KR102252540B1 - Ligand-metal complexes conjugated with benzothiazole derivatives and method for preparing it - Google Patents

Abstract

The present invention relates to a ligand-metal complex to which a benzocyazole derivative is bound and a method for preparing the same, and more particularly, to a ligand to which a benzocyazole derivative exhibiting tumor targeting and anticancer effect is bound, and a metal exhibiting anticancer effect is coordinated. It relates to a ligand-metal complex.
The metal complex of the present invention can exhibit excellent anticancer activity even at a low dosage concentration compared to the previously reported platinum-based anticancer agents due to its high tumor targetability, and can minimize side effects caused by the administration of anticancer agents, making it useful for the development of excellent anticancer drugs. Can be utilized.

Description

Ligand-metal complexes conjugated with benzothiazole derivatives and method for preparing it}

The present invention relates to a ligand-metal complex to which a benzocyazole derivative is bound and a method for preparing the same, and more particularly, to a ligand to which a benzocyazole derivative exhibiting tumor targeting and anticancer effect is bound, and a metal exhibiting anticancer effect is coordinated. It relates to a ligand-metal complex.

Many diseases are being treated with the development of modern medicine, but cancer is still one of the difficult diseases to treat. Cancer occupies the number 1 cause of death by disease in most countries, including Korea, and is on an increasing trend.

As a treatment method for cancer, chemotherapy, immunotherapy, surgical therapy, and radiation therapy are used. Among these, immunotherapy is considered to be an excellent treatment method for cancer in theoretical and experimental animals, but its therapeutic effect in clinical is insufficient and its use is limited to some cancers. Therefore, until now, chemotherapy has become the most important treatment method for cancer treatment, especially systemic treatment. Today, about 60 kinds of various anticancer drugs are used in clinical practice, and new anticancer drugs are continuously being developed as knowledge about cancer incidence and characteristics of cancer cells is well known.

Among the anticancer drugs developed so far, cis-platin, a useful drug, has a platinum (Pt) atom in the center of its molecular structure and is attached to the DNA double helix structure present in the nucleus of cancer cells, thereby inhibiting the replication of DNA. It is a platinum complex compound anticancer agent that exhibits antitumor activity (anticancer effect) that inhibits growth and proliferation and removes cancer cells. Cisplatin is widely used in the treatment of testicular cancer, ovarian cancer, lung cancer, head and neck cancer, bladder cancer, gastric cancer and cervical cancer, but hematopoietic toxicity such as anemia, gastrointestinal toxicity such as vomiting and nausea, nephrotoxicity such as kidney tubule damage, and neurotoxicity. The occurrence of side effects such as such as (RT Skeel, Handbook of Cancer Chemotherap y, pp.89-91, 1999) and loss of anticancer activity due to the acquisition of resistance of cancer cells were pointed out as problems. Accordingly, carboplatin, a second-generation platinum complex anticancer drug, was developed, but carboplatin greatly alleviated nausea, vomiting, and kidney toxicity, which are the main toxicities of cisplatin, but bone marrow toxicity is stronger than cisplatin, and has anticancer activity. Compared to cisplatin, it is relatively low and has a narrow range of anticancer action.

Therefore, there is a need to develop a new metal-based anticancer drug that exhibits stronger anticancer activity than cisplatin and has fewer side effects caused by platinum.

Accordingly, the present inventors have made diligent efforts to develop a metal-based ligand-metal complex that has less side effects than platinum, and as a result, the complex of a ligand-metal complex with a benzocyazole derivative exhibits the effect of targeting tumors and has side effects. The present invention was completed by conceiving that this small number of anticancer agents could be developed.

Accordingly, an object of the present invention is to provide a metal complex represented by the following formula (1):

[Formula 1]

Another object of the present invention is (a) protecting the amine group of 2,3-diaminopropanoic acid with di-tert-butyl dicarbonate;

(b) bonding benzocyazole aniline (BTA) to the carboxylic acid group of 2,3-diaminopropanoic acid;

(c) deprotecting the protected amine group using trifluoroacetic acid (TFA);

(d) preparing a ligand by binding 2-hydroxybenzaldehyde to the deprotected amine group; And

(e) to provide a method for producing the metal complex comprising the step of coordinating a metal to the ligand.

