CN102199150A - Optical active oxazolidinone derivatives as well as preparation methods and application to preparing medicaments - Google Patents
Optical active oxazolidinone derivatives as well as preparation methods and application to preparing medicaments Download PDFInfo
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Abstract
The invention discloses optical active oxazolidinone derivatives as well as preparation methods and application to preparing medicaments. The derivatives are compounds shown as the formula I and the formula II and comprise salts of the compounds shown as the formula I and the formula II and enantiomers and racemes of the compounds shown as the formula I and the formula II. Proved by pharmacodynamics test results, the compound in the formula I has the Xa factor inhibiting activity, therefore, the compound in the formula I in the invention can be used for preparing medicaments for preventing or treating diseases related to thrombus and embolism, in particular thrombotic diseases such as deep venous thrombosis, atrial fibrillation, acute coronary syndrome and the like. The invention also provides preparation methods of the compounds shown as the formula I and the formula II.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to optical activity De oxazolidone analog derivative and preparation method thereof and purposes in pharmacy, its She of You is Ji the purposes of oxazolidone analog derivative in preparation prevention or treatment thrombus and embolism relative disease medicine.
Background technology
The present invention relates to and oxazolidine ketone profit cut down husky class be 5-chloro-N-((5S)-2-oxo-3-[4-(3-oxo morpholine-4-yl) phenyl]-1,3-oxazolidine-5-yl } methyl) design, preparation method and the Xa factor of derivative of thiophene-2-carboxylic acid amine suppress active mensuration, they are used for the treatment of and/or prophylactic purposes and they are used to prepare the purposes of medicine, this medicine is used for the treatment of and/or preventing disease, especially thrombotic diseases such as dvt, atrial fibrillation, acute coronary artery syndrome.
(II) De oxazolidone compounds is to work as the selective depressant of factor Xa with as antithrombotics, the treatment thrombotic disease for formula (I) and formula.
Thrombotic disease is a kind of common disease, often shows as myocardial infarction, ischemia cerebral infarction, venous thromboembolism etc., and its sickness rate, disability rate and mortality ratio are very high.Annual per thousand philtrums have 1～3 people that multi-form thrombotic diseases takes place approximately, the heart, cerebrovascular thrombotic disease have become the dead head of China's population (particularly the elderly) because of (Wang Jianqing, Zhao Baoquan etc., Hebei medical science, 2007,13 (9)), and also having cumulative gesture in recent years, is one of the emphasis of contemporary medical science research and focus.
Thromboembolism can cause respective organization and (or) organ ischemic, anoxic, necrosis (arterial thrombus) and hemostasis, oedema (phlebothrombosis), be divided into arterialness thrombus, veins thrombus and capillary vessel thrombus.Phlebothrombosis comprises dvt and pulmonary infarction, dvt is mainly in lower limb, can cause pain, swelling, ulceration etc., the patient Chang Yin thrombus embolism lung that comes off causes life-threatening acute pulmonary embolism, deep venous thrombosis of lower limbs is the arch-criminal of pulmonary infarction, clinical in pulmonary infarction embolus more than 60% derive from lower-limb deep veins thrombus.Approximately have 2,000,000 Americans to suffer from dvt every year, 600,000 people suffer from pulmonary infarction, and wherein nearly 60,000 people die from pulmonary infarction.And the pulmonary infarction patient of MSDS express contract 80% does not have clinical symptom, and this brings difficulty for clinician's diagnosis and treatment work, thus the DVT of diagnosis and treatment in time, the generation of active prevention PE.The lower limb dvt is common in the adult patients of select a time hip replacement or knee replacements.
Be the formation of avoiding the vascular thrombosis embolism or the blood vessel of getting through the thrombus obturation again, the medicine that is used for thrombus treatment at present clinically mainly contains antiplatelet drug, anticoagulation medicine and thrombolysis medicine three major types.And wherein the above two mainly have restraining effect to the formation and the increase effect of thrombus, and the latter is dissolved established thrombus.In the market sale share, anticoagulant and antiplatelet drug are in the highest flight.
Proved that anticoagulant therapy is effective in the vascular disease Chinese style, in preventing and/or treating coronary artery vascular disease, peripheral vascular disease and cerebrovascular disease, in preventing and/or treating venous thrombosis and pulmonary infarction, had vital role.Anticoagulant comes antithrombotic by Trombin inhibiting and thrombin.Xa factor is positioned at the joint of endogenous and exogenous cruor pathway, and the main catalysis II factor (thrombogen) transforms to the IIa factor (zymoplasm).Owing to there is the amplification of bio signal in the coagulation process, an Xa inhibitor molecules can suppress the physiologic effect of 138 zymoplasm molecules, therefore X a factor inhibitors is than thrombin inhibitors more effective (Zhejiang Polytechnical University's journal, 2007,35 (1): 27-30).Many in addition animal blood coagulation experimental models are found, unique function of Xa factor is to promote blood coagulation and inflammation, use the Xa factor inhibitor than hemorrhage risk little (Annu.Rep Med Chem, 1997,32 of using thrombin inhibitors, 71-89), find that the Xa factor inhibitor demonstrates the effect of antithrombotic embolism in thrombotic model in the research of many animal experiments, and do not cause or (the Curr Top Med Chem 2001 that only faintly prolongs the bleeding time, 1,151-159).Therefore use the Xa factor inhibitor to need not monitoring, safer.The Xa factor inhibitor is more safer and more effective than thrombin inhibitors in a word, is optimized in the medicine of prevention and treatment thrombotic disease.
Profit is cut down the husky (Rivaroxaban of class, 1) be 5-chlorine N-((5S)-2-oxo-3-[4-(3-oxo morpholine-4-yl) phenyl]-1,3-oxazolidine-5-yl } methyl) thiophene-2-carboxylic acid amine, produce by Bayer/Johson ﹠ Johnson's research and development, be oxazolidine ketone selectivity Xa factor inhibitor.2008 in Canada and European Union's listing that gets the Green Light, went on the market in Australia in 2009, now at Chinese official listing, commodity be called visit auspicious appropriate.It is the first oral direct Xa factor inhibitor in the whole world, and Xa factor is had the selectivity of height, and its selectivity to serine protease FXa is 100000 multiples to other serine proteases (as zymoplasm, trypsinase, Taka-proteinase etc.).The Xa factor that can suppress free and bonding state is to not directly effect of hematoblastic gathering.In the clinical treatment that is used for hip replacement or knee replacements adult patients, with prevention phlebothrombosis and pulmonary infarction.
It is rapid that profit is cut down the oral post-absorption of husky class, can reach maximum peak concentration (Cmax) in 2～4 hours, and absolute bioavailability is up to 80%～100%; Its plasma concentration-time curve presents dose-dependence, and average t1/2 is 7～11 hours under the stable state; Drain with two channels, 1/3 drains in urine by kidney with prototype, and 2/3 metabolism composition is removed by kidney and ight soil approach.It treats window width, need not to carry out conventional sense after the medication, and is little with the food drug interaction.As the new active drug component of prevention and treatment thromboembolic disorders, this compound is carrying out deep clinical experiment at present.
Still need curative effect and security can both reach good equilibrated anticoagulant clinically, be surprisingly found out that now, the derivative that the oxazolidine ketone profit of formula (I) and formula (II) is cut down husky class has Xa factor inhibition activity.
Summary of the invention
Technical problem to be solved by this invention is design, synthetic novel oxazolidinone analog derivative, with exploitation good effect, the little anticoagulation medicine of side effect.
The invention discloses Guang and learn Huo oxazolidone analog derivative, it is characterized in that described derivative is represented suc as formula I and formula II compound:
R wherein
1The phenyl that replaces for straight or branched alkyl, phenyl, the Y non-replacement of hydrogen, 1～10 carbon or that X replaces; Wherein X is fluorine, chlorine, bromine, iodine, trifluoromethyl; Y is fluorine, chlorine, bromine, iodine, nitro, amino, trifluoromethyl, and Y group is in 2,3 or 4 of phenyl ring;
R
2Be straight or branched acyl group non-replacement or that X the replaces non-replacement of hydrogen, 1～10 carbon or the straight or branched alkyl that X replaces, 1～6 carbon; Wherein X is fluorine, chlorine, bromine, iodine, trifluoromethyl;
R
1With R
2Group can Cheng Huan, is the cycloalkyl group of 5-7 unit's non-replacement of cyclic or replacement;
Preferred R in formula I of the present invention and the formula II compound
1Be straight or branched alkyl, the phenyl non-replacement or that X replaces of hydrogen, 1～6 carbon, wherein X is fluorine, chlorine, bromine, iodine;
R
2Straight or branched acyl group for the non-replacement non-replacement of hydrogen, 1～6 carbon or the straight or branched alkyl that X replaces, 1～3 carbon;
R
1With R
2Group can Cheng Huan, is the cycloalkyl group of 5-6 unit's non-replacement of cyclic or replacement;
More preferably R in formula I of the present invention and the formula II compound
1Be methyl, ethyl, sec.-propyl, phenyl, trifluoromethyl; R
2Be hydrogen, methyl, ethanoyl.R
1With R
2Group can Cheng Huan, is cyclopentyl, cyclohexyl;
Preferred compound is as follows in formula I of the present invention and the formula II compound:
(S)-4-sec.-propyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides I-1
(S)-4-trifluoromethyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides I-2
(S)-4-phenyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides I-3
(S)-4-methyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-5-thiazole carboxamides II-4
(S)-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-5.6-dihydro-4H-cyclopentyl [d] thiazole-2-methane amide I-5
(S)-4-methyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides I-6
(S)-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-4,5.6,7-two tetrahydro benzos [d] thiazole-2-methane amide I-7
(S)-5-ethanoyl-4-methyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides I-8
(S)-4-ethyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides I-9
(S)-4,5-dimethyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides I-10
Compound of the present invention also comprises the enantiomer and the racemic modification of formula I and formula II compound.
Compound of the present invention also comprises the pharmacy acceptable salt of formula I and formula II compound, includes but not limited to the acid salt that The compounds of this invention and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, citric acid, tartrate, phosphoric acid, lactic acid, acetate, toxilic acid, fumaric acid, oxysuccinic acid, tussol, methylsulfonic acid, Phenylsulfonic acid, tosic acid, pamoic acid (palmoxiric acid), oxalic acid or succsinic acid.
Another object of the present invention has provided the preparation method of Guang Huo oxazolidone analog derivative formula I and formula II compound, following reaction formula:
Comprise the following steps:
Formula III compound (R
1R
2Thiazole-2-formic acid that group replaces) or its salt and formula IX compound (4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-yl] phenyl } morpholine-3-ketone) (their mol ratio is 2: 1～1: 2) carry out condensation reaction and obtain formula I or formula II compound in all kinds of SOLVENTS, used reaction solvent is selected from benzene, toluene, chloroform, normal hexane, hexanaphthene, methylene dichloride, 1, the 2-ethylene dichloride, methyl tertiary butyl ether, tetracol phenixin, ethyl acetate, propyl acetate, butylacetate, methyl alcohol, ethanol, acetone, tetrahydrofuran (THF), ether, acetonitrile, N, the mixed solvent of one or more in dinethylformamide or the methyl-sulphoxide, preferred toluene, methylene dichloride or acetone; The method of condensing that is adopted can be condensation reagent method, carboxylic acid halides method, mixed anhydride method, active ester method, is preferably chloride method, condensation reagent method; The condensation reagent that is adopted is selected from Carbodiimides condensation reagent (DCC, EDC), phosphorus positive ion or phosphoric acid ester condensation reagent (BOP, PyBOP, BOP-Cl, FDP, PyBrOP), urea positive ion type condensation reagent (HOBt, HOAt, HOOBt, PfOH, TBTU, HBPyU, HBTU), is preferably Carbodiimides condensation reagent (DCC, EDC), urea positive ion type condensation reagent HOBt; The acylating reagent that is adopted can be oxalyl chloride, sulfur oxychloride, PPh
3/ CCl
4, be preferably oxalyl chloride, sulfur oxychloride; Temperature of reaction is subzero 20 ℃ to 100 ℃, and preferred temperature is 0 ℃ to 75 ℃.
The synthetic reference literature of formula III compound or patent (chemical journal, 2006,64 (15): 1559-1564; Chem Comm, 2004,4:470-471; J Med Chem, 2008,51 (15): 4708-4714 Zhejiang Polytechnical University journal, 2007,35 (1): 27-30; Print 2007,21 (3): 5-10 during chemical industry; WO 2006078942A2; WO 2008095058A1; J Chem Soc, 1945,601-603; WO 2009005676A2; J Comb Chem, 2008,10:521-525) method is carried out; Formula IX compound (4-{4-[(5S)-5-(amino methyl)-2-oxo-1,3-oxazolidine-3-yl] phenyl morpholine-3-ketone) or the preparation of its salt can be with reference to patent CN1852902, US6875875, CN1906191 or J Med Chem, 2005, the method for 48:5900-5908 is carried out.
In above-mentioned reaction formula, R
1, R
2Such as in above-mentioned formula I and the formula II compound definition.
The preparation of the enantiomer of formula I of the present invention and formula II compound can be carried out with reference to above-mentioned synthetic method, the different enantiomer that just adopts formula IX compound as starting raw material.
The preparation of the racemic modification of formula I of the present invention and formula II compound is also carried out with reference to above-mentioned synthetic method, the different racemic modification that just adopts formula IX compound as starting raw material.
Another purpose of the present invention has provided Guang and has learned Huo oxazolidone analog derivative formula I and the purposes of formula II compound in pharmacy.
Pharmacodynamic experiment is the result show, general formula I of the present invention and formula II compound have certain certain Xa factor and suppress active.Above-mentioned experimental result prompting, The compounds of this invention or its pharmacy acceptable salt can be used to prepare the medicine of prevention or treatment thrombus and embolism relative disease, medicine in particular for preparation prevention or treatment dvt and pulmonary infarction, be specially adapted to the to select a time treatment of hip replacement or knee replacements adult patients is with the formation of prevention phlebothrombosis and pulmonary infarction.
The medicine of general formula I of the present invention and formula II compound is applicable to that also for example atrial fibrillation and those carry out among the patient of cardioversion, suffering from valvular heart disease or have among the patient of artificial heart valve prevention and treat cardiogenic thromboembolism suffering from acute, intermittent or stable irregular pulse, for example cerebral ischemia, apoplexy and systemic thromboembolism and local asphyxia.Medicine according to The compounds of this invention also is applicable to treatment disseminated intravascular coagulation (DIC).
The medicine of general formula I of the present invention and formula II compound is applicable to also and prevents and/or treats atherosclerotic blood vessel illness and inflammatory diseases that for example the wind-wetness syndrome of musculoskeletal system in addition, also is used to prevent and/or treat the Alzheimer's disease disease.In addition, can suppress tumor growth and metastasis according to the medicine of compound of the present invention forms, be used to suppress microangiopathy, relevant macular degeneration, diabetic retinopathy, diabetic nephropathy and other microangiopathy disease of age, with be used to prevent and/or treat thromboembolic complication, for example the venous thromboembolism of tumour patient is particularly carried out than major operation treatment or chemotherapy or radiotherapeutic tumour patient.
General formula I of the present invention and formula II compound also are applicable to the thrombotic medicine after also being fit to the preparation prevention or treating atheromatosis, myocardial infarction, apoplexy, ischemia cerebral thrombosis, peripheral arterial disease, acute coronary syndrome or coronary artery interventional procedure.
The present invention also provides the pharmaceutical composition of a kind of prevention or treatment thrombus and embolism relative disease, wherein contains formula I and formula II compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier for the treatment of significant quantity.Described pharmaceutical composition can be a dosage form conventional on the technology of pharmaceutics such as conventional tablet or capsule, slow releasing tablet or capsule, controlled release tablet or capsule, granule, powder, syrup, oral liquid, injection.
The dosage of pharmaceutical composition Chinese style I of the present invention and formula II compound is different and different with age etc. with symptom.For the adult, when oral administration, the lower limit of single administration amount is 5mg, and the upper limit is 20mg (preferred 10mg).Also can be according to different this dosage ranges that depart from of the difference and the formulation of disease degree.
Description of drawings
The proton nmr spectra of Fig. 1 Compound I-1;
The proton nmr spectra of Fig. 2 Compound I-2;
The proton nmr spectra of Fig. 3 Compound I-3;
The proton nmr spectra of Fig. 4 Compound I I-4;
The proton nmr spectra of Fig. 5 Compound I-5;
The proton nmr spectra of Fig. 6 Compound I-6;
The proton nmr spectra of Fig. 7 Compound I-7;
The proton nmr spectra of Fig. 8 Compound I-8;
The proton nmr spectra of Fig. 9 Compound I-9;
The proton nmr spectra of Figure 10 Compound I-10.
Embodiment
Specify content of the present invention below by embodiment.In the present invention, the embodiment of the following stated is in order better to set forth the present invention, is not to be used for limiting the scope of the invention.
Per-cent data among test and the embodiment are weight percentage below; The solvent ratios of liquid/liquid solution, thinning ratio and concentration data are based on the data of volume.
(S)-4-sec.-propyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides (I-1)
Under the ice bath, (0.58mmol 1.0eq) is dissolved among the methylene dichloride 1mL, and adding 1-hydroxyl-benzo-triazole then is that HOBt 0.24g (1.75mmol, 3.0eq), spend the night by stirring with raw material 4-sec.-propyl-2-thiazol formic-acid 0.1g.(0.88mmol, methylene dichloride 1.5eq) (1mL) solution slowly is added dropwise to this reaction solution, drip to finish stirs to add IX 0.17g behind the 1.5h (0.58mmol 1.0eq), is warming up to the stirring at room reaction gradually and spends the night with DCC 0.18g subsequently.With the white insolubles filtering in the reaction solution, cross post after the concentrating under reduced pressure filtrate and separate, obtain white solid product (0.12g, 46.15%).
1H?NMR(DMSO-d
6，300MHz)δ8.92(m，1H，NH)，7.60(s，1H，SCH)，7.55(d，2H，Ar-H，J＝8.94Hz)，7.39(d，2H，Ar-H，J＝8.97Hz)，4.92～4.83(m，1H，CH)，4.18(s，2H，OCH
2CO)，4.19(m，1H，OCHC
H 2NH)，3.95(t，2H，NC
H 2 CH
2O，J＝5.10Hz)，3.86(m，1H，CHC
H 2N)，3.69(t，2H，OC
H 2 CH
2N，J＝5.01Hz)，3.59(m，2H，OCHC
H 2NH?and?CHC
H 2N)，3.09(m，1H，C
H(CH
3)
2)，1.27(d，6H，CH(C
H 3 ) 2 ，J＝6.96Hz).
13C?NMR(DMSO-d
6，75MHz)δ165.92，164.20，162.26，159.80，154.03，137.09，136.45，125.89，118.43，118.11，70.93，67.70，63.44，48.98，47.54，42.17，30.30，22.23，22.18.MS(ESI，m/z)：467.1(M+Na).HRMS?calcd?for?C
21H
24N
4O
5S(M
+)m/z?444.1546，found?m/z444.1560.
Embodiment 2
(S)-4-trifluoromethyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides (I-2)
4-trifluoromethyl-2-thiazol formic-acid 0.1g (0.51mmol, 1.0eq), HOBt 0.21g (1.52mmol, 3.0eq), DCC 0.16g (0.76mmol, 1.5eq), (0.51mmol 1.0eq), makes white solid (0.20g with reference to the synthetic method of embodiment 1 to IX 0.15g, 83.33%), mp 196-196.5 ℃.
1H?NMR(DMSO-d
6，300MHz)δ9.33(m，1H，NH)，8.79(s，1H，SCH)，7.54(d，2H，Ar-H，J＝8.91Hz)，7.39(d，2H，Ar-H，J＝8.79Hz)，4.90～4.81(m，1H，CH)，4.18(s，2H，OCH
2CO)，4.19(m，1H，OCHC
H 2NH)，3.95(t，2H，NC
H 2 CH
2O，J＝5.00Hz)，3.92(m，1H，CHC
H 2N)，3.69(t，2H，OC
H 2 CH
2N，J＝5.01Hz)，3.62(m，2H，OCHC
H 2NH?and?CHC
H 2N).MS(ESI，m/z)：471.1(M+H)，488.2(M+NH
3).Anal.Calcd?forC
19H
17F
3N
4O
5S：C，48.51；H，3.64；N，11.91；O，17.01；S，6.82；F，12.12.Found：C，47.94；H，3.80；N，11.72.
(S)-4-phenyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides (I-3)
4-phenyl-2-thiazol formic-acid 0.2g (0.96mmol, 1.0eq), HOBt 0.4g (2.92mmol, 3.0eq), DCC 0.3g (1.46mmol, 1.5eq), IX 0.28g (0.96mmol, 1.0eq), make white solid (0.24g, 51.50%) with reference to the synthetic method of embodiment 1.
1H?NMR(CDCl
3，300MHz)δ7.92(d，2H，Ar-H，J＝7.67Hz)，7.83(t，1H，Ar-H，J＝6.39and?6.51Hz)，7.73(s，1H，SCH)，7.58(d，2H，Ar-H，J＝9.06Hz)，7.43(m，3H，Ar-H)，7.34(d，2H，Ar-H，J＝8.97Hz)，4.92(m，1H，CH)，4.33(s，2H，OCH
2CO)，4.15(t，1H，CHC
H 2NH，J＝8.85?and?9.06Hz)，4.02(t，2H，OCH
2C
H 2 N，J＝5.01Hz)，3.99～3.80(m，3H，CHC
H 2NH?and?CHC
H 2 N)，3.73(t，2H，OC
H 2 CH
2N，J＝5.06Hz).
13C?NMR(CDCl
3，75MHz)δ166.79，162.02，160.44，156.64，154.23，137.25，136.63，133.36，128.88，128.81，126.43，126.14，119.01，118.60，71.68，68.52，64.06，49.61，47.76，42.24.MS(ESI，m/z)：479.1(M+H)，501.0(M+Na)，517.0(M+K).HRMS?calcd?for?C
24H
22N
4O
5S(M
+)m/z?478.1389，found?m/z?478.1400.
(S)-4-methyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-5-thiazole carboxamides (II-4)
(1.05mmol 1.0eq) is suspended among the toluene 1mL, and (2.34mmol 2.2eq), is heated to 75 ℃ of reaction 3h, oxalyl chloride unnecessary in the reaction solution is steamed remove then, adds toluene 1mL to add oxalyl chloride 0.30g with 4-methylthiazol-5-thiazol formic-acid 0.15g.(0.70mmol 1.0eq) is dissolved among the acetone 1mL, is added in the toluene solution of above-mentioned acyl chlorides, adds catalytic amount Na then with IX 0.20g
2CO
3, be heated to 55 ℃ of reaction 6h, solvent evaporated, resistates extracts with methylene dichloride/water, and the organic phase anhydrous sodium sulfate drying is crossed the post separation and is obtained white solid (0.29g, 68.97%) behind the concentrating under reduced pressure.
1H?NMR(DMSO-d
6，300MHz)δ9.03(s，1H，SCH)，8.61(s，1H，NH)，7.57(d，2H，Ar-H，J＝8.82Hz)，7.40(d，2H，Ar-H，J＝8.82Hz)，4.86(m，1H，CH)，4.21(m，1H，OCHC
H 2NH)，4.19(s，2H，OCH
2CO)，3.96(t，2H，OCH
2C
H 2 N，J＝5.19Hz)，3.88(m，1H，OCHC
H 2N)，3.71(m，2H，OCHC
H 2NH?and?OCHC
H 2N)，3.61(t，2H，OC
H 2 CH
2N，J＝5.25Hz)，2.54(s，1H，CH
3).
13C?NMR(DMSO-d
6，75MHz)δ166.17，162.18，154.86，154.26，137.16，136.59，126.08，125.83，118.48，71.26，67.79，63.56，49.13，47.51，42.34，16.78.MS(ESI，m/z)：416.12(M+H)，439.2(M+Na).HRMS?calcd?for?C
19H
20N
4O
5S(M
+)m/z?416.1233，found?m/z?416.1246.
(S)-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-5.6-dihydro-4H-cyclopentyl [d] thiazole-2-methane amide (I-5)
5,6-dihydro-4H-cyclopentano thiazole-2-carboxylic acid 0.3g (1.78mmol, 1.0eq), HOBt 0.72g (5.32mmol, 3.0eq), DCC 0.55g (2.66mmol, 1.5eq), IX 0.52g (1.78mmol, 1.0eq), synthetic method with reference to embodiment 1 makes white solid (0.33g, 42.02%).
1H?NMR(CDCl
3，300MHz)δ7.55(d，3H，Ar-H?and?NH，J＝9.03Hz)，7.31(d，2H，Ar-H，J＝9.03Hz)，4.86(m，1H，CH)，4.31(s，2H，OCH
2CO)，4.08(m，1H，OCHC
H 2NH)，4.01(t，2H，OCH
2C
H 2 N，J＝5.03Hz)，3.84(m，3H，OCHC
H 2NH?andOCHC
H 2 N)，3.72(t，2H，OC
H 2 CH
2N，J＝5.01Hz)，2.95(t，2H，NC
H 2 CH
2，J＝7.19Hz)，2.85(t，2H，SC
H 2 CH
2，J＝7.34Hz)，2.53(m，2H，NCH
2C
H 2 CH
2S).
13C?NMR(CDCl
3，75MHz)δ166.75，163.71，160.95，141.73，137.27，136.69，126.16，119.04，71.70，68.56，64.10，49.65，47.65，41.85，27.72，26.98，26.77.MS(ESI，m/z)：443.12(M+H)，465.10(M+Na).HRMS?calcd?for?C
21H
22N
4O
5S(M
+)m/z?442.1389，found?m/z?442.1385.
Embodiment 6
(S)-4-methyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides (I-6)
(0.70mmol 1.5eq) is suspended among the methylene dichloride 1mL, adds 1 of catalytic amount DMF with 4-methyl-2-thiazol formic-acid 0.1g under the ice bath, (1.16mmol 2.5eq), stirs 2.5h to oxalyl chloride 0.15g, oxalyl chloride steaming unnecessary in the reaction solution is removed, obtain the yellow solid acyl chlorides.Add methylene dichloride 2mL then, IX 0.14g (0.47mmol, 1.0eq) with catalytic amount DMAP, spend the night, and leaves standstill to remove ice bath by stirring.Filtering white insolubles, filtrate methylene dichloride/water extraction, organic phase is crossed post after with anhydrous sodium sulfate drying behind the concentrating under reduced pressure and is separated and obtain white solid (0.13g, 67.04%).
1H?NMR(CDCl
3，300MHz)δ7.76(m，1H，NH)，7.56(d，2H，Ar-H，J＝8.88Hz)，7.33(d，2H，Ar-H，J＝9.00Hz)，7.14(s，1H，SCH)，4.88(m，1H，CH)，4.33(s，2H，OCH
2CO)，4.11(m，1H，OCHC
H 2NH)，4.03(t，2H，OCH
2C
H 2 N，J＝5.03Hz)，3.85(m，3H，OCHC
H 2NH?and?OCHC
H 2 N)，3.73(t，2H，OC
H 2 CH
2N，J＝5.09Hz)，2.46(s，3H，CH
3).
