KR101459195B1 - 4-nitroalkyl chroman derivatives having anticancer activity, method for preparing same and pharmaceutical composition containing same - Google Patents

Abstract

(화학식 1에서, R은 수소 또는 탄소수 1 내지 20의 알킬기이고, X는 수소, 메틸기, 메톡시기, 니트로기 또는 할로젠기이다.)A chroman derivative, an enantiomer thereof or a pharmaceutically acceptable salt thereof capable of inhibiting the proliferation of tumor cells and a process for producing the same are disclosed. The present invention provides a 4-nitroalkylchroman derivative represented by the following formula (1), an enantiomer thereof, or a pharmaceutically acceptable salt thereof.
[Chemical Formula 1]

(Wherein R is hydrogen or an alkyl group having 1 to 20 carbon atoms, and X is hydrogen, a methyl group, a methoxy group, a nitro group or a halogen group)

Description

TECHNICAL FIELD The present invention relates to a 4-nitroalkylchroman derivative having an anticancer activity, a method for producing the same, and a pharmaceutical composition comprising the 4-nitroalkylchroman derivative having anticancer activity,

More particularly, the present invention relates to a chroman derivative, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, which can effectively inhibit cancer progression, ≪ / RTI >

The present invention is derived from the research conducted with the support of the general researcher support project funded by the government (Ministry of Education, Science and Technology)

[Assignment number: 2011-0005371, Research title: Study on the method of selective synthesis of aromatic heterocyclic compounds using organic catalysts]

Chroman or dihydrobenzopyran is widely found in many biologically active natural products. Molecules containing these chroman functional groups not only exhibit a wide range of biological activities such as antiviral, antitumor, antimicrobial, sex pheromone and central nervous system activities, but also as biodegradable pesticides and photo-active substances Reference: (a) Ellis, GP; Lockhart, IM The Chemistry of Heterocyclic Compounds , Chromenes , Chromanones, and Chromones ; Ellis, GP, Ed .; Wiley-VCH; New York, 2007; Vol. 31, pp. 1-1196. (b) Geen, GR; Evans, JM; Vong, AK Comprehensive Heterocyclic Chemistry II : Pyrans and their Benzo Derivatives : Applications ; Katritzky, AR; Rees, CW; Scriven, EFV, Eds .; Pergamon Press, Oxford, UK, 1996; Vol. 5, pp. 469-500. (c) Horton, DA; Boume, GT; Smythe, ML Chem . Rev. 2003, 103 , 893-930).

Under such circumstances, the inventors of the present invention have found that certain chroman derivatives have a very strong cell proliferation inhibitory ability and have completed the present invention by confirming that they can be used as anticancer drugs.

It is an object of the present invention to provide a chroman derivative, an enantiomer thereof or a pharmaceutically acceptable salt thereof capable of inhibiting the proliferation of tumor cells and a method for producing the same.

Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer diseases and cancer diseases, which comprises a chroman derivative capable of inhibiting proliferation of tumor cells, an enantiomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient And to provide an anticancer pharmaceutical composition containing the same.

In order to solve the above problems, the present invention provides a 4-nitroalkylchroman derivative represented by the following formula (1), an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

(Wherein R is hydrogen or an alkyl group having 1 to 20 carbon atoms, and X is hydrogen, a methyl group, a methoxy group, a nitro group or a halogen group)

In addition, the alkyl 4-nitro-chroman derivative is (4S) -4-nitro-methyl-chroman-2-ol, (4S) -6-chloro-4-nitro-2-ol-methyl-chroman, (4S) -6 Ol, ( 4S ) -6,8-dichloro-4-nitromethylchroman-2-ol, ( 4S ) -6,8-dibromo-4- nitro methyl chroman-2-ol, (4S) -6-nitro-4-nitro-methyl-chroman-2-ol, (4S) -6-methyl-4-nitro-2-ol-methyl-chroman, (4S) ( 4S ) -7-methoxy-4-nitromethylchroman-2-ol and ( 4S ) -8-methoxy-4-nitromethyl 4-nitroalkylchroman derivatives, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the 4-nitroalkylchroman derivative is any one selected from the group consisting of cyanuric chloride, cyanuric chloride, and croman-2-ol.

Also, the 4-nitroalkylchroman derivative is a 4-nitroalkylchroman derivative, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the 4-nitroalkylchroman derivative has the ability to inhibit tumor cell proliferation.

The present invention also provides a 4-nitroalkylchroman derivative, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, wherein the tumor cell is a colon cancer tumor cell.

In order to solve the above-mentioned other problems, the present invention provides a pharmaceutical composition for an anticancer agent comprising the 4-nitroalkylchroman derivative, an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

According to another aspect of the present invention, there is provided a process for preparing a compound represented by the following formula (1), comprising reacting a compound represented by the following formula (2) with a compound represented by the following formula (4) There is provided a process for producing a nitroalkylchroman derivative.

(2)

(Wherein X is hydrogen, a methyl group, a methoxy group, a nitro group or a halogen group).

(3)

[Chemical Formula 4]

(In the formula (4), R is hydrogen or an alkyl group having 1 to 20 carbon atoms.)

[Chemical Formula 1]

(Wherein R is hydrogen or an alkyl group having 1 to 20 carbon atoms, and X is hydrogen, a methyl group, a methoxy group, a nitro group or a halogen group)

The reaction may also be carried out in a solvent selected from the group consisting of benzoic acid, 2-nitrobenzoic acid, 4-nitrobenzoic acid, 4-nitrobenzoic acid, Nitroalkylchroman derivative is carried out by adding at least one member selected from the group consisting of acetic acid, dichloroacetic acid, toluenesulfonic acid, lithium acetate and sodium acetate.

Also, the 4-nitroalkylchroman derivative is an S -isomer.

