JP2002530418A - Benzylglycosylamide as an inhibitor of smooth muscle cell proliferation - Google Patents

Abstract

(57) Abstract: The present invention provides a compound of formula (I) [wherein having the following structure, Y is C or N; wherein, n represents 0 to 3; X is (A); ^{R 1} and ^{R 2,} Each independently represents hydrogen, alkyl having 1 to 6 carbons, halo, acetyl, phenyl, CF ₃ , CN, OH, NO ₂ , NH ₂ , alkoxy having 1 to 6 carbons or alkoxynitrile having 1 to 6 carbons R ³ is hydrogen, acylamide having 2 to 6 carbon atoms or alkoxy having 1 to 6 carbon atoms; R ⁴ , R ⁵ , R ⁶ R ⁷ and R ⁸ are each independently hydrogen, 1 to 6 carbon atoms; R ⁹ and R ¹⁰ are each independently an acyl having 1 to 6 carbon atoms or maltose; benzyl substituted with R ¹ and R ² , or benzoyl substituted with R ¹ and R ² ; the ^{R 9} and ^{R 10} groups on the 4 'and 6' positions of, together, charcoal Number 1-6 alkyl, each two alkyl groups having 1 to 6 carbon atoms, pyridine substituted with R ^1, phenyl substituted with R ^1, benzyl substituted by R ^1, substituted with R ¹ 2-phenylethyl or 3-phenylpropyl substituted with R ¹ may form a cyclic acetal, or a pharmaceutically acceptable inhibitor thereof. Provide salt. 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. It relates to the use of glycosylamide.

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 compound of the present invention is characterized in that (a) the saccharide is an anomer
(b) having substantially different substituents on the sugar skeleton, and (c) having a higher activity on smooth muscle cell proliferation.

[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 sugar has anomeric amide, (b) the substituent on the benzyl group is different, and (c) the application (smooth muscle growth 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 (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) benzylglycosylamides which have no structural similarity to heparin, sulfated cyclodextrin, or sulfated lactobionic acid dimer; It differs from all the prior art in that it has adjacent sugar residues (is a disaccharide), (c) has a well-defined structure, and (d) is not sulfated.

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

[0008]

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Wherein Y is C or N; wherein n is 0 to 3; X is

[0010]

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R ¹ and R ² each independently represent hydrogen, alkyl having 1 to 6 carbons, halo, acetyl, phenyl, CF ₃ , CN, OH, NO ₂ , NH ₂ , R ³ is hydrogen, acylamide having 2 to 6 carbon atoms or alkoxy having 1 to 6 carbon atoms; R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each an alkoxy or an alkoxynitrile having 1 to 6 carbon atoms; independently hydrogen, acyl of 1 to 6 carbon atoms, benzyl substituted by ^{R 1} and ^{R 2} or,, ^{R 1} and ^{R 2} is benzoyl substituted by; ^{R 9} and ^{R 10} each independently The acyl having 1 to 6 carbon atoms or the R ⁹ and R ¹⁰ groups at the 4 ′ and 6 ′ positions of maltose together form 1 carbon atom.
6 alkyl, each two alkyl groups having 1 to 6 carbon atoms, substituted pyridine substituted with R ^1, phenyl substituted with R ^1, benzyl substituted with R ^1, with R ¹ 2- Phenylethyl or 3-phenylpropyl substituted with R ¹ may form a cyclic acetal.] Or a pharmaceutically acceptable salt thereof.

Alkyl includes both straight and branched moieties. Halogen means bromine, chlorine, fluorine and iodine. When Y is nitrogen, the pyridinecarboxamide is preferably pyridine 3-carboxamide.

