MXPA06008993A - Contrast agents for myocardial perfusion imaging - Google Patents

Abstract

The present disclosure is directed, in part, to compounds and methods for imaging myocardial perfusion, comprising administering to a patient a contrast agent which comprises a compound that binds MC-1, and an imaging moiety, and scanning the patient using diagnostic imaging.

Description

CONTRAST AGENTS FOR FORMATION OF IMAGES FOR MYOCARDIAL PERFUSION Field of the Invention The present disclosure relates to novel compounds comprising imaging portions, and their use for diagnosing certain disorders in a patient.

Background of the Invention The mitochondria are organelles enclosed in membrane distributed through the cytosol of most eukaryotic cells. Mitochondria are especially concentrated in myocardial tissue. Complex 1 ("MC-1") is a membrane-bound protein complex of 46 dissimilar subunits. This enzyme complex is one of the three complexes that transduce the energy that constitutes the respiratory chain in the mitochondria of mammals. This NADH-ubiquinone oxidoreductase is the entry point for most of the electrons that cross the respiratory chain, which eventually results in the reduction of oxygen to water (Q. Rev. Biophys, 1992, 25, 253-324). The known inhibitors of MC-1 include deglycine, piericidin A, ubicidin-3, rolliniastatin-1, rolliniastatin- REF: 174691 2 (bullatacin), capsaicin, pyridaben, fenpyro- matimate, amital, +, quinolines, and quinolones (BBA 1998, 1364 , 222-235). The present disclosure is based, in part, on the recognition that disrupting the normal function of the mitochondria could advantageously concentrate certain compounds in the mitochondria, and therefore in the myocardial tissue rich in mitochondria. If these compounds are labeled with an image forming portion, such as a built-in what can be detected, valuable diagnostic markers for myocardial perfusion imaging are therefore provided. For purposes of this specification, the compound is referred to as "labeling" when an image forming portion is bound to the compound.

Detailed Description of the Invention In one embodiment, the present disclosure provides a method for percussion imaging of the myocardium comprising administering to a patient a contrast agent comprising an image-forming portion and a compound selected from deglycine, pyridabena, pyridimiphene. , tebufepine, fenazaquine, a deguelin analogue, a pyridaben analogue, a pyridimifene analogue, a tebunpirate analogue, and a phenazaquin analogue; and review the patient using diagnostic imaging. In another embodiment the image forming portion is a radioisotope for nuclear medicine imaging, a paramagnetic species for use in MRI imaging, an echogenic entity for use in ultrasound imaging, a fluorescent entity for use in the formation of fluorescent images, or an active entity of light for use in the formation of optical images. In another embodiment, the present disclosure provides a contrast agent comprising an image-forming portion and a compound selected from deglycine, pyridaben, pyridimifen, tebufenpyrate, phenazaquin, a deglycine analogue, a pyridabene analogue, a pyridminifene analog, an analogue tebufenpirate, and a phenazaquin analog. In another embodiment, the imaging portion is a radioisotope for nuclear medicine imaging, a paramagnetic species for use in MRI imaging, an echogenic entity for use in ultrasound imaging, a fluorescent entity to be used in the formation of fluorescent images, or a light active entity for use in the formation of optical images. In another embodiment, the magnetic species for use in MRI imaging are Gd3 + 'Fe3 +, In3 +, or Mn2 +. In another embodiment, the echogenic entity for use in ultrasound imaging is an encapsulated tensoactive microsphere for fluorocarbon. In another modality, the radioisotope for nuclear medicine imaging is 1 C, 13N, 18FR, -123I, 1 SI, 99mTc, 9sTc, mln, SCu, S4Cu, 67Ga, or 68Ga. In another embodiment, the image forming portion is 18F. In another embodiment, the image forming portion is 99mTc.

In another embodiment, the present disclosure provides a contrast agent comprising an image-forming portion and a compound selected from deguelin, pyridaben, pyridimifen, tephoprim, phenazaquin, a deglycine analog, a pyridabene analog, a pyridimine analog, an annealed tebuf analogue, and a phenazaquin analogue wherein the contrast agent is of the formula (I) (I), where each A is independently selected from 0, CHR1, S, and NR1; B is selected from hydrogen, C? -C6 alkyl optionally substituted with an image forming portion, and an image forming portion; C is selected from hydrogen, C? -C6 alkyl optionally substituted with an image forming portion, an image forming portion, and a B bond; D is selected from hydrogen, C -C6 alkyl optionally substituted with an image forming portion, and an image forming portion; E is selected from hydrogen, C ?Ce alkyl optionally substituted with an image forming portion, and an image forming portion; or E and D, together with the carbon atom to which they are bound, form a double bond; or E and D, together with the carbon atom to which they are bound, form a cyclopropyl ring; it is a single or double link; R1, R2, R3, R4, R9, R10, R13, and R14, are each independently selected from hydrogen, alkyl C? -C6 optionally substituted with an image forming portion, and an image forming portion; R5 and R6 are each independently selected from hydrogen, C6-C6 alkyl optionally substituted with an image forming portion, halo, hydroxy, and an image forming portion; when R7 and R8 are independently selected from hydrogen, C? -C6 alkyl optionally substituted with an image forming portion, halo, hydroxy, and an image forming portion; or R5 and R7 together form an oxo group; or R6 and R8 together form an oxo group; or R7 is O and R8 is a bond to R7; with the proviso that when it is a double bond, R7 and R8 are absent; R11 is hydrogen or hydroxy; R12 is selected from hydrogen, Cx-Cs alkyl optionally substituted with an image forming portion, and an image forming portion; or R11 and R12 together form an oxo group or = CHR1; with the proviso that at least one image forming portion is presented in the formula (I). In another modality A is O; B and C are each independently CH3 or CH218F; D and E are each independently CH3 or CH218F; Rs, Rs, R9, and R10 are each independently hydrogen or 18F; and R11 and R12 together form an oxo group. In another embodiment, the contrast agent is selected from In another embodiment, the present disclosure provides a contrast agent comprising an image forming portion and a compound selected from deguelin, pyridaben, pyridimifen, tebufenpyda, phenazaquin, a deguelin analogue, a pyridaben analog, a pyridimifen analog, an analogue of tebufenpirada, and a phenazaquin analogue wherein the contrast agent is of the formula (II), (ID where G is or, where m is 0 or 1; b and each independently represents a single or double bond; R27, R30, R31, R32, R33, and R34 are independently selected from hydrogen, Cx-Cs alkyl optionally substituted with an image forming portion, and an image forming portion; when present, R28 is selected from "hydrogen and optionally substituted C? -C6 alkyl with an image forming portion, with the proviso that when it is a double bond, R28 is absent, when present, R29 is Ca-C6 alkyl optionally substituted with an image forming portion, with the proviso that when it is a double bond, R29 is absent; P is, wherein R35, R3e, R37, R38, and R39 are independently selected from hydrogen, C? -C6 alkyl optionally substituted with an image forming portion, and an image forming portion; when it occurs, P 'is hydrogen; or P and P 'together form an oxo group; with the proviso that when a 'is a double bond, P' is absent; Q is halo or haloalkyl; J is selected from N (R27), S, O, C (= 0), C (= 0) 0, NHCH2CH20, a bond, and C (= 0) N (R27), with each group being removed with its left end i linked to G and its right end linked to the carbon substituted with R21 and R22; when present, K is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -C6 alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; when present, L is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -C6 alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; M is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -C6 alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; or L and M, together with the atom to which it is linked, forms a carbocyclic ring of three or four members; n is 0, 1, 2, or 3; R21, R22, R23, R24, R25, and R26 are independently selected from hydrogen, C? -C6 alkyl optionally substituted with an image forming portion, and an image forming portion; and Y is selected from a bond, carbon and oxygen; with the proviso that when Y is a bond, K and L are absent and M is selected from aryl and heteroaryl; and with the proviso that when Y is oxygen, K and L are absent and M is selected from hydrogen, alkoxyalkyl, aryl, C? -C3 alkyl optionally substituted with an image forming portion, and heteroaryl; with the proviso that at least one image forming portion is presented in formula (II). In another embodiment R29 is C-C6 alkyl wherein C C-C3 alkyl is tert-butyl. In another embodiment R28 is C? -C6 alkyl wherein C? -C6 alkyl is methyl. In another embodiment, the present disclosure provides a "contrast agent" comprising an image-forming portion and a compound selected from deglycine, pyridaben, pyridimifen, tebufenpyda, phenazaquin, a deguelin analog, a pyridabene analog, a pyridimifen analog, a a tebufenpy analog, and a phenazaquin analogue wherein the contrast agent is of the formula (III) (III) where: J is selected from N (R27), S, 0, C (= 0), C (= 0) 0, NHCH2CH20, a bond, or C (= 0) N (R27), with each group that withdraws with its left end linked to G and its right end linked to the carbon substituted with R21 and R22; when present K is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -C6 alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; when present, L "is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -C6 alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; M is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C6-C6 alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; or L and M, together with the atom to which it is linked, forms a three- or four-membered carbocyclic ring; is halo or haloalkyl, n is 0, 1, 2, or 3; R21, R22, R23, R24, R25, R26, and R27 are independently selected from hydrogen, optionally substituted C6-C6 alkyl with an "image-forming portion" , and an image-forming portion; R29 is C? -C6 alkyl optionally substituted with an image forming portion; and Y is selected from a bond, carbon, and oxygen; with the proviso that when Y is a bond, K and L are absent and M is selected from aryl and heteroaryl; and with the proviso that when Y is oxygen, K and L are absent and M is selected from hydrogen, alkoxyalkyl, aryl, C? -C3 alkyl optionally substituted with an image forming portion, and heteroaryl; with the proviso that at least one image forming portion is presented in formula (III). In another embodiment J is O and R29 is C -C6 alkyl wherein the C ~ C6 alkyl is tert-butyl. In another embodiment, the contrast agent is selected from In another embodiment, the present disclosure provides a contrast agent comprising an image forming portion and a compound selected from deguelin, pyridaben, pyridimifen, tebufenpyda, phenazaquin, a deguelin analogue, a pyridaben analog, a pyridimifen analog, an analogue of tebufenpyrate, and a phenazaquin analogue wherein the contrast agent is of the formula (IV): (IV), where: J is selected from N (R27), S, O, C (= 0), C (= 0) 0, NHCH CH20, a bond, and C (= 0) N (R27), with each group that withdraws with its left end linked to G and its right end linked to carbon substituted with R21 and R22; when present K is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -C6 alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; L is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -C3 alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; M is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -C6 alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; or L and M, together with the atom to which it is linked, forms a carbocyclic ring of three or four members; Q is halo or haloalkyl; n is 0, 1, 2, or 3; p 2l p 22 p 23 p 24 25 26 p 7 p28 P351 p3S p37 p38 p39 are independently selected from. hydrogen, alkyl C -Ce optionally substituted with an image forming portion, and an image forming portion; and Y is selected from a bond, carbon, and oxygen, with the proviso that when Y is a bond, K and L are absent and M is selected from aryl and heteroaryl; and with the proviso that when Y is oxygen, K and L are absent and M is selected from hydrogen, alkoxyalkyl, aryl, C? -C6 alkyl optionally substituted with an imaging portion, and heteroaryl; with the proviso that at least one image forming portion is presented in formula (IV). In another embodiment J is C (= 0) N (H), and R28 is Cx-C6 alkyl wherein the C? -C6 alkyl is methyl. In another embodiment, the contrast agent is selected from In another embodiment, the present disclosure provides a contrast agent comprising an image forming portion and a compound selected from deguelin, pyridaben, pyridimifen, tebufenpyda, phenazaquin, a deguelin analogue, a pyridaben analog, a pyridimifen analog, an analogue of tebufenpirada and a fenazaquina analogue in which the contrast agent is of the formula (V) (V), wherein J is selected from N (R27), S, O, C (= 0), C (= 0) 0, NHCH2CH20, a bond, and C (= 0) N (R27); K is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -C6 alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; when present L is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -C6 alkyl optionally substituted with an image forming portion, heteroaryl, and an image-forming portion; when present M is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -C6 alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; or L and M, together with the atom to which it is linked, forms a carbocyclic ring of three or four members; T and U are independently selected from hydrogen, alkoxy, alkoxyalkyl, C? -C6 alkyl optionally substituted with an image forming portion, halo, and an image forming portion; or T and U together with the carbon atoms to which they are bonded, form a five or six membered aromatic or non-aromatic ring containing zero to two heteroatoms selected from oxygen, nitrogen, and sulfur wherein the ring is optionally substituted with one, two or three substituents independently selected from C 1 -C 6 alkyl optionally substituted with an image forming portion and an image forming portion; n is 0, 1, 2, or 3; and R21, R22, R23, R24, R25, R26, R27 and R34 are independently selected from hydrogen, alkyl C? -C6 optionally substituted with an image forming portion, and an image forming portion; Y is selected from a bond, carbon, and oxygen, with the proviso that when Y is a bond, K and L are absent and M is selected from aryl and heteroaryl; and with the proviso that when Y is oxygen, K and L are absent and M is selected from hydrogen, alkoxyalkyl, aryl, C? -C6 alkyl optionally substituted with an imaging portion, and heteroaryl; with the proviso that at least one image forming portion is presented in formula (V). In another embodiment J is 0. In another embodiment, the present disclosure provides a contrast agent comprising an image forming portion and a compound selected from deguelin, pyridaben, pyridimifen, tebufenpyda, phenazaquin, a deguelin analogue, a pyridaben analogue, a pyridimifene analogue, a tebufenpyrate analogue, and a phenazaquin analogue wherein the contrast agent is of the formula (VI) (VI), wherein R3 R '24 R25 R' 26 and R34 are independently selected from hydrogen, C? -C6 alkyl optionally substituted with an image forming portion, and an image forming portion; with the proviso that at least one image forming portion is presented in formula (VI). In another embodiment, the contrast agent is selected from Image-forming Portions The nuclear medicine contrast agents of the present disclosure include 1: LC, 13N, 18FR, 123I, 125I, 99mTc, 95Tc, luIn, S2Cu, 6Cu, S7Ga, or 68Ga. The xlC-palmitate has been used to test the oxidation of fatty acid and the 1: LC-acetate has been used to evaluate the oxidative metabolism in the myocardium (Circulation 1987, 76, 687-696). 13N-ammonia has been widely used for myocardial perfusion imaging (Circulation 1989, 80, 1328-37). 18F-based agents have been used as imaging agents for hypoxia and cancer (Drugs of the Future 2002, 27, 655-667). In 15- (p- (123I) -iodiphenyl) -pentadecanoic acid and 15- (p- (1231) -isophenyl) -3 (R, S) -methylpentadecanoic acid are two iodinating agents that have been used for the formation of images by myocardial metabolism. In one embodiment, the image forming portion employed in the present contrasts 18F. In addition, the image forming portions of the present disclosure may comprise one or more "X-ray absorbing" or "heavy" atoms of atomic number 20 or greater, further comprising an optical lens portion, L, between the molecular precursor portion and the , atoms that absorb X-rays. A heavy atom frequently used in X-ray contrast agents is iodine. Recently, X-ray contrast agents understand that metal sides (US Patent No. 5,417,959) and polykelets comprising a plurality of metal ions (US Patent No. 5,679,810) have been described. More recently, multinuclear group complexes have been described as X-ray contrast agents (U.S. Patent No. 5,804,161, WO 91/14460 and WO 92/17215). In certain embodiments of the present disclosure, the specific metals used in the X-ray contrast agents include Re, Sm, Ho, Pm, Y, Bi, Pd, La, Au. Au, Yb, Dy, Cu, Rh, Ag, and Ir. The MRI contrast agents of the present disclosure may comprise one or more analogous portions linked to one or more metal ions for magnetic, further comprising an optional freewheeling portion. , L, between the analogous portions and the metal ions for magnetic. Magnetic metal ions may be in the form of metal chelates or complexes or metal oxide particles. U.S. Patent Nos. 5,412,148, and 5,760,191, describe examples of chelators for metal ions for magnetic to be used in MRI contrast agents. U.S. Patent No. 5,801,228, U.S. Patent No. 5,567,411, and "U.S. Patent No. 5,281,704, describe, examples of polychelants useful for complexing more than one metal ion for magnetic to be used in MRI contrast agents. USA No. 5, 520,904, describes particulate compositions comprising metal ions for magnetic to be used as MRI contrast agents. Examples of specific metals include Gd +, Fe3 +, "In3 +, and Mn2 +." The ultrasound contrast agents of the present disclosure may comprise a plurality of analogous portions linked to or incorporated in a microbubble of a biocompatible gas, a liquid carrier, and a Tensoactive microsphere further comprises an optional linker portion, L, between the analogous portions and the microbubble In this context, the term "liquid carrier" means an aqueous solution and the term "surfactant" means any amphiphilic material that can produce a reduction. In the interfacial tension in a solution, a list of suitable surfactants to form the surfactant microspheres is described, for example, in EP072722A2 The term "surfactant microsphere" includes microspheres, nanospheres, liposomes, vesicles and the like.The biocompatible gas can be any physiologically acceptable gas, including for example, air, or a f-luo Rocarbon, such as a C3-C5 perforator, which - "" provides the difference in echogenicity and this - "way to contrast in ultrasound imaging. The gas can be encapsulated, contained or "- another way to enter into or through the myco- sphere to which the analogue portion is linked, optionally by means of a binding group, the link may be covalent, ionic or van der Waals forces. contrast include, for example, perfluorocarbons encapsulating lipids with a plurality of tumor neurovasculature receptor binding peptides, polypeptides or mimetic peptide Examples of gas filler imaging portions include those found in the US patent application No series 09 / 913,317, filed on August 16, 2001, and US Patent Nos. 5,088,499, 5,547,656, 5,228,446, 5,585, 122, and 5,846,517.

Chelators Many approaches to label compounds with 99mTc are known, including direct labeling of the compound or inclusion of a chelating portion ("chelator"). In one embodiment, the chelator is DADT, MAG3, MAMA, PAMA, or DOTA. The compounds of the description may optionally contain a chelator ("C"). In certain embodiments of the compounds of the disclosure, the chelator is a surfactant capable of forming a lipid microbubble or sphere filled with an echogenic substance. In certain other modalities the chelator is a linker unit that has a formula selected from: A1 -A¿ -A2 '-A1 wherein each A1 is independently selected from -NR6R47, -NHR53, -SH, -S (Pg), -OH, -PR46R47, -P (0) R48R49, and a bond to the compound that links MC-1; each A2 is independently selected from N (R53), N (R46), S, O, P (R46), and -OP (O) (R48) O-; A3 is N; A4 is selected from OH and OC (= 0) alkyl C? -C 0; A5 is OC (= 0) C? -C20 alkyl; each E is independently selected from C? -C16 alkylene substituted with 0-3 R50, C6-C10 arylene substituted with 0-3 R50, C3-C10 cycloalkylene substituted with 0-3 R50, substituted heterocyclylC? -C10 alkylene with 0-3 R50, C6-C10 aryl-C-C10 alkylene substituted with 0-3 R50, and heterocyclylene substituted with 0-3 Rs0; E1 is selected from a link and E; each E2 is independently selected from CX-C16 alkyl substituted with 0-3 R50, C6-C? aryl substituted with 0-3 R ?0, C3-C10 cycloalkyl substituted with 0-3 R50, substituted C?-C10 heterocyclylalkyl with 0-3 R50, C6-C10 aryl-Cx-C? alkyl or substituted with 0-3 R50, C? -C10 alkyl-C3-C10 aryl substituted with 0-3 R50, and heterocyclyl substituted with 0-3 RB0; E3 is C? -C10 alkylene substituted with 1-3 R59; Pg is a thiol protecting group; R46 and R47 are each independently selected from a bond to the compound that binds MC-1, hydrogen, C? -C? 0 alkyl substituted with 0-3 Rso, aryl substituted with 0-3 R50, C3-C10 cycloalkyl substituted with 0? -3 R50, C? -C10 heterocyclylalkyl substituted with 0-3 R50, C6-C6 aryl 0-Cx-C10 alkyl substituted with 0-3 R50, and heterocyclyl substituted with 0-3 R50; R48 and R49 are each independently selected from a bond to the compound that binds MC-1, -OH, C -C10 alkyl substituted with 0-3 R50, aryl substituted with 0-3 R50, C3-C10 cycloalkyl substituted with 0-3 R50, heterocyclylC? -C10 alkyl substituted with 0-3 R50, aryl C3-C? 0- C? -C10 alkyl substituted with 0-3 Rso, and heterocyclyl substituted with 0-3 R50; each R50 is independently selected from a bond to the compound that binds MC-1, = 0, halo, trifluoromethyl, cyano, -C02R51 ', -C (= 0) R51, -C (= 0) N (R51) 2, - CHO, -CH2OR51, -0C (= 0) R51, -0C (= 0) 0R51, -OR51, -OC (= 0) N (R51) 2, -NR51C (= 0) R51, -NR51C (= 0) 0R51, -NR51C (= 0) N (R51) 2, -NR51S02N (R51) 2, -NR51S02R51, -S03H, -S02R51, -SR51, -S (= 0) R51, -S02N (R51) 2, -N (R51) 2, NHC (= S) NHR51, = N0R51, N02, -C (= 0) NHOR51, -C (= 0) NHN (R51) 2, OCH2C02H, 2- (1-morpholino) ethoxy, alkyl C C5, C2-C alkenyl, C3-C6 cycloalkyl, C3-C3 cycloalkylmethyl, C2-C6 alkoxyalkyl, aryl substituted with 0-2 R51, and heterocyclyl; each R51 is independently selected from a bond to the compound that binds MC-1, hydrogen, C? -C6 alkyl, phenyl, benzyl and C? -Salkoxy; R53 is a coordinated link to a metal; each R59 is selected from R61, = 0, -C02R60, -C (= 0) Rso, -C (= O) N (R60) 2, -CH2ORS0, -OR60, -N (Reo) 2, and C2- alkenyl C4; each Rso is independently selected from R61, hydrogen, C? -C6 alkyl, phenyl, benzyl, and trifluoromethyl; Y RS1 is a bond to the compound that binds MC-1; wherein at least one of A1, R4S, R47, R48, R49, R50, R51, and R61 is a bond to the compound that binds MC-1.

Processing Methods Typically compounds labeled with 18F are synthesized by a displacement of Sn2 from a suitable starting group. These starting groups are preferably sulfonic acid ester such as toluenesulfonate (tosylate, TsO), methanesulfonate (mesylate, MsO), or trifluoromethanesulfonate (triflate, TfO). The leaving group may also be a halide, a phosphinhoxide (by means of a Mitsunobu reaction), or an internal starting group (such as an epoxide or cyclic sulfate). These compounds are made from highly activated dry K18F that is made "warmer" by the addition of cryptans such as krytofix [2.2.2]. Purification generally by means of salts by reverse phase chromatography (Sep-Pak). Representative methods of making the contrast agents are described in the following examples. The above chemical transformations can be effected by using techniques which would be readily apparent to one of ordinary skill in the art, once equipped with the teachings of current applications. Representative reaction solvents include, for example, DMF, NMP, DMSO, THF, ethyl acetate, dichloromethane and chloroform. The reaction mixture can be kept neutral or basic by the addition of an amine such as triethylamine or DIEA. The reactions can be carried out at ambient temperatures and protected from oxygen and water with a nitrogen atmosphere.

Temporarily, protecting groups can be used to avoid other reactive functionality, such as amines, thiols, alcohols, phenols and carboxylic acids, from participation in the reaction. Representative protecting groups of amine include, for example, tert-butoxycarbonyl and trityl (removed under medium acidic conditions), Fmoc (removed by the use of secondary amines such as piperidines) and benzyloxycarbonyl (removed by a strong acid or by catalytic hydrogenolysis) . The trityl group can also be used for the protection of thiols, phenols and alcohols. In certain embodiments, carboxylic acid protecting groups include, for example, tert-butyl ester (removed by a medium acid), benzyl ester (usually removed by catalytic hydrogenolysis) and alkyl esters such as methyl or ethyl (usually removed by a medium base). All protecting groups can be removed at the end of the synthesis by using the conditions described above for the individual protecting groups and the final product can be purified by techniques which would be readily apparent to one of ordinary skill in the art once equipped with the description current .

Use The contrast agents of the present disclosure can be used in an imaging method, including imaging methods in a patient comprising administering the contrast agent to the patient by injection, infusion or any other known method and training of images of the patient's area where the event of interest is located. The useful dose to be administered and the particular mode of administration will vary depending on factors such as the age, weight and region in particular to be treated, as well as the particular contrast agent used, the contemplated diagnostic use and the form of the formulation for example, suspension, emulsion, microsphere, liposomes or the like, as will be readily apparent to those skilled in the art. Typically, the dose is administered at lower levels and increased until a desirable diagnostic effect is achieved. In one embodiment, the contrast agents described above can be administered by intravenous injection, usually in saline, at a dose of from about 0.1 to about 100 mCi per 70 kg of body weight (and all combinations and sub-combinations of the ranges). of dose and the specific doses in them) or preferably at a dose of about 0.5 to about 50 mCi. The imaging is performed using techniques well known to the ordinarily skilled artisan.

For use as contrast agents in nuclear medicine, the compositions of the current description, doses, administered by intravenous injection, will typically be in the range of from about 0.5 μmol / kg to about 1.5 mmol / kg (and all combinations and subcombinations of dose ranges and specific doses therein), preferably about 0.8 μmol / kg to about 1.2 mmol / kg. For use as MRI contrast agents, the compositions of the current disclosure can be used as a similar form as other MRI agents as described in US Pat. No. 5,155,215; patent of E.U.A. No. 5,087,440; Magn. Reson. Med. 1986, 3, 808; Radiology 1988, 166, 835; and Radiology 1988, 166, 693. Generally, sterile aqueous solutions of the contrast agents can be administered to a patient intravenously in doses in the range of from about 0.01 to about 1.0 mmol per kilogram of body weight (and all combinations and subcombinations of dose ranges and specific doses therein). The ultrasound contrast agents of the present disclosure can be administered by intravenous injection in an amount from about 10 to about 30 μl (and all combinations and subcombinations of dose ranges and specific doses therein) of the echogenic gas per kilogram of body weight or infusion at a ratio of approximately 3 μl / kg / min. Another aspect of the current description is the diagnostic kits for the preparation of diagnostic agents for the detection, imaging and / or monitoring of myocardial perfusion. Diagnostic kits of the present disclosure comprise one or more vials containing the sterile, non-pyrogenic formulation, comprising a predetermined amount of a reagent of the present disclosure and optionally other components such as one or two auxiliary ligands such as tricine and acid. 3- [bis (3-sulfophenyl) phosphine] benzenesulfonic acid (TPPTS), reducing agents, transfer ligands, buffer solutions, lyophilization aids, stabilization aids, solubilization aids and bacteriostats. The kits may also comprise a reducing agent such as, for example, tin (II). Buffer solutions useful in the preparation of contrast agents and kits include, for example, buffer solutions of phosphate, citrate, sulfosalicylate and acetate. A more complete list can be found in the United States Pharmacopoeia. Lyophilization aids useful in the preparation of contrast agent and kits include for example, mannitol, lactose, sorbitol, dextran, FICOLL® polymer and polyvinylpyrrolidine (PVP). Stabilization aids useful in the preparation of contrast agents and kits include, for example, ascorbic acid, cysteine, monothioglycerol, sodium bisulfite, sodium metabisulfite, gentisic acid, and inositol. Solubilization aids in the preparation of contrast agents and kits include, for example, ethanol, glycerone, polyethylene glycol, propylene glycol, polyoxyethylene sorbitan monooleate, sorbitan monooleate, polysorbatps, poly (oxyethylene) -poly (oxypropylene) -poly (oxyethylene) block copolymers ("Pluronic") and lecithin. In certain embodiments, the solubilization aids are polyethylene glycol and Pluronics. Bacteriostats useful in the preparation of contrast agents and kits include, for example, benzyl alcohol, benzalkonium chloride, chlorobutanol and methyl, propyl or butyl paraben. A compound in a diagnostic kit can also serve more than one function. For example, a reducing agent for a radionuclide may also serve as a stabilization aid, or a buffering solution may also serve as a transfer ligand or a lyophilization aid may also serve as an auxiliary transfer or co-ligand.

