JP2002530424A - Benzyl maltoside 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 formula (I) having the structure (I) wherein X is (a) or a pharmaceutically acceptable salt thereof. . Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to substituted benzyls as smooth muscle cell proliferation inhibitors and as therapeutic compositions for treating diseases and conditions such as restenosis characterized by excessive smooth muscle proliferation. Concerning the use of maltoside.

BACKGROUND OF THE INVENTION [0002] All forms of vascular remodeling, such as angioplasty and venous bypass, are directed at damage that ultimately leads to smooth muscle cell (SMC) proliferation and subsequent deposition of large amounts of extracellular matrix. Produce a response (Clowes, AW)
; Lady, MA, Journal of Vascular
Surgery (J. Vasc. Surg.), 1991, 13, 885). These events are associated with atherosclerosis (Raines, EW); Ross, Earl (Ross, EW).
R.), British Heart Journal (Br. Heart J.), 1993, 69 (supplement) S.30)
And arteriosclerosis after transplantation (Isik, FF); McDonald, TO; Ferguson, M .; Yamanaka, E .; It is also a central process in the pathogenesis 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 (Herman, J.P.R.). , JPR); Hermans, WRM; Voss, J .; Serois, PW, Drugs, 1993, 4, 18, and 249). Selective SM
Successful approaches to C growth inhibition must not interfere with endothelial cell repair or the normal growth and function of other cells (Weissburg, P.
.L.); Grainger, DJ; Shanahan, See
M (Shanahan, CM); Metcalfe, JC, Cardiovascular Res., 1993, 27, 1191).

[0003] Glycosaminoglycan heparin and heparan sulfate are endogenous inhibitors of SMC proliferation and can also promote endothelial cell proliferation (Castellot, JJJr.); Wright, T Sea
.C.); Karnovsky, MJ, Seminars in
Seminars in Thrombosis and Hemostasis
), 1987, 13,489). However, the full clinical utility of heparin, heparin fragments, chemically modified heparin, low molecular weight heparin, and other heparins that mimic anionic polysaccharides has been linked to other pharmacology linked to the heterogeneity of various formulations. Trends (especially,
May be reduced by excessive bleeding resulting from anticoagulant effects (Borma, S.
n, S.), Chemical and Engineering News
ering News), 1993, June 28, 27).

[0004] PCT Patent Application Publication No. WO 96/14325 discloses acylated benzyl glycosides as inhibitors of smooth muscle cell proliferation. The compounds of the present invention differ in that the substituents on the sugar skeleton are different.

[0005] Zehavi, U., Carbohyd. Res.
1986, 151, 371 discloses 4-carboxy-2-nitrobenzyl 4-O-α-D-glucopyranosyl-β-D-glucopyranoside attached to a research polymer as an acceptor in glycogen synthesis reactions. . The compounds of the present invention differ in that (a) the substituent on the benzyl group is different and (b) the application (smooth muscle proliferation inhibition) is different.

US Pat. No. 5,498,775, PCT Application Publication No. WO 96/14324 and US Pat.
No. 4,64,827 describes polyanionic benzyl glycosides or cyclodextrins as smooth muscle cell proliferation inhibitors for treating diseases and conditions characterized by excessive smooth muscle proliferation. β-cyclodextrin tetradeca sulfate has been described as a smooth muscle cell proliferation inhibitor and an effective inhibitor of restenosis (Reilly, CF; Fujita, T.); McFall, RC; Stabilite, Eye
lito, II); Wai-se, E .; Johnson, Johns
on, RG), Drug Development Research
h), 1993, 29, 137). U.S. Patent No. 5,019,562 discloses anionic derivatives of cyclodextrin for treating pathological conditions associated with unwanted cell or tissue growth. PCT Application Publication No. WO 93/09790 discloses a growth inhibiting polyanionic derivative of cyclodextrin having at least two anionic residues per sugar residue. Meinetsberger (EP 312087 A2 and EP 312086 A2) describes 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) benzylmaltoside, which has no structural similarity to heparin, sulfated cyclodextrin, or sulfated lactobionic acid dimer, and (b) only two It differs from this prior art in that it has adjacent sugar residues (is a disaccharide) and (c) has a well-defined structure.

SUMMARY OF THE INVENTION The present invention provides a compound of formula I:

[0008]

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[Wherein, X is

[0010]

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Y is hydrogen, halogen, azide, or Het optionally substituted with R ¹⁰ ; Het is 1,3-dioxo-1,3-dihydroisoindol-2-yl, imidazole R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, acyl having 2 to 7 carbons, perfluoroacyl having 2 to 7 carbons, carbon Alkyl of number 1 to 6, carbon number of 1 to 6
R ⁵ is hydrogen, alkyl having 1 to 6 carbons, perfluoroalkyl having 1 to 6 carbons, halogen, nitrile, nitro or alkoxy having 1 to 6 carbons; R ⁶ and R ⁷ Is each independently hydrogen, acyl having 2 to 7 carbons, 2 to 2 carbons
7 perfluoroacyl, C1-6 alkyl, C1-6 perfluoroalkyl, C1-6 alkylsulfonyl, C1-6 perfluoroalkylsulfonyl, C6-10 arylsulfonyl or Carbon number 6-1
R ⁸ and R ⁹ are each independently hydrogen, alkyl having 1 to 6 carbons, alkyl having 1 to 6 carbons, haloalkyl having 1 to 6 carbons, 1 to 6 carbons Nitroloalkyl, nitroalkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, 6 to 6 carbons
Aryl having 10 to 10 carbon atoms, aryl having 6 to 10 carbon atoms substituted with R ¹¹ ,
2 aralkyl or aralkyl having 7 to 12 carbon atoms substituted by R ¹¹ ; R ¹⁰ is halogen, nitrile, nitro, amino, acylamino having 2 to 7 carbon atoms, perfluoroacylamino having 2 to 7 carbon atoms, Carboxyl, carboxaldehyde, perfluoroalkyl having 1 to 6 carbons, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, perfluoroalkoxy having 1 to 6 carbons, 2 to 7 carbons
Alkoxycarbonyl, C2-7 perfluoroalkoxycarbonyl,
Aryl having 6 to 10 carbon atoms, or mercapto; R ¹¹ is benzylmaltoside represented by halogen, nitrilo, nitro or perfluoroalkyl having 1 to 6 carbon atoms, or a pharmaceutically acceptable salt thereof.

Alkyl, alkoxy, alkylsulfonyl, acylamino, alkoxycarbonyl and acyl include both linear and branched moieties, optionally substituted with fluorine. Halogen means bromine, chlorine, fluorine and iodine. Aryl is defined as a fully unsaturated carbocyclic group having one or more rings of 6 to 10 carbon atoms which may be optionally substituted by fluorine. Phenyl and naphthyl groups are preferred.

[0013] 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 camphorsulfonic acid, and similarly known acceptable acids. Salts may be formed from organic and inorganic bases, and are preferably alkali metal salts, for example, sodium, lithium or potassium salts. Acid addition salts can be prepared when the compound of Formula I has a basic nitrogen.
Base addition salts may typically be prepared where the compound of formula I has a hydroxyl group.

The compounds of the present invention may have asymmetric carbon atoms, and some of the compounds of the present invention will have one or more asymmetric centers, and therefore will have optical isomers and diastereomers. May occur. Although not shown in Formula I for stereochemistry, the present invention is directed to such optical isomers and diastereomers; and resolved and enantiomerically pure R and S stereoisomers, as racemates; And other mixtures of R and S stereoisomers; and pharmaceutically acceptable salts thereof.

Preferred compounds of the present invention have the formula I:

[0016]

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[Wherein X is

[0018]

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Y is hydrogen, halogen, azide, or Het optionally substituted with R ¹⁰ ; Het is 1,3-dioxo-1,3-dihydroisoindol-2-yl or imidazole- R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen or acyl having 2 to 7 carbons; R ⁵ is hydrogen, alkyl or halogen having 1 to 6 carbons; R ⁶ And R ⁷ are each independently hydrogen or acyl having 2 to 7 carbons; R ⁸ and R ⁹ are each independently hydrogen or aryl having 6 to 10 carbons; R ¹⁰ is halogen, nitrile, Nitro, amino, acylamino having 2 to 7 carbon atoms, carboxyl, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons or aryl having 6 to 10 carbons] or a medicament thereof. It is acceptable salts.

More preferred compounds of the present invention have the formula I:

Embedded image [Where X is

Embedded image Y is hydrogen, iodo, azido, or, ^optionally, substituted with ^{R 10} Het; Het is 1,3-dioxo-1,3-dihydroisoindol-2-yl or imidazol-1-yl R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen or acetyl; R ⁵ is hydrogen, alkyl having 1 to 3 carbon atoms, or chloro; R ⁶ is hydrogen; R ⁷ is acetyl; R ⁸ is phenyl; R ⁹ is hydrogen; R ¹⁰ is nitro], or a pharmaceutically acceptable salt thereof.

