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WO2001000604A1 - Ligand de liaison avec le recepteur sigma-1 du cerveau - Google Patents

Ligand de liaison avec le recepteur sigma-1 du cerveau Download PDF

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Publication number
WO2001000604A1
WO2001000604A1 PCT/JP2000/004209 JP0004209W WO0100604A1 WO 2001000604 A1 WO2001000604 A1 WO 2001000604A1 JP 0004209 W JP0004209 W JP 0004209W WO 0100604 A1 WO0100604 A1 WO 0100604A1
Authority
WO
WIPO (PCT)
Prior art keywords
receptor
compound
brain
salt
sigma
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/JP2000/004209
Other languages
English (en)
Japanese (ja)
Inventor
Kiyoshi Matsuno
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.)
Santen Pharmaceutical Co Ltd
Original Assignee
Santen Pharmaceutical Co Ltd
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 Santen Pharmaceutical Co Ltd filed Critical Santen Pharmaceutical Co Ltd
Priority to AU55698/00A priority Critical patent/AU5569800A/en
Publication of WO2001000604A1 publication Critical patent/WO2001000604A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to a ligand consisting of a radiolabeled 1,4- (diphenylalkyl) piperazine derivative and having high affinity and selectivity for the sigma-1 receptor in the brain, and particularly to a brain diagnostic agent. And useful ligands.
  • the ligand according to the present invention is used to bind to the brain sigma 1 receptor for biochemical pharmacological analysis and diagnostic imaging by utilizing its high binding specificity and radioactivity.
  • sigma 1 receptor is associated with central nervous system diseases such as dementia and depression, and is also expressed on tumors such as melanoma. In addition, diagnosis was performed by measuring sigma-1 receptor. "5. Ligand for positron emission tomography (PET) using positron emitting nuclides and single photon emission computed tomography (SPECT) using single photon emitting nuclides Is also under development.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • a method for diagnosing the presence of a specific sigma 1 receptor by using a ligand having high affinity and selectivity for brain sidama 1 receptor is known.
  • diagnostic methods include a general examination of the density and distribution of the sidama 1 receptor in various parts of the brain in brain disorders such as Alzheimer's disease, dementia, depression, and schizophrenia, It can be used to prevent or improve neuronal degeneration, and It can also be used to evaluate drug efficacy.
  • the radiolabeled 1,4- (diphenylalkyl) piperazine derivative has affinity for the sigma receptor, and has cerebral nerve dysfunction such as dementia, depression, schizophrenia, anxiety, and immune It has been reported that it is useful as a therapeutic agent for abnormalities and diseases associated with endocrine abnormalities, gastrointestinal ulcers, etc. It has been reported that it is useful as a prophylactic or therapeutic agent for eye diseases, in particular, retinal diseases such as diabetic retinopathy and retinal vascular obstruction, and glaucoma (Japanese Patent Application Laid-Open No. H10-125609). No.) Research on the high affinity and selectivity of radiolabeled 1,4- (diphenylalkyl) piperazine derivatives for the brain sigma 1 receptor has not yet been performed and is a very interesting topic. o Disclosure of the invention
  • the present inventors have conducted intensive studies to find new usefulness of 1,4- (diphenylalkyl) piperazine derivatives, and have found that radiolabeled 1,4- (diphenylalkyl) piperazine derivatives are useful. Derivatives were found to show high affinity and selectivity for brain sigma 1 receptor. In other words, radiolabeled 1,4- (diphenylalkyl) piperazine derivatives utilize their high binding specificity and radioactivity for brain sigma 1 receptor, They have found that it can be a useful ligand for biochemical pharmacological analysis and diagnostic imaging.
  • the present invention relates to a brain sigma 1 receptor-binding ligand comprising a compound represented by the following general formula [I] or a salt thereof.
  • R 1 and R 2 represents a different lower alkoxy group rather also the same, or both the least of R 1 or R 2 is a lower alkoxy group containing a carbon atom having a mass number of 1 1.
  • a and B represent the same or different lower alkylene groups. ] The groups defined above will be described in more detail.
  • the lower alkoxy group refers to a lower alkoxy group having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, and a butoxy group
  • the lower alkylene refers to a methylene group, an ethylene group, or a propylene group.
  • lower alkylene having 1 to 6 carbon atoms such as a butyl group and a butylene group.
  • Preferred examples include a compound represented by the general formula [I], wherein each group is as follows, or a salt thereof;
  • A represents lower alkylene having 2 to 4 carbon atoms; and Z or
  • (b) B represents lower alkylene having 2 to 4 carbon atoms; and Z or
  • R 1 represents a methoxy group containing 11 carbon atoms
  • R 2 represents a methoxy group containing a carbon atom having a mass number of 11; That is, ⁇ 09
  • the above salts may be any salts that are acceptable as diagnostic agents, such as hydrochloride, sulfate, phosphate, lactate, maleate, fumarate, and oxalate. No. Further, the compound [I] may be in the form of a hydrate.
  • the dosage form of this ligand is usually an injectable solution.
  • the 11 C radioactivity in each organ of rats Bok measured at O Toganmakau printer.
  • the amount of organ taken up was expressed as a percentage of the amount of the compound injected relative to the number of grams of the organ.
  • Table 1 shows the measurement results for blood and brain.
  • Table 2 shows the measurement results for blood and brain.
  • the numbers are the mean soil standard deviation
  • the compound showed higher uptake in the brain than in the comparative compound, but the radioactivity level in blood was markedly higher. Was very low. This suggests that the compound is effectively taken up by the brain and disappears quickly from the blood, and is suitable for use in medical practice.
  • this compound shows high affinity and selectivity for sigma 1 receptor in the brain, and could be a useful ligand for brain biochemical and pharmacological analysis and diagnostic imaging It is.
  • the present invention relates to a ligand exhibiting high affinity and selectivity for the sigma 1 receptor in the brain, and particularly to a ligand useful as a brain diagnostic agent. Utilizing specificity and radioactivity, it is used to bind to brain sigma 1 receptor for biochemical pharmacological analysis and diagnostic imaging.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Optics & Photonics (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne vise à trouver de nouvelles utilisation de dérivés de 1,4-(diphénilalkyle)pipérazine radiomarqués. L'invention concerne plus particulièrement un ligand de liaison avec le récepteur sigma-1 du cerveau constitué d'un composé représenté par la formule générale (I) ou l'un de ses sels, mais de préférence un composé représenté par la formule générale (II) ou l'un de ses sels et présentant une haute affinité et une haute sélectivité pour le récepteur. Dans ces formules, R1 et R2 sont chacun indépendamment alkyle inférieur sous la réserve que l'un au moins de R1 et R2 soit alcoxy inférieur contenant un atome de carbone de masse atomique 11. En outre, A et B sont chacun indépendamment alkylène inférieur.
PCT/JP2000/004209 1999-06-30 2000-06-27 Ligand de liaison avec le recepteur sigma-1 du cerveau Ceased WO2001000604A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU55698/00A AU5569800A (en) 1999-06-30 2000-06-27 Brain sigma-1 receptor-binding ligand

