ⁵ represents a lower alkyl group or a phenyl group.
Y ¹¹ , Y ^21, and Y ³¹ each represent the same groups as Y ¹ , Y ^2, and Y ³ , but have a reactive group such as an amino group, a lower alkylamino group, a hydroxyl group, or a carboxyl group as a substituent thereof. In such cases, these shall be protected. X represents a leaving group. The leaving group represented by X is usually a halogen atom such as chlorine, bromine or iodine or a sulfonyloxy group (for example, an alkylsulfonyloxy group such as methanesulfonyloxy group or an aromatic sulfonyloxy group such as p-toluenesulfonyloxy group). Group) is used.

The isocyanate derivative represented by the general formula (2) and the amine derivative represented by the general formula (3) or an acid addition salt thereof are usually placed in a solvent at a temperature from 0 ° C. to the boiling point of the solvent, preferably. The urea derivative represented by the general formula (4) can be suitably obtained by reacting at room temperature to 120 ° C. and performing deprotection if necessary. The solvent may be any solvent as long as it does not hinder the reaction, for example, diethyl ether, tetrahydrofuran, ether solvents such as dioxane, benzene, aromatic hydrocarbon solvents such as toluene,
Ester solvents such as methyl acetate and ethyl acetate; halogenated hydrocarbon solvents such as dichloromethane, chloroform and dichloroethane; ketone solvents such as acetone and methyl ethyl ketone; nitriles such as acetonitrile; N, N-dimethylformamide; N, N-dimethylacetamide And the like. When the amine derivative represented by the general formula (3) is used in the form of an acid addition salt, the reaction can be suitably advanced by desalting as necessary. In this case, a tertiary amine such as triethylamine or pyridine is suitable as a desalting agent.

On the other hand, even when the amine derivative represented by the general formula (5) or an acid addition salt thereof and the isocyanate derivative represented by the general formula (6) are used, the urea derivative (4) can be obtained in the same manner as described above. Can be. Furthermore, the amine derivative represented by the general formula (5) is added with the carbonate halide or the sulfonyloxy carbonate represented by the general formula (7) at -20 ° C.
After reacting at room temperature to give a carbamic acid ester,
Furthermore, the amine derivative represented by the general formula (3) and -20 ° C
It can also be obtained by reacting at a temperature up to the boiling point of the solvent, preferably at room temperature to 100 ° C., and deprotecting if necessary. As the carbonate halide represented by the general formula (7), for example, methyl carbonate chloride, ethyl carbonate chloride, isobutyl carbonate chloride, phenyl carbonate chloride and the like can be used. The reaction is usually performed in a solvent, and any solvent may be used as long as the reaction is not hindered. Ester solvents such as dichloromethane, chloroform, chloroform and the like, N, N-dimethylformamide, dimethyl sulfoxide and the like. The use of a base may accelerate the reaction. As the base, sodium carbonate, potassium carbonate, triethylamine, pyridine, N, N-dimethylaminopyridine and the like are used.

In a similar manner, the amine derivative represented by the general formula (3) is reacted with the carbonate halide represented by the general formula (7), and then the compound is represented by the general formula (5). Can also be obtained by reacting with an amine derivative. When the amine derivatives represented by the general formulas (3) and (5) are used in the form of an acid addition salt, the reaction can be suitably advanced by desalting as required. In this case, a tertiary amine such as triethylamine or pyridine is suitable as a desalting agent.

The substituents of Y ¹ , Y ² and Y ^{3 of the} urea derivative represented by the general formula (4) thus obtained can be converted if necessary. . For example, a lower alkylthio group can be converted to a lower alkylsulfonyl group by oxidation, a hydroxyl group can be alkylated to obtain an ether form, and a nitro group can be converted to an amino group by reduction. The mono or dialkyl compound can be obtained by alkylating the amino group, or the amino group can be acylated. Also, a 3-chloropropoxy group can be converted to a 3- (1-imidazolyl) propoxy group. Further, a halogen atom such as bromine or iodine can be converted to a 1-propargyl group having a hydroxyl group, an amino group and the like at the 3-position using a palladium catalyst. Furthermore,
The provalgyl group can be converted to a propyl group by a hydrogenation reaction. Such a substituent conversion reaction can be carried out by a general technique usually performed in the field of synthetic organic chemistry.

As one of such conversions of the substituent, an alkylation reaction represented by the following formula can be carried out.

Embedded image (Wherein, E, Y ² , Y ³ , Y ²¹ , Y ³¹ and n represent the above-mentioned meanings. M ² represents an oxygen atom, a sulfur atom or a formula —NR ¹ — (R ¹ represents the above-mentioned meanings. Q ¹ represents the same group as Q, but when it has a reactive group such as an amino group, an alkylamino group, a hydroxyl group, a carboxyl group, etc., these are protected. .
G represents a leaving group. The leaving group represented by G is usually a halogen atom such as chlorine, bromine or iodine or a sulfonyloxy group (for example, an alkylsulfonyloxy group such as methanesulfonyloxy group, or an aromatic sulfonyloxy group such as p-toluenesulfonyloxy group). Group) is used.

A compound represented by the general formula (8) is dissolved in a solvent,
The compound represented by the general formula (10) can be obtained by reacting with the alkylating agent represented by the general formula (9) and performing deprotection if necessary. The reaction is usually carried out in a solvent at a temperature from 0 ° C to the boiling point of the solvent, preferably from room temperature to 100 ° C.
C. in the presence of a base. As a solvent, an ether solvent such as tetrahydrofuran or dioxane, an aromatic hydrocarbon solvent such as benzene or toluene, a ketone solvent such as acetone or methyl ethyl ketone, or dimethylformamide can be used.As a base, sodium hydride, potassium carbonate, or carbonate can be used. Sodium, triethylamine, pyridine and the like can be used. Potassium carbonate,
When sodium carbonate is used, the yield may be improved by adding sodium iodide or potassium iodide.

The starting compound (2) or (5) for synthesizing the compound (1) of the present invention can be synthesized, for example, by the following method or a method analogous thereto.

