DE102019112040A1 - 3- (4-Amino-2-methoxyphenyl) -2-cyanoacrylic acid derivatives and their use as precursors for the preparation of radiochemical compounds - Google Patents

Abstract

The invention relates to a compound of the general formula (E) -I or (Z) -IworinY is a hydroxyl group or an O-M + group, where M + is a cation; Z1 is selected from the group consisting of a substituted or unsubstituted C1 -C12-alkyl group, a substituted or unsubstituted C2-C12-alkenyl group, a substituted or unsubstituted C2-C12-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 Group -A1-X consists in whichA1 is a hydrocarbon chain with one to four substituted or unsubstituted methylene groups, wherein at least one oxygen atom can 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 Is a hydroxyl group; andZ2 is a radical bearing a leaving group AG, where Z2 is selected from the group consisting of a substituted or unsubstituted C1-C12-alkyl group, a substituted or unsubstituted C2-C12-alkenyl group, a substituted or unsubstituted C2-C12-alkynyl group, a substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted alkylaryl group, and substituted or unsubstituted arylalkyl group; or Z2-AG is a group -A2-AG, in whichA2 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; andAG is selected from the group consisting of a hydroxy, -NO2, halogen, a diazonium ion, a diazonium salt, a trialkylammonium ion, a trialkylammonium salt, a dialkoxyarene, a sulfoxide, a boronic acid, a boronic acid ester, a organotin compound, an iodonium ion, an iodonium salt, an iodonium ylide and a sulfonate.

Description

The invention relates to 3- (4-amino-2-methoxyphenyl) -2-cyanoacrylic acid derivatives, their use as precursors for the preparation of radiochemical compounds and a process for the preparation of the radiochemical compounds.

Out WO 2013/109972 A2 the derivatives of compound B shown below are known which have a functionalized benzene ring. Examples of such derivatives are compounds C and D, also shown below WO 2013/109972 A2 The compounds described are said to be monocarboxylate transporter inhibitors. The compounds described should therefore be suitable as potential anticancer agents. In WO 2013/109972 A2 describes the use of these compounds for the treatment of cancer and autoimmune diseases as well as for therapeutic changes in brain functions.

Monocarboxylate transporters (MCTs) are plasma membrane proteins that catalyze the transport of monocarboxylates such as lactates, pyruvates and ketone bodies across 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. MCT1 is known to be highly expressed in non-hypoxic areas of human colon, 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 IC ₅₀ against MCT1 is 11 nM, the IC ₅₀ against MCT4 6.4 nM.

The by Sadeghzadeh et. al. (Lecture at the 18th Radiochemical Conference, May 13-18, 2018, Marianske Lazne, Czeck Republic) The proposed radiosynthesis of [ ¹⁸ F] FACH should take place via a two-step synthesis using a precursor P-SdT, which has a tert-butyl protective group to protect the OH functionality.

It is therefore desirable to find precursors which enable a one-step synthesis of compounds such as [ ¹⁸ F] FACH and other 18F-labeled 3- (4-amino-2-methoxyphenyl) -2-cyanoacrylic acid derivatives. In this way, compounds such as [ ¹⁸ F] FACH and other 18F-labeled 3- (4-amino-2-methoxyphenyl) -2-cyanoacrylic acid derivatives should be obtained more quickly and in higher yields.

The object of the invention is to eliminate the disadvantages of the prior art. In particular, 3- (4-amino-2-methoxyphenyl) -2-cyanoacrylic acid derivatives are to be specified which are suitable as precursors for the one-step synthesis of radiolabeled compounds. Furthermore, the use of the 3- (4-amino-2-methoxyphenyl) -2-cyanoacrylic acid derivatives as precursors for the synthesis of the radiolabeled compounds and a process for the preparation of the radiolabeled compounds are to be given.

This object is achieved by the features of claims 1, 10 and 13. Expedient configurations of the inventions result from the features of the subclaims.

vorgesehen, worin

• Y eine Hydroxygruppe oder eine O^-M⁺-Gruppe ist, wobei M⁺ ein Kation ist;
• Z¹ aus der Gruppe ausgewählt ist, die aus einer substituierten oder unsubstituierten C₁-C₁₂-Alkylgruppe, einer substituierten oder unsubstituierten C₂-C₁₂-Alkenylgruppe, einer substituierten oder unsubstituierten C₂-C₁₂-Alkinylgruppe, einer substituierten oder unsubstituierten Arylgruppe, einer substituierten oder unsubstituierten Heteroarylgruppe, einer substituierten oder unsubstituierten Alkylarylgruppe, einer substituierten oder unsubstituierten Arylalkylgruppe und einer Gruppe -A¹-X besteht, worin A¹ eine Kohlenwasserstoffkette mit ein bis vier substituierten oder unsubstituierten Methylengruppen ist, wobei in der Kohlenwasserstoffkette zumindest ein Sauerstoffatom unter Ausbildung einer Ethergruppe angeordnet sein kann, und
• X aus der Gruppe ausgewählt ist, die aus einer Methylgruppe, einem Halogen und einer Hydroxygruppe besteht; und
• Z² ein Rest ist, der eine Abgangsgruppe AG trägt, wobei Z² aus der Gruppe ausgewählt ist, die aus einer substituierten oder unsubstituierten C₁-C₁₂-Alkylgruppe, einer substituierten oder unsubstituierten C₂-C₁₂-Alkenylgruppe, einer substituierten oder unsubstituierten C₂-C₁₂-Alkinylgruppe, einer substituierten oder unsubstituierten Arylgruppe, einer substituierten oder unsubstituierten Heteroarylgruppe, einer substituierten oder unsubstituierten Alkylarylgruppe und einer substituierten oder unsubstituierten Arylalkylgruppe besteht; oder Z²-AG eine Gruppe -A²-AG ist, worin
• A² eine Kohlenwasserstoffkette mit ein bis vier substituierten oder unsubstituierten Methylengruppen ist, wobei in der Kohlenwasserstoffkette zumindest ein Sauerstoffatom unter Ausbildung einer Ethergruppe angeordnet sein kann; und
• AG aus der Gruppe ausgewählt ist, die aus einem Hydroxy, -NO₂, Halogen, einem Diazonium-Ion, einem Diazonium-Salz, einem Trialkylammonium-Ion, einem Trialkylammonium-Salz, einem Dialkoxyaren, einem Sulfoxid, einer Boronsäure, einem Boronsäureester, einer zinnorganischen Verbindung, einem Iodonium-Ion, einem Iodonium-Salz, einem Iodonium-Ylid und einem Sulfonat besteht.

According to the invention, a compound of the general formula (E) -I or (Z) -I

provided in which

• 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 C ₁ -C ₁₂ -alkyl group, a substituted or unsubstituted C ₂ -C ₁₂ -alkenyl group, a substituted or unsubstituted C ₂ -C ₁₂ -alkynyl group, a substituted or unsubstituted one Aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkylaryl group, a substituted or unsubstituted arylalkyl group and a group -A ¹ -X, where A ^{1 is} a hydrocarbon chain with one to four substituted or unsubstituted methylene groups, with at least one in the hydrocarbon chain Oxygen atom can be arranged to form an ether group, and
• X is selected from the group consisting of a methyl group, a halogen, and a hydroxy group; and
• Z ^{2 is} a radical which carries a leaving group AG, where Z ² is selected from the group consisting of a substituted or unsubstituted C ₁ -C ₁₂ -alkyl group, a substituted or unsubstituted C ₂ -C ₁₂ -alkenyl group, a substituted or an unsubstituted C ₂ -C ₁₂ 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; and
• AG is selected from the group consisting of a hydroxy, -NO ₂ , halogen, 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 the formula (E) -I and the compounds of the formula (Z) -I are also referred to collectively as compounds of the formula I below. The compounds according to the invention of the formula I include both their (E) and their (Z) isomers. They also include mixtures of the (E) and (Z) isomers.

