JPH06500315A - benzamide derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] benzamide derivative The present invention relates to novel therapeutically effective benzamide derivatives, methods for their production, and and pharmaceutical compositions containing the same, as well as methods for their use.

The novel benzamide derivative of the present invention has the following formula (1) [wherein R+ is 1 G) may optionally contain more than one carbon-carbon double or triple bond; and Optionally interrupted by one or more heteroatoms, such as oxygen, sulfur or nitrogen atoms. may be optionally interrupted (and optionally interrupted by one or more sulfinyl or sulfonyl groups) a straight or branched alkyl group having up to about 20 carbon atoms, which may be , preferably alkylthioalkyl, alkylaminoalkyl or dialkyl a minoalkyl group, or more particularly, optionally /% rogens, such as bromine, iodine, ), preferably a chlorine atom, an amino group, each having up to about 3 carbon atoms alkoxy, alkylthio and alkylamino groups, and the formula -CONR'R' (Here, R6 represents a hydrogen atom or a methyl group, and R7 represents methyl, tri- 1 selected from the group having a fluoromethyl or trichloromethyl group) Alkyl, alkenyl, alkoxyalkyl, which may have one or more substituents Alkoxyalkoxyalkylalkoxyalkoxyalkoxyalkoxyalkyl group and the symbols R2 are the same or different and each contain up to about 6 hydrogen atoms. a straight-chain or branched alkyl group having carbon atoms, or optionally substituted GX However, TvX) represents an engineering group, or two groups R2 are bonded to them. having from 3 to about 8 carbon atoms together with carbon atoms and optionally oxygen, sulfur Saturated, which may contain one or more heteroatoms selected from yellow and nitrogen atoms or form an unsaturated ring, and R3 represents a hydrogen atom or about 6 represents a straight-chain or branched alkyl group having up to 6 carbon atoms, R4 is about 6 Straight-chain or branched alkoxy or alkylthio groups having up to 3 carbon atoms or dimethylamino group, or less than or equal to one nitrogen atom (both have one nitrogen atom). a 5- to 8-membered compound that has a nitrogen atom and is connected to the rest of the molecule through its nitrogen atom a heterocyclo group, such as imidazol-1-yl or pyrrolidin-1-yl and R5 represents a group of the formula -NR8R9 or -ORIO, where R8 or and R9 are the same or different and each represents a hydrogen atom, or one or more carbon-carbon double or triple bonds, and one or more carbon-carbon double or triple bonds. may be optionally interrupted by a heteroatom, such as an oxygen, sulfur or nitrogen atom ( , and optionally interrupted by one or more sulfinyl or sulfonyl groups. represents a straight-chain or branched alkyl group having up to about 10 carbon atoms; and R'' represents a hydrogen atom, or one or more carbon-carbon double or triple may optionally contain bonds and one or more heteroatoms, e.g. oxygen, sulfur. May be optionally interrupted by yellow or nitrogen atoms (and one or more sulfinyl atoms). up to about 10 carbon atoms, optionally interrupted by sulfonyl or sulfonyl groups represents a straight-chain or branched-chain alkyl group) compounds and their pharmaceutically acceptable salts.

As is clear to those skilled in the art, the compound of formula vinegar. All of the above forms and mixtures thereof, as well as methods for their production and separation. are included in the present invention.

Compounds of particular interest according to the invention include at least one of these symbols: (i) R' is alkyl, alkenyl, alkyl having 8 to 20 carbon atoms; xyalkyl, alkoxyalkoxyalkyl, alkoxyalkoxyalkoxy sialkyl or haloalkyl, such as a chloroalkyl group, preferably from 8 to 20 represents an alkyl or alkenyl group having 1, preferably 10 or 18 carbon atoms. death, (i) Each of the symbols R2 represents a hydrogen atom, or these two groups R2 are together with the carbon atoms attached to them, from 3 to 8, preferably 5 or forming a cycloalkyl ring having 6, for example 5, carbon atoms; (i i i) R' represents a hydrogen atom, (iv) R' is imidazole-1 -yl group or a straight group having up to 3, preferably 1 or 2 carbon atoms. chain or branched alkokenes or alkylthio groups, preferably methoxy, methyl represents thio or ethylthio, (v) R'' represents a hydrogen atom, or a straight chain having 3 or less carbon atoms; represents a branched alkyl group, e.g. methyl, and (vi) R' represents one or more oxygen or or 6 or less carbon atoms, optionally interrupted by sulfur atoms or sulfonyl groups. Straight-chain or branched alkyl or alkenyl groups having elementary atoms, preferably 3 or or alkyl, alkoxyalkyl or alkylthio having 4 carbon atoms an alkyl group or an alkenyl group having 5 carbon atoms, such as butyl, methoxy, ethyl, methylthioethyl, methoxypropyl, methylthiopropyl, methyl Represents sulfonylpropyl or methylbut-2-enyl group, (vii) R'' represents a hydrogen atom or has up to 6 carbon atoms, preferably up to 3 carbon atoms represents a straight-chain or branched alkyl group, such as methyl, Compounds and and pharmaceutically acceptable salts thereof.

Important compounds according to the invention include: A(Z)-N-(2- Methylthio)ethyl-4-methylthio-3-(octademo-9-enamide)ben Zuamide: B (Z)-N-(2-methoxy)ethyl-4-methylthio-3-( Octademo-9-enamide) benzamide; C 4-methoxy-3-(octade (Z)-methyl mo-9-enamido)benzoate; DN-(2-methylthio)ethyl-3-hexadecanamide-4-(methylthio) Benzamide: EN-butyl-3-hexadecanamide-4-(methylthio)benzamide; FN-(2-methoxy)ethyl-3-hexadecanamide-4-(methylthio)ben nzamide.

GN-butyl-3-dodecanamide-4-(methylthio)benzamide H N-, (2-methoxy)ethyl-3-dodecanamide-4-(methylthio)benzamide : IN-(2-methylthio)ethyl-3-dodecanamide-4-(methylthio)ben Zuamide; JN-Butyl-N-methyl-3-hexadecanamide-4-methoxybenzamide ; K (Z)-N-butyl-4-methoxy-3-(octagase-9-enamide) nzamide; LN-(2-methylthio)ethyl-3-(1-decylcyclopentanecarboxa) mido)-4-(methylthio)benzamide; M 4-methoxy-3-(octag Z-9-enamide) benzoic acid (Z)-sodium; N (Z)-4-methquin-3-(octagase-9-enamide)benzoic acid: ON-butyl-3-dodecanamide-4-(ethylthio)benzamide PN-butyl 4-ethylthio-3-hexadecanamide benzamide QN-butyl-4-ethyl Tylthio-3-hebutadecanamide benzamide RN-butyl-4-ethylthio- 3-octadecanamide benzamide S 4-ethylthio-3-hexadecanamide -N-(2-methylthioethyl)benzamide; T 4-ethylthio-3-heptadecanamide-N-(2-methylthioethyl)ben Nzuamide: U 3-hebutadecanamide-4-methylthio-N-(2-methylthioethyl)be Nzuamide: v 3-hebutadecanamide-N-(2-methoxyethyl)-4-(methylthio) Benzamide; W (Z)-N-butyl-3-octagase-9-enamide-4-(methylthio) Benzamide; X 4-ethylthio-N-(3-methylthiopropyl)-3-octadecanamide Benzamide; Y 4-ethylthio-3-hebutadecanamide-N-(3-methylthiopropyl) Benzamide; Z 4-ethylthio-3-hexadecanamide-N-(3-methylthiopropyl) Benzamide; AA 4-Methylthio-N-(2-methylthioethyl)-3-octadecanamide Benzamide: AB N-butyl-3-dodecanamide-4-methoxybenzamide: AC4-e Chilthio-3-hexadecanamide-N-(3-methoxypropyl)benzamide : AD N-butyl-3-octadecanamide-4-(methylthio)benzamide: AE 4-methylthio-N-(3-methylthiopropyl)-3-octadekanami Dobenzamide; AF 4-ethylthio-N-(3-methoxypropyl)-3-octadecanamide Benzamide: AG N-butyl-3-(5-chloropentanamide)-4-(ethylthio)ben Zuamide; AH3-(4-chlorobutanamide)-4-ethylthio-N-(3-methylthiop lopil) benzamide; AI 3-(5-chloropentanamide)-4-ethylthio-N-(3-methylthio Opropyl) benzamide; AJ methyl 3-hexadecanamide-4-methoxybenzoate; AK 3-hexa Decanamide-4-methoxybenzoic acid: AL 3-hexadecanamide-4-methoxy Sodium cybenzoate: AM 3-hexadecanamide-4-methoxy-N-(2 -methoxyethyl)benzamide; AN 3-hexadecanamide-4-methoxy-N-(3-methylbut-2-enyl ) Benzamide: AON-Butyl-4-methylthio-3-(5,9-dioxahexadecanamide) Benzamide: AP 4-methylthio-N-(3-methylthiopropyl)-3-(5゜9-di oxahexadecanamide) benzamide: AQ N-butyl-4-ethylthio- 3-(5,9,13-trioxahexadecanamide)benzamide; AR4-ethylthio-N-(3-methylthiopropyl)-3-(5゜9-dio (xahexadecanamide) benzamide: AS N-butyl-4-ethylthio-3 -(5,9-dioxahexadecanamide)benzamide; AT 4-ethylthio-N-(3-methoxypropyl)-3-(5,9-dio AU 4-ethylthio-N-(3-meth xypropyl)-3-(5,9゜13-trioxahexadecanamide)benz Amide; AV 4-ethylthio-N=(3-methoxypropyl)-3-(5-o xahexadecanamide) benzamide; AW 4-methylthio-N-(3-methy ruthiopropyl)-3-(5-oxahexadecanamide)benzamide; AX N-butyl-4-methylthio-3-(5-oxahexadecanamide)benzami Do; AY 4-methoxy-N-(3-methylthiopropyl)-3-(5,9-dioxy sahexadecanamide) benzamide: AZ 4-ethylthio-N=(3-methyl thiopropyl)-3-(5゜9.13-trioxahexadecanamide)benza Mido; BA 3-heptadecanamide-4-(imidazol-1-yl)benzoic acid Methyl; BBN-(3-methylsulfonylpropyl)-4-methylthio-3-(5,9- Dioxahexadecanamide) benzamide: BC4-ethylthio-N-(3-methane) methylthiopropyl)-3-(5゜9-dioxaoctadecanamide)benzamide ;BD N-butyl-4-ethylthio-3-(5,10-dioxahexadecana mido)benzamide; BE 4-ethylthio-N-(3-methylthiopropyl)-3-(6°10.1 4-trioxahexadecanamide) benzamide; BF 4-imidazole-1 -yl-N-(3-methylthiopropyl)-3-(5-oxahexadecanamide ) benzamide; and BG 3-hexadecanamide-4-imidazole-1- yl-N-(3-methylthiopropyl)benzamide.

