KR20140141904A - New psammapline A derivatives as anticancer agent, and pharamcetuical compositions containing the same - Google Patents

Abstract

The present invention relates to: a novel compound, which has an effect of inhibiting growth of cancer cells and is represented by chemical formula or a salt thereof. More specifically, the present invention provides a novel compound for which psammaplin A is a lead material, and a pharmaceutically accepted salt thereof. The novel compound can be expected to be applied for cancer treatment.

Description

TECHNICAL FIELD [0001] The present invention relates to a samaflirin A derivative having novel anticancer activity and a pharmaceutical composition containing the same,

The present invention relates to a novel samaplirin A derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and the like, which have an effect of inhibiting the growth of human cancer cells.

(1987) Tetrahedron Lett. 28:3229 / Rodriguez AD et al., (1987) Tetrahedron Lett. 28:4989 / Arabshahi LJ et al., (1987) Org Chem. 52:3584). 사마필린A 는 항균작용(Kim D et al., (1999) Arch Pharm Res. 22:25), 백혈병 세포주 P388의 성장억제작용

(1987) Tetrahedron Lett. 28:3229 / Jung J et al., (1995) J Nat Prod. 58:1722), DNA 토포이소머라제 억제효과(Kim D et al., (1999) Anticancer Res. 19:4085), 히스톤 디아세틸라제 억제효과

(2003) J Org Chem. 38:3688), DNA 기라제 억제효과(Kim D et al., (1999) Arch Pharm Res. 22:25), 파네실 효소 전이제 억제효과(Shin J et al., (2000) Tetrahedron. 56:9071), 루이신 아미노펩티다제 억제효과(Shin J et al., (2000) Tetrahedron. 56:9071), PPAR-감마 활성효과(Mora FD et al., (2006) J Nat Prod. 69:547), 그리고 유방암세포의 성장억제 효과(Mora FD et al., (2006) J Nat Prod. 69:547)가 있는 것으로 보고되어 있다. 최근 서울대학교 약학대학의 신종헌 교수 연구팀은 한반도 남해안에 서식하고 있는 해면동물로부터 사마필린A 를 분리하는데 성공하였고, 사마필린A 의 테트라 메틸화된 유도체가 사마필린A 자체보다 높은 암세포의 성장억제 효과를 나타낸다는 것을 보고하였다. 이는 사마필린A 의 구조변환을 통하여 효능이 우수한 항암제를 개발할 수 있다는 것을 시사한다. 사마필린A 유도체에 대해서는 MRSA항균 효능에 대한 구조활성 연구가 보고되었다(Nicolaou, KC et al., (2001) Chem Eur J. 7:4280 / Nicolaou, KC et al., (2001) Chem Eur J. 7:4296).
Psammapline A (Psammapline A) is a marine natural product whose structure has been separated and separated by three different research groups in 1987, and has a polymer structure in which a monomer having bromothyrosine structure is linked by a disulfide structure

(1987) Tetrahedron Lett. 28: 3229 / Rodriguez AD et al., (1987) Tetrahedron Lett. 28: 4989 / Arabshahi LJ et al., (1987) Org Chem. 52: 3584). Samapillin A is an antimicrobial activity (Kim D et al., (1999) Arch Pharm Res. 22:25), growth inhibitory effect of leukemia cell line P388

(1987) Tetrahedron Lett. 28: 3229 / Jung J et al., (1995) J Nat Prod. 58: 1722), DNA topoisomerase inhibitory effect (Kim D et al., (1999) Anticancer Res. 19: 4085), histone deacetylase inhibitory effect

(2003) J Org Chem. (1999) Arch Pharm Res. 22:25), panesyltransferase inhibitory effect (Shin J et al., (2000) Tetrahedron. 56: (Tetrahedron. 56: 9071), PPAR-gamma activity (Mora FD et al., (2006) J Nat Prod. 69: 547 ), And breast cancer cell growth inhibitory effects (Mora FD et al., (2006) J Nat Prod. 69: 547). Recently, a team of Professor Shin Jong-Heon of the College of Pharmacy at Seoul National University succeeded in isolating samaplirin A from sponges inhabiting the southern coast of the Korean Peninsula, and the tetramethylated derivatives of samapylline A showed higher growth inhibitory effects on cancer cells than samaplirin A itself . This suggests that it is possible to develop an anticancer agent having excellent efficacy through the structural transformation of samaplirin A. (2001) Chem Eur J. 7: 4280 / Nicolaou, KC et al., (2001) Chem Eur. J. et al. 7: 4296).

