Synthesis of 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1 H-β-carbolines as antileishmanial agents

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Synthesis of 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1 H-β-carbolines as antileishmanial agents

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  Original article Synthesis of 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1 H  - b -carbolines asantileishmanial agents Ravi Kumar a , Shahnawaz Khan a , Aditya Verma b , Saumya Srivastava b , Preeti Viswakarma b ,Suman Gupta b , Sanjeev Meena c , Neetu Singh c , Jayanta Sarkar c , Prem M.S. Chauhan a , * a Medicinal & Process Chemistry Division, Central Drug Research Institute, CSIR, Lucknow, India b Parasitology Division, Central Drug Research Institute, CSIR, Lucknow, India c Drug Target Discovery & Development Division, Central Drug Research Institute, CSIR, Lucknow, India a r t i c l e i n f o  Article history: Received 21 August 2009Received in revised form17 March 2010Accepted 7 April 2010Available online 14 April 2010 Keywords: Antileishmanial2-Amino-4,6-dichloropyrimidine2,4,6-TriaminopyrimidineTetrahydro- b -carboline a b s t r a c t A series of 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1 H  - b -carboline derivatives has been synthe-sized and evaluated for antileishmanial activity against  Leishmania donovani . Compound  8  exhibited bestantileishmanial activity with IC 50  value of 1.93  m g/ml against amastigotes, high selectivity index, and wasmore active than reference drugs sodium stilbogluconate and pentamidine.   2010 Elsevier Masson SAS. All rights reserved. 1. Introduction Leishmaniasis [1], a group of vector-borne parasitic diseasescaused by several protozoan parasite of genus  Leishmania , areendemicinlargeareasof thetropics,subtropicsandMediterraneanbasin. Phlebotomine sand  fl y transmits the parasitic agents byinoculation of the  fl agellate promastigotes in to mammalian host,wheretheyentermacrophagesdifferentiating and multiplying intoimmobile amastigotes [2]. Visceral Leishmaniasis [3] or Kala Azar is most common pathological form of the disease and caused by Leishmania donovani . From the socioeconomic point of view,Leishmaniasis are the second most important among all the para-siticdiseases[4].Morethan12millionpeoplearoundtheworldareaffectedbyLeishmaniasis, with1.5 e 2 millionnewcases and51,000deaths reported each year [5].Chemotherapy of patients with Leishmaniasis is still a seriousproblem as the treatment options are very limited. Pentavalentantimonialcompoundswerewidely usedasprimarytherapyfor50years but resistance has developed to them to such an extent inIndia that they can no longer be used in some regions [6]. Anti-monials may also cause acute pancreatitis and cardiac arrhythmia[7]. Only recently amphotericin B, pentamidine, and miltefosinhave been discovered as effective antileishmanial drugs. All thesedrugs suffer also from serious side effects associated with them.Major drawbacks associated with amphotericin B are, it ’ s prohibi-tively high cost, life threatening  fi rst dose anaphylaxis, nephro-toxicity and hypokalemicity [8]. Pentamidine is orally inactive andmay show renal, hepatic and pancreatic toxicity along with hypo-tension and dysglycemia [9]. Miltefosine, srcinally developed asanticancer drug, is the  fi rst orally active antileishmanial agent,which have good ef  fi cacyagainst both visceral as well as cutaneousleishmaniases but suffers from low therapeutic index, teratoge-nicity in animals, extremely long half life (6 e 8 days), and relativelow ef  fi cacy in HIV coinfected patients [10].In the light