CN1042910A - The allylamine derivatives that replaces, their production method and application thereof - Google Patents

The allylamine derivatives that replaces, their production method and application thereof Download PDF

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CN1042910A
CN1042910A CN89109196A CN89109196A CN1042910A CN 1042910 A CN1042910 A CN 1042910A CN 89109196 A CN89109196 A CN 89109196A CN 89109196 A CN89109196 A CN 89109196A CN 1042910 A CN1042910 A CN 1042910A
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竹沢弘
林正弘
岩沢善一
细井正明
飯田好昭
土谷羲已
堀江雅弘
亀井敏夫
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MSD KK
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Banyu Phamaceutical Co Ltd
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Priority claimed from PCT/JP1989/000522 external-priority patent/WO1990005132A1/en
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses the allylamine derivatives of the replacement that following general formula represents or its non-toxic salt and preparation method thereof,
Wherein, A 1, A 2, Q 1, Q 2, X, Y, R 1, R 2, R 3, R 4, R 5, R 6And R 7Be defined as in the description.Above-claimed cpd is used to suppress the Mammals squalene epoxidase, and is used for treating hypercholesterolemia.Hyperlipoidemia and arteriosclerosis.

Description

The allylamine derivatives that replaces, their production method and application thereof
The present invention relates to the allylamine derivatives of new replacement, more specifically say so and be applied to pharmaceutical field, especially for the allylamine derivatives and the salt thereof of treatment and prevention hypercholesterolemia, hyperlipoidemia and arteriosclerotic replacement, their production method and application thereof.
Arteriosclerosis is and age and the closely-related sex change artery disease of diet, and be considered to the cause of death of crown and arteriae cerebri disease-at present primary-cause.Owing to lipid begins arteriosclerosis in the deposition of big vascular endothelium, with age, its degree is increasing at an early age, demonstrate clinical symptom at last, as myocardial infarction and stenocardia, cerebralarteriosclerosis as the local asphyxia heart disease, as cerebrum block, and aneurysma.The increase of having known various blood fat is relevant with the deposition of this lipid, and particularly the increase of blood cholesterol is most important Hazard Factor, is the most effective treatment and prevention of arterial hardened means and make blood cholesterol levels be reduced to normal value.It is said that the cholesterol in human body more than 50% comes from do novo biosynthesizing.At present, be that the lovastatin of enzyme inhibitors and eptastatin are applied the hypercholesterolemia medicament clinically [as referring to A.W.Alberts etc. in de novo biosynthetic process, proc.Natl.Acad.Sci., 773957(1980) and Tsujita etc., Biochim.Biophs.Acta, 877 50(1986)].But it is biosynthetic early stage that the target enzyme 3-hydroxy-3-methyl glutaryl-CoA-reductase of these inhibitor is in cholesterol, therefore uses these medicines also can suppress other important biological metabolite dolichol and ubiquinone.Moreover, report that the inhibitor triparnol in cholesterol biosynthetic process later stage causes cataractous reason owing to the accumulation of desmosterol becomes.Because squalene epoxidase is in mid-term of cholesterol biosynthetic process, therefore wishing has the inhibitor of this kind of enzyme to solve this problem, and used as the hypercholesterolemia medicament of high safety.
Known that some compound is the inhibitor [see G.Petranyi etc., Science, 224 1239(1984)] of squalene epoxidase.But all these is developed as anti-mycotic agent, and they optionally suppress the fungi squalene epoxidase.Up to the present, do not suppress the inhibitor of mammalian enzyme, be not used as the inhibitor of anticholesteremic agent yet.
Primary and foremost purpose of the present invention provides a kind of lipid-lowering agent, and arteriosclerotic treatment and preventive, and it is better than the lipid-lowering agent of present use, and is safer.
In order to develop new arteriosclerosis agent, the inventor has studied has the active squalene epoxidase inhibitor of hypercholesterolemia, and the selectivity that the allylamine derivatives of having found the replacement of logical formula I has mammiferous squalene epoxidase suppresses, and has the activity of very strong hypercholesterolemia.
The invention provides the allylamine derivatives of the replacement of representing with following general formula, and non-toxic salt, their production method, and their application in treatment hypercholesterolemia, hyperlipoidemia and arteriosclerosis,
Wherein
A 1And A 2Identical or different, each represents methyne or nitrogen, oxygen or sulphur atom;
Q 1And Q 2Identical or different, each expression contains 1 or 2 heteroatomic group that is selected from a group that is made up of nitrogen, oxygen and sulphur atom, this group and adjacent carbon atom and A 1Or A 2Form 5 yuan or 6 yuan of aromatic rings together;
X and Y are identical or different, and each represents oxygen or sulphur atom, carbonyl, formula-CHR a-group, wherein R aExpression hydrogen atom or low alkyl group, or formula-NR b-group, wherein R bExpression hydrogen atom or low alkyl group, or X and Y form vinylene or ethynylene together;
R 1Expression contains 1-4 heteroatomic 5 yuan or 6 yuan of heterocyclic radicals of being selected from one group that is made up of nitrogen, oxygen and sulphur atom;
R 2Expression low alkyl group, allyl group, propargyl or cyclopropyl;
R 3And R 4Identical or different, each represents low alkyl group, perhaps forms cycloalkyl jointly with adjacent carbon atom together;
R 5Expression hydrogen atom, low alkyl group or lower alkoxy; With
R 6And R 7Identical or different, each represents hydrogen atom, halogen atom, hydroxyl, cyano group, low alkyl group, or lower alkoxy;
Condition be in X and Y expression Sauerstoffatom, sulphur atom or-NR b-(R wherein bAs definition) during group, another expression carbonyl or-CHR a-(R wherein aAs definition) group.
The present invention is described in detail in detail below.
Known to have following structural formula
Figure 891091963_IMG23
Naftifine and terbinafine are that the allylamine derivatives of representative has shown strong inhibitory activity to the squalene epoxidase of Mycophyta, and the result is used as anti-mycotic agent [see G.Petranyi etc., Science, 244 1239(1984)].But these compounds show hardly the squalene epoxidase of the mammal that comprises the people and suppress active, can not be as cholesterol synthetic inhibitor [see N.S.Ryder etc., Biochemical, Journal, 230765(1985)].
For develop can selectively acting in the Mammals squalene epoxidase and demonstrate the active medicine of hypercholesterolemia, the contriver has carried out extensive studies.As a result, the contriver finds, when the naphthalene nucleus of above mentioned naftifine and terbinafine by following formula 1,5 yuan of replacing of 3-or 6 yuan of aromatic ring yls can obtain Mammals squalene-epoxidase is shown the compound of strong inhibitory activity when substituting,
Figure 891091963_IMG24
R wherein 7, A 2And Q 2As the definition, on its 3-position by formula
Group replace R wherein 1, R 6, A 1, Q 1, X and Y be as definition.
The inventor finds that also squalene-epoxy the enzyme inhibition activity of general formula [I] compound is very selective, enzyme to Mycophyta shows activity hardly, and this compound is very valuable thing as treatment and prevention hypercholesterolemia, hyperlipoidemia and arteriosclerotic medicine.
Now, explain the definition and the specific examples of the various terms of mentioning in this description.
Term " rudimentary " is used for limiting group or compound, and it is no more than 6 to be meant that limited group or compound have, individual preferably no more than 4 carbon atoms.
Accordingly, for example low alkyl group includes alkyl straight chain or side chain of 1-6 carbon atom, as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl and hexyl.The example of lower alkoxy preferably includes the alkoxyl group of the straight or branched of 1-4 carbon atom, as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert.-butoxy.Cycloalkanes is meant the cycloalkanes of 3-6 carbon atom, and its specific examples is cyclopropane, tetramethylene, pentamethylene and hexanaphthene.Halogen atom is meant fluorine, chlorine, bromine or iodine atom.
Open the present invention is more specifically with the compound of general formula [I] expression, and various symbols used in the general formula [I] will be explained when enumerating preferred embodiment in detail.
Available R 1Expression, contain 1-4 example that is selected from heteroatomic 5 yuan or the 6 yuan heterocyclic radicals of nitrogen, oxygen and sulphur and comprise aromatic heterocycle, as pyrryl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, furazan base, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl and triazinyl group; Non-aromatic heterocyclic radical such as dihydro-thiophene base, tetrahydro-thienyl, pyrrolinyl, pyrrolidyl oxazolinyl oxazolidinyl isoxazoline-3-yl isoxazole alkyl, thiazolinyl, thiazolidyl, the isothiazoline base, the isothiazole alkyl, 1,2-dithiolane base, 1,3-dithiolane base, 1,2-dithiole base, 1,3-dithiole base, dihydro thiapyran base, tetrahydro thiapyran base, 1,4-dithiane base, 1,4-dithia English base (1,4-dithiinyl) 1,4-oxa-thia English base (1,4-oxathiinyl) with the thio-morpholinyl group.In these groups, thienyl, pyrryl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyridyl and dihydro-thiophene base are preferred.Particularly preferably be the 3-thienyl, 1-pyrryl, 5-oxazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyridyl, 2,3-dihydro-4-thienyl and 2,5-dihydro-3-thienyl group.
X and Y can be identical or different as mentioned above, and each represents Sauerstoffatom, sulphur atom, carbonyl, formula-CHR a-group-(R wherein aExpression hydrogen atom or low alkyl group) or formula-NR b-group (R wherein bExpression hydrogen atom or low alkyl group); Or X and Y represent vinylene or ethynylene together, and condition is expression Sauerstoffatom, sulphur atom or formula-NR in X and Y b-group, another expression carbonyl or formula-CHR a-group.Specifically, the group that usefulness-X-Y-represents can be, for example-and (CHR a) 2-,-CHR aO-,-OCHR a-,-CHR aS-,-SCHR a-,-CHR aNR b-,-NR bCHR a,-CHR aCO-,-COCHR a-,-COO-,-OCO-,-COS-,-SCO-,-CONR b-,-NR bCO-,-CH=CH-and-C ≡ C-(formula in, R aAnd R bDefinition as mentioned).Wherein, ethylene, (E)-vinylene, formula-CH 2O-group, formula-CH 2S-group and formula-CH 2The NH-group is preferred.
R 2Expression low alkyl group, allyl group, propargyl or cyclopropyl.The example of preferred low alkyl group is the straight or branched low alkyl group that 1-5 carbon atom arranged, as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-and amyl group.Methyl, ethyl, propyl group, allyl group or propargyl preferentially are elected to be R 2On substituting group, most preferably methyl, ethyl and propyl group.
R 3And R 4Identical or different, represent low alkyl group separately, perhaps when key connected together, their represented the naphthene group with adjacent carbons formation.Preferred low alkyl group is the straight chain low alkyl group that 1-4 carbon atom arranged, as methyl, ethyl, propyl group and butyl.Preferred naphthenic example is cycloalkanes such as cyclopropane, tetramethylene, pentamethylene and the hexanaphthene that 3-6 carbon atom arranged.
As R 3And R 4On substituting group, preferably methyl, ethyl, propyl group and form the group of cyclopropane ring, most preferably methyl with adjacent carbons.
R 5Expression hydrogen atom, low alkyl group or lower alkoxy.Preferred low alkyl group is the straight or branched low alkyl group that 1-5 carbon atom arranged, as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl and amyl group.The example of preferred lower alkoxy is the straight or branched alkoxyl group that 1-4 carbon atom arranged, as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert.-butoxy, wherein, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, propoxy-and isopropoxy are preferred, and methyl, ethyl and methoxyl group are most preferred.
The aromatic ring of expression can be identical or different, preferably comprise and contain 1-3 heteroatomic aromatic ring that is selected from a group that forms by nitrogen, oxygen and sulphur atom, for example benzene, pyrroles, furans, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazoles, 1,3,4-oxadiazole, 1,3,4-thiadiazoles, pyridine, pyridazine, pyrimidine, pyrazine and triazine ring.Use following formula
Figure 891091963_IMG27
The aromatic ring of expression particularly preferably is benzene or thiphene ring.
In the top aromatic ring, most preferably unsubstituted.If desired, they can have substituting group, as halogen atom, hydroxyl, cyano group, low alkyl group or lower alkoxy.Substituent example has hydroxyl, fluorine atom, chlorine atom, methyl, ethyl and methoxyl group.
Like this, the preferred embodiment of compound provided by the invention is the allylamine derivatives of the replacement of general formula [I], wherein R 1It is pyrryl, furyl, thienyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, the furazan base, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, the dihydro-thiophene base, tetrahydro-thienyl, pyrrolinyl, pyrrolidyl oxazolinyl oxazolidinyl isoxazoline-3-yl isoxazole alkyl, thiazolinyl, thiazolidyl, the isothiazoline base, the isothiazole alkyl, 1,2-dithiolane base, 1,3-dithiolane base, 1,2-dithiole base, 1,3-dithiole base, dihydro thiapyran base, tetrahydro thiapyran base, 1,4-dithiane base, 1,4-dithia English base, 1,4-oxa-thia English base or thio-morpholinyl; Use following formula
The expression 5 yuan or 6 yuan of aromatic rings can be identical or different, each represents benzene, pyrroles, furans, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazoles, 1,3,4-oxadiazole, 1,3,4-thiadiazoles, pyridine, pyridazine, pyrimidine, pyrazine or triazine ring; X and Y are identical or different, and each represents Sauerstoffatom, sulphur atom, carbonyl, formula-CHR a-group (R aExpression hydrogen atom or low alkyl group) or formula-NR b-group (R bExpression hydrogen atom or low alkyl group), or X and Y represent together vinylene or ethynylene [condition be among X and the Y one be Sauerstoffatom, sulphur atom or-NR b-group (R bAs the definition) time, another be carbonyl or-CHR a-group (R aAs definition)]; R 2Be low alkyl group, allyl group, propargyl or cyclopropyl; R 3And R 4Identical or different, each represents low alkyl group, or the two key naphthene group that expression forms jointly with adjacent carbons that connects together; R 5Be hydrogen atom, low alkyl group or lower alkoxy; R 6And R 7Identical or different, each represents hydrogen atom, halogen atom, hydroxyl, cyano group, low alkyl group or lower alkoxy.
The group of preferred general formula [I] compound comprises its Chinese style
Aromatic ring be benzene or thiphene ring.
The group of preferred general formula [I] compound is R wherein 1Be thienyl, pyrryl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyridyl or dihydro-thiophene base; Following formula
Aromatic ring be benzene or thiphene ring; And the aromatic ring of representing with following formula
Be benzene, pyrroles, furans, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazoles, 1,3,4-oxadiazole, 1,3,4-thiadiazoles, pyridine, pyridazine, pyrimidine, pyrazine or triazine ring.
The group of further preferred general formula [I] compound is R wherein 1Be 3-thienyl, 1-pyrryl, 5-oxazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyridyl, 2,3-dihydro-4-thienyl or 2,5-dihydro-3-thienyl; Use following formula
Figure 891091963_IMG32
The aromatic ring of expression is benzene or thiphene ring; And following formula
Figure 891091963_IMG33
The aromatic ring of expression is benzene, furans, thiophene, oxazole, isoxazole, thiazole, isothiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazoles, pyridine, pyridazine, pyrimidine or pyrazine ring.
The particularly preferred group of general formula [I] compound is R wherein 1Be 3-thienyl, 1-pyrryl, 5-oxazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyridyl, 2,3-dihydro-4-thienyl or 2,5-dihydro-3-thienyl; X is a methylene radical; Y is methylene radical, Sauerstoffatom, sulphur atom or imido grpup, or X and Y represent (E)-vinylene together; The aromatic ring of representing with following formula
Be benzene or thiphene ring; The aromatic ring that following formula is represented
Figure 891091963_IMG35
Be benzene, furans, thiophene, oxazole, isoxazole, thiazole, isothiazole, 1,3,4-oxadiazoles, 1,3,4-thiadiazoles, pyridine, pyridazine, pyrimidine or pyrazine ring; R 2Be low alkyl group, allyl group, propargyl or cyclopropyl; R 3And R 4Identical or different, as to represent to connect together low alkyl group or the two key separately expression forms with adjacent carbons cycloalkyl; R 5Expression hydrogen atom, low alkyl group or lower alkoxy; And R 6And R 7Identical or different, each represents hydrogen atom, halogen atom, hydroxyl, cyano group, low alkyl group or lower alkoxy.
The most preferred group of general formula [I] compound is R wherein 1Be 3-thienyl, 1-pyrryl, 5-oxazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyridyl, 2,3-dihydro-4-thienyl or 2,5-dihydro-3-thienyl; By following formula
The aromatic ring of expression is benzene or thiphene ring, uses following formula
The aromatic ring of expression is benzene, furans, thiophene, oxazole, isoxazole, thiazole, isothiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazoles, pyridine, pyridazine, pyrimidine or pyrazine ring; R 2Be methyl, ethyl or propyl group; R 3And R 4It is methyl; R 5Be methyl, ethyl or methoxyl group; And R 6And R 7It is hydrogen atom.
The allylamine derivatives that formula [I] replaces can acid salt form exist.The example of this acid salt comprises inorganic acid salt such as hydrochloride, hydrobromide, hydriodide, vitriol, nitrate, perchloride and phosphoric acid salt; And organic acid salt such as tosilate, benzene sulfonate, mesylate, oxalate, succinate, tartrate, Citrate trianion, fumarate and maleate.Those pharmaceutically acceptable non-toxic salt are preferred.Formula provided by the invention [I] compound can comprise steric isomer such as geometrical isomer and optical isomer.The present invention includes all these steric isomers and composition thereof.
The general method of The compounds of this invention is produced in narration below.
The compounds of this invention with general formula [I] expression can be produced with any one method among following method A, B, C, D, E and the F.
Figure 891091963_IMG38
Figure 891091963_IMG39
In the formula, Z represents leavings group; X aAnd Y bExpression carbonyl or formula-CHR a-(R wherein aDefinition as mentioned) group; X bAnd Y aExpression Sauerstoffatom, sulphur atom or formula-NR b-(R wherein bDefinition as mentioned) group; And A 1, A 2, Q 1, Q 2, R 1, R 2, R 3, R 4, R 5R 6And R 7Definition as mentioned.
Method A, B and C are the alkylations of the amine known in the Synthetic Organic Chemistry field, and therefore available known usual way itself is finished.In these methods each reacts available does not have the solvent of disadvantageous effect to carry out to reaction.The example of this solvent comprises aromatic hydrocarbons, as benzene, toluene and dimethylbenzene; Ether is as ether, tetrahydrofuran (THF) and dioxan; Halon is as methylene dichloride, chloroform and ethylene dichloride; Alcohol is as ethanol and Virahol; Dimethyl formamide, acetonitrile and dimethyl sulfoxide (DMSO); And their mixture.Usually, in method A, compound [II] and [III] are molar ratio reaction such as to be bordering on.In method B, compound [IV] and [V] are molar ratio reaction such as to be bordering on.In method C, compound [VI] and [VII] are molar ratio reaction such as to be bordering on.In addition, have in the reactant a kind of can be slightly excessive.The reaction conditions that use this moment is that temperature of reaction is generally-20 to 150 ℃, and preferably from the room temperature to the solvent boiling point, the reaction times is generally 5 minutes to 10 days, preferably 1 to 24 hour.For reacting balance is carried out, the above-mentioned alkali that is reflected at carries out under existing more favourable.The example of the alkali that use this moment is an alkalimetal hydride, as sodium hydride, lithium hydride and potassium hydride KH; Basic metal or alkaline earth metal hydroxides are as sodium hydroxide, potassium hydroxide and calcium hydroxide; Alkaline carbonate is as salt of wormwood and sodium bicarbonate; Organic amine is as triethylamine and pyridine.The amount of alkali does not have standard, can change in wide region, and general every mole of initial compounds is used 1 mole at least, preferably the 1-2 mol alkali.
Method D and E be used for synthetic with wherein-the X-Y-group is-COO-,-OCO-,-CONR b-,-NR bCO-,-CHR aO-,-OCHR a-,-CHR aS-or-SCHR a-(R wherein aAnd R bAs the definition) formula [I] compound corresponding compounds [I a] or [I b].Method D and E carry out in the solvent that reaction is not had disadvantageous effect, as tetrahydrofuran (THF), diox, chloroform, benzene, acetone, dimethyl formamide or methyl-sulphoxide, be compound [VIII] and [IX] reaction under method D situation, being compound [X] and [XI] under method E situation reacts to be bordering on etc. to have under a kind of slightly excessive condition in mol ratio or the used reactant.The reaction conditions of this moment such as used temperature and time according to raw materials used be different.Generally, temperature of reaction is-70 to 100 ℃, and preferably-20 to 50 ℃, the reaction times is 1 minute to 24 hours, preferably 30 minutes-5 hours.For reacting balance is carried out, this reaction is preferably under the alkali existence to be carried out.This moment, the example of used alkali comprised mineral alkali, as sodium hydride, lithium hydride, sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate and saleratus; And organic bases, as pyridine, triethylamine and dimethyl aminopyridine.The alkali number that uses does not have strict restriction, and common every mole of initial compounds is used at least 1 mole, preferably the 1-2 mole.
Method F be produce with wherein-the X-Y-group is-CH 2Corresponding formula [the I of the formula of NH-base [I] compound c] compound.
Method F makes compound [XII] and compound [X III] condensation form imines in benzene or alcohol, afterwards product is also finished originally.Used reagent in the reductive action for example can be sodium borohydride, cyano group sodium borohydride or lithium aluminum hydride.This reaction can be for example in methyl alcohol, ethanol or tetrahydrofuran (THF), 0 ℃ under the room temperature reaction finished in 1 to 6 hour.If formula [II], [III], [IV], [V], [VI], [VII], [VIII], [IX], [X], [XI], [XII] and [X III] initial compounds have such as hydroxyl or amino active function groups; except that hydroxyl, sulfydryl or the amino of participating in reaction; when needing; active function groups can be protected, and after reaction, blocking group be separated.Here used protecting group is the group that is easy under acidity or alkaline condition by the hydrolysis removal, and example comprises methoxyl methyl, THP trtrahydropyranyl, trityl, dimethyl-(tertiary butyl) silyl, formyl radical, ethanoyl, methoxycarbonyl, ethoxycarbonyl and tertbutyloxycarbonyl group.
The formula that obtains like this [I] purpose compound can be such as column chromatography, solvent extraction, precipitation, recrystallization method separately or be used in combination and separate and purifying.When needing, the compound [I] of free alkali form can be converted into its acid salt, or also can be converted into free alkali to acid salt.Free alkali is changed into the step of its acid salt, and acid salt is changed into the step of free alkali, the method with commonly used adopts corresponding acid or alkali to be easy to finish.
With the leavings group that Z represents, for example can be halogen atom, as chlorine, bromine or iodine atom, or organic sulfonyloxy, as mesyloxy or tolysulfonyl oxygen base.
Formula [II] to the initial compounds of [X III] be can buy on the market maybe can be by the described method of document, [J.Med.Chem.27 1539(1984), the same, 29 112(1986), Japanese publication specification sheets 32440/1981,123177/1982,208252/1983,45/1986,201850/1987 and 5059/1988], and following listed common method or basically with the preparation of the corresponding method of these methods.
The used initial compounds of the present invention can be with preparing such as the synthetic method of listing below.
Produce route [a]
Figure 891091963_IMG41
Figure 891091963_IMG42
Produce route [c]
Produce route [d]
Produce route [e]
Figure 891091963_IMG45
Produce route [f]
[in the formula, X cAnd Y cIdentical or different, each represents Sauerstoffatom, sulphur atom, carbonyl, formula-CHR a-group (R wherein aDefine as mentioned) or formula-NR b-group (R wherein bDefinition as mentioned); R 8The expression low alkyl group; R 9Expression hydrogen atom, low alkyl group or lower alkoxy; B represents hydrogen atom or blocking group; And A 1, A 2, Q 1, Q 2, X, Y, X a, X b, Y a, Y b, Z, R 1, R 2, R 3, R 4, R 5, R 6And R 7Definition as mentioned; Condition is to work as X cAnd Y cExpression Sauerstoffatom, sulphur atom or a formula-NR are arranged b-group (R wherein bAs definition) time, another expression carbonyl or formula-CHR a-(R wherein aDefinition as mentioned).]
Produce route (a)
Making the compound [X IV] and the step of compound [VIII] reacting generating compound [X VI] is at-20 to 100 ℃, in solvent, in the presence of alkali, make to be bordering on that equimolar compound [X IV] and [VIII] reaction finished in 2 to 3 hours such as sodium hydride, sodium hydroxide or salt of wormwood such as tetrahydrofuran (THF), chloroform or dimethylformamide.
The step of compound [X V] and [X] reacting generating compound [X VI] can the mode identical with [VIII] reactions steps with compound [X IV] be finished.
Make compound [X VI] and [X VIII] reacting generating compound [II a] step can be with for example making compound [X VI] and [X VIII] condensation in benzene or alcohol form imines, reduzate perhaps makes excessive compound [X VIII] and compound [X VI] reaction, and also finished originally simultaneously then.Agents useful for same can be such as sodium borohydride, cyano group sodium borohydride or lithium aluminum hydride in reduction this moment.Reaction can for example 0 ℃ to the room temperature in methyl alcohol, ethanol or tetrahydrofuran (THF) reaction finished in 1 to 6 hour.
The step that reducing compound [X VI] generates compound [X VII] is with for example making compound [X VI] quilt such as sodium borohydride, cyano group sodium borohydride or lithium aluminium hydride reduction agent, finishes in 1 to 5 hour to room temperature treatment in 0 ℃ in such as the solvent of methyl alcohol, ethanol or tetrahydrofuran (THF).
Compound [X VII] is changed into compound [IV a] step with for example in as the solvent of chloroform or methylene dichloride or do not having under the situation of solvent, use such as methylsulfonyl chloride sulphonating agent and triethylamine or such as the halogenating agent processing of thionyl chloride or phosphorus tribromide to room temperature in-20 ℃ and to finish in 1 to 5 hour.
