WO2002040463A1 - Compose macrocyclique - Google Patents

Compose macrocyclique Download PDF

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Publication number
WO2002040463A1
WO2002040463A1 PCT/JP2000/008172 JP0008172W WO0240463A1 WO 2002040463 A1 WO2002040463 A1 WO 2002040463A1 JP 0008172 W JP0008172 W JP 0008172W WO 0240463 A1 WO0240463 A1 WO 0240463A1
Authority
WO
WIPO (PCT)
Prior art keywords
macrocyclic compound
present
ester
salt
antioxidant
Prior art date
Application number
PCT/JP2000/008172
Other languages
English (en)
Japanese (ja)
Inventor
Takayuki Matsunaga
Satoshi Takahashi
Chika Hasegawa
Daisuke Fujita
Masao Mori
Haruo Saito
Jun Mori
Original Assignee
Toyama-Ken
Lead Chemical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Toyama-Ken, Lead Chemical Co., Ltd. filed Critical Toyama-Ken
Priority to PCT/JP2000/008172 priority Critical patent/WO2002040463A1/fr
Priority to AU2001214172A priority patent/AU2001214172A1/en
Publication of WO2002040463A1 publication Critical patent/WO2002040463A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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 novel macrocyclic compound or a salt or ester thereof, a method for producing the macrocyclic compound, and a use of the macrocyclic compound or a salt or ester thereof.
  • Novel macrocyclic compound having an action or a salt or ester thereof, a method for producing the macrocyclic compound from seaweed, and an antioxidant or antiviral agent containing the macrocyclic compound or a salt or ester thereof as an active ingredient It is about.
  • the targets of active oxygen in the living body are mainly lipids, nucleic acids, proteins, and the like. When these are damaged, various diseases and diseases are caused.
  • active oxygen generated in the body is a variety of diseases, for example, schizophrenia, brain disorders such as manic depression; adult respiratory distress syndrome, arteriosclerosis, hypertension, thrombosis and other cardiovascular disorders; nephritis, renal failure Alcoholic hepatitis; Cataract; Diabetes; Gastrointestinal tract disorders such as gastric and duodenal ulcers; Rheumatoid arthritis; Acceleration of carcinogenesis and aging; I have.
  • antioxidants are generally added to cosmetics and foodstuffs in an appropriate amount to prevent deterioration due to oxidation of fats and oils components contained in cosmetics and foodstuffs.
  • a synthetic antioxidant a natural antioxidant, or a combination thereof can be used.
  • a synthetic antioxidant dibutylhydroxydisole or butylhydroxytoluene (BHT) is used, and a natural antioxidant such as ascorbic acid or tocopherol is also used.
  • BHT butylhydroxydisole or butylhydroxytoluene
  • organ transplantation has been routinely performed due to the advancement and sophistication of medical technology. It is important to suppress rejection during organ transplantation, and therefore, patients who have undergone organ transplantation are usually given immunosuppressants. While immunosuppressants have the effect of suppressing rejection, they also have the disadvantage of weakening the immune function, which is the natural defense mechanism of the living body. As described above, since the administration of immunosuppressive drugs is becoming more common, patients who have undergone organ transplantation may always develop infections such as viruses and bacteria after transplantation surgery. In addition, with the aging of the population distribution, the number of people suffering from so-called lifestyle-related diseases such as cancer, chronic hepatitis, and circulatory disorders due to arteriosclerosis is increasing. Often there is a decline in functionality.
  • marine biological resources are diverse, and marine organisms inhabit different environments from terrestrial organisms. Therefore, marine biological resources have a biological activity that has a different skeleton (chemical structure) from terrestrial biological resources. Existence of substance is expected. Therefore, in recent years, in order to develop new physiologically active substances, for example, new pharmaceuticals, the search for the physiological activity of the components of marine organisms as well as terrestrial organisms has been actively conducted. At present, many marine resources are not yet used due to the lack of information.
  • An object of the present invention is to solve the above-mentioned problems of the prior art, and it is an object of the present invention to provide a compound having a novel and unique chemical structure which shows a strong bioactivity in a trace amount and is highly effective.
  • An object of the present invention is to develop and provide an efficient production method and various uses of the compound, for example, a use as a pharmaceutical.
  • the present invention relates to a method for producing a macrocyclic compound represented by the above formula (1), which is obtained by fractionating components extracted from seaweed.
  • the present invention also relates to an antioxidant characterized by containing a macrocyclic compound represented by the above formula (1) or a salt or ester thereof as an active ingredient. Further, the present invention relates to an antiviral agent comprising a macrocyclic compound represented by the above formula (1) or a salt or ester thereof as an active ingredient, and a macrocyclic compound of the present invention and a compound thereof. Derivatives, such as salts or esters thereof, exhibit antioxidant and / or antiviral effects in vivo. Therefore, the macrocyclic compound and the derivative thereof of the present invention exhibit various pharmacological actions based on the antioxidant action and / or antiviral action in vivo, and are useful for prevention and treatment of various diseases.
