CN1086816A - The preparation method of ethanolamine derivant - Google Patents

Abstract

The present invention relates to general formula (I) compound and physiologically acceptable salt and solvated compounds, their preparation method and the pharmaceutical composition that contains these derivatives.

The compounds of this invention is to β ₂-adrenoceptor has excitation, is used for the treatment of and reversibility respiratory obstruction diseases associated, as asthma and chronic bronchitis.

Description

The preparation method of ethanolamine derivant

The present invention relates to β ₂-adrenoceptor has the ethanolamine derivant of the novelty of excitation, and their preparation method, pharmaceutical composition and they application aspect medical.

Before this, ethanolamine derivant is described as the bronchodilator that β-adrenoceptor is had excitation.

For example, the Phenylethanolamine compound with following general formula has been described for british patent specification 2140800A number

R wherein ¹And R ²Represent hydrogen or C respectively _1-3Alkyl, m are the integers of 2-8, and n is the integer of 1-7, and Ar is the phenyl that replaces arbitrarily.

British patent specification 2162842A and European patent specification 0178919A have described the aminophenol compound with following general formula

R wherein ¹And R ²Represent hydrogen or C separately _1-3Alkyl, X represents C _1-7Alkylene, C _2-7Alkene support or C _2-7Alkynylene chain; Y represents C _1-6Alkylene, C _2-6Alkene support or C _2-6Alkynylene chain; The phenyl that the Ar representative is replaced arbitrarily by one or more specified substituent; O represents R ³CO-base or R ³NHCO-, R ³R ⁴NSO ₂-, R ⁵SO ₂-, R wherein ³Or R ⁴Represent hydrogen atom or C _1-3Alkyl, R ⁵Represent C _1-4Alkyl.

British patent specification 2165542A has described the process for dichloroaniline derivatives with following general formula:

R wherein ¹And R ²Represent hydrogen or C _1-3Alkyl, X represents C _1-6Alkylene or alkynylene chain; Y represents C _1-4Alkylene, C _2-4Alkene support or C _2-4Alkynylene chain, the phenyl that the Ar representative is replaced arbitrarily by one or more specified substituent.

We have found the compound of one group of novelty, and its structure is different from English Patent 2140800A, 2162842A, and 2165542A and the described compound of European patent 0178919A have gratifying effect.

The invention provides acceptable salt and solvate on compound with following general formula and the physiology thereof (as, hydrate):

Wherein Ar representative (a)

(R wherein ³Be C straight chain or side chain _1-3Alkylene),

(R wherein ⁴And R ⁵In a representation hydroxy, another represents hydrogen or halogen or hydroxyl),

(R wherein ⁶Be R ⁷CO-or R ⁷NHCO or R ⁷R ⁸NSO ₂-or R ⁹SO ₂-R wherein ⁷And R ⁸Represent hydrogen or C _1-3Alkyl, R ⁹Represent C _1-3Alkyl) p is 0 or 1 integer),

(R wherein ¹⁶And R ¹⁷Represent hydrogen or C _1-4Alkyl is perhaps worked as R ¹⁶When being hydrogen atom, R ¹⁷Also can represent C _1-4The alkoxyl group carboxylic group),

(R wherein ¹⁰Be C ₁₃Alkyl)

X represents a key or C _1-7Alkylene, C _2-7Alkene support or C _2-7Alkynylene chain.

Y represents a key or C _1-6Alkylene, C _2-6Alkene support or C _2-6Alkynylene chain, prerequisite are that the carbon atom summation of X and Y is 2-10,

R ¹And R ²Represent hydrogen or C respectively _1-3Alkyl, its prerequisite is R ¹And R ²In the carbon atom summation be no more than 4.

R ¹⁸Represent hydrogen or C _1-3Alkyl;

O represents in the following groups:

Wherein Z represention oxygen atom or sulphur atom;

R ¹¹Represent hydrogen or halogen or C _1-3Alkyl, nitro,

-(CH ₂) _tR-(CH ₂) _rCOR ¹³Perhaps SO ₂NR ¹⁴R ¹⁵;

R ¹²Represent hydrogen or C _1-3Alkyl, work as R ¹¹When being halogen, R ¹²It also is halogen;

The R representation hydroxy, C _1-3Alkoxyl group or NR ¹⁴R ¹⁵Base;

R ¹³Representation hydroxy, C _1-4Alkoxyl group or NR ¹⁴R ¹⁵Group;

R ¹⁴And R ¹⁵Represent hydrogen atom or C _1-4Alkyl or NR ¹⁴R ¹⁵Form a saturated amino heterocyclic group, this ring is 5-7 unit ring, contain arbitrarily on the ring one or more being selected from-O-or-S-or-NH-or-N(CH ₃The atom of)-group;

T is 1 to 3 integer;

R represents 0 to 3 integer;

Obviously, the compound with logical formula I contains one or more unsymmetrical carbons, thereby compound of the present invention comprises all enantiomorphs, and diastereomer and their mixture comprise racemic modification.Group

In carbon atom be that the compound of R configuration is a preferred compound.