The compounds described herein may have asymmetric centers. Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the current description. Many geometric olefin isomers, C = N double bonds, and the like may also be present in the compounds described herein and all such stable isomers are contemplated in the current description. It will be appreciated that the compounds of the present disclosure may contain asymmetrically substituted carbon atoms and may be isolated in racemic or optimally active forms. It is well known in the art how to prepare optically active forms such as by resolution of racemic forms or by synthesis from optically active starting materials. Two different isomers (cis and trans) of the peptide bond are known to occur; both may also be present in the compounds described herein and all such stable isomers are contemplated in the current description. The D and L isomers of a particular amino acid are designated herein by using a conventional 3-letter abbreviation of the amino acid as indicated by the following examples: D-Leu, or L-Leu. For the sake of simplicity, the connection points ("-") are not detailed. When an atom or compound is described to define a variable, it is understood that it is intended to replace the variable in a way that satisfies the valence of the atom or compound. For example, if a variable A "is identified as C (R80) = C (R80), both carbon atoms would form a part of the chain in order to satisfy their respective valencies When a variable is presented more than once in some substituent or in some formula, its definition each presented is independent of its definition each time it is presented again.So, for example, if a group, or plurality of groups is shown to be substituted with 0-2 R80, then the groups can optionally be substituted with up to two R80 and R80_ in each presence in each group is independently selected from the defined list of possible R80.Also by way of example for the group -N (R81) 2, each of the two substituents R81 on N it is independently selected from the defined list of possible R81.The combinations of substituents and / or variables are allowed only if such combinations result in stable compounds.When a bond to a substituent is shown Because it crosses the bond that connects two atoms in a ring, then such a substituent can bind to any atom in the ring.

Definitions The number of carbon atoms in any particular group is denoted earlier in the group recitation. For example, the term "aryl C3-C? 0" denotes an aryl group containing from 6 to 10 carbon atoms, and the term "Cg-C10 aryl-C? -C10 alkyl," refers to an aryl group of 6 to 10 carbon atoms bonded to the precursor molecular moiety through an alkyl group of 1 to 10 carbon atoms. The term "alkenyl," as used herein, refers to a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond. The term "alkoxy," as used herein, refers to a C 1 -C 4 alkyl group linked to the parent molecular moiety through an oxygen atom. The term "alkoxyalkyl," as used herein, refers to a C 1 -C 6 alkyl group substituted with one, two or three alkoxy groups. The term "alkyl," as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon. The term "alkylaryl," as used herein, refers to an alkyl group linked to the molecular precursor moiety through an aryl group. The term "alkylene," as used herein, refers to a divalent group derived from a straight or branched chain saturated hydrocarbon.

The term "alkyloxy," as used herein, refers to a C 1 -C 6 alkyl group bonded to the molecular precursor moiety through an oxygen atom. The term "analogous portion," as used herein, refers to the compounds of the present invention, which excludes the portion or portions that form images. The term "aryl," as used herein, refers to a phenyl group, or a bicyclic fused ring system wherein one or more of the rings is a phenyl group. Bicyclic fused ring systems consisting of a phenyl group fused to a monocyclic cycloalkenyl group, a monocyclic cycloalkyl group, or another phenyl group. The aryl groups of the present invention can be linked to the precursor molecular moiety through any substitutable carbon atom in the group. Representative examples of aryl groups include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The term "arylalkyl," as used herein, refers to an alkyl group substituted with one, two, or three aryl groups. The term "arylalkylene," as used herein, refers to a divalent arylalkyl group, wherein one point of attachment to the parent molecular moiety is in the aryl moiety and the other is in the alkyl moiety. The term "arylene," as used herein, refers to a divalent aryl group. As used herein, the terms "auxiliary" or "co-ligands" refer to ligands that serve to complete the coordination sphere of the -radionuclide together with the unit that binds the chelator or radionuclide of the reagent. For radiopharmaceuticals comprising a binary ligand system, the radionuclide coordination sphere comprises one or more chelators or is linked to units from one or more reagents and one or more helpers or co-ligands, with the proviso that there is a total of two types of ligands, chelators or link units. For example, a radiopharmaceutical comprises of a chelator or linker unit from a reagent and two of the same helpers or co-ligands and a radiopharmaceutical comprising two chelators or linkers from one or two reagents and an assistant or co-ligand both they are considered to comprise binary ligand systems. For radiopharmaceuticals comprising a ternary ligand system, the coordination sphere radionuclide comprises one or more chelators or linking units from one or more reagents and one or more than two different types of auxiliaries or co-ligands, with the proviso that find a total of three types of ligands, chelators or liaison units. For example, a radiopharmaceutical comprises a chelator or linker unit from a reagent and two different auxiliaries or co-ligands are considered to comprise a ternary ligand system. Auxiliary or co-ligands are useful in the preparation of radiopharmaceuticals and in diagnostic kits useful for the preparation of radiopharmaceuticals comprising one or more donor atoms of oxygen, nitrogen, carbon, sulfur, phosphorus, arsenic, selenium, and tellurium. A ligand can be a ligand transferred in the synthesis of a radiopharmaceutical and also serves as an adjuvant or co-ligand in another radiopharmaceutical. Whether a ligand is called a ransfer or helper or co-ligand depends on whether the ligand results in the radionuclide of coordination sphere in the radiopharmaceutical, which is determined by the coordination chemistry of the radionuclide and the chelator or unit of Reagent or reagents link. A "bacterioestate" is a component that inhibits the growth of the bacteria in a formulation either during storage before use, after a diagnostic kit is used to synthesize a radiopharmaceutical. The term "bubbles" or "microbubbles," as used herein, refers to vesicles that are generally characterized by the presence of one or more membranes or walls surrounding an internal void that is filled with a gas or precursor to this. Exemplary bubbles include, for example, liposomes, micelles, and the like. The terms "chelator" and "link unit," as used herein, refer to the portion or group in a reagent that links to a metal ion through one or more donor atoms. The term "contrast agent," as used herein, refers to an agent used for highly specific areas so that organs, blood vessels, and / or tissues are more visible. By increasing the visibility of the surfaces that are studied, the presence and extent of the disease and / or injury can be determined. The term "cycloalkenyl", as used herein, refers to a monocyclic, bicyclic, or monocyclic, non-aromatic, partially unsaturated ring system having three to fourteen carbon atoms and zero heteroatoms. Representative examples of cycloalkenyl groups include, but are not limited to, cyclohexenyl, octahydronaphthalenyl, and norbornylenyl. The term "cycloalkyl," as used herein, refers to a saturated monocyclic, bicyclic or tricyclic hydrocarbon ring system having 3 to 14 carbon atoms and zero heteroatoms. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, bicyclo [3.1.1] heptyl, and adamantyl. The term "C3-C10 cycloalkylene," as used herein, refers to a divalent cycloalkyl group containing from three to 10 carbon atoms. The term "diagnostic imaging", as used herein, refers to a method used to detect a contrast agent. A "diagnostic kit" or "kit" comprises a collection of components, called the formulation, in one or more vials that are used by the final user practitioner in a clinical setting or pharmacy to synthesize the radiopharmaceuticals diagnosed. The kit preferably provides all the components required to synthesize and use the diagnostic pharmacist except those that are commonly available to the end user user, such as water or saline for injection, a solution of the radionuclide, equipped to heat the kit during synthesis of the radiopharmaceutical, if required, necessarily equipped to administer the radiopharmaceutical to the patient such as syringes, protection, imaging equipment, and the like. The contrast agents are provided to the end user in its final form in a formulation typically contained in a vial, as either a lyophilized solid or an aqueous solution. The end user typically reconstitutes the lyophilized material with water or saline and the dose is withdrawn or adjusted to the patient, the dose of the aqueous solution formulation is removed as provided. The term "donor atom," as used herein, refers to the atom-directly linked to a metal by a chemical bond. The terms "halo" and "halogen," as used herein, refer to F, Cl, Br, or I. The term "haloalkyl," as used herein, refers to an alkyl group C? -C6 substituted by 1, 2, 3 or 4 halogen atoms. The term "heteroaryl," as used herein, refers to an aromatic 5 or 6 membered ring where at least one atom is selected from N, 0, and S, and the remaining atoms are carbon. The term "heteroaryl" also includes bicyclic systems wherein a heteroaryl ring is fused to a 4 or 6 membered aromatic or non-aromatic ring containing 0, 1, or 2 additional heteroatoms selected from N, O, and S. The heteroaryl groups are they bind to the precursor molecular moiety through any substitutable carbon or nitrogen atom in the group. Representative examples of heteroaryl groups include, but are not limited to, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzothienyl, furanyl, imidazolyl, indazolyl, indolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, and triazinyl. The term "heterocyclyl," as used herein, refers to a 5-, 6- or 7-membered ring containing 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, sulfur. The 5-membered ring has 0 up to 2 double bonds and the 5 and 6-membered rings having 0 up to three double bonds. The term "heterocyclyl" also includes bicyclic groups in which the heterocyclyl ring is fused to a phenyl group, a monocyclic cycloalkenyl group, a monocyclic cycloalkyl group, or another monocyclic heterocyclyl group. The heterocyclyl groups of the present invention can be linked to the molecular precursor moiety through a carbon atom or a nitrogen atom in the group. Examples of heterocyclyl groups include, but are not limited to, benzothienyl, furyl, imidazolyl, indolinyl, indolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrrolopyridinyl, pyrrolyl, thiazolyl, thienyl, and thiomorpholinyl. The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with 1, 2, or 3 heterocyclyl groups. The term "heterocyclylalkylene," as used herein, refers to a divalent heterocyclylalkyl group, wherein one point of attachment to the parent molecular moiety is in the heterocyclyl portion and the other is in the alkyl moiety. The term "heterocyclylene," as used herein, refers to a divalent heterocyclyl group. The term "hydroxy," as used herein, refers to -OH. The term "image-forming portion," as used herein, refers to a portion or portions of a molecule that allows detection, imaging, and / or monitoring of the presence and / or progression of conditions. , pathological disorders, and / or diseases. The term "linker group", as used herein, refers to a portion of a molecule that serves as a spacer between two other portions of the molecule. The linker groups can also serve other functions as described herein. Examples of linking groups include alkyl, aryl, ether, polyhydroxy, polyether, polyamine, heterocyclic, aromatic, hydrazido, peptide, linear, branched or cyclic peptoido, or other physiologically compatible covalent binders or combinations thereof.

As used herein, the term "lipid" refers to a synthetic or naturally occurring amphipathic compound comprising a hydrophilic component and a hydrophobic component. Lipids include, for example, fatty acids, neutral fats, phosphatides, glycolipids, aliphatic alcohols and waxes, terpenes and steroids. Exemplary compositions comprising a lipid compound include suspensions, emulsions and vesicular compositions. "Liposome" refers to a generally spherical group or aggregate of antipathetic compounds, includes lipid compounds, typically in the form of one or more concentric layers, for example, bilayers. It can also be referred to herein as lipid vesicles. A "lyophilization aid" is a component that has favorable physical properties for lyophilization, such as the glass transition temperature, and is generally added to the formulation to improve the physical properties of the combination of all components of the lyophilization formulation . The term "oxo", as used herein, refers to = 0. As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human tissues. and animals without excessive toxicity, irritation, allergic response, or other problem or complication, in proportion to a reasonable benefit / risk ratio. The term "pharmaceutically acceptable salt," as used herein, represents salts or zwitterionic forms of the compounds of the present invention which are water or soluble or dispersible oil, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication in proportion to a reasonable benefit / risk ratio, and are effective for their intended use.Salts may be prepared during the isolated and the purification of the compounds or separatively upon reaction of a suitable nitrogen atom with a suitable acid The representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorrate, camphorsulfonate; digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, bromohydrate, iodohid time, 2-hydroxyethanesulfonate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate. Examples of acids that can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids "such as oxalic, maleic, succinic, and citric." "Reagent" means a composed of this description capable of directing the transformation into a metallopharmaceutical of this description, the reagents may be used directly for the preparation of the metallopharmaceuticals of this description or may be a component in a kit of this description. What a reaction with a radionuclide, which is typically obtained as a relatively non-reactive, compound in the high oxidation state, by decreasing this oxidation state by transferring the electrons to the radionuclide, therefore this becomes more reactive. the preparation of radiopharmaceuticals and in diagnostic kits ú Useful for the preparation of radiopharmaceuticals include, for example, stannous chloride, stannous fluoride, formamidine sulfinic acid, ascorbic acid, cysteine, phosphines, and ferrous and cuprous salts. Other reducing agents are described, for example, in Brodack et. al., PCT Application 94/22496. A "stabilization aid" is a component that is typically added to the metalworker or diagnostic kit either to stabilize the metalworker or to prolong the shelf life of the kit before it is used more. Stabilization aids can be antioxidants, reducing agents or radical scavengers and can provide improved stability by reacting preferentially with species that degrade other components or the metallopharmaceuticals. By "stable compound" or "stable structure" is meant herein a compound that is sufficiently robust to survive isolated to a useful degree of purity from a reaction mixture, and the formulation into an effective pharmaceutical agent. A "solubilization aid" is a component that improves the solubility of one or more other compounds in the medium required for the formulation. The term "thiol protecting group", as used herein, refers to a group intended to protect a thiol group against undesirable reactions during synthetic procedures. Any thiol protecting group known in the art can be used. Examples of thiol protecting groups include, but are not limited to, the following: acetamidomethyl, benzamidomethyl, 1-ethoxyethyl, benzoyl, and triphenylmethyl. A "transfer ligand" is a ligand that forms an intermediate complex with a metal ion that is sufficiently stable to prevent unwanted side reactions but sufficiently unstable to convert to a contrast agent. The "formation of the intermediate complex is kinetically favored while the formation of the metallopharmaceutical is favored thermodynamically.The transfer ligands useful in the preparation of contrast agents and in diagnostic kits for the preparation of diagnostic radiopharmaceuticals include, for example, gluconate, glucoheptonate, mannitol, glucarate, N, N, N ', N'-ethylenediaminetetraacetic acid, pyrophosphate and methylene diphosphonate In general, the transfer ligands are comprised of oxygen or nitrogen donor atoms. The term "vesicle" refers to a spherical entity that is characterized by the presence of an internal void.In one embodiment the vesicles are formulated from lipids, including the various lipids described herein.In any given vesicle, the lipids may be the shape of a monolayer or bilayer, and the mono- or bilayer lipids can be used to form one or more In the case of more than one mono- or two-layer, the mono- or bilayers are generally concentric. The lipid vesicles described herein are such entities commonly referred to as liposomes, micelles, bubbles, microbubbles, microspheres and the like. In this manner, the lipids can be used to form a unilamellar vesicle (comprising a monolayer or bilayer), an oligolamellar vesicle (comprising about 2 or about 3 monolayers or bilayers) or a multilamellar vesicle (comprising more than about of three monolayers or bilayers). The internal void of the vesicles can be filled with a liquid, including, for example, an aqueous liquid, a gas, a gaseous precursor, and / or a solid or dissolved material, including, for example, a bioactive agent, as desired. As used herein, the term "vesicular composition" refers to a composition that is formulated of lipids and that comprises vesicles. The present description will now describe in connection with certain modalities that are not intended to limit the scope. Otherwise, the present disclosure covers all alternatives, modifications, and equivalents as may be included within the scope of the claims. In this way, the following examples will illustrate a practice of the present invention, it will be understood that the examples are for the purposes of illustrating certain modalities and are presented to provide that they are believed to be more useful and the description of these procedures and conceptual aspects will be readily understood.

Synthesis of Fenazaquin Analogue: For example: Synthesis of 4- [4- (2-hydroxyethyl) phenyl] -4-oxo-butyric acid methyl ester 1. Q cr ^ * ^ * CO2MB Phenethyl alcohol (2.50 g, 0.02 mol), anhydrous dichloromethane (150 mL), and methyl-4-chloro-4-oxobutyrate were added to a 250 mL dry flask under a nitrogen atmosphere. (6.02 g, 0.04 mol). The contents of the flask were cooled to 0 ° C with an ice bath. To the solution was added aluminum chloride (25 g, 0.2 mol) in portions with the care of avoiding a violent exotherm. The resulting yellowish mixture was stirred for 3 hours. At this point the reaction was quenched with ice water. The mixture was diluted with dichloromethane and transferred to a separatory funnel. The organic layer was washed with a saturated solution of sodium bicarbonate, brine and then dried over magnesium sulfate. Filtration and concentration of the filtrate under reduced pressure gave a yellow crude oil. The oil was suspended in anhydrous methanol (100 mL) and metallic sodium was added to the mixture until a pH of 9 was obtained. The mixture was stirred for 3 hours. The volume was reduced and then diluted with ethyl acetate. The solution was transferred to a separatory funnel and washed with 0.05N aqueous hydrochloric acid, brine and dried over magnesium sulfate. The solution was concentrated under reduced pressure to give a crude yellow oil with a mass of 5.88 g. Column chromatography [silica gel; Hexanes-ethyl acetate elution agent (3: 2)] provided the desired product (2.69 g, 57%). XE (CDC13) d (ppm): 2.65 (t, 2H); 2.81 (t, 2H); 3.19 (t, 2H); 3.6 (s, 3H); 3.75 (t, 2H); 7.22 (d, 2H); 7.81 (d, 2H). 13C (CDC13) d (ppm): 27.76, 33.03, 38.66, 51.52, 62.68, 127.97, 128.99, 134.47, 144.78, 173.21, 197.64.

Example IB Synthesis of 4- [4- (2-hydroxyethyl) phenyl] butyric acid methyl ester A mixture of Example IA (2.50 g, 11 mmol), 10% Pd / C (0.25 g, 0.23 mmol of Pd metal) in anhydrous methanol (25 mL) was degassed first to remove the air (two cycles of vacuum / H2) after which it was closed and a balloon filled with H2 was applied to it during 12 hours. After this time the reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure to give 2.32 g of crude material. Column chromatography [silica gel; Hexanes-ethyl acetate (2: 1) eluting agent] provided the desired product (0.92 g, 39%). XH (CDC13) d (ppm): 1.91-1.96 (m, 2H); 2.32 (t, 2H); 2.62 (t, 2H); 2.83 (t, 2H); 3.66 (s, 3H); 3.85 (t, 2H); 7.11-7.15 (m, 4H).

Example 1C Synthesis of 4- methyl ester. { 4- [2- (quinazolin-4-yloxy) ethyl] phenyl} Butyric A dry 50 mL flask was coupled with an addition funnel. To the flask were added 4-chloroquinazoline (592 mg, 3.6 mmol), anhydrous tetrahydrofuran (10 mL), and 60% by weight of sodium hydride (187 mg, 4.7 mmol). A solution of Example IB (800 mg, 3.6 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise using the addition funnel. The reaction was stirred for 3.5 hours. The reaction was diluted with ethyl acetate and quenched by the addition of 0.1 N aqueous hydrochloric acid. The mixture was transferred to a separatory funnel and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Column chromatography [silica gel; elution agent hexanes-ethyl acetate (4: 1)] provided the desired product (538 mg, 43%). i H (CDC13) d (ppm): 1.92-1.98 (m, 2H); 2.33 (t, 2H); 2.64 (t, 2H); 3.19 (t, 2H); 3.66 (s, 3H); 4.79 (t, 2H); 7.15 (d, 2H); 7.27 (d, 2H); 7.57 (t, ÍH); 7.83 (t, ÍH); 7.94 (d, ÍH); 8.15 (d, ÍH); 8.80 (s, 1H). 26.68, 33.59, 34.93, 35.03, 51.67, 67.89, 116.48, 123.72, 127.23, 127.82,. 128.87, 129.24, 133.74, 135.76, 139.90, 151.08, 154.56, 166.89, 174.10.

Example ID Synthesis of 4-. { 4- [2- (Quinazolin-4-yloxy) ethyl] phenyl} butan-l-ol To a dry 15 ml flask was added lithium aluminum hydride (233 mg, 6.0 mmol) and anhydrous diethyl ether (3 mL). The mixture was cooled with an ice bath. A solution of Example 1C (538 mg, 1.54 mmol) in anhydrous diethyl ether (3 mL) was added slowly with vigorous stirring. The bath was removed and the thick solution was stirred for 15 minutes. The reaction was quenched with water (0.233 mL), 15% aqueous sodium hydroxide (0.233 mL) and water (0.699 mL). The white solid was filtered and the filtrate was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give a clear oil. The oil was then dissolved in anhydrous dichloromethane (10 mL) and manganese (IV) oxide (500 mg, 5.8 mmol) was added to the solution. The mixture was stirred for 12 hours. Filtration through diatomaceous earth (Celite®) followed by concentration of the filtrate under reduced pressure yielded 395 mg of the crude product. Column chromatography [Silica gel; pentane-ethyl acetate elution agent (2: 3)] provided the desired product (225 mg, 49%). XH (CDC13) d (ppm): 1.55-1.61 (m, 2H); 1.65-1.68 (m, 2H); 2.61 (t, 2H); 3.17 (t, 2H); 3.64 (t, 2H); 4.79 (t, 2H); 7.12 (d, 2H); 7.23 (d, 2H); 7.56 (t, ÍH); 7.82 (t ÍH); 7.93 (d ÍH); 8. 14 (d, ÍH); 8.77 (s, ÍH). 13C (CDC13) d (ppm): '27.52, 32. 31, 34.89, 35.21, 62.81, 67.74, 116.67, 123.54, 127.08, 127.49, 128.63, 128.98, 133.61, 135.23, 140.64, 150.68, 154.29, 166.79.

Example 1E ester synthesis of 4-. { 4- [2- (quinazolin-4-yloxyethyl] phenyl] butyl of toluene-4-sulfonic acid To a dry 10 ml flask was added p-toluenesulfonyl chloride (32.5 mg, 0.17 mmol), 4- (dimethylamino) pyridine (20.7 mg, 0.17 mmol), Example ID (50.0 mg, 0.16 mmol), anhydrous dichloromethane (1 mL) and triethylamine (17.2 mg, 0.17 mmol). The resulting solution was stirred for 2 hours, concentrated under reduced pressure, and purified by column chromatography [silica gel; pentane-ethyl acetate elution agent (1.86: 1)] to provide the desired product (52 mg, 70%). 1H (CDC13) d (ppm): 1.64-1.68 (m, 4H); 2.44 (s, JH); 2.56 (t, 2H); 3.19 (t, 2H); 4.04 (t, 2H); 4.78 (t, 2H); 7.08 (d, 2H); 7.26 (d, 2H); 7.57 (t, ÍH); 7.78 (d, 2H); 7.84 (t, 1H), 8.14 (d, 1H); 8.80 (S, 1H).

Example 1F Synthesis of 4-. { 2- [4- (4-Fluorobutyl) phenyl] ethoxy} quinazoline A dry 5 ml flask was coupled with a reflux condenser. To the flask was added potassium fluoride (6.1 mg, 0.1 mmol), kryptofix (40 mg, 0.1 mmol) and anhydrous acetonitrile (0.5 mL). To the resulting solution was added a solution of Example IE (25 mg, 0.05 mmol) in anhydrous acetonitrile (1 mL). The flask was placed in an oil bath at 90 ° C. The solution was stirred for 1 hour. After cooling the reaction mixture was diluted with diethyl ether, transferred to a separatory funnel, and washed with 0.1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, and then brine. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. Column chromatography [silica gel; Elution agent hexanes-ethyl acetate (3: 1)] provided the desired product (10.7 mg, 63%). 1H (CDC13) d (ppm): 1.65-1.73 (m, 4H); 2.63 (t, 2H); 3.17 (t, 2H); 4.40 (t, ÍH); 4.48 (t, 1H); 4.77 (t, 2H); 7.13 (d, 2H); 7.24 (d, 2H); 7.55 (ÍH); 7.82 (t, ÍH); 7.92 (d, lH); 8.13 (d, ÍH); 8.78 (Yes H) . 13C (CDC13) d (ppm): 27.19 (d, 4JCF = 4.5), 30.20 (d, 3JCF = 19.5), 35.15 (d, 2JCF = 27.0), 67.94, 84.17 (d, 1JCF = 163.3), 116.93, 123.75, 127.26, 127.84, 128.82, 129. 23, 129.42, 133.77, 135.62, 138.21, 140.54, 151.08, 154.59. 19F (CDC13, CFC13 internal standard) d (ppm): - 218.59 (t of t, J = -27.6, -50.4).

Synthesis of Pyridaben analogues: Example 2A Synthesis of 4-phenylbutyl ester of butyric acid To 4-phenyl-1-butanol (7.0 g, 0.047 mol) was added anhydrous dichloromethane (20 mL). A solution of butyryl chloride (4.79 g, 0.045 mol) in anhydrous dichloromethane (20 mL) was added dropwise. The solution was stirred for 36 hours. At this point the reaction was concentrated under reduced pressure to give a crude oil. Column chromatography [silica gel; elution agent hexanes-ethyl acetate (3: 1)] provided the desired product (9.8 g, 94%) as a clear viscous liquid. ^ (CDCls) d (ppm): 0.94 (t, 3H); 1.61-1.71 (m, 6H); 2.27 (t, 2H); 2.64 (t, 2H); 4.08 (t, 2H); 7.16-7.19 (m, 3H); 7.25-7.29 (m, 2H). Example 2B Synthesis of 4- (4-Hydroxybutyl) enzoic acid methyl ester To aluminum chloride (6.7 g, 0.05 mol) in a 250 mL dry round bottom flask was added anhydrous dichloromethane (100 mL). The flask was cooled in an ice bath at 0 ° C. Oxalyl chloride (6.4 g, 0.05 mol) was added dropwise to the flask. The mixture was allowed to stir for 5 minutes. A solution of Example 2A (9.8 g, 0.044 mol) in anhydrous dichloromethane (50 mL) then it was added drop by drop. The mixture was allowed to stir for 4 hours at 0 aC. The reaction mixture was emptied into a separatory funnel containing ice and brine. The organic layer was washed with brine and dried over magnesium sulfate. Filtration and concentration under reduced pressure afforded 9.1 g of yellow oil. 9.0 g of this oil were suspended in methanol and the pH was adjusted to 2 and stirred for 48 hours. The reaction mixture was concentrated under reduced pressure. Column chromatography [silica gel; elution agent hexanes-ethyl acetate (2.57: 1)] provided the desired product (2.80 g, 31%) as a clear viscous liquid. "" "H (CDC1) d (ppm): 1.56-1.61 (m, 2H), 1.63-1.73 (, 2H), 2.67 (t, 2H), 3.64 (t, 2H), 3.88 (s, 3H); 7.23 (d, 2H); 7.93 (d, 2H).

