CN1222909A - Pyrazinone thrombin inhibitors - Google Patents

Pyrazinone thrombin inhibitors Download PDF

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Publication number
CN1222909A
CN1222909A CN 97195760 CN97195760A CN1222909A CN 1222909 A CN1222909 A CN 1222909A CN 97195760 CN97195760 CN 97195760 CN 97195760 A CN97195760 A CN 97195760A CN 1222909 A CN1222909 A CN 1222909A
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amino
methyl
alkyl
isophthalic acid
composition
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P·E·桑德森
T·A·莱尔
B·D·多尔西
R·J·瓦尔索罗纳
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Merck and Co Inc
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Merck and Co Inc
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Priority to CN 97195760 priority Critical patent/CN1222909A/en
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Abstract

Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having structure (a), for example (b).

Description

Pyrazinone thrombin inhibitors
Background of invention
Zymoplasm is a serine protease, and with its precursor forms, the form of thrombogen is present in the blood plasma.Zymoplasm is played an important role in the coagulation of blood process, and it is transformed into insoluble fibrin with plasma protein solution, Parenogen.
Edwards etc. (J.Amer.Chem.Soc., (1992) 114 volumes, 1854-1863 page or leaf) have described peptidyl alpha-oxo-benzoxazole, and this is the reversible inhibitor that a class comprises the serine protease of human leukocyte elastase and pancreatic elastase.
The Europe publication has been described the analogue of peptide enzyme substrates for No. 363284, and wherein the nitrogen-atoms of the amide group of peptide substrates disconnection is replaced by the carbonyl of hydrogen or replacement.
Australia's publication has been described for No. 86245677 equally for example peptidase inhibitors of fluorine methylene ketone or alpha-oxo-carboxy derivatives of the electrophilic ketone group of activatory part.
R.J.Brown etc. (J.Med.Chem., 37 volumes, 1259-1261 page or leaf (1994)) retouch
Stated the Nonpeptide inhibitors of the human leukocyte elastase with Orally active, it contains trifluoro ketone and pyridone part.
H.Mack etc. (J.Enzyme Inhibition, 9 volumes, 73-86 page or leaf (1995)) have described rigidity Amidinophenylalaninederivatives thrombin inhibitors, and it comprises the pyridone part as important core texture.
Summary of the invention
Present invention resides in the interior composition that suppresses thrombocyte loss, the formation of anticoagulant body, the formation of inhibition fibrinogen, suppresses thrombosis and the formation of inhibition embolus of mammalian body, it is included in the The compounds of this invention in the pharmaceutically acceptable carrier.These compositions can comprise anti-coagulant, anti-platelet agents and thrombolytic agent arbitrarily.In order to reach required restraining effect, can be added to these compositions in the blood, in blood products or the mammiferous organ.
The present invention comprises also that blood coagulation in prevention and treatment Mammals unstable angina, intractable angina pectoris, myocardial infarction, transient ischemia's outbreak, auricular fibrillation, thrombosis outbreak, embolism outbreak, venous thrombosis, the blood vessel is scattered, visual visible fibrinogen formation and reproduce obturation again in the blood vessel or the composition of restenosis.Said composition is included in the The compounds of this invention in the pharmaceutically acceptable carrier.These compositions can comprise anti-coagulant, anti-platelet agents and thrombolytic agent arbitrarily.
The present invention also comprise by covalently or non-covalently tie up additional copy invention compound in body surface to reduce the thrombotic method of Mammals body surface.Detailed description of the present invention and preferred version
The compounds of this invention is useful as thrombin inhibitors and has therapeutic value aspect the coronary artery disease for example preventing and treating that it is the following compound of structural formula or its pharmacy acceptable salt: Wherein W is
Hydrogen,
R 1,
R 1OCO,
R 1CO,
R 1(CH 2) nNHCO, or
(R 1) 2CH(CH 2) nNHCO，
Wherein n is 0-4; R 1Be
R 2,
R 2(CH 2) mC (R 12) 2, wherein m is 0-3 and each R 12Can be identical or different,
(R 2) (OR 2) CH (CH 2) P, wherein P is 1-4,
R 2C (R 12) 2(CH 2) m, wherein m is 0-3 and each R 12Can be identical or different, (R wherein 12) 2
Also can form C with C 3-7The ring of cycloalkyl representative,
R 2CH 2C (R 12) 2(CH 2) q, wherein m is 0-2 and each R 12Can be identical or different, (R wherein 12) 2Also can form C with C 3-7The ring of cycloalkyl representative,
(R 2) 2CH (CH 2) r, wherein r is 0-4 and each R 2Can be identical or different, (R wherein 2) 2
Also can form C with CH 3-7Cycloalkyl, C 7-12Bicyclic alkyl, C 10-16Saturated or the undersaturated 5-7 of tricyclic alkyl unit ring and this ring single or representative of two heterocycles contain 1-3 heteroatoms that is selected from N, O and S,
R 2O (CH 2) P, wherein P is 1-4, or
R 2(COOR 3) (CH 2) r, wherein r is 1-4; R 2And R 14Representative independently of one another
Unsubstituted or by one or more C 1-4Alkyl, C 1-4Alkoxyl group, halogen, hydroxyl, COOH, CONH 2Or SO 2NH 2The phenyl that replaces,
Naphthyl,
Xenyl,
5-7 unit's monocycle or 9-10 unit's bicyclic heterocycles or non-heterocycle, they can be saturated or undersaturated,
Wherein heterocycle contains the heteroatoms that 1-4 is selected from N, O and S, and heterocycle wherein or non-heterocycle be unsubstituted or replaced by halogen or hydroxyl,
Unsubstituted or by one or more hydroxyls, COOH, amino, aryl, C 3-7Cycloalkyl, CF 3, N (CH 3) 2, C 1-3The C that alkylaryl, heteroaryl or Heterocyclylalkyl replace 1-7Alkyl,
CF 3
The C that does not replace or replaced by aryl 3-7Cycloalkyl,
C 7-12Bicyclic alkyl, or
C 10-16Tricyclic alkyl; R 3Be
Hydrogen,
C 1-4Alkoxyl group,
C 3-7Cycloalkyl, or
Trifluoromethyl; X is
Hydrogen, or halogen; A is selected from one of following groups:
Y wherein 1And Y 2Independent separately representative
Hydrogen,
C 1-4Alkyl,
C 1-4Alkoxyl group,
C 3-7Cycloalkyl,
Halogen, or
Trifluoromethyl; R 4Be
Hydrogen,
C 1-4Alkyl,
C 1-4Alkoxyl group,
Halogen,
-OCH 2CF 3,
-OCH 2CN,
-COOH,
-OH,
-COOR 6, R wherein 6Be C 1-4Alkyl,
-CONR 7R 8, R wherein 7And R 8Independent separately hydrogen or the C of representing 1-4Alkyl,
-(CH 2) 1-4OH,
-CH 2NHC(O)CH 3,
-CH 2NHC(O)CF 3,
-CH 2NHSO 2CH 3,-SO 2NH 2,-(CH 2) 1-4SO 2NR 7R 8,-(CH 2) 1-4SO 2R 6, 5-7 unit's monocycle or 9-10 unit bicyclic heterocycles, they can be saturated or undersaturated heterocycles, it contains 1-4 heteroatoms that is selected from N, O and S ,-ZCH 2CO 2H ,-ZCH 2CO 2CH 3,-ZCH 2R 14,-ZCH 2CO 2(CH 2) 1-3CH 3,-Z (CHR 9) 1-3C (O) NR 10R 11Wherein
R 9Be hydrogen or C 1-4Alkyl,
R 10And R 11Independent separately representative
Hydrogen,
C 3-7Cycloalkyl,
Aryl,
Heteroaryl,
Heterocyclylalkyl,
-(CH 2) 1-2NCH 2CH 3，
Unsubstituted or by one or more hydroxyls, COOH, amino, aryl, heteroaryl or
The C that Heterocyclylalkyl replaces 1-4Alkyl, or
R 10And R 11The 4-7 unit cycloalkyl that forms not replacement together or replaced by hydroxyl, amino or aryl, wherein Z is O, S or CH 2Be hydrogen, halogen, C 1-4Alkyl, C 1-4Alkoxyl group, CF 3,
CN, or
CO 2NH 2, and R 12Be
Hydrogen,
Unsubstituted or by one or more C 1-4Alkyl, C 1-4Alkoxyl group, halogen, hydroxyl, COOH, CONH 2The phenyl that replaces,
Naphthyl,
Xenyl,
5-7 single heterocycle of unit or 9-10 unit two heterocycles, they can be saturated or undersaturated, wherein contain 1-4 heteroatoms that is selected from N, O and S,
C unsubstituted or that replaced by one or more hydroxyls, COOH, amino, aryl, heteroaryl or Heterocyclylalkyl 1-4Alkyl,
CF 3
C 3-7Cycloalkyl,
C 7-12Bicyclic alkyl, or
C 10-16Tricyclic alkyl.
In a compounds and the acceptable salt of its medicine, R 3Be C 1-4Alkyl.
In the subclass of this compounds and the acceptable salt of its medicine, A is selected from one of following groups:
Y wherein 1And Y 2Independent separately hydrogen or the C of representing 1-4Alkyl; R 4Be
Hydrogen,
Halogen,
-OCH 2CN，
-OH,
-ZCH 2CO 2H, or
-Z(CHR 9) 1-3C(O)NR 10R 11
Wherein
R 9Be hydrogen or C 1-4Alkyl and
R 10And R 11Independent separately representative
Hydrogen,
C 3-7Cycloalkyl,
-(CH 2) 1-2NCH 2CH 3, or
C 1-4Alkyl,
Wherein Z is O, S or CH 2R 5Be
Hydrogen,
Halogen, or
CF 3。
In one group of compound of this subclass compound and the acceptable salt of its medicine, W is H or R 1
In the subgroup compound of this group compound and the acceptable salt of its medicine, R 1Be
R 2,
R 2(CH 2) mC (R 12) 2, wherein m is 0-3 and each R 12Can be identical or different,
R 2C (R 12) 2(CH 2) m, wherein m is 0-3 and each R 12Can be identical or different, (R wherein 12) 2
Also can form C with C 3-7The ring of cycloalkyl representative,
(R 2) 2CH (CH 2) r, wherein r is 0-4 and each R 2Can be identical or different, (R wherein 2) 2
Also can form C with CH 3-7Cycloalkyl, C 7-12Bicyclic alkyl, C 10-16Tricyclic alkyl or 5-7
Unit saturated or undersaturated ring and this ring single or representative of two heterocycles contain 1-3 heteroatoms that is selected from N, O and S,
R 2O (CH 2) P, wherein P is 1-4; R 2And R 14Representative independently of one another
Unsubstituted or by C 1-4Alkyl, C 1-4Alkoxyl group, halogen, hydroxyl or SO 2NH 2Single or polysubstituted phenyl,
Single heterocycle of 5-7 unit or 9-10 unit two rings, they can be saturated or undersaturated heterocycle or non-heterocycle, and wherein heterocycle contains 1-4 heteroatoms that is selected from N, O and S, and heterocycle wherein or non-heterocycle be unsubstituted or replaced by halogen or hydroxyl,
Unsubstituted or by one or more hydroxyls, COOH, C 3-7Cycloalkyl, CF 3, N (CH 3) 2, C 1-3The C that alkylaryl, heteroaryl or Heterocyclylalkyl replace 1-7Alkyl,
CF 3Or
C unsubstituted or that replaced by aryl 3-7Cycloalkyl; And R 12Be
Hydrogen,
C unsubstituted or that replaced by one or more hydroxyls, COOH, amino, aryl, heteroaryl or Heterocyclylalkyl 1-4Alkyl.
In the family of this subgroup compound and the acceptable salt of medicine thereof, A is R wherein 5Be H, fluorine, chlorine, and R 10And R 11Independently be selected from separately
Hydrogen,
C 2H 5，
C 3H 5，
(CH 2) 2N(CH 3) 2,
C 3Cycloalkyl, R wherein 4Be OH, chlorine, H ,-OCH 2CN, fluorine ,-OCH 2COOH, R 5Be chlorine or CF 3, R 3Be CH 3Or CH 2CH 3X is H or chlorine; With W be PhCH 2CH 2, (CH 3) 3C-, HOOCCH 2, CF 3CH 2, (CH 3) 2N (CH 2) 2, PhCH 2O (CH 2) 2, PhCH (CH 3), PhCH 2CH (COOH), CH 3(CH 2) 5, PhCH 2, H, CH 3(CH 2) 4, CH 3CH 2CH (CH 3) CH 2, (Ph) 2CHCH 2, PhCH 2CH (CH 3), PhCH 2C (CH 3) 2, PhCH (CH 3) CH 2, (CH 3) 2CH, PhCH (OH) CH 2, PhC (CH 3) CH 2, (Ph) 2CHCH 2,
Figure A9719576000561
Figure A9719576000571
Figure A9719576000581
This type of examples for compounds is listed in down among the tabulation 1-4, and this compounds comprises (noticing that methyl is to link to each other with ring with singly-bound as usual):
Figure A9719576000591
Figure A9719576000601
Figure A9719576000611
A special example is compound 3-(2-styroyl amido)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone and acceptable salt of medicine thereof.A kind of special salt of this compound is 3-(2-styroyl amido)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone dihydrochloride.This salt one of can two kinds of crystal polymorphic forms preparation, represent (seeing the embodiment V) with " crystal form A " and " crystal form B " hereinafter.
Compound of the present invention can have chiral centre and generate all isomeric forms of racemoid, therefore, the present invention includes racemic mixture and single diastereomer or all isomeric forms of enantiomorph.Compound of the present invention also can be the crystalline polymorph thing, therefore, the present invention includes all crystalline polymorphs thing.
When any variable existence form in any component or formula I surpassed one time, with respect to the definition of every kind of other existence, the definition of every kind of existence was independently.Have only when these combinations can cause stable compound, just allow the such substituent and/or the combination of existence.
Some abbreviations that occur among the application are described as follows.
Dummy suffix notation protecting group BOC; (Boc) tert-butoxycarbonyl CBZ; (Cbz) carbobenzoxy-(Cbz) TBS; (TBDMS) t-butyldimethylsilyl activates basic HBT; (HOBT or HOBt) I-hydroxybenzotriazole hydrate symbol coupler bop reagent benzotriazole-1-base oxygen three-; (dimethylin)
Phosphorus hexafluorophosphate BOP-Cl two (2-oxo-3-oxazolidinyl) phosphine chlorine EDC 1-ethyl-3-(3-dimethylamino-propyl)
Carbodiimide hydrochloride
Other (BOC) 2O (BOC 2O) di-t-butyl carbonic ether n-Bu 4N+F-tetrabutylammonium nBuLi (n-Buli) n-Butyl Lithium DMF dimethyl formamide Et 3N (TEA) triethylamine EtOAc ethyl acetate TFA trifluoroacetic acid DMAP dimethyl aminopyridine DME dimethoxy-ethane NMM N-methylmorpholine DPPA diphenyl phosphoryl azide THF oxolane DIPEA diisopropylethylamine
Amino acid
The Ile Isoleucine
The Phe phenylalanine
The Pro proline(Pro)
The Ala L-Ala
The Val Xie Ansuan
Herein except that indicating especially, " alkyl " comprises having the straight chain of specifying carbonatoms and the saturated fatty alkyl (Me is a methyl, and Et is an ethyl, and Pr is a propyl group, and Bu is a butyl) of side chain; " alkoxyl group " representative is by the straight or branched alkyl of the continuous appointment carbonatoms of oxo bridge; " halogen " is meant fluorine, chlorine, bromine and iodine herein; The ion of the band single negative charge that " counter ion " representative is little, for example chlorion, bromide anion, hydroxide radical, acetate moiety, trifluoroacetic acid root, perchlorate, nitrate radical, benzoate anion, maleate, sulfate radical, tartrate anion, half tartrate anion, Phenylsulfonic acid root etc.
Term " C 3-7Cycloalkyl " comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl etc.
Term " C 7-12Bicyclic alkyl " comprise two ring [2,2,1] heptyl (norcamphyl), two ring [2,2,2] octyl groups, 1,1,3-trimethylammonium-two encircles [2,2,1] heptyl (bornyl) etc.
In this article except that have especially indicate, 6-10 unit's list or dicyclo, for example phenyl or naphthyl that term " aryl " representative is stable.Aromatic ring can not replace or by one or more C 1-4Low alkyl group, hydroxyl, alkoxyl group, halogen, the amino replacement.Term " heteroaryl " is meant that containing one or two is selected from the unsaturated ring of O, N or S heteroatomic 5-7 unit.
In this article except that have especially indicate, 5-7 unit's list that term " heterocycle " or " heterocyclic ring " representative are stable or dicyclo or the stable two heterocycles of 7-10 unit, they can be saturated or undersaturated, and constitute by carbon atom and 1-4 heteroatoms that is selected from N, O and S, wherein nitrogen and sulfur heteroatom can be by any oxidations, nitrogen heteroatom can be comprised that bicyclic groups and phenyl ring that any above heterocycle definition provides condense by quaternized arbitrarily.Particularly advantageous ring contains a Sauerstoffatom or sulphur atom, 1-4 nitrogen-atoms or Sauerstoffatom that links to each other with one or two nitrogen-atoms or sulphur atom.Heterocyclic ring can be connected with any heteroatoms or carbon atom to produce rock steady structure.The example of this class heterocyclic group comprises piperidyl, piperazinyl, 2-oxygen piperazinyl, 2-Oxypertine base, 2-oxygen pyrrolidyl, 2-oxo azatropylidene base, the azatropylidene base, pyrryl, the 4-piperidone base, pyrrolidyl, pyrazolyl, pyrazolidyl, imidazolyl, imidazolinyl, imidazolidyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl oxazolyl oxazolidinyl isoxazolyl isoxazole alkyl, morpholinyl, thiazolyl, thiazolidyl, isothiazolyl, quinuclidinyl, the isothiazole alkyl, indyl, quinolyl, isoquinolyl, benzimidazolyl-, thiadiazolyl group, benzopyranyl, benzothiazolyl benzoxazolyl, furyl, tetrahydrofuran base, THP trtrahydropyranyl, tetrazyl, thienyl, benzothienyl, thio-morpholinyl, the thiomorpholine sulfoxide, thiomorpholine Feng is with the oxadiazole base.Morpholino is identical with morpholinyl.
The drug acceptable salt of generalformula (existing with water or the solvable form of product of maybe can disperseing of oil) comprises habitual non-toxic salt, the salt that derives from mineral acid for example, for example hydrochloride, hydrobromate, vitriol, sulfamate, phosphoric acid salt, nitrate etc., the perhaps quaternary ammonium salt that generates from inorganic or organic acid or alkali.The example of acid salt comprises acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, Citrate trianion, camphorate, camsilate, cyclopentane propionate, digluconate, dodecyl sulfate, ethyl sulfonate, fumarate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, lactic acid salt, maleate, mesylate, the 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, 4,4 '-methylene-bis (3-hydroxyl-2-naphthoate), pectinic acid salt, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, vitriol, tartrate, thiocyanic acid is given as security, tosylate and undecane hydrochlorate.Alkali salt comprises ammonium salt, and an alkali metal salt is sodium and sylvite for example, and alkaline earth salt is calcium and magnesium salts for example, and the salt of organic bases is for example arginic acid salt, lysine salt etc. of dicyclohexyl ammonium salt, N-methyl D-glucose ammonium salt and amino acid salts for example.The group that contains nitrogen-atoms also can with some for example the reagent generation quaternization of elementary alkyl halide, for example methyl chloride, ethyl chloride, propyl chloride, Butyryl Chloride, monobromomethane, monobromoethane, propyl bromide, butyl bromide, methyl-iodide, iodoethane, propyl iodide and butyl iodide; Dialkyl sulfate such as Dimethylsulfate, diethyl sulfide hydrochlorate, dibutyl sulfide hydrochlorate and diamyl vitriol, long-chain halogenide is decyl chloride, lauryl chloride, myristyl chlorine, stearyl chloride, decyl bromide, lauryl bromide, myristyl bromine, stearic acylbromide, iododecane, lauryl iodine, myristyl iodine and stearic acyl iodides for example, aralkyl halogenide such as bromotoluene and phenethyl bromide etc.Thrombin inhibitors-therepic use-using method
Anticoagulant therapy is meant treatment and prevents various thrombotic diseases, especially for treatment and prevention coronary artery and cerebrovascular disease.Experience in this field readily recognizes that people needs anticoagulant therapy.Used herein term " patient " is meant that Mammals for example; Primate comprises people, sheep, horse, ox, pig, dog, cat, rat and mouse.
