WO1997001533A1 - Thiocarbamic acid derivatives - Google Patents

Abstract

Thiocarbamic acid derivatives represented by general formula (I) and salts thereof, wherein m is 0 or 1; A is 4,4-dimethyl-2-pentynyl or the like; R?1 and R3¿ are each hydrogen, formyl or lower alkyl; Z is nitrogen or CH; R2 is hydrogen, lower alkyl, lower acyl or like; R4 is a phenyl group having an arbitrary substituent or a 5- or 6-membered heterocycle containing at least one atom of oxygen, nitrogen or sulfur or a combination of two or more of them, the heterocycle being optionally substituted by an arbitrary group. They provide an antihypercholesterolemic agent, an antihyperlipemic agent, and a remedy or preventive for arteriosclerosis, each being safer than conventional drugs and exhibiting excellent anticholesterol activity.

Description

 Satsuki Itoda thiocarbamic acid derivative Technical field

 TECHNICAL FIELD The present invention relates to a novel genomic rubamic acid derivative having squalene epoxidase inhibitory activity or a salt thereof, a stereoisomer thereof, a pharmaceutical composition containing them, and a method for producing them. Background art

 In recent years, due to the aging of the population and changes in eating habits, it has been pointed out that arteriosclerosis and the associated frequency of occurrence of various coronary and cerebral artery diseases are increasing.

 Various factors are thought to be involved in the development of arteriosclerosis, and in particular, elevated blood cholesterol is one of the most important risk factors. Blood cholesterol lowering agents are said to be effective. Among these blood cholesterol lowering agents, inhibitors of cholesterol metabolism in vivo are highly evaluated for their clear mechanism of action and strong drug efficacy.

In order to inhibit cholesterol biosynthesis in a living body, it is said that it is useful to inhibit the activity of enzymes involved in the biosynthesis ₍ such cholesterol biosynthesis inhibitors include oral basin, Epps Yutin and Pravas Yutin have already been used clinically (

[Professional, National, Academic, Science

(Proc. Natl. Acad. Sci.), 77, 3957 (1980), etc.].

These known inhibitors target HMG-CoA reductase (HMG-CoA reductase). W

2 The enzyme is located at a relatively early stage in the cholesterol biosynthesis system. For this reason, the enzyme inhibition by the administration of the above-mentioned drug may also cause the inhibition of the synthesis of other physiologically important metabolites such as dolicholubiquinone. Also, it has been reported that triparanol, which is known as an inhibitor of an enzyme located late in the cholesterol biosynthesis system, can accumulate desmosterol, which causes cataract.

 On the other hand, squalene epoxidase inhibitors targeting squalene epoxidase, which is located in the middle stage of the cholesterol biosynthesis system, have no risk of inhibiting the synthesis of other metabolites or accumulating harmful substances in the living body It is expected to provide more safe anticholesterol drugs.

 Such squalene epoxidase inhibitors include (E) -N- (6,6-dimethyl-2-hepten-4-ynyl) _N-ethyl-1 3- [4- (3-Chenyl) -12-che Nylmethyloxy] benzylamine (NB-598) and other arylamine-based compounds (for example, Japanese Unexamined Patent Publication No. 3-114241, WO93 / 12069, WO94Z188) 91), dibenzylamine-based compounds (for example, WO 94Z18167, etc.), and allyl alcohol-based compounds (for example, JP-A-6-49023).

 On the other hand, thiocarbamic acid ester derivatives are known to be useful as antifungal agents or agricultural chemicals.

For example, compounds having antifungal activity have been reported in Japanese Patent Publication No. 39-113213, US Pat. No. 3,395,230, and Japanese Patent Application Laid-Open No. 57-176952. It is known that thiocarbamate esters having antifungal activity exhibit antibacterial activity by inhibiting steroid synthesis of bacteria, especially squalene epoxidase. Ma In addition, a compound having herbicidal activity has been reported in Japanese Patent Publication No. 62-54424.

 However, thiocarbamate derivatives with antifungal activity have been reported to show only weak activity against mammalian squalene epoxidase [Drugs of the Fuyya (Drugs). of the future), 18 (10), 911 (1993)].

 An object of the present invention is to provide an anti-hypercholesterolemic agent, an anti-hyperlipidemic agent, and a therapeutic or prophylactic agent for arteriosclerosis, which are safer and have an excellent anti-cholesterol effect as compared with existing drugs. It is to provide. Disclosure of the invention

 The present inventors have conducted intensive studies and found that a thiocarbamate derivative having a certain substituent has a high inhibitory activity against squalene epoxidase derived from mammals, and completed the present invention.

 That is, one of the present invention is represented by the general formula

[Where m represents 0 or 1, and A represents the formula [Π]

(Wherein R ⁵ and R ⁶ are the same or different and each represent a hydrogen atom, a halogen atom, a lower alkoxy group and a lower alkyl group or a lower alkoxy group which may be substituted with Z or a cyano group, or ⁵ and R ⁶ may be taken together to form a ring with a carbon chain represented by one (CH ₉ ) ^} K (CH 2) no 3) or a phenyl group represented by the formula: 111]

C-I Cs = »— R [1]

(Wherein R ⁷ represents a lower alkoxy group and a lower alkyl group which may be substituted with Z or a cyano group.). R ¹ and R represent a hydrogen atom, a formyl group or a lower alkyl group, and Z represents a nitrogen atom or a CH group. R ² is a hydrogen atom, a lower alkyl group, a lower acryl group, a lower alkyl group of a hydroquinine, a lower alkyl group of a lower alkoxy group, a lower alkyl group of a carboxyl substituent, a lower alkyl group of a carboxyl-substituted lower acyl group, a lower alkylsulfonyl group or an arylsulfonyl group Represents R ⁴ is a phenyl group having an optional substituent or a 5- or 6-membered heterocyclic ring containing one or more oxygen, nitrogen, or sulfur atoms or two or more atoms in combination. Represent. Any substituent may be substituted on the heterocycle < ] The thiocarbamic acid derivative and its salt characterized by being represented by these.

 Another one of the present invention is a compound represented by the general formula [V]:

[V]

(Wherein m, Z, R ¹ , R ² , R ³ , and R represent the same meaning as described above. <R ⁸ represents a hydrogen atom or a formyl group.) It is a derivative.

 Still another aspect of the present invention provides a compound represented by the general formula [VI]:

(Wherein m, Z, A, and R ¹ have the same meanings as described above.).

 One of the production methods of the present invention is a method represented by the following general formula [IV]:

 AO C S X [IV]

(In the formula, A represents the same meaning as described above, and X represents halogen.) Halogenated thioformate represented by the general formula [Va]

FT

o R ³

 1. O M, [V-a]

 m

(Wherein m, Z, R ³ , R ² , R ³ , and R ⁴ have the same meanings as described above.) A general formula CI characterized by reacting with an amine represented by the formula:

(Wherein m, Z, A, R ¹ , R ¹ , R ³ , and R ⁴ have the same meanings as described above).

R ²

0 R ³ヽ. Eight, R ⁴

[I]

Further, another one of the production methods of the present invention has a general formula as shown in the following reaction formula.

R ³

 HN [VII]

\ R ⁴

(Wherein R ³ and R have the same meanings as described above.) And a general formula [VI]

Formula (wherein m, Z, A, R ¹ is representative. The same meanings as those described above), characterized by reacting a compound represented by [I _a i

[la]

Wherein m, Z, A, R ¹ , R ³ , and R ⁴ have the same meanings as described above.

[VI] [n]

 [l a]

Still another one of the production methods of the present invention is a compound represented by the general formula [la] as shown in the following reaction formula.

(Wherein m, Z, A, R ¹ , R ³ and R ⁴ represent the same meaning as described above), and a general formula [IX]

R ² Y [IX]

(Wherein R ² Y is an alkylating agent having the aforementioned R ² or acylation Shows the agent. ) With the general formula [I]

Wherein m, Z, A, R ¹ , R ² , R ³ , and R ⁴ have the same meanings as described above.

The present invention also provides a squalene epoxidase inhibitor comprising the compound of the above general formula [I] or a salt thereof.

 Hereinafter, the present invention will be described in detail.

First, the compounds of the present invention represented by the general formulas [I], [V], and [VI] are detailed in detail ^ O

In the definition of the general formula of the present invention, unless otherwise specified, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms. Therefore, specific examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl (amyl) group and an isopentyl group. , Neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3 —Methylpentyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methyl Rupuropiru group and the like, preferably a methyl group, Echiru group, a propyl group, an isopropyl group, an isobutyl group, _{s ec} - a heptyl group, tert- butyl group, tert- pentyl group.

Examples of the lower alkoxy group include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butyne, pentyloxy, 1-methylbutyl Oxy, 2-methylbutyloxy, 3-methylbutyloxy, 1,2-dimethylpropyloxy, 1,1-dimethylpropyloxy, hexyloxy, 1-methylpentyloxy, 1- Tylpropyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 4-methylpentyloxy group, 1,2-dimethylbutyloxy group, 1,3-dimethylbutyloxy group, 2,3-dimethylbutyloxy group, 1,1-dimethylbutyi group Roxy group, 2,2-dimethylbutyloxy group, 3,3-dimethylbutyloxy group are preferred, and methoxy group, ethoxy group, propoxy group, ishipropoxy group, butoxy group, tert-butoxy group, 2-dimethylpropyloxy group and the like.

 Specific examples of the lower alkoxy group and the lower alkyl group which may be substituted with Z or a cyano group include, for example, a methoxymethyl group, a 1-methoxyl group, a 1-methoxy-1-methylethyl group, and a 1-ethoxy group. 1 1-Methylethyl group, 2-Methoxy-1 1-Methylethyl group, 2-Methoxy-1,1-dimethylethyl group, 1-Methoxypropyl group, 1-Methoxy-1 1-Methylpropyl group, 2-Methoxy-1 1, 1- Dimethylpropyl group, etc. and cyanomethyl group, 1-cyanoethyl group, 1-cyano-1-methylethyl group, 2-cyano-1-methylethyl group, 2-cyano1-1,1-dimethylethyl group, 2-cyano-1-methylpropyl group, 2-cyano-1, 1-dimethylpropyl group and the like. Preferably, 1-methoxy-1-methylethyl group, 1-ethoxy-11-methylethyl group, 2-methoxy-1,1-dimethylthioethyl group, 1-methoxy-1-methylpropyl group, etc., and 1-cyanoethyl group, 1 —Cyan-1-methylethyl group, 2-cyan-1,1-dimethylethyl group and the like.

Lower acetyl groups include formyl group, acetyl group, ethylcarbonyl group, propylcarbonyl group, 1-methylethylcarbonyl group, butylcarbonyl group, 1-methylpropylcarbonyl group, 2-methylpropylcarbonyl group, pentylcarbonyl group Examples thereof include a 1-methylbutylcarbonyl group, a 2-methylbutylcarbonyl group, a 3-methylbutylcarbonyl group, a 1-ethylpropylcarbonyl group, and a 2-ethylpropylpyrucarbyl group. Preferably, it is a formyl group, an acetyl group, an ethylcarbonyl group or the like. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Preferably, it is a fluorine atom, a chlorine atom, or a bromine atom.

 Examples of unsubstituted or substituted phenyl groups include phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, and 4-methoxyphenyl. Methoxyphenyl, 2-chlorochloro, 3-chlorochloro, 4-chlorochloro, 2-diphenyl, 3-dichloro, 4-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 3-chlorophenyl, 4 1-Cyanophenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl Lower alkyl groups, lower alkoxy groups, halogen atoms, nitro groups, cyano groups, amino groups, Examples thereof include a lower alkoxycarbonyl group or a phenyl group substituted with a hydroxy group. Preferable examples include a phenyl group, a methyl group, and a phenyl group in which a methoxy group is substituted at an arbitrary position.

A 5- or 6-membered heterocyclic ring containing one or more oxygen atoms, nitrogen atoms and sulfur atoms or a combination of each atom is 2-furyl, 3-furyl, 2 —Chenyl group, 3-Chenyl group such as phenyl group, 1-pyrrolyl group, 2-pyrrolyl group, pyrrolyl group such as 3-pyrrolyl group, 1-birazolyl group, 3-virazolyl group, 4-birazolyl group , 5 -Bilazolyl group such as virazolyl group, 2 1 year old xazolyl group, 4 year old xazolyl group, 5 year old oxazolyl group such as xazolyl group, 3 isoxazolyl group, 4 isoxazolyl group such as 4 isoxazolyl group-5-isoxazolyl group , 2-thiazolyl- 5-membered heterocycles such as thiazolyl groups such as 4 thiazolyl group and 5 thiazolyl group, isothiazolyl groups such as 3-isothiazolyl group, 4-isothiazolyl group and 5-isothiazolyl group, 2-pyridyl group and 3- Examples include 6-membered heterocyclic rings such as a pyridyl group and a pyridyl group such as a 4-pyridyl group. When there is a substituent on these heterocycles, the substituent is not particularly limited, but specifically, a lower alkyl group such as a methyl group and a lower alkoxycarboxy group such as a methoxycarbonyl group. And a benzyl group. Preferably 3-furyl, 2-phenyl, 3-phenyl, 1-pyrrolyl, 1-pyrazolyl, 4-thiazolinole, 3-isothiazolyl, 4-isothiazolyl, 2-methyl-3 It is a 5-membered heterocyclic ring such as —thenyl group, 2-methoxycarbonyl-3-enyl group.

Examples of the compound represented by the formula [1] include a 4-methoxyphenyl group, a 4-ethoxyphenyl group, a 4-tert-butyloxyphenyl group, a 3-tert-butyloxyphenyl group, and a 4-tert-butyl group. —Butylphenyl group, 3-tert-butylphenyl group, 4-chloro-3-tert-butylphenyl group, 4-bromo-3-tert-butylphenyl group, 4-fluoro—3-tert-butylphenyl group, 4-phenyl-3 — Tert-butylphenyl, 4-chloro-3-isopropylphenyl, 4-bromo-3-isopropylphenyl, 4-fluoro-3-isopropylphenyl, 4-phenyl-3-isopropylphenyl Phenyl, 4-chloro-3-ethylphenyl, 4-bromo-3-ethylphenyl, 4-fluoro-3-ethylphenyl, 4-phenyl-3-ethylphenyl, 4-chloro-3 Tylphenyl, 4-promo 3- 3-methylphenyl, 4-chloro-3-methoxy-phenyl, 4- (1-methoxy-1-methylethyl) phenyl, 4- (1-cyano 1-methylethyl) phenyl, 5 — Indanyl group, 1, 2, 3, 4-te _c is preferably the like can be given Torahai de port one 6-naphthyl group, 3- tert Buchirufuweniru group, 4-tert Buchirufu Eniru group, 4 one black port _ 3- tert butylphenyl group, 4-Bromo-1-tert-butylphenyl, 4-fluoro-3-tert-butylphenyl, 4-chloro-3-isopropylphenyl, 4-bromo-3-isopropylphenyl, 4-chloro-3-ethylphenyl 2-, 4-bromo-3-ethylphenyl, 4- (1-methoxy-1-methylethyl) phenyl, 4- (1-cyano-1-methylethyl) phenyl, 5-indanyl, 1,2 , 3,4-Tetrahydro-6-naphthyl group.

 Lower alkoxyalkyl groups include methoxymethyl, methoxyethyl, ethoxymethyl, (2-methoxyethoxy) methyl, 2- (2-methoxyethoxy) ethyl, 2- (2-methoxyethoxy) An ethoxymethyl group and the like can be mentioned.

 Examples of the hydroxy lower alkyl group include a methylol group, a 2-hydroxyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group, a 4-hydroxybutyl group, a 3-hydroxybutyl group, and a 2-hydroxybutyl group. And the like.

 The substitution position in the carboxyl-substituted lower alkyl group is preferably at the ω-position. Examples of the ω-hydroxyl-substituted alkyl group include a hydroxycarboxymethyl group, an ω-hydroxycarbonylethyl group, an ω-hydroxycarbonylpropyl group, an ω-hydroxycarbonylcarbonylbutyl group and an ω-hydroxycarbonylpentyl group. And ω-hydroxycarbonylhexyl group. Preferred are an ω-hydroxycarbonylmethyl group, an ω-hydroxycarbonylylethyl group, an ω-hydroxycarbonylpropyl group and the like.

The substitution position in the carboxyl-substituted lower acyl group must be Is preferred. Examples of the ω-carboxyl-substituted acetyl group include a hydroxycarbonylacetyl group, an ω-hydroxycarbonylpropanol group, an ω-hydroxycarbonylbutanoyl group, and an ω-hydroxycarbonyloxycarbonyl group. And ω-hydroxycarbonylhexanoyl groups. Preferred are a hydroxycarbonyl acetyl group, an ω-hydroxycarbonylpropanoyl group and the like. The lower alkylsulfonyl group includes a methyl sulfonyl group, a trifluorosulfone methanesulfonyl group, and the arylsulfonyl group includes a paratoluenesulfonyl group.

 The compounds of the present invention represented by the general formulas [I], [V], and [VI] contain an asymmetric carbon. Accordingly, the compounds of the present invention include mixtures of various optical isomers such as optically active isomers, racemates, diastereomers and the like, and isolated compounds thereof.

 These compounds of the present invention represented by the general formulas [I], [V], and [VI] have an amide residue, and thus may form an acid adduct. Examples of such salts include mineral acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid, formic acid, acetic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, maleic acid, lactic acid, and lactic acid. Examples thereof include acid adduct salts with organic acids and the like such as cornic acid, tartaric acid, citric acid and methanesulfonic acid. Further, the compound of the present invention

 Various hydrates, solvates and polymorphs of [I] [V] [VI] are also included.

Representative examples of the general formula [I] of the compound of the present invention are shown in Tables 1 to 12, but the present invention is not limited thereto. Ho

2]

 [εmine]

6 ΐ

LLW96iill A [Table 4]

[Table 5]

[Table 6]

7]

1 then 1ί L m K 'K'- ^J

 # Issue

 94 CH 0 Mc COCH, Mc Ph

05 CH 0 .c COCH ^ Mc P

96 N 0 Mc COCH 3 Mc Ph

97 N 0 Me COCH Me Ph

 D

 98 CH 〔） Mc COCH, Me

 1 \ = J—

 99 CII 0 Me COC Tsu Mc i! N MC Shirishi M3 MC

101 N 0 Mc COCH 3 Me

102 CH 0 Mc COCH Tsu COOH Me Ph

103 ax CH 0 Mc C0CH C00H Me Ph

104 CH 0 Me COCH ₂ CH ₂ COOH Me Ph

105 or CH 0 Me COCH ₂ CH ₂ COOH Me Ph

106 -HQ- N 0 Mc COCH CH ₂ COOH Mc Ph

107 CH 0 Me CH ₂ COOH Me Ph

108 CO * CH 0 Mc CH ₂ COOH Me Ph About 8]

9]

[10]

Compound Λ z m R1 R 2 R3 R4

140 CH 0 Me Me Mc NO _z

141 CH 0 Mc Mc Me

-HQ- Shi 1 * 1 V MC Mc Mc CN

143 CH 0 Mc Mc Me

144 CH 0 Mc Me Me OH

 -Q

145 CH 0 Mc Mc Mc

146 CH 0 Me Mc Mc Ph

(Hydrochloride)

 147 CH 0 Mc Mc Me

 (Hydrochloride)

 148 C 0 Mc 'H

 '(Hydrochloride) -HG ^ H Me

149 CH 0 Me Mc Me

 (Hydrochloride)

 150 CH Me Mc Mc

(Hydrochloride) CO "0

^ dm H003 ^Z HD N £ 91

UO ^Z U3 ^Z H3 N 991

m U0 ^Z HD ^Z U3 HD S9I

^ dm HO ^Z HD ^Z HD M

d HO ^Z HD ^Z HD N ε r i

^: H30 ² H3½3 N Z9 \

 Md 3W 191

^£ HD0 ^Z H3 3W HO 091

 Md HOOD ^ HD ^ HDOD ON N 6SI

3 HOOD ^Z H3 H30D 3W HD 8SI

Md HOOD ² HD ^Z HDOD 3W "I

H00D ^Z H30D 9SI

 HOOD ^ HDOD H3 SSI

 Md H00D 'HD03 N ΧΌ

Md aw HOOD ^Z HDOD N

 H303 N

 3W H3

 IU V

L ZLLlOI96d £ llDd ££ SI0 / L6 OAV [Table 1 2]

When R ⁸ is a hydrogen atom, the compound represented by the formula [V] is used as the compound [V-a] for the synthesis of the compound [I]. When R ⁸ is a formyl group, the compound represented by the formula [V] is deprotected or reduced to form a compound [Va], which is used for the synthesis of the compound [I].

