CN1269797A - Oligo-thiophenes useful as antimetastatic agents, preparation thereof and pharmaceutical composition containing same - Google Patents
Oligo-thiophenes useful as antimetastatic agents, preparation thereof and pharmaceutical composition containing same Download PDFInfo
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- CN1269797A CN1269797A CN98807766A CN98807766A CN1269797A CN 1269797 A CN1269797 A CN 1269797A CN 98807766 A CN98807766 A CN 98807766A CN 98807766 A CN98807766 A CN 98807766A CN 1269797 A CN1269797 A CN 1269797A
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
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Abstract
Oligo-thiophenes of formula (I) are disclosed wherein: A is a -CH2-CO-, -CH2CH2-CO- or -CH=CH-CO- group; B is a 2-thienyl or a phenyl group, which is substituted by an R group, or it is a natural or synthetic amino acid, linked to the A group via its N-terminus; or A-B is a -CH2CH2-NH-A.A.- group, wherein the A.A.-group is a natural or synthetic amino acid residue, linked to the CH2CH2-NH-group via its carboxy-terminus; R is hydrogen or a chlorine, bromine, iodine, fluorine, (C1-C4)alkyle, (C1-C4)alkylene- COOR', (C1-C4)alkylene-NH2, (C1-C4)alkylene-NR'2 or (C1-C4)alkylene-NHCOR' group; R' is hydrogen or a (C1-C4)alkyl group, isomers thereof, and salts thereof with pharmaceutically acceptable acids and bases. It is also claimed the use of the compounds of formula (I) as inhibitors of the uPA binding to the specific uPAR receptor, in particular their application as antitumor and antimetastatic agents.
Description
The present invention relates to oligothiophene, described oligothiophene randomly is connected with natural or synthesizing amino acid.
Found that above-claimed cpd has the uPA-uPAR antagonistic activity, and can be used as antitumor and/or antimetastatic agents.
Background of invention
Serine protease uPA (urokinase type plasminogen activator) catalyzing activation proplasmin makes it become Tryptase, and the gained Tryptase participates in multiple physiology and pathologic process.UPA is a kind of have catalytic " B " chain (amino acid/11 44-411) and N-terminal fragment (" ATF ", aa1-143) Multidomain protein, this N-terminal fragment contain growth factor-like structural domain (aa4-43) and Kringle structural domain (aa47-135).UPA is a kind of multifunctional protein that participates in tissue protein hydrolysis, cell migration, cell proliferation and growth factor activation.In fact, the uPA that is discharged by cell is the inactivation proenzyme, and promptly uPA is former.The Tryptase activation (generate active double chain form) former to strand uPA is subjected to the adjusting of tight control mechanism, and people also not exclusively understand for this mechanism.Most activity of uPA only are confined to cell surface and cell peripheral environment.Their need by be positioned at cell surface on specificity, high-affinity receptor (uPAR) just be accomplished after combining.The uPA of two kinds of forms has similar avidity when combining with uPAR.This binding interactions is by growth factor-like structural domain mediation people such as [, biology and The Chemicals (J.Biol.Chem.), 267,14151-56,1992] S.A.Rabbani.
The uPA acceptor is a kind of three domain glycoproteins, and wherein per three parts of motifs comprise about 90 the amino acid whose sequences [people such as M.Plough, biology and The Chemicals (J.Biol.Chem.), 268,17539-46,1993] of agreeing with that are rich in halfcystine.UPAR is anchored on the cytolemma by glycosyl-phosphatidyl inositol group (GPI anchor).UPAR is 10-10-10-9M in conjunction with the KD value of uPA, and this depends on the test system.UPA bonded master determiner is arranged in N-end structure territory 1.UPAR ruptures under the effect of uPA and Tryptase, discharges water-soluble structure territory 1, and discharges the uPAR (1+2+3) of three structural domains under the effect of Phospholipase C from cell surface.The uPAR of back one form is also because of having lost the GPI anchor water soluble that becomes.
Inhibition to uPA dependency phenomenon mainly reaches by two approach, promptly direct arrestin hydrolytic activity, or suppress the uPA receptors bind.Back one approach has the higher specific usefulness of acquisition, and this only is confined to carry out in the cell peripheral environment owing to described restraining effect.
Recently, found that by phage display technology and protein engineering specific specificity peptide class uPAR antagonist [is disclosed in respectively: people such as Goodson, international scientific institute journal (PNAS), 91,7129,1994; People such as Stratton-Thomas, protein engineering (Prot.Eng.), 5,463-470,1995].