A particularly preferred compound of the present invention is N- (5-{[4 ′, 6′-O-benzylidene-6-deoxy-6- (4-nitro-1H-imidazol-1-yl) -β- D-maltosyloxy] methyl} -2-methylphenyl) acetamide or a pharmaceutically acceptable salt thereof; N- (5-{[2,3,2 ′, 3′-tetra-O-acetyl-4 ′, 6'-O-benzylidene-6-
Deoxy-6- (4-nitro-1H-imidazol-1-yl) -β-D-maltosyl] oxymethyl} -2-chlorophenyl) acetamide or a pharmaceutically acceptable salt thereof; N- (5-{[4 ', 6'-O-benzylidene-6-deoxy-6- (4-nitro-1H-imidazol-1-yl) -β-D-maltosyl] oxymethyl} -2-chlorophenyl) acetamide or a pharmaceutically acceptable salt thereof N- {5-[(2,2 ', 3,3'-tetra-O-acetyl-4', 6'-O-benzylidene-6-
Deoxy-6-iodo-β-D-maltosyl) oxymethyl] -2-chlorophenyl} acetamide or a pharmaceutically acceptable salt thereof; N- {5-[(4 ′, 6′-O-benzylidene-6-deoxy -6-iodo-β-D-maltosyl) oxymethyl] -2-chlorophenyl} acetamide or a pharmaceutically acceptable salt thereof; N- (5-{[2,2 ′, 3,3′-tetra-O- Acetyl-4 ', 6'-O-benzylidene-6-
Deoxy-6- (1,3-dioxo-1,3-dihydroisoindol-2-yl) -β-D-
Maltosyl] oxymethyl} -2-chlorophenyl) acetamide or a pharmaceutically acceptable salt thereof; N- (5-{[4 ′, 6′-O-benzylidene-6-deoxy-6- (1,3-dioxo- 1,3-
Dihydroisoindol-2-yl) -β-D-maltosyl] oxymethyl} -2-chlorophenyl) acetamide or a pharmaceutically acceptable salt thereof; and N- {5-[(6-deoxy-6-O-azide) -4 ', 6'-O-benzylidene-β-D-maltosyl) oxymethyl] -2-chlorophenyl} acetamide or a pharmaceutically acceptable salt thereof.

The compounds of the present invention were prepared from commercially available raw materials or from raw materials that can be prepared using methods described in the literature according to the following scheme. This scheme is
1 illustrates the preparation of representative compounds of the invention.

[0023]

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[Wherein, Y and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸And R ⁹ Is as defined above]

Thus, maltosyl bromide 1 can be prepared at a temperature in the range of −40 ° C. to reflux temperature in an aprotic solvent such as acetonitrile, dichloromethane, ether, toluene or nitromethane, by mercuric bromide, Coupling with benzyl alcohol 2 in the presence of a catalyst such as mercury, silver triflate or silver perchlorate gives glycoside 3. The nitro group of 3 is reduced at ambient temperature to reflux temperature in a polar aprotic solvent such as ethyl acetate with a reducing agent such as stannous chloride or in the presence of a catalyst such as palladium on carbon. The anilino compound 4 can be obtained by reduction. 4 in an aprotic solvent such as dichloromethane or tetrahydrofuran in the presence of an amine base such as triethylamine, diisopropylethylamine or pyridine at a temperature in the range of −20 ° C. to ambient temperature to afford the amide 5 can be obtained. The acetate group of 5 can be displaced at ambient to reflux temperature by hydrolysis with a base such as sodium methoxide in methanol or aqueous sodium hydroxide in methanol to give 6. The 4 'and 6' groups are added at a temperature in the range of 25 ° C to reflux temperature in a polar aprotic solvent such as N, N-dimethylformamide in the presence of an acid catalyst such as camphorsulfonic acid or p-toluenesulfonic acid. , And acetal to obtain an acetal / ketal derivative 7. -20 ° C to 5 ° C at position 6
Selective tosylation in an aprotic solvent such as dichloromethane or tetrahydrofuran in the presence of p-toluenesulfonyl chloride and an amine base such as triethylamine, diisopropylamine or pyridine at a temperature in the range of Followed by reacylation with an acid anhydride in the presence of an amine base such as pyridine at a temperature in the range of 0 ° C. to ambient temperature to give 9. Displacement of tosylate 9 at ambient temperature in a polar aprotic solvent such as N, N-dimethylformamide with a suitable nucleophile that can be formed with a base such as sodium hydride or potassium carbonate to give 10 Can be. The acetate group of 10 can be displaced at ambient to reflux temperature by hydrolysis with a base such as sodium methoxide in methanol or aqueous sodium hydroxide in methanol to give 11. Alternatively, the tosylate 8 can be directly substituted without protecting the hydroxyl group to give 11.

The compounds of the present invention are useful as growth inhibitors. The following method illustrates the evaluation of representative compounds of the present invention in standard pharmacological assays that measure the ability of the evaluated compound to inhibit smooth muscle cell proliferation.

Effect of compounds on cell proliferation using ³ H thymidine transfer Human and porcine smooth muscle cells were tested at early passage (generally passages 3-7) under semi-confluent conditions did. Cultures were grown in medium 199 supplemented with 10% fetal calf serum and 2% antibiotic / antimycotic using 16 mm (24 well) multiwell culture dishes. Once semi-confluent, these cells were allowed to undergo 24-48 hours of serum-free defined media (AIM-V; Gibco) before beginning the experimental protocol.
)).

In general, compounds have been found to be more effective over longer preincubations, but the method begins by adding the compound, ³ H thymidine and serum / growth factors to serum-free synchronizing cells, Report the results accordingly.

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

At the end of the test procedure, the plate is placed on ice and ice-cold phosphate buffered saline (PBS)
, And incubated in ice-cold 10% trichloroacetic acid (TCA) for 30 minutes to remove acid-soluble protein. The solution was transferred to scintillation vials containing 0.4N HCl (500 μL / vial, neutralizing NaOH) and each well was 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 was obtained from cells that were maximally stimulated as a result of stimulation with growth factors or serum. Experimental data was obtained from cells stimulated maximally with growth factors or serum and treated with compounds. Data as _{IC 50,} shown in Table 1 below.

[0032]

[Table 1] Table 1

The compounds of the present invention are useful for treating or inhibiting a disease characterized by excessive smooth muscle cell proliferation (smooth muscle cell hyperproliferation). These compounds are particularly useful for hyperproliferative blood vessels characterized by smooth muscle cell hyperproliferation that most frequently arises from revascularization surgery and transplantation (e.g., balloon angioplasty, vascular transplantation surgery, coronary artery bypass surgery and heart transplantation). Useful for treating diseases (eg, restenosis). Other disease states in which unfavorable "cellular" vascular growth is present include hypertension, asthma and congestive heart failure. The compounds of the present invention are also useful as angiogenesis inhibitors. Angiogenesis (neovascularization), the process by which new capillaries are formed, is important primarily for a number of 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 as such or using a pharmaceutical carrier for administration. The proportion will be determined by the solubility and chemistry of the compound, the route of administration chosen, and standard pharmacological practices. The pharmaceutical carrier may be either solid or liquid.

As the solid carrier, one or more of which can also act as a flavoring agent, lubricant, solubilizer, suspending agent, filler, flow agent, compression aid, binder or tablet disintegrant 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 turn mixed 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. The powders and tablets preferably contain up to 99% of the 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 may contain other suitable pharmaceutical excipients, for example, solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, coloring agents, viscosity modifiers, stabilizers. Agent or an osmotic pressure adjusting agent. Suitable examples of liquid carriers for oral and parenteral administration include water (additives as described above (e.g.,
Cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols (e.g., glycols) and their derivatives, lecithin, and oils (e.g.,
Fractionated coconut 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 compositions for parenteral administration. Liquid carriers for pressurized compositions can be halogenated hydrocarbons or other pharmaceutically acceptable propellants.

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

The compounds of the present invention may be administered rectally or vaginally in the form of a conventional suppository.
When administered by intranasal or intrabronchial inhalation or insufflation, the compounds of the invention may be formulated in aqueous or semi-aqueous solutions. These can then be utilized in the form of an aerosol. The compounds of the present invention may be administered transdermally by the use of a transdermal patch containing the active compound and a carrier. Provided that the carrier is inert to the active compound, non-toxic to the skin, and allows for delivery of the systemically absorbable drug into the blood stream through the skin. Such carriers may take any number of forms, such as creams and ointments, pastes, gels, and closures. Creams and ointments may be viscous liquids or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes made of absorbent powder dispersed in petrolatum or hydrophilic petrolatum containing the active ingredient are also suitable. The active ingredient may be released into the bloodstream using a variety of closures, such as semipermeable membranes that cover the reservoir containing the active ingredient, if desired with a carrier, or a matrix containing the active ingredient. . Other closure devices are known in the literature.

