JP2003521460A - Acetylated benzylmaltoside as an inhibitor of smooth muscle cell proliferation - Google Patents

Abstract

(57) Abstract The present invention provides a smooth muscle cell proliferation inhibitor represented by the structural formula (I) or a pharmaceutically acceptable salt thereof. Embedded image

Description

Detailed Description of the Invention

TECHNICAL FIELD The present invention relates to substituted acyls as smooth muscle cell growth inhibitors and as therapeutic compositions for treating diseases and conditions such as restenosis characterized by excessive smooth muscle proliferation. Benzyl maltoside is used.

BACKGROUND OF THE INVENTION All forms of revascularization, such as angioplasty and venous bypass, are directed against damage that eventually leads to smooth muscle cell (SMC) proliferation and subsequent deposition of large amounts of extracellular matrix. Bring a response (Clowes, AW)
; Reidy, MA, Journal of Vascular
Surgery (J. Vasc. Surg.), 1991, 13, 885). These events are associated with atherosclerosis (Raines, EW; Ross, Earl).
R.), British Heart Journal (Br. Heart J.), 1993, 69 (Supplement) S.30)
And post-transplant arteriosclerosis (Isik, FF); McDonald, TO; Ferguson, M .; Yamanaka, E .; It is also a central process in the etiology of Gordon, American Journal of Pathology (Am. J. Pathol., 1992, 141, 1139). In the case of restenosis after angioplasty, a clinically relevant solution to regulate SMC proliferation by pharmacological interference has remained elusive (Herrman, JPR). , JPR); Hermans, WRM; Vos, J .; Serois, Serruys, PW, Drugs, 1993, 4, 18 and 249). Selective SM
A successful approach to C growth inhibition must not interfere with the repair of endothelial cells or the normal growth and function of other cells (Weissburg, P.
.L.); Grainger, DJ; Shanahan, Si.
M (Shanahan, CM); Metcalfe, JC, Cardiovascular Res., 1993, 27, 1191).

Glycosaminoglycan heparin and heparan sulphate are endogenous inhibitors of SMC proliferation and are also able to promote endothelial cell proliferation (Castellot, JJJr.); Wright, T
.C.); Karnovsky, MJ, Seminars in
Seminars in Thrombosis and Hemostasis
), 1987, 13, 489). However, the full clinical utility of heparin, heparin fragments, chemically modified heparins, low molecular weight heparins, and other heparins that mimic anionic polysaccharides has led to other pharmacology associated with heterogeneity of various formulations. Trends (especially,
Excessive bleeding resulting from anticoagulant effects may decrease (Borman, S (Borma)
n, S.), Chemical and Engineering News (Chemical and Engine)
ering News), 1993, June 28, 27).

PCT Patent Application Publication No. WO 96/14325 discloses acylated benzyl glycosides as smooth muscle cell growth inhibitors. The compounds of the present invention differ in that they have different substituents on the sugar backbone.

Zehavi, U .; Herchman, M., Carbohyd. Res., 1986, 151, 371 for research as receptors in glycogen synthesis reactions. Disclosed are polymer-bound 4-carboxy-2-nitrobenzyl 4-O-α-D-glucopyranosyl-β-D-glucopyranoside. The compounds of the present invention differ in that they have different substituents on the benzyl group and in different uses (suppression of smooth muscle proliferation).

US Pat. No. 5,498,775, PCT Application Publication No. WO 96/14324 and US Pat.
464,827 describes polyanionic benzyl glycosides or cyclodextrins as smooth muscle cell growth inhibitors for treating diseases and conditions characterized by excessive smooth muscle proliferation. β-Cyclodextrin tetradeca sulfate has been described as a smooth muscle cell growth inhibitor and an effective inhibitor of restenosis (Reilly, CF; Fujita, T.); McFall, RC; Stabilito, Ai (Stabi
lito, II); Wai-se, E .; Johnson, John G.
on, RG), Drug Development Research (Drug Development Researc
h), 1993, 29, 137). US Pat. No. 5,019,562 discloses anionic derivatives of cyclodextrins for treating pathological conditions associated with unwanted cell or tissue proliferation. PCT Application Publication No. WO 93/09790 discloses antiproliferative polyanionic derivatives of cyclodextrins having at least two anion residues per sugar residue. Meinetsberger (European Patent Application Publication Nos. EP 312087 A2 and EP 312086 A2) describe the antithrombotic and anticoagulant properties of sulfated bis-aldonic amides. U.S. Pat. No. 4,431,637 discloses polysulfated phenolic glycosides as modulators of the complement system. The compounds of the present invention are (a) benzyl maltosides which have no structural similarities to heparin, sulfated cyclodextrins, or sulfated lactobionic acid dimers, and (b) only two It differs from all prior art in that it has adjacent sugar residues (which are disaccharides), (c) has a well-defined structure, and (d) is unsulfated.

[0007] (Disclosure of the invention)   The present invention provides formula I:

[0008]

[Chemical 12]

[Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently hydrogen or C 2
~ C7 acyl, C2-7 haloacyl, C2-7 nitroacyl, C2-7 cyanoacyl, C3-8 trifluoromethylacyl, or benzoyl (wherein the phenyl moiety is R ⁸ is substituted with); ^{R 6} and ^{R 7} are each ^{independently, -OH, -OR 9, O-} tert- butyldimethylsilyl, each alkyl moiety per 1 to 6 carbon atoms O- trialkylsilyl , O-triphenylsilyl,

[0010]

[Chemical 13]

R ⁸ , R ¹⁰ , R ¹¹ and R ¹² are each independently hydrogen, —CN, —NO ₂ , halogen, CF ₃ , alkyl having 1 to 6 carbons, acetyl, benzoyl or 1 carbon. Alkoxy having 6 to 6; R ⁹ is acyl having 2 to 7 carbons, haloacyl having 2 to 7 carbons, nitroacyl having 2 to 7 carbons, cyanoacyl having 2 to 7 carbons, trifluoromethyl having 3 to 8 carbons. Acyl or benzoyl (wherein the phenyl moiety is substituted with R ⁸ ); Y is O, S, NH, NMe or CH ₂ ; W is halogen, —CN, CF ₃ , C 1-6 alkyl, haloalkyl having 1 to 6 carbon atoms, nitro alkyl of 1 to 6 carbon atoms, cyanoalkyl having 1 to 6 carbon atoms, alkoxyalkyl having 2 to 12 carbon atoms, having 1 to 6 carbon atoms alkoxy or,, ^{R 8} so Roh -, di - or tri - substituted phenyl; Z _{is, -NO 2, -NH 2, -NHR} 13 or ^{-NHCO-Het; R 13} is an acyl having 2 to 7 carbon atoms, 2 to 7 carbon atoms Haloacyl of 2 to 7 carbon atoms
Nitroacyl, C 2-7 cyanoacyl, C 3-8 trifluoromethylacyl, benzoyl (wherein the phenyl moiety is substituted with R ⁸ ), or R ¹³ is an α-amino acid (wherein The α-carboxyl group forms an amide with the nitrogen of Z); if the amino acid is glutamic acid or aspartic acid, it is a non-α-carboxyl group.
(Wherein the alkyl moiety is 1 to 6 carbon atoms) carboxylic acid alkyl ester is; Het is pyridyl substituted with R ^8, thienyl substituted with R ^8, furyl substituted with R ^8, R ⁸ in substituted oxazolyl, pyrazinyl substituted with ^{R 8,} pyrimidinyl substituted with ^{R 8,} or thiazolyl substituted with ^{R 8; R 14} is, ^{R 8,} -NH _2, -CO ₂ H, or carbon atoms 2-7 —NH-acyl; n = 0-3; provided that when Z is —NHR ¹³ and Y is O, at least one of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is hydrogen. Or at least one of R ⁶ and R ⁷ is OH] or a pharmaceutically acceptable salt thereof.

Alkyl includes both straight chain and branched moieties. Halogen means bromine, chlorine, fluorine and iodine. When R ¹³ is an α-amino acid,
The carboxyl moiety is present as an amide in which the amide nitrogen is attached to the phenyl ring of the compound of formula I. The following exemplifies the structure obtained when R ¹³ is alanine.

[0013]

[Chemical 14]

When the amino acid has a second carboxyl moiety, this moiety is an alkyl ester of the free acid. The example below shows aspartic acid methyl ester.

[0015]

[Chemical 15]

Preferred amino acids include alanine, arginine, aspartic acid, cystine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine,
Methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. Amino acids defined by R ¹¹ include both D and L amino acids.

Pharmaceutically acceptable salts include organic and inorganic acids such as acetic acid, propionic acid,
Lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, phthalic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, naphthalenesulfonic acid, Benzenesulfonic acid, toluenesulfonic acid,
It can be formed from camphor sulfonic acid, as well as known acceptable acids. Salts may be formed with organic and inorganic bases, preferably alkali metal salts, such as sodium, lithium or potassium salts. Acid addition salts can be prepared when Y has a nitrogen or the compound of formula I has a basic nitrogen. Base addition salts can typically be prepared when the compound of formula I has a hydroxyl group.

The compounds of the invention may have asymmetric carbon atoms or sulfoxide moieties,
Some of the compounds of this invention may possess one or more asymmetric centers and thus give rise to optical isomers and diastereomers. Although not shown with respect to stereochemistry in Formula I, the present invention is directed to such optical isomers and diastereomers; and racemic and resolved enantiomerically pure R and S stereoisomers; And other mixtures of R and S stereoisomers; as well as pharmaceutically acceptable salts thereof.

[0019]   Preferred compounds of the invention have the formula I:

[0020]

[Chemical 16]

[Wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently hydrogen or acyl having 2 to 7 carbon atoms; R ⁶ and R ⁷ are each independently -OH, -OR ⁹ , O-tert-butyldimethylsilyl,

[0022]

[Chemical 17]

R ⁸ , R ¹⁰ , R ¹¹ and R ¹² are each independently hydrogen, —CN, —NO ₂ , halogen, CF ₃ , alkyl having 1 to 6 carbons, acetyl, benzoyl or 1 carbon. 6 alkoxy; ^{R 9} is an acyl having 2 to 7 carbon atoms or benzoyl (wherein the phenyl moiety is substituted with ^{R 8),;} Y is O or S; W is halogen, 1 to carbon atoms 6 alkyl, 1 to 6 carbon haloalkyl, 1 to 6 carbon nitroalkyl, 1 to 6 carbon cyanoalkyl, 2 to 12 carbon
Alkoxyalkyl, alkoxy having 1 to 6 carbon atoms, or R ⁸ mono-,
Di - or tri - substituted phenyl; Z _{is, -NO 2, -NH 2, -NHR} 13 or ^{-NHCO-Het; R 13} is an acyl having 2 to 7 carbon atoms or benzoyl (where the phenyl moiety Is substituted with R ⁸ ) or R ¹³ is an α-amino acid (where the α-carboxyl group forms an amide with the nitrogen of Z); if the amino acid is glutamic acid or aspartic acid, then α-
(Wherein the alkyl moiety is 1 to 6 carbon atoms) carboxylic acid alkyl ester; Het is pyridyl substituted by R ^8, thienyl substituted with R ^8, furyl substituted with R ^8, substituted by R ⁸ oxazolyl, pyrazinyl substituted with ^{R 8,} pyrimidinyl substituted with ^{R 8,} or thiazolyl substituted with ^{R 8; R 14} is, ^{R 8,} -NH _2, -CO ₂ H or a carbon number from 2 7 —NH-acyl; n = 0-3; provided that when Z is —NHR ¹³ and Y is O, then at least one of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is hydrogen. Or at least one of R ⁶ and R ⁷ is OH] or a pharmaceutically acceptable salt thereof.

Particularly preferred compounds of the invention are 4-chloro-3-nitrobenzyl-β-D-maltoside heptaacetate or a pharmaceutically acceptable salt thereof; N- {5-[(hepta-O-acetyl- β-D-maltosyloxy) methyl] -2-chlorophenyl} -L-aspartamide-γ-tert-butyl ester or a pharmaceutically acceptable salt thereof; N- {2-chloro-5-[(2, 2 ', 3,3', 4 ', 6,6')-hepta-O-acetyl-β-D-
Maltosyloxymethyl] phenyl}-(9H-fluoren-9-ylmethoxycarbonyl) -L-alanine amide or a pharmaceutically acceptable salt thereof; 4-benzoyl-N- {2-chloro-5-[(2, 2 ', 3,3', 4 ', 6,6'-hepta-O-acetyl-β-D-maltosyl) oxymethyl] phenyl} benzamide or a pharmaceutically acceptable salt thereof; (4-chloro-3-- (Nitrobenzyl) hepta-O-acetyl-1-thio-β-D-maltoside or a pharmaceutically acceptable salt thereof; (3-amino-4-chlorobenzyl) hepta-O-acetyl-1-thio-β-D -Maltoside or a pharmaceutically acceptable salt thereof; N- {2-chloro-5-[(hepta-O-acetyl-β-D-maltosyl-1-thio) methyl]
Phenyl} acetamide or a pharmaceutically acceptable salt thereof; 5-[(hepta-O-acetyl-β-D-maltosyl) oxymethyl] -2-cyano-1-nitrobenzene or a pharmaceutically acceptable salt thereof; N- [2-chloro-5- (β-D-maltosyloxymethyl) phenyl] acetamide or a pharmaceutically acceptable salt thereof; N- {5- [6,6′-di-O- (tert-butyldimethylsilyl) ) -β-D-Maltosyloxymethyl] -2-methylphenyl} acetamide or a pharmaceutically acceptable salt thereof; N- {2-chloro-5- [6,6′-di-O- (tert-butyl) Dimethylsilyl) -β-D-maltosyloxymethyl] phenyl} acetamide or a pharmaceutically acceptable salt thereof; N- {2-chloro-5-[([6,6′-di-O-benzoyl-β- D-maltosyl] oxy) methyl] phenyl} acetamide or a pharmaceutically acceptable salt thereof; N- {2-chloro-5-[([6,6'-di-O-be Zoyl-2,2 ', 3,3', 4'-pentaacetyl-β-D-maltosyl] oxy) methyl] phenyl} acetamide or a pharmaceutically acceptable salt thereof; (4-chloro-3-nitrophenyl) Methyl-4-O- [6-O- (3-pyridinylcarbonyl) -α-D-glucopyranosyl] -β-D-glucopyranoside-6- (3-pyridinecarboxylate) or a pharmaceutically acceptable salt thereof ; (4-chloro-3-nitrophenyl) methyl-4-O- [6-O- (3-pyridinylcarbonyl) -α-D-glucopyranosyl] -β-D-glucopyranoside or pharmaceutically acceptable thereof Salt; N- [2-chloro-5-[[(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl) oxy] methyl] phenyl] -3-pyridinecarboxamide or a pharmaceutically acceptable salt thereof; Benzoic acid 6- {4-chloro-3-[(pyridine-3-carbonyl) amino] benzyloxy} -4,5-dihydroxy- -(3,4,5-Trihydroxy-6-hydroxymethyltetrahydropyran-2-yloxy) tetrahydropyran-2-ylmethyl ester or a pharmaceutically acceptable salt thereof; (4-chloro-3-nitrobenzyl)- 1-deoxy-1-thio-β-D-maltoside or a pharmaceutically acceptable salt thereof; N- {2-chloro-5-[(β-D-maltosyl-1-thio) methyl] phenyl} acetamide or a salt thereof Pharmaceutically acceptable salts; 5-{[6,6'-bis-O- (4-toluenesulfonyl) -β-maltosyl] oxymethyl
} -2-Methyl-1-nitrobenzene or a pharmaceutically acceptable salt thereof; 5-{[2,2 ', 3,3', 4'-penta-O-acetyl-6,6'-bis-O- (4-Toluenesulfonyl) -β-maltosyl] oxymethyl} -2-methyl-1-nitrobenzene or a pharmaceutically acceptable salt thereof; 5-{[6,6′-dideoxy-6,6′-bis (4 -Nitroimidazol-1-yl) -β-
Maltosyl] oxymethyl} -2-methyl-1-nitrobenzene or a pharmaceutically acceptable salt thereof; and 5-{[2,2 ′, 3,3 ′, 4′-penta-O-acetyl-6,6 ′ -Dideoxy-6,6'-bis (4-nitroimidazol-1-yl) -β-maltosyl] oxymethyl} -2-methyl-
1-nitrobenzene or a pharmaceutically acceptable salt thereof.