The present invention relates to have the oligothiophene of effective antagonistic activity.The many pairs of thiophene and three thiophene derivants as if manifested compelling biological property [Kagan, people such as J., organic chemistry magazine (J.Org.Chem.), 48,4317-20,1983 and the reference wherein quoted].But the overwhelming majority in them is to the nematode toxigenicity, and this toxic action strengthens when having ultraviolet ray to exist greatly.What study at most in this compounds is α-three thiophene, a kind of 20th century the seventies as the found first natural product that is obtained from plant of light toxin (phototoxin).Except that generating skin pigment, this compound also can act on nematode, microorganism, algae, human erythrocyte, insect larvae and ovum thereof and this effect and meet light and strengthen, and this compound can be used as weedicide and the seed inhibitor of sprouting.Active and the cytotoxic activity of photoconductive antivirus also has been seen in reporting [(a) people such as Cooper, bioorganic chemistry (Bioorg.Chem.), 13,362-374,1985 and the reference quoted; (b) people such as Rawls, chemistry and engineering science are reported (Chem.﹠amp; Engin.News), 21-23,1986; (c) people such as Evans, American Chemical Society can will (J.Am.Chem.Soc.), and 112,2694-2701,1990; (d) people such as Kyo, vegetable cell report (Plant Cell Rep.), 9,393-397,1990; (e) people such as Hudson, Planta Med., 59,447-450,1993; (f) people such as Hudson, ozonosphere (Chemosphere), 19,1329-1343,1989].Structure-activity relation studies show that and has 14 kinds of isomeric three thiophenes [people such as Jayasuriya, heterocycle is learned (Heterocycles), 24,2261-2264 and 2901-2904,1986] that do not replace.The thiophene ring compound has been widely used in the medicine of different field, but oligothiophene only is used as pharmacological agents and mentions [people such as Press, chemistry of heterocyclic compound (TheChemtstry of Heterocycles Compounds), the 44th volume, the 4th part, the III chapter is edited by Salo Gronowitz, 396-502,1989].
Shown that so far the uPA/uPAR system relates to multiple invasive bioprocess, for example metastases, trophoderm implantation, inflammation and vasculogenesis.So the uPAR antagonist should have the ability to block tumour invasiveness, pass and move and vasculogenesis.The preparation that contains the uPAR antagonist is signifying the new methods of treatment that is suitable for high invasive and transport property cancer, find that wherein uPA and uPAR are present in the invasive intralesional of tumour (for example mammary cancer, lung cancer, colorectal carcinoma, ovarian cancer) [people such as Dano all the time, " proteolysis and protein conversion " (Proteolysis and ProteinTurnover), Barret+Bond edits, Portlan Press, 1994, London].The uPAR level that detects in the blood plasma from the patient of mammary cancer and non-small cell type lung cancer increases to some extent.So as if the content of solubility uPAR reflects proteoclastic degree in the tumour, and may be closely related with patient's prognosis.UPA and uPAR level in the tumor tissues all are prognostic factors of many types of cancer.Except cancer, the uPAR antagonist also is applicable to the other diseases that those are mediated by uPA cell surface activity.So the Tryptase formation inhibitor that works by receptors bind type uPA has machine-processed type tumour static state, tamper resistance, anti-migration, angiogenesis inhibitor, arthritis, anti-inflammatory, osteoporosis disease, anti-retinopathy and contraception activity.The preferred oral route administration of these compounds, but also can be by intravenous injection, intramuscular injection, intranasal spraying or other usual manner administrations.
Invention is described
The present invention relates to the oligothiophene shown in the general formula (I), its isomer with and the salt that generates with pharmaceutically acceptable bronsted lowry acids and bases bronsted lowry:
Wherein :-A is-CH
2-CO-,-CH
2CH
2-CO-or-the CH=CH-CO-group;-B is 2-thienyl or phenyl, and it is replaced by the R group; Or natural or synthesizing amino acid,
It links to each other with the A group by its N-is terminal; Or A-B is-CH
2CH
2-NH-A.A.-base
Group, A.A. group wherein is natural or the synthesizing amino acid residue, this residue is by its carboxylic
Base end and CH
2CH
2-NH-group links to each other;-R is hydrogen or chlorine, bromine, iodine, fluorine, (C
1-C
4) alkyl, (C
1-C
4) alkylidene group-COOR ',
(C
1-C
4) alkylidene group-NH
2, (C
1-C
4) alkylidene group-NR '
2Or (C
1-C
4) alkylidene group-NHCOR '
Group;-R ' is hydrogen or (C
1-C
4) alkyl.
Described natural amino acid represents 20 kinds to be one of unitary a-amino acid of polypeptide monomer, for example glycine, L-Ala, Xie Ansuan, leucine, Isoleucine, phenylalanine, tryptophane, proline(Pro), Serine, Threonine, tyrosine, aspartic acid, L-glutamic acid, l-asparagine, glutamine, Methionin, arginine, Histidine, halfcystine or methionine(Met).
Synthesizing amino acid is to constitute with the compound that is connected the carboxyl of alpha-carbon atom by containing amino.
The pharmacologically acceptable salt of compound of the present invention comprises the additive salt of physilogically acceptable acid, for example hydrochloride, hydrobromate, vitriol, mesylate, right-tosylate, phosphoric acid salt, acetate, Citrate trianion, succinate, lactic acid salt, tartrate, fumarate and maleate.Also can be the salt that forms with alkali, for example sodium salt, sylvite, magnesium salts and calcium salt.Preferred compound be those wherein B be that amino acid or A-B are suc as formula-CH
2CH
2The compound of group shown in the-NH-A.A.-.
