WO2019203773A1 - Potentially anticarcinogenic novel isoindole-1,3-dione derivatives and synthesis method for such compounds - Google Patents

Abstract

The invention is related to novel isoindole-1,3-dione derivatives which are determined to be effective in vitro on certain cancer types (e.g., Lung, breast and cervical cancer) as well as the synthesis method of such compounds for use in the chemistry sector, pharmaceuticals industry and pharmacy sector.

Description

POTENTIALLY ANTICARCINOGENIC NOVEL ISOINDOLE-1 ,3-DIONE

DERIVATIVES AND SYNTHESIS METHOD FOR SUCH COMPOUNDS

Technical Field

The invention is related to potentially anticarcinogenic isoindole-1 ,3-dione derivative novel compounds and synthesis method for such compounds.

The invention is related to isoindole-1 ,3-dione derivative novel compounds which are determined to be effective in vitro on certain cancer types (e.g., lung, breast and cervical cancer) as well as the synthesis method of such compounds for use in the chemistry sector, pharmaceuticals industry and pharmacy sector.

Prior Art

Cancer refers to malignant tumors arising from irregular division and growth of cells of an organ or tissue in a living body. In general, cancer is a group of more than 100 diseases arising from uncontrolled growth of cells in various regions of a living body. Although there are numerous types of cancer, all of them start with uncontrolled growth of abnormal cells. If not treated, it may lead to serious conditions, even to death.

Commonly used treatment methods widely used in cancer include surgery, radiotherapy and chemotherapy. Less frequently, hormone therapies, biological treatment methods and targeted therapies are also used.

Chemotherapy is a treatment given by using anticarcinogenic drugs to destroy cancer cells or restrain the growth of such cells. It may be applied alone or along with surgery and radiotherapy in cancer treatment. The objective of applying chemotherapy in cancer treatment is to treat the illness. In other words, it aims to inhibit the growth of cancer cells, slow down its spread and take the disease under control.

Although there are currently various chemotherapeutical agents, chemotherapy has many disadvantages. Almost all chemotherapeutical substances are toxic, and chemotherapy causes severe and mostly dangerous side effects such as severe nausea, bone marrow depression and immunosuppression. Additionally, chemotherapeutical agents may also have undesirable characteristics such as low selectivity and development of simple or multi drug resistance. Due to these disadvantages, researches and developments on anticarcinogenic drugs still continue all around the world.

In anticarcinogenic molecules to be newly developed, it is aimed to improve the quality of life of individuals by eliminating complaints and symptoms related to the disease and chemotherapy; increase the recurrence of the disease after surgery or radiotherapy; and facilitate local therapies in applications before surgery or radiotherapy.

Isoindole derivative compounds have been attracting attention in recent years since they have anticarcinogenic activity¹. It was reported that such compounds are inhibitors of Protein Phosphatase 1 and 2A (PPA 1 and 2A) enzymes². It is suggested that they have anticarcinogenic effect due to this characteristic.

One of the patents found when a literature research is made on the current art for this subject is the national patent application no. TR2015/14635 titled ‘Antikanserojen Etkinlige Sahip N-Asetilpirazol Turevleri’ (‘Anticarcinogenic N-Acetylpyrazole Derivatives’). The invention of the said application is related to anticarcinogenic chalcone-isoindole derivative substances, and states that chalcone-isoindole derivative substances are effective on various cancer cells.

Another patent document is the Chinese patent application with publication no. CN101495450 (A) titled‘Isoindole Derivatives Useful in Pain, Gastrointestinal Diseases and Cancer Treatment’. The said patent mentions of isoindole derivatives synthesized for pharmaceutical compositions to be particularly used in pain management.

When the patents focusing on the synthesis of isoindole derivative molecules are searched, it is seen that there is a need for anticarcinogenic selective novel molecules and brief and cost-effective methods to synthesize such molecules.

Consequently, it was required to engage into a new development in the related technical field due to above-mentioned problems and insufficiency of current solutions on the issue.

