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WO1999033791A1 - Derives aliphatiques - Google Patents

Derives aliphatiques Download PDF

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Publication number
WO1999033791A1
WO1999033791A1 PCT/JP1998/005975 JP9805975W WO9933791A1 WO 1999033791 A1 WO1999033791 A1 WO 1999033791A1 JP 9805975 W JP9805975 W JP 9805975W WO 9933791 A1 WO9933791 A1 WO 9933791A1
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WO
WIPO (PCT)
Prior art keywords
compound
added
methanol
sulfo
mixture
Prior art date
Application number
PCT/JP1998/005975
Other languages
English (en)
Japanese (ja)
Inventor
Masahiko Kojima
Hirotsugu Ogawa
Yasunari Harada
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.
Priority to AU16915/99A priority Critical patent/AU1691599A/en
Publication of WO1999033791A1 publication Critical patent/WO1999033791A1/fr

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Classifications

    • 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 double-chain aliphatic conductor having a cell adhesion inhibitory action and a TNF- N production inhibitory action.
  • Cell adhesion occurs by intermolecular binding between selectin, a ⁇ protein expressed on one cell surface, and Lewis-type sugar chain, a ligand present on another cell surface. This cell adhesion is known to be involved in the expression of functions that are essential for vital activities, such as inflammatory response by leukocytes and immunity KJ3 ⁇ 4; hemostasis by platelets, and ⁇ cell metastasis (Symposium Inflammation and Immunity vol. .5 No.2 1996, page 44-50).
  • vascular endothelial cells and Lewis-type sugar chains present on the surface of leukocytes bind. Since this bond is weak, the vascular endothelial cells are not fixed to the vascular endothelial cells, but they go through the surface of the vascular skin cells. This binding then becomes more intimate due to the activated integrin, which triggers infiltration by a series of mechanisms by which leukocytes migrate out of the blood vessel.
  • An object of the present invention is to provide a novel diphthenic aliphatic starfish that is useful as a medicine, for example, as a therapeutic or preventive drug for inflammatory diseases.
  • the present inventors have conducted intensive studies and as a result, have found that a compound represented by the following structural formula satisfies the above-mentioned S, and completed the present invention.
  • R-and R S are the same or different and each represent a linear or branched alkyl, alkenyl, or acyl having 6 to 30 carbon atoms.
  • B is — (CH 2 ) m-, one (CH di Jn-NR e -CO-O-,
  • R ⁇ represents hydrogen or lower alkyl.
  • z represents an integer of 1 to 4, and ⁇ represents an integer of 0 to 12.
  • m represents an integer of 0 to 12, and
  • y represents an integer of 0 to 3.
  • R represents the following general formula (m), (IV) or (V).
  • R S represents hydrogen or a hydroxyl group
  • R 4 is hydrogen, a hydroxyl group, a sulfo or a (3-O-sulfo 0-D-galactobilanosinole) oxy.
  • R represents hydrogen, a hydroxyl group, sulfo or (3-O-sulfo / 3-D-galactobilanosyl); and R 4 is (3-O-sulfo-D-galactobilanosyl) oxo s
  • R 6 represents hydrogen or a peracid group.
  • R e is hydrogen
  • R 7 is (3-0-sulfogalactobilanosyl) oxy
  • R S is hydrogen or 1 1 fucosyl.
  • 6 is a hydroxyl group
  • R s is sulfo.
  • A may be replaced by a single bond, an oxygen atom, .0. (CH a ) q.NR a -or one or more alkyl or sulfo-lower alkyl! / ⁇ carbon atom Represents a firewood atom. Further, A may be substituted with a halogen, a hydroxyl group, an amino, a lower alkyl or a lower alkoxy, 1) a linear or branched lower alkyl or a lower alkoxy, or 2) one heteroatom atom Or a saturated or unsaturated monocyclic or polycyclic hydrocarbon having 3 to 10 carbon atoms, which may contain an oxygen, nitrogen or sulfur atom or more.
  • R a represents hydrogen or lower alkyl.
  • t represents an integer of 0 to 6.
  • k is 0 or 1.
  • q is an integer from 1 to 6. ]
  • the present invention also provides the above novel compound and a TNF-production inhibitor comprising, as an active ingredient, a known compound represented by the following general formula (VI), wherein R in the formula (I) or the formula (II).
  • R e and R 1 D are the same or different and each represent a hydroxyl group, lower alkyl having 1 to 4 carbon atoms or lower alkoxy.
  • R 1 and R 2 represent alkyl having 6 to 30 carbon atoms, such as hexyl, octyl, decyl, dodecyl, tridecyl, tetradecyl, hexadecyl, octadecyl, icosyl, or docosyl.
  • Penta: Sill, and Triacontyl.
  • C6 to C3 alkyl radicals include 3-hexyl, 4-octyl, 5-decel, 61-dodecel, 7-tetradecel, and 8-hexadece, 9-octadecyl, 10-icosyl, 11-docosenyl, 12-tetracosyl, 13- Hexagoseur, 14-octacose-l, and 15-triacontenyl can be mentioned.
  • 8-hexadecyl, 9-octadecenyl, and 10-icosyl are preferred.
  • acyl having 6 to 30 carbon atoms examples include hexanoyl, lauroyl, myristyl, palmitoyl, stearyl, oleoyl, and raidoyl. Particularly preferred are 8-hexadecenoyl, oleoyl, and 10-icosenoyl.
  • "lower alkyl J" includes straight-chain or branched-chain ones having from 6 to 6 carbon atoms, such as methinole, ethyl and propyl.
  • the “lower alkoxy J” in Takaaki Honaki includes straight-chain or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxydi, propoxy, isopropoxy, butoxy, isobutoxy, and t-butoxy. , T-pentyloxy, hexyloxy, isohexyloxy and the like.
