KR20080100886A - Pharmaceutical Compositions Containing Novel Octahydro Indeno Derivatives - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the treatment or prevention of cancer comprising an octahydro indeno derivative represented by the following formula (1), the pharmaceutical composition according to the present invention has a high cytotoxicity to cancer cells, such as anticancer agents or antibiotics It can be usefully used for medical purposes.

[Formula 1]

Description

Novel pharmaceutical composition comprising octahydro-indeno derivatives

1 is a graph showing the results of cytotoxicity test for esophageal cancer cells (HEC4) of octahydro indeno derivatives according to the present invention.

The present invention relates to a pharmaceutical composition comprising an octahydro indeno derivative that can be usefully used for medical purposes such as anticancer drugs or antibiotics because of having high cytotoxicity to cancer cells.

To date, various anticancer drugs have been developed, but not until the development of definitive therapeutic drugs. In addition, since cancer cells have a lot of resistance, it is desirable to develop an anticancer agent having a different action. In recent years, research on the development of an anticancer agent having tubulin polymerization inhibitory activity has been conducted. Tubulin is the main protein constituting the microtubules and exists as dimers. Microtubules are involved in the formation of spindles of mitotic devices in eukaryotic cells, and compounds that exhibit polymerization inhibitory activity of tubulin can inhibit the formation of microtubules and inhibit mitosis. Proliferation can be suppressed.

Otilions A and B represented by the following Chemical Formulas 2 and 3 are compounds isolated from Ottelia alismoides in the Nile Valley in 1998 and are reported to inhibit the proliferation of human cancer cells at extremely low concentrations (nM-pM) ( SN Ayyad, AS Judd.WT Shier, and TR Hoye, J. Org.Chem. 1998, 63, 8102-8106).

[Formula 2]

[Formula 3]

It is reported that the anticancer mechanism of the orthion is due to inhibition of tubulin polymerization (see C. Combeau et al, Mol. Pharm. 2000, 57, 553-563.). Colchicine, vinblastine, maytansine and the like are known as compounds that exhibit tubulin polymerization inhibitor until now, but Otillion A and B inhibit cancer cell proliferation at extremely low concentrations. It is a compound of considerable interest in. In addition, the structural features of orthion include α, β / γ, and δ-unsaturated ketones in the hexa hydro indene wheel, which is a central skeleton, and 3,4-dioxy benzyl as a substituent. The group and vinyl group couple | bond with the center skeleton. As such, the orthion A and B have attracted attention in that they have strong anticancer activity.

To date, the synthesis of orthion has been reported in several documents (G. Metha and K. Islam. Angew Chem. Int. Ed. 2002, 41, 2396-2398. And G. Mehta and K. Islam, Org. Lett 2002, 4, 288 1-2884.) These are all methods of synthesizing racemates, and there is a problem in that it is difficult to synthesize various derivatives including optically active agents which can improve the activity and reduce side effects.

Japanese Patent Laid-Open No. 2004-189723 discloses a manufacturing intermediate capable of synthesizing various derivatives including an optically active agent in the production of orionion, and a method for producing the orionion derivative using the same. International Publication No. WO97 / 021657 also discloses a process for the preparation of 4- (methoxybenzyl) indane derivatives having anticancer effects.

In addition, Goverdhan Mehta et al. Disclose a method for synthesizing orylion A and B from starting materials separated by enzymatic fractionation of racemic materials (see Tetrahedron Lett. 2003, 44, 6733), and Hiroshi Araki et al. A method for synthesizing one type of optically active orthion A and B from chiral starting materials synthesized in stages is disclosed (see Org. Lett. 2003, 5, 3903).

However, studies on the activity according to the structure of the orthionone derivatives have not been conducted so far, and there is a need for a new structure derivative having high physiological activity.

The present invention has been made in view of the above-described prior art, and an object of the present invention is to provide a pharmaceutical composition comprising an octahydro indeno derivative having high physiological activity.

The present invention relates to a compound represented by the following general formula (1), a compound represented by the following general formula (1), a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[Formula 1]

In the above formula

X represents oxygen, sulfur, or NH,

R ₁ represents hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl or alkoxy;

R ₂ and R ₃ each independently represent hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryl or heteroaryl;

R _4a and R _4b each independently represent hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxy, or R _4a and R _4b together with the carbon atoms on which they are substituted carbon, oxygen and Form a double bond with an atom selected from the group consisting of sulfur or form a heterocycle;

R _5a and R _5b each independently represent hydrogen, halo, hydroxy, alkyl, alkenyl, alkynyl, or alkoxy;

R _6a and R _6b each independently represent a hydrogen, halo, hydroxy, alkyl, alkenyl, alkynyl, alkoxy or carbonyl group;

R _7a and R _7b each independently represent hydrogen, halo, hydroxy, alkyl, alkenyl, alkynyl, or alkoxy;

R ₈ represents hydrogen, halo, hydroxy, alkyl, alkenyl, alkynyl, or alkoxy;

R _9a and R _9b each independently represent hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryl or heteroaryl, or R _9a and R _9b together with the carbon atom to which they are substituted Form a double bond with an atom selected from the group consisting of carbon, oxygen and sulfur or form a heterocycle.

The terms used in the definition of the substituents of the compound of formula 1 of the present invention are as follows.

"Halo" is -F, -Cl, -Br or -I.

"Alkyl" refers to a straight or branched chain saturated hydrocarbon having 1 to 12 carbon atoms unless otherwise specified. Examples of C _{1 -12} alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, isobutyl, sec- butyl and tert- butyl, isopentyl, neopentyl, isohexyl , Isoheptyl, isooctyl, isononyl and isodedecyl, but is not limited thereto.

"Cycloalkyl" unless otherwise stated, includes monocyclic and fused rings as non-aromatic, saturated hydrocarbon rings having 3 to 12 carbon atoms. Representative examples of C _{3 -12} cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl include, but are not limited to these.

"Alkenyl" refers to a straight or branched chain unsaturated hydrocarbon having 2 to 12 carbon atoms having at least one double bond unless otherwise stated. Examples of C _{2 -12} alkenyl groups include ethylene, propylene, 1-butylene, 2-butylene, isobutylene, sec- butylene, 1-pentene, 2-pentene, iso-pentene, 1-hexene, 2-hexene , 3-hexene, isohexene, 1-heptene, 2-heptene, 3-heptene, 1-octene, 2-octene, 3-octene, 4-octene, 1-nonene, 2-nonene, 3-nonene, 4- Nonenes, 1-decene, 2-decene, 3-decene, 4-decene and 5-decene.

"Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon having 2 to 12 carbon atoms, having one or more triple bonds, unless otherwise indicated. C _{2 -12} An example of an alkynyl group include acetylene, propyne, 1-butyne, 2-butyne, tin isobutoxy, sec- butyne, 1-pentyne, 2-pentyne, iso-pentyne, 1-hexyne, 2-hexyne, 3- Hexine, Isohexine, 1-heptin, 2-heptin, 3-heptin, 1-octin, 2-octin, 3-octin, 4-octin, 1-nonin, 2-nonin, 3-nonin, 4-nonin, 1 -Decines, 2-decines, 3-decines, 4-decines and 5-decines are included, but are not limited to these.

"Alkoxy" means an alkyl group having 1 to 12 carbon atoms bonded to an oxygen atom unless otherwise specified. Examples of C _{1 -12} alkoxy group, including, methoxy, ethoxy, propoxy, and butoxy are not limited to these.

In the compound of the formula (1) according to the present invention, alkyl preferably has 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms; Cycloalkyl has a preferable carbon number of 3 to 8, more preferably 3 to 6; Alkenyl preferably has 2 to 8 carbon atoms, more preferably 2 to 4 carbon atoms; Preferable carbon number of alkynyl is 2-8, More preferably, it is 2-4.

"Aryl" refers to a 6-12 membered aromatic cyclic compound unless otherwise stated. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and anthracenyl.

"Heteroaryl", unless stated otherwise, refers to a 6-12 membered aromatic cyclic compound containing one or more heteroatoms selected from the group consisting of O, N, and S. Examples of heteroaryl groups include, but are not limited to, furyl, pyrrolyl, pyrrolidinyl, thienyl, pyridyl, piperidyl, indolyl, quinolyl, thiazole, benzthiazole, triazole, and the like. no.