In order to achieve the above object of the present invention, the present invention provides a metal complex represented by the following formula (1):

[Formula 1]

In order to achieve another object of the present invention, the present invention comprises the steps of: (a) protecting the amine group of 2,3-diaminopropanoic acid with di-tert-butyl dicarbonate;

(b) bonding benzocyazole aniline (BTA) to the carboxylic acid group of 2,3-diaminopropanoic acid;

(c) deprotecting the protected amine group using trifluoroacetic acid (TFA);

(d) preparing a ligand by binding 2-hydroxybenzaldehyde to the deprotected amine group; And

(e) it provides a method for producing the metal complex comprising the step of coordinating the metal to the ligand.

Hereinafter, the present invention will be described in detail.

The present invention provides a metal complex represented by the following formula (1):

[Formula 1]

The metal complex of the present invention has a structure in which benzocyazole aniline (BTA), which is a benzocyazole derivative, is bound, and this type of metal complex is disclosed for the first time through the present invention.

Cisplatin, one of the most useful anticancer agents among the anticancer drugs developed to date, has a problem that unwanted side effects and resistance to drugs appear because it does not have tumor selectivity. In order to solve this problem, in the present invention, a benzocyazole derivative that has high tumor targeting and exhibits anticancer, anti-inflammatory, antimalarial, antimicrobial, and antiviral effects by itself is bound to a ligand, which is a new type of metal complex. The compound of formula 1 was developed.

In the metal complex of the present invention, the metal M coordinating with the ligand may be used without limitation, as long as it is a metal capable of forming a coordination bond with the ligand, preferably nickel (Ni), cobalt (Co), and copper (Cu ) And manganese (Mn). On the other hand, nickel, cobalt, copper, and manganese are known to exhibit lower toxicity than platinum in vivo and to inhibit proliferation against various cell types such as breast cancer, blood cancer, and liver cancer.

The metal complex of Formula 1, in which a benzocyazole derivative having a high tumor targeting property is bound, and a metal having a lower biotoxicity than platinum is coordinated, is compared with the previously reported platinum-based anticancer drugs due to its high tumor targetability. It can exhibit excellent anticancer activity even at a low dose concentration, and can minimize side effects caused by administration of anticancer drugs.

On the other hand, the present invention (a) protecting the amine group of 2,3-diaminopropanoic acid with di-tert-butyl dicarbonate; (b) bonding benzocyazole aniline (BTA) to the carboxylic acid group of 2,3-diaminopropanoic acid; (c) deprotecting the protected amine group using trifluoroacetic acid (TFA); (d) preparing a ligand by binding 2-hydroxybenzaldehyde to the deprotected amine group; And (e) coordinating a metal to the ligand.

Each step of the method for manufacturing a metal complex of the present invention is illustrated in detail as shown in FIG. 1.

(a) 2,3- Of diaminopropanoic acid Amine group Protecting with di-tert-butyl dicarbonate;

In the step (a), under the reaction conditions for binding benzocyazole aniline (BTA) to the carboxylic acid group of 2,3-diaminopropanoic acid in the next step, 2,3-diaminopropanoic acids react with each other This is the step of protecting the amine group to prevent the formation of the product.

Specifically, after dissolving 2,3-diaminopropanoic acid in distilled water, sodium hydrogen carbonate is added, and the reaction temperature is adjusted to -10 to 10°C. Thereafter, di-tert-butyl dicarbonate dissolved in dioxane was added to the reaction solution, followed by stirring at a temperature of -10 to 10°C for 10 minutes to 1 hour. Thereafter, after stirring at room temperature for at least 5 hours, the reaction solution is acidified to a pH of 2 to 4, and the product is extracted with an organic layer to be separated and purified. 2,3-Bis-tert-butoxycarbonylamino-propionic acid (2,3-Bis-tert-butoxycarbonylamino-propionic acid) is produced through the above-described process (a).