  • a represented by A which may be substituted by halogen, hydroxyl, amino, lower alkyl or lower alkoxy, and may contain one or more oxygen, nitrogen, or sulfur atoms as hetero atoms;
  • a saturated or unsaturated mono- or polycyclic hydrocarbon having 3 to 10 carbon atoms, citarob o-pan, cyclopentane, cyclohexane, cycloheptane, thiophene, furan, pyrrolidine, piperidine, piperazine , Pyran, pyrrole, imidazole, pyrazole, pyridine, virazine, pyrimidine, pyridazine, indole, oxazole, morpholine, benzene, naphthalene and the like.
  • the compound (I) or (II) of the present invention which is a sulfonic acid, includes, for example, an alkyl gold salt, a magnesium salt, a lithium salt, a sodium salt, and a potassium salt. Examples thereof include alkaline earth metal salts such as calcium salts and barium salts.
  • the compounds of the present invention represented by general formulas (I) and (II) can be produced, for example, by the following method.
  • R represents an integer of 0 to 11.
  • the compound of the present invention can be produced by reductive alkylation of the starting compound of Example 1. Specifically, for example, it can be produced by performing reductive alkylation with sodium cyanoborohydride.
  • a reaction solvent methanol, water, tetrahydrofuran (hereinafter, abbreviated as THF), ⁇ , ⁇ ⁇ ⁇ ⁇ -dimethylformamide (hereinafter, abbreviated as DMF) and the like can be used.
  • reaction can be carried out in a temperature range of 1, S to 2 mol, 1 to 24 hours, 0 to: L 00 °.
  • (b) B is-(CH a ) n .NR e .CO.O- ⁇ :
  • Al 3 Le derivative (9) For example, ⁇ , ⁇ 1 - carbonitrile register imidazole and pyridine, DMF, imidazo Ichiru ⁇ body by performing the reaction at 0 ⁇ l 00 in a solvent such as THF Obtainable. Further, the alcohol derivative (9) is reacted in a solvent such as chloroform and chloroform or DMP at 0 to 150 ° C in the presence of a base such as pyridine or triethylamine to give the carbonate derivative. Obtainable.
  • the compound of the present invention can be produced by reacting the compound of formula (1) with a compound such as DMF, pyridine, toluene, benzene, THF or the like at O: up to 150.
  • a base such as tritylamine may be added.
  • n is from 1 to: L2 ⁇ :
  • R 1 R s is as defined above.
  • P represents an integer of 0 to 11.
  • the compound of the present invention can be produced.
  • a sulfur trioxide pyridine compound By subjecting the compound to sulfuric acid esterification using the compound, the compound of the present invention can be produced.
  • the antisolvent DMF, pyridine, THF 1,4-dioxane, chloroform, methylene chloride, and the like can be used.
  • the reaction can be carried out in a temperature range of 0 ° C. for 124 hours, preferably 1.57 moles.
  • the compound of the present invention can be produced by reacting the raw material (1A), (IB) or (1C) with the alcohol derivative (9) according to the method (i). Can be.
  • R 1 and E a are as defined above.
  • Y is a group capable of activating a carboxy group, for example, a halogen such as an imidazolyl group, a fluorine atom, a hydrogen atom or an iodine, a phenoxy group, Can be reduced.
  • raw materials (1A), (1B), (1C), (ID), (IE), (IF), (l G) or a compound of (1H) and a compound of the general formula (4) in a solvent for example,
  • Examples of the ⁇ - reaction solvent which can produce the compound of the present invention by reacting at a temperature of 100 ° C. for 1 to 48 hours include DMF, pyridine, toluene, THF and chloroform.
  • the raw materials (1A), (1B), (1C), (ID), (IE), (IP), (1G) or (1H) and the compound of the general formula (5B) can be produced by performing reductive alkylation according to the above 15 (a).
  • R * represents protection of a hydroxyl group, for example, a pendyl group, a t.butyldimethylsilyl group, a t-butyldifurylsilyl group,
  • DCP represents ⁇ , ⁇ »-dicyclohexylcarboximide.
  • the raw material (1N), which is a hydroxycarboxylic acid attractant having a protected hydroxyl group, and an alcohol weiconductor (9) are, for example, converted into ⁇ , ⁇ '-dicyclohexylcarbo according to the above reaction formula.
  • an appropriate catalyst, pyridine, ⁇ , ⁇ -dimethyl.4-aminopyridine or the like can be added to promote the reaction.
  • the compound of the present invention can be produced by removing the protecting group of the obtained ester form by a conventional method and then performing sulfate esterification according to the method described in the above (b).
  • R 1 , E s , R e , A, n, t, and R * are as defined above.
  • the raw material (IN) is mixed with, for example, thiol chloride, phosphorus tri-viperide, phosphorus pentachloride, oxalyl chloride, etc. according to the above reaction formula, and if necessary, in an inert solvent such as benzene. It can be led to acid chloride ⁇ ⁇ under the condition of heating from reflux to closing. At this time, DMF, hexamethinolephosphoric triamide (hereinafter abbreviated as HMPA), pyridine or the like may be added as a reaction catalyst.
  • HMPA hexamethinolephosphoric triamide
  • the obtained acid chloride compound is treated with alcohol (9) and an appropriate solvent, for example, pyridine, triethylamine or dimethylamine in a solvent such as chloroform, dichloromethane, pyridine, ether, benzene, THF or DMF. Condensation between 110 ° and 50 ° in the presence of a base such as phosphorus gives an ester form.
  • an appropriate solvent for example, pyridine, triethylamine or dimethylamine in a solvent such as chloroform, dichloromethane, pyridine, ether, benzene, THF or DMF.
  • Condensation between 110 ° and 50 ° in the presence of a base such as phosphorus gives an ester form.
  • the method described in (b) above is applied to the method described in IB. 11 analogously, by ester sulfuric, it is possible to produce the compound of the present invention ⁇
  • the raw materials (1A), (IB), (1C), (1D), (IE), (IF), (1G) or (1H) and the compound of the general formula (6B) can be produced by performing reductive alkylation according to the above IS (a).
