JPH03141275A - Substituted allylamine derivative and its use - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is methyl, ethyl or propyl; R<2> is methyl or methoxy) or its salt. EXAMPLE:(E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-[4-(3-thienyl)-2- thienylmethyloxy]benzylamine. USE:A remedy and preventive for hypercholesterolemia, hyperlipemia and arteriosclerosis. It selectively inhibits squalene epoxidase and exhibits strong anticholesteric activity. PREPARATION:The objective compound of formula I can he produced by reacting a compound of formula II with a compound of formula III (Z is eliminable group) preferably in the presence of a base in a solvent (e.g. methylene chloride) at a temperature between -20 deg.C and the boiling point of the solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel substituted allylamine derivatives, further comprising:
Specifically, the present invention relates to substituted allylamine derivatives and non-toxic salts thereof useful in the field of medicine, particularly in the field of treatment and prevention of hypercholesterolemia, hyperlipidemia, and arteriosclerosis, and uses thereof.

Conventional technology Arteriosclerosis is a degenerative disease of the arteries that is closely related to aging and diet, and is a cause of coronary and cerebral artery disease, which is one of the most major causes of death in modern times. feared. Arteriosclerosis begins as lipid deposits on the intima of large blood vessels from a young age, and increases in scope and severity with age, leading to myocardial infarction, ischemic heart disease such as angina pectoris, and cerebral artery disease such as cerebral infarction. Clinical symptoms are manifested as sclerosis or aneurysm, and it is known that increases in various blood lipids are involved in this lipid deposition.

Among these, an increase in blood cholesterol is the most important risk factor, and reducing it to a normal value is the most effective means for treating and preventing arteriosclerosis. More than 50% of cholesterol in humans is de novo (de novo).
Lovastatin and nibstatin, which are enzyme inhibitors in the biosynthetic process, are currently used clinically as anticholesterol agents [A. ,w,A
Proceedings of the National Academy of Sciences (Proc. Natl. A. Lberts) et al.
cad, Sci, ) Volume 77, Page 3957 (198
0 year): Tsujita et al., Biochim, Biophs, Acta No. 87
7, p. 50 (1986), etc., 3-hydroxymethylglutaryleucoenzyme A reductase (HMG-CoA re
ductase).

Since they are located at an early stage of the cholesterol biosynthesis system, administration of these drugs has the disadvantage that the production of other physiologically important metabolites such as dolichol and ubiquinone is suppressed. Furthermore, it has been reported that tribalanol, which is a late stage inhibitor of the cholesterol biosynthesis system, causes cataracts due to the accumulation of desmostyrol. Since squalene epoxidase is located in the middle stage of the cholesterol biosynthesis system, its inhibitors are expected to solve these problems and become safer anti-cholesterol agents.

Several compounds are known to date as squalene epoxidase inhibitors [G, Petranyi et al.
244, p. 1239 (1984)], all of which were developed as antifungal agents that selectively act on fungal enzymes, inhibit mammalian enzymes, and have anticholesterolemic agents. There are no known drugs touted for its usefulness as a drug.

One of the main objects of the present invention is to provide an antihyperlipidemic agent that is safer and has superior anticholesterol effects compared to conventional antihyperlipidemic agents. Furthermore, the present invention aims to provide a therapeutic and preventive agent for arteriosclerosis.

Aiming to develop a new anti-arteriosclerotic agent, the present inventors searched for squalene epoxidase inhibitors with anti-cholesterol effects, and found that they have the following general formula [I]. The present invention was completed by discovering that the substituted allylamine derivatives shown above selectively inhibit squalene epoxidase in mammals and have a strong anti-cholesterol effect.

The present invention also relates to substituted furylamine derivatives represented by the general formula [wherein R1 represents a methyl group, ethyl group, or propyl group, and R1 represents a methyl group or a methoxy group], nontoxic salts thereof, and high It provides its use in the treatment of cholesterolemia, hyperlipidemia and arteriosclerosis.

Further, the present invention will be explained in detail.