Objective of Invention

The present invention is related to potentially anticarcinogenic isoindole-1 ,3-dione derivative novel compounds which meet the aforementioned requirements, eliminate all disadvantages and bring some additional advantages, and synthesis method for such compounds.

The primary objective of the invention is to provide isoindole-1 ,3-dione derivative novel compounds which are determined to be effective in vitro on certain cancer types (e.g., Lung, breast and cervical cancer) as well as the synthesis method of such compounds for use in the chemistry sector, pharmaceuticals industry and pharmacy sector.

Another objective of the invention is to provide selective isoindole-1 ,3-dione derivative novel compounds which may be used in pharmaceutical compositions as anticarcinogenic agents in the pharmaceutical industry and do not have any negative effect on healthy cells.

A similar objective of the invention is to improve the quality of life of individuals by eliminating complaints and symptoms related to the disease and chemotherapy; increase the recurrence of the disease after surgery or radiotherapy; and facilitate local therapies in applications before surgery or radiotherapy when synthesized isoindole-1 ,3- dione derivative novel compounds are used in pharmaceutical compositions as anticarcinogenic agents.

An objective of the invention is to use easily procured / synthesized chemical substances in the said method, and to develop a synthesis method with a high applicability by using addition, substitution, acetate and chromatography methods which are well known in the literature³ and can be implemented even under simple lab conditions.

An objective of the invention is to develop a new synthesis method which is unique and has a high level of applicability, added value and awareness as an alternative to other currently available synthesis methods.

An objective of this invention is to develop a cost-effective synthesis method as a result of using cheap reagents in the synthesis method and obtaining very high yields in reaction stages.

In order to achieve the above mentioned objectives, the invention is isoindole-1 , 3-dione derivative compound represented by Formula (I).

Formula (I)

Ri : -CH₃ , -CH2CH3 , -Ph, -CH₂Ph

R2: -OAc

R₃ : -Cl

In order to achieve the above mentioned objectives, the invention is isoindole-1 , 3-dione derivative compound represented by Formula (II).

Formula (II)

R1 : -CHs , -CH2CH3 , -Ph, -CH₂Ph

R2 = R4 :-OAc

In order to achieve the above-mentioned objectives, the invention is the synthesis method of the compounds represented by Formula (I) and Formula (II), wherein the method comprises process steps of;

a) synthesis of 3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1 , 3-dione (11) compound as a result of furan (9) and maleic anhydride (10) addition reaction,

b) synthesis of 2-alkyl/aryl-3a,4,7,7a-tetrahydro-1 /-/-4,7-epoxyisoindole-1 ,3(2/-/)-dione (12) compound as a result of the reaction of the compound synthesized in the process step‘a’ with primary amines (alkyl/aryl),

c) synthesis of isoindole-1 , 3-dione derivative compound as a result of the reaction of the compound synthesized in the process step‘b’ with acetyl chloride and/or acetic anhydride and sulfuric acid.

Structural and characteristic specifications as well as all advantages of the invention will be understood more clearly with the detailed description provided below, and thus, evaluation should be made by considering the detailed description. Compound Reference Numbers to Help to Clarify the Invention

(1) 5-chloro-2-methyl-1 ,3-dioxa-2,3,3a,4,5,7a-hexahydro-1 /-/-isoindole-4-yl acetate

(2) 5-chloro-2-ethyl-1 ,3-dioxa-2,3,3a,4,5,7a-hexahydro-1 /-/-isoindole-4-yl acetate (3) 2-benzyl-5-chloro-1 ,3-dioxa-2,3,3a,4,5,7a-hexahydro-1 /-/-isoindole-4-yl acetate

(4) 5-chloro-1 ,3-dioxa-2-phenyl-2,3,3a,4,5,7a-hexahydro-1 /-/-isoindole-4-yl acetate

(5) 2-ethyl-1 ,3-dioxa-2,3,3a,4,7,7a-hexahydro-1 /-/-isoindole-4, 7-diyl diacetate

