key: cord-017041-0zxoq68m
authors: Volochnyuk, Dmitriy M.; Grygorenko, Oleksandr O.; Gorlova, Alina O.
title: Fluorine-Containing Diazines in Medicinal Chemistry and Agrochemistry
date: 2014-06-13
journal: Fluorine in Heterocyclic Chemistry Volume 2
DOI: 10.1007/978-3-319-04435-4_7
sha: 
doc_id: 17041
cord_uid: 0zxoq68m

The combination of a fluorine atom and a diazine ring, which both possess unique structural and chemical features, can generate new relevant building blocks for the discovery of efficient fluorinated biologically active agents. Herein we give a comprehensive review on the biological activity and synthesis of fluorine containing, pyrimidine, pyrazine and pyridazine derivatives with relevance to medicinal and agrochemistry.

Abstract The combination of a fl uorine atom and a diazine ring, which both possess unique structural and chemical features, can generate new relevant building blocks for the discovery of effi cient fl uorinated biologically active agents. Herein we give a comprehensive review on the biological activity and synthesis of fl uorine containing, pyrimidine, pyrazine and pyridazine derivatives with relevance to medicinal and agrochemistry. Although being present in very small amounts, they are highly odiferous and can be detected at extremely low concentrations. Unlike other heterocycles found in many important natural products, pyridazines were discovered only after 1970, and relatively few pyridazines have thus far been isolated from natural sources.

As synthetic compounds, all diazines constitute an important pharmacophoric moiety present in many drugs acting on various pharmacological targets as well as agrochemicals.

Inspite of organofl uorine compounds are almost absent as natural products, ~25 % of drugs in the pharmaceutical pipeline and ~15 % of agrochemicals contain at least one fl uorine atom. One of the earliest synthetic fl uorinated drugs is the antineoplastic agent 5-fl uorouracil, derivative of pyrimidine, an antimetabolite fi rst synthesised in 1957. Since the advent of 5-fl uorouracil, fl uorine substitution is commonly used in contemporary medicinal and agrochemistry to improve metabolic stability, bioavailability and protein-ligand interactions. In this review only compound bearing fl uoro or fl uoroalkyl substituent in diazine ring are discussed. Among fl uorine containing diazines now 12 drugs and 10 agrochemicals are presented on the market. This review provides an information about fl uorinated diazines as drugs or agrochemicals and their mode of action as well as synthesis. The review is divided in two parts. First part dedicated to the medicinal and synthetic chemistry of fl uorinated diazines that have reached at least clinical development phase. The second one dedicated to the biological role and the chemistry of the marketed agrochemicals based on fl uorinated diazines.

It is widely accepted that compounds containing fl uorine atoms have a remarkable record in medicinal chemistry and play a continuing role in providing lead compounds for potential therapeutic applications. The reasons for that have been discussed extensively in a number of books and reviews [ 1 , 2 ] . In this view, fl uorine-containing diazines are not the exception; they have attracted attention of medicinal chemists since 1950s when Fluorouracil ( 1 ) was introduces as anti-cancer drug. Analysis of MDDR (MDL Drug Data Report) data retrieved 1,150 hits derived from fl uorine-containing diazines [ 3 ] . Nearly a third part of them is represented by anti-cancer agents (Fig. 1 ) ; other important classes (more than 100 examples) include compounds with antiviral (mainly anti-HIV) and antiarthritic activity.

According to MDDR, 106 compounds containing a fl uorinated diazine moiety have entered pre-clinical studies, 40 of them have reached clinical phase, and 12 of these have become drug substances (Fig. 2 ) . In the following sections, fl uorinecontaining diazine derivatives that have reached at least clinical development phase will be discussed, focusing on their aspects related to medicinal and synthetic organic chemistry.

The use of fl uorinated diazines as anti-cancer agents is the major fi eld of their application in medicinal chemistry. The fi rst representative of this class, Fluorouracil ( 1 ) was developed by Charles Heidelberger and co-workers in 1957 [ 4 ] . It was approved by U.S. FDA [ 5 ] in 1962 as antineoplastic agent in the treatment of advanced colorectal cancer. Fluorouracil represents a class of rationally designed anticancer agents which act as antimetabolites. The observation that rat hepatomas utilized radiolabeled uracil more avidly than normal tissues [ 6 ] implied that the enzymatic pathways for utilization of uracil or its close analogs differed between malignant and normal cells -a feature which might provide a target for antimetabolite chemotherapy. A minimal modifi cation of uracil by introducing a single fl uorine atom allowed for implementation of cellular uptake and metabolic activation of 1 via the same transport processes and enzymes involved in the case of uracil. However, in the case of essential biological targets, remarkable differences are observed due to unique properties of the fl uorine atoms, which result in inhibition of the metabolic and signal pathways involved. Although all the details of the mechanism by which Fluorouracil gives its biological effect are not elucidated, a remarkable progress has been made over the past half a century in elucidating its cellular and clinical pharmacology [ 7 , 8 ] .

The key steps in Fluorouracil metabolism are shown in Scheme 1 . Up to 80 % of 1 administered as injection is transformed to dihydrofl uorouracil (DHFU, 13 ) by dihydropyrimidine dihydrogenase (mostly in liver tissues). However, this metabolite is not involved into antineoplastic activity; instead, 13 itself and its further metabolites are responsible for most of the toxic effects of 1 . The main mechanism of activation of Fluorouracil is conversion to fl uorouridine monophosphate (FUMP, 14 ), either directly by orotate phosphoribosyltransferase, or via fl uorouridine (FUR, 15 ) through the sequential action of uridine phosphorylase and uridine kinase. 14 is then phosphorylated to give fl uorouridine diphosphate (FUDP, 16 ), which can be either phosphorylated again to the active metabolite fl uorouridine triphosphate (FUTP, 19 ) , or reduced to fl uorodeoxyuridine diphosphate (FdUDP, 18 ) by ribonucleotide reductase. In turn, 18 can either be dephosphorylated or phosphorylated to generate An alternative activation pathway involves the thymidine phosphorylase catalysed conversion of 1 to Floxuridine (FUDR, 4 ), which is then phosphorylated by thymidine kinase to give 19 . The metabolite of 1 -Floxuridine -is itself used as an anti-cancer agent [ 9 ] . It was launched in 1970 by Hospira Inc [ 5 ] . Upon rapid injection, most of Floxuridine is catabolized to Fluorouracil; hence similar effects on the organism are obtained in this case. On the contrary, when 4 is slowly administered into the arterial blood, it is mostly transformed to 19 ; thus toxic effects are diminished comparing to 1 [ 10 ] .

It has long been recognized that one of the main mechanisms underlying Fluorouracil action is inhibition of thymidylate synthase by fl uorodeoxyuridine monophosphate ( 19 ) [ 11 ] . Thymidylate synthase belongs to a class of enzymes required for DNA replication, and its activity is higher in rapidly proliferating cells. In particular, thymidylate synthase is responsible for methylation of deoxyuridine monophosphate (dUMP, 21 ) to deoxythymidine monophosphate (dTMP, 22 ) with the use of 5,10-methylenetetrahydrofolate ( 23 ) as a cofactor (Scheme 2 ) [ 12 ] . With fl uorodeoxyuridine monophosphate, a slowly-reversible ternary complex 24 is formed instead. Inhibition of thymidylate synthase leads to deoxyribonucleotide imbalance, and hence to interference with DNA synthesis and repair. Alternative mechanism of DNA-directed Fluorouracil effect is misincorporation of fl uorodeoxyuridine triphosphate ( 20 ) into DNA. Analogously, fl uorouridine triphosphate ( 17 ) is extensively incorporated into different RNA species, disrupting their normal processing and function [ 7 , 8 , 11 ] . Two principal approaches were used for the preparation of Fluorouracil (Scheme 3 ). One of the fi rst methods [ 13 , 14 ] commenced from ethyl fl uoroacetate which was subjected to Claisen condensation with ethyl formate to give 25 . The salt 25 was introduced into reaction with S -alkylisothiourea to give fl uoropyrimidines 26 , which were hydrolysed to give 1 . Several variations of this method were also described; their common drawback was the use of highly toxic fl uoroacetic acid derivatives. In an alternative approach, Fluorouracil was prepared by direct fl uorination of different pyrimidine derivatives, including uracil [ 15 ] , cytosine [ 16 ] , and orotic acid [ 17 ] . In the latter method, the initially obtained fl uoroorotic acid 27 was subjected to decarboxylation. The use of two-step reaction sequence was claimed to be advantageous due to simplifi ed product isolation and purifi cation.

Early synthesis of Floxuridine commenced from Fluorouracil ( 1 ) which was transformed into its mercury salt 28 and then allowed to react with 2-deoxy-Dribofuranosyl chloride derivative 29 (Scheme 4 ) [ 18 ] . The product 30 was subjected to alkaline hydrolysis to give Floxuridine ( 4 ).

As in the case of Fluorouracil, newer syntheses of Floxuridine relied on direct fl uorination of uracil derivatives. Fluorination of uridine 31 was done using fl uorine [ 19 ] , acetyl fl uoride [ 20 ] , and CF 3 OF [ 21 ] . The latter reagent gave good but still moderate yield of the product 4 (47 %). The use of a two-step reaction sequence, i.e. fl uorination of diacetoxy derivative 32 and hydrolysis, improved the yield of 4 to 82 % over two steps [ 21 , 22 ] .

Despite Fluorouracil remains the main agent for the treatment of certain cancer types ( i.e. colorectal) [ 23 ] , it displays various side effects due to its nonspecifi c cytotoxicity, poor distribution to tumor sites, and serious limitations in effectiveness due to drug resistance. Apart from modulation of Fluorouracil biological action through combination therapies [ 7 , 24 ] , a number of drugs and clinical candidates acting as prodrugs of 1 and/or 4 were developed (Table 1 ) . The fi rst example of Fluorouracil prodrug is Tegafur ( 3 ) developed in 1960s in Latvia [ 25 , 26 ] . Tegafur is an oral slow-release prodrug formulation of Fluorouracil which is readily absorbed through the gastrointestinal tract. The major pathway of metabolic activation of 3 includes hydroxylation by hepatic cytochrome P450 enzymes, mostly CYP2A6 (Scheme 5 ) [ 27 ] . Apart from Fluorouracil, 4-hydrohybutyraldehyde and succinic dialdehyde are also formed, which are further transformed into γ-butyrolactone and 4-hydrohybutyric acid [ 28 ] . Tegafur was shown to be 2-5 times more potent and less toxic than 1 ; hence lower doses of 3 can be utilized, resulting in decreased neurotoxicity without compromising the antitumor effects.

Another prodrug of Fluorouracil -Doxifl uridine ( 5 ), which also implies the idea of attachment of sugar-like moiety to the molecule of 1 , was launched in Japan in 1987 [ 29 ] . The mechanism of metabolic activation of 5 is rather simple and includes hydrolysis to Fluorouracil by thymidine phosphorylase [ 299 ] . Since the level of thymidine phosphorylase is signifi cantly higher in several types of solid tumours (in particular, colorectal, breast, and kidney cancers) as compared with normal tissues, Doxifl uridine possesses a higher therapeutic index for these types of cancers. The use of 5 is somewhat limited by gastrointestinal toxicity after oral administration due to release of 1 by intestinal pyrimidine nucleoside phosphorylase [ 30 ] .

Yet another sugar-modifi ed Fluorouracil derivative -OGT 719 ( 33 ), in which galactose is incorporated onto the fl uoropyrimidine moiety, was developed by Oxford GlycoSciences and had reached Phase I clinical study [ 31 ] . In 1999, the company decided to discontinue development of 33 as the results of Phase I/II clinical study were not suffi ciently strong to justify large scale Phase II studies. OGT 719 was rationally designed to reduce the systemic toxicity normally associated with Fluorouracil while retaining activity against tumors localized in the liver, in which it may be preferentially localized through the asialoglycoprotein receptors [ 32 ] . These receptors are present on the surface of hepatocytes and recognise various sugar-containing biomolecules through terminal galactose and N -acetylgalactosamine residues. The metabolic activation of OGT 719 occurs once the compound enters hepatocytes, where the galactose molecule is cleaved from the Fluorouracil residue.

Two derivatives of Floxuridine -TT-62 ( 34 ) and T-506 ( 35 ) have reached Phase II clinical trials in Japan [ 3 ] . The compounds showed signifi cant antitumor activity by oral administration; moreover, they slowly released Floxuridine, and the effective level of 4 was prolonged [ 33 , 34 ] . The gastro-intestinal disturbances and loss of body weight were serious side effects of 34 and 35 .

Several prodrugs of Flourouracil were obtained by acylation or carbamoylation of N-1 and/or N-3 atoms of the pyrimidine ring of 1 . In particular, an oral drug Carmofur ( 2 ) which is 1-hexylcarbamoyl derivative of 1 was launched in Japan in 1981 and later -in other countries [ 35 ] . The carbamate moiety in 2 decomposes gradually in neutral water or in basic conditions, but it is strongly resistant to acidic hydrolysis and hence can survive acid in the stomach. The 1-hexylcarbamoyl moiety also facilitates the rapid uptake of 2 through the cell membrane [ 36 ] . The metabolic activation of Carmofur involves oxidation and scission of the side-chain with slow release of 1 [ 37 ] . Two main routes of the side chain transformation are ω-oxidation and (ω-1)-oxidation: metabolites 40 -43 were detected after administration of Carmofur (Fig. 3 ) [ 38 ] . Non-enzymatic hydrolytic decomposition of 2 and its metabolites also contributes to release of 1 .