The compounds of the present invention were prepared from commercially available starting materials or starting materials that can be prepared using methods described in the literature according to the schemes below. This scheme is
7 illustrates the preparation of representative compounds of this invention.

Acetobromomaltose 1 was treated with mercuric bromide, mercuric cyanide, in an aprotic solvent such as acetonitrile, dichloromethane, ether, toluene or nitromethane at a temperature in the range of −40 ° C. to reflux temperature. Coupling with benzyl alcohol 2 in the presence of a catalyst such as silver triflate or silver perchlorate gives glycoside 3 (Scheme 1). This glycoside formation can also be performed using Schmidt's trichloroacetimidate coupling with zinc bromide in a solvent such as dichloromethane. The nitro group of 3 can be reduced with a reducing agent such as stannous chloride in a polar aprotic solvent such as ethyl acetate at ambient temperature to reflux temperature to give the anilino compound 4. 4 at a temperature in the range of 0 ° C. to ambient temperature in an aprotic solvent such as dichloromethane or tetrahydrofuran in the presence of an amine base such as triethylamine or diisopropylethylamine,
Alternatively (in sterically hindered systems) a strong base such as sodium hydride can be used to couple with the acid chloride to give the desired compound 5. The fully acetylated compound 5 is converted to its heptahydroxy compound 6 using a catalytic amount of sodium methoxide in methanol or aqueous sodium hydroxide solution in methanol at a temperature in the range of ambient temperature to reflux temperature. be able to.

As shown in Scheme 2, the C-6 and C-6 ′ positions are treated with t-butyldimethylchlorosilane, a tertiary base such as triethylamine, and a catalytic amount of 4-dimethylaminopyridine to form a silyl ether ( It can be selectively protected as 7).
In addition, the primary alcohols at the 6- and 6'-positions were initially in a 1: 1 mixture of tetrahydrofuran and the sterically hindered base 2,4,6-collidine at -40 ° C to ambient temperature overnight. , Can be selectively acylated using the appropriate acid chloride (Scheme 3). The remaining 5 secondary alcohols of the disaccharide can then be protected with acetic anhydride and triethylamine in a solvent such as dichloromethane to give the fully acetylated compound 8.

In Scheme 4, the two primary alcohol positions (C-6 and C-6 ′) are first converted to the tosylate using tosyl chloride and pyridine in a solvent such as dichloromethane and then obtained The resulting intermediate is all acetylated as above to give compound 9. Substitution of 9 tosylates can introduce heterocyclic ring systems at the 6 and 6'positions. Finally, the five secondary acetates are removed with a catalytic amount of sodium methoxide in methanol or aqueous sodium hydroxide in methanol at a temperature in the range of ambient temperature to reflux to give compound 10.

[0029]

[Chemical 18]

When R ₂ = OH or OTBDMS:

[0031]

[Chemical 19]

When R ₂ = ester bond:

[0033]

[Chemical 20]

When R ₂ = tosylate or imidazole:

[0035]

[Chemical 21]

The compounds of the present invention are useful as antiproliferative agents. The methods described below demonstrate the evaluation of representative compounds of the invention in standard pharmacological test procedures that determine the ability of the compounds evaluated to inhibit smooth muscle cell proliferation.

Effect of Compounds on Cell Proliferation with ³ H Thymidine Transfer Human and porcine smooth muscle cells were tested at early passage (generally 3-7 passages) under sub-confluent conditions. did. The cultures were grown in medium 199 supplemented with 10% fetal bovine serum and 2% antibiotic / antimycotic using 16 mm (24 well) multiwell culture dishes. Once semi-confluent, these cells were allowed to grow in serum-free synthetic medium (AIM-V; Gibco for 24-48 hours before starting the experimental protocol).
)).

In general, compounds have been found to be more effective at longer pre-incubations, however, the method is initiated by adding the compound, ³ H thymidine and serum / growth factor to serum-deprived synchronized cells, Report the results accordingly.

Compound was added to each well at a 50-fold dilution (20 μL / well) and the plate was added to 5
Incubated at 37 ° C. in% CO ₂ for 24-36 hours. First, the compound
It was dissolved in 0% ethanol and serially diluted in the medium. Compounds were evaluated according to routine procedures at concentrations of 1-100 μM. As a control, grade II porcine intestinal mucosal heparin (sodium salt) was evaluated in all cell preparations at a concentration of 0.1-100 μg / mL by routine procedures.

At the end of the test method, the plate was placed on ice and ice-cold phosphate buffered saline (PBS).
Washed 3 times with and incubated in ice-cold 10% trichloroacetic acid (TCA) for 30 minutes to remove acid-dissolved protein. The solution was transferred to scintillation vials containing 0.4 N HCl (500 μL / vial, neutralizing NaOH) and each well rinsed twice with water (500 μL) to a total volume of 2 mL / vial.

Data were obtained in triplicate for both control and experimental samples. Control (100%) data were obtained from cells maximally stimulated as a result of stimulation with growth factors or serum. Experimental data were obtained from cells maximally stimulated with growth factors or serum and treated with compound. The data is shown in Table 1 below as an IC ₅₀ .

[0042]

[Table 1] Table 1

The compounds of the present invention are useful in treating or inhibiting diseases characterized by excessive smooth muscle cell proliferation (smooth muscle cell hyperproliferation). These compounds are particularly applicable to hyperproliferative blood vessels characterized by smooth muscle cell hyperproliferation that most frequently results from revascularization and transplantation (eg, balloon angioplasty, vascular graft surgery, coronary artery bypass surgery and heart transplant). It is useful for treating diseases such as restenosis. Other disease states in which there is unfavorable "cellular" blood vessel growth include hypertension, asthma and congestive heart failure. The compounds of the present invention are also useful as inhibitors of angiogenesis. Angiogenesis, the process by which new capillaries are formed (neovascularization), is primarily important for many pathological events, including chronic inflammation and malignancy. Therefore, the compounds of the present invention are useful as anti-neoplastic agents.

The compounds of the present invention can be formulated neat or with a pharmaceutical carrier for administration. The proportion is determined by the solubility and chemical nature of the compound, the chosen route of administration, and standard pharmacological practice. The pharmaceutical carrier may be either solid or liquid.

As the solid carrier, one kind or a substance capable of acting also as a flavoring agent, lubricant, solubilizing agent, suspending agent, filler, fluidizing agent, compression aid, binder or tablet disintegrating agent The above substances can be mentioned. It can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain up to 99% of active ingredient. Suitable solid carriers include
For example, calcium phosphate, magnesium stearate, talc, sugar, lactose,
Dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or a pharmaceutically acceptable oil or fat. Liquid carriers include other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity modifiers, stabilizers. Agents or osmotic pressure regulators and the like. Suitable examples of liquid carriers for oral and parenteral administration include water (additives as described above (e.g.,
Partially containing cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols (e.g. glycols)) and their derivatives, lecithin, and oils (e.g.
Fractionated palm oil and peanut oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. The sterile solution can also be administered intravenously. The compounds of the present invention can also be administered orally either in liquid or solid composition form.

The compounds of the present invention may be administered rectally or vaginally in the form of conventional suppositories.
For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of the present invention may be formulated in aqueous or semi-aqueous solutions. These are then available in the form of aerosols. The compounds of the present invention may be administered transdermally by use of a transdermal patch containing the active compound and a carrier. However, the carrier should be inert to the active compounds, non-toxic to the skin, and should allow delivery of the drug for systemic absorption through the skin and into the bloodstream. Such carriers can take any number of forms, including creams and ointments, pastes, gels, and closures. Creams and ointments may be viscous liquids or semisolid emulsions of either oil-in-water or water-in-oil type. A paste consisting of absorbent powder dispersed in petrolatum containing the active ingredient or hydrophilic petrolatum is also suitable. The active ingredient may be released into the bloodstream using various closure devices, such as a semipermeable membrane covering a reservoir containing the active ingredient, optionally with a carrier, a matrix containing the active ingredient, and the like. . Other closures are known in the literature.

Dosage requirements will vary with the particular composition employed, the route of administration, the severity of the symptoms presenting and the particular patient being treated. Based on the results obtained with standard pharmacological test methods, the planned daily dose of active compound will be 0.1-10 mg / kg administered parenterally (preferably intravenously). Is. The daily dose for planned oral administration is about 10 times higher. Intravenous administration is continued for about 5 to 30 days after acute vascular injury (ie balloon angioplasty or transplantation), but appears to be longer for treatment of chronic disorders. Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter, the dose is increased until the optimum effect under these circumstances is reached. The exact dose for oral, parenteral, nasal or bronchial administration will depend on the experience of the individual patient being treated,
Determined by the administering physician. Preferably, the pharmaceutical composition is in unit dosage form, for example provided as tablets or capsules. In such dosage form, the composition is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged composition, for example, a packaged powder, a vial, an ampoule, a prefilled syringe or a solution-containing sachet. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such packaged form.

[0050]   The following provides the preparation of representative compounds of this invention.

Example 1 4-Chloro-3-nitrobenzyl-β-D-maltoside heptaacetate 4-Chloro-3-nitrobenzyl alcohol (6.70 g, 35.35%) in freshly distilled CH ₃ CN (239 mL). 7 mmol) and HgBr ₂ (14.2 g, 3
To a stirred solution of 9.3 mmol) was added Hg (CN) ₂ (9.02 g, 35.7 mmol) in one portion. After 0.5 hours, acetobromomaltose (25.0 g, 35.7 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction was then converted to H ₂ O:
Quench with brine (1: 1, 100 mL) and extract with 10% CH ₂ Cl ₂ : EtOAc. The combined organic extracts were dried (MgSO _4), and concentrated. Purification by flash chromatography (10:90 to 80:20 EtOAc: petroleum ether gradient) gave 51.9 g (90%) of the title compound as a smooth oil.
This was recrystallized from Et ₂ O: petroleum ether to give a glassy white solid.
Melting point 107-111 ° C; ¹ H NMR (CDCl ₃ ) δ 2.00 (s, 3H), 2.02
(s, 3H), 2.03, (s, 3H), 2.04 (s, 6H), 2.11 (s, 3H), 2.1
5 (s, 3H), 3.70 (ddd, J = 2.9, 4.2, 9.7Hz, 1H), 3.94-3.
98 (m, 1H), 4.01 to 4.07 (m, 2H), 4.20 to 4.28 (m, 2H), 4.5
4 (dd, J = 2.9, 12.3 Hz, 1H), 4.63-4.68 (m, 2H), 4.84-
4.94 (m, 3H), 5.06 (t, J = 10.1Hz, 1H), 5.26 (t, J = 9.2)
Hz, 1H), 5.36 (dd, J = 9.7, 10.3 Hz, 1H), 5.42 (d, J = 4.
2 Hz, 1 H), 7.43 (dd, J = 2.2, 8.3 Hz, 1 H), 7.53 (d, J = 8.
3 Hz, 1 H), 7.83 (d, J = 2.0 Hz, 1 H); IR (KBr) 3450, 29
50, 1755, 1550, 1375, 1230 and 1050 cm ⁻¹ ; mass spectrum [(+) ESI], m / z 823/825 (M + NH ₄ ⁺ ), 828/830 (M
+ Na) ⁺ ; Result of elemental analysis: Calculated value (as C ₃₃ H ₄₀ ClNO ₂₀ ): C, 49.17; H, 5.00; N,
1.74; Found: C, 49.16; H, 4.88; N, 1.71.

