CN102796091A - Substituted oxazolidinone compound and preparation method and application thereof - Google Patents
Substituted oxazolidinone compound and preparation method and application thereof Download PDFInfo
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- CN102796091A CN102796091A CN2011101355820A CN201110135582A CN102796091A CN 102796091 A CN102796091 A CN 102796091A CN 2011101355820 A CN2011101355820 A CN 2011101355820A CN 201110135582 A CN201110135582 A CN 201110135582A CN 102796091 A CN102796091 A CN 102796091A
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- GFNKTLQTQSALEJ-UHFFFAOYSA-N [O-][N+](c(cc1)ccc1N=C=O)=O Chemical compound [O-][N+](c(cc1)ccc1N=C=O)=O GFNKTLQTQSALEJ-UHFFFAOYSA-N 0.000 description 2
- 0 *c1ccc(C(NCC(CN2c(cc3)ccc3NC(N(*)*)=O)OC2=O)=O)[s]1 Chemical compound *c1ccc(C(NCC(CN2c(cc3)ccc3NC(N(*)*)=O)OC2=O)=O)[s]1 0.000 description 1
- LZNKQSRPAOVLNN-KRWDZBQOSA-N CCCN(CCC)C(Nc(cc1)ccc1N(C[C@H](CNC(c([s]1)ccc1Cl)=O)O1)C1=O)=O Chemical compound CCCN(CCC)C(Nc(cc1)ccc1N(C[C@H](CNC(c([s]1)ccc1Cl)=O)O1)C1=O)=O LZNKQSRPAOVLNN-KRWDZBQOSA-N 0.000 description 1
- FLJNNLIBQGOTOU-AWEZNQCLSA-N CCCNC(Nc(cc1)ccc1N(C[C@H](CNC(c([s]1)ccc1Cl)=O)O1)C1=O)=O Chemical compound CCCNC(Nc(cc1)ccc1N(C[C@H](CNC(c([s]1)ccc1Cl)=O)O1)C1=O)=O FLJNNLIBQGOTOU-AWEZNQCLSA-N 0.000 description 1
- XLVJOFHBTOKDPV-QGZVFWFLSA-N CCN(CC)C(Nc(cc1)ccc1N(C[C@H](CN(C(c1c2cccc1)=O)C2=O)O1)C1=O)=O Chemical compound CCN(CC)C(Nc(cc1)ccc1N(C[C@H](CN(C(c1c2cccc1)=O)C2=O)O1)C1=O)=O XLVJOFHBTOKDPV-QGZVFWFLSA-N 0.000 description 1
- NTMYIEAYSUBGRE-ZDUSSCGKSA-N CCN(CC)C(Nc(cc1)ccc1N(C[C@H](CN)O1)C1=O)=O Chemical compound CCN(CC)C(Nc(cc1)ccc1N(C[C@H](CN)O1)C1=O)=O NTMYIEAYSUBGRE-ZDUSSCGKSA-N 0.000 description 1
- INAOWOSITURWKE-UHFFFAOYSA-N CCN(CC)C(Nc(cc1)ccc1[N+]([O-])=O)=O Chemical compound CCN(CC)C(Nc(cc1)ccc1[N+]([O-])=O)=O INAOWOSITURWKE-UHFFFAOYSA-N 0.000 description 1
- TYMLOMAKGOJONV-UHFFFAOYSA-N Nc(cc1)ccc1[N+]([O-])=O Chemical compound Nc(cc1)ccc1[N+]([O-])=O TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a substituted oxazolidinone compound and a preparation method and application thereof, and belongs to the field of medicinal chemistry. Particularly, the invention relates to the substituted oxazolidinone compound shown as a general formula I, wherein R1 expresses chlorine, bromine, methyl or trifluoromethyl; and R2 and R3 respectively express hydrogen or C1-10 alkyl. The compound or a medicinal salt thereof is used as a direct Xa factor inhibitor, used as an antithrombotic agent and used for treating cardiovascnlar and cerebrovascular diseases and thromboembolism disease.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to Qu Dai De oxazolidone compound, and their preparation method and as the purposes of pharmaceutical preparations having antithrombotic activity.
Background technology
Thrombus is meant blood ingredient in the blood flow process, at a kind of half grumeleuse shape material of blood vessel or the formation of cardiac intima surface.Thrombosis and cardiovascular disorder are closely related, are to threaten one of healthy important diseases of the elderly.According to position, reason, structure and the character of its formation, can it be divided into white thrombus, red thrombus and mixed thrombus etc.Impel thrombotic factor a lot, mainly contain the unusual and abnormal hemodynamics of blood vessel endothelium injury, inside and outside blood coagulation system etc.
Along with further illustrating of thrombosis mechanism, to thrombotic characteristics and reason, researched and developed a lot of antithrombotic new drugs, the medicine of existing inhibition thrombosis (anticoagulation) and anticoagulant has thrombolytic medicine again.The former mainly is to the formation of thrombus and increases inhibitedly that the latter is dissolved established thrombus, thereby eliminates the harm that thrombotic diseases causes the mankind.