Other preferred compounds be those wherein B be the compound of 2-thienyl.
Particularly preferred compound be those wherein amino acid be the compound of tryptophane (triptophane).
Another object of the present invention provides the preparation method of a kind of formula (I) compound.
A further object of the present invention is that formula (I) compound is being treated the wherein effective disease of uPAR inhibitor, specifically be the application in tumour and tumor migration or the infringement, the invention still further relates to the pharmaceutical composition of the adulterant of one or more formulas (I) compound that contains pharmacy effective dose and pharmaceutically acceptable additive.The preparation of The compounds of this invention
Wherein B be natural or synthesizing amino acid (after this be called-A.A.-) formula (I) compound can begin preparation from intermediate shown in the formula (II):
This intermediate at first is converted into corresponding chloride derivative, subsequently in the presence of lewis acidic, by Friedel-Crafts reaction (Friedel-Craft reaction) and the reaction of intermediate shown in the formula (III):
Wherein A ' is-CH
2-,-CH
2CH
2-or-CH=CH-group and R " be (C
1-C
4) alkyl,
Preferably utilize thionyl chloride to the temperature of solvent boiling point intermediate (II) to be converted into acyl chlorides in room temperature, thionyl chloride is also as solvent.
Described Friedel-Crafts reaction is preferably to use SnCl
4As Lewis acid and in inert solvent, under the condition of-5 ℃-room temperature, carry out.
Gained intermediate (IV):
Be hydrolyzed to the corresponding acid (V) of formula V:
Appropriate reaction conditions comprises: use alkali, preferred alkali metal hydroxide; Be reflected in water, alcohol or its mixture and carry out; Temperature of reaction is 0 a ℃-room temperature.
Subsequently,, obtain imdazole derivatives with the carboxyl of carbonyl dimidazoles activated intermediate (V) for example, so preferred in inert solvent and under 0 ℃-50 ℃ the temperature with the amino acid reaction of formula-A.A.-, obtain the intermediate of formula (VI):
After this, preferably under acidic conditions, by with carboxylicesters-COOR " hydrolysis and formula (VI) intermediate is converted into corresponding formula (I) compound.
If usefulness formula in said process (III ') intermediate replacement formula (III) intermediate:
Can making wherein, A-B is-CH
2CH
2The formula of-NH-A.A.-group (I) compound.In this case, should behind Friedel-Crafts reaction, slough protecting group-COCF
3, and make gained intermediate and the N-BOC-amino acid condensation that passes through its activated carboxylic in advance.Remove protecting group BOC and obtain end product formula (I) compound later on.
Wherein B be formula (I) compound that replaces of 2-thienyl or phenyl and R group with above-mentioned implication can by the carboxyl functionality as stated above activatory formula (II) intermediate, react by Friedel-Crafts reaction and formula (VII) intermediate and to prepare:
Wherein A has above-mentioned implication and B ' is 2-thienyl or phenyl, and B ' can be replaced by aforesaid R group.
Two thiophene that one of them ring is replaced by the R substituting group are at-50 ℃--20 ℃ down and carbonic acid gas and highly basic such as butyllithium react and can obtain formula (II) intermediate.The two thiophene of starting raw material can be buied, or prepare according to one skilled in the art's known method.
Wherein A is-CH
2-CO-or-formula (VII) intermediate of CH=CH-CO-:
Can be from the wherein A that can commercial buy " be-CH
2-or-formula (VIII) intermediate of CH=CH-begins preparation:
Method is at first to make the carboxyl functionality be converted into corresponding acyl chlorides, and the compound with formula B-H carries out Friedel-Crafts reaction subsequently, and wherein B-H is thiophene or the phenyl that replaced by above-mentioned R group.
From A wherein be-the corresponding intermediate of CH=CH-CO-, at suitable catalyzer as (PPh
3)
3With the two key hydrogenations of the C=C of intermediate, can obtaining wherein, A is-CH under the existence of RhCl
2CH
2The formula of-CO-(VII) intermediate.
Similarly, can making wherein by the corresponding intermediate that has C=C through catalytic hydrogenation, A ' is-CH
2CH
2-formula (III) intermediate.Biological activity
Be disclosed in " biology, chemistry and Hou Pusaile coomb's test Coomb " (Biol.Chem.Hoppe.Seyler) 376 according to people such as Rettenberger, method described in the 587-94 (1995), whether the test The compounds of this invention is human body urokinase (uPA) inhibitor (ELISA test) that can combine with specific receptors uPARmAk (BIO-R4).
