TW201117806A - 2-[6-aryl-3(Z)-hexen-1,5-diynyl]-1,2,3-trimethoxybenzene compounds, and pharmaceutical compositions comprising the same - Google Patents

Abstract

Disclosed herein are novel 2-[6-aryl-3(Z)-hexen-1, 5-diynyl]-1, 2, 3-trimethoxybenzene compounds of formula (I): or a pharmaceutically acceptable salt thereof, wherein each of the substituents is given the definition as set forth in the Specification and Claims. Also disclosed are the uses of these compounds in the manufacture of pharmaceutical compositions for use in the treatment of cancers.

Description

201117806 VI. Description of the invention: [Technical field to which the invention pertains] The present invention relates to novel 2-[6-aryl-3(Z)-hexaplo-1,5-diyl]-1,2,3 Trimethoxy benzene compounds, which have been shown to have a broad and effective anticancer activity. The invention also relates to their use in the preparation of pharmaceutical compositions. [Prior Art]

Microtubules are an important component of the cytoskeleton, consisting of ct-tubulin and heterodimers of β-tubulin [size ( The dimensions are composed of 4 nm X 5 nm X 8 nm and a molecular weight of 100,000 daltons. It is known that microtubules and their dynamics play a key role in many biological processes, including: mitosis, intracellular transport, exocytosis, and Cell growth (YH Lo ei α/. (2008), /ϋ C/iem·, 51:2682-2688). During mitosis, tubulin in the cytoplasmic network is polymerized into microtubules that form a mitotic spindle, which will be used in the original cell. Duplicated chromosomes are correctly separated and then transferred to daughter cells. After completing the role of the mitotic spindle, the microtubules are depolymerized into tubulin. When microtubulin polymerization or microtubule deploymerization is disrupted, 201117806, the replicated chromosome cannot be smoothly transferred to the daughter cell, thus causing the cell to arrest in the cell division G2/M (G2/M phase) and activate apoptosis (apoptosis). It is known that when a cell changes to make its apoptotic machinery out of control, the cell forms cancer cells. Therefore, in recent years, inhibiting the proliferation of cancer cells by interfering with the kinetics of microtubules has become one of the important directions for the global study of anticancer drugs. The microtubule-targeted antimitotic drugs are ones that inhibit microtubule dynamics without altering the microtubule mass, thereby causing mitotic blocks and cell holes. Dead anticancer drugs. In general, microtubule-target anti-mitotic drugs can be distinguished into the following two categories depending on the utility: 1 • microtubule-destabilizing agents, such as the periwinkle bioassay (Fzwcfl alkaloids) ), cryptophycins, halichondrins, Estramustine, colchicines, Nocodazole, and Combretastatins Such drugs inhibit the polymerization of tubulin into microtubules at high concentrations, thereby blocking the formation of mitotic spindles during mitosis; and 2. microtubule-stabilizing agents such as paclitaxel ( Paclitaxel) [also known as Taxol], Docetaxel, epothilones, discodermolide, eleutherobins, lychee (sarcodictyins) and certain steroids with polyisoprenyl benzophenones, which bind to microtubules and Microtubule depolymerization is inhibited by diazepam microtubules. Colchicine is a kind of self-toxic colchicum (English name is film saffron, Latin name is Co/cA/cww I.) and is the first one to be

The microtubules found were de-suppressants. It is known that colchicine binds to β-tubulin at the interface between β-tubulin and α-tubulin, thereby inhibiting tubulin polymerization. Although colchicine plays an important role in elucidating the physical properties and biological functions of tubulin and microtubules, the high toxicity of colchicine limits its therapeutic application (TL Nguyen ei α/· (2005), "/. Med. CAem., 48:6107-6116) = Combretastatin A-4 (CA-4) is a South African willow tree (English name is South African willow, Latin) Natural stilbene (combene), which is isolated from Comfereiww calMm), has the following chemical formula (I):

OMe

CA-4 is one of the most potent anti-mitotic drugs in the combretastin family, which is resistant to cytotoxic effects of various human cancer 201117806 cell lines and in animal xenograft molding ( Activity in animal xenograft models) has been reported. CA-4 was evaluated as an experimental therapeutic for humans, however poor water solubility prevented CA-4 from developing into a drug (Y. Kong ei α/. (2005), C/zew as & 〇 /0 order, 12:1007-1014) 〇

In order to overcome the above disadvantages, researchers in the art have attempted to synthesize a novel compound having an activity of inhibiting the polymerization of tubulin based on the chemical structure of CA-4. For example, in Provot d α/· (2005), 46:8547-8550, O. Provot et al. disclose Z-enediynes (compound 4) having the following chemical formula (II):

OMe

(Π) In particular, Provot et al. exemplify the synthesis of the following compounds of formula (II): 2-[6-(4-methoxyphenyl)-3(Z)-hexene-1,5 -diynyl]-1,2,3-trimethoxyoxy{2-[6-(4-anisyl)-3(Z)-hexen-l,5-diynyl]-l,2,3-trimethoxybenzene } (Compound 4a), wherein X is CH, Rq is OMe 201117806, and R2 is Η; (Ζ)-2-[[4-(3,4,5-trimethoxyphenyl)but-3-ene -1-yne]-1-yl]-naphthalene {(Z)-2-[[4-(3,4,5-trimethoxyphenyl)but-3-en-1 -yn]-1 -yl]-naphthalene} (Compound 4b) wherein X is CH, and R丨-R2 is (-CH-)4; (Z)-2-[[4-(3,4,5-trimethoxyphenyl)butene-3 -en-1-yne]-1-yl]quinoline {(Z)-2-[[4-(3,4,5-trimethoxyphenyl)but-3-en-l-yn]-l-yl]quinoline } (Compound 4c), wherein X is N, and 丨-112 is (-CH-)4, (Z)-2-foxy-5-[[6-(3,4,5-trimethoxy) Phenyl)hex-3-ene-1,5-diyne]-1_yl]phenol {(Z)-2-Methoxy-5-[[6-(3,4,5-trimethoxyphenyl)hex-3-ene -l,5-diyn]-l-yl]phenol} (compound 4d) wherein X is CH, R丨 is OMe, and R2 is OH; and (Z)-2-methoxy-5-[[6 -(3,4,5-trimethoxyphenyl)hex-3 -ene-1,5-diacetyl]-1-yl]phenylamine {(Z)-2-Methoxy-5-[[6-(3,4,5-trimethoxyphenyl)hex-3-ene-l , 5- Diyn]-l-yl]phenylamine} (4 chelate 4e) wherein X is CH, R丨 is OMe, and R2 is NH2. 0. Provot et al. found that among compounds 4a to 4e, only compound 4e has an activity of inhibiting tubulin polymerization, and its inhibitory activity is about 50 times lower than that of CA-4. In addition, the compound of formula (II) is also less cytotoxic against KB, MCF7 and MCF7R cell lines than CompAir. The inventors disclose a series of aryl-substituted 201117806 acyclic enediyne compounds having the following chemical formula (III) in US 7,332,623 B2:

The definition of each substituent is as defined in the specification of US 7,332,623 B2 and the scope of the patent application. The aryl-substituted acyclic enediyne compounds of formula (III) have been shown to have inhibitory activity against topoisomerase I or have effects such as S phase or G2/M phase Blocker (S phase or G2/M phase blocker) In particular, in the overall disclosure of US 7,332,623 B2, 2-[6-(4-methoxyphenyl)- having the following formula (IV) is exemplified. Synthesis of 3-hexene-1,5-diynyl]benzonitrile {2-[6-(4-anisyl)-3-hexen-l,5-diynyl]benzonitrile}:

(IV) in a breast cancer cell (MCF7), non-small cell lung cancer cell (NCI-H460) with 201117806 and central nervous system cancer cell In the preliminary cytotoxicity test of (SF-268), 2-[6-(4-methoxyphenyl)-3-hexene-1,5-diynyl]benzonitrile did not The preset standard value [that is, the growth percentage of the cancer cells treated with the compound S 32%] was reached, and thus the preliminary cytotoxicity test was not passed. In a subsequent study, the inventors synthesized 2-[6-(2-trifluoromethylphenyl)-3(2)-hexene-1,5-diynyl] having the following chemical formula (V)] Aniline {2-[6-(2-trifluoromethylphenyl)-3 (Z)-hexen-l, 5-diynyl] aniline}

2-[6-(2-Trifluoromethylphenyl)-3(Z)-hexene-1,5·diynyl]aniline against approximately 60 tumor cell lines (especially central nervous system cancer cell SNB) -75) shows the most potent growth inhibitory activity and arrests cancer cells in the G2/M phase. In addition, 2-[6-(2-trifluoromethylphenyl)-3(Z)-hexene-1,5-diynyl]aniline also causes microtubule depolymerization and via the cysteine protease family Activation of the (caspase family) induces apoptosis. However, the inhibitory activity of 2·[6-(2-trifluoromethylphenyl)-3(Z)-hexene-1,5-201117806-fast-hydroxy]aniline on growth inhibition activity of cancer cells was higher than that of CA- 4 and color; fire, sputum, localized β and tubulin polymerization spurs > ancient skill is lower than LA-4 and colchicine (YH Lo α /. (2008), the same Above). Lang-[name

Base)-3(7)·hexamethylene-丨'5·di-free group] aniline inhibits tubulin polymerization in the same manner as colchicine, and 2_[6_(2_trismethylphenyl)·3(ζ) The trifluoromethylphenyl group of _1,5-diynyl]aniline is consistent in position with the trimethoxyphenyl group of colchicine. Based on the results of the above molecular docking experiments and the virtual screening of drugs, the inventors believe that the three methoxy groups on the phenyl group can impart growth inhibiting activity and tubulin polymerization inhibitory activity to a compound which is superior to cancer cells. Therefore, if a trimethoxymethyl group can be substituted for the trifluoromethyl group of 2_[6_(2-trifluoromethyl]phenyl)-3(fluorene)-hexene-fluorene, 5-diallyl]aniline The phenyl group should develop a new compound that is more potent and suitable for the treatment of a variety of cancers and tumors. SUMMARY OF THE INVENTION Accordingly, in a first aspect, the present invention provides a compound of the following formula (I): 10 201117806

