JP2002530417A - Benzyl lactobionamide as an inhibitor of smooth muscle cell proliferation - Google Patents

Abstract

(57) [Summary] The present invention provides a smooth muscle cell growth inhibitor represented by the formula (I) 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. It relates to the use of lactobionamide (benzyllactobionamide).

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] US Pat. No. 5,296,588, US Pat. No. 5,336,765 and European Patent Application Publication No. EP
550106 A1 describes an improved method for preparing N-substituted aldonamides. U.S. Pat.No. 5,310,542 and European Patent Application Publication EP 551675 A1 are used in oral hygiene compositions and act as antibacterial agents to form bacteria responsible for plaque and
Glycosides (particularly aldobionamides) that inhibit growth are also described.
U.S. Pat. No. 2,752,334 describes a process for preparing N-substituted lactobionamides and their use as emulsifiers (especially for cheese) and as antifungals. The compound of the present invention is a compound of the present invention, which is (a) acetylated or sulfated benzyl lactobionamide, (b) having a different substituent on the aromatic nucleus, and (c) a smooth muscle cell In that it is used as a growth inhibitor.

EP-A-312086 A2 and EP-A-312087 A2 describe polysulfates of bis-aldonic amide derivatives as anti-inflammatory and antithrombotic agents. The compound of the present invention is characterized in that (a) the compound is used as a smooth muscle cell growth inhibitor, (b) it is not a dimer at all, and (c) it has only two adjacent sugar residues. Saccharides).

[0006] (Klein, U .; Mohrs, K .; Wild, H .; Steglich, W .; Liebigs Analen der der. Liebigs Ann. Chem., 1987, 485-489) describes the use of all acetylated aldonamides to produce 3-substituted pyrazoles. The compound of the present invention, the compound (a) has a different substituent on the aromatic nucleus, (b) benzyl position is not substituted, (c) used as a smooth muscle cell proliferation inhibitor, and (d)
It differs in that it is not used as a precursor for pyrazole.

[0007] 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-si, E .; Johnson, John
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 compound of the present invention is (a) benzyl lactobionamide having no structural similarity to heparin or sulfated cyclodextrin, (b) a compound which is not a dimer at all, and (c) Has only two adjacent sugar residues (is a disaccharide); and
d) It differs from all the prior arts in having a clear structure.

[0008] PCT Patent Application Publication No. WO 96/14325 discloses acylated benzyl glycosides as smooth muscle cell proliferation inhibitors. The compounds of the present invention are different in that (a) the sugar skeleton is different, (b) the open-chain nucleus has an advantage in production as compared with the cyclic sequence, and (c) the substituents on the sugar skeleton are different. different.

(Zehavi, U .; Herchman, M., Carbohyd. Res., 1986, 151, 371) Disclosed 4-carboxy-2-nitrobenzyl 4-O-α-D-glucopyranosyl-β-D-glucopyranoside attached to a research polymer. The compounds of the present invention differ from those disclosed by Zehavi in that (a) the substituent on the benzyl group is different and (b) the application (smooth muscle growth inhibition) is different.

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

[0011]

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Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently an acyl having 2 to 7 carbons, R ⁹ is hydrogen, CN, NO ₂ , halo, haloacyl, nitroacyl having 2 to 7 carbons, cyanoacyl having 3 to 7 carbons, trifluoromethylacyl having 3 to 8 carbons, benzoyl or —SO ₃ H; CF ₃ , alkyl having 1 to 6 carbons or alkoxy having 1 to 6 carbons; R ¹⁰ is hydrogen, —NO ₂ , —NHR ¹¹ , —NHR ¹³ , —N (R ¹³ ) ₂ , —N
CH ₃ R ¹³ , —NHCO ₂ alkyl (where the alkyl portion has 1 to 6 carbon atoms),
Alkylsulfonamide having 1 to 4 carbon atoms,

[0013]

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Z is O or S; R ¹¹ is an α-amino acid (where the α-carboxyl group forms an amide with the nitrogen of R ¹⁰ ); if the amino acid is glutamic acid or aspartic acid,
The non-α-carboxylic acid is an alkyl ester (where the alkyl moiety has 1 to 6 carbons); R ¹² is hydrogen, CN, NO ₂ , halo, CF ₃ , alkyl having 1 to 6 carbons, carbon number R ¹³ is hydrogen, acyl having 2 to 7 carbons, haloacyl having 2 to 7 carbons, nitroacyl having 2 to 7 carbons, or 3 carbons. Or a pharmaceutically acceptable salt thereof, which is represented by the formula: (1) to (7) cyanoacyl, trifluoromethylacyl having 3 to 8 carbon atoms or benzoyl].

Alkyl includes both straight and branched moieties. Halogen means bromine, chlorine, fluorine and iodine. When R ¹¹ is an α-amino acid,
The carboxyl moiety exists as an amide where the amide nitrogen is attached to the phenyl ring of the compound of formula I. The following exemplifies the structure obtained when R ¹¹ is alanine.

