JPH10298134A - Squalene synthase inhibitor and new malonic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful as a treating agent for an infectious disease or a circulatory disease, etc. SOLUTION: A compound of formula I [A<1> and A<2> are each H, a (substituted) aromatic group; X<1> and X<2> are each a (substituted) 1-20C divalent aliphatic hydrocarbon residue; A<1> X<1> and A<2> X<2> cannot be a 1-3C alkyl or benzene at the same time], e.g. 2-dodecyl-2-(5-phenylpentyl)malonic acid. The compound can be obtained, for example, by reacting a malonic acid dialkyl ester of formula II [R is a 1-10C (substituted) alkyl, etc.], with an alkylating agent in the presence of a base (e.g. sodium hydride) in a solvent (e.g. tetrahydrofuran) at 0-100 deg.C for 0.5-48 hr to obtain a dialkylmalonic acid dialkyl ester of formula III and hydrolyzing the ester through the reaction with a base (e.g. sodium hydroxide or potassium hydroxide) in a solvent (e.g. methanol) at -10 to 100 deg.C for 0.5-24 hr to convert the ester moiety into the carboxylic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a malonic acid derivative which is expected as a drug for treating mycosis or a drug for treating hypercholesterolemia, hyperlipidemia and arteriosclerosis, for example.

[0002]

BACKGROUND ART Fungi (genus Candida, Aspergillus,
Amphotericin B, fluconazole, itraconazole and the like have been used for the treatment of infectious diseases caused by Cryptocox sp., Mucor sp., Etc. (Paul D. Ho).
eprich, Progress in Drug R
esearch, Vol. 44, 87-127 (199
5)). They inhibit the growth of fungi by inhibiting the biosynthesis of sterol, an essential component of fungal cell membranes, and causing fungal cell membrane damage.
It is hardly an ideal drug in terms of efficacy and safety.

[0003] Cholesterol biosynthesis inhibitors such as lovastatin, an HMG-CoA reductase inhibitor, have been used as therapeutic agents for arteriosclerosis and various diseases associated therewith. However, HMG such as lovastatin
The disadvantage of -CoA reductase inhibitors is that they inhibit the biosynthesis of other isoprene derivatives essential for living organisms because they inhibit the relatively upstream of the cholesterol biosynthesis pathway.

On the other hand, compounds which inhibit (or are expected to inhibit) cholesterol biosynthesis by inhibiting squalene synthase include squarestati.
ns and zaragozic acidids [J.
D. Bergstrom et al., Annu. Rev .. Mic
robiol. , Vol. 49, 607-639 (19
95)], JP-A-7-173120, JP-A-7-173120
138214, JP-A-7-173166,
JP-A-7-179429, JP-A-7-20793
No. 9, JP-A-7-112954 and the like are known.

These squalene synthase inhibitors are used as therapeutic agents for circulatory diseases by inhibiting the biosynthesis of cholesterol and as therapeutic agents for mycosis by inhibiting the biosynthesis of sterols in fungal cell membranes. Be expected. However, squalene synthase inhibitors have not yet been used as a therapeutic agent for mycosis, and there is no effective agent for treating circulatory diseases and the like.

[0006]

Therapeutic agents for infectious diseases such as antifungal drugs and circulating hypercholesterolemia, hyperlipidemia, arteriosclerosis, etc., which are safe and effective with less side effects than conventional drugs. A therapeutic agent for organ diseases is desired in the modern society.

[0007]

That is, the present invention relates to the following (1) to (11). (1) The following general formula (1)

[0008]

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(Wherein A ¹ and A ² each represent hydrogen or an aromatic ring group which may have a substituent. X ¹ and X 2
² is a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon residue having 1 to 20 carbon atoms, each of which may have a substituent. )) Or a pharmaceutically acceptable salt thereof as an active ingredient. (2) A squalene synthase inhibitor comprising the malonic acid derivative or a pharmaceutically acceptable salt thereof according to (1) as an active ingredient. (3) A therapeutic agent for an infectious disease or a cardiovascular disease, comprising the malonic acid derivative or a pharmaceutically acceptable salt thereof according to (1) as an active ingredient. (4) The therapeutic agent for infectious disease according to (3), wherein the infectious disease is mycosis. (5) The therapeutic agent for circulatory disease according to (3), wherein the circulatory disease is any of hypercholesterolemia / hyperlipidemia and arteriosclerosis. (6) The following general formula (1)

[0010]

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(Wherein A ¹ and A ² each represent hydrogen or an aromatic ring group which may have a substituent. X ¹ and X 2
² is a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon residue having 1 to 20 carbon atoms, each of which may have a substituent. However, this excludes the case where A ¹ X ¹ and A ² X ² are both alkyl groups having 1 to 3 carbon atoms, and both are benzyl groups. Or a pharmaceutically acceptable salt thereof. (7) A ¹ and A ² in the general formula (1) each represent hydrogen or a phenyl or naphthyl group which may have a substituent. (6) A novel malonic acid derivative according to (6) or a pharmaceutically acceptable salt thereof (8) 2-dodecyl-2- (5-phenylpentyl) malonic acid, 2-dodecyl-2- (4-phenylbutyl) malonic acid , 2-Farnesyl-2- {3- (β-naphthyl) propyl} malonic acid, 2-Farnesyl-2- {4
A novel malonic acid derivative selected from-(3-phenoxyphenyl) butyl dimalonic acid. (9) The following general formula (4)

[0012]

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(Wherein R represents a substituted or unsubstituted alkyl group having 1-10 carbon atoms or a substituted or unsubstituted aralkyl group having 7-10 carbon atoms),
Or the following general formula (2)

[0014]

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(In the formula, A ¹ represents hydrogen or an aromatic ring group which may have a substituent. X ¹ represents a linear or branched carbon atom which may have a substituent. Represents a saturated or unsaturated divalent aliphatic hydrocarbon residue having the formula 1 to 20. R represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, or a substituted or unsubstituted 7 to 10 carbon atoms. Obtained by alkylating a compound represented by the formula
The following general formula (3)

[0016]

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(Wherein A ¹ and A ² each represent hydrogen or an aromatic ring group which may have a substituent. X ¹ and X 2
² represents a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon residue having 1 to 20 carbon atoms, which may have a substituent. R represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 10 carbon atoms). , The following general formula (1)

[0018]

Embedded image

(Wherein A ¹ and A ² each represent hydrogen or an aromatic ring group which may have a substituent. X ¹ and X 2
² represents a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon residue having 1 to 20 carbon atoms, which may have a substituent. )). (10) The following general formula (2)

[0020]

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(In the formula, A ¹ represents hydrogen or an aromatic ring group which may have a substituent. X ¹ represents a linear or branched carbon atom which may have a substituent. Represents a saturated or unsaturated divalent aliphatic hydrocarbon residue having the formula 1 to 20. R represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, or a substituted or unsubstituted 7 to 10 carbon atoms. Aralkyl group). (11) The following general formula (3)

[0022]

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(Wherein A ¹ and A ² each represent hydrogen or an aromatic ring group which may have a substituent. X ¹ and X 2
² represents a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon residue having 1 to 20 carbon atoms, which may have a substituent. R represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms or a substituted or unsubstituted aralkyl group having 7 to 10 carbon atoms).

[0024]

BEST MODE FOR CARRYING OUT THE INVENTION In the definition of the general formula (1), the general formula (2) or the general formula (3), the aromatic ring group of A ¹ and A ² means a phenyl group or a naphthyl group, an aromatic group It means a heterocyclic group or the like, and among them, a phenyl group or a naphthyl group is preferable.

The substituents on the aromatic ring group of A ¹ and A ² include 2-phenoxyl group, 3-phenoxyl group, 4-phenoxyl group, 2- (2-benzyl) phenoxyl group,
3- (2-benzyl) phenoxyl group, 3- (3-benzyl) phenoxyl group, 3- (4-benzyl) phenoxyl group, 4- (2-benzyl) phenoxyl group, biphenyl group and the like. And preferably a 3-phenoxyl group, a 3- (2-benzyl) phenoxyl group, a biphenyl group and the like.

The linear or branched saturated divalent aliphatic hydrocarbon residue having 1 to 20 carbon atoms which may have a substituent of X ¹ and X ² is not particularly limited. And preferably propyl, butyl, pentyl and the like. Examples of the unsaturated divalent aliphatic hydrocarbon residue include A ¹ X ¹ ,
A ² X ² includes a geranyl group, a bishomogeranyl group, a farnesyl group and the like. Examples of the substituent of X ¹ and X ² include an alkoxy group having 1 to 3 carbon atoms, and a halogen atom such as fluorine and chlorine.

When A ¹ or A ² is hydrogen, preferred A ¹ X
¹ , A ² X ² includes a bishomogeneranyl group, a farnesyl group, a dodecyl group and the like. When A ¹ or A ² is an aromatic ring group which may have a substituent, preferred A ¹ X
¹ , A ² X ² includes 5-phenylpentyl, 4-phenylbutyl, 3- (β-naphthyl) propyl, 4-
(3-phenoxyphenyl) butyl, p-ta-phenylmethyl, 3- (2-benzylphenoxy) benzyl and the like.

Examples of the substituted or unsubstituted alkyl group having 1 to 10 carbon atoms for R include a linear or branched alkyl group having 1 to 10 carbon atoms. For example, a methyl group,
Examples include an ethyl group, an isopropyl group, a butyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group. Among them, a methyl group and an ethyl group are preferable. . Examples of the substituent include an alkoxy group having 1 to 3 carbon atoms. R
Examples of the substituted or unsubstituted aralkyl group having 7 to 10 carbon atoms include substituents such as a benzyl group and a p-methoxybenzyl group, an alkoxy group having 1 to 3 carbon atoms, and an alkyl group having 1 to 3 carbon atoms. And a benzyl group which may be used.

