Description:DESCRIPTION:
Field of the invention:
[0001] The present disclosure generally relates to the technical field of anti-cancer drugs and, in specific, relates to a method for synthesizing novel napthalamide derivatives 3,4- Difluoro aniline and 6-amino-2(3,4-difluorophenyl)-1H-benzol[de]isoquinoline-1,3(2h)-dione with anti-proliferative action for reducing the risk of cancer.
Background of the invention:
[0002] There is considerable interest in modulating the efficacy of currently used anti-proliferative agents to increase the rates and duration of antitumor effects associated with conventional antineoplastic agents.

[0003] Conventional anti-proliferative agents used in the treatment of cancer are broadly grouped as chemical compounds that affect the integrity of nucleic acid polymers by binding, alkylating, inducing strand breaks, intercalating between base pairs, or affecting enzymes that maintain the integrity and function of DNA and RNA; chemical agents that bind to proteins to inhibit enzymatic action (e.g., antimetabolites); or the function of structural proteins necessary for cellular integrity (e.g., antitubulin agents). Other chemical compounds that have been identified to be useful in the treatment of some cancers include drugs that block steroid hormone action for the treatment of breast and prostate cancer, photochemically activated agents, radiation sensitizers, and protectors. Although the clinical activity of currently approved anti-proliferative agents against many forms of cancer can be shown, improvements in tumor response rates, duration of response, and ultimately patient survival are still sought.

[0004] Studies of the characteristics of materials as well as the design and synthesis of novel 4-substituted 1, 8-naphthalimide structures have received a lot of attention in recent years. Naphthalimide core is considered one of the most versatile fluorophore units owing to its unique photophysical properties, which have been extensively explored in various real-world applications. Additionally, the naphthalimide ring can be substituted at the 3- or 4-position by amino or nitro groups. This not only allows the introduction of other functional groups, which can be used for targeting biomolecules, but can also have a major effect on the electronic properties with a consequent influence on the chemical, photochemical, and spectroscopic properties.

[0005] The introduction of various electron-donating or electron-accepting moieties at the C-4 position in the 1,8-naphthalimide unit opens a wide range of possibilities for altering the optical, fluorescence, thermal, electrochemical, electroluminescent, and photoelectrical properties of 1,8-naphthalimide compounds. The optical and photophysical properties of 1,8-naphthalimides are very sensitive to substitution in the aromatic ring. Fictionalisation with an amino function at the 3, 4, 5, or 6 position of the ring produces compounds that possess internal charge transfer (ICT) transitions. The resultant band in the absorption spectrum is shifted to the visible and shows a marked solvatochromic effect. Its UV-visible absorption and fluorescence emission energy fall within the visible region and can be tuned up to the near-IR region, which could provide an excellent platform to probe the microenvironment of biological systems.

[0006] In the area of anticancer research, the development of small molecules are capable of binding to deoxyribonucleic acid (DNA) and exhibiting anticancer activities has received enormous attention in recent times. Amongst the sites, it has been shown that 1,8-naphthalimides (benz[de]isoquinolin-1,3-diones) possess high anti-tumour activity towards various human and murine cells, and the aim of this review is to highlight their use as potential anticancer agents.

[0007] Another feature of the naphthalimides is their ability to target biomolecules, in particular nucleic acids. Indeed, many naphthalimides already form strong intermolecular complexes with mononucleotides. The planar nature of the aromatic core suggests that the molecule should intercalate itself between the base pairs of DNA, and this behavior has been assumed in many cases. However, it should always be borne in mind that small molecules can bind to DNA in a number of ways, for example, by binding to the grooves or externally (especially if the molecules show a propensity for stacking). Also, it is possible that the binding mode may depend on the DNA sequence.