"Heterocycle" means a 3- to 7-membered non-aromatic monocy, unless otherwise stated, wherein 1 to 4 of the ring carbon atoms are independently substituted with one or more heteroatoms selected from the group consisting of N, O or S Point to click cycloalkyl. Representative examples of heterocycles include morpholine, piperidine (eg 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (eg, 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothia Sol, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (eg 4-tetrahydro pyranyl), imidazoline, imidazolidinone, oxazoline, thiazolin, 2-pyrazoline, Pyrazolidines, and piperazine, but are not limited to these.

The alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryl and heteroaryl may each be optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, amino, alkyl and alkoxy. Alkyl and alkoxy in the substituents may also be optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, and amino.

A "carbonyl group" is a functional group in which a carbon atom forms a double bond with an oxygen atom, representing -C (O) H or -C (O) R, wherein R is alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy as defined above , Aryl or heteroaryl.

Preferred compounds of Formula 1 according to the present invention

X represents oxygen or sulfur,

R ₁ represents a hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, C _{1 -4} alkyl, C _{3 -6} cycloalkyl, C _{2 -4} alkenyl, C _{2 -4} alkynyl or C _{1 -4} alkoxy ;

R ₂ and R ₃ are each independently from hydrogen, F, Cl, Br, I, or represent a hydroxy, or halo, hydroxy, amino, C _{1 -4} alkyl, and the group consisting of C _{1 -4} alkoxy or substituted by one or more substituents selected unsubstituted C _{1 -4} alkyl, C _{3 -6} cycloalkyl, C _{2 -4} alkenyl, C _{2 -4} alkynyl, C _{1 -4} alkoxy, aryl or heteroaryl ;

R _4a and R _4b are each independently represent a hydrogen, fluorine, chlorine, bromine, iodine or hydroxy, halo, hydroxy, C _{1 -4} alkyl and C _{1 -4} least one substituent selected from the group consisting of alkoxy a substituted or unsubstituted C _{1 -4} alkyl, C _{3 -6} cycloalkyl, C _{2 -4} alkenyl ring, C _{2 -4} alkynyl or C _{1 -4,} or represent alkoxy, R _4a and R _4b are they carbon or oxygen atoms to form a double bond or form a heterocycle, wherein the carbon atom, or heterocyclyl forming a double bond with R _4a and R _4b together with the substituted carbon atom is C _{1 -4} alkyl, C _2-4 alkenyl, C _2-4 alkynyl and C _{1 -4} is unsubstituted or substituted by one or more substituents selected from the group consisting of alkoxy;

R _5a and R _5b each independently represents a hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, C _{1 -4} alkyl, C _{2 -4} alkenyl, C _2-4 alkynyl, or C _{1 -4} alkoxy ;

R _6a and R _6b are hydrogen, F, Cl, Br, I, hydroxy, C _{1 -4} alkyl, C _{2 -4} alkenyl, C _2-4 alkynyl, C _{1 -4} alkoxy, or carbonyl group, each independently Represent;

R _7a and R _7b each independently represent hydrogen, F, Cl, Br, I, hydroxy, C _{1 -4} alkyl, C _{2 -4} alkenyl, C _2-4 alkynyl, or C _{1 -4} alkoxy ;

R ₈ is hydrogen, F, Cl, Br, I, hydroxy, C _{1 -4} alkyl, C _{2 -4} alkenyl, C _{2 -4} alkenyl, or C _{1 -4} alkoxy;

R _9a and R _9b are each independently hydrogen, F, Cl, Br, I, or represent a hydroxy or substituted by halo, hydroxy, C _{1 -4} alkyl, C ₁ and at least one group selected from the group consisting of alkoxy _-4 substituted by a substituent or unsubstituted C _{1 -4} alkyl, C _{3 -6} cycloalkyl, C _{2 -4} alkenyl, C _{2 -4} alkynyl, C _{1 -4} alkoxy, or represent aryl or heteroaryl, R _9a and R _9b preferably form a double bond with a carbon or oxygen atom together with a substituted carbon atom or form a heterocycle.

Preferred R ₂ in the compound of Formula 1 is hydrogen or halo.

Preferred R _4a and R _4b in the compound of Formula 1 form a double bond or a heterocycle with an atom selected from the group consisting of carbon, oxygen, and sulfur together with the carbon atom to which they are substituted.

Preferred R _5a and R _5b in the compound of Formula 1 each independently represent hydrogen.

Preferred R _6a and R _6b in the compound of formula (1) will represent each independently hydrogen, C _{2 -4} alkenyl, or a carbonyl group.

In the compound of Formula 1, R _9a and R _9b are each independently hydrogen; Hydroxy; Or optionally substituted by halo, hydroxy, C _{1 -4} alkyl, amino and C _{1 -4} alkoxy substituted by one or more substituents selected from the group consisting of or to form an unsubstituted aryl or hete atoms and a double bond ring.

More preferred compound of Formula 1 according to the present invention is

X represents oxygen,

R ₁ is a hydrogen, or C _{1 -4} alkyl;

R ₂ and R ₃ are by one or more substituents selected from each independently hydrogen, fluorine, chlorine, bromine, or iodine, or represents, halo, hydroxy, C _1-4 alkyl, and C _{1 -4} alkoxy group consisting of substituted or unsubstituted C _{1 -4} alkyl, aryl or heteroaryl;

R _4a and R _4b form a double bond with a carbon atom or an oxygen atom, together with a substituted carbon atom, or form a heterocycle, wherein the carbon atom or hetero with a double bond together with R _4a and R _4b cycle is C _{1 -4} alkyl, C _{2 -4} alkenyl, C _{2 -4} alkynyl and C _{1 -4} is unsubstituted or substituted by one or more substituents selected from the group consisting of alkoxy;

R _5a and R _5b each independently represents hydrogen, or C _{1 -4} alkyl;

R _6a and R _6b are each independently hydrogen, C _{1 -4} alkyl, C _{2 -4} alkenyl, C _{2 -4} denotes the alkynyl, or the group;

R _7a and R _7b are each independently represents hydrogen, or C _{1 -4} alkyl;

R ₈ is a hydrogen, or C _{1 -4} alkyl;

R _9a and R _9b are each independently hydrogen or hydroxy; Or optionally substituted by halo, hydroxy, C _{1 -4} alkyl and C _{1 -4} alkoxy, or substituted by one or more substituents selected from the group consisting of a C _{1 -4} alkyl unsubstituted, C _{3 -6} cycloalkyl, C _{2 -4} alkenyl, C _{2 -4} alkynyl or C _{1 -4,} or represent alkoxy, or aryl, R _9a and R _9b is to form a carbon or oxygen atom with a double bond with the carbon atom to which they are substituted.

The most preferred compound of Formula 1 according to the present invention is

R ₂ represents hydrogen or iodine,

R _4a and R _4b together with the substituted carbon atoms form a double bond with a carbon or oxygen atom or form a heterocycle,

R _5a and R _5b each independently represent hydrogen,

R _6a and R _6b each independently represent hydrogen, C _{2 -4} alkenyl, or a carbonyl group,

R _9a and R _9b are each independently hydrogen; Hydroxy; Or optionally substituted by halo, hydroxy, C _{1 -4} alkyl and C _{1 -4} alkoxy, or substituted by one or more substituents selected from the group consisting of or represents unsubstituted aryl, R _9a and R _9b are they are substituted carbon atoms and Together, they form a double bond with an oxygen atom.

Preferred compounds of the formula 1 according to the present invention,

0,1,2a, 5,5a, 6,7,7a-octahydro-1-hydroxy-3-iodo-5- (1,3-dioxolan-2-yl) -indeno [7, 1-bc] furan-6-carboxaldehyde [6];

5a, 6,7,7a-tetrahydro-1-hydroxy-3-iodo-5- (1,3-dioxolan-2-yl) -6-vinylindeno [7,1-bc] furan -1,5 (0H, 2aH) -on [7];

5a, 6,7,7a-tetrahydro-3-iodo-5- (1,3-dioxolan-2-yl) -6-vinylindeno [7,1-bc] furan-1 (2aH, 5H) -one [8];

5a, 6,7,7a-tetrahydro-5- (1,3-dioxolan-2-yl) -6-vinylindeno [7,1-bc] furan-1 (2aH, 5H) -one [ 9];

0,1,2a, 5,5a, 6,7,7a-octahydro-1- (4-methoxy-3- (methoxymethoxy) phenyl) -5- (1,3-dioxolane-2 -Yl) -6-vinylindeno [7,1-bc] furan-1-ol [10]

5a, 6,7,7a-tetrahydro-1-hydroxy-1- (3-hydroxy-4-methoxyphenyl) -6-vinylindeno [7,1-bc] furan-5 (0H, 1H , 2aH) -one [11];

5a, 6,7,7a-tetrahydro-1-hydroxy-3-iodo-6-vinylindeno [7,1-bc] furan-1,5 (0H, 2aH) -one [12];

5a, 6,7,7a-tetrahydro-3-iodo-6-vinylindeno [7,1-bc] furan-1,5 (0H, 2aH) -dione [13];

5a, 6,7,7a-tetrahydro-6-vinylindeno [7,1-bc] furan-1,5 (0H, 2aH) -dione [14];

5a, 6,7,7a-tetrahydro-5-methylene-6-vinylindeno [7,1-bc] furan-1 (2aH, 5H) -one [15];

0,1,2a, 5,5a, 6,7,7a-octahydro-1- (4-methoxy-3- (methoxymethoxy) phenyl) -5-methylene-6-vinylindeno [7, 1-bc] furan-1-ol [16]; or

0,1,2a, 5,5a, 6,7,7a-octahydro-5- (1,3-dioxolan-2-yl) -6-vinylindeno [7,1-bc] furan-1 -All [17], including but not limited to.