It can be provided that the groups Z ¹ and Z ² , apart from the leaving group AG, are identical to one another. However, apart from the leaving group AG, they can also be different from one another.

In connection with the radical Z ² , the expression “unsubstituted” means that the radical Z ^{2 has} no further substituents apart from the leaving group AG. In connection with the radical Z ² , 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 which do not belong to the leaving group AG is deuterium (D) or tritium (T).

A substituted methylene group is understood to mean a methylene group in which one or two hydrogen atoms have each been replaced by a branched or unbranched C ₁ - to C ₆ -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 with the formation of an ether group. The methylene groups of the hydrocarbon chain can be substituted or unsubstituted independently of one another. For example, one or more of the methylene groups can be unsubstituted while other methylene groups are substituted. If several substituted methylene groups are present, the methyl groups can be substituted in the same way or in different ways.

In one example, A ¹ and A ² can each independently be - (CH ₂ ) _m - (O) _p - (CH ₂ ) _n -, where p is 0 or 1, m is an integer from 0 to 4, n is one Is an integer from 0 to 4 with the proviso that m + n is 1, 2, 3 or 4. If p is 0, then - (CH ₂ ) _m - (O) _p - (CH ₂ ) _n - is a hydrocarbon chain consisting of one to four unsubstituted methylene units. If p is 1, the hydrocarbon chain contains an ether group. The CH ₂ groups can be unsubstituted or substituted by one or two branched or unbranched C ₁ - to C ₆ -alkyl groups.

It can be provided that A ¹ and A ^2, independently of one another, are each a hydrocarbon chain with one to four unsubstituted methylene groups that does not contain any oxygen atoms.

It can be provided that 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 the preparation of a radiolabeled compound 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.

Compounds of the general formula I in which Y is a hydroxyl group have a carboxy group. The carboxy group forms an acid function that is neutral in relation to its charge. In the case of compounds of the general formula I in which Y is an O ^- M ⁺ group, the acid function which is formed by the C (O) O ^- M ⁺ unit can be present as a salt. M ⁺ denotes a cation. The cation can be, for example, an alkali metal ion. A preferred cation is selected from the group consisting of a sodium ion, a potassium ion and a lithium ion. In a preferred embodiment, Y is a hydroxyl group or an O ^- M ⁺ group in which M ^{+ is} a sodium ion, a potassium ion or a lithium ion.

It can be provided that AG is a sulfonate. The term “sulfonate” is understood to mean an R ^S —SO ₂ —O group. R ^S can be, for example, a branched or unbranched substituted or unsubstituted C ₁ -C ₆ -alkyl group, an aryl group or an alkylaryl group. Preferably R ^{S is} CH ₃ -, CF ₃ - or CH ₃ -C ₆ H ₄ -. The sulfonate can be selected, for example, from the group consisting of a toluenesulfonic acid ester group, a methylsulfonic acid ester group and a trifluoromethylsulfonic acid ester group. A toluenesulfonic 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 CF ₃ —SO ₂ —O—. Preferably AG is -OMs or -OTs. AG -OMs is particularly preferred.

It can be provided that AG is an organotin compound. This can be a tin organyl. The organotin compound can be, for example, alkyltin, the alkyl group (s) of which can be substituted or unsubstituted, one or more of the alkyl groups optionally having one or more heteroatoms, or aryltin, whose aryl group (s) can be substituted or unsubstituted, where one or more of the aryl groups optionally have one or more heteroatoms.

It can be provided that AG is a halogen. The halogen can be selected from the group consisting of fluorine, chlorine, bromine and iodine. The halogen is preferably selected from the group consisting of chlorine, bromine and iodine.

In one embodiment of the invention, a compound of the general formula (E) -IA and (Z) -IA is provided in which Z ^{1 is} -A ¹ -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 (E) -I and (Z) -I.

In one embodiment of the invention, a compound of the general formula (E) -IA and (Z) -IA is provided, in which X, Y, A ¹ and A ^{2 are} the in connection with formula (E) -I and (Z) - I have given meanings and AG is selected from the group consisting of a sulfonate, a halogen or an organotin compound.

It can be provided that 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).

• AG -OMs oder Halogen, bevorzugt -OMs ist;
• X eine Methylgruppe ist;
• Y ein Hydroxygruppe ist;
• A¹ -(CH₂)₂- ist; und
• A² -(CH₂)₃- ist.

In one embodiment, the invention relates to a compound of the general formula (E) -IA or (Z) -IA, in which

• AG is -OMs or halogen, preferably -OMs;
• X is a methyl group;
• Y is a hydroxy group;
• A ^{1 is} - (CH ₂ ) ₂ -; and
• A ^{2 is} - (CH ₂ ) ₃ -.

(E)-2-Cyano-3-(2-methoxy-4-((3-((methylsulfonyl)oxy)-propyl)(propyl)amino )phenyl)-acrylsäure; A2

(Z)-2-Cyano-3-(2-methoxy-4-((3-((methylsulfonyl)oxy)-propyl)(propyl)amino )phenyl)-acrylsäure; A3

(E)-2-Cyano-3-(2-methoxy-4-(propyl(3 -(tosyloxy)propyl)-amino)phenyl)acrylsäure A4

(Z)-2-Cyano-3-(2-methoxy-4-(propyl(3 -(tosyloxy)propyl)-amino)phenyl)acrylsäure. Preferred examples of compounds represented by the general formula (E) -IA or (Z) -IA are shown below Table 1 given. Table 1 connection structure Surname A1

(E) -2-cyano-3- (2-methoxy-4 - ((3 - ((methylsulfonyl) oxy) propyl) (propyl) amino) phenyl) acrylic acid; A2

(Z) -2-cyano-3- (2-methoxy-4 - ((3 - ((methylsulfonyl) oxy) propyl) (propyl) amino) phenyl) acrylic acid; A3

(E) -2-cyano-3- (2-methoxy-4- (propyl (3 - (tosyloxy) propyl) -amino) phenyl) acrylic acid A4

(Z) -2-Cyano-3- (2-methoxy-4- (propyl (3 - (tosyloxy) propyl) -amino) phenyl) acrylic acid.

Another preferred example is a mixture of compounds A1 and connection A2 . Another preferred example is a mixture of compound A3 and connection A4 . A particularly preferred connection is connection A1 .

• Z¹ aus der Gruppe ausgewählt ist, die aus einer substituierten oder unsubstituierten C₂-C₁₂-Alkenylgruppe, einer substituierten oder unsubstituierten C₂-C₁₂-Alkinylgruppe, einer substituierten oder unsubstituierten Arylgruppe und einer substituierten oder unsubstituierten Heteroarylgruppe besteht;
• Z² ein Rest ist, der eine Abgangsgruppe AG trägt, wobei Z² aus der Gruppe ausgewählt ist, die aus einer einer substituierten oder unsubstituierten C₂-C₁₂-Alkenylgruppe, einer substituierten oder unsubstituierten C₂-C₁₂-Alkinylgruppe und einer substituierten oder unsubstituierten Arylgruppe, besteht; und
• Y und AG die in Zusammenhang mit Formel (E)-I und (Z)-I angegebenen Bedeutungen haben.