Embedded image (Wherein, Y ¹¹ , Y ²¹ and n represent the above-mentioned meanings. R
⁶ represents a lower alkyl group. The starting compound represented by the general formula (11) can be prepared by a method described in the literature (for example, Tetrahedron Lett., 1996, 37 , 4073 and J. Chem. Soc., Chem. Commun., 1978, 18 , 786) or It can be synthesized by a method according to it. R ⁶
As the lower alkyl group represented by, methyl, ethyl,
1-4 carbon atoms such as propyl, isopropyl and butyl
Are suitable. By hydrolyzing the compound (11), a carboxylic acid derivative represented by the general formula (12) can be obtained. The hydrolysis reaction can be performed according to a known method. For example, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, and dimethoxyethane, at 0 ° C to 150 ° C, preferably at 0 ° C to 100 ° C, sodium hydroxide, potassium hydroxide, or an alkali such as barium hydroxide. It can be performed using an alkaline earth metal hydroxide. The carboxylic acid derivative represented by the general formula (12) can be led to the isocyanate derivative represented by the general formula (2) according to a known method. It can lead to the amine derivatives represented. For example, a carboxylic acid derivative (12) is prepared in the presence of a base such as triethylamine or N-methylmorpholine in a solvent at 0 to 120 ° C, preferably at room temperature to 80 ° C.
5 molar equivalents of diphenylphosphoryl azide (DPPA)
The azide compound is prepared by using an azidating agent such as the above, and then the reaction solution is directly heated to 0 to 150 ° C., preferably 30 to 100 ° C. without isolating the usually formed acid azide compound to give the compound (2) ) Can be obtained. Further, the compound (5) can be obtained by hydrolyzing the compound (2) in the same manner as in the hydrolysis of the compound (11).

The isocyanate derivative represented by the general formula (2) and the amine derivative represented by the general formula (5) can be further synthesized from an amide derivative represented by the general formula (13).

Embedded image (Wherein, Y ¹¹ , Y ²¹ and n represent the above-mentioned meanings. R
⁷ represents a lower alkyl group. The amide derivative (13) is obtained by reacting the ester derivative (11) with formamide in a solvent at room temperature to 100 ° C. using ammonium chloride, sodium methoxide, sodium ethoxide, sodium amide or the like as a catalyst if necessary. By doing so, it can be suitably obtained. The solvent may be any solvent as long as it does not hinder the reaction, for example,
Ether solvents such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbon solvents such as benzene and toluene, and amides such as N, N-dimethylformamide and N, N-dimethylacetamide are used. The amide derivative (13) is prepared by converting the ester derivative (11) in the presence or absence of a solvent and, if necessary, under pressure using an autoclave or the like at 0 ° C to 120 ° C, preferably at room temperature to 60 ° C. And treatment with excess liquid ammonia. As a solvent, methanol is generally used. Further, the derivative (13) can be further synthesized from a carboxylic acid derivative (12). Once the carboxylic acid derivative is once introduced into acid chloride or acid bromide, it is mixed with liquid ammonia or concentrated aqueous ammonia in a solvent at -10 ° C to 100 ° C, preferably 0 ° C.
The amide derivative represented by the general formula (13) can be obtained by reacting at a temperature of from 30 ° C to 30 ° C. The solvent may be any solvent as long as it does not hinder the reaction, for example, ether solvents such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbon solvents such as benzene and toluene, dichloromethane, chloroform, halogenated hydrocarbon solvents such as dichloroethane, N And amides such as N, N-dimethylformamide and N, N-dimethylacetamide.

The amide derivative (13) is dissolved in N, N-dimethylformamide at 0 ° C to 100 ° C, preferably at room temperature to 6 ° C.
The isocyanate derivative (2) can be obtained by reacting with lead tetraacetate at 0 ° C. Further, the amide derivative (13) can be converted to an amine derivative (5) by performing a Hofmann reaction.
The Hofmann reaction is carried out in a solvent at 0 ° C to 100 ° C,
The reaction can be carried out preferably at room temperature to 50 ° C. by reacting with 1 to 5 molar equivalents, preferably 1 to 1.5 molar equivalents of hypochlorite or hypobromite. As the hypochlorite or hypobromite, sodium hypobromite is usually used. The solvent may be any solvent as long as it does not hinder the reaction, for example, diethyl ether,
Ether solvents such as tetrahydrofuran and dioxane; aromatic hydrocarbon solvents such as benzene and toluene; halogenated hydrocarbon solvents such as dichloromethane, chloroform and dichloroethane; N, N-dimethylformamide;
Amides such as dimethylacetamide are used.

The compound of the present invention and its synthetic intermediate obtained by this synthesis method can be purified by a usual method. For example, it can be purified by column chromatography, recrystallization and the like. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether and tetrahydrofuran, ester solvents such as ethyl acetate, aromatic solvents such as toluene,
It can be appropriately selected from ketones such as acetone, hydrocarbons such as hexane, or a mixed solvent thereof depending on the compound.

In the above production, a hydroxyl group active in the reaction,
As a protecting group for protecting an amino group, a carboxyl group, or the like, a normal protecting group used in the field of synthetic organic chemistry may be used, and such a protecting group can be introduced and removed according to a usual method ( For example, Protective G
roups in Organic Synthesis, JOHN WILLEY & SONS, 199
1 year). For example, a protecting group for a hydroxyl group includes a methoxymethyl group and a tetrahydropyranyl group, and a protecting group for an amino group includes a tert-butyloxycarbonyl group. Such a hydroxyl-protecting group can be removed, for example, by reacting in a solvent such as hydrated methanol, hydrated ethanol, or hydrated tetrahydrofuran in the presence of an acid such as hydrochloric acid, sulfuric acid, or acetic acid. The group can be removed by, for example, reacting in a solvent such as aqueous tetrahydrofuran, methylene chloride, chloroform, or aqueous methanol in the presence of an acid such as hydrochloric acid or trifluoroacetic acid. As a form of protection when protecting a carboxyl group, for example, tert-
Butyl esters, orthoesters, acid amides and the like. In the case of tert-butyl ester, such a protective group is removed, for example, by reacting in the presence of hydrochloric acid in a water-containing solvent. In the case of an ortho ester, for example, water-containing methanol, water-containing tetrahydrofuran, water-containing 1 Treated with an acid in a solvent such as 2,2-dimethoxyethane,
Subsequently, the treatment is performed by treatment with an alkali such as sodium hydroxide. In the case of an acid amide, for example, hydrochloric acid,
The reaction can be carried out in a solvent such as water, hydrated methanol, or hydrated tetrahydrofuran in the presence of an acid such as sulfuric acid.

