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WO1995026969A1 - Derive de moranoline - Google Patents

Derive de moranoline Download PDF

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Publication number
WO1995026969A1
WO1995026969A1 PCT/JP1995/000609 JP9500609W WO9526969A1 WO 1995026969 A1 WO1995026969 A1 WO 1995026969A1 JP 9500609 W JP9500609 W JP 9500609W WO 9526969 A1 WO9526969 A1 WO 9526969A1
Authority
WO
WIPO (PCT)
Prior art keywords
dideoxy
glucitol
acetamido
compound
galacto
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1995/000609
Other languages
English (en)
Japanese (ja)
Inventor
Akira Hasegawa
Makoto Kiso
Yoshiaki Yoshikuni
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Shinyaku Co Ltd
Original Assignee
Nippon Shinyaku 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 Nippon Shinyaku Co Ltd filed Critical Nippon Shinyaku Co Ltd
Publication of WO1995026969A1 publication Critical patent/WO1995026969A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms

Definitions

  • the present invention relates to novel molanolin derivatives.
  • the compounds according to the present invention are useful in the field of medicine, for example, as anti-inflammatory agents and anti-viral agents. Background art
  • the sugar chains of sialic acid-containing glycolipids and glycoproteins have receptor functions for hormones, bacterial toxins, viruses, and others, and also recognize, differentiate, proliferate, and adhere to cells. It is becoming clear that it is deeply involved in basic and dynamic life phenomena such as cancer, immunity, and aging.
  • sialic acid derivatives have been attracting attention as useful substances having physiological activity, and researches on therapeutic, diagnostic and prophylactic agents for various diseases have been made.
  • JP-A-63-139193 JP-A-3-251593, and the like.
  • JP-A-62-20994 Japanese Patent Application Laid-Open Nos. 243074 and JP-A-62-20994.
  • JP-A-61-370000 JP-A-61-370000 and the like.
  • the present inventors have intensively studied various ⁇ -chain antigen derivatives containing sialic acid, and have found novel sugar chain antigen derivatives containing moranolin, which have excellent pharmacological actions as pharmaceuticals, and have already filed an international patent application. (WO93 / 15098).
  • sialic acid derivatives exist in the natural world as minor components, it has been extremely difficult to obtain these compounds as single pure compounds from living organisms. Therefore, research on sialic acid derivatives as pharmaceuticals has only just begun in recent years, and its clinical application is greatly expected. Disclosure of the invention
  • An object of the present invention is to provide a moranolin sugar chain antigen derivative which is useful as a medicament and has a novel structure.
  • the present inventors have conducted further studies and conducted intensive studies. As a result, the present inventors have found that the compound represented by the general formula [I] is suitable for the above object, and have completed the present invention.
  • R 1 represents a C8-C30 alkyl, a C8-C30 alkyl, or a C8-C30 alkyl
  • R 2 and R 3 are different and represent a galactosyl, sialyl galactosyl, or fucosyl group.
  • the compound according to the present invention is a novel compound that has not been described in the literature, and exhibits excellent pharmacological actions as described below.
  • the alkyl represented by R 1 in the general formula (I) is preferably a straight-chain or branched alkyl having 8 to 30 carbon atoms, for example, octyl, isooctyl, nonyl, isononyl, decyl, isodecyl, pendecyl, isopendecyl, Dodecyl, isododecyl, tridecyl, isotridecyl, tetradecyl, isotetradecyl, pentadecyl, isopentadecyl, hexadecinole, isohexadecyl, heptadecyl, isoheptadecyl, occtadecyl, isooctadecyl, nonadecyl, isononadecyl, etc. it can.
  • the alkenyl is preferably a straight-chain or branched one having 8 to 30 carbon atoms, for example, octyl, nonenyl, decenyl, pendenyl, dodecenyl, tridecyl, tetradecenyl, pentadecenyl, hexadeceyl. Heptadecenyl, octadecyl, nonadecel, icosenyl, and the like.