Test adopts microtiter plate (96 hole) to carry out.Used solution is as follows :-lavation buffer solution: the PBS-damping fluid (does not contain Mg
2+And Ca
2+)+0.05% polysorbas20;-cultivate damping fluid (IP): the PBS-damping fluid that contains 1% skim-milk (does not contain Mg
2+And Ca
2+);-BIO-R4 solution: be dissolved in the 50ng/ hole (0.5Tg/ml among the IP; The 100Tl/ hole);-uPAR solution: be dissolved in the PBS-damping fluid and (do not contain Mg
2+And Ca
2+) in 3ng/ hole (30ng/ml; The 100Tl/ hole);-blocking solution: the lavation buffer solution (37 ℃ of dissolvings down) that contains 1% skim-milk;-uPA solution: be dissolved in the 0.25ng/ hole (5ng/ml among the IP; The 50Tl/ hole).Detect solution (each microtiter plate): (1) 6ml (100mM Tris-Cl, pH 7.2+0.15% tween 80)+1.5ml (10Tg) is dissolved in the proplasmin in the double distilled water; (2) 6ml (100mM Tris-Cl, pH 7.2+0.15% tween 80)+1.5ml (7.5mg) is dissolved in the dyeing enzyme PL (Chromozyme PL) in the double distilled water.Must continuously stirring should detect solution.Substances: substances is dissolved among the DMSO.Adopt its maximum concentration 100Tg/ml as the test system.Prepare this solution with PBS.Three controlled trials of being carried out are: a) positive control: the PBS solution that contains 2%DMSO; B) negative control: do not have acceptor during detection and exist; C) inhibition contrast: 1) carry out inhibition test (IC with T 500 (MW=500 000)
95For
0.25mg/ml)；
2) uPA (175Tg/ml) with passivation carries out inhibition test (IC
90For
1Tg/ml) cultivating the following method of employing carries out:
Cultivated 1 hour under room temperature and jolting condition in each hole that will contain 100TI BIO-R4 (c=0.5Tg/ml).After lavation buffer solution washing 3 times, in each hole, add 200Tl/ hole blocking solution and be incubated 1 hour down at 37 ℃.After washing 3 times, each hole was cultivated l hour with 100Tl/ hole uPAR (c=30ng/ml) at room temperature with jolting the time, subsequently again with lavation buffer solution washing 3 times.Adding contains the solution and the contrast solution (50Tl/ hole) of substances and cultivated 30 minutes under the condition of room temperature and jolting respectively.Add 50Tl uPA solution (c=2.5ng/ml) again.At room temperature be incubated 1 hour after scouring 3 times.Detect in accordance with the following methods:
At room temperature use detection solution (1) and (2) of each 50Tl to cultivate.After 20 minutes, generate yellow (it is 1 that positive control is tested the dullness (extinction) that read) after 45-60 minute.Detect under 405nm with Dynatech MR 7000ELISA reader.Calculate the inhibition percentage according to following formula:
% inhibition=100-100 * [the E test-E feminine gender-contrast/E positive-contrast-E feminine gender-contrast]
The data rows of some representative compounds of the present invention is in Table I.Table I-BI0-R4 detects and tests-use IC
50(mM) restraining effect of the uPA (BIO-R4) of Biao Shi binding specificity uPAR acceptor
The present invention relates to contain the medicament of one or more formulas (I) compound.
In order to prepare medicament, in a known way formula (I) compound is mixed with suitable pharmaceutically acceptable carrier material, perfume compound, correctives and dyestuff and make for example tablet or coated tablet, or they are suspended with the suitable auxiliary material that adds or be dissolved in water or oil as in the sweet oil.
Material shown in the general formula (I) can be with liquid or solid form oral administration or parenterai administration.Preferred water is as the medium that contains injection solution stablizer, solubilizing agent and/or buffer reagent commonly used.Described additive can for example be: tartrate or borate buffer solution, ethanol, dimethyl sulfoxide (DMSO), complexing agent (for example ethylenediamine tetraacetic acid (EDTA)), the high molecular polymer (as liquid polyoxyethylene) of regulating viscosity or the polythene derivative of sorbitol anhydride.
The solid carrier material for example is: the silicic acid of starch, lactose, mannitol, methylcellulose gum, talcum, high dispersive, polymer fatty acid (for example stearic acid), gelatin, agar, calcium phosphate, Magnesium Stearate, animal and plant fat or solid high molecular polymer (for example polyoxyethylene glycol).The preparation that is suitable for oral administration can contain correctives and sweeting agent as required.
Dosage depends on patient's age, healthy state and body weight, the severity of disease, the type of the treatment that may carry out simultaneously, the frequency of treatment and the effect kind that will reach.The per daily dose of active compound is the 0.1-50mg/kg body weight normally.For the curative effect that obtains to expect, 0.5-40mg/kg/ days and preferred 1-20mg/kg/ days usually, but administration every day 1 time or be effective several times.
