CN1152915A - Quinoline derivatives as leukotriene antagonists - Google Patents

Abstract

The present invention relates to novel heterocyclic compounds of formula (I), in which X1 and X2 independently of each other stand for hydrogen or halogen; X3 and X4 independently of each other stand for hydrogen, halogen, nitro, cyano, trifluoromethyl, C1-C4 alkyl, C1-C4 alkoxy, carboxy or C1-C4 carbalkoxy; Z is a bond, O, S, S(O), S(O)2, NH or CH2; R1 is hydrogen or a straight or branched, saturated or unsaturated C1-C6 hydrocarbon chain; R3 is hydrogen, straight or branched, saturated or unsaturated C1-C12 hydrocarbon chain, unsubstituted or substituted phenyl or unsubstituted or substituted benzyl, the above mentioned substituents being one or more of X3 and X4 as defined above; or the group R1-[C]p-R3 stands for cyclopropyl; p may be 0 provided that Z is a bond, or p may be an integer from 1-6 if R1 = R3 = hydrogen; A is COOR2 or 1H-1,2,3,4-tetrazole in which R2 = R1 as defined above or R2 is a pharmaceutically acceptable cation. The present compounds are of value in the human and veterinary practice as leukotrien antagonists.

Description

Quinoline as leukotriene antagonist

The present invention relates to the unknown so far compound that is used for people and veterinary treatment, its pharmacy acceptable salt, its bioreversible derivative, the method for preparing described new compound, the pharmaceutical composition that contains new compound, the dose unit of pharmaceutical composition and use described composition and dose unit treatment patient's method.

Leukotriene is arachidonic acid metabolic formation through 5-lipoxygenase path, and it relates to many physiological pathology functions, dwindles as segmental bronchus, and plasma oozes out, coronary vasospasm, white cell chemotaxis and neutrophilic leukocyte degranulation 1.Therefore exploitation suppresses the 5-lipoxygenase and therefore suppresses the generation of leukotriene, or the compound with leukotriene antagonistic action merits attention especially.

International patent application No.PCT/DK88/00188 (publication number No.WO89/05294) has described a series of amino-benzene oxygen alkyl acids that have the antagonism leukotriene and suppress the quinolyl methoxyphenyl replacement of 5-lipoxygenase activity.

International patent application No.PCT/US89/02692 (publication number No.WO89/12629) described-and series has the acid that the active quinolyl ethyl of antagonism leukotriene phenoxymethyl phenoxyalkyl replaces.

International patent application No.PCT/DK93/00201 (publication number No.WO91/03466) has described isoserine (that is 3-amino-2 hydroxy propanoic acid) derivative that a series of N-phenyl with the active quinolyl methoxy replacement of antagonism leukotriene replace.

International patent application No.PCT/DK90/00254 (publication number No.WO94/03431) has described the Isoserine derivatives that a series of N-phenyl with the active quinolyl ethyl replacement of fine antagonism leukotriene replace.

Now, we are surprised to find, and definition is effective leukotriene antagonist as the compound of general formula I.

The new texture characteristics of these compounds, comprise a quinoline ring that is replaced by halogen arbitrarily, by E-CH=CH-be bonded to aniline between the position, and the further monobasic benzyl of coupling, shown in general formula I, this compound has the advantages that to keep the leukotriene antagonistic activity for a long time, particularly when human serum albumin exists.

The compounds of this invention has the general formula I structure Wherein, X ₁And X ₂Represent hydrogen atom or halogen independently of one another;

X ₃And X ₄Representative independently of one another, hydrogen atom, halogen atom, nitro, cyano group, trifluoromethyl, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, carboxyl or C ₁-C ₄Carbalkoxy;

Z is a key, O, S, S (O), S (O) ₂, NH, or CH ₂

R ₁Be hydrogen or straight or branched, saturated or unsaturated C ₁-C ₆Hydrocarbon chain;

R ₃Be hydrogen, straight or branched, saturated or unsaturated C ₁-C ₁₂Hydrocarbon chain, phenyl that does not replace or replace or the benzyl that does not replace or replace, above-mentioned substituting group are one or several definition X as above ₃And X ₄Or radicals R ₁-[C] _p-R ₃Represent cyclopropyl;

When Z represented key, p can be 0, or works as R ₁=R ₃During=hydrogen atom, p can be the integer of 1-6;

A is COOR ₂Or 1H-tetrazolium, wherein R ₂=R ₁Define as above, or R ₂It is pharmaceutically acceptable positively charged ion.

Preferably, X ₁And X ₂Represent hydrogen independently of one another, fluorine, chlorine; X ₃Represent hydrogen; X ₄Represent hydrogen, fluorine, chlorine, bromine; Z is at adjacent O or S; P is 1; R ₁Be hydrogen, R ₃Be hydrogen or straight or branched, saturated or unsaturated C ₁-C ₆Hydrocarbon chain, or phenyl; And A is COOR ₂, R wherein ₂Be hydrogen, C ₁-C ₃Alkyl, alkali metal cation, or tetrazolium-5-base.

Particularly preferred compound is selected from: E-2-[2-(3-(2-(7-chloroquinoline-2-yl)-ethyl) phenyl amino methyl) phenoxy group]-2 Methylpropionic acid, E-2-[2-(3-(2-(7-chloroquinoline-2-yl)-ethyl) phenyl amino methyl) phenoxy group]-2 methyl valeric acid, E-2-[2-(3-(2-(7-chloroquinoline-2-yl)-ethyl) phenyl amino methyl) phenoxy group] caproic acid, E-2-[2-(3-(2-(7-chloroquinoline-2-yl)-ethyl) phenyl amino methyl)-4-bromine phenoxy group] caproic acid, E-2-[2-(3-(2-(7-fluorine quinoline-2-yl)-ethyl) phenyl amino methyl] the phenoxy group caproic acid, ((2-(6 for 3-for E-2-[2-, 7-fluorine quinoline-2-yl)-and ethyl) the phenyl amino methyl) phenoxy group] caproic acid, sodium salt.

Compound as described herein contains one or several asymmetric center and therefore causes steric isomer; For example, enantiomer or diastereomer.The present invention includes all these possible steric isomers.

Therefore, particularly preferred compound is (S) (+)-E-2-[2-(3-(2-(7-chloroquinoline-2-yl)-ethyl) phenyl amino methyl) phenoxy group] caproic acid.

The salt of compound of Formula I of the present invention can be by obtaining with pharmaceutically acceptable mineral acid or organic acid reaction, spirit of salt for example, Hydrogen bromide and hydroiodic acid HI, phosphoric acid, sulfuric acid, nitric acid, tosic acid, methylsulfonic acid, formic acid, acetate, propionic acid, citric acid, tartrate, and toxilic acid, these examples are not to be used to limit the present invention.

The salt of compound of Formula I of the present invention also can be by obtaining with pharmaceutically acceptable mineral alkali or organic bases reaction.The salt that forms with pharmaceutically acceptable nontoxic alkali can be an alkali metal salt and alkaline earth salt, as lithium, and sodium, potassium, magnesium, calcium salt equally also can be ammonia and suitable no toxic amine, as C ₁-C ₆Alkylamine, for example, triethylamine, C ₁-C ₆Alkanolamine, for example, diethanolamine or trolamine, PROCAINE HCL, PHARMA GRADE, cycloalkanes amine, for example, dicyclohexylamine, benzyl amine, for example, N-methyl-benzyl amine, N-Ethylbenzyl amine, N-benzyl-β-phenylethylamine, N, N '-dibenzyl-ethylenediamin or dibenzyl amine, and heterocyclic amine, for example, morpholine, N-ethylpiperidine or the like.

Even entering enteron aisle, compound of the present invention can well be absorbed, in some cases, preferably compound of the present invention is made bioreversible derivative, promptly, prepare so-called prodrug, preferred derivative is that those physicochemical property can increase its solubleness under physiological pH and/or the compound of absorption and/or bioavailability.

These derivatives for example are the esters of the N-hydroxymethyl derivative of The compounds of this invention, and the preparation of this compounds is by The compounds of this invention secondary amine functional groups and formaldehyde ²³⁴⁵Prepared in reaction is then with the suitable acidic cpd or the activity derivatives reaction of this compounds, for example with bisul-phate ⁶, N, N-N-methylsarcosine, N, N-diethyl-Beta-alanine, or phosphoric acid ⁷, but other suitable acid that can form the biological reversible derivatization thing of the physicochemical property with hope also can be used.

