[go: up one dir, main page]

WO1998001164A1 - Ligands tricycliques radiomarques du recepteur d4 - Google Patents

Ligands tricycliques radiomarques du recepteur d4 Download PDF

Info

Publication number
WO1998001164A1
WO1998001164A1 PCT/CA1997/000465 CA9700465W WO9801164A1 WO 1998001164 A1 WO1998001164 A1 WO 1998001164A1 CA 9700465 W CA9700465 W CA 9700465W WO 9801164 A1 WO9801164 A1 WO 9801164A1
Authority
WO
WIPO (PCT)
Prior art keywords
iodide
compound according
radioisotopic
tin
loweralkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CA1997/000465
Other languages
English (en)
Inventor
Alfred Pollak
Robert Dunn-Dufault
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Resolution Pharmaceuticals Inc
Original Assignee
Resolution Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Resolution Pharmaceuticals Inc filed Critical Resolution Pharmaceuticals Inc
Priority to AU32509/97A priority Critical patent/AU3250997A/en
Publication of WO1998001164A1 publication Critical patent/WO1998001164A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
    • C07D337/02—Seven-membered rings
    • C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D337/14—[b,f]-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
    • C07D223/20—Dibenz [b, e] azepines; Hydrogenated dibenz [b, e] azepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D267/20—[b, f]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D281/16—[b, f]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D313/14—[b,f]-condensed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • This invention is in the field of medical diagnostics, and relates to radiolabeled compounds useful to image D4 receptor loci in brain tissue.
  • Neuronal cell receptors that bind the neurotransmitter dopamine constitute a group of at least five structurally distinct proteins that can now be produced using recombinant DNA techniques. These techniques have been applied to construct cell lines that incorporate the dopamine receptor in their membranes, to provide regenerable and homogeneous substrates with which chemical libraries can be screened to identify potential CNS-active drugs.
  • dopamine receptor ligands currently sold as pharmaceuticals exhibit the desired affinity and antagonism for the D4 receptor, yet interact non-selectively with related dopamine receptors, particularly the D2 receptor type, which results in significant side effects that include altered motor function and tachycardia.
  • this non-selective binding at the D4 receptor prevents the generation of an accurate image of the localisation and prevalence specifically of the D4 type of dopamine receptor. It would therefore be desirable to provide compounds that, in their radiolabeled state, bind at the D4 receptor with affinity and selectivity appropriate for diagnostic imaging purposes.
  • diagnostic imaging techniques as single photon emission tomography (SPECT)
  • SPECT single photon emission tomography
  • X -1' is selected from NH, O and S;
  • X 2 is selected from CH and N;
  • Z is selected from iodide, cyano, nitro, tri(loweralkyl)tin and a radioisotopic iodide; and R 1 is selected from H, lower alkyl, piperonyl, C ⁇ a-keny!, C M alkynyl and C M alkenyl substituted with one of iodide, tri(loweralkyl)tin and radioisotopic iodide; with the provisos that:
  • a radiopharmaceutical composition comprising the tricyclic compound of Formula I, selected from compounds wherein Z is a radioisotopic iodide and R 1 is C M alkenyl substituted with a radioisotopic iodide, and a pharmaceutically acceptable carrier, such as physiological buffered saline.
  • a method for imaging D4 receptors in vivo comprising the step of administering systemically to a patient an effective amount of the radiopharmaceutical composition, and then imaging the composition following its accumulation at D4 receptor sites in the brain.
  • lower alkyl refers to straight chain alkyl radicals containing from one to six carbon atoms, as well as branched chain alkyl radicals containing three to six carbon atoms; and includes methyl, ethyl, 1-methylethyl and the like.
  • C alkenyl refers to straight chain alkylene radicals containing from one to four carbon atoms, and branched chain alkylene radicals containing three to six carbon atoms; and includes vinyl, 2-propenyl and the like.