of above facts, there is an urgent need for the deve-lopment of more ef  fi cient, inexpensive, nontoxic, and innovativedrugs based on new molecular scaffold for the treatment of leish-maniases. In 1998, a tetrahydro- b -carboline alkaloid buchtienine[11]  1  (Fig. 1) was isolated from  Kopsia grif   fi thii  and found to havegood antileishmanial activity (0.30  >  IC 50  >  1.56  m g/ml) against L. donovani . A few years later, antileishmanial activity of harmine  2 (Fig. 1), a  b -carboline amine alkaloid [12] isolated from  Peganumharmala , was also reported. Pinheiro ’ s group isolated the pyrimi-dine- b -carboline alkaloid annomontine  3  (Fig. 1) from the bark of a Brazilian tree  Annona foetida  [13] having antileishmanial activityagainst  Leishmania braziliensis  with IC 50  value of 34.8  1.5  m g/ml. *  Corresponding author. Tel.:  þ 91 522 2262411; fax:  þ 91 522 2623405. E-mail addresses:  premsc58@hotmail.com, prem_chauhan_2000@yahoo.com(P.M.S. Chauhan). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$  e  see front matter    2010 Elsevier Masson SAS. All rights reserved.doi:10.1016/j.ejmech.2010.04.004 European Journal of Medicinal Chemistry 45 (2010) 3274 e 3280  In addition, synthetic 2-aminopyrimidines with hydrophobichandleat4-positionhasalsobeenreportedasgoodantileishmanialagents [14]. Prompted by this and in continuation of our effortstowards design and synthesis of novel nitrogen heterocylces asantileishmanial agent [15], a series of 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1 H  - b -carbolines has been synthesized andevaluated for antileishmanial activity against  L. donovani . 2. Chemistry  The synthetic strategy followed for synthesis of 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1 H  - b -carbolines  7 e 25  is de-picted in Scheme 1. It involves oxidation of 2-thiomethyl-4,6- dichloropyrimidine  4  with m-chloroperbenzoic acid to its sulfonederivative  5 . Nucleophilic substitution of methane sulfonyl groupof   5  with tryptamine furnished N-(2-(1 H  -indol-3-yl)ethyl)-4,6-dichloropyrimidin-2-amine  6  in good yield. Pictet Spengler cycli-zation [16] of   6  with variously substituted benzaldehydes underacidic conditions gave 2-(4,6-dichloropyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1 H  - b -carboline derivatives  7 e 19  in high yields.2-(4,6-Diaminopyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1 H  - b -carboline derivatives  20 e 23  and (4,6-Diaminopyrimidin-2-yl)-[2-(1 H  -indol-3-yl)-ethyl]-amines  24 e 25  were obtained in good toexcellentyieldsbytreatingthecorrespondingdichloroderivatives 6 , 8 ,  9 and  13 with amine nucleophiles.All the tetrahydro- b -carbolinederivatives  7 e 23  were obtained as racemic mixtures.   NHNNNH 2 N Annomontine  3 NHNO Harmine  2 NHNHNH HHHMeOOCHN Buchtienine  1 Fig. 1.  Natural  b -carboline alkaloids with antileishmanial activity. NNSClClCH 3 m-CPBA(a)NNSClClOCH 3 ONHHNCHONNNNClClHNN ClClTryptamine(b)(c)NHHNNN R 1 R 1 NNNNR 1 R 1 H(d)(d)5 6(±) 7-19(±) 20-2324-25RR RFor 24 R 1  = Morpholine,25 R 1  = N-methylpiperazine.For 20 R = 3,4-dioxymethylene,R 1  = N  -methylpiperazine.21 R = 3,4-dioxymethylene,R 1  = N  -ethylpiperazine.22 R = 4-methoxy,R 1  = morpholine,23 R = 3,4-dimethoxy,R 1  = morpholine.For 7 R = 3,4,5-trimethoxy,8 R= 3,4-dimethoxy9 R = 4-methoxy,10 R = 2-methoxy,11 R = 3-methoxy,12 R = 3-bromo,13 R = 3,4-dioxymethylene, 14 R = 4-benzyloxy.15 R = 4-ethyl,16 R = 4-methyl,17 R = 3,5-dimethoxy,18 R = 2,4-dimethoxy,19 R = 2,5-dimethoxy,4 Scheme 1.  Reagents and conditions : (a) DCM, 0   C to rt, 4 h; (b) Ethanol, re fl ux, 2 h; (c) PTSA, ethanol, re fl ux, 3 h; (d) Neat Amine, re fl ux, 10 h. R. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 3274 e  3280  3275  3. Antileishmanial activity   3.1. Antipromastigote activity The  L. donovani  promastigotes (MHOM/IN/80/Dd8; srcinallyobtained from Imperial College, London) were transfected with fi re fl y luciferase gene and the transfectants were maintained inmedium 199 (Sigma Chemical Co., USA) supplemented with 10%foetal calf serum (GIBCO) and 1% penicillin (50 U/ml), streptomycin(50  m g/ml) solution (Sigma) under pressure of G418 (Sigma). The  invitro  effect of the compounds on the growth of promastigotes wasassessed by monitoring the luciferase activity of viable cells aftertreatment. The transgenic promastigotes of late log phase wereseeded in 5    10 5 /100  m l medium 199 in 96-well  fl at-bottomedmicrotiter (MT) plates (CELLSTAR) and incubated for 72 h inmedium alone or in the presence of serial dilutions of drugs(1 e 10 m g/ml)inDMSO[17].ParalleldilutionsofDMSOwereusedascontrols. After incubation, an aliquot (50  m l) of promastigotesuspension was aspirated from each well of a 96-well plate andmixed with an equal volume of Steady Glo  reagent (Promega) andluminescence was measured by a luminometer. The values wereexpressed as relative luminescence unit (RLU). The inhibition of parasitic growth is determined by comparison of the luciferaseactivity of drug treated parasites with that of untreated controls bythe general formula: Percentage inhibition  ¼ ð N   n  100 Þ = N  where  N   is average relative luminescence unit (RLU) of controlwells and  n  is average RLU of treated wells.  3.2. Antiamastigote activity For assessing the activity of compounds against the amastigotestage of the parasite,mouse macrophagecell line (J774A.1) infectedwith promastigotes expressing luciferase  fi re fl y reporter gene wasused. Cells were seeded in a 96-well plate (1.5   10 4 cells/100  m l/well) in RPMI-1640 containing 10% foetal calf serum and the plateswere incubated at 37   C in a CO 2  incubator. After 24 h, the mediumwas replaced with fresh medium containing stationary phasepromastigotes (2.25    10 5 /100  m l/well). Promastigotes invade themacrophageandaretransformedintoamastigotes.Thetestmaterialinappropriateconcentrations(0.25 e 10 m g/ml)incompletemediumwasaddedafterreplacingthepreviousmediumandtheplateswereincubated at 37   C in a CO 2  incubator for 72 h. After incubation, thedrug containing mediumwas decanted and 50  m l PBS was added ineach well and mixed with an equal volume of Steady Glo  reagent.After gentle shaking for 1 e 2 min, the reading was taken inaluminometer[17].Theinhibitionofparasiticgrowthisdetermined by comparison of the luciferase activity of drug treated parasiteswith that of untreated controls as described above.IC 50  of antileishmanial activity were evaluated by logit regres-sion analysis.  3.3. Cytotoxicity assay The cell viability was determined using the MTT assay. J774A.1cell line was maintained in RPMI medium (Sigma), supplementedwith 10% foetal calf serum and 40 mg/ml gentamycin. Exponen-tially growing cells (1  10 4 cells/100  m l/well) were incubated withdifferent drug concentrations for 72 h and were incubated at 37   Cin a humidi fi ed mixture of CO 2  and 95% air in an incubator. Stocksolutions of compounds were initially dissolved in DMSO andfurtherdilutedwithfreshcompletemedium.Afterincubation,25 m lof MTT reagent (5 mg/ml) in PBS medium, followed by syringe fi ltrationwere added to each well and incubated at 37   C for 2 h. Atthe end of the incubation period, the supernatant was removed bytilting plate completely without disturbing cell layer and 150  m l of pure DMSO are added to each well. After 15 min of shaking thereadings were recorded as absorbance at 544 nm on a microplatereader. The cytotoxic effect was expressed as 50% lethal dose, i.e. asthe concentration of a compound which provoked a 50% reductionin cell viability compared to cell in culture medium alone. IC 50 values were estimated through the preformed template asdescribed by Huber and Koella [18]. 