The restraining effect of zymoplasm not only has the anticoagulation curative effect for the individuality that thrombus disease is arranged, and also is used under the situation that any needs suppress blood coagulation, for example prevents to solidify in the storage of whole blood process and prevents that other biological products that are used to test or store from solidifying.Therefore, thrombin inhibitors can be joined or contact with any medium that contains zymoplasm or analogue, the blood coagulation effect is suppressed, mammiferous blood is contacted with following material, and these materials are selected from blood vessel graft, stent, orthopaedic prosthesis, heart prosthesis and extracorporeal circulation system.
The compounds of this invention is for treatment or prevent that mammiferous venous thromboembolism from (for example blocking or inaccessible vein by separating thrombus; Block or inaccessible pulmonary artery by separating thrombus), cardiogenic thromboembolism (for example blocking or inaccessible heart by separating thrombus), artery thrombosis (for example form thrombus in artery, cause tissue infraction by arterial thrombus), atherosclerosis (for example atherosclerosis that is feature with irregular distributional class lipid deposition) is useful, it can reduce the tendency that the device that contact with blood lumps blood.
Available The compounds of this invention is treated or is prevented that the example of venous thromboembolism from comprising that phlebemphraxis, pulmonary artery block (pulmonary infarction), dvt forms, the thrombosis relevant with the chemotherapy of cancer and cancer, the thrombosis relevant with the heredity of thrombotic disease, for example protein C deficiency disease, protein s deficiency disease, antithrombin and the V Leiden factor, the thrombosis that causes by blood flow disorder, for example whole body lupus erythematosus (tissue inflammation disease).With regard to venous thromboembolism, The compounds of this invention is favourable for the opening that keeps inherent conduit.
The example of treatment of available The compounds of this invention or the cardiogenic thromboembolism that prevents comprises thromboembolism outbreak (isolating thrombus causes the neurodynia relevant with cerebral blood supply insufficiency), cardiogenic thromboembolism relevant with auricular fibrillation (meat fiber of going up ventricle apace ballism) at random, cardiogenic thromboembolism is relevant with prosthetic heart valve, mechanical heart valve for example, cardiogenic thromboembolism is relevant with heart disease.
The example of artery thrombosis comprises unstable angina (originating from the violent intrathoracic narrow pain of coronal), myocardial infarction (because blood supply insufficiency causes cardiomyocyte cell death), cardiac ischemia (because the local anemia that (for example artery narrows down) causes is blocked in blood supply), obturation again in skin transillumination coronary angioplasty process or after the process, restenosis behind skin transillumination coronary angioplasty, the inaccessible and cerebral vessels embolism disease of the graft of coronary artery bypass.About artery thrombosis, The compounds of this invention is favourable for keeping the opening of arteriovenous telescopic.
Atherosclerotic example comprises arteriosclerosis.
The device that contacts with blood comprises blood vessel graft, stent, orthopedic with prosthese, heart prosthesis and extracorporeal circulation system.
Thrombin inhibitors of the present invention can the through port formulation form administration, for example tablet, capsule (every kind of capsule includes and continues to discharge or releasing pattern regularly), pill, pulvis, granule, elixir, tincture, suspension, syrup and emulsion.They also can pass through the form administration of vein (pill or injection) administration, intraperitoneal administration, subcutaneous administration or intramuscular injection, and all form of medication all are well-known common technologies in the pharmaceutical technology.Effective but required compound nontoxic amount can be used as antithrombotics.In order to treat the embolism that scleroproein forms, can pass through eye drops or skin surface administration and oral administration or non-oral administration.
Thrombin inhibitors can be by the form administration of instillation or implantation preparation, and said preparation is prepared in the mode that allows activeconstituents to continue to discharge.Activeconstituents can be pressed into piller or small cylinder, and instils or implantation through subcutaneous or intramuscular.Implant can use the polymkeric substance or the synthetic siloxanes of inert material biological example degraded, for example other polymkeric substance of silicon rubber, silicone rubber or the production of Dow-Corning company.
Thrombin inhibitors also can be with liposome transfer system form administration, for example little individual layer capsule, big individual layer capsule and multilayer capsule.Liposome can be formed by various phosphatide, for example cholesterol, stearylamide or Yelkin TTS.
Thrombin inhibitors also can transmit as the independent carrier with the compound molecule coupling by monoclonal antibody.Thrombin inhibitors also can with the carrier of soluble polymer coupling as targeted drug.This base polymer comprises polyethylene oxide-polylysine that polyvinylpyrrolidone, pyran co-polymer, poly-hydroxyl-propyl group-MAAm-phenol, poly-hydroxyethyl-l-asparagine-phenol or palmityl residue replace.And, thrombin inhibitors also can with the biodegradable polymkeric substance coupling of a class, be beneficial to obtain controlled release drug, for example the multipolymer of poly(lactic acid), polyglycolic acid, poly(lactic acid) and polyglycolic acid, poly-epsilon-caprolactone, polyhydroxybutyrate, poe, poly-acetal, poly-dihydropyrane, polybutylcyanoacrylate and crosslinked or amphipathic hydrogel segmented copolymer.
The using dosage scope of thrombin inhibitors is selected according to various factors, comprises patient's type, kind, age, body weight, sex and patient's medication illness; Treat the severity of disease; Route of administration; Patient's kidney and the function of liver and all special compounds or its salt.The effective dose that experienced doctor or animal doctor could promptly determine and leave required medicine is to prevent, to resist or to stop advancing of disease.
The oral dosage of thrombin inhibitors, for significantly being acted on, use range from about 0.01mg per kilogram of body weight every day (mg/kg/ days) by about 30mg/kg/ days, preferred 0.025-7.5mg/kg/ days, more preferably 0.1-2.5mg/kg/ days, preferred 0.1-0.5mg/kg/ days (unless otherwise prescribed, the amount of activeconstituents is calculated with free alkali form) especially.For example, the patient of body weight 80kg, dosage is approximately from 0.8mg/ days to 2.4g/ days, and preferred 2-600mg/ days, more preferably 8-200mg/ days, most preferably 8-40 mg/kg/ days.The medicament that be administered once suitable every day contains the medicine of 0.8mg to 2.4g, preferred 2-600mg, more preferably 8-200mg, most preferably 8-40mg, for example 8mg, 10mg, 20mg and 40mg.Thrombin inhibitors can be divided into twice, three times every day or four administrations are favourable.For be administered twice every day, the medicament that is fit to that makes contains the 0.4mg-4g medicine, preferred 1-300mg, more preferably 4-100mg, most preferably 4-20mg, for example 4mg, 5mg, 10mg and 20mg.
Intravenously administrable, the patient obtains the active ingredient of capacity, and dosage is from 0.025-7.5mg/kg/ days, and preferred 0.1-2.5mg/kg/ days, more preferably 0.1-0.5mg/kg/ days.Such amount can be by many suitable mode administrations, for example in for some time that continues or the active ingredient of giving the large volume lower concentration in a day several times, give the active ingredient of small volume high density at short notice, for example once a day.Typically, habitual intravenous formulations can contain the active ingredient of about 0.01-1.0mg/ml concentration, for example 0.1mg/ml, 0.3mg/ml and 0.6mg/ml, and the dosage of every day is from 0.01-10.0ml/kg, for example 0.1ml/kg, 0.2ml/kg, 0.5ml/kg.Lift an example, the patient of body weight 80kg, the intravenous formulations that contains active ingredient concentration and be 0.5mg/ml injects twice, per injection 8ml, the active ingredient of promptly having injected 8mg every day every day.The conjugate base of the acceptable glucuronic acid of intravenously administrable, L-lactic acid, acetate, citric acid or the acceptable acid of any medicine/have a suitable surge capability in acceptable pH scope can be used as damping fluid.When the pH of damping fluid of selecting to be fit to and preparation, should be taken into account the solvability of medicine, according to the solvability of medicine, those skilled in the art can make one's options rapidly.
Compound also can use suitable intranasal administration carrier by the nasal cavity topical, or by subcutaneous administration, and the mode of using the subcutaneous administration preparation is known to those skilled in the art.As the transfer system of subcutaneous administration, successive administration is more effective than intermittent administration.
Thrombin inhibitors is generally with the mixture administration of activeconstituents with pharmaceutical diluents, vehicle or the carrier (this paper claims " carrier " material) that are fit to, according to the suitable carrier of predetermined dosage form selection, these formulations have oral, capsule, elixir, syrup etc., and selected carrier is consistent with habitual pharmacy practice.
For example, the formulation of oral administration such as tablet or capsule, the activeconstituents of medicine can combine with can be oral, nontoxic, the acceptable inert support of medicine, and inert support is lactose, starch, sucrose, glucose, methylcellulose gum, Magnesium Stearate, Lin Suanergai, calcium sulfate, mannitol, sorbyl alcohol etc. for example; For the liquid preparation of oral administration, the oral pharmaceutical composition can with any oral, nontoxic, for example ethanol, glycerine, water etc. combine the acceptable inert support of medicine.In addition, when needs or must the time, also can in mixture, add suitable tackiness agent, lubricant, disintegrating agent and tinting material.The tackiness agent that is fit to comprises starch, gelatin, natural carbohydrate such as glucose or beta lactose, Semen Maydis powder, and natural and synthetic gum is gum arabic, tragacanth gum or sodiun alginate, carboxymethyl cellulose, polyoxyethylene glycol, wax etc. for example.Employed lubricant comprises sodium oleate, sodium stearate, Magnesium Stearate, Sodium Benzoate, sodium-acetate, sodium-chlor etc. in these formulations.Disintegrating agent includes but not limited to, starch methylcellulose gum, agar, bentonite, xanthan gum etc.
The typical label that the thrombin inhibitors administration is fit to includes but not limited to following various standard ingredient:
The suggestion compositing range of vehicle in the label of dressing not
Vehicle General range (%) Preferable range (%) Most preferred range (%)
Mannitol Microcrystalline Cellulose Magnesium Stearate ?????10-90 ?????10-90 ????0.1-5.0 ?????25-75 ?????25-75 ????0.1-2.5 ?????30-60 ?????30-60 ????0.5-1.5
Mannitol, Microcrystalline Cellulose and Magnesium Stearate can replace with other pharmaceutically-acceptable excipients.
Thrombin inhibitors also can be united use with the anti-platelet agents that is fit to, include but are not limited to fibrinogen receptor anlagonists (for example be used for the treatment of or prevent unstable angina or be used to prevent the obturation again and the restenosis of postangioplasty), anti-coagulant is acetylsalicylic acid for example, thrombolytic agent is proplasmin activator or streptokinase for example, in various cardiovascular disease therapies, to obtain synergy, or lipid lowering agent comprises that antihypercholesterolemic crosses multi-agent (for example HMG CoA reductase inhibitor such as lovastatin, HMG CoA synthetase inhibitors etc.) and treat or prevent atherosclerosis.For example, the patient suffers from coronary artery disease and the patient is just accepting the angioplasty treatment, unites and uses fibrinogen deceptor antagonists and thrombin inhibitors to be beneficial to.Equally, can to improve with the former activator of tissue plasminogen be the thrombolysis efficient of notes effect again of mediation to thrombin inhibitors.Also thrombin inhibitors be can behind thrombosis, give earlier, and then the former activator of tissue plasminogen or other proplasmin activator given.
Thrombin inhibitors of the present invention can not use the dosage of other anti-platelet agents, anti-coagulant or thrombolytic agent identical with independent use thrombin inhibitors with the typical doses that other anti-platelet agents, anti-coagulant or thrombolytic agent that is fit to is united use, perhaps uniting the consumption that reduces thrombin inhibitors when using with anti-platelet agents, anti-coagulant or thrombolytic agent, this relies on patient's treatment to need.
Following synthetic method can be used for preparing compound of the present invention:
Following examples are that the contriver is used for explaining better the present invention, rather than are used for limiting to use range of the present invention or spirit.
Method 1 (illustrating) by the embodiment I
Initiator allylamine and acetaldehyde and prussiate condensation obtain amino-nitrile in steps A.In step B,, handle amino-nitrile with oxalyl chloride and obtain pyrazine ketone by Hoomaert method [J.Heterocyclic Chem., 20,919, (1983)].In step C with ruthenium tetroxide with olefin oxidation fracture and with the aldehyde of gained with oxygenant for example chromic acid be transformed into acid.In step D, in the presence of 4-Methoxybenzylamine, 3-position chloro is replaced by the amine of equivalent.Remaining chlorine is removed by the Raney nickel reduction in step e.In step F,, remove methoxy-benzyl by with the strong acid product of TFA treatment step E for example.At last, in step G, in the presence of ethyl-2-amino methyl-4-chlorophenoxy ethanamide, this acid and the amine coupling that is fit to obtain the final product method of this amine of preparation (below provide).
Figure A9719576000691
Figure A9719576000701
Form The compounds of this invention acid amides coupled reaction (for example step G) can for example dicyclohexyl carbodiimide or 1-ethyl-(3-dimethyl-aminopropyl) carbodiimide carry out with reagent by carbodiimide method.Other method of formation acid amides or peptide bond includes but not limited to the synthetic route by chloride of acid, trinitride, mixed anhydride or active ester.Typically, in liquid phase, carry out the acid amides coupled reaction, also can replace liquid phase synthesizing method with the solid-phase synthesis Merrifield technology generation of classics.Adding and removing one or more protecting groups also is the method for using always.
The improvement of method allows in corresponding synthesis step to make by the initial compounds that uses suitable reagent or suitable replacement and has different W, R in the main claim scope 3, X and A group.For example the initiator aldehyde in steps A can have side chains such as ethyl, sec.-propyl, cyclopropyl, trifluoromethyl, to obtain different R 3Equally, in step D, can there be different W groups by using suitable amine to make.By omit step e with by in step B, use reagent for example the oxalyl bromine make and can have different X groups.The amine of selecting to be fit in step G can obtain different A.The tangible changes and improvements of present method can make the visibly different product of phase Sihe, and this is conspicuous to those of ordinary skill in the art.
The method for preparing ethyl-2-amino methyl-4-chlorophenoxy ethanamide
The initial compounds of the improvement permission reagent that use is fit in specified synthesis step of this method or suitable replacement makes and have different R in the main claim scope 4And R 5Group.For example, in step F, select suitable amine will obtain different R 10And R 11The tangible changes and improvements of present method can make the visibly different product of phase Sihe, and this is conspicuous to those of ordinary skill in the art.Steps A: 4-chloro-salicylic aldehyde oxime
With hydroxylamine hydrochloride (16.7g, 0.24mol) and yellow soda ash (12.7g, aqueous solution 0.12mol) (120ml) is added to the 4-chloro-salicylic aldehyde that stirring, and (25.0g is in ethanol 0.16mol) (160ml) solution, and with gained solution reflux.Put cold reactant after 1 hour, add the crystalline precipitation that water (320ml) also passes through the filtering separation gained.Collect second batch of crystallization and merge the gained solid with similar methods, drying obtains title compound:
1H NMR (400Mz, CDCl 3) d6.92 (d, J=8.8Hz, 1H), 7.15 (d, J=2.6Hz, 1H), 7.23 (dd, J=2.6 and 8.8Hz, 1H), 7.26 (s, 1H), 8.16 (s, 1H), 9.71 (s, 1H). step B:2-hydroxyl-5-chlorobenzylamine
Under hydrogen (60psi), and the 4-chloro-salicylic aldehyde oxime that contains the vitriol oil (10ml) that will be in the Pa Er device (10g, 58.3mmol) and mixed ethanol liquid (100ml) jolting of 5%Rh/C (2.0g) 24 hours.Add water (100ml) and by this mixture of diatomite filtration.Concentrated filtrate is separated out crystallized product in solution.Solid collected by filtration is also further concentrated with filtrate, adds water and obtains second batch of crystallization, merges with the crystallization that obtains for the first time, obtains title compound after the drying, vitriol:
1H NMR (400Mz, CD 3OD) d4.07 (s, 2H), 6.88 (d, J=8.6Hz, 1H), 7.25 (dd, J=2.6 and 8.6Hz, 1H), 7.31 (d, J=2.6Hz, 1H). step C:N-tert-butoxycarbonyl-2-hydroxyl-5-chlorobenzylamine
At room temperature, will be at the 2-hydroxyl-5-chlorobenzylamine among the DMF (10ml) (1.22g, 4.77mmol is with the dithionate form), (BOC) 2O (1.56g, 7.16mmol) and N-methylmorpholine (1.05ml, 9.54mmol) mixed solution stirred 5 hours.Reactant distribution in water and ethyl acetate, is used 5%KHSO 4Solution (2 times), sodium hydrogen carbonate solution and salt water washing organic layer, dry (Na 2SO 4) and vacuum-evaporation get solid.Crude product ethyl acetate/hexane (1: 5,12ml) in recrystallization obtain title compound:
1H NMR (400Mz, CDCl 3) d1.44 (s, 9H, t-Bu), 4.17 (d, J=6.8Hz, 2H, CH2), 5.22 (brt, 1H, NH), 6.87 (d, J=8.6Hz, 1H, H-3), 7.03 (d, J=2.6Hz, 1H, H-6), 7.15 (dd, J=2.6 and 8.6Hz, 1H, H-4). step D: ethyl-2-tert-butoxycarbonyl amino methyl-4-chlorophenoxy ethyl ester
With N-tertbutyloxycarbonyl-2-hydroxyl-5-chlorobenzylamine (730mg, 2.83mmol), Cs 2CO 3(923mg, 2.83mmol) and ethyl bromoacetate (0.314ml 2.83mmol) stirred 2 hours at the mixing solutions of DMF (5ml).Crude product mixture is distributed in ethyl acetate and the water, with salt water washing organic layer, dry (Na 2SO 4) and vacuum-evaporation get oily matter, it is used in next step.Step e: 2-tert-butoxycarbonyl amino methyl-4-chlorophenoxyacetic acid
The product of step D is suspended in methyl alcohol/THF/ water (9ml) of 1: 1: 1, add hydronium(ion) oxidation lithium (126mg, 3.0mmol).Final vacuum was removed volatile matter and this solution of dilute with water in 16 hours, used the ethyl acetate washing soln, added the salt solution dispersion emulsion of capacity.Use 5%KHSO 4Solution acidifying water layer and use the dichloromethane extraction water layer, dry then (Na 2SO 4) and vacuum-evaporation get title compound, be solid:
1H NMR (400Mz, CDCl 3) d1.44 (s, 9H, t-Bu), 4.35 (br s, 2H, NCH 2), 4.62 (s, 2H, OCH 2), 5.04 (br s, 1H, NH), 6.74 (d, J=7.9Hz, 1H, H-3), 7.20 (d, J=2.6Hz, 1H, H-6), 7.24 (d is unclear, 1H, H-4). step F: ethyl-2-tert-butoxycarbonyl amino methyl-4-chlorophenoxy ethanamide
With EDC hydrochloride (249mg, 1.3mmol) be added to the 2-t-butoxycarbonyl amino methyl that the is stirring-4-chlorophenoxyacetic acid (316mg in DMF (4ml), 1.0mmol), HOBT (176mg, 1.3mmol), ethylamine hydrochloride (106mg, 1.3mmol) and N-methylmorpholine (0.396ml, 3.6mmol) mixing solutions in, stirred this mixture 16 hours.Reaction mixture is distributed in ethyl acetate and 5%KHSO 4In the solution, and use 5%KHSO 4Solution, water, NaHCO 3Solution and salt water washing organic layer, dry (Na 2SO 4) and vacuum-evaporation get solid (333mg), it is used in next step.Step G: ethyl-2-amino methyl-4-chlorophenoxy ethanamide
The product of step F is dissolved among methylene dichloride/TFA (3ml) of 2: 1 15 minutes final vacuum solvent evaporated.Resistates is soluble in water, and with washed with dichloromethane solution (twice).With the saturated sodium carbonate solution water layer that alkalizes, and add NaCl to saturated.Use the ethyl acetate extraction mixture, and dry (Na 2SO 4) organic layer and vacuum-evaporation obtains title compound, is crystalline solid: 1H NMR (300MHz, CDCl 3) d1.12 (t, J=7.3Hz, 3H, Me), 1.54 (s, 9H, t-Bu), 3.31 (quintet J=7.3Hz, 2H, CH 2Me), 3.90 (s, 2H, NCH 2), 4.58 (s, 2H, OCH 2), 6.80 (d, J=8.3Hz, 1H, H-3), 7.19-7.23 (m, 2H, H-4, H-6), 8.01 (br s, 1H, CONH).