As the compound represented by the general formula (1),
For example, the following compounds may be mentioned. 2-dodecyl-2- (5-phenylpentyl) malonic acid 2-undecyl-2- (5-phenylpentyl) malonic acid 2-decyl-2- (5-phenylpentyl) malonic acid 2-nonyl-2- (5 -Phenylpentyl) malonic acid 2-octyl-2- (5-phenylpentyl) malonic acid 2-heptyl-2- (5-phenylpentyl) malonic acid 2-hexyl-2- (5-phenylpentyl) malonic acid 2- t-butyl-2- (5-phenylpentyl) malonic acid 2-isopropyl-2- (5-phenylpentyl) malonic acid 2-farnesyl-2- (5-phenylpentyl) malonic acid 2-geranyl-2- (5 -Phenylpentyl) malonic acid 2- (11,11-dimethyldodecyl) -2- (5-phenylpentyl) malonic acid 2- (5-phenylpentyl) 2-Dodecyl-2- {5- (2-furyl) pentyl} malonate 2-stearylmalonic acid 2-dodecyl-2- {5- (3-furyl) pentyl} malonic acid 2-dodecyl-2- {5 -(2-pyridyl) pentyl｝
2-Dodecyl-2-malonate 5- {3- (3-pyridyl) pentyl}
2-dodecyl-2-malonate 5- {4- (4-pyridyl) pentyl}
2-Dodecyl-2- {5- (2-pyrimidyl) pentylmalonate} 2-Dodecyl-2- {5- (3-pyrimidyl) pentylmalonate 2-Dodecyl-2- {5- (4-) malonate Pyrimidyl) pentyl dimalonate 2,2-digeranylmalonic acid 2-dodecyl-2- (3-phenylpropyl) malonic acid 2-bishomogeranyl-2- (3-phenylpropyl)
2-Dodecyl-2- (4-phenylbutyl) malonic acid 2-Bishomogeneranyl 2- (4-phenylbutyl) malonate 2,2-Bis (5-phenylpentyl) malonic acid 2-Bishomogeneranyl malonate -2- (5-phenylpentyl)
2,2-bis (6-phenylhexyl) malonic acid 2-dodecyl-2- (6-phenylhexyl) malonic acid 2-bishomogeranyl-2- (6-phenylhexyl) malonic acid
2,2-Difarnesylmalonic acid 2-Farnesyl-2- {3- (2-naphthyl) propyl} malonic acid 2-Farnesyl-2- {3- (1-naphthyl) propyl} malonic acid 2-farnesyl- 2- {4- (3-phenoxyphenyl) butyl} malonate 2-farnesyl-2- {3- (3-phenoxyphenyl) butyl} malonate 2-farnesyl-2- {4- (2-phenoxyphenyl) butyl {2-Farnesyl-2-malonate}-(4- (4-phenoxyphenyl) butyl) malonate 2-Dodecyl-2-farnesylmalonate 2-dodecyl-2- [3- (β-naphthyl) propyl] malonate
2-Dodecyl-2- [4- (3-phenoxyphenyl) malonate
Butyl] malonic acid 2,2-didodecylmalonic acid 2-farnesyl-2- (ta-phenylmethyl) malonic acid 2-farnesyl-2- (biphenylmethyl) malonic acid 2-farnesyl-2- {3- (2- Benzyl) phenoxydibenzylmalonic acid 2,2-bis (bishomogeranyl) malonic acid Particularly preferred are the following compounds. 2-dodecyl-2- (5-phenylpentyl) malonic acid (01-3) 2-dodecyl-2- (4-phenylbutyl) malonic acid)
(05-3) 2-Farnesyl-2- {3- (β-naphthyl) propyl} malonic acid (13-2) 2-Farnesyl-2- {4- (3-phenoxyphenyl) butyl} malonic acid (14- 2)

The compound of the present invention can be produced, for example, as follows.

[0031]

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In the formula, A ¹ , A ² , X ¹ , and X ² are as described in the general formula (1). R is as described in the general formulas (2) and (3). In the general formulas (5) and (6), Y represents a leaving group such as a halogen atom or a sulfonyloxy group, and among them, a chlorine atom, a bromine atom, an iodine atom and the like are preferable.

In the general formulas (1) and (3),
When X ¹ A ¹ is equal to X ² A ² , the first step can be omitted. That is, the compound of the general formula (3) in which X ¹ A ¹ and X ² A ² are equal can be produced by subjecting the compound of the general formula (4) to a reaction in the second step. Hereinafter, each step will be described.

[First Step] In this step, the dialkyl malonate represented by the general formula (4) is mono-alkylated to produce the dialkyl monoalkyl malonate represented by the general formula (2). The reaction is carried out by reacting a malonic acid dialkyl ester represented by the general formula (4) with an alkylating agent represented by the general formula (5) in a solvent in the presence of a base.

As the solvent used in the reaction, tetrahydrofuran, diethyl ether, dimethylformamide and the like can be mentioned, and tetrahydrofuran and dimethylformamide are particularly preferable. Examples of the base include sodium hydride, sodium alkoxide, lithium diisopropylamide, and the like, with sodium hydride being particularly preferred. The reaction temperature is in the range of 0-100 ° C, preferably 10-70 ° C.
At ° C, the reaction time is in the range of 0.5-48 hours, preferably 1-24 hours.

[Second Step] This is a step of alkylating a monoalkylmalonic acid dialkyl ester represented by the general formula (2) to produce a dialkylmalonic acid dialkyl ester represented by the general formula (3). The reaction is carried out by reacting a dialkyl monoalkylmalonate represented by the general formula (2) with an alkylating agent represented by the general formula (6) in a solvent in the presence of a base.

When the first step is omitted, the malonic acid dialkyl ester represented by the general formula (4) is converted to a compound represented by the general formula (5) or (6) in a solvent in the presence of a base. The reaction is performed by reacting with an alkylating agent. In this case, it is preferable to use the base and the alkylating agent in an amount of at least 2 equivalents, preferably 2-3 equivalents, based on the dialkyl malonate represented by the general formula (4).

Examples of the solvent used in the reaction include tetrahydrofuran, diethyl ether, dimethylformamide and the like, and particularly preferred are tetrahydrofuran and dimethylformamide. Examples of the base include sodium hydride, sodium alkoxide, lithium diisopropylamide, and the like, with sodium hydride being particularly preferred. The reaction temperature is in the range of 0-100 ° C, preferably 10-70 ° C.
At 0 ° C, the reaction time is in the range of 0.5 to 48 hours, preferably 1 to 24 hours.

[Third Step] In this step, the ester portion of the dialkyl malonic acid dialkyl ester represented by the general formula (3) is hydrolyzed to produce the dialkyl malonic acid represented by the general formula (1). The reaction is carried out by reacting a dialkyl malonic acid dialkyl ester represented by the general formula (3) with a base in a solvent.

Examples of the solvent used in the reaction include tetrahydrofuran, methanol, ethanol and the like, with ethanol being particularly preferred. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, and potassium hydroxide is particularly preferred. The reaction temperature is in the range of -10 to 100 ° C, preferably 0-80 ° C, and the reaction time is in the range of 0.5-24 hours, preferably 0.5-80 ° C.
It is good to do it in 5 hours.

When the compound of the present invention or a pharmaceutical salt thereof is used as a therapeutic agent for hypercholesterolemia, hyperlipidemia or arteriosclerosis, it may be used alone or in combination with an excipient or carrier for injection or oral preparation. And so on. On the other hand, when the present compound is used as an antifungal agent, it is administered as an injection, an oral preparation, an external preparation, a suppository, or the like, alone or as a mixture with an excipient or carrier. Pharmaceutically acceptable excipients and carriers are selected, and their types and compositions are determined by the administration route and administration method. For example, water, alcohols or animal or vegetable oils such as soybean oil, peanut oil, sesame oil, mineral oil or synthetic oils are used as liquid carriers, and sugars such as lactose, maltose, sucrose, amino acids, hydroxypropyl cellulose, etc. are used as solid carriers. Organic derivatives such as cellulose derivatives and magnesium stearate are used.

The excipient used in the injection is mannitol,
Maltose, dextran, lactose, cyclodextrin, chondroitin sulfate, gelatin, and human serum albumin, but maltose, lactose, chondroitin sulfate,
Gelatin and human serum albumin are preferred. A freeze-dried preparation is prepared with these excipients at the time of administration and a suitable solvent for injection such as sterile water, physiological saline, dextrose,
It can also be administered by dissolving in an intravenous administration liquid such as an electrolyte solution amino acid solution.

In the composition of the present invention, the pH
For the purpose of adjustment or the like, an acid, an alkali or an appropriate amount of a buffer may be added.

The content of the present compound in the preparation varies depending on the preparation, but is usually 0.1 to 100% by weight, preferably 1 to 98% by weight. For example, in the case of an injection, the active ingredient is usually contained in an amount of 0.1 to 30% by weight, preferably 1 to 10% by weight. When administered orally, it is used in the form of tablets, capsules, powders, granules, liquids, dry syrups and the like together with the solid carrier or liquid carrier. Capsules, tablets, granules, powders generally contain 5 to 100% by weight, preferably 25 to 98% by weight, of the active ingredient.

The dose is determined depending on the age, body weight, symptoms, treatment purpose, etc. of the patient, but the therapeutic dose is generally 0.01 to 100 mg / kg day for parenteral administration and 0.05 to 100 mg for oral administration
About 500 mg / kg / day.

[0046]

The production examples of the compounds of the present invention will be described in more detail with reference to the following examples, which should not be construed as limiting the scope of the invention. In order to show the usefulness of the compound of the present invention, the results of pharmacological tests of the representative compounds of the present invention are shown in Test Examples. The NMR values in the examples are values measured using 200 MHz NMR with tetramethylsilane as an internal standard.

Example 01-1 Diethyl dodecylmalonate (01-1-1)
Synthesis of diethyl silmalonate (01-1-2) Malonic acid diethyl ester in a suspension of 60% sodium hydride (0.44 g, 0.011 mol) in dry dimethylformamide (12 mL) under argon atmosphere and stirring at room temperature (1.52 mL, 1.60 g, 0.01 mol)
Is slowly added and stirred at room temperature for 30 minutes. Then, 1-bromododecane (2.64 mL, 2.74 g, 0.011)
mol) and stirred at room temperature for 3 hours. Under ice-cooled stirring,
A saturated aqueous ammonium chloride solution is added to the reaction solution, and the mixture is extracted with ethyl acetate. The ethyl acetate extract is washed with brine and dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure to obtain a pale yellow liquid (3.50 g). This was separated by column chromatography (silica gel, 450 mL, n-hexane-ethyl acetate 49: 1).
-Diethyl didodecylmalonate (01-1-2, 0.7
57 g, 15%) as a colorless liquid. From the second fraction, diethyl dodecylmalonate (01-1-1, 1.5
33 g, 47%) as a colorless liquid. NMR (CDCl ₃ ) ppm: 0.880 (3H, t,
J = 6.8 Hz, Mex2), 1.252 (20H,
_{m, - (CH 2) 10} -), 1.266 (6H, t, J =
_{7.1Hz, -COOCH 2 CH 3 x2)} , 1.883
(2H, q, J = 7.0Hz , -CH 2 -), 3.30
9 (1H, t, J = 7.6 Hz, -CH (COOEt)
₂ ), 4.194 (4H, q, J = 7.1 Hz, -CO
OCH ₂ CH ₃ x2).

