CN1091438C - 0-acyl-4-phenyl-cyclohexanols, their salts, medicaments containing such compounds and their use, as well as a method of preparing them - Google Patents

Abstract

The present invention relates to 0-acyl-4-phenyl-cyclohexanol in a general formula I, a preparation method, medical compositions containing the compounds and a use of the medical compositions for the interference of ornitrol biosynthesis. In the general formula, n is 0 or 1; m is 1 or 2; p is 0 or 1; R<1> and R<2> respectively represent hydrogen, or lower alkyl, or alkenyl or alkynyl; the groups can be optionally substituted, or form a 5 to 7-section saturated monocyclic heterocyclic ring with nitrogen atoms in the middle of the groups; optionally, the heterocyclic ring can also be broken by oxygen, or sulphur atoms or imino groups; R<3>, R<4>, R<5> and R<6> represent hydrogen or lower alkyl; R<5> represents lowers alkoxyl groups; R<7> represents hydrogen, naphthenic bases, phenyl or substituted phenyl, naphthyl, tetralyl, thienyl and furyl or pyridyl; A represents chemical bonds, or alkyl at most containing 17 carbon atoms, alkenyl or alkynyl. An antihypercholesterolemic substance can be used for treating and preventing atherosclerosis and inhibit enzyme 2, 3-epoxy squalene-lanosterine-cyclase.

Description

According to O-acyl-4-phenyl-cycloalkanol, its salt of the 34th modification of PCT treaty, the medicine that contains these compounds and its purposes with and preparation method thereof

The present invention relates to O-acyl-4-phenyl-cycloalkanol, the physiologically acceptable salt that itself and organic and mineral acid form, the preparation method of these compounds and contain medicine of these compounds and uses thereof.

Compound of the present invention is the biosynthetic inhibitor of cholesterol, and particularly enzyme 2,3-epoxy squalene-lanosterol-cyclase, the inhibitor of the biosynthetic main enzyme of a kind of cholesterol.Compound of the present invention is applicable to treatment and prevention hyperlipidemia.The all diseases of hypercholesterolemia and atherosclerosis.But other Application Areas comprises the high outgrowth tetter of treatment, vascular disease, tumour, gallbladdergallstonecholetithiasis and mycosis.

The compound that plays interference effect in the cholesterol biosynthesizing is important for the many syndromess of treatment.Wherein at first be so-called hypercholesterolemia and hyperlipidemia, they are to produce that atherosclerotic blood vessel changes and its secondary disease for example coronary heart disease, cerebral ischemia, the risk factor of intermittent claudication and gangrene.

The importance that it has been generally acknowledged that too high serum ornitrol content is that it is to produce the primary hazard factor that atherosclerotic blood vessel changes.Vast amount of clinical is by reducing serum ornitrol content with the danger that reduces coronary heart disease (Current Opinion in Lipidology 2 (4), 234[1991]).Because most cholesterol is self synthetic in vivo, having only small part is from food, and therefore suppressing biosynthesizing is a kind of special effective means that reduces too high cholesterol content.

In addition, suppress biosynthetic other the possible Application Areas of cholesterol and comprise treatment high outgrowth tetter, vascular disease and tumour illness, treat and prevent gallbladdergallstonecholetithiasis and be used for the Mycophyta disease.Under latter event, be the biosynthesizing of disturbing the ergosterol that in fungi, is carried out, it is substantially similar to the cholesterol biosynthesizing in the human body cell.

The biosynthesizing of cholesteric biosynthesizing or ergosterol all is to be begun to be undertaken by a large amount of reactions steps by acetate.This many processes have a series of interference potential, and wherein example can have:

For inhibitory enzyme 3-hydroxy-3-methyl glutaryl base-coenzyme A (HMG-CoA) synthase can be to have the β-lactone of potential hypercholesterolemia effect and beta-lactam (referring to J.Antibiotics 40; 1356[1987]; US-A-4751237, EP-A-0462667, US-A-4983597).

The inhibitor of enzyme HMG-CoA-reductase enzyme be this it stop dihydroxy carboxylic acids and its δ-lactones of type (statintyp), what wherein be used for the treatment of hypercholesterolemia has a Luo Futanding (lovastatin); Xi Waku (simvastatin) and Pravastatin (pravastatin).

Other Application Areas of this compound be fungus transmission (US-A-4375475, EP-A-0113881, US-A-5106992), tetter (EP-A-0369263) and gallbladdergallstonecholetithiasis and neoplastic disease (US-A-5106992; Lancet 339,1154-1156[1992]).Other treatment possibility is by using Luo Futanding to suppress outgrowth smooth muscle cell (Cardiovasc.Drugs.Ther.5, Suppl.3,354[1991]).

The inhibitor of enzyme squalene synthetase is isoprenoid-(phosphinyl methyl) phosphonic acid ester for example, it is at EP-A-0409181 and J.Med.Chemistry 34,1912[1991] in described them and be suitable for treating hypercholesterolemia, gallbladdergallstonecholetithiasis and neoplastic disease, in addition, squalene it stop (squalestatin) have reduce cholesterol and antifungal effect (J.Antibiotics 45,639-647[1992] and J.Biol.Chemistry 267,11705-11708[1992].

The inhibitor of enzyme squalene-cyclooxygenase is a propylamine, as naftifungin (Naftifin) and Te Pingnafen (Terbinafin), they are as the medicine of antimycotic and in being used for the treatment of, and (J.Biol.Chemistry 265 to have the allylamine NB-598 of hypercholesterolemia effect, 18075-18078, [1990]) and have the fluorine squalene derivative (US-A-5011859) of hypocholesteremia effect.Other is disclosed to be piperidines and the Azadecalin with potential hypocholesteremia and/or anti-mycotic activity, its mechanism of action is still not fully aware of, and formation squalene epoxidase and/or 2, inhibitor (the EP-A-0420116 of 3-epoxy squalene-lanosterol-cyclase, EP-A-0468434, US-A-5084461 and EP-A-0468457).

Enzyme 2, the example of the inhibitor of 3-epoxy squalene-lanosterol-cyclase is phenylbenzene derivative (EP-A-0464465), aminoalkoxy benzyl derivative (EP-A-0410359) and piperidine derivative (J.Org.Chem.57,2794-2803, [1992]), they have antifungic action.In addition, these enzymes suppress by following material in mammalian cell: naphthalane (Decaline), Azadecalin (azadecaline) and 1,2 indane derivatives (Wo89/08450, J.Biol.Chemistry 254,11258-11263[1981], Biochem, Pharmacology 37,1955-1964[1988] and J64003144), also has 2-azepine-2,3-dihydro squalene and 2,3-epimino squalene (Biochem, Pharmacology34,2765-2777[1985]) squalene oxide-epoxide-enol ether (J.Chem.Soc.Perkin Trans, I, 1988,461) and 29-methylene radical-2,3-oxidation squalene (J.Amer.Chem.Soc 113,9673-9674[1991]).

At last, has the active steroid derivative of potential lipidemia, also can be used as the inhibitor of enzyme lanosterol-14 α-demethylase, they influence enzyme HMG-COA-reductase enzyme (US-A-5041452 simultaneously, J.Biol.Chemistry 266,20070-20078[1991], US-A-5034548).In addition, these enzymes are that the antifungal by pyrroles's type suppresses, and their constitute imidazoles and the triazole that N replaces.The example that belongs to this class comprises anti-mildew medicine KETOKONAZOL (ketoeonazol), the fluconazole (Fluconazol) that can buy from market.

The compound of following general formula I is new, is surprisingly found out that they are enzymes 2,3-epoxy shark alkene-lanosterol-cyclase (International Classification, highly efficient depressor EC5.4.99.7).

Enzyme 2, the committed step in 3-epoxy squalene-lanosterol-cyclase catalysis cholesterol or the ergosterol biosynthesizing is about to 2, and 3-epoxy squalene is transformed into lanosterol, and first has the structure of steroide in the biosynthesizing cascade.The inhibition of this kind of enzyme and early stage biosynthesizing step such as HMG-CoA is synthetic and the inhibitor of HMG-CoA in reducing compared and had higher optionally advantage.Because, suppress the mevalonic acid minimizing that these early stage biosynthesizing steps cause biosynthesizing to generate, thereby make the material dolichol that depends on mevalonic acid, the biosynthesizing of ubiquinone and isopentene group-uncle-RNA is subjected to negatively influencing (J.Biol.Chemistry 265,18075-18078[1990]).

With 2,3-epoxy squalene is transformed in the biosynthetic inhibition step behind the lanosterol, exists the danger that intermediate with steroide structure is built up in vivo, thereby causes relevant therewith toxic action.For example, triparanol has been described, a kind of 2,4-deoxidation cholesterol-reductase enzyme-inhibitor.This material removes (quote J.Biol.Chemisry 265 as proof, 18075-18078[1990]) from the market owing to form cataract, sauriasis and alopecia.

As what begin to have described, 2, existing in the literature indivedual description of the inhibitor of 3-epoxy squalene-lanosterol-cyclase.But the structure of this compound and the present invention hereinafter described structure of the compound of general formula I are different fully.

The invention provides antihypercholesterolemic material, they be suitable for the treatment and prevention of arterial atherosis, compare with known active substance, it is characterized in that having higher optionally hypercholesterolemia effect, thereby improved security.Therefore, compound-base of the present invention is used as enzyme 2 in its high validity, and the inhibitor of 3-epoxy squalene-lanosterol-cyclase also can suppress the biosynthesizing of the ergosterol in the fungal organism, thereby also be suitable for treating mycosis.

New 0-acyl-4-phenyl-cycloalkanol, its enantiomorph, diastereomer and the geometrical isomer that theme of the present invention provides a kind of general formula I with and salt, physiologically acceptable salt especially pharmaceutically useful, that form with organic acid or mineral acid,

In the formula:

N is 0 or 1,

M is 1 or 2,

P is 0 or 1,

R ¹And R ²Can be identical or different, represent hydrogen atom, the straight or branched alkyl that contains 1～6 carbon atom, the straight or branched alkenyl or the alkynyl that contain 3～6 carbon atoms, wherein two keys and triple bond separate with nitrogen-carbon bond, above-mentioned alkyl, alkenyl and alkynyl also can be replaced by amino, hydroxyl, alkoxyl group, alkyl-carbonyl oxygen, alkyl-carbonyl-amino, carboxyl, alkoxy carbonyl, aminocarboxyl or cyano group, wherein above-mentioned amino, hydroxyl, alkoxyl group, alkyl-carbonyl oxygen base and alkyl-carbonyl-amino are not connected with undersaturated carbon atom, be not connected with carbon atom on 1 yet, or

R ¹And R ²Form the saturated monocyclic heterocycle of 5 joints～7 joints with its intermediary nitrogen-atoms, and the methylene radical on 4 can be replaced in the saturated monocyclic heterocycle of 6 joints that so form by Sauerstoffatom or sulphur atom or the imino-that is replaced by alkyl in case of necessity,

R ³And R ⁴Can be identical or different, represent hydrogen atom or contain the alkyl of the straight or branched of 1～4 carbon atom,

R ⁵Represent hydrogen atom or contain the straight or branched alkyl of 1～4 carbon atom, or contain the alkoxyl group of 1～4 carbon atom,

R ⁶Represent hydrogen atom or contain the straight or branched alkyl of 1～4 carbon atom,

R ⁷Represent hydrogen atom; the cycloalkyl that contains 3～7 carbon atoms; randomly can be by fluorine; the chlorine or bromine atom; or by hydroxyl; alkyl; alkoxyl group; the phenyl alkoxyl group; phenyl; nitro; amino; alkylamino; dialkyl amido; alkyl-carbonyl-amino; cyano group; carboxyl; alkoxy carbonyl; aminocarboxyl; alkyl amino-carbonyl; dialkyl amino carbonyl; trifluoromethyl; alkyl-carbonyl oxygen; amino-sulfonyl; alkyl amino sulfonyl or dialkyl amino sulfonyl list or disubstituted phenyl; substituting group can be identical or different in the base; and two adjacent hydrogen atoms can be by methylene radical dioxy base or 1 on the phenyl; 2-ethylidene dioxy base group replaces; by two chlorine atoms or bromine atoms and an amino phenyl that replaces; naphthyl or tetralyl; by halogen atom or the thienyl that replaced by one or two alkyl; furans or pyridyl and

A represents a key, contain 1～17 carbon atom straight or branched alkylidene group or contain the alkylene group or the alkynylene of 2～17 carbon atoms.

