CN1333779A - Benzyllactobionamides as inhibitors of smooth muscle cell proliferation - Google Patents
Benzyllactobionamides as inhibitors of smooth muscle cell proliferation Download PDFInfo
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Abstract
This invention provides smooth muscle cell proliferation inhibitors of formula (I); or a pharmaceutically acceptable salt thereof.
Description
Background of invention
The benzyl lactobionic acid acid amides that the present invention relates to replace is for example purposes of the therapeutic composition of restenosis of the disease of feature and illness as inhibitors of smooth muscle cell proliferation and as being used for the treatment of with the excessive smooth muscle cell proliferation.
The reconstructing blood vessel of form of ownership for example angioplasty and venous bypass operation all can cause damage, and this damage finally can cause the propagation of smooth muscle cell (SMC) also to cause deposition (Clowes, the A.W. of a large amount of extracellular matrixs subsequently; Reidy, M.A. " vascular surgery magazine " (J.Vasc.Surg) 1991,13,885).These incidents still are atherosclerosis (RainesE.W.; Ross R. " Britain's heart journal " (Br.Heart J.) 1993,69 (supplement), S.30) and graft arteriosclerosis (Isik, F.F.; McDonald, T.O.; Ferguson, M.; Yamanaka, E.; Gordon " American Journal of Pathology " (Am.J.Pathol.) 1992,141,1139) central process of morbidity.For the restenosis of postangioplasty, control SMC propagation by pharmacological intervention clinically and be still insoluble problem (Herrman, J.P.R. at present; Hermans, W.R.M.; Vos, J.; SerruysP.W. " medicine " (Drugs) 1993,4,18 and 249).Any successful methods of selectivity inhibition SMC propagation must be able to not be disturbed normal propagation and function (Weissberg, the P.L. of endotheliocyte reparation or other cell; Grainger, D.J.; Shanahan C.M.; Metcalfe, J.C. " cardiovascular research " (Cardiovascular Res.) 1993,27,1191).
Glycosamino glucan heparin and Suleparoid are the endogenous inhibitor of SMC propagation, but still can promote endothelial cell growth (Castellot, J.J.Jr.; Wright, T.C.; Karnovsky, M.J., thrombosis and hemostasis discussion, 1987,13,489).But, because other pharmacology tendency that the ununiformity of various preparations is followed (particularly because anticoagulation is caused excessively hemorrhage) (Borman, S. " chemistry and engineering science news " (Chemical and Engineering News), on June 28th, 1993,27), whole clinical effectiveness of the anionic polysaccharide of the heparin of heparin, heparin fragment, chemically modified, low molecular weight heparin and other simulation heparin may be compromised.
US 5,296, and 588, US 5,336,765 and EP 550106A1 described the method for the glyconic acid acid amides that improved preparation N-replaces.US 5,310,542 and EP 551675-A1 the glucosides (particularly aldobionic acid acid amides) that is used for oral hygiene composition has also been described, this material plays antiseptic-germicide and suppresses to cause formation and/or the growth of the bacterium of dental plaque.US2,752,334 have described the method for the lactobionic acid acid amides that preparation N-replaces and as the purposes of emulsifying agent (especially for cheese) and anti-mycotic agent.The difference of The compounds of this invention is that compound of the present invention (a) is acetylize or Sulfated benzyl lactobionic acid acid amides, (b) the substituting group difference on the aromatic series parent nucleus, and (c) be as the smooth muscle cell antiproliferative.
EP 312086 A2 and EP 312087 A2 have described the multi-sulfate as two glyconic acid amide derivatives of anti-inflammatory agent and antithrombotic agent.The difference of The compounds of this invention is that this compound (a) is as the smooth muscle cell antiproliferative, is not dimer in nature (b), and (c) contains the saccharide residue of two vicinities (disaccharides) at the most.
(Klein, U.; Mohrs, K.; Wild, H.; Steglich, W.Liebigs Ann.Chem.1987 485-489.) has described the purposes that full acetylated glyconic acid acid amides is used to prepare the pyrazoles that 3-replaces.The difference of The compounds of this invention is the substituting group difference of this compound (a) on the aromatic series parent nucleus, (b) does not replace on the position of benzylic, (c) is as the smooth muscle cell antiproliferative, and (d) is not the precursor as pyrazole compound.
Patent US 5,498, and 775, WO 96/14324 and US 5,464,827 described polyanionic benzyl glucosides or the cyclodextrin that is used for the treatment of with the excessive smooth muscle cell proliferation inhibitors of smooth muscle cell proliferation that is the disease of feature and illness.Disclose wherein that beta-cyclodextrin 14 vitriol can be used as inhibitors of smooth muscle cell proliferation and be effective inhibitor (Reilly, the C.F. of restenosis; Fujita, T.; McFall, R.C.; Stabilito, I.I.; Wai-se E.; Johnson, R.G. " drug development " (Drug DevelopmentResearch) 1993,29,137).US 5019562 discloses the cyclodextrin anionic derivative that is used for the treatment of the pathology illness that is attended by undesirable cell or tissue growth.WO93/09790 discloses the antiproliferative cyclodextrin polyanionic derivative that has at least 2 negatively charged ion residues on each saccharide residue.The antithrombotic that Meinetsberger (EP 312087 A2 and EP312086 A2) has described Sulfated two glyconic acid acid amides forms and the anti-freezing characteristic.US 4431637 discloses the poly-sulfated phenose glycosides as the complement system conditioning agent.The difference of The compounds of this invention and all these prior aries is that this compound (a) is not have the benzyl lactobionic acid acid amides that is similar to heparin or sulfated cyclodextrin structure, (b) not dimer in nature, (c) do not contain saccharide residue (disaccharides), and (d) have defined structure more than two vicinities.
WO 96/14325 discloses the benzyl glucosides as the acidylate of inhibitors of smooth muscle cell proliferation.The difference of The compounds of this invention is (a) sugared skeleton difference, and (b) the chain parent nucleus of Duan Kaiing is arranged easier preparation than cyclic, and (c) the substituting group difference on the sugared skeleton.
(Zehavi, U.; Herchman, M. " sugar research " (Carbohyd.Res.) 1986,151,371) disclose 4-carboxyl-2-nitrobenzyl 4-O-α-D-glucopyranosyl-β-D-glucopyranoside, this material is connected on the polymkeric substance of studying as acceptor in the Glycogensynthase reaction.The compounds of this invention is that with the difference of the disclosed content of Zehavi the substituting group on (a) benzyl is different, and (b) purposes (anti-smooth muscle proliferation) difference.
