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WO1999047542A1 - Medicaments contenant en tant que principe actif des composes steroides glycosyles substitues en position 21 - Google Patents

Medicaments contenant en tant que principe actif des composes steroides glycosyles substitues en position 21 Download PDF

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Publication number
WO1999047542A1
WO1999047542A1 PCT/JP1999/001407 JP9901407W WO9947542A1 WO 1999047542 A1 WO1999047542 A1 WO 1999047542A1 JP 9901407 W JP9901407 W JP 9901407W WO 9947542 A1 WO9947542 A1 WO 9947542A1
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WO
WIPO (PCT)
Prior art keywords
bud
group
compound
ethyl acetate
stirred
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/JP1999/001407
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English (en)
Japanese (ja)
Inventor
Takayuki Ishii
Shigeki Nunomura
Masaaki Numata
Masami Iida
Noriko Tanaka
Chiaki Sato
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.)
NISSIN FOOD PRODUCTS CO Ltd
Nissin Food Products Co Ltd
Original Assignee
NISSIN FOOD PRODUCTS CO Ltd
Nissin Food Products 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 NISSIN FOOD PRODUCTS CO Ltd, Nissin Food Products Co Ltd filed Critical NISSIN FOOD PRODUCTS CO Ltd
Publication of WO1999047542A1 publication Critical patent/WO1999047542A1/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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin

Definitions

  • the present invention relates to a medicament which is mainly used as a therapeutic agent for asthma and is suitable as an anti-inflammatory agent for topical application, mainly comprising a compound in which the 21-position of a steroid compound is substituted with an acylated simple sugar.
  • the sugar-steroid compounds described in the above-mentioned documents have reduced side effects of the steroid compounds, they are still insufficient and need to be improved.
  • the present inventors also synthesized a compound in which a simple sugar was introduced into steroid and a glycosyl sulfide derivative in which the hydroxyl group of the simple sugar was modified with an acetyl group, and examined the pharmacological action. Confirmed that it was almost the same as the main body. This is presumably because simple sugars or acetylglycosyl derivatives thereof readily release the aglycone steroids by glycosidase which is generally present in vivo.
  • the present inventors have proposed modifying the hydroxyl group of a simple sugar in a sugar-steroid compound with a bulky protecting group, and have already proposed an international patent application (international publication number: WO 95 / 09 1 77).
  • the hydroxyl group of the simple sugar in the sugar-steroid compound is, for example, an arylcarbonyl group such as a toluoyl group (ortho, meta or paramethylbenzoyl group) or a benzoyl group, or a benzyl group. It is modified with an arylalkyl group such as a Z group or a bulky protecting group such as a parabenzoyl group. By doing so, the release of steroids due to glycosidases at sites other than the pathological site is suppressed, and side effects can be reduced.
  • an anti-inflammatory agent suitable as a therapeutic agent for asthma needs to have a stronger local anti-inflammatory action than a normal anti-inflammatory agent, and have a considerably lower toxicity.
  • an anti-inflammatory agent suitable as a therapeutic agent for asthma needs to have a stronger local anti-inflammatory action than a normal anti-inflammatory agent, and have a considerably lower toxicity.
  • anti-inflammatory agents suitable for the treatment of asthma, other allergic rhinitis and rheumatism must be low-toxic and have a strong local action. We have to go. Disclosure of the invention
  • the present invention has been made in view of the above problems, and has as its object to develop a compound suitable as an anti-inflammatory agent suitable for topical application (anti-inflammatory agent for topical application), particularly for asthma
  • Another object of the present invention is to provide an anti-inflammatory agent for topical application suitable as a therapeutic agent for allergic rhinitis rheumatism.
  • the present invention provides a medicine containing an effective amount of a specific compound group selected from the following compound groups of A and B.
  • R is a bulky functional group.
  • X is one 0—, — S— or one NH—
  • Y is -0-, one S- or one NH-
  • R is a bulky functional group
  • Q is one CH 2 -,-CH 2 CH, one, one 0-or one S-.
  • the present invention provides the following drugs.
  • a medicament comprising, as an active ingredient, a compound having a structure of “21-position carbon—X—sugar residue—Y—CZ—R of a readily metabolizable steroid compound”.
  • X is 0—, —S— or NH—
  • Y is one 0—, — S— or one NH—
  • R is a phenyl group.
  • the sugar is a monosaccharide selected from the group consisting of glucose, galactose, mannose, N-acetylglucosamine, N-acetylgalactosamine, glucuronic acid, galacturonic acid, fucose, rhamnose, arabinose, xylose and sialic acid;
  • the medicament according to any one of (1) to (3), which is a 2,3-dehydro form of a monosaccharide selected from the group.
  • the drug according to any one of (1) to (3), wherein the sugar is glucose.
  • the sugar is glucose, galactose, mannose, N-acetylglucosamine, N-acetylgalactosamine, glucuronic acid, galacturonic acid, fucose, rhamnose, arabinose, xylose, sialic acid, or a 2,3-deoxysaccharide of these monosaccharides.
  • the medicament according to any one of (1) to (3), which is an oligosaccharide containing a monosaccharide selected from the group consisting of hydro bodies as a constituent.
  • oligosaccharide is an oligosaccharide having 2 to 6 monosaccharides.
  • the term “easily metabolizable steroid compound” refers to a steroid compound that is normally metabolized in a living body for about 2 to 3 hours.
  • Budesonide is a typical example of a readily metabolizable steroid compound, but it is not limited to pudesonide, and any steroid compound that is metabolized in a living body in about 2 to 3 hours can be used. Good.
  • the term “bulky functional group” refers to, for example, a secondary or tertiary alkyl group (eg, an isobutyl group, an isopentyl group, an isohexyl group, a trimethylmethyl group).
  • a secondary or tertiary alkyl group eg, an isobutyl group, an isopentyl group, an isohexyl group, a trimethylmethyl group.
  • a cyclic alkyl group for example, a cyclopentyl group, a cyclohexyl group, a 4-aminocyclohexyl group, an adamantyl group
  • an aromatic group for example, a heterocyclic group.
  • the aromatic group may have a substituent such as a halogen atom, an alkyl group, an electron donating functional group (for example, an amino group, a hydroxy group, a methoxy group, an ethoxy group) or an aromatic group.
  • the aromatic ring may have a hetero atom such as nitrogen or oxygen.
  • Asyl groups of such compounds include toluoyl group (ortho, meta, para), benzoyl group, naphthyl group ((hi,?)), Terephthalyl group, methylterephthalyl group, nicotinol group, isonicotinoyl group, para-yl group.
  • any of the above alkyl groups may be unsaturated as well as saturated.
  • one isobutylene or one isobutylyne may be used.
  • not only a straight chain but also a branch may be present.
  • the cyclic alkyl group may have a branch and may contain an unsaturated bond.
  • the saccharide linked to position 21 of the easily metabolizable steroid compound may be a monosaccharide or an oligosaccharide.
  • the number of carbon atoms of the constituent monosaccharides of the monosaccharide or oligosaccharide is not particularly limited. Either xose, heptose or octose can be used. In this case, for example, in the case of hexose, any of agarose, altrose, glucose, galactose, gulose, eidose, mannose and evening loose can be used.
  • the glycoside may be in the form of a solid body or a body.
  • the oligosaccharide is preferably an oligosaccharide having 2 to 6 monosaccharides, which may be a hetero-oligosaccharide or a homo-oligosaccharide.
  • the monosaccharides and oligosaccharides may be in the dehydro form as already described, and when it is the 2,3-dehydro form, it is particularly suitable in practice.
  • any form of the drug or anti-inflammatory agent can be used as long as it is suitable for topical application.
  • the effective amount of the drug or anti-inflammatory agent is appropriately determined in consideration of the activity of the compound and the like. .
  • FIG. 1 is a diagram showing an example compound according to the present invention.
  • FIG. 2 is a view showing an example compound according to the present invention.
  • FIG. 3 is a view showing an example compound according to the present invention.
  • FIG. 4 is a view showing an example compound according to the present invention.