(b) 2,3- Of diaminopropanoic acid Carboxylic acid group Benzocyazole Aniline (BTA) Combining;

In step (b), 2,3-bis-tert-butoxycarbonylaminopropanoic acid produced through step (a) is dissolved in pyridine, and then benzocyazole aniline (BTA) dissolved in pyridine is slowly added. Step.

According to an embodiment of the present invention, the reaction must be carried out in a pyridine solvent, and THF (tetrahydrofuran), ACN (acetonitrile), MeOH, DCM (dichloromethane), chloroform, potassium carbonate, potassium hydroxide, potassium iodide The reaction did not occur under other solvent conditions such as. In addition, it was confirmed that the reaction occurred only when triphenyl phosphite was added when the reaction was carried out in a pyridine solvent.

Therefore, in the present invention, the step (b) is characterized in that the reaction proceeds by using pyridine as a solvent and adding triphenylphosphite.

After mixing 2,3-bis-tert-butoxycarbonylaminopropanoic acid and benzocyazole aniline in a pyridine solvent condition, the mixture is stirred for 5 to 1 hour, and triphenylphosphite is added. The reaction is stirred at 60 to 100°C, preferably 70 to 90°C, more preferably 75 to 85°C for 1 hour to 5 hours, and then stirred at room temperature overnight. The precipitate produced through this process was recrystallized to obtain [2-(4-Benzothiazol-2-yl phenylcarbamoyl)-2-tert-butoxycarbonylamino-ethyl]-carbamic acid-tert-butyl ester.

(c) Trifluoroacetic acid (TFA) Using the protected Amine group Deprotection The step of doing;

After dissolving the [2-(4-Benzothiazol-2-yl phenylcarbamoyl)-2-tert-butoxycarbonylamino-ethyl]-carbamic acid-tert-butyl ester produced in step (b) in a solvent, the trifluoroacetic acid solution was slowly added. It is a step to remove the protected amine group by adding. Through the deprotection, 2,3-Diamoniumtrifluoroacetate-N-(4-benzothiazol-2-yl-phenyl)-propionamide is obtained.

(d) above Deprotected Amine group 2- Hydroxybenzaldehyde Binding to prepare a ligand;

The 2,3-Diamoniumtrifluoroacetate-N-(4-benzothiazol-2-yl-phenyl)-propionamide produced in step (c) was dissolved in an organic solvent, and salicylaldehyde was slowly added while stirring at 30 to 50°C. The mixture is further stirred at 50 to 70° C. for 2 to 5 hours, and then cooled to room temperature.

(e) a metal to the ligand Coordination Letting go;

This is a step of preparing a ligand-metal complex by coordinating a metal to the ligand prepared in step (d). The metal M coordinating with the ligand in the metal complex of the present invention may be used without limitation as long as it is a metal capable of forming a coordination bond with the ligand according to the present invention, preferably nickel (Ni), cobalt (Co) , Copper (Cu) and manganese (Mn) are selected from the group consisting of.

The method of coordinating the metal to the ligand is not particularly limited, and a person skilled in the art may appropriately perform it based on the technical common knowledge in the art.

According to an embodiment of the present invention, the present inventors performed the following method to coordinate cobalt, nickel, or manganese with the ligand produced in step (d):

(i) After dissolving Co(II) acetate tetrahydrate, Ni(II) acetate tetrahydrate or Mn(II) acetate tetrahydrate in anhydrous ethanol, N-(4-Benzothiazol-, a ligand produced in step (d) above, 2-yl-phenyl) -2,3-bis-[(2-hydroxy-benzylidene)-amino]-propionamide was added, and the reaction was boiled at 70 to 100° C. for 1 to 5 hours.

(ii) After cooling the reaction product to room temperature, the resulting powder is filtered.

The metal complex of the present invention can exhibit excellent anticancer activity even at a low dosage concentration compared to the previously reported platinum-based anticancer agents due to its high tumor targetability, and can minimize side effects caused by the administration of anticancer agents, making it useful for the development of excellent anticancer drugs. Can be utilized.

1 is a diagram illustrating each step of a method for manufacturing a metal-complex according to the present invention.

Hereinafter, the present invention will be described in detail.

However, the following examples are merely illustrative of the present invention, and the contents of the present invention are not limited to the following examples.

