WO2004113319A1 - 新規クロメン化合物 - Google Patents
新規クロメン化合物 Download PDFInfo
- Publication number
- WO2004113319A1 WO2004113319A1 PCT/JP2003/007989 JP0307989W WO2004113319A1 WO 2004113319 A1 WO2004113319 A1 WO 2004113319A1 JP 0307989 W JP0307989 W JP 0307989W WO 2004113319 A1 WO2004113319 A1 WO 2004113319A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- extract
- antioxidant
- chromene
- virus
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/02—Algae
- A61K36/03—Phaeophycota or phaeophyta (brown algae), e.g. Fucus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
Definitions
- the present invention relates to a chromene compound, an antioxidant containing the compound, an antiviral agent, and a gastric acid secretion inhibitor.
- Oxygen is indispensable for survival because these organisms use the oxidative action of atmospheric oxygen to obtain energy for survival.
- highly reactive that is, highly toxic molecular species (active oxygen species) are generated in the living body. Therefore, living organisms have a self-protection mechanism that can suppress the generation of reactive oxygen species or can eliminate the generated reactive oxygen species.
- Oxidative damage is caused by some species.
- Targets of reactive oxygen species in the living body are mainly lipids, nucleic acids, proteins, and the like, and when these are damaged, various diseases are caused.
- reactive oxygen species generated in the living body can cause various diseases, for example, cerebral disorders such as schizophrenia and manic depression, adult respiratory distress syndrome, arterial stiffness, hypertension, cardiovascular disorders such as thrombosis, nephritis , Kidney disorders such as renal failure, liver disorders such as alcoholic hepatitis, liver cirrhosis, diabetic complications such as cataract and peripheral nerve disorder, gastrointestinal disorders such as gastric ulcer and duodenal ulcer, other rheumatoid arthritis, carcinogenesis, aging It is also known to be involved in progression and UV damage.
- cerebral disorders such as schizophrenia and manic depression, adult respiratory distress syndrome, arterial stiffness, hypertension
- cardiovascular disorders such as thrombosis, nephritis
- Kidney disorders such as renal failure
- liver disorders such as alcoholic hepatitis, liver cirrhosis
- diabetic complications such as cataract and peripheral nerve disorder
- gastrointestinal disorders such as gastric ulcer and duodenal ulcer, other rheumatoid arthritis, carcinogenesis
- antioxidants are generally added to cosmetics and foods in an appropriate amount in order to prevent deterioration of the fats and oils components contained in cosmetics and foods due to oxidation.
- a synthetic antioxidant a natural antioxidant, or a combination thereof can be used.
- BHT butylhydroxytoluene
- dibutylhydroxy-sol and the like are used as synthetic antioxidants
- ascorbic acid and tocopherol are used as natural antioxidants.
- the conventional synthetic antioxidants such as BHT described above have excellent antioxidant ability, but the purpose and amount of use are limited in terms of safety. Natural antioxidants that have no safety issues. Although it is expected to be applied to cosmetics and foods, its efficacy in vivo is generally low.
- virus infections such as the immunodeficiency syndrome (AIDS) caused by AIDS virus (HIV) infection have become a serious social problem.
- HIV immunodeficiency syndrome
- Reduced immune function is observed as a common symptom of AIDS patients, but in each case, a simple virus that has already been infected in childhood and is latently infected, such as a herpes virus such as human cytomegalovirus. In many cases, swirls recur and become severe.
- Synthetic drugs such as ashiku mouth building and ganshik mouth building are widely used as anti-herpes virus agents, but these anti-viral agents are often administered for a long period of time, causing side effects and resistant virus. Often develops, clinically overcome It is an important issue to be addressed.
- gastric ulcer has become a major problem as a lifestyle-related disease.
- Omebrazole and lansoprazole which are proton pump inhibitors that inhibit the final stage of the gastric acid secretion mechanism in place of receptor antagonists such as cimetidine-famotidine, are becoming mainstream in the treatment of gastric ulcers.
- receptor antagonists such as cimetidine-famotidine
- the first invention of the present application is the following formula (1):
- a chromene compound, a salt of the compound or an ester of the compound is chromene compound, a salt of the compound or an ester of the compound.