Method 2 (illustrating) by the embodiment III
The other method of preparation The compounds of this invention illustrates by the embodiment II.
In the presence of 2-t-butoxycarbonyl amino-5-amino methyl-6-picoline (preparation method of this amine is shown in hereinafter), the acid among the method I step C is carried out in this method steps A with the coupled reaction of the amine that is fit to.In step B, in the presence of phenylethylamine, 3-position chloro is replaced by the amine that is fit to, and removes the BOC protecting group and obtain final product in step C.
Method 2 (illustrating) by the embodiment II
Figure A9719576000761
The initial compounds of reagent that improved method permission use in specified synthesis step is suitable or suitable replacement makes and have different W, R in the main claim scope 3, X and A group.The tangible changes and improvements of present method can make the visibly different product of phase Sihe, and this is conspicuous to those skilled in the art.
The preparation for preparing the method 2-amino-5-cyano-6-picoline of 2-t-butoxycarbonyl amino-5-amino methyl-6-picoline
Will be at the 6-amino among the DMF (25ml)-3-bromo-2-picoline (20.0g, 0.107mol) (Maybridge) and cupric cyanide (I) (11.0g, mixture reflux 0.123mol) 4 hours.Vacuum-evaporation is removed DMF and resistates is distributed in ethyl acetate and 10% sodium cyanide solution.With 10% sodium cyanide solution and salt water washing organic layer, dry (Na 2SO 4) and vacuum-evaporation get brown solid.Be dissolved in it in ethyl acetate in a small amount and add hexane and make the product precipitation.Filtering mixt obtains title compound, is brown ceramic powder: 1H NMR (CDCl 3) d2.56 (s, 3H), 4.97 (br s, 2H), 6.33 (d, J=8.6Hz, 1H), 7.54 (d, J=8.6Hz, 1H) preparations of .2-t-butoxycarbonyl amino-5-cyano group-6-picoline
Will the 2-amino-5-cyano-6-picoline in the methylene dichloride (200ml) (10.0g, 75.1mmol), (BOC) 2O (1639g, 75.1mmol), triethylamine (11.5ml, 82.6mmol) and DMAP (0.92g, 7.5mmol) mixture stirred 3 hours.Add triethylamine (422ml) and (BOC) again 2O (1.64g) after 16 hours, washs (3 times) with the ethyl acetate diluted reaction mixture and with 1M AcOH, dry (Na 2SO 4) and vacuum-evaporation obtain dark brown solid.Crude product is purified by flash column chromatography (10% ethyl acetate/hexane) and is obtained title compound, is white solid: 1H NMR (CDCl 3) d1.52 (s, 9H), 2.62 (s, 3H), 7.46 (br s, 1H), 7.80 (d, J=8.8Hz, 1H), 7.88 (d, J=8.8Hz, 1H) preparations of .2-t-butoxycarbonyl amino-5-amino methyl-6-picoline
Under 60psi pressure, will the t-butoxycarbonyl amino of the 2-in the Pa Er device-5-cyano group-6-picoline (14.68g, 62.9mmol) and the mixture jolting of 10%Pd/C (1.5g) in Glacial acetic acid (150ml) 88 hours.By diatomite filtration reactant and vacuum-evaporation.Resistates is water-soluble and with this solution of washed with dichloromethane (2 times), then with the yellow soda ash alkalization with ethyl acetate extraction (2 times) reactant.The combined ethyl acetate layer, dry (Na 2SO 4) and vacuum-evaporation get solid.Crude product recrystallization (ethyl acetate/hexane) obtains title compound:
1H?NMR(CDCl 3)d1.50(s,9H),2.43(s,3H),3.81(s,2H),7.23(br?s,1H),7.57(d,J=8.3Hz,1H),7.70(d,J=8.3Hz,1H).
The initial compounds of reagent that improved method permission use in specified synthesis step is suitable or suitable replacement makes and have different Y in the main claim scope 1And Y 2Group.The tangible changes and improvements of present method can make the visibly different product of phase Sihe, and this is conspicuous to those skilled in the art.
Method 3 (illustrating) by the embodiment V
In steps A, the ester of glycine (being the benzyl ester herein) obtains amino-nitrile with acetaldehyde and prussiate condensation.The reaction of it and oxalyl chloride obtains pyrazine ketone in step B.In step C, 3-position chloro is replaced by the amine that is fit to, and is meant phenylethylamine herein.In step D this ester be hydrolyzed and in step e hydrogenolysis remove remaining chlorine.This acid and the amine coupling that is fit in step F, amine herein is meant 2-amino-5-amino methyl-6-picoline (preparation method of this amine is shown in hereinafter), obtains final product.
Figure A9719576000781
Figure A9719576000791
The preparation of 2-amino-5-amino methyl-6-picoline dihydrochloride
Under 60psi pressure, will the amino-5-cyano of the 2-in the Pa Er device-6-picoline (4.0g, 30.0mmol) and the mixture jolting of the ethanolic soln (80ml) of 10%Pd/C (3.08g), methyl alcohol (30ml), concentrated hydrochloric acid (6ml) and water (10ml) 25 hours.By the diatomite filtration reactant, get solid with 1: 1 ethanol/methanol rinse and vacuum-evaporation, grind with 5: 1 ethyl acetate/ethanol, obtain title compound (5.95g, 94%): 1H NMR (CD 3OD): d2.58 (s, 3H), 4.12 (s, 2H), 6.92 (d, J=9.2Hz, 1H), 7.93 (d, J=9.2Hz, 1H).
The tangible changes and improvements of present method can make the visibly different product of phase Sihe, and this is conspicuous to those skilled in the art.
Method 4
The product of method 3 step e and for example 2-t-butoxycarbonyl amino-5-amino methyl-6-picoline coupling of protected amine that is fit to, and then go protection to obtain final product.The tangible changes and improvements of present method can make the visibly different product of phase Sihe, and this is conspicuous to those skilled in the art.
Method 5 (illustrating) by embodiment L XX XII
Initiator allylamine and acetaldehyde and prussiate condensation obtain amino-nitrile in steps A.Amino-nitrile and oxalyl chloride are pressed Hoornaert method [J.Heterocyclic Chem., 20,919, (1983)] reaction and are made pyrazine ketone in step B.In step C, with ruthenium tetroxide with the fracture of this olefin oxidation and with the aldehyde of gained with oxygenant for example chromic acid be transformed into acid.In step D, 3-position chloro is replaced by the amine that is fit to, and is meant phenylethylamine herein.Remaining chlorine is removed by the Raney nickel reduction in step e.In step F, this acid and the amine coupling that is fit to are meant 3-amino methyl-6-BOC-amino-2-methyl pyridine herein.At last, in step G, with strong acid for example HCl gas remove the BOC group and obtain final product.
Method 5 (continuing)
Figure A9719576000811
Method 5 (continuing)
Figure A9719576000821
Form The compounds of this invention acid amides coupled reaction (for example step F) can for example dicyclohexyl carbodiimide or 1-ethyl-(3-dimethyl-aminopropyl) carbodiimide carry out with reagent by carbodiimide method.Other method that forms acid amides or peptide bond includes but not limited to the synthetic route of being undertaken by chloride of acid, trinitride, mixed anhydride or active ester.Typically, in liquid phase, carry out the acid amides coupled reaction, also can replace liquid phase synthesizing method with the solid-phase synthesis Merrifield technology generation of classics.Adding and removing one or more protecting groups also is the method for using always.
The initial compounds of reagent that improved method permission use in specified synthesis step is suitable or suitable replacement makes and has different W, R in the main claim scope 3, X and A group.For example the initiator aldehyde in steps A can have side chains such as ethyl, sec.-propyl, cyclopropyl, trifluoromethyl, obtains different R 3Equally, in step D, can there be different W groups by using suitable amine to make.By omit step e with by in step B, use reagent for example the oxalyl bromine make and can have different X groups.The amine of selecting to be fit in step F can obtain different A.Therefore, illustrational as the embodiment VI, the product of step e and the coupling of 2-hydroxy benzylamine derivative are meant ethyl-(2-amino methyl-4-chlorophenoxy)-ethanamide herein, obtain final product.The tangible changes and improvements of present method can make the visibly different product of phase Sihe, and this is conspicuous to those skilled in the art.
Following examples are that the contriver is used for explaining better the present invention, rather than are used for limiting to scope of the present invention or spirit.
The preparation of embodiment I 3-amino-6-methyl isophthalic acid-[ethyl-(2-methyl-formamido-methyl-4-chlorophenoxy)-kharophen]-2-pyrazine ketone
Figure A9719576000831
Steps A: α-(allyl amino)-propionitrile hydrochloride
Under 0 ℃, (20ml, (36ml is in water 0.48mol) (100ml) and ethanol (60ml) solution 0.24mol) to be added to allylamine with concentrated hydrochloric acid.Add then potassium cyanide (15g, 0.23mol) and acetaldehyde (11.2ml, 0.20mol), this mixture of reflux.Final vacuum was removed volatile matter and with the saturated residual solution of NaCl, was used dichloromethane extraction (three times) in 15 hours.Combining extraction liquid, dry (Na 2SO 4) and vacuum-evaporation obtain oily matter, it is dissolved among the 1M HCl (200ml).This solution of vacuum-evaporation obtains solid with 1: 1 toluene and methanol azeotropic, and reflux in ethyl acetate (200ml) is put coldly, filters and drying obtains title compound, is hydrochloride:
1H NMR (400MHz, CD 3OD) d1.72 (d, J=7.0Hz, 3H, CH 3), 3.78-3.90 (m, 2H, CH 2), 4.63 (q, J=7.0Hz, a-CH), 5.56-5.66 (m, 2H, CHCH 2), 5.91-6.02 (m, 1H, CHCH 2). step B:1-allyl group-3,5-two chloro-6-methylpyrazine ketone
With the oxalyl chloride that stirring (30.5ml, 0.35mol) and α-(allyl amino)-propionitrile hydrochloride (10.26g, 70mmol) the mixture (100ml) of orthodichlorobenzene be heated to 100 ℃ 15 hours.Vacuum evaporating solvent and by silica gel flash column chromatography (30% ethyl acetate normal hexane is a moving phase) the remaining dark oil thing of purifying obtains title compound, is the brown crystalline solid:
1H NMR (400Mz, CDCl 3) d2.48 (s, 3H, CH 3), 4.75 (m, 2H, NCH 2), 5.18 (m, 1H, CHCH AH B), 5.33 (m, 1H, CHCH AH B), 5.85-5.92 (m, 1H, CHCH AH B). step C:3,5-two chloro-6-methyl isophthalic acids-carboxymethyl pyrazine ketone
Stir down, with ruthenium trichloride hydrate (114mg, 0.547mmol) be added to the 1-allyl group-3 in water (75ml), acetonitrile (50ml) and tetracol phenixin (50ml) solution, 5-two chloro-6-methylpyrazine ketone (5.45g, 24.88mmol) and sodium periodate (21.82g is 0.102mol) in the mixture.After 3 hours, with dichloromethane extraction reaction mixture (4 times), combining extraction liquid, dry (Na 2SO 4) and vacuum-evaporation obtain soup compound.1H NMR (CDCl 3) it is 1: 1 the acid and the mixture of aldehyde to analyze demonstration.Crude mixture is dissolved in acetone (50ml) and add Jones reagent (2.7M) orange-yellow until the reactant maintenance.Use the ethyl acetate extraction reactant then, use the salt water washing then, dry (Na 2SO 4) and vacuum-evaporation get title compound, be brown solid: 1H NMR (400Mz, DMSO) d2.41 (s, 3H, Me), 4.86 (s, 2H, CH 2).Step D:3-(4-methoxybenzyl amino)-5-chloro-6-methyl isophthalic acid-carboxymethyl pyrazine ketone
With the 4-methoxybenzylamine (0.83ml, 6.33mmol) be added to stirring 3, (0.50g in dioxane solution 2.11mmol) (6ml), is warmed to 60 ℃ with the gained mixture to 5-two chloro-6-methyl isophthalic acids-carboxymethyl pyrazine ketone.After 16 hours, be distributed in chloroform and 10% citric acid solution reaction mixture and dry organic layer (Na 2SO 4) and vacuum-evaporation.By flash column chromatography (2% methyl alcohol/chloroform/2% acetate is moving phase) purification crude product,, be white solid with obtaining title compound after the toluene and methanol azeotropic drying: 1H NMR (300Mz, CD 3OD) d2.27 (s, 3H, CCH 3), 3.76 (s, 3H, OCH 3), 4.46 (s, 2H, CH 2), 4.87 (s, 2H, CH 2), 6.85 (d, J=8.8Hz, 1H, aryl H ' s), 7.27 (d, J=8.8Hz, 1H, aryl H ' is s). step e: 3-(4-methoxybenzyl amino)-6-methyl isophthalic acid-carboxymethyl pyrazine ketone
Raney nickel alloy (2g) is added to 3-(4-methoxybenzyl the amino)-5-chloro-6-methyl isophthalic acid-carboxymethyl pyrazine ketone that is stirring, and (448mg is in 1: 1 methyl alcohol 1.33mmol)/1M NaOH solution (50ml).After 2 hours,,, obtain white solid with methanol washing in 1: 1 and vacuum-evaporation filtrate by the diatomite filtration reaction mixture.Remove inorganic salt by preparation property HPLC (C18, water/acetonitrile/0.1%TFA gradient elution), obtain the tfa salt of title compound, be foams: 1H NMR (300Mz, CDCl 3) d2.15 (s, 3H, CCH 3), 3.81 (s, 3H, OCH 3), 4.63 (s, 4H, 2xCH 2), 6.57 (s, 1H, pyrazine ketone H), 6.91 (d, J=8.7Hz, 1H, aryl H ' s), 7.30 (1H aryl H ' is s) for d, J=8.7Hz. step F: 3-amino-6-methyl isophthalic acid-carboxymethyl pyrazine ketone
With 3-(4-methoxybenzyl amino)-6-methyl isophthalic acid-carboxymethyl pyrazine ketone (387mg, TFA solution (8ml) reflux 0.927mmol) 6 hours that is stirring.With methylene dichloride and ethyl acetate azeotropic vacuum-evaporation reactant.In crude product, add methyl alcohol and filtration and dry gained solid, obtain the tfa salt of title compound: 1H NMR (400Mz, CD 3OD) d2.21 (s, 3H, CH 3), 4.81 (s, 2H, CH 2), 6.56 (s, 1H, pyrazine ketone H). step G:3-amino-6-methyl isophthalic acid-[ethyl-(2-methylformamide ylmethyl-4 chlorophenoxy)-kharophen]-2-pyrazine ketone
With EDC hydrochloride (67mg, 0.35mmol) be added to the 3-that the is stirring amino-6-methyl isophthalic acid-carboxymethyl pyrazine ketone (80mg in DMF (1ml), 0.27mmol), HOBT (47mg, 0.35mmol), ethyl-(2-amino methyl-4-chlorophenoxy)-ethanamide (85mg, 0.35mmol) and N-methylmorpholine (0.11ml, 0.97mmol) in the mixture, stirred this mixture 16 hours.In reactant, add water, filter the solid and the vacuum-drying of collecting precipitation.Crude product is suspended in the ethyl acetate, and reflux is put cold-peace and is filtered then, obtains title compound after the drying, is white crystalline solid, and fusing point is greater than 200 ℃: 1H NMR (300Mz, DMSO) d0.97 (t, J=7.2Hz, 3H, CH 2CH 3), 2.02 (s, 3H, CH 3), 3.09 (quintet J=6.8Hz, 2H, CH 2CH 3), 4.37 (d, J=5.6Hz, 2H, CONHCH 2), 4.47 (s, 2H, CH 2CO), 4.63 (s, 2H, CH 2CO), 6.30 (br s, 2H, NH 2), 6.51 (s, 1H, pyrazine ketone H-5), 6.94 (d, J=9.3Hz, 1H, phenoxy group H-6), 7.28 (m, 2H remainders), 7.98 (brt, 1H, NH), 8.67 (brt, 1H, NH); MS (FAB) 408 (M+1) +.
The preparation of embodiment II 3-amino-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
By using embodiment 1, the method for step G prepares the hydrochloride of title compound by 3-amino-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and 2-amino-5-amino methyl-6-picoline dihydrochloride, and fusing point is greater than 200 ℃: MS (FAB) 303 (M+1) +
The preparation of embodiment III 3-(2-styroyl amino)-5-chloro-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576000862
Steps A: 3,5-two chloro-6-methyl isophthalic acids-(2-t-butoxycarbonyl amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
With EDC hydrochloride (249mg, 1.3mmol) be added in DMF (4ml) stirring 3,5-two chloro-6-methyl isophthalic acids-carboxyl methylpyrazine ketone (237mg, 1.0mmol), HOBT (176mg, 1.3mmol), 5-amino methyl-2-tert-butoxycarbonyl amino-6-picoline (237mg, 1.0mmol) and N-methylmorpholine (0.25ml 2.3mmol) in the mixture, stirred this mixture 2 hours.With ethyl acetate diluting reaction thing with 10% peaceful lemon acid solution, water, sodium hydrogen carbonate solution and salt solution washing reaction thing, dry (Na 2SO 4) and vacuum-evaporation obtain title compound, be foams: 1H NMR (400Mz, CDCl 3) d1.51 (s, 9H, t-Bu), 2.39 (s, 3H, CH 3), 2.59 (s, 3H, CH 3), 4.37 (d, J=5.5Hz, NHCH 2), 4.71 (s, 2H, CH 2CO), 6.76 (brt, 1H, NHCH 2), 7.14 (s, 1H, NHBOC), (7.44 d, J=8.3Hz, pyridine H-3), (7.66 d, J=8.3 Hz, pyridine H-3). step B:3-(2-styroyl amino)-5-chloro-6-methyl isophthalic acid-(2-tert-butoxycarbonyl amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
With styroyl amine (0.10ml, 0.80mmol) be added to stirring 3,5-two chloro-6-methyl isophthalic acids-(2-tert-butoxycarbonyl amino-6-methyl-5-methylene radical formamido-picolyl)-pyrazine ketone (182mg, 0.40mmol in the) De dioxane solution (0.8ml), gained solution is warmed to 60 ℃.After 16 hours, reaction mixture is distributed in water and the chloroform.Dry (Na 2SO 4) organic layer and vacuum-evaporation.Obtain title compound by quick silica gel column chromatography (ethyl acetate/hexane gradient elution, the ethyl acetate of 40-75%) purification. 1H NMR (300Mz, CDCl 3) d1.51 (s, 9H, t-Bu), 2.36 (s, 3H, CH 3), 2.41 (s, 3H, CH 3), 2.92 (t, J=7.1Hz, PhCH 2), 3.66 (q, J=7.1Hz, PhCH 2CH 2), 4.35 (d, J=5.4Hz, 2H, CONHCH 2), 4.63 (s, 2H, CH 2CO), 6.05 (brt, 1H, NH), 6.54 (brt, 1H, NH), 7.14 (s, 1H, NHBOC), 7.21-7.31 (m, 5H, Ph), 7.43 (d, J=8.3 Hz, 1H, pyridine H-3), 7.69 (d, J=8.3 Hz, 1H, pyridine H-4). step C:3-(2-styroyl amino)-5-chloro-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Under 0 ℃, (83mg, logical HCl gas is 10 minutes in ethyl acetate solution 0.153mmol) (10ml) to 3-(2-styroyl amino)-5-chloro-6-methyl isophthalic acid-(2-tert-butoxycarbonyl amino-6-methyl-5-methylene radical formamido-picolyl)-pyrazine ketone.Reactant is warmed to room temperature, after 1 hour, the solution degassing is obtained white precipitate, filter collecting precipitation and the dry hydrochloride that obtains title compound with argon. 1H NMR (400Mz, CD 3OD) d2.26 (s, 3H, CH 3), 2.50 (s, 3H, CH 3), 2.91 (t, J=7.0Hz, PhCH 2), 3.60 (t, J=7.0Hz, PhCH 2CH 2), 4.29 (s, 2H, CONHCH 2), 4.74 (s, 2H, CH 2CO), 6.82 (d, J=9.0Hz, 1H, pyridine H-3), 7.18-7.29 (m, 5H, Ph), 7.83 (d, J=9.0Hz, 1H, pyridine H-4); MS (FAB) 441 (M+1) +.