Example 2C Synthesis of 4- [4- (tert-Butyldimethylsilanyloxy) butyl] benzoic acid methyl ester To Example 2B (1.0 g, 4.8 mmol) was added anhydrous dimethylformamide (10 mL), imidazole (0.5 g, 7.2 mmol) and tert-butyldimethylsilyl chloride (1.08 g, 7.3 mmol). The solution was stirred in a bath with water for 2 hours. The reaction mixture was diluted with ethyl acetate, evacuated in a separatory funnel, washed with water (20 mL, 5x) then washed with a saturated solution of sodium bicarbonate (20 L, 2x). The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give the desired product (1.17 g, 75%) which was used without further purification in the next step. Example 2D Synthesis of. { 4- [4- (tert-Butyldimethylsilanyloxy) util] phenyl} - methanol To Example 2C (1.17 g, 3.6 mmol) anhydrous diethyl ether (14 mL) was added. The solution was cooled to 0 aC with an ice bath. Lithium aluminum hydride (0.28 g, 7.2 mmol) was added to the solution in portions. The mixture was stirred for 1 hour. Distilled water (0.28 mL) was added to the reaction mixture and the mixture was stirred for 5 minutes. Then a 15% aqueous solution of sodium hydroxide was added and the mixture was stirred for 5 minutes. Finally, distilled water (0.84 mL) was added and the mixture was stirred for 5 minutes. The white solid was removed by filtration. The filtrate was dried with magnesium sulfate, filtered, and concentrated to give 1.23 g of the crude product. Column chromatography [silica gel; Hexanes-ethyl acetate elution agent (4: 1)] provided the desired product (1.02 g, 96%) as a clear viscous liquid.

Example 2E Synthesis of 2-tert-Butyl-5-. { 4- [4- (tert-Butyldi-ethylsilanyloxy) butyl] enzyloxy} -4-chloro-2H-pyridazin-3 -one To a 25 ml dry bottom flask, coupled with a reflux condenser, the product of Example 2D (0.41 g, 1.4 mmol), 2-tert-butyl-4,5-dichloro-2H-pyridazin-3 was added. -one (0.93 g, 4.2 mmol), cesium carbonate (1.37 g, 4.2 mmol), and anhydrous dimethylformamide (11 mL). The reaction flask was placed in an oil bath at 68 ° C and the reaction was stirred for 12 hours. The reaction flask was removed from the oil bath and allowed to cool. The mixture was diluted with ethyl acetate, transferred to a separatory funnel and washed with water (25 mL, 5x). The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give 1.3 g of the crude product. Column chromatography [silica gel; elution agent hexanes-ethyl acetate (9: 1)] provided the desired product (594 mg, 89%). 1H (CDC13) d (ppm): 0.05 (s, 6H); 0.90 (s, 9H); 1.64 (s, 9H); 2.65 (t, 2H); 3.64 (t, 2H); 5.23 (s, 2H); 7.23 (d, 2H); 7.33 (d, 2H); 7.74 (s, 1H). 13C (CDC13) d (ppm): 18.57, 26.19, 27.75, 28.09, 32.58, 35.61, 63.14, 66.57, 72.14, 118.46, 125.41, 127.44, 129.23, 132.38, 143.72, 154.02, 159.30.

Example 2F Synthesis of 2-tert-Butyl-4-chloro-5- [4- (4-hydroxy-butyl) -benzyloxy] -2H-pyridazin-3-one To the product of Example 2E (594 mg, 1.45 mmol) was added anhydrous tetrahydrofuran (3 mL) and a 1.0 M solution of tert-butylammonium fluoride in tetrahydrofuran (2.9 mL, 2.9 mmol). The solution was stirred for 1 hour then concentrated under reduced pressure. Column chromatography [silica gel; pentane-ethyl acetate elution agent (1.8: 1)] provided the desired product (410 mg, 77%)? (CDC13) d (ppm): 1.61-1.64 (m, 11H); 1.67-1.74 (m, 2H); 2.68 (t, 2H); 3.68 (t, 2H); 5.23 (s, 2H); 7.23 (d, 2H); 7.33 (d, 2H); 7.74 (s, ÍH). 13C (CDC13) d (ppm): 27.43, 27.86, 32.56, 35.35, 62.74, 66.36, 71.88, 118.27, 125.18, 127.27, 128.99, 132.28, 143.17, 153.78, 159.07.

Example 2G Synthesis of 4- [4- (l-tert-butyl-5-chloro-6-oxo-l, 6-dihydro-pyridazin-4-yloxymethyl) -phenyl] -butyl ester of toluene-4-sulfonic acid TsCI To a 5 ml round bottom flask was added the product of Example 2F (200 mg, 0.55 mmol), p-toluenesulfonyl chloride (125 mg, 0.66 mmol), 4- (dimethylamino) pyridine (80 mg, 0.66 mmol), diisopropylethylamine (85 mg, 0.66 mmol) and anhydrous dichloromethane (2 mL). The resulting solution was stirred for 2 hours. The reaction mixture was diluted with ethyl acetate, transferred to a separatory funnel and washed with a 0.1N aqueous hydrochloric acid solution and then washed with brine. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give 299 mg of the crude product. Column chromatography [silica gel; pentane-ethyl acetate elution agent (3: 1)] provided the desired product (197 mg, 69%). ^ (CDCls) d (ppm): 1.62-1.70 (m, 13H); 2.43 (s, 3H); 2.58 (t, 2H); 4.03 (t, 2H); 7.15 (d, 2H); 7.29-7.33 (m, 4H); 7.72 (s, 1H); 7.77 (d, 2H). 13C (CDC13) d (ppm): 21.63, 26.98, 27.86, 28.34, 34.80, 66.37, 70.23, 71.81, 118.25, 125.12, 127.32, 127.87, 128.93, 129.82, 132.48, 133.15, 142.40, "144.72, 153.75, 159.05.

Example 2H Synthesis of 2-tert-butyl-4-chloro-5- (4- (4-fluorobutyl) benzyl) oxy 3 (2H) pyridazinone The product of Example 2G (57 mg, 0.10 mmol) was dissolved in 1 mL of acetonitrile and to this was added a mixture of KF-K222 (1: 1, 0.164 mmol) dissolved in 1 mL of acetonitrile. The whole mixture was then immersed in an oil bath at 90 ° C and heated to reflux for 15 minutes at which point the reaction was shown to be complete by CCD. The volatile components were removed in vacuo and the crude oil was purified by flash chromatography on silica gel (hexanes-ethyl acetate (4: 1)) to provide 28 mg of the desired product as an oil which solidified upon standing. 1H (CDC13) d (ppm): 1.6 (s, 9H), 1.7 (m, 4H), 2.6 (t, 2H), 4.44 (d of t, 2H, J = 47.4 &6 Hz), 5.2 (s) , 2H), 7.2 (d, 2H, J = 8.4 Hz), 7.3 (d, 2H, J = 8.4 Hz), 7.71 (s, 1H). 13C (CDC13) d (ppm): 26.8 (3JCF = 4.65 Hz), 27.8, 29.8 (2JCF = 19.8 Hz), 35.1, 66.3.71.8, 83.8 8 = 163.8 Hz), 118.2, 125.1, 127.2, 128.9, 132.3, 142.8, 153, 159. 19F (CDC13, CFC13 as internal standard) d (ppm): - 218.6 (t of t, J = -27.6, -50.4) Example 3A Synthesis of (+) - l-tert-butyldimethylsilyloxy-2-hydroxybutane / - TB SCI, Imidazole HO '> H DM F TBSO '> 0H A 50 mL round bottom flask was charged with (+) - 1,2-butanediol (lg, 11.09 mmol) and dimethylformamide (8 mL) was added followed by tert-butyldimethylsilyl chloride (2.5 g, 16.64 mmol) and imidazole ( 1.88 g, 27.7 mmol). The reaction mixture was stirred for 10 hours after which it was diluted with dichloromethane and emptied into a separatory funnel and washed with water (80 mL) and brine and dried over magnesium sulfate. After filtration and concentration the crude oil was purified by flash chromatography with silica gel (hexanes: ethyl acetate) to obtain IgM of the desired pure product in 45% yield. "" "H (CDC13) d (ppm): 3.6 (m, ÍH). 3.5 (m, HH), 3.4 (m, HH), 2.4 (s, 1H), 1.44 (m, 2H), 0.99 (t, 3H), 0.9 (s, 9H), 0.06 (s, 6H).

Example 3B Synthesis of (+) -4- (1-tert-butyldimethylsilyloxybut-2-oxy) methylbenzoate 4-Hydroxymethylbenzoate (l.lg, 7.34 mmol), the product of Example 3A (0.75g, 3.67 mmol) and triphenylphosphine (1972 g, 7. 34 mmol) were added to a round bottom flask and 8 mL tetrahydrofuran was added. The flask was cooled in an ice bath at 0 ° C after which diisopropylazodicarboxylate (1.485g, 7.34mmol) was added via syringe. The reaction mixture was stirred for 2 hours after which the reaction was considered complete by thin layer chromatography. All the solvent was removed under reduced pressure and the crude oil directly subjected to purification by flash chromatography with silica gel (hexanes: diethyl ether) to obtain 1.0 gm (83%) of the desired compound as a thick oil. ^? (CDC13) d (ppm): 7.9 (d, 2H), 6.9 (d, 2H), 4.3 (p, 1H, J = 5.4 Hz), 3.9 (s, 3H), 3.7 (2H), 1.78 (m, 1H), 1.7 (m, ÍH), 0.9 (t, 3H, J = 7.8 Hz), 0.89 (s, 9H), 0.05 (s, 3H), 0.01 (s, 3H). 13C (CDC13) d (ppm): 166.8, 162.8, 131.5, 122.3, 115.2, 80, 64.5, 51.7, 25.8, 24.1, 18.2, 9.5, -5.3.

Example 3C Synthesis of alcohol (±) -4- (1-tertbutyldimethylsilyloxybut-2-oxy) -benzyl To a solution of the product of Example 3B (lg, 2.95 mmol) in ether (15mL) was added lithium aluminum hydride. (0.336 g, 8.8 mmol) and the mixture was stirred under nitrogen for 1.5 hours. The reaction was complete as shown by CCD for this time and was turned off by the addition of 0.336 mL water, 0.336 mL of 15% NaOH solution and 1.00 mL water in succession. The resulting mixture was stirred for an additional 20 minutes after which the white precipitate formed was filtered and washed with ether. The filtrate was then dried over magnesium sulfate. Filtration and removal of the solvent gave 0.50g (54%) of the desired product as a white solid. XH (CDC13) d (ppm): 7.2 (d, 2H), 6.9 (d, 2H), 4.3 (p, ÍH), 3.77 (d of d, ÍH), 3.66 (d of d, 1H), 1.77- 1.72 (m, ÍH), 1.68-1.61 (m, 1H), 1.5 (t, ÍH, J = 5.4 Hz), 0.9 (t, 3H, J = 7.8 Hz), 0.89 (s, 9H), 0.04 (s) , 3H), 0.01 (s, 3H). 13C (CDC13) d (ppm): 158.5, 133, 128.4, 116.1, 80.1, 65, 64.5, 25.8, 24.1, 18.2, 9. 5, -5.3 EXAMPLE 3D Synthesis of (+) -2-tert-butyl 4-chloro-5- (4- (l-tert-butyldimethylsilyloxy-but-2-oxy) benzyl) oxy-3 (2H) -pyridazinone (+) -2-Tert-butyl-4-chloro-5-hydroxy-3 (2H) -pyridazinone (0.48 g, 2.417 mmol) was charged to a 100 mL round bottom flask and tetrahydrofuran (40 mL) was added. After the solution became clear, Example 3C (0.5g, 1611 mmol) and triphenylphosphine (0.633g, 2.417 mmol) were added to the flask and the flask was cooled to 0 ° C. Diisopropyl azodicarboxylate (0.488 g, 2.417 mmol, 0.468 mL) was then added via syringe and the reaction was stirred for two hours after which it was shown to be complete by CCD. The contents of the flask were then concentrated in vacuo and the crude oil obtained was purified by flash chromatography using silica gel. (hexanes: ethyl acetate) to obtain 0.33 g of the desired compound as an oil. 2H (CDC13) d (ppm): 7.72 (s, 1H), 7.2 (d, 2H), 6.9 (d, 2H), 5.2 (s, 2H), 4.2 (p, 1H), 3.75 (d of d, 1H), 3.68 (d of d, 1H), 1.75 (m, 2H), 1.65 (m, 1H), 1.6 (s, 9H), 0.99 (t, 3H), 0.85 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H). 13C (CDC13) d. (Ppm): 159.6, 159.3, 154, 129, 126.9, 125, 118. 5, 116.5, 80.3, 72.1, 66.5, 64.8, 28.1, 26, 24.4, 18.4, 9.6, -5.3 Example 3E Synthesis of (+) -2-tert-butyl-4-chloro-5- (4- (1-hydroxy-but-2-oxy) benzyl) oxy-3 (2H) -pyridazinone To the product of Example 3D (0.3 g, 0.6 mmol) in a 10 mL round bottom flask was added tetrahydrofuran (2 mL). In solution, tetrabutylammonium fluoride (1.8 mmol, 1. 8 mL, solution IM in THF) was added and the reaction mixture was stirred for 90 minutes. The contents were then concentrated under reduced pressure and the crude mixture was purified by flash chromatography using silica gel (hexanes: ethyl acetate) to obtain 185 mg (80%) of desired pure product. XH (CDC13) d (ppm): 7.74 (s, 1H), 7.3 (d, 2H), 6.9 (d, 2H), 5.2 (s, 2H), 4.3 (m, ÍH), 3.81-3.77 (two br s, 2H), 1.84 (br t, 1H), 1.77-1.69 (m, 2H), 1.64 (s, 9H), 0.98 (t, 3H); 13C (CDC13) d (ppm): 159.2, 158.9, 153.9, 129. 2, 127.5, 125.4, 116.6, 80.4, 71.9, 66.5, 64.2, 28, 23.5, 9. 7 • - - - Example 3F Synthesis of (+) -2-tert-butyl 4-chloro 5- (4- (1- tosyloxy-but-2-oxy) benzyl) oxy 3 (2H) -pyridazinone The product of Example 3E (0.05 g, 0.13 mmol) followed by dichloromethane (2 mL) was added to a 10 mL round bottom flask. Toluenesulfonyl chloride (0.075 g, 0.39 mmol), 4-N, N-dimethylaminopyridine (0.048 g, 0.39 mmol) and diisopropylethylamine (0.05 g, 0.39 mmol, 68.7 ml) were then added in succession to the reaction mixture and this was it stirred for 35 minutes. Water was then added to the mixture and the solution was emptied into a separatory funnel and the layers separated. The organic layer is washed with water and brine and dried over magnesium sulfate. The crude oil obtained after filtration and concentration was purified by flash chromatography with silica gel (hexanes: ethyl acetate) to obtain 54 mg (77%) of the desired compound as a thick, colorless oil. XH (CDC13) d (ppm): 7.74 (3H, two singlets), 7.3 (m, 4H), 6.8 (d, 2H), 5.2 (s, 2H), 4.38 (p, 1H), 4.15 (m, 2H ), 2.44 (s, 3H), 1.72 (m, 2H), 1.6 (s, 9H), 0.95 (t, 3H); 13C (CDC13) d (ppm): 159.2, 158.5, 153.9, 145.1, 133, 130, 129, 128.1, 127.2, 125.4, 118.5, 116.5, 71.9, 70.2, 66.6, 28.1, 24.2, 21.8, 9.4.

Example 3G Synthesis of (+) -2-tert-butyl-4-chloro 5- (4- (1-fluoro-but-2-oxy) benzyl) oxy-3 (2H) -pyridazinone The product of Example 3F (28mg, 52.4 mmol) was dissolved in 0.5 mL of acetonitrile in a 5 mL flask and to this was added a solution of potassium fluoride (4.5 mg, 78.6 mmol) and Kryptofix 222 (29.6 mg, 78.6 mmol). ) in 0.5 mL of acetonitrile. The previous solution was then immersed in an oil bath preheated to 90 ° C. The reaction was allowed to stir for 90 minutes after which all the volatiles were removed under reduced pressure and the crude mixture purified by preparative thin layer chromatography to obtain 13 mg (65%) of the desired pure compound. XH (CDC13) d (ppm): 7.72 (s), 1H), 7.3 (d, 2H), 6.9 (d, 2H), 5.23 (s, 2H), 4.57-4.59 (m, 2H), 4.4 (m, 4H), 1.74 (m, 2H), 1.6 ( s, 9H), 1.0 (t, 3H). 13C (CDC13) d (ppm): 159, 158.7, 153.7, 129, 127.5, 125.2, 118.3, 116.4, 83.85 (d, 1JCP = 172.2), 78, 71.1, 66.3, 27.8, 23.2, 9.48. 19F (CDC13, CFC13 as internal standard) d (ppm): -228 (d of t, J = -19, -60 Hz) Example 4A Synthesis of 4- (3-hydroxypropoxy) -benzoic acid methyl ester To a 250 L flask was added 3-bromo-1-propanol (4.17 g, 0.03 mol), anhydrous dimethylformamide (40 mL), methyl-4-hydroxybenzoate (3.0 g, 0.02 mol) and potassium carbonate (4.15 g, 0.03 mol). The flask was placed in an oil bath at 50 ° C and stirred for 12 hours. After cooling the reaction was diluted with ethyl acetate, transferred to a separatory funnel, washed with 0.1 N aqueous hydrochloric acid, water then brine. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to give 5.14 g of crude oil. Column chromatography [silica gel; elution agent hexanes-ethyl acetate (1.68: 1)] provided the desired product (1.25 g, 30%) as a white powder. XH (CDC13) d (ppm): 2.04-2.08 (m, 2H); 3.86-3.88 (m, 5H); 4.17 (t, 2H); 6.91 (d, 2H); 7.98 (d, 2H); 13C (CDC13) d (ppm): 31.89, 51.81, 59.88, 65.50, 114.06, 122.67, 131.57, 162.60, 166.84.

Example 4B Synthesis of 4- [3- (tert-butyldimethylsilanyloxy) ropoxy] benzoic acid methyl ester To a 50 mL flask was added Example 4A (300 mg, 1.4 mmol), anhydrous dimethylformamide (4 mL), tert-butyldimethylsilyl chloride (317 mg, 2.1 mmol), and imidazole (146 mg, 2. 1 mmol). The resulting solution was stirred for 2 hours.

At this point the reaction was diluted with ethyl acetate and transferred to a separatory funnel. The organic phase was washed with 0.1N aqueous hydrochloric acid (2x), water (2x), then brine. The organic layer was then dried over magnesium sulfate, filtered, and concentrated. Column chromatography [Silica gel; elution agent hexanes-ethyl acetate (9.5: 1)] - provided the desired product (413 mg, 91%). ^? (CDCl 3) d (ppm): 0.03 (s, 6H); 0.87 (s, 9H); 1.97-2.01 (, 2H); 3.79 (t, 2H); 3.87 (s, 3H); 4.11 (t, 2H); 6.90 (d, 2H); 7.97 (d, 2H); 13C (CDC13) d (ppm): 18.30, 25.89, 32.3, 51.78, 59.27, 64. "67, 114.08, 122.43, 131.56, 162.90, 166.90 Example 4C Synthesis of. { 4- [3- (tert-Butyldimethylsilanyloxy) propoxy] phenyl} methanol Example 4B (396 mg, 1.22 mmol) was added to a dry 50 mL flask together with anhydrous diethyl ether (10 mL). The flask was lowered into an ice bath. Lithium aluminum hydride (93 mg, 2.44 mmol) was added in portions to the reaction flask. The mixture was allowed to stir in the bath for 2 hours. The reaction was quenched with water (0.093 mL), 15% aqueous sodium hydroxide (0.093 mL) then water (0.279 mL). The white solid was filtered completely and the filtrate was dried over magnesium sulfate, filtered, and concentrated to give the desired product (291 mg, 80%). ^ (CDCls) d (ppm): 0.04 (s, 6H); 0.88 (s, 9H); 1.95-1.99 (m, 2H); 3.79 (t, 2H); 4.05 (t, 2H); 4.60 (s, 2H); 6.88-6.89 (m, 2H); 7.25-7.27 (m, 2H); (CDC13) d (ppm): 18.30, 25.91, 32.41, 59.50, 64.57, 65.10, 114.59, 128.60, 132.97, 158.75.

Example 4D Synthesis of 2-tert-butyl-4-chloro-5-. { 4- [3- (tert-Butyldimethylsilanyloxy) propoxy] benzyloxy} -2H-pyridazin-3 -one To a dry 25 ml flask was added Example 4C (211 mg, 0.71 mmol) and anhydrous tetrahydrofuran (3 mL). The flask was cooled in an ice bath. To the flask was added triphenylphosphine (187 mg, 0.71 mmol) and 2-tert-butyl-4-chloro-5-hydroxy-2H-pyridazin-3-one (142 mg, 0.71 mmol). Finally, diisopropyl azodicarboxylate (144 mg, 0.71 mmol) was added. The reaction mixture was allowed to stir in the ice bath for 1 hour. At this point the mixture was diluted with diethyl ether and transferred to a separatory funnel. The organic solution is washed with water and then brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Column chromatography [silica gel; Hexanes-ethyl acetate elution agent (9: 1)] provided the desired product (106 mg, 31%). XH (CDC13) d (ppm): 0.03 (s, 6H); 0.87 (s, 9H); 1.62 (s, 9H); 1.95-1.99 (m, 2H); 3.79 (t, 2H); 4.06 (t, 2H); 5.23 (s, 2H); 6.91-6.92 (m, 2H); 7.30- 7.31 (m, 2H); 7.72 (s, ÍH); 13C (CDC13) d (ppm): 18.29, 25.90, 27. 87, 32.34, 59.41, 64.63, 66.30, 71.89, 114.90, 118.34, 125.34, 126.68, 128.92, 153.79, 159.07, 159.55 Example 4? Synthesis of 2-tert-butyl-4-chloro-5- [4- (3-hydroxypropoxy) benzyloxy] -2H-pyridazin-3-one To a dry 10 ml flask was added Example 4D (100 mg, 0.21 mmol) together with anhydrous tetrahydrofuran (2 mL). To the flask was added a solution of 1.0 M tetrabutylammonium fluoride in tetrahydrofuran (0.42 mL, 0.42 mmol). The solution was stirred for 2 hours. At this point the reaction was concentrated under reduced pressure. Preparative thin layer chromatography [silica gel; elution agent hexanes-ethyl acetate (1: 1)] provided the desired product (57.8 mg, 76%). ^ (CDCls) d (ppm): 1.62 (s, 9H); 2.02-2.06 (m, 2H); 3.86 (t, 2H); 4.13 (t, 2H); 5.30 (s, 2H); 6.92-6.93 (m, 2H); 7.31-7.32 (m, 2H); 7.71 (s, ÍH); 13C (CDC13) d (ppm): 27.87, 31.97, 60.24, 65.67, 66.34, 71.81, 114.91, 118.37, 125.31, 127.06, 128.98, 153.76, 159.07, 159.27.

Example 4F Synthesis of 3- [4- (l-tert-butyl-5-chloro-6-oxo-l, 6-dihydro-pyridazin-4-yloxymethyl) phenoxy] propyl ester of toluene-sulfonic acid To a dry 5 ml flask was added Example 4E (40 mg, 0.11 mmol), 4-methyl-benzenesulfonyl chloride (31 mg, 0.16 mmol), 4- (dimethylamind) pyridin • (20 mg, 0.16 mmol) , diisopropylethylamine (16.6 mg, 0.16 mmol) and anhydrous dichloromethane (0.6 mL). The resulting solution was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure. Preparative thin layer chromatography [silica gel; pentane-ethyl acetate elution agent (3: 2)] gave the desired product (18.6 mg, 33%). "" "H (CDC13) d (ppm): 1.62 (s, 9H), 2.09-2.13 (m, 2H), 2.37 (s, 3H), 3.95 (t, 2H), 4.23 (t, 2H), 5.22 (s, 2H), 6.78 (d, 2H), 7.23 (d, 2H), 7.29 (d, 2H), 7.73-7.75 (m, 3H), 13C (CDC13) d (ppm): 21.60, 27.85, 28.81 , 63.15, 66.35, 66.87, 71.75, 114.76, 118.27, 125.18, 127.11, 127.83, 128.94, 129.80, 132.79, 144.80, 163.72, 158.90, 159.03.

Example 46 Synthesis of 2-tert-butyl-4-chloro-5- [4- (3-fluoropropoxy) enzyloxy] -2H-pyridazin-3-one "To a scintillation vial containing a suspension of Example 4F (4.5 mg, 8.64 x 10-3 mmol) in anhydrous acetonitrile (0.25 mL) was added a solution of potassium fluoride (1.6 mg, 4.07 x 10" 2 mmol) and kryptofix (15.0 mg, 4.07 x 10 ~ 2 mmol) in anhydrous acetonitrile (0.25 L). The vial was closed and lowered into an oil bath at 90 ° C. The reaction was allowed to stir for 40 minutes. The reaction was cooled and concentrated under reduced pressure. Preparative thin layer chromatography [silica gel; pentane-ethyl acetate elution agent (3: 2)] provided the desired product (0.8 mg, 25%). XH (CDC13) d (ppm): 1.62 (s, 9H); 2.14-2.20 (m, 2H); 4.09-4.11 (m, 2H); 4.60 (t, lH); 4.68 (t, lH); 5.24 (s, 2H); 6.92 (d, 2H); 7.32 (d, 2H); 7.72 (s, ÍH); 19F (CDC13, CFC13 as internal standard) d (ppm): -222.66 (t of t, J = 28.2, -50.4) Example 5A Synthesis of 4- (2-hydroxyethoxymethyl) benzoic acid methyl ester To a two-neck round-bottomed flask, which was equipped with a Dewar condenser, a solution of 4-hydroxymethylbenzoic acid methyl ester (2. "50 g, 0.015 mol) in anhydrous dichloromethane (30 mL) was added. cooled to -10 SC in a salt / ice bath. Ethylene oxide (1.10 mL) was added to the chilled solution dropwise followed by the addition of boron trifluoride etherate (0.51 mL). The reaction mixture was stirred for 45 minutes and then warmed at room temperature for 30 minutes to remove any excess ethylene oxide in the reaction mixture. The reaction mixture was then diluted with brine. The aqueous layer was extracted with dichloromethane (3 times). All organic layers were combined, dried over Na 2 SO, filtered, and concentrated to provide an oil. The crude material was purified using silica gel chromatography (4: 1 pentane: ethyl acetate) to provide the desired product (537 mg, 2.56 mmol) in 17% yield. XH (CDC138.36, 600 MHz): d (2H, d, J = 8.4 Hz), 7.41 (2H, d, J = 8.5 Hz), 4.62 (3H, s), 3.92 (2H, s), 3.78 (m, 2H), 3.63 (2H, m); ^ C (CDCl3167.1, 143.5, 130.0, 129.8, 127.5, 72.9, 72.0, 150 MHz): d 62.1, 52.3.

Example 5B Synthesis of 4- [2- (tert-butyldimethylsilanyloxy) ethoxymethyl] benzoic acid methyl ester C02Me TBD S-CI, Imidazole, DMF QTBCMS To a solution of the product of Example 5A (544.5 mg, 2.59 mmol) in anhydrous DMF (26 mL) was added imidazole (264 mg, 3.89 mmol) and TBDMS-Cl (586 mg, 3.89 mmol). The reaction medium is stirred at room temperature overnight and quenched with water.The aqueous layer was extracted with ethyl acetate (3x) .All combined organic layers were dried over Na 2 SO 4, filtered, and concentrated.The crude material was purified using chromatography on silica gel (4: 1 pentane: ethyl acetate) to provide the desired product (677.5 mg, 2.19 mmol) in 84% yield.

(CDCI38.OI, 600 MHz): d (2H, d, J = 8.3 Hz), 7.42 (2H, d, J = 8.4 Hz), 4.63 (2H, s), 3.91 (2H, s), 3.82 (2H , t, J = 5.0), 3.58 (2H, t, J = 5.1 Hz), 0.91 (9H, s), 0.07 (6H, s); JC (CDCI3I66.5, 143.5, 129.2, 128 126.5 72.1 71. 6 150 MHZ '62.3, 51.5, 25.4, 17.9, -5.8.