Example 01-2 2-Dodecyl-2- (5-phenylpentyl) malonic acid
Synthesis of diethyl (01-2) In an argon atmosphere, with stirring at room temperature, diethyl dodecylmalonate (01-1-1) was added to a suspension of 60% sodium hydride (73 mg, 1.83 mmol) in dry dimethylformamide (1 mL). , 500 mg, 1.52 mmol) in dry dimethylformamide (2 mL) is added slowly and stirred at room temperature for 1 hour. Then, a solution of (5-iodopentyl) benzene (501 mg, 1.83 mmol) in dry dimethylformamide (2 mL) is added, and the mixture is stirred at room temperature for 17.5 hours. Under ice-cooling and stirring, a saturated aqueous ammonium chloride solution is added to the reaction solution, and the mixture is extracted with ethyl acetate. The ethyl acetate extract is washed with brine and dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure to obtain a colorless liquid (0.823 g). This was separated by column chromatography (silica gel, 45 mL, n-hexane-ethyl acetate 49: 1), and diethyl 2-dodecyl-2- (5-phenylpentyl) malonate (01-2, 636 mg, 88) was used.
%) As a colorless liquid. NMR (CDCl ₃ ) ppm: 0.878 (3H, t,
J = 6.4 Hz, Me), 1.228 (6H, t, J =
_{7.1Hz, -COOCH 2 CH 3 x2)} , 1.247
(24H, br.s, - (CH 2) 10 -, - (CH 2)
_{2 -), 1.500-1.700 (2H,} m, -CH 2
−), 1.800-1.910 (4H, m, —CH ₂ −
x2), 2.586 (2H, t, J = 7.6 Hz, Ph)
CH ₂ ), 4.164 (4H, q, J = 7.1 Hz, −
COOCH ₂ CH ₃ x2), 7.110-7.320
(5H, m, Ph).

Example 01-3 2-Dodecyl-2- (5-phenylpentyl) malonic acid
Synthesis of (01-3) Diethyl 2-dodecyl-2- (5-phenylpentyl) malonate (01-2,628 mg, 1.3) under ice-cooling and stirring.
85% in a solution of 2 mmol) in ethanol (4 mL)
Solid potassium hydroxide (844 mg, 12.8 mmol)
Are added at room temperature for 4 hours, at 70 ° C. for 3 hours, and then at 80 ° C.
Stir at 30 ° C for 30 minutes. Water is added to the reaction solution, and the mixture is washed twice with ether. Under ice cooling and stirring, a 2M aqueous potassium hydrogen sulfate solution (7 mL) is added to the aqueous layer, and the mixture is extracted with ether. The ether extract is washed with saturated saline and dried over anhydrous sodium sulfate. The sodium sulfate was filtered off and the solvent was distilled off under reduced pressure to give 2-dodecyl-2- (5-phenylpentyl).
Malonic acid (01-3, 540 mg, 97%) is obtained as a light brown solid. Here, if possible, the obtained product is washed with n-hexane, ether or the like and purified. MS (ESI, NEG), m / z: 417 [M-
H] ^- , 373 [MH-CO ₂ ] ^- , 835 [2M-
_{^{H] - NMR (CDCl 3)}} ppm: 0.877 (3H, t,
J = 6.5 Hz, Me), 1.242 (24H, br.
_{s, - (CH 2) 10} -, - (CH 2) 2 -), 1.60
8 (2H, quint., J = 7.5 Hz, -CH
_{2 -), 1.850-2.010 (4H,} m, -CH 2
−x2), 2.576 (2H, t, J = 7.5 Hz, A
_{rCH 2), 6.700-7.800 (2H,} b, CO
OHx2), 7.100-7.320 (5H, m, -P
h).

Example 02-1 Synthesis of diethyl 2,2-digeranylmalonate (02-1)
Formed in an argon atmosphere, stirring at room temperature, 60% sodium hydride (96 mg, 2.4 mmol) in anhydrous tetrahydrofuran (4 mL) suspension of diethyl malonate in (0.16 mL, 1.05 mmol) was slowly added, Stir at room temperature for 30 minutes. Then add geranyl bromide (0.50 mL, 2.5 mmol) and stir at room temperature overnight. A buffer is added to the reaction mixture under ice-cooling and stirring, and the mixture is extracted with ether. The ether extract is washed with saturated saline and dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, the solvent of the filtrate was distilled off under reduced pressure, and the residue was subjected to column chromatography (silica gel, ether-n-
Hexane, 1:20) and diethyl 2,2-digeranylmalonate (02-1,415 mg, 91%).
Get. NMR (CDCl ₃ ) ppm: 1.230 (6H, t,
J = 7.1 Hz), 1.590 (12H, s), 1.6
76 (6H, s), 1.900-2.120 (8H,
m), 2.597 (4H, d, J = 7.4 Hz), 4.
154 (4H, q, J = 7.1 Hz), 4.920 −
5.110 (4H, m).

Example 02-2 Synthesis of 2,2-digeranylmalonic acid (02-2) Diethyl 2,2-digeranylmalonate (02-1,40)
4 mg, 0.93 mmol) of ethanol (1.3 m
L) 85% solid potassium hydroxide (300 m
g, 4.55 mmol), and the mixture is heated and stirred at 70 ° C. for 1.5 hours. The solvent was distilled off under reduced pressure, and water was added to the residue.
Wash twice with ether. Under ice-cooling and stirring, the aqueous layer is made acidic by adding a 2M aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate. The ethyl acetate extract is dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure to give 2,2-digeranylmalonic acid (02-2, solid, 3
24 mg, 92%). MS (ESI, NEG), m / z: 375 [M-
_{^{H] -, 331 [M-}} H-CO 2] -, 751 [2M-
H] ^- . NMR (CDCl ₃ ) ppm: 1.583 (6H,
s), 1.612 (6H, s), 1.667 (6H,
s), 1.900-2.120 (8H, m), 2.67.
8 (4H, d, J = 7.3 Hz), 4.970-5.1
00 (4H, m), 8.300-8.900 (2H,
b).

Example 03-1 Diethyl (3-phenylpropyl) malonate (03-
Synthetic malonic acid diethyl ester of 1.) (1.60 mL, 1.688)
g, 10.5 mmol), (3-bromopropyl) benzene (1.6 mL, 10.5 mmol), 60% sodium hydride (420 mg, 10.5 mmol) and anhydrous tetrahydrofuran (20 mL) as in Example 01-1. To give diethyl (3-phenylpropyl) malonate (03-1, 2.02 g, 69%). NMR (CDCl ₃ ) ppm: 1.253 (6H, t,
J = 7.1 Hz), 1.570-1.750 (2H,
m), 1.880-2.020 (2H, m), 2.64
4 (2H, t, J = 7.6 Hz), 3.338 (1H,
t, J = 7.5 Hz), 4.185 (4H, q, J =
7.1 Hz), 7.120-7.330 (5H, m).

Example 03-2 2-Dodecyl-2- (3-phenylpropyl) malonic acid
Synthesis of diethyl (03-2) diethyl ( 3-phenylpropyl) malonate (03-
1,01.672 g, 6.0 mmol), 1-bromododecane (1.7 mL, 7.08 mmol), 60% sodium hydride (288 mg, 7.2 mmol) and dry dimethylformamide (15 mL) were prepared in Example 01-2. And treated with diethyl 2-dodecyl-2- (3-phenylpropyl) malonate (03-2, 2.439 g, 9
1%). NMR (CDCl ₃ ) ppm: 0.880 (3H, t,
J = 6.5 Hz), 1.00-1.350 (20H,
m), 1.207 (6H, t, J = 7.1 Hz),
400-1.600 (2H, m), 1.790-1.9
70 (4H, m), 2.614 (2H, t, J = 7.5)
Hz), 4.145 (4H, q, J = 7.1 Hz),
7.120-7.320 (5H, m).

Example 03-3 2-Dodecyl-2- (3-phenylpropyl) malonic acid
Synthesis of (03-3) diethyl 2-dodecyl-2- (3-phenylpropyl) malonate (03-2, 2.415 g, 5.4 mmol)
l), 85% potassium hydroxide (1.51 g), and ethanol (7.5 mL) were treated in the same manner as in Example 01-3 to give 2-dodecyl-2- (3-phenylpropyl) malonic acid (03- 3,1.596 g, 76%). MS (ESI, NEG), m / z: 389 [M-
H] ^- , 345 [MH-CO ₂ ] ^- , 327 [MH
—CO ₂ —H ₂ O] ⁻ , 779 [2M−H] ⁻ . NMR (CDCl ₃ ) ppm: 0.877 (3H, t,
J = 6.4 Hz), 1.233 (20 H, s), 1.4
00-1.680 (2H, m), 1.800-2.05
0 (4H, m), 2.608 (2H, t, J = 7.5H
z), 7.110-7.310 (5H, m), 8.88
0-9.700 (2H, b).