Detailed Description Of The Invention
The invention provides benzyl lactobionic acid acid amides or its pharmacologically acceptable salt of formula I,
Wherein
R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Be independently of one another cyano-acyl, a 3-8 carbon atom of nitro acyl group, a 3-7 carbon atom of halo acyl group, a 2-7 carbon atom of acyl group, a 2-7 carbon atom of 2-7 carbon atom trifluoromethyl acyl group, benzoyl or-SO
3H;
R
9Be hydrogen, CN, NO
2, halogen, CF
3, the alkyl of a 1-6 carbon atom or the alkoxyl group of 1-6 carbon atom;
R
10Be hydrogen ,-NO
2,-NHR
11,-NHR
13,-N (R
13)
2,-NCH
3R
13,-NHCO
2Alkyl, moieties wherein contain 1-6 carbon atom, the alkylsulfamoyl group of 1-4 carbon atom,
Z is O or S;
R
11Be α carboxyl and R wherein
10Nitrogen form the a-amino acid of acid amides, wherein, if described amino acid is L-glutamic acid or aspartic acid, then non-α carboxylic acid is an alkyl ester, moieties wherein contains 1-6 carbon atom;
R
12Be hydrogen, CN, NO
2, halogen, CF
3, the alkyl of a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, the acyl group or the benzoyl of a 2-7 carbon atom;
R
12Be the acyl group of hydrogen, a 2-7 carbon atom, the halo acyl group of a 2-7 carbon atom, the nitro acyl group of a 2-7 carbon atom, the cyano-acyl of a 3-7 carbon atom, the trifluoromethyl acyl group or the benzoyl of a 3-8 carbon atom.
Alkyl comprises the part of straight chain and side chain.Halogen is meant bromine, chlorine, fluorine and iodine.Work as R
11When being a-amino acid, carboxy moiety exists with the form of acid amides and the nitrogen of acid amides is connected on the phenyl ring of formula I compound.Below be to work as R
11The example of formed structural formula when being L-Ala:
When amino acid contained second carboxy moiety, this part was the alkyl ester of free acid.What following example showed is the aspartic acid methyl esters.
Preferred amino acids comprises L-Ala, arginine, aspartic acid, Gelucystine, L-glutamic acid, glycine, Histidine, Isoleucine, leucine, Methionin, methionine(Met), phenylalanine, proline(Pro), Serine, Threonine, tryptophane, tyrosine and Xie Ansuan.R
11Defined amino acid comprises D and L amino acid.
Pharmacologically acceptable salt can form from organic and mineral acid, for example acetate, propionic acid, lactic acid, citric acid, tartrate, succsinic acid, fumaric acid, toxilic acid, propanedioic acid, amygdalic acid, oxysuccinic acid, phthalic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, methylsulfonic acid, naphthene sulfonic acid, Phenylsulfonic acid, toluenesulphonic acids, camphorsulfonic acid and similar acceptable known acid.Salt can also form preferred as alkali salt, for example sodium, lithium or potassium from organic and mineral alkali.When containing basic nitrogen, compound of the present invention can make acid salt, when formula I compound contains-SO
3During the H part, can prepare base addition salt usually.
The compounds of this invention can contain unsymmetrical carbon or sulfoxide part, and some compound of the present invention can contain one or more asymmetric centers, therefore can produce optical isomer and diastereomer.Although do not express the stereochemistry of formula I, present invention includes described optical isomer and diastereomer; And R racemic modification and fractionation, enantiomer-pure and S steric isomer; And other mixture and the pharmacologically acceptable salt thereof of R and S steric isomer.
Preferred The compounds of this invention is benzyl lactobionic acid acid amides or its pharmacologically acceptable salt of formula I,
Wherein
R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Be independently of one another 2-7 carbon atom acyl group or-SO
3H;
R
9Be hydrogen, CN, NO
2, halogen, CF
3, the alkyl of a 1-6 carbon atom or the alkoxyl group of 1-6 carbon atom;
R
10Be hydrogen ,-NO
2,-NHR
11,-NHR
13,-N (R
13)
2,-NCH
3R
13,-NHCO
2Alkyl, moieties wherein contain 1-6 carbon atom, the alkylsulfamoyl group of 1-4 carbon atom,
Z is O;
R
11Be α carboxyl and R wherein
10Nitrogen form the a-amino acid of acid amides, wherein, if described amino acid is L-glutamic acid or aspartic acid, then non-α carboxylic acid is an alkyl ester, moieties wherein contains 1-6 carbon atom;
R
12Be hydrogen, CN, NO
2, halogen, CF
3, the alkyl of a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, the acyl group or the benzoyl of a 2-7 carbon atom;
R
13Be the acyl group of hydrogen, a 2-7 carbon atom, the halo acyl group of a 2-7 carbon atom, the nitro acyl group of a 2-7 carbon atom, the cyano-acyl of a 3-7 carbon atom, the trifluoromethyl acyl group or the benzoyl of a 3-8 carbon atom.
Preferred The compounds of this invention is benzyl lactobionic acid acid amides or its pharmacologically acceptable salt of formula I,
Wherein
R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Be independently of one another ethanoyl or-SO
3H;
R
9Be hydrogen, CN, NO
2, halogen, CF
3, the alkyl of a 1-6 carbon atom or the alkoxyl group of 1-6 carbon atom;
R
10Be hydrogen ,-NO
2,-NHR
13,-N (R
13)
2
R
13It is the acyl group of a hydrogen or 2-7 carbon atom.
Particularly preferred The compounds of this invention is:
N-benzyl-eight-O-ethanoyl-lactobionic acid acid amides or its pharmacologically acceptable salt;
N-benzyl-eight-O-sulfo group-lactobionic acid acid amides or its pharmacologically acceptable salt;
N-(4-nitro-benzyl)-eight-O-ethanoyl-lactobionic acid acid amides or its pharmacologically acceptable salt;
N-(4-amino-benzyl)-eight-O-ethanoyl-lactobionic acid acid amides or its pharmacologically acceptable salt;
N-(3-amino-benzyl)-eight-O-ethanoyl-lactobionic acid acid amides or its pharmacologically acceptable salt;
N-[3-(acetylamino)-benzyl]-eight-O-ethanoyl-lactobionic acid acid amides or its pharmacologically acceptable salt; With
N-[3-(acetylamino)-benzyl]-eight-O-sulfo group-lactobionic acid acid amides or its pharmacologically acceptable salt.