In another embodiment, a compound of the general formula (E) -I or (Z) -I is provided in which

• Z ¹ is selected from the group consisting of a substituted or unsubstituted C ₂ -C ₁₂ alkenyl group, a substituted or unsubstituted C ₂ -C ₁₂ alkynyl group, a substituted or unsubstituted aryl group and a substituted or unsubstituted heteroaryl group;
• Z ^{2 is} a radical which carries a leaving group AG, where Z ² is selected from the group consisting of a substituted or unsubstituted C ₂ -C ₁₂ alkenyl group, a substituted or unsubstituted C ₂ -C ₁₂ alkynyl group and a substituted one or unsubstituted aryl group; and
• Y and AG have the meanings given in connection with formula (E) -I and (Z) -I.

• Z¹ aus der Gruppe ausgewählt ist, die aus Allyl, Propargyl, Phenyl und Pyridyl besteht, wobei Phenyl und Pyridyl besonders bevorzugt sind;
• Z² ein Rest ist, der eine Abgangsgruppe AG trägt, wobei Z² aus der Gruppe ausgewählt ist, die aus Allyl, Propargyl, Phenyl und Pyridyl besteht, wobei Phenyl und Pyridyl besonders bevorzugt sind; und
• Y und AG die in Zusammenhang mit Formel (E)-I und (Z)-I angegebenen Bedeutungen haben.

In one embodiment, a compound of the general formula (E) -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; and
• Y and AG have the meanings given in connection with formula (E) -I and (Z) -I.

• Z¹ aus der Gruppe ausgewählt ist, die aus einer substituierten oder unsubstituierten C₁-C₁₂-Alkylgruppe, einer substituierten oder unsubstituierten C₂-C₁₂-Alkenylgruppe, einer substituierten oder unsubstituierten C₂-C₁₂-Alkinylgruppe, einer substituierten oder unsubstituierten Arylgruppe, einer substituierten oder unsubstituierten Heteroarylgruppe, einer substituierten oder unsubstituierten Alkylarylgruppe, einer substituierten oder unsubstituierten Arylalkylgruppe und einer Gruppe -A¹-X besteht, worin
• A¹ eine Kohlenwasserstoffkette mit ein bis vier substituierten oder unsubstituierten Methylengruppen ist, wobei in der Kohlenwasserstoffkette zumindest ein Sauerstoffatom unter Ausbildung einer Ethergruppe angeordnet sein kann, und
• X aus der Gruppe ausgewählt ist, die aus einer Methylgruppe, einem Halogen und einer Hydroxygruppe besteht; und
• Z² ein Rest ist, der eine Abgangsgruppe AG trägt, wobei Z² eine substituierte oder unsubstituierte Arylgruppe oder eine substituierte oder unsubstituierte Heteroarylgruppe ist, vorzugsweise Phenyl oder Pyridyl ist;
• Y die in Zusammenhang mit Formel (E)-I und (Z)-I angegebene Bedeutung hat; und
• AG aus der Gruppe ausgewählt ist, die aus -NO₂, einem Halogen, einem Diazonium-Ion, einem Diazonium-Salz, einem Trialkylammonium-Ion, einem Trialkylammonium-Salz, einem Dialkoxyaren, einem Sulfoxid, einer Boronsäure, einem Boronsäureester, Alkylzinn, Arylzinn, einem Iodonium-Ion, einem Iodonium-Salz und einem Iodonium-Ylid besteht.

In one embodiment, a compound of the general formula (E) -I or (Z) -I is provided in which

• Z ¹ is selected from the group consisting of a substituted or unsubstituted C ₁ -C ₁₂ -alkyl group, a substituted or unsubstituted C ₂ -C ₁₂ -alkenyl group, a substituted or unsubstituted C ₂ -C ₁₂ -alkynyl group, a substituted or unsubstituted one Aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkylaryl group, a substituted or unsubstituted arylalkyl group and a group -A ¹ -X, in which
• 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 hydroxy group; and
• 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 heteroaryl group, preferably phenyl or pyridyl;
• Y has the meaning given in connection with formula (E) -I and (Z) -I; and
• AG is selected from the group consisting of -NO ₂ , a halogen, a diazonium 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.

• Z¹ Phenyl oder Pyridyl ist;
• Z² ein Rest ist, der eine Abgangsgruppe AG trägt, wobei Z² Phenyl oder Pyridyl ist;
• Y die in Zusammenhang mit Formel (E)-I und (Z)-I angegebene Bedeutung hat; und
• AG aus der Gruppe ausgewählt ist, die aus -NO₂, einem Halogen, einem Diazonium-Ion, einem Diazonium-Salz, einem Trialkylammonium-Ion, einem Trialkylammonium-Salz, einem Dialkoxyaren, einem Sulfoxid, einer Boronsäure, einem Boronsäureester, Alkylzinn, Arylzinn, einem Iodonium-Ion, einem Iodonium-Salz und einem Iodonium-Ylid besteht.

In one embodiment, a compound of the general formula (E) -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 (E) -I and (Z) -I; and
• AG is selected from the group consisting of -NO ₂ , a halogen, a diazonium 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.

An example of a boronic acid ester is 2,4,4,5,5-pentamethyl-1,3,2-dioxaborolane. Preferred iodonium ylides are sterically hindered spirocyclic iodonium ylides.

The term “halogen” refers to fluorine, chlorine, bromine or iodine unless otherwise specified.

Unless stated otherwise, the term “alkyl” 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. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like. The alkyl 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.

Unless otherwise stated, the term “heteroalkyl” relates 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 (O) _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, alkyl, cycloalkyl or cycloalkylalkyl is; 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, amino, acylamino, monoalkylamino or dialkylamino. 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.

Unless stated otherwise, the term “cycloalkyl” relates 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. Examples of 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.

Unless otherwise stated, the term “alkenyl” relates 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, which contain at least one has an olefinic double bond and more preferably has a single double bond. Examples of 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 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.

The term “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, the at least one has an olefinic triple bond and more preferably has a single triple bond. Examples of alkynyl groups include, but are not limited to, acetylenyl, propargyl, n-but-2-yn-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.

Unless otherwise indicated, the term “alkoxy” relates in particular to a group of the formula -OR, where R is an alkyl group, as defined herein. Examples of alkoxy components include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like. The alkoxy 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.

Unless otherwise stated, the term “aryl” relates to a cyclic, aromatic hydrocarbon group consisting of a mono-, bi- or tricyclic aromatic ring system with 5 to 10 ring atoms, preferably 5 or 6 ring atoms. The aryl group may optionally be a substituted aryl group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, adamantyl, naphthalenyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, benzo-pyioxanyl, benzofo-oxanyl, benzo-pyioxanyl, benzo-pyioxanyl, benzo-pyioxanyl, benzo-dioxanyl, benzo-pyioxanyl, fluorenyl, indenyl, phenanthryl, Benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl and the like, including partially hydrogenated derivatives thereof. A preferred example is phenyl. The term “substituted aryl group” relates in particular to an aryl group which may 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 from 0 to 5, R 'and R "are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl) or - (CR'R") _n -CONR ^{a '} R ^b' (where n is an integer from 0 to 5, R 'and R''are independently hydrogen or alkyl and R ^a' and R ^{b 'are} independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), is substituted.