The preparation of embodiment IV 3-benzyl amino-5-chloro-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
By use embodiment III, the method for step B and C, by 3,5-two chloro-6-methyl isophthalic acids-(tert-butoxycarbonyl amino-6-methyl-5-methylene radical formamido-picolyl)-pyrazine ketone and benzylamine prepare the tfa salt of title compound: MS (FAB) 428 (M+1) +
The preparation of embodiment V 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576000882
Steps A: N-(1-cyanoethyl) glycine benzyl hydrochloride
With TMSCN (18.8ml, 141mmol) careful (thermopositive reaction) be added to the glycine benzyl ester free alkali that is stirring (23.3g, 141mmol-be distributed in the hydrochloride in ethyl acetate and the salt solution, with saturated Na 2CO 3Solution alkalizes) and acetaldehyde (7.88ml, 141, in dichloromethane solution mmol) (50ml).After 4 hours, vacuum is removed volatile matter and resistates is dissolved in ethyl acetate, uses the salt water washing, dry (Na 2SO 4) and vacuum-evaporation obtain oily matter.This oily matter is dissolved in the ethyl acetate again, the ethanol liquid of adding 9.9MHCl (15.25ml 151mmol), obtains crystalline precipitate, and filtering separation obtains title compound with ethyl acetate and ether washing: 1H NMR (CD 3OD): d1.70 (d, J=7.0Hz, 3H, CH 3), 4.16 (d, J=16.8Hz, 1H, CH AH B), 4.21 (d, J=16.8Hz, 1H, CH AH B), 4.64 (q, J=7.0Hz, a-CH), 5.31 (s, 2H, CH 2O), and 7.35-7.44 (m, 5H, Ph). step B:1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone
With the oxalyl chloride that stirring (40.4ml, 463mmol) and N-(1-cyanoethyl) glycine benzyl hydrochloride (29.51g, 116mmol) 1,2-dichlorobenzene mixed solution (110ml) be heated to 100 ℃ 15 hours.The vacuum-evaporation volatile matter is also with quick silica gel column chromatography (hexane, use 30% ethyl acetate/hexane gradient elution then) the purification resistates gets solid, and reflux in 2: 5 ethyl acetate/hexane (140ml) is put cold, filter collection and obtain title compound, be the light green crystalline solid: 1H NMR (CDCl 3): d2.35 (s, 3H, CH 3), 4.88 (s, 2H, CH 2), 5.24 (s, 2H, CH 2), 7.38 (m, 5H, Ph). step C:3-(2-styroyl amino)-5-chloro-6-methyl isophthalic acid-(benzyloxycarbonyl methyl)-pyrazine ketone
(15.07ml 120mmol) is added to the 1-benzyloxycarbonyl methyl-3 that is stirring in ethyl acetate (80ml), and (13.09g is 40mmol) in the mixture, and with gained mixture reflux under argon atmospher for 5-two chloro-6-methylpyrazine ketone with phenylethylamine.After 2 hours, put cold reaction, with chloroform (500ml) dilution and with 5% citric acid solution and salt water washing, drying (Na 2SO 4) and vacuum-evaporation get title compound, be crystalline solid: 1H NMR (CDCl 3): d2.21 (s, 3H, CH 3), 2.93 (t, J=7.1Hz, 2H, PhCH 2), 3.67 (q, J=6.7Hz, 2H, CH 2NH), 4.79 (s, 2H, CH 2), 5.21 (s, 2H, CH 2), 6.10 (brt, 1H, NH), 7.20-7.39 (m, 10H, 2Ph). step D:3-(2-styroyl amino)-5-chloro-6-methyl isophthalic acid-carboxymethyl pyrazine ketone
Under 0 ℃, with LiOH.H 2(3.36g 80mmol) is added to THF/MeOH/H at 3: 3: 1 to O 2In the suspension of the step C product among the O (280ml), and this mixture is warmed to room temperature.The evaporation of 16 hours final vacuums is removed volatile matter and water (500ml) and is diluted this solution and wash with ethyl acetate.With the saturated water layer of NaCl and use 20%KHSO 4Solution (20ml) acidifying obtains precipitation, with 1: 1 ethyl acetate/THF (400ml) extraction.Organic phase drying (Na 2SO 4) and vacuum-evaporation obtain solid, with its reflux in 1: 1 ethyl acetate/hexane, put cold-peace and filter and collect, obtain title compound, be crystalline solid: 1H NMR (DMSO-d 6): d2.21 (s, 3H, Me), 2.86 (t, J=7.4Hz, 2H, PhCH 2), 3.47 (dt, J=5.9 and 7.4Hz, 2H, CH 2NH), 4.72 (s, 2H, CH 2CO 2), 7.18-7.31 (m, 5H, Ph), 7.46 (t, J=5.9Hz, 1H, NH), 13.30 (brs, 1H, COOH). step e: 3-(2-styroyl amino)-6-methyl isophthalic acid-carboxymethyl pyrazine ketone
(11.66g, (86% weight, 6.10g is 93.5mmol) in the aqueous solution (400ml) 36.2mmol) to be added to potassium hydroxide with 3-(2-styroyl amino)-5-chloro-6-methyl isophthalic acid-carboxymethyl pyrazine ketone.Gained solution with argon-degassed after, add 10%Pd/C (3.48g), under drum hydrogen, stir this mixture.After 16 hours, this mixture outgases with nitrogen, adds 10%Pd/C (3.0g) again, and this mixture of restir 7 hours under drum hydrogen is arranged, by diatomite filtration, and water (200ml) washing leaching cake.Use KHSO 4(7.8g, 57.3mmol) the gained precipitation is collected in the aqueous solution (35ml) acidifying filtrate and filtration, and water (200ml) is washed, and vacuum-drying obtained title compound in 16 hours, was crystalline solid: 1H NMR (DMSO-d 6): d2.07 (d, J=0.7Hz, 3H, Me), 2.84 (t, J=7.4Hz, 2H, PhCH 2), 3.47 (dt, J=5.9 and 7.4Hz, 2H, CH 2NH), 4.66 (s, 2H, CH 2CO 2), 6.67 (s, 1H, pyrazine ketone H-5), 6.88 (brt, J=5.9Hz, 1H, NH), 7.17-7.32 (m, 5H, Ph). step F: 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
With EDC.HCl (0.962g, 5.02mmol) be added to the 3-that is stirring (2-styroyl the amino)-6-methyl isophthalic acid-carboxymethyl pyrazine ketone (1.20g in dry DMF (10ml), 4.18mmol), 2-amino-5-amino methyl-6-picoline dihydrochloride (0.874g, 4.16mmol), HOBT.H 2O (0.678g, 5.02mmol) and N-methylmorpholine (2.30ml is in mixed solution 20.9mmol).After 16 hours, the vacuum-evaporation volatile matter is distributed in resistates in ethyl acetate and the 1M HCl solution.The pH that regulates water layer with saturated sodium carbonate solution is 10, filters collecting precipitation, and water and washing with alcohol obtain title compound, are free alkali.
This free alkali is used as generation 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone dihydrochloride (step G1), 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone dihydrochloride A type monohydrate (step G2, also be known as " crystalline polymorph thing A type monohydrate ") or the initiator of 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone dihydrochloride Type B monohydrate (step G3 also is known as " crystalline polymorph thing Type B monohydrate ").
In general, the production of 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone dihydrochloride A type monohydrate comprises that step a) is dissolved in 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone acetate and adds aqueous hydrochloric acid; B) remove the gained solid phase; And c) except that desolvating.The one side of present method, the amount that adds aqueous hydrochloric acid in step a) are the final water-contents in the acetate, are 1-5% weight.
In general, the production of 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone dihydrochloride Type B monohydrate is dissolved in hydrochloric acid by comprising a) with 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone; B) remove the gained solid phase; And c) except that desolvating.Step G1 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone dihydrochloride
Under 0 ℃, 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone free alkali is suspended in the ethanol (20ml), and under agitation add ethanol HCl (9.9M, 8.36mmol).This dihydrochloride is rapid crystallization in the mixture from then on, and after-filtration was collected crystallization in 30 minutes, use washing with alcohol, and drying obtained title compound in 16 hours under 0.5mmHg; 1H NMR (DMSO-d 6): d2.10 (s, 3H, CH 3), 2.45 (s, 3H, CH 3), 2.91 (t, J=7.6Hz, PhCH 2), 3.63 (br q, CH 2NH), 4.17 (d, J=5.5Hz, 2H, CONHCH 2), 4.62 (s, 2H, CH 2CO), 6.68 (s, 1H, pyrazine ketone H-5), 6.81 (d, J=9.0Hz, 1H, pyridine H-3), 7.21-7.31 (m, 5H, Ph), 7.76 (half-light d, 1H, pyridine H-4), 7.77 (br s, 2H, NH 2), 8.81 (brt, J=5.5Hz, 1H, CONH). step G2 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone dihydrochloride A type monohydrate
3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylene radical formamido-picolyl)-pyrazine ketone free alkali (680g) is dissolved in 6.0 liters of acetate, under stirring this mixture is warmed to 60 ℃ and gets solution.Filter this mixture and under 28 ℃, add the 7.6 liters of acetate and the HCl aqueous solution (734ml, 5N HCl and 147ml water) flushing filtrate in the solution of Xiang Fangleng.This mixture is added crystal seed and is warmed to 73 ℃, obtains thin crystal seed pad, puts through several hours then to be chilled to 20 ℃ and filter, and use the acetate washing leaching cake, uses 190 standard washing with alcohol then, 60 ℃ with the vacuum drying oven of nitrogen purge in drying, obtain title compound.
A type compound is with its its feature of differential scanning calorimetric curve mark, in an open cup, 5 ℃ of/minute heating rate, with under 5 ℃ in water logical nitrogen, by the extrapolation initial temperature is about 102 ℃, 112 ℃ of peak Wen Weiyue and heat of association are shown as endothermic process for about 115J/gm, are about 171 ℃ by the extrapolation initial temperature then, and 194 ℃ of peak Wen Weiyue and heat of association are shown as endothermic process for about 83J/gm.The low temperature heat absorption is the loss owing to water of hydration, and the high temperature heat absorption is because the resistates water decomposes fusing.The x ray powder diffraction pattern is characterised in that spectrum d-spacing is 13.06,12.16,7.40,5.71,4.92,4.48,4.40,3.63,3.07,2.98,2.86 and 2.62 .Step G3 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone dihydrochloride Type B monohydrate
In the container with one 100 liters of 8.12 liters of 2N hydrochloric acid addings, at room temperature add 1.62 liters of DI water then.In this container, add 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylene radical formamido-picolyl)-pyrazine ketone free alkali (3.30kg) and be heated to 82 ℃.After the ageing 15 minutes, add Solka flok (24g) and gained solution is passed through successive pipeline filter (20-50 micron) suction filtration.With 3.25 liters of DI water rinse original container (room temperature), merge mother liquor and be heated to 72 ℃.This solution put be chilled to 53 ℃, add crystal seed, be cooled to 25 ℃ continuously through 3 hours.In 30 minutes, in these slurries, drip concentrated hydrochloric acid (1.30 liters).These slurries are put be chilled to 20 ℃ and vacuum filtration separate solid.With 6.48 liters of 1N HCl washing leaching cakes.Use ethanol (190 standards then; 3 * 6.48 liters) washing.The vacuum-drying wet cake obtains title compound under the room temperature.
The Type B compound is with its feature of differential scanning calorimetric curve mark, in an open cup, in water, lead to nitrogen 5 ℃ of/minute heating rate with under 5 ℃, by the extrapolation initial temperature is about 120 ℃, 132 ℃ of peak Wen Weiyue and heat of association are shown as thermo-negative reaction for about 123J/gm, be about 160 ℃ by the extrapolation initial temperature then, 191 ℃ of peak Wen Weiyue and heat of association are shown as endothermic process for about 78J/gm.The low temperature heat absorption is the loss owing to water of hydration, and the high temperature heat absorption is because the resistates water decomposes fusing.The x ray powder diffraction pattern is characterised in that spectrum d-spacing is that the d-spacing of x ray powder diffraction pattern is 12.98,11.91,7.24,5.98,4.90,4.46,4.23,3.99,3.75,3.61,3.41,2.94,2.85and2.61 .
Embodiment VI 3-(2-styroyl amino)-6-methyl isophthalic acid [ethyl-(2-methylformamide ylmethyl-4-chlorophenoxy)-acetamido]-2-pyrazine ketone
Figure A9719576000931
With EDC hydrochloride (56mg, 0.29mmol) be added to the 3-that is stirring (2-styroyl the amino)-6-methyl isophthalic acid-carboxymethyl pyrazine ketone (91mg in DMF (1ml), 0.23mmol), HOBT (40mg, 0.29mmol), ethyl-(2-amino methyl-4-chlorophenoxy)-acetamide hydrochloride (82mg, 0.29mmol) and N-methylmorpholine (0.13ml, 1.17mmol) in the mixture, this mixture was stirred 16 hours.Reactant distribution in ethyl acetate and water, is added this emulsion of salt water-dispersion of capacity.The organic layer of collecting chaos also adds chloroform and the dissolve with methanol solid, dry this solution and evaporate solid.Be suspended in the ethyl acetate crude product and filtration, washing, then ethyl acetate is washed, and obtains title compound after the drying, is white crystalline solid, and fusing point is greater than 200 ℃: 1H NMR (400Mz, DMSO) d:0.97 (t, J=7.2Hz, 3H, CH 2CH 3), 2.03 (s, 3H, CH 3), 2.83 (t, J=7.4Hz, 2H, PhCH 2), 3.09 (quintet J=6.7Hz, 2H, CH 2CH 3), 3.47 (q, J=6.9Hz, 2H, PhCH 2CH 2), 4.37 (d, J=5.7Hz, 2H, CONHCH 2), 4.64 (s, 2H, CH 2CO), 6.63 (s, 1H, pyrazine ketone H-5), 6.77 (brt, 1H, NH), and 6.94 (d, J=8.4Hz, 1H, phenoxy group H-6), 7.16-7.30 (m, 7H, remainder), 7.98 (brt, 1H, NH), 8.67 (brt, 1H, NH) MS (FAB) 512 (M+1) +.