(i) or a pharmaceutically acceptable salt thereof, wherein: • The Ar group is selected from the group consisting of 2-nitrophenyl, 2-cyanophenyl, 2-methyl Oxyphenyl, 2-aminophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-aminotrifluoromethylphenyl'-based, 4-aminophenyl, 3- Aminophenyl, 2_n-pyridyl, 2-methylthiophenyl, 2,4-dimethoxyphenyl, 3-hydroxyphenyl, 4-methoxy-2-niodophenyl, 2_ Amino 4-methoxyphenyl and 5-amino-2-methoxyphenyl. In a second aspect, the present invention provides a pharmaceutical composition for inhibiting growth of a tumor/cancer cell comprising a compound having the chemical formula (1) or a pharmaceutically acceptable salt thereof as described above . In a first aspect, the present invention provides a pharmaceutical composition for inhibiting tubulin polymerization in a tumor/cancer cell, comprising a compound of the octamorphic formula (I) as described above or one of The above and other objects, features and advantages of the present invention will become apparent upon consideration of the appended claims appended claims appended claims 11 201117806 The detailed description of the invention is to be understood: if there is a cup ~ recognize this ^ 'any item is quoted here, the previous publication does not constitute - the following recognition: in Taiwan or any other country 'This publication forms part of the common general knowledge in this technique. For the purposes of this specification, it will be clearly understood that the term "comprising" means "including but not limited to," and the term "comprises" has a corresponding meaning. Definitions All technical and scientific terms used herein have the meaning as commonly understood by those skilled in the art to which the invention pertains. Those skilled in the art will recognize many that are similar or equivalent to those described herein. Method and material hoppers, which can be used to practice the invention. Of course, the invention is in no way limited by the methods and materials described. It is clear that the following definitions are used herein. In a previous study, The inventors attempted to synthesize 2 [6 (2,3-trifluoromethylphenyl)-3(Z)-hexene-1,5-diynyl]aniline, and found through pharmacological experiments. 2-[6-(2- Difluoromethyl phenyl)_3(Z)-hexene-i,5-diynyl]aniline has a growth inhibitory activity against cancer cells and a inhibition activity on tubulin polymerization, which is better than that of Ca·4 and colchicine. In the other previous study, the inventor Step by step: 2_[6_(2-difluoromethylphenyl)_3(Z)-hexene-1,5-diynyl]aniline inhibited tubulin polymerization in the same manner as colchicine, and A trifluoromethyl phenyl group of 2_[6·(2_trifluoromethylphenyl)·3(Ζ)-hexene-1,5-diynyl]aniline and trimethoxybenzene of colchicine The group is consistent in position. Therefore, the inventors believe that the three methoxy groups on the phenyl group can impart a cell growth inhibitory activity and a tubulin polymerization inhibitory activity to a compound. After having studied by a plurality of parties, the compound of the formula (I) of the present invention: ',

Ar (I) or a pharmaceutically acceptable salt thereof, wherein:

The Ar group is selected from the group consisting of 2 nitrophenyl, 2-cyanophenyl, 2-decyloxyphenyl, 2-aminophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-amino-5-trifluoromethylphenyl, 3-pyridyl, 4-aminophenyl, 3-aminophenyl, 2-pyridyl, 2-methylsulfide Phenylphenyl, 2,4-dimethoxyphenyl, 3-hydroxyphenyl, 4-methoxy-2-nitrophenyl, 2-amino-4-yloxyphenyl and 5-amine Base-2-methoxyphenyl. The compound of the formula (1) according to the present invention may be in the form of its free form or a pharmaceutically acceptable salt thereof. Further, the compound of the formula (I) according to the present invention may be present as a stereoisomer or as a solvate represented by a hydrate. Therefore, it is expected that these stereoisomers and solvates will be included in the technical concept of the present invention. Exemplary pharmaceutically acceptable salts include, but are not limited to, salts with 13 201117806 mineral acids such as cesium chloride, hydrogen bromide, sulfuric acid, and phosphoric acid; with organic acids [such as acetic acid, Malay) Salts of maleate, tartrate, methanesulfonate; and salts with amino acids such as arginine, aspartic acid, and glutamic acid. The compound of the formula (I) according to the present invention has been confirmed to have excellent tumor/cancer cell inhibition (especially human gastric adenocarcinoma cells, prostate cancer cells, breast cancer cells, human cervical epithelial cancer cells, oral squamous cell carcinoma cells). The activity of growth of hepatocellular carcinoma cells, ovarian cancer cells, human lung cancer cells, and human colon cancer cells. Accordingly, it is contemplated that the compounds of formula (I) or a pharmaceutically acceptable salt thereof of the present invention are useful in the preparation of pharmaceutical compositions for use in the treatment of tumors/cancers. Thus, the present invention provides a pharmaceutical composition for inhibiting the growth of a tumor/cancer cell comprising a compound of the formula (I) as described above or a pharmaceutically acceptable salt thereof. The pharmaceutical compositions according to the present invention may additionally comprise a pharmaceutically acceptable carrier which is conventionally used in the art to prepare pharmaceutical compositions. For example, the pharmaceutically acceptable carrier can include one or more of the following: a solvent, an emulsifier, a suspending agent, a decomposer, a binding agent, An excipient, a stabilizing agent, a chelating agent, a diluent, a gelling agent, a preservative, a lubricant, and the like. Things. The pharmaceutical composition according to the present invention can be administered parenterally or orally 14 201117806 (orally) in a suitable pharmaceutical form. Suitable pharmaceutical forms include sterile aqueous solutions or dispersions, sterile powders, tablets, troches, pills, capsules. And similar things. The inventors have found through further experiments that the compound of the formula (I) according to the present invention has an activity of inhibiting tubulin polymerization in a tumor/cancer cell, particularly a human breast cancer cell. This suggests that the compound of formula (I) according to the present invention exhibits anticancer activity by inhibiting the polymerization of tubulin. Accordingly, the present invention also discloses that the compounds of formula (I) or a pharmaceutically acceptable salt thereof are supplied for the preparation of a pharmaceutical composition for inhibiting tubulin polymerization in a tumor/cancer cell. use. Thus, the present invention provides a pharmaceutical composition for inhibiting tubulin polymerization in a tumor/cancer cell comprising a compound of the formula (1) or a pharmaceutically acceptable salt thereof as described above. As used herein, "inhibiting tubulin polymerization", "inhibiting microtubule regrowth," , "microtubule depolymerizing", and "microtubule depolymerization" ("microtubule depolymerizing") "microtubule destabiling"" can be used interchangeably and means the ability to inhibit tubulin from forming microtubules. In a preferred embodiment of the invention, the compound of formula (I) is 2-[6-(2) -Methoxyphenyl)-3(Z)-hexene-1,5·diynyl]-1,2,3-trimethoxybenzene, 2-[6-(2-aminophenyl)- 3(Z)-hexene-1,5-diynyl]·1,2,3- 15 201117806^Methoxybenzene or 2_[6,(2,yl)_3(2)_hexyl-^2 Alkynyl] cleavage. monomethoxybenzene. In a more preferred embodiment of the invention, the compound of formula (1) is 2·[6-aminophenyl)3(ζ)·己稀山5·二快基]- 1,2,3·三甲童其# 土本{2-[6-(2-3111111〇卩]1611乂1)-3(2)-116\611-1,5- diynyl]- l, 2,3-tnmethGxybenzene}. The pharmaceutical composition according to the present invention may additionally contain one which is To prepare a pharmaceutically acceptable carrier for a pharmaceutical composition. For example, the pharmaceutically acceptable carrier can include one or more of the following agents: φ solvent, emulsifier, suspending agent, decomposing agent, binder, excipient The stabilizer chelating agent, diluent, gelling agent, preservative, lubricant, and the like. The pharmaceutical composition according to the present invention may be administered parenterally or orally in a suitable pharmaceutical form. Suitable pharmaceutical forms include sterile aqueous solutions or dispersions, sterile powders, lozenges, tablets, pills, capsules, and the like. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in the following examples. For further explanation, it should be understood that the examples are for illustrative purposes only and are not to be construed as limiting the implementation of the invention. Examples of compounds according to the invention having the formula (1) may be as follows The reaction route is prepared with the operating procedure. As shown in Reaction Scheme 1, 4-trimethylsulfonylalkylene butylene-3-alkyne (4_ 16 201117806 trimethylsilyl-l-chlorobute N-3-yne) (compound a) is reacted with 1-ethynyl-3,4,5-trimethoxybenzene (compound a2) to give 2-[6 -trimethyldecyl-3(Z)-hexene-1,5-diynyl]-1,2,3-trimethylbenzene {2-[6 seven 111161; 11丫18 1-3 (2)-1^\611-1,5-(^1154]- l,2,3-trimethoxybenzene} (Compound a3). Compound a3 can be reacted with an aryl iodides of the formula Ar-I wherein the Ar groups have the same definitions as those defined for compounds 1-14, thereby obtaining the corresponding 2-[6 -aryl-3(Z)-hexene-1,5-diynyl]-i,2,3-trimethoxybenzi {2-[6-aryl-3(Z)-hexen-1,5-diynyl ]-1,2,3-trimethoxy benzene} (Compound 1-14). 201117806 Reaction pathway 1 TMS OCH3 , och3 + , C1 al a2 Reagents and reaction conditions: i. Pd(PPh3)4, Cul, n-BuNH2, B, 4 hours; and ii. Pd(PPh3)4, Cul, K2C03 , MeOH, 6 hours.

Alternatively, as shown in Reaction Scheme 2, 2-[6-(2-cyanophenyl)-3(Z)-hexene-1,5-diynyl]-1,2,3-trimethoxy Benzo {2-[6-(2<丫&11〇?1^1^1)-3(Z)-hexen-l,5-diynyl]-l,2,3-trimethoxy benzene} (Compound 2 Can be determined by 2-[6-trimethyldecyl-3(Z)-hexene-1,5-diynyl]benzi {2-[6-trimethylsilyl-3(Z)-hexen- 1,5-diynyl]benzonitrile} (Compound a4) was obtained by reacting with 5-iodo-l, 2,3-trimethoxybenzene (Compound a5). 18 201117806 Reaction pathway 2

As shown in Reaction Scheme 3, compound a3 is reacted with 4-iodo-3-nitroanisole (compound a6) to give 2-[6-(4-methoxy- 2-nitrophenyl)-3(2)-hexene-1,5-diynyl]-1,2,3-trimethoxybenzene {2-[6-(4-methoxy-2-nitrophenyl) -3(Z)-hexen-1,5-diynyl]-1,2,3-trimethoxybenzen} (Compound 15). Compound 15 can be treated with SnCl2.2H20 and MeOH to give 2-[6-(2-amino-4-methoxyphenyl)-3(2)-hexene-1,5-diynyl]- 1,2,3-trimethoxybenzene {2-[6-(2々111丨11〇-4-methoxyphenyl)-3(Z)-hexen-l ,5-diynyl]-1,2,3- Trimethoxybenzene} (Compound 16) ° 19 201117806

Reaction pathway 3

Och3

Reagent 舆 Reaction conditions: i. Pd(PPh3)4, Cul 'K2C03, MeOH, 6 hours; and ii. SnCl2 '2H20, MeOH, reflux 1.5 hours or monitored by TLC

2-oxooxy-5-nitro-O-methoxy-S-nitrophenol (compound a7) is treated with Tf20 and Et3N to give 2-decyloxy-5-nitrophenyl as shown in Reaction Scheme 4. - 2-methoxy-5-nitrophenyl-trifluoromesylate (compound a8). The reaction of the compound a8 with (trimethylsilyl) acetylene gives 2-methoxy-5-nitrophenyl-trimethylsulfanyl 2-methoxy-5-nitrophenyl -trimethylsilyl acetylene) (Compound a9), compound a9 was treated with K2C03 and Me〇H to give 2-methoxy-5-nitrophenyl acetylene (compound a10). The compound alO was then treated with SnCl2_2H20 and MeOH to give 2-methoxy-5-aminophenyl acetylene (compound all). Next, the reaction of the compound all with the compound al gives 1-(2-methoxy 20 201117806--5-aminophenyl)-6-tridecylsulfenyl-3(Z)-hexene-1,5-di Alkyne [1-(2-methoxy-5-aminophenyl)-6-trimethylsilyl-3(Z)-hexen-l, 5-diynes] (compound al2), compound al2 is reacted with compound a5 to give 2-[6 -(5-Amino-2-methoxyphenyl)-3(Z)-hexene-1,5-diynyl]-1,2,3-trimethoxybenzene {2-[6-( 5-&111111〇-2-11^11〇\丫卩1^1171)-3(2)-hexen-l,5-diynyl]-l,2,3-trimethoxybenzene} (Compound 17).