The 4-nitroalkylchroman derivative was further purified by a Chiralcel AD-H column and an AD-H guard column (5% i -PrOH: hexane, 1.0 ml / min Wherein the method further comprises the step of determining the enantiomeric selectivity by HPLC analysis using an analytical gas chromatograph, flow rate, [lambda] = 220 nm).

According to the present invention, it is possible to provide a specific chroman derivative, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, which can be effectively used as an anticancer agent, a preventive or therapeutic agent for cancer diseases.

Also, a method for synthesizing various chroman - 2 - ol derivatives having optical activity by asymmetric catalytic reaction of nitroalkane on o - hydroxycinnamic aldehyde using an organic catalyst, is characterized by the high chemical yield of chroman and the selective enantiomer Can be obtained.

Hereinafter, the present invention will be described in detail with reference to preferred embodiments. Prior to this, terms and words used in the present specification and claims should not be construed as limited to ordinary or dictionary terms, and the inventor should appropriately interpret the concepts of the terms appropriately The present invention should be construed in accordance with the meaning and concept consistent with the technical idea of the present invention. Accordingly, it is to be understood that the constituent features of the embodiments described herein are merely the most preferred embodiments of the present invention, and are not intended to represent all of the inventive concepts of the present invention, so that various equivalents, And the like.

The present invention discloses a 4-nitroalkylchroman derivative represented by the following formula (1), an enantiomer thereof, or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

(Wherein R is hydrogen or an alkyl group having 1 to 20 carbon atoms, and X is hydrogen, a methyl group, a methoxy group, a nitro group or a halogen group)

Hereinafter, the present invention will be described in more detail through a process for producing the 4-nitroalkylchroman derivative.

The production of the 4-nitroalkylchroman derivative according to the present invention can be carried out in the same manner as in the production of optically active chroman-2-ol derivatives, including a catalytic reaction step, without using a conventional heavy metal catalyst, The chiral chroman-2-ol derivative represented by the above formula (1) can be synthesized at a high yield.

The catalytic reaction step is a 1,4-addition reaction of the nitroalkane with an o -hydroxycinnamic aldehyde derivative in the presence of a chiral amine catalyst.

Here, the o -hydroxycinnamic aldehyde derivative, the chiral amine catalyst and the nitroalkane may be represented by the following Chemical Formulas 2 to 4, respectively.

(2)

(Wherein X is hydrogen, a methyl group, a methoxy group, a nitro group or a halogen group).

(3)

[Chemical Formula 4]

(In the formula (4), R is hydrogen or an alkyl group having 1 to 20 carbon atoms.)

The o -hydroxycinnamic aldehyde derivative and the nitroalkane may be reacted at a molar ratio of 1: 1 to 1: 5. When the molar ratio is less than 1: 1, the 1,4-addition reaction of the nitroalkane does not occur properly and the yield may be low. When the molar ratio is more than 1: 5, the yield of the nitroalkane may not be improved.

The chiral amine catalyst may be added in an amount of 2 to 20 mol% based on the o -hydroxycinnamic aldehyde derivative. If the content is less than 2 mol%, the catalytic reaction does not occur properly and the yield of the reaction may be low. When the content is more than 20 mol%, the yield of the reaction may be insufficient.

The following Reaction Scheme 1 briefly shows the organic catalytic reaction of the o -hydroxycinnamic aldehyde derivative with the nitroalkane in the preparation of the 4-nitroalkylchroman derivative according to the present invention.

[Reaction Scheme 1]

Referring to Reaction Scheme 1, the nitroalkane (4) is subjected to a 1,4-addition reaction with an o -hydroxycinnamic aldehyde derivative (2) in the presence of the chiral amine catalyst (3) to produce a chiral chroman- (1).

The catalytic reaction can be carried out in an organic solvent at a temperature of -10 to 25 ° C, preferably -5 to 10 ° C, more preferably -1 to 1 ° C. If the reaction temperature is lower than -10 ° C, the reaction rate may be slowed to prolong the reaction time. If the reaction temperature exceeds 25 ° C, the reaction may be terminated early and the reaction yield and enantioselectivity may decrease.

As the organic solvent, for example, methylene chloride, benzene, ethyl acetate, acetonitrile, toluene, tetrahydrofuran, isopropanol, ethanol, methanol, water, etc. may be used alone or as a mixture thereof, preferably isopropanol Can be used. At this time, the concentration of the organic solvent may be 0.1 to 1.0M, preferably 0.2 to 0.4M. If the concentration is less than 0.1 M, the reaction rate may be slowed, and if the concentration is more than 1.0 M, the dissolution of the reactant may not occur properly.

The reaction time of the catalytic reaction can be appropriately selected depending on the type of the reactant, but preferably 40 to 120 hours. If the reaction is carried out for less than 40 hours, the reaction may not be completed. If the reaction is carried out for more than 120 hours, the reaction may be completed before the reaction time becomes longer.

In the present invention, an acid or a base may be added as an additive in order to increase the reaction yield of the catalytic reaction. The acid or base may be any of those known in the art to which the present invention belongs and may be used without limitation. Examples thereof include 2-nitrobenzoic acid, 4-nitrobenzoic acid, acetic acid, dichloroacetic acid, toluenesulfonic acid, lithium acetate, Can be used alone or in a mixture thereof, preferably acetic acid can be used. At this time, when the acid is used, the concentration of the acid can be arbitrarily adjusted, but may be 5 to 15 mol%, preferably 9 to 11 mol%, of the amount of the o -hydroxycinnamic aldehyde derivative (2) used. If the acid concentration is less than 5 mol%, the reaction yield may be decreased, and if it exceeds 15 mol%, side reactions may occur.