Wherein, unless have givenly in addition, all abovementioned alkyls and alkoxyl group part all can contain 1～3 carbon atom, and above-mentioned halogen atom can be represented fluorine, the chlorine or bromine atom.

The compound of general formula (Ia) preferably, its enantiomorph, diastereomer and geometrical isomer with and salt, the especially pharmaceutically useful physiologically acceptable salt that forms with organic acid or mineral acid,

In the formula:

N, m and p represent 1 separately,

R ¹And R ²Can be identical or different, represent hydrogen atom, the straight or branched alkyl that contains 1～6 carbon atom, the alkenyl or the alkynyl that contain the straight or branched of 3-6 carbon atom, wherein its pair key and triple bond separate with nitrogen-carbon bond, abovementioned alkyl wherein, alkenyl and alkynyl can be by amino, hydroxyl, alkoxyl group, alkyl-carbonyl oxygen, alkyl-carbonyl-amino, carbonyl, alkoxy carbonyl, aminocarboxyl or cyano group replace, wherein above-mentioned amino, hydroxyl, alkoxyl group, alkyl-carbonyl oxygen and alkyl-carbonyl-amino are not connected on the undersaturated carbon atom and are not connected on 1 the carbon atom, or

R ¹And R ²Form the saturated monocyclic heterocycles of 5～7 joints with its intermediary nitrogen-atoms, wherein the methylene radical on 4 can be replaced by Sauerstoffatom or sulphur atom or the imino-that is replaced by alkyl in case of necessity in the saturated monocyclic heterocycle of 6 joints that forms like this,

R ³-R ⁶Can be identical or different, represent hydrogen atom or methyl separately,

R ⁷Represent hydrogen atom; the cycloalkyl that contains 3-7 carbon atom; randomly by fluorine; chlorine or bromine atom or by hydroxyl; alkyl; alkoxyl group; the phenyl alkoxyl group; phenyl; nitro; amino; alkylamino; dialkyl amido; alkyl-carbonyl-amino; cyano group; carboxyl; alkoxy carbonyl; aminocarboxyl; alkyl amino-carbonyl; dialkyl amino carbonyl; trifluoromethyl; alkyl-carbonyl oxygen; amino-sulfonyl; alkyl amino sulfonyl or dialkyl amino sulfonyl group list or disubstituted phenyl; wherein substituting group can be identical or different; and two adjacent hydrogen atoms can be by methylene-dioxy or 1 on phenyl; 2-ethylenedioxy group replaces; by two chlorine atoms or bromine atoms and an amino phenyl group that replaces; naphthyl or tetralyl group; by a fluorine atom or bromine atoms or the thienyl that replaced by one or two alkyl; furans or pyridyl and

A represents a key, contain 1～10 carbon atom straight or branched alkylidene group or contain the alkylene group or the alkynylene of 2-10 carbon atom,

Wherein unless otherwise prescribed, all abovementioned alkyl and alkoxyl group parts all can contain 1～3 carbon atom.

Particularly preferably be the compound of general formula I a, its enantiomorph, diastereomer and geometrical isomer with and salt, the physiologically acceptable salt that especially pharmaceutically useful and organic acid or mineral acid form.

In the formula:

N, m and p represent 1 separately,

R ¹Represent hydrogen atom, contain the straight or branched alkyl of 1～4 carbon atom, it can be by the aminocarboxyl group or at 2-, and 3-or 4-position are replaced by hydroxyl or alkoxyl group, or represent the 2-propenyl with

R ²Represent hydrogen atom, contain the alkyl or the 2-propenyl of 1～4 carbon atom, or

R ¹And R ²Form the saturated monocyclic heterocycle of 5 or 6 joints with its intermediary nitrogen-atoms, wherein in the saturated monocyclic heterocycle of 6 joints that so forms, can be replaced by Sauerstoffatom or the imino-that is randomly replaced by alkyl at 4 locational methylene radical,

R ³And R ⁶Represent hydrogen atom separately,

R ⁷Represent hydrogen atom, the cycloalkyl that contains 3～6 carbon atoms, in case of necessity in the 4-position by a fluorine, chlorine or bromine atom or by a mono-substituted phenyl of alkyl, alkoxyl group, phenyl, nitro or trifluoromethyl, by two chlorine atoms, chlorine atom and alkyl or amino or by two disubstituted phenyl groups of alkoxyl group, by two chlorine atoms and an amino trisubstd phenyl, 3, the 4-methylenedioxyphenyl, naphthyl or tetralyl, 2-furyl or the 2-thienyl or the 3-pyridyl that are replaced by a chlorine atom in the 5-position in case of necessity

A represents a key, and contain the straight or branched alkylidene group of 1～6 carbon atom or contain the alkylene group of 2～5 carbon atoms,

Wherein unless otherwise prescribed, all abovementioned alkyl and alkoxyl group parts all can contain 1～3 carbon atom.

The compound of general formula I a most preferably, its enantiomorph, diastereomer and geometrical isomer with and salt, the especially pharmaceutically useful physiologically acceptable salt that forms with organic acid or mineral acid.

In the formula:

N, m and p respectively do for oneself 1,

R ¹Represent hydrogen atom, contain the straight or branched alkyl of 1～4 carbon atom, it can be by the aminocarboxyl group or at 2-, and 3-or 4-position are replaced by a hydroxyl or alkoxy base, or represent a 2-propenyl,

R ²Represent hydrogen atom or contain the alkyl of 1～4 carbon atom,

R ³～R ⁶Represent hydrogen atom separately,

R ⁷Representative in case of necessity 4 by a fluorine, chlorine or bromine atom or by a methyl, trifluoromethyl, methoxyl group, the phenyl group that phenyl or nitro replace, 3, the 4-dichlorophenyl, the 2,4 dichloro benzene base, 4-chloro-3-aminomethyl phenyl, 4-amino-3-chloro-phenyl-, 3, the 4-Dimethoxyphenyl, 3,4-methylenedioxyphenyl, 4-amino-3,5-dichlorophenyl or 2-naphthyl group and

A represents a key, contains the straight or branched alkylidene group of 1～5 carbon atom or contains the alkylene group of 2 or 3 carbon atoms.

Wherein, unless otherwise prescribed, alkyl that all are above-mentioned and alkoxyl group part all can contain 1～3 carbon atom.

Particularly following compounds and its esters,

(1) cis-O-(4-chlorobenzene formacyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

(2) cis-O-(4-phenyl-3-butyryl radicals)-4-(4-dimethylaminomethyl phenyl)-hexalin

(3) trans-O-(4-chloro-phenyl-ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

(4) cis-O-(5-methyl caproyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

(5) trans-O-(2-phenyl propionyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

(6) trans-O-(4-fluorophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

(7) trans-O-(3,4-dichlorophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

(8) cis-0-(4-fluorine cinnamoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

(9) trans-0-(right-the tolyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-ring ethanol

(10) trans-0-(4-[trifluoromethyl]-phenyl acetyl)-4-(4-dimethylaminomethyl phenyl)-ring ethanol

(11) trans-0-(2-naphthyl ethanoyl)-4-(4 dimethylaminomethyl phenyl)-hexalin

(12) trans-0-(4-nitrophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

(13) trans-0-(4-bromophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

(14) trans-0-(2,4 dichloro benzene base ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

(15) trans-0-([4-amino-3-chloro-phenyl-] ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

(16) trans-0-(4-p-methoxy-phenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

(17) trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-methylamino aminomethyl phenyl)-hexalin.

The preparation method:

Formula I compound can prepare as follows:

A) with the 4-benzyl ring alkanol of general formula I I and the carboxylic acid or the reaction of its response derivative of general formula III:

N, m, p and R ¹-R ⁶Define as above,

R ⁷-A-COX (III)

In the formula (III)

R ⁷Define as above with A, the leavings group of X representation hydroxy or reaction, the halogen atom of chlorine or bromine atom for example, trimethylsiloxy group, sulfonyloxy as right-tosyloxy, as the N-heteroaryl of 1-imidazolyl or 1-benzotriazole base, or as neighbour-(N, N '-dicyclohexyl)-different urea group neighbour-different urea group.

Reaction preferably in solvent, as benzene, toluene, dimethylbenzene, two-isopropyl ether ， diox, tetrahydrofuran (THF), dimethyl formamide, methylene dichloride or chloroform, in case of necessity have alkali in the presence of, as triethylamine, pyridine or 4-dimethylaminopyridine, or have acid in the presence of, especially when the X representation hydroxy in the general formula III, for example in the presence of etherate of trifluoroboron or acid cation-exchanger, carry out, temperature of reaction is-10～150 ℃, but preferred-10～80 ℃.

If R ¹And/or R ²Have free hydroxyl group, amino or carboxylic group should be protected it by appropriate means before reaction so, for example hydroxyl are transformed into ether, as 2-methoxy ethoxy methyl ether, and tert-butyl ether or benzyl ether; Amino is transformed into carbamate groups, as three chloroethyls-, 9-fluorenyl methyl-or 2,4-dichloro benzyl carbamate groups and carboxyl is transformed into ester group; for example 2,2,2-three chloroethyls-; tert-butyl-or the benzyl ester group, and after reaction finishes, remove blocking group again by own perception method.

B) the 0-acyl-4-phenyl cycloalkanol of general formula I V and the amine of general formula V are reacted:

N, m, p, R ³～R ⁷With A definition as above, the leavings group of Y representative reaction as such as the chlorine or bromine atom or such as the sulfonyloxy of sulfonyloxy methyl oxygen base.

In the formula V

R ¹And R ²Definition as above.

Reaction is preferably at suitable solvent, and as ethanol, the trimethyl carbinol is in dimethyl formamide or the tetrahydrofuran (THF), in case of necessity have alkali in the presence of, salt of wormwood for example, sodium ethylate, potassium tert.-butoxide or sodium hydride carry out under condition of phase transition in case of necessity, and temperature of reaction is 0-100 ℃.

C) for preparing the compound of general formula I, R in the formula ¹Definition as above, R ²Representative contains the straight or branched alkyl of 1～6 carbon atom, and it can be by hydroxyl, alkoxyl group, alkyl-carbonyl oxygen, alkyl-carbonyl-amino, carboxyl, alkoxy carbonyl, aminocarboxyl or cyano group replace, hydroxyl wherein, alkoxyl group, alkyl-carbonyl oxygen or alkyl-carbonyl-amino are not connected on 1 the carbon atom:

The 0-acyl-4-phenyl cycloalkanol of general formula VI and the compound of general formula VII are reacted, N in the formula (VI), m, p, R ³～R ⁷With the definition of A as above, R ¹Have above-mentioned implication,

R ^2′-Z ¹ (V111)

In the formula (VII)

R ^{2 '}Representative contains the straight or branched alkyl of 1～6 carbon atom, and it can be by hydroxyl, alkoxyl group, alkyl-carbonyl oxygen, alkyl-carbonyl-amino, carboxyl, alkoxy carbonyl, aminocarboxyl or cyano group replace, hydroxyl wherein, alkoxyl group, alkyl-carbonyl oxygen or alkyl-carbonyl-amino are not connected on 1 the carbon atom, and Z ¹The leaving group of representative reaction because of, as halogen atom, or such as the sulfonyloxy of sulfonyloxy methyl oxygen base group such as the chlorine or bromine atom.

Reaction is preferably at solvent or solvent mixture, ethanol for example, the trimethyl carbinol, tetrahydrofuran (THF), in methyl-sulphoxide or the dimethyl formamide, in case of necessity have acid binding agent in the presence of, yellow soda ash for example, salt of wormwood, sodium hydroxide, sodium hydride, sodium methylate, potassium tert.-butoxide, triethylamine or pyridine, wherein last two kinds of whiles also can be used as solvent, carry out under condition of phase transition in case of necessity, temperature of reaction is 0～100 ℃, preferred 20～50 ℃.

In above-mentioned reaction, the reactive group of existence is hydroxyl for example, and amino, alkylamino, imino-or carboxyl can be removed after reaction finishes by common blocking group protection when reaction again.

The example of blocking group comprises: for hydroxyl, blocking group is a trimethyl silyl, ethanoyl, benzoyl; methyl, ethyl, the tertiary butyl; 2-methoxy ethoxy methyl, benzyl or THP trtrahydropyranyl are for amino; alkylamino or imino-, blocking group are ethanoyl, benzoyl; ethoxy carbonyl or benzyl, for carboxyl, blocking group is 2; 2,2-three chloro-ethyl esters, tertiary butyl ester or benzyl ester group.

