WO2023129116A2 - A drug for the treatment of type 2 diabetes mellitus disease and the nanoparticle thereof - Google Patents
A drug for the treatment of type 2 diabetes mellitus disease and the nanoparticle thereof Download PDFInfo
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- WO2023129116A2 WO2023129116A2 PCT/TR2022/051753 TR2022051753W WO2023129116A2 WO 2023129116 A2 WO2023129116 A2 WO 2023129116A2 TR 2022051753 W TR2022051753 W TR 2022051753W WO 2023129116 A2 WO2023129116 A2 WO 2023129116A2
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- nanoparticle
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- chloride
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- 229950010728 trelagliptin Drugs 0.000 description 1
- IWYJYHUNXVAVAA-OAHLLOKOSA-N trelagliptin Chemical compound C=1C(F)=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 IWYJYHUNXVAVAA-OAHLLOKOSA-N 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/625—Salicylic acid; Derivatives thereof having heterocyclic substituents, e.g. 4-salicycloylmorpholine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- the invention relates to a drug and to the nanoparticle form thereof , which provides treatment of type 2 diabetes ( Diabetes Mellitus ) disease using dipeptidylpeptidase-4 ( DPP-4 ) as an inhibitor .
- DPP-4 dipeptidylpeptidase-4
- the drug and nanoparticle synthesis methods of the invention are also within the scope of protection of the invention .
- Diabetes is among the important health problems today . This disease is common worldwide and the number of patients is increasing rapidly . This situation causes an increase in diabetes-related diseases and thus negatively af fects people ' s lives .
- Diabetes Mellitus is a disease that can cause serious complications i f the gland called the pancreas cannot produce enough insulin hormone or the produced insulin hormone cannot be used ef fectively .
- di f ferent types of diabetes exist , the most common type thereof is type 2 diabetes .
- 90% of diabetic patients consist of type 2 diabetic patients .
- Insulin secretion disorder and insulin resistance are prominent in Type 2 Diabetes Mellitus ( Type 2 DM) disease .
- Thi s disease is usually seen in people over 45 years of age , overweight , and with low physical activity .
- GLP-1 and the gastric inhibitor polypeptide/glucose- dependent insulin polypeptide are insulinotropic- acting incretin hormones responsible for 70% of postprandial glucose-dependent insulin secretion in humans.
- GLP-1 has mitogenic effects that lead to cell differentiation and an increase in beta cell mass. It causes weight loss due to decreased gastrointestinal motility and decreased appetite and food intake by acting on the central nervous system.
- GLP-1 has been shown to have beneficial effects in patients with myocardial ischemia and heart failure.
- Dipeptidyl peptidase 4 (DPP-4) is a serine protease that is localized on cell surfaces and plays an important role in glucose metabolism. It is responsible for the rapid degradation of incretins such as GLP-1 and GIP. DPP-4 inhibitors are a relatively new class of oral diabetes drugs, also known as gliptins. DPP-4 inhibitors prolong the duration of action of GLP- 1 by preventing the destruction of circulating incretin hormones .
- gliptins and retagliptin, omarigliptin, gosogliptin, denagliptin, carmegliptin, evogliptin, trelagliptin, melagliptin, dutagliptin can be given as examples thereof .
- these drugs are insuf ficient in terms of providing more stability to the compound and providing easier access and binding to the active site of the DPP-4 enzyme .
- undesirable side ef fects cannot be reduced in patients .
- the patent document No . US2006270701A1 may be referred to as an example of the current state of the art .
- Said document relates in particular to a novel pyrrolidine-based and thiazolidine-based dipeptidyl peptidase- IV ( DPP- IV) inhibitor developed to provide a method for the treatment of type 2 diabetes , similarly abnormal glucose tolerance , abnormal glucose homeostasis , and concomitant complications .
- DPP- IV dipeptidyl peptidase- IV
- the methods of various embodiments of the invention mentioned in the document include thionyl chloride , pyridine derivatives , and copper salts .
- Another example of the state of the art is the patent document No . US2010029650A1 .
- the said document is a patent file for bicyclic compounds which can be used as dipeptidyl peptidase IV inhibitors and the method of production thereof , in the treatment of metabolic disorders and especially type 2 diabetes mellitus and related disorders .
- the document features the use of aspirin, thionyl chloride , pyroline and pyridine chemicals as antiplatelet drugs in the production method of the said compounds .
- an ef fective drug and nanoparticle thereof have been developed for use in the treatment of type 2 Diabetes Mellitus disease as a dipeptidyl peptidase IV inhibitor, providing greater stability and easier access and binding to the active site of the DPP-4 enzyme , in terms of absorption and permeation into the cell wall .
