WO2020225386A1 - Dérivés de 3-(4-amino-2-méthoxyphényl)-acide 2-cyanoacrylique et leur utilisation en tant que précurseurs pour la production de liaisons radiochimiques - Google Patents

Dérivés de 3-(4-amino-2-méthoxyphényl)-acide 2-cyanoacrylique et leur utilisation en tant que précurseurs pour la production de liaisons radiochimiques Download PDF

Info

Publication number
WO2020225386A1
WO2020225386A1 PCT/EP2020/062772 EP2020062772W WO2020225386A1 WO 2020225386 A1 WO2020225386 A1 WO 2020225386A1 EP 2020062772 W EP2020062772 W EP 2020062772W WO 2020225386 A1 WO2020225386 A1 WO 2020225386A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
substituted
unsubstituted
compound
propyl
Prior art date
Application number
PCT/EP2020/062772
Other languages
German (de)
English (en)
Inventor
Rares-Petru Moldovan
Masoud SADEGHZADEH
Barbara Wenzel
Mathias Kranz
Rodrigo Teodoro
Friedrich-Alexander Ludwig
Steffen Fischer
Magali Toussaint
Winnie DEUTHER-CONRAD
Peter Brust
Original Assignee
Helmholtz-Zentrum Dresden-Rossendorf E.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Helmholtz-Zentrum Dresden-Rossendorf E.V. filed Critical Helmholtz-Zentrum Dresden-Rossendorf E.V.
Publication of WO2020225386A1 publication Critical patent/WO2020225386A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the invention relates to 3- (4-amino-2-methoxyphenyl) -2-cyanoacrylic acid derivatives, their use as precursors for the production of radiochemical compounds and a process for the production of the radiochemical compounds.
  • WO 2013/109972 A2 From WO 2013/109972 A2 the derivatives of the compound B shown below are known which have a functionalized benzene ring. Examples of such derivatives are compounds C and D, which are also shown below.
  • the compounds described in WO 2013/109972 A2 are said to be monocarboxylate transporter inhibitors. The compounds described should therefore be suitable as potential anticancer agents.
  • WO 2013/109972 A2 describes the use of these compounds for the treatment of cancer and autoimmune diseases and for therapeutic changes in brain functions.
  • Monocarboxylate transporters are plasma membrane proteins that catalyze the transport of monocarboxylates such as lactates, pyruvates and ketone bodies through the plasma membrane. They are involved in cell metabolism. To date, 14 isoforms are known, to which MCT1 and MCT4 belong. In the brain, MCT1 is expressed by endothelial cells, ependymal cells and astrocytes, MCT4 is only expressed by astrocytes. It is known that MCT1 is strongly expressed in non-hypoxic areas of human intestinal, brain, breast, lung and other tumors. It is therefore possible that compounds that inhibit or modulate the expression of MCT1 can be used clinically. It is also known that the compound FACH shown below shows high inhibitory activity against certain MCTs. The IC50 against MCT1 is 11 nM, the IC50 against MCT4 6.4 nM.
  • FACH is to be carried out via a two-step synthesis using a precursor P-SdT, which has a / er / butyl protective group to protect the OH functionality.
  • Y is a hydroxy group or an O M + group, where M + is a cation
  • Z 1 is selected from the group consisting of a substituted or unsubstituted Ci-Ci2-alkyl group, a substituted or unsubstituted C2-Ci2-alkenyl group, a substituted or unsubstituted C2-Ci2-alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkylaryl group, a substituted or unsubstituted arylalkyl group and a group -A ⁇ X, wherein
  • a 1 is a hydrocarbon chain with one to four substituted or unsubstituted methylene groups, it being possible for at least one oxygen atom to be arranged in the hydrocarbon chain to form an ether group, and
  • X is selected from the group consisting of a methyl group, a halogen, and a hydroxyl group; and Z 2 is a radical bearing a leaving group AG, where Z 2 is selected from the group consisting of a substituted or unsubstituted Ci-Ci2-alkyl group, a substituted or unsubstituted C2-Ci2-alkenyl group, a substituted or unsubstituted C2 -Ci2-alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkylaryl group and a substituted or unsubstituted arylalkyl group; or Z 2 -AG is a group -A 2 -AG, wherein
  • a 2 is a hydrocarbon chain with one to four substituted or unsubstituted methylene groups, it being possible for at least one oxygen atom to be arranged in the hydrocarbon chain to form an ether group;
  • AG is selected from the group consisting of a hydroxy, -NO2, bromine, chlorine, iodine, a diazonium ion, a diazonium salt, a trialkylammonium ion, a trialkylammonium salt, a dialkoxyarene, a sulfoxide, a boronic acid, a boronic acid ester, an organotin compound, an iodonium ion, an iodonium salt, an iodonium ylide and a sulfonate.
  • the compounds of formula (£) -I and the compounds of formula (Z) - 1 are also referred to collectively as compounds of formula I below.
  • the compounds of the formula I according to the invention include both their (£) and their (Z) isomers. They also include mixtures of the (£) and (Z) isomers.
  • the expression “unsubstituted” means that the radical Z 2 has no further substituents apart from the leaving group AG.
  • the term “substituted” also means that the radical Z 2 has one or more further substituents in addition to the leaving group AG. It can be provided that at least one of the hydrogen atoms of the radical Z 1 is deuterium (D) or tritium (T). It can be provided that at least one of the hydrogen atoms of the radical Z 2 that do not belong to the leaving group AG is deuterium (D) or tritium (T). It can be provided in particular that at least one of the hydrogen atoms of the radical Z 1 is deuterium (D).
  • all hydrogen atoms of the radical Z 1 are deuterium (D).
  • at least one of the hydrogen atoms of the radical Z 2 which do not belong to the leaving group AG is deuterium (D).
  • all hydrogen atoms of the radical Z 2 that do not belong to the leaving group AG are deuterium (D).
  • at least one of the hydrogen atoms of the methoxyphenyl group of the compound of the general formula (£) -I or (Z) -I is deuterium (D) or tritium (T).
  • at least one of the hydrogen atoms or all of the hydrogen atoms in the phenyl group can be deuterium.
  • one, two or three hydrogen atoms of the methoxy group can be deuterium.
  • the radical Z 1 is a substituted or unsubstituted Ci-C 12 alkyl group, it can be provided that at least one of the hydrogen atoms or all hydrogen atoms are deuterium.
  • the substituted or unsubstituted Ci-Ci2-alkyl group of the radical Z 1 can have two to seven deuterium atoms.
  • the radical Z 1 can be propyl, with 2, 3, 4, 5, 6 or 7 hydrogen atoms of the propyl group being deuterium.
  • the radical Z 1 is a group -A'-X, it can be provided that at least one of the hydrogen atoms or all hydrogen atoms of the group A 1 and / or the group X are deuterium.
  • the radical Z 2 is a substituted or unsubstituted Ci-C 12 alkyl group, it can be provided that at least one of the hydrogen atoms or all hydrogen atoms that do not belong to the leaving group AG are deuterium.
  • the substituted or unsubstituted Ci-Ci2-alkyl group of the radical Z 2 can have two to seven deuterium atoms.
  • the radical Z 2 -AG is a group -A 2 -AG, it can be provided that at least one of the hydrogen atoms or all Hydrogen atoms of group A 2 are deuterium.
  • the group A 2 is a propyl group, 2, 3, 4, 5 or 6 hydrogen atoms of the propyl group can be deuterium.
  • a substituted methylene group is understood to mean a methylene group in which one or two hydrogen atoms are replaced by a branched or unbranched C1 to C6 alkyl group. It can be provided that the hydrocarbon chain does not contain any heteroatoms. However, it can alternatively be provided that at least one oxygen atom is arranged in the hydrocarbon chain to form an ether group.
