WO2000056715A1 - Process of preparing 3s-3-amino-3-aryl propionic acid and derivatives thereof - Google Patents

Process of preparing 3s-3-amino-3-aryl propionic acid and derivatives thereof Download PDF

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Publication number
WO2000056715A1
WO2000056715A1 PCT/US2000/007492 US0007492W WO0056715A1 WO 2000056715 A1 WO2000056715 A1 WO 2000056715A1 US 0007492 W US0007492 W US 0007492W WO 0056715 A1 WO0056715 A1 WO 0056715A1
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WIPO (PCT)
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formula
compound
acid
pyridyl
salt
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PCT/US2000/007492
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English (en)
French (fr)
Inventor
Lorraine Scott
Frank John Villani, Jr.
Donald G. Walker
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Ortho-Mcneil Pharmaceutical, Inc.
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Application filed by Ortho-Mcneil Pharmaceutical, Inc. filed Critical Ortho-Mcneil Pharmaceutical, Inc.
Priority to AU39063/00A priority Critical patent/AU3906300A/en
Priority to HR20010766A priority patent/HRP20010766A2/hr
Priority to JP2000606577A priority patent/JP2002540100A/ja
Priority to SK1358-2001A priority patent/SK13582001A3/sk
Priority to EP00918212A priority patent/EP1163222A1/en
Priority to BR0009277-0A priority patent/BR0009277A/pt
Priority to NZ514383A priority patent/NZ514383A/xx
Priority to MXPA01009621A priority patent/MXPA01009621A/es
Priority to KR1020017012068A priority patent/KR20020016617A/ko
Priority to CA002367969A priority patent/CA2367969A1/en
Publication of WO2000056715A1 publication Critical patent/WO2000056715A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom

Definitions

  • the present invention is directed to a process for preparing 3S-3-amino-3-aryl propionic acid and derivatives thereof .
  • R 1 is aryl , heteroaryl, substituted aryl or substituted heteroaryl and R 2 is hydrogen, alkyl or aralkyl, or acid addition salts thereof, are useful as intermediates in the synthesis of compounds described in WO 97/41102, which is incorporated by reference herein.
  • Compounds described in WO 97/41102 are antagonists of the platelet fibrinogen receptor (gp Ilb/IIIa antagonist) and thus are useful for treating platelet-mediated thrombotic disorders such as arterial and venous thrombosis, acute myocardial infarction, reocclusion following thrombolytic therapy and angioplasty, inflammation, unstable angina and vaso-occlusive disorders.
  • gp Ilb/IIIa antagonist the platelet fibrinogen receptor
  • Known methods for preparing compounds of Formula I include an asymmetric Michael addition of lithium N- (trimethylsilyl) - (R) -phenethylamide to ethyl 3-pyridyl acrylate to give the ethyl ⁇ -aminoester [Rico, J.G. ; Landmark, R.J.; Rogers, T.E.; Bovy, P.R. J. Org. Chem. 1993, 58 , 7948]. This process results in inefficient formation of lithium amide and difficult removal of N- - methylbenzyl group .
  • J. Org. Chem. vol. 61, p. 2222 discloses a process wherein the lithium enolate of ethyl acetate is added to an enantiomerically pure sulfinimine, the product of which is purified by chromatography and deprotected under acidic conditions to afford the ⁇ -amino ester in greater than 90% ee .
  • the need for chromatography makes this process unattractive for large-scale production.
  • WO 98/02410 discloses a process of stereoselective addition of the Reformatsky reagent prepared from t- butylbromoacetate to the enantiomerically pure imine prepared from 3-pyridine carboxaldehyde and (R)-2- phenylglycinol .
  • Oxidative cleavage of the N- (l-phenyl-2- hydroxy ethyl) group with NaI0 4 in ethanol followed by acid hydrolysis affords the enantiomerically pure t-butyl ⁇ -amino ester.
  • Use of oxidizing agents makes this process unattractive for large-scale production.
  • WO 97/41102 discloses enzymatic resolution of the ( ⁇ ) ⁇ - phenylacetamido acid using penicillin amidase to afford the S-acid. This process, which utilizes enzymes, is inefficient and impractical for large scale production.
  • the invention is directed to a process of making a compound of formula I, as described above, comprising reacting a compound of formula II,
  • R 1 is aryl, heteroaryl, substituted aryl or substituted heteroaryl, at a pH range of between about 7 and about 11, to form a compound of formula III
  • the invention is directed to a novel crystal form of (3S) -3- [ ( tert-butoxy) carbonyl] amino- 3 - [3 ' -pyridyl] propionic acid, the intermediate of formula Va wherein Boc is ( ert-butoxy) carbonyl designated Form 2 and characterized by its x-ray powder diffraction patterns.
  • alkyl whether used alone or as part of a substituent group, shall include straight and branched chains containing 1 to 10 carbon atoms.
  • alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, n-hexyl and the like.
  • alkoxy shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n- hexyloxy and the like.
  • aryl shall refer to unsubstituted aromatic groups such as phenyl , napthyl , and the like.
  • the aryl group may be substituted with one or two substituents .
  • Suitable substituents on the aryl group are selected independently from the group consisting of halogen, alkyl, alkoxy, aralkyl , -NR 3 2 , wherein R 3 is alkyl; and R 4 CONH, wherein R 4 is phenyl or alkyl.
  • heteroaryl shall denote any five or six membered monocyclic ring structure containing at least one heteroatom selected from 0, N and S or a bicyclic ring system wherein the heteroaryl is fused to an aryl group.
  • heteroaryl groups include, but are not limited to, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridazinyl, furanyl, pyranyl, imidazolyl , thiophenyl , oxazolyl , isothiazolyl , isoxazolyl, furazanyl , benzothienyl , benzofuranyl , indolyl, isoindolyl, indolizinyl, indazolyl, purinyl , isoquinolyl, quinolyl , isothiazolyl, and the like.
  • the heteroaryl may be substituted with one or two substituents. Suitable substituents on the heteroaryl group are selected independently from the group consisting of halogen, alkyl, alkoxy, aralkyl, -NR 3 2 , wherein R 3 is alkyl; and R 4 C0NH, wherein R 4 is phenyl or alkyl .
  • the heteroaryl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure, except when the heteroaryl contains only one heteroatom, then the heteroaryl must be attached at a carbon atom.
  • the heteroaryl is pyridyl.
  • the preferred heteroaryl may be substituted with one or two substituents as described above.
  • the pyridyl is unsubstituted.
  • aralkyl shall mean any alkyl group substituted with an aryl group such as phenyl, napthyl and the like.
  • halogen shall mean chlorine, bromine, fluorine and iodine.
  • an acid of pKa less than or equal to three includes monochloroacetic, dichloroacetic, trichloroacetic, hydrochloric, hydrobromic, hydroiodic, perchloric, picric, nitric, sulfuric, phosphoric, methanesulfonic, tosic, trifluoromethanesulfonic, trifluoracetic, potassium bisulfate, sodium bisulfate, citric and the like.
  • inorganic base shall mean a base having a monovalent cation component, such as lithium carbonate, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, tetrabutyl ammonium hydroxide, trimethylbenzyl ammonium hydroxide and the like.