The 4-nitroalkylchroman derivative (1) produced by the above reaction can be obtained in various kinds depending on the kind of the o -hydroxycinnamic aldehyde derivative (2) and the nitroalkane (4) preferably S - isomers, e.g., (4S) methyl-4-nitro-chroman-2-ol, (4S) -6- chloro-4-nitro-methyl-chroman-2-ol, (4S) -6- bromo ( 4S ) -6,8-dichloro-4-nitromethylchroman-2-ol, ( 4S ) -6,8-dibromo-4-nitromethyl chroman-2-ol, (4S) -6-nitro-4-nitro-but-methyl-chroman-2-ol, (4S) -6-methyl-4-nitro-2-ol-methyl-chroman, (4S) -6 ( 4S ) -7-methoxy-4-nitromethylchroman-2-ol, ( 4S ) -8-methoxy- 2-ol and the like can be obtained.

In the present invention, the 4-nitroalkylchroman derivative prepared as described above is introduced into a chiralcel AD-H column and an AD-H guard column (5% i -PrOH : Hexane, 1.0 ml / min flow rate, [lambda] = 220 nm) to determine the enantiomeric selectivity.

The thus produced 4-nitroalkylchroman derivative (1), its enantiomer or pharmaceutically acceptable salt thereof according to the present invention exhibits an excellent effect for inhibiting the proliferation of tumor cells, particularly colon cancer cells, .

Accordingly, in the present invention, it is preferable to use a 4-nitroalkylchroman derivative of the above formula (1), an enantiomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, or a 4-nitroalkylchroman derivative of the above formula Isomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The pharmaceutical composition for an anticancer agent may contain 0.1 to 75% by weight, based on the total weight of the pharmaceutical composition, of the 4-nitroalkylchroman derivative of the formula 1, the enantiomer thereof or a pharmaceutically acceptable salt thereof, May be contained in an amount of 1 to 50% by weight.

The pharmaceutical composition for an anticancer agent according to the present invention can be formulated into various oral or parenteral administration forms. Examples of the formulations for oral administration include pills, light and soft capsules, liquids, suspensions, emulsions, syrups and granules. These formulations may contain lactose, dextrose, sucrose, A diluent such as mannitol, sorbitol, cellulosic or glycine, a lubricant such as silica, talc, stearic acid or a magnesium salt or calcium salt thereof, or polyethylene glycol. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, and may optionally contain starch, agar, alginic acid or their sodium Disintegrating agents such as salts, boiling mixtures, absorbents, coloring agents, flavoring agents, sweeteners, and the like. In addition, the representative formulation for parenteral administration is preferably an isotonic aqueous solution or suspension in a form for injection.

The composition may also be sterilized or contain adjuvants such as preservatives, stabilizers, wettable powders, emulsifying accelerators, salts for controlling osmotic pressure or buffers, and other therapeutically useful substances and may be prepared by conventional mixing, Can be formulated accordingly.

The oral or parenteral administration may be carried out in an amount of from about 2.5 to about 500 mg per day for mammals including humans, based on the 4-nitroalkylchroman derivative of Formula 1, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, 100 mg / kg, preferably 5 to 60 mg / kg, once or divided once a day by an oral or parenteral route.

Example  One: ( 4S )-4- Nitromethylchroman Ol (1a) Synthesis of

To the o -hydroxy cinnamaldehyde 2a (37 mg, 0.25 mmol) was added chiral amine catalyst 3 (0.025 mmol), isopropanol (0.8 ml) was added, and acetic acid (0.025 mmol) was added dropwise. Nitromethane (4a) (41 쨉 l, 0.75 mmol) was added at 0 째 C, stirred for 42 hours, and then subjected to silica gel chromatography using 20% ethyl acetate / hexane to obtain the title compound as colorless gum (49 mg, 88% yield, 98 % ee).

[a] ²⁰ _D -5.06 (c 1.0, CHCl ₃ );

_{^{1 H NMR (400MHz, CDCl 3}} ) 7.22-7.26 (m, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.89-7.01 (m, 2H), 5.78 (d, J = 2.4Hz, 0.63H ), 5.69 (brs, 0.37H) , 5.01 (dd, J = 9.2, 12.8 Hz, 0.63 H), 4.89 (dd, J = 5.2, 12.4 Hz, 0.37H), 4.75 (dd, J = 5.6, 12.8 Hz (D, J = 9.2,12.0 Hz, 0.37H), 3.92-4.01 (m, 0.37H), 3.73-3.82 (m, 0.63H), 3.10 (brs, 0.37H), 3.08 brs, 0.63H), 2.17-2.26 (m, 1.63H), 2.01-2.09 (m, 0.37H);

_{^{13 C NMR (100MHz, CDCl 3}} ) 151.8 (minor), 151.3 (major), 129.2 (major), 129.1 (minor), 129.0 (major), 126.8 (minor), 121.7 (major), 121.6 (minor), 119.9 minor, 119.8 (major), 117.9 (minor), 117.8 (major), 91.4 (major), 90.7 (minor), 80.6 (major), 79.3 (minor), 31.0 (minor), 30.9 (minor), 28.6 (major);

MS m / z (%) 209 (M ⁺ , 15), 157 (32), 129 (100), 83 (45), 57 (48);

Elemental analysis: C ₁₀ H ₁₁ NO _4: calculating the C, 57.41; H, 5.30; N, 6.70. Measuring phase C, 57.58; H, 5.58; N, 6.98;

The Chroman product, which had been reduced (Et ₃ SiH / BF ₃ .Et ₂ O, CH ₂ Cl ₂ ), was separated on a Chiralcel AD-H column and an AD-H guard column (2% ethanol: hexane, 1.0 ml / min flow rate, lambda = 220 nm) to determine the enantiomeric selectivity. ; R- isomer t _r = 17.2 min and S- isomer t _r = 26.3 min.