Compound of the present invention is prepared from the raw material that commercially available raw material maybe can make with the method the document according to following reaction scheme.These schemes have shown the preparation of representational The compounds of this invention.
With lactobionic acid-1, and the 5-lactone (1, * H.S.Isbell; H.L.Frush. " carbohydrate chemistry method " (Methods Carbohyd.Chem.) 1963,2,16-18.) and benzyl amine 2 (when using amine salt, under sodium carbonates' presence) at protonic solvent for example in the methyl alcohol, coupling generates glucoside 3 (reaction scheme 1) under 0 to 60 ℃ temperature.The reduction of 3 nitro can with reductive agent for example tin protochloride at polar aprotic solvent for example in the ethyl acetate, to reflux temperature, finish generate phenylamino compound 4 in room temperature.4 with the coupling of acyl chlorides can amine alkali for example triethylamine or diisopropyl ethyl amine in the presence of or with stronger alkali for example sodium hydride (for the sterically hindered system is arranged) for example to room temperature, finish generation purpose compound 5 at 0 ℃ in methylene dichloride or the tetrahydrofuran (THF) at aprotic solvent.Full acetylated compound 5 can be transformed into eight hydroxy intermediate in room temperature with the methanol solution or the aqueous NaOH methanol solution of catalytic amount sodium methylate to the temperature that refluxes.Available sulphur trioxide Trimethylamine 99 title complex further is transformed into eight sulfo group compounds 6 at polar solvent N for example in the dinethylformamide under refluxing.Can be with different ion exchange columns Dowex Na for example
+Or K
+The salt for preparing multiple sulfate groups.
Reaction scheme 1
Compound useful as antiproliferative agents of the present invention.Following method has shown in the standard pharmaceutical experimental technique of the ability that detects evaluated compound inhibition smooth muscle cell proliferation, to the evaluation result of representative compounds of the present invention.With
3The H thymidine mixes the effect of assessing compound on cell proliferation
Under inferior fusion conditions, detect the smooth muscle cell of people and pig in go down to posterity in early days (generally go down to posterity 3-7 generation).Make culture in 16mm (24 hole) porous culture dish, growth in the substratum 199 that has replenished 10% foetal calf serum and 2% microbiotic/antifungal agents.Under inferior fusion conditions, before beginning to test 24-48 hour, cell is placed the serum free medium (AIM-V that determines composition; Gibco) in.
Though compound is more effective when finding that the pre-incubation time is longer, in general, these methods be in the synchronization cell of serum-free, add compound,
3H thymidine and serum/somatomedin causes, and correspondingly writes down the result.
In each hole, add compound (20 μ L/ hole) and with culture plate insulation 24-26 hour under 37 ℃, 5% carbonic acid gas with 50 times of extent of dilution.Compound at first is dissolved in 50% ethanol then serial dilution to substratum.Conventional these compounds of estimating under 1 to 100 μ M concentration.In contrast, be the conventional II level pig intestinal mucosa heparin (sodium salt) of estimating in all cells goods of 0.1 to 100 μ g/mL in concentration.
When this experimental technique finishes, culture plate is placed on ice, wash 3 times with ice-cold phosphate buffered saline (PBS) (PBS), and be incubated 30 minutes to remove acid-soluble protein matter at ice-cold 10% trichoroacetic acid(TCA) (TCA).Solution is transferred in the flicker bottle that 0.4N HCl is housed by (500 μ L/ bottles with in and sodium hydroxide), and water (500 μ L) cleans each hole 2 times, cumulative volume is the 2mL/ bottle.
For contrast and experiment sample, obtain data in triplicate.Contrast (100%) data derive from the cell of maximal stimulation, as the result of somatomedin or serum stimulation.Experimental data must use by oneself somatomedin or serum maximal stimulation and with the cell of compound treatment.Data are with IC
50Or the form that suppresses per-cent is listed in the table below among the I.
Table 1
| The compound of embodiment | Pig smooth muscle cell antiproliferative IC50 |
| ?????????1 | ????????118μM |
| ?????????2 | ?????45％@500μM |
| ?????????4 | ?????30％@500μM |
| ?????????5 | ?????12％@500μM |
| ?????????7 | ????????122μM |
Compound of the present invention can be used for treatment or suppresses with smooth muscle cell proliferation excessive (smooth muscle cell hyper-proliferative) is the disease of feature.It is the excess proliferative vascular disease of feature that these compounds especially can be used for treating with the smooth muscle cell hyper-proliferative, restenosis for example, its modal cause is reconstructing blood vessel and transplanting, for example balloon angioplasty, vascular transplant, coronary artery bypass surgery and heart transplantation.Other disease that undesirable " cellularity " vascular proliferation can take place comprises hypertension, asthma and congestive heart failure.Compound of the present invention also can be used as the inhibitor of vasculogenesis.Vasculogenesis (neovascularity generation) forms new capillary vessel by this process, is some pathology affairs, comprises the first cause of chronic inflammatory diseases and malignant disease.Therefore compound of the present invention can be used as antineoplastic agent.
Compound of the present invention can be prepared separately or prepare with pharmaceutical carrier, and its ratio depends on solubleness and chemical property, route of administration and the standard pharmaceutical practice of this compound.Pharmaceutical carrier can be solid or liquid.
Solid carrier can comprise one or more materials, and it also can be used as correctives, lubricant, solubility promoter, suspending agent, weighting agent, glidant, compression aid, tackiness agent or tablet disintegrant; It also can be a coating material.In powder, carrier is finely divided solid, and it can mix with finely divided activeconstituents.In tablet, activeconstituents and the mixed of the carrier with necessary compacting character to suit, and be compressed to required shape and size.Preferred powder and tablet contain and are no more than 99% activeconstituents.Suitable solid carrier comprises, for example, and calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, polyvinylpyrrolidine, low melt wax and ion exchange resin.
