CN101812059B - Nitric oxide donor-type farnesyl thiosalicylic acid derivative, and preparation method and medical application thereof - Google Patents

Nitric oxide donor-type farnesyl thiosalicylic acid derivative, and preparation method and medical application thereof Download PDF

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CN101812059B
CN101812059B CN2010101460292A CN201010146029A CN101812059B CN 101812059 B CN101812059 B CN 101812059B CN 2010101460292 A CN2010101460292 A CN 2010101460292A CN 201010146029 A CN201010146029 A CN 201010146029A CN 101812059 B CN101812059 B CN 101812059B
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oxygen
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fta
oxadiazole
benzenesulfonyl
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张奕华
凌勇
赖宜生
叶小磊
季晖
彭司勋
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China Pharmaceutical University
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Abstract

The invention discloses a nitric oxide (NO) donor-type farnesyl thiosalicylic acid (FTA) derivative, and pharmaceutically acceptable salt, a preparation method and medical application thereof. The FTA derivative is a compound obtained by carrying out heterozygosis on a NO donor furazan nitrogen oxide and Ras protein inhibitor FTA by an ester bond or an amido bond. Pharmacological test results show that the FTA derivative can reserve the Ras protein inhibiting activity of FTA and simultaneously releases high-concertration NO to induce cancer cell apoptosis and enhance the inhibiting action on cancer cell proliferation; compared with the FTA, the FTA derivative has more excellent anti-tumor activity, and therefore, the compound can be suitable for treating various clinical malignant tumours.

Description

Nitric oxide donator type farnesyl thio-salicylic acid derivative, its preparation method and medicinal use thereof
Technical field
The present invention relates to pharmaceutical field; Be specifically related to one type of nitric oxide donator type farnesyl thio-salicylic acid derivative and pharmacy acceptable salt thereof; Their preparation method; Contain the medicinal compsns of these verivates and their medicinal use, particularly the application in the preparation antitumor drug.
Background technology
Alltrans farnesyl thiosalicylic acid (is called for short: FTA; Trade(brand)name: Salirasib) as new Ras protein inhibitor based on farnesyl transferase; Can competitive replace F-Ras and the F-Ras mutain combines with Galectins; Inhibition causes downstream signal path (comprising Raf and P13K signal path) and mTOR (tumorigenic stimulator, it can rely on or open the P13K signal path independently) by Ras, thus the growth of inhibition tumour cell.Research shows that FTA can suppress kinds of tumors (cerebral glioma, liver cancer, lung cancer, carcinoma of the pancreas, mammary cancer, colorectal carcinoma etc.) cell proliferation and migration (Haklai, R.; Elad-Sfadia, G.; Egozi, Y.et al.Cancer Chemother Pharmacol, 2008,61 (1): 89-96; Tsimberidou, A.M.; Rudek, M.A.; Hong, D.et al.Cancer Chemother Pharmacol, 2009,65 (2): 235-241; Zundelevich, A.; Elad-Sfadia, G.; Haklai, R.et al.Mol Cancer Ther, 2007,6 (6): 1765-1773).FTA treats the II phase clinical study well afoot of lung cancer and carcinoma of the pancreas at present.
Figure GSA00000083319200011
The farnesyl thiosalicylic acid (FTA, Salirasib)
Nitrogen protoxide (NO) is courier's material and an effector molecule important in the mammalian body.In recent years, the NO effect in generation, development and the death of tumour having become one of focus of tumor research and treatment (Mocellin S.Curr Cancer DrugTargets, 2009,9 (2): 214-236; Coulter JA, McCarthy HO, Xiang J, et al.Nitric Oxide, 2008,19 (2): 192-198).Big quantity research shows that the NO that continues lower concentration in the body can promote the growth of cell to suppress apoptosis; The NO of high density then produces cytotoxicity, inducing apoptosis of tumour cell, the diffusion and transfer (Huerta S, Chilka S, Bonavida B.Int J Oncol, 2008,33 (5): 909-927) that stop tumour cell.
The NO donor is meant one type of compound that discharges a certain amount of NO in vivo through enzyme or non-enzyme effect.Furazan oxynitride (Furoxan) is one type of important NO donor, has anti-tumor activity (Chen L, Zhang Y, Kong X, et al.J Med Chem, 2008,51 (15): 4834-4838) by the higher concentration NO of its generation.
For obtaining the compound more excellent than FTA anti-tumor activity, we have carried out the structural modification research of FTA.The invention discloses one type of furazan oxynitride class NO donator type FTA verivate and pharmacy acceptable salt thereof, do not see any report at present as yet this compounds with pharmaceutical use.
Summary of the invention
The present invention discloses one type of furazan oxynitride class NO donator type FTA verivate and pharmacy acceptable salt, its preparation method and medicinal use thereof with anti-tumor activity first.The pharmacological results shows; The Ras albumen that FTA verivate of the present invention can keep FTA suppresses active, discharges higher concentration NO simultaneously, cell death inducing; Enhancing is to the restraining effect of cancer cell multiplication; Have better anti-tumor activity than FTA, therefore, this compounds possibly be applicable to the multiple clinically malignant tumour of treatment.
New compound disclosed by the invention is FTA verivate and the pharmacy acceptable salt thereof shown in general formula I, the II:
In the general formula I: X representative-O-,-N-or-NH-; R representative-(CH 2) n-, n=2～6 ,-CH (CH 3) CH 2-,-CH (CH 3) (CH 2) 2-,-(CH 2) 2O (CH 2) 2-,-PhCH 2-,-(CH 2CH 2OH) CH 2CH 2-,-(CH 2) 2NH (CH 2) 2-,-(CH 2) 2NBoc (CH 2) 2-,-(CH 3) CH 2CH 2-,-(CH 2CH 2) 2NCH 2CH 2-,-(CH 2CH 2) 2CH (CH 2) n-, n=0～2 ,-(CH 2CH 2CH 2) CHCH 2-,-CH 2CH=CHCH 2-or-CH 2C ≡ CCH 2-;
Figure GSA00000083319200022
Among the general formula I I :-NH-A-CO-represents glycocoll, Beta-alanine, γ-An Jidingsuan, L-or D-type L-Ala, L-or D-type Xie Ansuan, L-or D-type leucine, L-or D-type Isoleucine, L-or D-type methionine(Met), L-or D-type halfcystine, L-or D-type phenylalanine(Phe), L-or D-type tyrosine, L-or D-type tryptophane, L-or D-type l-arginine, L-or D-type proline(Pro), L-or D-type histidine residues; X representative-O-,-N-or-NH-; R representative-(CH 2) n-, n=2～6 ,-CH (CH 3) CH 2-,-CH (CH 3) (CH 2) 2-,-(CH 2) 2O (CH 2) 2-,-PhCH 2-,-(CH 2CH 2OH) CH 2CH 2-,-(CH 2) 2NH (CH 2) 2-,-(CH 2) 2NBoc (CH 2) 2-,-(CH 3) CH 2CH 2-,-(CH 2CH 2) 2NCH 2CH 2-,-(CH 2CH 2) 2CH (CH 2) n-, n=0～2 ,-(CH 2CH 2CH 2) CHCH 2-,-CH 2CH=CHCH 2-or-CH 2C ≡ CCH 2-.
The preferred compound of the present invention is FTA verivate shown in the general formula I and medically acceptable salt thereof: X representative-O-,-N-or-NH-; R representative-(CH 2) n-, n=2～6 ,-CH (CH 3) (CH 2) 2-,-(CH 2) 2O (CH 2) 2-,-(CH 2CH 2OH) CH 2CH 2-,-(CH 2) 2NH (CH 2) 2-,-(CH 2) 2NBoc (CH 2) 2-,-(CH 3) CH 2CH 2-,-(CH 2CH 2) 2CH-,-(CH 2CH 2) 2NCH 2CH 2-,-(CH 2CH 2CH 2) CHCH 2-,-CH 2CH=CHCH 2-or-CH 2C ≡ CCH 2-.
The preferred compound of the present invention is that FTA verivate shown in the general formula I I and medically acceptable salt :-NH-A-CO-thereof represent glycocoll, Beta-alanine, L-or D-type L-Ala, L-or D-type phenylalanine(Phe), L-or D-type proline(Pro), L-or D-type leucine residue; X representative-O-,-N-or-NH-; R representative-(CH 2) n-, n=2～6 ,-CH (CH 3) (CH 2) 2-,-(CH 2) 2O (CH 2) 2-,-CH 2CH=CHCH 2-or-CH 2C ≡ CCH 2-.
The further preferred compound of the present invention is FTA verivate shown in the general formula I and medically acceptable salt thereof: X representative-O-,-N-or-NH-; R representative-(CH 2) n-, n=2～6 ,-CH (CH 3) (CH 2) 2-,-(CH 2) 2O (CH 2) 2-,-(CH 2CH 2OH) CH 2CH 2-,-(CH 2) 2NH (CH 2) 2-,-(CH 2) 2NBoc (CH 2) 2-,-(CH 3) CH 2CH 2-,-(CH 2CH 2) 2NCH 2CH 2-,-(CH 2CH 2) 2CH-,-(CH 2CH 2CH 2) CHCH 2-or-CH 2C ≡ CCH 2-;
The further preferred compound of the present invention is FTA verivate shown in the general formula I I and medically acceptable salt thereof:
-NH-A-CO-represents glycocoll, Beta-alanine, L-L-Ala, L-phenylalanine(Phe), L-proline(Pro) or L-leucine residue; X representative-O-,-N-or-NH-; R representative-(CH 2) n-, n=2～6 ,-CH (CH 3) (CH 2) 2-,-(CH 2) 2O (CH 2) 2-or-CH 2C ≡ CCH 2-.
