WO2007137135A2 - Analogues de roténone, méthode de préparation et d'utilisation - Google Patents

Analogues de roténone, méthode de préparation et d'utilisation Download PDF

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Publication number
WO2007137135A2
WO2007137135A2 PCT/US2007/069178 US2007069178W WO2007137135A2 WO 2007137135 A2 WO2007137135 A2 WO 2007137135A2 US 2007069178 W US2007069178 W US 2007069178W WO 2007137135 A2 WO2007137135 A2 WO 2007137135A2
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Prior art keywords
group
independently
different
same
lower alkyl
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PCT/US2007/069178
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English (en)
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WO2007137135A3 (fr
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James P. O'neil
Henry F. Van Brocklin
Nandanan Erathodiyil
Andrew R. Gibbs
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The Regents Of The University Of California
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Publication of WO2007137135A2 publication Critical patent/WO2007137135A2/fr
Publication of WO2007137135A3 publication Critical patent/WO2007137135A3/fr
Priority to US12/273,509 priority Critical patent/US8551448B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/16—Peri-condensed systems
    • 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
    • A61K51/0412—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K51/0421—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/22—Tin compounds
    • C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen

Definitions

  • tracers Although several tracers are currently available for perfusion imaging, all of these tracers suffer from one or more limitations which render them less than ideal agents for assessment of cardiac perfusion (e.g., limited extraction at high flow (Tc99m-sestamibi, Tl-201 Chloride) (Marshall et al, 1990), lack of ideal isotope (Tl- 201 chloride), high liver extraction (Tc99m-teboroxime and Tc99m-sestamibi) (Marshall et al, 1991).
  • Tc99m-sestamibi Tl-201 Chloride
  • Tc99m- 201 chloride high liver extraction
  • Tc99m-teboroxime and Tc99m-sestamibi Marshall et al, 1991.
  • the radiolabel is a gamma-radiation emitting radionuclide and the radiotracer is located using a gamma-radiation detecting camera (this process is often referred to as gamma scintigraphy).
  • the imaged site is detectable because the radiotracer is chosen either to localize at a pathological site (termed positive contrast) or, alternatively, the radiotracer is chosen specifically not to localize at such pathological sites (termed negative contrast).
  • Rotenone has a high affinity for mitochondria.
  • the myocardium is an organ rich in mitochrondria. Novel radiolabeled rotenone analogs that display efficient myocardial uptake and adequate myocardial retention are attractive candidates for clinical evaluation of myocardial blood flow.
  • Rotenone is a specific, high-affinity inhibitor of Complex I (NADH ubiquinone oxidoreductase), the proximal enzyme of the mitochondrial electron transport chain. Since rotenone inhibition defines the activity of Complex I, defects in radiotracer binding can be expected to reflect functional changes in the enzyme, and hence, abnormalities of the mitochondrial energy metabolism.
  • Complex I NADH ubiquinone oxidoreductase
  • the present invention provides rotenone analogs and methods of using them.
  • X is independently the same or different and is selected from the group consisting of O and S;
  • Xi is selected from the group consisting of SnMe 3 , SnBu 3 , B(-OCH 2 C(CH 3 ) 2 CH 2 O-), BF 3 K, ZnI, ZnBr, Br, Cl, F, CH 2 F, CH 2 CH 2 F, C 6 H 4 F, and CH 2 C 6 H 4 F;
  • X 2 is selected from the group consisting of O and S;
  • R is independently the same or different and is selected from the group consisting of H, lower alkyl, and a halogen; and R' is independently the same or different and is a lower alkyl; and
  • R" is independently the same or different and is selected from the group consisting of H and a lower alkyl; and
  • R 3 is independently the same or different and is selected from the group consisting of H, lower alkyl, and CH 2 F; and wherein the stereochemical configuration at any stereocenter is R, S or
  • X is independently the same or different and is selected from the group consisting of O and S, and wherein at least one X is S;
  • Xi is selected from the group consisting of SnMe 3 , SnBu 3 , 6(-OCH 2 C(CHs) 2 CH 2 O-), BF 3 K, ZnI, ZnBr, Br, Cl, I, F, CH 2 F, CH 2 CH 2 F, C 6 H 4 F, and CH 2 C 6 H 4 F;
  • X 2 is selected from the group consisting of O and S;
  • R is independently the same or different and is selected from the group consisting of H, lower alkyl, and a halogen;
  • R' is independently the same or different and is a lower alkyl; and
  • R' ' is independently the same or different and is selected from the group consisting of H and a lower alkyl; and
