CN103787907B - Aniline compound as farnesyltransferase inhibitor and application thereof - Google Patents

Abstract

The invention provides an aniline compound represented by a formula I shown in a drawing or pharmaceutically acceptable salts thereof, wherein X is independently selected from COOH and SO2NH2, R1 and R2 are independently selected from H, C1-C3alkyl or alkoxy, CF3, F, Cl, Br, I, NH2 and NO2 respectively, m and n are respectively integers of 0-5, and y is 0 or 1. The compound and the pharmaceutically acceptable salts thereof, provided by the invention, can be used as farnesyltransferase inhibitors or can be used for preparing drugs for preventing or treating diseases related to farnesyltransferase, thereby having good medicine preparation prospects.

Description

As the amino benzenes compounds and uses thereof of farnesyl transferase inhibitor

Technical field

The present invention relates to a kind of amino benzenes compounds as farnesyl transferase inhibitor and uses thereof.

Background technology

Posttranslational modification (Post-translational modification, PTM) has great importance to the maturation of albumen, and these posttranslational modifications comprise acetylize, alkylation, methylates and prenylation etc.Prenylation is then completed by farnesyl transferase catalysis.

Farnesyl transferase (farnesyltransferase, FTase) be a kind of zine ion metalloenzyme can carrying out posttranslational modification, catalysis can make farnesyl pyrophosphate ester (farnesyl pyrophosphate, FPP) farnesyl (isoprenoids of 15 carbon) in is transferred in a tetrapeptide structure of Ras albumen one of carbon tip, this tetrapeptide structure is CAAX (C: halfcystine, A: aliphatic amino acid, X: methionine(Met), L-glutamic acid or L-Ala), farnesyl is then connected on the sulphur atom of half Guang acid acid.After Ras albumen is by farnesylation, the isoprenoid of 15 carbon that one of carbon tip connects makes the hydrophobicity of Ras albumen increase, what Ras albumen can be more prone to is fixed on cytolemma, and the signal path in cell could normally carry out, and cell could grow normally, breeds, breaks up.

The sudden change of Ras albumen makes Ras albumen be in lasting active state, uncontrolled cellular proliferation, leads oncogenic formation.In the carcinoma of the pancreas of 90%, excessive (the Song Yan of Ras protein expression of sudden change is had been found that in 50% colorectal carcinoma and 30% lung cancer, Zhou Xiang, Li Huifang, Lu Tao, the progress of the antitumor inhibitor being target spot with Ras signal transduction pathway, Central-South pharmacy, 2009,7 (4), 293-296).Therefore, one of farnesyl transferase inhibitor focus becoming medicament research and development is studied.

Summary of the invention

Integrated use computer of the present invention medicinal design, pharmaceutical chemistry, molecular biology method and technology, designed and synthesized a series of phenylamino compounds, some of them compound has significant FTase inhibitory activity, possesses good patent medicine prospect.

The object of the invention is, provides a kind of such as formula amino benzenes compounds shown in I or its acceptable salt on pharmacology:

Wherein, X is independently selected from: COOH, SO ₂nH ₂; R ₁, R ₂independently be selected from H, C ₁~ C ₃alkyl or alkoxyl group, CF ₃, F, Cl, Br, I, NH ₂, NO ₂; M, n are respectively the integer of 0 ~ 5; Y is 0 or 1.

In the preferred embodiment of the present invention, X is COOH or SO ₂nH ₂; R ₁, R ₂independently be selected from H, C ₁the alkyl of ~ C2, CF ₃, F, Cl, Br; M, n are respectively 0,1 or 2.

In the preferred embodiment of the present invention, described amino benzenes compounds is following compound (1) ~ (23):

Another aspect of the present invention is a kind of pharmaceutical composition, and described pharmaceutical composition comprises amino benzenes compounds of the present invention or its pharmacy acceptable salt.

Preferably, can also comprise at described pharmaceutical composition: suitable thinner or filler: such as carbohydrate as lactose or sucrose, N.F,USP MANNITOL or sorbyl alcohol; Suitable cellulose preparation or calcium phosphate (such as tricalcium phosphate or secondary calcium phosphate); Suitable binding agent: such as starch paste, W-Gum, wheat starch, Starch rice, yam starch etc.

If needed, disintegrating agent also can be increased and/or with the suitable Drug coating etc. resisting gastric juice.Pharmaceutical composition provided by the invention can be made into multiple formulation, with oral or injection system administration.

Another aspect of the present invention is a kind of farnesyl transferase inhibitor, and it comprises amino benzenes compounds of the present invention or its pharmacy acceptable salt.

Another aspect of the present invention is the application as farnesyl transferase inhibitor of amino benzenes compounds of the present invention or its pharmacy acceptable salt.

Another aspect of the present invention is that amino benzenes compounds of the present invention or its pharmacy acceptable salt are preparing the application in farnesyl transferase inhibitor.

Another aspect of the present invention is amino benzenes compounds of the present invention or the application of its pharmacy acceptable salt in the medicine preparing prevention or treatment and farnesyl transferase relative disease.

Accompanying drawing explanation

Fig. 1 positive compound is in contrast for the IC of pyrrole method Buddhist nun ₅₀.

Embodiment

The synthetic method of amino benzenes compounds of the present invention is described in detail in detail below.

When X is carboxy CO OH, its main preparation process is as shown in synthetic route: with benzaldehyde derivative (shown in formula II compound) for starting raw material, first corresponding diacid (shown in formula III compound) is made into by methyl aceto acetate, again diacid is changed into acid anhydrides (shown in formula IV compound), finally obtain target compound (shown in formula I compound).

When X is sulfoamido SO ₂nH ₂time, its key step is as shown in following route: with benzaldehyde derivative (shown in formula II compound) for starting raw material, the Toluidrin (shown in formula VI compound) protected by N forms the ethenesulfonyl sulfonamide derivatives (shown in formula VII compound) that corresponding N protects, carry out Michael addition by dimethyl malonate and obtain diester compound (shown in formula VIII compound), monoester compound (shown in formula Ⅸ compound) is obtained by reacting by Krapcho decarboxylation acid esters, corresponding acid (shown in formula Ⅹ compound) is obtained through hydrolysis, corresponding acid amides (shown in formula Ⅺ compound) is formed again with corresponding aniline compound (shown in formula V compound), slough the protecting group on sulphonamide N again, obtain target compound (shown in formula I compound).

The present invention is further elaborated by the following examples, and these embodiments are only for illustration of the present invention and understand content of the present invention better, its protection domain do not limited the present invention in any way.