4. Results and discussion In vitro  antileishmanial evaluation of the 2-(4,6-dichloro-pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1 H  - b -carboline deri-vatives  7 e 19 , 2-(4,6-diaminopyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1 H  - b -carbolines  20 e 23 , and 2,4,6-triaminopyrimidines 24 e 25 showedencouragingresultsasdisplayedinTable1.Amongthe synthesized compounds 7 e 25 , twelve compounds exhibited morethan 80% inhibition against promastigotes at 10  m g/ml while sevencompounds i.e.  10 e 15  and  18  showed inhibition in the range of 33.57 e 79.65%. N-(2-(1 H  -indol-3-yl)ethyl)-4,6-dichloropyrimidin-2-amine 6 wasalsoscreened and foundto beexhibit99.78%inhibitionagainst promastigotes, but against amastigotes it showed pooractivity with IC 50  value of 7.34  m g/ml and selectivity indexof 2.80.Interestingly, the derivative  8  having 3,4-dimethoxyphenylgroup at C-1 of tetrahydro- b -carboline ring system, exhibited IC 50 value of 1.93  m g/ml against amastigotes and selectivity index of 15.43. Both selectivity index and IC 50  value of   8  were much betterthan that of reference drugs sodium stilbogluconate (SSG) andpentamidine. It can be observed in Table 1 that antileishmanialactivity is dependent on natureand position of substituents on arylring at C-1 of tetrahydro- b -carboline ring system. In comparison to 8 , presence of one moremethoxygroupas in  7 orone less methoxy  Table 1 In vitro  antileishmanial acitivity of compounds  6 e 25 .Compoundno. In vitro  screening CytotoxicityCC 50  ( m g/ml)Selectivityindex a (SI)Antipromastigoteactivity(% inhibitionat 10  m g/ml)Antiamastigoteactivity MQ/amast.Model IC 50 ( m g/ml) 6  99.78 7.34 20.59 2.80 7  81.68 3.81 ND N/A 8  93.06 1.93 29.78 15.43 9  81.68 3.57 ND N/A 10  38.79 NA ND N/A 11  44.33 NA ND N/A 12  79.65 7.79 14.03 1.81 13  33.57 NA ND N/A 14  36.85 NA ND N/A 15  60.24 4.46 30.66 6.87 16  84.15 6.00 24.59 4.09 17  90.57 NA ND N/A 18  54.14 NA ND N/A 19  85.34 NA ND N/A 20  99.96 0.49 2.80 5.71 21  99.94 0.48 2.50 5.20 22  97.25 4.48 67.67 15.10 23  85.31 NA ND N/A 24  99.72 3.05 19.35 6.34 25  100 1.74 18.37 10.55SSG 40 e 50 b 53.62 297.38 6.38Pentamidine 100 12.11 25.15 2.07NA: not active. ND: not determined. a Selectivity index (SI) de fi ned by the ratio CC 50  (J-774 A-1 cells)/IC 50  (Leishmaniaamastigotes). SSG: sodium stilbogluconate. b SSG shows 40 e 50% inhibition against promastigotes at 500  m g/ml. N/A: notapplicable. R. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 3274 e  3280 3276  group as in  9  led to approximately two folds decrease in activityagainst amastigotes. Compounds  7  and  9  were highly toxic against J774A.1 cells, so were not selective against amastigotes. Similarlycompounds  10  and  11  having 2-methoxy and 3-methoxy substit-uent, respectively were also found to be inactive against amasti-gotes. 3-Bromophenyl substituent in compound  12  was alsodetrimental to antiamastigote activity. 