Assign letters A to BG to compounds for ease of reference later in this specification. guess.

The compounds according to the invention are acylcoenzyme-A:cholesterol-O-acyl It is an inhibitor of transferase (ACAT; EC2, 3, 1, 26).

Therefore, they are valuable as anti-atherosclerotic agents and atherosclerotic agents. arteriosclerosis, hyperlipidemia, cholesterol ester storage disease, and intravenous transfer. Shows effectiveness in treating atheroma in explants.

Compounds within the scope of the invention have been implicated in pharmaceutical activity in humans and other animals. positive pharmaceutical activity as shown in the in vitro and in vivo tests described below. show.

In assays performed in vitro, microsomes (0.5% W/W Coles Liver of rats fed a diet supplemented with terol and 0.25% w/w cholic acid for 7 days. (prepared from internal organs) at a concentration of 0. According to the present invention of 5 μg/mL or 1 μg/mL In the presence of compounds were incubated with radiolabeled oleoyl-CoA. arise The degree of ACAT inhibition was less than 99%.

In vivo studies were similar to those described above and additionally 0.01% w, w When using rats fed a diet supplemented with the test compound of , after 3 days compared to control animals fed a cholesterol-supplemented diet without this drug. It has been shown to suppress the increase in plasma cholesterol concentration measured by 100%. It was.

Known methods (which have been previously used or described in the literature) having the formula I by applying or adapting the method It is possible to produce compounds.

In accordance with the characteristics of the invention, the general formula II shown below [wherein R3, R4 and R5 are Compounds with the general formula % and the general formula %) [In the formula, R1 and R2 are the same as defined above, and Zl is a halogen , such as a chlorine atom, or an alkoxycarbonyloxy group, such as a methoxycarboxylic A compound having carbonyloxy or ethoxycarbonyloxy, or is the general formula: %formula%() [wherein R1 and R2 are the same as defined above] Compounds of general formula I are prepared by reacting with

If Zl represents a halogen atom, the reaction may be carried out using a suitable base, e.g. a tertiary amine. , for example in the presence of triethylamine or pyridine.

In each case, the reaction is carried out in a suitable solvent, such as dichloromethane, optionally with heating. It can be done from

According to still further features of the invention, the general formula: % formula %() [wherein R'' optionally contains one or more carbon-carbon double or triple bonds. and one or more heteroatoms such as oxygen, sulfur or nitrogen atoms are optional. and one or more sulfinyl or sulfonyl groups. a straight chain or having up to about 10 carbon atoms, optionally interrupted by branched alkyl group] or the general formula: %formula%() [wherein R8 and R9 are as defined above] and the following: Formula VII shown below [wherein R1, R2, R3 and R4 are as defined above] and Z2 is a hydroxy group, a /10 group, for example a chlorine atom, or an atom. alkoxycarbonyloxy group, such as methoxycarbonyloxy or ethoxy Reacting with a compound having carbonyloxy or the corresponding anhydride. Compounds of formula I in which RIO is other than hydrogen are prepared by

These reaction conditions relate to the reaction between compounds having general formulas II and III. The conditions are the same as those described above.

If Z2 represents a hydroxy group, the reaction is preferably carried out using a condensing agent, such as dicyclo optionally in the presence of hexylcarbodiimide or a catalytic amount of an inorganic acid, e.g. It can be carried out in the presence of hydrochloric acid prepared in an incubator.

In each case, the reaction is carried out in a suitable solvent, such as dichloromethane, optionally with heating. It can be done from

According to a further feature of the invention, by interconversion of other compounds having formula I: A compound having the general formula (1) is prepared. For example, in accordance with a feature of the invention, (a) R3 and/or a compound having the formula ■ in which Ra and/or R9 are other than hydrogen; , by applying or adapting known methods for alkylation. and/or from compounds of formula I in which R8 and/or R9 represent a hydrogen atom according to still further features of the invention, (b) containing a sulfonyl group; 1 is a compound of formula I containing a sulfinyl or thio group. A compound having the formula ■ which is prepared by the oxidation of a compound and which contains a sulfinyl group is , using common oxidizing agents such as percarboxylic acids (e.g. m-chloroperbenzoic acid), The thio group is removed in an inert solvent such as dichloromethane at room temperature or below. prepared by oxidizing a compound of formula I containing; According to a further feature, (c) compounds of formula I in which RIJ represents a hydrogen atom are may optionally contain more than one carbon-carbon double or triple bond, and one or more carbon-carbon double or triple bonds; optionally interrupted by one or more heteroatoms, such as oxygen, sulfur or nitrogen atoms. and optionally interrupted by one or more sulfinyl or sulfonyl groups. a straight or branched chain alkyl group having up to about 10 carbon atoms, which may be From a compound having the formula I, hydration of the ester group -COORIG by known methods mineral acids, followed by decomposition, e.g. reaction with an alkali, e.g. aqueous sodium hydroxide solution; produced by neutralization, for example by treatment with dilute hydrochloric acid: and conversely, the present invention according to the further characteristic of (d) R'' is one or more carbon-carbon double or triple may optionally contain bonds and one or more heteroatoms, e.g. oxygen, sulfur. optionally interrupted by yellow or nitrogen atoms, and one or more sulfini up to about 10 carbon atoms, optionally interrupted by sulfonyl or sulfonyl groups Compounds of formula I representing a straight-chain or branched alkyl group having By applying or adapting, RIO has the formula I representing a hydrogen atom. Manufactured by esterifying a compound.