  • C ⁇ - 4 -dkynyl refers to straight chain alkynyl radicals containing from one to four carbon atoms, and branched chain alkylene radicals containing three to six carbon atoms; and includes propargyl, 2-propynyl and the like.
  • X and X are selected to provide a tricyclic ring structure which is a diazepine, an azepine, a thiazepine, a thiepine, an oxazepine or an oxepine.
  • the compound is a thiepine, i.e., X 1 is S and X 2 is
  • R 1 is desirably lower alkyl (for example methyl), a piperonyl group, C M alkenyl group or a ⁇ alkynyl group. In preferred embodiments, R 1 is selected from lower alkyl and piperonyl.
  • R 1 is a C M alkenyl group substituted with one of tri(loweralkyl)tin, iodide and radioisotopic iodide (including 123 I, 125 I and 131 I).
  • R 1 is 3- 123 I-2-propenyl.
  • Z is selected from cyano and a radioisotopic iodide including 123 I, l2S I and 131 I. In preferred embodiments, Z is selected from cyano and l23 I.
  • an appropriately substituted piperazine of Formula ⁇ is coupled with a tricyclic reagent of Formula HI, wherein X 3 is NH or CH 2 , in the presence of a Lewis acid, such as titanium tetrachloride or boron trifluoride-diethyl etherate, in an inert solvent at temperatures in the range of 100-150°C.
  • a Lewis acid such as titanium tetrachloride or boron trifluoride-diethyl etherate
  • Preferred conditions are titanium tetrachloride in toluene at 110°C.
  • the piperazines of Formula ⁇ can be obtained commercially or can be synthesized using well established procedures.
  • piperazine carboxaldehyde is treated with an alkylating reagent of the general formula, R'-X, wherein X is an appropriate leaving group such as chloride, bromide or iodide, in the presence of base, such as potassium carbonate or triethylamine, in an inert solvent such as acetone, acetonitrile or methylene chloride at temperatures in the range from 25-100°C.
  • base such as potassium carbonate or triethylamine
  • an inert solvent such as acetone, acetonitrile or methylene chloride
  • Preferred conditions are potassium carbonate in acetone at room temperature.
  • Removal of the carboxaldehyde protecting group can be accomplished using standard deprotection conditions (for example, aqueous sodium hydroxide at room temperature) to provide piperazines of Formula ⁇ .
  • Compounds of Formula I in which Z is limited to cyano or nitro and R 1 is a C alkenyl group substituted with tri(loweralkyl)tin, can be prepared by treating compounds of Formula I, wherein R 1 is a group, with a tri(loweralkyl)tin hydride under free radical conditions. Such reactions are performed, for example in the presence of an initiator, such as l,r-azobis(cyclohexanecarbonitrile), in an inert solvent, such as toluene, and at temperatures in the range from 50-110°C, preferably from 80-100°C.
  • an initiator such as l,r-azobis(cyclohexanecarbonitrile)
  • an inert solvent such as toluene
  • the starting tricyclic reagents of Formula in wherein X 1 is NH, O or S, X 3 is NH or CH 2 and Z is iodide, nitro or cyano, can either be purchased from commercial sources, or can be synthesized for example as described in numerous literature references, such as WO95/ 17400 published 29 June 1995.
  • Compounds of Formula I wherein R 1 is limited to lower alkyl, C M alkenyl, C 1 - 4 alkynyl or a piperonyl group and Z is tri(loweralkyl)tin can be prepared from compounds of Formula I, wherein Z is iodide, by reaction with hexa(loweralkyl)ditin reagents under standard palladium- catalysed cross coupling conditions.
  • Such conditions include, for example, treatment with hexa(loweralkyl)ditin reagents in the presence of a catalytic amount of tetra-ris(triphenylphosphine)palladium (0) in an inert solvent such as 1,2-dimethoxyethane at temperatures in the range from 50-100°C, preferably at about 80°C.
  • Compounds of Formula I in which either R 1 is a C M alkenyl group substituted with a radioisotopically labeled iodide or Z is a radioisotopically labeled iodide can be prepared, respectively, by reacting compounds of Formula I, in which either Z is tri(loweralkyl)tin or R 1 is a C M alkenyl group substituted with tri(loweralkyl)tin, with a solution of radioisotopically labeled sodium iodide (e.g. as a solution in IN NaOH) in the presence of an acid and hydrogen peroxide in an alcoholic solvent.
  • a solution of radioisotopically labeled sodium iodide e.g. as a solution in IN NaOH
  • Preferred conditions are hydrochloric acid in ethanol.