Example  2: ( 4S ) -6- Chloro -4- Nitromethylchroman Ol (1b) Synthesis of

Chiral amine catalyst 3 (0.025 mmol) was added to 2-hydroxy-5-chlorocinnamaldehyde 2b (46 mg, 0.25 mmol), isopropanol (0.8 ml) was added, acetic acid (0.025 mmol) do. Nitromethane (4a) (41 쨉 l, 0.75 mmol) was added at 0 째 C, stirred for 48 hours and then subjected to silica gel chromatography using 20% ethyl acetate / hexane to obtain the title compound as a white solid (56 mg, 92% % ee).

mp 87-88 [deg.] C;

_{^{[a] 20 D 13.5 (c}} 1.0, CHCl 3);

^{1 H NMR (400 MHz, CDCl} 3) δ 7.12-7.19 (m, 2H), 6.83 (d, J = 8.8 Hz, 1H), 5.76 (dd, J = 2.8, 5.6 Hz, 0.63H), 5.68 (dd , J = 3.6, 6.4 Hz, 0.37H), 5.03 (dd, J = 9.2, 12.8 Hz, 0.63H), 4.87 (dd, J = 4.8, 12.4 Hz, 0.37H), 4.72 (dd, J = 6.0, (D, J = 9.6, 12.8Hz, 0.37H), 3.88-3.94 (m, 0.37H), 3.71-3.77 (m, 0.63H), 3.32 (brs, 0.37H) 3.27 (brs, 0.63H), 2.15-2.24 (m, 1.63H), 1.96-2.03 (m, 0.37H);

¹³ H NMR (100 MHz, CDCl ₃ )? 150.4 (minor), 149.9 (major), 129.3 (major), 129.1 (minor), 128.6, 126.5 (major), 126.4 (minor), 121.5 major, 119.4 minor, 119.4 major, 90.7 minor, 80.2 major, 78.8 minor, 30.7 major, 30.6 minor, 29.6 minor, 28.3 major);

MS m / z (%) 243 (M ⁺ , 74), 181 (91), 153 (100), 125 (55), 89 (43), 64 (33);

Elemental analysis: C ₁₀ H ₁₀ ClNO ₄ : Calculated C, 49.30 H, 4.14 N, 5.75. Measuring phase C, 49.38 H, 4.24 N, 5.80;

The chroman product, which had been reduced (Et ₃ SiH / BF ₃ .Et ₂ O, CH ₂ Cl ₂ ), was separated on a Chiralcel OD-H column and an OD-H guard column (5% isopropanol: hexane, 1.0 ml / min flow rate, [lambda] = 220 nm) to determine the enantiomeric selectivity. ; S- isomer t _r = 34.2 min and R- isomer t _r = 42.2 min.

Example  3: ( 4S ) -6- Bromo -4- Nitromethylchroman Ol (1c) Synthesis of

Chiral amine catalyst 3 (0.025 mmol) was added to 2-hydroxy-5-bromocinnamaldehyde 2c (57 mg, 0.25 mmol), isopropanol (0.8 ml) was added, acetic acid (0.025 mmol) Drop it. Nitromethane (4a) (41 쨉 l, 0.75 mmol) was added at 0 째 C, stirred for 48 hours and then subjected to silica gel chromatography using 20% ethyl acetate / hexane to obtain the title compound as a white solid (66 mg, 91% yield, 98 % ee).

mp 84-85 [deg.] C;

_{^{[a] 20 D 18.7 (c}} 1.0, CHCl 3);

^{1 H NMR (400 MHz, CDCl} 3) 7.26-7.31 (m, 2H), 6.78 (d, J = 8.8 Hz, 1H), 5.76 (brs, 0.64H), 5.68 (dd, J = 2.4, 4.4 Hz, 0.36H), 5.04 (dd, J = 9.6, 13.2 Hz, 0.64H), 4.87 (dd, J = 4.8, 12.4 Hz, 0.36H), 4.71 (dd, J = 5.6, 12.8 Hz, 0.64H), 4.55 (dd, J = 9.6, 12.8 Hz, 0.36H), 3.89-3.94 (m, 0.36H), 3.71-3.77 (m, 0.64H), 3.37 (brs, , 1.96-2.03 (m, 0.36H);

^{13 C NMR (100 MHz, CDCl} 3) 151.0 (minor), 150.5 (major), 132.2 (major), 132.0 (minor), 131.6 (major), 129.4 (minor), 122.1 (minor), 121.9 (major), 119.8 (major), 119.6 (major), 113.6, 91.4 (major), 90.7 (minor), 80.2 (major), 78.8 (minor), 30.6, 29.6 (minor), 28.3 (major); MS m / z (%) 287 (M ⁺ , 55), 225 (100), 199 (58), 118 (97), 89 (46), 63 (42);

Elemental analysis: C ₁₀ H ₁₀ BrNO ₄ : Calculated C, 41.69 H, 3.50; N, 4.86. Measuring phase C, 41.67H, 3.57; N, 5.11;

The chroman product, which had been reduced (Et ₃ SiH / BF ₃ .Et ₂ O, CH ₂ Cl ₂ ), was separated on a Chiralcel OD-H column and an OD-H guard column (5% isopropanol: hexane, 1.0 ml / min flow rate, [lambda] = 220 nm) to determine the enantiomeric selectivity. ; S- isomer t _r = 34.1 min and R- isomer t _r = 44.6 min.

Example  4: ( 4S ) -6,8- Dichloro -4- Nitromethylchroman Ol (1d) Synthesis of

(0.025 mmol) was added to 2-hydroxy-3,5-dichlorocinnamaldehyde (2d) (54 mg, 0.25 mmol) and isopropanol (0.8 ml) . Nitromethane (4a) (41 μl, 0.75 mmol) was added at 0 ° C, stirred for 48 hours and then subjected to silica gel chromatography using 20% ethyl acetate / hexane to obtain the title compound as colorless gum (50 mg, 72% 99% ee).