As used herein, the term "pharmaceutically acceptable salts" refers to acid addition salts [these anions are , the beneficial pharmaceutical properties of compounds having formula I are due to the side effects attributable to these anions. Therefore, when used in therapeutic doses that do not impair the animal's organic tissue, relatively harmless], as well as salts formed when using bases, e.g. alkali metals. salts, such as sodium or potassium salts, and alkaline earth metals, such as potassium salts. Lucium or magnesium salts [these cations are compounds of formula I] ensure that the beneficial pharmaceutical properties of these cations are not compromised by the side effects attributed to these cations. relatively harmless to the animal's organic system when used in therapeutic doses. ] means.

In this specification, when referring to a compound having formula I, the context allows It should be understood that where applicable, reference is also made to their pharmaceutically acceptable salts. It is.

Acid addition salts suitable for use in medicine include salts derived from inorganic acids, such as the hydrochloride salt. , hydrobromide, phosphate, sulfate and nitrate, and derived from organic acids. Salts, such as oxalates, lactates, tartrates, acetates, salicylates, citric acids salt, propionate, succinate, fumarate, maleate, methylene-bis -β-Hydroxynaphtonites, gentisate and di-p-toluoyl alcohol It may be selected from lithates.

Salts of compounds having formula I are as effective as active compounds themselves. For example, using techniques well known to those skilled in the art, these salts and The purpose of purifying the crude compound by examining the difference in solubility between the compound and is valid.

From the crude compound of formula I by applying or adapting known methods, It is possible to produce salts and by applying or adapting known methods. It is possible to prepare crude compounds of formula I from the above salts by .

by conventional physical means, such as crystallization or chromatography, having the formula I It is possible to purify the compound.

By applying or adapting known methods, formulas II, III, rv, v, It is possible to produce compounds with Vl and VII.

For example, acid halides of formula VII in which Zl represents a halogen atom can be prepared by applying known methods. By using or adapting, the equivalents of formula VII in which Zl represents a hydroxy group For example, when Zl represents a chlorine atom, thionyl chloride Alternatively, it can be produced by reaction with oxalyl chloride.

Similarly, acid halides of formula III, in which Zl represents a halogen atom, can be prepared using known methods. By using or adapting the general formula: % formula %) [where R+ and R2 are the same as defined above] If Zl represents a chlorine atom, thionyl chloride or It can be produced by reaction with oxalyl chloride.

General formulas within formula VIII: R12-C(R”)zcOOH(IX) [wherein Rl2 is alkoxyalkyl or more specifically, alkoxyalkoxyalkyl, or especially alkoxy represents an alkoxyalkoxyalkyl group, and R2 is the same as defined above ] are key intermediates, and these compounds, their methods for their preparation, as well as in the synthesis of effective drugs, e.g. compounds of formula I. Their use forms a feature of the invention.

In accordance with a feature of the invention, e.g. alkali metal halides, e.g. sodium bromide and free radicals, e.g. 2. 6. With 6-tetramethyl-1-piperidinyloxy free radical By applying or adapting known methods by reaction, the general formula.

R12-C(R”)2CH20H(X) [wherein Rl2 and R2 are defined above] By oxidizing a compound having the formula IX as defined above, Manufacture the compound.

This reaction is preferably carried out using a base, such as an alkali metal carbonate or bicarbonate of water. in the presence of a solution and a suitable solvent such as acetonitrile, preferably at room temperature. , more particularly at room temperature or below.

The examples presented below illustrate the preparation of compounds according to the invention. Example 1 to 16 illustrate the production of compounds having the general formula (1), and Example 1 7 and 18 illustrate the preparation of key intermediates with general formula IX. and Reference Examples illustrate the preparation of other intermediates.

Oleic acid (4.20 g) and triethyl acetate in dichloromethane (50 mL) A stirred solution of amine (1.8 g) was dissolved in methyl chloroformate at -30°C. (1.7 g). After stirring the mixture for 2 hours, warm it up brought to ambient temperature. This was then dissolved in N-(2-methane) in dichloromethane (50 mL). methylthio)ethyl-4-methylthio-3-aminobenzamide (4.0g) and and triethylamine (2.5 g). This results in a transparent The solution was allowed to stand for 17 hours, then diluted with dichloromethane (250 mL) and followed by salt solution. Acid (20QmL: IN), sodium chloride aqueous solution, sodium hydrogen carbonate Wash with saturated aqueous solution (100 mL) and finally with aqueous sodium chloride solution, and wash with sulfuric acid. After drying over magnesium, it was concentrated under reduced pressure. This resulting residue is dissolved in diethyl Dissolved in ether (250 mL) and dissolved this solution in hydrochloric acid (2 x 150 mL: 2N) After washing with and drying over magnesium sulfate, it was concentrated under reduced pressure. This results in The residue was crystallized from a mixture of betrol (boiling point 40-60°C) and diethyl ether. Upon analysis, a waxy solid is obtained, which is then subjected to column chromatography using silica gel. Elution with ethyl acetate followed by t-butyl methyl ether. Colorless soft solid form with melting point 84-86°C by recrystallization from tel. (Z)-N-(2-methylthio)ethyl-4-methylthio-3-(octademo -9-enamide)benzamide (0.7 g) was obtained.

[Elemental analysis values: C, 67, 4; H, 9, 5; N, 5.1; S, 12° 2%: Calculated value knee C, 66, 88; H, 9, 29; N, 5, 38: S.

12.31%] Dry dichloromethane (50 mL) and dry triethylamine (2°79 mL) N-(2-methoxy)ethyl-3-amino-4-(methylthio)benzami A water-cooled solution of the salt (3.99 g) in dry dichloromethane (30 mL) The mixture was treated slowly with a solution consisting of chlorooleoyl (5 g). Bring this mixture to ambient temperature. After stirring at 30°C for 2.5 hours, it was concentrated under reduced pressure to leave a solid. This solid is acetic acid Dissolved in ethyl, and this solution was washed successively with hydrochloric acid (2N), sodium hydroxide solution. solution (IN) and water, dried over magnesium sulfate and then concentrated under reduced pressure. Shrunk.

The resulting residue was dissolved in a mixture of amyl acetate (65 mL) and ethyl acetate (5 mL). After crystallizing from toluene, a soft material with a melting point of 110-112℃ is obtained. (Z)-N-(2-methoxy)ethyl-4-methylthio-3 in the form of a pale white solid -(Octademo-9-enamide)benzamide (4.81 g) was obtained.

[Elemental analysis value; -C169,1:H19,8;N, 5.46;S, 6°5%; Calculated value knee C, 69,00; H, 9,58; N, 5.55: S.

6.35%] Dry dichloromethane (50 mL) and dry triethylamine (2°79 mL) A solution consisting of methyl 3-amino-4-methoxybenzoate (3.0 g) in Soaked with a solution of oleoyl chloride (5 g) in dry dichloromethane (30 mL). I processed it thoroughly. The mixture was stirred at ambient temperature for 45 minutes and then concentrated under reduced pressure. Ta. By crystallizing the obtained solid from aqueous ethanol, brown crystals (6,6 3g) was obtained, and this sample (250mg) was mixed with traces of methanol. By recrystallizing from ice-cold Betrol (boiling point 40-60℃), the melting point is 46-60℃. 4-Methoxy-3-(octademo-9-enami) in off-white crystalline form at 47°C. (Z)-methyl benzoate (195 mg) was obtained.

[Elemental analysis value Knee C 172.2; H, 9.65; N, 3.18%; Calculated value Knee C 172,77; H, 9,72; N in 3.14% cocyclomethane (20 mL) (Z)-4-methoxy-3-(octademo-9-enamide)benzoyl chloride ( 1,5g) [(Z)-4-methoxy-3-(octademo-9-enamide)benzoin Reaction of acid (itself prepared as described in Example 7 below) with thionyl chloride A stirred, water-cooled solution consisting of the prepared solution was dissolved in dry dichloromethane (10 mL). of butylamine (0.5 g). This mixture at ambient temperature After stirring for 1 hour, it was concentrated under reduced pressure. This resulting residue was purified from cyclohexane. After crystallization, by recrystallizing from a mixture of diethyl ether and pentane, (Z)-N-Butyl-4-methoxy-3 in the form of a gray solid with a melting point of 81-82 °C -(Octademo-9-enamide)benzamide (0,474 g) was obtained.

