WO1998008838A1 - Substituted amine derivatives - Google Patents

Abstract

This invention relates to substituted amine derivatives of formula (I) wherein each symbol is as defined in the description, and its pharmaceutically acceptable salt, to processes for preparation thereof, to pharmaceutical composition comprising the same, and to a use of the same for treating hypercholesterolaemic, hypertrigliceridaemic, hyperlipaemic and hyperlipoproteinaemic states in human being or animal.

Description

D E S C R I P-T I O N

SUBSTITUTED AMINE DERIVATIVES

TECHNICAL FIELD

This invention relates to novel substituted amine derivatives and pharmaceutically acceptable salts thereof.

More particularly, it relates to novel substituted amine derivatives and pharmaceutically acceptable salts thereof, which have inhibitory activity against the enzyme squalene epoxidase, to a process for preparation thereof, to a pharmaceutical composition containing the same, to a use of the same as a medicament, and to a method for treating or preventing fungal infections and hypercholesterolaemic, hypertriglyceridaemic, hyperlipaemic and hyperlipoproteinaemic states and their associated conditions in human being or animal.

Accordingly, one object of the present invention is to provide substituted amine derivatives and pharmaceutically acceptable salts thereof, which inhibit the activity of squalene epoxidase and therefore are capable of lowering blood serum cholesterol levels, blood serum triglyceride levels and blood lipid levels.

Another object of the present invention is to provide a process for preparation of substituted amine derivatives and pharmaceutically acceptable salts thereof.

A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said substituted amine derivatives and pharmaceutically acceptable salts thereof. Still further object of the .present invention is to provide a use of said substituted amine derivatives and pharmaceutically acceptable salts thereof as a medicament and a method for treating or preventing fungal infections and hypercholesterolaemic, hypertriglyceridaemic, hyperlipaemic and hyperlipoproteinaemic states and their associated conditions in human being or animal.

BACKGROUND ART High levels of blood cholesterol and blood lipids are conditions which are involved in the onset of arteriosclerosis. It is well known that inhibitors of 3- hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase are effective in lowering the level of blood serum cholesterol, especially low density lipoprotein cholesterol (LDL-C) . It has now been established that lowering LDL-C levels affords protection from coronary heart disease.

However, HMG-CoA reductase inhibitors block mevalonate production, which occurs at an early stage in the cholesterol synthetic pathway. Therefore, these compounds are thought to inhibit the synthesis of other biologically important substances derived from mevalonate such as ubiqumones, the dolichols, isopentenyl tRNA, and isoprenylated proteins.

Squalene epoxidase is located in the middle of the cholesterol synthetic pathway, past the branch points for ubiqumone and dolichol biosynthesis, and an agent capable of inhibiting the squalene epoxidase s expected to be a safer hypocholesterolaemic agent with less side effects.

INDUSTRIAL APPLICABILITY

The substituted amine derivatives of this invention inhibit squalene epoxidase and so inhibit cholesterol biosynthesis. They lower concentrations of cholesterol m blood. Thus they are useful for treating or preventing fungal infections and hypercholesterolaemic, hypertriglyceπdaemic, hyperlipaemic and hyperlipoproteinaemic states (e.g. familial hyperlipoprotememia such as familial hypercholesterolemia, familial type III hyperlipoprotememia and familial combined hyperlipidemia and arteriosclerosis such as atherosclerosis) and their associated conditions (e.g. obesity, diabetes, angina, myocardial infarction, cerebral vascular occlusion, arterial aneurism, peripheral vascular disease, recurrent pancreatitis and xanthomas) .

DISCLOSURE OF INVENTION

The object substituted amine derivatives of this invention are novel and can be represented by the following general formula (I) :

Ri

wherein

R is a heterocyclic group or aryl which may have 1 to 5 substituent (s) ; R is lower alkyl or lower alkenyl, R^J is lower alkyl or lower alkenyl, or

R^ and R , together with the carbon atom to which they are attached, represent cyclo (lower) alkane; R is hydrogen or lower alkyl; R⁵ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or cyclo (lower) alkyl; R is hydrogen or halogen;

R is hydrogen or halogen; R⁸ is lower alkyl or lower alkoxy (lower) alkyl;

_R9 -A²- is -CH₂~/ -0-, -0-CH₂- or - - (in which R⁹ is hydrogen or lower alkyl) ; and

-A³- and -A⁴- may be the same or different and each is a bond, -CH -, (in which R¹¹ and R¹² may be

the same or different and each is lower alkyl or lower alkenyl, or R^± and R , together with the carbon atom to which they are attached, represent cyclo (lower) alkane) , -CO-, -0- or

_

(in which R ,1¹0 is hydrogen or lower alkyl) , or -A³-A⁴- ιs -CH=CH- or -C≡C- .

It is to be noted that the object compound (I) may include one or more stereoisomers due to asymmetric carbon atom(s) and double bond(s), and all of such isomers and a mixture thereof are included within the scope of the present invention.

It is further to be noted isomerization or rearrangement of the compound (I) may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention.

It is also to be noted that the solvatmg form of the compound (I) (e.g. hydrate, etc.) and any form of the crystal of the compound (I) are included within the scope of the present invention.

The object compound (I) or a salt thereof can be prepared by the processes as illustrated in the following reaction schemes. Process 1

(ID (III) or a salt thereof or a salt thereof

(I) or a salt thereof

Process 2

or a salt thereof or a salt thereof

da) or a salt thereof wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, -A¹-, -A²-, -A³- and

-A - are each as defined above, X¹ is a leaving group, and Y³ is acid residue.

The starting compound (II) are novel and can be prepared by the following processes.

Process A

(IV) (V) or a salt thereof or a salt thereof

(Via) or a salt thereof

Process B

R¹ 13

(VI) or a salt thereof Elimination reaction of the hydroxy protective group

R¹-A¹-A²-C-A³-A⁴ J :H-OH

(Ha) or a salt thereof

Process C.

SO_?-R 14

(Ha (VII) or a salt thereof

R⁴

R¹-A¹ -A⁴ ≥α H-O-SO -R 14

(lib) or a salt thereof

wherein R¹, R², R³, R⁴, -A¹-, -A²-, -A³- and -A⁴- are each as defined above, R¹³ is a hydroxy protective group, R¹⁴ is lower alkyl or lower alkylphenyl, Y is acid residue, and Y^ is halogen.

The reactions of aforesaid processes can be carried out by the methods described later in this specification or the similar manners tnereto.

Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base for example, an organic amine salt (e.g., triethylamine salt, pyridme salt, picoline salt, ethanolamme salt, tnethanoiamine salt, dicyclohexylam e salt, N,N' -dibenzylethylenediamme salt, etc.); an inorganic acid addition salt (e.g., hydrochloπde, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, oxalate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.); a salt with a basic or acidic am o acid (e.g., argmine, aspartic acid, glutamic acid, etc.).

In the above and subsequent descriptions of the present specification, suitable examples and illustration of the various definitions which the present invention include within the scope thereof are explained in detail as follows.

The term "lower" is intended to mean 1 to 6 carbon atom(s), unless otherwise indicated.

Suitable "lower alkyl" and "lower alkyl" moiety in the terms "lower alkylphenyl" and "lower alkoxy ( lower ) alkyl" is straight or branched one having 1 to 6 carbon atom(s) and may include methyl, ethyl, 2-methyle.thyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like, in which the preferred one may be C-^-C^ alkyl. Suitable "lower alkoxy" moiety in the term "lower alkoxy (lower) alkyl" may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert- pentyloxy, hexyloxy and the like, in which tne preferred one may be ^ -C^ alkoxy.

Suitable "lower alkenyl" may include vinyl, l-(or 2-)- propenyl, 1- (or 2- or 3-)butenyl, 1- (or 2- or 3- or 4-)- pentenyl, 1- (or 2- or 3- or 4- or 5-)hexenyl, methylvmyl, ethylv yl, 1- (or 2- or 3-) methyl-1- (or 2-)propenyl, 1- (or 2- or 3-) ethyl-1- (or 2-)propenyl, 1- (or 2- or 3- or 4-)metnyl-l- (or 2- or 3-)butenyl, and the like, in which the preferred one may be C₂-C^ alkenyl.

Suitable "lower alkynyl" may include etnynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1 or 2 or 3- butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5- hexynyl, and the like, in which the preferred one may be C₂-C₄ alkynyl.

Suitable "cyclo (lower) alkyl" may include one having 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, and the like. Suitable "cyclo (lower) alkane" may include one having 3 to 6 carbon atoms, for example, cyclopropane, cyclobutane, cyclopentane, and the like.

Suitable "heterocyclic group" may be one containing at least one hetero atom selected from nitrogen, sulfur and oxygen atom, and may include saturated or unsaturateα, monocyclic or polycyclic heterocyclic group such as (1) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, lmidazolyl, pyrazolyl, pyridyl, pyrimidmyl, pyrazmyl, pyridazmyl, triazolyl [e.g. 4H-1,2, 4-trιazolyl, 1H-1 , 2, 3-tπazolyl, 2H-1 , 2 , 3-trιazolyl , etc.], tetrazolyl le.g. IH-tetrazolyl, 2H-tetrazolyl, etc.], etc. ;

(2) saturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s)

[e.g. pyrrolid yl, lmidazolid yl, pipeπdino, piperaz yl, etc.];

(3) unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atom(s), for example, indolyl, lsoindolyl, indolizinyl, benzimidazolyl, qu olyl, isoquinolyl, dazolyl, benzotriazolyl, tetrazolopyπdazmyl [e.g. tetrazolo [1, 5-b]pyrιdazmyl, etc.], etc.;

(4) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.;

(5) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, etc.;

(6) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g. 1, 2, 4-oxadιazolyl, 1, 3, -oxadιazolyl, 1, 2, 5-oxadιazolyl, etc.], etc.;

(7) saturateα 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) [e.g. morpholmyl, etc.j;

(8) unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) [e.g. benzoxazolyl , benzoxadiazolyl, etc.] ; (9) unsaturated 3 to 7-membered, preferably 5 or 6-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and _ to 3 nitrogen atom(s), for example, thiazolyl, thiadiazolyi [e.g., 1, 2, 4-thιadιazolyl, 1, 3, -thιadιazolyl, 1,2,5- thiadiazolyl, etc.], etc.; (10) saturated 3 to 7-membered, preferably 5 or 6-membered neteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) [e.g., thiazolidmyl, etc.];

(11) unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) [e.g., benzothiazolyl, benzothiadiazolyl, etc.];

(12) unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) or 1 to 2 oxygen atom(s) [e.g., benzothiophen, benzofuran, etc.]; and the like.

Suitable "aryl" may include phenyl, naphthyl, ana the like, which the preferred one is Cg-C__Q aryl and the most preferred one is phenyl.

Suitable "halogen" may include fluorine, chlorine, bromine, iodine and the like.

Suitable "leaving group" may include hydroxy, halogen as exemplified above, sulfonyloxy (e.g. methylsulfonyloxy, phenylsulfonyloxy, tolylsulfonyloxy, etc.), and the like.

Suitable "hydroxy protective group" may include lower alkyl as exemplified above, silyl which may have 1 to 3 substituent (s) , and the like. Suitaole "substituent" m the terms "aryl which may have

1 to 5 substituent (s) " and "silyl which may have 1 to 3 substituent (s) " may include lower alkyl as exemplified above, halogen as exemplified above, aryl as exemplified above, and the like. Suitable "acid residue" may include halogen as exemplified above, lower alkanoyloxy (e.g. acetyloxy, etc.), sulfonyloxy (e.g. methylsulfonyloxy, phenylsulfonyloxy, tolylsulfonyloxy, etc.), and the like.