The inventors of the present invention synthesized novel compounds showing the effect of inhibiting the growth of various human cancer cells as a result of carrying out a structural activity study using existing samafillin A as a lead substance in order to develop a substance having anticancer activity. Therefore, an object of the present invention is to provide a novel antitumor agent by synthesizing a novel samaplirin A derivative showing growth inhibitory effect on a cancer cell line.

However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.

(1) A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

                     [I]

In the above formula (I)

,X is hydrogen or an alkyl group having 1 to 5 carbon atoms,

,

1-naphthyl, 2-naphthyl, 9-anthracenyl group; X is

, R _{1 to} R ₅ each independently represent a hydrogen atom, a nitro group, a halogen atom, a cyano group, a hydroxy group, a dimethylamino group, a methylsulfonylamide group, a trifluoromethyl group, an alkyl group having 1 to 3 carbon atoms, An alkoxy group, a vinyl group, an aryl group, a phenoxy group or an alkoxy group, R ₃ and R ₄ may combine to form a 5-7 membered ring,

Y is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a vinyl, an aryl group, an allyl group,

An alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom, a trifluoromethyl group or a t-butyl group when the aromatic ring is a phenoxy group or a benzyl group, Group may be substituted.

(2) The method according to (1)

When any one of R _{1 to} R ₅ is a phenoxy group or an alkoxy group, the aromatic ring may be substituted with an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom, a trifluoromethyl group, Butyl group or a pharmaceutically acceptable salt thereof.

(3) The method according to (1)

Further, the R ₃ and R ₄ are united by allowing 5 to a compound or chemical agent in its 7 may form a ring of the original salts.

(4) A cancer cell growth inhibitor comprising a compound according to any one of (1) to (3) or a pharmaceutically acceptable salt thereof as an active ingredient.

(5) A pharmaceutical composition for chemotherapeutic treatment comprising a pharmaceutically effective amount of a compound according to any one of (1) to (3), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

(6) A method for treating cancer diseases, comprising administering to a subject a pharmaceutical composition according to (5).

The compounds according to the present invention are anticipated to have anticancer effects by inhibiting the growth of cancer cells.

The present invention is to provide a novel samaplirin A derivative compound having an anticancer activity or a pharmaceutically acceptable salt thereof. Specifically, it is intended to provide an anticancer agent which induces growth inhibition of human cancer cells through the novel compound or a pharmaceutically acceptable salt thereof. The present invention also provides a pharmaceutical composition for treating cancer comprising a novel compound having anticancer activity, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present invention also provides a method for treating cancer diseases, comprising administering the pharmaceutical composition to a subject.

The novel samaplirin A derivative compound having anticancer activity is a derivative having the existing samapylline A as a lead substance and can be represented by the following formula (I).

(I)

In the above formula (I)

, X is hydrogen or an alkyl group having 1 to 5 carbon atoms

,

1-naphthyl, 2-naphthyl, 9-anthracenyl group; X is

R _{1 to} R ₅ each independently represent a hydrogen atom, a nitro group, a halogen atom, a cyano group, a hydroxy group, a dimethylamino group, a methylsulfonylamide group, a trifluoromethyl group, an alkyl group having 1 to 3 carbon atoms, An alkoxy group, a vinyl group, an aryl group, a phenoxy group or an alkoxy group, R ₃ and R ₄ may combine to form a 5-7 membered ring,

Y is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a vinyl group, an aryl group, an allyl group, a phenyl group, a phenoxy group, a benzyl group or a benzyl group, An alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom, a trifluoromethyl group or a t-butyl group.

When any one of R _{1 to} R ₅ is a phenoxy group or an alkoxy group, the aromatic ring may have an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom,

A methyl group or a t-butyl group may be substituted.

In addition, R ₃ and R ₄ may be connected to each other through a substituent group as described above.

Also, R ₂ to R ₅ may be simultaneously substituted with the same or different substituents.