The preparation of embodiment VII [R]-3-(1-phenyl-2-propyl group amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576000941
With the method for embodiment V step C-F, by 1-carbobenzoxy-(Cbz) methyl-3,5-two chloro-6-methylpyrazine ketone and [R]-amphetamine prepare the hydrochloride of title compound: MS (FAB) 421 (M+1) +
The preparation of embodiment VIII [S] 3-(1-phenyl-2-propyl group amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576000942
Use the method for embodiment V step C-F, by 1-carbobenzoxy-(Cbz) methyl-3,5-two chloro-6-methylpyrazine ketone and [S]-amphetamine prepare the hydrochloride of title compound: MS (FAB) 421 (M+1) +
The preparation of embodiment IX 3-(1-phenyl-2-methyl-2-propyl group amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576000951
Use the method for embodiment V step C-F, by 1-carbobenzoxy-(Cbz) methyl-3,5-two chloro-6-methylpyrazine ketone and 1-phenyl-2-methyl-2-propylamine prepare the hydrochloride of title compound: MS (FAB) 435 (M+1) +
The preparation of embodiment X 3-(2-methyl-2-propyl group amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576000952
Use the method for embodiment V step C-F, by 1-carbobenzoxy-(Cbz) methyl-3,5-two chloro-6-methylpyrazine ketone and 2-methyl-2-propylamine prepare the hydrochloride of title compound: MS (FAB) 358 (M+1) +
The preparation of embodiment XI 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-4,6-dimethyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576000953
Use the method for embodiment V step F, by 3-(2-styroyl amino)-6-methyl isophthalic acid-methyl carboxyl pyrazine ketone and 2-amino-5-amino methyl-4,6 lutidine dihydrochlorides prepare the hydrochloride of title compound, and fusing point is greater than 200 ℃: MS (FAB) 421 (M+1) +
The preparation of embodiment XII [R, S] 3-(2-phenyl-1-propyl group amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576000961
Use the method for embodiment V step C-F, by 1-carbobenzoxy-(Cbz) methyl-3,5-two chloro-6-methylpyrazine ketone and racemic-2-phenyl-1-propylamine prepare the hydrochloride of title compound, and fusing point is greater than 200 ℃: MS (FAB) 421 (M+1) +
The preparation of embodiment X III 3-(2-propyl group amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment V step C-F, by 1-carbobenzoxy-(Cbz) methyl-3,5-two chloro-6-methylpyrazine ketone and 2-propylamine prepare the hydrochloride of title compound, and fusing point is greater than 200 ℃: MS (FAB) 345 (M+1) +
The preparation of embodiment IV 3-(2-phenoxy group ethylamino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576000971
Use the method for embodiment V step C-F, by 1-carbobenzoxy-(Cbz) methyl-3,5-two chloro-6-methylpyrazine ketone and 2-phenoxyethylamine prepare the hydrochloride of title compound, and fusing point is greater than 200 ℃: MS (FAB) 423 (M+1) +
Embodiment X V 3-[2-(4-hydroxy phenyl)-ethylamino]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576000972
Use the method for embodiment V step C-F, by 1-carbobenzoxy-(Cbz) methyl-3,5-two chloro-6-methylpyrazine ketone and 2-(4-hydroxy phenyl)-ethamine prepare the hydrochloride of title compound, fusing point 195-199 ℃: MS (FAB) 423 (M+1) +
The preparation of embodiment X VI 3-cyclopropyl amino-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576000981
Use the method for embodiment V step C-F, by 1-carbobenzoxy-(Cbz) methyl-3,5-two chloro-6-methylpyrazine ketone and cyclopropylamine prepare the tfa salt of title compound: MS (FAB) 343 (M+1) +
The preparation of embodiment X VII 3-cyclopropyl methylamino-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment V step C-F, by 1-carbobenzoxy-(Cbz) methyl-3,5-two chloro-6-methylpyrazine ketone and cyclopropyl-methylamine prepare the hydrochloride of title compound, and fusing point is greater than 200 ℃: MS (FAB) 357 (M+1) +
The preparation of embodiment X VIII [S] 3-(2-hydroxyl-2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576000991
Use the method for embodiment V step C-F, by 1-carbobenzoxy-(Cbz) methyl-3,5-two chloro-6-methylpyrazine ketone and [S]-2-hydroxyanilines prepare the hydrochloride of title compound, and fusing point is greater than 200 ℃: MS (FAB) 423 (M+1) +
The preparation of embodiment X IX [R] 3-(2-hydroxyl-2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576000992
Use the method for embodiment V step C-F, by 1-carbobenzoxy-(Cbz) methyl-3,5-two chloro-6-methylpyrazine ketone and [R]-2-hydroxyphenethylamine prepare the hydrochloride of title compound: MS (FAB) 423 (M+1) +
The preparation of embodiment XX 3-(2-cyclopropyl ethylamino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methyl formamido group picolyl)-pyrazine ketone Steps A: 4-phthalimido-1-butylene
100 ℃ be stirred in 4-bromo-1-butylene among the DMF (10ml) (1.01ml, 10.0mmol) and phthalimide potassium (1.85g, mixture 10.0mmol) 3 hours.Put the gained mixture cold and be distributed in ethyl acetate and water in.Water and salt water washing organic layer, dry (Na 2SO 4) and vacuum-evaporation obtain crystalline solid.By quick silica gel column chromatography (20% ethyl acetate/hexane wash-out) purification crude product, obtain title compound, be crystalline solid: 1H NMR (300Mz, CDCl 3) d2.45 (q, J=7.0Hz, 2H), 3.78 (t, J=7.0Hz, 2H), 5.04 (m, 2H), 5.76 (m, 1H), 7.71 (m, 2H), 7.84 (m, 2H). step B:2-phthalimido ethyl cyclopropane
With Suda method (synthetic method, 1981,714),, be crystalline solid with the Cyclopropanated title compound that obtains of 4-phthalimido-1-butylene: 1H NMR (400Mz, CDCl 3) d0.05 (m, 2H), 0.42 (m, 2H), 0.69 (m, 1H), 1.58 (q, J=7.1Hz, 2H), 3.77 (t, J=7.1Hz, 2H), 7.71 (m, 2H), 7.84 (n, 2H). step C:2-cyclopropyl ethamine
Will the 2-phthalimido ethyl cyclopropane in the ethanol (10ml) (1.40g, 6.50mmol) and hydrazine hydrate (0.32ml, 6,50mmol) mixture refluxes and stirred 1 hour.This mixture is put cold-peace adding concentrated hydrochloric acid, and (0.54ml 6.50mmol), gets dense thick precipitation.This mixture of vacuum-evaporation also is suspended in resistates in the 1MHCl solution (10ml), be warmed to 50 ℃ 5 minutes, put cold-peace and filter.Use washed with dichloromethane filtrate, vacuum-evaporation obtains the hydrochloride of title compound with the toluene/ethanol azeotropic, is crystalline solid: 1H NMR (400Mz, CD 3OD) d0.15 (m, 2H), 0.54 (m, 2H), 0.74 (m, 1H), 1.55 (q, J=7.3Hz, 2H), 3.01 (t, J=7.3Hz, 2H). step D:3-(2-cyclopropyl ethylamino)-5-chloro-6-methyl isophthalic acid-(benzyloxycarbonyl methyl)-pyrazine ketone
Under 80 ℃, will the 2-cyclopropyl ethylamine hydrochloride in toluene (1ml) and the water (0.5ml) (73mg, 0.60mmol), 1-carbobenzoxy-(Cbz) methyl-3,5-two chloro-6-methylpyrazine ketone (164mg, 0.50mmol) and sodium bicarbonate (101mg, mixture stirring 1.20mmol) 3 hours.Put cold reactant and it is distributed in methylene dichloride and 10% citric acid solution.Dry (Na 2SO 4) and the vacuum-evaporation organic layer obtain title compound, be crystalline solid: 1H NMR (400MHz, CDCl 3): d0.10 (m, 2H), 0.47 (m, 2H), 0.74 (m, 1H), 1.53 (q, J=7.0Hz, 2H), 2.21 (s, 3H, CH 3), 3.49 (q, J=6.6Hz, 2H), 4.80 (s, 2H), 5.22 (s, 2H), 6.18 (brt, 1H), 7.33-7.40 (m, 5H). step e: 3-(2-cyclopropyl ethylamino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use embodiment V step D-F method, prepare title compound by 3-(2-cyclopropyl ethylamino)-5-chloro-6-methyl isophthalic acid-(benzyloxycarbonyl methyl)-pyrazine ketone, fusing point is greater than 200 ℃: MS (FAB) 371 (M+1) +
The preparation of embodiment X XI 3-(2-styroyl amino)-6-ethyl-1-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment V, prepare the hydrochloride of title compound: MS (FAB) 421 (M+1) by propionic aldehyde +
The preparation of embodiment X XII 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001021
Use the method for embodiment V step F, prepare the hydrochloride of title compound by 3-(2-styroyl amino)-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and 2-amino-5-aminomethyl pyridine, fusing point is greater than 220 ℃: MS (FAB) 393 (M+1) +
The preparation of embodiment XX III 3-(5-indanyl methylamino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment V step C-F, by 1-carbobenzoxy-(Cbz) methyl-3,5-two chloro-6-methylpyrazine ketone and 5-indanyl methylamine prepare the tfa salt of title compound: MS (FAB) 434 (M+1) +
The preparation of embodiment XX IV 3-(2-styroyl amino)-6-methyl isophthalic acid-[ethyl (2-methylformamide ylmethyl phenoxy group)-acetamido]-pyrazine ketone
Figure A9719576001031
Use the method for embodiment VI, prepare title compound by 3-(2-styroyl amino)-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and ethyl-2-amino methyl phenoxy-acetamide: MS (FAB) 478 (M+1) +
The preparation of embodiment XX V 3-(4-methoxybenzyl amino)-6-methyl isophthalic acid-[ethyl (2-methylformamide ylmethyl-4-chlorophenoxy)-acetamido]-pyrazine ketone
Figure A9719576001032
Use the method for embodiment VI, by 1-carbobenzoxy-(Cbz) methyl-3,5-two chloro-6-methylpyrazine ketone and 4-methoxybenzylamine prepare title compound: m.p. is greater than 200 ℃, MS (FAB) 528 (M+1) +
The preparation of embodiment XX VI 3-(2-styroyl amino)-6-methyl isophthalic acid-(methylformamide ylmethyl-2-hydroxyl-5-chloro-phenyl-)-pyrazine ketone
Figure A9719576001041
Use the method for embodiment VI, prepare title compound by 3-(2-styroyl amino)-6-methyl isophthalic acid-carboxyl methylpyrazine ketone and 2-amino methyl-4-chlorophenol: MS (FAB) 427 (M+1) +
Embodiment XX VII 3-(2-styroyl amino)-6-methyl isophthalic acid-[ethyl-(2-methylformamide ylmethyl-4-chlorophenoxy) ethanoyl)-preparation of pyrazine ketone
Figure A9719576001042
Use the method for embodiment VI, prepare title compound by 3-(2-styroyl amino)-6-methyl isophthalic acid-carboxyl methylpyrazine ketone and 2-aminomethyl methyl-4-chlorophenoxyacetic acid ethyl ester: MS (FAB) 513 (M+1) +
Embodiment XX VIII 3-(2-methyl-2-propyl group amino)-6-methyl isophthalic acid-[ethyl-(2-methylformamide ylmethyl-4-chlorophenoxy) acetamido)-preparation of pyrazine ketone
Figure A9719576001051
Use the method for embodiment VI, prepare the tfa salt of title compound, fusing point 64-70 ℃ by 3-(2-methyl-2-propyl group amino)-6-methyl isophthalic acid-carboxyl methylpyrazine ketone: MS (FAB) 464 (M+1) +
The preparation of the trans 3-of embodiment XX IX racemize (2-benzyl ring hexyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001052
Use the method for embodiment V step C-E, follow usefulness method 4, by 1-carbobenzoxy-(Cbz) methyl-3,5-two chloro-6-methylpyrazine ketone and the trans 2-benzyl ring of racemize hexylamine prepare the hydrochloride of title compound: MS (FAB) 461 (M+1) +
The preparation of embodiment XXX racemize cis 3-(2-benzyl ring hexyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment V step C-E, follow usefulness method 4, by 1-carbobenzoxy-(Cbz) methyl-3,5-two chloro-6-methylpyrazine ketone and racemize cis 2-benzyl ring hexylamine prepare the hydrochloride of title compound: MS (FAB) 461 (M+1) +
The preparation of embodiment XX XI 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-4-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001062
Use the method for embodiment V step F, prepare the hydrochloride of title compound: MS (FAB) 393 (M+1) by 3-(2-styroyl amino)-6-methyl isophthalic acid-methyl carboxyl pyrazine ketone and 2-amino-4-aminomethyl pyridine +
The preparation of embodiment XX XII 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-3-methyl-4-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001071
Steps A: 2-tert-butoxycarbonyl amino-3-methyl-pyridine-N-oxide
Under 0 ℃, (1.0g adds 5%NaHCO in dichloromethane solution 4.8mmol) (25ml) to 2-tert-butoxycarbonyl amino-3-picoline 3(25ml).In 20 fens quick stirred mixture of clockwise, divide add for five times the 3-chloroperoxybenzoic acid (1.73g, 5mmol).Permission is spent the night in ice bath, uses 10%Na 2SO 3The all standing reaction mixture.Stir after 5 minutes, use the dichloromethane extraction water layer, Na 2SO 4Drying with activated carbon treatment with except that desolvating, obtains oily matter, and purifying with the thin silica gel chromatography of 50g (98: 2 to 96: 4 chloroform-methanol wash-outs) obtains title compound, is pale solid: 1H NMR (CDCl 3) δ 8.23 (s, 1H), 8.12 (d, 1H, 6.6Hz), 7.15 (d, 1H, 6.8Hz), 6.98 (t, 1H, 6.3Hz), 2.36 (s, 3H), 1.52 (s, 9H). step B:2-tert-butoxycarbonyl amino-3-methyl-methoxypyridine methyl sulfate
Under argon gas, to the 2-tert-butoxycarbonyl amino-3-methylpyridine N oxide that is stirring (620mg, add in dichloromethane solution 0.29mmol) (8ml) methyl-sulfate (262 μ 1,0.3mmol).The evaporation methylene dichloride spends the night under the argon gas of low discharge, obtains title compound, is light brown solid: 1H NMR (DMSO-d 6) δ 10.8 (s, 1H), 9.32 (d, 1H, 6.6 Hz), 8.50 (d, 1H, 7.8Hz), 7.98 (t, 1H, 7.1Hz), 4.28 (s, 3H), 3.37 (s, 3H)), 2.41 (s, 3H), 1.49 (s, 9H) step C:2-tert-butoxycarbonyl amino-4-cyano group-3-picolines
(651mg, 10mmol) reacting by heating is spent the night in 50 ℃ of water (4.5ml) will to go up step product and potassium cyanide.Water and 10% yellow soda ash diluting reaction thing are used chloroform extraction three times, merge organic layer, use the salt water washing, Na 2SO 4Dry and remove and desolvate, obtain dark oily matter, with its be dissolved in chloroform and by the thin silicagel column of 20g (1: 4-1: 3 ethyl acetate-hexane wash-out) purification obtains title compound, is colorless solid: 1H NMR (CDCl 3) 7.64 (d, 1H, 7.7Hz), 7.44 (d, 1H, 7.7Hz), 6.80 (s, 1H), 2.38 (s, 3H), 1.52 (s, 9H). step D:4-amino methyl-2 tert-butoxycarbonyl amino-3-picoline
In the Pa Er device under 55psi pressure, with 10%Pd-C (75mg) catalytic hydrogenation 2-tert-butoxycarbonyl amino-4-cyano group-3-picoline (175mg, 0.75mmol) and acetate (88 μ l, methyl alcohol 1.5mmol) (10ml) solution spends the night.Remove by filter catalyzer, concentrating under reduced pressure is distributed in resistates in chloroform and 10% yellow soda ash.Use the chloroform extraction water layer, merge organic layer, Na 2SO 4Dry and concentrated, obtain the 150mg title compound, be colorless oil:
1H NMR (CDCl 3) δ 7.48 (d, 1H, 7.7Hz), 7.02 (d, 1H, 7.7Hz), 6.69 (s, 1H), 3.88 (s, 2H), 2.28 (s, 3H), 1.51 (s, 9H). step e: 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-3-methyl-4-methylformamide ylmethyl pyridyl)-pyrazine ketone
The method of using method 4 prepares the tfa salt of title compound: MS (FAB) 407 (M+1) by 3-(2-styroyl amino)-6-methyl isophthalic acid-carboxyl methylpyrazine ketone and 4-amino methyl-2-tert-butoxycarbonyl amino-3-picoline +
Embodiment XXX III 3-[2-(2-pyridyl) ethylamino]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001081
Use the method for embodiment I step D, then use the method for embodiment V step e and F, by 3,5-two chloro-6-methyl isophthalic acid-carboxyl methylpyrazine ketone and 2-(2-pyridyl ethyl) amine prepare the hydrochloride of title compound, fusing point 209.5-212 ℃: MS (FAB) 408 (M+1) +
The preparation of embodiment XXX IV 3-(1-penta amino)-5-chloro-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001091
Use the method for embodiment V step F, by 3,5-two chloro-6-methyl isophthalic acid-carboxyl methylpyrazine ketone and amylamine prepare title compound: MS (FAB) 407 (M+1) +
Embodiment XXX V 3-[2-(4-morpholino) ethylamino]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001092
Use the method for embodiment I step D, then with the method for embodiment V step e and method 4, by 3,5-two chloro-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and 2-(4-morpholino ethyl) amine prepare the hydrochloride of title compound:
Analyze C20H29N7O33.7HCl3.05H 2O
Calculated value C39.69H6.46N16.20
Measured value C39.69H6.46N15.95
Embodiment XXX VI 3-[2 (S)-methyl isophthalic acid-butyl amino]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment I step D, then with the method for embodiment V step e and F, by 3,5-two chloro-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and 2-(S)-methyl isophthalic acid-butylamine prepare title compound, fusing point 188.5-193.5 ℃.
The preparation of embodiment XXX VII 3-(1-penta amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001102
Use the method for embodiment I step D, then with the method for embodiment V step e and F, by 3,5-two chloro-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and 1-amylamine prepare title compound, fusing point 115-118 ℃.
The preparation of embodiment XXX VIII 3-(2,2-hexichol ethylamino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001111
Use the method for embodiment I step D, then use the method for embodiment V step e and method 4, by 3,5-two chloro-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and 2, the 2-diphenyl-ethylamine prepares the hydrochloride of title compound:
Analyze C28H30N6O22.0HCl0.50H 2O
Calculated value C59.56H5.89N14.89
Measured value C59.53H5.72N14.59
The preparation of embodiment XXX IX 3-cyclohexyl amino-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001112
Use the method for embodiment I step D, then with the method for embodiment V step e, by 3,5-two chloro-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and hexahydroaniline prepare the hydrochloride of title compound, fusing point 221-227 ℃.
The preparation of embodiment X L3-(2-indanyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001121
Use the method for embodiment I step D, then with the method for embodiment V step e and method 4, by 3,5-two chloro-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and 2-amido dihydro indenes prepare the hydrochloride of title compound:
Analyze C23H26N6O22.0HCl1.0H 2O0.35EtOAc calculated value C54.25H6.12N15.56 measured value C54.20H5.85N15.54
Embodiment X L I 3-[2 (R)-hydroxyl-1-(S)-indanyl amino] preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001122
Use the method for embodiment I step D, then with the method for embodiment V step e and method 4, by 3,5-two chloro-6-methyl isophthalic acids-carboxymethyl pyrazine ketone and 2 (R)-hydroxyl-1 (S)-amido dihydro indenes prepares title compound, fusing point 280-283 ℃.
Embodiment X L II 3-[2-(3,4-methylenedioxyphenyl ethylamino)]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001131
Use the method for embodiment I step D, then with the method for embodiment V step e and method 4, by 3,5-two chloro-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and 2-(3,4-methylenedioxyphenyl base)-ethamine prepares the hydrochloride of title compound:
Analyze C23H26N6O4.3.0HCl.0.30EtOAc calculated value C49.57H5.40N14.33 measured value C49.94H5.25N14.48
Embodiment X L III 3-[2-(4-fluorobenzene ethylamino)] preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment I step D, then with the method for embodiment V step e and method 4, by 3,5-two chloro-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and 2-(4-fluorophenyl)-ethamine prepare the tfa salt of title compound: MS (FAB) 425 (M+1) +
Embodiment X L IV 3-[2-(4-pyridyl)-ethylamino]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001141
Use the method for embodiment I step D, then use the method for embodiment V step e and method 4, by 3,5-two chloro-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and 2-(4-pyridyl)-ethamine prepare the hydrochloride of title compound, fusing point 220-226 ℃: MS (FAB) 408 (M+1) +
The preparation of embodiment X L V racemize 3-(1-indanyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001142
Use the method for embodiment I step D, then with the method for embodiment V step e and method 4, by 3,5-two chloro-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and racemize 1-amido dihydro indenes prepare the hydrochloride of title compound:
Analyze C23H26N6O22.0HCl1.0H 2O calculated value C54.22H5.94N16.50 measured value C54.12H5.65N16.45
Embodiment X L VI racemize 3-[2-(2-THP trtrahydropyranyl)-ethylamino]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001151
Steps A: racemize 2-cyano methyl pyrans
With racemize 2-brooethyl pyrans (3.0g, 16mmol) and sodium cyanide (1.6g, DMF 33mmol) (50ml) mixing solutions is 100 ℃ of heated overnight.Solvent removed in vacuo also is distributed in resistates in methylene dichloride and the water.Use the dried over sodium sulfate organic phase.Except that desolvating and resistates chromatogram (4: 1 hexane/ethyl acetate) purification being obtained title compound: 1H NMR (CDCl 3) d1.35-1.91 (m, 6H), 2.50 (d, J=6.0Hz, 2H), 5.59 (m, 2H), 4.01 (m, 1H). step B: racemize 2-amino-ethyl pyrans
Under 55psi pressure, with 1: 1 ethanol of racemize 2-cyano methyl pyrans (4.2g) and 10%Pd/C (4.0g): the hydrogenation of ethyl acetate (150ml) mixture through catalytic is spent the night.By diatomite filtration reaction mixture, solvent removed in vacuo then.Resistates is distributed in chloroform and 10% sodium carbonate solution.Use the dried over sodium sulfate organic phase.Removing desolvates obtains title compound: 1H NMR (CDCl 3) d1.32-1.84 (m, 6H), 3.06 (m, 2H), 3.44 (m, 2H), 3.98 (m, 1H). step C: racemize 3-[2-(2-THP trtrahydropyranyl)-ethylamino]-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment V step C-E, follow the method for usefulness method 4, by 1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone and 2-(2-THP trtrahydropyranyl)-ethamine prepare the tfa salt of title compound: MS (FAB) 415 (M+1) +
Embodiment X L VII 3-[2-(3-pyridyl)-ethylamino]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001161
Use the method for embodiment I step D, then use the method for embodiment V step e and method 4, by 3,5-two chloro-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and 2-(3-pyridyl)-ethamine prepare the hydrochloride of title compound, and fusing point is greater than 250 ℃: MS (FAB) 408 (M+1) +
