PT103665B - NEW CHROMIUM DERIVATIVES, THEIR SYNTHETIC PROCESS AND THEIR USE AS ANTIOXIDANT / PRESERVATIVES - Google Patents

Abstract

The present invention relates to obtaining new chromium amides with the following general formulas A and B, wherein R1 and R2 represent, respectively: R1 = R2 = H; R1 = H, R2 = OH; R1 = OH, R2 = OCH3; R1 = R2 = OCH3; R1 = R2 = OH. These novel compounds, with different substitution patterns, were obtained through a reaction of a concomitant 3-carbonate or 2-carboxy-monomer and aniline (phenylamine), or their substituted derivatives, with appreciable yields. THE OBTAINMENT OF DIHYROXYLATED DERIVATIVES WAS PERFORMED BY A REACTION OF DESMETIPLICATION OF MONOMETOXYLATED CHROMONS. SOME OF THESE COMPOUNDS HAVE APPLICATION AS ANTIOXIDANT AGENTS / PRESERVATIVES IN THE PHARMACEUTICAL, COSMETIC AND / OR FOOD INDUSTRY.

Description

1

DESCRIPTION "NEW CHROMONE DERIVATIVES, THEIR SYNTHESIS PROCESS AND ITS USE AS ANTIOXIDANTS / CONSERVATIVES"

Technical Field of the Invention The present invention relates to processes for the synthesis of novel chromone carboxamides with different substitution patterns in the phenyl group. This type of carboxamides is described for the first time as a suitable phenolic structure for the development of promising new antioxidant agents, either as additives for industry (pharmaceutical, cosmetic and food) or for possible application in therapy.

state of art

Antioxidants may be defined as substances which, at a considerably lower concentration than that of the oxidizable substrate, retard the oxidative process, slowing the initial rate of the oxidation reaction or prolonging its induction period. Antioxidants may exert their activity through various mechanisms of action such as at the radical level (primary antioxidants), by complexation of pro-oxidant transition metals (eg iron or copper) or by complementary action, effecting regeneration. of primary antioxidants by yielding hydrogen atoms. Since oxygen is an essential component of aerobic organisms, the formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is an inevitable process. Although their formation occurs in the course of normal biological processes, these species pose a threat to biological systems and play a crucial role in various oxidative damage. The generally accepted mechanism of action for endogenous and exogenous (HA) primary antioxidants, important for inactivation of ROS and RNS, involves the transfer of electrons, or hydrogen atoms, to present radicals such as alkyl radicals ( R *), peroxy (ROO *) and alkoxy (RO *), which are converted to more stable products RH, ROOH and ROH, respectively. At the same time, the formation of new radical species (Δ *) occurs from the antioxidant molecules (HA), which, being sufficiently stable, prevent / minimize oxidative phenomena.

In recent years this subject has become an emerging topic of research, particularly in the field of Health or Food Sciences, especially in the development of phenolic-type antioxidants for therapeutic or preventive purposes or for use as additives in pharmaceuticals. and food. However, to date, phenolic primary antioxidants have not yet been synthesized which simultaneously satisfy all of the intended premises, mainly due to problems related to their solubility and toxicity. Thus, it is therefore necessary to search for new chemical families that meet, after the appropriate structural modifications, the desired requirements.

Chromones are a group of oxygenated heterocyclic compounds that is widely disseminated in the plant kingdom. These compounds have a benzo-Y-pyrone nucleus, corresponding to the chromone itself (4H-chromen-4-one, 3,4 # -1-benzopyran-4-one) whose numbering system (according to IUPAC) is as indicated in the structure. : 3 8