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP11/184620 1999-06-30
JP18462099 1999-06-30

Publications (1)

Publication Number Publication Date
WO2001000604A1 true WO2001000604A1 (fr) 2001-01-04

Family

ID=16156430

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2000/004209 Ceased WO2001000604A1 (fr) 1999-06-30 2000-06-27 Ligand de liaison avec le recepteur sigma-1 du cerveau

Country Status (2)

Country Link
AU (1) AU5569800A (fr)
WO (1) WO2001000604A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5498618A (en) * 1992-07-17 1996-03-12 Janssen Pharmaceutica N.V. 4-amino-N-(4-methyl-4-piperidinyl)-2-methoxybenzamides for treating smooth muscle contraction disorders
EP0711763A1 (fr) * 1993-07-28 1996-05-15 Santen Pharmaceutical Co., Ltd. Nouveau derive de 1,4-di(phenylalkyl)piperazine
EP0770400A2 (fr) * 1995-10-31 1997-05-02 Japan Science and Technology Corporation Acyl-L-carnitine marqué et agent diagnostique
WO1997043271A1 (fr) * 1996-05-10 1997-11-20 Janssen Pharmaceutica N.V. Derives de l'alkylaminobenzothiazole et alkylaminobenzoxazole

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5498618A (en) * 1992-07-17 1996-03-12 Janssen Pharmaceutica N.V. 4-amino-N-(4-methyl-4-piperidinyl)-2-methoxybenzamides for treating smooth muscle contraction disorders
EP0711763A1 (fr) * 1993-07-28 1996-05-15 Santen Pharmaceutical Co., Ltd. Nouveau derive de 1,4-di(phenylalkyl)piperazine
EP0770400A2 (fr) * 1995-10-31 1997-05-02 Japan Science and Technology Corporation Acyl-L-carnitine marqué et agent diagnostique
WO1997043271A1 (fr) * 1996-05-10 1997-11-20 Janssen Pharmaceutica N.V. Derives de l'alkylaminobenzothiazole et alkylaminobenzoxazole

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FUJIMURA K. ET AL.: "Synthesis, structure and quantitative structure-activity relationships of alpha receptor ligands, 1-(2-(3,4-dimethoxyphenyl)ethyl)-4-(3-phenylpropyl)piperazines", BIOORG. MED. CHEM., vol. 5, no. 8, 1997, pages 1675 - 1683, XP002931747 *
MATSUNO K. ET AL.: "Binding properties of SA4503, a novel and selective alpha 1 receptor agonist", EUR. J. PHARMACOL., vol. 306, no. 1-3, 1996, pages 271 - 279, XP002931746 *

Also Published As

Publication number Publication date
AU5569800A (en) 2001-01-31

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