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WO2008128058A1 - Nouveaux complexes de bisaminothiolate de gallium pour imagerie myocardique - Google Patents

Nouveaux complexes de bisaminothiolate de gallium pour imagerie myocardique Download PDF

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Publication number
WO2008128058A1
WO2008128058A1 PCT/US2008/060054 US2008060054W WO2008128058A1 WO 2008128058 A1 WO2008128058 A1 WO 2008128058A1 US 2008060054 W US2008060054 W US 2008060054W WO 2008128058 A1 WO2008128058 A1 WO 2008128058A1
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Prior art keywords
alkyl
alkoxy
complex
compound
gallium
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PCT/US2008/060054
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English (en)
Inventor
Hank F. Kung
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The Trustees Of The University Of Pennsylvania
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Publication of WO2008128058A1 publication Critical patent/WO2008128058A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/30—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/003—Compounds containing elements of Groups 3 or 13 of the Periodic Table without C-Metal linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention is directed to novel ligands and radioisotopic complexes useful as imaging agents for positron emission tomography (PET).
  • PET positron emission tomography
  • One aspect is related to novel gallium complexes having excellent myocardial uptake and retention, due to the lipid-solubility and cationic nature of such novel complexes.
  • the present invention is directed to novel radioisotopic complexes for positron emission tomography (PET) and, more specifically, to novel gallium complexes with enhanced lipid- solubility which possess utility as myocardial imaging agents.
  • PET positron emission tomography
  • PET is a technique whereby a three-dimensional reconstruction of in vivo radionuclide distribution is possible, providing images that map and quantitate tissue activity levels.
  • the demand for new and novel positron-emitting radiopharmaceuticals continues to increase as more institutions acquire instrumentation for PET imaging.
  • Gallium-67 and Gallium-68 there are two gallium radioisotopes: Gallium-67 and Gallium-68. Both possess nuclear properties that make them attractive for use in nuclear medicine.
  • the first, Gallium-67 is cyclotron-produced from Zn-68, has a half life of 78 hours and is commercially available as gallium chloride and gallium citrate.
  • the second, Gallium-68 has the distinction of being one of the few short-lived positron emitting radionuclides available from a parent/daughter generator system, 68 Ge/ 68 Ga.
  • Such generator systems for producing positron emitting isotope without an on-site cyclotron have been reported (Ehrhardt GJ, Welch MJ., J Nucl Med.
  • solid oxides such as, TiO 2 , ZrO 2 or SiO 2
  • a tin dioxide/1 N HCl generator also provided a sterile solution of Gallium-68 in ionic form, ready for use in the preparation of many radiopharmaceuticals see Loc'h C, Maziere B, Comar D. A new generator for ionic gallium-68. J Nucl Med. 1980;21 : 171-3.
  • the criteria for an ideal 68 Ge/ 68 Ga generator system include: 1) high efficient separation of 68 Ga from the column; 2) minimum amount of "parent breakthrough" - low level Of 68 Ge in the eluent; 3) stability of the column over time. All of the reported 68 Ga/ 68 Ge generator systems meet the basic criteria listed above; however, one major unmet need in the field of nuclear medicine is the lack of FDA approved commercial 68 Ge/ 68 Ga generator system for human use, which limits the potential for developing 68 Ga labeled radiopharmaceuticals for PET imaging see Breeman WA, Verbruggen AM.
  • the (68)Ge/(68)Ga generator has high potential, but when can we use (68)Gallium-labelled tracers in clinical routine? Eur J Nucl Med MoI Imaging. 2007.
  • Gallium complexes OfN 2 S 2 bisaminoethanethiolate,
  • Kung HF Liu B-L, Mankoff D, Kung M-P, Billings JJ, Francesconi LC, Alavi A.
  • a new myocardial imaging agent synthesis, characterization, and biodistribution of gallium-68-B AT-TECH. J Nucl Med. 1990;31 :1635-40, Francesconi LC, Liu B-L, Billings JJ, Carroll PJ, Graczyk G, Kung HF.
  • Synthesis, characterization and solid state structure of a neutral gallium(III) amino thiolate complex a potential radiopharmaceutical for PET imaging.