The benzo-y-pyrone nucleus is considered to be the pharmacophore of a large number of bioactive molecules of natural and / or synthetic origin and has interesting structural properties for the development of new compounds. Today this family of compounds is recognized for the existence of numerous biological effects, especially in folk medicine, namely anti-allergic, anti-inflammatory, antitumor, antiplatelet, antioxidant, antiviral and antifungal activities. These compounds further possess the ability to inhibit the activity of some enzymes, namely oxidoreductases, kinases, tyrosinases, lipoxygenases and cyclooxygenases. It should also be noted that chromones are present in appreciable amounts in the human diet and have so far been reported to have low mammalian toxicity. The biological relevance of this chemical family has led to the design and development of new antioxidants, which have the particularity of having a carbon structure that gives them a greater lipophilia when compared to commercial antioxidants, and also pyrone ring substituents that, when carrying the functions can give them the desired activity. In this sense, the synthesis of two series of chromone carboxamides, considered appropriate for the evaluation of antioxidant activity and structure-activity relationship (SAR) studies, was planned. The present invention has as its object the development of novel chromone-type antioxidant agents, namely derivatives having the carbamoyl function (-CONH-). Series A and Series B chromonic structure compounds were obtained and described for the first time except compounds 1, 6 and 7. However, it is important to note that compounds 1, 6 and 7 were previously obtained by separate synthetic processes. described in this patent and for another application purpose.

Accordingly, various methods for obtaining carboxamides 1, 6 and 7 have been disclosed, either by reacting the respective acid halide with the corresponding amine, by a photochemical reaction, or as products derived from a 4-oxo-4H- 1-benzopyran-3-aldonitronas (see DE 964055/57, ZA 6907546/70, US 3937837/76, JP 57059884 A2 / 82, US 7026314/02, US 6552054/02, Mahajan et al., Chem. Ind. (London) 1990, 8: 261-262), whereas in the present invention, new chromone carboxamides with different substitution patterns are obtained by a synthesis method which generally consists of a condensation reaction between the 3-carboxychromone (A) or 2-carboxychromone (B) and aniline (phenylamine) or their substituted derivatives (C).

It is further noted that this amide synthesis process was carried out in appreciable yields by a one-step reaction between the chromone carboxylic acid and the amine in the presence of a suitable coupling reagent. 5th

In addition, for these compounds various applications have been proposed, namely as analgesics (see Bastide et al., Therapie 1966, 21: 1361-1369), anti-asthmatics (see US 3937837/76 and DE 2356900/74), anticoagulants (see in Tronche et al., Ann. Pharm. Franc. 1965, 23: 573-577), 5HT1B receptor antagonists in the treatment of some psychiatric disorders such as anxiety and panic (US 7026314/02) and as adjuvants in the treatment of various diseases. (US 6552054/02), whereas in the present invention their application is distinct as it is intended for the formulation of compounds with antioxidant / preservative activity.

The processes commonly used for obtaining such amides are based on first obtaining an acyl halide by reacting a carboxylic acid with thionyl chloride. This intermediate reacts in the next step with a nucleophile, which in the present case corresponds to the amine, as described in US 3862143, US 4331606, US 5604247, US 6552054, US 6908917, US 6812225, US 7026314 and US 7045514). The process disclosed in the present invention is based on a carboxylic acid activation reaction by a specific reagent, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), followed by an in situ nucleophilic attack reaction. of the amine. Since in this process carboxylic acid is the key reagent, it is particularly advantageous to avoid the additional activation step corresponding to the formation of the acid halide. In addition, the use of BOP obviates one of the major problems inherent in the purification and removal of side products when using classic coupling agents (such as dicyclohexylcarbodiimide - DCC).

General Description of the Invention

The compounds described in this invention have the following general formula:

Series A Series B

Where R1 and R2 represent:

R 1 = R 2 = H R 1 = H; R 2 = OH R 1 = OH; R2 = OCH3 Ri = R2 = OCH3 Ri = R2 = OH

The synthesized Series A compounds are: (1) 3- (Phenylaminocarbonyl) chromone, (2) 3- (4-Hydroxyphenylaminocarbonyl) chromone, (3) 3- (3-Hydroxy-4-methoxyphenylaminocarbonyl) chromone, (4) 3- (3,4-Dimethoxyphenylaminocarbonyl) chromone and (5) 3- (3,4-Dihydroxyphenylaminocarbonyl) chromone.