Produce route (b)
Make the step of compound [X IX] and [XII] reacting generating compound [XX] in as the solvent of tetrahydrofuran (THF), handle these compounds such as the alkali of n-Butyl Lithium or sodium hydride and finished in 1 to 6 hour with for example using to the room temperature at 0 ℃.
Reducing compound [XX] generates compound [X VII a] step can be in solvent such as ether or tetrahydrofuran (THF), finished in 1 to 5 hour with the processing compound of the reductive agent as lithium aluminum hydride [XX].
Reducing compound [XX] or oxygenated compound [X VII a] generation compound [X VI a] step can with for example in toluene with diisobutyl aluminium hydride reducing compound [XX] or in methylene dichloride with pyridinium chlorochromate oxygenated compound [X VII a] finish.
With compound [X VII a] be converted into compound [IV b] step and make compound [X VI a] and [X VIII] reacting generating compound [II b] step can make compound [X VII] change into compound [IV with producing in the route (a) a] step and make compound [X VI] and compound [X VIII] reacting generating compound [II a] the identical mode of step finish.
Produce route (c)
Make compound [X XI] and compound [X XII] or make compound [XX III] and compound [XII] reacting generating compound [X VII a] step can with produce route (b) in compound [X IX] route identical with the step of compound [XII] reacting generating compound [XX] finished.
With compound [X VII a] be reduced into compound [X VII b] step can in the presence of as palladium carbon catalyst,, carry out catalytic reduction under the normal pressure and finish in 1 to 10 hour with for example in such as methyl alcohol or alcoholic acid solvent in room temperature.
With compound [X VII a] change into [X VII c] step can finish by following reaction: in the organic solvent such as methylene dichloride, chloroform or ether, in 0 to 60 ℃ makes compound [X VII a]; Perhaps use this form; perhaps protecting later on and bromine reaction 0.5-3 hour with suitable protecting group; concentrate gained solution to doing; then in the presence of the alkali that has such as sodium hydroxide or potassium hydroxide; in alcoholic solution, handled resistates 1-10 hour in the boiling point of solvent such as methyl alcohol, ethanol or Virahol.
With compound [X VII b] change into compound [IV c] step and with compound [X VII c] change into compound [IV d] step can be by compound [X VII] is changed into compound [IV a] step carry out.
Produce route (d)
Make compound [X VI b] and compound [V a] step of reacting generating compound [VI] makes compound [X VI] and compound [X VIII] reacting generating compound [II by producing in the route (a) a] the identical route of step carry out.
Here used compound [V a] can use, for example the Jia Buliaier method is produced, the alkali that this method is included in such as sodium hydroxide or salt of wormwood exists down, in 10 to 100 ℃ make compound [III] and phthalic imidine reacting generating compound [XX IV] in such as the solvent of tetrahydrofuran (THF) or dimethyl formamide, itself and hydrazine are reacted in such as ethanol or dimethyl formamide and generate compound [V a].
Produce route (e)
Make compound [X IV a] with the step of compound [X VIII] reacting generating compound [XX VII] can with make compound [X VI] and compound [X VIII] reacting generating compound [II A]The method that step is identical is carried out.Reducing compound [X IV a] generate compound [XX V], make its step that is converted into compound [XX VI] can produce reducing compound [X VI] generation compound [X VII] in the route (a) then, then it is converted into compound [IV a] the identical method of step carry out.
Make compound [XX VI] and compound [V] reacting generating compound [IX]; perhaps make compound [XX VII] and compound [III] reacting generating compound [XX VIII]; when needed then, the step of this product deprotection can the method identical with method A mentioned above or B be carried out.
The protecting group of representing with B in the used initial compounds in producing route (e) can be to be used as in the kinds of protect base of hydroxyl, sulfydryl or amino protecting group any one in the Synthetic Organic Chemistry field.Object lesson comprises methoxyl methyl, THP trtrahydropyranyl, trityl, tertbutyloxycarbonyl and dimethyl (tertiary butyl) silyl-group.
Produce route (f)
The step that reducing compound [XX IX] generates compound [XXX] is the partial reduction effect, and it has utilized the difference of carbonyl reactive behavior in reductive action of coexistence.It can be for example in such as ethanol or tetrahydrofuran solvent, with 1 to 2 normal such as sodium borohydride or diisobutyl aluminium hydride reductive agent make compound [XX IX]-20 ℃ to the room temperature reduction finished in 1-5 hour, perhaps catalyzer is being arranged, catalytic reduction was finished in 1 to 5 hour under existing as palladium-carbon.Compound [XXX] is changed into compound [XX XI], make the step of it and compound [V] reacting generating compound [XX XII] be converted into compound [XX VI] to compound [XX V] with producing in the route (e) then, its method identical with the step of compound [V] reacting generating compound [XX VIII] is carried out.
Make compound [XX XII] transform the step that generates compound [XXX III], wherein Y bBe formula-CHR a-group (R wherein aUnder the situation of pure product [XXX III] definition as mentioned), by also finishing originally, perhaps at Y bUnder the situation for the carboxylic acid product [XXX III] of carbonyl, finish by hydrolysis.Reducing compound [XX XII] generates the step of pure product [XXX III] and can the method identical with the step of producing middle reducing compound [X VI] the generation compound of route (a) [X VII] finish, perhaps to generate compound [X VII with the middle reducing compound [XX] of production route (b) a] the identical method of step finish.The step that hydrolysis compound [XX XII] generates corresponding carboxylic acid compound [XXX III] can contain in the solvent such as aqueous ethanol or water-containing tetrahydrofuran as the alkali of sodium hydroxide that waits mole or molar excess with for example compound [XX XII] being dissolved in, and maintenance solution was finished in 1 to 10 hour under room temperature to 100 ℃ temperature.
The step that compound [XXX III] transform is generated compound [XI] can be by in such as the solvent of chloroform or methylene dichloride or do not having to use under the condition of solvent and handle compound [XXX III] at-20 ℃ to the room temperature such as halogenating agents such as thionyl chloride or tribromo phosphorus and finished in 1 to 5 hour.
If desired, the product that obtains in above-mentioned each stage can be with carrying out purifying such as chromatography, recrystallization, solvent extraction, precipitation and distillation or separate, and these methods can be used separately or suitably be used in combination.
Can be easy to buy as the compound of the starting raw material of intermediate product as commodity, or be easy to by the method for describing in the document [for example, J.Med.Chem.27 1539(1984); The same, 29 112(1986); With Japanese publication specification sheets NOS.32440/1981,123177/1982,208252/1983,45/1986,201850/1987 and 5059/1988] and Synthetic Organic Chemistry in known synthetic method production.
The The compounds of this invention of general formula [I] expression is the useful compound that suppresses the Mammals squalene epoxidase very selectively, consumingly, and expection can be used as lipid-lowering agent or arteriosclerosis agent.
In order to prove this point, will provide drug test embodiment and acute toxicity test embodiment below.
Pharmacological testing embodiment 1
It is active that squalene epoxidase suppresses
(1) preparation of squalene epoxidase
Use J.Biol.Chem.245 1670(1970); And the same, 250 1572(1975) described in method prepare the rat squalene epoxidase.
Kill SD strain female rats with depletion method, with liver (PH7.5) extraction and homogenizing in 2 volume 0.1M Tutofusin tris-hydrochloric acid (Tris-Hcl) buffered soln, homogenate centrifugal 10 minutes at 9750Xg.Supernatant liquid centrifugal again 1 hour in 105000Xg.Settling was with 0.1M Tirs-Hcl buffered soln (PH7.5) washing, in 105000Xg centrifugal 1 hour then.The microsome that obtains is suspended in the 0.1M Tris-Hcl buffered soln (PH7.5), and like this, proteinic amount is 40mg/ml, and under ice-cooled, stirred suspension makes the enzyme dissolving when 2% Triton X-100 is arranged.After the dissolving, to containing 1mM EDTA and 1mM dithiothreitol (DTT), concentration is among 0.5% the Triton X-100 solution dilution, in 105000Xg centrifugal 1 hour.Partly use as squalene epoxidase in the test below of gained supernatant liquid part.
(2) measure the active method of squalene epoxidase
According to J.Biol.Chem 245 1670(1970) described method mensuration squalene epoxidase activity.
The dimethyl sulfoxide solution of 3 microlitre trial drugs is added the solution with following composition: the squalene epoxidase part 0.2ml[protein 0.4mg of preparation in (1), 0.5% Triton X-100,20 μ M Tris-Hcl buffered soln (PH7.5)], 100 μ M FAD, 1mM NADPH, 1mM EDTA and 8 μ M 3H-squalene-tween 80 emulsion, the cumulative volume of adjusting solution is to 0.3ml.Solution was cultivated 30 minutes in 37 ℃ under vibration.Then, add 0.3ml 10% methanolic potassium hydroxide with stopped reaction, reaction mixture at room temperature left standstill 1 hour.Not saponified with petroleum ether extraction, and under nitrogen gas stream, be evaporated to solvent dried.The resistates that obtains is dissolved in in a small amount the ether, and on the silica gel tlc plate that coated is good in advance in the point, then launches, decide gained with the ergosterol acetic ester thing of marking with benzene/ethyl acetate (99.5: 0.5) 3H-squalene-2, the position of 3-epoxide is on the TLC 3H-squalene-2, the 3-epoxide moiety scales off.TLC is partly immersed toluene type scintillator, use liquid scintillation counter measurement.As a result, measure the 50% inhibition concentration (IC of The compounds of this invention to squalene epoxidase 50Value).The results are shown in table 1.
Table 1
It is active that squalene epoxidase suppresses
Trial drug 50% inhibition concentration (IC 50, nM)
Embodiment 2 compounds 7
Embodiment 3 compounds 4
Embodiment 8 compounds 11
Embodiment 9 compounds 6
Embodiment 15 compounds 60
Embodiment 19 compounds 27
Embodiment 25 compounds 33
Embodiment 26 compounds 31
Embodiment 31 compounds 26
Embodiment 33 compounds 26
Embodiment 47 compounds 26
Embodiment 48 compounds 23
Embodiment 51 compounds 34
Embodiment 54 compounds 21
Embodiment 56 compounds 34
Embodiment 70 compounds 11
Embodiment 74 compounds 22
Embodiment 78 compounds 33
Pharmacological testing embodiment 2
Active to the biosynthetic inhibition of cholesterol in culturing cell:
Human hepatocellular (Hep-G 2) cell is at 10cm 2Ware in cultivate up to forming monolayer.Shift out the 1ml developing medium, add 1 μ C; (microcurie) [ 14C] (dimethyl sulfoxide solution of trial drug, cell were cultivated 6 hours in 37 ℃ in the air that contains 5% carbonic acid gas for sodium acetate and 1 μ.
After the cultivation, extract medium out, with the cell water cooling, with the salts solution washing of Dulbecco phosphate buffered.The cell that obtains is drawn together out with rubber policeman, centrifugal collection.The cell of collecting is dissolved in 400 μ l0.3N sodium hydroxide.With the solution extraction of 200 μ l portions, the remaining protein determination that is used for.
In 200 μ l extraction cell, add 15% ethanol potassium hydroxide, 75 ℃ of saponification 1 hour.Add water (1ml) then, mixture is not saponified to remove with 2ml petroleum ether extraction secondary.Petroleum ether extract 1ml water washing is evaporated to dried under nitrogen gas stream., launch resistates point sample on the good silica gel tlc plate of coated in advance with in a small amount chloroform with hexane/ether/acetate (85: 15: 4).Cholesterol and the squalene part on the TLC plate detects with iodine, and corresponding TLC is partly downcut.TLC is immersed toluene type scintillator, radioactivity is counted with liquid scintillation counter.The result is with press J.Biol.Chem.193 265(1951) the protein mass correction measured of described method.Calculate The compounds of this invention to the biosynthetic 50% inhibition concentration (IC of cholesterol in the Hep-G2 cell of cultivating 50), the results are shown in table 2.
Table 2
The biosynthetic inhibition of cholesterol is active in culturing cell
Trial drug 50% inhibition concentration (IC 50, nM)
Embodiment 2 compounds 53
Embodiment 3 compounds 11
Embodiment 8 compounds 12
Embodiment 9 compounds 11
Embodiment 15 compounds 54
Embodiment 19 compounds 9
Embodiment 25 compounds 6
Embodiment 26 compounds 5
Embodiment 31 compounds 22
Embodiment 33 compounds 25
Embodiment 42 compounds 30
Embodiment 47 compounds 10
Embodiment 48 compounds 10
Embodiment 51 compounds 33
Embodiment 74 compounds 29
Embodiment 78 compounds 17
Embodiment 80 compounds 52
Pharmacological testing embodiment 3
Suppress the biosynthetic in vivo test of cholesterol:
The SD female rats in 5 ages in week, is used in vivo test.Rat was stopped 9 days in opposite light circulation (being that be interlunation 6: 00 mornings to 6: 00 afternoons) environment, allow their ad lib solid feed and drinking-water.Before the 6th hour of dark 2 hours when cholesterol is synthetic when reaching maximum value oral administration trial drug.Trial drug is dissolved in the water that contains 5% methyl-sulphoxide and 2% tween 80 and with the 3mg/Kg(1ml/100g body weight) the oral dose administration.
Carrier with top equal volume is taken to control group.Taking trial drug after 1 hour, give administration in the rat peritoneum [ 14C] mark sodium acetate (56mCi/mmol), dosage is 20 μ Ci/100g body weight.At dark six hours, under etherization from abdomen arterial blood extracting sample, centrifugal separation plasma.
1ml blood plasma is mixed with the 2ml15% methanolic potassium hydroxide, be heated to 75 ℃ of saponification 3 hours.The sample that obtains 2ml petroleum ether extraction secondary.Extract 2ml distilled water wash evaporates under nitrogen gas stream at last.The gained resistates is dissolved in ether in a small amount, all solution point sample on the silica gel tlc plate that coated is good in advance.Thin layer plate is launched in the solvent system that hexane/ether/acetate (85: 15: 4) is formed, add lustre to, with the radioactivity of liquid flashing counter measuring cholesterol moiety with iodine.
The result is to generate in 1ml blood plasma 14The dpm value representation of C-cholesterol.The biosynthetic inhibition of cholesterol is biosynthetic with test group 14Relatively calculating of the amount of C-cholesterol and the amount of control group the results are shown in table 3.
Figure 891091963_IMG47
Acute toxicity test embodiment
Various investigational agents (compound 3,9,19,20,25,51, free alkali) are dissolved in the triglyceride level (MCT) of medium chain, to mouse oral administration (ddy, male, body weight 28 ± 2g, 2 every group).The mortality ratio that mensuration was taken medicine after a week is estimated acute toxicity.
Trial drug toxicity is very low, even does not also observe dead situation when the high dosage of 1000mg/kg.
As what seen by the test of front, The compounds of this invention suppresses squalene epoxidase consumingly, has so just suppressed the biosynthesizing of cholesterol.Correspondingly, they can be effectively used to the various diseases for the treatment of and preventing to be brought out by the biosynthetic increase of cholesterol, as obesity, and hyperlipoidemia, arteriosclerosis.Do not observe the inhibition activity of The compounds of this invention, and just Mammals is had distinctive activity the Mycophyta squalene epoxidase.The compounds of this invention also has hypotoxicity, so they are of great use as medicine.
General formula provided by the invention [I] compound can be made into and is suitable for oral and form administered parenterally, can be used for the treatment of hypercholesterolemia, hyperlipoidemia and arteriosclerosis.When the clinical application The compounds of this invention, can make preparation to them with the pharmaceutically acceptable auxiliary that is suitable for medicine type, and then take.The various auxiliarys that pharmaceutical field is commonly used all can use.The example of auxiliary comprises gelatin, lactose, sucrose, titanium dioxide, starch, crystalline cellulose, Vltra tears, carboxymethyl cellulose, cereal starch, Witcodur 272, white vaseline, silicoaluminate magnesium, anhydrous ca phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, Sorbitol Powder, sorbitan fatty acid esters, Spheron MD 30/70, sucrose fatty ester, polyoxyethylene hydrogenated castor oil, polyvinylpyrrolidone, Magnesium Stearate, light anhydrous silicic acid, talcum, vegetables oil, benzylalcohol, Sudan Gum-arabic, propylene glycol, polyalkylene glycol, cyclodextrin or carboxylic propyl cyclodextrin.
The preparation that contains the mixture preparation of these auxiliarys comprises, solid preparation for example, and as tablet, capsule, granula, powder and suppository, liquid preparation such as syrup, elixir and injection formulations.These preparations can prepare with known usual way in the pharmaceutical formulations field.Liquid preparation can be solution or the suspension in water or other the suitable medium.If desired, injection preparation dissolves in physiological saline or glucose solution, or also can add buffered soln or sanitas.
The 1.0-100%(weight that can contain the medicine total amount in these preparations).1.0%-60%(weight preferably) The compounds of this invention.They also can contain other treatment compounds effective.
As lipid-lowering agent, when arteriosclerosis agent or hypercholesterolemia, dosage of taking or number of times can be according to sexes The compounds of this invention, and the type of the severity of age, body weight, patient symptom and expection result of treatment is with scope and different.In general, during oral medication, dose is 0.01-20mg/kg preferably, perhaps divides and takes several times.During administered parenterally, preferably dose is 0.001-2mg/kg, or divides medication several times.
The following examples and reference example are described more specifically the present invention, should be appreciated that the present invention is not subjected to the restriction of these embodiment.
Embodiment 1
Preparation (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(2-furyl) benzyloxy] the benzylamine hydrochloride
190mg(E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-hydroxybenzene methylamine is dissolved in the 3ml anhydrous tetrahydro furan, ice-cooled and stir under add 31mg60% oil-containing sodium hydride, solution stirring 10 minutes.In gained solution, add the 3-(2-furyl)-ethereal solution (the making the 160mg3-(2-furyl) benzylalcohol of benzyl chloride and 73 μ l thionyl chloride in anhydrous diethyl ether in ice-cooled and stir under reaction 3 hours, then wash gained solution and prepare in advance with saturated sodium-chloride water solution and 5% sodium bicarbonate aqueous solution) and 1ml dimethyl formamide.Mixture is in stirred overnight at room temperature.In reaction soln, add 30ml water and 30ml ether, with mixture separation.Organic layer is separated,, use anhydrous sodium sulfate drying with the saturated sodium-chloride water solution washing.Evaporating solvent then.Resistates medium pressure liquid chromatography purifying [post: Lobar post, big or small B, Lichroprep Si 60F(E.Merck Co.); Eluting solvent: hexane/ethyl acetate=10/1 → 8/1] provide 63mg(productive rate 21%) free alkali of title compound, be water white oil.Free alkali is handled with methyl alcohol and hydrogenchloride, and recrystallization provides the hydrochloride of title in the ethylacetate/ether mixture m.p.115-116 ℃.
IR ν Pure MaximumCm -1: 2968,2488,1605,1497,1461,1266,789.
NMR（CDCl 3）δ：1.25（9H，s），2.60（3H，s），3.50-3.64（2H，m），4.00-4.13（2H，m），5.20（2H，s），5.78-5.84（1H，m），6.18-6.32（1H，m），6.47（1H，dd，J＝3.5Hz，2.0Hz），6.70（1H，d，J＝3.5Hz），7.05-7.11（2H，m），7.30-7.47（5H，m），7.62（1H，d，J＝7.1Hz），7.78（1H，s）.
Embodiment 2
Preparation (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[3-(1-pyrryl) benzyloxy] benzylamine:
100mg(E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-hydroxybenzene methylamine is dissolved in the 1ml anhydrous tetrahydro furan, ice-cooled and stir under in solution, add 20mg60% oil-containing sodium hydride, and mixture was stirred 10 minutes.Adding 100mg3-(1-pyrryl in gained solution) the 1ml dimethyl formamide solution of phenmethyl methanesulfonates, mixture at room temperature stirs and spends the night.Adding 20ml water and 30ml ether extract in solution.Organic layer is separated,, use anhydrous sodium sulfate drying with the saturated sodium-chloride water solution washing.Evaporating solvent, resistates provides 110mg(productive rate 70% with silica gel chromatography [Wakogel C-200,20g, elutriant: hexane/ethyl acetate=10/1-5/1]) title compound, be water white oil.
IR ν Pure MaximumCm -1: 2968,1596,1506,1488,1455,1341,1263,1071,786,726.
NMR（CDCl 3）δ：0.98（3H，t，J＝7.0Hz），1.19（9H，s），2.45（2H，q，J＝7.0Hz），3.03（2H，dd，J＝6.4Hz，1.6Hz），3.49（2H，s），5.06（2H，s），5.59（1H，dt，J＝15.9Hz，1.6Hz），6.01（1H，dt，J＝15.9Hz，6.4Hz），6.30（2H，t，J＝2.1Hz），6.80（1H，ddd，J＝8.3Hz，2.6Hz，0.8Hz），6.88（1H，d，J＝7.6Hz），6.96-6.98（1H，m），7.06（2H，t，J＝2.1Hz），7.17（1H，t，J＝7.8Hz），7.25-7.32（2H，m），7.39（1H，t，J＝7.8Hz），7.44-7.45（1H，m）.
Embodiment 3
Preparation (E)-N-ethyl-N-(6-methoxyl group-6-methyl-2-heptene-4-alkynyl)-and the 3-[3-(3-thienyl) benzyloxy]-the benzylamine hydrochloride
57.5mg(E)-N-ethyl-N-(6-methoxyl group-6-methyl-2-heptene-4-alkynyl)-3-hydroxybenzene methylamine is dissolved in the 0.5ml anhydrous tetrahydro furan, and under nitrogen atmosphere, adds 8.1mg60% oil-containing sodium hydride therein.Mixture at room temperature stirred 10 minutes, added the 53.7mg3-(3-thienyl in this solution) solution of the 1ml dimethyl formamide of phenmethyl methanesulfonates.Mixture at room temperature stirs and spends the night, the pressure reducing and steaming solvent.Resistates medium pressure liquid chromatography purifying [post: Lobar post, size A, Lichroprep Si 60(E.Merck Co.), elutriant: hexane/ethyl acetate=6/1-1/1] provide 81.6mg(productive rate 89%) free alkali of title compound, be water white oil.Free alkali is handled with hydrogenchloride and methyl alcohol, and recrystallization provides the title hydrochloride in ethyl acetate and ether mixture m.p.153-155 ℃.
IR ν Pure MaximumCm -1: 3340,2986,2932,1605,1455,1266,1173,1071,777.
NMR（CDCl 3）δ：1.41（3H，t，J＝7.2Hz），1.47（6H，s），2.90-3.20（2H，m），3.34（3H，s），3.40-3.80（2H，m），4.08（2H，br.s），5.22（2H，s），5.84（1H，d，J＝15.9Hz），6.36（1H，dt，J＝15.9Hz，7.9Hz），7.00-7.20（2H，m），7.33（1H，t，J＝7.9Hz），7.40-7.70（7H，m），7.73（1H，s）.
Embodiment 4
Preparation (E)-N-[6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(5-isoxazolyl) benzyloxy) benzyloxy] benzylamine:
The 106mg5-(3-aminomethyl phenyl) isoxzzole, 119mgN-bromo-succinimide and 2mg benzoyl peroxide be dissolved in the 10ml tetracol phenixin, and solution under agitation refluxed 3 hours.After the cooling, the filtering separation precipitation, concentrating under reduced pressure provides the 5-(3-2-bromomethylphenyl) isoxzzole, be faint yellow oily product.
The bromomethylation compound that obtains is dissolved in the 5ml dimethyl formamide.This solution is joined the 10ml tetrahydrofuran solution of phenates, phenates is by 171mg(E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3 hydroxybenzene methylamine and 30mg60% oil-containing sodium hydride prepare in advance, reaction mixture stirred 1 hour down ice-cooled, added water and ether alkene is released in reaction soln.Separate organic layer and use anhydrous magnesium sulfate drying.The filtering separation siccative, evaporating solvent, resistates medium pressure liquid chromatography [post: Lobar post, big or small A, Lichroprep Si 60(E.Merck Co.]; Elutriant: hexane/ethyl acetate 10/1-5/1] and preparation thin-layer chromatography [thin layer plate Kieselgel 60F 254, Art.5744(E.Merck Co.); Developping agent: hexane/ethyl acetate=3/1] purifying provides 19mg(productive rate 11%) title compound, be water white oil.
IR ν Pure MaximumCm -1: 2974,2788,1584,1491,1470,1266,786.
NMR（CDCl 3）δ：1.24（9H，s），2.19（3H，s），3.04（2H，dd，J＝6.5Hz，1.4Hz），3.47（2H，s），5.13（2H，s），5.65（1H，dt，J＝15.8Hz，1.4Hz），6.08（2H，dt，J＝15.8Hz，6.5Hz），6.55（1H，d，J＝1.9Hz），6.88（1H，ddd，J＝8.1Hz，2.6Hz，0.9Hz），6.70-6.75（1H，m），7.00-7.03（1H，m），7.24（1H，t，J＝8.1Hz），7.50-7.55（2H，m），7.77（1H，dt，J＝6.7Hz，1.9Hz），7.88-7.91（1H，m），8.30（1H，d，J＝1.9Hz）.
Embodiment 5
Preparation (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(1-imidazolyl) benzyloxy] benzylamine:
The 90mg1-(3-hydroxymethyl phenyl) imidazoles is dissolved in the 10ml chloroform, adds 100 μ l thionyl chloride, and mixture at room temperature stirred 3 hours.Solvent evaporated under reduced pressure.Resistates is dissolved in the mixture of ether and water.Separate organic layer, use 5% sodium bicarbonate aqueous solution and water washing successively, use anhydrous magnesium sulfate drying.The filtering separation siccative evaporates ether then and provides the 1-(3-chloromethyl phenyl) imidazoles, be faint yellow oily product.