Example 5C Synthesis of. { 4- [2- (tert-Butyldi-ethylsilanyloxy) ethoxymethyl] phenyl} methanol To a solution of the product of Example 5B (670 mg, 2.18 mmol) dissolved in anhydrous THF (22 L) was added a solution of LAH (1.0 M solution in THF, 2.18 mL, 2.18 mmol) dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water. The aqueous layer was extracted with ethyl acetate (3x). All the combined organic layers were dried over Na 2 SO 4, filtered, and concentrated to give an oil (587 mg, 1.98 mmol), which is used in the next step without any further purification (91% yield). - "" H (CDC13 7.34 (4H, s), 4.68 (2H, s), 4.57 (2H, s), 3.80, 600 MHz): d (2H, t, J = 5.2 Hz), 3.56 (2H, t, J = 5.3 Hz), 1.69 (ÍH, br s), 0.90 (9H, s), 0.07 (6H, s); 13C (CDCl3 140.4, 138.3, 128.0, 127.2, 73.2, 71.9, 65.4, 150 MHz): d 63.0, 26.2, 18.6, -5.0.

Example 5D Synthesis of 2-tert-butyl-5-. { 4- [2- (tert-Butyldimethylsilylanxy) ethoxymethyl] benzyloxy} -4-chloro-2H-pyridazin-3-one To a solution of the product of Example 5C (437 mg, 1.48 mmol) and 2-tert-butyl-4-chloro-5-hydroxy-2H-pyridazin-3-one (250 mg, 1.23 mmol) dissolved in anhydrous THF (12 mL) was added solid PPh3 (485 mg, 1.85 mmol) and diisopropyl azodicarboxylate (DIAD, 0.358 mL, 1.85 mmol). After the addition is complete, the reaction mixture is stirred at room temperature. After 20 hours, the reaction mixture was diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3x). All the combined organic layers were dried over Na 2 SO 4, filtered, and concentrated to provide an oil. The crude material was purified using silica gel chromatography (4: 1 pentane: ethyl acetate) to give the desired product 528 mg, 1.10 mmol) in 89% yield. aH (CDC13 7.70 (ÍH, s), 7.38 (4H, m), 5.30 (2H, s), 4.58, 600 MHz): d (2H, s), 3.80 (2H, t, J = 5.4 Hz), 3.57 (2H, t, J = 5.4 Hz), 1.63 (9H, br s), 0.90 (9H, s), 0.07 (6H, s); 13C (CDC13159.0, 153.7, 138.8, 134.4, 128.3, 127.3, 150 MHz): d 125.1, 118.5, 72.8, 71.7, 71.6, 66.4, 61.9, 29.7, 27.9, 25.6, -5.1; HRMS calculated for C2H37ClN204Si: 481.228389 ,. found 481.2282.

Example 5E Synthesis of 2-tert-butyl-4-chloro-5- [4- (2-hydroxyethoxyethyl) benzyloxy] -2H-pyridazin-3 -one To one. The product solution of Example 5D (528 mg, 1.09 mmol) dissolved in anhydrous THF (11 L) was added a solution of TBAF (1.0 M solution in THF, 0.61 mL, 1.65 mmol) dropwise. After the addition was complete, the reaction was stirred at room temperature for 1 hour and then quenched with water. The aqueous layer was separated and extracted with ethyl acetate (3x). All the combined organic layers were dried over Na 2 SO 4, filtered, and concentrated to provide an oil. The crude material was purified using silica gel chromatography (4: 1 hexanes: ethyl acetate) to provide the desired product (311 mg, 0.850 mmol) in 78% yield. XH (CDC13, 600 MHz): d 7.70 (H, s), 7.38 (4H, m), 5.30 (2H, s), 4.56 (2H, s), 3.76 (2H, t, J = 4.9 Hz), 3.60 (2H, t, J = 4.8 Hz), 2.00 (1H, br s), 1.61 (9H, br s); 13 C (CDCl3159.0, 153.6, 150 MHz): d 138.8, 134.4, 128.2, 127.2, 125.1, 118.3, 72.8, 71.6, 71.6, 66.4, 61.9, 27.8; HRMS calculated for C18H23C1N20: 367.141911, found 367.1419.

Example 5F: Synthesis of 2- [4- (l-tert-butyl-5-chloro-6-oxo-l, 6-dihydro-pyridazin-4-yloxymethyl) -benzyloxy] -ethyl ester of toluene-4 -sulfonic To a solution of the product of Example 5E (200 mg, 0.546 mmol) dissolved in anhydrous dichloromethane (5.50 mL) was added TsCl (125 mg, 0.656 mmol), DMAP (100 mg, 0.819 mmol) and triethylamine (0.091 mL, 0.656 mmol). ). The reaction mixture is stirred at room temperature. After 22 hours the reaction mixture was diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3x). All the combined organic layers were dried over Na 2 SO 4, filtered, and concentrated to provide an oil. The crude material was purified using silica gel chromatography (3: 2 pentane: ethyl acetate) to provide the desired product (232 mg, 0.447 mmol) in 82% yield. XH (CDC137.79, 600 MHz): d (2H, d, J = 8.3 Hz), 7.71 (ΔH, s), 7.38 (2H, d, J = 8.2 Hz), 7.32 (4H, m), 5.30 ( 2H, s), 4.50 (2H, s), 4.21 (2H, m), 3.69 (2H, m), 2.43 (3H, s), 1.63 (9H, br s); 13 C (CDCl3 159.0, 153.7, 144.8, 138.8, 150 MHz): d 134.4, 133.1, 129.8, 128.1, 128.0, 127.2, 125.1, 118.4, 72.8, 71.7, 69.2, 67.8, 66.4, 27.9, 21.6; HRMS calculated for C25H29C1N206: 521.150762, found 521.1503.

Example 5G Synthesis of 2-tert-butyl-4-chloro-5- [4- (2-fluoro-ethoxymethyl) -benzyl] -2H-pyridazin-3-one To a solution of the product of Example 5F (50 mg, 0.096 mmol) in anhydrous acetonitrile (1.0 mL) was added KF (11.2 mg, 0.192 mmol) and Kryptofix (72.4 mg, 0.192 mmol). After the addition was complete, the reaction mixture was heated to 90 ° C. After 10 minutes, the reaction mixture was cooled down to room temperature and diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3x). All the combined organic layers were dried over Na 2 SO, filtered, and concentrated to provide an oil. The crude material was purified using silica gel chromatography (4: 1 pentane: ethyl acetate) to provide the desired product (28 mg, 0.076 mmol) in 79% yield. XH (DMSO-ds, 600 MHz): d 8.22 (1H, s), 7.45 (2H, d, J = 8.20 Hz), 7.39 (2H, d, J = 8.24 Hz), 5.42 (2H, s), 4.60 (HH, m), 4.54 (2H, a), 4.52 (HH, m) , 3.71 (ÍH, m), 3.66 (1H, m), 1.57 (9H, s); 13 157.8, 153.8, 138.6, C (DMSO-d6, 150 MHz): d 134.6, 127.8, 127.7, 126.2, 115.6, 83.5 (82.4), 71.6, 71.2, 69.1 (69.0), 65.3, 27.4; 19F (DMSO-ds-221.74 (1F, m), 564 MHz): d HRMS calculated for C? 8H22ClFN203: 369.137575, found 369.1377.

E xample 6A Synthesis of 1- (4-hydroxymethylphenoxy) propan-2-one To a stirred solution of 4-hydroxybenzyl alcohol (1.0 g, 8.06 mmol) in acetone (80 mL) was added potassium carbonate (1.34 g, 9.68 mmol) and chloroacetone (0.771 mL, 9.68 mmol). After the addition was complete, the reaction mixture was heated to reflux. After 20 hours the reaction mixture was cooled down to room temperature and the solvent was removed. Water and ethyl acetate were added to the raw material. The aqueous layer was separated and extracted with ethyl acetate (3x, 100 mL). All the combined organic layers were dried over Na 2 SO 4, filtered, and concentrated to provide an oil. The crude material was purified using silica gel chromatography (gradient from 4: 1 to 1: 1 pentane: ethyl acetate) to provide the desired product (0.981 g, 5.45 mmol) in 98% yield. "aH (CDC13, 600 MHz): d 7.30 (2H, d, J = 8.7 Hz), 6.87 (2H, d, J = 8.7 Hz), 4.63 (2H, d, J = 5.7 Hz), 4.54" (2H , s), 2.27 (3H, s), 1.66 (ÍH, t, J = 5.8-Hz); 13 C (CDCl 3, 150 MHz): d 205.7, 157.3, 134.3, 128.8, 114.6, 73.1, 64.8, 26.6.

Example 6B Synthesis of 1- (4-hydroxymethyl-phenoxy) -propan-2-ol: To a solution of 1- (4-hydroxymethylphenoxy) -propan-2-one (1.26 g, 6.99 mmol) dissolved in methanol (60 mL) was added Solid NaBH (0.32 g, 8.39 mmol). After the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate (3x). All the combined organic layers were dried over Na 2 SO, filtered, and concentrated to give an oil (1.24 g, 6.81 mmol), which is used in the next step without any further purification (98% yield). - "? (CDC137.29, 600 MHz) ': d (2H, d, J = 8.4 Hz), 6.90 (2H, d, J = 8.5 Hz), 4.62 (2H, s), 4.21 (ÍH, m) , 3.94 (1H, dd, J = 9.2, 3.1 Hz), 3.82 (HH, m), 1.29 (3H, d, J = 6.4 Hz).

Example 6C Synthesis of 2-tert-butyl-4-chloro-5- [4- (2-hydroxypropoxy) benzyloxy] -2H-pyridazin-3 -one To a solution of the product of Example 6B (269 mg, 1.48 mmol) and 2-tert-butyl-4-chloro-5-hydroxy-2H-pyridazin-3-one (250 mg, 1.23 mmol) dissolved in anhydrous THF (18.5 mg). mL) was added solid PPh3 (485 mg, 1.85 mmol) and DIAD (0.358 mL, 1.85 mmol). After the addition is complete, the reaction mixture is stirred at room temperature. After 20 hours, the reaction mixture was diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3x).

All the combined organic layers were dried over Na 2 SO 4, filtered, and concentrated to provide an oil. The crude material was purified using silica gel chromatography (1: 1 pentane: ethyl acetate) to provide the desired product (234 mg, 0.634 mmol) in 51% yield. aH (CDC13 7.71 (1H, s), 7.33 (2H, d, 600 MHz): d J = 8.7 Hz), 6.94 (2H, d, J = 8.7 Hz), "5.24 (2H, s), 4.19 (1H , m), 3.95 (1H, dd, J = 9.2, 3.1 Hz), 3.81 (1H, dd, J = 9.2, 7.7 Hz), 1.62 (9H, s) 1.29 (3H, d, J = 6.4 Hz).

Example 6D Synthesis of 2- [4- (l-tert-butyl-5-chloro-6-oxo-l, 6-dihydro-pyridazin-4-yloxymethyl) -phenoxy] -1-methyl-ethyl acid ester toluene-4-sulfonic To a solution of the product of Example 6C (200 mg, 0.546 mmol) dissolved in anhydrous dichloromethane (6.0 mL) was added TsCl (125 mg, 0.656 mmol), DMAP (100 mg, 0.819 mmol) and triethylamine (0.0914 mL, 0.656 mmol). ). The reaction mixture is stirred at room temperature. After 22 hours the reaction mixture was diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3x). All the combined organic layers were dried over Na 2 SO 4, filtered, and concentrated to provide an oil. The crude material was purified using silica gel chromatography (70:30 pentane: ethyl acetate) to provide the desired product (166 mg, 0.319 mmol) in 58% yield. 2H (CDC137.80 (2H, d, 600 MHz): d J = 8.3 Hz), 7.72 (ÍH, s), 7.32 (2H, d, J = 7.9 Hz), 7.29 (2H, d, J = 8.7 Hz ), 6.74 (2H, d, J = 8.7 Hz), 5.22 (2H, s), 4.19 (1H, m), 4.02 (1H, dd, J = 10.4, 6.0 Hz) ", 3.93 (1H; _ dd, J = 10.4, 4.5 Hz), 2.44 (3H, s), 1.63 (9H, s) 1.42 (3H, d, J = 6.5 Hz), 13C (CDCl3 158.9, 150 MHz): d 158.3, 153.6, 144.6, 133.8 , 129.6, 128.8, 127.8, 127.4, 125.1, 118.0, 114.7, 76.8, 71.5, 69.7, 66.2, 27.7, 21.5, 17.6, HRMS calculated for C2SH29C1N206S: 521.150762, found 521.1505.

Example 6E Synthesis of 2-tert-butyl-4-chloro-5- [4- (2-fluoropropoxy) benzyl] -2H-pyridazin-3-one To a solution of the product of Example 6E (50 mg, 0.096 mmol) in anhydrous acetonitrile (1.0 L) was added KF (11.2 mg, 0.192 mmol) and Kryptofix (72.4 mg, 0.192 mmol). After the addition was complete, the reaction mixture was heated to 90 ° C. After 40 minutes, the reaction mixture was cooled down to room temperature and diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3x). All the combined organic layers were dried over Na 2 SO, filtered, and concentrated to provide an oil. The crude material was purified using preparative chromatography on a plate of thin-layer silica gel (4: 1 pentane: ethyl acetate) to isolate the desired product (12.5 mg, 0.034 mmol) in 41% yield (based on the recovered starting material), in addition to the unreacted starting material (5.8 mg, 0.011 mmol). "" "H (CDC13, 600 MHz): d 7.73 (ÍH, s) 7.34 (2H, d, J = 8.6 Hz), 6.95 (2H, d, J = 8.6 Hz), 5.25 (2H, s), 5.06 -4.96 (1H, m), 4.06 (2H, m), 1.63 (9H, s) 1.47 (3H, dd, J = 6.4, 23.6 Hz); 13C (DMSO-d6, 158.4, 157.8, 153.9, 129.8, 127.6 , 126.2, 115.5, 114.6, 89.0150MHz): d (88.0), 71.2, 70.4 (70.3), 65.3, 27.4, 16.9 (16.8); 19F (DMSO-dg, -178.20 (1F, m); 564 MHz) : d EMAR calculated for C? 8H22ClFN203: 369.137575, found 369.1370.

Example 7A Synthesis of 4- (3-oxobutyl) benzoic acid methyl ester To a solution of methyl-4-bromobenzoate (1.0 g, 4.65 mmol) in triethylamine (13 mL) was added 3-buten-2-ol (1 mL, 11.63 mmol), palladium (II) acetate (0.104 g, 0.465 mmol), and then triphenylphosphine (0.244 g, 0.93 mmol). The reaction was stirred in an oil bath at 75 ° C overnight under a nitrogen atmosphere. Observing by CCD (3: 1 hexane: ethyl acetate) the product and aryl bromide are shown. The reaction was cooled to room temperature and then concentrated. The water was then added followed by extraction with ethyl acetate. The organic layer is washed with water and brine, dried over Na 2 SO 4, filtered and concentrated. The crude product was purified by flash column chromatography (5: 1 to 3: 1 hexane: ethyl acetate) to obtain the product (250 mg, 26% yield). XH NMR (600 MHz, CDC13): d 7.95 (d, 2H, J = 8.4 Hz), 7.25 (d, 2H, J = 8.4 Hz), 3.90 (s, 3H), 2.95 (t, 2H, J = 7.45 Hz), 2.77 (t, 2H, J = 7.68 Hz), 2.14 (s, 3H).

Example 7B Synthesis of 2-tert-butyl-4-chloro-5- [4- (3-hydroxybutyl) benzyloxy] -2H-pyridazin-3-one To a solution of the product of Example 7A (505 mg, 2.447 mmol) in THF (19 mL) at 0 ° C was added a 1M solution (in THF) of lithium aluminum hydride (12.2 mL, 12.237 mmol) dropwise . After the addition was complete, the ice bath was removed and the reaction was stirred at ambient temperature for 1 hour under nitrogen atmosphere. Then, in succession, water (183 mL), 15% NaOH solution (183 mL), and water (548 mL) were added. The reaction was stirred for an additional 15 minutes before filtering and washed with THF. The filtrate was then concentrated under reduced pressure to obtain 4- (4-hydroxymethyl-phenyl) butan-2-ol as a brown oil (314 mg, 71% yield). Then to a solution of 2-tert-butyl-4-chloro-5-hydroxy-2H-pyridazin-3-one (234 mg, 1155 mmol) in THF (45 mL) was added 4- (4-hydroxymethylphenyl) butan -2-ol (312 mg, 1732 mmol), triphenylphosphine (454 mg, 1732 mmol), and then diisopropyl azodicarboxylate (DI7AD, 335 μL, 1732 mmol). The reaction was stirred at room temperature_ overnight under a nitrogen atmosphere. Thin layer chromatography (100% ethyl acetate) indicates the consumption of the starting pyridazinone material and the reaction was concentrated. The crude material was purified by flash column chromatography (4: 1 hexane-ethyl acetate to 100% ethyl acetate) to obtain a clear oil (200 mg, 48% yield). X H NMR (600 MHz, CDCl 3): d 7.73 (s, ÍH), 7.32 (d, 2H, J = 8.0), 7.24 (d, 2H, J = 8.0), 5.30 (s, ÍH), 5.27 (s, 2H), 3.83 (m, 1H), 2.80-2.76 (m, ÍH), 2.71-2.66 (m, 1H), 1.63 (s, 9H), 1.23 (d, 3H, J = 6.2); 13C (CDC13 159.3, 153.9, 143.2, 132.5, 129.2, 127.6, 125.4, 150 MHz): d EMAR calculated for C 118.5, 73.4, 67.6, 66. 6, 40.9, 32.0, 28.1, 23.9.9H25ClN203: 365.162647, found 365.1624.

Example 7C Synthesis of 3- [4- (l-tert-butyl-5-chloro-6-oxo-l, 6-dihydro-pyridazin-4-yloxymethyl) -phenyl] -1-methylpropyl acid of toluene-4 acid -sulfonic To a solution of the product of Example 7B (200 mg, 0.548 mmol) in pyridine (10 mL) was added p-toluenesulfonyl chloride (209 mg, 1096 mmol). The reaction was stirred at room temperature overnight under nitrogen atmosphere. It is reviewed by LC-MS showing a 1: 1 mixture of starting material and product. The reaction was diluted with ethyl acetate, and washed with 5% CuSO 4 until a clear blue aqueous solution was maintained. The organic layer was then dried over Na 2 SO 4, filtered, and concentrated. The crude material was purified by flash column chromatography (3: 1 hexane: ethyl acetate to 100% ethyl acetate) to recover the starting material (90 mgj and the product as a clear oil (74 mg, 47% yield). performance based on the recovered starting material).

^? NMR (600 MHz, CDC13): 7.80 (d, 2H, J = 8.3 Hz), 7.72 (s, 1H), 7.33 (d, 2H, J = 8.0 Hz), 7.30 (d, 2H, J = 8.1 Hz), 7.13 (d, 2H, J = 8.1 Hz), 5.27 (s, 2H), 4.66 (m, ÍH), 2.65 (m, ÍH), 2.54 (m, ÍH), 2.45 (s, 3H), 1.94 (m , 1H), 1.81 (m, ÍH), 1.63 (s, 9H), 1.26 (s, 3H).

Example 7D Synthesis of 2-tert-butyl-4-chloro-5- [4- (3-fluorobutyl) benzyloxy] -2H-pyridazin-3-one To a solution of the product of Example 7C (18.2 mg, 0.035 mmol) in acetonitrile (400 mL) was added potassium fluoride (4.1 mg., 0.070 mmol) and K222 (26.4 mg, 0.070 mmol). The reaction was stirred at 90 ° C for 20 minutes under nitrogen atmosphere, checked by LC-MS. The reaction is then cooled to room temperature and concentrated under reduced pressure. The crude material was purified by preparative thin layer chromatography (4: 1 hexane: ethyl acetate as eluent) to obtain the product as an oil (5 mg, 39% yield). H NMR (600 MHz, CDC13): d 7.70 (s, 1H), 7.34 (d, 2H, J = 7.9 Hz), 7.24 (d, 2H, J = 8.0 Hz), 5.28 (s, 2H), 4.71- 4.60 (m, 2H), 2.84-2.80 (m, 1H), 2.73-2.69 (m, 1H), 2.02-1.93 (m, 1H), 1.87-1.77 (m, ÍH), 1.63 (s, 9H), 1.35 (dd, 3H, J = 6.2 and 23.9 Hz); 13C (CDC13159.1, 153.8, 150MHz): d 142.4, 132.5, 129.0, 127.4, 125.2, 118.3, 90.4 (89.3), 71.9, 66.3, 38.5 (38.4), 31.1 (31.0), 27.9, 21.1 (21.0); 19F (CDC13-174.7, 564 MHz): d (1F,); HRMS calculated for C? 9H23ClFN202: 367.158310, found 367.1582.

Example 8A Synthesis of 4- [2-hydroxyethoxymethyl] benzoic acid methyl ester tetradeuterate A solution of methyl-4- (hydroxymethyl) benzoate (2.5 g, 15 mmol) in dichloromethane (30 mL) was added to a 2-neck flask dried to the flame. The reaction was purged with nitrogen and brought to -5 ° C. A Dewar condenser (also flame-dried) containing an acetone / dry ice bath (-78 ° C) was added to the flask and ethylene-tetradeuterate oxide was added (-55 drops). Then BF3-Et20 (510 mL, 0.0041 mmol) was added dropwise and the reaction was stirred at -5 ° C for 35 minutes under nitrogen atmosphere. Observing by CCD (100% ethyl acetate) shows the complete consumption of the starting material. The reaction is warmed to room temperature and vented - to remove any excess gas of ethylene oxide. The reaction was then diluted with brine and extracted with dichloromethane (2 times). The organics were dried over Na 2 SO 4, filtered, and concentrated under reduced pressure to obtain a crude oil. Purification by flash column chromatography (4: 1 pentane: ethyl acetate) gives the product as a clear oil (520 mg, 16% yield). X H NMR (600 MHz, CDC13) d 8.02 (d, 2 H, J = 8.2 Hz), 7.41 (d, 2 H, J = 8.1 Hz), 4.62 (s, 2 H), 3.92 (s, 3 H); 13C NMR (150 MHz, CDCl3167.1, 143.5, 130.8,) d 129.9, 127.5, 72.8, 52.4.

Example 8B Synthesis of tetradeuterate of 4- [2 - (tert-butyldimethylsilanyloxy) ethoxymethyl] benzoic acid methyl ester To a solution of the product of Example 8A (500 mg, 2334 mmol) in DMF (23 mL) was added tert-butyldimethylsilyl chloride (528 mg, 3.501 mmol) and imidazole (238 mg, 3.501). The reaction was stirred at room temperature for 5 hours under nitrogen atmosphere, observing by CCD (3: 1 pentane: ethyl acetate). Another 0.5 eq portion of tert-butyldimethylsilyl chloride (176 mg) and imidazole (79 mg) were added and the resulting mixture was stirred at room temperature overnight. Most of the starting material was consumed in 16 hours, as indicated by thin layer chromatography. The reaction was diluted with water and extracted with ethyl acetate (2 times). The combined organic layers were dried over Na 2 SO, filtered, and concentrated under reduced pressure to obtain a crude oil which was purified by passing through a thick pad of silica gel (3: 1 pentane: ethyl acetate) to obtain the product as a clear oil (602 mg). t NMR (600 MHz, CDC13): 8.00 (d, 2H, J = 8.3 Hz), 7.40 (d, 2H, J = 8.5 Hz), 4.62 (s, 2H), 3.90 (s, 3H), 0.90 (s) , 9H), 0.06 (s, 6H).

Example 8C Synthesis of hexadeuterate of. { 4- [2- (tert-Butyldimethylsilanyloxy) ethoxymethyl] phenyl} methanol To a solution of the product of Example 8B (610 mg, 1857 mmol) in THF (19 mL) at 0 ° C was added a 1M solution (in THF) of lithium aluminum deuteride (1.9 mL, 1857 mmol) dropwise. After completion of the addition the ice bath was removed and the reaction was stirred at room temperature for 3.5 hours under nitrogen atmosphere, observing by CCD (3: 1 pentane: ethyl acetate). The reaction was then diluted with water and extracted with ethyl acetate (2 times). The organics were dried over Na 2 SO, filtered, and concentrated under reduced pressure to obtain a clear oil (482 mg, 86% yield). The material was taken for the next step without further purification. 1 H NMR (600 MHz, CDC13): 7.33 (s, 4 H), 4.56 (s, 2 H), 0.89 (s, 9 H), 0.06 (s, 6 H).

Example 8D Synthesis of 2-tert-butyl-4-chloro-5 hexadeuterate. { 4- [2- (tert-Butyldimethylsilanyloxy) ethoxymethyl] benzyloxy} -2H- pyridazin-3-one To a solution of 2-tert-butyl-4-chloro-5-hydroxy-2H-pyridazin-3-one (212 mg, 1047 mmol) in THF (15 mL) was added the product of Example 8C (475 mg, 1.570 mmol), triphenylphosphine (412 mg, 1570 mmol), and then diisopropyl azodicarboxylate (DIAD, 304 μL, 1570 mmol).

The reaction was stirred at room temperature for 2 hours under nitrogen atmosphere. Thin layer chromatography (1: 1 hexane: ethyl acetate) indicates the consumption of the pyridazinone starting material and the reaction was concentrated in vacuo. The crude material was purified by flash column chromatography (90:10 pentane: ethyl acetate) to obtain a clear oil (336 mg, 66% yield).

^? NMR (600 MHz, CDC13): 7.70 (s, ÍH), 7.39 (m, 4H), 4.58 (s, 2H), 1. 63 (s, 9H), 0. 90 (s, 9H), 0. 07 (s, 6H); HRMS calculated for C24H3? DgClN204Si: 509. 24738, found 509. 2480 Example 8E Synthesis of 2-tert-butyl-4-chloro-5- [4- (2-hydroxyethoxymethyl) benzyloxy] -2H-pyridazin-3-one hexadeuterate To a solution of the product of Example 8D (330 mg, 0.677 mmol) in THF (7 mL) was added a 1M solution (in THF) of tetrabutylammonium fluoride (1 mL, 1016 mmol) dropwise. The reaction was stirred at room temperature for 2 hours under nitrogen atmosphere, observing by CCD (1: 1 hexane: ethyl acetate). The reaction was then concentrated under reduced pressure and passed through a thick pad of silica (100% ethyl acetate) to obtain the product as an oil containing a lower percentage of the corresponding silanol. The material was taken for the next step without further purification. X H NMR (600 MHz, CDC13): 7.72 (s, ÍH), 7.41 (s, 4H), 4.59 (s, 2H), 1.64 (s, 9H); 13 C NMR (150 MHz, rt, CDC13): 159.2, 153.9, 139.5, 134.5, 128.5, 127.5, 125.3, 118.6, 73.0, 66.6, 28.1; HRMS calculated for C25H23DgClN206S: 549.169754, found 549.1705.

Example 8F Synthesis of 2- [4- (l-tert-butyl-5-chloro-6-oxo-l, 6-dihydro-pyridazin-4-yloxymethyl) -benzyloxy] ethyl ester hexadeuterate of toluene-4-acid sulphonic To a solution of the product of Example 8E (250 mg, 0.670 mmol) in dichloromethane (7 mL) was added p-toluenesulfonyl chloride (153 mg, 0.805 mmol), N, N-dimethylaminopyridine (DMAP, 98 mg, 0.805 mmol ), and triethylamine "" (140 mL, 1,005 mmol). The reaction was stirred at room temperature overnight under nitrogen atmosphere. Thin layer chromatography (1: 1 hexane: ethyl acetate) indicated an almost complete consumption of alcohol. The reaction was concentrated under reduced pressure and the crude material was purified by flash chromatography (2: 1 hexane: ethyl acetate to 1: 1 hexane: ethyl acetate to 100% ethyl acetate) to recover the starting material (9 mg ) and the product (261 mg, 77% yield based on the recovered starting material) as a clear oil. aH NMR (600 MHz, CDC13): 7.76 (d, 2H, J = 8.3 Hz), 7.73 (s, ÍH), 7.36 (d, 2H, J = 8.1 Hz), 7.29 (m, 4H), 4.47 (s) , 2H), 2.40 (s, 3H), 1.61 (s, 9H); 13 C NMR (150 MHz, rt, CDCl 3): 159.0, 153.8, 145.0, 138.5, 134.4, 133.1, 129.9, 128.1, 128.0, 127.3, 125.2, 118.1, 72.7, 71.0, 37.0, 63.4, 28.0, 21.7.