The chemical structures of exemplary samapyrin derivative compounds of the present invention are shown in Table 1 below

The novel compounds of the present invention can be chemically synthesized by the methods shown in the following reaction schemes. However, this is for illustrative purposes only, and the present invention is not limited thereto.

[Reaction Scheme 1]

The general synthesis of compounds in the scope of formula (I) is as follows (Scheme 1) (Hong S et al., (2012) Tetrhedron Lett. 53: 4209). Substituted aryl aldehyde type substrate is condensed with ethyl acetoacetate (2) in a benzene solvent in which piperidine and acetic acid catalyst are present to synthesize alpha, beta -unsaturated ethylacetoacetate (3).

R is hydrogen or an alkyl group having 1 to 5 carbon atoms, 1-naphthyl, 2-naphthyl or 9-anthracenyl group in the above formula (I); When X is phenyl, R ₁ -R ₅ is a hydrogen atom, a nitro group, a halogen atom, a cyano group, a hydroxyl group, a dimethylamino group, a methylsulfonylamide group, a trifluoromethyl group, an alkyl group having 1 to 3 carbon atoms, An alkoxy group, a vinyl group, an aryl group, a phenoxy group, or a benzyl group.

Compound 3 was reacted with tributyltin hydride in a toluene solvent to synthesize ethyl acetoacetate (4) substituted at the alpha position. Then, butyl nitrite is added to compound 4 in the presence of an ethanolic ethoxide base to synthesize an oxime compound 5. Compound 5 was reacted with dihydropyrane in the presence of a p-toluenesulfonic acid catalyst to obtain Compound 6, which was then hydrolyzed with an aqueous 1N-KOH solution in an ethanol solvent to synthesize Compound 7. Compound 7 is then condensed with N-hydroxysuccinimide in dioxane solvent to synthesize compound 8. Compound 9 is prepared by reacting the synthesized compound 8 with cystamine in the presence of triethylamine base, followed by hydrolysis reaction using a 1 M-HCl ether solution as an acid catalyst to synthesize the samapylline A derivative 10. In the case of the compound 11 in which the oxime moiety is substituted, the compound 10 is synthesized by adding diazomethane, an alkyl halide, or the like under basic conditions.

The present invention provides an anticancer agent through a novel compound of formula (I) or a pharmaceutically acceptable salt thereof having anticancer activity.

The present invention also provides a pharmaceutical composition for the treatment of cancer, comprising a novel compound of formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and an adjuvant or diluent having anticancer activity. The pharmaceutical composition according to the present invention is expected to be effective for cancer treatment.

The pharmaceutical dosage forms of the compounds of the present invention may also be used in the form of their pharmaceutically acceptable salts and may be used alone or in combination with other pharmaceutically active compounds as well as in a suitable set. Salts of the compounds of the present invention are preferably pharmaceutically acceptable salts and may be prepared by presently known methods such as adding an inorganic base, an organic base, an inorganic acid, an organic acid, a basic or acidic amino acid to a compound according to the present invention .

The pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may include, but is not limited to, physiological saline, polyethylene glycol, ethanol, vegetable oil, and isopropyl myristate.

The compounds of the present invention may be formulated into ointments or creams for topical application and may be formulated in conventional aqueous vehicles such as saline, a water-soluble solvent such as 5% dextrose or a non-aqueous solvent such as vegetable oils, synthetic fatty acid glycerides, higher fatty acid esters or propylene glycol The compound may be dissolved, suspended or emulsified to formulate an injection. Formulations of the present invention may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.

The preferred dosage of the compound of the present invention varies depending on the condition and the weight of the patient, the degree of disease, the type of drug, the route of administration and the period of time, but can be appropriately selected by those skilled in the art. Preferably, however, the compound of the present invention is administered at a daily dose of 0.001 to 100 mg / kg body weight, more preferably 0.01 to 30 mg / kg body weight. The administration can be carried out once a day or divided into several times. In the pharmaceutical composition, the compound of the present invention should be present in an amount of 0.0001 to 10% by weight, preferably 0.001 to 1% by weight, based on the total weight of the total composition.

The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, humans, and the like in various routes. The method of administration is not limited and can be administered, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intramural or intracerbroventricular injection.