  • radioisotopic complexes also depend on the biodistribution properties of the specific radiopharmaceutical agents.
  • high definition imaging of heart tissue requires not only efficient myocardial uptake of the radiopharmaceutical agent but, as well, retention of the radioactivity in the targeted issue.
  • the ideal radioisotopic complex will exhibit a biodistribution pattern which will provide higher concentrations of the radioisotopic complex in the targeted tissue relative to the blood levels and relative to its concentration in adjacent non-targeted tissues.
  • radioisotopic complex designed for imaging the heart are high myocardial tissue uptake, good heart/blood ratios, and prolonged retention of the radiopharmaceutical concentrations in the myocardial tissues relative to that in the blood and of other tissues/organs in the thoracic cavity.
  • Gallium bisaminoethanethiolate complexes have a plus one charge.
  • the stabilizing counterion dissociated to form a Gallium bisaminothiolate (GaBAT) a plus one charge ion. It is believed that the highly lipophilic plus one charged complexes become trapped in the myocardial tissue similar to those 99m Tc myocardial imaging agents ( 99m Tc-MIBI and Tetrafosamine).
  • One aspect of the present invention is related to novel radioisotopic complexes having suitable organ uptake and retention.
  • One aspect is directed to Gallium radioisotropic complexes of tricyclohexyl analogs of bisaminoethanethiolate having improved myocardial uptake and retention.
  • a need continues to exist in the art for radioactive metal complexes useful for imaging.
  • a need continues to exist in the art for imaging agents for myocardial perfusion studies using PET.
  • the present invention is directed to compounds of Formula I and radioisotopic complexes of Formula II, wherein bisaminothiolate tricyclohexyl ligands and Gallium-68 bisaminothiolate tricyclohexyl complexes are generated.
  • Such complexes are highly lipophilic, possessing two additional methylene moieties with a plus one charge, whereby the radioactive complex is trapped in the myocardial tissue at an with increased incident, hence enhancing it's myocardial perfusion and retention and subsequent efficacy as an imaging agent.
  • This invention therefore relates to compounds of Formula I:
  • each of A 1 , A 2 and A 3 are the same or different, and are optionally substituted cycloalkyl, R 1 through R 6 are independently hydrogen or alkyl, whilst R 7 and R 8 are independently hydrogen or alkyl; and R P is hydrogen or a sulfhydryl protecting group.
  • a 1 , A 2 and A 3 are the same or different, and are optionally substituted cycloalkyl.
  • R 1 through R 6 are independently hydrogen or alkyl and R 7 and R 8 are independently hydrogen or alkyl and M is a metal, where in some embodiments is M is a radioisotope.
  • a " is a monovalent counterion, wherein some embodiments the counterion is a halide.
  • the complexes are radioisotopic complexes and imaging agents, with increased lipophilicity and a + 1 cationic charge.
  • complexes of Formula II are lipid-soluble, and that the compounds exhibit high uptake in the heart as well as in the liver, providing further evidence that the radioisotopic complexes of the present invention should therefore be useful as tracers for myocardial perfusion imaging.
  • the complexes of the invention also offer the advantage of being available to institutions not having the use of an on-site cyclotron.
  • kits for formation of radiodiagnostic imaging agents comprising a compound of Formula I provided in a vial.
  • One or more excipients for forming a chlelate can also be provided.
  • kits for formation of radiodiagnostic imaging agents comprising a compound of Formula I provided in a vial.
  • excipients for forming a chlelate can also be provided.
  • kits for formation of radiodiagnostic imaging agents comprising a compound of Formula I provided in a vial.
  • excipients for forming a chlelate can also be provided.
  • Another aspect of the present invention is directed to methods of radioimaging comprising administering a chelate of Formula II to a subject and thereafter imaging.
  • a preferred aspect is directed to myocardial perfusion imaging, employing a radiogallium complex of Formula II, and imaging using PET.