- the invention relates to a drug and to a nanoparticle thereof developed for use in the treatment of type 2 Diabetes Mellitus disease .
- the synthesis methods of the drug and the nanoparticle form are also within the protection scope of the invention .
- the obj ect of this invention is to sustain the activity of incretins by inhibiting the DPP-4 enzyme , which is responsible for regulating the secretion of the incretin hormone .
- Another object of the invention is the development of a drug and nanoparticle thereof with high stability, providing easy access and binding to the active site of the DPP-4 enzyme, with high absorption and efficacy by well permeating into the cell wall.
- Another object of the invention is to reduce the dose of drug administered to patients, thereby minimizing the chemicals and adverse effects to which the patient is exposed .
- Another object of the invention is to solve the overweight problem, which is a negative factor in the treatment of type 2 Diabetes Mellitus patients by providing weight loss/control .
- Another object of the invention is to obtain a drug with a low rate of hypoglycemia.
- the synthesis method of the drug of the invention generally includes the process steps of the synthesis of aspirin chloride (2) , and amide formation (3) from linking the aspirin chloride (2) with the amino acid (Proline (1) ) , and then, converting the carboxyl in a proline (1) to nitrile (4) .
- the nanoparticle (5) form of the drug according to the invention is obtained by using cyano derivatives as the organic part and CUSO4.5H2O as the inorganic part.
- the form of the nanoparticle (5) has flower-like hybrid structures.
- the synthesis method of the drug of the invention in its most general form comprises the following steps: a. synthesis of aspirin chloride (2) , b. synthesis of amide (3) from the resulting aspirin chloride (2) ; and c. synthesis steps of the nitrile (4) compound from the amide (3) compound obtained.
- Step a of the synthesis method of the invention includes the process steps of synthesis of aspirin chloride (2) by mixing aspirin with thionyl chloride and distilling until hydrogen chloride conversion is finished and cooling the reaction mixture and then heating with agitation.
- step a of the synthesis method comprises the following process steps: Mixing 19.5 mmol aspirin with 4.5 g thionyl chloride redistilled in a claisen flask and refluxed for 2 hours until the hydrogen chloride is completely released and cooling the reaction mixture by removing the condenser and heating the mixture at 60 °C for 3 minutes.
- Step b of the synthesis method according to an embodiment of the invention comprises the following process steps: adding aspirin chloride onto the proline (1) contained in the cooled chloroform and pyridine, stirring the resulting mixture and adding distilled water and chloroform to the mixture, separating the resulting organic phase, washing with distilled water, drying with anhydrous MgSCh, filtering, removing the solvent with toluene
- the obtained amide (3) purified by column chromatography by using silica gel .
- step b of the synthesis method of the invention comprises in more detail the following process steps: adding 19.5 mmol aspirin chloride dropwise onto the 19.5 mmol proline (1) contained in the chloroform and pyridine ice-cooled to -12°C, stirring the resulting mixture at rt for 24 hours and adding 300mL of distilled water and 400mL of chloroform to the mixture, separating the resulting organic phase, washing three times with 400 mL of distilled water, drying with anhydrous MgSCh, filtering, evaporating the solvent three times with toluene, the amide derivative (3) then purified by column chromatography by using silica gel.
- Step c of the synthesis method according to an embodiment of the invention comprises the following process steps: mixing the synthesized amide (3) compound and the ethyl carbamate, adding the thionyl chloride to the resulting mixture and mixing in the oil bath, following the reaction mixture by thin layer chromatography, filtering the solid phase after the reaction is completed, evaporating the organic phase and purifying by column chromatography to obtain the nitrile (4) compound .
- step c of the synthesis method of the invention comprises in more detail the process steps: mixing the 0.1 mole amide (3) compound and the 0.11 mole 50 mL of the ethyl carbamate in a three-neck round bottom flask at 75 °C, adding 7.3 mL of thionyl chloride dropwise to the resulting mixture over 0.5h and stirring the reaction mixture in the oil bath at 75-80 °C for 18h, following the reaction mixture by thin layer chromatography, filtering the solid phase after the reaction is completed, obtaining the nitrile (4) compound by evaporating the organic phase and purifying by column chromatography .
- the nanoparticle form and the synthesis method of the drug of the invention are also within the protection scope of the invention .
- cyano derivatives are used as the organic part and CUSO4 .
- 5H2O is used as the inorganic part .
- the synthesis method of the nanoparticle of the invention in its most general form, comprises the following process step : obtaining the nanoparticle ( 5 ) by synthesi zing the flowershaped organic and inorganic hybrid structures using the nitrile ( 4 ) compound and cyano derivatives .