21 201117806 Reaction pathway 4

Och3 h2n

All

Reagents and reaction conditions: i. Tf20, Et3N, CH2C12, 1 hour; ii. Pd(PPh3)4, Cul, "-BuNH2, Bδί, 4 hours; iii. K2C03, MeOH, 1 hour; iv. SnCl2, 2H20 , MeOH, refluxed for 2 hours or monitored by TLC, v. Pd (PPh3) 4, Cul, K2C03, MeOH, for 4 hours. And OCH3 '〇ch3 och3

H3co 22 17 201117806 Compounds of formula (1) according to the invention are shown in Table 1 below. Table 1. Compounds of formula (I) according to the invention

The aryl break of the compound IUPAC named Ar group 1 2-[6-(2-nitrophenyl)-3(Z)-hexene-1,5-diynyl]-1,2,3 -3-methoxyphenyl {2-[6-(2-nitrophenyl)-3(Z^-hexen-l,5-diynyl]-1,2,3-trimethoxybenzene} 2 - 2-phenylene-2-ene 2 2-[6-(2-Cyanophenyl)-3(Z)-hexene-1,5-diynyl]-1,2,3-trimethoxybenzene {2-[6_(2 -cyanophenyl)-3(Z)-hexen-1,5-diynyl]-1,2,3-trimethoxybenzene} 2-iodobenzonitril 3 2-[6-(2-methoxy Phenyl)-3(Z)-hexene-1,5-diynyl]-1,2,3-trimethoxybenzene {2-[6-(2-anisyl)-3(Z)-hexen- 1,5-diynyl]-l,2,3-trimethoxybenzene} 2-iodoanisole 4 2-[6-(2-Aminophenyl)-3(Z)-hexene -1,5-diynyl]-1,2,3-trimethoxybenzene {2-[6-(2-aminophenyl)-3(Z)-hexen-1,5-diynyl] -1,2, 3-trimethoxybenzene} Η η2ν7 2-iodoaniline 5 2-[6-(4-methoxyphenyl)-3(Z)-hexene-1,5-diynyl]-1, 2,3-trimethoxybenzene {2-[6-(4-anisyl)-3(Z)-hexen-l,5-diynyl]-1,2,3-trimethoxybenzene} Methyl test (4- Iodoanisole) 6 2-[6-(3-decyloxyphenyl)-3(Z)-hexene· 1,5-diynyl]-1,2,3-trimethoxybenzene {2-[6 -(3-anisyl)-3(Z)-hexen-1,5-diynyl]-1,2,3-trimethoxybenzene} och3 3 -Phenylphenylether Ether (3-iodoanisole)

23 201117806 7 2-[6-(2-Amino-5-trifluorodecylphenyl)-3(Z)-hexene-1,5-diynyl]-1,2,3-trioxyloxy Benzene {2-[6-(2-&11^11〇-5-trifluoromethylphenyl)-3(Z)-hexen-1,5-diynyl] -1,2,3-trimethoxybenzene} cf3 h2n7 2-峨2-2-iodo-4-trifluoromet hylaniline 8 2-[6-(3-.pyridyl)-3(Z)-hexene-1,5-diynyl]- 1,2,3-trimethoxybenzene {2-[6-(3-pyridinyl)-3(Z)-hexen-1,5-diynyl]-1 ,2,3-trimethoxybenzene} 3-iodopyridine (3 -iodopyridine ) 9 2-[6-(4-Aminophenyl)-3(Z)-hexene-1,5-diynyl]-1,2,3-trimethoxybenzene {2-[6 -(4-aminophenyl)-3(Z)-hexen- l,5-diynyl]-l,2,3-trimethoxybenzene} \ 4-iodoaniline 10 2-[6-(3-Amino Phenyl)-3(Z)-hexene-1,5-diynyl]-1,2,3-trimethoxybenzene (2-[6-(3-aminophenyl)-3(Z)-hexen- l,5-diynyl]-l,2,3-trimethoxybenzene} M nh2 3-iodoaniline 11 2-[6-(2-pyridyl)-3(Z)-hexene-1,5 -diynyl]-1,2,3-trimethoxybenzene {2-[6-(2-pyridinyl)-3(Z)-hexen-1,5-diynylj-1,2,3-trimethoxybenzene} Λ ', 2-iodopyridine 12 2-[6-(2-曱thiophenyl)-3(Z)-hexene-1.5-diynyl]-l,2,3-trimethoxybenzene {2-[6-(2- Thieanisyl)-3(Z)-hexen- 1.5- diynyl]-l,2,3- trimethoxy benzene} 2-iodothioanis ole 13 2-[6-(2,4- Dimethoxyphenyl)-3(Z)-hexene-1,5-diynyl]-1,2,3-trimethoxybenzene {2-[6-(2,4-dimethoxyphenyl)_ 3 (Z)-hexen- 1,5-diynyl]-1,2,3-trimethoxybenzene} \ )~ocH3 H3co' 2,4-dimethoxy-1-propiobenzene (2,4-dimethoxy-1- iodobenzene) 14 2-[6-(3-Hydroxyphenyl)-3(Z)-hexene-1,5-diynyl]-1,2,3-trimethoxybenzene (2-[6-( 3-hydroxylphenyl)-3(Z)-hexen-1,5-diynyl] -1,2,3-trimethoxy benzene} OH 3-iodophenol

24 201117806 15 2-[6-(4-Methoxy-2-nitrophenyl)-3(Z)·hexene-1,5-diynyl]-1,2,3-tridecyloxy Benzoquinone 2-[6-(4-11161;11〇\7-2-nitrophenyl)-3(Z)-hexen-l,5-diynyll-1,2,3-trimethoxybenzen} y_X0CH3 o2n7 4 -E-3 -Nitrophenylindolyl (4-iodo-3-nitroanisole) 16 2-[6-(2-Amino-4-methoxyphenyl)-3(Z)-hexene-1,5- Diacetyl]]-1,2,3-trimethoxybenzene {2-[6-(2-&11^11〇-4-methoxyphenyl)-3(Z)-hexen-1,5-diynyl] -1,2,3-trimethoxybenzene} /-0CH3 η2ν — 17 2-[6-(5-Amino-2-methoxyphenyl)-3(Z)-hexene-1,5-diynyl ]-1,2,3-trimethoxy stupid {Sl^-p-aminoJ-methoxyphenyO-S^-hexen-lJ-diynyl]-l,2,3-trimethoxybenzene} nh2 -0 h3co' — general procedure: A typical thin layer chromatography (TLC) is performed by using pre-coated silica gel 60 F254 plates (Merck), and by using a UV light. (254 nm) was detected.

The melting point of the compound synthesized in the following examples was detected using an MP-ID melting point detector (Fargo Instrument). Silica gel column chromatography by using a gel 60 [sieve mesh 40-63 μηι, manufactured by Merck] as a solid phase and combined for separation It is carried out with a purified eluent. W-NMR and 13C-NMR spectra were examined using a Varian Gemini-200 VT FT-NMR or a Varian Unity plus-400 FT-NMR nuclear magnetic resonance spectrometer (J 〇 25 201117806). The chemical shifts of 1H-NMR and 13C-NMR represented by δ (in ppm) are TMS (δ=0.0 ppm) and CDC13 (δ=77·0 ppm), respectively, as an internal standard, and the coupling constant is " / (in Hz) to indicate. High-resolution mass spectra were detected using a JEOL JM-SX 102 instrument.

Elemental analysis was performed using an Elementar vario EL III Heraeus CHNOS Rapid F002 elemental analyzer. Synthesis Example 1. 2-[6-Trimethyldecyl-3(Z)-hexene-1,5-diynyl]·1,2,3-trimethoxybenzene {2-[6-11^ 1116111;^1811丫1-3(2)-116 fork 611_1,5-<!1丫11^1]-1,2,3-food 1411161110 and >^61126116} (compound 33) 1-ethynyl-3,4,5-trimethoxybenzene (a2) (12 mmol) in diethyl ether (20 mL) (based on BR Kaafarani et al (2002), Photochemical and Photobiological Sciences, U942-95Q Deconstructed solution [containing Cul (3.2 mmol) and λ-BuNH2 (30 mmol)] force 4-trimethylsilyl-l-chlorobuten-3-yne (al) (12 mmol) in B-(25 mL) (It is a degassed solution [prepared according to the method described in Example 1 of the prior patent US 7,332.623 B2] of the inventor [containing Pd(PPh3)4 (0.8 mmol)]. The resulting reaction mixture was stirred at room temperature for 4 hours, then quenched with a saturated NH4C1 aqueous solution, followed by ethyl acetate (EA, 26 201117806).

EtOAc) (30 mL ><3) was extracted. The organic extract was collected and washed with saturated aqueous Na.sub.2CO.sub.3 (40 mL) then dried over anhydrous EtOAc. After the solvent was removed under vacuum, the residue was purified mjjjjjjjlilililililililililili The nature of the title compound was measured. Mp : 49-50 〇C ; ^-NMR (CDC13, 400 MHz) : δ 6.71 (s, 2H), 6.05 (d, 1H, J = 10.8 Hz), 5.87 (d , 1H, J = 10.8 Hz), 3.86 (s, 3H), 3.84 (s, 6H), 0.24 (s, 9H) ; , 3C-NMR (CDC13, 100MHz): δ 153.0 (2C), 139.2, 120.6, 119.1, 118.0, 108.9 (2C), 103.2, 102.3, 97.6, 86.2, 60.9, 56.1 (2C); HRMS calculated for C18H2203Si: Mr = 314.1338, found: 314.1338; elemental analysis, theoretical value: C (68.75%) ), Η (7·05%), actual values: C (68.50%), Η (7.06%). Synthesis Example 2. 2·[6-(2-Nitrophenyl)-3(fluorene)-hexene-1,5·diynyl]·1,2,3-trimethoxybenzene {2-[6 -(2-11心〇卩1161^1)-3(2)-116^11-1,5-diynyl]-l,2,3-trimethoxybenzene} (Compound 1) Pair with sterol (methanol, Degassed solution of compound a3 (12 mmol, obtained from Synthesis Example 1 above) in MeOH) (15 mL)