[0008] By addressing all the above-mentioned problems, there is a need for a method for synthesizing novel napthalamide derivatives 3,4- Difluoro aniline and 6-amino-2(3,4-difluorophenyl)-1H-benzol[de]isoquinoline-1,3(2h)-dione for anti-proliferative activity to reduce the risk of cancer.
Objectives of the invention:
[0009] The primary objective of the present invention is to provide a method for synthesizing novel napthalamide derivatives 3,4- Difluoro aniline and 6-amino-2(3,4-difluorophenyl)-1H-benzol[de]isoquinoline-1,3(2h)-dione for anti-proliferative activity to reduce the risk of cancer.
Summary of the invention:
[0010] The present disclosure proposes a method for synthesizing novel napthalamide derivatives for use in preparation of an anti-cancer drug. The following presents a simplified summary in order to provide a basic understanding of some aspects of the claimed subject matter. This summary is not an extensive overview. It is not intended to identify key/critical elements or to delineate the scope of the claimed subject matter. Its sole purpose is to present some concepts in a simplified form as a prelude to the more detailed description that is presented later.

[0011] In order to overcome the above deficiencies of the prior art, the present disclosure is to solve the technical problem to provide a method for synthesizing novel napthalamide derivatives for anti-proliferative activity, thereby reducing the risk of cancer.

[0012] According to one aspect, the invention provides a method for synthesizing a napthalamide derivative a 6-amino-2-(3, 4-difluorophenyl)-1H-benzo [de]isoquinoline-1, 3(2H)-dione for anti-proliferative action to reduce the risk of cancer. Initially, at one step, an acenapthalene is converted into a nitro acenapthalene using a nitration process. The acenapthalene is a raw material of at least one napthalamide derivative.

[0013] At another step, the nitro acenapthalene is converted into a 4-nitro-1,8-naphthalic anhydride by oxidation process. At another step, the 3,4 di flouro aniline is added to the 4-nitro-1,8-naphthalic anhydride in ethanol to obtain the reaction mixture, thereby refluxing the obtained reaction mixture under nitrogen atmosphere for a time period of 12 hr to obtain 2-(3, 4-difluorophenyl)-6 nitro-1H-benzo [de]isoquinoline-1, 3(2H)-dione.

[0014] Further at other step, the 2-(3, 4-difluorophenyl)-6 nitro-1H-benzo [de]isoquinoline-1, 3(2H)-dione is dissolved in a methanol solution of stannous chloride dehydrate and added with hydrochloric acid to obtain a reaction mixture. The reaction mixture is heated under reflux for a time period of 12 hr for reduction, thereby obtaining a 6-amino-2-(3, 4-difluorophenyl)-1H-benzo [de]isoquinoline-1, 3(2H)-dione.

[0015] In one embodiment, the preparation method for a nitro acenapthalene comprises initially, the acenapthalene is taken in a round bottom flask and added with a 1.5 equivalent of concentrated nitric acid to obtain the reaction mixture. The obtained reaction mixture is heated at a temperature of 68°C for a time period of 1 hr. The obtained reaction mixture is monitored by a thin layer chromatography (TLC).

[0016] In one embodiment, the reaction mixture is extracted with ethyl acetate and the reaction mixture is washed with a saturated brine solution to forming organic layers in the reaction mixture. The combined organic layers of the reaction mixture are dried over anhydrous Na2SO4 and concentrated in vacuo to obtain a crude product. Finally, the obtained crude product is purified by column chromatography on silica gel (60-120 mesh) using 15:85 ethyl acetate, thereby obtaining the desired product as brownish color solid with a 78% yield.

[0017] In one embodiment, the preparation method for the 4-nitro-1,8-naphthalic anhydride comprises, initially the obtained nitro acenapthalene is added to a solution of odium dihydrate in 25 ml of glacial acetic acid under stirring, thereby obtaining a reaction mixture. The obtained reaction mixture is heated under reflux at a temperature of 120°C for a time period of at least 6 hr, thereby obtaining a dark green liquor. The dark green liquor is washed with 20 ml of cold water and cooled down to obtain a yellow-orange residue.

[0018] In one embodiment, the obtained yellow-orange residue is washed with a small amount of glacial acetic acid and stirred into a 4% aqueous solution of sodium hydroxide to obtain a solution. The obtained solution is filtered by a Buchner funnel, and the filtered solution is neutralized with a 4% aqueous solution of hydrochloric acid to obtain a yield of 54% of an orange precipitate, thereby obtaining a crude product. Finally, the obtained crude product is purified by column chromatography on silica gel of 60-120 mesh using 15:85 ethyl acetate to obtain the desired product as a brownish color solid with 78% yield.

