WO2008095366A1 - Porphyrin derivatives, preparation methods and the uses as small molecular antioxidant thereof - Google Patents

Abstract

A porphyrin derivative and its pharmaceutical acceptable salt and its preparation method. The said porphyrin derivative is M-5,10,15,20-tetra[3-ethylene polyol monomethyl ether-substituted -phenyl]porphyrin, in which M is one of Fe, Mn, Co, Ni, Cu, Zn, Sn, Cr, V and Pt metal ions. The said porphyrin derivative can be used as small molecular antioxidant for regulating the concentration of peroxide between cells of human body or in cell, protecting the body to avoid the damage from peroxy radical or from other peroxide derived from peroxy radical, preventing or treating the diseases caused by the peroxide.

Description

 Porphyrin derivative, preparation method thereof and application thereof as small molecule antioxidant

 The invention relates to a substituted porphyrin derivative, a preparation method thereof and application thereof as a small molecule antioxidant, in particular to a porphyrin derivative, a preparation method thereof and a small molecule antioxidant for regulating human cell or intracellular peroxidation Application in terms of concentration.

Background technique

Peroxide is a product of normal physiological metabolism in the human body. Peroxides present in and between human cells include o ₂ _, oir, ONcxr and 3⁄4o ₂ . Since peroxides have high chemical activity, they can react with substances that make up human cells, such as cell membranes and chromosomes, leading to disease.

 Oxygen is active and can participate in important metabolic processes that play an important role in sustaining life. But oxygen can also cause damage to living things. In the body, oxygen is converted into a variety of peroxides that can damage deoxynucleotides, proteins, and phospholipids. The accumulation of these reactions can impair the function of the cells and even cause disease. Studies have shown that peroxides in cerebral thrombosis, chronic bronchitis, asthma, rheumatoid arthritis, cancer, Alzheimer's disease, Parkinson's disease, shock caused by septicemia, diabetes, due to human exposure to radiotherapy It plays a role in various diseases such as sequelae, AIDS, aging and heart failure.

Free radicals are a class of high energy labile compounds containing unpaired electrons. Harmful peroxides in the human body include 0 ₂ _, OH -, ONOO- and 3⁄40 ₂ . Such peroxides are produced by physiological reactions in the body, such as the process of re-oxygenation and radiotherapy. ONOCT is the product of the action of 0 ₂ _ and NO_. Radon is a free radical that is often produced during the course of radiotherapy. This free radical is the most active free radical in chemistry. It reacts with chemicals in the body and causes a chain reaction. It can even react with groups on deoxynucleotides to disrupt the inheritance and replication of cells. The toxic effects of radiotherapy on the human body may begin with the production of free radicals. Re-oxygenation of damaged tissue produces a large amount of peroxygen free radicals. There are three natural anti-free radical enzymes in the human body that can decompose free radicals. One is present in the cytoplasm, one is present in the mitochondria, and one is present in the cell matrix. All of the above three anti-free radical enzymes are high molecular substances having a molecular weight of 10,000 or more, which are present in human cells or between human cells, but cannot pass through the cell membrane. When the amount of free radicals in the human body is low, these naturally occurring enzymes can effectively decompose these free radicals, thereby protecting the human body. However, when the free radical content in the human body is high, these naturally occurring enzymes can only effectively decompose part of the free radicals. The remaining free radicals that cannot be decomposed can cause greater damage to the human body.

 Naturally occurring anti-free radical enzymes in the human body can catalyze the following reactions:

20 ₂ " + 2H + 0 ₂ + H ₂ 0 ₂ This reaction can remove oxygen radicals and generate hydrogen peroxide. Although hydrogen peroxide is not a free radical, it is toxic to cells. Hydrogen peroxide can be further affected by the body. Other enzymes inside are removed.

 Antioxidant enzymes play an important role in protecting the body against free radicals. However, the enzyme itself is a polymer which has a short half-life in the blood circulation and is inaccessible to the cells, which is costly, which limits its feasibility as a drug.