Unless stated otherwise, the term “heteroaryl” relates in particular to a monocyclic, bicyclic or tricyclic group having 5 to 12 ring atoms, at least one aromatic ring containing one, two or three ring heteroatoms selected from N, O or S where the remaining ring atoms are C. The heteroryl group can optionally be a substituted heteroaryl group. Examples of heteroaryl groups include, but are not limited to, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl, thiophenyl, furanyl, pyranyl, pyridyl, quinoline, quininyl, pyrazolyl, pyrimidyl, quininyl Benzofuranyl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, indazolyl, triazolyl, triazinyl, quinoxalinyl, the like, pazolecinyl, azolecinyl, azolepinyl, azolepinyl, azolecinyl, azolepinyl, azolepinyl, azolepinyl, azolepinyl, and the like, naphidyridiazolinyl, naphidyridiazolinyl, naphidyridiazinyl, the like, naphidyridiazolinyl, A preferred example is pyridinyl. The term “substituted heteraryl group” relates in particular to a heteroaryl group which may 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 from 0 to 5 is, R 'and R "are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl) or - (CR'R") _n -CONR ^a' R ^{b '} (wherein n is an integer from 0 to 5, R 'and R''are independently hydrogen or alkyl and R ^a' and R ^{b 'are} independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl).

Unless stated otherwise, the term “acyl” relates in particular to a group of the formula -C (= O) R, where R is hydrogen or alkyl, as defined herein.

Unless otherwise stated, the term “arylalkyl” relates 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. The term “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. Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, butylene, and the like. The alkylene 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.

Unless otherwise stated, the term “alkylaryl” relates 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. Examples of alkylaryl groups include, but are not limited to, o-tolyl, m-tolyl, p-tolyl, o-tert-butylphenyl, m-tert-butylphenyl, p-tert-butylphenyl, and the like.

The expression “at least one oxygen atom can be arranged in the hydrocarbon chain with the formation of an ether group” means that either no oxygen atom or at least one oxygen atom is arranged in the hydrocarbon chain with the formation of an ether group.

A process for the preparation of the compounds of the general formula (E) -I or (Z) -I is shown in Scheme 1. In the compounds of the general formula III, IV and V, 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 (E) -I, where Y is a hydroxyl group. The method is based on that described by Gurrapu S, Jonnalagadda SK, Alam MA, Nelson GL, Sneve MG, Drewes LR, et al. In Monocarboxylate transporter 1 inhibitors as potential anticancer agents. ACSMed Chem Lett 2015; 6 (5): 558, method described based on. The process is both for the preparation of the (E) isomer and the (Z) isomers suitable. The COOH group of the compound of the general formula V can be converted into a —COO ^— M ⁺ group in a subsequent step.

In step (a), 3-methoxyaniline (2) is converted into a compound of the general formula III by converting the primary amino group into a tertiary amino group by double alkylation. For this purpose, compound 2 (i) with Z ¹ X ¹ , where Z ^{1 has} the meaning given in connection with the general formula (E) -I or (Z) -I and X ^{1 is} fluorine, bromine, chlorine or iodine, preferably bromine , and then (ii) with Z ² X ² , where Z ^{2 has} the meaning given in connection with the general formula (E) -I or (Z) -I and X ^{2 is} fluorine, bromine, chlorine or iodine, preferably Iodine, is to be implemented. The reaction can be carried out in the presence of an inorganic salt such as K ₂ CO ₃ and in an organic solvent such as acrylonitrile. The reaction can take place at temperatures above room temperature, preferably under reflux.

In 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. For this purpose, the compound of the general formula III can be reacted with dimethylformamide (DMF) in the presence of phosphorus oxychloride (POCl ₃ ). The reaction can be carried out at temperatures above room temperature, for example at 80.degree.

In 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. For this purpose, 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 reaction can take place at temperatures above room temperature, preferably under reflux.

The following 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 those in connection with Scheme 1 explained steps (a), (b) and (c).

In step (a) 3-methoxyaniline (2) is converted to N- (3-fluoropropyl) -3-methoxy-N-propylaniline (3) (i) with Br (CH ₂ ) ₃ and then (ii) with I (CH ₂ ) ₃ F implemented. The reaction can be carried out in the presence of an inorganic salt such as K ₂ CO ₃ and in an organic solvent such as acrylonitrile. The reaction can take place at temperatures above room temperature, preferably under reflux.

In step (b) N- (3-fluoropropyl) -3-methoxy-N-propylaniline (3) is converted to 4 - ((3-fluoropropyl) (propyl) amino) -2-methoxybenzaldehyde (4). The reaction 3-methoxy-N-propylaniline (3) reacted with dimethylformamide (DMF) in the presence of phosphorus oxychloride (POCl ₃ ). The reaction can be carried out at temperatures above room temperature, for example at 80.degree.

In step (c) 4 - ((3-fluoropropyl) (propyl) amino) -2-methoxybenzaldehyde (4) is converted to FACH. The conversion can take place by means of a base-mediated condensation. For this purpose, 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 take place at temperatures above room temperature, preferably under reflux.

vorgesehen, worin

• Y eine Hydroxygruppe oder eine O^-M⁺-Gruppe ist, wobei M⁺ ein Kation ist;
• Z¹ aus der Gruppe ausgewählt ist, die aus einer substituierten oder unsubstituierten C₁-C₁₂-Alkylgruppe, einer substituierten oder unsubstituierten C₂-C₁₂-Alkenylgruppe, einer substituierten oder unsubstituierten C₂-C₁₂-Alkinylgruppe, einer substituierten oder unsubstituierten Arylgruppe, einer substituierten oder unsubstituierten Heteroarylgruppe, einer substituierten oder unsubstituierten Alkylarylgruppe, einer substituierten oder unsubstituierten Arylalkylgruppe und einer Gruppe -A¹-X besteht, worin
• A¹ eine Kohlenwasserstoffkette mit ein bis vier substituierten oder unsubstituierten Methylengruppen ist, wobei in der Kohlenwasserstoffkette zumindest ein Sauerstoffatom unter Ausbildung einer Ethergruppe angeordnet sein kann, und
• X aus der Gruppe ausgewählt ist, die aus einer Methylgruppe, einem Halogen und einer Hydroxygruppe besteht; und
• Z² ein Rest ist, der [¹⁸F]Fluorid trägt, wobei Z² aus der Gruppe ausgewählt ist, die aus einer substituierten oder unsubstituierten C₁-C₁₂-Alkylgruppe, einer substituierten oder unsubstituierten C₂-C₁₂-Alkenylgruppe, einer substituierten oder unsubstituierten C₂-C₁₂-Alkinylgruppe, einer substituierten oder unsubstituierten Arylgruppe, einer substituierten oder unsubstituierten Heteroarylgruppe, einer substituierten oder unsubstituierten Alkylarylgruppe und einer substituierten oder unsubstituierten Arylalkylgruppe besteht; oder Z²-[¹⁸F]F eine Gruppe -A²-[¹⁸F]F ist, worin
• A² eine Kohlenwasserstoffkette mit ein bis vier substituierten oder unsubstituierten Methylengruppen ist, wobei in der Kohlenwasserstoffkette zumindest ein Sauerstoffatom unter Ausbildung einer Ethergruppe angeordnet sein kann.

According to the invention, the use of a compound of the general formula (E) -I or (Z) -I as a precursor for the preparation of a compound of the general formula (E) -II or (Z) -II is also possible

provided in which

• 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 C ₁ -C ₁₂ -alkyl group, a substituted or unsubstituted C ₂ -C ₁₂ -alkenyl group, a substituted or unsubstituted C ₂ -C ₁₂ -alkynyl group, a substituted or unsubstituted one Aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkylaryl group, a substituted or unsubstituted arylalkyl group and a group -A ¹ -X, in which
• 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 hydroxy group; and
• Z ^{2 is} a radical which carries [ ¹⁸ F] fluoride, where Z ² is selected from the group consisting of a substituted or unsubstituted C ₁ -C ₁₂ -alkyl group, a substituted or unsubstituted C ₂ -C ₁₂ -alkenyl group, a substituted or unsubstituted C ₂ -C ₁₂ 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 (E) -II and compounds of the formula (Z) -II are also jointly referred to below as compounds of the formula II. The compounds of the formula II according to the invention include both their (E) and their (Z) isomers. They also include mixtures of the (E) 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.

To prepare a compound of the general formula (E) -II, a compound of the general formula (E) -I is used. To prepare a compound of the general formula (Z) -II, a compound of the general formula (Z) -I is used.

Compounds of the general formula II are ¹⁸ F-labeled compounds which can be used as radiopharmaceuticals, for example as radiotracers. In particular, 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). A compound of the general formula (II) can be used as a medicament for the diagnosis and therapy of 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. kidneys, liver, pancreas, intestines, lungs and brain can be used. The compounds of the general formula II are compounds which inhibit the expression of MCT, in particular of MCT1 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 MCT1 and MCT4.

The compounds of general formula I according to the invention are thus precursors for the radiosynthesis of radiopharmaceuticals of general formula II, for example from Radipharmka 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 the suitability of compounds of the general formula II for nuclear medicine imaging preclinically and clinically.

worin X, Y, A¹ und A² wie im Zusammengang mit der allgemeinen Formel (E)-IA oder (Z)-IA angegeben definiert sind. Zur Herstellung einer Verbindung der allgemeinen Formel (E)-IIA kann eine Verbindung der allgemeinen Formel (E)-IA eingesetzt werden. Zur Herstellung einer Verbindung der allgemeinen Formel (Z)-IIA kann eine Verbindung der allgemeinen Formel (Z)-IA eingesetzt werden.In one embodiment, the use of a compound of the general formula (E) -IA or (Z) -IA is provided as a precursor for the preparation of a compound of the general formula (E) -IIA or (Z) -IIA:

wherein X, Y, A ¹ and A ² are defined as indicated in connection with the general formula (E) -IA or (Z) -IA. A compound of the general formula (E) -IA can be used to prepare a compound of the general formula (E) -IIA. A compound of the general formula (Z) -IA can be used to prepare a compound of the general formula (Z) -IIA.

In a preferred example of a compound of the general formula (E) -IIA, X is a methyl group, Y is a hydroxyl group, A ¹ - (CH ₂ ) ₂ - and A ² - (CH ₂ ) ₃ -. This compound can be (E) -2-cyano-3- (4 - ((3 - ([ ¹⁸ F] fluoro) propyl) - (propyl) amino) -2-methoxyphenyl) acrylic acid ([ ¹⁸ F] FACH) act.

• (E)-2-Cyano-3-(2-methoxy-4-((3-((methylsulfonyl)oxy)propyl)(propyl)amino)-phenyl)acrylsäure;
• (Z)-2-Cyano-3-(2-methoxy-4-((3-((methylsulfonyl)oxy)propyl)(propyl)amino)-phenyl)acrylsäure;
• (E)-2-Cyano-3-(2-methoxy-4-(propyl(3-(tosyloxy)propyl)amino)phenyl)acrylsäure; oder
• (Z)-2-Cyano-3-(2-methoxy-4-(propyl(3-(tosyloxy)propyl)amino)phenyl)acrylsäure.

To prepare the compound [ ¹⁸ F] FACH or its (Z) isoform, one of the following compounds can be used as a precursor, for example:

• (E) -2-cyano-3- (2-methoxy-4 - ((3 - ((methylsulfonyl) oxy) propyl) (propyl) amino) phenyl) acrylic acid;
• (Z) -2-cyano-3- (2-methoxy-4 - ((3 - ((methylsulfonyl) oxy) propyl) (propyl) amino) phenyl) acrylic acid;
• (E) -2-cyano-3- (2-methoxy-4- (propyl (3- (tosyloxy) propyl) amino) phenyl) acrylic acid; or
• (Z) -2-Cyano-3- (2-methoxy-4- (propyl (3- (tosyloxy) propyl) amino) phenyl) acrylic acid.

vorgesehen, wobei eine Verbindung der allgemeinen Formel (E)-I oder (Z)-I

in Gegenwart eines [¹⁸F]-Fluorid-Anions und eines Phasentransferkatalysators zu einer Verbindung der allgemeinen Formel (E)-II oder (Z)-II umgesetzt wird.The invention also provides a process for the preparation of a compound of the general formula (E) -II or (Z) -II

provided, wherein a compound of the general formula (E) -I or (Z) -I

in the presence of an [ ¹⁸ F] fluoride anion and a phase transfer catalyst to give a compound of the general formula (E) -II or (Z) -II.

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, X, Y, Z ¹ , Z ² , A ¹ and A ² can therefore be found in the information on the compounds of general formula I according to the invention.

To prepare a compound of the general formula (E) -II, a compound of the general formula (E) -I is used. To prepare a compound of the general formula (Z) -II, a compound of the general formula (Z) -I is used.

In one embodiment of the process according to the invention, a compound of the general formula (E) -IA or (Z) -IA is converted into a compound of the general formula (E) -IIA or (Z) -IIA. A compound of the general formula (E) -IA can be used to prepare a compound of the general formula (E) -IIA. A compound of the general formula (Z) -IA can be used to prepare a compound of the general formula (Z) -IIA.

The process according to the invention can be a one-step process. The process according to the invention thus enables a one-step radiosynthesis of compounds of the general formula II. The compounds of the general formula can be radiopharmaceuticals, for example radiotracers. These compounds can be prepared significantly more efficiently and in a considerably shorter synthesis time by means of the process according to the invention. In addition to the development of a radiopharmaceutical, this allows access to novel drugs and makes an important contribution to them Evaluation. The method according to the invention 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, that is to say 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.

It can be provided that a phase transfer catalyst with a cation with the general formula N ⁺ (R ¹ R ² R ³ R ⁴ ) is selected for the activation and for the phase transfer of the [18F] fluoride, where R ¹ , R ² , R ³ and R ^{4 are} identical to or different from one another and are each unsubstituted or substituted C ₁ -C ₆ -alkyl. Preferably 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 each n-butyl. It can be provided that the phase transfer catalyst has an anion 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-n-butyl ammonium hydrogen carbonate. A phase transfer catalyst which has the cation tetra-n-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. In the phase transfer catalyst, the cation with the general formula N ⁺ (R ¹ 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 using known methods. For example, the [ ¹⁸ F] fluoride anion is produced in the cyclotron by irradiating at least 97% enriched H ₂ ¹⁸ O 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. A [2,2,2] cryptand (Kryptofix® or K222), tetra-n-butyl ammonium phosphate, hydroxide, oxalate, toluene sulfonate, or optionally other crown ethers such as 18-crown-6 are preferably used as PTC. After azeotropic drying in vacuo, 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 alternatively 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 control 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 method according to the invention is preferably carried out for a period of 1 to 60 minutes, more preferably 5 to 30 minutes and particularly preferably 10 to 20 minutes.

The method according to the invention can also be carried out as a microwave-assisted reaction. For this purpose, 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.

• 1 HPLC-Chromatogramme zum Nachweis der Produktreinheit von [¹⁸F]FACH; und
• 2 mittels PET erhaltene Aufnahmen zur Veranschaulichung der Wirkungen von [¹⁸F]FACH (2a) und FACH (2b).

The invention is explained in more detail below using exemplary embodiments, which are not intended to restrict the invention, with reference to the drawings. Show it

• 1 HPLC chromatograms to demonstrate the product purity of [ ¹⁸ F] FACH; and
• 2 Images obtained with PET to illustrate the effects of [ ¹⁸ F] FACH ( 2a) and FACH ( 2 B) .

Examples 1 to 7 describe the preparation of (E) -2-cyano-3- (2-methoxy-4 - ((3 - ((methylsulfonyl) oxy) propyl) (propyl) amino) phenyl) acrylic acid (compound A1 ) shown. Compound A1 is a compound of the general formula (E) -I in which AG is -OMs, X is a methyl group, Y ^{+ is} a hydrogen ion; A ^{1 is} - (CH ₂ ) ₂ - and A ^{2 is} - (CH ₂ ) ₃ -. Scheme 3 shows the synthetic route that was used to prepare compound A1. It should be noted that compound K corresponds to compound P-SdT mentioned in connection with the prior art.

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.

The structures of the compounds F to K and A1 shown in scheme 3 were confirmed by ¹ H-NMR, ¹³ C-NMR, ¹⁹ F-NMR and ESI mass spectroscopy. Compounds F through K were prepared as described in connection with Scheme 1.

Example 1 3 - ((3-Methoxyphenyl) (propyl) amino) propan-1-ol (Compound F)

1-Bromopropane (28 mmol) and potassium carbonate (50 mmol) were added to a solution of m-anisidine (20 mmol) in 50 ml of acetonitrile and the reaction mixture was refluxed overnight. After the reaction was complete, 100 ml of a 5% aqueous NaHCO ₃ solution were added and the reaction mixture was extracted with ethyl acetate (EA) (3 × 50 ml). The organic phase was then dried with anhydrous Mg ₂ SO ₄ and the solvent was removed on a rotary evaporator. The residue was purified by column chromatography (silica gel, EA / IH = 0.5: 9.5 up to 1: 9) and the monoalkylated aniline (compound E) was obtained in a yield of 52% [(TLC (silica gel, EA / IH , 2: 8): R _f = 0.65].

1-iodo-3-hydroxypropane (20 mmol) and potassium carbonate (30 mmol) were added to a solution of 3-methoxy-N-propylaniline (E, 11 mmol) in 50 ml of acetonitrile and the reaction mixture was refluxed overnight. After the completion of the reaction, 100 ml of a 5% aqueous NaHCO ₃ solution were added and the reaction mixture was extracted with ethyl acetate (3 × 50 ml). The organic phase was then dried with anhydrous Mg ₂ SO ₄ and the solvent was removed on a rotary evaporator. 3 - [(3-Methoxyphenyl) (propyl) amino] propan-1-ol (F) was obtained as a yellow oil in 88% yield.

TLC (silica gel, EA / IH, 2: 8): R _f = 0.19. ¹ H NMR (400 MHz, chloroform-d) δ 7.15 (t, J = 8.1 Hz, 1H), 6.38 (dd, J = 8.4, 2.4 Hz, 1H), 6 , 34-6.10 (m, 2H), 3.82 (s, 3H), 3.74 (t, J = 6.0 Hz, 2H), 3.44 (t, J = 7.1 Hz, 2H), 3.34-3.16 (m, 2H), 2.03 (s, 1H), 1.91-1.76 (m, 2H), 1.64 (h, J = 7.4 Hz , 2H), 0.95 (t, 1 = 7.4 Hz, 3H). ¹³ C NMR (101 MHz, chloroform-d) δ 160.87, 149.59, 129.91, 105.84, 100.60, 99.25, 60.81, 55.12, 53.28, 48 , 13, 30.15, 20.29, 11.46.

Example 2 3 - ((3-Methoxyphenyl) (propyl) amino) propyl acetate (Compound G)

Acetyl chloride (0.8 ml, 16.5 mmol, 1.5 equiv.) And pyridine (1.7 ml, 33 mmol, 3 equiv.) Were added to a solution of compound F in 50 ml of dichloromethane (DCM) (2 , 5 g, 11 mmol, 1 equiv.) And the reaction mixture was stirred overnight at room temperature. After 50 ml of ice-cold water had been added, the phases were separated and the organic phase was dried over anhydrous Mg ₂ SO ₄ . The solvent was then removed on a rotary evaporator and compound G was obtained as a yellowish oil, which was used in the next reaction step without further purification.

TLC (silica gel, EA / IH, 2: 8): R _f = 0.55. ¹ H-NMR (400 MHz, chloroform-d) δ 7.14 (t, J = 8.1 Hz, 1H), 6.46-6.07 (m, 3H), 4.14 (t, J = 6.3 Hz, 2H), 3.81 (s, 3H), 3.39 (t, J = 7.3 Hz, 2H), 3.24 (t, J = 7.7 Hz, 2H), 2 , 10 (s, 3H), 1.95 (t, J = 7.1 Hz, 2H), 1.63 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). ¹³ C NMR (101 MHz, chloroform-d) δ 171.08, 160.91, 149.32, 129.92, 105.33, 100.30, 98.83, 62.38, 55.10, 53 , 13, 47.72, 26.55, 20.97, 20.43, 11.44.

Example 3 3 - ((4-Formyl-3-methoxyphenyl) (propyl) amino) propyl acetate (Compound H)

POCl ₃ (11 mmol) was added dropwise at 0 ° C. to a solution of compound G (10 mmol) in 60 ml of dimethylformamide, and the reaction mixture was refluxed (80 ° C.) for 2 to 4 hours. Saturated aqueous Na ₂ CO ₃ solution was then added to the solution, and the solid was filtered off and washed with n-hexane. Compound H was obtained quantitatively as a yellow oil.

TLC (silica gel, EA / IH, 2: 8): R _f = 0.11. ¹ H-NMR (400 MHz, chloroform-d) δ 10.19 (s, 1H), 7.76 (d, J = 8.9 Hz, 1H), 6.39 (dd, J = 8.9, 2.3 Hz, 1H), 6.29 (s, 1H), 4.16 (t, J = 6.2 Hz, 2H), 3.93 (s, 3H), 3.57-3.42 ( m, 2H), 3.42-3.25 (m, 2H), 2.10 (s, 3H), 2.01 (m, 2H), 1.71 (m, 2H), 0.99 (t , J = 7.4 Hz, 3H).

Example 4 4 - ((3-Hydroxypropyl) (propyl) amino) -2-methoxybenzaldehyde (Compound I)

A solution of K ₂ CO ₃ (7 g, 50 mmol, 5 equiv.) In 70 ml of H ₂ O was added to a solution of compound H (2.5 g, 10 mmol, 1 equiv.) In 75 ml of methanol and the reaction mixture was stirred for 30 minutes at room temperature. Then 50 ml of a saturated aqueous NaCl solution and 100 ml DCM were added. The phases were separated and the organic phase was dried with anhydrous Mg ₂ SO ₄ . After removing the solvent on a rotary evaporator, it was possible to obtain compound I as a yellowish oil, which was used for the next reaction step without further purification.

