WO2009133647A1 - 高分子化環状二トロキシドラジカル化合物およびその使用 - Google Patents
高分子化環状二トロキシドラジカル化合物およびその使用 Download PDFInfo
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Definitions
- the present invention relates to a method for stabilizing a cyclic nitroxide radical compound, and a polymerized cyclic dioxide radical compound and use thereof.
- ESR electron spin resonance
- the ESRR method has been widely used in the environment inside and outside the living body, such as the generation and extinction of active oxygen, using signal analysis and spin trapping.
- ESR-active electron spin is known as an extremely unstable active species
- stable cyclic ditroxide radicals such as 2,2,6,6-tetramethylpiperidinoxy radical (TEMPO)
- TEMPO 2,2,6,6-tetramethylpiperidinoxy radical
- stabilizing radicals for example, see Non-Patent Document 1 below.
- these stable cyclic ditroxide radicals are difficult to handle because even radicals or stable electron spins are reduced in a short time in the presence of reducing species such as ascorbic acid in the organism. is the current situation.
- spin labeling method which is one of the above uses, is a method in which stable nitroxide radicals are used as a labeling agent and bound to protein or fatty acid sterolide, but this is a stable ditroxide radical. Is not intended to be further stabilized in the external environment, nor is it expected to be improved.
- edaravone is associated with the risk of side effects of acute renal failure (complications such as renal dysfunction, liver dysfunction, and heart disease).
- edaravone is administered in small doses in humans in multiple doses in terms of safety, compared to the doses that have seen significant effects in animal experiments, and there is room for improvement in terms of efficacy and safety. It is thought that there is.
- Non-Patent Document 3 these interactions result from protection against ionizing radiation, functional magnetic resonance imaging probes, prevention or treatment of cancer, control of hypertension and body weight, ischemia and reperfusion It has also been suggested that it can be used in therapeutic and research applications, including injury protection.
- the cyclic nitroxide compound Once the cyclic nitroxide compound enters the living body, it does not function as a radical scavenger when it is reduced by endogenous reducing agents such as ascorbic acid.
- the present inventors have heretofore proposed a novel material in which nanoparticles (or polymer micelles) by self-assembly of a parent-hydrophobic block copolymer in water enable drug carriers and nanodiagnosis.
- Patent Document 1 Special Table 200 1-5232 15 (or WO 96/32 967)
- Patent Document 2 WO 96Z33233 (or US Pat.
- Patent Document 3 WO 97 06202 (or US Pat) 5, 929, 1 77)
- Non-Patent Document 1 B. P. S. ou I ⁇ ⁇ ta I., Free Radical B io I ogy & Medicine 42 (2007) 1 632-1 650
- Non-Patent Document 2 J. Pharmorcol. Exp, Ther. 28 1: 92 1 -92 7, 1 997
- Non-Patent Document 3 James B. Mi c ce l l, ⁇ t a I. F r e R a d i c a I B i o l o & M e d i cine 42 (2007) 1 632—65 0
- stable cyclic nitroxy radicals such as Tempo I are called “stable” but function as radical scavengers, but they are reduced in a bioreductive environment and function as radical scavengers. Disappear.
- the cyclic nitroxyl radical is reduced in the living body in the presence of a reducing species such as ascorbic acid in a short time or easily, so that it itself is used for medical purposes as a contrast agent or therapeutic agent. It was difficult to do. Therefore, it would be meaningful if it was possible to provide a means for introducing and retaining radical species stably in a living body for a long time.
- the present inventors have introduced a stable nitroxide radical (such as TEMPO) into the hydrophobic segment of a specific block copolymer, and a new nanoparticle (RNP) that has a stable nitroxide radical mainly in the core region.
- a stable nitroxide radical such as TEMPO
- RNP nanoparticle
- such a polymeric micellar cyclic nitroxide radical compound can prevent or treat brain cell damage presumed to be caused by free radicals produced in the ischemic region or the like.
- the polymeric micellar cyclic nitroxide radical compound is It is presumed that it can be transferred into the brain without being restricted by the blood-brain barrier, and that it also functions as a radical scavenger in the brain. It was also confirmed that the compound did not show significant toxicity or serious side effects on the test animal when administered to an artery or vein at a dose capable of preventing or treating brain cell injury.
- the active oxygen and free radicals (or hydroxy radicals) in the brain Regardless of the mode of production, the compound can also prevent or treat a wide range of diseases or symptoms caused by active oxygen free radicals in the body where active oxygen free radicals are generated. it is conceivable that.
