[go: up one dir, main page]

WO2016097355A1 - Dérivés d'oxazolidinone marqués - Google Patents

Dérivés d'oxazolidinone marqués Download PDF

Info

Publication number
WO2016097355A1
WO2016097355A1 PCT/EP2015/080618 EP2015080618W WO2016097355A1 WO 2016097355 A1 WO2016097355 A1 WO 2016097355A1 EP 2015080618 W EP2015080618 W EP 2015080618W WO 2016097355 A1 WO2016097355 A1 WO 2016097355A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
mao
vivo imaging
compounds
precursor
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/EP2015/080618
Other languages
English (en)
Inventor
Gareth Edwin SMITH
Duncan George Wynn
Alexander Jackson
Ian Newington
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.)
GE Healthcare Ltd
Original Assignee
GE Healthcare 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 GE Healthcare Ltd filed Critical GE Healthcare Ltd
Publication of WO2016097355A1 publication Critical patent/WO2016097355A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57434—Specifically defined cancers of prostate
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere

Definitions

  • the present invention concerns compounds that target monoamine oxidase B (MAO- B).
  • the compound of the invention is a oxazolidinone derivative.
  • a labelled oxazolidinone derivative is also provided having use as an in vivo imaging agent for MAO-B.
  • the present invention also provides a precursor compound useful in the synthesis of this in vivo imaging agent, as well as a method for synthesis of said precursor compound.
  • Other aspects of the invention include a method for the synthesis of the in vivo imaging agent comprising use of the precursor compound, a kit for carrying out said method, and a cassette for carrying out an automated version of said method.
  • the invention provides a radiopharmaceutical composition comprising the in vivo imaging agent, as well as methods for the use of said in vivo imaging agent.
  • Monoamine oxidase B (MAO-B) is found in the brain primarily in nonneuronal cells such as astrocytes and radial glia (Westlund et al. (1988) Neuroscience 25: 20 439-456; Westlund et al. (1985) Science 230: 181-183; Levitt et al. (1982) Proc. Natl. Acad. Sci., USA, 79: 6385-6389). Its levels are known to increase with age and in association with neurodegenerative disease in both humans and mice (Saura et al. (1994) J Neural Transm Suppl41 : 89-94; Fowler et al. (1980) J Neural Transm 49: 1-20; Riederer et al. (1987) Adv Neurol45: 111-118; Gerlach et al. (1996) Neurology 47: S137-145).
  • MAO-B activity levels have been found to be doubled in the substantia nigra in
  • the publication suggests that the high brain uptake and slow plasma metabolism of [ n C]SL25.1188 in primates may make it a useful tool for PET imaging of MAO-B in vivo.
  • the present invention relates to compounds having selective binding for MAO-B as compared with MAO-A.
  • the invention also provides radioactive versions of these compounds, and precursor compounds for the synthesis of these radioactive
  • the radioactive compounds of the invention can find use for in vivo imaging applications.
  • the compounds of the invention are novel over those of the prior art and display good properties for binding to MAO-B.
  • R 1 is -(CH 2 ) n -R 2 wherein n is an integer of 1-4 and R 2 is Ci_ 5 tetrafluoroalkyl.
  • alkyl' ' refers to an alkyl substituent wherein four fluoro substituents taken the place of hydrogens.
  • alkyl alone or in combination, means a straight-chain alkyl radical containing preferably from 1 to 5 carbon atoms.
  • R 2 is Ci_ 4 tetrafluoroalkyl. In one embodiment the compound of the invention is:
  • At least one F is F. In one embodiment of compound of the invention is:
  • the present invention provides a precursor compound for the synthesis of the compound as defined hereinabove wherein said precursor compound is a compound of Formula II:
  • a "precursor compound” comprises a non-radioactive derivative of a radiolabeled compound, designed so that chemical reaction with a convenient chemical form of the detectable label occurs site-specifically; can be conducted in the minimum number of steps (ideally a single step); and without the need for significant purification (ideally no further purification), to give the desired in vivo imaging agent.
  • Such precursor compounds are synthetic and can conveniently be obtained in good chemical purity.
  • the terms “comprising” or “comprises” have their conventional meaning throughout this application and imply that the agent or composition must have the essential features or components listed, but that others may be present in addition.