3,4-Dioxymethylenephenyland benzyloxyphenyl derivatives  13  and  14  were inactive againstamastigotes. Higher IC 50  values and lower selectivity indices forcompounds 15 and  16 indicated that 4-methylorethyl substituentswere not good for antiamastigote activity. Excited by the goodantileishmanial activity of compound  8  and to extend the structureactivity relationship around phenyl ring compounds  17 e 19  havingtwo methoxy substituents at different positions on the phenyl ringattheC-1positionof  b -carbolineringsystemweresynthesizedandevaluated for antileishmanial activity but were inactive againstamastigotes. It indicates that 3,4-dimethoxyphenyl substituent atC-1 of tetrahydro- b -carboline ring system is necessary for theantileishmanial activity.Amongst 2-(4,6-diaminopyrimidin-2-yl)-1-phenyl-2,3,4,9-tet-rahydro-1 H  - b -carboline derivatives  20 e 22 , antiamastigote activi-ties of compounds  20  and  21  were good, but they didn ’ t haveselectivity indices comparable to that of   8 . Inhibitory potency of compound  22  against amastigotes was less, but value of selectivityindex was comparable to compound  8 . Compounds  20 e 23  weremore active than theircorresponding dichloro analogues (i.e.  9  and 13 ) and showed better selectivity indices. Taking a clue from aboveobservations, compound  23  was synthesized by substituting boththe chloro groups in compound  8  by morpholine. But to oursurpriseitwasfoundtobeinactiveagainstamastigotes.Compound 24 alsoinhibitedamastigoteswithIC 50 valueof3.05 m g/mlandpoorselectivity index. Similarly, compound  25  was as effective againstamastigotes as compound  8  but has lower selectivity index.Structure activity relationship reveals that 3,4-dimethox-yphenyl substituent at C-1 of tetrahydro- b -carboline ring systemin2-(4,6-dichloropyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1 H  - b -carboline derivatives increase the antileishmanial activity andthese results will be used as basis strategy point for the design of new molecules with improved antileishmanial activity.Effectiveness of certain molecules as both antiprotozoal andanticancer agents [19], antileishmanial and anticancer activities of tetrahydro- b -carboline derivatives [20] led us to screen all thesynthesized compounds  6 e 25  for their cytotoxicity against a panelof human cancer cell lines. Only compound  20  showed moderatecytotoxicity against C33A, MCF7, DU145, and KB cancer cell lineswith IC 50  values of 1.1, 1.2,1.5, and 2.0  m g/ml, respectively.In summary, synthesis and biological evaluation of the series 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetrahydro-1 H  - b -carbolinederivatives led us to discovery of compound  8  as good anti-leishmanial agent which is more active than SSG and pentamidine in vitro . Selectivity index of compound  8  is 2.4, and 7.4 folds higherthan SSG and pentamidine, respectively. These preliminary inves-tigations revealed that 2-(pyrimidin-2-yl)-1-phenyl-2,3,4,9-tetra-hydro-1 H  - b -carboline class can be served as prototype fordevelopment of more ef  fi cacious antileishmanial agents. In vivostudies and efforts directed towards SAR of the pyrimidine ring,modeofactionareinprogressinourlabandwillbereportedinduecourse. 5. Experimental The melting points were recorded on an electrically heatedmelting point apparatus and are uncorrected. IR spectra wererecorded on Beckman Aculab-10, Perkin Elmer 881 and FTIR Shi-madzu 8201PC spectrophotometers either on KBr discs or in neat.Nuclear magnetic resonance (NMR) spectra were recorded onBruker Avance DRX-300 MHz FT spectrometer using TMS as aninternal reference. Mass spectra were recorded on JEOL SX 102/DA6000 mass spectrometer using Argon/Xenon (6 kV, 10 mA).Chemical analysis was carried out on Carlo-Erba-1108 instrument. 