Embodiment

Embodiment 1

3-phenyl-4-(4-(4-fluorophenoxy) aniline formyl radical)-butyric acid (1)

The synthesis (1.4) of 4-(4-fluorophenoxy) aniline

By p-fluoronitrobenzene (705mg, 5.0mmol), p-fluorophenol (560mg, 5.0mmol) and salt of wormwood (2.07g, 15.0mmol) are dissolved in DMF (5mL).Reaction is warmed up to 70 DEG C, and stirring is spent the night.After TLC monitoring reaction terminates, reaction solution is dissolved in ethyl acetate, and with water and bittern extraction, is separated organic phase and uses anhydrous sodium sulfate drying, it is 990mg that the removing organic solvent that reduces pressure obtains faint yellow product 1.3, productive rate 85%.

¹H NMR(400MHz，DMSO-d ₆)：δ8.26(d，2H，J=8.8Hz)，7.37-7.11(m，4H)，7.12(d，2H，J=9.2Hz)。

By SnCl ₂h ₂o (2.25g, 10mmol) is dissolved in concentrated hydrochloric acid (10mL), then compound 1.3 will be entered (249mg, 1mmol) in mixed solution, and reaction solution is warmed up to back flow reaction 6 hours.Reaction terminate after, with aqueous sodium hydroxide solution by reaction solution pH regulator to 10.Finally with ethyl acetate and water extraction, be separated organic phase, and wash respectively with water and bittern, organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure obtains brown target product 1.4, is not purifiedly directly used in next step and reacts.

The synthesis (1.6) of 4-phenyl-dihydropyrane-2,6-diketone

Phenyl aldehyde (50mmol) and methyl aceto acetate (100mmol) are filled under ice cooling, 4 part mixing, more dropwise add piperidines (1.0mL).React 3 days under reaction solution being placed in room temperature, the solid ethyl alcohol recrystallization of generation obtains white solid.Obtained white solid is dissolved in the aqueous solution (60mL) of 50% potassium hydroxide, is warmed up to 80 DEG C of reactions 2 hours, adds frozen water after reaction terminates and be extracted with ethyl acetate, isolating aqueous phase, regulate pH to 1 aqueous phase concentrated hydrochloric acid.Be extracted with ethyl acetate again, be separated organic phase, and with anhydrous sodium sulfate drying, concentrating under reduced pressure to obtain white solid 1.5 by column chromatography for separation (sherwood oil: ethyl acetate=1:1) be 4.89g, productive rate 47%.

¹H NMR(400MHz，DMSO-d ₆):δ12.05(s，2H)，7.30-7.25(m，4H)，7.21-7.16(m，1H)，3.45-3.39(m，1H)，2.64(dd，2H，J ₁=6.4Hz，J ₂=16.0Hz)，2.55-2.49(m，2H)。

Compound 1.5 (1.0g) is dissolved in Acetyl Chloride 98Min. (2mL), and is heated to backflow, react 2 hours, after reaction terminates, in reaction solution, add sherwood oil, produce white solid, suction filtration, obtains white solid 1.6, not purified be directly used in next step reaction.

The synthesis of 3-phenyl-4-(4-(4-fluorophenoxy) aniline formyl radical)-butyric acid (1)

Compound 1.6 (190mg, 1.0mmol) and compound 1.4 (203mg, 1.0mmol) are dissolved in dioxane (2mL), and add triethylamine (0.1mL).Mixed solution was stirring at room temperature 3 hours.After reaction terminates, reaction solution is added to the water, and is extracted with ethyl acetate, be separated organic phase, and carrying out drying by anhydrous sodium sulphate, concentrating under reduced pressure also uses column chromatography (ethyl acetate: sherwood oil=2:3) and obtains compound as white solid 1 for 195mg, productive rate 50%.

¹H NMR(400MHz，DMSO-d ₆)：δ12.07(s，1H)，9.88(s，1H)，7.52(d，2H，J=8.8Hz)，7.29-7.28(m，4H)，7.21-7.17(m，3H)，7.01-6.98(m，2H)，6.98(d，2H，J=8.8Hz)，3.63-3.56(m，1H)，2.72-2.55(m，4H).

¹³C NMR(100MHz，DMSO-d ₆)：δ173.4，169.7，159.6，157.2，153.8，152.6，144.1，135.4，128.7，127.9，126.9，121.3，120.3，120.2，119.3，117.0，116.8，43.2，40.6，38.7。

HRMS(ESI)calcd for C ₂₃H ₂₀FNO ₄Na[M+Na] ⁺416.1274，found 416.1248。

Embodiment 2

3-phenyl-4-(4-(4-methoxyphenoxy) aniline formyl radical)-butyric acid (2)

Synthetic method is see embodiment 1, and difference is the compound 1.2 used in synthetic compound 1.4 process to replace with p methoxy phenol, and product is white solid, productive rate 61%.

¹H NMR(400MHz，DMSO-d ₆)：δ12.05(s，1H)，9.82(s，1H)，7.47(d，2H，J=8.8Hz)，7.29-7.27(m，4H)，7.21-7.15(m，1H)，6.93(s，4H)，6.85(d，2H，9.2Hz)，3.72-3.53(m，1H)，2.71-2.54(m，4H)。

¹³C NMR(100MHz，DMSO-d ₆)：δ173.3，169.6，155.8，153.6，150.7，144.1，134.7，128.7，127.9，126.8，121.3，120.4，118.4，115.5，55.9，43.2，40.6，38.7。

HRMS(ESI)calcd for C ₂₄H ₂₂NO ₅[M-H] ⁺404.1498，found 404.1502。

Embodiment 3

3-phenyl-4-(4-(3,4-Dichlorophenoxy) carbanilino)-butyric acid (3)

Synthetic method is see embodiment 1, and difference is the compound 1.2 used in synthetic compound 1.4 process to replace with 3,4-chlorophenesic acid, and product is white solid, productive rate 45%.