Cul (3.2 mmol) and K2C03 (30 mmol) were added to a degassed solution of 2-bromonitrobenzene (12 mmol) in MeOH (20 mL) [with Pd(PPh3)4 (0.8 mmol) ]. The resulting reaction mixture was allowed to stand at room temperature for 6 hours, then the solvent was removed in vacuo and then quenched with saturated aqueous NH.sub.4 C.sub.1, then EtOAc (20 mL &gt;&lt;3&gt; 27 201117806 The organic extracts were collected and washed with a saturated aqueous solution of Na.sub.2 C.sub.3 (4 mL), then dried over anhydrous MgSO.sub.4 and filtered. After the solvent was removed in vacuo, EtOAc m.性质The property of the title compound was measured, · Mp . 95-96 C ; *H-NMR (CDC13, 400 MHz) : δ 8.09 (dd, 1H, J = 8.4, 1.6 Hz), 7.69 (dd, 1H, J = 7.6, 1.6 Hz), 7.57 (td, 1H, J = 7.6, 1.2 Hz), 7.47 (td, 1H, J = 7.6, 1.6 Hz), 6.90 (s, 2H), 6.21 (d, 1H, J = L〇.8 Hz), 6.12 (d, 1H, J = 10.8 Hz), 3.88 (s, 3H), 3.87 (s, 6H) ; 13C-NMR (CDC13, 100 MHz) : δ 153.0 (2C), 149.1 , 139.3, 135.0, 132.8, 128.8, 124.7, 121.7, 118.7, 117.8, 117.7, 109.3 (2C), 99.2, 94.7, 92.2, 86.1, 60.9, 56.2 (2C); HRMS calculated for C2iH17N05: Mr = 363.1107 ' Found value .363.1111; elemental analysis, theoretical value: c (69.41%), Η (4_72%) 'N (3.85%), actual values: c (68.99%), Η (4.78%), Ν (3.35%). Synthesis Example 3. 2-[6-(2-Cyanophenyl)·3(Ζ)_hexaplo-1,5-diynyl]_ι,2,3-trimethoxybenzene {2-[6- (2&lt;丫珏11〇卩1161^1)-3(2&gt;|^611-1,5-diynyl]-l,2,3-trimethoxybenzeiie} (Compound 2) The title compound 2 can be synthesized by the following synthesis method Or prepared as 〇A, Synthesis Method 1: Compound 2 is generally prepared according to the procedure of the procedure 28 201117806 described in the above Synthesis Example 2, except that 2-iodobenzonitrile is used instead of 2-iodine nitrate. The compound 2 was purified by a gas chromatography column chromatography (hexane = EA = 3: 1) to obtain a brown solid (yield 77%). B. Synthesis Method 2: Compound 2 is basically based on The procedure described in Synthesis Example 2 above was carried out except that at room temperature, a 2-(6-trimethyl) group was added to methanol (MeOH) (10 mL).矽alkyl-3(Z)-hexan-1,5-diynyl)benzonitrile [2-(6-trimethylsilyl-3(Z)-hexen-l,5-diynyl)benzonitrile](a4)(10 M, which is based on 丫.11.1^〇&lt;3/· (2004), cfe Me ϋα/ C7zemz.5ir&gt;&gt;, 12:1047-1053 The degassed solution (prepared with Cul (0.5 mmol) and K2C〇3 (5 mmol)) was added to 5-iodo-1,2,3 in MeOH (10 mL). Degassed solution of 5-methoxy-benzene (5-iodo-l, 2,3-trimethoxybenzene) (a5) (10 mmol from Acros Organics) [containing Pd(PPh3)4 (0.5 mmol)]. After the resulting reaction mixture was stirred at room temperature for 6 hours or after TLC, the solvent was removed in vacuo and then quenched with saturated aqueous NH.sub.4Cl.sub.sub.sub.sub.sub.sub. The mixture was washed with a saturated aqueous Na.sub.2CO.sub.3 (40 mL). The title compound 2 (yield: 73%) was obtained as a brown solid. Mp: 66-67 〇C; !H-NMR (CDC13, 400 MHz): δ Ί.61 (dd, 29 201117806 1H, J = 7.2, 0.8 Hz), 7.62 (dd, 1H, J = 8.0, 0.8 Hz), 7.54 (td, 1H, J = 7.6, 1.6 Hz), 7.42 (td , 1H, J = 7.6, 1.2 Hz), 6.83 (s, 2H), 6.21 (d, 1H, J = 11.2 Hz), 6.13 (d, 1H, J = 10.8 Hz), 3.87 (s, 3H), 3.86 (s, 6H) ; , 3C-NMR (CDC13, 100 MHz) : δ 153.0 (2C), 132.7, 132.6, 132.2, 128.6, 127.0, 121.5 (2C), 117.8, 117.5, 117.3, 114.9, 109.3 (2C), 99.1, 93.2, 92.7, 86.0, 60.9, 56.2 (2C); Calculated for HRMS of C22H17N03: Mr = 343.1208, found: 343.1200. Synthesis Example 4·2-丨6-(2-methoxyphenyl)-3(Z)-hexene-1,5-diynylbu 1,2,3-trimethoxybenzene {2-[6 -(2-31^丫1)-3(2)-1|Technical 611-1,5-diynyl]-l,2,3-trimetlioxybenzene} (Compound 3) 2·[6-(2-Methyl fluorenyl) Phenyl)-3(Z)-hexene-1,5-diynyl]-1,2,3-trimethoxybenzene (Compound 3) is generally in accordance with the procedure described in Synthesis Example 2 above. It was prepared using 2-iodophenyl decyl ether instead of 2-iodonitrobenzene. Compound 3 was purified by a silica gel column chromatography (hexane / EA = 4: 1) to yield as a yellow solid (yield: 72%). The nature of the title compound was measured. Mp : 66-67〇C ; ]H-NMR (CDC13, 400 MHz) : δ 7.51 (dd, 1H, J = 7.6, 1.6 Hz), 7.31 (td, 1H, J = 7.6, 1.6 Hz), 6.92-6.88 (m, 2H), 6.75 (s, 2H), 6.16 (d, 1H, J = 10.4 Hz), 6.06 (d, 1H, J = 10.8 Hz), 3.86 (s , 3H), 3.84 (s, 6H), 3.82 (s, 3H); 13C-NMR (CDC13, 100 MHz): δ 160.0, 153.0 (2C), 139.0, 133.6, 130.2, 120.4, 119.8, 118.9, 118.2, 112.4,110.9,108.9 (2C), 97.5, 94.0, 91.5,86.7, 60.9, 56.1 (2C), 55·9 ; HRMS calculated for C22H20O4 30 201117806: Mr = 348.1362, found value 3484.362; elemental analysis, theoretical value : C (75.84%), Η (5.79%), actual values: c (75.43%), Η (6.04%). Synthesis Example 5. 2-[6-(2-Aminophenyl)-3(indenyl)-hexene-1,5-diynyl]-indole, 2,3-trimethoxybenzene {2-[6 -(2-811^11〇?11611丫1)-3(2&gt;||6*611-1,5-diynyl]-l,2,3-trimetlioxybeiizene} (Compound 4) 2·[6·(2 Aminophenyl)-3(Z)-hexene-1,5-diynyl]-1,2,3-trimethoxybenzene (Compound 4) is generally operated according to the procedure described in Synthesis Example 2 above. The procedure was carried out except that 2-iodoaniline was used instead of 2-iodonitrobenzene. Compound 4 was purified by gel column chromatography (hexane/EA = 4:1) to give a yellow solid. Rate 69%). The property of the title compound was measured. Mp : 131-132〇C ; !H-NMR (CDC13, 400 MHz) : δ 7.33 (dd, 1H, J = 8.0, 1.6 Hz), 7.13 ( (d, 1H, J = 10.8 Hz) ), 4.36 (bs, 2H), 3.87 (s, 3H), 3.84 (s, 6H); 13C-NMR (CDC13j 100 MHz): δ 153.0 (2C), 148.2, 139.1, 131.9, 130.2, 119.6, 118.1, 117.8, 117.7, 114.1, 109.2 (2C), 107.3, 97.2, 94.4, 93_2, 87.0, 60.9, 56.1 (2C); elemental analysis, theoretical value: C (75.66%), Η (5.74%), N (4.20%), actual values: C (75.26%), Η (5.43%), N (3.90%). Synthesis Example 6. 2-丨6-(4 -Methoxyphenyl)-3(2&gt;hexene-1,5-diynyl]-l,2,3-trimethoxybenzene {2-[6-(4-anisyl)-3(Z) _hexell-l,5-diyιlyl]-l,2,3-trimethoxybellzene} (Compound 5) 31 201117806 2-[6-(4-Methoxyphenyl)_3(z)·hexene_ι,5_二Alkynyl png • Trimethoxybenzene (Compound S) was prepared essentially according to the procedure described in Synthesis Example 2 above, except that 4-iodophenylmethyl ether was used instead of 2-iodime. Compound 5 was purified by a ruthenium column chromatography (hexane/EA = 4:1) as a yellow solid (yield: 62%). The title compound was measured. Mp: 37-38 〇C ; ^-NMR (CDC13, 400 MHz) : δ 7.45 (dt, 2H J = 9.2, 2.4 Hz), 6.84 (dt, 2H, J = 8.8, 2.8 Hz), 6.74 (s, 2H), 6.08 (d, 1H, J = 10.4 Hz), 6.03 (d, 1H, J = 10.4 Hz), 3.86 (s, 3H), 3.82 (s, 6H), 3.81 (s, 3H) ; 13C-NMR (CDC13, l〇〇 MHz) : δ 159.9, 153.1 (2C), 139.1, 133.2 (2C), 119.8, 118.5, 118.2, 115.2, 114.0 (2C), 108.8 (2C), 97.8, 97.4, 86.7, 86.4, 60.9, 56.1 (2C) , 55.3; HRMS calculated for C22H20O4: Mr = 348.1362, found: 348.1356. Synthesis Example 7. 2-[6-(3-Methoxyphenyl)_3(z)-hexene-1,5- Alkynyl-1,2,3-dimethoxybenzene {ZWO-anisyO-SCZ^-hexen-ljS-diynyl]-l,2,3-trimethoxybenzene}(Compound 6) 2-[6-(3·曱oxyphenyl)_3(Z)·hexene-1,5-diynyl]-l,2,3-trimethoxybenzene (compound 6) is substantially as described in Synthesis Example 2 above. It was prepared by operating procedures, except that 3-iodophenyl methyl ether was used instead of 2- The nitro group is a compound. The compound 6 is purified by hexane column chromatography (hexane / ea = 3: 1) to give a yellow oil (yield: 62%). (CDC13, 400 MHz): δ 7.22 (t, 1H, 7 = 8.0 Hz), 7.12 32 201117806 (dt, 1H, J = 7.2, 1.2 Hz), 7.05-7.04 (m, 1H), 6.88 (ddd, 1H) , J = 8.0, 2.4, 0.8 Hz), 6.74 (s, 2H), 3.86 (s, 3H), 3.82 (s, 6H), 3.77 (s, 3H) ; 13C-NMR (CDC13j 100 MHz) : δ 159.3 , 153.0 (2C), 139.1, 129.4, 128.4, 124.1, 119.7, 119.4, 118.0, 116.9, 114.8, 108.8 (2C), 97.8, 97.4, 87.2, 86.6, 60.7, 56.0 (2C), 55.2; HRMS for C22H20O4 Calculated value: = 348.1362, found value: 348.1363. Synthesis Example 8·2-[6·(2-Amino-5-trifluoromethylphenyl)_3(Z)hexene j,diynyl]-1,2,3-dimethoxybenzene (2 -[6_(2-Wang 111111〇-5_ trifluoromethylphenyl)-3(Z)-hexen-l,5-diynyl]-l,2,3-trimethoxybenzene}(Compound 7) 2-[6-(2-Amino 5-5-trifluoromethylphenyl)_3(Z)-hexene-1,5-diynyl]-1,2,3-dimethoxy (Compound 7) is generally based on the above Synthesis Example 2. The procedure described was followed by the preparation of '2-only 4-trifluorodecyl phenylamine instead of 2-iodonitrobenzene. Compound 7 by gel column chromatography (hexane/EA = 3: 1) Purified as a brown solid (yield: 78%). The title compound was measured. Mp: 131-132 〇C; 丨H-NMR (CDC13, 400 MHz): δ 7.57 (d, 1H) , J = 2.0 Hz), 7.34 (dd, 1H, J = 8.8, 2.4 Hz), 6.73 (s, 2H), 6.72-6.70 (m, 1H), 6.17 (d, 1H, J = 10.8 Hz), 6.13 (d, 1H, J = 10.8 Hz), 4.68 (bs, 2H), 3.88 (s, 3H), 3.83 (s, 6H) ; , 3C-NMR (CDC13, 100 MHz): δ 153.1, 150.4, 139.3, 129.1, 127.0, 125.6, 122.9, 119.8, 119.2, 119.0, 117.5, 113.5, 109.2 (2C), 106.9, 97.6, 93.9, 92.6 , 86.7,60.9,56.1 (2C); for 33 201117806 C22H18F3N03 HRMS calculated: Mr = 401.1239, found: 401.1245; elemental analysis, theoretical value: c (65.83%), Η (4.52%), N (3.49%) ), actual values: c (65.20%), Η (4.35%), Ν (3.08%). Synthesis Example 9· 2-[6·(3·pyridyl)_3(Ζ)·hexene-1,5- Diacetylene]-1,2,3·trimethylphenylbenzene {2-[6-(3-pyridinyl),3(Z)-hexen-l,5-diynyl]-l,2,3-trimethoxybenzene} Compound 8) 2-[6-(3-«Byridinyl)_3(z)-hexene-1,5-diynyl]-1,2,3-trimethoxybenzene (Compound 8) is substantially According to the procedure described in Synthesis Example 2 above, 'only 3-iodopyridine was used instead of 2-iodonitrobenzene. Compound 8 was purified by a silica gel column chromatography (hexane / EA = 3:1) to afford a brown solid (yield: 75%). The nature of the title compound was measured. Mp : 67-68〇C ; ^-NMR (CDC13, 400 MHz) : δ 8.77 (s, 1H), 8.55 (d, 1H, J = 4.4 Hz), 7.78 (dt , 1H, J = 8.0, 2.0 Hz), 7.29-7.26 (m, 2H), 6.73 (s, 2H), 6.16 (d, 1H, J = 10.8 Hz), 6.09 (d, 1H, J = 10.8 Hz) , 3.87 (s, 3H), 3.83 (s, 6H) ; , 3C-NMR (CDC13, 100 MHz) : δ 153.1 (2C), 152.2, 148.8, 138.4, 128.5, 123.1, 120.7, 120.4, 118.5, 117.7, 108.8 (2C), 98.4, 93.6, 90.6, 86_2, 60.9, 56_1 (2C); HRMS calculated for C2〇H17N03: Mr = 319.1208, found: 319.1213. Synthesis Example 10. 2-丨6-(4-Aminophenyl)-3(Z)-hexene-1,5-diynyl]·1,2,3-trimethoxybenzene {2-[6 4-(6-(4-aminophenyl)-3(Z) )-hexene-1,5-diynyl]-1,2,3-trimethoxy 34 201117806 The base benzene (compound 9) is generally prepared according to the procedure described in Synthesis Example 2 above, except 4-iodoaniline was used instead of 2-iodonitrobenzene. Compound 9 was purified by a ruthenium column chromatography (hexane / EA = 4: 1) to yield a yellow oil (yield: 89%). The nature of the title compound was measured..H-NMR (CDC13j 400 MHz): δ 7.32 (dd, 2H, 7 = 6.4, 2.0 Hz), 6.75 (s, 2H), 6.58 (d, 2H, J = 8.4 Hz), 6.08 (d, 1H, J = i〇.s Hz), 5.98 (d, 1H, J = 10.4 Hz), 3.87 (s, 3H), 3.83 (s, 6H); 13C-NMR (CDCI3, 100 MHz) : δ 153.0 (2C), 147.1, 138.9, spring 133.0, 120.1, 118.3, 117.5, 114.5 (2C), 112.3, 108.7 (2C), 98.9, 97.1, 86.9, 85.9, 60.9, 56.0 (2C); For C21H19NCX^ HRMS calculated: = 333.1365, found: 333.1369. Synthesis Example 11·2-[6-(3-Aminophenyl)-3(2)-hexene-1,5-diynyl]-i,2,3_trimethoxybenzene {2-[6- (3-31111110卩1|611丫1)-3(2)-1|€叉611-1,5-&lt;!1丫11;^1]-1,2,3-(1^11161:1 |〇叉5^61126116}(compound 10) φ 2-[6-(3-aminophenyl)-3(Z)-hexene-1,5-diynyl]-1,2,3-trimethyl The oxyl group (Compound 10) was prepared essentially according to the procedure described in Synthesis Example 2 above, except that 3-iodoaniline was used instead of 2-iodonitrobenzene. Compound 10 was obtained by gel column chromatography. (Hexane/EA = 4:1) was purified as a yellow oil (yield: 74%). </ RTI> </ RTI> </ RTI> NMR (CDCI3, 400 MHz): δ 7.09 (t, 1H, J= 7.6 Hz), 6.94 (dt, 1H, J = 7.6, 1.2 Hz), 6.83 (t, 1H, J = 0.8 Hz), 6.74 (s? 35 201117806 2H), 6.58 (ddd, 1H, J = 8.0 , 2.4, 0.8 Hz), 6.06 (s, 2H), 3.86 (s, 3H), 3.81 (s, 6H) ; 13C-NMR (CDC13, 100 MHz) : δ 153.1 (2C), 146.0, 129.3, 123.8, 122.2, 119.6, 119.4 (2C), 118.1, 117.8, 115.8, 108.9 (2C), 97.8, 97.7, 86.9, 86.7, 60.9, 56.1 (2C); HRMS calculated for C21H19N04 Mr = 333.1365, found: 333.1361. Synthesis Example 12. 2-丨6-(2-Pyridinyl)-3(Z)-hexene-1,5-diynyl]-l,2,3-trimethoxy Base benzene {2-[6-(2-卩&gt;^ along 11&gt;^)-3(2&gt;1|6 fork €11-1,5-diynyl]-l,2,3-trimethoxybenzene} (Compound 11 2-[6-(2-.pyridyl)_3(Z)-hexene-1,5-diynyl]-1,2,3-trimethoxybenzene (Compound 11) is generally based on the above The procedure described in Synthesis Example 2 was carried out except that 2-iodopyridine was used instead of 2-iodonitrobenzene. Compound 11 was obtained by silica gel column chromatography (hexane/EA = 3:1). Purified like a brown oil (yield 79%). The nature of the title compound was determined by \H-NMR (CDC13, 400 MHz): δ 8.58 (ddd, 1H, J = 4.8, 1.6, 0.8 Hz), 7.64 (td, 1H, J = 8.0, 2.0 Hz), 7.50 (dt, 1H, J = 8.0, 0.8 Hz), 7.23 (ddd, 1H, J = 7.6, 4.8, 1.2 Hz), 6.78 (s, 2H), 6.17 (d, 1H, J = 10.8 Hz), 6.09 (d, 1H, J = 10.8 Hz), 3.85 (s, 3H), 3.83 (s, 6H) ; nC-NMR (CDC13, l〇〇MHz) : δ 153.0 (2C), 143.3, 135.9, 127.3, 122.9 , 121.4, 118.5 (2C), 117.9, 109.0 (2C), 98.6, 96.1, 86.8, 86.4, 60.9, 56.0 (2C); HRMS calculated for C2〇H17N〇3: Mr = 319.1208, found: 319.1212. 36 201117806 Synthesis Example 13. 2-[6-(2-Methylthiophenyl)_3(Z)hexene_ι,5-diynylyl 1,2,3-trimethoxybenzene {2-[6 -(2-化1631^5^)-3(2)- h exen-1,5-diy ny 1]-1,2,3 - trim ethoxy benzene}(compound 12) 2-[6-(2- Methylthiophenyl)-3(Z)-hexene-1,5-diynyl]-l,2,3-trimethoxybenzene (Compound 12) is substantially as described in Synthesis Example 2 above. The procedure was followed, except that 2-iodophenylmethyl sulfide was used instead of 2-iodonitrobenzene. Compound 12 was purified by a Shih Hose column chromatography (H.sub.s. / EA = 3:1) as a yellow oil (yield 65%). The nature of the title compound was measured, , !H-NMR (CDC13s 400 MHz): δ 7.48 (dd, 1Η, J= 7.6, 1.2 Hz), 7.29 (td, 1H, /= 7.6, 1.2 Hz), 7.16 ( d, 1H, /= 8.0 Hz), 7-07 (td, 1H, J = 7.6, 1.2 Hz), 6.78 (s, 2Η), 6.17 (d, 1H, J = 10.4 Hz), 6.11 (d, 1H) , J = 10.8 Hz), 3.86 (s, 3H), 3.82 (s, 6H), 2.40 (S, 3H) ; 13C-NMR (CDC13j 100 MHz) : δ 152.9 (2C), 141.8, 139.0, 132.6, 129.0 , 124.2, 124.1, 121.2, 119.4, 119.1, 118.2, 109.2 (2C), 97.8, 94.6, 93.6, 86.7, 60.9, 56.1 (2C), 15.1; HRMS calculated for C22H20O3S: Mr = 346.1133, found: 346.1136 . Synthesis Example 14. 2-[6-(2,4-Dimethoxyphenyl)-3(Z)-hexene-1,5·diynylbu 1,2,3-trimethoxybenzene {l -K'OJ-dimethoxyplienyU-SCZ-hexeii-lJ-diynyll-lJJ-trimetlioxybeiizeiien compound 13) 2·[6-(2,4-dimethoxyphenyl)-3(Z)-hexene-1,5 -Diynyl]-1,2,3· 201117806 1-methoxy-1-ylbenzene (Compound 13) was prepared substantially according to the procedure described in Synthesis Example 2 above, except that 2,4-dimethyl was used. Alkyl _ _ _ benzene to replace 2- nitrobenzene. Compound 13 was purified by a gas chromatography column (hexanes / EA = 3 · s) as a yellow solid (yield: 49%). The title compound was measured. Mp: 77-78 〇C ; ^-NMR (CDC13, 400 MHz) : δ 7.41 (d, lH, J = 9.2 Hz), 6.75 (s, 2H), 6.44-6.41 (m, 2H), 6.14 (d, 1H, J = 10.4 Hz ), 6.01 (d, 1H, J = 10.8 Hz), 3.86 (s, 3H), 3.82 (s, 6H), 3.81 (s, 3H), 3.80 (s, 3H) ; 13C-NMR (CDC13, 100 MHz ) : δ ^1.6, 161.3, 153.0 (2C), 134.5, 120.2, 120.2, 118.4, 117.8, 108.9 (2C), 105.1, 104.9, 98.5, 97.1, 94.4, 90.4, 86.9, ό0·9' 56·1 ( 2C), 55.9, 55.5; elemental analysis, theoretical values: C (73.00%), Η (5.86%), actual values: c (72.99%), Η (6.00%). Synthesis Example 15. 2-[6-( 3-hydroxyphenyl)-3(indenyl)-hexene-1,5-diyl]-1,2,3-trimethoxybenzene {2-[6-(3-hydroxylphenyl)-3(Z) -hexen-l,5-diynyl,l,2,3-trimethoxybenzene} (Compound 14) 2-[6-(3-hydroxyphenylhexene-15-diynyl)&gt;12 3_trimethoxybenzene Compound 14) is generally prepared according to the procedure described in Synthesis Example 2 above, 'only using 3_ Phenol was used in place of 2-iodonitrobenzene. Compound 14 was purified by column chromatography (hexane / ea = 3: 1) to yield as a yellow solid (yield: 57%). Properties: Mp ·* 128-129〇C ; !H-NMR (CDC13, 400 MHz) : δ 7.17 (td, 38 201117806 1H, J = 8.0, 0.4 Hz), 7.08 (dt, 1H, J = 7.6, 1.2 Hz), 7.01-6.99 (m, 1H), 6.80 (ddd, 1H, J = 8.4, 2.4, 0.8 Hz), 6.74 (s, 2H), 6.07 (s, 2H), 5.27 (bs, 1H), 3.86 (s} 3H), 3.82 (s, 6H) ; 13C-NMR (CDC13, 100 MHz): δ 155.5, 153.0 (2C), 139.1, 129.6, 124.3, 124.2, 119.8, 119.4, 118.3, 118.1, 116.1, 108.9 PC), 97.8, 97.2, 87.4, 86.7, 61.0, 56.1 (2C); elemental analysis, theoretical values: C (75.43%), Η (5.43%), actual values: C (75.04%), Η (5.73%) ). Synthesis Example 16. 2-[6·(4-Methoxy-2-nitrophenyl)-3(indenyl)-hexene-1,5-diynyl]-1,2,3-trimethoxy Benzene {2-[6-(4-1116&lt;:11〇〇丫-2-nitrophenyl)-3(Z)-hexen-l,5-diynyl]-l,2,3-trimethoxybenzen} (Compound 15) A degassed solution [containing Cul (3.2 mmol) and K2C03 (30 mmol)] of compound a3 (12 mmo from the above Synthesis Example 1) in MeOH (15 mL) was added to MeOH. Degassed solution of 4-iodo-3-nitrophenylsole (a6) (12 mmol) (from Acros Organics) in [20 mL] Pd(PPh3)4 (〇8 mmol)]. After the reaction mixture was allowed to stand at room temperature for 6 hours, the solvent was removed in vacuo and then quenched with saturated aqueous NaHCI. The organic extracts were collected and washed with saturated aqueous Na.sub.3 (40 mL) then dried over anhydrous EtOAc EtOAc. After the solvent was removed in vacuo, EtOAc m. . The nature of the title compound was determined, 39 201117806 Mp : 97-98 〇C ; 'H-NMR (CDC13, 400 MHz) : δ 7.59-7.57 (m, 2H), 7.10 (dd, 1H, J = 8.8, 2.8 Hz), 6.89 (s, 2H), 6.15 (d, 1H, /= 10.8 Hz), 6.09 (d, 1H, 7= 10.8 Hz), 3.89 (s, 3H), 3.87 ' (s, 6H), 3.86 (s, 3H) ; nC-NMR (CDC13, 100MHz) : δ 159.7, , 153.0 (2C), 149.9, 139.1, 135.9, 120.6, 119.9, 118.1, 117.8, 110.7, 109.3, 109.2 (2C), 98.7, 93.0, 92.5, 86.2, 60.9, 56.1 (2C), 55.9; HRMS calculated for C22H19N06: Mr = 393.1212, found: 393.1210. Synthesis Example 17. 2-[6-(2-Amino-4-methoxyphenyl)-3(Z)-hexene-1,5-diynyl]-1,2,3·trimethoxy Benzene {2-[6-(2-31^11〇-4-methoxyphenyl)-3(Z)-hexen-l,5-diynyl]-l,2,3-trimethoxybenzene} (Compound 16) 0.1 g Compound 15 (0.25 mmol, obtained from Synthesis Example I6 above) was dissolved in 20 mL of methanol, followed by 286 mg of SnCldHA (1·27 mmol). The resulting reaction mixture was refluxed for 1.5 hours or monitored by TLC until the reaction was completed. After removing the methanol under vacuum, the NaHCCh solution was adjusted to a pH of 8.0 and then extracted with ethyl acetate (2 〇 mL x 3). Collect • Organic extracts and dry with anhydrous MgS〇4, then removed under vacuum