The compound represented by the formula [V] is a novel compound, and typical examples thereof are shown in Tables 13 to 16, but the present invention is not limited thereto.

[Table 13]

Compound 111 z R ¹ R2 R3 R4 R ⁸

172 0 cu H H H Ph H

173 0 CH H H 11 Ph CHO

174 0 CH Mc H II Ph II

175 0 CII Mc H H Ph CHO

176 0 CI I H H Mc Ph H

177 o cu H Mc Ph

 178 0 CH Mc Mc Mc Ph H

179 0 CH Mc Mc Mc Ph CHO

180 0 CH Mc H Mc Ph H

181 0 CH H H Mc •-CHO

 -ci

 182 0 CII Mc H Mc H

183 0 CH H H Mc CI CHO

184 o CH Mc H Mc CI H

I R JS n u I I CL n

180 U then H MC H Mc H

187 0 CH H H Mc CHO

188 0 CH Mc H Mc H

189 0 CH HH Mc CH ₃ CHO

190 0 CH Mc H Mc CH ₃ H

191 0 CH HH Mc H ₃ Q CHO

192 0 CH Mc H Mc H ₃ QH [Table 14]

3 2

[Table 16]

 Compound m z R1 R 2 R3? Λ R8

^ ir 3

226 0 CH Mc Mc Mc H ₃ QH

227 0 CH Mc Mc Mc H on Mr

«-Q- CH ₃ n

229 0 CH Mc Mc Mc H ₃ CQ H

 ·-©

230 0 CH Mc H Me H ₃ CQ H

 ·-©

231 0 CH Mc Mc Me _OC H ₃ H

232 o CH Mc Mc Mc H

233 0 CH Me Mc Mc H

234 0 CH Mc Me Mc then I H

235 0 CH Me Me Mc H

236 0 CH Mc Me Me H

237 0 CH Me H Mc H

238 0 CH Me Me Me H

239 1 CH Me Me Me Pli H

240 1 CH Mc Me Mc H 33 The compound represented by the formula [VI] is used for the synthesis of the compound [I]. The compound represented by the formula [VI] is a novel compound, and typical examples thereof are shown in Tables 17 and 18, but the present invention is not limited thereto.

 [Table 17]

 Compound wanderer Λ R1

 2 1 Mc 0 CH

242 ox Mc 0 CH

243 Mc 0 CH

244 Mc 0 CH

245 Mc 0 CH

246 Mc 0 CH

247 Mc 0 N

248 or Me 0 N

249 Mc 0 N

250 Mc 0 N

251 Mc 1 CH

252 ax Mc 1 CH

253 Me 1 CH

254 Mc 1 CH 01533

3 4

 [Table 18]

Compound name 号 R ¹ m Z

255 o c 0 N

256 Mc 0 N

257 Mc N

258 Mc N

259 ay Mc CH

260 CO "Mc N

261 Mc N

Manufacturing method

 The compound of the present invention can be produced by various methods, and typical production methods are shown below.

Manufacturing method 1

(In these formulas, m, Z, A, R ¹ , R ² , R ³ , R ⁴ , and X have the same meaning as described above.)

 The halogenated thioformate represented by the formula [IV] and the amine represented by the formula [Va] are subjected to quantification in the presence or absence of a base, in the absence of a solvent or in a solvent at room temperature to 150 ° C. It can be manufactured by reacting for minutes to hours.

Examples of the base include sodium hydroxide, hydroxide hydroxide, calcium hydroxide, sodium carbonate, carbonate carbonate, sodium hydrogen carbonate. And organic bases such as pyridine, triethylamine and trimethylenediamine.c Solvents include methanol, ethanol, propanol, isopropanol, acetone, Solvents such as methylethyl ketone, ethyl acetate, tetrahydrofuran, acetonitril, dimethylformamide, dimethyl sulfoxide, dichloromethane, hexane, and toluene can be used.

 The compound [IV] is not particularly limited as long as it is at least equimolar to the compound [Va].

The halogenated thioformate of the formula V] can be prepared by reacting the corresponding alcohol or phenolic compound with a halogenothiocarbinating agent such as thiophosgene in the presence or absence of a base in a solvent or in a solvent. Examples of the _c- base that can be produced by reacting at 0 ° C for several minutes to 24 hours include sodium hydroxide, hydroxide hydroxide, calcium hydroxide, sodium carbonate, and sodium hydrogencarbonate. Inorganic bases such as hydrogen carbonate and lime, alkaline metal hydrides such as sodium hydride and lithium hydride, alkaline hydrides such as calcium hydride, earth metal or pyridine, triethylamine, etc. D

 Examples of the solvent include water or an organic solvent such as n-hexane, cyclohexane, methyl ether, tetrahydrofuran, dichloromethane, chlorophonolene, benzene, toluene, and dimethylformamide. Further, a mixed solvent of water and the above organic solvent may be used.

The alcohol or phenolic compound and the halogenothiocarbonylating agent such as thiophosgene are preferably used in the reaction in an equimolar amount or in one molar excess of one. The compound represented by the formula [V] can be produced, for example, as follows.

 [Vb]

(In these formulas, Z, R ² , R ³ and R ⁴ represent the same meaning as described above, R ⁹ represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms, and examples thereof include those having 1 to 5 carbon atoms among the above-mentioned examples of lower alkyl groups. )

 That is, the amino alcohol 1c can be produced, for example, by reacting a two-port compound la having an epoxy group with an amino lb in a solvent such as methanol under heating and refluxing for several hours. .

Next, the amino ester form 1d is prepared by subjecting the amino alcohol form 1c and an alkylating agent having an R ² such as alkyl iodide or dialkyl sulfate to hydroxylation in a solvent such as tetrahydrofuran or dimethylformamide. It can be produced by reacting in the presence of a basic catalyst such as sodium, hydrogenated sodium, sodium carbonate, carbonated carbonate, etc., on ice or in the boiling range of the solvent.

 The imide 1e can be produced by reacting the amide 1d in a solvent such as ethanol in the presence of a hydrogen reduction catalyst such as platinum oxide or palladium carbon in a hydrogen atmosphere.

 Further, the amine 1e is reacted with, for example, formic acid or acetic acid or a derivative thereof to form an amide, and then the amide is reacted with a reducing agent such as lithium aluminum hydride in tetrahydrofuran. By doing so, the desired novel amine compound [Vb] can be produced.

Compound [V] can also be produced by the following method using amide compound 2a as a starting material.

[Vc]

(In the formula, Z, R ¹ , R ² , R ³ , and R represent the same meanings as described above.) That is, the amino alcohol 2c is composed of an amide compound 2a having an epoxy group and an amide compound 2a. The compound can be produced by reacting min 1b according to the method for producing the amino alcohol 1c.

Then § Mi Noe one ether body 2 d is the § Mi Roh alcohol derivative 2 c and R ² The alkylating agent can be produced by reacting the alkylating agent according to the method for producing the amino alcohol derivative 1d described above.

 Further, by reacting the aminoether compound 2d with a reducing agent such as lithium aluminum hydride in tetrahydrofuran, the desired novel amine compound LVc] can be produced.

 Compound V can also be produced by the method shown below.o

 V e

(In the formula, Z, R ¹ , R ² , R ³ , and R ⁴ represent the same meaning as described above.)

 That is, for example, the epoxy compound 3b is obtained by combining a phenol compound 3a with a glycidyl chloride (epichlorohydrin), glycidyl bromide (epipromohydrin) or other glycidyl halide (epihalohydrin) compound. Alternatively, in a solvent such as dimethylformamide, in the presence of a basic catalyst such as sodium hydroxide, sodium hydroxide, carbonated carbonate, sodium carbonate, hydrogenated sodium, and ice cooling. Or by reacting in the boiling range of the solvent.

Next, amino alcohol 3c is converted to epoxy 3b and amine lb. It can be produced by reacting in a solvent such as methanol under reflux for several hours.

Amino ether compound 3d is obtained by reacting an amino alcohol compound 3c with an alkylating agent having R ¹ and then reacting the obtained product with an alkylating agent having R ^2. Can be manufactured.

 Further, the desired novel amine compound [Vd] can be produced by reacting the aminoester 3d in, for example, hydrochloric acid at room temperature or under heating for several minutes to 24 hours.

 Further, the desired novel amide compound [V e] is obtained by reacting the amino alcohol 3c with a reducing agent such as lithium aluminum hydride in a solvent such as tetrahydrofuran or ether. It can be manufactured.

Manufacturing method 2

97

42

 CVi]

 [VI]

 [l a]

(Where m, Z, A, R ¹ , R ³ and R ⁴ are the same as above)

The compound represented by [la] in which R ² is a hydrogen atom in the compound [I] of the present invention includes a compound having an epoxy group represented by the formula [VI] and an amine represented by the formula [VII] Can be produced in the absence of a solvent, in the presence of a solvent or in the presence of a catalyst, by reacting at room temperature or under heating for several minutes to 24 hours.

This reaction may proceed without solvent, but usually a solvent is used ₍ such solvents as methanol, ethanol, propanol, isopropanol, acetone, methylethylketone, ethylethyl acetate, tetrahydrofuran, and acetatetonite). Solvents such as ril, dimethylformamide, dimethylsulfoxide, dichloromethane, hexane, and toluene can be used.

This reaction proceeds without a catalyst, but a catalyst may be used if necessary. it can. Examples of such a catalyst include lithium perchlorate, magnesium perchlorate, itttrium triflate, anhydrous cobalt chloride (II) n-butyllithium, lithium diisopropylamide and the like.

 The compound represented by the formula [VI] is a phenolic compound.

[Wherein m, Z, A, and R ¹ have the same meanings as described above. ] And glycidyl chloride (epichlorohydrin), glycidyl bromide (epipromohydrin), and other glycidyl halide (epihalohydrin) compounds, for example, in the presence of a base in the absence of a solvent or in a solvent, without ice-cooling. It can be produced by reacting at 150 ° C for several minutes to 24 hours.

 Solvents used in the reaction include tetrahydrofuran, ether, acetone, methylethylketone, ethylethyl acetate, acetonitril, benzene, toluene, xylene, chloroform, methylene chloride, methylene chloride, dimethylformamide, and dimethylsulfoform. Solvents such as oxides can be used o

 As the base, for example, inorganic bases such as sodium hydroxide, hydroxide hydroxide, calcium hydroxide, sodium carbonate, carbonate carbonate, sodium hydrogen carbonate, hydrogen carbonate carbonate, etc., and hydrogenated sodium Hydride, alkaline metal hydride such as lithium, and alkaline earth metal hydride such as calcium hydride.

Compound [V 1 H] and glycidyl halide are almost equimolar, respectively. Alternatively, it is preferable to subject one of the compounds to the reaction in a slight molar excess.

(In these formulas, m, Z, A, R ¹ , R ² , R ³ , and R ⁴ have the same meanings as described above.)

The compound of the present invention [I] in which R ² is other than hydrogen can also be obtained by reacting an alcohol compound represented by the formula [la] with a compound represented by the formula [IX] usually in a solvent in the presence of a base. Can be manufactured.

Specific examples of the alkylating agent represented by the formula [] include methyl iodide, chloro iodide, chilled bromide, propyl bromide, and isopropyl bromide. Butyl bromide, s-butyl bromide, and bromide Alkyl halides such as isoptyl, t-butyl bromide, chloromethyl methyl ether, 2-chloroethyl methyl ether, 2-bromoethyl methyl ether, 1-bromoacetic acid and 1-chloroacetic acid Sulphates such as dimethylsulphate and getylsulphuric acid, ρ-toluenesulfonic acid methyl ester, p-toluenesulfonic acid ethyl ester, D-toluenesulfonic acid propylate Methyl ester, methane sulfonic acid methyl ester, methane sulfonic acid ethyl ester, methane sulfonic acid propyl ester, trifluoro methane sulfonic acid methyl ester, trifluoro methane sulfonic acid ethyl ester, trifluoro methane sulfonic ester propyl ester, etc. And epoxy compounds such as ethylene oxide and propylene oxide. Examples of the acylating agent include acid halides such as acetyl chloride and propionyl chloride, and acid anhydrides such as acetic anhydride, propionic anhydride and butyric anhydride.

 Solvents used in the reaction include methanol, ethanol, propanol, isopropanol, acetone, methylethylketone, ethylacetate, getylether, tetrahydrofuran, acetonitrile, dimethylformamide, Solvents such as dimethylsulfoxide, dichloromethane, hexane, toluene, pyridine, zoletidine, N, N-dimethylaniline and the like can be mentioned.

 Examples of the base include inorganic bases such as sodium hydroxide, hydroxide hydroxide, calcium hydroxide, sodium carbonate, carbonate carbonate, sodium hydrogencarbonate, hydrogen carbonate carbonate, and the like; Metal hydrides such as lithium and lithium hydride, alkaline earth metals such as calcium hydride, and organic bases such as pyridine, triethylamine, diisopropylethylamine, trimethylenediamin, etc. Can be.

The compounds [Ia] and [] are preferably used in the reaction in substantially equimolar amounts, or one in a slight excess. Manufacturing method 4

 [X] [XI]

(In the formula, m, Z, A, R ¹ , R ² , R ³ , R ⁴ , and X have the same meaning as described above.)

 The compound [I] of the present invention is usually produced by reacting a phenolic compound [X] with an amide compound [XI] in a solvent in the presence of a base at room temperature or under heating for several minutes to 24 hours. Can be.

 Solvents used in the reaction include methanol, ethanol, propanol, isopropanol, acetone, methylethylketone, ethyl acetate, tetrahydrofuran, acetonitril, dimethylformamide, dimethylsulfoxide, Examples include solvents such as dichloromethane, hexane, toluene, pyridine, lutidine, and N, N-dimethylaniline.

As the base, for example, sodium hydroxide, hydroxylated lime, calcium hydroxide, sodium carbonate, carbonated lime, sodium hydrogen carbonate Inorganic bases such as potassium hydrogencarbonate, sodium hydride, lithium hydride and other alkali metal hydrides, calcium hydride and other alkaline earth metals or pyridine and triethylamine And organic bases such as trimethylene diamine.

 It is preferable that the compounds [X] and [XI] are subjected to the reaction in substantially equimolar amounts, or one in a slight excess.

Manufacturing method 5

(Where m, Z, A, R ¹ , 2, R 3 R 4

 X has the same meaning as described above. )

The compound [I] of the present invention can be produced usually by reacting a funinol compound [XII] with a halogenated thiocarbamate compound [XI] in a solvent in the presence of a base at room temperature or under heating for several minutes to 24 hours. Yes o Solvents used in the reaction include methanol, ethanol, propanol, isopropanol, acetone, methylethylketone, ethyl acetate, tetrahydrofuran, acetate, dimethylformamide, and dimethylsulfoxide. And solvents such as dichloromethane, dichloromethane, hexane, hexane, toluene, pyridine, lutidine and N, N-dimethylaniline.

 Examples of the base include inorganic bases such as sodium hydroxide, hydroxylated lime, calcium hydroxide, sodium carbonate, carbonated lime, sodium hydrogen hydride, sodium hydrogen hydride, and the like; sodium hydride, lithium hydride, and the like. Examples include hydrogenated alkaline earth metals such as metal hydrides and calcium hydrides, and organic bases such as pyridine, triethylamine, trimethylenediamine and the like.

 It is preferable that the compounds [Χ Π] and [XI に] are used in the reaction in substantially equimolar amounts or one of them is in a slight excess.

 Since the compound of the formula [I] extremely selectively and strongly inhibits squalene epoxidase in vivo, it is used as an anti-hypercholesterolemic agent, an anti-hyperlipidemic agent, and an anti-atherosclerotic agent. It is a useful compound that is expected to be used.

 The compound [I] of the present invention can be administered orally or parenterally, and when formulated into a form suitable for such administration, hypercholesterolemia, hyperlipidemia and arteriosclerosis can be obtained. It can be used for treatment and prevention of diseases.

When the compound of the present invention is used clinically, it is possible to add a pharmaceutically acceptable excipient in accordance with the dosage form and then administer the compound after formulating various preparations. As the additives at this time, various additives commonly used in the field of pharmaceutical preparations can be used, for example, gelatin, hydroxypropylmethylcellulose, carboxymethylcellulose, and the like. Corn starch, microcrystalline starch, white cellulose, magnesium metasilicate aluminate, calcium phosphate anhydrous, citrate, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester , Polysorbate, Sucrose fatty acid ester, Polyoxyethylene hydrogenated castor oil, Polyvinyl viridone, Magnesium stearate, Light gay anhydride, Talc, Vegetable oil, Benzine alcohol, Arabic gum, Propylene glycol And hydroxypropyl cyclodextrin, etc.

 Dosage forms formulated as a mixture with these excipients include, for example, solid preparations such as tablets, capsules, granules, powders or suppositories, or mouthwashes, elixirs or There are liquid preparations such as injections, which can be prepared according to a usual method in the field of preparations. In the case of liquid preparations, they may be dissolved or suspended in water or other appropriate medium before use. In particular, in the case of an injection solution, it may be dissolved or suspended in a physiological saline or glucose solution as necessary, and a buffer or a preservative may be added.

 The preparation of the present invention can contain the compound of the present invention at a ratio of 1. (! To 100% by weight, preferably 1.0 to 6% by weight, based on the whole drug. It may also contain other therapeutically effective compounds.

When the compound of the present invention is used as an antihyperlipidemic agent, an anti-atherosclerotic agent or an anti-hypercholesterolemia agent, the dosage and frequency of administration depend on the sex, age, weight, degree of symptoms and purpose of the patient. Although it depends on the type and range of therapeutic effects to be used, in general, oral administration is performed by dividing 0.01 to 20 nig Z kg per day into 1 to several times per adult, and In the case of administration, it is preferable to administer 0.1 to 0.2 mg of () () in 1 to several portions. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

Synthesis of 3- (2,3-epoxypropyloxy) nitrobenzene

To a suspension of 2.15 g of 60% oily sodium hydride in 20 ml of tetrahydrofuran was added 30 ml of a solution of 5 g of m-nitrophenol in 30 ml of tetrahydrofuran under ice-cooling, followed by stirring at room temperature for 10 minutes. The reaction solution was ice-cooled again, 1 Om1 of a dimethylformamide solution of 7.38 g of epihydric molybdenum was added, and the mixture was stirred at room temperature for 4 hours. After adding 3 GG ml of ice water and extracting three times with 1 ml of ethyl acetate, the organic layer was washed twice with 250 ml of water, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (eluent: n-hexane: ethyl acetate = 3: 1) to obtain 6.28 g of yellow crystals.