  • the methylene groups of the hydrocarbon chain can be independently substituted or unsubstituted. So one or more of the methylene groups can be unsubstituted, while other methylene groups are substituted. If several substituted methylene groups are present, the methylene groups can be substituted in the same way or in different ways.
  • a 1 and A 2 can each independently be - (CH2) m - (0) p - (CH 2 ) n -, where p is 0 or 1, m is an integer from 0 to 4, n is an integer from 0 to 4 with the proviso that m + n is 1, 2, 3 or 4. If p is 0, then - (QUj m - (0) p - (CH 2 ) n - is a hydrocarbon chain consisting of one to four unsubstituted methylene units. If p 1, the hydrocarbon chain contains an ether group.
  • the CH2 groups may be unsubstituted or substituted with one or two branched or unbranched Ci- to C ö alkyl groups.
  • a 1 and A 2 are each independently a hydrocarbon chain with one to four unsubstituted methylene groups that does not contain any oxygen atoms.
  • the compound of the general formula I according to the invention does not contain fluorine.
  • the compounds of the general formula I according to the invention have a leaving group AG which enables a radiolabeled compound to be prepared in a one-step synthesis.
  • the use of a protective group is not required. For example, no protecting group is required even if Y is a hydroxy group.
  • the leaving group AG enables a nucleophilic substitution of a compound of the general formula I with [ 18 F] fluoride at an aliphatic position.
  • Y is a hydroxyl group
  • the carboxy group forms an acid function that is neutral based on its charge.
  • the acid function which is formed by the C (0) 0 M + unit can be present as a salt.
  • M + denotes a cation.
  • the cation can, for example, be an alkali metal ion.
  • a preferred cation is selected from the group consisting of a sodium ion, a potassium ion and a lithium ion.
  • Y is a hydroxyl group or an O M + group in which M + is a sodium ion, a potassium ion or a lithium ion.
  • AG is a sulfonate.
  • sulfonate is understood to mean an R s -S0 2 -0 group.
  • R s can, for example, be a branched or unbranched substituted or unsubstituted C I -C O -alkyl group, an aryl group or an alkylaryl group.
  • R s is CH3-, CF3- or CH3-C6H4-.
  • the sulfonate can, for example, be selected from the group consisting of a toluene sulfonic acid ester group, a methyl sulfonic acid ester group and a trifluoromethyl sulfonic acid ester group.
  • a toluene sulfonic acid ester group is understood to mean an -OTs group, where Ts is tosyl.
  • a methyl sulfonic acid ester group is understood to mean an -OMs group, where Ms is mesyl.
  • a trifluoromethylsulfonic acid ester group is understood to mean CF3-SO2-O-.
  • AG is preferably -OMs or -OTs. AG -OMs is particularly preferred.
  • AG is an organotin compound.
  • This can be a tin organyl.
  • the organotin compound can it is, for example, alkyl tin, the alkyl group (s) of which may be substituted or unsubstituted, one or more of the alkyl groups optionally having one or more heteroatoms, or aryl tin, the aryl group (s) of which may be substituted or unsubstituted, with one or more of the Aryl groups optionally have one or more heteroatoms, act.
  • AG is a halogen which is selected from the group consisting of chlorine, bromine and iodine.
  • a compound of the general formula (£) -IA or (Z) - IA is provided in which Z 1 is -A ⁇ X and Z 2 is -A 2 -AG, where X, Y , A 1 , A 2 and AG have the meanings given in connection with formula (£) -I and (Z) -I.
  • a compound of the general formula (/) -IA or (Z) - IA in which X, Y, A 1 and A 2 are those in connection with formula (E) -I and (Z) -I have given meanings and AG is selected from the group consisting of a sulfonate, chlorine, bromine, iodine or an organotin connec tion.
  • At least one of the hydrogen atoms of the radical A 1 is deuterium (D) or tritium (T). It can be provided that at least one of the hydrogen atoms of the radical X is deuterium (D) or tritium (T). It can be provided that at least one of the hydrogen atoms of the residue A 2 is deuterium (D) or tritium (T). It can in particular be provided that at least one of the Hydrogen atoms of the residue A 2 , which do not belong to the leaving group AG, is deuterium (D). In one embodiment it can be provided that all hydrogen atoms of the radical A 2 which do not belong to the leaving group AG are deuterium (D).
  • At least one of the hydrogen atoms of the methoxyphenyl group of the compound of the general formula (A) -IA or (Z) -IA is deuterium (D) or tritium (T).
  • At least one of the hydrogen atoms or all hydrogen atoms in the phenyl group can be deuterium.
  • one, two or three hydrogen atoms of the methoxy group can be deuterium.
  • At least one of the hydrogen atoms or all hydrogen atoms of the group A 1 are deuterium. It can be provided that at least one of the hydrogen atoms or all hydrogen atoms of group X are deuterium. If A 2 is an unsubstituted carbon chain with two methylene groups and X is a methyl group, the A 2 -X group can form a propyl group which has 2, 3, 4, 5, 6 or 7 deuterium atoms.
  • group A 2 is a propyl group, 2, 3, 4, 5 or 6 hydrogen atoms of the propyl group can be deuterium.
  • the invention relates to a compound of the general formula (A) -IA or (Z) -IA, in which
  • AG is -OMs, -OTs, chlorine, bromine or iodine, preferably -OMs or -OTs;
  • X is a methyl group
  • Y is a hydroxy group
  • a 1 is - (CH2) 2-;
  • a 2 is - (CH 2 ) 3 -.
  • the invention relates to a compound of the general formula (A) -IA or (Z) -IA, in which
  • AG is -OMs, chlorine, bromine or iodine, preferably -OMs;
  • X is a methyl group;
  • Y is a hydroxy group
  • a 1 is - (CH2) 2-;
  • a 2 is - (CH 2 ) 3 -.
  • the invention relates to a compound of the general formula (£) -IA or (Z) - IA, in which
  • AG is -OMs, -OTs, chlorine, bromine and iodine, preferably -OMs or -OTs;
  • X is a methyl group
  • Y is a hydroxy group
  • a 1 is - (CH2) 2-;
  • a 2 - (CD 2 ) 3 - is.
  • the invention relates to a compound of the general formula (£) -IA or (Z) - IA, in which
  • AG is -OMs, chlorine, bromine and iodine, preferably -OMs;
  • X is a methyl group
  • Y is a hydroxy group
  • a 1 is - (CH2) 2-;
  • a 2 - (CD 2 ) 3 - is.
  • a compound of the general formula (A) -IB and (Z) -IB is provided, where Y and AG have the meanings given in connection with formula (£) -I and (Z) -I and X la , X 2a , X 3a , X 4a , X 4b , X 4c , X 5a , X 5b , X 6a , X 6b , X 7a , X 7b , X 7c , X 8a , X 8b , X 9a , X 9b , X 10a and X 10b are each independently hydrogen in its natural isotope ratio or deuterium, with the proviso that at least one of the radicals X la , X 2a , X 3a , X 4a , X 4b , X 4c , X 5a , X 5b , X 6a , X
  • a compound of the general formula (£) -IB or (Z) -IB in which Y has the meanings given in connection with formula (£) -I and (Z) -I and AG is derived from Group is selected which consists of a sulfonate, chlorine, bromine, iodine or an organotin compound.
  • Y is a hydroxy group and AG is -OMs or -OTs.
  • a compound of the general formula (/ ') -IB or (Z) -JB are X la , X 2a , X 3a , X 4a , X 4b , X 4c , X 5a , X 5b , X 6a , X 6b , X 7a , X 7b and X 7c are each hydrogen in its natural isotope ratio, while X 8a , X 8b , X 9a , X 9b , X 10a and X 10b are each hydrogen in its natural isotope ratio or deuterium, Y is a hydroxy group and AG is -OMs or -OTs, with the proviso that at least one of X 8a , X 8b , X 9a , X 9b , X 10a and X 10b is deuterium.
