WO2005092320A1 - 細胞を保護するための組成物 - Google Patents
細胞を保護するための組成物 Download PDFInfo
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- WO2005092320A1 WO2005092320A1 PCT/JP2005/005436 JP2005005436W WO2005092320A1 WO 2005092320 A1 WO2005092320 A1 WO 2005092320A1 JP 2005005436 W JP2005005436 W JP 2005005436W WO 2005092320 A1 WO2005092320 A1 WO 2005092320A1
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Classifications
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- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/32—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Definitions
- the present invention relates generally to the fields of food and medicine. More specifically, the present invention relates to compositions for protecting cells, which typically activate compounds having a formyl phenol-type structure, as well as compounds having a formyl bilol-type structure. And protects the cells by promoting their proliferation and suppressing their apoptosis.
- K252a a proteinase inhibitor
- K252a has a neuroprotective effect
- catechin, epicatechin , Epicatechin gallate, epigallocatechin gallate, and epigallocatechin gallate have a cell growth promoting action (myeloproliferative activity)
- Planta medica Vol. 69, pp. 321-326, 2003
- Promotes proliferation of hair follicle epithelial cells and skin keratinocytes Journal of Investigative Dermatology, Vol. 112, No. 51, pp.
- phosphatidic acid suppresses apoptosis of hair follicle cells (Journal of Investigative Dermatology, Vol. 121, pp. 448-456, 2003); docosahexaenoic acid is an apoptosis of retinal photoreceptors (Investigative Ophth almology & Visual Science, Vol. 44, No. 5, pp. 2252-2259, 2003) and apoptosis of neurons (Lipids, Vol. 38, No. 4, 453-457, 2003). Suppress each; and so on.
- An object of the present invention is to provide easily a compound having an action of protecting cells and a composition containing the compound as an active ingredient, which can be applied to uses such as foods and pharmaceuticals.
- the present inventors have conducted intensive studies on substances having an action of promoting cell proliferation, an action of suppressing apoptosis, and an action of protecting cells. As a result, compounds having a formylphenyl-type structure, A compound having a rubilol structure has been found to have these effects, and the present invention has been completed.
- the present invention relates to the following (1)-(11).
- composition for protecting cells which is represented by any one of the following formulas I-IV:
- R 1 is H, OR 3 , OR 4 , NHR 3 , NHR 4 , SR 3 , SR 4 , SO R 3
- R 3 is a substituted or unsubstituted straight-chain C 1 -C alkyl, and R 4 is a carboxyl group having the same meaning as the group defined and the group C (NHR 3 ) R 3 is also selected. Substitute with group
- n is an integer from 0-6;
- composition (2) The composition according to claim (1), 4 represented by Formula II Fuorumirufue - a compound having the Le-type structure, straight to the R 1 is substituted with terminal carboxyl groups Chain C-C alkyl, or amino acid substituted with terminal hydrazino or terminal amino group
- a composition comprising a compound.
- composition comprising a compound that is a—, ⁇ or ⁇ -daltamyl.
- a composition comprising:
- R 1 and R 2 are independently OR 4 , NHR 4 , SR 4 , SO 4
- R 3 is a substituted or unsubstituted linear C
- R 4 is linear C alkyl substituted with a carboxyl group
- n is an integer from 0-6; and a composition comprising a carrier.
- composition according to (6) comprising a compound of formula VI: [0010] [Formula 6]
- composition according to (1) wherein the cell is protected by suppressing its apoptosis.
- a composition for protecting cells is provided. This composition protects cells by promoting cell proliferation, suppressing apoptosis, etc., and helps to prevent AIDS, influenza, fulminant hepatitis, ulcerative colitis, pulmonary fibrosis, heart failure, autoimmune disease, rheumatoid arthritis, and brain ischemia. Foods or medicines for the prevention or treatment of various diseases such as blood, dementia, Parkinson's disease, periodontal disease, alopecia, cutaneous keratosis, etc., and reduction of rejection reactions associated with organ transplantation. Can be used as a drug for the purpose of avoidance.
- Alkyl refers to the ability of an aliphatic hydrocarbon such as methane, ethane,
- Alkyl can be straight or branched.
- Substituted alkyl refers to an alkyl substituted with one or more hydrogen atoms of alkyl, a group consisting of carboxyl amine, hydroxyl, formyl, and hydrazino selected from the group consisting of hydrogen, hydrogen, formyl, and hydrazino.
- Unsubstituted alkyl means an alkyl in which any hydrogen atom is replaced by another group.
- Forml refers to a group represented by CHO!
- Carboxyl refers to a group represented by COOH.
- Haldrazino refers to a group represented by HN—NH.
- Amino refers to a group represented by -NH!
- Forml-substituted phenol refers to phenylene in which a hydrogen atom of phenol is substituted by a CHO group.