 There are two effective methods for effectively removing peroxides in the human body that cannot be decomposed by natural anti-free radical enzymes in time. One is to add a capture agent. When the peroxide is formed, it is destroyed by the capture agent molecule. The amount of Parker molecules and the amount of free radicals are usually

1 : 1 relationship. Another method is to add a small molecule antioxidant (catalyst) that is catalytically decomposed as soon as the peroxide is formed. The advantage of using a small molecule catalyst is that a large amount of the drug can be used to remove a large amount of peroxide.

Manganese and iron porphyrin compounds have been used to study the feasibility of being a small molecule antioxidant. Duke University and Princeton University are pioneers in this area. Kachadourian, R. et al., /"orga'c Chemistry, 1999, 38, 391-396, disclose "Syntheses and Superoxide Dismuting Activities of Partially (1-4) - Chlorinated Derivatives of Manganese(III) meso-Tetrakis(N-ethylpyridinium-2-yl ) Porphyrin"; Ferrer-Sueta, et al., in Chemical Research in Toxicology, 1999, 12, 442-449, discloses "Catalytic Scavenging of Peroxynitrite by Isomeric Mn(III) N-Methylp ridylporph rins in the Presence of Reductants"; Lee, "Mechanisms of Iron Porphyrin Reactions with Peroxynitrite" is disclosed by J et al., J wr" of the American Chemical Society, 1998, 120, 7493-7501, and Lee, J. et al. are still at J wrwa/ of "Manganese Porphyrins as Redox-Coupled Peroxynitrite Reductases" is disclosed in the American Chemical Society, 1998, 120, 6053-6061. The above results show that manganese and iron porphyrin compounds have good anti-peroxide properties. Good biocompatibility and low toxicity.

 In summary, the development of a stable quality antioxidant with good pharmacokinetic properties and effective decomposition of peroxides will make a significant contribution to human health care.

Summary of the invention

 SUMMARY OF THE INVENTION An object of the present invention is to provide a porphyrin derivative which has good water solubility, thereby increasing the utility of using porphyrin as a medicament.

 Another object of the present invention is to provide a process for producing a porphyrin derivative which is simple, high in yield and suitable for mass production.

 A further object of the present invention is to provide a porphyrin derivative as a small molecule antioxidant for regulating the concentration of intercellular peroxide or intracellular peroxide in human cells.

 The porphyrin derivative protects the human body from peroxy radicals and other peroxides derived from peroxy radicals, and is used to prevent and treat diseases caused by the presence of harmful peroxides.

In order to achieve the above object, the technical solution adopted by the present invention is: a quinone derivative having the following structure:

I

Where R is

-C3⁄4CH ₂ (OCH ₂ CH ₂ ) _p OC _n H _2n+1 , m=2-10, n=l-10, p=0-10; M is one of the metal ions of the following metals: Fe, Mn , Co, Ni, Cu, Zn, Sn, Cr, Pd, Pt, V.

R is preferably -CH ₃ or -CH ₂ C3⁄4OC3⁄4, and M is preferably Fe(III) or Μη(ΠΙ). The present invention includes hydrochlorides, sulfates, acetates, phosphates and other salts which can be used medically as the metalloporphyrin derivatives of the formula I.

 The different metals of the metalloporphyrin derivatives of the invention have different properties. In the present invention, a complex of a porphyrin with iron or manganese is preferred.

The metalloporphyrin derivative of the present invention can be used as a small molecule antioxidant to achieve the purpose of treating diseases by reducing the content of 0 ₂ -radical, Off radical, ΟΝΟΟ- and 3⁄40 ₂ in human cells or tissues.

The metalloporphyrin derivative of the invention can be used for reducing or preventing damage to the human brain due to the formation of cerebral thrombosis, thereby achieving the purpose of treating cerebral thrombosis. The invention is equally applicable to the treatment of chronic bronchitis, asthma, rheumatoid arthritis, cancer, Alzheimer's disease, Parkinson's disease, shock caused by septicemia, diabetes, sequelae caused by radiotherapy of the human body, AIDS, Dry age-related macular degeneration, aging and heart failure diseases. The metalloporphyrin derivative of the invention is capable of catalyzing the decomposition of harmful peroxides in the human body and And can penetrate the cell membrane into the human body cells.