[0019] In one embodiment, the preparation method for the 2-(3, 4-difluorophenyl)-6 nitro-1H-benzo [de]isoquinoline-1, 3(2H)-dione comprises Initially, 3, 4 di flouro aniline of 1 g, 3.3 mmol is added to the -nitro-1,8-naphthalic anhydride 104 of 810 mg, 3.32 mmol in ethanol to obtain a reaction mixture. The obtained reaction mixture is heated under reflux nitrogen atmosphere for a time period of at least 12 hr and the reaction mixture is monitored upon completion by thin layer chromatography (TLC).

[0020] In one embodiment, the reaction mixture is cooled to a temperature of 0°C and diluted with 25 ml of cold water. The reaction mixture, upon dilution, is filtered through a Buchner funnel to obtain a pale yellow solid and washed with water followed by ethanol thereby obtaining a crude product. Finally, the obtained crude product is purified by a column chromatography on silica gel of 230–400 mesh using 5:95 ethyl acetate, thereby obtaining the desired product as pale yellow color solid.

[0021] In one embodiment, the preparation method for the 6-amino-2-(3, 4-difluorophenyl)-1H-benzo [de]isoquinoline-1, 3(2H)-dione comprises, initially the 2-(3, 4-difluorophenyl)-6 nitro-1H-benzo [de]isoquinoline-1, 3(2H)-dione 106 of 1.35 g, 2.544 mmol is dissolved in methanol and heated under nitrogen atmosphere. In one embodiment, the 2-(3, 4-difluorophenyl)-6 nitro-1H-benzo [de]isoquinoline-1, 3(2H)-dione 106 is added with a solution of stannous chloride dihydrate of 3.45 g, 15.26 mmols in 5 ml of concentrated hydrochloric acid drop wise to obtain a reaction mixture. The obtained reaction mixture is heated under reflux for a time period of at least 12 hr and filtered through a Buchner funnel to obtain a yellow solid. In one embodiment herein, the obtained yellow solid is washed with water followed by ethanol to obtain a crude product. Finally, the obtained crude product is purified by column chromatography on silica gel of 230- 400 mesh using 15:85 ethylacetate to obtain the desired product as yellow color solid.

[0022] Further, objects and advantages of the present invention will be apparent from a study of the following portion of the specification, the claims, and the attached drawings.
Detailed description of drawings:
[0023] The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate an embodiment of the invention, and, together with the description, explain the principles of the invention.

[0024] FIG. 1 illustrates a schematic view of a preparation method for a nitro acenapthalene in accordance to an exemplary embodiment of the invention.

[0025] FIG. 2 illustrates a schematic view of a preparation method for a 4-nitro-1,8-naphthalic anhydride, in accordance to an exemplary embodiment of the invention.

[0026] FIGs. 3A-3B illustrate a schematic view of a preparation method for a 2-(3, 4-difluorophenyl)-6 nitro-1H-benzo [de]isoquinoline-1, 3(2H)-dione, in accordance to an exemplary embodiment of the invention.

[0027] FIGs. 4A-4B illustrate a schematic view of a preparation method for a 6-amino-2-(3, 4-difluorophenyl)-1H-benzo [de]isoquinoline-1, 3(2H)-dione, in accordance to an exemplary embodiment of the invention.

[0028] FIG. 5 illustrates a flowchart of a method for synthesizing a napthalamide derivative for anti-proliferative action to reduce the risk of cancer, in accordance to an exemplary embodiment of the invention.
Detailed invention disclosure:
[0029] Various embodiments of the present invention will be described in reference to the accompanying drawings. Wherever possible, same or similar reference numerals are used in the drawings and the description to refer to the same or like parts or steps.

[0030] The present disclosure has been made with a view towards solving the problem with the prior art described above, and it is an object of the present invention to provide a method for synthesizing novel napthalamide derivatives 3,4- Difluoro aniline and 6-amino-2(3,4-difluorophenyl)-1H-benzol[de]isoquinoline-1,3(2h)-dione for anti-proliferative activity, thereby using as an anti-cancer drug for reducing the risk of cancer.