Solvent. The resulting residue was purified by EtOAc EtOAc EtOAc (EtOAc) The nature of the title compound was measured. Mp - 149-150 ° C; *H-NMR (CDC13} 400 MHz) : δ 7.24 (d, 40 201117806 1H, J = 8.8 Hz), 6.74 (s, 2H), 6.27 (dd, 1H, J = 8.4, 2.4 Hz), 6.16 (d, 1H, J = 10.8 Hz), 6.02 (d, 1H, J = 10.8 Hz), 3.87 (s, 3H), 3.84 (s, 6H) , 3.76 (s, 3H); 13C-NMR (CDC13j 100MHz): δ 161.3, 153.0 (2C), 149.8, 139.0, 133.1, 119.9, 117.9, 116.8, 109.1 (2C), 104.6, 100.3, 98.9, 96_7, 94.9 , 92.5, 87.2, 60.9, 56.1 (2C), 55.1; HRMS calculated for C22H21N04: Mr = 363.1471, found: 363.1472. Synthesis Example 18. 2-[6-(5-Amino-2-methoxyphenyl)-3(2)-hexene-1,5-diynyl]-1,2,3-trimethoxy Benzene {2-[6-(5-8111111〇-2-methoxyphenyl)-3(Z)-hexen-l,5-diynyl]-l,2,3-trimethoxybenzene} (Compound 17) A, 2-methoxy Synthesis of 2-methoxy-5-nitrophenyl-trifluoromesylate (Compound a8) 2-methoxy-5-Shirconia (2-methoxy-5-nitrophenol) (a7) (10 mol) (Lancaster Synthesis) was treated with Et3N (1 mL) and Tf20 (10 mol) in CH2C12 (10 mL), and then allowed to stand at room temperature for 1 hour. Thereafter, it was quenched with a saturated aqueous NH4Cl solution. After removing the solvent under vacuum, it was dried over anhydrous MgS04 and then filtered. After the solvent was removed in vacuo, the title compound was purified eluting elut elut elut elut elut elut elut elut elut elut . Synthesis of B, 2-methoxy-5-nitrophenyl acetylene (compound alo) obtained from the above item A in diethyl ether (20 mL) Compound 41 201117806 a8 (5 mmol) of degassed solution [containing Cul (0.25 mmol) and w-BuNH2 (10 mmol)] was added to a (tridecylalkyl) acetylene in diethyl ether (20 mL). (trimethylsilyl)acetylene] (5 mmol) degassed solution [containing Pd(PPh3)4 (0.25 mmol)]. The resulting reaction mixture was stirred at room temperature for 4 h then quenched with saturated aqueous NH.sub.4Cl.sub.sub. The organic extracts were collected and washed with saturated aqueous Na.sub.2CO.sub.3 (50 mL) then dried over anhydrous EtOAc. The solvent was removed under vacuum to give 2-methoxy-5-nitrophenyl-trimethylsilyl acetylene (Compound a9). Compound a9 was then treated with K2C03 (5 mol) and MeOH (10 mL) and then stirred at room temperature for one hour. Thereafter, it was quenched with a saturated aqueous NH4C1 solution. After removing the solvent under vacuum, it was dried with water-free MgS04 and then filtered. After the solvent was removed in vacuo, the title compound was purified mjjjjjjjjjjj