 The synthesis method of the metalloporphyrin derivative of the present invention is as follows:

 Where MX is a metal salt.

 The preparation method of the porphyrin derivative of the invention comprises the following steps: firstly reacting benzaldehyde having a meta substituent with pyrrole under a catalytic action of an organic acid at a certain temperature for 1 hour to 3 days, after distilling off the acid, remaining The product is isolated and purified to obtain a porphyrin. The molar ratio of benzaldehyde to pyrrole is 1:0.5-2, and the organic acid herein is a monobasic acid such as acetic acid, propionic acid, butyric acid, isobutyric acid, trifluoroacetic acid, trichloroacetic acid or the like, preferably propionic acid. The reaction temperature can be from room temperature to reflux depending on the acid.

 Then, the porphyrin and the metal salt are heated and reacted in a polar solvent for 1 to 24 hours, and after distilling off the solvent, the residue is separated and purified to obtain a porphyrin derivative (i.e., a metal-porphyrin complex). The molar ratio of porphyrin to metal salt is 1:1-10; the metal salt is any salt of any form of Fe, Mn, Co, M, Cu, Zn, Sn, Cr, Pt, V described above, preferably hydrochloride. And acetate; the solvent can be selected from hydrazine, hydrazine dimethylformamide, methanol, ethanol, acetonitrile, 1,4-dioxane, dimethyl sulfoxide, etc.; reaction temperature can be 30 视 depending on the reactants. To the reflux temperature.

 Cerebral thrombosis refers to the blockage of blood flow in the brain. Re-opening the bloodstream after surgery can cause further damage to the brain. This is called damage caused by re-oxygenation. Many scientists believe that at least some of the damage caused by cerebral thrombosis and reoxygenation is caused by free radicals. The porphyrin derivative of the present invention can be used as a small molecule antioxidant for treating cerebral thrombosis, and can reduce brain cell death and re-oxygenation damage caused by cerebral thrombosis, and the dosage is 0.5-100 g / kg body weight.

Acute myocardial infarction, commonly referred to as heart failure. It is due to the crown of the heart blood supply Caused by blockage of blood flow in the arteries leading to death of heart tissue. Long-term or permanent blood flow is blocked, causing partial myocardial hypoxia, which ultimately leads to the death of cardiomyocytes. If intervened by natural or medical means, blood flow is quickly cleared, and damage caused by infarction may be removed or reduced. However, the recanalization of blood flow can also cause damage to cardiomyocytes and their adjacent tissue cells. This type of injury is called ischemic re-oxygenation damage. Studies have shown that free radicals play an important role in the damage caused by blocked blood flow and the damage caused by ischemic re-oxygenation. Therefore, the porphyrin derivative of the present invention as a small molecule antioxidant can reduce tissue damage and benefit patients suffering from heart failure.

 Due to the large amount of free radicals generated during the radiotherapy process, it has a great side effect on the human body. The porphyrin derivative of the present invention can be used as a small molecule antioxidant to treat sequelae caused by radiotherapy in the human body and to act as an adjuvant therapy.

 Chronic bronchitis, asthma, rheumatoid arthritis, Alzheimer's disease, cancer, Parkinson's disease, shock caused by septicemia, diabetes, dry age-related macular degeneration, aging and other diseases are also directly related to free radicals The damage caused by the cells is related. Therefore, the porphyrin derivatives of the present invention can also be used as a small molecule antioxidant to treat these diseases.

 In practical use, the small molecule antioxidant of the metalloporphyrin derivative of the present invention can be classified into two types, oral and injection. As an oral solution, it may be formed into a tablet or a capsule, and the ratio of the active component may be between 0.1 and 80%. As the injection, a mixture of polyethylene glycol-400, anhydrous ethanol and water for injection is usually used as a solvent. The amount of the drug used is between 0.01 and 200 mg/kg/day. It is used as a small molecule antioxidant to treat diseases such as cerebral thrombosis and heart failure.

detailed description

 The invention is described in detail below with reference to the drawings and specific embodiments, which are intended to illustrate the invention and not to limit the invention.

