WO1998036757A1 - Remede contre l'ulcere gastro-duodenal - Google Patents
Remede contre l'ulcere gastro-duodenal Download PDFInfo
- Publication number
- WO1998036757A1 WO1998036757A1 PCT/JP1998/000650 JP9800650W WO9836757A1 WO 1998036757 A1 WO1998036757 A1 WO 1998036757A1 JP 9800650 W JP9800650 W JP 9800650W WO 9836757 A1 WO9836757 A1 WO 9836757A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- force
- imino
- oxy
- stands
- sodium salt
- Prior art date
Links
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- 125000000400 lauroyl group Chemical group O=C([*])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
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 125000001802 myricyl 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])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
- 125000001419 myristoyl group Chemical group O=C([*])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
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- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 239000001120 potassium sulphate Substances 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
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- AAEVYOVXGOFMJO-UHFFFAOYSA-N prometryn Chemical compound CSC1=NC(NC(C)C)=NC(NC(C)C)=N1 AAEVYOVXGOFMJO-UHFFFAOYSA-N 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
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- 239000002893 slag Substances 0.000 description 1
- 238000009491 slugging Methods 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])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
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
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- 239000004094 surface-active agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
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- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005303 weighing Methods 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
Definitions
- the present invention relates to a prophylactic or therapeutic agent for peptic ulcer comprising a Lewis-type sugar chain derivative as an active ingredient.
- the medicament according to the present invention suppresses peptic mucosal damage caused by activated leukocytes, prevents or treats ulcers, and is useful as an agent for preventing or treating ulcer recurrence.
- a Lewis-type sugar chain moranoline derivative binds to selectin to competitively inhibit leukocyte cell adhesion, thus preventing and treating inflammation and thrombus, rheumatism, asthma and immune diseases associated with inflammation.
- a patent application was filed as an agent (International Publication W093 / 85098).
- applications such as International Publication WO94 / 05152 and International Publication WO95 / 04751 have been filed, and there are descriptions on anti-inflammatory agents, therapeutic agents for immunological diseases, and anti-cancer agents.
- Lewis-type sugar chain derivatives which are anti-selectin agents, are effective in the prevention and treatment of peptic ulcers. There is no known preventive or therapeutic method.
- Causes of peptic ulcers include high acidity of stomach acid, increased autonomic nervousness, impaired blood circulation in the stomach wall, and stress.
- the anti-ulcer agent have demulcent that suppresses aggressive factors suppression agent gastric acid secretion to protect the mucosa, aggressive factors inhibitor called with H 2 blockers and proton Pont Bed inhibitors are currently used frequently.
- leukocytes when activated, release neutrophil elastase and reactive oxygen species, damage nearby vascular endothelial cells and tissues, and cause inflammation at the site.
- Gastric mucosal microcirculation is important in preventing gastric acid reverse diffusion, but activated eukaryotic leukocytes increase microcirculatory susceptibility to gastric mucosal damage caused by gastric acid when inflammation is induced.
- activated eukaryotic leukocytes increase microcirculatory susceptibility to gastric mucosal damage caused by gastric acid when inflammation is induced.
- There is a good possibility Abe H., Okajima. K., Okabe, ⁇ ⁇ , Takatsuki, ⁇ . And Binder, BR. J. Lab Clin. Med. 123: 874-881. 1994).
- the present invention provides a Lewis-type sugar chain derivative as a prophylactic or therapeutic agent for peptic ulcer (hereinafter referred to as a prophylactic / therapeutic agent) which is a novel use which has not been known before.
- a composition comprising a compound represented by the following general formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient prevents peptic ulcer.
- the present invention is a prophylactic / therapeutic agent for peptic ulcer comprising a Lewis-type sugar chain derivative represented by the following general formula [I] as an active ingredient.
- A— is one (CH i-, one (CH ⁇ n-NR e _CO_0—, one CO—0_, one (CH ⁇ n—CO—0—, or — (represents CH ⁇ n-0_ R e represents a hydrogen atom or lower alkyl, m represents an integer of 0 to 12, and n represents an integer of 2 to 12).
- R a and R b are the same or different and represent a saturated or unsaturated aliphatic hydrocarbon group or a saturated or unsaturated acyl group.