IR (KB r, cm ^-1 ) 3100, 1620, 1580, 1520, 1485, 1350, 1320, 1260, 1250, 1035

 NMR (CDC 13, δ ppm) 2.80 (dd,] = 2.7, 4.9 Hz, 1H), 2.90 -3.00 (m, 1H), 3.35-3.44 (m, 1H), 3.99 (dd, 6.0, 11.1 Hz, III), 4, 38 (dd, 2.8, 11. lilz, 1H), 7.24-7.33 (m, 1H), 7.45 (t, J = 8.2Hz, 1H), 7.76 (t, J = 2.2Hz, 1H) , 7.81-7.90 (m, 1H)

Example 2

 Synthesis of 3- (N_methyl-1-N-phenylamino) 1-11 (3-2 trophenoxy) 1-2-propanol

To a solution of 2 g of 3-(2,3-epoxypropyloxy) nitro πbenzene in 10 ml of methanol was added 1.15 g of N-methylaniline, and the mixture was refluxed for 6 hours. After allowing the reaction solution to cool, the solvent is distilled off under reduced pressure, and the residue is subjected to silica gel chromatography (developing solvent; n-hexane: ethyl acetate == 3). Purification in 1) gave 2.95 g of yellow crystals.

 NMR (CDC 13, δ ppm) 2.50 (brs, 1H), 3.02 (s, 311), 3.55 (d, J = 6.5 Hz, 2H), 4.03-4.22 ( m, 2H), 4.28-4.44 (m, III), 6.73-6.90 (m, 3H), 1.19-7.34 (m, 3H), 7.46 (t, J = 8.2 Hz, III), 7.77 (t, 1 = 4.6 Hz, 1H), 1, 82-1.90 (m, 1H)

 The following compounds were synthesized in the same manner.

 3-[N-Methyl-N- (3-Chenyl) amino] — 1 — (3 — Nitrophenoxy) 1 2 —Propanol

 Property: brown viscous material

1 R (NaC1, cm- ¹ ) 3430, 3100, 2930, 1550, 1530,

1340, 1245, 1090, 1040

 NMR (CDC 13, 5 PP m) 2.69 (d, J = 3.7 Hz, 1 H), 2.94 (s, 3 H). 3.39 (d, J = 6.3 Hz, 2 H), 4.03-4.20 (m, 2 H), 4.22-4.38 (m, 1 H), 6.05-6.10 (m, 1H), 6.82 ( dd, J = 5.2, 1.5Hz, 1H), 7.19-7.33 (m, 2H), 7.44 (t, J = 8.1Hz, 1H), 7.73- 7.92 (m,

2 H)

Example 3

 Synthesis of 2-Methoxy-3- (N-methyl_N-phenylamino) 1 1 — (3-Nitrophenoxy) propane

3- (N-methyl-N-phenylamino) — 1 — (32-Trophenoxy) 1-2 — Propanol 1.66 in 10 ml of a suspension of 264 mg of 60% oily sodium hydride in tetrahydrofuran under ice-cooling g of tetrahydrofuran solution (10 ml) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was ice-cooled again, 2 ml of a dimethylformamide solution of 1.94 g of methyl iodide was added, and the mixture was stirred at room temperature for 20 hours. Then, add 2G0nil of ice water to the reaction solution, extract twice with 80ml of ethyl acetate, and extract the organic layer twice with 2G0ml of water and 5Gml of saturated saline. Washed with water. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent; n-hexane: ethyl acetate = 4: 1) to give a yellow liquid. ί. 67 g were obtained.

Refractive index n _D ² ° ⁵ = 1.55812

IR (N a C 1, cm- ¹ ) 2940, 1600, 1530, 1505, 1350, 1240,

1110, 140

_{NMR (CDC 1 3, δ ppm} ) 3. 02 (s, 3H), I 46 3. 75 (m, 5H), 3. 78-3. 96 (m, 1H), 4. 01-4. 23 ( m, 2H), 6.66-6.88 (m,), 7.16-7.35 (m, 3H), 7.44 (t, J = 8. llh, 1H), 1.73-7.90 (m, 2H)

 The following compounds were synthesized in the same manner.

 2—Methoxy 3— [N—Methyl-N— (3-Chenyl) amino]-1- (3-ditropoxy) propane

 Property: brown viscous material

IR (N a C 1, cm— ¹ ) 3100, 2940, 1555, 1530, 1350,

1250, 1110

 NMR (CDC 13.5 ppm) 2.95 (s, 3H), 3.30-3.64 (m, 5H), 3.74-3.89 (m, 1H), 4.00 -4.24 (m, 2H), 5.94 (dd, J = 2.9, 1.8Hz, 1H), 6.79 (dd, J-5.2, 1.7Hz, 7.14-7.32 (m, 2H) 7.43 (t, J = 8.2Hz, 1H), 7.n-1.U (m, 2H)

Example 4

 1— (3—Aminophenoxy) -1-2-Methoxy 3 _ (N-methyl N-phenylamino) Synthesis of propane (Compound No. 221)

To a suspension of 56 mg of platinum oxide in 20 ml of ethanol was added 2-methoxy-13- (N-methyl-1-N-phenylamino) _1- (3-nitrophenoxy) propane 1.55 g of ethanol solution 20 ml, and At room temperature under hydrogen atmosphere Stirring was performed for 18 hours. After filtering the insoluble solid, the filtrate was concentrated, and the residue was purified by silica gel chromatography (developing solvent; n-hexane: ethyl acetate = 3: 1) to obtain 1.25 g of pale yellow oily substance. .

IR (N a C 1, cm -1) 3450, 3360, 2930, 1600, 1505, 1500, 1195 NMR (CDC 1 3, δ ppm) 3.01 (s, 3H), 3.43-4.10 (m, 10H), 6.24 -6.39 (ni, 311), 6.68-6.88 (m, 311), 7.06 (t, J = 7.91Iz, 1H), 7.18-7.33 (m, 2H)

 Example 5

 1— (3-Aminophenoxy) 1-2—Methoxy 3—Synthesis of [N-methyl N- (3-Chenyl) amino] propane (Compound No. 222)

Under an argon atmosphere, 2-methoxy-3- (N-methyl-N- (3-phenyl) amino) — 1- (3-nitrophenoxy) propane 8.76 g of ethanol solution of tin chloride (11) dihydrate After adding 30.65 g of the hydrate, 100 mL of an ethanol solution of 518 mg of sodium borohydride was slowly added dropwise at 60 ° C, and the mixture was stirred for 30 minutes. After allowing to cool at room temperature, 400 ml of ice water was added, and the mixture was made alkaline with a 3.5N-K0H aqueous solution. Ethanol was distilled off under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline ₍ dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure, and the residue was purified by gel chromatography. Developing solvent: n-hexane: ethyl acetate = 3: 2) was purified to obtain 6.1 g of a brown viscous substance.

IR (a C 1, cm— ¹ ) 3450, 3360, 2930, 1620, 1600, 1550, 1495, 1460, 1410, 1190, 1160

NMR (CDC 13 .5 ppm) 2.95 (s, 3 H), 3.28-3.84 (m, 8 H). 3.92-4.08 (m, 2 H) 5.93 (dd, J = 3.1, 1.6 Hz, 1 H ), 6.23-6.59 (m, 3H), 6.81 (dd, J = 5.2, 1.7Hz, lH), 7.06 (t, J = 8.1Hz, 1H), 7.20 (dd, 5.2, 3.2H z, 1 H)

Example 6

 Synthesis of 1- (N-Methyl-N-phenylamino) propane (Compound No. 223)

 2-Methoxy-1- (N-methyl-N-phenylamino) 1- (3-aminophenyloxy) 1-ethyl-3- (3'-dimethylamino) in 10 ml of methylene chloride solution containing 650 mg of propane and 157 mg of formic acid (Propyl) 20 ml of a methylene chloride solution of 652 mg of carpoimide was added dropwise under ice-cooling. After completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours, 50 ml of water was added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was washed twice with water, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent; n-hexane: ethyl acetate = 1: 1) to obtain 680 m of a colorless viscous substance.

IR (NaC1, cm " ¹ ) 3270, 2935, 1695, 1600, 1505, 1440, 1260, 1210, 750

 NMR (CDC 13, δ ppm) 3.02 (s, 3H), 3.42-3.72 (m, 511), 3.74-3.90 (m, III), 3.92-4.18 (m, 2H), 6.60-6.88 (m, 5H ), 6.95-7.55 (m, 5H), 8.37 (d, 1 / 2H), 8.68 (d, 1 / 2H)

 The following compounds were synthesized in the same manner.

 1 [3-(Hormylamino) phenoxy] — 2-Methoxy 1 3 1 [N-methyl-N- (3-Chenyl) amino] propane (Compound No. 224)

 Properties: reddish brown crystals

IR (KB r, cm ^-1 ) 3450, 2930, 1680, 1600, 1540, 1440,

1290, 1215 NMR (CDC 13, 5 ppm) 2.94 (s, 3H) .3.31- 3.60 (m, 5H), 3.7H.86 (m, 1H), 3.9H.16 (m, 2H), 5.90- 5.95 (m, 1 H), 6.60-6.82 (m, 3 H), 6.97-7.85 (m, 4 H), 8.33-8.73 (m, 1 H)

Example 7

 2-Methoxy-1- 1- [3- (Methylamino) phenoxy] -13- [N-Methyl-N-phenylamino] propane (Compound No. 8)

 Lithium aluminum hydride 94 mg in tetrahydrofuran 15 ml suspension under ice-cooling 11- [3 _ (formylamino) phenoxy] _ 2-methoxyquin _ 3-[N-methyl-N-phenylamino] propane 650 mg of tetrahydrofuran 5 ml of drofuran solution was slowly added. After the addition was completed, the mixture was heated under reflux for another 3 hours. After completion of the reaction, water was added dropwise, the generated solid was separated by filtration, and ether was added to the filtrate for extraction. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is subjected to silylation gel column chromatography (developing solvent; n-hexane: ethyl acetate = Purification by 4: 1) afforded 476 mg of the desired product as a pale yellow oil.

Refractive index n _D ²⁴ · ⁵ = 1.5842

1 R (NaC1, cm- ¹ ) 3410, 2940, 1615, 1600, 1510, 1200, 1165, 750

_{NMR (CDC 1 3, δ ppm} ) 2.83 (s, 3H), 3.01 (s, 3H), 3.44- 3.88 (in, 7H), 3.94-4.12 (m, 211), 6.19-6.26 (m, 3H), 6.66-6.84 (m, 3H), 7.09 (t, 8.1Hz, 1H), 7.19-7.32 (m, 2H)

 The following compounds were synthesized in the same manner.

2-Methoxy 1- [3- (Methylamino) phenoxy] — 3 -— [N-Methyl-N— (3-Chenyl) amino] propane (Compound No. No. 204)

 Softness: brown viscous material

IR (N a C 1, cm 1) 3400, 2930, 1625, 1550, 1510, 1497, 1200, 1162

 MR (CDC 13, 5 PP m) 2.82 (s, 3 H), 2.95 (s, 3 H), 3.30-3.62 (m, 5 H), 3.63-3.86 (m, 2 H), 3.94 -4.12 ( m, 2H), 5.91—5.97 (m, 1H), 6.16—6.34 (m, 3H), 6.78_6.85 (m, 1H), 7.08 (t, J = 8) Hz , 1 H), 1.Λ1-Ί.29 (m, 1 H)

Example 8

 3-[3-(Formylamino) phenoxy] ―] —Synthesis of propenoxide

 To a suspension of 5.96 g of 60% oily hydrogenated sodium dimethylformamide in 10 mn of dimethylformamide was added a solution of 20 g of 3- (formylamino) phenol in 65 ml of dimethylformamide under ice-cooling, and the mixture was allowed to stand at room temperature for 40 minutes. Stirred. The reaction solution was ice-cooled again, 10 ml of a dimethylformamide solution of 20.4 g of epihydric hydrin was added, and the mixture was further stirred at room temperature for 18 hours. After completion of the reaction, water and saturated saline were added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.

 After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent; benzene: ethyl acetate = 1: 1) to obtain 18.3 g of the desired product as a pale brown liquid.

IR (NaC1, cm- ¹ ) 3275, 1680, 1600, 1540, 1495, 1440, 1295, 1260, 1210

_{NMR (CDC 1 3, δ ppm} ) 2.57-4.38 (m, 5H), 6.57 - 8.78 (m, 611)

Example 9 1-[3- (formylamino) phenoquine] — 3- (N-methyl-N-phenylamino) —2-propanol (Compound No. 7)

 3 — [3- (Hormylamino) phenoxy] 1] monopropenoxide 1.5 ml of a methanol solution (30 ml) was added with N-methylaniline (915 mg) and heated under reflux for 14 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent; benzene: ethyl acetate = 1: 1) to obtain 7. g of the target compound as a colorless viscous substance.

IR (NaC1, cm- ¹ ) 3300, 2880, 1680, 1600, 1445, 1305, 1295, 1250, 1210, 1145

_{NMR (CDC 1 3, δ ppm} ) 2. 50 (d, J = 3. 0Hz, 1H), 3. 00 (s, 3H), 3. 53 (d, J = 6. 5Hz, 2H), 3. 85-4. 18 (m, 211), 4.20 -4. 40 (m, 1H), 6.60-

7.70 (m, 10H), 8.35-8.75 (m, 1H)

 The following compounds were synthesized in the same manner.

 1 [3-(formylamino) phenoxy] _ 3-(phenylamino)-2-propanol (Compound No. 173)

 Properties: colorless solid

 Melting point: 115-117. C

IR (KB r, cm- ¹ ) 3370, 1680, 1605, 1520, 1500, 1310, 1275, 1165, 1040

 NMR (DM SO-d,, δ ppm) 3.00-3.40 (m, 2H), 3.83-4, 10 (m, 3H), 5.21 (d, J = 4.5 Hz, 111 ), 5.50-5.63 (m, lil), 6.48-7.43 (ra, 9H),

8.23-8.90 (m, 1H), 10.05-10.23 (m, 1H)

 1 — [3- (formylamino) phenoxy] — 3 — [N-methyl-N- (3-methylphenyl) amino] -1-propanol (Compound No. 189)

Properties: yellow oil IR (N a C 1, cm— ¹ ) 3300, 2910, 1685, 1600, 1500, 1440, 1290, 1255, 1220, 1180, 1045

 NMR (CDC 13, 5 ppm) 2.30 (s, 3H), 2.58 (d, J = 2.5 Hz, 1H), 2.99 (s, 3H), 3.52 (d, J = 6.6 Hz, 2H), 3.90-4.18 (m, 2H), 4.20-4.40 (m, III), 6.54-6.85 (m, 5H), 6.92-7.90 (m, 411), 8.36-8.75 (m, 1H)

 1- [3- (formylamino) phenoxy] -1- [N-methyl-N- (2-methylphenyl) amino] -12-propanol (Compound No. 191)

 Properties: pale yellow oil

IR (NaC1, cm- ¹ ) 3270, 2950, 2870, 1690, 1600, 1545, 1495, 1440, 1290, 1220, 1160, 1105, 1050

_{NMR (CDC 1 3, δ ppm} ) 2.35 (s, 3H), 2.71 (s, 3H), 3.02 -3.30 (m, 3H), 3.93 -4.20 (m, 3H), 6.59 -6.78 (m, 2H), 6.98-7.62 (m, 7H), 8.32-8.75 (m, 1H)

 1- [3- (Hormylamino) phenoxy] -1-3- [N-methyl-N- (4-methylphenyl) amino] -12-propanol (Compound No. 187)

 Properties: pale brown oil

IR (NaC1, cm- ¹ ) 3320, 2930, 2880, 1690, 1610, 1520, 1500, 1450, 1295, 1260, 1220, 1050

 NMR (CDC 13, δ ppm) 2.26 (s, 3H), 2.58 (d, J = 3.9 Hz, 1H), 2.96 (s, 3H), 3.46 (d, 6.5 Hz, 2H), 3.92-4.15 (m , 2H), 4.18-4.39 (m, 1H), 6.58-6.90 (m, 4H), 6.95-7.65 (m, 5H), 8.36-8.75 (m, 1H)

 3— [N— (2-chlorophenyl) 1-N-methylamino] — 1— [3- (formylamino) phenoxy] -12-propanol (Compound No. 185)

Properties: Light brown viscous material IR (N a C l, cm " ¹ ) 3280, 2890, 1680, 1600, 1550,

1500, 1450, 1300, 1220

 NMR (CDC 13, 5 ppm) 2.77 and 2.79 (2 s, 3 H), 3.10-3.25 (m, 2 H), 3.62-4.20 (m, 4 TO, 6.55-7.40 (m, 8 H), 8.20 -9.00 (m, 2 H)

 3— [N— (3_methyl phenyl) 1-N-methylamino] — 1— [3- (formylamino) phenoxy] 1-2-propanol (Compound No. 183)

 Property: pale yellow viscous material

IR (N a C 1, cm— ¹ ) 3300, 2930, 2880, 1690, 1600, 1558, 1440, 1290, 1210, 1100, 1040

 NMR (CDC 13.5 ppm) 2.62 (brs, 1 H), 2.99 (s, 3 H), 3.45-3.62 (m, 2 H), 3.85-4.38 (m, 3 H), 6.55-7.50 (m , 8 H), 7.80-8.73 (m, 2 H)

 3— [N- (4-chlorophenyl) 1-N-methylamino] _ 1- [3- (formylamino) phenoxy] 1-2-propanol (Compound No. 181)

 Properties: Light brown viscous material

 NMR (CD C, δ ppm) 2.92 and 2.94 (2 s, 3 H), 3.48-3.62 (m, 3 H), 3.88-4.38 (m, 3 H), 6.48-6.88 (m, 4 H), 6.92 -7.41 (m, 4 H), 7.87—8.80 (m, 2 H)

1- [3- (formylamino) phenoxy] -1-3- [N- (4-methoxyphenyl) -1-N-methylamino] -1-propanol (Compound No. 193)

 Properties: viscous reddish brown

IR (N a C 1, cm— ¹ ) 3300, 2940, 1685, 1600, 1515, 1440, 1245, 1040 NMR (CDC 13, 5 ppm) 2.73 (brs, H) 2.91 (s, 3H), 3.38 (d, J = 6.6Hz, 2H), 3.77 (s, 3H), .94-4.37 ( m, 3 H), 6.60-7.05 (m, 6 H), 7, 10-7.62 (m, 3 H), 8.36-8.72 (m, 1 H)

 3- [N- (4-t-butylphenyl) -N-methylamino]-1- [3- (formylamino) phenoxy] -2-propanol (Compound No. 197)

 Properties: Light brown viscous material

IR (N a C 1, cm- ¹ ) 3300, 2960, 1685, 1520, 1497, 1445, 1363, 1295

 NMR CDC, <5 ppm) 1.30 (s, 9H), 2.95 and

2.97 (2 s, 3 H), 3.12 (brs, 1 H), 3.49 (d d, J = 6.5,

3.OH z, 2 H), 3.92-4.12 (m, 2 H), 4.20-4.39 (m,

1H), 6.62-6.90 (m, 4H), 7.00-7.38 (m, 4H), 7.90 -8.70 (m, 2H)

 1— [3- (formylamino) phenoxy] —3— [N-methyl-N- (3-Chenyl) amino] -1-propanol (Compound No. 199)

 Property: brown viscous material

IR (NaC1, cm- ¹ ) 3300, 2860, 1680, 1600, 1550, 1493, 1440, 1415, 1290, 1215, 1040

NMR (CDC 13, 5 ppm) 2.69 (d, J = 4.OHz, 1H), 2.93 (s, 3H), 3.38 (d, J = 6.5Hz, 2H), 3.85-4.37 (m , 3 H), 5.98-6.38 (m, 1 H), 6.60-7.95 (m, 7 H), 8.35-8.78 (m, 1 H) 1- [3- (formylamino) phenoxy] _3— [N-methyl-N- (1-pyrrolyl) amino] 1-2-propanol (Compound No. 205)

 Property: yellow viscous material

IR (NaC1, cm- ¹ ) 3300, 2870, 1683, 1675, 1600, 1540, 1495, 1440, 1290, 1260, 1215

 NMR (CDC 13, 5 PP m) 2.73 (brs, 1 H), 2.95 (s, 3 H), 3.05-3.30 (m, 2 H), 3.68-3. 85 (m, 1 H), 3.85-4.05 (m, 2 H). 6. 07-6.13 (m, 1 H), 6.56-7.70 (m, 7 H), 7.58 (brs, 1 H), 8.33-8.73 (m, 1 H)

Example 10

 1 — [3- (Methylamino) phenoxy] — 3 -— (N-methyl-1-N-phenylamino) synthesis of 2-propanol (Compound No. 180) Lithium aluminum hydride 2.58 g suspended in 100 ml of tetrahydrofuran In a drowned solution, under ice cooling, dissolve 12 g of [3- (formylamino) phenyl]-3- (N-methyl-N-phenylamino) -2-propanol in tetrahydrofuran 10 1 The solution was added dropwise. After completion of the dropwise addition, the mixture was heated under reflux for 4 hours, water was added, and the purified insoluble material was separated by filtration. The filtrate was washed with saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 2: 1). The product was obtained as a pale yellow liquid (2.08 g).