Example 1: 3-(2-methoxy B

100 g of m-hydroxybenzaldehyde was dissolved in 1 liter of DMF, and 226 g of anhydrous potassium carbonate was added. After stirring for 30 minutes, 81.3 g of 2-chloroethyl methyl ether was added, and the mixture was heated under reflux for 6 hours. DMF was evaporated under reduced pressure, dissolved in 500 liters of water, filtered, and the filtrate was extracted three times with dichloromethane. It was washed with a 2% sodium hydroxide solution (200 liters), washed with water three times, dried over anhydrous sodium sulfate, filtered, and evaporated. ESI-MS: [M+H]+, 181;]H R (DMSO-de): δ 3.31(s ₅ 3Η), 3.67 (t, J= 4.56 Hz, 2 H), 4.17 (t, J= 4.56 Hz, 2 H), 7.30 (m, 1 H), 7.43 (m, 1 H), 7.51 (m, 2 H), 9.97 (s, 1 H).

Example 2: Preparation of p-toluenesulfonic acid methoxyethyl ester

A mixture of 38 g of ethylene glycol monomethyl ether and 120 g of anhydrous pyridine was cooled to -6 ° C, 101 g of p-toluenesulfonyl chloride was added in portions, the temperature was controlled to not exceed 0 ° C, and stirring was continued after the addition. After 30 minutes, the ice was removed and reacted at room temperature for 4 hours. The reaction mixture was poured into a mixture of 250 liters of hydrochloric acid and 700 g of ice, and the mixture was stirred for 20 minutes, and extracted with EtOAc (EtOAc). 84 g of the product of Example 3: Preparation of 3-(2-methoxyethoxy)benzaldehyde

12 g of m-hydroxybenzaldehyde was dissolved in 150 liters of DMF, 27.6 g of anhydrous potassium carbonate was added, stirred, and 23 g of methoxyethyl p-toluenesulfonate was added thereto, and the mixture was heated under reflux for 3 hours, and distilled under reduced pressure. DMF, dissolved in 200 liters of water, extracted 3 times with dichloromethane, combined with extract, washed with 200 liters of 5% sodium hydroxide solution, washed 3 times with water, anhydrous sulfuric acid The sodium was dried, filtered, and the solvent was evaporated to give 16 g of product.

Example 4: Preparation of p-toluenesulfonic acid methoxyethoxyethyl ester

 A mixture of 30 g of diethylene glycol monomethyl ether and 79 g of anhydrous pyridine was cooled to -10 ° C in an ice bath, and 54 g of p-toluenesulfonyl chloride was added in portions, and the temperature was controlled to not exceed 0 ° C. After stirring for 30 minutes, the ice bath was removed and reacted at room temperature for 4 hours. The reaction mixture was poured into a mixture of 250 liters of hydrochloric acid and 500 g of ice, and the mixture was stirred for 20 minutes, and extracted twice with ethyl acetate. The mixture was combined, washed with water, dried over anhydrous sodium sulfate and evaporated. Obtained 82 grams of product.

Example S: Preparation of 3-[2-(2-methoxyethoxy)ethoxy]benzaldehyde

 18 g of m-hydroxybenzaldehyde was dissolved in 200 liters of DMF, 41.4 g of anhydrous potassium carbonate was added, stirred, and 41 g of methoxyethoxyethyl p-toluenesulfonate was added, and the mixture was heated under reflux for 3 hours, minus DMF was distilled off, dissolved in 300 ml of water, extracted three times with dichloromethane, and the combined extracts were washed with 5% sodium hydroxide solution, then washed with water three times, dried over anhydrous sodium sulfate and filtered. The solvent was distilled off to give 32 g of product.

