WO2021101469A1 - Médicament pour traitement anticancéreux et antiviral et son procédé de synthèse - Google Patents

Médicament pour traitement anticancéreux et antiviral et son procédé de synthèse Download PDF

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Publication number
WO2021101469A1
WO2021101469A1 PCT/TR2019/051247 TR2019051247W WO2021101469A1 WO 2021101469 A1 WO2021101469 A1 WO 2021101469A1 TR 2019051247 W TR2019051247 W TR 2019051247W WO 2021101469 A1 WO2021101469 A1 WO 2021101469A1
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WIPO (PCT)
Prior art keywords
mixture
stirring
water
hours
solution
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PCT/TR2019/051247
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English (en)
Inventor
Firas Shawqi Abdulrazzaq AL-GBURI
Seyithan TAYSI
Omeed Akbar Ali ALI
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Gaziantep Universitesi Rektorlugu
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Publication of WO2021101469A1 publication Critical patent/WO2021101469A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals

Definitions

  • the invention relates to a drug for use in anticancer and antiviral therapy comprising a nucleoside analogue that irreversibly stops the synthesis of DNA/RNA and the synthesis method thereof.
  • Nucleoside analogues are synthetic compounds that are structurally similar to natural nucleosides, used as antiviral or anticancer drugs, modified at one of their specific sites that interfere with DNA or RNA synthesis and limit or stop their replication. These are antimetabolites, a class of drugs that inhibit DNA synthesis directly or through inhibition of DNA precursor synthesis in de novo or salvage pathways.
  • Cytotoxicnucleoside analogues are the first chemotherapeutic agents to be administered for the medical treatment of cancer. These compounds have been developed to include various purine and pyrimidinenucleoside derivatives in both solid tumors and malignant blood diseases. These agents act as anti-metabolites competing with physiological nucleosides and interact with multiple intracellular targets to induce cytotoxicity.
  • Nucleoside analogues are administered to cells in forms that will enter the cells with nucleoside carriers before they are phosphorylated to the active triphosphate forms by kinases. These analogues may exhibit cytotoxic activity by being incorporated into DNA and RNA macromolecules and being modified and/or inhibiting various enzymes involved in nucleic acid synthesis such as DNA polymerases and ribonucleotide reductases. These effects result in inhibition of DNA synthesis or induction of apoptotic cell death as shown in figure 1.
  • the patent document CN103435672A of the known state of the art may be an example.
  • the present invention describes the structure and synthesis of a modified benzyl-containing novel nucleoside phosphate prodrug.
  • the invention describes a phosphate structure containing substituted benzyl, wherein the phosphate structure is shown as formula (I) and a formula (II).
  • Phosphate structure can be used as prodrugs for various nucleoside analogues including non-cyclic nucleoside, carbon ring nucleoside, furan ring nucleoside etc., and can increase the bioactivity of nucleoside compounds. It is therefore disclosed that the structure is applicable to the treatment of viral infections and cancer.
  • the molecule described in said document is a nucleotide and comprises a furan ring. Ribose or deoxyribose is in the form of a furan ring. The furan ring forms a common part of nucleosides and nucleotides found in all living things.
  • the compound described herein is not a nucleoside; it is a nucleotide and comprises a phosphate group. Since the phosphate group contains negative charges, it cannot enter the cell (due to its polar nature). Therefore, researchers have removed polarity by linking benzyl groups to the phosphate group to introduce the molecule of the subject matter into the cell. In this way, it enters the cell and binds to DNA with weak bonds. This binding with DNA is affected by other interactions that occur in the environment and it is always possible to separate weak bonds. This may lead to the elimination of inhibition of DNA.
  • Furo [2,3- djpyrimidine based derivatives as kinase inhibitors and anticancer agents.
  • This document describes Furo [2, 3-d] pyrimidine -based derivatives as kinase inhibitors and anticancer agents.
  • Furopyrimidines are fused heterocyclic ring systems. Structurally, they are bioisotere to purines, and implements pharmacological actions in various directions. They play an important role in different disease conditions.
  • Furo [2, 3-d] pyrimidine derivatives have been investigated for their inhibitory activity against different protein kinase enzymes.
  • Said document is considered to be the first study on the synthesis, anticancer activity of furo [2, 3-d] pyrimidine derivatives, inhibition of various protein kinase enzymes and structure-activity relationships reported until today.
  • the molecule described in said document is not a newly synthesized drug.
  • researchers have made some modifications on thymine and other pyrimidine bases, which prevent the formation of hydrogen (FI) bonds in the DNA double helix. It also serves as kinase inhibitors. In this respect, it acts by blocking the synthesis of nucleotides.
  • said document does not provide a drug which irreversibly stops DNA/RNA synthesis, taking into account the delivery mechanism and chemical structure of the molecule described.
  • the invention discloses a drug comprising a novel nucleoside analogue for use in anticancer and antiviral therapy.
  • the following embodiments of the invention include a furan ring.
  • the synthesis method of the drug of the invention is also within the scope of the invention.
  • furan ring is transformed into SP 3 hybridization.
  • the developed structure has the same structure as the furan ring (found in the structure of ribose/deoxyribose monosaccharide) of all natural nucleosides/nucleotides in the RNA/DNA structure.
  • the developed molecule enters the cells with this form, after entering the cell it is phosphatized by kinase enzymes and by competing with natural nucleotides, it enters the RNA/DNA synthesis chain and irreversibly stops RNA DNA synthesis.