Another oral prodrug of Fluorouracil, Atofl uding ( 36 ) is a diacyl derivative of 1 . Atofl uding has reached Phase III clinical trials in China [ 39 ] . The activation of 36 includes its fast non-enzymatic hydrolysis to 3o -toluyl-5-Fluorouracil ( 44 ) following oral administration; 44 is then slowly metabolized to 1 (Scheme 6 ) [ 40 ] . Since the acetyl group of Atofl uding is not stable and prone to decompose, impairing quality control for the preparation, a possibility of direct application of 44 was also considered [ 41 ] . An interesting idea was behind design of Emitefur ( 37 ), a prodrug of Fluorouracil which was developed by Otsuka Pharmaceutical and has reached Phase III clinical trials in Japan [ 3 , 42 , 43 ] . The structure of 37 contains the fragments of two biologically active components: Fluorouracil ( 1 ) and 3-cyano-2,6-dihydroxypyridine ( 45 ), which is a potent inhibitor of dihydropyrimidine dehydrogenase. Therefore, 37 is a double prodrug which not only delivers Fluorouracil but also prevents its enzymatic biotransformation to the dihydropyrimidine derivative 12 . Metabolic activation of 37 occurs via rapid cleavage of the ester bonds by esterase to give 45 and 1-ethoxymethyl-5-fl uorouracil ( 46 ) (Scheme 7 ). The intermediate 46 is further metabolized to 1 by microsomal enzymes in the liver [ 44 ] . All the prodrugs of Fluorouracil discussed above contained the fragment of 1 in their structure; their transformation to 1 included hydrolysis reaction as the key step. On the contrary, 5-fl uoro-2-pyrimidinone (5-FP, 38 ) which has been studied in Phase I clinical trials [ 45 ] is activated through oxidative process. In particular, pyrimidine 38 is transformed to 1 by aldehyde oxidase, which is present in high concentrations in the human livers but not in the gastrointestinal tract [ 46 ] .

Two prodrugs of 1 , Capecitabine ( 6 ) and Galocitabine ( 39 ), are 5-fl uorocytidine derivatives. Both the compounds were developed by Hoffman La Roche; whereas Capecitabine was launched in 1998, Galocitabine was terminated at Phase II clinical trials [ 47 ] . Both the compounds are close analogues as well as prodrugs of Doxifl uridine ( 5 ), which was used as the lead compound in their design. The main goals of such design were to minimize the mielotoxicity and to increase the tumor selectivity of 5 . In fact, Capecitabine ( 6 ) indeed demonstrated minimal mielotoxicity in clinical studies. Although the therapeutic indices of 39 were much higher in mice tumor models than in the case of 5 , it was not effi ciently metabolised to the active species in humans. The metabolic activation of 6 and 39 includes their hydrolysis by carboxylesterase or acylamidase in liver to give 5′-deoxy-5-fl uorocytidine ( 47 ), which is then transformed to 5 by cytidine deaminase (Scheme 8 ) [ 48 ] . Syntheses of Fluorouracil prodrugs relied on either chemical modifi cation of 1 or direct fl uorination of the corresponding pyrimidine derivatives. In particular, Tegafur ( 3 ) was obtained from 1 by reaction with 2,3-dihydrofuran [ 49 -54 ] , 2-chloro- [ 55 , 56 ] , 2-alkoxy- [ 57 ] , 2-acetoxytetrahydrofuran [ 58 , 59 , 300 ] , and 4-trimethylsilyloxybutyraldehyde dimethyl acetal ( 48 ) (Scheme 9 ) [ 60 ] . Alternatively, 3 was prepared via fl uorination of compound 49 [ 61 ] or ester 50 [ 62 ] . One of the early syntheses of Doxifl uridine ( 5 ) [ 63 , 64 ] commenced from Floxuridine ( 4 ) which reacted with thionyl chloride to give cyclic sulphite 51 (Scheme 10 ). Methanolysis of 51 upon treatment with sodium methylate gave 52 , which was reduced with tributyltin to give 5 . In an analogous approach, the compound 5 was prepared via iodide 53 , in turn obtained from 4 in two steps (Scheme 11 ) [ 65 ] . It should be noted that direct transformation of 4 into the corresponding iodide was done with low yield of the product, hence the protection strategy was necessary to use. Bromide 54 was a key intermediate in one more analogous scheme [ 66 ] . Several syntheses of Doxifl uridine relied on glycosylation of Fluorouracil derivative 55 . In particular, 5′-deoxyrybose derivatives 56 , 57 , and 58 were used for that purpose (Scheme 11 ) [ 67 , 68 ] . Finally, direct fl uorination of 5′-deoxyuridine derivatives with F 2 /N 2 [ 69 ] or AcOF [ 70 ] was also described.

Syntheses of OGT 719 ( 33 ) relied on glycosylation of the compound 55 (Scheme 12 ). Reaction of 55 with bromide 59 [ 71 , 72 ] or acetate 60 [ 73 ] gave tetraacetyl derivative 61 , which was transformed to 33 upon deprotection. With 60 as the glycosylating reagent, in situ generation of 55 from Fluorouracil was also described [ 74 ] . Synthesis of Carmofur ( 2 ) and Atofl uding ( 36 ) was performed in obvious and straightforward manner. Carmofur ( 2 ) was prepared by reaction of Fluorouracil ( 1 ) and n -hexylisocyanate (Scheme 15 ) [ 77 , 78 ] . Alternative approach included reaction of 1 with phosgene and then -with n -hexylamine. Early syntheses of 5-fl uoro-2-pyrimidinone ( 38 ) relied on desulfurization of Fluorouracil thio-derivatives. In particular, reaction of pyrimidine derivatives 68 with P 2 S 5 followed by treatment with Raney nickel and gave alkoxy derivative 69 , which was transformed to 38 upon acidic hydrolysis (Scheme 18 ) [ 83 ] . A more straightforward transformation sequence was also described; including reaction of Fluorouracil ( 1 ) with P 2 S 5 and reduction of thione 70 with Raney nickel [ 84 , 85 ] . Alternatively, the thione 70 was alkylated to give derivative 71 , which was either oxidated and then hydrolyzed [ 86 ] or subjected to reaction with hydrazine and then -silver oxide [ 301 ] ; in both cases, 38 was obtained. A completely different synthetic scheme commenced from fl uoroacetic acid which was subjected to Vilsmeiertype formylation to give 2-fl uoro-3-dimethylamino-acrolein ( 72 ) [ 87 ] . Reaction of 72 with triethyloxonium tetrafl uoroborate and dimethylamine gave the salt 73 , which led to 38 upon reaction with urea. Finally, 38 was also obtained by direct fl uorination of 2-pyrimidinone [ 88 , 89 ] .

Syntheses of Capecitabine ( 6 ) started from 5-fl uorocytosine ( 9 ) (see further sections for the preparation of 9 , which is used as antifungal drug). In particular, compound 70 reacted with 1,2,3-tri-O -acetyl-5-deoxy-β-D -ribofuranose ( 58 ) to give diacetyl derivative 72 , which was acylated with n -pentylchloroformate and then hydrolyzed, resulting in the formation of 6 (Scheme 19 ) [ 90 -95 ] . Variations of this method using a silyl derivative of 70 instead of 70 itself [ 68 , 96 ] , as well as 1-O -acetyl-2,3-O-isopropylidene-5-deoxy-D -ribofuranose ( 73 ) (Scheme 20 ) [ 96 ] or 1,2,3-tri-O -methoxycarbonyl-5-deoxy-D -ribofuranose [ 97 ] as the sugar sources were also reported. Syntheses of Galocitabine ( 39 ) were performed analogously to that of Capecitabine, 3,4,5-trimethoxybenzoyl chloride being used instead of npentylchloroformate at the corresponding steps [ 68 , 89 , 90 , 98 ] . [ 3 ] .

The active principle of both TAS-102 and FTC-092 with anti-cancer effect is Trifl uridine ( 7 ). As in the case of Fluorouracil, one of the mechanisms by which compound 7 exhibits its antitumor activity is inhibition of thymidylate synthase [ 100 ] . More precisely, Trifl uridine is transformed into α,α,α-trifl uorothymidine monophosphate ( 76 ) by thymidine kinase (Scheme 21 ); similarly to the Fluorouracil derivatives discussed in the previous sections, compound 76 is true inhibitor of thymidylate synthase. However, compound 7 exhibits an anticancer effect on colorectal cancer cells that have acquired Fluorouracil resistance as a result of the overexpression of thymidylate synthase. Therefore, an alternative mechanism of action is also in operation, namely, incorporation of α,α,α-trifl uorothymidine triphosphate ( 77 ) into DNA, which results in single-strand breaks, followed by double-strand breaks when the cells progress to a subsequent DNA replication phase [ 101 ] The major drawback of Trifl uridine ( 7 ) is its high susceptibility to biodegradation, which is catalysed by thymidine phosphorylase and gives α,α,α-trifl uorothymine ( 78 ) and 2-deoxy-α-Dribose 1-phosphate ( 79 ) [ 102 ] . In the case of TAS-102, this issue is overcome by co-administration of thymidine phosphorylase inhibitor Tipiracil ( 75 ) [ 103 ] , whereas improved biological effect of FTC-092 upon oral administration is achieved by its gradual biotransformation, mainly through the action of liver microsomes, releasing 7 over a long period [ 104 ] .

The fi rst synthesis of Trifl uridine commenced from trifl uoromethylacrylonitrile ( 80 ) which reacted with HBr and then with urea to give amide 81 in moderate yield. Hydrolysis of 81 was accompanied by cyclization and led to dihydropyrimidine 82 (Scheme 22 ). Two-step aromatization of 81 gave α,α,α-trifl uorothymine ( 78 ). Compound 78 was transformed to 7 in low yield (8 %) by enzymatic glycosylation [ 105 ] . The yield of the last step in this sequence was signifi cantly improved when 78 was preliminarily transformed to bis-silyl derivative 83 , and chloride 84 was used for glycosylation [ 106 , 107 ] An alternative approach to 7 was based on direct trifl uoromethylation of the corresponding deoxyuridine derivatives 32 or 84 , using CF 3 COOH-XeF 2 [ 108 ] and CF 3 I-Cu-HMPA [ 109 ] as the reagents, respectively (Scheme 23 ). FTC-092 ( 74 ) was prepared by regioselective benzylation of Trifl uridine ( 7 ) (Scheme 24 ) [ 110 ] . As in the case of 7 , direct trifl uoromethylation was also used for synthesis of 74 . The following sequence was established as the most practical: tritylation of 2′-deoxy-5-iodouridine ( 85 ), 3′-O -benzylation, N 3 -benzoylation, crosscoupling reaction with CF 3 Cu reagent, and acidic deprotection (Scheme 25 ) [ 111 ] . Alternatively, 74 was prepared in low yield by glycosylation of α,α,α-trifl uorothymine using the bis-silyl derivative 83 (Scheme 26 ) [ 112 ] . 

An approach to cancer treatment which relies on using fl uorinated uracil analogues as antimetabolites is the most recognised in the fi eld of fl uorinated diazines relevant to medicinal chemistry. However, other strategies are also gaining momentum; in particular, several compounds which act as kinase inhibitors ( i.e. 87 -92 ) have reached clinical development phase (Table 2 ) .

Compound LY-2835219 ( 87 ) is currently being developed by Eli Lilly and Co.; monomesylate salt of 87 has entered Phase I clinical trials in patients with advanced cancer in 2011 [ 113 ] . It acts as a potent oral inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), playing a key role in regulating cellular proliferation [ 114 ] . In particular, these cyclin D-dependent kinases facilitate progression of gap 1 cell cycle phase (G 1 ) by phosphorylating retinoblastoma susceptibility protein (Rb), which prevents association of Rb with E2F transcription factor, and thus relieves transcriptional repression by the Rb-E2F complex. In addition, these Fluorine-Containing Diazines in Medicinal Chemistry and Agrochemistry kinases also sequester CDK interacting and kinase inhibitory proteins (Cip/Kip) from their complexes with cyclin-dependent kinase 2 (CDK2), facilitating activation of CDK2 with cyclin E [ 115 ] Monomesylate salt of 87 inhibits CDK4 and CDK6 with IC50 values of 2 and 10 nM, respectively; moreover, it is able to cross blood-brain barrier and therefore has the potential for the treatment of brain tumors and metastases [ 114 ] .

Fostamatinib disodium (Tamatinib fosdium, 88 ), which is prodrug of Tamatinib ( 92 ) (Scheme 27 ), was discovered by Rigel; it is currently studied in Phase II clinical trials by Rigel and Astra Zeneca Plc. for treatment of B-cell lymphoma [ 113 ] . Apart from that, compound 88 is also investigated as agent for treatment of autoimmune thrombocytopenia and rheumatoid arthritis. Because of its poor pharmaceutical properties, Tamatinib ( 92 ) is orally administered as the methylene phosphate ( 88 ) is quickly cleaved to 92 by alkaline phosphatases that are present on the apical brush-border membranes of the intestinal enterocytes, after which the more hydrophobic 92 can be readily absorbed [ 116 ] . Tamatinib ( 92 ) acts as an ATP-competitive inhibitor of Spleen tyrosine kinase (Syk) -a non-receptor tyrosine kinase which is a key component of the B-cell receptor (BCR) signaling pathway [ 117 ] . It is shown that BCR-mediated signaling through Syk occurs to a greater degree and for a longer duration in neoplastic cells than in nonmalignant B-cells. Inhibition of the Syk pathway prevents chronic lymphocytic leukemia (CLL) cells from interacting with the microenvironment, and promotes proapoptotic signals.

R-763 ( 89 ), also known as AS-703569, is another kinase inhibitor discovered by Rigel. It was investigated in Phase I clinical trials for several types of tumors by Rigel and Merck Serono; the latest study was terminated in 2012, concerning a review of the available clinical data and low probability of completing the trial based on the observed recruitment rate [ 113 ] . Compound 89 inhibits Aurora kinases -serine/threonine kinases which are essential for cell proliferation, mainly due to regulation of gap 2 and mitotic cell cycle phases (G 2 /M). Over-expression of Aurora kinases is found in several human cancers and correlated with histological malignancy and clinical outcomes. Although the biological functions of two types of Aurora kinases (A and B) are different, in both cases their inhibition induces apoptosis of the cell, leading to similar phenotypes. Some other kinases are also inhibited by 89 , in particular Fms-like tyrosine kinase 3 (FLT3) [ 118 ] .