(FXa inhibitor, FXaI), Xa factor is the thrombin that a kind of formation to zymoplasm has vital role to the Xa factor suppressor factor.The alternative Xa factor that suppresses of FXaI prolongs the clotting time, reduces zymoplasm and generates and reach anti thrombotic action.Interaction between FXaI and common drug and food is very little, need not to adjust dosage and medication monitoring.The Xa factor suppressor factor that acts on Xa factor can be divided into indirect Xa factor suppressor factor and direct Xa factor suppressor factor.
Along with the aging of population, the increase of cardiovascular disease incidence rate, estimate that the market structure of anticoagulant will change, warfarin and the heparin of monopolization over half a century will be substituted by direct thrombin inhibitors of a new generation and Xa factor suppressor factor gradually.
Summary of the invention
The present invention utilizes area of computer aided medicinal design means such as Pharmacophore Model to set up the structure activity relationship model and the medicaments sifting model of Qu Dai De oxazolidone compound, has designed the Qu Dai De oxazolidone compound of a series of brand news on this basis.
Qu Dai De oxazolidone compound of the present invention is as direct Xa factor suppressor factor, and it has the selectivity of height to Xa factor, except that the Xa factor that can suppress to be unbound state, also can suppress the Xa factor of bonding state, and platelet aggregation is not directly acted on.The compounds of this invention has the bioavailability height, and the treatment spectrum of disease is wide, and dose-effect relationship is stable, and the anti-freezing effect is measurable, need not to monitor anticoagulating active, and is little with food and drug interaction, clinical characteristics such as easy to use.The pharmacology pharmacodynamic test shows that The compounds of this invention both can prevent and treat phlebothrombosis, can prevent and treat arterial thrombus again.Qu Dai De oxazolidone compound or pharmaceutically acceptable salt thereof of the present invention as pharmaceutical preparations having antithrombotic activity, is used to treat cardiovascular and cerebrovascular diseases and thromboembolism class diseases such as disseminated inravascular coagulation, pulmonary infarction, thromboembolism, cardiovascular diseases, venous thrombosis, heart trouble, cerebrovascular local asphyxia.
Qu Dai De oxazolidone compound of the present invention has as shown in the formula the structure shown in the I:
Formula I
Wherein, R
1Expression chlorine, bromine, methyl or trifluoromethyl; R
2And R
3Represent hydrogen or C1-10 alkyl independently of one another.
Further preferred on the basis of formula I, the oxazolidone compound of getting generation according to the invention is the compound as shown in the formula the II structure:
Formula II
Wherein, R
1Expression chlorine, bromine, methyl or trifluoromethyl; R
2And R
3Represent hydrogen or C1-10 alkyl independently of one another.
Further, among above-mentioned formula I and the formula II, R
1Be preferably chlorine.
Further, among above-mentioned formula I and the formula II, R
2And R
3Be preferably hydrogen or C1-6 alkyl independently of one another; More preferably, R
2And R
3Identical, and be the C1-6 alkyl; Most preferably be R
2And R
3Identical, and be the C1-4 alkyl.
The present invention is through the structure activity study to lead compound; Introduce new substituting group or functional group to bioactive molecule, synthesized a hundreds of new compound, and then according to " bioactive mensuration " test design; To the capable preliminary screening of all new compounds; According to the result of primary dcreening operation, carry out composition optimizes again, the new compound that primary dcreening operation is obtained is capable to be sieved again.Estimate with the whole animal model, carry out pharmacology, pharmacodynamics, toxicologic study, finally confirmed disclosed compound among the present invention.
Concrete, the compound of general formula of the present invention includes but not limited to following several kinds of Qu Dai De oxazolidone compounds:
(S)-5-chloro-N-(3-(4-(3, the 3-diethyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives, i.e. R among the formula I
1Be Cl, R
2Be ethyl, R
3Be ethyl;
(S)-5-chloro-N-(3-(4-(3, the 3-dimethyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives, i.e. R among the formula I
1Be Cl, R
2Be methyl, R
3Be methyl;
(S)-5-chloro-N-(3-(4-(3,3-dipropyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives, i.e. R among the formula I
1Be Cl, R
2Be propyl group, R
3Be propyl group;
(S)-5-chloro-N-(3-(4-(3,3-dibutyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives, i.e. R among the formula I
1Be Cl, R
2Be butyl, R
3Be butyl;
(S)-5-chloro-N-(3-(4-(3,3-diamyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives, i.e. R among the formula I
1Be Cl, R
2Be amyl group, R
3Be amyl group;
(S)-5-chloro-N-(3-(4-(3,3-dihexyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives, i.e. R among the formula I
1Be Cl, R
2Be hexyl, R
3Be hexyl;
(S)-5-chloro-N-(3-(4-(3-methyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives, i.e. R among the formula I
1Be Cl, R
2Be hydrogen, R
3Be methyl;
(S)-5-chloro-N-(3-(4-(3-ethyl carbamide) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives, i.e. R among the formula I
1Be Cl, R
2Be hydrogen, R
3Be ethyl;
(S)-5-chloro-N-(3-(4-(3-propyl group urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives, i.e. R among the formula I
1Be Cl, R
2Be hydrogen, R
3Be propyl group;
(S)-5-chloro-N-(3-(4-(3-N-Butylurea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives, i.e. R among the formula I
1Be Cl, R
2Be hydrogen, R
3Be butyl;
(S)-5-chloro-N-(3-(4-(3-amyl group urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives, i.e. R among the formula I
1Be Cl, R
2Be hydrogen, R
3Be amyl group;
(S)-5-chloro-N-(3-(4-(3-hexyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives, i.e. R among the formula I
1Be Cl, R
2Be hydrogen, R
3Be hexyl.