- Forml-substituted pyrrole refers to pyrrole in which a hydrogen atom of pyrrole is substituted by a CHO group.
- the "4-formyl-foil type structure” refers to a structure in which one hydrogen atom of a phenol is substituted with a CHO group, and the CHO group has another substituent at the p-position. Refers to the structure.
- the "2-formylvirol-type structure" means that one hydrogen atom located at the 2-position of pyrrole is
- terminal carboxyl group means a carboxyl group for substituting a hydrogen atom in a terminal (or head) functional group of a molecule.
- Terminal hydrazino group means a hydrazino group for replacing a hydrogen atom in a terminal (or head) functional group of a molecule.
- Terminal amino group means an amino group for substituting a hydrogen atom in a terminal (or head) functional group of a molecule.
- Amino acid means a compound having a carboxyl group and an amino group in a molecule, and a compound in which an amino group and a carboxyl group are bonded to the same carbon atom is referred to as an ⁇ -amino acid, and the relative distance increases. Therefore, they are referred to as ⁇ -, ⁇ - , ⁇ -, ⁇ amino acids in that order.
- “Aspartyl” means a group formed by removing one of the two carboxyl groups of aspartic acid, which is a monoaminodicarboxylic acid, from the hydroxyl group.
- “Glutamyl” means a group formed by removing a hydroxyl group from one of two carboxyl groups of glutamic acid, which is a monoaminodicarboxylic acid.
- the present invention provides a composition for protecting cells, comprising a compound represented by the general formula (I)-(VI).
- a composition for protecting cells comprising a compound represented by the general formula (I)-(VI).
- the compound represented by the above formula (I)-(VI) can protect cells by the combination of the formyl group and the R 1 group and the distance between them. It is thought to be related to activity.
- the compound represented by the above formula (I)-(VI) contained in the composition of the present invention may be a synthetic method, an enzymatic method, a production method using a microorganism, an extraction method from a natural product, or It can be produced using any method, such as a combination thereof.
- the compound represented by the above formula (I)-(III) or (V) can be typically synthesized using, for example, phenylhydrazine or argin as a starting material.
- Phenylhydrazine is a monoclinic crystal or a faint yellow transparent liquid obtained by diazolidizing a-line with sodium nitrite and hydrochloric acid and then reacting it with sodium sulfite.
- the compounds used in the present invention can be prepared starting from phenol hydrazine or phenyl. Phenylhydrazine or furin produces various derivatives by condensation reactions known to those skilled in the art.
- the compound used in the present invention can be synthesized utilizing such a condensation reaction.
- the compound having a formylphenol-type chemical structure is obtained by condensing phenol hydrazine and monoaminodicarboxylic acid (eg, glutamic acid) using a known method, and then presenting HC1ZA1C1 under the pressurized CO. It can be obtained by performing formylation below.
- monoaminodicarboxylic acid eg, glutamic acid
- the compound having a 2-formylvirol-type chemical structure represented by the above formula (IV) or (VI) is typically a commercially available pyrrole or a pyrrole-type compound, which is usually subjected to a chemical reaction.
- a chemical reaction By carrying out the alkylation reaction, arylation reaction and acylation reaction used in the above.
- substituent represented by R 2 may be alkyl of various or having a substituent, or have such have saturated or unsaturated. These compounds are prepared by starting from a pyrrole-type compound and adding thereto an alkylating agent usually used in a chemical reaction, such as the corresponding compound. An alkyl-containing halogenated alkyl or the like is added, and a suitable alkali, for example, a hexane solution of potassium carbonate or n-butyllithium is added. If necessary, an absorbent for the acid generated during the reaction ( For example, it can be obtained by stirring under a predetermined temperature condition in the presence of dimethylformamide).
- the formula of Formula (IV), substituent represented by R 2 can be a variety of substituted or without aliphatic or aromatic Ashiru of. These compounds are obtained by dissolving a pyrrole-type compound as a starting material in a suitable solvent such as pyridine, methylene chloride, tetrahydrofuran, etc., and forming an acylating agent such as an acid chloride or an acid anhydride. It can be obtained by stirring under a predetermined temperature condition in the presence of a suitable solvent, for example, a hexane solution of pyridine, triethylamine, n-butyllithium or the like. Further, by appropriately combining the above reactions, a compound represented by the formula (IV) or (VI) can be obtained.
- a suitable solvent for example, a hexane solution of pyridine, triethylamine, n-butyllithium or the like.
- the compound represented by the above formula (IV) or (VI) may be separated and purified from the fruiting body of basidiomycete or the mycelium of the cultured mycelium, in addition to the above-mentioned organic synthesis method.