Synthesis of C, 2-methoxy-5-aminophenyl acetylene (compound all) The compound a10 (3 mmol) obtained in the above item B was dissolved in 10 mL. In methanol, SnCl2-2H2 hydrazine (15 mol) was added. The resulting reaction mixture was refluxed for 2 hours or monitored by TLC until the reaction was completed. After removing the sterol under vacuum, the pH of the aqueous layer was adjusted to 8.5 with a 10% NaHCO3 solution, followed by extraction with ethyl acetate (20 mL x 3) 42 2011 17806. The organic extracts were collected and dried over Na 2 SO 4 then solvent was evaporated in vacuo. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc D, 1-(2-methoxy-5-aminophenyl)-6-trimethyldecyl-3(Z)-hexene-1,5-diyne [1-(2-methoxy-5) Synthesis of -aminophenyl)-6-trimethylsilyl-3(Z)-hexen-l,5-diynes (compound al2) Compound (5 mmol) obtained from above C in diethyl ether (20 mL) Degassed solution [containing Cul (0_25 mmol) and "-BuNH2 (10 mmol)] in a solution of 4-trimethyl-stone-butan-1-butene in diethyl ether (20 mL) Degassed solution of 3-trimethylsilyl-l-chlorobuten-3-yne (5 mmol) (containing Pd(PPh3)4 (0.25 mmol)]. The resulting reaction mixture was stirred at room temperature for 4 hours, then quenched with saturated aqueous NH.sub.4Cl.sub.sub.sub.sub.sub.sub.sub. The organic extract was collected and washed with saturated aqueous Na.sub.2CO.sub.3 (50 mL) then dried over anhydrous EtOAc. After the solvent was removed in vacuo, the title compound was purified mjjjjjjjjj . E, 2-[6-(5-Amino-2-methoxyphenyl)-3(Z)-hexene-1,5-diynyl]-1,2,3-trimethoxybenzene ( Synthesis of compound 17) a degassed solution of the compound al2 (12 mmol) obtained from the above item D in MeOH (20 mL) [ containing Cul (3.2 mmol) and K2C03 (15 mmol)] 5-A-43 201117806 l2,3-dimethoxybenzene (5-i〇do-l,2,3-trimethoxybenzene) (12 mmol) in MeOH (25 mL) Degassed solution [containing pd(pph3)4 (〇8 mm〇1)]. The resulting reaction mixture was stirred at room temperature for 4 hours, then quenched with a saturated aqueous solution of hydrazine, followed by extraction with Et EtOAc (3 〇 mL x 3). The organic extracts were collected and washed with a saturated aqueous solution of Na.sub.2 C.sub.3 (4.sub.mL), then dried over anhydrous MgSO.sub.4 and filtered. After the solvent was removed in vacuo, the residue formed was purified by EtOAc (EtOAc/EtOAc:EtOAc) %). The nature of the title compound was measured. Ή-NMR (CDC13, 400 MHz): δ 6.83 (s, 1H), 6.76 (s, 2H), 6.73-6.70 (m5 1H), 6.64 (d, 1H, J= 9.2 Hz), 6.13 (d, 1H, / = 10.8 Hz), 6.05 (d, 1H, J = 10.8 Hz), 3.86 (s, 3H), 3.82 (s, 6H), 3.77 (s, 3H) ; 3C-NMR (CDC13, 100MHz): δ 153.6, 153.0, 139.8, 120.8, 120.7, 119.9, 118.9, 118.2, 117.8, 117.2, 113.0, 112.8, 109.0 (2C), 97.5, 94.3, 91.1, 86.8, 60.9, 56.7 , 56.1 (2C); HRMS calculated for C22H2: N04: Mr = 363·1471 'Found value: 363.1472. Comparative Example 1. 2-[6-(4-Methoxyphenyl)-3-hexaplo-1,5-diynyl]benzonitrile {2-[6-(4-anisyl)-3-hexen -l,5-diynyl] Synthesis of benzonitrile} (Compound bl) 2-[6-(4-Methylphenyl)-3-hexene-1,5-diynyl]benzonitrile (bl) mainly It is prepared according to the method described in Example 14 of the prior patent US 7,332.623 B2 by the inventors. In short, in Pd(pph3)4, CUI, η- 201117806

In the presence of BuNH2 and diethyl ether, 2-(3-hexene-1,5-diyne)benzonitrile [2-(3-hexen-l,5-diyne)benzonitrile] and 4-methoxy The 4-anisyl iodide phase is reacted to give the title compound bl. Comparative Example 2·2-[6-(2-Trifluoromethylphenyl)-3(2)-hexene-1,5-diynyl]aniline {2-[6-(2-trifluoromehylphenyl)-3 Synthesis of (Z)-hexen-l,5-diynyl]aniline} (Compound b2) 2-[6-(2-Tri-Imethylphenyl)_3(Z)-hexene-1,5-diynyl Aniline (b2) is prepared according to the method described in YH Lo ei α/. (2008) (same as above)

Palladium-catalyzed bacterial head of 4-trimethylsilyl-l-chlorobuten-3-yne and 2-ethynylaniline Coupling reaction (palladium-catalyzed Sonogashira coupling reaction) to give 2-[6-tridecylsulfonyl-3(2)-hexene-1,5-di-fastyl] strepamine {2-[6-trimethylsilyl- 3(Z)-hex0n-l,5-diynyl]aniline} (yield 75%). Next, in the presence of K2C03 and MeOH, 2-[6-trimethyldecylalkyl-3(Z)-hexene-1,5-diynyl]aniline and 2-trifluoromethylphenylhydrazine ( 2-trifluoromehylphenyl iodide) was subjected to desilylation and a palladium-catalyzed coupling reaction to give the title compound b2. Pharmacological Examples In order to determine the biological activity of the compound 1-17 according to the present invention, the following analysis was carried out. Experimental materials: 1. The types and sources of the cell lines used in the following examples are shown below.

Table 2. Cell strain type and source cell strain name Purchase source cell line number non-small cell lung cancer cell A549 (ATC CCL-185 human stomach adenocarcinoma cell AGS) ATCC CRL -1739 prostate cancer cell PC-3 (ATCC CRL-1435 breast cancer cell BT483) ATCC HTB-121 human cervical epithelioid carcinoma cell HeLa (TCC CCL) -2 Hepatocellular carcinoma cell SK-Hep-l ATCC HTB-52 Ovarian cancer cell NIH-OVCAR-3 (ovarian cancer cell NIH-OVCAR-3) ATCC HTB-162 Human lung cancer cell NCI-H460 (human lung cancer cell NCI-H460) ATCC HTB-177 Human colon cancer cell SW620 ATCC CCL-227 Human breast cancer cell MDA-MB-231/ATCC (human breast carcinoma cell MDA-MB -231/ATCC ATCC HTB-26 Human fibroblast cell HS68 ATCC CRL-1635 Oral squamous cell carcinoma SAS (oral squamous cell carcinoma c Ell SAS) Academia Sinica Genome Research Center - Esophageal cancer cell CE81T (esophageal carcinoma cell CE81T) Academia Sinica Genome Research Center - 2. Cochicine, Nocoda sniffing 46 used in the following examples 201117806 (Nocodazole) and Taxol (Taxol) are all from Sigma USA. 3. BALB/cAnN-Foxnlnu/CriNarl nude mice used in the following examples were obtained from the National Experimental Research Laboratory Animal Center (National Laboratory). Animal Center). All experimental animals were housed in a separate air-conditioned animal room, and water and feed were adequately supplied. The breeding environment and experimental procedures of the experimental animals are in line with the international laboratory animal management standards.

Pharmacological Experiments 1. In vitro anticancer assay of compound 1-17 of the present invention: Experimental method · In vitro anticancer assay is referred to YL Chen W α/. (2008), less & less , the method described in 5:267-278

. 8 kinds of cancer cells (ie, non-small cell lung cancer cells Α549, human gastric adenocarcinoma AGS, prostate cancer cells PC-3, breast cancer cells ΒΤ483, human cervical epithelial cancer cells HeLa, oral squamous cell carcinoma SAS, hepatocellular carcinoma) The cells SK-Hep-Ι and esophageal cancer cells CE81T), as well as normal human fibroblasts HS68, were treated in a medium containing 10% fetal bovine serum (FBS) to treat the compound ι_ΐ7 of the present invention for 48 hours. . In addition, 'untreated cells were used as a control group. 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide {3-[4,5-Dimethylthiazol-2-yl]-2 during the last 1.5 hours 5-diphenyl tetrazolium bromide} (MTT '2 mg/mL, 20 mL) was added to the medium and cultured. The resulting tetrazolium salt is then dissolved by the addition of dimethyl sulfoxide (DMSO). The color was measured spectrophotometrically in a microtiter plate reader at 570 nm and used as a relative measure of the number of viable cells. The number of viable cells after treatment was compared with untreated control cells, and was used to determine the presence of (Ab a/Ab control) xl00 [where Ab represents the average absorbance (n=3)] Control growth percent 〇 killing 50% of the cells (IC5〇) by calculating the compound 1-17 of the present invention reduces the absorbance of the treated cells by 50% (compared with the control cells) The concentration of the lower one is determined from the linear portion of the curve (SD Heo is ^/. (1990), Cawcer 50: 3681-3690). Further, in the present experiment, colchicine was used as a positive control and subjected to the same experiment as the compound 1-17 of the present invention. Results: The experimental results obtained are shown in Table 3 below.

48 201117806

a : 泞淖 50% r箨 S recording (IC50) &gt; | | &amp; ^ batch > 皞涩 Su ^ life wearing 1-17 呤裼 面 面 尚 尚 尚 。 。 。 。 。 。 。 。 。 。 /. (靼牦b : *f &quot;&gt;钟&gt; Wet Μ;^涔c :&gt;Zhong You 漥^吟参3:1^0菡渺迕菡渺迕杀漭漆湿££·. colchicine 1 —» 5; Η-* I—* v〇00 --0 Os u&gt;K&gt; μ-^ Compound 0.07 8.66 11.66 Ln 9,74 Not detected e 6.42 3.99 5.56 7.93 16.91 12.41 Not detected e 12.09 0.57 0.52 0.79 Ut -ot-» A549 1_ cell line 0.05 6.09 9.53 2.78 σ\ — U) no e Ut L/1 0.13 4.73 8.23 not detected e not detected e 20.33 22.08 0.98 0.78 4.56 4.66 AGS 0.06 14.39 17.39 1 3.79 19.14 22.93 ►—» 〇\ 0.51 22.38 17.00 Not detected e Not detected e Not detected ° Not detected e 0.73 0.62 8.68 4.56 PC-3 μ-1 Ui 16.06 15.22 1 4.53 19.55 Not detected e 9.56 0.86 15.26 19.20 22.88 Κϊ Η-» N&gt;U&gt; Not detected e Not detected e 1.98 k&gt; U) 10.52 4.24 BT-483 0.66 4.67 15.87 2.26 10.06 12.77 5.00 0.39 10.50 U) OO !·—1 -0 24.76 19.73 17.40 0.64 0.57 H -* b -j 1.89 HeLa u&gt; Lh 11.42 12.81 0.65 7.83 Not detected e 12.28 1—« H-» oo 13.00 15.66 15.77 16.90 29.96 4.53 9.88 10.60 U&gt; SAS 0.78 5.42 13.27 1 4.28 to H- * 14.39 5.23 0.43 7.07 10.12 1_ 19.60 28.26 17.31 16.67 0.20 0.34 ΪΟ o U) SK-Hep-l oo 4.49 13.91 6.32 11.40 17.43 29.97 ON 00 5.02 11.70 not detected e 21.00 17.71 not detected e OO oo 6.95 6.39 〇\ v 〇i- CE81T not detected ° 1 〇1 σ 4.09 1 σ* 1 σ* 1 σ* not detected ° 1 &lt;T 1 σ 1 σ* no detected e 1 σ not detected e not detected e not Detected e not detected ° 1 〇· HS68 |&gt;3 泠呤1-17 s^^^sonvf (IC50; μΜ 夂49 201117806 It can be seen from Table 3 that the compound 1-17 of the present invention has a wide range And effective anticancer activity, especially compounds 3, 4 and 11. Therefore, it is expected that the compound of the formula (I) of the present invention can be used for the treatment of cancer, particularly human gastric adenocarcinoma, prostate cancer, breast cancer, human cervical epithelial cancer, oral squamous cell carcinoma, and hepatocellular carcinoma. Pharmacological Experiment 2. Effect of Compound 1-17 of the Invention on Cell Cycle of Human Cervical Epithelial Carcinoma Cell Line HeLa: This experiment mainly uses flow cytometry FACScan (Elite ESP, Beckman Coulter) The effect of Compound 1-17 of the present invention on the cell cycle of human cervical epithelial cancer cell HeLa was analyzed by the method described in YH Loe, α/. (2008) (supra). Experimental Method '· Human cervical epithelial cancer cells HeLa were treated with Compound 1-17 of the present invention for 24 hours, followed by centrifugation to collect cells. In addition, untreated cells were used as a control group. After washing with PBS, the cells were ice-cold 70°/. The ethanol was fixed for 30 minutes, then washed with PBS, and then treated with 1 mL of RNase A solution (1 mg/mL) at 37 ° C for 30 minutes. After that, it was centrifuged at 1,000 rpm for 5 minutes and the supernatant was removed, followed by the addition of 250 μM DNA staining solution [10 mg of propidium iodide (、), 0.1 mg of trisodium citrate) (trisodium citrate) and 0.03 mL of Triton X-100 were dissolved in 100 mL of water] and allowed to react at room temperature for 30 minutes in the dark. Thereafter, add 500 μl of PBS and use a flow cytometer FACScan (Flow cytometry FACScan, Elite ESP, Beckman 50 201117806)

Coulter) for cell cycle analysis, analyzing the DNA content of 10,000 cells each time. The cell cycle profile was analyzed from DNA content-histograms by using WinCycle software. When cells are in apoptosis, - the DNA contained in these cells is broken down by endonuclease

Thus, a Sub-Gl peak appears. The percentage of cells in the Sub-G1 phase was analyzed by using the Windows Multiple Document Interface (WinMDI) software. Further, in the present experiment, colchicine, nocodazole, and paclitaxel were used as a positive control group, and the same experiment was carried out with the compound 1-17 of the present invention. Results: The experimental results obtained are shown in Table 4 below.

51 201117806

Table 4. Effect of Compound 1-17 of the present invention on cell cycle of human cervical epithelial cancer cell line HeLa Percentage of cells in cells (%) Species concentration (μΜ) No compound treatment - Tol ~ colchicine 1 ~ 62? ~~ Nocodazole 0.33 ~~~ΤΓ2 ~~ Paclitaxel 1 65ΤΪ~~' 1 1 ~56Τ2 ~~~ 2 1 59.8 3 Ί 1 4 1 40.5 5 1 6 1 ^ΤοΤΓ 7 1 TJ 8 1 8.7 9 1 1ΪΤ5 ~~~ 10 1 30?4 11 1 48.7 12 1 28.3 13 1 9.4 14 1 11.6 15 1 9.7 16 1 10.1 17 1 "38.1 As can be seen from Table 4, the compound m of the present invention promotes human cervical epithelial cancer cell line HeLa The cell cycle is in Sub-G phase 1, especially compounds 1, 2, 3, 4' 10, 11 and 17. The inventors conclude from this that the compound of formula (1) of the present invention induces human cervical epithelial cancer cells The mechanism by which HeLa undergoes apoptosis' in turn causes cancer cells to die. Therefore, the compound of formula (I) of the present invention is expected to be useful for the treatment of cancer, particularly human cervical epithelial cancer. 52 201117806 Pharmacological Experiment 3. Phenyl Methoxy group Effect of the number of compounds on the anti-cancer activity of the compound (i. anti-cancer activity): To understand the effect of the number of methoxy groups on the phenyl group on the anticancer activity of the compound, the inventors chose the compound 2 of the present invention. The following experiment was carried out (having a trimethoxyphenyl group) and the compound bl (having a p-methoxyphenyl group) synthesized in Comparative Example 1 above. Experimental method · Related compound 2 and compound bl The in vitro anticancer assay was generally carried out in accordance with the method described in the above pharmacological experiment 1, except that Compound 8 and Compound bl were used to treat 8 cancer cells (i.e., non-small cell lung cancer cells A549, respectively). Prostate cancer cell PC-3, breast cancer cell line BT483, human cervical epithelial cancer cell line HeLa, ovarian cancer cell line NIH-◦VCAR-3, hepatocellular carcinoma cell line SK-Hep-Ι, human lung cancer cell NCI-H460, and human colorectal cancer cell SW620) The experimental data is expressed as the mean soil deviation value.Results: The experimental data obtained are shown in Table 5 below. 53 201117806 Table 5. Compound 2 and Chemicalization Evaluation of anti-proliferation of substance bl (Ι(:5〇;μΜ)3 cell line compound 2 bl A549 5.43±0.52 24.24±0.42 PC-3 14.57 Soil 2.98 No detectable BT-483 6.04 Soil 0.89 19.65 ± 2.39 HeLa 3.37± 1.45 11.46 Soil 2.48 NIH- OVCAR-3 3.91 ± 1.21 SK-Hep-1 not detected 5.87±0.35 14.01±1.76 NCI-H460 7.67±2.68 SW620 not detected 13.24 soil 1.95 25.41±2.21 a : Kill 50% The concentration of cells (IC5〇) was determined from the linear portion of the curve by calculating the concentration of compound 2 and compound bl which reduced the absorbance of the treated cells by 50% (compared to the control cells). (n=3). From the results shown in Table 5, it is understood that the compound 2 having one trimethoxyphenyl group is more effective in inhibiting the growth of cancer cells than the compound bl having a p-methoxyphenyl group. Pharmacological Experiments 4. Evaluation of the utility of the compound 4 of the present invention in inhibiting microtubule regrowth of human breast cancer cells MDA-MB-231/ATCC: This experiment mainly refers to YH Lo W a/. (2008) ( The inhibitory effect of Compound 4 of the present invention on microtubule regrowth of human breast cancer cell line MDA-MB-23 1/ATCC was analyzed as described in the above). Further, the compound b2 disclosed by Y.H. Lo et al. was used as a positive control group and subjected to the same experiment as the compound 4 of the present invention. Experimental Methods'· Human breast cancer cells MDA-MB-231/ATCC (lxlO4 cells) were seeded on glass coverslips and allowed to grow for 24 hours.