The chloromethyl compound that obtains is dissolved in the 1.5ml dimethyl formamide, adding is by 140mg(E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-tetrahydrofuran solution (1.5ml) and the 22mg60% oil-containing sodium hydride of N-methyl-phenates that 3-hydroxybenzene methylamine makes.Mixture reacts by embodiment 1-4 and provides 110mg(productive rate 57%) title compound, be water white oil.
IR ν Pure MaximumCm -1: 1599,1506,1491,1455,1311,1263,1056,1026,786.
NMR（CDCl 3）δ：1.24（9H，s），2.18（3H，s），3.36（2H，dd，J＝6.5Hz，1.4Hz），3.47（2H，s），5.13（2H，s），5.65（1H，dt，J＝15.8Hz，1.4Hz），6.07（1H，dt，J＝15.8Hz，6.5Hz），6.87（1H，ddd，J＝8.3Hz，2.7Hz，1.0Hz），6.92（1H，d，J＝8.3Hz），6.99-7.10（1H，m），7.22（1H，t，J＝1.4Hz），7.24（1H，t，J＝7.7Hz），7.31（1H，t，J＝1.4Hz），7.34-7.45（2H，m），7.50（1H，t，J＝7.7Hz），7.51（1H，s），7.88（1H，t，J＝1.4Hz）.
Carry out the reaction identical and obtain the compound of following embodiment 6-44 with embodiment 1-5; just want various initial compounds among the alternate embodiment 1-5, use corresponding 3-hydroxybenzene methylamine derivative and 3-heterocyclic radical benzyl halide derivative or methylsulfonyl derivative or their starting raw material.
Embodiment 6
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[3-(3-furyl) benzyloxy] benzylamine:
IR ν Pure MaximumCm -1: 2968,1458,1263,1161,1059,1038,1020,873,777.
NMR（CDCl 3）δ：1.03（3H，t，J＝7.1Hz），1.24（9H，s），2.50（2H，q，J＝7.1Hz），3.09（2H，d，J＝6.4Hz），3.54（2H，s），5.08（2H，s），5.64（1H，dt，J＝15.9Hz，1.5Hz），6.07（1H，dt，J＝15.9Hz，6.4Hz），6.71（1H，dd，J＝1.8Hz，0.9Hz），6.87（1H，dd，J＝7.8Hz，2.0Hz），6.92（1H，d，J＝7.6Hz），7.02（1H，br.s），7.22（1H，t，J＝7.8Hz），7.34（1H，dt，J＝7.4Hz，1.7Hz），7.39（1H，t，J＝7.1Hz），7.45（1H，dt，J＝7.4Hz，1.7Hz），7.48（1H，t，J＝1.7Hz），7.57（1H，br.s），7.75（1H，t，J＝1.4Hz）.
Embodiment 7
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[the 3-(2-thienyl) benzyloxy] benzylamine:
IR ν Pure MaximumCm -1: 2968,1599,1491,1455,1365,1266,1152,1026,786,696.
NMR（CDCl 3）δ：1.24（9H，s），2.18（3H，s），3.04（2H，dd，J＝6.6Hz，1.5Hz），3.47（2H，s），5.10（2H，s），5.65（1H，dt，J＝15.8Hz，1.5Hz），6.08（1H，dt，J＝15.8Hz，6.6Hz），6.86-6.93（2H，m），7.00（1H，br.s），7.23（1H，t，J＝7.8Hz），7.29（1H，dd，J＝5.1Hz，1.1Hz），7.33（1H，dd，J＝3.6Hz，1.1Hz），7.36-7.39（1H，m），7.40（1H，t，J＝7.6Hz），7.57（1H，dt，J＝7.6Hz，1.8Hz），7.68-7.71（1H，m）.
Embodiment 8
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(3-thienyl) benzyloxy] benzylamine:
IR ν Pure MaximumCm -1: 2968,1599,1491,1455,1365,1263,1026,774.
NMR（CDCl 3）δ：1.24（9H，s），2.18（3H，s），3.03（2H，dd，J＝6.6Hz，1.5Hz），3.47（2H，s），5.10（2H，s），5.64（1H，dt，J＝15.8Hz，1.5Hz），6.08（1H，dt，J＝15.8Hz，6.6Hz），6.86-6.92（2H，m），7.00（1H，br.s），7.23（1H，t，J＝8.0Hz），7.36（1H，dt，J＝7.6Hz，1.6Hz），7.39-7.40（2H，m），7.41（1H，t，J＝7.6Hz），7.46-7.48（1H，m），7.55（1H，dt，J＝7.6Hz，1.7Hz），7.67（1H，br.s）.
Embodiment 9
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[3-(3-thienyl) benzyloxy] the benzylamine hydrochloride:
m.p.168-169℃
IR ν Pure MaximumCm -1: 2974,2500,1602,1461,1266,1173,777,759,747.
NMR（CDCl 3）δ：1.25（9H，s），1.42（3H，t，J＝7.3Hz），2.95-3.06（2H，m），3.50-3.67（2H，m），4.08（2H，d，J＝5.3Hz），5.23（2H，s），5.80（1H，d，J＝15.7Hz），6.22（1H，dt，J＝15.7Hz，7.5Hz），7.06（1H，ddd，J＝8.3Hz，2.5Hz，0.8Hz），7.09（1H，d，J＝8.3Hz），7.33（1H，t，J＝8.1Hz），7.37-7.43（4H，m），7.51（1H，dd，J＝2.8Hz，1.5Hz），7.53-7.58（2H，m），7.73（1H，br.s）.
Embodiment 10
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-propyl group-3-[the 3-(3-thienyl) benzyloxy] the benzylamine hydrochloride
m.p.164-166℃
IR ν Pure MaximumCm -1: 2968,1605,1458,1266,777.
NMR（CDCl 3）δ：0.92（3H，t，J＝7.3Hz），1.25（9H，s），1.82-1.98（2H，m），2.73-2.92（2H，m），3.44-3.78（2H，m），4.09（2H，br.s），5.23（2H，s），5.78（1H，d，J＝15.6Hz），6.21（1H，dt，J＝15.6Hz，7.8Hz），7.04-7.09（2H，m），7.33（1H，t，J＝8.1Hz），7.35-7.43（4H，m），7.50（1H，dd，J＝2.5Hz，1.5Hz），7.53-7.57（2H，m），7.74（1H，s）.
Embodiment 11
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(1-pyrryl) benzyloxy] benzylamine:
IR ν Pure MaximumCm -1: 1596,1506,1488,1458,1341,1266,1029,786,726.
NMR（CDCl 3）δ：1.24（9H，s），2.18（3H，s），3.03（2H，dd，J＝6.6Hz，1.5Hz），3.47（2H，s），5.11（2H，s），5.64（1H，dt，J＝15.8Hz，1.5Hz），6.07（1H，dt，J＝15.8Hz，6.6Hz），6.35（2H，t，J＝2.2Hz），6.86（1H，ddd，J＝10.8Hz，2.3Hz，0.8Hz），6.91（1H，d，J＝7.8Hz），6.98-6.99（1H，m），7.10（2H，t，J＝2.2Hz），7.22（1H，t，J＝7.8Hz），7.25-7.50（4H，m）.
Embodiment 12
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-propyl group-3-[3-(1-pyrryl) benzyloxy] benzylamine:
IR ν Pure MaximumCm -1: 2968,1596,1506,1488,1455,1341,1263,1071,723.
NMR（CDCl 3）δ：0.85（3H，t，J＝7.4Hz），1.24（9H，s），1.47（2H，sex.，J＝7.4Hz），2.36（2H，t，J＝7.4Hz），3.06（2H，dd，J＝6.4Hz，1.6Hz），3.53（2H，s），5.11（2H，s），5.63（1H，dt，J＝15.9Hz，1.6Hz），6.05（1H，dt，J＝15.9Hz，6.4Hz），6.35（2H，t，J＝2.2Hz），6.85（1H，ddd，J＝8.2Hz，2.6Hz，0.9Hz），6.92（1H，d，J＝7.6Hz），7.00-7.03（1H，m），7.11（2H，t，J＝2.2Hz），7.21（1H，t，J＝7.8Hz），7.28-7.37（2H，m），7.44（1H，t，J＝7.8Hz），7.49（1H，t，J＝1.5Hz）.
Embodiment 13
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[the 3-(2-pyridyl)-benzyloxy] benzylamine:
IR ν Pure MaximumCm -1: 2968,1587,1464,1365,1263,1152,1026,768.
NMR（CDCl 3）δ：1.24（9H，s），2.18（3H，s），3.03（1H，dd，J＝6.5Hz，1.5Hz），3.47（2H，s），5.15（2H，s），5.64（1H，dt，J＝15.9Hz，1.5Hz），6.08（1H，dt，J＝15.9Hz，6.5Hz），6.86-6.92（2H，m），7.00（1H，br.s），7.22-7.27（3H，m），7.49-7.51（2H，m），7.75-7.77（2H，m），7.93-7.96（1H，m），8.08（1H，br.s），8.70（1H，dt，J＝4.8Hz，1.5Hz）.
Embodiment 14
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(3-pyridyl)-benzyloxy] benzylamine:
IR ν Pure MaximumCm -1: 2968,1599,1491,1458,1365,1263,1152,1023,783.
NMR（CDCl 3）δ：1.24（9H，s），2.18（3H，s），3.03（2H，dd，J＝6.5Hz，1.5Hz），3.47（2H，s），5.62（2H，s），5.64（1H，dt，J＝15.9Hz，1.5Hz），6.07（1H，dt，J＝15.9Hz，6.6Hz），6.87-6.93（2H，m），7.01（1H，br.s），7.23（1H，t，J＝7.9Hz），7.37（1H，ddd，J＝6.8Hz，5.0Hz，0.9Hz），7.48-7.57（3H，m），7.67（1H，br.s），7.87-7.91（1H，m），8.60（1H，dd，J＝4.8Hz，1.7Hz），8.86（1H，dd，J＝2.4Hz，0.9Hz）.
Embodiment 15
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[3-(3-pyridyl) benzyloxy] benzylamine:
IR ν Pure MaximumCm -1: 2968,1596,1458,1263,786,711.
NMR（CDCl 3）δ：1.02（3H，t，J＝7.1Hz），1.23（9H，s），2.50（2H，q，J＝7.1Hz），3.09（2H，d，J＝6.3Hz），3.54（2H，s），5.14（2H，s），5.63（1H，dd，J＝15.9Hz，1.4Hz），6.06（1H，dt，J＝15.9Hz，6.3Hz），6.87（1H，dd，J＝8.0Hz，2.7Hz），6.92（1H，d，J＝7.6Hz），7.03（1H，br.s），7.22（1H，t，J＝7.8Hz），7.36（1H，ddd，J＝7.6Hz，4.9Hz，1.2Hz），7.48-7.57（3H，m），7.66（1H，d，J＝1.2Hz），7.87-7.91（1H，m），8.60（1H，dd，J＝5.1Hz，1.8Hz），8.85（1H，dd，J＝2.7Hz，1.2Hz）.
Embodiment 16
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(4-pyridyl) benzyloxy] benzylamine:
IR ν Pure MaximumCm -1: 2972,1596,1490,1458,1364,1266,1152,1026,786.
NMR（CDCl 3）δ：1.24（9H，s），2.18（3H，s），3.04（1H，dd，J＝6.5Hz，1.5Hz），3.47（2H，s），5.14（2H，s），5.64（1H，dt，J＝15.8Hz，1.5Hz），6.08（1H，dt，J＝15.9Hz，1.5Hz），6.87-6.93（2H，m），7.00（1H，br.s），7.24（1H，t，J＝8.0Hz），7.51-7.54（4H，m），7.59-7.62（1H，m），7.59-7.62（1H，m），8.67（2H，dd，J＝4.5Hz，1.7Hz）.
Embodiment 17
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(2-oxazolyl) benzyloxy] benzylamine:
IR ν Pure MaximumCm -1: 2974,1590,1491,1458,1365,1266,1152,1026,798,729.
NMR（CDCl 3）δ：1.24（9H，s），2.18（3H，s），3.30（2H，dd，J＝6.6Hz，1.5Hz），3.46（2H，s），5.12（2H，s），5.63（1H，dd，J＝15.8Hz，1.5Hz），6.08（1H，dt，J＝15.8Hz，6.6Hz），6.85-6.92（2H，m），6.99-7.15（1H，m），7.22（1H，t，J＝7.7Hz），7.24（1H，d，J＝1.1Hz），7.48（1H，t，J＝7.7Hz），7.54（1H，d，J＝7.9Hz），7.72（1H，d，J＝1.1Hz），8.01（1H，dt，J＝7.9Hz，1.2Hz），8.13-8.16（1H，m）.
Embodiment 18
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(5-oxazolyl) benzyloxy] benzylamine:
IR ν Pure MaximumCm -1: 2968,1596,1458,1263,1152,1026,954,789,693.
NMR（CDCl 3）δ：1.24（9H，s），2.19（3H，s），3.04（2H，dd，J＝6.5Hz，1.4Hz），3.47（2H，s），5.11（2H，s），5.65（1H，dt，J＝15.9Hz，1.4Hz），6.08（1H，dt，J＝15.9Hz，6.5Hz），6.86-6.93（2H，m），7.00-7.02（1H，m），7.23（1H，t，J＝7.9Hz），7.38（1H，s），7.42-7.43（1H，m），7.45（1H，t，J＝7.6Hz），7.60-7.64（1H，m），7.74-7.76（1H，m），7.93（1H.s）.
Embodiment 19
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[3-(5-oxazolyl) benzyloxy] benzylamine:
IR ν Pure MaximumCm -1: 2968,1491,1458,1263,1107,954,789.
NMR（CDCl 3）δ：1.03（3H，t，J＝7.1Hz），1.24（9H，s），2.50（2H，q，J＝7.1Hz），3.09（2H，dd，J＝6.4Hz，1.5Hz），3.54（2H，s），5.11（2H，s），5.64（1H，dt，J＝15.8Hz，1.5Hz），6.07（1H，dt，J＝15.8Hz，6.4Hz），6.84-6.89（1H，m），6.93（1H，d，J＝7.7Hz），7.03（1H，br.s），7.23（1H，t，J＝7.7Hz），7.39（1H，s），7.40-7.49（2H，m），7.62（1H，dt，J＝6.6Hz，2.1Hz），7.75（1H，br.s），7.93（1H，s）.
Handle free alkali in habitual mode with hydrogenchloride-methyl alcohol and provide hydrochloride, m.p.160 ℃ (decomposition).
Embodiment 20
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-propyl group-3-[3-(5-oxazolyl) benzyloxy] benzylamine:
IR ν Pure MaximumCm -1: 2968,1596,1491,1455,1263,1107,954,789.
NMR（CDCl 3）δ：0.85（3H，t，J＝7.4Hz），1.47（2H，sex，J＝7.4Hz），2.37（2H，t，J＝7.4Hz），3.07（2H，dd，J＝6.4Hz，1.5Hz），3.53（2H，s），3.53（2H，s），5.10（2H，s），5.63（1H，dt，J＝15.9Hz，1.5Hz），6.06（1H，dt，J＝15.9Hz，6.4Hz），6.84-6.89（1H，m），6.92（1H，d，J＝7.8Hz），7.02（1H，br.s），7.22（1H，t，J＝7.8Hz），7.38（1H，s），7.40-7.49（2H，m），7.62（1H，dt，J＝6.6Hz，2.1Hz），7.75（1H，br.s），7.93（1H，s）.
Embodiment 21
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(4-isoxazolyl) benzyloxy] benzylamine:
IR ν Pure MaximumCm -1: 2974,1602,1494,1458,1266,756.
NMR（CDCl 3）δ：1.24（9H，s），2.19（3H，s），3.04（2H，dd，J＝6.5Hz，1.4Hz），3.48（2H，s），5.10（2H，s），5.65（1H，dt，J＝15.9Hz，1.4Hz），6.08（2H，dt，J＝15.9Hz，6.5Hz），6.85-6.95（2H，m），7.01（1H，br.s），7.24（1H，t，J＝8.0Hz），7.38-7.49（3H，m），7.57（1H，br.s），8.58（1H，s），8.70（1H，s）.
Embodiment 22
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(2-thiazolyl) benzyloxy] benzylamine:
IR ν Pure MaximumCm -1: 2972,1588,1490,1456,1364,1266,1148,1022,788,692.
NMR（CDCl 3）δ：1.19（9H，s），2.14（3H，s），2.99（2H，dd，J＝6.6Hz，1.4Hz），3.42（2H，s），5.08（2H，s），5.60（1H，dt，J＝15.8Hz，1.4Hz），6.04（1H，dt，J＝15.8Hz，6.6Hz），6.83（1H，dd，J＝8.1Hz，1.5Hz），6.87（1H，d，J＝8.1Hz），6.95（1H，d，J＝1.5Hz），7.18（1H，t，J＝7.8Hz），7.30（1H，d，J＝3.3Hz），7.42（1H，t，J＝8.1Hz），7.47（1H，d，J＝7.6Hz），7.83（1H，d，J＝3.3Hz），7.87（1H，d，J＝7.3Hz），8.01（1H，s）.
Embodiment 23
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(4-isothiazolyl) benzyloxy] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1590,1491,1458,1365,1263,1152,1026,780.
NMR（CDCl 3）δ：1.24（9H，s），2.18（3H，s），3.03（2H，dd，J＝6.5Hz，1.5Hz），3.47（2H，s），5.12（2H，s），5.64（1H，dt，J＝15.9Hz，1.5Hz），6.07（1H，dt，J＝15.9Hz，6.5Hz），6.85-6.94（2H，m），7.01（1H，t，J＝2.1Hz），7.23（1H，t，J＝7.9Hz），7.40-7.50（2H，m），7.55（1H，dt，J＝6.9Hz，1.9Hz），8.73（1H，s），8.79（1H，s）.
Embodiment 24
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(5-isothiazolyl) benzyloxy] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1590,1491,1458,1419,1368,1266,1152,786,756.
NMR（CDCl 3）δ：1.24（9H，s），2.19（3H，s），3.04（2H，dd，J＝6.2Hz，1.5Hz），3.48（2H，s），5.11（2H，s），5.65（1H，dt，J＝15.6Hz，1.5Hz），6.08（1H，dt，J＝15.6Hz，6.2Hz），6.88（1H，ddd，J＝8.2Hz，2.8Hz，1.0Hz），6.89-6.90（2H，m），7.00-7.03（1H，m），7.23（1H，t，J＝7.8Hz），7.43（1H，d，J＝2.1Hz），7.45-7.50（2H，m），7.54-7.59（1H，m），7.68-7.71（1H，m），8.48（1H，d，J＝2.1Hz）.
Embodiment 25
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[3-(1-imidazolyl) benzyloxy] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1506,1491,1458,1308,1263,1056,789.
NMR（CDCl 3）δ：1.02（3H，t，J＝7.1Hz），1.24（9H，s），2.49（2H，q，J＝7.1Hz），3.08（2H，dd，J＝6.4Hz，1.5Hz），3.54（2H，s），5.13（2H，s），5.64（1H，dt，J＝15.9Hz，1.5Hz），6.06（1H，dt，J＝15.9Hz，6.4Hz），6.85（1H，ddd，J＝8.0Hz，2.0Hz，0.9Hz），6.93（1H，d，J＝7.5Hz），7.00-7.05（1H，m），7.21（1H，t，J＝1.4Hz），7.23（1H，t，J＝8.0Hz），7.31（1H，t，J＝1.4Hz），7.33-7.53（4H，m），7.88（1H，t，J＝1.4Hz）.
Embodiment 26
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-propyl group-3-[3-(1-imidazolyl) benzyloxy] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1599,1506,1488,1455,1308,1263,1152,1056,786.
NMR（CDCl 3）δ：0.85（3H，t，J＝7.4Hz），1.24（9H，s），1.47（2H，sex，J＝7.4Hz），2.37（2H，t，J＝7.4Hz），3.06（2H，dd，J＝6.3Hz，1.5Hz），3.53（2H，s），5.13（2H，s），5.63（1H，dt，J＝15.6Hz，1.5Hz），6.05（1H，dt，J＝15.6Hz，6.3Hz），6.84（1H，ddd，J＝8.2Hz，3.4Hz，0.8Hz），6.93（1H，d，J＝7.6Hz），7.01（1H，br.s），7.21（1H，t，J＝1.4Hz），7.22（1H，t，J＝8.2Hz），7.31（1H，t，J＝1.4Hz），7.33-7.53（4H，m），7.88（1H，t，J＝1.4Hz）.
Embodiment 27
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(5-pyrimidyl) benzyloxy] benzylamine :-
IR ν Pure MaximumCm -1: 2974,1584,1455,1419,1266,786,756.
NMR（CDCl 3）δ：1.24（9H，s），2.19（3H，s），3.04（2H，d，J＝6.2Hz），3.47（2H，s），5.15（2H，s），5.64（1H，d，J＝15.9Hz），6.07（1H，dt，J＝15.9Hz，6.2Hz），6.82-6.93（2H，m），7.02（1H，br.s），7.23（1H，t，J＝7.5Hz），7.54-7.55（3H，m），7.67（1H，s），8.96（2H，s），9.22（1H，s）.
Embodiment 28
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(1,2, the 4-triazol-1-yl) benzyloxy] benzylamine :-
IR ν Pure MaximumCm -1: 2974,1599,1512,1458,1266,1215,1146,759.
NMR（CDCl 3）δ：1.23（9H，s），2.18（3H，s），3.03（2H，dd，J＝6.6Hz，1.5Hz），3.46（2H，s），5.14（2H，s），5.64（1H，dt，J＝15.9Hz，1.5Hz），6.06（1H，dt，J＝15.9Hz，6.6Hz），6.85（1H，ddd，J＝7.9Hz，2.7Hz，0.5Hz），6.92（1H，d，J＝7.9Hz），6.98-7.05（1H，m），7.23（1H，t，J＝7.9Hz），7.45-7.49（1H，m），7.53（1H，t，J＝7.8Hz），7.64（1H，dt，J＝7.8Hz，1.8Hz），7.80（1H，br.s），8.11（1H，s），8.58（1H，s）.
Embodiment 29
(E)-N-ethyl-N-(6-methoxyl group-6-methyl-2-heptene-4-alkynyl)-the 3-[3-(1-pyrryl) benzyloxy] benzylamine :-
IR ν Pure MaximumCm -1: 1605,1506,1341,1170,1149,1074,960,789,723,696.
NMR（CDCl 3）δ：1.09（3H，t，J＝6.9Hz），1.46（6H，s），2.56（2H，q，J＝6.9Hz），3.15（2H，dd，J＝6.5Hz，1.5Hz），3.35（3H，s），3.61（2H，s），5.12（2H，s），5.73（1H，dt，J＝15.9Hz，1.5Hz），6.20（1H，dt，J＝15.9Hz，6.5Hz），6.37（2H，t，J＝2.1Hz），6.86（1H，dd，J＝7.8Hz，1.6Hz），6.93（1H，d，J＝7.8Hz），6.99-7.05（1H，m），7.10（2H，t，J＝2.1Hz），7.23（1H，t，J＝7.5Hz），7.29-7.46（3H，m），7.48-7.50（1H，m）.
Embodiment 30
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(2,3-dihydro-4-thienyl) benzyloxy] benzylamine :-
IR ν Pure MaximumCm -1: 2968,2788,1584,1491,1455,1365,1263,1152,1023,783.
NMR（CDCl 3）δ：1.24（9H，s），2.18（3H，s），3.03（2H，dd，J＝6.6Hz，1.4Hz），3.11-3.19（2H，m），3.35-3.43（2H，m），3.46（2H，s），5.04（2H，s），5.64（1H，dt，J＝15.9Hz，1.4Hz），6.08（1H，dt，J＝15.9Hz，6.6Hz），6.59（1H，t，J＝2.1Hz），6.83-6.93（2H，m），6.97-7.00（1H，m），7.19-7.33（4H，m），7.39-7.42（1H，m）.
Embodiment 31
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[3-(2,3-dihydro-4-thienyl) benzyloxy] benzylamine :-
IR ν Pure MaximumCm -1: 2968,2926,1587,1491,1455,1365,1263,1149,777.
NMR（CDCl 3）δ：1.03（3H，t，J＝7.1Hz），1.24（9H，s），2.49（2H，q，J＝7.1Hz），3.08（2H，dd，J＝6.4Hz，1.5Hz），3.15（2H，dt，J＝8.4Hz，1.8Hz），3.38（2H，t，J＝8.4Hz），3.53（2H，s），5.04（2H，s），5.64（1H，dt，J＝15.8Hz，1.5Hz），6.07（1H，dt，J＝15.8Hz，6.4Hz），6.59（1H，t，J＝1.8Hz），6.82-6.87（1H，m），6.89-6.94（1H，m），6.98-7.02（1H，m），7.21（1H，t，J＝7.8Hz），7.23-7.35（3H，m），7.39-7.42（1H，m）.
Embodiment 32
(E)-N-ethyl-N-(6-methoxyl group-6-methyl-2-heptene-4-alkynyl)-3-[3-(2,3-dihydro-4-thienyl) benzyloxy] benzylamine :-
IR ν Pure MaximumCm -1: 1452,1380,1365,1254,1173,1149,1077,819,777,693.
NMR（CDCl 3）δ：1.04（3H，t，J＝7.0Hz），1.46（6H，s），2.51（2H，q，J＝7.0Hz），3.09-3.18（4H，m），3.35（3H，s），3.35-3.42（2H，m），3.54（2H，s），5.04（2H，s），5.68（1H，dt，J＝15.7Hz，1.8Hz），6.16（1H，dt，J＝15.7Hz，6.6Hz），6.59（1H，t，J＝1.6Hz），6.83-6.89（1H，m），6.90-6.95（1H，m），6.98-7.04（1H，m），7.21（1H，t，J＝7.5Hz），7.25-7.35（3H，m），7.39-7.40（1H，m）.
