WO2019134765A1 - Analogue de sartan - Google Patents

Analogue de sartan Download PDF

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Publication number
WO2019134765A1
WO2019134765A1 PCT/EP2018/077897 EP2018077897W WO2019134765A1 WO 2019134765 A1 WO2019134765 A1 WO 2019134765A1 EP 2018077897 W EP2018077897 W EP 2018077897W WO 2019134765 A1 WO2019134765 A1 WO 2019134765A1
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WO
WIPO (PCT)
Prior art keywords
sartan
compound
residue
group
acid
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PCT/EP2018/077897
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English (en)
Inventor
Xinyu Chen
Michael Decker
Takahiro Higuchi
Matthias Hoffmann
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Julius-Maximilians-Universitaet Wuerzburg
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Publication of WO2019134765A1 publication Critical patent/WO2019134765A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention concerns a sartan analogue comprising a fluorine atom, in particular a radioisotope of fluorine, in particular 18 F.
  • Sartan analogues comprising a fluorine atom are known in the art.
  • Sartans are angiotensin II subtype 1 receptor antagonists also called ATi receptor antagonists.
  • the renin angiotensin aldosterone system is a hormonal cascade that gen- erates angiotensin peptides and is the main regulator of blood pressure as well as fluid and electrolyte balance.
  • the key factor is octapeptide angiotensin II, which is generated in a well described cascade and stimulates mainly angiotensin II type 1 receptor (ATi), a G-protein coupled receptor (GPCR), and thereby initiates further downstream effects.
  • ATi receptors are mainly located in the heart, blood vessels and kidney. They are considered responsible for cardiovascular reactions, such as hypertension and heart failure (HF), the treatment of which is the major therapeutic target of ATi antagonists.
  • radionuclide techniques In contrast to anatomical techniques, such as computed tomography (CT), ultra- sound or radiography, molecular imaging using radionuclide techniques focuses on small-scale molecular events. It provides a non-invasive method for the moni- toring of functional changes in individual organs, with higher sensitivity, specificity and the possibility of quantifying these alterations.
  • Molecular imaging using radio- nucleotides can be performed, e. g., by means of positron emission tomography (PET) or single-photon emission computed tomography (SPECT).
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • WO 2004/062568 A2 discloses a contrast agent of formula V - L - Z, wherein V is a non-peptidic vector having affinity for the angiotensin II receptor, L is a bond, a spacer or a linker moiety and Z represents a moiety detectable in an in vivo imag- ing procedure of a human or animal body.
  • V may be losartan, valsartan, candesar- tan, eprosartan or derivatives thereof.
  • Z may comprise an imaging moiety compris- ing radionucleotides such as 90 Y, 99m Tc, 111 In, 47 Sc, 67 Ga, 51 Cr, 177m Sn, 67 Cu,
  • the compound may comprise a moiety Z carrying one or more imaging moieties M useful in the PET imaging modality. M may then be a radioemitter with positron-emitting properties, such as 18 F.
  • the document also discloses preparation of a contrast medium comprising a radioactive tracer for use in a method of diagnosis involving administering that contrast medium to a human or animal body and generating an image of at least part of that body.
  • a 11 C-labelled ATi-selective angiotensin-ll receptor antagonist is known from Mathews WB, Burns D, Dannals RF, Ravert FIAT, Naylor EM, "Carbon-11 labeling of a potent, nonpeptide, ATi-selective angiotensin-ll receptor antagonist: MK-996", Journal of Labelled Compounds and Radio-pharmaceuticals, 1995, 36(8): 729- 737.
  • the methoxyl analog [ 11 C]KR31173 of non-peptide ATi-selective antagonist SK1080 is the most intensively developed and investigated RAS tracer (Mathews WB, Yoo SE, Lee SH, Scheffel U, Rauseo PA, Zober TG, Gocco G, Sandberg K, Ravert HT, Dannals RF, Szabo Z, "A novel radioligand for imaging the ATi angio- tensin receptor with PET", Nucl. Med. Biol.
  • the problem to be solved by the present invention is to provide an alternative an- giotensin II receptor antagonist and in particular an alternative angiotensin II re- ceptor antagonist detectable by PET.
  • a further problem to be solved by the pre- sent invention is to provide such an angiotensin II receptor antagonist for specific uses and a method for synthesizing such an angiotensin II receptor antagonist.
  • a sartan analogue on basis of a sartan which sartan comprises an alkyl group or an alkoxy group is provided.
  • the sartan analogue only differs from the sartan by a replacement of the alkyl group or the alkoxy group or replacement of a methyl residue or a hydrogen residue of the alkyl group or of the alkoxy group by a fluorine atom.