  • the macrocyclic compound of the present invention or a salt or ester thereof is used for cerebral disorders such as schizophrenia and manic depression; cardiovascular disorders such as adult respiratory distress syndrome, arteriosclerosis, hypertension, and thrombosis; nephritis Various inflammations such as rheumatoid arthritis, alcoholic hepatitis, liver injury such as drug-induced inflammation; gastrointestinal disorders such as gastric ulcer; cataract, diabetes, carcinogenesis and aging, etc. It can be used as a prophylactic and therapeutic agent for other ultraviolet disorders. It can also be used as a fragrance and cosmetic material as a UV damage preventive agent.
  • cerebral disorders such as schizophrenia and manic depression
  • cardiovascular disorders such as adult respiratory distress syndrome, arteriosclerosis, hypertension, and thrombosis
  • nephritis Various inflammations such as rheumatoid arthritis, alcoholic hepatitis, liver injury such as drug-induced inflammation; gastrointestinal disorders such as gastric ulcer; cataract, diabetes, carcinogenesis and aging, etc
  • various foods and drinks for example, foodstuffs containing edible oils and various fats and oils (eg, edible oils, dressings, etc.), dairy products (eg, butter, cheese, yogurt) Etc.), instant foods (eg, instant 'ramen, instant coffee, etc.), retort foods, canned food, bottled foods, kneaded foods (eg, rice balls, rice beans, chikuwa etc.), dried foods, powdered foods, It can be added to processed foods (eg, ham and sausage), smoked foods, breads, rice, beverages, alcoholic beverages, confectionery and the like in appropriate amounts. ,
  • the macrocyclic compound of the present invention or a salt or ester thereof is applied to preventive and therapeutic agents for various diseases caused by viruses, for example, various infectious diseases and skin diseases caused by herpes virus infection. Is possible.
  • Figure 1 is a diagram showing a 13 C-NMR scan Bae spectrum (in CDC 1 3) of the macrocyclic compound of the present invention.
  • Figure 2 is a diagram showing a 'H- NMR spectra of the macrocyclic compounds of the present invention (in CDC 1 3).
  • Figure 3 is a diagram showing a 3, 1 8-Jiasechiru derivatives of 13 C-NMR spectrum (in CDC 1 3) of the macrocyclic compound of the present invention.
  • Figure 4 is a diagram showing a 3, a 1 8 Jiasechiru derivatives' H- NMR spectrum (in CDC 1 3) of the macrocyclic compound of the present invention.
  • the macrocyclic compound represented by the formula (1) has asymmetric carbon atoms at the 3- and 14-positions. Therefore, it should be understood that the macrocyclic compound represented by the formula (1) of the present invention includes stereoisomers based on the asymmetric carbon atom.
  • the alcoholic OH group at the 3-position and the 14-position and the phenolic OH group at the 18-position of the macrocyclic compound represented by the formula (1) are converted to a suitable base (for example, an alkali metal hydroxide) Or an ester with a suitable acid (eg, a carboxylic acid such as acetic acid). Further, if desired, the macrocyclic compound represented by the formula (1) May be led to various derivatives.
  • a suitable base for example, an alkali metal hydroxide
  • a suitable acid eg, a carboxylic acid such as acetic acid
  • An antioxidant or an antiviral agent can be prepared by mixing an appropriate amount of the macrocyclic compound represented by the formula (1) or a salt or ester thereof as an active ingredient.
  • various compounds that are pharmaceutically acceptable may be added in addition to the present macrocyclic compound or its salt or its ester. Conventional compounds can be used as the compound.
  • the antioxidant of the present invention may be used for various applications if suitable. Such applications are, for example, the prevention and treatment of diseases in humans and non-human animals that may or may suffer from various diseases induced by the damage of biological components by reactive oxygen.
  • the antiviral agent of the present invention can be used for various purposes if it is suitable. Such applications include, for example, the prevention and treatment of human or non-human animal illnesses that may or may suffer from viral diseases, the sterilization of virus-contaminated materials, and the prophylactic application of those that can be contaminated with viruses. (Application, spraying, spraying, etc.).
  • the form of use of the present antioxidant and the present antiviral agent may be appropriately selected according to the use.
  • the form of use of the present antioxidant and the present antiviral agent may be a powder, a granule, a tablet, a solution, an emulsifier, a dispersant, a paste and the like. These usage patterns may be used in combination.
  • the macrocyclic compound of the present invention can be easily obtained by fractionating components extracted from seaweed. Extraction of an active ingredient from seaweed. Fractionation of the active ingredient can be performed by a conventional means (for example, solvent extraction or separation using a column).
  • the seaweed used as a raw material of the present macrocyclic compound may be any one containing the present macrocyclic compound or a derivative thereof, and may be various types of seaweed.
  • the seaweed may be raw, dried, or processed.
  • a seaweed of the family Brassicaceae such as togemoku
  • Seaweed sperm is abundant in seas near Japan and is a seaweed that has rarely been used. Therefore, by performing the production method of the present invention, the seaweed Togemoku can be effectively used.
