CN103626749A - Substituted oxazolidinone compound, and pharmaceutical composition containing compound and application thereof - Google Patents
Substituted oxazolidinone compound, and pharmaceutical composition containing compound and application thereof Download PDFInfo
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- CN103626749A CN103626749A CN201210298561.5A CN201210298561A CN103626749A CN 103626749 A CN103626749 A CN 103626749A CN 201210298561 A CN201210298561 A CN 201210298561A CN 103626749 A CN103626749 A CN 103626749A
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- RGWBXXMKTBFLTJ-UHFFFAOYSA-N CC(C)(C(NI)=O)O Chemical compound CC(C)(C(NI)=O)O RGWBXXMKTBFLTJ-UHFFFAOYSA-N 0.000 description 1
- VCGTVWAYTIKLRQ-UHFFFAOYSA-N CC(C)(CCCN1)C1=O Chemical compound CC(C)(CCCN1)C1=O VCGTVWAYTIKLRQ-UHFFFAOYSA-N 0.000 description 1
- GGYVTHJIUNGKFZ-UHFFFAOYSA-N CN(CCCC1)C1=O Chemical compound CN(CCCC1)C1=O GGYVTHJIUNGKFZ-UHFFFAOYSA-N 0.000 description 1
- SAIZLRMQEYKOAT-UHFFFAOYSA-N CNC(C1(CC1)O)=O Chemical compound CNC(C1(CC1)O)=O SAIZLRMQEYKOAT-UHFFFAOYSA-N 0.000 description 1
- GSFNQBFZFXUTBN-UHFFFAOYSA-N Clc1ccc[s]1 Chemical compound Clc1ccc[s]1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 description 1
- BBLFVFFNJCTJSN-UHFFFAOYSA-N O=C(C=CC=C1)N1I Chemical compound O=C(C=CC=C1)N1I BBLFVFFNJCTJSN-UHFFFAOYSA-N 0.000 description 1
- MZSJUHDTQFOCAI-UHFFFAOYSA-N O=C(CCC1)N1I Chemical compound O=C(CCC1)N1I MZSJUHDTQFOCAI-UHFFFAOYSA-N 0.000 description 1
- VSEAAEQOQBMPQF-UHFFFAOYSA-N O=C1NCCOC1 Chemical compound O=C1NCCOC1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 description 1
- BVTOBMHHHIASPK-AWEZNQCLSA-N OCC(Nc(cc1OCCOCCF)ccc1N(C[C@H](CNC(c([s]1)ccc1Cl)=O)O1)C1=O)=O Chemical compound OCC(Nc(cc1OCCOCCF)ccc1N(C[C@H](CNC(c([s]1)ccc1Cl)=O)O1)C1=O)=O BVTOBMHHHIASPK-AWEZNQCLSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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Abstract
The invention relates to a substituted oxazolidinone compound and a pharmaceutical composition containing the compound and application thereof. Specifically, the invention discloses the compound represented by a formula (1) and a preparation method thereof. The compound has excellent effects on inhibition of activity of the factor Xa and on anticoagulation and can be used for treating and/or preventing thromboembolic diseases and the like.
Description
Technical field
The invention belongs to field of medicaments.Particularly, the medical composition and its use that the present invention relates to a kind of of replacement oxazolidinone compounds and comprise this compound.
Background technology
Coagulation process is the catalyzed reaction of a set of complexity, involves at least 30 kinds of different proteolytic enzyme.The net result of these reactions is that the Fibrinogen of solubility (fibrinogen) is converted into insoluble scleroproein (fibrin), and scleroproein forms stable blood clot, i.e. thrombosis again together with thrombocyte.Thrombosis will cause thrombotic disease (as venous thromboembolism (venous thromboembolism, VTE), atherosclerotic arterial thrombosis disease (atherothrombosis, the thrombus that plaque rupture causes) and psychogenic cerebral apoplexy (cardioembolic stroke) etc.).Thrombotic disease sickness rate is high, once form, has high lethality rate and disability rate.
Coagulation mode comprises two kinds: external/inherent path mode and take cell as basic pattern.Wherein, external/inherent path mode is that the startup of coagulation process is divided into external approach and inherent approach.External approach is the key step that starts coagulation process, sees through afterwards inherent approach and in succession successfully activates factor IX (Factor IX) and factor X (Factor X).Take cell as basic pattern be to see through identification to activate specific thrombin with thrombocyte or the cytolemma of tissue factor.Though be external/interior at path mode or take cell as basic coagulation mode, factor Xa is playing the part of extremely crucial role in coagulation process.
At present, all there are some shortcomings in the anticoagulation medicine on market, as first kind anticoagulation medicine heparin can not oral administration, and there is no selectivity, thereby cause hemorrhage excessive risk, particularly may cause hematencephalon and gastrointestinal hemorrhage; Equations of The Second Kind anticoagulant vitamin K antagon (as warfarin) is owing to non-selectively suppressing some vitamin K-dependent clotting factor in liver, cause onset slow, and there is equally hemorrhage excessive risk and narrower treatment window, need strict individuality adjustment and observation.
Therefore, be necessary very much to research and develop the better novel anticoagulation medicine of a kind of selectivity or pharmacodynamics performance.
Summary of the invention
The object of this invention is to provide the novel factor Xa that has of a class and suppress active compound, described compound can effectively prevent and/or treat thrombotic disease etc.
In first aspect present invention, oxazolidinone compounds or its pharmacy acceptable salt shown in a kind of formula (I) are provided, or its crystal formation, hydrate or solvate:
Wherein, R
1for
or
(wherein * represents the tie point with carbonyl), wherein, R
7for hydrogen, fluorine, chlorine, bromine or, C1-C4 alkyl;
R
2for replacing or the unsubstituted group that is selected from lower group:
Wherein, described replacement refers to have 1-3 and is selected from the substituting group of lower group: halogen, C1-C4 alkyl, OH;
R
3and R
4be selected from independently of one another lower group: hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano group, amino, C1-C4 alkyl, C1-C4 alkoxyl group, C1-C4 alkoxy C 1-C4 alkyl, C1-C4 alkoxy C 1-C4 alkoxyl group, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C4 alkoxyl group, C3-C6 cycloalkyloxy, C3-C6 cycloalkyloxy C1-C4 alkyl or C3-C6 cycloalkyloxy C1-C4 alkoxyl group;
R
5and R
6be selected from independently of one another lower group: hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano group, amino, C1-C4 alkyl, C1-C4 alkoxyl group, C3-C6 cycloalkyl or C3-C6 cycloalkyloxy;
Wherein the hydrogen in abovementioned alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy is replaced by hydroxyl, C1-C4 alkyl, C1-C4 alkoxyl group, one or more deuterium or one or more fluorine;
Or the one or more hydrogen atoms in formula (I) are replaced by D atom;
Supplementary condition are to work as R
3, R
5and R
4during for hydrogen, R
6be not hydrogen or fluorine (or other halogens); And
R
3and R
5be all hydrogen and R
4during for fluorine, chlorine, cyano group, trifluoromethyl or trifluoromethoxy, R
6be not following group: hydrogen, chlorine, methyl, ethyl, n-propyl, methoxyl group, oxyethyl group or methoxymethyl.
In another preference, R
3and R
4when different, be hydrogen.
In another preference, when the one or more hydrogen atoms in formula (I) are replaced by D atom, described formula (I) compound does not comprise the compound that contains following group: R
1for
wherein, R7 is chlorine; R
2for unsubstituted
and R
3, R
4, R
5and R
6be hydrogen independently of one another.
In another preference, R
1be
In another preference, R
2for
or
In another preference, R
1be
and R
2for
or
In another preference, R
2for
In another preference, R
3and R
4be selected from independently of one another lower group: hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano group, amino, C1-C4 alkoxyl group, C1-C4 alkoxy C 1-C4 alkoxyl group, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl C1-C4 alkoxyl group, C3-C6 cycloalkyl or C3-C6 cycloalkyloxy C1-C4 alkoxyl group;
R
5and R
6be selected from independently of one another lower group: hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano group, amino, C1-C4 alkoxyl group or C3-C6 cycloalkyloxy;
Wherein the hydrogen in abovementioned alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy is replaced by hydroxyl, C1-C4 alkyl, C1-C4 alkoxyl group, one or more deuterium or one or more fluorine.
In another preference, R
1be
r
2for
and R
3and R
4be selected from independently of one another lower group: hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano group, amino, C1-C4 alkoxyl group, C1-C4 alkoxy C 1-C4 alkoxyl group, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl C1-C4 alkoxyl group, C3-C6 cycloalkyl or C3-C6 cycloalkyloxy C1-C4 alkoxyl group; R
5and R
6be selected from independently of one another lower group: hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano group, amino, C1-C4 alkoxyl group or C3-C6 cycloalkyloxy; Wherein the hydrogen in abovementioned alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy is replaced by hydroxyl, C1-C4 alkyl, C1-C4 alkoxyl group, one or more deuterium or one or more fluorine.
In another preference, described compound is selected from lower group:
In another preference, described compound is the compound of embodiment 1～13 preparation.
In second aspect present invention, a kind of preparation method of pharmaceutical composition is provided, it comprises step: by pharmaceutically acceptable carrier and first aspect present invention Suo Shu oxazolidinone compounds or its pharmacy acceptable salt, or its crystal formation, hydrate or solvate mix, thereby form pharmaceutical composition.
In third aspect present invention, a kind of pharmaceutical composition is provided, it comprises (a) pharmaceutically acceptable carrier and (b) with first aspect present invention Suo Shu oxazolidinone compounds or its pharmacy acceptable salt, or its crystal formation, hydrate or solvate are activeconstituents.
In another preference, the content of described activeconstituents is 0.001～99.99 % by weight, is preferably 0.01～99.9 % by weight or 0.1～99 % by weight, is more preferably 1～50 % by weight or 2～40 % by weight.
In another preference, described pharmaceutical composition also comprises other medicine, and wherein said other medicine is selected from lower group: the second factor Xa inhibitor, antithrombotics, anti-platelet agents, thrombin inhibitors, thrombolytic agent, fibrinolytic agent or its combination.
In fourth aspect present invention, a kind of first aspect present invention Suo Shu oxazolidinone compounds or its pharmacy acceptable salt are provided, or the purposes of its crystal formation, hydrate or solvate or the pharmaceutical composition as described in third aspect present invention, its (a) is for the preparation of the pharmaceutical composition of anticoagulant factor Xa (FXa); (b) for the preparation of the pharmaceutical composition that is used for treating and/or preventing thromboembolic disorders; And/or (c) for stoping in vitro blood coagulation.
In another preference, thromboembolic disorders comprises the thromboembolic disorders in the chamber of artery cardiovascular thromboembolic disease, vein blood vessel thromboembolic disorders and heart.
In another preference, described thromboembolic disorders comprises: acute coronary syndrome (comprises myocardial infarction, as the first myocardial infarction or recurrent cardiac infarction, or stenocardia etc.), apoplexy, arteriosclerosis (as atherosclerosis etc.), arterial thrombosis, Coronary thrombosis, cerebral artery thrombosis forms, peripheral arterial occlusive disease, of short duration local asphyxia outbreak, venous thrombosis (as dvt forms), thrombophlebitis, cerebral embolism, renal infarction, pulmonary infarction, pulmonary hypertension, or the obstruction again after angioplasty or aorta or coronary bypass-forming operation and narrowing down again etc.
In fifth aspect present invention, a kind of first aspect present invention Suo Shu oxazolidinone compounds or its pharmacy acceptable salt are provided, or the preparation method of its crystal formation, hydrate or solvate, it comprises step: by formula (II) compound and the reaction of formula (III) compound, thus the formula of formation (I) compound;
Above-mentioned various in, R
1for
r
2, R
3, R
4, R
5, R
6and R
7definition the same, X represents halogen or hydroxyl (being preferably chlorine or bromine).
In another preference, described formula (II) compound makes as follows, and described method comprises step:
(1) by formula (IV) compound and the reaction of formula (V) compound, thus the formula of formation (VI) compound;
(2) compound (VI) is carried out to deprotection reaction, thus the formula of obtaining (VII) compound;
(3) hydroxyl of formula (VII) compound is changed into amino, thus the formula of obtaining (II) compound;
Wherein, R
2, R
3, R
4, R
5and R
6definition the same; X represents halogen (being preferably fluorine, bromine and iodine), and P represents hydroxy-protective group (be preferably trityl group, t-Butyldimethylsilyl, diphenyl methyl silica-based, to methoxy-benzyl, benzyl, methylsulfonyl or p-toluenesulfonyl).
In should be understood that within the scope of the present invention, above-mentioned each technical characterictic of the present invention and can combining mutually between specifically described each technical characterictic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, at this, tire out and state no longer one by one.
Embodiment
The inventor, by long-term and deep research, has been surprised to find that a class replaces oxazolidinone compounds and can effectively, optionally suppress anticoagulin Xa, has excellent anticoagulant active and anti-thrombosis activity and has lower IC
50with pharmacokinetics performance.On this basis, contriver has completed the present invention.
Term
As used herein, term " C1-C4 alkyl " represents to have the alkyl of 1 to 4 carbon atom, comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl etc., preferable methyl, ethyl, n-propyl and sec.-propyl.
As used herein, term " C1-C4 alkoxyl group " represents to have the alkoxyl group of 1 to 4 carbon atom, comprise methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy etc., preferably methoxyl group, oxyethyl group and positive propoxy.
As used herein, term " C3-C6 cycloalkyl " represents to have the cycloalkyl of 3 to 6 carbon atoms, comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
As used herein, term " C3-C6 cycloalkyloxy " represents to have the cycloalkyloxy of 3 to 6 carbon atoms, comprises cyclopropyl oxygen base, cyclobutyl oxygen base, cyclopentyloxy and cyclohexyl oxygen base.
As used herein, term " halogen " refers to fluorine, chlorine, bromine, iodine.
May represent R
1and R
2the formula of group in, the lines terminal by * mark is not carbon atom or CH
2group, but and R
1or R
2a part for the covalent linkage connecting.
Activeconstituents
As used herein, term " compound of the present invention " comprises oxazolidinone compounds or its pharmacy acceptable salt shown in formula (I), or its crystal formation, hydrate or solvate.Wherein, comprise oxazolidinone compounds or its pharmacy acceptable salt, crystal formation, hydrate or solvate shown in formula (I); And pharmacy acceptable salt or its crystal formation, hydrate or the solvate of oxazolidinone compounds shown in formula (I).
Wherein, term " pharmacy acceptable salt " refers to the formed salt that is suitable as medicine of the compounds of this invention and acid or alkali.Pharmacy acceptable salt comprises inorganic salt and organic salt.The preferred salt of one class is the compounds of this invention and the sour salt forming.The acid that is applicable to formation salt includes, but are not limited to: the mineral acids such as hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; The organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, phenylformic acid, methylsulfonic acid, ethyl sulfonic acid, tosic acid, Phenylsulfonic acid, naphthene sulfonic acid; And the amino acid such as proline(Pro), phenylalanine, aspartic acid, L-glutamic acid.Another kind of preferred salt is the salt that the compounds of this invention and alkali form, for example an alkali metal salt (for example sodium salt or sylvite), alkaline earth salt (for example magnesium salts or calcium salt) and ammonium salt.Or rudimentary alkanol ammonium salt and other pharmaceutically acceptable amine salt (such as methylamine salt, ethylamine salt, propylamine salt, dimethyl amine salt, trismethylamine salt, diethyl amine salt, triethyl amine salt, tert-butylamine salt, ethylenediamine salt, oxyethylamine salt, dihydroxy ethylamine salt, three oxyethylamine salt, and the amine salt being formed by morpholine, piperazine, Methionin respectively).
Term " solvate " refers to that the compounds of this invention and solvent molecule coordination form the title complex of specified proportion." hydrate " refers to the title complex that the compounds of this invention and water carry out coordination formation.
The compounds of this invention, removes R in formula (I)
1, R
2, R
3, R
4, R
5and R
6outside aforementioned definitions, also comprise that it is by isotopic labeling oxazolidinone compounds or its pharmacy acceptable salt, or its hydrate or solvate.One or more hydrogen atoms in preferred formula (I) can be replaced by D atom.Described isotope-labeled compound can make according to method provided by the invention, with isotope-labeled raw material, replaces nonisotopically labelled raw material.
Structure shown in formula (I), can also exist with enantiomorph or diastereomer form.Therefore, compound of the present invention also comprises enantiomorph, diastereomer or its combination of oxazolidinone compounds shown in formula (I).The compound of single steric configuration can obtain by ordinary method separated and purifying from enantiomorph or non-enantiomer mixture.
In addition, the compounds of this invention also comprises the prodrug of oxazolidinone compounds shown in formula (I).Term " prodrug " comprises it itself can being that have a biologic activity or inactive, after taking by appropriate means, it carries out metabolism or chemical reaction and changes a compounds of an accepted way of doing sth (I) in human body, or a compound of formula (I) salt or the solution that form.Described prodrug includes but is not limited to the forms such as the carboxylicesters, carbonic ether, phosphoric acid ester, nitric ether, sulfuric ester, sulfone ester, sulfoxide esters, aminocompound, carbaminate, azo-compound, phosphamide, glucoside, ether, acetal of described compound.
Preparation method
Those skilled in the art should understand, after the structure of cicada the compounds of this invention, can be by multiple method well known in the art, utilize known raw material, obtain compound of the present invention, such as chemosynthesis or the method extracted from plant, these methods all comprise in the present invention.Unless otherwise indicated or preparation method is provided, prepare compound of the present invention or its intermediate raw material used and be all known in the art maybe can be by commercially available.
More specifically describe the preparation method of formula of the present invention (I) structural compounds below, but these concrete grammars do not form any restriction to the present invention.The compounds of this invention can also be optionally by describe in this manual or various synthetic method known in the art combine and make easily, such combination can be easy to carry out by those skilled in the art in the invention.
As optimal way of the present invention, reaction process 1 or flow process 2 that can be by below and describe and prepare compound of the present invention.
Flow process 1
As shown in flow process 1, above-mentioned various in, R
2, R
3, R
4, R
5, R
6, R
7the same with the definition of X.Said method comprising the steps of:
(1) in inert solvent, at cuprous salt, in the situation that alkali and 1,2-, bis-amine ligands exist, by formula (VIII) compound and formula (XV) compound
carry out condensation reaction, thus the formula of obtaining (IX) compound;
Wherein, P
3and P
4cyclization forms as R
2shown lactan structure;
Described cuprous salt can be selected from: cuprous iodide, cuprous chloride, cuprous bromide, cuprous thiocyanate and Red copper oxide; Preferred cuprous iodide;
Described alkali can be selected from salt of wormwood, potassiumphosphate and cesium carbonate, preferably salt of wormwood or potassiumphosphate;
Described 1,2-bis-amine ligands are optional from N-methyl ethylenediamine, N, N '-dimethyl-ethylenediamine, N-butyl quadrol, 1,2-diamino-cyclohexane or N, N '-dimethylin hexanaphthene, preferred N, N '-dimethyl-ethylenediamine.
(2), in inert solvent, the nitro of formula (IX) compound is obtained to formula (X) compound through reduction reaction.
(3) in inert solvent, or under the common existence of Lewis acid, in the temperature range of-30 ℃～backflow, by formula (X) compound and formula (XI) compound
carry out ring-opening reaction, thus the formula of obtaining (XII) compound;
Wherein, P
1and P
2for the protecting group of amine, be preferably benzyl, to methoxy-benzyl, tert-butoxycarbonyl, phthaloyl, 2,3-phenylbenzene butylene diacyl;
Lewis acid can be selected from aluminum chloride, magnesium perchlorate, zinc chloride and Ytterbiumtriflate etc.
(4), under the existence of alkali, by formula (XII) compound and triphosgene, phosgene or N, N '-carbonyl dimidazoles carries out ring closure reaction, thus the formula of obtaining (XIII) compound;
Wherein, described alkali can be selected from 4-N, N dimethylamine yl pyridines, triethylamine, diisopropyl ethyl amine etc., preferred 4-N, N dimethylamine yl pyridines.
(5) formula (XIII) compound is carried out to deprotection reaction, thus the formula of obtaining (II) compound.
(6), when the X in formula (III) compound is halogen, in inert solvent, under the existence of alkali, formula (II) compound and formula (III) compound are carried out to condensation reaction, thus the formula of obtaining (XIV) compound; When the X in formula (III) compound is hydroxyl, in inert solvent, under the existence of dewatering agent and alkali, formula (II) compound and formula (III) compound are carried out to condensation reaction, thus the formula of obtaining (XIV) compound;
Wherein, described dewatering agent can be selected from N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (EDC.HCl), N, N '-diethyl carbodiimide, N, N '-dipropyl base carbodiimide, N, N '-di-isopropyl base carbodiimide, N, N '-dicyclohexylcarbodiimide, N, N '-carbonyl dimidazoles, O-benzotriazole-N, N, N ' N '-tetramethyl-urea hexafluorophosphate (HBTU), 2-(7-azepine-1H-benzotriazole-1-yl)-1, 1, 3, 3-tetramethyl-urea phosphofluoric acid ester (HATU), O-(1, 2-dihydro-2-Oxopyridyl)-1, 1, 3, 3-tetramethyl-urea a tetrafluoro borate (TPTU), 1-hydroxyl-benzotriazole (HOBt), benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP), or the mixture of they and alkali, wherein, described alkali can be selected from mineral alkali (as sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus), or organic bases (as 4-N, N dimethylamine yl pyridines, triethylamine, diisopropyl ethyl amine and N-methylmorpholine).
Reaction in above-mentioned each step is carried out in inert solvent, described inert solvent comprises methylene dichloride, trichloromethane, ethylene dichloride, methyl alcohol, ethanol, 1,4-dioxane, water, acetonitrile, normal hexane, toluene, tetrahydrofuran (THF), acetone, N, dinethylformamide, dimethyl sulfoxide (DMSO) etc., described reaction is carried out in-50～200 ℃.
Flow process 2
As shown in flow process 2, above-mentioned various in, R
2, R
3, R
4, R
5, R
6, R
7the same with the definition of X.Described method comprises step:
(1) under the existence of cuprous salt, alkali and 1,2-, bis-amine ligands, formula (IV) compound and formula (V) compound are carried out to condensation, thus the formula of obtaining (VI) compound;
Wherein, X is halogen, preferably iodine or bromine; P is hydroxyl protecting group, preferably trityl group, t-Butyldimethylsilyl, diphenyl methyl silica-based, to methoxy-benzyl, benzyl, methylsulfonyl or p-toluenesulfonyl;
Described cuprous salt can be selected from cuprous iodide, cuprous chloride, cuprous bromide, cuprous thiocyanate and Red copper oxide, preferably cuprous iodide;
Described alkali can be selected from salt of wormwood, potassiumphosphate and cesium carbonate, preferably salt of wormwood or potassiumphosphate;
Described 1,2-bis-amine ligands are optional from N-methyl ethylenediamine, N, N '-dimethyl-ethylenediamine, N-butyl quadrol, 1,2-diamino-cyclohexane or N, N '-dimethylin hexanaphthene, preferred N, N '-dimethyl-ethylenediamine.
(2) formula (VI) compound is carried out to ammoxidation, thus the formula of obtaining (II) compound.
(3) in inert solvent, formula (II) compound and formula (III) compound are carried out to condensation reaction, thus the formula of obtaining (XIV) compound.
Reaction in above-mentioned each step is carried out in inert solvent, described inert solvent comprises methylene dichloride, trichloromethane, ethylene dichloride, methyl alcohol, ethanol, 1,4-dioxane, water, acetonitrile, normal hexane, toluene, tetrahydrofuran (THF), acetone, DMF, dimethyl sulfoxide (DMSO) etc.; Described reaction is carried out in-50～200 ℃.
Pharmaceutical composition and application process
Because having excellent factor Xa, the compounds of this invention suppresses active, so the compounds of this invention or its pharmacy acceptable salt, or its various crystal formations, hydrate or solvate, and to contain the compounds of this invention be that the pharmaceutical composition of main active ingredient can be used as factor Xa (FXa) inhibitor, be used for the treatment of, prevent and alleviate the disease being mediated by factor Xa, also can be used for stoping solidifying of in vitro blood (particularly preserving blood or the biological sample that contains factor Xa).
According to prior art, the compounds of this invention can be used for prevention or treatment thromboembolic disorders disease, include, but is not limited to: (1) pulmonary embolism (pulmonary embolism): the embolus of PTE more than 90% from lower limb deep vein (as popliteal vein, femoral vein and iliac vein), also can be from pelvic veins, ovary, prostate gland PeV or uterine veins, minority can be from right heart mural thrombus.(2) body circulation arterial thrombosis: the embolus majority of body circulation arterial thrombosis is from the mural thrombus of the left heart and Arterial system (during as subacute bacterial endocarditis when heart valve vegetation, mitral stenosis the mural thrombus of left atrium mural thrombus, myocardial infarction); Minority betides the thrombus on atherosclerosis ulcer or aortic aneurysm surface; Only a few, from venacaval embolus, can enter the left heart by room, ventricular septal defect, and crossed embolism occurs.(3) thromboembolic complication also betides in microangiopathic hemolytic anemia, hemodialysis and heart valve repair operation.(4) after atherosclerosis, sacroiliitis, alzheimer's disease, tumour, myocardial infarction, stenocardia, angioplasty or aortocoronary bypass block again and narrow down again, apoplexy, of short duration local asphyxia outbreak, peripheral arterial occlusive disease, pulmonary infarction, dvt form, arterial thrombosis or gastrointestinal tract inflammation etc.(5) pulmonary hypertension.Described pulmonary hypertension comprises: 1) arterialness pulmonary hypertension (pulmonary arterial hypertension, PAH), as pulmonary hypertension, dependency pulmonary hypertension (associated with pulmonary arterial hypertension, APAH), persistent pulmonary hypertension of the new-born due to idiopathic pulmonary hypertension, inheritability pulmonary hypertension, medicine and poisonous substance.2) pulmonary hypertension due to left heart disease.3) pulmonary hypertension due to pulmonary disorder or hypoxemia, as chronic obstructive pulmonary disease, Interstitial Lung Disease, other pulmonary disorder, sleep apnea syndromes with restricted, obstructive or mixed ventilatory disorder.4) chronic thromboembolic states pulmonary hypertension (chronic thromboembolic pulmonary hypertension, CTEPH).5) not clear mechanism and (or) pulmonary hypertension due to number of mechanisms, as disease in the blood system: myeloproliferative disease, splenectomy; Systemic disease: sarcoidosis ,Fei langerhans cell histiocytosis, LAM, multiple neurofibromatosis, vasculitis; Metabolic disease: glycogenosis, gaucher's disease, thyroid disease etc.
Pharmaceutical composition of the present invention comprises the compounds of this invention in safe and effective weight range and pharmaceutically acceptable vehicle or carrier." safe and effective amount " refers to: the amount of compound is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect.Conventionally, pharmaceutical composition contains 1～2000mg the compounds of this invention/agent, more preferably, contains 1～200mg the compounds of this invention/agent.Preferably, described " potion " is a capsule or tablet.
" pharmaceutically acceptable carrier " refers to: one or more consistency solids or liquid filler or gelatinous mass, they are suitable for people uses, and must have enough purity and enough low toxicity." consistency " referred to herein as each component energy and compound of the present invention and blending mutually between them in composition, and the drug effect of not obvious reduction compound.Pharmaceutically acceptable carrier part example has Mierocrystalline cellulose and derivative (as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.) thereof, gelatin, talcum, solid lubricant (as stearic acid, Magnesium Stearate), calcium sulfate, vegetables oil (as soya-bean oil, sesame oil, peanut oil, olive wet goods), polyvalent alcohol (as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent (as tween
wetting agent (as sodium lauryl sulphate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
Pharmaceutical composition of the present invention can be diversified formulation, and the formulation that can make activeconstituents effectively arrive in mammalian body is all fine.As tablet, sugar coated tablet, pill, capsule, powder, particle, emulsion, syrup, solution, suspension, aerosol etc.Preferred pharmaceutical composition is solid-state composition, as the capsule of tablet, solid or liquid filling.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representational method of application comprises (but being not limited to): in oral, hypogloeeis, knurl, rectum, parenteral (transdermal, intraperitoneal, intravenously, intra-arterial, intramuscular or subcutaneous) and topical.Preferred oral administration and intravenously administrable.
Solid dosage for oral administration comprises capsule, tablet, pill, powder and granule.In these solid dosages, active compound mixes with at least one conventional inert excipient (or carrier), as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade, or mixes with following compositions: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; (b) tackiness agent, for example, Walocel MT 20.000PV, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose and gum arabic; (c) wetting Agent for Printing Inks, for example, glycerine; (d) disintegrating agent, for example, agar, calcium carbonate, yam starch or tapioca (flour), alginic acid, some composition silicate and sodium carbonate; (e) retarding solvent, for example paraffin; (f) absorb accelerator, for example, quaternary ammonium compound; (g) wetting agent, for example hexadecanol and glyceryl monostearate; (h) sorbent material, for example, kaolin; (i) lubricant, for example, talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and pill, formulation also can comprise buffer reagent.
Solid dosage is prepared as tablet, sugar-pill, capsule, pill and granule can adopt dressing and shell material, as casing and other material well known in the art.They can comprise opacifying agent, and, in the mode that in this composition, the release of active compound or compound can postpone certain part in digestive tube, discharge.The example of adoptable embedding component is polymeric material and Wax.If desired, active compound also can with above-mentioned vehicle in one or more form microencapsulation form.
Liquid dosage form for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup (as containing about 10-50wt% sugar) or tincture (as containing about 20-50wt% ethanol).Except active ingredient beyond the region of objective existence, liquid dosage form can comprise the conventional inert diluent adopting in this area, as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture of ethanol, Virahol, ethyl-carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, peanut oil, maize germ, sweet oil, Viscotrol C and sesame oil or these materials etc.
Except these inert diluents, composition also can comprise auxiliary agent, as wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and spices.
Except active ingredient beyond the region of objective existence, suspension can comprise suspension agent (as containing about 0.05-5wt% suspension agent), for example, mixture of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminum methylate and agar or these materials etc.
For the composition of parenteral injection, can comprise physiologically acceptable aseptic moisture or anhydrous solution, dispersion liquid, suspension (as oozed medium and contain 0.05～5wt% suspension agent of having an appointment waiting) or emulsion, and for being again dissolved into aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, thinner, solvent or vehicle comprises water, ethanol, polyvalent alcohol and suitable mixture thereof.
The formulation that is used for the compounds of this invention of topical comprises ointment, powder, patch, propellant and inhalation.Activeconstituents under aseptic condition with physiologically acceptable carrier and any sanitas, buffer reagent, or the propelling agent that may need is if desired mixed together.
The compounds of this invention can be individually dosed, or with other medicine Combined Preparation.The medicine of described other includes, but is not limited to: the second factor Xa inhibitor, antidiabetic medicine, antiplatelet drug, antibiotic medicine, anti-coagulant, inotropic agent and vasopressor (as adrenin, non-adrenin), thrombin inhibitors, thrombolytic agent, fibrinolytic agent, treatment medicine for ulcer and Antiatherosclerosis medicine.
In another preference, described other medicine comprises: warfarin, heparin, pentasaccharides, r-hirudin, argatroban, acetylsalicylic acid, Ibuprofen BP/EP, methoxy how propionic acid, sulindac, indomethacin, vialidon, Droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, Tirofiban, Eptifibatide, A Xi monoclonal antibody melagatran, organize pricker dissolved preferment activator, compound pricker dissolved preferment activator, urokinase, streptokinase or its combination.
While making pharmaceutical composition, the compounds of this invention of safe and effective amount to be applicable to need the Mammals (as people) for the treatment of, the effective dosage of dosage for pharmaceutically thinking while wherein using, during oral administration, day dosage is generally 0.01～500mg/kg body weight, be preferably 0.01～100mg/kg body weight, more preferably 0.01～30mg/kg body weight.Preferably with the dosage separating for 1～3 time, give every day, or with slowly-releasing form administration.During intravenous administration, a day dosage is generally 0.01～100mg/kg body weight, is preferably 0.01～50mg/kg body weight, more preferably 0.01～30mg/kg body weight.Certainly, concrete dosage also should be considered the factors such as compound used, route of administration, patient health situation, and these are all within skilled practitioners skill.
Major advantage of the present invention comprises:
(1) provide novel cpd shown in the formula (I) with good pharmacokinetics performance and good external factor Xa rejection and preparation method thereof.
(2) provide the purposes of the compounds of this invention, described compound has excellent anticoagulant factor xa activity, can pass through anticoagulant factor Xa, thus effectively treatment and or prevention thromboembolism associated conditions etc., there is fabulous prospect in medicine.
(3) provide a kind of pharmaceutical composition that the compounds of this invention is activeconstituents of take.
Below in conjunction with concrete enforcement, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise per-cent and umber calculate by weight.
The preparation of the chloro-N-of embodiment 1 (S)-5-((3-(2-methoxyl group-4-(3-oxo-morpholine) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides
The preparation of 1.14-(3-methoxyl group-4-nitrophenyl) morpholine-3-ketone (compound 13)
Under nitrogen protection; to 250mL reaction flask, add successively the bromo-2-methoxyl group-1-of 4-oil of mirbane (9.0g; 38.8mmol), morpholine-3-ketone (4.7g; 46.5mmol), cuprous iodide (0.36g; 1.9mmol), Anhydrous potassium carbonate (10.8g, 77.6mmol) and dry toluene (80mL).Under nitrogen protection, to it, add N, N '-dimethyl-ethylenediamine (0.345g, 3.9mmol).After back flow reaction 12h, temperature of reaction system is cooled to 25 ℃, water cancellation is reacted and is used dichloromethane extraction three times.Merge organic layer, and water and salt solution washing successively, anhydrous sodium sulfate drying used.Concentrate and obtain residue, and (petrol ether/ethyl acetate=6/1～4/1, v/v) purifying obtains white solid target product (7.0g, 71.6% yield) with silica gel column chromatography.
1H NMR(CD
3OD，400MHz):7.92(d,J=8.8Hz,1H),7.44(d,J=2.4Hz,1H),7.14(dd,J=8.8and2.4Hz,1H),4.33(s,2H),4.09(d,J=4.8Hz,1H),4.07(d,J=3.2Hz,1H),3.98(s,3H),3.89(d,J=4.0Hz,1H),3.87ppm(d,J=4.8Hz,1H)。
The preparation of 1.24-(4-amino-3-p-methoxy-phenyl) morpholine-3-ketone (compound 14)
At 25 ℃, 4-(3-methoxyl group-4-nitrophenyl) morpholine-3-ketone (0.85g, 3.37mmol) is dissolved in methyl alcohol (20mL), under nitrogen protection, to it, adds palladium/charcoal (0.04g) of 10%.Under hydrogen atmosphere, reaction 16h.Tlc (developping agent: ethyl acetate/petroleum ether=1/2) show and react completely.Reaction mixture is filtered to methylene dichloride for filter cake (5mL * 2) washing.Concentrated filtrate, to dry, obtains white solid target compound 4-(4-amino-3-p-methoxy-phenyl) morpholine-3-ketone (0.72g, 96% yield).
1H NMR(CDCl
3，400MHz):6.77(d,J=2.0Hz,1H),6.72(s,1H)),6.71(d,J=2.0Hz,1H),4.35(s,2H),4.03(t,J=5.2Hz,2H),3.87(s,3H),3.72ppm(t,J=5.2Hz,2H)。
1.3 (R)-2-(2-hydroxyl-3-(2-methoxyl group-4-(3-oxo-morpholine) phenyl amido) propyl group) isoindole-1, the preparation of 3-diketone (compound 15)
By N-(2,3-(S)-epoxypropyl) phthalic diamide (5.6g, 27.7mmol) and 4-(4-amino-3-p-methoxy-phenyl) morpholine-3-ketone (5.6g, 25.2mmol) join in the mixed solvent (volume ratio 9/1, altogether 100mL) of second alcohol and water.Above-mentioned suspension reflux is added N-(2,3-(S)-epoxypropyl) phthalic diamide (1.06g, 4.9mmol) after 15 hours.Continue stirring and refluxing 12h.After reacting completely, concentrated reaction mixture.Through silica gel column chromatography, (petrol ether/ethyl acetate=3/1～3/2, v/v) purifying obtains yellow solid target product (6.9g, 64.5% yield) to residue.
1H NMR(CDCl
3，400MHz):7.85-7.81(m,2H),7.73-7.69(m,2H),6.71(dd,J=8.4,2.0Hz,1H),6.69(d,J=2.0Hz,1H),6.59(d,J=8.4Hz,1H),4.27(s,2H),4.13-4.09(m,1H),3.98(t,J=5.2Hz,2H),3.90-3.82(m,2H),3.81(s,3H),3.67(t,J=5.2Hz,2H),3.26(dd,J=13.2,4.8Hz,1H),3.15ppm(dd,J=13.2,7.2Hz,1H)。
1.4 (S)-2-((3-(2-methoxyl group-4-(3-oxo-morpholine) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) isoindole-1, the preparation of 3-diketone (compound 16)
By (R)-2-(2-hydroxyl-3-(2-methoxyl group-4-(3-oxo-morpholine) phenyl amido) propyl group) isoindole-1,3-diketone (0.4g, 0.94mmol) join in tetrahydrofuran (THF) (10mL), add successively again N, N '-carbonyl dimidazoles (0.46g, 2.81mmol) with 4-methylamino pyridine (0.012g, 0.1mmol).Backflow (60 ℃) is reacted 12 hours.After reacting completely, be down to room temperature, add dehydrated alcohol (0.2mL), continue to stir 15min.Filter, filter cake is with after absolute ethanol washing, and vacuum-drying obtains white solid target product (0.3g, 71% yield).
1H NMR(CDCl
3，400MHz):7.93-7.89(m,2H),7.80-7.77(m,2H),7.42(d,J=8.4Hz,1H),7.02(d,J=2.0Hz,1H),6.90(dd,J=8.4,2.0Hz,1H),5.08-5.01(m,1H),4.37(s,2H),4.19(dd,J=14.0,6.8Hz,1H),4.08-4.04(m,3H),4.19(dd,J=14.0,5.2Hz,1H),3.87(s,3H),3.84(dd,J=9.6,5.6Hz,1H),3.77ppm(t,J=5.2Hz,2H)。
The preparation of 1.5 (S)-4-(4-(5-(amino methyl)-2-Yang Dai oxazolidine-3-yl)-3-p-methoxy-phenyl) morpholine-3-keto hydrochloride (compound 17)
By (S)-2-((3-(2-methoxyl group-4-(3-oxo-morpholine) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) isoindole-1,3-diketone (0.3g, 0.66mmol) join in ethanol (4mL), then add the aqueous solution (1.0mL) of 32wt% methylamine to it.Be warmed up to 65 ℃ and stir 3 hours, react completely.Be cooled to after 50 ℃, with concentrated hydrochloric acid, regulate pH to 2～3, have solid to separate out.Be cooled to 0 ℃ and stir after 1 hour, filter, filter cake washing with alcohol, vacuum-drying to constant weight obtains white solid target compound (0.22g, 93% yield) at 40 ℃.
1H NMR(DMSO-d6，400MHz):8.37(br,3H),7.40(d,J=8.4Hz,1H),7.21(d,J=2.0Hz,1H),7.02(dd,J=8.4,2.0Hz,1H),4.96-4.94(m,1H),4.22(s,2H),4.04(t,J=8.8Hz,1H),3.99(t,J=5.2Hz Hz,2H),3.83(s,3H),3.77(t,J=5.2Hz,2H),3.68(dd,J=9.2Hz,6.0Hz,1H),3.28-3.17ppm(m,1H)。
The preparation of the chloro-N-of 1.6 (S)-5-((3-(2-methoxyl group-4-(3-oxo-morpholine) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides
To single port flask (50mL), add (S)-4-(4-(5-(amino methyl)-2-Yang Dai oxazolidine-3-yl)-3-p-methoxy-phenyl) morpholine-3-keto hydrochloride (100mg, 0.28mmol) and triethylamine (117uL, 0.84mmol), 1-hydroxyl-benzotriazole (HOBT, 57mg, 0.42mmol) and N, N-METHYLFORMAMIDE (1.5mL), after stirring 30min under room temperature, add 5-chlorothiophene-2-formic acid (55mg, 0.34mmol) and N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (EDCHCl, 81mg, 0.42mmol).Under room temperature nitrogen protection, stir 24 hours, thin-layer chromatography monitoring reacts completely.Under stirring, add saturated sodium bicarbonate aqueous solution (25ml) and pure water (15ml), continue to stir 1 hour under room temperature, have a large amount of white solids to separate out, filter, solid washs with pure water.40 ℃ of vacuum-drying to constant weights obtain white solid target compound (80mg, 62% yield).
1H NMR(DMSO-d6，400MHz):δ9.00(t,J=6.0Hz,1H),7.74(d,J=4.0Hz,1H),7.29(d,J=8.4Hz,1H),7.23(d,J=4.0Hz,1H),7.16(d,J=2.0Hz,1H),6.98(dd,J=8.4,2.0Hz,1H),4.85-4.81(m,1H),4.21(s,2H),4.01-3.97(m,3H),3.76-3.74(m,5H),3.70-3.67(m,1H),3.66-3.55ppm(m,2H)；MS ES
+(m/z):466(M+H)
+。
The preparation of the chloro-N-of embodiment 2 (S)-5-((3-(2-hydroxyl-4-(3-oxo-morpholine) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides
By the chloro-N-of compound (S)-5-((3-(2-methoxyl group-4-(3-oxo-morpholine) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides (0.2g, 0.43mmol) be dissolved in anhydrous methylene chloride (3mL), be cooled to-50 ℃, to it, slowly drip anhydrous methylene chloride (1mL) solution of boron tribromide (220 μ L, 0.88mmol).After dripping, stir 30min, be warmed up to 25 ℃ of reaction 12h.Cool to-40 ℃, drip methyl alcohol (1mL) cancellation reaction.Add frozen water (5mL) diluting reaction.Separate organic layer, twice of dichloromethane extraction of water layer.Merge organic layer, water and salt solution washing successively, anhydrous sodium sulfate drying, concentrated, through Preparative TLC chromatographic separation, (methylene chloride/methanol=20/1 v/v) obtains white solid target product (0.11g, 56.7% yield) to residue.
1H NMR(DMSO-d6,400MHz):δ10.23(bs,1H),9.16(s,1H),7.82(d,J=4.4Hz,1H),7.22-7.20(m,2H),7.03(s,1H),6.82(dd,J=8.4,2.0Hz,1H),4.84-4.81(m,1H),4.16(s,2H),4.03-3.975(m,3H),3.73-3.62(m,3H),3.62-3.56ppm(m,2H)。
The chloro-N-of embodiment 3 (S)-5-((3-(2-(methoxyl group-d
3)-4-(3-oxo-morpholine) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) the preparation of thiophene-2-acid amides
Sodium hydroxide (18g, 0.45mol, 5.0eq) is joined in water (30mL), at 0 ℃, add deuterated methanol (3.24g, 90mmol, 1.0eq), and slowly drip tetrahydrofuran (THF) (30mL) solution of Tosyl chloride (20.6g, 0.11mmol, 1.2eq).Rise to stirred overnight at room temperature.At 25 ℃ of following acetic acid (20.6g) that drip, be neutralized to neutrality (pH～7), filter, layering, ethyl acetate for water layer (10mL) extraction; Filter cake water (30mL) dissolves, and is extracted with ethyl acetate (20mL); Merge organic phase, with saturated sodium carbonate (20mL), saturated aqueous common salt (20mL) washing, anhydrous sodium sulfate drying, concentrated, obtain light yellow liquid 4-toluene sulfonic acide-(the deuterated methyl of 1,1,1-tri-) ester 16.05g, purity 99%, yield 94%.
1H NMR(CDCl
3，400MHz):δ3.20(s,3H),7.71-7.75(m,2H),7.84-7.88ppm(m,2H)。
Under nitrogen protection; under room temperature by the chloro-N-of compound (S)-5-((3-(2-hydroxyl-4-(3-oxo-morpholine) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides (80mg; 0.18mmol) be dissolved in anhydrous N; in dinethylformamide (1mL); add salt of wormwood (122mg; 0.89mmol) and stir after 20min; to it, add 4-toluene sulfonic acide-(1; 1; the deuterated methyl of 1-tri-) ester (52mg; anhydrous DMF (0.5mL) solution 0.27mmol).After adding, in stirred overnight at room temperature.Frozen water cancellation reaction, and with dichloromethane extraction three times.Merge organic layer, successively water and salt solution washing.Anhydrous sodium sulfate drying, concentrated, residue obtains white solid target product (35mg, 42% yield) through Preparative TLC chromatographic separation and purification.
1H NMR(DMSO-d6，400MHz):δ9.00(t,J=6.0Hz,1H),7.74(d,J=4.0Hz,1H),7.29(d,J=8.4Hz,1H),7.23(d,J=4.0Hz,1H),7.16(d,J=2.0Hz,1H),6.98(dd,J=8.4,2.0Hz,1H),4.85-4.81(m,1H),4.21(s,2H),4.01-3.97(m,3H),3.76-3.74(m,2H),3.70-3.67(m,1H),3.66-3.55ppm(m,2H)。MS ES
+(m/z):469(M+H)
+。
The preparation of the chloro-N-of embodiment 4 (S)-5-((3-(2-(cyclo propyl methoxy)-4-(3-oxo-morpholine) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides
Under nitrogen protection; by the chloro-N-of compound (S)-5-((3-(2-hydroxyl-4-(3-oxo-morpholine) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides (0.113g; 0.25mmol) be dissolved in anhydrous N; in dinethylformamide (3mL); add cesium carbonate (0.163g; 0.50mol) and stir after 30min; to it, add Cyclopropyl Bromide (101mg; anhydrous DMF (0.5mL) solution 0.75mmol).After adding, be warmed up to 50 ℃ and stir 10h.Reaction solution drops to room temperature, with frozen water cancellation reaction, and with dichloromethane extraction three times.Merge organic layer, water and salt solution washing successively, anhydrous sodium sulfate drying, concentrated, residue obtains white solid target product through preparative liquid chromatography separation and purification.MS ES
+(m/z):506(M+H)
+。
The preparation of the chloro-N-of embodiment 5 (S)-5-((3-(2-(difluoro-methoxy)-4-(3-oxo-morpholine) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides
Under nitrogen protection; 0 ℃ by the chloro-N-of compound (S)-5-((3-(2-hydroxyl-4-(3-oxo-morpholine) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides (0.113g; 0.25mmol) be dissolved in anhydrous tetrahydro furan (2mL); add 35wt% aqueous sodium hydroxide solution (35mg; 0.30mmol) and stir after 30min, to the logical about 30min of difluorochloromethane of mixed solution.After having led to, be warmed up to 20 ℃ and also stir and spend the night.With frozen water cancellation reaction, and with dichloromethane extraction three times.Merge organic layer, water and salt solution washing successively, anhydrous sodium sulfate drying is concentrated, and residue obtains white solid target product through preparative liquid chromatography separation and purification lyophilize.MS ES
+(m/z):502(M+H)
+。
The preparation of the chloro-N-of embodiment 6 (S)-5-((3-(2-methoxyl group-4-(2-oxo pyridine-1 (2H)-yl) phenyl)-2-oxygen is for oxazolidine-5-yl) methyl) thiophene-2-acid amides
According to the preparation method of embodiment 1, difference is to replace morpholine-3-ketone by pyridine-2 (1H)-one.MSES
+(m/z):460(M+H)
+。
The preparation of the chloro-N-of embodiment 7 (S)-5-((3-(the fluoro-2-methoxyl group-4-of 5-(3-oxo-morpholine) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides
According to the preparation method of embodiment 1, difference is to replace the bromo-2-methoxyl group-1-of 4-oil of mirbane with the fluoro-5-methoxyl group-4-of the bromo-2-of 1-oil of mirbane.MS ES
+(m/z):484(M+H)
+。
The preparation of the chloro-N-of embodiment 8 (S)-5-((3-(2-oxyethyl group-4-(3-oxo-morpholine) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides
According to the preparation method of embodiment 3, difference is to replace 4-toluene sulfonic acide-(the deuterated methyl of 1,1,1-tri-) ester with 4-toluene sulfonic acide ethyl ester.MS ES
+(m/z):480(M+H)
+。
The chloro-N-of embodiment 9 (S)-5-(preparation of (3-(2-(2-(2-fluorine oxyethyl group) oxyethyl group-4-(3-oxo-morpholine) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides
According to the preparation method of embodiment 3, difference is to replace 4-toluene sulfonic acide-(the deuterated first of 1,1,1-tri-) ester with 4-toluene sulfonic acide-2-(2-fluorine oxyethyl group) ethyl ester.MS ES
+(m/z):542(M+H)
+。
The preparation of the chloro-N-of embodiment 10 (S)-5-((3-(2-(2-ring propoxy-oxyethyl group)-4-(3-oxo-morpholine) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides
According to the preparation method of embodiment 3, difference is to replace 4-toluene sulfonic acide-(the deuterated methyl of 1,1,1-tri-) ester with 4-toluene sulfonic acide-2-(2-encircles propoxy-) ethyl ester.MS ES
+(m/z):564(M+H)
+。
The preparation of the chloro-N-of embodiment 11 (S)-5-((3-(2-methoxyl group-4-(2-oxo-piperidine-1-yl) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides
The preparation of 11.11-(the bromo-3-p-methoxy-phenyl of 4-) piperidines-2-ketone
In there-necked flask, add to the bromo-3-anisidine of 4-(8.89g, 0.044mol) chlorobenzene (18mL) and tetrahydrofuran (THF) (12mL), stirring and dissolving.To it, slowly add the wet chemical (13.3g) of 40wt%.Above-mentioned mixed solution is cooled to 10 ℃, at 10～15 ℃, to it, slowly drips 5-bromine valeryl chloride (97%, 9.51g, 0.046mol).Keeping temperature is 10～15 ℃, and reaction solution stirs 4h.() keeps temperature is 10～15 ℃, to it, is added dropwise to tetrabutyl phosphonium bromide aqueous ammonium (0.25g is dissolved in 2mL water) and potassium hydroxide aqueous solution (6.16g is dissolved in 7mL water).After dripping, keeping temperature is 10～15 ℃, stirs 10h.Thin-layer chromatography detects (ethyl acetate: sherwood oil=1:1) reacted.With concentrated hydrochloric acid (37wt%, about 3g), reconciling pH value is 7 left and right, and is extracted with ethyl acetate (30mL * 3) three times.Merge organic layer, with hydrochloric acid (20mL * 2), the saturated sodium bicarbonate aqueous solution (20mL * 2) of 2N, water (20mL) and saturated aqueous common salt (20mL) wash successively, anhydrous sodium sulfate drying.And with gac (2g) decolouring 1h.Filter the concentrated residue that obtains of filtrate.Above-mentioned residue is obtained to target product (10.3g, 82.4% productive rate) through silica gel column chromatography.
11.2 (R)-5-(preparation of hydroxymethyl) oxazolidine-2-ketone
At 25 ℃, in there-necked flask, add water (40mL), (R)-3-aminopropyl-1,2-alcohol (2.0g, 21.96mmol) and sodium carbonate (8.16g, 76.88mmol).Under stirring, slowly add triphosgene (2.96g, 11.0mmol).React after 4 hours, with dilute hydrochloric acid (about 2N) neutralization reaction liquid, be about 7.5 to pH.Remove organic volatile.Residue is dissolved in dehydrated alcohol, removes by filter inorganics.Filtrate concentrating is directly used in next step reaction after doing.
11.3 (R)-5-(preparation of triphenyl methoxymethyl) oxazolidine-2-ketone
To adding methylene dichloride (120mL), (R)-5-in there-necked flask, (hydroxymethyl) oxazolidine-2-ketone (6.3g, 0.054mol) and pyridine (5.3mL, 0.065mol) stir and cool to 0～5 ℃.Control temperature, to it, add triphenylmethyl chloride (16.5g, 0.059mol), after adding, be warmed up to 25 ℃ and stir 15h.With dilute hydrochloric acid (about 2N) cancellation reaction, and with dichloromethane extraction three times.Merge organic layer, water and salt solution washing successively, anhydrous sodium sulfate drying, concentrated, residue obtains white solid target product (10.68g, 55% yield) through silica gel column chromatography (ethyl acetate/petroleum ether=2/1) separation and purification.
1H NMR(CDCl
3，400MHz):δ7.49～7.46(m,6H),7.36～7.32(m,6H),7.27～7.25(m,3H),4.80～4.73(m,1H),3.64(t,J=8.8Hz,1H),3.47(t,J=8.8Hz,1H),3.42(dd,J=10.0and4.0Hz,1H),3.25(dd,J=10.0and4.0Hz,1H)。
11.4 (R)-3-(2-methoxyl group-4-(2-oxo-piperidine-1-yl) phenyl)-5-(preparation of triphenyl methoxymethyl) oxazolidine-2-ketone
To Schlenk reaction tubes, add successively 1,4-dioxane and N, the mixed solvent (4/1 of dinethylformamide, v/v, 25mL), 1-(the bromo-3-p-methoxy-phenyl of 4-) piperidines-2-ketone (2.84g, 0.01mol), (R)-5-(triphenyl methoxymethyl) oxazolidine-2-ketone (7.19g, 0.02mol) and potassiumphosphate (4.25g, 0.02mol).Under argon shield, to it, add N, N '-dimethyl-ethylenediamine (0.176g, 0.002mol) and cuprous iodide (0.19g, 0.001mol).At 90 ℃ of tube sealing reaction 30h.Be cooled to 25 ℃, water cancellation reaction, and with dichloromethane extraction three times.Merge organic layer, water and salt solution washing successively, anhydrous sodium sulfate drying, concentrated, (petrol ether/ethyl acetate=1/3, v/v) purifying obtains white solid target product (2.25g, 40% yield) to silica gel column chromatography for residue.
The preparation of 11.5 (R)-1-(4-(5-(hydroxymethyl)-2-Yang Dai oxazolidine-3-yl)-3-p-methoxy-phenyl) piperidines-2-ketone
By (R)-3-(2-methoxyl group-4-(2-oxo-piperidine-1-yl) phenyl)-5-(triphenyl methoxymethyl) oxazolidine-2-ketone (2.0g, 3.56mmol) be dissolved in methylene dichloride (28mL) and methyl alcohol (3mL), under stirring, to it, add tosic acid with hydrate (1.36g, 7.12mmol), at 25 ℃, stir 12h.Water cancellation reaction, and with dichloromethane extraction three times.Merge organic layer, water and salt solution washing successively, anhydrous sodium sulfate drying, concentrated, (petrol ether/ethyl acetate=1/4, v/v) purifying obtains white solid target product (0.96g, 84% yield) to silica gel column chromatography for residue.
1H NMR(CDCl
3，400MHz):δ7.39(d,J=8.4Hz,1H),6.93(d,J=2.0Hz,1H),6.86(d,J=8.4and2.0Hz,1H),4.80-4.73(m,1H),4.02-3.92(m,2H),3.87-3.79(m,5H),3.64(t,J=6.0Hz,2H),2.58(t,J=6.0Hz,2H),1.98-1.94(m,4H)；MS ES
+(m/z):321(M+H)
+。
The preparation of 11.6 (R)-(3-(2-methoxyl group-4-(2-oxo-piperidine-1-yl) phenyl)-2-Yang Dai oxazolidine-5-yl) methylmethanesulfonate ester
By (R)-1-(4-(5-(hydroxymethyl)-2-Yang Dai oxazolidine-3-yl)-3-p-methoxy-phenyl) piperidines-2-ketone (0.81g, 2.52mmol) and triethylamine (0.72mL, 5.07mmol) be dissolved in methylene dichloride (10mL), be cooled to 0～5 ℃, to it, add methylsulfonyl chloride (0.42mL, 3.81mmol).After adding, keep 0～5 ℃ of stirring reaction 4h.Water cancellation reaction, and with dichloromethane extraction three times.Merge organic layer, use successively dilute hydrochloric acid (1N), water and salt solution washing, anhydrous sodium sulfate drying, concentrated, (methanol/ethyl acetate=1/25, v/v) purifying obtains white solid target product (0.81g, 81% yield) to silica gel column chromatography for residue.
The preparation of 11.7 (R)-1-(4-(5-(azido-methyl)-2-Yang Dai oxazolidine-3-yl)-3-p-methoxy-phenyl) piperidines-2-ketone
At 20 ℃, by (R)-(3-(2-methoxyl group-4-(2-oxo-piperidine-1-yl) phenyl)-2-Yang Dai oxazolidine-5-yl) methylmethanesulfonate ester (600mg, 1.5mmol) be dissolved in N, dinethylformamide (20mL), to it, add sodiumazide (200mg, 3.0mmol).Reaction system is warmed up to 70 ℃ and stirring reaction 6h.After cool to room temperature, with frozen water cancellation reaction, and with dichloromethane extraction three times.Merge organic layer, water and salt solution washing successively, anhydrous sodium sulfate drying, concentrated, residue is directly used in next step reaction.
11.8 (S)-5-(amino methyl)-3-(preparation of 2-methoxyl group-4-(2-oxo-piperidine-1-yl) phenyl) oxazolidine-2-ketone
By (R)-1-(4-(5-(azido-methyl)-2-Yang Dai oxazolidine-3-yl)-3-p-methoxy-phenyl) piperidines-2-ketone (0.345g, 1.0mmol) be dissolved in ether (10mL), cool to 0 ℃, to it, add triphenylphosphine (0.32g, 1.2mmol).Stirring reaction 6h.To it, add water (2mL) and be raised to room temperature, continuing to stir and spend the night.Frozen water diluting reaction, ethyl acetate aqueous layer extracted three times.Merge organic layer, water and salt solution washing successively, anhydrous sodium sulfate drying, concentrated, residue obtains target compound (0.16g, 50% yield) through preparation TLC separation and purification.
The preparation of the chloro-N-of 11.9 (S)-5-((3-(2-methoxyl group-4-(2-oxo-piperidine-1-yl) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides
In methylene dichloride (6mL), add successively (S)-5-(amino methyl)-3-(2-methoxyl group-4-(2-oxo-piperidine-1-yl) phenyl) oxazolidine-2-ketone (150mg, 0.47mmol), 5-chlorothiophene-2-formic acid (92mg, 0.56mmol) and N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (108mg, 0.56mmol), stirring at room 6h.Frozen water cancellation reaction, and with dichloromethane extraction water layer three times.Merge organic layer, successively with dilute sodium hydroxide aqueous solution, water and salt solution washing, anhydrous sodium sulfate drying, concentrated, residue obtains white solid target product (98mg, 45% yield) with preparative liquid chromatography separation and purification.MS ES
+(m/z):464(M+H)
+。
The preparation of the chloro-N-of embodiment 12 (S)-5-((3-(2-hydroxyl-4-(2-oxo-piperidine-1-yl) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides
According to the preparation method of embodiment 2, different is to replace the chloro-N-of (S)-5-((3-(2-methoxyl group-4-(3-oxo-morpholine) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides with the chloro-N-of (S)-5-((3-(2-methoxyl group-4-(2-oxo-piperidine-1-yl) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides.MS ES
+(m/z):448(M-H)
-。
The chloro-N-of embodiment 13 (S)-5-((3-(2-(methoxyl group-d
3)-4-(2-oxo-piperidine-1-yl) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) the preparation of thiophene-2-acid amides
According to the preparation method of embodiment 3, different is to replace the chloro-N-of (S)-5-((3-(2-hydroxyl-4-(3-oxo-morpholine) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides with the chloro-N-of (S)-5-((3-(2-hydroxyl-4-(2-oxo-piperidine-1-yl) phenyl)-2-Yang Dai oxazolidine-5-yl) methyl) thiophene-2-acid amides.MS ES
+(m/z):467(M+H)
+。
Embodiment 14 the compounds of this invention Bioactivities are evaluated
1, human blood coagulation Xa restraining effect IC
50mensuration
Human blood coagulation Xa (FXa) is a kind of serine protease, its enzymic activity by can be from chromogenic substrate for the specific chromogenic substrate of FXa the transformation assay of cancellation p-Nitroaniline.Because substrate has absorption peak at 405nm place, therefore measuring its enzymic activity can complete by spectrophotometry 405nm optical density.
Be determined in 96 orifice plates and carry out.Compound to be tested (embodiment 1～13 preparation arbitrary compound) is dissolved in DMSO, and is made into the test fluid of different concns, and with human blood coagulation Xa25 ℃ incubation 10 minutes.Take pure DMSO as blank.Add chromogenic substrate (such as 1mmol/L, F3301, Sigma), after 25 ℃ of incubation 20min, under 405nm, measure optical density.The measured value that contains material to be tested and the measured value that do not contain material to be tested relatively and by these data are calculated to IC
50value.
Result shows: compound of the present invention has lower IC
50value.The external IC of the compound of the embodiment of the present invention 1～13 preparation
50all lower than 50nM, wherein embodiment 1 and 3 Compound I C
50lower.
Table 1
| Compound | IC 50[nM] |
| Embodiment 1 | <1 |
| Embodiment 3 | <1 |
2, the mensuration of compound selective
For the selectivity of the compounds of this invention to human blood coagulation Xa is described, tested the compounds of this invention to other mankind's serine protease, as the restraining effect of trypsinase and zymoplasm.
For measuring the enzymic activity of trypsinase and zymoplasm, these enzymes are dissolved in to Tris damping fluid (10mmol/L Tris-Cl, pH8.0,20mmol/L CaCl
2) and in compound to be tested or blank solvent DMSO incubation 10min.Then add specificity chromogenic substrate (as the S-2238TM of the CS-05 of Biophen company (88) REF2290901 or Chromogenix company), after 37 ℃ of incubation 20min, under 405nm, measure optical density.The measured value that contains material to be tested and the measured value that do not contain material to be tested relatively and by these data are calculated to IC
50value.
Test result shows, the compounds of this invention has good selectivity to human blood coagulation Xa.
The mensuration of anti-thrombosis activity in embodiment 15 the compounds of this invention bodies
Adopt rat vein thrombus model to detect anti-thrombosis activity in the compounds of this invention body.
The Sprague-Dawley rat in 6～8 week age, 190～230 grams of body weight, anaesthetize by intraperitoneal administration vetanarcol (50mg/kg) after fasting on an empty stomach.Along navel white line, to Intersternal incision, open abdominal cavity, expose postcaval vein.By postcaval vein and left renal vein for intersection silk thread (4-0) and blunt pin (external diameter 0.9mm) knotting at postcaval vein, form local extravasated blood.Remove blunt pin.At the saturated test paper (0.3 * 1cm) of postcaval vein exterior applications 6%w/v iron trichloride, after 5min, remove test paper.With mosquito forceps, incision muscle layer and skin is temporarily closed.At the tissue of incision, spray the salt solution of temperature (37 ℃).Remove iron trichloride test paper after 1 hour, opening wound and take off thrombus, wiping the weight in wet base of measuring as early as possible thrombus after the unnecessary blood in surface.Using iron trichloride test paper, within first 1 hour, by compound to be tested (arbitrary compound of embodiment 1～13 preparation), through pharyngeal canal oral administration, positive control is through pharyngeal canal oral administration razaxaban, and negative control is blank.
Result shows, the compounds of this invention all has anti-thrombosis activity in good body.
Pharmacokinetic in the body of embodiment 16 the compounds of this invention
(1) 4 male Sprague-Dawley rat, body weight 220g left and right, after overnight fasting, gavage gives the mixing solutions [PEG400 and dimethyl sulfoxide (DMSO) are carrier] of 3mg/kg body weight compound to be tested (arbitrary compound of embodiment 1～13 preparation) and control compound razaxaban.After administration 0.083,0.25,0.5,1.0,2.0,4.0,6.0,8.0,12.0 and 24.0h eye socket blood sampling, with LC-MS/MS, measure the concentration of the compounds of this invention in blood plasma respectively.Pharmacokinetic parameter calculates in the Plasma Concentration of different time points based on every animal.
From table 2 result, find out, with respect to razaxaban, the compounds of this invention has pharmacokinetic properties in good body (as longer transformation period and better larger area under curve value (AUC)) in rat body, has better pharmacodynamics and result for the treatment of.Wherein, the transformation period of the compound of embodiment 1 and embodiment 3 is respectively 3.33 ± 0.59 hours and 3.35 ± 0.62 hours, compared with razaxaban significant prolongation (being respectively 35.9% and 36.7%); Area under curve (AUC0-∞) also significantly increases, and is respectively 2.5 times and 3.0 times of razaxaban AUC0-∞.These better pharmacokinetic properties may give these compounds better clinical therapeutic efficacy, lower production cost, and medication, meanwhile, also may give these compounds better security feature more easily.
Table 2 embodiment 1 and the pharmacokinetic data of embodiment 3 compounds in rat
| Compound | Razaxaban | Embodiment 1 | Embodiment 3 |
| T1/2(h) | 2.45±1.16 | 3.33±0.59 | 3.35±0.62 |
| T max(h) | 0.88±0.75 | 1.25±0.50 | 1.25±0.50 |
| C max(ng/mL) | 810±49 | 1751±191 | 2048±243 |
| AUC 0-t(ng·h/mL) | 2828±698 | 7258±1448 | 8471±1611 |
| AUC 0-∞(ng·h/mL) | 2854±701 | 7274±1444 | 8491±1608 |
| Vz(/F)(mL/kg) | 3746±1605 | 2050±591 | 1756±479 |
| CL(/F)(mL/h/kg) | 1095±242 | 424±81 | 363±67 |
| MRT(h) | 2.61±030 | 3.16±0.28 | 3.17±0.30 |
(2) 4 male rabbits, body weight 2kg left and right, after overnight fasting, gavage gives the mixing solutions [PEG400 and dimethyl sulfoxide (DMSO) are carrier] of 1mg/kg body weight compound to be tested (arbitrary compound of embodiment 1～13 preparation) and control compound razaxaban.After administration 0.083,0.25,0.5,1.0,2.0,4.0,6.0,8.0,12.0 and 24.0h ear edge vein exploitating blood, with LC/MS/MS, measure the concentration of the compounds of this invention in blood plasma respectively.Pharmacokinetic parameter calculates in the Plasma Concentration of different time points based on every animal.
Result shows, the compounds of this invention has pharmacokinetic properties in good body in rabbit body.
Embodiment 17 tablets
According to a conventional method, after above-mentioned substance is mixed, use conventional tabletting machine pressing mixt to obtain 1000 tablets.
Embodiment 18 injection liquids
The compounds of this invention (arbitrary compound of embodiment 1～13 preparation) is dissolved in sodium chloride solution or glucose solution with finite concentration, and above-mentioned mixed solution is canned obtains injection liquid in aseptic and pyrogen-free syringe.
All documents of mentioning in the present invention are all quoted as a reference in this application, just as each piece of document, are quoted as a reference separately.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (12)
1. the oxazolidinone compounds shown in formula (I) or its pharmacy acceptable salt, or its crystal formation, hydrate or solvate:
Wherein, R
1for
wherein, R
7for hydrogen, fluorine, chlorine, bromine or, C1-C4 alkyl;
R
2for replacing or the unsubstituted group that is selected from lower group:
Wherein, described replacement refers to have 1-3 and is selected from the substituting group of lower group: halogen, C1-C4 alkyl, OH;
R
3and R
4be selected from independently of one another lower group: hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano group, amino, C1-C4 alkyl, C1-C4 alkoxyl group, C1-C4 alkoxy C 1-C4 alkyl, C1-C4 alkoxy C 1-C4 alkoxyl group, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C4 alkoxyl group, C3-C6 cycloalkyloxy, C3-C6 cycloalkyloxy C1-C4 alkyl or C3-C6 cycloalkyloxy C1-C4 alkoxyl group;
R
5and R
6be selected from independently of one another lower group: hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano group, amino, C1-C4 alkyl, C1-C4 alkoxyl group, C3-C6 cycloalkyl or C3-C6 cycloalkyloxy;
Wherein the hydrogen in abovementioned alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy is replaced by hydroxyl, C1-C4 alkyl, C1-C4 alkoxyl group, one or more deuterium or one or more fluorine;
Or the one or more hydrogen atoms in formula (I) are replaced by D atom;
Supplementary condition are to work as R
3, R
5and R
4during for hydrogen, R
6be not hydrogen or fluorine; And
R
3and R
5be all hydrogen and R
4during for fluorine, chlorine, cyano group, trifluoromethyl or trifluoromethoxy, R
6be not following group: hydrogen, chlorine, methyl, ethyl, n-propyl, methoxyl group, oxyethyl group or methoxymethyl.
2. as claim 1 Suo Shu oxazolidinone compounds or its pharmacy acceptable salt, or its crystal formation, hydrate or solvate, it is characterized in that R
1be
3. as claim 1 Suo Shu oxazolidinone compounds or its pharmacy acceptable salt, or its crystal formation, hydrate or solvate, it is characterized in that R
2for
4. as claim 3 Suo Shu oxazolidinone compounds or its pharmacy acceptable salt, or its crystal formation, hydrate or solvate, it is characterized in that R
2for
5. as claim 1 Suo Shu oxazolidinone compounds or its pharmacy acceptable salt, or its crystal formation, hydrate or solvate, it is characterized in that R
3and R
4be selected from independently of one another lower group: hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano group, amino, C1-C4 alkoxyl group, C1-C4 alkoxy C 1-C4 alkoxyl group, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl C1-C4 alkoxyl group, C3-C6 cycloalkyl or C3-C6 cycloalkyloxy C1-C4 alkoxyl group;
R
5and R
6be selected from independently of one another lower group: hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano group, amino, C1-C4 alkoxyl group or C3-C6 cycloalkyloxy;
Wherein the hydrogen in abovementioned alkyl, alkoxyl group, cycloalkyl, cycloalkyloxy is replaced by hydroxyl, C1-C4 alkyl, C1-C4 alkoxyl group, one or more deuterium or one or more fluorine.
6. as claim 1 to 5 any one Suo Shu oxazolidinone compounds or its pharmacy acceptable salt, or its crystal formation, hydrate or solvate, it is characterized in that, described compound is selected from lower group:
7. the preparation method of a pharmaceutical composition, it is characterized in that, comprise step: by pharmaceutically acceptable carrier and claim 1 Suo Shu oxazolidinone compounds or its pharmacy acceptable salt, or its crystal formation, hydrate or solvate mix, thereby form pharmaceutical composition.
8. a pharmaceutical composition, is characterized in that, the oxazolidinone compounds or its pharmacy acceptable salt that comprise (a) pharmaceutically acceptable carrier and (b) with claim 1, stated, or its crystal formation, hydrate or solvate are activeconstituents.
9. pharmaceutical composition as claimed in claim 8, it is characterized in that, described pharmaceutical composition also comprises other medicine, and wherein said other medicine is selected from lower group: the second factor Xa inhibitor, antithrombotics, anti-platelet agents, thrombin inhibitors, thrombolytic agent, fibrinolytic agent or its combination.
10. oxazolidinone compounds or its pharmacy acceptable salt as claim 1, stated, or the purposes of its crystal formation, hydrate or solvate or pharmaceutical composition as claimed in claim 8, is characterized in that,
(a) for the preparation of the pharmaceutical composition of anticoagulant factor Xa (FXa);
(b) for the preparation of the pharmaceutical composition that is used for treating and/or preventing thromboembolic disorders; And/or
(c) for stoping in vitro blood coagulation.
11. 1 kinds of oxazolidinone compounds or its pharmacy acceptable salts that claim 1 is stated, or the preparation method of its crystal formation, hydrate or solvate, it is characterized in that, comprise step: by formula (II) compound and the reaction of formula (III) compound, thus the formula of formation (I) compound;
Above-mentioned various in, R
1for
r
2, R
3, R
4, R
5, R
6and R
7definition and claim 1 identical, X represents halogen or hydroxyl.
12. preparation methods as claimed in claim 11, is characterized in that, described formula (II) compound makes as follows, and described method comprises step:
(1) by formula (IV) compound and the reaction of formula (V) compound, thus the formula of formation (VI) compound;
(2) compound (VI) is carried out to deprotection reaction, thus the formula of obtaining (VII) compound;
(3) hydroxyl of formula (VII) compound is changed into amino, thus the formula of obtaining (II) compound;
Wherein, R
2, R
3, R
4, R
5and R
6definition and claim 1 identical, X represents halogen, P represents hydroxy-protective group.
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|---|---|---|---|---|
| WO2014183666A1 (en) * | 2013-05-17 | 2014-11-20 | 天津药物研究院 | Oxazolidinone derivate crystal form ii, preparation method therefor, and application thereof |
| CN104557928A (en) * | 2015-02-14 | 2015-04-29 | 佛山市赛维斯医药科技有限公司 | Blood coagulation factor Xa inhibitor containing bicycle-amide structure, as well as preparation and application thereof |
| CN109232457A (en) * | 2018-03-26 | 2019-01-18 | 华夏生生药业(北京)有限公司 | A kind of preparation method of Linezolid |
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| DE19962924A1 (en) * | 1999-12-24 | 2001-07-05 | Bayer Ag | Substituted oxazolidinones and their use |
| DE102007028319A1 (en) * | 2007-06-20 | 2008-12-24 | Bayer Healthcare Ag | Substituted oxazolidinones and their use |
| MX2010005545A (en) * | 2007-12-11 | 2010-07-30 | Bayer Schering Pharma Ag | Oxazolidinones for the treatment and/or prophylaxis of heart failure. |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014183666A1 (en) * | 2013-05-17 | 2014-11-20 | 天津药物研究院 | Oxazolidinone derivate crystal form ii, preparation method therefor, and application thereof |
| CN104557928A (en) * | 2015-02-14 | 2015-04-29 | 佛山市赛维斯医药科技有限公司 | Blood coagulation factor Xa inhibitor containing bicycle-amide structure, as well as preparation and application thereof |
| CN104557928B (en) * | 2015-02-14 | 2016-08-24 | 佛山市赛维斯医药科技有限公司 | A kind of containing bicyclic amide structure coagulation factor xa inhibitors, Its Preparation Method And Use |
| CN109232457A (en) * | 2018-03-26 | 2019-01-18 | 华夏生生药业(北京)有限公司 | A kind of preparation method of Linezolid |
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Application publication date: 20140312 |