Embodiment 33
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[3-(2,5-dihydro-3-thienyl) benzyloxy] benzylamine :-
IR ν Pure MaximumCm -1: 2968,2920,1587,1491,1455,1365,1263,1152,777.
NMR（CDCl 3）δ：1.02（3H，t，J＝7.1Hz），1.24（9H，s），2.49（2H，q，J＝7.1Hz），3.08（2H，dd，J＝6.4Hz，1.5Hz），3.53（2H，s），3.91-3.96（2H，m），4.11-4.15（2H，m），5.06（2H，s），5.64（1H，dt，J＝15.8Hz，1.5Hz），6.05（1H，dt，J＝15.8Hz，6.4Hz），6.26（1H，quint，J＝2.0Hz），6.82-6.87（1H，m），6.89-6.94（1H，m），6.99-7.01（1H，m），7.21（1H，t，J＝8.0Hz），7.34-7.37（3H，m），7.47-7.49（1H，m）.
Embodiment 34
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(1-pyrrolidyl) benzyloxy] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1608,1584,1506,1491,1458,1368,1266,1152,768.
NMR（CDCl 3）δ：1.24（9H，s），1.97-2.02（4H，m），2.18（3H，s），3.03（2H，dd，J＝6.6Hz，1.5Hz），3.29-3.31（4H，m），3.46（2H，s），5.01（2H，s），5.64（1H，dt，J＝15.9Hz，1.5Hz），6.08（1H，dt，J＝15.9Hz，6.5Hz），6.51（1H，dd，J＝8.3Hz，2.4Hz），6.62-6.64（1H，m），6.72（1H，d，J＝7.4Hz），6.85-6.90（2H，m），6.98（1H，t，J＝2.1Hz），7.20-7.22（2H，m）.
Embodiment 35
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[5-(3-thienyl)-2-thienyl methyl oxygen base] benzylamine :-
IR ν Pure MaximumCm -1: 2968,2926,1596,1446,1377,1260,1017,852,801,771.
NMR（CDCl 3）δ：1.04（3H，t，J＝7.0Hz），1.24（9H，s），2.50（2H，q，J＝7.0Hz），3.10（1H，dd，J＝6.3Hz，1.4Hz），3.54（2H，s），5.18（2H，s），5.64（1H，dt，J＝15.9Hz，1.4Hz），6.08（1H，dt，J＝15.9Hz，6.3Hz），6.86（1H，dd，J＝8.0Hz，2.7Hz），6.93（1H，d，J＝7.6Hz），7.00-7.04（2H，m），7.07（1H，d，J＝3.6Hz），7.22（1H，t，J＝8.0Hz），7.29（1H，dd，J＝5.2Hz，1.2Hz），7.33（1H，dd，J＝5.2Hz，4.5Hz），7.36（1H，dd，J＝4.5Hz，1.2Hz）.
Embodiment 36
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[2-(5-oxazolyl)-4-pyridylmethyl oxygen base] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1620,1491,1455,1365,1266,1113,957,831,762.
NMR（CDCl 3）δ：1.24（9H，s），2.19（3H，s），3.05（2H，dd，J＝6.5Hz，1.5Hz），3.48（2H，s），5.14（2H，s），5.65（1H，dt，J＝15.9Hz，1.5Hz），6.09（1H，dt，J＝15.9Hz，6.5Hz），6.86（1H，ddd，J＝7.9Hz，2.7Hz，0.9Hz），6.94（1H，d，J＝7.9Hz），7.00-7.01（1H，m），7.25（1H，t，J＝7.9Hz），7.32（1H，dt，J＝5.0Hz，0.8Hz），7.73（1H，s），7.76-7.77（1H，m），7.99（1H，s），8.64（1H，dd，J＝5.0Hz，0.8Hz）.
Embodiment 37
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[4-(5-oxazolyl)-2-pyridylmethyl oxygen base] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1617,1584,1494,1455,1263,1155,1113,957.
NMR（CDCl 3）δ：1.24（9H，s），2.19（3H，s），3.04（2H，d，J＝6.5Hz），3.48（2H，s），5.24（2H，s），5.64（1H，dt，J＝15.9Hz，1.7Hz），6.08（1H，dt，J＝15.9Hz，6.5Hz），6.88-6.95（2H，m），7.04-7.05（1H，m），7.19-7.27（1H，m），7.46（1H，dd，J＝5.4Hz，1.5Hz），7.59（1H，s），7.79（1H，m），8.00（1H，s），8.65（1H，d，J＝6.2Hz）.
Embodiment 38
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[5-(5-oxazolyl) chaff oxygen base] benzylamine :-
IR ν Pure MaximumCm -1: 2968,2926,1458,1263,1107,1020,963,789.
NMR（CDCl 3）δ：1.24（9H，s），2.19（3H，s），3.04（2H，dd，J＝6.5Hz，1.5Hz），3.47（2H，s），5.05（2H，s），5.65（1H，dt，J＝15.9Hz，1.5Hz），6.09（1H，dt，J＝15.9Hz，6.5Hz），6.53（1H，d，J＝3.4Hz），6.64（1H，d，J＝3.4Hz），6.87（1H，ddd，J＝8.1Hz，2.7Hz，0.8Hz），6.93（1H，d，J＝8.1Hz），7.00（1H，m），7.24（1H，t，J＝8.1Hz），7.30（1H，s），7.86（1H，s）.
Embodiment 39
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(5-oxazolyl)-5-furyl methyl oxygen base] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1584,1461,1269,1152,1098,1041,1032,891,831.
NMR（CDCl 3）δ：1.24（9H，s），2.20（3H，s），3.05（2H，dd，J＝6.5Hz，1.4Hz），3.48（2H，s），4.97（2H，s），5.66（1H，dt，J＝15.8Hz，1.4Hz），6.09（1H，15.8Hz，6.5Hz），6.75（1H，d，J＝0.8Hz），6.82-6.88（1H，m），6.92（1H，d，J＝7.8Hz），6.98（1H，br.s），7.23（1H，t，J＝7.8Hz），7.28（1H，s），7.54（1H，d，J＝0.8Hz），7.86（1H，s）.
Embodiment 40
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[2-(5-oxazolyl)-4-thiazolyl methyl oxygen base] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1596,1491,1455,1263,1158,1104,1059,1017,966,894.
NMR（CDCl 3）δ：1.19（9H，s），2.14（3H，s），3.00（2H，dd，J＝6.6Hz，1.4Hz），3.43（2H，s），5.22（2H，d，J＝0.96Hz），5.60（1H，dt，J＝15.8Hz，1.4Hz），6.03（1H，dt，J＝15.8Hz，6.6Hz），6.83（1H，ddd，J＝7.6Hz，2.6Hz，0.75Hz），6.89（1H，d，J＝7.6Hz），6.97（1H，m），7.19（1H，t，J＝7.6Hz），7.37（1H，t，J＝0.96Hz），7.63（1H，s），7.92（1H，s）.
Embodiment 41
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[6-(5-oxazolyl)-2-pyridylmethyl oxygen base] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1596,1452,1365,1260,1158,1107,804,786.
NMR（CDCl 3）δ：1.24（9H，s），2.18（3H，s），3.03（2H，dd，J＝6.5Hz，1.4Hz），3.46（2H，s），5.25（2H，s），5.64（1H，dt，J＝15.8Hz，1.4Hz），6.07（1H，dt，J＝15.8Hz，6.5Hz），6.86-6.91（1H，m），6.91-6.95（1H，m），7.01-7.04（1H，m），7.23（1H，t，J＝8.0Hz），7.51（1H，dd，J＝7.8Hz，0.9Hz），7.59（1H，dd，J＝7.8Hz，0.9Hz），7.72（1H，s），7.80（1H，t，J＝7.8Hz），7.99（1H，s）.
Embodiment 42
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[5-(5-oxazolyl)-3-pyridylmethyl oxygen base] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1590,1491,1455,1266,1152,1107,1026,963,759.
NMR（CDCl 3）δ：1.24（9H，s），2.19（3H，s），3.05（2H，dd，J＝6.6Hz，1.4Hz），3.48（2H，s），5.13（2H，s），5.65（1H，dt，J＝15.9Hz，1.4Hz），6.09（1H，dt，J＝15.9Hz，6.6Hz），6.88（1H，dd，J＝7.8Hz，2.6Hz），6.94（1H，d，J＝7.8Hz），7.01-7.04（1H，m），7.25（1H，t，J＝7.8Hz），7.49（1H，s），8.00（1H，s），8.05（1H，t，J＝2.0Hz），8.65（1H，d，J＝2.0Hz），8.90（1H，d，J＝2.0Hz）.
Embodiment 43
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[2-methyl-3-(1-pyrryl) benzyloxy] benzylamine hydrochloride :-
m.p.137-139℃
IR ν Pure MaximumCm -1: 2968,2500,1599,1497,1458,1332,1263,1038,723.
NMR（CDCl 3）δ：1.25（9H，s），2.18（3H，s），2.65（3H，s），3.48-3.61（1H，m），3.65-3.78（1H，m），3.95-4.08（1H，m），4.16-4.29（1H，m），5.21（2H，s），5.85（1H，d，J＝15.6Hz），6.20-6.36（1H，m），6.32（2H，t，J＝2.1Hz），6.79（2H，t，J＝2.1Hz），7.04-7.11（1H，m），7.24-7.30（2H，m），7.35（1H，t，J＝7.9Hz），7.51（1H，t，J＝4.5Hz），7.63（1H，br.s）.
Embodiment 44
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[6-methyl-3-(1-pyrryl) benzyloxy] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1590,1518,1488,1455,1341,1266,1026,723.
NMR（CDCl 3）δ：1.24（9H，s），2.19（3H，s），2.39（3H，s），3.04（2H，dd，J＝6.5Hz，1.5Hz），3.48（2H，s），5.06（2H，s），5.65（1H，dt，J＝15.9Hz，1.5Hz），6.08（1H，dt，J＝15.9Hz，6.5Hz），6.33（2H，t，J＝2.2Hz），6.86-6.95（2H，m），6.99-7.02（1H，m），7.07（2H，t，J＝2.2Hz），7.21-7.27（3H，m），7.50（1H，br.s）.
Embodiment 45
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(4-thiazolyl) benzyloxy] preparation of benzylamine :-
With 600mg2-chloro-4-(3-tolyl) thiazole is dissolved in 8ml tetracol phenixin and 2ml1, in the mixture of 2-ethylene dichloride, adds N-bromo-succinimide (511mg) and 3mg benzoyl peroxide, and make mixture stir backflow down 3 hours.After the cooling, throw out is separated from reaction mixture by filtering.With the sodium bicarbonate aqueous solution washing, and under reduced pressure steaming desolventizes, and obtains 4-(3-bromomethyl phenyl)-2-diuril azoles, be a faint yellow oily thing.
The bromomethylation compound that obtains is dissolved in the 2ml dimethyl formamide, then this solution being joined 8ml contains in advance by 388mg(E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-tetrahydrofuran solution of the phenates of N-methyl-3-hydroxy benzylamine and 68mg60% buttery sodium hydride preparation in.Mixture stirred 1 hour down ice-cooled, then restir 2 hours at room temperature.In reaction soln, add entry and ether, isolate organic layer, use anhydrous sodium sulfate drying.Remove by filter siccative, steaming under reduced pressure desolventizes.Residuum is through silica gel column chromatography purification (Wakogel C-200,80g, eluent: hexane/ethyl acetate=6/1 → 4/1), obtain 396mg(productive rate 57%) (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-and N-methyl-3-[3-(2-chloro-4-thiazolyl) benzyloxy] benzylamine is a faint yellow oily thing.
The ether compound (92mg) that obtains is dissolved in the 0.8ml acetate, under stirring this solution is heated to 57～60 ℃, add the 40mg zinc powder simultaneously.Mixture stirred after 30 minutes, will add yellow soda ash in its impouring frozen water, regulated pH value to 9.0.With this solution of ethyl acetate extraction, extract anhydrous sodium sulfate drying, and boil off solvent, residuum through medium pressure liquid chromatography purify [post: Lobar post, size B, Lichroprep Si60(E.Merck Co); Eluent: hexane/ethyl acetate=6/1 → 3/1], obtain 52mg(productive rate 60%) title compound, be a colorless oil.
IR ν Pure MaximumCm -1: 2968,1587,1491,1455,1365,1266,1026,789.
NMR（CDCl 3）δ：1.24（9H，s），2.18（3H，s），3.03（2H，dd，J＝6.5Hz，1.5Hz），3.47（2H，s），5.13（2H，s），5.64（1H，dt，J＝15.8Hz，1.5Hz），6.08（1H，dt，J＝15.8Hz，6.5Hz），6.86-6.92（2H，m），7.00（1H，br.s），7.22（1H，t，J＝7.8Hz），7.44-7.45（1H，m），7.57（1H，d，J＝2.0Hz），7.64（1H，t，J＝7.7Hz），7.87-7.91（1H，m），8.02（1H，br.s），8.84（1H，d，J＝2.0Hz）.
According to the method for embodiment 45, use tolyl by 5-(3-) the 5-(3-2-bromomethylphenyl that makes of thiazole)-the 2-bromethiazole [sees J.Org.Chem; 51,3375(1986); Org.React, 6 381; And Ann, 628(1981)] replacement 4-(3-2-bromomethylphenyl)-2-chloro thiazole.Make itself and corresponding 3-hydroxy benzylamine derivative condensation, and carry out the dehalogenation reaction, obtain the compound of embodiment 46 to 48.
Embodiment 46
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(5-thiazolyl) benzyloxy] benzylamine :-
IRν neat maxcm -1：2974，1590，1458，1266，873，789，693.
NMR（CDCl 3）δ：1.24（9H，s），2.19（3H，s），3.04（2H，dd，J＝6.6Hz，1.5Hz），3.47（2H，s），5.10（2H，s），5.64（1H，dt，J＝15.8Hz，1.5Hz），6.08（1H，dt，J＝15.8Hz，6.6Hz），6.88（1H，dd，J＝8.1Hz，1.8Hz），6.92（1H，d，J＝7.8Hz），7.00（1H，t，J＝1.8Hz），7.23（1H，t，J＝7.8Hz），7.42-7.44（2H，m），7.53-7.56（1H，m），7.65-7.66（1H，m），8.10（1H，d，J＝0.6Hz），8.76（1H，d，J＝0.6Hz）.
Embodiment 47
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[3-(5-thiazolyl) benzyloxy] benzylamine :-
IR ν Pure MaximumCm -1: 2972,1588,1490,1456,1364,1264,1152,1046,874,788.
NMR（CDCl 3）δ：0.96（3H，t，J＝7.0Hz），1.19（9H，s），2.46（2H，q，J＝7.0Hz），3.04（2H，d，J＝6.0Hz），3.50（2H，s），5.06（2H，s），5.60（1H，d，J＝15.8Hz），6.02（1H，dt，J＝15.8Hz，6.0Hz），6.82（1H，dd，J＝8.1Hz，2.1Hz），6.89（1H，d，J＝8.0Hz），6.98（1H，br.s），7.18（1H，t，J＝8.0Hz），7.38-7.41（2H，m），7.48-7.52（1H，m），7.62（1H，s），8.05（1H，d，J＝0.6Hz），8.71（1H，d，J＝0.6Hz）.
Embodiment 48
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-propyl group-3-[3-(5-thiazole) benzyloxy] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1490,1458,1364,1264,1152,872,788,694.
NMR（CDCl 3）δ：0.85（3H，t，J＝7.4Hz），1.24（9H，s），1.46-1.51（2H，m），2.37（2H，t，J＝7.1Hz），3.07（2H，dd，J＝6.4Hz，1.3Hz），3.53（2H，s），5.10（2H，s），5.63（1H，dd，J＝15.9Hz，1.3Hz），6.04（1H，dt，J＝15.9Hz，6.4Hz），6.86（1H，dd，J＝7.8Hz，1.8Hz），6.92（1H，d，J＝7.4Hz），7.20（1H，s），7.22（1H，t，J＝7.8Hz），7.43-7.44（2H，m），7.53-7.55（1H，m），7.66（1H，br.s），8.10（1H，s），8.76（1H，s）.
Embodiment 49
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(3-pyrryl) benzyloxy] preparation of benzylamine :-
Under 45 to 50 ℃ temperature; stirring isocyano-methyl acetate (280 microlitre) and 400 microlitres 1; 8-diazabicyclo [5.4.0]+-alkane-7-alkene (DBU) joins in the 20ml tetrahydrofuran (THF); add and contain 500mg(E)-N-(6; 6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-(3-formyl radical benzyloxy) tetrahydrofuran solution (5ml) of benzylamine, stir mixture 5 hours under said temperature then.Reaction mixture is cooled off, and neutralize with acetate.Decompression is steamed down and is desolventized, and adding ethyl acetate and water extract in residuum, isolate organic layer, use anhydrous magnesium sulfate drying, remove by filter siccative, and solvent evaporated.Then, residuum is through silica gel column chromatography purification [Wakogel C-200,30g, eluent: hexane/ethyl acetate: 5/1], obtain 140mg(productive rate 20%) (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-and N-methyl-3-[3-(2,4-dimethoxy carbonyl-3-pyrryl) benzyloxy] benzylamine is a faint yellow oily thing.
The pyrryl compound (32mg) that obtains is added in the mixture of 2g potassium hydroxide and 6ml water, under refluxing, mixture heating up was stirred 6 hours.After the cooling, in reaction mixture, add ether and extract.Extract anhydrous magnesium sulfate drying, and solvent evaporated.Residuum is through silica gel column chromatography purification [Wakogel C-200,30g; Eluent: hexane/ethyl acetate=10/1 → 2/1], obtain 12.4mg(productive rate 50%) title compound, be a faint yellow oily thing.
IRν neat maxcm -1：3440，2972，2928，2872，1610，1490，1454，1364，1266，1034，778.
NMR（CDCl 3）δ：1.24（9H，s），2.18（3H，s），3.03（2H，dd，J＝6.6Hz，1.5Hz），3.47（2H，s），5.08（2H，s），5.64（1H，dt，J＝15.8Hz，1.5Hz），6.09（1H，dt，J＝15.8Hz，6.6Hz），6.54-6.57（1H，m），6.82-6.92（3H，m），6.99-7.01（1H，m），7.10-7.13（1H，m），7.22（1H，t，J＝7.6Hz），7.23-7.28（1H，m），7.35（1H，t，J＝7.4Hz），7.49（1H，dt，J＝7.4Hz，1.7Hz），7.59-7.61（1H，m），8.20-8.40（1H，br）.
Embodiment 50
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(1,3,4-oxadiazole-2-yl) benzyloxy] preparation of benzylamine :-
With 173mg(E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-(3-methoxycarbonyl benzyloxy) benzylamine is dissolved in the 3ml ethanol, and the hydrazine hydrate of adding 100mg98%.Reflux down mixture heating up 3 hours.Decompression is down with after the reaction mixture evaporation, adds entry and ethyl acetate extracts in residuum.Isolate organic layer and use anhydrous sodium sulfate drying.Remove by filter siccative, solvent evaporated.Remaining carbohydrazide is added in the 4ml trimethyl orthoformate, and mixture was heated 8 hours under refluxing, after excessive trimethyl orthoformate is fallen in steaming, and the residuum mixture extraction of ethyl acetate and water.Isolate organic layer and use anhydrous sodium sulfate drying.Remove by filter siccative, decompression is solvent evaporated down.Residuum is through silica gel column chromatography [Wakogel C-200,30g; Eluent: hexane/ethyl acetate=2/1] and medium pressure liquid chromatography [post: Lobar post, size A, Lichroprep Si60(E.Merck Co.); Eluent: hexane/ethyl acetate=3/1 → 2/1] purify, obtain 18mg=(productive rate 10%) title compound, be a colorless oil.
IR ν Pure MaximumCm -1: 2974,1590,1491,1455,1368,1266,1152,960,726.
NMR（CDCl 3）δ：1.24（9H，s），2.19（3H，s），3.04（1H，dd，J＝6.5Hz，1.5Hz），3.47（2H，s），5.15（2H，s），5.65（1H，dt，J＝15.8Hz，1.5Hz），6.08（1H，dt，J＝15.8Hz，6.5Hz），6.85-6.90（1H，m），6.90-6.94（1H，m），7.00（1H，br.s），7.24（1H，t，J＝7.8Hz），7.55（1H，t，J＝7.6Hz），7.63-7.67（1H，m），8.05（1H，dt，J＝6.3Hz，1.5Hz），8.18（1H，br.s），8.49（1H，s）.
Embodiment 51
(E), (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-and N-methyl-3-[2-[3-(3-thienyl) phenyl]-vinyl] preparation of benzylamine hydrochloride :-
With 95mg(E)-the 3-[2-[3-(3-thienyl) phenyl] vinyl] benzyl chloride is dissolved in the 2ml dimethyl formamide.In this solution, add 58mg(E)-N-methyl-6,6-dimethyl-2-heptene-4-alkynylamine hydrochloride and 126mg salt of wormwood, mixture at room temperature stirs and spends the night.Decompression adds ether and water down with the reaction mixture distillation in residuum.Isolate organic layer and use anhydrous sodium sulfate drying.Remove by filter siccative, solvent evaporated, residuum is through silica gel column chromatography purification [Wakogel C-200,15g; Eluent: hexane → hexane/ethyl acetate=10/1], obtain 88mg(productive rate 67%) free alkali of title compound, be a colorless oil.
The above-mentioned free alkali that obtains is handled with hydrochloric acid-methanol solution, and with the mixture recrystallization of chloroform and hexane, obtains the hydrochloride of title, m.p.132-133 ℃.
IRν KBr maxcm -1：3430，2968，2482，1464，966，777，699.
NMR（CDCl 3）δ：1.25（9H，s），2.61（3H，s），3.56-3.61（2H，m），4.05-4.10（2H，m），5.84（1H，d，J＝15.9Hz），6.27（1H，dt，J＝15.9Hz，7.3Hz），7.12-7.29（2H，m），7.37-7.53（8H，m），7.58（1H，dt，J＝7.4Hz，1.9Hz），7.74（1H，br.s），7.79（1H，br.s）.
Except replacing initial compounds (E)-3-[2-[3-(3-thienyl with corresponding benzyl chloride, bromine or methanesulfonic salt derivative and 2-heptene-4-alkynylamine hydrochloride) phenyl] vinyl] benzyl chloride and (E)-N-methyl-6,6-dimethyl-2-heptene-4-alkynylamine hydrochloride can obtain the compound of embodiment 52 to 66 by the same procedure of embodiment 51.
Embodiment 52
(E), (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[2-[3-(3-thienyl) phenyl] vinyl] the benzyl amine hydrochlorate :-
m.p.174-176℃
IR ν Pure MaximumCm -1: 3436,2968,966,777,699.
NMR（CDCl 3）δ：1.25（9H，s），1.40-1.46（3H，m），2.98-3.01（2H，m），3.57-3.62（2H，m），4.07-4.09（2H，m），5.83（1H，d，J＝15.6Hz），6.25（1H，dt，J＝15.6Hz，7.3Hz），7.12-7.25（2H，m），7.30-7.53（9H，m），7.56（1H，d，J＝7.5Hz），7.74-7.75（1H，m），7.86（1H，br.s）.
Embodiment 53
(E), (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-propyl group-3-[2-[3-(3-thienyl) phenyl] vinyl] benzylamine :-
IR ν Pure MaximumCm -1: 2968,2806,1605,963,774,696.
NMR（CDCl 3）δ：0.89（3H，t，J＝7.2Hz），1.24（9H，s），1.47-1.57（2H，m），2.41（2H，t，J＝7.2Hz），3.11（2H，d，J＝6.4Hz），3.58（2H，s），5.66（1H，d，J＝15.8Hz），6.11（1H，dt，J＝15.8Hz，6.4Hz），7.16（2H，s），7.22-7.26（1H，m），7.30（1H，t，J＝7.2Hz），7.36-7.51（8H，m），7.73-7.74（1H，m）.
Embodiment 54
(E), (E)-N-ethyl-N-(6-methoxyl group-6-methyl-2-heptene-4-alkynyl)-the 3-[2-[3-(3-thienyl) phenyl] vinyl] benzylamine :-
IR ν Pure MaximumCm -1: 2980,2932,2818,1605,1251,1170,1149,1074,774,699.
NMR（CDCl 3）δ：1.08（3H，t，J＝7.1Hz），1.46（6H，s），2.55（2H，q，J＝7.1Hz），3.15（2H，dd，J＝6.4Hz，1.2Hz），3.36（3H，s），3.59（2H，s），5.71（1H，dt，J＝15.9Hz，1.2Hz），6.20（1H，dt，J＝15.9Hz，6.4Hz），7.16（2H，s），7.20-7.25（2H，m），7.31（1H，t，J＝7.5Hz），7.35-7.55（7H，m），7.74（1H，t，J＝2.3Hz）.
Embodiment 55
(E), (E)-N(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[2-[3-(1-pyrryl) phenyl] vinyl] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1605,1506,1341,1071,963,756,723,696.
NMR（CDCl 3）δ：1.24（9H，s），2.22（3H，s），3.08（2H，dd，J＝6.6Hz，1.5Hz），3.51（2H，s），5.67（1H，dt，J＝15.9Hz，1.5Hz），6.12（1H，dt，J＝15.9Hz，6.6Hz），6.37（2H，t，J＝2.1Hz），7.13（2H，t，J＝2.1Hz），7.15（2H，s），7.20-7.34（3H，m），7.37-7.44（3H，m），7.49-7.54（2H，m）.
Embodiment 56
(E), (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[2-[3-(1-pyrryl) phenyl] vinyl] benzylamine :-
IR ν Pure MaximumCm -1: 2968,2926,1608,1587,1506,1341,1071,963,723.