[Elemental analysis value knee C, 73.9; H, 10.4; N, 5.7%; calculated value knee C, 74,03; Hllo, 35; N, 5.76%] dry dichloromethane (50 mL ) in N-(2-methylthio)ethyl-3-amino-4-(methylthio)benz A solution consisting of amide (3.0 g) and dry triethylamine (3.0 g) was Composed of hexadecanoyl chloride (3.4 g) in dry dichloromethane (20 mL). was treated with a solution containing The solution was stirred at ambient temperature for 3 hours and then dichloromethane ( 250 mL). This solution was washed with hydrochloric acid (100 mL: IN). , dried over magnesium sulfate, concentrated under reduced pressure, and this resulting solid was reconstituted from a mixture of t-butyl methyl ether and ethanol (9:lv/v). By crystallization, N-(2-methylthio ) Ethyl-3-hexadecanamide-4-(methylthio)benzamide (5,14 g) was obtained.

[Elemental analysis value knee C165.3; H, 9.4: N, 5.6; S, 13°2%: Calculated value knee C165,54; H19,37:N, 5.66:S, 12.96%] in a similar manner, except using the appropriate acid chloride and appropriate benzamide derivative. By proceeding, the following was produced: a white color with a melting point of 125-126°C. N-Butyl-3-hexadecanamide-4-(methylthio)benzamide in crystalline form [Elemental analysis value K, 70.4; H, 10,18; N, 5.88; S.

6.95%: Calculated value knee C, 70, 54; H, 10, 15; N, 5.88: S.

6.73%], N-(2-methoxy)ethyl-3- in white crystalline form with melting point 115-117°C Hexadecanamide-4-(methylthio)benzamide, [Elemental analysis value: C,6 8,1; H, 9,9; N, 5.8; S, 6.88%; Calculated value knee C, 67, 74; H, 9, 69: N, 5.85; S.

6.70%], N-Butyl-3-dodecanamide-4- in white crystalline form with a melting point of 126-128°C (Methylthio)benzamide, [Elemental analysis: C, 68,4, H, 9,6; N ,6. 7;S, 7. 7%: Calculated value--C168,53; H19,58;N, 6.66;S.

7.62%], N-(2-methoxy)ethyl-3-de in white crystalline form with melting point 113-115°C Decanamide-4-(methylthio)benzamide, [elemental analysis value nee c, 65.3 ;H19,2;N,6. 6; S, 7. 6%; Calculated value knee C, 65,37; H, 9,06; N, 6.63:S.

7.59%], N-(2-methylthio)ethyl-3- in white crystalline form with melting point 102-104°C Dodecanamide-4-(methylthio)benzamide, [elemental analysis value nee C163, 1: H, s, 8; N, 6.7: S, 14°7%; Calculated value Knee C, 62, 97, H, 8, 73: N, 6.39; S.

14.62%], and Off-white powder form with a melting point of 66-68°C [vetrol (boiling point 100-120°C) °C) to ]N-butyl-N-methyl-3-hexadecanamide-4-methoxybe nzamide, [Elemental analysis value knee C173.2; H, 10.8; N, 5.61%; total) E value knee C, 73,37; H, 10,62; N, 5.90%].

1-decylcyclopentanecarboxylic acid (2 , 1 g) and thionyl chloride (3 mL) was heated under reflux for 3 hours. Ta. After concentrating the reaction mixture under reduced pressure, the resulting residue was dissolved in dichloromethane. (30 mL) and dry triethyl in dichloromethane (50 mL). Ruamine (2,4 g) and N-(2-methylthio)ethyl-3-amino-4- Added to a solution consisting of (methylthio)benzamide (2.16 g). this mixture After stirring for 1 hour at ambient temperature, it was diluted with dichloromethane (100 mL). , followed by hydrochloric acid (100 mL; IN) and aqueous sodium chloride solution (100 mL). ), potassium hydroxide aqueous solution (1.5 g in 100 mL), hydrochloric acid (100 mL; IN ), washed with aqueous sodium chloride solution (100 mL), and dried on magnesium sulfate. After drying, the mixture was concentrated under reduced pressure. The resulting residue was chromatographed using silica gel. The wax was purified by chromatography and eluting with t-butyl methyl ether. N-(2-methylthio)ethyl-3-(1-decylcyclopene) in solid form Tancarboxamide)-4-(methylthio)benzamide (3.15 g) was obtained. It was.

[Elemental analysis value K, 66, 2: H, 9, 4; N, 5.24: S, 12° 3% C27H44N202S2: 1/3: C5HnOl: related calculated value -C, 65,94; H2O, 27:N, 5.36; S, 12.28%] 4-Methoxy (Z)-methyl 3-(octagase-9-enamide)benzoate (6,12 g; performed Sodium hydroxide (0.6 g L water (20 mL) and A mixture of water and ethanol (200 mL) was heated under reflux for 1.5 hours.

This mixture [4-methoxy-3-(octagase-9-enamide)benzoic acid (Z) - contains sodium] after cooling to ambient temperature, mixture of crushed ice and concentrated hydrochloric acid. I poured it on top of things. Collecting this product and recrystallizing it from methanol (Z)-4-methoxy-3-(ol) in the form of a white powder with a melting point of 179-183°C. Cutagce-9-enamido)benzoic acid (4.14 g) was obtained.

[Elemental analysis value K172, 3; H2O, 5; N, 3. 3%; Calculated value knee c , 72.35; H, 9,57; N, 3.24%.

using the appropriate acid chloride and the appropriate aniline, and at the end of this reaction period As described in Example 5, except simply removing the solvent under pressure and crystallizing this residue. By proceeding in a similar manner as above, the following were prepared: N-Butyl in the form of white plates (from aqueous ethanol) with a melting point of 102-104°C -3-dodecanamide-4-(ethylthio)benzamide, [elemental analysis value C1 69,0; H, 9,9:N, 6.4; S, 7.4%: Calculated knee C, 69,08; H2O, 74; N, 6.45; S.

7.37%], N-Butyl-4- in white crystalline form (from aqueous ethanol) with melting point 89-91°C Ethylthio-3-hexadecanamide benzamide, [elemental analysis value: C, 70, 9; H, 10, 3; N, 5. 4: S, 6°57%; Calculated value knee C, 70, 97: H, 10, 27: N, 5.71; S, 6, 5 3% co, N-Butyl-4- in white crystalline form (from aqueous ethanol) with melting point 81-83°C Ethylthio-3-hebutadecanamide benzamide, [elemental analysis value C, 71, 1;Hllo, 7;N, 5.3;S, 6°09%: Calculated value knee C171,37:H,10,38;N,5.55;S.

6. 35%, N-Butyl-4- in white crystalline form (from aqueous ethanol) with melting point 80-82°C Ethylthio-3-octadecanamide benzamide, [elemental analysis value C, 71, 6; H, 10, 8: N, 5. 3;S, 6゜02%; Calculated value knee C, 71, 76; H, 10, 49: N, 5.40; S.

6.18%], 4-Ethylthio- in white crystalline form (from aqueous ethanol) with melting point 92-94°C 3-hexatadecanamide-N-(2-methylthioethyl)benzamide, [Elemental analysis values: C, 66.5; H, 9.7; N, 5.5; S, 12°5%; Calculated value knee C, 66,09; H, 9,51; N, 5.51; S.

12.60%], 4-Ethylthio- in white crystalline form (aqueous ethanol) with a melting point of 91-93°C 3-hebutadecanamide-N-(2-methylthioethyl)benzamide, [Elemental analysis value knee c, 66, 5; H, 9, 7; N, 5.　36　;S, 　12゜0%; Calculated value knee C, 66, 62; H, 9, 64; N, 5.36; S.

12.26%], A white crystalline form with a melting point of 101-102°C (aqueous ethanol followed by ethyl acetate). 3-hebutadecanamide-4-methylthio-N-(2-methylthioethyl) benzamide, [Elemental analysis value Knee C166.5; H19.8: N, 5.50; S, 12°6%: Calculated value knee C, 66, 09: H 19, 51; N, 5.51; S, 12.60% ,and A white crystalline form with a melting point of 115-116°C (aqueous ethanol followed by isopropyl) 3-heptadecanamide-N-(2-methoxyethyl)-4-(methyl ruthio)benzamide, [elemental analysis value K, 68, 4: Hllo, 10; N, 5.65;S.

6゜50%; Calculated value K 168,25; H, 9,82; N, 5.69; S, N-(2-meth xy)ethyl-3-amino-4-(methylthio)benzamide in an appropriate amount of 3-amino-4-(methylthio)benzamide. mino-N-butyl-4-(methylthio)benzamide and this product Proceeding in a manner similar to that described in Example 2, except that the product was crystallized from toluene. CZ) in the form of a soft light brown solid with a melting point of 118-120°C -N-butyl-3-octademo-9-enamide-4-(methylthio)benzami manufactured.

