CN1240431A - Process for preparation of N-[2-(dimethylamino) ethyl] acridine-4-carboxamide - Google Patents

Abstract

A process for producing an acridine carboxamide of formula (I) wherein each of R<1>, R<2>, R<5> and R<6>, which may be the same or different, is hydrogen or an organic substituent, x is an integer of 1 to 6 and Y is N(R)2 wherein R is C1-C6 alkyl, or a pharmaceutically acceptable salt thereof, which process comprises: (a) cyclising a compound of formula (II) wherein R<1>, R<2>, R<5> and R<6> are as defined above and R<3> is C1-C6 alkyl, aryl or aryl-C1-C3 alkyl, by treatment with a Lewis acid in an organic solvent, to obtain a compound of formula (III) wherein R<1>, R<2>, R<3>, R<5> and R<6> are as defined above; (b) treating either (i) the compound of formula (III) as defined above with a primary alkylamine of the formula (IV): NH2(CH2)xY, wherein x and Y are as defined above; or (ii) the carboxylic acid, obtainable by hydrolysing the compound of formula (III) as defined above under basic conditions, with a primary alkyl amine of formula the (IV) as defined above in the presence of a suitable coupling agent to obtain a compound of formula (I) as defined above; and (c) if desired, converting one compound of formula (I) into another compound of formula (I), and/or converting a compound of formula (I) into a pharmaceutically acceptable salt thereof. The aldehyde of formula (II) is obtained by oxidation of the corresponding alcohol, which in turn is produced by mild reduction of the corresponding carboxylic acid via an immidazolide intermediate.

Description

N-[2-(dimethylamino) ethyl] the preparation method preparation method of acridine-4-methane amide

The present invention relates to cancer therapy drug N-[2-(dimethylamino) ethyl] acridine-4-methane amide and its derivative new method of producing.

Acridine derivatives N-[(2-dimethylamino) ethyl] acridine-4-methane amide, be called DACA, be a kind of new DNA-intercalator (Schneider etc. with topoisomerase I and topoisomerase II inhibiting activities, Eur.J.Cancer Clin.Oncol, 1988,24 1783 and Finlay etc., Eur.J.Cancer 1996, and 32A 708).It has the activity of wide spectrum at the noumenal tumour in the animal, and is influence (Atwell etc., the J.Med Chem that relatively is not subjected to the multiple disease resistance of P-glycoprotein-mediation, 1987,30,664, Baguley etc., CancerChemother.Pharmacol 1995,36,244 and Finlay etc., CancerChemother.Pharmacol.1993,31,401).The analogue of some DACA is in the news, and in the mouse entity knurl many tangible activity (Atwell etc., ibid) that demonstrated.

The method of known production DACA, by reports such as Atwell, ibid, is displayed in the scheme 1.

Scheme 1 step (i) comprises the reduction of dihydroketoacridine (1), under when KOH exists, in aqueous ethanol, refluxing, handle with aluminium/mercury alloys, subsequently by generated 9,10-acridan product and FeCl ₃Reoxidation, provide intermediate azetidinecarboxylic acid (2).Step comprises (ii) with described acid (2) that with 1 1-carbonyl dimidazoles (CDI) and dimethyl formamide are handled, and use N subsequently, and the N-dimethyl-ethylenediamine is handled.

This method has a plurality of disadvantages.The one, the reductive condition harshness that in step (i), needs.This has limited the scope of described method, and makes it be not suitable for the production of the analogue of some substituent DACA that has reduction-sensitivity on described acridine ring.For example, when being used for the production of the derivative that the chloro-of DACA replaces, described method just observes the dechlorination effect.Another disadvantage of this currently known methods is that described intermediate azetidinecarboxylic acid (2) has the intensive tear-gas and urges the character of sneezing, and it has limited their use.

Found now that DACA and its derivative can be produced by the process that comprises cyclisation aldehyde precursor, this aldehyde precursor comprises esterification, rather than free, the carboxylic-acid functional group, and group that then will esterification in by the product of cyclisation is directly handled with primary alkyl amine.If necessary, the group of described esterification in by the product of cyclisation can at first be hydrolyzed and generate free carboxylic-acid functional group, and it is handled with described primary alkyl amine under the situation that suitable coupler exists then.Described aldehyde precursor is easily produced by the oxidation of corresponding alcohol, and it is produced through the imidazolide intermediate by the slight reduction reaction of corresponding carboxylic acid successively.

Therefore, the invention provides the method for the acridine methane amide of a preparation formula (I):

R wherein ¹, R ², R ⁵And R ⁶Each can be identical or different, be H, C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, aryloxy, aralkoxy, halogen, phenyl, CF ₃, NO ₂, NH ₂, N (R) ₂, NHCOR, NHCOOR, NHR ⁴, OH, SH, SR or S (R) ₂, R wherein ⁴Be H, COR, SO ₂R, COPh, SO ₂Ph or by OH or amino replace or unsubstituted C ₁-C ₆Alkyl and R are C ₁-C ₆Alkyl; Or R ¹And R ²Or R ⁵And R ⁶Form methylenedioxy group together; X is that 1 to 6 integer and Y are as the above-mentioned N that limits (R) ₂Or its pharmacy acceptable salt; This method comprises:

A. the compound of cyclisation formula (II)

R wherein ¹, R ², R ⁵And R ⁶Be as above-mentioned limit and R ³Be C ₁-C ₆Alkyl, aryl or aryl-C ₁-C ₃-alkyl, by in organic solvent, handling the compound of acquisition formula (III) with Lewis acid:

R wherein ¹, R ², R ³, R ⁵And R ⁶Be to limit as above-mentioned; With

(b) or (i) will as above-mentioned limit as described in formula (III) compound handle with the primary alkyl amine of formula (IV)

NH ₂(CH ₂) _XY(IV)

Wherein X and Y limit as above-mentioned, perhaps

The (ii) carboxylic acid that will obtain at hydrolysis under the alkaline condition such as the above-mentioned formula that limits (III) compound, when suitable coupler exists, with as the primary alkyl amine of the above-mentioned formula that limits (IV) handle, obtain as the compound of the above-mentioned formula that limits (I); And

(c) if necessary, a kind of compound of formula (I) can be converted into the another kind of compound of formula (I), and/or the compound of formula (I) is converted into its pharmacy acceptable salt.

In the embodiment preferred of this method, the R in the formula (II) ¹, R ², R ⁵And R ⁶Be H and the X in formula (IV) be 2 and Y be NMe ₂The formula that is generated (I) compound is the N-[(2-dimethylamino) ethyl] acridine-4-methane amide (DACA).