In the definition of logical formula I, the support of term alkene comprises cis and trans two kinds of structures.

Preferred compounds in the logical formula I is that those Z are the compound of O, and another kind of preferred compound is that Z is the compound of S, and general Q is in following two formulas

In logical formula I, the X chain can be a key ,-CH ₂-,-(CH ₂) ₂-(CH ₂) ₃-,-(CH ₂) ₄-,-(CH ₂) ₅-,-CH ₂C ≡ C-,-(CH ₂) ₂CH=CH-,-(CH ₂) ₂C ≡ C-,-CH=CHCH ₂-,-CH=CH(CH ₂) ₂-or-CH ₂C ≡ CCH ₂-.The Y chain can be a key ,-CH ₂-,-(CH ₂) ₂-,-(CH ₂) ₃-,-(CH ₂) ₄-,-(CH ₂) ₅-,-(CH ₂) ₆-,-CH=CH-,-C ≡ C-,-CH ₂CH=CH-or-CH ₂C ≡ C-.

The total number of carbon atoms in X and the Y chain is preferably in the 4-10 scope, for example, can be 4,5,6,7, and 8 or 9, apparent, X and Y are alkylenes, X generally is C ₃Or C ₄Alkylene, normally C _1-5, C for example ₁Or C ₂Alkylene.

R ¹, R ²And R ¹⁸Be respectively hydrogen or methyl, ethyl, propyl group or sec.-propyl.If R ¹And R ²In one be propyl group or sec.-propyl, then another is exactly hydrogen atom or methyl.R ¹, R ², R ¹⁸Preferably represent hydrogen or methyl, work as R ¹⁸Represent C _1-3During alkyl, best R ¹And R ²The both is a hydrogen.

One group of preferred compound is R in the formula ¹⁸Represent the compound of hydrogen atom.

The replacement situation of another group preferred compound is: R in the formula ¹And R ²Be hydrogen, perhaps R ¹Be hydrogen, R ²Be C _1-3Alkyl, particularly methyl, perhaps R ¹Be methyl, R ²It also is methyl.

Most convenient be R ¹, R ²And R ³All be hydrogen.

With regard to the definition of Ar in the logical formula I compound, R ³Can be-CH ₂-,

,-(CH ₂) ₂-or-(CH ₂) ₃-.

R ⁵In " halogen " can be chlorine or fluorine, R ⁷And R ⁸Be respectively hydrogen or methyl, ethyl, propyl group or sec.-propyl.R ⁹Can be methyl, ethyl, propyl group or sec.-propyl.R ¹⁰Can be methyl, ethyl or propyl group.R ¹⁶And R ¹⁷Be respectively hydrogen, perhaps methyl, ethyl, n-propyl, sec.-propyl, normal-butyl. isobutyl-, sec-butyl or tertiary butyl in addition, are worked as R ¹⁶When being hydrogen atom, R ¹⁷Can be methoxycarbonyl or ethoxycarbonyl.

Ar in the formula I compound can be

(R wherein ⁶Be HCO-, CH ₃CO-, NH ₂CO-, (CH ₃) ₂NSO ₂-or CH ₃SO ₂-),

In the formula I compound-NR ¹⁴R ¹⁵When representing a saturated heterocyclic, this ring can be 5,6,7 yuan of rings, and, in this ring, at random contain and be selected from-O-,-S-,-NH-or-N(CH ₃)-in heteroatoms or group, such-NR ¹⁴R ¹⁵Group comprises pyrrolidyl, piperidino-(1-position only), hexamethylene imine base, piperazinyl, N methyl piperazine base, morpholinyl, high morpholinyl, thia morpholinyl.

Radicals R ¹¹The substituting group of representative be hydrogen, chlorine, fluorine, bromine atoms or methyl, ethyl, propyl group ,-CH ₂OH ,-CH ₂N(CH ₃) ₂,-CH ₂N(CH ₂CH ₃) ₂,-COOH ,-COOCH ₃,-COO(CH ₂) ₂CH ₃,-CONH ₂,-CON(CH ₃) ₂,-CON(CH ₂CH ₃) ₂,-CON ,-SO ₂N(CH ₂CH ₃) ₂Deng group.

Substituent R ¹²Can be hydrogen atom, methyl, ethyl or propyl group, perhaps work as R ¹¹When being halogen atom, R ¹²Can be chlorine, fluorine or bromine.