[0033]

The present invention will be described in more detail with reference to the following Reference Examples and Examples, which should not be construed as limiting the invention. Reference Example 1 Synthesis of 2,2-bis (4-methoxyphenyl) cyclopropanoic acid

Embedded image

Ethyl 2,2-bis (4-methoxyphenyl) cyclopropanate (18.6 g, 0.057 mol) in ethanol (80 ml) was mixed with water (20 ml) and sodium hydroxide (4.56 g, 0.114 mol). The mixture was stirred for 2 hours under reflux with heating. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate and water. The solution was acidified using 2N hydrochloric acid, then separated, and the organic layer was dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the precipitated solid was crystallized from ethyl acetate and hexane. The crystals were collected by filtration and dried to give the title compound (12.8 g, yield 75%) as pale yellow-white crystals. ¹ H-NMR (CDCl ₃ , 270 MHz) δ; 1.66 (m, 1H), 2.04 (t, 1H), 2.42 (dd, 1H), 3.74
(s, 3H), 3.76 (s, 3H), 6.75-6.81 (m, 4H), 7.15 (d, 2
H), 7.22 (d, 2H)

Example 1 Synthesis of N- {2,2-bis (4-methoxyphenyl) cyclopropyl} -N '-(2,6-diisopropylphenyl) urea

Embedded image 2,2-bis (4-methoxyphenyl) cyclopropanoic acid (8.95 g, 0.030 mol) in DMF (dimethylformamide)
To a solution (50 ml) was added DPPA (diphenylphosphoryl azide; 9.70 ml, 0.045 mol) and triethylamine (6.27 m
l, 0.045 mol) at room temperature for 20 minutes at 50 ° C.
Stirred for hours. At 85 ° C, this reaction solution was added dropwise to a solution of 2,6-diisopropylaniline (8.49 ml, 0.045 mol) in DMF (dimethylformamide) (30 ml), and the solution was added at the same temperature.
Stir for 7 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, and the organic layer was dried over sodium sulfate.
After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (silica gel; 250 g, ethyl acetate: hexane = 1: 5, 1: 3, chloroform: methanol = 9: 1) to give an oily substance. The title compound was obtained. The oily title compound was crystallized from ethyl acetate and hexane, and the crystals were collected by filtration and dried to give the title compound (9.21 g, yield 65%) as white crystals. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 0.95-1.25 (brm, 12H), 1.37-1.50 (brm, 2H), 2.90-
3.15 (brm, 3H), 3.66 (s, 3H), 3.72 (s, 3H), 6.17 (s, 1
H), 6.78 (d, 2H), 6.83 (d, 2H), 7.07-7.30 (m, 8H)

Example 2 Synthesis of N- {2,2-bis (4-hydroxyphenyl) cyclopropyl} -N '-(2,6-diisopropylphenyl) urea

Embedded image N- {2,2-bis (4-methoxyphenyl) cyclopropyl} -N '-(2,6-diisopropylphenyl) urea (8.00 g, 0.017 mol) in methylene chloride (80 m
A methylene chloride solution (30 ml) of BBr ₃ (boron tribromide; 8.00 ml, 0.085 mol) was added dropwise to l) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. After the completion of the reaction, the reaction solution was poured into a mixed solvent of ethyl acetate and water, washed with water, and the organic layer was dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (silica gel; 500 g, ethyl acetate: hexane = 2: 1, 1: 1, 2: 3) to obtain the title compound as an oil. The oily title compound was crystallized from ethyl acetate and hexane, and the crystals were collected by filtration and dried to give the title compound (6.36 g, yield 85%) as white crystals. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 0.99-1.41 (m, 14H), 3.00-3.12 (brm, 3H), 6.10 (s,
1H), 6.59 (d, 2H), 6.67 (d, 1H), 7.05-7.21 (m, 8H),
9.13 (s, 1H), 9.22 (s, 1H)

Example 3 N- [2,2-bis {4- (3-
Pyridylmethoxy) phenyl {cyclopropyl] -N '
Synthesis of-(2,6-diisopropylphenyl) urea

Embedded image N- {2,2-bis (4-hydroxyphenyl) cyclopropyl} -N '-(2,6-diisopropylphenyl)
To a DMF solution (10 ml) of urea (445 mg, 1.0 mmol) was added potassium carbonate (829 mg, 6.0 mmol) and potassium iodide (50 mg,
0.3 mmol), 3-chloromethylpyridine hydrochloride (492 mg,
3.0 mmol) and stirred at 95 ° C. for 4 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with water, and the organic layer was dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (silica gel; 10%).
0 g, chloroform: methanol = 30: 1, 20: 1, 15: 1)
The title compound (129 mg, yield: 21%) was obtained as a pale yellow amorphous. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 0.95-1.38 (m, 12H), 1.35-1.48 (m, 2H), 2.85-3.19
(m, 3H), 5.06 (s, 2H), 5.11 (d, 2H), 6.21 (s, 1H), 6.8
7-6.94 (m, 4H), 7.09-7.31 (m, 8H), 7.38-7.44 (m, 2H),
7.79-7.86 (m, 2H), 8.50-8.54 (m, 2H), 8.62 (d, 1H),
8.65 (d, 1H)

Example 4 N- [2,2-bis {4- (3-
Pyridylmethoxy) phenyl {cyclopropyl] -N '
Synthesis of-(2,6-diisopropylphenyl) urea hydrochloride