- the synthesis method of the nanoparticle according to an embodiment of the invention comprises the following process steps : adding the resulting nitrile ( 4 ) compound to the phosphate-buf f ered salt solution containing water-soluble CuSO4 at certain concentrations and cyano derivatives at certain concentrations , incubation of the solution from room temperature for a certain period of time , centri fugation of the precipitate , which shows that flower-shaped organic and inorganic hybrid structures are formed after incubation, washing, drying and storage .
- the synthesis method of the nanoparticle of the invention comprises the following process steps : adding the resulting nitrile ( 4 ) compound to the water-soluble CuSO4 at certain concentrations and the l OmM phosphate- buf fered salt solution containing the cyano derivatives at certain concentrations such that pH becomes 5- 9 , incubating the solution at room temperature for 3 days , centrifugation of the blue precipitate, which shows that flower-shaped organic and inorganic hybrid structures are formed after incubation, washing, drying and storage several times.
- nitrile (4) compound The synthesized amide (3) (0.1 mole) and the ethyl carbamate (0.11 mole) are mixed in a 50 mL three-neck round bottom flask at 75°c. Then 7.3 mL of thionyl chloride is added dropwise over about 0.5 hours. The reaction mixture is stirred in an oil bath at 75-80 °C for 18 hours. The reaction mixture is followed by thin layer chromatography (TLC) . After the reaction is complete, the solid phase is filtered, the organic phase is evaporated and purified by column chromatography .
- TLC thin layer chromatography
- nanoparticle (5) form of the invention is synthesized using cyano derivatives to include organic-inorganic hybrid structures with flower-like shapes.
- organic-inorganic hybrid structures with flowerlike shapes are synthesized using cyano derivatives.
- cyano derivatives are used as the organic part (CUSO4.5H2O) .
- PBS phosphate buffered saline
- the blue-colored precipitate formed in the reaction vessel (which shows that shaped organic-inorganic hybrid structures with flower-like shapes are formed) is centri fuged and dried after several times of washing and stored for later applications .
- the organic molecule induces nucleation of copper phosphate crystals for the formation of leaf scaf folds and serves as a "glue” to bind the leaves together .
- These nanoscale leaf-shaped structures are connected to each other and create structures with flowerlike shapes . For this reason, the synthesi zed structures are called " Flower-Like Hybrid structures" .
- the drug of the invention is a DPP-4 inhibitor in the oral diabetes drug class .
- They are also known as gliptins .
- Circulating incretin prevents the breakdown of hormones and prolongs the duration of GLP- 1 .
- the newly synthesi zed agent sustains the activity of incretins by inhibiting DPP-4 , which is responsible for regulating the secretion of incretin hormone .
- Incretin on the other hand, stimulates beta cells in the pancreas to secrete insulin .
- glucose molecules are delivered to cells that receive glucose in an insulin-dependent manner and also work by increasing cell sensitivity to insulin . Additionally, it shows activity in repairing damaged beta cells in pancreatic tissue .
- the drug of the invention and the nanoparticle thereof has a small si ze and a small molecular weight . Due to its small molecular si ze , compound stability is easily achieved and maintained . In addition, due to its small molecular si ze, it can easily acces s and bind to the active site of the DPP-4 enzyme and thus , the enzyme can be inhibited .
- the compound Being of small si ze and molecular weight , another advantage of the drug is that the compound has small-si zed ef fective aggregates that allow the formation of nanof luorescent particles thereby assisting in increasing the ef fect of the drug prepared in terms of absorption and permeation into the cell wall .
- the nanoparticle form of the drug of the invention contains hybrid flower-shaped structures , resulting in increased stability of the nanocomposite compared to those without a nanostructure .
- it is the ability of molecules to penetrate the cell wall better than non-nano molecules , increasing the ease and speed of absorption and drug ef ficiency .
- a drug and nanoparticle that provides a low rate of hypoglycemia and good glycemic control have been developed in order to ef fectively treat type 2 Diabetes Mellitus disease by inhibiting DPP-4 enzyme and to solve the weight control problems of patients .
- the said drug and nanoparticle have the ability to penetrate cell walls , leading to high absorption rate , speed and ef fectiveness . Due to the small si ze and low molecular weight of the drug of the invention and the nanoparticle thereof , the dose given to the patients can be reduced, thus minimi zing the chemical and adverse ef fects to which the patient is exposed .