  • 11 cases of 0 12 may also be prepared as follows: ⁇ Arco Le ⁇ body Or
  • R 1 , R a , R ⁇ A, n, and t have the same meanings as described above.
  • Hal represents fluorine, chlorine, bromine, or iodine.
  • the raw material (1T) and the alcohol derivative (9), or the raw material (1U) and (12) obtained by halogenating the alcohol derivative (9) by an ordinary method can be obtained by, for example, adding water according to the above reaction formula. Reaction in the presence of a base such as sodium bromide gives an ether form.
  • the protective compound of the obtained ether compound is deprotected by a conventional method, and then subjected to sulfate esterification according to the method described in the above (b), whereby the compound of the present invention can be produced.
  • R 1 and R s are as defined above.
  • Y represents an integer of 0 to 3.
  • the raw material (1A), (IB), (1C), (ID), (IE), (IF), (1G) or (1H) is combined with the compound of the general formula (7B).
  • the compound of the present invention can be produced by performing reductive alkylation according to the above (a).
  • the raw material (1R) and the alcohol derivative (9) are condensed according to the method described in IE (c) above, for example, according to the above reaction formula 15, an ester form is obtained.
  • the compound of the present invention can be produced by esterification with sulfuric acid according to the method described in IE in (b) above.
  • R 1 , R ⁇ is the same as the previous section. 2 represents an integer of 1 to 4.
  • the raw materials (1, (1B), (1C), (1D), (IE), (IF), (1G) or (1H) and the compound of the general formula (8B) are
  • the compound of the present invention can be produced by performing reductive alkylation according to (a).
  • the compound of the present invention can also be produced, for example, by the following method.
  • the compound can also be produced by reacting the compound of the above IB (1 J) or (1K) or (1 L) with an alcohol derivative (10), followed by derevoylation, sulfate esterification, and deprotection. Reaction of the compound (1 J) or (1K) or (1L) with the alcoholic conductor (10) in a solvent using a Lewis acid catalyst, for example, in a temperature range of 20 to 40 for 1 to 48 hours By doing so, an ether compound can be produced.
  • a Lewis acid catalyst for example, in a temperature range of 20 to 40 for 1 to 48 hours
  • the anti-solvent include methylene chloride, chloroform, THF and the like.
  • the Lewis acid catalyst include boron trifluoride complex.
  • this ether compound is dissolved in a solvent using a catalyst,
  • a catalyst for example, by reacting at a temperature in the range of 0 to 50 ° for 0.5 to 24 hours, a delevroylated product can be produced.
  • the reaction solvent include methanol, ethanol, THF, DMF and the like.
  • the catalyst include hydrazine acetate.
  • the sulfated ester can be produced by subjecting the relylated compound to sulfuric acid esterification with a sulfur dioxide pyridine complex, for example.
  • the reaction solvent include ⁇ , ⁇ -dimethylformamide, pyridine, tetrahydrofuran, 1,4-dioxane, chloroform-form, and salted methylene.
  • the reaction can be carried out in a temperature range of 0 to 100 ° C. for 1 to 24 hours using 1 to 15 mol, preferably 1.5 to 7 mol of a sulfur pyridine compound.
  • the compound of the present invention can be produced by deprotecting this sulfate ester in a solvent at a temperature in the range of 0 ° to 50 ° C. using a base. Examples thereof include sodium methylate, sodium hydroxide, and lithium hydroxide.
  • the reaction solvent include methanol, ethanol, THF, 1,4-dioxane, and DMF.
  • the compound of the present invention can also be produced, for example, by the following method.
  • the compound of the present invention can be produced by sulfate esterification. Specifically, for example, it can be produced by sulfate esterification with a sulfur trioxide pyridine complex.
  • a reaction solvent DM, pyridine, TH? , 1,4-dioxane, chloroform, methylene chloride, etc.
  • the raw material (3A) is (5A) or (6A) or (7A) or (8A) or (10)
  • the sulfur trioxide pyridine complex is used in an amount of ⁇ ⁇ ⁇ to 15 moles, preferably 1.5 to 7 moles, 1 to 24 hours
  • the present compound to ⁇ Kira can be reacted at a temperature range of 0 to 100, for example, can also be produced by the following method.
  • the compound of the present invention (2A) or (2B) or (3B) or (5B) or ( ⁇ ) or (7 ⁇ ) or the source of (8!!
  • the amine compound can be produced by performing a reductive alkylidoliding .. Then, the amino group of the amine compound is protected with a suitable protecting group, for example, a 9-fluorenylmethoxycarbyl group.
  • the olebamate is prepared by using N- (9, fluorenylmethoxycarburoxy) succinimide and a saturated sodium bicarbonate solution in a solvent, for example, 12 ⁇ ;
  • the reaction is carried out for 0.5 to 48 hours in the following temperature range:
  • the reaction solvent include acetone, THF, DMFs 1,4-dioxane, etc.
  • the hydroxyl group of this carrier is sulfated.
  • the sulfur trioxide pyridine complex As a reaction solvent, DMF, pyridine, THF, 1,4-dioxane, chloroform, methylene chloride, etc.
  • the sulfur-pyridine complex is used in an amount of 1 to 15 moles, preferably 1.5 to 7 moles, and the reaction can be performed at a temperature of 1 to 24 hours and a temperature of 0 to 100.
  • a solvent for example, in a temperature range of 0 to 50,
  • the compound of the present invention can be produced by reacting for 5 to 48 hours and carrying out deprotection.
  • piperidine and the like are used as the base, and DMF and the like can be mentioned as the reaction solvent.
  • the 1,2-disubstituted aliphatic derivative represented by the general formula (I) according to the present invention can also be prepared according to the above (b).
  • Odani compound (1A) (In the formula, Me represents a methyl group, Ac represents an acetyl group, Z represents a benzyloxycarbonyl group, Bs: represents penzinole ⁇ , MeONa represents sodium methylate, CSA Represents dl-camphor-10-sulfonic acid, BzCl represents ffihibenzoyl, AcOH represents acetic acid, Py represents pyridine, SO a * Py represents a sulfur trioxide pyridine complex, and Pd-C represents palladium. . Represents carbon.)