When Z was Sauerstoffatom, group Q was R wherein ¹¹Represent hydrogen, C _1-3Alkyl (example: propyl group), COR ¹³(example: CO ₂CH ₃Or CO ₂H), CH ₂OH or-CONR ¹⁴R ¹⁵(R wherein ¹⁴And R ¹⁵The both represents C _1-4Alkyl, for example ethyl), and, R ¹²Represent those groups of hydrogen, or Q represents following group:

Moreover when Z was sulphur atom, group Q was R in the formula ¹¹Dai Qing, chlorine, alkyl are (for example: methyl), CONR ¹⁴R ¹⁵(CONEt for example ₂), CH ₂OH, COR ¹³(example: CO ₂CH ₃, CO ₂H) or SO ₂NR ¹⁴R ¹⁵(for example: SO ₂NEt ₂) and R ¹²Represent those groups of hydrogen, perhaps Q represents following group:

The invention provides following preferred compound:

α '-(((6-((5-(2-furyl) amyl group) oxygen base) hexyl) amino) methyl)-and 4-hydroxyl-1, the 3-xylyl alcohol,

N-(5-(2-((6-((6-(2-furyl) hexyl) oxygen base) hexyl) amino)-1-hydroxyethyl)-2-hydroxyphenyl) Toluidrin;

5-(3-((6-((2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl) amino) hexyl) oxygen base) propyl group)-and N, N-diethyl-2-furoylamide;

4-alkyl-α '-(((6-(3-(3-thienyl) propoxy-) hexyl) amino) methyl)-1, the 3-xylyl alcohol;

α '-(((6-(2-(benzo (b) thienyl) oxyethyl group) hexyl) amino) methyl)-and 4-hydroxyl-1, the 3-xylyl alcohol;

5-(1-hydroxyl-2-((6-((4-(2-thienyl) butoxy) hexyl) amino) ethyl)-1, the 3-Benzenediol;

α '-(((6-(2-(2-benzo (b) furyl) oxyethyl group) hexyl) amino) methyl)-4-hydroxyl-1, the 3-xylyl alcohol;

N-(5-(2-((6-(4-(2-benzo (b) furyl) butoxy) hexyl) amino)-1-hydroxyethyl)-2-hydroxyphenyl) Toluidrin;

4-hydroxyethyl-α '-(((6-(4-(2-thienyl) butoxy) hexyl) amino) methyl)-1, the 3-xylyl alcohol;

α '-(((1,1-dimethyl-6-(2-(2-thienyl) oxyethyl group) hexyl) amino) methyl)-4-alkyl-1,3 xylyl alcohol;

S-(2-((6-((2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl) amino) ethyl) oxygen base) ethyl)-and N, N-diethyl-2-thenoyl amine;

And acceptable salt and solvate on their physiology.

Acceptable salt comprises the sour salify of being made by mineral acid and organic acid, example hydrochloric acid salt, hydrogen bromide salt on the physiology that logical formula I compound suits, vitriol, phosphoric acid salt, maleic acid salt, tartrate, Citrate trianion, benzoate, 4-methoxyl group-benzoate, 2 or the 4-hydroxy benzoate, the 4-chloro benzoate, tosilate, naphthalenesulfonate, mesylate, sulfamate, ascorbate salt, salicylate, acetate, diphenyl acetic acid salt, triphenylacetic acid salt, fumarate, succinate, lactic acid salt, glutarate, gluconate, tricarballylic acid salt, hydroxyl naphthalene monocarboxylic acid salt, for example, 1-hydroxyl or 3-hydroxyl-2-naphthalene monocarboxylic acid salt or oleate.These compounds can also form salt with suitable alkali, resemble an alkali metal salt (for example sodium salt and sylvite) alkaline earth salt (example: calcium salt or magnesium salts), with organic bases (example: the salt of Xing Chenging triethylamine).

The compound of the salt that solubleness is very low in water is convenient to come administration with inhalation and insufflation especially, and salt like this has diphenyl acetic acid salt, 4,4 '-methylene-bis-3-hydroxyl-2-naphthalene monocarboxylic acid salt and 1-hydroxyl-3-hydroxyl-2-carboxylate salt.

According to the present invention, these compounds have excited β ₂The effect of-adrenergic receptor, and they have particularly advantageous function.This excitation obtains proof on isolating guinea pig trachea, show that these compounds can relax by PGF ₂Contraction due to α or the electricity irritation, and also observe lasting effect.

These compounds of the present invention can be used to treatment and reversibility respiratory tract obstruction diseases associated, as asthma and chronic bronchitis.

These compounds of the present invention are to treatment inflammation and allergic skin diseases, congestive heart failure, and depression, premature labor, glaucoma is that effectively it is low excessively also to can be used for improving hydrochloric acid in gastric juice, particularly the symptom of peptide ulceration.

Be used for the treatment of and prevent the reversibility obstructive airway disease that the human or animal suffers from according to the compound of the logical formula I that the present invention further provides and their suitable physiologically acceptable salt and solvated compounds.