Preferred especially compound of the present invention is:
Formula III
According to the IUPAC nomenclature, above-mentioned preferred especially formula III compound called after of the present invention: (S)-5-chloro-N-(3-(4-(3, the 3-diethyl urea) phenyl-2-oxo oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives.
The invention still further relates to the pharmaceutical salts (pharmacy acceptable salt) of formula I compound, include but not limited to the acid salt that formula I compound and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, Hydrocerol A, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetate, toxilic acid or phenylformic acid.
Formula I compound of the present invention can obtain through following preparation method: at first be p-Nitroaniline and TRIPHOSGENE 99.5 (triphosgene) prepared in reaction isocyanic ester, and isocyanic ester and amine NHR
2R
3Generate the nitrophenyl urea, the catalytic reduction nitro obtains the aminophenyl urea; The aminophenyl urea carries out ring-opening reaction with the epoxy construction that has a phthalic imidine, and title product that obtains and carbonyl dimidazoles (CDI) carry out cyclization, and hydrazinolysis falls phthalimide-based and obtains primary amine then; Primary amine and 5-position R
1Substituted thenoic acid reaction obtains the final objective compound.Reaction process is as follows:
In the above-mentioned reaction process, the said epoxy construction that has phthalic imidine can be an optical purity or mesomeric, and the corresponding synthetic formula I of institute compound is optical purity or racemization.
The compound method of enantiomorph and non-enantiomer mixture is that those skilled in the art are familiar with.The present invention includes any formula I compound antithrombotic acitivity, isolating racemization or optical activity form that has.
The present invention also comprises the pharmaceutical composition that comprises the carrier of approving on formula I compound and the physiology.The compounds of this invention can be through injection, suction or sprinkling or rectal administration, and per os, skin, parenteral give, or gives with the unit formulation formulation." injection gives " comprises vein, intramuscular, subcutaneous and parenteral injection, and uses infusion techn.Percutaneous drug delivery comprises external application or transdermal administration.One or more compounds can with one or more non-toxic carriers of pharmaceutically approving, and other activeconstituentss that depend on the needs coexistence.Oral compsns can be made the known appropriate method preparation in field according to any pharmaceutical composition.In order to improve the preparation mouthfeel, said compsn can contain one or more following reagent: thinner, sweeting agent, spices, tinting material and sanitas.Tablet contains activeconstituents, and they mix with the non-toxic excipients of pharmaceutically approving, be fit to tablet manufacturing.Said vehicle is inert diluent for example, for example lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example W-Gum or alginic acid; Tackiness agent, for example Magnesium Stearate, Triple Pressed Stearic Acid or talcum powder.Tablet can not have dressing, can wrap up with known technology yet, to postpone its disintegration and absorption in gi tract, secular continuous action is provided.For example, can adopt time-delay material such as glyceryl monostearate or distearin.Said compound also can be processed the form of releasing soon.Oral prepns can also be a hard gelatin capsule; Activeconstituents wherein mixes with for example inert solid diluent such as lime carbonate, calcium phosphate or kaolin mutually; Or soft gelatin capsule, activeconstituents wherein is with water or for example peanut oil, whiteruss or olive wet goods oil mix.
Said pharmaceutical composition also can use and contain active substance and the suitable waterborne suspension of making the mixed with excipients of waterborne suspension.Said vehicle is a suspension agent, for example Xylo-Mucine, methylcellulose gum, hydroxypropyl-methylcellulose gum, sodiun alginate, PVP K120, tragcanth and Sudan Gum-arabic; Dispersion agent or wetting agent can be natural phospholipids; The condensation product of for example Yelkin TTS, or oxyethane and lipid acid, for example polyoxyethylene stearic acid ester; Or the condensation product of oxyethane and long chain aliphatic alcohol; For example 17 oxygen ethene cetyl alcohols, or oxyethane and the condensation product of lipid acid with partial ester that hexitol becomes, for example single oleic acid polyoxyethylene sorbitan ester.Waterborne suspension also can contain one or more sanitass, for example ethylparaben or n-propyl, one or more tinting materials, one or more spices and one or more sweeting agents, for example sucrose or asccharin.Become in the dispersed powders or particle of waterborne suspension but be fit to add water, activeconstituents and dispersion agent or wetting agent, suspension agent mixes with one or more sanitass.Suitable dispersion agent or wetting agent and suspension agent can mentioned abovely be example.Can also contain other vehicle, for example sweeting agent, spices and tinting material.