[0016]

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

[0018]

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

Pharmaceutically acceptable salts include organic and inorganic acids such as acetic acid, propionic acid,
Lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, phthalic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, naphthalenesulfonic acid, Benzenesulfonic acid, toluenesulfonic acid,
It can be formed from 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 the present invention has a basic nitrogen. Base addition salts can typically be a compound of formula I is produced when having a -SO 3 _H moiety.

The compounds of the present invention may have an asymmetric carbon atom or a sulfoxide moiety,
Some of the compounds of the present invention have one or more asymmetric centers, and therefore may give rise to optical isomers and diastereomers. 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:

[0023]

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[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently an acyl having 2 to 7 carbon atoms or —SO ₃ H; R ⁹ is hydrogen, CN, NO ₂ , halo, CF ₃ , alkyl having 1 to 6 carbons or alkoxy having 1 to 6 carbons; R ¹⁰ is hydrogen, —NO ₂ , —NHR ¹¹ , —NHR ¹³ , -N ^{(R 13)} _2, -N
CH ₃ R ¹³ , —NHCO ₂ alkyl (where the alkyl portion has 1 to 6 carbon atoms),
An alkylsulfonamide having 1 to 4 carbon atoms,

[0025]

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Z is O; R ¹¹ is an α-amino acid (where the α-carboxyl group forms an amide with the nitrogen of R ¹⁰ ); if the amino acid is glutamic acid or aspartic acid,
The non-α-carboxylic acid is an alkyl ester (where the alkyl moiety has 1 to 6 carbons); R ¹² is hydrogen, CN, NO ₂ , halo, CF ₃ , alkyl having 1 to 6 carbons, carbon number R ¹³ is hydrogen, acyl having 2 to 7 carbons, haloacyl having 2 to 7 carbons, nitroacyl having 2 to 7 carbons, or 3 carbons. -7, cyanoacyl, trifluoromethylacyl having 3-8 carbon atoms, or benzoyl], or a pharmaceutically acceptable salt thereof.

A more preferred compound of the present invention is a compound of formula I:

[0028]

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Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently acetyl or —SO ₃ H; R ⁹ is hydrogen, CN, NO ₂ , halo, CF ₃ , alkyl having 1 to 6 carbons or alkoxy having 1 to 6 carbons; R ¹⁰ is hydrogen, —NO ₂ , —NHR ¹³ or —N (R ¹³ ) ₂ ; R ¹³ Is benzyl lactobionamide represented by the formula: hydrogen or acyl having 2 to 7 carbon atoms, or a pharmaceutically acceptable salt thereof.

Particularly preferred compounds of the present invention are N-benzylocta-O-acetyllactobionamide or a pharmaceutically acceptable salt thereof; N-benzylocta-O-sulfolactobionamide or a pharmaceutically acceptable salt thereof. N- (4-nitrobenzyl) octa-O-acetyllactobionamide or a pharmaceutically acceptable salt thereof; N- (4-aminobenzyl) octa-O-acetyllactobionamide or a pharmaceutically acceptable salt thereof N- (3-aminobenzyl) octa-O-acetyllactobionamide or a pharmaceutically acceptable salt thereof; N- [3- (acetylamino) benzyl] octa-O-acetyllactobionamide Or N- [3- (acetylamino) benzyl] octa-O-sulfolactobionamide 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.

Lactobiono-1,5-lactone (1, ^* HS Isbell)
HL Frush, Methods Carbohyd. Chem., 1963,2,16-18) at a temperature in the range of 0 ° C. to 60 ° C .; Coupling with benzylamine 2 in a protic solvent such as this (in the presence of sodium carbonate if an amine salt is used) gives glycoside 3 (Scheme 1). The anilino compound 4 can be obtained by reducing the nitro group of 3 with a reducing agent such as stannous chloride in a polar aprotic solvent such as ethyl acetate at ambient to reflux temperature. 4 in an aprotic solvent such as dichloromethane or tetrahydrofuran, in the presence of an amine base such as triethylamine or diisopropylethylamine, at a temperature ranging from 0 ° C. to ambient temperature, or
Coupling with an acid chloride using a strong base such as sodium hydride (for sterically hindered systems) gives the desired compound 5. The fully acetylated compound 5 is prepared using a catalytic amount of sodium methoxide in methanol or aqueous sodium hydroxide in methanol at a temperature in the range of ambient to reflux.
It can be converted to its octahydroxy intermediate. In addition, this intermediate
It can be converted to the octasulfo compound 6 with sulfur trioxide / trimethylamine complex in a polar solvent such as N, N-dimethylformamide under reflux. Many salts of sulfate groups can be made by using various ion exchange columns such as Dowex Na ⁺ or K ⁺ .

[0033]

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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 sub-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 at a 50-fold dilution to each well (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, _{IC 50} or inhibition rate as (%) are shown in Table 1 below.