- a method for stabilizing a cyclic nitroxide radical compound comprising: converting a cyclic ditroxide radical compound into a block copolymer comprising a poly (ethylene glycol) chain segment and a hydrophobic chain segment carrying a reactive group; And a step of covalently bonding to a functional group other than the reactive group of the copolymer, wherein the functional group is an amino group, an aminomethyl group, a hydroxy group, a hydroxymethyl group, a carboxyl group, or a carbomethyl group.
- the reactive group is a halogen atom, a carboxyl group, an isocyanate residue, an isothiocyanate residue, an ethyl residue, an acid anhydride residue, a boronic acid residue, a maleimide residue or an epoxy group
- the block copolymer is water in a form in which the cyclic nitroxide radical compound is covalently bonded. It can form polymer micelles in a solvent, the above method.
- a polymerized ditroxide radical compound obtainable by such a stabilization method.
- a poly (ethylene glycol) chain segment having ethylene glycol repeating units of 15 to 10 000 and a poly having 3 to 3,000 repeating units of styrene
- Contact Keru styrene repeat units preferably from 300/0, more preferably 5 0 ⁇ 1 ⁇ 2, even more preferably Is 80%, particularly preferably 100% is 1 CH 2 NH—, _C H 2 NHCH 2 —, 1 CH 2 0—, 1 CH 2 OCH 2 —, 1 CH at the 4-position of the phenyl group.
- the residue of the cyclic ditoxoxide radical compound is covalently bonded through a linking group selected from the group consisting of 2 OCO— and 1 CH 2 O CO 2 CH 2 —.
- the remainder of the position is a halogen atom, a hydrogen atom or a hydroxyl group
- the residue of the cyclic nitroxide radical compound is 2, 2, 6, 6-tetramethylpiperidine mono 1-oxyl 4-yl, 2, 2, 5,5-tetramethylpyrrolidine 1-oxyl 3-yl, 2, 2, 5, 5-tetramethylpyrroline 1-oxyl 3-yl and 2,4,4-trimethyl-1,3-oxazolidine 1 From 3-oxyl 2-yl, 2, 4, 4-trimethyl 1, 3, 3-thiazolidine 3-oxyl 1-2, and 2, 4, 4-trimethyl imidazolin 3-3-oxyl 2-
- the above polymerized ditroxide radical selected from the group consisting of Compounds.
- A represents unsubstituted or substituted C, a C 1 2 alkoxy group, and when substituted, the substituent represents a formyl group or a group of the formula R 1 R 2 CH—, where R 1 and R 2 are independently 1 C 4 alkoxy or R 1 and R 2 together are 1 OCH 2 CH 2 0—, 1 O (CH 2 ) 3 0— or 1 O (CH 2 ) 4 Represents 0—
- L represents a linking group selected from the group consisting of an atomized bond, one (CH 2 ) C S— and one CO (CH 2 ) C S—, where c is an integer of 1 to 5,
- X represents a chlorine, bromine or iodine atom
- n an integer from 20 to 5,000
- n an integer of 3 to 1,000
- R 1 R 2 CH— wherein A represents unsubstituted or substituted 1 C 1 2 alkoxy, and when substituted, the substituent represents a formyl group or a group of the formula R 1 R 2 CH—, where R 1 And R 2 are independently C ⁇ —CA alkoxy or R 1 and R 2 together are one OCH 2 CH 2 0—, one O (CH 2 ) 3 0— or one O (CH 2 ) 4 0 Represents —
- L 2 represents a linking group selected from the group consisting of methylimino, methyliminomethyl, methyloxy, methyloxymethyl, methyl ester and methyl ester methyl,
- R is at least 50% of the total number n of R 2, 2, 6, 6-tetramethylpiperidine 1 1 xylu 4 1, 2, 2, 5, 5-teramethylpyrrolidine 1 1 1-oxyl 3-yl, 2, 2, 5, 5-tetramethylpyrroline 1-oxyl 3-yl and 2, 4, 4-trimethyl 1, 3-oxazolidin 3-oxyl 2-yl, 2, 4 , 4 1-trimethyl-1,3-thiazolidine 1-oxyl 2-yl and 2,4,4-trimethylimidazoline 1 3-oxyl 2-yl Represents a residue of a xoxide radical compound, and when present, the remaining R is a hydrogen atom, a halogen atom or a hydroxy group,
- n an integer from 20 to 5,000
- n an integer of 3 to 1,000
- a reagent for detecting the presence of active oxygen or free radicals (or hydroxy radicals) in a living body comprising a compound represented by the above general formula (I I) and a pharmaceutically acceptable carrier.