On the other hand, the B series compounds comprise: (6) 2- (Phenylaminocarbonyl) chromone, (7) 2- (4-Hydroxyphenylaminocarbonyl) chromone, (8) 2- (3-Hydroxy-4-methoxyphenylaminocarbonyl) chromone, (9) 2- (3,4-Dimethoxyphenylaminocarbonyl) chromone and (10) 2- (3,4-Dihydroxyphenylaminocarbonyl) chromone. Structural elucidation of the synthesized compounds was performed by standard analytical techniques, namely infrared (IR) spectroscopy, nuclear magnetic resonance (NMR) (1H, 13C) and mass spectroscopy (MS).

In order to obtain the dihydroxylated chromone amides, and in order to prevent prior protection of the hydroxyl groups of the starting material, a demethylation reaction of the monomethoxylated chromones 3 and 8 was chosen. Cleavage of the alkoxyl groups was achieved. through processes familiar to those skilled in the art and include, for example, the methods described in " Protective Groups in Organic Synthesis " from T.W. Green and P.G.M. Wuts, Wiley & Sons (1991) being advantageous in this case the use of a solution of boron tribromide in inert solvent (dichloromethane). The coupling reagent selected in this case and upon preliminary study was an organophosphate compound, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) (see under "Comprehensive Organic Synthesis", "Selectivity, Strategy and Efficiency in"). Modern Organic Chemistry, Ed. BM Trost, I. Fleming, E. Winterfeldt, Vol. 6, Pergamon Press, 1991). In the described reaction, W, W-diisopropylethylamine (DIPEA) was also successfully used, with an improvement over the classical use of triethylamine, especially with regard to purification processes.

8 A

COOH O

B

COOH O

hfeN

W

Ri = R2 = H

R1 = H; R2 = OH

R1 = OH; R2 = OCH3 Ri = R2 = OCH3 Evaluation of antioxidant activity against different radicals was carried out by methods already described in the literature (C. Siquet, F. Paiva-Martins, JLFC Lima, S. Reis, F. Borges " Antioxidant activity of dihydroxy- and trihydroxyphenolic acids - a structure-activity study " Free Rad. Res., 2006, 40 (4), 433-442), showing that the most promising compounds correspond to chromones 2, 5, 7 and 10, which have the phenolic nucleus. The phenylaminocarbonyl group substituted by phenolic hydroxyl groups is referred to for the first time as a pharmacophor relevant to antioxidant activity. These types of compounds may thus be applied as antioxidant agents, at therapeutic or industrial level, in situations where it is necessary to prevent or minimize oxidative damage. The performance and relative chemical stability of the compounds make it possible to foresee their possible application in the Industry (Pharmaceutical, Cosmetic and Food). These compounds are further considered to be useful tools for the study of other biological activities, particularly those related to oxidative stress. 9th

Detailed Description of the Invention 1. Novel Cromonas-Derived Compounds

The chromone carboxamides obtained in this invention correspond to the introduction of phenylaminocarbonyl groups with different substitution patterns in the aromatic ring at the 3- or 2- positions of the γ-pyrone nucleus.