More preferred compound of Formula 1 according to the present invention,

0,1,2a, 5,5a, 6,7,7a-octahydro-1-hydroxy-3-iodo-5- (1,3-dioxolan-2-yl) -indeno [7, 1-bc] furan-6-carboxaldehyde [6];

5a, 6,7,7a-tetrahydro-3-iodo-5- (1,3-dioxolan-2-yl) -6-vinylindeno [7,1-bc] furan-1 (2aH, 5H) -one [8];

5a, 6,7,7a-tetrahydro-5- (1,3-dioxolan-2-yl) -6-vinylindeno [7,1-bc] furan-1 (2aH, 5H) -one [ 9];

5a, 6,7,7a-tetrahydro-1-hydroxy-1- (3-hydroxy-4-methoxyphenyl) -6-vinyl indeno [7,1-bc] furan-5 (0H, 1H , 2aH) -one [11];

5a, 6,7,7a-tetrahydro-1-hydroxy-3-iodo-6-vinylindeno [7,1-bc] furan-1,5 (0H, 2aH) -one [12];

5a, 6,7,7a-tetrahydro-3-iodo-6-vinylindeno [7,1-bc] furan-1,5 (0H, 2aH) -dione [13];

5a, 6,7,7a-tetrahydro-6-vinylindeno [7,1-bc] furan-1,5 (0H, 2aH) -dione [14]; or

0,1,2a, 5,5a, 6,7,7a-octahydro-1- (4-methoxy-3- (methoxymethoxy) phenyl) -5-methylene-6-vinylindeno [7, 1-bc] furan-1-ol [16].

The compound of Formula 1 of the present invention may be prepared and used in the form of a pharmaceutically acceptable salt or solvate, wherein the preparation of salts or solvates may be used with inorganic or organic acids or solvents commonly used in the art. Can be.

Examples of inorganic or organic acids that can be used in the preparation of pharmaceutically acceptable salts of the compounds of formula 1 of the present invention include inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid or nitric acid; Or organic acids such as citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, gluconic acid, succinic acid, formic acid, trifluoroacetic acid, oxalic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid or camphorsulfonic acid. It doesn't happen.

In the preparation of the solvates, solvents commonly used in the art and pharmaceutically acceptable may be used without limitation. Examples of the solvent include water or ether.

The compound represented by Chemical Formula 1 according to the present invention may be prepared by the same method as in Scheme 1 below.

Hereinafter, a method for preparing the compound of Formula 1 will be described in detail.

Iodine-substituted mono quinone ketal (1) can be prepared by subjecting iodine phenol as starting material to an oxidation reaction such as iodine benzene diacetate and an oxidation reaction under methanol solvent.

Cyclic ketals (2) can be prepared by subjecting monoketal (1) to substitution reaction with diols such as 1,2-ethanediol at low temperatures in the presence of Lewis acids such as BF ₃ .

Substituted monoketal (1 or 2) synthesized by the above method can be used as a dieno file for the [4 + 2] cyclization addition reaction to form a new hexagonal ring adduct when reacting with a diene. do. That is, when the substituted monoketal (1 or 2) is reacted with cyclopentadiene at a low temperature under a Lewis acid catalyst such as dichloroethylaluminum, a tricyclic compound (3) having an endo structure can be obtained in high yield.

The tricyclic compound (3) is reduced to alcohol (4) by a known method of reducing ketones to alcohol. In this case, when the reaction is carried out at low temperature in a methanol solvent by using a known Luche reduction method, a high yield of alcohol (4) can be obtained.

When the double bond of the alcohol (4) is cut through a low temperature ozone reaction or an oxidation reaction at room temperature using an osmium catalyst to form a dialdehyde, one side of the dialdehyde forms a ring with the alcohol to form an octahydro indinofuran derivative. (5) can be synthesized.

In order to control the relative steric structure of the other aldehyde, a derivative (6) having a steric structure of alpha position adjusted upward may be synthesized by using a catalytic amount of a base in a benzene solvent and raising the temperature to about 60 ° C., followed by stirring.

Aldehyde (6) can be converted to alcohol through known reduction reactions and can introduce substituted olefins through the Wittig reaction or the Wadsworth-Emmons reaction. In the above case, the octahydro indinofuran derivative (7) having the vinyl group introduced therein can be obtained by reacting the ligtides with an ide made from the methylphosphonyl salt.

The lactol (7) can be converted to the lactone derivative (8) by reacting at room temperature with an oxidizing agent such as pyridinium chlorochromate, and the iodine group is reduced with hydrogen when a reducing agent such as tributyltin hydride is used ( 9) can be prepared.

In addition, when the lactol (7) is reacted with tributyltin hydride, it is possible to synthesize the lactol derivative (17) in which iodine is substituted with hydrogen in good yield.

In addition, when the lactone derivative 9 is reacted with an alkyl or aryl metal reagent at low temperature, it may be added to an ester group to form a substituted lactol derivative 11. For example, the substituted derivative 10 in a yield of 67% can be synthesized by reacting substituted phenyl lithium with a pentane solvent at -78 ° C.

The cyclized ketal group was stirred at room temperature in an acidic solution containing water, whereby the derivatives 10 were ketones 11, the derivatives 7 were ketones 12, the lactones 9 were ketones 14, The lactones 8 can be converted into ketones 13, respectively.

On the other hand, the ketone (12) was changed to the lactone (13) through the above-described oxidation reaction, it is possible to synthesize a derivative of the lactone (14) with ketone by the reduction reaction. The methylene-substituted derivative 15 may be synthesized by subjecting the ketone to a vitig reaction, and an octahydro indinofuran derivative 16 may be prepared by the addition reaction of the aryl metal reagent described above.

Specific reaction conditions at each step of the method for preparing a compound of the present invention described above, that is, a solvent, a reactant, a catalyst, an addition amount, a reaction temperature and a reaction time are not particularly limited, and a person skilled in the art of synthesis of organic compounds According to the desired compound, suitable reaction conditions can be easily adopted and used.

In addition, the stereoisomer of the compound of the present invention can be selectively prepared using a chiral catalyst as described below.

The chiral catalysts are the Mikami catalyst (Org. Lett., 2001, 3, 1559) and the core catalyst (J. Am. Chem) which resulted in the [4 + 2] reaction of quinone monoketal substituted with diene with high stereoselectivity. Soc, 2002, 124, 9992, J. Am. Chem. Soc, 2003, 125, 6388) and modified forms of these catalysts can be used. In this case, chiral adducts (+)- 3 and (-)- 3 were reacted at -78 ° C for 2 hours using a core catalyst prepared by treating oxazaborolidine with a strong acid. Can be synthesized. Using these as starting materials, the stereoisomers may be synthesized by performing the preparation method of Scheme 1.

The present invention also relates to a pharmaceutical composition comprising the compound of formula 1 and a pharmaceutically acceptable carrier. The pharmaceutical composition according to the present invention may be particularly useful as an anticancer agent or an antiviral agent, and may also be useful for the treatment of infectious diseases caused by intracellular parasitic bacteria such as tuberculosis and leprosy.

Specifically, the pharmaceutical composition of the present invention can be used for various solid cancers such as various diseases associated with tumors, for example, lung cancer, liver cancer, stomach cancer, colon cancer, bladder cancer, prostate gland, breast cancer, ovarian cancer, cervical cancer, thyroid cancer, and melanoma. In addition, it can be usefully used for the treatment of various blood cancers, including leukemia.