<Example 1>

Preparation of Ligand Conjugated to Benzocyazole Derivatives

Synthesis of 2,3-Bis-tert-butoxycarbonylamino-propionic acid (a)

_{The mixture was stirred while adding sodium hydrogen carbonate (NaHCO 3} ) (9.07 g, 108 mmol) to 2,3-diaminopropionic acid monohydrobromide (5 g, 27 mmol) dissolved in 108 mL of tertiary distilled water. The cleanly dissolved gastric solution was cooled to 0°C by installing an ice-bath. To the cooled solution, di- tert- butyl dicarbonate (14.73 g, 67.5 mmol) dissolved in dioxane (67.5 mmol) was slowly added thereto. The mixture was stirred at 0° C. for 30 minutes, and then stirred at room temperature overnight. The stirred mixture was cooled to 0° C. by installing an ice-bath again, and acidified to a pH of 2-3 using a 3 M aqueous hydrochloric acid solution. After the reaction, the product was extracted into the organic layer using water, brine, and ethyl acetate, and anhydrous magnesium sulfate (MgSO ₄ ) was added to the organic layer to remove the remaining water and filtered. When the solvent was removed from the filtered liquid under reduced pressure, it became a colorless oil. The resulting oil was dried under reduced pressure to obtain a white solid. The product was confirmed in a developing solution of butanol/water/acetic acid (8:1:1) by a thin layer chromatography method, and an alcohol solution containing 2% ninhydrin was used for detection.

Yield: 95%. IR (KBr, cm ^-1 ): 35003300 (st. OH, st. NH), 29772931 (st. CH), 1741 (st. C=O acid), 1695 (st. C=O), 1527 (ds NH , st. si. NC=O), 1443 (dip NH). 1H-NMR (400 MHz, CDCl ₃ ) d (ppm): 1.45 (s, 18 H, CH ₃ ), 3.55 (m, 2H, CH ₂ ), 4.12 (s, 1H, CH), 4.275.17 (m , 1H, NH), 5.85 (s, 1H, OH), 2.05 (s, 1H, NH). Anal. Calcd for [C ₁₃ H ₂₄ O ₆ N ₂ .1/2EtOAc] C, 51.71; H, 8.04; N, 8.10; Found: C, 51.87; H, 8.15; N, 7.75.

Synthesis of [2-(4-Benzothiazol-2-ylphenylcarbamoyl)-2-tert-butoxycarbonylamino-ethyl]-carbamic acid tert butyl ester(b)

Benzothiazole aniline (5.20 g, 23.01 mmol) dissolved in pyridine (20 ml) in 2, 3-Bis-tert-butoxycarbonylamino-propionic acid (a) (7.00 g, 23.01 mmol, 1.0 eq) in pyridine (40 ml) was added. It was added slowly. After the mixture was further stirred for 10 minutes, Triphenyl phosphite (7.13 ml, 23.01 mmol) was added. The reaction solution was stirred at 80° C. for 3 hours, and then stirred at room temperature overnight. The resulting powder was filtered while washing with distilled water and acetone. The obtained precipitate was recrystallized using anhydrous acetonitrile to obtain a white solid.

Yield: 9.6 g (81.4%), Anal. Calcd for C ₂₆ H ₃₂ N ₄ O ₅ S: C, 60.92; H, 6.29; N, 10.93; S, 6.26. Found: C, 60.05; H, 6.36; N, 10.60; S, 5.98. 1H NMR (400 MHz, CDCl ₃ ): δ = 9.28 (s, 1H, NH) 8.068.01 (m, 3H, BTA), 7.897.85 (d, 1H, BTA), 7.687.64 (d, 2H,) BTA), 7.497.44 (t, 1H, BTA), 7.387.33 (t, 1H, BTA), 5.97-5.93 (s, 2H, NH), 4.023.98 (d, 1H, CH) 3.57-3.41 ( m, 2H, CH ₂ ), 1.50-1.40 (d, 18H, CH ₃ ).