54 201117806 After treatment with compound 4 (3.6 μM in DMEM) and compound b2 (3.6 μM in DMEM) at 37 ° C for 2 hours, the microtubules of these cancer cells were Microtubules) were depolymerized » In addition, untreated cells were used as a control group. The cells were then washed 3 times with PBS and then incubated at 37 ° C in pre-warmed DMEM for 10 to 15 minutes to allow microtubule regrowth.

Thereafter, the cells were washed 3 times with PBS, then fixed with 4% paraformaldehyde at 25 ° C for 5 minutes, followed by 0.5 at 25 ° C in PBS. % Triton X-100 was permeabilized for 5 minutes. The fixed cells were washed with PBS, followed by a blocking solution at 37 ° C [5% normal goat serum (NGS) / 1% bovine serum albumin (BSA) ), with PBS (pH 7_4)] blocked for at least 30 minutes. After the cells were briefly washed with PBS to remove goat serum, an anti-ninein antibody (500-fold diluted with blocking solution) was added (abcam, Cat. No. ab 4447) and An anti-tubulin antibody (1000-fold diluted with blocking solution) (Sigma, Cat. No. T9026) was used as a primary antibody and incubated at 37 ° C for 45 minutes. Then, it was washed several times with PBS. Thereafter, goat anti-rabbit IgG conjugated with Alexa Fluor® 488 (diluted 500-fold with blocking solution, green) (Invitrogen, Cat. No. A11008) and conjugated with Alexa were added. Fluor® 55 201117806 568 goat anti-mouse IgG (diluted 500-fold in blocking solution, red) (Invitrogen, Cat. No. A11004) as a secondary antibody, and at 37 It was incubated at ° C for 45 minutes and then washed several times with PBS. Thereafter, the cells were counter-stained by 4,6-diamidino-2-phenylindole (DAPI) (presenting blue). Then, it is mounted. Confocal images were obtained by using a 1X71 inverted microscope (OLYMPUS) controlled by FLUOVIEW software (Universal Imaging). All images were imported into Adobe Photoshop 7.0 software for contrast manipulation ° Results: Figures 1A to 1C show human breast cancer cells MDA-MB-231 without compound treatment, compound b2 treatment, and compound 4 treatment, respectively. The microtubes of /ATCC were incubated at 37 ° C for 10 to 15 minutes, and the results were observed with a 1×71 inverted microscope. As can be seen from Fig. 1A to Fig. 1C, the microtubules of the human breast cancer cell line MDA-MB-231/ATCC which were not treated with the compound were respectively treated by the compound 4 of the present invention and the compound b2 disclosed by YH Lo et al. Polymeric microtubules do not have the ability to regenerate. The inventors have inferred from this that the compound 4 according to the invention has a high potential to develop into a microtubule de-suppressant. Pharmacological Experiment 5. Evaluation of the effect of Compound 11 of the present invention on inhibiting the growth of breast cancer cell line BT483 in live sputum: To understand whether Compound 11 according to the present invention can exert anticancer effect on breast cancer 56 201117806 cell BT483 in vivo, this experiment Nude mice were tested for in vivo animal model test). Purple Splash Method · Subcutaneously injected breast cancer cell line BT483 (3×10 6 cells/100 μί) into the hind leg thigh of nude mice, when a tumor with a volume of about 250 mm 3 was developed (about 7-10 days), The nude mice were taken for the following experiment. In addition, 25 mg of Compound 11 was dissolved in a mixed solvent of dimethyl sulfoxide (DMSO), Tween 80, and PBS [DMSO/Tween 80/PBS, 1: 1 : 8 (v/v) /v)], and get a test solution for use. Tumor-bearing nude mice were randomly divided into an experimental group (n = 8) and a control group (η = 6), in which nude mice of the experimental group were intraperitoneally injected with the test solution (dose of 20 mg/kg), and The nude mice of the control group were intraperitoneally injected with the mixed solvent (dose of 1 〇mL/kg), and each group was injected once a day for 7 days and then discontinued for 7 days as a course of treatment. This treatment was repeated 2 times. The weight of nude mice was recorded every 3 days, and the change in tumor size of the thighs of the hind limbs of nude mice was measured with a caliper and continuously observed for more than 2 months. The tumor volume is calculated by the following formula: Formula: A = (BxC2)/2 where: A = tumor volume (mm3) B = length of the tumor (mm) C = width of the tumor (mm) MM · Figure 2 shows that the size of the tumor in the hind limbs of the nude mice with breast cancer cells after they were injected with the compound u of the present invention in the abdominal cavity 57 201117806. As can be seen from Fig. 2, the tumor volume of the control nude mice injected intraperitoneally with a mixed solvent gradually increased with time, and was intraperitoneally injected into the nude mice (4) of the compound (4) compound u. The volume is significantly reduced over time. The results of this experiment show that the compound 11 of the present invention can effectively slow down the growth of the tumor, reduce the size of the tumor, and even eliminate it. The inventors have inferred from this that the compound η according to the present invention has a high potential to develop into an anti-breast cancer drug. # All patents and documents cited in this specification are incorporated by reference in their entirety. In the event of a conflict, the detailed description of the case (including the definition) will prevail. Although the present invention has been described with reference to the specific embodiments described above, it is obvious that many modifications and variations can be made without departing from the scope and spirit of the invention. Restrictions on the scope of the patent application. BRIEF DESCRIPTION OF THE DRAWINGS: Fig. 1A to Fig. 1C show that microtubules of human breast cancer cells mda_mb_231/ATCC which have not been treated with a compound, treated with compound b2, and treated with compound 4 are cultured at 37 ° C for 1 〇 to After 15 minutes, the results obtained by observation with a 1×71 inverted microscope were scaled at 1 μm μm; and FIG. 2 shows that nude mice with breast cancer cells transplanted to the hind limbs were intraperitoneally injected with the compound u of the present invention, and they were in vivo. Tumor size varied over time, and nude mice injected intraperitoneally with a mixed solvent were used as a control group for 58 201117806. [Main component symbol description] (none)

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Claims (1)

201117806 VII. Patent application scope: 1 · A compound having the following chemical formula (I): Or a pharmaceutically acceptable salt thereof, wherein: The Ar group is selected from the group consisting of 2-nitrophenyl, 2·cyanophenyl, 2-methoxyphenyl, 2-aminophenyl, 4-methoxybenzene , 3-methylindenylphenyl, 2-amino-5·trifluoromethylphenyl, 3-d-pyridyl, 4-aminophenyl, 3-aminophenyl, 2-. Bipyridyl, 2-methylthiophenyl, 2,4-monomethylphenyl, 3-hydroxyphenyl, 4-methoxy-2-nitrophenyl, 2-amino-4-methoxy Phenylphenyl and 5-amino-2-methoxyphenyl. 2. A pharmaceutical composition for inhibiting growth of a tumor/cancer cell, the package 3 having a compound of the formula (1) or a pharmaceutically acceptable salt thereof as defined in the patent specification class. The pharmaceutical composition of the second patent term of the patent, wherein the tumor/cancer cell is derived from human adenocarcinoma cells, prostate cancer cells, breast cancer cells, human cervical epithelial cancer cells, oral squamous cell carcinoma cells. Hepatocellular carcinoma cells, ovarian cancer cells, human lung cancer cells, and human colon cancer cells. 60 201117806 4. A compound of formula (1), or a pharmaceutically acceptable salt thereof, as defined in claim 1 of the patent application, for the preparation of a pharmaceutical composition for inhibiting the growth of a tumor/cancer cell Use of the object. 5. The use of claim 4, wherein the tumor/cancer cell is selected from the group consisting of: human gastric adenocarcinoma cells, prostate cancer cells, breast cancer cells, human cervical epithelial cancer cells, oral squamous cell carcinoma cells, liver Cellular cancer cells, ovarian cancer cells, human lung cancer cells, and human colon cancer cells 〇6. A pharmaceutical composition for inhibiting tubulin polymerization in a tumor/cancer cell, which contains the first item of the patent application scope A compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein. 7. The pharmaceutical composition of claim 6, wherein the compound of formula (I) is selected from the group consisting of 2_[6_(2_decyloxyphenyl)-3 (Z)-hexene-i,5-diynyl]-l,2,3-trimethoxybenzene, 2-[6-(2-aminophenyl)-3(Z)-hexene-1, 5·diynyl]-1,2,3-trimethoxybenzene or 2-[6-(2-pyridyl)_3(Z)-hexene-1,5-diynyl]-1,2, 3-trimethoxy stupid. 8. The pharmaceutical composition according to claim 7, wherein the compound of formula (I) is 2-[6-(2-aminophenyl)-3(Z)-hexene-1,5- Diynyl]-1,2,3-trimethoxybenzene. 9' The pharmaceutical composition of claim 6, wherein the tumor/cancer cell is a human breast cancer cell. 10. A compound of formula (1) or a pharmaceutically acceptable salt thereof as defined in claim 1 of claim 1 for use in the preparation of a 61 201117806 for inhibiting microtubules in a tumor/cancer cell Use of a pharmaceutical composition of protein polymerization. 11. The use of claim 10, wherein the compound of formula (1) is selected from the group consisting of 2-[6-(2-methoxyphenyl)-3(2) -hexene-1,5-diynyl]-1,2,3-trimethoxybenzene, 2-[6-(2-aminophenyl)-3(2)-hexene-1,5 -diynyl]-1,2,3-trimethoxybenzene or 2-[6-(2-«pyridyl)-3(Z)-hexene-1,5-diynyl]-i, 2,3-trimethoxybenzene. 12. The use according to claim 11, wherein the compound of formula (1) is 2-[6-(2-aminophenyl)_3(Z)-hexa-1,5-diblock] 1,2,3-trimethoxybenzene. 13. The use of claim 10, wherein the tumor/cancer cell is a human breast cancer cell. 62