- Figure 1 A figure of the synthesis of the drug of the invention and the nanoparticle form thereof
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Abstract
The invention relates to the synthesis methods of a drug and nanoparticle thereof for the treatment of type-2 Diabetes Mellitus disease. The synthesis method of the drug of the invention in its most general form includes synthesis of aspirin chloride (2), synthesis of amide (3) from the aspirin chloride (2) obtained and synthesis of nitrile (4) compound from the amide (3) compound obtained. The synthesis method of the nanoparticle of the drug of the invention includes the process steps of obtaining the nanoparticle (5) by synthesizing the flower- shaped organic and inorganic hybrid structures using the obtained nitrile (4) compound and cyano derivatives.
Description
A DRUG FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS DISEASE
AND THE NANOPARTICLE THEREOF
Field of the Invention
The invention relates to a drug and to the nanoparticle form thereof , which provides treatment of type 2 diabetes ( Diabetes Mellitus ) disease using dipeptidylpeptidase-4 ( DPP-4 ) as an inhibitor . The drug and nanoparticle synthesis methods of the invention are also within the scope of protection of the invention .
Background of the Invention
Diabetes is among the important health problems today . This disease is common worldwide and the number of patients is increasing rapidly . This situation causes an increase in diabetes-related diseases and thus negatively af fects people ' s lives .
Diabetes Mellitus is a disease that can cause serious complications i f the gland called the pancreas cannot produce enough insulin hormone or the produced insulin hormone cannot be used ef fectively . As many as di f ferent types of diabetes exist , the most common type thereof is type 2 diabetes . 90% of diabetic patients consist of type 2 diabetic patients . Insulin secretion disorder and insulin resistance are prominent in Type 2 Diabetes Mellitus ( Type 2 DM) disease . Thi s disease is usually seen in people over 45 years of age , overweight , and with low physical activity .
Today, treatments cannot be provided by conventional methods in the treatment of diabetes . The increase in the epidemiological level of diabetes requires the development of new therapies along with research that will provide a
better understanding of the pathophysiology of diabetes. In cases that do not respond to metformin treatment, the preferred drugs may cause hypoglycaemia, weight gain and undesirable cardiac events. Excessive weight gain in patients with type 2 diabetes is an important factor that negatively affects treatment. Recently, in general, therapies have been developed based on incretin stimulation that provide effective glucose and weight control such as glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors. Glucagon-like peptide-1 receptor agonists are important therapies and may be used with single or combination therapies. Besides providing good glycemic control, lower rates of hypoglycemia and weight loss are important advantages of incretin-based therapies .
GLP-1 and the gastric inhibitor polypeptide/glucose- dependent insulin polypeptide (GIP) are insulinotropic- acting incretin hormones responsible for 70% of postprandial glucose-dependent insulin secretion in humans. In addition, GLP-1 has mitogenic effects that lead to cell differentiation and an increase in beta cell mass. It causes weight loss due to decreased gastrointestinal motility and decreased appetite and food intake by acting on the central nervous system. In addition, GLP-1 has been shown to have beneficial effects in patients with myocardial ischemia and heart failure.
Dipeptidyl peptidase 4 (DPP-4) is a serine protease that is localized on cell surfaces and plays an important role in glucose metabolism. It is responsible for the rapid degradation of incretins such as GLP-1 and GIP. DPP-4 inhibitors are a relatively new class of oral diabetes drugs, also known as gliptins. DPP-4 inhibitors prolong the
duration of action of GLP- 1 by preventing the destruction of circulating incretin hormones .
In the art , there are drugs that work by inhibiting DPP-4 enzyme and studies on the said drugs . As an example , it is known that many syntheses are made from the gliptin family . For example , approved gliptins such as sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, teneligliptin, anagliptin, and gemigliptin are in clinical use for the treatment of type-2 Diabetes Mellitus disease . In addition, there are many clinical studies and researches on gliptins , and retagliptin, omarigliptin, gosogliptin, denagliptin, carmegliptin, evogliptin, trelagliptin, melagliptin, dutagliptin can be given as examples thereof . It is known that these drugs are insuf ficient in terms of providing more stability to the compound and providing easier access and binding to the active site of the DPP-4 enzyme . In addition, due to the fact that the dose given to patients cannot be reduced, undesirable side ef fects cannot be reduced in patients .
The patent document No . US2006270701A1 may be referred to as an example of the current state of the art . Said document relates in particular to a novel pyrrolidine-based and thiazolidine-based dipeptidyl peptidase- IV ( DPP- IV) inhibitor developed to provide a method for the treatment of type 2 diabetes , similarly abnormal glucose tolerance , abnormal glucose homeostasis , and concomitant complications . The document mentions a drug composition containing components such as vildagliptin, sitagliptin, saxagliptin, aspirin, etc . In addition, the methods of various embodiments of the invention mentioned in the document include thionyl chloride , pyridine derivatives , and copper salts .