The present invention will further specify by the following example.Preparation example 1: two-thiophene-2-carboxylic acid synthetic
Be dissolved in the two thiophene of 15g in the 300ml tetrahydrofuran (THF) (THF) and under nitrogen, this solution be cooled to-40 ℃.Careful dropping 10.8ml is dissolved in the 10M butyllithium in the hexane, subsequently this red solution is kept 1 hour down and its impouring is equipped with in the flask of 500g dry ice (solidified carbon dioxide) at-10 ℃.Yellow suspension was dissolved in 1 hour, after this with in the gained solution impouring 1000ml 2N sodium hydroxide.After 30 minutes, isolate organic phase and concentrated solvent to small volume.In resistates, add 2N sodium hydroxide and water and use hexane wash, so with 37% hydrochloric acid with aqueous phase as acidified to pH 2, at room temperature kept 1 hour, filter out solid and also use the 50ml water washing.Behind 70 ℃ baking oven inner drying, obtain the 17.8g product, fusing point: 171-174 ℃.Preparation example 2:2-[3-(2-thienyl) acryl] thiophene synthetic
5g 3-(2-thienyl) acrylic acid solution that will be dissolved in the 30ml thionyl chloride heated 1 hour 30 minutes down at 50 ℃, removed unreacted thionyl chloride subsequently under decompression.In resistates, add 20ml heptane and drying twice, again it is dissolved in the 50ml methylene dichloride, cool off and drip the 2.43g thiophene solution that is dissolved in the 5ml methylene dichloride down at 0 ℃.Keeping temperature is under 0 ℃ the condition, drips 6.74ml SnCl again
4Solution in the 12ml methylene dichloride.Make reaction mixture at room temperature keep 2 hours, subsequently with in its impouring 200ml 2N hydrochloric acid.Water phase separated is also used the 100ml dichloromethane extraction.Organic phase is with dried over sodium sulfate and be evaporated to driedly, and (eluent: hexane/ethyl acetate 5: 1) purifying behind the recrystallization, obtains the 4.79g product to resistates from hexane through silica gel column chromatography.Fusing point: 105-107 ℃.Preparation example 3:2-[3-(2-thienyl) propionyl] thiophene synthetic
At room temperature, will be dissolved in 4.64g 2-[3-(2-thienyl) acryl in the 50ml anhydrous methylene chloride] thiophene solution and the hydrogenation of 0.97g three (triphenylphosphine) rhodium chloride spends the night.Subsequently reaction mixture is concentrated into do and through silica gel column chromatography (eluent: hexane/ethyl acetate 20: 1) purifying, obtain the 4.3g product, this product is an oily matter.Preparation example 4:2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethyl acetate synthetic
To be dissolved in the two thiophene-2-carboxylic acid (3g in the 20ml thionyl chloride; Preparation example 1) solution heated 1 hour 30 minutes down at 50 ℃, evaporated unreacted thionyl chloride subsequently, and resistates is handled 3 times and evaporation with the 10ml heptane.Be dissolved in resistates in the methylene dichloride and cooling under 0 ℃, drip 2-(thiophene-2-yl) ethyl acetate (2.19g) solution that is dissolved in the 5ml methylene dichloride then.Add the SnCl that is dissolved in the 10ml methylene dichloride subsequently
4(3ml) solution.Reaction mixture at room temperature kept 2 hours, subsequently with in its impouring 200ml 2N hydrochloric acid.(3 * 150ml) aqueous phase extracted are also collected organic extract liquid, with dried over sodium sulfate and be concentrated into dried with methylene dichloride.(eluent: hexane/ethyl acetate 8: 1) purifying obtains the 3.62g product to resistates (8g) through silica gel column chromatography.Preparation example 5:2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] acetate synthetic
Be suspended in 3.62g 2-[2-in 60ml ethanol and the 5ml water ((2,2 '-two thiophene-5 '-yl)-carbonyl) thiophene-5-yl] ethyl acetate suspension is 0 ℃ of cooling and add 11.35ml 2N sodium hydroxide down.Mixture at room temperature keeps spending the night, and then it is concentrated into small volume.After the acidifying, the product crystallization then with its filtering separation and 40 ℃ of following vacuum-dryings, is reclaimed the 2.4g product.Preparation example 6:4-[3-(2-thienyl) propionyl]-the 1-fluorobenzene
Be dissolved in 5g 2-(2-inferior thienyl)-4-fluorobenzene ethyl ketone in the 50ml anhydrous methylene chloride and add 0.97g three (triphenylphosphine) rhodium chloride.Order reaction hydrogenation 8 hours (the 470ml hydrogen reaction is arranged approximately) is concentrated into it dried subsequently and (eluent: hexane/ethyl acetate 20: 1) purifying obtains the 4.85g product through silica gel column chromatography.Preparation example 7:2-[2-(trifluoroacetamido)-1-ethyl] thiophene
2-(2-thienyl) ethamine (10g) solution that will be dissolved in the 100ml tetrahydrofuran (THF) is cooled to 0 ℃, drips the 9.05ml Trifluoroacetic Acid Ethyl Ester subsequently.After at room temperature stirring 4 hours, reaction mixture is concentrated into dried, obtains 18g oily matter, this oily matter is handled also saturated with the 90ml hexane with the 18ml ether.Cool off after 2 hours, filter collection and obtain the 12.15g product, fusing point: 45-47 ℃.Preparation example 8:2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl]-N-TFA base ethamine