Carriers used in the composition according to the present invention include carriers and vehicles commonly used in the pharmaceutical field, and specifically, ion exchange resins, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum albumin), buffer substances (E.g. various phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids), water, salts or electrolytes (e.g. protamine sulfate, disodium hydrogen phosphate, carbohydrogen phosphate, sodium chloride and zinc salts) , Colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose based substrates, polyethylene glycol, sodium carboxymethylcellulose, polyarylates, waxes, polyethylene glycols or wool, and the like. The compositions of the present invention may also further comprise lubricants, wetting agents, emulsifiers, suspending agents, preservatives and the like in addition to the above components.

The pharmaceutical compositions of the present invention may be prepared in parenteral dosage forms such as oral dosage forms or injections.

Examples of formulations for oral administration include tablets, troches, lozenges, water soluble or oily suspensions, prepared powders or granules, emulsions, hard or soft capsules, syrups or elixirs. For formulation into tablets and capsules, lactose, saccharose, sorbitol, mannitol, starch, amylopectin, binders such as cellulose or gelatin, excipients such as dicalcium phosphate, disintegrants such as corn starch or sweet potato starch, magnesium stearate Lubricating oils, such as calcium stearate, sodium stea fumarate or polyethylene glycol wax. In addition, the capsule formulation may contain a liquid carrier such as fatty oil in addition to the above-mentioned substances.

Formulations for case administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, and lyophilized preparations. Non-aqueous solvents and suspending solvents may be used vegetable oils such as propylene glycol, polyethylene glycol or olive oil, injectable esters such as ethyl oleate.

In one embodiment, the composition according to the invention may be prepared in an aqueous solution for parenteral administration. Preferably, a buffer solution such as Hanks' solution, Ringer's solution, or physically buffered saline may be used. Aqueous injection suspensions can be added with a substrate that can increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran.

Another preferred embodiment of the compositions of the present invention may be in the form of sterile injectable preparations of aqueous or oily suspensions. Such suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents (eg Tween 80) and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions (eg solutions in 1,3-butanediol) in nontoxic parenterally acceptable diluents or solvents. Vehicles and solvents that may be used include mannitol, water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally employed as a solvent or suspending medium. For this purpose any non-irritating non-volatile oil can be used including synthetic mono or diglycerides.

Hereinafter, the present invention will be described in more detail through examples according to the present invention, but the scope of the present invention is not limited to the examples given below.

< Production Example  1> 2- Iodo -4,4- Dimethoxycyclohexa -2,5- Dienon  Manufacture of (1)

The title compound was prepared by modifying the method of References (Camps, P. et. Al. Tetrahedron Lett. 2000 , 56, 8141) as follows. In a flask mixed with 2-iodophenol (1 g, 4.50 mmol) in MeOH (8 ml), iodo benzeneacetate (3 g, 9.31 mmol) dissolved in MeOH (24 mL) in a nitrogen atmosphere was 15 mL at 0 ° C. Injection at / h rate. Stir for 3 hours after reaction injection. Progress of the reaction was observed via TLC. The reaction mixture was purified by silica gel filter at high speed, evaporated to remove solvent, and purified by silica gel chromatography. (EtOAc: Hexane = 1: 10 → 1: 6) Viscous yellow liquid with title compound 790 mg ( 63%).

TLC R _f 0.39 (EtOAc: Hexane = 1: 3)

LRMS calcd for C8H9IO4: 279.96

Article of cyclo hexa-2,5-diethoxy non-2 - <Production Example 2> 2-iodo-4- (1, 3-dioxolane-2-yl)

DME (7.5 mL) was added to 2-iodo-4,4-dimethoxycyclohexadienone 2 (790 mg) and stirred, followed by ethylene glycol (786 μl, 14.1 mmol) and BF ₃ · Et ₂ O (348 μl, 2.82 mmol). Add at 50 ° C. The reaction mixture was slowly heated to 0 ° C. Progress of the reaction was observed via TLC. NH ₄ Cl aqueous solution was added to terminate the reaction, and the temperature was raised to room temperature. The mixture was washed with more water, and the organic layer was extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . The solvent was removed by evaporation and purified by silica gel chromatography. (EtOAc: Hexane = 1: 3) 720 mg (92%) of the title compound were obtained as a slightly yellow solid.

TLC R _f 0.3 (EtOAc: Hexane = 1: 3)

FT - IR 2357, 1636, 1134, 961, 820 cm? 1

₁ H NMR (300 MHz, CDCl 3) δ 7.39 (d, 1H, J = 3 Hz), 6.67 (dd, 1H, J = 3.0, 10.2 Hz), 6.34 (d, 1H, J = 10.2 Hz), 4.14 ( s, 4H)

¹³ C NMR (75 MHz, CDCl 3) δ 178.6, 151.9, 143.8, 126.1, 104.9, 99.5, 65.9

LRMS calcd for C8H7IO3: 277.94

< Production Example  3> 1,4,4a, 8a- Tetrahydro -7- Iodo - Spyro 1 , 3- Dioxorene -2,5 (8 H )-[1,4] Tanonaf Preparation of Talen-8-one (3)

Dichloromethane (1 mL) obtained by distillation in ketal monoquinone (2) (440 mg, 1.583 mmol) was added thereto, and ethyl aluminum dichloride (0.475 mL, 0.475 mmol) was slowly added dropwise at -78 ° C. Subsequently, Cychloropentadiene (0.39 mL, 4.749 mmol) was added, followed by stirring for about 15 minutes. Progress of the reaction was observed via TLC. Triethylamine (0.066mL, 0.475mmol) was added to complete the reaction. Then, the mixture was washed with more water. The organic layer was extracted with CH2Cl2 and dried over Na2SO4. The solvent was removed slightly by evaporation. The solvent was removed by evaporation and purified using Silicagel Chromatography. (EtOAc: Haxane = 1: 5) A slightly yellow liquid gave 547 mg (99.9%) of the title compound.

TLC R _f 0.34 (EtOAc: Hexane = 1: 3)

FT - IR 2981, 2880, 2357, 1671, 1604, 1339 cm? 1

¹ H NMR (300 MHz, CDCl3) δ 7.07 (d, 1H, J = 1 Hz), 6.08 (dd, 1H, J = 2.7, 5.4 Hz), 5.85 (dd, 1H, J = 2.7, 5.7 Hz), 4.0 (m , 4H), 3.28 (m, 3H), 2.84 (ddd, 1H, J = 3.6, 8.4, 12 Hz), 1.40 (m, 2H)

¹³ C NMR (75 MHz, CDCl3) δ 202.2, 153.8, 135.9, 133.4, 105.4, 65.5, 64.5, 50.8, 48.6, 46.6, 46.4, 34.9

LRMS calcd for C13H13IO3: 343.99

< Production Example  4> 1,4,4a, 8a- Tetrahydro -7- Iodo - Spyro 1 , 3- Dioxorene -2,5 (8 H )-[1,4] Tanonaf Preparation of Talen-8-ol (4)

MeOH (7.3 mL) was stirred in Diels-Alder adduct 3 (183 mg, 0.532 mmol) and CeCl ₃ .7H ₂ O (99 mg, 0.266 mmol) was added at 0 ° C. Stir while maintaining the temperature for 30 minutes. NaBH ₄ (20 mg, 0.532 mmol) was added at -78 ° C and stirred for 1 hour. Progress of the reaction was observed via TLC. Et ₃ N was added to terminate the reaction, and the temperature was raised to room temperature. NaHCO ₃ And washed with water and the organic layer was extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . The solvent was removed by evaporation to give the title compound.

TLC R _f 0.34 (EtOAc: Hexane = 1: 3)

< Example  1> 0,1,2a, 5,5a, 6,7,7a- Octahydro -1-hydroxy-3- Iodo -5- (1,3-dioxolan-2-yl)- Indeno [7,1-bc] furan -6- Carboxaldehyde  (5) Preparation

Reaction mixture 4 to CH ₂ Cl ₂ Further added to O ₃ at -78 ° C. Was bubbled. Progress of the reaction was observed via TLC. O _3, which terminate the reaction into the Me ₂ S and remain secure the needle to a nitrogen balloon flask septum gas was removed. After stirring for 1 hour, the temperature was raised to room temperature. The mixture was washed with more water, and the organic layer was extracted with CH ₂ Cl ₂ and dried over Na ₂ SO ₄ . The solvent was removed by evaporation to give the title compound.