Can be mixed with the prescription that makes things convenient for administration with any according to compound of the present invention.Thereby the present invention comprises also and contains the composition that a kind of logical formula I compound or its are fit to physiologically acceptable salt or solvate at least that the latter is as people or veterinary drug.These compositions and the physiology vehicle or the inert matter that are fit to, and any additional medicament uses together.

These compounds can be mixed with the form that is fit to suction or insufflation administration, or oral administration, oral cavity, non-enteron aisle, the form of local (comprising intranasal) or rectal administration.Preferably suck or the insufflation administration.

For the inhalation administration, from pressurized vessel, by adopting suitable propelling agent, as Refrigerant 12, dichloro tetrafluoro ethane, trichlorofluoromethane, carbonic acid gas or other suitable gas, or from atomizer discharge compound of the present invention with the form of aerosol spray.With regard to the pressure aerosol, determine dose unit by discharging metering valve.

For sucking or the insufflation administration, compound of the present invention can adopt the form of dry powder composite, for example the mixed powder of being made up of compound and the powder base that is fit to such as lactose or starch.Dust composition can unit dosage form exists, and as capsule or cartridge case, for example gelatina, or particulate packing is taken pulvis from above-mentioned formulation by means of inhalation or insufflation.

For oral administration, medicinal compositions can adopt tablet, capsule, and pulvis, solution, the form of syrup or suspension agent promptly adds suitable vehicle according to a conventional method and makes.

For orally administering.Medicinal compositions is made tablet according to a conventional method, drops, or lozenge.

Compound of the present invention also can bolus injection or continue infusion through parenterai administration.The preparation that is used for injecting is present in ampoule with unitary dose, perhaps is present in the multiple dose container with sanitas.Said composition can be taked the suspension in oiliness or aqueous carrier, solution or emulsion form, and contain preparaton such as suspension agent, stablizer and/or dispersion agent.Perhaps active ingredient is done powdering, prepares again as the former water that reduces phlegm and internal heat with appropriate carriers before use.

For topical, pharmaceutical composition is made ointment with general method, and washing lotion or milk liquid is use or oleaginous base for example, generally adds suitable viscosifying agent and/or solvent again.With regard to intranasal administration, said composition can adopt Sprayable, for example, makes the aqueous solution or suspension, aerosol with suitable propelling agent.

Compound of the present invention also can be mixed with the enterally administering composition, as contains the conventional suppository base such as the suppository or the enema,retention of theobroma oil or other glyceryl ester.

Oral with regard to above introduction, the oral cavity, rectum or Topically administrable compositions can be made control-released agent with ways customary with them.

Suggestion is 0.005 milligram to 100 milligrams to dosage every day of the active compound that human body uses, general branch one of this dosage or secondary administration.Impose correct dosage according to patient's age and situation and administering mode.Suitable dosage with the inhalation administration is 0.005 milligram to 20 milligrams, and oral is 0.02 milligram to 100 milligrams, and non-enteron aisle is 0.01 milligram to 2 milligrams with bolus drug administration by injection drug administration by injection, and infusion then is 0.01 milligram to 25 milligrams.

Following description relates to the compound of logical formula I and is used for preparing the preparation of their intermediate, except that specifying, and X, Y, Ar, R ¹, R ², R ¹⁸Identical with the definition of logical formula I with Q, hydroxyl and/or amino in the starting raw material need protection, and in the end a step is removed blocking group.The method of suitable blocking group is referring to " blocking group in the organic chemistry " (" Protective Groups in Organic chemistry ") Plenum Press, and 1973 and " blocking group in the organic synthesis " " Protective Groups in Organic Synthesis " Theodora Greene work (John Wiley and Sons Inc.1981).Therefore can be with aralkyl phenmethyl for example, diphenyl-methyl or trityl, or the derivative of THP trtrahydropyranyl is protected hydroxyl.The amino protecting group that is fit to comprises phenmethyl, 2-methylbenzene methyl, and diphenyl-methyl or trityl, acyl group resembles acetyl, tribromo-acetyl or trifluoroacetyl.Can use classic methods to remove blocking group, for example, exist down hydrogenolysis can remove aralkyl at metal catalyst (for example, be stated from the charcoal palladium).Hydrolysis under acidic conditions can make the THP trtrahydropyranyl fracture.Can remove acyl group with the hydrolysis of alkali (as sodium hydroxide or salt of wormwood) property, can remove the tribromo-acetyl base by reduction with zinc and acetate.In general formula (1), adopt habitual alkanisation method can make general formula (1) compound.

Thereby, for example, in method (a),, remove all protecting groups then as required by the logical formula II amine of alkanisation, can make R in the formula ¹It is the logical formula I compound of hydrogen atom.

Alkylation can realize with the alkylating agent of logical formula III representative:

(wherein L represents leavings group, halogen for example, as, chlorine, bromine or iodine, or alkyl sulfonyloxy, mesyloxy for example, tolysulfonyl oxygen base).

In suitable disacidify agent, as yellow soda ash, the mineral alkali that salt of wormwood is such, or triethylamine, diisopropylethylamine, the organic bases that pyridine is such, or oxyethane, the such epoxide of propylene oxide exists down, alkylated reaction is easier to carry out, and reaction is easy to carry out in following solvent, as acetonitrile, and ether, as: tetrahydrofuran (THF) or dioxane, ketone, as: butanone or methyl iso-butyl ketone (MIBK), substituted amide, as, dimethyl formamide, or chloroparaffin, as, chloroform.Reaction also can be carried out in envrionment temperature to this interval of solvent refluxing temperature.

According to another example (b) of alkanisation method, logical formula I compound (R wherein ¹Represent hydrogen atom) available logical formula II amine and logical formula IV compound, in the presence of reductive agent, carry out alkanisation, need remove all blocking groups more subsequently and make,

When Z was Sauerstoffatom, appropriate reductant comprised catalyst hydrogenation, and these catalyzer can be attached to the platinum on the charcoal, platinum oxide, palladium, Buddhist nun's Ruan nickel or rhodium.Reaction solvent comprises alcohol (as ethanol) or ester (as ethyl acetate) or ether (as tetrahydrofuran (THF)) or water, or the mixture of two or more above-mentioned solvents.Reaction can be carried out under normal temperature and pressure or high slightly temperature, pressure, is 20-100 ° as temperature, a pressure 1-10 normal atmosphere.On the other hand, when Z was oxygen or sulphur atom, reductive agent can be a hydride, as second boron or metal hydride, as sodium borohydride, sodium cyanoborohydride, or lithium aluminum hydride, when using these reductive agents, the whether suitable kind that depends on used hydride of solvent, but nothing more than being alcohol, as methyl alcohol or ethanol, or ether, as diethyl ether or tertiary butyl ether, or tetrahydrofuran (THF).

Form formula (V) imine intermediate with formula IV compound alkanisation formula II amine

Reduce imines under these conditions, obtain the formula I compound.

With regard to another logical method (2), can make logical formula I compound by reduction reaction.For example, will lead to the reduction of formula VI intermediate, and remove all protecting groups then as required, and can make logical formula I compound, formula VI is:

(X wherein ¹Represent reducible group and/or Ar and/or Q to contain reducible group, the meaning of other symbol is as described below, i.e. X ¹Be-CH(OH)-, the meaning of Ar and Q is identical with the definition of formula I).

Suitable reducible group comprises those wherein X ¹Be＞the C=0 group, Ar contains-CHO or-CO ₂R ¹⁹Substituting group (R wherein ¹⁹Represent hydrogen atom or alkyl (as C ₁₃) group).

Can be commonly used to reduce carboxylic acid, aldehyde with those, the reductive agent of ester and ketone carries out this reduction reaction.

Such as, the X in formula VI ¹Representative＞C=0 group and/or Ar contain-CHO or CO ₂R ¹⁹During substituting group, the such composite metal hydride of available lithium aluminum hydride is reduced into respectively-CH(OH)-or-CH ₂The OH group, reaction can be carried out in ether (as diethyl ether or tetrahydrofuran (THF)) or halogenated alkane (as methylene dichloride), and the temperature of reaction interval is 0 ℃ of reflux temperature to solvent.On the other hand, when Z is Sauerstoffatom, X ¹During representative＞C=0 group, preceding method (I) is being arranged, (b) the described catalyzer of part exist down with hydrogen reduction become-CH(OH)-.

Employing is converted into the method for another formula I compound with a certain formula I compound, also can make the formula I compound.

For example, the compound that meets formula I, wherein a R ¹¹Representative-(CH ₂) _rCOR ¹³, R ¹³Be hydroxyl, can obtain the R of respective compound by the hydrolysis of respective compound ¹³Represent C _1-4Alkoxyl group, hydrolysis can be carried out under alkaline condition (as sodium hydroxide).

According to another enforcement of mutual transformation approach, with R in the corresponding formula ¹¹Representative-(CH ₂) _rNR ¹⁴R ¹⁵The formula I compound reduction of (wherein r represents 0,1 or 2) can make R in the formula ¹¹Representative-(CH ₂) _rNR ¹⁴R ¹⁵The formula I compound.In the presence of appropriate solvent (such as diethyl ether or the such ether of tetrahydrofuran (THF)), can carry out this reduction reaction with the such hydride reducer of lithium aluminum hydride.

In above-described logical method, the formula I compound that obtains is possible be that form with salt exists.This salt generally is acceptable on the physiology, needs, and available classic methods converts this salt to corresponding free acid.