  • the starting compounds (1B) and (1K) can be produced, for example, according to the following synthesis scheme.
  • Lev represents a Reburinoiru group
  • DCC stands for ⁇ , ⁇ 1 -dihexyl carbyl carbonyl
  • * DMAP stands for ⁇ , ⁇ -dimethyl.4-aminopyridine
  • DBU stands for 1,8, diazabicyclo [5.4.0]
  • ⁇ represents E down
  • CCl a CN represents a trichloroacetimidate tolyl
  • BF 3 ⁇ OEt s represents a boron trifluoride ether complex
  • NH 2 NH a 'AcOH represents hydrazine acetate.
  • the starting compound (1C) can be produced, for example, according to the following synthesis scheme.
  • the urine compound (1D) can be produced, for example, according to the following synthesis scheme.
  • Haradani (1E) complies with the following synthesis scheme.
  • the starting compound (1G) can be produced, for example, according to the following E synthesis scheme:
  • Starting Compound (1H) Starting Compound (ID can be produced, for example, based on the method described in J. Carbohydr. Chem. 1995, 14, p353-368.
  • the starting compound (1J) can be produced, for example, according to the method for producing the compound (1B).
  • the Harada-dori (1H) can be produced by a method known per se. 28
  • the imidazole derivative can be obtained by reacting the alcohol syrup (9) with, for example, ⁇ , ⁇ '-potassium propyldimidazole in a solvent such as pyridine or DMFs THF at 03 ⁇ 4-100 !. , Alcohol derivative (9) is reacted with furoic acid dihydrofuran in a solvent such as puroform, DMF, etc. at 0 to 1503 ⁇ 4 in the presence of a base such as pyridine, triethylamine, etc. to obtain a fluorene carbonate conductor.
  • a solvent such as pyridine or DMFs THF at 03 ⁇ 4-100 !.
  • Alcohol derivative (9) is reacted with furoic acid dihydrofuran in a solvent such as puroform, DMF, etc. at 0 to 1503 ⁇ 4 in the presence of a base such as pyridine, triethylamine, etc.
  • the carpamet form is reacted with an appropriate oxidizing agent, for example, dimethyl sulfoxide (DMSO) in benzene, ⁇ , ⁇ 'dicyclohexylcarposimide (DCC) or in chloroform, pyridinium chromate, Dess.Martin reagent, etc. Oxidation at 0 to 50 by the method can give the aldehyde form of the starting compound (3B).
  • DMSO dimethyl sulfoxide
  • DCC ⁇ 'dicyclohexylcarposimide
  • chloroform pyridinium chromate
  • Dess.Martin reagent Dess.Martin reagent
  • the starting material compound (4) can be produced, for example, by reacting an alcohol beverage (9) with ⁇ , ⁇ '-carbodiimidazole, black carbonate carbonate, or phosgene.
  • R 1 R n is the same as defined above.
  • R * represents a hydroxyl-containing carbohydrate group, for example, benzyl group, butyldimethylsilyl group, t.butyldifursilyl tomb, lebrinoyl group, etc. it can.
  • the starting compounds (5A) and (5B) can be prepared, for example, by subjecting an alcohol derivative (9) and a hydroxycarboxylic acid-depleted hydroxyl group-protected compound to DMF, dichloromethane, chloroform by DCC or the like according to the above reaction formula. In solvents such as mouth form and THP, 0-100. Condenses at the temperature of C. If necessary, suitable catalyst, pyridine, ⁇ , ⁇ -dimethyl-4-aminoviridine And the like can be added to accelerate the reaction.
  • Compound (5A) can be produced by removing the protecting group of the obtained compound by a conventional method.
  • the compound (5B) can be produced by oxidizing the compound (5A) with a suitable oxidizing agent, for example, DMSO-DCC, pyridium chromate, or Dess-Martin reagent.
  • a suitable oxidizing agent for example, DMSO-DCC, pyridium chromate, or Dess-Martin reagent.
  • R * represents a hydroxyl-protecting group, and examples thereof include a benzyl group, a t-butyldimethylsilyl group, a t.butyldifursilyl group, and a levulinol group. I can do it.
  • the hydroxyl-protected hydroxycarboxylic acid derivative is combined with thiol chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, etc., and if necessary, benzene or the like.
  • thiol chloride phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, etc.
  • benzene or the like In an inert box medium, it can be converted to an acid chloride under conditions of room temperature to ripening reflux.
  • DMF hexamethylphosphoric triamide
  • pyridine hexamethylphosphoric triamide
  • the obtained acid chloride is combined with the alcohol derivative (9) in an appropriate solvent, for example, pyridine, triethylamine or dimethyla-line in a solvent such as chloroform, dichloromethane, pyridine, ether, benzene, THF or DMF.
  • an appropriate solvent for example, pyridine, triethylamine or dimethyla-line in a solvent such as chloroform, dichloromethane, pyridine, ether, benzene, THF or DMF.
  • (5A) was prepared by using a suitable oxidizing agent, for example, DMSO-DCC, pyridium chromate, Deee'Martiii reagent, etc., in a solvent such as chloroform, dichloromethane, benzene, acetotrile and the like.
  • a suitable oxidizing agent for example, DMSO-DCC, pyridium chromate, Deee'Martiii reagent, etc.
  • a solvent such as chloroform, dichloromethane, benzene, acetotrile and the like.
  • R 1 , R 2 and p are as defined above.
  • R ′′ represents alkyl.
  • Hal represents fluorine, chlorine, bromine, or iodine.
  • the starting compounds (6A) and (6B) are obtained, for example, by reacting an alcohol derivative (9) with a halogenated ester derivative in the presence of a base such as sodium hydrochloride, according to the above IS reaction formula.