[0040]

[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-benzylocta-O-acetyllactobionamide

Step 1 Lactobiono in warm MeOH (5 mL) by gentle heating
-1,5-lactone (0.480 g, 1.41 mmol, ^* HS ISBER (H
S. Isbell); HL Frush, Methods Carbohyd. Chem., 1963, 2, 16-18) in a stirred solution of benzylamine (0. .177 mL, 1.62 mmol) were added dropwise. The reaction was stirred at room temperature for 18 hours. After concentration, the oily residue was purified by recrystallization from i-PrOH to give the product (0.300 g, 48%) as a glassy white solid. ¹ H NMR (DMSO-d ₆ ) δ 3.26-3.36 (m, 2H), 3.3
6-3.41 (m, 1H), 3.46-3.55 (m, 3H), 3.55-3.64 (m, 2H)
, 3.66-3.74 (m, 2H), 4.02-4.07 (m, 1H), 4.12 (d, J = 5.
9 Hz, 1 H), 4.17 (dd, J = 1.5, 5.1 Hz, 1 H), 4.26 (d, J = 7.
0 Hz, 1 H), 4.30 (d, J = 6.4 Hz, 2 H), 4.46-4.52 (m, 2 H),
4.66 (t, J = 5.7 Hz, 1H), 4.78 (dd, J = 5.5, 9.7 Hz, 2H),
5.14 (d, J = 3.7 Hz, 1H), 5.25 (d, J = 5.7 Hz, 1H), 7.16−
7.24 (m, 1H), 7.24-7.32 (m, 4H), 8.13 (t, J = 6.2 Hz, 1
H); IR (Kbr) 3380,2930,2890,1650,1555,1455,
1430, 1400, 1370, 1325, 1280, 1220, 1125, 1080,
1045, 970, 880 and 710 cm ^-1 ; mass spectrum [(−) FAB],
m / z 446 (M−H) ⁻ ; result of elemental analysis: calculated value (as C ₁₉ H ₂₉ NO ₁₁ ): C, 51.00; H, 6.53; N, 3.1
3; Found: C, 50.87; H, 6.49; N, 3.12.

Step 2 N-benzyl lactobionamide (0.150) in DMF (3.4 mL) at room temperature
g, 0.335 mmol) and triethylamine (0.822 mL, 5.90 mmol) was added dropwise with acetic anhydride (0.278 mL, 2.95 mmol) followed by a catalytic amount of DMAP (0.0327 g, 0.268 mmol) was added dropwise. After 18 hours, the mixture was concentrated and the resulting residue was diluted with EtOAc (100 mL).
This layer was washed with 1N HCl (10 mL), saturated aqueous NaHCO ₃ (10 mL) and brine (10 mL), and then dried (MgSO ₄ ). After concentration, the residue was purified by flash chromatography (10:90 to 90:10 EtOAc: petroleum ether gradient) to give the product (0.221 g, 84%) as a glassy solid. Melting point 85-86 ° C; ¹ H NMR (CDCl ₃ ) δ 1.88 (s, 3H), 1.9
0 (s, 3H), 1.98 (s, 3H), 2.02 (s, 6H), 2.03 (s, 3H), 2.0
9 (s, 3H), 2.15 (s, 3H), 3.94-4.02 (m, 2H), 4.03 (d, J =
7.2 Hz, 1H), 4.11-4.19 (m, 2H), 4.23 (t, J = 20.4 Hz, 1
H), 4.27-4.37 (m, 2H), 4.79 (d, J = 7.9 Hz, 1H), 4.84-
4.95 (m, 2H), 5.14 (dd, J = 3.7, 10.1 Hz, 1H), 5.21-5.
24 (m, 2H), 5.45 (dd, J = 3.1, 6.4 Hz, 1H), 7.17-7.25 (
m, 3H), 7.26-7.32 (m, 2H), 8.58 (t, J = 1.9 Hz, 1H); IR
(Kbr) 3390, 2970, 1755, 1670, 1540, 1420, 1375,
1220, 1130, 1050, 950 and 610 cm ^-1 ; mass spectrum [(
+) FAB], m / z 784 (M + H) ⁺ , 806 (M + Na) ⁺ ; Elemental analysis: Calculated (as C ₃₅ H ₄₅ NO ₁₉ ): C, 53.64; H, 5.79; N , 1.7
9; Found: C, 53.51; H, 5.86; N, 1.82.