Dosage requirements will vary with the particular composition employed, the route of administration, the severity of the symptoms presented, and the particular patient being treated. Based on the results obtained in standard pharmacological assays, the planned daily dose of active compound will be between 0.1 and 10 mg / kg administered parenterally (preferably intravenously). It 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 (i.e., balloon angioplasty or transplantation), but will likely be continued for a longer period in the case of treatment of chronic disorders. Treatment will generally be initiated with small dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased until the optimum effect under such circumstances is reached. Precise dosages for oral, parenteral, nasal or intrabronchial 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 a tablet or capsule. In such 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, packeted powders, vials, ampoules, filled syringes or liquid sachets. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of such compositions in package form.

The following provides the preparation of representative compounds of the present invention.

Example 1 N- (5-{[4 ′, 6′-O-benzylidene-6-deoxy-6- (4-nitro-1H-imidazol-1-yl) -β-D-maltosyloxy ] Methyl} -2-methylphenyl) acetamide

[0042]

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Step 1 5- (Hepta-O-acetyl-β-D-maltosyloxymethyl) -2-methyl-1-nitto
Lobenzene Freshly distilled CH at ambient temperature₃Acetobromo in CN (129 mL)
Maltose (15.0 g, 0.0193 mol), 4-methyl-3-nitrobenzylal
Cole (4.18 g, 0.0251 mol) and HgBr₂(9.02 g, 0.025
Hg (CN)₂(6.34 g, 0.0251 mol) at once.
I got it. After 2.5 hours, brine (250 mL) was added and the mixture was extracted with EtOAc.
Issued. The combined organic extracts were washed with brine, (MgSO₄Dried) and concentrated
did. Purified by flash chromatography (30% acetone / hexane)
8.02 g (53%) of the title compound were obtained as a white solid. Melting point 68-74 ° C;
¹1 H NMR (DMSO-d₆) δ1.931 (s, 3H), 1.939 (s, 3H), 1.
947 (s, 3H), 1.967 (s, 3H), 1.972 (s, 3H), 2.012 (s, 3)
H), 2.073 (s, 3H), 3.93-4.01 (m, 4H), 4.13-4.21 (m, 2
H), 4.37 (d, 2H), 4.64-4.90 (m, 5H), 4.97 (t, 1H), 5.2
0 (dd, 1H), 5.27-1.33 (m, 2H), 7.48 (d, 1H), 7.52 (d, 1)
H), 7.88 (s, 1H); IR (KBr) 2950, 1750, 1230 and 10
50cm^-1Mass spectrum (FAB), m / z 808 (M + H); result of elemental analysis: calculated value (C₃₄H₄₃NO₂₀As): C, 51.98; H, 5.52; N, 1.7.
8; Found: C, 51.59; H, 5.45; N, 1.86.

Step 1 5- (hepta-O-acetyl-β-D-maltosyloxymethyl) -2-methylphenylamine 5- (hepta-O-acetyl-β-D-maltosyl in EtOAc (181 mL) (Oxymethyl) -2-methyl-1-nitrobenzene (7.11 g, 9.05 mmol)
And a solution containing tin (II) chloride dihydrate (14.3 g, 63.3 mmol)
Refluxed for 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. The combined organic extracts (with K ₂ CO ₃₎ dried and concentrated. Flash chromatography
(Gradient of 0%, 1%, 2% and 3% MeOH / CHCl ₃ ) to give 5- (hepta-O-acetyl-β-D-maltosyloxymethyl) -2-methylphenylamine 5
.39 g (79%) were obtained as a white foam. ¹ H NMR (DMSO-d ₆ ) δ 1.
93 (s, 3H), 1.94 (s, 3H), 1.95 (s, 3H), 1.97 (s, 3H), 1.
98 (s, 3H), 2.03 (s, 6H), 2.10 (s, 3H), 3.93-4.03 (m, 4
H), 4.14-4.23 (m, 2H), 4.32-4.41 (m, 2H), 4.58 (d, 1H)
), 4.68 (t, 1H), 4.76-4.88 (m, 4H), 4.98 (t, 1H), 5.22
(t, 1H), 5.28-5.31 (m, 2H), 6.37 (d, 2H), 6.49 (s, 1H)
, 6.87 (d, 1H).

Step 2 N- [5- (hepta-O-acetyl-β-D-maltosyloxymethyl) -2-methylphen
Nyl] acetamide At ambient temperature, 5- (hepta-O-acetyl-β-D-mer in THF (91 mL).
(Rutosyloxymethyl) -2-methylphenylamine (6.88 g, 9.10 mmol)
) And triethylamine (4.18 mL, 30.0 mmol) were added to a stirred solution.
Acetyl (0.714 mL, 10.0 mmol) was added dropwise. After 4 hours, the reaction is saturated.
NaHCO₃Quench with aqueous solution (100 mL), wash with brine (100 mL)
, Extracted with EtOAc. Combined organic extracts (K₂CO₃Dried) and concentrated
did. Flash chromatography (1%, 2% and 3% MeOH / CHCl ₃ Gradient) to give N- [5- (hepta-O-acetyl-β-D-maltosyloxime).
6.60 g (91%) of tyl) -2-methylphenyl] acetamide as a white foam
I got it.¹1 H NMR (DMSO-d₆) δ 1.93 (s, 3H), 1.94 (s, 3H),
1.95 (s, 3H), 1.979 (s, 3H), 1.984 (s, 3H), 2.03 (s, 3H)
H), 2.10 (s, 3H), 2.18 (s, 3H), 3.94-4.02 (m, 4H), 4.1
4-4.24 (m, 2H), 4.40 (d, 1H), 4.48 (d, 1H), 4.67-4.74
(m, 2H), 4.81-4.89 (m, 2H), 4.98 (t, 1H), 5.19-5.32 (
m, 3H), 6.98 (d, 1H), 7.17 (d, 1H), 7.33 (s, 1H), 9.27 (
s, 1H).

Step 3 N- [5- (β-D-maltosyloxymethyl) -2-methylphenyl] acetamide N- [5- (Hepta-O-acetyl-β-D-malto) in MeOH (198 mL) Siloxymethyl) -2-methylphenyl] acetamide (6.60 g, 8.27 mmol) and 25 wt% NaOMe in MeOH (0.893 g, 4.14 mmol)
) Was refluxed for 2.5 hours. The reaction was cooled to room temperature, concentrated and N- [
5- (β-D-maltosyloxymethyl) -2-methylphenyl] acetamide 4.09
g (98%) was obtained as a white foam. This material was used without further purification. An analytical sample, by reverse phase _{HPLC (C18,15% CH 3 CN /} H 2 O), as a white solid. Melting point 115 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 2.03 (s
, 3H), 2.16 (s, 3H), 3.04-3.09 (m, 2H), 3.21-3.56 (m,
7H), 3.57-3.62 (m, 2H), 3.70-3.73 (m, 1H), 4.26 (d, 1
H), 4.48-4.54 (m, 3H), 4.76 (d, 1H), 4.86-4.89 (m, 2H)
), 5.01 (d, 1H), 5.17 (d, 1H), 5.42 (d, 1H), 5.49 (d, 1H)
), 7.10 (d, 1H), 7.15 (d, 1H), 7.35 (s, 1H), 9.28 (s, 1H)
); IR (KBr) 3375, 2900, 1670 and 1025 cm ^-1 ; mass spectrum (FAB), m / z 504 (M + H), 526 (M + Na); result of elemental analysis: calculated value (C ₂₂ H ₃₃ NO _12. 0.5H as _{2 O): C, 51.56;} H, 6.
67; N, 2.73; Found: C, 51.78; H, 6.81; N, 2.75.