  • the compound (6A) can be produced by reducing the obtained ester to an alcohol with a suitable reducing reagent, for example, lithium aluminum hydroxide.
  • the compound (6A) with a suitable oxidizing agent, e.g., DMSO.DCC and black port chromic acid pyridine um, with Dees-Martin reagent and the like, black hole Holm, dichloromethane, benzene, Aseto - in the tolyl solvent, 0 £:
  • a suitable oxidizing agent e.g., DMSO.DCC and black port chromic acid pyridine um, with Dees-Martin reagent and the like, black hole Holm, dichloromethane, benzene, Aseto - in the tolyl solvent, 0 £:
  • the compound (6B) can be produced by oxidizing between 60 and 60.
  • R * represents a hydroxyl-protecting group. Benzyl group, t-butyldimethylsilyl group, butyldiphenylsilyl group, levulinyl group and the like.
  • the starting compounds (7A) and (7B) can be obtained, for example, by subjecting an argol derivative (9) and a hydroxycarboxylic acid derivative having a protected hydroxyl group to DMF, dichloromethane, and chloroform by DCC according to the above reaction formula. Condensation in a solvent such as THF, at a temperature of O; If necessary, the reaction can be promoted by adding an appropriate catalyst, pyridine, ⁇ , ⁇ .dimethyl-4-aminoviridine or the like. Compound (7 ⁇ ) can be produced by removing the protecting group of the obtained compound by a conventional method.
  • Compound (7.alpha) a suitable oxidation agent, for example, O which can be produced a compound (7 B) DMSO-DCC and black port chromic acid Pirijiyuumu, by oxidation with Dess-Marfchi reagent
  • R R ⁇ R y is as defined above.
  • the obtained acid chloride is combined with an alcohol rust conductor (9) and a suitable solvent, for example, pyridine, triethylamine or dimethylaline in a solvent such as chloroform, dichloromethane, pyridine, ether, benzene, THF or DMF.
  • a suitable solvent for example, pyridine, triethylamine or dimethylaline in a solvent such as chloroform, dichloromethane, pyridine, ether, benzene, THF or DMF.
  • a base of 10 1 to 50 0 The compound (7A) can be produced by deprotecting the protecting group by a conventional method after condensation between the compounds.
  • Compound (7A) was prepared using a suitable oxidizing agent, for example, DMSO-DCC, viridiumium chromate, Desa-Martin reagent, etc., in a solvent such as chloroform, dichloromethane, benzene, acetotril, etc.
  • the compound (7B)
  • the starting compounds (8A) and (8B) can be produced, for example, according to the above reaction formula.
  • an imidazole conductor can be obtained by reacting an alcoholic conductor (9) with, for example, ⁇ , ⁇ '-caprolidimidazole in a solvent such as pyridine, DMF, or THF at 0 to 1003 ⁇ 4. it can. Further, the alcohol derivative (9) is reacted with a carbonaceous carbonate in a solvent such as taroloform or DMF at 0 to 150 ° C in the presence of a base such as pyridine or triethylamine to give the carbonate derivative.
  • a solvent such as pyridine, DMF, or THF
  • the carbamate is converted to a suitable oxidizing agent, for example, dimethylsulfoxide (DMSO) - ⁇ , ⁇ -dicyclohexylcarbodiimide (DCC) in benzene, or chloroform 'pyridinium chromate in chloroform', Dees-Martin reagent. Oxidation at 0 ° to 50 ° by such a method as described above gives an aldehyde form of the starting compound (8B).
  • DMSO dimethylsulfoxide
  • DCC ⁇ -dicyclohexylcarbodiimide
  • chloroform 'pyridinium chromate in chloroform'
  • Dees-Martin reagent oxidizing agent
  • Oxidation at 0 ° to 50 ° by such a method as described above gives an aldehyde form of the starting compound (8B).
  • the pharmaceutically acceptable metal salt of the compound of the present invention can be produced by the method for producing the compound of the present invention, or by
  • the compound of the present invention thus produced can be produced by a method known per se in the form of a free acid or a metal salt, for example, condensation, liquid conversion, phase transfer, solvent extraction
  • the pharmaceutically acceptable metal salt of the compound (I) or ( ⁇ ) of the present invention can be produced by a method for producing the compound of the present invention described below, or by passing the compound of the present invention as a free acid through an appropriate ion exchange resin. Can be manufactured.
  • the compound of the present invention thus produced can be produced in a manner known per se in the form of a free acid or a metal salt, for example, concentration, liquid conversion, phase transfer, solvent extraction, enamelling, fractionation. It can be isolated and purified by chromatography.
  • the compound of the present invention has a favorable antagonistic action on selectin (E, P, L) and a cell adhesion inhibitory action.
  • the pharmaceutical composition containing as an active ingredient can be used as a therapeutic or prophylactic agent for diseases such as inflammation and thrombus formation associated with inflammation, rheumatism, asthma, infectious disease, immune disease, AIDS and cancer.
  • diseases such as inflammation and thrombus formation associated with inflammation, rheumatism, asthma, infectious disease, immune disease, AIDS and cancer.
  • the compound of the present invention has an inhibitory effect on TNF- ⁇ production, it is a preventive and therapeutic agent for TNF-mediated diseases, that is, prevention and treatment of chronic 'acute inflammatory diseases, autoimmune diseases, allergic diseases, etc. Useful as an agent.
  • the chronic inflammatory disease refers to a disease such as osteoarthritis, psoriatic arthritis, and inflammatory bowel disease (ulcerative colitis, Crohn's disease, etc.).
  • Acute inflammatory disease refers to diseases such as contact skin disease, adult respiratory failure syndrome, sepsis, etc. 1%
  • Autoimmune diseases include chronic rheumatoid arthritis, ankylosing spondylitis, systemic erythrotomatodes, glomerulonephritis, multiple sclerosis, polychondritis, scleroderma, dermatomyositis, zegener meat neuroblastoma disease, chronic active hepatitis i, primary biliary cirrhosis, disease gravis, idiopathic Suburu one, Grapes disease, monkeys 3 Ido one cis, writer syndrome, juvenile diabetes, autoimmune eye disease, self Indicates a disease such as an immune blood disease.