One more Aurora kinase inhibitor -PF-03814735 ( 90 ) -was developed by Pfi zer; it has been investigated in Phase I clinical trials for treatment of solid tumors (the study completed in 2012) [ 113 ] . PF-03814735 was generally well tolerated with manageable toxicities, and a recommended phase II dose could be established; however, clinical or metabolic antitumour activity was limited [ 119 ] . Similarly to R-763 ( 89 ), compound 90 inhibits both Aurora A and B kinases; other kinases are affected to a lesser extent [ 120 ] . Therefore, PF-03814735 ( 90 ) produces a block in cytokinesis, resulting in inhibition of cell proliferation and the formation of polyploid multinucleated cells.

AZD-1480 ( 91 ) was developed by AstraZeneca and studied in Phase I clinical trials for treatment of advanced solid malignancies (the study terminated in 2012) [ 113 ] . AZD-1480 is an ATP-competitive inhibitor of Janus kinase 2 (JAK2) -an intracellular non-receptor tyrosine kinase that transduce cytokine-mediated signals via the Janus kinase -signal transducer and activator of transcription (JAK-STAT) signaling pathway. In particular, inhibition of JAK2 blocks Stat3 signaling, associated with chronic cytokine stimulation in some tumors [ 121 ] . X-Ray diffraction study of complex formed by 91 and JAK2 shows that the donor-acceptor-donor hydrogen-bonding motif provided by aminopyrazole fragment forms three hydrogen bonds with an adenine binding pocket, whereas the fl uoropyrimidine ring occupies a nearby hydrophobic pocket [ 122 ] .

Synthesis of LY-2835219 ( 87 ) relied on selective functionalization of 2,4-dichloro-5-fl uoropyrimidine ( 93 ), which can be easily obtained from Fluorouracil ( 1 ) (Scheme 28 ) [ 123 ] . First, boronic ester 94 was prepared from aniline 95 in three steps, including benzimidazole ring construction and palladiumcatalyzed coupling with pinacol diborane. Suzuki-type reaction of 93 and 94 resulted in selective functionalization at C-4 of the pyrimidine ring and gave chloride 96 . Buchwald-Hartwig coupling of 96 with amine 97 (prepared in two steps from 1-ethylpiperazine ( 98 ) and ( 99 )) gave the fi nal product 87 . Analogously, selective functionalization of 93 was used for the preparation of Fostamatinib disodium ( 88 ) (Scheme 29 ). In particular, reaction of 93 with equimolar amount of amine 100 and then -with 3,4,5-trimethoxyaniline ( 101 ) gave Tamatinib ( 92 ) [ 124 ] . It should be noted that no detailed procedures of performing these transformations were given in the initial patent; moreover, synthesis of the starting compound (amine 100 ) is not documented to date. To obtain Fostamatinib disodium ( 88 ), compound 92 was treated with chloride 102 and Cs 2 CO 3 ; further deprotection subsequent and salt formation gave the target product 88 [ 125 ] . Similar approach was used for the synthesis of R-763 ( 89 ) (Scheme 30 ) [ 126 ] . In this case, lactam 102 , which was obtained from norbornadiene ( 103 ) and Graf isocyanate (ClSO 2 NCO), was protected with Boc 2 O and then subjected to ringopening with aqueous ammonia to give amide 104 . Deprotection of 104 followed by arylation with 93 gave an intermediate 105 , which was then treated with N -arylpiperazine derivative 106 (prepared in two steps from 4-fl uoro-3-methylnitrobenzene ( 107 )) to give racemic 89 . Optically pure 89 was obtained either by chiral stationary phase HPLC applied at different steps of the synthesis, or via enzymatic resolution of Boc-protected lactam 102 .

It is not surprising that synthesis of PF-03814735 ( 90 ) also followed analogous strategy, 2,4-dichloro-5-trifl uoromethylpyrimidine ( 111 ) being used as a key fl uorinated diazine building block instead of 93 (Scheme 31 ) [ 302 ] . The synthetic scheme commenced from amine 108 which was N -trifl uoroacetylated, then nitrated, and subjected to a change of the protecting group to give Boc derivative 109 . Two alternative pathways were developed for further transformations. In the fi rst one, compound 109 was reduced into fused aniline derivative 110 which reacted with 111 to give compound 112 . Deprotection of 112 followed by coupling with N -acetylglycine led to the formation of chloride 113 .

Alternatively, compound 109 was deprotected, coupled with N -acetylglycine, reduced catalytically and then arylated with 111 to give 113 . Finally, compound 113 reacted with cyclobutyl amine to give the fi nal product 90 as racemate. Both enantiomers of 90 were also obtained using this scheme if Boc derivative 109 was subjected to chiral stationary phase HPLC prior further transformations.

Although a similar strategy was used for the preparation AZD-1480 ( 91 ), in this case the fl uorinated diazine moiety is not in a central part of the molecule; hence a different approach was used for the construction of the fl uorinated 

The fi ght against HIV infection is another important fi eld where fl uorinated diazines have remarkable record, including approved drug Emricitabine ( 8 ) and 7 compounds that have reached clinical development phase (compounds 125 -131 ) ( Table 3 ) . All these compounds act as HIV reverse transcriptase inhibitors and fall into two categories: fl uorocytidine analogues ( 8 and 125-127 ) and trifl uoromethyl-substituted quinazolone derivatives ( 128 -131 ). Emtricitabine ( 8 ) was discovered in Emory University (Atlanta, USA); development of the drug was completed by Gilead Sciences, and the compound was approved by FDA under trade name Emtriva ® in 2003. It is also marketed in combinations with other anti-HIV agents, i.e. Tenofovir ( 132 , used as a prodrug) (Truvada ® ), Efavirenz ( 133 ) and Tenofovir (Atripla ® ), Rilpivirine ( 134 ) and Tenofovir (Complera ® ), and Elvitegravir ( 135 ), Cobicistat ( 136 ), and Tenofovir (Stribild ® ) [ 5 ] Emricitabine is a close analogue of Lamivudine ( 137 ), which is an example of nucleoside analogs -an important class of reverse transcriptase inhibitors, which has gained much attention since the initial success of the fi rst representative, Zidovudine ( 138 ) [ 128 ] (Fig. 5 ) .

Emtricitabine ( 8 ) was discovered in Emory University (Atlanta, USA); development of the drug was completed by Gilead Sciences, and the compound was approved by FDA under trade name Emtriva ® in 2003. It is also marketed in combinations with other anti-HIV agents, i.e. Tenofovir ( 132 , used as a prodrug) (Truvada ® ), Efavirenz ( 133 ) and Tenofovir (Atripla ® ), Rilpivirine ( 134 ) and Tenofovir (Complera ® ), and Elvitegravir ( 135 ), Cobicistat ( 136 ), and Tenofovir (Stribild ® ) [ 5 ] Emricitabine is a close analogue of Lamivudine ( 137 ), which is an example of nucleoside analogs -an important class of reverse transcriptase inhibitors, which has gained much attention since the initial success of the fi rst representative, Zidovudine ( 138 ) [ 128 ] .

Emtricitabine ( 8 ) is very similar to Lamivudine ( 137 ) with respect to its activity, convenience, safety and resistance profi le; the only remarkable difference is longer intracellular half-life of 8 . Analogously to 137 , the biologically active form of 8 is triphosphate 139 , which is formed by a stepwise phosphorylation of 8 (Scheme 33 ). Compound 139 can be considered as 2,3-dideoxycytidine trifosphate analogue and acts as a competitive inhibitor and alternate substrate of the normal deoxycytidine triphosphate ( 140 ). As a competitive inhibitor of the normal substrate, 139 inhibits incorporation of 140 into the growing DNA chain by viral reverse transcriptase; as an alternate substrate, it is incorporated into this chain (as 141 ) and acts as a chain terminator (since 141 is missing the 3′-hydroxyl group required for further chain elongation) [ 128 , 129 ] . Although Emtricitabine might have the potential for toxicity caused by interaction with human mitochondrial DNA enzymes, both in vitro and in vivo testing results show that this is not a serious issue. Low toxicity of 8 as compared to other nucleoside reverse transcriptase inhibitors is a remarkable advantage of this drug. As with all representatives of this class, the major drawback of 8 is rapid development of drug resistance by a single point mutation of viral reverse transcriptase [ 129 ] . The main route of elimination of 8 is renal excretion, mostly unchanged (86 % of the dose). The metabolic transformations of Emtricitabine include oxidation of the sulphur atom to form the 3′-sulfoxide diastereomers (9 %) and conjugation with glucuronic acid to give 2′-O -glucuronide (4 %) [ 130 ] .

A racemic form of Emtricitabine, Racivir, was also studied in clinics by Pharmasset and has reached Phase II trials [ 113 ], designed to measure its effi cacy in patients harbouring virus resistant to Lamivudine. It was shown that D (+)enantiomer 125 is less potent and more toxic than Emtricitabine itself. One of the reasons behind lower potency of 125 is that 8 is phosphorylated by deoxycitidine kinase to a greater extent; therefore, the active form ( 139 ) is formed more readily for (-)-enantiomer [ 131 , 132 ] .

Elvucitabine ( 126 ) and its enantiomer Dexelvucitabine ( 127 ) were discovered in Yale University (New Haven, USA) and Emory University (Atlanta, USA), respectively. Both compounds were further developed by commercial companies (Achillion Pharmaceuticals and Incyte Co., respectively), and have reached Phase II clinical trials [ 113 ] . Development of 127 was terminated due to inability to pair with other cytidine analogues and higher risk of hyperlipasemia. Phase II studies of 126 were suspended because of bone marrow suppression in several patients [ 133 ] . The mode of action of Elvucitabine is quite similar to that of Emtricitabine; the major advantages of 126 include long plasma half-life (up to ten times greater than that of 8 ) and superior potency against common resistance mutations [ 134 ] .

Four compounds DPC-961 ( 128 ), DPC-961 ( 129 ), DPC-083 ( 130 ), and DPC-082 ( 131 ) were developed by DuPont Pharmaceuticals as non-nucleoside reverse transcriptase inhibitors. Al the compounds have reached Phase I clinical trials; DPC-083 ( 130 ) was further progressed into Phase II trials by Bristol-Myers Squibb after the company had acquired DuPont Pharmaceuticals; however, the development was stopped in 2003 due to poor pharmacokinetics [ 135 ] . The compounds are close analogues of Efavirenz ( 133 ) -a non-nucleoside reverse transcriptase inhibitor approved by FDA in 1998 [ 5 ] . All the compounds 128 -131 showed similar to Efavirenz activity towards wild-type virus in vitro ; however, they were more effective towards singlemutation variants and showed lower plasma serum protein binding [ 136 , 137 ] .

It might be assumed that mechanism of action of 128 -131 is similar to that of Efavirenz, which is known to bind within the non-nucleoside inhibitor binding pocket of reverse transcriptase [ 138 ] , both spatially and also functionally associated with the substrate-binding site.

Metabolism of DPC-961 ( 128 ) was studied in rats. Analogously to Efavirenz, the main metabolite is glucuronide conjugate 142 (more than 90 % of excreted dose in the bile) (Scheme 34 ). However, a glutatione conjugate 143 was also isolated, which is presumably formed via oxirene intermediate 144 ; in this view, metabolism of 128 was different from that of 133 [ 139 ] . approach starting from D-mannose or D-galactose was used for the preparation of D-enantiomer 125 [ 141 ] .

Most of the methods describing the preparation of Emtricitabine (and Racivir) rely on the construction of 1,3-oxathiolane ring by reaction of glycolaldehyde or glyoxalic acid derivatives with mercaptoacetic acid or mercaptoacetic aldehyde (which exists as 1,4-ditiane 154 ). For example, one of the fi rst of syntheses of this type commenced from allyl alcohol which was silylated and then subjected to ozonolysis to give glycolaldehyde derivative 155 (Scheme 36 ) [ 142 ] . Reaction of 155 with mercaptoacetic acid afforded 1,3-oxathiolane 156 , which was reduced with LiAlH(O t Bu) 3 or DIBAL and then acetylated to form 157 . Finally, reaction of 157 with silylated fl uorocytosine derivative 158 followed by deprotection led to the formation of racemic 8 (Racivir). More than 15 preparations described in patents are variations of the above synthetic scheme. In particular, to obtain optically pure Emtricitabine, lipase-catalyzed enzymatic resolution, as well as chiral stationary phase HPLC was used [ 143 ] . However, the most effective procedure included separation of menthyl derivatives. This method evolved signifi cantly since the fi rst publication (which in fact relied on separation of all the 4 possible diastereomers) [ 144 ] ; one of the recent multigram preparations is shown in the Scheme 37 [ 145 ] . The fi rst step of the synthesis included formation of methyl ester 159 from glyoxalic acid and L -menthol. Reaction of 159 with 1,4-ditiane 154 gave 1,3-oxathiolane 160 as a mixture of cis diastereomers.

Compound 160 was transformed to chloride 161 by treatment with thionyl chloride and methanesulfonic acid. Reaction of 161 and 158 led to the formation of 162 , which was separated as a single diastereomer by transformation to oxalate and subsequent crystallization. Finally, reduction of 162 with NaBH 4 gave Emtricitabine ( 8 ) which was isolated as hydrochloride.

An interesting variation of the method was patented by Glaxo Wellcome Inc [ 146 ] . Their synthesis was started from 2,4-dichloro-5-fl uoropyrimidine ( 93 ) (Scheme 38 ). Reaction of 93 with NaOEt and then -with anion of 2,2-dimethoxyethanol gave pyrimidine derivative 163 , which upon detection formed aldehyde 164 . Reaction of 164 and 154 led to the formation of 1,3-oxathiolane 165 , which was acetylated to give 166 . Treatment of 166 with TMSOTf resulted in rearrangement leading to 167 , which was transformed to racemic 8 (Racivir) by reaction with ammonia.

A number of methods for the preparation of Elvucitabine ( 126 ) were reported in the literature. In the fi rst synthetic scheme developed in Yale University [ 147 ] , 2′-deoxy-5-fl uoro-β-L-uridine ( 168 ), which is enantiomer of Floxuridine ( Synthesis of Elvucitabine ( 126 ) developed by chemists from Vion Pharmaceuticals commenced from lactone 171 (Scheme 40 ), which can be obtained in 4 steps from D-glutamic acid [ 148 ] . Phenylselenation of enolate generated from 171 proceeded highly diastereoselectively and led to 172 .