Example 2 N-benzyl octa-O-sulfolactobionamide octa sodium salt N-benzyl lactobionamide (0.76) in DMF (59.4 mL) at room temperature
0 g, 1.70 mmol) in a stirred solution was added sulfur trioxide / trimethylamine complex (9.
(46 g, 68.0 mmol) was added and the mixture was heated to 70 ° C. After 4 days, the mixture was cooled to 0 ° C. and quenched with H ₂ O (60 mL). at this point,
Without heating the solution was concentrated and the resulting residue was in H _{2 O} (about 20-25 mL) slurried in, and filtered. The filtrate was applied to a G-10 Sephedex column. The resulting compound was collected and applied directly to a Dowex Na ⁺ ion exchange column to give the product (1.47 g, 68%) as a glassy solid after elution. Melting point> 200 ° C. (decomposition); ¹ H NMR (D ₂ O) δ 3.86 (t, J = 6.2 Hz,
1H), 3.98-4.14 (m, 3H), 4.19-4.47 (m, 5H), 4.52-4.5
7 (m, 1H), 4.67-4.86 (m, 3H), 4.92-4.96 (m, 2H), 7.10
-7.18 (m, 1H), 7.19-7.29 (m, 4H); IR (Kbr) 3490,295
0,2320,1680,1570,1500,1450,1270,1190,107
0, 1025, 920, 820, 700, 620 and 580 cm- ¹ ; mass spectrum [(-) ESI], (m-zNa) / z 608.9 (M-2Na) ^2- , 398.3 (
M-3Na) ^3-; Elemental analysis: Calculated _{(as C 19 H 21 NO 35 S 8} Na 8 · 3H 2 O): C, 17.32;
H, 2.07; N, 1.06; Found: C, 17.12; H, 2.08; N, 1.03.

Example 3 N- (4-Nitrobenzyl) octa-O-acetyllactobionamide Lactobiono-1,5-lactone (5.00 g, 14.0 g, in warm MeOH (53 mL) by gentle heating) 7 mmol, ^* HS IS BER (H
.S. Isbell); 3-nitrobenzyl in a stirred solution of HL Frush, Methods Carbohyd. Chem., 1963, 2, 16-18). Amine HCl salt (3.56 g, 19.1 mmol) was added dropwise. After cooling the reaction to 0 ° C., Na ₂ CO ₃ (1.56 g, 14.7 mmol) was added and then stirred at room temperature for 4 days. After concentration, the oily residue was concentrated in DMF (
74 mL). To this stirred solution at room temperature was added triethylamine (40.6 mL).
, 292 mmol) were added dropwise followed by acetic anhydride (13.7 mL, 146 mmol) and finally a catalytic amount of DMAP (1.63 g, 13.4 mmol). After 2 hours, the mixture was concentrated and the resulting residue was diluted with EtOAc (500 mL). This layer was washed with 1N HCl (50 mL), saturated aqueous NaHCO ₃ (50 mL) and brine (50 mL), and then dried (MgSO ₄ ). After concentration, the residue was purified by flash chromatography (gradient of 0% to 40% acetone: CHCl ₃ ) to give the product (7.23 g, 59%) as a white foam. Melting point 100-103
° C .; ¹ H NMR (CDCl ₃ ) δ 1.98 (s, 3H), 2.03 (s, 3H), 2.04
(s, 3H), 2.05 (s, 3H), 2.08 (s, 6H), 2.16 (s, 3H), 2.18
(s, 3H), 3.91 (t, J = 7.0 Hz, 1H), 4.01 (dd, J = 5.7, 12.
5 Hz, 1 H), 4.07 (dd, J = 7.0, 11.2 Hz, 1 H), 4.18 (dd, J
= 6.4, 11.2 Hz, 1H), 4.31 (dd, J = 4.0, 6.6 Hz, 1H), 4.4
7 (dd, J = 5.5, 15.8 Hz, 1H), 4.54 (dd, J = 2.9, 12.5 Hz,
1H), 4.63 (d, J = 7.9 Hz, 1H), 4.64 (dd, J = 6.8, 15.8 H)
z, 1H), 5.00 (dd, J = 3.3, 10.3 Hz, 1H), 5.09 (td, J = 2.
9,5.7 Hz, 1H), 5.17 (dd, J = 7.9, 10.3 Hz, 1H), 5.38 (d
d, J = 1.1, 3.5 Hz, 1H), 5.59 (dd, J = 4.0, 5.7 Hz, 1H), 5
.63 (d, J = 5.7 Hz, 1H), 6.66 (t, J = 6.2 Hz, 1H), 7.41 (d
, J = 8.8 Hz, 2H), 8.16-8.21 (m, 2H); IR (Kbr) 3400,2
980,1755,1670,1560,1525,1420,1380,1360,1
220, 1125, 1050, 950, 900, 860 and 600 cm ⁻¹ ; mass spectrum [(−) FAB], m / z 828 (M) ⁻ ; result of elemental analysis: calculated value (C ₃₅ H ₄₄ N ₂ O ₂₁₎ · 0.5H as _{2 O): C, 50.18;} H, 5
.41; N, 3.34; Found: C, 50.21; H, 5.36; N, 3.29.