Any suitable Lewis acid all can be used in the step (a).An example is a trifluoroacetic acid, and it is to use under room temperature, nitrogen.Selectable step (a) can be used boron trifluoride by in suitable solvent, or with its suitable mixture, the compound of processing formula (II) carries out.Suitable mixture comprises described acetate mixture.In one embodiment, use the BF of 1 slight excessive mole ₃(stoichiometric quantity), for example 2 molar equivalents (molarequivalents).Described BF ₃Usually with its etherate BF ₃O (Et) ₂Form use.With BF ₃O (Et) ₂The suitable solvent of Shi Yonging comprises EtOAc and CH together ₂Cl ₂Then, in either case, obtain described formula (III) compound with the Tetrafluoroboric acid salt form of its formula (IIIa):

R wherein ¹, R ², R ³, R ⁵And R ⁶As above-mentioned qualification.

When using BF ₃The time, the generation of described a tetrafluoro borate (IIIa) can be expressed as follows:

The a tetrafluoro borate of described formula (IIIa) is settled out from reaction mixture and can be easily shifted out by filtering.With mineral alkali, for example yellow soda ash and solvent such as ethyl acetate or methylene dichloride join in the solid that leaches, and produce the compound of described formula (III).Then it is further used the amine of formula (IV) to handle.The benefit of this method is that a tetrafluoro borate is to produce with quantitative yield almost, and can easily make it carry out next step reaction and do not need the reagent or the by product of excessive separation.This just makes method of the present invention be easy to operate under technical scale, particularly because can increase output.

In some cases, before the amine processing with described formula (IV) in step (b), may need the compound of the described formula of hydrolysis (III) to become corresponding acid.This can be, for example, if the compound of described formula (III) itself is unsettled situation to oxidation.Hydrolysis is to carry out under weak basic condition, for example, handles with alkali metal hydroxide (as NaOH or KOH) in such as alcoholic acid solution.Any suitable coupler all can be used in the reaction of acid described in the step (b) and the amine of formula (IV), and for example 1,1 '-carbonyl dimidazoles.

The compound of described formula (II) is produced by the alcohol of the correspondence of the described formula V of oxidation:

R wherein ¹, R ², R ³, R ⁵And R ⁶Be to limit as above-mentioned.

Oxygenizement is to carry out under any suitable oxidizing condition.Manganese oxide (IV) (MnO ₂), for example with the solid form in polar solvent such as ethyl acetate or acetone, be preferred oxygenant.For example, MnO ₂The suspended matter that can be used as in acetone adds in the alcohol of formula V, and allows at room temperature to react.Reaction was carried out several days usually, such as 2 or 3 days, to reach complete.Can be randomly, the alcohol of described formula V and MnO ₂Mixture can be in ethyl acetate reflux together, for example spend the night.

The alcohol of described formula V prepares by following process:

(a) with the compound of formula (VI):

R wherein ¹, R ², R ³, R ⁵And R ⁶As above-mentioned qualification, with 1,1 '-carbonyl dimidazoles is handled in polar solvent, the compound of acquisition formula (VII):

R wherein ¹, R ², R ³, R ⁵And R ⁶Such as above-mentioned qualification and

(b) imidazolide of reduction as the above-mentioned formula that limits (VII).

In above-mentioned steps (a), described polar organic solvent can be THF for example.Described reagent at room temperature stirs usually up to reacting completely.In step (b), described reductive action usually by with the compound of formula (VII) with excessive metal matrix reductive agent, for example sodium borohydride is handled and is carried out.In this case, the solution that obtains from step (a) suitably can be joined in the suspended matter of sodium borohydride water of stirring.

The use of intermediate formula (VII) imidazolide, make under gentle condition generating polynomial (VI) carboxylic acid to the reductive action of the alcohol of formula V quite easily.

The compound of formula (VI) is a compound known, perhaps can produce by known method, and for example in polar solvent, when copper catalyst and alkali exist, the anthranilic acid of heating-type (VIII) together: R wherein ¹And R ²As above-mentioned qualification, and the 2-iodobenzoic acid ester of formula (IX) and producing:

R wherein ³, R ⁵And R ⁶Be to limit as above-mentioned.

Described copper catalyst suitably is made up of copper (I) halogenide and copper powder.Polar solvent for example can be, ethylene glycol or butane-2,3-glycol.Any suitable alkali all can be used, for example N-ethylmorpholine.

In the compound of the formula (I) for preparing by method of the present invention, in described trinucleated chromophoric group, described substituent R ¹And R ²Can occupy any one position of ring position 5 to 8, and substituent R ⁵And R ⁶Can occupy any one position of ring position 1 to 4.Therefore, each R ¹And R ²Can with combine to any one position of the described ring position of the intermediate of (VIII) in precursor compound and formula (III) with (V), this ring position is equivalent to the position 5 to 8 of final formula (I) compound.Similarly, R ⁵And R ⁶Can with combine to any one position of the described ring position of the intermediate of (VIII) in precursor compound and formula (III) with (V), this ring position is equivalent to the position 1 to 4 of final formula (I) compound.

In a preferred series of compounds, R ⁵And R ⁶The both is H.This a series of described in compound be the compound of general formula (Ia):

R wherein ¹, R ², X and Y such as above-mentioned to formula (I) qualification.Therefore formula (Ia) is the preferred embodiment of formula (I).Common R ¹And R ²In one be hydrogen, another be hydrogen or as above-mentioned any one locational substituting group that is combined in ring position 5 to 8 that formula (I) is limited.

In the preferred series of formula (I) compound, R ¹And R ²Each, it can be identical or different, all is H, C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, halogen, phenyl, CF ₃, NO ₂, NH ₂, as the above-mentioned N that limits (R) ₂Or OH, X is that 1 to 3 integer and Y are as the above-mentioned N that limits (R) ₂

Usually in formula (I), R ¹Be H and R ²Be H or substituting group, rather than be combined in the H on the position 5,6 or 7 of described acridine ring.For example, R ¹Be H and R ²Be in the position 5 and be C ₁-C ₆Alkyl, CF ₃, phenyl, halogen or group N (R) ₂Or R ¹Be H and R ²Be on position 6 and be halogen, CF ₃Or aforesaid N (R) ₂Or R ¹Be H and R ²Be on position 7 and be C ₁-C ₆Alkyl, phenyl, OH, halogen, CF ₃Or N (R) ₂

Can be randomly, R ¹Not H.For example, work as R ²Be as during the above-mentioned position 5 that limits, R ¹Be in the position 6,7 or 8, preferred 6 or 7, and be C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, halogen, phenyl, CF ₃, NO ₂, NH ₂, as the above-mentioned N that limits (R) ₂Or OH.Work as R ²Be as during the above-mentioned position 6 that limits, R ¹Be in the position 5,7 or 8, preferred 5 or 7, and be C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, halogen, phenyl, CF ₃, NO ₂, NH ₂, N (R) ₂Or OH.Work as R ²Be as during the above-mentioned position 7 that limits, R ¹Be in the position 5,6 or 8, preferred 5 or 6, and be C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, halogen, phenyl, CF ₃, NO ₂, NH ₂, N (R) ₂Or OH.