[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 Y is nitrogen or 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 formula I of the present invention are those wherein n is 0-1; R ¹ and R ² are each independently hydrogen, halogen, CF ₃ , OH, NO ₂ ,
Is ^{R 3,} hydrogen, acetamido or methoxy;; NH _2, methoxy, butoxy or butoxy nitrile ^{R 4, R 5, R 6} , R 7 and ^{R 8} are each independently hydrogen, acyl of 1 to 6 carbon atoms R ⁹ and R ¹⁰ are each independently an acyl having 1 to 6 carbon atoms, or R ⁹ and R ¹⁰ groups at the 4 ′ and 6 ′ positions of maltose are taken together to form benzylidene. A compound forming a ring or a pharmaceutically acceptable salt thereof (all other substituents are as defined above).

More preferred compounds of formula I are: n is 0; R ¹ and R ² are each independently hydrogen or halogen; R ³ is hydrogen; R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ is each independently hydrogen, acyl having 1 to 6 carbons or benzoyl; R ⁹ and R ¹⁰ are each independently acyl having 1 to 6 carbons or 4 ′ and 6 of maltose The R ⁹ and R ¹⁰ groups in the 'position are together a compound forming a benzylidene ring or a pharmaceutically acceptable salt thereof (all other substituents being as defined above).

A particularly preferred compound of the present invention is 6-chloro-N- (hepta-O-acetyl-β-D-cellobiosyl) -3-pyridinecarboxamide; N- (4 ′, 6′-O-benzylidene-β -D-cellobiosyl) -6-chloronicotinamide; 2-chloropiperidine-5-carboxylic acid (6-O-benzoyl-4 ', 6'-O-benzylidene-1-deoxy-β-D-cellobiosyl) amide; 2,6-dimethoxy-N- (hepta-O-acetyl-β-D-cellobiosyl) -3-pyridinecarboxamide; N- (hepta-O-acetyl-β-D-cellobiosyl) -3-chloro-4-fluoro N- (4 ′, 6′-O-benzylidene-β-D-cellobiosyl) -2-chloro-4-fluorobenzamide; or a pharmaceutically acceptable salt thereof.

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

[0019]

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In Scheme 1, Y, n, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
R ⁸ , R ⁹ and R ¹⁰ are as defined above.

Thus, cellobiosylamine 1 can be prepared at room temperature in a suitable solvent system such as benzene, ethanol, dichloromethane, triethylamine, EEDQ, DEC / HOB
Benzoic acid derivative 2 in the presence of a coupling agent such as T or DCC / HOBT
And glycoside 3 is obtained. This glycoside is prepared by coupling amine 1 to substituted acid chloride 2 in a suitable solvent system such as tetrahydrofuran, dichloromethane, acetonitrile and ethyl acetate in the presence of triethylamine to give glycoside 3. You can also. When R ³ is a nitro group, the nitro group can be substituted with stannous chloride or metallic iron at ambient temperature to reflux temperature in a polar aprotic solvent such as ethyl acetate, or in a polar protic solvent such as ethanol or methanol. The anilino compound 4 can be obtained by reduction with a reducing agent such as, or by catalytic reduction in the presence of a catalyst such as palladium on carbon. 4 with an acid chloride or sulfonyl chloride in a non-protic solvent such as dichloromethane or tetrahydrofuran in the presence of an amine base such as triethylamine or diisopropylethylamine at a temperature in the range of −20 ° C. to ambient temperature; The desired compound 5 is obtained.

Removal of the 3 or 5 acetate group at ambient temperature to reflux by hydrolysis with a catalytic amount of sodium methoxide in methanol or a base such as aqueous sodium hydroxide in methanol provides 6 be able to. After hydrolysis of the acetate groups, the hydroxyl groups at the 4 'and 6' positions of the maltose are reduced at ambient temperature to 70 ° C in a polar aprotic solvent such as acetonitrile or dimethylformamide in an acid such as camphorsulfonic acid or toluenesulfonic acid. Reaction with benzaldehyde dimethyl acetal in the presence of a catalyst can give a benzylidene derivative. 6-hydroxyl group at -78 ° C to ambient temperature,
Selective benzoylation in a collidine / tetrahydrofuran mixture can afford 7. Reacylation with acid anhydride in the presence of an amine base such as pyridine or triethylamine at a temperature in the range of 0 ° C. to ambient temperature gives 8;

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 passages (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 method, 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 was 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.