  • alkyl alcohol shall denote a hydroxy derivative of the above described straight or branched chain alkyl groups .
  • S and R shall denote the presence of a stereogenic center having the S or R configuration.
  • R 1 is unsubstituted phenyl, substituted phenyl, unsubstituted pyrimidyl, substituted pyrimidyl, unsubstituted pyridyl, substituted pyridyl, unsubstituted napthyl or substituted naphthyl .
  • Suitable substituents are selected independently from the group consisting of halogen, alkyl, alkoxy, aralkyl, -NR 3 2 , wherein R 3 is alkyl, and R 4 CONH, wherein R 4 is phenyl or alkyl.
  • R 1 is 2 -pyridyl, 3 -pyridyl, 4- pyridyl, 6-methylpyridyl , 5-bromopyridyl , 6-chloropyridyl or 5, 6-dichloropyridyl .
  • R 1 is 3-pyridyl.
  • R 2 is alkyl, more preferably methyl or ethyl, most preferably methyl .
  • the acid is an acid of pKa less than or equal to three, as defined above, other than potassium bisulfate, sodium bisulfate and citric acid.
  • the compound of formula I is a hydrochloric acid addition salt.
  • the present invention is directed to a process of making a compound of formula I
  • a compound of formula II a known compound or compound prepared by known methods [Profft, V.E.; Becker, F.J., J. Prakt . Chem. 1965, 30 (1 -2) , 18] is reacted with di- ert-butyl dicarbonate in an organic solvent such as 1,4-dioxane, tert-butanol or tetrahydrofuran, preferably tetrahydrofuran, with addition of an aqueous solution of an inorganic base, as previously defined, preferably sodium hydroxide, at a temperature in the range of about 0° to about 100°C, preferably at a temperature between about 0° and about 35°C, at a pH in the range of about 7 to about 11, preferably at a pH of between about 9.9 and about 10.2, to form the compound of formula III.
  • an organic solvent such as 1,4-dioxane, tert-butanol or tetrahydrofuran, preferably te
  • the desired compound of formula III is isolated by removal of the organic solvent by evaporation under reduced pressure, followed by acidification of the remaining aqueous solution by addition of an acid of pKa of less than or equal to three, as defined above, preferably sodium bisulfate or citric acid, to a pH of between about 3.5 and about 6.5, preferably to a pH of about 3.8, filtration or extraction with an organic solvent, such as methylene chloride, 1, 2-dichloroethane, chloroform, dioxane, toluene, alkyl acetate such as ethyl acetate or mixtures thereof, preferably ethyl acetate, and optionally removal of the organic solvent by evaporation under reduced pressure.
  • an organic solvent such as methylene chloride, 1, 2-dichloroethane, chloroform, dioxane, toluene, alkyl acetate such as ethyl acetate or mixtures thereof, preferably ethyl
  • the compound of formula III is reacted with at least 0.5 equivalents of (IR, 2S) -(-) ephedrine, preferably 0.5 to 1.0 equivalent of (IR, 2S) -(-) ephedrine, in an alkyl acetate solvent, preferably ethyl acetate, at a temperature from about 25° to about 78°C, to form the salt of formula IV.
  • the salt of formula IV is reacted with an inorganic base, as previously defined, preferably, sodium hydroxide, in water to form a carboxylate salt of the compound of formula V (dissolved in the aqueous solution) .
  • the desired compound of formula V is isolated by removal of the (IR, 2S) -(-) ephedrine by extraction with an organic solvent which is largely immiscible with water such as methylene chloride, 1 , 2-dichloroethane, alkyl acetate or aromatic hydrocarbon, such as toluene, or ketone, such as methyl-isobutyl ketone, followed by acidification of the remaining aqueous solution by addition of an acid of pKa less than or equal to three, as defined above, preferably sodium bisulfate or sulfuric, to a pH of between about 3.5 and about 6.5, preferably to a pH of about 3.8, and filtration to afford the compound of formula V.
  • an inorganic base as previously defined,
  • the aqueous solution containing the compound of formula V is heated to a temperature in the range of about 70-80°C prior to extraction with the toluene and cooled to about room temperature after extraction with the toluene and prior to acidification.
  • the compound of formula V is reacted with an acid of pKa less than or equal to three, as defined above, other than potassium bisulfate, sodium bisulfate and citric acid, preferably hydrochloric acid, in a C ⁇ -C ⁇ 0 alkyl alcohol, preferably methanol , at a temperature less than about 25°C, to form the corresponding compound of formula I , which is isolated by conventional methods, such as filtration.
  • Form 2 of the compound of formula Va may be characterized by its x-ray powder diffraction pattern utilizing a Siemens D5000 diffractometer and the following system conditions:
  • reaction flask was charged with 300g (264.3 mL) (2.8 mol) of cold 3-pyridine carboxaldehyde and 60 mL of absolute ethanol. A reaction temperature of 13 °C resulted. With good stirring, 291.36g (2.8 mol) malonic acid was added in one portion (solid addition) over about 2 min, followed by 90 mL ethanol. Immediately following this addition, 323.73g (4.2 mol) ammonium acetate was added over about 10 min (solid addition), followed by 250 mL ethanol. During this addition, the reaction cooled to about 38°C. The bright orange mixture was heated to and maintained under gentle reflux for 5h. The heating mantle was removed, and the mixture was allowed to cool to ambient temperature overnight.