5.1. Typical procedure for synthesis of compound  6  To a solution of 2-thiomethyl-3,5-dichloropyrimidine  4  (1equivalent) in dry DCM was added m-chloroperbenzoic acid (3equivalent) at 0   C and stirred for 3 h with gradual rise in temper-ature to room temperature. Then, reaction was quenched by satu-ratedsolutionofsodiumbicarbonateanddilutedwithDCM.Organicphase was separated, dried by Na 2 SO 4  and evaporated  in vacuo .White solid so obtained was re fl uxed with equivalent amount of tryptamine in ethanol for 2 h. After TLC analysis showed completionof the reaction, ethanol was evaporated at reduced pressure andpuri fi ed by column chromatography to obtain pure compound  6 . 5.1.1. N-(2-(1H-indol-3-yl)ethyl)-4,6-dichloropyrimidin-2-amine( 6  ) Yield: 68%, mp 132 e 134   C; IR (KBr): 3692, 3477, 3019, 2928,2857, 1573, 1522, 1430, 1216, 1093, 1044 cm  1 ;  1 H NMR (CDCl 3 ,300 MHz):  d  (ppm) 8.00 (s,1H), 7.66 (d,1H,  J  ¼ 8.1 Hz), 7.37 (d,1H,  J  ¼ 9.6Hz),7.16(t,1H,  J  ¼ 7.8 Hz),7.22(t,1H,  J  ¼ 6.9 Hz),7.04 (s,1H),6.59 (s, 1H), 5.67 (s, 1H), 3.78 (q, 2H,  J   ¼  6.6 Hz), 3.08 (t, 2H,  J  ¼ 6.9Hz); 13 CNMR(CDCl 3 ,75MHz):161.57,136.46,127.24,122.27,122.10, 119.62, 119.55, 118.81, 112.61, 111.23, 108.72, 96.18, 41.73,25.08. Anal. calcd. for C 14 H 12 Cl 2 N 4 : C 54.74, H 3.94, N 18.24; Found:C 54.37, H 3.56, N 17.93%. 5.2. General procedure for synthesis of compounds  7  e 19 The mixture of compound  6  (1 equivalent) and substitutedbenzaldehyde (1 equivalent) was re fl uxed in ethanol inpresence of catalytic amount of PTSA for 3 h. After completion of reaction,solvent was removed  in vacuo  and resulting solid residue wascolumn chromatographed to afford respective compounds withyields in the range of 65 e 75%. 5.2.1. 2-(4,6-Dichloropyrimidin-2-yl)-1-(3,4,5-trimethoxyphenyl)- 2,3,4,9-tetrahydro-1H- b -carboline ( 7  ) Yield: 75%; mp: 198 e 200   C; IR (KBr): 3289, 3101, 2994, 2937,2843,1579,1509,1457,1350,1324,1298,1247,1183,1120 cm  1 ;  1 HNMR (CDCl 3 , 300 MHz):  d  (ppm) 8.05 (bs, 1H), 7.57 (d, 1H,  J   ¼ 7.5 Hz), 7.31 (d, 1H,  J   ¼  7.5 Hz), 7.20 e 7.13 (m, 2H), 6.91 (s, 1H),6.71 (s, 2H), 6.58 (s,1H), 5.07 (dd,1H,  J  ¼ 13.2, 3.3 Hz), 3.85 (s, 3H),3.77 (s, 6H), 3.49 e 3.39 (m, 1H), 3.09 e 2.92 (m, 2H);  13 C (CDCl 3 ,75MHz):163.9,160.30,152.91,137.58,136.56,135.19,131.44,126.57,122.08, 119.58, 118.29, 111.08, 110.60, 108.05, 105.99, 60.61, 55.97,54.64, 38.64, 21.24. Anal. calcd. for C 24 H 22 Cl 2 N 4 O 2 : C 59.39, H 4.57,N 11.54; Found: C 59.02, H 4.28, N 11.33%. 5.2.2. 2-(4,6-Dichloropyrimidin-2-yl)-1-(3,4-dimethoxyphenyl)- 2,3,4,9-tetrahydro-1H- b -carboline ( 8  ) Yield: 72%, mp 209 e 211   C; IR (KBr): 3371, 3105, 3007, 2945,2838, 1682, 1581, 1512, 1459, 1384, 1346, 1304, 1269, 1245,1136 cm  1 ;  1 H NMR (CDCl 3 , 300 MHz):  d  (ppm) 7.81 (s,1H), 7.59 (d,1H,  J   ¼  7.5 Hz), 7.33 e 7.14 (m, 4H), 7.16 (s, 1H), 6.84 e 6.74 (m, 2H),6.58 (s,1H), 5.01 (dd,1H,  J  ¼ 13.4, 4.2 Hz), 3.86 (s, 3H), 3.85 (s, 3H),3.49 e 3.40 (m, 1H), 3.12 e 2.96 (m, 2H);  13 C NMR (CDCl 3 , 75 MHz):160.30,148.95,148.81,136.38,132.07,131.76,126.65,122.17,120.91,119.61, 118.33, 112.32, 111.03, 110.76, 110.59, 108.04, 55.84, 55.78,54.13, 38.21, 21.14. Anal. calcd. for C 23 H 20 Cl 2 N 4 O 2 : C 60.67, H 4.43, N12.30; Found: C 60.48, H 4.14, N 12.11%. R. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 3274 e  3280  3277  5.2.3. 2-(4,6-Dichloropyrimidin-2-yl)-1-(4-methoxyphenyl)- 2,3,4,9-tetrahydro-1H- b -carboline ( 9 ) Yield: 69%; mp: 191 e 193   C; IR (KBr): 3872, 3399, 2930, 2844,1586, 1511, 1454, 1369, 1304, 1249, 1178 cm  1 ;  1 H NMR (CDCl 3 ,300 MHz):  d  (ppm) 7.43 (d, 1H,  J   ¼  7.5 Hz), 7.23 e 7.17 (m, 3H),7.07 e 6.97(m,2H),6.90(s,1H),6.70(d,2H,  J  ¼ 8.4Hz),6.44(s,1H),4.80(dd,1H,  J  ¼ 13.2,4.8Hz),3.65(s,3H),3.28 e 3.18(m,1H),2.88 e 2.74(m,2H);  13 C (CDCl 3  þ  CD 3 OD, 75 MHz): 164.78, 163.65, 162.73, 139.76,135.45, 135.29, 133.21, 129.90, 125.14, 122.58, 121.46, 117.06, 114.44,113.33,111.28,58.58,57.06,41.37,24.36.Anal.calcd.forC 22 H 18 Cl 2 N 4 O:C 62.13, H 4.27, N 13.17; Found: C 61.83, H 4.02, N 12.93%. 