[0031] According to one exemplary embodiment of the invention, FIG. 1 refers to a schematic view of a preparation method for nitro acenapthalene 102. Initially, acenapthalene is taken in a round bottom flask and added to a 1.5 equivalent of concentrated nitric acid to obtain a reaction mixture. The obtained reaction mixture is heated at a temperature of 68°C for a time period of 1 hr. The obtained reaction mixture is monitored by a thin layer chromatography (TLC).

[0032] In one embodiment herein, the reaction mixture is extracted with ethyl acetate and the reaction mixture is washed with saturated brine solution to forming organic layers in the reaction mixture. The combined organic layers of the reaction mixture are dried over anhydrous Na2SO4 and concentrated in vacuo to obtain a crude product. Finally, the obtained crude product is purified by column chromatography on silica gel (60-120 mesh) using 15:85 ethyl acetate, thereby obtaining the desired product as brownish color solid with 78% yield. The nuclear magnetic resonance (NMR) spectrum of the nitro acenapthalene 102 is recorded in CDCL3 solvent.

[0033] According to another exemplary embodiment of the invention, FIG. 2 refers to a schematic view of a preparation method for a 4-nitro-1,8-naphthalic anhydride 104. Initially, the obtained nitro acenapthalene 102 is added to a solution of odium dihydrate in 25 ml of glacial acetic acid under stirring, thereby obtaining a reaction mixture. The obtained reaction mixture is heated under reflux at a temperature of 120°C for a time period of at least 6 hr, thereby obtaining a dark green liquor. The dark green liquor is washed with 20 ml of cold water and cooled down to obtain a yellow-orange residue.

[0034] In one embodiment herein, the obtained yellow-orange residue is washed with a small amount of glacial acetic acid and stirred into a 4% aqueous solution of sodium hydroxide to obtain a solution. The obtained solution is filtered by a Buchner funnel, and the filtered solution is neutralized with a 4% aqueous solution of hydrochloric acid to obtain a yield of 54% of an orange precipitate, thereby obtaining a crude product. Finally, the obtained crude product is purified by column chromatography on silica gel of 60–120 mesh using 15:85 ethyl acetate to obtain the desired product as brownish color solid with 78% yield. The NMR spectrum of the 4-nitro-1,8-naphthalic anhydride 104 is recorded in CDCL3 solvent.

[0035] According to another exemplary embodiment of the invention, FIGs. 3A-3B refers to a schematic view of a preparation method for a 2-(3, 4-difluorophenyl)-6 nitro-1H-benzo [de]isoquinoline-1, 3(2H)-dione 106. Initially, 3, 4 di flouro aniline of 1 g, 3.3 mmol, is added to the -nitro-1,8-naphthalic anhydride 104 of 810 mg, 3.32 mmol, in ethanol to obtain a reaction mixture. The obtained reaction mixture is heated under reflux nitrogen atmosphere for a time period of at least 12 hr and the reaction mixture is monitored upon completion by thin layer chromatography (TLC).

[0036] In one embodiment herein, the reaction mixture is cooled to a temperature of 0°C and diluted with 25 ml of cold water. The reaction mixture upon dilution is filtered through a Buchner funnel to obtain a pale yellow solid and washed with water followed by ethanol thereby obtaining a crude product.Finally, the obtained crude product is purified by a a column chromatography on silica gel of 230-400 mesh using 5:95 ethyl acetate, thereby obtaining desired product as pale yellow color solid.

[0037] According to another exemplary embodiment of the invention, FIGs. 4A-4B refers to a schematic view of a preparation method for a 6-amino-2-(3, 4-difluorophenyl)-1H-benzo [de]isoquinoline-1, 3(2H)-dione 108. Initially, the 2-(3, 4-difluorophenyl)-6 nitro-1H-benzo [de]isoquinoline-1, 3(2H)-dione 106 of 1.35 g, 2.544 mmol is dissolved in methanol and heated under nitrogen atmosphere.