  • FIG. 1 illustrates a preferred retro-synthetic route of compounds of Formula I from synthons of
  • FIG. 2 provides a scheme for a preferred synthetic route for synthesizing compounds of
  • FIG. 3 provides a scheme for a preferred synthetic route for synthesizing compounds of
  • FIG. 4 A depicts a TLC profile of a preferred embodiment of the present invention, complex
  • FIG. 4B provides the structure of a preferred embodiment of the present invention, complex
  • FIG. 4C provides the structure of preferred embodiment of the present invention, complex 67 / G- a-
  • FIG. 4D provides a comparison of the heart uptake of two embodiments of the present invention
  • FIG. 5 Autoradiography of a preferred embodiment of the present invention, 67 / Ga-B, in healthy Sprague Dawley rat heart (upper row) and in a Sprague Dawley rat which underwent a procedure to have the anterior branch of the left main coronary artery permanently ligated (lower row).
  • FIG.6 X-ray Crystal (Ortep diagram) of the a preferred embodiment of the present invention, complex 67 Ga-B
  • the present invention is directed to novel compounds useful for forming radioisotopic complexes, radioisotopic complexes, their use as imaging agents for positron emission tomography (PET) and, in certain embodiments, to novel gallium complexes with enhanced myocardial uptake and retention, due to the lipid-solubility and cationic nature of such novel complexes.
  • PET positron emission tomography
  • Radioisotopic complexes of Formula II are prepared from radioisotopes such as, for example, 68 Gallium or 67 Gallium, wherein the complexes formed are stable 1 charged cations.
  • the radioisotopic complexes of the present invention display enhanced lipophilicity and enhanced uptake in the heart and greater retention in said tissue, therefore such Gallium complexes will be useful as myocardial profusion imaging agents.
  • Such examples of radioisotopes are mentioned only by way of illustration and without implied limitation, 6 8 Gallium and 67 Gallium radioisotopes are preferred.
  • the present invention is directed to compounds of Formula I, or pharmaceutically acceptable salts thereof; wherein A 1 , A 2 and A 3 are the same or different cycloalkyl, wherein at least one of A 1 , A 2 or A 3 is substituted, R 1 through R 6 are independently hydrogen or alkyl and R 7 and R 8 are independently hydrogen or alkyl; and R P is hydrogen or sulfhydryl protecting group.
  • a 1 , A 2 and A 3 are independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, any of which is optionally substituted.
  • a 1 , A 2 and A 3 are independently selected from the group consisting of cyclopentyl, cyclohexyl or cycloheptyl, which are optionally substituted.
  • the compound A 1 , A 2 and A 3 are optionally mono, di or tri substituted with substituents that are independently amino, hydroxy, nitro, nitroso, cyano, isocyano, azido, thiol, carboxy, (Ci_ 6 )alkyl, amino(Ci_ 6 )alkyl, hydroxy(Ci_ 6 )alkyl, halo(Ci_ 6 )alkyl, cyano(Ci_ 6 )alkyl, thio(Ci_ 6 )alkyl, carboxy(Ci_ 6 )alkyl, aryl(Ci_ 6 )alkyl, (Ci_ 6 )alkoxy(Ci_ 6 )alkyl, (C 2 _ 6 )alkeny
  • a 1 , A 2 and A 3 are cyclohexyl optionally substituted by hydroxy, alkoxy, fluoroalkoxy, hydroxyalkoxy, alkoxyalkoxy, fluoroalkoxyalkoxy, 18 fluoroalkoxyalkoxy or hydroxyalkoxyalkoxy.
  • a 1 is unsubstituted.
  • a 2 is unsubstituted.
  • A is mono substituted at the 2 position or mono substituted at the 3 position.
  • A is mono substituted at the 4 position and substituted with a substituent that is methoxy, 3-fluoropropoxy, 3-hydroxypropoxy and X- ((CR a R b )2 ⁇ ) n , wherein X is halo or hydroxy and R a and R b are each independently hydrogen or C i_4 alkyl and n is an integer from 1 to 10, preferably 1 to 6 and most preferably 2-4.
  • R 1 through R 8 are independently hydrogen or (d_ 6 )alkyl. In some embodiments R 1 through R 8 are independently hydrogen, methyl, ethyl, propyl, a butyl, pentyl and hexyl, wherein the group may be straight chained or branched and in further embodiments R 1 through R 8 are each hydrogen. In some embodiments of the compound of Formula I, R p is hydrogen, methoxymethyl, methoxyexthoxyethyl, p- methoxybenzyl and benzyl. In some embodiments, each R p is hydrogen.
