JPH02169571A - Substituted allylamine derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [A is methine, N, O or S; Q is group forming a 5 or 6-membered aromatic group together with adjacent C and A and may contain hetero atoms of N, O or S; X is methylene, methine or none; Y is methylene, methine or carbonyl; R and R<1> are H, halogen, cyano, OH, lower alkyl, (substituted) phenyl, etc.; R<2> is H or lower alkyl; R<3> is H, lower alkyl; lower alkenyl, etc.; R<4> and R<5> are H or halogen; R<6> is (substituted) acyclic hydrocarbon group, (substituted) phenyl, etc.]. EXAMPLE:(E)-N-(6, 6-dimethyl-2-hepten-4-ynyl)-N-methyl-3-(2-isoindolinyl) benzylamine. USE:A remedy and preventive for hypercholesterolemia, hyperlipemia and arteriosclerosis. PREPARATION:The objective compound is produced by reacting a substituted amine derivative of formula II with a compound of formula III (Z is eliminable group).

Description

[Detailed description of the invention] Birth! Kamitashina butt disaster The present invention relates to novel substituted allylamine derivatives.

More specifically, the present invention relates to substituted allylamine derivatives and salts thereof useful in the field of medicine, particularly in the field of treatment and prevention of hypercholesterolemia, hyperlipidemia, and arteriosclerosis, as well as processes for their production and uses thereof.

Traditionally, arteriosclerosis is a degenerative disease of the arteries that is closely related to aging and diet, and is the cause of coronary and cerebral artery disease, which is one of the most major causes of death in modern times. It is feared as Arteriosclerosis begins as lipid deposits in the intima of large blood vessels from a young age, and increases in scope and severity with age.

In turn, it manifests as clinical symptoms such as myocardial infarction, ischemic heart disease such as angina pectoris, cerebral arteriosclerosis such as cerebral infarction, or aneurysm, but it is believed that increases in various blood lipids are involved in this lipid deposition. It has been known.

Among these, increased blood cholesterol is the most important risk factor, and lowering it to normal levels is the most effective means of treating and preventing arteriosclerosis. In humans, more than 50% of cholesterol is produced de novo (da
lovastatin and brapastatin, which are enzyme inhibitors in the biosynthetic process, are currently used clinically as anticholesterol agents [A. ,u,
Alberts) et al.

Proceedings National Academy of Sciences (Proc. Natl. Acad. Sci.)
, Volume 77.

No. 3957 (1980); Tsujita et al., Biochimica
Biophysica Acta (Biochfm.Bioph
s. Acta), Volume 877, Page 50 (1986)
etc.]. However, the target enzyme of these inhibitors, 3-
and droxymethylglutaryleukoenzyme A reductase (ItMG-CoAreductase) are located in the early stages of the cholesterol biosynthesis system, so administration of these drugs increases the production of other physiologically important metabolites such as dolichol and ubiquinone. The disadvantage is that even the production can be suppressed.

Furthermore, triparanol, which is a late stage inhibitor of the cholesterol biosynthesis system, has been reported to cause 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 anticholesterol agents.

Several compounds are known to date as squalene epoxidase inhibitors [G, Petranyi et al.
224, p. 1239 (1984)].

All of them were developed as antifungal agents that selectively act on fungal enzymes, and there are no known agents that inhibit mammalian enzymes and have been touted as being useful as anticholesterol agents.

One of the main objects of the present invention is to provide an anti-hyperlipidemic agent that is safer and has superior anti-cholesterol effects compared to conventional anti-hyperlipidemic agents. The purpose of this invention is to provide an agent for treating and preventing arteriosclerosis.

Section W Rokusho Ushie The present inventors searched for squalene epoxidase inhibitors with anticholesterol effects with the aim of developing new anti-arteriosclerotic agents. The present invention was completed by discovering that substituted allylamine derivatives selectively inhibit squalene epoxidase in mammals and have strong anticholesterolemic effects.

Namely, 2 the present invention relates to a compound of the general formula [wherein A represents a methine group, a nitrogen atom, an oxygen atom or a sulfur atom; Q represents one or two atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom; 5- or 6-membered which may contain a terror atom and together with the adjacent carbon atom and A
A group forming an aromatic ring of members (the aromatic ring may have one substituent or two same or different substituents selected from the group consisting of a halogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxy group) ); X represents a methylene group or a methine group or is absent; Y represents a methylene group.

Represents a methine group or a carbonyl group: R and R" may be the same or different, and each is a hydrogen atom.

Halogen atom, cyano group, hydroxyl group, lower alkyl group, lower alkoxy group, lower alkenyl group, lower alkynyl group, lower hydroxyalkyl group, lower alkenyloxy group, optionally substituted phenyl group, optionally substituted hetero Represents a cyclic group; R1 represents a hydrogen atom or a lower alkyl group; R' represents a hydrogen atom, a lower alkyl group, or a lower alkenyl group.

Represents a lower alkynyl group or a cycloalkyl group; R4 and R1 may be the same or different, respectively.

Represents a hydrogen atom or a halogen atom; R" is an optionally substituted acyclic hydrocarbon group (the acyclic hydrocarbon group has one or two unsaturated bonds selected from the group consisting of double bonds and triple bonds) ), an optionally substituted cycloalkenyl group, or an optionally substituted phenyl group, respectively], their non-toxic salts, their production methods, and hypercholesterolemia and its use in the treatment of hyperlipidemia, hyperlipidemia and arteriosclerosis.

Furthermore, the present invention will be explained in detail.

It has been known that allylamine derivatives represented by caftifin-5-tilbinafin, which has the following structural formula %, exhibit strong inhibitory activity against fungal squalene epoxidase, and are therefore useful as antifungal agents. [G. Petranyi et al. 2 Science (Sci.
ence), Volume 224, Page 1239 (1984)
However, these compounds show little inhibitory activity against squalene epoxidase in mammals, including humans, and cannot serve as inhibitors of cholesterol synthesis [N.・Rider (N, S, Ryde
r) etc., Biochemical Journal (Biochem
, J.), Vol. 230, p. 765 (1985)] 6 Therefore, the present inventors aimed to develop a drug that selectively acts only on mammalian squalene epoxidase and exhibits anticholesterolemic effects. As a result of intensive research aimed at
When substituted with a group substituted with a bicyclic heterocyclic group represented by R, R', It has been found that the following compound can be obtained. The inventors also discovered that the squalene epoxidase inhibitory effect of the compound represented by formula [I] is extremely selective;
The present invention was completed based on the discovery that it shows almost no activity against fungal enzymes and is extremely valuable as a drug for treating or preventing hypercholesterolemia, hyperlipidemia, and arteriosclerosis.

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 4 carbon atoms.

Therefore, examples of lower alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, 5ec-butyl group, tert-butyl group, pentyl group, impentyl group, neopentyl group, hexyl group, etc. Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms.

Examples of lower alkenyl groups include vinyl group, 1-propenyl group, isopropenyl group, allyl group, 1-methyl-1-propenyl group, 2-methyl-1-propenyl group,
1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1.3-butadienyl group, 2-methyl-1-butenyl group, 3 -methyl-1,3-butadienyl group, 2-
Ethyl-1-butenyl group, 3-methyl-2-butenyl group, 1-pentenyl group, 2-pentenyl group, l,3-pentagenyl group, 214-pentagenyl group, 3-methyl-2-pentenyl group, ■-hexenyl straight-chain or branched alkenyl groups having 2 to 6 carbon atoms containing one or two double bonds in the carbon chain, such as 2-hexenyl groups, and lower alkynyl groups. teeth.