Embodiment X L VIII 3-[2-(4-imidazolyl)-ethylamino]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001162
Use the method for embodiment V step C-E and the method for method 4, by 1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone and histamine prepare the hydrochloride of title compound: MS (FAB) 397 (M+1) +
Embodiment I L3-[2-(3-indyl)-ethylamino]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment V step C-E and method 4, by 1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone and tryptamines prepare title compound, fusing point 195-197 ℃: MS (FAB) 446 (M+1) +
Embodiment L3-{2-[3-(6-fluorine)-indyl]-ethylamino }-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001172
Use the method for embodiment V step C-E and method 4, by 1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone and 6-fluorine tryptamines prepare the tfa salt of title compound: MS (FAB) 464 (M+1) +
The preparation of embodiment L I 3-(2-cyclopentyl ethylamino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001181
Use the method for embodiment V step C-E and method 4, by 1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone and 2-cyclopentyl ethamine prepare the hydrochloride of title compound: MS (FAB) 399 (M+1) +
Embodiment L II 3-[2-(4-aminomethyl phenyl)-ethylamino]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment V step C-F, by 1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone and 2-(4-aminomethyl phenyl) ethamine prepare title compound, fusing point 254.5-260 ℃: MS (FAB) 421 (M+1) +
Embodiment L III 3-[2-(2-thienyl)-ethylamino]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001191
Use the method for embodiment I step D, then with the method for embodiment V step e and method 4, by 3,5-two chloro-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and 2-(2-thienyl) ethamine prepare title compound, fusing point 245.5-249.5 ℃: MS (FAB) 413 (M+1) +
Embodiment L IV racemize 3-[1-(3-pyridyl)-2-propyl group amino]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment V step C-E, follow the method for usefulness method 4, by 1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone and 1-(3-pyridyl)-2-propylamine (are pressed method preparations such as Burger; J.Org.Chem.1957,22,143) hydrochloride of preparation title compound: MS (FAB) 422 (M+1) +
Analyze C22H27N7O24.1HCl1.0EtOAc calculated value C47.38H5.98N14.88 measured value C47.37H6.11N14.88
Embodiment L V racemize 3-[2-(3-pyridyl)-1-propyl group amino]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001201
Steps A: 2-(3-pyridyl)-1-nitropropane
With anhydrous CeCl 3(8.63g, anhydrous THF solution 35.0mmol) (200ml) is cooled to 0 ℃, drip MeMgBr (1.0M in ether, 11.7ml, 35.0mmol).Stir after 1.5 hours, solution is cooled to-40 ℃ and in 15 minutes, drip 3-(2-nitroethylene base) pyridine (can get) (1.50g, THF solution (5ml) 10.0mmol) from TCI-USA.After 5 minutes, with reaction of Glacial acetic acid (1ml) all standing and vacuum concentration.Resistates is dissolved in the methylene dichloride (200ml), with NaOH (1 * 50ml, 1N) and water (1 * 50ml) washing, dried over sodium sulfate, filter and vacuum concentration, obtain title compound by flash column chromatography (30 * 150mm silicagel column, ethyl acetate/dichloromethane (1: 3)) purification resistates, be oily matter: 1H NMR (400MHz, CDCl 3) d1.40 (d, J=6.9Hz, 3H), 3.62-3.71 (m, 1H), 4.53-4.62 (m, 2H), 7.26-7.36 (m, 1H), 7.54-7.59 (m, 1H), 8.48-8.53 (m, 2H). step B:2-(3-pyridyl)-1-propylamine
Under argon gas atmosphere, (0.91g adds 10%Pd/C (1.00g) in ethanol 5.48mmol) (20ml) and 12N HCl (0.1ml) solution to 2-(3-pyridyl)-1-nitropropane.Find time solution also with the hydrogen purge several times, put vigorous stirring under the hydrogen atmosphere.After 14 hours, this mixture and several times of finding time, diatomite filtration and wash with ethanol (200ml) with the argon gas purge.Vacuum is removed volatile matter, resistates is distributed among methylene dichloride (100ml) and the NaOH (50ml, 10%), with methylene dichloride (2 * 100ml) aqueous layer extracted.Merge organic layer, MgSO 4Drying is filtered, and vacuum concentration also passes through flash column chromatography (20 * 150mm silicagel column, CH 2Cl 2/ NH 3Saturated CH 2Cl 2/ MeOH60: 39: 1) the purification resistates obtains title compound, is oily matter: 1H NMR (400MHz, CDCl 3) d1.28 (d, J=6.8Hz, 3H), 2.74-2.85 (m, 1H), and 2.87-2.92 (m, 2H), 7.23-7.26 (m, 1H), and 7.51-7.54 (m, 1H), 8.47-8.49 (m, 2H). step C: racemize 3-[2-(3-pyridyl)-1-propyl group amino]-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment V step C-F, by 1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone and 2-(3-pyridyl)-1-propylamine prepare title compound: analyze C22H27N7O20.1H 2O calculated value C62.42H6.48N23.10 measured value C62.08H6.28N23.55
Embodiment L VI 3-[2-methyl-2-(2-pyridyl)-1-propyl group amino]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001211
Steps A: 2-methyl-2-(2-pyridyl)-propionitrile
(1.00g, gradation adds NaH (60% weight fraction is dispersed in the mineral oil for 0.743g, 18.58mmol) in dry DMF 8.44mmol) (20ml) solution to the 2-pyridyl acetonitrile that is cooled to 0 ℃.After 10 minutes, through 15 minutes by syringe add methyl iodide (1.31ml, 21.11mmol).After 1 hour, reactant is diluted in the ethyl acetate (200ml), water (5 * 20ml) and salt solution (1 * 20ml) washing and dried over mgso.Filtering solution, vacuum remove volatile matter and by flash column chromatography (30 * 150mm silicagel column, ethyl acetate/hexane gradient elution 1: 4-1: 3) purification oily matter, obtain title compound, be colorless oil: 1H NMR (400MHz, CDCl 3) d1.77 (s, 6H), 7.22-7.27 (m, 1H), 7.59 (dd, J=7.8and0.9Hz, 1H), 7.71-7.75 (m, 1H), 8.59-8.61 (m, 1H). step B:2-methyl-2-(2-pyridyl)-propylamine
Under argon gas atmosphere, (gradation adds LiAlH among the 1.018g, anhydrous ether solution 6.97mmol) (25ml) to 2-methyl-2-(2-pyridyl)-propionitrile 4(0.538g, 14.17mmol).After 1 hour, (1.0ml, 1N), water (8ml), (20ml) all standing that adds diethyl ether then reaction was also stirred 10 hours to add water (1ml), NaOH.Solution filters by Celite pad and uses ether: methyl alcohol (1: 1) (200ml) washs.Vacuum concentrated filtrate and with resistates by flash column chromatography (30 * 150mm silicagel column, CH 2Cl 2/ NH 3Saturated CH 2Cl 2/ MeOH gradient elution 60: 39: 1-60: 38: 2-60: 37: 3) purify, obtain title compound, be resin: 1H NMR (400MHz, CDCl 3) d1.21 (br s, 2H), 1.38 (s, 6H), 2.98 (s, 2H), 7.05-7.14 (m.1H), 7.34-7.38 (m, 1H), and 7.60-7.64 (m, 1H), 8.59-8.61 (m, 1H). step C:3-(2-methyl-2-(2-pyridyl)-1-propyl group amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment V step C-E, follow the method for usefulness method 4, by 1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone and 2-methyl-2-(2-pyridyl)-1-propylamine prepare the hydrochloride of title compound: MS (FAB) 436 (M+1) +
Analyze C23H29N7O23.0HCl0.3EtOAc
Calculated value C50.87H6.07N17.16
Measured value C50.52H5.76N16.88
Embodiment L VII racemize 3-{1-[5-(2-methylamino pyridyl)]-2-propyl group amino }-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001231
Steps A: 6-(t-butoxycarbonyl amino)-nicotinic acid methyl ester
To the 6-amino-nicotinic acid (2.00g, chloroform/methanol 14.48mmol) (90ml: 30ml) add in the solution (TMS) diazomethane (the 2.0M hexane solution, 25ml).Add acetate (0.1ml) after 15 minutes, vacuum concentration is to getting resistates.Grind with ethyl acetate/hexane (2: 1), getting 6-amino-nicotinic acid methyl esters after the filtration is light yellow solid.It is directly used in next step.To 6-amino-nicotinic acid methyl esters (1.86g, add in dichloromethane solution 12.22mmol) (90ml) the dimethyl dicarbonate butyl ester (2.69g, 12.34mmol), 4-dimethylaminopyridine (0.15g, 1.22mmol) and triethylamine (2.00ml, 14.66mmol).After 14 hours, with ethyl acetate (400ml) diluting reaction and with citric acid (1 * 50ml, 10%), water (1 * 50ml) and salt solution (1 * 50ml) washs, dried over mgso, filtration, vacuum concentration.By flash column chromatography (40 * 150mm silicagel column, ethyl acetate/hexane gradient elution 1: 6,1: 5,1: 3) purification resistates, obtain title compound, be white solid: 1H NMR (400MHz, CDCl 3) d1.56 (s, 9H), 3.91 (s, 3H), 8.06 (d, J=8.2Hz, 1H), 8.24-8.27 (m, 1H), 8.57 (br s, 1H), 8.93 (dd, J=0.7 and 2.4Hz, 1H). step B:2-(t-butoxycarbonyl amino)-5-pyridylaldehyde
To be cooled to-30 ℃ 6-(tert-butoxycarbonyl amino)-nicotinic acid methyl ester (2.20g, drip in anhydrous THF solution 8.72mmol) (50ml) DIBAL-H (the 1.0M hexane solution, 34.8ml, 34.8mmol).After 1 hour, added saturated Rochelle salt solution of 40ml and vigorous stirring 10 hours.Vacuum is removed volatile matter and is used methylene dichloride (3 * 50ml) aqueous layer extracted.Water (1 * 50ml) and salt solution (1 * 50ml) washing organic layer, dry (MgSO 4), filter and vacuum concentration.Resistates is directly used in next step.(4.12g drips DMSO (2.54g, methylene dichloride 32.46mmol) (9ml) solution in methylene dichloride 32.46mmol) (30ml) solution to the oxalyl chloride that is cooled to-78 ℃.After 20 minutes, power be added in thick alcohol in the methylene dichloride (35ml) (1.82g, 8.11mmol), then add triethylamine (4.92g, 48.66mmol).Remove ice bath and stirring reaction 1 hour at room temperature, add water (30ml).Separates two solution is also used methylene dichloride (2 * 50ml) aqueous layer extracted.Water (1 * 50ml) and salt solution (1 * 50ml) washing organic layer, dry (MgSO 4), filter and vacuum concentration.By flash column chromatography (30 * 150mm silicagel column, ethyl acetate/dichloromethane 1: 11) purification resistates, obtain title compound, be colorless solid: 1H NMR (400MHz, CDCl 3) d1.55 (s, 9H), 7.79 (br s, 1H), 8.13-8.14 (m, 2H), 8.71 (dd, J=1.1 and 1.8Hz, 1H), 9.96 (s, 1H). step C:2-(t-butoxycarbonyl amino)-5-[1-(2-nitro propenyl)]-pyridine
To 2-(tert-butoxycarbonyl amino)-5-pyridylaldehyde (1.20g, add in the N-methylmorpholine solution (40ml) 5.40mmol) nitroethane (2.20g, 27.0mmol), Potassium monofluoride (0.144g, 2.49mmol) and 18-hat-6 (0.036g).Add after 1 hour diacetyl oxide (2.20g, 21.6mmol) and the 4-Dimethylamino pyridine (0.05g) of catalytic amount.Pour all standing reaction in the 200ml ice after 12 hours into.With methylene dichloride (3 * 75ml) aqueous layer extracted and water (2 * 50ml) and salt solution (organic layer that 1 * 50ml) washing merges, dry (MgSO 4), filter and vacuum concentration.With methylene dichloride grinding residues and solid collected by filtration, obtain title compound, be light yellow solid: 1H NMR (400MHz, CDCl 3) d1.54 (s, 9H), 2.47 (d, J=0.9Hz, 3H), 7.41 (br s, 1H), 7.76 (dd, J=2.3 and 8.8Hz, 1H), 8.04 (s, 1H), 8.05 (d, J=8.8Hz, 1H), 8.33 (d, J=2.4Hz, 1H). step D: racemize 1-[5-(2-methylamino pyridyl)]-the 2-propylamine
To 2-(the t-butoxycarbonyl amino)-5-[1-(2-nitro propenyl) that is cooled to 0 ℃]-pyridine (adding borane THF title complex among the 0.20g, THF solution (8ml) 0.716mmol) (4.30ml, 1.0MTHF solution, 4.30mmol).Remove ice bath and add NaBH 4(0.0135g 0.358mmol) and with reaction is warmed to 65 ℃.After 24 hours, reactant is poured in the ice (50ml), transferring pH with 3N HCl is 2, warm 2 hours at 65 ℃.Regulating pH with NaOH (1N) solution is 8 and solvent removed in vacuo.With methylene dichloride (3 * 75ml) aqueous layer extracted and water (2 * 50ml) and salt solution (organic layer that 1 * 50ml) washing merges, dry (MgSO 4), filter and vacuum concentration.By flash column chromatography (15 * 150mm silicagel column, CH 2Cl 2/ NH 3Saturated CH 2Cl 2/ MeOH60: 37: 3) the purification resistates obtains title compound, is oily matter: 1H NMR (400MHz, CDCl 3) d1.09 (d, J=6.2Hz, 3H), 2.37-2.42 (m, 1H), 2.54 (dd, J=5.5 and 13.7Hz, 1H), 2.90 (d, J=4.9Hz, 3H), 3.03-3.09 (m, 1H), 4.62 (br s, 1H), 6.34-6.37 (m, 1H), 7.26-7.33 (m, 1H), 7.89-7.92 (m, 1H). step e: racemize 3-{1-[5-(2-methylamino pyridyl)]-2-propyl group amino }-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment V step C-F,, 5-two chloro-6-methylpyrazine ketone and racemize 1-[5-(2-methylamino pyridyl) by 1-benzyloxycarbonyl methyl-3]-the 2-propylamine prepares the hydrochloride of title compound: MS (FAB) 451 (M+1) +
Analyze C23H30N8O22.45HCl1.25CH2Cl2 calculated value C45.08H5.45N17.35 measured value C45.03H5.48N17.37.
The preparation of embodiment L VIII 3-(2-methyl-2-phenyl-1-propyl group amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001251
Use the method for embodiment V step C-F, by 1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone and 2-methyl-2-phenyl-1-propylamine prepare title compound, fusing point 179-181 ℃: MS (FAB) 435 (M+1) +
Embodiment L IX 3-[2-methyl-2-(3, the 4-methylenedioxyphenyl)-1-propyl group amino]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001261
Use the method for embodiment V step C-F, by 1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone and 2-methyl-2-(3, the 4-methylenedioxyphenyl)-method of 1-propylamine (with embodiment L VI steps A and B), by 3,4-methylenedioxyphenyl acetonitrile preparation) hydrochloride of preparation title compound: MS (FAB) 479 (M+1) +
Analyze C25H30N6O42.10 HCl0.7H2O calculated value C52.88H5.95N14.80 measured value C52.88H5.96N14.51.
Embodiment L X racemize 3-[1-(3, the 4-methylenedioxyphenyl)-2-propyl group amino]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001262
Steps A: racemize 1-(3, the 4-methylenedioxyphenyl)-2-propylamine
Under argon gas atmosphere, to 1-(3, the 4-methylenedioxyphenyl)-2-nitro propylene (0.938g, dehydrated alcohol 4.53mmol) (40ml), methyl alcohol (8ml) and HCl (4N, 4ml) add in the solution Pd/C (10%, 0.902g).(balloon, 1 normal atmosphere) stirred this mixture 14 hours under hydrogen atmosphere.By diatomite filtration, with ethanol (200ml) washing, vacuum-drying obtains title compound, is the light brown solid: 1H NMR (400MHz, CDCl 3) d1.35 (d, J=6.6Hz, 3H), 2.76 (dd, J=8.6 and 13.5Hz, 1H), 3.09 (dd, J=5.9 and 13.5Hz, 1H), 3.41-3.49 (m, 1H), 5.94 (s, 2H), 6.27-6.77 (m, 3H). step B: racemize 3-[1-(3, the 4-methylenedioxyphenyl)-2-propyl group amino]-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment V step C-E, follow the method for usefulness method 4, by 1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone and 1-(3, the 4-methylenedioxyphenyl)-2-propylamine prepare the hydrochloride of title compound: MS (FAB) 465 (M+1) +
Analyze forC24H28N6O42.40HCl0.65EtOAc calculated value C52.43H5.89N13.79 measured value C52.39H5.57N13.82.
Embodiment L XI 3-[2-(4-sulfonamido phenyl) ethylamino] preparation of-6 methyl isophthalic acids-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment V step C-E, follow the method for usefulness method 4, by 1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone and 4-(2-amino-ethyl) benzsulfamide prepare the hydrochloride of title compound, fusing point 214-221 ℃: MS (FAB) 486 (M+1) +
Embodiment L XII 3-[2-(3, the 4-difluorophenyl) ethylamino]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment V step C-E, follow the method for usefulness method 4, by 1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone and 2-(3, the 4-difluorophenyl) ethamine prepares the hydrochloride of title compound, and fusing point is greater than 235 ℃: MS (FAB) 443 (M+1) +
The preparation of embodiment L X III 3-(3,4-(methylenedioxy) benzylamino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment V step C-E, follow the method for usefulness method 4, by 1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone and 3,4-methylene-dioxy benzylamine prepares the hydrochloride of title compound, and fusing point is greater than 255 ℃: MS (FAB) 437 (M+1) +
The preparation of embodiment L X IV 3-(1-phenyl-1-tetramethylene ylmethyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001291
Use the method for embodiment V step C-E, follow the method for usefulness method 4, by 1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone and 1-phenyl-1-tetramethylene base methylamine is (with the method for embodiment L VI step B, by the preparation of 1-phenyl-1-cyclobutyl nitrile) hydrochloride of preparation title compound, fusing point 252-259 ℃: MS (FAB) 447 (M+1) +
The preparation of embodiment L X V 3-(1-phenyl-1-cyclopropane ylmethyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Use the method for embodiment V step C-E, follow the method for usefulness method 4, by 1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone and 1-phenyl-1-cyclopropane base methylamine (with the method for embodiment L VI step B, by 1-phenyl-1-cyclopropyl nitrile preparation) preparation title compound: MS (FAB) 433 (M+1) +
Embodiment L X VI 3-[2-(2, the 5-difluorophenyl) ethylamino]-preparation of 6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone
Figure A9719576001301
Use the method for embodiment V step C-F, by 1-benzyloxycarbonyl methyl-3,5-two chloro-6-methylpyrazine ketone and 2-(2, the 5-difluorophenyl) ethamine prepare the tfa salt of title compound: MS (FAB) 443 (M+1) +
Embodiment L X VII 3-[2-(2 pyridyl) ethylamino]-5-chloro-6-methyl isophthalic acid-[ethyl-(2-methylformamide ylmethyl-4-chlorophenoxy)-acetamido]-2-pyrazine ketone
Figure A9719576001302
Use the method for embodiment III step B, by 3,5-two chloro-6-methyl isophthalic acids-[ethyl-(2-methyl-formamido-methyl-4-chlorophenoxy)-acetamido]-pyrazine ketone are [with the method for embodiment III steps A, by 3,5-two chloro-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and ethyl-2-amino methyl-4-chlorophenoxy]-ethanamide) preparation] and 2-(2-pyridyl) ethamine prepare title compound, fusing point 207-209 ℃.
Embodiment L X VIII 3-[2-(2-pyridyl) ethylamino]-6-methyl isophthalic acid-[ethyl-(2-methylformamide ylmethyl-4-chlorophenoxy)-acetamido]-2-pyrazine ketone
Use the method for embodiment V step F, by 3-[2-(2-pyridyl) ethylamino]-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and ethyl-2-amino methyl-4-chlorophenoxy)-ethanamide prepares title compound, fusing point 195-197 ℃.
Embodiment L X IX 3-[2-(4-morpholino) ethylamino]-6-methyl isophthalic acid-[cyclopropyl-(2-methylformamide ylmethyl-4-chlorophenoxy)-acetamido]-2-pyrazine ketone
Use the method for embodiment V step F, by 3-[2-(4-morpholino) ethylamino]-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and cyclopropyl-2-amino methyl-4-chlorophenoxy)-ethanamide prepares title compound:
Analyze C25H33N6O5Cl0.45H2O
Calculated value C55.49H6.31N15.53
Measured value C55.14H6.16N16.13
Embodiment L XX 3-[2-(2-pyridyl) ethylamino]-6-methyl isophthalic acid-[cyclopropyl-(2-methylformamide ylmethyl-4-chlorophenoxy)-acetamido]-2-pyrazine ketone
Use the method for embodiment V step F, by 3-[2-(2-pyridyl) ethylamino]-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and cyclopropyl-2-amino methyl-4-chlorophenoxy)-ethanamide prepares title compound, fusing point 196-199 ℃: MS (FAB) 525 (M+1) +
Embodiment L X XI 3-[2 (S)-methyl isophthalic acid-butyl amino]-6-methyl isophthalic acid-[cyclopropyl-(2-methylformamide ylmethyl-4-chlorophenoxy)-acetamido]-2-pyrazine ketone
Figure A9719576001322
Use the method for embodiment V step F, by 3-[2 (S)-methyl isophthalic acid-butyl amino]-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and cyclopropyl-2-amino methyl-4-chlorophenoxy)-ethanamide prepares title compound, fusing point 195-198 ℃: MS (FAB) 490 (M+1) +
Embodiment L X XII 3-(1-amyl group amino)-6-methyl isophthalic acid-[ethyl-(2-methylformamide ylmethyl-4-chlorophenoxy)-acetamido]-2-pyrazine ketone
Use the method for embodiment V step F, by 3-(1-amyl group amino)-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and ethyl-2-amino methyl-4-chlorophenoxy)-ethanamide prepares title compound, fusing point 125-127 ℃:
Embodiment L XX III 3-(2,2-hexichol ethylamino)-6-methyl isophthalic acid-[cyclopropyl-(2-methylformamide ylmethyl-4-chlorophenoxy)-acetamido]-2-pyrazine ketone
Figure A9719576001332
Use the method for embodiment V step F, by 3-(1-amyl group amino)-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and cyclopropyl-2-amino methyl-4-chlorophenoxy)-ethanamide prepares title compound, fusing point 153-159 ℃: MS (FAB) 600 (M+1) +
Embodiment L XX IV 3-(cyclohexyl amino)-6-methyl isophthalic acid-[cyclopropyl-(2-methylformamide ylmethyl-4-chlorophenoxy)-acetamido]-2-pyrazine ketone
Use the method for embodiment V step F, by 3-(cyclohexyl amino)-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and cyclopropyl-2-amino methyl-4-chlorophenoxy)-ethanamide prepares title compound, fusing point 114-121 ℃: MS (FAB) 502 (M+1) +
Embodiment L XX V 3-[2-(2-pyridyl) ethylamino]-6-methyl isophthalic acid-(2,5-dichloro benzyl-acetamido)-2-pyrazine ketone
Figure A9719576001342
Use the method for embodiment V step F, by 3-[2-(2-pyridyl) ethylamino]-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and 2, the 5-dichloro-benzylamine prepares title compound, fusing point 188-191 ℃: MS (FAB) 446 (M+1) +
Embodiment L XX VI 3-[2-(2-pyridyl) ethylamino]-6-methyl isophthalic acid-(3-benzyl chloride yl acetamide base)-2-pyrazine ketone
Use the method for embodiment V step F, by 3-[2-(2-pyridyl) ethylamino]-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and 3-chlorobenzylamine prepare title compound, fusing point 201-207 ℃: MS (FAB) 412 (M+1) +
Embodiment L XX VII 3-[2-(2-pyridyl) ethylamino]-6-methyl isophthalic acid-(3-chloro-6-(cyano group methoxyl group) benzyl acetamido)-2-pyrazine ketone
Use the method for embodiment V step F, by 3-[2-(2-pyridyl) ethylamino]-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and 3-chloro-6-(cyano group methoxyl group) benzylamine prepare title compound, fusing point 207-211 ℃.