Concretely, the FTA verivate shown in general formula I, the II is preferably from following compounds:
N-{2-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] ethyl } farnesyl thiosalicylic acid acid amides
(compound number: I 1, down together)
N-{ [2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group } the inferior acid amides (I of piperazinyl farnesyl thiosalicylic acid 2)
4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)]-the 2-alkynyl } farnesyl thiosalicylic acid butyl ester (I 3)
N-{4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] piperidyl } the inferior acid amides (I of farnesyl thiosalicylic acid 4)
N-{3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl group } farnesyl thiosalicylic acid acid amides (I 5)
N-{N-methyl-2-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] ethyl } the inferior acid amides (I of farnesyl thiosalicylic acid 6)
1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] } farnesyl thiosalicylic acid propyl ester (I 7)
N-{2-{ [(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] methoxyl group } pyrrolidyl } the inferior acid amides (I of farnesyl thiosalicylic acid 8)
2-{N-tertbutyloxycarbonyl-2-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] ethylamino-} farnesyl thiosalicylic acid ethyl ester (I 9)
2-{ [2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] ethylamino-} farnesyl thiosalicylic acid ethyl ester (I 10)
N-{N-[2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] hydroxyethyl } farnesyl thiosalicylic acid ethanamide (I 11)
N-{ acetate-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl ester } farnesyl thiosalicylic acid acid amides (II 1)
N-{ acetate-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] butyl ester } farnesyl thiosalicylic acid acid amides (II 2)
N-{ acetate-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)]-2-alkynes-butyl ester } farnesyl thiosalicylic acid acid amides (II 3)
N-{ acetate-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] ethanamide } farnesyl thiosalicylic acid acid amides (II 4)
N-{2-propionic acid-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl ester } farnesyl thiosalicylic acid acid amides (II 5)
N-{2-propionic acid-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group] ethyl ester } farnesyl thiosalicylic acid acid amides (II 6)
N-{2-Pyrrolidine formic acid-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] butyl ester } the inferior acid amides (II of farnesyl thiosalicylic acid 7)
N-{2-propionic acid-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] butyl ester } farnesyl thiosalicylic acid acid amides (II 8)
N-{2-propionic acid-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)]-2-alkynes-butyl ester } farnesyl thiosalicylic acid acid amides (II 9)
N-{2-phenylpropionic acid-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group] ethyl ester } farnesyl thiosalicylic acid acid amides (II 10)
N-{2-Pyrrolidine formic acid-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl ester } the inferior acid amides (II of farnesyl thiosalicylic acid 11)
N-{2-Pyrrolidine formic acid-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)]-2-alkynes-butyl ester } the inferior acid amides (II of farnesyl thiosalicylic acid 12)
N-{2-Pyrrolidine formic acid-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group] ethyl ester } the inferior acid amides (II of farnesyl thiosalicylic acid 13)
N-{ acetate-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group] ethyl ester } farnesyl thiosalicylic acid acid amides (II 14)
N-{N '-[2-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl group]-the 2-propionic acid amide } farnesyl thiosalicylic acid acid amides (II 15)
N-{2-isocaproic acid-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl ester } farnesyl thiosalicylic acid acid amides (II 16)
N-{ propionic acid-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group] ethyl ester } farnesyl thiosalicylic acid acid amides (II 17)
Another object of the present invention is to provide the preparation method of general formula I of the present invention, the said compound of II.
FTA verivate shown in the general formula I prepares through following manner: 2-oxygen-3; 4-two benzenesulfonyls-1; 2, the 5-oxadiazole generates furazan oxynitride (1) with hydrocarbon based diol or the reaction of alkyl hydramine under the sodium hydroxide effect, and FTA is at N; N '-NSC 57182 (DCC) and DMAP effect are descended and furazan oxynitride (1) reaction makes compound of Formula I, and its synthetic route is following:
Figure GSA00000083319200051
Wherein, the definition of X and R as previously mentioned.
Furazan oxynitride (1) reference (Acta Pharmaceutica Sinica, 2001,36 (11): 821-826) preparation.The organic solvent that reaction is adopted is selected from methylene dichloride, chloroform, THF, ETHYLE ACETATE, ethyl formate, methyl acetate, 1; The mixture of 2-ethylene dichloride, benzene, toluene, dioxane, DMF or above-mentioned solvent preferentially adopts anhydrous methylene chloride or anhydrous tetrahydro furan.
FTA verivate shown in the general formula I I prepares through following manner: under DCC and DMAP effect; Furazan oxynitride (1) generates midbody (3) with amino acid (2) reaction of Boc protection; Take off Boc through trifluoroacetic acid (TFA) and obtain compound (4); Under 1-ethyl-(3-dimethylaminopropyl) carbodiimide (EDC) and DMAP effect, make with the FTA reaction, its synthetic route is following:
Figure GSA00000083319200061
Wherein, the definition of X and R as previously mentioned.
The organic solvent that reaction is adopted is selected from methylene dichloride, chloroform, THF, ETHYLE ACETATE, ethyl formate, methyl acetate, 1; The mixture of 2-ethylene dichloride, benzene, toluene, dioxane, DMF or above-mentioned solvent preferentially adopts anhydrous methylene chloride, anhydrous tetrahydro furan or DMF.
A purpose more of the present invention provides general formula I of the present invention, the application of II compound in preparation medicine for treating tumor thing.
Further purpose of the present invention is to provide a kind of pharmaceutical composition that contains general formula I of the present invention, II compound and the pharmaceutically acceptable carrier or the auxiliary material of effective dosage.
The compounds of this invention can be processed preparation for administration separately or with one or more pharmaceutically acceptable carrier combinations.For example, solvent, thinner etc. can be used the oral dosage form administration, but like tablet, capsule dispersed powders, granule etc.The various formulations of pharmaceutical composition of the present invention can prepare according to the method for knowing in the pharmaceutical field.Can contain the for example activeconstituents of 0.05%～90% weight with carrier combinations in these medicinal prepnss, the activeconstituents of weight between more common about 15%～60%.The compounds of this invention dosage can be 0.005～5000mg/kg/ days, also can exceed this dosage range according to the different using dosages of disease severity or formulation.
The compounds of this invention can with other antitumor drugs for example alkylating agent (like endoxan or cis-platinum), antimetabolite (like 5 FU 5 fluorouracil or hydroxyurea), topoisomerase enzyme inhibitor (like NSC 94600), mitotic inhibitor (like taxol or vinealeucoblastine(VLB)), DNA intercalating agent (like Zorubicin) combined utilization, in addition can also with the radiotherapy combined utilization.These other antitumor drugs or radiotherapy can give with The compounds of this invention simultaneously or at different time.Thereby these combination therapys can produce synergy helps to improve result of treatment.
Be the part pharmacological testing and the result of The compounds of this invention below:
The structure that the compound code name of pharmacological testing part is corresponding see Table 1 with table 2.
Figure GSA00000083319200071
Table 1 formula I part of compounds code name and corresponding structure thereof
Figure GSA00000083319200072
Figure GSA00000083319200073
Table 2 formula II part of compounds code name and corresponding structure thereof
Figure GSA00000083319200074
Figure GSA00000083319200081
1, anti tumor activity in vitro research
1.1 the blue colourimetry antitumor activity in vitro of tetramethyl-nitrogen azoles
Adopt the tetramethyl-nitrogen blue colourimetry of azoles (MTT) to estimate the antiproliferative activity of The compounds of this invention by routine to 13 kinds of human cancer cell strains.Mtt assay has been widely used in the responsive mensuration of large-scale screening anti-tumor medicine, cell toxicity test and tumour radiotherapy etc.Suo Lafeini (Sorafenib) is widely used clinically at present antitumor drug, and its action target is exactly the Ras signal pathway, therefore selects it as positive control drug.
Human cancer cell strain: breast cancer cell MCF-7, MDA-MB-231, liver cancer cell Hep G2, Hep 3B, BEL-7402, kidney cancer cell 786-O, OS-RC-2, lung cell A549, H460, H520, brain cancer cell U251, U87, stomach cancer cell SGC-7901.
Experimental technique is following: get and be in one bottle in cell in good condition exponential phase of growth, add 0.25% tryptic digestion, attached cell is come off, process every milliliter and contain 2 * 10 4～4 * 10 4The suspension of individual cell.Obtained cell suspension is inoculated on 96 orifice plates, and every hole 180 μ L put constant temperature CO 2Cultivated 24 hours in the incubator.Change liquid, (with the PBS dilution, test-compound concentration is respectively 1 * 10 to compound with DMSO dissolving back to add test-compound -7, 1 * 10 -6, 1 * 10 -5Mol/L), every hole 20 μ L cultivated 48 hours.MTT is added in 96 orifice plates, every hole 20 μ L, reaction is 4 hours in the incubator.Supernatant is removed in suction, adds DMSO, every hole 150 μ L, and jolting is 5 minutes on the dull and stereotyped shaking table.Use enzyme-linked immunosorbent assay instrument in the optical density of wavelength, calculate cell inhibitory rate as the every hole of mensuration, 570nm place.Experimental result is shown in table 3-4.
Cell inhibitory rate=(negative control group OD value-tried thing group OD value)/negative control group OD value * 100%.
Table 3 The compounds of this invention is to the active (IC of part tumor cell proliferation inhibition 50, μ mol/L)
Figure GSA00000083319200101
Sorafenib: Suo Lafeini; NA: non-activity.
Table 4 The compounds of this invention is to the active (IC of part tumor cell proliferation inhibition 50, μ mol/L)
Figure GSA00000083319200102
Sorafenib: Suo Lafeini; NA: non-activity.
Through the test of a series of tumour cells, find that these compounds are stronger to the kidney cancer cell effect, OS-RC-2 human renal carcinoma cell particularly, most of target compound cytoactive is stronger than lead compound FTA, a lot of compound I C 50Value is all less than 1 μ mol/L, wherein compound I 1, I 2, I 4, II 1, II 3, II 6, II 12, II 13, II 14Suo Lafeini is strong for the specific activity positive control drug, its IC 50Value is all less than 0.25 μ mol/L; See I from 786-O human renal carcinoma cell test case 1, I 4, II 12, II 13, II 14Cytoactive is all active strong than parent compound FTA, and quite active with positive control drug Suo Lafeini, and the majority of compounds activity is all above guide's thing FTA;
In human glioma cell U87 and U251, compound I 2, II 12, II 13, II 14IC 50Value and Suo Lafeini are in an one magnitude, and the majority of compounds activity is all above parent compound FTA;
For human breast cancer cell MCF7, compound I 4, II 3, II 6, II 12Active quite active with positive control drug Suo Lafeini, and human breast cancer cell MDA-MB-231, compound I 2, II 6, II 12, II 13Specific activity positive control drug Suo Lafeini is strong slightly or quite, the majority of compounds activity is all above parent compound FTA;
For human lung cancer cell A549, H460 and H520, whole compound activity trend comparison is consistent, and compound is more weak at human lung cancer cell A549's specific activity H460 and H520, wherein compound I 2, II 12And II 13Than positive control drug Suo Lafeini is strong slightly or quite, the majority of compounds activity is all above parent compound FTA;
For human liver cancer cell Hep3B, compound I 2, II 3, II 6, II 12And II 13IC 50Value and Suo Lafeini are in an one magnitude, and gastric carcinoma cells SGC-7901, I 2, II 12And II 13Than positive control drug Suo Lafeini is strong slightly or quite, the majority of compounds activity is all above parent compound FTA.
From the whole antitumor spectra of compound; In the FTA verivate series compound that the furazan oxynitride is modified; The amino acid whose furazan oxynitride overall activity of middle connection is better than not connecting amino acid active; And the amino acid whose kind of linking group is influential to activity, and the influence of its pair cell cytotoxic activity is proline(Pro)＞glycocoll, L-Ala＞phenylalanine(Phe) in proper order.And for the compound that contains same amino acid, furazan oxynitride donor linking group carbon chain lengths influences activity equally, and is better with 4 carbon atoms.Such as all containing L-Ala but the active order of company carbochain different compounds be: II 6＞II 9＞II 5＞II 8
The pharmacological results shows that The compounds of this invention has restraining effect in various degree to human tumor cell's propagation, and most antitumor activity of compound and positive control drug Suo Lafeini quite or be superior to Suo Lafeini and significantly are better than FTA.