NMR（CDCl 3）δ：1.07（3H，t，J＝6.8Hz），1.24（9H，s），2.54（2H，q，J＝6.8Hz），3.14（2H，dd，J＝6.5Hz，1.5Hz），3.60（2H，s），5.67（1H，dt，J＝15.9Hz，1.5Hz），6.10（1H，dt，J＝15.9Hz，6.5Hz），6.37（2H，t，J＝2.2Hz），7.13（2H，t，J＝2.2Hz），7.12-7.16（2H，m），7.25-7.34（3H，m），7.38-7.44（3H，m），7.50（1H，s），7.52-7.54（1H，m）.
Embodiment 57
(E), (E)-N-ethyl-N-(6-methoxyl group-6-methyl-2-heptene-4-alkynyl)-the 3-[2-[3-(1-pyrryl) phenyl] vinyl] benzylamine :-
IR ν Pure MaximumCm -1: 1605,1506,1341,1170,1149,1074,960,789,723,696.
NMR（CDCl 3）δ：1.09（3H，t，J＝6.9Hz），1.46（6H，s），2.56（2H，q，J＝6.9Hz），3.15（2H，dd，J＝6.5Hz，1.5Hz），3.35（3H，s），3.61（2H，s），5.73（1H，dt，J＝15.9Hz，1.5Hz），6.20（1H，dt，J＝15.9Hz，6.5Hz），6.37（2H，t，J＝2.7Hz），7.12-7.16（4H，m），7.25-7.35（3H，m），7.38-7.45（3H，m），7.50-7.54（2H，m）.
Embodiment 58
(E), (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[2-[3-(3-pyridyl) phenyl] vinyl] benzylamine :-
IRν neat maxcm -1：3016，2974，1605，1473，1365，1266，1215，963，759，711.
NMR（CDCl 3）δ：1.07（3H，t，J＝7.1Hz），1.24（9H，s），2.55（2H，q，J＝7.1Hz），3.13（1H，dd，J＝6.7Hz，1.5Hz），3.60（2H，s），5.70（1H，dt，J＝15.9Hz，1.5Hz），6.10（1H，dt，J＝15.9Hz，6.7Hz），7.19（2H，s），7.23-7.59（8H，m），7.71（1H，br.s），7.89-7.94（1H，m），8.61（1H，dd，J＝4.8Hz，1.6Hz），8.89（1H，d，J＝1.6Hz）.
Embodiment 59
(E), (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[2-[3-(5-oxazolyl) phenyl] vinyl] benzylamine :-
IR ν Pure MaximumCm -1: 2968,2926,1263,1107,960,798,756,696.
NMR（CDCl 3）δ：1.07（3H，t，J＝7.0Hz），1.24（9H，s），2.51-2.58（2H，m），3.12-3.14（2H，m），3.58-3.62（2H，m），5.68（1H，d，J＝15.7Hz），6.10（1H，dt，J＝15.7Hz，6.1Hz），7.15-7.57（10H，m），7.81（1H，t，J＝1.5Hz），7.94（1H，s）.
Embodiment 60
(E), (E)-N-ethyl-N-(6-methoxyl group-6-methyl-2-heptene-4-alkynyl)-the 3-[2-[3-(5-oxazolyl) phenyl] vinyl] benzylamine :-
IR ν Pure MaximumCm -1: 3128,2984,2936,2820,1604,1582,1506,968.
NMR（CDCl 3）δ：1.08（3H，t，J＝7.0Hz），1.46（6H，s），2.56（2H，q，J＝7.0Hz），3.15（2H，d，J＝6.3Hz），3.36（3H，s），3.60（2H，s），5.71（1H，dt，J＝15.8Hz，1.5Hz），6.21（1H，dt，J＝15.8Hz，6.3Hz），7.13（1H，d，J＝16.1Hz），7.14（1H，d，J＝16.1Hz），7.32（1H，t，J＝7.5Hz），7.41（1H，s），7.42-7.45（2H，m），7.49-7.50（2H，m），7.51-7.52（1H，m），7.55（1H，dt，J＝7.5Hz，1.6Hz），7.81（1H，t，J＝1.6Hz），7.94（1H，s）.
Embodiment 61
(E), (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-propyl group-3-[2-[3-(1-pyrryl) phenyl] vinyl] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1608,1506,1341,1071,960,723,696.
NMR（CDCl 3）δ：0.89（3H，t，J＝7.3Hz），1.24（9H，s），1.48-1.60（2H，m），2.42（2H，t，J＝7.3Hz），3.12（2H，d，J＝6.2Hz），3.58（2H，s），5.66（1H，d，J＝15.8Hz），6.10（1H，dt，J＝15.8Hz，6.2Hz），6.37（2H，t，J＝2.2Hz），7.14（2H，t，J＝2.2Hz），7.13-7.15（2H，m），7.22-7.34（3H，m），7.38-7.42（3H，m），7.48-7.52（1H，m），7.52-7.54（1H，m）.
Embodiment 62
(E), (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[2-[3-(1-imidazolyl) phenyl] vinyl] benzylamine :-
IR ν Pure MaximumCm -1: 2972,2864,1608,1588,1504,1308,1060,962.
NMR（CDCl 3）δ：1.10（3H，t，J＝7.2Hz），1.25（9H，s），2.57（2H，q，J＝7.2Hz），3.18（2H，dd，J＝6.3Hz，1.5Hz），3.61（2H，s），5.64（1H，dt，J＝15.9Hz，1.5Hz），6.06（1H，dt，J＝15.9Hz，6.3Hz），7.14（1H，d，J＝16.0Hz），7.19（1H，d，J＝16.0Hz），7.21-7.58（9H，m），7.67-7.74（1H，m），7.91（1H，br.s）.
Embodiment 63
(E), (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-2-[2-[3-(3-thienyl) phenyl] vinyl]-4-pyridylmethyl amine :-
IR ν Pure MaximumCm -1: 1602,1479,1458,1365,1263,1203,975,852,774.
NMR（CDCl 3）δ：1.24（9H，s），2.34（3H，s），3.10（2H，dd，J＝7.0Hz，1.6Hz），3.52（2H，s），5.68（1H，dt，J＝15.8Hz，1.6Hz），6.10（1H，dt，J＝15.8Hz，7.0Hz），7.14（1H，d，J＝5.6Hz），7.23（1H，d，J＝16.4Hz），7.41-7.48（4H，m），7.49-7.55（3H，m），7.68（1H，d，J＝16.4Hz），7.81（1H，t，J＝1.8Hz），8.54（1H，d，J＝4.7Hz）.
Embodiment 64
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[2-[3-(3-thienyl) phenyl] ethyl] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1458,1365,963,774,699.
NMR（CDCl 3）δ：1.24（9H，s），2.16（3H，s），2.95（4H，s），3.02（2H，dd，J＝6.6Hz，1.5Hz），3.45（2H，s），5.63（1H，dt，J＝15.9Hz，1.5Hz），6.08（1H，dt，J＝15.9Hz，6.6Hz），7.07-7.25（5H，m），7.27-7.52（6H，m）.
Embodiment 65
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[2-[3-(1-pyrryl) phenyl] ethyl] benzylamine :-
IR ν Pure MaximumCm -1: 2968,2928,2864,2796,1610,1594,1506,726.
NMR（CDCl 3）δ：1.03（3H，t，J＝7.1Hz），1.24（9H，s），2.48（2H，q，J＝7.1Hz），2.95（4H，s），3.06（2H，dd，J＝6.2Hz，2.3Hz），3.53（2H，s），5.62（1H，dt，J＝15.8Hz，2.3Hz），6.06（1H，dt，J＝15.8Hz，6.2Hz），6.33（2H，t，J＝2.2Hz），7.04（2H，t，J＝2.2Hz），7.04-7.08（2H，m），7.13-7.17（3H，m），7.19-7.23（2H，m），7.31（1H，t，J＝7.8Hz）.
Embodiment 66
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[2-[3-(3-pyridyl) phenyl] ethyl] benzylamine :-
IR ν Pure MaximumCm -1: 2968,2932,2866,1473,1458,1365,789,705.
NMR（CDCl 3）δ：1.02（3H，t，J＝7.3Hz），1.24（9H，s），2.50（2H，q，J＝7.3Hz），2.96-2.99（4H，m），3.01（1H，d，J＝6.4Hz），3.54（1H，s），5.63（1H，d，J＝16.2Hz），6.08（1H，dd，J＝16.2Hz，6.4Hz），7.06-7.11（1H，m），7.15-7.27（4H，m），7.32-7.42（4H，m），7.83（1H，dt，J＝8.4Hz，1.8Hz），8.60（1H，br.s），8.80（1H，br.s）.
Embodiment 67
(E), (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-and N-ethyl-5-[2-[3-(3-thienyl) phenyl] vinyl] preparation of chaff amine :-
With 18mg(E)-N-(6; 6-dimethyl-2-heptene-4-alkynyl)-and N-ethyl-5-formyl radical chaff amine and 19mg dimethyl-3-(3-thienyl) benzylphosphonic acid ester [by the 3-(3-thienyl) bromotoluene and trimethyl phosphite condensation synthesize] is dissolved in the dimethyl formamide, and adds the oily sodium hydride of 2.6mg60%.Mixture at room temperature stirs and spends the night.Decompression is concentrated reaction mixture down, and residuum gets pure [thin layer plate: Kieselgel 60F through the preparation thin-layer chromatography 254, Art, 5715(E.Merck Co.); Developping agent: hexane/ethyl acetate=3/1], obtain 15mg(productive rate 55%) title compound, be a faint yellow oily thing.
IR ν Pure MaximumCm -1: 2968,1602,1458,1365,1266,1020,960,774.
NMR（CDCl 3）δ：1.16（3H，t，J＝7.0Hz），1.24（9H，s），2.58-2.68（2H，m），3.25（2H，d，J＝6.8Hz），3.77（2H，s），5.73（1H，d，J＝15.9Hz），6.13（1H，dt，J＝15.9Hz，6.8Hz），6.25-6.35（2H，m），6.90（1H，d，J＝16.4Hz），7.04（1H，d，J＝16.4Hz），7.32-7.52（6H，m），7.67（1H，br.s）.
Except replacing initiator (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl with corresponding formyl radical derivative)-N-ethyl-5-formyl radical chaff amine, carry out the compound that same reaction among the embodiment 67 can obtain embodiment 68 and 69.
Embodiment 68
(E), (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-4-[2-[3-(3-thienyl) phenyl] vinyl]-2-pyridyl methylamine :-
IR ν Pure MaximumCm -1: 2968,2868,1602,1450,1266,966,777.
NMR（CDCl 3）δ：1.24（9H，s），2.35（3H，s），3.20-3.27（2H，m），3.74-3.79（2H，m），5.72（1H，d，J＝15.7Hz），6.18（1H，dt，J＝15.7Hz，6.6Hz），7.19（1H，d，J＝16.4Hz），7.19-7.63（9H，m），7.76（1H，m），8.52（1H，d，J＝5.3Hz）.
Embodiment 69
(E), (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[2-[3-(3-thienyl) phenyl] vinyl]-5-isoxazolyl methylamine :-
IR ν Pure MaximumCm -1: 2968,2926,1440,1365,963,852,774.
NMR（CDCl 3）δ：0.88（3H，t，J＝7.1Hz），1.25（9H，s），2.53-2.68（2H，m），3.17-3.28（2H，m），3.81（1H，s），5.71（1H，d，J＝15.9Hz），6.08（1H，dt，
J＝15.9Hz，6.5Hz），6.40-6.48（1H，m），7.15-7.25（2H，m），7.38-7.53（5H，m），7.56（1H，dt，J＝7.1Hz，2.1Hz），7.73（1H，s）.
Embodiment 70
(E)-and N-(6,6-dimethyl-2-octene-4-alkynyl)-N-ethyl-3-[3-(3-thienyl) benzyloxy] preparation of benzylamine :-
With 50mgN-ethyl-3-[3-(3-thienyl) benzyloxy] benzylamine hydrochloride is dissolved in the 1.5ml dimethyl formamide, and adding 30mg1-bromo-6,6-dimethyl-2-octene-4-alkynes (ratio of E type and Z type is about 4: 1 mixture) and 65mg yellow soda ash.Mixture at room temperature stirs and spends the night, and the dilute with water reaction mixture is used extracted with diethyl ether then.Extract washs with saturated sodium chloride aqueous solution, and uses anhydrous sodium sulfate drying.Remove by filter siccative, boil off solvent then.Residuum through medium pressure liquid chromatography purify [post: Lobar post, size A, Lichroprep Si 60(E.Merck Co.); Eluent: hexane/ethyl acetate=7/1], obtain 39mg(productive rate 63%) title compound, be a colorless oil.
IRν neat maxcm -1：2968，2926，2800，1584，1491，1458，1260，774.
NMR（CDCl 3）δ：0.97（3H，t，J＝7.3Hz），1.00-1.10（3H，m），1.18（6H，s），1.44（2H，q，J＝7.3Hz），2.45-2.60（2H，m），3.05-3.15（2H，m），3.50-3.60（2H，m），5.11（2H，s），5.65（1H，d，J＝15.9Hz），6.07（1H，dt，J＝15.9Hz，6.4Hz），6.85-6.90（1H，m），6.90-6.95（1H，m），7.01-7.06（1H，m），7.22（1H，t，J＝8.0Hz），7.35-7.45（4H，m），7.47（1H，dd，J＝2.3Hz，1.8Hz），7.55（1H，dt，J＝7.0Hz，1.8Hz），7.66-7.69（1H，m）.
Embodiment 71
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-4-hydroxyl-3-[3-(3-thienyl) benzyloxy] preparation of benzylamine hydrochloride :-
To contain the 32mg3-(3-thienyl) dimethyl formamide solution (1ml) of bromotoluene joins by 40mg(E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-tetrahydrofuran solution (1.5ml) of the phenates of the oily sodium hydride preparation of N-methyl-3-hydroxyl-4-methoxymethyl oxygen base benzylamine and 5mg60% in.Mixture at room temperature stirred 2 hours, added ether in reaction mixture, and removed by filter insoluble inorganic salt, and filtrate under reduced pressure concentrates.In the mixture with the hydrochloric acid-methyl alcohol that is dissolved in 1ml10% of residuum and 1ml tetrahydrofuran (THF), and this solution at room temperature left standstill 2 hours.Decompression down concentrates reaction mixture, and adds 5% sodium bicarbonate aqueous solution and ether extract in residuum, isolates organic layer, uses anhydrous magnesium sulfate drying, removes by filter siccative, and solvent is steamed.Residuum gets pure [Wakogel C-200,5g through silica gel column chromatography; Eluent: hexane/ethyl acetate=3/1], obtain 31mg(productive rate 56%) free alkali of title compound, be a colorless oil.This free alkali is handled with hydrochloric acid-methanol solution, and with the mixture recrystallization of ether and isopropyl ether, obtains the hydrochloride of title, m.p.88-90 ℃.
IR ν Pure MaximumCm -1: 2968,1521,1464,1446,1281,777.
NMR（CDCl 3）δ：1.25（3H，s），3.39-3.54（1H，m），3.59-3.74（1H，m），3.83-4.00（1H，m），4.01-4.20（1H，m），5.31（2H，s），5.81（1H，d，J＝15.6Hz），5.91（1H，br.s），6.21（1H，dt，J＝15.6Hz，7.7Hz），6.80（1H，d，J＝7.8Hz），6.91（1H，d，J＝7.8Hz），7.38-7.48（4H，m），7.50-7.55（1H，m），7.56-7.62（1H，m），7.75（1H，s），7.82（1H，s）.
Except with corresponding methoxymethyl oxygen base benzyl amine derivative and/or 3-(5-oxazolyl) the benzyl methane sulfonate replaces initial compounds (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-hydroxyl-4-methoxymethyl oxygen base benzylamine and/or 3-(3-thienyl) bromotoluene, carry out the compound that same reaction among the embodiment 71 can obtain embodiment 72 and 73.
Embodiment 72
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-2-hydroxyl-3-[3-(5-oxazolyl) benzyloxy] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1476,1365,1245,1107,1035,954,789,750,693.
NMR（CDCl 3）δ：1.13（3H，t，J＝7.0Hz）1.23（9H，s），2.63（2H，q，J＝7.0Hz），3.20（2H，d，J＝7.0Hz），3.78（2H，s），5.18（2H，s），5.62（1H，d，J＝15.7Hz），6.08（1H，dt，J＝15.7Hz，7.0Hz），6.59-6.64（1H，m），6.67（1H，t，J＝8.0Hz），6.84（1H，dd，J＝8.0Hz，1.8Hz），7.37（1H，s），7.38-7.50（2H，m），7.60（1H，dt，J＝7.0Hz，1.8Hz），7.77（1H，s），7.91（1H，s）.
Embodiment 73
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-4-hydroxyl-3-[3-(5-oxazolyl) benzyloxy] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1518,1461,1365,1275,1200,1119,795,759.
NMR（CDCl 3）δ：1.24（9H，s），2.19（3H，s），2.96-3.12（2H，m），3.44（2H，s），5.16（2H，s），5.65（1H，d，J＝16.1Hz），6.08（1H，dt，J＝16.1Hz，6.7Hz），6.80（1H，dt，J＝8.0Hz，1.7Hz），6.89（1H，d，J＝8.0Hz），7.02（1H，br.s），7.39（1H，s），7.39-7.42（1H，m），7.48（1H，t，J＝7.6Hz），7.65（1H，dt，J＝7.6Hz，1.6Hz），7.73（1H，s），7.93（1H，s）.
Embodiment 74
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[3-(3-thienyl) benzyl amino] preparation of benzylamine :-
With 90mg(E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-amino-benzylamine and 63mg3-(3-thienyl) phenyl aldehyde is dissolved in the 2.5ml anhydrous methanol, have molecular sieve 3a in the presence of, this solution at room temperature stirred spends the night.By filtering molecular sieve is separated from reaction mixture.Then, add the 12.5mg sodium borohydride, mixture is restir 30 minutes at room temperature.Boil off solvent under the decompression, residuum is dissolved in the mixture of methylene dichloride and water.Isolate organic layer and use anhydrous magnesium sulfate drying.Remove by filter siccative, and boil off solvent.Residuum is through silica gel column chromatography purification [Wakogel C-2005g; Eluent: hexane/ethyl acetate=10/1 → 5/1], obtain 80mg(productive rate 55%) title compound, be a faint yellow oily thing.
IR ν Pure MaximumCm -1: 2968,2926,1608,1491,774.
NMR（CDCl 3）δ：1.01（3H，t，J＝7.1Hz），1.24（9H，s），2.49（2H，q，J＝7.1Hz），3.08（2H，dd，J＝6.4Hz，1.5Hz），3.48（2H，s），4.37（2H，s），5.63（1H，dt，J＝15.9Hz，1.5Hz），6.06（1H，dt，J＝15.9Hz，6.4Hz），6.51-6.56（1H，m），6.66-6.69（1H，m），7.11（1H，t，J＝8.0Hz），7.31（1H，dt，J＝7.8Hz，1.7Hz），7.35-7.40（3H，m），7.45（1H，t，J＝2.2Hz），7.51（1H，dt，J＝7.8Hz，1.7Hz），7.61（1H，br.s）.
Except the benzaldehyde derivative that replaces with corresponding 3-amino-benzylamine derivative and/or 3-replaces initial compounds (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-amino-benzylamine and/or 3-(3-thienyl) phenyl aldehyde, carry out the compound that same reaction among the embodiment 74 can obtain embodiment 75 to 80.
Embodiment 75
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(3-thienyl) benzyl amino] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1608,1491,1458,1365,774.
NMR（CDCl 3）δ：1.24（9H，s），2.18（3H，s），3.02（2H，dd，J＝6.5Hz，1.4Hz），3.42（2H，s），4.37（2H，s），5.63（1H，dt，J＝15.8Hz，1.4Hz），6.07（1H，dt，J＝15.8Hz，6.5Hz），6.52-6.56（1H，m），6.65-6.68（2H，m），7.11（1H，t，J＝7.9Hz），7.30（1H，dt，J＝7.5Hz，1.4Hz），7.35-7.40（3H，m），7.45（1H，t，J＝2.1Hz），7.51（1H，dt，J＝7.5Hz，1.7Hz），7.61（1H，br.s）.
Embodiment 76
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[3-(1-pyrryl) benzyl amino] benzylamine :-
IR ν Pure MaximumCm -1: 2968,1608,1506,1338,1071,783,726.
NMR（CDCl 3）δ：1.00（3H，t，J＝7.1Hz），1.24（9H，s），2.47（2H，q，J＝7.1Hz），3.07（2H，dd，J＝6.5Hz，1.5Hz），3.48（2H，s），4.39（2H，s），5.62（1H，dt，J＝15.8Hz，1.5Hz），6.05（1H，dt，J＝15.8Hz，6.5Hz），6.33（2H，t，J＝2.2Hz），6.49-6.53（1H，m），6.66-6.69（2H，m），7.08（2H，t，J＝2.2Hz），7.10（1H，t，J＝8.1Hz），7.24-7.32（2H，m），7.36-7.42（2H，m）.
Embodiment 77
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(5-oxazolyl) benzyl amino] benzylamine :-
IR ν Pure MaximumCm -1: 2974,1611,1506,1494,1458,1107,954,696.
NMR（CDCl 3）δ：1.20（9H，s），2.14（3H，s），3.05（2H，dd，J＝6.6Hz，1.5Hz），3.42（2H，s），4.38（2H，s），5.59（1H，dt，J＝15.9Hz，1.5Hz），6.03（1H，dt，J＝15.9Hz，6.6Hz），6.52（1H，dt，J＝8.0Hz，1.0Hz），6.67-6.69（2H，m），7.11（1H，t，J＝8.0Hz），7.35-7.42（3H，m），7.57（1H，dt，J＝7.4Hz，1.6Hz），7.68（1H，br.s），7.91（1H，s）.
Embodiment 78
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[3-(5-oxazolyl) benzyl amino] benzylamine :-
IR ν Pure MaximumCm -1: 2968,2926,1611,1506,1494,1476,1266,1107,954,789,759,696.
NMR（CDCl 3）δ：1.00（3H，t，J＝7.1Hz），1.24（9H，s），2.48（2H，q，J＝7.1Hz），3.07（2H，dd，J＝6.4Hz，1.5Hz），3.48（2H，s），4.38（2H，s），5.62（1H，dt，J＝15.9Hz，1.5Hz），6.05（1H，dt，J＝15.9Hz，6.4Hz），6.50-6.54（1H，m），6.67-6.69（2H，m），7.11（1H，t，J＝7.9Hz），7.36（1H，s），7.37-7.44（2H，m），7.57（1H，dt，J＝7.2Hz，1.7Hz），7.68（1H，br.s），7.91（1H，s）.
Embodiment 79
(E)-N-ethyl-N-(6-methoxyl group-6-methyl-2-heptene-4-alkynyl)-the 3-[3-(3-thienyl) benzyl amino] benzylamine :-
IRν
Figure 891091963_IMG48
cm -1：3412，3100，2980，2932，2818，1608，1491，1473，1365.
NMR（CDCl 3）δ：1.04（3H，t，J＝7.0Hz），1.46（6H，s），2.50（2H，q，J＝7.0Hz），3.13（2H，d，J＝6.0Hz），3.52（2H，s），4.37（2H，s），5.67（1H，d，J＝16.2Hz），6.16（1H，dt，J＝16.2Hz，6.0Hz），6.52-6.57（1H，m），6.66-6.72（2H，m），7.12（1H，t，J＝7.8Hz），7.29-7.40（4H，m），7.45（1H，t，J＝2.2Hz），7.51（1H，dt，J＝7.5Hz，2.1Hz），7.61（1H，br.s）.
Embodiment 80
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-propyl group-2-[3-(3-thienyl) benzyl amino]-4-pyridyl methylamine :-
IR ν Pure MaximumCm -1: 2968,1611,1569,1515,1464,1368,1269,774.
NMR（CDCl 3）δ：0.81（3H，t，J＝7.3Hz），1.24（9H，s），1.40（2H，sex，J＝7.3Hz），2.32（2H，t，J＝7.3Hz），3.03（2H，dd，J＝6.4Hz，1.4Hz），3.42（3H，s），4.53（2H，s），5.59（1H，dt，J＝15.9Hz，1.4Hz），5.99（1H，dt，J＝15.9Hz，6.4Hz），6.48（1H，d，J＝1.6Hz），6.58（1H，dd，J＝5.4Hz，1.6Hz），7.27-7.31（1H，m），7.34-7.40（3H，m），7.45（1H，t，J＝1.8Hz），7.50（1H，dt，J＝7.6Hz，1.7Hz），7.59（1H，br.s），7.96（1H，dt，J＝7.6Hz，1.7Hz）.
Embodiment 81
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[N '-methyl-3-(3-thienyl) benzyl amino] preparation of benzylamine :-
The 100mg(E that will in embodiment 74, obtain)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-and N-ethyl-3-[3-(3-thienyl) benzyl amino] benzylamine is dissolved in the 3ml acetonitrile, the formalin and the 22.7mg sodium cyanoborohydride that add 0.1ml35%, and mixture at room temperature stirred 30 minutes.Decompression is evaporation reaction mixture down, residuum is dissolved in the mixture of ethyl acetate and water, isolates organic layer, and uses anhydrous magnesium sulfate drying.Remove by filter siccative, boil off solvent.Residuum is through silica gel column chromatography purification [Wakogel C-200,5g; Eluent: hexane/ethyl acetate=10/1 → 6/1], obtain 55mg(productive rate 53%) title compound, be a faint yellow crystalline solid, m.p.51～52 ℃.
IR ν Pure MaximumCm -1: 2974,2926,1605,1500,1368,1218,762.