Preferred embodiments of the object compound (I) are as follows :

R¹ is a heterocyclic group (more preferably unsaturated 3 to 7-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s), most preferably thienyl) or aryl (more preferably Cg-C₁₀ aryl, most preferably phenyl) which may have 1 to 5 (more preferably 1 or 5) substituent (s) (more preferably halogen (s), most preferably fluorine (s) or chlorine ( s) ) ; R² is lower alkyl (more preferably C-^-C^ alkyl, most preferably methyl or ethyl) or lower alkenyl (more preferably ^2'^ alkenyl, most preferably propenyl) , R³ is lower alkyl (more preferably C_^-C^ alkyl, most preferably methyl or ethyl) or lower alkenyl (more preferably C₂-C₄ alkenyl, most preferably propenyl), or R² and R³, together with the carbon atom to which they are attached, represent cyclo (lower) alkane (more preferably cyclo (C_β-Cg) alkane) ; R⁴ is hydrogen or lower alkyl (more preferably C^-C^ alkyl) ; R⁵ is hydrogen, lower alkyl (more preferably C-^-C^ alkyl, most preferably methyl, ethyl or propyl) , lower alkenyl

(more preferably C₂-C^ alkenyl), lower alkynyl (more preferably C -C₄ alkynyl) or cyclo (lower) alkyl (more preferably cyclo (C₃-C₆) alkyl) ; R° is hydrogen or halogen; R⁷ is hydrogen or halogen;

R⁸ is lower alkyl (more preferably C-^-C^ alkyl, most preferably tert-butyl) or lower alkoxy (lower) alkyl (more preferably C-^.C^ alkoxy (C^-C^) alkyl, most preferably 2- methoxy-2-methylethyl) ; -A¹- is -CH₂- or -CO-;

R⁹ -A²- is -CH₂-, -0-, -0-CH₂- or _N- (in which R⁹ is hydrogen or lower alkyl (more preferably C-^-C^ alkyl, most preferably methyl) ) ; and -A³- and -A⁴- may be the same or different and each is a bond, -CH_?-, -C- (in which R¹¹ and R¹² may be

/ \ R¹² the same or different and each is lower alkyl (more preferably C -^ -C^ alkyl, most preferably methyl) or lower alkenyl (more preferably C ~C₄ alkenyl), or R¹¹ and R¹², together with the carbon atom to which they are attached, represent cyclo (lower) alkane (more preferably cyclo (C₃-C₆) alkane) ) , -CO-, -0- or

(in which R ,1ⁱ0^U is hydrogen or lower alkyl (more preferably C^-C^ alkyl, most preferably methyl)), or -A³-A⁴- is -CH=CH or -C=C-.

More preferred compounds of the object compound (I) are the compounds of the following formulae (I-A), (I-B), (I-C), (I-D), (I-E) , (I-F), (I-J) and (I-K) :

R^

wherein

R¹ is a heterocyclic group (more preferably unsaturated 3 to 7-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s), most preferably thienyl) or aryl (more preferably Cg-C_]__Q aryl, most preferably phenyl) which may have 1 to 5 (more preferably 1 or 5) substituent (s) (more preferably halogen (s), most preferably fluorine (s) or chlorine (s) ) ;

R is C_]_-C alkyl (more preferably methyl or ethyl, most preferably methyl) or ^2^~^A ^a kenyl (more preferably propenyl) ,

R is C-^-C^_j alkyl (more preferably methyl or ethyl, most preferably methyl) or C₂-C^ alkenyl (more preferably propenyl) , or

R² and R³, together with the carbon atom to which they are attached, represent cyclo (C₃-Cg) lkane; R⁴ is hydrogen or C^-C^ alkyl; R⁵ is hydrogen, C-^ -C^ alkyl (more preferably methyl, ethyl or propyl, most preferably ethyl), C₂-C₄ alkenyl, C₂~C₄ alkynyl or cyclo (C₃-Cg) alkyl; R° is hydrogen or halogen; R is hydrogen or halogen; R⁸ is C-^-C^ alkyl (more preferably tert-butyl) or C2~C_d alkoxy (C -C₄) alkyl (more preferably 2-methoxy-2- methylethyl) ; and R¹¹ is C -C^ alkyl (more preferably methyl or ethyl, most preferably methyl) or C -C alkenyl (more preferably propenyl) , is _ -C_Δ_ alkyl (more preferably methyl or ethyl, most preferably methyl) or C^-C^ alkenyl (more preferably propenyl) , or

R 11 and

, together with the carbon atom to which they are attached, represent cyclo (C ~Cg) alkane .

Most preferred compounds of the object compound (I) are the compounds of the following formulae (I-G) and (I-H):

P

wherein

R is unsaturated 3 to 7-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) (more preferably thienyl, most preferably 3-thιenyl) or Cg-C₁₀ aryl (more preferably phenyl) which may have 1 to 5 (more preferably 1 or 5) substituent (s) (more preferably halogen(s), most preferably fluorine (s) or chlorine (s) ; R- is C_t -Cq alkyl (more preferably methyl or ethyl, most preferably methyl) or C₂-C₄ alkenyl (more preferably propenyl) , R^J is ^ -Cq alkyl (more preferably methyl or ethyl, most preferaoly methyl) or C2-C alkenyl (more preferaoly propenyl) , or R² and R , together with the carbon atom to which they are attached, represent cyclo (C₃-Cg) alkane; and

R is tert-butyl or 2-methoxy-2-methylethyl .

The processes for preparing the object and starting compounds of the present invention are explained m detail in the following.

Process 1

The compound (I) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with the compound (III) or a salt thereof.

This reaction is usually carried out the presence of an inorganic or an organic base.

Suitable inorganic base may include an alkali metal (e.g., sodium, potassium, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkali metal hydrogen carbonate (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), alkali earth metal carbonate (e.g., calcium carbonate, etc.), or the l i ke .

Suitable organic base may include tri (lower) alkylamine (e.g., triethylamine, N, N-diisopropylethylamine, etc.), alkyllithiu (e.g., methyllithium, butyllithium, etc.), lithium diisopropylamide, lithium hexamethyldisilazide, alkali metal hydride (e.g., sodium hydride, potassium hydride, etc.) or the like.

The reaction is usually carried out in a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, N, N-dimethylformamide or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.

The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

Process 2

The compound (la) or a salt thereof can be prepared by reacting the compound (VIII) or a salt thereof with the compound (IX) or a salt thereof.

The reaction can be carried out in a similar manner to that of the Process A described later, and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process A.

Process A

The compound (Via) or a salt thereof can be prepared by reacting the compound (IV) or a salt thereof with the compound (V) or a salt thereof.

This reaction is usually carried out in a solvent such as acetonitrile, benzene, N, N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene chloride, chloroform, diethyl ether, pyridine or any other solvent which does not adversely affect the reaction. The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

The reaction is usually carried out in the presence of a base. Suitable base may include the inorganic base such as alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxide (e.g., magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g., magnesium carbonate, calcium carbonate, etc.), alkali metal hydride (e.g., sodium hydride, potassium hydride, etc.) and the like, and the organic base such as tn (lower) alkylamino (e.g., trimethylam e, triethylamine, diisopropylethylamme, etc.), di (lower) alkylanilme (e.g., dimethylanil e, etc.), pyridine, 4- (dimethylam o) p πdme and the like.

The compound (IV) or a salt thereof can be prepared by the methods disclosed in the Preparations described later or similar manners thereto.

Process B

The compound (Ila) or a salt thereof can be prepared by subjecting the compound (VI) or a salt thereof to elimination reaction of the hydroxy protective group. The reagent to be used this reaction may include halotnalkylsilane (e.g., lodotrimethylsilane, etc.), alkali metal thioalkoxide (e.g., sodium thioethoxide, etc.), alkali metal sulfide (e.g., sodium sulfide, etc.), alkali metal diphenylphosphide (e.g., lithium diphenylphosphide, etc.), aluminum halide (e.g., aluminum chloride, aluminum bromide, etc.), boron tπhalide (e.g., boron trichloride, boron tribromide, etc.), pyridine hydrochlonde, alkylmagnesium nalide (e.g., ethylmagnesium iodide, etc.), lithium halide (e.g., lithium chloride, etc.), tetraalkylammonium halide (e.g., tetrabutylammonium fluoride, etc.), a combination of ethionine and sulfonic acid (e.-g., ethanesulfonic acid, etc.), and the like.

The reaction is usually carried out a conventional solvent such as water, alcohol (e.g., methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, αioxane, dichloromethane, ethylene dichloride, cnloroform, N,N- dimethylformamide, N, -dimethylacetamide, or any other organic solvent which does not adversely affect the reaction. The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.

Process

The compound (lib) or a salt thereof can be prepared by reacting the compound (Ila) or a salt thereof with the compound (VII) .

This reaction is usually carried out in the presence of a base such as tn (lower) alkylamine (e.g., trimethylamme, triethylamine, diisopropylethylamme, etc.), di (lower) alkylanilme (e.g., dimethylanilme, etc.) and the like.

This reaction is usually carπeα out a solvent such as benzene, N, N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene chloride, chloroform, dietnyl ether or any other solvent which does not adversely affect the reaction. The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

The object compound (I) and a pharmaceutically acceptable salt thereof of this invention inhibit squalene epoxidase and so inhibit cholesterol biosynthesis.

Therefore, they can lower blood serum cholesterol levels and blood lipid levels and are useful for the treatment or prevention of hypercholesterolemia, hyperlipemia, hyperlipoprotememia and atherosclerosis human being or animal. In order to illustrate the. usefulness of the object compound (I) and a pharmaceutically acceptable salt thereof, the pharmacological test data of the representative compound of this invention is shown in the following.

Test 1 Inhibition of squalene epoxidase

(1) Preparation of squalene epoxidase

Human hepato a (Hep G2) cells grown in 225-cm² flasks were incubated for 18 hours in medium containing 10^" lipoprotein-deflcient serum (LPDS) . After incubation, the cells were washed and harvested by trypsin treatment. After centrifugation (1000 x g, 5 mm at 4°C) , the pellet was frozen and kept at -80°C until use. After thawing and rupture of the cells by sonication (for 5 sec at 0°C) in 0.1 M Tris-HCl, pH 7.5, 1 mM EDTA, the cell homogenate was mixed with one fourth volume of 21 Trιton^R X-100 (final concentration of detergent, 0.4o). Tne mixture stood at 0°C for 20-60 mm and aliquots of the mixture were assayed for squalene epoxidase activity.

(2) Determination of squalene epoxidase activity

Squalene epoxidase activity was determined according to the method of Tai and Bloch (J. Biol. Chem. 247, 3767, 1972) with some modifications. Aliquot of the mixture described above were incubated for 90 mm at 37°C a final volume of 0.3 ml containing 0.1 M Tris-HCl, pH 7.5, 1 mM EDTA, 1 mM NADPK, 0.1 mM FAD, 0.4 mM AM01618, 0.1

X-100, and 8 μM [ H]squalene (0.1 μCi) dispersed in 0.075 Tween 80 with tert compound dissolved in dimethyl sulfoxide (DMSO) . The reaction was stopped by the addition of 0.3 ml of 10 methanolic KOH. After heating for 60 mm at 75°C, nonsaponiflab e materials were extracted from tne mixture with 2 ml of petroleum ether. The extracts were evaporated under a nitrogen stream. The residue, taken up in a small volume of diethyl ether, was spotted on a silica gel TLC plate which was then developed in benzene-ethyl acetate (99.5:0.5). The radioactivity of the band corresponding to authentic 2, 3-oxιdosqualene was counted by a liquid scintillation counter. The test compound activity (IC5_Q) was calculated as the concentration of the compound giving 50 _t inhibition of 2, 3-oxιdosσualene synthesis relative to the control assay.

Results :

Test 2 Inhibition of cholesterol synthesis in Hep G2 cells

Cholesterol synthesis in Hep G2 cells was determined accordmg to the method of Brown, et al. (J. Biol. Chem. 253, 1121, 1978) with some modifications. Hep G2 cells were seeded at 3 x 10° cells/10-cιrr dish. On day 6, the medium was replaced with fresh medium containing 10 human LPDS . On the next day, the cells were preincubated for 1 hour with test compound dissolved DMSO (final 0.2 ) and then 1 uCi/ml of [¹⁴C] acetate was added. After 2 hours of incubation, the cells were washed with phosphate-buffered saline (pH 7.4) and then dissolved in aqueous 15. KOH. The lipids m the cell lysate were saponified with 15 KOH in 50 ethanol for 1 hour at 75°C. The nonsaponiflable lipids were extracted with petroleum ether. Sterols were isolated from these extracts as digitomde, redissolved m methanol and counted by a liquid scintillation counter. The inhibition of cholesterol synthesis was determined by comparing the percentage of [ C] cholesterol formed drug- treated cells with that in control cells. Respective inhibitory concentrations 50° were calculated.

Results

The pharmaceutical composition of this invention can be used the form of a pnarmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the object compound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation) , nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation or intravesical administration. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carrier for taolets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions, and any other form suitable for use. And, if necessary, in addition, auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The obiect compound (I) or a pharmaceutical acceptable salt thereof is/are included in the pharmaceutical composition an amount sufficient to produce the desired effect upon the process or condition of diseases.

For applying the composition to human being or animal, it is preferable to apply it by intravenous, intramuscular, pulmonary, or oral administration, or insuf lation. While the dosage of therapeutically effective amount of the object compound (I) varies from and also depends upon the age and condition of each individual patient to be treated, the case of intravenous administration, a daily dose of 0.01 - 20 g of the object compound (I) per kg weight of human being or animal, in the case of intramuscular administration, a daily dose of 0.1 - 20 mg of the object compound (I) per kg weight of human being or animal, in case of oral administration, a daily dose of 0.5 - 50 mg of the object compound (I) per kg weight of human being or animal is generally given for treating or preventing the aforesaid diseases.