- Active oxygen or free radical comprising
- the polymerized nitroxide radical compound as described above is not limited by theory, but by self-organizing in an aqueous medium, the nitroxide radical moiety is supported in the core region, and the sil region is Form polymer micelles with dozens of nanoparticle diameters that can be regarded as having poly (ethylene glycol) chains (see the structure under high pH in Figure 20 for a conceptual diagram of polymer micelles).
- a polymeric micelle encapsulating a cyclic nitroxide radical is stably maintained for a long time even in the presence of a reducing species such as glutathione or ascorbic acid as described above.
- the high molecular weight ditroxide radical compound of the present invention effectively eliminates active oxygen and reactive radical species at the disease site, so anti-inflammatory agents, antihypertensive agents, high-fat plasma therapeutic agents, weight loss agents It is a new material that can be used as a completely new drug, such as suppressing necrosis to normal cells in radiotherapy.
- the present invention provides a new type contrast agent and Not only medical oxidants that can control redox reactions, such as cerebral infarction, myocardial infarction, cerebral edema, denervation symptoms, inflammation, hypertension, hyperlipidemia, obesity, cerebrovascular injury and nerve cells It provides compounds that are expected to serve as therapeutic agents for damage, as well as antihypertensive agents, anti-inflammatory agents, and antioxidants and supplements for foods.
- FIG. 1 is a graph (a) and 1 H NMR spectrum showing the results of size exclusion chromatography of the product acetal-PEG-wa-PCMS obtained in Production Example 1.
- Figure 2 is the 1 HN MR spectrum of the product acetal PEG— —PCMS— ⁇ —TEM PO obtained in Production Example 2.
- FIG. 3 is a graphical representation showing the behavior of removal of unreacted low molecular weight TEMPO by purification of the reaction product of Production Example 2 followed by ESR signal measurement.
- Figure 4 shows the results of dynamic light scattering (DLS) measurement of nanoparticles ( ⁇ —T EM PO—RNP) by an acetal loop PEG—6—P CMS—V—T EM PO obtained in Production Example 3. In the figure shown.
- DLS dynamic light scattering
- Figure 5 shows the ESR spectrum (a) of nanoparticles by ⁇ —T EM PO—RNP obtained in Production Example 3 and the ESR spectrum (b) in a dilute solution of low molecular weight T EM PO.
- Figure 6 shows the fluctuation of the ES R spectrum with the change in pH of the micelle aqueous solution of N—T EM P O—R N P and O—T EM P O—R N P.
- FIG. 7 is a graphical representation showing the results of a reduction resistance test using TEM POL of ⁇ —TEMPO—RNP and glutathione of low molecular weight TEMPO.
- FIG. 8 is a graphical representation showing the results of a reduction resistance test of ⁇ —T EM P O—R NP T EM P O L and low molecular weight T EM P O L with ascorbic acid.
- FIG. 9 is a graph showing the change in blood concentration showing the results of the pharmacokinetics of / V—TEM P O—RN P TEM P O L and low molecular TEM P O.
- Fig. 10 is a graph showing changes in blood concentration showing the results of pharmacokinetics of O-TEMPO-RNP.
- Figure 11 is a TTC-stained photograph of a cerebral section in test 5.
- the upper row is the non-administered control group
- the middle row is the Tempo I administration group
- the lower row is the ⁇ -TEMPO-RNP mice.
- the left-hand photo in the middle and rear stages is the intravenous administration group
- the right-hand photo is the arterial administration group.
- FIG. 12 is a graphical representation of the results of quantifying the infarct area (inf r a c t vo l um e) in the results of TTC staining in test 5.
- T empomicell ⁇ (0 i ⁇ and ia are groups in which nanoparticles solution was administered intravenously and intraarterially, respectively.
- Tempoiv and ia are groups and examples in which solution of Tempo I was administered intravenously, respectively. .
- Fig. 13 is a graph showing the symptom of cerebral infarction in Trial 5 ( ⁇ ⁇ ⁇ ro I o g I c a ys y m t p t o m s c o r e).
- FIG. 14 is a graphical representation of the results of fluctuations in mean blood pressure during administration of physiological saline (S aline), Blank—NP, and ⁇ / — ⁇ EMPO—RNP in Test 5 (2).
- Fig. 15 is a display of the results of quantifying the infarct area (in f ra c t vo I u me) in the results of TTC staining in Test 5 (2).
- Fig. 16 shows the symptom of cerebral infarction in Study 5 (2).
- the neurosymptom score ( ⁇ ⁇ u r o l o g i c a l s y m p t o m s c o r e) is omitted from the Kufno table.
- Figure 17 shows the ESR spectrum of / V—TEMPO—RNP and hydrazine-reduced RNP ( ⁇ / - ⁇ EMPO—RNP—H).