  • R 3 is independently the same or different and is selected from the group consisting of H, lower alkyl, and CH 2 F; and
  • X is independently the same or different and is selected from the group consisting of O and S;
  • Xi is selected from the group consisting of SnMe 3 , SnBu 3 , B(-OCH 2 C(CH 3 ) 2 CH 2 O-), BF 3 K, ZnI, ZnBr, Br, Cl, I, F, CH 2 F, CH 2 CH 2 F, C 6 H 4 F, and CH 2 C 6 H 4 F;
  • X 2 is selected from the group consisting of O and S;
  • R is independently the same or different and is selected from the group consisting of H, lower alkyl, and halogen;
  • R' is independently the same or different and is a lower alkyl;
  • R" is independently the same or different and is selected from the group consisting of H and lower alkyl; and
  • R 3 is independently the same or different and is selected from the group consisting of H, lower alkyl, and CH 2 F; and wherein the stereochemical configuration at any stereocenter is R, S or a
  • X is independently the same or different and is selected from the group consisting of O and S;
  • Xi is selected from the group consisting of SnMe 3 , SnBu 3 , B(-OCH 2 C(CH 3 ) 2 CH 2 O-), BF 3 K, ZnI, ZnBr, Br, Cl, F, CH 2 F, CH 2 CH 2 F, C 6 H 4 F, and CH 2 C 6 H 4 F;
  • X 2 is selected from the group consisting of OH, OR, OPg, SH, SR, and SPg;
  • R is independently the same or different and is selected from the group consisting of H, lower alkyl, and a halogen;
  • R' is independently the same or different and is a lower alkyl; and
  • R' ' is independently the same or different and is selected from the group consisting of H and a lower alkyl;
  • R 3 is independently the same or different and is selected from the group consisting of H, lower alkyl, and CH 2 F;
  • X is independently the same or different and is selected from the group consisting of O and S, and further wherein at least one X is S;
  • Xi is selected from the group consisting of SnMe 3 , SnBu 3 , 6(-OCH 2 C(CHs) 2 CH 2 O-), BF 3 K, ZnI, ZnBr, Br, Cl, I, F, CH 2 F, CH 2 CH 2 F, C 6 H 4 F, and CH 2 C 6 H 4 F;
  • X 2 is selected from the group consisting of OH, OR, OPg, SH, SR, and SPg;
  • R is independently the same or different and is selected from the group consisting of H, lower alkyl, and a halogen; and
  • R' is independently the same or different and is a lower alkyl; and
  • R" is independently the same or different and is selected from the group consisting of H and a lower alkyl;
  • R 3 is independently the same or different and is selected from the group consisting of
  • X is independently the same or different and is selected from the group consisting of O and S;
  • Xi is selected from the group consisting of SnMe 3 , SnBu 3 , B(-OCH 2 C(CH 3 ) 2 CH 2 O-), BF 3 K, ZnI, ZnBr, Br, Cl, I, F, CH 2 F, CH 2 CH 2 F, C 6 H 4 F, and CH 2 C 6 H 4 F;
  • X 2 is selected from the group consisting of OH, OR, OPg, SH, SR, and SPg;
  • R is independently the same or different and is selected from the group consisting of H, lower alkyl, and halogen;
  • R' is independently the same or different and is a lower alkyl;
  • R" is independently the same or different and is selected from the group consisting of H and lower alkyl;
  • R 3 is independently the same or different and is selected from the group consisting of H, lower alkyl, and CH 2 F; and wherein the stereo
  • the present invention provides a compound having the structure:
  • X is independently the same or different and is selected from the group consisting of O and S;
  • R is independently the same or different and is selected from the group consisting of H, lower alkyl, and halogen;
  • R' is independently the same or different and is a lower alkyl;
  • R' ' is independently the same or different and is selected from the group consisting of H and lower alkyl;
  • R 3 is independently the same or different and is selected from the group consisting of H, lower alkyl, and CH 2 F;
  • R 4 is independently the same or different and is selected from the group consisting of H, alkyl, and aryl;
  • R5 is selected from the group consisting of CH 2 CH(OH)CH 2 F, CH 2 C 6 H 4 F, COC 6 H 4 F, and CH 2 CH 2 F; and wherein the stereochemical configuration at any stereocenter is R,
  • X is independently the same or different and is selected from the group consisting of O and S;
  • R is independently the same or different and is selected from the group consisting of H, lower alkyl, and halogen;
  • R' is independently the same or different and is a lower alkyl;
  • R' ' is independently the same or different and is selected from the group consisting of H and lower alkyl;
  • R 3 is independently the same or different and is selected from the group consisting of H, lower alkyl, and CH 2 F;
  • R 4 is independently the same or different and is selected from the group consisting of H, alkyl, and aryl;
  • R 5 is selected from the group consisting of 11 CH 3 and 11 CH 3 CH 2 ; and wherein the stereochemical configuration at any stereocenter is R, S or a mixture of these configurations.