Embedded image A solution of N- [2,2-bis {4- (3-pyridylmethoxy) phenyl} cyclopropyl] -N '-(2,6-diisopropylphenyl) urea (129 mg, 0.206 mmol) in THF (tetrahydrofuran) (5.0 ml), a 1N hydrochloric acid ether solution (0.515 ml) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, an excess amount of ether was added to the reaction solution, and the precipitated crystals were collected by filtration and dried to give the title compound (99 mg, yield 87%) as white crystals. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 0.93-1.35 (m, 12H), 1.38-1.49 (brm, 2H), 2.85-3.
20 (brm, 3H), 5.24 (s, 2H), 5.27 (d, 2H), 6.90-6.97
(m, 4H), 7.02-7.34 (m, 8H), 7.93 (d, 1H), 7.95 (d, 1
H), 8.45 (d, 2H), 8.81 (d, 1H), 8.82 (d, 1H), 8.90 (s,
1H), 8.93 (s, 1H)

Example 5 N- [2,2-bis [4- {3-
Synthesis of (1-piperidyl) propoxydiphenyl] cyclopropyl] -N '-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 3, N- {2,2-bis (4-hydroxyphenyl) cyclopropyl} -N ′-(2,6-
The title compound was synthesized from diisopropylphenyl) urea and 1- (3-chloropropyl) piperidine hydrochloride. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 0.95-1.52 (brm, 26H), 1.78-1.92 (brm, 4H), 2.27-
2.52 (brm, 8H), 2.85-3.23 (brm, 3H), 3.30-3.45 (brm,
4H), 3.87-3.98 (m, 4H), 6.18 (s, 1H), 6.75-6.83 (m, 4
H), 7.07-7.28 (m, 8H)

Example 6 N- [2,2-bis [4- {3-
Synthesis of (1-piperidyl) propoxydiphenyl] cyclopropyl] -N '-(2,6-diisopropylphenyl) urea hydrochloride

Embedded image In the same manner as in Example 4, N- [2,2-bis [4- {3-
(1-Piperidyl) propoxydiphenyl] cyclopropyl] -N '-(2,6-diisopropylphenyl) urea hydrochloride was synthesized. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 1.00-1.20 (brm, 12H), 1.25-1.50 (m, 4H), 1.70-1.
80 (m, 12H), 2.10-2.22 (m, 4H), 2.72-3.13 (m, 10H),
3.56-3.61 (m, 2H), 3.94-3.99 (m, 4H), 6.33 (s, 1H),
6.78-6.84 (m, 4H), 7.07-7.30 (m, 8H), 10.20 (brs, 1H)

Example 7 N- [2,2-bis {4- (2-
Diethylaminoethoxy) phenyl @ cyclopropyl]
Synthesis of -N '-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 3, N- {2,2-bis (4-hydroxyphenyl) cyclopropyl} -N ′-(2,6-
The title compound was synthesized from diisopropylphenyl) urea and N, N-diethylaminoethyl chloride hydrochloride. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 0.94 (q, 12H), 0.90-1.30 (m, 12H), 1.32-1.46 (br
m, 2H), 2.70 (t, 2H), 2.75 (t, 2H), 2.90-3.17 (brm, 3
H), 3.88-3.99 (m, 4H), 6.18 (brs, 1H), 6.75-6.83 (m,
4H), 7.07-7.28 (m, 8H)

Example 8 N- [2,2-bis {4- (2-
Diethylaminoethoxy) phenyl @ cyclopropyl]
Synthesis of -N '-(2,6-diisopropylphenyl) urea hydrochloride

Embedded image In the same manner as in Example 4, N- [2,2-bis {4- (2-
Diethylaminoethoxy) phenyl｝ cyclopropyl]
The hydrochloride salt of -N '-(2,6-diisopropylphenyl) urea was synthesized. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 1.00-1.27 (m, 24H), 1.38-1.50 (m, 2H), 1.75 (t, 2
H), 3.00-3.27 (brm, 8H), 3.59 (t, 2H), 4.22-4.48 (m,
4H), 6.38 (s, 1H), 6.84-6.90 (m, 4H), 7.07-7.35 (m, 8
H), 10.20 (brs, 1H), 10.51 (brs, 1H)

Example 9 N- [2,2-bis [4- {3-
Synthesis of (benzyloxy) propoxydiphenyl] cyclopropyl] -N '-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 3, N- {2,2-bis (4-hydroxyphenyl) cyclopropyl} -N ′-(2,6-
The title compound was synthesized from diisopropylphenyl) urea and benzyl 3-bromopropyl ether. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 0.95-1.25 (m, 12H), 1.33-1.45 (brm, 2H), 1.88-2.
00 (m, 4H), 2.85-3.25 (brm, 3H), 3.53 (t, 2H), 3.57
(t, 2H), 3.96 (t, 2H), 4.02 (t, 2H), 4.44 (s, 2H), 4.
46 (s, 2H), 6.17 (s, 1H), 6.75-6.83 (m, 4H), 7.06-7.3
1 (m, 18H)

Example 10 N- [2,2-bis [4- {3
-(Hydroxy) propoxydiphenyl] cyclopropyl] -N '-(2,6-diisopropylphenyl) urea

Embedded image N- [2,2-bis [4- {3- (benzyloxy) propoxy} phenyl] cyclopropyl] -N '-(2,6
−Diisopropylphenyl) urea (370 mg, O.50 mmo
10% palladium-carbon (50% wet, 185 mg) was added to a methanol solution (10 ml) of l), and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel; 30 g, hexane: ethyl acetate: methanol = 10: 10: 1) to give the title compound (162 mg, yield 58%) as a white amorphous. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 1.00-1.26 (m, 14H), 1.78-1.84 (m, 4H), 3.08-3.15
(m, 3H), 4.48-3.54 (m, 4H), 3.92-3.98 (m, 4H), 4.51
(t, 2H), 6.76-6.84 (m, 5H), 7.12-7.23 (m, 7H), 7.44
(s, 1H)

Reference Example 2 Synthesis of 2,2-diphenylcyclopropanoic acid

Embedded image In the same manner as in Reference Example 1, the title compound was synthesized from ethyl 2,2-diphenylcyclopropanate. ¹ H-NMR (CDCl ₃ , 300 MHz) δ; 1.65 (dd, 1H), 2.10 (dd, 1H), 2.48 (dd, 1H), 7.16
-7.35 (m, 10H)