- the second invention of the present application is the following formula (1) extracted from Sargassum micracanthum); It relates to the extract containing the chromene compound represented by these.
- the third invention of the present application is directed to an antimicrobial agent characterized in that the compound comprises a chromene compound according to the first invention, a salt of the compound or an ester of the compound, and / or an extract according to the second invention as an active ingredient.
- the compound comprises a chromene compound according to the first invention, a salt of the compound or an ester of the compound, and / or an extract according to the second invention as an active ingredient.
- an antibacterial agent comprising the chromene compound according to the first aspect, a salt of the compound or an ester of the compound, and / or an extract according to the second aspect as an active ingredient. Pertains to viral agents.
- a fifth invention of the present application is a gastric acid comprising a chromene compound according to the first invention, a salt of the compound or an ester of the compound, and / or an extract according to the second invention as an active ingredient. It relates to a secretion inhibitor.
- Marine marine resources are diverse, and marine life grows in a different environment from terrestrial organisms. Therefore, some marine resources include bioactive substances that have a different skeleton (chemical structure) from terrestrial organisms. Existence is expected. Therefore, the present inventors collected various marine organisms and searched for physiologically active substances. As a result, the following formula (1) obtained from an extract of the seaweed Togemoku belonging to the family Brassicaceae was obtained.
- the 11′- and 12′-alcoholic OH groups and the phenolic OH group at the 6-position of the chromene compound represented by the formula (1) can be formed with a suitable base (for example, an alkali metal hydroxide) and a salt. Or an ester with a suitable acid (eg, carboxylic acid such as acetic acid). Furthermore, if desired, the chromene compound represented by the formula (1) may be converted to various derivatives. In addition, these salts, esters and derivatives may of course be extracted and purified from the seaweed Togemoku.
- physiologically active components from seaweed are extracted with warm water (for low-temperature substances, low-temperature extraction) for water-soluble substances, and with organic solvents for lipophilic substances.
- organic solvent for extracting the chromene compound of the present invention one or more kinds of commonly used solvents such as methanol, ethanol, ethyl acetate, acetonitrile, and chloroform can be used. It is desirable to repeat the extraction process at least twice in order to increase the extraction efficiency.
- the extract containing the chromene compound of the present invention can be used as a raw material in a seaweed sponge of the family Brassicaceae i ⁇ D rgassum micracanthwn power, preferably methanol extraction, followed by black mouth form-methanol extraction.
- a different organic solvent can be used for each extraction step, and separation and concentration means such as a centrifuge and a rotary evaporator can be used to distill off the extraction solvent.
- separation and concentration means such as a centrifuge and a rotary evaporator can be used to distill off the extraction solvent.
- fresh or dried seaweed Togemoku can be used as a raw material.
- the extract obtained in this way can be directly applied to various fields such as food, cosmetics and pharmaceuticals, but if necessary, dissolve the extract in an organic solvent such as ethanol, but do not dissolve in it It can be purified by the ability to remove substances or by dissolving and fractionating in a solvent having a different polarity.
- silica gel column chromatography can be used to isolate the chromene compound.
- the extract containing the chromene compound of the present invention is separated, for example, by normal-phase silica gel column chromatography and then further subjected to reverse-phase silica gel (0DS) column chromatography, followed by normal-phase silica gel flash column chromatography.
- chromene compounds Separation and further purification by high performance liquid chromatography in reverse phase mode can afford chromene compounds.
- the chromene compound represented by the formula (1), a salt of the compound, an ester of the compound, or an extract from seaweed togemoku containing the chromene compound is added as an active ingredient in an appropriate amount to provide antioxidant properties.
- An agent, an antiviral agent or a gastric acid secretion inhibitor can be prepared.
- the antioxidant, antiviral agent or gastric acid secretion inhibitor is pharmaceutically acceptable, in addition to the chromene compound, a salt of the compound or an ester of the compound, and an extract from seaweed Togemoku containing the chromene compound.
- Various compounds may be added, and the compounds used may be conventional ones.
- the form of use of the antioxidant, antiviral agent or gastric acid secretion inhibitor of the present invention may be appropriately selected according to the intended use, and examples thereof include powders, granules, tablets, solutions, emulsifiers, dispersants, pastes and the like. May be used in combination.