To be dissolved in the two thiophene-2-carboxylic acid (3.4g in the 25ml thionyl chloride; Preparation example 1) solution heated 2 hours down at 50 ℃.Reaction mixture is concentrated into dried, subsequently it is dissolved in again in the heptane and reconcentration to doing.Repeat aforesaid operations, again resistates be dissolved in the methylene dichloride, cool off and drip 3.3g 2-[2-(the trifluoroacetamido)-1-ethyl that is dissolved in the 20ml methylene dichloride down at 0 ℃] thiophene (preparation example 7) solution, drip SnCl subsequently
4(3.8ml) solution in the 3.8ml methylene dichloride.Reaction mixture was at room temperature kept stirring 2 hours, subsequently with (4 * 100ml) extract in its impouring 200ml 2N hydrochloric acid and with tetrahydrofuran (THF).Merge organic extract liquid, with dried over sodium sulfate and vapourisation under reduced pressure solvent.Obtain 18g dark oil thing, through silica gel column chromatography (eluent: purifying hexane/tetrahydrofuran (THF) 2: 1).From hexane (100ml) recrystallization and 50 ℃ of following vacuum-dryings, obtain the 4.3g product.Fusing point: 168-170 ℃.Preparation example 9:2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethamine
Under agitation, to be dissolved in 2-[2-in the 800ml methyl alcohol ((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl at 0 ℃ of following refrigerative]-N-TFA base ethamine (10g; Preparation example 8) add the 2N sodium hydroxide of 60.17ml in the solution, with reaction mixture 50 ℃ of following heated overnight.Subsequently mixture is concentrated into small volume, adds entry (500ml) again, with chloroform (4 * 200ml) extractions.Merge organic extract liquid, with dried over sodium sulfate and be concentrated into dried.Crystallization from ethyl acetate (16ml)/hexane (16ml) mixture obtains the 5.1g product, fusing point: 102-104 ℃.Embodiment 1:N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] tryptophane (triptophane) ethyl ester synthetic
To be suspended in 2.34g2-[2-among the anhydrous THF of 150ml ((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] suspension of acetate (preparation example 5) and 1.74g carbonyl dimidazoles kept 1 hour down at 40 ℃.Mixture is cooled to 20 ℃ also drips the 2.45g tryptophane ethyl ester solution that is dissolved among the anhydrous THF of 10ml.After 2 hours, reaction mixture is concentrated into dried, subsequently it is dissolved in the ethyl acetate, wash and use the 200ml chloroform extraction with water.Organic phase is concentrated into dried, obtains the 7g resistates, (eluent: hexane/ethyl acetate 4: 1-2: 1) purifying obtains the 2.79g product through silica gel column chromatography with it.Embodiment 2:N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] tryptophane synthetic
To be dissolved in 2.2g N-[2-[2-in 320ml ethanol and the 10ml water ((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] tryptophane ethyl ester (embodiment 1) solution is 0 ℃ of cooling down, drips 4.43ml 2N sodium hydroxide subsequently.After following 4 hours of the room temperature, mixture is concentrated into small volume, adds entry, wash and be acidified to pH=2 with ethyl acetate.Use the ethyl acetate extraction water, the organic extract liquid dried over sodium sulfate is concentrated into driedly, and (eluent: purifying chloroform/methanol/acetate 9: 1: 0.25) obtains the 1.16g product, fusing point to resistates: 166-168 ℃ through silica gel column chromatography.Embodiment 3:2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] propionyl] thiophene synthetic
Two thiophene-2-carboxylic acid (preparation example 1) solution of 1g that will be dissolved in the 5ml thionyl chloride heated 1 hour 30 minutes down at 50 ℃, evaporated unreacted thionyl chloride subsequently, added heptane and evaporation once more in resistates.Resistates is dissolved in the methylene dichloride,, drips 2-[3-(2-thienyl) propionyl that is dissolved in the 3ml anhydrous methylene chloride 0 ℃ of cooling down] thiophene (1g; Preparation example 3) solution.Under the condition of 0 ℃ of maintenance, drip 1.05ml SnCl then
4Solution in the 3ml anhydrous methylene chloride.Subsequently reaction mixture was at room temperature kept 1 hour, again with in its impouring 100ml 2N hydrochloric acid, (3 * 100ml) extractions are with dried over sodium sulfate and be concentrated into dried with ethyl acetate.(eluent: hexane/ethyl acetate 5: 1) purifying obtains the 1.02g product, fusing point to resistates (3g): 124-126 ℃ through silica gel column chromatography.Embodiment 4:2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] acryl] thiophene synthetic
Two thiophene-2-carboxylic acid (preparation example 1) solution of 0.24g that will be dissolved in the 3ml thionyl chloride heated 1 hour 30 minutes down at 50 ℃, evaporated unreacted thionyl chloride subsequently, added heptane and evaporation once more in resistates.Resistates is dissolved in the methylene dichloride,, drips 2-[3-(2-thienyl) acryl that is dissolved in the 3ml anhydrous methylene chloride 0 ℃ of cooling down] thiophene (0.3g; Preparation example 2) solution.Under the condition of 0 ℃ of maintenance, drip 0.31mlSnCl again
4Solution in the 3ml anhydrous methylene chloride.Subsequently reaction mixture was at room temperature kept 4 hours, in mixture, add 0.3ml SnCl again