- Figure 18 shows a graphical representation of the time course of ESR signal intensity observed in the oxidizing environment of pH 5.6 and pH 7.4 of hydrazine reduced RNP (A-T EM P O- RN PH). It is.
- FIG. 19 is a schematic diagram illustrating the pH responsiveness of nanoparticles (V—TEM P O—RNP) by acetal I P E G—one P CMS— ⁇ / —T EMP O of the present invention.
- the cyclic nitroxide radical compound that can be covalently bonded to the hydrophobic segment of the block copolymer is advantageous in the spin labeling method, for example.
- a wide range of compounds can be stabilized without being limited to the so-called stable nitroxide radical compounds used in the present invention.
- the block copolymer that can be used in such a stabilization method is, as defined above, a poly (ethylene glycol) chain segment (A) and a hydrophobic chain carrying a reactive group. It comprises a segment (B) and is preferably an AB type diblock copolymer, but may be an ABA type triblock copolymer or an AB BA type tetrablock copolymer. However, among such copolymers, preferred are those represented by the general formula (I)
- A represents unsubstituted or substituted C 1 2 alkoxy, and when substituted, the substituent is a formyl group R 1 R 2 CH— (wherein R 1 and R 2 are independently C, one C 4 alkoxy or R 1 and R 2 together are one OCH 2 CH 2 0—, ⁇ 0 ( CH 2 ) 3 0— or 1 O (CH 2 ) 4 0—.
- n represents 1 or 2, and may be substituted with one phenyl group or a benzhydryl group at the non-bonding terminal — a C, 2 alkyl group, and n is 3 to 1 , 000, preferably 5-500, more preferably 10-300, representing a whole number of polyamino acid ester chain segments;
- R 2 represents a hydrogen atom or a C 1 15 alkyl group, preferably Represents a methyl group
- n represents an integer of 3 to 1,000, preferably 5 to 500, more preferably 10 to 300,
- n represents an integer of 3 to 1,000, preferably 5 to 500, more preferably 10 to 300,
- n represents a C 12 alkyl group which may be substituted with one phenyl group or benzhydryl group at the non-bonding end
- n is 3 to 1,000, preferably 5 to 500, more preferably 1 represents an integer from 0 to 300
- n represents an integer of 3 to 1,000, preferably 5 to 500, more preferably 10 to 300,
- n represents a C 12 alkyl group which may be substituted by one phenyl group or a benzhydryl group at the non-bonding end
- n is 3 to 1,000, preferably 5 to 500, More preferably represents an integer from 10 to 300
- L represents a chlorine, bromine or iodine atom
- n 3 to
- n is 3 to 1,000, preferably 5 to 500, more preferably 10
- n represents an integer of 3 to 1,000, preferably 5 to 500, more preferably 10 to 300,
- n represents an integer of 3 to 1,000, preferably 5 to 500, more preferably 10 to 300, poly (glycidyl methacrylate) chain segment of
- n represents an integer of 3 to 1,000, preferably 5 to 500, more preferably 10 to 300,
- n represents an integer of 3 to 1, OOO, preferably 5 to 500, more preferably 10 to 300,
- n represents an integer of 3 to 1,000, preferably 5 to 500, more preferably 10 to 300,
- n represents a C 1 2 alkyl group which may be substituted by one phenyl group or benzhydryl group at the non-bonding terminal
- n is 3 to 1,000, preferably 5 to 500, more preferably Represents an integer from 1 to 300
- a and b independently represent an integer of 3 to 500.
- n represents an integer of 3 to 1,000, preferably 5 to 500, more preferably 10 to 300,
- n represents an integer of 3 to 1, 0 00, preferably 5 to 5 0 0, more preferably 1 0 to 3 0 0,
- Z is a hydrogen atom, hydroxy, C, mono-C 2 alkyloxy which may be substituted by one phenyl group or benzhydryl group at the non-bonding end, or one phenyl group at the non-bonding end or C 1 C optionally substituted by a benzhydryl group
- Dialkyl copolymers representing alkylcarbonyl can be enumerated.
- hydrophobic chain segment carrying the reactive group of the block copolymer has the formula
- n represents a poly (halomethylstyrene) chain segment represented by an integer of 3 to 1,000, and a block copolymer can be preferably used.
- block copolymers are known, for example, those in which the hydrophobic segment represents a polyamino acid ester chain segment are disclosed in Japanese Patent No. 2 6 90 2 76 (or US Pat. No. 5, 4 4 4). 9, 5 1 3) and the like, and those representing poly ((meth) acrylic acid ester chain segments are known from Patent Document 3.
- Other block copolymers are those of the above block copolymers. Refer to the manufacturing method or manufacturing example 1 described later in this specification. It can be easily obtained by those skilled in the art.