Liquid vehicle is used to prepare solution, suspensoid, emulsion, syrup, elixir and pressurized compositions.Activeconstituents can dissolve or be suspended in medicinal fluid carrier such as water, organic solvent or the mixture of the two or medicinal oil or the fat.Liquid vehicle can contain other appropriate drug additive such as solubility promoter, emulsifying agent, buffer reagent, sanitas, sweeting agent, correctives, suspending agent, thickening material, tinting material, viscosity modifier, stablizer or osmotic pressure regulator.Oral and parenterai administration comprises that with the suitable example of liquid vehicle (part contains as above additive to water, as derivatived cellulose, the preferably carboxymethyl cellulose sodium solution), alcohol (comprising monohydroxy-alcohol and polyvalent alcohol) and derivative, Yelkin TTS and oil (for example fractionated Oleum Cocois and peanut oil) as glycerine.For parenterai administration, carrier can also be ester such as the ethyl oleate and the palmitinic acid isopropyl esters of oil.The sterilising liq carrier can be used for the composition of the sterilising liq form of parenterai administration.Pressurized compositions can be halohydrocarbon or other medicinal propellant with liquid vehicle.
The composition of liquid medicine of sterile solution agent or suspensoid form can pass through, and for example, intramuscular, intraperitoneal or subcutaneous injection are used.Sterile solution also can intravenous administration.Compound of the present invention also can be with the form oral administration of liquid or solid composition.
Compound of the present invention can be with the form rectum or the vagina administration of conventional suppository.By sucking in the nose or in the segmental bronchus or when being blown into administration, compound of the present invention can be mixed with the aqueous solution or aqueous solution, can use with the form of aerosol then.Compound of the present invention also can carry out transdermal administration with transdermal patch, described transdermal patch contain active compound and to this active compound be inert, nontoxic and allow this reagent to enter the carrier of blood flow by the integumentary system absorption to skin.This carrier can be following any form: creme and ointment, paste, gel and closure device.Creme and ointment can be the thick liquid or the semi-solid emulsion of oil-in-water-type or water-in-oil-type.Also suit by being scattered in the paste that the Vaseline that contains activeconstituents or the absorbent powder in the wetting ability Vaseline form.There is multiple closure device can be used for activeconstituents is discharged in the blood flow, contains activeconstituents and contain or carrier-free storage storehouse or contain the matrix of activeconstituents as what semi-permeable membranes covered.Other closure device is known in the document.
Needed dosage with used particular composition, route of administration, have the seriousness of symptom and the special object of being treated changes.According to the result who obtains in the standard pharmaceutical experimental technique, active compound dosage every day of expectation is 0.1 to 10mg/kg parenterai administration (preferred intravenously), and the day oral dosage of expectation is wanted high about 10 times.Intravenous administration expection after acute vascular damage (being balloon angioplasty or transplanting) will continue about 5-30 days, to the longer time of treatment needs of chronic disease.Treatment is general from the low dose less than this compound optimal dose.After this, increase this dosage to the best effect that arrives under these environment; In oral, the non-enteron aisle, nose or the exact dosage desired of administration in the segmental bronchus by the administration doctor according to the experience of treat individuality is determined.Preferred this pharmaceutical composition is a unit dosage, as tablet or capsule.In these forms, said composition is subdivided into the unitary dose that contains an amount of activeconstituents; Unit dosage can be a packaged composition, for example the sachet of packaged powders, bottle, ampoule, prefilled syringe or dress liquid.Unit dosage can be, for example, capsule or tablet itself, or it can be the packaged form of an amount of any of these composition.
The preparation method of representative compounds of the present invention is provided below.
Embodiment 1N-benzyl-eight-O-ethanoyl-lactobionic acid acid amides step 1
Under heating leniently, to the lactobionic acid-1 that stirs, 5-lactone (0.480g, 1.41mmol, * H.S.Isbell; H.L.Frush. " carbohydrate chemistry method " (Methods Carbohyd.Chem.) 1963,2, drip in hot MeOH (5mL) solution 16-18.) benzyl amine (0.177mL, 1.62mmol).With reaction solution stirring at room 18 hours.After concentrating, the oily resistates by carrying out purifying with the Virahol recrystallization, is obtained glassy white solid product (0.300g, 48%);
1H NMR (DMSO-d
6) δ 3.26-3.36 (m, 2H), 3.36-3.41 (m, 1H), 3.46-3.55 (m, 3H), and 3.55-3.64 (m, 2H), 3.66-3.74 (m, 2H), 4.02-4.07 (m, 1H), 4.12 (d, J=5.9Hz, 1H), 4.17 (dd, J=1.5,5.1Hz, 1H), 4.26 (d, J=7.0Hz, 1H), 4.30 (d, J=6.4Hz, 2H), 4.46-4.52 (m, 2H), 4.66 (t, J=5.7Hz, 1H), 4.78 (dd, J=5.5,9.7Hz, 2H), 5.14 (d, J=3.7Hz, 1H), 5.25 (d, J=5.7Hz, 1H), and 7.16-7.24 (m, 1H), 7.24-7.32 (m, 4H), 8.13 (t, J=6.2Hz, 1H); IR (KBr) 3380,2930,2890,1650,1555,1455,1430,1400, and 1370,1325,1280,1220,1125,1080,1045,970,880 and 710cm
-1Mass spectrum [(-) FAB], m/z 446 (M-H)
-Ultimate analysis calculated value C
19H
29NO
11: C, 51.00; H, 6.53; N, 3.13, measured value: C, 50.87; H, 6.49; N, 3.12. step 2
To the N-benzyl-lactobionic acid acid amides (0.150g that stirs, 0.335mmol) and triethylamine (0.822mL, under room temperature, drip in DMF 5.90mmol) (3.4mL) solution diacetyl oxide (0.278mL, 2.95mmol), add then catalytic amount DMAP (0.0327g, 0.268mmol).After 18 hours, mixture concentrated and with the resistates that obtains with EtOAc (100mL) dilution.This layer is washed dry then (MgSO with 1N HCl (10mL), saturated sodium bicarbonate aqueous solution (10mL) and salt solution (10mL)
4).After concentrating, with resistates by purification by flash chromatography (10: 90 to 90: 10 EtOAc: the sherwood oil gradient) obtain product (0.221g, 84%), be vitreous solid, mp 85-86 ℃;
1H NMR (CDCl
3) δ 1.88 (s, 3H), 1.90 (s, 3H), 1.98 (s, 3H), 2.02 (s, 6H), 2.03 (s, 3H), 2.09 (s, 3H), 2.15 (s, 3H), 3.94-4.02 (m, 2H), 4.03 (d, J=7.2Hz, 1H), 4.11-4.19 (m, 2H), 4.23 (t, J=20.4Hz, 1H), 4.27-4.37 (m, 2H), 4.79 (d, J=7.9Hz, 1H), 4.84-4.95 (m, 2H), 5.14 (dd, J=3.7,10.1Hz, 1H), 5.21-5.24 (m, 2H), 5.45 (dd, J=3.1,6.4Hz, 1H), and 7.17-7.25 (m, 3H), 7.26-7.32 (m, 2H), 8.58 (t, J=1.9Hz, 1H); IR (KBr) 3390,2970,1755,1670,1540,1420,1375,1220, and 1130,1050,950 and 610cm
-1Mass spectrum [(+) FAB], m/z 784 (M+H)
+, 806 (M+Na)
+Ultimate analysis calculated value C
35H
45NO
19: C, 53.64; H, 5.79; N, 1.79, measured value: C, 53.51; H, 5.86; N, 1.82.