Other example comprise with molecule in acid functional group form ester, as simple ester, for example, methyl or ethyl, the acyloxy alkyl, alcoxyl carbonyl oxyalkyl or aminoacyl oxyalkyl ester, they in vivo or externally be easy to hydrolysis.

In the above-mentioned ester, below we are preferred: the alkyloyloxyethyl methyl with 3-6 carbon atom, 1-(alkyloyloxyethyl) ethyl with 4-6 carbon atom, alcoxyl carbonyl oxygen methyl with 3-6 carbon atom, have 1-(the alcoxyl carbonyl oxygen) ethyl of 4-6 carbon atom and have the alpha-amino group alkyloyloxyethyl methyl of 2-6 carbon atom.

Other preferred ester has lactone, for example 3-benzo [C] furanonyl) (3-phthalidyl), acyl group (4-crotonolactonyl) in the 4-crotons, the γ-Ding Nei acyl-4-base (ester of γ-butyrolacton-4-yl).

Equally, being also included within the scope of the invention is methoxyl methyl, the aminoalkyl ester that cyano methyl or list or dialkyl group replace, as, 3-dimethyl aminoethyl, 2-diethylamino ethyl, or 3-dimethylaminopropyl ester.

Preferred those environment good absorption in intestines, and in absorption process or to absorb posthydrolysis be the ester of compound of Formula I.

These examples are not to be used to limit the present invention, other relate to the method that can improve The compounds of this invention physicochemical property and solubleness and can use at this yet.

5-lipoxidase inhibitor and leukotriene antagonist will be used for the treatment of asthma, allergy, rheumatoid arthritis, arthritis vertebralis, gout, atherosclerosis, hyperplasia or inflammatory skin disease, as psoriasis and allergic eczema, chronic inflammation intestinal disease and other inflammation situation, stenocardia is followed in vasospasm, pulmonary hypertension, cystic fibrosis, adult's respiratory distress syndrome, local asphyxia and reperfusion damage, migraine, or the like ⁸(referring to E.J.Goetzl, D.G.Payan andD.W.Godman, J.Clin, Immunol, 4 (1984) 79).

The evaluation of specificity 5-lipoxidase inhibitor and leukotriene antagonist is a kind of new route, aspect the treatment diversity clinical disease extensive connotation is being arranged.

The metabolic inhibitor of arachidonic acid can use usefulness [1- ¹⁴C] arachidonate mark and use calcium ion carrier A 23187 ⁹The mouse peritonaeum white corpuscle that stimulates is identified.Observe The compounds of this invention and suppress metabolism at analytical concentration 10 μ M.

Leukotriene antagonist adds pure white triolefin D by observing the guinea pig ileum bar in physiological buffer ₄(LTD ₄) ⁹The contraction of Shi Yinqi is identified.When compound of the present invention is adding LTD ₄Add the ileum sample before, can be observed significantly to special-LTD ₄The inhibition that inductive shrinks.Being suppressed at minimum concentration is that 0.1-1nM takes place.On the other hand, by 10 ^-7The contraction that the histamine of M causes is shunk even can not suppress its inductive with The compounds of this invention at micro-molar concentration.

The character of research leukotriene antagonist receptor binding and the relation of its inhibition smooth muscle contraction are very important.Can by leukotriene antagonist in the Guinea pig lung membrane and [ ³H] LTD ₄Bonding LTD ₄Acceptor ^9,10The direct competitive analysis carry out the research of receptor binding.Measure pIC ₅₀Value, it be antagonist suppress [ ³H] LTD ₄Bonding reaches the negative logarithm of 50% o'clock concentration.With OT3665 ¹¹Compare the pIC of The compounds of this invention ₅₀Value is also unaffected (referring to table 1) when 0.1% human serum albumin exists.Table 1 have or do not have in the presence of 0.1% human serum albumin [ ³H] LTD ₄Bonding (pIC with Guinea pig lung membrane ₅₀, mean value+SD (n) or individual values)

Compound	Albumin-free	Albumin is arranged
			Embodiment 14	?????9.1-9.0	?????9.3-9.3
Embodiment 20	?????8.9-9.1	?????9.2-8.6
			Embodiment 12	???8.5±0.1(5)	???8.7±0.2(5)
Embodiment 64	???8.7±0.3(5)	???9.0±0.3(5)
			Embodiment 54	?????8.4-8.5	?????8.8-8.6
Embodiment 43	?????8.7-8.3	?????8.6-8.4
			Embodiment 44	?????8.5-8.8	?????8.6-8.6
???OT?3665	???8.2±0.1(7)	???7.±0.1(3)

Leukotriene antagonistic action LTD in the anaesthetized guinea pig body ₄The inductive segmental bronchus dwindles and detects ⁹With compound intravenous injection 10 minutes, measure bronchoconstriction after oral 4,8 and 24 hours.ED ₅₀The value representative suppresses leukotriene inductive bronchoconstriction and reaches 50% o'clock dosage.ED ₅₀Value is calculated by 2-3 dosage regression analysis.The results are shown in following Table II.Table II

Compound	??ED 50mg/kg ??i.v.10min	?ED 50mg/kg ?p.o.4h	??ED 50mg/kg ??p.o.8h	??ED 50mg/kg ??p.o.24h
					Embodiment 14	????0.009	??0.17	???0.99	???10.51

Embodiment 20	???0.002	????0.24	????nd.	????11.33
					Embodiment 12	???0.002	????0.24	????0.22	????3.10
Embodiment 64	???0.006	????0.15	????0.19	????7.86
					Embodiment 54	???0.010	????0.60	????4.01	????19.68
Embodiment 43	???0.0007	????0.17	????nd.	????8.59
					Embodiment 44	???0.002	????0.04	????nd.	????2.80
?OT366511	???0.42	????11.60	????＞30	????nd.

Nd.=does not do these according to embodiment 14,20, and 12,64,54,43 and 44 compound has the LTD stronger and longer time than OT3665 ₄Antagonistic action.

The invention still further relates to the method for preparing The compounds of this invention.

In one embodiment, use the amine of general formula I I, it prepares referring to document 12 or embodiment 2,

Wherein, X ₁And X ₂Define as above, with the compound reaction of general formula III, preparation compound of Formula I.Compound of formula III prepares referring to document 13 or embodiment 25,

R wherein ₁, R ₃, X ₃, X ₄, A, Z and p definition are as above, Y can form " easily leavings group ", therefore, Y typical example such as halogen atom are as chlorine, bromine or iodine, or the alkyl or aryl sulfonyloxy, but also can use other leaving group such as alkyl sodium sulfate ester group, chloro sulfonyloxy, sulfurous acid alkyl ester group, mono phosphoric acid ester or dialkyl group ester group and itrate group.

Be reflected in the suitable inert organic solvents and carry out, as methyl alcohol, ethanol, dimethyl formamide or hexamethyl phosphoric triamide, but equally also can use other solvent; Be reflected at about room temperature or be higher than room temperature and in the temperature range of the boiling point of solvent for use, carry out.But some the time suitable temperature with reaction mixture be cooled to and be lower than room temperature, this mainly depends on the character of employed compound of formula III.Reaction also can be carried out in the presence of organic bases, as pyridine, and triethylamine, sodium methylate or sodium ethylate, or in the presence of suitable mineral alkali, as alkali metal hydroxide, alkaline carbonate or alkali metal hydrocarbonate, but can use other alkali equally.The crude product of compound of Formula I, available filtering method is collected as fruit instant such as dilute with water, or with suitable solvent, as ether, ethyl acetate, methylene dichloride or chloroform are after extracting from reaction mixture.If after it is converted into salt with the alkyl acid of suitable above-mentioned definition or organic acid, available for example recrystallization or chromatography purification.

In another embodiment, can the amine of general formula I I be converted into compound of Formula I by standard reductive alkylation reaction, for example with the carbonyl compound reaction of general formula I V, general formula I V compound can obtain or according to document 13,14 from commercial, 15,16 method preparation, Wherein, R ₁, R ₃, X ₃, X ₄, A, Z and p define as above, hydrogenation or reduction in the presence of appropriate catalyst then, for example, with alkali metal borohydride reaction reduction.If words can like this, need not be isolated intermediate, so-called Schiff alkali carrying out hydrogenation or reduction simultaneously with the carbonyl compound reaction easily.