- the chromene compound of the present invention can be extracted from many seaweeds, considering the efficiency of the extraction and the like, the seaweeds that can be actually used will be limited to some.
- the raw material of the seaweed Togemoku may be raw, dried or processed.
- Seaweed Togemoku is a seaweed that is abundant in the seas around Japan and hardly ever used. Therefore, it can be obtained at low cost, and the cost of extracting and purifying the chromene compound can be reduced.
- the method for extracting the kumumen compound of the present invention the method for purifying the compound, the chemical structure analysis, the antioxidant effect, the antiviral effect, and the inhibitory effect on the proton pump, that is, the inhibitory effect on gastric acid secretion are as described in the following Examples. However, the examples are illustrative of the present invention and do not limit the technical scope of the present invention.
- TLC thin layer chromatography
- Compound (1) is a light brown oily substance, and its molecular formula is C 27 H 40 O 4 . From the high resolution mass statue (HRFABMS), it is ⁇ 3 / ⁇ 428.2979 ([M + H +], Zl + 1.8mmu) (calculated value nZ 429.3005). The measured infrared absorption spectrum was (film) max 3400 (hydroxyl group), 2980 (carbon-carbon stretching vibration), 1590 (conjugated double bond), 1240 (phenyl ether) cm- 1 . .
- UV absorption spectrum was UV (MeOH) ⁇ max 230, 265 nm (substituted aromatic) and 334 nm (aromatic conjugated carbon-carbon double bond). Also, iH-NMR scan Bae spectrum (CDC1 3) and 13 C-NMR spectrum of (CDC1 3) shown in Table 1.
- the antioxidant activity '1 ⁇ was determined by measuring the radical scavenging activity of 1,1-diphenyl-2-picrylhydrazyl (DPPH) having a free radical in the molecule by the Pruss method. That is, 0.2 ml of a sample dissolved in ethanol at each concentration was added to 1.0 ml of an O.lmMDPPH ethanol solution, reacted at 37 ° C. for 20 minutes, and the absorbance was measured at 517 ⁇ . Reduced absorbance as DPPH radical erasing activity relative to the control group (test substance concentration O ⁇ g / ml), was calculated 50% erasure concentration (IC 5.).
- DPPH 1,1-diphenyl-2-picrylhydrazyl
- Lipid peroxidation inhibitory activity was measured using the extract (1) obtained in Test Example 1, the compound (1) obtained in Test Example 2 and ⁇ -tocopherol as test substances.
- the antiviral effect was measured according to the plaque assay method.
- Vei'o cells derived from African green kidney cells were transplanted into a 48-well plate and cultured, and the cells were simply infected with virus 1 (HSV-1 HF strain) and simple virus 2 (HSV-2).
- UW268 strain) and measles virus were each infected at 0.1 to 0.2 PFU / cell for 1 hour. Adding fresh medium to the infected cells were further cultured in C0 2 incubator.
- the test substance was added at the same time as the infection by adding the virus, or when added immediately after the infection, the test substance was added together when adding a new medium.
- the cells were collected 24 hours after the infection, and the cells were repeatedly frozen and thawed three times. Thereafter, the virus-infected solution was diluted 10 to 105 times to infect Vero cells separately cultured in a 35 mra dish.
- a medium supplemented with 0.5% methylcellulose was overlaid thereon, and the cells were stained with crystal violet the next day to determine the number of plaques that appeared.
- the concentration ( IC5Q ) that inhibited virus growth by 50% as compared to the control without the test substance was determined.
- non-virus-infected Vero cells were cultured in a medium supplemented with various concentrations of test substances. After culturing for 72 hours, the cells were stained with trypan blue and the number of viable cells was counted. The cytotoxic concentration (CC 5 ) that inhibited the growth of Vei'o cells by 50% compared to the control without the test substance was determined.
- the antiviral effect of the test substance was evaluated. That is, the ratio of CC 50 to IC 50 of the test substance (selection index: CCsoZlCJ was calculated.