Example 04-1 2- Bishomogeranyl -2- (3-phenylpropyl)
Synthesis of diethyl malonate (04-1) Diethyl ( 3-phenylpropyl) malonate (03-1, 139 mg, 0.5
mmol) in dry dimethylformamide (1 mL), 60% sodium hydride (22 mg) is added, and the mixture is stirred at room temperature for 35 minutes. Next, a solution of bishomogeneranyl methanesulfonate (156 mg, 0.5 mmol) in dry dimethylformamide (1 mL) was added, and the mixture was added at room temperature for 2 hours and 40 minutes, at 50 ° C for 1 hour and 15 minutes, and further at 80 ° C.
And stir for 5 hours. Add phosphate buffer to the reaction mixture and extract with ether. The ether extract is washed with water (twice) and brine (twice) and dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, the solvent of the filtrate was distilled off under reduced pressure, and the obtained crude product was separated by column chromatography (silica gel, 45 mL, ether-n-hexane 1:15), and 2-bishomogeneous was obtained. This gives diethyl geranyl-2- (3-phenylpropyl) malonate (04-1,112 mg, 51%). NMR (CDCl ₃₎ ppm: 1.055-1.270
(2H, m), 1.210 (6H, t, J = 7.1H
z), 1.410-1.600 (2H, m), 1.56
6 (3H, s), 1.577 (3H, s), 1.597
(3H, s), 1.810-2.130 (10H,
m), 2.613 (2H, t, J = 7.5 Hz), 4.
147 (4H, q, J = 7.1 Hz), 5.020-
5.140 (2H, m), 7.120-7.320 (5
H, m).

Example 04-2 2- Bishomogeranyl -2- (3-phenylpropyl)
Synthesis of Malonic acid (04-2) 2-Bishomogeneranyl-2- (3-phenylpropyl)
Diethyl malonate (04-1,110 mg, 0.25 m
mol), potassium hydroxide (200 mg, 3.6 mmol)
l) and ethanol (1 mL) were treated in the same manner as in Example 01-3, and 2-bishomogeneranyl-2- (3-phenylpropyl) malonic acid (04-2, 84 mg, 87%) was obtained.
I got MS (ESI, NEG), m / z: 385 [M-
H] ^- , 341 [MH-CO ₂ ] ^- , 771 ｛2M-
H] ^- . NMR (CDCl ₃₎ ppm: 1.120-1.400
(2H, m), 1.400-1.700 (2H, m),
1.546 (3H, s), 1.580 (3H, s),
1.663 (3H, s), 1.800-2.100 (1
0H, m), 2.500-2.650 (2H, m),
4.970-5.120 (2H, m), 5.300-
6.400 (2H, b), 7.070-7.290 (5
H, m).

Example 05-1 Diethyl (4-phenylbutyl) malonate (05-1)
Synthesis of malonic acid diethyl ester (1.60 mL, 10.5 m
mol), (4-iodobutyl) benzene (1.30)
g, 5.0 mmol), 60% sodium hydride (42
0 mg, 10.5 mmol) and anhydrous tetrahydrofuran (20 mL) were treated as in Example 01-1,
Diethyl (4-phenylbutyl) malonate (05-1,
1.06 g, 73%). NMR (CDCl ₃ ) ppm: 1.251 (6H, t,
J = 7.2 Hz), 1.300-1.450 (2H,
m), 1.657 (2H, quintet, J = 7.5).
Hz), 1.840-2.00 (2H, m), 2.6
11 (2H, t, J = 7.7 Hz), 3.307 (1
H, t, J = 7.5 Hz), 4.183 (4H, q, J
= 7.1 Hz), 7.120-7.325 (5H,
m).

Example 05-2 2-Dodecyl-2- (4-phenylbutyl) malonate di
Synthesis of ethyl (05-2) diethyl (4-phenylbutyl) malonate (05-1,
585 mg, 2.0 mmol), 1-bromododecane (0.53 mL, 2.2 mmol), 60% sodium hydride (88 mg, 2.2 mmol) and dry dimethylformamide (4 mL) were treated in the same manner as in Example 01-2. This gave diethyl 2-dodecyl-2- (4-phenylbutyl) malonate (05-2,756 mg, 82%). NMR (CDCl ₃ ) ppm: 0.879 (3H, t,
J = 6.8 Hz), 1.216 (6H, t, J = 7.1)
Hz), 1.250 (22H, s), 1.629 (2
H, quintet, J = 7.7 Hz), 1.790 −
1.950 (4H, m), 2.606 (2H, t, J =
7.7 Hz), 4.154 (4H, q, J = 7.1H)
z), 7.110-7.310 (5H, m).

Example 05-3 2-Dodecyl-2- (4-phenylbutyl) malonic acid
Synthesis of (05-3) diethyl 2-dodecyl-2- (4-phenylbutyl) malonate (05-2, 745 mg, 1.62 mmol),
Potassium hydroxide (454 mg, 8.1 mmol) and ethanol (2.3 mL) were treated in the same manner as in Example 01-3 to give 2-dodecyl-2- (4-phenylbutyl) malonic acid (05-3,661 mg). , Solid, quantitative). MS (ESI, NEG), m / z: 403 [M-
H] ^- , 359 [MH-CO ₂ ] ^- . NMR (CDCl ₃ ) ppm: 0.875 (3H, t,
J = 6.8 Hz), 1.247 (22H, m), 1.6
36 (2H, quintet, J = 7.7 Hz), 1.
870-2.050 (4H, m), 2.603 (2H,
t, J = 7.7 Hz), 7.110-7.310 (5
H, m), 8.000-9.000 (2H.b).

Example 06-1 2- bishomogeranyl -2- (4-phenylbutyl) ma
Synthesis of diethyl lonate (06-1) Diethyl ( 4-phenylbutyl) malonate (05-1,
146 mg, 0.5 mmol), bishomogeneranyl iodide (156 mg, 0.53 mmol), 60% sodium hydride (22 mg) and dry dimethylformamide (2 mL) were treated in the same manner as in Example 01-2 to give 2-bis There was obtained diethyl homogeranyl-2- (4-phenylbutyl) malonate (06-1,207 mg, 91%). NMR (CDCl ₃₎ ppm: 1.100-1.300
(4H, m), 1.216 (6H, t, J = 7.1H
z), 1.540-1.7720 (2H, m), 1.58
1 (3H, s), 1.598 (3H, s), 1.678
(3H, s), 1.800-2.150 (10H,
m), 2.603 (2H, t, J = 7.8 Hz), 4.
155 (4H, q, J = 7.1 Hz), 5.020 −
5.140 (2H, m), 7.110-7.310 (5
H, m).

Example 06-2 2- Bishomogeranyl -2- (4-phenylbutyl) ma
Synthesis of Lonic Acid (06-2) Diethyl 2-bishomogeranyl-2- (4-phenylbutyl) malonate (06-1,200 mg, 0.44 mm)
ol), potassium hydroxide (200 mg), and ethanol (1 mL) were treated in the same manner as in Example 01-3, and 2-bishomogeranyl-2- (4-phenylbutyl) malonic acid (06-2, 170 mg, 97%, liquid). MS (ESI, NEG), m / z: 399 [M-
H] ^- , 355 [MH-CO ₂ ] ^- . NMR (CDCl ₃₎ ppm: 1.200-1.400
(4H, m), 1.550-1.7720 (2H, m),
1.582 (3H, s), 1.593 (3H, s),
1.675 (3H, s), 1.890-2.140 (1
0H, m), 2.604 (2H, t, J = 7.7H)
z), 5.020-5.140 (2H, m), 7.11
0-7.320 (5H, m), 7.400-8.600
(2H, b).

Example 07-1 Diethyl (5-phenylpentyl) malonate (07-1)
-1) and 2,2-bis (5-phenylpentyl) malo
Synthesis of diethyl malonate (07-1-2) Malonic acid diethyl ester (0.80 mL, 5.3 mm)
ol), (5-iodopentyl) benzene (1.37)
g, 5.0 mmol), 60% sodium hydride (21
0 mg, 5.3 mmol) and anhydrous tetrahydrofuran (10 mL) were treated in the same manner as in Example 01-1.
-Phenylpentyl) malonate diethyl (07-1-)
1,874 mg, 57%) and diethyl 2,2-bis (5-phenylpentyl) malonate (07-1-2,38)
%). Diethyl (5-phenylpentyl) malonate (07-1
-1): NMR (CDCl ₃ ) ppm: 1.260 (6H, t,
J = 7.1 Hz), 1.300-1.400 (4H,
m), 1.530-1.700 (2H, m), 1.80
0-1.950 (2H, m), 2.595 (2H, t,
J = 7.7 Hz), 3.302 (1H, t, J = 7.5)
Hz), 4.188 (4H, q, J = 7.1 Hz),
7.120-7.320 (5H, m). Diethyl 2,2-bis (5-phenylpentyl) malonate (07-1-2): NMR (CDCl ₃ ) ppm: 1.221 (6H, t,
J = 7.1 Hz), 1.080-1.420 (8H,
m), 1.530-1.700 (4H, m), 1.80
0-1.910 (4H, m), 2.581 (4H, t,
J = 7.7 Hz), 4.157 (4H, q, J = 7.1)
Hz), 7.110-7.320 (10H, m).

Example 07-2 2,2-bis (5-phenylpentyl) malonic acid (07
-2) Synthesis of diethyl 2,2-bis (5-phenylpentyl) malonate (07-1-2, 415 mg, 0.92 mmol),
Potassium hydroxide (514 mg, 9.2 mmol) and ethanol (2.5 mL) were treated in the same manner as in Example 01-3, and 2,2-bis (5-phenylpentyl) malonic acid (07-2, 357 mg, 98%). MS (ESI, NEG), m / z: 395 [M-
H] ^- , 351 [MH-CO2] ^- , 791 [2M-
H] ^- . NMR (CDCl ₃₎ ppm: 1.150-1.43
5 (8H, m), 1.510-1.680 (4H,
m), 1.850-2.100 (4H, m), 2.56
7 (4H, t, J = 7.6 Hz), 7.110-7.3
10 (10H, m), 9.500-10.400 (2
H, b).

Example 08-1 2- Bishomogeneranyl -2- (5-phenylpentyl)
Synthesis of diethyl malonate (08-1) Diethyl ( 5-phenylpentyl) malonate (07-1)
-1,153 mg, 0.5 mmol), bishomogeranyl iodide (175 mg, 0.6 mmol), 60% sodium hydride (22 mg) and dry dimethylformamide (2 mL) were treated in the same manner as in Example 01-2. 2-
Diethyl bishomogeranyl-2- (5-phenylpentyl) malonate (08-1, 151 mg, 64%) was obtained. NMR (CDCl ₃₎ ppm: 1.100-1.450
(6H, m), 1.229 (6H, t, J = 7.1H
z), 1.500-1.720 (2H, m), 1.58
6 (6H, s), 1.677 (3H, s), 1.800
−2.140 (10H, m), 2.584 (2H, t,
J = 7.6 Hz), 4.164 (4H, q, J = 7.1)
Hz), 5.088 (2H, t, J = 6.6 Hz),
7.110-7.320 (5H, m).