  • FIG. 5 is a view showing an example compound according to the present invention.
  • FIG. 6 is a view showing an example compound according to the present invention.
  • FIG. 7 is a view showing an example compound according to the present invention.
  • FIG. 8 is a diagram showing a sugar donor according to the example compound of the present invention.
  • FIG. 9 is a diagram showing a sugar donor according to an example compound according to the present invention.
  • Drugs or anti-inflammatory agents containing the above compounds can be used alone or in combination as ointments, creams, lotions, and tapes (external coatings only) for the skin.
  • the compound of the present invention not only has an effect of inhibiting the production of granuloma growth and an effect of inhibiting croton oil ear edema, but also the body weight and thoracic weight due to drug administration or application. It has little effect on spleen weight, adrenal weight and white blood cell count, is less toxic than conventional steroids, and is safer.
  • the compounds according to the present invention include eczema, dermatitis group (including progressive keratoderma dermatosis, female melanosis of the face, lichen wisdom, radioactive dermatitis, and sun dermatitis), pruritus skin, and prurigo group Lichen measles, stroflus, fixed urticaria, insect bites, psoriasis, palmar pustulosis, lichen planus, lichen lichen, ciliated red pityriasis, gibberella pityriasis, erythema ( Malignant lymphoma due to erythroderma), chronic discoid lupus erythematosus, drug eruptions, poisoning eruptions, alopecia areata, burns (including scars, keloids), erythema, jubiling herpes dermatitis (pemphigoid (Including acne), hemorrhoids, tympanic plastic surgery, inner
  • the compound according to the present invention can be applied to colitis by oral administration, but the local action and effect of the compound according to the present invention can be more exerted by topical administration in the form of a laxative or the like.
  • the anti-inflammatory agent for topical application according to the present invention is suitable for a therapeutic agent for asthma, a therapeutic agent for allergic rhinitis, a therapeutic agent for rheumatism, or a therapeutic agent for dermatitis because of its strong local action, and at the same time, has low toxicity.
  • it is particularly suitable as a therapeutic agent for asthma.
  • a therapeutic agent for asthma it is administered by inhalation
  • when it is used as a therapeutic agent for allergic rhinitis it is administered by instillation
  • it is used as a therapeutic agent for rheumatism it is administered into the joint cavity.
  • Administer or apply the drug when using as dermatitis, apply the therapeutic agent.
  • the above compound is obtained by protecting a hydroxyl group of a simple sugar or an acylated sugar of a simple sugar as a starting material with a toluoyl group or an acetyl group, and then halogenating this anomeric position. It can be obtained by reacting a molecular sieve with a steroid compound such as budesonide in the presence of a Lewis acid such as silver carbonate, silver triflate, silver perchlorate or tin tetrachloride.
  • a Lewis acid such as silver carbonate, silver triflate, silver perchlorate or tin tetrachloride.
  • the above compound can be easily deprotected by deprotection using MeONa / MeOH, an aqueous sodium hydroxide solution or the like.
  • D-galactose sugar donor 340 mg, 0.55 mol
  • budesonide 215 mg, 0.5 mmol
  • MS 4 A lg
  • Silver triflate 200 mg, 0.78 ol
  • dichloromethane 2 mL
  • This tetraol compound (76 mg, 0.13 mmol) was dissolved in pyridine (5 mL), and 2-furoyl chloride (33.4 mg, 2.56 mmol) and a catalytic amount of 4-dimethylaminopyridine were added. Stirred. Methanol was added to the reaction solution, and the mixture was stirred for 30 minutes and dried under reduced pressure. The residue was purified by silica gel column chromatography (75 g, toluene / ethyl acetate, 2: 1) and then by Sephadex LH-20 (methanol) to obtain a compound (57 mg, 50%).
  • the tetraol compound (77 mg, 0.13 bandol) synthesized in Example 12 was dissolved in pyridine (5 mL), and isoptyryl chloride (292 l, 2.80 mmol) and a catalytic amount of 4-dimethylaminopyridine were added. Stir for 42 hours. Add methanol to the reaction mixture and stir for 30 minutes. After stirring, the mixture was dried under reduced pressure. The residue was purified by silica gel column chromatography (75 g, toluene / ethyl acetate, 3: 1) and then purified by Sephadex LH-20 (methanol) to obtain Compound 13 (44 mg, 39 mg).
  • a D-lactose sugar donor (1.07 g, 1.0 t ol) and budesonide (430 mg, 1.0 t ol) were dissolved in dichloromethane (20 mL), and the mixture was dissolved at room temperature under a stream of argon with MS 4A (lg). Stirred for 10 minutes. To this reaction solution was added silver triflate (385 mg, 1.50 ol), and the mixture was added at room temperature.
  • Example 21 B ⁇ 22S, 22R D-glucose sugar donor 1 (15.2 g, 23.1 tmol) and budesonide (6.0 g, 13.9 ⁇ 01) were dissolved in dichloromethane (10 mL), and the mixture was stirred with MS4A (38 g) at room temperature under an argon stream for 10 minutes. After the reaction solution was cooled to 0 ° C, silver triflate (5.37 g, 20.9 mmol) was added, and the mixture was stirred for 16 hours. The reaction solution was diluted with chloroform and washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine.
  • a D-galactose sugar donor H (465 mg, 0.65 bandol) and budesonide (215 mg, 0.5 mmol) were dissolved in dichloromethane (8 mL), and the mixture was stirred with MS 4 A (lg) at room temperature under an argon stream for 10 minutes.
  • Silver triflate 200 mg, 0.78 mmol was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours.
  • dichloromethane (lmL) of Jl (72 mg, 0.10 mmol) was added, and the mixture was further stirred at room temperature for 12 hours.
  • L-rhamnose sugar donor ⁇ (727 mg, 1.2 ol) and budesonide (430 mg, 1.0 ol) were dissolved in dichloromethane (20 mL), and the mixture was stirred with MS 4A (lg) for 10 minutes at room temperature under an argon stream. .
  • Silver triflate (385 mg, 1.50 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 17 hours.
  • the leachate weight and thymus weight are shown in Tables 1 and 2 as the inhibition rate (%) with respect to the control group. From the regression curve of the least-squares method, 30% effusion inhibitory concentration and 30% thymic atrophy concentration were determined. The results of the 30% leachate inhibitory concentration and the 30% thymic atrophy concentration were ranked according to Table 3, and the total leachate and thymus ranks are shown in Table 4 as the overall rank.
  • the compound para-to1-G1c-DF which has already been filed in an international application (International Publication Number: WO95 / 091777), has an overall rank of 6, and turns steroids into easily metabolized steroids. It has been shown that the compound according to the present invention has enhanced action and reduced side effects. From the above, it was found that the compound of the present invention is a safe anti-inflammatory steroid drug with few systemic side effects.
  • Inhibition rate (%) DO dose 0.01 ⁇ ng / rat 0.1 mg / rat 1 mg / rat 3 mg / rat 10 mg / rat Substance Sake liquor Thymus weight; Luke liquor Thymus weight Leachate volume Thymus weighing; Thymus weight; s

