WO1995026969A1 - Derive de moranoline - Google Patents
Derive de moranoline Download PDFInfo
- 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
Links
- LXBIFEVIBLOUGU-JGWLITMVSA-N duvoglustat Chemical class OC[C@H]1NC[C@H](O)[C@@H](O)[C@@H]1O LXBIFEVIBLOUGU-JGWLITMVSA-N 0.000 title claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 125000002446 fucosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O)[C@@H](O1)C)* 0.000 claims abstract description 3
- 125000002519 galactosyl group Chemical group C1([C@H](O)[C@@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 claims abstract description 3
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 42
- 230000021164 cell adhesion Effects 0.000 abstract description 10
- 206010028980 Neoplasm Diseases 0.000 abstract description 6
- 201000011510 cancer Diseases 0.000 abstract description 6
- 206010061218 Inflammation Diseases 0.000 abstract description 4
- 230000004054 inflammatory process Effects 0.000 abstract description 4
- 208000007536 Thrombosis Diseases 0.000 abstract description 3
- 125000003342 alkenyl group Chemical group 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 102100037505 Secretin Human genes 0.000 abstract 1
- 108010086019 Secretin Proteins 0.000 abstract 1
- 125000000304 alkynyl group Chemical group 0.000 abstract 1
- 208000006673 asthma Diseases 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- 229960002101 secretin Drugs 0.000 abstract 1
- OWMZNFCDEHGFEP-NFBCVYDUSA-N secretin human Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(N)=O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)C1=CC=CC=C1 OWMZNFCDEHGFEP-NFBCVYDUSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- -1 sialyl galactosyl Chemical group 0.000 description 31
- 229960002920 sorbitol Drugs 0.000 description 25
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 22
- 235000010356 sorbitol Nutrition 0.000 description 22
- 239000002253 acid Substances 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 19
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 17
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 11
- 239000007995 HEPES buffer Substances 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 5
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 5
- 230000001464 adherent effect Effects 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- KSMVZQYAVGTKIV-UHFFFAOYSA-N decanal Chemical compound CCCCCCCCCC=O KSMVZQYAVGTKIV-UHFFFAOYSA-N 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 239000000427 antigen Substances 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 239000003443 antiviral agent Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 208000026278 immune system disease Diseases 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- LXBIFEVIBLOUGU-UHFFFAOYSA-N Deoxymannojirimycin Natural products OCC1NCC(O)C(O)C1O LXBIFEVIBLOUGU-UHFFFAOYSA-N 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 2
- 229920001429 chelating resin Polymers 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 238000002523 gelfiltration Methods 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 2
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000001196 nonadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 231100000699 Bacterial toxin Toxicity 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 229930186217 Glycolipid Natural products 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102000006386 Myelin Proteins Human genes 0.000 description 1
- 108010083674 Myelin Proteins Proteins 0.000 description 1
- 239000004727 Noryl Substances 0.000 description 1
- 229920001207 Noryl Polymers 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 241000594009 Phoxinus phoxinus Species 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 102000003800 Selectins Human genes 0.000 description 1
- 108090000184 Selectins Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- GZCGUPFRVQAUEE-UHFFFAOYSA-N alpha-D-galactose Natural products OCC(O)C(O)C(O)C(O)C=O GZCGUPFRVQAUEE-UHFFFAOYSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000688 bacterial toxin Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000003493 decenyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000005066 dodecenyl group Chemical group C(=CCCCCCCCCCC)* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 210000005012 myelin Anatomy 0.000 description 1
- 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001736 nosyl group Chemical group S(=O)(=O)(C1=CC=C([N+](=O)[O-])C=C1)* 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000005063 tetradecenyl group Chemical group C(=CCCCCCCCCCCCC)* 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
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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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.
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 |
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ID=13225592
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1995/000609 WO1995026969A1 (fr) | 1994-03-31 | 1995-03-30 | Derive de moranoline |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO1995026969A1 (fr) |
Cited By (1)
| 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)
| 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 |
-
1995
- 1995-03-30 WO PCT/JP1995/000609 patent/WO1995026969A1/fr active Application Filing
Patent Citations (1)
| 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)
| 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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