[0029]

[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 compound of the present invention can be formulated as it is 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.

[0033] 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.

The 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 6-Chloro-N- (hepta-O-acetyl-β-D-cellobiosyl) -3-pyridinecarboxamide

Step 1 Hepta-O-acetyl-1-β-cellobiosylamine Hepta-O-acetyl-1-β-cellobiosylamine was obtained from A. Bertho
[Justus Libigs Annalen der Chemie (Justus Li
ebigs Ann. Chem.), 562, 229 (1949)].

Step 2 6-Chloro-N- (hepta-O-acetyl-β-D-cellobiosyl) -3-pyridinecarboxamide Hepta-O-acetyl- in dichloromethane (1.5 mL) and tetrahydrofuran (1.5 mL) To a stirred mixture of 1-β-cellobiosylamine (0.20 g, 0.3147 mmol) and triethylamine (0.064 g, 0.63 mmol)
6-Chloronicotinoyl chloride (0.5 g, 0.32 mmol) was added in one portion.
After 12 hours, the reaction was diluted with dichloromethane (10 mL) and water (5 mL), 10%
Washed sequentially with sodium hydroxide (5 mL) and brine (10 mL), (MgSO ₄
Dried) and concentrated. Flash chromatography (50% -60% EtO
Purification (Ac / petroleum ether gradient) afforded the title compound as an off-white solid. ¹ H NMR (CDCl ₃ ) δ 1.99 (s, 3H), 2.01 (s, 3H), 2.04 (s, 3H)
6H), 2.06 (s, 3H), 2.10 (s, 3H), 2.12 (s, 3H), 3.65-3.
69 (m, 2H), 3.79-3.81 (m, 2H), 4.06 (dd, J = 12.3, 2.4
Hz, 1H), 4.14-4.18 (m, 1H), 4.38 (dd, J = 12.5, 4.6 Hz)
, 1H), 4.50 (d, J = 11.6, 1H), 4.51 (d, J = 7.9, 1H), 4.9
0-4.96 (m, 2H), 5.07 (apparent t, J = 9.7, 1H), 5.15 (apparent t, J = 9.2, 1H), 5.30 -5.37 (m, 4H), 7.04 (d, J = 8.6
, 1H), 7.42 (dd, J = 8.3, 0.7 Hz, 1H), 8.02 (dd, J = 8.1,
2.6Hz, 2H), 8.73 (dd, J = 7.4, 0.7Hz, 1H); IR (KBr) 3
400, 1750, 1550, 1245 and 1075 cm ^-1 ; mass spectrum (
+ ESI), m / z 775 (M + H), 797 (M + Na).

Example 2 N- (4 ′, 6′-O-benzylidene-β-D-cellobiosyl) -6-chloronicotinamide

Step 1 6-Chloro-N- (β-D-cellobiosyl) nicotinamide 6-Chloro-N- (hepta-O-β-D-cellobiosyl) -3-pyridinecarboxamide (1040 mg) in methanol (10 mL) (1.34 mmol) was added 0.075 mL of a 0.34 M solution of sodium methoxide. The reaction was stirred overnight and quenched with Dowex H + resin. After 0.5 hour, the solution was filtered and concentrated in vacuo to give the title compound as a white solid. Melting point 193 ° C
¹ H NMR (D ₂ O-d ₂ ) δ 3.19 (t, J = 8.1 Hz, 1 H), 3.25-3.
48 (m, 4H), 3.58-3.62 (m, 4H), 3.70-3.83 (m, 3H), 4.4
0 (d, J = 7.9 Hz, 1 H), 5.08 (d, J = 9.2 Hz, 1 H), 7.49 (d, J
= 8.6 Hz, 1H), 8.09 (dd, J = 8.3 Hz, 2.4 Hz, 1H), 8.63 (
d, J = 2.0 Hz, 1H); IR (KBr) 3375, 2900, 1660, 1575
And 1060 cm ^-1; mass spectrum (-FAB), m / e 479 (M-H); Elemental analysis: Calculated _{(as C 18 H 25 ClN 2 O 11} · H 2 O): C, 43.34 H, 5.
46; N, 5.61; Found: C, 43.48; H, 5.55; N, 5.47.