_{^{[a] 20 D -7.68 (c}} 1.0, CHCl 3);

^{1 H NMR (400 MHz, CDCl} 3) 7.31-7.34 (m, 1H), 7.05-7.08 (m, 1H), 5.91 (dd, J = 2.8, 5.6Hz, 0.66H), 5.83 (dd, J = 3.6 , 6.4 Hz, 0.34H), 5.04 (dd, J = 8.8, 13.2 Hz, 0.66H), 4.86 (dd, J = 4.8, 12.4 Hz, 0.34H), 4.72 (dd, J = 6.0, 13.2 Hz, 0.66 (M, 1H), 4.58 (dd, J = 9.2,12.8 Hz, 0.34H), 3.92-3.97 (m, 0.34H), 3.75-3.81 (m, 1.66H), 2.01-2.07 (m, 0.34H);

^{13 C NMR (100 MHz, CDCl} 3) 146.6 (minor), 146.1 (major), 129.6 (major), 129.4 (minor), 127.3 (major), 126.2 (minor), 126.1 (minor), 125.0 (major), Minor, 123.6 major, 123.0 minor, 122.7 major, 91.8 major, 91.3 minor, 80.0 major, 78.4 minor, 30.7 major, 30.4 minor, 29.5 (minor), 28.1 (major);

MS m / z (%) 277 (M ⁺ , 72), 215 (97), 175 (100), 131 (48), 89 (52)

Elemental analysis: C ₁₀ H ₉ Cl ₂ NO ₄ : Calculated C, 43.19 H, 3.26; N, 5.04. Measuring phase C, 43.32 H, 3.60; N, 4.89;

The Chroman product, which had been reduced (Et ₃ SiH / BF ₃ .Et ₂ O, CH ₂ Cl ₂ ), was separated on a Chiralcel AD-H column and an AD-H guard column (5% isopropanol: hexane, 1.0 ml / min flow rate, [lambda] = 220 nm) to determine the enantiomeric selectivity. ; S- isomer t _r = 51.0 min and R- isomer t _r = 80.1 min.

Example  5: ( 4S ) -6,8- Dibromo -4- Nitromethylchroman 2-ol (1e) Synthesis of

Chiral amine catalyst 3 (0.025 mmol) was added to 2-hydroxy-3,5-dibromosinanaldehyde 2e (77 mg, 0.25 mmol), isopropanol (0.8 ml) was added, acetic acid mmol) is added dropwise. Nitromethane (4a) (41 쨉 l, 0.75 mmol) was added at 0 째 C, stirred for 48 hours and then subjected to silica gel chromatography using 20% ethyl acetate / hexane to obtain the title compound as colorless gum (67 mg, 73% yield, 98 % ee).

_{^{[a] 20 D -7.91 (c}} 1.0, CHCl 3);

^{1 H NMR (400 MHz, CDCl} 3) 7.62-7.64 (m, 1H), 7.23-7.26 (m, 1H), 5.90 (brs, 0.66H), 5.83 (dd, J = 3.2, 6.4 Hz, 0.34H) , 5.04 (dd, J = 8.8,13.2Hz, 0.66H), 4.86 (dd, J = 4.8,12.4Hz, 0.34H), 4.71 (dd, J = 6.0, 13.2Hz, 0.66H), 4.57 (M, 2H, J = 9.2,12.8 Hz, 0.34H), 3.92-3.98 (m, 0.34H), 3.75-3.81 (m, 0.66H) 2.07 (m, 0.34H);

^{13 C NMR (100 MHz, CDCl} 3) 148.0 (minor), 147.5 (major), 135.1 (major), 135.0 (minor), 130.9 (major), 128.6 (minor), 123.5 (minor), 123.1 (major), 113.5, 113.1 minor, 113.0 major, 92.0 major, 91.4 minor, 80.1 major, 78.4 minor, 30.7 major, 30.5 minor, 29.6 minor, 28.2 major );

MS m / z (%) 365 (M ⁺ , 45), 331 (85), 303 (100), 252 (48), 143 (62), 87 (34), 63 (33) _{Calcd for C 10 H 9 Br 2} NO 4: C, 32.73 H, 2.47; N, 3.82. Found: C, 32.43; H, 2.57; N, 3.69

Elemental _{analysis: C 10 H 9 Br 2 NO} 4: calculating the C, 32.73 H, 2.47; N, 3.82. Measuring phase C, 32.43H, 2.57; N, 3.69;

The Chroman product, which had been reduced (Et ₃ SiH / BF ₃ .Et ₂ O, CH ₂ Cl ₂ ), was separated on a Chiralcel AD-H column and an AD-H guard column (5% isopropanol: hexane, 1.0 ml / min flow rate, [lambda] = 220 nm) to determine the enantiomeric selectivity. ; S- isomer t _r = 55.8 min and R- isomer t _r = 77.2 min.

Example  6: ( 4S ) -6-nitro-4- Nitromethylchroman Ol (1f) Synthesis of

Chiral amine catalyst 3 (0.025 mmol) was added to 2-hydroxy-5-nitrocinnamide aldehyde 2f (48 mg, 0.25 mmol), isopropanol (0.8 ml) was added, acetic acid (0.025 mmol) do. Nitromethane (4a) (41 μl, 0.75 mmol) was added at 0 ° C, stirred for 48 hours and then subjected to silica gel chromatography using 20% ethyl acetate / hexane to obtain the desired compound as a white solid (44 mg, 69% yield, 96 % ee).

mp 98-99 [deg.] C;

_{^{[a] 20 D 26.0 (c}} 1.0, CHCl 3);

^{1 H NMR (400 MHz, CDCl} 3) 8.11-8.17 (m, 2H), 7.00 (d, J = 9.6 Hz, 1H), 5.88 (dd, J = 2.8, 6.0Hz, 0.63H), 5.81 (dd, J = 4.0, 6.4 Hz, 0.37H ), 5.09 (dd, J = 9.2, 13.2 Hz, 0.63H), 4.98 (dd, J = 4.8, 12.0 Hz, 0.37H), 4.78 (dd, J = 5.6, 13.2 (M, 1H), 4.69 (dd, J = 8.8,13.2 Hz, 0.37H), 3.99-4.05 (m, 0.37H), 3.83-3.91 2.21-2.34 (m, 1.63H), 2.03-2.10 (m, 0.37H);