  • the present invention is also directed to the production of metal chelates whereby in some embodiments, a metal chelate is produced by mixing a compound of Formula I with a metal salt.
  • the metal salt is a salt of a metal that is Technetium-99m, Rhenium-188, Cobalt-57, cold Gallium, Gallium-68, Gallium-67, Indium-111, Iodine-123, Krypton-81m, Rubidium-82, Strontium-92, or Thallium-201.
  • the metal is gallium.
  • the metal chelate is stabilized by counterion that is halide, sulfate, nitrate, carboxylate or phosphate. In some embodiments said counterion is halide.
  • the present invention is also directed to complexes of Formula II or pharmaceutically acceptable salts thereof; wherein A 1 , A 2 and A 3 are the same or different cycloalkyl, wherein at least one of A 1 , A 2 or A 3 is substituted, R 1 through R 6 are independently hydrogen or alkyl and R 7 and R 8 are independently hydrogen or alkyl, and M is a metal
  • a 1 A 2 and A 3 are independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, any of which are optionally substituted.
  • a 1 , A 2 and A 3 are independently cyclopentyl, cyclohexyl or cycloheptyl, which are optionally substituted. In some embodiments A 1 , A 2 and A 3 are optionally mono, di or tri substituted with substituents that are amino, hydroxy, nitro, nitroso, cyano, isocyano, azido, thiol, carboxy, (Ci_ 6 )alkyl, amino(Ci_ 6 )alkyl, hydroxy(Ci_ 6 )alkyl, halo(Ci_ 6 )alkyl, cyano(Ci_ 6 )alkyl, thio(Ci_ 6 )alkyl, carboxy(Ci_ 6 )alkyl, aryl(Ci_ 6 )alkyl, (Ci_ 6 )alkoxy(Ci_ 6 )alkyl, (C 2 .
  • a 1 , A 2 and A 3 are cyclohexyl optionally substituted by hydroxy, alkoxy, fluoroalkoxy, hydroxyalkoxy, alkoxyalkoxy, fluoroalkoxyalkoxy, 18 fluoroalkoxyalkoxy or hydroxyalkoxyalkoxy.
  • a 1 is unsubstituted
  • a 2 is unsubstituted.
  • a 3 is mono substituted at the 2 position, in some embodiments A 3 is mono substituted at the 3 position.
  • a 3 is mono substituted at the 4 position and in some embodiments A 3 is substituted with a substituent selected from the group comprising a methoxy, a 3-fluoropropoxy, 3-hydroxypropoxy and X- ((CR a R b ) 2 ⁇ ) n , wherein X is halo or hydroxy and R a and R b are each independently hydrogen or C i_4 alkyl and n is an integer from 1 to 10, preferably 1 to 6 and most preferably 2-4.
  • R 1 through R 8 are independently hydrogen or (Ci_ 6 )alkyl. In some embodiments R 1 through R 8 are independently hydrogen, methyl, ethyl, propyl, a butyl, pentyl or hexyl, wherein the group may be straight chained or branched. In some embodiments R 1 through R 8 are each hydrogen.
  • M is a metal that is Technetium-99m, Rhenium-188, Cobalt-57, Gallium-68, Gallium-67, cold Gallium, Indium-I l l, Iodine-123, Krypton-81m, Rubidium-82, Strontium-92, or Thallium-201.
  • M is Gallium-68, in some embodiments M is Gallium-67 and in some embodiments M is cold Gallium whilst A is substituted with a radioactive 18-Fluoropropoxy to produce a radioactive complex.
  • complexes of Formula II are stabilized by a counterion A " , that is halide, sulfate, nitrate, carboxylate or phosphate.I
  • the counterion is halide.
  • the present invention is also directed to radioactive imaging kits comprising a first vial of a compound of Formula I, and second vial of a salt of a radioactive metal, wherein the contents of the first vial and the contents of the second vial are mixed to form a radioisotopic complex suitable for use as an imagining agent.