Step 4 N- {5-[(4 ′, 6′-O-benzylidene-β-D-maltosyloxy) methyl] -2-me
Tylphenyl} acetamide N- [5- (β-D-maltosyloxymethyl) -2-methylphenyl] acetamide (
1.88 g, 3.83 mmol), benzaldehyde dimethyl acetal (0.80
7 mL, 5.36 mmol) and p-toluenesulfonic acid monohydrate (72.7 mg
, 0.383 mmol) was heated to 60 ° C. After 4 hours,
Nsaldehyde dimethyl acetal (0.403 mL, 2.68 mmol) and
Ruenesulfonic acid monohydrate (36.4 mg, 0.192 mmol) was added and the reaction was
Heated at 60 ° C. for 16 hours. K to reactant₂CO₃And continue heating for 0.5 hours
Was. The hot solution was filtered and the filtrate was concentrated. Reversed phase HPLC (C18, 15% CH
₃CN / H₂O) to give 1.26 g (56%) of the title compound as a white solid.
I got it. Melting point 190-197 ° C;¹1 H NMR (DMSO-d₆) δ2.04 (s, 3
H), 2.16 (s, 3H), 3.08 (t, 1H), 3.35-3.40 (m, 3H), 3.4
5 (t, 1H), 3.53-3.59 (m, 2H), 3.64-3.75 (m, 3H), 4.11
(dd, J = 5.1, 2.4 Hz, 1H), 4.28 (d, 1H), 4.50 (d, 1H), 4.
67 (t, 1H), 4.77 (d, 1H), 5.13 (d, 1H), 5.21 (br s, 1H)
, 5.29 (brs, 1H), 5.49 (brs, 1H), 5.57 (s, 1H), 5.6
1 (br s, 1H), 7.10 (d, 1H), 7.16 (d, 1H), 7.34-7.38 (m
, 4H), 7.42-7.45 (s, 2H), 9.28 (s, 1H); IR (KBr) 3400
, 2900, 1650 and 1075 cm^-1Mass spectrum (+ ESI), m /
z 609 (M + NH₄), 614 (M + Na); Result of elemental analysis: Calculated value (C₂₉H₃₇NO₁₂・ 0.5H₂O): C, 57.99; H, 6.
30; N, 2.37; Found: C, 57.80; H, 6.39; N, 2.50. Found: C, 57.85; H, 6.33; N, 2.27.

Step 5 N- (5- [4 ′, 6′-O-benzylidene-6-O- (4-toluenesulfonyl) -β-D-maltosyloxy] methyl-2-methylphenyl) acetamide 0 ° C. And N- {5-[(4 ′, 6′-O-benzylidene-) in pyridine (2.4 mL).
β-D-maltosyloxy) methyl] -2-methylphenyl} acetamide (0.711
g, to a stirred solution of 1.20 mmol) was added a solution of _{CH 2} Cl 2 (1.5mL) p- toluenesulfonyl chloride in the (0.275 g, 1.44 mmol). 2
After hours, more p-toluenesulfonyl chloride (0.275 g, 1.44 mmol) in CH ₂ Cl ₂ (1.5 mL) was added and the solution was stirred at 0 ° C. for 2 hours. The reaction was quenched with ice cold H ₂ O (50 mL) and extracted with EtOAc. The combined organic extracts were saturated aqueous NaHCO ₃ (2 ×) and saturated CuSO ₄ aqueous (2 ×).
Times), brine (2 times) and washed sequentially) dried (Na ₂ SO _4, and concentrated. Purification by reverse phase HPLC (C18, 50% CH ₃ CN / H ₂ O) gave 0.42 of a white solid.
1 g (47%) was obtained. Melting point 115-121 ° C ¹ ; ¹ H NMR (DMSO-d ₆ ) δ
2.05 (s, 3H), 2.17 (s, 3H), 2.33 (s, 3H), 3.05 (t, 1H),
3.24-3.44 (m, 4H), 3.52 (t, 1H), 3.58-3.62 (m, 3H), 3
.95 (d, 1H), 4.13 (dd, 1H), 4.28 (d, 1H), 4.33 (d, 1H),
4.41 (d, 1H), 4.59 (d, 1H), 5.05 (d, 1H), 5.57 (s, 1H),
7.06 (d, 1H), 7.16 (d, 1H), 7.33-7.47 (m, 8H), 7.78 (d
, 2H), 9.29 (s, 1H); IR (KBr) 3375, 2900, 1650, 135
0.11175 and 1075 cm ^-1 ; mass spectrum (FAB), m / z 746 (
M + H), 768 (M + Na); Result of elemental analysis: Calculated (as C ₃₆ H ₄₃ NO ₁₄ S.H ₂ O): C, 56.61; H, 5.94
N, 1.83; Found: C, 56.61; H, 5.77; N, 1.80.

Step 6 N- (5-{[4 ′, 6′-O-benzylidene-6-deoxy-6- (4-nitro-1H-imidazol-1-yl) -β-D-maltosyloxy] Methyl} -2-methylphenyl) acetamide 4-nitroimidazole (51.5 mg) in DMF (1.5 mL) at ambient temperature
To a stirred solution of 0.456 mmol) _was added K 2 CO ₃ (28.6mg, a 0.207 mmol). After 0.5 hour, the reaction was charged with N- (5-[-
Solution of 4 ', 6'-O-benzylidene-6-O- (4-toluenesulfonyl) -β-D-maltosyloxy] methyl} -2-methylphenyl) acetamide (0.309 g, 0.414 mmol) Was added and the reaction was heated at 100 ° C. for 4 hours. The reaction was cooled to room temperature, quenched with ice-cold H ₂ O (40 mL) and extracted with EtOAc. Organic extract (
(Na ₂ SO ₄ ) and concentrated. Reversed phase HPLC (C18, 35% CH ₃ CN
/ H ₂ O) and then crystallized from EtOAc / hexane to give a white solid 7
3 mg (26%) were obtained. Melting point 158 ° C; ¹ H NMR (DMSO-d ₆ ) δ 2.04 (
s, 1H), 2.15 (s, 1H), 3.08 (t, 1H), 3.24-3.49 (m, 4H),
3.62 (d, 1H), 3.65 (d, 1H), 3.76 (t, 1H), 3.87-3.93 (m
, 1H), 4.23-4.34 (m, 4H), 4.47-4.51 (m, 2H), 5.20 (d,
1H), 5.37 (brs, 2H), 5.58 (brs, 1H), 5.59 (s, 1H),
5.88 (brs, 1H), 6.91 (d, 1H), 7.12 (d, 1H), 7.21 (s, 1)
H), 7.36-7.40 (m, 3H), 7.44-7.47 (m, 2H), 7.81 (s, 1H)
), 8.39 (s, 1H), 9.27 (s, 1H); IR (KBr) 3375, 2925, 1
660, 1550, 1500, 1375, 1350, 1300 and 1075 cm ^−
1; mass spectrum (FAB), m / z 687 (M + H); Elemental analysis: Calculated _{(as C 32 H 38 N 4 O 13} .0.9H 2 O): C, 54.68; H, 5 .7
1; N, 7.97; Found: C, 54.97; H, 5.47; N, 7.58.

Example 2 N- (5-{[2,3,2 ′, 3′-tetra-O-acetyl-4 ′, 6′-O-benzylidene-6-
Deoxy-6- (4-nitro-1H-imidazol-1-yl) -β-D-maltosyl] oxymethyl} -2-chlorophenyl) acetamide

[0051]

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Step 1 N- (5-{[4 ′, 6′-O-benzylidene-6-O- (4-toluenesulfonyl) -β-D-
Maltosyl] oxymethyl} -2-chlorophenyl) acetamide Follow the method of Example 1 in pyridine (5.7 mL) at 0 ° C.
N- {5-[(4 ′, 6′-O) produced using 4-chloro-3-nitrobenzyl alcohol
-Benzylidene-β-D-maltosyl) oxymethyl] -2-chlorophenyl} acetoa
To a stirred solution of amide (1.50 g, 2.86 mmol) was added CH.₂Cl₂(3mL)
P-Toluenesulfonyl chloride (0.657 g, 3.44 mmol)
added. After 2 hours, the reaction was cooled to ice-cold H₂Quench with O (50 mL) and add brine (10
mL) and extracted with EtOAc. The combined organic extracts were washed with saturated NaHCO
₃Aqueous solution (3 times), saturated CuSO₄Wash sequentially with aqueous solution (3 times) and brine (3 times)
, (Na₂SO₄Dried) and concentrated. Flash chromatography (5%
And 10% MeOH / CH₂Cl₂Gradient) to give the title compound 0.903.
g (41%) was obtained as a white solid. 105-120 ° C;¹H NMR (D
MSO-d₆) δ 2.08 (s, 3H), 2.33 (s, 3H), 3.04-3.09 (m, 1
H), 3.27-3.45 (m, 4H), 3.49-3.53 (m, 1H), 3.60-3.65
(m, 3H), 3.95 (d, 1H), 4.13 (dd, 1H), 4.29-4.33 (m, 2H
), 4.46 (d, 1H), 4.62 (d, 1H), 5.05 (d, 1H), 5.33-5.35.
(m, 2H), 5.55 (d, 1H), 5.57 (s, 1H), 5.75 (d, 1H), 7.18
(d, 1H), 7.35-7.47 (m, 8H), 7.78 (d, 2H), 9.53 (s, 1H)
Mass spectrum (+ ESI), m / z 766/768 (M + H), 783/785 (
M + NH₄); Result of elemental analysis: Calculated value (C₃₅H₄₀NCLO₁₄S ・ H₂As O): C, 53.60; H, 5.4
0; N, 1.79; Found: C, 53.46; H, 5.18; N, 1.80.