Tne following Preparations and Examples are given for the purpose of illustrating this invention in more detail.

Preparation 1

A mixture of 3-hydroxybenzaldehyde (5.00 g) , ethyl 2-bromoacetate (13.7 g) , potassium iodide (0.68 g) , potassium carbonate (8.48 g) and acetone (50 ml) was refluxed for 4 hours. The reaction mixture was allowed to cool and the insoluble material was filtered off through Celite. The filtrate was concentrated under reduced pressure and tne residual oil was dissolved in ethyl acetate (50 ml) . The solution was washed with brine (50 ml), dried over magnesium sulfate and then evaporated to give an oil which was chromatographed on silica gel (140 g) . Elution with dichloromethane provided ethyl 2- ( 3-formvlphenoxy) acetate as

IR (Neat) : 2983, 1755, 1701, 1593 crn^-1

NMR (CDC1₃, 200MHz, δ) : 1.31 (3H, t, J=7.1Hz), 4.28

(2H, q, J=7.IHz), 4.69 (2H, s), 7.20-7.54 (4H, m) , 9.97 (1H, s)

Preparation 2 A solution of ethyl 2- (3-formylphenoxy) acetate (8.45 g) in ethanol (24 ml) was added dropwise to an ice-cooled mixture of sodium borohydride (1.8^ g) and ethanol (120 ml) below 10°C. The solution was stirred at 4°C for 30 minutes and then concentrated vacuo. The residue was extracted with ethyl acetate and water. The organic layer was washed with brine, dried, filtrated and then evaporated to give ethyl 2- [3- (hydroxymethyl) phenoxy] acetate as an oil (7.04 g) . IR (Neat) : 3400, 1755, 1591 cm^-1 NMR (CDC1₃, 200MHz, δ) : 1.30 (3H, t, J=7.1Hz), 2.10

(1H, t, J=4.6Hz), 4.27 (2H, q, J=^'7.lHz), 4.6-1 (2H, s), 4.65 (2H, d, J=4.6Hz), 6.80-6.99 (3H, m) , 7.27 (1H, t, J=8.5Hz)

Preparation 3

To a solution of ethyl 2- [3- (hydroxymethyl ) phenoxy] - acetate (2.00 g) and lmidazole (1.29 g) in N-dimethylformamide (10 ml) was added tert-butyldi ethylsilyl chloride (1.58 g) at 0°C. After being stirred at 0°C for 1.5 hours, the reaction mixture was dilated with water (20 ml) and extracted with hexane - ethyl acetate (1:1, 20 ml) . The extract was washed successively with water and brme, dried, and concentrated to dryness to give ethyl 2-F3-(tert- butyldimethylsilyloxymethyl) phenoxy] cetate as a colorless

IR (Neat) : 2954, 2931, 1762, 1594 cm^-1

NMR (CDC1₃, 200MHz, δ) : 0.10 (6H, s), 0.95 (9H, s),

1.30 (3H, t, J=7.1Hz), 4.28 (2H, q, J=7.1Hz), 4.63 (2K, s), 4.72 (2H, s), 6.79 (1H, near d, J=8.1Fz), 6.91-6.95 (2H, m) , 7.25 (1H, t, J=8.1Hz)

Preparation 4

To a solution of ethyl 2-[3-(tert- Dutyldimethylsilyloxymethyl) pnenoxy] acetate (1.00 g) m diethvl ether (10 ml) was added methvlmagnesium bromide (3 M solution in diethvl ether, 3.1 ml) at 0°C. A.fter being stirred for an hour, the reaction mixture was quenched by the addition of saturated ammonium chloride solution (10 ml) and extracted with ethyl acetate (10 ml) . The extract was washed successively with water and brine, dried, and concentrated to dryness to give 1- [3- (tert-butyldimethylsilyloxymethyl ) - phenoxy] methyl-1-methylethanol as a colorless oil (0.94 g) . IR (Neat) : 3400, 2950, 2850, 1605, 1590 cm^"1 NMR (CDC1₃, 200MHz, δ) : 0.10 (6H, s), 0.95 (9H, s), 1.34 (6H, s), 2.27 (1H, s), 3.79 (2H, s), 4.72 (2H, s), 6.78 (1H, d, J=8.0Hz), 6.91 (1H, d, J=8.0Hz), 6.93 (1H, s), 7.24 (1H, t, J=8.0Hz)

Preparation 5 1- [3- (tert-Butyldimethylsilyloxymethyl) phenoxy] ethyl-1- ethylpropanol was prepared from ethyl 2-[3-(tert- butyldimethylsilyloxymethyl ) phenoxy] acetate and ethylmagnesium bromide according to a similar manner to that of Preparation 4. IR (Neat) : 3467, 2958, 2858, 1593 cm^"1

NMR (CDCI3, 200MHz, δ) : 0.10 (6H, s), 0.93 (6H, t,

J=7.5Hz), 0.95 (9H, s), 1.66 (4H, q, J=7.5Hz), 2.07 (1H, s), 3.82 (2H, s), 4.72 (2H, s), 6.77-6.82 (1H, m) , 6.89-6.93 (2H, m) , 7.23 (1H, t, J=8.1Hz)

Preparation 6

1- [3- 'tert-Butyldimethylsilyloxymethyl) phenoxy] ethyl- 1- (2-propenyl) -3-buten-l-ol was prepared from ethyl 2-[3-(tert- butyldimethylsilyloxymethyl ) phenoxy] acetate and allylmagnesium bromide accordmg to a similar manner to that of Preparation 4.

IR (Neat) : 3566, 3076, 2931, 2858, 1597 cm^"1

NMR (CDC1₃, 200MHz, δ) : 0.10 (6H, s), 0.95 (9H, s),

2.27 (1H, s), 2.39-2.44 (4H, m) , 3.82 (2H, s), ^ .72 (2H, s), 5.09-5.18 (4H, m) , 5.80-6.00 (2K, ) , 6 . 77- 6 . 92 ( 3H, m) , 7 . 23 ( 1H, t , J=8 . 1Hz )

Preparation 7

To an ice-cooled solution of l-[3-(tert- butyldimethylsilyloxymethyl) phenoxy]methyl-l-methylethanol (320 mg) in N, N-dimethylforma ide (3 ml) was added sodium hydride (60°, dispersion in mineral oil, 62 mg) , and the mixture was stirred at 4°C for 20 minutes. To the reaction mixture was added a solution of 3- (bromomethyl) thiophene (219 mg) in N, N-dimethylformamide (1 ml). After being stirred at room temperature for 6 hours, the reaction mixture was poureα into ice-water and extracted with ethyl acetate. The extract was washed with br e, dried and concentrated to give an oil which was chromatographed on a column of silica gel witn hexane - ethyl acetate (20:1, V/V). 1- (tert-Butyldimethyl- silyloxymethyl ) -3- [2-methyl-2- ( 3-thιenylmethoxy) propyloxy] - benzene was obtained as a colorless oil (197 mg) . IR (Neat) : 2950, 2860, 1605, 1590 cm^"1 NMR (CDC1₃, 200MHz, δ) : 0.10 (6H, s), 0.95 (9H, s), 1.39 (6H, s), 3.90 (2H, s), 4.59 (2H, s), 4.71 (2H, s), 6.83 (1H, d, J=8.0Hz), 6.90 (1H, d, J=8.0Hz), 6.92 (1H, s), 7.05 (1H, dd, J=4.9 ana 1.2Hz), ^".19 (1H, s), 7.23-7.28 (2K, m)

Preparation 8

1- (tert-Butyldimethylsilyloxy ethyl) -3- [2-ethyl-2- (3- thienylmethoxy) butyloxy] benzene was prepared from l-[3-(tert- butyldimethylsil loxymethyl) henoxy] methyι-1-ethylpropanol and 3- (bromomethyl) thiophene accordmg to a similar manner to that of Preparation 7.

IR (Neat) : 2954, 2858, 1595 cm^"1

NMR (CDC1₃, 200MHz, δ) : 0.10 (6H, s), 0.92 (6h, t,

J=7.5Hz), 0.95 (9H, s), 1.76 (4H, q, J=7.5Hz), 3.91

(2H, s) , 4.50 (2H, s), 4.72 (2H, s), 6.79-6.82 (1H, m) , 6.89-6.92 (2H, ) , 7.05-7.10 (1H, m) , 7.19-7.33 (3H, m)

Preparation 9

1- (tert-Butyldimethylsilyloxymethyl) -3- [2- (2-propenyl) - 2- (3-thιenylmethoxy) -4-pentenyloxy] benzene was prepared from 1- [3- (tert-butyldimethylsilyloxymethyl) phenoxy] methyl-1- (2- propenyl) -3-buten-l-ol and 3- (bromomethyl) thiophene according to a similar manner to that of Preparation 7. IR (Neat) : 3076, 2929, 1595 cm^"1 NMR (CDC1₃, 200MHz, δ) : 0.10 (6H, s), 0.95 (9h, s) ,

2.54 (4H, d, J=7.3Hz), 3.93 (2H, s), 4.64 (2H, s), 4.72 (2H, s), 5.08-5.16 (4H, m) , 5.79-6.00 (2H, m) , 6.78-6.92 (3H, ) , 7.06 (1H, dd, J= .9 and 1.3Hz), 7.19-7.35 (3H, m)

Preparation 10

To a solution of 1- [3- (tert-butyldimethylsilyloxy- methyl) phenoxy]methyl-l-methylethanol (343 mg) and 4- (dimethylammo) pyridine (270 mg) m pyπdme (4 mi ι was added 3-thιophenecarbonyl chloride (194 mg) . The mixture was stirred at room temperature for 4 days and then poured into 1 M solution of hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed successively with saturated aqueous sodium nydrogen carbonate solution and brme, dried and concentrated m vacuo. The residue was chromatograpned on a column of silica gel with hexane - ethyl acetate (10:1, V/V) to give 1- (tert-butyldimethylsilyloxy- methyl) -3- [2-methy1-2- ( 3-thienylcarponyloxy) propyloxvl benzene as an oil (436 mg) . IR (Neat) : 2950, 2860, 1710, 1605, 1590 cm^"1

NMR (CDC1₃, 200MHz, δ) : 0.10 (6H, s), 0.94 (9K, s),

1.69 (6H, s), 4.19 (2H, s) , 4.71 (2H, s), 6.82 (1H, d, J=8.2Hz), 6.89-6.93 (2H, ) , 7.23 (1H, t, J=S.2Hz), 7.25 (1H, dd, J=5.1 and 3.1Hz), 7.44 (Ik, dd, J=5.1 and 1.2Hz), 7.98 (IK, αα, J=3.1 and 1 . 2Hz )

Preparation 11

To an ice-cooled solution of l-(tert- butyldimethylsilyloxy ethyl) -3- [2-methyl-?- (3- thienylmethoxyjpropyloxy] benzene (189 mg⁾ m tetrahydrofuran (2 ml) was added tetrabutylammonium fluoride (1.0 M solution m tetrahydrofuran, 0.70 ml). Tne mixture was stirred at 4°C for 30 minutes and then diluted with ethyl acetate. The solution was washed with water, dried and concentrated in vacuo. The residue was chromatographed on a column of silica gel with hexane - ethyl acetate (2:1, V/V) to give 3- [2- methyl-2- ( 3-thιenylmethoxy) propyloxy] benzyl alcohol as a colorless oil (129 mg) . IR (Neat) : 3400, 2980, 1605, 1585 cm^-1

NMR (CDC1₃, 200MHz, δ) : 1.40 (6H, s), 1.67 (1H, t,

J=6.0Hz), 3.91 (2H, s) , 4.58 (2H, s), 4.67 (2H, d, J-δ.OHz), 6.86 (1H, d, J=8.0Hz), 6.94 (1H, d, J=8.0Hz), 6.96 (IK, s), 7.05 (1H, dd, J=4.9 and 1.2Hz), 7.19 (1H, br s), 7.27 (1H, t, J=8.0Hz),

7.27 (IK, dd, J=4.9 and 3.0Hz)

Preparation 12

3- [2-Ethyl-2- ( 3-thιenylmethoxy) butyloxy] benzyl alconoi was prepared from 1- (tert-butyldimethylsilyloxymethyl ) -3- [2- ethyl-2- (3-thιenylmethoxy) butyloxy] benzene and tetrabutylammonium fluoride accordmg to a similar manner to that of Preparation 11.