- W and Y are different from each other, one represents 1-galactopyranosyl and the other represents 1-fucopyranosyl.
- the 1-galactosamine Topiranoshiru a hydrogen atom of the 3-position of the water » is one S0 3 H, one CH 2 COOH, or
- R c and R d are the same or different and each represents a lower alkyl, a lower alkenyl, or a hydroxyl group).
- a and R together represent alkyl, alkenyl, alkynyl, alkoxycarbonyl, or aralkyl, both of which may be substituted.
- the Lewis-type sugar chain derivative according to the present invention includes a sialyl Lewis-type sugar chain derivative represented by any of the following general formulas [II] and [III].
- E is a straight-chain or branched-chain alkyl having 1 to 30 carbon atoms, an alkenyl having 2 to 30 carbon atoms or an alkynyl having 2 to 30 carbon atoms, and Substituted with an alkoxycarbonyl having 2 to 30 carbon atoms, an alkoxyalkoxyalkyl having 3 to 30 carbon atoms, an alkoxyalkoxyalkamidoalkyl having 5 to 30 carbon atoms, or benzyl substituted with an alkoxy having 1 to 20 carbon atoms.
- Moranolin or GlcNAc ⁇ (l-3) Gal ⁇ (l ⁇ l) OEt When E is GlcNAc ⁇ (l ⁇ 3) Gal ⁇ (l ⁇ l) OEt, Fuc in the formula is bound to GlcNAc.
- Neu5Ac stands for sialic acid
- Gal stands for power
- lactose GlcNAc stands for N-acetylc '
- lucosamine GlcNAc stands for N-acetylc '
- Fuc stands for refucos
- OEt stands for ethoxy (the same applies hereinafter).
- Q is a straight-chain or branched-chain alkyl atom having 1 to 30 carbon atoms, alkyl having 2 to 30 carbon atoms, alkenyl having 2 to 30 carbon atoms, or alkynyl having 2 to 30 carbon atoms. Substituted with an alkoxycarbonyl having 2 to 30 carbon atoms, an alkoxyalkoxyalkyl having 3 to 30 carbon atoms, an alkoxyalkoxyalkoxyamide alkyl having 5 to 30 carbon atoms, or benzyl substituted with an alkoxy having 1 to 20 carbon atoms. Represents molanolin or GlcNAc which may be present.
- GlcNAc molanolin
- the "saturated or unsaturated aliphatic hydrocarbon group” includes linear or branched ones having 1 to 30 carbon atoms, for example, pentyl, hexyl, octyl, decyl, dodecyl , Tetradecyl, palmityl, stearyl, icosanil, docosanil, tetracosanil, hexakosanil, octacosanil, isohexyl, 9-dodecenyl, 9-tetradecenyl, 9-hexadecenyl, 6-octadecenyl, oleyl, 9-docosenyl, 13-docosenyl, Examples thereof include linoleyl, 7-linolenyl, and monolinolenyl. Among them, linear alkyl or alkenyl having 12 to 20 carbon atoms is preferable.
- saturated or unsaturated acyl includes linear or branched ones having 1 to 30 carbon atoms, such as, for example, norrelyl, isovaleryl, hexanoyl, octactyl, decanoyl, lauroyl, and myristoyl. , ⁇ perimitoyl, stearoyl, oleoyl, 6-octadecenoyl, 13-docosenoyl, arakidoyl, eridoyl, 9,12-octadecadienol, 6,9,12-octadecatrienoyl, 9,12,15- Octadecatrienol. Of these, straight-chain C12-20 acyl is preferred.
- examples of the “lower alkyl” of lower alkyl and lower alkylthio, lower alkylamino and lower alkoxy include, for example, linear or branched ones having 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl and hexyl.
- examples of the “lower alkenyl” include straight-chain or branched-chain ones having 2 to 6 carbon atoms. Representative examples thereof include vinyl, aryl, propyl, and isopropyl. , 2-butenyl, 2-pentenyl and 2-hexenyl.
- examples of the “alkyl” represented by A and R together include a linear or branched alkyl having 1 to 30 carbon atoms, such as methyl, ethyl, propyl, isopropyl, and the like.
- alkyl represented by A and R together includes an alkyl substituted with a 5-membered unsaturated heterocyclic ring which is unsubstituted or substituted with lower alkyl.