Embodiment 2N-benzyl-eight-O-sulfo group-lactobionic acid acid amides eight sodium salts
To the N-benzyl-lactobionic acid acid amides that stirs (0.760g, under room temperature, add in DMF 1.70mmol) (59.4mL) solution sulphur trioxide Trimethylamine 99 title complex (9.46g, 68.0mmol); Then with this mixture heating up to 70 ℃.After 4 days, mixture is cooled to 0 ℃ and water (60mL) termination reaction.Then, solution is concentrated under the condition that does not heat, with the resistates that obtains at H
2O (~ 20-25mL) the middle slurries that form filter then.Filtrate is gone up to G-10 Sephedex post.The compound that collection obtains is also directly gone up Dowex Na
+On the ion exchange column, behind wash-out, obtain product (1.47g, 68%), be vitreous solid, mp＞200 ℃ (decomposition);
1H NMR (D
2O) δ 3.86 (t, J=6.2Hz, 1H), 3.98-4.14 (m, 3H), 4.19-4.47 (m, 5H), 4.52-4.57 (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) 3490,2950,2320,1680,1570,1500,1450,1270, and 1190,1070,1025,920,820,700,620 and 580cm
-1Mass spectrum [(-) ESI], (m-zNa)/z 608.9 (M-2Na)
2-, 398.3 (M-3Na)
3-Ultimate analysis calculated value C
19H
21NO
35S
8Na
83H
2O:C, 17.32; H, 2.07; N, 1.06, measured value: C, 17.12; H, 2.08; N, 1.03.
Embodiment 3N-(4-nitro-benzyl)-eight-O-ethanoyl-lactobionic acid acid amides
Under heating leniently, to the lactobionic acid-1 that stirs, 5-lactone (5.00g, 14.7mmol, * H.S.Isbell; H.L.Frush. " carbohydrate chemistry method " (Methods Carbohyd.Chem.) 1963,2, add in hot MeOH (53mL) solution 16-18.) 3-nitro-benzyl amine hydrochlorate (3.56g, 19.1mmol).Reaction mixture is cooled to 0 ℃, adds yellow soda ash (1.56g, 14.7mmol) stirring at room 4 days then.After concentrating, the oily resistates is added among the DMF (74mL).In in the solution of this stirring, drip under the room temperature triethylamine (40.6mL, 292mmol), add then diacetyl oxide (13.7mL, 146mmol) and the DMAP of catalytic amount (1.63g, 13.4mmol).After 2 hours, mixture concentrated and with the resistates that obtains with EtOAc (500mL) dilution.This layer is washed dry then (MgSO with 1N HCl (50mL), saturated sodium bicarbonate aqueous solution (50mL) and salt solution (50mL)
4).After concentrating, resistates is passed through purification by flash chromatography (0% to 40% acetone: CHCl
3Gradient) obtains white foam shape product (7.23g, 59%), mp 100-103 ℃;
1H 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=7.0Hz, 1H), 4.01 (dd, J=5.7,12.5Hz, 1H), 4.07 (dd, J=7.0,11.2Hz, 1H), 4.18 (dd, J=6.4,11.2Hz, 1H), 4.31 (dd, J=4.0,6.6Hz, 1H), 4.47 (dd, J=5.5,15.8Hz, 1H), 4.54 (dd, J=2.9,12.5Hz, 1H), 4.63 (d, J=7.9Hz, 1H), 4.64 (dd, J=6.8,15.8Hz, 1H), 5.00 (dd, J=3.3,10.3Hz, 1H), 5.09 (td, J=2.9,5.7Hz, 1H), 5.17 (dd, J=7.9,10.3Hz, 1H), 5.38 (dd, J=1.1,3.5Hz, 1H), 5.59 (dd, J=4.0,5.7Hz, 1H), 5.63 (d, J=5.7Hz, 1H), 6.66 (t, J=6.2Hz, 1H), 7.41 (d, J=8.8Hz, 2H), 8.16-8.21 (m, 2H); IR (KBr) 3400,2980,1755,1670,1560,1525,1420,1380, and 1360,1220,1125,1050,950,900,860 and 600cm
-1Mass spectrum [(-) FAB], m/z 828 (M)
-Ultimate analysis calculated value C
35H
44N
2O
210.5H
2O:C, 50.18; H, 5.41; N, 3.34, measured value: C, 50.21; H, 5.36; N, 3.29.
Embodiment 4N-(4-amino-benzyl)-eight-O-ethanoyl-lactobionic acid acid amides
To contain N-(4-nitro-benzyl)-eight-O-ethanoyl-lactobionic acid acid amides (6.97g, 8.41mmol) and tin protochloride (II) dihydrate (13.3g, ethyl acetate 58.9mmol) (167mL) solution refluxed 4 hours.Reaction solution is cooled to room temperature, uses saturated sodium bicarbonate aqueous solution termination reaction (until being alkalescence) carefully,, stir and filtered then in 0.5 hour with ethyl acetate (163mL) dilution.With the separation of biphase filtrate and with the water ethyl acetate extraction.The organic extract liquid drying (sodium sulfate) that merges is concentrated then.Obtain the glassy white solid product of 4.61g (69%), mp87-91 ℃ by purification by flash chromatography (0 to 30% methyl alcohol/chloroform gradient);
1H 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), 2.12 (s, 3H), 2.15 (s, 3H), 3.70 (s, 2H), 3.75 (td, J=0.9,6.6Hz, 1H), and 4.00-4.17 (m, 3H), 4.25-4.38 (m, 3H), 4.50 (dd, J=2.9,12.3Hz, 1H), 4.59 (d, J=7.9Hz, 1H), 4.95 (dd, J=3.5,10.3Hz, 1H), and 5.03-5.07 (m, 1H), 5.17 (dd, J=7.9,10.5Hz, 1H), 5.33 (dd, J=1.1,3.5Hz, 1H), 5.58 (dd, J=3.1,6.6Hz, 1H), 5.61 (d, J=6.8Hz, 1H), 6.38 (t, J=5.7Hz, 1H), and 6.62-6.67 (m, 2H), 7.02-7.07 (m, 2H); IR (KBr) 3390,2980,1745,1670,1630,1530,1425,1375, and 1220,1125,1060,950,900,840,755 and 620cm
-1Mass spectrum [(+) FAB], m/z 799 (M+H)
+, 821 (M+Na)
+Ultimate analysis calculated value C
35H
46N
2O
192.5H
2O:C, 49.82; H, 6.09; N, 3.32, measured value: C, 49.84; H, 5.43; N, 3.33.