  • Alkyl is preferably a straight-chain or branched one having 8 to 30 carbon atoms, for example, octyl, noryl, decinyl, pendecyl, dodecyl, tridecyl, tetradecyl. Pentadecyl, hexadecyl, hebutadecyl, octadecyl, nonadecyl, and icosyl.
  • Examples of the compound according to the present invention include the following compounds in addition to the compounds described in the examples relating to the production method described below, but these are examples of one compound of the present invention. Inventive compounds are not limited to these.
  • the molanolin derivative represented by the general formula (I) can be produced, for example, by the following method. Can be
  • R 1 is the same as described above, and is represented similarly below.
  • the added amounts of acetic acid and water are preferably 1/100 to 1/10 of the solvent.
  • the reaction temperature is preferably from 0 to 50 ° C.
  • the reaction time varies depending on the reaction temperature, but is usually 0.5 to 24 hours.
  • the catalyst palladium hydroxide on carbon is preferable, but is not limited thereto.
  • the reaction temperature is preferably from 0 to 50 ° C.
  • the reaction time varies depending on the reaction temperature, but is usually 0 to 48 hours.
  • the alkoxide is preferably sodium methoxide
  • the alkaline aqueous solution is preferably an aqueous hydration aqueous solution, but is not limited thereto.
  • the compound [II], the compound [IV], and the compound [V] used as a starting material for the production of the compound of the present invention can be produced by the method described in WO93 / 15098.
  • Compounds that have cell adhesion inhibitory activity inhibit the adhesion of leukocytes or cancer cells to endothelial cells by antagonistically inhibiting selectins present in endothelial cells.Thus, inflammation and thrombosis associated with inflammation, rheumatism, It is useful for the prevention and treatment of infectious diseases, immune diseases, AIDS and cancer.
  • the compound according to the present invention which exhibits a better cell adhesion inhibitory activity than the compound described in WO93 / 15098, is a better antiviral agent, anti-inflammatory agent, therapeutic agent for thrombosis, therapeutic agent for rheumatism It is useful as a therapeutic agent for infectious diseases, anti-AIDS, immune disease and cancer.
  • the compound of the present invention When the compound of the present invention is administered as a medicament, the compound of the present invention is used as such or in a pharmaceutically acceptable nontoxic and inert carrier, for example, 0.1% to 99.5%, preferably 0.5% to 90%. As a composition, it is administered to animals, including humans.
  • the carrier one or more solid, semi-solid, or liquid diluents, fillers, and other formulation aids are used.
  • the pharmaceutical compositions are desirably administered in unit dosage form.
  • the pharmaceutical composition of the present invention can be administered orally, intraosseously, topically (e.g., transdermally), or rectally. Can be administered. Needless to say, it is administered in a dosage form suitable for these administration methods. For example, intragroup administration is particularly preferred.
  • the dose as an anti-inflammatory therapeutic agent in consideration of the patient's condition such as age, body weight, etc., administration route, nature and extent of the disease, etc.
  • the amount of the active ingredient of the invention the range of 100 ms to 3 gZ days per day for humans is preferably
  • 500 mg to lgZ days The human range is common. In some cases, lower doses may be sufficient, and conversely, higher doses may be required. It is desirable to administer the drug in two or three divided doses a day.
  • the measured optical rotation temperatures are all 25 eC .
  • Step 1 (Methyl 5-acetamido-4,7,8,9-tetra-0-acetyl-1,3,5-dideoxy D-glycero ⁇ -D-galacto-2-nonuroviranosilone) 1 (2 ⁇ 3) — ⁇ — (2, 4, 6-tree ⁇ -benzoyl-; 3-D-galactovilanosyl) 1 (1 ⁇ 4) -1 0— [( ⁇ -L-fucoviranosyl) 1 (1 ⁇ 3)] -2- 0-Acetyl- ⁇ -decyl-1,5-dideoxy-1,5-imino D-glucitol Obtained according to the method described in WO93 / 15098 ⁇ (methyl-5-acetamido 4,7,8,9-tetra-0-acetyl- 3,5-dideoxy D-glycerol ⁇ -D-galacto-2-nonuloviranosylonate 1 (2 ⁇ 3) -0— (2