- 5-member ring As the hetero atoms of the unsaturated heterocyclic ring, there can be mentioned those having 1 or 2 carbon atoms, oxygen and nitrogen.
- thiophene, furan, pyrrol, or imidazole can be mentioned.
- furfuryl, 5-methyl-furfuryl, 2-thenyl, 5-methyl-2-thenyl and the like are preferable.
- alkenyl represented by A and R together includes alkenyl having 3 to 30 carbon atoms, and is preferably aryl, oleyl, vaccenyl, linoleyl, or arachidonyl s.
- examples of the “alkynyl” represented by A and R together include an alkynyl having 3 to 30 carbon atoms, for example, 2-propyl, 3-butynyl, 2-octynyl, 9-decynyl , 9-year-old kutadecinyl, 9-pentacosynyl and the like.
- alkoxycarbonyl represented by A and R together includes those having 2 to 30 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, octyloxycarbonyl, Siloxycarbonyl, pentadecyloxycarbonyl and the like are preferred.
- examples of "aralkyl” represented by A and R together include benzyl which may be substituted with alkoxy having 1 to 20 carbon atoms, such as methoxybenzyl, propoxybenzyl, Pentyloxybenzyl, heptoxybenzyl, nonyloxybenzyl, pendecyloxybenzyl, tridecyloxybenzyl, pentadecyloxybenzyl, heptadecyloxybenzyl, eicosiloxybenzyl and the like are preferable, and hexyloxybenzyl is particularly preferable.
- a benzene ring is unsubstituted, or as at least one substituent, a hydroxyl group, a lower alkoxy having 1 to 6 carbon atoms, a lower alkyl, a lower alkylamino, a halogen, a cyano , Carbamoyl, nitro, substituted with C 2 -C 6 acylamino lower alkyl, lower alkylthio or carboxy, C 7 And lower phenyl lower alkyl.
- m-methoxyphenethyl, P-fluorophenethyl, 4- (m-dimethylaminophenyl) butyl, 5- (m-cyanophenyl) pentyl, 6- (P-carbamoylphenyl) hexyl, 3- ( 2,4-Dinitrophenyl) propyl is preferred, and in particular, (3,4-dihydroxyphenyl) propyl, (4-hydroxy-3-methoxyphenyl) propyl, P-methylbenzyl, m-bromobenzyl and P- Xyloxybenzyl, m- (propionylaminomethyl) benzyl, P- (norrelylaminoethyl) phenethyl, 4- (3-methylthio-4-hydroxyphenyl) butyl and P-carboxybenzyl are preferred.
- the compound according to the present invention can be used for treatment as it is, but can be used in the form of a pharmaceutically acceptable salt by a known method.
- pharmaceutically acceptable salts include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, acetic acid, citric acid, sake, maleic acid, succinic acid, fumaric acid, and P-toluene.
- examples thereof include salts of organic acids such as sulfonic acid, benzenesulfonic acid, and methanesulfonic acid.
- an alkyl metal salt such as a lithium salt, a sodium salt, and a potassium salt
- a magnesium salt such as a calcium salt
- Alkaline earth metal salts can be mentioned.
- the hydrochloride can be obtained by dissolving the compound of the present invention in an alcohol solution of hydrochloric acid.
- Some unsaturated aliphatic hydrocarbon groups or unsaturated acyl groups have E and Z isomers, both of which are included in the present invention.
- Pill [(2,3-Si ', ore W “xy”). Pill] -1,5-te, oxy-1,5-imi D-co, and sodium salt
- Mouth pill -1,5-de, oxy-1,5-imino-D-quin 'sodium salt 0- (3-0-S ⁇ --D-force, Lactohi.lanosyl)-(l ⁇ 4) -0- [(a -L-fucopyranosyl)-(1 ⁇ 3)] - ⁇ - [3- [ ⁇ - [(1,3-si, Lauroy W. Xif. ⁇ ha.n-2-yl) oxy; / * ,, nil] amino] f. Mouth pill]-1,5-siloxane, tert-oxy-1,5-imino-D- ,, renthol sodium salt
- Pill-D- 0- (3-0- ⁇ ⁇ - ⁇ -D-force, lactopyranosyl)-(1 ⁇ 4)-0- [(a-L-fucopyral)-(1 ⁇ 3)]-1,5-cy ,,,,,,,,,,,,, 5-imino-N- (2,3-cy, human ,, D xyphenyl). Pill-D- ;; Lenthol sodium salt
- Preferred compounds of the present invention include, for example, 0- (3-0- ⁇ ⁇ -D-force, 'lactoviranosyl)-(1 ⁇ 3) -0-[( ⁇ -lefcoviranosyl)-(1 ⁇ 4)]- ⁇ - [1- (2,3-shi, olay; W xy).