Removing thereafter of employed blocking group; preferably in water solvent; as at water; isopropanol; in tetrahydrofuran (THF)/water Huo diox/water, example hydrochloric acid or sulfuric acid in the presence of acid, or in the presence of alkali metal base as sodium hydroxide or potassium hydroxide; under 0-100 ℃ temperature, preferably under the boiling point of reaction mixture, implement by hydrolysis.But benzyl is preferably removed by hydrogenolysis, it be in the presence of catalyzer as palladium/carbon, in solvent as methyl alcohol, ethanol, ethyl acetate or Glacial acetic acid add sour example hydrochloric acid in case of necessity, under 0～50 ℃ temperature, preferably at room temperature hydrogen pressure is 1～7 crust, carries out under preferred 3～5 crust.

The method that the compound of the general formula I of preparation is as stated above known by oneself for example crystallization or chromatogram is purified and is separated.

In addition, the compound of the general formula I that obtains can be transformed into its acid salt if desired, especially be transformed into and be used for medicine and its physiologically acceptable salt inorganic or that organic acid forms.The example of acid comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, fumaric acid, succsinic acid, lactic acid, citric acid, tartrate or toxilic acid.

In formula I compound of the present invention, according to the position or the substituent R of naphthenic hydrocarbon substitution in ring base ¹～R ⁷Form, steric isomer can take place, as diastereomer, the form of geometrical isomer or optically active isomer.The present invention had both comprised that pure steric isomer also comprised its mixture.

Initial compounds:

The initial compounds of general formula I I can prepare as follows:

1, the 4-benzyl ring alkane ketone of reduction general formula VIII

In the formula:

N, m, p and R ¹～R ⁶As above definition.

Select appropriate reductant, for example sodium borohydride or three-second month in a season-butyl lithium borohydride (L-Selectride) but conditioned reaction, to make it mainly to form the e of general formula I I compound, e-isomer or e, a-isomer.

The ketone of general formula VIII can prepare by currently known methods, for example by with the organometallic compound reaction of the monoethylene glycol ketal of general formula I X with general formula X, and then usefulness water-splitting, with the two key hydrogenations and the hydrolysis ketone acetal group of gained.

In the formula

N and R ¹～R ⁵Definition as above, Me represent lithium atom or-the MgHal base, wherein Hal represents halogen atom, preferably the chlorine atom.

In addition, can change method, after above-mentioned reactions steps is finished, for example incite somebody to action wherein R by alkylation keto-enol thing-ion ⁶The ketone that is the general formula (VIII) of hydrogen atom is transformed into R ⁶Be the general formula VIII ketone that contains 1～4 carbon atom alkyl.

Other method of preparation general formula VIII compound is that the dicarboxylic ester with general formula X I carries out the Michael Diekmann cyclisation, presses currently known methods saponification and decarboxylationization then

In the formula

N, m, p and R ¹～R ⁶Define as above R ⁸And R ⁹Can be identical or different, represent alkyl, aralkyl or aryl.

2, the initial compounds of general formula I V can pass through with corresponding aldehyde and hydrogen halide; for example hydrochloric acid or Hydrogen bromide; the halogen 0-acyl-4-phenyl cycloalkanol of general formula X II that methylates in the presence of Fred-Ke fork-like farm tool used in ancient China Ford catalyzer such as zinc chloride; replacing halogen atom by suitable in addition reaction leavings group in case of necessity prepares

In the formula

M, p, R ⁵～R ⁷Define as above with A.

3, the initial compounds of general formula VI is that 0-acyl-4-phenyl-cycloalkanol by general formula X III prepares by removing its blocking group,

In the formula

N, m, p, R ¹, R ³～R ⁷Define as above Z with A ²Represent suitable blocking group.The example of blocking group comprise tert-butoxycarbonyl-, 1-(3,5-two-tert-butyl-phenyl)-1-methyl ethoxy carbonyl-or 2-(4-pyridyl) ethoxy carbonyl-group.The compound of general formula X III can be by being similar to brown method synthetic in the method 1.

The initial compounds of general formula III and V is known or by known method preparation in the document in the prior art.

The compound of general formula I has useful biological nature.They are the biosynthetic inhibitor of cholesterol, and especially enzyme 2, the inhibitor of 3-epoxy squalene-lanosterol-cyclase.According to its biological nature, they are particularly suitable for treatment and prevent especially hypercholesterolemia of hyperlipidemia, high fat egg blood and high tri-glyceride blood and the atherosclerotic blood vessel variation that causes thus and its secondary disease be coronary heart disease for example, cerebrum ischemia, intermittent claudication and gangrene etc.

In order to treat these diseases, the compound of general formula I can be applied to separately in the monotherapy or with other the reduction cholesteric material or reduce the lipid matter keying action, wherein preferably with compound with oral administration, in case of necessity, with rectal administration, the material that is used in combination comprises:

The gallic acid of-binding resin, for example QUESTRAN (chlestramine), the courage that disappears protect, (cholestipol) etc.,

-suppress the compound of cholesterol resorption, for example Sitosterol and Xin Meisu,

-disturb the biosynthetic compound of cholesterol, for example HMG-CoA reductase inhibitor such as Luo Futanding (lovastatin) Xi Waku (simvastatin) and Pravastatin (ptavastatin) etc.,

-squalene-cox-2 inhibitors for example NB598 and similar compounds and

-squalene-synthetase inhibitors for example isoprenoid-(phosphinyl methyl) phosphonic acid ester and squalene it stop (squalestatin).

Other binding substance that can select to use be cellulose ester class (fibrates) as clofibrate, Bezalip Tablets, gemfibrozil etc., nicotinic acid, its derivative and similar substance such as acipimox and probucol.

The compound of general formula I is suitable for treating and too high hyperplasia diseases associated.Because being a kind of basic cell, cholesterol forms, so for hyperplasia is cell fission, must exist with enough amounts.As mentioned above, with the HMG-CoA-reductase inhibitor that stops (statin) type Luo Futanding with it suppress smooth muscle cell case description come inhibition of cell proliferation by suppressing the cholesterol biosynthesizing.

As the example with too much hyperplasia diseases associated at first is tumor disease.Show by the HMG-CoA-reductase inhibitor in cell cultures and experiment in vivo and to reduce serum ornitrol or to disturb the cholesterol biosynthesizing to reduce growth of tumor (Lancet 339,1154-1156[1992]).Thereby compound of Formula I of the present invention might be applicable to the treatment tumor disease based on the biosynthetic effect of its inhibition cholesterol.Find that they can be used alone or promote known treatment mechanism.

Other example is high outgrowth tetter, as psoriasis, and rodent cancer, squamous cell carcinoma, keratosis and keratinization disorder.Term used herein " psoriasis " is meant the high outgrowth tetter that changes the skin regulation mechanism.Especially produce pathology, these pathologies formation epidermal hyperplasias, the expression of the inflammatory reaction of skin and adjusting molecule is as the first of the lymphokines and the struvite factor and secondary variation.The morphologic feature of psoriatic skin is that the increase of epidermic cell is upgraded, the epidermis of thickening, and the abnormal keratinization of inflammation skin penetrates corium and polymorphonuclear leukocyte penetrates epidermis, causes the increase of basal cell.What exist in addition is hyperkeratosis and Parakeratotic cell.Term " keratosis ", " rodent cancer ", " squamous cell carcinoma " and " keratinization disorder " is meant high outgrowth dermatosis, the regulation mechanism that wherein is used for hyperplasia and differentiation skin cells has been subjected to interference.

The compound of general formula I is effectively as the high outgrowth antagonist of skin, promptly as suppressing the high outgrowth medicine of people's keratinocyte.Therefore, they are suitable for treating outgrowth dermatosis such as psoriasis, rodent cancer, keratinization disorder and keratosis.In order to treat these diseases, can therefore, they can be used with the monotherapy form or be used in combination with the compound of general formula I with oral or local mode medication with known active substance.

Other example is by surgical operation, as PTCA (through the saturating chamber of skin coronary angioplasty) or the caused high hyperplasia vascular disease based on smooth muscle cell proliferation of bypass operation, as angiostenosis and vascular occlusion.As mentioned above, this class hyperplasia can suppress as Luo Futanding by the HMG-CoA-reductase inhibitor that it stops type (Statintyp) as known.Suppress the biosynthetic effect of cholesterol according to it, the compound of general formula I also is suitable for treatment and prevents these diseases.Therefore, they can be used separately or be used in combination, preferably use with oral form with the heparin of known active substance such as intravenously administrable.

Other possible application of formula I compound of the present invention is treatment and prevention gallbladdergallstonecholetithiasis.The formation of gallbladdergallstonecholetithiasis be since in the bile ratio that is not suitable for of cholesterol-bile acide cause, therefore, wherein surpass cholesteric solubleness, cholesterol precipitates with the form of calculus.Its effect (when especially combining with ursodesoxycholic acid) of being parked in dissolving gallbladdergallstonecholetithiasis aspect of HMG-CoA-reductase inhibitor Lip river husband is described in Gastroenterology 102, No.4, Pt.2, A319[1992] in.According to its mode of action, the compound of general formula I also is important in the gallbladdergallstonecholetithiasis disease being used for the treatment of and preventing.Therefore, they can be used separately or be used in combination, for example combine treatment, preferably oral administration with ursodesoxycholic acid or shock wave lithotripsy with known therapy.

The compound of general formula I also is suitable for treatment owing to pathomycete such as Candida albicans, aspergillus niger, sycosis trichophyton, Penicillium, the infection that Cladosporium etc. caused.As mentioned above, the biosynthetic final product of cholesterol is not a cholesterol in the fungal organism, but the ergosterol that plays a major role for the integrity and the function of fungal cell membrane.Therefore suppress the ergosterol biosynthesizing and can cause destroying growth, also may the kill fungi organism.

In order to treat mycosis, can be with the compound of general formula I with oral or topical.They can use separately or combine use with known antifungal property material, especially with the preparation that disturbs biosynthetic other step of sterol, for example KETOKONAZOL and fluconazole are used in combination as the lanosterol-alcohol-14 α-demethylase inhibitor of the special flat naphthalene sweet smell (terbinafin) that suppresses squalene-cyclooxygenase and Bifonazole (naftifin) or pyrroles's type.

Other range of application of compound of Formula I is to be used for Poultry farming.By it stops reducing existing (the FASEB Journal 4 of description of technology of egg cholesterol content to laying hen administration HMG-CoA-reductase inhibitor Lip river husband, A533, Abstracts 1543[1990]) technology of producing low cholesterol egg is interesting, this is because the egg by edible low cholesterol amount can reduce cholesteric load in the human body under the prerequisite that does not change food habits.To the biosynthetic restraining effect of cholesterol, The compounds of this invention also can be used for Poultry farming and preferably this material is used as fodder additives to produce low cholesterol egg according to it.

Measure the biological activity of compound of Formula I by following method:

I: mensuration is attached to and can uses in the sedimentary steroid of digitonin ¹⁴The inhibiting rate of C-acetic ester.

Method:

After people's hepatoma cells (HEP-G2) cultivated 3 days, again no cholesteric medium moderate stimulation 16 hours, the material (oneself is dissolved in the methyl-sulphoxide, and final concn is 0.1%) that adding will be tested between this stimulation period.Adding 200 μ Mol/l 2- ¹⁴Behind the C-acetic ester, incubation 2 hours again in 37 ℃ insulation can.

After cytolysis and sterol ester saponification, the extraction back adds the sterol of digitonin and precipitation separation.Measure by institute's bonded in the sedimentary sterol of digitonin by scintillation counting ¹⁴The C-acetic ester.

Detecting test concentrations is 10 ^-7Mol/l and 10 ^-8Inhibition effect during mol/l.Experiment shows that the compd A-Q of general formula I has good inhibition effect under this test concentrations, is 10 in concentration for example ^-8Inhibition effect during mol is at least 50%.