Example 4 N- (4-aminobenzyl) octa-O-acetyllactobionamide N- (4-Nitrobenzyl) octa-O-acetyllactobionamide (6.97 g) in EtOAc (167 mL) , 8.41 mmol) and tin (II) chloride dihydrate
(13.3 g, 58.9 mmol) was refluxed for 4 hours. The reaction was cooled to room temperature and carefully quenched with saturated aqueous NaHCO ₃ (until basic),
Dilute with EtOAc (163 mL), stir for 0.5 h, and filter. The two phase filtrates were separated and the aqueous phase was extracted with EtOAC. The combined organic extracts were _(Na 2 SO ₄₎
Dry and concentrate. Flash chromatography (0% to 30% methanol /
Purification with CHCl ₃ gradient) gave 4.61 g (69%) of the product as a glassy white solid. Melting point 87-91 ° C; ¹ H NMR (CDCl ₃ ) δ 1.97 (s, 3
H), 2.01 (s, 3H), 2.04 (s, 3H), 2.05 (s, 3H), 2.07 (s, 3H)
H), 2.09 (s, 3H), 2.12 (s, 3H), 2.15 (s, 3H), 3.70 (s, 2H)
H), 3.75 (td, J = 0.9, 6.6 Hz, 1H), 4.00-4.17 (m, 3H),
4.25-4.38 (m, 3H), 4.50 (dd, J = 2.9, 12.3 Hz, 1H), 4.
59 (d, J = 7.9 Hz, 1H), 4.95 (dd, J = 3.5, 10.3 Hz, 1H),
5.03-5.07 (m, 1H), 5.17 (dd, J = 7.9, 10.5 Hz, 1H), 5.
33 (dd, J = 1.1, 3.5 Hz, 1H), 5.58 (dd, J = 3.1, 6.6 Hz, 1
H), 5.61 (d, J = 6.8 Hz, 1H), 6.38 (t, J = 5.7 Hz, 1H), 6.
62-6.67 (m, 2H), 7.02-7.07 (m, 2H); IR (Kbr) 3390,2
980,1745,1670,1630,1530,1425,1375,1220,1
125, 1060, 950, 900, 840, 755 and 620 cm ^-1 ; mass spectrum [(+) FAB], m / z 799 (M + H) ⁺ , 821 (M + Na) ⁺ ; result of elemental analysis: calculated value (C ₃₅₎ H ₄₆ N ₂ O ₁₉ · 2.5 H ₂ O): C, 49.82; H, 6
.09; N, 3.32; Found: C, 49.84; H, 5.43; N, 3.33.

Example 5 N- (3-aminobenzyl) octa-O-acetyllactobionamide The title compound was prepared in the same manner as in Example 4 using N- (3-nitrobenzyl) octa-O- Prepared from acetyl lactobionamide as a glassy foam (5.90 g, 63%). Melting point 90-93 ° C; ¹ H NMR (CDCl ₃ ) δ 1.97 (s, 3H
), 2.01 (s, 3H), 2.04 (s, 3H), 2.05 (s, 3H), 2.07 (s, 3H)
), 2.09 (s, 3H), 2.14 (s, 3H), 2.15 (s, 3H), 3.76-3.83
(m, 3H), 4.03-4.18 (m, 4H), 4.29-4.41 (m, 2H), 4.50 (
dd, J = 2.9, 12.3 Hz, 1H), 4.60 (d, J = 7.9 Hz, 1H), 4.9
7 (d, J = 3.5, 10.5 Hz, 1H), 5.03-5.08 (m, 1H), 5.17 (d
d, J = 7.9, 10.5 Hz, 1H), 5.34 (dd, J = 0.9, 3.3 Hz, 1H),
5.59 (dd, J = 3.3, 6.6 Hz, 1H), 5.65 (d, J = 6.6 Hz, 1H),
6.45 (t, J = 5.9 Hz, 1H), 6.55-6.62 (m, 3H), 7.09 (t, J
= 7.9 Hz, 1H); IR (Kbr) 3460, 3390, 2980, 1745, 16
70,1630,1610,1530,1500,1465,1435,1375,12
25,1170,1130,1055,955,750,700,630 and 610
cm ^-1 ; mass spectrum [(+) FAB], m / z 799 (M + H) ⁺ , 821 (M
+ Na) ^+; Elemental analysis: Calculated _{(as C 35 H 46 N 2 O 19} · 1H 2 O): C, 51.47; H, 5.9
N; 3.43; Found: C, 51.40; H, 5.70; N, 3.25.