- Antiviral activity of compound (1) as shown in Table 4, both antiproliferative activity when you ⁇ Ka ⁇ in the case you Yopi virus ⁇ Ka ⁇ 1 hour after the addition at the same time as the virus was observed, IC 50 values , Number and extremely low concentration. On the other hand, cytotoxicity to normal cells is relatively weak, and the selection index is more than 10 particularly for simple herpes virus 1 (HF), simple herpes virus 2 (UW268), and measles virus. Was observed. Table 4 Antiviral activity of modified ⁇ (1) and ⁇ -tocopherol
- Test substance Winores CC50 Suppressed chick 1 (3 ⁇ 40 (CC ⁇ C
- Antiviral activity against human cytomegalovirus was measured using the compound (1) obtained in Test Example 2 and ⁇ -tocopherol as test substances.
- the antiviral effect was measured according to the plaque assay method.
- HEL cells were transplanted and cultured in a 48-well plate, and infected with human cytomegalovirus (Towne strain) at 0.1 to 0.2 PFU / cell for 1 hour. Adding fresh medium to the infected cells were further cultured in C0 2 incubator base one coater in. The test substance was added at the same time as infection by adding a virus, or when added immediately after infection, was added together when adding a new medium. After harvesting the cells 24 hours after the infection, the cells were repeatedly frozen and thawed three times, and then the virus-infected solution was diluted 10 to 105 times to infect HEL cells separately cultured in a 35-mm dish.
- the medium was supplemented with 0.5% methylcellulose, and the cells were stained with crystal violet the next day to determine the number of plaques that appeared.
- the concentration (IC 5 ) that inhibited virus growth by 50% compared to the control without the test substance was determined.
- HEL cells not infected with the virus were cultured for 72 hours in a medium supplemented with various concentrations of a test substance, and then stained with trypan blue to count the number of viable cells.
- the cytotoxic concentration (CC 5 ) that inhibited the growth of HEL cells by 50% compared to the control without the test substance was determined. From the above results, the antiviral effect of the test substance was evaluated. That is, CC 5 of the test substance. And IC 5 . (Selection index: CC 5, ZIC 5 ) was calculated.
- Antiviral activity of compound (1) as shown in Table 5, both antiproliferative activity when you ⁇ Ka ⁇ case was added Caro and virus added 1 hour after the same time as the virus was observed, IC 5. The values were extremely low, from 0.22 to 0.51 ⁇ . On the other hand, cytotoxicity to normal cells was relatively weak, and the selection index was 63 to 111, indicating safety.
- p-NPP p-nitrophenyl phosphate
- the proton pump inhibitory activity of the extract (1) and the compound (1) was determined to be IC 5 as shown in Table 6 below.
- the values were 32 and 4.1 z gZml, respectively.
- This activity is traditional typical proton pump inhibitor is a Omeburazoru (IC 5 values:. 280 gZml) are each approximately 9-fold and about 70 fold of the activity of the extract (1) and the compound (1) Was found to have a very strong proton pump activity, that is, a gastric acid secretion inhibitory action.
- the chromene compound of the present invention the salt of the compound or the ester containing the compound and the extract containing the chromene compound from the seaweed Togemoku have a higher safety 14 against the human body, and are more powerful, have antioxidants, It has an effect of more effectively acting as an active ingredient of an antiviral agent and a gastric acid secretion inhibitor.
- the antioxidant, antiviral agent and gastric acid secretion inhibitor containing the chromene compound or the extract containing the chromene compound from the seaweed Togemoku of the present invention are useful as pharmaceuticals, cosmetics or foods.
- the antioxidant action, antiviral action and gastric acid secretion inhibitory action of the chromene compound, the salt of the compound or the ester of the compound of the present invention do not offset the effects of each other, so that a new structure having a new structure is obtained.
- the chromene compound of the present invention can be obtained from a seaweed naturally present in a large amount as a raw material, for example, a seaweed Togemoku of the family Brassicae. Since the seaweed sperm has abundant resources and is available at a low price, the cost of extracting and purifying the chromene compound of the present invention can be reduced.
- An extract containing the chromene compound of the present invention, a salt of the compound or an ester of the compound and a chromene compound from a seaweed sprout, has an antioxidant action (for example, an anti-lipid peroxidative action), an antiviral action, and a suppression of gastric acid secretion.