4And mixture at room temperature kept spending the night.In reaction mixture impouring 200ml 2N hydrochloric acid, (3 * 50ml) extractions are with dried over sodium sulfate and be concentrated into dried with ethyl acetate.Resistates (1.3g) obtains the 0.37g product through silica gel column chromatography (eluent: hexane/ethyl acetate 5: 1, and then use the pure ethyl acetate wash-out) purifying.Embodiment 5:2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] propionyl]-4-fluorobenzene synthetic
Two thiophene-2-carboxylic acid (preparation example 1) solution of 1.06g that will be dissolved in the 10ml thionyl chloride heated 1 hour 30 minutes down at 50 ℃, subsequently mixture were concentrated into dried.Resistates is handled 2 times with the 20ml heptane, adds the 30ml methylene dichloride at last, be cooled to 0 ℃ and drip 4-[3-(2-thienyl) propionyl that is dissolved in the 5ml methylene dichloride]-1-fluorobenzene (1.08g; Preparation example 6) solution.Be maintained at about under 0 ℃ the temperature, drip the SnCl that is dissolved in the 5ml methylene dichloride
4(1.07ml) solution at room temperature stirred reaction mixture 2 hours subsequently.In reaction mixture impouring 150ml 2N hydrochloric acid, again with ethyl acetate extraction and organic phase is concentrated into dried.(eluent: purifying methylene dichloride) after the crystallization, obtains the 1g product, fusing point: 138-140 ℃ to resistates from the ethyl acetate/hexane mixture through silica gel column chromatography.Embodiment 6:
According to the method described in above-mentioned preparation example and the embodiment, make following Oligopoly thiophene derivative :-N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene--5-yl] ethanoyl] glycine;-N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] L-Ala;-N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] phenylalanine;-N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] tyrosine;-N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] leucine;-N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] Methionin;-N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] Serine;-N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] Isoleucine;-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] propionyl]-the 4-fluorobenzene;-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] propionyl]-the 4-chlorinated benzene;-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] propionyl]-the 2-bromobenzene;-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] propionyl]-4-(carboxymethyl) benzene;-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] propionyl]-4-(amino methyl) benzene;-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] propionyl]-3-(dimethylaminomethyl) benzene;-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] propionyl]-2-(tertiary butyl) benzene;-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] acryl]-the 4-fluorobenzene;-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] acryl]-the 4-chlorinated benzene;-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] acryl]-the 2-bromobenzene;-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] acryl]-4-(carboxymethyl) benzene;-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] acryl]-4-(amino methyl) benzene;-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] acryl]-3-(dimethylaminomethyl) benzene;-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] acryl]-2-(tertiary butyl) benzene; Embodiment 7:4-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] B aminocarbonyl]-2-(uncle-butoxy carbonyl amino) butyric acid
With glutamic acid N-BOC (0.88g) and 1, the mixture of 1 '-carbonyl dimidazoles (0.63g) in the 40ml tetrahydrofuran (THF) at room temperature kept stirring 2 hours, drip the 2-[2-be dissolved in the 40ml tetrahydrofuran (THF) ((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl subsequently] ethamine (1.11g; Preparation example 9) solution and with reaction mixture 50 ℃ of following heated overnight.Decompression is evaporating solvent down, resistates is dissolved in the ethyl acetate and with saturated aqueous potassium hydrogen sulfate washs.The solid that filters to isolate (initial reactant) is concentrated into organic phase dried.Resistates (2.5g) was through silica gel column chromatography (eluent 1) chloroform/methanol 15: 2; 2) chloroform/methanol is 9: 1) purifying, obtain the 0.42g product.Embodiment 8:4-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] B aminocarbonyl]-the 2-aminobutyric acid
4-[2-[2-in being suspended in the 28ml methylene dichloride ((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] B aminocarbonyl]-2-(uncle-butoxy carbonyl amino) butyric acid (0.28g; Embodiment 7) add the 0.39ml trifluoroacetic acid in the suspension.The dark-coloured solution of gained at room temperature stirred spend the night, be concentrated into dried subsequently.Resistates is dissolved in the dehydrated alcohol (15ml) again, then with its reconcentration to doing and this operation being repeated 1 time.Resistates (0.3g) is suspended in the 20ml hexane, at room temperature stirred 1 hour, filtration is also dry under 30 ℃ vacuum, obtains the 0.2g product.1H-NMR is (at d6-DMSO+D
2Among the O): 1.9ppm (m, 2H); 2.18ppm (m, 2H); 3.05ppm (m, 2H); 3.36ppm (br m, 2H); 3.7ppm (t, 1H); 7.1ppm (m, 2H); 7.5ppm (m, 3H); 7.9ppm (m, 2H); 8.61ppm (br t, 1H).Embodiment 9:
Begin with suitable amino acid according to embodiment 7 and 8 described methods, can obtain following oligothiophene :-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethylamino] leucyl amine;-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethylamino] the phenyl alanimamides;-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethylamino] silk amide;-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethylamino] lysyl amine;-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethylamino] isoleucyl-amine;-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethylamino] histidyl-amine;-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethylamino] tyramine amide;
Claims (9)
1. the oligothiophene of general formula (I), its isomer and the salt that become with pharmaceutically acceptable bronsted lowry acids and bases bronsted lowry thereof:
Wherein :-A is-CH
2-CO-,-CH
2CH
2-CO-or-the CH=CH-CO-group;-B is 2-thienyl or phenyl, and it is replaced by the R group; Or natural or synthesizing amino acid,
It links to each other with the A group by its N-is terminal; Or A-B is-CH
2CH
2-NH-A.A.-base
Group, A.A. group wherein is natural or the synthesizing amino acid residue, this residue is through its carboxyl
End and CH
2CH
2-NH-group links to each other;-R is hydrogen or chlorine, bromine, iodine, fluorine, (C
1-C
4) alkyl, (C
1-C
4) alkylidene group-COOR ', (C
1-C
4) alkylidene group-NH
2, (C
1-C
4) alkylidene group-NR '
2Or (C
1-C
4) alkylidene group-NHCOR '
Group;-R ' is hydrogen or (C
1-C
4) alkyl.
2. the described oligothiophene of claim 1, wherein B is an amino acid.
3. the described oligothiophene of claim 2, wherein A-B is suc as formula-CH
2CH
2Group shown in the-NH-A.A.-.
4. the described oligothiophene of claim 1-3, wherein said amino acid is tryptophane (triptophane).
5. the described oligothiophene of claim 1, wherein B is the 2-thienyl.
6. the described oligothiophene of claim 1, it is selected from:
-N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] tryptophane;
-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] propionyl] thiophene;
-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] acryl] thiophene;
-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] propionyl]-the 4-fluorobenzene;
-N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] glycine;
-N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] L-Ala;
-N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] phenylalanine;
-N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] tyrosine;
-N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] leucine;
-N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] Methionin;
-N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] Serine;
-N-[2-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] ethanoyl] Isoleucine;
-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] propionyl]-the 4-fluorobenzene;
-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] propionyl]-the 4-chlorinated benzene;
-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] propionyl]-the 2-bromobenzene;
-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] propionyl]-4-(carboxymethyl) benzene;
-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] propionyl]-4-(amino methyl) benzene;
-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] propionyl]-3-(dimethylaminomethyl) benzene;
-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] propionyl]-2-(tertiary butyl) benzene;
-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] acryl]-the 4-fluorobenzene;
-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] acryl]-the 4-chlorinated benzene;
-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] acryl]-the 2-bromobenzene;
-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] acryl]-4-(carboxymethyl) benzene;
-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] acryl]-4-(amino methyl) benzene;
-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] acryl]-3-(dimethylaminomethyl) benzene;
-2-[3-[2-((2,2 '-two thiophene-5 '-yl) carbonyl) thiophene-5-yl] acryl]-2-(tertiary butyl) benzene;
7. pharmaceutical composition wherein contains one or more pharmaceutically acceptable vehicle (eccipient) as described compound of claim 1-6 and fusion of pharmacy effective dose.
8. the described compound of claim 1-6 has application in the antitumor and antimetastatic activity medicine in preparation.
9. the described compound of claim 1-6 is as the inhibitor of the uPA of binding specificity uPAR acceptor.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP97113191 | 1997-07-31 | ||
| EP97113191.7 | 1997-07-31 |
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| JP (1) | JP2001512116A (en) |
| KR (1) | KR20010022500A (en) |
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| AR (1) | AR020308A1 (en) |
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| WO2003051347A1 (en) * | 2001-12-19 | 2003-06-26 | Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw | Use of urokinase receptor antagonists to modulate ischemiareperfusion injury |
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1998
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| AU8807998A (en) | 1999-02-22 |
| JP2001512116A (en) | 2001-08-21 |
| WO1999006393A1 (en) | 1999-02-11 |
| KR20010022500A (en) | 2001-03-15 |
| AR020308A1 (en) | 2002-05-08 |
| HRP980420A2 (en) | 1999-04-30 |
| EP1000054A1 (en) | 2000-05-17 |
| ZA986800B (en) | 2000-01-31 |
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| AU738104B2 (en) | 2001-09-06 |
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