Example 6: Preparation of 5,10,15,20-tetra [3-(2-methoxyethoxy)phenyl]porphyrin

54 g of 3-(2-methoxyethoxy)benzaldehyde was added to 2 liters of propionic acid and added to 30.6 g. Acetic anhydride, heated to a slight reflux, 20.1 g of pyrrole was added dropwise in a quarter of an hour, heating was continued for 6 hours, propionic acid was distilled off under reduced pressure, and the residue was separated to obtain 5 g of 5,10,15,20-tetra [3- (2-Methoxyethoxy)phenyl]porphyrin. ESI-MS: [M+H]+, 911; 3⁄4 NMR (DMSO-d ₆ ): δ -3.0 (s, br, 2 H) 3.33 (s, 12 H), 3.73 (t, J = 4.56 Hz, 8 H), 4.29 (t ₅ J = 4.56 Hz, 8 H), 7.43 (m, 4 H), 7.70 (m, 4 H), 7.79 (m, 8 H), 8.88 (s, 8 H). Example 7: Preparation of 5,10,15,20-tetrakis[3-(2-methoxyethoxy)phenyl]porphyrin

 71.8 g of 3-(2-methoxyethoxy)benzaldehyde and 27 g of pyrrole were each diluted to 100 liters with propionic acid, and charged into a 100 liter dropping funnel. 1.8 liters of propionic acid and 30.6 g of acetic anhydride were added to a 3-liter three-necked flask, heated to 105 ° C, and the above two solutions were added dropwise at the same rate. After 6.7 hours, the temperature was maintained at 110 ° C for three days, and filtered. The cake was washed with propionic acid, and the filtrate was evaporated under reduced pressure to propionic acid. The residue was purified and purified to give 19 g of 5,10,15,20-tetra[3-(2-methoxyethoxy)phenyl] Porphyrin.

Example 8: Preparation of 5,10,15,20- 0 [3-[2-(2-methoxyethoxy)ethoxy]phenyl]porphyrin

20.5克 3-[ 2 - ( 2 -甲氧基乙氧基) 乙氧基]苯甲醛加入到 500毫 升丙酸中，加入 9.3克乙酸酐， 加热至稍微回流， 在一刻钟内滴加 6.1 克吡咯， 继续加热回流 6小时， 减压蒸出丙酸， 剩余物经分离得到 3.5克 5, 10，15，20-四[3- [ 2 - ( 2 -甲氧基乙氧基)乙氧基]苯基]卟啉。 ESI-MS: [M+H]+, 1087;】H NMR (DMSO-d₆): δ -3.0 (s, br, 2 H) 3.20 (s, 12 H), 3.45 (t, J = 4.80 Hz, 8 H), 3.60 (t, J = 5.04 Hz, 8 H), 3.80 (t, J = 5.04 Hz, 8 H), 4.29 (t, J = 4.80 Hz, 8 H)， 7.43 (m, 4 H), 7.70 (m, 4 H), 7.79 (m, 8 H), 8.87 (s， 8 H).

20.5 g of 3-[2-(2-methoxyethoxy)ethoxy]benzaldehyde was added to 500 ml of propionic acid, 9.3 g of acetic anhydride was added, heated to a slight reflux, and 6.1 g was added dropwise in a quarter of an hour. Pyrrole, heating under reflux for 6 hours, distilling off propionic acid under reduced pressure, and the residue was separated to give 3.5 g of 5,10,15,20-tetra[3-[2-(2-methoxyethoxy)ethoxy. ]Phenyl]porphyrin. ESI-MS: [M+H]+, 1087;]H NMR (DMSO-d ₆ ): δ -3.0 (s, br, 2 H) 3.20 (s, 12 H), 3.45 (t, J = 4.80 Hz , 8 H), 3.60 (t, J = 5.04 Hz, 8 H), 3.80 (t, J = 5.04 Hz, 8 H), 4.29 (t, J = 4.80 Hz, 8 H), 7.43 (m, 4 H ), 7.70 (m, 4 H), 7.79 (m, 8 H), 8.87 (s, 8 H).