For example, ethynyl group, 1-propynyl group, propargyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group,
3-methyl-1-butynyl group, 3,3-dimethyl-1-
Butynyl group, l-pentynyl group, 2-pentynyl group, 3
-pentynyl group, 1,3-pentacyinyl group, 1-ethynyl-2-propynyl group, 4-methyl-2-pentynyl group.

Examples include straight-chain or branched alkynyl groups having 2 to 6 carbon atoms and containing one or two triple bonds in the carbon chain, such as 2-hexynyl group.

Lower hydroxyalkyl group is hydroxymethyl group, 1
-Hydroxyethyl group, 1-hydroxypropyl group, 3
- Means a hydroxyalkyl group having 1 to 4 carbon atoms such as hydroxypropyl group, and the lower alkoxy group is preferably a methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, 5ec
-Butoxy group or tert-butoxy group having 1 or more carbon atoms
Examples include four straight-chain or branched alkoxy groups, and the lower alkenyloxy group includes, for example, a 2-propenyloxy group.

2-methyl-2-propenyloxy group, 2-methyl-2
-Butenyloxy groups, 3-methyl-2-butenyloxy groups, and other linear or branched alkenyloxy groups having 3 to 6 carbon atoms are included. Cycloalkyl group.

3 or more carbon atoms such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, etc.
7 cycloalkyl groups, and examples of cycloalkenyl groups include 1-cyclopentenyl group, 2-cyclopentenyl group, 3-cyclopentenyl group, 2,4-cyclobentadienyl group, l -cyclohexenyl group, 1,3-cyclohexagenyl group, l,4-cyclohexagenyl group.

Examples include cycloalkenyl groups having 5 to 7 carbon atoms and containing one or two double bonds in the ring, such as 1-cyclohebutenyl group.

Heterocyclic groups include 9, for example, furyl group, tetrahydrofuryl group,
Pyrrolyl group, pyrrolidinyl group, imidazolyl group, pyrazolyl group, oxasilyl group, isoxasilyl group, furazanyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, thienyl group.

Pyridyl group, piperidyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, piperazinyl group.

Morpholinyl group, thiomorpholinyl group, oxadiazolyl group, thiadiazolyl group, triazolyl group.

Examples include 5- or 6-membered heterocyclic groups having 1 to 3 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms on the ring, such as triazinyl groups. The halogen atom can be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Furthermore, 1 selected from the group consisting of double bonds and triple bonds.
Examples of acyclic hydrocarbon groups which may contain one or two unsaturated bonds include methyl group, ethyl group, propyl group,
Isopropyl group, butyl group.

Isobutyl group, 5ec-butyl group, tert-butyl group.

Pentyl group, isopentyl group, tert-pentyl group.

Neopentyl group, hexyl group, 1,2.2-trimethylpropyl group, l,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 1.1
-dimethylpentyl group, 3.3-dimethylpentyl group,
4,4-dimethylpentyl group, 2,4.4-trimethylpentyl group.

Heptyl group, octyl group, nonyl group, decanyl group.

Undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group.

Heptadecyl group, vinyl group, ethynyl group, allyl group, isopentenyl group, 1-pentenyl group, propargyl group,
l-propynyl group, 1-butenyl group, 2-butenyl group,
3-butenyl group, l-butynyl group, 2-butynyl group, 3
-butynyl group, 1-methyl-1-propenyl group, 2-methyl-1-propenyl group, l-methyl-2-propenyl group, 2-methyl-2-propenyl group, l,2-dimethyl-1-propenyl group , 1,2-dimethyl-2-propenyl group, 2-methyl-■-butenyl group, 2-methyl-2-
Butenyl group, 3-methyl-1-butenyl group, 3-methyl-1-butynyl group, 3,3-dimethyl-1-butenyl group, 3,3-dimethyl-1-butynyl group, 3,3-dimethyl-1 -pentenyl group, 3,3-dimethyl-1-pentynyl group, 3-ethyl-1-pentenyl group, 3-ethyl-
1-pentynyl group, 4-ethyl-1-hexenyl group, 4
-ethyl-1-hexynyl group, 1. l-dimethyl-2-
hexenyl group, 1,1,4,4-tetramethyl-2-
Pentynyl group, 1,3-butadienyl group, 2-methyl-
1,3-butadienyl group, 1,3-pentadienyl group,
4-penten-2-ynyl group, 3-penten-1-ynyl group, 3-methyl-3-buten-1-ynyl group.

5.5-dimethyl-1,3-hexagenyl group, 5,5
-1 carbon number such as dimethyl-3-hexen-1-ynyl group
~17 pieces.

Preferably, 5 to 10 straight chain or branched saturated hydrocarbon groups or straight chain or branched unsaturated hydrocarbon groups having one or two double bonds and/or triple bonds are included.

Next, in order to more specifically disclose the compound of the present invention represented by the above-mentioned formula [I], various symbols used in formula [I1] will be explained in more detail by giving preferred specific examples thereof. do.

R and R'' may be the same or different, and a hydrogen atom,
hydroxyl group, amino group, halogen atom such as fluorine atom or chlorine atom, lower alkyl group such as methyl or ethyl group, lower alkenyl group such as 1-methylethynyl group, lower alkynyl group such as propargyl group, hydroxymethyl group or 1- Lower hydroxyalkyl groups such as hydroxyethyl groups.

a lower alkoxy group such as a methoxy group or an ethoxy group,
Lower alkenyloxy groups such as 2-methyl-propenyloxy groups, phenyl groups, or for example furyl, thienyl, pyrrolyl, oxacylyl groups.

Thiazolyl group, isoxasilyl group, isothiazolyl group, imidazolyl group, thiadiazolyl group, oxadiazolyl group, pyridyl group, pyrazinyl group.

Pyrimidyl group, pyridazinyl group, triazinyl group.

means a heterocyclic group such as a tetrahydrofuryl group, a pyrodinyl group, a piperidinyl group, a piperazinyl group, a tetrahydropyranyl group, a 1-morphonyl group or a thiomorphonyl group,
Among these, in particular, a hydrogen atom or a hydroxyl group, which means an unsubstituted case, an amino group, a fluorine atom, a chlorine atom, a cyano group, a methyl group, a hydroxymethyl group, a methoxy group, a phenyl group, a 2-furyl group, and a 2-thienyl group. group, l-pyrrolyl group, 5
-oxasilyl group, 5-thiazolyl group, l-imidazolyl group, 5-ynoxasilyl group, 2-(1,3,4-
oxadiazolyl) group, 2-(1,3,4-thiadiazolyl) group, 3-pyridyl group, 2-pyrimidinyl group, 4
-pyrimidinyl group, pyrazinyl group, 3-pyridazinyl group, 2-(1,3,5-triazinyl) group, etc. are preferred.

The hydrogen atom or lower alkyl group represented by R1 is 2
For example, a hydrogen atom, a methyl group, an ethyl group.