Example 2 N- {5-[(hepta-O-acetyl-β-D-maltosyloxy) methyl] -2-chlorophenyl} -L-aspartamide-γ-tert-butyl ester

Step 1 2-Chloro-5- (hepta-O-acetyl-β-D-maltosyloxymethyl) phenylamine 4-chloro-3-nitrobenzyl-β-D-maltoside in EtOAc (479 mL) A solution containing heptaacetate (Example 1, 19.3 g, 23.9 mmol) and tin (II) chloride dihydrate (37.7 g, 167 mmol) was refluxed for 2 hours. The reaction was cooled to room temperature, carefully quenched with saturated aqueous NaHCO ₃ (until basic), diluted with EtOAc (250 mL), stirred for 0.5 h and filtered. The biphasic filtrate was separated and the aqueous phase was extracted with EtOAc. Combine the combined organic extracts (
It was dried (Na ₂ SO ₄ ) and concentrated. Flash chromatography (0% to 1
Purified with 2% acetone / CHCl ₃ gradient) to give 17.8 g (96%) of 2-chloro-5- (hepta-O-acetyl-β-D-maltosyloxymethyl) phenylamine as a glassy solid. I got it as a thing. Melting point 78-79 ° C; ¹ H NMR (CDCl ₃ ) δ 2.00
(s, 9H), 2.026 (s, 3H), 2.032 (s, 3H), 2.11 (s, 3H), 2.
16 (s, 3H), 3.00-5.00 (bs, 2H), 3.64-3.68 (m, 1H), 3.
97 (ddd, J = 2.4, 4.2, 10.1 Hz, 1H), 4.02-4.07 (m, 2H)
, 4.24 (dd, J = 2.2, 3.7, 1H), 4.27 (dd, J = 2.6, 4.0 Hz,
1H), 4.50-4.57 (m, 3H), 4.74 (d, J = 12.1Hz, 1H), 4.8
3-4.90 (m, 2H), 5.05 (t, J = 10.1Hz, 1H), 5.22 (t, J = 9)
.2 Hz, 1 H), 5.35 (dd, J = 9.7, 10.5 Hz, 1 H), 5.42 (d, J =
4.0Hz, 1H), 6.62 (dd, J = 2.0, 8.1Hz, 1H), 6.76 (d, J =
2.0 Hz, 1H), 7.21 (d, J = 8.1, 1H); IR (KBr) 3450,335
0,2950,1755,1650,1425,1375,1230 and 1050c
m ⁻¹ ; mass spectrum [(+) ESI], m / z 776/778 (M + H) ⁺ , 79
8/800 (M + Na) ⁺ ; Elemental analysis results: Calculated value (as C ₃₃ H ₄₂ ClNO ₁₈ ): C, 51.07; H, 5.45; N,
1.80; Found: C, 50.94; H, 5.52; N, 1.60.

Step 2 N- {5-[(hepta-O-acetyl-β-D-maltosyloxy) methyl] -2-chlorophenyl}-(9H-fluoren-9-ylmethoxycarbonylamino) -L-aspar Toamido-4-tert-butyl ester N- (9H-fluoren-9-ylmethoxycarbonylamino) -L-aspartic acid-4-tert-butyl ester (0.117 g in CH ₂ Cl ₂ (3 mL) at room temperature.
, 0.284 mmol) and DMF (catalytic amount) in a stirred solution of oxalyl chloride (2
4.8 μL, 0.284 mmol) was added dropwise. After 5 minutes at room temperature, 1 more at 40 ° C
Heat for 0 minutes. Thus, the production of the acid chloride raw material was completed. At this point, a second stirred solution of NaH (0.0103 g, 0.258 mmol) and CH ₂ Cl ₂ (4 mL) at room temperature was added to 2-chloro-5- (hepta-O-acetyl-β-D-. Maltosyloxymethyl) phenylamine (0.200 mg, 0.258 mmol) was added. After 10 minutes, the above acid chloride solution was added dropwise to this solution. The reaction was stirred at room temperature for 1 hour then diluted with EtOAc (100 mL). This layer was washed with 1 N HCl (10 mL), saturated NaHCO ₃ solution (10 mL) and brine (10 mL) before being washed with (MgS
O ₄ in) and then dried. After concentration, the oily residue was flash chromatographed (10:
Purify with 90-70: 30 EtOAc: petroleum ether gradient) to give the product (0.
157 g, 52%) was obtained as a white foam. Melting point 103-105 ° C; ¹ H N
MR (CDCl ₃ ) δ 1.46 (s, 9H), 1.99 (s, 3H), 2.00 (s, 3H),
2.01 (s, 3H), 2.02 (s, 3H), 2.03 (s, 3H), 2.10 (s, 3H),
2.16 (s, 3H), 2.70 (dd, J = 5.9, 17.4Hz, 1H), 2.96-3.
06 (m, 1H), 3.67 (ddd, J = 2.6, 4.2, 9.7Hz, 1H), 3.96 (
ddd, J = 2.4, 3.7, 10.3 Hz, 1H), 4.00-4.06 (m, 2H), 4.
22-4.28 (m, 3H), 4.42-4.48 (m, 1H), 4.48-4.56 (m, 2H)
), 4.58 (dd, J = 2.2, 10.1 Hz, 2H), 4.68-4.76 (m, 1H),
4.81-4.91 (m, 3H), 5.05 (t, J = 10.1 Hz, 1H), 5.22 (t,
J = 9.2Hz, 1H), 5.35 (dd, J = 9.7, 10.5Hz, 1H), 5.41 (
d, J = 4.0 Hz, 1H), 6.07-6.15 (m, 1H), 7.00 (dd, J = 2.0)
, 8.1Hz, 1H), 7.28-7.36 (m, 3H), 7.40 (t, J = 7.2Hz, 2
H), 7.57-7.62 (m, 2H), 7.77 (d, J = 7.5Hz, 2H), 8.31 (
d, J = 1.8 Hz, 1H), 8.86 (s, 1H); IR (KBr) 3380, 2960,
1755, 1600, 1540, 1440, 1420, 1375, 1230, 1160
And 1050 cm ⁻¹ ; mass spectrum [(+) FAB], m / z 1169 (M +
^{H) +, 1191 (M +} Na) +; Elemental analysis: Calculated _{(as C 56 H 65 ClN 2 O 23} · 2.0H 2 O): C, 55.79;
H, 5.77; N, 2.32; Found: C, 55.89; H, 5.45; N, 2.25.

Step 3 N- {5-[(Hepta-O-acetyl-β-D-maltosyloxy) methyl] -2-chlorophenyl} -L-aspartamide-γ-tert-butyl ester DMF (room temperature 20% piperidine (2.00 mL, 20.2 mL in 10 mL)
To a stirred solution of N- {5-[(hepta-O-acetyl-β-D-maltosyloxy) methyl] -2-chlorophenyl}-(9H-fluoren-9-ylmethoxycarbonylamino) -L. -Aspartamide-4-tert-butyl ester (0.300 g, 0.25
6 mmol) was added. After 1 hour at this temperature, the solution was concentrated under high vacuum. At this point, the residue was diluted with cold H ₂ O (20 mL) and then extracted with Et ₂ O (50 mL). The layer was dried (Na ₂ SO ₄ ) and after concentration the resulting oil was purified by flash chromatography (20:80 to 90:10 EtOAc: petroleum ether gradient) to give the product (0 .186 g, 77%) was obtained as a white solid. Melting point 85-87 ° C; ¹ H NMR (CDCl ₃ ) δ 1.45 (s, 9H), 1.89 (s, 2H
), 1.99 (s, 6H), 2.01 (s, 3H), 2.02 (s, 3H), 2.03 (s, 3H)
), 2.10 (s, 3H), 2.16 (s, 3H), 2.68 (dd, J = 8.1, 16.7H)
z, 1H), 2.91 (dd, J = 3.7, 16.7 Hz, 1H), 3.64-3.69 (m,
1H), 3.80 (dd, J = 3.7, 8.3 Hz, 1H), 3.93-3.98 (m, 1H)
, 3.99-4.05 (m, 2H), 4.21-4.27 (m, 2H), 4.50 (dd, J =
2.6, 12.1Hz, 1H), 4.56 (d, J = 3.7Hz, 1H), 4.59 (d, J =
8.1Hz, 1H), 4.81-4.91 (m, 3H), 5.05 (t, J = 10.1Hz, 1
H), 5.22 (t, J = 9.4 Hz, 1 H), 5.34 (dd, J = 9.4, 10.3 Hz,
1H), 5.40 (d, J = 4.0 Hz, 1H), 6.98 (dd, J = 2.0, 8.1 Hz,
1H), 7.34 (d, J = 8.1Hz, 1H), 8.42 (d, J = 2.0Hz, 1H),
10.28 (s, 1H); IR (KBr) 3380,2960,1755,1600,15
40, 1440, 1420, 1375, 1235, 1140 and 1040 cm ^-1
Mass spectrum [(+) FAB], m / z 947/949 (M + H) ⁺ , 969/97
1 (M + Na) ⁺ ; Result of elemental analysis: Calculated value (as C ₄₁ H ₅₅ ClN ₂ O ₂₁ ): C, 51.98; H, 5.85; N
Found: C, 51.62; H, 5.89; N, 2.95.

Example 3 N- {2-chloro-5-[(2,2 ′, 3,3 ′, 4 ′, 6,6 ′)-hepta-O-acetyl-β-D-
Maltosyloxymethyl] phenyl}-(9H-fluoren-9-ylmethoxycarbonyl) -L-alaninamide The title compound is N- (9H-fluoren-9-ylmethoxycarbonylamino) -L-
2-Chloro-5- (hepta) was prepared using alanine and a method similar to Step 2 of Example 2.
White foam from -O-acetyl-β-D-maltosyloxymethyl) phenylamine
(2.50 g, 36%). Melting point> 96 ° C. (decomposition); ¹ H NMR (DM
SO-d ₆ ) δ 1.33 (dd, J = 7.2 Hz, 3H), 1.918 (s, 3H), 1.9
19 (s, 3H), 1.94 (s, 3H), 1.966 (s, 3H), 1.97 (s, 3H),
2.01 (s, 3H), 2.07 (s, 3H), 3.91-4.02 (m, 4H), 4.12-4
.24 (m, 3H), 4.24-4.34 (m, 3H), 4.34-4.40 (m, 1H), 4.
53 (d, J = 12.7Hz, 1H), 4.68-4.75 (m, 2H), 4.84 (d, J =
4.0Hz, 1H), 4.86 (d, J = 2.6Hz, 1H), 4.97 (t, J = 9.7H)
z, 1H), 5.21 (t, J = 9.7Hz, 1H), 5.27 (d, J = 3.7Hz, 1H)
, 5.27-5.32 (m, 1H), 7.08 (dd, J = 1.8, 8.1 Hz, 1H), 7.
32 (t, J = 7.2Hz, 2H), 7.40 (t, J = 7.5Hz, 2H), 7.47 (d,
J = 8.1Hz, 1H), 7.69-7.78 (m, 4H), 7.88 (d, J = 7.5Hz,
2H), 9.42 (s, 1H); IR (KBr) 3360, 3010, 2950, 1755
, 1590, 1535, 1440, 1420, 1370, 1230, 1050 and 7
55 cm ⁻¹ ; mass spectrum [(+) ESI], m / z 1069.2 (M + H) ⁺ ,
_{1086.2 / 1088.2 (M + NH 4} ) +; Elemental analysis: Calculated _{(as C 51 H 57 ClN 2 O 21} · 3.5H 2 O): C, 54.09;
H, 5.70; N, 2.47; Found: C, 53.67; H, 5.11; N, 2.34.

Example 4 4-benzoyl-N- {2-chloro-5-[(2,2 ′, 3,3 ′, 4 ′, 6,6′-hepta-O-acetyl-β-D-maltosyl) ) Oxymethyl] phenyl} benzamide The title compound was 2-chloro-5- (hepta-O-acetyl-β-D-maltosyl) using p-benzoylbenzoic acid and a method similar to Step 2 of Example 2. (Oxymethyl)
Prepared from phenylamine as a white foam (0.240 g, 94%). Melting point> 84 ° C. (decomposition); ¹ H NMR (DMSO-d ₆ ) δ1.93 (s, 3H), 1.94 (s
, 6H), 1.97 (s, 6H), 2.01 (s, 3H), 2.08 (s, 3H), 3.93-4
0.03 (m, 4H), 4.15 (dd, J = 4.6, 12.3 Hz, 1H), 4.21 (dd,
J = 4.6,12.1 Hz, 1H), 4.39 (dd, J = 2.2,11.9 Hz, 1H),
4.70 (ABq, J = 12.7 Hz, Δδ = 0.14,2H), 4.74 (dd, J = 8.
1,9.7 Hz, 1 H), 4.86 (dd, J = 4.0, 10.5 Hz, 1 H), 4.90 (d
, J = 8.1 Hz, 1H), 4.98 (t, J = 9.7 Hz, 1H), 5.21 (dd, J =
9.7, 10.5 Hz, 1H), 5.28 (d, J = 4.0 Hz, 1H), 5.31 (dd, J
= 8.6, 9.4 Hz, 1H), 7.22 (dd, J = 2.0, 8.3 Hz, 1H), 7.52
(d, J = 2.0 Hz, 1H), 7.55-7.62 (m, 3H), 7.69-7.74 (m, 1)
H), 7.76-7.80 (m, 2H), 7.85-7.88 (m, 2H), 8.11-8.14
(m, 2H), 10.30 (s, 1H); IR (KBr) 3400, 3010, 2950, 1
755, 1675, 1650, 1590, 1530, 1440, 1420, 1370, 1
230, 1130 and 1040 cm ^-1 ; mass spectrum [(+) FAB], m / z
984/986 (M + H) ⁺ , 1006/1008 (M + Na) ⁺ ; Results of elemental analysis: Calculated value (as C ₄₇ H ₅₀ ClNO ₂₀ ): C, 57.35; H, 5.12; N,
1.42; Found: C, 57.11; H, 5.03; N, 1.32.