  • the term 'comprising' includes as a preferred subset “consisting essentially of which means that the composition has the components listed without other features or components being present.
  • the term “leaving group” refers to a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Known leaving groups include halogens, e.g. selected from chloro, iodo, or bromo, aryl sulphonates and alkyl sulphonates.
  • said leaving group is selected from tosylate (OTs), mesylate (OMs), nosylate (ONs), brosylate (OBs).
  • OTs tosylate
  • OMs mesylate
  • ONs nosylate
  • brosylate OBs
  • the present invention provides a method for the synthesis of the compound as defined hereinabove wherein one fluoro is 18 F wherein said method comprises reaction of the precursor compound of Formula II as defined hereinabove with [ 18 F]fluoride.
  • Precursor compounds and methods of introducing radioactive isotopes into organic molecules are well-known in the art. A good overview is provided in the "Handbook of Radiopharmaceuticals: Radiochemistry and Applications” (Wiley 2003; Welch and Redvanley, Eds.).
  • the present invention provides a pharmaceutical formulation comprising the compound as defined hereinabove together with a biocompatible carrier in a form suitable for mammalian administration.
  • a “pharmaceutical formulation” is a composition comprising the compound of the invention, together with a biocompatible carrier in a form suitable for mammalian administration.
  • the "biocompatible carrier” is a fluid, especially a liquid, in which the compound is suspended or dissolved, such that the formulation is physiologically tolerable, i.e. can be administered to the mammalian body without toxicity or undue discomfort.
  • the biocompatible carrier is suitably an injectable carrier liquid such as sterile, pyrogen-free water for injection; an aqueous solution such as saline (which may advantageously be balanced so that the final product for injection is either isotonic or not hypotonic); an aqueous solution of one or more tonicity- adjusting substances (e.g.
  • the biocompatible carrier may also comprise biocompatible organic solvents such as ethanol. Such organic solvents are useful to solubilise more lipophilic compounds or formulations.
  • the biocompatible carrier is pyrogen-free water for injection, isotonic saline or an aqueous ethanol solution.
  • the pH of the biocompatible carrier for intravenous injection is suitably in the range 4.0 to 10.5.
  • the present invention provides an in vivo imaging method for determining the distribution and/ or extent of expression of monoamine oxidase B (MAO-B) in a subject comprising:
  • in vivo imaging refers to those techniques that noninvasively produce images of all or part of the internal aspect of a subject.
  • suitable in vivo imaging procedures for use with this aspect of the invention are single-photon emission tomography (SPECT) and positron-emission tomography (PET).
  • SPECT single-photon emission tomography
  • PET positron-emission tomography
  • the compound of the invention may be administered as the pharmaceutical formulation of the invention, e.g. parenterally, i.e. by injection.
  • parenteral administration steps to ensure that the radiopharmaceutical composition is sterile and apyrogenic also need to be taken.
  • said in vivo imaging method is carried out repeatedly during the course of a treatment regimen for said subject, said regimen comprising administration of a drug to combat a MAO-B condition.
  • MAO-B condition refers to any condition is which MAO-B activity is abnormal.
  • MAO-B conditions include neurodegenerative diseases, non- limiting examples of which include Parkinson's disease and Alzheimer's disease.
  • the in vivo imaging method of the invention can be carried out before, during and after treatment with a drug to combat a MAO-B condition.
  • the in vivo imaging procedure is PET.
  • PET has excellent sensitivity and resolution, so that even relatively small changes in a lesion can be observed over time, which is particularly advantageous for treatment monitoring.
  • said in vivo imaging method of the fifth aspect of the invention can be understood to be carried out from step (ii) wherein the subject is already administered with said compound of the invention.
  • the fifth aspect of the invention can be understood to be the compound of the invention for use in said in vivo imaging method.