(6) 1 ,3-dioxa-2-phenyl-2,3,3a,4,7,7a-hexahydro-1 /-/-isoindole-4, 7-diyl diacetate

(7) 2-benzyl-1 ,3-dioxa-2,3,3a,4,7,7a-hexahydro-1 /-/-isoindole-4, 7-diyl diacetate (8) 2-methyl-1 ,3-dioxa-2, 3, 3a, 4,7, 7a-hexahydro-1 /-/-isoindole-4, 7-diyl diacetate

(9) furan

(10) maleic anhydride

(11) 3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1 ,3-dione

(12) 2-alkyl/aryl-3a,4,7,7a-tetrahydro-1 /-/-4,7-epoxyisoindole-1 ,3(2/-/)-dione

Detailed Description of the Invention

In this detailed description, potentially anticarcinogenic isoindole-1 ,3-dione derivative novel compounds and synthesis method of such compounds of the invention are described in a way to enable better understanding of the subject matter without bringing any limiting effect.

General formulas of isoindole-1 ,3-dione derivative novel compounds, which are the subject of the invention, are as shown below.

Formula (I) Formula (II)

Ri: -CH₃ , -CH2CH3 , -Ph, -CH₂Ph

R2 = R4: -OAc

R₃ : -Cl The general structure of the invention is isoindole-1 ,3-dione derivative compounds represented by Formula (I) and Formula (II), and their chemical formulas and nomenclature are provided in Table 1 below:

Table 1 : Novel lsoindole-1 ,3-dione derivatives of the invention

The invention also includes the synthesis method of isoindole-1 ,3-dione derivative novel compounds shown above. In the general synthesis method represented by chemical formulas below, 3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1 ,3-dione (11) compound is synthesized as a result of of the reaction of adding furan (9) and maleic anhydride (10) compounds with the method known in the literature³⁴. 2-alkyl/aryl-3a,4,7,7a- tetrahydro-1 /-/-4,7-epoxyisoindole-1 ,3(2/-/)-dione derivatives (12) are synthesized as a result of the reaction of the compound No. 11 with primary amines (NH2-CH3, NH2- CH2CH3, NH₂-Ph, NH2-CH₂Ph)³’⁴.

The following compounds are obtained from epoxide ring opening reactions of compounds No. 12:

(1) 5-chloro-2-methyl-1 ,3-dioxa-2,3,3a,4,5,7a-hexahydro-1 /-/-isoindole-4-yl acetate

(2) 5-chloro-2-ethyl-1 ,3-dioxa-2,3,3a,4,5,7a-hexahydro-1 /-/-isoindole-4-yl acetate

(3) 2-benzyl-5-chloro-1 ,3-dioxa-2,3,3a,4,5,7a-hexahydro-1 /-/-isoindole-4-yl acetate

(4) 5-chloro-1 ,3-dioxa-2-phenyl-2,3,3a,4,5,7a-hexahydro-1 /-/-isoindole-4-yl acetate

(5) 2-ethyl-1 ,3-dioxa-2,3,3a,4,7,7a-hexahydro-1 /-/-isoindole-4, 7-diyl diacetate

(6) 1 ,3-dioxa-2-phenyl-2,3,3a,4,7,7a-hexahydro-1 /-/-isoindole-4, 7-diyl diacetate

(7) 2-benzyl-1 ,3-dioxa-2,3,3a,4,7,7a-hexahydro-1 /-/-isoindole-4, 7-diyl diacetate

(8) 2-methyl-1 ,3-dioxa-2, 3, 3a, 4,7, 7a-hexahydro-1 /-/-isoindole-4, 7-diyl diacetate

General synthesis method of novel isoindole-1 ,3-dione derivatives of the invention:

Reactions are performed in accordance with the Literature³.

a) Synthesis of 3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1 ,3-dione (11):

As the starting material of the said synthesis, furan (9) and maleic anhydride (10) are used.