The physiologically acceptable salt of formula I compound is to react in the presence of appropriate solvent by formula I compound and suitable acid or alkali to make, and these solvents are acetonitriles, acetone, chloroform, ethyl acetate or alcohol (as methyl alcohol, ethanol or Virahol).

Acceptable salt also can prepare with habitual method other salt (comprising other physiologically acceptable salt) by the formula I compound on the physiology.

When needs formula I compound specific enantiomeric, the racemic modification of available classic methods fractionation formula I compound promptly.

For instance, suitable optically active acid that has can be used to generate salt with the racemic modification of formula I compound, the isometry salt that obtains like this can be separated into diastereo-isomerism salt with the method for fractional crystallization, therefrom isolate the enantiomorph of formula I, isolating method is to convert salt to required free alkali.

Moreover, with any method in the methods described herein, by the synthetic enantiomeric compounds that obtains formula I of suitable optical activity intermediate.

Specific diastereomer in the compound that formula I is represented can obtain by classic methods, such as, use any method described herein, synthesize with suitable asymmetric starting raw material, perhaps the mixture of the isomers by making the formula I compound is transformed into the derivative of suitable diastereomer, as, salt, this salt can separate by the methods such as fractional crystallization of classics.

X in the formula ¹The logical formula VI midbody compound of expression＞C=0 group can be by formula (VII)

Halogenated ketone (Hal represents halogen atom here, and any hydroxyl and/or amino in the Ar base can optionally be protected) makes with the reaction of general formula (VIII) amine, and formula (VIII) is:

(R here ²⁰Be hydrogen atom, or when Z is Sauerstoffatom, R ²⁰Be the group that can change hydrogen by catalytic hydrogenation into).

This reaction can exist down at alkali (as, diisopropylethylamine), realizes that solvent has dimethyl formamide, the ester of ethyl acetate and so on, the ether of tetrahydrofuran (THF) and so in solvent cold or heat.

The amine of formula II and shape can be known compounds as the halogenated ketone of (VII) formula, also can be prepared by the method that is similar to these known compounds of preparation.

Formula III, (IV) and (VIII) intermediate can prepare by being similar to those methods that prepare known compound, and appropriate means comprises method that those are described and the method for introducing as embodiment hereinafter in british patent specification 2140800A.

The invention has been described for following examples, and temperature is ℃ that except that being specifically noted, " doing " refers to carry out drying with sal epsom or sodium sulfate.Thin-layer chromatography (t.l.C) is at SiO ₂On carry out.Dodge column chromatography (FCC) and on silica gel (Merck 9385), carry out, except that specifying, use a kind of in the following solvent system: A-toluene: ethanol: 0.88.B-ethyl acetate: methyl alcohol: triethylamine.The omission form is expressed as follows: the DMF-dimethyl formamide; DEA-N, the N-diisopropylethylamine; TAB-four-n-butylamine bisul-phate.

Intermediate 1 is referring to following α '-(aminomethyl)-4-hydroxyl-1,3-xylyl alcohol.

Intermediate 2

2-((4-(6-bromine hexyl) oxygen base) butyl) thiophene

Will be by 1,6-dibromo-hexane (9.5 gram), 2-thiophene butanols (2.0 gram), TAB(0.25 gram) and the mixture formed of 50% the NaOH aqueous solution (8 milliliters) 23 ℃ of following high degree of agitation 18 hours.This mixture dilutes with 50 ml waters, diethyl ether (2 * 20 milliliters) extraction, and extract is water (50 milliliters) and salt solution (50 milliliters) washing successively, and dry and volatilization under vacuum condition then obtains a kind of xanchromatic oil (11 gram).Be used in the FCC purifying on the silica gel, use hexanaphthene and hexanaphthene-ethyl acetate (4:1) wash-out respectively, the product that so obtains (5.2 gram) is after vacuum distilling, obtain the title compound (3.6 gram) of colorless oil, b.p.185-195 ℃/0.8torr.T.L.c.(ethyl acetate-cyclohexane 1:4) Rf0.73.

Intermediate 3

2-(2-(6-bromine hexyl) oxygen base) benzo (b) thiophene ethyl)

Will be by 2-benzo (b) thiophene ethanol (2.20 gram), 1,6-dibromo-hexane (2.59 milliliters), TAB(0.25 gram), the mixture of the aqueous sodium hydroxide solution of 1.25M (9 milliliters) and ether (20 milliliters) composition at room temperature stirs and spends the night.This mixture water (50 milliliters) dilution, ether (3 * 50 milliliters) extraction will merge, dried extract evaporates.Residual oil FCC purifying, (100:0 → 98:2) make eluent obtains colourless buttery title compound (2.73 gram) to hexanaphthene-diethyl ether.

Ultimate analysis C ₁₆H ₃₁BrOS:

Measured value: C, 56.55; H, 6.3; Br, 23.8; S, 9.4.