The form of pharmaceutical composition of the present invention can also be non-aqueous liquid preparation, oily suspensions for example, and this can be through being suspended in activeconstituents peanut oil, sweet oil, til or peanut wet goods vegetables oil or such as preparing in the MO such as whiteruss.This oily suspensions can contain thickening material, for example beeswax, paraffinum durum or Tego Alkanol 16.In order to improve mouthfeel, can add above-mentioned sweeting agent and spices.Said compsn can be guaranteed the quality such as inhibitors such as xitix through adding.
The form of pharmaceutical composition of the present invention can also be an O/w emulsion.Oil phase can be such as sweet oil or peanut wet goods vegetables oil or MO such as liquid beeswax for example, or their mixture.Suitable emulsifying agent can be natural gums such as tragcanth and Sudan Gum-arabic, or natural phospholipid, for example soybean lecithin or Yelkin TTS: the partial ester that lipid acid and dewatering hexitol form, for example but oleic acid anhydro sorbitol vinegar; The condensation product of said partial ester and oxyethane, for example single oleic acid Sorbitan ethoxylate.Said emulsion also can contain sweeting agent and spices.
Sweeting agent obtain syrup agent such as the also available for example glycerine of The compounds of this invention, W 166, sorbyl alcohol or sucrose.This type preparation also can contain demulcen, sanitas and spices and tinting material.
Said compound can also suppository form be used for rectum or vagina administration.This based composition can be solid-state under the said vehicle normal temperature through medicine and suitable non-stimulated mixed with excipients are prepared, but is liquid in rectal temperature or vagina temperature, and therefore, its can melt and discharge medicine at rectum or intravaginal.Such material comprises theobroma oil and polyoxyethylene glycol.
In specification sheets of the present invention and claim, the name of compound all is according to chemical structural formula, if the name and the chemical structural formula of compound is not inconsistent when representing same compound, is as the criterion with chemical structural formula.
Combine embodiment at present, the present invention further described:
Embodiment
Embodiment 1: (S)-and 5-chloro-N-(3-(4-(3, the 3-diethyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives (formula III compound)
1a:1,2-epoxy group(ing)-3-phthalimide-based propane synthetic
With phthalic imidine (compound 1, phthalimide) 2.94g (0.02mol) is fed in the 250mL there-necked flask, adds 45mL anhydrous tetrahydro furan (THF), stirs, and can not all dissolve, under the nitrogen protection, lucifuge adds triphenyl phosphorus (Ph
3P) behind 5.24g (0.02mol), (S)-Racemic glycidol (compound 2) 1.7g (0.023mol), drip diethyl azodiformate (DEAD) 3.48g (0.02mol), exothermic heat of reaction is lowered the temperature with ice-water bath; After dripping, remove ice-water bath, the stirring at room reaction is spent the night, and revolves dried solvents tetrahydrofurane; Get yellow solid, add the 30mL ether, stirring at room 1-2h, suction filtration; To filtrate concentrates, and gets 2.72g white solid (compound 3) behind the gained bullion column chromatography purification, and yield is 67%.
1HNMR(300MHz，CDCl
3)：δ7.87(m，2H)，7.75(m，3H)，3.98(dd，J＝5.1，14.1Hz，1H)，3.83(d，J＝4.8，14.4Hz，1H)，3.26(m，1H)，2.83(dd，J＝4.5，4.5Hz，1H)，2.70(dd，J＝2.4，4.8Hz，1H).MS(ESI+)：m/z?204.1[M+H]
+，226.0[M+Na]
+
Synthesizing of 1b:4-nitrophenyl isocyanic ester:
1g (7.24mmol) 4-N-methyl-p-nitroaniline is dissolved in the 30mL ETHYLE ACETATE, 1.06g (3.61mmol) TRIPHOSGENE 99.5 is dissolved in the 30mL ETHYLE ACETATE (EA), the ethyl acetate solution with TRIPHOSGENE 99.5 under the room temperature splashes into reaction system; 15min drips complete, has a large amount of white solids to separate out, and again reaction system slowly is warming up to 70 ℃ and insulation reaction 5.5h; TLC detects demonstration and reacts completely; System is reduced to room temperature, solvent is revolved dried back take unreacted TRIPHOSGENE 99.5 out of with ETHYLE ACETATE, 3 times (50mL/ time); Get bullion 1.5g, directly be used for step reaction down.
1c:1,1-diethylammonium-3-(4-nitrophenyl) urea synthetic:
The ice-water bath temperature control is with diethylamine (Et
2NH) 70mL (0.67mol) is a solvent, adds 12g (0.073mol) 4-nitrophenyl isocyanic ester to system in batches, again system is returned back to stirring at room 2h, and suction filtration gets solid 16.43g (94.8%).