In the experimental examples of the present invention, SM-3, SM-7, SM-18 and SM-20 compounds are expected to inhibit the growth of colorectal cancer and lung cancer cells and be applicable to the treatment of cancer diseases. (See Example 25).

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.

[ Example ]

Example  1. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (2-( hydroxyimino ) -3- 페닐propamide ) ( SM -1) Manufacturing method

According to the method of Scheme 1, SM-1 was obtained using benzaldehyde as a starting material. (Total yield: 21%).

^{1 H-NMR (300MHz, CD} 3 OD): δ = 7.26-7.09 (m, 10H), 3.90 (s, 4H), 3.49 (t, J = 6.6Hz, 4H), 2.77 (t, J = 6.78Hz , 4 H) ppm

Example  2. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (2-( hydroxyimino ) -3- (p-tolyl) propanamide) ( SM -2) Manufacturing method

According to the method of Scheme 1 above, SM-2 was obtained using 4-methylbenzaldehyde as a starting material. (Total yield: 24%).

¹ H-NMR (300 MHz, CD ₃ OD):? = 7.06 (dd, _{J 1 = 36.35Hz, J 2 =} 8.04Hz, 8H), 3.85 (s, 4H), 3.47 (t, J = 6.57Hz, 4H), 2.76 (t, J = 6.78Hz, 4H), 2.23 (s, 6H) ppm

Example  3. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (3- (4- ( tert - butyl ) phenyl ) -2- (hydroxyimino) propanamide) ( SM -3) Manufacturing method

According to the method of Scheme 1 above, SM-3 was obtained using 4-tert-butylbenzaldehyde as a starting material. (Total yield: 28%).

^{1 H-NMR (300MHz, CD} 3 OD): δ = 7.25 ~ 7.15 (m, 8H), 3.86 (s, 4H), 3.47 (t, J = 6.6Hz, 4H), 2.76 (t, J = 6.96Hz , 4H), 1.25 (s, 18H) ppm

Example  4. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (3- (4- fluorophenyl ) -2- (hydroxyimino) propanamide) ( SM -4) Manufacturing method

4-fluorobenzaldehyde was used as a starting material according to the method of Scheme 1 to obtain SM-4. (Total yield: 12%).

^{1 H-NMR (300MHz, CD} 3 OD): δ = 7.29 ~ 7.24 (m, 4H), 6.96 ~ 6.88 (m, 4H), 3.87 (s, 4H), 3.50 (t, J = 6.6Hz, 4H) , 2.79 (t, J = 6.96 Hz, 4 H) ppm

Example  5. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (3- (4- klorophenyl ) -2- (hydroxyimino) propanamide) ( SM -5) Manufacturing method

According to the method of Scheme 1 above, SM-5 was obtained using 4-chlorobenzaldehyde as a starting material. (Total yield: 27%).

^{1 H-NMR (300MHz, CD} 3 OD): δ = 7.23 ~ 7.15 (m, 8H), 3.87 (s, 4H), 3.49 (s, 4H), 2.75 (s, 4H), ppm

Example  6. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (3- (4- bromophenyl ) -2- (hydroxyimino) propanamide) ( SM -6) Manufacturing method

According to the method of Scheme 1, SM-6 was obtained using 4-bromobenzaldehyde as a starting material. (Total yield: 15%).

^{1 H-NMR (300MHz, CD} 3 OD): δ = 7.37 ~ 7.33 (m, 4H), 7.20 ~ 7.16 (m, 4H), 3.86 (s, 4H), 3.50 (t, J = 6.75Hz, 4H) , 2.78 (t, J = 6.96 Hz, 4 H) ppm

Example  7. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (3- (3,4- dichlorophenyl ) -2- (hydroxyimino) propanamide) ( SM -7) Production method

SM-7 was obtained by using 3,4-dichlorobenzaldehyde as a starting material according to the method of Reaction Scheme 1 above. (Total yield: 22%).

^{1 H-NMR (300MHz, CD} 3 OD): δ = 7.40 (d, J = 2.01Hz, 2H), 7.35 ~ 7.32 (m, 2H), 7.21 ~ 7.16 (m, 2H), 3.87 (s, 4H) , 3.51 (t, J = 6.78 Hz, 4H), 2.80 (t, J = 6.75 Hz, 4 H) ppm

Example  8. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (3- (3,5- dichlorophenyl ) -2- (hydroxyimino) propanamide) ( SM -8) Manufacturing method

According to the method of Scheme 1 above, SM-8 was obtained using 3,5-dichlorobenzaldehyde as a starting material. (Total yield: 19%).