IR (Neat) : 3390, 2970, 2877, 1591 cm^~- NMR (CDCI3, 200MHz, δ) : 0.92 (6H, t, J=7.5Hz), 1.60

(IK, br s), 1.76 (4H, q, J=7.5Hz), 3.92 (2H, s), 4.50 (2H, s), 4.67 (2H, s), 6.83-6.96 (3H, m) , 7.06 (1H, dd, J=4.9 and 1.3Hz), 7.19-7.31 (3H, m)

Preparation 13 3- [2- (2-Propenyl) -2- (3-thιenylmethoxy) -4- pentenyloxy] benzyl alcohol was prepared from l-(tert- butyldimethylsilyloxymethyl) -3- [2- (2-propenyl) -2- (3- thienylmethoxy) -4-pentenyloxy]benzene according to a similar manner to that of Preparation 11.

IR (Neat) : 3410, 3074, 2927, 1593 cm^-1

NMR (CDC1₃, 200MHz, δ) : 1.66 (1H, s), 2.54 (4H, d,

J=7.6Hz), 3.94 (2H, s), 4.63 (2H, s), 4.67 (2H, s), 5.09 (2H, s), 5.15 (2H, α, J=4.5Hz), 5.79-6.00 (2H, m) , 6.82-6.96 (3H, m) , 7.06 (1H, dd, J= .9 and

1.3Hz), 7.19-7.31 (3H, m)

The following compound (Preparation 14) was obtained accordmg to a similar manner to that of Preparation 11.

Preparation 14

3- [2-Methy1-2- (3-thιenylcarbonyloxy) propylox ] benzyl alcohol

IR (Neat) : 3400, 3120, 2990, 2940, 1710, 1585, 1520 cm^-1

NMR (CDCI3, 200MHz, δ) : 1.69 (1H, t, J=5.8Hz), 1.69

(6H, s), 4.22 (2H, s), 4.66 (2H, d, J=5.8Hz), 6.S7 (IK, d, J=8.0Hz), 6.94 (1H, d, J=8.0Hz), 6.96 (IK, s), 7.26 (1H, dd, J=5.0 and 3.1Hz), 7.26 (IK, t, J=8.0Hz), 7.45 (1H, dd, J=5.0 and 1.2Hz), 7.99 (IK, dd, J=3.1 and 1.2Hz)

Example 1

To an ice-cooled solution of 3- [2-methyl-2- ( 3- thienylmethoxy) propyloxy] benzyl alcohol (120 πg) in a mixture of tetrahydrofuran (2 ml) and triethylamine (114 μl) was addeα ethanesulfonyl chloride (38 μl) . The mixture was stirred at 4°C for 40 minutes and then poured into ice-water. The mixture was extracted with ethyl acetate, and the extract was washed with brme, dried and concentrated in vacuo to give 1- (methylsulfonyloxymethyl ) -3- [2-methyl-2- (3- thienylmethoxy) propyloxy] benzene . The product was dissolved in N, -dimethylformamide (2 ml) and the solution was added tc an ice-cooled mixture of (E) -N-ethyl-N- (6, 6-dimethyl-2- hepten-4-ynyl) amine (102 mg) and potassium carbonate (170 mg) in N, N-dimethylformamide (1 ml). The final mixture was stirred at room temperature for 7 hours and then poured into ice-water. The mixture was extracted with ethyl acetate and the extract was washed with brine, dried and concentrated. The residue was chromatographed on a column of silica gel with toluene - ethyl acetate (10:1, V/V) to give (E)-N-ethyl- N- (6, 6-dimethyl-2-hepten-4-ynyl) -3- [2-methyl-2- (3- thienylmethoxy) propyloxy] benzylam e as an oil (130 mg) . IR (Neat) : 2980, 2800, 1600, 1585 cm^"1 NMR (CDC1₃, 200MHz, δ) : 1.03 (3H, t, J=7.1Hz), 1.24

(9H, s), 1.40 (6H, S), 2.50 (2H, σ, J=7.1Hz), 3.09

(2H, dd, J=6.4 and 1.4Hz), 3.53 (2K, s), 3.89 (2H, s), 4.59 (2H, s), 5.64 (1H, d, J=15.9Hz), 6.08 (1H dt, J=15.9 and 6.4Hz), 6.78 (1H, d, J=8.0Hz), 6.90 (IK, d, J=8.0Hz), 6.92 (1H, s), 7.05 (1H, dd, J=5.C and 1.3Hz), 7.20 (1H, t, J=8.0Hz), 7.20 (1H, br s), 7.26 (1H, dd, J=5.1 and 3.0Hz) MS (APCI) m/z : 440 (M+H)

The following compound (Example 2) was obtained accordmg to a similar manner to that of Example 1.

Example 2

(E) -N-Ethyl-N- (6, 6-dimethyl-2-hepten-4-ynyl ) -3- [2- methyl-2- ( 3-thιenylcarbonyloxy) propyloxy] benzylamine IR (Neat) : 2980, 1710, 1585, 1520 cm^"1 NMR {CDCI3, 200MHz, δ) : 1.03 (3H, t, J=7.1Hz), 1.23

(9K, s), 1-70 (6H, s), 2.50 (2K, σ, J-7.1Kz), 3.09 (2K, dd, J=6.4 and 1.4Hz), 3.52 (2H, s), 4.19 (2H, s), 5.64 (1H, d, J=15.9Hz), 6.08 (1H, dt, J=15.9 and 6.4Hz), 6.80 (1H, d, J=8.0Hz), 6.91 (IF, d, J=8.0Hz), 6.93 (1H, s), 7.20 (1H, t, J=8.0Hz), 7.26 (1H, dd, J=5.0 and 3.0Hz), 7.45 (1H, dd, J=5.0 and 1.2Hz), 7.99 (1H, dd, J=3.0 and 1.2Hz) MS (APCI) m/z : 454 (M+H)

Example 3

(1) To an ice-cooled solution of 3- [2-ethyl-2- ( 3- thienylmethoxy) butyloxy] benzyl alcohol (309 mg) m a mixture of tetrahydrofuran (3 ml) and triethylamine (0.27 ml) was added methanesulfonyl chloride (0.09 ml). The mixture was stirred at 0°C for 20 minutes and then quenched by the addition of water (3 ml) . The mixture was extracted with ethyl acetate, and the extract was washed successively witr water and br e, dried and concentrated m vacuo to give 1- (methylsulfonyloxymethyl) -3- [2-ethyl-2- (3-thιenylmethoxy) - butyloxy] enzene (383 mg) as an oil which was used for next reaction without further purification.

(2) A mixture of 1- (methylsulfonyloxymethyl) -3- [2-ethyl-2- (3-thιenylmethoxy) butyloxy]benzene (383 mg) , (E) -N-ethyl-N- ( 6, 6-dιmethyl-2-hepten-4-ynyl) amme (175 mg) and potassium carbonate (173 mg) N, N-dimethylformamide (3.8 ml) was stirred at room temperature for 4 hours, and then poured into water. The mixture was extracted with ethyl acetate, and the extract was washed successively with water and brme, dried and concentrated. The residue was chromatographed on a column of silica gel with hexane - ethyl acetate (20:1, V/V) to give (E) -N-ethyl-N- (6, 6-dιmethyl-2-hepten-4-ynyl ) -3- [2- ethyl-2- ( 3-thιenylmethoxy) butyloxy] benzylamme as an on (274 mg) .

IR (Neat) : 2970, 1597 cm^-1

NMR (CDC1₃, 200MHz, δ) : 0.93 (6H, t, J=7.5Hz), 1.04 (3H, t, J=7.1Hz), 1.24 (9H, s), 1.77 (4H, q, J=7.5Hz), 2.51 (2H, q, J=7.1Hz), 3.07 (2K, dd, J=6.4 and 1.5Hz), 3.52- (2H, s), 3.90 (2H, s;, 4.50 (2H, s), 5.64 (1H, d, J=15.9Hz), 6.09 (1H, dd, J=15.9 and 6.4Hz), 6.78-6.92 (3H, m) , 7.07 (1H, αd, J=4.9 and 1.3Hz), 7.16-7.29 (3H, m) MS (APCI) m/z : 468 (M+H)

Example 4

(1) 1- (Methylsulfonyloxymethyl) -?- [2- (2-prcpenyl) -2- (3- thienylmethoxy) -4-pentenyloxy] benzene was prepared accordmg to a similar manner to that of Example 3-(l) .

(2) (E) -N-Ethyl-N- (6, 6-dιmethyl-2-hepten-4-ynyl ) -3- [2- (2- propenyl) -2- ( 3-thienylmethoxy) -4 -pentenyloxy] benzylamme was prepared accordmg to a similar manner to that of Example 3- (2) .

IR (Neat) : 3074, 2970, 1597 cm^"1

NMR (CDC1₃, 200MHz, δ) : 1.04 (3H, t, J=7.1Hz), 1.24 (9H, s), 2.51 (2H, q, J=7.1Hz), 2.55 (4H, d, J=7.3Hz), 3.09 (2H, dd, J=6.4 and 1.4Hz), 3.53 (2H, s), 3.93 (2H, s), 4.64 (2H, s), 5.09-5.17 (4H, m) ,

5.64 (1H, d, J=15.9Hz), 5.80-5.93 (2H, m) , 6.08 (IK, dd, J=15.9 and 6.4Hz), 6.77-6.93 (3H, IP) , 7.06 (1H, dd, J=4.9 and 1.3Hz), 7.16-7.29 ;3H, m) MS (APCI) m/z : 492 (M+H)

Example 5

Condensation of 1- (methylsulfonyloxymethyl ) -3- [2-methyl- 2- (3-thιenylmethoxy) propyloxy] benzene (330 mg) and (E)-N- ( 6, 6-dιmethyl-2-hepten-4-ynyl ) -N-methylamme (148 mg) was carried out accordmg to a similar manner to that of Example 3- (2) to give (E) -N-methyl-N- ( 6, 6-dιmethyl-2-hepten-4-ynyl ) - 3- [2-methyl-2- (3-thιenylmethoxy) propyloxy] enzylamme as an

IR (Neat) : 2970, 1591 cm^"1 NMR (CDCI3, 200MHz, δ) : 1.24 (9H, s), 1.40 (6H, s), 2.19 (3H, s), 3.04 (2H,- dd, J=6.5 and 1.3Hz), 3.45 (2H, s), 3.90 (2H, s), 4.59 (2H, s), 5.65 (IH, d, J=15.8Hz), 6.10 (IH, dt, J=15.8 and 6.5Hz), 6.79- 6.91 (3H, m) , 7.06 (IH, dd, J=4.9 and 1.2Hz), 7.17- 7.29 (3H, m)

MS (APCI) m/z : 426 (M+H)

Example 6

Condensation of 1- (methylsulfonyloxymethyl ) -3- [2-methyl- 2- ( 3-thienylmethoxy) proρyloxy]benzene (378 mg) and (E)-N- (6, 6-dimethyl-2-hepten-4-ynyl) -N-propylamine (201 mg) was carried out according to a similar manner to that of Example 3- (2) to give (E) -N-propyl-N- ( 6, 6-dιmethyl-2-hepten-4-ynyl ) - 3- [2-methyl-2- ( 3-thienylmethoxy) propyloxy] benzylamine as an oil (288 mg) .