Calculated value: C, 56.3; H, 6.2; Br, 23.4; S, 9.4%.

Example 1

N-(5-(2-((6-(4-(2-benzo (b) furyl) butoxy) hexyl) amino)-1-hydroxyethyl)-2-hydroxyphenyl) Toluidrin phenylformic acid (salt)

With 2-(4-((6-bromine hexyl) oxygen base) butyl) benzo (b) furans (790 milligrams), (5-(2 amino-1-hydroxyethyl)-2-hydroxyphenyl) Toluidrin (1.07 gram) and DEA(1.2 gram) be dissolved in the DMF(20 milliliter) solution 100 ℃ of stirrings 3 hours down, solvent volatilizees under vacuum, residue (2.2 gram) is light brown, this residue FCC purifying, system A(90:10:1 → 80:20:1) make elutriant obtains faint yellow oily free alkali (45 milligrams).This alkali is dissolved in the methyl alcohol (10 milliliters), handles with phenylformic acid (11 milligrams), the residue after the solvent evaporates obtains title compound (55 milligrams) after ether (10 milliliters) development, and its outward appearance is the light brown solid.m.p.79-80°。

Ultimate analysis: C ₂₇H ₃₈N ₂O ₆S.C ₇H ₆O ₂0。85H ₂O

Measured value: C, 62.3; H, 7.1; N, 4.5; S, 5.0.

Calculated value: C, 62.2; H, 7.0; N, 43; S, 4.9%

Example 2

N-(5-(2-((6-(4-(2-benzo (b) furyl) butoxy) hexyl) amino)-1-hydroxyethyl)-2-hydroxyphenyl) Toluidrin 4,4 '-methylene-bis (3-hydroxyl-2-naphthalene monocarboxylic acid) salt (2:1)

Will be by 2-(4-((6-bromotrifluoromethane) oxygen base) butyl) benzo (b) furans (2.0 gram), N-(5-(2-amino-1-hydroxyethyl)-2-hydroxyphenyl) Toluidrin (3.48 gram) and DEA(1.0 milliliter) be dissolved in the DMF(25 milliliter) solution that forms is under nitrogen atmosphere, 80 ℃ were heated 4 hours, stay a dark-brown oily matter behind the vacuum volatilization solvent, use the FCC purifying, system A(90:10:1) makes elutriant, obtain immobilising yellow oily free alkali (1.2 gram), with the free alkali (34 milligram) of a part in methyl alcohol (20 milliliters) one reflux of Pamoic acid (170 milligrams) in methyl alcohol (5 milliliters) 0.5 hour, obtain title compound (521 milligrams) after the evaporation clear liquid, its outward appearance is yellow spumescence, m.p.99-101 ℃

Ultimate analysis: C ₂₇H ₃₈N ₂O ₆S.1/2C ₂₃H ₁₆O ₆.0.5H ₂O

Measured value: C, 63.9; H, 6.5; N, 3.7; S, 4.25

Calculated value: C, 64.1; H, 6.6; N, 3.9; S, 4.4%

Example 3

α '-(((6-(2-benzo (b) thienyl) oxyethyl group) hexyl) amino) methyl)-and 4-hydroxyl-1, the 3-xylyl alcohol

With intermediate 3(1.55 gram), intermediate 1(1.00 gram), the DEA(1.20 milliliter) with the DMF(14 milliliter) under nitrogen atmosphere in 95; 100 ℃ were stirred 1 hour down, the refrigerative mixture evaporates (1 Torr), saturated aqueous solution (50 milliliters) with sodium bicarbonate is handled, use ethyl acetate (3 * 540 milliliters) extraction again, extract is merged, evaporation, the silica obtained FCC post that imposes on are gone up at silica gel (Merck 7,734 5 grams) in dry back.With the wash-out of the system B(94:5:1 that provides → 89:10:1), obtain m.p111-114.5 ℃ of the title compound (414 milligrams) of white solid again through the ether preparation, T.L.c.(NEt ₃Deactivation SiO ₂, system B89:10:1) and Rf0.06

Example 4

5-(1-hydroxyl-2-((6-(4-(2-thienyl) butoxy) hexyl) amino) ethyl)-1, the 3-Benzenediol, (E)-2-butylene diacid (2:1) (salt)

With intermediate 2(800 milligram) be dissolved in exsiccant DMF(1 milliliter) solution that forms is at 100 ℃, stir down, adding is by 5-(2-amino-1-hydroxyethyl)-1,3-Benzenediol (700 milligrams) and DEA(1.29 gram) be dissolved in exsiccant DMF(15 milliliter) in the solution that forms, 100 ℃ were stirred 2 hours down, solvent evaporation are fallen residue FCC purifying, use the A(80:20:1 of system) elution, get a yellowish oil (550 milligrams).Methyl alcohol (5 milliliters) solution that in oil and methyl alcohol (5 milliliters) solution, adds furans acid (100 milligrams), methyl alcohol is evaporated, Residual oil and the development of exsiccant ether obtain cream-coloured powdered title compound (550 milligrams), the m.p.123-124 ° of A80:20:1 of T.L.c.(system) Rf0.25.