¹H NMR(400MHz，DMSO-d ₆)：δ12.07(s，1H)，9.95(s，1H)，7.60-7.56(m，3H)，7.30-7.29(m，4H)，7.21-7.19(m，2H)，7.03(d，2H，J=8.8Hz)，6.94(d，1H，J=8.4Hz)，3.65-3.55(m，1H)，2.73-2.55(m，4H)。

¹³C NMR(100MHz，DMSO-d ₆)：δ173.3，169.8，157.7，150.8，144.0，136.4，132.4，131.9，128.7，127.9，126.9，125.2，121.3，120.5，119.8，118.3，43.2，38.7。

HRMS(ESI)calcd for C ₂₃H ₂₀ClNO ₄[M+H] ⁺444.0769，found 444.0778。

Embodiment 4

3-phenyl-4-(4-(4-chlorophenoxy) aniline formyl radical)-butyric acid (4)

Synthetic method is see embodiment 1, and difference is the compound 1.2 used in synthetic compound 1.4 process to replace with para-chlorophenol, and product is white solid, productive rate 54%.

¹H NMR(400MHz，DMSO-d ₆)：δ12.07(s，1H)，9.91(s，1H)，7.54(d，2H，J=8.8Hz)，7.39(d，2H，J=8.4Hz)，7.29-7.28(m，4H)，7.19-7.18(m，1H)，6.99-6.95(m，4H)，3.62-3.55(m，1H)，2.72-2.55(m，4H)。

¹³C NMR(100MHz，DMSO-d ₆)：δ173.3，169.7，159.9，151.6，144.0，135.9，130.2，128.7，127.9，127.0，126.8，121.3，120.1，119.9，43.1，38.7。

HRMS(ESI)calcd for C ₂₃H ₂₀ClNO ₄Na[M+Na] ⁺432.0979，found 432.0949。

Embodiment 5

3-phenyl-4-(4-(3-chlorophenoxy) aniline formyl radical)-butyric acid (5)

Synthetic method is see embodiment 1, and difference is the compound 1.2 used in synthetic compound 1.4 process to replace with m-Chlorophenol, and product is white solid, productive rate 51%.

¹H NMR(400MHz，DMSO-d ₆)：δ12.08(s，1H)，9.94(s，1H)，7.56(d，2H，J=8.4Hz)，7.37(t，1H，J=8.4Hz)，7.30-7.27(m，5H)，7.20-7.14(m，2H)，7.01(d，2H，J=8.4Hz)，6.97(s，1H)，6.90(d，1H，J=8.0Hz)，3.60-3.57(m，1H)，2.71-2.55(m，4H)。

¹³C NMR(100MHz，DMSO-d ₆)：δ173.3，169.7，159.1，151.0，144.0，136.2，134.4，131.8，128.7，127.9，126.9，123.2，121.3，120.5，117.8，116.6，43.2，38.7。

HRMS(ESI)calcd for C ₂₃H ₂₀ClNO ₄Na[M+Na] ⁺432.0979，found 432.0938。

Embodiment 6

3-phenyl-4-(4-(3-bromine phenoxy group) aniline formyl radical)-butyric acid (6)

Synthetic method is see embodiment 1, and difference is the compound 1.2 used in synthetic compound 1.4 process to replace with m-bromoacetophenone, and product is white solid, productive rate 29%.

¹H NMR(400MHz，DMSO-d6)：δ12.07(s，1H)，9.94(s，1H)，7.56(d，2H，J=8.8Hz)，7.33-7.29(m，6H)，7.20-7.19(m，1H)，7.10(s，1H)，7.01(d，2H，8.4Hz)，7.95(d，1H，7.2Hz)，3.62-3.55(m，1H)，2.73-2.55(m，4H)。

¹³C NMR(100MHz，DMSO-d6)：δ173.3，169.7，159.2，151.0，144.1，136.2，132.1，128.7，127.9，126.9，126.1，122.6，121.3，120.6，120.5，117.0，116.6，43.2，38.7。

HRMS(ESI)calcd for C ₂₃H ₂₀BrNO ₄Na[M+Na] ⁺476.0473，found 476.0490。

Embodiment 7

3-phenyl-4-(4-(4-bromine phenoxy group) aniline formyl radical)-butyric acid (7)

Synthetic method is see embodiment 1, and difference is the compound 1.2 used in synthetic compound 1.4 process to replace with p bromophenol, and product is white solid, productive rate 37%.

¹H NMR(400MHz，DMSO-d ₆)：δ12.06(s，1H)，9.91(s，1H)，7.55-7.50(m，4H)，7.29-7.28(m，4H)，7.19-7.18(m，1H)，6.98(d，2H，J=8.4Hz)，6.90(d，2H，J=8.0Hz)，3.63-3.55(m，1H)，2.72-2.55(m，4H)。

¹³C NMR(100MHz，DMSO-d ₆)：δ173.3，169.7，157.4，151.4，144.0，135.9，133.1，128.7，127.9，126.9，121.3，120.23，120.20，114.9，43.2，38.7。

HRMS(ESI)calcd for C ₂₃H ₂₀BrNO ₄Na[M+Na] ⁺476.0473，found 476.0443。

Embodiment 8

3-phenyl-4-(4-(4-4-trifluoromethylphenopendant) aniline formyl radical)-butyric acid (8)

Synthetic method is see embodiment 1, and difference is the compound 1.2 used in synthetic compound 1.4 process to replace with p-trifluoromethyl-phenol, and product is white solid, productive rate 36%.

¹H NMR(400MHz，DMSO-d ₆)：δ12.09(s，1H)，9.97(s，1H)，7.70(d，2H，J=8.4Hz)，7.60(d，2H，J=8.4Hz)，7.30-7.27(m，4H)，7.20-7.19(m，1H)，7.09-7.06(m，4H)，3.63-3.56(m，1H)，2.73-2.56(m，4H)。

¹³C NMR(100MHz，DMSO-d ₆)：δ173.4，169.8，161.5，150.3，144.0，136.6，128.8，128.7，127.9，127.84，127.80，127.76，126.9，126.1，123.8，123.5，123.4，123.2，122.9，121.3，121.1，120.7，117.7，43.2，40.6，38.7。

HRMS(ESI)calcd for C ₂₄H ₂₀F ₃NO ₄Na[M+Na] ⁺466.1242，found 466.1214。

Embodiment 9

3-phenyl-4-(4-(4-nitrophenoxy) aniline formyl radical)-butyric acid (9)

Synthetic method is see embodiment 1, and difference is the compound 1.2 used in synthetic compound 1.4 process to replace with p-NP, and product is yellow solid, productive rate 59%.