[Elemental analysis value knee C171,:3:H,10,OWN,5. 59; S, 6°37%; Calculated value knee C171,66:Hllo,02;N,5.57:S.

6.38%].

Example 10 The procedure was as described in Example 5 except that the appropriate acid chloride and appropriate aniline were used. By proceeding in a similar manner, the following were produced: Colorless crystalline form with melting point of 75-76°C (t-butyl methyl ether and methanol) 4-ethylthio-N-(3-methylthiopropyl)-3-octa of Decanamide benzamide, [elemental analysis [nee C, 67,4; H, 10, OWN, 5.0; S, 11°6%; Calculated value knee C, 67, 59: H, 9, 88: N, 5.08; S.

11.64%], A white crystalline form with a melting point of 74-77°C (of t-butyl methyl ether and methanol). 4-ethylthio-3-hebutadecanamide-N-(3-methylthio) propyl) benzamide, [elemental analysis value C, 67,5; H, 10,00; N , 5.30:S.

11.70%: Calculated value knee C, 67, 11; H, 9, 76; N, 5.22: S.

11.95%], A white crystalline form with a melting point of 75-78°C (of t-butyl methyl ether and methanol). 4-ethylthio-3-hexadecanamide-N-(3-methylthio propyl) benzamide, [elemental analysis value C, 66,5: H, 9,7; N, 5 ．． 11; S, 11°9%: Calculated value Knee C166, 62; H19, 64: N, 5.36; S, 12.26% , A white crystalline form with a melting point of 104-106°C (t-butyl methyl ether and methanol). 4-methylthio-N-(2-methylthioethyl)-3-oc Tadecanamide benzamide, [Elemental analysis value Knee c, 66, 6, H, 9,9 :N, 5.2; S, i2゜0%: Calculated value knee C166,62: H19,64;N, 5.36;S.

12.26%], N in white crystalline form (from t-butyl methyl ether) with melting point 107-109 °C -Butyl-3-dodecanamide-4-methoxybenzamide, [elemental analysis value C ,70,9;H,10,10;N,6.72%:Calculated value knee C,71,24;H , 9,96:N, 6.93%], white crystalline form with a melting point of 78-80°C (acetonyl 4-ethylthio-3-hexadecanamide-N-(3-methoxypyl) lopil) benzamide, [Elemental analysis value -C, 68.4, H19, 93: N, 5.1; S, 6°21%: Calculated value -C168,73:H19,94;N, 5.　53　;　S.

6. 33%, White powder form (t-butyl methyl ether and methanol) with a melting point of 115-118°C. of N-butyl-3-tadecanamide-4-(methylthio) nzamide, [Elemental analysis value Knee C171.6; Hllo, 7; N, 5.13; S, 5°79% ; Calculated value knee C, 71, 38; H, 10, 38; N, 5.55; S, 6, 35 %Ko , 4-Methylthio-N-( 3-methylthiopropyl)-3-octadecanamide benzamide, [Elemental analysis values K, 66, 6; H, 9, 85; N, 4. 83:S, 1 1.65%; Calculated value Knee (:, 67.12; H19, 76; N, 5.22.S, 11.94 %　　　、 4-Ethylthio-N-( 3-methoxypropyl)-3-octadecanamide benzamide, [elemental analysis value -C169,7; H, 10,3; N, 5.07: S, 5°87%.

Calculated value knee C169,62:Hllo,18;N,5.24+S,5499%] , N in the form of a white powder (from t-butyl methyl ether) with a melting point of 104-105 °C -Butyl-3-(5-chloropentanamide)-4-(ethylthio)benzamide , [Elemental analysis value knee C, 58, 2: H 17, 4; C 1, 9, 6; N, 7° 5: S , 8.6%; Calculated value knee C, 58, 28; H, 7, 34; C 1, 9, 56: N.

7.55:S, 8.64%], White powder form (of t-butyl methyl ether and methanol) with a melting point of 80-81°C. 3-(4-chlorobutanamide)-4-ethylthio-N-(3-methyl H , 6, 87, CI, 9. 5, N, 7°3; S, 15.7%; Calculated value knee C152,49; H16,48; C1,9,11;N.

7.20; S, 16.49%], Pale yellow powder form (t-butyl methyl ether and methanol) with a melting point of 95-96°C. 3-(5-chloropentanamide)-4-ethylthio-N-(3 -Methylthiopropyl)benzamide, [Elemental analysis value: 53.7; H, 6,87; C1,8,8; N, 6°82: S, 15.6%: Calculated value Knee C153, 65; H, 6, 75; CL s, 80: N.

6.85; S, 15.91%] and a colorless needle-like form with a melting point of 109-110°C methyl 3-hexadecanamide-4-methoxybenzoate (from ethanol), [Elemental analysis value Knee C171.1: H19.9; N, 3.26%; Calculated value Knee C, 71,56; H, 9,85; N, 3.34%].

(Z)-methyl 4-methoxy-3-(octademo-9-enamido)benzoate an equivalent of methyl 3-hexadecanamide-4-methoxybenzoate (described in Example 10) Proceeding in the same manner as described in Example 7, except replacing Sodium 3-hexadecanamide-4-methoxybenzoate was prepared by 3- in the form of colorless needles (from ethanol) with a melting point of 198-200 °C. Hexadecanamide-4-methoxybenzoic acid was produced.

[Elemental analysis value knee C, 71,1; H, 9,8; N, a, 40%; calculated value knee C, 71,07; H, 9,69; N, 3.45%].

3-Hexadecanamido-4-methoxybenzoic acid (4,04 g; described in Example 11) A mixture of Shitoshita (prepared) and thionyl chloride (1.3 mL) was added to boiling toluene. (100 mL) for 3 hours. The solvent was removed under reduced pressure. residual acid After dissolving the chloride in dry dichloromethane (35 mL), it was dissolved in dichloromethane. 2-Methoxyethylamine (3 mL) and dry triethylamine in methane (115 mL) 1.6 mL). 2 days at ambient temperature After standing for a while, the solution was mixed with hydrochloric acid (2 x 200 mL; 2N) and water (2 x 2 00 mL), it was dried over potassium carbonate and concentrated under reduced pressure. did. The resulting residue was subjected to chromatography on silica gel and By elution with a mixture of ether and dichloromethane, a melting point of 7. 3-hexadecanamide-4-methoxy-N-(2- Methoxyethyl)benzamide (2.0 g) was obtained.

[Elemental analysis value knee c, 69.8; H, 10.3; N, 5.90%: Calculated value knee C, 70,09: H, 10,02; N, 6.06%].

3-hexadecanamide-4-methoxyben chloride in dichloromethane (50 mL) Zoyl[3-hexadecanamido-4-methoxybenzoic acid (2°02g; Example 1 (prepared as described in Section 1) and thionyl chloride] in dichloromethane. 3-Methylbutychloride hydrochloride in ethanol (100 mL) and triethylamine (1 mL) Added to a stirring solution consisting of -2-dynylamine (0.98 g). This mixture The mixture was stirred at ambient temperature for 1 hour and then sequentially added with water (100 mL), sodium hydroxide, and aqueous solution (100 mL: 2N), dilute hydrochloric acid (100 mL: 2N) and water ( 100 mL), it was dried over magnesium sulfate and It was concentrated with The resulting residue was subjected to chromatography using silica gel, 3-hexade was eluted with a mixture of methanol and dichloromethane. Kanamide-4-methoxy-N-(3-methylbut-2-enyl)benzamide ( 0.6 g) was obtained, consisting of betrol (boiling point 40-60°C) and diethyl ether. After crystallization from a mixture of there were.

[Elemental analysis value knee C, 73,2: H, 10,3; N, 5.60%; calculated value knee ( :, 73.68:Hllo, 24;N, 5.93%].