1H?NMR(300MHz，CDCl
3)：δ8.16(dd，J＝2.1，6.9Hz，2H)，7.56(dd，J＝2.1，6.9Hz，2H)，6.65(s，1H)，3.40(q，J＝7.2Hz，4H)，1.25(t，J＝7.2Hz，6H).MS(ESI+)：m/z238.26[M+H]
+
1d:3-(4-aminophenyl)-1,1-diethyl urea synthetic:
With 3.5g (14.7mmol) 1,1-diethylammonium-3-(4-nitrophenyl) urea joins in the 120mL ETHYLE ACETATE (EA), and incomplete dissolving is turbid solution; Add 0.5g 5% palladium carbon again, use the reduction of hydrogenation appearance catalytic hydrogenation, 0.04MPa (hydrogen exchange three times); The TLC monitoring reaction is complete behind the 3h; Through the zeyssatite suction filtration, filter cake uses ETHYLE ACETATE to give a baby a bath on the third day after its birth time (50mL/ time) with system, and mother liquor revolves dried sorrel oily matter 2.36g (77.1%).
1H?NMR(300MHz，CDCl
3)：δ7.16(d，J＝8.4Hz，2H)，6.66(d，J＝8.4Hz，2H)，6.09(s，1H)，3.58(br?s，2H)，3.37(q，J＝7.2Hz，4H)，1.23(t，J＝7.2Hz，6H).MS(ESI+)：m/z?208.14([M+H]
+)
1e: (R)-3-(4-(3-phthalimide-based-2-hydroxyl third amino) phenyl)-1,1-diethyl urea synthetic:
With 700mg (3.38mmol) 3-(4-aminophenyl)-1; The 1-diethyl urea adds in the 10mL methyl alcohol, adds 1.03g (5.07mmol) 1 again, 2-epoxy group(ing)-3-phthalimide-based propane; Be warming up to 50 ℃; The TLC monitoring reaction is complete behind the 20h, system is revolved dried, and thick product column chromatography purification gets 240mg (17.3%) light yellow solid.
1H?NMR(300MHz，DMSO-d
6)：δ7.84(m，4H)，7.72(s，1H)，7.09(d，J＝8.4Hz，2H)，6.51(d，J＝8.7Hz，2H)，5.09(m，2H)，4.00(m，1H)，3.59(m，2H)，3.29(q，J＝6.9Hz，4H)，3.11(m，1H)，2.97(m，1H)，1.06(t，J＝6.9Hz，6H).MS(ESI+)：m/z?411.47[M+H]
+
1f: (S)-3-(4-(5-(phthalimide-based) methyl-2-Yang Dai oxazolidine-3-yl) phenyl)-1,1-diethyl urea synthetic:
With 35.8mg (0.087mmol) (R)-3-(4-(3-phthalimide-based-2-hydroxyl third amino) phenyl)-1, the 1-diethyl urea is dissolved in the 5mL THF, adds 28.3mg (0.175mmol) N under the nitrogen protection; N '-carbonyl dimidazoles (CDI); Add 2mg (0.016mmol) 4-Dimethylamino pyridine (DMAP) again, slowly be warming up to backflow, the TLC monitoring reaction is complete behind the insulation 18h; System is revolved dried, thick product column chromatography purification gets 24mg (63%) off-white color solid.
1H?NMR(300MHz，CDCl
3)：δ7.90(dd，J＝2.2，5.4Hz，2H)，7.76(dd，J＝2.2，5.4Hz，2H)，7.41(m，4H)，6.30(s，1H)，4.98(m，1H)，4.16(dd，J＝6.6，14.1Hz，1H)，4.11(dd，J＝8.7，10.8Hz，1H)，3.97(dd，J＝6.0，14.1Hz，1H)，3.88(dd，J＝6.0，9.0Hz，1H)，3.39(q，J＝7.2Hz，4H)，1.24(t，J＝7.2Hz，6H).MS(ESI+)：m/z?437.46[M+H]
+
1g: (S)-3-(4-(5-(amino) methyl-2-Yang Dai oxazolidine-3-yl) phenyl)-1,1-diethyl urea synthetic:
With 507mg (1.16mmol) (S)-3-(4-(5-(phthalimide-based) methyl-2-Yang Dai oxazolidine-3-yl) phenyl)-1; The 1-diethyl urea is dissolved in the 10mL ethanol; Add 116mg (2.32mmol) Hydrazine Hydrate 80 under the nitrogen protection; The TLC monitoring reaction is complete after stirring 5h under the room temperature, system is revolved dried, and thick product column chromatography purification gets 122mg (33.8%) white solid.