A linear or branched lower alkyl group having 1 to 4 carbon atoms such as a propyl group or an isopropyl group is preferred, and a hydrogen atom is particularly preferred.

Examples of the hydrogen atom, lower alkyl group, lower alkenyl group, lower alkynyl group or cycloalkyl group represented by R'' include a methyl group and an ethyl group.

Straight-chain or branched lower alkyl groups having 1 to 5 carbon atoms, such as propyl, isopropyl, butyl, isobutyl, or pentyl; for example, allyl, 2-butenyl, 2-pentenyl, 2-methyl - Straight chain or branched lower alkenyl group having 3 to 5 carbon atoms such as 2-propenyl group or 3-methyl-2-butenyl group; carbon number such as propargyl group, 2-butynyl group or 2-pentynyl group 3 to 5 linear or branched lower alkynyl groups;
Or, a cycloalkyl group having 3 to 5 carbon atoms such as a cyclopropyl group, a cyclobutyl group or a cyclopentyl group is preferable, and a methyl group, an ethyl group, a propyl group, an allyl group or a propargyl group are particularly preferable, and among these, a methyl group, an ethyl group or propyl group is most preferred.

The hydrogen atom or halogen atom represented by R4 and R'' is preferably a hydrogen atom, a fluorine atom or a chlorine atom,
Particularly preferred is a hydrogen atom.

Furthermore, the double bond formed by the two carbon atoms to which both R4 and R' are bonded has two geometric isomers: trans type (E type) and cis type (Z type).

Among these, trans type is preferred.

An optionally substituted acyclic hydrocarbon group represented by R' (the acyclic hydrocarbon group contains one or two unsaturated bonds selected from the group consisting of double bonds and triple bonds) (may be).

For example, hydroxyl group, halogen atom, cycloalkyl group.

It may be substituted with a lower alkoxy group, or a phenyl group which may be substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group.

and a linear chain having 1 to 17 carbon atoms, preferably 3 to 12 carbon atoms, which may contain one or two unsaturated bonds selected from the group consisting of double bonds and triple bonds in its carbon chain, or means a branched acyclic hydrocarbon group.

Preferably 1, for example, isopropyl group, tet't-butyl group, isopentyl group, tert-pentyl group, neopentyl group, isopropoxymethyl group, tert-
Butoxymethyl group, 2-(isopropoxy)ethyl group.

2-(term-butoxy)ethyl group, 2-methoxy-
2-methylpropyl group, p-(tert-butyl)benzyl group, phenethyl group, α-methylbenzyl group, α,
α-dimethylbenzyl group, 3-phenylp-Ovir group,
2-(p-fluorophenyl)ethyl group, 2-(p-
Substituted or unsubstituted saturated hydrocarbon groups such as (tert-butyl)phenyl)ethyl group, α,α-dimethyl-p-fluorobenzyl group, or α,α-dimethyl-p-(tert-butyl)benzyl group; for example, 2- Cyclopropylvinyl group, 2-(1-methylcyclopropyl)vinyl group, 1-propenyl group, 1-butenyl group, 3-methyl-
1-butenyl group, 3.3-dimethyl-1-butenyl group,
3-methoxy-3-methyl-1-butenyl group, 1-pentenyl group, 3-methyl-1-pentenyl group, 3.3-dimethyl-1-pentenyl group, 3-ethyl-1-pentenyl group, 1- xenyl group, 1-hebutenyl group, 1-octenyl group, styryl group, 2-(p-fluorophenyl)vinyl group, 2-ip-(tert-butyl)phenyl)vinyl group, 3-methyl-3-phenyl- 1-butenyl group, 3-methyl-3-(p-fluorophenyl)-1
-butenyl group, 3-methyl-3-[p-(tert-butyl)phenyl)-1-butenyl group, 1,3-butadienyl group, 3-methyl-1,3-butadienyl group, l, 3
-Pentagenyl group, 3-methyl-1,3-pentagenyl group, 4-methyl-1,3-pentagenyl group, 3.
Formula of 4-dimethyl-1,3-pentadienyl group, 1,3-hexadienyl group, 5,5-dimethyl-1,3-hexadienyl group, etc.: %Formula% Lower alkyl group that may be substituted or 1, for example, a 2-cyclopropylethynyl group, 2
-(1-methylcyclopropyl)ethynyl group,! -zolopynyl group, l-butynyl group, 3-methyl-1-butynyl group, 3.3-dimethyl-1-butynyl group, 3-methoxy-3-methyl-1-butynyl group, l-pentynyl group, 3
-Methyl-1-pentynyl group, 3,3-dimethyl-1-
pentynyl group, 3-ethyl-1-pentynyl group.

1-hexynyl group, l-hebutynyl group, 1-octynyl group, 2-phenylethynyl group, 2-(p-fluorophenyl)ethynyl group, 2-(p-(tert-butyl)phenyl)ethynyl group, 3 -Methyl-3-phenyl-
1-butynyl group.

3-methyl-3-(p-fluorophenyl)-1-butynyl group.

3-methyl-3-(p-(tert-butyl)phenyl 1-1-butynyl group, 3-buten-1-ynyl group, 3-
Methyl-3-buten-1-ynyl group, 3-pentene-1
-ynyl group, 3-methyl-3-penten-1-ynyl group, 4-methyl-3-penten-1-ynyl group, 3,4-
Dimethyl-3-penten-1-ynyl group, 3-hexen-1-ynyl group or 5,5-dimethyl-3-hexen-1-ynyl group, etc.
a has the above-mentioned meaning), and the like.
Among these, especially.

For example, 3,3-dimethyl-1-butenyl group, 3-methoxy-3-methyl-1-butenyl group, 1-pentenyl group,
3.3-dimethyltobentenyl group, 3-ethyl-1
-pentenyl group, 1-sexenyl group, 3,3-dimethyl-1-hexenyl group, l-hebutenyl group, ■-octenyl group, 3-methyl-1,3-butadienyl group, 1,3-
Pentagenyl group, 4-methyl-1,3-pentagenyl group, 1.3-hexagenyl group, 5.5-dimethyl-
1,3-hexagenyl group, 2-cyclopropylvinyl group, 2-(1-methylcyclopropyl)vinyl group, 2
- Cyclopentylvinyl group, 2-cyclohexylvinyl group, etc. with the formula CH=CH-Rb (where Rb has 3 to 6 carbon atoms and may be substituted with one lower alkoxy group having 1 to 4 carbon atoms) a cycloalkyl group having 3 to 6 carbon atoms which may be substituted with an alkyl group or alkenyl group or an alkyl group having 1 to 4 carbon atoms; or 1, for example, 3.3- Dimethyl-1-butynyl group, 3-methoxy-3-methyl-1-butynyl group, 1-pentynyl group, 3.3-dimethyl-1-pentynyl group, 3
-ethyl-1-pentynyl group, 1-sexynyl group, 3,
3-dimethyl-1-hexynyl group, 1-hebutynyl group,
l-octynyl group, 3-methyl-3-buten-1-ynyl group, 3-penten-1-ynyl group, 4-methyl-3-ynyl group
Penten-1-ynyl group, 3-hexen-1-ynyl group, 5,5-dimethyl-3-hexen-1-ynyl group, 2
-Formula CEC- such as cyclopropylethynyl group, 2-(1-methylcyclopropyl)ethynyl group, 2-cyclopentylethynyl group, 2-cyclohexylethynyl group, etc.
A group represented by Rb (wherein Hb has the above meaning) is preferred, more preferred.

group or an alkoxy group having 1 to 4 carbon atoms, and Rd
and Re may be the same or different and represent a hydrogen atom, a methyl group, an ethyl group, or both together represent a cyclopropyl group.