  • the solid was collected by suction filtration (50 min) and washed with 400 mL methanol (30 min) .
  • the filtercake was washed with a second portion of 200 mL methanol (10 min) .
  • the filtercake was partially dried under suction for about 60 min.
  • the solids were dried in vacuo at 35-40°C to constant weight (38h) to yield 303.38g (65.2%) 3-amino- 3- (3 ' -pyridyl) propionic acid as a white powder.
  • the reaction flask was charged with 594.52g of a mixture of 3 -amino-3- (3 ' -pyridyl) propionic acid and trans- 3- (3 ' -pyridyl) acrylic acid and 1,600 L methanol. With good stirring, the slurry was heated to and maintained under gentle reflux for 1.25h. The slurry was filtered while hot, and was washed with 2 x 80 mL, then 160 mL warm (>50°C) methanol (30 min) . The filtercake was partially dried under suction for about 1.25h. Further drying in vacuo at 35-40°C for 21.5h gave 540.22g (90.9% weight recovery) product as a white powder.
  • the reaction flask was charged with 540.12g of a mixture of 3 -amino-3- (3 ' -pyridyl) propionic acid and trans- 3- (3 ' -pyridyl) acrylic acid and 1,600 mL methanol. With good stirring, the slurry was heated to and maintained under gentle reflux for 5-6h. The slurry was filtered while hot, and was washed with 3 x 160 mL warm (>50°C) methanol (35 min) . The filtercake was partially dried under suction for about 1.75h yielding 814.45g (>100% weight recovery) product as a white solid (wet cake) .
  • a 1L constant pressure addition funnel was charged with 407 mL tetrahydrofuran (THF) and 365.3 mL (1.54 mol) di- tert-butyl dicarbonate.
  • a second 1L constant pressure addition funnel was charged with 771 mL (1.54 mol) 2M sodium hydroxide solution.
  • the tetrahydrofuran solution of the di- tert-butyl dicarbonate was added in a slow stream over about 25 min with pH monitoring. Once the pH reached about 9.90, concomitant addition of the 2M sodium hydroxide solution was started. External cooling was applied to maintain the reaction temperature at ⁇ 35°C.
  • the reaction was maintained at pH 9.9-10.2 during the addition of the tetrahydrofuran/di- ert-butyl dicarbonate solution. Following its addition, the addition funnel which contained the dicarbonate/tetrahydrofuran solution was rinsed forward with 81 mL fresh tetrahydrofuran. Addition of the remaining amount of 2M sodium hydroxide solution was continued so as to maintain a pH in the range of 9.9-10.2. Following addition of the remaining amount of 2M sodium hydroxide solution, the pH probe was removed and the reaction was stirred at ambient temperature for 17h. With good stirring, the pH was lowered from 7.68 at 21°C to 3.87 at 27°C by portionwise addition of 393.
  • the reaction beaker was charged with 303.47g (0.67 mol) (3S) -3- [ ( ert-butoxy) carbonyl] amino-3- (3' - pyridyl) propionic acid, (IR, 2S) -(-) -ephedrine salt and 792 mL milliquat water. After stirring 5 min, the pH of the slurry was 7.32 at 21°C. A total of 595 mL (0.60 mol) 1M sodium hydroxide solution was added in a slow pour over about 2 min with good stirring to a pH of 11.00 at 23 °C.
  • the slurry was warmed to ambient temperature and stirred for 2h.
  • the slurry was cooled 30 min in an ice water bath.
  • the solid was collected by suction filtration and washed with 2 x 65 mL cold (0-5°C) methanol (5 min) .
  • the filtercake was partially dried under suction for about 20 min. Further drying in vacuo at ambient temperature for 14h gave 105.21g (77.9%) product as a white, crystalline powder.
  • the aqueous phase was extracted with toluene (4 x 17.4 g) at 70°C-80°C.
  • the aqueous phase was then cooled to 15°C-25°C, filtered, and the filter washed with water (2.5 g) .
  • To the unified filtrates was added a solution of sodium hydrogensulphate monohydrate (9.50 g, 0.069 mol) in water (12.1 g) , resulting in a pH of 3.6-3.9 and crystallized product.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/US2000/007492 1999-03-22 2000-03-21 Process of preparing 3s-3-amino-3-aryl propionic acid and derivatives thereof WO2000056715A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
AU39063/00A AU3906300A (en) 1999-03-22 2000-03-21 Process of preparing 3s-3-amino-3-aryl propionic acid and derivatives thereof
HR20010766A HRP20010766A2 (en) 1999-03-22 2000-03-21 Process of preparing 3s-3-amino-3-aryl propionic acid and derivatives thereof
JP2000606577A JP2002540100A (ja) 1999-03-22 2000-03-21 ３ｓ−３−アミノ−３−アリールプロピオン酸を製造する方法およびそれの誘導体
SK1358-2001A SK13582001A3 (sk) 1999-03-22 2000-03-21 Spôsob prípravy kyseliny 3S-3-amino-3-arylpropiónovej a jej derivátov
EP00918212A EP1163222A1 (en) 1999-03-22 2000-03-21 Process of preparing 3s-3-amino-3-aryl propionic acid and derivatives thereof
BR0009277-0A BR0009277A (pt) 1999-03-22 2000-03-21 Processo de preparação de ácido propiÈnico de 3s-3-amino-3-arila e derivados deste
NZ514383A NZ514383A (en) 1999-03-22 2000-03-21 Process of preparing 3S-3-amino-3-aryl propionic acid and derivatives thereof
MXPA01009621A MXPA01009621A (es) 1999-03-22 2000-03-21 Procedimiento para la preparacion de acido 3s-3-amino-3-aril propionico, y derivados del mismo.
KR1020017012068A KR20020016617A (ko) 1999-03-22 2000-03-21 3ｓ-3-아미노-3-아릴 프로피온산 및 그의 유도체의 제조방법
CA002367969A CA2367969A1 (en) 1999-03-22 2000-03-21 Process of preparing 3s-3-amino-3-aryl propionic acid and derivatives thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US12622799P 1999-03-22 1999-03-22
US60/126,227 1999-03-22