Step 2 N- (4 ′, 6′-O-benzylidene-β-D-cellobiosyl) -6-chloronicotinamide 6-chloro-N- (β-D-cellobiosyl in dimethylformamide (6 mL)
) Nicotinamide (0.33 g, 0.6683 mmol), benzaldehyde dimethyl acetal (0.15 mL, 1.0 mmol) and camphorsulfonic acid (10
(mg, 0.043 mmol) was heated at 70 ° C. After 4 hours, the reaction was cooled to ambient temperature and quenched with 0.5 mL of 1 N NaOH solution. The solution was concentrated and purified by flash chromatography (2%, 5-10% MeOH / methylene chloride gradient) to give the title compound as a white solid. 230 ° C
¹ H NMR (DMSO-d ₆ ) δ 3.13-3.16 (m, 1H), 3.33-3.45 (
m, 7H), 3.63-3.75 (m, 3H), 4.18-4.22 (m, 1H), 4.51 (d
, J = 1.5 Hz, 1 H), 4.55 (d, J = 7.7 Hz, 1 H), 4.62 (apparent t, J = 5.8 Hz, 1 H), 4.98 (apparent). t, J = 8.8 Hz, 1H), 5.1
9 (d, J = 5.3 Hz, 1 H), 5.38 (d, J = 4.4 Hz, 1 H), 5.35 (d, J
= 5.1 Hz, 1H), 5.59 (s, 1H), 7.35-7.38 (m, 3H), 7.42-
7.45 (m, 2H), 7.67 (d, J = 8.3 Hz, 1H), 8.29 (dd, J = 8.3
, 2.4 Hz, 1 H), 8.88 (d, J = 2.6 Hz, 1 H), 9.20 (d, J = 8.6 H)
z, 1H); IR (KBr) 3400, 2900, 1650 and 1075 cm ^-1 ;
Mass spectrum (+ FAB), m / e 569 (M + H); Elemental analysis: Calculated _{(as C 25 H 29 ClN 2 O 11} · 1.0H 2 O): C, 51.16;
H, 5.32; N, 4.77; Found: C, 51.22; H, 5.26; N, 4.68.

Example 3 2-Chloropiperidine-5-carboxylic acid (6-O-benzoyl-4 ', 6'-O-benzylidene-1-deoxy-β-D-cellobiosyl) amide Dry tetrahydrofuran (1.5 mL) And anhydrous 2,4,6-collidine (1.5 mL)
)), A solution of N- (4 ', 6'-O-benzylidene-β-D-cellobiosyl) -6-chloronicotinamide (0.22 g, 0.39 mmol) cooled to -40 ° C for 0.5 hour did. Benzoyl chloride (0.076 mL, 0.507 mmol) was added slowly and the reaction was warmed to ambient temperature overnight. Dilute the reaction with ethyl acetate (30 mL) and add 1N H
Cl (15 mL), saturated aqueous sodium bicarbonate solution (15 mL) and brine (15 m
L). The organic layer was dried (MgSO ₄ ) and filtered. Evaporation and flash chromatography (2%, 5% to 10% MeOH / methylene chloride gradient) gave the title compound as a white solid. 260 ° C
¹ H NMR (DMSO-d ₆ ) δ 3.17-3.28 (m, 1H), 3.35-3.47 (
m, 4H), 3.55 (dt, J = 8.8, 5.9 Hz, 1H), 3.64-3.71 (m, 2
H), 3.82-3.86 (m, 1H), 4.17 (dd, J = 10.1, 4.2 Hz, 1H)
, 4.48 (dd, J = 12.1, 4.6 Hz, 1H), 4.57-4.65 (m, 2H), 4
.86 (d, J = 3.1 Hz, 1H), 5.09 (apparent t, J = 9.0 Hz, 1H),
5.33 (d, J = 5.3 Hz, 1H), 5.37 (d, J = 4.6 Hz, 1H), 5.50 (
s, 1H), 5.57 (d, J = 5.1 Hz, 1H), 7.35-7.37 (m, 3H), 7.
39-7.42 (m, 2H), 7.55 (t, J = 7.2 Hz, 2H), 7.63-7.69 (
m, 2H), 7.96 (d, J = 8.6 Hz, 2H), 8.27 (dd, J = 8.3, 2.6H)
z, 1H), 8.86 (d, J = 2.6 Hz, 1H), 9.22 (d, J = 9.0 Hz, 1H)
IR (KBr) 3400, 2900, 1650, 1275 and 1100 cm ^-1
; Mass spectrum (-FAB), m / z 671 (M-H); Elemental analysis: Calculated _{(C 32 H 33 ClN 2 O} 12 · 1.0H 2 O: C, 55.62; H, 5 .1
0; N, 4.05; Found: C, 55.80; H, 4.99; N, 4.01.