A solution of 5,9-dioxahexadecanoyl chloride [5,9-di Oxahexadecanoic acid (2.0 g; prepared as described in Example 17) and octchloride prepared in dichloromethane (25 mL) from 3-amino in chloromethane (25 mL) and triethylamine (2,5 g) -N-Butyl-4-(methylthio)benzamide (1,83 g) A clear solution was produced. Open at 65 to ambient temperature ! After that, the solution was concentrated under reduced pressure to about 10 mL. T-button this residue. diluted hydrochloric acid (100 ml) L; 0.5N), aqueous sodium hydroxide solution (100mL; 2% w/v) and dilute After washing with hydrochloric acid (100 mL; 0.5 N), dry and concentrate under reduced pressure. did. The resulting residue was subjected to chromatography on silica gel and N-butyl-4 was obtained in the form of a pale yellow waxy solid by elution with chill. -Methylthio-3-(5,9=dioxahexadecanamide)benzamide (2, 05g) was obtained.

[Elemental analysis value knee C, 65, 4; H, 9, 6: N, 5.　93　;S, 6゜ 42%: Calculated value knee C, 64,96; H, 9,23; N, 5.83; S.

6.67%].

Proceeding in the same manner except using appropriate acids and appropriate anilines. The following was prepared: 4-methylthio- in the form of a pale yellow waxy solid. N-(3-methylthiopropyl)-3-(5,9-dioxahexadecanamide) Benzamide, [Elemental analysis value K, 61.0; H2S, 9:N, 5.36; S, 12°4%; Calculated value knee C, 60, 90; H, 8, 65; N, 5.46; S.

12.51%], N-butyl-4-ethylthio-3-(5,9,13-trio) in the form of a tan oil (xahexadecanamide) benzamide, [elemental analysis value C, 62,5; H, 9 , 1:N, 5.7;S, 6.43%: Calculated value knee C, 62,87; H, 8,93; N, 5.64; S.

6.46%], Pale yellow waxy solid form (dissolved using a mixture of dichloromethane and methanol) 4-ethylthio-N-(3-methylthiopropyl)-3-(5,9-dio) (xahexadecanamide) benzamide, [elemental analysis value: C161,4; H,8 ,91;N, 5.34;S.

12.0%; Calculated value knee C, 61,56; H, 8,80; N, 5.32; S.

12.17%], N- in the form of a pale brown oil (eluted with a mixture of dichloromethane and methanol) Butyl-4-ethylthio-3-(5,9-dioxahexadecanamide)benza Mido, [Elemental analysis values: C, 65.4; H, 9.6; N, 5.5; S, 6.26%; Calculated value knee C, 65,55; H, 9,37; N, 5.66: S.

6.48%], 4- in the form of a pale brown oil (eluted with a mixture of dichloromethane and methanol) Ethylthio-N-(3-methoxypropyl)-3-(5,9-dioxahexade Kanamide) Benzamide, [Elemental analysis value knee c, 63.2: H, 9, 1; N, 5 ．． 2. S, 6°12%; Calculated value knee C, 63, 50, H, 9, 08: N, 5.48: S.

6.28%], 4-ethylthio-N-(3-methoxypropyl)-3-(5 ,9,13-trioxahexadecanamide)benzamide, [Elemental analysis value NiC ,60,5;H,s,7;N,5.16;S,6°08%; Calculated knee C, 60,91; H, 8,65; N, 5.46, S.

6.25%], In the form of a light brown oil that solidifies on standing (mixture of dichloromethane and methanol) 4-ethylthio-N-(3-methoxypropyl)-3-(5-o (xahexadecanamide) benzamide, [elemental analysis value: 66, 4: H, 9, 8:N, 5.　35　;S,　6゜24%; Calculated value knee C, 66, 10; H, 9, 51; N, 5.51; S.

6.30%], In the form of a light brown oil that solidifies on standing (mixture of dichloromethane and methanol) 4-methylthio-N-(3-methylthiopropyl)-3-(5- Oxahexadecanamide) Benzamide, [Elemental analysis value: C, 63, 6; H, 9,3; N, 5.48; S, 11°9%; Calculated value knee C, 63,49; H, 9,08: Ns 5.17; S.

12.55%], In the form of a light brown oil that solidifies on standing (mixture of dichloromethane and methanol) N-butyl-4-methylthio-3-(5-oxahexadekanami) c) benzamide, [Elemental analysis value knee C, 68.0; H, 9.9:N, 5.6:S, 6.24%: Calculated value knee C, 67,74; H, 9,69; N, 5.85; S.

6.70%], 4- in the form of a pale brown oil (eluted with a mixture of dichloromethane and methanol) Methoxy-N-(3-methylthiopropyl)-3-(5,9-dioxahexade Kanamide) Benzamide, [Elemental analysis value -C, 62,5; H, 9,2; N, 5 ．． 48; S, 6゜19%; Calculated value knee C, 62, 87: H, 8, 93; N, 5.64; s.

6.46%], and 4- in the form of a pale brown oil (eluted with a mixture of dichloromethane and methanol) Ethylthio-N-(3-methylthiopropyl)-3-(5,9゜13-trioxy (sahexadecanamide) benzamide, [elemental analysis value C, 58, 2; H, 8, 5; N, 4.96; 5111°3%: Calculated value knee C159.06; H, 8.39; N, 5.30; S.

12.13%].

3-Amino-4-(imidazol-1-yl)an in dry pyridine (60 mL) Methyl zoate C2,Og: A stirred solution prepared as described in Reference Example 1. Heptadecanoyl chloride (2.79 g) was added dropwise to the solution over 10 minutes.

Once the reaction is complete (as judged by thin layer chromatogram), add water (300 mL). added. The precipitated solid was collected, washed with water, dried, and then diluted with hydrochloric acid (1 mL). Dissolved by heating in ethyl acetate (60 mL). cooling The solid that crystallized was then collected, washed with diethyl ether, and dried at 80°C. Upon drying, in the form of white crystals of hydrated hydrochloride with a melting point of 106-109 °C, Methyl 3-hebutadecanamide-4-(imidazol-1-yl)benzoate was obtained. It was.

[Elemental analysis value K, 64, 7: H, 8, 6; N, 7.　9　;C1,6゜8 3; Water 3.8%; Calculated value for C25H4sNsos・HCl-H,0 C,64,72;H , 8,99; N, 7.81; C1, 6,59; water, 3.35%].

Applying or adapting the methods described above, more particularly in the previous examples. The following was produced by: a pale brown oil that solidifies on standing. N-(3-methylsulfonylpropyl)-4-methylthio-3-(5,9-di oxahexadecanamide) benzamide, 4-ethylthio-N-(3-methylthiopropyl)-3-( in the form of a light brown oil 5,9-dioxaoctadecanamide)benzamide, [elemental analysis value nee C, 63 , 1: H19.5; N, 4.37%; Calculated value knee C162,78; H, 9,08 ; N, 5.05%], N-butyl-4-ethylthio-3-(5 , 10-dioxahexadecanamide) benzamide, 4-ethyl in the form of a light brown oil. Chilthio-N-(3-methylthiopropyl)-3-(6,10,14-trioxy (sahexadecanamide) benzamide, [elemental analysis value C, 58, 0; H, 8, 5; N, 5. 30;S, 11゜0%: Calculated value knee C, 59,06: H, 8,39, N, 4.95; S.

12.13%], 4-imidazol-1-yl-N-(3- methylthiopropyl')-3-(5-oxahexadecanamide)benzamide, [Elemental analysis value Knee C, 66, O; H, 8,9; N, 10°7%; Calculated value Knee C, 65,62; H, 8,74; N, 10.56%], and 3-hexadecanamide-4-imidazo in the form of a white powder with a melting point of 104-105°C ol-1-yl-N-(3-methylthiopropyl)benzamide, [Elemental analysis value K, 68, 6; H2O. 4; N, 10.7%: Calculated value knee C, 68,14; H, 9,15; N, 10.60%.

5, 9. Maintained at a temperature of 0°C to 10°C. 13-) Dioxahexadeca ton-1-ol (11.5g), 2. 2. 6. 6-tetramethyl-1- Piperidinyloxy free radical (0.25g), sodium bicarbonate water Consisting of solution (450 mL; 5% W/V) and acetonitrile (450 mL) Sodium bromide trihydrate (35,0 g ) was added. After stirring the mixture for 4 hours at ambient temperature, add enough hydrochloric acid and Carefully add aqueous sodium sulfate solution (and adjust the pH to 2 to 4 to avoid excessive oxidation). The reaction was quenched by consuming the agent. Add this solution to t-butylmethyl Extract with methyl ether (4x 200 mL) and combine the organic solutions to remove the salt. After washing with an aqueous sodium chloride solution and drying, the mixture was concentrated under reduced pressure. This resulting residue The residue was distilled at an oven temperature of 170°C and a pressure of 0.1 mmHH. 5.9. in the form of a colorless mobile oil. 13-trioxahexadecanoic acid (1 0.3 g) was obtained.