  • the alkyl group may be methyl, e. g. in case of tasosartan.
  • the alkyl group is butyl.
  • the advantage of the sartan analogue according to the invention is that the struc- ture activity relationship (SAR) of the sartan analogue differs not or only very little from the SAR of the sartan on which a sartan analogue is based.
  • Fluorine is of smaller size than hydrogen and has neutral properties as well.
  • the modification maintains the affinity of the basic sartan to the ATi receptor or influences this affin ity only little.
  • the modification of the basic sartan for introducing the fluorine atom is sterically smaller than the modifications known in the state of the art described above.
  • the pharmacodynamics and pharmacokinetics of the sartan analogue according to the invention can be improved with respect to its basic sartan, for instance, by de- creased liver uptake and/or decreased metabolism.
  • the fluorine atom may be a radioactive isotope of fluorine and in particular 18 F allowing to use the sartan analogue as a PET tracer the sartan analogue corn- prising a non-radioactive fluorine atom may be advantageous with respect to its pharmacodynamics and pharmacokinetics and therefore may be used as a medic- ament.
  • the medicament may be a medicament for the treatment of cardiovascular diseases such as hypertension or heart failure.
  • the sartan analogue comprising the non-radioactive fluorine atom can be used to explore different ways of syntheses that can then be used for syn- thesis of a sartan analogue comprising a radioactive isotope of fluorine.
  • the sartan analogue comprising a non-radioactive fluorine atom may also be used for exploring pharmacokinetics, pharmacodynamics and receptor binding of the sartan analogue.
  • the sartan is tasosartan or the alkyl group or the alkoxy group comprises at least two consecutive terminal carbon atoms.
  • the fluorine atom in the sartan analogue may then be located at the terminal carbon atom.
  • the sartan is saprisartan or eprosartan.
  • the sartan analogue may include i. a biphenyl group, ii. an imidazole group or a benzimidazole group and/or iii. a tetrazole residue, an oxadiazolone residue, or a carboxy residue.
  • the sartan may be candesartan or azilsartan.
  • the alkyl group may be linear and comprise more than two carbon atoms.
  • the sartan may be losartan, irbesartan, olmesartan, candesartan, valsartan, telmisartan, milfasartan, pomisartan, pratosartan, ripisartan, or fimasartan, in par- ticular losartan, irbesartan, candesartan, or valsartan.
  • the sartan ana- logue may be F-valsartan ((S)-2-(N-((2'-(1 H-tetrazol-5-yl)-[1 ,T-biphenyl]-4-yl)me- thyl)-5-fluoropentanamido)-3-methylbutanoic acid), in particular 18 F-valsartan.
  • the sartan analogue accord- ing to the invention may be used in a diagnostic method for detecting and localiz ing angiotensin II receptors for diagnosing disorders in a human or animal body by an imaging technique in vivo.
  • the sartan analogue is adminis- tered to the human or animal body and subsequently an image of at least a part of that body is generated on basis of a radioactive emission of the radioactive isotope.
  • the imaging technique may be or may comprise positron emission tomog- raphy (PET).
  • the invention further concerns a method for synthesizing a sartan analogue ac- cording to the invention comprising the following steps: a) Providing a precursor of the sartan analogue and in case said precursor comprises a/the carboxy residue, protecting the carboxy residue by coupling a pro- tection group to the C-atom of the carboxy group via an ester binding and in case said precursor comprises a/the tetrazole residue or an/the oxadiazolone residue, protecting the acidic NH-group in said residue by coupling a protection group to the N-atom of said NH-group, b) replacing the alkyl group, the alkoxy group, the methyl residue or the hydro- gen residue to be replaced by the fluorine atom by a leaving group coupled via an ester binding to the rest of the precursor or by iodine or bromide, c) incubating the molecule resulting from step b) together with a fluoride and a fluoride complex
  • the precursor may be a molecule that differs from the sartan analogue according to the invention only at the position that will be oc cupied by the fluorine atom in the sartan analogue.
  • the precursor is a molecule comprising the alkyl group or the alkoxy group, wherein the molecule is a compound used in synthesis of the sartan analogue.
  • the protection group may be benzyl or terf-butyl.
  • the cryptand may be
  • the leaving group may be a tosyl group, iodine, or bromine.
  • the crown ether may be 18-crown-6, the polar aprotic solvent may be dimethylformamide (DMF) or acetonitrile.
  • the acid may be hydrochloric acid, hydrobromic acid, trifluoroacetic acid, trichloroacetic acid, or formic acid.
  • the sartan analogue may be fluorine valsartan.