  • said in vivo imaging method can be understood to be the use of said compound of the invention in the manufacture of the pharmaceutical composition of the invention for the in vivo imaging of a MAO-B condition.
  • the present invention provides a method of diagnosis of a condition in which MAO-B expression is abnormal wherein said method of diagnosis comprises the in vivo imaging method as defined hereinabove as well as the further step (iv) of attributing the distribution and extent of MAO-B expression to a particular clinical picture.
  • the sixth aspect of the invention can be understood to be the compound of the invention for use in said method of diagnosis.
  • said method of diagnosis can be understood to be the use of said compound of the invention in the manufacture of the pharmaceutical composition of the invention for the diagnosis of a MAO-B condition.
  • Figure 1 illustrates the NMR characterisation data for (5S)-5-(methoxymethy)-3-(6- (2,4,4,4-tetrafluorobutoxy)-benzo[d]isoxazol-3-yl)oxazolidin-2-one.
  • Example 1 describes the synthesis of (5S)-5-(methoxymethy)-3-(6-(2,4,4,4- tetrafluorobutoxy)benzo[d]isoxazol-3-yl)-oxazolidin-2-one
  • Example 2 describes the synthesis of a fluorine- 18 radiochemistry precursor for the compound of Example 1.
  • Example 3 scribes the synthesis of (5S)-5-(methoxymethy)-3-(6-(4,4,4-trifluoro-2- [ 18 F]fluorobutoxy)benzo[d]isoxazol-3-yl)-oxazolidin-2-one
  • Example 4 descrives an in vitro inhibition method to assess binding for MAO-A and MAO-B.
  • MAO A monoamine oxidase A
  • MAO B monoamine oxidase A
  • reaction mixture was cooled to 0°C, quenched by water (70 mL). It was then extracted with dichloromethane (3 x 100 mL). Combined organic layer was washed with saturated NaCl solution (100 mL), dried over anhydrous Na 2 S0 4 , filtered and concentrated.
  • diethyl ether (20 mL) afforded (5S)- 5-(methoxymethy)-3-(6-(2,4,4,4-tetrafluorobutoxy)-benzo[(i]isoxazol-3-yl)oxazolidin- 2-one [mixture of diastereoisomers] as white solid (0.370 mg, 54.2%).
  • the two diastereoisomers was further separated by SFC to obtain pure diastereomer Product 1 (104 mg, 15.25%) and Product 2 (106 mg, 15.55%).
  • Example 2 Synthesis of a fluorine-18 radiochemistry precursor for the compounds of Example 1.
  • reaction mixture was quenched with ice water and crude product was extracted with DCM (3x50 mL). The combined organic layer was washed with aqueous 10%) NaHC0 3 solution (2 X 50 ml) and then dried over anhydrous sodium sulfate and removed under reduced pressure.
  • the crude was purified by initially by column chromatography (60-120 mesh silica gel) using 40% Ethyl acetate in pet ether and then with Prep HPLC (eluent H 2 0: ACN; pure product eluted at 80% ACN in H 2 0) to yield pure racemic 4,4,4-trifluoro-l-((3-((S)- 5-(methoxymethyl)-2-oxooxazolidin-3-yl)benzo[d]isoxazol-6-yl)oxy)butan-2-yl 4- methylbenzenesulfonate (410 mg) as a colorless gummy oil.
  • the two diastereoisomers was further separated by SFC to obtain pure Product 1 (140 mg, 20.08%>) and Product 2 (140 mg, 20.08%).
  • Fluorine- 18 radio labelling is achieved using direct labelling of the compound of Example 2 with [ 18 F]fluoride.
  • Example 4 In vitro inhibition ofMAO-A and MAO-B Assay development was carried out based on the standard protocol provided in product insert for Amplex Red Monoamine Oxidase Assay Kit from Life Technologies.
  • Negative control/"MIN 1% DMSO Buffer without enzyme (substrate alone)
  • Stock solution will be prepared from solid samples and serial dilutions will be made on a semi-log scale while maintaining the final concentration of the DMSO in the assay as determined under tolerability study.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • Pathology (AREA)
  • Analytical Chemistry (AREA)
  • Cell Biology (AREA)
  • General Physics & Mathematics (AREA)
  • Food Science & Technology (AREA)
  • Organic Chemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Oncology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Psychiatry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne des composés se liant de manière sélective à la MAO-B par rapport à la MAO-A. L'invention concerne également des versions radioactives de ces composés, et des composés précurseurs pour la synthèse de ces composés radioactifs. Les composés radioactifs de l'invention peuvent s'utiliser dans des applications d'imagerie in vivo.
PCT/EP2015/080618 2014-12-19 2015-12-18 Dérivés d'oxazolidinone marqués Ceased WO2016097355A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1422759.9 2014-12-19
GB201422759 2014-12-19