Another example of the state of the art is the patent document No . US2010029650A1 . The said document is a patent file for bicyclic compounds which can be used as dipeptidyl peptidase IV inhibitors and the method of production thereof , in the treatment of metabolic disorders and especially type 2 diabetes mellitus and related disorders . The document features the use of aspirin, thionyl chloride , pyroline and pyridine chemicals as antiplatelet drugs in the production method of the said compounds .
It is believed that the drugs mentioned in the aforementioned documents do not have adequate ef fects in terms of absorption and permeation through the cell wall .
In order to eliminate these disadvantages , an ef fective drug and nanoparticle thereof have been developed for use in the treatment of type 2 Diabetes Mellitus disease as a dipeptidyl peptidase IV inhibitor, providing greater stability and easier access and binding to the active site of the DPP-4 enzyme , in terms of absorption and permeation into the cell wall .
Detailed Description of the Invention
The invention relates to a drug and to a nanoparticle thereof developed for use in the treatment of type 2 Diabetes Mellitus disease . The synthesis methods of the drug and the nanoparticle form are also within the protection scope of the invention .
The obj ect of this invention is to sustain the activity of incretins by inhibiting the DPP-4 enzyme , which is responsible for regulating the secretion of the incretin hormone .
Another object of the invention is the development of a drug and nanoparticle thereof with high stability, providing easy access and binding to the active site of the DPP-4 enzyme, with high absorption and efficacy by well permeating into the cell wall.
Another object of the invention is to reduce the dose of drug administered to patients, thereby minimizing the chemicals and adverse effects to which the patient is exposed .
It is another object of the invention to provide good glycemic control by inhibiting DPP-4 enzyme.
Another object of the invention is to solve the overweight problem, which is a negative factor in the treatment of type 2 Diabetes Mellitus patients by providing weight loss/control .
Another object of the invention is to obtain a drug with a low rate of hypoglycemia.
The synthesis method of the drug of the invention generally includes the process steps of the synthesis of aspirin chloride (2) , and amide formation (3) from linking the aspirin chloride (2) with the amino acid (Proline (1) ) , and then, converting the carboxyl in a proline (1) to nitrile (4) .
The nanoparticle (5) form of the drug according to the invention is obtained by using cyano derivatives as the organic part and CUSO4.5H2O as the inorganic part. The form of the nanoparticle (5) has flower-like hybrid structures.
The synthesis method of the drug of the invention in its most general form comprises the following steps: a. synthesis of aspirin chloride (2) , b. synthesis of amide (3) from the resulting aspirin chloride (2) ; and c. synthesis steps of the nitrile (4) compound from the amide (3) compound obtained.
Step a of the synthesis method of the invention according to one embodiment includes the process steps of synthesis of aspirin chloride (2) by mixing aspirin with thionyl chloride and distilling until hydrogen chloride conversion is finished and cooling the reaction mixture and then heating with agitation.
In more detail, step a of the synthesis method according to an embodiment of the invention comprises the following process steps: Mixing 19.5 mmol aspirin with 4.5 g thionyl chloride redistilled in a claisen flask and refluxed for 2 hours until the hydrogen chloride is completely released and cooling the reaction mixture by removing the condenser and heating the mixture at 60 °C for 3 minutes.
Step b of the synthesis method according to an embodiment of the invention comprises the following process steps: adding aspirin chloride onto the proline (1) contained in the cooled chloroform and pyridine, stirring the resulting mixture and adding distilled water and chloroform to the mixture, separating the resulting organic phase, washing with distilled water, drying with anhydrous MgSCh, filtering, removing the solvent with toluene The obtained amide (3) purified by column chromatography by using silica gel .
In an embodiment of the invention, step b of the synthesis method of the invention comprises in more detail the following process steps: adding 19.5 mmol aspirin chloride dropwise onto the 19.5 mmol proline (1) contained in the chloroform and pyridine ice-cooled to -12°C, stirring the resulting mixture at rt for 24 hours and adding 300mL of distilled water and 400mL of chloroform to the mixture, separating the resulting organic phase, washing three times with 400 mL of distilled water, drying with anhydrous MgSCh, filtering, evaporating the solvent three times with toluene, the amide derivative (3) then purified by column chromatography by using silica gel.
Step c of the synthesis method according to an embodiment of the invention comprises the following process steps: mixing the synthesized amide (3) compound and the ethyl carbamate, adding the thionyl chloride to the resulting mixture and mixing in the oil bath, following the reaction mixture by thin layer chromatography, filtering the solid phase after the reaction is completed, evaporating the organic phase and purifying by column chromatography to obtain the nitrile (4) compound .