Example 9: Preparation of iron (III)-5,10,15,20-tetra[3-(2-methoxyethoxy)phenyl]porphyrin hydrochloride

 18.5 g of 5,10,15,20-tetra[3-(2-methoxyethoxy)phenyl]porphyrin was dissolved in 500 ml of DMF, and 26.6 g of ferrous chloride tetrahydrate was added and heated. Reflux for 3 hours. DMF was distilled off under reduced pressure, and the residue was dissolved in dichloromethane, filtered, and the filtrate was washed twice, evaporated to dryness, Mass Spectrum: [(M-Cl-)+], 964ο Example 10: Cobalt (ΠΙ)- 5,10,15,20-tetrakis[3-(2-methoxyethoxy)phenyl]porphyrin vinegar Preparation of acid salt

Dissolve 1 gram of 5,10,15,20-tetra[3-(2-methoxyethoxy)phenyl]porphyrin in 100 liters In DMF, 1.91 g of Co (C3⁄4COO) ₂ ·4Η ₂ 0 was added and heated under reflux for 6 hours. DMF was evaporated under reduced pressure. The residue was dissolved in dichloromethane, filtered, and the filtrate was washed twice, evaporated and evaporated. 0.7 g of cobalt-porphyrin acetate was obtained. Mass Spectrum: [(Μ-CH ₃ COO-)+] ₅ 967.

Example 11: Preparation of Manganese (Nb)-5,10,15,20-tetra[3-(2-methoxyethoxy)phenyl]P-Pholine Acetate

1 g of 5,10,15,20-tetrakis[3-(2-methoxyethoxy)phenyl]porphyrin was dissolved in 100 liters of DMF, and 1.38 g of Co(C3⁄4COO) ₂ ·4 Η ₂ 0 was added. After heating under reflux for 3 hours, hydrazine and dimethyl dimethyl amide were distilled off under reduced pressure, and the residue was dissolved in dichloromethane, filtered, and the filtrate was washed twice with water, and evaporated to dryness. - Porphyrin acetate. Mass Spectrum: [(Μ-CH ₃ COO-)+], 963.

Example 12: Preparation of copper (II)-5, 10, 15,20-tetra [3-(2-methoxyethoxy)phenyl]porphyrin

1 g of 5,10,15,20-tetra[3-(2-methoxyethoxy)phenyl]porphyrin was dissolved in 100 liters of DMF, and 1.38 g of CuCl ₂ '23⁄40 was added and heated to reflux for 4 hours. The hydrazine was distilled off under reduced pressure, and dimethylformamide was evaporated. The residue was dissolved in dichloromethane, filtered, and the filtrate was washed twice with water and evaporated to dryness. Mass spectrometry: [Μ+Η] ⁺ , 972ο

Example 13: Iron (ΠΙ)-5,10,15,20-tetra[3-[2-(2-methoxyethoxy)ethoxy]phenyl] Preparation of porphyrin hydrochloride

1 g of 5, 10, 15, 20-tetrakis[3-[2-(2-methoxyethoxy)ethoxy]phenyl]porphyrin was dissolved in 100 liters of DMF, and 1.38 g of FeCl _{2 was added.} 4H ₂ 0 was heated to reflux for 5 hours, N,N-dimethylformamide was evaporated under reduced pressure, the residue was dissolved in dichloromethane, filtered, and the filtrate was washed twice with water and evaporated to dryness. (III) - porphyrin hydrochloride. Mass spectrometry: [(M-Cl-)+], 1140

Example 14: Preparation of #-5,10,15,20-tetra [3-[2-(2-methoxyethoxy)ethoxy]phenyl]porphyrin hydrochloride

0.5 g of 5,10,15,20-tetra[3-[2-(2-methoxyethoxy)ethoxy]phenyl]porphyrin was dissolved in 50 liters of DMF, and 0.75 g of MnCl _{2 was added.} The mixture was heated to reflux for 5 hours. The hydrazine and dimethylformamide were evaporated under reduced pressure. The residue was dissolved in dichloromethane and filtered. The filtrate was washed twice with water and evaporated to dryness. - porphyrin hydrochloride. Mass Spectrum: [(M-Cl-)+], 1139. Example 15: iron ^{(ΠΙ) - 5, 10,1 5} , 2 0- four | ^[2 - ⁽² - methoxyethoxy) ethoxy] phenyl] porphyrin hydrochloride pharmaceutical formulations, process Test data