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EP (1) EP1163222A1 (en10)
JP (1) JP2002540100A (en10)
KR (1) KR20020016617A (en10)
CN (1) CN1362948A (en10)
AU (1) AU3906300A (en10)
BR (1) BR0009277A (en10)
CA (1) CA2367969A1 (en10)
CZ (1) CZ20013403A3 (en10)
HR (1) HRP20010766A2 (en10)
HU (1) HUP0201347A3 (en10)
MX (1) MXPA01009621A (en10)
NZ (1) NZ514383A (en10)
RU (1) RU2228929C2 (en10)
SK (1) SK13582001A3 (en10)
WO (1) WO2000056715A1 (en10)
YU (1) YU74401A (en10)

Cited By (3)

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WO2002096424A1 (en) * 2001-05-25 2002-12-05 Queen's University At Kingston Hetereocyclic beta-aminoacids and their use as anti-epileptogenic agents
US6610855B2 (en) 1999-03-22 2003-08-26 Mcneil Pharmaceutical, Inc. Synthesis of 3-amino-3-aryl propanoates
US7268164B2 (en) 1997-03-12 2007-09-11 Queens University At Kingston Anti-epileptogenic agents

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Publication number Priority date Publication date Assignee Title
HUP0201347A3 (en) * 1999-03-22 2002-12-28 Ortho Mcneil Pharm Inc Process of preparing 3s-3-amino-3-aryl propionic acid and derivatives thereof
CN101982458B (zh) * 2010-09-14 2013-11-06 北京欧凯纳斯科技有限公司 3-氨基-3-芳基丙酸及其制备方法

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WO1997041102A1 (en) * 1996-05-01 1997-11-06 Ortho Pharmaceutical Corporation Carboxamide derivatives of pyrrolidine, piperidine and hexahydroazepine for the treatment of thrombosis disorders

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ZABLOCKI J A ET AL: "POTENT IN VITRO AND IN VIVO INHIBITORS OF PLATELET AGGREGATION BASED UPON THE ARG-GLY-ASP SEQUENCE OF FIBRINOGEN. (AMINOBENZAMIDINO)SUCCINYL (ABAS) SERIES OF ORALLY ACTIVE FIBRINOGEN RECEPTOR ANTAGONISTS", JOURNAL OF MEDICINAL CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 38, no. 13, 1995, pages 2378 - 2394, XP000579664, ISSN: 0022-2623 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7268164B2 (en) 1997-03-12 2007-09-11 Queens University At Kingston Anti-epileptogenic agents
US6610855B2 (en) 1999-03-22 2003-08-26 Mcneil Pharmaceutical, Inc. Synthesis of 3-amino-3-aryl propanoates
WO2002096424A1 (en) * 2001-05-25 2002-12-05 Queen's University At Kingston Hetereocyclic beta-aminoacids and their use as anti-epileptogenic agents

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RU2228929C2 (ru) 2004-05-20
HUP0201347A3 (en) 2002-12-28
US20020068829A1 (en) 2002-06-06
KR20020016617A (ko) 2002-03-04
NZ514383A (en) 2004-01-30
MXPA01009621A (es) 2003-07-21
US20040063960A1 (en) 2004-04-01
AU3906300A (en) 2000-10-09
YU74401A (sh) 2004-07-15
HRP20010766A2 (en) 2002-12-31
US20030176471A1 (en) 2003-09-18
EP1163222A1 (en) 2001-12-19
CN1362948A (zh) 2002-08-07
CZ20013403A3 (cs) 2002-07-17
US6673926B2 (en) 2004-01-06
BR0009277A (pt) 2002-02-05
SK13582001A3 (sk) 2003-02-04
CA2367969A1 (en) 2000-09-28
JP2002540100A (ja) 2002-11-26

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