^{1 H-NMR (300MHz, CD} 3 OD): δ = 7.17 ~ 7.08 (m, 6H), 3.78 (s, 4H), 3.43 (t, J = 6.78Hz, 4H), 2.73 (t, J = 6.78Hz , 4 H) ppm

Example  9. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (2-( hydroxyimino ) -3- (2,3,5-trichlorophenyl) propanamide) ( SM -9) Manufacturing method

SM-9 was obtained by using 2,3,5-trichlorobenzaldehyde as a starting material according to the method of Scheme 1 above. (Total yield: 20%).

^{1 H-NMR (400MHz, CD} 3 OD): δ = 7.42 (d, J = 2.44Hz, 2H), 7.05 (d, J = 2.36Hz, 2H), 4.01 (s, 4H), 3.55 (t, J = 6.64 Hz, 4H), 2.85 (t, J = 6.72 Hz, 4 H) ppm

Example  10. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (2-( hydroxyimino ) -3- (4-nitrophenyl) propanamide) ( SM -10) Manufacturing method

According to the method of Scheme 1, SM-10 was obtained using 4-nitrobenzaldehyde as a starting material. (Total yield: 24%).

^{1 H-NMR (300MHz, CD} 3 OD): δ = 8.10 ~ 8.06 (m, 4H), 7.51 ~ 7.44 (m, 4H), 4.01 (s, 4H), 3.51 (t, J = 6.6Hz, 4H) , 2.81 (t, J = 6.78 Hz, 4 H) ppm

Example  11. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (2-( hydroxyimino ) -3- (4-methoxyphenyl) propanamide) ( SM -11) Manufacturing method

According to the method of Scheme 1 above, SM-11 was obtained using 4-methoxybenzaldehyde as a starting material. (Total yield: 24%).

^{1 H-NMR (300MHz, CD} 3 OD): δ = 7.19 ~ 7.14 (m, 4H), 6.77 ~ 6.73 (m, 4H), 3.82 (s, 4H), 3.70 (s, 6H), 3.48 (t, J = 6.75 Hz, 4H), 2.76 (t, J = 6.75 Hz, 4 H) ppm

Example  12. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (3- (4- ethoxyphenyl ) -2- (hydroxyimino) propanamide) ( SM -12) Manufacturing method

According to the method of Scheme 1 above, SM-12 was obtained using 4-ethoxybenzaldehyde as a starting material. (Total yield: 21%).

^{1 H-NMR (300MHz, DMSO} -d 6): δ = 11.79 (s, 2H), 8.04 (t, J = 5.7Hz, 2H), 6.95 (dd, J 1 = 94.95Hz, J 2 = 8.4Hz, 8H), 3.94 (q, J = 7.2Hz, 4H), 3.73 (s, 4H), 3.41 (q, J = 6.6Hz, 4H), 2.81 (t, J = 7.2Hz, 4H) ppm

Example  13. ((2E, 2'E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (2-( hydroxyimino ) -3- (4-propoxyphenyl) propanamide) ( SM -13) Manufacturing method

According to the method of Scheme 1 above, SM-13 was obtained using 4-propoxybenzaldehyde as a starting material. (Total yield: 20%).

^{1 H-NMR (300MHz, DMSO} -d 6): δ = 11.78 (s, 2H), 8.04 (t, J = 5.7Hz, 2H), 6.95 (dd, J 1 = 93.3Hz, J 2 = 8.4Hz, 8H), 3.85 (t, J = 6.6Hz, 4H), 3.73 (s, 4H), 3.41 (q, J = 6.6Hz, 4H), 2.81 (t, J = 7.2Hz, 4H), 1.68 (sextet, J = 6.6 Hz, 4H), 0.94 (t, J = 7.5 Hz, 6 H) ppm

Example  14. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (3- (4- butoxyphenyl ) -2- (hydroxyimino) propanamide) ( SM -14) Manufacturing method

According to the method of Scheme 1 above, SM-14 was obtained using 4-butoxybenzaldehyde as a starting material. (Total yield: 24%).