Example 08-2 2- Bishomogeneranyl -2- (5-phenylpentyl)
Synthesis of malonic acid (08-2) 2-Bishomogeneranyl-2- (5-phenylpentyl)
Diethyl malonate (08-1,143 mg, 0.30 m
mol), potassium hydroxide (200 mg, 3.6 mmol)
l) and ethanol (1 mL) were treated in the same manner as in Example 01-3, to give 2-bishomogeneranyl-2- (5-phenylpentyl) malonic acid (08-2, 120 mg, 95 mg).
%). MS (ESI, NEG), m / z: 413 [M-
H] ^- , 369 [MH-CO ₂ ] ^- , 827 [2M-
H] ^- . NMR (CDCl ₃₎ ppm: 1.180-1.430
(6H, m), 1.500-1.720 (2H, m),
1.574 (3H, s), 1.592 (3H, s),
1.675 (3H, s), 1.890-2.130 (1
0H, m), 2.575 (2H, t, J = 7.5H
z), 5.000-5.130 (2H, m), 7.12
0-7.320 (5H, m).

Example 09-1 Diethyl (6-phenylhexyl) malonate (09-1)
-1) and 2,2-bis (6-phenylhexyl) malo
Synthesis of diethyl malonate (09-1-2) diethyl malonate (1.4 mL, 9.2 mmol)
l), (6-Iodohexyl) benzene (865 mg,
3.0 mmol), 60% sodium hydride (368 m
g, 9.2 mmol) and anhydrous tetrahydrofuran (18 mL) were treated in the same manner as in Example 01-1.
Diethyl phenylhexyl) malonate (09-1-1,
555 mg, 58%) and diethyl 2,2-bis (6-phenylhexyl) malonate (09-1-2,212 m
g, 29%). Diethyl (6-phenylhexyl) malonate (09-1)
_{-1): NMR (CDCl 3)} ppm: 1.250-1.390
(6H, m), 1.260 (6H, t, J = 7.1H
z), 1.500-1.690 (2H, m), 1.80
0-1.950 (2H, m), 2.591 (2H, t,
J = 7.6 Hz), 3.301 (1H, t, J = 7.6)
Hz), 4.189 (4H, q, J = 7.1 Hz),
7.115-7.320 (5H, m). Diethyl 2,2-bis (6-phenylhexyl) malonate (09-1-2): NMR (CDCl3) ppm: 1.020-1.380
(12H, m), 1.224 (6H, t, J = 7.0H
z), 1.500-1.700 (4H, m), 1.79
0-1.920 (4H, m), 2.586 (4H, t,
J = 7.7 Hz), 4.158 (4H, q, J = 7.0)
Hz), 7.115-7.330 (10H, m).

Embodiment 09-22,2-bis (6-phenylhexyl) malonic acid (09
Synthesis of -2) 2,2-bis (6-phenylhexyl) malonic acid diethyl
(09-1-2, 203 mg, 0.42 mmol),
Potassium hydroxide (300 mg) and ethanol (1.
5 mL) was treated in the same manner as in Example 01-3,
(6-phenylhexyl) malonic acid (09-2,17
2 mg, solid, 96%). MS (ESI, NEG), m / z: 423 [M-
H]^-, 379 [MH-CO _Two]^-, 847 [2M-
H]^-. NMR (CDCl_Three) Ppm: 1.315 (12H, b
r. s), 1.500-1.700 (4H, m), 1.
850-2.000 (4H, m), 2.580 (4H,
t, J = 7.6 Hz), 7.110-7.320 (10
H, m), 9.000-10.000 (2H, b).

Example 10-1 Preparation of diethyl 6-phenylhexylmalonate (10-1)
Synthetic sodium hydride (60%, 368 mg, 9.20 mm
ol), THF (18 mL), diethyl malonate (1.
40 mL, 1.477 g, 9.22 mmol) 1-iodo-6-phenylhexane (0.865 mg, 3.00)
mmol) and THF (24 mL) in Example 01-
The same treatment as in Example 1 was performed to obtain diethyl 6-phenylhexylmalonate (10-1, 555.0 mg, 58%).

Example 10-2 2-Dodecyl-2- (6-phenylhexyl) malonic acid
Synthesis of diethyl (10-2) sodium hydride (60%, 50.0 mg, 1.250)
0 mmol), diethyl 6-phenylhexylmalonate (10-1, 360.0 mg, 1.1235 mmol)
l), DMF (6 mL), and 1-bromododecane (0.33 mL, 0.3425 mg, 1.3742 mm)
ol) was treated in the same manner as in Example 01-2 to give diethyl 2-dodecyl-2- (6-phenylhexyl) malonate (1).
0-2, 500.0 mg, 91%). NMR (CDCl ₃ ) ppm: 0.88 (3H, t, J
= 6.5 Hz), 1.23 (6H, t, J = 7.1H)
z), 1.23-1.37 (26H, m), 1.51-
1.67 (2H, m), 1.81 to 1.89 (4H,
m), 2.59 (2H, t, J = 7.7 Hz), 4.1
6 (4H, q, J = 7.1 Hz), 7.12 to 7.32
(5H, m).

Example 10-3 2-Dodecyl-2- (6-phenylhexyl) malonic acid
Synthesis of (10-3) diethyl 2-dodecyl-2- (6-phenylhexyl) malonate (10-2, 487.0 mg, 0.9964 m)
mol), ethanol (3 mL), and potassium hydroxide (0.6 g) were treated in the same manner as in Example 01-3 to give 2-dodecyl-2- (6-phenylhexyl) malonic acid (10%).
-3, 423.0 mg, 98%). MS (ESI, NEG), m / Z: 431 [M-
H] ^- , 863 [2M-H] ^- . NMR (CDCl ₃ ) ppm: 0.88 (3H, t, J
= 6.5 Hz) 1.14 to 1.41 (26H, m),
1.52 to 1.67 (2H, m), 1.83 to 2.00
(4H, m), 2.58 (2H, t, J = 7.6H
z), 7.12-7.31 (5H, m), 8.87 (2
H, brs).

Example 11-1 2-Bishomogeranyl-2- (6-phenylhexyl)
Synthesis of diethyl malonate (11-1) Sodium hydride (60%, 22.0 mg, 0.550
0 mmol) in DMF (1 mL), diethyl 6-phenylhexylmalonate (10-1, 160.0 mg, 0.1 mL).
4993 mmol), DMF (2 mL), and bishomogeneranyl mesylate (156.0 mg, 0.6230
mmol) was treated in the same manner as in Example 04-1 to obtain diethyl 2-bishomogeranyl-2- (6-phenylhexyl) malonate (11-1, 214.0 mg, 88%). _{NMR (CDCl 3) ppm: 1.10~1.37} (8
H, m), 1.23 (6H, t, J = 7.1 Hz),
1.58 (3H, brs), 1.59 (3H, br)
s), 1.60 to 1.71 (2H, m), 1.67 (3
H, brs), 1.81 to 2.12 (10H, m),
2.59 (2H, t, J = 7.7 Hz), 4.16 (4
H, q, J = 7.1 Hz), 5.03 to 5.13 (2
H, m), 7.14-7.31 (5H, m).

Example 11-2 2-Bishomogeranyl-2- (6-phenylhexyl)
Synthesis of malonic acid (11-2) 2-bishomogeranyl-2- (6-phenylhexyl)
Diethyl malonate (11-1, 204.0 mg, 0.4
209 mmol), ethanol (1.5 mL), and potassium hydroxide (0.3 g) were treated in the same manner as in Example 01-3, to give 2-bishomogeranyl-2- (6-phenylhexyl) malonic acid (11-2). , 172.0 mg, 95%). MS (ESI, NEG), m / Z: 427 [M-
H] ^- , 855 [2M-H] ^- . _{NMR (CDCl 3) ppm: 1.15~1.38} (8
H, m), 1.52 to 1.62 (2H, m), 1.58
(3H, brs), 1.59 (3H, brs), 1.6
7 (3H, brs), 1.90 to 2.12 (10H,
m), 2.58 (2H, t, J = 7.6 Hz), 5.0
2 to 5.12 (2H, m), 7.12 to 7.31 (5
H, m), 7.50 (2H, brs).

Example 12-1 Diethyl 2,2-difarnesylmalonate (12-1-
1) and diethyl farnesylmalonate (12-1-
2) Synthetic sodium hydride (60%, 4.80 g, 120 mmol)
l), diethyl malonate (1.60 g, 9.99 mmol)
l), THF (16 mL), and farnesyl bromide (3.42 g, 11.99 mmol) in Example 01-1.
And treated with diethyl 2,2-difarnesylmalonate (12-1-1, 1.40 g, 25%) and diethyl farnesylmalonate (12-1-2, 1.67 g,
46%). Diethyl 2,2-difarnesylmalonate (12-1-
1) NMR (CDCl ₃ ) ppm: 1.23 (6H, t, J)
= 6.1 Hz), 1.60 (18H, brs), 1.6
8 (6H, brs), 1.90 to 2.12 (16H,
m), 2.60 (4H, d, J = 7.5 Hz), 4.1
5 (4H, q, J = 6.1 Hz), 4.95 to 5.12
(6H, m). Farnesyl diethyl malonate _{(12-1-2) NMR (CDCl 3)} ppm: 1.26 (6H, t, J
= 7.1 Hz), 1.59 (3H, d, J = 1.0H)
z), 1.60 (3H, brs), 1.64 (3H, b
rs), 1.68 (3H, brs), 1.91-2.1.
2 (8H, m), 2.60 (2H, t, J = 7.6H
z), 3.33 (1H, t, J = 7.7 Hz), 4.1
9 (4H, q, J = 7.1 Hz), 5.04 to 5.14
(3H, m).

Example 12-2 Synthesis of 2,2-difarnesylmalonic acid (12-2) Diethyl 2,2-difarnesylmalonate (12-1-
1,592.0 mg, 1.0406 mmol), ethanol (3 mL) and potassium hydroxide (0.6 g) were treated in the same manner as in Example 01-3 to give 2,2-difarnesylmalonic acid (12-2, 526.0 mg, 99%). MS (FAB, POS), m / Z: 513 [M +
H｝ ⁺ , 535 [M + Na] ⁺ . NMR (CDCl ₃ ) ppm: 1.58 (6H, d, J
= 0.8 Hz), 1.59 (6H, d, J = 0.8H)
z), 1.62 (6H, d, J = 0.8 Hz), 1.6
7 (6H, d, J = 0.7 Hz), 1.89 to 2.12
(16H, m), 2.68 (4H, d, J = 7.5H
z), 4.99-5.12 (6H, m), 8.56 (2
H, brs).