Phenylselenide 172 was reduced with DIBAL and then acetylated to give acetate 173 as a mixture of anomers. Reaction of 173 with 158 was also diastereoselective due to the steric effect of bulky phenylselenyl substituent and gave β anomer 174 in almost quantitative yield. Oxidative elimination of the selenide substituent from 174 and subsequent deprotection gave Elvucitabine ( 126 ) as a single enantiomer. An analogous synthesis was described by chemists from Emory University [ 149 ] .

Syntheses of Dexelvucitabine ( 127 ) [ 150 ] and later -Elvucitabine ( 126 ) [ 151 ] were described, starting from D-and L-xylose, respectively, both using almost the same methodology. In particular, D-xylose was transformed into the dibenzoyl derivative [ 152 ] . Compound 184 was subjected to bromoacylation with excess of 2-acetoxy-2methylpropionyl bromide ( 185 ) to give a mixture of esters 186 and 187 . This mixture was subjected to reductive elimination to give 188 , which was transformed to 127 upon alcoholysis.

Another synthesis of 127 relied on palladium mediated Ferrier rearrangementtype glycosidation of a furanoid glycal (Scheme 43 ) [ 153 ] . The initial steps of 

Fluorine-Containing Diazines in Medicinal Chemistry and Agrochemistry the synthesis were quite similar to those shown in Scheme 41 . The major difference was the use of polymer-supported PPh 3 at the glycal generation step, which allowed for isolation of unstable glycal 189 with more than 90 % purity. Palladium-catalyzed reaction of 189 with 5-fl uorocytosine ( 9 ) was accompanied by Ferrier-type rearrangement and led to derivative 190 , which was transformed to 127 upon deprotection.

All the reported syntheses of DPC-961 ( 128 ) and DPC-963 ( 129 ) commenced from the corresponding o -amino-α,α,α-trifl uoroacetophenones 191 (Scheme 44 ). In the fi rst preparations of 128 and 129 , 191 reacted with TMSNCO to give adducts 192 , which were transformed to cyclic imines 193 upon dehydratation. Reaction of 193 with lithium cyclopropylacetylenide gave racemic 128 and 129 , which were subjected to chiral stationary phase HPLC to isolate 128 and 129 as pure enantiomers [ 136 , 137 ] . Several improvements were reported for this synthetic scheme. In particular, diastereoselective additions of lithium cyclopropyl acetylenide to the derivatives of 193 containing residues of α-phenylethyl amine or campheic acid were developed [ 154 , 155 ] . Moreover, an enantioselective modifi cation of this method employing amino alcohol 194 as an asymmetric catalyst was discovered [ 156 , 157 ] . Another enantioselective method involved reaction of the derivatives of 193 and cyclopropyl acetylene itself, catalysed by amino alcohol derivatives ( e.g. 195 ) and Zn(OTf) 2 [ 158 ] .

DPC-083 ( 130 ) and DPC-082 ( 131 ) were obtained by reduction of 128 and 129 , respectively, with LiAlH 4 [ 136 , 137 ] . Recently, an alternative approach to the synthesis of 130 was reported, which relied on enantioselective organocatalytic Mannich-type reaction of imine derivative 196 and cyclopropyl methyl ketone (Scheme 45 ) [ 159 ] . Although enantioselectivity of the key step was moderate ( ee 75 %), it could be easily enhanced to >99 % by a single recrystallization of intermediate 197 . 

Apart from anti-HIV drugs discussed in the previous section, two additional antiviral agents can be mentioned: Trifl uridine ( 7 ) and Favipiravir ( 198 ) . Trifl uridine ( 7 ) was mentioned above as a component of Phase III investigational drug TAS-102. It is however more known as an ophthalmic anti-herpes agent launched by Glaxo Wellcome (now merged into GlaxoSmithKline) in 1980 [ 5 ] . It is effective against herpetic keratitis, and seems to be especially useful in 'diffi cult' cases [ 160 ] . High susceptibility to biodegradation of Trifl uridine is advantageous for its use as ophthalmic drug, as its action in other tissues is thus prevented. As in the case of anti-tumor activity, the mechanism of antiviral action of 7 involves the inhibition of viral replication. Trifl uridine does this by incorporating into viral DNA during replication, which leads to the formation of defective proteins and an increased mutation rate [ 161 ] . Inhibition of thymidylate synthetase also seems to contribute into antiviral effect of 7 . The details of these processes, as well as synthesis of 7 were discussed in the above sections.

Favipiravir ( 198 ) has been discovered by Toyama Chemicals; it is currently in Phase III (Japan) and Phase II (USA) clinical trials [ 113 , 162 ] . Favipiravir is under development as an agent against infl uenza virus, however, it was also tested against other RNA viruses, including arenaviruses, bunyaviruses, West Nile virus (WNV), yellow fever virus (YFV), and foot-and-mouth disease virus (FMDV) [ 163 ] . A proposed mechanism of action of 198 includes its biotransformation into ribofuranosyltriphosphate derivative 199 (Scheme 46 ), which inhibits infl uenza virus RNA polymerase in the host cells [ 164 ] . [ 166 , 167 ] . Acidic hydrolysis of 205 gave amide 206 , which upon mild alkaline hydrolysis led to 198 . Alternatively, compound 198 was obtained by mild alkaline hydrolysis of 205 followed by reaction with H 2 O 2 -NaOH, or by reaction of 205 with allyl or benzyl alcohol, removal of the protection, and hydrolysis. Recently, an improved version of this method was patented, which allowed authors to claim its industrial applicability [ 168 ] .

One more method for the preparation of 198 commenced from pyrazine derivative 207 , which was transformed to dichloride 208 using Sandmeyer reaction (Scheme 49 ) [ 166 ] . Hydrolysis of the ester moiety in 208 followed by one-pot chloroanhydride formation, introduction of fl uorine atom and amination gave derivative 209 , which was transformed into 198 by diazotization and subsequent hydrolysis. Several other approaches to the synthesis of Favipiravir were also described, most of them relying on direct fl uorination of pyrazine derivatives with molecular fl uorine [ 166 ] All they were low-yielding and allowed for the preparation of milligram quantities of the fi nal product.

A single compound is discussed in this category, namely GSK-1322322 ( 210 ), which was developed by GlaxoSmithKline and has reached Phase II clinical trials in bacterial skin infections [ 113 ] and Phase III -in community-acquired bacterial pneumonia [ 169 ] . Compound 210 acts as an inhibitor of peptide deformylase -an enzyme that removes the formyl group during eubacterial peptide elongation. Bacterial protein synthesis initiates with formyl-methionyl-tRNA and, consequently, all polypeptides newly synthesized in bacteria contain an N -formylmethionine terminus. This residue is further removed in two steps catalyzed by peptide deformylase and methionine aminopeptidase, respectively. Inhibition of peptide deformylase increase production of bacterial N -formylated polypeptide, which prevents bacteria growth and possibly triggers an enhanced immune response [ 170 ] . Peptide deformylase is a metalloprotease, which mostly utilizes Fe 2+ in its active site. It was shown for analogs of 210 that N -formyl-N -hydroxylamine function coordinated to metal ion when the inhibitor was bound to the enzyme [ 171 ] .

Synthesis of 210 was started from preparation of chiral diamine 211 (Scheme 50 ) [ 172 ] . In particular, D -serine methyl ester was converted to N -benzyl derivative 212 , which was transformed into carboxylic acid 212 using reaction with chloroacetyl chloride and subsequent hydrolysis. Carboxylic acid 212 was subjected to coupling with benzyl amine, reduction, reaction with ethyl oxalyl chloride and reductive cyclization to give bicyclic compound 213 . Finally, 211 Two-step reduction of 213 led to the formation of diamine 211 , which was isolated as dihydrochloride. Reaction of 211 with dichloro derivative 215 and then -hydrazine hydrate gave the product 216 , which was coupled with carboxylic acid 217 and subjected to catalytic hydrogenation to give 210 . 

Two drugs were launched as anti-fungal agents to date: Flucytosine ( 9 ) (Valeant, 1971) and Voriconazole ( 10 ) (Pfi zer, 2002) (Fig. 6 ) [ 5 ] . Flucytosine itself has no antifungal activity; its activity results from the rapid conversion into Fluorouracil ( 1 ) within susceptible fungal cells [ 173 ] . The mechanism of cytotoxic effect of Fluorouracil has been discussed in the previous sections. Flucytosine is taken up by fungal cells by cytosine permease, which is the transport system for cytosine and adenine. Inside the fungal cells, 9 is deaminated to 1 by cytosine deaminase. The specifi city of this step is crucial for the narrow antifungal spectrum of 9 : mammalian cells as well as fungi lacking cytosine deaminase are not sensitive to 9 . On the other hand, Fluorouracil itself cannot be used as an antifungal drug, since it is only poorly taken up by fungal cells and is too toxic to human cells. The major drawback of Flucytosine is rapid development of resistance in fungi, either by mutations or by increased synthesis of pyrimidines; this limits the use of 9 as a single antifungal agent. Monotherapy with Flucytosine is currently only used in some cases of chromoblastomycosis and in uncomplicated candidosis; in all other cases, 9 is used together with other agents, usually Amphotericin B [ 173 ] .

The effect of Voriconazole ( 10 ) is exerted within the fungal cell membrane. In particular, cytochrome P450-dependent 14-α-lanosterol demethylase is inhibited, which prevents the conversion of lanosterol ( 217 ) to ergosterol ( 218 ) -an important component of yeast and fungal cell membranes which does not occur in mammalians (Scheme 51 ). This mechanism results in the accumulation of toxic methylsterols and inhibition of fungal cell growth and replication [ 174 ] . Voriconazole is active against many fungal infections, including invasive aspergillosis, Pseudallescheria , Scedosporium , Fusarium infections [ 175 ] . It is also proposed for empirical antifungal therapy [ 176 ] . An important advantage of Voriconazole is high oral bioavailability (96 %). The most common side effect, which is unique for Voriconazole among other azole antifungals, is a reversible disturbance of vision (photopsia): it occurs in nearly a third of patients but rarely leads to discontinuation of the drug [ 174 ] . Resistance to Voriconazole still remains uncommon, although an increase of resistance and continued surveillance with greater use of the drug has been reported [ 177 ] .

The fi rst synthesis of Flucytosine ( 9 ) has been reported in 1957 [ 13 , 14 ] . The synthetic scheme is quite similar to that for Fluorouracil ( 1 ); in the case of 9 , compound 27 was subjected to reaction with PCl 5 and then -liquid ammonia to give 219 , which was transformed to 9 upon hydrolysis (Scheme 52 ). In an alternative method, compound 70 (prepared from Fluorouracil) reacted with SOCl 2 to give 220 , which was transformed to 9 upon reaction with ammonia in methanol [ 84 ] . Another synthesis commenced from 2,5-difl uoro-4-chloropyrimidine, which, however, is not readily accessible [ 178 ] . Flucytosine was also obtained by direct fl uorination of cytosine using CF 3 OF (85 % yield) [ 179 , 180 ] , fl uorine [ 181 , 182 ] , and AcOF [ 20 ] . Despite numerous syntheses of Voriconazole ( 10 ) were documented, they all followed the same synthetic strategy, namely, addition of anion 221 to ketone 222 , followed by isolation of necessary diastereomeric pair and its resolution with 10-camphorsulphonic acid (Scheme 53 ). Three different approaches were used for the generation of anion 221 or the corresponding organometallic species. First of them relied on deprotonation of the pyrimidine derivative 222 (prepared from the fl uorinated keto ester 223 or dichloro derivative 93 ) by strong bases such as LDA (Scheme 54 ) [ 183 -189 ] .

The main drawback of this method was low diastereoselectivity of the key step; therefore tedious separation of diastereomers was necessary. Another approach to generation of 221 relied on ZnCl 2 -catalyzed decarboxylation of salts 224 , prepared from 225 (Scheme 55 ) [ 190 ] . In this case, the desired diastereomeric pair was obtained with much better selectivity (6.5: 1). The last approach relied on Reformatsky-type reaction involving 222 and bromides 226 (prepared from 223 [ 191 , 192 ] or its thio analogues [ 193 -195 ] ) or sulfonates 227 (prepared from 93 ) (Scheme 56 ) [ 196 , 197 ] . In this case, good diastereoselectivities were obtained. 

Seven compounds designed as agents acting at central and/or peripheral nervous system have reached at least Phase II clinical trials, and only one of them was launched (Table 4 ) [ 3 , 113 ] . These compounds address different biological targets and act as skeletal muscle relaxants (Afl oqualone ( 11 )), antipsychotics 

A representative of fl uorinated diazines, Afl oqualone ( 11 ), was launched in 1983 in Japan as a central acting muscle relaxant [ 198 ] . It is an analogue of Methaqualone ( 234 ) (Fig. 7 ) -a drug widely used as a hypnotic, for the treatment of insomnia, and as a sedative and muscle relaxant in 1970s, but reclassifi ed as a Schedule I controlled substance in USA in 1984 [ 199 ] .

The mechanism of action of Afl oqualone is not well studied. It was shown that its site of action is different from that of other central acting muscle relaxants, i.e. Mephenesin, Chlormesazone or Diazepam [ 200 ] . GABA-enhancing effect was also demonstrated [ 303 ] . The main routes of metabolism of 11 in human include N -acetylation, followed by hydroxylation at the 2′-methyl and acetyl methyl carbons, as well as glucuronidation of the aromatic amino group. This pattern of metabolism is similar to that observed in monkeys and rats, but drastically different from that in dogs [ 304 ] .

Synthesis of Afl oqualone commenced from 5-nitroanthranilic acid ( 235 ) which was transformed to amide 236 via the corresponding chloroanhydride (Scheme 57 ) [ 201 ] . Catalytic reduction of 236 followed by acetylation gave 237 , which reacted with chloroacetyl chloride to form quinazoline 238 . Nucleophilic substitution of chlorine atom in 238 with fl uorine led to the formation of 239 , which upon deprotection gave Afl oqualone ( 11 ). Alternatively, compound 236 was subjected to acylation with fl uoroacetyl chloride or anhydride to give amide 240 [ 202 ] . Refl uxing of 240 with acetic anhydride gave quinazoline 241 , which was reduced to Afl oqualone either by catalytic hydrogenation or using SnCl 2 .