Embodiment 5N-(3-amino-benzyl)-eight-O-ethanoyl-lactobionic acid acid amides
Title compound with method preparation similar to Example 4, is glassy foam (5.90g, 63%), mp 90-93 ℃ from N-(3-nitro-benzyl)-eight-O-ethanoyl-lactobionic acid acid amides;
1H 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=2.9,12.3Hz), 4.60 (d, J=7.9Hz, 1H), 4.97 (d, J=3.5,10.5Hz, 1H), and 5.03-5.08 (m, 1H), 5.17 (dd, J=7.9,10.5Hz, 1H), 5.34 (dd, J=0.9,3.3Hz, 1H), 5.59 (dd, J=3.3,6.6Hz, 1H), 5.65 (d, J=6.6Hz, 1H), 6.45 (t, J=5.9Hz, 1H), 6.55-6.62 (m, 3H), 7.09 (t, J=7.9Hz, 1H); IR (KBr) 3460,3390,2980,1745,1670,1630,1610,1530, and 1500,1465,1435,1375,1225,1170,1130,1055,955,750,700,630 and 610cm
-1Mass spectrum [(+) FAB], m/z 799 (M+H)
+, 821 (M+Na)
+Ultimate analysis calculated value C
35H
46N
2O
191H
2O:C, 51.47; H, 5.92; N, 3.43, measured value: C, 51.40; H, 5.70; N, 3.25.
Embodiment 6N-[3-(acetylamino)-benzyl]-eight-O-ethanoyl-lactobionic acid acid amides
Under 0 ℃ to N-(3-amino-benzyl)-eight-O-ethanoyl-lactobionic acid acid amides that stirs (2.90g, 3.63mmol) and triethylamine (1.11mL, dripping acetyl chloride in THF 7.99mmol) (45mL) solution (0.310mL, 4.36mmol).After under this temperature 0.5 hour, it is warming up to room temperature and continues stirring 72 hours.Then, reaction solution is concentrated add then among the EtOAc (300mL).Organic solution is washed dry then (MgSO with 1N HCl (30mL), saturated sodium bicarbonate aqueous solution (30mL) and salt solution (30mL)
4).After concentrating, resistates is passed through purification by flash chromatography (5% to 60% acetone: CHCl
3Gradient) obtains product (2.35g, 77%), be glassy white foam, mp 120-123 ℃;
1H NMR (CDCl
3) δ 1.98 (s, 3H), 2.00 (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=6.4,11.2Hz, 1H), 4.30 (dd, J=3.3,6.8Hz, 1H), 4.35 (dd, J=5.9,14.9Hz, 1H), 4.46-4.53 (m, 2H), 4.62 (d, J=7.9Hz, 1H), 4.98 (dd, J=3.3,10.3Hz, 1H), 5.05 (td, J=2.9,5.7Hz, 1H), 5.19 (dd, J=7.9,10.3Hz, 1H), 5.36 (dd, J=1.1,3.5Hz, 1H), 5.56 (dd, J=3.1,6.8Hz, 1H), 5.69 (d, J=6.8Hz, 1H), 6.64 (t, J=5.9Hz, 1H), 6.96 (d, J=7.7Hz, 1H), 7.21-7.30 (m, 2H), 7.66 (dd, J=1.1,8.1Hz, 1H), 7.81 (s, 1H); IR (KBr) 3390,2990,1755,1675,1620,1560,1490,1425, and 1375,1220,1130,1055,950,755 and 610cm
-1Mass spectrum [(+) FAB], m/z841 (M+H)
+, 863 (M+Na)
+Ultimate analysis calculated value C
37H
48N
2O
203H
2O:C, 49.66; H, 6.08; N, 3.13, measured value: C, 49.46; H, 5.37; N, 3.04.
Embodiment 7N-[3-(acetylamino)-benzyl]-eight-O-sulfo group-lactobionic acid acid amides eight sodium salt steps 1
To contain N-[3-(acetylamino)-benzyl]-eight-O-ethanoyl-lactobionic acid acid amides (2.09g, 2.49mmol) and the MeOH solution of 25 weight %NaOMe (42.6 μ L, MeOH 0.746mmol) (62.7mL) solution refluxed 2 hours.Reaction mixture is cooled to room temperature concentrates then, with the resistates MeOH that obtains: Et
2O (30: 70) development obtains product (1.11g, 88%), is glassy white solid, mp＞170 ℃ (decomposition);
1H NMR (DMSO-d
6) δ 2.01 (s, 3H), 3.16 (d, J=4.4Hz, 2H), 3.31-3.42 (m, 1H), 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=7.7Hz, 1H), 7.19 (t, J=7.7Hz, 1H), 7.38 (s, 1H), 7.48 (d, J=8.1Hz, 1H), 8.09 (t, J=6.2Hz, 1H), 9.86 (s, 1H); IR (KBr) 3380,2920,2320,1660,1620,1600,1560,1495, and 1430,1370,1320,1275,1080,1050,880,780 and 700cm
-1Mass spectrum [(+) FAB], m/z 527 (M+Na)
+Ultimate analysis calculated value C
21H
32N
2O
121.5H
2O:C, 47.45; H, 6.64; N, 5.27, measured value: C, 47.86; H, 6.73; N, 4.95.Step 2
Title compound is from N-[3-(acetylamino)-benzyl]-the lactobionic acid acid amides is with method similar to Example 2 preparation, is tawny solid (1.76g, 66%) mp＞211 ℃ (decomposition);
1H NMR (D
2O) 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) 3440,2950,1640,1565,1495,1430,1250,1125, and 1060,1020,920,820,695,620 and 580cm
-1Mass spectrum [(-) ESI], m/z 1297 (M-Na)
-, 1195 (M-SO
3Na+H-Na)
-, (m-zNa)/z637.4 (M-2Na)
2-Ultimate analysis calculated value C
19H
24N
2O
36S
8Na
86H
2O:C, 17.65; H, 2.54; N, 1.96, measured value: C, 17.31; H, 2.13; N, 1.87.