Example 13-1 2-Farnesyl-2- {3- (2-naphthyl) propyl
Synthesis of diethyl rumalonate (13-1) Sodium hydride (60%, 18.0 mg, 0.45 m)
mol), diethyl farnesylmalonate (12-1-
2,136.9 mg, 0.3756 mmol), DMF
(2 mL), and 1-iodo-3- (2-naphthyl) propane (133.5 mg, 0.4508 mmol) were treated in the same manner as in Example 01-2.
There was obtained diethyl {-{3- (2-naphthyl) propyl} malonate (13-1, 66.3 mg, 33%). NMR (CDCl ₃ ) ppm: 1.19 (6H, t, J
= 7.1 Hz), 1.58 (6H, brs), 1.60.
(3H, brs), 1.67 (3H, brs), 1.8
7 to 2.08 (10H, m), 2.62 (4H, d, J
= 7.3 Hz), 2.77 (2H, t, J = 7.5H)
z), 4.13 (4H, q, J = 7.1 Hz), 4.8
8 to 4.97 (1H, m), 5.03 to 5.13 (2
H, m), 7.30 (1H, d, J = 1.7 Hz),
7.36 to 7.49 (2H, m), 7.58 (1H, b
rs), 7.73-7.82 (3H, m).

Example 13-2 2-Farnesyl-2- {3- (2-naphthyl) propyl
Synthesis of Rumalonic Acid (13-2) Diethyl 2-farnesyl-2- {3- (2-naphthyl) propyl} malonate (13-1, 59.0 mg, 0.1%).
1107 mmol), ethanol (2 mL), and potassium hydroxide (0.4 g) were treated in the same manner as in Example 01-3 to give 2-farnesyl-2- {3- (2-naphthyl) propyl} malonic acid (13-mmol). 2,51.2 mg, 97%)
I got MS (FAB, POS), m / Z: 477 [M +
H] ⁺ , 499 [M + Na] ⁺ . NMR (CDCl ₃ ) ppm: 1.56 (6H, br)
s), 1.59 (3H, brs), 1.67 (3H, b
rs), 1.90-2.08 (10H, m), 2.68.
(4H, d, J = 7.5 Hz), 2.27 (2H, t,
J = 7.4 Hz), 4.98-5.12 (3H, m),
7.27 (1H, dd, J = 8.3, 1.8 Hz),
7.36 to 7.48 (2H, m), 7.57 (1H, b
rs), 7.74 (1H, d, J = 8.1 Hz), 7.
75 (1H, d, J = 8.3 Hz), 7.78 (1H,
d, J = 9.7 Hz).

Example 14-1 2-Farnesyl-2- {4- (3-phenoxyphenyl)
B) Synthesis of diethyl butyl malonate (14-1) Sodium hydride (60%, 17.9 mg, 447.5)
mmol) in DMF (1 mL) and diethyl farnesylmalonate (12-1-2, 135.7 mg, 0.372).
3 mmol), DMF (2 mL), and 1-iodo-4
-(3-phenoxyphenyl) butane (157.4 m
g, 0.4468 mmol) was treated in the same manner as in Example 01-1, and diethyl 2-farnesyl-2- {4- (3-phenoxyphenyl) butyl} malonate (14-1,1) was used.
76.7 mg, 81%). _{NMR (CDCl 3) ppm: 1.11~1.27} (2
H, m), 1.21 (6H, t, J = 7.1 Hz),
1.52 to 1.67 (2H, m), 1.58 (3H, b
rs), 1.59 (6H, brs), 1.67 (3H,
brs), 1.83 to 2.11 (10H, m), 2.5
7 (2H, d, J = 7.3 Hz), 2.59 (2H,
t, J = 7.5 Hz), 4.15 (4H, q, J = 7.
1 Hz), 4.90 to 4.99 (1H, m), 5.04
-5.12 (2H, m), 6.78-7.37 (9H,
m).

Example 14-2 2-Farnesyl-2- {4- (3-phenoxyphenyi)
Synthesis of butyl) malonic acid (14-2) Diethyl 2-farnesyl-2- {4- (3-phenoxyphenyl) butyl} malonate (161.1 mg, 0.1%).
2736 mmol), ethanol (3 mL), and potassium hydroxide (0.6 g) were treated in the same manner as in Example 01-3 to give 2-farnesyl-2- {4- (3-phenoxyphenyl) butyl} malonic acid (14 -2,110.5m
g, 76%). MS (FAB, POS), m / Z: 533 [M +
H] ⁺ , 555 [M + Na] ⁺ . _{NMR (CDCl 3) ppm: 1.25~1.36} (2
H, m), 1.53-1.67 (2H, m), 1.57
(3H, brs), 1.59 (6H, brs), 1.6
7 (3H, brs), 1.90 to 2.11 (10H,
m), 2.57 (2H, d, J = 7.7 Hz), 2.6
7 (2H, t, J = 7.7 Hz), 4.94 to 5.12
(3H, m), 6.78-7.36 (9H, m), 7.
50 (2H, brs).

Example 15-1 Diethyl 2-dodecyl-2-farnesylmalonate (1
5-1) Synthetic sodium hydride (60%, 19.1 mg, 477.5)
mmol), diethyl farnesylmalonate (12-1)
−2, 144.9 mg, 0.3975 mmol), DM
F (1 mL) and 1-bromododecane (118.9 m
g, 0.4771 mmol) in the same manner as in Example 01-2 to give diethyl 2-dodecyl-2-farnesylmalonate (15-1, 174.1 mg, 84%). NMR (CDCl3) ppm: 0.88 (3H, t, J
= 6.6Hz), 1.20 to 1.27 (20H, m),
1.21 (6H, t, J = 7.0 Hz), 1.59 (6
H, brs), 1.61 (3H, brs), 1.68.
(3H, brs), 1.89 to 2.12 (10H,
m), 2.61 (2H, t, J = 7.3 Hz), 4.1
6 (4H, q, J = 7.0 Hz), 4.92-5.01
(1H, m), 5.04-5.14 (2H, m).

Example 15-2 2-Dodecyl-2-farnesylmalonic acid (15-2)
Synthesis of diethyl 2-dodecyl-2-farnesylmalonate (1
5-1, 166.8 mg, 0.3191 mmol), ethanol (2 mL), and potassium hydroxide (0.4 g)
Was treated in the same manner as in Example 01-3 to give 2-dodecyl-2-
Farnesylmalonic acid (15-2, 139.5 mg, 9
4%). MS (FAB, POS), m / Z: 477 [M +
H] ⁺ , 499 [M + Na] ⁺ . NMR (CDCl ₃ ) ppm: 0.88 (3H, t, J
= 6.5 Hz), 1.15 to 1.36 (20H, m),
1.58 (3H, d, J = 1.0 Hz), 1.59 (3
H, d, J = 1.0 Hz), 1.62 (3H, d, J =
1.0 Hz), 1.68 (3H, d, J = 1.0H)
z), 1.88-2.12 (10H, m), 2.69
(2H, t, J = 7.6 Hz), 4.98-5.13
(3H, m), 9.00 (2H, brs).

Example 16-1 2-Dodecyl-2- [3- (β-naphthyl) propyl] ma
Synthesis of diethyl lonate (16-1) Diethyl dodecylmalonate (01-1-1,100 m
g, 0.304 mmol), β- (3-iodopropyl) naphthalene (108 mg, 0.365 mmol),
60% sodium hydride (14.6 mg, 0.365 m
mol) and anhydrous tetrahydrofuran (1 mL) were treated as in Example 01-2 to give 2-dodecyl-2- [3
-(Β-naphthyl) propyl] diethyl malonate (16-
1,136 g, 90%) as a colorless syrup. NMR (CDCl ₃ ) ppm: 0.881 (3H, t,
J = 6.8 Hz, Me), 1.189 (6H, t, J =
_{7.4Hz, -COOCH 2 CH 3 x2)} , 1.000
-1.400 (20H, m, - ( CH 2) 10), 1.5
_{00-1.680 (2H, m, -CH 2} -), 1.80
_{0-2.100 (4H, m, -CH 2} -x2), 2.7
82 (2H, t, J = 7.4 Hz, NpCH ₂ );
138 (4H, q, J = 7.1 Hz, -COOCH ₂ C
_{H 3 x2), 7.296 (1H} , dd, J = 8.4,
1.6 Hz, ArH), 7.350-7.500 (2
H, m, ArHx2), 7.595 (1H, s, Ar)
H), 7.720-7.820 (3H, m, ArHx
3).

Example 16-2 2-Dodecyl-2- [3- (β-naphthyl) propyl] ma
Synthesis of lonic acid (16-2) diethyl 2-dodecyl-2- [3- (β-naphthyl) propyl] malonate (16-1,118 mg, 0.238 m
mol), 85% potassium hydroxide (427 mg), and ethanol (2 mL) were treated in the same manner as in Example 01-3, and 2-dodecyl-2- [3- (β-naphthyl) propyl] malonic acid (16-2 , 93 mg, 89%) as a colorless solid. MS (FAB, POS) m / z: 440M ⁺ , 88
2 [2M + H] ⁺ , 463 [M + Na] ⁺ . NMR (CDCl ₃ ) ppm: 0.875 (3H, t,
J = 6.0 Hz, Me), 1.226 (20 H, m, −
_{(CH 2) 10), 1.580-1.800} (2H, m,
-CH _2- ), 1.850-2.100 (4H, m,-
CH ₂ −x2), 2.778 (2H, t, J = 7.1H)
z, NpCH ₂ ), 7.285 (1H, m, ArH),
7.350-7.490 (2H, m, ArHx2),
7.582 (1H, s, ArH), 7.710-7.8
20 (3H, m, ArHx3), 6.500-8.50.
0 (2H, b, COOHx2).