C ₁-C ₆Alkyl group can be straight chain or side chain, and for example be, C ₁-C ₄Alkyl such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl or the tertiary butyl.C ₁-C ₆Alkoxy base also can be straight chain or side chain, and for example be, C ₁-C ₄Alkoxyl group such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, sec-butoxy or tert.-butoxy.Halogen for example is, fluorine, chlorine, bromine or iodine.Aromatic yl group for example is, C ₆-C ₁₂Aromatic yl group such as phenyl or naphthyl.At aryl-C ₁-C ₃Aryl moiety in alkyl, aralkoxy or the aryloxy group can be C ₆-C ₁₂Aromatic yl group, for example phenyl or naphthyl.Therefore, aryl-C ₁-C ₃The example of alkyl group comprises phenyl-C ₁-C ₃-alkyl group is as benzyl and styroyl.

Described formula (I) compound can be converted into pharmaceutically-acceptable acid addition by ordinary method.For example, described acid salt can be contacted in a usual manner with the required acid of appropriate amount by free alkali and prepare.Suitable salt comprises two kinds of organic acid salt and inorganic acid salts.The example of suitable acid is hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, propanedioic acid, Whitfield's ointment, toxilic acid, fumaric acid, succsinic acid, xitix, methylsulfonic acid and analogue thereof.According to structure and condition, described compound can form the form of polycation.

Optional a kind of formula (I) compound is converted into another kind of formula (I) compound can be undertaken by ordinary method.For example, the fluorine-based group in formula (I) compound can be replaced by amino or thiol group, generates amine or thioether respectively; Thiol group in formula (I) compound can be generated thioether by alkylation; Amino group can be generated the N-Acetyl Groups by acidylate; Can be reduced generation amine with nitryl group.These all are conventional the conversion in organic chemistry.

The amine of described general formula (IV) is compound known, and is commercial available or by the method preparation of describing in the literature.The special example of this compound comprises NH ₂(CH ₂) ₂NMe ₂[X be 2 and Y be N (CH ₃) ₂].

Can be configured to composition medicinal or that the animal doctor uses by described formula (I) compound of described method production of the present invention and their salt.Therefore, as method as described in above-mentioned limit of the present invention may further include with formula (I) compound or its pharmacy acceptable salt with pharmaceutically or veterinarily acceptable carrier or thinner preparation form composition medicinal or that the animal doctor uses.Described composition is prepared so that it is applicable to human or animal patient's administration by the method for following routine usually.

Described composition can for example, be used for orally give such as the form with tablet, capsule, sugar-coat or film coated tablet, liquor or suspension with the preparation of several formulations form, perhaps is used for parenteral and gives, for example intramuscular, intravenously or subcutaneous giving.Therefore, described formula (I) compound can be used for injection or infusion by preparation.

For example, described solid oral dosage form can contain and described active compound thinner together, as lactose, glucose, sucrose, Mierocrystalline cellulose, W-Gum or yam starch; Lubricant such as silicon-dioxide, talcum powder, hard ester acid, magnesium stearate or calcium and/or polyoxyethylene glycol; Tackiness agent such as starch, gum arabic, gelatin, methylcellulose gum, carboxymethyl cellulose or polyvinylpyrrolidone; Disintegrating agent such as starch, alginic acid, alginate or sodium starch glycollate; Effervescent mixture, dyestuff; Sweeting agent; Wetting agent such as Yelkin TTS, Spheron MD 30/70, dodecyl sulfate.This preparation can for example be used the method for mixing, granulating, compressing tablet, sugar coating or film-coat with known method production.

The liquid dispersion of orally give can be syrup, emulsion and suspensoid.Described syrup for example can contain as carrier, sucrose or saccharose with glycerol and/or N.F,USP MANNITOL and/or sorbyl alcohol.Particularly syrup for example can contain as carrier, sucrose or saccharose with glycerol and/or N.F,USP MANNITOL and/or sorbyl alcohol.Only can contain not metabolism especially for diabetic subject's syrup as carrier is glucose or very a small amount of metabolism is only arranged is the product of glucose, for example sorbyl alcohol.Described suspensoid and emulsion can contain as carrier, for example natural gum, agar, sodiun alginate, pectin, methylcellulose gum, carboxymethyl cellulose or polyvinyl alcohol.

The suspensoid or the solution that are used for intramuscularly can contain and active compound pharmaceutically acceptable carrier together, as sterilized water, sweet oil, ethyl oleate, dibasic alcohol such as propylene glycol and if necessary, and the Xylotox of appropriate amount.Common described formula (I) compound is configured to the aqueous solution of hydrochloride or other pharmacy acceptable salt.The solution that is used for intravenous injection or infusion can contain carrier, for example, generally is the sterilized water of water for injection.

The present invention will further set forth in embodiment subsequently:

Embodiment 1:2-[N-(2-carboxyphenyl) amino] preparation of methyl benzoate.

With anthranilic acid (16.48g, 120mmol), 2-iodobenzoic acid methyl esters (39.3g, 150mmol), N-ethylmorpholine (38.1ml; 34.5g, 300mmol), ethylene glycol (120ml), cuprous chloride (3g) and copper powder (99%; 0.6g) mixture in oil bath, stir 6 hours (internal temperature, about 130 ℃) in 140 ℃.Described reaction mixture is cooled and topples over lentamente in the mixture of the ethyl acetate (300ml) that enters stirring and 1M hydrochloric acid (300ml), and thereafter, described reaction mixture is filtered removes insoluble boundary material.Described filter bed washs with ethyl acetate (200ml).