All three compounds discussed in this section ( i.e. 228 -230 ) have reached Phase II clinical trials as agents for treatment Schizophrenia. Development of BMY-14802 ( 228 ) was discontinued more than 10 years ago. Fluorine-Containing Diazines in Medicinal Chemistry and Agrochemistry noted that relative role of these two targets in biological effect of 228 was debated in the literature. Whereas in pigeons, the effect was serotonergically mediated primarily through 5-HT 1A receptors [ 203 ] , in other model systems, these interactions did not seem to contribute signifi cantly to the potential antipsychotic action of the compound [ 204 ] . Although studies in animal models supported for the suggestion that BMY-14802 ( 228 ) may possess antipsychotic properties [ 205 ] , clinical trials showed lack of effi cacy in Schizophrenia treatment [ 206 ] . Recently, BMY-14802 was proposed as a promising candidate for clinical trials of L -DOPA-induced dyskinesia -a common side effect observed during prolonged use of L -DOPA in Parkinson disease patients [ 207 ] . It was shown that the compound suppresses abnormal involuntary movements related to L -DOPA-induced dyskinesia via its 5-HT 1A agonistic effect.

ABT-925 ( 229 ) developed by Abbott is a selective D3 receptor antagonist [ 208 ] . It was suggested that selective antagonists of D3 receptor might be promising antipsychotic agents lacking the presumed D2 receptor-mediated side effects, although D3 antagonists may express their effect via mechanisms that cannot be refl ected by the commonly used animal models [ 209 ] . It was shown that ABT-925 produced cognitive signals but did not achieve suffi cient D3 receptor occupancy at the doses used in clinical studies [ 210 ] . Nevertheless, these studies allowed for the assumption that the development and clinical testing of newer D3 receptor antagonists with higher potency at D3 receptors, enabling suffi cient receptor occupancy, is highly warranted [ 211 ] .

On the contrary, JNJ-37822681 ( 230 ) is a D2 highly selective receptor antagonist and hence acts in a mode analogous to that of most marketed antipsychotics [ 212 ] . JNJ-37822681 is characterized by a rapid dissociation rate from the dopamine D2 receptor, which was hypothesized to confer antipsychotic effi cacy and improved tolerability [ 213 ] . Clinical studies in patients with an acute exacerbation of schizophrenia showed that JNJ-37822681 had similar biological activity but lesser tendency to induce weight gain compared to a known antipsychotic drug, Olanzapine ( 242 ) [ 214 ] (Fig. 8 ) .

Synthesis of BMY-14802 ( 228 ) commenced from pyrimidine derivative 243 which reacted with piperazine 244 to give derivative 245 (Scheme 58 ) [ 215 , 216 ] . Reduction of the compound 245 followed by deprotection gave amine 246 , which was alkylated with chloride 247 and then subjected to acidic hydrolysis to form ketone 248 . Reduction of 248 allowed BMY-14802 ( 228 ) to be obtained. Pure enantiomers of 228 were also obtained. To achieve this, the following methods were used: resolution of 228 with using reaction with α-phenylethyl isocyanate [ 217 ] or lipase-catalyzed acetylation or hydrolysis [ 218 ] , alkylation of 245 with enantiopure alcohols 249 [ 219 ] ; and microbial reduction [ 305 ] or Ru-catalyzed enantioselective hydrogenation [ 220 ] of 248 . ABT-925 ( 229 ) was obtained starting from amidine 250 and ethyl trifl uoroacetoacetate to give pyrimidine 251 (Scheme 59 ) [ 221 ] . Reaction of 251 with SOCl 2 and then -piperazine led to the formation of amine 252 . Selective alkylation of 252 with 1-bromo-3-chloropropane gave chloride 253 , which reacted with thiouracil anion to form ABT-925 ( 229 ).

BMY-21502 ( 231 ) was developed by Bristol-Myers Squibb as nootropic agent ( i.e. for cognition disorders) and has reached Phase II clinical studies. The compound was effective in vitro [ 223 ] as well as in animal models [ 223 -227 , 306 ] that may predict cognitive enhancement. The mode of action of BMY-21502 is poorly understood. It was shown that the compound has an anti-anoxic action, and activation of the CNS cholinergic system is involved as one of the causative mechanisms for this effect [ 228 ] . Clinical trials showed that BMY-21502 was not significantly superior to placebo in Alzheimer's disease; moreover, although generally well tolerated, 231 also had a higher rate of discontinuations [ 229 , 230 ] .

Synthesis of BMY-21502 ( 231 ) optimized for large scale preparations commenced from malonodiamide and ethyl trifl uoroacetate, which reacted to give pyrimidine 255 (Scheme 61 ) [ 231 ] . Compound 255 was transformed into dichloro derivative 256 upon treatment with POCl 3 . Reaction of 256 with piperidine 257 (prepared from 4-pyridinylmethyl chloride in two steps) gave 258 , which was reduced catalytically to form BMY-21502 ( 231 ). Alternatively, BMY-21502 was obtained by arylation of 257 with 4-chloro-2-trifl uoromethylpyrimidine ( 259 ) [ 232 ] .

Synthesis of JNJ-37822681 ( 230 ) was quite trivial and relied on selective functionalization of 4-aminopiperidine core, fi rst with 3-chloro-6-trifl uoromethylpyridazine ( 254 ) and then -with 3,4-difl uorobenzaldehyde (Scheme 60 ) [ 222 ] . . BW-4030W92 ( 232 ) was developed as a CNS-acting antihyperalgesic agent ( i.e. for treatment of increased sensitivity to pain). It is an analogue of anticonvulsant drug Lamotrigine ( 260 ) (Fig. 9 ) , used n the treatment of epilepsy and bipolar disorder [ 233 ] . Like Lamotrigine, BW-4030W92 binds to the transmembrane segment S6 in domain IV of α subunit of voltage-gated sodium channels (Na v ), thus acting as a pore blocker [ 234 ] . It is assumed that neuropathic pain is partially mediated by an increase in the density of Na V channels in injured axons and their dorsal root ganglions. Clinical studies in patients with chronic neuropathic pain showed that although BW-4030W92 signifi cantly lowered allodynia severity at the fi rst day, the effect did not maintain in further treatment [ 235 ] . GW-842166X ( 233 ) is a selective CB2 receptor full antagonist which has potent analgesic, anti-infl ammatory and anti-hyperalgesic actions. It was selected as a clinical candidate after lead optimization of a pyrimidine ester 261 (GK02076, Fig. 9 ) , identifi ed in a focused screen as a partial agonist at the CB2 receptor with micromolar potency [ 236 ] . The compound was evaluated as an analgesic for treatment of infl ammatory pain (Phase I trials) and dental pain (Phase II trials) [ 113 ] . In the latter study, single doses of GW842166 failed to demonstrate clinically meaningful analgesia in the setting of acute dental pain [ 237 ] . Fluorine-Containing Diazines in Medicinal Chemistry and Agrochemistry trifl uoride (DAST) to give racemic 232 . Alternatively, nitrile 263 reacted with ethyl fl uoroacetatet -BuOK and then -ethyl iodide to give enol ether 267 , which was transformed to racemic 232 by reaction with guanidine. Resolution of enantiomers of 232 was achieved by crystallization of dibenzoyl-L -tartaric acid salt; the more active R -enantiomer was isolated.

In the synthesis of GW-842166X ( 233 ), commercially available pyrimidine 268 reacted with 2,4-dichloroaniline to give ester 269 , which was subjected to hydrolysis followed by amide coupling with 4-aminomethyltetrahydropyran ( 270 ) to afford 233 (Scheme 63 ) [ 236 , 239 , 240 ] . 

In the previous sections, compounds targeting cancer cells or nervous system, as well as those fi ghting foreign organisms were discussed.

Three compounds do not fall into any of these categories. Fostamatinib disodium ( 88 ) was mentioned above as an anti-cancer investigational drug, but it was also studied as agent for autoimmune diseases, i.e. rheumatoid arthritis (currently in Phase III) and autoimmune thrombocytopenia (in Phase II). Gemigliptin ( 12 ) was approved as an anti-diabetic drug in South Korea in 2012. PF-04634817 ( 271 ) was discontinued after Phase I studies as an agent for liver fi brosis; nevertheless, it is currently investigated in diabetic nephropathy (Fig. 10 ) (Phase II, October 2012) [ 113 ] .

As it was mentioned in the previous sections, the active principle of Fostamatinib disodium ( 88 ) is Tamatinib ( 92 ), which is formed by enzymatic hydrolysis of 88 in the intestine. As in the case of lymphoma, the effect of 88 in autoimmune diseases is related to inhibition of Spleen tyrosine kinase (Syk) by 92 [ 241 , 242 ] . As Syk has the central role in transmission of activating signals within B cells, inhibition of this enzyme lowers expression of a number of proinfl ammatory cytokines and hence leads to immunosuppression [ 243 ] . Fostamatinib has shown signifi cant effi cacy in the treatment of patients with rheumatoid arthritis not responding to Methotrexate ( 272 ) (a drug which is used conventionally in therapy), although a number of adverse events were observed [ 244 ] . If these results are confi rmed once Phase III studies are completed, it may fi nd a place in the treatment of patients with rheumatoid arthritis with poor response to conventional therapy (Fig. 11 ) . Gemigliptin ( 12 ) was developed by LG Life Sciences as an inhibitor of dipeptidyl peptidase 4 (DPP-4) -a target of oral drugs used to treat used to treat type 2 diabetes (characterized by high blood glucose in the context of insulin resistance and relative insulin defi ciency) [ 245 ] . The fi rst representative of this class, Sitagliptin ( 273 ) was launched in 2006. In human body, Gemigliptin is metabolized to LC15-0636, which is a major active metabolite, by cytochrome P450 3A4 isozyme [ 246 ] . Inhibition of DPP-4 results in increase of incretin levels (which is normally inactivated by DPP-4), in particular glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP) [ 247 ] . Incretins inhibit glucagons release and stimulate insulin secretion, which leads to decrease in glucose blood levels. Clinical trials showed effi cacy and safety of Gemigliptin administered once daily as a monotherapy, [ 248 ] as well as in addition to Metformin ( 274 ) [ 249 ] for type 2 diabetes patients.

PF-04634817 ( 271 ) is a Phizer's investigational drug, initially developed as agent for liver fi brosis -formation of excess fi brous connective tissue in liver [ 250 ] . The development of the compound was discontinued since February 2012 after Phase I trials. Recently, a Phase II study of PF-04634817 in diabetic nephropathya progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli [ 251 ] -was registered [ 113 ] . PF-04634817 is an antagonist of chemokine receptors ( i.e. CCR2 and CCR5) [ 252 ] . These chemokine receptors are important players in the traffi cking of monocytes/macrophages and in the functions of other cell types relevant to pathogenesis of many diseases [ 253 ] , including liver fi brosis [ 307 ] and diabetic nephropathy [ 254 ] .

Gemigliptin ( Synthesis of optically active PF-04634817 ( 271 ) based on commercially available (-)-Vince Lactam as chirality source. Starting from (-)-Vince Lactam the chiral key 4-amino-2-cyclopentene-1-carboxylic acid derivative 286 was synthesized. The compound 286 is dimethyl pyrrole protected form of corresponding aminoacid, which was subjected to amide coupling with Boc-protected diamine 287 to give amine 288 (Scheme 65 ) [ 252 ] . Removing of the pyrrole function followed by catalytic hydrogenation gave amine 289 , which was subjected to reductive amination of ketone 290 , separation of diastereomers, deprotection and then -arylation with pyrimidine derivative 291 to afford the fi nal product, 271 .

Agrochemistry is one of more important fi eld of application of the fl uorinated compounds which is widely recognized [ 256 , 257 ] (Fig. 12 ).

Uracil derivatives Butafenacil ( 292, Inspire®, Rebin®) and Benzfendizone ( 293 ) were introduced as herbicides in 1998, whereas their pyridazine-derived analogue Flufenpyr-ethyl ( 295 ) -in 2000 [ 258 ] . Butafenacil (developed by Syngenta AG) is used for weed control in grapes, nut crops, pome and stone fruits and also as a cotton defoliant [ 259 ] . It was registered in Australia and approved by U. S. environmental protection agency. Benzfendizone (developed by FMC Corporation) is a post-emergence herbicide that provides good control of grass and broadleaf weeds in tree fruits and vines, as a cotton defoliant, and in total vegetation control [ 256 ] . Flufenpyr-ethyl (developed by Sumitomo Chemical Company) was registered in USA for use on corn, soybeans and sugarcane [ 259 ] . The most recent example is Safl ufenacil ( 294 , Kixor®), introduced by BASF in 2009 for preplant burndown and selective PRE dicot weed control in multiple crops, including corn. [ 260 ] . Compounds 292 -295 act as inhibitors of protoporphyrinogen oxidase (Protox) -an enzyme in the chloroplasts of the plant cells that oxidizes protoporphyrinogen IX ( 303 ) to produce protoporphyrin IX ( 304 ) (Scheme 66 ) [ 261 ] . In turn, 304 is a precursor molecule for both chlorophyll and heme. When protoporphyrinogen oxidase is inhibited, protoporphyrinogen IX is accumulated and transferred from chloroplasts into the cytoplasm, where non-enzymatic conversion of 303 to 304 occurs. When present in cytoplasm, 304 is cytotoxic due to interaction with oxygen upon action of light, which results in formation of singlet O 2 molecules. 1 O 2 causes lipid peroxidation, membrane disruption and plant cell death. Butafenacil is known to be eye, skin and respiratory tract irritant in humans [ 262 ] . It also demonstrated very high toxic effect to algae, and moderate toxicity to fi sh, aquatic invertebrates and honeybees. For Benzfendizone and Flufenpyr-ethyl, no reports on toxic effects are available. Acute mammalian toxicology studies of Safl ufenacil indicate that herbicide has low toxicity for mammals after ingestion, dermal exposure or inhalation. It is not an irritant for eyes and skin and does not act as a sensitizer.