  • RNA DNA Unlike existing drugs in the art, it stops the synthesis of RNA DNA by irreversibly binding to the RNA DNA synthesis chain by phosphodiester bonds.
  • thermodynamic quantum chemical data are widely used to investigate the reaction mechanisms of organic compounds.
  • the spontaneity of a chemical reaction and the stability of the reaction products can be estimated from thermodynamic properties such as Enthalpy, Gibbs free energy (Cohen, N., Benson, S., W, 1993. "Estimation of heats of formation of organic compounds by additivity methods.”, Chemical Reviews, 93, 2419-2438).
  • Free energy is the main criterion representing the interaction between the molecules making a bond.
  • the size and signal of free energy is important to determine the likelihood of the formation of bimolecular structures. Larger negative values indicate improved thermodynamic properties. From our calculations, negative values were obtained, which means that no additional energy consumption is required to bond, that is the reaction can take place automatically (Garbett, N., C, Chaires, J., B, 2012. "Thermodynamic studies for drug design and screening.”, Expert Opinion on Drug Discovery., 7, 299- 314).
  • the free energy value of the 2-deoxythymidine molecule was determined to be -874.918273 Eh.
  • the free energy of the synthesized drug of the invention was determined as -1756.889248 Eh, in other words higher (Table 1).
  • the drug of the invention binds to the DNA chain with strong phosphodiester bonds, thereby irreversibly stopping DNA synthesis.
  • the drug of the invention is bound to the DNA double strand by the natural procedure, thereby causing replication to stop due to the absence of the OH group attached to C3 in the furan ring. In this way, it causes the cancer cell division to stop.
  • the furan ring of the anticancer drug of the invention can enter HIV and cancer cells and will interfere with natural nucleosides by binding to DNA double strand, because it has SP 3 hybridization, the structure of the natural nucleosides found in the receiver’s body.
  • the invention will not show side effects of anticancer nucleoside analogues known in the art to the receiver. These causes can be used in the treatment of patients having HIV, and any type of cancer.
  • a 3 L, three-necked, round bottom flask is prepared as equipped with a Claisen adapter containing a top mixer and racket, a 500 mL dropper funnel, an additional funnel and a thermometer.
  • thymidine 0.82 mol
  • pyridine 750 mL, 9.65 mol
  • the mixture is stirred and then cooled in an ice bath to 0-3 °C and charged to the dropping funnel with p-toluenesulfonyl chloride (1.8mol). Then p-toluenesulfonyl chloride is added dropwise. The temperature was raised to 10 °C over 40 minutes.
  • the viscous solution is poured into a cold (4 °C) toluene (3 L), precipitating a beige solid.
  • the temperature of the mixture rises to 7 °C upon addition of DMSO solution.
  • the mixture is spun occasionally for 20 minutes and then filtered on an 18.5 cm Buchner funnel.
  • the collected yellowish oily solid is washed twice with cold toluene and allowed to dry for 1 hour under suction.
  • the solid is dissolved in 300 mL of water, upon which two layers are formed.
  • the mixture is placed in a separatory funnel and the upper layer (containing residual toluene) is discarded.
  • the aqueous layer is placed in a 1 L beaker equipped with a pH probe, a magnetic stir bar and a thermometer.
  • the invention can be used in the treatment of HIV and cancer, which are important health problems. For patients exposed to acute and late side effects due to chemotherapy, a more comfortable treatment chance can be created and leads to significant improvement in chemotherapy. In addition, the success of radiotherapy to be given together with the developed nucleoside analogue will increase. Successful treatment of cancer patients without interruption of chemotherapy will allow avoiding additional costs such as interruption and resumption of treatment.
  • the invention is a drug for anticancer and antiviral therapy comprising a nucleoside analogue having the molecular structure shown in Figure 2, wherein the nucleoside analogue comprises a furan ring with SP 3 hybridization that is irreversibly linked to the RNA/DNA synthesis chain by phosphodiester linkages. All natural nucleosides/nucleotides in the RNA/DNA structure have the same structure as the furan ring.
  • the synthesis method of the present invention comprises the following process steps: i. adding 5 ml of acetic anhydride and 0.01 ml of sulfuric acid to a solution of 5.1 mmol of D- deoxyribose in 10 ml of concentrated acetic acid, stirring the resulting solution at room temperature for 12 hours, then adding 50 ml of water to the mixture and extracting the mixture 3 times with 40 ml of chloroform, drying it over MgS04 and evaporating it under reduced pressure to obtain the acetylated sugar, ii.
  • step i acetyl chloride; in step iv methanesulfonyl chloride and in step v sodium hydroxide may be used.
  • a nucleoside analogue obtained by the above-mentioned synthesis method and a drug comprising said nucleoside analogue is within the scope of the invention.
  • Figure 1 A Figure relating to the known state of the art.
  • Figure 2 A view of the structure of the nucleoside analogue of the present invention.
  • Figure 3 The illustration of the stopping of the DNA synthesis by the nucleoside analogue of the present invention.
  • Figure 4 The illustration of the synthesis steps according to an embodiment of the invention.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un médicament pour une thérapie anticancéreuse et antivirale comprenant un analogue nucléosidique comprenant un cycle furane avec une hybridation SP3 liée de manière irréversible à la chaîne de synthèse d'ARN/ADN par des liaisons phosphodiester. Le procédé de synthèse dudit analogue nucléosidique est également contenu dans le cadre de l'invention.
PCT/TR2019/051247 2019-11-21 2019-12-30 Médicament pour traitement anticancéreux et antiviral et son procédé de synthèse WO2021101469A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201918165 2019-11-21
TR2019/18165 2019-11-21