1H?NMR(300MHz，CDCl
3)：δ7.40(m，4H)，6.39(s，1H)，4.64(m，1H)，4.16(dd，J＝6.6，14.1Hz，1H)，4.09(dd，J＝8.7，10.8Hz，1H)，4.09(m，1H)，4.01(dd，J＝8.7，8.7Hz，1H)，3.78(dd，J＝6.9，8.7Hz，1H)，3.35(q，J＝7.2Hz，4H)，3.07(dd，J＝4.2，13.8Hz，1H)，2.96(dd，J＝6.0，13.8Hz，1H)，2.54(br?s，2H)，1.22(t，J＝7.2Hz，6H).MS(ESI+)：m/z?307.36[M+H]
+
1h: (S)-5-chloro-N-(3-(4-(3, the 3-diethyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives synthetic:
With 400mg (1.307mmol) (S)-3-(4-(5-(amino) methyl-2-Yang Dai oxazolidine-3-yl) phenyl)-1, the 1-diethyl urea is dissolved among the 8mLDMF (N, dinethylformamide); Add the acid of 211.7mg (1.307mmol) 5-chlorothiophene, 229mg (1.699mmol) HOBT, 325.7mg (1.699mmol) 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDCI) to system successively; 337.8mg (2.614mmol) DIEA (N, N-diisopropylethylamine), stir 5h under the room temperature after TLC (EA: Pe=2: 1) monitoring reaction is complete; Add 50mL methylene dichloride and 50mL tap water to reaction system, behind the separatory water with 100mL ethyl acetate extraction twice, the combined ethyl acetate layer; Wash twice (100mL/ time); Wash once (100mL/ time) with saturated common salt again, anhydrous sodium sulfate drying filters; Concentrate, get 310mg (52.7%) white solid behind the gained bullion column chromatography purification.
1H NMR (300MHz, CDCl
3): δ 7.34 (m, 5H), 6.97 (t, J=6.3Hz, 1H), 6.86 (d, J=3.9Hz, 1H); 6.36 (s, 1H), 4.79 (m, 1H), 4.00 (m, 1H), 3.76 (m, 2H); 3.66 (m, 1H), 3.37 (q, J=7.2Hz, 4H), 1.23 (t, J=7.2Hz, 6H) .MS (ESI+): m/z 451.94 [M+H]
+
Embodiment 2: (S)-and 5-chloro-N-(3-(4-(3, the 3-dimethyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives
The preparation method is with embodiment 1, and wherein the diethylamine among the step 1c replaces with n n dimetylaniline.
1H?NMR(300MHz，CDCl
3)：δ7.34(m，5H)，6.97(t，J＝6.3Hz，1H)，6.86(d，J＝3.9Hz，1H)，6.36(s，1H)，4.79(m，1H)，4.00(m，1H)，3.76(m，2H)，3.66(m，1H)，3.31(s，6H).MS(ESI+)：m/z?423.1[M+H]
+
Embodiment 3: (S)-and 5-chloro-N-(3-(4-(3,3-dipropyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives
The preparation method is with embodiment 1, and wherein the diethylamine among the step 1c replaces with dipropyl amine.
1H?NMR(300MHz，CDCl
3)：δ7.34(m，5H)，6.97(t，J＝6.3Hz，1H)，6.86(d，J＝3.9Hz，1H)，6.36(s，1H)，4.79(m，1H)，4.00(m，1H)，3.76(m，2H)，3.66(m，1H)，3.31(t，J＝7.2Hz，4H)，1.50-1.42(m，4H)，1.21(t，J＝7.2Hz，6H).MS(ESI+)：m/z?479.1[M+H]
+
Embodiment 4: (S)-and 5-chloro-N-(3-(4-(3,3-dibutyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives
The preparation method is with embodiment 1, and wherein the diethylamine among the step 1c replaces with dibutylamine.
1H?NMR(300MHz，CDCl
3)：δ7.34(m，5H)，6.97(t，J＝6.3Hz，1H)，6.86(d，J＝3.9Hz，1H)，6.36(s，1H)，4.79(m，1H)，4.00(m，1H)，3.76(m，2H)，3.66(m，1H)，3.37(q，J＝7.2Hz，4H)，1.50-1.37(m，8H)，1.21(t，J＝7.2Hz，6H).MS(ESI+)：m/z507.2[M+H]
+
Embodiment 5: (S)-and 5-chloro-N-(3-(4-(3,3-diamyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives
The preparation method is with embodiment 1, and wherein the diethylamine among the step 1c replaces with diamylamine.
1H?NMR(300MHz，CDCl
3)：δ7.34(m，5H)，6.97(t，J＝6.3Hz，1H)，6.86(d，J＝3.9Hz，1H)，6.36(s，1H)，4.79(m，1H)，4.00(m，1H)，3.76(m，2H)，3.66(m，1H)，3.37(q，J＝7.2Hz，4H)，1.50-1.37(m，12H)，1.21(t，J＝7.2Hz，6H).MS(ESI+)：m/z534.2[M+H]
+
Embodiment 6: (S)-and 5-chloro-N-(3-(4-(3,3-dihexyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives
The preparation method is with embodiment 1, and wherein the diethylamine among the step 1c replaces with dihexylamine.