1.2 influence to normal liver cell growth
Receive the reagent thing
The FTA verivate series one active better target compound I that the furazan oxynitride is modified 1, I 2, I 4, II 1, II 3, II 6, II 12, II 13, II 14, alltrans farnesyl thiosalicylic acid (FTA) is as control drug, totally 10 compounds.
Material, reagent and method
Method is the same, and people's normal liver cell is LO2, and nutrient solution is for containing 10% heat-inactivated fetal bovine serum, the RPMI1640 cell culture medium of penicillium mould 100u/mL and Streptomycin sulphate 100u/mL, and the drug-treated time is 48 hours, concentration is chosen and is seen Fig. 7.
The result
The FTA derivative I that part furazan oxynitride is modified 2, II 12, II 6, I 4Under less than 12.5 μ mol/L (in effective inhibition concentration scope that the Hep3B cell is grown, seeing Fig. 7) concentration, there is not tangible LO2 cytotoxicity, visible significant cytotoxicity in the 25-100 μ mol/L concentration range.This shows I 2, I 4, II 6, II 12Liver cancer Hep3B cell is had certain selectivity, and selectivity order is I 2＞II 12＞II 6＞I 4, I wherein 2And II 12IC to people's normal liver cell LO2 50Value is than they IC to human liver tumor cell Hep3B 50Be worth big approximately two one magnitude (see figure 1)s.
1.3 discharging, external NO detects
The select target compound I 1, I 3, II 3, II 6And II 12～II 14In breast cancer cell MCF-7, MDA-MB-231, stomach cancer cell SGC-7901, lung cell A549 and brain cancer cell U251, U87, carry out the mensuration of NO burst size: get and be in one bottle in cell in good condition exponential phase of growth; Add 0.25% tryptic digestion; Attached cell is come off, process every milliliter and contain 2 * 10 4～4 * 10 4The suspension of individual cell.Obtained cell suspension is inoculated on 96 orifice plates, and every hole 180 μ L put constant temperature CO 2Cultivate 24h in the incubator.Change liquid, (with the PBS dilution, tried substrate concentration is 10-4mol/L to compound with DMSO dissolving back to add test-compound.Get supernatant 2mL and 500 μ LGriess reagent mix in the centrifugation of 300min time point, room temperature was placed 10 minutes, surveyed absorption value at the 540nm place, calculated NO concentration according to typical curve.The burst size of NO is equivalent to nitrate salt (NO with it 3 -)/nitrite (NO 2 -) scale show (see figure 2).
External NO releasing research result shows compound I I 3, II 6And II 12～II 14Between the NO burst size be more or less the same, but compare I 1, I 3Much bigger, the maximum burst size of NO reaches 1.6 μ mol/L.Results suggest; It is relatively large that compound with cytotoxic activity discharges the amount of NO; And the amount that active compound more weak or non-activity discharges NO is lower, this result and document (Megson IL, WebbDJ.Expert Opin Investig Drugs; 2002,11 (5): 587-601) higher concentration NO of report is consistent to the conclusion that tumour cell has strong CDCC.
1.4Ras inhibition active testing
Adopt the Western blotting to detect target compound II 6Ras to tumour cell MDA-MB-231 suppresses active.Get and be in exponential phase of growth cell in good condition and process every milliliter and contain 1.5 * 10 5The suspension of individual cell is inoculated on 96 orifice plates, puts constant temperature CO 2Cultivate 24h in the incubator.Change liquid, add 1 μ M, 5 μ M test-compound II 6, negative control adds equivalent PBS, continues to cultivate 8h.Trysinization, PBS cleans twice.Sample is resuspended among the PBS, abandons supernatant, and cell places 2mL EP pipe to add protein cleavage liquid; 200 μ L/ pipe; The piping and druming back is in ice bath reaction 30min repeatedly, and in the centrifuging and taking supernatant 2mL EP pipe, employing SDS-PAGE (gum concentration is 12%) separates and transfers on the nitrocellulose membrane.Film is put in 5% the skim-milk confining liquid of at present joining, and sealing finishes with a small amount of Blot wash that remaining milk powder rinsing is clean, and one anti-ly is diluted to working concentration with TBST, 500 μ L/ bars, and the room temperature shaking table reacts 1h, can put 4 ℃ thereafter and spend the night.Reaction is cut off valve bag after finishing, and discarded antibody places ware to clean 4 times with TBST each bar film.Resist to working fluid concentration 500 μ L/ bars with two of TBST dilution peroxidase mark.By preceding method envelope and shaking table reaction, abandon two after reaction finishes and resist, clean 4 times with TBST.PIERCE luminescent solution A liquid+B liquid equal-volume mixing pours in the valve bag that makes, and behind the reaction 5min film is transferred to exposure image (see figure 3) in BIO-RAD gel imaging appearance magazine.
We have investigated target compound II 6Whether keep the original Ras of FTA and suppress active, adopt the II of blank control group and different concns 6The immunoblotting assay (see figure 3) is carried out in influence to the relevant Ras downstream signal path of MDA-MB-231 cell, finds II 6Under 1 μ M and 5 μ M concentration, can significantly suppress Akt, ERK, the phosphorylation of Raf molecule has still kept after prompting NO donor and the FTA heterozygosis Ras albumen has been suppressed active.
2, activity in vivo research
2.2I 2Acute toxicity test
Purpose
Mouse single intraperitoneal injection trial-product method is adopted in this experiment, observes chmice acute toxic reaction and death condition that trial-product causes.
Experiment material
Trial-product title: I 2(China Medicine University new drug research center provides).
Reference substance: i.e. solvent is absolute ethyl alcohol and glucose injection.
Animal
A cleaning level mouse, 5-6 age in week, body weight 18-22g, sex: male and female half and half.
Experimental technique
Dosage design and medicine configuration: according to the prerun result, official test dosage is made as 585.9,468.8,375.0,300.0 and 240.0mgg/kg, and the dosage spacing is 1: 0.8.Establish the solvent control group simultaneously.Medicine adds 20% anhydrous alcohol solution earlier, with the glucose injection dilution, gets the solution that final concentration is respectively 195.3mg/ml, 156.2mg/ml, 125.0mg/ml, 100mg/ml, 80mg/ml again.
Medication and approach: adopt the intraperitoneal injection approach.The administration of mouse once abdominal cavity injection, administration volume 0.6ml/20g body weight, abdominal injection speed 0.6ml/60Sec.
Detection method and data logging: the animal fasting is 2-4 hour before the administration.Detail record animals administer time, toxic reaction time and toxic reaction symptom.Calculate medium lethal dose(LD&-{50}) LD according to animal dead The data Bliss method 50Value and 95% fiducial limit (seeing table 5).
Experimental result
585.9mg/kg spasm, tic appear in 8 mouse after the dose groups administration, wherein 2 death at once; 468.8mg/kg spasm, tic appear in 4 mouse after the dose groups administration; 375.0/kg 2 movable minimizings of mouse after the dose groups administration; 300.0mg/kg 1 movable minimizing of mouse after the dose groups administration; Reduce 240.0mg/kg mouse is movable after the dose groups administration, behavioral activity recovers normal gradually after 10 minutes.
Table 5, mouse peritoneal injection I 2The LD of solution 50Test-results
Figure GSA00000083319200141
2.2I 2Intraperitoneal administration is to the experimental therapy effect purpose of human liver cell property liver cancer SMMC-7721 Nude Mice
According to the requirement of SFDA new drug preclinical study governing principle, test I 2People's liver cancer SMMC-7721 bare mouse different species transplanted tumor is had or not growth-inhibiting effect and action intensity.
Tried thing
The I2 injection liquid provides lot number by China Medicine University medicine research centre: 100117.Positive control drug is Suo Lafeini (Sorafenib), and Shanghai BeiKa Medicine Technology Co., Ltd produces, lot number: 091105.
Transplanted tumor
Select human liver cell property liver cancer SMMC-7721 Nude Mice for use, it is subcutaneous and set up to be inoculated in nude mouse by human liver cell property liver cancer SMMC-7721 cell strain.The cell inoculation amount is 2 * 10 7, inoculation is used after forming and in the nude mouse body, passing for 3 generations again behind the transplanted tumor.
Animal
Female BALB/cA nude mouse, age in days 35-40 days, body weight 18-22g provided (laboratory animal production licence: SCXK (army) 2007-004) by Institute of Experimental Animals, Chinese Academy of Medical Sciences.Animal is grouped as follows:
12 of blank groups (solvent control)
6 of positive controls (FTA 16mg/kg i.p.)
6 of positive controls (Sorafenib 20mg/kg i.p.)
6 of medication therapy groups (I260mg/kg i.p.)
6 of medication therapy groups (I230mg/kg i.p.)
6 of medication therapy groups (I215mg/kg i.p.)
TP
The tumor tissue of getting the growth animated period cuts into 1.5mm 3About, under aseptic condition, it is subcutaneous to be inoculated in nude mouse right side armpit.Nude Mice is treated tumor growth to 100～300mm with vernier caliper measurement transplanted tumor diameter 3After with the animal random packet.Use the method for measuring the knurl footpath, dynamic observe by the antineoplastic effect of examination thing.The measurement number of times of diameter of tumor is that each the measurement need claim also that simultaneously mouse is heavy 3 times weekly.The administration group is intravenously administrable 3 times weekly, and administration volume 0.4mL/ only.Positive controls is intravenously administrable 3 times weekly, and negative control group is given equivalent saline water simultaneously.
Detect index and method of calculation
(1) gross tumor volume (tumor volume, TV), calculation formula is:
TV＝1/2×a×b 2
Wherein a, b represent length and width respectively.
(2) relative tumour volume (relative tumor volume, RTV), calculation formula is:
RTV＝TV t/TV 0。
TV wherein 0(d during for minute cage administration 0) gross tumor volume, TV tGross tumor volume when measuring each time.
(3) relative tumor proliferation rate T/C (%), calculation formula is:
T/C(％)＝(T RTV/C RTV)×100
T RTV: treatment group RTV; C RTV: negative control group RTV.
Test-results is with the evaluation index of relative tumor proliferation rate T/C (%) as anti-tumor activity.
Experimental result and discussion:
I2 sees table 6 and Fig. 4 to the experimental treatment result of people's liver cancer SMMC-7721 Nude Mice.Experimental result is following, medicine I to be measured 2(60mg/kg), I 2(30mg/kg), I 2(15mg/kg), positive drug FTA (16mg/kg), Sorafenib (20mg/kg) are all with intraperitoneal injection, and every day 1 time, administration is 21 times altogether; After the administration 21 days, administration is after 21 days, and the average knurl volume of blank group is 1378mm 3, the average knurl volume of FTA control group is 664mm 3, the Sorafenib group is 397mm 3, I 2High dose group is 479mm 3, I 2Middle dose groups is 732mm 3, I 2Low dose group is 793mm 3, the T/C (%) of people's liver cancer SMMC-7721 Nude Mice is respectively 59.56%, 28.46%, 43.38%, 52.56%, 58.95%.Do not find simultaneously I 2Body weight to laboratory animal has obvious restraining effect.