- Mouth pill -1,5-the ', oxy-1,5-imino-D-co,> sodium sodium salt, 0- (3-0-su,-/ 3-D-force), lactoviranosyl )-(1 ⁇ 4) -0- [( ⁇ -lefucoviranosyl)-(1 ⁇ 3)]- ⁇ - [3- [ ⁇ - [(1,3-si, oleoyl, a good kiss. 2-yl) oxy power. Mouth pill] -1,5-si, te, oxy-1,5-imino-D-, lentol sodium salt.
- the compounds according to the present invention include, for example, the methods described in Japanese Patent Application No. 8-155801, Japanese Patent Publication No. 59-43459, International Publication W095 / 83068, Japanese Patent Application Laid-Open No. 61-205455, and the like. It can be manufactured according to. Further, the compounds according to the present invention have extremely low toxicity.
- the compound of the present invention when administered as a prophylactic / therapeutic agent for peptic ulcer, it can be used alone, or in combination with or mixed with a medicament that can be administered simultaneously.
- the compound of the present invention is used as a pharmaceutical composition containing, as it is or in a pharmaceutically acceptable nontoxic and inert carrier, for example, 0.01% to 99.5%, preferably 0.1% to 90%. Can be administered.
- 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 (such as transdermally), or rectally. Needless to say, it is administered in a dosage form suitable for these administration methods.
- oral administration or intravenous administration is preferred.
- the amount of the active ingredient of the present invention is generally in the range of 10 mg / day to 10 mg / day, preferably in the range of 100 mg to 5 g / day. In some cases, lower doses may be sufficient, and conversely, higher doses may be required. It is also desirable to administer the drug divided into two or three times a day.
- solid or liquid dosage units such as powders, powders, fine granules, tablets, dragees, films, capsules, granules, suspensions, liquids, syrups, drops, sublingual tablets It can be done with other dosage forms.
- Powders are prepared by comminuting the compound of the present invention to an appropriate degree. Powders are prepared by comminuting the compound of the present invention with a suitable finely divided material and then admixing it with a similarly finely divided pharmaceutical carrier, such as edible carbohydrates such as starch and mannitol. If necessary, flavoring agents, preservatives, dispersing agents, coloring agents, flavors and the like may be added.
- Capsules are prepared by first filling powdered powders, powders or granules as described in the section on tablets as described above into a forcepsel shell, such as gelatin forcepsels. Manufactured. Lubricants and superplasticizers such as colloidal silica, talc, magnesium stearate, calcium stearate, and solid polyethylene glycol are mixed with the powdered state, and then the filling operation is performed. You can also do it.
- disintegrants and solubilizers such as carboxymethylcellulose, carboxymethylcellulose, calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, sodium carboxymethyl starch, calcium carbonate, sodium carbonate This would improve the efficacy of the medicament when the forcepsel was taken.
- the fine powder of the compound of the present invention is suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and a surfactant, and this is wrapped in a gelatin sheet to form a soft capsule.
- Tablets are prepared by adding an excipient to form a powder mixture, granulating or slugging, and then adding a disintegrant or lubricant or by tableting the powder mixture directly.
- the powder mixture is prepared by mixing the appropriately powdered substance with the above-mentioned diluents and bases and, if necessary, binding agents (eg, sodium carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, poly).
- the powder mixture can be first moistened with a binder such as syrup, starch paste, acacia, cellulose solution or polymer solution, stirred and mixed, dried and ground to form granules.
- a binder such as syrup, starch paste, acacia, cellulose solution or polymer solution, stirred and mixed, dried and ground to form granules.