In a 250 ml three-neck glass flask with rounded bottom under an argon atmosphere, maleic anhydride (5.0 g, 50.99 mmol) and furan (5.2 g, 76.5 mmol) are dissolved in 30 mL of toluene. The solution is boiled under condenser and stirred for 24 hours. A white residue precipitates during this time. The solid precipitate is separated by filtering and washed with cold diethyl ether twice. The solvent is removed in a vacuum (Rotary evaporator) and the solid part is crystalized from the MeOH/diethyl ether solvent mixture. The compound of 3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1 ,3-dione (11) is obtained as colorless crystals. Yield: 8.22 g (97 %).

The said synthesis may be performed with a reaction temperature of 100 - 150 °C, and reaction duration of 6-30 hours. Nitrogen atmosphere may also be used instead of argon atmosphere. The duration and heat of reaction should be observed during the said synthesis step. Otherwise, the yield would decrease and maleic acid would remain in the medium. This makes the purification process more difficult.

b) Synthesis of 2-alkyl/aryl-3a,4,7,7a-tetrahydro-1 H-4,7-epoxyisoindole-1 ,3(2H)- dione (12):

As the starting material of the said synthesis, the compound of 3a,4,7,7a-tetrahydro-4,7- epoxyisobenzofuran-1 ,3-dione (11) which is obtained from the previous step and primary amines (NH2-CH3, NH2-CH2CH3, NH₂-Ph, NH2-CH2P).

3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1 ,3-dione (11) (1.50 g, 9.03 mmol) and primary amine (alkyl/aryl) (0.55 g, 9.03 mmol) are dissolved in 15 mL of methanol (MeOH). The resulting solution is boiled under a condenser for 24 hours. In the meantime, the color of the medium turns dark to orange. The solution brought to room temperature at the end of this duration starts to crystallize within 2 hours. After leaving the mixture to rest in the fridge for 1 night, the precipitate is collected by filtering with a vacuum. The compound of 2-alkyl/aryl-3a,4,7,7a-tetrahydro-1 /-/-4,7-epoxyisoindole- 1 ,3(2/-/)-dione (12) is obtained as white crystals.

The said synthesis may be performed with a reaction temperature of 50 - 70 °C, and reaction duration of 6-40 hours. The duration and heat of reaction should be observed during the said synthesis step. Furthermore, leaving solutions to rest in the fridge, thereby ensuring a better precipitation in this step decreases the loss of substance in the filtering process.

c) Synthesis of isoindole-1 ,3-dione derivatives (1-8):

Synthesis of isoindole-1 ,3-dione derivatives No. 1-4 from epoxide ring opening reactions of compounds No. 12: As the starting material of the said synthesis, the compounds of 2-alkyl/aryl-3a,4,7,7a-tetrahydro-1 /-/-4,7-epoxyisoindole-1 ,3(2/-/)-dione (12) which is obtained in the process step‘b’ are used.

In a round-bottom flask, 2-alkyl/aryl-3a,4,7,7a-tetrahydro-1 /-/-4,7-epoxyisoindol-1 ,3(2 H)- dione (12) (1.0 g) was dissolved with 2-3 ml_ of Ac20(acetic anhydride) and then 1 -1.5 ml_ of AcCI (acetyl chloride) was added to this slurry solution. After that, three drops of H2SO4 (sulfuric acid) were added drop by drop and the resulting solution was stirred for 48 h at room temperature (25 Ό). In this reaction, when the amount of acid added is decreased, the formation time of the product expected to occur increases up to a few days, and a lower yield is obtained. When the amount of acid is increased, the reaction is completed in less than 48 hours but aromatic compounds form as side products. Therefore, it has been determined as a result of trials made that the use of 3-4 drops of sulfuric acid (H2SO4) is the optimum condition. Another point in this reaction is the finding from NMR spectrum evaluations that the diacetate-containing product is formed at first following the start of the reaction. The products of chloro-acetyl which are present at 1 -2 positions according to each other are formed on this diacetyl-containing product. As the reaction duration elapses, the peak height of the hydrogen atom in the carbon linked to the chlorine atom increases in time. After, it is understood with NMR spectrum that the reaction is completed, the reaction is stopped and the AcCI which remains after the reaction is removed in an evaporator. The residue is filtered through Finisterre filter and the solution is concentrated in the evaporator. Then, the remaining part is crystalized over the DCM/Flexane (dichloromethane/hexane) solvent mixture. The resulting crystals are dried. Isoindole-1 ,3-dione derivatives (1-4) were crystallized from CFI2CI2 / hexane to give 1 ,2-chloroacetate derivatives. Thus, isoindole-1 ,3-dione derivatives (1-4) are obtained as white crystals.