For example, 3-methyl-1-butynyl group, 3.3-dimethyl-1-butynyl group, 3-methoxy-3-methyl-1-butynyl group.

A group such as 3-methyl-1-pentynyl group, 3-ethyl-1-pentynyl group, 3-methyl-1-hexynyl group, 2-cyclopropylethynyl group or 2-(1-methylcyclopropyl)ethynyl group Among these, 3,3-dimethyl-1-butynyl group and 3-methoxy-3-methyl-1
-butynyl group is most preferred.

The optionally substituted cycloalkenyl group represented by R8 is substituted with, for example, a hydroxyl group, a halogen atom, a lower alkoxy group, or a phenyl group optionally substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group. It can be a cycloalkenyl group @1
For example, 1-cyclopentenyl group, 3-methyl-1-cyclopentenyl group, 3-ethyl-1-cyclopentenyl group, 3.3-dimethyl-1-cyclopentenyl group, 3-methoxy-1-cyclopentenyl group, 3 -methoxy-3-
Methyl-1-cyclopentenyl group, 3-cyclopropyl-1-cyclopentenyl group, ■-cyclohexenyl group,
2-methyl-1-cyclohexenyl group, 3-methyl-1
-cyclohexenyl group, 3,3-dimethyl-1-cyclohexenyl group, 3-cyclopropyl-1-cyclohexenyl group, etc. are preferable, and the optionally substituted phenyl group represented by R+ is 9 For example, a phenyl group which may be substituted with a hydroxyl group, a halogen atom, a lower alkyl group or a lower alkoxy group is included, and preferably one such as a phenyl group, a 4-hydroxyphenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, 4-methylphenyl group, 4-ethylphenyl group.

4-propylphenyl group, 4-isopropylphenyl group, 4-butylphenyl group, 4-isobutylphenyl group,
4-(tert-butyl)phenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 3,4-dimethoxyphenyl group or 2.6-
Examples include dichlorophenyl group.

Formula: [wherein X and Y are 2-isoindolyl group, 2-(1,2-dihydroisoquinolyl) group or 2-(1,2,3,4-tetrahydroisoquinolyl) group Among these, the 5- or 6-membered aromatic ring represented by 2-isoindolyl group or 2-(having the meaning of 1,2,3,4-tetrahydroinquinolyl) is particularly 9, for example, a benzene ring. , virol ring.

Furan ring, thiophene ring, oxazole ring, isoxazole ring, thiazole ring, imidazole ring.

Among them, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a triazine ring, etc. are preferred.

Especially benzene ring, furan ring, thiophene ring, oxazole ring, inoxazole ring, and thiazole ring.

A pyridine ring or a pyrimidine ring is preferred, and a benzene ring is most preferred.

Further, the aromatic ring is most preferably unsubstituted, but may be a halogen atom or a hydroxyl group as the case may be.

It may have one or two same or different substituents selected from the group consisting of a lower alkyl group and a lower alkoxy group, two of which include, for example, a hydroxyl group, a fluorine atom,
Substituents such as a chlorine atom, methyl group, and ethyl group are preferred.

The substituted allylamine derivatives of formula [I] can exist in the form of acid addition salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate, etc. , nitrates, perchlorates or phosphates; or 1 such as p-toluenesulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate, tartrate, citric acid. salts, organic acid salts such as fumarates and maleates, and pharmaceutically acceptable non-toxic salts are particularly preferred;
The compound may exist in stereoisomers such as geometric isomers and optical isomers depending on the form of its substituents.
The present invention also includes all these stereoisomers and mixtures thereof.

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

The compound of formula [I1 of the present invention is 1, for example, the following production methods A and B.
, and C can be used.

[In the formula, Z represents a leaving group; R3' is a lower alkyl group,
Represents a lower alkenyl group, lower alkynyl group or cycloalkyl group; also A, Q, X, Y, R, R'.

R'', R', R', R' and R1 have the above meanings] The above production methods A, B and C are all alkylation reactions of amines well known in the field of organic synthetic chemistry, This can therefore be done using conventional means known per se.For example, 2.

Solvent 1: Aromatic hydrocarbons such as benzene, toluene or xylene, such as benzene, toluene or xylene, such as ethyl ether.

Ethers such as tetrahydrofuran or dioxane; halogenated hydrocarbons such as methylene chloride, chloroform or dichloroethane; alcohols such as ethanol or isopropanol; dimethylformamide, acetonitrile, dimethylsulfoxide or mixtures thereof as solvents. 9 In the case of normal production method A, compound CUE and compound [I1? ), in the case of production method B, compound [IV] and compound [V], and in the case of production method C, compound [■a] and compound [VI] are reacted in approximately equimolar ratios, or either one of This is done by reacting in slight excess. The reaction conditions employed at this time are 9. The reaction temperature is generally -20°C to 150°C, preferably from room temperature to the boiling point of the solvent, and the reaction time is usually 5 minutes to 10 days, preferably 110 to 240°C. It can be time. Also in this reaction.

In order to facilitate the reaction, it is advantageous to carry out the reaction in the presence of a base, and the bases used in this case include 2 alkali metal hydrides such as sodium hydride, lithium hydride or potassium hydride; sodium,
Alkali metal or alkaline earth metal hydroxides such as potassium hydroxide or calcium hydroxide; for example sodium carbonate.

Examples include alkali metal carbonate salts such as potassium carbonate or sodium hydrogen carbonate; or organic amines such as triethylamine or pyridine. The amount of these bases to be used is not critical and can be varied over a wide range, but in general, it should be equimolar or in excess (9) preferably 1 to 5 moles relative to each raw material compound. can.

9 In the above manufacturing method, the formula [I
a], [I[], [[[I], [rV], [V
] and [Vr] apart from the amino group participating in one reaction in the compound.

When reactive functional groups such as hydroxyl groups or amino groups are present, if necessary, these reactive functional groups can be suitably protected before the reaction, and these protective groups can be removed after two reactions. Protective groups used in this case include those that can be easily deprotected by hydrolysis under acidic or alkaline conditions, such as methoxymethyl group, tetrahydropyranyl group, trityl group, dimethyl-(tert-butyl)silyl group. , formyl group, acetyl group, methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group, or phthalyl group.

The target compound of the formula [I1 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,
- The free base of the compound of the present invention represented by the formula I can be converted into its acid addition salt, and vice versa, the acid addition salt can be converted into its free base. The step of converting a free base into its acid addition salt, and the step of converting an acid addition salt into its free base, can be easily carried out by a conventional method using the corresponding acid or base.

In addition, the leaving group represented by Z is 1, 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 used in the above production method A-C [■a-[V
I] can be grooved as a commercially available product or by a manufacturing method described in the literature [Journal of Medicinal Chemistry (
J, Med, Chem,), Volume 27, Page 1539 (
1984); Journal of Medicinal Chemistry (J, Med, Chet), Vol. 29, No. 1
12 pages (1986); JP-A-56-32440 and JP-A-57-123177.