NMR（CDCl 3）δ：0.99（3H，t，J＝7.0Hz），1.23（9H，s），2.47（2H，q，J＝7.0Hz），3.02（3H，s），3.06（1H，dd，J＝6.3Hz，1.4Hz），3.51（2H，s），4.56（2H，s），5.61（1H，dt，J＝15.8Hz，1.4Hz），6.05（1H，dt，J＝15.8Hz，6.3Hz），6.63-6.71（2H，m），6.78-6.79（1H，m），7.12-7.19（2H，m），7.31-7.38（3H，m），7.41（1H，dd，J＝2.7Hz，1.5Hz），7.46-7.49（2H，m）.
Embodiment 82
(E), (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-and N-ethyl-5-[2-[3-(3-thienyl) phenyl] vinyl]-preparation of (1,3,4-oxadiazole-2-yl) methylamine :-
With 57mg(E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethylamino acetyl hydrazides is [by (E)-N-ethyl-6,6-dimethyl-2-heptene-4-alkynylamine and monobromo-acetic acid methyl esters are in condensation in the presence of sodium bicarbonate, the reaction of product and hydrazides comes synthetic then] and the 20mg sodium bicarbonate join in the 1ml diox adding 3-(3-thienyl in mixture) cinnamyl chloride De dioxane solution (1ml).The 3-(3-thienyl) cinnamyl chloride is by the 50mg3-(3-thienyl) styracin [by the 3-(3-thienyl) phenyl aldehyde and propanedioic acid have in the presence of piperidines/pyridine and under the heating condensation synthetic] and the 0.3ml thionyl chloride prepare.Above-mentioned reaction mixture was at room temperature stirred 30 minutes.Remove by filter inorganic salt, and under reduced pressure boil off solvent.Residuum is dissolved in the 0.8ml phosphoryl chloride, and solution was stirred 16 hours 65 ℃ the time.In reaction mixture impouring frozen water, and the adding sodium bicarbonate neutralizes.Use ethyl acetate extraction solution then, the extract anhydrous magnesium sulfate drying, and boil off solvent.Residuum is through silica gel column chromatography purification [Wakogel C-200,10g; Eluent: hexane/ethyl acetate=3/1], obtain 37mg(productive rate 36%) title compound, be a colorless oil.
IR ν Pure MaximumCm -1: 2972,1648,1364,1266,964,854,778.
NMR（CDCl 3）δ：1.13（3H，t，J＝7.1Hz），1.24（9H，s），2.65（2H，q，J＝7.1Hz），3.26（2H，dd，J＝6.8Hz，1.5Hz），3.95（2H，s），5.73（1H，dt，J＝15.9Hz，1.5Hz），6.07（1H，dt，J＝15.9Hz，6.8Hz），7.09（1H，d，J＝16.3Hz），7.39-7.50（4H，m），7.51（1H，dd，J＝3.1Hz，1.7Hz），7.60（1H，d，J＝16.3Hz），7.62（1H，dt，J＝7.4Hz，1.8Hz），7.76（1H，t，J＝1.8Hz）.
Embodiment 83
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[3-(1-pyrryl) benzamido) preparation of benzylamine :-
With 83mg(E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-and N-ethyl-3-amino-benzylamine and 100mg3-(1-pyrryl) phenylformic acid is dissolved in the mixture of 1ml methylene dichloride and 2ml tetrachloro furans, and adding 92mgN, N '-dicyclohexyl carbodiimide (DCC).Mixture was at room temperature stirred 3 hours, the vapourisation under reduced pressure reaction mixture, and residuum is dissolved in methylene dichloride.Remove by filter insoluble material, and use 5% sodium bicarbonate aqueous solution successively, 5% hydrochloric acid and the washing of saturated sodium chloride aqueous solution.Use anhydrous sodium sulfate drying, and boil off solvent.Residuum is through silica gel column chromatography purification [Wakogel C-200,20g; Eluent: hexane/ethyl acetate=10/1 → 3/1], obtain 98mg(productive rate 61%) title compound, be a faint yellow oily thing.
IRν neat maxcm -1：2968，1653，1593，1554，1503，1443，1341，723.
NMR（CDCl 3）δ：1.05（3H，t，J＝7.1Hz），1.23（9H，s），2.52（2H，q，J＝7.1Hz），3.10（2H，dd，J＝6.7Hz，1.6Hz），3.56（2H，s），5.65（1H，dt，J＝15.8Hz，1.6Hz），6.08（1H，dt，J＝15.8Hz，6.7Hz），6.37（2H，t，J＝2.5Hz），7.11-7.15（3H，m），7.31（1H，t，J＝7.8Hz），7.48-7.58（3H，m），7.62-7.70（2H，m），7.91-7.94（2H，m）.
Embodiment 84
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(1,3,4-triazol-1-yl) benzyloxy] preparation of benzylamine:
With 430mg3-(1,3,4-triazol-1-yl) ethyl benzoate [basically according to J.Med.Chem, 5 383(1962) method described synthetic] is dissolved in the mixture of 20ml tetrahydrofuran (THF) and 20ml diox, adds the 100mg lithium aluminum hydride.Mixture was at room temperature stirred 2 hours.Decompression is concentrated reaction mixture down, and residuum is distributed between ethyl acetate and water.Isolate organic layer, use anhydrous sodium sulfate drying.Remove by filter siccative, and steaming desolventizes.Residuum is through silica gel column chromatography purification [Wakogel C-200,20g; Eluent: chloroform/methanol=20/1], obtain 240mg(productive rate 69%) 1-(3-hydroxymethyl phenyl)-1,3, the 4-triazole.
The alkylol cpd that 220mg is obtained is dissolved in the 20ml chloroform, and adds the 2ml thionyl chloride.Mixture at room temperature stirred 2 hours.Decompression is concentrated reaction mixture down, and it is distributed between chloroform and water.Isolate organic layer, sodium bicarbonate aqueous solution with 5% and the washing of saturated sodium chloride aqueous solution.Behind anhydrous magnesium sulfate drying, under reduced pressure steam and desolventize, obtain 143mg(productive rate 59%) the 1-(3-chloromethyl phenyl)-1,3, the 4-triazole.
The chloro methyl compound that 38mg is obtained is dissolved in the 2ml dimethyl formamide, and this solution joined contain in advance by 60mg(E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-tetrahydrofuran solution (2ml) of the phenates of the oily sodium hydride preparation of N-methyl-3-hydroxybenzyl amine and 14mg60% in.Mixture at room temperature stirred 5 hours.Adding ether in reaction mixture separates it with water.Collect isolated organic layer, and use anhydrous magnesium sulfate drying.Decompression is steamed down and is desolventized.Residuum through medium pressure liquid chromatography purify [post: Lobar post, size A, Lichroprep Si 60(E.Merck Co.); Eluent: hexane/ethyl acetate=1/1 → 1/5], obtain 48mg(productive rate 59%) title compound, be a faint yellow oily thing.
IRν neat maxcm -1：2968，1599，1518，1491，1452，1368，1269，1152，1092，1032，786，762.
NMR（CDCl 3）δ：1.24（9H，s），2.19（3H，s），3.03（2H，dd，J＝6.6Hz，1.5Hz），3.48（2H，s），5.15（2H，s），5.64（1H，dt，J＝15.3Hz，1.5Hz），6.05（1H，dt，J＝15.3Hz，6.6Hz），6.87（1H，ddd，J＝7.8Hz，2.7Hz，1.2Hz），6.93（1H，d，J＝7.8Hz），6.99-7.02（1H，m），7.24（1H，t，J＝7.8Hz），7.35（1H，dt，J＝6.9Hz，2.4Hz），7.50-7.59（3H，m），8.50（2H，s）.
Embodiment 85
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[3-(3-thienyl) the benzyl sulfo-] preparation of benzylamine :-
With the 10mg3-[3-(3-thienyl) benzyl thio phenyl formaldehyde is dissolved in the 1ml ethanol, and adding 1.8mg sodium borohydride.Mixture at room temperature stirred 30 minutes.Boil off solvent under the decompression, adding ether and water extract in residuum.Isolate organic layer, and use anhydrous magnesium sulfate drying.Filter to isolate siccative, steaming desolventizes.Residuum is dissolved in the 1ml ethyl acetate, and adds 4.4mg methylsulfonyl chloride and 5.9mg triethylamine.Mixture at room temperature stirred 10 minutes.Remove by filter sedimentary triethylamine hydrochloride, and steaming desolventizes.Residuum is dissolved in the 1ml dimethyl formamide, and adds (E)-N-ethyl-6,6-dimethyl-2-heptene-4-alkynylamine hydrochloride and 10mg salt of wormwood.Mixture at room temperature stirs and spends the night.Decompression is concentrated reaction mixture down, and residuum is dissolved in the ether.Remove by filter insoluble substance, and under reduced pressure steaming desolventizes.Residuum is through preparation thin-layer chromatography purification [thin layer plate: Kieselgel 60F 254, Art, 5744(E.Merck Co.); Developping agent: hexane/ethyl acetate=5/1] obtain 7.5mg(productive rate 51%) title compound, be a colorless oil.
IR ν Pure MaximumCm -1: 1478,1363,1265,844,777.
NMR（CDCl 3）δ：1.00（3H，t，J＝7.1Hz），1.24（9H，s），2.44（2H，q，J＝7.1Hz），3.03（2H，d，J＝6.5Hz），3.49（2H，s），4.15（2H，s），5.62（1H，d，J＝15.9Hz），6.04（1H，dt，J＝15.9Hz，6.5Hz），7.13-7.42（8H，m），7.45（1H，t，J＝1.7Hz），7.46-7.51（2H，m）.
Embodiment 86
(E), (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-and N-ethyl-3-[2-[3-(5-thienyl) phenyl] vinyl] preparation of benzylamine :-
With 116mg(E)-the 3-[2-[3-(5-thiazolyl) phenyl] vinyl] methyl benzoate [by (E)-3-[2-(3-bromo phenyl that 3-methoxycarbonyl benzyl dimethyl phosphate and 3-bromobenzene formaldehyde condensation are obtained) vinyl] methyl benzoate and the condensation of 5-trimethylammonium stannyl thiazole be synthetic: referring to " Synthesis " 757(1986)] be dissolved in the 3ml tetrahydrofuran (THF), and at the ice-cooled 14mg lithium aluminum hydride that adds down.Mixture was stirred 30 minutes.In its impouring water, add ether and extract.The extract anhydrous magnesium sulfate drying removes by filter siccative, and steaming desolventizes.Residuum is dissolved in the mixture of 3ml ethyl acetate and 3ml methylene dichloride, and adds 31 microlitre methylsulfonyl chlorides and 70 microlitre triethylamines.Mixture at room temperature stirred 30 minutes.Remove by filter triethylamine hydrochloride, and under reduced pressure steaming desolventizes.Residuum is dissolved in the 3ml dimethyl formamide, and adds 81mg(E)-N-ethyl-6,6-dimethyl-2-heptene-4-alkynylamine hydrochloride and 42mg yellow soda ash.Mixture at room temperature stirred 3 hours.Decompression is concentrated reaction mixture down, and adding ether and water extract in residuum.Collect isolated organic layer, use anhydrous magnesium sulfate drying.Remove by filter siccative, and steaming desolventizes.Residuum through medium pressure liquid chromatography purify [post: Lobar post, size A, Lichroprop Si 60(E.Merck Co.); Eluent: hexane/ethyl acetate=8/1 → 6/1], obtain 63mg(productive rate 36%) title compound, be a colorless oil.
IR ν Pure MaximumCm -1: 2968.2872,1605,1458,1392,1365,1266,963,876,795.
NMR（CDCl 3）δ：1.07（3H，t，J＝7.1Hz），1.24（9H，s），2.54（2H，q，J＝7.1Hz），3.11（1H，d，J＝6.7Hz），3.59（2H，s），5.67（1H，d，J＝15.9Hz），6.11（1H，dt，J＝15.9Hz，6.7Hz），7.15（2H，s），7.29-7.57（7H，m），7.69（1H，dd，J＝3.6Hz，1.7Hz），8.12（1H，s），8.77（1H，s）.
Embodiment 87
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[3-(3-tetrahydro-thienyl) benzyloxy] preparation of benzylamine :-
With the 25mg3-(3-tetrahydro-thienyl) phenylcarbinol is dissolved in the 5ml ether, and adds 15 microlitre methylsulfonyl chlorides and 30 microlitre triethylamines.Ice-cooled down with mixture stirring 1 hour.Remove by filter sedimentary triethylamine hydrochloride, and boil off solvent.Residuum is dissolved in the 1ml dimethyl formamide, this solution is joined 10ml to be contained in advance by 100mg(E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-dimethyl formamide of the phenates of the oily sodium hydride preparation of N-methyl-3-hydroxy benzylamine and 30mg60% in.Mixture at room temperature stirred 3 hours, to wherein adding entry and ether dilutes.Isolate organic layer, and use dried over mgso, remove by filter siccative, steaming desolventizes again.Residuum through medium pressure liquid chromatography purify [post: Lobar post, size A, Lichroprep Si 60(E.Merck Co); Eluent: hexane/ethyl acetate=20/1 → 10/1], obtain 42mg(productive rate 75%) title compound, be a colorless oil.
IR ν Pure MaximumCm -1: 1446,1365,1272,1152,1026,885,786,693.
NMR（CDCl 3）δ：1.24（9H，s），2.07（1H，ddt，J＝12.2Hz，10.6Hz，8.5Hz），2.19（3H，s），2.42（1H，dq，J＝12.2Hz，4.6Hz），2.88-3.01（3H，m），3.04（2H，dd，J＝6.6Hz，1.5Hz），3.17（1H，dd，J＝10.2Hz，6.7Hz），3.29-3.41（1H，m），3.47（2H，s），5.04（2H，s），5.64（1H，dt，J＝15.8Hz，1.5Hz），6.07（1H，dt，J＝15.8Hz，6.6Hz），6.86（1H，ddd，J＝8.2Hz，2.6Hz，1.4Hz），6.91（1H，d，J＝7.5Hz），6.99（1H，br.s），7.19-7.35（4H，m），7.37（1H，br.s）.
Except with corresponding benzyl alcohol derivative and (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-hydroxy benzylamine replaces initiator 3-(3-tetrahydro-thienyl) phenylcarbinol and (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-hydroxy benzylamine outside, carry out the compound that same reaction among the embodiment 87 can obtain embodiment 88 and 89.
Embodiment 88
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[3-(3,4-dihydro-2H-thiapyran-5-yl) the benzyloxy benzylamine :-
IR ν Pure MaximumCm -1: 2968,2926,2866,1599,1491,1455,1263,777.
NMR（CDCl 3）δ：1.03（3H，t，J＝7.1Hz），1.24（9H，s），2.14-2.23（1H，m），2.50（2H，q，J＝7.1Hz），2.46-2.58（2H，m），2.88-2.93（2H，m），3.09（2H，d，J＝6.5Hz），3.54（2H，s），5.04（2H，s），5.64（1H，dt，J＝15.9Hz，1.5Hz），6.06（1H，dt，J＝15.9Hz，6.5Hz），6.45（1H，s），6.85（1H，dd，J＝8.4Hz，2.0Hz），6.92（1H，d，J＝7.2Hz），7.00（1H，br.s），7.19-7.36（4H，m），7.39（1H，br.s）.
Embodiment 89
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[3-(5,6-dihydro-2H-thiapyran-3-yl) benzyloxy] benzylamine :-
IR ν Pure MaximumCm -1: 3034,2968,2926,1740,1602,1491,1458,1263.
NMR（CDCl 3）δ：1.04（3H，t，J＝7.1Hz），1.24（9H，s），2.45-2.59（4H，m），2.77（2H，t，J＝5.7Hz），3.09（2H，d，J＝6.5Hz），3.50（2H，dd，J＝3.9Hz，2.1Hz），3.55（2H，br.s），5.05（2H，s），5.65
（1H，d，J＝15.9Hz），6.07（1H，dt，J＝15.9Hz，6.5Hz），6.11-6.17（1H，m），6.83-6.89（1H，m），6.92（1H，d，J＝7.5Hz），7.01（1H，br.s），7.19-7.36（4H，m），7.40（1H，br.s）.
Embodiment 90
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[4-(3-thienyl)-2-thienyl methoxyl group] preparation of benzylamine hydrochloride :-
With 100mg2-hydroxymethyl-4-(3-thienyl) thiophene is suspended in the 5ml chloroform, and stir and add 2 microlitre dimethyl formamides and 80 microlitre thionyl chloride down, and mixture was stirred 30 minutes ice-cooled.Ice-cooled down, with excessive saturated sodium bicarbonate aqueous solution this solution that neutralizes.Isolate organic layer,, and use anhydrous magnesium sulfate drying with saturated sodium chloride aqueous solution washing.Remove by filter siccative, boil off chloroform, obtain 2-chloro methyl-4-(3-thienyl) thiophene is a pale yellow powder.
The dimethyl formamide solution (3ml) of the chloro methyl compound that obtains is joined by with 165mg(E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-hydroxy benzylamine is dissolved in the 3ml anhydrous tetrahydro furan, and at the ice-cooled oily sodium hydride that adds 26mg60% that stirring down, in the phenates solution that mixture stirring 10 minutes is prepared.Mixture was at room temperature stirred 3 hours, use 20ml water and 30ml ethyl acetate extraction then.Isolate organic layer,, and use anhydrous magnesium sulfate drying with saturated sodium chloride aqueous solution washing.Steaming desolventizes, residuum through medium pressure liquid chromatography purify [post: Lobar post, size B, Lichroprep Si 60F(E.Merck Co.); Eluent: hexane/ethyl acetate=20/1 → 10/1], and use recrystallizing methanol, obtain 179mg(productive rate 78%) the free alkali of compound of title, be a white needles thing (m.p.67～68 ℃).This free alkali is handled with hydrochloric acid-methanol solution, and uses re-crystallizing in ethyl acetate, obtains the hydrochloride of title compound, m.p.128-129 ℃.
IR ν Pure MaximumCm -1: 2974,2926,2608,1602,1458,1266,1179,786
NMR（CDCl 3）δ：1.25（9H，s），1.34-1.41（3H，m），2.90-3.05（2H，m），3.45-3.60（2H，m），4.00-4.08（2H，m），5.35（2H，s），5.78（1H，dt，J＝15.9Hz，2.1Hz），6.18（1H，dt，J＝15.9Hz，6.9Hz），7.00-7.10（2H，m），7.15-7.40（5H，m），7.49-7.65（2H，m）.
Embodiment 91
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[4-(3-thienyl)-2-thienyl methoxyl group] preparation of benzylamine maleate :-
With (the E)-N-(6 that obtains among the 100mg embodiment 90,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-[4-(3-thienyl)-2-thienyl methoxyl group] benzylamine is dissolved in the 1ml methylene dichloride, and in this solution, add the 1ml dichloromethane solution that contains the 26mg toxilic acid.Steaming desolventizes, residuum ether recrystallization.Obtain 115mg(productive rate 90%) the maleate of title compound, fusing point is 100～102 ℃.
IR ν Pure MaximumCm -1: 3466,2974,1584,1497,1389,1371,1266,1185,786
NMR（CDCl 3）δ：1.26（9H，s），1.30（3H，t，J＝4.1Hz），3.02（2H，q，J＝4.1Hz），3.62（2H，br.s），4.09（2H，s），5.23（2H，s），5.82（1H，d，J＝15.6Hz），5.95（1H，dt，J＝15.6Hz，7.3Hz），6.99（1H，d，J＝7.5Hz），7.25（1H，dd，J＝7.5HZ，2.1Hz），7.12-7.16（1H，m），7.29-7.39（6H，m）
Embodiment 92-96
Except (the E)-N-(6 that replaces with corresponding 3-hydroxy benzylamine derivative using among the embodiment 90,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-hydroxy benzylamine, repeat the method among the embodiment 90, can obtain the compound of embodiment 92 to 96.
Embodiment 92
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-[4-(3-thienyl)-2-thienyl methoxyl group] benzylamine :-
Figure 891091963_IMG49
：2974，2788，1584，1488，1455，1269，1026，783.
NMR（CDCl 3）δ：1.24（9H，s），1.60（3H，s），3.04（2H，dd，J＝6.6Hz，1.5Hz），3.47（2H，s），5.22（2H，s），5.65（1H，dt，J＝15.9Hz，1.5Hz），6.01（1H，dt，J＝15.9Hz，6.6Hz），6.85-6.94（2H，m），6.99-7.01（1H，m），7.23（1H，t，J＝7.8Hz），7.29-7.36（5H，m）.
Embodiment 93
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-propyl group-3-[4-(3-thienyl)-2-thienyl methoxyl group] benzylamine :-
：2968，2872，1584，1455，1263，1029，783.
NMR（CDCl 3）δ：0.86（3H，t，J＝7.3Hz），1.24（9H，s），1.46-1.52（2H，m），2.36-2.40（2H，m），3.07（2H，dd，J＝6.3Hz，1.4Hz），3.53（2H，s），5.21（2H，s），5.63（1H，dt，J＝15.9Hz，1.4Hz），
6.06（1H，dt，J＝15.9Hz，6.3Hz），6.86（1H，ddd，J＝7.8Hz，2.6Hz，0.9Hz），6.93（1H，d，J＝7.8Hz），7.01-7.03（1H，m），7.21（1H，t，J＝7.8Hz），7.28-7.35（5H，m）.
Embodiment 94
(E)-N-(6-methoxyl group-6-methyl-2-heptene-4-alkynyl)-N-methyl-3-[4-(3-thienyl)-2-thienyl methoxyl group] benzylamine :-
：2986，1455，1365，1251，1170，1152，1074，1023，783
NMR（CDCl 3）δ：1.46（6H，s），2.20（3H，s），3.06（2H，dd，J＝7.8Hz，1.5Hz），3.35（3H，s），3.48（2H，s），5.22（2H，s），5.69（1H，dt，J＝15.8Hz，1.5Hz），6.18（1H，dt，J＝15.8Hz，7.8Hz），6.87-6.94（2H，m），6.99-7.01（1H，m），7.21-7.36（6H，m）
Embodiment 95
(E)-N-ethyl-N-(6-methoxyl group-6-methyl-2-heptene-4-alkynyl)-the 3-[4-(3-thienyl)-2-thienyl methoxyl group] benzylamine :-
：1455，1377，1365，1254，1173，1149，1074，1032，837，783
NMR（CDCl 3）δ：1.04（3H，t，J＝7.1Hz），1.46（6H，s），2.50（2H，q，J＝7.1Hz），3.10（2H，dd，J＝6.4Hz，1.4Hz），3.35（3H，s），3.54（2H，s），5.22（2H，s），5.69（1H，dt，J＝15.8Hz，1.4Hz），6.16（1H，dt，J＝15.8Hz，6.4Hz），6.86（1H，ddd，J＝7.9Hz），2.7Hz，1.0Hz），6.93（1H，d，J＝7.9Hz），7.00-7.10（1H，m），7.23（1H，t，J＝7.9Hz），7.29（1H，dd，J＝4.6Hz，1.3Hz），7.33-7.39（4H，m）.
Embodiment 96
(E)-N-(6-methoxyl group-6-methyl-2-heptene-4-alkynyl)-N-propyl group-3-[4-(3-thienyl)-2-thienyl methoxyl group] benzylamine :-
Figure 891091963_IMG53
：1455，1365，1254，1173，1152，1077，1032，783.
NMR（CDCl 3）δ：0.87（3H，t，J＝7.3Hz），1.39-1.58（2H，m），2.38（2H，t，J＝7.3Hz），3.09（2H，dd，J＝6.4Hz，1.4Hz），3.35（3H，s），3.54（2H，s），5.22（2H，s），5.68（1H，dt，J＝15.9Hz，1.4Hz），6.16（1H，dt，J＝15.9Hz，6.4Hz），6.87（1H，dd，J＝7.9Hz，2.9Hz），6.93（1H，d，J＝7.9Hz），7.00-7.03（1H，m），7.22（1H，t，J＝7.9Hz），7.30（1H，dd，J＝4.5Hz，1.4Hz），7.32-7.36（4H，m）.
Embodiment 97
Contain of the preparation of the compound of embodiment 19 as the pulvis of activeconstituents :-
The compound (hydrochloride) of 25 parts of embodiment 19 is dissolved in the mixture of 500 parts of ethanol and 500 parts of chloroforms, and adds 75 parts of polyvinylpyrrolidone K-30.It is dried under reduced pressure to adopt ordinary method that mixture is evaporated to.With gained solid abrasive fine powder, and with 250 parts of lactose, 145 parts of W-Gums and 5 parts of magnesium stearates mix, and form the pulvis that every 500mg contains the activeconstituents of 25mg.
Embodiment 98
Contain of the capsular preparation of the compound of embodiment 19 as activeconstituents :-
The compound (hydrochloride) of 25 parts embodiment 19 is dissolved in the mixture of 500 parts of ethanol and 500 parts of chloroforms, and adds 72.5 parts of polyvinylpyrrolidone K-30 and 2.5 parts of Tween60(tweens).It is dried under reduced pressure to adopt ordinary method that mixture is evaporated to.The solid abrasive that obtains is become fine powder, and with 50 parts of lactose, 45 parts of W-Gums and 5 parts of magnesium stearates mix.Powder is packed in the hard gelatine capsule with the amount of each capsule 200mg, make the capsule that contains the 25mg activeconstituents in each capsule.
Embodiment 99
Contain of the capsular preparation of the compound of embodiment 19 as activeconstituents :-
The compound (hydrochloride) of 25 parts of embodiment 19 is suspended in 1000 parts of water, and adds 150 parts of beta-cyclodextrins.Mixture was at room temperature stirred 12 hours, add 1000 parts of water again, and with mixture restir 3 hours at room temperature.Adopt ordinary method with the mixture freeze-drying, and the flocculence solid that obtains is ground gently, particle is packed in the hard gelatine capsule, make the capsule that each capsule contains the 10mg activeconstituents with the amount of each capsule 70mg.
Following reference example has illustrated the general synthetic method of the initial compounds that uses among the embodiment in front.