IR (Neat) : 2968, 1591 cm^"1

NMR (CDC1₃, 200MHz, δ) : 0.87 (3H, t, J=7.3Hz), 1.24

(9H, s), 1.40 (6H, s), 1.43-1.54 (2H, m) , 2.34-2.42 (2H, m) , 3.08 (2H, dd, J=6.3 and 1.4Hz), 3.52 (2H, s), 3.89 (2H, s), 4.59 (2H, s), 5.64 (IH, d,

J=15.8Hz), 6.10 (IH, dt, J=15.8 and 6.3Hz), 6.77- 6.92 (3H, m) , 7.06 (IH, dd, J=4.9 and 1.3Hz), 7.16- 7.29 (3K, m) MS (APCI) m/z : 454 (M+H)

Example 7

To a solution of (E) -N-ethyl-N- ( 6, 6-dimethyl-2-hepten-4- ynyl) -3- [2-methyl-2- (3-thienylmethoxy) propyloxy] benzylamine (22.6 g) in acetone was added oxalic acid (4.63 g) . The mixture was stirred at room temperature for 30 minutes to give a clear solution which was concentrated in vacuc . The syrupy residue was crystallized with a mixture of ethyl acetate (230 ml) and hexane (235 ml) to give (E) -N-ethyl-M- (6, 6-dιmethyl-2-hepten-4-ynyl) -3- [2-methyl-2- (3- thienylmethoxy) propyloxy] benzylamine oxalate (20.5 g) . p : 77- 83 °C ( dec . )

IR (K3r) : 3429, 2972, 2605, 2495, 1720, 1605 cm^"1 NMR (CDC1₃, 200MHz, δ) : 1.25 (9H, s), 1.34 (3H, t, J=7.3Hz), 1.39 (6H, s), 3.09 (2K, q, J=7.3Hz), 3.68 (2H, d, J=7.0Hz), 3.88 (2K, s), 4.15 (2H, s),

4.56 (2H, s), 5.83 (IH, d, J=15.7Hz), 6.04 (IH, dt, J=I5.7 and 7.0Hz), 6.95-7.35 (7H, ) MS (APCI) m/z : 440 Anal, for C₂₉H₃₉ OgS Calcd. : C 65.75, K 7.44, N 2.64^r

Found : C 66.01 , H 7.61, N 2.63^",

Example 8

To a solution of (E) -N-ethyl-N- ( 6, 6-dιmethyl-2-hepten-4- ynyl) -3- [2-methyl-2- (3-thienylmethoxy) propyloxy] benzylamme (58.9 g) m ethyl acetate (600 ml) was added hydrogen chloride (4.0 M solution in ethyl acetate, 50.3 ml), and the solution was concentrated to dryness. The residue was crystallized with a mixture of ethyl acetate (590 ml) and nexane (590 ml) to give (E) -N-ethyl-N- ( 6, 6-dιmethyl-2-hepten- -ynyl) -3- [2-methyl-2- ( 3-thienylmethoxy) propyloxy] benzylam e hydrochloride (44.2 g) . mp : 116-119°C (dec.)

IR (KBr) : 2972, 2929, 2603, 2564, 2495, 1589 cm^"1 NMR (CDCI3, 200MHz, δ) : 1.25 (9H, s), 1.40 (6H, s),

1.44 (3H, t, J=7.6Hz), 3.00-3.10 (2K, ) , 3.50-3.70 (2K, m) , 4.01 (2H, s), 4.07 (2K, d, J=5.6Hz), 4.58 (2H, s), 5.82 (IH, d, J=15.7Hz), 6.24 (IH, dt, J=15.7 and 7.6Hz), 6.98-7.43 (7H, m) , 12.70 (IH, br s)

Anal, for C₂₇H₃₈C1N0₂S

Calcd. : C 68.10, H 8.06, N 2.94 Found : C 68.45, H 8.30, N 2.88

Preparation 15 To an ice-cooled solution o-f 3- [2-methyl-2- (3- thienylmethoxy) propyloxy] benzyl alcohol (500 mg) in a mixture of tetrahydrofuran (5 ml) and triethylamine (0.48 ml) was added methanesulfonyl chloride (0.16 ml) . The mixture was stirred at 4°C for 20 minutes and then poured into ice-water. The mixture was extracted with ethyl acetate, and the extract was washed with brme, dried and concentrated m vacuo to give 1- (methylsulfonyloxymethyl) -3- [2-methyl-2- (3- thienylmethoxy) propyloxy] benzene (630 mg) as an oil which was used for next reaction without further purification.

Preparation 16

To an ice-cooled solution of l-f3-(tert- butyldimethylsilyloxymethyl) phenoxy] methy -1-methylethanol (2.0 g) in N, N-dimethylformamide (30 ml) was added sodium hydride (600 dispersion in mineral oil, 0.39 g) , and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 2- (bromomethyl) thiophene (1.37 g) . After being stirred at room temperature for 5 hours, tne reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brme, dried and concentrated to give an oil which was chromatographed on a column of silica gel with hexane - ethyl acetate (25:1, V/V). 1- (tert-Butyldimethylsilyloxymethyl) -3- [2-methyl-2- (2- thienylmethoxy) propyloxy] benzene was obtained as a colorless oil (962 mg) .

IR (Neat) : 2952, 2931, 2858, 1591 cm^"1

NMR (CDC1₃, 200MHz, δ) : 0.10 (6H, s), 0.95 (9K, s^,

1.40 (6H, s), 3.90 (2H, s), 4.71 (2H, s), ^.^ ( 2 , s), 6.81 (IH, m) , 6.86-7.02 (4H, m) , 7.19-7.31 (2H, m)

Preparation 17

Ethyl 2- (3-formylphenoxy) -2-methylpropιonate (3.20 g) was prepared from 3-hydroxybenzaldehyde (25.0 g) and etny 2- bromoisobutyrate (31.6 ml) according to a similar manner to that of Preparation 1.

IR (Neat) : 2989, 2940, 1734, 1699, 1583 cm^"1 NMR (CDC1₃, 200MHz, δ) : 1.26 (3H, t, J=7.1Hz), 1.63 (6H, s), 4.25 (2H, q, J=7.1Hz), 7.03-7.53 (4H, ) ,

9.94 (IH, m)

Preparation 18

Ethyl 2- [3- (hydroxymethyl ) phenoxy] -2-methylpropιonate (2.81 g) was prepared from ethyl 2- ( 3-formylphenoxy) -2- methylpropionate (3.20 g) according to a similar manner to that of Preparation 2.

IR (Neat) : 3516, 2985, 1734, 1585 cm^"1 NMR (CDCI3, 200MHz, δ) : 1.25 (3H, t, J=7.1Hz), 1.60 (6H, S), 1.93 (IH, s), 4.24 (2H, q, J=7.1Hz), 4.63

(2H, s), 6.73 (IH, m) , 6.88 (IK, br s), 6.96-7.26 (2H, m)

Preparation 19 Ethyl 2- [3- ( tert-butyldimethylsilyloxymethyl ) phenoxy] -2- methylpropionate (2.85 g) was prepared from ethyl 2- [3- (hydroxymethyl ) phenoxy] -2-methylpropιonate (2.80 g) accordmg to a similar manner to that of Preparation 3. IR (Neat) : 2954, 2933, 1736, 1601 crA NMR (CDCI3, 200MHz, δ) : 0.09 (6H, S; , 0.94 (9H, s),

1.24 (3H, t, J=7.1Hz), 1.59 (6H, s), 4.23 (2H, q, J=7.1Hz), 4.68 (2H, s), 6.70 (IH, m) , 6.83-7.22 (3H, m)

Preparation 20

The following compounds were obtained according to a similar manner to that of Preparation 4.

(1) 3- [3- (tert-Butyldimethylsilyloxymethyl) phenoxy] -2,3- dιmethvl-2-butanol IR (Neat) : 3477, 2981, 2954, 1599, 1587 cm^"1 NMR (CDC1₃, 200MHz, δ) : 0.10 (6H, s) , 0.94 (9H, s), 1.24 (6H, s), 1.33 (6H, s), 2.79 (IH, br s), 4.72 (2H, s), 6.86 (IH, m) , 6.97-7.27 (3H, )

(2) (E)-4-[3-[ [N-Ethyl-N-( (E)-6, 6-dιmethyl-2-hepten-4-ynyl) ammo]methyl ] phenyl] -2-methyl-3-buten-2-ol IR (Neat) : 3350, 2980, 2800, 1600 cm^"1 NMR (CDCI3, 200MHz, δ) : 1.04 (3H, t, J=7.1Hz), 1.24 (9H, s), 1.43 (6H, s), 1.63 (IH, br s), 2.51 (2H, q, J=7.1Hz), 3.09 (2H, dd, J=6.4 and 1.4Hz), 3.54 (2H, s), 5.65 (IH, d, J=15.9Hz), 6.09 (IH, dt, J=15.9 and 6.4Hz), 6.36 (IH, d, J=16.1Hz), 6.59 (IH, d, J=16.1Hz), 7.17-7.27 (3H, ) , 7.35 (Ih, s) MS (APCI) m/z : 340 (M+H)

Preparation 21

The following compounds were obtained accordmg to a similar manner to that of Preparation 7.

1 1- (tert-Butyldimethylsilyloxymethyl) -3- [1, l-dιmethyl-2- ( 3-thιenylmetnoxy) ethoxy] benzene

(2) 1- ( tert-Butyldimethylsilyloxymethyl) -3- [ 1, 1, 2-trιmethyl- 2- ( 3-thιenylmethoxy) propyloxy] benzene

IR (Neat) : 2980, 2953, 1600, 1585 cm^-1

NMR (CDCI3, 200MHz, δ) : 0.09 (6H, s), 0.94 (9K, s),

1.30 (6H, s), 1.42 (6H, s), 4.64 (2H, s), 4.70 (2H, s), 6.88 (IH, m) , 6.99-7.29 (6H, m)

(3) 1- (tert-Butyldimethylsilyloxymethyl) -3- [2-methyl-2- (benzyloxy) propyloxy] benzene

IR (Neat) : 2954, 2931, 2858, 1593 cm^_1 NMR (CDCI3, 200MHz, δ) : 0.10 (6H, s), 0.95 (9H, s), 1.41 (6H, s), 3.92 (2K, s), 4.62 (2K, s), 4.71 (2H, s ) , 6 . 81 ( IH , m) , 6 . 84 -7 . 35 ( 8H , m)

(4) 1- (tert-Butyldimethylsilyloxymethyl) -3- [2- [ (2- fluorophenyl ) methoxy] -2-methylpropyloxy] benzene IR (Neat) : 2954, 2931, 2858, 1589 cm^"1

NMR (CDC1₃, 200MHz, δ) : 0.10 (6H, s), 0.95 (9H, s),

1.41 (6H, s), 3.92 (2H, s), 4.64 (2H, s), 4.71 (2H, s), 6.81 (IH, m) , 6.89-7.27 (6H, m) , 7.47 (IK, m)

(5) 1- (tert-Butyldimethylsilyloxymethyl) -3- [2- [ (2- chlorophenyl ) methoxy] -2-methylpropyloxy] benzene IR (Neat) : 2954, 2929, 2856, 1593 cm^"1 NMR (CDCI3, 200MHz, δ) : 0.10 (6H, s), 0.95 (9H, s),

1.42 (6K, s), 3.94 (2H, s), 4.67 (2H, s), 4.71 (2H, s), 6.82 (IH, m) , 6.88-7.34 (6H, m) , 7.55 (IH, )

(6) 1- (tert-Butyldimethylsilyloxymethyl) -3- [2-methyl-2-

[ (2,3,4,5, 6-pentafluorophenyl ) methoxy] propyloxy] benzene IR (Neat) : 2954, 2933, 2858, 1591, 1506 cm^"1 NMR (CDCI3, 200MHz, δ) : 0.10 (6H, s) , 0.94 (9H, s),

1.40 (6H, s), 3.89 (2H, s), 4.65 (2H, t, J=1.7Hz), 4.72 (2H, s), 6.79 (IH, m) , 6.90-6.92 (2K, m) , 7.23 (IH, t, J=8.0Hz)

Preparation 22

The following compounds were obtained according to a similar manner to that of Preparation 11.

(1) 3- [2-Methyl-2- (2-thienylmethoxy) propyloxy] benzyl alcohol IR (Neat) : 3388, 2975, 2929, 2871, 1591 cm^"1

NMR (CDCI3, 200MHz, δ) : 1.41 (6H, s), 1.69 (IH, t,

J=6.0Hz), 3.91 (2H, s), 4.67 (2H, d, J=6.0Kz), 4.75 (2H, s), 6.87 (IH, m) , 6.91-7.03 (4H, m) , 7.22-7.34 (2H, m) (2) 3- [1, 1-Dimethy1-2- ( 3-thienylmethoxy) ethcxy] benzyl alcohol

IR (Neat) : 3419, 2976, 2864, 1598, 1583 cm^"1 NMR (CDC1₃, 200MHz, δ) : 1.31 (6H, s) , 1.60 (IH, br s), 3.44 (2H, s), 4.54 (2H, d, J=8.9Hz), 4.62 (2H, s) , 6.87-7.33 (7H, m)

(3) 3- [ 1, 1, 2-Tπmethyl-2- ( 3-thienylmethoxy) propyloxy] benzyl alcohol IR (Neat) : 3381, 2993, 2945, 1599, 1583 cm^"1

NMR (CDCI3, 200MHz, δ) : 1.31 (6H, s) , 1.43 (6H, s) ,

1.60 (IH, br s), 4.63 (2H, s), 4.64 (2H, s), 6.88- 7.30 (7K, m)

(4) 3- [2-Methyl-2-[ (2, 3, 4,5, 6-pentafluorophenyl ) methoxy] - propyloxy] benzyl alcohol mp : 66-69°C

IR (KBr) : 3458, 2983, 2937, 2881, 1603, 1506 cm^"1 NMR (CDC1₃, 200MHz, δ) : 1.41 (6H, s) , 1.61 (IH, br s), 3.90 (2H, s), 4.65 (2H, t, J=1.7Hz), 4.68 (2H, s), 6.85 (IH, m) , 6.93-6.96 (2H, m) , 7.27 (IH, t, J=8.1Hz)

(5) 3- [2-Methyl-2- (benzyloxy) propyloxy] benzyl alcohol IR (Neat) : 3400, 2976, 2929, 2872, 1589 cm^"1

NMR (CDCI3, 200MHz, δ) : 1.41 (6H, s), 1.64 (IH, br s), 3.93 (2H, s), 4.57 (2H, s), 4.66 (2K, s), 6.84- 6.97 (3H, ) , 7.20-7.37 (6H, m)

(6) 3- [2- [ (2-Fluorophenyl) methoxy] -2-methylpropyloxy] benzyl alcohol

IR (Neat) : 3400, 2978, 2931, 2875, 1589 cm^"1 NMR (CDC1₃, 200MHz, δ) : 1.41 (6H, s), 1.65 (IK, br ε), 3.93 (2H, s), 4.64 (2H, s), 4.66 (2H, s), 6.84- 7.31 (7H, m) , 7.47 (IH, m) (7) 3- [2- [ (2-Chlorophenyl) methoxy] -2-meth lpropyloxy] benzyl alcohol

IR (Neat) : 3381, 2976, 2929, 2875, 1593 cm^"1 NMR <CDC1₃, 200MHz, δ) : 1.42 (6H, s) , 1.64 (IH, br s), 3.95 (2H, s), 4.66 (4H, s), 6.86-6.98 (3K, m) ,

7.14-7.34 (4H, m) , 7.55 (IH, m)

Preparation 23

Tne following compounds were obtained according to a similar manner to that of Example 3-(l) .