^{13 C NMR (100 MHz, CDCl} 3) 157.4 (minor), 156.9 (major), 141.9, 125.4 (major), 125.1 (major), 124.9 (minor), 122.9 (minor), 120.8 (minor), 120.5 (major ), 118.7 (major), 118.6 (minor), 92.0 major, 91.3 minor, 79.7 major, 78.1 minor, 30.6 major, 30.2 minor, 29.2 minor, );

HRMS: [M ^+] calculated phase _{C 10 H 10 N 2 O 6} : 254.0539, measured 254.0537 phase;

The Chroman product, which had been reduced (Et ₃ SiH / BF ₃ .Et ₂ O, CH ₂ Cl ₂ ), was separated on a Chiralcel AD-H column and an AD-H guard column (5% isopropanol: hexane, 1.0 ml / min flow rate, [lambda] = 220 nm) to determine the enantiomeric selectivity. ; S- isomer t _r = 88.8 min and R- isomer t _r = 103.6 min.

Example  7: ( 4S ) -6- methyl -4- Nitromethylchroman 2-ol (1 g)

Chiral amine catalyst 3 (0.025 mmol) was added to 2-hydroxy-5-methyl cinnamaldehyde (2 g) (41 mg, 0.25 mmol), isopropanol (0.8 ml) was added, acetic acid (0.025 mmol) do. Nitromethane (4a) (41 쨉 l, 0.75 mmol) was added at 0 째 C, stirred for 48 hours and then subjected to silica gel chromatography using 20% ethyl acetate / hexane to obtain the title compound as colorless gum (50 mg, 89% yield, 99 % ee).

_{^{[a] 20 D 9.62 (c}} 1.0, CHCl 3);

^{1 H NMR (400 MHz, CDCl} 3) 7.01-7.04 (m, 1H), 6.94 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 5.72 (dd, J = 2.4, 5.2 Hz, 0.63 H), 5.63 (brs, 0.37H ), 5.03 (dd, J = 9.2, 12.8 Hz, 0.63H), 4.88 (dd, J = 4.8, 12.4 Hz, 0.37H), 4.73 (dd, J = 5.6, 12.8 (D, J = 9.6, 12.4Hz, 0.37H), 3.85-3.93 (m, 0.37H), 3.68-3.75 (m, 0.63H), 3.53 (brs, 0.37H), 3.41 (brs, 0.63H), 2.30 (s, 3H), 2.13-2.21 (m, 1.63H), 1.97-2.04 (m, 0.37H);

^{13 C NMR (100 MHz, CDCl} 3) 149.6 (minor), 149.0 (major), 131.0 (major), 130.9 (minor), 129.9 (major), 129.8 (minor), 129.2 (major), 127.1 (minor), Minor, 119.4 major, 117.6 minor, 117.5 major, 91.4 major, 90.7 minor, 80.6 major, 79.4 minor, 31.1 minor, 30.9 major, 30.1 (minor), 28.7 (major), 20.6 (minor), 20.5 (major);

HRMS: [M ⁺ ] Calculated C ₁₁ H ₁₃ NO ₄ : 223.0845, measured 223.0848;

The Chroman product, which had been reduced (Et ₃ SiH / BF ₃ .Et ₂ O, CH ₂ Cl ₂ ), was separated on a Chiralcel AD-H column and an AD-H guard column (5% isopropanol: hexane, 1.0 ml / min flow rate, [lambda] = 220 nm) to determine the enantiomeric selectivity. ; S- isomer t _r = 7.3 min and R- isomer t _r = 8.6 min.

Example  8: ( 4S ) -6- Methoxy -4- Nitromethylchroman 2-ol (1h) Synthesis of

A chiral amine catalyst 3 (0.025 mmol) was added to 2-hydroxy-5-methoxy cinnamaldehyde 2h (45 mg, 0.25 mmol), isopropanol (0.8 ml) was added, acetic acid (0.025 mmol) Drop it. Nitromethane (4a) (41 μl, 0.75 mmol) was added at 0 ° C, stirred for 48 hours and then subjected to silica gel chromatography using 20% ethyl acetate / hexane to obtain the target compound as colorless gum (53 mg, 88% % ee).

_{^{[a] 20 D -6.08 (c}} 1.0, CHCl 3);

^{1 H NMR (400 MHz, CDCl} 3) 6.77-6.83 (m, 2H), 6.66 (s, 1H), 5.70 (brs, 0.63H), 5.62 (brs, 0.37H), 5.01 (dd, J = 9.2, 12.8 Hz, 0.63H), 4.84 ( dd, J = 4.8, 12.4 Hz, 0.37H), 4.73 (dd, J = 6.0, 12.4 Hz, 0.63H), 4.53 (dd, J = 9.6, 13.2 Hz, 0.37H ), 3.83-3.91 (m, 0.37H), 3.77 (s, 3H), 3.69-3.75 (m, 0.63H), 3.51 (brs, m, 0.37H);

^{13 C NMR (100 MHz, CDCl} 3) 154.1, 145.7 (minor), 145.1 (major), 120.5 (minor), 120.3 (major), 118.6 (major), 118.5 (minor), 115.4 (major), 114.8 (minor ), 113.3 (major), 111.9 (minor), 91.4 major, 90.6 minor, 80.6 major, 79.3 minor, 55.8 31.2 major, 31.0 minor, (major)

MS m / z (%) 239 (M ⁺ , 100), 191 (48), 149 (98), 121 (34), 91 (44)

Elemental analysis: C ₁₁ H ₁₃ NO ₅ : Calculated C, 55.23 H, 5.48; N, 5.86. Measuring phase C, 55.56 H, 5.60; N, 5.85;

The Chroman product, which had been reduced (Et ₃ SiH / BF ₃ .Et ₂ O, CH ₂ Cl ₂ ), was separated on a Chiralcel AD-H column and an AD-H guard column (10% ethanol: hexane, 1.0 ml / min flow rate, [lambda] = 220 nm) to determine the enantiomeric selectivity. ; R- isomer t _r = 7.6 min and S- isomer t _r = 13.5 min.