Be reflected in the suitable inert organic solvents and carry out, as methyl alcohol, ethanol, but equally also can use other solvent.Be reflected at about room temperature, but some the time suitable temperature with reaction mixture be cooled to and be lower than room temperature, or be heated in the temperature range of boiling point of solvent for use and carry out, this mainly depends on the character of employed reactant general formula I I and general formula I V compound.

In the 3rd embodiment, make the compound of general formula V, it prepares as embodiment 3 Wherein, X ₁, X ₂, X ₃, and X ₄Definition as above, and Z is O, S or NH, with the compound reaction of general formula VI, general formula VI compound can be from commercial acquisition or can be according to document 17,18,19 method preparation, R wherein ₁, R ₃, A, p and Y definition as above form required compound of Formula I.

General formula V compound can react by the phenyl aldehyde of general formula I I compound with suitable replacement, uses sodium borohydride (NaBH then ₄) the reduction preparation.

Following schema I illustrates general formula V, the preparation of compound:

Schema I

Compound of the present invention is used for effectively treating the pharmaceutical composition of above-mentioned disease.

The amount (following finger active ingredient) that reaches the required compound of Formula I of result of treatment is certainly according to specific compound, and route of administration is with mammiferous different and change.Appropriate vol was the 0.1-20mg/kg body weight when compound of Formula I was used for whole body therapeutic, preferred 0.1-10mg/kg weight of mammal, for example 0.2-10mg/kg; Taking medicine one or several times every day, is that 5mg is to 5g for the general per daily dose of adult.

In spray composite, the anti-asthma dosage of suitable compound of Formula I is 1 μ g-5mg compound/kg body weight, and preferred dosage is 1 μ g-1mg/kg weight of mammal, for example 1 μ g-0.5mg/kg.

Although can active ingredient is individually dosed with the form of raw material chemicals, preferably make the form administration of pharmaceutical composition.Usually, active ingredient can account for 0.1%-100% (weight ratio) in pharmaceutical composition.Usually, the dose unit of composition contains the active ingredient of 0.07mg-1g.When being used for topical, active ingredient accounts for 1%-2% (weight ratio) in the preferred pharmaceutical compositions, but active ingredient can reach 10%w/w at most.The pharmaceutical composition that is applicable to nose or orally administering should contain 0.1-20%w/w, for example, and the 2%w/w active ingredient.

" dose unit " is meant the unit, promptly can be used for single dose to patient's administration, and be easy to use and pack, as physics and chemically stable dosage unit, it both can contain the mixture that active ingredient also can contain active ingredient and solid or liquid medicine diluent or carrier.

The pharmaceutical composition that animal doctor of being easy to of the present invention or people cure the disease contains active ingredient and pharmaceutically acceptable carrier and other treats component arbitrarily.Carrier must " can accept " to be meant other component item coupling and harmless to the person of benefiting from composition.

Pharmaceutical composition comprise be fit to oral, eye usefulness, rectum,, parenteral (comprise subcutaneous, intramuscular and intravenously), through eye, intraarticular, part, nose, or the form of orally administering.

Pharmaceutical composition is made generally in dosage unit form, and known method preparation in available any pharmaceutical field.All methods all comprise active ingredient and the carrier-bound step that contains one or more annexing ingredients.Usually, preparation of compositions is by with active ingredient and liquid vehicle thorough mixing evenly or be dispersed in the solid carrier, or the both carries out, and then, if desired, it is shaped to desired form.

The present invention is suitable for form such as the capsule that oral pharmaceutical composition is made dispersal unit, sachet, and tablet or lozenge, and wherein contain the active ingredient of predetermined dose; Make powder or granula; In moisture or water-free liquid, make solution or suspension; Or make O/w emulsion or water-in-oil emulsion.The all right bolus of active ingredient, the form administration of electuary or paste.

The pharmaceutical composition that is used for rectal administration can comprise the suppository of active ingredient and carrier or the form administration of enema.

Be applicable to that the pharmaceutical composition of parenteral admin is generally the aseptic oily or the aqueous compositions of active ingredient, preferably its hemisotonic with the person of benefiting from.

The pharmaceutical composition that is applicable to intraarticular or dosing eyes can be made into the sterile aqueous preparations that active ingredient is a microcrystalline form, for example, and aqueous crystallite suspension.Microcrystallite form or Biodegradable polymeric system also can be used for active ingredient at intraarticular and dosing eyes.

The pharmaceutical composition that is suitable for part or dosing eyes comprises liquid or semiliquid, as oil-in-water or water-in-oil emulsion, and ointment or paste; Or solution or suspension, as drops.

The pharmaceutical composition that is applicable to nose or orally administering comprises the self-propelled or spraying type composition of pulvis, as aerosol and sprays.

Other pharmaceutical composition that is applicable to nasal administration comprises fine powder, and it can promptly, suck nasal cavity with the container that powder is housed near nose fast by the form administration of snuff.

Except said components, composition of the present invention also can contain one or more annexing ingredients.

Composition also can contain other therapeutical chemistry compound, be used for the treatment of above-mentioned pathologic condition, for example, glucocorticosteroid, antihistaminic agent, platelet activation factor (PAF) antagonist, anti-choline energy reagent, methyl xanthine, beta-adrenergic reagent, salicylate, indomethacin (indomethacin), Flufenamic Acid salt (flufenamate), Naproxen Base, timegadine, sodium chloraurate, Trolovol, the serum cholesterol reductive agent, retinoid (retinoids), zinc salt, and azulfidine (salicylazosulfapyridin) is (Salazopyrin).

Be described in further detail the present invention with following embodiment:

Embodiment 1E-2-[3-(2-quinoline-2-yl) ethyl) phenyl amino methyl] phenylium step 1 E-3-[(2-quinoline-2-yl) ethyl]-N-(2-carboxyl methoxyl group benzylidene)]-aniline

To E-3-[2-(quinoline-2-yl) ethyl] aniline (0.5g; 2mmo1) add 2-formyl radical phenylium (0.36g in (EP 0,206 751 AMerck Frosst Canada Inc. can obtain) solution in ether (150ml); 2mmol) the solution in ether (50ml), and stirring at room 4 hours.

Filtration gained precipitation, with ether washing and dry, obtaining the title compound fusing point is 201-203 ℃.This compound is directly used in next step.Step 2 E-2-[3-(2-quinoline-2-yl) ethyl) phenyl amino methyl] phenylium

(0.41g 1mmol) adds sodium borohydride (0.1g) in the suspension in ethanol (10ml) to the Schiff alkali that obtains to step 1.Stirring at room 2 hours.In this reaction mixture, add entry (5ml) and in vacuum-evaporation.Residuum water (10ml) is handled, and gained solution is neutralized to pH7 with the acetate (0.5ml) that dilutes.

Filtration gained precipitation with the MeOH development, is filtered, with methyl alcohol and ether washing.Obtain fusing point and be 108-111 ℃ title compound.

Embodiment 2E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl] phenylium step 1 E-3-[2-(7-chloroquinoline-2-yl) ethyl] oil of mirbane

(3.6g, 20mmol) (3.0g, 20mmol) solution in diacetyl oxide (20ml) stirred 4.5 hours at 130 ℃ with the 3-nitrobenzaldehyde with 7-chlorine quinaldine red.Mixture is cooled to room temperature and filtering-depositing, precipitation water and ether washing.Obtaining the title compound fusing point is 181-183 ℃, and is directly used in next step.Step 2 E-3-[2-(7-chloroquinoline-2-yl) ethyl] aniline

To SnCl ₂(15.0g) in the solution in concentrated hydrochloric acid (40ml), (5.1g, the 16mmol) solution in acetate (75ml) stir this mixture 1 hour at 80 ℃ the oil of mirbane that adding step 1 obtains.Reaction mixture is cooled to room temperature, and is evaporated to dried.