  • the pale yellow oily substance has the following formula (2):
  • the compound was a 3,18-diacetylated compound of the macrocyclic compound represented by the formula (1).
  • the properties of the 3,18_diacetylated product are shown below.
  • the seaweed Togemoku was extracted with methanol, and the residue was extracted with a mixed solvent of mixed form: methanol (3: 1) to obtain an extract.
  • This extract was subjected to silica gel column chromatography (7.2 x 33 cm), extracted with a mixed solution of chloroform and methanol, and placed on a thin layer chromatography (TLC) plate.
  • TLC thin layer chromatography
  • the amounts of raw materials and reagents used were appropriately selected according to the required amount of the present macrocyclic compound.
  • TSA thiobarbituric acid
  • the antiviral activity was measured according to the plaque assay method. African green monkey kidney-derived Vero cells were transplanted into a 48-well plate, cultured, and infected with simple herpes virus type 1 (HSV-1 HF strain) at 0.1 to 0.2 PFU / cell for 1 hour. Was. Adding fresh medium to the infected cells were further cultured in C 0 2 Inkyube Isseki scratch. The test substance was added at the same time as the infection with the addition of HSV-1 or, if added immediately after infection, together with the addition of fresh medium. Harvest 24 hours after infection, freeze and thaw three times repeatedly, then dilute the virus infection solution 10- to 10-fold, and infect 35-mm dishes with separately cultured Vero cells. Was.
  • Vero cells 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.
  • concentration (CC 5 ) that inhibited cell proliferation by 50% as compared to the control without the test substance was determined.
  • the antiviral effect of the test substance was evaluated. That is, the test substances CC 5Q and IC 5 .
  • the ratio selection index: CC 5 / IC 5 ) was calculated, and when the selection index was 10 or more, it was determined that there was an antiviral effect.
  • the antiviral effect of the present macrocyclic compound was suppressed when it was added to the virus simultaneously with infection with the virus and when added immediately after the infection.
  • The% inhibitory concentrations were extremely low, 0.23 g / m 1 and 0.26 g / m 1, respectively.
  • the toxicity of this macrocyclic compound to normal cells is relatively weak, and the concentration that inhibits cell proliferation by 50% is 7.9 gZm1, and the concentration ratio (selection index: CC 5 o / I Cso ) was 30 or more.
  • the macrocyclic compound of the present invention or a salt thereof or an ester thereof has excellent antioxidant activity and antiviral activity, and has low toxicity and high safety, so that it can be effectively used as a pharmaceutical or a related product.
  • the macrocyclic compound of the present invention can easily obtain a sufficient amount from a naturally occurring seaweed such as the seaweed Togemoku of the family Brassicaceae. Since the seaweed Togemoku has not been used so far, it has abundant resources and can be mass-produced if necessary.
  • This macrocyclic compound or its salt or its ester is based on its antioxidant activity (for example, anti-lipid peroxidation activity), and in the medical field, for example, cerebral disorders such as schizophrenia and manic depression; adult respiratory distress syndrome, Cardiovascular disorders such as 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; Promotes carcinogenesis and aging; and is useful as a prophylactic or therapeutic agent for other ultraviolet disorders.
  • the macrocyclic compound or a salt or ester thereof can also be used as an active ingredient such as a sunscreen, a fragrance, a cosmetic, etc. as an agent for preventing ultraviolet damage.
  • the macrocyclic compound or a salt or ester thereof is used as a highly safe antioxidant in various foods and drinks, for example, food products including edible oils and various fats and oils, dairy products, instant foods, It is widely applicable to retort foods, canned foods, bottled foods, pastes, dried foods, powdered foods, processed foods, smoked foods, breads, rice, beverages, alcoholic beverages, and confectionery.
  • the macrocyclic compound or a salt or ester thereof can be used as a prophylactic or therapeutic agent for various viral diseases, for example, various systemic and local diseases caused by viral infection, based on its antiviral activity. Useful.
  • the antioxidant and antiviral effects of the present macrocyclic compound or its salt or its ester do not cancel each other's action and effect, so that this macrocyclic compound or its salt or its ester has a novel structure It is also applicable as a new type of pharmaceutical raw material.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Toxicology (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé macrocyclique représenté par la formule suivante (1), ses sels ou ses esters. Ce composé, qui peut être obtenu par fractionnement de composants extraits d'une algue marine (par exemple, ∫i⊃Sargassum micracanthum Endlicher∫/i⊃ appartenant à la famille des ∫i⊃Sargasses∫/i⊃), exerce d'excellents effets antioxydants et antiviraux ∫i⊃in vivo∫/i⊃, c'est pourquoi il est utilisé en tant que principe actif d'antioxydants ou d'antiviraux.
PCT/JP2000/008172 2000-11-20 2000-11-20 Compose macrocyclique WO2002040463A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/JP2000/008172 WO2002040463A1 (fr) 2000-11-20 2000-11-20 Compose macrocyclique
AU2001214172A AU2001214172A1 (en) 2000-11-20 2000-11-20 Macrocyclic compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP2000/008172 WO2002040463A1 (fr) 2000-11-20 2000-11-20 Compose macrocyclique