Example 8G To a solution of the product of Example 8F (14 mg, 0.027 mmol) in acetonitrile (300 mL) was added potassium fluoride (3.1 mg, 0.053 mmol) and K222 (20 mg, 0.053 mmol). The reaction was stirred at 90 ° C for 10 minutes under nitrogen atmosphere, observing by CCD (1: 1 hexane: ethyl acetate). The reaction is then cooled to room temperature and concentrated under reduced pressure. The crude material was purified by preparative CCD (2: 1 hexane: ethyl acetate) to obtain the product as an oil (6.2 mg, 62% yield). ^? NMR (600 MHz, CDCl 3): 7.70 (s, 1H), 7.40 (s, 4H), 4.61 (s, 2H), 1.63 (s, 9H); 13 C NMR (150 MHz, rt, CDCl 3): 158.5, 153.1, 138.2, 133. 8, 127.7, 126.8, 124.6, 117.8, 72.4, 65.9, 27.3; 19! NMR (564 MHz, CDCl 3): -225.2 (m, 1F).

Purification and Radiosynthetic Procedures for the Preparation of Fenazaquine and Piradaben Complexes Radiolabelled with the Fluorine-18 Radionuclide The fluorine-18 (18F) used in the development is produced by means of bombardment of enriched 0xigen-18 protons (180) as H2180 using approximately 10 MeV protons per PETnet (Woburn, MA). The expression for this nuclear reaction is: O18 ( P,?) 18R. A similar procedure was used for all radiosynthetic reactions. All the glassware is silanized to prevent adhesion of the material to the walls of the container and optimize the transfer. A dedicated, dedicated CLAR unit was used for purification for all compounds. A specific dedicated CLAR unit was used for the radioanalytical analyzes of the final product. 18F is typically received from the supplier deposited in a processed column (column 18F) enclosed in lead protection. Column 18F contains the sodium salt coordinated either with alumina or a quaternary ammonium salt housed in a glass column. The ends of the column are connected by Tygon ™ flexible tubing with male and female Luer ™ connection fittings. 18F is removed from the column using the following method. 1. A solution of 15 mg of potassium carbonate (K2C03) in 1 mL of distilled / deionized water (H20) and a 90 mg solution of 4, 7, 13, 16, 21, 24-hexaoxa-l, 10- diazabicyclo [8.8.8] hexacosane (Kryptofix ™; K222) dissolved in 4 mL of anhydrous acetonitrile (CH3CN) were combined and shaken gently, ensuring that the layers do not separate, forming the column eluting solution (CES). 2. An aliquot of one mL of CES was removed from the vial described in step three using a 3 mL syringe and the syringe was attached to the male Luer ™ connector of the Tygon ™ flexible tubing connected to the 18F column. 3. A narrow gauge needle was attached to the Luer ™ female connector of the other Tygon ™ tubing connected to the 18F column, and the needle was inserted through the rubber septum adapted to a 15 mL pear-shaped glass flask. 24/40 Pyrex ™. 4. The 15 mL pear-shaped flask was ventilated with the needle and the flask was wetted with dry nitrogen. The wetting needle is connected to the vacuum line and the flow is adjusted such that CES is slowly drawn through the 18F column in the 15 mL pear-shaped flask. 5. The vacuum and gas flow N2 is adjusted in such a way that the contents of the flask are reduced to dryness. The anhydrous CH3CN (1 mL) was added via syringe to the flask, using vacuum to conduct the transfer. The vacuum and flow of N2 gas are balanced to remove the acetonitrile. This procedure was repeated twice, after which the vacuum was removed. 6. The contents of the flask were removed by syringe and the radioactivity was quantified. Solution 18t was used directly in the synthesis of radiolabelling. The following steps describe the radiolabelling of phenazaquin and pyridabene analogs with 18t. As previously stated, these steps were the same for each of the compounds. The following reaction scheme describes a representative scenario for all 18 F-phenazaquin and pyridabeno analogs: 7. The toluene sulfonate ester precursor for the desired phenazaquin or pydabene analog (2.5 mg) was dissolved in CH3CN (0.5 mL) in a cone-layered 5 mL Wheaton ™ glass vial with a magnetic stir bar. The vial was immersed in an oil bath heated to 90 ° C. The solution of the 18t described above was added to the reaction vial, the resulting mixture was heated at 90 ° C for 30 minutes. 8. The contents were transferred to a 50 mL silanized round bottom flask containing distilled / deionized water (25 mL), and the contents of the flask were removed by syringe, and deposited on a Waters ™ Oasis HLB column. (hydrophilic-lipophilic balance), allowing unreacted fluoride and unwanted salts to pass through the eluate. 9. The organic components were eluted from the column in a conical 5 L vial using dichloromethane, (3 mL, CH2C12). The eluent was purified by means of preparative HPLC (Phenomenex LUNA C-18 250 x 10 mm column, 5u particle, 100A pore gradient elution 90/10 H20 / CH3CN CH3CN). The appropriate fractions were concentrated and analyzed for radiochemical yield and radiochemical purity (analytical HPLC). The solution was concentrated to dryness in vacuo, and dissolved in the appropriate volume of 10% ethanolic saline for injection and / or biological studies. Additionally the following compounds can be prepared following the described procedures: Example 1 - Deguelina Analogs Synthesis of 4'-bromo-rot-2'-inonic acid: Rotenone (5.0 g, 12.7 mmol) dissolved in dichloromethane (30 mL) is rapidly added to a cooled solution (-10 ° C) of boron tribromide (3.15 g, 12.7 mmol) in dichloromethane (32.7 mL). The reaction mixture is stirred for exactly two minutes and then evaporated to dryness. The resulting raw material * coffee is dissolved in the minimum amount of methanol and cooled to 0 ° C to initiate crystallization. Brown crystals are collected and dried to result in 4'-bromo-rot-2'-inonic acid (3.24 g).

Synthesis of 4'-hydroxy-rot-2'-enonic acid: The silver oxide (1.0 g, 4.24 mmol) is added to a solution of 4'-bromo-rot-2'-enonic acid (2.0 g, 4.24 mmol) dissolved in acetone (80 mL). After finishing the addition, the reaction mixture continues stirring in the dark. After 24 h the reaction mixture is filtered through celite and the filtrate is concentrated to produce a yellow oil. The crude material is dissolved in the minimum amount of dichloromethane and cooled to 0 ° C to initiate crystallization. The 4'-hydroxy-rot-2'-enonic acid (1.0 g) can be collected as yellow crystals.

Synthesis of (6aS, 12aS) -1 '-hydroxy-dextrose: The solid PhSe-Cl (370.87 mg, 1.94 mmol) is added to a cooled solution (-30 ° C) of 4-hydroxy-rot-2'-enonic acid (725.5) mg, 1.71 mmol) in dichloromethane (20 mL). After the addition is complete, the reaction mixture is allowed to warm to room temperature for 2 h and stirring is continued at room temperature for an additional hour. After three hours of total reaction time, the reaction mixture is concentrated to produce a yellow oil. The crude material is dissolved in THF (20 mL) and cooled to 0 ° C. Hydrogen peroxide (30% in water, 0.354 mL) is added. After the addition is complete, the reaction mixture is stirred at 0 ° C for one hour and then stirred at room temperature overnight. The next day, the reaction mixture is diluted with diethyl ether. The organic layer is separated and washed with 5% NaHC03 (2x), dried over Na2SO and concentrated to yield (6aS, 12aS) -7'-hydroxymethyglycine as an amorphous yellow solid.

Synthesis of (6aS, 12aS) -1'-toluenesulfonylglutein: To a stirred solution of (6aS, 12aS) -7 'hydroxy deglycine (30 mg, 0.073 mmol) in dichloromethane (1.5 mL) is added TsCl (15.3 mg, 0.080 mmol ) and pyridine (6.47 mL, 0.080 mmol). After the addition is complete, the reaction mixture continues stirring at room temperature. After 48h the reaction is -50% complete according to the LCMS and concentrated. The crude material is purified using silica gel chromatography (gradient from 100% dichloromethane to 25% acetone in dichloromethane) to yield (6aS, 12aS) -7'-toluenesulfonylglutein as a yellow oil.

Synthesis of (6aS, 12aS) -1'-methanesulfonylglutein: To a stirred solution of (6aS, 12aS) -7'-hydroxydeglycine (50 mg, 0.122 mmol) in dichloromethane (0.5 mL) is added MsCl (9.48 mL, 0.122 mmol ) and triethylamine (17.0 mL, 0.122 mmol). After the addition is complete, the reaction mixture continues stirring at room temperature. After 3 h, additional equivalents of MsCl and triethylamine are added because the reaction is only -80% complete. After 24 h the reaction is complete and diluted with water. The aqueous layer is extracted with dichloromethane. All the combined organic layers were dried over Na 2 SO 4, filtered, and concentrated to yield a yellow oil. Chromatography on silica gel (gradient from 100% dichloromethane to 5% acetone in dichloromethane) produces (6aS, 12aS) -7'-methanesulfonylgluine (48 mg) as a "yellow oil.

Synthesis of (6aS, 12aS) -1 '- [18F] fluorodeguelina: A vacutainer prepared with thin-walled silanes from ml with a plunger prepared with silanes is charged with tetrabutyl ammonium hydroxide (5 uL, solution at 40% w / v in water), and a solution of 18F "in water (lOmCi, 200 uL) .The resulting mixture is evaporated to dryness under a flow of nitrogen at 100 ° C. The residue is further dried by addition and repeated evaporation of CH3CN (3 x 200 uL) An additional aliquot of CH3CN is added and concentrated under vacuum without heating Before the complete elimination of the solvent, THF (150 uL) is added, the vial is unfolded inwards and (6aS, 12aS) -7'-Methanesulfonylglutein (2mg) is added in one portion.The vial is reclosed and heated at 65 ° C for 30 minutes.After cooling, the vial is diluted with water (4mL ) and passes through a silica gel cartridge (Waters Light pre-charged C-18 Sep-Pak) to load the sample.The cartridge is rinsed with water and eluted with CH3CN (2 mL) .The acetonitrile is evaporated and the The residue is purified by means of HPLC to result in (6aS, 12aS) -7 '- [18F] fluorodeguelin free from the pure carrier.

Synthesis of (6aS, 12aS) -7 '- [18F] fluorodeguelina: A vacutainer prepared with 10 ml thin walled syllables with a plunger prepared with silanes is charged with tetrabutyl ammonium hydroxide (5 uL, 40% solution p / v in water), and a solution of 18F ~ in water (lOmCi, 200 uL). The resulting mixture is evaporated to dryness under a flow of nitrogen at 100 ° C. The residue is further dried by addition and repeated evaporation of CH 3 CN (3 x 200 uL). An additional aliquot of CH3CN is added and concentrated under vacuum without heating. Prior to complete removal of the solvent, THF (150 uL) is added, the vial is split inward and (6aS, 12aS) -1'-toluenesulfonylglutein (2mg) is added in one portion. The vial is reclosed and heated at 65 ° C for 30 minutes. After cooling, the vial is diluted with water (4 mL) and passed through a silica gel cartridge (Waters Light pre-charged C-18 Sep-Pak) to load the sample. The cartridge is rinsed with water and eluted with CH3CN (2 mL). The acetonitrile is evaporated and the residue is purified by means of HPLC to result in the pure carrier (6aS, 12aS) -7 '~ [18F] fluorodeguelin.

Synthesis of (-) -rot-2'-enonic acid: Solid sodium cyanoborohydride (264 mg, 4.20 mmol) is added to a solution of 4'-bromo-rot-2'-enonic acid (500 mg, 1.05 mmol) dissolved in HMPA. After the addition is complete, the reaction mixture is heated to 70 ° C. After 2.5 h the reaction it was cooled to room temperature and diluted with water. The aqueous layer is extracted with a mixture of diethyl ether / hexane (3/1). The organic layer was dried over Na 2 SO 4, filtered, and concentrated to yield a clear oil. Chromatography on silica gel (gradient from 20% hexane in dichloromethane to 5% acetone in dichloromethane) yields (-) -rot-2'-enonic acid (162.2 mg) as a clear oil.

Synthesis of (6aS, 12aS) -deguelin: The solid PhSe-Cl (185 mg, 0.972 mmol) is added to a cooled (-30 ° C) solution of (-) -rot-2'-enonic acid (350 mg, 0.884) mmol) in dichloromethane (10.5 mL). After the addition is complete, the reaction mixture is allowed to warm to room temperature for 2 hours and stirring is continued at room temperature for an additional hour. After three hours of total reaction time, the reaction mixture is concentrated to produce a yellow oil. The crude material is dissolved in THF (10.5 mL) and cooled to 0 ° C. Hydrogen peroxide (30% in water, 0.177 mL) is added. After the addition is complete, the reaction mixture continues stirring at 0 ° C for one hour and then stirred at room temperature overnight. The next day the reaction mixture is diluted with diethyl ether. The organic layer is separated and washed with 5% NaHC03 (2x), dried over Na2SO4 and concentrated to yield (6aS, 12aS) -degulin as an amorphous yellow solid.

Synthesis of ether (6aS) -deguelin enol: To a solution of degueline (245 mg, 0.622 mmol) in methanol (20 ml) is added p-TsOH monohydrate (118.3 mg, 0.622 mmol) and trimethyl orthoformate (68.14 mL, 0.622 mmol). After the addition is complete, the reaction mixture is heated to reflux for 8 h and then stirring is continued at room temperature overnight. The next day the reaction mixture is diluted with water. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with saturated NaHCO3, dried over Na2SO4 and concentrated to yield the (6aS) -glycine enol ether as an amorphous yellow solid.

Synthesis of (6aS) -4 ', 5'-dihydro-4', 5'-epoxidegollin enol: To a cooled (0 ° C) solution of (6aS) -deoluene enol ether (50 mg, 0.123 mmol) in dichloromethane (0.5 ml) m-CPBA (45 mg, 0.184 mmol) is added. After the addition is complete, the reaction mixture continues stirring at room temperature. After 6.5 h the reaction is diluted with water. The aqueous layer is extracted with dichloromethane. All the combined organic layers were dried over Na 2 SO, concentrated and purified using silica gel chromatography (gradient 100 dichloromethane to 30% in dichloromethane) to yield the ether of (6aS) -4 ', 5'-dihydro-4', 5 'epoxideguelina enol.

Synthesis of (6aS, 12aS) -4 ', 5', -dihydro-4 '[18F] flouro, 5' hydroxydeglycine: A vacutainer prepared with 10 ml thin-walled silanes with a plunger prepared with silanes is charged with hydroxide tetrabutyl ammonium (5 uL, 40% w / v solution in water), and a solution of 18F "in water (lOmCi, 200 uL) The resulting mixture is evaporated to dryness under a nitrogen flow at 100 ° C. The residue is further dried by addition and repeated evaporation of CH3CN (3 x 200 uL) .An additional aliquot of CH3CN is added and concentrated under vacuum without heating.Before the complete removal of the solvent, THF (150 uL) is added, the vial it unfolds inward and the ether of (6aS) -4 '5' -dihydro-4 ', 5' epoxideguelin enol (2 mg) is added in one portion.The vial is reclosed and heated to 65 ° C during 30 minutes After cooling to room temperature, a solution of trifluoroacetic acid (500 mL) and water (300 mL) is added slowly. The reaction vessel is closed and allowed to stand at 60 ° C for 2 min. After cooling to room temperature, the vial is diluted with water (4 mL) and passed through a silica gel cartridge (Waters Light pre-loaded C-18 Sep-Pak) to load the sample. The cartridge is rinsed with water and eluted with CH3CN (2 mL). The acetonitrile is evaporated and the residue is purified by means of HPLC to give (6aS, 12aS) -4 ', 5', -di- hydro-4 '[18F] flouro, 5'-hydroxydeglycine free of the pure carrier.

Synthesis of (6aS, 12aS) -2-0-desmethyldeguelin; The (6aS, 12aS) -deguelin (251 mg, 0.638 mmol) and sodium methanethiolate (125 mg, 1.78 mmol) are dissolved in 4 ml of N, N-dimethylacetamide and heated at 80 ° C for 26 h. The reaction mixture is diluted to 50 ml with water and extracted with dichloromethane. The aqueous layer is then made acidic with 5% HCl and extracted again with dichloromethane. All organic layers were dried over Na 2 SO, concentrated, and purified using silica gel chromatography (100% dichloromethane to 30% acetone 'in dichloromethane) to yield (6aS, 12aS) -2-0-demethyldeglycine.

Synthesis of (6aS, 12aS) -2 [F] fluorometoxideguelina [18F] F is made by irradiating [180] water (> 94a%; 400 mL) in silver target chambers with 17 meV protons from a cyclotron of 103 cm AVF. The typical irradiation is 45 min. Of duration with a beam current of 10 mA yielding around 18 GBq [18F] of fluoride. After irradiation, the target water is transported by means of silicon tubing to the synthesis apparatus. This apparatus consists of a borosilicate vessel (5 ml), containing potassium carbonate (5 mg, 36 mmol) and K2.2.2 (18 mg, 48 mmol) in acetonityryl (1 mL). The target water is evaporated under reduced pressure and He flux. Three portions of acetonitrile are added at 110 ° C. The reaction chamber is allowed to cool down to room temperature and dibromomethane (50 mL) in acetonitrile (1 mL) is added to the mixture 18F / K2.2.2- dry. The reaction mixture is heated again to 110 ° C and the volatiles are transferred to preparative HP with He as a carrier. The column is heated to 100 ° C and [18F] CH2BrF is separated from the solvents and other reagents.

Freshly obtained [18F] CH2BrF is added to the vial containing (6aS, 12aS) -2-0-desmethyldeglycine (2 mg) in ACN (150 uL). The vial is reclosed and heated at 65 ° C for 30 minutes. After cooling, the vial is diluted with water (4 mL) and passed through a silica gel cartridge (Waters Light pre-loaded C-18 Sep-Pak) to load the sample. The cartridge is rinsed with water and eluted with CH3CN (2 mL). The acetonitrile is evaporated and the residue is purified by means of HPLC to result in pure carrier (6aS, 12aS) -2 [18F] fluorometoxideguelina.

Synthesis of (6aS, 12aS) -2 [18.F] fluoroetoxideguelina Toluenesulfonyl chloride (38.3 g, 0.201 mol) and pyridine (15.9 g, 0.201 mol) are added to a solution of ethane-1, 2-diol (5 g, 0.081 mol)) in dichloromethane (100 mL) at 0 ° C. After the addition is complete, the reaction is stirred at room temperature overnight. In the morning the reaction mixture is diluted with water. The aqueous layer is extracted with dichloromethane, dried over Na 2 SO 4, and concentrated. The crude material is purified using silica gel chromatography (4: 1 hexanes ethyl acetate to 100% ethyl acetate) to obtain the ditosyl ethane in good yield. A vacutainer prepared with 10 ml thin-walled silanes with a plunger prepared with silanes is charged with tetrabutyl ammonium hydroxide (8.5 uL, 40% w / v solution in water), and a solution of 18F "in water (10mCi). , 340 uL). The resulting mixture is evaporated to dryness under a flow of nitrogen at 100 ° C. The residue is further dried by addition and repeated evaporation of CH 3 CN (3 x 200 uL). An additional aliquot of CH3CN is added and concentrated under vacuum without heating. Prior to the complete removal of the solvent, THF (150 uL) is added, the vial is unfolded inward and 1,2-ditoluenesulfonate ethane (3.4 mg) is added in one portion. The vial is reclosed and heated to 85 ° C for 30 minutes. After cooling to room temperature, the solvent is removed under reduced pressure to yield the [18F] fluoroethyl tosylate precursor (2.0 mg, 0.010 mmol). (6aS, 12aS) -2-0-demethyldeglycine (3.8 mg, 0.010 mmol) and tetrabutylammonium hydroxide (2.6 mg, 0.010 mmol) are added in DMF (0.25 mL) and the reaction mixture is again heated to 60 ° C. . After 15 min. The reaction mixture is cooled to room temperature, the vial is diluted with water (4 mL) and passed through a silica gel cartridge (Waters Light pre-charged C-18 Sep-Pak) to load the sample. The cartridge is rinsed with water and eluted with CH3CN (2 mL). The acetonitrile is evaporated and the residue is purified by means of HPLC to result in the pure carrier (6aS, 12aS) -2 [18F] fluoroethoxideglycine.

Synthesis of (6aS) -4 ', 5'-dihydro-5'-hydroxyglycine enol ester: The ether of (6aS) -4 ', 5'-dihydro-4', 5'-epoxideguelin enol (1.0 g, 2.35 mmol) is dissolved in THF (20 mL) and cooled to 0 ° C. Aluminum hydride and lithium (2.35 mL of 1 M THF solution) are added dropwise to the stirring solution. After the addition is complete, the reaction mixture is stirred at room temperature overnight. In the morning the reaction is quenched with water. The aqueous layer is extracted with ethyl acetate. All organic layers were dried over Na2SO4, concentrated and purified using silica gel chromatography (100% dichloromethane to 30% acetone in dichloromethane) to yield the ether of (6aS) -4 ', 5'-dihydro-5' - hydroxideglycine enol.

Synthesis of (6aS) -4 ', 5'-dihydro-5'-toluenesulfonylglutein enol ether: To a stirred solution of ether (6aS) -4 ', 5'-dihydro-5'-hydroxygluolin enol (31 mg, 0.073 mmol) in dichloromethane (1.5 mL) is added TsCl (15.3 mg 0.080 mmol) and pyridine. (6.47 mL, 0.080 mmol). After the addition is complete, the reaction mixture continues stirring at room temperature. After 28h the reaction is complete according to LCMS and concentrated. The crude material is purified using silica gel chromatography (gradient from 100% dichloromethane to 25% acetone in dichloromethane) to yield the ether of (6aS) -4 ', 5'-dihydro-5'-toluenesulfonylgludenainol.

Synthesis of (6aS, 12aS) -4 ', 5'-dihydro-5' [18F] flourodeguelin: A vacutainer prepared with thin-walled 10 ml silanes with a plunger prepared with silanes is charged with tetrabutyl ammonium hydroxide (5 uL, 40% w / v solution in water), and a solution of 18F "in water (lOmCi, 200 uL) The resulting mixture is evaporated to dryness under a flow of nitrogen at 100 degrees C. The residue is further dried by addition and repeated evaporation of CH3CN (3 x 200 uL). An additional "aliquot of CH3CN is added and concentrated. Low vacuum without heating. Prior to complete removal of the solvent, THF (150 uL) is added, the vial is unfolded inward and the ether of (6aS) -4 ', 5'-dihydro-5'-toluenesulfonylglutein enol (2 mg) is added in one portion. The vial is reclosed and heated to 65 degrees C for 30 minutes. After cooling to room temperature, a solution of trifluoroacetic acid (500 mL) and water (300 mL) is added slowly. The reaction vessel is closed and allowed to stand at 60 ° C for 2 min. After cooling to room temperature, the vial is diluted with water (4 mL) and passed through a silica gel cartridge (Waters Light pre-charged C-18 Sep-Pak) to load the sample. The cartridge is rinsed with water and eluted with CH 3 CN (2 mL). The acetonitrile is evaporated and the residue is purified by means of HPLC to result in free (6aS, 12aS) -4 ', 5'-dihydro-5' [18F] flourodeguelin of the pure carrier.

Synthesis of (6aS) -4 ', 5'-dihydro-5' -carbonylglycine enol ether: The ether of (6aS) -4 ', 5'-dihydro-5'-hydroxygluoline enol (1.0 g, 2.3 mmol) dissolved in dichloromethane (20 mL) is added to a solution of PCC (0.51 g, 2.3 mmol) in dichloromethane (20 mL). After stirring at room temperature for 2 h, the reaction is filtered through a pad of celite and concentrated. The crude material is purified by chromatography on silica gel (100% dichloromethane to 30% acetone in dichloromethane) to produce the ether of (6aS) -4 ', 5'-dihydro-5'-carbonylglycine enol.

Synthesis of (6aS) -5 '-trimethylstannylglutein enol ether: To a solution of 2,4,6-triisopropylbenzenesulfonyl hydrazide (33.0 g, 0.10 mole) in ACN (100 mL) is added ether of (6aS) -4 ', 5'-dihydro-5'-carbonylideglycine enol (42.4 g, 0.10 mol) of 5 'ether -carbonyl deglycine enol and 10 mL of concentrated hydrochloric acid. The solution is stirred at room temperature and then cooled to 0 ° C for 4 h. The trisyl hydrazone derivative is collected as a solid. A solution of the trisyl hydrazone derivative (38.3 mmol, 22.67 g) in 200 mL of TMEDA-hexanes (1: 1) is processed with metal with exactly 2.0 equivalents of sec -butyllithium / cyclohexane (76.6 mmol s-BuLi, -80 ° C) and is allowed to warm to -10 ° C until evolution of N2 ceases (40 min.) A recently sublimed trimethyl chloride solution (50 mmol, 9.97 g, 1.3 equiv.) In 30 mL of hexane is added all at once. The aqueous work is followed by distillation through a short path apparatus under reduced pressure to give the ether of (6aS) - 5'-trimethylstannylglycine enol.

Synthesis of (6aS, 12aS) -5 '[F] flourodeguelina A vacutainer prepared with 10 ml thin-walled silanes with a plunger prepared with silanes is charged with tetrabutyl ammonium hydroxide (5 uL, 40% w / v solution in water), and a solution of 18, in water (10mCi, 200 uL). The resulting mixture is evaporated to dryness under a flow of nitrogen at 100 degrees C. The residue is further dried by addition and repeated evaporation of CH 3 CN (3 x 200 uL). An additional aliquot of CH3CN is added and concentrated under vacuum without heating. Prior to complete removal of the solvent, THF (150 uL) is added, the vial is unfolded inwardly and ether (6aS) -5'-trimethylstannylglycine enol (2 mg) is added in one portion. The vial is reclosed and heated to 65 degrees C for 30 minutes. After cooling to room temperature, a solution of trifluoroacetic acid (500 mL) and water (300 mL) is added slowly. The reaction vessel is closed and allowed to stand at 60 ° C for 2 min. After cooling to room temperature, the vial is diluted with water (4 L) and passed through a silica gel cartridge (Waters Light pre-charged C-18 Sep-Pak) to load the sample. The cartridge is rinsed with water and eluted with CH3CN (2 mL). The acetonitrile is evaporated and the residue is purified by means of HPLC to result in free (6aS, 12aS) -5 '[18F] flourodeguelin of the pure carrier.

Synthesis of ether (ßaS) -4 ', 5'-dihydro-4' hydroxydeglycine enol: The ether of (6aS) -deguelin enol (155.0 mg, 0.38 mmol) and catecholborane (0.40 mL of THF solution l.OM, 0.40 mmol) are added to a solution of catalyst A (0.003 g, 1 mol%) in THF ( 0.5 mL). Catalyst A is prepared in accordance with the procedures found in WO 95/13284. The mixture is stirred under nitrogen for 2 h, then quenched with EtOH (0.5 mL), NaOH (2.0 M in water, 0. 5 mL) and hydrogen peroxide (30% in water, 0.5 mL), with stirring for two additional hours. The reaction mixture is extracted with diethyl ether. The organic layer is washed with 1.0 M NaOH, dried over Na2SO4, and purified using silica gel chromatography (100% dichloromethane to 30% acetone in dichloromethane to yield the ether of (6aS) -4 ', 5'-dihydro -4 'hydroxideguelin enol.