Step 2 N- (5-{[2,3,2 ′, 3′-tetra-O-acetyl-4 ′, 6′-O-benzylidene-6-
O- (4-Toluenesulfonyl) -β-D-maltosyl] oxymethyl} -2-chlorophenyl) acetamide At 0 ° C., N- (5-{[4 ′, 6′-) in CH ₂ Cl ₂ (20 mL). O-benzylidene-6-O- (4-toluenesulfonyl) -β-D-maltosyl] oxymethyl} -2-chlorophenyl) acetamide (0.782 g, 1.02 mmol), pyridine (0.99)
1 mL, 12.3 mmol) and 4-dimethylaminopyridine (0.457 g, 4.
Acetic anhydride (0.764 mL, 8.17 mmol) was added to a stirred solution of (08 mmol). After 2 hours, the reaction was diluted with diethyl ether (100 mL) and water (twice)
NaHCO ₃ aqueous solution (2 times), saturated CuSO ₄ aqueous solution (2 times), brine
Washed sequentially (twice), dried (Na ₂ SO ₄ ) and concentrated. Purification by flash chromatography (1%, 2% and 3% MeOH / CH ₂ Cl ₂ gradient)
0.942 g (99%) of the title compound was obtained as a white solid. Melting point 116-12
2 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 1.91 (s, 3H), 1.92 (s, 3H), 1
.96 (s, 3H), 2.00 (s, 3H), 2.08 (s, 3H), 2.29 (s, 3H), 3
.68 (dd, 1H), 3.77 (t, 1H), 3.85 (t, 1H), 3.90 (t, 1H),
3.97-4.00 (m, 1H), 4.21 (dd, 1H), 4.32 (s, 2H), 4.39 (
d, 1H), 4.56 (d, 1H), 4.60 (d, 1H), 4.78 (d, 1H), 4.86 (
dd, 1H), 5.17-5.30 (m, 3H), 5.65 (s, 1H), 7.03 (d, 1H).
, 7.34-7.41 (m, 7H), 7.46 (d, 1H), 7.59 (s, 1H), 7.80 (
d, 2H), 9.52 (s, 1H); mass spectrum (+ ESI), m / z 934/93.
6 (M + H); Elemental analysis results: Calculated (as C ₄₃ H ₄₈ NClO ₁₈ S): C, 55.27; H, 5.17; N
, 1.50; Found: C, 55.07; H, 5.05; N, 1.47.

Step 3 N- (5-{[2,3,2 ′, 3′-tetra-O-acetyl-4 ′, 6′-O-benzylidene-6-
Deoxy-6- (4-nitro-1H-imidazol-1-yl) -β-D-maltosyl] oxo
Cimethyl} -2-chlorophenyl) acetamide At ambient temperature, 4-nitroimidazole (41.0 mg) in DMF (1 mL)
, 0.363 mmol) in 60% sodium hydride / mineral oil (13.2 mg,
(0.330 mmol) was added and the mixture was stirred for 0.5 h. Add DMF (
N- (5-{[2,3,2 ', 3'-tetra-O-acetyl-4', 6'-O in 1.5 mL).
-Benzylidene-6-O- (4-toluenesulfonyl) -β-D-maltosyl] oxymethyl
A solution of {-2-chlorophenyl) acetamide (0.308 g, 0.330 mmol)
Was added and the reaction was heated at 100 ° C. for 16 hours. Cool the reaction to room temperature and add ice-cold H ₂ Quenched with O (50 mL) and extracted with EtOAc. Organic extract (Na₂S
O₄Dried) and concentrated. Flash chromatography (1%, 2% and
3% MeOH / CHCl₃Gradient) and then CH 2₂Cl₂/ Petroleum ether
Crystallization afforded 0.110 g (38%) of the title compound as a white solid. Fusion
132-142 ° C;¹1 H NMR (DMSO-d₆) δ 1.93 (s, 3H), 1.9
3 (s, 3H), 1.97 (s, 3H), 2.01 (s, 3H), 2.07 (s, 3H), 3.7
8 (t, 1H), 3.87-3.95 (m, 3H), 4.11 (t, 1H), 4.27 (d, 1H)
), 4.31-4.37 (m, 2H), 4.46 (d, 1H), 4.65-4.76 (m, 3H)
, 4.96 (dd, J = 5.9, 4.4 Hz, 1H), 5.24 (t, 1H), 5.30 (d,
1H), 5.38 (t, 1H), 5.65 (s, 1H), 6.86 (dd, 1H), 7.34-
7.41 (m, 6H), 7.49 (s, 1H), 7.87 (s, 1H), 8.48 (s, 1H),
9.50 (s, 1H); IR (KBr) 3400, 2925, 1760, 1375, 123
0 and 1050cm^-1Mass spectrum (+ FAB), m / z 875/877 (
M + H); Result of elemental analysis: Calculated value (C₃₉H₄₃N₄ClO₁₇As): C, 53.52; H, 4.95; N
, 6.40; Found: C, 53.25; H, 4.85; N, 6.03.

Example 3 N- (5-{[4 ′, 6′-O-benzylidene-6-deoxy-6- (4-nitro-1H-imidazol-1-yl) -β-D-maltosyl] oxy Methyl} -2-chlorophenyl) acetamide

[0056]

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N- (5-{[2,3,2 ′, 3′-tetra-O-acetyl in MeOH (6.24 mL)
4 ', 6'-O-benzylidene-6-deoxy-6- (4-nitro-1H-imidazole-
1-yl) -β-D-maltosyl] oxymethyl} -2-chlorophenyl) acetamide (
0.208 g, 0.238 mmol) and 25% by weight sodium in methanol
A stirred solution containing methoxide (25.7 mg, 0.119 mmol) was added at 65 ° C.
Heated. After 3 hours, the reaction was cooled to ambient temperature and concentrated in vacuo. Flash
Chromatography (10% MeOH / CHCl₃), Followed by CH₂Cl
₂/ Crystallization from petroleum ether to give 0.133 g (79%) as a white solid
Was. 144-151 ° C;¹1 H NMR (DMSO-d₆) δ 2.08 (s, 3H),
3.06-3.12 (1H), 3.28 (m, 1H), 3.39-3.51 (m, 3H), 3.6
1-3.69 (m, 2H), 3.77-3.82 (m, 1H), 3.87-3.93 (m, 1H)
, 4.23-4.31 (m, 3H), 4.39 (d, 1H), 4.47 (dd, 1H), 4.5
4 (d, 1H), 5.20 (d, 1H), 5.35 (d, 1H), 5.36 (d, 1H), 5.5
6-5.59 (m, 2H), 7.05 (dd, 1H), 7.35-7.48 (m, 6H), 7.5
4 (s, 1H), 7.80 (s, 1H), 8.37 (s, 1H), 9.50 (s, 1H); IR (
KBr) 3400, 2900, 1690, 1540, 1300 and 1065 cm^−
1Mass spectrum (+ FAB), m / z 707/709 (M + H); result of elemental analysis: calculated value (C₃₁H₃₅N₄ClO₁₃・ H₂As O): C, 51.35; H, 5.1
4; N, 7.73; Found: C, 51.16; H, 5.07; N, 7.36.

Example 4 N- {5-[(2,2 ′, 3,3′-tetra-O-acetyl-4 ′, 6′-O-benzylidene-6-
Deoxy-6-iodo-β-D-maltosyl) oxymethyl] -2-chlorophenyl} acetamide

[0059]

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N- (5-{[2,3,2 ′, 3′-tetra-O-acetyl-) in DMSO (11 mL)
4 ', 6'-O-benzylidene-6-O- (4-toluenesulfonyl) -β-D-maltosyl]
A solution containing (oxymethyl) -2-chlorophenyl) acetamide (1.026 g, 1.098 mmol) and sodium iodide (1.646 g, 10.98 mmol) was heated at 85 ° C. for 1 hour. The reaction was cooled to room temperature, poured into _{H 2} O (110mL). The resulting precipitate is collected, dissolved in CH ₂ Cl ₂ and (with Na ₂ SO ₄ )
Dry and concentrate. Flash chromatography (40% acetone / hexane
) And crystallized from EtOAc / hexane to give 0.723 g (74
%) As a white solid. 133-138 ° C; ¹ H NMR (DMSO-
d ₆ ) δ 1.92 (s, 3H), 1.94 (s, 3H), 1.98 (s, 3H), 2.00 (s, 3H)
3H), 2.07 (s, 3H), 3.48 (dd, J = 10.5, 5.7 Hz, 1H), 3.6
2-3.70 (m, 2H), 3.74-3.82 (m, 3H), 3.92 (t, J = 9.0 Hz,
1H), 4.33 (d, J = 5.3 Hz, 1H), 4.58 (d, J = 12.7 Hz, 1H)
, 4.65-4.70 (m, 1H), 4.76 (d, J = 12.7 Hz, 1H), 4.87-4
.93 (m, 2H), 5.27 (t, J = 9.9 Hz, 1H), 5.31 (d, J = 4.2 Hz)
, 1H), 5.35 (t, J = 9.0 Hz, 1H), 5.64 (s, 1H), 7.09 (dd,
J = 8.3, 1.8 Hz, 1H), 7.35-7.39 (m, 5H), 7.46 (d, J = 8.
1Hz, 1H), 7.65 (s, 1H), 9.52 (s, 1H); IR (KBr) 3400,
2950, 1750, 1375, 1240 and 1050 cm ^-1 ; mass spectrum (+ FAB), m / z 890/892 (M + H); result of elemental analysis: calculated (as C ₃₆ H ₄₁ NClIO ₁₅ ): C, 48.58. H, 4.64; N
, 1.57; found: C, 48.82; H, 4.61; N, 1.50.