Conventionally, as a result of formulating the naphthalene ring moiety in the above-mentioned naphtifine and tilbinafine as follows, it was found that allylamine derivatives represented by naphtifine and tilbinafine, which have the following formula, exhibit strong inhibitory activity against fungal squalene epoxidase. As a result, it is known to be useful as an antifungal agent [G, Petra, et al., Sci.
nce), Vol. 244, p. 1239 (1984)]. However, these compounds show almost no inhibitory activity against squalene epoxidase in mammals including humans, and cannot serve as inhibitors of cholesterol synthesis [N. , S. Ryder
), etc., Biochemical Journal (Biochem,
J.), Vol. 230, p. 765 (1985)]
.

Therefore, the present inventors have developed a drug that selectively acts only on squalene epoxidase in mammals and exhibits anti-cholesterol effects. We have discovered that a compound can be obtained that exhibits strong inhibitory activity against squalene epoxidase. The inventors also found that the squalene epoxidase inhibitory effect of the compound represented by the general formula [I] is extremely selective, shows almost no activity against fungal enzymes, and causes hypercholesterolemia. They discovered that the present invention is extremely valuable as a drug for treating or preventing hyperlipidemia and arteriosclerosis, and completed the present invention.

The substituted allylamine derivative [+] of the present invention can exist in the form of an acid addition salt, such as hydrochloride, hydrobromide, hydroiodide, sulfate. , nitrates, perchlorates or phosphates: or, for example, p-toluenesulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate, tartrate, citric acid. Examples include organic acid salts such as salts, fumarates, and maleates, and pharmaceutically acceptable non-toxic salts are particularly preferred.

(Left below) Next, a general method for producing a compound according to the present invention will be described.

The compound of formula [I] of the present invention can be prepared, for example, by the following production methods A and B.
, C, and D.

[Manufacturing method A] [Manufacturing method B] [I] [Manufacturing method C] [■] [Manufacturing method D] [In the formula, Z represents a leaving group and has the following meaning] Item c [! ] R' and R1 are the above-mentioned production methods A, B, and C are all alkylation reactions of amines that are well known in the field of organic synthetic chemistry, and therefore, they can be carried out using conventional means that are known per se. be able to. Thus, for example, the reaction can be carried out using solvents which in no case have an adverse effect on the reaction; 1 aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as ethyl ether, tetrahydrofuran or dioxane; e.g. methylene chloride, chloroform or In the case of production method A, compound [Ill] and compound [ II+],
In the case of production method B, compound [rV] and compound [V], and in the case of production method C, compound [VI] and compound [■],
The reaction can be carried out by reacting them in approximately equimolar ratios or by reacting one of them in slight excess. Regarding the reaction conditions employed at this time, the reaction temperature is generally from -20°C to the boiling point of the solvent, preferably from 0°C to 150°C, and the reaction time is usually from 5 minutes to 10 days, preferably from 1 hour to 2
It can be 4 hours. In addition, in this reaction, it is advantageous to conduct it in the presence of a base in order to proceed smoothly. Examples of the base used in this case include alkali hydrides such as sodium hydride, lithium hydride, or potassium hydride. Metals; alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or calcium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate or sodium bicarbonate; or triethylamine or pyridine, etc. Examples include organic amines. The amount of these bases to be used is not critical and can be varied over a wide range, but generally it is equimolar or in excess, preferably 1 to 2 mol, relative to each raw material compound. can.

The manufacturing process is an alkylation reaction of phenolic hydroxyl groups.
For example, ethanol, isopropanol, tetrahydrofuran, dioxane, chloroform.

In a solvent that does not adversely affect the reaction, such as benzene, acetone, dimethylformamide or dimethyl sulfoxide,
Usually, the reaction is carried out by reacting the compound [■] and the compound CDD in a substantially equimolar ratio, or by reacting either one in a slight excess. At this time, reaction conditions such as reaction temperature and reaction time vary depending on the raw materials used, but
Generally, the reaction temperature is within the range of -70°C to 100°C, preferably -20°C to 50°C, and the reaction time is conveniently 1 minute to 24 hours, preferably 30 minutes to 5 hours. It is. In addition, in order to proceed with the reaction smoothly, this reaction is preferably carried out in the presence of a base. Examples of bases used in this case include sodium hydride, lithium hydride, sodium hydroxide, potassium hydroxide, carbonate Examples include inorganic bases such as sodium, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate, and organic bases such as pyridine, triethylamine, and dimethylaminopyridine.Although the amount used is not strictly limited, usually, Equimolar or excess amount for each raw material compound,
Preferably, it can be used within the range of 1 to 2 mol.

The target compound of formula [I] of the present invention obtained in the above steps can be isolated and purified by, for example, column chromatography, solvent extraction, precipitation, recrystallization, etc. alone or in an appropriate combination. . Furthermore, if necessary,
A compound of formula [I] that can convert the free base of the compound of the present invention represented by general formula [I] into its acid addition salt, or vice versa. The step of converting the free base of into its acid addition salt and the step of converting the acid addition salt into its free base can be easily carried out by a conventional method using the corresponding acid or base.

Note that the leaving group represented by Z includes, for example, a chlorine atom,
Examples include halogen atoms such as bromine atoms and iodine atoms, and organic sulfonyloxy groups such as methanesulfonyloxy groups and p-toluenesulfonyloxy groups.

Raw material compounds [■] to [IX] used in the above production methods A-D
] can be purchased as a commercial product or manufactured using a method described in the literature [Journal of Medicinal Chemistry (J, M
ed, Chem,) Volume 27, Page 1539 (1984
); Journal of Medicinal Chemistry (J, 'Med.

Chew, ) Vol. 29, p. 112 (1986); JP-A No. 56-32440, No. 57-123177, No. 58-208252, No. 61-45, No. 62-20
No. 1850, No. 63-5059, etc.] and the following general manufacturing methods or methods analogous thereto.

The raw material compound used in the present invention can be produced, for example, by the following synthesis method.

(Space below) Production route (a) Production route (b) [VI] [Difficulty] [I11 [XIV] Production route (c) [X■] Deprotecting group [XI! [] [In the formula, B represents a hydrogen atom or a protecting group, and R'', R8 and Z have the above-mentioned meanings] Production route (a) Compound [X] is reacted with compound [■] to form compound [ X
The process of producing [] is carried out in the presence of a base such as sodium hydride, sodium hydroxide or potassium carbonate in a solvent such as tetrahydrofuran, chloroform or dimethylformamide at -20 to 100°C in an approximately equimolar ratio. This can be carried out by reacting compound [X] and compound [■] for 2 to 3 hours.

Reacting compound [XI] with compound [X II+],
The step of producing compound [■] is, for example, by condensing compound [X] with compound [X] in benzene or alcohol in advance to form an imine, followed by reduction, or by reducing excess compound [X IO3]. This can be carried out by reacting with a compound [Kari] and reducing it at the same time.

Examples of reagents used for the reduction include sodium borohydride, sodium cyanoborohydride, and lithium aluminum hydride.

The reaction conditions at this time are 1 to 6, for example, 1 to 6 at 0°C to room temperature in methanol, ethanol, or tetrahydrofuran.
There are methods such as time reaction.

The step of producing compound [XI[] by reducing compound [Xl] is carried out at 0° C. to room temperature in a solvent such as methanol, ethanol, or tetrahydrofuran, for example, using sodium borohydride, sodium cyanoborohydride, or hydrogenation. This can be carried out by treating with a reducing agent such as aluminum lithium for 1 to 5 hours.

The step of converting compound [XII] to compound [rV] is
For example, in the absence of a solvent or in a solvent such as chloroform or methylene chloride, a halogenating agent such as thionyl chloride or phosphorous tribromide or methanesulfonyl chloride and a sulfonylating agent such as triethylamine are combined at a temperature between 0°C and room temperature. This can be done by treating for ~5 hours.

Production route (b) The step of reacting compound [XI] with compound [Val to produce compound [~]co is a step of reacting compound [XI] with compound C
It can be carried out in the same manner as the step of producing compound [[I] by reacting X[[[].

In addition, the compound [Val used in this case is, for example, compound [II[] is treated with phthalimide at 10°C to 100°C in the presence of a base such as sodium hydroxide or potassium carbonate in a solvent such as tetrahydrofuran or dimethylformamide. The compound [XrV] is produced by a reaction, and then this is reacted with hydrazine in, for example, ethanol or dimethylformamide to produce the compound [Val, which can be produced by the so-called Gabriel method.

Production route (c) The step of producing compound [X■] by reacting compound [XVl with compound [X m] is to react compound [XI] with compound [X m] to produce compound [■ ], and the process of producing compound [XVl by reducing compound [XVl].
VT] and then converting it into compound [X
can be performed in the same way as the step of converting into .

Alternatively, compound [X■] may be reacted with compound [V], or
Alternatively, the step of reacting compound [X■] with compound [ml to produce compound [X This can be done by a similar method.

In addition, in the compound of general formula [XV] which is the raw material compound of this production route (C), the protecting group represented by B in the formula is commonly used in the field of organic synthetic chemistry as a protecting group for a hydroxyl group. For example, methoxymethyl group, tetrahydropyranyl group,
Examples include trityl group, tert-butoxycarbonyl group, and dimethyl-tert-butylsilyl group.

The products obtained in each of the above steps are purified or isolated, if necessary, by performing known purification methods such as column chromatography recrystallization, solvent extraction, precipitation, distillation, etc. alone or in appropriate combinations. be able to.

Compounds that serve as starting materials for these raw material intermediates can be purchased as commercial products or described in literature [journals, etc.]
of Medicinal Chemistry (J, Med, Ch
Em, Volume 27, Page 1539 (1984); Journal of Medicinal Chemistry (J.

Med, Chem, Volume 29, Page 112 (198
6); Japanese Patent Publication No. 56-32440, 57-1231
No. 77, No. 58-208252, No. 61-45, No. 62-201850, No. 63-5059, etc.] or by using known synthetic methods in organic synthetic chemistry.

The compound of the present invention represented by the general formula [I] inhibits squalene epoxidase in mammals extremely selectively and strongly, and can be used as an antihypercholesterolemic agent, an antihyperlipidemic agent, and an antihyperlipidemic agent. It is a useful compound expected to be used as an arteriosclerotic agent.

In order to prove this, pharmacological test examples and acute toxicity test examples will be given and explained below.

Pharmacological test examples Squalene epoxidase inhibitory action (1) Preparation of squalene epoxidase Human squalene epoxidase was published in the Journal of Biological Chemistry (J, Biol.

Chew, ) vol. 245, p. 1670 (1970)
; vol. 250, p. 1572 (1975).

That is, human hepatoma (Hep-G2) cells are cultured at 37° C. in 5% dicarbonate atmosphere. After culturing, the cells are scraped and collected by centrifugation. 0.
Suspend in IM Tris-HCI buffer (pH 7,5) and homogenize at 975
Centrifuge for 10 minutes at 0Xg. The resulting supernatant was further centrifuged at 1,105,000X for 1 hour, and the precipitate was then centrifuged at 0.
．． After washing with IN Tris-HCI buffer (pH 7,5), centrifugation is performed at 1105000×Te for 1 hour. The obtained microsomes were diluted to a protein content of 40+ag/liQ. IM Tris-HCI buffer (p) 17.5
) in the presence of 2% Triton x-too under water cooling,
Stir to solubilize. After this solubilization treatment, ED
Triton X-10 with TA and lsM dithiothreitol
Dilute the 0 concentration to 0.5% and centrifuge at 1105000X for 1 hour. The obtained supernatant is used as a squalene epoxidase fraction in the test described below.

(2) Method for measuring squalene epoxidase activity The measurement of human squalene epoxidase activity is described in the Journal of Biological Chemistry (J. Biol.
, Che@, ) Volume 245, Page 1670 (197
This is done according to the method described in Year 0).

That is, the squalene epoxidase fraction (7) prepared in (1) was 0.2aQ [protein amount 0. h+g, 0.5% Triton x-100, 20 μN Tris-HCI buffer (
pH 7,5)], 100 μM FAD, l+a? l
Add 3 μQ of a dimethyl sulfoxide solution of the test drug to a solution consisting of NADPH, IBM EDTA, and 8 μM “H-Squalene Root Vienna 80 suspension, and make a total volume of 0.3
aQ and shaken for 30 minutes at 37°C.

The reaction was stopped by adding 0.3 ml of 10% potassium hydroxide-methanol solution, and the mixture was allowed to stand at room temperature for 1 hour.Next, unsaponifiable substances were extracted with petroleum ether, and then concentrated to dryness under a nitrogen stream. The obtained residue was dissolved in a small amount of ethyl ether and prepared as Pre-coated SilicagelT.
Spotted on LC, benzene-ethyl acetate (99,5:
0.5). The position of the generated H-squalene-2゜3-epoxide on TLC was confirmed using ergosterol acetate as a marker.
Cut out the H-squalene-2,3-epoxide part.

The TLC piece is immersed in a toluene scintillator and measured using a liquid scintillation counter.

As a result, the 50% inhibitory concentration (IC, value) of the compound of the present invention against human squalene epoxidase was determined, and the results are shown in the table.

Acute Toxicity Test Example The test drug (compound of Example 1; hydrochloride) was suspended in a 0.5% methylcellulose aqueous solution and administered intraperitoneally to mice (ddy male mice, weight 28±2 g, 4 mice per group).

Acute toxicity was investigated from the mortality rate 2 weeks after administration.

The toxicity of each test drug was extremely low, and no deaths were observed even at a high dose of 1000 mg/kg.

As is clear from the above results, the compounds of the present invention strongly inhibit squalene epoxidase and reduce cholesterol.
Since it inhibits the biosynthesis of cholesterol, various diseases caused by the enhancement of the biosynthetic mechanism of cholesterol, such as obesity,
It is effective in treating and preventing diseases such as hyperlipidemia and arteriosclerosis. Further, the squalene epoxidase inhibitory effect of the compound of the present invention is not observed in fungi and the like and is specific to mammals, and furthermore, the toxicity is low, so the present invention is extremely useful in the pharmaceutical field.

The compound of formula [+] of the present invention can be administered orally or parenterally, and by formulating it into a form suitable for such administration, it can be used to treat hypercholesterolemia, hyperlipidemia and When using the compound of the present invention clinically, which can be used to treat and improve arteriosclerosis, etc., it is administered after being formulated into various formulations by adding pharmaceutically acceptable additives according to the dosage form. It is also possible. As additives in this case, various additives commonly used in the pharmaceutical field can be used, such as gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and corn starch. , microcrystalline wax, white petrolatum, magnesium aluminate metasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyvinyl Examples include pyrrolidone, magnesium stearate, light silicic anhydride, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene gellicol, cyclodextrin or hydroxypropylcyclodextrin.

Dosage forms formulated as a mixture with these additives include solid preparations such as tablets, capsules, granules, powders or suppositories, or liquid preparations such as syrups, elixirs or injections. These can be prepared according to conventional methods in the pharmaceutical field.

In addition, in the case of liquid preparations, they may be dissolved or suspended in water or other appropriate medium, and especially in the case of injections, they may be dissolved in physiological saline or glucose solution as necessary. Alternatively, it may be suspended, and a buffer or preservative may be added.

These formulations contain the compounds of this invention at a total dosage of 1.0 to 10
It can be contained in a proportion of 0% by weight, preferably 1.0 to 60% by weight. These formulations may also contain other therapeutically effective compounds.

When the compound of the present invention is used as an antihyperlipidemic agent, an antiarteriosclerotic agent, or an antihypercholesterolemic agent, the dosage and frequency of administration should be determined depending on the patient's sex, age, weight, severity of symptoms, and so on. Although it varies depending on the type and scope of the desired therapeutic effect, in general, in the case of oral administration, the dose is 0.01 to 0.01 per day for adults.
It is preferable to administer 201 g/kg in one to several doses, and in the case of parenteral administration, 0.001 to 2 mg/kg@1 to several doses.

The present invention will be described in more detail below with reference to Examples and Reference Examples, but the present invention is not limited to these Examples.

(Left below) Suspend 2-hydroxymethyl-4-(3-thienyl)thiophene loomg in 5iQ of chloroform, stir with water cooling, add 2μQ of dimethylformamide and 80% thionyl chloride.
Add μQ and stir for 30 minutes. Neutralize with excess saturated aqueous sodium bicarbonate solution under water cooling, separate the organic layer, wash with saline, and dry over anhydrous magnesium sulfate. After the drying agent is filtered off, chloroform is distilled off to obtain 2-chloromethyl-4-(3-thienyl)thiophene as a pale yellow powder.

Dimethylformamide solution 3+aff of the chloromethyl compound obtained above was mixed with 16511 g of (E)-N-(6,6-dimethyl-2=hepten-4-ynyl)-N-ethyl-3-hydroxybenzylamine in anhydrous tetrahydrofuran. It was added to a phenolate solution prepared by dissolving in 3IIQ, adding 26 mg of 60% oily sodium hydride under stirring under water cooling, and stirring for 10 minutes. After stirring at room temperature for 3 hours, 20% of water was added.
Extract by adding mΩ and 30 mQ of ethyl acetate. After the organic layer is separated, it is washed with brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue was subjected to medium pressure liquid chromatography [column: Lobar column, 5
izeB, Lichroprep St 60F (manufactured by Merck & Co., Ltd.), elution solvent: hexane l ethyl acetate = 207
1-10/1) and recrystallized from methanol to give 179 mg of the free base of the title compound (yield 78%).
, a+, p, 68-69°C) are obtained as white needles. After treatment of the above free base with a hydrogen chloride-methanol solution, recrystallization from ethyl acetate yields the title hydrochloride salt, amount, p.
, 128-129°C.

(E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-( obtained in Example 1 above)
Dissolve 100 μ of 4-(3-thienyl)-2-thienylmethyloxy]benzylamine in 1 mfl of methylene chloride, add 1 wQ of a solution of 26 μ of maleic acid in methylene chloride, evaporate the solvent, and recrystallize from ethyl ether. Then, the title maleic hydrochloride 115B (yield 90%), m, p, 1
00-102°C is obtained.

1179.786 NMR (CDC1,) δ: 1.25 (90, s), 1.
34-1.41 (30,s), 2.90-3.05 (2
1 (, l1l), 3.45-3.60 (2H, +a),
4.00-4.08 (2H.

m), 5.35 (2H, s), 5.78 (IH, dt,
J=15.9Hz, 2.1)1z).

6.18 (IH, dt, J=15.9Hz, 6.9Hz
), 7.00-7.10 (2H.

■), 7.15-7.40 (5H, i), 7.49-7
．． 65 (2H, 5) 1266.1185.786 NMR (CDC1,) δ: 1.26 (9H, s), 1.
30 (38,t, J=4.1)Iz).

3.02 (2H, q, J = 4.1Hz), 3.62 (2
H, br, s), 4.09 (2B.

s), 5.23 (2H, s), 5.82 (IH, d, J
=15.6Hz), 5.95(1B, dt, J=15
．． 6Hz, 7.3Hz), 6.99 (LH, d, J=7
．． 5Hz), 7.25 (IH, dd, J=7.5Hz,
2.1Hz), 7.12-7.16 (IH, m), 7
．． 29-7.39 (6Fl, m) (E) of Example 1 above
-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-hydroxybenzylamine was replaced with various corresponding 3-hydroxybenzylamine derivatives, and the rest was as in Example 1. A similar reaction is carried out to obtain the compounds of Examples 3-7.