[0038] In one embodiment herein, the 2-(3, 4-difluorophenyl)-6 nitro-1H-benzo [de]isoquinoline-1, 3(2H)-dione 106 is added with a solution of stannous chloride dihydrate of 3.45 g, 15.26 mmols in 5 ml of concentrated hydrochloric acid drop wise to obtain a reaction mixture. The obtained reaction mixture is heated under reflux for a time period of at least 12 hr and filtered through a Buchner funnel to obtain a yellow solid.In one embodiment herein, the obtained yellow solid is washed with water followed by ethanol to obtain a crude product. Finally, the obtained crude product is purified by column chromatography on silica gel of 230- 400 mesh using 15:85 ethylacetate to obtain the desired product as yellow color solid.

[0039] According to another exemplary embodiment of the invention, FIG. 5 refers to a flowchart 500 of a method for synthesizing a napthalamide derivative a 6-amino-2-(3, 4-difluorophenyl)-1H-benzo [de]isoquinoline-1, 3(2H)-dione 108 for anti-proliferative action to reduce the risk of cancer. At step 502, the acenapthalene is converted into the nitro acenapthalene 102 using a nitration process. The acenapthalene is a raw material for at least one napthalamide derivative.

[0040] At step 504, the nitro acenapthalene 102 is converted into the 4-nitro-1,8-naphthalic anhydride 104 by the oxidation process. At step 506, the 3,4 di flouro aniline is added to the 4-nitro-1,8-naphthalic anhydride in ethanol to obtain the reaction mixture, thereby refluxing the obtained reaction mixture under nitrogen atmosphere for a time period of 12 hr to obtain the 2-(3, 4-difluorophenyl)-6 nitro-1H-benzo [de]isoquinoline-1, 3(2H)-dione 106.

[0041] At step 508, the 2-(3, 4-difluorophenyl)-6 nitro-1H-benzo [de]isoquinoline-1, 3(2H)-dione is dissolved in a methanol solution of stannous chloride dehydrate and added to hydrochloric acid to obtain a reaction mixture. The reaction mixture is heated under reflux for a time period of 12 hr for reduction, thereby obtaining a 6-amino-2-(3, 4-difluorophenyl)-1H-benzo [de]isoquinoline-1, 3(2H)-dione 108.

[0042] Numerous advantages of the present disclosure may be apparent from the discussion above. In accordance with the present disclosure, a method for synthesizing novel napthalamide derivatives is disclosed. The proposed invention provides a method for synthesizing novel napthalamide derivatives 3,4- Difluoro aniline and 6-amino-2(3,4-difluorophenyl)-1H-benzol[de]isoquinoline-1,3(2h)-dione for anti-proliferative activity, for reducing the risk of cancer.

[0043] It will readily be apparent that numerous modifications and alterations can be made to the processes described in the foregoing examples without departing from the principles underlying the invention, and all such modifications and alterations are intended to be embraced by this application.
, Claims:CLAIMS:
I/We Claim:
1. A method for synthesizing a napthalamide derivative 6-amino-2-(3, 4-difluorophenyl)-1H-benzo [de]isoquinoline-1, 3(2H)-dione (108) for anti-proliferative action to reduce the risk of cancer, comprising:
converting an acenapthalene into a nitro acenapthalene (102) using a nitration process, wherein the acenapthalene is a raw material of at least one napthalamide derivative;
converting the nitro acenapthalene (102) into a 4-nitro-1,8-naphthalic anhydride (104) by oxidation process;
adding 3,4 di flouro aniline to the 4-nitro-1,8-naphthalic anhydride in ethanol to obtain a reaction mixture, thereby refluxing the obtained reaction mixture under nitrogen atmosphere for a time period of 12 hr to obtain a 2-(3, 4-difluorophenyl)-6 nitro-1H-benzo [de]isoquinoline-1, 3(2H)-dione (106); and

dissolving the 2-(3, 4-difluorophenyl)-6 nitro-1H-benzo [de]isoquinoline-1, 3(2H)-dione in methanol solution of stannous chloride dehydrate and adding hydrochloric acid to obtain a reaction mixture, wherein the reaction mixture is heated under reflux for a time period of 12 hr for reduction, thereby obtaining a 6-amino-2-(3, 4-difluorophenyl)-1H-benzo [de]isoquinoline-1, 3(2H)-dione (108).