Example 5 N- {5-[(4 ′, 6′-O-benzylidene-6-deoxy-6-iodo-β-D-maltosyl) oxymethyl] -2-chlorophenyl} acetamide

[0062]

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N- (5-{[4 ′, 6′-O-benzylidene-6-O- (4-toluenesulfonyl) -β-D-
Maltosyl] oxymethyl} -2-chlorophenyl) acetamide (0.201 g, 0.2
262 mmol) to give the title compound according to the method of Example 4. After purification by flash chromatography (10% MeOH / CH ₂ Cl ₂ )
Crystallization from tOAc / hexane afforded 0.090 g (70%) of the title compound as a white solid. Melting point 115-130 ° C; ¹ H NMR (DMSO-d ₆ ) δ 2.0
7 (s, 3H), 3.08-3.13 (m, 1H), 3.28-3.29 (m, 2H), 3.37
-3.40 (m, 3H), 3.50-3.61 (m, 3H), 3.67-3.74 (m, 2H),
4.10-4.14 (m, 1H), 4.39 (d, 1H), 4.69 (ABq, J = 12.4H
z, Δδ = 0.08, 2H), 5.19 (d, 1H), 5.32-5.36 (m, 2H), 5.
51 (d, 1H), 5.58 (s, 1H), 5.60 (d, 1H), 7.23 (dd, 1H),
7.35-7.40 (m, 3H), 7.42-7.46 (m, 3H), 7.67 (s, 1H), 9
.52 (s, 1H); IR (KBr) 3400, 2900, 1675, 1540, 1420
And 1070 cm ^-1 ; mass spectrum (+ FAB), m / z 722/724 (M
+ H); Elemental analysis results: Calculated (as C ₂₈ H ₃₃ NClIO ₁₁ ): C, 46.59; H, 4.61; N
, 1.94; Found: C, 46.21; H, 4.66; N, 2.04.

Example 6 N- (5-{[2,2 ′, 3,3′-tetra-O-acetyl-4 ′, 6′-O-benzylidene-6-
Deoxy-6- (1,3-dioxy-1,3-dihydroisoindol-2-yl) -β-D-
Maltosyl] oxymethyl} -2-chlorophenyl) acetamide

[0065]

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N- (5-{[2,3,2 ′, 3′-tetra-O-acetyl-) in DMF (7.0 mL)
4 ', 6'-O-benzylidene-6-O- (4-toluenesulfonyl) -β-D-maltosyl]
Oxymethyl} -2-chlorophenyl) acetamide (0.654 g, 0.700 mm)
Mol) and phthalimide potassium salt (0.142 g, 0.770 mmol)
The resulting solution was heated at 100 ° C. for 1 hour. The reaction was cooled to room temperature and H₂O (70m
L). The resulting precipitate was collected and CH₂Cl₂Dissolved in H₂In O (
(Once), wash (Na)₂SO₄Dried) and concentrated. Flash chromatography
Purified by feed (40% acetone / hexane) to give 0.246 g (39%) of the title compound.
Was obtained as a white solid. Melting point 210-215 ° C;¹1 H NMR (DMSO-d
₆) δ 1.93 (s, 3H), 1.94 (s, 3H), 2.00 (s, 3H), 2.10 (s, 3H)
H), 2.05 (s, 3H), 3.78 (t, J = 9.6 Hz, 1H), 3.91-4.03 (
m, 6H), 4.25 (d, J = 12.5 Hz, 1H), 4.31 (dd, J = 10.3, 4.
8Hz, 1H), 4.38 (d, J = 12.5Hz, 1H), 4.68-4.75 (m, 2H)
, 4.96 (dd, J = 10.3, 4.0 Hz, 1H), 5.24-5.29 (m, 2H), 5
.32 (d, J = 4.0 Hz, 1H), 5.64 (s, 1H), 6.79 (dd, J = 8.1,
1.5Hz, 1H), 7.31 (d, J = 8.1Hz, 1H), 7.34-7.41 (m, 6H
), 7.82-7.86 (m, 2H), 7.89-7.92 (m, 2H), 9.44 (s, 1H)
IR (KBr) 3400, 2900, 1750, 1710, 1375, 1240 and
And 1050cm^-1Mass spectrum (+ FAB), m / z 909/911 (M + H
); Result of elemental analysis: Calculated value (C₄₄H₄₅N₂ClO₁₇As): C, 58.12; H, 4.99; N
, 3.08; Found: C, 57.77; H, 4.85; N, 2.98.

Example 7 N- (5-{[4 ′, 6′-O-benzylidene-6-deoxy-6- (1,3-dioxo-1,3-)
Dihydroisoindol-2-yl) -β-D-maltosyl] oxymethyl} -2-chlorophenyl) acetamide

[0068]

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N- (5- {2,2 ′, 3,3′-tetra-O-acetyl-4 ′, 6′-O-benzylidene-6-deoxy-6- (1,3-dioxo-1, The title compound was prepared according to the method of Example 3 using 3-dihydroisoindol-2-yl) -β-D-maltosyl] oxymethyl} -2-chlorophenyl) acetamide to give 0.145 g (88%). Was obtained as a white solid. 226-233 ° C .; ¹ H NMR (DMSO-d ₆ ) δ 2.07 (s,
3H), 3.12-3.16 (m, 1H), 3.39-3.47 (m, 4H), 3.57-3.6
8 (m, 3H), 3.81 (dd, J = 14.2, 9.8 Hz, 1H), 3.93-3.94 (
m, 1H), 4.04-4.07 (m, 1H), 4.17 (d, J = 7.9 Hz, 1H), 4.
22 (dd, J = 9.8, 4.9 Hz, 1H), 4.35 (ABq, J = 12.0 Hz, Δδ
= 0.05, 2H), 5.19 (d, J = 4.0 Hz, 1H), 5.27 (d, J = 5.5H)
z, 1H), 5.39 (d, J = 5.1 Hz, 1H), 5.58 (s, 1H), 5.59 (d,
J = 2.0 Hz, 1H), 5.84 (d, J = 6.4 Hz, 1H), 6.94 (dd, J = 8
.2, 2.0 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.37-7.40 (m,
4H), 7.45-7.48 (m, 2H), 7.81-7.84 (m, 2H), 7.88-7.9
0 (m, 2H), 9.45 (s, 1H); IR (KBr) 3400, 2900, 1710, 1
400 and 1070 cm ^-1 ; mass spectrum (+ FAB), m / z 741/7.
43 (M + H); Elemental analysis: Calculated _{(as C 36 H 37 N 2 ClO 13} · 0.75H 2 O): C, 57.30;
H, 5.14; N, 3.71; Found: C, 57.37; H, 5.11; N, 3.58.

Example 8 N- {5-[(6-Deoxy-6-O-azido-4 ′, 6′-O-benzylidene-β-D-maltosyl) oxymethyl] -2-chlorophenyl} acetamide

[0071]

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Step 1 N- {5-[(2,2 ′, 3,3′-tetra-O-acetyl-6-deoxy-6-azido-4 ′, 6
'-O-benzylidene-β-D-maltosyl) oxymethyl] -2-chlorophenyl} acetamide N- (5-{[2,3,2', 3'-tetra-O-acetyl-) in DMF (29 mL) 4
', 6'-O-benzylidene-6-O- (4-toluenesulfonyl) -β-D-maltosyl] oxymethyl} -2-chlorophenyl) acetamide (0.897 g, 0.960 mmol) and sodium azide ( (0.103 g, 1.58 mmol) was heated at 50 ° C. for 2 days. The reaction was cooled to room temperature, quenched with H 2 _O, E
Extracted with tOAc, dried (Na ₂ SO ₄ ) and concentrated. Purification by flash chromatography (40% acetone / hexane) afforded 0.692 g of the title compound (9
0%) as a solid. ¹ H NMR (DMSO-d ₆ ) δ 1.94 (s, 3H),
1.96 (s, 3H), 1.98 (s, 3H), 2.00 (s, 3H), 2.08 (s, 3H),
3.57-3.88 (m, 4H), 3.91-3.97 (m, 2H), 4.02-4.05 (m, 4H)
1H), 4.23 (dd, 1H), 4.59 (d, J = 12.7 Hz, 1H), 4.71-4.
78 (m, 2H), 4.86-4.92 (m, 2H), 5.22-5.36 (m, 3H), 5.6
4 (s, 1H), 7.08 (dd, J = 8.3, 1.8 Hz, 1H), 7.38 (s, 5H),
7.47 (d, J = 8.2 Hz, 1H), 7.65 (s, 1H), 9.53 (s, 1H).