Table 6.I 2Influence (X ± SD, gross tumor volume: the mm of unit to transplanted tumor in nude mice SMMC-7721 growth volume change 3)
Figure GSA00000083319200161
Description of drawings
Fig. 1 .I2, I4, II6, II12 is to the selectivity of liver cancer Hep3B cell and people's normal liver cell LO2
Fig. 2 part of compounds NO in tumour cell discharges
Fig. 3 II 6Ras to tumour cell MDA-MB-231 suppresses active
Fig. 4 .I 2Influence to people's liver cancer SMMC-7721 bare mouse different species transplantation tumor gross tumor volume
Embodiment
In order further to illustrate the present invention, provide a series of embodiment below, these embodiment are illustrative fully, they only are used for the present invention is specifically described, and are not to be understood that to be limitation of the present invention.The used FTA of the present invention is a prepared in laboratory, content＞98%.
Embodiment 1
The preparation of 2-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] ethamine (1a)
With 3mL (50mmol) thanomin and 1.85g (5mmol) 2-oxygen-3,4-two benzenesulfonyls-1,2, the 5-oxadiazole is dissolved among the 20mLTHF; The ice bath cooling splashes into 2.5mol/LNaOH solution 2mL, and room temperature reaction 0.5h adds 2.5mol/LNaOH solution 1mL; It is complete until raw material reaction to continue stirring, pours 80mL water into, methylene dichloride (3 * 20mL) extractions, saturated common salt water washing; Anhydrous sodium sulfate drying concentrates the methanol recrystallization; White solid (1a) 0.93g, yield 66%, mp:102～104 ℃.
N-{2-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] ethyl } farnesyl thiosalicylic acid acid amides (I 1) preparation
18.0g (0.50mmol) FTA and 14.0mg (0.65mmol) DCC are dissolved in the anhydrous CH of 15mL 2Cl 2In, stirring at room 30 minutes, the DMAP of adding 0.18g (0.60mmol) 1a and catalytic amount, room temperature reaction 24 hours; Filter, concentrate, column chromatography [ETHYLE ACETATE: sherwood oil (60～90 ℃)=1: 3 (V: V)] separate water white transparency oily thing 0.21g; Yield 67%, IR (KBr, cm -1) v:2922,1713,1654,1618,1551,1454,1374,1164; 1H NMR (CDCl 3, 300MHz): δ 8.02 (d, 2H, J=7.8Hz, Ar-H), 7.70 (m, 2H, Ar-H), 7.55 (t, 2H, J=7.8Hz, Ar-H), 7.36 (m, 2H, Ar-H), 7.18 (m, 1H, Ar-H), 7.20 (m, 1H, Ar-H), 5.25 (m, 1H, SCH 2C H), 5.08 (m, 2H, 2 * CH 2C H=CCH 3), 4.64 (t, 2H, J=4.8Hz, C H 2O), 3.96 (m, 2H, NC H 2CH 2), 3.53 (d, 2H, J=7.2Hz, SC H 2), 3.35 (m, 1H, NC H 2), 1.89-2.02 (m, 8H, 2 * CHC H 2C H 2CH), 1.50-1.68 (m, 12H, 4 * CH=CC H 3); ESI-MS (m/z): 626 [M+H] +.
Embodiment 2
N-{ [2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group } preparation of piperazine (1b)
Preparing method with reference to 1a makes faint yellow solid by hydroxyethyl piperazine, yield 55%, mp:90～92 ℃.
3-{4-[3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propoxy-]-1,4-dioxo butoxy } farnesyl thio-methyl salicylate (I 2) preparation
N-{ [2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group } the inferior acid amides (I of piperazinyl farnesyl thiosalicylic acid 2) preparation
With reference to I 1The preparation method, make water white transparency oily thing, yield 61% by FTA and 1b reaction.IR(KBr，cm -1)v：2926，1731，1648，1551，1454，1371，1167； 1H?NMR(CDCl 3，300MHz)：δ8.05(d，2H，J＝7.8Hz，Ar-H)，7.75(m，1H，Ar-H)，7.61(m，2H，Ar-H)，7.38(m，H，Ar-H)，7.28(m，3H，Ar-H)，5.28(m，1H，SCH 2C H)，5.08(m，2H，2×CH 2C H＝CCH 3)，4.58(t，2H，J＝5.1Hz，C H 2O)，3.84(d，2H，J＝4.5Hz，NCH 2)，3.56(m，2H，SCH 2)，2.91(m，4H，CONC H 2C H 2)，2.63(m，4H，2×C H 2NC H 2)，1.89-2.04(m，8H，2×CHC H 2C H 2CH)，1.50-1.67(m，12H，4×CH＝CC H 3)；ESI-MS(m/z)：695[M+H] +；
Embodiment 3
The preparation of 4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)]-2-butyne-1-alcohol (1c)
With reference to the preparation method of 1a, make white solid by the 2-butyne glycol, yield 63%, mp:110～112 ℃.
4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)]-the 2-alkynyl } farnesyl thiosalicylic acid butyl ester (I 3) preparation
With reference to I 1The preparation method, make water white transparency oily thing, yield 65%, IR (KBr, cm by FTA and 1c reaction -1) v:2934,1724,1618,1548,1453,1357,1167; 1H NMR (CDCl 3, 300MHz): δ 8.06 (d, 2H, J=7.8Hz, Ar-H), 8.01 (d, 1H, J=7.8Hz, Ar-H), 7.74 (t; 1H, J=7.2Hz, Ar-H), 7.62 (m, 2H, Ar-H), 7.47 (t, 1H, Ar-H); 7.33 (m, 1H, Ar-H), 7.20 (m, 1H, Ar-H), 5.33 (m, 1H, SCH 2C H), 5.12 (m, 4H, 2 * CH 2C H=CCH 3, COOCH 2), 5.00 (s, 2H, OCH 2), 3.60 (d, 2H, J=7.2Hz, SC H 2), 1.88-2.04 (m, 8H, 2 * CHC H 2C H 2CH), 1.48-1.68 (m, 12H, 4 * CH=CC H 3); ESI-MS (m/z): 651 [M+H] +.
Embodiment 4
The preparation of 4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] piperidines (1d)
With reference to the preparation method of 1a, make white solid by the 4-hydroxy piperidine, yield 79%, mp:70～72 ℃.
N-{4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] piperidyl } the inferior acid amides (I of farnesyl thiosalicylic acid 4) preparation
With reference to I 1The preparation method, make water white transparency oily thing, yield 68%, IR (KBr, cm by FTA and 1d reaction -1) v:2932,1721,1616,1553,1453,1371,1165; H NMR (CDCl 3, 300MHz): δ 8.05 (m, 2H, Ar-H), 7.77 (t, 1H, J=7.2Hz, Ar-H), 7.63 (m, 2H, Ar-H), 7.40 (m, H, Ar-H), 7.26 (m, 3H, Ar-H), 5.27 (m, 1H, SCH 2CH), 5.18 (m, 2H, 2 * CH 2C H=CCH 3), 5.08 (m, 1H, OCH), 3.88 (m, 2H, SC H 2), 3.47 (m, 4H, N (CH 2) 2), 1.89-2.02 (m, 12H, 2 * CHC H 2C H 2CH, CH (CH 2) 2), 1.50-1.68 (m, 12H, 4 * CH=CC H 3); ESI-MS (m/z): 666 [M+H] +.
Embodiment 5
The preparation of 3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propylamine (1e)
Preparing method with reference to 1a makes white solid by Propanolamine, yield 70%, mp:57～59 ℃.
N-{3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl group } farnesyl thiosalicylic acid acid amides (I 5) preparation
With reference to I 1The preparation method, make water white transparency oily thing, yield 67%, IR (KBr, cm by FTA and 1e reaction -1) v:2952,1733,1656,1616,1552,1434,1386,1164; 1H NMR (CDCl 3, 300MHz): δ 8.00 (d, 2H, J=7.5Hz, Ar-H), 7.74 (t, 1H, J=7.5Hz, Ar-H), 7.61 (m, 3H, Ar-H), 7.40 (m, 2H, Ar-H), 7.30 (m, 1H, Ar-H), 5.26 (m, 1H, SCH 2C H), 5.07 (m, 2H, 2 * CH 2C H=CCH 3), 4.59 (t, 2H, J=6.0Hz, OC H 2), 3.71 (d, 2H, J=7.8Hz, SC H 2), 3.55 (d, 2H, J=7.5Hz, NCH 2), 2.26 (m, 2H, NCH 2C H 2), 1.89-2.02 (m, 8H, 2 * CHC H 2C H 2CH), 1.50-1.68 (m, 12H, 4 * CH=CC H 3); ESI-MS (m/z): 630 [M+H] +
Embodiment 6
The preparation of N-methyl-2-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] ethamine (2f)
With reference to the preparation method of 1a, make white solid by the N Mono Methyl Ethanol Amine, yield 50% directly drops into next step reaction.N-{N-methyl-2-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] ethyl } the inferior acid amides (I of farnesyl thiosalicylic acid 6) preparation
With reference to I 1The preparation method, make water white transparency oily thing, yield 65%, IR (KBr, cm by FTA and 2c reaction -1) v:2956,1733,1618,1454,1359,1157; 1H NMR (CDCl 3, 300MHz): δ 8.07 (d, J=7.5Hz, 2H, Ar-H), 7.94 (m, 1H, Ar-H), 7.76 (m, 1H, Ar-H), 7.59 (m, 3H, Ar-H), 7.31 (m, 2H, Ar-H), 5.30 (m, 1H, SCH 2C H), 5.07 (m, 2H, 2 * CH 2C H=CCH 3), 4.77 (m, 2H, OC H 2), 4.06 (d, 2H, J=7.8Hz, SC H 2), 3.53 (m, 2H, NCH 2), 3.02 (m, 3H, NCH 3), 1.89-2.02 (m, 8H, 2 * CHC H 2C H 2CH), 1.50-1.68 (m, 12H, 4 * CH=CC H 3); ESI-MS (m/z): 630 [M+H] +
Embodiment 7
The preparation of 1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl alcohol (1g)
Preparing method with reference to 1a makes white solid by 1,3 butylene glycol, yield 88%, mp:101～103 ℃.