- a linking group or a repeating unit in the general formula that defines the block copolymer used in the present invention is represented by a formula, it is intended to be incorporated in the general formula in the described direction. ing.
- the cyclic nitroxide radical can be used without limitation as long as it can be stabilized by the method of the present invention.
- the cyclic nitroxide radical compound strongly intended to be stabilized in the present invention is 4 Mono-substituted 2, 2, 6, 6-tetramethylpiperidine 1-oxyl, 3-substituted 2, 2, 5, 5— ⁇ tramethylpyrrolidine 1-oxyl, 3-substituted 2, 2, 5, 5— ⁇ tra Methylpyrroline 1-oxyl, 2-substituted 2, 4, 4 -trimethyl-1,3-oxazolidin-3-oxyl, 2-substituted 2,4,4-trimethyl-1,1,3-thiazolidine 3-oxyl and 2 —Substituted 1, 2, 4, 4-trimethyl-imidazoline 1-oxyl selected from the group consisting of 4 mono-substituted, 3_-substituted or 2 mono-substituted substituents, amino group, aminomethyl group and hydroxyl group, hydroxy It is selected from
- Functional groups other than radicals of the cyclic nitroxide radical compound for example, amino group, aminomethyl group, hydroxyl group, hydroxymethyl group, carboxyl group or carbomethyl group
- reactive groups of the block copolymer halogen atom, particularly , Chlorine, bromine or iodine atom, carboxyl group, isocyanato residue, isothiocyanate residue, ester residue, acid anhydride residue, boronic acid residue, maleimide residue or epoxy group
- the method for forming a bond can be carried out by a known condensation reaction, addition reaction, or aminolysis via a functional group (amino group) of a cyclic nitroxide radical compound in the case of an ester residue.
- Such a reaction is carried out in an aqueous solvent (which may contain water and an organic solvent miscible with water, for example, lower alcohol, dioxane, dimethylformamide, methyl sulfoxide, etc.) Trimethylamine, triethanolamine, etc.) or inorganic bases (potassium carbonate, sodium carbonate, sodium hydroxide, etc.) and other condensing agents known in the art may be used.
- an aqueous solvent which may contain water and an organic solvent miscible with water, for example, lower alcohol, dioxane, dimethylformamide, methyl sulfoxide, etc.
- Trimethylamine, triethanolamine, etc. Trimethylamine, triethanolamine, etc.
- inorganic bases potassium carbonate, sodium carbonate, sodium hydroxide, etc.
- any polymer that can form polymer micelles in an aqueous solvent can be used in the present invention.
- a high molecular weight compound of a cyclic ditroxide radical compound produced by a method for stabilizing a cyclic ditroxide radical compound using the block copolymer as described above is provided.
- a preferred embodiment is a poly (ethylene glycol) chain segment having ethylene glycol repeating units of 15 to 10,000, and a poly (styrene) having 3 to 3,000 repeating units of styrene.
- A represents unsubstituted or substituted C 1 2 alkoxy, and when substituted, the substituent is a formyl group
- a formula R, R 2 CH— (wherein R 1 and R 2 are independently C 4 alkoxy or R 1 and R 2 together represent one OCH 2 CH 2 0—, —0 (CH 2 ) 3 0— or one O (CH 2 ) 4 0—.
- R 1 and R 2 are independently C 4 alkoxy or R 1 and R 2 together represent one OCH 2 CH 2 0—, —0 (CH 2 ) 3 0— or one O (CH 2 ) 4 0—.
- L 2 is methylimino (one CH 2 NH—), methyliminomethyl (one CH 2 NH CH 2 one), methyloxy (one CH 2 0—), methyloxymethyl (one CH 2 OCH 2 —), methyl ester (One CH 2 OCO—) and methyl ester methyl (one CH 2 OCOCH 2 —) represent a linking group selected from the group consisting of:
- R is the total number of R at least 5 ⁇ / ⁇ is 1, 2, 6, 6-tetramethylpiperidine 1 —oxyl 4-yl, 2, 2, 5, 5— ⁇ tramethylpyrrolidine 1 1-oxyl 3-yl, 2, 2, 5, 5-tetramethylpyrroline 1-oxino! ⁇ 1 3-yl and 2, 4, 4 trimethyl-1,3-oxazolidine 3-oxyl 2-yl, 2 , 4, 4 1-trimethyl-1,3-thiazolidine 1-oxyl-2-yl and 2,4,4-trimethyl-imidazoline 1-oxyl 2-yl Represents the residue of a radical compound, and when present, the remaining R is a hydrogen atom, a halogen atom or a hydroxyl group,
- n represents an integer of 20 to 5,000, preferably 30 to 3,000, more preferably 40 to 1,000, and
- n an integer of 3 to 1,000, preferably 5 to 500, more preferably 10 to 500,
- the polymerized nitroxide radical compound is provided. Further, in the general formula (II), 1 is an atomized bond or 101 "1 2 01 to 1 2 5—and L 2 is methylimino or methyliminomethyl; and
- a polymerized dinitroxide radical compound which is a residue of a cyclic nitroxide radical compound represented by any of the above, is also particularly preferred in that it provides PH responsiveness to the stabilization of polymer micelles that can be formed from these compounds. Offered as a thing.