Synthesis of (6aS) -4 ', 5'-dihydro-4' -carbonylglycine enol ester: The ether of (6aS) -4 ', 5'-dihydro-5'-hydroxygluoline enol (1.0 g, 2.3 mmol) dissolved in dichloromethane (20 mL) is added to a solution of PCC (0.51 g, 2.3 mmol) in dichloromethane (20 mL). After stirring at room temperature for 2 h, the reaction is filtered through a pad of celite and concentrated. The crude material is purified by chromatography on silica gel (100% dichloromethane up to 30% acetone in dichloromethane) to yield the ether of (6aS) -4 ', 5'-dihydro-4'-carbonylgluoline enol.

Synthesis of (6aS) -4'-trimethylstannylglycine enol ether: To a solution of 2,4,6-triisopropylbenzenesulfonyl hydrazide (33.0 g, 0.10 mol) in ACN (100 mL) is added ether of (6aS) -4 ', 5'-dihydro-4'-carbonylgluoyl enol (42.4 g, 0.10 mol) and 10 mL of concentrated hydrochloric acid. The solution is stirred at room temperature and then cooled to 0 ° C for 4 h. The trisyl hydrazone derivative is collected as a solid. A solution of the trisyl hydrazone derivative (38.3 mmol, 22.67 g) in 200 mL of TMEDA-hexanes (1: 1) is processed with metallo with exactly 2.0 equivalents of sec-butyllithium / cyclohexane (76.6 mmol s-BuLi, -80 CC ) and allowed to warm up to -10 ° C until evolution of N ceases (40 min.) A solution of recently sublimed trimethyltin chloride (50 mmol, 9.97 g, 1.3 equiv.) in 30 mL hexane is added all in one time. The aqueous work is followed by distillation through a short path apparatus under reduced pressure to give the ether of (6aS) -4'-trimethylstannylglycine enol.

Synthesis of (6aS, 12aS) -4 '[F] fluorodeguelin: A vacutainer prepared with thin-walled 10 ml silanes with a plunger prepared with silanes is charged with tetrabutyl ammonium hydroxide (5 uL, 40% w / v solution in water), and a solution of 18F "in water (lOmCi, 200 uL) The resulting mixture is evaporated to dryness under a flow of nitrogen at 100 degrees C. The residue is further dried by addition and repeated evaporation of CH3CN (3 x 200 uL) .An additional aliquot of CH3CN is added and concentrated under vacuum without heating.Before complete removal of the solvent, THF (150 uL) is added, the vial is split inward and ether (6aS) -5'-trimethylstanildeglycine enol (2mg) is added in one portion.The vial is reclosed and heated to 65 degrees C for 30 minutes.After cooling to room temperature a solution of trifluoroacetic acid (500 mL) and water (300 mL) is slowly added in. The reaction vessel is closed and allowed to stand at 60 ° C for 2 min.After cooling to room temperature, the vial is diluted with water (4 mL) and passes through a silica gel cartridge (Waters Light pre-loaded C-18 Sep-Pak) to load the sample.The cartridge is rinsed with water and eluted with CH3CN (2 mL). The acetonitrile is evaporated and the residue is purified by means of HPLC for ultar the free (6aS, 12aS) -4 '[18F] flourodeguelina of the pure carrier.

Synthesis of 2,4-dihydroxy-6-nitro-benzaldehyde: The 2,4-dimethoxy-6-nitro-benzaldehyde (135 mg, 0.638 mmol) and sodium methanethiolate (125 mg, 1.78 mmol) are dissolved in 4 ml of N, N-dimethylacetamide and heated at 80 ° C for 26 h . The reaction mixture is diluted to 50 ml with water and extracted with dichloromethane. The aqueous layer is then made acidic with 5% HCl and extracted again with dichloromethane. All organic layers were dried over Na 2 SO 4, concentrated, and purified using silica gel chromatography (100% dichloromethane to 30% acetone in dichloromethane) to yield 2,4-dihydroxy-6-nitro-benzaldehyde.

Synthesis of 2,4-dihydroxy-5-nitro-benzaldehyde: 2, 4-dimethoxy-5-nitro-benzaldehyde (135 mg, 0.638 mmol) and sodium methanethiolate (125 mg, 1.78 mmol) are dissolved in 4 ml of N, N-dimethylacetamide and heated at 80 ° C for 26 h. The reaction mixture is diluted to 50 ml with water and extracted with dichloromethane. The aqueous layer is then made acidic with 5% HCl and extracted again with dichloromethane. All organic layers were dried over Na2SO4, concentrated, and purified using silica gel chromatography (100% dichloromethane to 30% acetone in dichloromethane) to yield 2,4-dihydroxy-5-nitro-benzaldehyde.

Synthesis of 5-hydroxy-2, 2-dimethyl-8-nitro-2H ~ cromene-6-carbaldehyde: A solution of 2,4-dihydroxy-5-nitro-benzaldehyde (10.61 g, 58 mmol) in Me 2 CO (6 mL) is added over a period of 5.5 h to a stirred solution of 3-methyl-but-2-enal (4.00 g). g, 29 mmol) in pyridine (2.29 g, 2.34 mL, 29 mmol) at 120 ° C. After finishing the addition the heating continues for an additional 18h. The Me2CO is evaporated and the pyridine is removed by azeotropic distillation with toluene to yield the crude product. The crude product is purified using silica gel chromatography with 1% ethyl acetate in hexanes to give 5-hydroxy-2,2-dimethyl-8-nitro-2H-chromen-6-carbaldehyde.

Synthesis of 5-hydroxy-2, 2-dimethyl-7-nitro-2H-cromene-6-carbaldehyde: A solution of 2,4-dihydroxy-6-nitro-benzaldehyde (10.61 g, 58 mmol) in Me2CO (6 mL) is added over a period of 5.5 h to a stirred solution of 3-methyl-but-2-enal (4.00 g, 29 mmol). in pyridine (2.29 g, 2.34 mL, 29 mmol) a 120 ° C. After finishing the addition the heating continues for an additional 18h. The Me2CO is evaporated and the pyridine is removed by azeotropic distillation with toluene to yield the crude product. The crude product is purified using silica gel chromatography with 1% ethyl acetate in hexanes to give 5-hydroxy-2,2-dimethyl-7-nitro-2H-chromen-6-carbaldehyde.

Synthesis of 5-methoxy-2,2-dimethyl-7-nitro-2H-chromene-6'-carbaldehyde: A mixture of 5-hydroxy-2, 2-dimethyl-7-nitro-2H-chromene-6-carbaldehyde (2.34 g, 10 mmol), K2C03 (4.12 g, 29.8 mmol) and. Mel (2.13 g, 0.94 mL, 15 mmol in Me 2 CO (40 mL) was refluxed for 4 h and stirred at room temperature overnight.The mixture was concentrated, treated with water (15 mL) and extracted with dichloromethane. The combined organic layers are washed with water, dried over Na 2 SO, and the solvent is removed in vacuo to yield an oil, which is processed by chromatography with 3% Me 2 C0 in hexane to give 5-methoxy-2,2-dimethyl- 7-nitro-2H-chromene-6-carbaldehyde.

Synthesis of 5-methoxy-2, 2-dimethyl-8-nitro-2H-chromene-6-carbaldehyde: A mixture of 5-hydroxy-2,2-dimethyl-8-nitro-2H-chromene-carbaldehyde (2.34 g, 10 mmol), K2C03 (4.12 g, 29.8 mmol) and Mel (2.13 g, 0.94 mL, 15 mmol in Me 2 CO (40 mL) was refluxed for 4 h and stirred at room temperature overnight.The mixture was concentrated, treated with water (15 mL) and extracted with dichloromethane.The combined organic layers were washed with water, dry over Na2SO, and the solvent is removed in vacuo to yield an oil, which is processed by chromatography with 3% Me2CO in hexane to give 5-methoxy-2,2-dimethyl-8-nitro-2H-chromene-6-carbaldehyde .

Synthesis of 4-but-2-ynyloxy-l, 2-dimethoxybenzene: To the 3,4-dimethoxy phenol (15.4 g, 0.1 mol) in DMF (100 mL) is added propargyl bromide (14.15 g, 0.12 mol) and potassium carbonate (11.88 g, 0.12 mol). The reaction is stirred at room temperature for 12 h, saturated NH 4 Cl and diethyl ether are added. The organic layers are washed with water, brine and dried over Na2SO4. The crude material is filtered through a pad of silica (1: 1 hexanes: dichloromethane) to give 4-but-2-ynyloxy-1,2-dimethoxybenzene as a yellow oil.

Synthesis of 4- (3,4-dimethoxy-phenyloxy) -1- (5-methoxy-2,2-dimethyl-8-nitro-2H-chromen-6-yl) -but-2-yn-1-one: To a solution of 4-but-2-ynyloxy-1,2-dimethoxybenzene (1.66 g, 8.66 mmol) in THF (75 mL) is added n-butyl lithium (5.54 ml of 1.6 M solution in THF, 8.86 mmol) at -78 ° C.

After 30 min., The 5-methoxy-2,2-dimethyl-8-nitro-2H-chromene-6-carbaldehyde (2.17g, 8.25 mmol) in THF (50 mL) is added. The reaction is stirred for 1 h and then quenched with saturated NHC1 and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over Na2SO4. The resulting crude material is dissolved in dichloromethane (20 mL) and MnO2 (5.3 g, 61 mmol) is added. After the reaction is stirred overnight at room temperature, ether is added and the suspension is filtered through a pad of celite and silica gel to give 4- (3,4-dimethoxy-phenyloxy) -1- (5). -methoxy-2, 2-dimethyl-8-nitro-2H-chromen-6-yl) -but-2-in-l-on.

Synthesis of 4- (3,4-dimethoxy-phenyloxy) -1- (5-methoxy-2,2-dimethyl-7-nitro-2H-chromen-6-yl) -but-2-in-l-one: To a solution of 4-but-2-ynyloxy-1,2-dimethoxy-benzene (1.66 g, 8.66 mmol) in THF (75 mL) is added n-butyl lithium (5.54 mL of 1.6 M solution in THF, 8.86 mmol. ) at -78 ° C. After 30 min., 5-methoxy-2,2-dimethyl-7-nitro-2H-chromene-6-carbaldehyde (2.17g, 8.25 mmol) in THF (50 mL) is added. The reaction is stirred for 1 h and then quenched with saturated NHC1 and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over Na 2 SO 4. The resulting crude material is dissolved in dic.loromethane (20 mL) and Mn02 (5.3 g, 61 mmol) is added. After the reaction is stirred overnight at room temperature, ether is added and the suspension is filtered through a pad of celite and silica gel to give 4- (3,4-dimethoxy-phenyloxy) -1- ( 5-methoxy-2,2-dimethyl-7-nitro-2H-chromen-6-yl) -but-2-in-l-one.

Synthesis of (6,7-dimethoxy-2H-chroman-3-yl) - (5-methoxy-2,2-dimethyl-7-nitro-2H-chromen-6-yl) -methanone: Into a flame-dried 10 ml round bottom flask, add 4- (3, 4-dimethoxy-phenyloxy) -1- (5-methoxy-2,2-dimethyl-7-nitro-2H-chromen-6-yl) -but-2-yn-1-one (61.6 mg, 0.135 mmol) and PtCl2 (1.8 mg, 5 mol%). The flask is evacuated and washed with argon three times, followed by the addition of toluene (1.8 mL, 0.1 m). The reaction is allowed to stir at 55 ° C for 10 hours and then concentrated. The crude material is purified using silica gel chromatography (7: 3 hexanes: ethyl acetate) to result (6,7-dimethoxy-2H-chroman-3-yl) - (5-methoxy-2,2-dimethyl- 7-nitro-2H-chromen-6-yl) -methanone.

Synthesis of (6,7-dimethoxy-2H-chroman-3-yl) - (5-methoxy-2,2-dimethyl-8-nitro-2H-chromen-6-yl) -methanone: Into a flame-dried 10 ml round bottom flask is added 4- (3,4-dimethoxy-phenyloxy) -1- (5-methoxy-2,2-dimethyl-8-nitro-2H-chromen-6-). il) -but-2-in-l-one (61.6 mg, 0.135 mmol) and PtCl2 (1.8 mg, 5 mol%). The flask is evacuated and washed with argon three times, followed by the addition of toluene (1.8 mL, 0.1 m). The reaction is allowed to stir at 55 ° C for 10 hours and then concentrated. The crude material is purified using silica gel chromatography (7: 3 hexanes: ethyl acetate) to give (6 7-dimethoxy-2H-chroman-3-yl) - (5-methoxy-2,2-dimethyl- 8-nitro-2H-chromen-6-yl) -methanone.

Synthesis of (+/-) -10-nitrodeguelina: To a flame-dried 10 ml round bottom flask is added (6,7-dimethoxy-2H-chroman-3-yl) - (5-methoxy-2,2-dimethyl-8-nitro-2H-chromen- 6-yl) -metanone (50.2 mg, 0.111 mmol) and dichloromethane (2.0 mL). The solution is cooled to -78 ° C and boron trichloride (0.133 mL, 1 M solution in dichloromethane, 0.133 mmol) is added. After stirring for 1 h the reaction was quenched with saturated NH 4 Cl, extracted with ethyl acetate, dried over Na 2 SO 4, and concentrated. The crude material is dissolved in EtOH, saturated with potassium acetate and refluxed for 1 h. After cooling to room temperature, ethyl acetate and water are added to the reaction mixture. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over Na 2 SO, and concentrated. The crude material is filtered through a pad of silica (3: 1 hexanes, ethyl acetate) to yield (+/-) -10-nitrodeguelin.

Synthesis of (+/-) 11-nitrodeguelina: To a flame-dried 10 ml round bottom flask is added (6,7-dimethoxy-2H-chroman-3-yl) - (5-methoxy-2,2-dimethyl-7-nitro-2H-chromen- 6-yl) -metanone (50.2 mg, 0.111 mmol) and dichloromethane (2.0 mL). The solution is cooled to -78 ° C and boron trichloride (0.133 mL, 1 M solution in dichloromethane, 0.133 mmol) is added. After stirring for 1 h the reaction was quenched with saturated NHC1, extracted with ethyl acetate, dried over Na2SO4, and concentrated. The crude material is dissolved in EtOH, saturated with potassium acetate and refluxed for Ih. After cooling to room temperature, ethyl acetate and water are added to the reaction mixture. The aqueous layer is extracted with ethyl acetate. Combined organic layers are washed with brine, dried over Na2SO4, and concentrated. The crude material is filtered through a pad of silica (3: 1 hexanes, ethyl acetate) to produce (+/-) -11-nitrodeguelin.

Synthesis of (+/-) - !! - [F] fluorodeguelina A vacutainer prepared with thin-walled 10 ml silanes with a plunger prepared with silanes is charged with tetrabutyl ammonium hydroxide (5 uL, 40% w / v solution in water), and a solution of 18F "in water (lOmCi, 200 uL) The resulting mixture is evaporated to dryness under a flow of nitrogen at 100 ° C. The residue is further dried by addition and repeated evaporation of CH 3 CN (3 x 200 uL). An additional aliquot of CH 3 CN is added and concentrated under vacuum without heating Prior to the complete elimination of the solvent, THF (150 uL) is added, the vial is unfolded inwards and (+/-) -11-nitrodeguelina (2 mg) is added in one portion. It is closed again and heated to 65 ° C for 30 minutes.After cooling to room temperature, the vial is diluted with water (4 mL) and passed through a silica gel cartridge (Waters Light pre-charged C- 18 Sep-Pak) to load the sample.The cartridge is rinsed with water and eluted with CH3CN (2 mL). Onitrile is evaporated and the residue is purified by means of HPLC to result in the carrier pure-free (+/-) -11- [18F] fluorodeguelina Synthesis of (+/-) -10- [F] fluorodeguelin: A vacutainer prepared with thin-walled 10 ml silanes with a plunger prepared with silanes is charged with tetrabutyl ammonium hydroxide (5 uL, solution at 40% w / v in water), and a solution of 18F "in water (lOmCi, 200 uL) The resulting mixture is evaporated to dryness under a flow of nitrogen at 100 ° C. The residue is further dried by addition and repeated evaporation of CH3CN (3 x 200 uL) An additional aliquot of CH3CN is added and concentrated under vacuum without heating Prior to complete removal of the solvent, THF (150 uL) is added, the vial is unfolded inwards and (+/-) -10-nitrodeglycine (2 mg) is added in one portion.The vial is reclosed and heated at 65 ° C for 30 minutes.After cooling to room temperature, the vial is diluted with water (4 mL) and passes through a silica gel cartridge (Waters Light pre-loaded C-18 Sep-Pak) to load the sample.The cartridge is rinsed with water and eluted with CH3CN (2 mL). acetonitrile is evaporated and the residue is purified by means of HPLC to result in free (+/-) -10- [18F] fluorodeguelin of the pure carrier.

Example 2 - Tebufenpyrate analogues Synthesis of 5-N- (4-tert-butylbenzyl) carboxamido-3 ' (methoxycarbonyl) -1-methylpyrazole: A mixture of 3- (methoxycarbonyl) -l-methyl-5-carboxylic acid (20 mmol) and thionyl chloride (30 mmol) is heated to reflux for 30 minutes. Excess thionyl chloride is removed under vacuum, and the residue is dried azeotroped with dry benzene. The resulting crude acyl chloride was dissolved in THF (10 mL) and stirred while cooling to 0 degrees C, while a solution of 4-tert-butylbenzylamine (22 mmol) and diisopropylethylamine (25 mmol) in THF (5 mL) it is added drop by drop. The reaction mixture is stirred at room temperature for 1 hour, and refluxed briefly to complete the reaction. The mixture is cooled and poured into ice water (100 mL) and extracted with ether (3 x 100 mL). The organic compounds are dried (saturated aqueous NaCl, Na 2 SO), filtered and concentrated. Purification of the residue by means of flash column chromatography (silica gel, gradient elution with 0-20% ethyl acetate / hexanes) yields 5-N- (4-tert-butylbenzyl) carboxamido-3- (methoxycarbonyl) - 1-methylpyrazole.

Synthesis of methyl 5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-l-methyl-3-pyrazolylcarboxylate: A solution of 5-N- (4-tert-butylbenzyl) carboxamido-3- (methoxycarbonyl) -1-methylpyrazole (0.1 mole) and thionyl chloride (0.13 mole) in 1,2-dichloroethane (15 mL) is heated to reflux for two hours. The reaction mixture is cooled and concentrated in vacuo. The residue is partitioned between dichloromethane (100 mL) and saturated aqueous NaHCO3 (100 mL), ensuring that the pH of the aqueous phase is > 7. The aqueous layer is separated and extracted with dichloromethane (2 x 100 mL), and the organic compounds are dried (saturated aqueous NaCl, Na 2 SO 4), filtered and concentrated. Recrystallization of the residue (EtOH-water) yields pure methyl 5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-l-methyl-3-pyrazolylcarboxylate.

Synthesis of 5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-l-methyl-3-pyrazolyl carboxylic acid: A solution of methyl 5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-l-methyl-3-pyrazolylcarboxylate (50 mmol) in dioxane (33 mL) and water (75 mL) is treated with a solution of H2SO4 (conc., 1 L) in water (1.5 mL). The resulting mixture is heated to reflux to remove the starting material. The resulting mixture is concentrated in vacuo to the point of saturation (removal of dioxane), and cooled to 0 ° C overnight. The resulting precipitate is collected by filtration and dried. The filtrate is extracted. with dichloromethane (3 x 100 mL) and the organic compounds are dried (saturated aqueous NaCl, Na 2 SO 4), filtered and concentrated. Recrystallization of the residue (ethyl acetate-methanol) yields pure 5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-l-methyl-3-pyrazolyl carboxylic acid.

Synthesis of 1- (5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-1-methyl-3-pyrazolyl) -1-ethanone: A solution of 5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-l-methyl-3-pyrazolyl carboxylic acid (20 mmol) in thionyl chloride (30 mmol) is heated at reflux for 15 minutes. The mixture is cooled and concentrated in vacuo. Benzene (10 mL) is added, and it is first stirred at atmospheric pressure, then under vacuum. The resulting acid chloride is used directly in the next step. A flask is charged with solid anhydrous copper bromide (25 mmol), and it was wetted with argon. Tetrahydrofuran (125 mL) is added. The resulting suspension is cooled to -78 ° C while a solution of methylmagnesium bromide (17.8 mL, 2.9M in diethyl ether) is added dropwise. The mixture is stirred while cooling to -78 ° C for 20 minutes. The above-prepared acid chloride is dissolved in THF (10 mL) and cooled to -78 ° C. The acid chloride is slowly added to the cuprate by means of a cannula, allowing the addition solution to run under the side of the reaction flask to re-cool. The acid chloride flask is rinsed with THF (5 mL), which is again cooled and added by means of a cannula. The bath is removed and the mixture is stirred at room temperature for 30 minutes. Methanol (4 mL) is added to quench the reaction, and the mixture is poured into saturated aqueous JSTHC1 (200 mL). The mixture is stirred for one hour to dissolve the copper salts and the organic layer is separated. The aqueous phase is washed with dichloromethane (2 x 200 mL) and the organic compounds are dried (saturated aqueous NaCl, Na 2 SO 4), filtered and concentrated. The residue is purified by chromatography (silica gel, gradient elution 10-30% ethyl acetate-hexanes) to give 1- (5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-1 -methyl-3-pyrazolyl) -1-ethanone pure.

Synthesis of 5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-3- (1-hydroxyethyl) -1-methylpyrazoline: Sodium borohydride (20 mmol) is added as a solid in one portion to a stirred solution of 1- (5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-l-methyl-3-pyrazolyl) - 1-ethanone (10 mmol) in ethanol (15 mL) at room temperature. The mixture is stirred to remove it from the starting ketone. More sodium borohydride is added if necessary. The water (2 mL) is added, the mixture is concentrated and the mixture is divided between water (100 mL) and dichloromethane (2 x 100 mL). The organic compounds are dried (saturated aqueous NaCl, Na 2 SO 4), filtered and concentrated. The residue is purified by chromatography (silica gel, gradient elution 10-30% ethyl acetate-hexanes) to give 5-N- (4-tert-butyl) benzyl carboxamido-4-chloro-3- ( Pure 1-hydroxyethyl) -1-methylpyrazoline.

Synthesis of 5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-l-methyl-3- (1-p-toluenesulfonatoethyl) pyrazoline: Synthesis of 5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-l-methyl-3- (1-p-toluenesulfonatoethyl) pyrazoline: A solution of 5-N- (4-tert-butyl) benzyl carboxamido-4-chloro-3- (1-hydroxyethyl) -1-methylpyrazoline (5 mmole) and p-toluenesulfonyl chloride (5.5 mmole) in pyridine (12 mL) is stirred at room temperature for four hours. The solution is concentrated and divided between water (100 mL) and dichloromethane (2 x 100 mL). The organic compounds are dried (saturated aqueous NaCl, Na 2 SO), filtered and concentrated. The residue is purified by chromatography (silica gel, gradient elution 2-20% ethyl acetate-hexanes) to give 5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-1-methyl- Pure 3- (1-p-toluenesulfonatoethyl) pyrazoline.

Synthesis of 5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-l-methyl-3- (1- [18F] fluoroethyl) pyrazoline (by means of tosylate): A vacutainer prepared with thin-walled 10 ml silanes with a plunger prepared with silanes is charged with tetrabutyl ammonium hydroxide (5 uL, 40% w / v solution in water), and a solution of 18F "in water (lOmCi, 200 uL) The resulting mixture is evaporated to dryness under nitrogen flow at 100 ° C. The residue is further dried by addition and repeated evaporation of CH 3 CN (3 x 200 uL). An additional aliquot of CH 3 CN is added and concentrated under vacuum without heating Prior to the complete elimination of the solvent, THF (150 uL) is added, the vial is unfolded inward and 5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-1-methyl-3- Pure (1-p-toluenesulfonatoethyl) pyrazoline (2 mg) is added in one portion as a solid.The vial is reclosed and heated to 65 ° C for 30 minutes.After cooling, the vial is diluted with water ( 4 mL) and passes through a silica gel cartridge (Waters Light pre-charged C-18 Sep-Pak) to load the sample. tucho is rinsed with water and eluted with CH3CN (2 mL). The acetonitrile is evaporated and the residue is purified by means of HPLC to give 5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-1-methyl-3- (1- [18F] fluoroethyl) pyrazoline free. pure carrier.

Synthesis of 5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-l-methyl-3- (1-methanesulfonatoethyl) pyrazoline: A solution of 5-N- (4-tert-butyl) benzyl carboxamido-4-chloro-3- (1-hydroxyethyl) -1-methylpyrazoline (5 mmol) and methanesulfonyl chloride (5.5 mmol) in pyridine (12 mL) it is stirred at room temperature for four hours. The solution is concentrated and divided between water (100 mL) and dichloromethane (2 x 100 mL). The organic compounds are dried (saturated aqueous NaCl, Na 2 SO), filtered and concentrated. The residue is purified by chromatography (silica gel, gradient elution 2-20% ethyl acetate-hexanes) to give 5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-1-methyl- 3- (1-Methanesulfonate-ethyl) pyrazoline pure.

Synthesis of 5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-l-methyl-3- (1- [18F] fluoroethyl) pyrazoline (by means of mesylate): A vacutainer prepared with thin-walled 10 ml silanes with a plunger prepared with silanes is charged with tetrabutyl ammonium hydroxide (5 uL, 40% w / v solution in water), and a solution of 18F ~ in water (lOmCi, 200 uL). The resulting mixture is evaporated to dryness under a flow of nitrogen at 100 ° C. The residue is further dried by addition and repeated evaporation of CH 3 CN (3 x 200 uL). An additional aliquot of CH3CN is added and concentrated under vacuum without heating. Prior to complete removal of the solvent, THF (150 uL) is added, the vial is unfolded inward and 5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-l-methyl-3- (1-methanesulfonate) ) Pure pyrazoline (2 mg) is added in one portion as a solid. The vial is reclosed and heated to 65 degrees C for 30 minutes. After cooling, the vial is diluted with water (4 mL) and passed through a silica gel cartridge (Waters Light pre-loaded C-18 Sep-Pak) to load the sample. The cartridge is rinsed with water and eluted with CH3CN (2 mL). The acetonitrile is evaporated and the residue is purified by means of HPLC to give free carrier 5-N- (4-tert-butyl) benzylcarboxamido-4-chloro-methyl-3- (1- [18F] fluoroethyl) pyrazoline. pure.

Synthesis of 4-tert-butyl-3-nitrobenzamide: A mixture of 4-tert-butyl-3-nitrobenzoic acid (0.1 mole), hydroxybenzotriazole (HOBt, 0.12 mole) and dicyclohexylcarbodiimide (DCC, 0.11 mole) in dichloromethane (100 mL) is stirred at room temperature while a solution of ammonia in 2-propanol (2.0M, 75 mL, 0.12 mol) is added rapidly. The mixture is stirred for two hours at room temperature, and emptied into aqueous NaHCO3 (5%, 200 L). The layers are separated, and the aqueous phase is extracted with dichloromethane (2 x 200 mL). The organic compounds are washed (2 x 200 mL 5% aq NaHCO 3), dried (saturated aqueous NaCl, NaSO 4), filtered and concentrated. The product is recrystallized from EtOH-. water to result in pure 4-tert-butyl-3-nitrobenzamide.