In an embodiment of the invention, step c of the synthesis method of the invention comprises in more detail the process steps: mixing the 0.1 mole amide (3) compound and the 0.11 mole 50 mL of the ethyl carbamate in a three-neck round bottom flask at 75 °C, adding 7.3 mL of thionyl chloride dropwise to the resulting mixture over 0.5h and stirring the reaction mixture in the oil bath at 75-80 °C for 18h, following the reaction mixture by thin layer chromatography, filtering the solid phase after the reaction is completed, obtaining the nitrile (4) compound by evaporating the organic phase and purifying by column chromatography .
The nanoparticle form and the synthesis method of the drug of the invention are also within the protection scope of the invention .
In the synthesis method of the nanoparticle of the drug according to the invention, cyano derivatives are used as the organic part and CUSO4 . 5H2O is used as the inorganic part .
The synthesis method of the nanoparticle of the invention, in its most general form, comprises the following process step : obtaining the nanoparticle ( 5 ) by synthesi zing the flowershaped organic and inorganic hybrid structures using the nitrile ( 4 ) compound and cyano derivatives .
The synthesis method of the nanoparticle according to an embodiment of the invention comprises the following process steps : adding the resulting nitrile ( 4 ) compound to the phosphate-buf f ered salt solution containing water-soluble CuSO4 at certain concentrations and cyano derivatives at certain concentrations , incubation of the solution from room temperature for a certain period of time , centri fugation of the precipitate , which shows that flower-shaped organic and inorganic hybrid structures are formed after incubation, washing, drying and storage .
In more detail , the synthesis method of the nanoparticle of the invention comprises the following process steps : adding the resulting nitrile ( 4 ) compound to the water-soluble CuSO4 at certain concentrations and the l OmM phosphate- buf fered salt solution containing the cyano derivatives at certain concentrations such that pH becomes 5- 9 , incubating the solution at room temperature for 3 days , centrifugation
of the blue precipitate, which shows that flower-shaped organic and inorganic hybrid structures are formed after incubation, washing, drying and storage several times.
In an embodiment of the invention, the process steps comprised in the synthesis methods of the invention are described in detail below.
Synthesis of aspirin chloride (2) :
Mixed with 4.5 g of thionyl chloride redistilled in a 19.5 mmol aspirin claisen flask, distilled for 2 hours until hydrogen chloride conversion is finished. The reaction mixture is allowed to cool, then the condenser is removed and the mixture is heated by shaking at 60 °C for 3 minutes. Acid chloride is obtained at the end of these processes.
Synthesis of amide (3) from aspirin chloride:
[ (2- (Chlorocarbonyl) phenyl acetate) ] (19.5 mmol) aspirin chloride (2) is added dropwise onto the ice-cooled (-12 °C) chloroform and (pyrolidine-2-carboxylic acid) proline (1) (19.5 mmol) in pyridine. The resulting mixture is stirred at room temperature for 24 hours, (300 mL) of distilled water and (400 mL) of chloroform are added. The organic phase to be formed is separated, washed with distilled water 3 times (400 mL) and dried with anhydrous MgSCh, filtered and the solvent is removed by evaporating with toluene 3 times (50 mL) . The remaining organic phase is purified in the silica gel column.
Synthesis of nitrile (4) compound:
The synthesized amide (3) (0.1 mole) and the ethyl carbamate (0.11 mole) are mixed in a 50 mL three-neck round bottom flask at 75°c. Then 7.3 mL of thionyl chloride is added dropwise over about 0.5 hours. The reaction mixture is stirred in an oil bath at 75-80 °C for 18 hours. The reaction mixture is followed by thin layer chromatography (TLC) . After the reaction is complete, the solid phase is filtered, the organic phase is evaporated and purified by column chromatography .
Synthesis of the nanoparticle (5) form of the drug of the invention :
One skilled in the art knows that some organic molecules form complexes with Cu(II) ions. However, these complexes can also be synthesized as hybrid structures with flowerlike shapes under appropriate conditions. The nanoparticle (5) form of the invention is synthesized using cyano derivatives to include organic-inorganic hybrid structures with flower-like shapes.
In the method of preparing the nanoparticle (5) form of the invention, organic-inorganic hybrid structures with flowerlike shapes are synthesized using cyano derivatives.