 Prescription: Specifications: 2ml: 20mg

 Porphyrin hydrochloride 20.5mg Polyethylene glycol-400 (PEG-400) (50%) 1.0ml Anhydrous ethanol (30%) 0.6ml Sodium deoxycholate O.lg Water for injection (20%) 0.4ml iOml / support process:

 1. Washing the bottle: The ampoule is dried according to the conventional method, and sterilized for use.

 2, dosing: separately take the prescription amount of polyethylene glycol-400 and anhydrous ethanol mixed evenly, add the prescription amount of sodium deoxycholate, stir and dissolve; then add the prescription of the main drug, stir, ultrasonic dissolution, adjust pH, add water for injection to the full amount.

 3. The above solution is finely filtered with a 0.22 um-0.45 um microporous membrane, and the liquid is checked for visible foreign matter.

 4. Determination of intermediates: Determination of content and pH.

 5. According to the content test results, determine the filling amount and fill it in 2ml ampoules.

6. Sterilization leak detection: steam sterilization at 100 ° C for 30 minutes.

 7, full inspection, packaging, storage.

Example 16: Main pharmacodynamic study of iron(III)-5,10,15,20-tetrakis[3-(2-methoxyethoxy)phenyl]porphyrin hydrochloride (SW100-7) Test

First, the test materials

1.1 drugs

Drugs required: Positive control drug amifostine (Beijing Lumei Xinyue Biotechnology Center),

SW100-7 (赛文).

Preparation of the drug: amifostine, formulated with normal saline to form a 14mg/ml solution; SW100-7 The drug solution of 1 mg/ml and 0.2 mg/ml O.lmg/ml was separately prepared with dimethyl sulfoxide. 1.2 reagent

 Reagents required: dimethyl sulfoxide, saline, glacial acetic acid, gentian violet, distilled water.

 Preparation of reagents:

 White blood cell dilution: 1 ml of glacial acetic acid and 1 ml of gentian violet 1 ml, add distilled water to 100 ml, and mix well.

 1.3 Test equipment

 Electronic balances, balances, microscopes, micro-capsules, blood cell counting plates, blood covers, syringes, cuvettes, glass rods, hair dryers.

 Second, test methods and results

 Sixty healthy mice were randomly divided into 6 groups, 10 in each group, half male and half female. The first group was normal control group, intraperitoneal injection of normal saline, no irradiation; the second group was irradiated control group, intraperitoneal injection of normal saline and irradiation; the third group was positive control group, intraperitoneal injection of amifostine and irradiation; The fourth group was the high-dose group, intraperitoneal injection of l100/ml SW100-7 and irradiation; the fifth group was the middle dose group, intraperitoneal injection of 0.2mg/ml SW100-7 and irradiation; the sixth group was low dose group , SW100-7 was injected intraperitoneally with O.lmg/ml and given irradiation. Each mouse was weighed (m), and immediately after intraperitoneal injection according to the dose of 0.005 m ml, a whole body irradiation was performed with 60 Ο > γ ray, and the absorbed dose rate was 0.175 Gy/min, and the total absorbed dose was 7.20 Gy. The total number of white blood cells was counted on the fourth day after irradiation, and the results are shown in Table 1.

 Table 1: List of white blood cell counts (unit: unit / liter)

It can be seen from the table that except for the female group in the high-dose group and the female group in the middle-dose group, the number of white cells after irradiation in the other SW 100-7 group mice was higher than that in the irradiated control group. SW100-7 has a certain cytoprotective effect. From test data not The dose-response relationship of SW100-7 was found. The number of white blood cells in the male and female mice in the positive control group was lower than that in the irradiated control group, which may be caused by the experimental error.