No. 58-208252, No. 61-45, No. 62-2
No. 01850, No. 63-5059; Japanese Patent Application No. 1983-
296.840 etc.] and their general manufacturing methods shown below or methods analogous thereto.

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

(Left below) Manufacturing route (a) Manufacturing route (b) [! [In the formula, R1 each represents a hydrogen atom, a hydroxyl group, a lower alkyl group, or a lower alkoxy group;

Q, X, Y, Z, R, R', R1, R', R', R'' and R' have the meanings given above.

Production route (a) The process of producing a compound [Kari] by reacting a compound [■] with a compound [■] is a process in which the compound [■] is reacted with the compound [■] in two usually equal moles of each other.
and compounds such as sodium hydroxide.

In the presence of a base such as potassium carbonate or sodium hydrogen carbonate 2 For example, without a solvent or in a solvent such as ethanol, benzene, dimethylformamide, acetic acid, etc.

at a temperature of room temperature to 200°C, preferably 70 to 150°C,
This can be carried out by heating the reaction for 2 to 10 hours.

Compound [■] is reacted with compound [[X] to form compound [X].
] and then reacting it with formaldehyde under acidic conditions to produce compound [XI].1 For example, equimolar amounts of compound [■] and compound [IX] are combined with, for example, sulfur hydroxide, lithium carbonate, In the presence of a base such as potassium, sodium bicarbonate, pyridine or triethylamine, for example in the absence of a solvent, or ethanol, tetrahydrofuran,
In a solvent such as benzene or dimethylformamide, 0 to 2
Compound [X] is synthesized by reacting at a temperature of 00°C, preferably room temperature to 100°C, for 1 to 5 hours.

In solvents such as acetic acid, acetic anhydride, trifluoroacetic acid, etc.

9 equimolar or excess molar of paraformaldehyde in the presence of an acid such as hydrogen chloride, sulfuric acid or polyphosphoric acid at room temperature to
at a temperature of 200°C, preferably between 80 and 150°C,
This can be carried out by heating the reaction for 2 to 10 hours.

Compound [X[] is reduced to form compound [X! The step of producing I] is 9, for example, at 0°C to room temperature, in a solvent such as ethanol, benzene or tetrahydrofuran, with a reducing agent such as sodium borohydride, diisobutylaluminum hydride or lithium aluminum hydride. This can be done by time processing.

The step of producing compound [■] by reacting compound [Xl] with compound [X I[I] is 1, for example, by reacting compound [X[] with compound [X [[+]
to form an imine or amide by condensation and then reduction.

Alternatively, it can be carried out by reacting the excess compound [X m] with the compound [X m] 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, for example, in methanol, ethanol or tetrahydrofuran.

There is a method of reacting at 0°C to room temperature for 1 to 6 hours.

The step of converting compound [Xn] into compound [IV] is.

For example, without a solvent or in a solvent such as chloroform or methylene chloride, with a halogenating agent such as thionyl chloride or phosphorus tribromide, or a sulfonylating agent such as methanesulfonyl chloride and triethylamine, at a temperature range of -20°C to room temperature.
This can be done by treating for 5 hours.

Gloss/Lz-t-Engineering Compound [Xl] is reacted with compound [XV] to form compound [
The process of producing Ial can be carried out in the same manner as the process of producing compound [I1] by reacting compound [)a] with compound CXm1. In addition, the compound [Xv] used at this time is 1, for example, the compound [m] is mixed in the presence of a base such as sodium hydroxide or potassium carbonate, and 1
Compound [XI
Compound [XV] is prepared by preparing compound [XV] and then reacting it with hydrazine in, for example, ethanol or dimethylformamide. The so-called Gabriel
el) method etc.

(Left below) The products obtained in each of the above steps may be subjected to known purification methods such as chromatography, recrystallization, solvent extraction, precipitation, or distillation, if necessary, either alone or in combination as appropriate. It can be purified or isolated by

Compounds that serve as starting materials for these raw material intermediates can be purchased as commercial products or described in literature [Journal of Medicinal Chemistry (J.

Med, Chem, ), Volume 27, Page 1539, (
1984); Journal of Medicinal Chemistry (J, Med.

Chem, ) + Volume 29, Page 112 (1986);
JP 56-32440, JP 57-123177,
No. 58-208252, No. 61-45, No. 62-2
It can be easily obtained by referring to publications such as No. 01850 and No. 63-5059, or by using synthetic methods known in organic synthetic chemistry.

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

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

Pharmacological Test Example 1 Squalene Epoxidase Inhibitory Effect (1) Preparation of Squalene Epoxidase Rat squalene epoxidase was reported in the Journal of Biological Chemistry (J.

Biol, Chel, ), vol. 245, p. 1670 (1970); vol. 250, p. 1572 (1970);
5).

That is, SD female rats are killed by exsanguination and then their livers are removed. The liver was doubled in volume to 0. IM Tris-Hf,
Homogenize with Q buffer (pH 7.5) and add 9750
Centrifuge for 10 minutes at Xg. The obtained upper groove is further to
Centrifuge for 1 hour in sooox5 and then centrifuge the pellet at 0. I
After washing with M Tris-1 (CQ buffer (pH 7,5) t', centrifugation at 1105000X for 1 hour.
0. IM Tris-HCQ buffer (pH 7
, 5) in the presence of 2% Triton X-100 under water cooling.

Stir to solubilize. After this solubilization treatment, 1mMEDT
Dilute Triton 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 squalene epoxidase activity is carried out in accordance with the Journal of Biological Chemistry (J, Biol, Cb
ew, ), Vol. 245, p. 1670 (1970).

That is, 0.2 mfl of the squalene epoxidase fraction prepared in (1) [protein amount 0.4 mg, 0.5% Triton X-100, 20 μN Tris-H (, Q buffer (PH 7,5)], 100 μM FAD, 1 cod NA
To a solution consisting of DPH, 1 mW EDTA, and 8 μM H-squalate Vienna 80 suspension, 3 μQ of a dimethyl sulfoxide solution of the test drug was added.

The total amount was adjusted to 0.3mM, and the reaction was carried out with shaking at 37°C for 30 minutes.

The reaction was stopped by adding 0.3a of 10% potassium hydroxide-methanol solution and left at room temperature for 1 hour.Then the non-saponifiable materials were extracted with petroleum ether.

Under nitrogen flow! Awi Dry. The obtained residue was dissolved in a small amount of ethyl ether and pre-coated.
Spotted on Silica-gel TLC and developed with benzene-ethyl acetate (99.5:0.5). In addition, TL of the generated 3H-squalene-2,3-epoxide
The position in C was confirmed using ergosterol acetate as a marker.

Cut out the 'H-squalene-2,3-epoxide part of TLC. 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 squalene epoxidase was determined.

The results are shown in Table 1.

Table 1 Squalene epoxidase inhibitory effect Pharmacological test example 2 Cholesterol in 1M Human H
After culturing epatoIla (Hep-G2) cells until they become a monolayer in a 10 cnl Schare, 1 mQ of the culture medium was replaced, 1 μCi of "°C-sodium acetate and 1 μQ of a dimethyl sulfoxide solution of the test drug were added, and 5% carbon dioxide was added. Incubate for 6 hours at 37°C in mixed air.