- the extract obtained by heating and extracting the fruiting body or cultured mycelium of the basidiomycete is separated and purified using a gel filtration column, a hydrophobic gel column, an ion exchange column, or the like, whereby the above formula (IV) or The compound represented by (VI) can be obtained.
- the compound represented by the above formula (I)-(VI) is contained in the composition of the present invention together with a force that can be used as an active ingredient of the composition for protecting cells as it is or an appropriate carrier. Can be done.
- the term "cell” is generally used in its ordinary sense as used in the art, and typically refers to any differentiated cell or cloned cell present in a multicellular organism. Cells in cultured culture. As used herein, the term “protecting a cell” refers to preventing the viability of the cell from decreasing when the cell is placed under conditions that survive, grow and die, increasing the rate of growth. And that the cell mortality is reduced. Typically, protection of a cell can be achieved by promoting cell growth or proliferation, suppressing cell apoptosis, and the like.
- Apoptosis is generally controlled by a gene to maintain the life of an individual. Cell death. Apoptosis is known to play an important role in cell turnover, maintenance of endocrine system homeostasis, and the establishment of the immune system in mature individuals, who are forced to establish morphogenesis and neural networks in ontogeny. It has been.
- apoptosis plays an important role not only in the fundamental part of life phenomena, but also suppresses or enhances it, thereby causing cancer, autoimmune diseases (systemic erythematosus, rheumatoid arthritis, insulin dependence It has been shown to be deeply involved in the development of many diseases, including diabetes, multiple sclerosis), AIDS, hepatitis, and degenerative diseases of the central nervous system (Alzheimer's disease, Parkinson's disease). Therefore, a composition having an effect of suppressing apoptosis can artificially control apoptosis and be a useful tool for proper treatment of apoptotic disease.
- Apoptosis is generally defined by the following morphological and biochemical changes of cells.
- the present invention provides a composition comprising the compound represented by the above formula (I)-(VI) alone or in combination with a stabilizing compound, a carrier such as a diluent, or other components or drugs. I do.
- the composition of the present invention is used in such a form that the compound represented by the above formula (I)-(VI) protects cells in a living body to which the compound is administered.
- composition of the present invention can be provided in the form of various foods and pharmaceutical preparations.
- Such foods and pharmaceutical preparations may contain the compound represented by formula (I)-(VI) alone or as a mixture with any other active ingredient as an active ingredient.
- Such foods and pharmaceutical preparations can take any dosage form known in the technical field of pharmaceuticals.
- the composition of the present invention is administered orally or parenterally.
- composition of the present invention is orally administered, without limitation, in the form of a dosage form including tablets, capsules, powders, pills, powders, fine granules, granules, syrups, and troches. Is done.
- Such a dosage form includes, as excipients, sugars such as sorbitol, ratatose, glucose, and lactose; inorganic substances such as dextrin, starch, calcium carbonate, and calcium sulfate; crystalline cellulose; distilled water; , Corn oil, olive oil, cottonseed oil, and the like, and may include any of the materials generally employed.
- sugars such as sorbitol, ratatose, glucose, and lactose
- inorganic substances such as dextrin, starch, calcium carbonate, and calcium sulfate
- crystalline cellulose distilled water
- Corn oil olive oil, cottonseed oil, and the like, and may include any of the materials generally employed.
- Such a dosage form also includes additives such as a binder, a lubricant, a dispersant, a suspending agent, an emulsifier, a diluent, a buffer, an antioxidant, and a bacteriostatic agent at the time of formulation. obtain.
- additives such as a binder, a lubricant, a dispersant, a suspending agent, an emulsifier, a diluent, a buffer, an antioxidant, and a bacteriostatic agent at the time of formulation.
- Such carotenoids are known in the art.
- composition of the present invention may contain the compound represented by the above formula (I)-(VI) in a wide range in a compounding amount depending on the intended effect.
- a food or medicament for example, in the above-mentioned use as an oral medicament, depending on the symptoms, age, etc. of the disease, the range of 0.01 to 50% by weight, preferably 0.1 to 20% by weight. It can be compounded in the range, particularly preferably in the range of 110% by weight.
- the oral dose of the compound represented by the above formula (I)-(VI) contained in the composition of the present invention is usually in the range of 10 to 100 mg, preferably 50 to 500 mg per adult. And more preferably in the range of 100-300 mg.
- composition of the present invention is administered parenterally, without limitation, in the form of an injection containing the compound represented by the above formula (I)-(VI).
- injections may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or Buffered saline.
- the compositions of the present invention are administered parenterally, without limitation, in the form of an aqueous injection suspension containing the compound of formula (I)-(VI).
- This aqueous injection suspension may contain substances that increase its concentration (e.g., carboxymethylcellulose, sorbitol, dextran), and may optionally contain fatty acids such as sesame oil, or oleic acid. It can also be prepared as an oily injection suspension which further contains a synthetic fatty acid ester such as ethyl acid and triglyceride.