Example 11 Synthesis of N- (2,2-diphenylcyclopropyl) -N '-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 1, the title compound was synthesized from 2,2-diphenylcyclopropanoic acid and 2,6-diisopropylaniline. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 0.90-1.22 (brm, 12H), 1.49-1.58 (m, 2H), 2.90-3.
10 (m, 2H), 3.20-3.24 (m, 1H), 6.26 (s, 1H), 7.07-7.4
3 (m, 13H)

Reference Example 3 Synthesis of 2,2-bis (4-fluorophenyl) cyclopropanoic acid

Embedded image In the same manner as in Reference Example 1, the title compound was synthesized from ethyl 2,2-bis (4-fluorophenyl) cyclopropanate. ¹ H-NMR (CDCl ₃ , 300 MHz) δ; 1.62 (dd, 1H), 2.08 (dd, 1H), 2.46 (dd, 1H), 6.81
-6.98 (m, 4H), 7.18-7.30 (m, 4H)

Example 12 N- {2,2-bis (4-fluorophenyl) cyclopropyl} -N '-(2,6-
Synthesis of diisopropylphenyl) urea

Embedded image In the same manner as in Example 1, the title compound was synthesized from 2,2-bis (4-fluorophenyl) cyclopropanoic acid and 2,6-diisopropylaniline. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 0.90-1.30 (m, 12H), 1.49-1.58 (m, 2H), 2.80-3.20
(brm, 3H), 6.33 (brs, 1H), 7.04-7.12 (m, 6H), 7.18
(t, 2H), 7.34-7.42 (m, 4H)

Reference Example 4 Synthesis of 2,2-bis (4-chlorophenyl) cyclopropanoic acid

Embedded image In the same manner as in Reference Example 1, the title compound was synthesized from ethyl 2,2-bis (4-chlorophenyl) cyclopropanate. ¹ H-NMR (CDCl ₃ , 300 MHz) δ; 1.62 (dd, 1H), 2.09 (dd, 1H), 2.48 (dd, 1H), 7.07
-7.26 (m, 8H)

Example 13 Synthesis of N- {2,2-bis (4-chlorophenyl) cyclopropyl} -N '-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 1, the title compound was synthesized from 2,2-bis (4-chlorophenyl) cyclopropanoic acid and 2,6-diisopropylaniline. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 0.85-1.30 (m, 12H), 1.50-1.64 (m, 2H), 2.70-2.88
(brm, 1H), 2.90-3.16 (brm, 1H), 3.18-3.23 (brm, 1H),
6.36 (brs, 1H), 7.05-7.37 (m, 12H)

Reference Example 5 Synthesis of 2,2-bis (4-methylphenyl) cyclopropanoic acid

Embedded image In the same manner as in Reference Example 1, the title compound was synthesized from ethyl 2,2-bis (4-methylphenyl) cyclopropanate. ¹ H-NMR (CDCl ₃ , 270 MHz) δ; 1.62 (dd, 1H), 2.04-2.09 (m, 1H), 2.27 (s, 3H),
2.28 (s, 3H), 2.46 (dd, 1H), 7.02-7.25 (m, 8H)

Example 14 Synthesis of N- {2,2-bis (4-methylphenyl) cyclopropyl} -N ′-(2,6-diisopropylphenyl) urea

Embedded image In the same manner as in Example 1, the title compound was synthesized from 2,2-bis (4-methylphenyl) cyclopropanoic acid and 2,6-diisopropylaniline. ¹ H-NMR (CDCl ₃ , 300 MHz) δ; 0.98-2.20 (m, 12H), 1.40-1.48 (m, 2H), 2.20 (s, 3
H), 2.27 (s, 3H), 2.95-3.09 (m, 1H), 3.13-3.19 (m, 1
H), 6.17 (brs, 1H), 7.00-7.28 (m, 12H)

Example 15 Synthesis of N- {2,2-bis (4-methoxyphenyl) cyclopropyl} -N ′-{2,4-bis (methylthio) -6-methylpyridin-3-yl} urea

Embedded image In the same manner as in Example 1, the title compound was synthesized from 2,2-bis (4-methoxyphenyl) cyclopropanoic acid and 3-amino-2,4-bis (methylthio) -6-methylpyridine. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 1.33-1.37 (m, 1H), 1.44-1.49 (m, 1H), 2.38 (s, 6
H), 2.43 (s, 3H), 3.06-3.12 (m, 1H), 3.66-3.71 (m, 6
H), 6.20 (brs, 1H), 6.75-6.84 (m, 5H), 7.18-7.31 (m,
5H)

Example 16 N- {2,2-bis (4-methoxyphenyl) cyclopropyl} -N '-{2,4-bis (methylthio) -6-methylpyridin-3-yl} urea hydrochloride Synthesis

Embedded image In the same manner as in Example 4, N- {2,2-bis (4-methoxyphenyl) cyclopropyl} -N ′-{2,4-bis (methylthio) -6-methylpyridin-3-yl} urea The hydrochloride was synthesized. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 1.36 (t, 1H), 1.43-1.47 (m, 1H), 2.40 (s, 3H), 2.
43 (s, 3H), 2.46 (s, 3H), 3.06-3.13 (m, 1H), 3.66 (m,
3H), 3.70 (s, 3H), 6.30 (brs, 1H), 6.77 (d, 1H), 6.82
(d, 1H), 6.92 (s, 1H), 7.20 (d, 1H), 7.29 (d, 1H), 7.
42 (s, 1H)

Example 17 N- (2,2-diphenylcyclopropyl) -N '-{2,4-bis (methylthio)
Synthesis of -6-methylpyridin-3-yldiurea

Embedded image As in Example 1, 2,2-diphenylcyclopropanoic acid and 3-amino-2,4-bis (methylthio) -6
-The title compound was synthesized from -methylpyridine. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 1.46 (t, 1H), 1.56 (t, 1H), 2.33 (s, 6H), 2.43 (s,
3H), 3.14-3.21 (m, 1H), 6.84 (s, 1H), 7.08-7.45 (m,
11H)