Residuum water (150ml) is handled and is added NaOH solution, makes it become alkaline solution (pH9).Use ethyl acetate (30ml) extraction 2 times then, drying, vacuum-evaporation, obtaining the title compound fusing point is 127-128 ℃, and is directly used in next step.Step 3 E-3-[2-(7-chloroquinoline-2-yl) ethyl]-N-(2-carboxyl methoxyl group benzylidene) aniline

(4.23g 15mmol) in the solution in ether (500ml), adds 2-formyl radical phenylium (2.7g, 15mmol) solution in ether (300ml) to the aniline that obtains to step 2.With mixture stirring at room 2.5 hours.Filtration gained precipitation is with ether washing and dry.Obtaining the title compound fusing point is 191-192 ℃. this compound is directly used in next step.Step 4 E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl] phenylium

The Schiff alkali that obtains to step 3 (5.5g, 12.5mmol) in the suspension in methyl alcohol (75ml), under stirring at room with added sodium borohydride (1.25g) in 1.5 hours in batches.Reaction mixture is with water treatment and add 3N acetate (10ml) and fully stir and be acidified to pH5-6.Reaction mixture stirring at room 12 hours, is filtered, wash with water.

To precipitate drying, with dioxan (75ml) recrystallization, obtaining title compound is the orange/yellow solid crystallization, and fusing point is 187-189 ℃.

Embodiment 3E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] ethyl hexanoate step 1 E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenol

According to embodiment 2; the method of step 3; but replace 2-formyl radical phenylium with salicylic aldehyde; obtain E-3-[2-(7-chloroquinoline-2-yl) ethyl]-N-(2-hydroxyl benzylidene) aniline is intermediate; do not need to separate; proceed embodiment 2, step 4, obtaining the title compound fusing point is 151-152 ℃.Step 2 E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] ethyl hexanoate

With E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) and phenol (7.0g, 18mmol), 2-bromocaproic acid ethyl ester (4.9g, 22mmol), salt of wormwood (10g, 72mmol) and the mixture of acetone (350ml) refluxed 40 hours, volatile material is removed in vacuum-evaporation then.Residuum is dissolved in ether, goes out the hydrochloride of title compound with excessive a little 1N hydrochloric acid acidizing and precipitation.The gained hydrochloride filters, and handles with 1N sodium bicarbonate (200ml) and ether.Separate organic layer, with (MgSO ₄) drying, vacuum-evaporation obtains title compound, is 84-86 ℃ with obtaining fusing point behind the ethyl alcohol recrystallization.

Embodiment 4-11

According to embodiment 3, the method for step 2, but replace 2-bromocaproic acid ethyl ester with the suitable brominated ester, obtain the compound of Table III.

Table III

Embodiment No	??R 1	???R 2	????R 3	Fusing point ℃	Note
						???4	??H	?CH 2CH 3	????CH 3	???????-
???5	?CH 3	?CH 2CH 3	????CH 3	????212-213	Hydrochloride
						???6	??H	?CH 2CH 3	??CH 2CH 3	?????85-87
???7	??H	?CH 2CH 3	??CH(CH 3) 2	???????-
						???8	??H	?CH 2CH 3	??(CH 2) 7CH 3	?????87-88
???9	??H	?CH 2CH 3	??(CH 2) 9CH 3	?????64-66
						???10	??H	??CH 3	????C 6H 5	????143-145
???11	??H	?CH 2CH 3	??CH 2CH 2CH 3	???138-45(dec.)

Embodiment 12E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] caproic acid

With embodiment 3, and the ethyl ester of step 2 (6.3g, 12mmol), the Lithium Oxide 98min hydrate (10g, 250ml), water (100ml), methyl alcohol (200ml), and the mixture of tetrahydrofuran (THF) (200ml) was stirring at room 4 hours.After the filtration, mixture vacuum-evaporation is obtained the crude product of title compound.Behind ethyl alcohol recrystallization, obtain fusing point and be 181-182 ℃ title compound.

Embodiment 13-21

According to the method for embodiment 12, but replace E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group with the ester in the Table III] ethyl hexanoate, obtain the compound of Table IV.

Table IV

Embodiment No-R ₁R ₃Fusing point ℃

13????????????????H???????????????CH ₃???????183-184

14????????????????H?????????????CH ₂CH ₃?????201-202

15???????????????CH ₃????????????CH ₃????????171-172.5

16????????????????H????????????CH(CH ₃) ₂????223-224

17????????????????H???????????(CH ₂) ₇CH ₃???130-132

18????????????????H???????????(CH ₂) ₉CH ₃???115-117

19????????????????H?????????????C ₆H ₅???????198

20????????????????H???????????CH ₂CH ₂CH ₃???193-195

21??????????????CH ₂CH ₃???????CH ₂CH ₃??????176-177

Embodiment 22E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl] the phenyl ethyl thioacetate

With embodiment 2, (0.85g, 3mmol), (1.07g, 4.4mmol) the mixture stirring at room in dimethyl sulfoxide (DMSO) (25.0ml) is 96 hours for saleratus (2.0g) and 2-chloromethyl phenyl ethyl thioacetate for the aniline that step 2 obtains.

Gained mixture water (25.0ml) dilution and with ethyl acetate (2 * 25.0ml) extracting twice.

With the extraction liquid drying, evaporation, and products therefrom ether recrystallization obtains fusing point and is 101-106 ℃ title compound.

Embodiment 23E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl] the phenyl thioacetic acid

Ester (0.5g, 1mmol) NaOH (1.0ml) hydrolysis in ethanol (10.0ml) of usefulness 2N with embodiment 22.Solution was refluxed 2 hours and water (10.0ml) dilution.With acetate (0.5ml) the acidifying after-filtration precipitation of 3N, and water and ethyl acetate washing.

With obtaining fusing point behind the acetate recrystallization is 205-207 ℃ title compound.

Embodiment 24E-2-[3-(2-(quinoline-2-yl) ethyl) phenyl amino methyl] phenyl thioacetic acid step 1 E-2-[3-(2-(quinoline-2-yl) ethyl) phenyl amino methyl] the phenyl ethyl thioacetate

Method according to embodiment 22, with E-3-[2-(quinoline-2-yl) ethyl] and aniline (referring to embodiment 1, step 1) replaces E-3-[2-(7-chloroquinoline-2-yl) ethyl] aniline, use the flash chromatography purifying, use ethyl acetate/hexane (3: 7) wash-out, the title compound that obtains is used for next step.Step 2 E-2-[3-(2-(quinoline-2-yl) ethyl) phenyl amino methyl] the phenyl thioacetic acid

According to the method for embodiment 23, the ethyl ester that uses step 1 to obtain replaces E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl] the phenyl ethyl thioacetate, obtain title compound.

Product is developed with ethyl acetate, obtained fusing point and be 177-179 ℃ title compound.

Embodiment 25E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenyl sulfo-] caproic acid step 1 E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenyl sulfo-] ethyl hexanoate

According to the method for embodiment 22, replace 2-chloromethyl phenyl phenyl ethyl thioacetate with 2-(2-2-bromomethylphenyl sulfo-) ethyl hexanoate (it prepares referring to following appendix), obtain title compound.The gained ester need not be further purified and can be used for next step.Step 2 E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenyl sulfo-] caproic acid

According to the method for embodiment 12, the ester that uses step 1 to obtain replaces E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] ethyl hexanoate, obtaining the title compound fusing point is 169-172 ℃.

Appendix is used for the preparation of 2-(the 2-2-bromomethylphenyl sulfo-) ethyl hexanoate of step 1

Steps A 2-(2-carboxyl phenyl sulfo-) ethyl hexanoate

2-thiobenzoic acid (7.7g) and 2-bromocaproic acid ethyl ester (12g) in the methanol solution (100ml) of 1N potassium hydroxide solution in stirring at room 16 hours.After the vacuum-evaporation, the gained material is water-soluble, uses extracted with diethyl ether.The aqueous solution is with excessive a little 4N hcl acidifying, and with extracted with diethyl ether 3 times.The organic layer that merges extraction, drying, vacuum-evaporation obtains title compound, can be directly used in next step.Step B 2-(2-hydroxy phenyl sulfo-) ethyl hexanoate

To the carboxylic acid (6.0g) that steps A obtains, in the mixture of triethylamine (3.0g) and tetrahydrofuran (THF) (50ml), ,-7 ℃～-10 ℃, slowly add Vinyl chloroformate (1.9g) in stirring down.Behind the restir 30 minutes, filter and to make the solution clarification, under 10 ℃ of stirrings, add sodium borohydride (2.7g) then, again with 1 hour adding methyl alcohol (15ml) be used to reduce the intermediate acid anhydrides.Behind the restir 2 hours, the gained mixture is used twice of extracted with diethyl ether then with the careful acidifying of 4N hydrochloric acid (100ml).Organic extract salt water washing, drying, vacuum-evaporation obtains the 6.0g title compound and is used for next step.Step C 2-(2-2-bromomethylphenyl sulfo-) ethyl hexanoate

In the solution of triphenylphosphine (5.3g) in acetonitrile (40ml), under stirring and refrigerative condition, add bromine (3.2g).After about 10 minutes, slowly add the solution of material (6.0g) in acetonitrile (30ml) that step B obtains, and stirred 3 hours.The gained mixture is in vacuum-evaporation, and residuum is handled with ice, water and ether.Separate organic layer, use cold water washing, drying, vacuum-evaporation obtains the 6.0g title compound and is used for embodiment 25, step 1.