After organic phase was separated from filtrate, the extracting waterbearing stratum was then with ethyl acetate washing lotion (the above-mentioned filter bed of 2 * 100ml) continuous washing.The organic extract that merges stirs and filters with gac (3g).Described filtrate is with about 1.5% ammonia soln (1 * 400ml and 2 * 150ml) extractings.The ammoniated extract of described merging is joined in 1M hydrochloric acid stirring, excessive lentamente, and described product is collected by filtering, and (3 * 100ml) wash and drain (weight in wet base, about 60g) with hot water.After 55 ℃ of vacuum-drying, obtain described title compound (27.8g, 85.4%).(through HPLC purity～90%a/a; Main impurity is the dicarboxylic acid of described correspondence).Fusing point 196-198 ℃. ¹HNMR (CDCl ₃) δ 3.93 (3, s COOMe), 6.92 (2H, m, J=7.5, H-4, H-4 '), 7.26 (s, solvent C HCl ₃), 7.38 (2H, m, H-5, H-5 '), 7.51 (2H, br.t, J=8.9, H-6, H-6 '), 7.98 (1H, dd, J=7.9 and 1.1, H-3 '), 8.09 (1H, J=7.9, H-3), 10.82 (1H, br.s, NH).

Embodiment 2:2-[N-(2-methylol) phenylamino] preparation of methyl benzoate.

With 1, (19.5g 120mmol) joins in tetrahydrofuran (THF) (HPLC level 1 '-carbonyl dimidazoles, described product (the 27.1g that embodiment 1 270ml) produces, 100mmol), and described mixture at room temperature stirred spend the night, obtain the brown solutions of imidazolide intermediate.TLC method (SiO ₂: 10%MeOH/CH ₂Cl ₂Under the ultraviolet ray of 254nm, develop) show that described reaction is completely.

This solution is joined the sodium borohydride of the stirring in water (375ml) with the time that surpasses 30 minutes, and (12.5g is 330mmol) in the suspension.Originally, the yellow jelly precipitation is arranged, when adding end, it has become lark suspension and temperature is 37 ℃.TLC (SiO ₂: EtOAc develops under the ultraviolet ray of 254nm) show that described reductive action is completely.Further stirring described mixture after 30 minutes, excessive sodium borohydride is destroyed by the dense HCl (35ml) that adds, and maintains the temperature at below 30 ℃ with the method for ice bath.The pH of described mixture is approximately 7.Add EtOAc (300ml) and saturated sodium bicarbonate solution (200ml), described mixture stirs in short-term, separates organic phase later on.(volume of the water that abandons is 690ml).Described faint yellow organic solution is separated and vacuum concentration with salt solution (100ml) washing.(3 * 100ml) revaporization obtain the described title compound (27.6g＞100%) of tawny oily matter, and HPLC is determined as about 90%a/a by EtOAc.Slowly crystallization during sample is stored, molten some 69-71 ℃. ¹HNMR(CDCl ₃)δ1.93(br.s，1H，OH)，3.91(s，3H，COOCH ₃)，4.72(s，2H，CH ₂OH)，6.74(ddd，J＝8.0，7.0，1.1Hz，1H，H-5)，7.08-7.44(m，6H，H-3，3’，4，4’，5’，6’)，7.97(dd，J＝8.0，1.6Hz，1H，H-6)，9.59(br.s，1H，NH)。

Embodiment 3:2-[N-(2-formyl radical) phenylamino] preparation of methyl benzoate

Will the product (27.6g, about 100mmol) of the described embodiment 2 among the EtOAc (300ml) and manganese oxide (IV) (＜5 microns, activation～85%MnO ₂) (55g, 2wts) stirring and spend the night (17h) that reflux.TLC (SiO ₂: EtOAc) show complete reaction develop under the ultraviolet ray of 254nm (described aldehyde can be seen and be yellow spotting under daylight).Gac (2.7g) and diatomite (2.7g) are added in the described warm mixture that stirs 30 minutes, and filter by bed of diatomaceous earth.(2 * 100ml) wash this bed with EtOAc.

Described glassy yellow filtrate carefully vacuum concentration is shifted out from vaporizer and water (50ml) washing to the volume of half.When described product begins crystallization and resistates when condensing into the true yellow solid, described organic phase is separated, vacuum concentration to low volume (weight, 47g).Add hexane (200ml) and stir the described xln of pulverizing simultaneously, 1 hour this product of after-filtration with hexane wash and 40 ℃ of vacuum-dryings, obtains described title compound (19.6g, 76.7%).HPLC 94.5%a/a, molten some 110-112 ℃. ¹H NMR (CDCl ₃) δ 3.95 (s, 3H, COOCH ₃), 6.95-7.03 (m, 2H, H-4 ', 5), 7.41-7.45 (m, 2H, H-5 ' 6), 7.50 (br d, J=8.5Hz, 1H, H-3 or H-6 '), 7.61 (br d, J=8.2Hz, 1H, H-6 ' or H-3), 7.65 (dd, J=7.7,1.7Hz, 1H, H-3 '), 8.01 (dd, J=7.9,1.7Hz, 1H, H-6), 10.00 (s, 1H, CHO), 11.26 (br s, 1H, NH).

Embodiment 4: the preparation of acridine-4-carboxylate methyl ester.

The described aldehyde that will produce at the embodiment in the ethyl acetate (250ml) of degasification 3 (12.75g 50mmol) stirs under nitrogen, and with surpass 15 minutes time adding boron trifluoride acetate mixture (25ml, 33.8g, 180mmol).Before interpolation was finished, it was orange solids that described a tetrafluoro borate begins crystallization.Described mixture continues to stir under room temperature, nitrogen to spend the night.Dense thick orange precipitation is shifted out by filtration, washs and drains with EtOAc (20ml), hexane (50ml) on filter.(20g is through HPLC purity about 92%).

This solid is added in the mixture of EtOAc (250ml) and saturated sodium carbonate solution (150ml).Flaxen organic layer is separated and washs with saturated brine solution (30ml).TLC (SiO ₂: 10%MeOH is in CH ₂Cl ₂In under the ultraviolet ray of 254nm, develop) show a point basically.The described organic solution of vacuum-evaporation obtains being easy to the described title compound (11.5g, 97%) of the faint yellow oily thing of crystalline.HPLC shows that this material is approximately 90% purity.Described material need not be further purified the preparation that promptly can be used for DACA. ¹H NMR (CDCl ₃) δ 4.12 (s, 3H, COOCH ₃), 7.53-7.58 (m, 2H, H-2 and H-6 or H-7), 7.79 (ddd, J=8.8,6.6,1.4Hz, 1H, H-7 or H-6), 8.00 (dd, J=8.0,1.0Hz, 1H, H-1) 8.12-8.14 (m, 2H, H-5,8), 8.30 (dd, J=8.7,0.9Hz, 1H, H-3), 8.80 (s, 1H, H-9).