  • Allergic diseases include atopic dermatitis, asthmatic diseases, allergic rhinitis and the like.
  • the toxicity of the compound of the present invention such as cytotoxicity is low, it can be predicted that the safety of the compound of the present invention for animals including humans is high.
  • the compounds of the present invention When administered the compounds of the present invention as a medicament, the compounds of the present invention as such or in a pharmaceutically acceptable nontoxic and inert carrier, for example, 0. 1% ⁇ 9. 5 %, preferably 0 - 5% pharmaceutical compositions containing ⁇ 9 ⁇ _O can be administered to animals including humans.
  • a pharmaceutically acceptable nontoxic and inert carrier for example, 0. 1% ⁇ 9. 5 %, preferably 0 - 5% pharmaceutical compositions containing ⁇ 9 ⁇ _O can be administered to animals including humans.
  • a pharmaceutically acceptable nontoxic and inert carrier for example, 0. 1% ⁇ 9. 5 %, preferably 0 - 5% pharmaceutical compositions containing ⁇ 9 ⁇ _O can be administered to animals including humans.
  • a pharmaceutically acceptable nontoxic and inert carrier for example, 0. 1% ⁇ 9. 5 %, preferably 0 - 5% pharmaceutical compositions containing ⁇ 9 ⁇ _O can be administered to animals including humans.
  • the carrier at least
  • the dose of the compound of the present invention as a medicament can be adjusted in consideration of the condition of the patient such as age and weight, the administration route, the nature and severity of the disease, the indication, the compound of the present invention to be selected, and the like. Desirably, the amount of the compound of the present invention for an adult is usually in the range of 5 mg to 500 mg / S / human, preferably 30 mg to 100 mg / human / day for an adult. in some cases it is appropriate delta, to sufficient even below this, also may require more doses reversed. Also, it can be administered by dividing into 2 to 3 days a day.
  • solid or liquid S units such as powders, capsules, tablets, dragees, powders, suspensions, solutions, syrups, drops, sublingual tablets, and other dosage forms. It can be carried out.
  • a non-agent can be produced by appropriately dividing the compound of the present invention.
  • Powders may be prepared by comminuting the compound of the present invention to a suitable fineness and then combining it with a similarly finely divided pharmaceutical carrier, for example, edible carbohydrates such as starch, mantle and the like. it can. Flavoring agents, preservatives, dispersing agents, coloring agents, fragrances and other substances can be mixed as necessary.
  • Capsule preparations are prepared by first filling powdered powders, powders or tablets as described above into granules as described in the section on capsules, such as gelatin capsules. Can be manufactured.
  • Lubricants and superplasticizers such as colloidal silica, talc, magnesium stearate, calcium stearate, and solid polyethylene glycol, are mixed into a powder state, and then the filling operation is performed. You can do it too. Addition of disintegrants and solubilizers such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, canolepoxymethyl starch sodium, calcium carbonate, sodium carbonate, etc. The effectiveness of the medicine when the capsule is taken can be improved. Further, the fine powder of the compound of the present invention can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, or a surfactant, and wrapped with a gelatin sheet to prepare a soft capsule.
  • disintegrants and solubilizers such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, canolepoxymethyl starch sodium
  • Tablets are mixed with excipients to form a powder mixture, granulated or slugged and then It can be manufactured by tableting after adding a disintegrant or a lubricant.
  • the powder mixture is prepared by mixing a suitably powdered substance with the diluent or base described above and, if necessary, a binder (eg, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose).
  • the powder mixture can be first moistened with a binder, for example, a paste, starch paste, gum arabic, a cellulose solution or a polymer solution, mixed by stirring, dried and pulverized to obtain granules.
  • a binder for example, a paste, starch paste, gum arabic, a cellulose solution or a polymer solution, mixed by stirring, dried and pulverized to obtain granules.
  • the granules thus produced can be prevented from adhering to one another by adding stearic acid, stearates, talc, mineral oil and the like as lubricants.
  • the mixture thus pulverized can then be bored.
  • the uncoated tablets thus produced can be coated with film or bran.
  • the compound of the present invention can be directly tableted after mixing with a fluid inert carrier without going through the steps of granulation or slugging as described above.
  • Transparent or translucent protective coatings consisting of a closed shellac coating, coatings of bran or polymeric materials, and polish coatings made of plastics can also be used.
  • ⁇ dosage forms such as, for example, solutions, tips, troches, elixirs and the like, can also be presented in dosage unit form so that a given quantity contains a certain quantity of the compound of the invention.
  • Syrups can be prepared by dissolving the compound of the present invention in a suitable flavored solution
  • elixirs can be prepared by using a non-toxic alcoholic carrier.
  • Emulsifiers are formulated by dispersing the compound of the present invention in a non-toxic carrier.
  • Solubilizers and emulsifiers eg, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters
  • preservatives e.g, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters
  • flavor enhancers eg, palmit oil, Saccharin
  • Others 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 'molecular' wax or the like.
  • Intra-tissue administration can be carried out by using a liquid dosage unit form for subcutaneous, intramuscular or intravenous injection, for example, in the form of a liquid or suspension.
  • a liquid dosage unit form for subcutaneous, intramuscular or intravenous injection for example, in the form of a liquid or suspension.
  • These compounds may be obtained by suspending or dissolving a fixed amount of the compound of the present invention in a non-toxic carrier suitable for the purpose of, for example, an aqueous or oily medium, and then sterilizing the liquid or solution. It can be manufactured by Non-toxic salts or salt solutions can be added to make the injection isotonic. Further, a stabilizer, preservative 1 ”, an emulsifier and the like can be used in combination.