- alkyl portion of C, 1 C, 2 alkoxy can be straight chain or branched alkyl, eg, methyl, ethyl, propyl, is
- Examples include O-propyl, butyl, ⁇ SO-butyl, S-butyl, tert-butyl, pentyl, hexyl, heptyl, and dodecanyl.
- A represents an alkoxy group substituted by the formula R 1 R 2 CH—, and R 1 and R 2 are independently C, —C 4 alkoxy or R 1 and R 2 are combined together.
- the linking group in the block copolymer is not limited because it can be replaced by how the poly (ethylene glycol) chain segment and poly (styrene) are bonded.
- a poly (ethylene glycol) chain segment is produced by anion-living polymerization and then living polymerization of halomethylstyrene is continued, then, becomes a valence bond.
- the linking group is obtained by radical polymerization of halomethylstyrene in the presence of the derivative. 2 CH 2 S— or 1 COCH 2 CH 2 S—.
- 2 can include a linking group selected from the group consisting of methylimino, methyliminomethyl, methyloxy, methyloxymethyl, and the like.
- a linking group is conveniently a block copolymer, for example of the general formula (III) A- (CH 2 CH 2 O) m -L ⁇ (CH 2 CH) n -H
- A represents unsubstituted or substituted C 1 2 alkoxy, and when substituted, the substituent is a formyl group
- R 1 R 2 CH— (wherein R 1 and R 2 are independently 1 C 4 alkoxy or R 1 and R 2 together represent 1 OCH 2 CH 2 0—, 1 O (CH 2 ) 3 O— or 1 O (CH 2 ) 4 0—.
- X represents a chlorine, bromine or iodine atom
- n an integer from 20 to 5,000
- n an integer of 3 to 1,000
- copolymer represented by the general formula (I I I) is not described in the literature as far as the present inventors know, and is provided as another embodiment of the present invention.
- R is at least 50% of the total number n of R, preferably at least 75%, more preferably at least 90%, particularly preferably 100% is 2, 2, 6, 6-tetramethylpiperidine 1-oxyl 4-yl, 2, 2,4,4-tetramethylpyrrolidine 1-oxyl 3-yl, 2, 2, 4, 4-tetramethylpyrroline 1-oxyl 3- 2,4,4-Trimethyl-1,3, Oxazolidine-1,3-Oxylu-2-yl, 2,4,4-Trimethyl-1,3-Thiazolidine 3-Oxylu-2-yl and 2, Represents a residue of a cyclic ditroxide radical compound selected from the group consisting of 4, 4-trimethyl-imidazoline 1-oxyl 2-yl, and when present, the remaining R is a hydrogen atom, halogen Represents an atom or a hydroxyl group.
- the proportion of residues of the cyclic nitroxide radical compound in the total number n of R is, for example, the above general formula
- the reaction of the copolymer of (III) and the cyclic nitroxide radical compound can be controlled, for example, by controlling the reaction time.
- n can be an integer from 20 to 5,000, preferably 35 to 3,000, more preferably 60 to 500, and n is 3 to 5 000, preferably It can also be an integer from 10 to 300, more preferably from 15 to 100.
- the polymerized nitroxide radical compound of the present invention is the original action of the cyclic nitroxide radical compound even under reducing conditions (for example, see also Non-Patent Document 1). It can be used as an antioxidant inside and outside the living body.
- active oxygen or free radical (if in vivo) is used as a further specific use example of the compound stabilized by the above-described method and the more specifically described compound.
- ⁇ Hydroxy radicals can be used for the prevention or treatment of diseases or symptoms.
- in vivo means in vivo animals such as humans, mammals, fish and the like, and examples thereof include organs, organs and body fluids.
- Diseases or symptoms involving active oxygen or hydroxy radicals include, but are not limited to, cerebral infarction, myocardial infarction, cerebral edema, denervation symptoms, inflammation, hypertension, hyperlipidemia, obesity, cerebrovascular injury and nerves Cell damage, more specifically cerebral infarction, cerebral edema, and neurological deficits, cerebral infarction (especially arromthrombotic cerebral infarction, lacunar infarction, cerebral embolism), cerebral vasospasm (especially after subarachnoid hemorrhage) Tempered cerebral artery stenosis), moyamoya disease (especially viral ring artery occlusion), cerebral main artery occlusion ⁇ stenosis, mesenteric vascular occlusion.