After culturing, the medium was removed by suction, cooled with water, and then Du
Wash with lbecco's buffered saline solution. The obtained cells are scraped off with a rubber policeman and collected by centrifugation. After lysing the collected cells with 400 μQ of 0.3N sodium hydroxide, 200 μA of the cells will be used for extraction, and the rest will be used as a sample for protein quantification.

Add 15% potassium hydroxide-ethanol to 200 μQ of the extracted sample, add condensate lωQ saponified at 75° C. for 1 hour, and extract unsaponified substances twice with 2 mQ of petroleum ether.

The obtained petroleum ether extract was washed with 1 mQ of water and condensed to dryness under a stream of nitrogen. The residue was subjected to Pre-coated Silicagel TLC using a small amount of chloroform.
Spotted on, hexane-ethyl (te)tt-MIN
I (85:15:4) was developed, and the cholestyrol squalene moiety was detected by iodine on TLC.
Cut out the relevant TLC part. The TLC piece is immersed in a toluene-based scintillator, and radioactivity is measured using a liquid scintillation counter. The results are published in the Journal of Biological Chemistry (J, Biol, C
Corrected by the amount of protein measured by the method described in Hem., Volume 193, Page 265 (1951). This results in a 50% inhibitory concentration (IC,
The results are shown in Table 2.

Table 2 Cholesterol biosynthesis inhibition effect in cultured cells As is clear from the above results, the compounds of the present invention 8 strongly inhibit squalene epoxidase.

Since it inhibits cholesterol biosynthesis, various diseases caused by advances in the cholesterol biosynthesis mechanism2
For example, it is effective in treating and preventing diseases such as obesity, hyperlipidemia, and arteriosclerosis. In addition, squalene of the compound of the present invention
The epoxidase inhibitory effect is not observed in fungi and is specific to mammals, and furthermore, the toxicity is low, making the present invention extremely useful in the pharmaceutical field.

The compound of formula [I] of the present invention can be administered orally or parenterally, and by formulating it in a form suitable for such administration, it can be used to treat hypercholesterolemia, hyperlipidemia and ischemia. When using the compound of the present invention clinically, which can be used for the treatment and improvement of sclerosis, it may be administered after making various formulations by adding pharmaceutically acceptable additives according to the dosage form. It is 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, corn starch.

Microcrystalline wax, white petrolatum.

Magnesium aluminate metasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate.

Hydroxypropyl cellulose, sorbitol.

Sorbitan fatty acid ester, polyvinylpyrrolidone, magnesium stearate, light silicic anhydride.

Talc, vegetable oil, benzyl alcohol, gum arabic,
Examples include propylene glycol and polyalkylene gelylcol.

Dosage forms formulated as a mixture with these additives include 1 solid preparations such as tablets, capsules, 11 granules, powders or suppositories, 9 liquids such as syrups, elixirs or injections. There are formulations, and these formulations can be prepared according to conventional methods in the pharmaceutical art. In addition.

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

These formulations contain 1 compound of the 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 also

It 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 number of administrations should be determined according to the patient's sex and age.

Although it varies depending on body weight, severity of symptoms, and type and range of desired therapeutic effect, generally when administered orally.

For adults, 0.01 to 20 mg/kg per day, divided into one to several doses, and for parenteral administration, 0.001 to 20 mg/kg per day.
It is preferable to administer 2 mg/kg in one to several divided doses.

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

Example 1 3-(2-isoindolinyl)benzyl chloride 50I
Dissolve 1 g of I in dimethylformamide L mm, (E
)-N-methyl-6,6-dimethyl-2-heptene-4
Add 39 μl of -ynylamine hydrochloride and 142 μl of potassium carbonate and stir overnight at room temperature. 1. Concentrate the reaction solution under reduced pressure. Ethyl ether and water are added to the residue to separate the layers. The organic layer is separated and dried over anhydrous magnesium sulfate. do. After filtering off the desiccant, the solvent was distilled off, and the residue was purified by silica gel column chromatography (Wakogel C-200, 10 g, elution solvent: hexane/ethyl acetate=]O/1) to obtain 38 mg of the second title compound (yield 52%) is colorless crystalline powder, m
, p, 81-83°C.

NMR (CDCQ, )δ: 1.24 (9FI, s)
, 2.23 (3H, s), 3.07 (2H.

dd, J=6.6Hz, 1.5Hz), 3.50 (2H
, s), 4.67 (4H, s).

5.66 (IJ(, dd, Jg15.9+1z, 2.8
Hz), 6.12 (IH, dt, JI: 15.9Hz,
6.4Hz), 6.57(LH,ddd,,I'8.6
Hz, 2.0Hz.

1.1Hz), 6.66-6.70 (2H1m), 7.
23 (IH, t, J=7.51 (Z), 7.26-7.
37(4H,I) The same procedure as in Example 1 was used except that the corresponding 3-position substituted penzyl chloride was used in place of 3-(2-isoindolinyl)benzyl chloride used as the raw material in Example 1 above. The reaction was carried out to obtain the compounds of Examples 2 and 3.

Example 2 Pale yellow oil [preparative thin layer chromatography (91 layer plate: Kieselgel 60Fl14; developing solvent:
Purified by hexane/ethyl acetate = 571) 38O NMR (CDCQ, ) δ: 1.24 (911, s)
, 2.26 (3H, s), 2.35 (3H.

s), 3.04-3.17 (2H, m), 3.54 (2
H,s), 4.60 (2H,s).

4.68 (2H, s), 5.68 (LH, d, J=15
．． 9Hz), 6.14 (IH.

dt, J=15.9Hz, 6.6Hz), 6.56-
6.62 (IH, m), 6.66-6.72 (2H1+
11) 17.06-7.10 (IH, 111), 7.
14-7.28 (3H.

ff1) t, J=5.9Hz), 3.05(2H, dd, J=
6.6) 1z, 1.5Hz).

3.48 (2H, s), 3.56 (2H, t, J=5.
9Hz), 4.41 (2H, s).

5.66 (IH, dt, J: 15.9) 1z, 1.5H
z), 6.10 (IH, dt, J=15.9Hz, 6
．． 6Hz), 6.75(11(,d,J=7.6Hz)
, 6.86 (LH.

dd, J near, 6Hz, 1.5Hz), 6.99 (LH
, t, J=1.5Hz).

7.14-7.26 (5H, a+) Example 4 Example 3 Colorless oil [purified by silica gel column chromatography (Wakogel C-200, elution solvent: hexane/ethyl acetate = 20/1)] N? IR(CDCQ)
, ) δ: 1.24 (9H, s), 2.21 (3B, s
), 2.99 (2H.

60 mg of 3-[5-(2-furyl)-2-isoindolinyl]benzyl alcohol was dissolved in 2 d of methylene chloride.

1 g of methanesulfonyl chloride 25II and 33 mg of triethylamine are added, and the mixture is stirred at room temperature for 30 minutes. In the second solution, (E)-N-methyl-6,6-dimethyl-2-hebuten-4-ynylamine hydrochloride 46M and potassium carbonate 52M
mg of dimethylformamide solution (2 components) was added, and the mixture was stirred overnight at room temperature, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography (Wakogel C-200, 10g
, elution solvent: hexane/ethyl acetate = 571).