(1) 1- (Methylsulfonyloxymethyl) -3- [2-methyl-2- (2- thienylmethoxy) propyloxy] benzene

(2) 1- (Methylsulfonyloxymethyl) -3- [1, l-dιmethyl-2- (3- tnienylmethoxy) ethoxy] benzene

(3) 1- (Methylsulfonyloxymethyl) -3- [1, 1, 2-trιmethyl-2- (3- thienylmethoxy) propyloxy] benzene

(4 ) 1- (Methylsulfonyloxymethyl) -3- [ 2-methyl-2- (benzyloxy) propyloxy] benzene

(5) 3- [2- [ (2- Fluorophenyl) methoxy] -2-methylpropyloxy] -1- (methylsαlfonyloxymethyl) benzene

(6) 3— [2— L (2-Chlorophenyl) methoxy] -2-methylpropyloxy] -1- (methylsulfonyloxymethyl ) benzene

(7) 1- (Methylsulfonyloxymethyl) -3- [2-methyl-2- [ (2, 3,4,5, 6- pentafluorophenyl ) methoxy] propyloxy] benzene

Preparation 24

To a stirred suspension of lithium aluminum hydride (0.27 g) tetrahydrofuran (15 ml) was added dropwise a solution of ethyl 2- [3- (tert-butyldimethylsilyloxymethyl) - phenoxy] -2-methylpropιonate (1.48 g) in tetrahydrofuran (8 ml) at 20°C. The mixture was stirred at the same temperature for 15 minutes, and then sodium fluoride (1.19 g) and water (0.38 ml) was added to the mixture. The insoluble material was removed by filtration and the filter cake was washed with ethyl acetate. The filtrate and washings were combined and concentrated in vacuo . The residue was extracted with ethyl acetate, and the extract was washed with brme, dried and concentrated to dryness to give 2-[3-(tert- butyldimethylsilyloxymethyl ) phenoxy] -2-methyl-l-propanol as

IR (Neat) : 3440, 2954, 2858, 1601 cm^~] NMR (CDC1₃, 200MHz, δ) : 0.10 (6H, s), 0.94 (9H, s), 1.27 (6H, s), 2.21 (IH, t, J=6.5Hz), 3.59 (2K, dd,

J=6.5 and 1.3Hz), 4.71 (2H, s), 6.86 (IH, m) , 6.98- 7.27 (3H, )

Preparation 25 To a solution of (E) -N-ethyl-N- ( 6, 6-dιmethyl-2-hepten-4- ynyl)-3-bromobenzylamιne (SYNLETT, 1995, 931-932, 1.86 g) tetrahydrofuran (15 ml) was added dropwise butyllithium (1.6 M solution m hexane, 3.8 ml) at -78°C, and the mixture was stirred at the same temperature for 20 minutes. To the above solution was added N,N-dιmethylformamιde (1.3 ml), and the mixture was stirred at -78°C for 30 minutes and then σuenched by the addition of 1 M citric acid solution (6 ml). After dilution in ethyl acetate, the mixture was washed successively with saturated sodium hydrogen carbonate solution, water and brine. The organic layer was separated, dried and concentrated in vacuo. The residue was chromatographed on a column of silica gel with hexane - ethyl acetate (6:1, V/V) to give 3- [ [N-ethyl-N- ( (E) -6, 6-dιmetnyl-2- hepten-4-ynyl) ammo] methyl ]benzaldehyαe as an oil (1.12 g) . IR (Neat) : 2970, 2800, 1700, 1600, 1585 cm^"1 NMR (CDC1₃, 200MHz, δ) : 1.05 (3H, t, J-7.1Hz), 1.24

(9H, s), 2.52 (2H, q, J=7.1Hz), 3.10 (2H, dd, J=6.4 and 1.4Hz), 3.62 (2H, s), 5.65 (IH, dt, J=15.8 and 1.4Hz), 6.07 (IH, dt, J=15.8 and 6.4Hz), 7.47 (IH, t, J=7.5Hz), 7.62 (IH, d, J=7.5Hz), 7.76 (IH, d,

J=7.5Hz), 7.85 (IH, s), 10.02 (IH, s) MS (APCI) m/z : 284 (M+H)

Prepara on 26 To an ice-cooled suspension of sodium hydride (60°„ dispersion in mineral oil, 199 mg) in tetrahydrofuran (2 ml) was added a solution of triethyl pnosphonoacetate (1.06 g) in tetrahydrofuran (2 ml), and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture was added a solution of 3- [[ (N-ethyl-N- ( (E) -6, 6-dιmethyi-2- hepten-4-ynyl ) ammo] methyl] benzaldehyde (673 mg) in tetrahydrofuran (5 ml) below 10°C, and the mixture was stirred at 4°C for an hour and then quenched by the addition of 1 M citric acid solution (5 ml) . After dilution in ethyl acetate, the mixture was washed successively with saturated sodium hydrogen carbonate solution, water and brme. The organic layer was separated, drieα and concentrateα vacuo. The residue was chromatographed on a column of silica gel with hexane - ethyl acetate (8:1, V/V) to give ethyl (E)-3- [3- [ [N-ethyl-N- ( (E) -6, 6-dιmethyl-2-hepten-4-ynyl ) ammo] - methyl] phenyl ] acrylate as an oil (616 mg) .

IR (Neat) : 2980, 2800, 1715, 1640 cm^"1 NMR (CDC1₃, 200MHz, δ) : 1.04 (3H, t, J=^"7.lHz), 1.24 (9H, s), 1.34 (3H, t, J=7.1Hz), 2.50 (2H, q, J=7.1Hz), 3.09 (2H, dd, J=6.4 and 1.4Hz), 3.56 (2H, s), 4.27 (2H, q, J=7.1Hz), 5.64 (IK, d, J=15.8Hz), 6.07 (IH, dt, J=15.8 and 6.4Hz), 6.44 (IH, d, J=16.0Hz), 7.31-7.42 (3H, m) , 7.50 (IH, s), 7.69 (IH, d, J=16.0Hz) MS (APCI) m/z : 354 (M+H) Pre ar ion 7

To a mixture of N, O-dimethylhydroxylamme hydrochloπde (6.14 g) , 3, 3-dιmethylacrylιc acid (6.0 g) and 1-hydroxybenzotrιazole (8.50 g) in dichloromethane (90 ml) was added a solution of 1- (3-dιmethylammopropyl) -3- ethylcarbodnmide (11.5 ml) in dichloromethane (10 ml) below ICC. The mixture was stirred at room temperature for 5.5 hours and then diluted with dichloromethane. The solution was washed successively with water and br e, dried and concentrated vacuo. The residue was chromatographed on a column of silica gel with hexane - ethyl acetate (4:1, V/V) to give N-methoxy-N-methyl-3, 3-dιmethylacrylamιde as an oil (4.75 g) .

IR (Neat) : 2950, 1655 cm^"1 NMR (CDC1₃, 200MHz, δ) : 1.91 (3H, s) , 2.14 (3H, s),

3.20 (3H, s), 3.68 (3H, s), 6.12 (IH, br s)

Preparation 28

To a solution of 3-bromothιophene (7.26 g) m ether (45 ml) was added dropwise butyllithium (1.7 M solution in hexane, 25.2 ml) below -60°C, and the mixture was stirred at -78°C for 30 minutes. To the mixture was added a solution of N-methoxy-N-methyl-3, 3-dιmethylacrylamιde (4.25 g) ether (30 nl) below -60°C, and the mixture was stirred at -78°C for 90 minutes. After being quenched by the addition of 1 M citric acid solution (15 ml), the reaction mixture was allowed to warm to room temperature, washed successively with water and brine, dried and concentrated m vacuo. The residue was chromatographed on a column of silica gel with hexane - ethyl acetate (20:1, V/V) to give 3-methyl-l- (3- thienyl ) -2-buten-l-one as a solid (4.75 g) . mp : 55-56°C

IR (Nujol) : 3100, 1645, 1600, 1510 cm^-1 NMR (CDCI3, 200MHz, δ) : 2.00 (3H, s), 2.24 (3H, s), 6.66 (IH, br s), 7.30 (IH, dd, J=5.1 and 2.9Hz), 7.58 (IH, dd, J=5.1 and 1.2Hz), 8.01 (IH, dd, J=2.9 and 1.2Hz) MS (APCI) m/z : 167 (M+H)

Preparation 29

3-Methyl-l- (3-thιenyl) -2-buten-l-one (500 mg) was dissolved in 30 o methylamme solution ethanol (5 ml), and the mixture was kept at room temperature for 6 hours and then- concentrated in vacuo. After dilution ethyl acetate, the residue was extracted with 1 M hydrochloric acid solution (25 ml) . The aqueous phase was treated with 1 M sodium hydroxide solution (30 ml) and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to dryness to give 3-methyl-3-methylammo- 1- ( 3-thιenyl ) -1- butanone (484 mg) .

IR (Neat) : 3350, 2970, 1660, 1510 cm.^"1

NMR (CDC1₃, 200MHz, δ) : 1.20 (6H, s), 1.82 (IH, s),

2.34 (3H, s), 2.98 (2H, s), 7.31 (IH, dd, J=5.1 and 2.9Hz), 7.54 (IH, dd, J=5.1 and 1.2Hz), 8.04 (IH, dd, J=2.9 and 1.2Hz)

Preparation 30

To a solution of (E) -N-ethyl-N- ( 6, 6-dιmethyl-2-hepten-4- ynyl ) -3-bromobenzylamme (1.68 g) tetrahydrofuran (15 ml) was added butyllithium (1.6 M solution in hexane, 3.5 ml) at -78°C, and the mixture was stirred at the same temperature for 30 minutes. To the solution was added a few lumps of dry ice, and the mixture was stirred at -78°C for an hour and then quenched by the addition of 1 M hydrochloric acid solution (5.5 ml). Tne mixture was extracted with ethyl acetate, and the extract was dried and concentrated in vacuo. The residue was crystallized from ethyl acetate - acetone (4:1, V/V) to give 3- [ TN-ethyl-N- ( (E) -6, 6-dιmethyl-2-hepten- 4-ynyl ) ammo] methyl ] benzoic acid (1.17 g) . mp : 131-133°C IR (Nujol) : 2650, 1655, 15.80 cm^"1

NMR (CDC1₃, 200MHz, δ) : 1.24 (9H, s), 1.29 (3H, t, J=7.1Hz), 2.92 (2H, q, J=7.1Hz), 3.55 (2H, d, J=6.9Hz), 3.91 (2H, s), 5.79 (IH, d, J=15.7Hz), 6.19 (IH, dt, J=15.7 and 6.9Hz), 7.25-7.^2 (2H, ) ,

8.05 (IH, m) , 8.72 (IH, br s) MS (APCI) m/z : 300 (M+H)

Preparation 31 To a solution of (E) -N-ethyl-N- ( 6, 6-dιmethyl-2-hepten-4- ynyl) -3-bromobenzylamme (335 mg) in tetrahydrofuran (3 ml) was added butyllithium (1.6 M solution in hexane, 0.69 ml) at -78°C, and the mixture was stirred at the same temperature for 20 minutes. To the solution was added a solution of N-methoxy-N-methyl-3, 3-dιmethylacrylamιde (158 mg) in tetrahydrofuran (1 ml), and the mixture was stirred at -78°C for 2 hours and then quenched by the addition of 1 M citric acid solution (1 ml). After dilution in ethyl acetate, the mixture was washed successively with saturated sodium hydrogen carbonate solution, water and br e. The organic layer was dried and concentrated in vacuo. The residue was chromatographed on a column of silica gel with hexane - ethyl acetate (6:1, V/V) to give 1- [3- [ [N-ethyl-N- ( (E) -6, 6- dιmetnyl-2-hepten-4-ynyl) ammo] ethyl] phenyl] -3-methyl-2- buten-1-one as an oil (91 mg) .