  • the compound of the present invention is soluble or insoluble in water having a low melting point, such as polyethylene glycol, cocoa butter, semi-synthetic fats and oils (such as Witebsol, registered trademark), and higher esters (such as palmitic acid).
  • a low melting point such as polyethylene glycol, cocoa butter, semi-synthetic fats and oils (such as Witebsol, registered trademark), and higher esters (such as palmitic acid).
  • Myristyl ester and a suppository prepared by suspending or suspending in a mixture thereof.
  • topical administration can be carried out in dosage forms such as soft If, poultice, plaster, patch, remention, eye drops, nasal drops and the like.
  • Descendants include fats, fatty oils, lanolin, petrolatum, paraffin, wax, resins, plastics, greases, alcohols, glycerin, water, emulsifiers, entrainers or other agents;
  • the compounds of the present invention can be added, mixed and manufactured based on the ability to use additives as materials or based on these.
  • a poultice can be produced by mixing powder of the compound of the present invention with glycerin, water or other suitable liquid substances and adding an essential oil component.
  • the blaster agent is prepared from fat, fatty oil, fatty acid salt, wax, resin, plastic, refined lanolin, rubber, or a mixture thereof, or ⁇ SflJ, and the compound of the present invention is uniformly mixed.
  • Point 3 can be produced by dissolving or dissolving a fixed amount of the compound of the present invention in sterilized purified water, physiological saline, distilled water for injection, or the like, to a constant volume. The best form to apply kissing
  • the obtained residue is dissolved in a mixture of tetrahydrofuran (30 ml), methanol (30 ml) and an 80% acetic acid solution (30 ml), and stirred at room temperature for 3 hours to carry out a reaction for the production of orthoester. After completion of the reaction, the reaction solution was concentrated under reduced pressure after confirming with C (1: 1 ethyl acetate-n-hexane). The resulting residue was dissolved in methylene chloride, and the organic layer was washed with saturated sodium bicarbonate, water, dried over sodium sulfate, and concentrated under reduced pressure to give compound (20) (4.1 g). ).
  • the compound (20) (4.1 g) was dissolved in methylene chloride (50 ml), levulinic anhydride (1.05 g), ⁇ , ⁇ '-dicyclohexylcarbodiimide (2.2 s) and Four -Dimethylaminopyridine (0.15 g) was added, and the mixture was stirred for 2 hours. After completion of the reaction, it was confirmed by TLC (1: 1 ethyl acetate-n-hexane), insolubles were separated, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (Dicogel C-300 lOOg) to obtain Compound (21) (4.1 g) from eluent 2: 3 ethyl acetate-hexane.
  • Trimethylsilyl methanesulfonate (1.2 ml) was added in four portions to cleave the orthoester, and the solid was separated and washed with methylene chloride methylene chloride. This was washed with sodium chloride solution, dried over sodium sulfate, decompressed and reduced, and the resulting residue was subjected to silica gel column chromatography (Pecogel C-300, 1300 g), and eluate 1: 1 Compound (31) (20.0 g) was obtained from ethyl acetate-hexane.
  • the crude compound (36) (3.0 g) was dissolved in 1,4-dioxane (110 ml), and 2N-hydrochloric acid was added.
  • the compound (51) (607 mg) was dissolved in ethanol (14 ml), hydrazine acetate (104 mg) was added, and the mixture was stirred at room temperature for 3 hours. After concentrating ffi, the resulting syrup was subjected to silica gel column chromatography (40 g of Co-gel C-300, 40 g), and eluent 1: 2 ethyl acetate was converted to sun ⁇ 52) (44 Omg).
  • Idani ⁇ 1 (66) (1.49 g) was dissolved in 1,4-dioxane (30 mU, 2N-3 ⁇ 43 ⁇ 4 (9 ml)) and heated at room temperature for 3 hours. The residue was dissolved in mouth form, washed with saturated sodium carbonate solution and water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in benzene (25 ml), and trimethyl orthoacetate ( 3.59 ml) and DL-camphor-1-10-sulfonic acid (32 mg) were added, and the mixture was stirred at room temperature for 3 hours.After completion of the treatment, SJM was added with a saturated sodium hydrogencarbonate solution, water, and thorium.
  • the compound was dissolved in a mixture of tetrahydrofuran (15 ml), methanol (15 ml) and 80% acid (X 5 ml), and the mixture was dissolved at room temperature. The mixture was stirred overnight, and the orthoester was opened (1 ⁇ ⁇ : after completion), the anti-JS3 ⁇ 4 was H ⁇ E-shortened and further dissolved in toluene. The solvent was completely distilled off twice by azeotropic distillation to obtain a monohydroxyl compound, which was dissolved in pyridine (15 ml), added with sulfur oxide pyridine (1.53 g), and allowed to stand at room temperature overnight.
  • the compound (71) (0.21 g) was obtained as a colorless waxy body after purification by chromatography (10 g of Kogenore C-300, 10 g of black form: methanol 98: 2 to 90:10).
  • the ligated compound (76) (133 mg) was added to pyridine (2 ml), and sulfur trioxide pyridin experiment (165 mg) was added thereto. Under ice-cooling, methanol was added to the solution to reduce the concentration and then concentrated. am was dissolved in methanol, and applied to Abarite IR-120B (Na 20 ml column to extract methanol.
  • the compound (78) (270 mg) was dissolved in pyridine (5 ml), and the mixture was stirred at room temperature with pure pyridium trioxide & (140 mg). Add methanol to ⁇ ! 1 to give! ⁇ , And compress; ⁇ Dissolve the residue in methanol, treat with Amberlat IR-120B ⁇ Na +>, and perform silica gel column chromatography ( ⁇ —Genole C-1). Purification was performed using 300 10 g of methylene chloride: methano-85 / 15), and the reaction was carried out to obtain a diamide 1 (79) (226 mg) as a white powder.
  • the bacteria in the w are carried out, and the bacteria are tat.