Synthesis of 4-tert-butyl-3- [F] fluorobenzylamine A vacutainer prepared with thin-walled 10 ml silanes with a plunger prepared with silanes is charged with tetrabutyl ammonium hydroxide (5 uL, 40% w / v solution in water), and a solution of 18F "in water (lOmCi, 200 uL) The resulting mixture is evaporated to dryness under nitrogen flow at 100 ° C. The residue is further dried by addition and repeated evaporation of CH 3 CN (3 x 200 uL). An additional aliquot of CH 3 CN is added and concentrated under vacuum without heating Prior to the complete elimination of the solvent, dioxane (150 uL) is added, the vial is split inward and 4-tert-butyl-3-nitrobenzamide (1 mg, ca. 4.5 umoles) is added in one portion The vial is reclosed and heated at 100 ° C for 25 minutes, after cooling, a solution of lithium aluminum hydride bis (tetrahydrofuran) in toluene (1 .OM, 50 uL, 50 umoles) is added, and the mixture is heated to 50 degrees C for five minutes.The vial is cooled and the The contents are diluted with water (4 mL) and passed through a silica gel cartridge (Waters Light pre-loaded C-18 Sep-Pak) to load the sample. The cartridge is rinsed with water and eluted with CH3CN (2 mL). The acetonitrile is evaporated and the residue is purified by means of HPLC to give free 4-tert-butyl-3- [18F] fluorobenzylamine of the pure carrier. The solvent is evaporated and the material is used directly in the following procedure.

Synthesis of 5-N- (4-tert-butyl-3- [18F] fluoro) benzylcarboxamido-4-chloro-3-ethyl-1-methylpyrazoline: To a stirred mixture of 3-ethyl-l-methylpyrazole-5-carboxylic acid (50 umoles), dicyclohexylcarbodiimide (DCC, -umol, administered as an aliquot from a stock solution in dichloromethane), hydroxybenzotriazole (HOBt, 60 umoles) in methylene chloride (200 uL), a solution of 4-tert-butyl-3- [18F] is added fluorobenzylamine (prepared above) in dichloromethane (100 uL). The mixture is stirred at room temperature for ten minutes at room temperature, concentrate and dissolve in acetonitrile-water (1: 4, 3 mL). The mixture is passed through a silica gel cartridge (Waters Light pre-loaded C-18 Sep-Pak) to load the sample. The cartridge is rinsed with water and eluted with CH3CN (2 mL). The acetonitrile is evaporated and the residue is purified by means of HPLC to give pure 5-N- (4-tert-butyl-3- [18F] fluoro) benzylcarboxamido-4-chloro-3-ethyl-1-methylpyrazoline free of pure carrier .

Example 3 - Pyridaben analogs Synthesis of 2-tert-butyl-4,5-dichloro-3 (2H) -pyridazinone: To mucochloric acid (4.0 g, 23.6 mmol) in water (35 ml) at 0 ° C was added anhydrous Na 2 CO 3 (1.21 g, 11.5 mmol). This was stirred until a clear solution was obtained and to this was added tert-butylhydrazine hydrochloride (2.94g, 23.6 mmol). A precipitate begins to form after a few minutes. The reaction was stirred for an additional 2.5 hrs after which it was filtered. The yellow precipitate was washed with cold water and dried to give 4.81 g of the crude hydrazone. To 4.32 g of the crude hydrazone was added 40 ml of acetic acid and the solution was refluxed for 25 minutes. The solution was then cooled and concentrated. This was then taken in dichloromethane and washed with sodium carbonate and water. The organic layer was then dried and concentrated to give a yellow solid which was purified by column chromatography using hexanes: chloroform (1: 1 to 0: 100) as the eluting solvent. This provides 2.4 g of the former as a white solid.

Synthesis of 2-tert-Butyl-4-chloro-5-thio-3 (2H) -pyridazinone: To 0.5 g of 2-tert-Butyl-4,5-dichloro-3 (2H) -pyridazinone was added 7 ml of water and sodium sulphide (0.53 g, 6.81 mmol) and the mixture was heated to 80 SC until all the solid dissolved. The solution was then cooled to room temperature and the concentrated HCl is carefully added to give a yellow precipitate, which was filtered and washed with cold water. Crystallization from hexanes gives the product as a white solid (270 mg). Synthesis of 2-tert-butyl-4-chloro-5- (4-tert -butylbenzyl) thio 3 (2H) -pyridazinone: To 220 mg of 2-tert-butyl-4-chloro-5-thio-3 (2H) -pyridazinone in 4 ml DMF was added 4-tert-butylbenzyl bromide (226 mg, lmmol) and Na 2 CO 3. The reaction mixture was stirred for 16 hrs at room temperature after which it was extracted into ethyl acetate, washed with water and purified by column chromatography (silica gel, ethyl acetate / hexanes) as the elution This provides the above-mentioned compound.

Synthesis of 2-tert-butyl-4-fluoro-5- (4-tert-butylbenzyl) thio 3 (2H) -pyridazinone: A round bottom flask is charged with 2-tert-butyl-4-chloro-5- (4-tert-butylbenzyl) thio 3 (2H) -pyridazinone (100 mg, 0.27 mmol) and to this is added potassium fluoride (23.4 mg, 0.40 mmol) and 2 ml of dimethyl sulfoxide. It is heated up to 120 ° C for 6 hours. The reaction mixture is then poured into water and extracted with ethyl acetate. This is washed with water and dried. Purification by flash chromatography (silica gel, ethyl acetate / hexanes) gave the above-mentioned compound.

Synthesis of 2-tert-butyl-4- [18F] -fluoro-5- (4-tert-butylbenzyl) thio 3 (2H) -pyridazinone: To a 5 ml reaction vial containing 500 mCi of 18F in 35Omg of 180 water is added to 1 ml of solution consisting of 10 mg of Kryptofix, 1 mg of potassium carbonate, 0.005 ml of water and 0.95 ml of acetrile. The vial is heated until all the solvents are removed and dry acetrile (1 ml) is added to the vial. This is also removed by evaporation. The 2-tert-butyl-4-chloro-5- (4-tert-butylbenzyl) thio 3 (2H) -pyridazinone (5 mg) in acetrile is then added thereto. The vial is sealed and heated for 30 minutes at 100 ° C. The mixture is diluted with dichloromethane and passed through a Sep-Pak and eluted with tetrahydrofuran. The solvent is evaporated to obtain the above-mentioned compound.

Synthesis of 4- (4-methylphenyl) butanol: To lithium aluminum hydride (427 mg, 11.2 mmol) suspended in dry ether (5 ml) at 0 ° C is added 1 g of 4- (4-methylphenyl) butanoic acid (5.614 mmol) dissolved in dry ether (lOml) during a period of 30 minutes. The reaction mixture was then warmed to room temperature and stirred for 4 hours. The water (0.43 ml), NaOH (15% solution, 0.43 g) and water (1.29 ml) are then added successively and the resulting solution is stirred for 30 minutes. The precipitate is filtered and washed with ether and dried. This is then concentrated and purified by flash chromatography (silica gel, ethyl acetate / hexanes) as the elution medium.

Synthesis of 4- (4-methylphenyl) -butyl tert-butyldimethylsilyl ether: The 4- (4-methylphenyl) butanol (0.5 g, 3.04 mmol) is dissolved in 5 ml DMF and to this is added imidazole (310 mg, 4.56 mmol) and tert-butyldimethylsilyl chloride (685 mg, 4.56 mmol). The reaction is stirred for 4 hrs after which it is extracted into ethyl acetate and washed with water to remove all the DMF. The organic layer is then dried and concentrated. The crude mixture is then purified by flash chromatography using a mixture of ethyl acetate-hexanes as the elution medium to give the above-mentioned product.

Synthesis of 4- (4-bromomethylphenyl) butyl tert-butyldimethylsilyl ether: To a 50 ml round bottom flask is added 4- (4-methylphenyl) butyl tert-butyldimethylsilyl ether (0.25 g, 0.89 mmol), N-bromosuccinimide (0.158 g, 0.89 mmol), benzoyl peroxide (2.17 mg, 0.0089mmol) and 10 ml of carbon tetrachloride. This mixture is refluxed overnight after which it is cooled and filtered. The filtrate is concentrated and the resulting crude residue is purified by flash chromatography in ethyl acetate-hexanes to give the product.

Synthesis of 2-tert-butyl-4-chloro-5- (4- (4-tert-butyldimethylsilyloxybutyl) benzyl) thio-3 (2H) -pyridazinone: To the flask containing 2-tert-butyl-4-chloro-5-thio-3 (2H) -pyridazinone (0.2 g, 0.917 mmol) is added 5 ml of DMF followed by cesium carbonate (0.358 g, 1.1 mmol) and 4- (4-Bromomethylphenyl) -butyl tert-butyldimethylsilyl ether (0.391g, 1.1 mmol). The mixture is heated to 60 ° C for 2 hrs after which it is cooled, extracted into ethyl acetate, washed, dried and concentrated. The crude mixture is then purified by chromatography using silica gel and a mixture of ethyl acetate-hexanes as the elution agent. This produces the above mentioned product.

Synthesis of 2-tert-butyl-4-chloro-5- (4- (4-hydroxybutyl) benzyl) thio-3 (2H) pyridazinone: To 0.2 g 2-tert-butyl-4-chloro-5- (4- (4-tert-butyldimethylsilyloxybutyl) benzyl) thio-3 (2H) -pyridazinone (0.404 mmol) is added 5 ml of 1% HCl concentrated in ethanol. The reaction mixture is stirred for 30 minutes after which it is extracted into ethyl acetate, washed with water and dried. The purification (silica gel; EtOAC / hexanes) of the crude mixture obtained after the concentration gives the desired product.

Synthesis of 2-tert-butyl-4-chloro-5- (4- (4-toluens To a 15 ml round bottom flask loaded with 2-tert-butyl-4-chloro-5- (4- (4-hydroxybutyl) benzyl) thio-3 (2H) -pyridazinone (0.15 g, 0.39 mmol) was add pyridine. The toluenesulfonyl chloride (88.9 mg, 0.42 mmol) is then added thereto and the mixture is stirred for 2 hours. The reaction mixture is diluted with ethyl acetate, washed with 5% copper sulfate solution and then with water and dried. After removing the solvent on the rotary evaporator, the crude is purified by flash chromatography using ethyl acetate-hexanes as the elution mixture.

Synthesis of 2-tert-butyl-4-chloro-5- (4- (4-fluorobutyl) benzyl) thio-3 (2H) -pyridazinone: To a round bottom flask is added 2-tert-butyl-4-chloro-5- (4- (4-toluenesulfonyloxybutyl) benzyl) thio-3 (2H) -pyridazinone (0.05 g, 0.093 mmol) and to this is added tetrabutylammonium fluoride (1.0 M solution in THF, 0.93 μL, 0.93 mmol) followed by 0.2 mL of THF. The reaction is heated to 60 C and stirred at this temperature for 30 minutes. The mixture is then cooled and concentrated and the crude is subjected to flash chromatography to obtain the above-mentioned compound.

Synthesis of 2-tert-butyl-4-chloro-5- (4- (4- rrl8B.F) fluorobutyl) benzyl) thio-3 (2H) -pyridazinone: The aqueous 18F (16 mCi, 0.1 ml) is added to the vacutainer containing 5 μl of tetrabutylammonium hydroxide (40% by weight solution in water). The mixture is concentrated under nitrogen in an oil bath and 250 μl of acetonitrile is added and this is also concentrated under nitrogen. 100 μl of THF is then added thereto followed by 5 mg of 2-tert-butyl-4-chloro-5- (4- (4-toluensulfonyloxybutyl) benzyl) thio-3 (2H) -pyridazinone. The mixture is then heated in an oil bath at 70 ° C for 30 minutes. This is then diluted with water, applied to C18 Sep-Pak and eluted with acetonitrile to obtain the above-mentioned compound.

Synthesis of (4-tert-butylphenyl) ethane 1,2 diol To a 100 ml round bottom flask is added 20 ml of tert-butanol, 20 ml of water and 5.6 g of AD-mix-β. The solution is stirred and cooled to 0C. The tert-butyl styrene (0.64g, 4 mmol) is added to the mixture and the resulting solution is stirred overnight at 0C. The solid sulfate (6g) is added and the mixture is stirred for an additional 30 minutes. The solution was then extracted into ethyl acetate, washed with water and dried. The crude is then purified by flash chromatography (silica gel, ethyl acetate / hexanes) to "produce the product.

Synthesis of l-tert-butyldimethylsilyloxy-2-hydroxy-2- (4-tert-butylphenyl) ethane • (4-tert-butylphenyl) ethane 1,2 diol (0.5 g, 2.57 mmol) was dissolved in DMF in a 25 ml round bottom flask and imidazole (0.210 g, 3.09 mmol) and tert-chloride were added thereto. butyldimethylsilyl (0.46 g, 3.09 mmol). The mixture is stirred for 6 hours after which it is extracted into dichloromethane and the organic layer is washed with water and dried.

Purification by flash chromatography (silica gel, ethyl acetate / hexanes) yields the above-mentioned product.

Synthesis of 2-tert-butyl-4-chloro-5- (2-tert-butyldimethylsilyloxy-1- (4-tert-butylphenyl) -1-ethyl) oxy-3 (2H) -pyridazinone To a solution of 2-tert-butyl-4,5-dichloro-3 (2H) -pyridazinone (0.5 g, 2.27 mmol) in DMF (10 mL) were added anhydrous cesium carbonate (0.74 g, 2.27 mmol) and 1 -tert-butyldimethylsilyloxy 2-hydroxy 2- (4-tert-butylphenyl) ethane (0.7 g, 2.27 mmol). The mixture is stirred for 2 hours at 70 ° C and then cooled to room temperature and ethyl acetate is added thereto. The solution is then washed with water, dried and concentrated and the residue is subjected to purification by flash chromatography (silica gel, ethyl acetate / hexanes) to give the above compound.

Synthesis of 2-tert-butyl-4-chloro-5- (2-hydroxy-1- (4-tert-butylphenyl) -1-ethyl) oxy-3 (2H) -pyridazinone: A 25 ml round bottom flask is charged with 2-tert-butyl-4-chloro-5- (2-tert-butyldimethylsilyloxy-1- (4-tert-butylphenyl) -1-ethyl) oxy-3 (2H) pyridazinone (0.5 g, 1.01 mmol) and thereto is added 5 ml of 1% concentrated HCl in ethanol. The solution is stirred for one hour after which it is poured into water and extracted with ethyl acetate. The ethyl acetate is removed using the rotary evaporator and subjected to flash chromatography using silica gel and ethyl acetate / hexanes mixture as the elution medium.

Synthesis of 2-tert-butyl-4-chloro-5- (2-p-toluenesulfonyloxy-1- (4-tert-butylphenyl) -1-ethyl) oxy-3 (2H) -pyridazinone: To a 15 ml round bottom flask loaded with 2-tert-butyl-4-chloro-5- (2-hydroxy-1- (4-tert-butylphenyl) -1-ethyl) oxy-3 (2H) -pyridazinone (0.25 g, 0.66 mmol) pyridine is added. Toluenesulfonyl chloride (0.15 g, 0.79 mmol) is then added thereto and the mixture is stirred for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with 5% copper sulfate solution and then with water and dried. After removing the solvent on the rotary evaporator the crude is purified by flash chromatography using ethyl acetate-hexanes as the elution mixture.

Synthesis of 2-tert-butyl-4-chloro-5- (2-fluoro-1- (4-tert-butylphenyl) -1-ethyl) oxy-3 (2H) -pyridazinone: To a 15 ml round bottom flask loaded with 2-tert-butyl-4-chloro-5- (2-p-toluenesulfonyloxy-1- (4-tert-butylphenyl) -1-ethyl) oxy-3 (2H) pyridazinone (0.2 g, 0.375 mmol) is added 3. 5 ml of tetrabutylammonium fluoride solution (1M in THF, 3.75 mmol). The mixture is stirred first at room temperature for 15 minutes after which it is heated for 15 minutes at 100 ° C. The solution is then cooled to room temperature and to this is added dichloromethane followed by water. The layers are separated and the organic layer is washed with water and then dried. The organic layer is then concentrated and subjected to purification using flash chromatography with silica gel (ethyl acetate / hexanes) to obtain the above compound.

Synthesis of 2-tert-butyl-4-chloro-5- (2- rrl8a, F] -fluoro-1- (4-tert-butylphenyl) -1-ethyl) oxy-3 (2H) -pyridazinone: 18F aqueous (16 mCi, 0.1 ml) is added to a vacutainer containing 5μl of tetrabutylammonium hydroxide (40% by weight solution in water). The mixture is concentrated under nitrogen in an oil bath and 250 μl of acetonitrile is added and this is also concentrated under nitrogen. 100 μl of THF is then added thereto followed by 5 mg of 2-tert-butyl-4-chloro-5- (2-p-toluenesulfonyloxy-1- (4-tert-butylphenyl) -1-ethyl) oxy-3. (2H) -pyridazinone. The mixture is then heated in an oil bath at 70 ° C for 30 minutes. This is then diluted with water, and a C18 Sep-Pak is applied and eluted with acetonitrile to obtain the above-mentioned compound.

Synthesis of 2-tert-butyl-4-methyl-5-chloro-3 (2H) -pyridazinone: The 2-tert-butyl-4,5-dichloro-3 (2H) -pyridazinone (5g, 22.72 mmol) dissolved in 12 ml of ether was added dropwise to 15 ml of an ethereal solution of methylmagnesium bromide (3M in ether) at 5 ° C. After the addition was complete, the solution was stirred at 5 ° C for 2 hours. 10 ml of 6N HCl solution is then added slowly and the solution is stirred for 10 minutes. The mixture is then extracted with diethyl ether. The ether layer is then washed with water and dried. The crude product obtained after concentrating the ether is subjected to flash chromatography (silica gel; ethyl acetate / hexanes: 9: 1) to give the product.

Synthesis of 2-tert-butyl-4-bromomethyl-5-chloro-3 (2H) pyridazinone: The 2-tert-butyl-4-methyl-5-chloro-3 (2H) -pyridazinone (3g, 15 mmol) is dissolved in 25ml of carbon tetrachloride and to this is added N-bromosuccinimide (2.6g, 15mmol) and peroxide. Benzoyl (14mg) The mixture was then refluxed for 6 hours after which it is cooled and filtered. The filtrate is washed with water and dried. After removing the organic solvent the crude residue obtained is purified by flash chromatography (silica gel, ethyl acetate / hexanes: 9: 1) to obtain the product.

Synthesis of 2-tert-butyl-4-hydroxymethyl-5-chloro-3 (2H) pyridazinone: 2-tert-Butyl-4-bromomethyl-5-chloro-3 (2H) -pyridazinone (2g, 7.19 mmol) and calcium carbonate (3.5 gm) are added to a 1: 1 mixture of dioxane-water (40 ml). The mixture is refluxed for 6 hours after which 30 ml of 3N HCl solution is added thereto. The solution is stirred for 10 minutes after which dioxane is removed under reduced pressure. The resulting solution is then extracted with dichloromethane and the dichloromethane layer is washed and dried. The crude product obtained after concentration is purified by flash chromatography (ethyl acetate / hexanes: 1: 2).

Synthesis of 2-tert-butyl-4-tert-butyldimethylsilyloxymethyl-5-chloro-3 (2H) -pyridazinone: The 2-tert-butyl-4-hydroxymethyl-5-chloro-3 (2H) -pyridazinone (1 g, 4.62 mmol) is dissolved in DMF in a 25 ml round bottom flask and imidazole (0.377 g, 5.0) is added thereto. mmol) and tert-butyldimethylsilyl chloride (0.762 g, 3.09 mmol). The mixture is stirred for 10 hours after which it is extracted into dichloromethane and the organic layer is washed with water and dried. Purification by flash chromatography (silica gel, ethyl acetate / hexanes) yields the above-mentioned product.

Synthesis of 2-tert-butyl-4-tert-butyldimethylsilyloxymethyl-5- (4-tert-butylbenzyl) thio-3 (2H) -pyridazinone: To a solution of 2-tert-butyl-4-tert-butyldimethylsilyloxymethyl-5-chloro-3 (2H) -pyridazinone (1.5 g, 4.54 mmol) in DMF (10 ml) is added anhydrous cesium carbonate (2.9 g, 9.09 mmol). ) and 4-tert-butylbenzyl mercaptan (1.02g, 4.54 mmol). The mixture is stirred for 2 hours at 70 ° C and then cooled to room temperature and ethyl acetate is added thereto. The solution is then washed with water, dried and concentrated and the residue is subjected to purification by flash chromatography (silica gel, ethyl acetate / hexanes) to give the above compound.

Synthesis of 2-tert-butyl-4-hydoxymethyl-5- (4-tert-butylbenzyl) thio-3 (2H) -pyridazinone: To a 15 ml round bottom flask loaded with 2-tert-butyl-4-tert-butyldimethylsilyloxymethyl-5- (4-tert-butylbenzyl) thio-3 (2H) -pyridazinone (2 g, 4.2 mmol) is added tetrabutylammonium fluoride (IM in THF, 21 ml, 21 mmol). The mixture is stirred at room temperature first for 5 hours and to this is added dichloromethane followed by water. The layers are separated and the organic layer is washed with water and dried. The organic layer is then concentrated and subjected to purification using flash chromatography with silica gel (ethyl acetate / hexanes) to obtain the above compound.

Synthesis of 2-tert-butyl-4-p-toluenesulfonyloxymethyl-5- (4-tert-butylbenzyl) thio-3 (2H) -pyridazinone: To a 15 ml round bottom flask is charged with 2-tert-butyl-4-hydroxymethyl-5- (4-tert-butylbenzyl) thio-3 (2H) -pyridazinone (1.0 g, 2.77 mmol) pyridine is added. The p-toluenesulfonyl chloride (0.79g, 4.15 mmol) is then added thereto and the mixture is stirred for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with 5% copper sulfate solution and then with water and dried. After removing the solvent on the rotary evaporator the crude is purified by flash chromatography using (silica gel; ethyl acetate / hexanes) as the elution mixture to give the product.

Synthesis of 2-tert-butyl-4-fluoromethyl-5- (4-tert-butylbenzyl) thio-3 (2H) -pyridazinone: To a 15 ml round bottom flask is charged with 2-tert-butyl-4-p-toluenesulfonyloxymethyl-5- (4-tert-butylbenzyl) thio-3 (2H) -pyridazinone (0.5 g, 0.972 mmol) is added 4.86 ml of tetrabutylammonium solution fluoride (IM in THF, 4.86 mmol). The mixture is stirred - first at room temperature for 15 minutes after which it is heated for 15 minutes at 100 ° C. The solution is then cooled to room temperature and to this is added dichloromethane followed by water. The layers are separated and the organic layer is washed with water and then dried. The organic layer is then concentrated and subjected to purification using flash chromatography with silica gel (ethyl acetate / hexanes) to obtain the above compound.

Synthesis of 2-tert-butyl-4- [18F] fluoromethyl-5- (4-tert-butylbenzyl) thio-3 (2H) -pyridazinone: 18F aqueous (50 mCi, 0.1 ml) is added to a vacutainer containing 5 μl of tetrabutylammonium hydroxide (40% by weight solution in water). The mixture is concentrated under nitrogen in an oil bath and 250 μl of acetonitrile is added and this is also concentrated under nitrogen. 100 μl of THF is then added thereto followed by 5 mg of 2-tert-butyl-4-p-toluenesulfonyloxymethyl-5- (4-tert-butylbenzyl) thio-3 (2H) -pyridazinone. The mixture is then heated in an oil bath at 70 ° C for 30 minutes. This is then diluted with water, applied to a C18 Sep-Pak and eluted with acetonitrile to obtain the above-mentioned compound.

Example 4 - Phenazakin analogs Synthesis of 4-chloro quinazoline: 4-Quinazolone (5g, 34.2 mmol), phosphorus pentachloride (10.26g, 47.9 mmol) and phosphorus oxychloride (40 mL) were refluxed for two hours at 115-118C. The phosphorus oxychloride was removed in vacuo and the residue was extracted into ether. The whole mixture is then emptied into a container containing crushed ice and again extracted with ether. The ether layer is then washed with sodium bicarbonate and dried. The ether is then removed under reduced pressure and the crude material is recrystallized from hexanes to result in the product.

Synthesis of 4- (4-methylphenyl) butanol; To the lithium aluminum hydride (427 mg, 11.2 mmol) suspended in dry ether (5 ml) at 0 ° C is added 1 g of 4- (4-methylphenyl) butanoic acid (5.614 mmol) dissolved in dry ether (lOml) during a period of 30 minutes. The reaction mixture is then allowed to warm to room temperature and stirred for 4 hours. Then water (0.43 ml), NaOH (15% solution, 0.43 g) and water (1.29 ml) were added successively and the resulting solution was stirred for 30 minutes. The resulting precipitate is filtered and washed with ether and dried. The filtrate is then concentrated and purified by flash chromatography using ethyl acetate-hexanes as the elution medium.

Synthesis of 4- (4-methylphenyl) butyl tert-butyldimethylsilyl ether: 4- (4-Methylphenyl) butanol (0.5g, 3.04 mmol) is dissolved in 5ml DMF and to this is added imidazole (310mg, 4.56 mmol) and tert-butyldimethylsilyl chloride (685 mg, 4.56 mmol). The reaction is stirred for 4 hours after which it is extracted into ethyl acetate and washed with water to remove all DMF. The organic layer is then dried and concentrated. The crude mixture is then purified by flash chromatography using a mixture of ethyl acetate-hexanes as the elution means to result in the above-mentioned product.

Synthesis of 4- (4-bromo-methylphenyl) butyl tert-butyldimethylsilyl ether: To a 50 ml round bottom flask is charged 4- (4-methylphenyl) butyl tert-butyldimethylsilyl ether (0.25 g, 0.89 mmol). N-bromosuccinimide (0.158 g, 0.89 mmol), benzoyl peroxide (2.17 mg, 0.0089 mmol) and 10 ml carbon tetrachloride. This mixture is refluxed overnight after which it is cooled and filtered. The filtrate is concentrated and the resulting crude residue is purified by flash chromatography in ethyl acetate-hexanes to give the product.

Synthesis of 4- (4-tert-butyldimethylsilyloxybutyl) phenylacetic acid: 4- (4-Bromomethylphenyl) butyl tert-butyldimethylsilyl ether (0.2 g, 0.561 mmol) in dry ether is added dropwise to Mg moldings (13.77mg, 0.561 mmol). Some iodide crystals were then added to initiate the reaction and the mixture is refluxed overnight under a nitrogen atmosphere. The solution is then cooled and CO 2 gas is bubbled for 10 minutes. It is stirred continuously for an additional 2 hours after which water is added to the reaction mixture. The mixture is then extracted with ethyl acetate, washed and dried. After removing the organic solvent under reduced pressure the crude is purified by flash chromatography (silica gel, ethyl acetate / hexanes) to produce the desired product. • Synthesis of 2-hydroxyethyl-4- (4-tert-butyldimethylsilyloxybutyl) benzene: 4- (4-Tert-Butyldimethylsilyloxybutyl) phenylacetic acid (0.25 g, 0.775 mmol) dissolved in dry ether is added dropwise to a suspension of lithium aluminum hydride in ether (44.2 mg, 1.16 mmol). The reaction mixture is stirred for 5 hours after which water (45 μl), NaOH (15% solution, 45 μl) and water (135 μl) are successively added and the reaction mixture is stirred for an additional 30 minutes. The resulting precipitate is filtered and washed with ether. The ether filtrate is then washed with water and dried. After concentrating the ether, the product obtained is purified by flash chromatography (silica gel, ethyl acetate / hexanes).

