Bertorelli, R

Burnett, Da

Greenlee, Wj

Grilli, Mariagrazia

Li, C

Lozza, G

Qiang, L

Reggiani, A.

Sasikumar, Tk

English

SASIKUMAR TK

QIANG L

BURNETT DA

GREENLEE WJ

LI C

GRILLI, Mariagrazia

BERTORELLI R

LOZZA G

REGGIANI A.

Archivio Istituzionale della Ricerca- Università del Piemonte Orientale

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2474–2477Contents lists available at ScienceDirectBioorganic & Medicinal Chemistry Lettersjournal homepage: www.elsevier .com/ locate/bmclA-ring modifications on the triazafluorenone core structureand their mGluR1 antagonist propertiesT. K. Sasikumar a,*, Li Qiang a, Duane A. Burnett a, William J. Greenlee a, Cheng Li a, Mariagrazia Grilli b,Rosalia Bertorelli b, Gianluca Lozza b, Angelo Reggiani baMerck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USAb Schering-Plough Research Institute, San Raffaele Science Park, Via Olgettina, 58, 20132 Milan, Italya r t i c l e i n f o a b s t r a c tArticle history:Received 3 February 2010Revised 26 February 2010Accepted 1 March 2010Available online 10 March 2010Keywords:mGluR1 antagonistNeuropathic pain0960-894X/$ - see front matter  2010 Elsevier Ltd.doi:10.1016/j.bmcl.2010.03.004* Corresponding author. Tel.: +1 908 740 4373; faxE-mail addresses: sasikumartk@ yahoo.com,merck.com (T.K. Sasikumar).A-ring modifications on the triazafluorenone core structure were investigated. Five membered heterocy-cles such as pyrazoles and isothiazoles are not tolerated. It has been found that the pyrimidine nucleuswas very well tolerated on the left hand side. Amino pyrimidine compounds 24 and 27 showed accept-able PK profile with significant brain penetration. Compound 9 served as a versatile intermediate for anumber of chemical transformations. 2010 Elsevier Ltd. All rights reserved.NNNHNONONNNNOClNNHNONHOSNNNONOMeH2NO2S1 23 4Figure 1. Representative mGluR1 antagonists.NNNR1R2NN5/6RA CThe metabotropic glutamate receptors (mGluRs) perform a vari-ety of functions in the central and peripheral nervous systems.They are members of the G-protein coupled receptors and form afamily of eight subtypes (mGlu1 to mGlu8) and are assigned tothree groups. Group I mGluRs (mGluR1 and mGluR5) are widelystudied and are involved in the central sensitization of pain andother neurological disorders.1–6 There have been remarkable ad-vances in the development of small molecules that inhibitsmGluR1 activity which are useful for the treatment of neuropathicor chronic pain models in rodents. Some of the very recent exam-ples from literature (1–4) are given below in Figure 1.7–11Compound 1, originated from the public domain, was identifiedas a potent mGluR1 antagonist from our high throughput screeningassay. We as well as others have extensively studied the N-aro-matic substitution pattern on the C-ring as well as the amino sub-stitutions on the A-ring of triazafluorenone (Fig. 1). It has beendemonstrated that a large number of amino substitutions(NR1R2) and a variety of aromatic rings (Ar) are tolerated in the tri-cyclic framework.7,8 A thorough literature survey indicated thatthe A-ring modifications such as reduction/enlargement of theexisting ring are unknown. Thus we decided to modify the lefthand side, keeping the thienopyrimidone part as an invariable(structure 5) as shown in Figure 2. Additionally we planned to openup the A-ring and strategically position the basic nitrogens in themolecule. Compound 4 is a close example from the literature thatAll rights reserved.: +1 908 740 7164.thavalakulamgar.sasikumar@does not have the left hand side ring system.11 Earlier in this pro-gram we found that a simple primary amino group is very well tol-SNOArSOArB5Figure 2. General SAR plans.SNNONHNNH2SNNONSNH213 149a bSNNONNNc13aScheme 2. Reagents and conditions: (a) NH2NH2H2O, MeOH, 70 C, 98%; (b) NaSHin DMF/H2O, then Cl–NH2, see text; (c) NaH, MeI.SNNNOOSNNNOOSNNNORSNNNONOHabb,c15 1618, R = H19, R = OH17Scheme 3. Reagents and conditions: (a) MeOTf, then NaBH4 (1 equiv) 60%; (b)NaBH4, THF; (c) NH2OHHCl, DMF.T. K. Sasikumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2474–2477 2475erated in the triazafluorenone core structure,8 thus we decided toprepare compounds with free primary amino group on the lefthand side of the newly designed structure. A convenient