¹H NMR(400MHz，DMSO-d ₆)：δ12.09(s，1H)，10.00(s，1H)，8.22(d，2H，J=9.2Hz)，7.63(d，2H，J=8.8Hz)，7.30-7.29(m，4H)，7.21-7.17(m，1H)，7.11(d，2H，8.8Hz)，7.08(d，2H，J=9.2Hz)，3.63-3.56(m，1H)，2.73-2.55(m，4H)。

¹³C NMR(100MHz，DMSO-d ₆)：δ173.3，169.9，163.8，149.7，144.0，142.5，137.1，128.7，127.9，126.9，126.6，121.4，117.3，43.2，40.7，38.7。

HRMS(ESI)calcd for C ₂₃H ₂₁N ₂O ₆[M+H] ⁺421.1400，found 421.1402。

Embodiment 10

3-phenyl-4-(4-(4-amino-benzene oxygen) aniline formyl radical)-butyric acid (10)

Be dissolved in methyl alcohol by compound 9 (500mg), and add Pd/C (50mg), add hydrogen balloon, reaction is spent the night, and product is yellow solid, productive rate 64%.

¹H NMR(400MHz，DMSO-d ₆)：δ9.76(s，1H)，7.41(d，2H，J=9.2Hz)，7.28-7.27(m，4H)，7.20-7.16(m，4H)，6.77(d，2H，9.2Hz)，6.70(d，2H，J=8.8Hz)，6.70(d，2H，J=8.8Hz)，3.60-3.52(m，1H)，2.70-2.53(m，4H)。

¹³C NMR(100MHz，DMSO-d ₆)：δ173.4，169.5，154.8，146.9，145.6，144.1，134.0，128.7，127.9，126.9，121.3，120.9，117.5，115.4，43.2，40.6，38.8。

HRMS(ESI)calcd for C ₂₃H ₂₁N ₂O ₄[M-H] ⁺389.1501，found 389.1505。

Embodiment 11

3-phenyl-4-(4-(4-sec.-propyl phenoxy group) aniline formyl radical)-butyric acid (11)

Synthetic method is see embodiment 1, and difference is the compound 1.2 used in synthetic compound 1.4 process to replace with australol, and product is white solid, productive rate 45%.

¹H NMR(400MHz，DMSO-d ₆)：δ12.08(s，1H)，9.88(s，1H)，7.51(d，2H，J=8.4Hz)，7.29-7.28(m，4H)，7.23-7.18(m，3H)，6.92(d，2H，J=8.4Hz)，6.87(d，2H，J=8.0Hz)，3.62-3.55(m，1H)，2.90-2.81(m，1H)，2.72-2.55(m，4H)。

¹³C NMR(100MHz，DMSO-d ₆)：δ173.3，169.6，155.7，152.5，144.1，143.5，135.2，128.7，128.1，127.9，126.8，121.2，119.5，118.3，43.1，38.7，20.7。

Embodiment 12

3-phenyl-4-(4-(4-chlorine benzyloxy) aniline formyl radical)-butyric acid (12)

The synthesis (12.4) of 4-(4-chlorine benzyloxy) aniline

Compound 12.1 (300mg, 2.0mmol) and compound 12.2 (411mg, 2.0mmol) are joined in DMSO (2mL), then add salt of wormwood (6mmol, 830mg), normal-temperature reaction is spent the night.After reaction terminates, with water and extraction into ethyl acetate, be separated and obtain organic phase, anhydrous sodium sulfate drying, concentrate to obtain yellow solid product 12.3.

¹H NMR(400MHz，DMSO-d ₆)：δ8.26(d，2H，J=8.8Hz)，7.37-7.11(m，4H)，7.12(d，2H，J=9.2Hz)。

Be dissolved in by compound 12.3 (300mg, 1.03mmol) in methyl alcohol (5mL), then add the aqueous solution of 2N potassium hydroxide in this solution, reaction is heated to backflow and spends the night.After reaction terminates, by reaction solution water and extraction into ethyl acetate, be separated organic phase, dry concentrated, obtain compound 12.4, be not purifiedly directly used in next step reaction.

The synthesis of compound 12

Synthetic method is see the process (can indicate certain step concrete of embodiment 1) by compound 1.4 and 1.6 synthetic compound 1 in embodiment 1, and product is white solid, productive rate 62%.

¹H NMR(400MHz，DMSO-d ₆)：δ12.02(s，1H)，9.69(s，1H)，7.47-7.45(m，4H)，7.41(d，2H，8.8Hz)，7.28(d，4H，J=4.4Hz)，7.20-7.17(m，1H)，6.91(d，2H，J=8.8Hz)，3.61-3.31(m，1H)，2.72-2.56(m，4H)。

¹³C NMR(100MHz，DMSO-d ₆)：δ173.3，169.3，154.4，144.1，136.7，133.0，132.8，129.9，128.9，128.7，127.9，126.8，121.1，115.3，68.9，43.1，38.7。

Embodiment 13

3-phenyl-4-(4-(2-fluorine benzyloxy) aniline formyl radical)-butyric acid (13)

Synthetic method is see embodiment 12, and difference is the compound 12.2 used in synthetic compound 12.4 process to replace with adjacent fluorobenzyl bromide, and product is white solid, productive rate 54%.

¹H NMR(400MHz，DMSO-d ₆)：δ12.02(s，1H)，9.69(s，1H)，7.51-7.47(m，1H)，7.38-7.34(m，3H)，7.24-7.11(m，7H)，6.89(d，2H，J=8.8Hz)，5.03(s，2H)，3.56-3.48(m，1H)，2.67-2.49(m，4H)。

¹³C NMR(100MHz，DMSO-d ₆)：δ173.4，169.4，162.0，159.6，154.4，144.1，133.1，131.1，131.8，130.7，128.7，127.9，126.8，125.0，124.9，124.5，124.3，121.1，115.9，115.7，115.2，64.14，64.10，43.2，38.7。

HRMS(ESI)calcd for C ₂₃H ₂₀BrNO ₄[M-H] ⁺406.1455，found 406.1454。

Embodiment 14

3-(4-p-methoxy-phenyl)-4-(4-(4-chlorophenoxy) aniline formyl radical)-butyric acid (14)

Synthetic method is see embodiment 1, and difference is the phenyl aldehyde used in synthetic compound 1.6 process to replace with aubepine, and product is white solid, productive rate 61%.