Example 4 (2,6-Dimethoxy-N- (hepta-O-acetyl-β-D-cellobiosyl) -3-pyridinecarboxamide 2 in benzene-ethanol (1: 1, v / v, 4 mL) To a stirred solution of 2,6-dimethoxynicotinic acid (0.051 g, 0.26 mmol) was added 2-ethoxy-N-carbonyl-1,2-dihydroquinoline (0.071 g, 0.29 mmol) in one portion. 0.5 hours later, hepta-O-acetyl-1-β-cellobiosylamine (0.151 g)
, 0.24 mmol) was added and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in methylene chloride. The organic layer was washed sequentially with 1N hydrochloric acid, water, 1% sodium bicarbonate and water, dried (MgSO ₄ ) and concentrated. Purification by flash chromatography (40% to 60% EtOAc / petroleum ether gradient) afforded the title compound as a white solid. 127 ° C .; ¹ H NMR (C
DCl ₃ ) δ 1.98 (s, 3H), 1.99 (s, 3H), 2.01 (s, 3H), 2.04
(s, 6H), 2.10 (s, 3H), 2.12 (s, 3H), 3.63-3.67 (m, 1H)
, 3.80-3.85 (m, 2H), 3.96 (s, 3H), 3.99-4.07 (m, 1H),
4.07 (s, 3H), 4.17 (dd, J = 12.6, 4.2 Hz, 1H), 4.37 (dd
, J = 12.5, 4.4 Hz, 1H), 4.44-4.47 (m, 1H), 4.51 (d, J =
7.9 Hz, 1H), 4.94 (apparent t, J = 8.1 Hz, 1H), 5.03-5.1
6 (m, 2H), 5.33 (t, J = 9.7 Hz, 1H), 5.39 (t, J = 9.4 Hz, 1
H), 6.41 (d, J = 9.4 Hz, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.
41 (d, J = 8.8 Hz, 1H); IR (KBr) 3400, 2950, 1750, 12
45 and 1050 cm ^-1 ; mass spectrum (+ FAB), m / e 801 (M +
H), 823 (M + Na ); Elemental analysis: Calculated _{(as C 34 H 44 ClN 2 O 20} · 0.5H 2 O): C, 50.43;
H, 5.60; N, 3.46; Found: C, 50.56; H, 5.52; N, 3.31.