In the synthesis of organic/inorganic hybrid structures with flower-like shapes, cyano derivatives are used as the organic part (CUSO4.5H2O) . Incubate the solution at room temperature for 3 days by adding CuSO4 dissolved in water at certain concentrations to 10 mM phosphate buffered saline (PBS) solution (pH 5-9) containing certain concentrations of cyano derivatives. After incubation, the blue-colored precipitate formed in the reaction vessel (which shows that shaped organic-inorganic hybrid structures with flower-like
shapes are formed) is centri fuged and dried after several times of washing and stored for later applications .
In the synthesis of organic/ inorganic hybrid structures with flower-like shapes , primary copper phosphate crystals occur in the first stage of the formation mechanism. At this stage , organic molecules predominantly form complexes through the coordination of Cu ( I I ) ions and N atoms , especially in organic molecules . These formed complexes become the nucleation sites of the primary crystals of copper phosphate . In the second stage of growth, organic molecules and primary crystals become large pellets . The kinetic control of copper phosphate crystals results from the individual copper-binding regions on the surface of the aggregates , resulting in the formation of individual leaves . In the last stage , anisotropic growth results in the formation of a branched and flower-like structure . In this proposed growth process , the organic molecule induces nucleation of copper phosphate crystals for the formation of leaf scaf folds and serves as a "glue" to bind the leaves together . These nanoscale leaf-shaped structures are connected to each other and create structures with flowerlike shapes . For this reason, the synthesi zed structures are called " Flower-Like Hybrid structures" .
The drug of the invention is a DPP-4 inhibitor in the oral diabetes drug class . They are also known as gliptins . Circulating incretin prevents the breakdown of hormones and prolongs the duration of GLP- 1 . The newly synthesi zed agent sustains the activity of incretins by inhibiting DPP-4 , which is responsible for regulating the secretion of incretin hormone . Incretin, on the other hand, stimulates beta cells in the pancreas to secrete insulin . When insulin is secreted, glucose molecules are delivered to cells that
receive glucose in an insulin-dependent manner and also work by increasing cell sensitivity to insulin . Additionally, it shows activity in repairing damaged beta cells in pancreatic tissue .
One of the most important advantages of the drug of the invention and the nanoparticle thereof is that it has a small si ze and a small molecular weight . Due to its small molecular si ze , compound stability is easily achieved and maintained . In addition, due to its small molecular si ze, it can easily acces s and bind to the active site of the DPP-4 enzyme and thus , the enzyme can be inhibited .
Being of small si ze and molecular weight , another advantage of the drug is that the compound has small-si zed ef fective aggregates that allow the formation of nanof luorescent particles thereby assisting in increasing the ef fect of the drug prepared in terms of absorption and permeation into the cell wall .
The technical advantage is that the nanoparticle form of the drug of the invention contains hybrid flower-shaped structures , resulting in increased stability of the nanocomposite compared to those without a nanostructure . In addition, it is the ability of molecules to penetrate the cell wall better than non-nano molecules , increasing the ease and speed of absorption and drug ef ficiency .
Due to the invention, a drug and nanoparticle that provides a low rate of hypoglycemia and good glycemic control have been developed in order to ef fectively treat type 2 Diabetes Mellitus disease by inhibiting DPP-4 enzyme and to solve the weight control problems of patients . The said drug and nanoparticle have the ability to penetrate cell walls ,
leading to high absorption rate , speed and ef fectiveness . Due to the small si ze and low molecular weight of the drug of the invention and the nanoparticle thereof , the dose given to the patients can be reduced, thus minimi zing the chemical and adverse ef fects to which the patient is exposed .