Example 5 (4-Chloro-3-nitrobenzyl) hepta-O-acetyl-1-thio-β-D-maltoside Hepta-O-acetyl-1-thio-β-maltose in acetone (20 mL) (
(2.0 g, 3.065 mmol) [PL Durette; TY Shen, Carb Hydrate Research (Carb. Res.), 1978.
, 67,484-490] in a stirred solution of 4-chloro-3-nitrobenzyl bromide (0.844
mg, 3.37 mmol), and potassium carbonate (0.42) in water (10 mL).
A solution of 3 mg, 3.065 mmol) was added. The mixture was boiled under reflux for 30 minutes, cooled and concentrated. The residue was extracted with dichloromethane, and the combined extracts were washed with water and brine, dried (MgSO _4), and concentrated. Purification by flash chromatography (40% -60% EtOAc / petroleum ether gradient) afforded 1.588 g (63%) of the title compound as a white solid. Melting point 73-75
° C; ¹ H NMR (CDCl ₃ ) δ 1.99 (s, 3H), 2.00 (s, 3H), 2.02
(s, 3H), 2.03 (s, 6H), 2.11 (s, 3H), 2.15 (s, 3H), 3.61
-3.64 (m, 1H), 3.80 (d, J = 13.6Hz, 1H), 3.94-4.00 (m,
3H), 4.08 (dd, J = 12.3, 2.4 Hz, 1H), 4.18-4.27 (m, 2H
), 4.36 (d, J = 9.9 Hz, 1 H), 4.50 (dd, J = 12.1, 2.6 Hz, 1)
H), 4.85 (dd, J = 10.5, 4.0 Hz, 1H), 4.90 (apparent t, J =
9.9Hz, 1H), 5.05 (apparent t, J = 9.9Hz, 1H), 5.23 (apparent t, J = 9.2Hz, 1H), 5.34 (apparent t, J = 9.7 Hz, 1H),
5.40 (d, J = 4.0Hz, 1H), 7.47 (dd, J = 8.4,2.0Hz, 1H),
7.51 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H); IR (K
Br) 3500, 2950, 1750, 1250 and 1050 cm ⁻¹ ; mass spectrum [(+) FAB], m / z 822 (M + H) ⁺ , 844 (M + Na) ⁺ ; Results of elemental analysis: calculated value (C ₃₃ H _40). ClNO ₁₉ S): C, 48.21; H, 4.90; N
, 1.70; Found: C, 47.75; H, 4.86; N, 1.65.

Example 6 (3-Amino-4-chlorobenzyl) hepta-O-acetyl-1-thio-β-D-maltoside The title compound was prepared using the same method as in Step 1 of Example 2 ( Prepared from 4-chloro-3-nitrobenzyl) hepta-O-acetyl-1-thio-β-D-maltoside as a white solid. Melting point 78 ° C; ¹ H NMR (CDCl ₃ ) δ 1.99 (s, 9H), 2.
02 (s, 3H), 2.03 (s, 3H), 2.11 (s, 3H), 2.18 (s, 3H), 3.
57-3.60 (m, 1H), 3.73 (ABq, J = 13.0 Hz, Δδ = 0.16,2H
), 3.95-4.08 (m, 3H), 4.17 (bs, 2H), 4.23 (d, J = 4.2H)
z, 2H), 4.27 (dd, J = 7.7, 4.4 Hz, 1H), 4.31 (d, J = 4.4H)
z, 1H), 4.34 (d, J = 10.1 Hz, 1H), 4.44 (dd, J = 12.1, 3.
3 Hz, 1 H), 4.84 (dd, J = 10.5, 4.0 Hz, 1 H), 4.88 (apparent t, J = 9.9 Hz, 1 H), 5.03 (apparent t , J = 9.9Hz, 1H), 5.
35 (apparent t, J = 9.0Hz, 1H), 5.35 (apparent t, J = 9.4H
z, 1H), 5.40 (d, J = 4.0Hz, 2H), 6.60 (dd, J = 8.1, 2.0H
z, 1H), 6.73 (d, J = 2.0Hz, 1H), 7.18 (d, J = 8.13Hz, 1
H); IR (KBr) 3500,2950,1750,1245 and 1050 cm ^{- 1;} mass spectrum [(-) FAB], m / z 790 (M-H) -; Elemental analysis: Calculated _{(C 33} H ₄₂ ClNO ₁₇ ): C, 50.03; H, 5.34; N,
1.77; Found: C, 49.55; H, 5.21; N, 1.71.

Example 7 N- {2-chloro-5-[(hepta-O-acetyl-β-D-maltosyl-1-thio) methyl]
Phenyl} acetamide The title compound was obtained from (3-amino-4-chlorobenzyl) hepta-O-acetyl-1-thio-β-D-maltoside as a white solid using a method similar to Step 1 of Example 9. Manufactured as a product. Melting point 80-81 ° C; ¹ H NMR (CDCl ₃ ) δ 1.99 (s, 9H
), 2.03 (s, 6H), 2.11 (s, 3H), 2.16 (s, 3H), 2.25 (s, 3H)
), 3.61-3.65 (m, 1H), 3.82 (ABq, J = 13.2 Hz, Δδ = 0.1
4, 2H), 3.94-4.11 (m, 3H), 4.34 (d, J = 10.1Hz, 1H), 4
.53 (dd, J = 12.3, 2.6 Hz, 1H), 4.83-4.91 (m, 2H), 5.0
5 (apparent t, J = 9.7Hz, 1H), 5.20 (apparent t, J = 9.0Hz,
1H), 5.34 (apparent t, J = 10.3Hz, 1H), 5.39 (d, J = 4.2)
Hz, 1H), 7.00 (dd, J = 8.1, 2.2Hz, 1H), 7.33 (d, J = 8.4)
Hz, 1H), 7.62 (s, 1H), 8.31 (s, 1H); IR (KBr) 3400, 2
955, 1750, 1245 and 1050 cm ^-1 ; mass spectrum [(+) FA
B], m / z 834 (M + H) ⁺ , 856 (M + Na) ⁺ ; Results of elemental analysis: Calculated value (as C ₃₅ H ₄₄ ClNO ₁₈ S): C, 50.39; H, 5.32; N
Found: C, 49.99; H, 5.07; N, 1.59.

Example 8 5-[(Hepta-O-acetyl-β-D-maltosyl) oxymethyl] -2-cyano-1-nitrobenzene

Step 1 4-Methyl-2-nitrobenzonitrile (2.04) in α-bromo-2-nitro-p-tolunitrile CCl ₄ (50 mL)
g, 12.6 mmol), N-bromosuccinimide (2.24 g, 12.6 mmol)
) And azobisisobutyronitrile (0.103 g, 0.630 mmol) was irradiated with a 300 watt floodlight for 2 hours. The reaction was diluted with CH ₂ Cl ₂ (50 mL), filtered and concentrated. Purify by flash chromatography (35% and 40% ether / petroleum ether gradient),
1.44 g (47%) of the title compound was obtained as a yellow oil. ¹ H NMR (DMS
O-d ₆ ) δ 4.90 (s, 2H), 8.05 (dd, J = 8.0, 1.5Hz, 1H), 8.
18 (d, J = 8.0, 1H), 8.52 (s, 1H).

Step 2 α-Hydroxy-2-nitro-p-tolunitrile α-Bromo-2-nitro-p-tolunitrile (1.228 g, 5.095 mmol) in ethanol: water (4: 1, 25 mL) and Sodium formate (0.8664
g, 12.74 mmol) was refluxed for 2 hours. The reaction was cooled to room temperature, diluted with 20% CH ₂ Cl ₂ / EtOAc, washed with H ₂ O (3 times), (M
It was dried (gSO ₄ ) and concentrated. Purify by flash chromatography (1%, 2% and 3% MeOH / CHCl ₃ gradient) to give 0.695 g (77%) of the title compound.
%) As a white solid. ¹ H NMR (DMSO-d ₆ ) δ4.71 (d, 2H
), 5.75 (t, 1H), 7.89 (dd, J = 7.9Hz, 1H), 8.14 (d, J = 7)
.9 Hz, 1H), 8.32 (s, 1H).

[0064]   Process 3   5-[(hepta-O-acetyl-β-D-maltosyl) oxymethyl] -2-cyano-1-ni
Trobenzene   Freshly distilled CH at ambient temperature_ThreeAcetobromoma in CN (34 mL)
Lactose (2.39 g, 3.41 mmol), α-hydroxy-2-nitro-p-torni
Trilyl (0.789 g, 4.43 mmol) and HgBr_Two(1.60g, 4.43
Hg (CN) in a stirred solution of_Two(1.12 g, 4.43 mmol) at once
added. After 16 hours, brine (50 mL) was added and the mixture was added 10% CH._TwoCl _Two / Extracted with EtOAc. The combined organic extracts were washed with brine (three times) and washed with (Mg
SO_FourDried) and concentrated. Flash chromatography (1%, 2% and
And 3% MeOH / CHCl_ThreeGradient) and 1.941 g (71%) of the title compound.
) Was obtained as a foam. The analytical sample was recrystallized from EtOAc / Hexane before the E
Obtained by recrystallisation from tOH to give a white solid. Melting point 155-15
7 ° C;¹1 H NMR (DMSO-d₆) δ1.93 (s, 3H), 1.94 (s, 3H), 1
.97 (s, 3H), 1.99 (s, 3H), 2.01 (s, 3H), 2.06 (s, 3H), 3
.93-4.01 (m, 4H), 4.36 (d, J = 11.0Hz, 1H), 4.77 (dd,
J = 9.6, 8.0 Hz, 1H), 4.83-4.88 (m, 2H), 4.93-5.00 (m,
3H), 5.21 (dd, J = 10.3, 9.7 Hz, 1H), 5.27 (d, J = 3.7H)
z, 1H), 5.30-5.34 (m, 1H), 7.84 (dd, J = 7.9, 1.5Hz, 1
H), 8.18 (d, J = 7.9 Hz, 1H), 8.27 (s, 1H); IR (KBr) 34
50, 2950, 2225, 1750, 1225 and 1050 cm^-1Mass spec
Cuttle [(+) FAB], m / z 797 (M + H)⁺;   Elemental analysis results:   Calculated value (C₃₄H₄₀N_TwoO₂₀As): C, 51.26; H, 5.06; N, 3.
52;   Found: C, 51.06; H, 5.02; N, 3.31.

[0065]   Example 9   N- [2-chloro-5- (β-D-maltosyloxymethyl) phenyl] acetamide

Step 1 N- [2-chloro-5- (hepta-O-acetyl-β-D-maltosyloxymethyl) phenyl] acetamide 2-chloro-5- (hepta in THF (265 mL) at 0 ° C. -O-acetyl-β-
Acetyl chloride (2.26 mL, 31.8 mmol) was added dropwise to a stirred solution of D-maltosyloxymethyl) phenylamine (20.6 g, 26.5 mmol) and triethylamine (8.13 mL, 58.3 mmol). did. After 0.5 hour at this temperature, it was warmed to room temperature and stirred for a further 6 hours. At this point, the reaction was concentrated and washed with EtOAc (
700 mL). This organic solution was treated with 1N HCl (70 mL), saturated NaH.
After washing with aqueous CO ₃ solution (70 mL) and brine (70 mL) (with MgSO ₄ ).
Dried. After concentration, the residue is flash chromatographed (20: 80-10).
Purify with 0: 0 EtOAc: petroleum ether gradient) to give the product (16.2 g, 7
5%) as a glassy solid. Melting point 84-86 ° C; ¹ H NMR (CDC
l ₃ ) δ 2.00 (s, 6H), 2.020 (s, 3H), 2.027 (s, 3H), 2.03
(s, 3H), 2.11 (s, 3H), 2.16 (s, 3H), 2.24 (s, 3H), 3.66
-3.69 (m, 1H), 3.94-3.98 (m, 1H), 4.00-4.06 (m, 2H),
4.22-4.28 (m, 2H), 4.50-4.61 (m, 3H), 4.80-4.91 (m,
3H), 5.05 (t, J = 10.1Hz, 1H), 5.22 (t, J = 9.2Hz, 1H)
, 5.35 (dd, J = 9.4, 10.5 Hz, 1H), 5.41 (d, J = 4.0 Hz, 1
H), 6.99 (dd, J = 2.0, 8.1 Hz, 1 H), 7.34 (d, J = 8.1 Hz, 1
H), 7.62 (s, 1H), 8.32 (s, 1H); IR (KBr) 3400, 2950,
1750, 1690, 1600, 1540, 1425, 1375, 1230 and 10
50 cm ⁻¹ ; mass spectrum [(+) ESI], m / z 818/820 (M + H) ⁺
, 840 (M + Na) ⁺ ; Result of elemental analysis: Calculated value (as C ₃₅ H ₄₄ ClNO ₁₉ ): C, 51.38; H, 5.42; N,
1.71; Found: C, 51.03; H, 5.36; N, 1.59.

Step 2 N- [2-chloro-5- (β-D-maltosyloxymethyl) phenyl] acetamide N- [2-chloro-5- (hepta-O-acetyl) in MeOH (27.6 mL). -β
A solution containing -D-maltosyloxymethyl) phenyl] acetamide (0.945 g, 1.12 mmol) and 25 wt% NaOMe (19.2 μL, 0.336 mmol) in MeOH was refluxed for 2.5 hours. did. The reaction was cooled to room temperature, concentrated,
The residue obtained was triturated with Et ₂ O to give the product (0.583 g, 99%) as a foam. ¹ H NMR (DMSO-d ₆ ) δ2.07 (s, 3H), 3.03-3.
16 (m, 2H), 3.19-3.49 (m, 7H), 3.55-3.62 (m, 2H), 3.6
7-3.73 (m, 1H), 4.28 (d, J = 7.7Hz, 1H), 4.33-5.76 (b
s, 7H), 4.67 (ABq, J = 12.5 Hz, Δδ = 0.22, 2H), 5.01 (d
, J = 3.7 Hz, 1 H), 7.21 (dd, J = 1.8, 8.1 Hz, 1 H), 7.44 (d
, J = 8.1 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 9.33-9.69 (b
s, 1H); IR (KBr) 3400, 2900, 1680, 1600, 1540, 14
30, 1375, 1310, 1150 and 1035 cm ^-1 ; mass spectrum [(
+) ESI], m / z 524/526 (M + H) ⁺ , 546 (M + Na) ⁺ ; Results of elemental analysis: Calculated value (as C ₂₁ H ₃₀ ClNO ₁₂ 1.0 MeOH): C, 47.53;
H, 6.16; N, 2.52; Found: C, 47.94; H, 6.34; N, 2.42.