Studies of the structure-activity relationship (SAR) of uracile derivatives as protox inhibitor showed that presence of a polyfl uorinated alkyl group at position 6 of the uracil ring critical. Alkyl groups such as methyl at position 6 of the uracil ring resulted in compounds with low or no biological activity [ 263 ] .

Limited data are available on the synthesis of Butafenacil ( 292 ). In particular, it was prepared by esterifi cation of carboxylic acid 305 , [ 264 ] as well as by reaction of isocyanate 306 with ester 307 (Scheme 67 ) [ 265 ] . Preparation of neither 305 nor 306 was disclosed in the corresponding patents, although synthesis of carboxylic acid 305 was partially described elsewhere [ 266 ] .

Benzfendizone ( 293 ) was obtained from ethyl trifl uoromethylaminocrotonate ( 308 ) which reacted with isocyanate 309 in the presence of NaH and then directly methylated to give 310 (Scheme 68 ) [ 267 ] . Demethylation of phenol moiety in 310 followed by alkylation with benzyl chloride 311 gave Benzfendizone. In the preparation of Flufenpyr-ethyl ( 295 ), hydrazones 318 or 319 were the key synthetic intermediates (Scheme 70 ) [ 269 -271 ] . Both compounds 318 and 319 were prepared by reaction of dibromoketone 320 and the corresponding hydrazines 321 and 322 , in turn obtained by reduction of diazonium salts 323 and 324 . Alternatively, hydrazone 319 was prepared by reaction of 324 and ethyl trifl uoroacetoacetate, followed by hydrolysis and decarboxylation.

Further transformations of 319 included reaction with (carbethoxylidene)triphenylphosphorane resulting in the formation of pyridazine derivative 327 . Acidic hydrolysis of 327 led to 328 , which was alkylated with ethyl bromoacetate to give 295 (Scheme 71 ). Alternatively, either 318 or 319 reacted with methylmalonic acid to give adducts 329 or 330 , which underwent cyclization upon heating with carboxylic acid and a base to give 331 and 327 , respectively. Both 331 and 327 were transformed to Flufenpyr-ethyl ( 295 ) as described above (Scheme 72 ).

Compounds discussed in this section are derivatives or analogues of sulfonylurea herbicides -agrochemicals which began the present low-dose era of herbicide chemistry in 1970s [ 257 ] . Primisulfuron-methyl ( 299 ) (from Ciba-Geigy Corporation and Syngenta AG) is a sulfonylurea derivative introduced in 1990

[ 262 ]. It is used for post-emergence control of actively growing weeds in corn and in non-cropland areas [ 272 ] . Cloransulam-methyl ( 296 ), Florasulam ( 298 ), and Diclosulam ( 297 ), all developed by Dow AgroSciences, are examples of the triazolopyrimidine sulfonanilide herbicides; they were introduced in 1998, 1999, and 2000, respectively. Cloransulam-methyl is used for soil-applied and post-emergence control of broadleaf weeds in soybeans [ 273 ] . Florasulam is a highly-selective broadleaf herbicide which is registered for use in cereals in many countries around the world. Diclosulam-based products are registered for use to control annual and certain perennial broadleaf weeds; they can be can be applied as soil, foliar, or burndown treatments in crops such as sugar cane, peanuts and soybeans and in forestry applications.

Compounds 296 -299 inhibit acetohydroxy acid synthase (AHAS), formerly known as acetolactate synthase. Its activity is not present in animals, but it has been found in all plants where measurements have been attempted. Acetohydroxy acid synthase catalyses the fi rst step in production of branched amino acids (leucine, valine and isoleucine) (Scheme 73 ), which are obviously needed for the protein synthesis and cell growth. The compounds 296 -299 seem to bind within the substrate-access channel of the enzyme, thus blocking α-ketocarboxylate access to the active site. While these herbicides are undoubtedly highly successful, resistance developed due to mutations within AHAS is becoming a serious problem [ 274 , 275 ] . Primisulfuron-methyl is a slightly toxic for skin, inhalation and eye exposure, with little metabolic activity in mammalian. It is slightly toxic to freshwater fi sh, aquatic organisms and to marine shrimp and has no toxic effect on birds and honeybees [ 276 ] . Cloransulam-methyl can be highly toxic to certain aquatic plants and algae on an acute basis; it is practically nontoxic to other non-plant organisms. Florasulam is highly toxic to aquatic organisms and slightly toxic to birds, and Diclosulam is very highly toxic to aquatic organisms [ 272 ] .

In contrast to uracile herbecides in which CF 3 -group is critical for activity in fl uorinated triazolopyrimidine series fl uorine atom responsible for the methabolitic transformation of the herbecides. The different metabolic pathway of the triazolopyrimidine herbicide diclosulam and Cloransulam-methyl are guided by the fl uorine atom at the 7-position on the triazolopyrimidine ring system (Scheme 74 ). The predominance of one pathway is very crop specifi c. In cotton, 296 and 297 are metabolized by the displacement of the 7-fl ouro substituent on the triazolopyrimidine ring by a hydroxy group, forming 332 . Its soybean selectivity is attributed to facile conjugation with homo-glutathion (homoGSH), which displaces the 7-fl uoro substituent ( 333 ). This mechanism was found to only occur in soybeans for these herbecides. In maize and wheat, 296 and 297 are detoxifi ed by hydroxylation at the 4-th position on the aniline moiety ( 334 ) followed by subsequent glycosidation [ 277 ] . Cloransulam-methyl ( 296 ) and Diclosulam ( 297 ) were obtained by reaction of sulfonyl chloride 340 with the corresponding aniline derivatives (Scheme 75 ). Synthesis of 340 commenced from dichloropyrimidine 335 [ 278 ] , which reacted with KF and then -hydrazine hydrate to give 337 . Reaction of 337 with CS 2 /Et 3 N and then -benzyl chloride was accompanied by Dimroth rearrangement and gave The synthesis of Primisulfuron-methyl ( 299 ) started from reaction of diethyl malonate and thiourea (Scheme 77 ) [ 284 ] . The resulting pyrimidine derivative 348 was methylated, difl uoromethylated and then oxidized to give sulfone 351 . Reaction of 351 with aqueous ammonia gave heteroaromatic amine 352 , which was transformed to Primisulfuron-methyl ( 299 ) upon treatment with isocyanate 353 .

Fluoxastrobin ( 300 ) is a pesticide from Bayer CropScience for the control of fungal diseases, which was registered by U. S. environmental protection agency (EPA) in 2005 [ 276 ] . Fluoxastrobin is used on peanuts, tuberous and corm vegetables, leaf petiole vegetables, fruiting vegetables and turf. Fluacrypyrim ( 301 ) was discovered by BASF AG and introduced in 2002 by Nippon Soda Co., shows acaricidal effect against all stages of tetranychid [ 285 ] . Both 299 and 300 are representative of strobilurin family with parent compound Strobilurin A ( 354 ) (Fig. 13 ) , discovered in late 1970s [ 286 ] . Interestingly, Fluacrypyrim ( 301 ) is the fi rst representative of strobilurin family which is not used as a fungicide.

Strobilurins are the part of the larger group of the so-called quinone outside inhibitors (QoI) -compounds which act at the quinol outer binding site of the cytochrome bc 1 complex. This enzyme, also referred to as ubiquinol: ferricytochrome c reductase, or complex III, is the third complex in the electron transport chain -a cascade of enzymes which couples electron transfer between NADH and O 2 with the transfer of H + ions across a membrane to generate chemical energy in the form of adenosine triphosphate (ATP) [ 287 ] . The overall result of the reaction catalyzed by cytochrome bc 1 complex is reduction of ferricytochrome c by oxidation of ubiquinol ( 355 ) and the concomitant pumping of 4 protons from the mitochondrial matrix to the intermembrane space. The mechanism of this process is too sophisticated to be discussed herein. It is important that the enzyme has two binding sites for the substrate 355 or its oxidized form 356 (Fig. 14 ) , i.e. outer (Q 0 ) and inner (Q 1 ), and the quinone outside inhibitors bind to the outer site. This leads to inhibition of mitochondrial respiration -a process which is essential to all living organisms. The selective biological effect of quinone outside inhibitors on certain organisms ( i.e. fungi or mites) is achieved by differential penetration and degradation between various species, leading to a combination of high fungicidal (or acaricidal, in the case of 301 ) potency and good crop safety [ 288 ] . Unfortunately, resistance has already evolved to this class of pesticides in some plant pathogens in certain geographical areas [ 289 ] . Although the in vitro fungicidal activity of the natural strobilurin A was discovered soon, its agrobiological testing in vivo was diffi cult because of its volatility and the inherent lability of the ( E,Z,E )-triene system, which resulted in rapid photolytic or metabolic degradation. The unusual structural simplicity of this natural product soon made it a target for chemical derivatization. Below a set of isosterical replacement in a course of lead optimization of natural strobirulin A leading to commercial synthetic products shown on the Fig. 15 .

The fi rst sequence leads to fi rst commercialized strobilurin azoxystrobin (1996, Amistar®, Syngenta) and than to fl uoxastrobin ( 300 ), which structure combines a methoximino 5,6-dihydro-1,4,2-dioxazin-2-yl toxophore (Bayer toxofore) with an optimally adjusted side-chain bearing a 6-(2-chlorophenoxy)-5-fl uoro-pyrimidin-4yl-oxy moiety as an essential element. Fluoxastrobin ( 300 ) has an advantage as no reorientation of the toxophore is necessary for binding to the target. The SARs studies indicate that the fl uorine atom has a benefi cial effect on the phytotoxicity and leaf systemicity. Another sequence leads to Picoxystrobin (2002, Acanto®, Syngenta), which has a 6-CF 3 -pyridin-2-yl moiety in its arylalkyl ether side-chain. An indication switch from the fungicidally to acaricidally active strobilurin type with β-methoxyacrylate pharmacophore is achieved by exchange of the 6-CF 3pyridin-2-yl moiety in the arylalkyl ether side-chain of Picoxystrobin with a 2-i PrO-6-CF 3 -pyrimidin-4-yl moiety to give fl uacrypyrim ( 301 ).

Fluoxastrobin ( 300 ) was obtained by reaction of compounds 359 and 360 in the presence of K 2 CO 3 (Scheme 78 ) [ 290 ] . Compound 359 was prepared by reaction of 4,5,6-trifl uoropyrimidine ( 358 ) with potassium o -chlorophenolate. In turn, 358 was obtained from 5-chloro-4,6-difl uoropyrimidine ( 357 ) by reaction with KF. Preparation of Fluacrypyrim ( 301 ) started with reaction of O -isopropylisourea hydrochloride and ethyl trifl uoroacetoacetate to give pyrimidine 361 (Scheme 80 ) [ 292 ] . Alkylation of 361 with bromide 362 (or the corresponding chloride 363 [ 293 , 294 ] ) in the presence of alkali or K 2 CO 3 gave Fluacrypyrim. Cu 2 O-catalyzed alkylation of 361 was also developed for the synthesis of 300 [ 295 ] . Compounds 362 and 363 were obtained using several closely related methods. In particular, TiCl 4 -mediated reaction of chloride 366 and methyl orthoformate was used to obtain 363 (Scheme 81 ) [ 293 , 294 ] . Alternatively, 366 reacted with methyl formate in the presence of TiCl 4 -Et 3 N to give 367 , which was treated with p -toluenesulfonic acid in methanol to give 363 . Yet another method included reaction of 367 with methyl orthoformate to give 368 , which was transformed to 363 upon treatment with methanesulfonic acid.

Another approach to Fluacrypyrim ( 301 ) commenced from pyrimidine derivative 364 , which reacted with methyl formate in the presence of TiCl 4 -Et 3 [ 293 , 294 ] . Methylation of 365 using methyl orthoformate or dimethyl sulphate and alkali led to the formation of 301 .

The last pesticide from this section is Flufenerim (Flumfen® 302 ), which is under development by Ube Industries as an insecticide. It is reported to control aphids, whitefl ies, and cotton leafworm, but has no activity against thrips [ 296 ] . Since Flufenerim is chemically related to Pyrimidifen (Miteclean® 369 ) (Fig. 16 ) , it was initially believed to have similar mechanism of action, i.e. inhibition of the mitochondrial electron transport of NADH dehydrogenase (NADH: ubiquinone oxidoreductase, complex I) -an enzyme which transfers electrons from NADH to ubiquinone and hence opens the electron transport chain cascade. Nevertheless, it was shown that 302 reduced activity of acetylcholinesterase -an effect which possibly can be addressed to interaction with other systems [ 297 ] .

Flufenerim ( 302 ) was prepared from 4,5-dichloro-6-ethylpyrimidine ( 347 ) (Scheme 82 ) [ 298 ] . Compound 370 was chlorinated with chlorine gas; the product 371 thus obtained was subjected to nucleophilic substitution with AcOK to give acetate 372 , which upon hydrolysis and subsequent reaction with diethylaminosulphur trifl uoride (DAST) gave fl uoride 374 . Finally, reaction of 374 with amine 375 led to the formation of Flufenerim ( 302 ).

Since discovery of the fi rst fl uorinated diazine -antineoplastic agent 5-fl uorouracil more than 20 compounds from the class were introduced into the market. Undoubtedly the success was achieved due to joint progress of medicinal chemistry, agrochemistry as well as synthetic methods of heterocyclic and fl uoroorganic chemistry. The continued progresses in these fi elds of science allow us to predict that the number of fl uorine containing diazines as drugs or agrochemicals on the market will be increased. Recent trends in using of perfl uorinated diazines as core scaffold for the synthesis of a diverse array of polysubstituted fl uorinated diazines for HTS increases probability of these compounds as potential hits and leads. Also the new methodologies of direct introduction of fl uorinated substituent, like Baran approach, continue to appear facilitating further investigation. Moreover in the chemical space covered by fl uorinated diazines remains "white spots". Thus diazine scaffold decorated by important in med and agrochem fl uorinated fragments such as -CHF 2 , -CH 2 CF 3 , -OCF 3 , -SCF 3 , -SF 5 not investigated because the synthetic chemistry of these compounds on development phase or not developed at all. Therefore the comprehensive investigations in the fi eld of fl uorinated diazines still are interesting both for academic and industrial scientists. 