Publications (1)

Publication Number Publication Date
WO2002040463A1 true WO2002040463A1 (fr) 2002-05-23

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PCT/JP2000/008172 WO2002040463A1 (fr) 2000-11-20 2000-11-20 Compose macrocyclique

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WO (1) WO2002040463A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004113319A1 (fr) * 2003-06-24 2004-12-29 Toyama-Ken Nouveau compose de chromene
KR101277794B1 (ko) 2011-03-23 2013-06-27 대한민국 신규한 화합물 및 이의 용도
US9181298B2 (en) 2003-06-18 2015-11-10 Ocera Therapeutics, Inc. Intermediates for macrocyclic compounds

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0075523A1 (fr) * 1981-09-23 1983-03-30 Laboratoires Goemar S.A. Nouveaux médicaments à base d'extraits d'algues, et formulations correspondantes
EP0295956A2 (fr) * 1987-06-18 1988-12-21 Kureha Kagaku Kogyo Kabushiki Kaisha Utilisation d'un polysaccharide lié a une protéine pour préparer un médicament destiné au traitement du SIDA.
JPH02289523A (ja) * 1989-02-10 1990-11-29 Kibun Kk 逆転写酵素阻害剤
JPH04239593A (ja) * 1991-01-23 1992-08-27 Nippon Suisan Kaisha Ltd 抗酸化剤

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0075523A1 (fr) * 1981-09-23 1983-03-30 Laboratoires Goemar S.A. Nouveaux médicaments à base d'extraits d'algues, et formulations correspondantes
EP0295956A2 (fr) * 1987-06-18 1988-12-21 Kureha Kagaku Kogyo Kabushiki Kaisha Utilisation d'un polysaccharide lié a une protéine pour préparer un médicament destiné au traitement du SIDA.
JPH02289523A (ja) * 1989-02-10 1990-11-29 Kibun Kk 逆転写酵素阻害剤
JPH04239593A (ja) * 1991-01-23 1992-08-27 Nippon Suisan Kaisha Ltd 抗酸化剤

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9181298B2 (en) 2003-06-18 2015-11-10 Ocera Therapeutics, Inc. Intermediates for macrocyclic compounds
US10040751B2 (en) 2003-06-18 2018-08-07 Ocera Therapeutics, Inc. Intermediates for macrocyclic compounds
WO2004113319A1 (fr) * 2003-06-24 2004-12-29 Toyama-Ken Nouveau compose de chromene
KR101277794B1 (ko) 2011-03-23 2013-06-27 대한민국 신규한 화합물 및 이의 용도

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Publication number Publication date
AU2001214172A1 (en) 2002-05-27

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