Step 2 N- {5-[(6-Deoxy-6-azido-4 ′, 6′-O-benzylidene-β-D-maltosyl) oxymethyl] -2-chlorophenyl} acetamide N- {5- [(2,2 ', 3,3'-tetra-O-acetyl-6-deoxy-6-azido-4', 6
The title compound was prepared according to the method of Example 3 using '-O-benzylidene-β-D-maltosyl) oxymethyl] -2-chlorophenyl} acetamide to give 0.127 g (82%) of a white solid. Obtained. 203-204 ° C; ¹ H NMR (DMSO-
d ₆ ) δ 2.07 (s, 3H), 3.10-3.16 (m, 1H), 3.35-3.41 (m, 3
H), 3.45-3.58 (m, 4H), 3.62-3.70 (m, 3H), 4.09-4.15
(m, 1H), 4.40 (d, J = 7.7 Hz, 1H), 4.67 (ABq, J = 12.2H
z, Δδ = 0.09, 2H), 5.13 (d, J = 4.0 Hz, 1H), 5.33 (d, J =
5.1 Hz, 1 H), 5.36 (d, J = 5.1 Hz, 1 H), 5.54 (d, J = 3.3 H)
z, 1H), 5.57 (s, 1H), 5.68 (d, J = 6.6 Hz, 1H), 7.19 (dd
, J = 8.3, 1.8 Hz, 1H), 7.34-7.39 (m, 3H), 7.42-7.46 (m
, 3H), 7.65 (s, 1H), 9.52 (s, 1H); IR (KBr) 3400,285
0, 2100, 1700, 1300 and 1070 cm ^-1 ; mass spectrum (+ F
AB) 637 (M + H) ; Elemental analysis: Calculated _{(as C 28 H 33 N 4 ClO 11} ): C, 52.79; H, 5.22; N
, 8.80; Found: C, 52.63; H, 5.05; N, 8.56.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 9/14 A61P 9/14 11/06 11/06 29/00 29/00 35/00 35/00 43 / 00 105 43/00 105 C07H 19/04 C07H 19/04 19/052 19/052 (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, B A, BB, BG, BR, BY, CA, CH, 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, KZ, 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, ZWF terms (reference 4C057 CC02 CC03 DD03 JJ20 LL03 LL06 4C086 AA01 AA02 AA03 EA02 EA11 MA01 NA14 ZA36 ZA45 ZA94 ZB21 ZB26

Claims (16)