  • the present invention provides a compound having the structure:
  • X is independently the same or different and is selected from the group consisting of O and S;
  • R is independently the same or different and is selected from the group consisting of H, lower alkyl, and halogen;
  • R' is independently the same or different and is a lower alkyl;
  • R' ' is independently the same or different and is selected from the group consisting of H and lower alkyl;
  • R 3 is independently the same or different and is selected from the group consisting of H, lower alkyl, and CH 2 F;
  • R 4 is selected from the group consisting of 11 CH 3 , 12 CH 3 , 11 CH 3 CH 2 , and 12 CH 3 CH 2 ; and wherein the stereochemical configuration at any stereocenter is R, S or a mixture of these configurations.
  • the present invention provides a compound having the structure:
  • X is independently the same or different and is selected from the group consisting of O and S;
  • X 2 is selected from the group consisting of O and S;
  • R is independently the same or different and is selected from the group consisting of H, lower alkyl, and halogen;
  • R' is independently the same or different and is a lower alkyl;
  • R" is independently the same or different and is selected from the group consisting of H and lower alkyl;
  • R 3 is selected from the group consisting of 11 CH 3 , 11 CH 3 CH 2 , and 12 CH 3 CH 2 H 2 F; and wherein the stereochemical configuration at any stereocenter is R, S or a mixture of these configurations.
  • X is independently the same or different and is selected from the group consisting of O and S;
  • R is independently the same or different and is selected from the group consisting of H, lower alkyl, and halogen;
  • R' is independently the same or different and is a lower alkyl;
  • R' ' is independently the same or different and is selected from the group consisting of H and lower alkyl;
  • R 2 is selected from the group consisting Of 11 CH 3 , 12 CH 3 , 11 CH 3 CH 2 , and 12 CH 3 CH 2; and
  • R 3 is independently the same or different and is selected from the group consisting of H, lower alkyl, and CH 2 F; wherein the stereochemical configuration at any stereocenter of the compound is R, S or a mixture of these configurations.
  • one or more halogen in the compounds disclosed herein may be further defined as a halogen isotope.
  • halogen isotopes that may be incorporated in the compounds of the present invention include, 18 F, 19 F, 35 Cl, 37 Cl, 75 Br, 76 Br, 77 Br, 79 Br, 80 Br, 80m Br, 81 Br, 120 I, 121 I, 122 I, 123 I, 124 I, 125 I, 127 I, and 131 I.
  • one or more carbon in the compounds disclosed herein may be further defined as a carbon isotope, such as 12 C or 11 C.
  • one or more Se in the compounds disclosed herein may be further defined as a Se isotope, such as 73 Se or 75 Se.
  • the present invention provides a kit comprising, in suitable container means, at least one rotenone analog compound of the present invention.
  • the rotenone analog may be provided in the kit as a labeled rotenone analog or it may be provided as an unlabelled intermediate compound.
  • a diagnostic kit of the present invention may comprise, for example, a labeled rotenone analog and a pharmaceutically acceptable vehicle.
  • the kit may have a single container means or it may have distinct container means for each compound.
  • the diagnostic kit may further comprise a syringe or other device for administering a labeled rotenone analog and a pharmaceutically acceptable vehicle to a subject.
  • the diagnostic kit may further comprise instructions for using the components of the kit.
  • the present invention provides a method of imaging a region in a patient comprising: (a) administering to a patient a diagnostically effective amount of a composition comprising a labeled rotenone analog and a pharmaceutically effective vehicle; (b) exposing a region of the patient to radiation; and (c) obtaining an image of the region of the patient.
  • the region is the heart. In other aspects of the invention the region is the brain.
  • the composition is administered in a volume of about 1 to 10 mL.
  • the concentration of the labeled rotenone analog administered to the patient is about 1.0 to 50 millicuries. In some embodiments the concentration is about 1.0 to 10, 10 to 20, 20 to 30, 30 to 40, or 40 to 50 millicuries.
  • the composition is administered by intraarterial injection or intravenous injection.
  • the present invention provides a method of imaging blood flow in a patient comprising: (a) administering to a patient a diagnostically effective amount of a composition comprising a labeled rotenone analog and a pharmaceutically effective vehicle; (b) exposing the patient to radiation; and (c) obtaining an image of the patient.
  • the image may be of the patient's whole body or it may be a region of the patient such as the heart or brain.
  • the composition is administered in a volume of about 1 to 10 mL.
  • the concentration of the labeled rotenone analog administered to the patient is about 1.0 to 50 millicuries. In some embodiments the concentration is about 1.0 to 10, 10 to 20, 20 to 30, 30 to 40, or 40 to 50 millicuries.