- brain disorders such as schizophrenia and manic depression; cardiovascular disorders such as adult respiratory distress syndrome, arteriosclerosis, hypertension, and thrombosis; renal disorders such as nephritis and renal failure; alcoholic liver disorders; Cataract; Diabetes; Gastrointestinal disorders such as gastric ulcer and duodenal ulcer; Rheumatoid arthritis; Acceleration of carcinogenesis and aging; Other prophylactic and therapeutic agents against ultraviolet damage; Preventive medicine) and food field (foodstuffs containing edible oils and other fats and oils, dairy products, instant foods, retort foods, canned foods) Bottled, pastes, dried food, powdered food, processed food, smoked foods, breads, Gohanrui, beverages, alcoholic beverages, may be suitably practiced in confectionery highly safe as an antioxidant) such as.
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Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2005500923A JPWO2004113319A1 (ja) | 2003-06-24 | 2003-06-24 | 新規クロメン化合物 |
AU2003244179A AU2003244179A1 (en) | 2003-06-24 | 2003-06-24 | Novel chromene compound |
PCT/JP2003/007989 WO2004113319A1 (ja) | 2003-06-24 | 2003-06-24 | 新規クロメン化合物 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/JP2003/007989 WO2004113319A1 (ja) | 2003-06-24 | 2003-06-24 | 新規クロメン化合物 |
Publications (1)
Publication Number | Publication Date |
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WO2004113319A1 true WO2004113319A1 (ja) | 2004-12-29 |
Family
ID=33524184
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2003/007989 WO2004113319A1 (ja) | 2003-06-24 | 2003-06-24 | 新規クロメン化合物 |
Country Status (3)
Country | Link |
---|---|
JP (1) | JPWO2004113319A1 (ja) |
AU (1) | AU2003244179A1 (ja) |
WO (1) | WO2004113319A1 (ja) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS63301770A (ja) * | 1987-06-02 | 1988-12-08 | Towa Kasei Kogyo Kk | 海藻エキス含有液状組成物の製造方法 |
JPH02289523A (ja) * | 1989-02-10 | 1990-11-29 | Kibun Kk | 逆転写酵素阻害剤 |
WO2002040463A1 (fr) * | 2000-11-20 | 2002-05-23 | Toyama-Ken | Compose macrocyclique |
-
2003
- 2003-06-24 WO PCT/JP2003/007989 patent/WO2004113319A1/ja active Application Filing
- 2003-06-24 AU AU2003244179A patent/AU2003244179A1/en not_active Abandoned
- 2003-06-24 JP JP2005500923A patent/JPWO2004113319A1/ja active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS63301770A (ja) * | 1987-06-02 | 1988-12-08 | Towa Kasei Kogyo Kk | 海藻エキス含有液状組成物の製造方法 |
JPH02289523A (ja) * | 1989-02-10 | 1990-11-29 | Kibun Kk | 逆転写酵素阻害剤 |
WO2002040463A1 (fr) * | 2000-11-20 | 2002-05-23 | Toyama-Ken | Compose macrocyclique |
Non-Patent Citations (3)
Title |
---|
KATO T. ET AL.: "Structure and synthesis of active component from a marine alga, sargassum tortile, which induces the settling of swimming larvae of coryne uchidai", CHEMISTRY LETTERS, no. 4, 1975, pages 335 - 338, XP002984622 * |
MATSUNAGA T.: "Shokuyo kaisochu ni fukumareru kosanka seibun no riyo kenkyu (2) -kasio yurai kosanka seibun no kosanka seikatsu no hikaku to tonyobyo mouse ni taisuru kasankazai no koka-", ANNUAL REPORT OF TOYAMA PREFECTURAL INSTITUTE FOR PHARMACEUTICAL RESEARCH, no. 29, 2002, pages 26 - 31, XP002984621 * |
MORI J. ET AL.: "Inhibitory activity on lipid peroxidation of extracts from marine brown alga", PHYTOTHER. RES., vol. 17, no. 5, May 2003 (2003-05-01), pages 549 - 551, XP002984620 * |
Also Published As
Publication number | Publication date |
---|---|
AU2003244179A8 (en) | 2005-01-04 |
JPWO2004113319A1 (ja) | 2006-07-27 |
AU2003244179A1 (en) | 2005-01-04 |
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