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WO2021101469A1 true WO2021101469A1 (fr) 2021-05-27

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114191924A (zh) * 2021-11-15 2022-03-18 福建福清万年青水泥有限公司 一种用于水泥生产的除粉尘装置

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2258708C2 (ru) * 1999-05-04 2005-08-20 Эксикон А/С Аналоги l-рибо-знк
US20150105341A1 (en) * 2013-10-11 2015-04-16 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2258708C2 (ru) * 1999-05-04 2005-08-20 Эксикон А/С Аналоги l-рибо-знк
US20150105341A1 (en) * 2013-10-11 2015-04-16 Alios Biopharma, Inc. Substituted nucleosides, nucleotides and analogs thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
POPOVA E. ET AL.: "Synthesis and in vitro Biological Evaluation of Novel Thymidine Analogs Containing 1H-1,2,3-Triazolyl, 1H-Tetrazolyl, and 2H-Tetrazolyl Fragments", NUCLEOSIDES, NUCLEOTIDES, AND NUCLEIC ACIDS, 2019, pages 1532 - 2335 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114191924A (zh) * 2021-11-15 2022-03-18 福建福清万年青水泥有限公司 一种用于水泥生产的除粉尘装置
CN114191924B (zh) * 2021-11-15 2023-01-06 福建福清万年青水泥有限公司 一种用于水泥生产的除粉尘装置

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