  • the composition is administered by intravenous injection.
  • FIG. 1 shows a synthetic pathway in accordance with one embodiment of the present invention for the synthesis of Z and E rotenone isomers.
  • FIG. 2 shows a synthetic pathway in accordance with one embodiment of the present invention for the synthesis of halo vinyl intermediates.
  • FIG. 3 shows a synthetic pathway in accordance with one embodiment of the present invention for the synthesis of Z and E isomers of the present invention.
  • FIG. 4 shows a synthetic pathway in accordance with one embodiment of the present invention for the synthesis of halo vinyl intermediates.
  • FIG. 5 shows a comparison of the E and Z isomers of iodorotenone analogs in perfusion studies.
  • FIG. 6 shows a comparison of the E and Z isomers of iodorotenone anologs in perfusion studies.
  • FIG. 7 shows a synthetic pathway in accordance with one embodiment of the present invention for the synthesis of fluorine-labeled rotenone analogs.
  • FIG. 8 shows a synthetic pathway in accordance with one embodiment of the present invention for the synthesis of fluorine-labeled rotenone analogs.
  • FIG. 10 shows a synthetic pathway in accordance with one embodiment of the present invention for the synthesis of fluorine-labeled rotenone analogs.
  • FIG. 11 shows a synthetic pathway in accordance with one embodiment of the present invention for the synthesis of carbon- labeled rotenone analogs.
  • FIG. 12 shows a synthetic pathway in accordance with one embodiment of the present invention for the synthesis of carbon- labeled rotenone analogs.
  • FIG. 13 shows a synthetic pathway in accordance with one embodiment of the present invention for the synthesis of carbon- labeled rotenone analogs.
  • FIG. 14 shows a synthetic pathway in accordance with one embodiment of the present invention for the synthesis of carbon- labeled rotenone analogs.
  • FIG. 16 shows the NMR NOESY spectra confirming the configuration of Z-iodorotenone.
  • FIG. 17 shows planar images in canine injected with Z-iodorotenone or E-iodorotenone.
  • Rotenone is a natural product of the Leguminosae plant family and has been used as an insecticide, pesticide and fish poison, and has been used in mitochondrial energy metabolism studies.
  • Rotenone is a specific, high-affinity inhibitor of Complex I (NADH ubiquinone oxidoreductase), the proximal enzyme of the mitochondrial electron transport chain. Since rotenone inhibition defines the activity of Complex I, defects in radiotracer binding can be expected to reflect functional changes in the enzyme, and hence, abnormalities of the mitochondrial energy metabolism.
  • Complex I NADH ubiquinone oxidoreductase
  • the present invention provides novel rotenone analogs labeled with halogen isotopes or carbon isotopes. Labeled with single photon and positron emitting isotopes, the rotenone analogs of the present invention are useful in, for example, clinical imaging applications as tracers to measure cardiac blood flow and detect regions of ischemia.
  • the rotenone analogs disclosed herein have superior extraction and retention properties to other tracers (e.g., 99m Tc-sestamibi and 99m Tc- tetrofosmin) currently in clinical use.
  • tracers e.g., 99m Tc-sestamibi and 99m Tc- tetrofosmin
  • Those of ordinary skill in the art will be able to make the rotenone analogs of the present invention in view of the description provided herein and the chemical synthesis schemes shown in FIG. 1, FIG. 2, FIG. 3, FIG. 4, FIG. 7, FIG. 8, FIG. 9, FIG. 10, FIG. 11, FIG. 12, FIG. 13,
  • the rotenone analogs may be labeled with halogen isotopes.
  • halogen isotopes include, 18 F, 19 F, 35 Cl, 37 Cl, 75 Br, 76 Br, 77 Br, 79 Br, 80 Br, 80m Br, 81 Br, 120 I, 121 I, 122 I, 123 I, 124 I, 125 I, 127 I, and 131 I.
  • Other isotopes that may be used with the compounds of the present invention include, for example, 11 C, 73 Se, and 75 Se. These are non-limiting examples of isotopes.
  • the terminal haloolefin group of rotenone is a useful functionality in the design of mechanism based radiotracers. Because the potency of these tracers often depends on the geometry of the olefin, there is considerable interest in developing stereospecific methods for these molecules.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen.
  • electron- withdrawing group is recognized in the art, and denotes the tendency of a substituent to attract valence electrons from neighboring atoms, i.e., the substituent is electronegative with respect to neighboring atoms.
  • a quantification of the level of electron-withdrawing capability is given by the Hammett sigma (o) constant. This well known constant is described in many references, for instance, March (1977).
  • alkyl refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e. g., C1-C30 for straight chain, C3-C30 for branched chain), and more preferably 20 or fewer.
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.