Example  9: ( 4S ) -7- Methoxy -4- Nitromethylchroman Ol (1i) Synthesis of

Chiral amine catalyst 3 (0.025 mmol) was added to 2-hydroxy-4-methoxy cinnamaldehyde 2i (45 mg, 0.25 mmol), isopropanol (0.8 mL) was added, acetic acid (0.025 mmol) Drop it. Nitromethane (4a) (41 쨉 l, 0.75 mmol) was added at 0 째 C, stirred for 48 hours and then subjected to silica gel chromatography using 20% ethyl acetate / hexane to obtain the title compound as colorless gum (44 mg, 74% yield, 98 % ee).

_{^{[a] 20 D -15.8 (c}} 1.0, CHCl 3);

^{1 H NMR (400 MHz, CDCl} 3) 7.02 (d, J = 8.4 Hz, 1H), 6.54-6.58 (m, 1H), 6.44 (d, J = 2.4 Hz, 1H), 5.72 (brs, 0.63H) , 5.63 (dd, J = 2.4 , 4.8 Hz, 0.37H), 4.97 (dd, J = 9.2, 12.8 Hz, 0.63H), 4.82 (dd, J = 4.8, 12.0 Hz, 0.37H), 4.71 (dd, J = 6.4, 12.8 Hz, 0.63H ), 4.50 (dd, J = 9.2, 12.0 Hz, 0.37H), 3.81-3.88 (m, 0.37H), 3.78 (s, 3H), 3.66-3.72 (m, 0.63 H), 3.48 (br s, 1H), 2.12-2.20 (m, 1.63H), 1.96-2.03 (m, 0.37H);

^{13 C NMR (100 MHz, CDCl} 3) 160.3 (major), 160.2 (minor), 152.9 (minor), 152.2 (major), 129.8 (major), 127.6 (minor), 112.0 (minor), 111.9 (major), 108.4 major, 108.3 minor, 102.7 major, 91.5 major, 90.9 minor, 80.7 major, 79.5 minor, 55.4 31.1 minor, ), 29.7 (minor), 28.8 (major);

MS m / z (%) 239 (M ⁺ , 75), 195 (84), 175 (100), 124 (64), 77 (42), 41 (24);

Elemental analysis: C ₁₁ H ₁₃ NO ₅揃 1/3 H ₂ O: Calculated C, 53.88 H, 5.62; N, 5.71. Measuring phase C, 54.02 H, 5.27; N, 5.89;

The Chroman product, which had been reduced (Et ₃ SiH / BF ₃ .Et ₂ O, CH ₂ Cl ₂ ), was separated on a Chiralcel AD-H column and an AD-H guard column (10% ethanol: hexane, 1.0 ml / min flow rate, [lambda] = 220 nm) to determine the enantiomeric selectivity. ; R- isomer t _r = 14.1 min and S- isomer t _r = 32.2 min.

Example  10: ( 4S )-8- Methoxy -4- Nitromethylchroman 2-ol (1j) Synthesis of

Chiral amine catalyst 3 (0.025 mmol) was added to 2-hydroxy-3-methoxy cinnamaldehyde 2j (45 mg, 0.25 mmol), isopropanol (0.8 ml) was added thereto and acetic acid (0.025 mmol) Drop it. Nitromethane (4a) (41 μl, 0.75 mmol) was added at 0 ° C, stirred for 48 hours and then subjected to silica gel chromatography using 20% ethyl acetate / hexane to obtain the title compound as a pale yellow solid (50 mg, 83% , 99% ee).

mp 118-119 [deg.] C;

_{^{[a] 20 D 9.77 (c}} 1.0, CHCl 3);

^{1 H NMR (400 MHz, CDCl} 3) 6.74-6.92 (m, 3H), 5.89 (brs, 0.66H), 5.78 (brs, 0.34H), 5.08 (dd, J = 9.2, 12.8 Hz, 0.66H), (Dd, J = 4.8,12.4 Hz, 0.34H), 4.74 (dd, J = 6.0,13.2Hz, 0.66H), 4.69 (brs, 0.66H), 4.66 J = 9.2, 12.4 Hz, 0.34H ), 3.90-3.98 (m, 0.34H), 3.86 (s, 3H), 3.74-3.79 (m, 0.66H), 2.16-2.45 (m, 1.66H), 2.01- 2.06 (m, 0.34H);

^{13 C NMR (100 MHz, CDCl} 3) 148.6 (minor), 148.5 (major), 141.4 (minor), 140.8 (major), 121.1 (major), 121.0 (minor), 120.8 (major), 120.7 (major), Minor, 110.6 (minor), 110.5 (major), 91.6 (major), 90.9 (minor), 80.4 (major), 79.3 (minor), 55.8 (minor), 55.7 (major) 30.8 (minor), 30.7 (major), 29.9 (minor), 28.5 (major);

MS m / z (%) 239 (M ⁺ , 100), 191 (62), 149 (78), 103 (46), 77 (52), 51 (28)

Elemental analysis: C ₁₁ H ₁₃ NO ₅ : Calculated C, 55.23 H, 5.48; N, 5.86. Measuring phase C, 55.36 H, 5.60; N, 5.73;

The Chroman product, which had been reduced (Et ₃ SiH / BF ₃ .Et ₂ O, CH ₂ Cl ₂ ), was separated on a Chiralcel AD-H column and an AD-H guard column (2% ethanol: hexane, 1.0 ml / min flow rate, lambda = 220 nm) to determine the enantiomeric selectivity. ; R- isomer t _r = 44.2 min and S- isomer t _r = 46.4 min.

The chiral chroman-2-ol derivatives synthesized according to Examples 1 to 10 are summarized in Table 1 below.