Embodiment L XX VIII 3-[2-(2-pyridyl) ethylamino]-6-methyl isophthalic acid-(2-fluoro-5-(trifluoromethyl) benzyl acetamido)-2-pyrazine ketone
Figure A9719576001361
Use the method for embodiment V step F, by 3-[2-(2-pyridyl) ethylamino]-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and 2-fluoro-5-trifluoromethyl) benzylamine prepares title compound, fusing point 181-184 ℃.
Embodiment L XX IX 3-[2-(4-pyridyl) ethylamino]-6-methyl isophthalic acid-[cyclopropyl-(2-methylformamide ylmethyl-4-chlorophenoxy)-acetamido]-2-pyrazine ketone
Figure A9719576001362
Use the method for embodiment V step F, by 3-[2-(4-pyridyl) ethylamino]-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and cyclopropyl-2-amino methyl-4-chlorophenoxy)-ethanamide prepares title compound, fusing point 190-192.5 ℃: MS (FAB) 525 (M+1) +
Embodiment L XXX 3-[2-(3, the 4-methylenedioxyphenyl) ethylamino]-6-methyl isophthalic acid-[cyclopropyl-(2-methylformamide ylmethyl-4-chlorophenoxy)-acetamido]-2-pyrazine ketone
Figure A9719576001371
Use the method for embodiment V step F, by 3-[2-(3, the 4-methylenedioxyphenyl) ethylamino]-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and cyclopropyl-2-amino methyl-4-chlorophenoxy)-ethanamide prepares title compound, fusing point 202-204 ℃: MS (FAB) 568 (M+1) +
Embodiment L XX XI 3-(2-styroyl amino)-6-methyl isophthalic acid-[3-chloro-6-(carboxymethoxyl) benzyl acetamido]-2-pyrazine ketone
Use the method for embodiment V step F, then, prepare title compound by 3-(2-styroyl amino)-6-methyl isophthalic acid-carboxymethyl pyrazine ketone and 2-amino methyl-4-chlorophenoxyacetic acid ethyl ester: MS (FAB) 485 (M+1) with the method hydrolysis of embodiment V step D +
The preparation of embodiment L XX XII 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylene radical formamido-picolyl)-2-pyrazine ketone
Figure A9719576001381
Steps A: α-(allyl amino)-propionitrile hydrochloride
At 0 ℃, to the allylamine that is stirring (36ml, add in water 0.48mmol) (100ml) and ethanol (60ml) solution concentrated hydrochloric acid (20ml, 0.24mol).Add then potassium cyanide (15g, 0.23mol) and acetaldehyde (11.2ml, 0.20mol), this mixture of reflux.After 15 hours, vacuum is removed volatile matter and with the saturated resistates of NaCl, is used dichloromethane extraction (three times).With the extraction liquid drying (Na that merges 2SO 4) and vacuum-evaporation obtain oily matter, it is dissolved among the 1M HCl (200ml).Vacuum evaporated solution gets solid with 1: 1 toluene and methanol azeotropic, this solid of reflux in ethyl acetate (200ml), and cooling is filtered and drying, gets the hydrochloride of title compound:
1H NMR (400MHz, CD 3OD) d1.72 (d, J=7.0Hz, 3H, CH 3), 3.78-3.90 (m, 2H, CH 2), 4.63 (q, J=7.0Hz, a-CH), 5.56-5.66 (m, 2H, CHCH 2), 5.91-6.02 (m, 1H, CHCH 2). step B:1-allyl group-3,5-two chloro-6-methylpyrazine ketone
The oxalyl chloride that will in orthodichlorobenzene (100ml), stir (30.5ml, 0.35mol) and α-(allyl amino)-propionitrile hydrochloride (10.26g, mixture 70mmol) 100 ℃ the heating 15 hours.Vacuum evaporating solvent and by quick silica gel column chromatography (with 30% ethyl acetate/hexane wash-out) the remaining dark oil thing of purifying obtains title compound, is the brown crystal: 1H NMR (400Mz, CDCl 3) d2.48 (s, 3H, CH 3), 4.75 (m, 2H, NCH 2), 5.18 (m, 1H, CHCH AH B), 5.33 (m, 1H, CHCH AH B), 5.85-5.92 (m, 1H, CHCH AH B). step C:3,5-two chloro-6-methyl isophthalic acids-methylene radical carboxyl pyrazine ketone
With trichlorine ruthenium hydrate (114mg, 0.547mmol) be added to the 1-allyl group-3 that is stirring, 5-two chloro-6-methylpyrazine ketone (5.45g, 24.88mmol) and sodium periodate (21.82g is in water 0.102mol) (75ml), acetonitrile (50ml) and tetracol phenixin (50ml) solution.After 3 hours, with dichloromethane extraction reaction mixture (four times) and dry (Na 2SO 4) extraction liquid and the vacuum-evaporation that merge, slurries.1H NMR (CDCl 3) analyze and to be shown as 1: 1 the acid and the mixture of aldehyde.Crude product is dissolved in acetone (50ml) and adds Jones reagent (2.7M) and keep orange-yellow until reactant.Use the ethyl acetate extraction reactant, use the salt water washing then, dry (Na 2SO 4) and vacuum-evaporation obtain title compound, be brown solid: 1H NMR (400Mz, DMSO) d2.41 (s, 3H, Me), 4.86 (s, 2H, CH 2). step D:3-(2-styroyl amino)-5-chloro-6-methyl isophthalic acid-methylene radical-carboxyl pyrazine ketone
To stirring in diox (6ml) 3, (0.50g, (0.80ml 6.33mmol) and with gained solution is warmed to 60 ℃ to 5-two chloro-6-methyl isophthalic acids-methylene radical carboxyl pyrazine ketone 2.11mmol) to add phenylethylamine in the solution.After 16 hours, reaction mixture is distributed in methylene dichloride and 10% citric acid solution.Dry (Na 2SO 4) organic layer and vacuum-evaporation, obtain brown solid, purify by flash column chromatography (with methyl alcohol/chloroform/2% acetate gradient elution, 2-5% methyl alcohol), with getting title compound after the methylbenzene azeotropic drying, be white solid: 1H NMR (300Mz, DMSO) d2.19 (s, 3H, Me), 2.84 (t, J=7.0Hz, 2H, PhCH 2), 3.45 (q, J=7.0Hz, 2H, CH 2NH), 4.70 (s, 2H, CH 2CO 2), 7.18-7.31 (m, 5H, Ph), 7.46 (br t, 1H, NH). step e: 3-(2-styroyl amino)-6-methyl isophthalic acid-methylene radical-carboxyl pyrazine ketone
(158mg adds Raney nickel alloy (1g) in 1: 1 methyl alcohol 0.49mmol)/1M NaOH (24ml) solution to the 3-that is stirring (2-styroyl amino)-5-chloro-6-methyl isophthalic acid-methylene radical carboxyl pyrazine ketone.After 2 hours, by the diatomite filtration reaction mixture, with methanol washing in 1: 1, vacuum-evaporation filtrate obtained white solid.The crude product that these inorganic salt pollute is purified by preparation property HPLC (C18, water/acetonitrile/0.1%TFA wash-out) and is obtained title compound, is foams: 1H NMR (400Mz, DMSO) d2.11 (s, 3H, Me), 2.87 (t, J=7.6Hz, 2H, PhCH 2), 3.53 (br s, 2H, CH 2NH), 4.68 (s, 2H, CH 2CO 2), 6.68 (s, 1H, pyrazine ketone H-5), 7.20-7.31 (m, 5H, Ph), 8.16 (br s, 1H, NH). step F: 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-tertbutyloxycarbonyl-amino-6-methyl-5-methylene radical formamido-methyl-pyridyl)-pyrazine ketone
With EDC hydrochloride (56mg, 0.29mmol) be added to 3-(2-benzene the ethylamino)-6-methyl isophthalic acid-methylene radical-carboxyl pyrazine ketone (91mg that in DMF (1ml), is stirring, 0.23mmol), HOBT (40mg, 0.29mmol), 5-amino methyl-2-t-butoxycarbonyl amino-6-picoline (70mg, 0.29mmol) and N-methylmorpholine (0.13ml, 1.17mmol) mixture in, this mixture was stirred 16 hours.With ethyl acetate diluting reaction thing and washing with water, dry (Na 2SO 4) and vacuum-evaporation.By quick silica gel column chromatography (ethyl acetate/hexane wash-out, 80-100% ethyl acetate) purification crude product, obtain title compound: 1H NMR (300Mz, CDCl 3) d1.51 (s, 9H, t-Bu), 2.26 (s, 3H, CH 3), 2.36 (s, 3H, CH 3), 2.93 (t, J=7.0Hz, PhCH 2), 3.65 (q, J=7.0Hz, PhCH 2CH 2), 4.36 (d, J=5.6Hz, 2H, CONHCH 2), 4.61 (s, 2H, CH 2CO), 5.91 (br t, 1H, NH), 6.65 (brt, 1H, NH), 6.77 (s, 1H, pyrazine ketone H-5), 7.12 (s, 1H, NHBOC), and 7.21-7.32 (m, 5H, Ph), (7.42 d, J=8.5Hz, 1H, pyridine H-3), (7.68 d, J=8.5Hz, 1H, pyridine H-4). step G:3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylene radical formamido-picolyl)-pyrazine ketone
At 0 ℃, (85mg, logical HCl gas is saturated by HCl gas to solution in ethyl acetate 0.17mmol) (10ml) suspension to the 3-that is stirring (2-styroyl amino)-6-methyl isophthalic acid-(2-tert-butoxycarbonyl amino-6-methyl-5-methylene radical-formamido-picolyl) pyrazine ketone.After 2 hours, with nitrogen mixture is outgased under the room temperature, filter the dihydrochloride that obtains title compound, be white crystal, fusing point is greater than 200 ℃: 1H NMR (300Mz, CD 3OD) d2.18 (s, 3H, CH 3), 2.52 (s, 3H, CH 3), 3.00 (t, J=7.4Hz, PhCH 2), 3.68 (t, J=7.4Hz, PhCH 2CH 2), 4.33 (d, J=5.4Hz, 2H, CONHCH 2), 4.76 (s, 2H, CH 2CO), 6.55 (s, 1H, pyrazine ketone H-5), 6.84 (d, J=9.3Hz, 1H, pyridine H-3), 7.23-7.31 (m, 5H, Ph), 7.86 (d, J=9.3Hz, 1H, pyridine H-4); MS (FAB) 407 (M+1) +. external test proteolytic enzyme restraining effect
The tryptic mensuration of people's α-zymoplasm and people is published in thrombosis research with Lewis etc. substantially, 70 volumes, the method in 173 pages (1993).
This measuring method carries out in 25 ℃ 0.05MTRIS damping fluid Ph7.4,0.15M NaCl, 0.1%PEG.Also comprise 1mM CaCl in the tryptic mensuration 2Its principle is measured the time-dependent relation of (405nm) p-Nitroaniline for measuring the hydrolysis rate to p-nitroanilide (pna) substrate with Thermomax96 orifice plate reader.Sar-PR-pna is used to measure people's α-zymoplasm (Km=125um) and bovine trypsin (Km=125um).Concentration 8270cm to the p-nitroanilide substrate -1M -1The specific absorbance absorption that is determined at the 342nm place determine.
Suppress the high effective inhibitor of degree at some zymoplasms and (in the research of Ki＜10nM), adopt sensitiveer active measuring method.In this measuring method, increase (exciting) by producing relevant fluorescence at 400nm at the 500nm place with 7-amino-4-trifluoromethyl tonka bean camphor, measure the catalyzed by thrombin hydrolysis rate (Km=27um) of fluorogenic substrate Z-GPR-afc.The optical density of 7-amino-4-trifluoromethyl tonka bean camphor that the concentration of Z-GPR-afc storing solution produces by measure branch storing solution such as zymoplasm complete hydrolysis at 380nm is determined.
The substrate storing solution that determination of activity decuples ultimate density≤0.1Km at least by dilution is for containing enzyme or inhibitor equilibrated enzyme solution carries out.In controlled trial, measure between enzyme and inhibitor and reach the required time of balance.First speed (the V that product forms when measuring the unrestraint agent O) and product forms when having inhibitor first speed (V i).Suppose Km/[S], the competitive inhibitory effect of [I]/e and [I]/e can ignore (wherein [S], [I] and e represent total substance concentration, inhibition total concn and enzyme total concn respectively), the equilibrium constant (Ki) of inhibitor decomposition can be from the V shown in the equation 1 O/ V iObtain with the relational expression of [I].
V O/V i=1+[I]/Ki????(1)
The activity that measure to show thus shows, compound of the present invention for treatment unstable angina, intractable angina pectoris, myocardial infarction, transient ischemic attack, auricular fibrillation, thrombosis outbreak, thrombus outbreak, dvt, intravascular coagulation distribution and again various diseases such as obturation or restenosis organ be effective.The compounds of this invention to the inhibition activity (representing) of human thrombin with Ki less than 24nM.By it tryptic inhibition of people active (with the Ki representative) is at least 1000nM and proves that these are preferred compounds.
Other compound in the following table explanation scope of the invention.Suppress active and represent Ki more than or equal to 1nM, or represent Ki less than 1nM with " * * " with " * ".
Table 1
Figure A9719576001421
X Y KiH NHC 2H 5* H NHC 3H 5H NH (CH 2) 2N (CH 3) 2F NHC 2H 5F NHC 3H 5F NH (CH 2) 2N (CH 3) 2
Table 2
Figure A9719576001431
R?????????????Ki
C 3H 5
C 3H 5CH 2
t-C 4H 9?????????*
HO 2CCH 2
CF 3CH 2?(CH 3) 2N(CH 2) 2
Table 3
R????????????????KiPhCH 2C(CH 3) 2???????*??PhCHCH 3PhCH 2CHCO 2H??n-C 6H 13
Table 4
Figure A9719576001451
R
PhCH 2C(CH 3) 2
PhCHCH 3
PhCH 2CHCO 2H
n-C 6H 13
Other typical compound of the present invention has the active compound of inhibition (representing with Ki) to show below to human thrombin.The same table is the same, suppress active and represent Ki more than or equal to 1nM with " * ", or " * * " represents Ki less than 1nM.
Figure A9719576001461
Figure A9719576001471
Figure A9719576001481
Figure A9719576001501
Figure A9719576001531
Figure A9719576001541
Figure A9719576001551
Figure A9719576001561
Figure A9719576001581
Figure A9719576001591
Figure A9719576001601
Figure A9719576001611
Figure A9719576001621
Figure A9719576001631
Figure A9719576001641
Figure A9719576001651
Figure A9719576001661
The thrombus obturation is measured in the in vivo test of embodiment L XXX III
(Kurtz etc. study at thrombus with the iron(ic) chloride method of inspection in the rat body, 60 phases, describe in 269 pages (1990)) measure the activity in vivo of thrombin inhibitors of the present invention with 3-(2-phenylethyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylene radical formamido-picolyl)-2-pyrazine ketone.With dialdehyde-urethane (dial-urethane) solution (0.1ml/100gm body weight i.P.) anesthesia male Sprague-Dawley rat (body weight 200-350 gram), use and manage 23 metering needles that link to each other with 12 inches long PE50 and thrust the tail lateral vein.Test tube is linked to each other with T-valve by a test tube joint.Salt solution (contrast) or test compound are by the tail ductus venosus administration that is fit to.PE205 pipe with 0.75 inch long carries out tracheostomy.Expose right carotid and the Duo Puleshi volume of blood flow detector of a 1.3mm diameter is placed on the vascular.Use heating lamp to keep body temperature at 37 ℃.
Optional 6 rats are by tail vein continuous intravenous injection salt solution or test compound.The medicine-feeding rate of test compound is 10ug/kg/min.At start injection preceding 60 minutes, covered on the carotid artery that exposes away from the volume of blood flow detector by the saturated WhatmanNo.1 filter paper of 35% iron trichloride with one 3 square millimeters.If the thrombus obturation does not take place after using iron trichloride, or the thrombus of organ obturation stops after 30 minutes continuation injection 90 minutes (amount to and injected 150 minutes).Inaccessible timing definition is from using the time of iron trichloride to organ thrombus obturation.Stop to measure (having thrombus obturation or thrombus not to inject again 90 minutes in inaccessible back 30 minutes after using iron trichloride to animal),, be added in the Trisodium Citrate of 0.3ml3.8% by the cardiac puncture 3ml that takes a blood sample.
The result of this test shows that test compound is very effective.Give the rat of test compound, the thrombus obturation only takes place in none.
Embodiment L XXX IV tablet formulation
Each is self-contained 25.0 years old, 50.0 and the tablet of the following active compound of 100.0mg is prepared by following explanation: 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylene radical formamido-picolyl)-2-pyrazine ketone (active compound I), 3-(2-styroyl amino)-6-methyl isophthalic acid-[ethyl-(2-methylene radical formamido-methyl-4-chlorophenoxy)-acetamido]-2-pyrazine ketone (active compound II) and 3-amino-6-methyl isophthalic acid-[ethyl-(2-methylene radical formamido-methyl-4-chlorophenoxy)-acetamido]-2-pyrazine ketone (active compound III).
The composition table of 25-100 milligram active compound
Milligram number composition A B C D E F G H I active compound I 25 50 100------active compound II---25 50 100---active compound------25 50 100
III Microcrystalline Cellulose 37.25 100 200 37.25 100 200 37.25 100 200 improved edible 37.25 4.25 8.5 37.25 4.25 8.5 37.25 4.25 8.5 W-Gum Magnesium Stearates 0.5 0.75 1.5 0.5 0.75 1.5 0.5 0.75 1.5
All active compounds, Mierocrystalline cellulose and the mixing of part W-Gum also are granulated into 10% corn starch paste.The particle of gained is sieved, dry and mix with the W-Gum and the Magnesium Stearate of remainder.Then the particle of gained is pressed into every and contains 25.0,50.0 and the tablet of 100.0mg activeconstituents respectively.
Embodiment L XXX V tablet formulation
3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone dihydrochloride A type monohydrate (active compound (IV) tablet typical composed as follows:
Composition 0.25mg ??????2mg ?????10mg ?????50mg
Active compound IV mannitol Microcrystalline Cellulose Magnesium Stearate 0.500％ 49.50％ 49.50％ 0.500％ ????1.000％ ????49.25％ ????49.25％ ????0.500％ ????5.000％ ????47.25％ ????47.25％ ????0.500％ ????14.29％ ????42.61％ ????42.61％ ????0.500％
2,10 and the tablet of 50mg with the water dispersant coating of hydroxypropylcellulose, Vltra tears and titanium dioxide, account for sheet heavy 2.4%.Prepare tablet by direct compacting
Activator IV, mannitol and Microcrystalline Cellulose sieved by the sieve mesh (being generally 250-750um) of specified size and in the blending machine that is fit to, mix.Mixture being mixed to substantially (typically being 15-30 minute) medicine is evenly distributed in the dry powder of gained.Magnesium Stearate is sieved and be added in the blending machine, then, remix (typically being 2-10 minute) is pre-compressing tablet mixture.This pre-compressing tablet mixture makes the sheet that obtains that suitable physical strength and acceptable disintegration time (size and dose according to compressing tablet become) be arranged then the external force system of pressing down (typical pressures range is the 0.5-2.5 metric ton).2,10 and the 50mg tablet, with the aqueous dispersions ash disposal and the coating of water-soluble polymers and pigment.Prepare tablet by dry granulation
The compacting mixed powder also grinds again and obtains specifying size particles under each comfortable suitable external force.Then this particle and Magnesium Stearate are mixed also compressing tablet as stated above.