  • the methods of imaging comprise administering the radioisotopic complex to a subject and thereafter imaging said subject.
  • the method of imaging will comprise myocardial perfusion imaging, comprising administering the radioisotopic complex of Formula II to a subject; thereafter imaging the heart of said subject.
  • said subject will in be human and in some embodiments said subject will be mammalian.
  • Complexes of Formula II of the present invention have a formal cationic charge of +1.
  • N 2 S 2 bisaminothiolate
  • Figure 1 depicts how the final N 2 S 2 ligand, Structure 1, can be achieved from Structures, II and III.
  • No-carrier-added [ 67 Ga] citrate (1 mCi/mL) is added to the N 2 S 2 ligand (1 mg) in 0.5 rnL of water.
  • the mixture is vortexed and heating at 75 0 C for 0.5 hr.
  • the percent labeling yield is measured by thin-layer chromatography (Silica gel plate, developing solvent: acetone: acetic acid 3:1, v/v) see FIG 4A.
  • the radiochemical purity (RCP) of [ 67 GaJBiaminothiolate-tricyclohexyl complex (FIG 4B) is determined to be > 90%. This material was used directly for animal studies. The effect of acidity and reaction time on the formation of this complex can also be determined by the same TLC technique.
  • Biodistribution studies were performed using utilizing Sprague Dawley rats. (Tables 1 and 2). Under isoflurane anesthesia, 0.2 ml of saline solution (containing 10-100 mCi of radioactive tracer) was injected into the femoral vein. The rats were sacrificed at the time indicated by cardiac excision while under anesthesia. Organs of interest were removed and weighed, and the radioactivity was counted. The percent dose per organ was calculated by comparing the tissue counts to counts of 1% of the initial dose (aliquots of the injected material diluted 100 times) measured at the same time.
  • the [ 67 Ga]biaminothiolate-tricyclohexyl (Ga-B) complex was also compared to other myocardial perfusion imaging complexes including the [ 67 Ga]biaminothiolato-tetraethyl-cyclohexyl (Ga-A) complex of the prior invention (FIG 4C). It can be seen from FIG 5 that in vivo bio-distribution of this novel 67 Gallium-complex which are tested in normal rats exhibited excellent heart uptake and retention with a heart uptake compared to 1.68 % dose/organ (Ga-A) after 2 minutes and a retention of 0.9, compared to 0.26 % dose/organ for Gallium-A after 60 minutes.
  • GaJBiaminothiolate- tricyclohexyl (Ga-B) complex suggests that this agent, as well as related complexes within the scope of Formula II should provide an enhanced myocardial perfusion imaging in comparison to the less lipophilic complexes.
  • Complexes of the present invention also indicate that the highly lipophilic plus one charged complexes are trapped in the myocardial tissue in a similar fashion to 99m Tc myocardial imaging agents as presented in Tables 3, and 4 for the bio-distribution in Sprague Dawley rats after an IV injection of [Tc-99m] sestaMIBI via the femoral vein.

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  • Organic Chemistry (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne des composés de formule I : et des sels pharmaceutiquement acceptables de ceux-ci; dans laquelle A1, A2 et A3 sont des groupes cycloalkyle identiques ou différents, où au moins l'un de A1, A2 ou A3 est substitué. R1 à R6 sont indépendamment des atomes d'hydrogène ou des groupes alkyle, R7 et R8 sont indépendamment des atomes d'hydrogène ou des groupes alkyle et RP est un atome d'hydrogène ou un groupe protecteur sulfhydryle. L'invention concerne également des complexes, où lesdits composés chélatent les ions métalliques radioactifs, tels que le gallium. Les complexes de la présente invention sont utiles comme agents d'imagerie de perfusion myocardique.