A=cis-0-(4-chlorobenzene formacyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

B=cis-0-(4-phenyl-3-crotonoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

C=is trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

D=cis-0-(5-methyl caproyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

E=is trans-0-(2-phenyl propionyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

F=is trans-0-(4-fluorophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

G=is trans-0-(3,4-dichlorophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

H=cis-0-(4-fluorine cinnamoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

I=is trans-0-(right-the toluene ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

J=is trans-0-(the 4-[trifluoromethyl]-phenyl acetyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

K=is trans-0-(2-naphthyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

L=is trans-0-(4-oil of mirbane ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

M=is trans-0-(4-bromophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

N=is trans-0-(2,4 dichloro benzene base ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

O=is trans-0-([4-amino-3-chloro-phenyl-] ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

P=is trans-0-(4-p-methoxy-phenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

Q=is trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-methylamino aminomethyl phenyl)-hexalin.

Listed the above-claimed cpd inhibition in the following table ¹⁴C-acetic ester bonded percentage ratio:

mol/l 10 ^-7 10 ^-8

A -85 -51

B -87 -58

C -83 -66

D -88 -53

E -89 -53

F -86 -66

G -89 -74

H -86 -51

I -90 -72

J -89 -87

K -86 -54

L -83 -67

M -84 -64

N -85 -67

O -79 -51

P -73 -52

Q -79 -50

As mentioned above, oneself has described enzyme-2 in the literature, indivedual inhibitor of 3-epoxy shark alkene-lanosterol-cyclisation alcohol, but their structure is very different with the compound of general formula I of the present invention.Relevant configuration aspects, the compound near compound of Formula I of the present invention is described in EP 0468457.Therefore, for ease of relatively, be 10 by said determination method mensuration test concentrations ^-5Mol and 10 ^-6The embodiment 1 of the document during mol/l.The gained inhibiting value is 41% or 13%.This shows that these compounds in the document obviously are not so good as the compound of general formula I of the present invention.

II. measure behind the oral administration in the intravital activity of rat

To enzyme 2, the inhibition of 3-epoxy squalene-lanosterol-cyclase causes 2 in liver and the blood plasma, the increasing of 3-epoxy squalene amount.Therefore, can with produced 2, the amount of 3-epoxy squalene is as whole animal usefulness observed value.Measure by following method:

Male Wistar rat (body weight 160-190g) is suspended in the material in 1.5% the methylcellulose gum by the oesophagus administration.After the administration 5 hours, descend later the eye socket mode to take blood by venous plexus.Press Bligh and Dyer method (Canad.J.Biochem.Physiol 37,912[1959]) and handle blood plasma.Go up purifying at a preparation post (Vor-saule), carry out HPLC then and analyze.Use the peak of proofreading and correct material evaluation and quantitative gained.With the repeatability that is marked with detected result in one.

With 0.1 and the concentration of 1.0mg/kg test.Following table listed that above-mentioned substance B, C, J, M, N and P obtain in rat plasma 2, the data of 3-epoxy squalene amount.In the control animal group, under experiment condition, there is not 2 of measurability, 3-epoxy squalene amount.

In blood plasma (rat) 2, the amount of 3-epoxy squalene

2,3-epoxy squalene [μ g/ml]

Material 0.1mg/kg 1.0mg/kg

B 0.4 1.1

C 0.6 4.2

J 0.5 3.6

M 0.6 3.5

N 0.1 2.2

P 0.3 0.9

So far do not address enzyme 2 from document, the inhibitor of 3-epoxy squalene-lanosterol-cyclase is to suppress the cholesteric biosynthesizing in the full animal.

The compound of therapeutic dose is a totally nontoxic.For example at the oral 100mg/kg of rat, reach 5 days 1 time every day after, take Compound C and be free from side effects, mouse is taken compound J and M, also is free from side effects.

In order to be used for pharmacy, the method itself that the compound of general formula I is known by oneself can be processed into oral and conventional medicine preparation local application.

The preparation of oral administration comprises for example tablet, drageeing and capsule, and the preparation that is used for rectal administration is suppository preferably.

Topical formulations comprises jelly, ointment, lotion, and ointment, pulvis, aerosol and other use the habitual formulation of medicine on skin.The consumption of the local active substance that uses is every restraint agent 1～50mg, preferably every restraint agent 5～20mg.Except using on skin, topical formulations of the present invention also can be used in the mucosal treatment of topical therapeutic.For example topical formulations can be used for the oral cavity, on the mucous membrane of following colon etc.

Per daily dose oral or rectal application is 1～1200mg for the people of 60kg body weight, and preferred per daily dose is 5～100mg.Per daily dose preferably is divided into 1～3 time and uses.

When using, compound can be mixed with containing about 1～1000mg every day the active substance of preferred 10～300mg and administration in the part.Per daily dose preferably divides to be taken for 1～3 time.

In order in Poultry farming, to use, the active substance of general formula I can be added in the feed of animal according to a conventional method to produce low cholesteric egg.The concentration of the active substance in the full feed is generally 0.01～1%, is preferably 0.05～0.5%.

Active substance can add in the feed.Therefore, the present invention's feed of being used for laying hen for example also comprises corn, soyflour, digested tankage, edible-fat and soya-bean oil outward except active substance and vitamin-mineral mixt commonly used.The compound of above-mentioned general formula I is mixed in the feed as active substance, and its concentration is 0.01～1%, is preferably 0.05～5%.

The following examples explain the present invention:

In the following embodiments, the DC precoated plate that uses E.Merck.Damstadt company to produce carries out thin-layer chromatography to be measured, and plate is appointed as:

A) silica gel 60F ₂₅₄

B) aluminum oxide F ₂₅₄(E type)

The preparation of initial compounds:

Embodiment 1

4-(4-dimethylaminomethyl phenyl)-pimelinketone

A) 4-(4-dimethylaminomethyl phenyl)-4-hydroxy-cyclohexanone-ethylene ketal

To 36.4g (0.17mol) 4-bromo-N, the N-dimethyl benzyl amine is cooled in-70 ℃ the solution the 250ml anhydrous tetrahydro furan, drip the 1.6mol solution of 112ml (0.179mol) n-Butyl Lithium in hexane in nitrogen atmosphere with under stirring, temperature can not be above-65 ℃.Orange solution in-70 ℃ of following restir 15 minutes, was added 27.6g (0.172mol) 1 then in 10 minutes, the 4-cyclohexanedione-solution of monoethylene glycol ketal in the 110ml tetrahydrofuran (THF), simultaneous temperature must be no more than-65 ℃.

Earlier reaction mixture was stirred 30 minutes down at-70 ℃, be stirred under the exterior cooling+20 ℃ of temperature not having then, pour in the 600ml frozen water and use the 200ml ethyl acetate extraction.Separate organic phase with ethyl acetate aqueous phase extracted repeatedly.The organic extract that merges is with dried over sodium sulfate and carry out vacuum concentration, with diisopropyl ether recrystallization residue.Obtain 41.9g (85% theoretical value) 4-(4-dimethylaminomethyl phenyl)-4-hydroxy-cyclohexanone-second diketone ketal, fusing point is 84～86 ℃.

B) 1-(4-dimethylaminomethyl) phenyl-4-ethylenedioxy-1-tetrahydrobenzene

With 22.4g (0.077mol) 4-(4-dimethylaminomethyl phenyl)-4-hydroxy-cyclohexanone-ethylene ketal, 15.0g (0.079mol) right-toluenesulphonic acids monohydrate, the mixture of 39ml ethylene glycol and 240ml toluene is reflux 3.5 hours under agitation, removes the reaction water of generation continuously.Pour in the 200ml water through the refrigerative reaction mixture, be adjusted to PH12-13 with 2N NaOH.Separate organic phase, with toluene aqueous phase extracted repeatedly.The organic extract that merges is with dried over sodium sulfate and carry out vacuum concentration.Obtain the title compound of 21g (about 100%) yellow oily.

C) 1-(4-dimethylaminomethyl) phenyl-4-ethylenedioxy-1-hexanaphthene

Add 5g palladium/barium sulfate catalyzer in rough 1-(4-dimethylaminomethyl) phenyl-solution of 4-ethylenedioxy-1-hexanaphthene in 200ml ethyl acetate and 100ml methyl alcohol, hydrogenation is 1.5 hours under the hydrogen pressure of 5 crust.Concentrate in a vacuum after isolating catalyzer.Obtain the yellowish brown buttery title compound of 20g (100%).

D) 4-(4-dimethylaminomethyl) phenyl-pimelinketone

The mixture of the 1-that 20g (0.077mol) is rough (4-dimethylaminomethyl) phenyl-4-ethylenedioxy-1-hexanaphthene and 110ml 2N hydrochloric acid at room temperature stirred 3.5 hours.The water that is produced repeatedly extracts with ethyl acetate; Remove organic extract.Under the cooling, the sodium hydroxide solution with 50% is regulated water to PH13-14, again with ethyl acetate extraction several times.The organic extract that merges is with saturated sodium chloride solution washing, with dried over sodium sulfate and vacuum concentration.Obtain 14g (79% theoretical value) 4-(4-dimethylaminomethyl) phenyl-pimelinketone, fusing point is 64-67 ℃ a light yellow product.With sherwood oil 60/90 recrystallization analytical sample.

Fusing point: 65～67 ℃

C ₁₅H ₂₁NO(231，34)

Calculated value: C 77.88 H 9.15 N 6.05

Measured value: 77.69 9.32 5.98

Example II

Trans-4-(4-dimethylaminomethyl phenyl)-hexalin

To being cooled to 11.1g (0.048mol) 4-(4-dimethylaminomethyl phenyl)-pimelinketone of-10 ℃ in the solution of 100ml anhydrous methanol, under agitation, add 1.82g (0.048mol) sodium borohydride in batches.Reaction mixture was at room temperature reacted 1.5 hours, carry out vacuum concentration subsequently.In residue, add entry, use the concentrated hydrochloric acid acidifying, at room temperature stirred 30 minutes, be adjusted to alkalescence with 50% sodium hydroxide solution, and with chloroform extraction several times.The extract that merges is with dried over sodium sulfate and carry out vacuum concentration.Will by instead/residue that cis 4-(4-dimethylaminomethyl phenyl)-hexalin mixture (cis composition＜10%) is formed carries out column chromatography purify (neutral alumina, activity level III, ICN; Sherwood oil/methyl ethyl ketone=5: 1).

The acquisition fusing point is 63～65 ℃ a white crystals.

Yield: 8.8g (79% theoretical value).

C ₁₅H ₂₃NO(233.36)

Calculated value: C 77.21 H 9.93 N 6.00

Measured value: 77.34 10.02 5.89

EXAMPLE III

Cis-4-(4-dimethylaminomethyl phenyl)-hexalin

With the anhydrous tetrahydrofuran solution of 1mol three-sec-butyl lithium borohydride of 50ml (0.05mol) under nitrogen atmosphere with the dilution of 100ml anhydrous tetrahydro furan, then under-65～-70 ℃ of stirrings and in 10 minutes, add 5.8g (0.025mol) 4-(4-dimethylaminomethyl the phenyl)-solution of pimelinketone in the 50ml anhydrous tetrahydro furan.Make reaction mixture-70 ℃ of down reactions 3 hours subsequently, then at 1 hour internal heating to room temperature.Use 20ml 75% ethanolic soln hydrolysis afterwards, organo-borane alkaline hydrogen peroxide (10ml 6MNaOH/15ml 30%H ₂O ₂) oxidation.Separate organic phase, water is saturated and use the 50ml ethyl acetate extraction with salt of wormwood.The organic extract that merges is with dried over sodium sulfate and carry out vacuum concentration.To carry out column chromatography purification (neutral alumina, activity level III, ICN by the grease-like residue of cis/trans-4-(4-dimethylaminomethyl phenyl)-hexalin mixture (trans composition＜5%); Sherwood oil/methyl ethyl ketone=5: 1).

Product is a colorless oil.

Yield: 4.1g (71% theoretical value).

¹H-NMR-spectrum (200MHZ, CDCl ₃); The signal of representing with ppm:

1,5-2,0(2m，8H)；2,25(s，6H)；2,4-2,65(m，1H)；3,4(s，2H)；

4,1-4,18(m，1H)；7,15-7,3(m，4H).

EXAMPLE IV

Trans-0-acyl group-4-(4-chloromethyl phenyl)-hexalin

A) 4-phenylcyclohexanol

To being cooled to-10 ℃ 31.4g (0.18mol) 4-benzyl ring hexanone in the solution of 500ml anhydrous methanol, under agitation add 6.8g (0.18mol) sodium borohydride in batches.Reaction mixture was reacted 0.5 hour down at-10 ℃, at room temperature reacted 3 hours, carry out vacuum concentration then.In residue, add entry and use the 2N hcl acidifying.The suspension that produces was stirred 1 hour suction strainer crystallized product, the dry diisopropyl ether recrystallization of also using.Obtain 21g (66% theoretical value) 4-phenylcyclohexanol, fusing point is 112～114 ℃.