IR (N a C 1, cm ^-1 ) 3530, 3410, 2930, 1590, 1500, 1200, 1165, 750

NMR (CDC 13, δ ppm) 2.50 (brs, 1H), 2.82 (s, 3H), 3.00 (s, 3H), 3.53 (d, J = 6.5 Hz, 2H) , 3.60 -4.40 (m, 4H), 6.15-6.34 (m, 3H), 6.70 -6.88 (m, 3H), 7.09 (t, J = 8. 1Hz, 1H), 7.18-7, 34 (m, 2H) Similarly, the following compounds were synthesized.

 3-[N— (2-chlorophenyl) -1-N-methylamino] 1 1 1

 [3- (Methylamino) phenoxy] _ 2 propanol (Compound No. 186)

 Softness: pale brown oil

IR (N a C 1, cnT ¹ ) 3430, 2940, 1625, 1490, 1210, 1 Π5, 1060, 765

_{NMR (CDC 1 3, δ ppm} ) 2.73 - 2.90 (m, 611), 3.05 - 3.50 (m, 411), 3.93 -4.30 (m, 3H), 6. 〗 7- 6.40 (m, 311), 6.95- 7.46 (m, 511)

 3— [N- (3-chlorophenyl) -N-methylamino] — 1—

 [3- (Methylamino) phenoxy] 1-propanol (Compound No. 184)

 Properties: pale brown oil

IR (N a C 1, crT ¹ ) 3560, 3410, 2940, 1600, 1500, 1200, 1170, 995, 760

 NMR (C D C 13.5 ppm) 2.83 (s, 3H), 3.00 (s, 3H), 3.43-

3.62 (m, 2H), 3.84-4.07 (m, 2H), 4.19-4.37 (m, 1H), 6.i8- 6.37 (m, 3H), 6.60-6.80 (m, 3H), 7.11 (q, J : 7.3Hz, 2H)

 3-[N-(4-chlorophenyl) 1N methylamino] 1 1 —

 [3- (Methylamino) phenoxy] _ 2 propanol (Compound No. 182)

 Properties: yellow oil

IR (N a C 1, cm- ¹ ) 3520, 3410, 2930, 1615, 1595, 1500, 1200, 1165, 810

 NMR (CDC 13 .δ ppm) 1.60 (brs, 1H), 2.40 (brs, 1H), 2.83 (s, 3H), 2.98 (s, 3H), 3.51 (d, J = 5.0Hz, 2H), 3.85 -4.10 (m, 2H), 4.15-

4.35 (m, 1H), 6.17-6.37 (m, 3H), 6.72 (d, J = 9.1Hz, 2H), 7.00- 7.23 (m, 3-[N-(4-methoxyphenyl) 1 N-methylamino]-1-[3-(methylamino) phenoxy] 1-2-propanol (Compound No. 194)

 Properties: light brown liquid

IR (NaC1, cm- ¹ ) 3410, 2940, 1618, 1520, 1245, 1200, 1165, 1040, 735

 NMR (CDC 13, δ ppm) 2.82 (s, 3H), 2.92 (s, 3H), 3.10 (brs, III), 3.40 (d, J = 6.5 Hz, 2H) , 3.78 (s, 311), 3.90-4.08 (m, 2H), 4.15-4.33 (m, III), 6.18-6.35 (m, 3H), 6 .85 (s, 4H), 7.055-7.18 (m, 1H)

 3-[N— (p-tert-butylphenyl) -N-methyl] — 1 —

 [3- (Methylamino) phenoxy] 1-2-propanol (Compound No. 198)

 Properties: yellow liquid

IR (N a C 1, cm- ¹ ) 3410, 2960, 1615, 1500, 1205, 1168, 820, 135

_{NMR (CDC 1 3, δ ppm} ) 1. 39 (s, 911), 2. 84 (s, 3H), 2. 90 (s, 3H), 3. 51 (d, J = 6. 4Hz, 2H) , 3.99-4.10 (m, 2H), 4.23-4.40 (m, 1H), 6.19-6.38 (m, 3H), 6.80 (d, J = 9. 0Hz, 2H), 7.03-7.19 (m, 1H), 7.30 (d, J = 8.9Hz, 2H)

 1 — [3 — (Methylamino) phenoxy] 1-3 — (phenylamino) 1-2-propanol (Compound No. Π4)

 Properties: yellow oil

IR (NaC1, cm- ¹ ) 3400, 2930, 1600, 1500.1320, 1300, 1260, 1200, 1160, 1045

NMR (CDC 13 »S ppm) 2.59 (brs, 1H), 2.83 (s, 3H), 3.29 (dd, J = 7.0, 13.0 Hz, 1H), 3.44 ( dd, J = 4.5, 12.8Hz, 1H) ₍ 3.65-4.38 (m, 5H), 6.16-6.23 (t, J = 2.2Hz, 1H), 6.23-6.36 (m, 2H), 6.64-6.892 (m, 3H), 7.04-7.30 (in, 3H)

 3- [N-methyl-N- (4-methylphenyl) amino] -1-1 [3 _. (Methylamino) phenoxy] _2-propanol (Compound No. 188)

 Properties: yellow oil

IR (N a C 1, cm— ¹ ) 3420, 2920, 1620, 1520, 1200, 1165, 1050

 NMR (CDC 13.5 PP m) 2.26 (s, 3H), 2.52 (d, J = 4.2Hz, 1H), 2.82 (s, 3H), 2.96 (s, 3H), 3. 47 (d, J = 6.5 Hz, 2 H), 3.73 (brs, 1 H), 3.92—4.10 (m, 2 H), 4.18—4.36 (m, 1 H), 6.12-6.32 (m, 3 H ), 6.75 (d, J = 8.7Hz, 2H), 7.00-7.18 (m, 3H)

 3- [N-methyl_N_ (2-methylphenyl) amino] 1-11 [3- (methylamino) phenoxy] 1-2-propanol (Compound No. 192)

 Properties: pale yellow oil

IR (N a C 1, cm ^-1 ) 3400, 2920, 1610, 1490, 1200, 1160, 1040

 NMR (CDC 13.5 P pm) 2.36 (s, 3H), 2.71 (s, 3H), 2.81 (s, 3H) 2.97-3.27 (m, 3H), 3.72 (brs, 1H), 3.92—4.22 (m, 3H), 6.Π—6.33 (m, 3H), 6.98-T.25 (m, 5H)

 3- [N-methyl-N- (3-methylphenyl) amino] — 1- [3- (methylamino) phenoxy] _2-propanol (Compound No. 190)

Properties: pale brown oil IR (N a C 1, cm— ¹ ) 3400, 2910, 1600, 1495, 1195, 1160, 1040

 NMR (CDC 13, 5 ppm) 2.30 (s, 3H), 2.48 (d, J = 3.7Hz, 1II), 2.83 (s, 3H), 2.99 (s, 3H), 3.52 (d , J-6.5H z, 2 H), 3.75 (brs, 1 H), 3.95-4.10 (m, 2 H) .4.20-4.39 (m, 1 H), 6.Π _ 6.35 (m, 3H),

6.55-6.70 (m, 3 H), 7.02-7.20 (m, 2 H)

 3- [N-Methyl-N- (3-Chenyl) amino] _1-1 [3- (methylamino) phenoxy] _2-propanol (Compound No.

200)

 Properties: pale brown oil

IR (N a C 1, cm— ¹ ) 3400, 2920, 2870, 1615, 1550, 1495, 1415, 1195, 1160

 NMR (CDC 13, 5 ppm) 2.55 (d, J = 3.8 Hz, 1 H), 2.83 (s, 3 H), 2.94 (s, 3 H), 3.39 (d, J = 5.9 Hz, 2 H ), 3.72 (brs, 1 H), 3.9H.08 (m, 2 H), 4.14 — 4.33 (m, 1 H), 5.99-6.06 (m, 1 H), 6.14-6.32 (m,

3H), 6.78-6.85 (1H), 7.02-7.13 (m, 1H), 7.16-

7.28 (m, 1 H)

 3-[N-Methyl-N- (1-pyrrolyl) amino] — 1— [3- (Methylamino) phenoxy] _2-propanol (Compound No.

206)

 Property: Brown oily substance

IR (N a C 1, cm— ¹ ) 3400, 2920, 2870, 1615, 1510, 1500, 1450, 1200, 1160, 1060

 NMR (C D C 13, <5 ppm) 2.69 (brs, 1 H), 2.82 (s,

3H), 2.94 (s, 3H), 3.06-3.30 (m, 2H), 3.66-3.83 (m, 2H). 3.84-4.05 (m, 2H), 6.06—6.17 (m, 3H), 6.19-6.32 (m, 2H), 6 84—6.94 (m, 2H), 7.07 (t, J = 8.1Hz, 1H)

Example 11

 Synthesis of 3- (N-methyl-1-N-phenylamino) 1-111 [3- (N-methylformylamino) phenoxy] -12-propanol (Compound No. 5)

1- [3- (formylamino) phenoxy] — 3— (N-methyl-1-N-phenylamino) 1 2— in a solution of 68 mg of 60% oily sodium hydride suspended in 3 l of tetrahydrofuran under ice cooling A solution of 500 mg of propanol in 15 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 30 minutes _(the reaction solution was ice-cooled again, 3 ml of a dimethylformamide solution of 241 mg of methyl iodide was added, and the mixture was further stirred at room temperature for 2 hours. After completion of the reaction, water and saturated saline were added to the reaction solution, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting product was subjected to silica gel chromatography (developing solvent; benzene: ethyl acetate = 2: 1) to obtain nOmg of the desired product as a pale brown viscous substance.

1 R (NaC1, cm- ¹ ) 3420, 2940, 1680, 1610, 1510, 1345, 1220, 1120, 1050

NMR (CDC 13.5 ppm) 2.57 (d, J = 4.4 Hz, 1 H), 3.00 (s, 3 H), 3.30 (s, 3 H), 3.54 (d, J = 6.5 Hz, 2 H). 3.95-4.15 (m, 2 H) _Λ 4.23-4.40 (m, 1 H)-6.70-6.88 (m, 6 H), 7.20-7.39 (m, 3H), 8.49 (s, 1H)

Example 12

2-(Ethoxycarbonylmethoxy) 1 3-(N-methyl-N- [Phenylamino] 1] — [3 — (N-methylformylamino) phenoxy] synthesis of propane

 3- (N-methyl-1-N-phenylamino) 1-11 [3- (N-methylformylamino) phenoxy] -12-propanol 370 mg, acetonitrile suspension of potassium carbonate ninig 4 ml of an acetonitrile solution of 207 mg of ethyl bromoacetate was added to IG ml, and the mixture was heated under reflux for 4 hours. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the desired crude product was obtained as a pale yellow oil.

1 R (N a C 1, cm— ¹ ) 2930, 2900, 1750, 1680, 1600,

1505, 1340, 1210, 1130

 NMR (CDC 13, <5 PP m) 1.25 (t, J = 7.3Hz, 3H), 3.02 (s, 3H), 3.30 (s, 3H), 3. 62— 3. 75 (m,

2H), 3.98-4.35 (m, 7H), 6.65-6.86 (m, 6H), 7.16-7.38 (m, 3H), 8.49 ( s, 1 H)

Example 13

 2- (Carboxymethoxy) 1 3 — (N-methyl-N-phenylamino) 1 1 — [3- (N-methylamino) phenoxy] propane

Synthesis of (Compound No.Π0)

 2- (Ethoxycarbonylmethoxy) -3- (N-methyl-N-phenylamino) _1- [3— (N-methylformylamino) phenoxy] Propane 59 mg in dioxane-1 N hydrochloric acid mixed solvent ( The mixture was dissolved in 10 ml of a volume ratio and heated under reflux for 1 hour. After water was added to the reaction solution, it was neutralized with a 10% NaOH aqueous solution. After extraction with black form, the extract was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the desired crude product was obtained as a brown oily product.

IR (N a C 1, cm— ¹ ) 3400, 2910, 2850, 1738, 1600, 1510, 1200, 1125

 NMR (CDC 13, 5 ppm) 2.82 (s, GH), 2.98 (s, 3H), 3.35—3.61 (m, 2H), 4.0 "s, 3H 4.34 (s,

2 H), 6.13-6.34 (m, 3 H), 6.55 (brs, 2 H), 6.60-7.18 (m, 3 H), 7.09 (t, J = 8. 1H z, 1 H), 1.23—7.36 (m, 2 H)

Example 14

 2-Methoxy-3— [N-Methyl-N— (3-Chenyl) amino] 1-1—Synthesis of [3- (N-methylformylamino) phenoxy] -propane (Compound No. 201)

 A solution of 1.2 g of 60% oil-based sodium hydride suspended in 15 mj of dimethylformamide was cooled under ice-cooling to obtain a solution of 1- [3- (formylamino) phenoxy] — 3— [N-methyl-1-N— (3— [Chenyl) amino] —2-propanol 3.75 g of a dimethylformamide solution (20 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was ice-cooled again, 3.85 g of methyl iodide was added, and the mixture was further stirred at room temperature for 16 hours. After completion of the reaction, water and saturated saline were added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate.

 After evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography (eluent: n-hexane: ethyl acetate = 3: 2) to obtain 820 mg of the desired product as a brown oil.

IR (NaC1, cm- ¹ ) 2920, 2860, 1660, 1600, 1545, 1495, 1410, 1340, 1220, 1110, 1040

_{NMR (CDC 1 3, 5 ppm} ) 2. 58 - 2. 62 Γπι, 1 H), 2.95 (s, 3 H), 3. 25 - 3. 48 (m, 5 H), 3. 95-4. 13 (m, 2 H), 19-4.39 (m, 1 H), 6.02-6.10 (m, 1 H), 6.70—7.40 (m, 6 H), 8. 50 (s, 1H) Example 15

 2-Methoxy-1-3- [N-methyl-N- (3-Chenyl) amino]-1- [3- (Methylamino) phenoxy] -propane (Compound No. 204)

 2-Methoxy 3— [N-Methyl-1-N— (3-Chenyl) amino]-1- [3- (N-methylformylamino) phenoxy] —Propane lOOmg mixed with dioxane-1N hydrochloric acid The residue was dissolved in 10 ml of a solvent (1Z1; vZv), and the mixture was heated under reflux for 1.5 hours. After allowing the reaction solution to cool, ice water was added thereto, and the mixture was rendered alkaline with a 15% aqueous sodium hydroxide solution. After extraction with a black hole form, the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, iiig of the desired product was obtained as a brown viscous substance.

 I R (Na C 1, cm—up) 3400, 2930, 1625, 1550, 1510, 1497, 1200, 1162

NMR (CDC) ₃ , 5 ppm) 2.83 (s, 3H) 2.95 (s, 3H), 3.30-3.62 (m, 5H), 3.63-3.86 (m, 2H), 3.94 -4. 12 (m, 2H), 5.91—5.97 (m, 1H), 6.16—6.34 (m, 3H), 6.78— 6.85 (m, 1H), 7.08 (t, J = 8.1Hz, 1H), 7.17-7.29 (m, 1H)

Example 16

 O-(p-tert-butylphenyl) = N-methyl-N-

 (2,3-Epoxypropoxy) -1-pyridyl] thiocarbamate (Synthesis of Compound No. 24Π)

0— (p-tert-butylphenyl) = N-methyl-N— (6-hydroxy-2-pyridyl) thiocarbamate 1.5 g and 677 mg of carbonated lithium in 10 ml of dimethylformamide solution in 10 ml of epibromohydrid 781 _mg was added and the mixture was stirred at room temperature for 15 hours. Then, after adding 300 ml of water and extracting with ethyl acetate, the organic layer was washed with water and saturated sodium hydrogen carbonate. Washed with aqueous solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel gel chromatography (developing solvent; n-hexane: acetic acid = 4: 1) to give the colorless viscous substance of the desired product. 1.06 g of the product were obtained.

IR (NaC1, cm- ¹ ) 2955, 1595, 1570, 1505, 1460, 1430, 1265, 1185, 1020

 NMR (CDC 1,, δ ppm) 1.32 (s, 9H), 2.76 (dd, J = 2.7, 4.8 Hz, 1H), 2.87-2.93 (m, 1H), 3.33- 3.45 (m, 111), 3.74 ( s, 311), 4.20 (dd, J = 6.2, 12.llz, 1H), 4.64 (dd, J = 3.0, 12.1Hz, 1H), 6.72 id, J = 7.7Hz, 1H), 6.95-7.10 (m , 3H), 7.39 (d, 8.8 Hz, 2H), 7.64 (t, J = 8.2 Hz, 1H) The following compounds were synthesized in the same manner.