IR (Neat) : 2980, 2800, 1665, 1615 cm^"1 MM? (CDCI3, 200MHz, δ) : 1.04 (3H, t, J=7.1Hz), 1.24 (9H, s), 2.03 (3H, s), 2.21 (3H, s), 2.51 (2K, q, J=7.1Hz), 3.09 (2H, dd, J=6.3 and 1.4Hz), 3.61 (2H, s), 5.65 (IH, dt, J=15.9 and 1.4Hz), 6.08 (IH, dt,

J=15.9 and 6.3Hz), 6.75 (IH, ) , 7.38 (IH, t, J=7.8Hz), 7.52 (IH, d, J=7.8Hz), 7.79 (IH, d, J=7.8Hz), 7.86 (IH, s) MS (APCI) m/z : 338 (M-^H) Example 9

A mixture of 1- (methylsulfonyloxymethyl ) -3- [2-methyl-2- (3-thιenylmethoxy) propyloxy] benzene (383 mg) , (E) -N-ethyl-N- (6-methoxy-6-methyl-2-hepten-4-ynyl) amine (205 mg) and potassium carbonate (185 mg) in N, N-dimethylformamide (4 ml) was stirred overnight at room temperature, and then poured into water. The mixture was extracted with ethyl acetate, and the extract was washed successively with water and brine, dried and concentrated. The residue was chromatographed on a column of silica gel with hexane - ethyl acetate (20:1, V/V) to give (E) -N-ethyl-N- ( 6-methoxy-6-methyl-2-hepten-4-ynyl ) -3- [2-methyl-2- ( 3-thιenylmethoxy) propyloxy] benzylam e as an oil (275 mg) .

IR (Neat) : 2978, 2933, 1589 cm^"1 NMR (CDC1₃, 200MHz, δ) : 1.05 (3H, t, J=7.1Kz), 1.40

(6H, s), 1.46 (6H, s), 2.52 (2H, q, J=7.1Hz), 3.12 (2H, d, J=6.3Hz), 3.35 (3H, s), 3.54 (2H, s), 3.89 (2H, s), 4.59 (2H, s), 5.69 (IH, d, J=15.9Hz), 6.18 (IH, dt, J=15.9 and 6.3Hz), 6.79-6.83 (IH, ) , 6.89-6.93 (2H, m) , 7.06 (IH, dd, J=4.9 and 1.2Hz),

7.17-7.33 (3H, m) MS (APCI) m/z : 456 (M+H)

Example 10 Condensation of 1- (methylsulfonyloxymethyl) -3- [2-methyl-

2- (2-thιenylmethoxy) propyloxy]benzene (516 mg) and (E)-N- ethyl-N- (6, 6-dιmethyl-2-hepten-4-ynyl) amme (253 mg) was carried out according to a similar manner to that of Example 3- (2) to give (E) -N-ethyl-N- ( 6, 6-dιmethyl-2-hepten-4-ynyl ) -3- [2-methyl-2- (2-thιenylmethoxy) propyloxy] benzylamme as an OJ.1 (364 mg) .

IR (Neat) : 2967, 2929, 2589 cm^"1

NMR (CDCl₃, 200MHz, δ) : 1.04 (3H, t, J=^"MHz), 1.24

(9H, s), 1.41 (6H, s), 2.51 (2H, q, J=7.1Hz), 3.09 (2H, dd, J=6.4 and 1.4Hz), 3.53 (2H, s), 3.90 (2H, s), 4.76 (2H, s), 5.64- (IH, d, J=15.9Hz), 6.08 (IK, dt, J=15.9 and 6.4Hz), 6.80 (IH, m) , 6.89-7.26 (6H, m) MS (APCI) m/z : 440 (M+H)

Example 11

Condensation of 1- (methylsulfonyloxymethyl) -3- [1, 1- dιmethyl-2- ( 3-thienylmethoxy) ethoxy] benzene (333 mg) and (E)- N-ethyl-N- (6, 6-dimethyl-2-hepten-4-ynyl) amine (163 mg) was carried out according to a similar manner to that of Example 3- (2) to give (E) -N-ethyl-N- ( 6, 6-dimethyl-2-hepten-4-ynyl) -3- [1, l-dimethyl-2- (3-thienylmethoxy) ethoxy] benzylamine as an oil (88 mg) .

IR (Neat) : 2970, 1592 cm^-1 NMR (CDCi₃, 200MHz, δ) : 1.02 (3H, t, J=7.1Hz), 1.23

(9H, s), 1.30 (6H, s), 2.49 (2H, q, J=7.1Hz), 3.08

(2H, dd, J=6.4 and 1.4Hz), 3.43 (2H, s), 3.51 (2H, s), 4.62 (2H, s), 5.64 (IH, d, J=15.8Hz), 6.06 (IH, dt, J=15.8 and 6.4Hz), 6.87 (IH, m) , 7.00-7.33 (6H, m)

MS (APCI) m/z : 440 (M+H)

Example 12

Condensation of 1- (methylsulfonyloxymethyl ) -3- [ 1, 1, 2- tπmethyl-2- (3-thienylmethoxy) propyloxy] benzene (441 mg) and (E) -N-ethyl-N- (6, 6-dimethyl-2-hepten-4-ynyl) amine (202 mg) was carried out according to a similar manner to that of Example 3- (2) to give (E) -N-ethyl-N- ( 6, 6-dimethyl-2-hepten-4- ynyl) -3- [1, 1, 2-trimethyl-2- (3-thienylmethoxy) propyloxy] - benzylamine as an oil (188 mg) .

IR (Neat) : 2970, 1587 cm^"1

NMR (CDC1₃, 200MHz, δ) : 1.03 (3H, t, J=7.1Hz), 1.24 (9K, s), 1.30 (6H, s), 1.43 (6H, s), 2.49 (2H, q, J=7.1Hz), 3.09 (2H, dd, J=6.4 and 1.4Hz), 3.52 (2H, s), 4.64 (2H, s), 5.64 (IH, d, J=15.8Hz), 6.07 (IH, dt, J=15.8 and 6.4Hz), 6.87 (IH, m) , 6.98-7.30 (6H, m) MS (APCI) m/z : 468 (M+H)

Example 13

Condensation of 1- (methylsulfonyloxy ethyl) -3- [2-methyl- 2- (benzyloxy) propyloxy] benzene (496 mg) and (E) -N-ethyl-N- ( 6, 6-dιmethyl-2-hepten-4-ynyl) amme (247 mg) was carried out according to a similar manner to that of Example 3- (2) to give (E) -N-ethyl-N- ( 6, 6-dιmethyl-2-hepten-4-ynyl ) -3- [2- methyl-2- (benzyloxy) propyloxy] benzylamme as an oil (368 mg) . IR (Neat) : 2970, 2929, 1593 cm^-1 NMR (CDC1₃, 200MHz, δ) : 1.04 (3H, t, J=7.1Hz), 1.24

(9K, s), 1.41 (6H, s), 2.51 (2H, q, J=7.1Hz), 3.10 (2H, d, J=6.4Hz), 3.53 (2H, s), 3.91 (2K, s,, 4.58

(2H, s), 5.64 (IH, d, J=15.9Hz), 6.09 (IH, dt, J=15.9 and 6.4Hz), 6.81 (IH, m) , 6.89-6.93 (2H, m) , 7.16-7.38 (6H, m) MS (APCI) m/z : 434 (M+H)

Example 14

The following compounds were obtained according to a similar manner to that of Example 3- (2).

(1) (E) -N-Ethyl-N- (6, 6-dιmethyl-2-hepten-4-ynyl ) -3- [2-[ (2- fluorophenyl) methoxy] -2-methylpropyloxy] benzylam e IR (Neat) : 2970, 2929, 1589 cm^"1 NMP (CDCI3, 200MHz, δ) : 1.04 (3H, t, J=7.1Hz), 1.23

(9H, s), 1.42 (6H, s), 2.50 (2H, Q, J=7.1Hz), 3.09 (2H, d, J=6.4Hz), 3.52 (2K, s), 3.9ι (2H, s), 4.64

(2H, s), 5.64 (IK, d, J=15.9Hz), 6. OS (IH, dt, J=i5.9 and 6.4Hz), 6.81 (IH, , 6.88-7.26 (6H, m) , 7.44 (IH, m) MS (APCI) m/z : 452 (M+H) (2) (E) -N-Ethyl-N- ( 6-methoxy-6-methyl-2-hepten-4-ynyl ) -3- [2- [ (2-fluorophenyl ) methoxy] -2-methylpropyloxy] benzylam e IR (Neat) : 2978, 2933, 1589 cm^"1

NMR (CDC1₃, 200MHz, δ) : 1.06 (3H, t, J=7.1Hz), 1.42 (6H, s), 1.46 (6H, s) , 2.53 (2H, q, J=7.1Hz), 3.12

(2H, d, J=6.3Hz), 3.35 (3H, s), 3.54 (2H, s), 3.92 (2H, s), 4.64 (2H, s), 5.69 (IH, d, J=15.9Hz), 6.19 (IH, dt, J=15.9 and 6.3Hz), 6.82 (IH, m) , 6.89-7.26 (6H, ) , 7.47 (IH, m) MS (APCI) m/z : 468 (M+H)

(3) (E) -N-Ethyl-N- (6, 6-dimethyl-2-hepten-4-ynyl) -3- [2- [ (2- chlorophenyl) methoxy] -2-methylpropyloxy] enzylamine IR (Neat) : 2970, 2929, 1593 cm^"1 NMR (CDCI3, 200MHz, δ) : 1.04 (3H, t, J=7.1Hz), 1.24

(9H, s), 1.43 (6H, s), 2.51 (2H, q, J=7.1Hz), 3.10 (2H, d, J=6.4Hz), 3.53 (2H, s), 3.93 (2H, s), 4.67 (2H, s), 5.65 (IH, d, J=15.9Hz), 6.09 (IH, dt, J=15.9 and 6.4Hz), 6.81 (IH, m) , 6.89-6.93 (2K, ) , 7.14-7.34 (4H, m) , 7.56 (IH, )

MS (APCI) m/z : 468 (M+H)

(4) (E) -N-Ethyl-N- (6, 6-dιmethyl-2-hepten-4-ynyl ) -3- [ 2- ethy1-2- [(2,3,4,5, 6-pentafluorophenyl ) methoxy] - propyloxy] benzylamine

IR (Neat) : 2972, 2931, 1589, 1506 cm^"1

NMR (CDCI3, 200MHz, δ) : 1.05 (3H, t, J=7.1Hz), 1.23

(9H, s), 1.41 (6H, s), 2.52 (2H, q, J=7.1Hz), 3.10 (2H, d, J=6.4Hz), 3.54 (2H, s), 3.88 (2H, s), 4.66 (2H, t, J=1.7Hz), 5.65 (IH, d, J=15.9Hz), 6.06 (IH, dt, J=15.9 and 6.4Hz), 6.79 (IH, m) , 6.89-6.93 (2H, m) , 7.20 (IH, t, J=8.0Hz) MS (APCI) m/z : 524 (M+H)

Example 15 Condensation of (E) -4- [3- [ [N-ethyl-N- ( (E) -6, 6-αιmethyl- 2-hepten-4-ynyl) ammo] ethyl] phenyl] -2-methyl-3-buten-2-ol (200 mg) and 3- (bromomethyl ) thiophene (125 mg) was carried out according to a similar manner to that of Preparation 7 co give (E) -N-ethyl-N- ( 6, 6-dιmethyl-2-hepten-4-ynyl ) -3- [ (E) -3- methyl-3- (3-thιenylmethoxy) -1-butenyl] benzylamme as an oil (71 mg) .