  • X 4a , X 4b , X 4c , X 5a , X 5b , X 6a , X 6b , X 7a , X 7b , X 7c X 8a , X 8b , X 9a , X 9b , X 10a and X 10b are each hydrogen in its natural isotope ratio, while X la , X 2a and X 3a are each hydrogen in its natural isotope ratio or deuterium, Y is a hydroxyl group , and AG is -OMs or -OTs, with the proviso that at least one of the radicals X la , X 2a , X 3a is deuterium.
  • a compound of the general formula (E) -IB or (Z) -IB are X la , X 2a , X 3a , X 5a , X 5b , X 6a , X 6b , X 7a , X 7b , X 7c X 8a , X 8b , X 9a , X 9b , X 10a and X 10b are each hydrogen in its natural isotope ratio, while X 4a , X 4b and X 4c are each hydrogen in its natural isotope ratio or deuterium, Y is a hydroxyl group , and AG is -OMs or -OTs, with the proviso that at least one of X 4a , X 4b , X 4c , is deuterium.
  • Another preferred example is a mixture of compound Al and compound A2.
  • Another preferred example is a mixture of compound A3 and compound A4.
  • a particularly preferred compound is compound Al.
  • Another particularly preferred compound is compound A1 -de
  • Z 1 is selected from the group consisting of a substituted or unsubstituted C2-Ci2-alkenyl group, a substituted or unsubstituted C2-Ci2-alkynyl group, a substituted or unsubstituted aryl group and a substituted or unsubstituted heteroaryl group;
  • Z 2 is a radical bearing a leaving group AG, where Z 2 is selected from the group consisting of a substituted or unsubstituted C2-Ci2-alkenyl group, a substituted or unsubstituted C2-Ci2-alkynyl group and a substituted or unsubstituted aryl group ; and
  • Y and AG have the meanings given in connection with formula (£) -I and (Z) -I.
  • a compound of the general formula (£) -I or (Z) -I is provided in which
  • Z 1 is selected from the group consisting of allyl, propargyl, phenyl and pyridyl, with phenyl and pyridyl being particularly preferred
  • Z 2 is a radical bearing a leaving group AG, where Z 2 is selected from the group consisting of allyl, propargyl, phenyl and pyridyl, with phenyl and pyridyl being particularly preferred;
  • Y and AG have the meanings given in connection with formula (£) -I and (Z) -I.
  • Z 1 is selected from the group consisting of a substituted or unsubstituted Ci-Ci2-alkyl group, a substituted or unsubstituted C2-Ci2-alkenyl group, a substituted or unsubstituted C2-Ci2-alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkylaryl group, a substituted or unsubstituted arylalkyl group and a group -A ⁇ X, wherein
  • a 1 is a hydrocarbon chain with one to four substituted or unsubstituted methylene groups, it being possible for at least one oxygen atom to be arranged in the hydrocarbon chain to form an ether group, and
  • X is selected from the group consisting of a methyl group, a halogen, and a hydroxyl group
  • Z 2 is a radical bearing a leaving group AG, where Z 2 is a substituted or unsubstituted aryl group or a substituted or unsubstituted hetero ryl group, preferably phenyl or pyridyl;
  • Y has the meaning given in connection with formula (£) -I and (Z) -I;
  • AG is selected from the group consisting of —NO2, chlorine, bromine, iodine, a dia- zonium ion, a diazonium salt, a trialkylammonium ion, a trialkylammonium salt, a dialkoxyarene, a sulfoxide, a boronic acid , a boronic acid ester, alkyl tin, aryl tin, an iodonium ion, an iodonium salt and an iodonium ylide.
  • a compound of the general formula (£) -I or (Z) -I is provided in which
  • Z 1 is phenyl or pyridyl
  • Z 2 is a radical bearing a leaving group AG, where Z 2 is phenyl or pyridyl;
  • Y has the meaning given in connection with formula (£) -I and (Z) -I;
  • AG is selected from the group consisting of -NC, chlorine, bromine, iodine, a dia- zonium ion, a diazonium salt, a trialkylammonium ion, a trialkylammonium salt, a dialkoxyarene, a sulfoxide, a boronic acid , a boronic acid ester, alkyl tin, aryl tin, an iodonium ion, an iodonium salt and an iodonium ylide.
  • boronic acid ester is 2,4,4,5,5-pentamethyl-1,3,2-dioxaborolane.
  • Preferred iodonium ylides are sterically hindered spirocyclic iodonium ylides.
  • halogen refers, unless otherwise stated, to fluorine, chlorine, bromine or iodine.
  • alkyl relates, unless otherwise specified, in particular to a saturated aliphatic hydrocarbon group with a branched or unbranched carbon chain with 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms and particularly preferably 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sfc-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.
  • the alkyl group can optionally be substituted with one or more substituents, each substituent independently being hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino or dialkylamino, unless specifically stated otherwise.
  • heteroalkyl relates, unless otherwise indicated, in particular to an alkyl radical as defined herein, where one, two or three hydrogen atoms are replaced by a substituent independently selected from the group consisting of -OR a , -NR b R c and -S (0) n R d (where n is an integer from 0 to 2), with the proviso that the point of attachment of the heteroalkyl radical is a carbon atom, where R a is hydrogen, acyl, Is alkyl, cycloalkyl or cycloalkylalkyl; R b and R c are independently hydrogen, acyl, alkyl, cycloalkyl or cycloalkylalkyl; and when n is 0, R d is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl, and when n is 1 or 2, R d is alkyl, cycloalkyl, cycloalkylalkyl,
  • Representative examples include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2- Hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl and the like.
  • cycloalkyl relates, unless otherwise stated, in particular to saturated, carbocyclic groups which consist of mono- or bicyclic rings.
  • the cycloalkyl group can optionally be substituted with one or more substituents, each substituent independently being hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino or dialkylamino, unless specifically stated otherwise.
  • cycloalkyl components include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, including partially unsaturated derivatives thereof such as cyclohexenyl, cyclopentenyl and the like.
  • alkenyl relates, unless otherwise stated, in particular to an unsaturated aliphatic hydrocarbon group with a branched or unbranched carbon chain with 2 to 12 carbon atoms, preferably 2 to 8 carbon atoms and particularly preferably 2 to 6th Carbon atoms that have at least one olefinic double bond and more preferably a single double bond.
  • alkenyl groups include, but are not limited to, vinyl, allyl, methallyl, 1,1-dimethylallyl, propenyl, butenyl, pentadienyl, hexenyl, octenyl, and the like. An allyl group is preferred.
  • the alkenyl group may optionally be substituted with one or more substituents, each substituent independently being hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino or dialkylamino, unless specifically stated otherwise.
  • alkynyl relates, unless otherwise stated, in particular to an unsaturated aliphatic hydrocarbon group with a branched or unbranched carbon chain with 2 to 12 carbon atoms, preferably 2 to 8 carbon atoms and particularly preferably 2 to 6 carbon atoms having at least one olefinic triple bond and more preferably a single triple bond.
  • alkynyl groups include, but are not limited to, acetylenyl, propargyl, // - but-2-in-1-yl, and the like. A propargyl group is preferred.
  • the alkynyl group can optionally be substituted with one or more substituents, each substituent independently being hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino or dialkylamino, unless specifically stated otherwise.
  • alkoxy relates, unless otherwise indicated, in particular to a group of the formula -OR, in which R is an alkyl group, as defined herein.
  • alkoxy components include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