1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] } farnesyl thiosalicylic acid propyl ester (I 7) preparation
With reference to I 1The preparation method, make water white transparency oily thing, yield 65%, IR (KBr, cm by FTA and 1g reaction -1) v:2947,1730,1616,1552,1454,1380,1164; 1H NMR (CDCl 3, 300MHz): δ 8.08 (d, 2H, J=7.8Hz, Ar-H), 7.93 (d, 1H, J=7.5Hz, Ar-H), 7.73 (m; 1H, Ar-H), 7.64 (m, 2H, Ar-H), 7.43 (t, 1H, J=7.2Hz, Ar-H); 7.30 (m, 1H, Ar-H), 7.16 (m, 1H, Ar-H), 5.40 (m, 1H, SCH 2C H), 5.31 (m, 2H, OC H), 5.08 (m, 2H, 2 * CH 2C H=CCH 3), 4.56 (t, 2H, J=6.0Hz, OC H 2), 3.56 (d, 2H, J=7.2Hz, SC H 2), 2.28 (m, 2H, CHC H 2), 1.89-2.02 (m, 8H, 2 * CHC H 2C H 2CH), 1.50-1.68 (m, 12H, 4 * CH=CC H 3), 1.47 (d, 3H, J=6.3Hz, CHC H 3); ESI-MS (m/z): 655 [M+H] +
Embodiment 8
2-{ [(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] methoxyl group } preparation of tetramethyleneimine (1h)
With reference to the preparation method of 1a, make faint yellow solid by L-dried meat ammonia alcohol, yield 88% directly carries out next step reaction.
N-{2-{ [(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] methoxyl group } pyrrolidyl } the inferior acid amides (I of farnesyl thiosalicylic acid 8) preparation
With reference to I 1The preparation method, make water white transparency oily thing, yield 65% by FTA and 1h reaction.IR(KBr，cm -1)v：2933，1730，1616，1552，1454，1380，1164； 1H?NMR(CDCl 3，300MHz)：δ8.05(m，2H，Ar-H)，7.93(m，1H，Ar-H)，7.76(m，1H，Ar-H)，7.61(m，2H，Ar-H)，7.43(t，1H，J＝7.2Hz，Ar-H)，7.39(m，1H，Ar-H)，7.29(m，1H，Ar-H)，5.19(m，1H，SCH 2C H)，5.07(m，2H，2×CH 2C H＝CCH 3)，4.90(m，1H，NCH)，4.65(m，2H，OC H 2)，3.51(d，2H，J＝7.8Hz，SC H 2)，3.30(m，2H，NCH 2)，1.89-2.02(m，8H，2×CHC H 2C H 2CH)，1.50-1.68(m，12H，4×CH＝CC H 3)，1.50-1.67(m，4H，CHCH 2CH 2)；ESI-MS(m/z)：666[M+H] +；
Embodiment 9
2-{ [2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] ethylamino-} preparation of ethanol (1i)
Preparing method with reference to 1a makes faint yellow solid by diethylolamine, and yield 65% directly drops into next step reaction.
The preparation of N-hydroxyethyl { N-[2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] ethyl } the carbonic acid tert-butyl ester (1i-1)
At the anhydrous CH of the 10mL of 0.33g (1.00mmol) 1i and 0.2mL triethylamine 2Cl 2In, slowly adding 0.26g (1.20mmol) tert-Butyl dicarbonate, stirred overnight at room temperature extracts CH with 10mL water and saturated NaCl respectively with reaction solution 2Cl 2Layer is used anhydrous sodium sulfate drying, revolves the dried 0.39g of obtaining product 1i-1 and directly casts single step reaction, yield 91%.
2-{N-tertbutyloxycarbonyl-2-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] ethylamino-} farnesyl thiosalicylic acid ethyl ester (I 9) preparation
With reference to I 1The preparation method, make water white transparency oily thing, yield 70%, mp:82～84 ℃ by FTA and 1i-1 reaction.IR(KBr，cm -1)v：2952，1728，1618，1550，1452，1352，1164； 1H-NMR(300MHz，CDCl 3)δ：8.05(d，2H，J＝8.1Hz，Ar-H)，7.70(m，1H，Ar-H)，7.58(m，2H，Ar-H)，7.40(m，2H，Ar-H)，7.23(m，2H，Ar-H)，5.24(t，1H，J＝7.5Hz，SCH 2C H)，5.06(t，2H，J＝6.9Hz，2×CH 2C H＝CCH 3)，4.35(m，2H，OC H 2)，3.84(m，2H，OC H 2)，3.73(m，4H，C H 2NC H 2)，3.58(d，2H，J＝7.2Hz，SC H 2)，1.89-2.02(m，8H，2×CHC H 2C H 2CH)，1.50-1.68(m，12H，4×CH＝CC H 3)；1.38(s，9H，3CH 3)；ESI-MS(m/z)：870[M+H] +.
Embodiment 10
2-{ [2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] ethylamino-} farnesyl thiosalicylic acid ethyl ester (I 10) preparation
To go up step product 0.38g (0.50mmol) I 9Be dissolved in 4mL CH 2Cl 2In, the ice bath cooling slowly drips the 2mL trifluoroacetic acid, rises to room temperature, and reaction 2h removes solvent and unreacted trifluoroacetic acid under reduced pressure, adds 10mL CH again 2Cl 2, slowly drip the 1.5mL triethylamine, drip off and stir 30min, reaction solution is washed CH with 10mL water and saturated NaCl respectively 2Cl 2Layer is used anhydrous sodium sulfate drying, revolves the dried 0.39g of obtaining product I 10Water white transparency oily thing 0.42g, yield 62.8%.IR(KBr，cm -1)v：2958，1731，1652，1622，1552，1454，1377； 1H?NMR(CDCl 3，300MHz)：δ7.96(d，1H，J＝7.8Hz，Ar-H)，7.91(d，2H，J＝7.2Hz，Ar-H)，7.62(t，1H，J＝7.5Hz，Ar-H)，7.49(m，2H，Ar-H)，7.30(m，2H，Ar-H)，7.16(m，1H，Ar-H)，6.22(brs，1H，NH)，5.33(m，3H，SCH 2C H，2×CH 2C H＝CCH 3)，4.37(m，4H，C H 2O)，3.73(m，4H，C H 2NHC H 2)，3.58(d，2H，J＝7.2Hz，SC H 2)，1.89-2.02-(m，8H，2×CHC H 2C H 2CH)，1.50-1.68(m，12H，4×CH＝CC H 3)；ESI-MS(m/z)：770[M+H] +.
Embodiment 11
N-{N-[2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] hydroxyethyl } farnesyl thiosalicylic acid ethanamide (I 11) preparation
0.36g (1.00mmol) FTA is dissolved in the anhydrous CH of 10mL 2Cl 2In, dripping the 0.5mL oxalyl chloride, room temperature reaction 4h removes solvent under reduced pressure and unreacted gets oxalyl chloride, and the farnesyl sulfo-bigcatkin willow acyl chlorides of using system again is with the anhydrous CH of 10mL 2Cl 2Dissolving slowly splashes into the anhydrous CH of 10mL that contains 0.33g (1.00mmol) 1i and 0.2mL triethylamine under ice bath 2Cl 2In, at stirring at room 12h, filter, concentrate, column chromatography [ETHYLE ACETATE: sherwood oil (60～90 ℃)=1: 5 (V: V)] separate water white transparency oily thing 0.42g, yield 62.8%.IR(KBr，cm -1)v：2958，1731，1652，1622，1552，1454，1377； 1H?NMR(CDCl 3，300MHz)：8.05(d，2H，J＝8.1Hz，Ar-H)，7.70(m，1H，Ar-H)，7.58(m，2H，Ar-H)，7.40(m，2H，Ar-H)，7.23(m，2H，Ar-H)，5.25(t，1H，J＝6.6Hz，SCH 2C H)，5.06(m，4H，2×CH 2C H＝CCH 3，NC H 2)，4.55(m，2H，OC H 2)，4.12(m，1H，OH)3.84(m，2H，HOC H 2)，3.15(m，2H，NCH 2)，3.54(d，2H，J＝7.2Hz，SC H 2)，2.92(t，2H，J＝5.1Hz，HOCH 2C H 2)，1.89-2.00(m，8H，2×CHC H 2C H 2CH)，1.51-1.65(m，12H，4×CH＝CC H 3)；ESI-MS(m/z)：770[M+H] +.
Embodiment 12
The preparation of N-Boc-glycocoll-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl ester (3-1g)
0.37g (1.1mmol) 1g is dissolved in the anhydrous CH of 15mL 2Cl 2In, add 0.18g (1.0mmol) N-t-butoxycarbonyl glycine, the DMAP of 0.26g (1.25mmol) DCC and catalytic amount; Room temperature reaction 24h; Filter, concentrate, column chromatography [ETHYLE ACETATE: sherwood oil (60～90 ℃)=1: 3 (V: V)] separate white solid 0.29g; Yield 60%, mp:84～86 ℃.ESI-MS(m/z)：471.6[M+H] +；IR(KBr，cm -1)v：3436，2977，2937，1747，1714，1616，1552，1514，1452，1367，1166； 1H-NMR(300MHz，CDCl 3)δ：1.35～1.37(m，3H，CH 3，)，1.43(s，9H，3CH 3)，3.89～3.90(d，2H，NCH 2)，4.46～4.50(t，2H，OCH 2，J＝6.0Hz)，5.01(brs，1H，NH)，5.19～5.25(m，1H，OCH)，7.60～7.66(m，2H，ArH)，7.74～7.76(m，1H，ArH)，8.05～8.08(m，2H，ArH).
The preparation of glycocoll-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl ester trifluoroacetate (4-1g)
0.25g (0.52mmol) 3-1g is dissolved in 10mL CH 2Cl 2In, the ice bath cooling slowly drips the 2mL trifluoroacetic acid, rises to room temperature, and reaction 2h removes solvent and unreacted trifluoroacetic acid under reduced pressure, obtains 4-1g, ESI-MS (m/z): 372.1 [M+H] +
N-{ acetate-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl ester } farnesyl thiosalicylic acid acid amides (II 1) preparation
The 4-1g of above-mentioned preparation is dissolved among the 15mL DMF, adds 0.20g (1.60mmol) DMAP, stirred 30 minutes, add 0.20g (0.43mmol) FTA; 0.25g (1.30mmol) EDC, room temperature reaction 24h, impouring 200mL water, ETHYLE ACETATE (3 * 50mL) extractions; Merge organic layer, the saturated common salt washing, anhydrous sodium sulfate drying filters; Concentrate, column chromatography [ETHYLE ACETATE: sherwood oil (60～90 ℃)=1: 2 (V: V)] separate, get water white transparency oily thing 0.15g, yield 45%.IR(KBr，cm -1)：3424，2927，1753，1629，1552，1450，1371，1168； 1H?NMR(CDCl 3，300MHz)：δ8.05(d，2H，J＝8.1Hz，Ar-H)，7.70(m，1H，Ar-H)，7.58(m，2H，Ar-H)，7.40(m，2H，Ar-H)，7.29(m，2H，Ar-H)，5.25(t，1H，J＝6.6Hz，SCH 2C H)，5.06(m，4H，2×CH 2C H＝CCH 3，NC H 2)，4.48(t，2H，J＝6.0Hz，C H 2O)，4.25(m，1H，OC H)，3.54(d，2H，J＝7.5Hz，SC H 2)，2.20(m，2H，OCHC H 2)，1.98-2.05(m，8H，2×CHC H 2C H 2CH)，1.51-1.68(m，12H，4×CH＝CC H 3)，1.39(d，3H，J＝6.3Hz，CHC H 3)；MS(ESI)m/z＝712[M+1] +.