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

Abstract

L'invention se rapporte à des médicaments contenant en tant que principe actif des composés ayant la structure suivante. Ces médicaments sont utilisés en tant qu'agents anti-inflammatoires destinés à l'administration topique ainsi qu'en tant qu'agents convenant à la fois à l'administration topique et au traitement de l'asthme, de la rhinite allergique et des rhumatismes. Les composés ci-dessus sont des composés stéroïdes facilement métabolisables, substitués au niveau de l'atome de carbone en position 21 par un substituant de formule X- (reste de saccharide) Y-CZ-R, où X représente O-, -S- ou NH- ; Y représente O-, -S- ou NH- ; Z représente =O ou =S et R représente phényle.
PCT/JP1999/001407 1998-03-19 1999-03-19 Medicaments contenant en tant que principe actif des composes steroides glycosyles substitues en position 21 Ceased WO1999047542A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10/92352 1998-03-19
JP9235298 1998-03-19

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005022979A (ja) * 2003-06-30 2005-01-27 Otsuka Chemical Co Ltd いす形６員環単糖化合物
WO2010104187A1 (fr) 2009-03-09 2010-09-16 三笠製薬株式会社 Composé stéroïde
JP2016069339A (ja) * 2014-09-30 2016-05-09 三笠製薬株式会社 炎症性腸疾患治療薬
EP4192840A4 (fr) * 2020-08-10 2024-03-13 P.I.F. Entrepreneurs Ltd. Conjugués de médicament ciblant des macrophages
RU2845060C1 (ru) * 2020-08-10 2025-08-13 П.И.Ф. Антрепренёз Лтд. Нацеленные на макрофаги конъюгаты лекарственных средств

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07109286A (ja) * 1993-10-12 1995-04-25 Mect Corp ネオヘスペリドース誘導体
JPH08217790A (ja) * 1995-02-16 1996-08-27 Toyama Chem Co Ltd 単糖誘導体または単糖誘導体を含有する脂肪乳剤
JPH08283285A (ja) * 1995-04-12 1996-10-29 Nissin Food Prod Co Ltd 抗炎症作用を有する糖脂質

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07109286A (ja) * 1993-10-12 1995-04-25 Mect Corp ネオヘスペリドース誘導体
JPH08217790A (ja) * 1995-02-16 1996-08-27 Toyama Chem Co Ltd 単糖誘導体または単糖誘導体を含有する脂肪乳剤
JPH08283285A (ja) * 1995-04-12 1996-10-29 Nissin Food Prod Co Ltd 抗炎症作用を有する糖脂質

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005022979A (ja) * 2003-06-30 2005-01-27 Otsuka Chemical Co Ltd いす形６員環単糖化合物
WO2010104187A1 (fr) 2009-03-09 2010-09-16 三笠製薬株式会社 Composé stéroïde
CN102348714A (zh) * 2009-03-09 2012-02-08 三笠制药株式会社 甾族化合物
JPWO2010104187A1 (ja) * 2009-03-09 2012-09-13 三笠製薬株式会社 ステロイド化合物
US8765696B2 (en) 2009-03-09 2014-07-01 Mikasa Seiyaku Co., Ltd. Steroid compound
CN102348714B (zh) * 2009-03-09 2015-01-07 三笠制药株式会社 甾族化合物
JP2016069339A (ja) * 2014-09-30 2016-05-09 三笠製薬株式会社 炎症性腸疾患治療薬
EP4192840A4 (fr) * 2020-08-10 2024-03-13 P.I.F. Entrepreneurs Ltd. Conjugués de médicament ciblant des macrophages
RU2845060C1 (ru) * 2020-08-10 2025-08-13 П.И.Ф. Антрепренёз Лтд. Нацеленные на макрофаги конъюгаты лекарственных средств

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