  • compounds of Formula I wherein R 1 is a C M alkenyl group substituted with a radioisotopically labeled iodide and Z is a radioisotopically labeled iodide can be prepared by reacting compounds of Formula I, wherein Z is tri(loweralkyl)tin and R 1 is a C alkenyl group substituted with tri(loweralkyl)tin.
  • Compounds of Formula I, wherein Z is iodide and R 1 is a C ⁇ a-keny! group substituted with iodide can be prepared by reacting compounds of Formula I, wherein Z is tri(loweralkyl)tin and R 1 is a C M alkenyl group substituted with tri(loweralkyl)tin, under standard iodination conditions, for example using iodine in an inert solvent such as chloroform at room temperature.
  • Compounds of Formula I wherein Z is tri(loweralkyl)tin and R 1 is a C M alkenyl group substituted with tri(loweralkyl)tin, can be prepared by reacting compounds wherein Z is iodide and R 1 is C 1 _ alkynyl under free radical conditions in the presence of a tri(loweralkyl)tin hydride and an initator as described above.
  • the compounds are selected from:
  • the compounds are selected from:
  • the compounds are selected from 2- 123 I-10-(4-methyl-l-piperazinyl)-dibenzo[b,flthiepine; 2- ,23 I -10-(4-piperonyl-l-piperazinyl)-dibenzo[b,f
  • the compounds of the invention are formulated as radiopharmaceutical compositions together with any physiologically and radiologically tolerable vehicle appropriate for administering the compound systemically. Included among such vehicles are phosphate buffered saline solutions, buffered for example to pH 7.4.
  • the present compounds will be administered to patients by intravenous injection or infusion at doses suitable (e.g. between 1 and 10 mCi) to generate an image of the compound as localised within the brain using for example a gamma camera. It is further contemplated that the method of the present invention can usefully be applied to patients suspected of suffering from schizophrenia. For these patients, diagnosis can be aided or confirmed by determining the intensity of radiolabeled compound relative to the brain of a healthy patient; greater image intensity is indicative of an overabundance of D4 receptor, and is hence indicative of a schizophrenic condition.
  • doses suitable e.g. between 1 and 10 mCi
  • the method of the present invention can usefully be applied to patients suspected of suffering from schizophrenia. For these patients, diagnosis can be aided or confirmed by determining the intensity of radiolabeled compound relative to the brain of a healthy patient; greater image intensity is indicative of an overabundance of D4 receptor, and is hence indicative of a schizophrenic condition.
  • 2-Chlorophenyl acetic acid (40.0 g, 0.235 mol) was dissolved in concentrated sulfiiric acid (200 mL) and the resulting solution cooled to -10°C with vigorous stirring. A solution of nitric acid (30 mL) and sulfiiric acid (30 mL) was then added dropwise over 1 hour and the thickened slurry was allowed to warm to 0°C. Ice water (500 mL) was then added, maintaining the temperature at 0°C. The solution was stirred and allowed to warm gradually to room temperature overnight. The resulting white solid was filtered, washed with copious amounts of water and dried over KOH in vacua. A pure sample of 2-chloro- 5-nitrophenyl acetic acid (44.35 g, 87.6%) was obtained by recrystallization in acetic acid.
  • Example 8(a) 2-Cvano- 10- ( 4-f3-( tributvltinV2- ⁇ ropen- l-vl "
  • Example 7a in dry dioxane (6 mL) under argon were added hexamethylditin (36 mg, 0.10 mmol) and tetrakis(triphenylphosphine)palladium (0) (10 mg, 0.092 mmol). The resulting solution was heated to 80°C for 2.5 hours and then cooled to room temperature, followed by the addition of water (8 mL). The product was extracted into dichloromethane (4x 2 mL) and the organics were combined, dried over sodium sulfate and concentrated. The resulting black oil was purified on a preparative silica gel plate using methanol/ethyl acetate (1:9) as eluent to provide the title compound as a yellow solid (20mg, 36.4%).
  • Example 11 2- (Radioisotopie-iodol- 10-f4-methyl- 1 -piperazinvD-dibenzorb . flthiepine
  • a solution of radioisotopically labeled sodium iodide (6 ⁇ L in 0.1 N NaOH) in ethanol (300 ⁇ L) is prepared in a reactivial and to this is added sequentially, the solution 2-trimethylstannyl-10- (4-methyl-l-piperazinyl)-dibenzo[b,f]thiepine, hydrochloric acid (0.3 N, 17 ⁇ L) and hydrogen peroxide (3%, 100 ⁇ L).