 0— [6— (1,2,3,4—tetrahydrodonaphthyl)] = N—methyl-1-N— [6— (2,3-epoxypropoxy) -12-pyridyl] thiocarbamate (Compound No. 248)

 Properties: viscous brown substance

1 R (N a C 1, cm— ¹ ) 2930, 1595, 1575, 1440, 1370, 1265, 1240, 1180, 1150, 1025

 NMR (CDC 13, 5 ppm) 1.66-1.90 (m, 4H), 2.62-2.85 (m, 5H), 2.91 (t, J = 4.1Hz, 1H), 3.32-3.45 (m, l H), 3.73 (s, 3H) .4.20 (dd, J = 12.2, 6.2Hz, lH), 4.64 (dd, J = 12.1, 3.OHz, 1H), 6.50-6.95 (m, 3H), 7.05 (dd, J = 8.1, 3.9Hz, 2H), 7. "(t, J = 8.3Hz, 1H)

0— [p—tert-butylphenyl) = N—methyl-1-N— [3- (2,3-epoxypropoxy) phenyl] thiocarbamate (Compound No. 241) Properties: colorless viscous material

IR (NaC1, cm " ¹ ) 2960, 1600, 1480, 1380, 1235, 1210, 1180, 1120, 1 M0, 1040

 NMR (CDC 13, 5 ppm) 1.30 (s, 9H), 2.76 (dd, J = 4.8, 2.6Hz, 1H) .2.92 (t, J = 4.1Hz , 1H), 3.26-3.44 (m, 1H), 3.70 (s, 3H), 3.95 (dd, J = 11.0, 5.8Hz, lH), 4 25 (dd, J = 11.0, 3.1Hz, 1H), 6.80_7.0 "m, 5H). I 22-7.48 (m, 3H)

 0— [6— (1,2,3,4-tetrahydronaphthyl)] = N—methyl-1-N— [3- (2,3-epoxypropoxy) phenyl] thi talented rubamate (Compound No. 242)

 Properties: colorless oil

1 R (N a C 1, cm ^-1 ) 2940, 1605, 1495, 1380, 1220, 1175, 1045

_{NMR (CDC 1 3, 5 ppm} ) 1. 68 - 1. 90 (m, 4 H), 2. 63 - 2. 87 (m, 5 H), 2. 92 (t, J = 4.7H z, 1 H), 3.31-3.42 (m, 1 H). 3.70 (s, 3H) 3.95 (cld, J = 11.1, 5.7Hz, lH), 4.25 (dd, J = 11.0, 3.1Hz, 1H), 6.66-7.15 (m, 5H) .7.24-7.39 (m, 2H)

Example Π

 Synthesis of 0- (p-tert-butylphenyl) = N-methyl-N- [3- (2,3-epoxypropoxy) phenylmethyl] thiocarbamate (Compound No. 251)

0— (p-tert-butylphenyl) = N-methyl-N— (3-hydroxyphenylmethyl) thiocarbamate 326 mg and carbonic acid 166 mg in 2 ml dimethylformamide solution 164 m _g was added and stirred at room temperature for 20 hours. Add water to the reaction mixture The organic layer was washed with saturated saline. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; benzene: ethyl acetate = 30: 1) to obtain 252 mg of a colorless liquid.

IR (NaC1, cm- ¹ ) 2955, 1600, 1580, 1500, H 00, 1263, 1205, 1 Π5, 1140, 1103

 NMR (CDC 13, δ ppm) [1.33 (s), 1.34 (s), 9H], 2.74-2.84 (m, III), 2.93 (t, J. 7 Hz, 1H) , 3.18-3.50 (m, 411), 3.97 (dd, J = 5.5, 11.0 Hz, 1H), 4.19-4.33 (m, 1H), [4 89 (s), 5.17 (s), 2H], 6.82-7.07 (m, 5H), 7.22-?. 46 (m, 3H)

 The following compounds were synthesized in the same manner.

 0— [6— (1,2,3,4-tetrahydronaphthyl)] = N—methyl-1-N— [3- (2,3_epoxypropoxy) phenylmethyl] thiocarbamate (Compound No. 252)

IR (N a C 1, cm " ¹ ) 3445, 2930, 1595, 1505, 1490, 1445, 1400, 1260, 1235, 1220, 1165, 1150, 910, 730

 NMR (C D C 13, δ ppm) 1.73-1.93 (m, 4H), 2.41 (rs, 1H),

2.70-2.92 (m, 4H), [3.02 (s), 3.03 (s), 3H], [3.23 (s), 3.44 (s), 3H],

3.56 (d, J = 6.6 Hz, 211), 3.98-20 (m, 211), 4.23- 4.42 (ra, III), [4.89 (s), 5.18 (s), 211], 6. 76-7. 18 (m, 9H), 7.20-7.40 (m, 3H)

Example

 Synthesis of O— (p-tert-butylphenyl) = N— [3-—2-hydroxy-1-3- (N-methyl-N-phenylamino) propoxy] phenyl] thiocarbamate (Compound No. 1)

P- (tert-butylphenyl) = 1- (3-aminophosphonyl) -3- (N-methyl-N-phenylamino) 1-2-propanol in 5 ml of acetonitrile solution of 330 mg of cloform thioformate 282 mg of 2-propanol 5 ml of acetonitrile solution was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 18 hours, and then a saturated sodium hydrogen carbonate solution was added to the reaction solution. After the reaction solution was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (developing solvent; n-hexane: ethyl acetate). : 1) to give colorless crystals 4ι.

 Melting point: 46-47.5 ° C

IR (KB r, cm ~ ^] ) 3250, 2970, 1600, 1505, 1380, 1215, 1160, 840, 750

NMR (CDC 1> δ ppm) 1.35 (s, 9H), 3.04 (s, 3H), 3.55-3.62 (m, 2H) ₍ 3.98-4.10 (m, 211), 4.25- 4.40 (m, 1H), 6.62-7.55 (m, 13H), 8.40 (bs, 1H)

 The following compounds were synthesized in a similar manner.

 0— (ρ-tert-butylphenyl) = N-methyl-N— [3- [2-hydroxy-3- (N-methyl-1-N-phenylamino) propoxy] phenyl] thiocarbamate (Compound No. 14)

 Properties: Light brown viscous material

1 R (N a C 1, cm " ¹ ) 3440, 2950, 1600, 1490, 1450, 1240, 1210, 1Π 0, 1120, 745

_{NMR (CDC 1 3, δ ppm} ) 1. 31 (s, 9H), 2.47 (d, J = 4. 3Hz, 1H),

3.00 (s, 3H), 3.54 (d, 6.5 Hz, 2H), 3.71 (bs, 3H), 3.95-4.12 (m, 2H),

4.23 -4.40 (m, 1H), 6.70-7.05 (m, 8H), 7.20-7.42 (m, 5H)

 0-[6— (1,2,3,4-tetrahydronaphthyl)] = N—methyl-N— [3- [2-hydroxy-13- (N-methyl-N-phenylamino) propoxy] phenyl] thiocarbame G (Compound No. 26)

Property: yellow viscous material IR (N a C 1, cm ^-1 ) 3450, 2940, 1600, 1490, 1445, 1380, 1240, 1220, 1170, 1120, 1040

 NMR (CDC 13, δ ppm) 1.65-1.88 (m, 411), 2.Π (d, J = 4.5Hz, 1H), 2.62-2.90 (m, 4H), 3.00 (s, 3H), 3.54 ( d, J = 6.6Hz, 2H), 3.71 (s, 311), 3.95-4.18 (m, 2H), 4.22-4.40 (m, III), 6.65-7.14 (m, 9H), 1.19-1.44 (m, 3H)

 0-(p—tert-butylphenyl) = N—methyl _N— [3—

 [2-Hydroxy-1-3- [N-methyl-1-N- (4-chlorophenyl) amino] propoxy] phenyl] thiocarbamate (Compound No. 性) Properties: pale yellow oil

1 R (a C 1, cm - 1) 3450, 2960, 1595, 1500.1380, 1240, 1210 NMR (CD C 1 3, δ ppm) 1.31 (s, 9H), 2.45 (brs, 1H) (2.98

(s, 3H), 3.45-3.55 (m, 2H), 3.1 \ (s, 3H), 3.90-4.15 (m, 211), 4.20-4.38 (m, 1H), 6.65-7.05 (m, 8H), 7.10-7.45 (m, 4H)

 0— (p—tert-butylphenyl) = N—methyl-N— [3—

 [2-Hydroxy-1-3- [N-methyl-N- (3-chlorophenyl) amino] propoxy] phenyl] thiocarbamate (Compound No. 16) Properties: Colorless viscous substance

IR (N a C 1, cm ^-1 ) 3420, 2950, 1600, 1490, 1380, 1200

NMR (CDC 13, δ ppm) 1.32 (s, 9H), 2.54 (brs, 1H), 3.00 (s, 3H), 3.40-3.80 (m, 5H), 3.90-4.15 (m, 2H), 4.25 (brs , 1H), 6.60 -6.80 (m, 3H), 6.82-7.22 (m, 611), 7.22 -7.48 (m, 3H)

 0— (p-tert-butylphenyl) = N-methyl-N— [3—

[2-Hydroxy-1-3- [N-methyl-N- (4-methylphenyl) amino] propoxy] phenyl] thiocarbamate (Compound No. 20) Properties: pale yellow viscous substance 9

7 5

IR (N a C 1, cm ^-1 ) 3420, 2960, 1600, 1520, 1480, 1380, 1235, 1210, 1175, 1120, 1105

 NMR (CDC 13, δ ppm) 1.31 (s, 9H), 2.26 (s, 3H), 2.53 (d, J MHz, III), 2.96 (s, 3H), 3.47 ( d, J = 6.6Hz, 2H), 3.71 (brs, 3H), 3.98-4.18 (m, 2H), 4.22-4.40 (m, 1H), 6.75 (m, 2H), 6.82-7.13 (m, 711), 7.23- 7.43 (m, 3H)

 0— (p—tert-butylphenyl) = N—methyl-N— [3—

 [2-Hydroxy-3- [N-methyl-N- (3-methylphenyl) amino] propoxy] phenyl] thiocarbamate (Compound No. 19) Properties: pale yellow viscous substance

IR (N a C 1, cm— ¹ ) 3410, 2960, 1605, 1510, 1490, 1380, 1215

 NMR (CDC 1, δ ppm) 1.31 (s, 9H), 2.29 (s, 311), 2.98 (s, 311), 3.52 (d, J = 6.3 Hz, 2H), 3.71 ( brs, 311), 3.95-4.18 (m, 2H), 4.20-4.39 (m, 1H), 6.52-6.70 (m, 3H), 6.72-7.05 (m, 5H) , 7.05-7.20 (m, 1H), 7.22-7.42 (m, 3H)

 0-(p-tert-butylphenyl) = N-methyl-N— [3—

 [2-Hydroxy-3- (N-methyl-N- (2-methylphenyl) amino] propoxy] phenyl] thiocarbamate (Compound No. 18) Properties: Colorless viscous substance

1 R (NaC1, cm- ¹ ) 3460, 2960, 1600, 1495, 1380, 1240, 1215, 1180, 1110

_{NMR (CDC 1 3, δ ppm} ) 1. 31 (s, 9H), 2. 35 (s, 311), 2. 71 (s, 3H), 3. 03- 3. 30 (m, 3H), 3 71 (brs, 3H), 3.94-4.22 (m, 3H), 6.80-7. 42 (m, 12H)

0— (4-Methyl-1-N-phenyl) = N—Methyl-1-N —— [2-Hydroxy-1-3 -— (N-Methyl-1-N-phenylamino) Propoxy] phenyl] thiocarbamate (Compound No. 26)

 Properties: colorless viscous material

IR (Na C 1, cm- ¹ ) 3430, 2930, 1600, 1470, 1380, 1220, 1165, 1120, 1040,? 30

 NMR (CDC 13, 5 ppm) 1.23 (t, J = 7.1 Hz, 3H), 2.40 (bs, 1H), 2.74 (q, J = 1.4 Hz, 2H), 3. 01 (s, 3H), 3.45-3.62 (m, 2H), 3.72 (s, 3H), 3.95-4.20 (m, 211), 4.25-4.45 ( m, III), 6.70-7.05 (m, 811), 7.18-7.45 k 411)

 0—5—indani —methyl-N_ [3-—2-hydroxy—3— (N-methyl_N-phenylamino) propoxy] phenyl] thiocarbamate (Compound No. 25)

 Properties: colorless viscous material

IR (KB r, cm- ¹ ) 3430, 2930, 1600, 1500, 1480, 1380, 1220, 1115

_{NMR (CDC 1 3, δ ppm} ) 2. 08 (q, J = 7. 3Hz, 2H), 2. 80-2. 97 (m, 4H), 3. 00 (s, 3H), 3. 53 ( d, 6.5 Hz, 2H), 3.71 (brs, 3H), 3.95-4.14 (m, 2H), 4.24-4.40 (m, 1H), 6.68- 7. 02 811), 7.10-7.40 (m, H)

 0-(3-te rt-butyl-4-phenyl) = N-Methyl-N-[3-[2-Hydroxy-13-(N-methyl-N-phenylamino) propoxy] phenyl] thiocarbamate ( Compound No. 27) Property: colorless viscous substance

1 R (KB r, cm ^-1 ) 3450, 2960, 2930, 1600, 1510, 1490, 1450, 1380, 1230, 1210

_{NMR (CDC 1 3, δ ppm} ) 1. 45 (s, 9H), 3. 00 (s, 3H), 4. 53 (d, 6. 5Hz, 2H), 3. 70 (bi s, 3H), 3.97-4.18 (tn, 2H), 4.22-4.40 (m, 1H), 6.70-7.07 (m, 8H), 7.19-7.42 (m, 4H ) 0— (p-tert-butylphenyl) = N-methyl-N —- [2-hydroxy-3- (N-methyl-1-N— (2-chlorophenyl) amino] propoxy] phenyl] thiocarbamate ( (Compound No. 15)

 Properties: colorless oil

1 R (NaC1, cm ^-1 ) 2962, 1602, 1589, 1479,] 379, 1209, 1173

_{NMR (CDC 1 3, 5 ppm} ) 1. 31 (s, 9 H), 2. 82 (s, 3 H). 3. 12- 3. 50 (m, 3 H), 3. 71 (s, 3 H), 3.96-4.24 (m, 3H), 6.83-7.14 (m, 6H), 7.16-7.50 (m, 6H)

0— (p-tert-butylphenyl) = N-methyl-1-N— [3- [2-hydroxy-1-3-N-methyl-1-N— (4-methoxyphenyl) amino] propoxy] phenyl] thiocarbame G (Compound No. 21)

 Property: yellow viscous material

1 R (a C 1, cm- ¹ ) 3430, 2960, 1600, 1515, 1485, 1380, 1240, 1210

 NMR (CDC 1 J, δ ppm) 1.32 (s, 9H), 2.50-3.10 (m, 4H), 3.40 (d, J = 6.5Hz, 2H), 3 60—3.85 (m, 6 H). 3.95-4. 18 (m, 2 H), 4.1H. 36 (m, 1 H)-6.80-7.10 (m, 9 H), 7.20-7.45 (m, 3 H)

 O-(p-tert-butylphenyl) = N-methyl-N- [3-[2-hydroxy-3- [N-methyl-N- (4-tert-butylphenyl) amino] propoxy] phenyl] thiocarbamate ( (Compound No. 23)

Softness: yellow oil IR (N a C 1, cm ^-1 ) 3430, 2960, 1605, 1520, 1485,

1380, 1235, 1210, 1180, 735

 NMR (C DC 13, <5 ppm) 1.25-1.2 (m, 18H), 2.60 (brs, 1H), 2.99 (s, 3H), I50 (d, J = 6.5Hz,

2H), 3.72 (s, 3H), 3.95-4.20 (m, 2H), 4.22-4.40 (m, 1H), 6.78-7.10 (m, 7H), 7.22-7.48 (m, 5H )

0— (m-tert-butylphenyl) = N—methyl-1-N— [3-—2-hydroxy-3 -— [N—methyl-1-N— (3-phenyl) amino] propoxy] phenyl] thiocarbamate ( Compound No. 33) Property: reddish brown oil

1 R (NaC1, cm- ¹ ) 3440, 2960, 2870, 1600, 1585, 1545, 1480, 1375, 1260, 1230, 1195, 1165, 1115

 NMR (C D C 1, <5 ppm) 1.32 (s, 9 H), 2.64

 (brs, 1 H), 2.94 (s, 3 H), 3.39 (d, J = 6.3 Hz, 2 H), 3.72 (s, 3 H), 3.95-4.15 (m, 2 H), 4.20-4.36 (m, 1 H), 6.06 (dd, J = 3.1, 1.6 Hz, 1 H), 6.76—7.10 (m, 6 H), 7 · 16-7.43 (m, 4 H)

 0-(p-tert-butylphenyl) = N-methylenol N- [3-[2-hydroxy3- 3- [N-methyl-N- (1-pyrrolyl) rmino] propoxy] funinyl] thiocarbamate (Compound No. 45) Property: pale yellow viscous material

1 R (KB r, cm- ¹ ) 3450, 2960, 1600, 1485, 1380, 1210, 1175, 1105

NMR (CDC 13, 5 ppm) 1.31 (s, 9H) 2.72 (d, J = 2.9Hz, 1H), 2.95 (s, 3H), 3.07-3.32 (m, 2H), 3.65-3.84 (m, 4H), 3.85-4.05 (m, 2H), 6.07-6.16 (m, 2H). 6.79-7.08 (m, 7H), 7.25-7.46 (m, 3H) W 3

79 Example 19

 0— (p—tert-butylphenyl) = N—methyl-N— [3—

 Synthesis of [2-hydroxy-3- (phenylamino) propoxy] phenyl] thiocarbamate (Compound No. 10)

 1- [3- (Methylamino) phenoxy] -3- (phenylamino) 1-2-propanol 410 mg of acetonitrile solution in 15 ml of p-

10 ml of a solution of 344 ntg of (tert-butylphenyl) = chlorothioformate in acetonitrile was added dropwise, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, a saturated sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent; n-hexane: ethyl acetate = 2: 1) to give a colorless solid.

351 mg was obtained.

 Properties: colorless solid

1 R (KB r, cm ^-1 ) 3410, 2960, 1605, 1510, 1490, 1380, 1215 NMR (CDC 13. <5 ppm) 1.31 (s, 9H), 1.60 (BRS, 1H), 2.52

(BRS, 1H), 3.31 (dd, J = 7.0, 12.9Hz, 1H), 3.46 (dd, J = 4.4, 13.0Hz, 1H), 3.71 (brs, 3H), 4.02-4.15 (m, 2H), 4.21-4.36 (m, 1H), 6.62-6.82 (m, 3H), 6.83-7.15 (m, 5H), 7.18-7.46 (m, 5H)

 Example 20

 0— (p—tert-butylphenyl) = N—methyl-N—

 Synthesis of [2-Methoxy-13- (N-methyl-N-phenylamino) propoxy] funinyl] thiocarbamate (Compound No. 54)

2-Methoxy 11- [3- (Methylamino) phenoxy] — 3- (N-methyl-N-phenylamino) Propane 20 g dissolved in acetonitrile 5 ml was added at room temperature to p- (tert- (Butyltyl) = chlorothioformate 150mg dissolved in acetonitrile 5ml The solution was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 18 hours, and a saturated sodium hydrogen carbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography.

(Developing solvent; n-hexane; acetic acid 6: 1) to give 296 mg of a viscous target compound.

 Refractive index 25

 n a 1.5695

IR (NaC1, cm- ¹ ) 2760, 1600, 1500, 1480, 1380, 1210, 1175, 1120, 840, 745, 695

 NMR (CDC 13, δ ρπι) 1.31 (s, 911), 3.00 (s, 311), 3.49 (s, 3H), 3.50-3.85 (m, 6H), 3 90 -4. 20 (m, 211), 6.65-7.10 (m, 8H), 1.15-7.45 (m, 5H)

 The following compounds were synthesized in a similar manner.