[Elemental analysis value Knee C 159,52: H, 9,99%; Calculated value Knee C, 59,9; H, 10.9%].

5, 9. Appropriate amount of 13-trioxahexadecan-1-ol 5,9-Dioxahexadecan-1-ol and 5-oxahexadecan-1 - Proceed in the same manner except for replacing with ol, but after concentration under reduced pressure. The remaining residue is taken up in t-butyl methyl ether and the solid is removed by filtration. By removing and concentrating again under reduced pressure before distilling, the following is made: Prepared: 5,9-dioxahexadecanoic acid in the form of a colorless mobile oil, [elemental analysis Value knee C, 64, 9; H, 11, 3%: Calculated value knee C, 64, 58: H, 10, 84%] and 5-ol in the form of a colorless mobile oil that solidifies (melting point 28-30°C). xahexadecanoic acid, [Elemental analysis value Knee C, 68.5: H, 11.6%; Calculated value Knee C, 69,72; H, 11,70%.

Example 18 Compounds INTd, INTe and INTf By proceeding in a manner similar to that described in Example 17, the following were prepared: 6.10.14-Trioxahexadecanoic acid in the form of a colorless mobile oil, [ Elemental analysis value knee C157,5; Hllo, 0%; calculated value knee C,59,52:H 19.99% co, in the form of a colorless mobile oil with a boiling point of 97-105℃ 10.1mmHH 5,10-dioxahexadecanoic acid, [Elemental analysis value knee C, 66.1; H, 11.5%; calculated value knee (:, 64.58 ;Hllo, 84% Co, and 5,9-dioxahex in the form of a colorless mobile oil Sadecanoic acid, [elemental analysis value: C166.2; H, 11.4%; calculated value: C1 66, 63; Hllll, 18%].

Reference example 1 Boiling ethanol (IN) containing water (35 mL) and hydrochloric acid (1.5 mL; IN) 4-(imidazo Reduction of methyl (19°3 g)-1-yl-3-nitrobenzoate was carried out.

Recrystallization from ethyl acetate gives a pale yellow crystalline form with a melting point of 161-165°C. Methyl 3-amino-4-(imidazol-1-yl)benzoate (9.7 g) was gotten.

Reference example 2 4-Fluoro-3-ditho in dry tetrahydrofuran (100 mL) at ambient temperature. React methyl lobenzoate (17.0g) with imidazole (13.0g) It is a large yellow solid form (t-butyl methyl ether) with a melting point of 71-74°C. Methyl 4-(imidazol-1-yl)-3-nitrobenzoate (1 4.68 g) was obtained.

Reference example 3 Iron in boiling ethanol (750 mL) with hydrochloric acid (95 mL; 0.5 N) By reacting with powder (55,0 g), 4-ethylthio-N-(3-methoxy Reduction of (cypropyl)-3-nitrobenzamide (47.0 g) was carried out. t-bu Recrystallization from methyl ether produces a fine crystal with a melting point of 73-75°C. 3-amino-4-ethylthio-N-(3-methoxypropyl) in the form of cream-colored needles Benzamide (32.4 g) was obtained.

Reference example 4 3-methoxypropylamine and 4-ethylthio-3-nitrobenzoyl chloride After the reaction, by recrystallizing from toluene, a product with a melting point of 101-103℃ is obtained. 4-ethylthio-N-(3-methoxypropyl)-3-nitrobene in the form of a yellow solid The nzamide was obtained with a yield of 74%.

Reference example 5 3-(3-propoxypropoxy)propane in dichloromethane (30 mL) A solution consisting of 1-ol (25.39 g) and dry pyridine (11.47 g) was Stir in dichloromethane (90 mL) maintained at a temperature below 0 °C. Added to trifluoromethanesulfonic anhydride (49°Ig) solution over 10 minutes. . The mixture was stirred for 3 hours without further cooling, then ice-cold water (100 mL ) and dried. This solution was filtered and dichloromethane (150 mL ) and then diluted with potassium carbonate (27.0 g) and 4-hydroxybutylene acrylate. (25°2 g) under an argon atmosphere at ambient temperature overnight. next, This mixture was heated under reflux for 8 hours. This mixture was filtered and the residue was dissolved in dichloromethane. After washing with water (300 mL), the filtrate was treated with hydrochloric acid (250 mL; IN) and Washed with water (2x 250 mL). After drying and concentrating under reduced pressure, the remaining residue is , sodium hydroxide in water (65 mL) after dissolving in ethanol (300 mL). The mixture was stirred for 4 hours with a solution consisting of 11.4 g (11.4 g). Pour this solution under reduced pressure. Concentrate to approximately 180 mL and dilute with t-butyl methyl ether (1 liter). After dilution, it was washed with water (2 x 400 mL). Remains after drying and concentration under reduced pressure By distilling the residue under reduced pressure, the boiling point is 109-113°C10. lmm 5.9,134 rioxahexadecane-1-ol in the form of a colorless mobile oil of Hg (16.9 g) was obtained.

An appropriate amount of 3 in place of 3-(3-propoxypropoxy)propan-1-ol Proceed in a similar manner, but using -heptyloxypropan-1-ol. By doing so, the boiling point is 123-125℃10. colorless mobile oil form at lmmHg 5,9-dioxahexadecane-1-ol was prepared.

Reference example 6 Diethyl ether (20 To a stirred solution of aluminum chloride (38,98 g) in Lithium aluminum hydride (3.5 g) was carefully added. Add this mixture to 2 o'clock After stirring for 30 minutes, 2-decyl-1,3-dioxepane (30.7 g ) was added. The mixture was stirred under reflux for 8 hours and then cooled to ambient temperature. water (50 mL) followed by diethyl ether (500 mL) was added dropwise. aqueous fraction After extraction with diethyl ether (3x 200 mL), the organic solutions were combined and dried. It was dry.

After removing the solvent, the residue was distilled to give a boiling point of 126-127 ℃10. 5-oxahexadecan-1-ol (25 , 24g) was obtained.

The present invention also provides compounds of formula I, together with a pharmaceutically acceptable carrier or coating. or drugs containing a small amount of their pharmaceutically acceptable salts. Pharmaceutical preparations are also included within the scope of this invention. In clinical practice, the present invention The compounds may be administered parenterally, rectally or orally.

Solid compositions for oral administration include compressed tablets, tablets, powders and granules. Ru. In the solid composition, one or more of these active compounds and at least Mixed with one inert diluent such as starch, sucrose or lactose . These compositions also contain, as is common practice, additional substances other than inert diluents, For example, a lubricant such as magnesium stearate may be included.

Liquid compositions for oral administration may contain inert diluents commonly used in the art. A pharmaceutically acceptable solvent containing diluents such as water and liquid paraffin. Includes emulsions, solutions, suspensions, syrups and elixirs. The above composition Besides inert diluents, the product also contains adjuvants, such as wetting and suspending agents, and It may also contain sweeteners, seasonings, flavors and preservatives. for oral administration The composition according to the invention may also contain 1 Capsules made of absorbable material, such as gelatin, containing more than one active substance Contains cells.

Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic Includes organic systems, solutions, suspensions and emulsions. Organic solvent or suspending medium Examples of substances include propylene glycol, polyethylene glycol, vegetable oils, e.g. Leaves oil, as well as injectable organic ethers such as ethyl oleate. . These compositions may also contain adjuvants such as stabilizers, preservatives, wetting agents, emulsifying agents, etc. It may also contain agents, dispersants, and the like. For example, using a bacteria-retaining filter. these compositions by filtration, mixing of disinfectants with these compositions, irradiation, or heating. It is possible to sterilize. Dissolve in sterile water or other methods immediately before use. solid sterile composition form capable of being dissolved in any type of injectable sterile medium; It is also possible to produce them in

Solid compositions suitable for rectal administration include those formulated according to known methods and having formula I. Included are suppositories containing at least one compound that

Although it is possible to vary the percentage of active material in the compositions of the invention, These should be in proportions that will give the appropriate dose. clearly It is also possible to administer several unit dosage forms at approximately the same time. clothes to use The dose is determined by the physician and this depends on the desired therapeutic effect, route of administration, depending on the treatment and duration of treatment, as well as on the patient's condition. Oral administration in adults is generally from about 0.5 to about 70, preferably about 70 per kg of body weight per day. Doses range from 1 to about 10 mg.