¹H NMR(400MHz，DMSO-d ₆)：δ12.03(1H)，9.90(1H)，7.55(d，2H，J=8.8Hz)，7.39(d，2H，J=8.8Hz)，7.20(d，2H，J=8.4Hz)，6.99-6.95(m，4H)，6.84(d，2H，J=8.4Hz)，3.71(s，3H)，3.57-3.50(m，1H)，2.68-2.53(m，4H)。

¹³C NMR(100MHz，DMSO-d ₆)：δ173.4，168.8，158.2，156.9，151.5，135.94，135.87，130.2，128.8，127.0，121.3，119.8，114.1，55.4，43.4，40.9，37.9。

Embodiment 15

3-(4-tolyl)-4-(4-(4-chlorophenoxy) aniline formyl radical)-butyric acid (15)

Synthetic method is see embodiment 1, and difference is the phenyl aldehyde used in synthetic compound 1.6 process to replace with p-tolyl aldehyde, and product is white solid, productive rate 55%.

¹H NMR(400MHz，DMSO-d ₆)：δ12.04(s，1H)，9.91(s，1H)，7.55(d，2H，J=9.2Hz)，7.39(d，2H，J=8.8Hz)，7.17(d，2H，J=8.0Hz)，7.08(d，2H，J=8.0Hz)，6.97-6.95(m，4H)，3.58-3.51(m，1H)，2.69-2.53(m，4H)，2.25(s，3H)。

¹³C NMR(100MHz，DMSO-d ₆)：δ173，4，169.7，156.9，151.5，141.0，135.9，135.8，130.2，129.3，127.7，127.0，121.2，120.1，119.8，43.2，38.3，21.1。

HRMS(ESI)calcd for C ₂₄H ₂₃ClNO ₄[M+H] ⁺424.1316，found 424.1315。

Embodiment 16

3-(4-chloro-phenyl-)-4-(4-(4-chlorophenoxy) aniline formyl radical)-butyric acid (16)

Synthetic method is see embodiment 1, and difference is the phenyl aldehyde used in synthetic compound 1.6 process to replace with 4-chloro-benzaldehyde, and product is white solid, productive rate 54%.

¹H NMR(400MHz，DMSO-d ₆)：δ12.12(s，1H)，9.93(s，1H)，7.54(d，2H，J=8.8Hz)，7.39(d，2H，J=8.4Hz)，7.34-7.30(m，4H)，6.99-6.95(m，4H)，3.62-3.54(m，1H)，2.73-2.55(m，4H)。

¹³C NMR(100MHz，DMSO-d ₆)：δ173.2，169.5，156.9，151.6，143.0，135.8，131.4，130.2，129.9，128.6，127.0，121.3，120.1，119.8。

HRMS(ESI)calcd for C ₂₃H ₂₀Cl ₂NO ₄[M-H] ⁺444.0769，found 444.0771。

Embodiment 17

3-(4-hydroxy phenyl)-4-(4-(4-chlorophenoxy) aniline formyl radical)-butyric acid (17)

Compound 14 (500mg, 1.14mmol) is dissolved in methylene dichloride (50mL) under ice bath, then dropwise adds dichloromethane solution (6mL, the 1.0M in CH of boron tribromide ₂cl ₂), after temperature being raised to room temperature, reaction carries out 30 minutes.After reaction terminates, in reaction solution, carefully add water extract reaction of going out, and remove methylene dichloride, then be extracted with ethyl acetate, be separated organic phase and concentrate drying, column chromatography for separation (ethyl acetate: sherwood oil=2:1) obtains white solid, productive rate 53%.

¹H NMR(400MHz，DMSO-d ₆)：δ12.00(s，1H)，9.87(s，1H)，7.54(d，2H，J=9.2Hz)，7.39(d，2H，J=9.2Hz)，7.07(d，2H，J=8.8Hz)，6.98-6.95(s，4H)，6.66(d，2H，J=8.8Hz)，3.51-3.44(m，1H)，2.65-2.50(m，4H)。

¹³C NMR(100MHz，DMSO-d ₆)：δ173.5，169.9，156.9，156.2，151.5，135.9，134.1，130.2，128.7，121.3，120.1，119.8，115.4，43.5，41.0，40.0。

HRMS(ESI)calcd for C ₂₃H ₁₉ClNO ₅[M-H] ⁺424.0952，found 424.0952。

Embodiment 18

2-phenyl-3-(4-(3-chlorophenoxy) aniline formyl radical) the third sulphonamide (18)

N, N-bis-(4-methoxy-benzyl) Toluidrin (19.4)

Compound 18.1 (6.80g, 50mmol) and compound 18.2 (6.85g, 50mmol) are dissolved in ethanol (100mL), reflux is after 2 hours.After reaction terminates, by the solvent of reaction system except dry, then the oily matter obtained is dissolved in ethanol (100mL), under ice bath, adds sodium borohydride (2.8g, 73.6mmol) several times, reflux 2 hours.Except desolventizing after reaction terminates, by the oily matter ethyl acetate that obtains and water extraction, anhydrous sodium sulfate drying, except desolventizing obtains compound 18.3, is not purifiedly directly used in next step.

Compound 18.3 (7.32g, 28.5mmol) is dissolved in methylene dichloride (60mL), under ice bath, adds methylsulfonyl chloride (3.25g, 28.5mmol), then rise to normal-temperature reaction 5 hours.After reaction terminates, extract with methylene dichloride and water, be separated organic phase, anhydrous sodium sulfate drying, it is white solid 6.03g that evaporating column chromatographic separation (ethyl acetate: sherwood oil=1:4) obtains compound 18.4, productive rate 63%.

¹H NMR(400MHz，DMSO-d ₆)：δ7.19(d，4H，J=8.4Hz)，6.89(d，4H，J=8.8Hz)，4.19(s，4H)，3.74(s，6H)，2.89(s，3H)。

MS(EI)m/z：335[M] ⁺。

The synthesis of compound 18.6

By compound 18.4 (2.01g, 15mmol) be placed in the low-temp reaction bottle of 100mL, and be cooled to-20 DEG C, the anhydrous tetrahydrofuran solution of LiHMDS is dropwise added in low-temp reaction bottle, reaction solution adds diethyl chloro-phosphate (2.60g after stirring half an hour, 15mmol). after one hour, add phenyl aldehyde (1.59g, 15mmol), then reaction solution rises to room temperature reaction one hour, after reaction terminates, to reaction solution water and extraction into ethyl acetate, be separated organic phase, anhydrous sodium sulfate drying, it is white solid 4.87g that evaporating column chromatographic separation (ethyl acetate: sherwood oil=1:10) obtains compound 18.6, productive rate 77%.