Example 17-1 2-Dodecyl-2- [4- (3-phenoxyphenyl)
Synthesis of diethyl butyl] malonate (17-1) Diethyl dodecylmalonate (01-1-1,100 m
g, 0.304 mmol), phenyl [3- (4-iodobutyl) phenyl] ether (129 mg, 0.36
5 mmol), 60% sodium hydride (14.6 m
g, 0.365 mmol) and anhydrous tetrahydrofuran (1 mL) were treated in the same manner as in Example 01-2, and diethyl 2-dodecyl-2- [4- (3-phenoxyphenyl) butyl] malonate (17-1, 153 g) was used. , 91%)
Was obtained as a colorless syrup. NMR (CDCl ₃ ) ppm: 0.877 (3H, t,
J = 6.7 Hz, Me) 1.216 (6H, t, J =
_{7.1Hz, -COOCH 2 CH 3 x2)} , 1.246
(22H, s, - (CH 2) 10, -CH 2 -), 1.6
10 (2H, quint., J = 7.7Hz, -CH 2
-), 1.790-1.940 (4H, m , -CH 2 -
x2), 2.582 (2H, t, J = 7.7 Hz, Ar
CH ₂ ), 4.154 (4H, q, J = 7.1 Hz, −
COOCH ₂ CH ₃ x2), 6.770-7.390
(9H, m, -PhOPh).

Example 17-2 2-Dodecyl-2- [4- (3-phenoxyphenyl)
Synthesis of butyl] malonic acid (17-2) 2-dodecyl-2- [4- (3-phenoxyphenyl)
[Butyl] diethyl malonate (17-1,136 mg,
0.246 mmol), 85% potassium hydroxide (433
mg, 6.56 mmol), and ethanol (2 mL)
Was treated in the same manner as in Example 01-3 to give 2-dodecyl-2-
[4- (3-Phenoxyphenyl) butyl] malonic acid (17-2, quantitative) was obtained as an orange syrup. MS (FAB, POS) m / z: 496M ^+. , 519
[M + Na] ⁺ . NMR (CDCl ₃ ) ppm: 0.879 (3H, t,
J = 6.5 Hz, Me), 1.248 (22H, m,-
(CH ₂ ) ₁₀ , —CH ₂ —), 1.612 (2H, qu
int. , J = 7.5 Hz, -CH _2- ), 1.870
_{-2.050 (4H, m, -CH 2} -x2), 2.57
1 (2H, t, J = 7.5 Hz, ArCH ₂ ), 6.7
80-7.400 (9H, m, -PhOPh), 6.0
00-8.000 (2H, b, COOHx2).

Example 18-1 Synthesis of 2,2-didodecylmalonic acid (18-1) Diethyl 2,2-didodecylmalonate (01-1-2,
745 mg, 1.50 mmol), 85% potassium hydroxide (1.006 g, 15.2 mmol), and ethanol (5 mL) were treated in the same manner as in Example 01-3.
-Didodecylmalonic acid (18-1,583 mg, 88
%) As a colorless solid. MS (FAB, POS) m / z: 441 [M + H] ⁺ ,
463 [M + Na] ⁺ , 882 [2M + H] ⁺ , 904
[2M + Na] ⁺ . NMR (CDCl ₃ ) ppm: 0.880 (6H, t,
J = 6.2 Hz, Mex2), 1.254 (40H,
_{s, - (CH 2) 10} x2), 1.890-2.010
_{(4H, m, -CH 2 -x2} ), 6.500-8.50
0 (2H, b, -COOHx2).

Example 19-1 2-Farnesyl-2- (terphenylmethyl) malone
Synthesis of diethyl acidate (19-1) sodium hydride (60%, 13.6 mg, 0.340
0 mol), diethyl farnesylmalonate (12-1)
−2, 103.3 mg, 0.2834 mmol), DM
F (4 mL) and terphenylmethyl chloride (9
4.8 mg, 0.3401 mmol) in Example 01-2.
And treated with diethyl 2-farnesyl-2- (terphenylmethyl) malonate (19-1, 46.1 m).
g, 27%). NMR (CDCl ₃ ) ppm: 1.25 (6H, t, J
= 7.1 Hz), 1.59 (3H, d, J = 1.0H)
z), 1.61 (3H, d, J = 1.0 Hz), 1.6
2 (3H, d, J = 1.0 Hz), 1.67 (3H,
d, J = 1.0 Hz), 1.94 to 2.17 (8H,
m), 2.56 (2H, d, J = 7.0 Hz), 3.2
8 (2H, s), 4.19 (4H, q, J = 7.1H
z), 5.06-5.18 (3H, m), 7.16 (2
H, d, J = 8.2 Hz), 7.30 to 7.55 (5
H, m), 7.61 to 7.67 (6H, m).

Example 19-2 2-Farnesyl-2- (terphenylmethyl) malone
Synthesis of acid (19-2) diethyl 2-farnesyl-2- (terphenylmethyl) malonate (19-1, 41.8 mg, 0.0689 m)
mol), ethanol (2 mL), THF (2 mL),
And potassium hydroxide (0.4 g) were treated in the same manner as in Example 01-3 to obtain 2-farnesyl-2- (terphenylmethyl) malonic acid (19-2, 37.0 mg, 98%). MS (FAB, POS), m / Z: 551 [M +
H] ⁺ , 573 [M + Na] ⁺ . NMR (CDCl ₃ ) ppm: 1.59 (6H, br)
s), 1.66 (6H, brs), 1.91-2.12
(8H, m), 2.79 (2H, d, J = 6.8H
z), 3.38 (2H, s), 5.03-5.15 (3
H, m), 5.80 (2H, brs), 7.24-7.
62 (13H, m).

Example 20-1 2-Farnesyl-2- {3- (2-benzyl) pheno
Synthesis of diethyl xylbenzylbenzylmalonate (20-1) Sodium hydride (60%, 13.7 mg, 0.342)
5 mol), diethyl farnesylmalonate (12-1)
−2, 103.9 mg, 0.2850 mmol), DM
F (4 mL) and α-chloro-3- (2-benzyl)
Phenoxytoluene (105.6 mg, 0.3420 m
mol) was treated in the same manner as in Example 01-2, and diethyl 2-farnesyl-2- {3- (2-benzyl) phenoxy} benzylmalonate (20-1, 41.9 mg, 23
%). NMR (CDCl ₃ ) ppm: 1.18 (6H, t, J
= 7.1 Hz), 1.55 (3H, brs), 1.59
(6H, brs), 1.67 (3H, brs), 1.9
2 to 2.12 (8H, m), 2.49 (2H, d, J =
6.7 Hz), 3.17 (2H, s), 3.95 (2
H, s), 4.06 (2H, q, J = 7.1 Hz),
4.09 (2H, q, J = 7.1 Hz), 5.02 to
5.13 (3H, m), 6.56-6.58 (1H,
m), 6.73-6.78 (2H, m), 6.83-
6.88 (1H, m), 7.00 to 7.30 (9H,
m).

Example 20-2 2-Farnesyl-2- {3- (2-benzyl) pheno
Synthesis of xy { benzylmalonic acid (20-2) Diethyl farnesyl {3- (2-benzyl) phenoxy} benzylmalonate (20-1, 35.0 mg, 0.1%).
0550 mmol), ethanol (2 mL), THF
(2 mL) and potassium hydroxide (0.4 g) were treated in the same manner as in Example 01-3 to give 2-farnesyl-2- {3
-(2-benzyl) phenoxydibenzylmalonic acid (2
0-2, 31.3 mg, 98%). MS (FAB, POS), m / Z: 581 [M +
H] ⁺ , 603 [M + Na] ⁺ . NMR (CDCl ₃ ) ppm: 1.56 (6H, br)
s), 1.59 (3H, brs), 1.67 (3H, b
rs), 1.89-2.11 (8H, m), 2.71.
(2H, d, J = 7.1 Hz), 3.24 (2H,
s), 3.95 (2H, s), 4.98-5.12 (3
H, m), 5.90 (2H, brs), 6.71 (1
H, d, J = 0.9 Hz), 6.80 to 6.87 (3
H, m), 7.00 to 7.31 (9H, m).

Example 21-1 Diethyl 2,2-bis (bishomogeneranyl) malonate
Synthetic sodium hydride of (21-1) (60%, 61.7 mg, 1.542
5 mmol), diethyl malonate (98.8 mg, 0.1 mg).
6168 mmol), DMF (7 mL), and bishomogeneranyl iodide (450.6 mg, 1.5421 mm)
ol) was treated in the same manner as in Example 01-2 to give diethyl 2,2-bis (bishomogeneranyl) malonate (21-1,9).
8.6 mg, 33%). NMR (CDCl ₃ ) ppm: 1.83 to 1.14
1.29 (4H, m), 1.24 (6H, t, J = 7.
1 Hz), 1.57 (6H, brs), 1.59 (6
H, brs), 1.68 (6H, d, J = 1.0H)
z), 2.12 (16H, m), 4.17 (4H, q,
J = 7.1 Hz), 5.03 to 5.14 (4H, m).

Example 21-2 2,2-Bis (bishomogeranyl) malonic acid (21-
Synthesis of 2) Diethyl 2,2-bis (bishomogeranyl) malonate (21-1, 93.2 mg, 0.1907 mmol),
Ethanol (4 mL) and potassium hydroxide (0.8
g) was treated in the same manner as in Example 01-3, and 2,2-bis (bishomogeneranyl) malonic acid (21-2,80.8 m
g, 95%). MS (FAB, POS), m / Z: 433 [M +
H] ⁺ , 455 [M + Na] ⁺ . _{NMR (CDCl 3) ppm: 1.19~1.36} (4
H, m), 1.58 (6H, brs), 1.59 (6
H, brs), 1.67 (6H, brs), 1.90-
2.12 (16H, m), 5.03 to 5.13 (4H,
m), 5.40 (2H, brs).