Example 5 N- (Hepta-O-acetyl-β-D-cellobiosyl) -3-chloro-4-fluorobenzamide The title compound is prepared as a white solid according to the method of Step 2 of Example 1. did. 203-205 ° C .; ¹ H NMR (CDCl ₃ ) δ 1.99 (s, 3H), 2.
01 (s, 3H), 2.04 (s, 6H), 2.05 (s, 3H), 2.10 (s, 3H), 2.
13 (s, 3H), 3.64-3.68 (m, 1H), 3.79-3.80 (m, 2H), 4.0
5 (dd, J = 12.5, 2.0 Hz, 1H), 4.14-4.19 (m, 1H), 4.37 (
dd, J = 12.5, 4.4 Hz, 1H), 4.48-4.53 (m, 2H), 4.91-4.
99 (m, 2H), 5.05-5.17 (m, 2H), 5.33 (t, J = 9.2 Hz, 1H)
, 5.40 (t, J = 9.2 Hz, 1H), 6.80 (d, J = 9.0 Hz, 1H), 7.0
2-7.07 (m, 1H), 7.14 (dd, J = 8.3, 2.6 Hz, 1H), 7.67 (d
d, J = 8.6, 6.1 Hz, 1H); IR (KBr) 3400,2930,1750,1
245 and 1050 cm ^-1 ; mass spectrum (-ESI), m / z 789.9 /
791.9 (M-H); Elemental analysis: Calculated _{(as C 33 H 39 ClFNO 18):} C, 50.04; H, 4.96; N
, 1.77; Found: C, 50.00; H, 4.91; N, 1.85.

Example 6 N- (4 ′, 6′-O-benzylidene-β-D-cellobiosyl) -2-chloro-4-fluorobenzamide

Step 1 N- (β-D-cellobiosyl) -2-chloro-4-fluorobenzamide The title compound was prepared as a white solid according to the method of Step 1 of Example 2. Mp 65 ° C. _{^{(decomposition); 1 H NMR (CD 3}} OD-d 4) δ 3.22-3.42 (m,
5H), 3.51-3.62 (m, 3H), 3.67 (dd, J = 11.9, 5.3 Hz, 1H
), 3.83-3.90 (m, 3H), 4.43 (d, J = 7.9 Hz, 1H), 5.07 (d,
J = 9.2 Hz, 1H), 7.12-7.17 (m, 1H), 7.29 (dd, J = 8.8,2
.6Hz, 1H), 7.61 (dd, J = 8.6,6.2Hz, 1H), 8.53 (s, 1H)
IR (KBr) 3400, 2930, 1600 and 1050 cm ^-1 ; mass spectrum (-FAB), m / z 496/498 (M-H).

Step 2 N- (4 ′, 6′-O-benzylidene-β-D-cellobiosyl) -2-chloro-4-fluorobenzamide The title compound is obtained as a white solid according to the method of Example 2, Step 2. It was manufactured as a product. Mp 135-138 ° C; ¹ H NMR (CD ₃ OD-d ₄ ) δ 3.34-3.91 (
m, 11H), 4.28-4.31 (m, 1H), 4.59 (d, J = 7.9 Hz, 1H), 5
.09 (d, J = 9.2 Hz, 1H), 5.58 (s, 1H), 7.16 (dt, J = 8.3,
2.6 Hz, 1 H), 7.29-7.52 (m, 4 H), 7.60 (dd, J = 8.8, 5.9)
Hz, 1H), 7.97-7.99 (m, 3H); IR (KBr) 3400, 2900, 15
50 and 1075 cm ^-1 ; mass spectrum (+ FAB), m / e 586 (M +
H), 608 (M + Na).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 9/12 A61P 9/12 9/14 9/14 11/06 11/06 29/00 29/00 35 / 00 35/00 43/00 105 43/00 105 (81) Designated country 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, 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, ZW (72) Inventor Forake Orwemimo Adebayo United States 08512 New Jersey Cranberry, Chestnut Willow Bee 2, 6th F term (reference) 4C057 AA17 CC03 DD03 HH02 4C086 AA01 AA02 AA03 EA07 MA01 MA04 NA14 ZA39 ZA51 ZB21 ZB26

Claims (14)