5.2.4. 2-(4,6-Dichloropyrimidin-2-yl)-1-(2-methoxyphenyl)- 2,3,4,9-tetrahydro-1H- b -carboline ( 10  ) Yield: 65%; mp: 182 e 184   C; IR (KBr): 3426, 3399, 3022, 1644,1587, 1512, 1453, 1217 cm  1 ;  1 H NMR (CDCl 3 , 300 MHz):  d  (ppm)7.63(d,1H,  J  ¼ 7.5Hz),7.23 e 7.17(m,3H),7.07 e 6.87(m,5H),6.45(s,1H), 4.83 (dd,1H,  J  ¼ 12.4, 4.2 Hz), 3.89 (s, 3H), 3.34 e 3.23 (m,1H),2.89 e 2.77 (m, 2H);  13 C (CDCl 3  þ  CD 3 OD, 75 MHz): 165.16, 163.25,160.58,139.23,138.47,135.42,135.28,133.21,129.94,125.15,122.52,121.44,117.06,114.47,113.33,111.48,56.58,54.06,40.34,23.98.Anal.calcd. for C 22 H 18 Cl 2 N 4 O: C 62.13, H 4.27, N 13.17; Found: C 61.86, H4.07, N 13.02%. 5.2.5. 2-(4,6-Dichloropyrimidin-2-yl)-1-(3-methoxyphenyl)- 2,3,4,9-tetrahydro-1H- b -carboline ( 11 ) Yield: 73%; mp: 175 e 177   C; IR (KBr): 3451, 3399, 3023, 2844,1642, 1511, 1454, 1217 cm  1 ;  1 H NMR (CDCl 3 , 300 MHz):  d  (ppm)7.42 e 7.23 (m, 4H), 7.13 e 6.97 (m, 3H), 6.85 (d, 1H,  J  ¼ 7.2 Hz), 6.73(d,1H,  J  ¼ 7.8 Hz), 6.46 (s,1H), 4.81 (dd,1H,  J  ¼ 13.2, 4.8 Hz), 3.65 (s,3H), 3.31 e 3.23 (m, 1H), 2.89 e 2.84 (m, 2H);  13 C (CDCl 3  þ  CD 3 OD,75 MHz): 161.25, 159.60, 159.19, 141.18, 136.24, 131.31, 128.95,126.04, 121.13, 120.28, 118.53, 117.56, 114.18, 112.77, 110.94, 108.96,107.53, 54.72, 53.80, 37.80, 20.51. Anal. calcd. for C 22 H 18 Cl 2 N 4 O: C62.13, H 4.27, N 13.17; Found: C 61.78, H 4.16, N 12.99%. 5.2.6. 1-(3-Bromophenyl)-2-(4,6-dichloropyrimidin-2-yl)-2,3,4,9-tetrahydro-1H- b -carboline ( 12  ) Yield: 65%; mp: 158 e 160   C; IR (KBr): 3686, 3459, 3019, 1727,1569, 1510, 1445, 1375, 1216 cm  1 ;  1 H NMR (CDCl 3 , 300 MHz): d  (ppm) 7.59 (m, 2H), 7.45 (d, 1H,  J   ¼  7.8 Hz), 7.39 e 7.32 (m, 2H),7.25 e 7.14 (m, 3H), 7.03 (s, 1H), 6.61 (s, 1H), 4.94 (dd, 1H,  J   ¼  13.2,4.5Hz),3.46 e 3.34 (m,1H),3.15 e 2.86 (m,2H);  13 C(CDCl 3 ,75MHz):160.35,141.85,136.39,131.57,131.54,130.68,130.19,127.29,126.63,122.81 122.50, 119.89, 118.48, 111.16, 111.13, 108.63, 53.78, 38.33,20.94. Anal. calcd. for C 21 H 15 BrCl 2 N 4 : C 53.19, H 3.19, N 11.82;Found: C 52.84, H 2.92, N 11.66%. 5.2.7. 1-(Benzo[d][1,3]dioxol-5-yl)-2-(4,6-dichloropyrimidin-2-yl)- 2,3,4,9-tetrahydro-1H- b -carboline ( 13 ) Yield: 68%; mp: 173 e 175   C; IR (KBr): 3404, 2922, 1572, 1509,1435,1304,1240cm  1 ; 1 HNMR(CDCl 3 ,300MHz): d (ppm)7.73(bs,1H), 7.55 (d, 1H,  J   ¼  7.5 Hz), 7.30 (d, 1H,  J   ¼  7.8 Hz), 7.22 e 7.11 (m,2H), 6.99 e 6.93 (m, 2H), 6.88 (d, 1H,  J   ¼  8.1 Hz), 6.73 (d, 1H,  J  ¼ 7.8Hz),6.56(s,1H),5.93(d,2H,  J  ¼ 1.8Hz),4.95(dd,1H,  J  ¼ 13.2,4.8 Hz), 3.41 e 3.32 (m,1H), 2.99 e 2.85 (m, 2H);  13 C (CDCl 3 þ CD 3 OD,75 MHz): 164.18, 151.60, 151.28, 140.39, 137.70, 136.73, 135.59,133.57, 130.36, 126.07, 125.65, 123.01, 121.95, 112.85, 112.28, 111.87,111.80,104.98, 57.86, 41.86, 24.82. Anal. calcd. for C 22 H 16 Cl 2 N 4 O 2 : C60.15, H 3.67, N 12.75; Found: C 59.91, H 3.46, N 12.54%. 5.2.8. 1-(4-(Benzyloxy)phenyl)-2-(4,6-dichloropyrimidin-2-yl)- 2,3,4,9-tetrahydro-1H- b -carboline ( 14 ) Yield:74%;mp:184 e 186  C;IR(KBr):3407,2924,2845,1571,1508,1446,1238,1172 cm  1 ;  1 H NMR (CDCl 3 , 300 MHz):  d  (ppm) 7.68 (s,1H),7.55(d,1H,  J  ¼ 7.2Hz),7.42 e 7.29(m,8H),7.21 e 7.11(m,2H),7.02(s,1H), 6.90(d, 2H,  J  ¼ 8.7 Hz), 6.55 (s,1H), 5.03 (s, 2H), 4.94(dd,1H,  J  ¼  13.8, 4.5 Hz), 3.38 e 3.31 (m,1H), 2.99 e 2.91 (m, 2H);  13 C (CDCl 3 ,75MHz):160.30,158.81,136.82,136.28,132.01,131.84,130.00,128.64,128.06, 127.46, 126.71, 122.21, 119.72, 118.35, 114.82, 111.00, 110.75,108.11, 70.03, 53.66, 38.04, 21.07. Anal. calcd. for C 28 H 22 Cl 2 N 4 O: C67.07, H 4.42, N 11.17; Found: C 66.83, H 4.18, N 10.98%. 