Fluorine in medicinal chemistry

Fluorine in medicinal chemistry: a century of progress and a 60-year retrospective of selected highlights

Elsevier MDL, version 2012.1

Fluorinated pyrimidines, a new class of tumourinhibitory compounds

United States food and drug administration www.fda.gov

Studies in 2-acetylaminofl uorene carcinogenesis. 3. The utilization of uracil-2-C-14 by preneoplastic rat liver and rat hepatoma

-fl uorouracil: mechanisms of action and clinical strategies

5-fl uorouracil: forty-plus and still ticking. A review of its preclinical and clinical development

Medicinal chemistry of anticancer drugs

Cancer drug discovery and development: combination cancer therapy: modulators and potentiators

Fluorouracil: biochemistry and pharmacology

The catalytic mechanism and structure of thymidylate synthase

The synthesis of 5-fl uoropyrimidines

Process for fl uorinating uracil and derivatives thereof

Process for production of 5-fl uorouracil and its derivatives

Process for producing 5-fl uorouracil

Preparation of thymidine and deoxyfl uorouridine, and intermediates therefor

Über die Reaktion von Uracil und seinen Nucleosiden mit elementarem Fluor

Reaction of acetyl hypofl uorite with pyrimidines. Part 3. Synthesis, stereochemistry, and properties of 5-fl uoro-5,6-dihydropyrimidine nucleosides

Nucleic acid related compounds. 21. Direct fl uorination of uracil and cytosine bases and nucleosides using trifl uoromethyl hypofl uorite. Mechanism, stereochemistry, and synthetic applications

Nucleic acid related compounds. III. Facile synthesis of 5-fl uorouracil bases and nucleosides by direct fl uorination

Clinical colorectal cancer: ode to 5-fl uorouracil

5-fl uorouracil derivatives: a patent review

Verfahren zur Herstellung von N1-(2′Tetrahydrofuryl)-und N1-(2′Tetrahydropyranyl)-Derivaten 5-substituierter Urazile und deren Alkalimetallsalzen USSR 2218

N1-(2′-furanidyl)-derivatives of 5-substituted uracils

Involvement of microsomal cytochrome P450 and cytosolic thymidine phosphorylase in 5-fl uorouracil formation from tegafur in human liver

Formation pathways of γ-butyrolactone from the furan ring of tegafur during its conversion to 5-fl uorouracil

Comparison of gastrointestinal toxicity of 5-FU derivatives

A phase I safety and pharmacokinetic study of OGT 719 in patients with liver cancerю

A novel, orally administered nucleoside analogue, OGT 719, inhibits the liver invasive growth of a human colorectal tumor, C170HM2

Antitumor effect and tumor level of 5-fl uoro-2′-deoxyuridylate following oral administration of tetradecyl 2′-deoxy-5-fl uoro-5′-uridylate

Antitumor activity of T-506, a novel synthetic FUDR derivative, on murine colon cancer and its hepatic metastasis

Synthesis and antitumor activity of 5-fl uorouracil derivatives

Sensitivity to six antitumor drugs differs between primary and metastatic liver cancers

Metabolism of 1-hexylcarbamoyl-5-fl uorouracil (HCFU), a new antitumour agent, in rats, rabbits and dogs

Low dose 1-hyxylcarbamoyl-5-fl uorouracil (HCFU) recommended for cirrhotic patients with hepatocellular carcinoma

Phase III clinical study of a new anticancer drug atofl uding

Atofl uding

N(3)-o-toluyl-fl uorouracil inhibits human hepatocellular carcinoma cell growth via sustained release of 5-FU

A phase II trial of a new 5-fl uorouracil derivative, BOF-A2 (Emitefur), for patients with advanced gastric cancer

Effi cacy of a new 5-fl uorouracil derivative, BOF-A2, in advanced non-small cell lung cancer. A multi-center phase II study

Phase I assessment of the pharmacokinetics, metabolism, and safety of emitefur in patients with refractory solid tumors

Phase I clinical trial of 5-fl uoro-pyrimidinone (5FP), an oral prodrug of 5-fl uorouracil (5FU)

5-fl uoro-2-pyrimidinone, a liver aldehyde oxidase-activated prodrug of 5-fl uorouracil

Capecitabine preclinical studies: from discovery to translational research

Metabolism of capecitabine, an oral fl uorouracil prodrug: 19 F NMR studies in animal models and human urine

Process for producing 5-fl uorouracil derivative with a calcium chloride catalyst

Process for the preparation of 1-(2-tetrahydrofuryl)-5-fl uorouracil

Method for the preparation of derivatives of uracil

Process for the preparation of N.sup.1-(2′-furanidyl)-5-fl uoro-uracil

Synthesis of tetrahydro-2-furyl derivatives of 5-substituted uracils

Liepin'sh E (1981) Nitrogen-containing organosilicon compounds C. Reaction of 5-fl uoro-2,4-bis-O-(Trimethylsilyl)uracil with 2,3-dihydrofuran

Analogs of pyrimidine nucleosides I. N,(atetrahydrofuryl) derivatives of natural pyrimidine bases and their antimetabolites

The synthesis of 1 (tetrahydro-2-furanyl)-5-fl uorouracil (ftorafur) via direct fl uorination

Synthetic studies on chemotherapeutics. II. Synthesis of phenyl-substituted 1,4-dihydro-4-oxonicotinic acid derivatives. [Studies on the syntheses of heterocyclic compounds. Part 704

Analogs of pyrimidine nucleosides

Facile synthesis of tetrahydro-2-furylated pyrimidines and purines using a new catalyst of cesium chloride

A novel synthesis of 5-fl uorouracil derivatives having oxacycloalkane moieties

Synthesis of 1-(tetrahydro-2-furanyl)-5-fl uorouracil (Ftorafur) via direct fl uorination

Studies on fl uorinated pyrimidines. I. A new method of synthesizing 5-fl uorouracil and its derivatives

5′-halogeno-2′,3′-cyclic sulphite isomers in the preparation of 5′-halogeno nucleosides. Synthesis of 5′-deoxyuridine and 5′-deoxy-5-fl uorouridine

5′-halogeno-2′,3′-sulphites in the synthesis of 2′,5′-dideoxy-5-fl uorouridine and related analogues

Fluorinated pyrimidine nucleosides. 3. Synthesis and antitumor activity of a series of 5′-deoxy-5-fl uoropyrimidine nucleosides

149. stereospezifi sche synthese des cancerostatikums 5'-desoxy-5-fl uor-uridin (5-DFUR) und seiner 5′-deuterierten derivate

Rapid continuous synthesis of 5-deoxyribonucleosides in fl ow via Brønsted acid catalyzed glycosylation

Preparation, antibacterial effects and enzymatic degradation of 5-fl uorouracil nucleosides

Reaction of acetylhypofl uorite with pyrimidines. Part 3. Synthesis, stereochemistry and properties of 5-fl uor-5,6-dihydropyrimidine-nucleosides

GB 080491 Chem Abstr

Synthesis and antitumor activity of phagocytic conjugates of 5-fl uorouracil with albumin

Synthesis of F-18 labeled nucleoside analogues

Therapeutic compounds with pyrimidine base

5-fl uoro-2′-deoxyuridine derivatives and a process for the preparation thereof

Novel 5-fl uoro-2-deoxyuridine derivatives and salts thereof, process for producing the same, and antitumor agents containing the same

5-fl uorouracil derivatives. I. The synthesis of 1-carbamoyl-5-fl uorouracils

1-carbamoyl-5-fl uorouracil derivatives

Studies on the syntheses of heterocyclic compounds. 845. Studies on the synthesis of chemotherapeutics. 10. Synthesis and antitumor activity of N -acyl-and N -(alkoxycarbonyl)-5-fl uorouracil derivatives

Synthesis of 5-fl uorouracil derivatives containing an inhibitor of 5-fl uorouracil degradation

5-fl uorouracil derivatives

5-fl uorouracil derivatives

Derivatives of pyrimidine

Some derivatives of 5-fl uoropyrimidine

Antitumor properties of 2(1 H )-pyrimidinone riboside (zebularine) and its fl uorinated analogs

Synthesen mit substituierten Malondialdehyden, XIX. Darstellung fl uorsubstituierter Carbo-und Heterocyclen

Verfahren zur herstellung von 5-fl uorpyrimidin-2-on und seinen N -1-substituierten derivaten

A simple synthesis of 5-fl uoro-2-pyrimidinone and its N 1 -substituted derivatives

N4-(substituted-oxycarbonyl)-5′-deoxy-5-fl uorocytidine compounds, compositions and methods of using same

The design and synthesis of a new tumor-selective fl uoropyrimidine carbamate, capecitabine

Processes related to making capecitabine

Process for the preparation of capecitabine

Combination therapy for the treatment of cancer using cox-2 inhibitors and dual inhibitors of EGFR

Synthesis and biological activity evaluation of cytidine-5′-deoxy-5-fl uoro-N-[(alkoxy/aryloxy)] carbonyl-cyclic 2′,3′-carbonates

Process for preparing capecitabine

Methods for preparing capecitabine and beta-anomer-rich trialkyl carbonate compound used therein

A novel combination antimetabolite, TAS-102, exhibits antitumor activity in FU-resistant human cancer cells through a mechanism involving FTD incorporation in DNA

Trifl uorothymidine exhibits potent antitumor activity via the induction of DNA double-strand breaks

Thymidine phosphorylase. Substrate specifi city for 5-substituted 2′-deoxyuridines

Potentiation of the antitumor activity of α, α, α-trifl uorothymidine by the co-administration of an inhibitor of thymidine phosphorylase at a suitable molar ratio in vivo

Antitumor activity of FTC-092, a masked 5-trifl uoromethyl-2′-deoxyuridine derivative

Syntheses of 5-trifl uoromethyluracil and 5-trifl uoromethyl-2′-deoxyuridine

Alternative synthesis of 2′-deoxy-5-(trifl uoromethyl)-uridine and the α-anomer thereof

The synthesis of 2′-deoxy-5-trifl uoromethyluridine utilizing a coupling reaction

Direct perfl uoroalkylation including trifl uoromethylation of aromatics with perfl uoro carboxylic acids mediated by xenon difl uoride

Studies on organic fl uorine compounds. Part 35. Trifl uoromethylation of pyrimidine and purine nucleosides with trifl uoromethyl-copper complex

Studies on antitumor agents. 8. Antitumor activities of O -alkyl derivatives of 2′-deoxy-5-(trifl uoromethyl)uridine and 2′-deoxy-5-fl uorouridine

Studies on antitumor agents. IX. Synthesis of 3′-O -benzyl-2′-deoxy-5-trifl uoromethyluridine

US 4898936 113. ClinicalTrials.gov: a service of the U.S. National Institutes of Health

Abstract B234: LY2835219, a potent oral inhibitor of the cyclindependent kinases 4 and 6 (CDK4/6) that crosses the blood-brain barrier and demonstrates in vivo activity against intracranial human brain tumor xenografts

Cyclin-dependent kinase pathways as targets for cancer treatment

Metabolism of fostamatinib, the oral methylene phosphate prodrug of the spleen tyrosine kinase inhibitor R406 in humans: contribution of hepatic and gut bacterial processes to the overall biotransformation

Tyrosine kinase inhibitors as potential drugs for B-cell lymphoid malignancies and autoimmune disorders

Preclinical characterization of Aurora kinase inhibitor R763/AS703569 identifi ed through an imagebased phenotypic screen

Phase I, open-label, multicentre, dose-escalation, pharmacokinetic and pharmacodynamic trial of the oral aurora kinase inhibitor PF-03814735 in advanced solid tumours

PF-03814735, an orally bioavailable small molecule aurora kinase inhibitor for cancer therapy

The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors

Discovery of 5-chloro-N 2-[(1 S )-1-(5-fluoropyrimidin-2-yl)ethyl]-N 4-(5-methyl-1 H -pyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480) as a novel inhibitor of the Jak/Stat pathway

Pyrimidinediamine compounds for use in the treatment or prevention of autoimmune diseases

-Aminopyrazole)pyrimidine derivatives for use as tyrosine kinase inhibitors in the treatment of cancer

Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV

Emtricitabine, a new antiretroviral agent with activity against HIV and hepatitis B virus

Pharmacokinetics of antiretrovirals in pregnant women

The 5′-triphosphates of the (-) and (+) enantiomers of cis-5-fl uoro-1-[2-(hydroxymethyl)-1,3-oxathiolane-5-yl]cytosine equally inhibit human immunodefi ciency virus type 1 reverse transcriptase

The antihepatitis B virus activities, cytotoxicities, and anabolic profi les of the (-) and (+) enantiomers of cis-5-fl uoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine

New nucleoside reverse transcriptase inhibitors for the treatment of HIV infections

Overview of antiretroviral agents

Expanded-spectrum nonnucleoside reverse transcriptase inhibitors inhibit clinically relevant mutant variants of human immunodefi ciency virus type 1

Inhibition of clinically relevant mutant variants of HIV-1 by quinazolinone nonnucleoside reverse transcriptase inhibitors

Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase

Characterization of novel glutathione adducts of a non-nucleoside reverse transcriptase inhibitor, (S)-6-chloro-4-(cyclopropylethynyl)-4-(trifl uoromethyl)-3,4-dihydro-2(1H)-quinazolinone (DPC 961), in rats. Possible formation of an oxirene metabolic intermediate from a disubstituted alkyne

Asymmetric synthesis and biological evaluation of β-L-(2 R ,5 S )-and α-L-(2 R ,5 R )-1,3-oxathiolane-pyrimidine and -purine nucleosides as potential anti-HIV agents

Structure-activity relationships of β-D-(2S,5R)-and α-D-(2S,5S)-1,3-oxathiolanyl nucleosides as potential anti-HIV agents

Method for the synthesis, compositions and use of 2′-deoxy-5-fl uoro-3′-thiacytidine and related compounds