- the granules thus produced can be prevented from adhering to each other by adding stearic acid, stearic acid salts, talc, mineral oil and the like as a lubricant.
- the mixture thus lubricated is then tableted.
- the uncoated tablets thus produced can be coated with a film or coated with sugar.
- the compound according to the present invention may be directly tableted after mixing with a fluid inert carrier without going through a granulating / slagging step as in the following.
- a transparent or translucent protective coating consisting of a shellac hermetic coating, or alternatively or on top of it, a coating of sugar or a polymeric material, and a polish coating of wax can also be used.
- compositions such as solutions, syrups, elixirs and the like can also be presented in dosage unit form so that a given quantity contains a certain amount of the compound according to the invention.
- Syrups are prepared by dissolving the compound of the present invention in an aqueous solution containing a suitable sweetening agent, and elixirs are prepared by using a non-toxic alcoholic carrier.
- Suspensions are formulated by dispersing the compound of the invention in a non-toxic carrier.
- Solubilizers and emulsifiers eg For example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavor enhancers (eg, palmit oil, saccharin) and the like can also be added as needed.
- emulsifiers eg For example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters, preservatives, flavor enhancers (eg, palmit oil, saccharin) and the like can also be added as needed.
- dosage unit formulations for oral administration can be microencapsulated.
- the formulation can also provide a prolonged action or sustained release by coating or embedding in a polymer or the like.
- Administration into tissues can be performed by using a liquid dosage unit form for subcutaneous, intramuscular or intravenous injection, for example, a solution or suspension.
- a liquid dosage unit form for subcutaneous, intramuscular or intravenous injection for example, a solution or suspension.
- a fixed amount of the compound of the present invention is suspended or dissolved in a non-toxic liquid carrier suitable for injection, such as an aqueous or oily medium, and the suspension or solution is sterilized. It is manufactured by Non-toxic salts or salt solutions may be added to make the injection solution isotonic.
- Rectal administration can be carried out by preparing the compound of the present invention as a solid soluble or insoluble in water having a low melting point and using a suppository.
- the present invention will be described more specifically with reference to formulation examples and test examples of the preparation of the compound according to the present invention, but the present invention is not limited thereto.
- the compound A of the present invention 0- (3-0-sulfo- / 3-D-force, lactovilanosyl)-(1 ⁇ 4) -0-[( ⁇ -lefcoviranosyl)-(1 ⁇ 3)]- ⁇ -[4- ⁇ -[(1,3-cyleoleoxy 7 ° roha.n-2-yl) oxylity 1 ⁇ 2 ,, nil] aminop, tyl] -1,5-si ', te ,, Oxy-1,5-imino-D-coke,> sodium sodium salt was used.
- Manesium stearate 5mg After weighing and mixing at a ratio of, the tablets are manufactured using a tableting machine.
- the compound of the present invention is dissolved in physiological saline to make a 1 OW / V /% solution. After filtering this solution through a membrane filter and a run filter, fill in 1 ml, 2 ml, 5 ml, 10 ml or 20 ml aliquots according to each volume, sterilize in autoclave, and inject. To manufacture.
- Compound A of the present invention was dissolved in a 5% glucose solution, and administered via tail vein (15 mg kg) immediately before indomethacin administration.
- the control group received only a 5% solution of potassium sulphate.
- famotin injection an anti-ulcer drug, was diluted with saline, and the tail vein was administered at a dose of lmg / kg. More injected.
- T-Se T-Se was evaluated by measuring the activity (hereinafter referred to as MPO).
- MPO the activity
- 3 hours after oral administration of indomethacin the removed stomach was transferred to a centrifuge tube, and 5 ml of a 50 mM potassium phosphate buffer (pH 6.0) containing 1% bromide hexate and siltrimethylammonium was added.
- the cells were crushed with a lithotron (Nilion) (20,000 rpm, 4 times for 10 seconds).
- the stomach tissue crushed liquid was treated three times for 10 seconds in an ultrasonic cleaner, and then centrifuged at 3,000 (3,000 rpm, 30 minutes).
- the lesion index after oral administration of indomethacin (30 mg / kg) was 36 mm as shown in FIG.
- the compound A of the present invention 15 mg / kg was administered immediately before administration of indomethacin, the lesion index was reduced to 10 mm (p ⁇ 0.05). This value was almost the same as the index (approximately 7 mm) for the group treated with famotitis and the parent drug.