Embodiment 5:N-[2-(dimethylamino) ethyl] preparation of acridine-4-methane amide (DACA)

Acridine-4-carboxylate methyl ester that embodiment 4 is produced (11.2g 47mmol) use N, the N-dimethyl-ethylenediamine (20ml, 16.2g, 184mmol) dilution and on rotatory evaporator the described solution of distillation to remove the micro-EtOAc (weight is lost about 1.5g) of remnants.Under nitrogen, in 120 ℃ of oil baths, heated described mixture 7 hours then, and keep somewhere cool overnight in described bath, be dissolved in the toluene (50ml) this mixture and the vacuum concentration agglutination.

Residue is dissolved among the EtOAc (150ml), and (2 * 100ml) wash with the 1M aqueous sodium carbonate.Separate described organic layer, stir with gac (1.5g) and diatomite (1.5g), and filter by bed of diatomaceous earth.Wash this bed with EtOAc, described filtrate of vacuum concentration and washings become tawny oily matter, it is crystallized into beige solid apace, develop this solid and filtration with hexane (100ml), obtain the target compound of light beige solid, with hexane (50ml) washing and in 40 ℃ of vacuum-dryings (10.4g, 75.4%).HPLC, 90-95%a/a, fusing point 105-108 ℃. ¹HNMR (DMSO) δ 2.34 (6H, s, N (CH ₃) ₂), 2.58 (2H, t, J=6.1, CH ₂N (CH ₃) ₂), 3.61 (2H, m, J=11.2 and 6.0, CONHCH ₂), 7.67 (1H, m, J=7.1,6.4 and 0.7, H-7), 7.71 (1H, dd, J=8.3 and 7.1, H-2), 7.95 (1H, m, J=7.7,6.7 and 1.4, H-6), 8.18 (1H, dd, J=8.2 and 1.3, H-8), 8.18 (1H, dd, J=8.9 and 0.8, H-5), 8.31 (1H, dd, J=8.4 and 1.5, H-1), 8.74 (1H, dd, J=7.1 and 1.6, H-3), 9.23 (1H, s, H-9), 11.73 (1H, br.t, J=4.7, CONH).

Embodiment 6:[2-(dimethylamino) ethyl] acridine-4-methane amide, dihydrochloride, the preparation of trihydrate

The product of embodiment 5 in being dissolved in toluene (20.7ml) and EtOH (9ml) mixed solution (2.93g, 100mmol) the middle concentrated hydrochloric acid (2.0ml, approximately 200mmol) that drips.The salt precipitation occurs, this phenomenon is finished by adding EtOAc (8.6ml).This mixture is cooled to 5 ℃, further stirred 1 hour and filtered out yellow crystal salt, (3 * 20ml) washings are also drained on filter, obtain target compound 3.9g (its 2HCl3H with EtOAc ₂The theoretical value of O, 4.2g).HPLC shows that it is approximately 98%a/a.

With described salt in 70 ℃ of mixed solutions that are dissolved in EtOH (20ml) and water (2ml), this salt of recrystallization.Keep diluting the solution that is obtained with EtOAc (20ml) under this mixeding liquid temperature (approximately 60-70 ℃).Slowly cool off this mixed solution then, produce the dihydrochloride trihydrate of yellow crystal body.1 hour this compound of after-filtration of cooling in ice bath, use EtOH: EtOAc: water is that (2 * 10ml) wash, and drain on filter, equilibrate to constant weight then in stink cupboard, obtain pure salt (3.6,85.7%) for 10: 10: 1 refrigerative mixed solution.HPLC is 99.2%a/a. ¹HNMR (DMSO) δ 2.90 (6H, s, N (CH ₃) ₂), 3.46 (2H, m, CH ₂N (CH ₃) ₂), 3.98 (2H, m, CONHCH ₂), 7.75 and 7.80 (2H, t and br.t, H-7 (7.75) and H-2 (7.80)), 8.02 (1H, m, H-6), 8.28 (1H, d, H-8), 8.46 (1H, d, H-1), 8.51 (1H, d, H-5), 8.77 (1H, d, H-3), 9.43 (1H, s, H-9), 10.65 (1H, br.s, NH ⁺(CH ₃) ₂), 11.45 (1H, br.t, CONH).

Embodiment 7:[2-(dimethylamino) ethyl] preparation of acridine-4-methane amide

Aldehyde (the 3.0g that will in embodiment 3, produce; 11.76mmole) at CH ₂Cl ₂In stirred solution saturated with nitrogen, under nitrogen, drip boron trifluoride etherate (3.33g; 23.5mmole; 2 equivalents), this solution becomes orange (the solid dissolving of 2-3 minute postprecipitation), then along with the precipitation of yellow solid, becomes clean garnet.Continue to stir this solution 4 hours until by TLC (SiO ₂CH ₃OH: CH ₂CL ₂/ 1: 40) described reaction is finished in demonstration.Add 1M Na ₂CO ₃(15ml) solution (pH7) and stirred this solution 5 minutes, the organic layer below separating is used 1MNa then ₂CO ₃(15ml) washing.Use CH ₂Cl ₂(10ml) aqueous layer of extracting merging is added in the main organic layer behind the separation organic layer.With the organic layer of the described merging of salt solution (10ml) washing, reduce by about 1/2 volume after, from CH ₂Cl ₂Heavily evaporation (20ml).Add N, N-dimethyl-ethylenediamine (NNDMEDA) (5.1ml, 47.04mmole, 4 equivalents) also concentrates this reaction mixture to remove any residual CH ₂Cl ₂

The described residue of (110-120 ℃) heating spends the night in oil bath, by TLC (SiO ₂10%CH ₃OH: CH ₂Cl ₂) obtain orange/brown oily matter, (20ml) dilutes this oily matter with toluene, concentrates then to reduce volume to remove excessive N NDMEDA.Dilute described residue with EtOAc (25ml), use 1M NaHCO then ₃Solution (15ml) washing.Separate organic layer, water (separate by 2 * 10ml) washing backs.The organic layer that merges was stirred 30 minutes with gac (300mg), diatomite (300mg).Filter by the exsiccant bed of diatomaceous earth, and wash concentrated filtrate agglutination thing (3.2g), its rapid crystallization with EtOAc.With EtOAc (2ml) and hexane (20ml) development, obtain Huang-brown solid.Filter this solid,, obtain dark yellow solid target compound (2.65g, 77%) with hexane wash final vacuum drying (40 ℃).Acquisition is reported the same with embodiment 5 products ¹The HNMR data.

Embodiment 8: from formula (VI) compound formula (I) compound

Scheme 2

Carry out scheme 2 described serial reactions to produce DACA (compound 3a) and analogue 3b to 3g series.Each of these compounds, its substituent R in whole proposal 2 ¹And R ²Following definitions is arranged.