Synthesis of 4- (2- (4- (4-tert-butyldi-ethylsilyloxybutyl) phenyl) ethoxy) quinazoline: The 2-hydroxyethyl-4- (4-tert-butyldimethylsilyloxybutyl) benzene (0.3 g, 0.97 mmol) is dissolved in dry tetrahydrofuran and sodium hydride (24 mg, 1 mmol) is added thereto. The resulting solution is stirred at room temperature for 30 minutes after which 4-chloroquinazoline (0.164 g, 1 mmol) is added to the above solution. The solution was then stirred for 6 hours after which water is added to the mixture. The solution was then extracted into dichloromethane. The organic layer is washed, dried and then concentrated to yield the crude product which is purified by flash chromatography (silica gel, ethyl acetate / hexanes) to give the product.

Synthesis of 4- (2- (4- (4-hydroxybutyl) phenyl) ethoxy) quinazoline: To 4- (2- (4- (4-tert-butyldimethylsilyloxybutyl) phenyl) ethoxy) quinazoline (0.4g, 0.916 mmol) is added tetrabutylammonium solution fluoride (IM TBAF in THF, 4.58 mL, 4.58 mmol). The solution is stirred for 2 hours after which water is added to the reaction and this is extracted into ethyl acetate. The organic layer is then washed with water, dried and concentrated. The residue obtained is purified by flash chromatography (silica gel, ethyl acetate / hexanes) Synthesis of 4- (2- (4- (4-p-toluenesulfonyloxybutyl) phenyl) ethoxy) quinazoline: A 15 ml round bottom flask is charged with 4- (2- (4- (4-hydroxybutyl) phenyl) ethoxy) quinazoline (0.25 g, 0.77 mmol) dissolved in pyridine (5 ml). p-Toluenesulfonyl chloride (0.15 g, 0.79 mmol) is then added thereto and the mixture is stirred for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with 5% copper sulfate solution and then with water and dried. After removing the solvent on the rotary evaporator the crude is purified by flash chromatography using silica gel (ethyl acetate / hexanes) to give the product.

Synthesis of 4- (2- (4- (4-fluorobutyl) phenyl) ethoxy) quinazoline: 4- (2- (4- (4-p-Toluenesulfonyloxybutyl) phenyl) ethoxy) quinazoline (0.3g, 0.63mmol) is added to a solution of potassium fluoride / kryptofix 222 in 5 ml THF (1: 1 radius, 3.15 mmol each). After stirring at room temperature for 15 minutes the solution was then refluxed for 20 minutes. This is then cooled and water is added to it. The solution was then extracted into dichloromethane and washed with water and dried. The crude product is purified by flash chromatography with silica gel (ethyl acetate / hexanes) to give the product.

Synthesis of 4- (2- (4- (4- [iBF] -fluorobutyl) phenyl) ethoxy) quinazoline: To a 5 ml reaction vial containing 100 mCi of 18F in 30Omg of 180 water is added a 1 ml solution consisting of 10 mg of Kryptofix, 1 mg of potassium carbonate, 0.005 ml of water and 0.95 ml of acetonitrile. The vial is heated until all solvents are removed and dry acetonitrile (1- ml) is added to the vial. This is also removed by evaporation. The 4- (2- (4- (4-p-toluenesulfonyloxybutyl) phenyl) ethoxy) quinazoline (5 mg) in acetonitrile is then added thereto. The vial is sealed and heated for 30 minutes at 100 ° C. The mixture is diluted with dichloromethane and passed through a Sep-Pak and eluted with tetrahydrofuran. The solvent is evaporated to obtain the above-mentioned compound.

Synthesis of 4-Chloro-2-Quinazolone: 2-Cyanophenyl isocyanate (5g, 34.7 mmol) was suspended in di-n-butyl ether. The HCl gas was then passed the suspension at 80 ° C for 7 hours. The resulting precipitate is filtered, dried and recrystallized from chlorobenzene to yield the above product.

Synthesis of 4 - (2 - 4 - tert -butylphenyl) -ethoxy) -2-Quinazolone: The 2- (4-tert-butylphenyl) ethanol (0.3 g, 1.68 mmol) is dissolved in dry tetrahydrofuran (7 mL) to which is added sodium hydride (48.5 mg, 2.02 mmol). The resulting solution is stirred at room temperature for 30 minutes after which 4-chloro-2-Quinazolone (0.302 g, 1.68 mmol) is added to the above solution. The solution was then stirred for 6 hours after which water is added to the mixture. The solution was then extracted into dichloromethane. The organic layer is washed, dried and then concentrated to yield the crude product which is purified by flash chromatography (silica gel, ethyl acetate / hexanes) to give the product.

Synthesis of 4- (2- (4-tert-butylphenyl) -ethoxy) -2- (trifluoromethanesulfonyloxy) -quinazoline: 4- (2- (4-tert-Butylphenyl) -ethoxy) -2-Quinazolone (0.25g, 0.775 mmol) is dissolved in dichloromethane (5 mL) and trifluoromethanesulfonic anhydride (0.328g, 1.16 mmol) and diisopropylethyl amine ( 0.3g, 2.32 mmol) is added to it. The reaction is stirred overnight after which it is diluted with dichloromethane and washed with water. The organic layer is then dried and concentrated. The crude product obtained is isolated by flash chromatography (silica gel, ethyl acetate / hexanes). _ Synthesis of 4- (2- (4-tert-butylphenyl) -ethoxy) -2-fluoro-quinazoline: A 15 ml round bottom flask is charged with 4- (2- (4-tert-butylphenyl) -ethoxy) -2- (trifluoromethanesulfonyloxy) -quinazoline (0.3 g, 0.66 mmol). The tetrabutylammonium solution fluoride (IM in THF, 3.3 ml, 3.3 mmol) was then added thereto and the solution was refluxed for 60 minutes. The mixture is then cooled and water is added to it. This is then extracted with dichloromethane, washed with water and dried. The crude product obtained after concentration is purified by flash chromatography with silica gel (ethyl acetate / hexanes) to obtain the desired compound.

Synthesis of 4- (2 - (4-tert-butyl-phenyl) -ethoxy) -2 - [18F] -fluoro-quinazoline: The aqueous 18F (16 mCi, 0.1 ml) is added in a vacutainer containing 5 μl of tetrabutylammonium hydroxide (40% by weight solution in water). The mixture is concentrated under nitrogen in an oil bath at 100 ° C and 250 μl of acetonitrile is added and this is also concentrated under nitrogen. The procedure is repeated twice and then 100 μl of acetonitrile is added thereto and the contents are subjected to vacuum. Without letting dry THF dry then it is added thereto followed by 5 mg of 4- (2- (4-tert-butylphenyl) -ethoxy) -2- (trifluoromethanesulfonyloxy) -quinazoline. The mixture is then heated in an oil bath at 70 ° C for 30 minutes. This is then diluted with water, applied to a C18 Sep-Pak, rinsed with water and eluted with acetonitrile to obtain the above-mentioned compound.

Synthesis of 6-Nitro-4 (3H) -Quinazolone: A mixture of 5-nitroanthranilic acid (2g, 14.6 mmol) and formamide (2.9ml, 72 mmol) was irradiated at 15 OC in a microwave (powder: 60W) until the CCD showed that the reaction was complete (20 minutes). After cooling, the reaction mixture is rinsed with ethyl acetate and evaporated under reduced pressure. The crude is purified by flash chromatography (silica gel, ethyl acetate / hexanes) to give the above product.

Synthesis of 6-Nitro-4-chloroquinoline: 6-Nitro-4 (3H) -Quinazolone (lg, 5.23 mmol) and P0C13 (7.1ml) were mixed together and irradiated at 100C (powder: 70W) for 10 minutes. POCl3 is evaporated in vacuo and the residue is dissolved in ethyl acetate and washed with saturated NaHCO 3, dried and concentrated. This is purified by flash chromatography (silica gel, ethyl acetate / hexanes) to give the above product.

Synthesis of 6-Nitro-4- (2- (4-tert-butylphenyl) ethoxy) quinazoline: The 2- (4-tert-butylphenyl) ethanol (1.Og, 5.59 mmol) is dissolved in dry tetrahydrofuran (7 ml) and sodium hydride (48.5 mg, 2.02 mmol) is added thereto. The resulting solution is stirred at room temperature for 30 minutes after which 6-Nitro-4-chloroquinazoline (1.17 g, 5.6 mmol) is added to the above solution. The solution was then stirred for 6 hours after which water is added to the mixture. The solution was then extracted into dichloromethane. The organic layer is washed, dried and then concentrated to yield the crude product which is purified by flash chromatography (silica gel, ethyl acetate / hexanes) to give the product.

Synthesis of 6-Fluoro-4- (2- (4-tert-butylphenyl) ethoxy) quinazoline: To a 25 ml round bottom flask is added potassium fluoride (82.6 mg, 1.42 mmol) and kryptofix 222 (0.53 g, 1.42 mmol). The above mixture is stirred in THF for 20 minutes after which 6-Nitro-4- (2- (4-tert-butylphenyl) ethoxy) quinazoline (O.lg, 0.284 mmol) is added thereto. The solution is refluxed for 30 minutes after which it cools and water is added to it. This is then extracted into dichloromethane, washed with water and dried. Purification by flash chromatography (silica gel; ethyl acetate / hexanes) to give the above compound.

Synthesis of 6- [BF] -Fluoro-4- (2- (4-tert-butylphenyl) ethoxy) quinazoline: To a 5 ml reaction vial containing 50 mCi of 18F in 30Omg of 180.water is added to 1 ml of solution consisting of 10 mg "of Kryptofix, 1 mg potassium carbonate, 0.005" ml water and 0.95 ml of acetonitrile. The vial is heated until all solvents are removed and dry acetonitrile (1 ml) is added to the vial. This is also removed by evaporation. The 6-Nitro-4- (2- (4-tert-butylphenyl) ethoxy) quinazoline (5 mg) in acetonitrile is then added thereto. The vial is sealed and heated for 30 minutes at 100 ° C. The mixture is diluted with dichloromethane and passed through a Sep-Pak and eluted with tetrahydrofuran. The solvent is evaporated to obtain the above-mentioned compound.

Synthesis of (4-tert-butylphenyl) ethane 1,2 diol: To a 100 ml round bottom flask is added 20 ml tert butanol, 20 ml water and 5.6 g AD-mix-β. The solution is stirred and cooled to 0 ° C. Tert-butyl styrene (0.64 g, 4 mmol) is added to the mixture and the resulting solution is stirred overnight at 0 ° C. Solid sodium sulfite (6g) is added and the mixture is stirred for an additional 30 minutes. The solution was then extracted into ethyl acetate, washed with water and dried. The crude is then purified by flash chromatography (silica gel, ethyl acetate / hexanes) to give the product.

Synthesis of l-tert-butyldimethylsilyloxy-2-hydroxy-2- (4-tert-butylphenyl) ethane: The (4-tert-butylphenyl) ethane 1,2 diol (0.5 g, 2.57 mmol) is dissolved in DMF in a 25 ml round bottom flask and imidazole (0.210 g, 3.09 mmol) and tert-chloride are added thereto. butyldimethylsilyl (0.46 g, 3.09 mmol). The mixture is stirred for 6 hours after which it is extracted into dichloromethane and the organic layer is washed with water and dried. Purification by flash chromatography (silica gel; Purification by flash chromatography (silica gel, ethyl acetate / hexanes) to provide the above-mentioned product.

Synthesis of l-tert-butyldimethylsilyloxy-2-tetrahydropyranyloxy-2- (4-tert-butylphenyl) ethane: The l-Tert-butyldimethylsilyloxy-2-hydroxy-2- (4-tert-butylphenyl) ethane (0.5 g, 1.622 mmol) is dissolved in dichloromethane and to this is added dihydropyran (0.163g, 1.94mmol) and toluenesulfonic acid (33mg-, 0. 194mmol). The reaction is stirred for 2 hours after which the mixture is washed with water and dried. The crude residue obtained after the concentration is purified by flash chromatography (silica gel; ethyl acetate / hexanes) to obtain the product.

Synthesis of l-hydroxy-2-tetrahydropyranyloxy-2- (4-tert-butylphenyl) ethane: To the l-tert-butyldimethylsilyloxy-2-tetrahydropyranyloxy-2- (4-tert-butylphenyl) ethane (0.4 g, 1.0 mmol) is added tetrabutylammonium solution fluoride (IM TBAF in THF, 5 ml, 5.0 mmol). The solution is stirred for 2 hours after which water is added to the reaction and this is extracted into ethyl acetate. The organic layer is then washed with water, dried and concentrated. The residue obtained is purified by flash chromatography (silica gel, ethyl acetate / hexanes).

Synthesis of 4- (2-tetrahydropyranyloxy-2- (4-tert-butylphenyl) ethoxy) quinazoline: The l-Hydroxy-2-tetrahydropyranyloxy-2- (4-tert-butylphenyl) ethane (0.3 g, 1.07 mmol) is dissolved in dry tetrahydrofuran (7 ml) and sodium hydride (30.96 mg, 1.29 mmol) is added thereto. The resulting solution is stirred at room temperature for 30 minutes after which 4-chloroquinazoline (0.175 g, 1.07 mmol) is added to the above solution. The solution was then stirred for 6 hours after which water was added to the mixture. The solution was then extracted into dichloromethane. The organic layer is washed, dried and then concentrated to yield the crude product which is purified by flash chromatography (silica gel, ethyl acetate / hexanes) to give the product.

Synthesis of 4- (2-hydroxy-2 - (4-tert-butylphenyl) ethoxy) quinazoline: 4 - (2-Tetrahiropyranyloxy-2- (4-tert-butylphenyl) ethoxy) quinazoline (0.25 g, 0.615 mmol) is dissolved in 5 ml ethanol and pyridinium-p-toluenesulfonate (15.4 mg, 0.061 mmol) is add to it. The solution is heated to 55 ° C and stirred at that temperature for 4 hours. The ethanol is removed and the crude is purified by flash chromatography (silica gel, ethyl acetate / hexanes).

Synthesis of 4- (2-p-toluenesulfonyloxy-2- (4-tert-butylphenyl) ethoxy) quinazoline: A 15 ml round bottom flask is charged with 4- (2-hydroxy-2- (4-tert-butylphenyl) ethoxy) quinazoline (0.25 g, 0.77 mmol) dissolved in pyridine (5 ml). The p-toluenesulfonyl chloride (0.15 g, 0.79 mmol) is then added thereto and the mixture is stirred for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with 5% copper sulfate solution and then with water and dried. After removing the solvent on the rotary evaporator the crude is purified by flash chromatography using silica gel (ethyl acetate / hexanes) to give the product.

Synthesis of 4- (2-fluoro-2- (4-tert-butylphenyl) ethoxy) quinazoline: A 15 ml round bottom flask is charged with 4- (2-p-toluenesulfonyloxy-2- (4-tert-butylphenyl) ethoxy) quinazoline (0.3 g, 0.84 mmol). Fluoride of tetrabutylammonium solution (1M in IHF, 4.2 ml, 4.2 mmol) is then added thereto and the solution is heated to reflux for 60 minutes. The mixture is then cooled and water is added to it. This is then extracted with dichloromethane, washed with water and dried. The crude product obtained after the concentration is purified by flash chromatography with silica gel (ethyl acetate / hexanes) to obtain the desired composition.

Synthesis of 4- (2- rrl8 ° F] -fluoro-2- (4-tert-butylphenyl) ethoxy) quinazoline: 18F aqueous (16 mCi, 0.1 ml) is added to a vacutainer containing 5μl of tetrabutylammonium hydroxide (40% by weight solution in water). The mixture is concentrated under nitrogen in an oil bath at 100 ° C and 250 μl of acetonitrile is added and this is also concentrated under nitrogen. The procedure is repeated twice and then 100 μl of acetonitrile is added thereto and the contents are subjected to vacuum. Without letting the dry THF then add to it followed by 5 mg of 4- (2-p-toluenesulfonyloxy-2- (4-tert-butylphenyl) ethoxy) quinazoline. The mixture is then heated in an oil bath at 70 ° C. for ~~ 30 minutes.This is then diluted with water, applied to a C18 Sep-Pak, rinsed with water and eluted with acetonitrile to obtain the compound It will be apparent to one of ordinary skill in the art that the present description is not limited to the above illustrative examples and that it can be grouped into other specific forms without departing from the essential attributes thereof. the examples are considered in all respects as illustrative and not restrictive, reference is made to the appended claims, rather than the foregoing examples, and all changes which are within the meaning and equivalence range of the claims are therefore pretend that they are covered in the present.

It is noted that with this date, the best method known to the applicant to carry out the practice of said invention, is that which is clear from the present description of the invention.

Claims (25)

2. Having described the invention as above, the content of the following claims is claimed as property. 1. A method for imaging myocardial perfusion, characterized by administering to a patient a contrast agent comprising an image forming portion and a compound selected from deglycine, pyridaben, pyridimifen, tebufenpyrad, fenazaquin, a deglycine analog, an analogue of pyridaben, a pyridimifen analog, a tebufenpyrad analog, and a phenazaquin analog; and review of the patient using diagnostic imaging. 2. The method according to claim 1, further characterized in that the imaging portion is a radioisotope for nuclear medicine imaging, paramagnetic species for use in MR1 imaging, an echogenic entity to be used in the formation of ultrasound images, a fluorescent entity for use in fluorescent imaging, or as a light active entity for use in optical imaging.
3. 3. A contrast agent, characterized in that it comprises an image forming portion and a compound selected from deguelin, pyridaben, pyridimifen, tebufenpyrad, phenazaquin, a deguelin analogue, an analogue of pyridaben, a pyridimiphen analog, a tebufenpyrad analog, and a phenazaquin analog.
4. 4. The contrast agent according to claim 3, characterized in that the imaging portion is a radioisotope for nuclear medicine imaging, paramagnetic species for use in MRI imaging, an echogenic entity for use in training. of ultrasound images, a fluorescent entity for use in fluorescent imaging, or a light active entity for use in optical imaging
5. 5. The contrast agent according to claim 4, characterized by the paramagnetic species for use in MRI imaging is Gd3 +, Fe3 +, In3 +, or Mn2 +
6. 6. The contrast agent according to claim 4, characterized in that the echogenic entity for use in ultrasound imaging is a tensoactive microsphere encapsulated by fluorocarbon.
7. 7. The contrast agent according to claim 4, characterized in that the radiois mole for imaging nuclear medicine is X1C, 13N, 18F, 123I, 125I, 99mTc, 95Tc, allln, 62Cu / 64Cu, 67Ga, 68Ga or.
8. 8. The contrast agent according to claim 3, characterized in that the image forming portion is 18F.
9. 9. The contrast agent according to claim 3, characterized in that the image forming portion is 99? NTc.
10. 10. The contrast agent according to claim 3 of the formula (I) (I), characterized in that each A is independently selected from O, CHR1, S, and NR1; B is selected from hydrogen, C-C6 aligyl optionally substituted with an image forming portion, and an image forming portion; C is selected from hydrogen, C? -C6 alkoyl optionally substituted with an image forming portion, an image forming portion, and a B bond; D is selected from hydrogen, C? -C6 alkyl optionally substituted with an image forming portion, and an image forming portion; E is selected from hydrogen, C al-C6 alkyl optionally substituted with an image forming portion, and an image forming portion; or E and D, together with the carbon atom to which they are bound, form a double bond; or E and D, together with the carbon atom to which they are bonded, form a cyclopropyl ring; it is a single or double link; R1, R2, R3, R4, R9, R10, R13, and R14 are each. independently selected from hydrogen, C? -C6 alkyl optionally substituted with an image forming portion, and an image forming portion; R5 and R6 are each independently selected from hydrogen, C-C6 alkyl optionally substituted with an image forming portion, halo, hydroxy, and an image forming portion; when present, R7 and R8 are independently selected from hydrogen, C6-C6 alkyl optionally substituted with an image forming portion, halo, hydroxy, and an image forming portion; or R5 and R7 together form an oxo group; or R6 and R8 together - they form an oxo group; or R7 is O and R8 is a bond to R7; with the proviso that when a is a double bond, R7 and R8 are absent; R11 is hydrogen or hydroxy; R12 is selected from hydrogen, C? -C6 aligyl optionally substituted with an image forming portion, and an image forming portion; or R11 and R12 together form an oxo group or = CHR1; with the proviso that at least one image forming portion is present in the formula (I).
11. 11. The contrast agent according to claim 10, characterized in that A is 0; B and C are each independently CH3 or CH218F; D and E are each independently CH3 or CH218F; R5, R6, R9, and R10 are each independently hydrogen or 18F; and R11 and R12 together form an oxo group.
12. 12. The contrast agent according to claim 3, characterized in that it is selected from
13. 13. The contrast agent according to claim 3 of the formula (II),
14. (II) characterized or ue where m is 0 or 1; b: ^ = and each independently represent a single or double bond; R-27 R '30 R' 31 R 32 R '33 and R are independently selected from hydrogen, optionally substituted Ca-C6 alkyl with an image forming portion, and an image forming portion; when present, R28 is selected from hydrogen and C? -C6 alkenyl optionally substituted with an image forming portion, with the proviso that when it is a double bond, R28 is absent; when present, R29 is C? -C6 alkyl optionally substituted with an image forming portion, with the proviso that when it is double bond, R is absent;
15. P is wherein R35, R36, R37, R38, and R39 are independently selected from hydrogen, Ci-Cß alkyl optionally substituted with an image forming portion, and an image forming portion; when it occurs, P 'is hydrogen; or P and P 'together form an oxo group; with the proviso that when it is a double bond, P 'is absent; Q is halo or haloalkyl; J is selected from N (R27), S, O, C (= 0), C (= 0) 0, NHCH2CH20, a bond, and C (= 0) N (R27), with each group removed with its -extreme left linked to G and its right end linked to -carbon substituted with R21 and R22; when present, K is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -C6 alkyl optionally substituted with an image forming portion, heteroaryl and an image forming portion; when present, L is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -C6 alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; M is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -Cg alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; or L and M, together with the atom to which they are bound, form a carbocyclic ring of three or four members. n is 0, 1, 2, or 3;
16. R, 2'1 -, X22, R- > 2"3, R-2" 4% R-, 2"5, and are independently selected from hydrogen, C? -C6 alkyl optionally substituted with an image forming portion, and an image forming portion, and Y is selected of a bond, carbon and oxygen, with the proviso that when Y is a bond, K and L are absent and M is selected from aryl and heteroaryl, and with the proviso that when Y is oxygen, K and L are absent and M is selected from hydrogen, alkoxyalkyl, aryl, C? -C6 alkyl optionally substituted with an image forming portion, and heteroaryl, with the proviso that at least one imaging portion is present in the formula (II). The contrast agent according to claim 13, characterized in that R29 is C? -C6 alkyl characterized in that the C-C6 alkyl is tert-butyl 15. The contrast agent according to claim 13, characterized in that R28 is alkyl C? -C6 characterized by the alkyl C-C6 is methyl 16. The contrast agent according to claim 3 of the formula (III)
17. (III) characterized in that: J is selected from N (R27), S, 0, C (= 0), C (= 0) 0,
18. NHCH2CH20, a bond, or C (= 0) N (R27), with each group being removed with its left end i linked to G and its right end linked to the carbon subsituted with R21 and R22; when present, K is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -C6 alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; when present, L is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -Cg alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; M is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -C6 alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; or L and M, together with the atom to which they are bound, form a carbocyclic ring of three to four members; Q is halo or haloalkyl; n is 0, 1, 2, or 3; R21, R22, R23, R24, R25, R26, and R27 are independently selected from hydrogen, C? -Cg alkoyl optionally substituted with an image forming portion, and an image forming portion; R29 is C? -Cg alkyl optionally substituted with an image forming portion; and Y is selected from a bond, carbon, and oxygen; with the proviso that when Y is a bond, K and L are absent and M is selected from aryl and heteroaryl; and with the proviso that when Y is oxygen, K and L are absent and M is selected from hydrogen, alkoxyalkyl, aryl ,. C? -Cg alkyl optionally substituted with an image forming portion, and heteroaryl; with the proviso that at least one image forming portion is present in the formula (III) • 17. The contrast agent according to claim 16, characterized in that J is O and R29 is C? -Cg alkyl characterized in that the alkyl C? -Cg is tert-butyl. 18. The contrast agent according to claim 3, characterized in that the contrast agent is selected from
19. The contrast agent according to claim 3 of formula (IV): characterized in that: J is selected from, S, O, C (= 0), C (= 0) 0, NHCH2CH20, a bond, and C (= 0) N (R27), with each group removed with its end left linked to G and its right end linked to the carbon substituted with R21 and R22; when present, K is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C ?Ce alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; L is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -Cg alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; M is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -Cg alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; or L and M, together with the atom to which they are bound, form a carbocyclic ring of three to four members; Q is halo or haloalkyl; n is 0, 1, 2, or 3; R21 R22 R23 R24 R25 R26 R27 R28 R35 R36 R37 R38 v
20. R39 are independently selected from hydrogen, C? -Cg alkyl optionally substituted with an image forming portion, and an image forming portion; and Y is selected from a bond, carbon, and oxygen, with the proviso that when Y is a bond, K and L are absent and M is selected from aryl and heteroaryl; and with the proviso that when Y is oxygen, K and L are absent and M is selected from hydrogen, alkoxyalkyl, aryl, C? -Cg alkyl optionally substituted with an imaging portion, and heteroaryl; with the proviso that at least one image forming portion is present in the formula (IV). 20. The contrast agent according to claim 19, characterized in that J is C (= 0) N (H), and R28 is C? -Cg alkyl wherein the C? -Cg alkyl is methyl.
21. 21. The contrast agent according to claim 3, characterized in that the contrast agent is selected from
22. 22. The contrast agent according to claim 3 of formula (V) (V), characterized in that J is selected from N (R27), S, O, C (= 0), C (= 0) 0, NHCH2CH20, a bond, and C (= 0) N (R27); K is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -C6 alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; when present, L is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -C6 alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; when present, M is selected from hydrogen, alkoxyalkyl, alkyloxy, aryl, C? -C6 alkyl optionally substituted with an image forming portion, heteroaryl, and an image forming portion; or L and M, together with the atom to which they are bound, form a carbocyclic ring of three to four members; T and U are independently selected from hydrogen, alkoxy, alkoxyalkyl, C? -Cg alkyl optionally substituted with an image forming portion, halo, and an image forming portion; or T and U, together with the carbon atom to which they are bound, form a five or six membered aromatic or non-aromatic ring containing zero to two heteroatoms selected from oxygen, nitrogen and sulfur; wherein the ring is optionally substituted with one, two, or three substituents independently selected from C 1 -C 6 alkyl optionally substituted with an image forming portion and an image forming portion; n is 0, 1, 2, 0 3; and R, 2"1, R, 22, R, 23, R, 24, R, 2" 5, R, 26, R, 27, and R, 3 ° 4 'are independently selected from hydrogen, C? alkyl? C6 optionally substituted with an image forming portion, and an image forming portion; Y 'is selected from a bond, carbon, and oxygen, with the proviso that when Y is a bond, K and L are absent and M is selected from aryl and heteroaryl; and with the proviso that when Y is oxygen, K and L are absent and M is selected from hydrogen, alkoxyalkyl, aryl, C? -C6 alkyl optionally substituted with an imaging portion, and heteroaryl; with the proviso that at least one image forming portion is present in the formula (V).
23. 23. The contrast agent according to claim 22, characterized in that J is O.
24. 24. The contrast agent according to claim 22 of formula (VI) (VI), characterized in that R23, R24, R25, R26, and R34 are independently selected from hydrogen, C-C6 alkyl optionally substituted with an image forming portion, and an image forming portion; with the proviso that at least one image forming portion is present in the formula (VI).
25. 25. The contrast agent according to claim 3 characterized in that the contrast agent is selected from