5.2.9. 2-(4,6-Dichloropyrimidin-2-yl)-1-(4-ethylphenyl)-2,3,4,9-tetrahydro-1H- b -carboline ( 15 ) Yield: 72%; mp: 187 e 189   C; IR (KBr): 3396, 3123, 3055, 2926,1581, 1509, 1436, 1372, 1303, 1237, 1188 cm  1 ;  1 H NMR (CDCl 3 ,300MHz): d (ppm)7.73(s,1H),7.58(d,1H,  J  ¼ 7.5Hz),7.36 e 7.29(m,2H), 7.23 e 7.15 (m, 4H), 7.06 (s, 1H), 6.57 (s, 1H), 4.98 (dd, 1H,  J  ¼ 13.2, 4.5 Hz), 3.49 e 3.35 (m,1H), 3.12 e 2.93 (m, 2H), 2.64 (q, 2H,  J   ¼  7.8 Hz), 1.23 (t, 3H,  J   ¼  7.8 Hz);  13 C (CDCl 3 , 75 MHz): 160.37,144.57,136.85,136.31,131.84,128.75,128.08,126.74,122.20,119.72,118.35, 111.01, 110.72, 108.12, 54.02, 38.19, 28.57, 21.08, 15.51. Anal.calcd. for C 23 H 20 Cl 2 N 4 : C 65.25, H 4.76, N 13.23; Found: C 64.95, H4.52, N 12.97%. 5.2.10. 2-(4,6-Dichloropyrimidin-2-yl)-1-p-tolyl-2,3,4,9-tetrahydro-1H- b -carboline ( 16  ) Yield: 70%; mp: 216 e 218   C; IR (KBr): 3691, 3401, 3020, 1728,1569, 1510, 1445, 1372, 1217 cm  1 ;  1 H NMR (CDCl 3 , 300 MHz): d  (ppm) 7.70 (s, 1H), 7.58 (d, 1H,  J   ¼  7.5 Hz), 7.31 e 7.25 (m, 3H),7.24 e 7.11 (m, 4H), 7.05 (s, 1H), 6.57 (s, 1H), 4.98 (dd, 1H,  J   ¼  13.2,4.2 Hz), 3.43 e 3.35 (m, 1H), 3.03 e 2.94 (m, 2H), 2.33 (s, 3H);  13 C(CDCl 3 , 75 MHz): 161.92, 160.35, 138.23, 136.61, 136.31, 131.81,129.26,128.64,126.72,122.19,119.70,118.34,110.99,110.72,108.12,54.01, 38.19, 21.16, 21.06. Anal. calcd. for C 22 H 18 Cl 2 N 4 : C 64.56, H4.43, N 13.69; Found: C 64.36, H 4.15, N 13.43%. 5.2.11. 2-(4,6-Dichloropyrimidin-2-yl)-1-(3,5-dimethoxyphenyl)- 2,3,4,9-tetrahydro-1H- b -carboline ( 17  ) Yield: 75%, mp 194 e 196   C; IR (KBr): 3418, 3105, 3010, 2945,1640, 1511, 1218, 1136 cm  1 ;  1 H NMR (CDCl 3 , 300 MHz):  d  (ppm)8.93(s,1H),7.53(d,1H,  J  ¼ 7.2Hz),7.32 e 7.29(m,1H),7.28 e 6.97(m,4H), 6.88 e 6.78 (m, 2H), 6.56 (s, 1H), 5.40 (dd, 1H,  J   ¼  9.7, 3.6 Hz),4.19(s,3H), 4.02 e 3.73 (m,4H),2.98 e 2.96(m, 2H); 13 C NMR(CDCl 3 ,75 MHz): 161.67, 160.71, 153.04, 145.87, 136.16, 135.25, 133.01,126.49, 125.08, 121.91, 119.38, 118.19, 117.46, 111.52, 111.20, 108.51,108.04, 60.84, 55.90, 50.94, 41.65, 21.28. Anal. calcd. forC 23 H 20 Cl 2 N 4 O 2 : C 60.67, H 4.43, N 12.30; Found: C 60.39, H 4.21, N12.14%. 5.2.12. 2-(4,6-Dichloropyrimidin-2-yl)-1-(2,4-dimethoxyphenyl)- 2,3,4,9-tetrahydro-1H- b -carboline ( 18  ) Yield: 69%, mp 205 e 207   C; IR (KBr): 3374, 3105, 2838, 1673,1570,1501,1459,1384,1273,1220cm  1 ; 1 HNMR(CDCl 3 ,300MHz): d  (ppm) 8.18 (s,1H), 7.53 (d,1H,  J  ¼ 7.2 Hz), 7.18 e 7.09 (m, 3H), 6.96(d,1H,  J  ¼ 8.4 Hz), 6.55 (s,1H), 6.57 (d, 2H,  J  ¼ 2.4 Hz), 6.38 (dd,1H,  J  ¼ 8.4,2.4Hz),5.09(dd,1H,  J  ¼ 8.4,2.2Hz),3.96(s,3H),3.79(s,3H),3.59 e 3.55 (m, 1H), 2.94 e 2.91 (m, 2H);  13 C NMR (CDCl 3 , 75 MHz):161.51, 160.69, 158.52, 136.13, 133.22, 129.01, 126.80,121.94,121.15,119.54, 118.26, 111.05, 109.44, 108.25, 104.66, 99.70, 56.30, 55.50,50.15,40.08,21.16.Anal.calcd.forC 23 H 20 Cl 2 N 4 O 2 :C60.67,H4.43,N12.30; Found: C 60.43, H 4.22, N 12.19%. 5.2.13. 2-(4,6-Dichloropyrimidin-2-yl)-1-(2,5-dimethoxyphenyl)- 2,3,4,9-tetrahydro-1H- b -carboline ( 19 ) Yield: 72%, mp 186 e 188   C; IR (KBr): 3370, 3009, 2948, 2838,1682,1581,1386,1346,1273,1220cm  1 ; 1 HNMR(CDCl 3 ,300MHz): d  (ppm) 8.59 (s, 1H), 7.51 (d, 1H,  J   ¼  7.5 Hz), 7.30 e 7.28 (m, 1H),7.16 e 7.09 (m, 3H), 7.00 e 93 (m,1H), 6.79 e 6.71 (m, 2H), 6.55 (s,1H), R. Kumar et al. / European Journal of Medicinal Chemistry 45 (2010) 3274 e  3280 3278
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