Example 6 N- [3- (acetylamino) benzyl] octa-O-acetyllactobionamide N- (3-aminobenzyl) octa-O-acetyllactobiom in THF (45 mL) at 0 ° C Namide (2.90 g, 3.63 mmol) and triethylamine (1.
To a stirred solution of 11 mL, 7.99 mmol) was added acetyl chloride (0.310 mL, 4.
36 mmol) was added dropwise. After 0.5 hours at this temperature, warm to room temperature and continue for 72 hours.
Stirred for hours. At this point, the reaction was concentrated and dissolved in EtOAc (300 mL). The organic solution was combined with 1N HCl (30 mL), saturated aqueous NaHCO ₃ (30 mL).
) And brine (30 mL) before drying (MgSO ₄ ). After concentration,
The residue was purified by flash chromatography (gradient of 5% to 60% acetone: CHCl ₃ ) to give the product (2.35 g, 77%) as a glassy white foam. 120-123 ° C; ¹ H NMR (CDCl ₃ ) δ 1.98 (s, 3H), 2.0
0 (s, 3H), 2.05 (s, 3H), 2.06 (s, 3H), 2.075 (s, 3H), 2.
082 (s, 3H), 2.14 (s, 3H), 2.15 (s, 3H), 2.17 (s, 3H),
3.84-3.90 (m, 1H), 4.00-4.08 (m, 2H), 4.21 (dd, J = 6.9.
4, 11.2 Hz, 1H), 4.30 (dd, J = 3.3, 6.8 Hz, 1H), 4.35 (d
d, J = 5.9, 14.9 Hz, 1H), 4.46-4.53 (m, 2H), 4.62 (d, J
= 7.9 Hz, 1H), 4.98 (dd, J = 3.3, 10.3 Hz, 1H), 5.05 (t
d, J = 2.9, 5.7 Hz, 1H), 5.19 (dd, J = 7.9, 10.3 Hz, 1H),
5.36 (dd, J = 1.1, 3.5 Hz, 1H), 5.56 (dd, J = 3.1, 6.8 Hz)
, 1H), 5.69 (d, J = 6.8 Hz, 1H), 6.64 (t, J = 5.9 Hz, 1H),
6.96 (d, J = 7.7 Hz, 1H), 7.21-7.30 (m, 2H), 7.66 (dd,
J = 1.1, 8.1 Hz, 1H), 7.81 (s, 1H); IR (Kbr) 3390, 299
0,1755,1675,1620,1560,1490,1425,1375,122
0, 1130, 1055, 950, 755 and 610 cm ^-1 ; mass spectrum [(
+) FAB], m / z 841 (M + H) +, 863 (M + Na) +; Elemental analysis: Calculated _{(as C 37 H 48 N 2 O 20} · 3H 2 O): C, 49.66; H , 6.0
8; N, 3.13; Found: C, 49.46; H, 5.37; N, 3.04.

Example 7 N- [3- (acetylamino) benzyl] octa-O-sulfolactonamide octa sodium salt

Step 1 N- [3- (acetylamino) benzyl] octa-MeOH in MeOH (62.7 mL)
A solution containing O-acetyl lactobionamide (2.09 g, 2.49 mmol) and 25 wt% NaOMe in MeOH (42.6 μL, 0.746 mmol) was added to a solution of 2%.
Refluxed for hours. The reaction was cooled to room temperature and concentrated. The residue obtained is washed with MeOH: E
Trituration with t ₂ O (30:70) provided the product (1.11 g, 88%) as a glassy white solid. Melting point> 170 ° C. (decomposition); ¹ H NMR (DMSO-d ₆ ) δ
2.01 (s, 3H), 3.16 (d, J = 4.4 Hz, 2H), 3.31-3.42 (m, 1
H), 3.47-3.63 (m, 4H), 3.68-3.73 (m, 2H), 4.01-4.14
(m, 3H), 4.14-4.33 (m, 4H), 4.44-4.53 (m, 2H), 4.63-
4.70 (m, 1H), 4.73-4.87 (m, 2H), 5.12-5.19 (bs, 1H),
5.19-5.25 (bs, 1H), 6.95 (d, J = 7.7 Hz, 1H), 7.19 (t,
J = 7.7 Hz, 1H), 7.38 (s, 1H), 7.48 (d, J = 8.1 Hz, 1H),
8.09 (t, J = 6.2 Hz, 1H), 9.86 (s, 1H); IR (KBr) 3380,
2920, 2320, 1660, 1620, 1600, 1560, 1495, 1430,
1370, 1320, 1275, 1080, 1050, 880, 780 and 700c
m ^-1; mass spectrum [(+) FAB], m / z 527 (M + Na) +; Elemental analysis: Calculated _{(as C 21 H 32 N 2 O 12} · 1.5H 2 O): C, 47 .45; H, 6
.64; N, 5.27; Found: C, 47.86; H, 6.73; N, 4.95.

Step 2 The title compound was prepared as a tan solid (1.76 g, 66%) from N- [3- (acetylamino) benzyl] lactobionamide using a method similar to Example 2. Melting point> 211 ° C. (decomposition); ¹ H NMR (D ₂ O) δ 1.98-2.01 (m, 3H)
, 3.74-3.92 (m, 1H), 3.98-4.17 (m, 3H), 4.20-4.56 (m
, 6H), 4.66-4.85 (m, 3H), 4.87-4.98 (m, 2H), 6.96-7.
08 (m, 2H), 7.18-7.27 (m, 1H), 7.30-7.36 (m, 1H); IR (
Kbr) 3440, 2950, 1640, 1565, 1495, 1430, 1250, 1
125, 1060, 1020, 920, 820, 695, 620 and 580 cm- ¹ ; mass spectrum [(-) ESI], m / z 1297 (M-Na) ^- , 1195 (M-
_{SO 3 Na + H-Na)} -, (m-z Na) / z 637.4 (M-2Na) 2-; Elemental analysis: Calculated _{(C 19 H 24 N 2 O} 36 S 8 Na 8 · 6H 2 O): C, 17.65
H, 2.54; N, 1.96; Found: C, 17.31; H, 2.13; N, 1.87.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) // A61K 31/7032 A61K 31/7032 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD) , RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, D , 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 BB02 DD01 JJ05 4C086 AA01 AA02 AA03 EA05 MA01 MA04 NA14 ZA36 ZB26 ZC02