startingmaterial (6) was available for this strategy. Compound 6 was con-verted to the amide 7 and cyclized to the thienopyrimidone 8 ingood yields. The methyl sulfide moiety was oxidized to the methylsulfone by use of hydrogen peroxide and this intermediate 9 servedas a versatile intermediate for various transformations. Compound9 was treated with amines such as pyrrolidine and imidazole tofurnish compounds 10 and 11. Compound 11 was treated withhydroxylamine to get compound 12 as shown in Scheme 1. Ami-doxime 12 (mixture of cis and trans) may have all the requisitefunctionalities to bind to the receptor. These compounds weretested in the human mGluR1 assay12 and found to be inactive(compounds 10, 11 and 12: h-mGluR1 IC50 >1000 nM).Next we turned our attention to the introduction of a five mem-bered ring in place of the pyridine nucleus as shown in Scheme 2.As can be seen from Figure 1, pyrazole moiety was well toleratedin a related system (compound 4 in which the thiophene ring is ab-sent). Compound 9 was treated with hydrazine to afford theaminopyrrazole structure 13. Aminoisothiazole compound 14was prepared according to the literature procedure.13 Methyl sul-fone compound 9 was treated with NaSH and the resulting thiolderivative was cyclized with chloramine (prepared from NaOCland NH4OH)14 to generate compound 14. Unfortunately thesemodifications also generated compounds with only micromolaractivity. One compound showed a human IC50 of 670 nM (per-methylated compound 13a). All attempts to prepare an amino oxa-thiazole A-ring analog were unsuccessful.To break up the extended planar aromatic system, we next tar-geted the saturated A-ring of the tricyclic system. Methyl triflateactivation of compound 1515 followed by varying equivalents ofNaBH4 afforded compounds 16, 18 and 19 in good yields as illus-trated in Scheme 3. Oxime analog 17was also prepared. Any effortsto reduce the oxime functionality to amine were unsuccessful. AllSNSNH2OOSNSNH2HNOab6 78SNNOSNSNONO OSNSNON9cd e10 11NNSNNONNNSNNONNNHO NH2f12Scheme 1. Reagents and conditions: (a) p-toluidine, Me3Al, Tol, rt, 98%; (b)(EtO)3CH, 72%; (c) H2O2, HOAc, 73%; (d) pyrrolidine, DMF, 60%; (e) imidazole, DMF,100 C, 84%; (f) NH2OHHCl, K2CO3, EtOH, 80 C, 50%.compounds showed only micromolar activity in the mGluR1 assay.Similar results were obtained with compounds 20 and 21, whichwere prepared from intermediate 9 by treatment with diaminesas shown in Scheme 4.Since all our attempts to introduce five or seven membered A-ring system gave only micromolar active compounds, we turnedour focus to six membered ring systems. Compound 9 was treatedwith urea and thiourea to form compound 22 and 23, respectively.The methyl sulfone also can be reacted with guanidine and substi-tuted guanidines to form diamino pyrimidines as shown in Scheme5. Compound 22 showed no activity in the mGluR1 assay, but com-pound 23 has shown excellent mGluR1 activity. This compoundhas a human IC50 of 3.1 nM which is more than 300-fold more po-tent than the hydroxyl analog 22. Similar results were obtained forthe amino compound 24 with an IC50 of 2.1 nM. Slightly biggerSNNOSNNO20 219a bNNHNNHNH2 NH2Scheme 4. Reagents and conditions: (a) ethylene diamine, DMF, 100 C, 58%; (b)1,2-diaminocyclohexane, DMF, 100 C, 60%.SNNOSNNO22 239a bNNNNNH2 NH2HO HSc dSNNO24NNNH2H2NSNNO25; R = Me26; R = PyrrolidineNNNH2HNRScheme 5. Reagents and conditions: (a) urea, DMF, 80 C, 72%; (b) thiourea, DMF,100 C, 49%; (c) guanidineHCl, DMF, 100 C, 80%; (d) R-guanidineHCl, DMF, 100 C.a6SNH2ONNNH2NSONH2 b2476 T. K. Sasikumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2474–2477groups such as methylamino or pyrrolidine are not tolerated asshown in Table 1.Since small functional moieties such as –SH and –NH2 are verywell tolerated in the A-ring, we investigated more functionalgroups at that position. Compounds 27–29 were synthesized bythe reaction of compound 9 with different amidines under basicconditions (Scheme 6). Methyl and cyclopropyl analogs 27(IC50 = 27 nM) and 29 (IC50 = 326 nM) were tolerated, however tri-fluoromethyl analog 28 did not showed any mGluR1 activity. Thisdifference in potency might be explained by electron withdrawingeffect of the trifluoromethyl group.Table 1mGluR1 binding properties for compounds 1, 