^{1 H-NMR (300MHz, DMSO} -d 6): δ = 11.78 (s, 2H), 8.04 (t, J = 5.7Hz, 2H), 6.95 (dd, J 1 = 93Hz, J 2 = 8.4Hz, 8H ), 3.89 (t, J = 6.6Hz, 4H), 3.73 (s, 4H), 3.41 (q, J = 6.6Hz, 4H), 2.81 (t, J = 7.2Hz, 4H), 1.65 (quintet, J = 6.3Hz, 4H), 1.40 (sextet, J = 7.5Hz, 4H), 0.91 (t, J = 7.8Hz, 6H) ppm

Example  15. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (3- (4- ( cyclopentyloxy ) phenyl ) -2- (hydroxyimino) propanamide) ( SM -15) Manufacturing method

According to the method of Scheme 1 above, SM-15 was obtained using 4-cyclopentoxybenzaldehyde as a starting material. (Total yield: 22%).

^{1 H-NMR (300MHz, DMSO} -d 6): δ = 11.78 (s, 2H), 8.04 (t, J = 5.7Hz, 2H), 6.92 (dd, J 1 = 99.15Hz, J 2 = 8.4Hz, 8H), 4.72 (t, J = 6Hz, 4H), 3.72 (s, 4H), 3.41 (q, J = 6.6Hz, 4H), 2.81 (t, J = 7.2Hz, 4H), 1.88 ~ 1.82 (m , 4H), 1.67-1.50 (m, 12H) ppm

Example  16. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (2-( hydroxyimino ) -3- (4-phenoxyphenyl) propanamide) ( SM -17) Manufacturing method

According to the method of Scheme 1, SM-16 was obtained using 4-phenoxybenzaldehyde as a starting material. (Total yield: 16%).

^{1 H-NMR (300MHz, CD} 3 OD): δ = 7.31 ~ 7.22 (m, 8H), 7.07 ~ 7.01 (m, 2H), 6.92 ~ 6.88 (m, 4H), 6.84 ~ 6.80 (m, 4H), 4.88 (s, 4H), 3.51 (t, J = 6.57 Hz, 4H), 2.80 (t, J = 6.75 Hz,

Example  17. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (3- (4- ( benzyloxy ) phenyl ) -2- (hydroxyimino) propanamide) ( SM -18) Manufacturing method

According to the method of Scheme 1, 4-benzoxybenzaldehyde was used as a starting material to obtain SM-17. (Total yield: 20%).

^{1 H-NMR (300MHz, CD} 3 COCD 3): δ = 10.97 (s, 2H), 7.55 (t, J = 5.7Hz, 2H), 7.42 ~ 7.17 (m, 14H), 6.86 ~ 6.81 (m, 4H J = 6.6 Hz, 4H), 2.82 (t, J = 6.9 Hz, 4H), 5.01 (s, 4H), 3.81

Example  18. (2E, 2'E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (3- (4- ( benzyloxy ) -3- klorophenyl ) -2- (hydroxyimino) propanamide) ( SM -19) Manufacturing method

According to the method of Scheme 1 above, SM-18 was obtained using 3-chloro-4-benzoxybenzaldehyde as a starting material. (Total yield: 16%).

^{1 H-NMR (300MHz, CDCl} 3): δ = 10.14 (s, 2H), 7.30 ~ 7.01 (m, 14H), 6.72 ~ 6.65 (m, 2H), 4.89 (s, 4H), 3.75 (s, 4H ), 3.42 (s, 4 H), 2.57 (s, 4 H) ppm

Example  19. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (2-( hydroxyimino ) -3- (naphthalen-2-yl) propanamide) ( SM -20) Manufacturing method

According to the method of Scheme 1, 2-naphthylaldehyde was used as a starting material to obtain SM-19. (Total yield: 32%).

^{1 H-NMR (300MHz, CD} 3 OD): δ = 7.73-7.67 (m, 8H), 7.42-7.30 (m, 6H), 4.07 (s, 4H), 3.41 (q, J = 6.39Hz, 4H) , 2.70 (t, J = 6.78 Hz, 4 H) ppm

Example  20 (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (2-( hydroxyimino ) -3- (naphthalen-1-yl) propanamide) ( SM -21) Manufacturing method

According to the method of Scheme 1 above, 1-naphthylaldehyde was used as a starting material to obtain SM-20. (Total yield: 28%).