TLC (silica gel, EA / IH, 1: 1): R _f = 0.15. ¹ H NMR (400 MHz, chloroform-d) δ 10.16 (s, 1H), 7.73 (d, J = 8.9 Hz, 1H), 6.38 (d, J = 9.0 Hz , 1H), 6.28 (s, 1H), 3.91 (s, 3H), 3.76 (t, J = 5.8 Hz, 2H), 3.57 (t, J = 7.3 Hz , 2H), 3.36 (dd, J = 8.6, 6.9 Hz, 2H), 1.97-1.84 (m, 2H), 1.70 (h, J = 7.5 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H).

Example 5 tert-Butyl- (E) -2-cyano-3- (4 - ((3-hydroxypropyl) (propyl) amino) -2-methoxyphenyl) acrylate (Compound J)

Tert-butyl cyanoacetate (15 mmol) and piperidine (5 mmol) were added to a solution of compound I (5 mmol) in 20 ml of acetonitrile, and the reaction mixture was heated under reflux (80 ° C.) overnight. After conversion was complete, the solution was poured into a mixture of 3M HCl (10 ml) in ice and stirred for 10 to 15 minutes. The yellow compound J formed almost quantitatively was then separated off using a Buchner funnel.

TLC (silica gel, EA / IH, 1: 1): R _f = 0.18. ¹ HNMR (300 MHz, chloroform-d) δ 8.56 (s, 1H), 8.35 (d, J = 9.2 Hz, 1H), 6.38 (dd, J = 9.1, 2, 4 Hz, 1H), 6.20 (s, 1H), 3.85 (s, 3H), 3.73 (t, J = 5.8 Hz, 2H), 3.55 (dd, J = 8, 1, 6.4 Hz, 2H), 3.38-3.28 (m, 2H), 1.92-1.84 (m, 2H), 1.67 (dt, J = 9.4, 7, 4 Hz, 2H), 1.57 (s, 9H), 0.95 (t, J = 7.4 Hz, 3H). ¹³ C NMR (101 MHz, chloroform-d) δ 165.50, 162.26, 154.25, 148.09, 131.17, 118.57, 109.22, 105.34, 93.05, 91 , 01, 59.70, 55.43, 52.84, 52.57, 47.79, 30.13, 20.62, 14.18, 11.35. HRFT-MS (ESI +): m / z = 375.2340 (calcd 375.2278 for C ₂₁ H ₃₁ N ₂ O ₄ ⁺ [M + H] ⁺ ).

Example 6 tert-Butyl- (E) -2-cyano-3- (2-methoxy-4 - ((3 - ((methylsulfonyl) oxy) propyl) (propyl) -amino) phenyl) acrylate (compound K)

Methanesulfonyl chloride (30 μl, 0.4 mmol, 1.2 equiv.) And Et ₃ N (130 μl, 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 NaHCO ₃ - Solution was 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 MgSO ₄ . By removing the solvent on a rotary evaporator, it was possible to obtain compound K as a yellowish solid and to use it in the next synthesis step without further purification.

TLC (silica gel, EA / IH, 1: 1): R _f = 0.22. ¹ H NMR (400 MHz, chloroform-d) δ 8.57 (t, J = 0.5 Hz, 1H), 8.36 (dd, J = 9.2, 0.5 Hz, 1H), 6 .32 (dd, J = 9.2, 2.4 Hz, 1H), 6.07 (d, J = 2.5 Hz, 1H), 4.30 (t, J = 5.8 Hz, 2H) , 3.85 (s, 3H), 3.64-3.48 (m, 2H), 3.42-3.26 (m, 2H), 3.03 (s, 3H), 2.15-2 .01 (m, 2H), 1.67 (q, J = 7.6 Hz, 2H), 1.55 (s, 9H), 0.96 (t, J = 7.4 Hz, 3H). ¹³ C NMR (101 MHz, chloroform-d) δ 163.63, 161.89, 153.25, 147.23, 131.10, 118.40, 109.67, 105.03, 94.59, 93 , 15, 82.15, 67.35, 55.46, 52.98, 47.22, 37.45, 28.10, 27.20, 20.60, 11.35. HRFT-MS (ESI +): m / z = 453.2134 (calcd 453.2054 for C ₂₂ H ₃₃ N ₂ O ₆ S ⁺ [M + H] ⁺ ).

Example 7

(E) -2-cyano-3- (2-methoxy-4 - ((3 - ((methylsulfonyl) oxy) propyl) (propyl) amino) phenyl) acrylic acid (compound A1)

Trifluoroacetic acid (200 μl) was added to a solution of K (20 mg, 0.044 mmol) in 200 μl 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 was used for the radiofluorination without further purification.

Example 8

(E) -2-cyano-3- (4 - ((3 - ([ ¹⁸ F] fluoro) propyl) (propyl) amino) -2-methoxyphenyl) acrylic acid (compound [ ¹⁸ F] FACH)

Compound [ ¹⁸ F] FACH was prepared in a one-step radiosynthesis using the synthetic route shown in Scheme 4.

Carrier-free [ ¹⁸ F] fluoride in 100 to 400 μl target water was added to a solution of 50 to 150 μl tetra-n-butylammonium hydrogen carbonate solution (TBAHCO ₃ , 0.075 M) in 1 ml acetonitrile. The aqueous [ ¹⁸ F] fluoride was then dried by means of azeotropic distillation in vacuo and under a stream of nitrogen within 7 to 12 minutes. A laboratory microwave device (75 W, 50-60 ° C, power cycling mode) was used for this. Acetonitrile was again added during the drying procedure (2 × 1.0 ml) and the resulting dry [ ¹⁸ F] TBAF was dissolved in 300 to 500 μl of acetonitrile. 0.5 to 2.0 mg of precursor A1 (scheme 4), dissolved in 100 to 250 μl of acetonitrile, were added to this solution and ¹⁸ F labeling was carried out at 100 ° C. for 10 to 20 minutes. The radiochemical yields determined by radio HPLC for this step were between 40 and 60%. 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 was 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.

The identity check of the ¹⁸ F-labeled main product [ ¹⁸ F] FACH was carried out after its isolation by means of HPLC (radio and UV detection) by co-injection of the reference compound (E) -2-cyano-3 - (4 - ((3 - (fluor ) propyl) (propyl) amino) -2-methoxyphenyl) acrylic acid (FACH) ( 1 ).

Example 9

Evidence of the inhibitory effect of the compound FACH on MCT1 and MCT4

IC ₅₀ values for the reference compound (FACH) are shown in Table 2 below. The IC ₅₀ 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. Table 2 connection MCT1 IC ₅₀ [nM] MCT4 IC ₅₀ [nM] SUBJECT 11 6.4

The IC ₅₀ values were determined as described in Gurrapu, op. Cit.

2a shows a PET image obtained with [ ¹⁸ F] FACH in a CD-1 mouse. 2 B shows PET images of inhibition experiments carried out with α-cyano-4-hydroxycinnamate (CHC) and FACH. It can be seen that the inhibitory effect of FACH exceeds that of CHC. In the 2 The PET images shown are each total images over 60 min. The specification "SUV" denotes the standardized uptake value, the specification "Baseline" denotes the baseline.