 0— [6— (1,2,3,4-tetrahydronaphthyl)] = N—Methyl-1-N— [3— “2-Methoxy-1-3- (N-methyl-1-N-phenylamino) propoxy] phenyl ] Thiocarbamate (Compound No. 55)

 Properties: colorless glass

1 R (N a C 1, cm ^-1 ) 2930, 1600, 1490, 1450, 1375, 1220, 1170, 1120, 695

_{NMR (CDC 1 3, δ ppm} ) 1. 70 -. 1. 95 (m, 4H), 2. 65 -2 90 (m, 4H), 3. 03 (s, 3H), 3. 45 - 3. 90 (m, 9H), 3.95-4.15 (m, 2H), 6.65-7.15 (m, 9H), 1.20-7.45 (m, 3H)

 O-(4,4-dimethyl_2-pentynyl) = N-methyl-N-

 [3-—2-Methoxy-13- (N-methyl-1-N-phenylamino) propoxy] phenyl] thiocarbamate (Compound No. Π)

Property: yellow viscous material IR (NaC1, cm- ¹ ) 2970, 2245, 1600, 1510, 1475, 1380, 1230, 750

 MR (CDC 13, δ ρπι) 1.20 (s, 9H), 3.01 (s, 3H), 3.40-3.75 (m, 8H), 3.75-3.88 (m, 1H), 3.95-4.15 (m, 2H), 5.08 (s, 2H), 6.65 -6.95 (m, 6H), 1.18-7.40 (m, 3H)

 0— (p—tert-butylphenyl) = N— [3— [2-methoxy

— 3 — (N-methyl-1-N-phenylamino) propoxy] phenyl] thiocarbamate (Compound No. 7)

 Property: yellow viscous material

Refractive index n = ²⁵ = 1.5779

1 R (N a C 1, cm ^-1 ) 3240, 2960, 1600, 1505, 1370, 1160, 1105, 910, 735

_{NMR (CDC 1 3, δ ppm} ) 1. 38 (s, 9H), 3. 02 (s, 3H), 3. 45- 3. 78 (m, 5H), 3. 78- 3. 94 (m, 1H), 3.94-4.16 (m, 211), 6.68-6.90 (m, 4H), 6.90-7.35 (m, 7H), 7.46 (d, J = 8.7 Hz, 2H), 9.18 (bs, 1H)

 0— (4-Methoxyphenyl) = N—Methyl-N— [3-—2-Methoxy-3_ [N-Methyl-N— (3-Chenyl) amino] propoxy] phenyl] thiocarbamate (Compound No. 82)

 Properties: yellow oil

1 R (NaC1, cm "" ¹ ) 2930, 1600, 1545, 1505, 1455,

1380, 1290, 1235, 1200, 1165, 1115

_{NMR (CDC 1 3, 5 ppm} ) 2. 95 (s, 3 H), 3. 30 -. 3. 61 (m, 5 H), 3. 61-3 85 (m, 7 H), 3. 95 -4. 18 (m,

2 H), 5.92-5.97 (m, 1 H), 6.78-7.05 (m, 7 H), 7.15 — 7.40 (m, 3 H)

 O— (3-ethyl 4-chlorophenyl) = N-methyl-N—

[3 -— [2-Methoxy-1-3-N-methyl-N_ [3_Chenyl) W 9701533

8 2 Amino] propoxy] phenyl] thiocarbamate (Compound No. 78) Properties: yellow oil

IR (N a C 1, cm " ¹ ) 2970, 2930, 1600, 1555, 1490, 1470, 1380, 1220, 1170, 1110

 NMR (CDC 1 o, 5 p pm) 1.23 (t, J = 7.3 Hz, 3 H), 2.74 (q, J = 7.3 Hz, 2 H), 2.96 (s, 3 H) , 3.29 -3.84 (m, 9 H), 3.98-4.20 (m, 2 H), 5.93-5.96 (m, 1 H), 6.75-7.05 (m, 6 H) , 7.15-7.42 (m, 3 H)

 0— [4-(1-Methoxy 1-methylethyl) phenyl] = N 1-Methyl-1 N— [3-—2-Methoxy-1 3— [N-Methyl-1 N— (3-Chenyl) amino] Propoxy] phenyl] thiocarbamate (Compound No. 80)

 Property: yellow viscous material

IR (N a C 1, cm— ¹ ) 2980, 2930, 1600, 1550, 1485, 1380, 1235, 1205, 1175, 1120

 NMR (CDC 13, <5 ppm) 1.52 (s, 6H), 2.9 "s, 3H, 3.06 (s, 3H), 3.30-3.60 (m, 5H), 3.61-3.86 (m, 4H), 3.95—4.14 (m, 2H), 5.93 (dd, J = 3.0, 1.7Hz, 1H). 6.79 (dd, J = 5.1, L3Hz, 1H), 6.82-7.08 (m, 5H), 7.12-7.21 (m, 1H), 7.2H.46 (m, 3 H)

 O— [4— (1-Cyan-1-methylethyl) phenyl] = N—Methyl-N— [3- [2-Methoxy-3— [N—Methyl-1-N— (3-Chenyl) amino] Proboxy] Fanil] thiocarbamate

(Compound No. 81)

Properties: Light brown viscous material 1 R (NaCl, cm- ¹ ) 2930, 2240, 1600, 1550, 1485, 1380, 1235, 1205, 1175, 1115

 NMR (CDC 13, ά ppm) 1.72 (s, 6 H), 2.94 (s, 3 H), 3.37—3.59 (m, 5 H) 3.36-3.85 ( m, 4 H), 3.95 — 4.15 (m, 2 H), 5.93 (s, 1 H), 6.75-7.58 (m, 10H) Example 21

 0— (p—tert-butylphenyl) = N-methyl-N— [3- [2- (carboxymethoxy) 13- (N-methyl-N-phenylamino) propoxy] phenyl] thiocarbamate (compound number ion Synthesis of

 2- (Carboxymethoxy) 1 3— (N-methyl-1-N-phenylamino) 1-1— [3- (N-methylamino) phenoxy] 29 mg of propane in 4 ml of acetonitrile solution p — ( 3 ml of an acetonitrile solution of 344 mg of tert-butylbutyl) = chlorothioformate was added dropwise, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, saturated saline was added, and the mixture was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent; liquid form: methanol = 12: 1) to obtain 23 mg of a pale yellow solid. Obtained.

 Properties: pale yellow solid

 Melting point: <30 ° C

IR (reflective aluminum plate, em- ¹ ) 2960, 1726, 1601, 1508, 1487, 1380, 1211, 1Π6, 1124

 NMR (C D C 13 .S ppm) 1.30 (s, 9H), 2.98 (s, 3H), 3.25.

3.80 (m, 6H), 4.07 (brs, 3H), 4.35 (s, 2H), 6.70-7.18 (m, 7H), 1, 20-7.50 (m, 6H) Example 22

 0-(p-tert-butylphenyl) = N-methyl-N— [6—

 Synthesis of [2-hydroxy-3- (N-methyl-1-N-phenylamino) propoxy] —2-pyridyl] thiocarbamate (Compound No. 29)

 0— (p-tert-butylphenyl) = N-methyl-1-N— [6- [2,3-epoxypropoxy] -12-pyridyl] thiocarbamate 30Ging and 86 mg of lithium perchlorate in acetonitrile 91 mg of N-methylaniline was added to 4 ml, and the mixture was stirred at 60 ° C. for 19 hours. Water and saturated saline were added and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: n-hexane: acetic acid = 3: 1) to obtain 26 mg of a pale yellow viscous substance as a target substance.

1 R (N a C 1, cm " ¹ ) 3400, 2960, 1595, 1505, 1425, 1365, 1265, 1185, 730

NMR (CDC 1 J, δ ppm) 1.33 (s, 9H), 3.03 (s, 3H), 3.51 (d, J = 6.1 Hz, 2H) _f 3.72 (s, 3H), 4.29-4.58 (m, 3H) , 6.65- 6.85 (m, 4H), 6.95-7.10 (i, 3H), 7.18-7.35 (m, 2H), 7.39 (d, J = 6.? Hz, 2H), 1.64 (t, J = 8.2Hz , 1H)

 The following compounds were synthesized in the same manner.

 0— [6— (1,2,3,4-tetrahydronaphthyl)] = N—methyl-1-N— [6-—2-hydroxy-1-3- (N-methyl-1-N-phenylamino) propoxy] 2-pyridyl] thiocarbamate (Compound No. 30)

Property: pale yellow viscous material IR (N a C 1, cm- ¹ ) 3440, 2940, 1600, 1500, 1430, 1365,

1330, 1265, 1180, 1150, 745

_{NMR (CD C 1 3, δ} ppm) 1.70 - 1.95 (m, 4H), 2.66-3.18 (m, 8H), 3.51 (d, 6.1Hz, 2H), 3.72 (s, 3H), 4.24 -4.59 (m , 3H), 6.65-6.90 (m, 6H), 7.06 (d, 7.6Hz, 2H), 7.Π-7.32 (m, 2H), 7.65 (t, J = 7.7Hz, 1H)

0— (p—tert-butylphenyl) = N-methyl-1-N— [6- [2-hydroxy-3 -— [N-methyl-N— (3-phenyl) amino] propoxy] —2-pyridyl] thiocarbamate (Compound No. 40)

 Properties: pale yellow solid

 Melting point: 30 ° C or less

IR (microscopic diamond cell, neat, cm " ¹ ) 3469, 2960,

2900, 2867, 2796, 1598, 1571, 1550, 1506, 1461, 1427, 1363, 1326, 1267,

1262, 1184, 1172, 1151, 1069, 1022, 1014, 989, 860, 835, 804, 744 NMR (CDC 1 o, δ ppm) 1.32 (s, 9H), 2.95 (s, 3H), 3.36 (d, J = 6.22Hz, 2H), 3.73 (s, 3H), 4.24 -4.54 (m, 3H), 6.04- 6.06 (m, 1H), 6.70 -7.45 (m, 8H), 7.65 (t, J = 7.62Hz , 1H)

 0-[6— (1, 2, 3, 4—tetrahydrodronaphthyl)] = N— Methyl-1-N— [3 -— [2-Hydroxy-1-3-—N—Methyl-1-N—

(3-Chenyl) amino] propoxy] phenyl] thiocarbamate (Compound No. 32)

 Properties: pale yellow crystal

 Melting point: 38-40 ° C

1 R (microscopic diamond cell, neat, cm " ¹ ) 3434, 2925,

2850, 1602, 1591, 1484, 1444, 1413, 1413, 1380, 1317, 1288, 1241, 1218, 1168, 1155, 1120, 1091, 1085, 1043, 993, 973, 939, 908, 865, 831, 800,

779, 742 NMR (CDC 13, δ pm) 1.70-1.90 (m, 4H), 2.55 -2.85 (m, 5H), 2.94 (s, 3H), 3.39 (d, J = 6.48Hz, 2H), 3.70 (s, 3H), 3.95-4.10 (m, 2H), 4.20-4.35 (m, 1H), 6.04-6. 07 (m, 1H), 6.65-7.40 (m, 9H)

 0— (p-tert-butylphenyl) = N-methyl-1-N— [3-—2-hydroxy-13— [N-methyl-1-N— (3-phenyl) amino] propoxy] phenyl] thiocarbamate (compound No. 31) Property: pale brown oil

1 R (microscopic diamond cell, neat, cm- ¹ ) 3480, 3116,

2998, 2904, 2804, 1598, 1591, 1550, 1506, 1484, 1413, 1378, 1321, 1282,

1267, 1234, 1209, 1170, 1118, 1106, 1039, 862, 835, 744

 NMR (CDC 1, δ ppm) 1.31 (s, 9H), 2.55 (brs, 1H), 2.93 (s, 3H), 3.38 (d, not 6.5 Hz, 2H), 3.72 (s, 3H), 4.00-4.10 (m, 2H), 4.20- 4.30 (m, 1H), 6.05-6.06 (m, 1H), 6. 80- 6.95 (m, 6H), 1.20-7, 40 (m, 4H)

0-[6— (1,2,3,4-tetrahydronaphthyl)] = N— Methyl-N— [6-[2-Hydroxy-1 3 -— [N—Methyl-N—

(3-Chenyl) amino] Proboxy] — 2-Pyridyl] thiocarbamate (Compound No. 41)

 Properties: pale yellow crystal

 Melting point: 44- 45 ° C

1 R (microscopic diamond cell, neat, cm- ¹ ) 3482, 2927,

2861, 2798, 1600, 1573, 1550, 1477, 1467, 1427, 1413, 1369, 1330, 1268, 1240, 1222, 1197, 1180, 1153, 1132, 1024, 991, 921, 862, 827, 740 NMR (CDC 1 ₃ , ά ρπι) 1.70-1.90 k 4Η), 2.65 -2.90 (m, 4Η), 2.95 (s, 3H), 3.36 (d, J = 5.34 Hz , 2H), 3.72 (s, 3H), 4.20-55 (m, 3H),

6.00-6.08 (m, 1H), 6.70-6.90 (m, 4H), 7.00-7.30 (m, 3H), 7.65 (t, J =

7.98Hz, 1H) 0- (p-tert-butylphenyl) = N-methyl-N— [3- [2-hydroxy_3— (N-methyl-1-N-phenylamino) propoxy] phenylmethyl] thiocarbamate (Compound No. 128)

 Properties: colorless viscous material

1 R (NaC1, cm- ¹ ) 3430, 2960, 1600, 1505, 1450, 1400, 1265, 1210, 1180, 1145, 1110

 NMR (CDC 13, δ ppm) [1.33 (s), 1.35 (s), 9H], 2, 60 (brs, 1H), [3.02 (s), 3.03 (s), 3H], [3.23 (s) , 3.44 (s), 3H], 3.56 (d, J = 6.2 Hz, 2H), 3.97-4.16 (m, 2H), 4.20-4.40 (m, 1H), [4.89 (s), 5.Π (s ), 2H], 6.75-7.12 (m, 8H), 7.20-7.49 (m, 5H)

 0— [6-(1,2,3,4-tetrahydronaphthyl)] = N— [3 -— [2-hydroxy-13- (N-methyl-1-N-phenylamino) propoxy] phenylmethyl] thiocarbamate (compound No. 129) Property: colorless viscous substance

1 R (NaC 1, cm " ¹ ) 3440, 2920, 1600, 1505, 1490, 1400, 1260, 1240, 1220, 1150, 1040

_{NMR (CDC 1 3, (5} ppm) 1.72 - 1.95 (m, 4 H), 2.42 (brs, 1 H) 2.65 -. 2.90 (m, 4 H), 3.02 (s, 3 H), 3.21 -3. ? 0 (m, 5 H), 3.95-4.19 (m, 2 H), 4.23-4.42 (m, 1 H), [4.89 (s), 5.18 (s), 2 H], 6.72— 7.19 (m, 2H) 9 H), 7.20-7.42 (m, 3 H)

 0— (p—t ert—butylphenyl) = N—methyl-1-N— [3- [2-hydroxy-1 3 -— [(3-Chenyl) amino] propoxy] phenyl] thiocarbamate (Compound No. 11)

 Properties: colorless solid

 Melting point: 60-61 ° C

IR (KB r, cm " ¹ ) 3380, 2960, 1600, 1560, 1480, 1380, 1230, 1205, 1175

 NMR (CDC 13, <5 ppm) 1.31 (s, 9H) 2.59 (brs, 1H). 3.19-3.46 (m, 2H). 3.71 (s, 3H) H), 4.02 -4.38 (m, 4H), 6.05 (dd, J = 2.9, 1.5Hz, 1H), 6.67 (dd, J = 5.1, 1.5Hz , 1 H), 6.75—7.08 (m, 5 H), 7.19 (dd, J = 5.1, 2.9 Hz, 1 H), 7 · 23—7.46 (m, 3 H)

 0— (p—tert-butylphenyl) = N—methyl-1-N— [6- [2-hydroxy-3 -— [(3-Chenyl) amino] propoxy] —2-pyridyl] thiocarbamate (Compound No. 12 )

 Properties: light brown solid

 Melting point: 51-5 C

IR (microscopic diamond cell, neat, cm- ¹ ) 3363,

2960, 1598, 1562, 1461, 1425, 1365, 1328, 1261, 1186, 1176

_{NMR (CDC 1 3, 5 ppm} ) 1. 32 (s, 9 H), 3. 02- 3.44 (m, 3 H), 3. 74 (s, 3 H), 4. 1 H. 56 (m, 4 H), 6.02-6.07 (m, 1 H), 6.63-6.11 (m, 2 H), 6.94-7.10 (m, 3 H), J.14-7. 22 (m, 1 H), 7.37 (d, J = 7.9 Hz,

2 H). 7.67 (t, J = 8. lH z, 1 H)

 0-[6— (1,2,3,4-tetrahydrodronaphthyl)] = N—Methyl-1-N— [6-—2-Hydroxy-1-3-[(3-Chenyl) amino] propoxy] —2— Pyridyl] thiocarbamate (Compound No. 13)

 Properties: light brown solid

 Melting point: 63-65 ° C

1 R (microscopic diamond cell, neat, cm " ¹ ) 3346,

3251, 2927, 1599, 1572, 1425, 1367, 1267, 1180, 1151 W

89

_{NMR (CDC 1 3, δ ppm} ) 1. 59 (brs, 2 H). 1. 75-

I. 85 (m, 4 H), 2.70— 2.Π (m, 4 H) 3.25 (d d, J =

13.0, Ϊ.5Hz, lH), 3.37 (dd, J = 13.0.0, 4.OHz, 1H), 3.74 (s, 3H) .4.25-4. 33 (m, l H), 4.43 (dd, J =

II. 5, 6.5 Hz, lH), 4.50 (dd, J = 11.5, 3.5 Hz, 1 H), 6.06 (dd, J = 3.0, 1.5 Hz, 1 H) ) 6.67-6.85 (m, 4 H), 7.04—7 · 10 (m, 2 H), 7.19 (dd, J-4.5, 3.5 Hz, 1 H), 7.68 (t, J = 8.OH z, 1 H)

 0— (p-tert-butylphenyl) = N—methyl-1-N— [3— [2-hydroxy-1-3 -— ((2-methoxycarbonyl-2-enyl) amino] propoxy] phenyl] thiocarbame G (Compound No. 25)

 Properties: colorless viscous material

1 R (N a C 1, cm- ¹ ) 3380, 2960, 1670, 1575, 1490, 1440, 1395, 1380, 1 Π5, 1105

 NMR (CDC 13.5 ppm) 1.31 (s, 9H), 2.67 (brs, 1H), 3.40—3.76 (m, 6H), 3.82 (s, 3H) , 3.98-4.28 (m, 3 H), 6.70 (d, J = 5.5 Hz, 1 H), 6.82-7.13 (m, 5 H), 7.25-7.42 (m, 4H)

 Example Π

 0— (p—tert-butylphenyl) = N—methyl-N—

 Synthesis of [2-propoxy_3- (N-methyl-1-N-phenylamino) propoxy] phenyl] thiocarbamate (Compound No. 91)

0- (p-tert-butylphenyl) = N-methyl-N— [3- (2-hydroxy-1-3 -— (N-methyl-1-N—) in 2 ml of a suspension of 33 mg of 60% sodium hydride in tetrahydrofuran under ice-cooling Phenyl) Aminob Roboxy] Phenyl] Thiocarbamate 247mg of tetrahydrofura The solution was added with 6 ml and stirred at room temperature for 10 minutes. The reaction solution was again ice-cooled, 4 ml of a dimethylformamide solution of 128 mg of propyl bromide was added, and the mixture was further stirred at room temperature for 16 hours. Thereafter, 200 ml of ice water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography (developing solvent; n-hexane: acetic acid = 6: 1) to obtain 107 mg of the desired product as a pale yellow oil.