Example 18 N- (2,2-diphenylcyclopropyl) -N '-{2,4-bis (methylthio)
Synthesis of -6-methylpyridin-3-yl diurea hydrochloride

Embedded image In the same manner as in Example 4, N- (2,2-diphenylcyclopropyl) -N ′-{2,4-bis (methylthio)-
6-Methylpyridin-3-yl diurea hydrochloride was synthesized. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 1.46 (t, 1H), 1.59 (t, 1H), 2.38 (s, 6H), 2.43 (s,
3H), 3.14-3.21 (m, 1H), 6.32 (brs, 1H), 6.84 (s, 1
H), 7.10-7.45 (m, 12H)

Example 19 N- {2,2-bis (4-fluorophenyl) cyclopropyl} -N '-{2,4-
Bis (methylthio) -6-methylpyridin-3-yl
Urea Synthesis

Embedded image In the same manner as in Example 1, the title compound was synthesized from 2,2-bis (4-fluorophenyl) cyclopropanoic acid and 3-amino-2,4-bis (methylthio) -6-methylpyridine. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 1.43-1.55 (m, 2H), 2.38 (s, 6H), 2.43 (s, 3H), 3.
11-3.16 (m, 1H), 6.85 (s, 1H), 7.01-7.12 (m, 5H), 7.2
9-7.47 (m, 5H)

Example 20 N- {2,2-bis (4-fluorophenyl) cyclopropyl} -N '-{2,4-
Bis (methylthio) -6-methylpyridin-3-yl
Synthesis of urea hydrochloride

Embedded image In the same manner as in Example 4, N- {2,2-bis (4-fluorophenyl) cyclopropyl} -N ′-{2,4-bis (methylthio) -6-methylpyridin-3-yl} urea The hydrochloride was synthesized. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 1.46-1.55 (m, 2H), 2.41 (s, 6H), 2.45 (s, 3H), 3.
08-3.15 (m, 1H), 6.89 (s, 1H), 7.03 (d, 5H), 7.10 (d,
2H), 7.30-7.43 (m, 6H)

Example 21 Synthesis of N- {2,2-bis (4-chlorophenyl) cyclopropyl} -N ′-{2,4-bis (methylthio) -6-methylpyridin-3-yl} urea

Embedded image In the same manner as in Example 1, the title compound was synthesized from 2,2-bis (4-chlorophenyl) cyclopropanoic acid and 3-amino-2,4-bis (methylthio) -6-methylpyridine. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 1.54-1.57 (m, 2H), 2.37 (s, 6H), 2.42 (s, 3H), 3.
10-3.19 (m, 1H), 6.82 (s, 1H), 7.30-7.42 (m, 10H)

Example 22 Synthesis of N- {2,2-bis (4-chlorophenyl) cyclopropyl} -N ′-{2,4-bis (methylthio) -6-methylpyridin-3-yl} urea hydrochloride

Embedded image Hydrochloric acid of N- {2,2-bis (4-chlorophenyl) cyclopropyl} -N '-{2,4-bis (methylthio) -6-methylpyridin-3-yl} urea in the same manner as in Example 4. The salt was synthesized. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 1.72-1.77 (m, 1H), 2.39 (s, 6H), 2.44 (s, 3H), 3.
14-3.16 (m, 1H), 3.56-3.61 (m, 1H), 6.87 (s, 1H), 7.2
7-7.42 (m, 10H)

Example 23 Synthesis of N- {2,2-bis (4-methylphenyl) cyclopropyl} -N ′-{2,4-bis (methylthio) -6-methylpyridin-3-yl} urea

Embedded image In the same manner as in Example 1, the title compound was synthesized from 2,2-bis (4-methyllophenyl) cyclopropanoic acid and 3-amino-2,4-bis (methylthio) -6-methylpyridine. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 1.37 (t, 1H), 1.49-1.51 (brm, 1H), 2.19 (s, 3H),
2.38 (s, 6H), 2.43 (s, 3H), 3.10-3.18 (m, 1H), 6.83
(s, 1H), 6.99-7.29 (m, 10H)

Example 24 N- {2,2-bis (4-methylphenyl) cyclopropyl} -N ′-{2,4-bis (methylthio) -6-methylpyridin-3-yl} urea hydrochloride Synthesis

Embedded image In the same manner as in Example 4, N- {2,2-bis (4-methylphenyl) cyclopropyl} -N ′-{2,4-bis (methylthio) -6-methylpyridin-3-yl} urea The hydrochloride was synthesized. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 1.37 (t, 1H), 1.48-1.50 (brm, 1H), 2.19 (s, 3H),
2.26 (s, 3H), 2.40 (s, 3H), 2.42 (s, 3H), 2.46 (s, 3
H), 3.09-3.13 (m, 1H), 6.91 (s, 1H), 6.99-7.28 (m, 9
H), 7.38 (d, 1H)

Example 25 N- (2,2-diphenylcyclopropyl) -N '-{2-isopropyl-5- (1
Synthesis of (imidazolylmethyl) phenyl diurea

Embedded image In the same manner as in Example 1, the title compound was synthesized from 2,2-diphenylcyclopropanoic acid and 2-isopropyl-5- (1-imidazolylmethyl) aniline. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 1.04 (d, 3H), 1.05 (d, 3H), 1.48 (t, 1H), 1.58 (d
d, 1H), 2.84-2.89 (m, 1H), 3.24-3.28 (m, 1H), 5.11 (s,
2H), 6.43 (d, 1H), 6.86 (s, 1H), 6.89 (s, 1H), 7.09-
7.40 (m, 12H), 7.45 (d, 1H), 7.51 (s, 1H), 7.72 (s, 1
H)

Example 26 N- (2,2-diphenylcyclopropyl) -N '-{2-isopropyl-5- (1
Synthesis of (imidazolylmethyl) phenyl diurea hydrochloride