  • aralkyl refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • aryl as used herein includes 5-, 6- and 7- membered single -ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or “heteroaromatics.”
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties,-CF 3 ,-CN, or the like.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • ortho, meta and para apply to 1,2-, 1, 3-and 1 ,4-disubstituted benzenes, respectively.
  • the names 1, 2-dimethylbenzene and ortho- dimethylbenzene are synonymous.
  • heterocyclyl or “heterocyclic group” refer to 3-to 10-membered ring structures, more preferably 3-to 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be polycycles.
  • Heterocyclyl groups include, for example, azetidine, azepine, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine , isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cimnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phen
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety,-CF3,-CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, sily
  • polycyclyl or “polycyclic group” refer to two or more rings (e. g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e. g. , the rings are"fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety,- CF 3 , -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, si
  • Carbocycle refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
  • nitro means -N02 ;
  • halogen designates- F,-C1, -Br or-I ;
  • sulfhydryl means -SH ;
  • hydroxyl means-OH; and
  • sulfonyl means -SO 2 -.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula:
  • R 9 , Ri 0 - and R' 1O each independently represent a group permitted by the rules of valence.
  • acylamino is art-recognized and refers to a moiety that can be represented by the general formula:
  • R 9 is as defined above, and R'n represents a hydrogen, an alkyl, an alkenyl or -(CH2) m -Rs, where m and Rs are as defined above.
  • amino is art recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula:
  • Rg and Rio are as defined above.
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH 2 V-Rg, wherein m and Rs are defined above.
  • Representative alkylthio groups include methylthio, ethyl thio, and the like.
  • carbonyl is art recognized and includes such moieties as can be represented by the general formula:
  • X is a bond or represents an oxygen or a sulfur
  • Rn represents a hydrogen, an alkyl, an alkenyl, -(CH 2 )I n -Rs or a pharmaceutically acceptable salt
  • R'u represents a hydrogen, an alkyl, an alkenyl or -(CH 2 ) m -R8, where m and Rs are as defined above.
  • X is an oxygen and R ⁇ or R'u is not hydrogen
  • the formula represents an "ester”.
  • X is an oxygen, and Rn is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when Rn is a hydrogen, the formula represents a "carboxylic acid".
  • alkoxyl or "alkoxy” as used herein refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An "ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl,-O- alkenyl, -O-alkynyl, -O-(CH 2 ) m -R8, where m and R 8 are described above.
  • R 41 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
  • triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p- toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively.
  • a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations, the contents of which are hereby incorporated by reference in its entirety for all purposes.
  • R 4 1 is as defined above.
  • sulfonyl refers to a moiety that can be represented by the general formula:
  • R 44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • sulfoxido refers to a moiety that can be represented by the general formula:
  • R 44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.
  • a “selenoalkyl” refers to an alkyl group having a substituted seleno group attached thereto.
  • Exemplary “selenoethers” which may be substituted on the alkyl are selected from one of -Se-alkyl, -Se-alkenyl, -Se-alkynyl, and-Se-(CH 2 ) m -R7, m and R 7 being defined above.
  • Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
  • each expression e. g. alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • protecting group P g
  • P g protecting group
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • a list of illustrative, but not exhaustive protecting groups is disclosed in Greene abd Wuts (1991), the contents of which are hereby incorporated by reference in its entirety.
  • Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof (e. g. , functioning as analgesics), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound in binding receptors.
  • the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.
  • the present invention also relates to imaging agents containing a radionuclide as described above, in an amount sufficient for imaging, together with a pharmaceutically acceptable vehicle.
  • Imaging agents incorporating a gamma-emitting nuclide which, because of physical or metabolic properties of its coordinated ligands, localize in a specific organ after they are administered to the patient.
  • the resultant images can reflect organ structure or function.
  • the radiolabel is a gamma-radiation emitting radionuclide and the radiotracer is located using a gamma- radiation detecting camera (this process is often referred to as gamma scintigraphy).
  • the imaged site is detectable because the radiotracer is chosen either to localize at a pathological site (termed positive contrast) or, alternatively, the radiotracer is chosen specifically not to localize at such pathological sites (termed negative contrast).
  • radiological vehicles include, human serum albumin; aqueous buffer solutions, e.g tris (hydromethyl) aminomethane (and its salts), phosphate, citrate, bicarbonate, etc.; alcohols, including ethanol, propylene glycol, etc; sterile water; physiological saline; and balanced ionic solutions containing chloride and or dicarbonate salts or normal blood plasma cations such as calcium, potassium, sodium, and magnesium.
  • the concentration of the imaging agent according to the present invention in the radiological vehicle should be sufficient to provide satisfactory imaging, for example, when using an aqueous solution, the dosage is about 1.0 to 50 millicuries.