¹H NMR(400MHz，DMSO-d ₆)：δ7.64-7.50(m，5H)，7.38(d，1H，J=15.8Hz)，7.24-7.18(m，5H)，6.86(d，4H，J=8.4Hz)，4.21(s，4H)，3.71(s，6H)。

MS(EI)m/z：423[M] ⁺。

The synthesis of compound 18.7

Compound 18.6 is dissolved in acetonitrile (20mL), then sodium methylate (1.08g is added, methyl alcohol (20mL) solution 20mmol), add dimethyl malonate (2.65g again, 20mmol), reaction solution reflux two days. after reaction terminates, concentrate and use water and extraction into ethyl acetate, be separated in machine phase, anhydrous sodium sulfate drying evaporating column chromatographic separation (ethyl acetate: sherwood oil=1:5) obtains compound 18.7 for white crystal 3.14g, productive rate 57%.

¹H NMR(400MHz，DMSO-d ₆)：δ7.31-7.23(m，5H)，7.06(d，4H，J=8.0Hz)，6.83(d，4H，J=8.4Hz)，4.09(d，2H，J=15.2Hz)，3.94(d，1H，J=9.2Hz)，3.91(d，2H，J=15.2Hz)，3.85-3.80(m，1H)，3.72(s，6H)，3.70-3.63(m，4H)，3.46-3.42(dd，1H，J ₁=2.8Hz，J ₂=14.4Hz)，3.36(s，3H)。

MS(ESI)m/z：555[M+H] ⁺。

Compound 18.9 synthesizes

Compound 18.7 (360mg, 0.65mmol) is dissolved in DMF (2mL), and instills two and drip, then add lithium chloride (196mg, 3.25mmol), reaction backflow 5 hours.After reaction terminates, with water and extraction into ethyl acetate, be separated organic phase, anhydrous sodium sulfate drying, and concentrated obtain crude oil (18.8).Compound 18.8 is dissolved in methyl alcohol (5mL), then adds water (2mL) solution of a water and lithium hydroxide (137mg, 3.25mmol), reaction stirred overnight at room temperature.After reaction terminates, with water and extraction into ethyl acetate, be separated organic phase, anhydrous sodium sulfate drying, it is 255mg that concentrated and column chromatography for separation (ethyl acetate: sherwood oil=1:2) obtains white crystalline Compound 18.9, productive rate 81%.

¹H NMR(400MHz，DMSO-d ₆)：δ12.15(s，1H)，7.32-7.20(m，5H)，7.13(d，4H，8.8Hz)，6.85(d，4H，8.8Hz)，4.18(d，2H，J=15.2Hz)，4.08(d，2H，J=14.8)，3.73(s，6H)，3.54-3.48(m，2H)，3.28-3.23(dd，1H，J ₁=4.8Hz，J ₂=12.8Hz)，2.96-2.90(dd，1H，J ₁=4.4Hz，J ₂=16.0Hz)，2.64-2.58(dd，1H，J ₁=9.2Hz，J ₂=16.0Hz)。

The synthesis of compound 18.10

By compound 18.9 (97mg, 0.20mmol) and corresponding amine compound, namely 4-(4-chlorophenoxy) aniline is dissolved in DMF, and add HBTU (92mg, 0.24mmol) with DIPEA (32mg, 0.24mmol), room temperature reaction spends the night.After reaction terminates, with water and extraction into ethyl acetate, be separated organic phase, anhydrous sodium sulfate drying, it is 107mg that concentrated and column chromatography for separation (ethyl acetate: sherwood oil=1:3) obtains compound as white solid 18, productive rate 78%.

¹H NMR(400MHz，CDCl ₃)：δ9.89(s，1H)，7.51(d，2H，J=8.8Hz)，7.38(d，2H，J=8.8Hz)，7.31-7.21(m，5H)，7.13(d，4H，J=8.8Hz)，6.96(d，2H，J=9.2Hz)，6.95(d，2H，J=8.8Hz)，6.84(d，2H，J=8.8Hz)，4.19(d，2H，J=15.2Hz)，4.07(d，2H，J=15.2)，3.74-3.69(m，7H)，3.55(dd，1H，J ₁=6.8Hz，J ₂=14.4Hz)，3.53-3.35(m，1H)，2.93(dd，1H，J ₁=5.6Hz，J ₂=15.2Hz)，2.71(dd，1H，J ₁=9.2Hz，J ₂=14.8Hz)。

¹³C NMR(100MHz，DMSO-d ₆)：δ169.1，159.1，156.9，151.6，142.6，135.7，130.3，130.2，128.7，128.5，128.2，127.2，127.1，121.3，120.1，119.8，114.2，57.1，55.5，49.8，42.6，37.7。

The synthesis of compound 18

Compound 18.10 (50mg, 0.073mmol) is dissolved in methylene dichloride (1mL), and adds trifluoroacetic acid (1mL), reaction stirring at normal temperature 3 hours.After reaction terminates, except desolventizing, with water and extraction into ethyl acetate, be separated organic phase, anhydrous sodium sulfate drying, it is 21mg that concentrated and column chromatography for separation (methylene dichloride: methyl alcohol=50:1) obtains compound as white solid 18, productive rate 65%.

¹H NMR(400MHz，DMSO-d ₆)：δ9.89(s，1H)，7.50(d，2H，J=8.8Hz)，7.38(d，2H，J=8.8Hz)，7.33-7.27(m，3H)，7.21-7.18(m，2H)，6.96(d，2H，J=9.2Hz)，6.95(d，2H，J=9.2Hz)，6.86(s，2H)，3.78-3.71(m，1H)，3.54-3.49(dd，1H，J ₁=7.2Hz，J ₂=14.4Hz)，3.31-3.26(dd，1H，J ₁=6.0Hz，J ₂=14.4Hz)，3.02-2.97(dd，1H，J ₁=5.6Hz，J ₂=14.8Hz)，2.76-2.70(dd，1H，J ₁=7.2Hz，J ₂=14.8Hz)。

¹³C NMR(100MHz，DMSO-d ₆)：δ169.3，156.9，151.6，143.3，135.8，130.2，128.7，127.1，121.3，120.1，119.8，60.1，42.5，37.9。

HRMS(ESI)calcd for C ₂₂H ₂₁ClN ₂O ₄S[M+Na] ⁺467.0808，found 467.0806。

Embodiment 19

2-phenyl-3-(4-(3,4-dichlorophenoxy) aniline formyl radical) the third sulphonamide (19)

Synthetic method is see embodiment 18, and difference is the 4-used in synthetic compound 18.10 process (4-chlorophenoxy) aniline to replace with 4-(3,4-dichlorophenoxy) aniline, and obtaining product is white solid, productive rate 29%.