Synthesis of isoindole-1 ,3-dione derivatives No. 5-8 from epoxide ring opening reactions of compounds No. 12: As the starting material of the said synthesis, 2- alkyl/aryl-3a,4,7,7a-tetrahydro-1 /-/-4,7-epoxyisoindole-1 ,3(2/-/)-dione (12) which is obtained in the process step‘b’ is used.

In a round-bottom flask, 2-alkyl/aryl-3a,4,7,7a-tetrahydro-1 /-/-4,7-epoxyisoindol-1 ,3(2 H)- dione (12) (1.0 g) was dissolved in 2-3 ml_ of AC2O (acetic anhydride). After the addition of 3 drops of H2SO4 slowly, the color of the solution starts to darken within hours and the reaction mixture was stirred at room temperature for 48 hours. At the end of this duration, the dark red colored solution is concentrated in the evaporator. The residue is dissolved with a little amount of ethyl acetate and filtered through Finisterre filter. The filtrate with a lighter color is removed in the evaporator. It is crystallized over DCM/Hexane solvent mixture. The resulting crystals are dried. Thus, lsoindole-1 ,3- dione derivatives 5-8 are obtained as white crystals.

The said syntheses may be performed with a reaction temperature between -10 °C to 50 °C, and reaction duration of 2-60 hours. The acid concentration should be observed during the reaction. Lower amounts of acid extend the duration of the reaction and higher amounts of acid increase the formation of aromatic side products.

TLC (thin layered chromatography) and silica gel column chromatography are not used while performing these reactions. It has been determined that the product completely turns into an aromatic product in purifications made with this and similar fillers. Therefore, purification is made by using crystallization method. In vitro studies made with novel isoindole-1 ,3-dione derivatives of the invention:

In vitro studies made on novel isoindole-1 ,3-dione derivatives of the invention have found that such compounds have an anticarcinogenic effect on certain cancer types (e.g., Lung, breast and cervical cancer) and do not have any adverse effect on healthy cells.

Since chemotherapy has severe side effects, targeted therapy is very popular and important in cancer treatment. Tyrosine kinases are the targets focused mostly since they are needed for cell growth and metastasis. Active tyrosine kinas forms may lead to tumor growth and proliferation, angiogenesis, metastasis and antiapoptotic effects. Indole derivatives are tyrosine kinase inhibitors. These derivatives have been used as chemotherapy drugs for years.

Biological activities of novel isoindole-1 ,3-dione derivatives of the invention have been researched, for example on cervical cancer cells HeLa line. Cytotoxic effects of these compounds have been researched with MTT analysis and their IC50 values have been determined.

Result of the research determined that these compounds have toxicity in HeLa cells with ICso values of 140.60 mM, 382.82 mM, 366.44 mM, 542.00 mM, 255.86 mM, 148.59 mM, and 171 .40 mM.

REFERENCES

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Claims

1. Isoindole-1 ,3-dione derivative compound represented by Formula (I), wherein;

Formula (I) Ri is -CH₃ , -CH2CH3 , -Ph, -CH₂Ph,

R2 is -OAc,

R3 is -Cl.