Publications (1)

Publication Number Publication Date
WO2016097355A1 true WO2016097355A1 (fr) 2016-06-23

Family

ID=54937083

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2015/080618 Ceased WO2016097355A1 (fr) 2014-12-19 2015-12-18 Dérivés d'oxazolidinone marqués

Country Status (1)

Country Link
WO (1) WO2016097355A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996038444A1 (fr) * 1995-06-02 1996-12-05 Synthelabo Derives d'oxazolidinone, leur preparation et leur application en therapeutique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996038444A1 (fr) * 1995-06-02 1996-12-05 Synthelabo Derives d'oxazolidinone, leur preparation et leur application en therapeutique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HICKS, JUSTIN W. ET AL: "Radiosynthesis and ex vivo evaluation of [18F]-(S)-3-(6-(3-fluoropropoxy)benzo[d]isoxazol-3-yl)-5- (methoxymethyl)oxazolidin-2-one for imaging MAO-B with PET", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 25, no. 2, 2015, pages 288 - 291, XP002755461, DOI: 10.1016/J.BMCL.2014.11.048 *
SABA, WADAD ET AL: "[11C]SL25.1188, a new reversible radioligand to study the monoamine oxidase type B with PET: Preclinical characterization in nonhuman primate", SYNAPSE, vol. 64, no. 1, 2010, pages 61 - 69, XP002755462, DOI: 10.1002/SYN.20703 10.1002/SYN.20703 *

Similar Documents

Publication Publication Date Title
US12070513B2 (en) PSMA-binding agents and uses thereof
US20110250136A1 (en) Fluorinated benzothiazole derivatives, preparation method thereof and imaging agent for diagnosing altzheimer's disease using the same
JP5851493B2 (ja) 原発性高アルドステロン症の両側性状態と片側性状態との鑑別診断のためのｐｅｔ放射性医薬
EP3684781A1 (fr) Composés activés par bioréduction, leurs promédicaments, produits radiopharmaceutiques, les compositions et leurs applications dans la gestion théranostique multimodale de l'hypoxie, dont le cancer
CN114230505A (zh) 一种氟-18标记靶向p2x7受体分子探针的制备及其动物模型pet成像应用
WO2016097339A1 (fr) Dérivés de coumarine marqués
WO2016097355A1 (fr) Dérivés d'oxazolidinone marqués
EP2900278B1 (fr) Produit radiopharmaceutique pour le diagnostic et la thérapie des cancers de la glande surrénale.
AU2013319747A1 (en) F-18 radiolabeled compounds for diagnosing and monitoring kidney function
US9186424B2 (en) Aryloxyanilide imaging agents
WO2016097351A1 (fr) Dérivés de thiazolylhydrazone marqués au 18f
JP2014521628A (ja) 新規化合物
US20180064742A1 (en) Pet imaging tracer for imaging prostate cancer
JP7284490B2 (ja) モノアミンオキシダーゼｂイメージングプローブ
KR101824412B1 (ko) 종양 진단용 방사성 동위원소 표지 화합물 및 전구체 화합물
WO2016097345A1 (fr) Dérivés de chromone marqués
CN113845448A (zh) 一种放射性18f标记化合物及其应用
JPH085882B2 (ja) 新規なヨ−ドスピロペリド−ル誘導体およびその製造法
HK1195053A (en) Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15813446

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15813446

Country of ref document: EP

Kind code of ref document: A1