TLC R _f 0.2 (EtOAc: Hexane = 1: 1)

< Example  2> 0,1,2a, 5,5a, 6,7,7a- Octahydro -1-hydroxy-3- Iodo -5- (1,3- Diok Soran-2-yl)- Indeno [7,1-bc] furan -6- Carboxaldehyde  (6) Preparation

Benzene (20 mL) was added to Aldehyde 5 (454 mg), the mixture was stirred, and DBU (about 2 mL) was added to raise the temperature to 65 ° C. The mixture was stirred for 2 hours and the progress of the reaction was observed through TLC. The temperature was raised to room temperature, washed with more water, and the organic layer was extracted with EtOAc and dried over Na 2 SO 4. The solvent was removed by evaporation and purified by silicagel chromatography (EtOAc: Hexane = 2: 1) to obtain the title compound. The overall yield of 3 steps from 4 was 86% and the yield of each step was 95%.

TLC Rf 0.45 (EtOAc: Hexane = 2: 1)

¹ H NMR (300 MHz, CDCl3) δ 9.61 (d, 1H, J = 3.3 Hz), 6.41 (t, 1H, J = 1.2 Hz), 5.36 (s, 1H), 4.71 (d, 4H, J = 7.8 Hz), 3.96 (m, 4H), 3.27 (q, 1H, J = 7.5 Hz), 3.01 (m, 1H), 2.85 (m, 1H), 2.57 (m, 1H), 2.0 (m, 1H), 1.79 (ddd, 1H, J = 7.5, 13.5, 21.3 Hz)

¹³ C NMR (75 MHz, CDCl3) δ 202.6, 139.1, 106.9, 103.4, 78.0, 65.3, 65.0, 52.8, 50.9, 49.0, 43.2, 31.7

LRMS calcd for C13H15IO5: 378.00

< Example  3> 5a, 6,7,7a- Tetrahydro -1-hydroxy-3- Iodo -5- (1,3- Dioxoran -2-yl) -6-vinylindeno [7,1- bc Furan-1,5 (0H, 2 aH Preparation of On- (7)

THF (7.5 mL) was added to Ph3CH3Br (463 mg, 1.3 mmol), followed by stirring. NaHMDS (580 μl, 1.15 mmol) was slowly added at 0 ° C., and the temperature was maintained for 1 hour. Aldehyde 6 (109 mg, 0.288 mmol) with THF (1.5 mL) was added using cannular. The mixture was stirred for 2 hours and the progress of the reaction was observed through TLC. aq NH4Cl was added to terminate the reaction, and the temperature was raised to room temperature. The mixture was washed with more water, and the organic layer was extracted with EtOAc and dried over Na 2 SO 4. The solvent was removed by evaporation and purified by silica gel chromatography. (EtOAc: Hexane = 1: 1) 95 mg (88%) of the title compound as a white solid.

TLC R _f 0.77 (EtOAc: Hexane = 2: 1)

¹ H NMR (300 MHz, CDCl 3) δ 6.42 (t, 1H, J = 1.2 Hz), 5.78 (m, 1H), 5.36 (s, 1H), 4.93 (td, 2H, J = 18.9, 31.2 Hz), 4.69 (d , 1H, J = 18.9 Hz), 3.21 (q, 1H, J = 7.5 Hz), 2.87 (m, 1H), 2.48 (m, 1H), 1.99 (m, 2H), 1.74 (m, 2H)

¹³ C NMR (75 MHz, CDCl3) δ 141.1, 139.6, 113.4, 108.2, 103.8, 100.7, 78.3, 64.3, 50.1, 49.6, 45.1, 44.1, 37.5

LRMS calcd for C14H17IO4: 376.02

< Example  4> 5a, 6,7,7a- Tetrahydro -3- Iodo -5- (1,3- Dioxoran 2-yl) -6- Vinyl indeno [7,1-bc] furan Preparation of -1 (2aH, 5H) -one (8)

CH2Cl2 (20 mL) was added to PCC (182 mg, 0.484 mmol) and celite (182 mg), followed by stirring. Lactol 8 (34.6 mg, 0.092 mmol) was added slowly at 0 ° C. After the injection, the temperature was raised to room temperature and stirred to observe the progress of the reaction through TLC. The reaction mixture was filtered through silica gel filter, evaporated to remove solvent, and purified by silica gel chromatography. (EtOAc: Hexane = 1: 1) As a white solid, 150 mg (83%) of the title compound were obtained.

TLC R _f 0.41 (EtOAc: Hexane = 1: 1)

FT - IR 3072, 2889, 2359, 1775, 1636 cm? 1

¹ H NMR (300 MHz, CDCl 3) δ 6.55 (t, 1H, J = 1.2 Hz), 5.83 (m, 1H), 5.05 (m, 1H), 4.99 (m, 2H), 3.96 (m, 4H), 3.43 (dd, 1H, J = 9.6, 17.7 Hz), 3.25 (t, 1H, J = 9.6 Hz), 2.36 (m, 1H), 2.25 (m, 1H), 2.11 (ddd, 1H, J = 8.4, 11.4, 19.8 Hz), 1.89 (m, 1H)

¹³ C NMR (75 MHz, CDCl3) δ 177.5, 141.3, 139.9, 114.7, 106.6, 65.6, 64.2, 50.6, 45.0, 40.2, 38.9, 19.9

LRMS calcd for C14H15IO4: 374.00

< Example  5> 5a, 6,7,7a- Tetrahydro -5- (1,3- Dioxoran -2-yl) -6-vinylindeno [7,1-bc] furan-1 (2 aH Of 5,5H) -one (9)

A reflux condenser was installed in a two-neck round bottom flask and nitrogen was charged. At room temperature, compound 8 (77 mg, 0.205 mmol) was stirred with benzene solvent and n-Bu3SnH (1.23 mmol) was added. The temperature was raised to 80 ~ 90 ° C and reacted for 6 hours. After completion of the reaction, the solvent was removed, and the remaining crude reactant was separated by column (E.A: n-Hexane = 1: 3) to obtain the title compound (42 mg, 82% yield).

TLC R _f = 0.39 (EA: Hexane = 1: 1)

¹ H NMR (300 MHz, CDCl 3): 6.02 (dd, J = 7.5, 10.5 Hz, 1H), 5.86 (m, 2H), 4.97 (m, 3H), 4.02 (m, 2H), 3.92 (m, 2H ), 3.38 (q, J = 9.6 Hz, 1H), 3.21 (t, J = 9.6 Hz, 1H), 2.27 (m, 2H), 2.10 (ddd, J = 1.8, 3.0, 11.1 Hz, 1H), 1.90 (td, J = 9.6, 12.3 Hz, 1H)

Example 6 0,1,2a, 5,5a, 6,7,7a-octahydro-1- (4-methoxy-3- (methoxymethoxy) phenyl) -5- (1,3- Dioxoran-2-yl) -6- Vinyl indeno [7,1-bc] furan -1-ol (10) Preparation

Stir in pentene in 4-Bromo-1-methoxy-2- (methoxymethoxy) benzene (69.7mg), add t-BuLi (1.7M, 207μl) at -78 ℃, and keep the temperature for 2 hours 30 minutes. Stirred. Lactol compound 9 (35 mg) containing THF (1 ml) was added at -78 ° C. After the injection, the mixture was stirred at -78 ° C for 1 hour, and then heated to room temperature and stirred to observe the progress of the reaction by TLC. When the reaction proceeded completely, aq NH 4 Cl was added at 0 ° C. to terminate the reaction. After washing with water and EtOAc, the organic layer was extracted and dried over Na2SO4. The solvent was removed by evaporation and purified by silica gel chromatography (EtOAc: Hexane = 1: 1) to obtain 39.3 mg (67%) of the title compound.

¹ H NMR (300 MHz, CDCl 3) δ 2.28 (d, 1H, J = 1.8), 7.16 (dd, 1H, J = 8.4), 6.86 (d, 1H, J = 8.4), 6.14 (dd, 1H, J = 10.2), 5.80 (d, 1H, J = 10.5), 5.73 (m, 1H), 5.22 (s, 2H), 4.85 (m, 1H), 4.80 (s, 1H), 4.73 (m, 1H), 3.96 (m, 4H), 3.88 (s, 3H), 3.51 (s, 3H), 3.32 (q, 1H, J = 7.8), 2.93 (m, 1H), 2.53 (s, 1H), 2.40 (m, 1H), 1.37 (m, 2H)

< Example  7> 5a, 6,7,7a- Tetrahydro -1-hydroxy-1- (3-hydroxy-4- Methoxyphenyl ) -6-vinyl indeno [7,1- bc] furan -5 (0H, 1H, 2 aH Preparation of On- (11)

To alkylation lactol 10 (38.6 mg) was added THF / Acetone / 1N H2SO4 (0.4 ml / 0.4 ml / 0.4 ml) at 0 ° C. After the injection, the temperature was raised to room temperature and stirred. When the starting material disappeared by TLC observation, the reaction was terminated by adding aq NaHCO 3. After washing with water, the organic layer was extracted with EtOAc and dried over Na2SO4. The solvent was removed by evaporation and purified by silica gel chromatography (EtOAc: Hexane = 1: 1) to obtain 17.4 mg (57%) of the title compound.

¹ H NMR (300 MHz, CDCl 3) δ 7.11 (d, 1H, J = 2.1), 7.02 (dd, 1H, J = 8.4), 6.92 (dd, 1H, J = 10.2), 6.83 (m, 1H), 6.09 (d, 1H, J = 10.2), 5.53 (m, 1H), 4.89 (m, 2H), 4.84 (m, 1H), 3.90 (s, 3H), 3.40 (m, 1H), 3.07 (m, 1H), 2.53 (m, 2H), 2.41 (m, 2H)

Example 8 5a, 6,7,7a-tetrahydro-1-hydroxy-3-iodo-6-vinylindeno [7,1-bc] furan-1,5 (0H, 2 aH Preparation of) -on (12)

Compound 7 (20 mg) and a mixed solvent (THF: Acetone = 1: 1) were sequentially added to a one-neck round bottom flask, and 1N H 2 SO 4 (0.2 ml) was added at 0 ° C. The temperature was gradually raised to room temperature and stirred. After overnight, the reaction was terminated with sat NaHCO 3, extracted with H 2 O, E.A, and dried over Na 2 SO 4. After column separation (E.A: n-Hexane = 1: 1), the title compound (15 mg, 85% yield) was obtained as a white solid.

TLC R _f = 0.44 (EA: Hexane = 1: 1)

¹ H NMR (300 MHz, CDCl 3): 6.87 (s, 1H), 5.60 (m, 1H,), 5.43 (s, 1H), 5.01 (m, 3H), 3.31 (q, J = 7.8 Hz, 1H) , 3.02 (t, J = 8.4 Hz, 1H), 2.79 (br, 1H), 2.64 (m, 1H), 2.44 (q, J = 8.1 Hz, 1H), 1.96 (ddd, J = 6.6, 13.5, 19.8 Hz, 1H), 1.77 (m, 1H) 13 C NMR (75 MHz, CDCl 3): δ 194.9, 140.7, 137.8, 116.6, 104.0, 102.1, 79.8, 54.5,51.6, 49.5, 44.9, 37.6 FT-IR 2359, 1650 cm ?One

LRMS calcd for for C12H13IO3: 331.99

Example 9 Preparation of 5a, 6,7,7a-tetrahydro-3-iodo-6-vinylindeno [7,1-bc] furan-1,5 (0H, 2aH) -dione (13)

After filling the one-neck round bottom flask with nitrogen, PCC (100 mg, 0.46 mmol) and celite (100 mg) were added, and CH 2 Cl 2 solvent was added thereto and stirred at room temperature. 12 (31 mg, 0.093 mmol) was added slowly with CH2Cl2 solvent. After stirring at room temperature for 6 hours, the mixture was filtered through silica gel and celite, and then the solvent was removed. After column separation (E.A: n-Hexane = 1: 3), the title compound (29 mg, 94% yield) was obtained.

TLC : R _f = 0.38 (EA: n-Hexane = 1: 1)

¹ H NMR (300 MHz, CDCl 3): 6.55 (t, J = 1.2 Hz, 1H), 5.83 (m, 1H,), 5.05 (m, 1H), 4.99 (m, 2H), 3.96 (m, 4H) , 3.43 (dd, J = 9.6, 17.7 Hz, 1H), 3.25 (t, J = 9.6 Hz, 1H), 2.36 (m, 1H), 2.25 (m, 1H), 2.11 (ddd, J = 8.4, 11.4 , 19.8 Hz, 1H), 1.89 (m, 1H) 13C NMR (75MHz, CDCl3): δ 177.5, 141.3, 139.9, 114.7, 106.6, 65.6, 64.2, 50.6, 45.0, 40.2, 38.9, 19.9 FT-IR (2930) , 2357, 1776, 1671, 1608, 1342 cm? 1) LRMS calcd for for C12H11IO3: 329.98

< Example  10> 5a, 6,7,7a- Tetrahydro -6- Vinyl indeno [7,1-bc] furan Preparation of -1,5 (0H, 2aH) -dione (14)

A two-neck round bottom flask was equipped with a reflux condensor, filled with nitrogen, and stirred compound 13 (58 mg, 0.18 mmol) in a benzene solvent at room temperature and n-Bu3SnH (1.05 mmol) was added. The temperature was raised to 80 ~ 90 ° C. and reacted for 5 hours. After completion of the reaction, the solvent was removed, and the remaining crude reactant was separated by column (E.A: n-Hexane = 1: 3) to obtain the title compound (28 mg, 80% yield).

TLC : R _f = 0.26 (EA: n-Hexane = 1: 1)

¹ H NMR (300 MHz, CDCl 3): 6.83 (dd, J = 6.0, 10.5 Hz, 1H), 6.14 (dd, J = 9.9, 10.5 Hz, 1H), 5.69 (m, 1H), 5.09 (m, 3H ), 3.54 (q, J = 17.7 Hz, 1H), 3.40 (t, J = 9.3 Hz, 1H), 2.49 (m, 2H), 1.92 (m, 1H), 1.36 (dd, J = 14.7 Hz, 1H )

< Example  11> 5a, 6,7,7a- Tetrahydro -6- Vinyl indeno [7,1-bc] furan -1,5 (0H, 2 aH )- Dion  Manufacture of 15

The one-neck round bottom flask was vacuum dried and filled with nitrogen, and then stirred with Ph3CH3Br (323 mg, 0.904 mmol) and THF (7.5 mL). NaHMDS (401 μl, 0.80 mmol) 2M solution was added slowly at 0 ° C. and stirred for 1 hour. Compound 14 (41 mg, 0.20 mmol) was added slowly to the reaction vessel with THF solvent. The mixture was stirred for another 1 hour, and the reaction was terminated with sat NH 4 Cl, and the temperature was slowly raised to room temperature. After extraction with Sat brine, E.A, dried over Na 2 SO 4. After removal of solvent, column separation (E.A: Hexane = 1: 1) gave the title compound (12 mg, 30% yield).

TLC : R _f = 0.77 (EA: n-Hexane = 1: 1)

¹ H NMR (300 MHz, CDCl 3): 6.34 (dd, J = 9.6, 9.9 Hz, 1H), 5.90 (dd, J = 6.6, 9.9 Hz, 1H), 5.82 (m, 1H), 5.15 (s, 1H ), 5.05 (ddd, J = 8.1, 10.5, 11.1 Hz, 1H), 4.99 (dd, J = 4.2 Hz, 1H), 4.96 (dd, J = 0.9, 1.8 Hz, 1H), 4.90 (s, 1H) , 3.27 (q, J = 9 Hz, 1H), 3.18 (q, J = 9 Hz, 1H), 2.44 (dd, J = 2.4, 11.1 Hz, 1H) 2.34 (dd, J = 7.2, 12.9 Hz, 1H), 2.09 (m, 1H), 1.84 (td, J = 8.7, 12.9 Hz, 1H)

< Production Example  5> (1R, 4S, 4 aR ,8 aS ) -1,4,4a, 8a- Tetrahydro -7- Iodo - Spyro 1 , 3-dioxene-2,5 (8 H )-[1,4] Metanonaphthalene Preparation of -8-one (3)

Stir CH2Cl2 (1.5 mL) to oxazaborolidine (0.160 mmol) catalyst made by reference ((S) -form, Ryu, DH et al J. Am. Chem. Soc, 2002, 124, 9992) and trifluoromethanesulfonic acid (12 Μl, 0.133 mmol) was added slowly at -30 ° C. Solid 2 (185 mg, 0.665 mm ol) was dissolved in CH 2 Cl 2 (1.5 mL) and added at -78 ° C. Cyclopentadiene (218 μl, 2.66 mmol) was added slowly and stirred for 2 hours. Progress of the reaction was observed via TLC. Et3N (20 µl) was added to terminate the reaction. The solvent was removed by evaporation and purified by silica gel chromatography. (EtOAc: Hexane = 1: 5) 220 mg (94%) of the title compound were obtained as a slightly yellow liquid.