Test Example  1: Colorectal cancer ( Human colorectal cancer ) Cytotoxicity ( Cell viability ) Measure

10,000 human chromogenic cancer cells (HCT116 cells) were placed in 96-well plates in RPMI1640 medium containing 10% fetal bovine serum (FBS) and 1% antibiotics, After 24 hours of incubation in an incubator under CO ₂ conditions, the chroman compound is added to the medium so that the final concentration is 10 μM and cultured for another 24 hours. After the incubation, the medium was removed and the OD (optical density) was measured with a microplate reader device every 10 minutes while the medium was replaced with a medium containing 10% CCK-8 solution (Dojindo, Japan) do. The degree of inhibition of viability of the compound is calculated as a percentage of the group to which no chroman compound is added as 100%.

The results of the cytotoxicity test for human colorectal cancer of the chiral chroman-2-ol derivative compounds synthesized according to Examples 1 to 10 are shown in Table 2 below.

Test Example  2: Colorectal cancer ( Human colorectal cancer ) cell TCF / LEF Luciferase  activation( luciferase activity ) Measure

10,000 human HCT116 (human colorectal cancer cell) cells transfected with a TCF / LEF reporter gene were transfected with 10% FBS (fetal bovine serum) and 1% antibiotic After incubation for 24 hours in an incubator under the conditions of 37 ° C and 5% CO ₂ , the chroman compound was added to the medium so as to have a final concentration of 10 μM, and the medium was again cultured for 24 hours in RPMI 1640 medium containing antibiotics Time culture. After removing the medium, wash the cells with cold PBS (1X cold phosphate buffer saline) and add 25 μl of lysis buffer. After storing in a freezer at -80 ° C for about 30 minutes, dissolve the cell for about 1 hour while shaking the plate. After dissolution, transfer 10 μl of the plate to a white 384-well plate, and add 25 μl of a solution of luciferase assay substrate and buffer to each well. After that, the OD was measured with a microplate reader instrument and the luciferase activity was calculated by comparing with the group without addition of the chroman compound.

The results of TCF / LEF luciferase activity test of the chiral chroman-2-ol derivative compounds synthesized according to Examples 1 to 10 are shown in Table 3 below.

Test Example  3: lung cancer Human lung cancer)  Cytotoxicity Cell viability )Measure

10,000 human lung cancer cell (A549) cells were placed in a 96-well plate in RPMI1640 medium containing 10% fetal bovine serum (FBS) and 1% antibiotics, After 24 hours of incubation in an incubator under CO ₂ conditions, the chroman compound is added to the medium so that the final concentration is 10 μM and cultured for another 24 hours. After the culture, the medium is removed and the OD is measured with a microplate reader device every 10 minutes while the medium is replaced with a medium containing 10% CCK-8 solution (Dojindo, Japan). Calculate the degree of inhibition of viability of the compound as a percentage by taking the group to which the compound is not added as 100%.

The results of human colorectal cancer cytotoxicity tests of the chiral chroman-2-ol derivative compounds synthesized according to Examples 1 to 10 are shown in Table 4 below.

Test Example  4: lung cancer Human lung cancer ) cell TCF / LEF  Luciferase activity ( luciferase activity ) Measure

10,000 human lung cancer cell lines transfected with a TCF / LEF reporter gene were transfected with 10% FBS (fetal bovine serum) and 1% antibiotic After incubation for 24 hours in an incubator under the conditions of 37 ° C and 5% CO ₂ , the chroman compound was added to the medium so as to have a final concentration of 10 μM, and the medium was again cultured for 24 hours in RPMI 1640 medium containing antibiotics Time culture. After removing the medium, wash the cells with cold PBS (1X cold phosphate buffer saline) and add 25 μl of lysis buffer. Store in a freezer at -80 ° C for about 30 minutes, dissolve the cell for about 1 hour while shaking the plate. After dissolution, transfer 10 μl of the plate to a white 384-well plate, and add 25 μl of a solution of luciferase assay substrate and buffer to each well. After that, the OD was measured with a microplate reader instrument and the luciferase activity was calculated by comparing with the group without addition of the chroman compound.

The TCF / LEF luciferase activity test results of the chiral chroman-2-ol derivative compounds synthesized according to Examples 1 to 10 are shown in Table 5 below.

From the test results shown in Tables 2 to 5 in Test Examples 1 to 4 above, it can be confirmed that the 4-nitroalkylchroman derivative according to the present invention exhibits excellent HDAC (histone deacetylase) inhibitory activity.

The preferred embodiments of the present invention have been described in detail above. It will be understood by those of ordinary skill in the art that various changes in form and details may be made therein without departing from the spirit and scope of the present invention as defined by the appended claims.

Accordingly, the scope of the present invention is defined by the appended claims rather than the foregoing detailed description, and all changes or modifications derived from the meaning, range, and equivalence of the claims are included in the scope of the present invention Should be interpreted.

Claims (9)

A pharmaceutical composition for anti-colon cancer, comprising a 4-nitroalkylchroman derivative, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, having the ability to inhibit the proliferation of colon cancer cells.
[Chemical Formula 1]

(Wherein R is hydrogen or an alkyl group having 1 to 20 carbon atoms, and X is hydrogen, a methyl group, a methoxy group, a nitro group or a halogen group) The method according to claim 1,
The alkyl 4-nitro-chroman derivative is (4S) -4-nitro-methyl-chroman-2-ol, (4S) -6- chloro-4-nitro-methyl-chroman-2-ol, (4S) -6- bromo ( 4S ) -6,8-dichloro-4-nitromethylchroman-2-ol, ( 4S ) -6,8-dibromo-4-nitromethyl chroman-2-ol, (4S) -6-nitro-4-nitro-but-methyl-chroman-2-ol, (4S) -6-methyl-4-nitro-2-ol-methyl-chroman, (4S) -6 ( 4S ) -7-methoxy-4-nitromethylchroman-2-ol and ( 4S ) -8-methoxy- 2-ol. ≪ RTI ID = 0.0 > 21. < / RTI >
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