Embodiment 13
The preparation of 4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] butanols (1j)
With reference to the preparation method of 1a, by 1, the 4-butyleneglycol makes white solid, yield 89%, mp:70～72 ℃.
The preparation of N-Boc-glycocoll-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] butyl ester (3-1j)
Preparing method with reference to 3-1g makes white solid by 1j, yield 78%, mp:60～62 ℃.ESI-MS(m/z)：471.8[M+H] +；IR(KBr，cm -1)v：3357，2977，2933，1726，1685，1623，1558，1525，1454，1371，1163； 1H-NMR(300MHz，CDCl 3)δ：1.45(s，9H，3CH 3)，1.85～1.87(m，2H，CH 2)，1.95～1.99(m，2H，CH 2)，3.92～3.94(d，2H，NCH 2)，4.23～4.27(t，2H，OCH 2，J＝6.0Hz)，4.44～4.48(t，2H，OCH 2，J＝6.0Hz)，5.06(brs，1H，NH)，7.61～7.66(m，2H，ArH)，7.77～7.79(m，1H，ArH)，8.04～8.07(m，2H，ArH).
The preparation of glycocoll-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] butyl ester trifluoroacetate (4-1j)
Preparing method with reference to 4-1g is made by 3-1j, ESI-MS (m/z): 372.4 [M+H] +
N-{ acetate-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] butyl ester } farnesyl thiosalicylic acid acid amides (II 2) preparation
With reference to II 1The preparation method, make water white transparency oily thing, yield 50%, IR (KBr, cm by FTA and 4-1j reaction -1): 3259,2928,1727,1621,1559,1450,1163; 1H NMR (CDCl 3, 300MHz): δ 8.04 (d, 2H, J=7.2Hz, Ar-H), 7.73 (m, 2H, Ar-H), 7.58 (m, 2H, Ar-H), 7.36 (m, 2H, Ar-H), 7.27 (m, 1H, Ar-H), 5.24 (t, 1H, J=7.5Hz, SCH 2C H), 5.06 (t, 2H, J=6.9Hz, 2 * CH 2C H=CCH 3), 4.79 (m, 2H, NC H 2), 4.45 (t, 2H, J=6.0Hz, COOCH 2CH 2CH 2C H 2O), 4.28 (m, 4H, NC H 2COOC H 2CH 2), 3.55 (d, 2H, J=7.5Hz, SC H 2), 1.99 (m, 10H, 2 * CHC H 2C H 2CH, COOCH 2CH 2C H 2), 1.51-1.69 (m, 14H, 4 * CH=CC H 3, COOCH 2C H 2); MS (ESI) m/z=712 [M+1] +.
Embodiment 14
The preparation of N-Boc-glycocoll-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)]-2-alkynes-butyl ester (3-1c)
Preparing method with reference to 3-1g makes white solid by 1c, yield 68%, mp:88～90 ℃.IR(KBr，cm -1)v：3434，2979，1758，1704，1620，1548，1450，1359，1163； 1H-NMR(300MHz，DMSO-d6)δ：1.38(s，9H，3CH 3)，3.70～3.75(m，2H，NCH 2)，4.88(s，2H，OCH 2)，5.22(s，2H，OCH 2)，7.28(brs，1H，-NH-)，7.73～7.75(m，2H，ArH)，7.88～7.93(m，1H，ArH)，8.00～8.03(m，2H，ArH)；ESI-MS(m/z)：467.9[M+H] +.
The preparation of glycocoll-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)]-2-alkynes-butyl ester trifluoroacetate (4-1c)
Preparing method with reference to 4-1g is made by 3-1c, ESI-MS (m/z): 368.3 [M+H] +.
N-{ acetate-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)]-2-alkynes-butyl ester } farnesyl thiosalicylic acid acid amides (II 3) preparation
With reference to II 1The preparation method, make water white transparency oily thing, yield 55%, IR (KBr, cm by FTA and 4-1c reaction -1): 3418,2928,1758,1617,1548,1451,1361,1169; 1H NMR (CDCl 3-d 6): δ 8.06 (d, 2H, J=7.5Hz, Ar-H), 7.74 (m, 2H, Ar-H), 7.61 (t, 2H, J=7.5Hz, Ar-H), 7.30 (m, 3H, Ar-H), 5.24 (m, H, SCH 2C H), 5.06 (m, 4H, 2 * CH 2CH 2C H=CCH 3, C H 2O), 4.86 (s, 2H, COOC H 2), 4.31 (d, 2H, J=5.4Hz, NC H 2), 3.55 (d, H, J=7.8Hz, SCH 2), 1.98-2.12 (m, 8H, 2 * CHC H 2C H 2CH), 1.42-1.67 (m, 12H, 4 * CH 3); MS (ESI) m/z=708 [M+1] +.
Embodiment 15
The preparation of N-Boc-glycocoll-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] ethanamide (3-1a)
With reference to the preparation method of 3-1g, make white solid, yield 50.2%, mp:107～111 ℃ by 1a reaction.
N-{ acetate-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] ethanamide } farnesyl thiosalicylic acid acid amides (II 4) preparation
With reference to II 1The preparation method, make water white transparency oily thing, yield 49.4%, IR (KBr, cm with FTA reaction behind the 3-1a deprotection base -1) v:3406,2927,1724,1654,1550,1452,1388,1186; 1H NMR (CDCl 3, 300MHz): δ 8.04 (d, 2H, J=7.2Hz, Ar-H), 7.73 (m, 2H, Ar-H), 7.58 (m, 2H, Ar-H), 7.36 (m, 2H, Ar-H), 7.27 (m, 1H, Ar-H), 6.64 (m, 1H, CONH), 5.24 (t, 1H, J=7.5Hz, SCH 2C H), 5.06 (t, 2H, J=6.9Hz, 2 * CH 2C H=CCH 3), 4.52 (m, 2H, OCH 2), 4.28 (m, 4H, NC H 2, COOC H 2CH 2), 3.55 (d, 2H, J=7.5Hz, SC H 2), 1.99 (m, 8H, 2 * CHC H 2C H 2CH), 1.51-1.69 (m, 12H, 4 * CH=CC H 3); ESI-MS (m/z): 683 [M+H] +
Embodiment 16
The preparation of N-Boc-L-L-Ala-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl ester (3-2g)
With reference to the preparation method of 3-1g, make white solid, yield 72.3%, mp:98～101 ℃ by N-tert-butoxycarbonyl-l-alanine and 1g reaction.
N-{2-propionic acid-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl ester } farnesyl thiosalicylic acid acid amides (II 5) preparation
With reference to II 1The preparation method, make water white transparency oily thing, yield 41%, [α] with FTA reaction behind the 3-2g deprotection base 25 D:-8.1; IR (KBr, cm -1): 3297,2924,1737,1633,1555,1450,1356,1168; 1H NMR (CDCl 3-d 6): δ 8.06 (d, 2H, J=7.8Hz, Ar-H), 7.71 (m, 2H, Ar-H), 7.59 (m, 2H, Ar-H), 7.51 (m, 1H, Ar-H), 7.38 (m, 2H, Ar-H), 5.18 (m, 2H, SCH 2C H, NC H), 5.08 (m, 2H, 2 * CH 2C H=CCH 3), 4.74 (m, 1H, OC H), 4.46 (t, 2H, J=6.0Hz, OC H 2CH 2), 3.54 (d, 2H, J=7.5Hz, SC H 2), 2.17 (m, 2H, OCH 2C H 2), 1.98 (m, 8H, 2 * CHC H 2C H 2CH), 1.59-1.67 (m, 12H, 4 * CH=CC H 3), 1.51 (d, 2H, J=7.2Hz, NCHC H 3), 1.38 (d, 2H, J=6.0Hz, OCHC H 3); MS (ESI) m/z=726 [M+1] +.
Embodiment 17
2-{ [2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group } preparation of ethanol (1k)
With reference to the preparation method of 1a, make white solid by a condensed ethandiol, yield 70%, mp:57～59 ℃.
N-Boc-L-L-Ala-2-{ [2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group } preparation of ethyl ester (3-2k)
With reference to the preparation method of 3-1g, make faint yellow solid, yield 53.3%, mp:127～129 ℃ by N-tert-butoxycarbonyl-l-alanine and 1k reaction.
N-{2-propionic acid-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group] ethyl ester } farnesyl thiosalicylic acid acid amides (II 6) preparation
With reference to II 1The preparation method, make water white transparency oily thing, yield 52.8%, [α] with FTA reaction behind the 3-2k deprotection base 15 D:-19.2; IR (KBr, cm -1): 3421,2928,1739,1640,1614,1554,1452,1356,1168; 1H NMR (CDCl 3, 300MHz): δ 8.04 (d, 2H, J=7.8Hz, Ar-H), 7.70 (m, 2H, Ar-H), 7.59 (m, 3H, Ar-H), 7.34 (m, 2H, Ar-H), 5.27 (t, 1H, J=7.2Hz, SCH 2C H), 5.05 (m, 2H, 2 * CH 2C H=CCH 3), 4.84 (m, 1H, NC H), 4.54 (m, 2H, COOCH 2CH 2OCH 2C H 2O), 4.38 (m, 2H, COOC H 2CH 2), 3.93 (m, 2H, COOCH 2CH 2OC H 2), 3.83 (t, 2H, J=4.2Hz, COOCH 2C H 2), 3.54 (d, 2H, J=7.8Hz, SC H 2), 2.01 (m, 8H, 2 * CHC H 2C H 2CH), 1.52-1.67 (m, 12H, 4 * CH=CCH 3), 1.38 (d, 3H, J=7.5Hz, NCHC H 3); MS (ESI) m/z=742 [M+1] +.
Embodiment 18
The preparation of N-Boc-L-proline(Pro)-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] butyl ester (3-3j)
With reference to the preparation method of 3-1g, make faint yellow oily thing, yield 60.2% by Boc-L-proline(Pro) and 1j reaction.
N-{2-Pyrrolidine formic acid-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] butyl ester } the inferior acid amides (II of farnesyl thiosalicylic acid 7) preparation
With reference to II 1The preparation method, make water white transparency oily thing, yield 34.8%, [α] with FTA reaction behind the 3-3j deprotection base 24 D:-14.5; IR (KBr, cm -1): 3437,2926,1743,1619,1552,1449,1365,1169; 1H NMR (CDCl 3, 300MHz): δ 8.04 (d, 2H, J=7.5Hz, Ar-H), 7.75 (m, 1H, Ar-H), 7.60 (m, 2H, Ar-H), 7.34 (m, 1H, Ar-H), 7.32 (m, 2H, Ar-H), 7.20 (m, 1H, Ar-H), 5.27 (t, 1H, J=7.5Hz, SCH 2C H), 5.05 (t, 2H, J=5.1Hz, 2 * CH 2C H=CCH 3), 4.67 (m, 1H, NC H), 4.47 (t, 2H, J=6.0Hz, COOCH 2CH 2CH 2C H 2O), 4.29 (m, 2H, COOC H 2CH 2), 3.57 (d, 2H, J=7.8Hz, SC H 2), 3.35 (m, 1H, NC H 2), 2.02 (m, 10H, C H 2CHCOO, 2 * CHC H 2C H 2CH), 1.90 (m, 2H, COOCH 2CH 2C H 2), 1.53-1.67 (m, 16H, 4 * CH=CC H 3, COOCH 2C H 2, NCH 2C H 2); MS (ESI) m/z=752 [M+1] +.