[Claims] 1. Structure: embedded image Wherein Y is C or N; wherein n is 0 to 3; X is R ¹ and R ² are each independently hydrogen, alkyl having 1 to 6 carbons, halo, acetyl, phenyl, CF ₃ , CN, OH, NO ₂ , NH ₂ , alkoxy having 1 to 6 carbons or carbon having 1 to 6 carbons R ³ is hydrogen, acylamide having 2 to 6 carbon atoms or alkoxy having 1 to 6 carbon atoms; R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently , Hydrogen, acyl having 1 to 6 carbons, benzyl substituted with R ¹ and R ² , or benzoyl substituted with R ¹ and R ² ; R ⁹ and R ¹⁰ each independently have 1 carbon The acyl at -6 or the R ⁹ and R ¹⁰ groups at the 4 ′ and 6 ′ positions of maltose together form one carbon atom.
6 alkyl, each two alkyl groups having 1 to 6 carbon atoms, substituted pyridine substituted with R ^1, phenyl substituted with R ^1, benzyl substituted with R ^1, with R ¹ 2- Phenylethyl or 3-phenylpropyl substituted with R ¹ , which may form a cyclic acetal.] Or a pharmaceutically acceptable salt thereof. 2. n is 0 to ¹ ; R ¹ and R ² are each independently hydrogen, halogen, CF ₃ , OH, NO ₂ ,
Is ^{R 3,} hydrogen, acetamido or methoxy;; NH _2, methoxy, butoxy or butoxy nitrile ^{R 4, R 5, R 6} , R 7 and ^{R 8} are each independently hydrogen, acyl of 1 to 6 carbon atoms R ⁹ and R ¹⁰ are each independently an acyl having 1 to 6 carbon atoms, or R ⁹ and R ¹⁰ groups at the 4 ′ and 6 ′ positions of maltose are taken together to form benzylidene. The compound according to claim 1, which forms a ring, or a pharmaceutically acceptable salt thereof. 3. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein n is 0; R ¹ and R ² are each independently hydrogen or halogen; and R ³ is hydrogen. 4. 6-Chloro-N- (hepta-O-acetyl-β-D-cellobiosyl)-
The compound according to claim 1, which is 3-pyridinecarboxamide, or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 1, which is N- (4 ′, 6′-O-benzylidene-β-D-cellobiosyl) -6-chloronicotinamide, or a pharmaceutically acceptable salt thereof. 6. A 2-chloropiperidine-5-carboxylic acid (6-O-benzoyl-4 ′).
2,6'-O-benzylidene-1-deoxy-β-D-cellobiosyl) amide.
Or a pharmaceutically acceptable salt thereof. 7. The compound according to claim 1, which is 2,6-dimethoxy-N- (hepta-O-acetyl-β-D-cellobiosyl) -3-pyridinecarboxamide, or a pharmaceutically acceptable salt thereof. 8. N- (hepta-O-acetyl-β-D-cellobiosyl) -3-chloro-
The compound according to claim 1, which is 4-fluorobenzamide, or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 1, which is N- (4 ′, 6′-O-benzylidene-β-D-cellobiosyl) -2-chloro-4-fluorobenzamide, or a pharmaceutically acceptable salt thereof. 10. 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 Y is C or N; wherein n is 0 to 3; X is R ¹ and R ² are each independently hydrogen, alkyl having 1 to 6 carbons, halo, acetyl, phenyl, CF ₃ , CN, OH, NO ₂ , NH ₂ , alkoxy having 1 to 6 carbons or carbon having 1 to 6 carbons R ³ is hydrogen, acylamide having 2 to 6 carbon atoms or alkoxy having 1 to 6 carbon atoms; R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently , Hydrogen, acyl having 1 to 6 carbons, benzyl substituted with R ¹ and R ² , or benzoyl substituted with R ¹ and R ² ; R ⁹ and R ¹⁰ each independently have 1 carbon The acyl at -6 or the R ⁹ and R ¹⁰ groups at the 4 ′ and 6 ′ positions of maltose together form one carbon atom.