QUOTES INCLUDED IN THE DESCRIPTION

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Patent literature cited

• WO 2013/109972 A2 [0002]

Claims (16)

Compound of the general formula (E) -I or (Z) -I

wherein 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 C ₁ -C ₁₂ -alkyl group, a substituted or unsubstituted C ₂ -C ₁₂ -alkenyl group, a substituted or unsubstituted C ₂ -C ₁₂ -alkynyl group, a substituted or unsubstituted one Aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkylaryl group, a substituted or unsubstituted arylalkyl group and a group -A ¹ -X, where A ^{1 is} a hydrocarbon chain with one to four substituted or unsubstituted methylene groups, with at least one in the hydrocarbon chain Oxygen atom may be arranged 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 C ₁ -C ₁₂ -alkyl group, a substituted or unsubstituted C ₂ -C ₁₂ -alkenyl group, a substituted one or an unsubstituted C ₂ -C ₁₂ 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, in which 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; and AG is selected from the group consisting of a hydroxy, -NO ₂ , halogen, 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. Connection after Claim 1 , characterized in that at least one of the hydrogen atoms of the radical Z ^{1 is} deuterium (D) or tritium (T) and / or 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) is. Connection after Claim 1 or Claim 2 , characterized in that the compound is a compound of the general formula (E) -IA or (Z) -IA

is where AG is selected from the group consisting of a sulfonate, a halogen, and an organotin compound; X is selected from the group consisting of a methyl group, a halogen, and a hydroxy group; Y is a hydroxy group or an O ^- M ⁺ group, where M ^{+ is} a cation; and A ¹ and A ² are each independently 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. A compound according to any one of the preceding claims, characterized in that the sulfonate is 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. Compound according to any one of the preceding claims, characterized in that AG is halogen or -OMs. Compound according to any one of the preceding claims, characterized in that M ^{+ is} an alkali metal ion. Connection after Claim 6 , characterized in that the alkali metal ion is selected from the group consisting of a sodium ion, a potassium ion and a lithium ion. Connection to one of the Claims 3 to 7th , characterized in that AG is halogen or -OMs; X is a methyl group; Y is a hydroxy group; A ^{1 is} - (CH ₂ ) ₂ -; and A ^{2 is} - (CH ₂ ) ₃ -. Compound according to one of the preceding claims, characterized in that it is one of the following compounds: (E) -2-cyano-3- (2-methoxy-4 - ((3 - ((methylsulfonyl) oxy) propyl) (propyl) amino) phenyl) acrylic acid; (Z) -2-cyano-3- (2-methoxy-4 - ((3 - ((methylsulfonyl) oxy) propyl) (propyl) amino) phenyl) acrylic acid; (E) -2-cyano-3- (2-methoxy-4- (propyl (3- (tosyloxy) propyl) amino) phenyl) acrylic acid; (Z) -2-Cyano-3- (2-methoxy-4- (propyl (3- (tosyloxy) propyl) amino) phenyl) acrylic acid. Use of a connection according to one of the Claims 1 to 9 as a precursor for the preparation of a compound of the general formula (E) -II or (Z) -II

wherein 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 C ₁ -C ₁₂ -alkyl group, a substituted or unsubstituted C ₂ -C ₁₂ -alkenyl group, a substituted or unsubstituted C ₂ -C ₁₂ -alkynyl group, a substituted or unsubstituted one Aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkylaryl group, a substituted or unsubstituted arylalkyl group and a group -A ¹ -X, in which 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 [ ¹⁸ F] fluoride, where Z ² is selected from the group consisting of a substituted or unsubstituted C ₁ -C ₁₂ -alkyl group, a substituted or unsubstituted C ₂ -C ₁₂ -alkenyl group, a substituted or unsubstituted C ₂ -C ₁₂ 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 pe -A ² - [ ¹⁸ F] F, in which A ^{2 is} a hydrocarbon chain with one to four substituted or unsubstituted methylene groups, at least one oxygen atom being arranged in the hydrocarbon chain to form an ether group can. Use after Claim 10 , characterized in that a compound of the general formula (E) -IA or (Z) -IA for the preparation of a compound of the general formula (E) -IIA or (Z) -IIA

is used wherein X is selected from the group consisting of a methyl group, a halogen and a hydroxy group; Y is a hydroxy group or an O ^- M ⁺ group, where M ^{+ is} a cation; and A ¹ and A ² are each independently 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. Use after Claim 11 , characterized in that for the preparation of a compound of the general formula (E) -IIA or (Z) -IIA, in which X is a methyl group; Y is a hydroxy group; A ^{1 is} - (CH ₂ ) ₂ -; and A ^{2 is} - (CH ₂ ) ₃ -; one of the following compounds is used as a precursor: (E) -2-cyano-3- (2-methoxy-4 - ((3 - ((methylsulfonyl) oxy) propyl) (propyl) amino) -phenyl) acrylic acid; (Z) -2-cyano-3- (2-methoxy-4 - ((3 - ((methylsulfonyl) oxy) propyl) (propyl) amino) phenyl) acrylic acid; (E) -2-cyano-3- (2-methoxy-4- (propyl (3- (tosyloxy) propyl) amino) phenyl) acrylic acid; (Z) -2-Cyano-3- (2-methoxy-4- (propyl (3- (tosyloxy) propyl) amino) phenyl) acrylic acid. Process for the preparation of a compound of the general formula (E) -II or (Z) -II

wherein 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 C ₁ -C ₁₂ -alkyl group, a substituted or unsubstituted C ₂ -C ₁₂ -alkenyl group, a substituted or unsubstituted C ₂ -C ₁₂ -alkynyl group, a substituted or unsubstituted one Aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted alkylaryl group, a substituted or unsubstituted arylalkyl group and a group -A ¹ -X, where A ^{1 is} a hydrocarbon chain with one to four substituted or unsubstituted methylene groups, with at least one in the hydrocarbon chain Oxygen atom may be arranged 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 [ ¹⁸ F] fluoride, where Z ² is selected from the group consisting of a substituted or unsubstituted C ₁ -C ₁₂ -alkyl group, a substituted or unsubstituted C ₂ -C ₁₂ -alkenyl group, a substituted or unsubstituted C ₂ -C ₁₂ 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 pe -A ² - [ ¹⁸ F] F, in which A ^{2 is} a hydrocarbon chain with one to four substituted or unsubstituted methylene groups, at least one oxygen atom being arranged in the hydrocarbon chain to form an ether group can; wherein a compound of the general formula (E) -I or (Z) -I

in which AG the in Claim 1 and Y, Z ¹ and Z ^{2 have} the meanings given in connection with the general formula (E) -II or (Z) -II, in the presence of a [ ¹⁸ F] fluoride anion and a phase transfer catalyst to form a compound of the general formula (E) -II or (Z) -II is implemented. Procedure according to Claim 13 , characterized in that for the preparation of a compound of the general formula (E) -IIA or (Z) -IIA

wherein X is selected from the group consisting of a methyl group, a halogen, and a hydroxy group; Y is a hydroxy group or an O ^- M ⁺ group, where M ^{+ is} a cation; and A ¹ and A ^2, independently of one another, are each 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; a compound of the general formula (E) -IA or (Z) -IA

in which AG the in Claim 2 and X, Y, A ¹ and A ^{2 have} the meanings given in connection with the general formula (E) -IIA or (Z) -IIA, in the presence of the [ ¹⁸ F] fluoride anion and the phase transfer catalyst a compound of the general formula (E) -IIA or (Z) -IIA is implemented. Procedure according to Claim 13 or Claim 14 , characterized in that the process is a one-step process. Method according to one of the Claims 13 to 15th , characterized in that the radical Y of the compound of the general formula (E) -I or (Z) -I has no protective group during the reaction.

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