IR (NaC1, cm- ¹ ) 2960, 1600, 1505, 1480, 1380, 1210, 1175, 1120, 910, 735

 NMR (CDC 13, δ ppm) 0.93 (t, J = 7.4 Hz, 3H), 1.33 (s, 9H), 1.5-1.70 (m, 2H), 3.04 (s, 3H), 3.40- 3.80 (m , 7H), 3.83-4.10 (m, 3H), 6.65-7.10 (m, 8H), 7.20-7.45 (m, 5H)

Example 24

 O-(3-ethyl-1 4-chlorophenyl) = N-methyl-N-

 Synthesis of [3-—2-Methoxy-13- (N-methyl-1-N-phenylamino) propoxy] phenyl] thiocarbamate (Compound No. 57)

To 1 ml of a suspension of 8 mg of 60% oily sodium hydrogenated tetrahydrofuran in 1 ml of tetrahydrofuran was added 0- (3-ethyl-4-chlorophenyl) = N-methyl--[3- [2-hydroxy-1-3-N A solution of 135 mg of —methyl-1-N-phenylamino) propoxy] phenyl] thiocarbamate in 3 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was ice-cooled again, 3 ml of a dimethylformamide solution of 45 mg of methyl iodide was added, and the mixture was stirred at room temperature for 24 hours. After water was added to the reaction solution and extracted with ethyl acetate, the organic layer was washed with saturated saline. After drying over anhydrous magnesium sulfate, the residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 4: 1) to obtain 82 mg of a yellow viscous substance. Property: yellow viscous material IR (N a C 1, cm ^-1 ) 2940, 1600, 1470, 1380, 1220, 1160, 1120

 NMR (CDC 13, δ ppm) 1.23 (t, J = 7.3 Hz, 3H), 274 (q, J = 7.3 Hz, 2H), 3.02 (s, 3H), 3.45 -3, 92 (m, 9H), 3.96-4.16 (m, 2H), 6.65-7.10 (m, 8H), 7.16-7.45 (m, 4H)

 The following compounds were synthesized in the same manner.

 0— (p-tert-butylphenyl) = N-methyl-N— [6- [2-Methoxy-3- (N-methyl-1-N-phenylamino) propoxy] -12-pyridyl] thiocarbamate (Compound No. 72 )

 Properties: brown oil

IR (N a C 1, cm- ¹ ) 2960, 1595, 1505, 1425, 1365, 1265,

1185, 730

 NMR (C D C 13 »δ ppm) 1.33 (s, 9H), 3.03 (s, 3H), 3.41-

3.93 (m, 9H), 4.41 (dq, 1 = 12.1 Hz, 4.4 Hz, 2H), 6.65 -6.85 (m, 4H), 6.95- 7.10 (m , 3H), 1.18-7.35 (m, 2H), 1.39 (d, J = 8.9 Hz, 2H), 1.64 (t, J = l. 5 Hz, 1H)

 0— [6— (1,2,3,4-tetrahydronaphthyl)] = N _methyl-1-N— [6- [2-Methoxy-1-3- (N-methyl-1-N-phenylamino) propoxy] — 2-pyridyl] thiocarbamate (Compound number? 3)

 Property: yellow viscous material

IR (N a C 1, cm " ¹ ) 2930, 1600, 1505, 1435, 1370, 1265, 1180 NMR (CDC 13 .δ ppm) 3.04 (s, 3H), 3.40-3.95 ( m, 9H),

4.41 (dq, 1 = 11.6 Hz, 4.3 Hz, 2H), 6.65-6.37 (m, 6H), 7.06 (dd, J = 7.6 Hz, 4.1 Hz, 2H) , 7.17-7.32 (m, 2H), 7.65 (t, J = 7.7Hz, 1H)

 0-(p-tert-butylphenyl) = N-methyl-N— [3—

[2-Methoxy-1-3- [N-methyl-N- (4-chlorophenyl)] Amino] propoxy] phenyl] thiocarbamate (Compound No. 61) Properties: yellow viscous substance

IR (NaC1, cm- ¹ ) 2960, 1595, 1505, 1440, 1380, 1235, 1210, 1120, 1110, 810

 NMR (CDC 13, δ ppm) 1.31 (s, 9H), 3.00 (s, 3H), 3.40-3.90 (m, 9H), 3.90-4.15 (m, 2H), 6.65 -7.05 (m, 8H), 7.10-7.45 (m, 4H) "

0— (p—tert-butylphenyl) = N—methyl-N— [3—

 [2-Methoxy-1-3- [N-methyl-N- (3-chlorophenyl) amino] propoxy] phenyl] thiocarbamate (Compound No. 60) Properties: Yellow viscous substance

1 R (NaC1, cm " ¹ ) 2960, 1600, 1500, 1380, 1240, 1210, 1175, 1120, 1105, 840

 NMR (CDC 13 .δ ppm) 1.33 (s, 9H), 3.01 (s, 3H), 3.42-3.57 (m, 4H), 3.62-3.88 (m, 5H), 3.94-4 . 14 (m, 2H), 6.58-6.77 (m, 3H), 6.84-7.20 (m, 6H), 1.24-7.48 (m, 3H)

 0— (p-tert-butylphenyl) = N—methyl-N— [3—

 [2-Methoxy-3— [N-methyl-1-N— (2-chlorophenyl) amino] propoxy] phenyl] thiocarbamate (Compound No. 59)

IR (N a C 1, cm " ¹ ) 2960, 1600, 1590, 1480, 1380, 1235, 1210, 1175, 1120, 1055, 1040

 NMR (C D C 13, δ ppm) 1.32 (s, 9H), 2.88 (s, 3H), 3.22-

3.44 (m, 2H), 3.50 (s, 3H), 3.60-3.84 (i, H), 4.03 (dd,] = 10.2Hz, 1H),

4.21 (dd, 10.1Hz, 3.6Hz, 1H), 6.80-7.10 (m, 6H), 7.10-7.45 (m, 6H) 0-(p-tert-butylphenyl) = N-methyl-N— [3 —

[2-Methoxy-1-3- [N-methyl-N- (4-methylphenyl) amino] propoxy] phenyl] thiocarbamate (Compound No. 64) Properties: Colorless viscous substance IR (N a C 1, cm— ¹ ) 2980, 1610, 1530, 1490, 1385, 1240, 1220, 1180, 1130, 1110

 NMR (CDC 13, δ ppm) 1.30 (s, 9H), 2.24 (s, 3H), 2.97 (s, 3H), 3.38-3.91 (m, 9H), 3.94-4.14 (m, 2H), 6.69 ( d, J = 8.5Hz, 2H), 6.75- 7.12 (m, 7H), 7.21-7.43 (m, 3H)

 0— (p—tert-butylphenyl) = N—methyl-N— [3—

 [2-Methoxy-1-3- [N-methyl-N- (3-methylphenyl) amino] propoxy] phenyl] thiocarbamate (Compound No. 63) Properties: Colorless viscous substance

IR (NaC1, cm- ¹ ) 2960, 1600, 1500, 1480, 1380, 1210, 1Π5, 1120, 1110

_{NMR (CDC 1 3, δ ppm} ) i.30 (s, 9H), 2.21 (s, 3H), 3.00 (s, 3H), 3.3-3.57 (m, 4H), 3.57 - 3.90 (m, 5H), 3.92-4.14 (m, 2H), 6.43-6.62 (m, 3H), 6.62-7.20 (m, 6H), 7.20- 7.43 (m, 3H)

 0-(p-tert-butylphenyl) = N-methyl-N- [3—

 [2-Methoxy-3- (N-methyl-N- (2-methylphenyl) amino] propoxy] phenyl] thiocarbamate (Compound No. 62) Properties: pale yellow oil

1 R (NaC1, cm- ¹ ) 2960, 1600, 1495, 1380, 1235, 1210, 1175, 1110, 1050

 NMR (CDC 13.5 ppm) 1.31 (s, 9H), 2.29 (s, 3H), 2.12 (s, 3H), 3.05- 3.33 (m, 2H), 3.49 (s, 3H), 3.58-3.78 (m , 4H), 3.98 (dd, J = 5.5, 10.0Hz, 1H), 4.14 (dd, J = 3.6, 10.0Hz, 1H), 6.78-7.05 (m, 6H), 7.08 -7.44 (m, 6H)

0— (p—tert-butylphenyl) = N-methyl-N— [3 -— [2-methoxy-1-3- [N-methyl-N— (4-methoxyphenyl) amino] propoxy] phenyl] thiocarbamate (Compound No. 67) Property: yellow viscous material

IR (NaC1, cm " ¹ ) 2960, 1600, 1510, 1480, 1380, 1240, 1205, 1175, 1120, 1110, 1040

 NMR (CDC 13, δ ppm) 1.30 (s, 9H), 2.96 (s, 3H), 3.38- 3.93 (m, 12H), 3.94-4.17 (m, 2H), 6.70-7.10 (m, 8H), 7.20 -7.45 (m, 4H)

 0— (p—tert-butylphenyl) = N—methyl-N— [3—

 [2-Methoxy-1-3- [N-methyl-N- (4-tert-butylphenyl) amino] propoxy] phenyl] thiocarbamate (Compound No. 68)

 Properties: yellow oil

IR (N a C 1, cm " ¹ ) 2960, 1600, 1520, 1485, 1380, 1210, 1Π 5, 1120, 1110, 730

 NMR (CD C ", 5 ppm) 1.20- 1.35 (m, 18H), 3.03 (s, 3H), 3.40-3.80 (m, 8H), 3.81-4.18 (m, 3H), 6.75-7.05 (m, 8H ), 7.20-7.45 (m, 4H)

 0—5-Indanyl = N-methyl-N— [3- [2-Methoxy-3- (N-methyl-1-N-phenylamino) propoxy] phenyl] thiocarbamate (Compound No. 56)

 Properties: colorless viscous material

1 R (N a C 1, cm " ¹ ) 2935, 1600, 1505, 1470, 1435, 1390, 1280

 NMR (CDC 1 J .δ ppm) 2.08 (q, J = 7.4Hz, 2H), 2.80-2.94 (m, 4H), 3.00 (s, 3H), 3.44-3.90 (m, 9H), 3.94-4.15 ( m, 2H), 6.62-7.02 8H), 7.10-7.40 (m, 4H)

0— (3-tert-butyl-1-4-chlorophenyl) = N-methyl-1-N- [3-—2-methoxy-1-3- (N-methyl-1-N-phenylamido G) Proboxoxy] phenyl] thiocarbamate (Compound No. 58) Properties: Colorless viscous substance

IR (NaC 1, cm- ¹ ) 2960, 2940, 1600, 1510, 1465, 1445,

1230, 1205, 1040

 NMR (CDC 1, δ ppm) 1.5 (s, 9H), 3.00 (s, 3H), 3.45- 3.90 (m, 9H), 3.94-4.16 (m, 2H), 6.64-7.10 (m, 8H) , 7.16-7.42 (m, 4H)

0— (p—tert-butylphenyl) = N—methyl-N— [3—

 [2-Methoxy-1-3- [N-methyl-1-N- (3-Chenyl) amino] propoxy] phenyl] thiocarbamate (Compound No. 74)

 Properties: pale yellow oily substance

1 R (micro transmission diamond cell, neat, cm " ¹ ) 2962, 2631,

2873, 1596, 1591, 1550, 1508, 1484, 1413, 1378, 1319, 1288, 1236, 1211, 1174, 1118, 1108, 1056, 1016, 863, 835, 779, 748

 NMR (CDC 1 o, δ ppm) 1.30 (s, 9H), 2.94 (s, 3H), 3.30-3.60 (m, 5H), 3.60-3.90 (m, 4H), 3.95-4.10 (m, 2H), 5.91-5.93 (m, 1H), 6.75 -7.05 (m, 6H), 7.14-7.45 (m, 4H)

 O-(p-tert-butylphenyl) = N_methyl-N- [6—

 [2-Methoxy-1-3- [N-methyl-N- (3-Chenyl) amino] propoxy] -12-pyridyl] thiocarbamate (Compound No. 89) Properties: pale yellow oil

IR (microreflective aluminum plate, cm " ¹ ) 2960, 2900, 2865, 2825, 1596, 1571, 1548, 1504, 1461, 1454, 1427, 1367, 1328, 1270, 1218, 1186, 1151, 1130, 1112, 1074 , 1056, 1012, 1074, 1056, 1012, 985, 941, 885, 860, 835, 800, 738

_{NMR (CD C 1 3, (} 5 ppm) 1.32 (s, 9H), 2.96 (s (3H), 3.32- 3.58 (m, 5H), 3.70- 3.86 (m, 4H), 4.39 (dq, 11.52, 4.4 Hz, 2H), 5.90-5.93 (m, 1H), 6.70- 7.44 (m, 8H), 1.63 (t, 7.94Hz, 1H) 0— [6— (1,2,3,4-tetrahydronaphthyl)] = N—Methyl-1-N— [3— [2-Methoxy-1-3-—N—Methyl-1-N— (3-Chenyl) α [Mino] Proboxy] Phenyl] Thiocarbamate

(Compound No. 75)

 Properties: pale yellow oil

1 R (microscopic diamond cell, neat, cm " ¹ ) 2927, 2875,

2831, 1600, 1585, 1584, I 486, 1444, 1415, 1378, 1319, 1288, 1240, 1216, 1168, 1116, 935, 862, 829, 782, 746

 NMR (CDC 13, 5 ppm) 1.65-1.90 k 4H), 2.60-2.85 (m, 4H), 2.93 (s, 3H), 3.30- 3.85 (m, 9H), 3.95-4.10 (m, 2H), 5.90- 5.98 (m, 1H), 6.63-7.40 (m, 9H)

 O- [6— (1,2,3,4—tetrahydrodronaphthyl)] = N—methyl-N— [6— [2-methoxy-1-3-—N-methyl-N— (3-Cenyl) amino ] Proboxy] — 2-pyridyl] thiocarbamate (Compound No. 90)

 Properties: pale yellow oil

IR (microreflective aluminum plate, cm " ¹ ) 3083, 2927, 2856, 1598, 15 T3, 1556, 1496, 1471, 1419, 1365, 1326, 1263, 1238, 1222, 1195, 1178, 1151, 1122, 1074, 1054, 1022, 989, 943, 917, 908, 865, 829, 802, 794, 740

NMR (CDC 13, δ ppm) 1.70-1.90 (m ₍ 4H), 2.68 -2.85 (m, 4H), 2.96 (s, 3H), 3.30- 3.65 (m, 5H), 3.65- 3.90 (i, H ), 4.40 (dd,〗 = 11. ", 4.4Hz, 2H), 5.86-5.95 (m, 1H), 6.70-6.85 (m, 4H), 7.00-7.30 (m, 3H), 7.62 (t, J = 8.3Hz, 1H)

0— (m-tert-butylphenyl) = N—methyl—N— [3- [2-methoxy-3- (N-methyl-N— (3-phenyl) amino] propoxy] phenyl] thiocarbamate (Compound No. Π) Property: pale yellow viscous material

IR (NaCl, cm- ¹ ) 2955, 1600, 1585, 1550, 1480, 1375, 1230, 1195, 1165, 1120

 NMR (CDC 13, 5 ppm) 1.31 (s, 9H), 2.94 (s,

3 H), 3.31-3.87 (m, 9 H), 3.96-4.25 (m, 2 H), 5.91 -5.95 (m, 1 H), 6, 74—7.08 ( m, 6 H), 7.11-7.42 (m,

4 H)

 0— (p-tert-butylphenyl) = N—methyl-1-N— [3-—2-methoxy-1-3- [N-methyl-1-N— (1—pyrrolyl) amino] propoxy] phenyl] thiocarbamate (compound No. 87) Property: colorless viscous material

IR (N a C l, cm ^-1 ) 2960, 1600, 1505, 1480, 1380, 1210, 1175, 1110

 NMR (CDC 13, 5 ppm) 1.31 (s, 9H), 2.90 (s, 3H), 3.12-3.32 (m, 3H), 3.41 (s, 3H), 3 71 (s, 3H), 3.88-4.13 (m, 2H), 6.06-6.14 (m, 2H), 6.80—7.04 (m, 7H), 7.26 — 7.45 (m, 3 H)

 0-(p-tert-butylphenyl) = N-methyl-N_ [3- [2-methoxy-13- (N-methyl-1-N-phenylamino) propoxy] phenylmethyl] thiocarbamate (Compound No. 131) Properties: colorless Viscous material

1 R (NaCl, cm " ¹ ) 2960, 2930, 1600, 1505, 1400, 1265, 1210, 1Π 5, 1140, 1105, 735

 NMR (CDC 1, δ pm) [1.32 (s), 1.34 (s), 9H], [3.03 (s), 3.04 (s), 3H], 3.43 (s, 3H), 3.45-4 18 (m, 8H), [4.88 (s), 5.16 (d), 2H], 6.70-7.15 (m, 7H), 7.18-7.45 (m, 6H)

0— [6— (1,2,3,4—Tetrahidronaphthyl)] = N— Methyl-N— [3 -— [2-Methoxy-3- (N-methyl-N-phenylamino) propoxy] phenylmethyl] thiocarbamate (Compound No. 132)

 Property: yellow viscous material

 I R (N a C 1, cm -1 2930, 1595, 1505, 1490, 1260, 1235, 1220, 1150, 730

 NMR (CDC 13 δ ppm) 1.75-1.90 (m, I), 2.65 -2.90 (m, 4H), [3.03 (s), 3.04 (s),], [3.23 (s), 3.44 (s), :, 3.45- 4.20 (m, 8H), [4.89 (s), 5.18 (d), 2H 6.65-7.40 (m, 12H)

Example 25

 0-(p-tert-butylphenyl) = N-methyl-N- [3—

 Synthesis of [2-Methoxy-3- (phenylamino) propoxy] phenyl] thiocarbamate (Compound No. 46)

 To a suspension of 24 mg of 60% oil-based hydrogenated sodium 24 mg in tetrahydrofuran 2 ml was added ice-cooled 0- (p-tert-butylphenyl) = N-methyl-N— [3- [2-hydroxy-3 -— (phenylamino) 5) A solution of 255 mg of propoxy] phenyl] thiocarbamate in 5 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 50 minutes. The reaction solution was again ice-cooled, 4 ml of a dimethylformamide solution of 78 mg of methyl iodide was added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline. After drying over anhydrous magnesium sulfate, the residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 4: 1) to obtain 82 mg of a pale yellow viscous substance.

 Property: pale yellow viscous material

1 R (N a C 1, cm " ¹ ) 3390, 2960, 1600, 1510, 1490, 1380, 1210, 1180, 1120, 1110

NMR (CDC 13, 5 pi) 1.32 (s, 9H), 3.25- 3.93 (m, 9H), 4.04-4.22 (m, 2H), 6.63-7.15 (m, 8H), 7.15-7.46 (m, 5H) The following compounds were synthesized in the same manner.

 0— (p-tert-butylphenyl) = N-methyl-1-N— [3- [2-methoxy-3-([3-Chenyl] amino] propoxy] phenyl '] thiocarbamate (Compound No. 48)

 Properties: Yellow oil

1 R (NaCl, cm- ¹ ) 3400, 2960, 1600, 1560, 1485, 1380, 1210, 1Π5

_{NMR (CDC 1 3, 5 ppm} ) 1. 31 (s, 9 H), 3.25 (dd, J = 12.8, 6. OH z, 1 H), 3. 35- 3. 55 (m, 4 H), 3.71 (s, 3H), 3.77—3.91 (m, 1H), 3.9H. 20 (m, 3H), 6.02 (dd, J = 3.0, 1.5Hz) , l H), 6.66 (dd, J = 5.1, 1.4 Hz, 1 H), 6.82—7.40 (m, 5 H), 7.17 (dd, J = 5.1, 2.9 Hz, 1 H) 7.24-7.43 (m, 3 H)

 0— (p—tert—butylphenyl) = N—methyl—N— [6-1- [2-methoxy-1-3-((3-Chenyl) amino] propoxy] —2-pyridyl] thiocarbamate (Compound No. 50)

 Properties: reddish brown crystals

 Melting point: 68-70 ° C

1 R (microscopic diamond cell, neat, cm- ¹ ) 3467, 3413, 2958, 1598, 1427, 1365, 1267, 1186

 NMR (C DC 13, ά p p m) 1.34 (s, 9 H), 3.18

3.60 (m, 5H), 3.64-3.95 (m, 4H) 4.08 (brs, 1H).