1H?NMR(300MHz，CDCl
3)：δ7.34(m，5H)，6.97(t，J＝6.3Hz，1H)，6.86(d，J＝3.9Hz，1H)，6.36(s，1H)，4.79(m，1H)，4.00(m，1H)，3.76(m，2H)，3.66(m，1H)，3.37(q，J＝7.2Hz，4H)，1.50-1.27(m，16H)，1.21(t，J＝7.2Hz，6H).MS(ESI+)：m/z562.2[M+H]
+
Embodiment 7: (S)-and 5-chloro-N-(3-(4-(3-methyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives
The preparation method is with embodiment 1, and wherein the diethylamine among the step 1c replaces with methylamine.
1H?NMR(300MHz，CDCl
3)：δ7.34(m，5H)，6.97(t，J＝6.3Hz，1H)，6.86(d，J＝3.9Hz，1H)，6.36(s，1H)，5.98(s，1H)，4.79(m，1H)，4.00(m，1H)，3.76(m，2H)，3.66(m，1H)，3.31(s，3H).MS(ESI+)：m/z?409.1[M+H]
+
Embodiment 8: (S)-and 5-chloro-N-(3-(4-(3-ethyl carbamide) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives
The preparation method is with embodiment 1, and wherein the diethylamine among the step 1c replaces with ethamine.
1H?NMR(300MHz，CDCl
3)：δ7.34(m，5H)，6.97(t，J＝6.3Hz，1H)，6.86(d，J＝3.9Hz，1H)，6.36(s，1H)，5.98(s，1H)，4.79(m，1H)，4.00(m，1H)，3.76(m，2H)，3.66(m，1H)，3.37(q，J＝7.2Hz，2H)，1.23(t，J＝7.2Hz，3H).MS(ESI+)：m/z：423.1[M+H]
+
Embodiment 9: (S)-and 5-chloro-N-(3-(4-(3-propyl group urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives
The preparation method is with embodiment 1, and wherein the diethylamine among the step 1c replaces with propylamine.
1H?NMR(300MHz，CDCl
3)：δ7.34(m，5H)，6.97(t，J＝6.3Hz，1H)，6.86(d，J＝3.9Hz，1H)，6.36(s，1H)，5.98(s，1H)，4.79(m，1H)，4.00(m，1H)，3.76(m，2H)，3.66(m，1H)，3.31(t，J＝7.2Hz，2H)，1.50-1.42(m，2H)，1.21(t，J＝7.2Hz，3H).MS(ESI+)：m/z?437.1[M+H]
+
Embodiment 10: (S)-and 5-chloro-N-(3-(4-(3-N-Butylurea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives
The preparation method is with embodiment 1, and wherein the diethylamine among the step 1c replaces with butylamine.
1H?NMR(300MHz，CDCl
3)：δ7.34(m，5H)，6.97(t，J＝6.3Hz，1H)，6.86(d，J＝3.9Hz，1H)，6.36(s，1H)，5.98(s，1H)，4.79(m，1H)，4.00(m，1H)，3.76(m，2H)，3.66(m，1H)，3.37(q，J＝7.2Hz，2H)，1.50-1.37(m，4H)，1.21(t，J＝7.2Hz，3H).MS(ESI+)：m/z?451.1[M+H]
+
Embodiment 11: (S)-and 5-chloro-N-(3-(4-(3-amyl group urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives
The preparation method is with embodiment 1, and wherein the diethylamine among the step 1c replaces with amylamine.
1H?NMR(300MHz，CDCl
3)：δ7.34(m，5H)，6.97(t，J＝6.3Hz，1H)，6.86(d，J＝3.9Hz，1H)，6.36(s，1H)，5.98(s，1H)，4.79(m，1H)，4.00(m，1H)，3.76(m，2H)，3.66(m，1H)，3.37(q，J＝7.2Hz，4H)，1.50-1.37(m，6H)，1.21(t，J＝7.2Hz，6H).MS(ESI+)：m/z?465.1[M+H]
+
Embodiment 12: (S)-and 5-chloro-N-(3-(4-(3-hexyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives
The preparation method is with embodiment 1, and wherein the diethylamine among the step 1c replaces with hexylamine.
1H?NMR(300MHz，CDCl
3)：δ7.34(m，5H)，6.97(t，J＝6.3Hz，1H)，6.86(d，J＝3.9Hz，1H)，6.36(s，1H)，5.98(s，1H)，4.79(m，1H)，4.00(m，1H)，3.76(m，2H)，3.66(m，1H)，3.37(q，J＝7.2Hz，4H)，1.50-1.37(m，8H)，1.21(t，J＝7.2Hz，6H).MS(ESI+)：m/z?465.1[M+H]
+
Experimental example 13: The compounds of this invention and the sharp mensuration contrast of cutting down the husky IC50 of class
Compound, the profit of experimental drug: embodiment of the invention 1-12 preparation cut down husky class, FXa (thrombin)
Experimental procedure:
1. doubling dilution The compounds of this invention and profit are cut down husky class, obtain the test sample of series concentration respectively.