Embodiment 19
The preparation of N-Boc-L-L-Ala-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] butyl ester (3-2j)
With reference to the preparation method of 3-1g, make white solid, yield 61.9%, mp:107～109 ℃ by N-tert-butoxycarbonyl-l-alanine and 1j reaction.
N-{2-propionic acid-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] butyl ester } farnesyl thiosalicylic acid acid amides (II 8) preparation
With reference to II 1The preparation method, make water white transparency oily thing, yield 51.7%, [α] with FTA reaction behind the 3-2j deprotection base 24 D:-3.9; IR (KBr, cm -1): 3262,2927,1730,1625,1555,1450,1372,1167; 1H NMR (CDCl 3, 300MHz): δ 8.04 (d, 2H, J=7.5Hz, Ar-H), 7.69 (m, 2H, Ar-H), 7.60 (m, 2H, Ar-H), 7.54 (d, 1H, J=6.6Hz, Ar-H), 7.41 (d, 1H, J=7.8Hz, Ar-H), 7.29 (m, 1H, Ar-H), 5.24 (t, 1H, J=7.5Hz, SCH 2C H), 5.05 (t, 2H, J=6.9Hz, 2 * CH 2C H=CCH 3), 4.79 (m, 1H, NC H), 4.44 (t, 2H, J=6.0Hz, COOCH 2CH 2CH 2C H 2O), 4.26 (t, 2H, J=6.0Hz, COOC H 2CH 2), 3.54 (d, 2H, J=7.8Hz, SC H 2), 1.99 (m, 8H, 2 * CHC H 2C H 2CH), 1.88 (m, 2H, COOCH 2CH 2C H 2), 1.51-1.69 (m, 17H, 4 * CH=CC H 3, COOCH 2C H 2, NCHC H 3); MS (ESI) m/z=726 [M+1] +.
Embodiment 20
The preparation of N-Boc-L-L-Ala-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)]-2-alkynes-butyl ester (3-2c)
With reference to the preparation method of 3-1g, make yellow solid, yield 53.7%, mp:113～115 ℃ by N-tert-butoxycarbonyl-l-alanine and 1c reaction.
N-[2-propionic acid-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)]-2-alkynes-butyl ester] farnesyl thiosalicylic acid acid amides (II 9) preparation
With reference to II 1The preparation method, make with FTA reaction behind the 3-2c deprotection base, water white transparency oily thing receives 44.1%, [α] 15 D:-15.8; IR (KBr, cm -1): 3421,2926,1749,1622,1548,1451,1362,1169; 1H NMR (CDCl 3, 300MHz): δ 8.06 (d, 2H, J=7.8Hz, Ar-H), 7.72 (m, 2H, Ar-H), 7.61 (m, 3H, Ar-H, N H), 7.44 (m, 1H, Ar-H), 7.33 (m, 1H, Ar-H), 7.29 (m, 1H, Ar-H), 5.24 (t, 1H, J=7.5Hz, SCH 2C H), 5.05-5.13 (m, 4H, 2 * CH 2CH=CCH 3, COOC H 2), 4.90 (m, 3H, NC H, C H 2O), 3.54 (d, 2H, J=7.8Hz, SC H 2), 1.98 (m, 8H, 2 * CHC H 2C H 2CH), 1.50-1.69 (m, 15H, 4 * CH=CC H 3, NCHC H 3); MS (ESI) m/z=722 [M+1] +.
Embodiment 21
N-Boc-phenylalanine(Phe)-2-{ [2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group } preparation of ethyl ester (3-4k)
With reference to the preparation method of 3-1g, make white solid, yield 58%, mp:108～109 ℃ by Boc-L-phenylalanine(Phe) and 1k reaction.
N-{2-phenylpropionic acid-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group] ethyl ester } farnesyl thiosalicylic acid acid amides (II 10) preparation
With reference to II 1The preparation method, make water white transparency oily thing, yield 60%, [α] with FTA reaction behind the 3-4k deprotection base 26 D:-2.5; IR (KBr, cm -1): 3286,2923,1737,1642,1612,1552,1453,1355,1157; 1H NMR (CDCl 3, 300MHz): δ 8.03 (d, 2H, J=7.5Hz, Ar-H), 7.71 (m, 2H, Ar-H), 7.57 (m, 3H, Ar-H), 7.48 (m, 1H, Ar-H), 7.26-7.41 (m, 6H, Ar-H), 5.16-5.22 (m, 3H, 3 * CH 2C H=CCH 3), 4.52 (t, 2H, J=4.5Hz, COOC H 2), 4.27 (m, 3H, NC H, OC H 2), 3.89-3.96 (m, 4H, OCH 2C H 2OC H 2), 3.21-3.36 (m, 4H, SC H 2, CHC H 2), 2.01 (m, 8H, 2 * CHC H 2C H 2CH), 1.47-1.67 (m, 12H, 4 * CH=CCH 3); MS (ESI) m/z=818 [M+1] +.
Embodiment 22
The preparation of N-Boc-L-proline(Pro)-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl ester (3-3g)
With reference to the preparation method of 3-1g, make faint yellow oily thing, yield 58.7% by Boc-L-proline(Pro) and 1g reaction.
N-{2-Pyrrolidine formic acid-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl ester } the inferior acid amides (II of farnesyl thiosalicylic acid 11) preparation
With reference to II 1The preparation method, make faint yellow solid, yield 37.2%, [α] with FTA reaction behind the 3-3g deprotection base 25 D:-18.6; IR (KBr, cm -1): 3326,2927,1743,1626,1552,1449,1368,1169; 1H NMR (CDCl 3, 300MHz): δ 8.07 (d, 2H, J=7.5Hz, Ar-H), 7.71 (m, 1H, Ar-H), 7.61 (m, 2H, Ar-H), 7.34 (m, 2H, Ar-H), 7.22 (m, 2H, Ar-H), 5.22 (t, 1H, J=6.3Hz, SCH 2C H), 5.08 (t, 2H, J=5.1Hz, 2 * CH 2C H=CCH 3), 4.67 (m, 1H, NC H), 4.65-4.50 (m, 2H, NC H, OC H), 3.80 (m, 2H, OC H 2), 3.52 (d, 2H, J=7.2Hz, SC H 2), 3.30 (m, 2H, NC H 2), 2.29 (m, 2H, OCHC H 2), 1.98 (m, 8H, 2 * CHC H 2C H 2CH), 1.52-1.67 (m, 16H, NCHC H 2, 4 * CH=CC H 3, NCH 2C H 2), 1.24 (d, 3H, J=6.3Hz, CHC H 3); MS (ESI) m/z=752 [M+1] +.
Embodiment 23
The preparation of N-Boc-L-proline(Pro)-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)]-2-alkynes-butyl ester (3-3c)
With reference to the preparation method of 3-1g, make faint yellow oily thing, yield 60.0% by Boc-L-proline(Pro) and 1c reaction.
N-{2-Pyrrolidine formic acid-4-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)]-2-alkynes-butyl ester } the inferior acid amides (II of farnesyl thiosalicylic acid 12) preparation
With reference to II 1The preparation method, make water white transparency oily thing, yield 46.1%, [α] with FTA reaction behind the 3-3c deprotection base 25 D:-30.3; IR (KBr, cm -1): 3439,2926,1752,1618,1548,1450,1362,1169; 1H NMR (CDCl 3, 300MHz): δ 8.07 (d, 2H, J=7.2Hz, Ar-H), 7.74 (m, 1H, Ar-H), 7.61 (m, 2H, Ar-H), 7.37 (m, 2H, Ar-H), 7.28 (m, 2H, Ar-H), 5.24 (t, 1H, J=7.5Hz, SCH 2C H), 5.08 (m, 4H, 2 * CH 2C H=CCH 3, COOC H 2), 4.82 (m, 2H, C H 2O), 4.71 (t, 1H, J=3.9Hz, NC H), 3.57 (d, 2H, J=7.5Hz, SC H 2), 3.30 (m, 2H, NC H 2), 2.29 (m, 2H, OCHC H 2), 1.98 (m, 10H, 2 * CHC H 2C H 2CH, NCHC H 2), 1.58-1.75 (m, 14H, 4 * CH=CC H 3, NCH 2C H 2); MS (ESI) m/z=748 [M+1] +.
Embodiment 24
N-Boc-L-proline(Pro)-2-{ [2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group } preparation of ethyl ester (3-3k)
With reference to the preparation method of 3-1g, make colorless oil, yield 81.8% by Boc-L-proline(Pro) and 1k reaction.
N-{2-Pyrrolidine formic acid-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group] ethyl ester } the inferior acid amides (II of farnesyl thiosalicylic acid 13) preparation
With reference to II 1The preparation method, make water white transparency oily thing, yield 48.3%, [α] with FTA reaction behind the 3-3k deprotection base 25 D:-19.1; IR (KBr, cm -1): 3434,2917,1744,1628,1552,1448,1360,1170; 1H NMR (CDCl 3, 300MHz): δ 8.04 (d, 2H, J=8.1Hz, Ar-H), 7.73 (m, 2H, Ar-H), 7.61 (m, 2H, Ar-H), 7.23-7.39 (m, 3H, Ar-H), 5.27 (t, 1H, J=6.3Hz, SCH 2C H), 5.08 (t, 2H, J=5.1Hz, 2 * CH 2C H=CCH 3), 4.57 (t, 2H, J=4.5Hz, COOC H 2), 4.39 (t, 3H, J=4.5Hz, C H 2OCN), 4.11 (m, 1H, NC H), 3.93 (t, 2H, J=4.5Hz, COOCH 2C H 2O), 3.83 (t, 2H, J=4.5Hz, COOCH 2OC H 2), 3.55 (d, 2H, J=7.5Hz, SC H 2), 3.33 (m, 2H, NC H 2), 1.96-2.04 (m, 10H, NCHC H 2, 2 * CHC H 2C H 2CH), 1.52-1.67 (m, 14H, 4 * CH 3, NCH 2C H 2); MS (ESI) m/z=768 [M+1] +.