Synthesis of 2,3-Diamoniumtrifluoroacetate-N-(4-benzothiazol-2-yl-phenyl)-propionamide(c)

[2-(4-Benzothiazol-2-ylphenylcarbamoyl)-2-tert-butoxycarbonylamino-ethyl]-carbamicacid-tert-butyl ester(b) (1.5 g) dissolved in dichloromethane at 0 ℃ by installing an ice-bath , 2.92 mmol) trifluoroacetic acid solution (10 ml) was slowly added. The resulting yellow solution was removed from the solvent and ether was added to obtain a precipitate. The resulting precipitate was washed three more times with ether and filtered to obtain a pale yellow solid.

Yield: 90%, 1H NMR (400 MHz, MeOH-d): δ = 8.75 (s, 1H, NHO 8.017.99 (d, 2H, BTA), 7.97.89 (d, 2H, BTA), 7.827.78 (d, 2H, BTA), 7.45 (t, 1H, BTA), 7.35 (t, 1H, BTA) 4.43 (t, 1H, CH) 3.623.55 (dd, 1H, CH ₂ ) 3.51-3.44 (dd, 2H, CH ₂ ) 1.94 (s, 2H, NH).Anal.Calcd for (C ₁₆ H ₁₆ N ₄ OS): C, 44.45; H, 3.36; N, 10.37; S, 5.93.Found: C, 43.43; H, 3.54; N, 10.28; S, 5.56.

N-(4- Benzothiazol -2- yl - phenyl )-2,3- bis - [(2- hydroxy - benzylidene )- amino ]-propionamide (L _One ) Of the synthesis

2, 3-Diamoniumtrifluoroacetate-N-(4-benzothiazol-2-yl-phenyl)-propion-amide (c) (540 mg, 1 mmol) was dissolved in absolute ethanol and stirred at 40 °C while salicylaldehyde (salicylaldehyde) ( 0.270 ml, 2.1 mmol) was slowly dropped. The reaction was stirred at 60° C. for 3 hours, and then cooled to room temperature. The resulting suspension was washed with ethanol and diethyl ether, and then filtered to obtain a white solid.

Yield: 85%. 1H NMR (400 MHz, CDCl ₃ ): δ = 12.8 (s, 2H, Ar-OH) 12.01 (s, 1H, NH) 8.45 (s, 1H, CH) 8.36 (s, 1H, CH) 8.07-8.01 ( m, 3H, BTA), 7.907.86 (d, 1H, BTA), 7.717.66 (d, 2H, BTA), 7.497.44 (t, 1H, BTA), 7.417.38 (t, 1H, BTA) 7.36-7.25 (m, 3H, Ar-CH) 7.22-7.18 (d, 1H, Ar-CH) 7.04-6.81 (m, 4H, Ar-CH) 4.424.36 (m, 2H, CH ₂ ) 4.09-3.03 (m, 1H, CH). FT-IR: (KBr, cm ^-1 ) = 3299.9 w, 1665 s, 1633 s, 1524 s, 1407 s, 749 s. LC/MS: m/z (%): 521.2 (100.0%). Anal. Calcd. for (C ₃₀ H ₂₄ N ₄ O ₃ S): C, 69.21; H, 4.65; N, 10.76; S, 6.16. Found: C, 68.08; H, 4.59; N, 10.62; S, 6.24.

<Example 2>

Preparation of Ligand-Metal Complexes

CoL _One Synthesis of

N-(4-Benzothiazol-2-yl-phenyl) -2,3-bis- dissolved in absolute ethanol (15ml) while Co (II) acetate tetrahydrate (296 mg, 1.15 mmol) was dissolved in absolute ethanol (10ml) [(2-hydroxy-benzylidene)-amino]-propionamide (L ₁ ) (500 mg, 0.96 mmol) was added. The reactant was boiled at 80 °C by installing a reflux device. After 3 hours, the reaction was cooled to room temperature, washed with ethanol and diethyl ether, and the resulting powder was filtered off. The obtained powder was dried under vacuum to obtain a reddish brown solid.

Yield: 53.5%. FT-IR: (KBr, cm ^-1 ) = 3054 w, 1669 s, 1601 s, 1536 s, 1444 m, 1311 m. LC/MS: m/z (%) = 577.2 (100.0%). Anal.Calcd for (C ₃₀ H ₂₂ CoN ₄ O ₃ SH ₂ O): C, 60.50; H,4.06; N, 9.41; S, 5.38, Found: (C ₃₀ H ₂₂ CoN ₄ O ₃ S): C, 59.33; H, 3.77; N, 9.12; S, 5.54.