IR (Neat) : 2980 cm^"1

NMR (CDC1₃, 200MHz, δ) : 1.05 (3H, t, J=7.1Hz), 1.24 (9K, s), 1.46 (6H, s), 2.52 (2H, q, J=^~.lHz), 3.11

(2H, dd, J=6.4 and 1.3Hz), 3.56 (2K, s), 4.44 (2H, s), 5.65 (IH, d, J=15.9Hz), 6.09 (IK, dt, J=15.9 and 6.4Hz), 6.28 (IH, d, J=16.4Hz), 6.55 (IH, d, J=16.4Hz), 7.06 (IH, dd, J=4.9 and 1.2Kz), 7.19- 7.30 (5H, ) , 7.35 (IH, s)

MS (APCI) m/z : 436 (M+H)

Example 16

To a solution of (E) -4- [ 3- [ [N-ethyl-N- ( (E) -6, 6-dιmetnyl- 2-hepten- -ynyl) ammo 1 methyl] phenyl] -2-methyl-3-buten-2-ol (192 mg) and 4- (dimethylammo) pyridine (207 mg) pyridine (2 ml) was added 3-thιophenecarbonyl chloride (166 mg) . The mixture was stirred at room temperature for 24 hours and then poured into ice-water. The mixture was extracted with ethyl acetate, and the extract was washed with water, drieα and concentrated in vacuo. The residue was chromatographed on a column of aluminum oxide (neutral) with hexane - ethy acetate (9:1, V/V) to give (E) -N-ethyl-N- ( 6, 6-dιmethyl-2- hepten-4-ynyl) -3- [ (E) -3-methyl-3- ( 3-thιenylcarbonyloxy) -1- butenyl] benzylamme as an oil (156 mg) . IR (Neat) : 2980, 2800, 1710 cm^"1 NMR (CDCI3, 200MHz, δ) : 1.04 (3H, t, J=7.1Hz), 1.24

(9H, s), 1.75 (6H, s), 2.50 (2H, q, J=7.1Hz), 3.09 (2K, dd, J=6.4 and 1.4Hz), 3.5* (2h, s > , 5.64 (IK, d, J=15.8Hz), 6.09 (IH, dt, J=15.8 and 6.4Hz), 6.59 (2H, s), 7.21-7.30 (4H, m) , 7.34 (IH, s) , 7.50 (IH, dd, J=5.0 and 1.2Hz), 8.06 (IH, dd, J=3.0 and 1.2Hz) MS (APCI) m/z : 450 (M-rH)

Example 17

To a mixture of 3- [ [N-ethyl-N- ( (E) -6, 6-dιmethyl-2- heρten-4-ynyl) amino] methyl ] benzoic acid (150 mg) , 3-methyl-3- methylammo-1- (3-thιenyl) -1-butanone (119 mg) and 1-hydroxybenzotrιazole (81 mg) in N,N-dιmethylformamιde (2 ml) was added 1- (3-dιmethylammopropyl ) -3-etnylcarbod ιmιde hydrochloride (115 mg) . The mixture was stirred at room temperature for overnight and then poured into water. The mixture was extracted with ethyl acetate, and the extract was dried and concentrated in vacuo. The residue was chromatographed on a column of silica gel with hexane - ethyl acetate (2:1, V/V) to give 3- [ [N-ethyl-N- ( (E) -6, 6-dιmethyl-2- hepten-4-ynyl) am o] ethyl] -N-methyl-N- [1, 1-dimethyl-3-oxo-3- (3-thιenyl ) propyl ] benzamide as an oil (92 mg) . IR (Neat) : 2980, 2800, 1670, 1630, 1585, 1510 cm^"1

NMR (CDC1₃, 200MHz, δ) : 1.02 (3H, t, J=7.1Hz), 1.24

(9H, s), 1.64 (6H, s), 2.48 (2H, q, J=7.1Hz), 2.90 (3H, s), 3.07 (2H, dd, J=6.4 and 1.4Hz), 3.53 (2H, s), 3.77 (2H, s), 5.63 (IH, d, J=15.9Kz), 6.05 (IH, dt, J=15.9 and 6.4Hz), 7.15 (IH, d, J=8.0Hz), ^"7.22-

^"' . 34 (4H, n) , 7.58 (IH, dd, J=5.1 and 1.2Hzj, 8.21 (IK, dd, J=2.9 and 1.2Hz) MS (APCI) m/z : 479 (M+H)

Example 18

1- [3- [ [N-Ethyl-N- ( (E) -6, 6-dιmethyl-2-hepten-4- ynyl) ammo] methyl ] phenyl 1 -3-methyl-2-buten-l-one (84 mg) was dissolved in 30" methylamme solution m ethanol (2 mi), and the mixture was kept at room temperature for overnight and then concentrated in vacuo. To an ice-cooled solution of the above residue and triethylamine (70 μl) tetrahydrofuran (1.5 ml) was added 3-thιophenecarbonyl chloride (166 mg) , and the mixture was stirred at 4°C for 2 hours and then poured into water. The mixture was extracted with ethyl acetate, and tne extract was v/ashed with brme, dried and concentrated in vacuo. The residue was chromatographed on a column of silica gel with hexane - ethyl acetate (2:1, V/V) to give N-methyl-N- [3- [3- [N-ethyl-N- ( (E) -6, 6-dιmethyl-2-hepten-4- ynyl ) ammo] metnylphenyl ] -1, 1-dimethyl-3-oxopropyI ] -3- thiophenecarboxamide as an oil (31 mg) .

IR (Neat) : 2970, 2800, 1680, 1625 cm^"1

NMR (CDC1₃, 200MHz, δ) : 1.03 (3H, t, J=7.1Hz), 1.24

(9K, s), 1.62 (6H, s) , 2.49 (2H, q, J=7.1Hz), 3.06 (3K, s), 3.08 (2H, d, J=6.3Hz), 3.58 (2K, s), 3.89 (2H, s), 5.64 (IH, d, J=15.8Hz,, 6.07 (IK, dt,

J=15.8 and 6.3Hz), 7.11 (IH, dd, J=5.0 and 1.2Hz), 7.24 (IH, dd, J=5.0 and 2.9Hz), 7.36 (IK, d, J=7.6Hz), 7.42 (IH, dd, J=2.9 and 1.2Hz), 7.53 (IH, d, J=7.6Hz), 8.24 (IH, d, J=7.6Hz), 7.87 (IH, s) MS (APCI) m/z : 479 (M+H)

Claims

C L A I M S

1. A substituted amme derivative of the following formula :

wherein

R¹ is a heterocyclic group or aryl which may have 1 to 5 substituent (s) ; R^ is lower alkyl or lower alkenyl, R³ is lower alkyl or lower alkenyl, or

9 -i

R^ and R , together with the carbon atom to which they are attached, represent cyclo (lower) alkane;

R is hydrogen or lower alkyl;

R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or cyclo (lower ) alkyl;

R⁶ is hydrogen or halogen; η

R is hydrogen or halogen; p

R is lower alkyl or lower alkoxy (lower ) alkyl ; -A¹- is -CH₂- or -CO-;

R⁹ -A²- is -CH₂-, -0-, -0-CH₂- or _j!j- (in which R⁹ is hydrogen or lower alkyl); and

-A - aanndd --AA -- mmaa^y be the same or different and each is a bond, -CH ~, (m which R 1 ^J1- and R 1 -^■? may

be the same or different and each is lower alkyl or lower alkenyl, or R¹¹ and R¹ , together with the carbon atom to which they are attached, represent cyclo (lower) alkane) , -CO-, -0- or _R10 _A (in which R¹⁰ is hydrogen or lower alkyl), or -A³-A⁴- is -CH=CH- or -C=C-, and a pharmaceutically acceptable salt thereof.

2. A compound of claim 1, wherein

R¹ is an unsaturated 3 to 7-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) or Cg-C-_[_g aryl which may have 1 to 5 haloge (s); R² is C_]_-C₄ alkyl or C₂-C₄ alkenyl,

R³ is C -C₄ alkyl or C₂~C₄ alkenyl, or

_{9 3} R^ and R , together with the carbon atom to which they are attached, represent cyclo (C₃-Cg) alkane; R⁴ is hydrogen or C-_j_-C₄ alkyl; R⁵ is hydrogen, C_]_-C₄ alkyl, C₂~C₄ alkenyl, C₂~C^ alkynyl or cyclo (C₃-Cg) alkyl;

R is hydrogen or halogen;

R is hydrogen or halogen;

R⁸ is C-_[_-C alkyl or C-_]_-C₄ alkoxy (C₁-C₄ ) alkyl; -A¹- is -CH₉ or -CO-; q

^Δ R^y

-A²- is -CH₂-, -0-, -0-CH₂- or _N_ (in which R⁹ is hydrogen or C-^-C^ alkyl) ; and -A³- and -A - may be the same or different and each is a bond, -CH_?-, (m which R¹¹ and R¹² may

be the same or different and each is C-^-C^ alkyl or ^c2~^c4 ^alkenyl, or R¹¹ and R¹², together with the carbon atom to which they are attached, represent cyclo (C₃-C₆) alkyl) , -CO-, -0- or

_R10

_J!J_ (m which R¹⁰ is hydrogen or C_j_-C₄ alkyl), or

-A³-A⁴- is -CH=CH- or -C=C- . 3 A compound of claim 2, wherein

R¹ is thienyl or phenyl which may have 1 to 5 fluorine (s) or chlorine (s); R² is methyl, ethyl or propenyl; R is methyl, ethyl or propenyl;

A

R^ is hydrogen;

P⁵ is ethyl;

R⁶ is hydrogen; is nydrogen;

R⁸ is tert-butyl or 2-methoxy-2-methylethyl;

; and

-A/ -0-.

The compound of claim 3, which is selected from the group consisting of

(1) (E) -N-Ethyl-N- (6, 6-dιmethyl-2-hepten-4-ynyl ) -3- [2- methyl-2- (3-thιenylmethoxy) propyloxy] benzylam e,

(2) (E) -N-Ethyl-N- ( 6-methoxy-6-methyl-2-hepten-4-ynyl ) 3- [2-methyl-2- (3-thιenylmethoxy) propyloxy] - benzylamme and

(3) (E) -N-Ethyl-N- (6, 6-dιmethyl-2-hepten-4-ynyl ) -3- [1, l-dιmethyl-2- (3-thιenylmethoxy) ethoxy] - benzylamme .

5. A process for preparing a compound of the formula

R¹

wherein

R- is a heterocyclic group or aryl which may have 1 to 5 substituent (s) ; 9

R is lower alkyl or lower alkenyl,

3 R is lower alkyl or lower alkenyl, or T

R^ and R , together with the carbon atom to which they are attached, represent cyclo (lower) alkane;

R is hydrogen or lower alkyl;

R is hydrogen, lower alkyl, lower alkenyl, lower alkynyl or cyclo (lower) alkyl;

R" is hydrogen or halogen;

R is hydrogen or halogen; R° is lower alkyl or lower alkoxy (lower) alkyl;

R⁹ -A²- is -CH₂-, -0-, -0-CH₂- or _N- (m which R⁹ is hydrogen or lower alkyl); and -A³- and -A⁴- may be the same or different and each is a bond, (m which R¹¹ and R¹² may

be the same or different and each is lower alkyl or lower alkenyl, or R¹ and R¹ , together with the carbon atom to which they are attached, represent cyclo (lower) alkane) , -CO-, -0- or

_R10 _j!]_ (in which R¹⁰ is hydrogen or lower alkyl), or -A³-A⁴- is -CH=CH- or -C≡C-, or a salt thereof, which comprises

or a salt thereof with a compound of the formula R- R^βR⁷

HN-CH _' ^■C=C-C≡C- R⁽

or a salt thereof to provide a compound of the formula

or a salt thereof, in the above formulae, R¹' R², R³, R⁴, R⁵, R^β, R⁷, R⁸, -A¹-, -A²-, -A³- and -A - are each as defined above, and

X¹ is a leaving group, or

2 ) reacting a compound of the formula

or a salt thereof with a compound of the formula

R¹-A¹-Y³

or a salt thereof to provide a compound of the formula

or a salt thereof, in the above formulae, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, -A¹-, -A³- and -A⁴- are each as defined above, and

Y is acid residue.

6. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers and/or excipient.

7. A use of the compound of claim 1 or a salt thereof for the manufacture of a medicament.

8. A method for treating or preventing hypercholesterolaemic, hyperlipaemic or hyperlipoproteinaemic states and associated conditions which comprises administrating a compound of claim 1 or a pharmaceutically acceptable salt thereof to human being or animal.

9. A use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for therapeutic treatment or prevention of hypercholesterolaemic, hypertriglycendaemic, hyperlipaemic or hyperlipoproteinaemic states and associated conditions in human being or animal.

10. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament.