JPH03287584A - Substituted allylamine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (A<1> and A<2> are methine, N, O or S; Q<1> and Q<2> are group to form 5- or 6-membered aromatic ring together with adjacent C, A<1> and A<2> wherein said ring may contain one or two hetero atoms selected from N, O and S; X and Y are O, S, carbonyl, etc.; n is 3-5; R<1> is 5- or 6-membered hetero-ring containing 1-4 hetero atoms; R<2> and R<3> are H, halogen, etc.; R<4> and R<5> are lower alkyl, etc.; R<6> is H or lower alkyl; R<7> and R<8> are H, halogen, etc.). EXAMPLE:(E)-1-(6,6-dimethyl-2-hepten-4-ynyl)-2-[3-[3-(3-thienyl)- benzyloxyloxy]phenyl]piperidine. USE:Agent for depressing blood cholesterol level. PREPARATION:A cycloamine derivative of formula II is made to react with an enyne derivative having eliminable group of formula III in the presence of a base (e.g. sodium hydride) in a solvent (e.g. benzene) at 0-150 deg.C for 1-24hr.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel substituted allylamine derivatives, more particularly in the field of medicine, particularly in the field of mammalian squalene.
The present invention relates to substituted allylamine derivatives and salts thereof, which selectively inhibit epoxidase and are useful in the fields of treatment and prevention of hypercholesterolemia, hyperlipidemia, and arteriosclerosis, and uses thereof.

In recent years, due to the aging of the population and changes in dietary habits, it has been pointed out that the frequency of occurrence of arteriosclerosis and associated overturning and cerebral artery disease has increased. Although various factors are thought to be responsible for the occurrence of arteriosclerosis, an increase in blood cholesterol is said to be one of the most important risk factors. In fact, blood cholesterol lowering agents with various mechanisms of action have been developed, and some of them are being applied clinically [Agents Used-to-Treat Hyperlibidemia, Drug Evaluator]. Agents Sixth Edition (AgentsUs)
ed to Treat Hyperlipid
emia, Drug Evaluations 6th
edition), 903-926 (1986)]
.

Among these blood cholesterol-lowering agents, inhibitors of in vivo cholesterol biosynthesis are highly evaluated for their clear mechanism of action and sharpness [Proceedings of the National Academy of Sciences].・Science (Proc, Natl, Acad, Sci,), 3957 (1980)]. However, currently known cholesterol biosynthesis inhibitors are inhibitors of the early stage and late stage of the cholesterol biosynthesis process, so they simultaneously inhibit cholesterol biosynthesis and produce various other physiologically important biological products. However, there are problems in that the accumulation of precursors caused by inhibition may cause other diseases.

The present inventors previously demonstrated that a series of substituted allylamine derivatives selectively inhibited squalene epoxidase, which is located in the middle stage of the cholesterol biosynthesis system in mammals, and as a result, they were found to be different from existing cholesterol biosynthesis inhibitors. It was reported that it is useful as a new blood cholesterol-lowering agent with a different mechanism of action [Japanese Patent Application No. 63-296840, European Patent Publication No. 318860].

Regarding mammalian squalene epoxidase inhibitors, there have been several recent reports in addition to those reported by the present inventors, but the activity of all of the described compounds is extremely low [Journal of・Chemical Research Shipses (J.

Chem, Re5search (S)), 18-1
9 (1988); Journal of American
Chemical Society (J, Am, Chem, Soc
), 111.1508-1510 (1989); Journal of Medicinal Chemistry (J,M
ed, Chem,), 32.2152-2158 (19
89); JP-A-64-3144].

The main purpose of the present invention is to treat hypercholesterolemia, which is safer than existing cholesterol biosynthesis inhibitors and has an excellent blood cholesterol lowering effect.
The object of the present invention is to provide a therapeutic and preventive agent for hyperlipidemia and arteriosclerosis.

・ The present inventors previously reported that a series of substituted allylamine derivatives selectively inhibit squalene epoxidase in mammals and, in addition, have a strong blood cholesterol-lowering effect [ Japanese Patent Application No. 63-296840, European Patent Publication No. 318860]. As a result of further intensive research, we have discovered that the substituted allylamine derivative represented by the following formula [I] has even superior medicinal efficacy and safety compared to the previously reported compound group. Completed the invention. That is, the present invention relates to the general formula [where A1 and At are the same or different and represent a methine group, a nitrogen atom, an oxygen atom, or a sulfur atom; Ql and Q2 are the same or different and represent a nitrogen atom, an oxygen atom, and a sulfur atom; may contain one or two heteroatoms selected from the group consisting of atoms, and adjacent carbon atoms and A1 or A2
represents a group that forms a 5- or 6-membered aromatic ring with X and Y, which may be the same or true, and each represents an oxygen atom,
A sulfur atom, a carbonyl group, the formula CHR”- (where,
R1 represents a hydrogen atom or a lower alkyl group) or a group represented by the formula NR''- (where Rh represents a hydrogen atom or a lower alkyl group), or
and Y together represent a vinylene group or an ethynylene group; n represents an integer of 3 to 5, and R1 represents 1 to 4 atoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms. Represents a 5- or 6-membered heterocyclic group containing a terror atom; R2 and R3 represent a hydrogen atom, a halogen atom, or a lower alkyl group; R4 and R6 are the same or different and represent a lower alkyl group, or both indicates a group that is bonded to form a cycloalkane with adjacent carbon atoms,
Re represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, R7 and R1 are the same or different and are a hydrogen atom,
Indicates a halogen atom, hydroxyl group, cyano group, lower alkyl group, or lower alkoxy group. However, either one of X and Y is an oxygen atom, a sulfur atom, or a compound of the formula NR'- (where,
R5 has the above meaning),
The other is a carbonyl group or has the formula CHR''- (where R
Substituted allylamine derivatives and non-toxic salts thereof, and the use of these compounds in the treatment of hypercholesterolemia, hyperlipidemia and arteriosclerosis. This is what we provide.

Next, definitions of various terms mentioned in the description of this specification and specific examples thereof will be explained.

The term "lower" is used to mean that the group or compound to which this term is attached has no more than 6 carbon atoms, preferably no more than 5 carbon atoms. Therefore, examples of lower alkyl groups include methyl group, ethyl group, propyl group, isopropyl group,
Butyl group, isobutyl group, 5ec-butyl group, tgyt
- Straight chain or branched alkyl groups having 1 to 5 carbon atoms such as butyl group and pentyl group, and lower alkyl groups,
As the oxy group, preferably a methoxy group, an ethoxy group,
Examples include straight-chain or branched alkoxy groups having 1 to 4 carbon atoms, such as propoxy group, impropoxy group, butoxy group, isobutoxy group, 5ec-butoxy group, and tart-butoxy group.

Cycloalkane means a cycloalkane having 3 to 6 carbon atoms, specifically cyclopropane, cyclobutane,
Mention may be made of cyclopentane or cyclohexane. A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Next, in order to more specifically disclose the compound of the present invention represented by the above-mentioned formula [I], the various symbols used in formula [I] will be described in more detail by giving preferred specific examples thereof. explain.

Examples of the 5- or 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms represented by R1 include pyrrolyl group, furyl group, and thienyl group. group, oxasilyl group, isoxasilyl group, thiazolyl group, inthiazolyl group, imidazolyl group, pyrazolyl group, oxadiazolyl group, thiadiazolyl group, triazolyl group, tetrazolyl group, furazanyl group,
Aromatic heterocyclic groups such as pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, such as dihydrothienyl group, mitetrahydrochenyl group, pyrrolinyl group, pyrrolidinyl group, oxazolinyl group, oxazolidinyl group, isoxazolinyl group, isoxazolidinyl group, thiazolinyl group, thiazolidinyl group, isothiazolinyl group, isothiazolidinyl group, 1,2-dithiolanyl group, l,3-dithiolanyl group, l,2-dithiolyl group, 1,3-dithiolyl group, Dihydrothiopyranyl group, tetrahydrothiopyranyl group, 1,4-dithianyl group, 1
．． Non-aromatic heterocyclic groups such as 4-furazanyl group, 1,4-oxathiinyl group or thiomorpholinyl group, etc.
Among these, thienyl group, pyrrolyl group, oxasilyl group, inoxasilyl group, thiazolyl group, isothiazolyl group,
An imidazolyl group, a pyridyl group, a dihydrothienyl group, etc. are preferred, and particularly a 3-thienyl group, a 1-pyrrolyl group, a 5-oxasilyl group, a 4-isoxasilyl group,
5-isoxasilyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 3-pyridyl group, 2.3-
Dihydro-4-thienyl group, 2,5-dihydro-3-thienyl group, etc. are preferred.

As described above, X and Y may be the same or different, and each is an oxygen atom, a sulfur atom, a carbonyl group, or a compound of the formula CHR'- (where R1 represents a hydrogen atom or a lower alkyl group). The group represented or the formula NR''- (wherein,
Rh represents a hydrogen atom or a lower alkyl group), or X and Y together represent a vinylene group or ethynylene group, provided that either X or Y is an oxygen atom, When a sulfur atom or a group of the formula NR'- is represented, the other is a carbonyl group or a group of the formula CH
The group represented by R''- is represented by the group represented by the formula xy-, specifically, the group represented by the formula ny (CHR'')*-,
-CHR"O-, -0CHR"-, -CHR"S-.

-5CHR'-, -CHR@NR"-, -NRIICH
R''-, -CHR'CO-.

-COCHR'-, -Coo-, -0CO-, -COS
-, -3CO-.

-CONR''-, -NR''CO-, -CH=CH-, -
means a group represented by c*c- (wherein R1 and R1' have the above-mentioned meanings), and among these, in particular, an ethylene group, (E)-vinylene group or a group of the formula niCH,O- A group represented by the formula OCHg-, a group represented by the formula OCHg-, a group represented by the formula OCH,S-
A group represented by the formula 5CHa-, a group represented by the formula CH, NH-, or a group represented by the formula 'NHCH1
A group represented by is preferred.

R2 and R3 represent a hydrogen atom, a halogen atom, or a lower alkyl group, and preferred halogen atoms include, for example, fluorine or chlorine atoms, and preferred lower alkyl groups include, for example, methyl, ethyl, and propyl. and straight-chain or branched lower alkyl groups having 1 to 3 carbon atoms such as isopropyl group and isopropyl group.

R4 and Rs are the same or different and represent a lower alkyl group, or a group in which both are bonded together to form a cycloalkane with adjacent carbon atoms, and preferred lower alkyl groups include, for example, methyl group, ethyl group, Examples include linear lower alkyl groups having 1 to 4 carbon atoms such as propyl or butyl groups, and preferred cycloalkanes include 3 carbon atoms such as cyclopropane, cyclobutane, cyclopentane or cyclohexane. ~6 cycloalkanes may be mentioned. Among these, especially
Substituents for R6 and R@ include methyl group, ethyl group,
A probyl group or a group forming a cyclopropane ring together with adjacent carbon atoms is preferred, and a methyl group is most preferred.

R6 represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group, and preferred lower alkyl groups include, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a 5ec-butyl group, and a -monobutyl group. or a linear or branched lower alkyl group having 1 to 5 carbon atoms such as a pentyl group, and preferred lower alkoxy groups include a methoxy group, an ethoxy group, a propoxy group, an inpropoxy group, a butoxy group. , imbutoxy group, 5ec-butoxy group or -1-butoxy group, etc. having 1 carbon number
5 to 4 linear or branched alkoxy groups. Among these, in particular, methyl group, ethyl group, propyl group,
Isopropyl, methoxy, ethoxy, propoxy or isopropoxy groups are preferred, and methyl, ethyl, methoxy or ethoxy groups are most preferred.

Examples of the ring include the same or different benzene ring, pyrrole ring, furan ring, thiophene ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, 1,3.4-oxadiazole ring, 1 ,3.
4-Thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, etc., one or more selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom
Preference is given to aromatic rings which may contain 3 heteroatoms, with particular preference given to this ring or the thiophene ring.

Further, the aromatic ring is usually most preferably unsubstituted, but in some cases, it may be substituted with a substituent such as a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, or a lower alkoxy group. Examples include a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a methoxy group, and the like.

Thus, in the compound provided by the present invention, preferred examples include R' being a pyrrolyl group, a furyl group, a thienyl group, an oxasilyl group, an isoxasilyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a pyrazolyl group, an oxadiazolyl group. group, thiadiazolyl group, triazolyl group, tetrazolyl group, furazanyl group, pyridyl group,
Pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, dihydrothienyl group, tetrahydrothienyl group, pyrrolinyl group, pyrrolidinyl group, oxazolinyl group, oxazolidinyl group, isoxazolinyl group, isoxazolidinyl group, thiazolinyl group, thiazolidinyl group , inthiazolinyl group, isothiazolidinyl group, 1.
2-dithiolanyl group, 1.3-dithiolanyl group, 1.2
-dithiolyl group, 1,3-dithiolyl group, dihydrothiopyranyl group, tetrahydrothiopyranyl group, 1,4-dithianyl group, 1,4-dithianyl group, 1,4-oxathiinyl group or thiomorpholinyl group Yes: or 6-membered aromatic rings are the same or different, such as benzene ring, pyrrole ring, furan ring, thiophene ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring,
imidazole ring, 1,3.4-oxadiazole ring, 1
, 3.4-thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring or triazine ring; X and Y may be the same or different, and each represents an oxygen atom, a sulfur atom, a carbonyl group, a A group represented by CHR'- (where Ra represents a hydrogen atom or a lower alkyl group) or a group represented by the formula NR''- (where R8 represents a hydrogen atom or a lower alkyl group). or both X and Y are a vinylene group or an ethynylene group [provided that either X and Y is an oxygen atom, a sulfur atom, or a group of the formula NR'- (where R is the above-mentioned the other is a carbonyl group or a group of the formula CHR''-, where R1 has the meaning given above; is a hydrogen atom, a halogen atom, or a lower alkyl group; R4 and R1 are the same or different and are lower alkyl groups, or a group where both combine to form a cycloalkane with adjacent carbon atoms, and R6 is Is a hydrogen atom, lower alkyl group or lower alkoxy group; R? and substituted allylamine derivatives of formula [I] above, wherein R1 is the same or different and is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group or a lower alkoxy group, and the aromatic ring is a benzene ring or A thiophene ring is preferred, and more preferably R1 is a thienyl group, a pyrrolyl group, an oxasilyl group, an isoxasilyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a pyridyl group, or a dihydrothienyl group; Benzene ring, pyrrole ring, furan ring, thiophene ring, oxazole ring, isoxazole ring, thiazole ring, inthiazole ring, imidazole ring, 1,3.4-oxadiazole ring, 1,3
．． 4-thiadiazole ring, pyridine ring, pyridazine ring,
Those which are a pyrimidine ring, a pyrazine ring or a triazine ring are preferable, and among these, in particular, R1 is a 3-thienyl group,
l-pyrrolyl group, 5-oxasilyl group, 4-isoxasilyl group, 5-isoxasilyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-inchazolyl group, 5-isothiazolyl group, 3 - The aromatic ring represented by a pyridyl group, 2,3-dihydro-4-thienyl group, or 2,5-dihydro is a benzene ring or a thiophene ring, and a dofuran ring, a thiophene ring, an oxazole ring, an isoxazole ring, a thiazole ring, an iso Thiazole ring, 1,3
．． A 4-oxadiazole ring, a 1,3,4-thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring or a pyrazine ring is preferred.

More preferable compound groups include R1 being a 3-thienyl group, 1-pyrrolyl group, 5-oxasilyl group, 4-isoxasilyl group, 5-isoxasilyl group, 4-thiazolyl group, 5-thiazolyl group, 3- Isothiazolyl group, 4-
isothiazolyl group, 5-inchazolyl group, 3-pyridyl group, 2.3-dihydro-4-thienyl group or 2.5-
is a dihydro-3-thienyl group: X is a methylene group; Y is a methylene group, an oxygen atom, a sulfur atom, or an imino group, or Y is a methylene group; X is a methylene group, an oxygen atom, a sulfur atom or an imino group, or the aromatic ring in which both X and Y are combined is a benzene ring or a thiophene ring, and h'' ran ring, thiophene ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring. ring, 1.3.4
-Oxadiazole ring, 1,3.4-thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring or pyrazine ring, and R2 and R3 are a hydrogen atom, a halogen atom, or a lower alkyl group having 1 to 3 carbon atoms and: R4 and R5 are the same or different lower alkyl groups having 1 to 4 carbon atoms, or both are bonded together to form a cycloalkane with adjacent carbon atoms; R7 is hydrogen atom, a lower alkyl group having 1 to 5 carbon atoms, or a lower alkoxy group having 1 to 4 carbon atoms: R7 and R8 are the same or different, and are a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, or a lower alkyl group having 1 to 4 carbon atoms; It is a compound that is a lower alkyl group having 1 to 3 carbon atoms or a lower alkoxy group having 1 to 3 carbon atoms. Among these, R1 is particularly 3-thienyl group, l-pyrrolyl group, 5-oxasilyl group, 4-isoxasilyl group, 5-
isoxasilyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group,
The aromatic ring formed by a 5-isothiazolyl group, 3-pyridyl group, 2,3-dihydro-4-thienyl group, or 2,5-dihydro-3-thienyl group is a benzene ring, a furan ring, a thiophene ring,
Oxazole ring, isoxazole ring, thiazole ring,
isothiazole ring, 1,3.4-oxadiazole ring,
1,3.4-thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring or pyrazine ring; R1 and R
Compounds in which 3 is a hydrogen atom, a fluorine atom, or a methyl group; R4 and R6 are a methyl group; R4 is a methyl group, an ethyl group, a methoxy group, or an ethoxy group; and R' and R1 are hydrogen atoms are preferred. .

The substituted allylamine derivative of formula [I] can exist in the form of an acid addition salt, such as hydrochloride, hydrobromide, hydroiodide, sulfate, etc. , nitrates, perchlorates or phosphates; or e.g. p-toluenesulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate, tartrate, citric acid. salts, organic acid salts such as fumarates or maleates, and pharmaceutically acceptable non-toxic salts are particularly preferred. Moreover, the formula [I] of the present invention
Depending on the aspect of the substituent, the compound may have geometric isomerism,
Although stereoisomers such as diastereoisomerism or optical isomerism may exist, the present invention also includes all these stereoisomers.

Next, a general method for producing the compound according to the present invention will be explained.

The compound of formula [I] of the present invention can be produced, for example, using either of the following production methods A or B.

[Production method A] [In the formula, L represents a leaving group; A\A2, Q', Q'',
X.

Y, R'SR", R3, R', R5, R1, R7, R
8 and n have the above-mentioned meanings] A cyclic amine derivative represented by the general formula [II] and the general formula [
The condensation reaction with an enyne derivative having a leaving group represented by I[I] is an alkylation reaction of secondary amines well known in the field of organic synthetic chemistry, and is usually a reaction between compound [R1 and compound [1]. [[]] in a suitable solvent, preferably in the presence of a base. Suitable solvents that can be used in this case include solvents that do not adversely affect the reaction, such as aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as ethyl ether, tetrahydrofuran or dioxane; such as methylene chloride,
Halogenated hydrocarbons such as chloroform or dichloroethane; Alcohols such as ethanol or isopropanol; Aprotic polar solvents such as dimethylformamide, acetonitrile, dimethyl sulfoxide;
or a mixture thereof: or a mixture thereof with water, and is usually carried out by reacting Compound [I]] and Compound [I][] in equimolar ratios or in a slight excess of either one. The reaction conditions adopted at this time are:
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 to 24 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 used is generally equimolar or in excess, preferably 1 to 2 moles, relative to each raw material compound.

In addition, in the above manufacturing method, the formula [I
In the compound of [I], apart from the amino group participating in the reaction,
When reactive functional groups such as hydroxyl groups or amino groups are present, the reaction can be carried out after appropriately protecting these reactive functional groups, if necessary, and these protective groups can be removed after the reaction. Protective groups used in this case include those that are easily eliminated by hydrolysis under acidic or alkaline conditions, such as methoxymethyl group, tetrahydropyranyl group, trityl group, dimethyl(tert-butyl)silyl group, formyl group, etc. group, acetyl group, methoxycarbonyl group, ethoxycarbonyl group, or tert-butoxycarbonyl group.

[Production method B] [In the formula, x' is a group represented by the formula CHR"Z'C, where Zl represents a leaving group and R" has the above meaning] or a group represented by the formula COZ"-( In the formula, τ represents a leaving group), and Yl is an optionally protected hydroxyl group, mercapto group, or a group of the formula NR'- (wherein, R1 has the above meaning) Xl represents a group represented by the formula CHR''- (wherein R has the meaning described above) or a carbonyl group; r represents an oxygen atom, a sulfur atom, or a carbonyl group '- (in the formula, R' has the above meaning); A1, A2, Ql, Q'',
R', R'', R3, R4, R1, R6, R', R1
, n and L have the above-mentioned meanings] Production method B comprises - in the compound of the present invention represented by the formula [I],
X is a group represented by the formula CHR"- (wherein R" has the above meaning) or a carbonyl group, and Y is an oxygen atom, a sulfur atom, or a carbonyl group represented by the formula NR'- (wherein R' is a method for producing a compound having the above-mentioned meaning.

This production method uses a cyclic secondary amine compound [TV] and a compound [I
After condensing [I], removing the protecting group as necessary,
This is then carried out by reacting compound [VI]. The reaction between compound [rV] and compound [ml is the same as the alkylation reaction of secondary amine in production method A,
Therefore, the reaction can be suitably carried out under the same reaction conditions as those described in Production Method A. Moreover, the compound [IV
] Examples of the protecting group include methoxymethyl group,
Tetrahydrobi-ranyl group, trityl group, dimethyl (t
Examples include a tert-butyl)silyl group, a formyl group, an acetyl group, and a tert-butoxycarbonyl group.

Next, compound [V] produced by the condensation of compound [IV] and compound [I][] is deprotected as necessary, and then reacted with compound [VI], which is usually carried out using a solvent that does not participate in the reaction. Among these, it can be carried out preferably in the presence of a base. The solvent used at this time is appropriately selected depending on the type of raw material compound to be reacted, and examples include benzene,
Preferable solvents include toluene, ethyl ether, tetrahydrofuran, methylene chloride, chloroform, dimethylformamide, acetonitrile, dimethyl sulfoxide, and mixtures of these solvents. In addition, the raw material compounds [V] and [VI
] is usually used in equimolar amounts or the compound [V
I] is preferably used in slight excess. The reaction temperature and reaction time are usually appropriately selected from a wide range of -70° C. to 150° C. and 5 minutes to 10 days depending on the reaction species.

The target compound of the present invention obtained in the above steps can be isolated and purified by, for example, column chromatography, solvent extraction, recrystallization, etc. alone or in an appropriate combination. Furthermore, if necessary, the free base of the compound of the present invention represented by formula [1] can be converted into its acid addition salt, or vice versa. The step of converting the free base of the compound of formula [I] 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. can be done.

Note that the leaving group represented by L and Zl includes, for example, a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom, or an organic sulfonyloxy group such as a methanesulfonyloxy group or a p-toluenesulfonyloxy group. . Examples of the leaving group represented by T include groups that form activated derivatives of carboxylic acids, such as chlorine atom, bromine atom, ethoxycarbonyloxy group, and benzotriazol-1-yloxy group.

Raw material compound [II
] and [IV] are general formulas or -mathematical formulas [wherein, A1, A, Ql, (pSxSy1y', R1
, R and R have the above-mentioned meanings] is reacted with 1,3-dimercaptopropane in the presence of an acid catalyst (e.g. trifluoroborane etherate) to form a thioacetal, Formula: L'-(C
HI), -L" (wherein L' and Lz are the same or different and represent a leaving group, and n has the above meaning) with a strong base (for example, butyllithium or diisopropylaminolithium). (e.g., lithium hydride or sodium hydride) to form a compound of the general formula or -Formula 1 [wherein A'SA'', Ql, Q2, L2,X5YSY'
SR', R7, R8 and n have the abovementioned meanings] is obtained. Furthermore, these compounds are reacted with sodium azide to form an azide compound, and then reacted with N-bromosuccinimide (NBS) in aqueous acetone to form a ketone body, and then reacted with triphenylphosphine to form the general formula or -numerical formula [ In the formula, A', A", Q', Q", X, Y, Y',
R', R7, R number and n have the above-mentioned meanings] can be obtained. Next, if these compounds are reduced using a reducing agent such as sodium borohydride or lithium aluminum hydride, the compound [R
1 and compound [fV] are obtained.

In addition, compound [■] and compound [■] are
96840, European Patent Publication No. 318860, or Japanese Patent Application No. 1-291008, or a method similar thereto, Compound [I] 11 can be produced by the method described in the literature [Journal of Medicinal Application No. Chemistry (J, Med, Chem,) Volume 27, No. 15
39 pages (1984): JP-A-57-123177]
Alternatively, it can be manufactured by a similar method.

The products obtained in each of the above steps can be isolated and purified, for example, by column chromatography, solvent extraction, or recrystallization alone or in an appropriate combination.

The compound of the present invention represented by the general formula [I] extremely selectively and strongly inhibits squalene epoxidase in mammals, and is 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 point, a test example will be given and explained below.

Test Examples Squalene Epoxidase (1) Preparation of Squalene Epoxidase Human squalene epoxidase was prepared in the Journal of Biological Chemistry (J, Biol.

Chem,) Volume 245, Page 1670 (197
250, p. 1572 (1975)
Prepare according to the method described in .

That is, 5 human Hep-G2 cells were
% carbon dioxide mixed air at 37°C. After the culture is completed, the cells are scraped and collected by centrifugation.

Homogenize 0.1M Tris-H (suspended in J buffer (pH 7,5) 1X 1O'ce11/m/),
Centrifuge at 9750Xg for 10 minutes and then centrifuge the pellet at 0.
After washing with 1M Tris-H (J buffer (pH 7,5), centrifugation is carried out at 1105000X for 1 hour. The obtained microsomes are washed with 0.1M Tris-H (J buffer) so that the protein amount is 20 mct/rnl. liquid (pH 7,
5) and solubilized by stirring in the presence of 1% Triton X-100 while cooling with water. After this solubilization treatment, 1mM E
DTA and 1mM dithiothreitol tritritriX-1
Dilute the 00 concentration to 0.125% and centrifuge at 1105000X for 1 hour. The obtained supernatant is used as a squalene epoxidase fraction in the test described below.

(2) Measuring method of squalene epoxidase activity The measurement of human squalene epoxidase activity is described in the Journal of Biological Chemistry (J, Bio
Chem, Volume 245, Page 1670 (197
This is done according to the method described in Year 0).

That is, 0.2 m of the squalene epoxidase fraction prepared in (1)/[protein amount 0.4 mg, 0.1% Triton X-100, 20, uM Tris-HC7 buffer (pH 7,5)], 100μM FAD, 1mM N
A dimethyl sulfoxide solution 34 of the test drug was added to a solution consisting of a suspension of ADPH, 1mM EDTA and 8μM H-squalene-Tweeter 80, and the total volume was adjusted to 0.3m/ml.
Then, shake and react at 37°C for 60 minutes. The reaction is stopped by adding 0.3 rrLl of 10% potassium hydroxide-methanol solution and heated at 75°C for 1 hour. Next, unsaponifiable substances are 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 Silicagel T.
Spotted on LC, benzene-ethyl acetate (99,5:
0.5). The position of the generated 3H-squalene-2,3-epoxide on TLC is confirmed using ergosterol acetate as a marker, and the 3H-squalene-2,3-epoxide portion of the TLC is cut out. The TLC piece is immersed in a toluene scintillator and measured using a liquid scintillation counter. This results in
5 of the compounds of the present invention against squalene epoxidase
The 0% inhibitory concentration (IC, value) was determined and the results are shown in the following table.

Table Human Squalene Epoxidase Inhibitory Effect As is clear from the above results, the compounds of the present invention
Because it strongly inhibits epoxidase and inhibits cholesterol biosynthesis, it is effective against various diseases caused by the enhancement of cholesterol biosynthesis, such as obesity, hyperlipidemia, and arteriosclerosis. Effective for treatment and prevention. 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 [1] 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 arteriosclerosis. It can be used for the treatment and improvement of diseases, etc. When using the compound of the present invention clinically, it is also possible to prepare various formulations by adding pharmaceutically acceptable additives according to the dosage form, and then administer the compound. 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 glycol, cyclodextrin or hydroxypropyl cyclodextrin.

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 a liquid preparation, it may be dissolved or suspended in water or other appropriate medium at the same time. Moreover, especially in the case of an injection, it may be dissolved or suspended in physiological saline or glucose solution, and a buffer or a preservative may be added as necessary.

These preparations contain the compound of the present invention at a total dosage of 1.0 to 100%.
It can be contained in a proportion of 1.0 to 60% 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, antiarteriosclerotic agent, or antihypercholesterolemic agent, the dosage and frequency of administration should be determined depending on the patient's sex, age, weight, severity of symptoms, and purpose. Although it varies depending on the type and scope of the therapeutic effect, in general, in the case of oral administration, the dose per day for adults is 0.01~
It is preferable to administer 20 mct/kct in one to several doses, and in the case of parenteral administration, to administer 0.001 to 2 mg/kg in one to several doses.

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

Example 1 10 mg of 3-(3-thienyl)benzyl bromide and (
E)-1-(6,6-dimethyl-2-hebuten-4-ynyl)-2-(3-hydroxyphenyl)piperidine 7
．． Dissolve 4 mg in 1.5 m/dimethylformamide,
Add 17 mg of potassium carbonate and stir at 50°C for 3 hours. The reaction solvent is distilled off, ethyl acetate and water are added to the residue for extraction, and the organic layer is separated, washed with water, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off, and the residue was subjected to medium pressure liquid chromatography [column: Lobarcol
umn, 5ize A, Lichroprep S
i 60F (manufactured by Merck & Co., Ltd.), elution solvent: hexane/
Purification with ethyl acetate=271] gives 6.8 my of the title compound (yield: 58%) as a colorless oil.

IRv'::cm-': 2968.2868.27
94.1599.1488°1446, 1383.12
63.960.771NMR (CDC1,) δ: 1
．． 22 (9H, s), 1.30-1.82 (6
H, m), 2.05 (IH, ddd, J = 6.3
Hz.

3.4Hz, 3.3Hz), 2.50 (IH, dd
, J = 14.3Hz, 7.8Hz), 3.03
(IH, dd, J = 6.3Hz.

3.4Hz), 3.09 (IH, d, J = 11.
8Hz).

3.15 (IH, ddd, J = 14.3Hz,
4.8Hz, 1.9Hz), 5.10 (2H,s),
5.50 (LH, dt, J= 15.9Hz, 1.9
Hz), 5.95 (IH, dt, J=15.9Hz,
4.8Hz), 6.86 (IH, dd, J = 8
．． 0Hz, 2.7Hz), 6.92 (IH, d, J
= 8.0Hz).

7.02 (LH, brs), 7.21 (IH, t,
J=8.0Hz), 7.40-7.50 (5H, m)
, 7.56 (IH.

dt, J = 7.8Hz, 2.0Hz), 7.70
(LH, br s) Starting compounds 3-(3-thienyl)benzyl bromide and (E) -1-(6,6-dimethyl-2-hebuten-4ynyl)-2-(3-hydroxyphenyl)piperidine 4-(3-thienyl) instead of
Example 1 was carried out in the same manner as in Example 1 except for using thenyl bromide or (E)-1-(6,6-dimethyl-2-hebuten-4-ynyl)-2-(3-hydroxyphenyl)pyrrolidine. A few compounds were obtained.

Example 2 IRv:cm-': 2968.1602,148
8.1455NMR (CDCJs) δ: 1.22
(9H, s), 1.60-2.00 (3H.

m), 2.10-2.30 (2H, m), 2.65
(LH9dd, J = 16.0Hz, 8.0Hz),
3.22-3.35 (3B, m), 5.10 (2
H, s), 5.65 (IH, dJ -15.9Hz)
, 6.00-6.12 (IH, m).

6.86 (II(, dd, J=8.0Hz, 2.5
Hz), 6.93 (IH, d, J = 8.0Hz)
7.02 (IH, brs).

7.21 (IH, t, J=7.8Hz), 7.38~
7.49 (5H, m), 7.55 (LH, dt, J=
7.8Hz, 2.0Hz), 7.68 (IH, brs
) Example 3 IRv:cm-': 2968.1602,145
8,1284.12631155.840,786,6
99 NMR<CDCb>6: 1.22 (9H, s),
1.60-1.95 (3Hm), 2.14-2.
16 (IH, m), 2.23 (LH.

dd, J = 6.3Hz, 3.6Hz), 2.51
(IH, dd.

J = 14.3Hz, 7.8Hz), 3.24~3
．． 32 (3H.

m), 5.60 (IH, dt, J = 15.9H
z, 1.9Hz).

6.05 (IH, dt, J = 15.9Hz, 7.
8Hz), 6.88 (IH, dd, J=7..9Hz
, 3.0Hz), 6.98 (IH.

d, J = 7.9Hz), 7.05 (IH, brs
), 7.23 (IH, t, J = 7.9Hz),
7.30-7.38 (5H.

m) Reference examples will be described below to explain the general synthesis method of the raw material compounds used in the above examples.

Reference example 1 3-hydroxybenzaldehyde 3. Dissolve Oy in 30 ml of the salt ichmethylene, 2.5 ml of 1,3-pro/<dithiol and 3.0 ml of boron trifluoride etherate.
and stirred at -40"C for 5 hours. The solvent was distilled off and the residue was post-treated in a conventional manner, followed by silica gel column chromatography [Fuko-gel C-200,) 09. Elution solvent: benzene/ethyl acetate. = 8/1] and recrystallized from hexane-ethyl acetate to obtain 2-(
4.5 g of 3-hydroxyphenyl)-1,3-dithiane
is obtained.

The above dithiane compound 2.0Q is dimethylformamide 1O
rrL! 4.3 g of potassium carbonate and 1.8 rrLl of methoxymethyl chloride were added, and the mixture was stirred overnight. The solvent was distilled off, the residue was post-treated by a conventional method, and then subjected to silica gel column chromatography [Wagogel CC-200sa,
Elution solvent: hexane/ethyl acetate = 20/l] to obtain 2.0 g of 2-(3-methoxymethyloxyphenyl)-1,3-dithiane as a colorless oil.

330 mg of the above methoxymethyl compound was dissolved in 60 m/ml of tetrahydrofuran, and 15% n-butyllithium-hexane solution (0.9 rIt) was prepared at -78°C. After stirring for 5 minutes, 557 mg of 1.4-dibromobutane was added at -40°C.
Add 20 ml of a tetrahydrofuran solution and stir for 1 hour.

After distilling off the solvent and post-treating the residue by a conventional method, it was subjected to silica gel column chromatography [Fuko-gel C-20
0,509, Elution solvent: hexane/ethyl acetate = 20/
If purified at 1F, colorless oily 2-(4-bromobutyl)-2-(3-methoxymethyloxyphenyl)-1
,3-dithiane 369 mg are obtained.

370 mg of the above bromine compound was dissolved in dimethylformamide 5
Sodium azide 123ry+(7
and stirred at 60'C for 1 hour. After distilling off the solvent and post-treating the residue by a conventional method, the azide compound obtained was dissolved in acetone 5R.
N-bromosuccinimide 1 and OQ were added at -5°C, and the mixture was stirred for 5 minutes. The solvent was distilled off, and the residue was purified by conventional method by silica gel column chromatography [Fuko-gel C-200, 209, elution solvent: hexane/ethyl acetate = 10/11] to obtain colorless oily 1. -3(3-methoxymethyloxyphenyl)-
108 mg of 5-azido-1-pentanone are obtained.

When 108 mg of the pentanone derivative obtained above is treated with 322 mg of triphenylphosphine, 6-(3-
41 mg (yield: 46%) of methoxymethyloxyphenyl)-2,3,4,5-tetrahydropyridine is obtained (J, Chem, Soc, Chem, Com
mun, 1224-1228 (1982)).

40mg of the above ring-closed product was added to 5rrL of methanol! After adding 7 rng of sodium borohydride under water cooling and stirring for 5 minutes, 74 mg of (E)-N-ethyl-6,6-dimethyl-2-hebuten-4-ynylbromide was added and stirred at room temperature for 4 hours. The solvent was distilled off, and the residue was post-treated in a conventional manner and purified by silica gel column chromatography [Wakogel C-200, 2ct, elution solvent: hexane/ethyl acetate = 4/1] to obtain (E) as a colorless oil. -1-
(6,6-dimethyl-2-hebuten-4-ynyl)-2
14 mg of (3-methoxymethylphenyl)piperidine are obtained.

14 rng of the above piperidine derivative was dissolved in 1 ml of tetrahydrofuran, 3 drops of concentrated hydrochloric acid was added, and the mixture was stirred at 60° C. for 3 hours. The solvent is distilled off and the residue is worked up in a conventional manner to obtain 11 mg of the title compound as a colorless oil.

(E) -1-(6,6-dimethyl-2
-hepten-4-ynyl)-2-(3-hydroxyphenyl)pyrrolidine is obtained.

The compound of the present invention inhibits squalene epoxidase in mammals, thereby inhibiting cholesterol biosynthesis and lowering blood cholesterol levels. 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.

Claims (5)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [I] [In the formula, A^1 and A^2 are the same or different and represent a methine group, nitrogen atom, oxygen atom, or sulfur atom; Q^ 1 and Q^2 may be the same or different and may contain one or two heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, and adjacent carbon atoms and A^
Represents a group that forms a 5- or 6-membered aromatic ring with 1 or A^2; X and Y may be the same or different, and each represents an oxygen atom, a sulfur atom, a carbonyl group, and the formula: -CHR^
A group or formula represented by a- (where R^a represents a hydrogen atom or a lower alkyl group): -NR^b- (here, R
^b represents a hydrogen atom or a lower alkyl group), or both X and Y together represent a vinylene group or ethynylene group; n represents an integer from 3 to 5; R^1 represents a 5- or 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms; R^2 and R^3 are hydrogen atoms , represents a halogen atom or a lower alkyl group; R^4 and R^5 are the same or different and represent a lower alkyl group,
Or a group in which both of them combine to form a cycloalkane with adjacent carbon atoms; R^6 represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group; R^7 and R^
8 are the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a lower alkyl group, or a lower alkoxy group. However, when either one of X and Y represents an oxygen atom, a sulfur atom, or a group represented by the formula: -NR^b- (where R^b has the above meaning), the other is a carbonyl group. or a group represented by the formula: -CHR^a- (where R^a has the above-mentioned meaning)] and a non-toxic salt thereof. (2) R^1 is a pyrrolyl group, a furyl group, a thienyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a pyrazolyl group, an oxadiazolyl group, a thiadiazolyl group, a triazolyl group,
Tetrazolyl group, furazanyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, dihydrothienyl group, tetrahydrothienyl group, pyrrolinyl group, pyrrolidinyl group, oxazolinyl group, oxazolidinyl group, isoxazolinyl group, isoxazolyl group Dinyl group, thiazolinyl group, thiazolidinyl group, isothiazolinyl group, isothiazolidinyl group, 1,2-dithiolanyl group, 1,3-dithiolanyl group, 1,2-dithiolyl group, 1,3-dithiolyl group, dihydrothiopyrani 1,4-dithianyl group, 1,4-dithienyl group, 1,4-oxathiinyl group, or thiomorpholinyl group; Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or formula▲ formula,
There are chemical formulas, tables, etc. The 5-membered or 6-membered aromatic rings represented by ▼ are the same or different, such as benzene ring, pyrrole ring, furan ring, thiophene ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring,
imidazole ring, 1,3,4-oxadiazole ring, 1
, 3,4-thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring or triazine ring, and the non-toxic salt thereof according to claim 1. (3) A hypercholesterolemia treatment agent comprising a substituted allylamine derivative represented by the general formula [I] or a nontoxic salt thereof according to claim 1. (4) A hyperlipidemia treatment agent comprising a substituted allylamine derivative represented by the general formula [I] or a nontoxic salt thereof according to claim 1. (5) An agent for treating arteriosclerosis, comprising a substituted allylamine derivative represented by the general formula [I] or a nontoxic salt thereof according to claim 1.