Description of the Figures
Figure 1 A figure of the synthesis of the drug of the invention and the nanoparticle form thereof
Description of the Reference Numbers in Figures
1 . Proline
2 . Aspirin chloride 3 . Amide
4 . Nitrile
5 . Nanoparticle
Claims
Claims The synthesis method of a drug for the treatment of Type- 2 Diabetes Mellitus disease, comprising: a. synthesizing aspirin chloride (2) , b. synthesizing amide (3) from the resulting aspirin chloride (2) ; and c. synthesizing nitrile (4) compound from the amide (3) compound obtained. A method of synthesis of a drug according to claim 1, wherein step a consists of: mixing aspirin with thionyl chloride and distilling until hydrogen chloride conversion is finished, synthesizing aspirin chloride (2) by cooling the reaction mixture and then heating with agitation. A method of synthesis of a drug according to claim 2, wherein step a consists of: mixing 19.5 mmol aspirin with re-distilled 4.5 g thionyl chloride in a claisen flask and distilling for 2 hours until hydrogen chloride conversion is finished; and synthesizing aspirin chloride (2) by cooling the reaction mixture and then removing the condenser and heating the balloon with agitation at 60 °C for 3 minutes . A method of synthesis of a drug according to claim 1 or 2, wherein step b consists of: adding aspirin chloride dropwise onto the proline (1) contained in the cooled chloroform and pyridine, stirring the resulting mixture and adding distilled water and chloroform to the mixture,
separating the resulting organic phase, washing with distilled water, drying with anhydrous MgSCh, filtering, removing the solvent with toluene, and synthesizing amide (3) by purifying the remaining organic phase in the silica gel column. A synthesis method of a drug according to claim 4, wherein step b consists of: adding 19.5 mmol aspirin chloride dropwise onto the 19.5 mmol proline (1) contained in the chloroform and pyridine ice-cooled to -12°C, stirring the resulting mixture at rt for 24 hours and adding 300 mL of distilled water and 400 mL of chloroform to the mixture, separating the resulting organic phase, washing three times with 400 mL of distilled water, drying with anhydrous MgSCh, filtering, evaporating the solvent three times with toluene, and synthesizing amide (3) by purifying the remaining organic phase in the silica gel column. A synthesis method of a drug according to claim 1, 2 or 4, wherein step c consists of: mixing the synthesized amide (3) compound and the ethyl carbamate, adding thionyl chloride to the resulting mixture and mixing the reaction mixture in the oil bath, following the reaction mixture by thin layer chromatography, filtering the solid phase after the reaction is completed, evaporating the organic phase and purifying by column chromatography to obtain the nitrile
(4) compound.
7. A synthesis method of a drug according to claim 6, wherein step c consists of: mixing the 0.1 mole amide (3) compound and the 0.11 mole 50 mL of the ethyl carbamate in a three-neck balloon at 75 °C, adding 7.3 mL of thionyl chloride to the resulting mixture over 0.5h and stirring the reaction mixture in the oil bath at 75-80 °C for 18h, following the reaction mixture by thin layer chromatography, filtering the solid phase after the reaction is completed, evaporating the organic phase and purifying by column chromatography to obtain the nitrile (4) compound.
8. A drug synthesized by a method according to any of the above claims.
9. The drug according to claim 8, comprising aggregates that allow the formation of nanof luorescent particles.
10. Use of a drug according to claim 8 as an enzyme inhibitor of DPP-4.
11. The synthesis method of the nanoparticle of a drug according to claim 8, comprising the process steps of obtaining the nanoparticle (5) by synthesizing the flower-shaped organic and inorganic hybrid structures using the nitrile (4) compound and cyano derivatives.
12. A synthesis method of a nanoparticle according to claim
11, characterized in that CUSO4.5H2O is used as an inorganic part of cyano derivatives as an organic part.
16
13. A synthesis method of a nanoparticle according to claim
11, comprising: adding the nitrile (4) compound to the phosphate- buffered salt solution containing water-soluble CuSCh at certain concentrations and cyano derivatives at certain concentrations, incubating the solution at room temperature for a certain period, centrifuging, washing, drying and storing the precipitate which shows that flower-shaped organic and inorganic hybrid structures are formed after incubation.
14. A synthesis method of a nanoparticle according to claim 13, comprising: adding the nitrile (4) compound to the water-soluble CuSO4 at certain concentrations and the lOmM phosphate- buffered salt solution containing the cyano derivatives at certain concentrations such that pH becomes 5-9, incubating the solution at room temperature for 3 days.
15. Nanoparticle (5) synthesized by a method according to any one of claims 11 to 14.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TRTR2021/022289 | 2021-12-31 | ||
| TR2021/022289A TR2021022289A2 (en) | 2021-12-31 | 2021-12-31 | A DRUG FOR THE TREATMENT OF TYPE 2 DIABETES MELLITUS AND THE NANOPARTICULE OF THIS DRUG |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2023129116A2 true WO2023129116A2 (en) | 2023-07-06 |
| WO2023129116A3 WO2023129116A3 (en) | 2023-08-31 |
Family
ID=85117784
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2022/051753 WO2023129116A2 (en) | 2021-12-31 | 2022-12-30 | A drug for the treatment of type 2 diabetes mellitus disease and the nanoparticle thereof |
Country Status (2)
| Country | Link |
|---|---|
| TR (1) | TR2021022289A2 (en) |
| WO (1) | WO2023129116A2 (en) |
-
2021
- 2021-12-31 TR TR2021/022289A patent/TR2021022289A2/en unknown
-
2022
- 2022-12-30 WO PCT/TR2022/051753 patent/WO2023129116A2/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2023129116A3 (en) | 2023-08-31 |
| TR2021022289A2 (en) | 2022-02-21 |
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