  • the method may corn- prise the following steps: a) Providing 5-chlorovaleric acid, b) protecting the carboxyl group by esterification with a benzyl group for ob- taining a compound 12, c) replacing chlorine in compound 12 by iodine through Finkelstein reaction for obtaining a compound 13, d) replacing the iodine in compound 13 with tosylate using silver tosylate for obtaining a compound 14, e) removing the benzyl ester in compound 14 selectively under mild hydro- genation condition without affecting the tosylate for obtaining an acid, f) reacting said acid with oxalyl chloride in dichloromethane to form an acid chloride, g) reacting said acid chloride with (S)-terf-butyl 3-methyl-2-(((2'-(1 -trityl-1 H-te- trazol-5-y
  • the method may comprise the following steps when the sartan ana- logue is fluorine valsartan: a) Providing 5-chlorovaleric acid, b) protecting the carboxyl group by esterification with a benzyl group for ob- taining a compound 12, c) replacing chlorine in compound 12 by iodine through Finkelstein reaction for obtaining a compound 13, d) replacing the iodine in compound 13 with tosylate using silver tosylate for obtaining a compound 14, e) Incubating compound 14, a fluoride and 18-crown-6 in dimethylformamide at a temperature between 90 and 150 °C for obtaining a compound 15, f) removing the benzyl ester in compound 15 selectively under mild hydro- genation condition without affecting the tosylate for obtaining an acid, g) reacting said acid with oxalyl chloride in dichloromethane to form an acid chloride, h) reacting said acid chloride
  • the fluoride may be 18 F-fluoride.
  • Fig. 1 shows the chemical structures of valsartan and 18 F-valsartan
  • Fig. 2 shows a reaction scheme for two different syntheses of fluorine valsar- tan
  • Fig. 3 shows PET images of rat kidneys 10 minutes after i. v. injection of 18 F- valsartan
  • Fig. 4 shows dynamic coronal PET images of rat kidneys at different times af- ter i. v. injection of 18 F-valsartan
  • Fig. 5 shows a reaction scheme for the synthesis of w-F-irbesartan (MD149),
  • Fig. 6 shows a reaction scheme for synthesis of a-F-irbesartan (MD147)
  • Fig. 7 shows a reaction scheme for the preparation of precursor compound 39 and radiolabeling of this compound to achieve [ 18 F]MD147,
  • Fig. 8 shows the results of radioligand competition binding studies on human
  • Fig. 9 shows dynamic coronal and sagittal PET images of pig kidneys at differ ent times after i. v. injection of [ 18 F]MD147,
  • Fig. 10 A shows PET images of rat kidneys after i. v. injection of 18 F-irbesartan
  • Fig. 10 B shows results of kidney tracer uptake in rats after i. v. injection of 18 F- irbesartan and
  • Fig. 10 C shows results of tracer uptake in several rat organs after i. v. injection of
  • FIG. 1 The chemical structures of valsartan and the 18 F-labelled radiotracer [ 18 F] F-valsar- tan (FV45) are shown in Fig. 1 .
  • Valsartan is shown on the left side of Fig. 1 and [ 18 F]FV45 on the right side of Fig. 1 .
  • 5-Chlorovaleric acid 5 was first esterified to protect the carboxyl group.
  • "Bn" means benzyl in the figures. Chlorine in compound 12 was replaced by iodine through Finkelstein reaction. This gave the possibility of replacing the iodine in compound 13 with tosylate using silver tosylate, which was obtained by mixing equal molar quantities of silver oxide with 4-toluenesulfonic acid in acetonitrile in darkness. The fluorine could therefore be introduced to the "tail" of the acyl chain for subsequent synthesis of non-radioactive "cold" reference. By this means fluori- nation conditions could also be tested as a reference for the radiolabeling proce- dure.
  • the acid 16 was reacted with oxalyl chloride in dry dichloromethane to form the acid chloride 17, which was then reacted with diphe- nyl valinate moiety 7, and formed the precursor 10 available for labeling after puri fication and characterization.
  • the "cold" reference FV45 was synthesized analo- gously as the precursor, with the only difference of using benzyl valinate 20 in- stead of terf-butyl ester. Benzyl ester is more stable during the preparation, whereas terf-butyl ester in the precursor will be conveniently removed after the la- beling together with trityl group in acidic condition.
  • the mix- ture was cooled, diluted with 1 mL of mixture solution of water and acetonitrile (1 : 1 ), and applied to the semi-preparative HPLC column (ZORBAX Eclipse XDB- C18, 5 pm, 9.4 x 250 mm, linear gradient of 50-95% methanol with 0.1 % formic acid, 3 mL/min).