  • the resulting solution is swirled, adequately shielded and left stoppered for 15 minutes at room temperature.
  • D2 and D4 receptor-binding affinities of the compounds of Formula 1 were evaluated as described in WO95/ 17400 (incorporated herein by reference) for their ability to reduce binding of 3 H-spiperone as compared to the reference compound clozapine.
  • the potency of the test compound to reduce 3 H-spiperone binding directly correlated to its binding affinity for the receptor.
  • the D4 receptor was utilised in the form of membrane preparations obtained from HEK 298 cells stably transfected with human D4 receptor (D4.2 sub-type).
  • D2 receptor was utilised in the form of membrane preparations obtained from G ⁇ (rat pituitary) cells stably transfected with the human D2 receptor (short isofor ).
  • the total spiperone binding assay was started by the addition of 500 ⁇ l (50 ⁇ g protein) membrane homogenate to a solution of 900 ⁇ l incubation buffer and 100 ⁇ l (0.25 nM final cone.) 3 H-spiperone.
  • the binding reaction was stopped and the samples were filtered under vacuum and filters were then washed 3 times with 5 ml ice cold 50 mM Tris buffer (pH 7.4). Individual filter disks were put in scintillation vials (Biovials, Bechman). Ready Protein Plus liquid s nt ⁇ lant (5 ml, Beckman) was added and the vials counted by liquid scintillation spectrophotometry (Beckman LSC 6500) after equilibrating for three hours at room temperature to determine total binding ( ⁇ ).
  • Non-specific binding for D4 was assayed by incubating membrane homogenate, 3 H- spiperone and fresh dopamine. Filtrate was counted using the same procedure as in the total binding assay described above to give the non-specific binding value (NSB). Non-specific binding for D2 was similarly assessed, with the exception that (-) sulpiride was used in place of dopamine.
  • test compounds were initially assayed at 1 and 0.1 ⁇ M and then at a range of concentrations chosen such that the middle dose would cause about 50% inhibition of 3 H- spiperone binding.
  • Specific binding in the absence of test compound (Bo) was the difference of total binding (B-) minus non-specific binding (NSB) and similarly specific binding (in the presence of test compound) (B) was the difference of displacement binding (Bo) minus non-specific binding (NSB).
  • IC 50 was determined from an inhibition response curve, logit-log plot of %B/B Q VS concentration of test compound.
  • Ki was calculated by the Cheng and Prustoff transformation:
  • Ki IC 50 / (l + [Lj7K D ) where [L] is the concentration of H-spiperone used in the assay and K D is the dissociation constant of 3 H-spiperone determined independently under the same binding conditions.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés tricycliques radiomarqués utiles pour visualiser in vivo des récepteurs D4. Lesdits composés tricycliques sont de la formule (I), dans laquelle X1 est sélectionné dans le groupe constitué par NH, O et S; X¿2? est sélectionné dans le groupe constitué par CH et N; Z est sélectionné dans le groupe constitué par un iodure, cyano, nitro, un étain tri(alcyl inférieur) et un iodure radio-isotope; et R?1¿ est sélectionné dans le groupe constitué par H, alkyle inférieur, pipéronyl, alcényleC¿1-4?, alcynyleC1-4 et alcényleC1-4 substituté soit par un iodure, soit par un étain tri(alkyle inférieur), soit par un iodure radio-isotope; à condition que 1) si l'un de Z et R?1¿ est radio-isotope, l'autre de Z et R1 n'est pas un iodure ou ne contient pas d'iodure; et 2) si l'un de Z et R1 est un étain tri(alkyle inférieur) ou contient un étain tri(alkyle inférieur), l'autre de Z et R1 n'est pas un iodure ou un iodure marqué par radio-isotope ou ne contient pas d'iodure ou d'iodure marqué par radio-isotope. Ces composés radiopharmaceutiques sont utiles, en particulier pour visualiser l'emplacement d'un récepteur D4 dans le cerveau humain, et permettent donc d'aider à diagnostiquer la schizophrénie ou d'autres états pathologiques impliquant le récepteur D4.
PCT/CA1997/000465 1996-07-08 1997-06-30 Ligands tricycliques radiomarques du recepteur d4 Ceased WO1998001164A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU32509/97A AU3250997A (en) 1996-07-08 1997-06-30 Tricyclic radiolabeled d4 receptor ligands