- any of the above compounds can be used as an active ingredient as long as it is effective for such diseases or symptoms.
- Preferred compounds include those represented by the above general formula (II), and More preferred is a compound represented by the general formula (II), wherein is an atomized bond or one CH 2 CH 2 S—, L 2 is methylimino or methyliminomethyl, and
- a polymerized ditroxide radical compound which is a residue of a cyclic nitroxide radical compound represented by any of the above.
- L 2 is methylimino or methyliminomethyl
- the decay of polymer micelles containing cyclic nitroxide radicals under acidic pH conditions is promoted, and the radicals are released into the surrounding environment, so that (See Non-Patent Document 1 above). Therefore, it can be expected that the action of the cyclic ditroxide radical can be selectively exerted at an inflammatory site or the like that is usually known to be in an acidic state.
- diluents typically include pure water, deionized water, or physiological saline, and these solutions may contain a buffer. it can. These liquids may contain water-miscible organic solvents such as ethanol and dimethyl sulfoxide as long as they do not adversely affect the stability of the polymeric micelle formed by the compound represented by formula (I). Good.
- excipient examples include sugars or sugar alcohols such as polyethylene glycol (macrogol), glucose, lactose, mannitol, etc. of various molecular weights that can be used in pharmaceutical preparations.
- sugars or sugar alcohols such as polyethylene glycol (macrogol), glucose, lactose, mannitol, etc. of various molecular weights that can be used in pharmaceutical preparations.
- the brain embedding agent include a form in which the compound is contained in a coated matrix layer of a sunflower placed in the brain.
- the food-acceptable diluent or excipient (or carrier) can be based on the above-mentioned pharmaceutically acceptable one.
- the optimal dose varies depending on the patient's age, symptoms, age, gender, etc., but is not limited, but the dose of the composition according to the present invention is cyclic nitroxydrazica
- the standard is 0.1 to 90 Omg / kg, preferably 1 to 25 OmgZ kg per day for adults, and can be administered once or in three divided doses.
- Acetal 1 PEG—Wai PCMS was synthesized according to the following synthesis scheme 1:
- Heterobifunctional polyethylene glycol having an acetal group at one end and a thiol group at the ⁇ -terminus (acetal-PEG-S ⁇ ) ( ⁇ ⁇ : 4, 600; 0.02 mm o I, 9 2 mg) was added to the reaction vessel.
- acetal-PEG-S ⁇ ⁇ ⁇ : 4, 600; 0.02 mm o I, 9 2 mg
- the operation of blowing nitrogen gas was repeated 3 times to make the inside of the reaction vessel a nitrogen atmosphere.
- Add 1 mL of azobisisobutyronitrile benzene (0.0 1 mm o IL) solution and chloromethylstyrene (1 mm o I, 0.13 8 mL) to the reaction vessel, and heat to 60 ° C. And stirred for 24 hours.
- T EM PO low molecular weight
- ⁇ -T EM P O-RNP was prepared using PEG-6-P CMS- ⁇ -T EM PO.
- Fig. 5a This is because the hydrophobicity of TEM PO decreases due to the formation of a solid phase in which the hydrophobic C CMS—T EM PO segment ⁇ is agglomerated as a particle core.
- the spectrum is considered to have changed from three lines to one line.
- the O-T EM PO-RNP is shown in Fig. 5a. It was confirmed that it shows a broad single-line spectrum in the same way as the ⁇ —T EM PO—RNP shown in Fig. It is thought to be similar to that described for ⁇ EM P O- R N P.
- Test 1 pH response of ⁇ —TEMPO—RNP and 0—TEMPO—RNP
- the average particle size and ESR spectrum of the ⁇ - ⁇ EM PO- RNP obtained in Production Example 4 with respect to ⁇ H change were measured by dynamic light scattering (DLS) and ESR.
- DLS dynamic light scattering
- the unimodal particles with an average particle size of 40 nm did not change the scattering intensity, but in the acidic range, the scattering intensity decreased and the particle size decreased. Increased.
- the ESR measurement showed that the ESR spectrum of RNP at neutral pH and basic pH was a single broad line, but under acidic conditions, the spectrum shape changed from a single line to a triple line. It became clear that it changed (the upper part of Fig. 6).
- O-TEMPO-RNP shows the same ESR signal in any pH region (lower part of Fig. 6).