¹H NMR(400MHz，CDCl ₃)：δ9.92(s，1H)，7.58(d，1H，J=9.2Hz)，7.53(d，2H，J=9.2Hz)，7.33-7.27(m，4H)，7.21-7.19(m，2H)，7.01(d，2H，J=9.2Hz)，6.94-6.91(dd，1H，J ₁=5.2Hz，J ₂=9.2Hz)，6.85(s，2H)，3.78-3.71(m，1H)，3.54-3.49(dd，1H，J ₁=7.6Hz，J ₂=15.2Hz)，3.31-3.26(dd，1H，J ₁=6.0Hz，J ₂=14.0Hz)，3.03-2.97(dd，1H，J ₁=5.6Hz，J ₂=15.2Hz)。

¹³C NMR(100MHz，DMSO-d ₆)：δ169.3，157.6，150.9，143.3，136.3，132.4，131.9，128.7，128.0，127.1，125.2，121.3，120.5，119.8，118.3，60.1，42.5，37.9。

HRMS(ESI)calcd for C ₂₂H ₂₀Cl ₂N ₂O ₄S[M+Na] ⁺501.0419，found 501.0421。

Embodiment 20

2-(4-p-methoxy-phenyl)-3-(4-(3,4-dichlorophenoxy) aniline formyl radical) the third sulphonamide (20)

Synthetic method is see embodiment 18, and difference is the phenyl aldehyde used in synthetic compound 18.6 process to replace with aubepine; 4-(4-chlorophenoxy) aniline used in synthetic compound 18.10 process replaces with 4-(3,4-dichlorophenoxy) aniline, and obtaining product is white solid, productive rate 77%.

¹H NMR(400MHz，CDCl ₃)：δ9.91(s，1H)，7.58(d，1H，J=8.8Hz)，7.54(d，2H，J=9.2Hz)，7.23(d，2H，8.8Hz)，7.20(d，1H，J=2.8Hz)，7.02(d2H，J=8.8Hz)，6.94-6.91(dd，1H，J ₁=2.8Hz，J ₂=8.8Hz)，6.85(d，2H，J=8.8Hz)，6.82(s，2H)，3.71-3.66(m，4H)，3.51-3.46(dd，1H，J ₁=3.46Hz，J ₂=14.4Hz)，3.27-3.22(dd，1H，J ₁=5.2Hz，J ₂=14.8Hz)，2.73-2.66(dd，1H，J ₁=9.2Hz，J ₂=14.8Hz)。

HRMS(ESI)calcd for C ₂₃H ₂₀BrNO ₄[M+Na] ⁺531.0524，found 531.0522。

Compound provided by the invention is to farnesyl transferase vitro inhibition active effect:

The abduction delivering of 1.FTase

1.1 preculture

PRSFDuet-FNT α β-BL21 (this bacterial strain is from Professor Gerrit J.K.Praefcke) the bacterium liquid getting 30 μ l preservations is inoculated in that resistance LB substratum of 5mL card, kantlex final concentration is 50 μ g/mL, 37 DEG C, 230rpm shaking table overnight incubation.

1.2 enlarged culturing

The bacterium liquid getting 3.0mL incubated overnight is seeded in the LB substratum of 500mL sterilizing, adds the kantlex that final concentration is 50 μ g/mL, 37 DEG C, the cultivation of 230rpm shaking table.

1.3 abduction delivering

When constant temperature culture is 0.6 to OD600, adding inductor IPTG to final concentration is 0.5mM, and ZnCl ₂be 0.5mM to final concentration, 16 DEG C, 230rpm induces 16h.

1.4 collect thalline

At bacterium liquid 4 DEG C, the centrifugal 20min of 4000rpm, outwells supernatant substratum, is again hanged by thalline with sterilized water, again with the centrifugal 10min of 10000rpm rotating speed, abandons supernatant, and bacterial sediment is in-80 DEG C of preservations.

The purifying of 2.FTase

2.1 ultrasonication

With 20mL lysis buffer (50mM Tris, 200mM NaCl, 50 μMs of ZnCl ₂, 5mM MgCl ₂, 1mM beta-mercaptoethanol, 20mM imidazoles, pH7.7) thalline is hanged, ultrasonication 5 times (300W, works 5 seconds, and 10 seconds, interval works 30 times) on ice bath.The cell homogenates obtained after fragmentation is the centrifugal 30min of 10000rpm at 4 DEG C, and supernatant is treated and resin-bonded.

2.2 protein purification

Ni-NTA chromatography column pre-treatment: after bleeding off ethanol, washes 3-4 time, in conjunction with NiSO ₄20min, washes 3-4 time, balances with elution buffer.

By the albumen supernatant liquor in previous step and pretreated Ni post resin-bonded 4h, reload in chromatography column, after protein liquid stream is complete, with elution buffer (50mM tris buffer, 200mM NaCl, 50 μMs of ZnCl of 80mL ₂, 5mM MgCl ₂, 1mM beta-mercaptoethanol, 20mM imidazoles, pH7.7) divide and flow through chromatography column four times, foreign protein is washed off as far as possible, then add about 10ml elution buffer (50mM tris buffer, 200mM NaCl, 50 μMs of ZnCl ₂, 5mM MgCl ₂, 1mM beta-mercaptoethanol, 200mM imidazoles, pH7.7), make it slowly flow out, coutroi velocity often drips for about 10 seconds, is in charge of collection.Albumen is loaded in MD34-14 dialysis tubing, with dialysis buffer liquid (50mM tris buffer, 200mM NaCl, 50 μMs of ZnCl in 4 DEG C of chromatography cabinets ₂, 5mM MgCl ₂, 1mM beta-mercaptoethanol, pH7.7) dialyse at twice, each 4-5h, is concentrated into about 1ml with micropore evaporating pipe afterwards.Albumen is put in 4 DEG C temporarily to preserve, detects molecular weight of albumen and purity for SDS-PAGE.After sampling, add 20% glycerine, in-80 DEG C of preservations.

2.3 SDS-PAGE electrophoresis detection protein concentration and purity

The each sample of collection is got 10 μ l, add the sample loading buffer of equivalent, boil ten minutes, the centrifugal 2min of 4000rpm boiling on sample device 100 DEG C.SDS-PAGE gel is prepared according to the preparation method of glue in experimental technique, install electrophoresis system, after adding electrophoretic buffer, select loading volume according to glue hole, be generally 10 μ l, connect electrode, electrophoresis is carried out with 90V voltage, tetrabromophenol sulfonphthalein changes 120V voltage into after entering separation gel, when tetrabromophenol sulfonphthalein just runs out of separation gel, stops electrophoresis.Unload offset plate, peel off glue and put into staining fluid and to dye 2-3h, add destainer, be placed on 80rpm decolorization swinging table and decolour.After purifying completely, by gel imaging system record experimental result, purity is 75.4%.