  • the imaging agent should be administered so as to remain in the patient for about 1 to 3 hours, although both longer and shorter time periods are acceptable. Therefore, convenient ampules containing 1 to 10 mL of aqueous solution may be prepared.
  • Labeled rotenone analogs of the present invention may be used with imaging techniques such as positron emission tomography (PET) and Single Photon Emission Computed Tomography (SPECT).
  • PET imaging is a diagnostic examination that involves the acquisition of physiologic images based on the detection of radiation from the emission of positrons from a radionuclide compound administered to the patient. The radionuclide compound is typically administered via intravenous injection. Different colors or degrees of brightness on a PET image represent different levels of tissue or organ function.
  • SPECT imaging is a three-dimensional technique combined with computer assisted reconstruction of images of organs to reveal both anatomy and function. As with PET imaging, patients undergoing SPECT imaging are administered a radioactive tracer.
  • PET and SPECT images may be used to evaluate a variety of diseases, and are commonly used in the fields of oncology, cardiology, and neurology.
  • rotenone has high affinity to Complex I of the mitochondrial electron transport chain.
  • labeled rotenone analogs may be used to investigate abnormalities in mitochondrial function. Such abnormalities may be associated with, for example, ischemia. Due to its affinity for mitochondria, rotenone is particularly well suited for use with tissues rich in mitochondria, such as the myocardium and brain.
  • PET or SPECT scans of the heart using rotenone radionulcides can be used to determine blood flow to the heart muscle and help evaluate signs of coronary artery disease. This information can assist health care providers in the diagnosis, localization, and risk stratification of patients with known or suspected coronary artery disease.
  • Complex I NADH-quinone oxidoreductase
  • Complex I is one of three energy-transducing enzyme complexes of the respiratory chain in mitochondria. It is the point of entry for the major fraction of electrons that traverse the respiratory chain eventually resulting in the reduction of oxygen.
  • Mammalian Complex I is composed of 46 subunits and contains noncovalently bound FMN and several iron-sulfur clusters as prosthetic groups.
  • the novel rotenone analogs of the present invention provide valuable research tools for the study of Complex I and associated pathologies, including neurodegenerative diseases like Parkinson's disease and Huntington's disease.
  • the novel rotenone analogs can be used as in vitro, in situ, or in vivo markers of Complex I.
  • Formulations in accordance with certain embodiment of the present invention comprise an effective amount of one or more of the rotenone radionuclides described above and formulated together with one or more pharmaceutically acceptable carriers and/or diluents.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15)
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • kits will thus comprise, in suitable container means, at least one rotenone analog and/or rotenone analog intermediate.
  • the kits will generally include at least one vial, test tube, flask, bottle, syringe or other container, into which a component may be placed, and preferably, suitably aliquoted. Where there is more than one component in the kit, the kit also will generally contain a second, third or other additional container into which the additional components may be separately placed. However, various combinations of components may be comprised in a container. Such kits may be useful in diagnostic and/or research purposes.
  • a diagnostic kit of the present invention may comprise a labeled rotenone analog and a pharmaceutically acceptable vehicle.
  • the diagnostic kit of the present invention may comprise an unlabeled rotenone analog intermediate.
  • the kit may have a single container means or it may have distinct container means for each compound.
  • the diagnostic kit may further comprise a syringe or other device for administering the labeled rotenone analog and a pharmaceutically acceptable vehicle to a subject.
  • the diagnostic kit may further comprise instructions for using the components of the kit.
  • Z-7'-iodorotenone and E-7'-iodorotenone compounds were also evaluated in canines.
  • Two 20-25 kg dogs were anesthetized with iv sodium pentathol and maintained on inhaled isoflurane.
  • Four to six mCi of Z-[ 123 I]Iodorotenone or E- [ 123 I]Iodorotenone was injected in a front leg vein.
  • Dual head planar imaging was carried out using the GE Millenium SPECT scanner with Hawkeye xray CT. The scanning protocol was serial 4 m whole body scans over the first hour, 8m whole body scans from l-2h and 30 min whole body scans out to 7 h post injection of the tracer.
  • the planar images are shown in FIG. 17.
  • the E-iodorotenone showed greater heart uptake and retention.
  • the heart is clearly visable out to 4.5 hours.
  • the Z- iodorotenone washed out of the heart faster and cleared through the gallbaldder and stomach more rapidly. No thyroid blocking agent was introduced prior to the scan.
  • the bright spot in the throat region in the Z-iodorotenone scan is salivary gland. The uptake of both compounds in the thyroid was minimal.