Industrial applicability

 The invention provides a porphyrin derivative, a preparation method thereof and application thereof as a small molecule antioxidant, and the porphyrin derivative of the invention has good water solubility and can treat sequelae caused by human body receiving radiotherapy, To the role of adjuvant therapy; and to protect the body from peroxygen free radicals and other peroxides derived from peroxy radicals by regulating the concentration of intercellular or intracellular peroxides, preventing and treating harmful peroxidation A disease caused by the presence of a substance. Moreover, the porphyrin derivative can also be used for reducing or preventing damage to the human brain due to the formation of cerebral thrombosis, thereby achieving the purpose of treating cerebral thrombosis. The same applies to the treatment of chronic bronchitis, asthma, rheumatoid arthritis, cancer, Alzheimer's disease, Parkinson's disease, shock caused by septicemia, diabetes, sequelae caused by radiotherapy, AIDS, dryness Sexual age-related macular degeneration, aging and heart failure diseases.

Claims

Claim  A porphyrin derivative having the structure of formula I or a pharmaceutically acceptable salt thereof:

 I Wherein R is -CJH^. -C _n H _2n+1 , -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _p OC _m H _2m . ₁ ^--CH ₂ CH ₂ (OCH ₂ CH ₂ )pOC _n H _{2n +1} , m=2-10, n=l-10, p=0-10; M is one of the metal ions of the following metals: Fe, Mn, Co, Ni, Cu, Zn, Sn, Cr, Pd , Pt, V.  The P-porphyrin derivative according to claim 1, wherein R is a methyl group. The porphyrin derivative according to claim 1, wherein R is -CH ₂ CH ₂ OCH ₃ .  4. The porphyrin derivative according to any one of claims 1 to 3, wherein M is Fe(III).  The porphyrin derivative according to any one of claims 1 to 3, wherein M is Μη(ΙΠ).  The porphyrin derivative according to any one of claims 1 to 5, wherein the pharmaceutically acceptable salt is a hydrochloride, a sulfate, an acetate or a phosphate.  A method for producing the porphyrin derivative according to any one of claims 1 to 6, which comprises the steps of: 1) First, the benzaldehyde having a meta-substituent and pyrrole are reacted under the catalysis of an organic acid for 1 hour to 3 days, and after distilling off the acid, the residue is separated and purified to obtain a porphyrin; 2) Then, the porphyrin and the metal salt are heated and reacted in a polar solvent for 1 to 24 hours, and after distilling off the solvent, the residue is separated and purified to obtain a porphyrin derivative.  8. The method for producing a porphyrin derivative according to claim 7, wherein in step 1), the molar ratio of benzaldehyde to pyrrole is 1:0.5-2, and the organic acid is a monobasic acid. The temperature is from room temperature to reflux temperature.  The method for producing a porphyrin derivative according to claim 7 or 8, wherein in the step 1), the organic acid is acetic acid, propionic acid, butyric acid, isobutyric acid, trifluoroacetic acid or three Chloroacetic acid.  The method for producing a porphyrin derivative according to any one of claims 7-9, wherein in step 2), the molar ratio of the porphyrin to the metal salt is 1:1-10; The metal salt is any salt of any of Fe, Mn, Co, Ni, Cu, Zn, Sn, Cr, Pt, V; the solvent is selected from the group consisting of hydrazine, hydrazine dimethylformamide, methanol, ethanol, acetonitrile, 1,4-Dioxane or dimethyl sulfoxide; reaction temperature is 30 Torr to reflux temperature.  11. The method for producing a porphyrin derivative according to any one of claims 7 to 10, wherein in the step 2), the metal salt is a hydrochloride or an acetate.  12. Philippine claims 1-6 any of the porphyrin derivatives described in the preparation for the treatment of cerebral thrombosis, chronic bronchitis, asthma, rheumatoid arthritis, cancer, Alzheimer's disease, Parkinson's disease, by defeat Healing-induced shock, diabetes, sequelae caused by radiation therapy in humans, AIDS, dry age-related macular degeneration, aging and heart failure.  13. Use of the porphyrin derivative according to any one of claims 1 to 6 for the preparation of a medicament for the sequelae caused by the human body receiving radiotherapy.