  • the alkoxy group can optionally be substituted by one or more substituents, each substituent being independently hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino or dialkylamino, unless specifically stated otherwise.
  • aryl refers, unless otherwise specified, to a cyclic, aromatic hydrocarbon group consisting of a mono-, bi- or tri cyclic aromatic ring system with 5 to 10 ring atoms, preferably 5 or 6 ring atoms.
  • the aryl group can optionally be a substituted aryl group.
  • aryl groups include, but are not limited to, phenyl, naphthyl, adamantyl, naphthalenyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfodyl, uranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylendioxy phenyl, ethylenedioxy phenyl and the like, including partially hydrogenated derivatives therefrom.
  • a preferred example is phenyl.
  • substituted aryl group relates in particular to an aryl group, which can optionally be independently substituted with one to four substituents, preferably one or two substituents selected from alkyl, cycloalkyl, heteroalkyl, hydroxyalkyl, halogen, nitro, cyano, hydroxy, alkoxy, amino , Acylamino, monoalkylamino, dialkylamino, haloalkyl, haloalkoxy, urea, amido, alkanesulfonyl, -COR (where R is hydrogen, alkyl, phenyl or phenylalkyl), - (CR'R ”) n -COOR (where n is an integer of 0 to 5, R 'and R "are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylal
  • heteroaryl relates, unless stated otherwise, in particular to a monocyclic, bicyclic or tricyclic group having 5 to 12 ring atoms, where at least one aromatic ring has one, two or three ring heteroatoms selected from N, O or S, with the remaining ring atoms being C.
  • the heteroaryl group can optionally be a substituted heteroaryl group.
  • heteroaryl groups include, but are not limited to, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidylinyl, Quinazolinyl, benzofuranyl, benzothiophenyl, Benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, indazolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, azolizolyl
  • substituted heteraryl group relates in particular to a heteroaryl group, optionally independently with one to four substituents, preferably one or two substituents selected from alkyl, cycloalkyl, heteroalkyl, hydroxyalkyl, halogen, nitro, cyano, hydroxy, alkoxy, amino , Acylamino, monoalkylamino, dialkylamino, haloalkyl, haloalkoxy, urea, amido, alkanesulfonyl, -COR (where R is hydrogen, alkyl, phenyl or phenylalkyl), - (CR'R ”) n -COOR (where n is a Is an integer from 0 to 5, R 'and R "are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl) or - (
  • arylalkyl relates, unless otherwise indicated, in particular to a group of the formula -R e R f , where R e is an alkylene group and R f is an aryl group, as defined herein.
  • the arylalkyl group may optionally be a substituted arylalkyl group. Examples of arylalkyl groups include, but are not limited to, benzyl, phenylethyl, 3- (3-chlorophenyl) -2-methylpentyl, and the like.
  • alkylene relates in particular to a saturated aliphatic hydrocarbon group with a branched or unbranched carbon chain with 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms and particularly preferably 1 to 6 carbon atoms.
  • alkylene groups include, but are not limited to, methylene, ethylene, propylene, Butylene and the like.
  • the alkylene group may optionally be substituted with one or more substituents, each substituent being independently hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino or dialkylamino, unless specifically stated otherwise.
  • alkylaryl relates, unless otherwise indicated, in particular to a group of the formula -R g R h , where R g is an aryl group and R h is an alkyl group, as defined herein.
  • the alkylaryl group may optionally be a substituted alkylaryl group.
  • alkylaryl groups include, but are not limited to, o-tolyl, m-tolyl, p-tolyl, o-te / V-butyl phenyl, m-tert-butylphenyl, p- / er / -butylphenyl, and the like.
  • At least one oxygen atom can be arranged in the hydrocarbon chain with formation of an ether group means that either no oxygen atom or at least one oxygen atom is arranged in the hydrocarbon chain with formation of an ether group.
  • a radical which is referred to as deuterium or D is understood to mean a radical which has deuterium in a frequency which is at least 3000 times greater than the natural frequency of deuterium. Assuming a natural abundance of deuterium of 0.015%, a 3000 times higher abundance means a deuterium incorporation of 45%.
  • a hydrogen radical not designated as deuterium or D is a radical that contains hydrogen in its natural isotope ratio. nis has.
  • isotopologues refers to molecules that differ only in their isotopic composition. They have the same chemical formula and that the same bonding conditions between the atoms, but differ in at least one atom that has a different number of neutrons.
  • the relationship between the abundance of an isotope in a compound and the natural abundance of the isotope is referred to as the "isotope enrichment factor".
  • the isotope enrichment factor should be at least 3000 (45% incorporation of deuterium for a remainder called deuterium) for each atom designated as deuterium.
  • the isotope enrichment factor can be at least 3500 (52.5% incorporation of deuterium), at least 4000 (60% incorporation of deuterium), at least 4500 (67.5% incorporation of deuterium), at least 5000 (75% incorporation of deuterium), at least 5500 (82.5% incorporation of deuterium), at least 6000 (90% incorporation of deuterium), at least 6333.3 (95% incorporation of deuterium), at least 6466.7 (97% incorporation of deuterium), at least 6600 ( 99% incorporation of deuterium), or at least 6633.3 (99.5% incorporation of deuterium).
  • a compound which, according to the invention, should have at least one deuterium atom can be viewed as a group of isotopologues.
  • the proportion of isotopologues that make up a compound can vary.
  • a compound which, according to the invention, should have at least one deuterium atom contains ge smaller amounts of isotopologues which have 'H hydrogen atoms instead of one or more of the indicated deuterium atoms.
  • the relative amount of these isotopologues, based on the compound, should be less than 55% of the compound.
  • the relative amount of these isotopologues is less than 50%, less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1% or less than 0.5%.
  • a process for the preparation of the compounds of the general formula (E) -I or (Z) -I is shown in Scheme 1.
  • Z 1 and Z 2 have the meanings given in connection with the general formula (E) -I or (Z) -I.
  • the compound of the general formula V corresponds to the compound of the general formula (£) -I, where Y is a hydroxyl group.
  • Monocarboxylate transporter 1 inhibitors as potential anticancer agents.
  • step (a) 3-methoxyaniline (2) is converted to a compound of the general formula III by converting the primary amino group into a tertiary amino group by double alkylation.
  • the reaction can be carried out in the presence of an inorganic salt such as K2CO3 and in an organic solvent such as acrylonitrile. The reaction can take place at temperatures above room temperature, preferably under reflux.
  • step (b) the compound of the general formula III is converted to the compound of the general formula IV.
  • the conversion can take place by means of a Vilsmeier-Haack reaction.
  • the compound of general formula III can be converted with dimethylformamide (DMF) in the presence of phosphorus oxychloride (POCI 3 ).
  • the reaction can be carried out at temperatures above room temperature, for example at 80 ° C.