The compounds described are as follows: 3- (phenylaminocarbonyl) chromone, 3- (4-hydroxyphenylaminocarbonyl) chromone, 3- (3-hydroxy-4-methoxyphenylaminocarbonyl) chromone, 3- (3,4-dimethoxyphenylaminocarbonyl) chromone, 3 - (3,4-dihydroxyphenylaminocarbonyl) chromone, 2- (phenylaminocarbonyl) chromone, 2- (4-hydroxyphenylaminocarbonyl) chromone, 2- (3-hydroxy-4-methoxyphenylaminocarbonyl) chromone, 2- (3,4-dimethoxyphenylaminocarbonyl) chromone and 2- (3,4-dihydroxyphenylaminocarbonyl) chromone. The structural elucidation of these compounds was performed by standard analytical techniques, namely IR, 1 H-NMR, 13 C and DEPT) and MS spectroscopy. Melting points were obtained under a Köfler microscope (Reichert Thermovar) and uncorrected. 2. Chromone Carboxamide Synthesis Process The synthesis process advocated herein is an equimolar condensation reaction between the carboxylic acid and the respective amine, which is translated as follows: To a solution of 3-carboxychromone or 2-carboxylic acid Carboxychromone in DMF and DIPEA cooled to 0 ° C is added a solution of BOP in CH 2 Cl 2 (in equimolar amount). 10

After stirring the solution at the stated temperature for 30 minutes, the commercial amine (phenylamine or 4-hydroxyphenylamine or 3-hydroxy-4-methoxyphenylamine or 3,4-dimethoxyphenylamine) is added and then increased. temperature to room temperature. Stirring should be continued for 4 h. 3. Chromone carboxamide demethylation process To a suspension of methoxylated chromone carboxamide (0.80 mmol) in anhydrous dichloromethane in an argon atmosphere cooled to -80 ° C, a solution of 1 M BBr3 (6 mL) is added. allowing to react until room temperature is reached.

Example 1

Obtaining 3- (phenylaminocarbonyl) chromone [W-Phenyl-4-οχο-4H-chromone-3-carboxamide] (1) and 2- (phenylaminocarbonyl) chromone [(N-Phenyl-4-oxo-4i-chromone- 2-carboxamide) (6) To a solution of 3-carboxychromone (A) or 2-carboxychromone (B) (2.63 mmol; 0.50 g) in DMF (6 mL) and DIPEA (0, 37 mL), cooled to 0 ° C, was added a solution of BOP (2.63 mmol, 1.16 g) in CH 2 Cl 2 (6 mL). After stirring the solution at said temperature for 30 min, phenylamine (2.63 mmol; 0.24 mL) was added. After gradually raising the temperature to room temperature, stirring was continued for a further 4 h. After this time the solvent was removed with the aid of reduced pressure. Purification of the desired product was by column chromatography (silica gel; petroleum ether / ethyl ether in various proportions). The fractions containing the desired product were combined, the solution was discolored with activated charcoal and crystallized from ethyl acetate.

Compound (1): Yield: 81%; 210-213 ° C Compound (6): Yield: 60%; MP: 239-242 ° C

Example 2

Obtaining 3- (4-hydroxyphenylaminocarbonyl) chromone [N- (4-Hydroxyphenyl) -4-oxo-4'-chromone-3-carboxamide] (2) and 2- (4-hydroxyphenylaminocarbonyl) chromone [N- (4- Hydroxyphenyl) -4-oxo-4'-chromone-2-carboxamide] (7) To a solution of 3-carboxychromone (A) or 2-carboxychromone (B) (2.63 mmol; 0.50 g) in DMF (6 mL) and in DIPEA (0.37 mL) cooled to 0 ° C, a solution of BOP (2.63 mmol, 1.16 g) in CH 2 Cl 2 (6 mL) was added. After stirring the solution at said temperature for 30 min, 4-hydroxyphenylamine (2.63 mmol; 0.29 g) was added. Stirring was continued for approximately 4 h, after gradually raising the temperature to room temperature. After the reaction, the solvent was removed under reduced pressure. Purification of the desired product was by column chromatography (silica gel; petroleum ether / ethyl ether in various proportions). The fractions containing the desired product were combined, the solution was discolored with activated charcoal and crystallized from ethyl acetate.