Reference example 1
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-preparation of N-methyl-3-hydroxy benzylamine :-
The methanol solution of 10.0g3-hydroxy benzaldehyde and 9.55g40% methylamine is mixed, and steaming desolventizes then.The Schiff's base that obtains is dissolved in the 50ml ethanol, stirring and ice-cooled down, add the 10.0g sodium borohydride.At room temperature mixture is stirred and spend the night.Decompression is steamed down and is desolventized, to wherein adding ethyl acetate and saturated sodium chloride aqueous solution extracts.Isolate organic layer, and use anhydrous sodium sulfate drying.Steaming desolventizes, and residuum is through silica gel column chromatography purification [Wakogel C-100,100g; Eluent: methylene chloride=10/1 → 5/1], obtain 8.88g(productive rate 79%) N-methyl-3-hydroxy benzylamine, be a light yellow crystal, m.p.138-140 ℃.
The N-methylamine compound (8.88g) and the 18.0g salt of wormwood that obtain are joined in the 30ml dimethyl formamide, at room temperature stir, add and contain 13.0g1-bromo-6, the dimethyl formamide solution (10ml) of 6-dimethyl-2-heptene-4-alkynes (E-type and Z type ratio are 3: 1 mixture).Mixture at room temperature stirs and spends the night.After reaction finished, steaming desolventized.Residuum is with the mixture extraction of ethyl acetate and saturated sodium chloride aqueous solution.Isolate organic layer, and use anhydrous magnesium sulfate drying.Remove by filter siccative.Boil off solvent.Residuum is through silica gel column chromatography purification [Wakogel C-200,300g; Eluent: hexane/ethyl acetate=10/1], obtain 7.94g(overall yield 39%) title compound, be a light yellow crystal, m.p.76-77 ℃.
Except the methanol solution with ethamine or propylamine or propylamine replaces initial methylamine-methanol solution, and as required, replace 1-bromo-6 with 1-bromo-6-methoxyl group-6-methyl-2-heptene-4-alkynes, outside 6-dimethyl-2-heptene-4-alkynes, carry out same reaction in the reference example 1 and can obtain the 3-hydroxy benzylamine derivative that in embodiment 1 to 48, uses, (E)-N-(6 for example, 6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-hydroxy benzylamine, (E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-propyl group-3-hydroxy benzylamine or (E)-N-ethyl-N-(6-methoxyl group-6-methyl-2-heptene-4-alkynyl)-the 3-hydroxy benzylamine.
Reference example 2
The 3-(2-furyl) preparation of benzyl chloride :-
With the 3-(2-furyl) ethyl benzoate [J.Chem.Soc, (B), 1971,2305] is dissolved in the 5ml anhydrous diethyl ether, stirring and adds the 23mg lithium aluminum hydride down ice-cooled, mixture was stirred 40 minutes.After reaction finishes, in reaction mixture, add entry and ether extracts.Handle extract with ordinary method, obtain 170mg(productive rate 83%) the 3-(2-furyl) phenylcarbinol.
Reference example 3
The 3-(1-pyrryl) preparation of benzyl methane sulfonate :-
One subcutin between 1.6g is dissolved in the 10ml Glacial acetic acid, and adds 2 of 1.3g, the 5-dimethoxy-tetrahydrofuran heats mixture 2 hours under refluxing, and boils off solvent, and residuum is dissolved in ethyl acetate and the water.Isolate organic layer, handle, use the hexane recrystallization at last, obtain 1.7g(productive rate 82% with ordinary method) pure 3-(1-pyrryl) ethyl benzoate, be a colourless spicule, m.p.64-65 ℃.
The pyrryl compound that 1.1g is obtained is dissolved in the 30ml ether, is stirring and down adds the 0.2g lithium aluminum hydride ice-cooled, and mixture was stirred 1 hour.In reaction mixture, add entry and ether extracts.Extract is handled with ordinary method, uses the mixture recrystallization of ethyl acetate and hexane then, obtains 0.80g(productive rate 91%) the 3-(1-pyrryl) phenylcarbinol, be a colourless spicule, m.p.66-68 ℃.
The alkylol cpd that 170mg is obtained is dissolved in the 10ml methylene dichloride and adds the 120mg methylsulfonyl chloride and the 150mg triethylamine, and mixture was stirred in ice-cooled 1 hour.Wash reaction mixture with water, and use anhydrous magnesium sulfate drying, boil off solvent, obtain 230mg(productive rate 92%) title compound, be a faint yellow oily thing.
Reference example 4
The 3-(3-thienyl) preparation of benzyl methane sulfonate :-
790mg magnesium is suspended in the 1ml anhydrous tetrahydro furan, and adds the glycol dibromide of trace.After being measured to the generation of bubble, at room temperature, and in 1.5 hours, stirring and be added dropwise to the tetrahydrofuran solution (12ml) that contains 5g 3-bromobenzaldehyde dimethylacetal.Mixture was stirred 30 minutes under 45 to 55 ℃ temperature, add the tetrahydrofuran solution (6ml) of two (diphenylphosphine) ethane chlorination nickel (II) of 80mg and 3-bromo thiophene then.Mixture was at room temperature stirred 3 hours.Saturated aqueous ammonium chloride solution is joined in the reaction mixture, and remove by filter insoluble substance.Add the ethyl acetate extraction reaction mixture, extract is handled with ordinary method, and through silica gel column chromatography purification [Wakogel C-100,70g; Eluent: hexane/ethyl acetate=50/1 → 10/1], obtain 1.35g(productive rate 27%) the 3-(3-thienyl) phenyl aldehyde dimethyl acetic acid ester, m.p.45-46 ℃.
The thienyl compounds (1.35g) that obtains is dissolved in the mixture of 4ml1N hydrochloric acid and 8ml tetrahydrofuran (THF).Solution is at room temperature stirred 1 hour, and under reduced pressure steaming desolventizes.Residuum extracts with ethyl acetate and water.Handle extract with ordinary method, obtain 1.05g(productive rate 96%) the 3-(3-thienyl) phenyl aldehyde, m.p.44-45 ℃.
The aldehyde cpd that 1.05g is obtained is dissolved in the 15ml ethanol, and adds the 250mg sodium borohydride.Mixture at room temperature stirred 30 minutes.Decompression is concentrated reaction mixture down, and extracts residuum with ethyl acetate and water.Handle extract with ordinary method, through silica gel column chromatography purification [Wakogel C-100,20g; Eluent: hexane/ethyl acetate=5/1], obtain 960mg(productive rate 86%) the 3-(3-thienyl) benzylalcohol, m.p.89-90 ℃.
300mg is obtained alkylol cpd is dissolved in the 7ml ethyl acetate, and in this solution, stirring and ice-cooled down, add the 320mg triethylamine and contain the ethyl acetate solution (1ml) of 270mg methylsulfonyl chloride.Mixture at room temperature stirred 30 minutes.Remove by filter the salt that is precipitated out,, and use anhydrous magnesium sulfate drying with saturated sodium bicarbonate aqueous solution washing reaction mixture.Decompression is steamed down and is desolventized, and obtains title compound, is a pale yellow powder.
In reference example 4, when the Hete rocyclic derivatives that replaces with corresponding bromine replaces the initiator 3 bromo thiophene, can obtain the 3-(3-furyl) benzyl derivative, 3-(2-thienyl benzyl derivative, the 3-(2-pyridyl) benzyl derivative, the 3-(3-pyridyl) benzyl derivative and 3-(4-pyridyl) benzyl derivative.
Reference example 5
The preparation of 5-(3-aminomethyl phenyl) isoxazole :-
1.56g3-ethynyl toluene is dissolved in the 20ml ether, and is stirring under-70 ℃, add 8.5ml1.5M just-butyllithium-hexane solution and 1.2ml ethyl formate.Mixture was stirred 20 minutes under uniform temp.In reaction mixture impouring frozen water, and isolate organic layer.Boil off solvent, obtain 900mg(productive rate 47%) the 3-(3-aminomethyl phenyl)-the 2-propynal, be a colorless oil.
The aldehyde that 130mg is obtained is dissolved in the 20ml ethanol, and adds the aqueous solution that 5ml contains the 70mg hydroxyl hydrochloride.Decompression down boils off solvent, residuum through the medium pressure liquid chromatography purification [post: Lobar post, size A, Lichroprep Si 60(E.Merck Co.); Eluent: hexane/ethyl acetate=10/1], obtain 122mg(productive rate 85%) the 3-(3-aminomethyl phenyl)-2-propine aldoxime, be a faint yellow oily thing.
The oxime compound that 122mg is obtained is dissolved in the 20ml ethanol, and adds the aqueous sodium hydroxide solution of 1 1N.Solution was placed 3 minutes, added 3 1NHCl stopped reactions.Boil off solvent, the mixture extraction of residuum water and ether under the decompression.Isolate organic layer, steam solvent, obtain 106mg(productive rate 87%) title compound, be a faint yellow oily thing.
Reference example 6
1-(3-hydroxymethyl phenyl) preparation of imidazoles :-
With 230mg1-(3-ethoxy carbonyl phenyl) imidazoles [referring to J.Am.Chem.Soc., 79,4922(1957)] be dissolved in the 10ml ether, and adding the 50mg lithium aluminum hydride, mixture at room temperature stirred 2 hours.In reaction mixture impouring frozen water, isolate organic layer, and use anhydrous magnesium sulfate drying.Remove by filter siccative, boil off solvent, residuum is through silica gel column chromatography purification [Wakogel C-200,20g then; Eluent: chloroform/methanol=20/1], obtain 160(productive rate 92%) title compound, be a colorless oil.
Reference example 7
The 3-(2-oxazolyl) preparation of bromotoluene :-
200mg2-(3-aminomethyl phenyl) oxazole [basically according to Ang.Chem, 75, the method for describing in 165(1963) is synthetic] is dissolved in the 5ml tetracol phenixin, and adds the benzoyl peroxide of 231mgN-bromo-succinimide and catalytic amount.Mixture stirs down and refluxed 2 o'clock.Reaction removes by filter insoluble substance, and under reduced pressure boils off solvent after finishing, and obtains title compound.
Use similar methods, can synthesize the 3-(2-thiazolyl) bromotoluene.
Reference example 8
The 3-(5-oxazolyl) preparation of benzylalcohol :-
With the 400mg3-(hydroxymethyl) (by preparing with equimolar sodium borohydride reduction isophthalic aldehyde, 574mg joins in the 10ml methyl alcohol a tosyl group methyl carbylamine and 406mg salt of wormwood phenyl aldehyde.Stirring and under refluxing with mixture heating up 1 hour.Decompression is concentrated reaction mixture down, and residuum extracts with ethyl acetate and water.Handle extract with ordinary method, through silica gel column chromatography purification [Wakogel C-200,50g; Eluent: hexane/ethyl acetate=1/1], obtain 375mg(productive rate 73%) title compound, be a white powder.
When above-mentioned alkylol cpd with reference example 3 in identical method when carrying out methylsulfonyl, can obtain the 3-(5-oxazolyl) benzyl methylsulfonyl ester, be a colorless oil.
Reference example 9
The 3-(4-isoxazolyl) preparation of bromotoluene :-
With 185mg4-(3-aminomethyl phenyl) isoxazole [referring to J.Heterocyclic Chem, 11,51(1974); And J.Chem.Soc, the Perkin II, 1121(1977)] be dissolved in the 8ml tetracol phenixin, and add the benzoyl peroxide of 206mgN-bromo-succinimide and catalytic amount.Mixture under agitation refluxed 3 hours.Remove by filter insoluble substance, and steaming desolventizes.Residuum is through silica gel column chromatography purification [Wakogel C-200,30g; Eluent: hexane/ethyl acetate=10/1], obtain 210mg(productive rate 76%) title compound, be a colourless powder.
When the same reaction of carrying out reference example 9, use the 4-(3-aminomethyl phenyl but remove) and isothiazole [referring to J.Prakt.Chem, 318,507(1976)], the 5-(3-aminomethyl phenyl) isothiazole [referring to J.Heterocyclic Chem., 11,55(1974); Heterocyclic, 19,1080(1982)], or 1-(3-aminomethyl phenyl)-1,2, the 4-triazole is [referring to J.Org, Chem., 21,1037(1956), with the open No.4173/1976 of Japan's special permission] when replacing initiator 4-(3-aminomethyl phenyl) isoxazole, can obtain the 3-(4-isothiazolyl) bromotoluene, the 3-(5-isothiazolyl) bromotoluene, the 3-(5-pyrimidyl) bromotoluene, or 3-(1,2, the 4-triazol-1-yl) bromotoluene.
Reference example 10
3-(2,3-dihydro-4-thienyl) preparation of benzylalcohol benzylalcohol and 3-(2,5-dihydro-3-thienyl) :-
Ice-cooled down, the tetrahydrofuran solution (10ml) of tetrahydro thiophene-3-ketone is being stirred in the tetrahydrofuran solution (15ml) that is added drop-wise to the refined reagent of being made by 2.31g 3-bromobenzaldehyde dimethylacetal and 0.36g MAGNESIUM METAL of Green.After adding, mixture was at room temperature stirred 1 hour.In reaction mixture impouring frozen water, add the extracted with diethyl ether product, handle extract with ordinary method, obtain 1.20g(productive rate 47%) crude product 3-(3-hydroxy tetrahydro-3-thienyl) benzaldehyde dimethyl acetal.
The alkylol cpd that 1.20g is obtained is dissolved in the mixture of 20ml tetrahydrofuran (THF) and 3ml10%HCl.After at room temperature placing 2 hours, adding ether and water dilute in solution.Isolate organic layer, and under reduced pressure steaming desolventizes.Residuum is dissolved in the 20ml methylene dichloride, and adds 1.0ml methylsulfonyl chloride and 2.0ml triethylamine.Mixture stirred 30 minutes down ice-cooled.In reaction mixture impouring frozen water, isolate organic layer, and steaming under reduced pressure desolventizes to doing.Residuum is dissolved in the 10ml ethanol, and adds the 0.2g sodium borohydride.Solution was at room temperature stirred 1 hour.Decompression is concentrated reaction mixture down, and adding ether and water extract in residuum.Handle extract with ordinary method, product through medium pressure liquid chromatography purify [Lobar post, size B, Lichroprep Si60(E.Merck Co.); Eluent: hexane → hexane/ethyl acetate 10/1], obtain 0.45g(productive rate 50%) 3-(2,3-dihydro-4-thienyl) benzylalcohol and 0.20g(productive rate 22%) 3-(2,5-dihydro-3-thienyl) benzylalcohol.
Reference example 11
The 3-(1-pyrrolidyl) preparation of benzylalcohol :-
With 0.25g N-(3-ethoxy carbonyl phenyl) succinimide [it is synthetic to add thermal condensation by m-anthranilic acid ethyl ester and succinyl oxide in acetate] is dissolved in the 5ml anhydrous tetrahydro furan, stirring and ice-cooled down, add the 0.17g lithium aluminum hydride.Mixture kept at room temperature 30 minutes, and reflux is 4 hours then, after reaction finishes, added ethyl acetate and water.Isolate organic layer, handle with ordinary method then, and with medium pressure liquid chromatography purify [Lobar post, size B, Lichroprep Si 60(E.Merck Co.); Eluent: hexane/ethyl acetate=10/1], obtain 84mg(productive rate 47%) title compound, be a colorless oil.
When the alkylol cpd that obtains carries out methylsulfonyl with the same procedure in the reference example 4, can obtain the 3-(1-pyrrolidyl) the benzyl methanesulfonates is a colorless oil.
Reference example 12
The 5-(3-thienyl) preparation of thienyl methyl alcohol :-
The 5g3-bromo thiophene is dissolved in the 35ml anhydrous diethyl ether, stirring and under the cooling of-70 to-65 ℃ temperature, add 19 milliliter 15% just-butyllithium-hexane solution and 10.5g tributyltin chloride, mixture stirred 1 hour under said temperature, at room temperature stirred then 1 hour.Sodium bicarbonate aqueous solution washing reaction mixture with saturated boils off solvent then, and residuum is purified with underpressure distillation, obtains 8.5g(productive rate 74%) tributyl (3-thienyl) tin, b.p.150-158 ℃/2mmHg.
1.19 above-mentioned tin compound and 0.56g5-bromo thiophene-2-formaldehyde are dissolved in the 3ml toluene, add the 20mg tetrakis triphenylphosphine palladium, mixture heated and stirred 7 hours under refluxing, potassium fluoride aqueous solution and 5% wet chemical washing reaction mixture with 10%.Boil off solvent, residuum is through silica gel column chromatography purification [Wakogel L-200,50g; Eluent: hexane/ethyl acetate=10/1], obtain 0.36g(productive rate 63%) the 5-(3-thienyl) thiophene-2-formaldehyde.
In the 4ml tetrahydrofuran (THF), the aldehyde cpd that obtains with 15.6mg lithium aluminium hydride reduction 144mg is handled with ordinary method then, obtains 134mg(productive rate 92%) title compound, be a colorless oil.
Reference example 13
The 2-(5-oxazolyl)-preparation of 4-piconol :-
With 1.07g pyridine-2, the 4-dimethyl dicarboxylate is dissolved in the 20ml toluene, stirring and under-80 to-70 ℃ of coolings, with the toluene solution that dripped the diisobutyl aluminium hydride of 6.04ml 1M in 2.5 hours, mixture stirred 1 hour under uniform temp.In reaction mixture impouring frozen water, add ether.Isolate organic layer, handle with ordinary method, then with medium pressure liquid chromatography purify [Lobar post, size B, Lichroprep Si 60(E.Merck Co.); Eluent: hexane/ethyl acetate=4/1 → 3/1], obtain 0.27g(productive rate 30%) 2-formyl radical iso methyl nicotinate, be a colourless crystalline powder.
The formylation compound that 203mg is obtained is dissolved in the 8ml methyl alcohol, and adds the salt of wormwood of 240mg ptoluene-sulfonyl methyl carbylamine and 170mg.Mixture heating up was refluxed 10 minutes, and decompression is evaporated to reaction mixture dried down.Residuum extracts with methylene dichloride and water.Handle organic layer with ordinary method, obtain 224mg(productive rate 91%) the 2-(5-oxazolyl) iso methyl nicotinate, be a pale yellow powder.
102mg is obtained De oxazolyl compound is dissolved in the 2ml anhydrous tetrahydro furan, stirring and ice-cooled down, add the 14mg lithium aluminum hydride.Mixture was stirred 30 minutes under uniform temp, and in reaction mixture impouring frozen water, and the adding methylene dichloride extracts.Use the conventional processing extract, and through silica gel column chromatography purification [Wakogel C-200,5,5g; Eluent: methylene chloride=50/1 → 20/1], obtain 49.5mg(productive rate 56%) title compound, be a faint yellow crystalline powder.
Reference example 14
The 5-(5-oxazolyl)-preparation of 3-piconol :-
With 1.67g pyridine-3, the 5-dimethyl dicarboxylate is dissolved in the 30ml anhydrous tetrahydro furan, stirring and ice-cooled down, the lithium aluminum hydride that adds 162mg, mixture stirred 30 minutes under this temperature, and in reaction mixture impouring frozen water, and the adding ether extracts.Handle extract with ordinary method, obtain thick 5-hydroxymethyl nicotinic acid methyl ester.This crude product is dissolved in the 20ml methylene dichloride, and adds the 2.2g pyridinium chloro-chromate, mixture at room temperature stirs and spends the night.In reaction mixture impouring frozen water, isolate organic layer, handle with ordinary method, and through silica gel column chromatography purification [Wakogel C-200,80g; Eluent: chloroform/methanol=20/1], obtain 0.37g(productive rate 26%) 5-formyl radical nicotinic acid methyl ester, m.p.96-97 ℃.
The formylation compound that obtains with 110mg carries out the reduction reaction of reference example 13 Zhong De oxazolylizations as starting material, obtains 77mg(productive rate 64%) title compound, be a colorless oil.
When with pyridine-2, the 6-dimethyl dicarboxylate replaces initiator pyridine-3, when the 5-dimethyl dicarboxylate carries out same reaction in the reference example 14, obtains the 6-(5-oxazolyl)-the 2-piconol.
Reference example 15
The preparation of 5-(5-methylol-2-furyl) oxazole :-
300mg5-formyl furfuryl alcohol [referring to Japan special permission open No.154758/1979] is dissolved in the 10ml methyl alcohol, and adds 502mg ptoluene-sulfonyl methyl carbylamine and 329mg salt of wormwood.Mixture heating up refluxed 1 hour, and decompression is concentrated reaction mixture down, and residuum is water-soluble and mixture ethyl acetate.Isolate organic layer, use anhydrous magnesium sulfate drying.Remove by filter siccative, and under reduced pressure boil off solvent.Residuum is through silica gel column chromatography purification [Wakogel C-200,45g; Eluent: hexane/ethyl acetate=3/2 → 1/1], obtain 260mg(productive rate 66%) title compound, be a light yellow crystal powder.
Reference example 16
4-methylol-2-(5-oxazolyl) preparation of thiazole :-
With 1.5g thiazole-2, the 4-diethyl dicarboxylate is suspended in the 15ml ethanol, and under-10 ℃, adds the ethanolic soln that 0.16g sodium borohydride and 3ml contain 0.58g calcium chloride.Mixture stirred 2 hours under said temperature, added the reductive agent of acetone decomposing excessive, and under reduced pressure boiled off solvent.In residuum, add dilute sulphuric acid, remove by filter insoluble calcium sulfate.With wet chemical the pH of filtrate is transferred to 10, use chloroform extraction then.Chloroform layer anhydrous magnesium sulfate drying, and vapourisation under reduced pressure is to doing, residuum is handled with isopropyl ether, obtains 0.78g(productive rate 64%) 2-hydroxymethylthiazole-4-carboxylic acid, ethyl ester, be a clear crystal powder.
The methylol compound that 0.78g is obtained is dissolved in the 40ml chloroform, and adds the active magnesium dioxide of 25g, and mixture at room temperature stirred 5 days.Remove by filter precipitation, the filtrate vapourisation under reduced pressure obtains 0.67g(productive rate 87% to doing) 2-formyl thiazole-4-carboxylic acid, ethyl ester, be a colourless spicule.
With the 60mg2-(5-oxazolyl) thiazole-4-carboxylic acid ethyl ester is (by the above-mentioned formylation compound that obtains of 80mg; the prepared in reaction that 91mg ptoluene-sulfonyl methyl carbylamine and 60mg salt of wormwood are described according to reference example 13] be dissolved in the 3ml ethanol, in this solution, add 6.6mg sodium borohydride and 24mg calcium chloride.Mixture at room temperature stirred 1 hour.Decompression is concentrated reaction mixture down, and adds 10% sulfuric acid in residuum.The precipitation of the generation of filtering separation adds salt of wormwood and regulates its pH value to 10 in filtrate.Add the chloroform extraction product, the extract anhydrous magnesium sulfate drying, and boil off solvent.Residuum is purified through the preparation thin-layer chromatography.Thin layer plate: Kieselgel 60 F254, Art.5744(E.Merck.Co.); Developping agent: hexane/ethyl acetate=1/4], obtain 20mg(productive rate 25%) title compound, be a white crystalline powder.
Reference example 17
The preparation of 5-(5-methylol-3-furyl) oxazole :-
With 408mg furans-3,5-dimethyl dicarboxylate [with reference to seeing J.Chem.Soc.Perkin I, 1130(1973)] is dissolved in the 4ml anhydrous tetrahydro furan, and adds the 59mg lithium aluminum hydride.Mixture at room temperature stirs and spends the night.In reaction mixture impouring water, and add ethyl acetate and extract, handle extract with ordinary method, and through silica gel column chromatography purify [Wakogel C-200,20g; Eluent: hexane/ethyl acetate=2/1], obtain 44mg(productive rate 13%) 5-methylol-furans-3-carboxylate methyl ester, be a colorless oil.
The alkylol cpd that 44mg is obtained is dissolved in the 2ml chloroform, and adds pyridinium chloro-chromate.Mixture at room temperature stirs and spends the night.In reaction mixture impouring frozen water, isolate organic layer, handle with ordinary method, through silica gel column chromatography purification [Wakogel C-200,20g; Eluent: hexane/ethyl acetate=3/1], obtain the pure formylation compound of 28mg.It is dissolved in the 2ml methyl alcohol, and adds 35mg ptoluene-sulfonyl methyl carbylamine and 25mg salt of wormwood.Mixture was refluxed 30 minutes, and handles, obtain the 30mg5-(5-oxazolyl with ordinary method)-furans-3-carboxylate methyl ester.The compound that obtains is dissolved in the 2ml tetrahydrofuran (THF), and at the ice-cooled 6mg lithium aluminum hydride that adds down.Mixture was stirred 30 minutes under said temperature.In reaction mixture impouring frozen water, and add ether and extract, handle extract, obtain 22mg(productive rate 48% with ordinary method) title compound, be a faint yellow oily thing.
Reference example 18
6-methyl-3-(1-pyrryl) preparation of benzylalcohol :-
158mg3-amino-6-methyl-toluate is dissolved in the 3ml acetate, and adds the 2.5-dimethoxy-tetrahydrofuran.With mixture reflux 1 hour.Decompression is evaporated to reaction mixture dried down.Residuum is through silica gel column chromatography purification [Wakogel C-200,10g; Eluent: hexane/ethyl acetate=10/1], obtain 185mg(productive rate 87%) the 3-(1-pyrryl)-the 6-methyl-toluate, m.p.56-57 ℃.
The pyrryl compound that 180mg is obtained is dissolved in the 2ml ether, and adds the lithium aluminum hydride of 24mg.Mixture was at room temperature stirred 30 minutes.In reaction mixture, add entry and ether.Isolate organic layer, and use anhydrous magnesium sulfate drying.Remove by filter siccative, and boil off solvent, obtain the 155mg(quantitative yield) title compound, be a clear crystal powder, m.p.70-71 ℃.