  • step (c) the compound of the general formula IV is converted to the compound of the general formula V.
  • the conversion can take place by means of a base-mediated condensation.
  • the compound of the general formula IV is reacted with cyanoacetic acid.
  • the reaction can be carried out in the presence of piperidine in an organic solvent such as acrylonitrile.
  • the conversion can take place at temperatures above room temperature, preferably under reflux.
  • scheme 2 illustrates the preparation of the compound FACH by means of the process explained in connection with scheme 1.
  • Steps (a), (b) and (c) are based on steps (a), (b) and (c) explained in connection with scheme 1.
  • step (a) 3-methoxyaniline (2) is converted to A- (3 -fluoropropyl) -3-methoxy-A-propylaniline (3) (i) with Br (CH2) 3 and then (ii) implemented with I (CH2) 3F.
  • the reaction can be carried out in the presence of an inorganic salt such as K2CO3 and in an organic solvent such as acrylonitrile. The reaction can take place at temperatures above room temperature, preferably under reflux.
  • step (b) V- (3-fluoropropyl) -3-methoxy-V-propylaniline (3) is converted to 4 - ((3-fluoropropyl) (propyl) amino) -2-methoxybenzaldehyde (4).
  • the conversion can take place by means of a Vilsmeier-Haack reaction.
  • DMF dimethylformamide
  • POCI3 Phosphoroxy chloride
  • step (c) 4 - ((3-fluoropropyl) (propyl) amino) -2-methoxybenzaldehyde (4) is converted to FACH.
  • the implementation can take place by means of a base-mediated condensation.
  • compound 4 is reacted with cyanoacetic acid.
  • the reaction can be carried out in the presence of piperidine in an organic solvent such as acrylonitrile.
  • the reaction can be carried out at temperatures above room temperature, preferably under reflux.
  • Y is a hydroxy group or an O M + group, where M + is a cation
  • Z 1 is selected from the group consisting of a substituted or unsubstituted Ci-Ci2-alkyl group, a substituted or unsubstituted C2-Ci2-alkenyl group, a substituted or unsubstituted C2-Ci2-alkynyl group, a substituted or unsubstituted aryl group , a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkylaryl group, a substituted or unsubstituted arylalkyl group and a group -A ⁇ X, wherein A 1 is a hydrocarbon chain with one to four substituted or unsubstituted methylene groups, it being possible for at least one oxygen atom to be arranged in the hydrocarbon chain to form an ether group, and
  • X is selected from the group consisting of a methyl group, a halogen, and a hydroxyl group
  • Z 2 is a radical which carries [ 18 F] fluoride, where Z 2 is selected from the group consisting of a substituted or unsubstituted Ci-Ci2-alkyl group, a substituted or unsubstituted C2-Ci2-alkenyl group, a substituted or unsubstituted C2 -Ci2-alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkylaryl group and a substituted or unsubstituted arylalkyl group; or Z 2 - [ 18 F] F is a group -A 2 - [ 18 F] F, wherein
  • a 2 is a hydrocarbon chain with one to four substituted or unsubstituted methylene groups, it being possible for at least one oxygen atom to be arranged in the hydrocarbon chain to form an ether group.
  • the compounds of the formula (/ ',) - II and compounds of the formula (Z) - II are also referred to collectively below as compounds of the formula II.
  • the compounds of the formula II according to the invention include both their (£) and their (Z) isomers. They also include mixtures of the (£) and (Z) isomers.
  • the compound of the general formula I differs from the compound of the general formula II only in that the substituent AG is replaced by [ 18 F] fluorine. All other substituents, ie Y, Z 1 and Z 2 including X, A 1 and A 2 , are unchanged and are in the same position. Details on the substituents Y, Z 1 and Z 2 and also X, A 1 and A 2 can therefore be found in the information on the compounds of general formula I according to the invention.
  • Compounds of the general formula II are 18 F-labeled compounds which can be used as radiopharmaceuticals, for example as radiotracers.
  • the compounds of the general formula II can be used as radiotracers for monocarboxylate transporters.
  • the compounds of the general formula II can be used as radiopharmaceuticals, in particular as radiopharmaceuticals for nuclear medicine imaging of monocarboxylate transporters by means of positron emission tomography (PET).
  • PET positron emission tomography
  • a compound of the general formula (II) can be used as a drug for diagnosing and treating tumors, for example breast, lung, pancreas, kidney, prostate tumors and gliomas. It can also be used as a drug for the diagnosis and treatment of diseases or changes in various organs such as B.
  • the compounds of the general formula II are compounds which inhibit the expression of MCT, in particular MCT 1 and MCT4. They can therefore be used as radiopharmaceuticals for the diagnosis and therapy of diseases which are associated with the expression of MCT, in particular of MCT1 and MCT4.
  • the compounds of the general formula I according to the invention are thus precursors for the radiosynthesis of radiopharmaceuticals of the general formula II, for example of radiopharmaceuticals for nuclear medicine imaging of monocarboxylate transporters by means of positron emission tomography.
  • the compounds of the general formula I according to the invention are precursors which make it possible to evaluate preclinically and clinically the suitability of compounds of the general formula II for nuclear medicine imaging.
  • the use of a compound of the general formula (A) -IA or (Z) -IA is provided as a precursor for the preparation of a compound of the general formula (£) -IIA or (Z) - II A: (Formula (£) -IIA) (Formula (Z) - II A) in which X, Y, A 1 and A 2 are defined as given in connection with the general formula (£) -IA or (Z) -IA.
  • a compound of the general formula (/ ⁇ ) -IA can be used.
  • a compound of the general formula (Z) -IA can be used to prepare a compound of the general formula (Z) - IIA.
  • X is a methyl group
  • Y is a hydroxy group
  • This compound can be (E ) -2-cyano-3- (4 - ((3 - ([ 18 F] fluoro) propyl) (propyl) amino) -2-methoxyphenyl) acrylic acid ([ 18 F] FACH).
  • One embodiment of a compound of the general formula (A) -IIA is a compound of the general formula (A) -IIB, in which Y has the meaning given in connection with formula (£) -I and X la , X 2a , X 3a , X 4a , X 4b , X 4c , X 5a , X 5b , X 6a , X 6b , X 7a , X 7b , X 7c , X 8a , X 8b , X 9a , X 9b , X 10a and X 10b have the meanings given in connection with formula (A) -IB, where at least one of the radicals X la , X 2a ,
  • X la , X 2a , X 3a , X 4a , X 4b , X 4c , X 5a , X 5b , X 6a , X 6b , X 7a , X 7b and X 7c are each hydrogen in its natural isotope ratio
  • X 8a , X 8b , X 9a , X 9b , X 10a and X 10b are each hydrogen in its natural isotope ratio or deuterium
  • Y is a hydroxy group, with the proviso that at least one of the radicals X 8a , X 8b , X 9a , X 9b , X 10a and X 10b is deuterium.
  • X la , X 2a , X 3a , X 4a , X 4b , X 4c , X 8a , X 8b , X 9a , X 9b , X 10a and X 10b each hydrogen in its natural isotope ratio
  • X 5a , X 5b , X 6a , X 6b , X 7a , X 7b and X 7c are each hydrogen in its natural isotope ratio or deuterium
  • Y is a hydroxyl group, with the proviso that at least one of X 5a , X 5b , X 6a , X 6b , X 7a , X 7b and X 7c is deuterium .
  • X 10b are each hydrogen in its natural isotope ratio, while X la , X 2a , X 3a are each hydrogen in its natural isotope ratio or deuterium, and Y is a hydroxyl group, with the proviso that at least one of the radicals X la , X 2a , X 3a is deuterium.