NiL _One Synthesis of

N-(4-Benzothiazol-2-yl-phenyl)-2, 3-bis dissolved in absolute ethanol (15 ml) while Ni (II) acetate tetrahydrate (216 mg, 0.87 mmol) was dissolved in absolute ethanol (10 ml) -[(2-hydroxy-benzylidene)-amino]-propionamide (L ₁ ) (300 mg, 0.58 mmol) was added. The reaction was boiled at 85°C by installing a reflux device. After 3 hours, the reaction was cooled to room temperature, washed with ethanol and diethyl ether, and the resulting powder was filtered off. The filtered powder was dried under reduced pressure to obtain a reddish brown solid.

Yield: 52.6%. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ = 10.60 (s, 1H, NH) 8.14-8.06 (dd, 3H, BTA), 8.02 (t, 2H, CH) 7.90 (s, 1H, BTA) , 7.867.83 (d, 2H, BTA), 7.53 (t, 1H, BTA) 7.44 (t, 1H, BTA) 7.297.15 (m, 4H, Ar-CH), 6.756.71 (m, 2H, Ar) -CH) 6.56-6.48 (m, 2H, Ar-CH) 4.31 (m, 1H, CH) 4.10 (m, 1H, CH ₂ ) 3.98 (m, 1H, CH ₂ ). FT-IR: (HBr, cm ^-1 ) = 3010 w, 1665 s, 1602 s, 1527 s, 1446 s, 1316 s 749 s. Anal. calcd. For (C ₃₀ H ₂₂ N ₄ NiO ₃ S): C, 62.42; H, 3.84; N, 9.71; S, 5.55, Found: C, 62.17; H, 3.90; N, 9.16; S, 5.45.

MnL _One Synthesis of

Manganese (II) acetate tetrahydrate (113 mg, 0.46 mmol) dissolved in absolute ethanol (10 ml) and N-(4-Benzothiazol-2-yl-phenyl) -2,3- dissolved in absolute ethanol (15 ml) bis-[(2-hydroxy-benzylidene)-amino]-propionamide (L ₁ ) (300 mg, 0.58 mmol) was added. The reactant was boiled at 85° C. by installing a reflux device. After 3 hours, the reaction was cooled to room temperature, washed with ethanol and diethyl ether, and the resulting powder was filtered off. The filtered powder was dried under reduced pressure to obtain a light brown solid.

Yield: 39%. Light brown powder. LC/MS: m/z (%) = 573.2 (100%). FT-IR: (HBr, cm ^-1 ) = = 3010 w, 1665 s, 1602 s, 1527 s, 1446 s, 1316 s 749 s. Anal. Calcd for (C ₂₀ H ₁₄ N ₂ O ₂ Mn): C, 62.73; H, 3.87; N, 9.77; S, 5.59. Found: C, 60.50; H, 4.06; N, 9.41; S: 5.38

The metal complex of the present invention can exhibit excellent anticancer activity even at a low dosage concentration compared to the previously reported platinum-based anticancer agents due to its high tumor targetability, and can minimize side effects caused by the administration of anticancer agents, making it useful for the development of excellent anticancer drugs. It can be utilized, so it has excellent industrial applicability.

Claims (4)

Metal complex represented by the following formula (1):
[Formula 1]

In the above formula, M is selected from the group consisting of nickel, cobalt, copper and manganese.
delete (a) protecting the amine group of 2,3-diaminopropanoic acid with di-tert-butyl dicarbonate;
(b) bonding benzocyazole aniline (BTA) to the carboxylic acid group of 2,3-diaminopropanoic acid;
(c) deprotecting the protected amine group using trifluoroacetic acid (TFA);
(d) preparing a ligand by binding 2-hydroxybenzaldehyde to the deprotected amine group; And
(e) Coordinating a metal selected from the group consisting of nickel, cobalt, copper and manganese to the ligand. delete

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