[Claims] 1. Structure: embedded image [Wherein X is Y is hydrogen, halogen, azido, or, if ^desired, may Het optionally substituted with ^{R 10;} Het is 1,3-dioxo-1,3-dihydroisoindol-2-yl, imidazol-1 R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, acyl having 2 to 7 carbons, perfluoroacyl having 2 to 7 carbons, 1 to 1 carbon or 6 alkyls, 1-6 carbon atoms
R ⁵ is hydrogen, alkyl having 1 to 6 carbons, perfluoroalkyl having 1 to 6 carbons, halogen, nitrile, nitro or alkoxy having 1 to 6 carbons; R ⁶ and R ⁷ Is each independently hydrogen, acyl having 2 to 7 carbons, 2 to 2 carbons
7 perfluoroacyl, C1-6 alkyl, C1-6 perfluoroalkyl, C1-6 alkylsulfonyl, C1-6 perfluoroalkylsulfonyl, C6-10 arylsulfonyl or Carbon number 6-1
R ⁸ and R ⁹ are each independently hydrogen, alkyl having 1 to 6 carbons, alkyl having 1 to 6 carbons, haloalkyl having 1 to 6 carbons, 1 to 6 carbons Nitroloalkyl, nitroalkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, 6 to 6 carbons
Aryl having 10 to 10 carbon atoms, aryl having 6 to 10 carbon atoms substituted with R ¹¹ ,
2 aralkyl or aralkyl having 7 to 12 carbon atoms substituted with R ¹¹ ; R ¹⁰ is halogen, nitrile, nitro, amino, acylamino having 2 to 7 carbon atoms, perfluoroacylamino having 2 to 7 carbon atoms, Carboxyl, carboxaldehyde, perfluoroalkyl having 1 to 6 carbons, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, perfluoroalkoxy having 1 to 6 carbons, 2 to 7 carbons
Alkoxycarbonyl, C2-7 perfluoroalkoxycarbonyl,
Aryl having 6 to 10 carbons or mercapto; R ¹¹ is halogen, nitrilo, nitro or perfluoroalkyl having 1 to 6 carbons] or a pharmaceutically acceptable salt thereof. 2. R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen or acyl having 2 to 7 carbons; R ⁵ is hydrogen, alkyl having 1 to 6 carbons or halogen; R ⁶ and R ⁷ are each independently hydrogen or acyl having 2 to 7 carbons; R ⁸ and R ⁹ are each independently hydrogen or aryl having 6 to 10 carbons; R ¹⁰ is halogen, The compound according to claim 1, which is nitrile, nitro, amino, acylamino having 2 to 7 carbon atoms, carboxyl, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons or aryl having 6 to 10 carbons. Above acceptable salts. 3. R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen or acetyl; R ⁵ is hydrogen, alkyl having 1 to 3 carbons, or chloro; R ⁶ hydrogen; R ⁷ Is acetyl; R ⁸ is phenyl; R ⁹ hydrogen; R ¹⁰ is nitro; or a pharmaceutically acceptable salt thereof. 4. N- (5-{[4 ′, 6′-O-benzylidene-6-deoxy-6- (4-nitro-1H-imidazol-1-yl) -β-D-maltosyloxy] The compound according to claim 1, which is methyl} -2-methylphenyl) acetamide, or a pharmaceutically acceptable salt thereof. 5. N- (5-{[2,3,2 ', 3'-tetra-O-acetyl-4', 6'-O-
Benzylidene-6-deoxy-6- (4-nitro-1H-imidazol-1-yl) -β-D-
The compound according to claim 1, which is [maltosyl] oxymethyl} -2-chlorophenyl) acetamide, or a pharmaceutically acceptable salt thereof. 6. N- (5-{[4 ′, 6′-O-benzylidene-6-deoxy-6- (4-nitro-1H-imidazol-1-yl) -β-D-maltosyl] oxymethyl 2. The compound according to claim 1, which is} -2-chlorophenyl) acetamide, or a pharmaceutically acceptable salt thereof. 7. N- {5-[(2,2 ', 3,3'-tetra-O-acetyl-4', 6'-O-
2. The compound according to claim 1, which is benzylidene-6-deoxy-6-iodo-β-D-maltosyl) oxymethyl] -2-chlorophenyl} acetamide, or a pharmaceutically acceptable salt thereof. 8. N- {5-[(4 ′, 6′-O-benzylidene-6-deoxy-6-iodo)
The compound according to claim 1, which is -β-D-maltosyl) oxymethyl] -2-chlorophenyl} acetamide, or a pharmaceutically acceptable salt thereof. 9. N- (5-{[2,2 ', 3,3'-tetra-O-acetyl-4', 6'-O-
Benzylidene-6-deoxy-6- (1,3-dioxo-1,3-dihydroisoindole
2. The compound according to claim 1, which is -2-yl) -β-D-maltosyl] oxymethyl} -2-chlorophenyl) acetamide, or a pharmaceutically acceptable salt thereof. 10. N- (5-{[4 ′, 6′-O-benzylidene-6-deoxy-6- (1,1,
The compound according to claim 1, which is 3-dioxo-1,3-dihydroisoindol-2-yl) -β-D-maltosyl] oxymethyl} -2-chlorophenyl) acetamide, or a pharmaceutically acceptable salt thereof. 11. The method according to claim 11, which is N- {5-[(6-deoxy-6-O-azido-4 ′, 6′-O-benzylidene-β-D-maltosyl) oxymethyl] -2-chlorophenyl} acetamide. Item 7. The compound according to item 1, or a pharmaceutically acceptable salt thereof. 12. A method for treating or inhibiting a hyperproliferative vascular disorder in a mammal in need thereof, comprising administering to said mammal an effective amount of a structure: [Wherein X is Y is hydrogen, halogen, azido, or, if ^desired, may Het optionally substituted with ^{R 10;} Het is 1,3-dioxo-1,3-dihydroisoindol-2-yl, imidazol-1 R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, acyl having 2 to 7 carbons, perfluoroacyl having 2 to 7 carbons, 1 to 1 carbon or 6 alkyls, 1-6 carbon atoms
R ⁵ is hydrogen, alkyl having 1 to 6 carbons, perfluoroalkyl having 1 to 6 carbons, halogen, nitrile, nitro or alkoxy having 1 to 6 carbons; R ⁶ and R ⁷ Is each independently hydrogen, acyl having 2 to 7 carbons, 2 to 2 carbons
7 perfluoroacyl, C1-6 alkyl, C1-6 perfluoroalkyl, C1-6 alkylsulfonyl, C1-6 perfluoroalkylsulfonyl, C6-10 arylsulfonyl or Carbon number 6-1
R ⁸ and R ⁹ are each independently hydrogen, alkyl having 1 to 6 carbons, alkyl having 1 to 6 carbons, haloalkyl having 1 to 6 carbons, 1 to 6 carbons Nitroloalkyl, nitroalkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, 6 to 6 carbons
Aryl having 10 to 10 carbon atoms, aryl having 6 to 10 carbon atoms substituted with R ¹¹ ,
2 aralkyl or aralkyl having 7 to 12 carbon atoms substituted by R ¹¹ ; R ¹⁰ is halogen, nitrile, nitro, amino, acylamino having 2 to 7 carbon atoms, perfluoroacylamino having 2 to 7 carbon atoms, Carboxyl, carboxaldehyde, perfluoroalkyl having 1 to 6 carbons, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, perfluoroalkoxy having 1 to 6 carbons, 2 to 7 carbons
Alkoxycarbonyl, C2-7 perfluoroalkoxycarbonyl,
Aryl having 6 to 10 carbon atoms, or mercapto; R ¹¹ is halogen, nitrilo, nitro or perfluoroalkyl having 1 to 6 carbon atoms] or a pharmaceutically acceptable salt thereof. Method consisting of. 13. A method of treating or inhibiting restenosis in a mammal in need thereof, wherein said mammal is provided with an effective amount of a structure: [Wherein X is Y is hydrogen, halogen, azido, or, if ^desired, may Het optionally substituted with ^{R 10;} Het is 1,3-dioxo-1,3-dihydroisoindol-2-yl, imidazol-1 R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, acyl having 2 to 7 carbons, perfluoroacyl having 2 to 7 carbons, 1 to 1 carbon or 6 alkyls, 1-6 carbon atoms
R ⁵ is hydrogen, alkyl having 1 to 6 carbons, perfluoroalkyl having 1 to 6 carbons, halogen, nitrile, nitro or alkoxy having 1 to 6 carbons; R ⁶ and R ⁷ Is each independently hydrogen, acyl having 2 to 7 carbons, 2 to 2 carbons
7 perfluoroacyl, C1-6 alkyl, C1-6 perfluoroalkyl, C1-6 alkylsulfonyl, C1-6 perfluoroalkylsulfonyl, C6-10 arylsulfonyl or Carbon number 6-1
R ⁸ and R ⁹ are each independently hydrogen, alkyl having 1 to 6 carbons, alkyl having 1 to 6 carbons, haloalkyl having 1 to 6 carbons, 1 to 6 carbons Nitroloalkyl, nitroalkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, 6 to 6 carbons
Aryl having 10 to 10 carbon atoms, aryl having 6 to 10 carbon atoms substituted with R ¹¹ ,
2 aralkyl or aralkyl having 7 to 12 carbon atoms substituted by R ¹¹ ; R ¹⁰ is halogen, nitrile, nitro, amino, acylamino having 2 to 7 carbon atoms, perfluoroacylamino having 2 to 7 carbon atoms, Carboxyl, carboxaldehyde, perfluoroalkyl having 1 to 6 carbons, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, perfluoroalkoxy having 1 to 6 carbons, 2 to 7 carbons
Alkoxycarbonyl, C2-7 perfluoroalkoxycarbonyl,
Aryl having 6 to 10 carbon atoms, or mercapto; R ¹¹ is halogen, nitrilo, nitro or perfluoroalkyl having 1 to 6 carbon atoms] or a pharmaceutically acceptable salt thereof. Method consisting of. 14. The method of claim 13, wherein the restenosis results from an angioplasty, a revascularization, or an organ or tissue transplant. 15. A method for 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: [Wherein X is Y is hydrogen, halogen, azido, or, if ^desired, may Het optionally substituted with ^{R 10;} Het is 1,3-dioxo-1,3-dihydroisoindol-2-yl, imidazol-1 R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, acyl having 2 to 7 carbons, perfluoroacyl having 2 to 7 carbons, 1 to 1 carbon or 6 alkyls, 1-6 carbon atoms
R ⁵ is hydrogen, alkyl having 1 to 6 carbons, perfluoroalkyl having 1 to 6 carbons, halogen, nitrile, nitro or alkoxy having 1 to 6 carbons; R ⁶ and R ⁷ Is each independently hydrogen, acyl having 2 to 7 carbons, 2 to 2 carbons
7 perfluoroacyl, C1-6 alkyl, C1-6 perfluoroalkyl, C1-6 alkylsulfonyl, C1-6 perfluoroalkylsulfonyl, C6-10 arylsulfonyl or Carbon number 6-1
R ⁸ and R ⁹ are each independently hydrogen, alkyl having 1 to 6 carbons, alkyl having 1 to 6 carbons, haloalkyl having 1 to 6 carbons, 1 to 6 carbons Nitroloalkyl, nitroalkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, 6 to 6 carbons
Aryl having 10 to 10 carbon atoms, aryl having 6 to 10 carbon atoms substituted with R ¹¹ ,
2 aralkyl or aralkyl having 7 to 12 carbon atoms substituted by R ¹¹ ; R ¹⁰ is halogen, nitrile, nitro, amino, acylamino having 2 to 7 carbon atoms, perfluoroacylamino having 2 to 7 carbon atoms, Carboxyl, carboxaldehyde, perfluoroalkyl having 1 to 6 carbons, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, perfluoroalkoxy having 1 to 6 carbons, 2 to 7 carbons
Alkoxycarbonyl, C2-7 perfluoroalkoxycarbonyl,
Aryl having 6 to 10 carbon atoms, or mercapto; R ¹¹ is halogen, nitrilo, nitro or perfluoroalkyl having 1 to 6 carbon atoms] or a pharmaceutically acceptable salt thereof. Method consisting of. 16. Structure: embedded image [Wherein X is Y is hydrogen, halogen, azido, or, if ^desired, may Het optionally substituted with ^{R 10;} Het is 1,3-dioxo-1,3-dihydroisoindol-2-yl, imidazol-1 R ¹ , R ² , R ³ and R ⁴ are each independently hydrogen, acyl having 2 to 7 carbons, perfluoroacyl having 2 to 7 carbons, 1 to 1 carbon or 6 alkyls, 1-6 carbon atoms
R ⁵ is hydrogen, alkyl having 1 to 6 carbons, perfluoroalkyl having 1 to 6 carbons, halogen, nitrile, nitro or alkoxy having 1 to 6 carbons; R ⁶ and R ⁷ Is each independently hydrogen, acyl having 2 to 7 carbons, 2 to 2 carbons
7 perfluoroacyl, C1-6 alkyl, C1-6 perfluoroalkyl, C1-6 alkylsulfonyl, C1-6 perfluoroalkylsulfonyl, C6-10 arylsulfonyl or Carbon number 6-1
R ⁸ and R ⁹ are each independently hydrogen, alkyl having 1 to 6 carbons, alkyl having 1 to 6 carbons, haloalkyl having 1 to 6 carbons, 1 to 6 carbons Nitroloalkyl, nitroalkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, 6 to 6 carbons
Aryl having 10 to 10 carbon atoms, aryl having 6 to 10 carbon atoms substituted with R ¹¹ ,
2 aralkyl or aralkyl having 7 to 12 carbon atoms substituted by R ¹¹ ; R ¹⁰ is halogen, nitrile, nitro, amino, acylamino having 2 to 7 carbon atoms, perfluoroacylamino having 2 to 7 carbon atoms, Carboxyl, carboxaldehyde, perfluoroalkyl having 1 to 6 carbons, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, perfluoroalkoxy having 1 to 6 carbons, 2 to 7 carbons
Alkoxycarbonyl, C2-7 perfluoroalkoxycarbonyl,
Aryl having 6 to 10 carbon atoms, or mercapto; R ¹¹ is halogen, nitrilo, nitro or perfluoroalkyl having 1 to 6 carbon atoms] or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier. A pharmaceutical composition comprising: