CN104530080A - Oxazolidinone compounds and application thereof in drugs - Google Patents

Oxazolidinone compounds and application thereof in drugs Download PDF

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Publication number
CN104530080A
CN104530080A CN201410758847.6A CN201410758847A CN104530080A CN 104530080 A CN104530080 A CN 104530080A CN 201410758847 A CN201410758847 A CN 201410758847A CN 104530080 A CN104530080 A CN 104530080A
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group
compound
amino
alkyl
oxo
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CN104530080B (en
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张瑾
周平健
林继华
阳传文
熊绍辉
黄常伟
左应林
王晓军
张英俊
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Guangdong HEC Pharmaceutical
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Guangdong HEC Pharmaceutical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Abstract

The invention relates to novel oxazolidinone compounds or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically-acceptable salts or prodrugs of the novel oxazolidinone compounds. The invention also relates to application of the novel oxazolidinone compounds or the stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically-acceptable salts or prodrugs of the novel oxazolidinone compounds as drugs and particularly relates to application of the novel oxazolidinone compounds or the stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically-acceptable salts or prodrugs of the novel oxazolidinone compounds to preparation of drugs for inhibiting factors Xa.

Description

Oxazolidinone compounds and the application in medicine thereof
Invention field
The invention belongs to pharmaceutical field, be specifically related to a kind of Xin oxazolidinone compounds, pharmaceutical composition, and as preparing the purposes of medicine, particularly as purposes and the purposes being used for the treatment of thromboembolic disorders of the medicine for the preparation of factor Xa inhibitor.
Background technology
Short blood coagulation (hemostasis) and anticoagulation (anti-bolt) are the mechanism of two kinds of opposition in Hematological System of Professional Workers, each other contradiction keep relative equilibrium, and the process of this accurate harmony maintains the integrity of the recycle system.When in body, anti-freezing Fibrinolytic System reduces gradually, then there is blood coagulation when blood coagulation and anticoagulant functions overbalance in blood, thus cause thrombus or embolism, and then cause the thrombotic diseases such as such as myocardial infarction, apoplexy, DVT, pulmonary infarction.Thrombotic disease endangers the most serious disease in cardiovascular disorder, is the first killer of human health.
Along with illustrating further of Thrombosis Mechanism, for thrombotic feature and reason, researched and developed a lot of antithrombotic new drug, the medicine of existing inhibition thrombosis (anticoagulation) and anticoagulant, has again thrombolytic medicine.The former is mainly to the formation of thrombus with increase inhibited, and established thrombus mainly dissolves by the latter, thus eliminates the harm that thrombotic diseases causes the mankind.
Blood coagulation Xa factor is a kind of serine protease, can be zymoplasm by conversion of prothrombin, is an anticoagulation target spot having clinical value, is formed and have consequence in activation blood coagulation waterfall at control zymoplasm.Xa factor is positioned at the joint of inside and outside source property coagulation pathway, and the major catalytic II factor is factor converting to IIa, and the bio signal existed due to coagulation process amplifies, and a blood coagulation Xa factor inhibitor can suppress the physiologic effect of 138 thrombogen molecules.
WO 2001047919 discloses the blood coagulation Xa factor inhibitor with following structure, and it all has height restraining effect, the inside and outside source property approach of interruptible price blood coagulation waterfall, the generation of Trombin inhibiting and thrombosis to Xa factor that is free or that combine.
The chloro-nitrogen of its representation compound 5--((5S)-2-oxygen-3-[-4-(3-oxygen-4-morpholinyl) phenyl]-1,3-azoles alkane-5-base-2-thiophene-carboxylic acid amides goes on the market in 2008 as first Xa factor inhibitor medicaments, general razaxaban by name or Rivaroxaban.
WO 2003026652 discloses the compound 4 with blood coagulation resisting function, 5,6,7-tetrahydrochysene-1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-1H-pyrazolo [3,4-c] pyridine-3-carboxamide, this compound in Europe listing, was used for the treatment of thromboembolism and acute arterial coronary syndrome, general Eliquis by name or Apixaban in 2011.
WO 2004058715 discloses blood coagulation Xa factor inhibitor N'-(5-chloropyridine-2-base)-the N-[(1S being used for the treatment of venous thromboembolism; 2R; 4S)-4-(dimethylamino formyl radical)-2-[(5-methyl-6; 7-dihydro-4H-[1; 3] thiazole [5; 4-c] pyridine-2-carbonyl) amino] cyclohexyl] oxamide, this compound went on the market in 2011 in Japan, general Yi Dushaban or Edoxaban by name.
Effective and the special inhibitor of Xa factor can as potential valuable therapeutical agent to treat thromboembolic disorders.The invention provides a kind of new Xa factor inhibitor-oxazolidinone compounds, pharmacy acceptable salt or its prodrug, this compounds effectively can treat thrombotic disease.
Summary of the invention
The invention provides a kind of Xin oxazolidinone compounds, or its pharmaceutical composition, can effectively treat the thrombotic disease relevant to supressor Xa.
On the one hand, the present invention relates to a kind of compound, it is compound shown in general formula (I), or the steric isomer of compound shown in formula (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:
Wherein,
A is optional monosubstituted or polysubstituted C 1-C 9heteroaryl, wherein substituting group is selected from H, halogen, amino, cyano group, carboxyl, hydroxyl, C 1-C 4alkyl or C 1-C 4alkoxyl group;
B is optional monosubstituted or polysubstituted C 2-C 10heterocyclic radical, wherein substituting group is selected from H, oxo, halogen, amino, C 1-C 4alkyl or C 1-C 4alkoxyl group.
In some embodiments,
A is optional monosubstituted or polysubstituted C 1-C 6heteroaryl, wherein substituting group is selected from H, halogen, amino, cyano group, carboxyl, hydroxyl, C 1-C 4alkyl or C 1-C 4alkoxyl group;
B is optional monosubstituted or polysubstituted C 2-C 6heterocyclic radical, wherein substituting group is selected from H, oxo, halogen, amino, C 1-C 4alkyl or C 1-C 4alkoxyl group.
In other embodiments,
A is subformula or wherein, X 1, X 2, X 3and X 4respective is independently N or CR 1; R 1respective is independently H, halogen, amino, cyano group, carboxyl, hydroxyl, C 1-C 4alkyl or C 1-C 4alkoxyl group; With, each X 5for NH, O or S; Wherein, each A subformula is independent optionally by H, halogen, amino, cyano group, carboxyl, hydroxyl, C 1-C 4alkyl or C 1-C 4the substituting group of alkoxyl group replaced;
B is subformula or wherein each B subformula is independent optionally by H, oxo, halogen, amino, C 1-C 4alkyl or C 1-C 4one or more substituting groups in alkoxyl group replaced.
In other embodiments,
A is optionally monosubstituted or polysubstituted pyridyl, thienyl, pyrazinyl, thiazolyl, furyl, pyrimidyl, imidazolyl or pyridazinyl, and wherein substituting group is selected from H, fluorine, chlorine, bromine, amino, cyano group, carboxyl, hydroxyl, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy or isopropoxy;
B is optionally monosubstituted or polysubstituted piperidyl, piperazinyl, pyrrolidyl, imidazolidyl, morpholinyl, 2-oxo-pyrrolidine base, 3-oxo-morpholin-4-base or oxazolidinyl, and wherein substituting group is selected from H, oxo, H, fluorine, chlorine, bromine, amino, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy or isopropoxy.
In other embodiments, the present invention relates to one of them compound following,
Or its steric isomer, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug.
On the other hand, the present invention relates to a kind of pharmaceutical composition, comprise the arbitrary described compound of the present invention, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.
On the other hand, the present invention relates to the arbitrary described compound of the present invention or the pharmaceutical composition purposes in the medicine of preparation, prevention, process or treatment thrombotic disease.
In certain embodiments, purposes of the present invention, wherein said thrombotic disease is myocardial infarction, stenocardia, to block and restenosis after revascularization or aorta Coronary artery bypass, apoplexy, the outbreak of of short duration local asphyxia, peripheral arterial occlusive disease, pulmonary infarction or venous thrombosis again.
In certain embodiments, purposes of the present invention is described compound or the described pharmaceutical composition purposes for the preparation of the medicine for the treatment of disseminated inravascular coagulation (DIC).
On the other hand, the present invention relates to the arbitrary described compound of the present invention or the purposes of described pharmaceutical composition in preparation supressor Xa medicine.
The present invention comprises the application of the compounds of this invention and pharmacy acceptable salt thereof, for the production of pharmaceutical prod treatment patient thrombotic disease, comprises the disease that those are described in the invention.The present invention comprises pharmaceutical composition, and this pharmaceutical composition comprises compound representated by formula (I) and the pharmaceutically acceptable carrier of at least one, vehicle, thinner, assistant agent, the effective therapeutic dose needed for vectorial combination.
The present invention comprises treatment equally or alleviates patient's thrombotic disease, or the method to this illness sensitivity, and the treatment significant quantity that the method comprises the representative compound of use formula (I) is treated patient.
Thrombotic disease of the present invention is myocardial infarction, stenocardia, to block and restenosis after revascularization or aorta Coronary artery bypass, apoplexy, the outbreak of of short duration local asphyxia, peripheral arterial occlusive disease, pulmonary infarction or venous thrombosis again.
Unless other aspects show, the steric isomer that compound of the present invention is all, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, salt and pharmaceutically acceptable prodrug all belong to scope of the present invention.
Specifically, salt is pharmacy acceptable salt.It must be applicable to chemistry or toxicologically that term " pharmaceutically acceptable " comprises material or composition, relevant with other components of composition preparation and the Mammals that is used for the treatment of.
The salt of compound of the present invention also comprise for the preparation of or purifying formula (I) shown in the salt of enantiomer of compound separation shown in the intermediate of compound or formula (I), but not necessarily pharmacy acceptable salt.
If compound of the present invention is alkaline, then conceivable salt can be prepared by any suitable method that document provides, and such as, uses mineral acid, example hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid etc.Or use organic acid, as acetic acid, toxilic acid, succsinic acid, amygdalic acid, fumaric acid, propanedioic acid, pyruvic acid, oxalic acid, hydroxyethanoic acid and Whitfield's ointment; Pyrans saccharic acid, as glucuronic acid and galacturonic acid; Alpha-hydroxy acid, as citric acid and tartrate; Amino acid, as aspartic acid and L-glutamic acid; Aromatic acid, as phenylformic acid and styracin; Sulfonic acid, as tosic acid, ethyl sulfonic acid, etc.
If compound of the present invention is acid, then conceivable salt can be prepared by suitable method, e.g., uses mineral alkali or organic bases, as ammonia (uncle's ammonia, parahelium, tertiary ammonia), and alkali metal hydroxide or alkaline earth metal hydroxides, etc.Suitable salt comprises, but is not limited to, from the organic salt that amino acid obtains, as glycine and arginine, and ammonia, as uncle ammonia, parahelium and tertiary ammonia, and ring-type ammonia, as piperidines, morpholine and piperazine etc., and from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminium and lithium obtain inorganic salt.
On the other hand, the present invention relates to the preparation of compound shown in formula (I), the method for abstraction and purification.
Content noted earlier only outlines some aspect of the present invention, but is not limited to these aspects.These aspects and otherwise content will do more specifically complete description below.
Embodiment
definition and general terms
Present detailed description certain embodiments of the present invention, the example is by the structural formula of enclosing and chemical formula explanation.The invention is intended to contain all to substitute, amendment and equivalent technical solutions, they include in the scope of the invention of such as claim definition.Those skilled in the art will appreciate that many or methods of being equal to similar with described herein and material can be used in putting into practice the present invention.The present invention is never limited to method as herein described and material.Combined document, patent and (include but not limited to defined term, term application, described technology, etc.) in one or more different from the application or conflicting situations of analogous material, be as the criterion with the application.
As described in the invention, compound of the present invention can optionally replace by one or more substituting group, as general formula compound above, or special example inside picture embodiment, subclass, and the compounds that the present invention comprises.Should be appreciated that " optional replacement " this term can exchange use with " substituted or non-substituted " this term.Generally speaking, term " replacement " represent give the one or more hydrogen atoms in structure replace by concrete substituting group.Unless other aspects show, an optional substituted radical can replace in each commutable position of group.Not only one or more substituting groups that position can be selected from concrete group in given structural formula replaced, and so substituting group can replace in each position identical or differently." optionally monosubstituted or polysubstituted " represents in the present invention can carry out a substituent replacement, multiple substituent replacement in each commutable position of group of the present invention or not replace.
In addition, it should be noted that, unless otherwise explicitly pointed out, adopted in the present invention describing mode " each ... be independently " and " ... be independently of one another " and " ... be independently " can exchange, all should be interpreted broadly, it both can refer in different group, did not affect mutually between concrete option expressed between same-sign, also can represent in identical group, not affect mutually between concrete option expressed between same-sign.
" optionally " or " optionally " means that subsequently described event or environment can maybe need not occur, and this explanation comprises the occasion that this thing or environment occur or do not occur.Such as, " optionally by heterocyclic group that alkyl replaces " mean alkyl can but must not exist, this explanation comprises sight that heterocyclic group replaced by alkyl and heterocyclic group not by sight that alkyl replaces.
At each several part of this specification sheets, the come into the open substituting group of compound of the present invention is open according to radical species or scope.Particularly point out, each the independently sub-combinations thereof that the present invention includes each member of these radical species and scope.Such as, term " C 1-C 6alkyl " refer in particular to independent disclosed methyl, ethyl, C 3alkyl, C 4alkyl, C 5alkyl and C 6alkyl.
At each several part of the present invention, describe connection substituting group.When this structure clearly needs linking group, be interpreted as linking group for the Ma Kushi variable cited by this group.Such as, if this structure needs linking group and Ma Kushi group definition for this variable lists " alkyl " or " aryl ", then should be appreciated that, " alkyl " or " aryl " alkylidene group or the arylene group of connection should be represented respectively.
The term " alkyl " that the present invention uses or " alkyl group ", represent containing 1 to 20 carbon atom, saturated straight or branched univalent hydrocarbyl group, wherein, the substituting group that described alkyl group can optionally be described by one or more the present invention replace.In some embodiments, alkyl group contains 1-12 carbon atom; In another embodiment, alkyl group contains 1-6 carbon atom; In yet another embodiment, alkyl group contains 1-4 carbon atom; In yet another embodiment, alkyl group contains 1-3 carbon atom.The example of alkyl group comprises, but is not limited to, methyl (Me ,-CH 3), ethyl (Et ,-CH 2cH 3), n-propyl (n-Pr ,-CH 2cH 2cH 3), sec.-propyl (i-Pr ,-CH (CH 3) 2), normal-butyl (n-Bu ,-CH 2cH 2cH 2cH 3), isobutyl-(i-Bu ,-CH 2cH (CH 3) 2), sec-butyl (s-Bu ,-CH (CH 3) CH 2cH 3), the tertiary butyl (t-Bu ,-C (CH 3) 3), n-pentyl (-CH 2cH 2cH 2cH 2cH 3), 2-amyl group (-CH (CH 3) CH 2cH 2cH 3), 3-amyl group (-CH (CH 2cH 3) 2), 2-methyl-2-butyl (-C (CH 3) 2cH 2cH 3), 3-methyl-2-butyl (-CH (CH 3) CH (CH 3) 2), 3-methyl isophthalic acid-butyl (-CH 2cH 2cH (CH 3) 2), 2-methyl-1-butene base (-CH 2cH (CH 3) CH 2cH 3), n-hexyl (-CH 2cH 2cH 2cH 2cH 2cH 3), 2-hexyl (-CH (CH 3) CH 2cH 2cH 2cH 3), 3-hexyl (-CH (CH 2cH 3) (CH 2cH 2cH 3)), 2-methyl-2-amyl group (-C (CH 3) 2cH 2cH 2cH 3), 3-methyl-2-amyl group (-CH (CH 3) CH (CH 3) CH 2cH 3), 4-methyl-2-amyl group (-CH (CH 3) CH 2cH (CH 3) 2), 3-methyl-3-amyl group (-C (CH 3) (CH 2cH 3) 2), 2-methyl-3-amyl group (-CH (CH 2cH 3) CH (CH 3) 2), 2,3-dimethyl-2-butyl (-C (CH 3) 2cH (CH 3) 2), 3,3-dimethyl-2-butyl (-CH (CH 3) C (CH 3) 3), n-heptyl, n-octyl, etc.
Term " alkoxyl group " represents that alkyl group is connected with molecule rest part by Sauerstoffatom, and wherein alkyl group has implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-12 carbon atom.In one embodiment, alkoxy base contains 1-6 carbon atom; In another embodiment, alkoxy base contains 1-4 carbon atom; In yet another embodiment, alkoxy base contains 1-3 carbon atom.The example of alkoxy base comprises, but is not limited to, methoxyl group (MeO ,-OCH 3), oxyethyl group (EtO ,-OCH 2cH 3), 1-propoxy-(n-PrO, n-propoxy-,-OCH 2cH 2cH 3), 2-propoxy-(i-PrO, i-propoxy-,-OCH (CH 3) 2), 1-butoxy (n-BuO, n-butoxy ,-OCH 2cH 2cH 2cH 3), 2-methyl-l-propoxy-(i-BuO, i-butoxy ,-OCH 2cH (CH 3) 2), 2-butoxy (s-BuO, s-butoxy ,-OCH (CH 3) CH 2cH 3), 2-methyl-2-propoxy-(t-BuO, t-butoxy ,-OC (CH 3) 3), 1-pentyloxy (n-pentyloxy ,-OCH 2cH 2cH 2cH 2cH 3), 2-pentyloxy (-OCH (CH 3) CH 2cH 2cH 3), 3-pentyloxy (-OCH (CH 2cH 3) 2), 2-methyl-2-butoxy (-OC (CH 3) 2cH 2cH 3), 3-methyl-2-butoxy (-OCH (CH 3) CH (CH 3) 2), 3-methyl-l-butoxy (-OCH 2cH 2cH (CH 3) 2), 2-methyl-l-butoxy (-OCH 2cH (CH 3) CH 2cH 3), etc.
Term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
Term " amino " refers to "-NH 2"; Term " carboxyl " refers to "-C (=O) OH "; Term " hydroxyl " refers to "-OH "; Term " cyano group " refers to "-CN ".
Term "=O " or " oxo ", refer to group=O of being directly connected with the carbon atom of hydrocarbon ring (i.e. cycloalkenyl group, aryl, heterocycle or heteroaryl ring) and wherein N or S be the N-oxide compound of the atom of heterocycle or heteroaryl ring, sulfone or sulfoxide.Such as, 2-oxo-pyrrolidine base, 3-oxo-morpholin-4-base, oxo-1,3-thiazoles alkyl, 2-piperidone base, 3,5-dioxopiperidine bases, pyrimidine dione base, tetramethylene sulfone base, 1,1-dioxothiomorpholinyl.
Term " heterocyclic radical " and " heterocycle " commutative use herein, all refer to and comprise the saturated of 3-12 annular atoms or undersaturated monocycle, dicyclo or three rings of part, wherein at least one annular atoms is selected from nitrogen, sulphur and Sauerstoffatom.Unless otherwise indicated, heterocyclic radical can be carbon back or nitrogen base, and-CH 2-group can optionally by-C (O)-substitute.The sulphur atom of ring can optionally be oxidized to S-oxide compound.The nitrogen-atoms of ring can optionally be oxidized to N-oxygen compound.Some of them embodiment is, containing 2-10 annular atoms in heterocyclic radical is carbon atom; Other embodiment is, containing 2-6 annular atoms in heterocyclic radical is carbon atom.The example of heterocyclic radical comprises, but be not limited to, N-piperidyl, piperidin-4-yl, piperazine-4-base, N-pyrrolidyl, pyrrolidin-3-yl, pyrrolidin-2-yl, tetrahydrofuran base, oxazolidinyl, Oxyranyle, azelidinyl, oxetanylmethoxy, thietanyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, dihydrofuran base, tetrahydro-thienyl, dihydro-thiophene base, 1, 3-dioxy cyclopentyl, two sulphur cyclopentyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, alkyl dioxin, dithiane base, thioxane base, homopiperazine base, homopiperidinyl, oxepane alkyl, thia suberane base, oxygen azepine base, diaza base, sulphur azepine base, indoline base, 1,2,3,4-tetrahydro isoquinolyl, 1,3-Ben Bing bis-Evil cyclopentadienyl, 2-oxa--5-azabicyclo [2.2.1]-5-in heptan base.-CH in heterocyclic radical 2-group is included, but not limited to 2-oxo-pyrrolidine base, 3-oxo-morpholin-4-base, oxo-1,3-thiazoles alkyl, 2-piperidone base, 3,5-dioxopiperidine bases and pyrimidine dione base by the example of-C (O)-replacement.The example that in heterocyclic radical, sulphur atom is oxidized includes, but not limited to tetramethylene sulfone base, 1,1-dioxothiomorpholinyl.Heterocyclyl groups can be independently optionally described by the present invention substituting group replaced.
Term " heteroaryl " represents containing 5-12 annular atoms, or 5-10 annular atoms, or the monocycle of 5-6 annular atoms, dicyclo and three-ring system, wherein at least one member ring systems is aromatic, and at least one member ring systems comprises one or more heteroatoms, wherein each member ring systems comprises 5-7 former molecular ring, and has one or more attachment point to be connected with molecule rest part.Term " heteroaryl " can exchange with term " hetero-aromatic ring " or " heteroaromatics " and use.In one embodiment, 5-10 former molecular heteroaryl comprises the heteroatoms that 1,2,3 or 4 is independently selected from O, S and N.Described heteroaryl groups can be substituted or non-substituted, wherein substituting group can be, but be not limited to, fluorine, chlorine, bromine, oxo (=O), cyano group, nitro, carboxyl, hydroxyl, amino, amino methyl, formamyl, methylamino-, phenylamino, hydroxymethyl, methyl sulphonyl, amino-sulfonyl, ethanoyl, methoxyl group, phenoxy group, trifluoromethoxy, methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydrofuran base, tetrahydro-thienyl, Pyrrolidine base, imidazolyl, imidazolinyl, piperidyl, piperazinyl, morpholinyl, thienyl, thiazolyl, furyl, pyrryl, phenyl, pyridyl, pyrimidyl,-C (=NH) NH 2or trifluoromethyl etc.Heteroaryl groups can be independently optionally described by the present invention substituting group replaced.
The example of heteroaryl groups comprises, but be not limited to, 2-furyl, 3-furyl, TMSIM N imidazole base, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrryl, 2-pyrryl, 3-pyrryl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, pyridazinyl (as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazyl (as 5-tetrazyl), triazolyl (as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (as 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thio biphosphole base, 1, 3, 4-thio biphosphole base, 1, 2, 5-thio biphosphole base, pyrazinyl, 1, 3, 5-triazinyl, also following dicyclo is comprised, but be never limited to these dicyclos: benzimidazolyl-, benzofuryl, benzothienyl, indyl (as 2-indyl), purine radicals, quinolyl is (as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl is (as 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl), imidazo [1, 2-a] pyridyl, pyrazolo [1, 5-a] pyridyl, pyrazolo [1, 5-a] pyrimidyl, imidazo [1, 2-b] pyridazinyl, [1, 2, 4] triazolo [4, 3-b] pyridazinyl, [1, 2, 4] triazolo [1, 5-a] pyrimidyl, [1, 2, 4] triazolo [1, 5-a] pyridyl, etc..
Any structural formula that the present invention provides is also intended to represent these compounds not by the form of the form of isotopic enrichment and isotopic enrichment.The compound of isotopic enrichment has the structure of the general formula description that the present invention provides, except one or more atom is replaced by the atom with selected nucleidic mass or total mass number.The Exemplary isotopes can introduced in the compounds of this invention comprises the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine, as 2h, 3h, 11c, 13c, 14c, 15n, 17o, 18o, 18f, 31p, 32p, 35s, 36cl and 125i.
In addition, particularly deuterium is (that is, for higher isotope 2h or D) replacement can provide some treatment advantage, these advantages are brought by metabolic stability is higher.Such as, Half-life in vivo increases or volume requirements reduces or therapeutic index improves brings.Should be appreciated that the deuterium in the present invention is seen as the substituting group of formula (I) compound.The concentration of such higher isotope particularly deuterium can be defined by the isotopic enrichment factor.Term used in the present invention " the isotopic enrichment factor " refers to specified ratio between isotopic isotopic abundance and natural abundance.If the substituting group of the compounds of this invention is designated as deuterium, this compound has at least 3500 (each deuterium at D atom place 52.5% of specifying mixes) to each D atom of specifying, at least 4000 (deuterium of 60% mixes), at least 4500 (deuterium of 67.5% mixes), at least 5000 (deuterium of 75% mixes), at least 5500 (deuterium of 82.5% mixes), at least 6000 (deuterium of 90% mixes), at least 6333.3 (deuterium of 95% mixes), at least 6466.7 (deuterium of 97% mixes), the isotopic enrichment factor of at least 6600 (deuterium of 99% mixes) or at least 6633.3 (deuterium of 99.5% mixes).It can be the such as D that isotropic substance replaces that the pharmaceutically useful solvate of the present invention comprises wherein recrystallisation solvent 2o, acetone-d 6, DMSO-d 6those solvates.
" thrombotic disease " used in the present invention refers to the disease of being drawn by thrombosis and thromboembolism two kinds of pathologic processes, also known as thrombotic diseases.Thrombosis refers under certain condition, and shaped components in blood is partially formed embolus at Ink vessel transfusing or cardiac intima, causes vasculature part or blocks completely, the pathologic process of corresponding site blood supply obstacle.Thromboembolism is that thrombus is come off by forming part, and with in blood flow process, part or all of artery-clogging, causes the pathologic process of blood vessel or global ischemia, anoxic, necrosis, extravasated blood and oedema.The example of thrombotic disease includes but not limited to arterial cardiovascular thromboembolic disorders, intravenous cardio thromboembolic disorders and the thromboembolic disorders in the chamber of heart.This type of disease more specifically example comprises, but be not limited to, myocardial infarction, stenocardia (comprising unstable angina), acute coronary syndrome, to block and restenosis after revascularization or aorta Coronary artery bypass, apoplexy, the outbreak of of short duration local asphyxia, peripheral arterial occlusive disease, arterial thrombus, Coronary thrombosis, cerebral artery thrombosis formation, cerebral embolism, renal infarction, pulmonary infarction, thrombophlebitis, venous thrombosis or venous thrombosis again, etc.
Term used in the present invention " study subject " refers to animal.Typically described animal is Mammals.Study subject, such as, also refer to primate (the such as mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird etc.In certain embodiments, described study subject is primate.In other embodiments, described study subject is people.
Term used in the present invention " patient " refers to people or other animals.In some embodiments, " patient " refers to people.
Term as used in the present invention " treatment " any disease or illness, some embodiment middle fingers improve disease or illness (namely slow down or stop or palliate a disease or the development of its at least one clinical symptom) wherein.In other embodiments, " treatment " refers to relax or improve at least one body parameter, comprises the body parameter may not discovered for patient.In other embodiments, " treatment " refer to from health (such as stablizing perceptible symptom) or physiology (such as stablizing the parameter of health) or above-mentioned two aspects regulate disease or illnesss.In other embodiments, " treatment " refer to prevent or postpone the outbreak of disease or illness, generation or deterioration.
" steric isomer " refers to have identical chemical constitution, but atom or the group compound that spatially arrangement mode is different.Steric isomer comprises enantiomer, diastereomer, conformer (rotational isomer), geometrical isomer (cis/trans) isomer, atropisomer, etc.
" chirality " is that have can not the molecule of overlapping character with its mirror image; And " achirality " refer to can be overlapping with its mirror image molecule.
" enantiomer " refer to two of a compound can not be overlapping but be mutually the isomer of mirror.
" diastereomer " refers to two or more chiral centres and the steric isomer of its molecule not mirror image each other.Diastereomer has different physical propertiess, as fusing point, boiling point, spectral quality and reactivity.Non-enantiomer mixture is by high resolution analysis operation as electrophoresis and chromatogram, and such as HPLC is separated.
Stereochemical definitions Sum fanction used in the present invention generally follows S.P.Parker, Ed., McGraw-Hill Dictionary of ChemicalTerms (1984) McGraw-Hill Book Company, New York; And Eliel, E.and Wilen, S., " Stereochemistry of OrganicCompounds ", John Wiley & Sons, Inc., New York, 1994.
Many organic compound exist with optical active forms, and namely they have the ability that the plane of plane polarized light is rotated.When describing optically active compound, prefix D and L or R and S is used to represent the absolute configuration of molecule about one or more chiral centre.Prefix d and l or (+) and (-) are the symbols being used to specify plane polarized light rotation caused by compound, and wherein (-) or l represent that compound is left-handed.Prefix is the compound of (+) or d is dextrorotation.Concrete steric isomer is an enantiomer, and the mixture of this isomer is called enantiomeric mixture.The 50:50 mixture of enantiomer is called racemic mixture or racemic modification, when not having stereoselectivity or stereospecificity in chemical reaction or process, can occur this situation.
According to the selection of starting material and method, the compounds of this invention can with in possible isomer or their mixture, and the form of such as racemic modification and non-corresponding isomer mixture (this depends on the quantity of unsymmetrical carbon) exists.Optically active (R)-or (S)-isomer can use chiral synthon or chiral reagent preparation, or use routine techniques to split.If compound contains a double bond, substituting group may be E or Z configuration; If containing dibasic cycloalkyl in compound, the substituting group of cycloalkyl may have cis or transconfiguration.
The mixture of any steric isomer of gained can be separated into pure or substantially pure geometrical isomer according to the difference in component physicochemical property, enantiomer, diastereomer, such as, by chromatography and/or Steppecd crystallization.
Term " tautomer " or " tautomeric form " refer to the constitutional isomer transformed mutually by low energy barrier (low energy barrier) with different-energy.If tautomerism is possible (as in the solution), then can reach the chemical equilibrium of tautomer.Such as, proton tautomer (protontautomer) (also referred to as Prototropic tautomers (prototropic tautomer)) comprises the mutual conversion undertaken by proton shifting, as keto-enol isomerization and imine-enamine isomerizations.Valence tautomerism body (valence tautomer) comprises the mutual conversion undertaken by the restructuring of some bonding electronss.The specific examples of keto-enol tautomerism is the change of pentane-2,4-diketone and 4-hydroxyl penta-3-alkene-2-keto tautomer.Another example tautomeric is phenol-keto tautomerism.A specific examples of phenol-keto tautomerism is the change of pyridine-4-alcohol and pyridine-4 (1H)-one tautomer.Unless otherwise noted, all tautomeric forms of the compounds of this invention all within the scope of the present invention.
Term used in the present invention " prodrug ", represents a compound and is converted into the compound shown in formula (I) in vivo.Such conversion by prodrug be hydrolyzed in blood or blood or tissue in through enzymatic conversion be the impact of precursor structure.Prodrug compounds of the present invention can be ester, and in existing invention, ester can have phenyl ester class, aliphatics (C as prodrug 1-24) ester class, acyloxymethyl ester class, carbonic ether, amino formate and amino acid esters.Such as, a compound in the present invention comprises hydroxyl, namely its acidylate can be obtained the compound of prodrug form.Other prodrug form comprises phosphoric acid ester, if these phosphate compounds are that di on parent obtains.Can with reference to Publication about Document about the complete discussion of prodrug: T.Higuchi and V.Stella, Pro-drugs asNovel Delivery Systems, Vol.14of the A.C.S.Symposium Series, Edward B.Roche, ed., BioreversibleCarriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.Rautio et al, Prodrugs:Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S.J.Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.
" meta-bolites " refers to concrete compound or its salt in vivo by product that metabolism obtains.The meta-bolites of a compound can be identified by the known technology in affiliated field, and its activity can be characterized by such method of test that adopts as described in the present invention.Such product can be by passing through oxidation to drug compound, and reduction, hydrolysis, amidated, desamido-effect, esterification, fat abstraction, enzymatic lysis etc. method obtains.Correspondingly, the present invention includes the meta-bolites of compound, comprise and compound of the present invention and Mammals fully contacted the meta-bolites that for some time produces.
" pharmacy acceptable salt " used in the present invention refers to organic salt and the inorganic salt of compound of the present invention.Pharmacy acceptable salt in affiliated field known by us, as document: S.M.Berge et al., J.Pharmaceutical Sciences, 66:1-19, described in 1977.The salt that pharmaceutically acceptable nontoxic acid is formed comprises, but is not limited to, and reacting with amino group the inorganic acid salt formed has hydrochloride, hydrobromate, phosphoric acid salt, vitriol, perchlorate, and organic acid salt is as acetate, oxalate, maleate, tartrate, Citrate trianion, succinate, malonate, or obtain these salt by additive method such as ion exchange method described on books document.Other pharmacy acceptable salts comprise adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, bisulfate, borate, butyrates, camphorate, camsilate, cyclopentyl propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodate, 2-hydroxy-ethanesulfonate salt, lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, pivalate, propionic salt, stearate, thiocyanate-, tosilate, undecylate, valerate, etc..The salt obtained by suitable alkali comprises basic metal, alkaline-earth metal, ammonium and N +(C 1-4alkyl) 4salt.The quaternary ammonium salt that the compound that the present invention also intends the group contemplating any comprised N is formed.Water-soluble or oil soluble or dispersion product can be obtained by quaternization.Basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium, etc.Pharmacy acceptable salt comprises suitable, nontoxic ammonium further, the amine positively charged ion that quaternary ammonium salt and gegenions are formed, as halogenide, and oxyhydroxide, carboxylate, hydrosulfate, phosphoric acid compound, nitric acid compound, C 1-8azochlorosulfonate acid compound and aromatic sulphonic acid compound.
Pharmacologically acceptable salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes.Generally speaking, such salt can react by making the suitable alkali of the free acid form of these compounds and stoichiometry (oxyhydroxide, carbonate, supercarbonate etc. as Na, Ca, Mg or K), or by making the suitable acid-respons of the free alkali form of these compounds and stoichiometry be prepared.Such reaction is carried out usually in water or organic solvent or the mixture of the two.Usually, when suitable, need to use non-aqueous media as ether, ethyl acetate, ethanol, Virahol or acetonitrile.At such as " Remington ' s Pharmaceutical Sciences ", the 20th edition, Mack PublishingCompany, Easton, Pa., (1985); " pharmaceutical salts handbook: character, choice and application (Handbook of Pharmaceutical Salts:Properties; Selection; and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) other can be found to be suitable for the list of salt in.
" solvate " of the present invention refers to the associated complex that one or more solvent molecule and compound of the present invention are formed.The solvent forming solvate comprises, but is not limited to, water, Virahol, ethanol, methyl alcohol, methyl-sulphoxide, ethyl acetate, acetic acid, monoethanolamine.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.
In addition, compound disclosed by the invention, comprise their salt, also can obtain, for their crystallization with their hydrate forms or the form comprising its solvent (such as ethanol, DMSO, etc.).Compound is come into the open in the present invention can with pharmaceutically acceptable solvent (comprising water) inherently or by design forming solvate; Therefore, the present invention be intended to comprise solvation and the form of non-solvation.
Time term " blocking group " or " PG " refer to a substituting group and other reacted with functional groups, be commonly used to block or protect special functional.Such as; " amino blocking group " refer to a substituting group be connected with amino group block or protect in compound amino functional; suitable amido protecting group comprises ethanoyl; trifluoroacetyl group; tertbutyloxycarbonyl (BOC; Boc), carbobenzoxy-(Cbz) (CBZ, Cbz) and the sub-methoxycarbonyl (Fmoc) of 9-fluorenes.Similarly, " hydroxy-protective group " refers to that the substituting group of hydroxyl is used for blocking or protecting the functional of hydroxyl, and suitable blocking group comprises ethanoyl and silyl." carboxy protective group " refers to that the substituting group of carboxyl is used for blocking or protecting the functional of carboxyl, and general carboxyl-protecting group comprises-CH 2cH 2sO 2ph; cyano ethyl; 2-(TMS) ethyl; 2-(TMS) ethoxyl methyl; 2-(p-toluenesulfonyl) ethyl, 2-(p-nitrophenyl alkylsulfonyl) ethyl, 2-(diphenylphosphino) ethyl; nitro-ethyl, etc.Can reference for the general description of blocking group: T W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; AndP.J.Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
the compounds of this invention and pharmaceutical composition, preparation, administration and purposes
According to another aspect, the feature of pharmaceutical composition of the present invention comprises the compound shown in formula (I), the compound listed by the present invention, or the compound in embodiment, and pharmaceutically acceptable carrier, assistant agent, or vehicle.In composition of the present invention, patient's thrombotic disease can be treated or be alleviated to the amount of compound or effectively as Xa factor inhibitor.
There is free form in compound of the present invention, or suitable, as pharmaceutically acceptable derivates.According to the present invention, pharmaceutically acceptable derivates comprises, but be not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt of ester class, or can directly or indirectly according to other any adducts or derivatives of needing administration of patient, the compound described by other aspects of the present invention, its meta-bolites or its residue.
As described in the invention, the pharmaceutically acceptable composition of the present invention comprises pharmaceutically acceptable carrier, assistant agent further, or vehicle, these are applied as the present invention, comprise any solvent, thinner, or other liquid excipients, dispersion agent or suspension agent, tensio-active agent, isotonic agent, thickening material, emulsifying agent, sanitas, solid binder or lubricant, etc., be suitable for distinctive target formulation.As with described by Publication about Document: In Remington:The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, LippincottWilliams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, the content of comprehensive document herein, show that different carriers can be applicable to preparation and their known preparation methods of pharmaceutically acceptable composition.Except carrier medium and the inconsistent scope of compound of the present invention of any routine, such as produced any bad biological effect or the interaction produced in harmful mode with any other component of pharmaceutically acceptable composition, their purposes is also the scope that the present invention considers.
The material that can be used as pharmaceutically acceptable carrier comprises, but be not limited to, ion-exchanger, aluminium, aluminum stearate, Yelkin TTS, serum protein, as human serum protein, buffer substance is as phosphoric acid salt, glycine, Sorbic Acid, potassium sorbate, the partial glyceride mixtures of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, potassium hydrogen phosphate, sodium-chlor, zinc salt, colloidal silicon, Magnesium Trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymer, lanolin, sugar, as lactose, dextrose plus saccharose, starch is as W-Gum and potato starch, Mierocrystalline cellulose and its derivative as Xylo-Mucine, ethyl cellulose and rhodia, natural gum powder, Fructus Hordei Germinatus, gelatin, talcum powder, auxiliary material is as cocoa butter and suppository wax, oily as peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soya-bean oil, glycol compound, as propylene glycol and polyoxyethylene glycol, ester class is as ethyl oleate and Ethyl Lauroyl acid esters, agar, buffer reagent is as magnesium hydroxide and aluminium hydroxide, Lalgine, pyrogen-free water, isotonic salt, Lin Ge (family name) solution, ethanol, phosphate buffer solution, and other nontoxic proper lubrication agent are as Sulfuric acid,monododecyl ester, sodium salt and Magnesium Stearate, tinting material, releasing agent, coating agents, sweeting agent, seasonings and spices, sanitas and antioxidant.
The compounds of this invention can be applied with the form of oral preparation, as tablet, and capsule (wherein each comprises the formula of sustained release or time controlled released), pill, pulvis, granula, elixir, tincture, suspension agent, syrup, and emulsifying agent.They also can with intravenously (bolus or transfusion), intraperitoneal, and subcutaneous or intramuscular form is used, and the dosage form of all uses is all known by the those of ordinary skill of pharmaceutical field.They can be used separately, but generally select to use together with a kind of pharmaceutical carriers by based on selected method of application and the pharmacy practice of standard.
The dosage regimen of the compounds of this invention by different with known various factors, as the characteristics of pharmacokinetics of particular agent and pattern thereof and route of administration; The race of recipient, age, sex, healthy state, medical conditions and body weight; The nature and extent of symptom; The kind of parallel treatment; The frequency for the treatment of; The approach of dispenser, the kidney of patient and liver function, and the effect that hope reaches.A doctor or animal doctor can make decision and the medicine being with effective amount prevents, offsets or stop the development of thromboembolic disorders.
According to general governing principle, in order to reach the effect of specifying, each activeconstituents used day oral dosage scope be about 0.001 between 1000mg/kg body weight, preferably, between about 0.01 to 100mg/kg body weight.And, most preferably, between about 1.0 to 20mg/kg body weight/day.Use for intravenous, in the infusion process of conventional rate most preferred dosage range be about 1 to about 10mg/kg body weight/minute.The compounds of this invention can to use once a day, or can with every day at twice, use for three times or four times.
Compound of the present invention can use through the local of suitable nasal carrier and use with intranasal form, or uses with cutaneous routes through the subsides of skin medicine by using.When using with the form of transdermal delivery system, the dosage used during whole medication is continuous print instead of interval.
Typically, this compound and the suitable pharmaceutical diluents selected according to the form used and conventional pharmacy practice, vehicle, or carrier (referring to pharmaceutical carriers at this) is mixed to be used, and method of application can be oral tablet, capsule, elixir, syrup etc.
Such as, use for tablet or capsules per os, active medicine component can combine, as lactose with a kind of oral, atoxic, pharmaceutically acceptable inert carrier, starch, sucrose, glucose, methylcellulose gum, Magnesium Stearate, Si Liaodengji dicalcium phosphate feed grade, calcium sulfate, N.F,USP MANNITOL, sorbyl alcohol etc.; For Orally administered in liquid form, oral drug components can with any oral, atoxic, pharmaceutically acceptable inert carrier combine, as ethanol, glycerine, water etc.And, when needs or required time, suitable tackiness agent, slipping agent, decomposing agents and tinting material also can join in mixture.Suitable tackiness agent comprises starch, gelatin, natural sugar as glucose or beta lactose, corn sweetener, natural gum that is natural and synthesis as gum arabic, tragacanth, or sodiun alginate, carboxymethyl cellulose, polyethylene glycol, wax etc.The lubricant applied in these formulations comprises sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium acetate, sodium-chlor etc.Decomposition agent includes, but not limited to starch, methylcellulose gum, agar, wilkinite, xanthan gum, etc.
The compounds of this invention also can be used with the form of liposomal delivery system, as the vesica of little individual layer, and the vesica of large individual layer and multilamellar vesicle.Liposome can be formed by different phosphatide, as cholesterol, and stearylamine, or phosphatidylcholine.
The compounds of this invention also with the polymkeric substance coupling of solubility, this polymer is as the pharmaceutical carriers of target.Such polymer comprises polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyl methacrylate amine-phenol, poly-hydroxyethyl l-asparagine phenol, or with polyethylene oxide-polylysine that palmitoyl residues replaces.And, the compounds of this invention can with a class Biodegradable polymeric coupling, for completing controllable drug release, such as, poly(lactic acid), polyglycolic acid, the multipolymer of poly(lactic acid) and polyglycolic acid, poly epsilon caprolactone lactone, polyhydroxybutyrate, poe, polyacetal, poly-dihydropyrane, polybutylcyanoacrylate, and the crosslinked or amphipathic blocking-up multipolymer of hydrogel.
Be suitable for the per unit dosage of the formulation (pharmaceutical composition) used, the activeconstituents of about 1mg to about 100mg can be contained.In these pharmaceutical compositions, the weight of activeconstituents generally will account for about 0.5-95% of the gross weight of composition.
Gelatine capsule can contain activeconstituents and powder carrier, as lactose, and starch, derivatived cellulose, Magnesium Stearate, stearic acid, etc.Similar thinner can be used to make compressed tablets.The product of Tablet and Capsula as sustainable release can be manufactured to be provided in the medicine of continuous release in for some time.The tablet of compression can add sugar-coat or wrap thin film to cover any offending taste and to make tablet and air exclusion, or adds that the bag of enteric solubility is optionally decomposed by gastrointestinal disturbances road.
Orally administered liquid dosage form can containing tinting material and food flavouring to improve the acceptance of patient.
Usually, water, a kind of suitable oil, salt solution, the dextrose (glucose) of hydration, and relevant sugar soln and glycol (as propylene glycol or polyoxyethylene glycol) are the Suitable carriers of parenteral solution.Without the water-soluble salt of solution preferably containing activeconstituents that enteron aisle is used, suitable stablizer, and buffer substances that may be necessary.Antioxidant is suitable stablizer, and as sodium bisulfite, S-WAT, or vitamins C, both also can combinationally use separately and also can use citric acid and its salt and EDETATE SODIUM salt.In addition, parenteral solution also contains sanitas, as geramine, and methyl-or propyl group-p-Hydroxybenzoate, and chlorobutanol.
Wherein compound of the present invention and other anti-freezing agent combination, such as, for every kg patient body weight, a kind of per daily dose can be the compound of the formula (I) of about 0.1 to 100mg and second antithrombotics of about 1 to 7.5mg.For a kind of Tabules, compound of the present invention can be generally that each dose unit has about 5 to 10mg, and the amount of the second anti-agglutinant is that each dose unit has approximately from 1 to 5mg.Wherein, other anti-freezing reagent specifically comprises, but be not limited to, Eliquis, razaxaban, Yi Dushaban, shellfish Qu Shaban, dabigatran, bemiparin, Enoxaparin Sodium, Tinzaparin sodium, Danaparoid sodium, piperylene sodium, nadroparin calcium, Ardeparin Sodium, Parnaparin Sodium etc.
According to general governing principle, the compounds of this invention and a kind of antiplatelet agent combination are used, general per daily dose can be that per kilogram patient body weight about 0.01 arrives the compound of the formula (I) of 25mg and the antiplatelet reagent of about 50 to 150mg, and preferably approximately 0.1 arrives the compound of the formula (I) of 1mg and the antiplatelet reagent of about 1 to 3mg.
When compound and the thrombolytics combined administration of formula (I), general per daily dose can be the compound of per kilogram patient body weight about 0.1 to the formula (I) of 1mg, and under thrombolytics existent condition, compared with general dosage when using separately with thrombolytics, when thrombolytics is used together with the compound of formula (I), the dosage of thrombolytics can reduce about 70-80%.
When two or more aforesaid second therapeutical agents are used together with the compound of formula (I), usually, additional or the collaborative effect of therapeutical agent when considering co-administered, the amount of each component in typical per daily dose and typical formulation, relative to usual dosage when using separately, can decline to some extent.
Especially, when providing as a single dose unit, between the activeconstituents that there is combination, there is the possibility of chemical reaction.Due to this reason, when the compound of formula (I) and the second therapeutical agent are in a single dose unit during united, their compound method will make the minimize physical contact between activeconstituents (namely be, reduce), although active ingredient combinations is in a single dose unit.Such as, a kind of activeconstituents can be enteric coating bag quilt.By enteric coating bag by a kind of activeconstituents, likely not only make the contact between the activeconstituents of associating minimize, but also a kind of release in the gastrointestinal tract likely controlled in these compositions is not so that the one of these components discharge and discharge in small intestine under one's belt.It is further that activeconstituents a kind of also can superscribe the material affecting its sustained release in the gastrointestinal tract and can be used for the physical contact reduced between the activeconstituents of associating, the component of sustained release also can extraly with enteric coating bag by so that this composition only discharges in enteron aisle.Another method is also had to relate to the formula of associating product, a kind of polymer coating of lasting and/or enteric release of one of them component, and another component also uses polymer as a kind of HYDROXY PROPYL METHYLCELLULOSE (HPMC) of low viscosity rank or other suitable material bag quilt known in the field, to reach the object of further separate active ingredients.The reaction of polymer coating pair and other component defines a kind of obstruction additionally.
Once understanding present disclosure, these and other make the minimized method of contact between the component of associating product of the present invention be clearly for those skilled in the art, no matter they are used with single formulation or use with the form be separated, but be in the identical time or use in an identical manner.
The compound that the present invention relates to or its pharmaceutical salts or its hydrate can be effective to prevent, process, treat or alleviate patient's thrombotic disease, particularly effectively can treat myocardial infarction, stenocardia, block and restenosis after revascularization or aorta Coronary artery bypass, apoplexy, the outbreak of of short duration local asphyxia, peripheral arterial occlusive disease, pulmonary infarction or venous thrombosis.
the general synthetic method of the compounds of this invention
Usually, compound of the present invention can be prepared by method described in the invention, unless there are further instruction, wherein substituent definition such as formula (I) or shown in.Reaction scheme below and embodiment are used for illustrating content of the present invention further.
Those skilled in the art will realize that: chemical reaction described in the invention can be used for preparing many other compounds of the present invention suitably, and is all contemplated within the scope of the present invention for the preparation of other method of compound of the present invention.Such as; synthesis according to the compound of those non-illustrations of the present invention can successfully be completed by modifying method by those skilled in the art; as suitable protection interference group, by the reagent that utilizes other known except described in the invention, or reaction conditions is made the amendment of some routines.In addition, reaction disclosed in this invention or known reaction conditions are also applicable to the preparation of other compounds of the present invention admittedly.
The embodiments described below, unless other aspects show that all temperature are decided to be degree Celsius (DEG C).Reagent is bought in goods providers as Ling Kai medicine, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, all not through being further purified, unless other aspects show during use.General reagent from Xi Long chemical plant, Shantou, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao buy obtain.
Below reacting is generally under nitrogen or argon gas positive pressure or on anhydrous solvent, overlap a drying tube (unless showing in other), the soft rubber ball that reaction flask is suitable all beyond the Great Wall, and substrate is squeezed into by syringe.Glassware is all dried.
Chromatographic column uses silicagel column.Silica gel (300-400 order) is purchased from Haiyang Chemical Plant, Qingdao.NMR (Nuclear Magnetic Resonance) spectrum is with CDC1 3or DMSO-d 6for solvent (reporting in units of ppm), with TMS (0ppm) or chloroform (7.25ppm) as reference standard.In time there is multiplet, abbreviation below will be used: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, quartet), dt (doublet of triplets, two triplet).Coupling constant, represents with hertz (Hz).
Algorithm (MS) data are measured by the spectrograph of the Agilent6320 series LC-MS being equipped with G1312A binary pump and a G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315B DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Algorithm (MS) data are measured by the spectrograph of the Agilent6120 series LC-MS being equipped with G1311A quaternary pump and G1316A TCC (column temperature remains on 30 DEG C), G1329A automatic sampler and G1315D DAD detector applies are in analysis, and ESI source is applied to LC-MS spectrograph.
Above two kinds of spectrographs are provided with Agilent Zorbax SB-C18 post, and specification is 2.1 × 30mm, 5 μm.Volume injected is determined by sample concentration; Flow velocity is 0.6mL/min; The peak value of HPLC records reading by the UV-Vis wavelength at 210nm and 254nm place.Moving phase is the formic acid acetonitrile solution (phase A) of 0.1% and the formic acid ultrapure water solution (phase B) of 0.1%.Condition of gradient elution is as shown in table 1:
Table 1
Time (min) A(CH 3CN，0.1％HCOOH) B(H 2O，0.1％HCOOH)
0-3 5-100 95-0
3-6 100 0
6-6.1 100-5 0-95
6.1-8 5 95
Compound purifying is evaluated by Agilent 1100 series of high efficiency liquid chromatography (HPLC), wherein UV detects at 210nm and 254nm place, Zorbax SB-C18 post, specification is 2.1 × 30mm, 4 μm, 10 minutes, flow velocity was 0.6mL/min, (0.1% aqueous formic acid) of (the 0.1% formic acid acetonitrile solution) of 5-95%, column temperature remains on 40 DEG C.
The use of brief word below runs through the present invention:
HBTU benzotriazole-N, N, N', N'-tetramethyl-urea hexafluorophosphate
Pd/C palladium/carbon
M, mol/L mol/L
Mg milligram
Mmol mmole
ML milliliter
Min minute
μ L microlitre
V/v, V/V volume ratio
DEG C degree Celsius
Following synthetic schemes describes preparation the present invention and to come into the open the step of compound.
Synthetic schemes 1
The method that compound (I) can be described by synthetic schemes 1 prepares, and wherein A, B have definition of the present invention.Compound (1) and compound (2) are at cuprous iodide, part is (as N, N'-dimethyl-ethylenediamine) and alkali (as salt of wormwood) exist under, carry out linked reaction through high temperature in a solvent, obtain compound (3); Compound (3) under the catalysis of Pd/C in atmosphere of hydrogen deprotection obtain compound (4); Compound (4) and compound (5) carry out condensation reaction and obtain target compound (I).
Below in conjunction with embodiment, compound provided by the invention, pharmaceutical composition and application thereof are further described.
embodiment
Implement 1:8-(5-chlorothiophene-2-formyl radical)-3-(4-(3-oxo-morpholine) phenyl)-1-oxa--3,8-diaza spiro [4.5] decane-2-ketone
Step 1:2-(1-benzyl-4-hydroxy piperidine-4-base) ethyl acetate
Under nitrogen atmosphere, in 100mL tri-mouthfuls of round-bottomed flasks, add the tetrahydrofuran solution (37.5mL, 75mmol) of the lithium diisopropylamine of 2M.Mixed solution is chilled to-70 DEG C, slowly injects ethyl acetate (6.9g, 75mmol) with syringe, then drips tetrahydrofuran (THF) (10mL) solution of 1-benzyl piepridine-4-ketone (9.5g, 50mmol) slowly.Reaction solution rises to-20 DEG C, adds ethyl acetate (10mL), with saturated ammonium chloride solution (30mL × 2) washing, and organic phase anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=3/1), obtains colorless oil (9.52g, 68.4%).
MS(ESI,pos.ion)m/z:278.2(M+1)。
Step 2:2-(1-benzyl-4-hydroxy piperidine-4-base) acethydrazide
In round-bottomed flask, add the hydrazine hydrate (40mL) of 2-(1-benzyl-4-hydroxy piperidine-4-base) ethyl acetate (9.52g, 34.32mmol) and 85%, be heated to 100 DEG C and stir 2 hours.Add water (20mL) in reaction solution, be cooled with an ice bath, suction filtration obtains white solid (8.1g, 90.0%).
MS(ESI,pos.ion)m/z:264.2(M+1)。
Step 3:8-benzyl-1-oxa--3,8-diaza spiro [4.5] decane-2-ketone
In water (30mL) solution of 2-(1-benzyl-4-hydroxy piperidine-4-base) acethydrazide (8.12g, 30.84mmol), add concentrated hydrochloric acid be acidified to pH=2-3.Be chilled to 10 DEG C with ice bath, in mixed solution, slowly drip the water (10mL) of Sodium Nitrite (2.55g, 36.96mmol).Be heated to 60 DEG C stir 20 minutes.Then be chilled to room temperature, add the aqueous sodium hydroxide solution alkalization of 20% to pH=9-10.Be extracted with ethyl acetate (50mL × 3) mixed solution, merge organic phase, with saturated aqueous common salt (60mL) washing, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (ethyl acetate/methanol (v/v)=20/1), obtains white solid (5.5g, 72.4%).
MS(ESI,pos.ion)m/z:247.2(M+1)。
Step 4:4-(4-iodophenyl) morpholine-3-ketone
Isosorbide-5-Nitrae-diiodo-benzene (2g, 6.06mmol), morpholine-3-ketone (700mg, 6.92mmol), salt of wormwood (2.5g, 18.1mmol), cuprous iodide (230mg, 1.21mmol), N is added successively in tube sealing 1, N 2-dimethyl-ethylenediamine (110 μ L, 1.21mmol) and dimethyl sulfoxide (DMSO) (6mL).Under nitrogen atmosphere, mixed solution is heated to 120 DEG C of stirrings 10 hours.Mixed solution is chilled to room temperature, adds water (20mL) cancellation, and methylene dichloride (15mL × 3) extracts, anhydrous sodium sulfate drying.Thick product, through column chromatography purification (petrol ether/ethyl acetate (v/v)=1/5), obtains white solid (1.22g, 66.4%).
MS(ESI,pos.ion)m/z:304.0(M+1)。
Step 5:8-benzyl-3-(4-(3-oxo-morpholine) phenyl)-1-oxa--3,8-diaza spiro [4.5] decane-2-ketone
8-benzyl-1-oxa--3 is added successively in tube sealing, 8-diaza spiro [4.5] decane-2-ketone (300mg, 1.22mmol), 4-(4-iodophenyl) morpholine-3-ketone (370mg, 1.22mmol), salt of wormwood (340mg, 2.46mmol), cuprous iodide (34.6mg, 0.250mmol), N 1, N 2-dimethyl-ethylenediamine (30 μ L, 0.25mmol) and dimethyl sulfoxide (DMSO) (5mL).Under nitrogen atmosphere, mixed solution is heated to 120 DEG C of stirrings 10 hours.Reaction solution is chilled to room temperature, adds water (20mL) cancellation, and methylene dichloride (15mL × 3) extracts, anhydrous sodium sulfate drying.Thick product, through column chromatography purification (ethyl acetate/methanol (v/v)=9/1), obtains white solid (400mg, 77.9%).
MS(ESI,pos.ion)m/z:422.2(M+1)。
Step 6:3-(4-(3-oxo-morpholine) phenyl)-1-oxa--3,8-diaza spiro [4.5] decane-2-ketone
To 8-benzyl-3-(4-(3-oxo-morpholine) phenyl)-1-oxa--3,8-diaza spiro [4.5] decane-2-ketone (450mg, 10% palladium carbon (500mg) is added in ethanol (5mL) solution 1.07mmol), under an atmosphere of hydrogen, mixed solution is heated to 30 DEG C of stirrings 16 hours.Suction filtration, filtrate decompression boils off solvent, obtains white solid (310mg, 87.6%).
MS(ESI,pos.ion)m/z:322.2(M+1)。
Step 7:8-(5-chlorothiophene-2-formyl radical)-3-(4-(3-oxo-morpholine) phenyl)-1-oxa--3,8-diaza spiro [4.5] decane-2-ketone
To 5-chlorothiophene-2-formic acid (99mg, N 0.609mmol), triethylamine (120 μ L are added in dinethylformamide (3mL) solution, 0.863mmol), 3-(4-(3-oxo-morpholine) phenyl)-1-oxa--3,8-diaza spiro [4.5] decane-2-ketone (100mg, 0.302mmol) with HBTU (170mg, 0.448mmol).After mixed solution at room temperature stirs 1 hour, add water (15mL), with ethyl acetate (10mL × 2) extraction, merge organic phase.Organic phase saturated aqueous common salt (10mL) washing, anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (ethyl acetate/methanol (v/v)=50/1), obtains white solid (6.5mg, 4.5%).
MS(ESI,pos.ion)m/z:476.1(M+1)；
1H NMR(400MHz,CDCl 3):δ7.5-7.57(d,2H)；7.37-7.35(d,2H)；7.12-7.11(d,1H)；6.89-6.88(d,1H)；4.34(s,2H),4.32-4.31(t,2H)；4.05-4.04(t,2H)；3.79(S,2H),3.77-3.76(t,2H)；3.54-3.51(m,2H),2.11-2.08(d,2H),1.87-1.83(m,2H)。
Embodiment 2:8-(6-chloronicotinoyl base)-3-(4-(3-oxo-morpholine) phenyl)-1-oxa--3,8-diaza spiro [4.5] decane-2-ketone
To 6-chlorine apellagrin (95mg, N 0.603mmol), triethylamine (120 μ L are added in dinethylformamide (3mL) solution, 0.863mmol), 3-(4-(3-oxo-morpholine) phenyl)-1-oxa--3,8-diaza spiro [4.5] decane-2-ketone (100mg, 0.302mmol, see embodiment 1 step 6) and HBTU (170mg, 0.448mmol).Mixed solution, stirring at room temperature 1 hour, adds water (15mL) and with ethyl acetate (10mL × 2) extraction, merges organic phase, with saturated aqueous common salt (10mL) washing, and anhydrous sodium sulfate drying.Filter, pressure reducing and steaming solvent, thick product, through column chromatography purification (ethyl acetate/methanol (v/v)=50/1), obtains white solid (28mg, 19.7%).
MS(ESI,pos.ion)m/z:471.2(M+1)；
1H NMR(400MHz,CDCl 3):δ8.54-8.53(d,1H),7.82-7.81(d,2H)；7.96-7.90(d,2H)；7.69-7.67(d,2H)；7.37-7.35(d,2H)；4.34(s,2H),4.05-4.03(t,2H)；3.83-3.81(t,2H)；3.78(s,2H),3.78-3.76(t,2H)；3.64-3.59(m,2H),2.04-2.02(d,2H),1.99-1.98(m,2H)。
biological activity test
Mankind FXa enzyme level is tested
The enzymic activity of mankind's factor Xa (FXa) is by the transformation assay for the specific chromogenic substrate of FXa.To this, p-Nitraniline is fallen in factor Xa cracking from chromogenic substrate.This is determined as follows to state and carries out on microwell plate.
Tester is dissolved in the methyl-sulphoxide of 10% by different concns, (10nM is dissolved in 50mM Tris to get compound 5 μ L and mankind FXa, 150mM NaCl, pH=8.3) 10 μ L mix, 15min is hatched in 25 DEG C of constant incubators, FXa chromophoric substrate (800 μMs, sigma) 5 μ L is added, in 25 DEG C of 405nm place kinetic test absorbances after hatching.By the test mixing thing containing test substances and not containing test substances control mixture relatively and calculate IC by these data 50value.
Anticoagulation effect in vitro is tested
The clotting time of compounds extend rabbit plasma
1, the preparation of each concentration compound
Get each compound working fluid (100mM) of 4 μ L, be diluted to the working fluid of each concentration with methyl-sulphoxide liquid.
2, the preparation of plasma sample
Get some rabbits, auricular vein injects 3% pentobarbital solution (30mg/kg) anesthesia, with the vacuum test tube aorta abdominalis blood sampling containing 3.8% Sodium Citrate 0.2mL to 2mL, collect multitube, turn upside down mixing for several times, leave standstill 10min, in the centrifugal 10min of 3000rpm, draw each pipe blood plasma, all blood plasma is mixed to same centrifuge tube, 1.6mL often pipe packing, it is for subsequent use to insert rapidly-80 DEG C of Refrigerator stores.
3, application of sample and mensuration clotting time PT and APTT
Get out 1.5mL EP manage, often pipe adds 180 μ L plasma specimens; In each pipe blood specimen, add the medicine of 4 μ L respective concentration respectively, control group adds 4 μ L dimethyl sulfoxide solutions, and concussion mixing, hatches 5min for 37 DEG C; PT and APTT is measured with Sysmex CA1500 Automatic coagulometer; Draw amount effect curve, matching is carried out to curve, calculate the concentration (CT of the test compounds that the clotting time of sening as an envoy to doubles thus 2).
Table 2 compound is to the restraining effect of people FXa activity and anticoagulation effect in vitro
Conclusion: the compounds of this invention has good factor Xa inhibit activities, has the effect extending the clotting time simultaneously.
The solubleness test of compound
In 15mL tapered tube, add water (10mL), vibration limit, limit adds sample, until sample stops dissolving, and 37 DEG C of water bath with thermostatic control jolting 24h, jolting speed 40rpm.After jolting terminates, sample is filtered through water system millipore filtration (0.45 μm, Φ 13mm), discard just filtrate, precision pipettes subsequent filtrate (500 μ L), adds diluent acetonitrile-water (500 μ L, v/v=60/40), the two mixing, obtains need testing solution.
Get need testing solution (40 μ L), adopt HPLC to detect, by one point external standard method calculation sample concentration, and calculate compound solubility.
The solubleness of table 3 compound in water
Numbering Compound solubility (mg/mL)
Embodiment 1 0.23
Embodiment 2 0.26
Conclusion: the compounds of this invention has good solubleness.
In the description of this specification sheets, specific features, structure, material or feature that the description of reference term " embodiment ", " some embodiments ", " example ", " concrete example " or " some examples " etc. means to describe in conjunction with this embodiment or example are contained at least one embodiment of the present invention or example.In this manual, to the schematic representation of above-mentioned term not must for be identical embodiment or example.And the specific features of description, structure, material or feature can combine in one or more embodiment in office or example in an appropriate manner.In addition, when not conflicting, the feature of the different embodiment described in this specification sheets or example and different embodiment or example can carry out combining and combining by those skilled in the art.
Although illustrate and describe embodiments of the invention above, be understandable that, above-described embodiment is exemplary, can not be interpreted as limitation of the present invention, and those of ordinary skill in the art can change above-described embodiment within the scope of the invention, revises, replace and modification.

Claims (8)

1. a compound, it is compound shown in general formula (I), or the steric isomer of compound shown in formula (I), geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug:
Wherein,
A is optional monosubstituted or polysubstituted C 1-C 9heteroaryl, wherein substituting group is selected from H, halogen, amino, cyano group, carboxyl, hydroxyl, C 1-C 4alkyl or C 1-C 4alkoxyl group;
B is optional monosubstituted or polysubstituted C 2-C 10heterocyclic radical, wherein substituting group is selected from H, oxo, halogen, amino, C 1-C 4alkyl or C 1-C 4alkoxyl group.
2. compound according to claim 1, wherein,
A is optional monosubstituted or polysubstituted C 1-C 6heteroaryl, wherein substituting group is selected from H, halogen, amino, cyano group, carboxyl, hydroxyl, C 1-C 4alkyl or C 1-C 4alkoxyl group;
B is optional monosubstituted or polysubstituted C 2-C 6heterocyclic radical, wherein substituting group is selected from H, oxo, halogen, amino, C 1-C 4alkyl or C 1-C 4alkoxyl group.
3. compound according to claim 1, wherein,
A is subformula wherein, X 1, X 2, X 3and X 4respective is independently N or CR 1; R 1respective is independently H, halogen, amino, cyano group, carboxyl, hydroxyl, C 1-C 4alkyl or C 1-C 4alkoxyl group; With, each X 5for NH, O or S; Wherein, each A subformula is independent optionally by H, halogen, amino, cyano group, carboxyl, hydroxyl, C 1-C 4alkyl or C 1-C 4the substituting group of alkoxyl group replaced;
B is subformula wherein each B subformula is independent optionally by H, oxo, halogen, amino, C 1-C 4alkyl or C 1-C 4one or more substituting groups in alkoxyl group replaced.
4. compound according to claim 1, wherein,
A is optionally monosubstituted or polysubstituted pyridyl, thienyl, pyrazinyl, thiazolyl, furyl, pyrimidyl, imidazolyl or pyridazinyl, and wherein substituting group is selected from H, fluorine, chlorine, bromine, amino, cyano group, carboxyl, hydroxyl, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy or isopropoxy;
B is optionally monosubstituted or polysubstituted piperidyl, piperazinyl, pyrrolidyl, imidazolidyl, morpholinyl, 2-oxo-pyrrolidine base, 3-oxo-morpholin-4-base or oxazolidinyl, and wherein substituting group is selected from H, oxo, H, fluorine, chlorine, bromine, amino, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, positive propoxy or isopropoxy.
5. compound according to claim 1, comprises one of them compound following,
Or the steric isomer of said structure, geometrical isomer, tautomer, oxynitride, hydrate, solvate, meta-bolites, pharmacy acceptable salt or prodrug.
6. a pharmaceutical composition, comprises the compound described in any one of claim 1-5, and pharmaceutically acceptable carrier, vehicle, thinner, assistant agent, vehicle or their combination.
7. the compound described in any one of claim 1-5 or pharmaceutical composition according to claim 6 are being prepared, preventing, are being processed or treat the purposes in the medicine of thrombotic disease.
8. the compound described in any one of claim 1-5 or the purposes of pharmaceutical composition according to claim 6 in preparation supressor Xa medicine.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997011940A1 (en) * 1995-09-29 1997-04-03 Eli Lilly And Company Spiro compounds as inhibitors of fibrinogen-dependent platelet aggregation
CN1434822A (en) * 1999-12-24 2003-08-06 拜尔公司 Substituted oxazolidinones and their use in the field of blood coagulation
CN1578660A (en) * 2001-09-21 2005-02-09 百时美施贵宝公司 Lactam-containing compounds and derivatives thereof as factor xa inhibitors
CN1751025A (en) * 2002-12-25 2006-03-22 第一制药株式会社 Diamine derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997011940A1 (en) * 1995-09-29 1997-04-03 Eli Lilly And Company Spiro compounds as inhibitors of fibrinogen-dependent platelet aggregation
CN1434822A (en) * 1999-12-24 2003-08-06 拜尔公司 Substituted oxazolidinones and their use in the field of blood coagulation
CN1578660A (en) * 2001-09-21 2005-02-09 百时美施贵宝公司 Lactam-containing compounds and derivatives thereof as factor xa inhibitors
CN1751025A (en) * 2002-12-25 2006-03-22 第一制药株式会社 Diamine derivatives

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