[0092]

[Test example]

Test Example 1 Measurement of Squalene Synthase Inhibitory Activity Squalene synthase inhibitory activity was measured as follows using the enzyme solutions shown in Test Examples 2 and 3 described below.
Of 0.125μCi / ml [1- ³ H] farnesyl pyrophosphate (NEN 15Ci / mmole), 4.84
mM farnesyl pyrophosphate, 1 mM NADPH
(Reduced nicotinamide adenine dinucleotide phosphate), 5.5 mM MgCl ₂ , 11 mM KF, 3 m
M DTT, 1 mg squalene, 50 mM HEPES
Buffer solution (pH 7.4) and test agent (aqueous solution or DMS
O solution) (in a total volume of 200 μl) in the enzyme solution prepared in Test Examples 2 and 3 (protein amount: 2-5 μg for fungal enzyme, for mammalian enzyme)
20 to 50 μg) and reacted at 30 ° C. for 30 minutes. The reaction was stopped by adding 200 μl of ethanol,
400 μl heptane was added and mixed. Collect the heptane layer after centrifugation, and use a liquid scintillation counter.
The radioactivity was measured at. The% inhibition of squalene synthase inhibitory activity was calculated by the formula: {1- (sample-blank) / (control-blank)} × 1
00. IC ₅₀ values were determined by plotting the concentration of test compound versus the log of% inhibition. The IC ₅₀ is the concentration of inhibitor giving 50% inhibition determined from such a plot. Table 1 shows the results.

[0093]

[Table 1]

Test Example 2 Preparation of squalene synthase Preparation of fungal enzyme The fungus was YPG [0.5% Bactoyeast extract, Difc
o), 1% Bacto peptone
e, Difco) and 2% glucose] medium until the late logarithmic phase, and then the cells were spun at low speed (1500 × g,
5 min, 4 ° C) and washed with 0.1 M phosphate buffer (pH 7.0). The cells were placed in a buffer for cell disruption [0.1 M phosphate buffer (pH 7.0), 3
0 nM nicotinamide, 5 mM MgCl ₂ , 5 mM
Glutathione], and sonicated (1 minute x 10 times) with an ultrasonic homogenizer at ice temperature to disrupt the cells. This was centrifuged at a low speed to remove unbroken cells, and further centrifuged at 8000 × g (4 ° C.) to separate the supernatant. This was used as an enzyme solution, and the amount of the protein was quantified, aliquoted and stored at -80 ° C.

Determination of antifungal activity by liquid microdilution method The activity against fungi was determined by a liquid microdilution method using a 96-well plate. Compound is 5mg in DMSO
After dissolving at 1 / ml, a two-fold dilution series was prepared with DMSO, and 1 μl was dispensed into each well of the microplate. RPMI medium (RPMI1640 medium adjusted to pH 7.0 with 0.165 M MOPS) or SDB (Sabou) was added to each well of the microplate.
radidextroth broth) [1% Bacto peptone, Difc
o) and 2% glucose] medium was dispensed in an amount of 99 μl each. Candida albicans is YPGA [0.5
% Bactoy Extract (Bacto eye)
ast extract, Difco), 1% Bacto peptone, Difc
o), 1.5% Bacto agar,
Difco) and 2% glucose]
After 2 or 2 days of culture, the cells were
The cells were suspended in an SDB medium to give 2 × 10 ³ cells / ml. Aspergillus fumigatus spores are fully sporulated PDA (potato dextrose aga).
r) The cells were collected from the slant medium with physiological saline containing 0.05% Tween 80, and diluted with the medium to obtain 5 × 10 3 spores / ml of the inoculum. Inoculate each with 10
0 μl was dispensed into each well of the microplate. Final drug concentrations tested ranged from 25 to 0.2 μg / ml. Microplates for Candida
After incubation at 35 ° C for 15 to 24 hours, the turbidity was measured using a microplate reader, and the concentration at which the growth was inhibited by 50% compared to the control without drug (I
_C50 ) was determined. 27 ° C for Aspergillus
After incubation for 48 to 36 hours, the turbidity was measured, and the IC ₅₀ was determined. Table 2 shows the results.

[0096]

[Table 2]

Test Example 3 Preparation of Rat Enzyme Rat liver enzyme solution was prepared as follows. After bleeding the rat, the liver was removed, and ice-cooled homogenization buffer [50 mM MOPS (pH 7.4), 40 mM
mM MgCl ₂ , 1 mM EDTA, 10 mM
2-mercaptoethanol] at 10 ml per 5 g of liver
In addition, it was finely chopped using scissors. This was homogenized by reciprocating 50 times in ice with a Teflon homogenizer. Centrifugation (5000 × g, 10
, 4 ° C), the supernatant obtained was filtered through a gauze, and further centrifuged at 15000 xg for 15 minutes at 4 ° C, and the supernatant was filtered through the gauze. This was used as an enzyme solution, and the amount of the protein was quantified, aliquoted and stored at -80 ° C.

Assay for Cholesterol Biosynthesis Inhibitory Activity The cholesterol biosynthesis inhibition test was carried out using human liver cancer-derived Hep.
This was performed using the G2 cell line. HepG for 6-hole plate
2 cells were placed at 2 million cells / ml and cultured in a 37 ° C, 5% CO 2 incubator for 2 days.
[ ^14C ] Sodium acetate of Ci was added, and the cells were further cultured for 2 hours. After culturing the cells, 1 ml of a saponification solution (15%
Potassium hydroxide, 50% ethanol, 0.1% pyrogallol) and after saponification at 90 ° C for 2 hours,
1.5 ml of heptane was added, cholesterol was extracted into the heptane layer, and the extract was dried under reduced pressure. The dried product was redissolved in a small amount of heptane, and the developing solvent (heptane: diisopropyl ether: ethyl acetate: acetic acid = 60: 40: 3).
4.7: 4) to develop on thin layer chromatography and measure the radioactivity of the developed cholesterol, compared to the control without drug,
The concentration at which cholesterol biosynthesis was inhibited by 50% (IC
₅₀ ) asked. Table 3 shows the results.

[0099]

[Table 3]

[0100]

The compound of the present invention has a strong squalene synthase inhibitory activity, and is used as a therapeutic agent for infectious diseases such as a therapeutic agent for mycosis or circulating in hypercholesterolemia, hyperlipidemia, arteriosclerosis and the like. It is useful as a medicament such as a remedy for organ diseases.

──────────────────────────────────────────────────の Continued on front page (51) Int.Cl. ⁶ Identification code FI A61K 31/19 AED A61K 31/19 AED C07C 51/353 C07C 51/353 (72) Inventor Ryuji Ikeda 239 Iwanacho, Takasaki City, Gunma Prefecture. (72) Inventor Kazutoshi Takashio 239 Iwanacho, Takasaki City, Gunma Prefecture

Claims (11)

[Claims] [Claim 1] The following general formula (1) (Wherein, A ¹ and A ² each represent hydrogen or an aromatic ring group which may have a substituent. X ¹ and X ² each represent a linear or Branched carbon number 1
-20 represents a saturated or unsaturated divalent aliphatic hydrocarbon residue. )) Or a pharmaceutically acceptable salt thereof as an active ingredient. 2. A squalene synthase inhibitor comprising the malonic acid derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 3. A therapeutic agent for an infectious disease or a cardiovascular disease, comprising the malonic acid derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 4. The therapeutic agent for infectious diseases according to claim 3, wherein the infectious disease is mycosis. 5. The therapeutic agent for cardiovascular disease according to claim 3, wherein the cardiovascular disease is hypercholesterolemia / hyperlipidemia or arteriosclerosis. 6. A compound represented by the following general formula (1): (Wherein, A ¹ and A ² each represent hydrogen or an aromatic ring group which may have a substituent. X ¹ and X ² each represent a linear or Branched carbon number 1
-20 represents a saturated or unsaturated divalent aliphatic hydrocarbon residue. However, A ¹ X ¹ and A ² X ^{2 each} have 1 to 1 carbon atoms.
Excludes the case of 3 alkyl groups and both benzyl groups. Or a pharmaceutically acceptable salt thereof. 7. The novel malonic acid derivative according to claim 6, wherein A ¹ and A ² in the general formula (1) are hydrogen or an optionally substituted phenyl group or naphthyl group, or a pharmaceutically acceptable salt thereof. Salt 8. Dodecyl-2- (5-phenylpentyl) malonic acid, 2-dodecyl-2- (4-phenylbutyl) malonic acid, 2-farnesyl-2- {3- (β-naphthyl) propyl ｝ Malonic acid, 2-farnesyl-2-
Novel malonic acid derivatives selected from {4- (3-phenoxyphenyl) butyl} malonic acid. 9. A compound represented by the following general formula (4): Wherein R represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms or a substituted or unsubstituted aralkyl group having 7 to 10 carbon atoms, or a compound represented by the following general formula ( 2) (In the formula, A ¹ represents hydrogen or an aromatic ring group which may have a substituent. X ¹ may have a substituent.
It represents a straight-chain or branched-chain saturated or unsaturated divalent aliphatic hydrocarbon residue having 1 to 20 carbon atoms. R is 1-10 carbon atoms
Or a substituted or unsubstituted alkyl group, or
10 represents a substituted or unsubstituted aralkyl group), which is obtained by alkylating a compound represented by the following general formula (3): (Wherein A ¹ and A ² each represent hydrogen or an aromatic ring group which may have a substituent. X ¹ and X ² each represent a linear or branched group which may have a substituent. Chain carbon number 1-2
And 0 represents a saturated or unsaturated divalent aliphatic hydrocarbon residue. R represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, or a substituted or unsubstituted aralkyl group having 7 to 10 carbon atoms), which is converted into a carboxylic acid. , The following general formula (1): (Wherein A ¹ and A ² each represent hydrogen or an aromatic ring group which may have a substituent. X ¹ and X ² each represent a linear or branched group which may have a substituent. Chain carbon number 1-2
And 0 represents a saturated or unsaturated divalent aliphatic hydrocarbon residue. )). 10. The following general formula (2): (In the formula, A ¹ represents hydrogen or an aromatic ring group which may have a substituent. X ¹ may have a substituent.
It represents a straight-chain or branched-chain saturated or unsaturated divalent aliphatic hydrocarbon residue having 1 to 20 carbon atoms. R is 1-10 carbon atoms
Or a substituted or unsubstituted alkyl group, or
10 represents a substituted or unsubstituted aralkyl group). 11. The following general formula (3): (Wherein A ¹ and A ² each represent hydrogen or an aromatic ring group which may have a substituent. X ¹ and X ² each represent a linear or branched group which may have a substituent. Chain carbon number 1-2
And 0 represents a saturated or unsaturated divalent aliphatic hydrocarbon residue. R represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms or a substituted or unsubstituted aralkyl group having 7 to 10 carbon atoms)