2. The method as claimed in claim 1, wherein the method for preparing the nitro acenapthalene (102) by nitration process, comprises:
taking acenapthalene in a round bottom flask and adding a 1.5 equivalent of concentrated nitric acid to obtain a reaction mixture;
heating the obtained reaction mixture at a temperature of 68°C for a time period of 1 hr;
monitoring the obtained reaction mixture by thin layer chromatography (TLC);
extracting the reaction mixture with ethyl acetate and washing the reaction mixture with saturated brine solution, thereby forming organic layers to the reaction mixture;
drying the combined organic layers of the reaction mixture over anhydrous Na2SO4 and concentrated in vacuo, thereby obtaining a crude product; and
purifying the crude product by column chromatography on silica gel (60-120 mesh) using 15:85 ethyl acetate, thereby obtaining the desired product as brownish color solid with 78% yield.
3. The method as claimed in claim 1, wherein the method of preparing the 4-nitro-1,8-naphthalic anhydride (104), comprises:
adding nitro acenapthalene (102) to a solution of sodium dihydrate in 25 ml glacial acetic acid under stirring, thereby obtaining a reaction mixture;
heating the obtained reaction mixture under reflux at a temperature of 120°C for a time period of at least 6 hr, thereby obtaining a dark green liquor;
washing the dark green liquor with 20 ml of cold water and cooled down to obtain a yellow-orange residue;
washing the yellow-orange residue with a small amount of glacial acetic acid with stirring to a 4% aqueous solution of sodium hydroxide, thereby obtaining a solution;
filtering the solution by a Buchner funnel and neutralizing the filtered solution with a 5% aqueous solution of hydrochloric acid to obtain a yield of 54% of an orange precipitate, thereby obtaining a crude product; and
purifying the obtained crude product by column chromatography on silica gel of 60-120 mesh using 15:85 ethyl acetate to obtain the desired product as brownish color solid with 78% yield.
4. The method as claimed in claim 1, wherein the method of preparing the 2-(3, 4-difluorophenyl)-6 nitro-1H-benzo [de]isoquinoline-1, 3(2H)-dione (106), comprises:
adding 3, 4 di flouro aniline of 1 g, 3.3 mmol to the 4-nitro-1,8-naphthalic anhydride (104) of 810 mg, 3.32 mmol in ethanol, thereby obtaining a reaction mixture;
heating the obtained reaction mixture under reflux nitrogen atmosphere for a time period of at least 12 hr and monitoring the reaction mixture upon completion by thin layer chromatography (TLC);
cooling the reaction mixture to 0°C and diluting with 25 ml of cold water;
filtering the reaction mixture through a Buchner funnel to obtain a pale yellow solid and washing with water followed by ethanol thereby obtaining a crude product; and
purifying the crude product by a column chromatography on silica gel of 230-400 mesh using 5:95 ethyl acetate, thereby obtaining desired product as pale yellow color solid.
5. The method as claimed in claim 1, wherein the method of preparing the 6-amino-2-(3, 4-difluorophenyl)-1H-benzo [de]isoquinoline-1, 3(2H)-dione (108), comprises:
dissolving 2-(3, 4-difluorophenyl)-6 nitro-1H-benzo [de]isoquinoline-1, 3(2H)-dione (106) of 1.35 g, 2.544 mmol in methanol and heating under nitrogen atmosphere;
adding a solution of stannous chloride dihydrate of 3.45 g, 15.26 mmols in 5 ml of concentrated hydrochloric acid drop wise to the 2-(3, 4-difluorophenyl)-6 nitro-1H-benzo [de]isoquinoline-1, 3(2H)-dione (106), thereby obtaining a reaction mixture;
heating the obtained reaction mixture under a reflux for a time period of at least 12 hr and filtering through a Buchner funnel, thereby obtaining a yellow solid;
washing the obtained yellow solid with water followed by ethanol to obtain a crude product; and
purifying the crude product by column chromatography on silica gel of 230-400 mesh using 15:85 ethylacetate to obtain the desired product as yellow color solid.