[page 104↓]

6  Summary

Our research aimed to the development of new non-peptide calcineurin inhibitors. Such compounds are of eminent importance as immuno-suppressants and are used in the treatment of heart insufficiency. Based on a positive test of a few compounds (pyrazolopyrimidines and pyrazolotriazines), a general structure 8 (Figure 6.1)of potential calcineurin-inhibiting compounds was hypothesized in our group.

Figure 6.1 General Structure 8

The structural feature represents an assembly of a heterocyclic core (nitrogen containing aromatic heterocycle), furnished with two aryl groups and one side chain with a terminal heteroatom functionality. It was necessary to prove to what extend this hypothesis is valid and which structure-activity relations exist.

Investigations in Karanik’s thesis [16b] concentrated on pyrazolo[1,5-a]pyrimidines, pyrazolo[1,5-a]triazines and pyrimidines, where the aryl groups and the saturated chain (Y = NH, O, or S) were varied (Figure 6.2).

Figure 6.2 General Structures of Karanik’s thesis

In the present thesis, we tried to vary the central N-heterocyclic cores, the side chains and its position of attachment. In the general structure 8, Y can be CH2 and CH2NH, besides NH, O, and S, and the aliphatic chain can be saturated and unsaturated. As a synthetic strategy, [page 105↓]Pd-catalyzed coupling reactions were used to introduce side chains and/or aryl substituents into the central heterocycle. In this way the utility of such reactions to heterocyclic systems, which were neglected so far, could be figured out.

Halogen substituted diaryl heterocycles are important intermediates in the synthesis of general structures 8. In order to introduce aryl groups into the heterocyclic core, Suzuki reaction was applied as the key step, for example, synthesis of 9-benzyl-8-bromo-6-phenylpurine (185) and 3,5-diphenyl-2-iodopyridine (284). (Scheme 6.1)

Scheme 6.1

If heterocycles with more than one halo-leaving group were used as starting materials, aryl group could be introduced by regioselective Suzuki coupling, e. g. synthesis of 5-chloro-3,7-diphenylpyrazolo[1,5-a]pyrimidine (120), 7 (or 9)-benzyl-2-chloro-6-phenylpurine (140 and 184) and 2-chloro-4,6-diarylpyrimidines (240 and 255). (Scheme 6.2)

Scheme 6.2


[page 106↓]

Other starting haloheterocycles were obtained either by replacement of hydroxyl groups or by halogenation of the unfunctionalized position of the heterocycles. More than 30 compounds of corresponding halo-heterocycles were synthesized. (Figure 6.3)

Figure 6.3

The introduction of the desired side chains by C-C bond formation reactions was achieved by Sonogashira coupling and Heck coupling. Buchwald-Hartwig amination and nucleophilic substitution were used to establish side chains which are connected to the core heterocycle by heteroatom-C bonds.

Sonogashira reaction turned out to be the most effective and convenient method to introduce ω-functionalized alkynyl group into the heterocyclic cores. Further catalytic hydrogenation of the alkyne moiets led to ω-functionalized alkyl substituted diaryl heterocycles. (Scheme 6.3) Five bicyclic and six monocyclic core heterocycles could be successfully submitted to this reaction sequence.


[page 107↓]

Several reaction conditions and Pd-catalysts were tested. It turned out that Pd/C was advantageous over other commonly used Pd(II) or Pd(0) pre-catalysts in a number of cases (104a and 321 as starting material).

Scheme 6.3

Heck reaction of 3-iodopyrazolo[1,5-a]pyrimidines (104a-h) or 7-bromo-pyrido[2,3-b]pyrazine (193) with olefins, allowed to introduce ω-functionalized alkenyl groups into these heterocyclic cores. (Scheme 6.4)

Scheme 6.4

Buchwald-Hartwig amination of 6-bromoimidazo[1,2-a]pyridine (218), 7-bromo-pyrido[2,3-b]pyrazine (193) or 4-bromooxazole (310) with ω-functionalized alkylamines, allowed the introduction of aminoalkyl chains, which are tethered to the heterocyclic cores by a heteroatom. (Scheme 6.5)


[page 108↓]

Scheme 6.5

Our synthetic affords contributed to the general knowledge about the scope and limitation of Pd-catalyzed reactions in heterocyclic chemistry.

By nucleophilic substitution, a series of purines, pyrimidines, and pyrazolo[1,5-a]pyrimidines with a side chain (X = O, S, NH, or CH2NH) were synthesized (Figure 6.4).

Figure 6.4

Compared with the compounds of high activity independently obtained in our group by other methodology, the positions of connections of the side chains and aryl groups in the pyrazolo[1,5-a]pyrimidine series could be varied. According to the testing results of the compounds, we found out that the connection of the side chain to position 7 of pyrazolopyrimidine core is most effective for calcineurin inhibition as compared with other connection sites. The necessity of a basic amino group at the terminus of the side chain was manifested by our results. It was further detected, that the side chain can be unsaturated. (Figure 6.5)


[page 109↓]

Figure 6.5

Novel pyrimidines, where the amino substituted side chain was connected to position 2 rather than to position 4, revealed that these two positions are similar effective with respect to calcineurin inhibition.

Prior to the present thesis, compounds of the general structure 8 were investigated only with pyrazolopyrimidine, pyrazolotriazine and pyrimidine as central heterocyclic core. In the course of this thesis, novel compounds with purine, pyridopyrazine, imidazopyridine, imidazopyridazine, imidazole, oxazole, pyrazole, pyridine, and pyrazine were developed and tested.

The enzyme inhibiting test showed that, unfortunately, all these heterocyclic systems are not as effective as pyrazolopyrimidines, pyrazolotriazines and pyrimidines.

The structural model 8 of potential calcineurin inhibitors could be refined and important contributions to its scope and limitations were provided. The results further demonstrate the vast versatility of Pd-catalyzed coupling reactions in new areas of heterocyclic chemistry.

In the present work, more than 180 compounds were synthesized. Among them, about 130 compounds are new products. 86 of them fit into the general structure 8.

Five publications arouse from these results. Two of them have been published, one is in press. Another two are under preparation.


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