13C?NMR(CDCl
3，75MHz)δ166.84，161.18，160.56，154.39，154.26，137.34，136.72，126.23，119.98，119.08，71.74，68.60，64.16，49.70，47.75，42.04，17.01.MS(ESI，m/z)：417.1(M+H)，439.1(M+Na).HRMS?calcd?for?C
19H
20N
4O
5S(M
+)m/z?416.1233，found?m/z?416.1236.
(S)-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-4,5.6,7-two tetrahydro benzos [d] thiazole-2-methane amide (I-7)
With 4,5,6,7-tetrahydro benzothiazol-2-carboxylic acid 0.1g (0.55mmol, 1.2eq) be dissolved among the methylene dichloride 2mL, adding HOBt 0.092g under the ice bath (0.68mmol, 1.5eq), EDC 0.13g (0.68mmol, 1.5eq) and the catalytic amount triethylamine, and adding IX 0.13g behind the stirring 30min (0.45mmol, 1.0eq), stir 3h, remove ice bath.Filtering white insolubles is crossed the post separation and is obtained product (0.21g, 84.0%) after filtrate decompression concentrates.
1H?NMR(CDCl
3，300MHz)δ7.73(m，1H，NH)，7.57(d，2H，Ar-H，J＝8.94Hz)，7.33(d，2H，Ar-H，J＝8.85Hz)，4.87(m，1H，CH)，4.33(s，2H，OCH
2CO)，4.09(m，1H，OCHC
H 2NH)，4.03(t，2H，OCH
2C
H 2 N，J＝5.01Hz)，3.85(m3H，OCHC
H 2NH?and?OCHC
H 2 N)，3.74(t，2H，OC
H 2 CH
2N，J＝5.00Hz)，2.81(m，4H，NC
H 2 CH
2and?SC
H 2 CH
2，J＝13.89Hz)，1.88(m，4H，SCH
2C
H 2 C
H 2 CH
2N).
13C?NMR?(CDCl
3，75MHz)δ166.74，160.72，157.85，154.18，151.97，137.22，136.67，136.36，126.13，119.01，71.69，68.52，64.07，49.62，47.64，41.82，26.56，23.92，22.95，22.58.MS(ESI，m/z)：455.2(M-H).HRMS?calcd?for?C
22H
24N
4O
5S(M
+)m/z?456.1546，found?m/z?456.1550.
(S)-5-ethanoyl-4-methyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides (I-8)
5-ethanoyl-4-methyl-2-thiazol formic-acid 0.1g (0.54mmol; 1.5eq); HOBt 0.073g (0.54mmol; 1.5eq), EDC 0.10g (0.54mmol, 1.5eq); IX 0.10g (0.43mmol; 1.0eq), make white solid (0.14g, 87.5%) with reference to the synthetic method of embodiment 7.
1H?NMR(CDCl
3，300MHz)δ7.80(m，1H，NH)，7.53(d，2H，Ar-H，J＝8.94Hz)，7.33(d，2H，Ar-H，J＝8.85Hz)，4.89(m，1H，CH)，4.33(s，2H，OCH
2CO)，4.09(m，1H，OCHC
H 2NH)，4.13(m，1H，OCHC
H 2NH)，4.03(t，2H，OCH
2C
H 2 N，J＝5.04Hz)，3.96～3.82(m，3H，OCHC
H 2NH?and?OCHC
H 2 N)，3.74(t，2H，OC
H 2 CH
2N，J＝4.98Hz)，2.73(s，3H，COCH
3)，2.58(s，3H，CH
3).
13C?NMR(CDCl
3，75MHz)δ190.43，166.78，161.94，159.80，159.00，154.06，137.36，136.54，126.18，119.01，71.45，68.54，64.08，49.62，47.65，42.21，30.75，18.15.MS(ESI，m/z)：459.1(M+H)，481.1(M+Na)，497.1(M+K).HRMS?calcd?forC
21H
22N
4O
6S(M
+)m/z?458.1338，fournd?m/z?458.1340.
Embodiment 9
(S)-4-ethyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides (I-9)
(0.52mmol, 1.5eq), (1.54mmol, 4.5eq), (0.34mmol, 1.0eq), the synthetic method of reference compound embodiment 6 makes white solid (0.11g, 74.42%) to IX 0.10g to oxalyl chloride 0.20g to 4-ethyl-2-thiazol formic-acid 0.08g.
1H?NMR(CDCl
3，300MHz)δ7.75(m，1H，NH)，7.57(d，2H，Ar-H，J＝8.88Hz)，7.33(d，2H，Ar-H，J＝8.79Hz)，7.15(s，1H，SCH)，4.89(m，1H，CH)，4.33(s，2H，OCH
2CO)，4.12(m，1H，OCHC
H 2NH)，4.03(t，2H，OCH
2C
H 2 N，J＝5.00Hz)，3.96～3.78(m，3H，OCHC
H 2NH?andOCHC
H 2 N)，3.74(t，2H，OC
H 2 CH
2N，J＝7.50Hz)，2.82(q，2H，C
H 2 CH
3，J＝5.03Hz)，1.31(t，3H，CH
2C
H3，J＝7.56Hz).
13C?NMR(CDCl
3，75MHz)δ166.77，161.18，160.59，154.21，137.30，136.65，126.17，119.05，118.67，71.73，68.55，64.09，49.65，47.71，42.01，24.69，13.39.MS(ESI，m/z)：431.4(M+H)，453.4(M+Na).
(S)-4,5-dimethyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides (I-10)
4,5-dimethyl-2-thiazol formic-acid 0.1g (0.64mmol, 1.2eq), HOBt 0.21g (1.59mmol, 3.0eq), EDC0.30g (1.59mmol, 3.0eq), IX 0.15g (0.53mmol, 1.0eq), the synthetic method of reference compound embodiment 7 makes white solid (0.16g, 70.11%).MS(ESI，m/z)：431.1(M+H)，453.1(M+Na)，469.1(M+K).
Embodiment 11
Evaluated biological activity--Xa factor suppresses active mensuration
1. ultimate principle: human Xa factor is a kind of serine protease, acts on mutually with its specificity chromogenic substrate, can be from chromogenic substrate the cancellation p-Nitroaniline.Because substrate has absorption peak at the 405nm place, therefore measure its enzymic activity and can finish by the variation of spectrophotometry 405nm optical density.
2. experimental technique and result: described mensuration is following carries out in 96 microwell plates.Derivative is dissolved among the DMSO with seven concentration gradients, and 25 ℃ of incubation 10min add Xa factor (20ng/ μ L is dissolved in 50mmol/L Tris damping fluid [C, C, C-three (hydroxymethyl)-aminomethane], among the pH=8.4), then together at 25 ℃ of incubation 10min.Do blank with pure DMSO.Add the substrate (400 μ mol/L Pefachrome FXa) that adds lustre to, behind 25 ℃ of incubation 20min, measure delustring at 405nm.The delustring that will contain the test mixing thing of test substances compares and calculates thus inhibiting rate with the control mixture that does not contain test substances.Active testing the results are shown in Table 1.、
Table?1.Screening?of?10?compunds?against?Human?FXa?at?100μM
Claims (17)
1. Guang learns Huo oxazolidone analog derivative, it is characterized in that described derivative is represented suc as formula I and formula II compound:
R wherein
1The phenyl that replaces for straight or branched alkyl, phenyl, the Y non-replacement of hydrogen, 1～10 carbon or that X replaces; Wherein X is fluorine, chlorine, bromine, iodine, trifluoromethyl; Y is fluorine, chlorine, bromine, iodine, nitro, amino or trifluoromethyl, and Y group is in 2,3 or 4 of phenyl ring;
R
2Be straight or branched acyl group non-replacement or that X the replaces non-replacement of hydrogen, 1～10 carbon or the straight or branched alkyl that X replaces, 1～6 carbon; Wherein X is fluorine, chlorine, bromine, iodine or trifluoromethyl;
R
1With R
2Group can Cheng Huan, is the cycloalkyl group of 5-7 unit's non-replacement of cyclic or replacement.
2. the Guang according to claim 1 learns Huo oxazolidone analog derivative, it is characterized in that R in described formula I and the formula II compound
1Be straight or branched alkyl, the phenyl non-replacement or that X replaces of hydrogen, 1～6 carbon, wherein X is fluorine, chlorine, bromine or iodine;
R
2Straight or branched acyl group for the non-replacement non-replacement of hydrogen, 1～6 carbon or the straight or branched alkyl that X replaces, 1～3 carbon;
R
1With R
2Group can Cheng Huan, is the cycloalkyl group of 5-6 unit's non-replacement of cyclic or replacement.
3. the Guang according to claim 1 learns Huo oxazolidone analog derivative, it is characterized in that R in described formula I and the formula II compound
1Be methyl, ethyl, sec.-propyl, phenyl or trifluoromethyl; R
2Be hydrogen, methyl or ethanoyl; R
1With R
2Group can Cheng Huan, is cyclopentyl or cyclohexyl.
4. learn Huo oxazolidone analog derivative according to each Guang among the claim 1-3, it is characterized in that, described derivative comprises the pharmacy acceptable salt of formula I and formula II compound, comprises the acid salt that compound and following acid form: hydrochloric acid, Hydrogen bromide, sulfuric acid, citric acid, tartrate, phosphoric acid, lactic acid, acetate, toxilic acid, fumaric acid, oxysuccinic acid, tussol, methylsulfonic acid, Phenylsulfonic acid, tosic acid, pamoic acid (palmoxiric acid) or oxalic acid or succsinic acid.
5. learn Huo oxazolidone analog derivative according to each Guang among the claim 1-3, it is characterized in that described derivative comprises the enantiomer and the racemic modification of formula I and formula II compound.
6. the Guang according to claim 1 learns Huo oxazolidone analog derivative, it is characterized in that described derivative comprises following compounds:
(S)-4-sec.-propyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides I-1
(S)-4-trifluoromethyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides I-2
(S)-4-phenyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides I-3
(S)-4-methyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-5-thiazole carboxamides II-4
(S)-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-5.6-dihydro-4H-cyclopentyl [d] thiazole-2-methane amide I-5
(S)-4-methyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides I-6
(S)-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-4,5.6,7-two tetrahydro benzos [d] thiazole-2-methane amide I-7
(S)-5-ethanoyl-4-methyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides I-8
(S)-4-ethyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides I-9
(S)-4,5-dimethyl-N-((2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl) methyl)-2-thiazole carboxamides I-10
As among the claim 1-6 as described in each Guang learn the purposes of Huo oxazolidone analog derivative in the medicine of preparation prevention or treatment disease.
As among the claim 1-6 as described in each Guang learn Huo oxazolidone analog derivative under situation about being fit to, use with inertia, excipient composition that nontoxic pharmacy is suitable.
As among the claim 1-6 as described in each Guang learn the medicine of Huo oxazolidone analog derivative and the combination of other active ingredient.