TLC R _f 0.34 (EtOAc: Hexane = 1: 3)

FT - IR 2981, 2880, 2357, 1671, 1604, 1339 cm? 1

[α] 26D -492 ° (c 0.5, CHCl 3)

HPLC (chiralcel OJ-H), iPrOH / hexane (v / v = 10: 90), flow rate 1.0 mL min-1): tR = 19.7 min (R-form major, 95% ee), tR = 22.5 min ( S-form major, 97% ee)

¹ H NMR (300 MHz, CDCl 3) δ 7.07 (d, 1H, J = 1 Hz), 6.08 (dd, 1H, J = 2.7, 5.4 Hz), 5.85 (dd, 1H, J = 2.7, 5.7 Hz), 4.0 (m, 4H), 3.28 (m, 3H), 2.84 (ddd, 1H, J = 3.6, 8.4, 12 Hz), 1.40 (m, 2H)

¹³ C NMR (75 MHz, CDCl3) δ 202.2, 153.8, 135.9, 133.4, 105.4, 65.5, 64.5, 50.8, 48.6, 46.6, 46.4, 34.9

LRMS calcd for C13H13IO3: 343.99

< Production Example  6> (1S, 4R, 4 aS ,8 aR ) -1,4,4a, 8a- Tetrahydro -7- Iodo Spiro {1,3-dioxoene-2,5 (8H)-[1,4] meth Tanonaf Tallen-8-one} (3)

Example 16 was carried out in the same manner as that of (S) -form instead of (R) -form oxazaborolidine. The physical properties and analytical data of the obtained compound were the same, and the optical rotation value due to polarization was opposite. (95% yield, 95% ee, [α] ²⁶ _D + 490 ° (c 0.5, CHCl 3))

< Example  12> (0S, 1S, 2 aS , 5 aS , 6S, 7 aS ) -1,1,2a, 5,5a, 6,7,7a- Octahydro -1-hydroxy-3- Iodo -5- (1,3- D Oxoran-2-yl)- Indeno [7,1-bc] furan -6- Carboxaldehyde  (6) Preparation

Chiral (-)-6 was synthesized through Example 4-6 using (-)-3 (97% ee) as a starting material, and the structure thereof was confirmed through analytical data.

[α] ²⁶ _D -170 ° (c 0.5, CHCl 3)

< Example  13> Preparation of Chiral Derivative Compound (-)-7, (+)-8

The chiral derivative compounds (-)-7 and (+)-8 were synthesized in the same manner as in Examples 3 and 4, respectively, and the structures thereof were confirmed through analytical data, and the optical rotation data was as follows.

(-)-7; [α] ²⁶ _D -376 ° (c 0.5, CHCl3), (+)-8; [α] 26D + 46 ° (c 0.5, CHCl 3)

< Example  14> Preparation of Chiral Derivative Compound (-)-12, (-)-13

In the same manner as in Examples 3 and 4, the chiral derivative compounds (-)-12 and (-)-13 were synthesized by (-)-7 and (-)-12 as starting materials, respectively. The structure was confirmed and each optical rotation data was as follows.

(-)-12; [α] ²⁶ _D -427 ° (c 0.5, CHCl3), (-)-13; [α] 26D -214 ° (c 0.5, CHCl 3)

The structures and compound names of the novel octahydro indeno derivatives synthesized through Examples 1 to 14 are summarized in Table 1 below.

< Test Example  1> MTT Assay

The cancer cell line for MTT assay was HEC4, a human esophageal cancer cell line. Cancer cells (HEC4) were treated to a size of 8 × 103 cells per well using a 96-well plate, and then incubated at 37 ° C. for 6 hours. Thereafter, 0.2 mg of each compound of NPS1-4, 2 mg of each compound of NPS5-13 in 80 μL of DMSO were treated with 1 μL of each fraction in each well, and then incubated at 37 ° C. for 24 hours. After removing the medium, and washed with 100 μL of PBS buffer. MTT reagent was treated with 40 μL of each well, and then wrapped with silver foil to prevent light from being incubated at 37 ° C. for 3 hours. After removing the MTT solution, DMSO was treated with 100 μL in each well, and then wrapped with silver foil again and incubated at 37 ° C. for 5-10 minutes. Since the ELISA reader was measured at 570 nm and the results are shown in Table 2 and FIG. In FIG. 1, * means that 1/10 of the other amount is used. Unlike NPS 1, which has almost no cancer cell killing effect, NPS 2-NPS 7, NPS10, 11 showed very high cancer cell killing activity and showed cancer cell viability within 10%. Cancer cell viability was shown within 40%.

1 time Episode 2 3rd time 4 times Average control standard (%) STDEV STDEV (%) control 0.234 0.241 0.216 0.241 0.233 100 0.01180 5.06607 NPS1 0.23 0.251 0.253 0.271 0.25125 107.833 0.017 7.202 NPS2 0.019 0.021 0.021 0.019 0.02 8.584 0.001 0.496 NPS3 0.016 0.019 0.015 0.016 0.0165 7.082 0.002 0.743 NPS4 0.022 0.022 0.023 0.02 0.02175 9.335 0.001 0.540 NPS5 0.015 0.017 0.016 0.015 0.01575 6.760 0.001 0.411 NPS6 0.008 0.007 0.007 0.007 0.00725 3.112 0.001 0.215 NPS7 0.011 0.011 0.012 0.01 0.011 4.721 0.001 0.350 NPS8 - - - - ㅡ ㅡ ㅡ ㅡ ㅡ ㅡ ㅡ ㅡ NPS9 0.026 0.021 0.022 0.025 0.0235 10.0858 0.0024 1.0217 NPS10 0.018 0.017 0.017 0.019 0.01775 7.6180 0.0010 0.4109 NPS11 0.014 0.014 0.013 0.013 0.0135 5.7940 0.0006 0.2478 NPS12 0.082 0.09 0.084 0.09 0.0865 37.1245 0.0041 1.7696 NPS13 0.05 0.056 0.043 0.06 0.05225 22.4249 0.0074 3.1805

Since the compound of Formula 1 of the present invention has high cytotoxicity against cancer cells even in a very small amount, it may be used in medical applications such as anticancer agents or antibiotics.

Claims (11)

A composition for the treatment or prophylaxis of cancer comprising the compound represented by Formula 1 and a pharmaceutically acceptable carrier: [Formula 1]

In the above formula X represents oxygen, sulfur, or NH, R ₁ represents hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl or alkoxy; R ₂ and R ₃ each independently represent hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryl or heteroaryl; R _4a and R _4b each independently represent hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, or alkoxy, or R _4a and R _4b together with the carbon atoms on which they are substituted carbon, oxygen and Form a double bond with an atom selected from the group consisting of sulfur or form a heterocycle; R _5a and R _5b each independently represent hydrogen, halo, hydroxy, alkyl, alkenyl, alkynyl, or alkoxy; R _6a and R _6b each independently represent a hydrogen, halo, hydroxy, alkyl, alkenyl, alkynyl, alkoxy or carbonyl group; R _7a and R _7b each independently represent hydrogen, halo, hydroxy, alkyl, alkenyl, alkynyl, or alkoxy; R ₈ represents hydrogen, halo, hydroxy, alkyl, alkenyl, alkynyl, or alkoxy; R _9a and R _9b each independently represent hydrogen, halo, hydroxy, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryl or heteroaryl, or R _9a and R _9b together with the carbon atom to which they are substituted Form a double bond with an atom selected from the group consisting of carbon, oxygen and sulfur or form a heterocycle. The method of claim 1, X represents oxygen or sulfur, R ₁ represents hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, C _1-4 alkyl, C _3-6 cycloalkyl, C _2-4 alkenyl, C _2-4 alkynyl or C _1-4 alkoxy ; R ₂ and R ₃ each independently represent hydrogen, fluorine, chlorine, bromine, iodine, or hydroxy or are selected from the group consisting of halo, hydroxy, amino, C _1-4 alkyl, and C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, aryl or heteroaryl unsubstituted or substituted by one or more substituents; R _4a and R _4b each independently represent hydrogen, fluorine, chlorine, bromine, iodine or hydroxy, or at least one substituent selected from the group consisting of halo, hydroxy, C _1-4 alkyl, and C _1-4 alkoxy Substituted or unsubstituted by C _1-4 alkyl, C _3-6 cycloalkyl, C _2-4 alkenyl, C _2-4 alkynyl or C _1-4 alkoxy, or R _4a and R _4b are To form a double bond with a carbon or oxygen atom with a substituted carbon atom or to form a heterocycle, wherein the carbon atom or heterocycle together with R _4a and R _4b forms a C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and C _1-4 is unsubstituted or substituted by one or more substituents selected from the group consisting of alkoxy; R _5a and R _5b each independently represent hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, or C _1-4 alkoxy ; R _6a and R _6b are hydrogen, F, Cl, Br, I, hydroxy, C _1-4 alkyl, C _{2 -4} alkenyl, C _{2 -4} alkynyl, C _{1 -4} alkoxy, or carbonyl group, each independently Represent; R _7a and R _7b each independently represent hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, or C _1-4 alkoxy ; R ₈ represents hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, or C _1-4 alkoxy; R _9a and R _9b each independently represent hydrogen, fluorine, chlorine, bromine, iodine, or hydroxy or at least one selected from the group consisting of halo, hydroxy, C _1-4 alkyl, and C _1-4 alkoxy C _1-4 alkyl, C _3-6 cycloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, aryl or heteroaryl unsubstituted or substituted by a substituent, or R _9a and R _9b are characterized in that they form a double bond with a carbon or oxygen atom or a heterocycle together with a substituted carbon atom. The method of claim 1, R ₂ represents hydrogen or halo. The method of claim 1, And R _4a and R _4b together with the substituted carbon atoms form a double bond or an heterocycle with an atom selected from the group consisting of carbon, oxygen and sulfur. The method of claim 1, R _5a and R _5b are each independently hydrogen. The method of claim 1, R _6a and R _6b each independently represent a hydrogen, a C _2-4 alkenyl, or a carbonyl group. The method of claim 1, R _9a and R _9b are each independently hydrogen; Hydroxy; Or optionally substituted by halo, hydroxy, C _{1 -4} alkyl, amino and C _{1 -4} alkoxy, or substituted by one or more substituents selected from the group consisting of or represent an unsubstituted aryl or heteroaryl, R _9a and R _9b are they substituted To form a double bond with carbon or an oxygen atom together with the carbon atom. The method of claim 2, X represents oxygen, R ₁ represents hydrogen or C _1-4 alkyl; R ₂ and R ₃ each independently represent hydrogen, fluorine, chlorine, bromine, or iodine or are substituted by one or more substituents selected from the group consisting of halo, hydroxy, C _1-4 alkyl, and C _1-4 alkoxy Substituted or unsubstituted C _1-4 alkyl, aryl or heteroaryl; R _4a and R _4b form a double bond with a carbon atom or an oxygen atom, together with a substituted carbon atom, or form a heterocycle, wherein the carbon atom or hetero with a double bond together with R _4a and R _4b The cycle is unsubstituted or substituted by one or more substituents selected from the group consisting of C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl and C _1-4 alkoxy; R _5a and R _5b each independently represent hydrogen or C _1-4 alkyl; R _6a and R _6b each independently represent hydrogen, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, or carbonyl group; R _7a and R _7b each independently represent hydrogen or C _1-4 alkyl; R ₈ represents hydrogen or C _1-4 alkyl; R _9a and R _9b are each independently hydrogen or hydroxy; Or C _1-4 alkyl, C _3-6 cycloalkyl, C _2-4 unsubstituted or substituted by one or more substituents selected from the group consisting of halo, hydroxy, C _1-4 alkyl, and C _1-4 alkoxy Alkenyl, C _2-4 alkynyl or C _1-4 alkoxy, or aryl, or R _9a and R _9b are characterized in that they form a double bond with a carbon or oxygen atom together with the substituted carbon atom. . The method of claim 8, R ₂ represents hydrogen or iodine, R _4a and R _4b together with the substituted carbon atoms form a double bond with a carbon or oxygen atom or form a heterocycle, R _5a and R _5b each independently represent hydrogen, R _6a and R _6b each independently represent hydrogen, C _{2 -4} alkenyl, or a carbonyl group, R _9a and R _9b are each independently hydrogen; Hydroxy; Or optionally substituted by halo, hydroxy, C _{1 -4} alkyl and C _{1 -4} alkoxy, or substituted by one or more substituents selected from the group consisting of or represents unsubstituted aryl, R _9a and R _9b are they are substituted carbon atoms and A composition comprising forming a double bond with an oxygen atom. The compound of claim 1, 0,1,2a, 5,5a, 6,7,7a-octahydro-1-hydroxy-3-iodo-5- (1,3-dioxolan-2-yl) -indeno [7, 1-bc] furan-6-carboxaldehyde [6]; 5a, 6,7,7a-tetrahydro-1-hydroxy-3-iodo-5- (1,3-dioxolan-2-yl) -6-vinylindeno [7,1-bc] furan -1,5 (0H, 2aH) -on [7]; 5a, 6,7,7a-tetrahydro-3-iodo-5- (1,3-dioxolan-2-yl) -6-vinylindeno [7,1-bc] furan-1 (2aH, 5H) -one [8]; 5a, 6,7,7a-tetrahydro-5- (1,3-dioxolan-2-yl) -6-vinylindeno [7,1-bc] furan-1 (2aH, 5H) -one [ 9]; 0,1,2a, 5,5a, 6,7,7a-octahydro-1- (4-methoxy-3- (methoxymethoxy) phenyl) -5- (1,3-dioxolane-2 -Yl) -6-vinylindeno [7,1-bc] furan-1-ol [10] 5a, 6,7,7a-tetrahydro-1-hydroxy-1- (3-hydroxy-4-methoxyphenyl) -6-vinylindeno [7,1-bc] furan-5 (0H, 1H , 2aH) -one [11]; 5a, 6,7,7a-tetrahydro-1-hydroxy-3-iodo-6-vinylindeno [7,1-bc] furan-1,5 (0H, 2aH) -one [12]; 5a, 6,7,7a-tetrahydro-3-iodo-6-vinylindeno [7,1-bc] furan-1,5 (0H, 2aH) -dione [13]; 5a, 6,7,7a-tetrahydro-6-vinylindeno [7,1-bc] furan-1,5 (0H, 2aH) -dione [14]; 5a, 6,7,7a-tetrahydro-5-methylene-6-vinylindeno [7,1-bc] furan-1 (2aH, 5H) -one [15]; 0,1,2a, 5,5a, 6,7,7a-octahydro-1- (4-methoxy-3- (methoxymethoxy) phenyl) -5-methylene-6-vinylindeno [7, 1-bc] furan-1-ol [16]; or 0,1,2a, 5,5a, 6,7,7a-octahydro-5- (1,3-dioxolan-2-yl) -6-vinylindeno [7,1-bc] furan-1 A composition, which is -all [17]. The method of claim 10, wherein the compound of Formula 1, 0,1,2a, 5,5a, 6,7,7a-octahydro-1-hydroxy-3-iodo-5- (1,3-dioxolan-2-yl) -indeno [7, 1-bc] furan-6-carboxaldehyde [6]; 5a, 6,7,7a-tetrahydro-3-iodo-5- (1,3-dioxolan-2-yl) -6-vinylindeno [7,1-bc] furan-1 (2aH, 5H) -one [8]; 5a, 6,7,7a-tetrahydro-5- (1,3-dioxolan-2-yl) -6-vinylindeno [7,1-bc] furan-1 (2aH, 5H) -one [ 9]; 5a, 6,7,7a-tetrahydro-1-hydroxy-1- (3-hydroxy-4-methoxyphenyl) -6-vinylindeno [7,1-bc] furan-5 (0H, 1H , 2aH) -one [11]; 5a, 6,7,7a-tetrahydro-1-hydroxy-3-iodo-6-vinylindeno [7,1-bc] furan-1,5 (0H, 2aH) -one [12]; 5a, 6,7,7a-tetrahydro-3-iodo-6-vinylindeno [7,1-bc] furan-1,5 (0H, 2aH) -dione [13]; 5a, 6,7,7a-tetrahydro-6-vinylindeno [7,1-bc] furan-1,5 (0H, 2aH) -dione [14]; or 0,1,2a, 5,5a, 6,7,7a-octahydro-1- (4-methoxy-3- (methoxymethoxy) phenyl) -5-methylene-6-vinylindeno [7, 1-bc] furan-1-ol [16].

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