  • (E) -PB are X la , X 2a , X 3a , X 5a , X 5b , X 6a , X 6b , X 7a , X 7b - X 7c X 8a , X 8b , X 9a , X 9b , X 10a and
  • X 10b are each hydrogen in its natural isotope ratio
  • X 4a , X 4b , X 4c are each hydrogen in its natural isotope ratio or deuterium
  • Y is a hydroxyl group, with the proviso that at least one of the radicals X 4a , X 4b , X 4c is deuterium.
  • X is a methyl group
  • Y is a hydroxy group
  • a 1 - ⁇ CY 2- and A 2 - (CD2) 3-.
  • This compound can be Ej-2-cyano-3- (4 - ((3 - ([ 18 F] fluoro) propyl-1,1,2,3,3-d 6 ) (propyl ) amino) -2-methoxyphenyl) acrylic acid ([ 18 F] FACH-de) trade.
  • a compound of the general formula (A) -IA or (Z) -IA is converted into a compound of the general formula (A) -IIA or (Z) -IIA.
  • a compound of the general formula (A) -IIA can be used.
  • a compound of the general formula (Z) -IA can be used to prepare a compound of the general formula (Z) -IIA.
  • a compound of the general formula (A) -IB is converted into a compound of the general formula (A) -IIB.
  • the process according to the invention can be a one-step process.
  • the process according to the invention thus enables a one-step radio synthesis of compounds of the general formula II.
  • the compounds of the general formula II can be radiopharmaceuticals, for example radiotracers.
  • radiopharmaceuticals for example radiotracers.
  • these compounds can be produced more efficiently and in a considerably shorter synthesis time.
  • This allows access to novel drugs and makes an important contribution to their evaluation.
  • the inventive The method is based on the knowledge that the introduction of the radionuclide fluorine-18 is possible via nucleophilic substitution (S N 2) of a leaving group AG at the aliphatic position.
  • the process according to the invention enables a compound of the general formula II to be prepared from a compound of the general formula I without the need to protect the radical Y of the compound of the general formula I, ie its acid function.
  • the use of protective groups to protect the acid function of the compound of general formula I is not necessary.
  • the radiofluorination provided according to the method is nevertheless successful. High radiochemical yields can be achieved.
  • a phase transfer catalyst with a cation with the general formula IS ⁇ R ⁇ R 4 is selected, where R 1 , R 2 , R 3 and R 4 are identical to or different from one another and are each unsubstituted or substituted Ci-Cö-alkyl.
  • R 1 , R 2 , R 3 and R 4 are each unsubstituted C 1 -C 6 -alkyl, more preferably propyl, butyl or pentyl, particularly preferably in each case // - butyl.
  • the phase transfer catalyst has an anion which is selected from the group comprising hydrogen carbonate, hydrogen sulfate, oxalate, phosphate and toluene sulfonate. Hydrogen carbonate and phosphate are highly preferred.
  • a particularly preferred phase transfer catalyst is tetra - // - butyl ammonium hydrogen carbonate.
  • a phase transfer catalyst which has the cation tetra - // - butyl ammonium is also referred to below as TBA.
  • the phase transfer catalyst is used to activate and phase transfer the [ 18 F] fluoride anion.
  • the cation with the general formula N + (R 3 R 2 R 3 R 4 ) and the anion can be present in a stoichiometric ratio.
  • the phase transfer catalyst is preferably in a polar solution, particularly preferably in a solution with water or a water-containing solvent mixture.
  • the solvent mixture can, for example, be water to which an alcohol such as ethanol has been added. The addition of alcohol serves to stabilize the solution.
  • the phase transfer catalyst can be provided, for example, as a 0.001 to 0.1 M solution, in particular as a 0.075 M solution.
  • the [ 18 F] fluoride anion can be prepared by known methods.
  • the [ 18 F] fluoride anion in the cyclotron is produced by irradiating at least 97% enriched FL 18 0 with protons with an energy of 9.6 MeV.
  • the aqueous [ 18 F] fluoride solution obtained in this way can be fixed on an anion exchange cartridge (QMA) and transferred to a reaction vessel with the aid of a phase transfer catalyst (PTC), such as crown ethers, quaternary ammonium salts or alkali or alkaline earth salts be convicted.
  • QMA anion exchange cartridge
  • PTC phase transfer catalyst
  • a [2,2,2] cryptand (Kryptofix® or K222), tetra - // - butyl ammonium phosphate, hydroxide, oxalate, toluene sulfonate, or optionally other crown ethers such as 18-crown are preferably used as PTC -6 used.
  • the compound of the general formula I is dissolved in an organic solvent and added to the dried reaction mixture.
  • the organic solvent can be a non-protic, polar solvent such as acetonitrile, dimethylformamide (DMF), N, N-dimethylacetamide (DMAA), N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), or mixtures thereof act.
  • Acetonitrile is preferably used as the solvent.
  • the organic solvent can also be protic, polar solvents such as tert-BuOH, tert-amyl alcohol or other alcohols.
  • the process according to the invention is preferably carried out with thermal reaction conditions in a closed reaction vessel at elevated temperature.
  • the temperature is preferably between 50 and 150 ° C, particularly preferably 80 and 120 ° C, particularly preferably 100 ° C.
  • the invention is carried out for a period of time from 1 to 60 minutes, more preferably from 5 to 30 minutes and particularly preferably from 10 to 20 minutes.
  • the method according to the invention can also be carried out as a microwave-assisted reaction.
  • microwaves with a power of 50 to 150 W, preferably 65 to 85 W and particularly preferably 75 W are radiated into a closed special reaction vessel.
  • Example 8 shows the use of compound A1 as a precursor for the preparation of the radiofluorinated compound E ) -2-cyano-3- (4 - ((3 - ([ 18 F] fluoro) propyl) (propyl) amino) -2-methoxyphenyl) acrylic acid (compound [ 18 F] FACH) in a one-step synthesis.
  • Scheme 3A illustrates the preparation of (£) -2-cyano-3- (2-methoxy- 4 - ((3 - ((methylsulfonyl) oxy) propyl-l, l, 2,2,3,3- d 6 ) (propyl) amino) phenyl) acrylic acid
  • Compound A l -de is a compound of the general formula (£) - 1, in which AG is -OMs, X is a methyl group, Y + is a hydrogen ion; A 1 is - (CH2) 2- and A 2 is - (CÜ2) 3-.
  • Methanesulfonyl chloride (30 ml, 0.4 mmol, 1.2 equiv.) And Et3N (130 ml, 0.9 mmol, 3 equiv.) Were added to a solution of the compound J (100 mg, 0.3 mmol, 1 equiv.) In 5 ml DCM and the reaction mixture stirred for 30 minutes at room temperature. Then 10 ml of a saturated aqueous NaHCCE- Solution added, the aqueous phase extracted with DCM (2 ⁇ 10 ml) and the combined organic phases washed with aqueous NaCl solution (10 ml) and dried over anhydrous MgSCL. By removing the solvent on a rotary evaporator, compound K could be obtained as a yellowish solid and used in the next synthesis step without further purification.
  • Trifluoroacetic acid 200 ml was added to a solution of K (20 mg, 0.044 mmol) in 200 ml DCM and the reaction mixture was stirred for 2 hours at room temperature. After removing the solvent on a rotary evaporator, the product, compound A1, (21 mg, 0.044 mmol) was obtained as a yellow solid and used for the radiofluorination without further purification.
  • Carrier-free [ 18 F] fluoride in 100 to 400 m ⁇ target water was added to a solution of 50 to 150 m ⁇ / tVra-n-butylammonium hydrogen carbonate solution (TBAHCO3, 0.075 M) in 1 ml of acetonitrile.
  • TBAHCO3, 0.075 M m ⁇ / tVra-n-butylammonium hydrogen carbonate solution
  • the aqueous [ 18 F] fluoride was then dried by means of azeotropic distillation in vacuo and under nitrogen flow over the course of 7 to 12 minutes.