Example 10 N- {5- [6,6′-di-O- (tert-butyldimethylsilyl) -β-D-maltosyloxymethyl] -2-methylphenyl} acetamide CH ₂ Cl at room temperature ₂ : N- [5- (β-D-maltosyloxymethyl) -2-methylphenyl] acetamide (Example 1, Example 2) in DMF (1: 1, 12 mL).
Prepared from 4-methyl-3-nitrobenzyl alcohol and acetobromomaltose using a method similar to Step 1 of Example 9 and Example 9 (1.5 g, 2.98 mmol).
) Was added to DMAP (0.109 g, 0.892 mmol), followed by triethylamine (1.66 mL, 11.9 mmol), and finally TBDMSCl.
(1.35 g, 8.96 mmol) was added. After 18 hours, the solvent was removed under high vacuum and the residue diluted with EtOAc (200 mL). This organic layer was added to 1N HCl (20 m
L), saturated aqueous NaHCO ₃ solution (20 mL) and brine (20 mL), then dried (MgSO ₄ ). After concentration, the residue was flash chromatographed (
Purify with 0: 100 to 25:75 MeOH: CHCl ₂ gradient) to give the product (1
6.2 g, 75%) was obtained as a white foam. Melting point 111-114 ° C; ¹ H N
MR (CDCl ₃ ) δ 0.067 (s, 6H), 0.080 (s, 3H), 0.084 (s,
3H), 0.89 (s, 9H), 0.90 (s, 9H), 2.07 (s, 3H), 2.16 (s,
3H), 3.25-3.28 (m, 1H), 3.34-3.38 (m, 1H), 3.45-3.5
2 (m, 3H), 3.65-3.78 (m, 4H), 3.84-3.94 (m, 4H), 4.28
(d, J = 7.7 Hz, 1 H), 4.64 (ABq, J = 12.1 Hz, Δδ = 0.27,2
H), 4.65-4.69 (bs, 1H), 4.74-4.78 (m, 1H), 4.97 (d, J
= 3.3 Hz, 1H), 5.25-5.30 (m, 1H), 5.63-5.68 (bs, 1H)
, 6.99 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.5
4 (s, 1H), 7.59-7.63 (bs, 1H); IR (KBr) 3400, 2930,
2870, 1670, 1600, 1550, 1450, 1375, 1255, 1125,
1050, 840 and 790 cm ⁻¹ ; mass spectrum [(+) FAB], m / z
754 (M + Na) ⁺ ; Result of elemental analysis: Calculated value (as C ₃₄ H ₆₁ NO ₁₂ Si ₂ .0.5H ₂ O): C, 55.11;
H, 8.43; N, 1.89; Found: C, 54.91; H, 8.36; N, 1.85.

Example 11 N- {2-chloro-5- [6,6′-di-O- (tert-butyldimethylsilyl) -β-D-maltosyloxymethyl] phenyl} acetamide Using a method similar to Example 10, N- [2-chloro-5- (β-D-
Maltosyloxymethyl) phenyl] acetamide to white foam (0.845 g)
, 59%). Melting point 93-98 ° C; ¹ H NMR (CDCl ₃ ) δ0.
07 (s, 12H), 0.88 (s, 9H), 0.89 (s, 9H), 2.18 (s, 3H),
3.25-3.31 (m, 1H), 3.41-3.46 (m, 1H), 3.49-3.58 (m,
3H), 3.69-3.79 (m, 4H), 3.85 (d, J = 4.0Hz, 1H), 3.87
-3.92 (m, 2H), 3.92 (d, J = 2.6Hz, 1H), 4.32 (d, J = 7.7)
Hz, 1H), 4.53-4.58 (m, 1H), 4.68 (ABq, J = 12.5Hz, Δ
δ = 0.25, 2H), 4.71-4.75 (m, 1H), 5.00 (d, J = 3.5Hz, 1
H), 5.25 (dd, J = 2.0, 6.4 Hz, 1H), 5.69 (s, 1H), 6.98-
7.04 (m, 1H), 7.25-7.29 (m, 1H), 7.66 (s, 1H), 8.25 (s
, 1H); IR (KBr) 3400, 2930, 2880, 1675, 1600, 155
0,1460,1420,1365,1250,1050,850 and 800 cm ^{- 1;} Mass spectrum [(+) FAB], m / z 774/776 (M + Na) +; Elemental analysis: Calculated _(C 33 _{H 58} ClNO ₁₂ Si ₂ .0.5H ₂ O): C, 52.0
5; H, 7.81; N, 1.84; Found: C, 52.16; H, 7.82; N, 1.80.

Example 12 N- {2-chloro-5-[([6,6'-di-O-benzoyl-β-D-maltosyl] oxy) methyl] phenyl} acetamide-40 ° C in THF (20. To a stirred solution of N- [2-chloro-5- (β-D-maltosyloxymethyl) phenyl] acetamide (1.00 g, 1.91 mmol) in 0 mL) was added collidine (20.0 mL, 151 mmol). After the addition of benzyl chloride (0
0.532 mL, 4.58 mmol) was added dropwise. After 2 hours at this temperature, the mixture was warmed to room temperature and further stirred for 18 hours. At this point, using a high vacuum, the solvent was evaporated, and the residue was purified by flash chromatography (2% ~20% MeOH: gradient of CHCl ₃₎
Purification at afforded the product (0.500 g, 36%) as a glassy white solid. Melting point 99-100 ° C; ¹ H NMR (CDCl ₃ ) δ2.12 (s, 3H), 3.41
-3.51 (m, 3H), 3.59-3.68 (m, 2H), 3.77 (t, J = 9.2Hz, 1
H), 3.85 (t, J = 9.2 Hz, 1H), 4.06-4.12 (m, 1H), 4.30-
4.34 (m, 2H), 4.40-5.35 (bs, 3H), 4.51 (dd, J = 5.3, 1)
2.1 Hz, 1 H), 4.57 (ABq, J = 12.5 Hz, Δδ = 0.22, 2H), 4.
59 (d, J = 10.5 Hz, 1H), 4.80 (d, J = 11.0 Hz, 1H), 5.07
(d, J = 3.1Hz, 1H), 5.45-5.66 (bs, 1H), 5.75-5.95 (b
s, 1H), 6.86 (dd, J = 1.3, 8.3Hz, 1H), 7.12 (d, J = 8.3H)
z, 1H), 7.23 (t, J = 7.7Hz, 2H), 7.33-7.52 (m, 4H), 7.
70 (s, 1H), 7.91-7.96 (m, 4H), 8.14 (s, 1H); IR (KBr)
3400, 2900, 1720, 1620, 1600, 1550, 1450, 1425,
1375, 1320, 1225, 1100 and 1060 cm ⁻¹ ; mass spectrum [(+) FAB], m / z 732 (M + H) ⁺ , 754 (M + Na) ⁺ ; Results of elemental analysis: calculated value (C ₃₅ H ₃₈ ClNO _14). · 0.5H as _{2 O): C, 56.72;} H,
5.30; N, 1.89; Found: C, 56.62; H, 5.04; N, 1.90.

Example 13 N- {2-chloro-5-[([6,6′-di-O-benzoyl-2,2 ′, 3,3 ′, 4′-pentaacetyl-β-D-maltosyl ] Oxy) methyl] phenyl} acetamide N- {5-[([6,6′-di-O-benzoyl-β-D-maltosyl] oxy) methyl] in CH ₂ Cl ₂ (5.0 mL) at room temperature. -2-chlorophenyl} acetamide (0.1
22 g, 0.167 mmol) and triethylamine (0.256 mL, 1.84
Acetic anhydride (0.0865 mL, 0.916 mmol) was added dropwise to a stirred solution of (mmol) and then a catalytic amount of DMAP (0.0102 g, 0.0835 mmol) was added dropwise. After 18 hours, the mixture was diluted with EtOAc (50 mL). 1N this layer
Washed with HCl (5 mL), saturated aqueous NaHCO ₃ (5 mL) and brine (5 mL), then dried (MgSO ₄ ). After concentration, the residue was purified by flash chromatography (2% -20% acetone: CHCl ₃ gradient) to give the product (1.68 g
, 94%) as a fine white powder (0.120 g, 76%). Melting point 97-1
00 ° C; ¹ H NMR (CDCl ₃ ) δ 1.96 (s, 3H), 1.99 (s, 3H), 2.
01 (s, 3H), 2.03 (s, 3H), 2.04 (s, 3H), 2.22 (s, 3H), 3.
80-3.84 (m, 1H), 4.06-4.10 (m, 1H), 4.18-4.22 (m, 3H)
), 4.53 (dd, J = 4.0, 12.3 Hz, 1 H), 4.58 (d, J = 9.7 Hz, 1)
H), 4.61 (d, J = 5.1Hz, 1H), 4.76-4.79 (m, 1H), 4.79-
4.82 (m, 1H), 4.86 (dd, J = 4.0, 10.5 Hz, 1H), 4.92 (dd
, J = 7.7, 9.2 Hz, 1H), 5.15 (t, J = 9.9 Hz, 1H), 5.27 (t,
J = 9.0Hz, 1H), 5.41 (dd, J = 9.7, 10.3Hz, 1H), 5.47 (
d, J = 4.2Hz, 1H), 6.95 (dd, J = 1.8, 8.1Hz, 1H), 7.29 (
d, J = 8.3 Hz, 1H), 7.41-7.50 (m, 4H), 7.52-7.62 (m, 3)
H), 7.98-8.01 (m, 2H), 8.07-8.09 (m, 2H), 8.30 (s, 1H
); IR (KBr) 3400, 2950, 1760, 1725, 1620, 1600, 1
550, 1450, 1425, 1375, 1275, 1245, 1120, 1050 and 710 cm ⁻¹ ; mass spectrum [(+) FAB], m / z 942 (M + H) ⁺ ,
964 (M + Na) ⁺ ; Result of elemental analysis: Calculated value (as C ₄₅ H ₄₈ ClNO ₁₉ · 2.0H ₂ O): C, 55.25; H,
5.36; N, 1.43; Found: C, 55.18; H, 4.87; N, 1.36.

[0072]   Example 14   (4-chloro-3-nitrophenyl) methyl-4-O- [6-O- (3-pyridinylcarbo
Nyl) -α-D-glucopyranisyl] -β-D-glucopyranoside-6- (3-pyridinical
(Boxylate)   N- [2-chloro-5- (β-D-maltoxy) in THF (9.8 mL) at -40 ° C.
A mixture of luoxymethyl) phenyl] acetamide (0.500 g, 0.977 mmol) was added.
Collidine (9.8 mL, 74.3 mmol) was added dropwise to the stirred solution, followed by nicotino chloride.
Il hydrochloride (0.417 g, 2.34 mmol) was added dropwise. After 2 hours at this temperature,
The mixture was warmed to room temperature and further stirred for 42 hours. At this point, after concentrating under high vacuum,
Diluted with EtOAc (250 mL). The solid was filtered off and further EtOAc (50
(mL). The filtrate is concentrated and the resulting oily residue is flash chromatographed.
Raffy (40: 2: 1 to 10: 2: 1 EtOAc: EtOH: H_Two(Gradient of O)
Purified in to give the product (0.159 g, 23%) as a white solid. Melting point 1
45-147 ° C;¹1 H NMR (DMSO-d₆) δ3.15-3.25 (m, 2H), 3
.32-3.35 (m, 1H), 3.43 (dd, J = 5.3, 9.2Hz, 1H), 3.45-
3.52 (m, 1H), 3.54 (t, J = 8.8Hz, 1H), 3.70-3.76 (m, 1)
H), 3.91 (ddd, J = 1.3, 5.5, 9.7 Hz, 1H), 4.29-4.38 (m,
2H), 4.41 (d, J = 7.7Hz, 1H), 4.53-4.58 (m, 1H), 4.67
-4.72 (m, 1H), 4.72 (ABq, J = 13.6Hz, Δδ = 0.07, 2H),
5.11 (d, J = 4.8Hz, 2H), 5.35 (d, J = 5.7Hz, 1H), 5.42 (
d, J = 5.1Hz, 1H), 5.70 (d, J = 2.6Hz, 1H), 5.74 (d, J =
5.9 Hz, 1 H), 7.42 (ddd, J = 0.6, 4.8, 7.9 Hz, 1 H), 7.50
(ddd, J = 0.7, 4.8, 7.9 Hz, 1H), 7.62 (dd, J = 1.8, 8.3H
z, 1H), 7.67 (d, J = 8.3Hz, 1H), 8.01 (d, J = 1.8Hz, 1H)
, 8.16 (tt, J = 2.0,8.6Hz, 2H), 8.66 (dd, J = 1.8,4.8H
z, 1H), 8.77 (dd, J = 1.8, 4.8 Hz, 1H), 8.97 (dt, J = 1.3)
, 9.2Hz, 2H); IR (KBr) 3480, 3390, 3110, 2900, 172
5,1590,1550,1475,1420,1390,1360,1340,128
5,1175,1140,1090,1050 and 1015cm^-1Mass spec
Tor [(+) FAB], m / z 722/724 (M + H)⁺, 744/746 (M + Na) ⁺ ;   Elemental analysis results:   Calculated value (C₃₁H₃₂ClN_ThreeO₁₅・ 1.5H_TwoAs O): C, 49.71;
H, 4.71; N, 5.61;   Found: C, 49.68; H5 4.53; N5 5.59.

[0073]   Example 15   (4-chloro-3-nitrophenyl) methyl-4-O- [6-O- (3-pyridinylcarbo
Nyl) -α-D-glucopyranosyl] -β-D-glucopyranoside   The title compound was prepared in the same manner as in Example 14, except that N- [2-chloro-5- (β-D-
Maltosyloxymethyl) phenyl] acetamide to white glass (0.07)
0 g, 10%). Melting point> 85 ° C (decomposition);¹1 H NMR (DMSO-d ₆ ) δ3.07-3.14 (m, 1H), 3.14-3.23 (m, 1H), 3.25-3.36
(m, 2H), 3.36-3.47 (m, 3H), 3.51-3.58 (m, 1H), 3.67-
3.73 (m, 1H), 3.83-3.89 (m, 1H), 4.29-4.34 (m, 2H), 4
.54-4.62 (m, 2H), 4.79 (ABq, J = 13.4 Hz, Δδ = 0.17,2
H), 5.05-5.08 (m, 2H), 5.31 (d, J = 5.7Hz, 1H), 5.34 (
d, J = 5.1Hz, 1H), 5.56 (d, J = 6.4Hz, 1H), 5.59 (d, J =
3.1 Hz, 1 H), 7.56 (ddd, J = 0.9, 4.8, 8.1 Hz, 1 H), 7.71
(dd, J = 2.0, 8.3 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 8.09
(d, J = 1.5 Hz, 1H), 8.33 (dt, J = 1.8, 7.9 Hz, 1H), 8.81
(dd, J = 1.8,4.8Hz, 1H), 9.10 (dd, J = 0.7,2.0Hz, 1H)
IR (KBr) 3390, 2910, 1730, 1625, 1600, 1540, 14
75,1410,1360,1290,1140,1120 and 1040cm^-1
Mass spectrum [(+) FAB], m / z 617/619 (M + H)⁺;   Elemental analysis results:   Calculated value (C₂₅H₂₉ClN_TwoO₁₄・ 1.5H_TwoAs O): C, 46.63;
H, 5.01; N, 4.35;   Found: C, 46.58; H, 4.88; N, 4.26.