The following examples illustrate pharmaceutical compositions according to the invention.

Composition Example 1 In accordance with the usual method, each N-butyl-3-hexadecanamide-4-(methylthio)benzamide starch 6 0mg Magnesium stearate 1mg Gelatin capsules of No. 2 size containing the following were produced.

Copy and translation of amendment) Submission (Article 484-8 of the Patent Law) February 12, 1993 stomach

Claims (14)

[Claims] 1. formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼I [wherein R1 optionally contains one or more carbon-carbon double or triple bonds] may be optionally interrupted by one or more heteroatoms, and One or more sulfinyl or sulfonyl groups may be optionally interrupted; alkoxy, especially halogen atoms, amino groups, each having up to 3 carbon atoms; , alkylthio and alkylamino groups, and formula -CONR6R7, where R6 represents a hydrogen atom or a methyl group, and R7 represents methyl, trifluoromethane. one or more substituents selected from groups having a methyl or trichloromethyl group) straight-chain or branched chains having up to 20 carbon atoms, which may have substituents; represents a rukyl group, and the symbols R2 are the same or different and each has 6 hydrogen atoms. Straight-chain or branched alkyl groups having carbon atoms or optionally substituted represents a phenyl group which may be present, or the two groups R2 are together with the elementary atoms, having from 3 to 8 carbon atoms and optionally oxygen, sulfur or and one or more heteroatoms selected from nitrogen atoms. R3 represents a hydrogen atom or has 6 or less carbon atoms. Represents a straight chain or branched alkyl group having atoms, R4 is a carbon atom of up to 6 represents a straight-chain or branched alkoxy or alkylthio group, or represents a dimethylamino group or has at least one nitrogen atom and a 5- to 8-membered heterocyclo linked to the rest of the molecule through its nitrogen atom and R5 represents a group of the formula -NR8R9 or -OR10, where R8 and and R9 are the same or different and each represents a hydrogen atom, or one or more may optionally contain carbon-carbon double or triple bonds, and one or more may be optionally interrupted by heteroatoms, and one or more sulfinyl or has up to 10 carbon atoms, optionally interrupted by sulfonyl groups represents a straight-chain or branched-chain alkyl group, and R10 represents a hydrogen atom, or may optionally contain one or more carbon-carbon double or triple bonds, and may be optionally interrupted by one or more heteroatoms, and one or more up to 10 carbons, optionally interrupted by finyl or sulfonyl groups Represents a group having a linear or branched alkyl group having atoms] and pharmaceutically acceptable salts thereof. 2. R1 is alkylthioalkyl, alkylaminoalkyl or dialkyl 2. A compound according to claim 1, which represents a minoalkyl group. 3. R1 is alkyl, alkenyl, alkoxyalkyl, alkoxyalkoxy Claim 1 representing an alkyl or alkoxyalkoxyalkoxyalkyl group Compounds described. 4. The heterocyclo group represented by R4 is imidazol-1-yl or pyrrolidine-1 A compound according to any one of the preceding claims, which is a -yl group. 5. At least one of the symbols is: (i) R1 or alkyl, alkenyl, alkyl having from 8 to 20 carbon atoms; xyalkyl, alkoxyalkoxyalkyl, alkoxyalkoxyalkoxy represents a sialkyl or haloalkyl group, and (ii) each symbol R2 represents a hydrogen atom. or these two groups R together with the carbon atoms attached to them , forming a cycloalkyl group having 3 to 8 carbon atoms, (i ii) R3 represents a hydrogen atom, (iv) R4 represents an imidazol-1-yl group or has up to 3 carbon atoms; represents a straight-chain or branched alkoxy or alkylthio group having (v) R8 represents a hydrogen atom, or a linear chain having three or less carbon atoms; represents a branched alkyl group, (vi) R9 is optionally substituted with one or more oxygen or sulfur atoms or sulfonyl groups; Straight-chain or branched alkyl having up to 6 carbon atoms, optionally containing or represents an alkenyl group, and (vii) R10 represents a hydrogen atom, or 6 A value selected from represents a straight-chain or branched alkyl group having carbon atoms of: and other symbols are the same as defined in claim 1. Compounds described. 6. (i) R1 is alkyl or alkenyl having 8 to 20 carbon atoms; represents the group, (ii) a symbol represented by two groups R2 together with the carbon atoms bonded to them; the alkyl ring has 5 or 6 carbon atoms, and (iv) the alkyl ring represented by R4 is the alkoxy or alkylthio group has 1 or 2 carbon atoms, (v) R8 represents a potion or methyl, (vi) R9 represents 3 or 4 Alkyl, alkoxyalkyl or alkylthioalkyl group having carbon atoms or represents an alkenyl group having 5 carbon atoms, (vii) R10 represents a hydrogen atom or a straight chain having 3 or less carbon atoms or a branched alkyl group. 7. (i) R1 is an alkyl or alkenyl group having 10 to 18 carbon atoms; represents a group, (ii) a symbol represented by two groups R2 together with the carbon atoms bonded to them; the loalkyl ring has 5 carbon atoms, and (iv) the alkoxy represented by R4 or the alkylthio group is methoxy, methylthio or ethylthio, (vi) R9 is butyl, methoxyethyl, methylthioethyl, methoxypropyl methylthiopropyl, methylsulfonylpropyl or methylbut-2-ethyl represents a nyl group, (vii) Claim 5 or 6, wherein R10 represents a hydrogen atom or a methyl group. Compounds listed. 8. Ben according to claim 1 shown above as any one of compounds A to BG Zuamide derivatives or pharmaceutically acceptable salts thereof. 9. (A) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼II [In the formula, R3, R4 and R5 are as requested. as defined in Range 1] and the general formula: R1-C(R2)2COZ1III [wherein R1 and R2 are the same as defined in claim 1, and Z1 represents a halogen atom or an alkoxycarbonyloxy group] Object or general formula: [R1-C(R2)2CO]2O1V [wherein R1 and R2 are the same as defined in claim 1] or (B) R5 is a group OR10 (where R10 is hydrogen), the general formula: R11OHV [wherein R11 optionally contains one or more carbon-carbon double or triple bonds] may be optionally interrupted by one or more heteroatoms, and may be optionally interrupted by one or more sulfinyl or sulfonyl groups, Represents a straight or branched alkyl group having 10 or less carbon atoms] or a compound having the general formula: HNR8R9VI [wherein R8 and R9 are the same as defined in claim 1] Compound and general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼VII [In the formula, R1, R2, R3 and R4 is the same as defined above, and Z2 is a hydroxy group, a halogen atom , or represents an alkoxycarbonyloxy group] or a corresponding anhydride, (C) then optionally, A compound having general formula (I) is added to another compound having general formula (I) by a known method. and (D) then optionally converting into a pharmaceutically acceptable salt. A method for producing a compound described in Scope 1. 10. one as defined in claim 1 together with a pharmaceutically acceptable carrier or coating. Contains a benzamide derivative having general formula (I) or a pharmaceutically acceptable salt thereof. Pharmaceutical composition. 11. one as defined in claim 1 together with a pharmaceutically acceptable carrier or coating. benzamide derivatives having general formula (I) or pharmaceutically acceptable amounts thereof; Acylcoenzyme-A: Cholesterol-O-acyltransferase A pharmaceutical composition effective in the treatment of conditions reversible by an inhibitor of. 12. A benzamide derivative having the general formula (I) as defined in claim 1 or Acylcoenzyme-A: Coles, comprising administering a pharmaceutically acceptable salt thereof. Treatment of conditions reversible by inhibitors of terol-O-acyltransferase Treatment method. 13. General formula: R12-C(R2)2COOHIX [wherein R12 is alkoxyalkyl, alkoxyalkoxyalkyl or represents an alkoxyalkoxyalkoxyalkyl group, and R2 is The same as defined in 1]. 14. General formula: R12-C(R2)2CH2OHX [wherein R2 is the same as defined in claim 1, and R12 is as defined in claim 1] by oxidizing a compound having the same as defined in range 13 of , comprising converting the group -CH2OH to the group -COOH. Method for manufacturing compounds.