Embodiment L XXX VI intravenous formulation
The intravenous formulation of 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone dihydrochloride A type monohydrate (active compound IV) is by preparation method's preparation of general intravenous formulation.Composition is estimated scope active compound IV 0.12-0.61mgD-glucuronic acid *0.5-5mg mannitol NF 50-53mg1N sodium hydroxide q.s pH3.9-4.1 water for injection q.s1.0ml
Exemplary composition A-C shows below:
Composition A B C active compound IV 0.61mg *0.30 *0.15 * *The D-glucuronic acid *1.94mg 1.94mg 1.94mg mannitol NF 51.2mg 51.2mg 51.2mg1N sodium hydroxide q.spH4.0 q.spH4.0 q.spH4.0 water for injection q.s1.0ml q.s1.0ml q.s1.0ml *0.50mg free alkali *0.25mg free alkali * *0.12mg free alkali
Various other buffering acids, for example L-lactic acid, acetate, citric acid or the acceptable acid of any medicine/in the acceptable pH scope of intravenously administrable, have the conjugate base of suitable surge capability can replace glucuronic acid.

Claims (44)

1. the following compound of general formula and its pharmacy acceptable salt,
Figure A9719576000021
Wherein W is
Hydrogen,
R 1,
R 1OCO,
R 1CO,
R 1(CH 2) nNHCO, or
(R 1) 2CH(CH 2) nNHCO，
Wherein n is 0-4; R 1Be
R 2，
R 2(CH 2) mC (R 12) 2, wherein m is 0-3 and each R 12Can be identical or different,
(R 2) (OR 2) CH (CH 2) P, wherein P is 1-4,
R 2C (R 12) 2(CH 2) m, wherein m is 0-3 and each R 12Can be identical or different, (R wherein 12) 2
Also can form C with C 3-7The ring of cycloalkyl representative,
R 2CH 2C (R 12) 2(CH 2) q, wherein m is 0-2 and each R 12Can be identical or different, (R wherein 12) 2Also can form C with C 3-7The ring of cycloalkyl representative,
(R 2) 2CH (CH 2) r, wherein r is 0-4 and each R 2Can be identical or different, (R wherein 2) 2
Also can form C with CH 3-7Cycloalkyl, C 7-12Bicyclic alkyl, C 10-16Tricyclic alkyl or full
With or undersaturated 5-7 unit is single or the ring of two heterocycles representative and this ring contain 1-3 heteroatoms that is selected from N, O and S,
R 2O (CH 2) P, wherein P is 1-4, or
R 2(COOR 3) (CH 2) r, wherein r is 1-4; R 2And R 14Representative independently of one another
Unsubstituted or by one or more C 1-4Alkyl, C 1-4Alkoxyl group, halogen, hydroxyl, COOH, CONH 2Or SO 2NH 2The phenyl that replaces,
Naphthyl,
Xenyl,
5-7 unit's monocycle or 9-10 unit's bicyclic heterocycles or non-heterocycle, they can be saturated or undersaturated,
Wherein heterocycle contains the heteroatoms that 1-4 is selected from N, O and S, and heterocycle wherein or non-heterocycle be unsubstituted or replaced by halogen or hydroxyl,
Unsubstituted or by one or more hydroxyls, COOH, amino, aryl, C 3-7Cycloalkyl, CF 3, N (CH 3) 2, C 1-3The C that alkylaryl, heteroaryl or Heterocyclylalkyl replace 1-7Alkyl, CF 3
The C that does not replace or replaced by aryl 3-7Cycloalkyl,
C 7-12Bicyclic alkyl, or
C 10-16Tricyclic alkyl; R 3Be
Hydrogen,
C 1-4Alkoxyl group,
C 3-7Cycloalkyl, or
Trifluoromethyl; X is
Hydrogen, or
Halogen;
A is selected from one of following groups:
Figure A9719576000031
Y wherein 1And Y 2Independent separately representative
Hydrogen,
C 1-4Alkyl,
C 1-4Alkoxyl group,
C 3-7Cycloalkyl,
Halogen, or
Trifluoromethyl; R 4Be
Hydrogen,
C 1-4Alkyl,
C 1-4Alkoxyl group,
Halogen,
-OCH 2CF 3，
-OCH 2CN，
-COOH,
-OH，
-COOR 6, R wherein 6Be C 1-4Alkyl,
-CONR 7R 8, R wherein 7And R 8Independent separately hydrogen or the C of representing 1-4Alkyl,
-(CH 2) 1-4OH,
-CH 2NHC(O)CH 3,
-CH 2NHC(O)CF 3,
-CH 2NHSO 2CH 3,
-SO 2NH 2,
-(CH 2) 1-4SO 2NR 7R 8,
-(CH 2) 1-4SO 2R 6,
5-7 unit's monocycle or 9-10 unit bicyclic heterocycles, they can be saturated or undersaturated heterocycles, it contains 1-4 heteroatoms that is selected from N, O and S,
-ZCH 2CO 2H,
-ZCH 2CO 2CH 3,
-ZCH 2R 14，
-ZCH 2CO 2(CH 2) 1-3CH 3,
-Z(CHR 9) 1-3C(O)NR 10R 11
Wherein
R 9Be hydrogen or C 1-4Alkyl,
R 10And R 11Independent separately representative
Hydrogen,
C 3-7Cycloalkyl,
Aryl,
Heteroaryl,
Heterocyclylalkyl,
-(CH 2) 1-2NCH 2CH 3，
Unsubstituted or by one or more hydroxyls, COOH, amino, aryl, heteroaryl or
The C that Heterocyclylalkyl replaces 1-4Alkyl, or
R 10And R 11The 4-7 unit cycloalkyl that forms not replacement together or replaced by hydroxyl, amino or aryl,
Wherein Z is O, S or CH 2R 5Be
Hydrogen,
Halogen,
C 1-4Alkyl,
C 1-4Alkoxyl group,
CF 3，
CN, or
CO 2NH 2, and R 12Be
Hydrogen,
Unsubstituted or by one or more C 1-4Alkyl, C 1-4Alkoxyl group, halogen, hydroxyl, COOH, CONH 2The phenyl that replaces,
Naphthyl,
Xenyl,
5-7 single heterocycle of unit or 9-10 unit two heterocycles, they can be saturated or undersaturated, wherein contain 1-4 heteroatoms that is selected from N, O and S,
Unsubstituted or by one or more hydroxyls, COOH, amino, aryl, heteroaryl or assorted
The C of cycloalkyl substituted 1-4Alkyl,
CF 3
C 3-7Cycloalkyl,
C 7-12Bicyclic alkyl, or
C 10-16Tricyclic alkyl.
2. the compound of claim 1 and its pharmacy acceptable salt, wherein R 3Be C 1-4Alkyl.
3. the compound of claim 2 and its pharmacy acceptable salt, wherein A be selected from following groups it
Y wherein 1And Y 2Independent separately hydrogen or the C of representing 1-4Alkyl; R 4Be
Hydrogen,
Halogen,
-OCH 2CN,
-OH,
-ZCH 2CO 2H, or
-Z(CHR 9) 1-3C(O)NR 10R 11
Wherein
R 9Be hydrogen or C 1-4Alkyl and
R 10And R 11Independent separately representative
Hydrogen,
C 3-7Cycloalkyl,
-(CH 2) 1-2NCH 2CH 3, or
C 1-4Alkyl,
Wherein Z is O, S or CH 2R 5Be
Hydrogen,
Halogen, or
CF 3。
4. the compound of claim 3 and its pharmacy acceptable salt, wherein W is hydrogen or R 1
5. the compound of claim 4 and its pharmacy acceptable salt, wherein R 1Be
R 2,
R 2(CH 2) mC (R 12) 2, wherein m is 0-3 and each R 12Can be identical or different,
R 2C (R 12) 2(CH 2) m, wherein m is 0-3 and each R 12Can be identical or different, (R wherein 12) 2
Also can form C with C 3-7The ring of cycloalkyl representative,
(R 2) 2CH (CH 2) r, wherein r is 0-4 and each R 2Can be identical or different, (R wherein 2) 2
Also can form C with CH 3-7Cycloalkyl, C 7-12Bicyclic alkyl, C 10-16Tricyclic alkyl or 5-7
Unit saturated or undersaturated ring and this ring single or representative of two heterocycles contain 1-3 heteroatoms that is selected from N, O and S, or
R 2O (CH 2) P, wherein P is 1-4; R 2And R 14Representative independently of one another
Unsubstituted or by C 1-4Alkyl, C 1-4Alkoxyl group, halogen, hydroxyl or SO 2NH 2Single or
Polysubstituted phenyl,
5-7 unit's monocycle or 9-10 unit two rings, they can be saturated or undersaturated heterocycle or non-heterocycle,
Wherein heterocycle contains 1-4 heteroatoms, heterocycle wherein or non-heterocycle that is selected from N, O and S
Be unsubstituted or replaced by halogen or hydroxyl,
Unsubstituted or by one or more hydroxyls, COOH, C 3-7Cycloalkyl, CF 3, N (CH 3) 2, C 1-3The C that alkylaryl, heteroaryl or Heterocyclylalkyl replace 1-7Alkyl,
CF 3Or
C unsubstituted or that replaced by aryl 3-7Cycloalkyl; And R 12Be
Hydrogen,
Unsubstituted or by one or more hydroxyls, COOH, amino, aryl, heteroaryl or assorted
The C of cycloalkyl substituted 1-4Alkyl.
6. the compound of claim 5 and its pharmacy acceptable salt, wherein A is
Figure A9719576000081
R wherein 5Be H, fluorine, chlorine, and R 10And R 11Independently be selected from separately
Hydrogen,
C 2H 5,
C 3H 5,
(CH 2) 2N(CH 3) 2,
C 3Cycloalkyl,
Figure A9719576000082
Figure A9719576000091
R wherein 4Be OH, chlorine, H ,-OCH 2CN, fluorine ,-OCH 2COOH, R 5Be chlorine or CF 3,
Figure A9719576000092
R 3Be CH 3Or CH 2CH 3X is H or chlorine; With W be
PhCH 2CH 2,
(CH 3) 3C-,
HOOCCH 2,
CF 3CH 2,
(CH 3) 2N(CH 2) 2,
PhCH 2O(CH 2) 2,
PhCH(CH 3),
PhCH 2CH(COOH),
CH 3(CH 2) 5,
PhCH 2,
H,
CH 3(CH 2) 4,
CH 3CH 2CH(CH 3)CH 2,
(Ph) 2CHCH 2,
PhCH 2CH(CH 3),
PhCH 2C(CH 3) 2,
PhCH(CH 3)CH 2,
(CH 3) 2CH,
PhCH(OH)CH 2,
PhC(CH 3)CH 2,
(Ph) 2CHCH 2,
Figure A9719576000101
Figure A9719576000111
Figure A9719576000121
Figure A9719576000131
7. the compound of claim 6 and its pharmacy acceptable salt are selected from following compound:
Figure A9719576000141
Figure A9719576000151
Figure A9719576000191
Figure A9719576000201
Figure A9719576000211
Figure A9719576000221
Figure A9719576000231
Figure A9719576000241
Figure A9719576000261
Figure A9719576000271
Figure A9719576000281
Figure A9719576000291
Figure A9719576000301
Figure A9719576000311
Figure A9719576000321
Figure A9719576000331
Figure A9719576000351
Figure A9719576000371
8. the compound of claim 7 and its pharmacy acceptable salt, wherein compound be selected from following,
Figure A9719576000391
Figure A9719576000401
9. the compound of claim 8 and its pharmacy acceptable salt, wherein compound is 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone.
10. the salt of claim 9 is 3-(2-styroyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone dihydrochlorides.
11. the salt of claim 10 exists with the crystal form A monohydrate form of polymorphic form.
12. the salt of claim 11, with its feature of differential scanning calorimetric curve mark, in an open cup, 5 ℃ of/minute heating rate, with under 5 ℃ in water logical nitrogen, be about 102 ℃ by the extrapolation initial temperature, 112 ℃ of peak Wen Weiyue and heat of association are shown as endothermic process for about 115J/gm, be about 171 ℃ by the extrapolation initial temperature then, 194 ℃ of peak Wen Weiyue and heat of association are shown as endothermic process for about 83J/gm; Be characterised in that with the x ray powder diffraction pattern spectrum d-spacing is 13.06,12.16,7.40,5.71,4.92,4.48,4.40,3.63,3.07,2.98,2.86 and 2.62 .
13. the salt of claim 10 exists with the crystal form B monohydrate form of polymorphic form.
14. the salt of claim 13, with its feature of differential scanning calorimetric curve mark, in an open cup, in water, lead to nitrogen 5 ℃ of/minute heating rate with under 5 ℃, by the extrapolation initial temperature is about 120 ℃, 132 ℃ of peak Wen Weiyue and heat of association are shown as thermo-negative reaction for about 123J/gm, are about 160 ℃ by the extrapolation initial temperature then, and 191 ℃ of peak Wen Weiyue and heat of association are shown as endothermic process for about 78J/gm; Be characterised in that with the x ray powder diffraction pattern spectrum d-spacing is 12.98,11.91,7.24,5.98,4.90,4.46,4.23,3.99,3.75,3.61,3.41,2.94,2.85 and 2.61 .
15. one kind is suppressed thrombotic composition in the blood, contains the compound and the pharmaceutically acceptable carrier of claim 1.
16. a method that suppresses zymoplasm in the blood comprises that adding right in blood requires 15 composition.
17. one kind is suppressed the method that the blood platelet aggregates forms, and comprises that adding right in blood requires 15 composition.
18. one kind is suppressed thrombotic method in the blood, comprises that adding right in blood requires 15 composition.
19. one kind is suppressed thrombotic method in the blood, comprises that adding right in blood requires 1 compound and fibrinogen deceptor antagonists.
20. the compound of a claim 1 or its pharmacy acceptable salt are being made Trombin inhibiting, are suppressing thrombosis, treating thrombosis or are being prevented application in the mammiferous thrombosis medicine.
21. the method for the treatment of or preventing mammiferous venous thromboembolism and pulmonary infarction comprises the composition to Mammals claim 15.
22. a treatment or the method for preventing mammiferous dvt to form comprise the composition to Mammals claim 15.
23. the method for the treatment of or preventing mammiferous cardiogenic thromboembolism comprises the composition to Mammals claim 15.
24. a treatment or the method for preventing the mammiferous thromboembolism outbreak of people and other comprise the composition to Mammals claim 15.
25. treatment or the prevention thrombotic method relevant with cancer chemotherapy with mammiferous cancer comprise the composition to Mammals claim 15.
26. the method for the treatment of or preventing mammiferous unstable angina comprises the composition to Mammals claim 15.
27. the method for the treatment of or preventing mammiferous myocardial infarction comprises the composition to Mammals claim 15.
28. the method for the cardiogenic thromboembolism that treatment or prevention are relevant with mammiferous auricular fibrillation comprises the composition to Mammals claim 15.
29. the method for the cardiogenic thromboembolism that treatment or prevention are relevant with mammiferous prosthetic heart valve comprises the composition to Mammals claim 15.
30. the method for the cardiogenic thromboembolism that treatment or prevention are relevant with mammiferous heart disease comprises the composition to Mammals claim 15.
31. one kind the treatment or prevent mammiferous atherosclerotic method, comprise composition to Mammals claim 15.
32. treat or prevent mammiferous heredity thrombotic disease for one kind, protein C deficiency disease for example, the protein s deficiency disease, the thrombotic method that the anticoagulin III is relevant with anticoagulin V Leiden comprises the composition to Mammals claim 15.
33. one kind the treatment or prevent for example relevant thrombotic method of systemic lupus erythematous of mammiferous acquired character thrombotic disease, comprise composition to Mammals claim 15.
34. a treatment or the method for preventing mammiferous ischemic heart disease comprise the composition to Mammals claim 15.
35. the method for the device blood coagulation that an attenuating contacts with blood tendency comprises the composition to this device coating claim 15.
36. treat or prevent Mammals in the inaccessible again method in skin transillumination coronary angioplasty process or after the process, comprise composition for one kind to Mammals claim 15.
37. a treatment or the method for preventing mammiferous restenosis behind skin transillumination coronary angioplasty comprise the composition to Mammals claim 15.
38. a treatment or prevent the method for the obturation that mammiferous coronary bypass grafting thing causes comprises the composition to Mammals claim 15.
39. the method for the treatment of or preventing mammiferous cerebrovascular occlusion disease comprises the composition to Mammals claim 15.
40. one kind keeps implanting the open method of mammiferous venous incubation, comprises the composition to Mammals claim 15.
41. one kind keeps the open method of mammalian body inner catheter, comprises the composition to Mammals claim 15.
42. a method for preparing 3-(2-phenylethyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone dihydrochloride crystal form A monohydrate may further comprise the steps:
A) be dissolved in 3-(2-phenylethyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone in the acetate and add aqueous hydrochloric acid;
B) reclaim the solid phase that obtains; With
C) remove wherein solvent.
43. the method for claim 42, wherein the amount of aqueous hydrochloric acid is that to make the final weight in wet base in the acetate be 1-5%.
44. a method for preparing 3-(2-phenylethyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone dihydrochloride crystal form B monohydrate may further comprise the steps:
A) 3-(2-phenylethyl amino)-6-methyl isophthalic acid-(2-amino-6-methyl-5-methylformamide ylmethyl pyridyl)-pyrazine ketone is dissolved in the hydrochloric acid solvent;
B) reclaim the solid phase that obtains; With
C) remove wherein solvent.
CN 97195760 1996-04-23 1997-04-18 Pyrazinone thrombin inhibitors Pending CN1222909A (en)

Priority Applications (1)

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CN 97195760 CN1222909A (en) 1996-04-23 1997-04-18 Pyrazinone thrombin inhibitors

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Application Number Priority Date Filing Date Title
GB9609714.2 1996-05-09
US60/043,009 1997-04-14
US60/016,041 1997-04-14
CN 97195760 CN1222909A (en) 1996-04-23 1997-04-18 Pyrazinone thrombin inhibitors

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CN104387376A (en) * 2014-10-30 2015-03-04 广东东阳光药业有限公司 Pyridone compound as well as composition and applications thereof
WO2015120777A1 (en) * 2014-02-14 2015-08-20 四川海思科制药有限公司 Pyridone or pyrimidone derivative, preparation method therefor and application thereof
WO2016011940A1 (en) * 2014-07-25 2016-01-28 江苏恒瑞医药股份有限公司 Indole-amide derivative, preparation method therefor and application thereof in medicine

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WO2015120777A1 (en) * 2014-02-14 2015-08-20 四川海思科制药有限公司 Pyridone or pyrimidone derivative, preparation method therefor and application thereof
CN105829298A (en) * 2014-02-14 2016-08-03 四川海思科制药有限公司 Pyridone or pyrimidone derivative, preparation method therefor and application thereof
US10174020B2 (en) 2014-02-14 2019-01-08 Sichuan Haisco Pharmaceutical Co., Ltd. Pyridone or pyrimidone derivative, preparation method therefor and application thereof
WO2016011940A1 (en) * 2014-07-25 2016-01-28 江苏恒瑞医药股份有限公司 Indole-amide derivative, preparation method therefor and application thereof in medicine
CN105658641A (en) * 2014-07-25 2016-06-08 江苏恒瑞医药股份有限公司 Indole-amide derivative, preparation method therefor and application thereof in medicine
CN104387376A (en) * 2014-10-30 2015-03-04 广东东阳光药业有限公司 Pyridone compound as well as composition and applications thereof

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