Example 16 N- [2-chloro-5-[[(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl) oxy] methyl] phenyl] -3-pyridinecarboxamide

Step 1 N- [2-chloro-5-[[[2,3,6-tri-O-acetyl-4-O- (2,3,4,6-tetra-O-acetyl-α- D-glucopyranosyl) -β-D-glucopyranosyl] oxy] methyl] phenyl] -3-pyridinecarboxamide 2-chloro-5- (hepta-O-acetyl-β-D- in 0 ° C THF (3 mL).
To a stirred solution of maltosyloxymethyl) phenylamine (0.200 g, 0.258 mmol) and triethylamine (0.119 mL, 0.851 mmol) was added nicotinoyl chloride hydrochloride (0.0551 mg, 0.310 mmol). It was After 0.5 hour at this temperature, it was warmed to room temperature and stirred for a further 18 hours. At this point, the solid was filtered off and washed with more THF (10 mL). Then the filtrate is concentrated and EtO
Dissolved in Ac (100 mL). This organic solution was added to H ₂ O (10 mL) and brine.
After washing with (10 mL), it was dried (Na ₂ SO ₄ ). After concentration, the residue was purified by preparative plate chromatography (10:90 MeOH: CHCl ₃ ) to give the product (0.183 g, 80%) as a white foam. Melting point 83-86 ° C; ¹
1 H NMR (CDCl ₃ ) δ 1.99 (s, 3H), 2.00 (s, 3H), 2.02 (s, 3)
H), 2.03 (s, 3H), 2.04 (s, 3H), 2.10 (s, 3H), 2.16 (s, 3)
H), 3.67-3.72 (m, 1H), 3.93-3.98 (m, 1H), 4.04 (dd, J
= 2.2,11.9 Hz, 2H), 4.25 (dt, J = 3.7,12.5 Hz, 2H), 4.
53 (dd, J = 2.9, 12.3 Hz, 1H), 4.60 (d, J = 7.7 Hz, 1H),
4.64 (d, J = 12.5Hz, 1H), 4.83-4.93 (m, 3H), 5.05 (t,
J = 10.1Hz, 1H), 5.23 (t, J = 9.4Hz, 1H), 5.34 (dd, J =
9.7, 10.5 Hz, 1H), 5.41 (d, J = 4.2 Hz, 1H), 7.07 (dd, J
= 2.0 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.48 (ddd, J = 0)
.9,4.8,7.9 Hz, 1H), 8.23 (ddd, J = 1.5,2.2,7.9 Hz, 1H
), 8.43 (s, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.82 (dd, J = 1)
.5, 4.8 Hz, 1 H), 9.15 (dd, J = 0.7, 2.2 Hz, 1 H); IR (KBr
) 3400, 2950, 1755, 1675, 1600, 1550, 1420, 1375
, 1235 and 1050 cm ⁻¹ ; mass spectrum [(+) FAB], m / z 88
^{1 (M + H) +,} 903 (M + Na) +; Elemental analysis: Calculated _{(as C 39 H 45 ClN 2 O 19} · 2.0H 2 O): C, 51.07;
H, 5.38; N, 3.05; Found: C, 50.80; H, 4.83; N, 2.89.

[0076]   Process 2   N- [2-chloro-5-[[(4-O-α-D-glucopyranosyl-β-D-glucopyranosi
) Oxy] methyl] phenyl] -3-pyridinecarboxamide   The title compound was prepared in the same manner as in Step 2 of Example 9 using N- [2-chloro-5- [
[[2,3,6-Tri-O-acetyl-4-O- (2,3,4,6-tetra-O-acetyl-α-D-
Glucopyranosyl) -β-D-glucopyranosyl] oxy] methyl] phenyl] -3-pyrid
Prepared from gincarboxamide as a white foam (1.97g, 57%). Fusion
Point> 106 ° C (decomposition);¹1 H NMR (DMSO-d₆) δ 3.02-3.13 (m, 2H)
, 3.19-3.29 (m, 2H), 3.31-3.39 (m, 1H), 3.39-3.50 (m
, 3H), 3.55-3.63 (m, 2H), 3.70-3.76 (m, 1H), 4.09 (q,
J = 5.3Hz, 1H), 4.31 (d, J = 7.9Hz, 1H), 4.49-4.55 (m,
2H), 4.60 (d, J = 12.5Hz, 1H), 4.84-4.91 (m, 3H), 5.0
1 (d, J = 3.7Hz, 1H), 5.26 (d, J = 5.1Hz, 1H), 5.43 (d, J
= 6.4 Hz, 1H), 5.52 (d, J = 3.1 Hz, 1H), 7.35 (dd, J = 2.
0,8.3Hz, 1H), 7.54 (d, J = 8.1Hz, 1H), 7.56-7.60 (m,
2H), 8.31 (dt, J = 2.0, 7.9 Hz, 1H), 8.77 (dd, J = 1.5, 4)
.8 Hz, 1 H), 9.12-9.14 (m, 1 H), 10.34 (s, 1 H); IR (KBr
) 3390, 2910, 2320, 1660, 1590, 1525, 1475, 1450
, 1420,1360,1310,1190,1140,1080 and 1030cm ^-1 Mass spectrum [(+) FAB], m / z 587 (M + H)⁺, 609 (M + N
a)⁺;   Elemental analysis results:   Calculated value (C₂₅H₃₁ClN_TwoO₁₂・ 1.5H_TwoAs O): C, 48.90;
H, 5.58; N, 4.56;   Found: C, 49.18; H5 5.52; N5 4.32.

Example 17 Benzoic acid 6- {4-chloro-3-[(pyridine-3-carbonyl) amino] benzyloxy} -4,5-dihydroxy-3- (3,4,5-trihydroxy-6) -Hydroxymethyltetrahydropyran-2-yloxy) tetrahydropyran-2-ylmethyl ester hydrochloride (R) -N- [5-[[[6-O-benzoyl-4-- in 0 mL of MeOH (10 mL).
O- [4,6-O- (phenylmethylene) -α-D-glucopyranosyl] -β-D-glucopyranosyl] oxy] methyl] -2-chlorophenyl] -3-pyridinecarboxamide (manufactured in other inventions see a record) (0.275 g, to a stirred solution of 0.353 mmol) was 1.0 M HCl (0.388 mL, a 0.388 mmol) was added in the Et ₂ O. After 10 minutes at this temperature, the mixture was warmed to room temperature and further stirred for 15 minutes.
The mixture was concentrated to a thin oil then triturated with Et ₂ O (5 mL). At this point, the solid that had formed was filtered off and further washed with Et ₂ O (4 times, 2 mL). The solid was then dried under high vacuum to give the product (0.200 g, 70%).
Was obtained as an off-white solid (86% pure, contaminated with 14% HCl salt of SM). Melting point> 157 ° C. (decomposition); ¹ H NMR (DMSO-d ₆ ) δ3.09-3.19 (m
, 2H), 3.24 (dd, J = 3.7, 9.4Hz, 1H), 3.34-3.41 (m, 1H)
, 3.41-3.65 (m, 5H), 3.71 (dd, J = 6.8, 8.1Hz, 1H), 4.
20-5.04 (m, 12H), 5.05 (d, J = 3.7Hz, 1H), 7.28 (dd, J
= 2.0, 8.3 Hz, 1H), 7.46-7.55 (m, 4H), 7.60-7.66 (m, 1)
H), 7.82 (dd, J = 5.1, 7.9 Hz, 1H), 7.94-7.99 (m, 2H),
8.58 (d, J = 7.7 Hz, 1H), 8.90 (dd, J = 1.5, 5.3 Hz, 1H),
9.23 (d, J = 1.5Hz, 1H), 10.54 (s, 1H); IR (KBr) 3400
, 2910, 2850, 2110, 1720, 1690, 1630, 1590, 1530
, 1440, 1420, 1320, 1275, 1120, 1070, 1050, 1025
And 715 cm ⁻¹ ; mass spectrum [(+) ESI], m / z 691.2 (MH)
Cl + H) ⁺ ; Result of elemental analysis: Calculated value (as C ₃₂ H ₃₅ ClN ₂ O ₁₃ .HCl.0.5H ₂ O): C, 52
.89; H, 5.06; N, 3.74; Found: C, 52.99; H, 5.27; N, 3.46.

Example 18 (4-Chloro-3-nitrobenzyl) -1-deoxy-1-thio-β-D-maltoside The title compound was prepared using the same method as in Step 2 of Example 9 (4 Prepared from -chloro-3-nitrobenzyl) -hepta-O-acetyl-1-thio-β-D-maltoside as a white solid. Melting point 90-93 ° C; ¹ H NMR (DMSO-d ₆ ) δ 3.03-3
.74 (m, 11H), 3.80 (d, J = 6.2Hz, 1H), 3.86 (d, J = 13.4)
Hz, 1H), 4.01-4.08 (m, 2H), 4.58 (bd, 2H), 4.98 (bd,
3H), 5.20-5.67 (bs, 3H), 7.65-7.72 (m, 2H), 8.03 (d,
J = 1.76 Hz, 1 H); IR (KBr) 3400, 2930, 1550, 1300 and 1075 cm ⁻¹ ; mass spectrum [(−) FAB], m / z 526 (MH) ⁻ ; Results of elemental analysis: calculated _{(as C 19 H 26 ClNO 12 S ·} H 2 O): C, 41.80; H, 5.
13; N, 2.56; Found: C, 41.35; H, 4.89; N, 2.40.

[0079]   Example 19   N- {2-chloro-5-[(β-D-maltosyl-1-thio) methyl] phenyl} acetami
Do   The title compound was prepared in the same manner as in Step 2 of Example 9 using N- {2-chloro-5- [
(Hepta-O-acetyl-β-D-maltosyl-1-thio) methyl] phenyl} acetami
Produced as a white solid. Melting point 120-125 ° C;¹1 H NMR (CD _Three OD-d_Four) δ 2.17 (s, 3H), 3.23-3.33 (m, 3H), 3.41 (dd,
J = 9.9, 3.7 Hz, 1H), 3.52-3.83 (m, 8H), 3.89 (dd, J = 1
2.3, 2.0 Hz, 1H), 4.00 (d, J = 13.2 Hz, 1H), 4.20 (d, J =
9.9Hz, 1H), 5.15 (d, J = 4.0Hz, 1H), 7.20 (dd, J = 8.4,
1.8Hz, 1H), 7.37 (d, J = 8.4Hz, 1H), 7.74 (s, 1H); IR (
KBr) 3400, 2900, 1600, 1550 and 1050 cm^-1Mass
Vector [(-) FAB)], m / z 538 (MH)⁻;   Elemental analysis results:   Calculated value (C₂₁H_ThirtyClNO₁₁S 1.0H_TwoAs O): C, 45.20;
H, 5.78; N, 2.51;   Found: C, 45.43; H5 5.62; N5 2.43.

Example 20 5-{[6,6′-bis-O- (4-toluenesulfonyl) -β-maltosyl] oxymethyl
} -2-Methyl-1-nitrobenzene

Step 1 5-[(β-Maltosyl) oxymethyl] -2-methyl-1-nitrobenzene 5-[(Hepta-O-acetyl-β-maltosyl) oxymethyl] -2- in MeOH (25 mL) Methyl-1-nitrobenzene (using the same method as in Example 1
Made from methyl-3-nitrobenzyl alcohol and acetobromomaltose) (
0.835 g, 1.06 mmol) and 25 wt% NaOMe (0.115 g, 0.15 g).
The stirred solution containing 531 mmol) / MeOH was refluxed for 4 hours. The reaction was cooled to ambient temperature and concentrated under vacuum. Reverse phase HPLC _(C18,25% CH 3 CN:
Purification by H ₂ O), to give the title compound 0.380g (73%) as a white foam. ¹ H NMR (DMSO-d ₆ ) δ 2.50 (s, 3H), 3.60-3.21 (m, 2H)
, 3.22-3.57 (m, 7H), 3.59-3.65 (m, 2H), 3.71-3.73 (m
, 2H), 4.31 (d, 1H), 4.51-4.54 (m, 2H), 4.67 (d, 1H), 4
.87-4.91 (m, 3H), 5.02 (d, 1H), 5.29 (d, 1H), 5.44 (d,
1H), 5.53 (d, 1H), 7.48 (d, 1H), 7.64 (dd, 1H), 8.01 (
s, 1H).

[0082]   Process 2   5-{[6,6'-bis-O- (4-toluenesulfonyl) -β-maltosyl] oxymethyl
} -2-Methyl-1-nitrobenzene   5-[(β-maltosyl) oxymethyl]-in pyridine (4.5 mL) at 0 ° C
To a stirred solution of 2-methyl-1-nitrobenzene (0.380 g, 0.774 mmol).
, CH_TwoCl_TwoP-toluenesulfonyl chloride (0.81 mL) in (4.5 mL)
A solution of 2 g, 4.25 mmol) was added dropwise over 5 hours. The reaction product is H_TwoO (30
(mL) and extracted with EtOAc. Combine the combined organic extracts with saturated NaH
CO_ThreeAqueous solution (3 times), saturated CuSO_FourWash sequentially with aqueous solution (3 times) and brine (3 times)
Clean, (MgSO_FourDried) and concentrated. Preparative HPLC (C18, 65% CH
_ThreeCN: H_TwoO) to give 0.373 g (59%) of the title compound as a white solid.
I got it. Melting point 85-92 ° C;¹1 H NMR (DMSO-d₆) δ 2.34 (s, 3H)
, 2.40 (s, 3H), 2.48 (s, 3H), 3.01-3.10 (m, 2H), 3.12-
3.17 (m, 1H), 3.23-3.40 (m, 3H), 3.51-3.55 (m, 2H), 4
.02-4.14 (m, 3H), 4.23-4.29 (m, 2H), 4.63 (ABq, J = 1
3.1 Hz, Δδ = 0.05, 2H), 4.92 (d, 1H), 5.01 (d, 1H), 5.2
2 (d, 1H), 5.36 (d, 1H), 5.48 (d, 1H), 5.54 (d, 1H), 7.3
9 (d, 2H), 7.45-7.48 (m, 3H), 7.60 (dd, 1H), 7.71-7.7
7 (m, 4H), 7.96 (s, 1H); IR (KBr) 3380,2920,1600,1
530, 1360 and 1175 cm^-1Mass spectrum [(+) FAB], m / z
 822 (M + Na)⁺;   Elemental analysis results:   Calculated value (C₃₄H₄₁NO₁₇S_Two・ H_TwoAs O): C, 49.93; H, 5.1
7; N, 1.75;   Found: C, 49.77; H, 4.94; N, 1.70.