1026.783 NMR (CDCI, ) δ: 1.24 (9H, s), 1
．． 60 (38,s), 3.04 (2H.

dd, J=6.6)1z, 1.5Hz), 3.47(2
H,s), 5.22(2H,s).

5.65 (IH, dt, J=15.9Hz, 1.5Hz
), 6.01 (IH, dt, J=15.9Hz, 6.6
Hz), 6.85-6.94 (2H, m), 6.99-
7.01(18,i), 7.23(1)1. 7.
8Hz), 7.29-7.36 (5H, l11) Kanpeiken ± 1-propyl-3-(4-(3-thienyl)-2-thienylmethyl83 River (CDCI, ) δ: 0.86 (3H, t, J=7.
3Hz), 1.24 (9H, s).

1.46-1.52 (2H, m), 2.36-2.40
(21, m), 3.07 (2H.

dd, J”6.3Hz peak 4Hz), 3.53(2H,s
), 5.21 (20,s).

5.63 (IH, dt, J=15.9Hz, 1.4Hz
), 6.06 (IH, dt, J: 15.9Hz, 6.3
Hz), 6.86 (ddd, IH, J=7.8Hz, 2
．． 6Hz.

0.9Hz), 6.93(l)1. d, J=7.8Hz
), 7.01-7.03 (IH.

m), 7.21 (IH, t, J=7.8Hz), 7.2
8-7.35 (5H, m) Madadan 1074.1023.783 NNR (CDCI, ) δ: 1.46 (6H, s), 2
．． 20 (3H, s), 3.06 (2H.

dd, J=7.8Hz, 1.5Hz), 3.35 (3H
, s), 3.48 (2H, s).

5.22 (2H, S), 5.69 (IH, dt, J=1
5.8Hz, 1.5Hz).

6.18 (IH, dt, J'15.8Hz, 7.8Hz
), 6.87-6.94 (2H.

m), 6.99-7.01 (IH, m), 7.21-7
．． 36 (6H, +a) Raikigo and 1074.1032,837,783 NMR (CDCI, ) δ: 1.04 (3H, t, J=
7. IHz), 1.46 (6H, S).

2.50 (2H, q, J = 7.1Hz), 3.10 (2
H, dd, J = 6.4Hz.

1.4Hz), 3.35 (3H, s), 3.54 (2H
, s), 5.22 (2H, s).

5.69 (IH, dt, J=15.8Hz, 1.4Hz
), 6.16 (IH, dt, J=15.8Hz, 6.4
Hz), 6.86 (IH, ddd, J=7.4Hz, 2
．． 7Hz.

1.0Hz), 6.93 (IH, d, J=7.9Hz)
, 7.00-7.10 (IH.

s), 7.23 (IH, t, J=7.9Hz), 7.2
9 (IH, dd, J=4.6Hz.

1.3Hz), 7.33-7.39 (4H9Il) 1032.783 NMR (CDC1,) δ: 0,87 (3) 1. t, J=
7.3Hz), 1.39-1.58 (28゜),
2.38 (28,t, J=7.3Hz), 3.09 (2
H, dd, J = 6.4Hz.

1.41(z), 3.35(3H,s), 3.54(2
H,s), 5.22(2H,s).

5.68<18. dt, J=15.9) 1z, 1.4H
z), 6.16 (IH, dt, J=15.9Hz, 6.
4Hz), 6.87 (IH, dd, J=7.9Hz, 2
．． 9Hz).

6.93 (IH, d, J=7.9Hz), 7.00-7
．． 03 (IH, m), 7.22 (IH, t, J = 7.9
Hz), 7.30 (IH, dd, J=4.5Hz, 1.
4Hz).

7.32-7.36 (4H, a) (The following is a blank space) Reference examples are described below to explain the general synthesis method of the raw material compounds used in the above examples.