  • a laboratory microwave device 75 W, 50-60 ° C, power cycling mode was used for this.
  • the isolation of the radiotracer [ 18 F] FACH was carried out by means of semi-preparative HPLC (Reprosil-Pur C18-AQ or Reprosil-Gold; 250 ⁇ 10 mm) with 46% acetonitrile / 54% 20 mM aqueous ammonium formate pH 4 as eluent with a flow of 3.5 ml / min.
  • the collected product fraction was finally purified by means of solid phase extraction and the Radiotracer formulated in 0.9% NaCl solution with 10% ethanol. With start activities of approx. 2 GBq, approx. 300 MBq [ 18 F] FACH could be obtained.
  • IC o values for the reference compound (FACH) are shown. The IC o values were determined in order to further demonstrate that the compound [ 18 F] FACH prepared in Example 8 can be obtained in a one-step synthesis by means of the process according to the invention.
  • IC 50 values were as in Gurrapu, loc. a. O., described determined.
  • FIG. 2a shows a PET image obtained with [ 18 F] FACH in a CD-1 mouse.
  • FIG. 2b shows PET images of inhibition experiments which were carried out with ⁇ -cyano-4-hydroxycinnamate (CHC) and FACH. It can be seen that the inhibitory effect of FACH exceeds that of CHC.
  • the PET recordings shown in FIG. 2 are each total images over 60 minutes.
  • the specification "SUV” denotes the standardized uptake value
  • Baseline denotes the baseline.
  • Compound A l -de was synthesized in an analogous manner to compound Al. As shown in Scheme 3A, compound E was used as a starting point.
  • Compound F-do was prepared like compound F in Example 1, except that 3-bromo-1-propanol-do was used instead of 1-iodo-3-hydroxypropanol.
  • Compound G-de was prepared as Compound G in Example 2, except that Compound Fd f was used in place of Compound F.
  • Compound H-de was prepared as compound H in Example 3, except that compound G-de was used in place of compound G.
  • Compound I-de was prepared as Compound I in Example 4, except that Compound H-de was used in place of Compound H.
  • Compound J-de was prepared as Compound J in Example 5, except that Compound I-de was used in place of Compound I.
  • Compound -de was established as Compound K in Example 6, except that Compound J-de was used instead of Compound J.
  • Compound Al -de was prepared as compound Al in Example 7, except that compound -de was used in place of compound K.
  • Compound [ 18 F] FACH-d 6 was prepared like compound [ 18 F] FACH in Example 3, except that compound Al-dr was used in place of compound Al.
  • Compound A5 is an example of a compound according to the invention which has an aryl group as substituent Z 2 .
  • the corresponding connection of the general Formula (Z) -I is (Z) -2-cyano-3- (2-methoxy-4 - ((6-nitropyridin-2-yl) (propyl) amino) phenyl) acrylic acid (Compound A6).
  • 6-nitropyridin-2-amine (M, 3.0 mmol, 1.2 equiv.) was added and the reaction mixture was conducted at 105 ° C. under an argon atmosphere. The reaction was monitored by TLC and stopped after 30 minutes. After cooling to room temperature, the reaction mixture was diluted with diethyl ether (Et 2 O), the solids were filtered and washed with Et 2 O. The solvents were evaporated in vacuo and the oily residue was then purified by column chromatography.
  • CDCI 3 / CD 3 OD d 164.39, 160.51, 156.43, 155.70, 150.30, 148.24, 139.62, 130.62, 118, 14, 117.66, 116, 35, 115.78, 107.90, 107.54, 101.63, 55.82, 52.13, 20.95, 11.16.
  • Carrier-free [ 18 F] fluoride was collected in 1.5 ml of water on a Sep-Pak Accell Plus QMA Carbonate Plus light cartridge (Waters GmbH, Eschborn, Germany). The activity was 400 m ⁇ an aqueous solution of potassium carbonate (K2CO3, 1.8 mg, 13 pmol) in a V-shaped vial of 4 ml, pre-filled with crypto fix ® 2.2.2 (K2. 2. 2, 11 mg , 29 pmol) in 1 ml ACN, eluted.
  • K2CO3 potassium carbonate
  • crypto fix ® 2.2.2 K2. 2. 2, 11 mg , 29 pmol
  • the aqueous [ 18 F] fluoride was azeotroped under vacuum and nitrogen flow within 7-10 min using a single-mode microwave (75 W, at 50-60 ° C, power cycling mode; Discover PETWave from CEM GmbH Kamp-Lintfort, Germany). Two aliquots of ACN (2 x 1.0 ml) were added during the drying process and the final complex was obtained in dried form. A solution of 1.0 mg of compound A5 in 750 ml of DMSO was added, and 18 F labeling was carried out at 130 ° C. To determine the radiochemical yields of the labeling process, samples were taken at different times (5, 10, 15 and 20 minutes) and analyzed by radio-HPLC and radio-TLC.
  • the reaction mixture was diluted with 2.0 ml of aqueous NH4HCO2 (adjusted to pH 4 with formic acid) and 2.0 ml of MeOH / water (1: 1) and directly to an isocratic semi - Preparative RP-HPLC column for the isolation of [ 18 F] Q is applied.
  • the collected fraction was radiotracer with 40 ml of water required for final purification by sorption on a Sep- Pak ® CI 8 light cartridge (Waters GmbH, Eschborn, Germany), washed and then eluted with 1.3 ml of ethanol.
  • the ethanolic solution was concentrated under a gentle stream of argon at 70 ° C. to a final volume of 10-50 ml.
  • the radiotracer was then diluted in isotonic saline to obtain the final target compound [ 18 F] Q, which contains 10% EtOH (v / v).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un composé de formule générale (E)-I ou (Z)-I, Y étant un groupe hydroxy ou un groupe O-M+-, M+ étant un cation ; Z1 étant choisi dans le groupe constitué d'un groupe alkyle en C1-C12 substitué ou non substitué, d'un groupe alcényle en C2-C12 substitué ou non substitué, d'un groupe alcynyle en C2-C12 substitué ou non substitué, d'un groupe aryle substitué ou non substitué, d'un groupe hétéroaryle substitué ou non substitué, d'un groupe alkyle aryle substitué ou non substitué, d'un groupe aryle alkyle substitué ou non substitué et d'un groupe -A1-X, A1 étant une chaîne hydrocarbonée comportant 1 à 4 groupes méthyle substitués ou non substitués, au moins un atome d'oxygène pouvant être disposé dans la chaîne hydrocarbonée pour former un groupe éther, et X étant choisi dans le groupe constitué d'un groupe méthyle, d'un halogène et d'un groupe hydroxy ; et Z2 étant un radical porteur d'un groupe partant AG, Z2 étant choisi dans le groupe constitué d'un groupe alkyle en C1-C12 substitué ou non substitué, d'un groupe alcényle en C2-C12 substitué ou non substitué, d'un groupe alcynyle en C2-C12 substitué ou non substitué, d'un groupe aryle substitué ou non substitué, d'un groupe hétéroaryle substitué ou non substitué, d'un groupe alkyle aryle substitué ou non substitué et d'un groupe aryle alkyle substitué ou non substitué ; ou Z2-AG étant un groupe -A2-AG, A2 étant une chaîne hydrocarbonée comportant 1 à 4 groupes méthyle substitués ou non substitués, au moins un atome d'oxygène pouvant être disposé dans la chaîne hydrocarbonée pour former un groupe éther ; et AG étant choisi dans le groupe constitué d'un hydroxy, de -NO2, de chlore, de brome, d'iode, d'un ion diazonium, d'un sel de diazonium, d'un ion trialkylammonium, d'un sel de trialkylammonium, d'un dialkoxyarène, d'un sulfoxide, d'un acide boronique, d'un ester d'acide boronique, d'un composé organostannique, d'un ion iodonium, d'un sel d'iodonium, d'un ylide d'iodonium et d'un sulfonate.
PCT/EP2020/062772 2019-05-08 2020-05-07 Dérivés de 3-(4-amino-2-méthoxyphényl)-acide 2-cyanoacrylique et leur utilisation en tant que précurseurs pour la production de liaisons radiochimiques WO2020225386A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102019112040.3A DE102019112040A1 (de) 2019-05-08 2019-05-08 3-(4-Amino-2-methoxyphenyl)-2-cyanoacrylsäure-Derivate und deren Verwendung als Präkursoren für die Herstellung radiochemischer Verbindungen
DE102019112040.3 2019-05-08