Example 21 5-{[2,2 ′, 3,3 ′, 4′-penta-O-acetyl-6,6′-bis-O- (4-toluenesulfonyl) -β-maltosyl] oxy Methyl} -2-methyl-1-nitrobenzene at 0 ° C. 5-{[6,6′-bis-O- (4-toluenesulfonyl) -β-maltosyl] oxymethyl} -2-methyl-1-nitrobenzene ( 1.79 g, 2.24 mmol), pyridine (5.43 mL, 67.1 mmol) and 4-dimethylaminopyridine (1.2
To a stirred solution containing 5 g, 11.2 mmol), acetic anhydride (2.09 mL, 22.
4 mmol) was added dropwise. After 3 hours, the reaction eventually returned to room temperature. This solution was diluted with diethyl ether (100 mL), washed with H ₂ O (2 times), saturated aqueous NaHCO ₃ solution (2 times), saturated CuSO ₄ aqueous solution (2 times), and brine (2 times). , (N
a ₂ SO ₄ ) and concentrated. Flash chromatography (3%, 4%
And 5% MeOH: CHCl ₃ gradient) to give 1.785 g (79%) of the title compound as a white solid after crystallization from EtOAc: hexane.
Melting point 83 ° C .; ¹ H NMR (DMSO-d ₆ ) δ1.910 (s, 3H), 1.918 (s)
, 3H), 1.920 (s, 3H), 1.924 (s, 3H), 1.932 (s, 3H), 2.
36 (s, 3H), 2.42 (s, 3H), 2.51 (s, 3H), 3.66 (t, 1H), 3.
86 (dd, 1H), 3.92-3.96 (m, 1H), 4.06 (dd, 1H), 4.16-
4.29 (m, 3H), 4.51-4.60 (m, 2H), 4.64-4.72 (m, 2H), 4
.79 (d, 1H), 4.89 (t, 1H), 5.06-5.13 (m, 2H), 5.24 (t,
1H), 7.43 (d, 2H), 7.47-7.50 (m, 4H), 7.74-7.77 (m, 4)
H), 7.84 (s, 1H); mass spectrum [(+) FAB], m / z 1010 (M + H)
) ⁺ ; Result of elemental analysis: Calculated value (as C ₄₄ H ₅₁ NO ₂₂ S ₂ ): C, 52.32; H, 5.09; N,
1.39; Found: C, 52.46; H, 5.15; N, 1.41.

Example 22 5-{[6,6′-dideoxy-6,6′-bis (4-nitroimidazol-1-yl) -β-
Maltosyl] oxymethyl} -2-methyl-1-nitrobenzene At ambient temperature, 4-nitroimidazole (0.478 g) in DMF (8 mL) was used.
(4.23 mmol) to a stirred solution of K ₂ CO ₃ (0.278 g, 2.01 mmol).
Was added. After 0.5 h, the reaction was added to 5-{[6,6'- in DMF (20 mL).
Bis-O- (4-toluenesulfonyl) -β-maltosyl] oxymethyl} -2-methyl-1
-A solution of nitrobenzene (1.61 g, 0.201 mmol) was added and the reaction was adjusted to 10
Heat at 0 ° C. for 24 hours. The reaction was concentrated under vacuum. Reversed phase HPLC (C18,
_30% CH 3 CN: Purification by _{H 2} O), to give the title compound 0.40g (29%) as a white foam. Melting point 146 ° C; ¹ H NMR (DMSO-d ₆ ) δ 2.48 (s,
3H), 2.89 (t, 1H), 3.08 (t, 1H), 3.20-3.29 (m, 2H), 3.
40-3.47 (m, 2H), 3.64 (dt, 1H), 3.88 (dd, 1H), 3.97-
4.03 (m, 2H), 4.21-4.27 (m, 2H), 4.43-4.47 (m, 2H), 4
.59 (d, 1H), 5.11 (d, 1H), 5.17 (d, 1H), 5.40 (br s, 1H
), 5.57 (br s, 1H), 5.68 (br s, 1H), 5.84 (br s, 1H),
7.41-7.46 (m, 2H), 7.65 (d, 1H), 7.74 (d, 1H), 7.85 (s
, 1H), 8.22 (d, 1H), 8.25 (d, 1H); mass spectrum [(+) FAB],
m / z 682 (M + H ) +; Elemental analysis: Calculated _{(as C 26 H 31 N 7 O 15} · 2H 2 O): C, 43.52; H, 4.9
2; N, 13.66; Found: C, 43.90; H, 4.72; N, 13.31.

Example 23 5-{[2,2 ′, 3,3 ′, 4′-penta-O-acetyl-6,6′-dideoxy-6,6′-bis- (4-nitroimidazole-1 -Yl) -β-maltosyl] oxymethyl} -2-methyl
-1-Nitrobenzene 4-nitroimidazole (0.177 g in DMF (3 mL) at ambient temperature)
To a stirred solution of 1.57 mmol) was added K ₂ CO ₃ (0.103 g, 0.747 mmol). After 0.5 h, the reaction was treated with 5-{[2,2 ', in DMF (7 mL).
3,3 ', 4'-Penta-O-acetyl-6,6'-bis-O- (4-toluenesulfonyl) -β-
Maltosyl] oxymethyl} -2-methyl-1-nitrobenzene (0.754 g, 0.7
47 mmol) solution was added and the reaction was heated at 100 ° C. for 4 h. At ambient temperature, the reaction was quenched with ice-cold _{H 2} O (50mL), and extracted with EtOAc. The organic extract was dried (Na ₂ SO ₄ ) and concentrated. Flash chromatography (
5%, 6% and 7% MeOH: CHCl ₃ gradient) and EtOAc:
After crystallizing from hexane, 0.315 g (47%) of the title compound was obtained as a white solid. Melting point 140 ° C .; ¹ H NMR (DMSO-d ₆ ) δ1.92 (s, 3H), 1
.93 (s, 3H), 1.94 (s, 6H), 2.08 (s, 3H), 2.49 (s, 3H), 3
.64 (dd, 1H), 3.91 (t, 1H), 4.00-4.06 (m, 1H), 4.27-4
.40 (m, 5H), 4.54 (d, 1H), 4.74-4.79 (m, 3H), 4.96 (dd
, 1H), 5.22-5.30 (m, 3H), 7.33 (dd, 1H), 7.43 (d, 1H),
7.69 (d, 1H), 7.72 (d, 1H), 7.77 (d, 1H), 8.26 (d, 1H),
Mass spectrum [(+) FAB], m / z 892 (M + H) ⁺ ; Result of elemental analysis: Calculated value (as C ₃₆ H ₄₁ N ₇ O ₂₀ ): C, 48. 49; H, 4.63; N, 1
1.00; Found: C, 48.32; H, 4.52; N, 10.90.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 9/12 A61P 9/12 11/06 11/06 29/00 29/00 35/00 35/00 43 / 00 105 43/00 105 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, H, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG , KP, KR, K Z, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Robert Emmet McDebit United States 08873 Summer, New Jersey Set, Howarth Place No. 232 (72) Inventor Paul Jeffrey Drings United States 18940 Eagle Road 1012 F, Newtown, PA Pennsylvania F Term (reference) 4C057 BB03 DD01 JJ20 4C086 AA01 AA02 AA0 3 EA07 MA01 MA04 NA14 ZA36 ZA42 ZA59 ZB11 ZB21 ZB26

Claims (8)