6 alkyl, each two alkyl groups having 1 to 6 carbon atoms, substituted pyridine substituted with R ^1, phenyl substituted with R ^1, benzyl substituted with R ^1, with R ¹ 2- Phenylethyl or 3-phenylpropyl substituted with R ¹ may form a cyclic acetal, or a pharmaceutically acceptable salt thereof. The method that consists of doing. 11. 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 Y is C or N; wherein n is 0 to 3; X is R ¹ and R ² are each independently hydrogen, alkyl having 1 to 6 carbons, halo, acetyl, phenyl, CF ₃ , CN, OH, NO ₂ , NH ₂ , alkoxy having 1 to 6 carbons or carbon having 1 to 6 carbons R ³ is hydrogen, acylamide having 2 to 6 carbon atoms or alkoxy having 1 to 6 carbon atoms; R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently , Hydrogen, acyl having 1 to 6 carbons, benzyl substituted with R ¹ and R ² , or benzoyl substituted with R ¹ and R ² ; R ⁹ and R ¹⁰ each independently have 1 carbon The acyl at -6 or the R ⁹ and R ¹⁰ groups at the 4 ′ and 6 ′ positions of maltose together form one carbon atom.
6 alkyl, each two alkyl groups having 1 to 6 carbon atoms, substituted pyridine substituted with R ^1, phenyl substituted with R ^1, benzyl substituted with R ^1, with R ¹ 2- Phenylethyl or 3-phenylpropyl substituted with R ¹ may form a cyclic acetal, or a pharmaceutically acceptable salt thereof. The method that consists of doing. 12. The method of claim 11, wherein the restenosis results from an angioplasty, a revascularization, or an organ or tissue transplant. 13. A method of inhibiting angiogenesis in a malignant tumor, sarcoma or neoplastic tissue of a mammal in need thereof, comprising administering to said mammal an effective amount of a structure: Wherein Y is C or N; where n is 0 to 3; X is R ¹ and R ² are each independently hydrogen, alkyl having 1 to 6 carbons, halo, acetyl, phenyl, CF ₃ , CN, OH, NO ₂ , NH ₂ , alkoxy having 1 to 6 carbons or carbon having 1 to 6 carbons R ³ is hydrogen, acylamide having 2 to 6 carbon atoms or alkoxy having 1 to 6 carbon atoms; R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently , Hydrogen, acyl having 1 to 6 carbons, benzyl substituted with R ¹ and R ² , or benzoyl substituted with R ¹ and R ² ; R ⁹ and R ¹⁰ each independently have 1 carbon The acyl at -6 or the R ⁹ and R ¹⁰ groups at the 4 ′ and 6 ′ positions of maltose together form one carbon atom.
6 alkyl, each two alkyl groups having 1 to 6 carbon atoms, substituted pyridine substituted with R ^1, phenyl substituted with R ^1, benzyl substituted with R ^1, with R ¹ 2- Phenylethyl or 3-phenylpropyl substituted with R ¹ may form a cyclic acetal, or a pharmaceutically acceptable salt thereof. The method that consists of doing. 14. Structure: embedded image Wherein Y is C or N; wherein n is 0 to 3; X is R ¹ and R ² are each independently hydrogen, alkyl having 1 to 6 carbons, halo, acetyl, phenyl, CF ₃ , CN, OH, NO ₂ , NH ₂ , alkoxy having 1 to 6 carbons or carbon having 1 to 6 carbons R ³ is hydrogen, acylamide having 2 to 6 carbon atoms or alkoxy having 1 to 6 carbon atoms; R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently , Hydrogen, acyl having 1 to 6 carbons, benzyl substituted with R ¹ and R ² , or benzoyl substituted with R ¹ and R ² ; R ⁹ and R ¹⁰ each independently have 1 carbon The acyl at -6 or the R ⁹ and R ¹⁰ groups at the 4 ′ and 6 ′ positions of maltose together form one carbon atom.
6 alkyl, each two alkyl groups having 1 to 6 carbon atoms, substituted pyridine substituted with R ^1, phenyl substituted with R ^1, benzyl substituted with R ^1, with R ¹ 2- Or a pharmaceutically acceptable salt thereof, or a phenylethyl or a cyclic acetal which may be substituted with 3-phenylpropyl substituted with R ^1. A pharmaceutical composition comprising a carrier for use.