Example 5

α '-(((6-(2-(2-benzo (b) thienyl) oxyethyl group) hexyl) amino) methyl)-4-hydroxyl-1, the 3-xylyl alcohol, 4,4 '-methylene-bis (3-hydroxyl-2-naphthalene monocarboxylic acid) salt (2:1)

Will be by α '-(((6-(2-(2-benzo (b) thienyl) oxyethyl group) hexyl) amino) methyl)-4-hydroxyl-1,3-xylyl alcohol (0.378 gram) is dissolved in the solution of methyl alcohol (20 milliliters) through 4,4 '-methylene-bis (3-hydroxyl-2-naphthalene monocarboxylic acid) (165 milligrams) handles post-heating and refluxed 1 hour, mixture is chilled to room temperature, filter the back vaporising under vacuum, be used for obtaining m.p.86-93 ℃ of yellow foamed title compound (380 milligrams) after the ether development.

Ultimate analysis: C ₂₅H ₃₈NO ₄S.0.5.C ₂₃H ₁₆O ₆.0.4H ₂O

Measured value: C, 67.9; H, 6.8; N, 2.15; S, 4.9.

Calculated value: C, 68.0; H, 6.5; N, 2.2; S, 5.0%

Below be the formulation examples of The compounds of this invention, compound of the present invention represented herein in term " active ingredient "

Tablet (directly compression)

Milligram/sheet

Active ingredient 2.0

Microcrystalline Cellulose USP 196.5

Magnesium stearate BP 1.5

Compressing tablet weight 200.0

Through suitable sieve, with mixed with excipients, is 7 millimeters punch press compressing tablet with diameter with active ingredient.

The tablet of other intensity can prepare by ratio that changes active ingredient and Microcrystalline Cellulose or the method that changes compressing tablet weight.

Tablet can be with suitable filmogen by routine techniques at its surperficial topped last layer film, such as using Vltra tears, perhaps wrap up in steamed bun stuffed with sugar.

Metering pressurized aerosol (suspension aerosol)

Milligram/time every

0.100 26.40 milligram of fine powder active ingredient

0.010 2.64 milligram of oleic acid Bp

23.64 5.67 milligrams of trichlorofluoromethane Bp

Refrigerant 12 Bp 61.25 14.70 grams

Active ingredient can be worn into very tiny particle with fluid, and oleic acid is mixed at 10-15 ℃ with trichlorofluoromethane, in the mixing tank of high-shear, medicine is mixed with this solution then.This suspension quantitatively adds in the aerosol canister of aluminum, and the suitable quantitative valve that can carry 85 milligrams of suspensoids is screwed on the tube, by this valve methyl chlorofluoride is added to be pressed in the tube.

Suck cartridge case

Milliliter/every

Fine powder active ingredient 0.200

Lactose BP 25.0

With before common film-making level lactose mixes in high energy mixers, active ingredient needs grind to form very tiny particle in fluid can grind, and by suitable packing machine pulverulent mixture is injected into hard gelatin capsule No. 3.The fine powder inhalation machine control of the content of cartridge case such as Glaxo Rotahalex class.

Claims (2)

1, the preparation method of formula I compound and physiologically acceptable salt thereof

In the formula, R ¹And R ²Each represents hydrogen atom;

R wherein ³Be methylene radical, R ⁴And R ⁵It respectively is hydroxyl;

The X representative contains the alkylidene group of 4 carbon atoms;

Y represents C _1-3Alkylidene chain;

R ¹⁸Represent hydrogen atom;

The Q representative

Here Z represents sulphur;

R ¹¹And R ¹²Each represents hydrogen;

The method is characterized in that,

(a) with formula III alkylating agent alkylation formula II amine, said formula II and formula III are respectively:

Ar wherein, R ², R ¹⁸, Q, the definition of X and Y is the same, and L represents halogen atom;

If need, and then remove any retentivity group;

When the formula I compound that obtains is the enantiomorphous mixture, selectively this mixture is split to obtain required enantiomorph;

As required, gained formula I compound or its salt is changed into physiologically acceptable salt.

2, in accordance with the method for claim 1, wherein, the formula I compound is selected from:

α '-[[[6-[2-(benzo [b] thienyl) oxyethyl group] hexyl] amino] methyl]-4-hydroxyl-1, the 3-xylyl alcohol;

5-[1-hydroxyl-2-[[6-[[4-(2-thienyl) butoxy] hexyl] amino] ethyl]-1, the 3-Benzenediol;

And the physiologically acceptable salt of above-claimed cpd.