B) 0-acyl-4-phenyl hexalin

To 20.3g (0.115mol) 4-phenylcyclohexanol, in the mixture of 14.2ml (0.15mol) acetic anhydride and 29ml triethylamine,, stir adding 2.3g (0.02mol) 4-dimethylaminopyridine down, thereby under thermopositive reaction, form clear thorough liquid in room temperature.Heated 3 hours down at 80 ℃, then reaction mixture is poured in the frozen water, the sedimentary crystallized product of suction strainer is dissolved in the ether, with the sodium hydrogen carbonate solution washing, and dry and vacuum concentration.Obtain 23g (92% theoretical value) 0-acyl-4-phenyl hexalin.At first obtain the oily product, but crystallization when placing.Fusing point: 43～45 ℃.

C) trans-0-acyl group-4-(4-chloromethyl phenyl)-hexalin

Merge with 26.0g (0.86mol) Paraformaldehyde 96 and 26.0g (0.19mol) zinc chloride to the solution of 24.3g (0.11mol) 0-acyl-4-phenyl hexalin in the 1300ml methylene dichloride.Under agitation; In this suspension, fed hydrogenchloride 2.5 hours, and simultaneous temperature rises to about 30 ℃, and form uniform solution basically.Mixture was at room temperature reacted 15 hours again, and reaction mixture under agitation is hydrolyzed in about 1.5 premium on currency.Separate organic phase, water repeatedly extracts with methylene dichloride again, and two organic phases are merged.Washing is to neutral, and drying is evaporation in a vacuum also.Make residual yellow oil crystallization with the diisopropyl ether development, with diisopropyl ether recrystallization solid product.The acquisition fusing point is 87～89 ℃ a white crystal.

Yield: 12.7g (43% theoretical value)

C ₁₅H ₁₉ClO ₂(266.77)

Calculated value: C 67.53 H 7.18 C 113.29

Measured value: 67.68 7.29 13.11

EXAMPLE V

Suitable/trans-0-(4-chloro-phenyl-ethanoyl)-4-(uncle 4-N-[-butoxy carbonyl] the methylamino methyl) phenyl-hexalin

A) 4-(4-methylamino methyl) phenyl-4-hydroxy-cyclohexanone-ethylene ketal

In nitrogen atmosphere, under-30～-25 ℃, in the solution of 460ml anhydrous tetrahydro furan, add the hexane solution of 300ml (0.48mol) 1.6mol n-Butyl Lithium earlier to 94g (0.47mol) 4-bromo-(N-methyl)-benzyl amine, add 52.5g (0.48mol) trimethylchlorosilane then.Reaction mixture was stirred 15 minutes, then-75 ℃ of coolings down under this temperature.Then add the hexane liquation of the n-Butyl Lithium of 320ml (0.51mol) 1.6mol more in addition, make temperature be no more than-70 ℃.Mixture was stirred 20 minutes down in-75 ℃ again, added 76g (0.47mol) 1 then in 20 minutes, the 4-cyclohexanedione-solution of monoethylene glycol ketal in the 200ml tetrahydrofuran (THF) makes temperature be no more than-65 ℃ simultaneously.Reaction mixture was stirred 30 minutes down at-70 ℃ earlier, do not having to be stirred to temperature under the exterior cooling situation and be raised to again+20 ℃.Then in ice-cooled aqueous ammonium chloride solution, decompose and several times with dichloromethane extraction.The organic extract dried over sodium sulfate that merges is isolated solvent, residue diisopropyl ether recrystallization.Obtain 77g (59% theoretical value) 4-(4-methylamino methyl) phenyl-4-hydroxy-cyclohexanone-ethylene ketal, fusing point is 95～97 ℃.

B) 1-(4-methylamino methyl) phenyl-4-ethylenedioxy-1-tetrahydrobenzene

With 68g (0.24mol) 4-(4-methylamino methyl)-phenyl-4-hydroxy-cyclohexanone-ethylene ketal, 51g (0.27mol) tosic acid monohydrate, the mixture of 150ml ethylene glycol and 900ml toluene is reflux 2.5 hours under agitation, removes the reaction water of generation continuously.Be adjusted to alkalescence (pH12～13) through the refrigerative reaction mixture with the 1N sodium hydroxide solution, separate organic layer, water is repeatedly used ethyl acetate extraction.The organic phase that merges is with dried over sodium sulfate and carry out vacuum concentration.Obtain 1-(the 4-methylamino methyl) phenyl-4-1-ethylenedioxy-1-tetrahydrobenzene of 63g (about 100 theoretical values) yellow oily.

C) 1-(uncle 4-N-[-butoxy carbonyl]-methylamino methyl) phenyl-4-ethylenedioxy-1-tetrahydrobenzene

In the rough 1-of 63g (0.24mol) (the 4-methylamino methyl) phenyl-4-ethylenedioxy-solution of 1-tetrahydrobenzene in the 350ml anhydrous tetrahydro furan, add the solution of 58g (0.26mol) two-tert-butyl two carbonic ethers, under cooling, make temperature remain on 15～20 ℃ at the 100ml anhydrous tetrahydro furan.Remove the CO of generation ₂After, at room temperature mixture to be placed 10 hours again, solvent is fallen in vacuum distilling, and residue mixes with water and with extracted with diethyl ether several times.After with dried over sodium sulfate and evaporation, the 1-of acquisition 84g (about 100% theoretical value) yellow oily (the 4-N-[tert-butoxycarbonyl]-the methylamino methyl) phenyl-4-ethylenedioxy-1-tetrahydrobenzene.

D) 4-(uncle 4-N-[-butoxy carbonyl]-methylamino methyl) benzyl ring hexanone

In the rough 1-of 84g (0.24mol) (uncle 4-N-[-butoxy carbonyl]-methylamino methyl) phenyl-solution of 4-ethylenedioxy-1-tetrahydrobenzene in methanol/ethyl acetate (250+250ml), add 10g palladium/barium sulfate catalyzer, and in room temperature, 3 Ba Qing depress hydrogenation.Separating liquiding catalyst distills solvent in a vacuum, and the oily residue is dissolved in the acetone (1400+140ml), after adding 8.5g (0.034mol) toluenesulphonic acids pyridine, and reflux 15 hours.Distill solvent subsequently in a vacuum, add water in the residue, and with dichloromethane extraction several times.After organic phase is used dried over sodium sulfate and evaporation, the faint yellow oily 4-of acquisition 61g (77% theoretical value) (uncle 4-N-[-butoxy carbonyl]-the methylamino methyl) phenyl-pimelinketone, long-time placement is just solidified.Fusing point: 55～57 ℃.

E) 4-(uncle 4-N-[-butoxy carbonyl]-methylamino methyl) phenyl-hexalin (suitable/trans mixture)

To at-10 ℃ of following refrigerative 11g (0.035mol) 4-(4-N-[tert-butoxycarbonyl]-methylamino methyl) solution of phenyl-pimelinketone in the 70ml anhydrous methanol, under agitation add 1.31g (0.035mol) sodium borohydride in batches.Reaction mixture was reacted 0.5 hour down in-10 ℃, and reaction is 2 hours under room temperature, then carries out vacuum concentration.Adding entry in the residue also at room temperature stirred 1 hour.The solid product that suction strainer forms thus is dissolved in it in ethyl acetate, and this solution is dry on sodium sulfate.After concentrating in a vacuum, obtain suitable-and the mixture of trans 4-(uncle 4-N-[-butoxy carbonyl]-methylamino methyl) phenyl-hexalin of 8.6g (77% theoretical value) colorless oil.Be separated into pure isomer (neutral alumina, activity level III, ICN by column chromatography; Petrol ether/ethyl acetate=3: 1).

R _fValue (aluminum oxide, petrol ether/ethyl acetate=3: 1):

(0.21 trans) and 0.31 (cis).

F) 0-(4-chloro-phenyl-ethanoyl)-4-(uncle 4-N-[-butoxy carbonyl]-methylamino methyl) phenyl-hexalin (suitable/trans mixture)

With 0.54g (0.0032mol) 4-chlorophenylacetic acid, 0.52g (0.0032mol) N, the mixture of N '-carbonyl dimidazoles and 20ml dimethylbenzene under agitation heated 1 hour down at 60 ℃.The solution that then adds the 10ml dimethylbenzene of 0.85g (0.0027mol) 4-(uncle 4-N-[-butoxy carbonyl]-methylamino methyl)-phenyl-hexalin (suitable/trans mixture), reaction mixture are again 160 ℃ of heating 8 hours down.Concentrate in a vacuum after the cooling, add water in the residue, and use ethyl acetate extraction.Organic phase is also evaporated in a vacuum with dried over sodium sulfate.Obtain 1.3g (about 100% theoretical value) reddish-brown oily 0-(4-chloro-phenyl-ethanoyl)-4-(uncle 4-N-[-butoxy carbonyl]-methylamino methyl) phenyl-hexalin (suitable/trans mixture).

R _fValue (aluminum oxide; Petrol ether/ethyl acetate=3: 1):

(0.78 trans) and 0.85 (cis).

Synthesize following material by similar method:

(1) trans-0-(4-chloro-phenyl-ethanoyl)-4-(uncle 4-N-[-butoxy carbonyl]-methylamino methyl) phenyl-hexalin

By trans-4-(uncle 4-N-[-butoxy carbonyl]-methylamino methyl) phenyl-hexalin and 4-chlorophenylacetic acid/N, N '-carbonyl dimidazoles makes.

White crystal.

Fusing point: 94～96 ℃.

The preparation of final product

Embodiment 1

Trans-0-(4-chlorobenzene acyl group)-4-(4-dimethylaminomethyl phenyl)-hexalin

To 1.0g (0.0043mol) trans-4-(4-dimethylaminomethyl phenyl)-hexalin and the solution of 0.6ml triethylamine in the 50ml methylene dichloride, under agitation drip 0.75g (0.0043mol) 4-chloro-benzoyl chloride, and reflux 3 hours.The cooling back adds 50ml water, regulates mixture to PH12～13 with sodium hydroxide solution, isolates the methylene dichloride phase, and water is repeatedly used dichloromethane extraction.The organic phase dried over sodium sulfate that merges, and carry out vacuum concentration.With solid residue with column chromatography purify (neutral alumina, activity level III, ICN; Petrol ether/ethyl acetate=40: 1).The acquisition fusing point is 94～95 ℃ a white crystal.

Yield: 1.1g (69% theoretical value)

¹H-NMR-composes (200MHz, CDCL ₃); The signal of representing with ppm:

1,55-1,8(m，4H)；1,9-2,1(m，2H)；2,15-2,3(s+m，6+2H)；

2,5-2,7(m，1H)；3,4(s，2H)；4,9-5,1(m，1H)；7,15-7,3(m，4H)；

7,4(d，2H)；8,0(d，2H).

Synthesize following material by similar method:

(1) trans-0-ethanoyl-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and Acetyl Chloride 98Min./triethylamine preparation.

Colourless soup compound.

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

1,45-1,7(m，4H)；1,9-2,05(m，2H)；2,05-2,15(s+m，3+2H)；2,23

(s，6H)；2,4-2,65(m，1H)；3,4(s，2H)；?4,7-4,9(m，1H)；7,1-7,3

(m，4H).

(2) trans-0-butyryl radicals-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and butyryl chloride/triethylamine preparation.

Colorless oil.

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

0,9-1,02(t，3H)；1,45-1,75(m，6H)；1,89-2,05(m，2H)；

2,05-2,18(m，2H)；2,18-2,38(s+t，6+2H)；2,4-2,6(m，1H)；3,4

(s，2H)；4,7-4,9(m，1H)；7,1-7,3(m，4H).

(3) trans-0-encircles propionyl-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and cyclopropyl acyl chlorides/triethylamine preparation.

The colourless wax shape.

¹H-NMR-composes (200MHz, CDCL ₃); The signal of representing with ppm:

0,81-0,87(m，2H)；0,95-1,02(m，2H)；1,45-1,7(m，4H)；1,9-2,0

(m，2H)；2,05-2,15(m，2H)，2,24(s，6H)；2,4-2,63(2m，2H)；3,4

(s，2H)；4,73-4,83(m，1H)；7,12-7,25(m，4H).

(4) trans-0-hexamethylene acyl-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and cyclohexyl acyl chlorides/triethylamine preparation.

White crystal.

Fusing point: 66～68 ℃.

(5) cis-0-(4-chloro-phenyl-ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By cis-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-chlorophenyl acetyl chloride/triethylamine preparation

Colorless oil.

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

1,5-1,75(m，6H)；1,88-2,05(m，2H)；2,25(s，6H)；2,4-2,65

(m，1H)；3,4(s，2H)；3,65(s，2H)；5,05-5,15(m，1H)；7,08

(d，2H)；7,2-7,4(m，6H).

(6) trans-0-(4-phenyl-3-butyryl radicals)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-phenyl-3-butyryl chloride/triethylamine preparation.

White crystal.

Fusing point: 90～91 ℃.

(7) cis-0-(4-phenyl-3-butyryl radicals)-4-(4-dimethylaminomethyl phenyl)-hexalin

By cis-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-phenyl-3-butyryl chloride/triethylamine preparation.

White crystal.

Fusing point: 71～73 ℃.

Embodiment 2

Trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

Mixture to 0.43g (0.0025mol) 4-chlorophenylacetic acid and 30ml dimethylbenzene adds 0.41g (0.0025mol) N, and N '-carbonyl dimidazoles is along with CO ₂Emit, generate white product.Make reaction mixture under agitation 60 ℃ the heating 1 hour, add then 0.5g (0.0021mol) trans-4-(4-dimethylaminomethyl phenyl)-hexalin.With mixture under agitation 160 ℃ the heating 2 hours, cool off under the room temperature, add entry, and be adjusted to PH12～13 with the 2N sodium hydroxide solution.Separating dimethyl benzene, water merge organic phase with ethyl acetate extraction several times, and be dry and concentrated in a vacuum.With solid residue with column chromatography purify (alkali alumina, activity level III, ICN; Petrol ether/ethyl acetate=10: 1).The acquisition fusing point is 75～77 ℃ a white crystal.

Yield: 0.7g (86% theoretical value).

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

1,4-1,7(m，4H)；1,8-2,15(m，4H)；2,25(s，6H)；2,4-2,6

(m，1H)；3,38(s，2H)；3,6(s，2H)；4,7-4,9(m，1H)；7,1-7,35

(m，8H)。

Synthesize following material by similar approach:

(1) trans-0-(5-methyl caproyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 5-methylhexanoic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

35～36 ℃ of fusing points.

(2) cis-0-(5-methyl caproyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By cis-4-(4-dimethylaminomethyl phenyl)-hexalin and 5-methylhexanoic acid/N, N '-carbonyl dimidazoles preparation.

Colorless oil.

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

0,9(d，6H)；1,15-1,32(m，2H)；1,5-1,88(m，9H)；1,95-2,1

(m，2H)；2,25(s，6H)；2,3(d，2H)；2,48-2,69(m，1H)；3,4

(s，2H)；5,08-5,18(m，1H)；7,12-7,3(m，4H).

(3) trans-0-cyclohexyl ethanoyl-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and cyclohexyl acetic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 37～39 ℃

(4) trans-0-(2-butyryl radicals)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and Ba Dousuan/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 69～71 ℃.

(5) trans-0-(2-caproyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 2-caproic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 40～42 ℃.

(6) trans-0-(3-cyclohexyl propionyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 3-cyclohexylpropionic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 46～47 ℃.

(7) trans-0-benzoyl-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and phenylformic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 68～70 ℃.

(8) trans-0-(4-chloro-3-methyl benzoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-chloro-3-tolyl acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 100～102 ℃

(9) trans-0-(2-naphthoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-naphthoic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 110～112 ℃

(10) trans-0-phenyl acetyl-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and phenylacetic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 38～40 ℃

(11) trans-0-(4-fluorophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-fluorophenyl acetate/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 68～70 ℃

(12) cis-0-(4-fluorophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By cis-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-fluorophenyl acetate/N, N '-carbonyl dimidazoles preparation

Colorless oil.

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

1,5-1,75(m，6H)；1,85-2,05(m，2H)；2,3(s，6H)；2,4-2,65

(m，1H)；3,43(s，2H)；3,65(s，2H)；5,05-5,15(m，1H)；7,0-7,15

(m，4H)；7,2-7,38(m，4H).

(13) trans-0-(4-bromophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-bromophenyl acetate/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 72～74 ℃

(14) trans-0-(3,4-dichlorophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 3,4-dichlorophenylacetic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 95～97 ℃

(15) cis-0-(3,4-dichlorophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By cis-4-(4-dimethylaminomethyl phenyl)-hexalin and 3,4-dichlorophenylacetic acid/N, N '-carbonyl dimidazoles preparation.

Colorless oil.

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

1,5-1,75(m，6H)；1,9-2,05(m，2H)；2,28(s，6H)；2,4-2,65

(m，1H)；3,4(s，2H)；3,62(s，2H)；5,8-5,17(m，1H)；7,05-7,3

(m，5H)；7,35-7,49(m，2H).

(16) trans-0-(2,4 dichloro benzene base ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 2,4 dichloro benzene guanidine-acetic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 78～80 ℃

(17) trans-0-(p-methylphenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and p-methylphenyl acetate/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 40～42 ℃

(18) trans-0-(4-[trifluoromethyl]-phenyl acetyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-(trifluoromethyl)-phenylacetic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 73～75 ℃.

(19) trans-0-(4-p-methoxy-phenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-anisole guanidine-acetic acid/N, N '-carbonyl dimidazoles preparation formula.

White crystal.

Fusing point: 47～49 ℃.

(20) trans-0-(4-nitrophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-nitrophenyl acetate/N, N '-carbonyl dimidazoles preparation.

Yellow crystals.

Fusing point: 136～137 ℃.

(21) trans-0-(3-[4-fluorophenyl]-propionyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 3-(4-fluorophenyl)-propionic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 58～59 ℃.

(22) trans-0-(3-[4-fluorophenyl]-propionyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 3-(4-chloro-phenyl-)-propionic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 85～87 ℃.

(23) trans-0-(4-xenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-biphenyl acetic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 88～89 ℃.

(24) trans-0-(4-naphthyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 2-naphthyl acetic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 85～87 ℃.

(25) trans-0-[2-(1,2,3, the 4-tetrahydrochysene) naphthoyl]-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 2-(1,2,3, the 4-tetrahydrochysene) naphthoic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 95～96 ℃.

(26) cis-0-[2-(1,2,3, the 4-tetrahydrochysene) naphthoyl]-4-(4-dimethylaminomethyl phenyl)-hexalin

By cis-4-(4-dimethylaminomethyl phenyl)-hexalin and 2-(1,2,3, the 4-tetrahydrochysene) naphthoic acid/N, N '-carbonyl dimidazoles preparation.

Colorless oil.

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

1,55-1,85(m，6H)；1,9-2,1(m，3H)；2,15-2,32(s+m，6+1H)；

2,4-2,65(m，1H)；2,72-2,95(m，3H)；3,05(d，2H)；3,4(s，2H)；

5,1-5,2(m，1H)；7,05-7,3(2m，8H).

(27) trans-0-(2-phenyl propionyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 2-phenylpropionic acid/N, N '-carbonyl dimidazoles preparation.

The colourless wax shape.

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

1,25-1,7(d+m，3+3H)；1,8-2,15(m，5H)；2,3(s，6H)；2,38-2,6

(m，1H)；3,4(s，2H)；3,7(q，1H)；4,68-4,9(m，1H)；7,15

(d，2H)；7,18-7,38(d+m，2+5H).

(28) cis-0-(2-phenyl propionyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By cis-4-(4-dimethylaminomethyl phenyl)-hexalin and 2-phenylpropionic acid/N, N '-carbonyl dimidazoles preparation formula.

Colorless oil.

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

1,3-1,7(d+m，3+6H)；1,8-2,05(m，2H)；2,25(s，6H)；2,35-2,58

(m，1H)；3,4(s，2H)；3,78(q，1H)；5,0-5,1(m，1H)；7,0(d，2H)；

7,2(d，2H)；7,25-7,4(m，5H).

(29) trans-0-(4-fluorine cinnamoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-fluoro cinnamic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 118-120 ℃

(30) cis-0-(4-fluorine cinnamoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By cis-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-fluoro cinnamic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 66-68 ℃.

(31) trans-0-(4-cinnamoyl chloride base)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-chloro-cinnamic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 131-133 ℃.

(32) cis-0-(4-cinnamoyl chloride base)-4-(4-dimethylaminomethyl phenyl)-hexalin

By cis-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-chloro-cinnamic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 88-89 ℃

(33) trans-0-(4-[trifluoromethyl]-cinnamoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-(trifluoromethyl)-styracin/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 134-136 ℃.

(34) cis-0-(4-[trifluoromethyl]-cinnamoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By cis-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-(trifluoromethyl)-styracin/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 61-63 ℃

(35) trans-0-(5-chloro-2-thenoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 5-chloro-2-Thiophene Carboxylic Acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 95-97 ℃

(36) trans-0-nicotinoyl-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and nicotinic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 86-88 ℃.

(37) trans-0-(2-furoyl base)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and pyromucic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 58-60 ℃.

(38) trans-0-(3,4-Dimethoxyphenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 3,4-dimethoxy benzene guanidine-acetic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 32-34 ℃

(39) trans-0-(4-amino-3-chloro-phenyl-ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-amino-3-chlorophenylacetic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 83-85 ℃

(40) trans-0-(4-amino-3,5-dichlorophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 4-amino-3,5-dichlorophenylacetic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 78-80 ℃.

(41) trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-diethylamino methyl phenyl)-hexalin

By trans-4-(4-diethylamino methyl phenyl)-hexalin and 4-chlorophenylacetic acid/N, N '-carbonyl dimidazoles preparation.

Colorless oil.

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

1,05(t，6H)；1,4-1,72(m，4H)；1,9-2,2(m，4H)；2,4-2,6

(q+m，5H)；3,5(s，2H)；3,6(s，2H)；4,7-4,9(m，1H)；7,12

(d，2H)；7,18-7,35(m，6H).

(42) trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-dipropyl aminomethyl phenyl)-hexalin

By trans-4-(4-dipropyl aminomethyl phenyl)-hexalin and 4-chlorophenylacetic acid/N, N '-carbonyl dimidazoles preparation.

Colorless oil.

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

0,88(t，6H)；1,38-1,7(m，8H)；1,9-2,19(m，4H)；2,35(q，4H)；

2,4-2,6(m，1H)；3,5(s，2H)；3,6(s，2H)；4,7-4,9(m，1H)；7,1

(d，2H)；7,15-7,38(m，6H).

(43) trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-[N-methyl butyl amino]-aminomethyl phenyl)-hexalin

By trans-4-(4-[N-methyl butyl amino]-aminomethyl phenyl)-hexalin and 4-chlorophenylacetic acid/N, N '-carbonyl dimidazoles preparation.

Colorless oil.

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

0,9(t，3H)；1,2-1,7(m，8H)；1,8-2,15(m，4H)；2,18(s，3H)；

2,35(t，2H)；2,4-2,6(m，1H)；3,41(s，2H)；3,6(s，2H)；

4,7-4,9(m，1H)；7,1(d，2H)；7,2-7,35(m，6H).

(44) trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-diallyl aminomethyl phenyl)-hexalin

By trans-4-(4-diallyl aminomethyl phenyl)-hexalin and 4-chlorophenylacetic acid/N, N '-carbonyl dimidazoles preparation.

Colorless oil.

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

1,4-1,75(m，4H)；1,9-2,2(m，4H)；2,4-2,6(m，1H)；3,0-3,18

(dd，4H)；3,5(s，2H)；3,6(s，2H)；4,7-4,9(m，1H)；5,1-5,3

(m，4H)；5,75-6,0(m，2H)；7,12(d，2H)；7,15-7,38(m，6H).

(45) trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-[N-pyrrolidone]-aminomethyl phenyl)-hexalin

By trans-4-(4-[N-pyrrolidone]-aminomethyl phenyl)-hexalin and 4-chlorophenylacetic acid/N, N '-carbonyl dimidazoles preparation formula.

White crystal.

Fusing point: 57-59 ℃.