Publications (1)

Publication Number Publication Date
WO2020225386A1 true WO2020225386A1 (fr) 2020-11-12

Family

ID=70617132

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2020/062772 WO2020225386A1 (fr) 2019-05-08 2020-05-07 Dérivés de 3-(4-amino-2-méthoxyphényl)-acide 2-cyanoacrylique et leur utilisation en tant que précurseurs pour la production de liaisons radiochimiques

Country Status (2)

Country Link
DE (1) DE102019112040A1 (fr)
WO (1) WO2020225386A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013109972A2 (fr) 2012-01-20 2013-07-25 Regents Of The University Of Minnesota Composés thérapeutiques

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0821432D0 (en) * 2008-11-24 2008-12-31 Gen Electric Imaging ligands
WO2015004029A1 (fr) * 2013-07-08 2015-01-15 Technische Universität München Marquage au 18f de molécules aromatiques et hétéroaromatiques contenant des groupements d'acide carboxylique non protégés

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013109972A2 (fr) 2012-01-20 2013-07-25 Regents Of The University Of Minnesota Composés thérapeutiques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GURRAPU SJONNALAGADDA SKALAM MANELSON GLSNEVE MGDREWES LR ET AL.: "In Monocarboxylate transporter 1 inhibitors as potential anticancer agents", ACS MED CHEM LETT, vol. 6, no. 5, 2015, pages 558
MASOUD SADEGHZADEH ET AL: "Development and radiosynthesis of the first 18 F-labeled inhibitor of monocarboxylate transporters (MCTs)", JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, vol. 62, no. 8, 24 April 2019 (2019-04-24), GB, pages 411 - 424, XP055709308, ISSN: 0362-4803, DOI: 10.1002/jlcr.3739 *

Also Published As

Publication number Publication date
DE102019112040A1 (de) 2020-11-12

Similar Documents

Publication Publication Date Title
AU2009278279B2 (en) DAA-pyridine as peripheral benzodiazepine receptor ligand for diagnostic imaging and pharmaceutical treatment
WO2008052788A1 (fr) Acide l-glutamique marqué au [f-18], l-glutamine marquée au [f-18], leurs dérivés et leur utilisation, ainsi que leur procédé de fabrication
EP2231659A1 (fr) Ligands de la protéine de translocation
CN112094259B (zh) 碘(iii)-介导的放射性氟化
WO2017069834A2 (fr) Applications de synthèse organique de solutions de sel de fluorure non aqueuses
EP3481437B1 (fr) Précurseurs de radiofluoration
DE1668420A1 (de) N-substituierte Perfluoralkylsulfonamide
CH634308A5 (de) Verfahren zur herstellung neuer pyrimidonderivate.
DE2359536C2 (de) 2,6-Diaminonebularinderivate
DE4311023A1 (de) Bifunktionelle chalkogenatom-unterbrochene Chelatbildner von Typ XN¶1¶S¶1¶O¶1¶ für radioaktive Isotope, deren Metallkomplexe sowie ihre Verwendung in Diagnostik und Therapie, diese enthaltende pharmazeutische Mittel und Verfahren zu ihrer Herstellung
CN103601645B (zh) 1-(苯乙基氨基)丙烷-2-醇类化合物或其盐的制备方法
WO2008138605A2 (fr) Procédé de production de bromure de n-méthylnaltrexon
WO2020225386A1 (fr) Dérivés de 3-(4-amino-2-méthoxyphényl)-acide 2-cyanoacrylique et leur utilisation en tant que précurseurs pour la production de liaisons radiochimiques
EP0853488A2 (fr) Agents de chelation amidosulfoniques sulfures bifonctionnels du type xsns pour isotopes radioactifs
WO2023202568A1 (fr) Composé de sel d'ammonium quaternaire, son procédé de préparation et son utilisation
WO2020260196A1 (fr) Dérivés de 7-(3-(4-(2-([18f]fluor)éthoxy)phényl)propyl)-2-(furane-2-yl)-7h-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine deutérés
Satyamurthy et al. N-Fluoro lactams: rapid, mild, and regiospecific fluorinating agents
WO2019086074A1 (fr) Dérivés de la 4-(furan-2-yl)-1h-pyrazolo[3,4-d]pyrimidin-6-amine et leur utilisation
DE102006029795A1 (de) Neue Harnstoff-Derivate und deren Verwendungen
DE102011052348B3 (de) Präkursorverbindungen für die Radiosynthese von [18F]Norchlor-fluor-homoepibatidin
WO2022008006A1 (fr) Dérivés de n-(4,5-diméthylthiazolo -2(3h)-ylidène) -2,2,3,3-tétraméthylcyclopropane-1-carboxamide deutérés et tritiés et leur utilisation
DE102018129693B4 (de) Pyrrolopyridin-Derivate und deren Verwendung
DE102019110904B4 (de) N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-acetamid-Derivate und deren Verwendung
DE102010063974B4 (de) Pharmakologische Wirkstoffe und Radiodiagnostika mit 18F-markierter 3-Aryl- oder 3-Heteroaryl-1,2,4-oxadiazoleinheit und Verfahren zu deren Herstellung
EP2890700B1 (fr) Dérivés halogénés de benzoxazine et leur utilisation

Legal Events

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

Ref document number: 20724824

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20724824

Country of ref document: EP

Kind code of ref document: A1