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US67692196A 1996-07-08 1996-07-08
US08/676,921 1996-07-08

Publications (1)

Publication Number Publication Date
WO1998001164A1 true WO1998001164A1 (fr) 1998-01-15

Family

ID=24716572

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA1997/000465 Ceased WO1998001164A1 (fr) 1996-07-08 1997-06-30 Ligands tricycliques radiomarques du recepteur d4

Country Status (2)

Country Link
AU (1) AU3250997A (fr)
WO (1) WO1998001164A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003000670A1 (fr) * 2001-06-26 2003-01-03 Neuromolecular, Inc. A11-piperazinyldibenzo (b, f) (1, 4) oxazepines et thiazepines, en tant qu'agents antipsychotiques atypiques a faible affinite pour le recepteur d2
WO2003039255A1 (fr) * 2001-11-05 2003-05-15 Basf Aktiengesellschaft Derives de dibenzothiepine substitues utilises comme agents insecticides, acaricides et nematicides
CN109456285A (zh) * 2018-10-29 2019-03-12 安徽省庆云医药股份有限公司 一种雷诺嗪的制备方法
EP3812373A4 (fr) * 2018-06-21 2021-06-16 National Institutes For Quantum And Radiological Science And Technology Nouveau composé se liant à un récepteur sur mesure, procédé d'imagerie pour récepteur sur mesure, agoniste ou antagoniste, agent thérapeutique, agent de diagnostic d'accompagnement, et procédé d'imagerie pour cellule nerveuse

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4044101A (en) * 1974-12-21 1977-08-23 Asahi Kasei Kogyo Kabushiki Kaisha Method of treating exhaust gases containing nitrogen oxides and sulfurous acid gas
WO1995017400A1 (fr) * 1993-12-23 1995-06-29 Allelix Biopharmaceuticals Inc. Derives tricycliques de n-heterobicyclylbiperazinyle ou n-heterobicyclylpiperadinyle utiles comme ligands se fixant sur le recepteur de la dopamine
WO1996018629A1 (fr) * 1994-12-12 1996-06-20 Allelix Biopharmaceuticals Inc. Ligands du recepteur 5-ht2
WO1996018622A1 (fr) * 1994-12-12 1996-06-20 Allelix Biopharmaceuticals Inc. Composes de n-methyl-piperazine presentant une affinite pour le recepteur de la dopamine
WO1996018621A1 (fr) * 1994-12-12 1996-06-20 Allelix Biopharmaceuticals Inc. Composes substitues par alkyle, presentant une affinite pour le recepteur de la dopamine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4044101A (en) * 1974-12-21 1977-08-23 Asahi Kasei Kogyo Kabushiki Kaisha Method of treating exhaust gases containing nitrogen oxides and sulfurous acid gas
WO1995017400A1 (fr) * 1993-12-23 1995-06-29 Allelix Biopharmaceuticals Inc. Derives tricycliques de n-heterobicyclylbiperazinyle ou n-heterobicyclylpiperadinyle utiles comme ligands se fixant sur le recepteur de la dopamine
WO1996018629A1 (fr) * 1994-12-12 1996-06-20 Allelix Biopharmaceuticals Inc. Ligands du recepteur 5-ht2
WO1996018622A1 (fr) * 1994-12-12 1996-06-20 Allelix Biopharmaceuticals Inc. Composes de n-methyl-piperazine presentant une affinite pour le recepteur de la dopamine
WO1996018621A1 (fr) * 1994-12-12 1996-06-20 Allelix Biopharmaceuticals Inc. Composes substitues par alkyle, presentant une affinite pour le recepteur de la dopamine