  • NMR spectra of the E-iodorotenone and Z-iodorotenone are shown in FIG. 15 and FIG. 16. These NOESY spectra show the through space interactions of the protons on the molecule. From this one may determine the structure of the molecule. These spectra conf ⁇ med the configuration of E- and Z-iodorotenone.
  • Rotenol Acetate Synthesis Rotenol (1.58 g, 4.0 mmol) was dissolved in dry CH 2 Cl 2 (20 mL) and cooled to 0 0 C under argon atmosphere. Added dimethylaminopyridine (DMAP, 586 mg, 4.8 mmol) followed by acetic anhydride (449 mg, 0.415 mL, 4.4 mmol) and the mixture was stirred for 1 hour. Added a few drops of methanol and the solvent was evaporated. The crude residue was purified by flash column chromatography on silica gel using EtOAc:Hexane (1 :5) to afford the acetate as white crystalline solid (1.72 g, 98 %); m. p.
  • DMAP dimethylaminopyridine
  • acetic anhydride 449 mg, 0.415 mL, 4.4 mmol
  • Z-Iodorotenol Synthesis Z-Iodoacetate (5.0 g, 8.87 mmol) was dissolved in minimum amount Of CH 2 Cl 2 (10 mL) and added to a 1 :1 mixture of MeOH:H 2 O (32 mL) followed by solid potassium carbonate (3.7 mg, 27 mmol). The mixture was heated at 60 0 C for 4 hours with vigorous stirring. The mixture was cooled to room temperature, water was added (100 mL), and extracted with CH 2 Cl 2 (3 x 100 mL).
  • Z-Iodorotenone Synthesis To a solution of Z-iodorotenol (250 mg, 0.478 mmol) in dry acetonitrile (5 rnL) was added activated manganese dioxide (625 mg, 7.18 mmol) at once under argon atmosphere and the mixture was stirred vigorously at room temperature for 1 minute. The mixture was filtered through a pad of celite, washed several times with dichloromethane, and evaporated to get a residue, which was purified by flash column chromatography on silica gel using EtOAc:hexane (1 :3 to 3:7) to furnish Z-iodorotenone as a colourless solid (92 mg, 37 %).
  • E/Z-Bromorotenone Synthesis To a solution of E/Z-bromorotenol (100 mg, 0.21 mmol) in dry acetonitrile (5 mL) was added activated manganese dioxide (275 mg, 3.2 mmol) at once under argon atmosphere and the mixture was stirred vigorously at room temperature for 1 minute. The mixture was filtered through a pad of celite, washed several times with dichloromethane, and evaporated to get a residue, which was purified by flash column chromatography on silica gel using EtOAc:hexane (1 :3 to 3:7) bromorotenone as a colourless solid (40 mg, 40 %). m. p.
  • Trimethyl Tin Rotenol Acetate Synthesis Z-Iodorotenol (564 mg, 1 mmol) was dissolved in dry THF (5 mL) under argon. Added hexamethylditin, (393 mg, 1.2 mmol) Pd catalyst (2 mg), and LiCl (51 mg, 1.2 mmol) successively and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the crude residue was chromatographed on silica gel using EtOAc:Hexane (1 :3) to afford the trimethyl tin compound as white powder (384 mg, 64 %).
  • Z-Tributylstannylrotenol Synthesis Z-Tributyltinrotenol acetate (364 mg, 0.5 mmol) was dissolved in minimum amount of CH 2 Cl 2 (1 mL) and added to a 1 :1 mixture of methanol: water (10 mL). Added solid potassium carbonate (345 mg, 2.5 mmol) and the mixture was stirred vigorously overnight at room temperature. Added more water (25 mL) and extracted with dichloromethane (3 x 25 mL).
  • Fluororotenol Fluoroacetate (456 mg, 1 mmol) was dissolved in minimum amount of CH 2 Cl 2 (1 mL) and added a 1 : 1 mixture of MeOH : H 2 O (10 mL) followed by solid potassium carbonate (500 mg, 5 mmol). The mixture was heated at 60 0 C for 4h with vigorous stirring. Cooled to room temp, added more water (25 mL) and extracted with CH 2 Cl 2 (3 x 25 mL).
  • Fluororotenol Fluoroacetate (456 mg, 1 mmol) was dissolved in minimum amount of CH 2 Cl 2 (1 mL) and added a 1 : 1 mixture of MeOH : H 2 O (10 mL) followed by solid potassium carbonate (500 mg, 5 mmol). The mixture was heated at 60 0 C for 4h with vigorous stirring. Cooled to room temp, added more water (25 mL) and extracted with CH 2 Cl 2 (3 x 25 mL).