Claims (9)
1. compound in structural formula I or its pharmacologically acceptable salt,
Wherein
R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Be independently of one another cyano-acyl, a 3-8 carbon atom of nitro acyl group, a 3-7 carbon atom of halo acyl group, a 2-7 carbon atom of acyl group, a 2-7 carbon atom of 2-7 carbon atom trifluoromethyl acyl group, benzoyl or-SO
3H;
R
9Be hydrogen, CN, NO
2, halogen, CF
3, the alkyl of a 1-6 carbon atom or the alkoxyl group of 1-6 carbon atom;
R
10Be hydrogen ,-NO
2,-NHR
11,-NHR
13,-N (R
13)
2,-NCH
3R
13,-NHCO
2Alkyl, moieties wherein contain 1-6 carbon atom, the alkylsulfamoyl group of 1-4 carbon atom,
Z is O or S;
R
11Be α carboxyl and R wherein
10Nitrogen form the a-amino acid of acid amides, wherein, if described amino acid is L-glutamic acid or aspartic acid, then non-α carboxylic acid is an alkyl ester, moieties wherein contains 1-6 carbon atom;
R
12Be hydrogen, CN, NO
2, halogen, CF
3, the alkyl of a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, the acyl group or the benzoyl of a 2-7 carbon atom;
R
13Be the acyl group of hydrogen, a 2-7 carbon atom, the halo acyl group of a 2-7 carbon atom, the nitro acyl group of a 2-7 carbon atom, the cyano-acyl of a 3-7 carbon atom, the trifluoromethyl acyl group or the benzoyl of a 3-8 carbon atom.
2. the compound or pharmaceutically acceptable salt thereof of claim 1, wherein
R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Be independently of one another 2-7 carbon atom acyl group or-SO
3H;
Z is O.
3. the compound or pharmaceutically acceptable salt thereof of claim 2, wherein
R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Be independently of one another ethanoyl or-SO
3H;
R
10Be hydrogen ,-NO
2,-NHR
13,-N (R
13)
2
R
13It is the acyl group of a hydrogen or 2-7 carbon atom.
4. the compound of claim 1, described compound is:
A) N-benzyl-eight-O-ethanoyl-lactobionic acid acid amides or its pharmacologically acceptable salt;
B) N-benzyl-eight-O-sulfo group-lactobionic acid acid amides or its pharmacologically acceptable salt;
C) N-(4-nitro-benzyl)-eight-O-ethanoyl-lactobionic acid acid amides or its pharmacologically acceptable salt;
D) N-(4-amino-benzyl)-eight-O-ethanoyl-lactobionic acid acid amides or its pharmacologically acceptable salt;
E) N-(3-amino-benzyl)-eight-O-ethanoyl-lactobionic acid acid amides or its pharmacologically acceptable salt;
F) N-[3-(acetylamino)-benzyl]-eight-O-ethanoyl-lactobionic acid acid amides or its pharmacologically acceptable salt; Or
G) N-[3-(acetylamino)-benzyl]-eight-O-sulfo group-lactobionic acid acid amides or its pharmacologically acceptable salt.
5. treatment or suppress the method for excess proliferative vascular disease in Mammals, this method comprise, to the formula I of described administration significant quantity compound or pharmaceutically acceptable salt thereof:
Wherein
R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Be independently of one another cyano-acyl, a 3-8 carbon atom of nitro acyl group, a 3-7 carbon atom of halo acyl group, a 2-7 carbon atom of acyl group, a 2-7 carbon atom of 2-7 carbon atom trifluoromethyl acyl group, benzoyl or-SO
3H;
R
9Be hydrogen, CN, NO
2, halogen, CF
3, the alkyl of a 1-6 carbon atom or the alkoxyl group of 1-6 carbon atom;
R
10Be hydrogen ,-NO
2,-NHR
11,-NHR
13,-N (R
13)
2,-NCH
3R
13,-NHCO
2Alkyl, moieties wherein contain 1-6 carbon atom, the alkylsulfamoyl group of 1-4 carbon atom,
Z is O or S;
R
11Be α carboxyl and R wherein
11Nitrogen form the a-amino acid of acid amides, wherein, if described amino acid is L-glutamic acid or aspartic acid, then non-α carboxylic acid is an alkyl ester, moieties wherein contains 1-6 carbon atom;
R
12Be hydrogen, CN, NO
2, halogen, CF
3, the alkyl of a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, the acyl group or the benzoyl of a 2-7 carbon atom;
R
13Be the acyl group of hydrogen, a 2-7 carbon atom, the halo acyl group of a 2-7 carbon atom, the nitro acyl group of a 2-7 carbon atom, the cyano-acyl of a 3-7 carbon atom, the trifluoromethyl acyl group or the benzoyl of a 3-8 carbon atom.
6. treatment or suppress the method for restenosis in Mammals, this method comprise, to the formula I of described administration significant quantity compound or pharmaceutically acceptable salt thereof:
Wherein
R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Be independently of one another cyano-acyl, a 3-8 carbon atom of nitro acyl group, a 3-7 carbon atom of halo acyl group, a 2-7 carbon atom of acyl group, a 2-7 carbon atom of 2-7 carbon atom trifluoromethyl acyl group, benzoyl or-SO
3H;
R
9Be hydrogen, CN, NO
2, halogen, CF
3, the alkyl of a 1-6 carbon atom or the alkoxyl group of 1-6 carbon atom;
R
10Be hydrogen ,-NO
2,-NHR
11,-NHR
13,-N (R
13)
2,-NCH
3R
13,-NHCO
2Alkyl, moieties wherein contain 1-6 carbon atom, the alkylsulfamoyl group of 1-4 carbon atom,
Z is O or S;
R
11Be α carboxyl and R wherein
10Nitrogen form the a-amino acid of acid amides, wherein, if described amino acid is L-glutamic acid or aspartic acid, then non-α carboxylic acid is an alkyl ester, moieties wherein contains 1-6 carbon atom;
R
12Be hydrogen, CN, NO
2, halogen, CF
3, the alkyl of a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, the acyl group or the benzoyl of a 2-7 carbon atom;
R
13Be the acyl group of hydrogen, a 2-7 carbon atom, the halo acyl group of a 2-7 carbon atom, the nitro acyl group of a 2-7 carbon atom, the cyano-acyl of a 3-7 carbon atom, the trifluoromethyl acyl group or the benzoyl of a 3-8 carbon atom.