(46) trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-[N-piperidino-(1-position only)]-aminomethyl phenyl)-hexalin

By trans-4-(4-[N-piperidino-(1-position only)]-aminomethyl phenyl)-hexalin and 4-chlorophenylacetic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 87-89 ℃.

(47) trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-[N-morpholino] aminomethyl phenyl)-hexalin

By trans-4-(4-[N-morpholino] aminomethyl phenyl)-hexalin and 4-chlorophenylacetic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 114-116 ℃.

(48) trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-[N-methyl-N '-piperazinyl] aminomethyl phenyl)-hexalin

By trans-4-(4-[N-methyl-N '-piperazinyl] aminomethyl phenyl)-hexalin and 4-chlorophenylacetic acid/N, N '-carbonyl dimidazoles preparation.

White crystal.

Fusing point: 97-99 ℃.

(49) trans-0-(3, the 4-[methylene-dioxy]-phenyl acetyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

By trans-4-(4-dimethylaminomethyl phenyl)-hexalin and 3,4-(methylene-dioxy)-phenylacetic acid/N, N '-carbonyl dimidazoles preparation.

Colorless oil.

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

1,4-1,7(m，4H)，1,8-2,0(m，2H)，2,0-2,15(m，2H)，2,25

(s，6H)，2,4-2,6(m，1H)，3,38(s，2H)，3,5(s，2H)，4,7-4,9

(m，1H)，5,94(s，2H)，6,7-6,85(m，3H)，7,1-7,3(m，4H).

Embodiment 3

Cis-0-(4-chlorobenzene formacyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

With 0.24g (0.001mol) cis-4-(4-dimethylaminomethyl phenyl)-hexalin, 0.34ml (0.0025mol) triethylamine and 0.12g (0.001mol) dimethyl aminopyridine is dissolved in the 20ml methylene dichloride, add 0.175g (0.001mol) 4-chloro-benzoyl chloride then, and at room temperature stirred 12 hours.In reaction mixture, add entry, be adjusted to PH12-13 with sodium hydroxide solution again.Isolate methylene dichloride, water is repeatedly used dichloromethane extraction, and the organic phase of merging is also carried out vacuum concentration with saturated salt solution washing, drying.Residue is with column chromatography purify (neutral alumina, activity level III, ICN; Petrol ether/ethyl acetate=45: 1)

White crystal.

Fusing point: 96-97 ℃.

Yield: 0.27g (73% theoretical value).

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

1,7-2,0(m，6H)；2,1-2,25(m，2H)；2,28(s，6H)；2,55-2,75

(m，1H)；3,4(s，2H)；5,33-5,4(m，1H)；7,15-7,3(m，4H)；7,45

(d，2H)；8,2(d，2H).

Embodiment 4

Trans-0-ethanoyl-4-(4-diethylamino methyl phenyl)-hexalin

To 1g (3.75mol) trans-solution of 0-ethanoyl-4-(4-chloromethyl phenyl)-hexalin in the 10ml dimethyl formamide adds 0.52g (3.75mmol) salt of wormwood and 0.27g (3.75mmol) diethylamine.Make this mixture under agitation 50 ℃ warm 6 hours, then add entry and use dichloromethane extraction.With the organic phase drying, vacuum concentration, residue advance the purification of thing column chromatography (alkali alumina, activity level III, ICN; Petrol ether/ethyl acetate=15: 1).

Colorless oil.

Yield: 0.79g (69% theoretical value).

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

1,05(t，6H)；1,45-1,75(m，4H)；1,9-2,2(s+m，7H)；2,4-2,6

(q+m，5H)；3,55(s，2H)；4,68-4,9(m，1H)；7,12(d，2H)；7,28

(d，2H).

Synthesize following material by similar method:

(1) trans-0-ethanoyl-4-(4-dipropyl aminomethyl phenyl)-hexalin

By trans-0-ethanoyl-4-(4-chloromethyl phenyl)-hexalin and dipropyl amine preparation.

Colorless oil.

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

0,9(t，6H)；1,35-1,75(m，8H)；1,9-2,2(s+m，7H)；2,3-2,6

(q+m，5H)；3,5(s，2H)；4,65-4,9(m，1H)；7,1(d，2H)；7,25

(d，2H).

(2) trans-0-ethanoyl-4-(4-[N-methyl butyl amino]-aminomethyl phenyl)-hexalin

By trans-0-ethanoyl-4-(4-chloromethyl phenyl)-hexalin and the preparation of N-methyl butyl amine

Colorless oil.

¹H-NMR-composes (200MHz, CDCl ₃); The ppm signal:

0,9(t，3H)；1,2-1,75(m，10H)；1,9-2,2(2s+m，8H)；2,38

(t，2H)；2,4-2,6(m，1H)；3,45(s，2H)；4,7-4,9(m，1H)；7,15

(d，2H)；7,25(d，2H).

(3) trans-0-ethanoyl-4-(4-diallyl aminomethyl phenyl)-hexalin

By trans-0-ethanoyl-4-(4-chloromethyl phenyl)-hexalin and diallylamine preparation.

Colorless oil.

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

1,4-1,7(m，4H)，1,9-2,18(s+m，7H)；2,4-2,6(m，1H)；3,09

(dd，4H)；3,52(s，2H)；4,7-4,9(m，1H)；5,01-5,3(m，4H)；

5,75-6,0(m，2H)；7,12(d，2H)；7,35(d，2H).

(4) trans-0-ethanoyl-4-(4-[N-pyrrolidyl] aminomethyl phenyl)-hexalin

By trans-0-ethanoyl-4-(4-chloromethyl phenyl)-hexalin and tetramethyleneimine preparation.

Clear crystal.

Fusing point: 43-45 ℃.

(5) trans-0-ethanoyl-4-(4-[N-morpholino] aminomethyl phenyl)-hexalin

By trans-0-ethanoyl-4-(4-chloromethyl phenyl)-hexalin and morpholine preparation.

Clear crystal.

Fusing point: 53-55 ℃.

(6) trans-0-ethanoyl-4-(4-[N-piperidino-(1-position only)] aminomethyl phenyl)-hexalin

By trans-0-ethanoyl-4-(4-chloromethyl phenyl)-hexalin and piperidines preparation.

Clear crystal.

Fusing point: 62-64 ℃.

(7) trans-0-ethanoyl-4-(4-[N-methyl-N '-piperidino-(1-position only)] aminomethyl phenyl)-hexalin

By trans-0-ethanoyl-4-(4-chloromethyl phenyl)-hexalin and the preparation of N-methyl piperidine.

Clear crystal.

Fusing point: 50-52 ℃.

Embodiment 5

Trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-methylamino aminomethyl phenyl)-hexalin

To 8.9g (0.019mol) trans-solution of 0-(4-chloro-phenyl-ethanoyl)-4-(4-N-[tert-butoxycarbonyl]-methylamino methyl) phenyl-hexalin in the 200ml methylene dichloride adds the 35ml trifluoroacetic acid and at room temperature stirred 2 hours.Volatilizable component is distilled in a vacuum, and residue dissolves in the methylene dichloride, and extremely neutral with saturated sodium hydrogen carbonate solution washing.Organic phase is with dried over sodium sulfate and carry out vacuum concentration.With residual yellow oil with column chromatography purify (alkali alumina, activity level III, ICN; Petrol ether/ethyl acetate/methyl alcohol=10: 10: 1).Obtain molten point and be 65-67 ℃ yellow crystals.

Yield: 6.4g (91% theoretical value).

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

1,4-1,7(m，4H)，1,8-2,0(m，2H)，2,0-2,2(m，2H)，2,4-2,6

(s+m，3+1H)，3,58(s，2H)，3,7(s，2H)，4,7-4,9(m，1H)，

7,1-7,35(m，8H).

Synthesize following material by similar approach:

(1) 0-(4-chloro-phenyl-ethanoyl)-4-(4-methylamino aminomethyl phenyl)-hexalin (suitable/trans mixture)

By 0-(4-chloro-phenyl-ethanoyl)-4-(4-N-[tert-butoxycarbonyl]-methylamino methyl) phenyl-hexalin (suitable/trans mixture) and trifluoroacetic acid preparation.

Yellow oil.

R _fValue (aluminum oxide; Petrol ether/ethyl acetate/methyl alcohol=10: 10: 1): 0.28-0.53.

Embodiment 6

O-(4-chloro-phenyl-ethanoyl)-4-(4-N-[carboxamido methyl]-the methylamino methyl) phenyl-hexalin (suitable/trans mixture)

With 1.0g (0.0027mol) 0-(4-chloro-phenyl-ethanoyl)-4-(4-methylamino aminomethyl phenyl)-hexalin (suitable/trans mixture); 0.5g (0.0027mol) iodo-acetamide (Iodacetamid), the mixture of 0.37g (0.0027mol) salt of wormwood and 5ml dipotassium base methane amide is under agitation warm 2 hours in 50 ℃.Add entry after being chilled to room temperature, use the ethyl acetate extraction mixture.The organic phase dried over sodium sulfate distills volatile constituent in a vacuum, and with residue with column chromatography purify (alkali alumina, activity level III, ICN; Petrol ether/ethyl acetate/methyl alcohol=60: 40: 2.5).

Acquisition is at 110 ℃ of sintering, at the white crystals product of 128-132 ℃ of fusing.

¹H-NMR-composes (200MHz, CDCl ₃); The signal of representing with ppm:

1,4-1,75(m，5H)，1,8-2,2(m，3H)，2,32(dd，3H)；2,4-2,63

(m，1H)，3,0(dd，2H)，3,5-3,7(dd+dd，2+2H)，4,7-4,9(m，0,5H)，

5,08-5,15(m，0,5H)，7,0-7,4(m，8H).

Synthesize following material by similar approach:

(1) trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-N-[ethoxycarbonyl methyl]-methylamino methyl) phenyl-hexalin

By trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-methylamino aminomethyl phenyl)-hexalin; Ethyl bromoacetate and salt of wormwood/dimethyl formamide preparation.

White solid product.

Fusing point: 40-42 ℃.

(2) trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-N-[3-hydroxypropyl]-methylamino methyl) phenyl-hexalin

By trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-methylamino aminomethyl phenyl)-hexalin, 3-bromopropyl alcohol and salt of wormwood/dimethyl formamide preparation.

White crystal.

Fusing point: 75-77 ℃.

Embodiment 7

Trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin-hydrochloride

In room temperature with under stirring, to 0.39g (0.001mol) trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-dimethylaminomethyl the phenyl)-solution of hexalin in the 10ml diethyl ether in, be added dropwise to the aqueous isopropanol of 1.5 times of equimolar hydrogenchloride.The throw out that is generated was at room temperature kept 1 hour, and suction strainer repeats with diethyl ether washing and dry.The acquisition fusing point is 231-233 ℃ a white crystal.

Yield: 0.32g (76% theoretical value).

C ₂₃H ₂₉Cl ₂NO ₂(422.40)

Calculated value: C 65.40 H 6.92 N 3.32 Cl 16.79

Measured value: 65.33 7.06 3.45 16.92

Embodiment 8

Trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin-tartrate

In the 7ml dehydrated alcohol, dissolve in the anhydrous tartrate of 0.15g (0.001mol) earlier, and then the dissolving 0.39g (0.001mol) trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin.Then add diethyl ether and make clear solution become the slight erosion that mixes, placed 8 hours down in+4 ℃.The sedimentary crystallized product of suction strainer is with diethyl ether washing and dry.

Fusing point: 169-171 ℃.

Yield: 0.46g (86% theoretical value).

C ₂₇H ₃₄ClNO ₈(536.02)

Calculated value: C 60.50 H 6.39 N 2.61 Cl 6.61

Measured value: 60.37 6.38 2.65 6.73

The following examples have been described the preparation of pharmaceutical administration forms:

Example I

Contain 5mg trans-tablet of 0-(4-chloro-phenyl-ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

Form:

1 tablet comprises:

Active substance 5.0mg

Lactose 148.0mg

Yam starch 65.0mg

Magnesium Stearate 2.0mg

220.0mg

The preparation method:

10% slurry is made in the yam starch heating, and with active substance, lactose and remaining yam starch mix, and with the granulation by the screen cloth of 1.5mm sieve aperture of above-mentioned slurry.Particle is dry under 45 ℃, mix again with above-mentioned same screen cloth development, and with Magnesium Stearate, compacting is in flakes.

Sheet is heavy: 220mg

Punch die: 9mm

Example II

Contain 5mg trans-drageeing of 0-(4-chloro-phenyl-ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

To coat the coating material of forming by sugar and talcum by the tablet that embodiment 1 makes by currently known methods, the drageeing of making will be polished with beeswax.

The heavy 300mg of drageeing

EXAMPLE III

Contain 5mg trans-suppository of 0-(4-chloro-phenyl-ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

Form:

A suppository comprises:

Active substance 5.0mg

Suppository material (Witepsol W45 for example ^R) 1695.0mg

1700.0mg

The preparation method:

The active substance of fine powdered is suspended in through dissolving and in 40 ℃ of following refrigerative suppository materials.Under 37 ℃, this material poured into refrigerative suppository mould slightly.

The heavy 1.7g of suppository

EXAMPLE IV

Contain 5mg trans-capsule of 0-(4-[trifluoromethyl]-phenyl acetyl)-4-(4-dimethylaminomethyl-phenyl)-hexalin

Form:

1 capsule comprises:

Active substance 5.0mg

Lactose 82.0mg

Starch 82.0mg

Magnesium Stearate 1.0mg

170.0mg

The preparation method:

Powdered mixture is mixed fully, and, pick up continuously and survey its final weight with the capsule filler hard gelatin capsule of packing into No. 3.

EXAMPLE V

Contain 5mg trans-tablet of 0-(4-bromophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

Form:

1 tablet comprises:

Active substance 5.0mg

Lactose 148.0mg

Yam starch 65.0mg

Magnesium Stearate 2.0mg

220.0mg

The preparation method:

10% slurry is made in the potato heating, and with active substance, lactose and remaining potato mix, and with the screen cloth granulation of above-mentioned slurry by the 1.5mm sieve aperture.With particle 45 ℃ down dry, mixes again by same screen cloth development, and with Magnesium Stearate and suppresses in blocks.

Sheet is heavy: 220mg

Punch die: 9mm

Example VI

Contain 1g trans-paste of the topical application of 0-(4-chloro-phenyl-ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin

The preparation of compound of Formula I topical application has following composition:

1, active substance 1.0g

2, Stearyl alcohol 4.0g

3, cetyl alcohol 4.0g

4, mineral oil 3.0g

5、Polysorbat60 4.5g

6 sorbitan monostearate 4.5g

7, propylene glycol 10.0g

8, nipagin 0.18g

9, propylparaben 0.02g

10, water adds to 100.00g

With component 2-6 80 ℃ of heating up to they whole fusings.Then component 1 is dissolved in the oil phase, component 7 and 10 90 ℃ of heating, and is dissolved in thus obtained aqueous phase with component 8 and 9.Then water is added in the oil phase and fast and stirs, to obtain suspension.Subsequently suspension is cooled off down so that their solidify for a long time at 50 ℃, also at room temperature cool off preparation further the stirring.

The following examples have been described the preparation of layer chicken feed.

Example VII A

The layer chicken feed that contains trans-0-(4-chloro-phenyl-ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin as active substance

Corn 633g/kg

Soyflour 260g/kg

Digested tankage 40g/kg

Edible-fat 25g/kg

Soya-bean oil 17g/kg

Secondary calcium phosphate 12g/kg

Lime carbonate 6g/kg

Accurate element-inorganic substance mixture the 5g/kg that gives birth to

Active substance 2g/kg

Obtain the 1kg feed after the component of above-mentioned amount carefully mixed.

Claims (13)

1, the O-acyl-4-phenyl-hexalin of general formula I, its enantiomorph, diastereomer and geometrical isomer and salt thereof,

In the formula:

N, m and p are 1,

R ¹And R ²Can be identical or different, represent hydrogen atom, contain the straight or branched alkyl of 1～6 carbon atom, contain the straight or branched alkenyl of 3～6 carbon atoms, wherein its pair key separates with nitrogen-carbon bond, above-mentioned alkyl by or not by hydroxyl, C _1-3Alkyl-carbonyl oxygen, carboxyl, C _1-3Alkoxy carbonyl or aminocarboxyl replace, and wherein above-mentioned hydroxyl and alkyl-carbonyl oxygen are not connected with carbon atom on 1, or

R ¹And R ²Form the saturated monocyclic heterocycle of 5-7 unit with its intermediary nitrogen-atoms, wherein in 6 yuan of saturated monocyclic heterocycles that so form, the methylene radical on 4 can be by Sauerstoffatom or by imino-or C _1-3Alkyl imino replaces,

R ³-R ⁶All represent hydrogen atom,

R ⁷Represent hydrogen atom, contain the cycloalkyl of 3～7 carbon atoms, randomly can be by fluorine, chlorine or bromine atom or by C _1-3Alkyl, C _1-3Alkoxyl group, phenyl, nitro, amino, C _1-3Alkylamino, two-(C _1-3Alkyl) amino or trifluoromethyl list or disubstituted phenyl, by two chlorine atoms or bromine atoms and an amino trisubstd phenyl, naphthyl or tetralyl, furans or pyridyl or the thienyl that is replaced by halogen atom, wherein above-mentioned phenyl is under disubstituted situation, and its substituting group can be identical or different, and two adjacent hydrogen atoms can be by methylene radical dioxy base or 1 on the phenyl, 2-ethylidene dioxy base group replace and

A represents a key, contain 1～6 carbon atom straight or branched alkylidene group or contain the alkylene group of 2～5 carbon atoms.

2, according to the compound of the general formula I of claim 1, R wherein ¹And R ²Can be identical or different, represent hydrogen atom, contain the straight chained alkyl of 1～6 carbon atom, contain the straight alkenyl of 3～6 carbon atoms.

3, according to the compound of the general formula I of claim 1, it is O-acyl-4-phenyl-hexalin of general formula I a, its enantiomorph, diastereomer and geometrical isomer with and the physiologically acceptable salt that forms with organic acid or mineral acid

In the formula:

N, m and p represent 1 separately,

R ¹Represent hydrogen atom, the 2-propenyl contains the straight chained alkyl of 1-4 carbon atom, this alkyl by or not by the aminocarboxyl group or at 2-, 3-or 4-position are replaced by hydroxyl,

R ²Represent hydrogen atom or contain the straight chained alkyl of 1-4 carbon atom,

R ³-R ⁶Represent hydrogen atom separately,

R ⁷Represent hydrogen atom, C _3-6Cycloalkyl, randomly in 4 positions by fluorine, chlorine or bromine atom, or by methyl, trifluoromethyl, methoxyl group, phenyl, or the phenyl group of nitro replacement, 3, the 4-dichlorophenyl, 2,4 dichloro benzene base, 4-chloro-3-aminomethyl phenyl, 4-amino-3-chloro-phenyl-, 3,4-Dimethoxyphenyl, 3, the 4-methylenedioxyphenyl, 4-amino-3,5-dichlorophenyl, 2-naphthyl or 2-(1,2,3,4-tetrahydrochysene) naphthyl, furans or pyridyl or the thienyl that is replaced by a chlorine atom and

A represents a key, contains the straight-chain alkyl-sub-of 1～5 carbon atom or contains the alkylene group of 2-3 carbon atom.

4, according to the compound of the O-acyl-4-phenyl-hexalin of claim 1, the physiologically acceptable salt that itself and organic acid or mineral acid form, it is selected from:

(1) cis-O-(4-chlorobenzene formacyl)-4-(4-dimethylaminomethyl phenyl)-hexalin;

(2) cis-O-(4-phenyl-3-butyryl radicals)-4-(4-dimethylaminomethyl phenyl)-hexalin;

(3) trans-O-(4-chloro-phenyl-ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin;

(4) cis-O-(5-methyl caproyl)-4-(4-dimethylaminomethyl phenyl)-hexalin;

(5) trans-O-(2-phenyl propionyl)-4-(4-dimethylaminomethyl phenyl)-hexalin;

(6) trans-O-(4-fluorophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin;

(7) trans-O-(3,4-dichlorophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin;

(8) cis-O-(4-fluorine cinnamoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin;

(9) trans-O-(right-the tolyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin;

(10) trans-O-(4-[trifluoromethyl]-phenyl acetyl)-4-(4-dimethylaminomethyl phenyl)-hexalin;

(11) trans-O-(2-naphthyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin;

(12) trans-O-(4-nitrophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin;

(13) trans-O-(4-bromophenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin;

(14) trans-O-(2,4 dichloro benzene base ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin;

(15) trans-O-([4-amino-3-chloro-phenyl-] ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin;

(16) trans-O-(4-p-methoxy-phenyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin;

(17) trans-O-(4-chloro-phenyl-ethanoyl)-4-(4-methylamino aminomethyl phenyl)-hexalin; With

(18) trans-O-(phenyl acetyl)-4-(4-methylamino aminomethyl phenyl)-hexalin.

5, according to the compound of the O-acyl-4-phenyl-hexalin of claim 4, the physiologically acceptable salt that itself and organic acid or mineral acid form, it is selected from:

Trans-O-(right-the tolyl ethanoyl)-4-(4-dimethylaminomethyl phenyl)-hexalin; With

Trans-O-(phenyl acetyl)-4-(4-methylamino aminomethyl phenyl)-hexalin.

6, pharmaceutical composition, except randomly containing one or more inert supports and/or thinner, it comprises in the claim 1～5 each compound.

7, each compound is used to prepare the purposes that suppresses the biosynthetic pharmaceutical composition of cholesterol in the claim 1～5.

8, the purposes that each compound is used to prepare treatment or prevents the pharmaceutical composition of hyperlipidemia in the claim 1～5.

9, each compound is used to prepare the purposes of treatment and the pharmaceutical composition of too high hyperplasia diseases associated in the claim 1～5.

10, the purposes that each compound is used to prepare prevention and treats the pharmaceutical composition of gallbladdergallstonecholetithiasis in the claim 1～5.

11, each compound is used to prepare the purposes for the treatment of mycotic pharmaceutical composition in the claim 1～5.

12, each compound is used to prepare the purposes of the feed of the laying hen that produces low cholesterol egg in the claim 1～5.

13, prepare the method for each compound in the claim 1～5, it is characterized in that:

A) with the 4-Santosol 360 alcohol of general formula I I and the carboxylic acid or the reaction of its response derivative of general formula III, temperature of reaction is-10～150 ℃;

In the formula (II): n, m, p and R ¹-R ⁶By each defines among the claim 1-5;

R ⁷-A-COX (III)

In the formula (III):

R ⁷With A by each defines among the claim 1-5, the leavings group of X representation hydroxy or reaction, or

B) the O-acyl-4-phenyl cycloalkanol of general formula I V and the amine of general formula V are reacted, temperature of reaction is 0～100 ℃,

In the formula (IV):

N, m, p, R ³～R ⁷With A by each defines in the claim 1～5, the leavings group of Y representative reaction,

In the formula V:

R ¹And R ²Have each implication of determining among the claim 1-5, or

C) for preparing the compound of general formula I, R in the formula ¹The implication that has in the claim 1～5 each, and R ²Representative contains the straight or branched alkyl of 1～6 carbon atom, and it can be by hydroxyl, C _1-3Alkyl-carbonyl oxygen, carboxyl, C _1-3Alkoxy carbonyl or aminocarboxyl replace, wherein hydroxyl and alkyl-carbonyl oxygen are not to be connected on the carbon atom of 1 position; The O-acyl-4-phenyl cycloalkanol of general formula VI and the compound of general formula VII are reacted, and temperature of reaction is 0～100 ℃;

In the formula (VI):

N, m, p, R ³～R ⁷With each defines among A such as the claim 1-5, R ¹Have above-mentioned definition,

R ^2’-Z ¹ (VII)

In the formula (VII):

R ^{2 '}Representative contains the straight or branched alkyl of 1-6 carbon atom, and it can be by hydroxyl, C _1-3Alkyl-carbonyl oxygen, carboxyl, C _1-3Alkoxy carbonyl or aminocarboxyl replace, and wherein hydroxyl and alkyl-carbonyl oxygen are not to be connected on the carbon atom of 1 position, and the leavings group of Z ' representative reaction,

If desired; with existing any hydroxyl, amino, alkylamino or carboxyl in the general formula I I-VII compound; before reacting, protect with blocking group; after reacting, remove blocking group again, and/or the compound of thus obtained general formula I is changed into the salt that itself and mineral acid or organic acid form.