Obniska, Jolanta

Zagórska, Agnieszka

Zejc, Alfred

Acta Poloniae Pharmaceutica - Drug Research

English

Jagiellonian Univeristy Repository

A cia P o lon iac  P h arm ac eu tics  -  D ru g  R esea rch , V ol. 59 N o. 3 pp . 2 0 9 -2 1 3 . 2iK)2 ISSN  000 1 -6 8 3 7  P o lish  P h arm ac eu tica l SocietySYNTHESIS AND ANTICONVULSANT PROPERTIES OF NEW I-PHENYL AND l-PHENYLAMINO-3-PHENYLPYRROLIDINE-2,5-DIONE DERIVATIVESJO L A N TA  O BN ISK A , A LFR ED  ZEJC and A G N IESZK A  Z A G O R SK  AD epartm ent o f Pharm aceutical C hem istry, C ollegium  M edicum  o f the Jagiellonian U niversity, 9 M edyczna Str., 30 -688  K rakow, PolandA bstract: A series o f  N -ary l and N -am in o ary l 3 -p h en y l p y rro lid in c -2 ,5 -d io n e s  w ere  syn thesized  and tested for an ticonvu lsan t activ ity  in the m axim um  elec tro shock  seizure (M E S ) and pentetrazol seizure th resho ld  (sc M et) tests. S tructu res o f  the novel com pounds w ere confirm ed  by elem ental and spectral analyses.K eyw ords: an ticonvu lsan t ac tiv ity , p y rro !id in e -2 ,5 -d io n e , succin im ides.In search for a  new com pounds with predic­table anticonvulsant properties, our attention was draw n to a group o f  3 -pheny lpy rro lid ine-2 ,5 -d io - ne w ith different substituents at the nitrogen atom  (1,2). Previous reports (3,4,5) show ed the anticon­vulsant activity o f N -p y rid y l-3 -a ry lp y rro lid in e - 2 ,5 -d io n e  w hich d isp layed  p ro tec tion  against M ES. In add ition , it w as a lso  repo rted  that a sig n ifican t effec t on the ac tiv ity  o f  th is co m ­pounds being  exerted  by the p resence, position  and ch a rac te ris tic  o f  the substituen ts  in pyrid ine m oiety . C rysta llo g rap h ic  in ves tiga tions (6,7) show ed that th e ir  pharm aco log ica l p ropertie s w e­re connec ted  w ith the con fo rm ation . T he co n fo r­m ation o f  pharm aco log ica lly  inactive  m o lecu les d iffers from  that o f  m o lecu les w ith a confirm ed  activ ity .This report w ill provide further structure-ac- tivity studies on the 3 -p h en y lp y rro lid ine-2 ,5 -d io ­nes in w hich pyridine m oiety is replaced by the aryl ring w ith m ethyl o r chloro substituents [comp. I -V II ]  o r by the phenylam ino or diphenylam ino m oiety [comp. V III-X I] .The requirem ent for NH group linking the pyrro lid ine- 2 ,5 -d ione  system  to the arom atic ring w as also investigated. A ccordingly, a series o f new N -ary l substituted 3 -p h en y lp y rro lid ine-2 ,5 -d io ­nes, w as synthesized and evaluated for anticonvul­sant activity.As the starting materials for the synthesis 3 -(2 -ch lo ro p h en y l)- , 3 -(3 -ch lo ro p h en y l)- , 3 - ( 4 -  ch lo ropheny l)-,3 -(3 -fluo ropheny l)- , 3 -(3 -b ro m o - ph en y l)- and 3-phenylsuccin ic  acids synthesized by the m ethod o f  M iller et al (8 ), as m odified by L ange et al. (9) w ere used. The acids w ere cyclized to I-pheny l or l-pheny lam ino -3 -pheny lpy rro lid i- n e-2 ,5 -d io n e  derivatives [I—XI] by heating them atca. 190°-200°C for 1.5-2 h w ith appropriate aryla- m ine (Schem e 1) o r w ith arylhydrazine.E X PE R IM E N T A L  C hem istryM elting points (°C) w ere uncorrected, 'H  N M R  spectra [I -X I] w ere recorded