10. be used to orally use as the medicine that Guang learns Huo oxazolidone analog derivative as described in each among the claim 1-6.
11. as among the claim 1-6 as described in each Guang learn the purposes of Huo oxazolidone analog derivative in the medicine of preparation prevention or treatment thrombus and embolism relative disease.
12. the thrombotic disease in the context of the present invention is particularly including for example following illness: the ST fragment raise (STEMI) scheming infarction and do not have the scheming infarction of ST fragment rising (non-STEMI), stable angina pectoris, unstable angina pectoris, coronary artery is intervened for example angioplasty or aorta coronary artery bypass absorption again and restenosis afterwards, terminal arteriosclerosis obliterans, pulmonary infarction, dvt and Renal vein thrombus, temporary ischemic morbidity and thrombosis thromboembolism type apoplexy.
13. as among the claim 1-6 as described in each Guang learn Huo oxazolidone analog derivative and be applicable to that also preparation prevents and/or treats the medicine of dvt and pulmonary infarction.Be specially adapted to the to select a time treatment of hip replacement or knee replacements adult patients is with the formation of prevention phlebothrombosis and pulmonary infarction.Be applicable to also that according to the medicine of compound of the present invention for example atrial fibrillation and those carry out among the patient of cardioversion, suffering from valvular heart disease or have among the patient of artificial heart valve prevention and treat cardiogenic thromboembolism suffering from acute, intermittent or stable irregular pulse, for example cerebral ischemia, apoplexy and systemic thromboembolism and local asphyxia.Also be applicable to treatment disseminated intravascular coagulation (DIC) according to compound of the present invention.
14. also be fit to prevent and/or treat atherosclerotic blood vessel illness and inflammatory diseases as the medicine that Guang learns Huo oxazolidone analog derivative as described in each among the claim 1-6, the wind-wetness syndrome of musculoskeletal system for example, in addition, also be used to prevent and/or treat the Alzheimer's disease disease.In addition, can suppress tumor growth and metastasis according to the medicine of compound of the present invention forms, be used to suppress microangiopathy, relevant macular degeneration, diabetic retinopathy, diabetic nephropathy and other microangiopathy disease of age, with be used to prevent and/or treat thromboembolic complication, for example the venous thromboembolism of tumour patient is particularly carried out than major operation treatment or chemotherapy or radiotherapeutic tumour patient.
15. also be fit to thrombotic medicine behind preparation prevention or treatment atheromatosis, myocardial infarction, apoplexy, ischemia cerebral thrombosis, peripheral arterial disease, acute coronary syndrome or the coronary artery interventional procedure as the medicine that Guang learns Huo oxazolidone analog derivative as described in each among the claim 1-6.
16. a pharmaceutical composition that prevents or treat thrombus and embolism relative disease is characterized in that, contains formula I or formula II compound or its pharmacy acceptable salt and pharmaceutically acceptable carrier in the described pharmaceutical composition.
17. the pharmaceutical composition as claim 16 is characterized in that, described pharmaceutical composition is tablet, capsule, slow releasing tablet, granule, powder, syrup, oral liquid or injection.Oral is the form of medication that suits, it works according to prior art, and send according to compound of the present invention apace and/or with improved procedure, its contain crystal and/or noncrystal and/or solubilized form according to compound of the present invention, tablet (no coating or sugar coated tablet, for example have enteric coating or have postpone and sustained release can not dissolve or soluble dressing) for example according to compound function of the present invention, quickly disintegrated tablet in the oral cavity, or film/thin slice, film/the lyophilize thing capsule (for example hard or soft capsule), coated tablet, granula, particle, powder, emulsion, suspension agent, aerosol or solution.Can carry out administered parenterally, comprise intravenously, intra-arterial injection, intracardiac, in the backbone or in the tube chamber, intramuscular injection, subcutaneous, intracutaneous, transdermal, intraperitoneal.Also other form of medication be can carry out,, dropping liquid or sprays etc. comprised as nasal administration.Oral administration is preferred.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102504018A (en) * | 2011-10-28 | 2012-06-20 | 沈阳药科大学 | Melittin pamoate capable of being continuously released and preparation agent thereof |
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|---|---|---|---|---|
| CN1434822A (en) * | 1999-12-24 | 2003-08-06 | 拜尔公司 | Substituted oxazolidinones and their use in the field of blood coagulation |
| US20050080081A1 (en) * | 2001-02-09 | 2005-04-14 | Alexander Straub | Substituted oxazolidinones and their use in the field of blood coagulation |
| WO2009156082A1 (en) * | 2008-06-28 | 2009-12-30 | Bayer Schering Pharma Aktiengesellschaft | Oxazolidinones for the treatment of chronic obstructive pulmonary disease (copd) and/or asthma |
-
2011
- 2011-04-01 CN CN2011100816482A patent/CN102199150A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1434822A (en) * | 1999-12-24 | 2003-08-06 | 拜尔公司 | Substituted oxazolidinones and their use in the field of blood coagulation |
| US20050080081A1 (en) * | 2001-02-09 | 2005-04-14 | Alexander Straub | Substituted oxazolidinones and their use in the field of blood coagulation |
| WO2009156082A1 (en) * | 2008-06-28 | 2009-12-30 | Bayer Schering Pharma Aktiengesellschaft | Oxazolidinones for the treatment of chronic obstructive pulmonary disease (copd) and/or asthma |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102504018A (en) * | 2011-10-28 | 2012-06-20 | 沈阳药科大学 | Melittin pamoate capable of being continuously released and preparation agent thereof |
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