Claims (9)

[Claims] 1. Structure: embedded image [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently an acyl having 2 to 7 carbons, a haloacyl having 2 to 7 carbons, R ⁹ is hydrogen, CN, NO ₂ , halo, CF ₃ , nitroacyl having 2 to 7 carbon atoms, cyanoacyl having 3 to 7 carbon atoms, trifluoromethylacyl having 3 to 8 carbon atoms, benzoyl or —SO ₃ H; Alkyl having 1 to 6 carbons or alkoxy having 1 to 6 carbons; R ¹⁰ represents hydrogen, —NO ₂ , —NHR ¹¹ , —NHR ¹³ , —N (R ¹³ ) ₂ , —N
CH ₃ R ¹³ , —NHCO ₂ alkyl (where the alkyl portion has 1 to 6 carbon atoms),
An alkylsulfonamide having 1 to 4 carbon atoms, Z is O or S; R ¹¹ is α- amino acids (where the α- carboxyl group to form nitrogen and amide R ^10); Note that if the amino acid is glutamic acid or aspartic acid,
The non-α-carboxylic acid is an alkyl ester (where the alkyl moiety has 1 to 6 carbons); R ¹² is hydrogen, CN, NO ₂ , halo, CF ₃ , alkyl having 1 to 6 carbons, carbon number R ¹³ is hydrogen, acyl having 2 to 7 carbons, haloacyl having 2 to 7 carbons, nitroacyl having 2 to 7 carbons, or 3 carbons. Or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (I): (Cyanoacyl, trifluoromethylacyl having 3 to 8 carbon atoms, or benzoyl). 2. The method according to claim ¹ , wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are
2. The compound according to claim 1, wherein Z is O, or a pharmaceutically acceptable salt thereof, each independently having 2 to 7 carbon atoms or -SO ₃ H. 3. R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are
R ¹⁰ is hydrogen, —NO ₂ , —NHR ¹³ or —N (R ¹³ ) ₂ ; R ¹³ is hydrogen or acyl having 2 to 7 carbon atoms, each independently being acetyl or —SO ₃ H; 2. The compound according to 2 or a pharmaceutically acceptable salt thereof. 4. A) N-benzylocta-O-acetyllactobionamide or a pharmaceutically acceptable salt thereof; b) N-benzylocta-O-sulfolactobionamide or a pharmaceutically acceptable salt thereof C) N- (4-nitrobenzyl) octa-O-acetyllactobionamide or a pharmaceutically acceptable salt thereof; d) N- (4-aminobenzyl) octa-O-acetyllactobionamide or a salt thereof A) a pharmaceutically acceptable salt; e) N- (3-aminobenzyl) octa-O-acetyllactobionamide or a pharmaceutically acceptable salt thereof; f) N- [3- (acetylamino) benzyl] octa- O-acetyllactobionamide or a pharmaceutically acceptable salt thereof; or g) N- [3- (acetylamino) benzyl] octa-O-sulfolactobionamide or a pharmaceutically acceptable salt thereof. Item 7. The compound according to Item 1. 5. A method of 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 R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently an acyl having 2 to 7 carbons, a haloacyl having 2 to 7 carbons, R ⁹ is hydrogen, CN, NO ₂ , halo, CF ₃ , nitroacyl having 2 to 7 carbon atoms, cyanoacyl having 3 to 7 carbon atoms, trifluoromethylacyl having 3 to 8 carbon atoms, benzoyl or —SO ₃ H; Alkyl having 1 to 6 carbons or alkoxy having 1 to 6 carbons; R ¹⁰ represents hydrogen, —NO ₂ , —NHR ¹¹ , —NHR ¹³ , —N (R ¹³ ) ₂ , —N
CH ₃ R ¹³ , —NHCO ₂ alkyl (where the alkyl portion has 1 to 6 carbon atoms),
An alkylsulfonamide having 1 to 4 carbon atoms, Z is O or S; R ¹¹ is α- amino acids (where the α- carboxyl group to form nitrogen and amide R ^10); Note that if the amino acid is glutamic acid or aspartic acid,
The non-α-carboxylic acid is an alkyl ester (where the alkyl moiety has 1 to 6 carbons); R ¹² is hydrogen, CN, NO ₂ , halo, CF ₃ , alkyl having 1 to 6 carbons, carbon number R ¹³ is hydrogen, acyl having 2 to 7 carbons, haloacyl having 2 to 7 carbons, nitroacyl having 2 to 7 carbons, or 3 carbons. Or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula I having 1 to 7 cyanoacyl, 3 to 8 trifluoromethylacyl, or benzoyl]. 6. A method of treating or inhibiting restenosis in a mammal in need thereof, comprising administering to said mammal an effective amount of a structure: [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently an acyl having 2 to 7 carbons, a haloacyl having 2 to 7 carbons, R ⁹ is hydrogen, CN, NO ₂ , halo, CF ₃ , nitroacyl having 2 to 7 carbon atoms, cyanoacyl having 3 to 7 carbon atoms, trifluoromethylacyl having 3 to 8 carbon atoms, benzoyl or —SO ₃ H; Alkyl having 1 to 6 carbons or alkoxy having 1 to 6 carbons; R ¹⁰ represents hydrogen, —NO ₂ , —NHR ¹¹ , —NHR ¹³ , —N (R ¹³ ) ₂ , —N