2. active detection the: the FXa (thrombin) and 10 μ l solvent (DMSO) or the dilute samples that add 145 μ l in 96 orifice plates respectively; The FXa substrate that adds 145 μ l then; 25 ℃ of incubation 10min of mixing; In the OD value that 405nm measures 0min and 10min respectively, use computes inhibiting rate: I%=(Δ OD with ELIASA
Lyase-Δ OD
Sample) * 100%/Δ OD
LyaseThe final concentration of FXa is 1nmol/L.The final concentration of chromophoric substrate is 200 μ mol/L.
Experimental result is seen table 1 and table 2:
Table 1. profit is cut down the restraining effect of husky class
The restraining effect of table 2. The compounds of this invention
Experiment conclusion:
The compounds of this invention has very high inhibition activity for thrombin FXa, is superior to the reference substance profit and cuts down husky class, shows that The compounds of this invention has very strong antithrombotic acitivity.
Claims (11)
1. compound or pharmaceutically acceptable salt thereof shown in the formula I:
Formula I
Wherein, R
1Expression chlorine, bromine, methyl or trifluoromethyl; R
2And R
3Represent hydrogen or C1-10 alkyl independently of one another.
2. compound or pharmaceutically acceptable salt thereof as claimed in claim 1 is characterized in that, said is optically active, has the structure shown in the formula II:
Formula II
Wherein, R
1, R
2And R
3Such as claim 1 definition.
3. according to claim 1 or claim 2 compound or pharmaceutically acceptable salt thereof is characterized in that R
1Be chlorine.
4. according to claim 1 or claim 2 compound or pharmaceutically acceptable salt thereof is characterized in that R
2And R
3Independent separately is hydrogen or C1-6 alkyl.
5. compound or pharmaceutically acceptable salt thereof as claimed in claim 4 is characterized in that R
2And R
3Identical, and be the C1-4 alkyl.
6. compound or pharmaceutically acceptable salt thereof as claimed in claim 2 is characterized in that, said compound is selected from one of following compounds:
(S)-5-chloro-N-(3-(4-(3, the 3-diethyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives;
(S)-5-chloro-N-(3-(4-(3, the 3-dimethyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives;
(S)-5-chloro-N-(3-(4-(3,3-dipropyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives;
(S)-5-chloro-N-(3-(4-(3,3-dibutyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives;
(S)-5-chloro-N-(3-(4-(3,3-diamyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives;
(S)-5-chloro-N-(3-(4-(3,3-dihexyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives;
(S)-5-chloro-N-(3-(4-(3-methyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives;
(S)-5-chloro-N-(3-(4-(3-ethyl carbamide) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives;
(S)-5-chloro-N-(3-(4-(3-propyl group urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives;
(S)-5-chloro-N-(3-(4-(3-N-Butylurea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives;
(S)-5-chloro-N-(3-(4-(3-amyl group urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives;
(S)-5-chloro-N-(3-(4-(3-hexyl urea) phenyl-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives.
7. compound or pharmaceutically acceptable salt thereof as claimed in claim 6 is characterized in that, said compound is a compound shown in the formula III.
Formula III
8. according to claim 1 or claim 2 compound or pharmaceutically acceptable salt thereof; It is characterized in that the pharmaceutical salts of said compound is the acid salt of formula I or formula II compound and following acid formation: hydrochloric acid, Hydrogen bromide, sulfuric acid, Hydrocerol A, tartrate, phosphoric acid, lactic acid, pyruvic acid, acetate, toxilic acid or phenylformic acid.
9. the preparation method of the said compound of claim 1, reaction process is as follows:
At first be p-Nitroaniline and TRIPHOSGENE 99.5 prepared in reaction isocyanic ester, isocyanic ester and amine NHR
2R
3Generate the nitrophenyl urea, the catalytic reduction nitro obtains the aminophenyl urea; The aminophenyl urea carries out ring-opening reaction with the epoxy construction that has a phthalic imidine, and title product that obtains and carbonyl dimidazoles carry out cyclization, and hydrazinolysis falls phthalimide-based and obtains primary amine then; Primary amine and 5-position R
1Substituted thenoic acid reaction obtains compound shown in the formula I, wherein, and R
1Expression chlorine, bromine, methyl or trifluoromethyl; R
2And R
3Represent hydrogen or C1-10 alkyl independently of one another.
10. a pharmaceutical composition contains claim 1 or 2 described compound or pharmaceutically acceptable salt thereofs as effective constituent, and contains pharmaceutical carrier.
11. claim 1 or the 2 described compound or pharmaceutically acceptable salt thereofs purposes in the preparation antithrombotic reagent.
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| CN112048049A (en) * | 2019-06-06 | 2020-12-08 | 中国科学院化学研究所 | Luminescent polymer and preparation method and application thereof |
| CN113980239A (en) * | 2021-11-09 | 2022-01-28 | 美瑞新材料股份有限公司 | Method for preparing thermoplastic polyurethane elastomer by using nitroaniline isomer mixture and product thereof |
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