2.4 Bradford methods survey protein concentration

Survey the method for protein concentration with Bradford, first drawing standard curve, do two groups parallel.

After vibration mixing, room temperature places 5-10min, and take protein content as X-coordinate, light absorption value (A595) is ordinate zou, drawing standard curve.

Albumen after concentrated is diluted 20 times, gets 2 μ l, add 198 μ l staining fluids, read light absorption value.

Recording protein concentration is 35mg/ml, altogether 1ml.

3. farnesyl transferase is lived and is measured

The measuring method that farnesyl transferase is lived mainly carries out according to the method for David L.Pompliano.Red for substrate N-sulphonyl-GCVLS (a kind of polypeptide of modification, GCVLS represented amino acid sequence) is used DMSO melt into 1mM, and farnesyl pyrophosphate ester (FPP) is with detecting damping fluid (50mM tris buffer, 20 μMs of ZnCl ₂, 10mMMgCl ₂, 5mM dithiothreitol (DTT), 0.02% glucopyranoside, pH7.5) and be diluted to 10 μMs.Farnesyl transferase dialysis buffer liquid is diluted to different concns gradient (25 μMs, 20 μMs, 10 μMs, 5 μMs, 2.5 μMs).

According to the reaction system of table 1, BioTek-Synergy2 microplate reader is utilized to carry out enzyme test experiments alive.Reaction is totally 50 μ l, first detection damping fluid is joined in 384 orifice bores, add the enzyme of the red sulphonyl-GCVLS (a kind of polypeptide of modification, GCVLS represented amino acid sequence) of N-and different concns again, last addition method Thessaloniki pyrophosphate initial action.After reaction starts, exciting 340nm, launch first order fluorescence absorption intensity was detected at 505nm place change every 30 seconds, detecting whole reaction process is 10 minutes.Obtain fluorescence curve over time, and then determine best enzyme condition alive.

Table 1 farnesyl transferase (Ftase) surveys live body system

Assay buffer	The red sulphonyl-GCVLS (1mM) of N-	Farnesyl pyrophosphate ester (10 μMs)	Farnesyl transferase
				44.4μl	0.1μl	5μl	0.5μl

4. the screening of farnesyl transferase inhibitor (FTT)

The 4.1 positive IC for pyrrole method Buddhist nun ₅₀

Positive compound DMSO is dissolved into the mother liquor of 5mM, redilution becomes concentration gradient (50 μMs, 25 μMs, 10 μMs, 5 μMs, 2 μMs, 1 μM, 0.5 μM, 0.1 μM, 0.05 μM).Required damping fluid is calculated according to the hole count that will add, the amount of the red sulphonyl-GCVLS of N-and farnesyl transferase (final concentration 0.2 μM), premix, join in 384 orifice plates with the volley of rifle fire, add the positive of 0.1 μ l concentration gradient more respectively for pyrrole method Buddhist nun, incubated at room 10 minutes, adds substrate farnesyl pyrophosphate ester, reading.Each experiment establish 3 parallel, be blank with DMSO, obtain the IC for pyrrole method Buddhist nun ₅₀figure (accompanying drawing 1).

4.2 primary dcreening operation

After enzyme lives test, suitable enzyme concn (0.2 μM) is selected to carry out the screening of inhibitor.Being diluted by compound DMSO, carry out primary dcreening operation with 10 μMs, is positive control for pyrrole method Buddhist nun.Reaction system is as table 2:

Table 2 screening compound system

Assay buffer	The red sulphonyl-GCVLS (1mM) of N-	Compound (10 μMs)	FTase	FPP(10μM)
					44.2μl	0.1μl	0.2μl	0.5μl	5μl

5 experimental results

As shown in table 3 below from experimental result, enzyme inhibition activity when known group x is carboxyl is best, and be secondly sulphonamide, acid amides is then the most weak; R ₂for little hydrophobic group and y be 0 time, the inhibit activities of enzyme is better, and what illustrate that this part occupies is enzyme hydrophobic active pocket, and space is less; R ₁should be less hydrophilic radical, as hydroxyl or amino.

Table 3 compound 1-20 is to the IC of FTase ₅₀

Claims (6)

1. an amino benzenes compounds, it is compound shown in formula I or its acceptable salt on pharmacology:

Wherein, X is COOH or SO ₂nH ₂; R ₁and R ₂independently be selected from: H, C ₁~ C ₃alkyl or alkoxyl group, CF ₃, F, Cl, Br, I, NH ₂or NO ₂middle one; M and n is respectively the integer of 0 ~ 5; Y is 0 or 1;

But do not comprise following compounds:

2. amino benzenes compounds as claimed in claim 1, it is characterized in that, described aminated compounds is one of following compounds or its acceptable salt on pharmacology:

3. a pharmaceutical composition, is characterized in that, described pharmaceutical composition comprises the amino benzenes compounds described in claim 1 or 2.

4. the application of amino benzenes compounds in the medicine preparing prevention or treatment and farnesyl transferase relative disease;

Wherein, described for amino benzenes compounds be compound shown in formula I or its acceptable salt on pharmacology:

Wherein, X is COOH or SO ₂nH ₂; R ₁and R ₂independently be selected from: H, C ₁~ C ₃alkyl or alkoxyl group, CF ₃, F, Cl, Br, I, NH ₂or NO ₂middle one; M and n is respectively the integer of 0 ~ 5; Y is 0 or 1.

5. the application of pharmaceutical composition in the medicine preparing prevention or treatment and farnesyl transferase relative disease;

Wherein, compound shown in described pharmaceutical composition contained I or its acceptable salt on pharmacology:

Wherein, X is COOH or SO ₂nH ₂; R ₁and R ₂independently be selected from: H, C ₁~ C ₃alkyl or alkoxyl group, CF ₃, F, Cl, Br, I, NH ₂or NO ₂middle one; M and n is respectively the integer of 0 ~ 5; Y is 0 or 1.

6. the application as described in claim 4 or 5, wherein said is prostate cancer, lung cancer, mammary cancer, carcinoma of the pancreas or colorectal carcinoma with farnesyl transferase relative disease.