Embedded image In the same manner as in Example 4, N- (2,2-diphenylcyclopropyl) -N ′-{2-isopropyl-5- (1-
An imidazolylmethyl) phenyl diurea hydrochloride was synthesized. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 1.04 (d, 3H), 1.06 (d, 3H), 1.48 (t, 1H), 1.59 (d
d, 1H), 2.92 (septet, 1H), 3.24-3.28 (m, 1H), 5.36 (s,
2H), 6.69 (d, 1H), 7.02 (s, 1H), 7.17-7.39 (m, 12H),
7.64-7.79 (m, 4H), 9.29 (s, 1H)

Example 27 N- (2,2-diphenylcyclopropyl) -N '-{2-tert-butyl-5-
Synthesis of (1-imidazolylmethyl) phenyl) urea

Embedded image In the same manner as in Example 1, the title compound was synthesized from 2,2-diphenylcyclopropanoic acid and 2-tert-butyl-5- (1-imidazolylmethyl) aniline. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 1.14 (s, 9H), 1.49 (t, 1H), 1.58 (dd, 1H), 5.33
(s, 2H), 6.79 (d, 1H), 7.03 (d, 1H), 7.12-7.38 (m, 13
H), 7.58 (s, 1H), 7.68 (s, 1H), 9.02 (s, 1H)

Example 28 N- (2,2-diphenylcyclopropyl) -N '-{2-tert-butyl-5-
Synthesis of (1-imidazolylmethyl) phenyl diurea hydrochloride

Embedded image In the same manner as in Example 4, N- (2,2-diphenylcyclopropyl) -N ′-{2-tert-butyl-5-
A hydrochloride salt of (1-imidazolylmethyl) phenyl diurea was synthesized. ¹ H-NMR (DMSO-d ₆ , 300 MHz) δ; 1.16 (s, 9H), 1.49 (t, 1H), 1.58 (dd, 1H), 3.22-
3.29 (m, 1H), 5.37 (s, 2H), 6.82 (d, 1H), 7.05-7.38
(m, 15H), 7.71 (s, 1H), 7.78 (s, 1H), 9.27 (s, 1H)

Reference Example 6 Synthesis of ethyl 2,2-diphenylcyclopropanate Anhydrous copper sulfate (958 mg, 6.0 mmol) was added to a benzene solution (100 ml) of 1,1-diphenylethylene (18 g, 0.10 mol).
Was added thereto, and a solution of ethyl diazoacetate (34.3 g, 0.30 mmol) in hexane (50 ml) was added dropwise to the solution under heating and reflux. After completion of the dropwise addition, the mixture was stirred for 8 hours under reflux with heating. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (silica gel; 600 g, hexane: ethyl acetate = 1: 0, 2).
0: 1, 10: 1) to give the title compound (16.4 g, yield
58%) as a colorless oil. ¹ H-NMR (CDCl ₃ , 300 MHz) δ; 1.00 (t, 3H), 1.57 (dd, 1H), 2.17 (dd, 1H), 2.53
(dd, 1H), 3.91 (q, 2H), 6.85-7.37 (m, 10H)

The ACAT inhibitory activity of the compound of the present invention is evaluated by the following method. Experimental example Measuring enzyme specimen ACAT of ACAT inhibitory activity in preparations prepared from rabbit liver literature (J. Lipid. Research, 30, 6
81-690, 1989) from the livers of New Zealand white rabbits loaded with a 1% cholesterol diet for one month. ACAT activity is described in the literature (J. Lipid.
Research, 24, 1127-1134, 1983 according to the method according to the method described in), using the endogenous cholesterol contained in the ^[1-14 C] oleoyl -CoA and liver microsomal fraction of radioactive substance The enzyme activity was calculated from the radioactivity of the produced labeled cholesterol oleate. Table 1 shows the obtained results.

[0069]

Table 1 Table 1 Test compound ACAT inhibitory activity (Example No.) IC ₅₀ (nM) １１ 11 17 ──────────────────────── ──

2. Measurement of ACAT inhibitory activity on rat intraperitoneal macrophages
t Biophysica Acta, 1126 , 73-80, 1992). ACAT activity is described in the above literature (Biochi
mica et Biophysica Acta, 1126 , 73-80, 1992) according to the method described in [9,
10- ³ H] oleic acid and literature (Biochimica et Biophy
sica Acta, 1213 , 127-134, 1994), the enzymatic activity was calculated from the radioactivity of labeled cholesteryl oleate produced using exogenous cholesterol contained in the reconstituted liposomes. Table 2 shows the obtained results.

[0071]

TABLE 2 Test compound ACAT inhibitory activity (Example No.) IC ₅₀ (nM) １１ 11 141 ──────────────────────── ──

[0072]

EFFECT OF THE INVENTION The pyridone derivative or an acid addition salt thereof of the present invention strongly inhibits ACAT activity in a sample prepared from rabbit liver and in macrophages derived from rat intraperitoneal cavity. Therefore, not only as a blood lipid lowering agent, but also arteriosclerosis itself or various diseases related to arteriosclerosis, such as cerebral infarction, cerebral thrombosis, transient cerebral hemorrhage, angina pectoris, myocardial infarction, peripheral thrombosis and occlusion It is useful for prevention and treatment.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) A61K 31/4164 A61K 31/415 606 31/44 31/44 31/4406 602 31/4453 31/445 601 C07D 213/30 C07D 213/30 213/75 213/75 233/61 101 233/61 101 295/08 295/08 Z (72) Inventor Naohito Ohashi 3-1-198 Kasuganaka, Konohana-ku, Osaka Sumitomo Pharmaceutical Co., Ltd. F-term (reference) 4C055 AA01 BA01 BA03 BA05 BA06 BA47 BB01 BB02 CA02 CA06 CA16 CA53 CB04 CB08 CB10 CB17 DA01 DA47 DB01 DB02 EA01 4C086 AA01 AA02 AA03 BC17 BC21 BC38 MA01 MA04 NA14 NA15 ZA42 ZA33 A206 ZA42 ZA45 A206 NA14 NA15 ZA42 ZA45 ZC20 ZC33 4H006 AA01 AA03 AB23 BJ20 BJ50 FC22 RA26

Claims (16)