59 mg (% yield) of the title compound are obtained.

Pale yellow oil NMR (CDCQ, ) δ: 1.25 (9H, s),
2.25 (3H, s), 3.09 (2H.

d, J=6.6Hz), 3.52 (2H, s), 4.
67 (4H, s), 5.68 (1B.

dt, J=15.9Hz peak 4Hz), 6.13(], H
, dt, J=15.9Hz.

6.6Hz), 6.49(IH, dd,, I'3.4H
z mountain 8Hz), 6.56-6.61 (IH, m), 6.
66 (IH, dd, J=3.4Hz, 0.7Hz).

6.67-6.73 (2H, w), 7.24 (IH, t
, J=7.9Hz), 7.35(LH,d, Jl18.
1Hz), 7.48 (IH, dd, J: 1.8Hz, 0
．． 7Hz).

7.59-7.66 (2H, m) Dissolved in a mixture of 1.2 m of ethanol and 0.3 d of tetrahydrofuran, 180 mg of tin powder and 0.36 ml of concentrated hydrochloric acid!
and stirred for 30 minutes under water cooling, then stirred at room temperature for 1 hour.

Add 90 mg of tin powder and 0.31 d of concentrated hydrochloric acid to the reaction solution,
Stir for 1 hour at room temperature, then stir for 20 hours under reflux. 6. After the reaction is complete, insoluble materials are filtered off, and the filtrate is dried under reduced pressure.
Add a potassium carbonate aqueous solution and chloroform, filter off the generated precipitate, and separate the organic layer. Chloroform was distilled off under reduced pressure, and the residue was subjected to preparative thin layer chromatography [thin layer plate: K
iesel gel 60F, 4. Art.

5744 (manufactured by Merck & Co., Ltd.), developing solvent: hexane/ethyl acetate = 171] to obtain 10+ g (yield 9.6%) of the title compound as a colorless oil.

Example 5 (E)-N-(8,6-dimethyl-2-hebutene-4-
1305.756,735 NMR (CDCQ, ) δ: 1.24 (9H, s),
2.22 (3H, s), 3.08 (2H.

d, J116.6Hz), 3.55 (2H, s), 4.
89 (2H, s), 5.67 (IH.

dt, J=15.8Hz, 1.5Hz), 6.11(I
H, dt, JI 115.8Hz.

6.6Hz), 7.14 (1M, d, J: 8.0Hz)
, 7.37 (IH, t, J=8.0Hz), 7.48-
7.54 (2H, +a), 7.55-7.63 (18,
m).

7.76-7.78 (IH, m), 7.83-7.88
(IH, e), 7.93 (IH.

dd, J=7.2Hz, 1.4Hz) Example 6 25 mg of 3-(1,2,3,4-tetrahydro-2-isoquinolyl)benzyl chloride was dissolved in dimethylformamide 1-, and (E)-N- Propyl-6,6-dimethyl-2-hepten-4-ynylamine hydrochloride 25mg
Add 40 mg of potassium carbonate and stir overnight at room temperature6.
After reducing the pressure of the reaction solution e and m, ethyl ether and water were added to the residue to separate the layers.

The organic layer is separated and dried over anhydrous magnesium sulfate.

After filtering off the desiccant, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (Wakogel C-200, 30 g,
Elution solvent: hexane/ethyl acetate = 10/1) to obtain 28 mg (yield 72%) of the title compound 9 as a colorless oil.

5O NMR (CDCQ, ) δ: 0.88 (3B, t, J
=7.3Hz) 11.24 (9H, s).

1.47-1.56 (2H, m), 2.40 (2■, t
, J=7.3Hz), 2.99(2H,t, J=5.8
Hz), 3.10 (2H, dd,, I'5.9Hz, 1
．． 3Hz).

3.54 (2H, s), 3.56 (28, t, J=5.
8Hz), 4.40 (2H, s).

5.66 (18, dt, J=15.8Hz, 1.3Hz
), 6.09 (1B, dt, J=15.8Hz, 5.9
Hz), 6.77 (IH, d, J=7.8Hz), 6.
85 (IH.

dd,, J'7.8Hz, 2.0Hz>, 6.98-7
．． 05 (IH, m), 7.14-7.26 (5H, a) Reference Example 1 1.82 g of pale m-aminobenzoic acid of 3-2-isoindolinylbenzyl chloride was mixed with ethanol 15- and benzene 15af! Dissolved in a mixture of α,α°-dibromo-0-xylene 1. Add OOg and reflux for 3 hours. After evaporating the solvent under reduced pressure, the residue was extracted with a system of ethyl acetate and water.

After separating the organic layer, it was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (Wakogel C-100, 50 g).

Elution solvent: methylene chloride) to purify 3-(2
-isoindolinyl)benzoic acid 230 mg (yield 25%)
) is a light green crystalline powder, m, p, 217-219°C,
obtained as. The above isoindoline derivative 220m
g was suspended in 10 d of ethyl ether, 52.411 Ig of lithium aluminum hydride was added thereto, and the mixture was stirred at room temperature for 1 hour.

Ice water and ethyl ether were added to the reaction solution, and after filtering off insoluble matter, the organic layer was separated. The organic layer was then washed with water, dried, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (Wako Gel C-100, 30 g , Elution solvent: hexane/
When purified by ethyl acetate = 1071), 3-
(2-isoindolinyl)benzyl alcohol 200m
g (yield 96%) is white crystalline powder, m, p, 129
-130°C.

14,011 g of the above alcohol is dissolved in 1-chloroform, 0.12 m2 of thionyl chloride and 1 drop of dimethylformamide are added, and the mixture is stirred at room temperature for 30 minutes.

After evaporating the solvent, a 5% aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue for extraction, and the organic layer was washed with water.

After drying, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (Wakogel C-100, 15 g).

Elution solvent: hexane) to yield 2 title compound 7
8.5 mg (yield 60%) is pale yellow powder, m, p, 8
8-90°C.

In place of the raw material α,α°-dibromo-0-xylene.

3-methyl-α,α′-dibromo〇-xylene or 2
-bromomethylphenethyl bromide (J, Am, Ch
ea+, Soc, .

78.2439 (1956)), and in the same manner as in Reference Example 1, 3-(4-methyl-2-isoindolinyl)benzyl chloride or 3-( 1,2,3,4-tetrahydro-2
-isoquinolyl)benzyl chloride can be synthesized.

Reference Example 2 1.5 g of 4-aminophthalic acid dimethyl ester hydrochloride was dissolved in a mixture of 2.75 d of concentrated hydrochloric acid and water IM, an aqueous solution (4-) of 422 rng of sodium nitrite was added, and after stirring for 30 minutes under water cooling, Aqueous solution of chloride #1122 (1d
) and 1.1 g of furan in acetone solution (long>) and stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, the organic layer was washed with water, dried, and the solvent was distilled off to remove the residue. Silica gel column chromatography (Wako gel C
-200.60 g, elution solvent: hexane/ethyl acetate = 10/1 → 511) to obtain 239 mg of dimethyl ester of 4-(2-furyl)phthalic acid (yield: 15
%) is obtained as a colorless oil.