????R 1	????R 2	Compound
			????H ????H ????H ????H ????H ????6-Me ????7-Me	????H ????5-CF 3????6-Me ????6-Br ????6-CF 3????7-Me ????5-Cl	????a ????b ????c ????d ????e ????f ????g

With 2-[N-(2-carboxyphenyl) amino] methyl benzoate 4a (10g, 36.9mmole) solution in dry THF (200ml) with 1,1 '-(8.97g 55.4mmole) handles carbonyl dimidazoles.Stir this reaction mixture 15 hours under the room temperature, then described THF solution slowly is added in the NaBH in the water (200ml) ₄(7.00g) in the suspension, and need not separation of intermediates imidazolide 5a.In fact described reaction is moment, when described adding finishes, with the described mixture of concentrated hydrochloric acid cancellation, at CH ₂Cl ₂(200ml) and NaHCO ₃Distribute (200ml), and use Na ₂SO ₄Dry described organic layer.Remove and to desolvate and in sherwood oil/EtOAc (4: 1), by fast-classification silica gel plug filtered residue, obtain 2-[N-(2-methylol) phenyl amino] methyl benzoate 6a (7.85g, 83%).Fusing point (CH ₂The Cl/ sherwood oil) 69-71 ℃. ¹HNMR(CDCl ₃)δ1.93(br.s，1H，OH)，3.91(s，3H，COOH?CH ₃)，4.72(s，2H，CH ₂OH)，6.74(ddd，J＝8.0，7.0，1.1Hz，1H，H-5)，7.08-7.44(m，6H，H-3，3’、4，4’5’，6’)，7.97(dd，J＝8.1，1.6Hz，1H，H-6)，9.59(br.s，1H，NH)。

Under the room temperature, (7.74g is 30mmol) at Me for 6a ₂Stirred solution MnO among the CO (200ml) ₂(10g) suspension was handled 3 days.Remove by filter MnO ₂(diatomite), and Me is removed in decompression ₂CO obtains 2-[N-(2-formyl) phenyl amino] methyl benzoate 7a (7.70g, 100%).Crystalline sample from the EtOAc/ sherwood oil, its fusing point are 110-112 ℃. ¹HNMR (CDCl ₃) δ 3.95 (s, 3H, COOCH ₃), 6.95-7.03 (m, 2H, H-4 ', 5), 7.41-7.45 (m, 2H, H-5 ', 6), 7.50 (br d, J=8.5Hz, 1H, H-3 or H-6 '), 7.61 (br d, J=8.2Hz, 1H, H-6 ' or H-3), 7.65 (dd, J=7.7,1.7Hz, 1H, H-3 '), 8.01 (dd, J=7.9,1.7Hz, 1H, H-6), 10.00 (s, 1H, CHO), 11.26 (br s, 1H, NH).

(210mg 0.82mmol) is positioned over in the flask of purging with nitrogen gas, adds trifluoroacetic acid (10ml) then, stirs the solution that obtained under the room temperature 24 hours with described aldehyde 7a.Removal of solvent under reduced pressure obtains crude product acridine-4-carboxylate methyl ester 8a (183mg, 94%).Use CH ₂Cl ₂(100ml) dilute and use Et ₃N this compound that neutralizes.Removal of solvent under reduced pressure by the quick silica gel short column filtered residue in EtOAc/ sherwood oil (1: 3), obtains the acridine-4-carboxylate methyl ester (8a) (1.83g, 98%) of orange. ¹HNMR (CDCl ₃) δ 4.12 (s, 3H, COOCH ₃), 7.53-7.58 (m, 2H, H-2 and H-6 or H-7), 7.79 (ddd, J=8.8,6.6,1.4Hz, 1H, H-7 or H-6), 8.00 (dd, J=8.0,1.0Hz, 1H, H-1), 8.12-8.14 (m, 2H, H-5,8), 8.30 (dd, J=8.7,0.9Hz, 1H, H-3), 8.80 (s, 1H, H-9).

(1.83g, 7.72mmol) and N, (removal of solvent under reduced pressure then is at CH for 3.40g, the 38.6mmol) solution in third-1-alcohol (80ml), and under refluxing, described mixture being heated 3 days under nitrogen for the N-dimethyl-ethylenediamine with purging with nitrogen gas 8a ₂Cl ₂(100ml) with 1M Na ₂CO ₃Distribute described residue (100ml).The evaporation organic layer carries out chromatography to described residue on aluminum oxide, use CH ₂Cl ₂/ MeOH (199: 1) wash-out obtains N-[2-(dimethylamino) ethyl] acridine-4-methane amide 3a (1.38g, 61%), 191-195 ℃ of fusing point (two HCl salt), in full accord with authentic sample.

Adopt similar step production compound 3b to 3g respectively from initial compounds 4b to 4g.3b has good beam split and analytical characteristics to all compounds of 3g.Produce intermediate aldehydes 7a from initial compounds 4a to 4g as follows to the productive rate of 7g (step (i) and (ii)):

????4	Productive rate (4-7)	????7
			????4a ????4b ????4c ????4d ????4e ????4f ????4g	????83％ ????100％ ????82％ ????67％ ????77％ ????60％ ????44％	????7a ????7b ????7c ????7d ????7e ????7f ????7g

Embodiment 9: the preparation of acridine-4-carboxylic acid

In the acridine-4-carboxylate methyl ester (183mg) of preparation in embodiment 4, be added in NaOH de-gassed solution among the water-soluble EtOH (1: 1,2M) (35ml).Under 50 ℃, stirred this mixture 3 hours, after obtaining clear soln, with ice AcOH neutralization.(3 * 50ml) extractings and then by the silica gel chromatography chromatography, with EtOAc/ sherwood oil (1: 4) wash-out, obtain acridine-4-carboxylic acid (160mg, 87%), fusing point (Me with EtOAc ₂CO) 196-197 ℃ (document (lit), fusing point 202-204 ℃).

By same method, other compound hydrolysis of formula (III) is become corresponding acridine-4-carboxylic acid.