Reference Example 3 - Hydroxybenzaldehyde lo, Og and 9.55 g of 40% methylamine-methanol solution were mixed, and then the solvent was distilled off. The resulting Schiff base was dissolved in 50 ml of ethanol.
Sodium borohydride 1 is dissolved in Q and stirred with water cooling.
After adding 0.0 g, stir at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate and saturated brine. After separating the organic layer, it was dried over anhydrous sodium sulfate, and then the solvent was distilled off, and the residue was purified by silica gel column chromatography [Lugu Gel C-100. −
3-hydroxybenzylamine 8.88g (yield 79%)
pale yellow crystals, m. p. 138-140°C.

8.88 g of the N-methylamine compound obtained above and tS. of potassium carbonate. Og to dimethylformamide 30IIIQ
in addition to 1-bromo-6,6-dimethyl- under stirring at room temperature.
A dimethylformamide solution (10 m
After the reaction is complete, the solvent is distilled off, and the residue is extracted with a system of ethyl acetate and saturated brine.

After separating the organic layer, it is dried over anhydrous magnesium sulfate, the desiccant is filtered off, the solvent is distilled off, and the residue is purified by silica gel column chromatography [Woccogel C-200, 300 10/1]. 7.94 g of the title compound as yellow crystals (total yield 39%), ta. p, 7ro1 77
℃ is obtained.

A methanol solution of ethylamine or propylamine is used in place of the raw material methylamine-methanol solution, and if necessary, 1-bromo-6,6-dimethyl-2-hepten-4-yne is replaced with 1-bromo-6,6-dimethyl-2-hepten-4-yne. 6-methoxy-
When the same reaction as in Reference Example 1 above was carried out using 6-methyl-2-hepten-4-yne, (E)-N-(6.

6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-hydroxybenzylamine, (E)-N-(6
, 6-dimethyl-2-hepten-4-ynyl)-N-
Propyl-3-hydroxybenzylamine or (E)-
The 3-hydroxybenzylamine derivatives used in Examples 1 to 7, such as N-ethyl-N-(6-methoxy-6-methyl-2-hepten-4-ynyl)-3-hydroxybenzylamine, are obtained.

Effects of the Invention The compounds of the present invention inhibit cholesterol biosynthesis and lower blood cholesterol levels by inhibiting squalene epoxidase in mammals. Therefore, it can be expected to be effective as a therapeutic and preventive agent for diseases caused by excess cholesterol, such as obesity, hyperlipidemia, arteriosclerosis, and associated heart and brain diseases.

Procedural amendment (voluntary) December 5, 1999

Claims (5)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [I] [In the formula, R^1 represents a methyl group, ethyl group, or propyl group, and R^2 represents a methyl group or methoxy group] A substituted allylamine derivative or a non-toxic salt thereof. (2) (E) -N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-[4-(3-thienyl)-2-thienylmethyloxy]benzylamine, (
E) -N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-[4-(3-thienyl)-2
-thienylmethyloxy]benzylamine, (E)-N
-(6,6-dimethyl-2-hepten-4-ynyl)-
N-propyl-3-[4-(3-thienyl)-2-thienylmethyloxy]benzylamine, (E)-N-(6
-methoxy-6-methyl-2-hepten-4-ynyl)
-N-methyl-3-[4-(3-thienyl)-2-thienylmethyloxy]benzylamine, (E)-N-ethyl-N-(6-methoxy-6-methyl-2-heptene-
4-ynyl)-3-[4-(3-thienyl)-2-thienylmethyloxy]benzylamine or (E)-N
-(6-methoxy-6-methyl-2-hepten-4-ynyl)-N-propyl-3-[4-(3-thienyl)-
2-Thienylmethyloxy]benzylamine or a non-toxic salt thereof. (3) A hypercholesterolemia treatment agent containing the substituted allylamine derivative represented by the general formula [I] or a nontoxic salt thereof according to claim 1. (4) A hyperlipidemia treatment agent containing a substituted allylamine derivative represented by the general formula [I] or a nontoxic salt thereof according to the first claim. (5) An agent for treating arteriosclerosis containing the substituted allylamine derivative represented by the general formula [I] or a non-toxic salt thereof according to claim 1.