PCT/US2008/060054 2007-04-13 2008-04-11 Nouveaux complexes de bisaminothiolate de gallium pour imagerie myocardique WO2008128058A1 (fr)

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Cited By (5)

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WO2012084862A1 (fr) 2010-12-22 2012-06-28 Bayer Cropscience Ag Procédé de production de sels de cis-1-ammonium-4-alkoxycyclohexancarbonitrile
WO2012101047A1 (fr) 2011-01-25 2012-08-02 Bayer Cropscience Ag Procédé de production de dérivés de la 1-h-pyrrolidine-2,4-dione
US9579408B2 (en) 2011-02-11 2017-02-28 Washington University PET/SPECT agents for applications in biomedical imaging
CN110691771A (zh) * 2018-10-03 2020-01-14 河北兰升生物科技有限公司 顺式-对位取代的环己基氨基腈盐及其制备方法
CN112094241A (zh) * 2020-09-19 2020-12-18 浙江凯普化工有限公司 一种1,4-二氮杂螺[5,5]十一烷-3-酮的制备方法

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KR101999937B1 (ko) * 2010-12-22 2019-07-12 바이엘 인텔렉쳐 프로퍼티 게엠베하 시스-1-암모늄-4-알콕시시클로헥산카보니트릴 염의 제조 방법
US20120197035A1 (en) * 2010-12-22 2012-08-02 Bayer Cropscience Ag Process for the Preparation of cis-1-ammonium-4-alkoxycyclohexanecarbonitrile Salts
CN103270020A (zh) * 2010-12-22 2013-08-28 拜耳知识产权有限责任公司 制备顺-1-铵-4-烷氧基环己甲腈盐的方法
KR20130133218A (ko) * 2010-12-22 2013-12-06 바이엘 인텔렉쳐 프로퍼티 게엠베하 시스-1-암모늄-4-알콕시시클로헥산카보니트릴 염의 제조 방법
US8680316B2 (en) * 2010-12-22 2014-03-25 Bayer Cropscience Ag Process for the preparation of cis-1-ammonium-4-alkoxycyclohexanecarbonitrile salts
JP2014509304A (ja) * 2010-12-22 2014-04-17 バイエル・インテレクチユアル・プロパテイー・ゲー・エム・ベー・ハー シス−１−アンモニウム−４−アルコキシシクロヘキサンカルボニトリル塩類を調製する方法
KR101910212B1 (ko) * 2010-12-22 2018-10-19 바이엘 인텔렉쳐 프로퍼티 게엠베하 시스-1-암모늄-4-알콕시시클로헥산카보니트릴 염의 제조 방법
WO2012084862A1 (fr) 2010-12-22 2012-06-28 Bayer Cropscience Ag Procédé de production de sels de cis-1-ammonium-4-alkoxycyclohexancarbonitrile
JP2017025074A (ja) * 2010-12-22 2017-02-02 バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングＢａｙｅｒ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ ＧｍｂＨ シス−１−アンモニウム−４−アルコキシシクロヘキサンカルボニトリル塩類を調製する方法
US9272997B2 (en) 2011-01-25 2016-03-01 Bayer Intellectual Property Gmbh Process for the preparation of 1-H-pyrrolidine-2,4-dione derivatives
EP3372580A1 (fr) 2011-01-25 2018-09-12 Bayer CropScience Aktiengesellschaft Procédé de production de dérivés de la 1-h-pyrrolidine-2,4-dione
US8859782B2 (en) 2011-01-25 2014-10-14 Bayer Cropscience Ag Process for the preparation of 1-H-pyrrolidine-2,4-dione derivatives
WO2012101047A1 (fr) 2011-01-25 2012-08-02 Bayer Cropscience Ag Procédé de production de dérivés de la 1-h-pyrrolidine-2,4-dione
US9579408B2 (en) 2011-02-11 2017-02-28 Washington University PET/SPECT agents for applications in biomedical imaging
CN110691771A (zh) * 2018-10-03 2020-01-14 河北兰升生物科技有限公司 顺式-对位取代的环己基氨基腈盐及其制备方法
CN110691771B (zh) * 2018-10-03 2020-10-09 河北兰升生物科技有限公司 顺式-对位取代的环己基氨基腈盐及其制备方法
CN112094241A (zh) * 2020-09-19 2020-12-18 浙江凯普化工有限公司 一种1,4-二氮杂螺[5,5]十一烷-3-酮的制备方法
CN112094241B (zh) * 2020-09-19 2023-04-18 浙江凯普化工有限公司 一种1,4-二氮杂螺[5,5]十一烷-3-酮的制备方法

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