[Claims] 1. A compound of the general formula (1) (Wherein, Y ¹ and Y ² each independently represent a cycloalkyl group, an aryl group, a heterocyclic group, a substituted cycloalkyl group, a substituted aryl group, or a substituted heterocyclic group. Here, Y ¹ and Y 2 ² may be substituted on the same carbon on the cycloalkyl ring, Y ³ is an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkylalkyl group, a cycloalkenylalkyl group, an aryl group, Aralkyl group, heteroarylalkyl group, heterocyclic group, substituted alkyl group, substituted alkenyl group, substituted alkynyl group, substituted cycloalkyl group, substituted cycloalkenyl group, substituted cycloalkylalkyl group, substituted cycloalkenylalkyl group, substituted aryl group, Substituted aralkyl group, substituted heteroarylalkyl group, or substituted heterocycle Salts .n is acceptable as cycloalkyl derivative or a prodrug thereof or a pharmaceutically represented by.) Showing a 1 or 2 representing a. 2. The cycloalkyl derivative according to claim 1, wherein one to ^three of Y ¹ , Y ² and Y ³ are an aryl group, a heterocyclic group, a substituted aryl group, or a substituted heterocyclic group. Or their pharmaceutically acceptable salts. 3. The cycloalkyl derivative according to claim 1, wherein Y ³ is an aryl group, a heterocyclic group, a substituted aryl group, or a substituted heterocyclic group, a prodrug thereof, or a pharmaceutically acceptable salt thereof. 4. A cycloalkyl group substituted with 1 to ³ of Y ¹ , Y ² and Y ³ , a substituted aryl group,
Or a substituted heterocyclic group wherein at least one of the substituents is a group represented by the formula -M ¹ -EQ [M ¹ is a bond, an oxygen atom, a sulfur atom or a formula -NR ^1- (R ¹ is hydrogen Represents an atom or a lower alkyl group), E represents a divalent aliphatic hydrocarbon group having 1 to 15 carbon atoms or a phenylene group which may contain an unsaturated bond, Q represents a hydrogen atom, Hydroxyl group, carboxyl group, lower alkoxycarbonyl group, benzyloxycarbonyl group, halogen atom, cyano group, benzyloxy group, lower alkoxy group, lower alkanoyloxy group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, alkyl substitution Or an unsubstituted benzenesulfonyloxy group,
Lower alkanoylamino group, lower alkoxycarbonylamino group, lower alkylsulfonamide group, phthalimide group, cycloalkyl group, cycloalkenyl group, aryl group, aralkyl group, heteroarylalkyl group, heterocyclic group, substituted aryl group, substituted heterocycle Group, formula -NR ²
R ³ ｛R ² and R ³ are each independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a di-lower alkylamino-substituted lower alkyl group, a lower alkoxy-substituted lower alkyl group, a cycloalkyl group, a lower alkoxycarbonyl Group, a heteroarylmethyl group, or an aralkyl group, or R ² and R ³ are bonded to each other, and together with the nitrogen atom to which they are bonded,
⁴ - (. R ⁴ is hydrogen atom, a lower alkyl group, a phenyl group, a lower alkoxycarbonyl group or a benzyl group,) one, or an oxygen atom one may include, the number of carbon atoms constituting the ring Represents 4 to 8 saturated cyclic amino groups. ｝ Or a formula —C (＝ O) NR ² R ³ (R ² and R ³ represent the same meaning as above). The cycloalkyl derivative according to any one of claims 1 to 3, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. 5. The cycloalkyl derivative according to claim 4, wherein 1 to ³ of Y ¹ , Y ² and Y ³ are a substituted phenyl group, a prodrug thereof, or a pharmaceutically acceptable salt thereof. 6. The cycloalkyl derivative according to claim 5, wherein Y ¹ and Y ² are both substituted phenyl groups, a prodrug thereof, or a pharmaceutically acceptable salt thereof. 7. The cycloalkyl derivative according to claim 4, wherein M ¹ is an oxygen atom, a prodrug thereof, or a pharmaceutically acceptable salt thereof. 8. Q is a hydrogen atom, a hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group, a benzyloxycarbonyl group, a benzyloxy group, a lower alkoxy group, a lower alkanoyloxy group, a lower alkanoylamino group, a heterocyclic group, and a substituted heterocyclic ring. group or cycloalkyl derivative or acceptable salt thereof a prodrug or pharmaceutical according to any one of claims 4-7 is of formula -NR ² R ^3,. 9. E is alkylene having 1 to 4 carbon atoms, Q is a substituted or unsubstituted pyridyl group, 1,2,4
- triazol-1-yl group or a cycloalkyl derivative or acceptable salt thereof a prodrug or pharmaceutical according to claim 8, which is a formula -NR ² R ^3,. 10. The cycloalkyl derivative or prodrug thereof or a pharmaceutically acceptable salt thereof according to claim 4, wherein M ¹ is a bond. 11. Q is a hydrogen atom, a hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group, a benzyloxycarbonyl group, a benzyloxy group, a lower alkoxy group, a lower alkanoyloxy group, a lower alkanoylamino group, a heterocyclic group, and a substituted heterocyclic ring. group or cycloalkyl derivative or acceptable salt thereof a prodrug or pharmaceutical according to claim 10 which is a formula -NR ² R ^3,. 12. The cycloalkyl derivative or prodrug thereof or the medicament thereof according to any one of claims 1 to 11, wherein both Y ¹ and Y ² are substituted on the same carbon on the cycloalkyl ring. Acceptable salt. 13. The cycloalkyl derivative according to any one of claims 1 to 12, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein n is 1. 14. A pharmaceutical comprising the cycloalkyl derivative according to claim 1 or a prodrug thereof or a pharmaceutically acceptable salt thereof. 15. Inhibition of acyl-CoA: cholesterol acyltransferase (ACAT) containing, as an active ingredient, the cycloalkyl derivative according to any one of claims 1 to 13 or a prodrug thereof or a pharmaceutically acceptable salt thereof. Agent. 16. A therapeutic agent for hyperlipidemia or arteriosclerosis, comprising as an active ingredient the cycloalkyl derivative according to any one of claims 1 to 13, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.