Compound (2): Yield: 51%; 277-281 ° C Compound (7): Yield: 55%; MP: 290-293 ° C

Example 3 12

Obtaining 3- (3-hydroxy-4-methoxyphenylaminocarbonyl) chromone [N- (3-Hydroxy-4-methoxyphenyl) -4-oxo-4H-chromone-3-carboxamide] (3) and 2- (3-hydroxy -4-methoxyphenylaminocarbonyl) chromone [N- (3-Hydroxy-4-methoxyphenyl) -4-oxo-4H-chromone-2-carboxamide] (8) To a solution of 3-carboxychromone (A) or 2-carboxychromone (B), (0.53 mmol; 0.10 g) in DMF (1.5 mL) and DIPEA (0.075 mL), cooled to 0 ° C, added a solution of BOP (0.53 mmol; 0.23 g) in CH 2 Cl 2 (1.5 mL). After stirring the solution at said temperature for approximately 30 min, 3-hydroxy-4-methoxyphenylamine (0.53 mmol; 0.07 g) was added. Stirring was continued for approximately 4 h, after gradually raising the temperature to room temperature. After the reaction, the solvent was removed under reduced pressure. Purification of the desired product was by column chromatography (silica gel; petroleum ether / ethyl acetate and ethyl acetate / methanol in various proportions). The fractions containing the desired product were combined, the solution was discolored with activated charcoal and crystallized from ethyl acetate.

Compound (3): Yield: 57%; MP: 266-267 ° C Compound (8): Yield: 45%; MP: 255-257 ° C

Example 4

Obtaining 3- (3,4-dimethoxyphenylaminocarbonyl) chromone [N- (3,4-Dimethoxyphenyl) -4-oxo-4'-chromone-3-carboxamide] (4) and 2- (3,4-dimethoxyphenylaminocarbonyl) chromone [N- (3,4-Dimethoxyphenyl) -4-oxo-4'-chromone-2-carboxamide)] (9) 13 To a solution of 3-carboxychromone (A) or 2-carboxychromone (B), (5 , 26 mmol; 1.00 g) in DMF (15 mL) and DIPEA (0.75 mL) cooled to 0 ° C, added a solution of BOP (5.26 mmol; 2.30 g) in CH 2 Cl 2 (15 mL). After stirring the solution at said temperature for 30 min, 3,4-dimethoxyphenylamine (26 mmol; 0.80 g) was added. Stirring was continued for approximately 4 h, after gradually raising the temperature to room temperature. After the reaction, the solvent was removed under reduced pressure. Purification of the desired product was by column chromatography (silica gel; petroleum ether / ethyl acetate and ethyl acetate / methanol in various proportions). The fractions containing the desired product were combined, the solution was discolored with activated charcoal and crystallized from ethyl acetate.

Compound (4): Yield: 45%; MP: 196-198 ° C.

Compound (9): Yield: 50%; MP: 248-254 ° C.

Example 5

Obtaining 3- (3,4-dihydroxyphenylaminocarbonyl) chromone [N- (3,4-Dihydroxyphenyl) -4-oxo-4'-chromone-3-carboxamide] (5) and 2- (3,4-dihydroxyphenylaminocarbonyl) chromone [N- (3,4-Dihydroxyphenyl) -4-oxo-4'-chromone-2-carboxamide)] (10) To a suspension of 3- (3-hydroxy-4-methoxyphenylaminocarbonyl) chromone [or 2- (3- hydroxy-4-methoxyphenylaminocarbonyl) chromone] (0.80 mmol, 0.25 g) in anhydrous dichloromethane, under argon atmosphere cooled to -80 ° C, a solution of BBr3 (6 mL of 1 M solution in dichloromethane) was added. ), allowing to react until it reaches room temperature. After destroying BBr3 with methanol, insolubilization of a product was performed which was subjected to column chromatography (silica gel; chloroform and chloroform / methanol in various proportions).

Compound (5): Yield: 65%; MP: 270-272 ° C Compound (10): Yield: 50%; MP: 280-283 ° C

Lisbon, February 27, 2007

Claims (1)

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