CH ₃ R ¹³ , —NHCO ₂ alkyl (where the alkyl portion has 1 to 6 carbon atoms),
An alkylsulfonamide having 1 to 4 carbon atoms, Z is O or S; R ¹¹ is α- amino acids (where the α- carboxyl group to form nitrogen and amide R ^10); Note that if the amino acid is glutamic acid or aspartic acid,
The non-α-carboxylic acid is an alkyl ester (where the alkyl moiety has 1 to 6 carbons); R ¹² is hydrogen, CN, NO ₂ , halo, CF ₃ , alkyl having 1 to 6 carbons, carbon number R ¹³ is hydrogen, acyl having 2 to 7 carbons, haloacyl having 2 to 7 carbons, nitroacyl having 2 to 7 carbons, or 3 carbons. Or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula I having 1 to 7 cyanoacyl, 3 to 8 trifluoromethylacyl, or benzoyl]. 7. The method of claim 6, wherein the restenosis results from an angioplasty, a revascularization, or an organ or tissue transplant. 8. A method of inhibiting angiogenesis in a malignant tumor, sarcoma, or neoplastic tissue of a mammal in need thereof, comprising administering to the mammal an effective amount of a structure: [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently an acyl having 2 to 7 carbons, a haloacyl having 2 to 7 carbons, R ⁹ is hydrogen, CN, NO ₂ , halo, CF ₃ , nitroacyl having 2 to 7 carbon atoms, cyanoacyl having 3 to 7 carbon atoms, trifluoromethylacyl having 3 to 8 carbon atoms, benzoyl or —SO ₃ H; Alkyl having 1 to 6 carbons or alkoxy having 1 to 6 carbons; R ¹⁰ represents hydrogen, —NO ₂ , —NHR ¹¹ , —NHR ¹³ , —N (R ¹³ ) ₂ , —N
CH ₃ R ¹³ , —NHCO ₂ alkyl (where the alkyl portion has 1 to 6 carbon atoms),
An alkylsulfonamide having 1 to 4 carbon atoms, Z is O or S; R ¹¹ is α- amino acids (where the α- carboxyl group to form nitrogen and amide R ^10); Note that if the amino acid is glutamic acid or aspartic acid,
The non-α-carboxylic acid is an alkyl ester (where the alkyl moiety has 1 to 6 carbons); R ¹² is hydrogen, CN, NO ₂ , halo, CF ₃ , alkyl having 1 to 6 carbons, carbon number R ¹³ is hydrogen, acyl having 2 to 7 carbons, haloacyl having 2 to 7 carbons, nitroacyl having 2 to 7 carbons, or 3 carbons. Or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula I having 1 to 7 cyanoacyl, 3 to 8 trifluoromethylacyl, or benzoyl]. 9. Structure: embedded image [Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently an acyl having 2 to 7 carbons, a haloacyl having 2 to 7 carbons, R ⁹ is hydrogen, CN, NO ₂ , halo, CF ₃ , nitroacyl having 2 to 7 carbon atoms, cyanoacyl having 3 to 7 carbon atoms, trifluoromethylacyl having 3 to 8 carbon atoms, benzoyl or —SO ₃ H; Alkyl having 1 to 6 carbons or alkoxy having 1 to 6 carbons; R ¹⁰ represents hydrogen, —NO ₂ , —NHR ¹¹ , —NHR ¹³ , —N (R ¹³ ) ₂ , —N
CH ₃ R ¹³ , —NHCO ₂ alkyl (where the alkyl portion has 1 to 6 carbon atoms),
An alkylsulfonamide having 1 to 4 carbon atoms, Z is O or S; R ¹¹ is α- amino acids (where the α- carboxyl group to form nitrogen and amide R ^10); Note that if the amino acid is glutamic acid or aspartic acid,
The non-α-carboxylic acid is an alkyl ester (where the alkyl moiety has 1 to 6 carbons); R ¹² is hydrogen, CN, NO ₂ , halo, CF ₃ , alkyl having 1 to 6 carbons, carbon number R ¹³ is hydrogen, acyl having 2 to 7 carbons, haloacyl having 2 to 7 carbons, nitroacyl having 2 to 7 carbons, or 3 carbons. Or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and a pharmaceutically acceptable carrier.