^{1 H-NMR (300MHz, CD} 3 OD): δ = 8.08 (d, J = 8.04Hz, 2H), 7.69 (d, J = 7.68Hz, 2H), 7.56 (dd, J 1 = 7.32Hz, J 2 = 1.83Hz, 2H), 7.40 ~ 7.29 (m, 4H), 7.23 ~ 7.15 (m, 4H), 4.24 (s, 4H), 3.30 (t, J = 6.78Hz, 4H), 2.57 (t, J = 6.78 Hz, 4 H) ppm

Example  21. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (3- (anthracen-9-yl) -2- (hydroxyimino) propanamide) ( SM -22) Manufacturing method

SM-21 was obtained by using 9-anthracenylaldehyde as a starting material according to the method of Scheme 1 above. (Total yield: 23%).

^{1 H-NMR (300MHz, pyridine} -d 5): δ = 14.41 (s, 2H), 8.98 (d, J = 8.79Hz, 4H), 8.82 (t, J = 5.67Hz, 2H), 8.42 (s, 2H), 8.01 (d, J = 8.4Hz, 4H), 7.60 ~ 7.53 (m, 4H), 7.46 ~ 7.41 (m, 4H), 5.34 (s, 4H), 3.36 (q, J = 6.24Hz, 4H ), 2.50 (t, J = 6.39 Hz, 4 H) ppm

Example  22. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (3- (4- ( benzyloxy ) phenyl ) -2- (methoxyimino) propanamide) ( SM -23) Manufacturing method

SM-17 was obtained by using 4-benzoxybenzaldehyde as a starting material according to the method of Reaction Scheme 1, and excess diazomethane was then reacted with toluene-ethanol (5: 2) solvent to obtain SM-22. (Total yield: 12%).

^{1 H-NMR (300MHz, CDCl} 3): δ = 7.34 ~ 7.20 (m, 10H), 7.13 (d, J = 8.58Hz, 4H), 6.98 (t, J = 5.85Hz, 2H), 6.78 (d, J = 8.61Hz, 4H), 4.92 (s, 4H), 3.90 (s, 6H), 3.76 (s, 4H), 3.52 (q, J = 6.21Hz, 4H), 2.71 (t, J = 6.39Hz, 4H) ppm

Example  23. (2E, 2 ' E) -N, N ' - ( disulfanediylbis ( ethane -2,1- diyl )) bis (2- (methoxyimino) -3- (4-methoxyphenyl) propanamide) ( SM -24) Production method

SM-11 was obtained by using 4-methoxybenzylamine as a starting material in the same manner as in Example 1, and then excess diazomethane was allowed to react in a toluene-ethanol (5: 2) solvent to obtain SM-23 . (Total yield: 8%).

^{1 H-NMR (300MHz, CDCl} 3): δ = 7.19, 6.72 ~ 6.65 (d, J = 8.61Hz, 4H), 7.04 (t, J = 6.06Hz, 2H), 6.79 ~ 6.74 (m, 4H) ( m, 2H), 3.96 (s , 6H), 3.82 (s, 4H), 3.73 (s, 6H), 3.58 (q, J = 6.21Hz, 4H), 2.78 (t, J = 6.42Hz, 4H) ppm

Example  25. Samapillin A person in vitro of a derivative compound With lung cancer  Measurement of Growth Inhibitory Effect on Colon Cancer Cell Lines

    In order to confirm the growth inhibitory effect of the samples obtained in Examples 1-24 on human lung cancer and colon cancer cell lines in vitro, experiments were conducted as described below by applying the methods described in the literature. (Lee SK et al (2008) Chem Biol Interact 115: 215-28). The human lung cancer cell line A549 and the colon cancer cell line HCT116 were distributed from the American Cell Line Bank (ATCC, Manassas, VA, USA).