7. the method for claim 6, restenosis are wherein transplanted by angioplasty, reconstructive vascular operation or organ or tissue and are caused.
8. the method that suppresses the vasculogenesis in malignant tumour, sarcoma or the tumor tissues in Mammals, this method comprise, to the formula I of described administration significant quantity compound or pharmaceutically acceptable salt thereof:
Wherein
R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Be independently of one another cyano-acyl, a 3-8 carbon atom of nitro acyl group, a 3-7 carbon atom of halo acyl group, a 2-7 carbon atom of acyl group, a 2-7 carbon atom of 2-7 carbon atom trifluoromethyl acyl group, benzoyl or-SO
3H;
R
9Be hydrogen, CN, NO
2, halogen, CF
3, the alkyl of a 1-6 carbon atom or the alkoxyl group of 1-6 carbon atom;
R
10Be hydrogen ,-NO
2,-NHR
11,-NHR
13,-N (R
13)
2,-NCH
3R
13,-NHCO
2Alkyl, moieties wherein contain 1-6 carbon atom, the alkylsulfamoyl group of 1-4 carbon atom,
Z is O or S;
R
11Be α carboxyl and R wherein
10Nitrogen form the a-amino acid of acid amides, wherein, if described amino acid is L-glutamic acid or aspartic acid, then non-α carboxylic acid is an alkyl ester, moieties wherein contains 1-6 carbon atom;
R
12Be hydrogen, CN, NO
2, halogen, CF
3, the alkyl of a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, the acyl group or the benzoyl of a 2-7 carbon atom;
R
13Be the acyl group of hydrogen, a 2-7 carbon atom, the halo acyl group of a 2-7 carbon atom, the nitro acyl group of a 2-7 carbon atom, the cyano-acyl of a 3-7 carbon atom, the trifluoromethyl acyl group or the benzoyl of a 3-8 carbon atom.
9. pharmaceutical composition, it contains formula I compound or pharmaceutically acceptable salt thereof and pharmaceutical carrier:
Wherein
R
1, R
2, R
3, R
4, R
5, R
6, R
7And R
8Be independently of one another cyano-acyl, a 3-8 carbon atom of nitro acyl group, a 3-7 carbon atom of halo acyl group, a 2-7 carbon atom of acyl group, a 2-7 carbon atom of 2-7 carbon atom trifluoromethyl acyl group, benzoyl or-SO
3H;
R
9Be hydrogen, CN, NO
2, halogen, CF
3, the alkyl of a 1-6 carbon atom or the alkoxyl group of 1-6 carbon atom;
R
10Be hydrogen ,-NO
2,-NHR
11,-NHR
13,-N (R
13)
2,-NCH
3R
13,-NHCO
2Alkyl, moieties wherein contain 1-6 carbon atom, the alkylsulfamoyl group of 1-4 carbon atom,
Z is O or S;
R
11Be α carboxyl and R wherein
10Nitrogen form the a-amino acid of acid amides, wherein, if described amino acid is L-glutamic acid or aspartic acid, then non-α carboxylic acid is an alkyl ester, moieties wherein contains 1-6 carbon atom;
R
12Be hydrogen, CN, NO
2, halogen, CF
3, the alkyl of a 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, the acyl group or the benzoyl of a 2-7 carbon atom;
R
13Be the acyl group of hydrogen, a 2-7 carbon atom, the halo acyl group of a 2-7 carbon atom, the nitro acyl group of a 2-7 carbon atom, the cyano-acyl of a 3-7 carbon atom, the trifluoromethyl acyl group or the benzoyl of a 3-8 carbon atom.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US19898298A | 1998-11-24 | 1998-11-24 | |
| US09/198,982 | 1998-11-24 |
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|---|---|
| CN1333779A true CN1333779A (en) | 2002-01-30 |
Family
ID=22735720
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|---|---|
| EP (1) | EP1133507A2 (en) |
| JP (1) | JP2002530417A (en) |
| CN (1) | CN1333779A (en) |
| AU (1) | AU5706699A (en) |
| BR (1) | BR9915641A (en) |
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| WO (1) | WO2000031092A2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2308536T3 (en) * | 2004-08-05 | 2008-12-01 | Ivax Drug Research Institute Ltd | POLYSULPHATED GLYCOSIDES AND SALTS OF THE SAME. |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3734815A1 (en) * | 1987-10-14 | 1989-04-27 | Luitpold Werk Chem Pharm | POLYSCHWEFELSAEUREESTER OF BIS-ALDONSAEUREAMIDEN AND THEIR DERIVATIVES, METHOD FOR THEIR PREPARATION AND MEDICAMENTS |
| IL115745A (en) * | 1994-11-07 | 2000-11-21 | American Home Prod | Acylated benzylglycosides and pharmaceutical compositions containing them |
-
1999
- 1999-02-04 AU AU57066/99A patent/AU5706699A/en not_active Abandoned
- 1999-11-23 CA CA002351061A patent/CA2351061A1/en not_active Abandoned
- 1999-11-23 WO PCT/US1999/027774 patent/WO2000031092A2/en not_active Application Discontinuation
- 1999-11-23 BR BR9915641-5A patent/BR9915641A/en not_active Application Discontinuation
- 1999-11-23 EP EP99944107A patent/EP1133507A2/en not_active Withdrawn
- 1999-11-23 CN CN99813573A patent/CN1333779A/en active Pending
- 1999-11-23 JP JP2000583920A patent/JP2002530417A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| EP1133507A2 (en) | 2001-09-19 |
| JP2002530417A (en) | 2002-09-17 |
| AU5706699A (en) | 2000-06-13 |
| WO2000031092A2 (en) | 2000-06-02 |
| WO2000031092A3 (en) | 2001-01-18 |
| CA2351061A1 (en) | 2000-06-02 |
| BR9915641A (en) | 2001-08-07 |
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| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
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