4.40-4.54 (m, 2 H), 5.98-6.03 (m, 1 H), 6.62-6.11 (m, 2 H), 6.94-7.11 (m, 3 H), 7. 12-7. 24 (m, 1 H),

7.38 (d, J = 8.5Hz, 2H), 763 (t, J = 8.3Hz, 1H) W 1

1 0 0 Example 26

 0— (p-tert-butylphenyl) = N—methyl-1-N— [3-—2-methoxy-3-—N-methyl-N— (2-methoxycarbonyl-1-3-enyl) amino] propoxy] phenyl Synthesis of Thiocarbamate (Compound No. 86)

 0- (p-tert-butylphenyl) = N-methyl-N- [3-[2-hydroxy) was added to 2 ml of a dimethylformamide suspension of 16 mg of 60% oil-based hydrogenated sodium under ice-cooling. 3 ml of a solution of 42 mg of 3-([2-methoxycarbonyl-13-phenyl) amino] propoxy] phenyl] thiocarbamate was added, followed by stirring at room temperature for 50 minutes. The reaction solution was ice-cooled again, 3 ml of a dimethylformamide solution of 41 mg of methyl iodide was added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, and extracted with ethyl acetate. Then, the organic layer was washed with saturated saline. After drying with anhydrous magnesium sulfate, gel gel lamb chromatography

(Developing solvent: benzene: ethyl acetate = 30: 1) to obtain 15 mg of a pale yellow viscous substance.

1 R (NaC1, cm- ¹ ) 2950, 1700, 1600, 1535, 1485, 1460, 1440, 1380, 1240

 NMR (CDC 1 J, 5 ppm) 1.30 (s, 9H), 3.10 (s, 3H), 3.42-3.91 (m, 12H), 3.92-4.14 (m, 2 H), 6.75—7.06 (m, 6 H), 7.20—7.44 (m, 4 H)

 Example 27

 0— (p—tert-butylphenyl) = N—methyl-N— [3 -— [2-acetoxy-13- (N-methyl-1-N-phenylamino) propoxy] phenyl] thiocarbamate (Compound No. 94) Synthesis of

0— (ρ—tert-butylphenyl) = N—methyl-N— [3-—hydroxy-1-3- (N-methyl-1-N-phenylamino) pro To a methylene chloride solution (123 ml) containing 123 mg of [poxy] phenyl] thiocarbamate and 22 mg of pyridine, 1 ml of a methylene chloride solution containing 2 lmg of acetyl chloride was added dropwise, followed by stirring at room temperature for 24 hours. Thereafter, 50 ml of water was added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, remove the residue by gel chromatography (Developing solvent; II-hexane: acetic acid =

6: 1) to give 29 mg of the desired colorless glassy substance.

IR (N a C 1, cm— ¹ ) 2960, 1735, 1595, 1505, 1485, 1380,

1230, 1210, 1175, 730

 NMR (C DC 13, δ ppm) 1.32 (s, 9H), 2.03 (s, 3H), 2.97 (s,

3H), 3.54-3.86 (m, 5H), 4.04 -4.26 (m, 2H), 5.36 -5.52 (m, 1H), 6.65-

7. 10 (m, 8H), 1, 15-7. 45 (m, 5H)

Example 28

 O-(ρ-tert-butylphenyl) = N-methyl-N—

 Synthesis of [2- (3-hydroxycarbonylpropanoyloxy) -13- (N-methyl-1-N-phenylamino) propoxy] phenyl] thiolbamate (Compound No. 104)

To 2 ml of a dimethylformamide suspension containing 19 mg of 60% oily sodium hydrogen hydride, 0- (p-tert-butylphenyl) = N-methyl-N- [3-—2-hydroxy-1-3- (N-methyl-1-N-phenylamino) propoxy] phenyl] thiocarbamate 153 mg of dimethylformamide solution (4 ml) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was cooled again on ice, 3 ml of a dimethylformamide solution containing 38 mg of succinic anhydride was added, and the mixture was stirred at room temperature for 4 hours. After adding water to the reaction solution and extracting with ethyl acetate, the organic layer was washed with saturated saline. After drying over anhydrous magnesium sulfate, the residue was purified by silica gel column chromatography (developing solvent; chloroform: meanol = 12: 1) to obtain 100 mg of the desired product. Properties: light brown viscous substance to solid

 Melting point: 30 ° C

IR (N a C 1, cm— ¹ ) 2960, 1735, 1600, 1505, 1480, 1380, 1210, 1170

 NMR (CDC 13, δ ppm) 1.31 (s, 9H), 2.42- 2.70 (m, 4H), 2.96 (s, 3H), 3.40-3.82 (m, 5H), 4.00-4.20 (m, 2H), 5.38 -5.58 (m, 1H), 6.63-7.15 (m, 8H), 7.18-7.45 (m, 5H)

Example 29

 0— (ρ-tert-butylphenyl) = N—methyl—N— [3—

 Synthesis of [2-Methoxymethoxy-3- (N-methyl-1-N-phenylamino) propoxy] phenyl] thiocarbamate (Compound No. 115)

 0— (p-tert-butylphenyl) = 1S [—methyl-N- [3- [2-hydroxy-13- (N-methyl-N-phenylamino) propoxy] phenyl] thiocarbamate 59mg of ethyldiisopropyl 0.1 ml of methyl methyl ether was added to 3 ml of the min solution under ice-cooling, and the mixture was stirred for 30 minutes. Then, after stirring at room temperature for further 20 hours, saturated sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed again with a saturated sodium bicarbonate solution, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent; n-hexane: acetic acid-5: 1) to obtain 4 lmg of a target substance as a pale yellow oil.

IR (N a C 1, cm " ¹ ) 2960, 1600, 1510, 1490, 1380, 1210, 1175, 1105, 1030

NMR (CDC 13, δ ppm) 1.31 (s, 9H), 3.00 (s, 3H), 3.38 (s, 3H), 3.50-3.80 (m, 5H), 3.98 -4.30 (m, 3H), 4.75 (g , J = 6.5Hz, 2H), 6.65- 7.10 (m, 8H), 7.15-?. 45 (m, 5H) Example 30

 Synthesis of 0— (p-tert-butylphenyl) N-methyl _N_-[2-Methoxy-3- (N-ethyl-1N (3-Cenyl) Rino] propoxy] phenyl] thiocarbamate (Compound No. 92)

 To 2 ml of a suspension of 16 mg of 60% oily hydrogenated sodium dimethylformamide in 0 ml of ice-cooled 0- (p-tert-butylphenyl) = N-methyl-N- [3- [2-methoxy3-] (3-Chenyl) amino] propoxy] phenyl] thiocarbamate 50 mg in dimethylformamide solution (6 ml) was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was cooled again on ice, 3 ml of a dimethylformamide solution of 33 mg of iodide chill was added, and the mixture was stirred at room temperature for 48 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline. After drying over anhydrous magnesium sulfate, the residue was purified by silica gel column chromatography (developing solvent; n-hexane: ethyl acetate = 7: 1) to obtain ll mg of a colorless viscous substance.

IR (N a C l, cm " ¹ ) 2960, 1600, 1560, 1490, 1380, 1230, 1210

_{NMR (CDC 1 3, <5} ppm) 1.13 (t, J = 6.9H z, 3 H), 1.31 (s, 9 H), 3.20 - 3.54 (m, 7 H), 3.62-3.86 (m, 4 H ) 3.96-4.14 (m, 2 H), 5.93 (dd, J = 2.9, 1.8 Hz, lH), 6.77 (dd, J = 5.0, 1.3 Hz, 1 H), 6.81-7.40 (m, 5 H), 7.13-7.43 (m, 4 H)

Example 31

0-(p-tert-butylphenyl) = N-methyl-N- [3-[2-methoxy-1-3- [N- (3-Chenyl) formylamino] propoxy] phenyl] thiocarbamate (Compound No. 93) Synthesis 0— (p—tert-butylphenyl) = N-methyl-N— [3- [2-Methoxy-1-3-((3-Chenyl) amino] propoxy] phenyl] 39 mg of thiocarbamate and 12 mg of formic acid in methylene chloride To 2 ml of the solution, 4 ml of a methylene chloride solution containing 33 mg of 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide was added dropwise under ice cooling. After completion of the dropwise addition, the mixture was stirred at room temperature for 14 hours, water was added to the reaction solution, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (developing solvent; n-hexane: ethyl acetate = 2: 1) to obtain 34 _{mg of} a colorless viscous substance.

IR (NaC1, cm- ¹ ) 2950, 1680, 1600, 1540, 1490, 1380, 1240, 1210, 1175

 NMR (CDC 13, ά ppm) 1.31 (s, 9 H), 3.43 and 3.46 (2 s, 3 H), 3.70 (s, 3 H), 3.81—4.16 (m, 5 H ), 6.77—7.10 (m, 7 H), 7.22—7.50 (m, 4 H), 8.33 and 8.52 (2 s, 1 H)

Example 32

 0- (p-tert-butylphenyl) = N-methyl-N— [3- [2-methoxy-13- (N-methyl-1-N-phenylamino) propoxy] phenyl] thiocarbamate hydrochloride (Compound No. 146) Synthesis

0— (p—tert—butylphenyl) = N—methyl—N— [3- [2-methoxy-13- (N-methyl-1-N-phenylamino) propoxy] phenyl] thiocarbamate 119 mg of ethanol solution in 2 mi Then, 0.05 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off, and the residue was washed with petroleum ether to obtain 76 mg of a colorless powder. Melting point: 61-63 ° C IR (KB r, cm— ¹ ) 3440, 2960, 1600, 1490, 1380, 1210 1Π5, 1120

NMR (CDC 13, 5 ppm) 1.30 (s, 9H), L60 (brs, 1H). 3.15-3.40 (m, 6H), 3.69 (brs, 5H), 3.95-4.40 (m, 3 H), 6.77-7.05 (m, 5 H) _N 7.22-7.75 (m, 8 H)

 The following compounds were synthesized in the same manner.

 0— (p—tert-butylphenyl) = N—methyl—N— [3- [2-methoxy-13- [N-methyl-N— (3-phenyl) amino] propoxy] phenyl] thiocarbamate hydrochloride ( Compound number

147)

 Properties: reddish brown powder

 Melting point: 68-70 ° C

1 R (KB r, cm— ¹ ) 3410, 2960, 1600, 1485, 1380, 1230 1210, 1070

 NMR (CDC 13, 5 ppm) 1.30 (s, 9 H), 2.82 (brs, 1 H), 3.15—3.45 (m, 6 H), 3.45—3.88 (m, 5 H) 3.90-4.40 (m, 3 H), 6.78-7.18 (m, 5 H) ヽ 1.22-7.60 (m, 6 H)

 O-(p-tert-butylphenyl) = N-methyl-1-N--[2-methoxy-1 3-[(3-Chenyl) amino] propoxy] phenyl] thiocarbamate hydrochloride (Compound No. 148)

 Properties: brown solid

 Melting point: 89-91 ° C

NMR (CDC 1 o, ά ppm) 1.29 (s, 9H), 3.40—3.74 (m, 10H) .4.00-4.18 (m, 3H), 6.76-7.02 (m, 5H), 7.23—7.40 ( m, 5H), 7.75 (brs, 1H) 0 6

[Efficacy test]

 The squalene-epoxidase inhibitory activity and the cholesterol biosynthesis inhibitory activity of the compound of the present invention were confirmed by the following methods.

 (1) Preparation of rat squalene epoxidase

The rat's squalene epoxidase can be found in the Journal of Lipid Research * _N 31, 2095

(1990). After the male SD rat was exsanguinated and killed, the liver was perfused with 0.1 M Tris-HCl (pH 7.5, 4 ° C). The liver is removed and 3% by weight Z volume% of 0.1 M Tris-HCl (pH

7. Homogenized at 5.4 ° C.) and centrifuged at 1500 × g for 15 minutes. The supernatant was further centrifuged at 105,000 X g for 30 minutes, and the obtained microsomes were suspended in 0.1 M Tris-HCl (pH 7.5, 4 ° C). Stored at ° C.

 (2) Squalene / epoxidase activity measurement method

Measurements of squalene epoxidase activity, the journal O blanking Lee pitch de research (Journal of Lipid Research) _N 31 volumes, was carried out in accordance with the method described on pages 2095 (1990). Squalene epoxidase fraction (protein content 1.0 mg / ml) prepared in (1), 0.067 M tris-hydrochloric acid (pH 7.5), 0.1% triton X-10 0, 0.3 mM AM 0-16 18, 0.1 lmM FAD, 1.0 mM EDTA, 1.0 mM NADPH, 4Μ3 H-squalene-tween 80 The solution was added to make a total volume of 0.3 ml, and reacted at 37 ° C for 60 minutes. The reaction was stopped by adding 3 ml of a 10% potassium hydroxide / methanol solution Q. The reaction was carried out at 37 ° C for 30 minutes. The extracted substance was extracted with petroleum ether and concentrated to dryness. The obtained residue was dissolved in a small amount of ethyl ether, spotted on a thin layer gel, and developed with ethyl benzene monoacetate (99.5: 0.5). Generate A portion of the 3H-squalene-2,3-epoxide thus obtained was cut out and measured with a liquid scintillation counter. Thus, the inhibition rate of the compound of the present invention with respect to squalene epoxidase was determined.

 (3) Test results

From the above test, the concentration of the compound of the present invention that inhibits squalene-epoxidase by 50% (IC5 ₍₎ value) was determined. The results are shown in Table 19. Table 20 shows the inhibition rate of squalene-epoxidase activity at 1 M.

As is clear from the above results, the compound of the present invention potently inhibits squalene epoxidase and inhibits cholesterol biosynthesis, and thus enhances the cholesterol biosynthesis mechanism and / or enhances cholesterol biosynthesis. It is effective for treating and preventing various diseases caused by overdose, such as hypercholesterolemia, hyperlipidemia, and arteriosclerosis.

[Table 9] Compound number IC50 (nM)

46 98.7

50 64.7

54 95.0

55 33.6

56 66.4

57 42.5

58 37.7

63 145.0

64 63.0

67 136.0

71 336.0

72 15.9

73 51.4

74 2.90

75 6.93

89 6.30

90 39.6

91 51.4

94 75.0

1 15 100.0

131 121.0

132 206.0 0 9

[Table 20]

 Inhibition with compound number 1 / M ^

 10 41.7

14 98.5

26 45.3

32 46.0

46 63.4

50 91.7

54 96.1

55 98.6

56 94.9

57 97.0

58 100.0

60 33.9

61 38.9

62 43.0

63 81.9

64 97.9

67 100.0

71 80.7

72 90.7

73 92.9

74 100.0

75 100.0

89 100.0

90 100.0

91 95.7

94 97.0

1 15 85.0

131 97.9

132 82.5 Industrial applicability

 As described above, the compound of the present invention is a novel substance having a thiocarbamate skeleton completely different from conventionally known amide-based or arylamine-based compounds, and furthermore, squalene-epoxy derived from mammals. It has high inhibitory activity against dase. Further, the compound of the present invention can be suitably produced by the production method of the present invention.

Claims

1 Range of request

1. General formula [I]

[Where m represents 0 or 1, and A represents the formula [ΙΙΊ

(Wherein R ⁵ and R ° are the same or different and represent a hydrogen atom, a halogen atom, a lower alkoxy group and a lower alkyl group or a lower alkoxy group which may be substituted by Z or a cyano group, or ⁵ and 6 may be taken together to form a ring by a carbon chain represented by one (CH ₂ ) ₄ —, — (CH ₂ ) —.) Or a phenyl group represented by the formula: One CH. -C = CR '[m]

(Wherein R ⁷ represents a lower alkoxy group and a lower alkyl group which may be substituted with Z or a cyano group.). R ¹ and R ^d represent a hydrogen atom, a formyl group or a lower alkyl group, and Z represents a nitrogen atom or a CH group. R ² is a hydrogen atom, a lower alkyl group, a lower acryl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a carboxyl-substituted lower alkyl group, a carboxy-substituted lower alkyl group, a lower alkylsulfonyl group, or an arylsulfonyl group Represents a group. R ⁴ is a phenyl group having an arbitrary substituent, or contains one or more atoms of oxygen, nitrogen, or sulfur atoms or two or more atoms in combination with each other. Represents a heterocyclic ring. An arbitrary substituent may be substituted on the heterocyclic ring. ] The thiocarbamic acid derivative and its salt characterized by being represented by these.

2. General formula [V]

(Wherein m, Z, R ¹ , R ² , R ³ , and R have the same meanings as described above ₍ R ⁸ represents a hydrogen atom or a formyl group)). Derivatives.

3. —General formula [VI]

(Wherein m, Z, A, and R ¹ have the same meanings as described above).

4. General formula [IV]

 AO C S X [IV]

 (Wherein A has the same meaning as described above, and X represents halogen.) A halogenated thioformate represented by the general formula [Va]

[Va]

Wherein m, Z, R ¹ , R ² , R ³ , and R ⁴ have the same meaning as described above, and a general formula [I]

(Wherein m, Z, A, R ¹ , R ² , R ³ , and R represent the same meanings as described above).

[I] 1 5

5. General formula

R ^a

 HN /

R

(Wherein R ³ and R ⁴ have the same meanings as described above.) And a general formula [VI]

(Wherein m, Z, A, and R ¹ have the same meanings as described above). A compound represented by the following general formula [ _Ia ]:

[la]

(In the formula, m, Z, A, R ¹ , R ³ , and R represent the same meaning as described above.)

 [VI]

 [l a]

 6. —General formula [l a]

(Wherein m, Z, A, R ¹ , R ³ and R ⁴ represent the same meaning as described above), and a general formula [IX] RY [IX]

(Wherein R ² Y represents an alkylating agent or an acylating agent having the aforementioned R ² ).

[I]

(Wherein m, Z, A, R ¹ , R ² , R ³ , and R represent the same meaning as described above).

7. A squalene epoxidase inhibitor comprising the compound of claim 1 or a salt thereof.

8. The compound according to claim 1, 2 or 3, wherein the compound of the general formula [I], [V] or [VI] is an optically active substance-racemic form or a mixture or an isolated form of optical isomers such as diastereomers. A compound as described.

9. The compound according to claim 1, 2 or 3, wherein the compound of the general formula [I], [V] or [VI] contains an acid adduct thereof.

10. The compound according to claim 1, 2 or 3, wherein the compound of the general formula [I], [V] or [VI] is a hydrate-solvate or a compound containing a crystalline polymorph thereof.

1 1. The squalene epoxidase inhibitor according to claim 7, wherein the compound of the general formula [I] is an optically active compound, a racemic compound, or a mixture or an isolated product of optical isomers such as diastereomers.

12. The squalene epoxidase inhibitor according to claim 7, wherein the compound of general formula [I] contains an acid adduct thereof.

1 3. The squalene-epoxidase inhibitor according to claim 7, wherein the compound of the general formula [I] is a hydrate, solvate or crystal polymorph thereof.