- MPO is an enzyme located in neutrophils, and this increased enzymatic activity reflects increased neutrophil accumulation.
- the group administered with indomethacin alone showed an increase in MPO activity. Its activity was about three times that of the group that received saline instead of indomethacin (p ⁇ 0.05).
- Compound A of the present invention suppressed the increase of MPO activity by indomethacin to about the same level as the physiological saline administration group (p-0.05).
- famotin significantly increased the MPO activity, which was 1.5 times higher than that of the group administered with indomethacin alone (5%, lucose).
- FIG. 1 is a view showing a comparison of the lesion index between the compound A of the present invention and famotin.
- FIG. 2 is a graph showing a comparison of the MPO activities of gastric mucosa of compound A of the present invention and famotin.
- N indicates the number of animals used.
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Abstract
L'invention concerne un agent prophylactique ou thérapeutique contre l'ulcère gastro-duodénal, comprenant un dérivé de moranoline asialotrisaccharidique représenté par la formule générale (I), un sel acceptable sur le plan pharmaceutique de celui-ci ou un solvate du dérivé ou du sel, formule dans laquelle -A- représente -(CH2)m-, -(CH2)n-NRe-CO-O-, -CO-O-, -(CH¿2?)n-CO-O-, ou -(CH2)n-O- (où R?e¿ représente un atome d'hydrogène ou un alkyle inférieur; m représente un nombre entier compris entre 0 et 12 et n représente un nombre entier compris entre 2 et 12); R représente (a) ou (b) (où Ra et Rb peuvent être identiques ou différents et ils représentent chacun un groupe hydrocarbure aliphatique saturé ou insaturé ou un groupe acyle saturé ou insaturé); et W ainsi que Y sont différents, l'un représente 1-galactopyranosyle et l'autre représente 1-fucopyranosyle, à condition que l'atome d'hydrogène du groupe hydroxyle en position 3 de 1-galactopyranosyle puisse être substitué par n'importe quel groupe choisi parmi (IV) (où Rc et Rd peuvent être identiques ou différents et représentent chacun un alkyle inférieur, alcényle inférieur ou un groupe hydroxyle).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9/38105 | 1997-02-21 | ||
| JP3810597 | 1997-02-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1998036757A1 true WO1998036757A1 (fr) | 1998-08-27 |
Family
ID=12516201
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1998/000650 WO1998036757A1 (fr) | 1997-02-21 | 1998-02-16 | Remede contre l'ulcere gastro-duodenal |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO1998036757A1 (fr) |
Citations (5)
| 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 |
| WO1995013068A1 (fr) * | 1993-11-12 | 1995-05-18 | Nippon Shinyaku Co., Ltd. | Composition medicamenteuse pour la circulation |
| WO1995025113A1 (fr) * | 1994-03-15 | 1995-09-21 | Sloan-Kettering Institute For Cancer Research | Composes synthetiques qui se fixent a h. pylori, et utilisations de ces composes |
| WO1995026969A1 (fr) * | 1994-03-31 | 1995-10-12 | Nippon Shinyaku Co., Ltd. | Derive de moranoline |
| WO1995026970A1 (fr) * | 1994-04-01 | 1995-10-12 | Nippon Shinyaku Co., Ltd. | Derive de moranoline |
-
1998
- 1998-02-16 WO PCT/JP1998/000650 patent/WO1998036757A1/fr active Application Filing
Patent Citations (5)
| 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 |
| WO1995013068A1 (fr) * | 1993-11-12 | 1995-05-18 | Nippon Shinyaku Co., Ltd. | Composition medicamenteuse pour la circulation |
| WO1995025113A1 (fr) * | 1994-03-15 | 1995-09-21 | Sloan-Kettering Institute For Cancer Research | Composes synthetiques qui se fixent a h. pylori, et utilisations de ces composes |
| WO1995026969A1 (fr) * | 1994-03-31 | 1995-10-12 | Nippon Shinyaku Co., Ltd. | Derive de moranoline |
| WO1995026970A1 (fr) * | 1994-04-01 | 1995-10-12 | Nippon Shinyaku Co., Ltd. | Derive de moranoline |
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