Embodiment 26E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenyl amino] and caproic acid step 1 E-2-[3-(2-(7-(chloroquinoline-2-yl) ethyl) phenyl amino methyl] oil of mirbane

According to embodiment 2, step 3 and 4 method, but replace 2-formyl radical phenylium with the 2-nitrobenzaldehyde obtain fusing point and are 150-151 ℃ title compound.Step 2 E-2-[3-(2-(7-(chloroquinoline-2-yl) ethyl) phenyl amino methyl] aniline

Under agitation, (3.85g, 9mmol) and in the mixture of concentrated hydrochloric acid (75ml), add the tin protochloride dihydrate (13.7g, 60mmol), reaction mixture is in stirred overnight at room temperature in batches for the nitro-compound that obtains to step 1.Mixture carefully adds the concentrated sodium hydroxide aqueous solution and makes solution reach strong basicity pH value with the ice dilution.Filtering mixt, residuum washes with water, is dissolved in acetone then.Filter settled solution, dilute with water precipitation title compound.Filter to collect product, use ethyl alcohol recrystallization, obtain fusing point and be 129-131 ℃ title compound.Step 3 E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenyl amino] ethyl hexanoate

(1.6g, 4mmol), (1.8g, 8mmol), the mixture of sodium bicarbonate (1.8g) and hexamethyl phosphoric triamide (30ml) stirred 48 hours at 60 ℃ 2-bromocaproic acid ethyl ester the aniline that step 2 obtains.Add again 2-bromocaproic acid ethyl ester (0.9g, 4mmol), sodium bicarbonate (0.9g), with mixture 60 ℃ of restir 72 hours.The gained mixture is poured into ice/water and used extracted with diethyl ether 3 times.Merge organic extract layer, wash with water, drying, vacuum-evaporation obtains the oily title compound, can be directly used in next step.Step 4 E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenyl amino] caproic acid

According to the method for embodiment 12, but use the ester of step 3 to replace E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] ethyl hexanoate, obtain fusing point and be 169-171 ℃ title compound.

Embodiment 27E-2-[3-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] and caproic acid step 1 E-3-[3-(2-(7-(chloroquinoline-2-yl) ethyl) phenyl amino methyl] phenol

According to embodiment 2, step 3 and 4 method, but replace 2-formyl radical phenylium with the 3-hydroxy benzaldehyde obtain fusing point and are 179-180 ℃ title compound.Step 2 E-2-[3-(3-(2-(7-(chloroquinoline-2-yl) ethyl) phenyl amino methyl] phenoxy group] ethyl hexanoate

According to embodiment 3, the method for step 2, the phenol replacement E-2-[3-that use step 1 position replaces (2-(7-(chloroquinoline-2-yl) ethyl) phenyl amino methyl] phenol, obtain the oily title compound, be directly used in next step.Step 3 E-2-[3-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] caproic acid

According to the method for embodiment 12, but use the ethyl ester of step 2 to replace E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] ethyl hexanoate, obtain fusing point and be 183-185 ℃ title compound.

Embodiment 28E-2-[4-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] and caproic acid step 1 E-4-[3-(2-(7-(chloroquinoline-2-yl) ethyl) phenyl amino methyl] phenol

According to embodiment 2, step 3 and 4 method, but replace 2-formyl radical phenylium with the 4-hydroxy benzaldehyde obtain fusing point and are 194-195 ℃ title compound.Step 2 E-2-[4-(3-(2-(7-(chloroquinoline-2-yl) ethyl) phenyl amino methyl] phenoxy group] ethyl hexanoate

According to embodiment 3, the method for step 2, the phenol replacement E-2-[3-of use step 1 para-orientation (2-(7-(chloroquinoline-2-yl) ethyl) phenyl amino methyl] phenol, obtain the oily title compound, be directly used in next step.Step 3 E-(2-[4-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] caproic acid

According to the method for embodiment 12, but use the ethyl ester of step 2 to replace E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] ethyl hexanoate, obtain fusing point and be 173-175 ℃ title compound.

Embodiment 29E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl)-6-methoxyl group phenoxy group] ethyl hexanoate step 1 E-2-[3-(2-(7-(chloroquinoline-2-yl) ethyl) phenyl amino methyl]-the 6-methoxyphenol

According to embodiment 2, step 3 and 4 method, but replace 2-formyl radical phenylium with 2-hydroxyl-3-methoxybenzaldehyde obtain fusing point and are 139-140.5 ℃ title compound.Step 2 E-2-[2-(3-(2-(7-(chloroquinoline-2-yl) ethyl) phenyl amino methyl]-6-methoxyl group phenoxy group] ethyl hexanoate

According to embodiment 3, the method for step 2, the phenol replacement E-2-[3-of use step 1 (2-(7-(chloroquinoline-2-yl) ethyl) phenyl amino methyl] phenol, obtaining the title compound fusing point is 101-102.5 ℃.

Embodiment 30E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl)-6-methoxy phenoxy] caproic acid

According to the method for embodiment 12, but use embodiment 26, the ethyl ester of step 2 replaces E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] ethyl hexanoate, obtain fusing point and be 173-174 ℃ title compound.

Embodiment 31E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl] phenylformic acid step 1 E-3-[2-(7-(chloroquinoline-2-yl) ethyl]-N-(2-carboxyl benzylidene) aniline

To embodiment 2, (2.8g 10mmol) in the solution of methyl alcohol (50.0ml), adds the solution of 2-carboxyl benzaldehyde in methyl alcohol (15.0ml) to the aniline of step 2.Form precipitation immediately,, filter, wash with ether stirring at room 2 hours.

Obtain fusing point and be 226-228 ℃ title compound.This compound is directly used in next step.Step 2 E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl] phenylformic acid

(0.82g 2mmol) in the solution of ethanol (10.0ml), adds sodium borohydride (0.2g) to the Schiff alkali that obtains to step 1.

Stir after 1 hour, filter collecting precipitation and wash with ether.Reaction product water (30.0ml) is handled, and with 3N acetate (1.5ml) acidifying.

Filter and collect the gained precipitation, wash with water, obtaining the title compound fusing point is 223-226 ℃.

Embodiment 32E-4-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl] phenylformic acid step 1 E-3-[2-(7-(chloroquinoline-2-yl) ethyl]-N-(4-carboxyl benzylidene) aniline

According to embodiment 31, the method for step 1, but use the 4-carboxyl benzaldehyde to replace the 2-carboxyl benzaldehyde, obtain the title compound fusing point greater than 250 ℃.Analyze: C ₂₅H ₁₇ClN ₂O ₂Calculated value: %C72.72; H4.15; %N6.79; %Cl8.59;

Analytical value: %C72.40; %H4.26; %N6.79; %Cl8.70.Step 2 E-4-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl] phenylformic acid

According to embodiment 31, the method of step 2, but with 3-[2-(7-(chloroquinoline-2-yl) ethyl]-N-(4-carboxyl benzylidene) aniline replace E-3-[2-(7-(chloroquinoline-2-yl) ethyl]-N-(2-carboxyl benzylidene) aniline, obtain fusing point and be 248-250 ℃ title compound.

Embodiment 33E-2-[3-(2-(quinoline-2-yl) ethyl) phenyl amino methyl] the phenylacetic acid ethyl ester

With 2-2-bromomethylphenyl ethyl acetate (6.0g, 23mmol), 3-[2-(quinoline-2-yl) ethyl] aniline is (referring to embodiment 1, step 1) (5.0g, 20mmol), saleratus (10.0g, 100mmol) and the mixture of dimethyl sulfoxide (DMSO) (100ml) in stirring at room 3 hours.Reaction mixture is poured in the water, precipitation separation, and with chromatogram (SiO ₂) purifying, obtain fusing point and be 108-109 ℃ title compound.