2. Isoindole-1 ,3-dione derivative compound represented by Formula (II), wherein;

Formula (II)

R1 is -CH3 , -CH2CH3 , -Ph, -CH₂Ph,

R2 and R4 is -OAc.

3. A synthesis method for compounds according to Claim 1 or 2, characterized by comprising process steps of; a) synthesis of 3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1 ,3-dione (11) compound as a result of furan (9) and maleic anhydride (10) addition reaction, b) synthesis of 2-alkyl/aryl-3a,4,7,7a-tetrahydro-1 /-/-4,7-epoxyisoindole-1 ,3(2/-/)- dione (12) compound as a result of the reaction of the compound synthesized in the process step‘a’ with primary primary amines (alkyl/aryl), c) synthesis of isoindole-1 ,3-dione derivative compound as a result of the reaction of the compound synthesized in the process step‘b’ with acetyl chloride and/or acetic anhydride and sulfuric acid.

4. The synthesis method according to Claim 3, wherein reaction temperature is

100 - 150 °C and reaction duration is 6-30 hours in the process step‘a’.

5. The synthesis method according to Claim 3, wherein reaction temperature is 50-70 °C and reaction duration is 6-40 hours in the process step‘b’.

6. The synthesis method according to Claim 3, wherein the reaction temperature is (-10) - 50 °C and the reaction duration is 2-60 hours in the method step‘c’.

7. The synthesis method according to Claim 3, wherein the process step ‘a’ comprises sub-steps of;

dissolving furan (9) and maleic anhydride (10) under argon or nitrogen atmosphere,

boiling the resulting solution under a condenser by stirring,

separating the precipitate formed at the end of the reaction by filtering, washing the precipitate with solvent,

removing the solvent in the vacuum,

crystallizing the remaining solid part from the solvent mixture,

obtaining the compound of 3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-

1 ,3-dione (11) as colorless crystals.

8. The synthesis method according to Claim 7, wherein furan (9) and maleic anhydride (10) are dissolved in toluene.

9. The synthesis method according to Claim 7, wherein the precipitate is washed with diethyl ether twice.

10. The synthesis method according to Claim 7, wherein the said solvent mixture is methanol/diethyl ether.

11. The synthesis method according to Claim 3, wherein the process step ‘b’ comprises sub-steps of;

dissolving the compound of 3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran- 1 ,3-dione (11) synthesized in method step‘a’ and primary amine (alkyl/aryl) in solvent,

boiling the resulting solution under a condenser by stirring,

cooling and leaving the solution to rest in the fridge at the end of the reaction,

collecting the resulting precipitate by filtering with vacuum,

obtaining compound of 2-alkyl/aryl-3a,4,7,7a-tetrahydro-1 H-4,7- epoxyisoindol-1 ,3(2/-/)-dione (12) as white crystals.

12. The synthesis method according to Claim 11 , wherein said solvent is methanol.

13. The synthesis method according to Claim 3 or 11 , wherein the said primary amine is selected among

NH2-CH3, NH2-CH2CH3, NH₂-Ph or NH2-CH₂Ph.

14. The synthesis method according to Claim 3, wherein the process step ‘c’ comprises sub-steps of;

dissolving the compound of 2-alkyl/aryl-3a,4,7,7a-tetrahydro-1 H- 4,7- epoxyisoindole-1 ,3(2/-/)-dione (12) synthesized in the process step‘b’ with acetyl chloride and/or acetic anhydride,

- dropping sulfuric acid in the resulting solution and stirring it,

concentrating the solution in the evaporator at the end of the reaction duration,

dissolving the residue with solvent and filtering it,

removing the filtrate in the evaporator,

- crystallizing the remaining solid part from the solvent mixture.

15. The synthesis method according to Claim 14, wherein the residue is dissolved with ethyl acetate and filtered.

16. The synthesis method according to Claim 14, wherein said solvent mixture is dichloromethane/hexane.

17. The use of compounds according to Claim 1 or 2 as anticarcinogenic agents.