  • the average overall radiochemical yield was 21.8 ⁇ 8.5% (decay- corrected based on starting activity, calculated from 5 times of labeling records) and > 99% radiochemical purity.
  • 5 mL water was added to the collected solution containing radioactive tracer.
  • Benzyl 5-chlorovalerate 12 (3.17 g, 13.98 mmol) was dissolved in acetone. So- dium iodide (2.60 g, 17.35 mmol) was added to the solution. This mixture was heated to reflux under argon for 5 h. The formed white solid was filtered off and the filtrate was removed under vacuum. The residue was diluted with diethyl ether (30 ml_) and washed with water (10 ml_) and then brine (10 ml_). The organic phase was dried over sodium sulfate and concentrated under vacuum to afford the product as colorless oil (3.51 g, 79%).
  • Radiolabeling of compound 39 to [ 18 F]MD147 was performed analogously to that of compound 10 to [ 18 F]FV45.
  • [ 18 F]F _ produced via proton bombardment of H2 18 0 was isolated by trapping on Sep-Pak Light QMA cartridge, followed by washing with 3 mL water. Fluoride was eluted with a mixture of a solution of K2CO3 in 0.3 mL of water (50.6 mM) and a solution of Kryptofix 2.2.2. (14 mg) in 0.7 mL of acetonitrile into a sealed glass vial. The solution was dried with azeotropic condi- tion under argon flow at 120 °C.
  • the radiolabeled [ 18 F]MD147 was ob- tained at retention time 14 min. Overall, the total synthesis time of labeling is ⁇ 120 min. The average overall radiochemical yield was 25.6 ⁇ 7.1 % (decay-cor- rected based on starting activity, calculated from 5 times of labeling records) and > 99% radiochemical purity.
  • 5 ml_ water was added to the collected solution containing radioactive tracer. The solution was then passed through a Sep-Pak plus cartridge (C18), washed with 4 ml_ of water and eluted with 3 ml_ of diethyl ether. The organic solution was concentrated at 50 °C and could be diluted with saline to appropriate concentration for the imaging studies.
  • [ 18 F]FV45 was obtained as described above. Rats were maintained under anes- thesia by 2% isoflurane during the whole experiment. [ 18 F]FV45 (20-25MBq) was administered via the tail vain. A 60 min list-mode PET acquisition was started shortly after injection. The data obtained in rats demonstrated distinct [ 18 F]FV45 accumulation in the kidneys: tissue activity, mainly renal cortex, was fast and high in the control animal after 10 min of injection (Fig. 3 left and Fig. 4 above). Cold (non-labeled) valsartan, which was administered 3 hours (oral, 30 mg) and 10 min (i.
  • assay buffer 50 mM Tris*HCI, 5 mM MgC , pH 7.4
  • Fig. 8 Nonspecific binding of 125 l-Sar 1 -lle 8 -AII was estimated in the presence of 10 M unlabeled All. Specific binding was defined as total binding mi- nus nonspecific binding. All data were generated in triplicates. Results are ex- pressed as percent of control 125 l-Angiotensin II binding. In Fig.
  • ICso of angiotensin II is 1 .96 nM. The results show clear binding of all tested compounds with ICso values similar to that of All.
  • Fig. 9 shows dynamic kidney uptake of [ 18 F]MD147 as control (top) and after blocking by selective ATi receptor blocker irbesartan (bottom) with time frames of 30 to 45 min after tracer administration.
  • "SUV" means "standardized uptake value”.
  • Fig. 9, top shows a high tracer uptake as there is a high density of ATi re- ceptors present. This effect was reduced by the injection of 2 mg/kg of irbesartan 10 min before injection of tracer proving specific binding (Fig. 9, bottom).
  • [ 18 F]MD147 (10 MBq) was injected intravenously in anaesthetized rats (Wister, anaesthetized with 2% isoflurane). PET-data were acquired and reconstructed into images of 5 min time frames.
  • Fig. 10 A shows dynamic kidney uptake of
  • the good up- take of tracer into kidney tissue proves the suitability of [ 18 F]MD147 for renal imag- ing.
  • Selective binding of tracer was confirmed by the pretreatment with non-la- belled irbesartan 5 min before tracer injection. The pretreatment significantly re- prised renal retention with no clear delineation of kidneys 10 min after tracer ad- ministration.
  • Uptake of [ 18 F]MD147 is expressed as SUV.