Intermediates in the synthesis of 1,3-oxathiolane nucleoside enantiomers

Processes for the diastereoselective synthesis of nucleoside analogues

Novel process for the preparation of cis -nucleoside derivative

Design and synthesis of 2′,3′-dideoxy-2′,3′-didehydro-beta-L-cytidine (beta-L-d4C) and 2′,3′-dideoxy 2′,3′-didehydro-beta-L-5-fl uorocytidine (beta-L-Fd4C), two exceptionally potent inhibitors of human hepatitis B virus (HBV) and potent inhibitors of human immunodefi ciency virus (HIV) in vitro

Stereoselective syntheses of β-L-FD4C and β-L-FddC

Synthesis and biological evaluation of 2′,3′-didehydro-2′,3′-dideoxy-5-fl uorocytidine (D4FC) analogues: discovery of carbocyclic nucleoside triphosphates with potent inhibitory activity against HIV-1 reverse transcriptase

Synthesis and comparative evaluation of two antiviral agents: β-L-Fd4C and β-D-Fd4C

Method for synthesizing beta-l-fl uoro-2′,3′didehydcytidine (β-L-Fd4C)

Method for the synthesis of 2′,3′-dideoxy-2′,3′-didehydronucleosides

Synthesis of D-D4FC, a biologically active nucleoside via an unprecedented palladium mediated Ferrier rearrangement-type glycosidation with an aromatization prone xylo-furanoid glycal

A new asymmetric 1,4-addition method: application to the synthesis of the HIV non-nucleoside reverse transcriptase inhibitor DPC 961

General scope of 1,4-diastereoselective additions to a 2(3H)-quinazolinone: practical preparation of HIV therapeutics

An effi cient chiral moderator prepared from inexpensive (+)-3-carene: synthesis of the HIV-1 non-nucleoside reverse transcriptase inhibitor DPC 963

NMR spectroscopic investigations of mixed aggregates underlying highly enantioselective 1,2-additions of lithium cyclopropylacetylide to quinazolinones

Highly enantioselective construction of a chiral tertiary carbon center by alkynylation of a cyclic N-acyl ketimine: an effi cient preparation of HIV therapeutics

Highly enantioselective construction of a quaternary carbon center of dihydroquinazoline by asymmetric mannich reaction and chiral recognition

Trifl uridine: a review of its antiviral activity and therapeutic use in the topical treatment of viral eye infections

Physical and biological consequences of incorporation of antiviral agents into virus DNA

Fluorine-Containing Diazines in Medicinal Chemistry and Agrochemistry

T-705 (favipiravir) and related compounds: novel broad-spectrum inhibitors of RNA viral infections

Mechanism of action of T-705 against infl uenza virus

Nitrogen-containing heterocyclic carboxamide derivatives or salts thereof and antiviral agents comprising the same

Novel pyrazine derivatives or salts thereof, pharmaceutical composition containing the same, and production intermediates thereof

Organic amine salt of 6-fl uoro-3-hydroxy-2-pyrazinecarbonitrile and method for producing the same

Method for producing dichloropyrazine derivative

Antibiotic R&D gets a dose of funding

Method for producing dichloropyrazine derivative

Antibiotic activity and characterization of BB-3497, a novel peptide deformylase inhibitor

Peptide deformylase inhibitors

Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions

II pharmacology and clinical use of voriconazole

Voriconazole: a new triazole antifungal agent

Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever

Multiple-triazole-resistant aspergillosis

Process for the preparation of 5-fl uorocytosine

Nucleic acid related compounds. 21. Direct fl uorination of uracil and cytosine bases and nucleosides using trifl uoromethyl hypofl uorite. Mechanism, stereochemistry, and synthetic applications

A direct synthesis of 5-fl uorocytosine and its nucleosides using trifl uoromethyl hypofl uorite

Über synthesen von difl uoraminopyrimidinen

Process for preparing 5-fl uorocytosine salt

Triazole antifungal agents

Novel antifungal 2-aryl-1-(1 H -1,2,4-triazol-1-yl)butan-2-ol derivatives with high activity against

Process for the preparation of voriconazole

Process for preparing voriconazole

Improved process for the preparation of (2 R ,3 S )-2-(2,4-difl uorophenyl)-3-(5-fl uoropyrimidin-4-yl)-1-(1 H -1,2,4-triazol-1-yl)butan-2-ol (Voriconazole)

Improved process for the preparation of (2 R ,3 S )-2-(2,4-difl uorophenyl)-3-(5-fl uoropyrimidin-4-yl)-1-(1 H -1,2,4-triazol-1-yl)butan-2-ol

Process for the preparation of voriconazole

A process for making voriconazole

Preparation of triazoles by organometallic addition to ketones and intermediates therefor

An improved process for the preparation of voriconazole and intermediates thereof

Process for the production of voriconazole

Intermediates of voriconazole and preparation method of voriconazole using the same

Process for preparing voriconazole by using new intermediates

A novel process to manufacture (2R,3S)-2-(2,4-difl uorophenyl)-3-(5-fl uoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

Section VII. Worldwide market introductions

The encyclopedia of addictive drugs

Pharmacological studies on 6-amino-2-fl uoromethyl-3-( o -tolyl)-4(3 H )-quinazolinone (afl oqualone), a new centrally acting muscle relaxant (I)

Studies on biologically active halogenated compounds. 1. Synthesis and central nervous system depressant activity of 2-(fl uoromethyl)-3-aryl-4(3 H )-quinazolinone derivatives

Discriminative stimulus characteristics of BMY 14802 in the pigeon

A role for sigma binding in the antipsychotic profi le of BMY 14802

The sigma ligand BMY-14802 as a potential antipsychotic: evidence from the latent inhibition model in rats

BMY 14802, a sigma receptor ligand for the treatment of schizophrenia

The sigma-1 antagonist BMY-14802 inhibits L -DOPA-induced abnormal involuntary movements by a WAY-100635-sensitive mechanism

In vitro characterization of the selective dopamine D3 receptor antagonist A-437203. 32th annual meeting, society of neuroscience

Effect of dopamine D3 antagonists on PPI in DBA/2J mice or PPI defi cit induced by neonatal ventral hippocampal lesions in rats

A double-blind, randomized, placebocontrolled study of the dopamine D3 receptor antagonist ABT-925 in patients with acute schizophrenia

Dopamine D3 receptor antagonism -still a therapeutic option for the treatment of schizophrenia

Third generation antipsychotic drugs: partial agonism or receptor functional selectivity

Pharmacology of JNJ-37822681, a specifi c and fast-dissociating D2 antagonist for the treatment of schizophrenia

A double-blind, randomized, placebo-controlled study with JNJ-37822681, a novel, highly selective, fast dissociating D2 receptor antagonist in the treatment of acute exacerbation of schizophrenia

Agents for treatment of brain ischemia

Antipsychotic 1-fl uorophenylbutyl-4-(2-pyrimidinyl)piperazine derivatives

Synthesis and biological characterization of α-(4-fl uorophenyl)-4-(5-fl uoro-2-pyrimidinyl)-1-piperazinebutanol and analogues as potential atypical antipsychotic agents

Resolution of α-(4-fl uorophenyl)-4-(5-fl uoro-2-pyrimidinyl)-1-piperazinebutanol (BMS 181100) and α-(3-chloropropyl)-4-fl uorobenzenemethanol using lipase-catalyzed acetylation or hydrolysis

Evaluation of the effects of the enantiomers of reduced haloperidol, azaperol, and related 4-amino-1-arylbutanols on dopamine and σ receptors

Asymmetric hydrogenation of amino ketones using chiral RuCl 2 (diphosphine)(1,2-diamine) complexes

Piperidin-4-yl-pyridazin-3-ylamine derivatives as fast dissociating dopamine 2 receptor antagonists

A 1-heteroaryl-4-piperidinyl-methyl pyrrolidinone, BMY 21502, delays the decay of hippocampal synaptic potentiation in vitro

Effect of BMY 21502 on acquisition of shape discrimination and memory retention in monkey

Effect of BMY 21502 on classical conditioning of the eyeblink response in young and older rabbits

BMY 21502 and piracetam facilitate performance of two-choice win-stay water-escape in normal rats

Effects of oral BMY 21502 on Morris water task performance in 16-18 month old F-344 rats

Effects of BMY-21502 on anoxia in mice

Effi cacy and safety of BMY 21502 in Alzheimer disease

The use of the computerized neuropsychological test battery (CNTB) in an effi cacy and safety trial of BMY 21,502 in Alzheimer's disease

Process for large-scale production of BMY 21502

Cerebral function enhancing diazinylpiperidine derivatives

Small molecule blockers of voltage-gates sodium channels

Molecular determinants of voltage-dependent gating and binding of pore-blocking drugs in transmembrane segment IIIS6 of the Na + channel α subunit

A multicenter, double-blind, randomized, placebo-controlled crossover evaluation of a short course of BW-4030W92 in patients with chronic neuropathic pain

Discovery of 2-[(2,4-dichlorophenyl)amino]-N -[(tetrahydro-2 H -pyran-4-yl)methyl]-4-(trifl uoromethyl)-5-pyrimidinecarboxamide, a selective CB2 receptor agonist for the treatment of infl ammatory pain

A randomized, controlled study to investigate the analgesic effi cacy of single doses of the cannabinoid receptor-2 agonist GW842166, ibuprofen or placebo in patients with acute pain following third molar tooth extraction

Optically active phenyl pyrimidine derivatives as analgesic agents

Pyrimidine derivatives and their use as CB2 modulators

Combination of CB2 modulators and PDE4 inhibitors for use in medicine

Role of spleen tyrosine kinase inhibitors in the management of rheumatoid arthritis

Of mice and men: an open-label pilot study for treatment of immune thrombocytopenic purpura by an inhibitor of Syk

Fostamatinib, a Syk inhibitor prodrug for the treatment of infl ammatory diseases

The status of fostamatinib in the treatment of rheumatoid arthritis

Recent advances in non-peptidomimetic dipeptidyl peptidase 4 inhibitors: medicinal chemistry and preclinical aspects

Effects of ketoconazole and rifampicin on the pharmacokinetics of gemigliptin, a dipeptidyl peptidase-Fluorine-Containing Diazines in Medicinal Chemistry and Agrochemistry IV inhibitor: a crossover drug-drug interaction study in healthy male Korean volunteers

An update in incretin-based therapy: a focus on dipeptidyl peptidase 4 inhibitors

A multicentre, multinational, randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the effi cacy and safety of gemigliptin (LC15-0444) in patients with type 2 diabetes

Effi cacy and safety of the dipeptidyl peptidase-4 inhibitor gemigliptin compared with sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone

Liver fi brosis

Infl ammation and the pathogenesis of diabetic nephropathy

-aminocyclopentanecarboxamides as chemokine receptor modulators

Dual targeting of CCR2 and CCR5: therapeutic potential for immunologic and cardiovascular diseases

Chemokine receptor genotype is associated with diabetic nephropathy in Japanese with type 2 diabetes

Dipeptidyl peptidase-IV inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent

Fluorine-containing agrochemicals: an overview of recent developments. In: Tressaud A (ed) Fluorine and the environment: agrochemicals, archaeology, green chemistry & water

Agricultural products based on fl uorinated heterocyclic compounds. In: Petrov VA (ed) Fluorinated heterocyclic compounds: synthesis, chemistry, and applications

A history of weed control in the United States and Canada -a sequel

The pesticide book, 6th edn. MeisterPro Information Resources

Advanced technologies for parasitic weed control

Protoporphyrinogen oxidase inhibitor: an ideal target for herbicide discovery

Synthesis and chemistry of agrochemicals V

Process for the production of 3-aryl-uracils

Synthesis and chemistry of agrochemicals VI

Method for producing sulfonic acid diamides

Pyridazin-3-one derivatives, their use, and intermediates for their production

Production of pyridazine herbicides

Herbicidal composition. US 6218338 272

Structure and mechanism of inhibition of plant acetohydroxyacid synthase

Acetohydroxyacid synthase and its role in the biosynthetic pathway for branched-chain amino acids

environmental protection agency offi cial site www.epa.gov

Weed management in peanut ( Arachis hypogaea ) with diclosulam preemergence

N -arylsulfi limine compounds and their use as catalysts in the preparation of N -arylarylsulfonamide compounds

Preparation of N -arylarylsulfonamide compounds

Process for heterocyclic sulfonyl chloride compounds

Preparation of N-arylarylsulfonamide compounds

pyrimidinyl)amino)carbonyl)amino)sulfonyl)benzoic acid methyl ester (Primisulfuron)

Acaricides -biological profi les, effects and uses in modern crop protection

Review of strobilurin fungicide chemicals

Lehninger principles of biochemistry

Recent developments in the mode of action of fungicides

Mechanisms of resistance to QoI fungicides in phytopathogenic fungi

Halogen pyrimidines and its use thereof as parasite abatement means

-Alkoxy-6-trifl uoromethylpyrimidin-4-yl)oxymethylene]phenylacetic acid derivatives, their preparation and intermediate therefor, and use thereof

Processes for producing acrylic acid derivative

Processes for producing acrylic acid derivative

Methods for highly selectively o -alkylating amide compounds with the use of copper salts

Flufenerim, a novel insecticide acting on diverse insect pests: biological mode of action and biochemical aspects

Inhibitors of mitochondrial electron transport: acaricides and insecticides

4-phenethylaminopyrimidine derivative, and agricultural and horticultural chemical for controlling noxious organisms containing the same

Kinetics and metabolism of a new fl uoropyrimidine, 5′-deoxy-5-fl uorouridine

Studies on tetrahydrofuryl-5-fl uorouracils. IV. Mode of reaction of 5-fl uorouracil with 2-acetoxytetrahydrofuran

Preparation of 2-pyrimidinone and derivatives

Pyrimidine derivatives for the treatment of abnormal cell growth

Effects of afl oqualone on vestibular nystagmus and the lateral vestibular nucleus

Identifi cation and measurement of urinary metabolites of afl oqualone in man

Biocatalytic synthesis of some chiral drug intermediates by oxidoreductases

The nootropic compound BMY-21502 improves spatial learning ability in brain injured rats

Modifi cation of chemokine pathways and immune cell infi ltration as a novel therapeutic approach in liver infl ammation and fi brosis