Embodiment 34E-2-[3-(2-(quinoline-2-yl) ethyl) phenyl amino methyl] phenylacetic acid

In room temperature, slowly with E-2-[3-(2-(quinoline-2-yl) ethyl) phenyl amino methyl] (2.7g 6.3mmol) is added in the 2N sodium hydroxide (25ml) in the solution in ethanol (25ml) the phenylacetic acid ethyl ester.Mixture was obtained settled solution in 5 minutes in 50 ℃ of stirrings, and water (100ml) dilutes then, and precipitates title compound with excessive a little acetate.Through chromatogram (SiO ₂) purifying, obtain fusing point and be 165-166.5 ℃ title compound.

Embodiment 35E-2-[3-(2-(7-chloroquinoline-2-yl) base) phenyl amino methyl] the phenylacetic acid ethyl ester

According to the method for embodiment 33, but with E-3-[2-(7-chloroquinoline-2-yl) ethyl] aniline (referring to embodiment 2, step 2) replaces E-3-[2-(quinoline-2-yl) ethyl] aniline, obtaining the title compound fusing point is 94.5-96 ℃.

Embodiment 36E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl] phenylacetic acid

Method according to embodiment 34, but with E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl] phenylacetic acid ethyl ester replacement E-2-[3-(2-(quinoline-2-yl) ethyl) phenyl amino methyl] the phenylacetic acid ethyl ester, obtaining the title compound fusing point is 174-176 ℃.

Embodiment 37E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenyl] ethyl propionate

According to the method for embodiment 33, but replace 2-2-bromomethylphenyl ethyl acetate with 2-2-bromomethylphenyl-ethyl 3--propanoate, obtaining title compound is two hydrochloric acid dihydrates, and fusing point is 173 ℃ of dec..

Embodiment 38E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenyl] propionic acid

Method according to embodiment 34, but with E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl] aminomethyl phenyl) ethyl propionate replacement E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl] the phenylacetic acid ethyl ester, obtaining the title compound fusing point is 179-181 ℃.

Embodiment 39E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] Sodium n-caproate

With E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] caproic acid (2.5g, 5mmol, the preparation referring to embodiment 12) be dissolved in the mixture of 1N aqueous sodium hydroxide solution (5.5ml, 10% is excessive) and water.Filter settled solution, use the 0.75mol water crystallization, the precipitation title compound, fusing point is 120 ℃.

Embodiment 40E-2-[3-(2-(6,7-two-fluorine quinoline-2-yl) ethyl) phenyl amino methyl] phenylium step 1 E-3-[2-(6,7-difluoro-quinoline-2-yl) ethyl] oil of mirbane

According to embodiment 2, the method for step 1, but use 6, and 7-difluoro quinaldine red replaces 7-chlorine quinaldine red, and obtaining the title compound fusing point is 175-176 ℃.Step 2 E-3-[2-(6,7-difluoro-quinoline-2-yl) ethyl] aniline

According to embodiment 2, the method for step 2 makes the oil of mirbane and the SnCl of the replacement that step 1 obtains ₂Reaction, obtaining the title compound fusing point is 169-171 ℃.Step 3 E-2-[3-(2-(6,7-difluoro-quinoline-2-yl) ethyl) phenyl amino methyl] phenylium

According to embodiment 2, step 3 and 4 method, but use E-3-[2-(6,7-difluoro-quinoline-2-yl) ethyl] aniline replaces E-3-[2-(7-chloroquinoline-2-yl) ethyl] aniline, obtaining the title compound fusing point is 157-159 ℃.

Embodiment 41E-2-[3-(2-(7-fluorine quinoline-2-yl) ethyl) phenyl amino methyl] phenylium

According to embodiment 2, step 3 and 4 method, but use E-3-[2-(7-fluorine quinoline-2-yl) ethyl] aniline replaces E-3-[2-(7-chloroquinoline-2-yl) ethyl] aniline, obtaining the title compound fusing point is 199-201 ℃.

Embodiment 42E-2-[2-(3-(2-(7-fluorine quinoline-2-yl) ethyl) phenyl amino methyl] phenoxy group ethyl hexanoate step 1 E-2-[3-(2-(7-fluorine quinoline-2-yl) ethyl) phenyl amino methyl] phenol

According to embodiment 3, the method for step 1, but use E-2-[3-(2-(7-fluorine quinoline-2-yl) ethyl] and aniline replacement E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl] aniline, obtaining the title compound fusing point is 174.5-175.0 ℃.Step 2 E-2-[2-(3-(2-(7-fluorine quinoline-2-yl) ethyl) phenyl amino methyl] the phenoxy group ethyl hexanoate

With 2-bromocaproic acid ethyl ester (0.63ml, 3.5mmol), phenol (obtaining) from step 1 (0.93g, 2.5mmol), saleratus (0.75g) and N, the mixture of dinethylformamide (25ml) was stirring at room 3 hours.Reaction mixture is poured in water (25ml) and the 4N hydrochloric acid (3ml).Filtering-depositing, and water and ether washing.

Obtain the hydrochloride of title compound, fusing point is 174.5-175 ℃.

Embodiment 43E-2-[2-(3-(2-(7-fluorine quinoline-2-yl) ethyl) phenyl amino methyl] the phenoxy group caproic acid

According to the method for embodiment 12, but use the ester of embodiment 42 to replace embodiment 3, the ester of step 2, obtaining the title compound fusing point is 181-183 ℃.

Embodiment 44E-2-[2-(3-(2-(6,7-two-fluorine quinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] caproic acid, sodium salt step 1 E-2-[3-(2-(6,7-difluoro-quinoline-2-yl) ethyl) phenyl amino methyl] phenol

According to embodiment 3, the method for step 1, but use E-2-[3-(2-(6,7-difluoro-quinoline-2-yl) ethyl] and aniline replacement E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl] aniline, obtaining the title compound fusing point is 158-160 ℃.Step 2 E-2-[2-(3-(2-(6,7-difluoro-quinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] ethyl hexanoate

According to embodiment 42, the method for step 2, the phenol that step 1 is obtained replaces embodiment 42, the phenol that step 1 obtains, the hydrochloride fusing point that obtains title compound is 182-184 ℃.Step 3 E-2-[2-(3-(2-(6,7-difluoro-quinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] caproic acid, sodium salt

(0.85g's ester that step 2 is obtained 1.5mmol) refluxed 3.5 hours in the solution of ethanol (20ml) and 2N sodium hydroxide (2ml).Vacuum is steamed and is removed ethanol, filtering-depositing, water and ether washing.The sodium salt fusing point that obtains title compound is 238-240 ℃.

Embodiment 45-49

According to embodiment 3, the method for step 1, but replace salicylic aldehyde with suitable aldehyde, obtain the compound of Table V. Table V

Embodiment No.	????X 3	Fusing point ℃	Note
				??????45	????6-F	???183-185
??????46	????4-Br	???202-204
				??????47	???4-COOH	???138-dec.
??????48	????4-NO 2	???193-195
				??????49	????4-CH 3	???176-177

Embodiment 50-58

According to embodiment 3, the method for step 2, but replace wherein phenol, or according to the method for embodiment 12 with phenol suitable in the Table V, but use suitable ester to replace wherein ester, obtain the compound of Table VI.

Table VI

Embodiment No.	????X 3	????R 2	Fusing point ℃	Note
					?????50	????6-F	???C 2H 5	????203-205	Hydrochloride
?????51	????4-Br	???C 2H 5	????98-100.5
					?????52	???4-NO 2	???C 2H 5	Oil

???53	???6-F	??H	???183-185
					???54	???4-Br	??H	???197-198
???55	??4-NO 2	??H	???221-223
					???56	??4-CH 3	??H	???168-170
???57	??4-COOH	??H	????173- ??175(dec.)
					???58	??4-NH 2	??H	????162- ??164(dec.)