  • the data reveal that tracer [ 18 F]MD147 is taken up into all rele- vant tissues expressing ATi receptors such as heart, kidney and lung, while tracer uptake can be reduced significantly by blocking with non-radioactive drug irbesar- tan 5 min before tracer injection. Almost no uptake into other organs such as mus- cle could be detected. Metabolic degradation might be the cause of bone accumu- lation of 18 F-fluoride, but there was minimal bone uptake at current imaging stud- ies, indicating high metabolic stability of the tracer during the timeframe of the PET-study.

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Abstract

L'invention concerne un analogue de sartan sur la base d'un sartane qui comprend un groupe alkyle ou un groupe alcoxy, l'analogue de sartan étant différent du sartan seulement par un remplacement du groupe alkyle ou du groupe alcoxy ou le remplacement d'un résidu méthyle ou d'un résidu d'hydrogène du groupe alkyle ou du groupe alcoxy par un atome de fluor.
PCT/EP2018/077897 2018-01-08 2018-10-12 Analogue de sartan WO2019134765A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004062568A2 (fr) 2003-01-09 2004-07-29 Amersham Health As Agent de contraste

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004062568A2 (fr) 2003-01-09 2004-07-29 Amersham Health As Agent de contraste

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
A. M. AMIN ET AL: "Radioiodination and biological evaluation of valsartan as a tracer for cardiovascular disorder detection", NATURAL SCIENCE, vol. 05, no. 04, 1 January 2013 (2013-01-01), pages 526 - 531, XP055484080, ISSN: 2150-4091, DOI: 10.4236/ns.2013.54066 *
ARKSEY N; HADIZAD T; ISMAIL B; HACHEM M; VALDIVIA AC; BEANLANDS RS; DEKEMP RA; DASILVA JN: "Synthesis and evaluation of the novel 2-[18F]fluoro-3-propoxy-triazole-pyridine-substituted losartan for imaging AT receptors", BIOORG. MED. CHEM., vol. 22, no. 15, 2014, pages 3931 - 7, XP029009845, DOI: doi:10.1016/j.bmc.2014.06.011
DION VAN DER BORN ET AL: "Fluorine-18 labelled building blocks for PET tracer synthesis", CHEMICAL SOCIETY REVIEWS, vol. 46, no. 15, 1 January 2017 (2017-01-01), pages 4709 - 4773, XP055484032, ISSN: 0306-0012, DOI: 10.1039/C6CS00492J *
HACHEM M; TIBERI M; ISMAIL B; HUNTER CR; ARKSEY N; HADIZAD T; BEANLANDS RS; DEKEMP RA; DASILVA JN: "Characterization of 18F-FPyKYNE-losartan for imaging AT receptors", J. NUCL. MED., vol. 57, no. 10, 2016, pages 1612 - 7, XP055483242, DOI: doi:10.2967/jnumed.115.170951
HIGUCHI T; FUKUSHIMA K; XIA J; MATHEWS WB; LAUTAMAKI R; BRAVO PE; JAVADI MS; DANNALS RF; SZABO Z; BENGEL FM: "Radionuclide imaging of angiotensin II type 1 receptor upregulation after myocardial ischemia-reperfusion injury", J. NUCL. MED., vol. 51, no. 12, 2010, pages 1956 - 1961
M. HACHEM ET AL: "Characterization of 18F-FPyKYNE-Losartan for Imaging AT1 Receptors", THE JOURNAL OF NUCLEAR MEDICINE, vol. 57, no. 10, 19 May 2016 (2016-05-19), US, pages 1612 - 1617, XP055483242, ISSN: 0161-5505, DOI: 10.2967/jnumed.115.170951 *
MATHEWS WB; BURNS D; DANNALS RF; RAVERT HAT; NAYLOR EM: "Carbon-11 labeling of a potent, nonpeptide, ATi-selective angiotensin-II receptor antagonist: MK-996", JOURNAL OF LABELLED COMPOUNDS AND RADIO-PHARMACEUTICALS, vol. 36, no. 8, 1995, pages 729 - 737
MATHEWS WB; YOO SE; LEE SH; SCHEFFEL U; RAUSEO PA; ZOBER TG; GOCCO G; SANDBERG K; RAVERT HT; DANNALS RF: "A novel radioligand for imaging the AT angiotensin receptor with PET", NUCL. MED. BIOL., vol. 31, no. 5, 2004, pages 571 - 574, XP004517603, DOI: doi:10.1016/j.nucmedbio.2003.10.014
ZOBER TG; MATHEWS WB; SECKIN E; YOO SE; HILTON J; XIA J; SANDBERG K; RAVERT HT; DANNALS RF; SZABO Z: "PET imaging of the AT receptor with [''C]KR31173", NUCL. MED. BIO., vol. 33, no. 1, 2006, pages 5 - 13

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