Dissolve 239 mg of the above furyl compound in 2 parts of tetrahydrofuran, add 70 mg of lithium aluminum hydride, and stir at room temperature for 30 minutes. Add water and ethyl ether to the reaction solution, separate the ether layer, and dilute the aqueous layer with ethyl ether. Extract 4 more times. The ether layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give 4-(2-
186 ml of benzene-1,2-dimetatool (yield 99%) is obtained as a colorless crystalline residue.

Dissolve the above dimethatol compound 167■ in methylene chloride (5d), add 225+ng of methanesulfonyl chloride and 250mg of triethylamine, and stir at room temperature overnight. 6. Wash the reaction solution with a saturated aqueous sodium bicarbonate solution, then evaporate the solvent, and dissolve the residue in benzene. 5d and dissolved in ethanol 5d,
Add 595 ml of 3-aminobenzoic acid and heat under reflux for 8 hours. After cooling, a solution of diazomethane in ethyl ether was added for esterification, and after concentration under reduced pressure, the residue was purified by silica gel column chromatography (Wakogel C-200, log, elution solvent: hexane/ethyl acetate = 871) to give 3-[5- (2-furyl)-2-isoindolinyl]benzoic acid methyl ester 161 mg (yield 62%)
) is obtained as a colorless crystalline powder.

109 mg of the above ester compound was added to 5 d of tetrahydrofuran.
Add 13IIIg of lithium aluminum hydride and stir at room temperature for 30 minutes. 1. Water and ethyl ether are added to the reaction mixture for extraction. After drying the organic layer, the solvent is distilled off to give the title compound 98 [(yield: 99%) is obtained as a colorless oil.

Reference Example 3 100 μm of N-(a+-tolyl)phthalimide was mixed with carbon tetrachloride.

1 g of N-bromosuccinimide 75II dissolved in
and 1M benzoyl peroxide were added, and the mixture was stirred under reflux for 3 hours.

After filtering off insoluble matter, the solvent was distilled off, ethyl acetate and water were added to the residue to separate the layers, and the organic layer was separated, washed with condensed water, and dried.

Then, the solvent was distilled off, and the residue was purified by silica gel column chromatography (Wako Gel C-200, 10 g, elution solvent: hexane/ethyl acetate = 10/1 → 5/1) to obtain N-(m-bromomethylphenyl). 200III g of phthalimide (quantitative yield) as a colorless crystalline powder.

m, p, 148-150°C.

70 mg of the above bromomethyl compound was dissolved in dimethylformamide 3d, and 41.6 m of (E)-N-methyl-6,6-dimethyl-2-hebuten-4-ynylamine hydrochloride was added.
g and 153 mg of potassium carbonate were added and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, water and ethyl acetate were added to the residue to separate the layers, the organic layer was washed with water, dried, and the solvent was distilled off.

The residue was then subjected to silica gel column chromatography (Wakogel C-200, 10 g, elution solvent: hexane/
Purification by ethyl acetate (1071-571) gives 50 mg (59% yield) of the title compound as a colorless wave.

Reference Example 4 6,6-dimethyl-2-hepten-4-ynyl bromide (E form: 2
1.5 g of methanol solution (I
Add M) dropwise over 1 hour. After adding 1 drop, stir at room temperature for 3 hours. 6. After concentrating the reaction solution under reduced pressure, add 5% aqueous sodium hydroxide solution and methylene chloride to the residue to separate the liquid and collect the mM. It is then dried with anhydrous magnesium sulfate. After filtering off the drying agent, the solvent was distilled off, and the residue was purified by silica gel column chromatography (Wakogel C-100, 100 g, elution solvent: methylene chloride/methanol = IO/1) to obtain the free base of the title compound. This was then treated with hydrogen chloride-methanol and crystallized by adding hexane to give 1.1 g (yield 68%) of the title compound 9 as colorless prism crystals.
p, 176-178°C.

obtained as.

Procedural amendment (voluntary) X Example: The compound of the present invention inhibits cholesterol biosynthesis and lowers blood cholesterol levels by inhibiting squalene epoxidase in 1 liter mammals. Therefore, diseases caused by excess cholesterol2 such as obesity,
It can be expected to be effective as a therapeutic and preventive agent for hyperlipidemia, arteriosclerosis, and associated heart and brain diseases.

2. Name of the invention 3. Person who makes corrections Relationship to the incident: Patent applicant

Claims (5)

[Claims] (1) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] [In the formula, A represents a methine group, nitrogen atom, oxygen atom, or sulfur atom; Q consists of a nitrogen atom, an oxygen atom, and a sulfur atom. may contain one or two heteroatoms selected from the group and together with the adjacent carbon atoms and A are 5- or 6-membered
A group forming a member aromatic ring (the aromatic ring may have one substituent or two same or different substituents selected from the group consisting of a halogen atom, a hydroxyl group, a lower alkyl group, and a lower alkoxy group) represents; X represents a methylene group or a methine group or is absent; Y represents a methylene group, a methine group or a carbonyl group; R and R^1 may be the same or different, and each represents a hydrogen atom , halogen atom, cyano group, hydroxyl group, lower alkyl group, lower alkoxy group, lower alkenyl group, lower alkynyl group, lower hydroxyalkyl group, lower alkenyloxy group, optionally substituted phenyl group, optionally substituted Represents a heterocyclic group; R^2 represents a hydrogen atom or lower alkyl group; R^3
represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a cycloalkyl group; R^4 and R^5 may be the same or different, and each represents a hydrogen atom or a halogen atom; R^ 6 is an optionally substituted acyclic hydrocarbon group (the acyclic hydrocarbon group may contain one or two unsaturated bonds selected from the group consisting of double bonds and triple bonds), substituted An optionally substituted allylamine derivative and a non-toxic salt thereof. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] [In the formula, A, Q, X, Y, R, R^1, R^2 and R^
3 has the meaning defined in the first claim], or its appropriately protected compound has the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [III] [In the formula, Z indicates a leaving group; R^4, R^5 and R^6
has the meaning defined in the first claim] or an appropriately protected derivative thereof, and then, if necessary, the protecting group is removed, or the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ [IV] A compound represented by [wherein A, Q, X, Y, R, R^1, R^2 and Z have the above meanings] or an appropriately protected derivative thereof , general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [V] Substituted amine derivatives represented by [wherein R^3, R^4, R^5 and R^6 have the above meanings], or a compound represented by the general formula [I] according to the first claim, characterized in that the compound is treated with an appropriately protected compound thereof, and then, if necessary, the protecting group is removed, and then, if necessary, it is converted into a non-toxic salt. A method for producing substituted allylamine derivatives and non-toxic salts thereof. (3) A hyperlipidemia treatment agent comprising a substituted allylamine derivative represented by the general formula [I] and a nontoxic salt thereof according to the first claim as an active ingredient. (4) An agent for treating arteriosclerosis, which contains as an active ingredient a substituted allylamine derivative represented by the general formula [I] and a non-toxic salt thereof according to the first claim. (5) A high cholesterol treatment agent comprising a substituted allylamine derivative represented by the general formula [I] and a nontoxic salt thereof according to the first claim as an active ingredient.