  • PBS Dulbecco * s Phosphate Buffer Saline
  • Nissui ⁇ - ⁇ a -Minimum Essential Medium
  • GIBCO BRL Dulbecco * s Phosphate Buffer Saline
  • Nissui ⁇ - ⁇ a -Minimum Essential Medium
  • GIBCO BRL Dulbecco * s Phosphate Buffer Saline
  • Nissui ⁇ - ⁇ a -Minimum Essential Medium
  • G 18 Geneticin; manufactured by GIBCO BRL
  • FCS ⁇ fetal serum
  • e Selectin IgG chimera package lectic from each selectin cDNA: Lectin: ⁇ region, EGP region, and two ⁇ « ⁇ 3 ⁇ 4 gene sequences that cooperate with the white castle using PCR method.
  • Mouse cDNA was obtained from the Smiero ⁇ ? RNA using inversion. From this cDNA, a gene sequence coding for the CH2, CH3, and ty portions of IgGl was recovered by PCR, and then ligated to the 3 'of each selectin gene. The gene sequence encoding this chimera was incorporated into an animal cell expression vector (pSVK3-neoR) containing ⁇ H synthase, which was then electroporated.
  • pSVK3-neoR animal cell expression vector
  • the chimera that had been sequentially purified by A (50 ml) was eluted with 3 M f ⁇ T sodium phosphate containing lOmM is, HCl (pH 7.4).
  • the eluate subjected to T -1 V was analyzed by 4 on the plate, and the amount of chimera recovered was measured as the amount of mouse IgG Fc by E-ISA.
  • selectin-ABC selestatin-bin-stref'toavicin * complex
  • Table glaze U The numerical values in Table 1 are the obtained TO values of 50% P. If no inhibition rate of 50% or more was obtained at 3 mg / ml, the inhibition rate at that level was indicated.
  • This »Akira compound has a Mowonorin type command is a tetrasaccharide SLe x for much stronger selectin i ⁇ inhibitory as compared to 3 ⁇ 4 90
  • Human monocytic leukemia cell line THP-1 was transformed from 10% fetal bovine serum (FBS), 5X 10 ⁇ 3 ⁇ 42-mercaptoethanol, lOOjug I ml streptomycin, 100U / ml ⁇ silicon3 ⁇ 4 ⁇ 3 ⁇ 4 RPMI- It was adjusted to 5 ⁇ 10 5 ⁇ / ml in a 160 medium and dispensed into a 96 ⁇ : n culture plate in 200 1 I ⁇ . Next, the purple purple dissolved in fiber phosphate solution (PBS) was used to obtain various concentrations, and incubated at 37 °: 5% 0% for 15 minutes.
  • FBS fetal bovine serum
  • PBS fiber phosphate solution

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux dérivés aliphatiques à chaîne double pouvant être utilisés comme remèdes contre les maladies inflammatoires. Les composés susmentionnés comprennent ceux représentés par la formule générale (I) ou (II), ainsi que les sels pharmaceutiquement acceptables de ceux-ci. Dans lesdites formules, R1 et R2 sont identiques ou différents et représentent chacun alkyle C¿6-30? linéaire ou ramifié, alcényle ou acyle, p représente un nombre entier pouvant aller de 0 à 6, et R représente moraline éventuellement substituée ou glucose. Etant donné qu'ils ont un effet inhibant l'adhésion cellulaire et la production de TNF-α, ces composés peuvent être utilisés comme médicaments.
PCT/JP1998/005975 1997-12-26 1998-12-25 Derives aliphatiques WO1999033791A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU16915/99A AU1691599A (en) 1997-12-26 1998-12-25 Aliphatic derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/360373 1997-12-26
JP36037397 1997-12-26

Publications (1)

Publication Number Publication Date
WO1999033791A1 true WO1999033791A1 (fr) 1999-07-08

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WO (1) WO1999033791A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9301923B2 (en) 2009-12-23 2016-04-05 Novartis Ag Lipids, lipid compositions, and methods of using them
US10342761B2 (en) 2014-07-16 2019-07-09 Novartis Ag Method of encapsulating a nucleic acid in a lipid nanoparticle host

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS53111196A (en) * 1976-12-31 1978-09-28 Hoechst Ag Hand feeling improving agent
JPH04248996A (ja) * 1990-09-20 1992-09-04 Boehringer Mannheim Gmbh 体液中のホスホリパーゼの測定法
JPH05507473A (ja) * 1990-06-06 1993-10-28 ヘンケル・コマンディットゲゼルシャフト・アウフ・アクチェン グリセリンエーテルスルフェートの製造方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS53111196A (en) * 1976-12-31 1978-09-28 Hoechst Ag Hand feeling improving agent
JPH05507473A (ja) * 1990-06-06 1993-10-28 ヘンケル・コマンディットゲゼルシャフト・アウフ・アクチェン グリセリンエーテルスルフェートの製造方法
JPH04248996A (ja) * 1990-09-20 1992-09-04 Boehringer Mannheim Gmbh 体液中のホスホリパーゼの測定法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DONG ZHONGYUN, QI XIAOXIA, FIDLER ISAIAH J., "Tyrosine Phosphorylation of Mitogen-Activated Protein Kinases is Necessary for Activation of Murine Macrophages by Natural and Synthetic Bacterial Products", J. EXP. MED., 1993, Vol. 177, No. 4, p. 1071-1077. *
GIGG ROY, "The Allyl Ether as a Protecting Group in Carbohydrate Chemistry. Part 10. Synthesis of 3-0-(.beta.-D-Galactopyranosyl 3-Sulfate)-2-0-Hexadecanoyl-1-0-Hexadecyl-L -Glycerol, 'Seminolipid'", J. CHEM. SOC., PERKIN TRANS. 1, 1979, No. 3, p. 712-718. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9301923B2 (en) 2009-12-23 2016-04-05 Novartis Ag Lipids, lipid compositions, and methods of using them
US10342761B2 (en) 2014-07-16 2019-07-09 Novartis Ag Method of encapsulating a nucleic acid in a lipid nanoparticle host

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