- Test 2 Reduction tolerance of ⁇ / —T EM PO—RNP radicals to glutathione Normally, the cells are in a reducing environment and high concentrations (0.5 mM to 1 OmM) of glutathione are present, but in blood It is known that it exists only about 1/100 to 1 / 1,000 in cells. Therefore, small molecule TEMPO with a stable radical is easily reduced when it enters the cell, and rapidly loses the ESR signal intensity.
- Test 3 Reduction resistance of / V—TEM P O—R N P radical to ascorbic acid (A s A)
- Test 5 Treatment of cerebral ischemia model rat
- mice (3 weeks old) were acclimated for 1 week and then inhaled by anesthesia with isoflurane.
- the common carotid artery was occluded with an embolic thread and reperfused 2 hours later.
- / V—TEM PO—RNP (2 O mg / mL) was injected at a concentration of 120 mg / mL from the femoral vein (or common carotid artery) at a rate of 1 mL. After 24 hours, the mice were sacrificed by Nembutal injection anesthesia.
- TTC 2, 3, 5-triphenyltetrazol chloride
- FIG 11 shows an example of a TTC stained brain photograph.
- the red stained area (shown as black shading in the figure) is the live cell, and the white area is the dead cell.
- the N-T EM PO-RNP intravenously administered group has clearly increased red areas and significantly prevented cell death, especially in the penumbra, which is said to be a pharmacological treatment area during cerebral ischemia. It was found that the tendency was remarkable in the area.
- T m p o I was less effective than N—TEM P O—R N P in the intravenous administration group. This is thought to be because Te m p o I was reduced by reducing components in the blood after intravenous administration. It is speculated that T EM P O has been polymerized and allowed to form micelles, thus providing a certain level of protection from the external environment of the living body.
- the drugs or controls tested are as follows: ⁇ — ⁇ EM PO— RNP, group not administered after reperfusion as control, ⁇ — T EM PO— group administered ⁇ ⁇ ⁇ mpo I at the same molar concentration as T EM PO in RN, 100% physiological Saline-administered group, methoxy PEG--PCMS micelles without TEM PO Also called BI ank -NP.
- nitroxide radicals in Tempo I act on vasodilation at the time of administration, and thus blood pressure falls, but it is thought that nitroxide radicals are protected at the time of administration by polymerizing micelles. Therefore, it is considered that nitroxydradical can be effectively used for scavenging free radicals in the brain.
- ⁇ —TEP OR NP significantly reduced cerebral infarct area compared to saline, Blank NP, and T em pol (Fig. 15, respectively, p ⁇ 0. 0 1, 0. 0 5, 0 ⁇ 05).
- the higher brain protective effect of / V—TEM P O—R N P compared to T e m p o l is considered to be due to the retention and transfer of lysable radicals to the affected area due to polymer micelles.
- Neurological symptom score (0: Hold the tail and lift both forelimbs when lifted. No defects.
- Oxidative stress induced by reactive oxygen (ROS) has been shown to be involved in the pathogenesis of various disorders and diseases.
- ROS reactive oxygen
- Oxidative stress induced by reactive oxygen (ROS) has been shown to be involved in the pathogenesis of various disorders and diseases.
- ROS reactive oxygen
- ESR imaging has recently attracted attention as a tool for visualizing redox reactions in the body.
- Various ESR imaging probes have been developed so far, but low-molecular ESR probes have a short half-life in blood and do not have the ability to specifically accumulate at a target site. Observation with is difficult.
- pH is decreased in inflammatory sites and cancer tissues that are thought to be involved in oxidative stress. Therefore, we investigated the possibility of developing a new ESR probe that can visualize ROS by utilizing the decay of ⁇ EM PO- RNP under acidic conditions.
- ESR probe (/ —TEMPO—RNP—H) capable of visualizing ROS 5 mg Zm L meth- oxime P E G—Wai P C M S— ⁇ —T E M P O in DMF solution 1
- N-T EM P O- RNP-H (4 6 m, 60 0 L), H 2 0 2 aqueous solution (500 mM, 60 ⁇ L) and horseradish peroxidase (HRP) / l
- HRP horseradish peroxidase
- HRP horseradish peroxidase
- the method for stabilizing a cyclic nitroxide radical provided by the present invention and the polymerized compound provided by the method particularly achieve stabilization of a stable radical in vivo. It can be used in the medical and diagnostic fields.
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JP2011078706A (ja) * | 2009-10-09 | 2011-04-21 | Univ Of Tsukuba | 表面の生体適合性の改質方法 |
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US8980241B2 (en) | 2015-03-17 |
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US20110142787A1 (en) | 2011-06-16 |
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