When replace initiator 3-amino-when the 6-methyl-toluate carries out the same reaction of reference example 18, can obtain 2-methyl-3-(1-pyrryl with 3-amino-2-methyl methyl benzoate) benzylalcohol.
Reference example 19
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-(3-formyl radical benzyloxy) preparation of benzylamine :-
The dimethyl formamide solution (1.5ml) of 90mg3-chloromethylbenzene formaldehyde is joined by 150mg(E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-the oily sodium hydride of N-methyl-3-hydroxy benzylamine, 23.2mg60% and the phenates solution that the 1ml tetrahydrofuran (THF) is made in, mixture at room temperature stirred spends the night.Boil off solvent under the decompression, residuum is handled with ordinary method with ethyl acetate-water extraction, and through silica gel column chromatography purification [Wakogel C-200,15g; Eluent: hexane/ethyl acetate=10/1 → 5/1], obtain 85mg(productive rate 39%) title compound, be a colorless oil.
When replacing initiator 3-chloromethylbenzene formaldehyde to carry out the same reaction of reference example 19 with the 3-bromomethyl-benzoic acid methyl ester, can obtain (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl-N-methyl-3-(3-methoxycarbonyl benzyloxy) benzylamine.
Reference example 20
(E)-and the 3-[2-[3-(3-thienyl) phenyl] preparation of vinyl chloride :-
With the 2.40g3-(3-thienyl) benzyl chloride is dissolved in the 40ml toluene, and adding 3.62g triphenylphosphine, and mixture heating up refluxed 50 hours.Make reaction mixture cooling, filter the crystal of collecting precipitation, obtain 3.60g(productive rate 66%) the 3-(3-thienyl) Bian base triphenyl phosphonium chloride.
1.21g is obtained the De phosphonium salt be dissolved in the 45ml ethanol, and add 0.35g3-formyl radical benzylalcohol and 0.27g sodium ethylate.Mixture was at room temperature stirred 2 hours.Boil off solvent under the decompression, residuum distributes between ethyl acetate and water, handle with ordinary method, and through silica gel column chromatography purification [Wakogel C-300,100g; Eluent: hexane/ethyl acetate=10/1 → 5/1], obtain 0.34g(productive rate 46%) the 3-[2-[3-(3-thienyl of E type) phenyl] vinyl] the Z type compound of benzylalcohol and 0.34g.
(E)-type alcohol that 0.20g is obtained is dissolved in the 6ml chloroform, and adds 0.15ml thionyl chloride and a dimethyl formamide, and mixture was at room temperature stirred 1 hour.Decompression is concentrated reaction mixture down, and residuum distributes between ether and water, handle with ordinary method, and through silica gel column chromatography purification [Wakogel C-100,20g; Eluent: hexane/ethyl acetate=20/1], obtain 0.19g(productive rate 87%) title compound, be a clear crystal powder, m.p.79-81 ℃.
When except that the benzyl chloride that replaces with corresponding 3-or bromo when carrying out the same reaction of reference example 20 the initiator 3-(3-thienyl benzyl chloride, can obtain (E)-3-[2-[3-(5-oxazolyl) phenyl] vinyl] benzyl chloride, (E)-and the 3-[2-[3-(5-thiazolyl) phenyl] vinyl] benzyl chloride and (E)-3-[2-[3-(1-imidazolyl) phenyl] vinyl] benzyl chloride.
Reference example 21
(E)-and the 3-[2-[3-(1-pyrryl) phenyl] vinyl benzyl alcohol :-
With the 560mg3-(dimethoxy-methyl) benzyl three phenyl phosphonium bromides are [by with phosphorus tribromide bromination 3-methylol phenyl aldehyde, then product is dissolved in the anhydrous methanol, have right-toluenesulphonic acids in the presence of carry out acetalation, make itself and triphenylphosphine react to synthesize] Phosphonium and 180mg3-(1-pyrryl again) phenyl aldehyde [by in chloroform with pyridinium chloro-chromate oxidation 3-(1-pyrryl) benzylalcohol synthesizes] be dissolved in the 20ml methyl alcohol.Add the 110mg sodium methylate, and mixture was at room temperature stirred 3 hours.Decompression is concentrated reaction mixture down, adds ethyl acetate and water extracts in residuum, handles organic layer with ordinary method, through medium pressure liquid chromatography purify [Lobar post, size B, Lichroprep Si60(E.Merck Co.); Eluent: hexane/ethyl acetate=10/1], obtain 135mg(productive rate 42%) E-type 3-[2-[3-(1-pyrryl) phenyl] vinyl] benzaldehyde dimethyl acetal and its Z-type compound of 127mg.
(E)-type acetal that 135mg is obtained is dissolved in the mixture of 5ml tetrahydrofuran (THF) and 5ml2NHCl, and solution was at room temperature stirred 3 hours, boils off solvent under the decompression then, handles residuum with ordinary method.The formylation compound that obtains is dissolved in the 10ml ethanol, and adds the 40mg sodium borohydride.Mixture was at room temperature stirred 30 minutes, under reduced pressure concentrated reaction mixture.Residuum distributes between ethyl acetate and water, handles with ordinary method, through silica gel column chromatography purification [Wakogel C-100,20g; Eluent: hexane/ethyl acetate=5/1], obtain 78mg(productive rate 67%) title compound, be a clear crystal powder, m.p.108-110 ℃.
When using the 3-(3-pyridyl) phenyl aldehyde replacement initiator 3-(1-pyrryl) when phenyl aldehyde carries out the same reaction of reference example 21, can obtain (E)-3-[2-[3-(3-pyridyl) phenyl] vinyl] benzylalcohol.
Reference example 22
The 3-[2-[3-(3-thienyl) phenyl] ethyl] preparation of benzylalcohol :-
With 81mg(Z)-the 3-[2-[3-(3-thienyl) phenyl] vinyl] benzylalcohol is dissolved in the 3ml ethanol, and having in the presence of palladium-carbon of 15mg10%, catalytic reduction is 15 hours at normal temperatures and pressures.Removing by filter catalyzer, and boil off solvent, obtain the title compound of quantitative yield, is a colorless oil.
When with (Z)-3-[2-[3-(1-pyrryl) phenyl) vinyl benzyl alcohol or (Z)-3-[2-[3-(3-pyridyl) phenyl] vinyl] benzylalcohol replaces initiator (Z)-3-[2-[3-(3-thienyl) phenyl] vinyl] when benzylalcohol carries out reduction reaction identical in the reference example 22, can obtain the 3-[2-[3-(1-pyrryl) phenyl] ethyl] benzylalcohol and 3-[2-[3-(3-pyridyl) phenyl] ethyl] benzylalcohol.
Reference example 23
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-preparation of N-ethyl-5-formyl radical chaff amine :-
The 100mg5-hydroxymethylfurfural is dissolved in the 2ml anhydrous diethyl ether, is stirring and down add the diethyl ether solution (1ml) that contains 30 microlitre phosphorus tribromides, mixture was stirred 10 minutes under said temperature ice-cooled.Reaction mixture washs with saturated sodium bicarbonate aqueous solution, then, add 183mg(E)-N-ethyl-6,6-dimethyl-2-heptene-4-alkynylamine hydrochloride, 136mg salt of wormwood and 3ml dimethyl formamide, mixture is at room temperature stirred the decompression concentrated reaction mixture down that spends the night, residuum distributes between ether and water, handles with ordinary method, and purifies through silica gel column chromatography, obtain 132mg(productive rate 53%) title compound, be a faint yellow oily thing.
Reference example 24
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-preparation of N-methyl-4-formyl radical-2-pyridyl methylamine :-
With 160mg(E)-N-(6; 6-dimethyl-2-heptene-4-alkynyl)-N-methyl-4-ethoxy carbonyl-2-pyridyl methylamine is [by making 4-ethoxy carbonyl-2-piconol tosylation with p-toluenesulfonyl chloride and triethylamine; make then the product of tosylation with (E)-N-methyl-6; 6-dimethyl-2-heptene-4-alkynylamine condensation is synthesized] be dissolved in the 2ml toluene; stirring and under the cooling of-75 to-70 ℃ temperature, adding the toluene solution of 0.56ml1M diisobutyl aluminium hydride.Mixture was stirred 40 minutes under said temperature.In reaction mixture impouring frozen water, and add ether.Isolate organic layer, handle with ordinary method, through medium pressure liquid chromatography purify [Lobar post, size A, Lichroprep Si 60(E.Merck Co.); Eluent: hexane/ethyl acetate=4/1], obtain 15mg(productive rate 11%) title compound, be a faint yellow oily thing.
When using (E)-N-(6; 6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-ethoxy carbonyl-5-isoxazolyl methylamine is [by carrying out bromination with N-bromosuccinimide to 5-methyl-isoxazole-3-carboxylic acid, ethyl ester; then the product of bromination with (E)-N-ethyl-6; 6-dimethyl-2-heptene-4-alkynylamine condensation is synthesized] replacement initiator (E)-N-(6; 6-dimethyl-2-heptene-4-alkynyl)-N-methyl-4-ethoxy carbonyl-when 2-pyridyl methylamine carries out the same reaction of reference example 24; can obtain (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-formyl radical-5-isoxazolyl amine.
Reference example 25
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-preparation of N-methyl-3-hydroxyl-4-methoxymethyl oxygen base benzylamine :-
The oily sodium hydride of 3g3.4-Dihydroxy benzaldehyde and 0.87g60% is suspended in the 13ml tetrahydrofuran (THF), and adds the dimethyl formamide solution (10ml) that contains 3.3ml methoxymethyl chlorine, mixture was at room temperature stirred 1 hour.Decompression is concentrated reaction mixture down, and residuum distributes between ethyl acetate and water, handles organic layer with ordinary method, then through silica gel column chromatography purification [Wakogel C-200,150g; Eluent: hexane/ethyl acetate=4/1], obtain 1.78g(productive rate 45%) 3-hydroxyl-4-methoxymethyl oxygen benzaldehyde.
The methoxymethyl oxycompound that 360mg is obtained is dissolved in the methanol solution of 6ml40% methylamine, and adds the 151mg sodium borohydride, and mixture was at room temperature stirred 1 hour.Decompression is concentrated reaction mixture down, and residuum distributes between ethyl acetate and water, isolates organic layer, boils off solvent.Residuum is dissolved in the 10ml dimethyl formamide, adds 361mg1-bromo-6,6-dimethyl-2-heptene-4-alkynes (E-type and 3: 1 mixture of Z-type) and 276mg salt of wormwood at room temperature stir mixture and to spend the night.Decompression is concentrated reaction mixture down, and residuum distributes between ether and water.Isolate organic layer, handle, through silica gel column chromatography purification [Wakogel C-200,30g with ordinary method; Eluent: hexane/ethyl acetate=3/1], obtain 140mg(productive rate 22%) title compound, be a faint yellow oily thing.
When with 2, the 3-Dihydroxy benzaldehyde replaces initiator 3, the 4-Dihydroxy benzaldehyde, and with methoxymethyl chlorine and triethylamine alkylation selectivity in chloroform is combined to 3-hydroxyl-2-methoxymethyl oxygen benzaldehyde, carry out the same reaction of reference example 25 then, can obtain (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-methyl-3-hydroxyl-2-methoxymethyl oxygen base benzylamine.
Reference example 26
(E)-and N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-amino-benzylamine :-
With the 6.0gN-(3-2-bromomethylphenyl) phthalimide [by with N-bromosuccinimide in tetracol phenixin between N-(-tolyl) phthalimide carries out bromination and synthesizes] be dissolved in the 100ml dimethyl formamide, and adding 3.82g(E)-N-ethyl-6,6-dimethyl-2-heptene-4-alkynylamine hydrochloride and 7.87g salt of wormwood at room temperature stirs mixture and to spend the night.Decompression is concentrated reaction mixture down, residuum extracts with ethyl acetate-water, isolate organic layer, boil off solvent, then with a spot of ether washing residuum, obtain 5.5g(productive rate 72%) (E)-N-(6,6-dimethyl-2-heptene-4-alkynyl)-N-ethyl-3-phthalimido benzylamine, m.p.96-98 ℃.
The benzylamine compound that 150mg is obtained is dissolved in the 5ml ethanol, and adds the 23mg hydrazine, and mixture was at room temperature stirred 30 minutes.Remove by filter throw out.And boil off solvent.Residuum distributes between methylene dichloride and water.Handle organic layer with ordinary method, through silica gel column chromatography purification [Wakogel C-100,5g; Eluent: hexane/ethyl acetate=10/1 → 3/1], obtain 95mg(productive rate 95%) title compound, be a light yellow crystal powder, m.p.65-66 ℃.
Reference example 27
The 3-[3-(3-thiophene) benzyl sulfo-] preparation of phenyl aldehyde :-
0.3g sulphur is joined in the tetrahydrofuran solution (20ml) of the refined reagent of making by 1.0g3-bromo benzaldehyde dimethyl acetal and 0.4g magnesium of Green, and mixture was at room temperature stirred 2 hours.Add the 0.3g lithium aluminum hydride, and mixture was stirred 3 hours 40 ℃ the time.In reaction mixture impouring frozen water, add hydrochloric acid and carry out acidifying, add ether and extract.Handle extract with ordinary method, boil off solvent, obtain 0.36g(productive rate 60%) 3 sulfydryl phenyl aldehydes.
The sulfhydryl compound that 60mg is obtained is dissolved in the 5ml dimethyl formamide, and adds the 50mg3-(3-thienyl) the oily sodium hydride of bromotoluene and 30mg60%, mixture at room temperature stirred 3 hours.In reaction mixture impouring frozen water, handle with ordinary method, through medium pressure liquid chromatography purify [post: Lobar post, size A, Lichroprep Si60(E.Merck Co.); Eluent: hexane/ethyl acetate=30/1 → 10/1], obtain 2.3mg(productive rate 4%) title compound, be a colorless oil.
Reference example 28
The 3-(3-tetrahydro-thienyl) preparation of benzylalcohol :-
To obtain 3-(2 in the 30mg reference example 10,5-dihydro-3-thienyl) benzylalcohol is dissolved in the 25ml ethanol, having in the presence of palladium-carbon of 50mg10%, at 3.5Kg/cm 2Hydrogen pressure under, catalytic reduction 8 hours.Remove by filter catalyzer, and under reduced pressure boil off solvent, obtain 25mg(productive rate 82%) title compound, be a colorless oil.
Reference example 29
3-(3,4-dihydro-2H-thiapyran-5-yl) preparation of benzylalcohol benzylalcohol and 3-(5,6-dihydro-2H-thiapyran-3-yl) :-
Is starting material with 534mg with 3-bromo benzaldehyde dimethyl acetal and tetrahydric thiapyran-3-ketone, 3-(tetrahydrochysene-3-hydroxyl-3-thiapyran base according to the preparation of the same reaction of reference example 10) benzaldehyde dimethyl acetal is dissolved in the 5ml ethyl acetate, stirring and ice-cooled down, add 187 microlitre methylsulfonyl chlorides and 553 microlitre triethylamines, mixture was stirred 30 minutes.Remove by filter triethylamine hydrochloride, and steaming desolventizes.Residuum is dissolved in the 20ml benzene, and adds uncle-butanols potassium of 373mg90%, mixture was at room temperature stirred 15 hours.In reaction mixture, add ether and water, use the ordinary method treating mixture.The 3-dihydro thiapyran benzaldehyde dimethylacetal that obtains is dissolved in the mixture of 3ml1NHCl and 6ml tetrahydrofuran (THF), solution was at room temperature stirred 3 hours.Decompression is concentrated reaction mixture down, and residuum distributes between ether and water, handles with ordinary method.The formylation compound that obtains is dissolved in the 20ml tetrahydrofuran (THF), and adds the lithium aluminum hydride of 380mg, mixture stirred 1 hour down ice-cooled.In reaction mixture impouring frozen water, handle with ordinary method, through silica gel column chromatography purification [Wakogel C-200,20g; Eluent: hexane/ethyl acetate=2/1], obtain 7mg(productive rate 2%) title compound 3-(3,4-dihydro-2H-thiapyran-5-yl) benzylalcohol and 4mg(productive rate 1%) 3-(5,6-dihydro-2H-thiapyran-3-yl) benzylalcohol.
The compounds of this invention has suppressed cholesteric biosynthesis by suppressing mammiferous squalene epoxidase, has reduced the content of blood cholesterol. In addition, expect that they can become the disease that effective treatment and prevention cause because of excessive cholesterine, such as the medicament of obesity, high fat of blood, artery sclerosis and heart disease and concurrent cerebral disease.

Claims (16)

1, the allylamine derivatives and the non-toxic salt thereof of the replacement represented of following general formula,
Figure 891091963_IMG2
Wherein
A 1And A 2Identical or different, each represents methyne or nitrogen, oxygen or sulphur atom;
Q 1And Q 2Identical or different, each expression contains 1 or 2 heteroatomic group that is selected from a group that nitrogen, oxygen and sulphur atom form, this group and adjacent carbon atom and A 1Or A 2Form five yuan or hexa-atomic aromatic ring together;
X and Y are identical or different, and each represents oxygen or sulphur atom, carbonyl, formula-CHR 8-group, wherein R aExpression hydrogen atom or low alkyl group or formula-NR b-group, wherein R bExpression hydrogen atom or low alkyl group, perhaps X and Y form vinylene or ethynylene together;
R 1Expression contains 1-4 heteroatomic five yuan or the hexa-member heterocycle base that are selected from one group that is made up of nitrogen, oxygen and sulphur atom;
R 2Expression low alkyl group, allyl group, propargyl or cyclopropyl;
R 3And R 4Identical or different, each represents low alkyl group, perhaps forms naphthene group jointly with adjacent carbon atom together;
R 5Expression hydrogen atom, low alkyl group or lower alkoxy; With
R 6And R 7Identical or different, each represents hydrogen atom, halogen atom, hydroxyl, cyano group, low alkyl group or lower alkoxy;
Condition be in X and Y expression Sauerstoffatom, sulphur atom or-NR b-(R wherein bAs definition) during group, another expression carbonyl or-CHR a-(R wherein 8As definition) group.
2, the allylamine derivatives of the described replacement of claim 1 and non-toxic salt thereof, wherein R 1Be pyrryl, furyl, thienyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, the furazan base, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, the dihydro-thiophene base, tetrahydro-thienyl, pyrrolinyl, pyrrolidyl oxazolinyl oxazolidinyl isoxazoline-3-yl isoxazole alkyl, thiazolinyl, thiazolidyl, the isothiazoline base, the isothiazole alkyl, 1,2-dithiolane base, 1,3-dithiolane base, 1,2-dithiole base, 1,3-dithiole base, dihydro thiapyran base, tetrahydro thiapyran base, 1,4-dithiane base, 1,4-dithia English base (1,4-dithiinyl), 1,4-oxa-sulphur English base (1,4-oxathiinyl), or thio-morpholinyl; Use formula
Figure 891091963_IMG3
They are identical or different for five yuan of expression or hexa-atomic aromatic ring, and each represents benzene, pyrroles, furans, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazoles, 1,3,4-oxadiazole, 1,3,4-thiadiazoles, pyridine, pyridazine, pyrimidine, pyrazine or triazine ring.
3, the allylamine derivatives of the described replacement of claim 2 and non-toxic salt thereof, its Chinese style
The aromatic ring of expression is benzene or thiphene ring.
4, the allylamine derivatives of the described replacement of claim 1 and non-toxic salt thereof, wherein R 1Be thienyl, pyrryl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl, imidazolyl, pyridyl or dihydro-thiophene base; Formula
Figure 891091963_IMG5
The aromatic ring of expression is benzene or thiphene ring; Following formula
The expression five yuan or hexa-atomic aromatic ring be benzene, pyrroles, furans, thiophene, oxazole, isoxazole, thiazole, isothiazole, imidazoles, 1,3,4-oxadiazole, 1,3,4-thiadiazoles, pyridine, pyridazine, pyrimidine, pyrazine or triazine ring.
5, the described allylamine derivatives of claim 4 and non-toxic salt, wherein R 1Be 3-thienyl, 1-pyrryl, 5-oxazolyl, 4-isoxazolyl, 5-isoxazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyridyl, 2,3-dihydro-4-thienyl or 2,5-dihydro-3-thienyl.
6, the allylamine derivatives and the non-toxic salt thereof of claim 4 or 5 described replacements, its Chinese style
The expression five yuan or hexa-atomic aromatic ring be benzene, furans, thiophene, oxazole, isoxazole, thiazole, isothiazole, 1,3,4-oxadiazole, 1,3,4-thiadiazoles, pyridine, pyridazine, pyrimidine or pyrazine ring.
7, the allylamine derivatives of the described replacement of claim 4,5 or 6 and non-toxic salt thereof, wherein X is a methylene radical, Y is methylene radical, Sauerstoffatom, sulphur atom or imido grpup, or X and Y represent (E)-vinylene together.
8, the allylamine derivatives of the described replacement of claim 7 and non-toxic salt thereof, wherein R 2Be methyl, ethyl or propyl group, R 3And R 4Be methyl, and R 5Be methyl, ethyl or methoxyl group.
9, the allylamine derivatives of the replacement of the described general formula of production claim 1 [I] and the method for non-toxic salt thereof comprise the substituted amine derivatives or its protected compound that make general formula [II] expression,
A wherein 1, A 2, Q 1, Q 2, X, Y, R 1, R 2, R 6And R 7As claim 1 definition,
With the compound reaction of general formula [III] expression,
Figure 891091963_IMG9
Wherein Z represents leavings group, R 3, R 4And R 5As claim 1 definition,
Then, if desired, remove blocking group;
Perhaps make compound or its protected derivative of general formula [IV] expression,
Figure 891091963_IMG10
A wherein 1, A 2, Q 1, Q 2, X, Y, R 1, R 6, R 7Define as mentioned with Z, with the replacement amine reaction of general formula [V] expression,
R wherein 2, R 3, R 4And R 5Definition as mentioned,
Then, if desired, remove blocking group;
Then, when needed compound is converted into its non-toxic salt.
10, the allylamine derivatives that replaces of the general formula [I] that provides of production claim 1 and the method for non-toxic salt thereof comprise allylamine derivatives or its protected derivative of the replacement that makes general formula [VI],
Figure 891091963_IMG12
A wherein 1, A 2, Q 1, Q 2, X, Y, R 1, R 3, R 4, R 5, R 6And R 7As claim 1 definition,
With the compound reaction of general formula [VII],
R wherein 2As claim 1 definition, Z is a leavings group, then, if desired, removes blocking group, when needed product is changed into non-toxic salt then.
11, produce general formula [I a] expression the replacement allylamine derivatives and the method for non-toxic salt,
Figure 891091963_IMG13
A wherein 1, A 2, Q 1, Q 2, X a, Y a, R 1, R 2, R 3, R 4, R 5, R 6And R 7As hereinafter definition, it comprises compound or its protected derivative that makes general formula [VIII] expression,
X wherein aExpression carbonyl or formula-CHR a-group (R wherein aExpression hydrogen atom or low alkyl group), Z represents leavings group, and A 1, Q 1, R 1And R 6As claim 1 definition, with substituted amine derivatives or its protected compound reaction of general formula [IX] expression,
Y wherein aThe expression Sauerstoffatom, sulphur atom, or formula-NR b-group (R wherein bExpression hydrogen atom or low alkyl group), and A 2, Q 2, R 2, R 3, R 4, R 5And R 7As claim 1 definition,
Then, if desired, remove blocking group; When needed product is converted into non-toxic salt then.
12, produce general formula [I b] expression the replacement allylamine derivatives and the method for non-toxic salt,
Figure 891091963_IMG16
A wherein 1, A 2, Q 1, Q 2, X b, Y b, R 1, R 2, R 3, R 4, R 5, R 6And R 7As hereinafter definition, comprise the compound or its protected derivative that make general formula [X] expression,
Figure 891091963_IMG17
X wherein bExpression Sauerstoffatom, sulphur atom or formula-NR b-group (R wherein bExpression hydrogen atom or low alkyl group), and A 1, Q 1, R 1And R 6As claim 1 definition,
With substituted amine derivatives or its protected radical reaction of general formula [XI] expression,
Figure 891091963_IMG18
Y wherein bExpression carbonyl or formula-CHR a-group (R wherein aExpression hydrogen atom or low alkyl group), Z represents leavings group, and A 2, Q 2, R 2, R 3, R 4, R 5And R 7As claim 1 definition,
Then, if desired, remove blocking group; When needed product is converted into non-toxic salt then.
13, produce general formula [I c] expression the replacement allylamine derivatives and the method for non-toxic salt,
A wherein 1, A 2, Q 1, Q 2, R 1, R 2, R 3, R 4, R 5, R 6And R 7As hereinafter definition,
Comprise the compound that makes general formula [XII] expression
A wherein 1, Q 1, R 1And R 6As claim 1 definition,
With the compound reaction of general formula [X III] expression,
A wherein 2, Q 2, R 2, R 3, R 4, R 5And R 7As claim 1 definition, then, reduzate,
14, treat hypercholesteremic medicament, it contains allylamine derivatives or its non-toxic salt that the described general formula of claim 1 [I] replaces.
15, the medicament of treatment hyperlipoidemia, it contains allylamine derivatives or its non-toxic salt of the replacement of the described general formula of claim 1 [I].
16, treat arteriosclerotic medicament, it contains allylamine derivatives or its non-toxic salt of the replacement of the described general formula of claim 1 [I].
CN89109196A 1988-11-11 1989-11-11 The allylamine derivatives that replaces, their production method and application thereof Pending CN1042910A (en)

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PCT/JP1989/000522 WO1990005132A1 (en) 1988-11-11 1989-05-25 Substituted allylamine derivatives, process for their preparation and their use
JPPCT/JP89/00522 1989-05-25

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CN115724823A (en) * 2021-08-27 2023-03-03 中国科学院大连化学物理研究所 Method for preparing dihydrothiophene derivative
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