  • Step 2 (5-acetamido-3,5-dideoxy D—glycerol ⁇ —D—galactol 2-nonuloviranosylic acid) 1 (2 ⁇ 3) -0- (/ 3-D—galactobilanosyl) 1 (1 ⁇ 4) 1
  • O [( ⁇ -L-fucoviranosyl) 1 (1 ⁇ 3)] 1-decyl-1,5-dideoxy 1,5-iminin D-glucitol
  • Step 10 (Methyl 5-acetamido-4,7,8,9-tetra-0-acetyl-1-3,5-dideoxy-1 D-glycero ⁇ -D-galacto-2-nonurobiranosylone) 1 (2 ⁇ 3 ) — ⁇ — (2, 4, 6—tree ⁇ —Benzoru) 9-1 D—Galactovilla nosyl) 1 (1 ⁇ 3) — ⁇ — C ( ⁇ —L-fucoviranosyl) 1 (1 ⁇ 4)) 1 2— ⁇ One acetyl- ⁇ -decyl 1, 5-dideoxy 1, 5-imino D-glucitol
  • Step 2 (5-acetamido-3,5-dideoxy-D-glycerol ⁇ -D-galacto-2-nonuloviranosylic acid) one (2 ⁇ 3) -0- ( ⁇ one D-galactoviranosyl) one (1 ⁇ 3) 1
  • HUVEC HUVEC
  • RPMI / FCS / HEPES medium RPMMI-1640, 10% FCS , 25mM HEPES, pH7.4
  • 10 U / RPM ⁇ of RPMI / FCS / HEPES containing IL-1 ⁇ was added, and the mixture was incubated at 4 o'clock (activation).
  • HUVECs were washed three times with 100 ⁇ l of RPMI / FCS / HEPES and 50 ⁇ l of RPMI / FCS / HEPES (Control) or a compound of 501 dissolved in RPMI / FCS / HEPES ( (300 g / ml) and incubated for 30 minutes at room temperature.
  • the immobilized HL60 cells 50 ⁇ l were added to each well and incubated at room temperature for 45 minutes.
  • Each well was filled with RFMI / FCS / HEPES, sealed using a microplate seal to prevent air bubbles from entering, the plate was inverted, and left undisturbed for 1 hour to remove unbound HL60 cells.
  • the number of adherent cells was determined by the activity of myelin peroxidase ( ⁇ ), an enzyme present in HL60 cells. Add 50 ⁇ l of a phosphate buffer (50 mM, ⁇ 6.0) containing 0.5% hexadecyltrimethylammonium bromide ( ⁇ ) to each well, and incubate for 30 minutes at room temperature to remove ⁇ from the cells. Was solubilized. At the same time, a known number of HL60 cells treated in the same manner were prepared in a row of 96 ⁇ elburate as a standard.
  • ⁇ myelin peroxidase
  • Example 1 of the present invention inhibited cell adhesion by 41% (P ⁇ 0.01).
  • the compound of Example 2 of the present invention inhibited cell adhesion by 63% (F ⁇ 0.01).
  • the compound according to the present invention exhibited a strong cell adhesion inhibitory action. From these results, it was shown that the compound according to the present invention is useful as a medicament for preventing and treating diseases caused by cell adhesion, such as inflammation, immune disease, and viral infection.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé représenté par la formule générale (I), dans laquelle R1 représente alkyle C¿8?-C30, alcényle C8-C30 ou alcynyle C8-C30; et R?2¿ ainsi que R3 représentent chacun indépendamment galactosyle, sialylgalactosyle ou fucosyle. Ledit composé est utile dans le traitement d'inflammations accompagnées de la formation de thrombus, de l'asthme et de rhumatismes, ainsi que dans la prévention et le traitement de l'immunopathie et du cancer, du fait qu'il présente une activité inhibant l'adhésion cellulaire et inhibe la sécrétine par antagonisme.
PCT/JP1995/000609 1994-03-31 1995-03-30 Derive de moranoline Ceased WO1995026969A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP6331094 1994-03-31
JP6/63310 1994-03-31

Publications (1)

Publication Number Publication Date
WO1995026969A1 true WO1995026969A1 (fr) 1995-10-12

Family

ID=13225592

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1995/000609 Ceased WO1995026969A1 (fr) 1994-03-31 1995-03-30 Derive de moranoline

Country Status (1)

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WO (1) WO1995026969A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998036757A1 (fr) * 1997-02-21 1998-08-27 Nippon Shinyaku Co., Ltd. Remede contre l'ulcere gastro-duodenal

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993015098A1 (fr) * 1992-01-31 1993-08-05 Nippon Shinyaku Co., Ltd. Derive d'une chaine de sucre du type lewis

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993015098A1 (fr) * 1992-01-31 1993-08-05 Nippon Shinyaku Co., Ltd. Derive d'une chaine de sucre du type lewis

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998036757A1 (fr) * 1997-02-21 1998-08-27 Nippon Shinyaku Co., Ltd. Remede contre l'ulcere gastro-duodenal

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