22–29SNNOMeNNNH2R22-29Compd R h-mGluR1 IC50a (nM) h-mGluR5 IC50 (nM)1 9.5 >300022 –OH >1000 >300023 –SH 3.1 >300024 –NH2 2.1 >300025 –NHMe >1000 >300026 –Pyrrolyl >1000 >300027 –CH3 27 >300028 –CF3 >1000 >300029 –Cyclopropyl 326 >3000a An average of at least three measurements performed on human mGlu1/5receptors. The standard error was 10%, and variability was less than twofold fromassay to assay.SNSNONO O9SNNO27; R = CH328; R= CF329; R = CpNNNH2RaScheme 6. Reagents and conditions: (a) alkyl imidamide, DMF, TEA, 100 C (50–70%).The methyl pyrimidine compound 27 showed an excellentinhibitory activity that encouraged us to study the SAR in detail,keeping the left hand side constant and varying the C-ring aro-matic groups. Readily available compound 6 was treated withH2O2 to produce methylsulfone 30 which was then cyclized withacetamidine to form aminopyrimidine compound 31 in goodyields. Compound 31 was treated with DMF–DMA to form inter-mediate 32 in quantitative yield. Heating a solution of compound32 with appropriate aromatic amine in presence of acetic acidyielded the final compound in good yields (Scheme 7). As shownin Table 2, a variety of aromatic groups are tolerated at this posi-tion. For example, simple phenyl ring (33) showed an IC50 of16 nM. Methoxy (34) and fluoro (35) derivatives showed slightlyless activity (188 and 68 nM, respectively) where as the chloroderivative (36) showed excellent potency of 11 nM.We have shown that the amino pyrimidine structures are po-tent in the mGluR1 assay and having achieved a desirable levelof potency, we focused our attention on the pharmacokinetic prop-erties of these molecules. The PK profile of representative examplesare shown in Table 3. Compounds 24 and 27 showed reasonable ratAUC and the former compound exhibited a brain concentration of100 ng/g @ 6 h. All mGluR1 active compounds were exquisitelyselective over mGluR5.In summary, we have tried to modify the A-ring of triazafluor-enone lead structure and found that 2-alkyl or 2-amino pyrimi-c31OSNNNNONH2RSOO OSNOONNNNN303227, 33-36dScheme 7. Reagents and conditions: (a) H2O2, HOAc; (b) acetamidamideHCl, TEA,DMSO, 100 C, 58% (two steps); (c) DMF–DMA, DMF, 100 C; (d) amine, HOAc,160 C.Table 2mGluR1 binding properties for compounds 27, 33–36SNNORNNNH227, 33-36Compd R h-mGluR1 IC50a (nM) h-mGluR5 IC50 (nM)27 –CH3 27 >300033 –H 16 >300034 –OMe 188 >300035 –F 68 >300036 –Cl 11 >3000a An average of at least three measurements performed on human mGlu1/5receptors. The standard error was 10%, and variability was less than twofold fromassay to assay.Table 3PK profile of selected compoundsSNNNNONH2RParameters R = NH2 (24) R = CH3 (27)Human mGluR1 IC50 (nM) 2.1 27Rat mGluR1 Ki (nM) 9.3 115.2Human mGluR5 IC50 (nM) >3000 >3000Efflux substrate No NoRat PK, (10 mg/kg), AUC (ng h/mL)16 965 2112Brain concn @ 6 h (ng/g) 100 29Brain/plasma 0.9 0.2T. K. Sasikumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2474–2477 2477dines are very well tolerated. A highly versatile intermediate 9 hasbeen used to probe the SAR of the A-ring of these tricyclics. Com-plementary C-ring changes have also been explored. A very com-prehensive SAR study on the pyrimidine core will be publishedelsewhere.References and notes1. Higgins, G. A.; Miczek, K. A. Psychopharmacology 2005, 179, 1.2. Kew, J. N. C.; Kemp, J. A. Psychopharmacology 2005, 179, 4.3. Steckler, T.; Lavreysen, H.; Oliveira, A. M.; Aerts, N.; Van Craenendonck, H.;Prickaerts, J.; Megens, A.; Lesage, A. S. J. Psychopharmacology 2005, 179, 198.4. Niswender, C. M.; Jones, C. K.; Conn, P. J. Curr. Top. Med. Chem. 2005, 5, 847.5. Kunishima, N.; Shimada, Y.; Tsuji, Y.; Sato, T.; Yamamoto, M.; Kumasaka, T.;Nakanishi, S.; Jingami, H.; Morikawa, K. Nature 2000, 407, 971.6. Constantino, G.; Macchiarulo, A.; Pellicciari, R. Bioorg. Med. Chem. 2001, 9, 847.7. Zheng, G. Z.; Bhatia, P.; Daanen, J.; Kolasa, T.; Patel, M.; Latshaw, S.; Kouhen, O.F. E.; Chang, R.; Uchic, M. 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A-ring modifications on the triazafluorenone core structure and their mGluR1 antagonist properties

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A-ring modifications on the triazafluorenone core structure and their mGluR1 antagonist properties

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