  • Methylrotenol Trimethyltinrotenol (25 mg, 0.05 mmol), Pd(PPh 3 ) 4 (6 mg, 0.005 mmol), triphenylphosphine (1.5 mg, 0.005 mmol), copper iodide (1.0 mg, 0.005 mmol) and potassium carbonate (0.7 mg, 0.005 mmol) were mixed together in dry DMF (0.5 mL) under argon and was stirred for 2 minutes at room temperature. Added methyl iodide (64 mg, 28 ⁇ L, 4.5 mmol) in one portion and the mixture was stirred at room temperature for 5 minutes followed by 60 0 C for 5 minutes and 80 0 C for 15 minutes. The starting material was completely consumed.
  • Methylrotenol acetate Wittig salt (113 mg, 0.27 mmol) was suspended in dry THF (3 rnL) and cooled to 0 0 C in an ice bath under argon atmosphere. A solution Of (TMS) 2 NNa (1 M solution in THF, 0.25 rnL, 0.25 mmol) was added dropwise and the mixture was stirred for 15 minutes at 0 0 C. The suspension got dissolved in to an yellow-orange solution. The solution was cooled to -78 0 C and a solution of ketoacetate (100 mg, 0.23 mmol) was added dropwise. Reaction mixture stirred at -78 0 C for 4 h and then allowed to come to room temperature.
  • TMS (TMS) 2 NNa (1 M solution in THF, 0.25 rnL, 0.25 mmol) was added dropwise and the mixture was stirred for 15 minutes at 0 0 C. The suspension got dissolved in to an yellow-orange solution. The solution was cooled to

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Abstract

La présente invention concerne des analogues de roténone et des méthodes de fabrication et d'utilisation de ceux-ci. Lesdits analogues de roténone sont marqués par des isotopes monophotoniques et d'émission de positons et sont utiles dans des applications d'imagerie clinique en tant que traceurs pour mesurer la circulation sanguine cardiaque et détecter des régions d'ischémie.
PCT/US2007/069178 2006-05-18 2007-05-17 Analogues de roténone, méthode de préparation et d'utilisation WO2007137135A2 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102336764A (zh) * 2011-06-21 2012-02-01 兰州大学 自旋标记鱼藤酮肟酯及其制备方法和用途
CN103044440A (zh) * 2012-12-31 2013-04-17 深圳市华农生物工程有限公司 一种鱼藤酮临界萃取方法
WO2014065510A1 (fr) * 2012-10-24 2014-05-01 Korea Atomic Energy Research Institute Nouveaux dérivés de roténone et utilisation de ceux-ci
JP2014520821A (ja) * 2011-07-13 2014-08-25 ノルディオン （カナダ） インク． 放射標識されたロテノン誘導体及びこれらのｓｐｅｃｔ画像化における使用

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WO2003086476A1 (fr) * 2002-04-08 2003-10-23 Biostream, Inc. Derives de rotenone a marquage au technetium, et procedes d'utilisation correspondants
US20050192458A1 (en) * 2002-04-30 2005-09-01 Goodman Mark M. Tumor imaging compounds

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Publication number Priority date Publication date Assignee Title
WO2003086476A1 (fr) * 2002-04-08 2003-10-23 Biostream, Inc. Derives de rotenone a marquage au technetium, et procedes d'utilisation correspondants
US20050192458A1 (en) * 2002-04-30 2005-09-01 Goodman Mark M. Tumor imaging compounds

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102336764A (zh) * 2011-06-21 2012-02-01 兰州大学 自旋标记鱼藤酮肟酯及其制备方法和用途
CN102336764B (zh) * 2011-06-21 2013-10-30 兰州大学 自旋标记鱼藤酮肟酯及其制备方法和用途
JP2014520821A (ja) * 2011-07-13 2014-08-25 ノルディオン （カナダ） インク． 放射標識されたロテノン誘導体及びこれらのｓｐｅｃｔ画像化における使用
WO2014065510A1 (fr) * 2012-10-24 2014-05-01 Korea Atomic Energy Research Institute Nouveaux dérivés de roténone et utilisation de ceux-ci
KR101422189B1 (ko) 2012-10-24 2014-07-22 한국원자력연구원 신규한 로테논 유도체 및 이를 유효성분으로 함유하는 비만 예방 및 치료용 약학적 조성물
US20150225416A1 (en) * 2012-10-24 2015-08-13 Korea Atomic Energy Research Institute Novel Rotenone Derivatives and a Use Thereof
US9328123B2 (en) 2012-10-24 2016-05-03 Korea Atomic Energy Research Institute Rotenone derivatives and a use thereof
CN103044440A (zh) * 2012-12-31 2013-04-17 深圳市华农生物工程有限公司 一种鱼藤酮临界萃取方法
CN103044440B (zh) * 2012-12-31 2015-11-18 深圳市华农生物工程有限公司 一种鱼藤酮临界萃取方法

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