Embodiment 25
N-Boc-glycocoll-2-{ [2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group } preparation of ethyl ester (3-1k)
Preparing method with reference to 3-1g makes white solid by 1k, yield 80%, mp:89～91 ℃.IR(KBr，cm -1)v：3359，2979，2941，1755，1681，1625，1562，1529，1456，1363，1164； 1H-NMR(300MHz，DMSO-d6)δ：1.37(s，9H，3CH 3)，3.63～3.71(m，4H，OCH 2，NCH 2)，3.79～3.82(m，2H，OCH 2)，4.18～4.21(m，2H，OCH 2)，4.50～4.53(m，2H，OCH 2)，7.19(brs，1H，NH)，7.72～7.77(m，2H，ArH)，7.88～7.93(m，1H，ArH)，8.01～8.03(m，2H，ArH)；ESI-MS(m/z)：487.7[M+H] +.
Glycocoll-2-{ [2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group } preparation of ethyl ester trifluoroacetate (4-1k)
Preparing method with reference to 4-1g is made by 3-1k, ESI-MS (m/z): 388.1 [M+H] +.
N-{ acetate-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group] ethyl ester } farnesyl thiosalicylic acid acid amides (II 14) preparation
With reference to II 1The preparation method, make water white transparency oily thing 0.22g, yield 53%, IR (KBr, cm by FTA and 4-1k reaction -1): 3422,2927,1749,1628,1553,1449,1362,1168; 1H NMR (CDCl 3, 300MHz): δ 8.05 (d, 2H, J=8.1Hz, Ar-H), 7.73 (m, 2H, Ar-H), 7.62 (m, 2H, Ar-H), 7.39-7.42 (m, 4H, Ar-H), 5.27 (t, 1H, J=6.3Hz, SCH 2C H), 5.08 (t, 2H, J=5.4Hz, 2 * CH 2C H=CCH 3), 4.56 (t, 2H, J=4.5Hz, COOC H 2), 4.40 (t, 3H, J=4.5Hz, C H 2OCN), 4.31 (s, 1H, NC H 2), 3.93 (t, 2H, J=4.5Hz, COOCH 2C H 2O), 3.84 (t, 2H, J=4.5Hz, COOCH 2OC H 2), 3.54 (d, 2H, J=7.5Hz, SC H 2), 2.01 (m, 8H, 2 * CHC H 2C H 2CH), 1.47-1.67 (m, 12H, 4 * CH 3); MS (ESI) m/z=728 [M+1] +.
Embodiment 26
N-Boc-{N '-2-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl group }-preparation of L-alanimamides (3-3e)
With reference to the preparation method of 3-1g, make white solid, yield 50.2%, mp:127～131 ℃ by N-tert-butoxycarbonyl-l-alanine and 1e reaction.
N-{N '-[2-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl group]-the 2-propionic acid amide } farnesyl thiosalicylic acid acid amides (II 15) preparation
With reference to II 1The preparation method, make water white transparency oily thing, yield 39.4%, IR (KBr, cm with FTA reaction behind the 3-3e deprotection base -1) v:3402,2907,1714,1624,1550,1452,1388; 1H NMR (CDCl 3, 300MHz): δ 8.03 (d, 2H, J=8.1Hz, Ar-H), 7.72 (m, 2H, Ar-H), 7.60 (m, 2H, Ar-H), 7.21-7.35 (m, 3H, Ar-H), 6.64 (m, 1H, CONH), 6.29 (d, 1H, J=9.0Hz, NH), 5.27 (t, 1H, J=6.3Hz, SCH 2C H), 5.08 (t, 2H, J=5.1Hz, 2 * CH 2C H=CCH 3), 4.56 (t, 2H, J=4.5Hz, COOC H 2), 4.31 (m, 2H, NC H 2), 3.73 (m, 2H, COOCH 2C H 2), 3.54 (d, 2H, J=7.5Hz, SC H 2), 2.01 (m, 8H, 2 * CHC H 2C H 2CH), 1.45-1.64 (m, 12H, 4 * CH 3), 1.50 (d, 2H, J=7.2Hz, NCHC H 3); ESI-MS (m/z): 711 [M+H] +.
Embodiment 27
The preparation of N-Boc-L-leucine-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl ester (3-5g)
With reference to the preparation method of 3-1g, make colorless oil, yield 90.1% by Boc-L-leucine and 1g reaction.
N-{2-isocaproic acid-1-methyl-3-[(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] propyl ester } farnesyl thiosalicylic acid acid amides (II 16) preparation
With reference to II 1The preparation method, make water white transparency oily thing, yield 51.2%, IR (KBr, cm with FTA reaction behind the 3-5g deprotection base -1) v:3413,2846,1717,1616,1551,1515,1454,1380,1169; 1H NMR (CDCl 3, 300MHz): δ 8.05 (d, 2H, J=8.1Hz, Ar-H), 7.70 (m, 1H, Ar-H), 7.58 (m, 2H, Ar-H), 7.40 (m, 2H, Ar-H), 7.29 (m, 2H, Ar-H), 5.25 (t, 1H, J=6.6Hz, SCH 2C H), 5.06 (m, 3H, 2 * CH 2C H=CCH 3, NC H), 5.13～5.21 (m, 1H, OCH), 4.45～4.50 (t, 2H, J=6.0Hz, OCH 2), 3.54 (d, 2H, J=7.5Hz, SC H 2), 2.20 (m, 2H, OCHC H 2), 1.91-2.05 (m, 10H, CHC H 2CH, 2 * CHC H 2C H 2CH), 1.56-1.68 (m, 12H, 4 * CH=CC H 3), 1.37-1.51 (m, 4H, OCHC H 3, CH 3C HCH 3), 0.80～1.08 (m, 6H, 2CH 3); .ESI-MS (m/z): 768 [M+H] +.
Embodiment 28
N-Boc-Beta-alanine-2-{ [2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group } preparation of ethyl ester (3-6k)
With reference to the preparation method of 3-1g, make colorless oil, yield 29.9% by Boc-Beta-alanine and 1k reaction.
N-{ propionic acid-2-[[2-(4-benzenesulfonyl-5-oxygen-1,2, the oxygen of 5-oxadiazole-3-)] oxyethyl group] ethyl ester } farnesyl thiosalicylic acid acid amides (II 17) preparation
With reference to II 1The preparation method, make water white transparency oily thing, yield 35.7%, IR (KBr, cm-1) v:3415,2935,1731,1650,1550,1454,1388,1186 with FTA reaction behind the 3-6k deprotection base; 1H NMR (CDCl 3, 300MHz): δ 8.04 (d, 2H, J=8.1Hz, Ar-H), 7.72 (m, 2H, Ar-H), 7.61 (m, 2H, Ar-H), 7.39-7.41 (m, 4H, Ar-H), 6.22 (brs, 1H, NH), 5.25 (t, 1H, J=6.3Hz, SCH 2C H), 5.07 (t, 2H, J=5.4Hz, 2 * CH 2C H=CCH 3), 4.56 (t, 2H, J=4.5Hz, COOC H 2), 4.40 (t, 3H, J=4.5Hz, C H 2OCN), 4.30 (s, 1H, NC H 2), 3.93 (t, 2H, J=4.5Hz, COOCH 2C H 2O), 3.82 (t, 2H, J=4.5Hz, COOCH 2OC H 2), 3.54 (d, 2H, J=7.5Hz, SC H 2), 1.96-2.01 (m, 8H, 2 * CHC H 2C H 2CH), 1.47-1.66 (m, 12H, 4 * CH 3); ESI-MS (m/z): 742 [M+H] +.

Claims (5)

1. the farnesyl thio-salicylic acid derivative shown in the general formula I or its medically acceptable salt:
Figure FSB00000686545700011
In the general formula I:
X representative-O-or-NH-, R representative-(CH 2) n-, n=2～6 ,-CH (CH 3) CH 2-,-CH (CH 3) (CH 2) 2-,-(CH 2) 2O (CH 2) 2-,-PhCH 2-,-(CH 2) 2NH (CH 2) 2-,
Figure FSB00000686545700012
-CH 2CH=CHCH 2-or-CH 2C ≡ CCH 2-;
Or X representative-NR 1, R 1Be methyl or 2-hydroxyethyl, R is an ethyl;
Or-X-R-representes:
2. farnesyl thio-salicylic acid derivative according to claim 1 or its medically acceptable salt is characterized in that, in the general formula I:
X representative-O-or-NH-; R representative-(CH 2) n-, n=2～6 ,-CH (CH 3) (CH 2) 2-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2NH (CH 2) 2-,
Figure FSB00000686545700014
Or-CH 2C ≡ CCH 2-;
Or X representative-NR 1, R 1Be methyl or 2-hydroxyethyl, R is an ethyl;
Or-X-R-representes:
Figure FSB00000686545700015
3. the preparation method of the described farnesyl thio-salicylic acid derivative of claim 1 is characterized in that:
Farnesyl thio-salicylic acid derivative shown in the general formula I prepares through following manner: 2-oxygen-3; 4-two benzenesulfonyls-1; 2, the 5-oxadiazole generates furazan oxynitride (1) with the H-O-R-X-H reaction under the sodium hydroxide effect, and farnesyl thiosalicylic acid (FTA) is at N; N '-NSC 57182 (DCC) and DMAP effect are descended and furazan oxynitride (1) reaction makes compound of Formula I, and its synthetic route is following:
Figure FSB00000686545700021
Wherein, the definition of X and R according to claim 1.
4. a pharmaceutical composition is gone up the described compound of Formula I of claim 1 and the pharmaceutically acceptable carrier of effective dose and is formed by treatment.
5. the purposes of the described compound of Formula I of claim 1 in preparation anti-liver cancer, lung cancer, mammary cancer, the cancer of the brain, cancer of the stomach medicine.
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CN102702052B (en) * 2012-06-18 2013-12-11 南通大学 Novel diamine-containing farnesyl thiosalicylic acid derivative and preparation method and medicinal application thereof
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CN111072682A (en) * 2019-11-07 2020-04-28 沈阳药科大学 Chelidonine furazan nitric oxide donor derivative and preparation method and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101402667A (en) * 2008-09-11 2009-04-08 中国药科大学 Glycosylation modified nitric oxide donor type oleaolic acid compounds, preparation and uses thereof
CN101530411A (en) * 2009-04-14 2009-09-16 中国药科大学 Application for taking NO donor-type compounds as P-glycoprotein inhibitors and tumor multi-drug resistance reversal agents

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101402667A (en) * 2008-09-11 2009-04-08 中国药科大学 Glycosylation modified nitric oxide donor type oleaolic acid compounds, preparation and uses thereof
CN101530411A (en) * 2009-04-14 2009-09-16 中国药科大学 Application for taking NO donor-type compounds as P-glycoprotein inhibitors and tumor multi-drug resistance reversal agents

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Medicinal Chemistry》.2010,第18卷3448-3456. *
Yong Ling, et al.Synthesis and evaluation of nitric oxide-releasing derivatives of farnesylthiosalicylic acid as anti-tumor agents.《Bioorganic & Medicinal Chemistry》.2010,第18卷3448-3456.
Yong Ling, et al.Synthesis and evaluation of nitric oxide-releasing derivatives of farnesylthiosalicylic acid as anti-tumor agents.《Bioorganic &amp *

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