- a tablet having the following composition was prepared: 4 (4 daltamyl) aminobenzaldehyde (a compound 1: obtained by synthesis as in the following reference example; the same applies hereinafter) 10.
- Tablets were prepared by homogenizing each component and tableting the mixture with a single-shot tableting machine (a compact molding machine manufactured by Kikusui Seisakusho Co., Ltd.) to obtain tablets having a diameter of 5 mm and a weight of 15 mg.
- Example 2 Production of granule 90.0 g of D-mannitol, 5.5 g of crospovidone (polyplasdone XL), 2 g of hydroxypropylcellulose, and 4 (4-glutamyl) aminobenzaldehyde (compound l) 2 g) were mixed in a mortar, and kneaded by adding 18 ml of purified water. The kneaded product was extruded and granulated by a granulator (Fuji Baudal) and dried by a dryer to obtain granules.
- a granulator Fruji Baudal
- 4— (4-Daltamyl) aminobenzaldehyde (Compound 1) 10. Add 90.Og of lactose to Og and mix evenly to contain 4 (4 Daltamyl) aminobenzaldehyde (Compound 1) A powder was obtained. Next, glycerin was swelled and dissolved by adding 30% by weight of glycerin to 100 parts by weight of gelatin to obtain a gelatin sheet. Add the powder containing 4- (4-daltamyl) aminobenzaldehyde (Compound 1) to a 250 mg (equivalent to 25 mg of 4- (4 daltamyl) aminobenzaldehyde) per capsule. Soft force capsules were manufactured by the Accoriel method, which is a type of squeezing and punching method.
- the activity of the composition of the present invention to promote cell proliferation was measured.
- the proliferation activity of the Jurkat cell was measured according to the MTT method (Cell Culture III, 4477-4482, (1984)).
- MTT Cell Culture III, 4477-4482, (1984)
- this method involves taking [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] (MTT) into cells and producing MTT formazan.
- MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide]
- Is a colorimetric assay at a wavelength of 570 nm (reference 650 nm) to measure cell proliferation activity.
- Jurkat cells are cultured in a DMEM medium (manufactured by Gibconed Earth) containing 5% fetal calf serum at 37 ° C in a 5% CO atmosphere until the early logarithmic growth phase, at which point the concentrations shown in Table 1 are obtained.
- DMEM medium manufactured by Gibconed Earth
- the Jurkat cells were cultured in DMEM medium (manufactured by Gibcone Earth) containing 5% fetal calf serum at 37 ° C and 5% CO until the early logarithmic growth phase, at which time 4 (4 daltamyl) aminobenzone
- Table 2 shows the relative value of the amount of mono-oligonucleosome in the cell.
- Example 7 Effect of reducing toxicity of cells to anticancer drug
- Jurkat cells human T-cell line
- RPMI-1640 medium manufactured by Gibco
- fetal bovine serum 37 ° C and 5% CO until the exponential growth phase.
- N-Boc-1-benzylglutamic acid (964mg9642.86mmol, 2) was dissolved in 30ml of THF and cooled to 0 ° C, and dicyclohexylcarbodiimide (DCC) (619mg, 3mmol) was caloried. The mixture was stirred at ° C for 30 minutes. Next, paraaminobenzaldehyde hydrochloride (630 mg, 4 mmol, 1), 0.4 ml of pyridine and N, N, -dimethylaminopyridine (DMAP) (349 mg, 2.86 mmol) were added to the mixture, and the water bath was added. Removed and stirred at room temperature for 1 hour.
- DCC dicyclohexylcarbodiimide
- reaction solution 0.3 ml of triethylamine was added to the reaction solution, and the mixture was further stirred for 16 hours. Then, the reaction solution was filtered under reduced pressure, washed with 1M HC1, 5% NaHCO and water, washed with 30 ml of ethyl acetate, dried, and concentrated under reduced pressure.
- the compounds represented by the above formulas (I) and (VI) having a formyl-fell type structure or a formyl virol type structure have cell growth promoting activity and apoptosis suppressing activity. It has been shown that a composition having a typical cell protecting activity and capable of providing a composition effective as a cell growth promoting agent, an apoptosis inhibitor, and a cell protecting agent can be provided.
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WO2003051382A1 (fr) * | 2001-12-14 | 2003-06-26 | Sundory Co., Ltd. | Procédé d'induction d'apoptose et compositions pour cette dernière |
JP2003238438A (ja) * | 2002-02-08 | 2003-08-27 | Kyowa Engineering Co Ltd | 外因子から生体を防御する組成物 |
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JPWO2019107310A1 (ja) * | 2017-11-29 | 2020-11-19 | マイコロジーテクノ株式会社 | ピロール系化合物 |
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