Embodiment 59E-2-[3-(2-(7-fluorine quinoline-2-yl) ethyl) phenyl amino methyl] phenylium step 1 E-3-[2-(7-chloroquinoline-2-yl) ethyl]-N-(2-carboxyl ar-methoxy-benzylidene) aniline

According to embodiment 2, the method for step 3, but use E-3-[2-(7-fluorine quinoline-2-yl) ethyl] aniline replacement E-3-[2-(7-chloroquinoline-2-yl) ethyl] aniline, obtaining the title compound fusing point is 208-210 ℃.Step 2 E-2-[3-(2-(7-fluorine quinoline-2-yl) ethyl) phenyl amino methyl] phenylium

According to embodiment 2, the method for step 4, but the Schiff alkali that uses step 1 to obtain replaces embodiment 2, the Schiff alkali that step 3 obtains, and behind recrystallization from n-propyl alcohol, obtaining the title compound fusing point is 199-201 ℃.

Embodiment 60E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] caproic acid pivalyl oxygen methyl ester hydrochloride

With E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl)-phenyl amino] caproic acid (0.5g, 1mmol), salt of wormwood (0.3g, 2.2mmol) and Chloro methyl pivalate (0.18ml, mixture 1.2mmol) in dimethyl formamide (10.0ml) stirring at room 3 hours.

Mixture is filtered, and gained solution is in vacuum-evaporation, and residuum is developed with 4N hydrochloric acid (5.0ml).

Filter and collect the gained precipitation, wash with water, obtaining the title compound fusing point is 153-155 ℃.

Embodiment 61E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] caproic acid [(N, N-dimethylamino) carbonyl] methyl ester hydrochloride

The acid that embodiment 11 is obtained (0.5ml, 1mmol), triethylamine (0.20ml, 1.5mmol) and sodium iodide (0.015g, 0.1mmol) at N, the mixture in the dinethylformamide (10ml) adds 2-chloro-N, the N-N,N-DIMETHYLACETAMIDE (0.15ml, 1.5mmol).With this mixture stirring at room 24 hours.Filtering mixt, the evaporation of gained solution for vacuum.Collecting precipitation is filtered in the development of residuum water, washes with water.

The gained solid is dissolved in ethyl acetate and filters.Filtrate concentrates with silica gel column chromatography (ethyl acetate: hexane, 7: 3), obtains brown oil.

Gained oil HCI/Et ₂The O development.

Obtain the hydrochloride of title compound, fusing point is 99 ℃ of dec.

Embodiment 62E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] caproic acid [(N, N-diethylamino) carbonyl] methyl ester hydrochloride

According to the method for embodiment 61, but use 2-chloro-N, the N-diethyl acetamide replaces 2-chloro-N,N-dimethylacetamide, and obtaining the title compound fusing point is 120-122 ℃.

Embodiment 63E-2-[3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] caproic acid [(N, N-diallyl amino) carbonyl] methyl esters

According to the method for embodiment 61, but use 2-chloro-N, N-diallyl ethanamide replaces 2-chloro-N,N-dimethylacetamide, and obtaining the title compound fusing point is 103-105 ℃.

Embodiment 64 (S) (+)-E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] caproic acid step 1 (+)-E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] ethyl hexanoate

With E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] and capronate (5.3g, 10.0mmol) and Lipozyme ^R(motionless Mucor miehei lipase) (530mg, 6.1Baun/g) (100ml, pH8) mixture in was stirring at room 120 hours at uncle's butyl ether (100ml) and phosphate buffered saline buffer.Filter by Decalit, obtain two-phase also separately with the ethyl acetate washing then.Organic phase drying (MgSO ₄) and evaporation.Product with ethanol (96%) crystallization, obtains the 2.5g title compound with silica gel chromatography purifying (ethylacetate/ether), can be directly used in next step.

Fusing point: 99-100 ℃

[α] _D ²⁰=30.3 ° of (c=1.04, acetone) steps 2 (S) (+)-E-ethyl-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] caproic acid

To (+)-E-2-[2-(3-(2-(7-quinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] ethyl hexanoate (10.6g, 20mmol) (obtain) being dissolved in the solution of methyl alcohol (300ml) and tetrahydrofuran (THF) (150ml) and add LiOH mono-hydrate (4.3g from step 1,102.5mmol) solution in water (45ml), this mixture was stirred 4 hours.Then, with the evaporation of this mixture, in water-soluble again/methyl alcohol 3: 1, use acetate (50%aq) to be acidified to pH=3-4 then.Filtering-depositing, drying with ethanol (dehydrated alcohol) recrystallization, obtains crude product (10.3g) reduction 0.9eq ethanol, and fusing point is 142/150 ℃ (decomposition).[α] _D ²⁰＝23.4(c＝0.99，DMSO)。

Obtain pure products with the acetonitrile recrystallization again, fusing point is 187-188 ℃, [α] _D ²⁰=24.5 ° (c=1.12, DMSO).

Embodiment 65E-5-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] amyl group-1H-tetrazolium step 1 E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] the amyl group hydroxamic acid

To E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] capronate (2.6g, 5.3mmol) (from embodiment 3, step 2 obtains) in the solution of methyl alcohol (50ml), slowly add hydroxylamine hydrochloride (1.4g, 20.15mmol) and KOH (5ml, 5M is in methyl alcohol).After the stirring at room 72 hours, adding acetate (50% aqueous solution) is 3-4 up to the pH value.Filtering-depositing and at air drying obtains the 2.1g title compound, can be directly used in next step.Step 2 E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] the amyl group nitrile

To the product of step 1 (2.1g, 4.1mmol) add in the solution in benzene (50ml) phosphorus tribromide (phosphortribromide) (0.8ml, 8.5mmol).Reflux and after 5 hours mixture is cooled off, pour into then in the frozen water, use NaHCO then ₃Alkalization.Use ethyl acetate extraction, drying, the silica gel chromatography purifying is used in evaporation, obtains the 1.6g title compound, can be directly used in next step.Step 3 E-5-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] amyl group-1H-tetrazolium

To E-2-[2-(3-(2-(7-chloroquinoline-2-yl) ethyl) phenyl amino methyl) phenoxy group] (1.6g 3.3mmol) (obtains from step 2) adding NaN in the solution among DMF (40ml) the amyl group nitrile ₃(1.65g, 25.4mmol) and NH ₄Cl (1.4g, 26.4mmol).Mixture was 115-120 ℃ of heating 5 hours, and frozen water is poured in cooling into then.With filtration of crude product,, obtain the 600mg title compound with ethanol (dehydrated alcohol) crystallization.Fusing point: 210-212 ℃ (decomposition).

Embodiment 66 aerosols (S) (+)-E-2-[2-(3-(2-(7-chloroquinoline-2-yl)-ethyl) phenyl amino methyl) phenoxy group] the single fluoro trichloromethane 595g of caproic acid (active substance) 1000mg sorbitan olein (Sorbitan trioleate) 700mg methyl chlorofluoride 798g

Active substance is micronization in jet mill.Most of particulate diameter should be less than 5 μ m.

Be dissolved in the sorbitan olein in a spot of single fluoro trichloromethane and heat the enriched material that active substance prepares medicine.And with the careful homogenizing of enriched material.Enriched material is transferred in the sealed vessel with refrigeration system.Remaining ingredient under agitation is cooled to-50 ℃ of addings.

The container that suitable aerosol is used is suitable with having immediately behind the pharmaceutical composition of calculated amount of packing into.The metering valve sealing of driving mechanism.The active substance of each ejection 50 μ g.

Embodiment 67 tablets, (S), (+)-E-2-[2-, (3-, (2-, (7-chloroquinoline-2-yl)-ethyl) phenoxy group phenyl amino methyl)] caproic acid, (active substance) 100mg lactose 75mg starch 12mg methylcellulose gum 2mg Xylo-Mucine, (CMC-Na) 10mg Magnesium Stearate 1mg

With active substance, lactose and starch mix in suitable mixing tank, and get wet with 5% methylated cellulose aqueous solution 15cps.Continue to mix and form up to small-particle.If desired, make wet granular pass through suitable filter screen, and in suitable moisture eliminator, be dried to water content and be less than 1%, for example fluidized-bed or drying oven.Dried particles is mixed by the filter screen of 1mm and with CMC-Na.Add Magnesium Stearate, mixing continues for some time.

Use suitable flaker to make the heavy tablet of 200mg from particle.

The pharmaceutical composition that embodiment 68 is used to inject (S) (+)-E-2-[2-(3-(2-(7-chloroquinoline-2-yl)-ethyl) phenyl amino methyl) phenoxy group] caproic acid (active substance) 1% sodium-chlor q.s. water for injection add-on reaches 100%

With active substance soluble in water be used for the injection.Use sodium-chlor solution to be made isoosmotic.With solution pack into ampoule and the sterilization.

1?R.A.Lewis，K.F.Austen?and?R.J.Soberman，New?Eng.J.Med.323(1990)

645.

2?R.G.Kallen?and?W.P.Jencks，J.Biol.Chem.241(1966)5864.

3?C.J.Martin?and?M.A.Marini，J.Biol.Chem.242(1967)5736.

4?M.Levy?and?D.E.Silberman，J.Biol.Chem.118(1937)723.

5?S.Lewin?and?D.A.Humphany，J.Chem.Soc.B(1966)210.

6?B.C.Jain，B.H.lyer，and?P.C.Guha，Science?and?Culture?11(1946)568.

7?S.A.Varia，S.Schuller，K.B.Sloan?and?V.J.Stella，J.Pharm.Sci.，73

(1985)1068?and?following?papers.

8?E.J.Goetzl，D.G.Payan?and?D.W.Godman，J.Clin.Immunol.4(1984)

79

9?I.?Ahnfelt-Ronne，D.Kirstein?and?C.Kaergaard-Nielsen，European?J.

Pharmacol.155(1988)117.

10?S.?Mong，H.-L.Wu，M.O.Scott，M.A.Lewis，M.A.Clarke，B.M.Weichman，

C.M.Kinzig，J.G.Gleason?and?S.T.Crooke，J.Pharmacol.Exp.Ther.234

(1985)316.

11?International?Appl.No.PCT/DK88/00188(Publ.No.WO89/05294)，Ex.9.

12?EP?0206?751?A?Merck?Frosst?Canada?Inc.

13?C.R.Edwards，M.J.Readhead?and?N.J.Tweedle，J.Heterocyclic?Chem.24

(1987)495.

14?J.Bernstein，H.L.Yale，K.Losee，M.Holsing，J.Martins?and?W.A.Lott，J.

Am.Chem.Soc.73(1951)906.

15?L.A.Flippin，J.M.Muchowski?and?D.S.Carter，J.Org.Chem.58(1993)

2463.

16?EP?572?712?A?Sumitomo?Seika?Chem.Co.Ltd.

17?Y.Ogata，T.Sugimoto?and?M.Inaishi，in：Organic?Synthesis，coll.vol.VI

(1988)，ed.W.E.Noland(John?Wiley，New?York)p.90.

18?D.N.Harpp，L.Q.Bao，in：Organic?Syntheses?col.vol?VIII(1993)，ed.J.P.

Freemann(John?Wiley，New?York)p.190.

19?B.Koppenhoefer?and?V.Schurig，in?ibid，p.119.

Claims (10)

1, hydrolyzable ester in the compound of general formula I, its pharmacy acceptable salt and body: Wherein, X ₁And X ₂Represent hydrogen atom or halogen independently of one another; X ₃And X ₄Those skins are represented independently, hydrogen atom, halogen atom, nitro, cyano group, trifluoromethyl, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, carboxyl or C ₁-C ₄Carbalkoxy; Z is a key, O, S, S (O), S (O) ₂, NH, or CH ₂R ₁Be hydrogen or straight or branched, saturated or unsaturated C ₁-C ₆Hydrocarbon chain; R ₃Be hydrogen, straight or branched, saturated or unsaturated C ₁-C ₁₂Hydrocarbon chain, phenyl that does not replace or replace or the benzyl that does not replace or replace, above-mentioned substituting group are one or several definition X as above ₃And X ₄Or radicals R ₁-[C] _p-R ₃Represent cyclopropyl; When Z represented key, p can be 0, or works as R ₁=R ₃During=hydrogen atom, p can be the integer of 1-6; A is COOR ₂Or 1H-tetrazolium, wherein R ₂=R ₁Define as above, or R ₂It is pharmaceutically acceptable positively charged ion.

2, the compound of claim 1, wherein X ₁And X ₂Represent hydrogen independently of one another, fluorine or chlorine; X ₃Represent hydrogen; X ₄Represent hydrogen, fluorine, chlorine or bromine; Z is at adjacent O or S; P is 1; R ₁Be hydrogen, R ₃Be hydrogen or straight or branched, saturated or unsaturated C ₁-C ₆Hydrocarbon chain, or phenyl; And A is COOR ₂, R wherein ₂Be hydrogen, C ₁-C ₃Alkyl, alkali metal cation, or tetrazolium-5-base.

3, the salt of claim 1 is selected from and spirit of salt, Hydrogen bromide and hydroiodic acid HI, and phosphoric acid, sulfuric acid, nitric acid, tosic acid, methylsulfonic acid, formic acid, acetate, propionic acid, citric acid, tartrate, the salt that becomes with toxilic acid, and lithium, sodium, potassium, magnesium, calcium salt equally also can be an ammonia, C ₁-C ₆Alkylamine, C ₁-C ₆Alkanolamine, PROCAINE HCL, PHARMA GRADE, cycloalkanes amine, benzyl amine, and heterocyclic amine salts.

4, the compound of claim 1 is selected from: E-2-[2-(3-(2-(7-chloroquinoline-2-yl)-ethyl) phenyl amino methyl) phenoxy group]-2 Methylpropionic acid; E-2-[2-(3-(2-(7-chloroquinoline-2-yl)-ethyl) phenyl amino methyl) phenoxy group]-2 methyl valeric acid; E-2-[2-(3-(2-(7-chloroquinoline-2-yl)-ethyl) phenyl amino methyl) phenoxy group] caproic acid; E-2-[2-(3-(2-(7-chloroquinoline-2-yl)-ethyl) phenyl amino methyl)-4-bromine phenoxy group] caproic acid; E-2-[2-(3-(2-(7-fluorine quinoline-2-yl)-ethyl) phenyl amino methyl] the phenoxy group caproic acid; E-2-[2-(3-(2-(6,7-difluoro-quinoline-2-yl)-ethyl) phenyl amino methyl) phenoxy group] caproic acid, sodium salt; And salt and pure enantiomeric form.

5, the compound of claim 1 is (S) (+)-E-2-[2-(3-(2-(7-chloroquinoline-2-yl)-ethyl) phenyl amino methyl) phenoxy group] caproic acid.

6, pharmaceutical composition contains arbitrary or several compound of claim 1-5 and required auxiliary agent.

7, a kind of method for the treatment of patient disease is characterized in that taking any one or a few compound of the claim 1-5 of effective dose to the patient, if desired, can take with one or more other therapeutic activity components.

8, the method for claim 7 is used for the treatment of and the disease of preventing comprises: asthma, allergy, rheumatoid arthritis, arthritis vertebralis, gout, atherosclerosis, hyperplasia or inflammatory skin are unusual, chronic inflammation intestinal disease and other inflammation situation, stenocardia is followed in vasospasm, pulmonary hypertension, cystic fibrosis, adult's respiratory distress syndrome, local asphyxia and reperfusion damage, migraine.

9, the method for compound of preparation claim 1 wherein a) is used the amine of general formula I I,

Wherein, X ₁And X ₂Define as above, with the compound reaction of general formula III,

R wherein ₁, R ₃, X ₃, X ₄, A, Z and p define as above, and Y can form " easily leavings group "; Or b) with the reaction of the carbonyl compound of general formula I V the amine of general formula I I is converted into compound of Formula I,

Wherein, R ₁, R ₃, X ₃, X ₄, A, Z and p definition are as above, then in the presence of appropriate catalyst hydrogenation or with alkali metal borohydride reaction reduction, if words easily, can with the carbonyl compound reaction after carry out hydrogenation or reduction continuously, like this, need not isolate intermediate, so-called Schiff alkali; Or c) make the compound of general formula V,

Wherein, X ₁, X ₂, X ₃, and X ₄Definition as above, and Z is O, S or NH, with the compound reaction of general formula VI,

R wherein ₁, R ₃, A, p and Y definition as above form required compound of Formula I.

10, the compound of claim 1 is used to prepare treatment and prevents the medicine of following a series of diseases: asthma, allergy, rheumatoid arthritis, arthritis vertebralis, gout, atherosclerosis, hyperplasia or inflammatory skin are unusual, chronic inflammation intestinal disease and other inflammation situation, stenocardia is followed in vasospasm, pulmonary hypertension, cystic fibrosis, adult's respiratory distress syndrome, local asphyxia and reperfusion damage, migraine.