A549 and HCT116 cells were incubated with 10% fetal bovine serum (FBS, 100 units / mL penicillin, 100 μg / mL streptomycin and 250 ng / mL amphotericin ratio 1 to 2 times per week at 37 ° C, 5% CO ₂ , using a Roswell Park Memorial Institute (RPMI) medium 1640, RPMI 1640) containing amphotericin B All cells were lysed from liquid nitrogen and then used in the experiment after passage over 3 times.

The effects of the compounds obtained in Examples 1 and 2 on cell growth were determined by sulforhodamine B (SRB) method (Lee et al (1998) Chemico-Biol Interact 115: 215-228).

In detail, the lung cancer and colon cancer cell lines used in the present invention were subcultured in RPMI medium containing 10% FBS, 1% PSF, etc., and 10 μl of a sample dissolved in 10% DMSO in each well of a 96- 190 μl (5 × 10 ⁴ cells / ml) of the cell suspension was added and cultured for 3 days. 190 μl of the cell suspension was added to at least 16 wells and incubated for 30 minutes, and used as a zero-day control before the experiment. The cultured cells were fixed with 10% TCA (trichloroacetic acid), stained with SRB solution, dissolved in 10 mM Tris-base, and then absorbed at 515 nm. 10% DMSO was used as a control, and the cell survival rate according to the treatment of each test substance was measured using the following equation (1).

[Equation 1]

% Survival rate = (OD (0-day)) / (OD (10% DMSO) -OD (0-day)) X 100

When the control group without the sample was taken as 100%, the value of the sample treatment group was expressed as a percentage of the control group, and the treatment of each test substance was calculated by the mean value ± SEM of the double or triple test. The IC ₅₀ value is the concentration of the test substance relative to the 50% survival rate. The effects of the compounds obtained in Examples 1 and 2 on lung cancer and colon cancer cell lines are shown in Table 2.

As shown in Table 2, SM-3, SM-7, SM-12, SM-17, SM-18 and SM-19 among samapillin A derivatives And exhibited inhibitory activity equivalent to that of the control compound ellipticine.

compound A549-LC ₅₀ (mM) HCT166-LC ₅₀ (mM) Ellipticine 2.38 0.91 Samapillin A 4.56 6.54 SM-1 6.55 6.22 SM-2 6.09 5.63 SM-3 1.78 1.67 SM-4 3.50 3.78 SM-5 2.58 2.03 SM-6 5.89 7.24 SM-7 1.60 1.46 SM-8 2.28 2.11 SM-9 5.09 4.24 SM-10 2.66 1.80 SM-11 2.81 4.39 SM-12 1.37 1.61 SM-13 13.48 15.54 SM-14 41.13 23.75 SM-15 1.40 5.34 SM-16 > 100 20.35 SM-17 1.12 1.57 SM-18 1.63 1.07 SM-19 1.20 1.30 SM-20 > 100 > 100 SM-21 > 100 > 100 SM-22 > 100 > 100 SM-23 > 100 > 100

Claims (6)

A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof:

[I]
In the above formula (I)
X is hydrogen or an alkyl group having 1 to 5 carbon atoms,

,
1-naphthyl, 2-naphthyl, 9-anthracenyl group; X is

, R _{1 to} R ₅ each independently represent a hydrogen atom, a nitro group, a halogen atom, a cyano group, a hydroxy group, a dimethylamino group, a methylsulfonylamide group, a trifluoromethyl group, an alkyl group having 1 to 3 carbon atoms, An alkoxy group, a vinyl group, an aryl group, a phenoxy group or an alkoxy group, R ₃ and R ₄ may combine to form a 5-7 membered ring,
Y is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a vinyl, an aryl group, an allyl group,
An alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom, a trifluoromethyl group or a t-butyl group when the aromatic ring is a phenoxy group or a benzyl group, Group may be substituted.
The method according to claim 1,
When any one of R _{1 to} R ₅ is a phenoxy group or an alkoxy group, the aromatic ring may be substituted with an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a halogen atom, a trifluoromethyl group, Butyl group or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
Further, the R ₃ and R ₄ are united by allowing 5 to a compound or chemical agent in its 7 may form a ring of the original salts.
A cancer cell growth inhibitor comprising the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.
A pharmaceutical composition for the treatment of chemotherapy comprising a pharmaceutical effective amount of a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
A method for treating cancer diseases, comprising administering to a subject a pharmaceutical composition according to claim 5.