[Claims] 1. Structure: [In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently hydrogen, a carbon number of 2
~ C7 acyl, C2-7 haloacyl, C2-7 nitroacyl, C2-7 cyanoacyl, C3-8 trifluoromethylacyl, or benzoyl (wherein the phenyl moiety is R ⁸ is substituted with); ^{R 6} and ^{R 7} are each ^{independently, -OH, -OR 9, O-} tert- butyldimethylsilyl, each alkyl moiety per 1 to 6 carbon atoms O- trialkylsilyl , O-triphenylsilyl, embedded image R ⁸ , R ¹⁰ , R ¹¹ and R ¹² are each independently hydrogen, —CN, —NO ₂ , halogen, CF ₃ , alkyl having 1 to 6 carbons, acetyl, benzoyl or 1 to 6 carbons. Alkoxy; R ⁹ is acyl having 2 to 7 carbons, haloacyl having 2 to 7 carbons, nitroacyl having 2 to 7 carbons, cyanoacyl having 2 to 7 carbons, trifluoromethylacyl having 3 to 8 carbons, or benzoyl (wherein the phenyl moiety is substituted with ^{R 8);} Y is O, S, NH, NMe or _CH 2; W is halogen, -CN, CF _3, alkyl having 1 to 6 carbon atoms, C1-C6 haloalkyl, C1-C6 nitroalkyl, C1-C6 cyanoalkyl, C2-C12 alkoxyalkyl, C1-C6 alkoxy, or R ⁸ mono- , Di-again Tri - substituted phenyl; Z is -NO _2, -NH _2, -NHR ¹³ or ^{-NHCO-Het; R 13} is an acyl having 2 to 7 carbon atoms, having 2 to 7 carbon atoms haloacyl, 2 carbon atoms ~ 7
Nitroacyl, C 2-7 cyanoacyl, C 3-8 trifluoromethylacyl, benzoyl (wherein the phenyl moiety is substituted with R ⁸ ), or R ¹³ is an α-amino acid (wherein The α-carboxyl group forms an amide with the nitrogen of Z); if the amino acid is glutamic acid or aspartic acid, it is a non-α-carboxyl group.
(Wherein the alkyl moiety is 1 to 6 carbon atoms) carboxylic acid alkyl ester is; Het is pyridyl substituted with R ^8, thienyl substituted with R ^8, furyl substituted with R ^8, R ⁸ in substituted oxazolyl, pyrazinyl substituted with ^{R 8,} pyrimidinyl substituted with ^{R 8,} or thiazolyl substituted with ^{R 8; R 14} is, ^{R 8,} -NH _2, -CO ₂ H, or carbon atoms 2-7 —NH-acyl; n = 0-3; provided that when Z is —NHR ¹³ and Y is O, at least one of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is hydrogen. Or at least one of R ⁶ and R ⁷ is OH] or a pharmaceutically acceptable salt thereof. 2. R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently hydrogen or acyl having 2 to 7 carbon atoms; R ⁶ and R ⁷ are each independently -OH. , —OR ⁹ , O-tert-butyldimethylsilyl, embedded image R ⁹ is acyl having 2 to 7 carbon atoms, or benzoyl (wherein the phenyl moiety is substituted with R ⁸ ); Y is O or S; R ¹³ is acyl having 2 to 7 carbon atoms, or benzoyl (Wherein the phenyl moiety is replaced by R ⁸ ) or R ¹³ is an α-amino acid (where the α-carboxyl group forms an amide with the nitrogen of Z); wherein the amino acid is glutamic acid or asparagine If it is an acid, it is non-α-
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the carboxylic acid is an alkyl ester (wherein the alkyl moiety has 1 to 6 carbon atoms). 3. A) 4-chloro-3-nitrobenzyl-β-D-maltoside heptaacetate or a pharmaceutically acceptable salt thereof; b) N- {5-[(hepta-O-acetyl-β- D-maltosyloxy) methyl] -2-chlorophenyl} -L-aspartamide-γ-tert-butyl ester or a pharmaceutically acceptable salt thereof; c) N- {2-chloro-5-[(2, 2 ', 3,3', 4 ', 6,6')-hepta-O-acetyl-β
-D-maltosyloxymethyl] phenyl}-(9H-fluoren-9-ylmethoxycarbonyl) -L-alaninamide or a pharmaceutically acceptable salt thereof; d) 4-benzoyl-N- {2-chloro-5 -[(2,2 ', 3,3', 4 ', 6,6'-Hepta-
O-acetyl-β-D-maltosyl) oxymethyl] phenyl} benzamide or a pharmaceutically acceptable salt thereof; e) (4-chloro-3-nitrobenzyl) hepta-O-acetyl-1-thio-β-D -Maltoside or a pharmaceutically acceptable salt thereof; f) (3-amino-4-chlorobenzyl) hepta-O-acetyl-1-thio-β-D-maltoside or a pharmaceutically acceptable salt thereof; g) N -{2-chloro-5-[(hepta-O-acetyl-β-D-maltosyl-1-thio) methyl] phenyl} acetamide or a pharmaceutically acceptable salt thereof; h) 5-[(hepta-O- Acetyl-β-D-maltosyl) oxymethyl] -2-cyano-
1-nitrobenzene or a pharmaceutically acceptable salt thereof; i) N- [2-chloro-5- (β-D-maltosyloxymethyl) phenyl] acetamide or a pharmaceutically acceptable salt thereof; j) N- { 5- [6,6'-di-O- (tert-butyldimethylsilyl) -β-D-maltosyloxymethyl] -2-methylphenyl} acetamide or a pharmaceutically acceptable salt thereof; k) N- { 2-chloro-5- [6,6'-di-O- (tert-butyldimethylsilyl) -β-D-
Maltosyloxymethyl] phenyl} acetamide or a pharmaceutically acceptable salt thereof; l) N- {2-chloro-5-[([6,6'-di-O-benzoyl-β-D-maltosyl] oxy) Methyl] phenyl} acetamide or a pharmaceutically acceptable salt thereof; m) N- {2-chloro-5-[([6,6'-di-O-benzoyl-2,2 ', 3,3', 4] '-Pentaacetyl-β-D-maltosyl] oxy) methyl] phenyl} acetamide or a pharmaceutically acceptable salt thereof; n) (4-chloro-3-nitrophenyl) methyl-4-O- [6-O- (3-Pyridinylcarbonyl) -α-D-glucopyranosyl] -β-D-glucopyranoside-6- (3-pyridinecarboxylate) or a pharmaceutically acceptable salt thereof; o) (4-chloro-3-nitro (Phenyl) methyl-4-O- [6-O- (3-pyridinylcarbonyl) -α-D-glucopyranosyl] -β-D-glucopyranoside or pharmaceutically acceptable thereof P) N- [2-chloro-5-[[(4-O-α-D-glucopyranosyl-β-D-glucopyranosyl) oxy] methyl] phenyl] -3-pyridinecarboxamide or a pharmaceutically acceptable salt thereof. Q) Benzoic acid 6- {4-chloro-3-[(pyridine-3-carbonyl) amino] benzyloxy} -4,5-dihydroxy-3- (3,4,5-trihydroxy-6- Hydroxymethyltetrahydropyran-2-yloxy) tetrahydropyran-2-ylmethyl ester or a pharmaceutically acceptable salt thereof; r) (4-chloro-3-nitrobenzyl) -1-deoxy-1-thio-β-D -Maltoside or a pharmaceutically acceptable salt thereof; s) N- {2-chloro-5-[(β-D-maltosyl-1-thio) methyl] phenyl} acetamide or a pharmaceutically acceptable salt thereof; t) 5-{[6,6'-bis-O- (4-toluenesulfonyl) -β-maltosyl] oxymethyl} -2-me Chill-1-nitrobenzene u) or a pharmaceutically acceptable salt thereof; v) 5-{[2,2 ′, 3,3 ′, 4′-penta-O-acetyl-6,6′-bis-O— (4-Toluenesulfonyl) -β-maltosyl] oxymethyl} -2-methyl-1-nitrobenzene or a pharmaceutically acceptable salt thereof; w) 5-{[6,6′-dideoxy-6,6′-bis (4-Nitroimidazol-1-yl)-
β-maltosyl] oxymethyl} -2-methyl-1-nitrobenzene or a pharmaceutically acceptable salt thereof; or x) 5-{[2,2 ′, 3,3 ′, 4′-penta-O-acetyl- 6,6'-dideoxy-6,6 '
The compound according to claim 1, which is -bis (4-nitroimidazol-1-yl) -β-maltosyl] oxymethyl} -2-methyl-1-nitrobenzene or a pharmaceutically acceptable salt thereof. 4. A method of treating or inhibiting a hyperproliferative vascular disorder in a mammal in need thereof, wherein the mammal has an effective amount of a structure: [In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently hydrogen, a carbon number of 2
~ C7 acyl, C2-7 haloacyl, C2-7 nitroacyl, C2-7 cyanoacyl, C3-8 trifluoromethylacyl, or benzoyl (wherein the phenyl moiety is R ⁸ is substituted with); ^{R 6} and ^{R 7} are each ^{independently, -OH, -OR 9, O-} tert- butyldimethylsilyl, each alkyl moiety per 1 to 6 carbon atoms O- trialkylsilyl , O-triphenylsilyl, R ⁸ , R ¹⁰ , R ¹¹ and R ¹² are each independently hydrogen, —CN, —NO ₂ , halogen, CF ₃ , alkyl having 1 to 6 carbons, acetyl, benzoyl or 1 to 6 carbons. Alkoxy; R ⁹ is acyl having 2 to 7 carbons, haloacyl having 2 to 7 carbons, nitroacyl having 2 to 7 carbons, cyanoacyl having 2 to 7 carbons, trifluoromethylacyl having 3 to 8 carbons, or benzoyl (wherein the phenyl moiety is substituted with ^{R 8);} Y is O, S, NH, NMe or _CH 2; W is halogen, -CN, CF _3, alkyl having 1 to 6 carbon atoms, C1-C6 haloalkyl, C1-C6 nitroalkyl, C1-C6 cyanoalkyl, C2-C12 alkoxyalkyl, C1-C6 alkoxy, or R ⁸ mono- , Di-again Tri - substituted phenyl; Z is -NO _2, -NH _2, -NHR ¹³ or ^{-NHCO-Het; R 13} is an acyl having 2 to 7 carbon atoms, having 2 to 7 carbon atoms haloacyl, 2 carbon atoms ~ 7
Nitroacyl, C 2-7 cyanoacyl, C 3-8 trifluoromethylacyl, benzoyl (wherein the phenyl moiety is substituted with R ⁸ ), or R ¹³ is an α-amino acid (wherein The α-carboxyl group forms an amide with the nitrogen of Z); if the amino acid is glutamic acid or aspartic acid, it is a non-α-carboxyl group.
(Wherein the alkyl moiety is 1 to 6 carbon atoms) carboxylic acid alkyl ester is; Het is pyridyl substituted with R ^8, thienyl substituted with R ^8, furyl substituted with R ^8, R ⁸ Oxazolyl substituted with, R ⁸ substituted pyrazinyl, R ⁸ substituted pyrimidinyl, or R ⁸ substituted thiazolyl; R ¹⁴ is R ⁸ , —NH ₂ , —CO ₂ H or the number of carbon atoms. 2-7 —NH-acyl; n = 0-3; provided that when Z is —NHR ¹³ and Y is O, at least one of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is hydrogen. Or at least one of R ⁶ and R ⁷ is OH] or a pharmaceutically acceptable salt thereof. 5. A method of treating or inhibiting restenosis in a mammal in need thereof, wherein the mammal has an effective amount of a structure: [In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently hydrogen, a carbon number of 2
~ C7 acyl, C2-7 haloacyl, C2-7 nitroacyl, C2-7 cyanoacyl, C3-8 trifluoromethylacyl, or benzoyl (wherein the phenyl moiety is R ⁸ is substituted with); ^{R 6} and ^{R 7} are each ^{independently, -OH, -OR 9, O-} tert- butyldimethylsilyl, each alkyl moiety per 1 to 6 carbon atoms O- trialkylsilyl , O-triphenylsilyl, embedded image R ⁸ , R ¹⁰ , R ¹¹ and R ¹² are each independently hydrogen, —CN, —NO ₂ , halogen, CF ₃ , alkyl having 1 to 6 carbons, acetyl, benzoyl or 1 to 6 carbons. Alkoxy; R ⁹ is acyl having 2 to 7 carbons, haloacyl having 2 to 7 carbons, nitroacyl having 2 to 7 carbons, cyanoacyl having 2 to 7 carbons, trifluoromethylacyl having 3 to 8 carbons, or benzoyl (wherein the phenyl moiety is substituted with ^{R 8);} Y is O, S, NH, NMe or _CH 2; W is halogen, -CN, CF _3, alkyl having 1 to 6 carbon atoms, C1-C6 haloalkyl, C1-C6 nitroalkyl, C1-C6 cyanoalkyl, C2-C12 alkoxyalkyl, C1-C6 alkoxy, or R ⁸ mono- , Di-again Tri - substituted phenyl; Z is -NO _2, -NH _2, -NHR ¹³ or ^{-NHCO-Het; R 13} is an acyl having 2 to 7 carbon atoms, having 2 to 7 carbon atoms haloacyl, 2 carbon atoms ~ 7
Nitroacyl, C 2-7 cyanoacyl, C 3-8 trifluoromethylacyl, benzoyl (wherein the phenyl moiety is substituted with R ⁸ ), or R ¹³ is an α-amino acid (wherein The α-carboxyl group forms an amide with the nitrogen of Z); if the amino acid is glutamic acid or aspartic acid, it is a non-α-carboxyl group.
(Wherein the alkyl moiety is 1 to 6 carbon atoms) carboxylic acid alkyl ester is; Het is pyridyl substituted with R ^8, thienyl substituted with R ^8, furyl substituted with R ^8, R ⁸ Oxazolyl substituted with, R ⁸ substituted pyrazinyl, R ⁸ substituted pyrimidinyl, or R ⁸ substituted thiazolyl; R ¹⁴ is R ⁸ , —NH ₂ , —CO ₂ H or the number of carbon atoms. 2-7 —NH-acyl; n = 0-3; provided that when Z is —NHR ¹³ and Y is O, at least one of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is hydrogen. Or at least one of R ⁶ and R ⁷ is OH] or a pharmaceutically acceptable salt thereof. 6. The method of claim 5, wherein restenosis results from angioplasty, revascularization, or organ or tissue transplant. 7. A method of inhibiting angiogenesis in a malignant tumor, sarcoma or neoplastic tissue of a mammal in need thereof, wherein the mammal has an effective amount of a structure: [In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently hydrogen, a carbon number of 2
~ C7 acyl, C2-7 haloacyl, C2-7 nitroacyl, C2-7 cyanoacyl, C3-8 trifluoromethylacyl, or benzoyl (wherein the phenyl moiety is R ⁸ is substituted with); ^{R 6} and ^{R 7} are each ^{independently, -OH, -OR 9, O-} tert- butyldimethylsilyl, each alkyl moiety per 1 to 6 carbon atoms O- trialkylsilyl , O-triphenylsilyl, embedded image R ⁸ , R ¹⁰ , R ¹¹ and R ¹² are each independently hydrogen, —CN, —NO ₂ , halogen, CF ₃ , alkyl having 1 to 6 carbons, acetyl, benzoyl or 1 to 6 carbons. Alkoxy; R ⁹ is acyl having 2 to 7 carbons, haloacyl having 2 to 7 carbons, nitroacyl having 2 to 7 carbons, cyanoacyl having 2 to 7 carbons, trifluoromethylacyl having 3 to 8 carbons, or benzoyl (wherein the phenyl moiety is substituted with ^{R 8);} Y is O, S, NH, NMe or _CH 2; W is halogen, -CN, CF _3, alkyl having 1 to 6 carbon atoms, C1-C6 haloalkyl, C1-C6 nitroalkyl, C1-C6 cyanoalkyl, C2-C12 alkoxyalkyl, C1-C6 alkoxy, or R ⁸ mono- , Di-again Tri - substituted phenyl; Z is -NO _2, -NH _2, -NHR ¹³ or ^{-NHCO-Het; R 13} is an acyl having 2 to 7 carbon atoms, having 2 to 7 carbon atoms haloacyl, 2 carbon atoms ~ 7
Nitroacyl, C 2-7 cyanoacyl, C 3-8 trifluoromethylacyl, benzoyl (wherein the phenyl moiety is substituted with R ⁸ ), or R ¹³ is an α-amino acid (wherein The α-carboxyl group forms an amide with the nitrogen of Z); if the amino acid is glutamic acid or aspartic acid, it is a non-α-carboxyl group.
(Wherein the alkyl moiety is 1 to 6 carbon atoms) carboxylic acid alkyl ester is; Het is pyridyl substituted with R ^8, thienyl substituted with R ^8, furyl substituted with R ^8, R ⁸ Oxazolyl substituted with, R ⁸ substituted pyrazinyl, R ⁸ substituted pyrimidinyl, or R ⁸ substituted thiazolyl; R ¹⁴ is R ⁸ , —NH ₂ , —CO ₂ H or the number of carbon atoms. 2-7 —NH-acyl; n = 0-3; provided that when Z is —NHR ¹³ and Y is O, at least one of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is hydrogen. Or at least one of R ⁶ and R ⁷ is OH] or a pharmaceutically acceptable salt thereof. 8. Structure: embedded image [In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently hydrogen, a carbon number of 2
~ C7 acyl, C2-7 haloacyl, C2-7 nitroacyl, C2-7 cyanoacyl, C3-8 trifluoromethylacyl, or benzoyl (wherein the phenyl moiety is R ⁸ is substituted with); ^{R 6} and ^{R 7} are each ^{independently, -OH, -OR 9, O-} tert- butyldimethylsilyl, each alkyl moiety per 1 to 6 carbon atoms O- trialkylsilyl , O-triphenylsilyl, R ⁸ , R ¹⁰ , R ¹¹ and R ¹² are each independently hydrogen, —CN, —NO ₂ , halogen, CF ₃ , alkyl having 1 to 6 carbons, acetyl, benzoyl or 1 to 6 carbons. Alkoxy; R ⁹ is acyl having 2 to 7 carbons, haloacyl having 2 to 7 carbons, nitroacyl having 2 to 7 carbons, cyanoacyl having 2 to 7 carbons, trifluoromethylacyl having 3 to 8 carbons, or benzoyl (wherein the phenyl moiety is substituted with ^{R 8);} Y is O, S, NH, NMe or _CH 2; W is halogen, -CN, CF _3, alkyl having 1 to 6 carbon atoms, C1-C6 haloalkyl, C1-C6 nitroalkyl, C1-C6 cyanoalkyl, C2-C12 alkoxyalkyl, C1-C6 alkoxy, or R ⁸ mono- , Di-again Tri - substituted phenyl; Z is -NO _2, -NH _2, -NHR ¹³ or ^{-NHCO-Het; R 13} is an acyl having 2 to 7 carbon atoms, having 2 to 7 carbon atoms haloacyl, 2 carbon atoms ~ 7
Nitroacyl, C 2-7 cyanoacyl, C 3-8 trifluoromethylacyl, benzoyl (wherein the phenyl moiety is substituted with R ⁸ ), or R ¹³ is an α-amino acid (wherein The α-carboxyl group forms an amide with the nitrogen of Z); if the amino acid is glutamic acid or aspartic acid, it is a non-α-carboxyl group.
(Wherein the alkyl moiety is 1 to 6 carbon atoms) carboxylic acid alkyl ester is; Het is pyridyl substituted with R ^8, thienyl substituted with R ^8, furyl substituted with R ^8, R ⁸ in substituted oxazolyl, pyrazinyl substituted with ^{R 8,} pyrimidinyl substituted with ^{R 8,} or thiazolyl substituted with ^{R 8; R 14} is, ^{R 8,} -NH _2, -CO ₂ H, or carbon atoms 2-7 —NH-acyl; n = 0-3; provided that when Z is —NHR ¹³ and Y is O, at least one of R ¹ , R ² , R ³ , R ⁴ and R ⁵ is hydrogen. Or at least one of R ⁶ and R ⁷ is OH] or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.