Embodiment 10: from acridine-4-carboxylic acid precursor preparation formula (I) compound

Universal method

In the time of 20 ℃, step that will be by embodiment 9 produces from formula (III) compound, wherein R ¹Be H and R ²Be that the 7-ethyl is substituent, (472mg, 1.99mmol), with 1, (650mg 3.98mmol) stirs until become one (approximately 12h) 1 '-carbonyl dimidazoles the suspension of 7-ethyl acridine-4-carboxylic acid in dry DMF (10ml) together.Then this solution is cooled to 0 ℃ and also uses N, (0.73g 9.96mmol) handled 5 minutes the N-dimethyl-ethylenediamine.Decompression removes down and desolvates, at CH ₂Cl ₂(50ml) with 1M K ₂CO ₃(30ml) distribute described resistates between the aqueous solution.Evaporate after washing organic layer with water, on aluminum oxide, described resistates is carried out chromatography.Use CH ₂Cl ₂/ MeOH (19: 1) wash-out, N-[2-(dimethylamino) ethyl of acquisition yellow oil]-7-ethyl acridine-4-methane amide (10a) (288mg, 48%). ¹H?NMR(CDCl ₃)δ1.35(t，J＝7.6Hz，3H?CH ₂CH ₃)，2.36(s，6H，N(CH ₃) ₂)，2.61(t，J＝6.1Hz，2H，CH ₂N(CH ₃) ₂)，2.89(q，J＝7.6Hz，2H，CH ₂CH ₃)，3.63(q，J＝5.6Hz，2H，CH ₂)，7.73(dd，J＝8.2，7.2Hz，1H，H-2)，7.90(dd，J＝9.0，1.9Hz，1H，H-6)，7.99(br?s，1H，H-8)，8.18(d，J＝8.9Hz，1H，H-5)，8.34(dd，J＝8.5，1.4Hz，1H，H-1)，8.73(dd，J＝7.1，1.5Hz，1H，H-3)，9.21(s，1H，H-9)，11.81(br?t，J＝4.7Hz，1H，CONH)。Dihydrochloride, 173-175 ℃ of molten point (EtOAc/MeOH).

Produce following formula (I) compound with above-mentioned universal method:

N-[2-(dimethylamino) ethyl-5-ethyl acridine-4-methane amide (compound 10b) (70%), molten point (CH ₂Cl ₂/ sherwood oil) 106-108 ℃; Dihydrochloride, 214-217 ℃ of molten point (EtOAc/MeOH).

The N-[2-of yellow oil (dimethylamino) ethyl]-5-sec.-propyl acridine-4-methane amide (compound 10c) (76%), dihydrochloride, 213-215 ℃ of molten point (EtOAc/MeOH).

N-[2-(dimethylamino) ethyl]-5-fluoro acridine-4-methane amide (compound 10d) (73%), 95-98.5 ℃ of molten point (hexane).

N-[2-(dimethylamino) ethyl]-5-bromo acridine-4-methane amide (compound 10e) (52%), molten some 149-150 ℃.

N-[2-(dimethylamino) ethyl]-5-trifluoromethyl acridine-4-methane amide (compound 10f) (74%).Hydrochloride, molten some 207-211 ℃ (EtOAc/MeOH).

N-[2-(dimethylamino) ethyl]-6-fluoro acridine-4-methane amide (compound 10g) (87%), molten point (from MeOH/EtOAc crystalline dihydrochloride) 203-204 ℃ (decomposition).

N-[2-(dimethylamino) ethyl]-6-bromo acridine-4-methane amide (compound 10h) (67%), 161-163 ℃ of molten point (from MeOH/EtOAc crystalline dihydrochloride).

The N-[2-of yellow oil (dimethylamino) ethyl]-7-sec.-propyl acridine-4-methane amide (compound 10i) (97%), dihydrochloride, 182-187 ℃ of molten point (MeOH/EtOAc).

N-[2-(dimethylamino) ethyl]-7-tert-butyl acridine-4-methane amide (compound 10j) (92%), molten point (CH ₂Cl ₂/ sherwood oil) 128-129 ℃.

N-[2-(dimethylamino) ethyl]-7-phenylacridine-4-methane amide (compound 10k) (64%), molten point (CH ₂Cl ₂/ sherwood oil) 115-116.5 ℃; Hydrochloride, 83-85 ℃ of molten point (MeOH/EtOAc).

N-[2-(dimethylamino) ethyl]-7-fluoro acridine-4-methane amide (compound 101) (74%), 128.5-130 ℃ of molten point (MeOH/EtOAc).

N-[2-(dimethylamino) ethyl]-7-bromo acridine-4-methane amide (compound 10m) (84%), 181.5-183 ℃ of molten point (from MeOH/EtOAc crystalline dihydrochloride).

Embodiment 11: from acridine-4-carboxylate methyl ester precursor preparation formula (I) compound

Universal method

With aldehyde 2-[N-(2-formylphenyl) amino of trifluoroacetic acid (TFA) in (20ml)] (2g, N is used in 7.84mmol) solution degasification and being positioned in the double-neck flask to methyl benzoate then ₂This bottle of purge.At room temperature, N ₂Under stirred this solution 15 hours, under reduced pressure remove described TFA then.Use CH ₂Cl ₂(100ml) dilute the oily matter that is obtained, and use Et ₃N this solution that neutralizes.Under reduced pressure remove and desolvate, filter described resistates, obtain the acridine-4-carboxylate methyl ester (1.83g, 98%) of orange by the quick silica gel short column in the EtOAc/ sherwood oil (1: 3). ¹HNMR (CDCl ₃) δ 4.12 (s, 3H CO ₂CH ₃), 7.53-7.58 (m, 2H, H-2 and H-6 or H-7), 7.79 (ddd, J=8.8,6.6,1.4Hz, 1H, H-7 or H-6), 8.00 (dd, J=8.0,0.8Hz, 1H, H-1), 8.12-8.14 (m, 2H, H-5,8), 8.30 (dd, J=8.7,0.8Hz, 1H, H-3), 8.80 (s, 1H, H-9).

With just-(1.83g, 7.72mmol) and N, (3.40g, 38.6mmol) solution (80ml) is used purging with nitrogen gas to the N-dimethyl-ethylenediamine, under refluxing, described mixture is heated 3 days under nitrogen for acridine-4-carboxylate methyl ester in the propyl alcohol.The removal of solvent under reduced pressure thing is at CH ₂Cl ₂(100ml) with 1M Na ₂CO ₃Distribute described residue (100ml), the evaporation organic layer also carries out chromatography to residue on aluminum oxide, use CH ₂Cl ₂/ MeOH (199: 1) wash-out obtains N-[2-(dimethylamino) ethyl] acridine-4-methane amide (DACA) (1.47g, 61%).162-165 ℃ of fusing point (crystalline dihydrochloride from MeOH/EtOAc).

Produce following formula (I) compound with above-mentioned universal method:

N-[2-(dimethylamino) ethyl]-6-trifluoromethyl acridine-4-methane amide (compound 11a) (92%), 188-189.5 ℃ of fusing point (MeOH/EtOAc).

Embodiment 12: medicinal compositions

Can be by following preparation tablet, every heavy 0.15g also contains a kind of of 25mg formula (I) compound:

10.000 the composition of sheet

Formula (I) compound (250g)

Lactose (800g)

W-Gum (415g)

Talcum powder (30g)

Magnesium Stearate (5g)

Formula (I) compound, lactose and the W-Gum of half are mixed.Firmly oppress the sieve of this mixture then by aperture 0.5mm.Suspension W-Gum (10g) in warm water (90ml) becomes powder with the grain that pastes that is obtained.Dry this particle also ground the sieve of aperture 1.4mm, added remaining starch, talcum powder and Magnesium Stearate, carefully mixed and suppress in blocks.

Claims (10)

1. the method for the acridine methane amide of production formula (I):

R wherein ¹, R ², R ⁵And R ⁶Each, can be identical or different, be H, C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, aryloxy, aralkoxy, halogen, phenyl, CF ₃, NO ₂, NH ₂, N (R) ₂, NHCOR, NHCOOR, NHR ⁴, OH, SH, SR or SR ₂, R wherein ⁴Be H, COR, SO ₂R, COPh, SO ₂Ph or by OH or amino replace or unsubstituted C ₁-C ₆Alkyl and R are C ₁-C ₆Alkyl; Or R ¹And R ²Or R ⁵And R ⁶, form methylenedioxy group together; X is 1 to 6 integer and Y such as the above-mentioned N that limits (R) ₂Or its pharmacy acceptable salt; This method comprises:

(a) compound of cyclisation formula (II) R wherein ¹, R ², R ⁵And R ⁶As above-mentioned qualification and R ³Be C ₁-C ₆Alkyl, aryl or aryl-C ₁-C ₃-alkyl, by in organic solvent, handling the compound of acquisition formula (III) with Lewis acid:

R wherein ², R ³, R ⁵And R ⁶As above-mentioned qualification; With

(b) or (i) will handle with the primary alkyl amine of formula (IV) as the above-mentioned formula that limits (III) compound:

NH ₂(CH ₂) _XY (IV) wherein X and Y limits as above-mentioned; Perhaps

The (ii) carboxylic acid that will obtain at hydrolysis under the alkaline condition such as the above-mentioned formula that limits (III) compound, when suitable coupler exists, with as the primary alkyl amine of the above-mentioned formula that limits (IV) handle, obtain as the compound of the above-mentioned formula that limits (I); And

(c) if necessary, a kind of compound of formula (I) can be converted into the another kind of compound of formula (I), and/or the compound of formula (I) is converted into its pharmacy acceptable salt.

2. according to the process of claim 1, the R in formula (II) wherein ¹, R ², R ⁵And R ⁶Be H and the X in formula (IV) be 2 and Y be N (CH ₃) ₂, so that the acridine methane amide of the described formula (I) that produces is N-[2-(dimethylamino) ethyl] acridine-4-methane amide.

3. according to the method for claim 1 or 2, wherein step (a) can be used boron trifluoride by in suitable solvent, or with its suitable mixture, the compound of processing formula (II) carries out, and obtains a tetrafluoro borate of described formula (IIIa):

R wherein ¹, R ², R ³, R ⁵And R ⁶Defined in claim 1, be used in EtOAc or CH subsequently ₂Cl ₂In mineral alkali handle described salt, produce described formula (III) compound.

4. according to any one the method in the aforementioned claim, it further comprises the compound that is produced described formula (II) by the alcohol of the correspondence of the described formula V of oxidation:

R wherein ¹, R ², R ³, R ⁵And R ⁶Defined in claim 1.

5. according to the method for claim 4, it comprises the alcohol of producing described formula V by following reaction:

(a) with the compound of formula (VI):

R wherein ¹, R ², R ³, R ⁵And R ⁶Defined in claim 1, with 1,1 '-carbonyl dimidazoles is handled in polar solvent, the compound of acquisition formula (VII):

R wherein ¹, R ², R ³, R ⁵And R ⁶As defined in claim 1 and

(b) compound of reduction as the above-mentioned formula that limits (VII).

6. according to the method for claim 5, it further comprises the compound of producing described formula (VI), by in polar solvent, exists down in copper catalyst and alkali, together the anthranilic acid of heating-type (VIII): R wherein ¹And R ²Defined in claim 1, and the 2-iodobenzoic acid ester of formula (IX):

R wherein ³, R ⁵And R ⁶Defined in claim 1.

7. produce N-[2-(dimethylamino) ethyl of following formula] method of acridine-4-methane amide (DACA):

This method comprises:

(i) with the compound of formula (VI):

R wherein ¹, R ², R ⁵And R ⁶Be H and R ³Be C ₁-C ₆Alkyl, aryl-C ₁-C ₃-alkyl or aryl, with 1,1 '-carbonyl dimidazoles is handled in organic solvent, the compound of acquisition formula (VII):

R wherein ¹, R ², R ⁵And R ⁶Be H and R ³As above-mentioned qualification;

(ii) under the situation that water exists,, obtain the compound of formula V with the compound of sodium borohydride processing as the above-mentioned formula that limits (VII):

R wherein ¹, R ², R ⁵And R ⁶Be H and R ³As above-mentioned qualification;

The (iii) compound of oxidation such as the above-mentioned formula V that limits, the compound of acquisition formula (II):

R wherein ¹, R ², R ⁵And R ⁶Be H and R ³As above-mentioned qualification;

(iv) in organic solvent, handle with Lewis acid, the compound of cyclisation such as the above-mentioned formula that limits (II), the compound of acquisition formula (III):

R wherein ¹, R ², R ⁵And R ⁶Be H and R ³As above-mentioned qualification; With

(v) will handle with the primary alkyl amine of formula (IV) as the above-mentioned formula that limits (III) compound:

NH ₂(CH ₂) _XY (IV) wherein X be 2 and Y be N (CH ₃) ₂, obtain DACA.

8. according to the method for claim 7, it further comprises the compound that produces described formula (VI), by in polar solvent, and when copper catalyst and alkali exist, the anthranilic acid of heating-type (VIII) together:

R wherein ¹And R ²Defined in claim 7, and the 2-iodobenzoic acid ester of formula (IX): R wherein ³, R ⁵And R ⁶Defined in claim 7.

9. according to the method for claim 7 or 8, it further comprises DACA is converted into its pharmacy acceptable salt.

10. according to any one method in the aforementioned claim, it further comprises with pharmaceutically acceptable carrier or thinner, prepares described formula (I) compound or DACA, or the pharmacy acceptable salt of formula (I) compound or DACA.