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003000670A1 (fr) * 2001-06-26 2003-01-03 Neuromolecular, Inc. A11-piperazinyldibenzo (b, f) (1, 4) oxazepines et thiazepines, en tant qu'agents antipsychotiques atypiques a faible affinite pour le recepteur d2
US6890919B2 (en) 2001-06-26 2005-05-10 Shitij Kapur Atypical antipsychotic agents having low affinity for the D2 receptor
EP1593676A1 (fr) * 2001-06-26 2005-11-09 Neuromolecular, Inc. 8-Chloro-11-(4-(2'-hydroxyéthyl)piperazin-1-yl)-dibenzo[b,f][1,4]oxazépine à activité antipsychotique atypique et à faible affinité pour le récepteur dopamine D2
WO2003039255A1 (fr) * 2001-11-05 2003-05-15 Basf Aktiengesellschaft Derives de dibenzothiepine substitues utilises comme agents insecticides, acaricides et nematicides
EP3812373A4 (fr) * 2018-06-21 2021-06-16 National Institutes For Quantum And Radiological Science And Technology Nouveau composé se liant à un récepteur sur mesure, procédé d'imagerie pour récepteur sur mesure, agoniste ou antagoniste, agent thérapeutique, agent de diagnostic d'accompagnement, et procédé d'imagerie pour cellule nerveuse
CN109456285A (zh) * 2018-10-29 2019-03-12 安徽省庆云医药股份有限公司 一种雷诺嗪的制备方法

Also Published As

Publication number Publication date
AU3250997A (en) 1998-02-02

Similar Documents

Publication Publication Date Title
US6486326B2 (en) iso-CBI and iso-CI analogs of CC-1065 duocarmycins
KR930002491B1 (ko) 도파민 수용체 리간드 및 영상화제
US5602124A (en) 5-HT2 receptor ligands
US5725838A (en) Radiolabeled D4 receptor ligands
US20090004106A1 (en) Radioligands for the 5 -Ht1b Receptor
BG62048B1 (bg) Хиполипидемични 1,4-бензотиазепин-1,1-диоксиди
US5602121A (en) Alkyl-substituted compounds having dopamine receptor affinity
JP3001998B2 (ja) 膵イメージング用γ線放出ＣＣＫ−Ａ拮抗薬
WO1992005154A1 (fr) Nouveaux ligands d'azote-soufre utiles dans des agents d'imagerie radiographique
PL120774B1 (en) Process for preparing derivatives of trans-2-substituted-5-arylo-2,3,4,4a,5,9b-hexahydro-1h-pyrido/4,3-b/indole ril-2,3,4,4a,5,9b-geksagidro-1h-pirido/4,3-b/indola
WO1998001164A1 (fr) Ligands tricycliques radiomarques du recepteur d4
CA2343106A1 (fr) Antagonistes radiomarques du recepteur de la neurokinine 1
CN1031060C (zh) 新颖酯类的制造方法
US5602120A (en) Benzyl-substituted compounds having dopamine receptor affinity
CN102171218A (zh) 适用于使神经炎症显像的吲哚衍生物
US5674877A (en) Muscarinic receptor ligands
Brouillette et al. Anticonvulsant activities of phenyl-substituted bicyclic 2, 4-oxazolidinediones and monocyclic models. Comparison with binding to the neuronal voltage-dependent sodium channel
US5976497A (en) Dopamine D4 receptor ligands
WO2006073886A1 (fr) Dihydrate d'olanzapine pamoate
Martin et al. Conformationally restricted tricyclic antidepressants. 1. Octahydrodibenzazepinonaphthyridines as rigid imipramine analogs
KR960006732B1 (ko) 방사성 벤조디아제핀 유도체 및 그의 제조방법
WO1998043976A1 (fr) Derives de biphenyle et compositions medicinales
DE2627994A1 (de) 1-acyl-1,2,3,4-tetrahydro-6-chinolinole und deren herstellung
CA2597798A1 (fr) Phno fluoree et analogues de ladite substance
JP2674232B2 (ja) １，５―ベンゾチアゼピン誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT

121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 98504602

Format of ref document f/p: F

NENP Non-entry into the national phase

Ref country code: CA

122 Ep: pct application non-entry in european phase