in CD CL solution by using TM S as an internal standard (B ruker VM 250 M H z N M R  Spectrom eter). The chrom atography was perform ed w ith M erck silica gel G F 2 5 4  precoated T LC  sheets using the follow ing developing system s: A -  chloroform : aceton (9:1), B -  chloroform : methanol: acetic acid (60: 10: 5). Spots were detected by their absorption under UV light and visualization w ith 0.05 mol L in 10% HC1.1-P heny l and l-pheny lam ino -3 -pheny lpy rro - lid in e - 2 ,5 -d ione  derivatives [I -  XI].G eneral procedure.An appropriate arylam ine or arylhydrazine (0.02 mole) w ere dissolved in 25 ml o f w ater and appropriate 2 -substitu te  succinic acid (0 . 0 2  mole) w as gradually added. The m ixture was heated in oil bath with sim ultaneous distillation o f water. A fter com plete rem oval o f water, the tem perature o f the reaction m ixture was raised up to 190-200l’C and m aintained for 1.5 h. The crude product was recrystallized from  ethanol.Physicochem ical data, 'H  NM R data, yields and elem entary analysis results o f the com pounds synthesized w ere presented in Table la , b.P harm acologyC om pounds I-X I  w ere pharm acologically pre-evaluated  within the A ntiepileptic D rug D eve­lopm ent (ADD) Program , Epilepsy Branch, Neuro-2092 1 0 JOLANTA OBNISKA et al.Schem e 1.S chem e 2.logical D isorders Program  National Institutes o f  the N eurological and C om m unicative D isorders and Stroke (N IN CD S), by using the testing procedures described elsew here (10,11). Phase I studies invol­ved three tests: m axim um  electroshock seizure (M ES), subcutaneous pentylenetetrazole (sc M et), and the neurotoxicity (TO X ). The M ES test is a m odel for generalized ton ic-c lon ic  seizures. In this test, an electrical stim ulus o f  0.2 s in duration (50 mA in m ice at 60 Hz) is delivered via corneal electrodes. M ice are tested for 30 min. and 4 h withthe follow ing doses: 30, 100, 300 m g/kg o f  test com pound (12).The scM et is a m odel for com pounds that raise a  seizure threshold. In scM et test a dose o f m etrazol is 85m g/kg in mice. T his produces clonic seizures during a period o f  at least 5 seconds in 97%  o f tested anim als. T he m etrazol is adm inistrated sub- cutaneously. The test com pounds are adm inistrated intraperitoneally , suspended in 0.5%  m ethylcellu- lose at the doses o f 30, 100, 300 m g/kg (13). N eurotoxicity, induced by a test com pound, isS y n th e s is  a n d  a n t ic o n v u ls a n t  p ro p e r t ie s  o f  n e w  1 -p h e n y l a n d .. 211T able la . E xperim en tal data  fo r com pounds I - V I INo. MolecularFormulaWeightYield % Mp. [”C]Analysis cal./found 'H NMR/CDCF/5 R,/solvent%C %H %NI c I7h ,a n ,265.373120-12277.0576.935.755.665.285.382.53 (3H, s, CH-0, 2.75-2.90 (IH , d, imide), 3.35-3.42 (1H, q, imide), 4 .0 8 A 4 0  (1H, q, imide), 7.10-7.60 (9FI, m, arom)0.67A0.82BII C nH uO jN iC l.F317.7450104-10564.2164.274.124.074.404.262.15 and 2.19 (3H, 2 s, CH,), 2.96-3.00 (1H, td, imide), 3.40-3.51 (1H, dq, imide), 4 .20- 4.32 (1H, q, imide), 6.99-7.40 (7H, m, arom)0.80A0.79BIII C .hH ^ A N .F297.334857-6072.7972.305.435.294.724.482.32 (3H, s, CHj), 2.74-2.83 (1H, d, imide), 3.14-3.24 (1H, d, imide), 3.97-4.02 (1H, q, imide), 4.42-4.74 (2H, q, CH2), 6.87-7.38 (8H, m, arom)0.72A0.84BIV C n H A N .C l299.7565148-15068.0668.054.704.634.674.512.18 and 2.21 (H, 2s, C H ,), 2 .97 -3 .04  (1H, td, im ide), 3 .3 8 -3 .5 0  (1H, dq, im i­de), 4 .1 8 -4 .2 9  (1H, dq, im ide), 7 .08 -7 .45  (7H, m, arom)0.78A0.86BV c ,6h „ o 2n ,c i2320.7058132-13459.8760.023.453.434.364.122.92-3.00 (1H, dd, imide), 3.33-3.42 (1H, q, imide), 4.15-4.20 (1H, q, imide), 7.23-7.49 (8H, m, arom)0.82A0.79BVI C n H iA N iB r344.225258-6159.3658.984.104.024.073.902 .15 -2 .18  (3H, d, CH.,), 2 .9 2 -2 .9 6  and 3 .0 1 -3 .0 6  (1H, dt, im ide), 3 .33 -3 .48  (1H, dq, imide), 4.14-4.24 (1H, q, imide), 7 .20- 7.48 (8H, m, arom)0.80A0.85BVII C ,7H ,A N ,B r344.225062-6459.3659.134.104.144.073.722.15-2.18 (3H, 2s, CH,), 2.92-3.05 (IH , dq, imide), 3.23-3.49 (1H, dq, imide), 4.14—4.24 (1H, dq, imide), 7.07-7.50 (8H, m, arom)0.72A0.83BT ab le  lb . E xperim ental da ta  fo r com pounds V 11I-X INo. MolecularFormulaWeightYield % Mp. mAnalysis cal./found 'H NMR/CDCl.,/8 Rr/solvent%C %H %NV III C A ÏM A N ,342.4060 112-11677.0676.855.314.928.348.192.89-3.00 (1H, dd, CHum ide), 3.24-3.39 (1H, dd, CH2imide), 4.09-4.17 (1H, q, CH imide), 7.09-7.42 (15H, m, arom)0.73A0.84BIX C |f,H |A N 2Cl300.7468158-15963.8563.824.354.019.319.182.91-2.94 (1H, dd, CH,imide), 3.27-3.41 (1H, dd, CHńmide), 4.37-4.45 (1H, q, CH imide), 6.30 (1H, s NH), 6.85-7.45 (9H, m, arom)0.84A0.94BX C22H |70 2N2C1376.8374159-16170.0970.434.554.857.437.462.91-2.94 (1H, dd, CH2imide), 3.27-3.41 (1H, dd, CHjimide), 4.37-4.45 (1H, q, CH imide), 6.30 (1H, s NH), 6.85-7.45 (9H, m, arom)0.79A0.89BXI C i A A N .C l300.7465173-17463.8564.284.354.319.318.812.90-3.03 (IH , m, imide), 3.26-3.35 (1H, m, imide), 4.34-4.42 (IH , m, imide), 6.69-6.80 (2H, m, arom), 7.13-7.51 (7H, m, arom), 8.44 (IH , s, NH)0.69A0.87B212 JOLANTA OBNISKA et al.T able 2a. A nticonvu lsan t S creen ing  P ro jec t (A SP) Phase I T est results in m ice (com p. I -V I I )Comp. DoseActivityTox1” ASPdlMES"’ sc Met1’1mg/kg 0.5 h 4 h 0.5 h 4 h 0.5 h 4 h class30 0/1 0/1 0/1 0/1 0/4 0/2I 100 1/3 0/3 0/1 0/1 0/8 0/4 1300 1/1 0/1 4/5 0/1 0/4 0/230 0/1 0/1 0/1 0/1 0/4 0/2II 100 0/3 0/3 0/1 0/1 0/8 0/4 3300 0/1 0/1 0/1 0/1 0/4 0/230 0/1 0/1 0/1 0/1 0/4 0/2III 100 0/3 0/3 0/1 0/1 0/8 0/4 2300 1/1 0/1 1/1 0/1 0/4 0/230 0/1 0/1 0/1 0/1 0/4 0/2IV 100 0/3 0/3 0/1 0/1 0/8 0/4 3300 0/1 0/1 0/1 0/1 0/4 0/230 0/1 0/1 0/1 0/1 0/4 0/2V 100 0/3 0/3 0/1 0/1 0/8 0/4 3300 0/1 0/1 0/1 0/1 0/4 0/230 1/4 0/1 0/1 0/1 0/4 0/2VI 100 3/3 0/3 0/1 0/1 0/8 0/4 1300 1/1 0/1 1/1 0/1 0/4 0/230 0/1 0/1 0/1 0/1 0/4 0/2VII 100 1/3 0/3 0/1 0/1 0/8 0/4 1300 1/1 0/1 3/5 0/1 1/4 0/2* T onic extension“'M axim al elec troshock  test (num ber o f  an im als p ro tec ted /num ber o f  an im als tested) h,S ubcu taneous pen ty lenete trazo le  testclR otorod toxicity  (num ber o f  an im als exh ib iting  tox ic ity /num ber o f  an im als tested) c’T he classification  is as follow s:1 -an ticonvu lsan t activ ity  at doses 100 m g/kg o r less2 -an lico n v u lsan t ac tiv ity  at doses grea ter than 100 m g/kg3 -co m p o u n d  inactive at 300  m g/kgT ab le 2b. A nticonvu lsan t S creen ing  P ro jec t (A SP ) P hase 1 T est results in m ice (com p. V I I I -X I )Comp. DoseActivityTox° A S P1’MES"’ sc Met1”mg/kg 0.5 h 4 h 0.5 h 4 h 0.5 h 4 h class30 0/1 0/1 0/1 0/1 0/4 0/2 *V III 100 0/3 0/3 0/1 0/1 0/8 0/4 2300 0/1 0/1 1/5 0/1 0/2 0/230 0/1 0/1 0/1* 0/1 0/4 0/2IX 100 0/3 0/3 0/1 0/1 0/8 0/4 2300 0/1 0/1 1/5 0/1 0/4 0/230 0/1 0/1 0/1* 0/1 0/4 0/2X 100 0/3 0/3 0/1 0/1 0/8 0/4 3300 0/1 0/1 0/1 0/1 1/4 0/230 0/1 0/1 0/1 0/1 0/4 0/2XI 100 0/3 0/3 0/1 0/1 0/8 0/4 3300 0/1 0/1 0/1 0/1 0/4 0/2* T onic extension;l,M axim al electroshock  test (num ber o f  an im als p ro tec ted /num ber o f  an im als tested) h,Subcu taneous pen ty lenete trazo le  testc>R otorod tox icity  (num ber o f  an im als exh ib iting  tox ic ity /num ber o f  an im als tested) cT h e  classification  is as follow s:1 -an ticonvu lsan t ac tiv ity  at doses 100 m g/kg o r less2 -an tico n v u lsan t ac tiv ity  at doses g rea ter than 100 m g/kg3 -co m p o u n d  inactive at 300  m g/kgS y n th e s is  a n d  a n tic o n v u ls a n t  p ro p e r t ie s  o f  n e w  1 -p h e n y l  an d . 213detected in m ice using a rotorod test. U ntreated control mice, when placed on a 6 r.p.m . rotation rod can m aintain their equilibrium  for a prolonged time. N eurotoxicity is indicated by the inability of a mouse m aintaining equilibrium  for one m inute in each o f  the three successive trials (14). R esults are given in Table 2a, b.R ESU LTSIn a series o f l,3 -d ip h en y lp y rro lid in e-2 ,5 - diones [I—VII] com pounds I, III, VI, and VII show ed som e anticonvulsant properties in phase I o f screening project. The l-(2 -m eth y lp h e - n y l)-3 -pheny lpy rro lid ine-2 ,5 -d ione  I and three analogues o f this com pound III, VI, VII were found to be effective in this screening procedure. T he m ost potent in M ES test w as l- (2 -m e th y l-  pheny l)-3 -(3 -b ro m o p h en y l)p y rro lid in e -2 ,5 -d io n e  VI, w hich protected all anim als after 0.5 h at 30, 100 and 300 m g/kg. The l- (4 -m e th y lp h e n y l)-3 -  (3 -fluoropheny l)pyrro lid ine-2 ,5 -d ione  III had an­ticonvulsant properties but only at a dose o f 300 m g/kg. T his com pounds in the scM et test at a dose o f 300 m g/kg show ed m arginal anticonvulsant properties. Som e activity was recorded in the scM et test also for com pounds I, VI, VII (active at 300 m g/kg at 4h).The presence and position o f the m ethyl group in N -ary l moiety appears to be essential for the anticonvulsant activity in this group o f  com pounds. The m ost potent in M ES test w ere com pounds with the methyl group in position 2 or 4  o f  the 1-phenyl ring v/z., I, VI and V II. The change o f  the brom  atom for chlor substituents on the 3-pheny l ring in com pounds IV and V made them  inactive. This effect m aybe is connected with low er lipophilicity. The m ethylene bridge in com pound III decreased the activity. Introduction o f the second substituents (-C1) in the 4 -position  o f  the 1-phenyl ring led to an inactive com pound II.In a series o f  1-phenylam ino derivatives X, XI w ere devoid o f  anticonvulsant activity. C om ­pounds V III, IX w ere active only in the scM et test at 0.5 h using 300 mg/kg. This result suggests that the NH group, linking I-pheny l ring w ith 3 -pheny- lpy rro lid ine-2 ,5 -d ione  m oiety, is probably not ne­cessary for anticonvulsant activity.A cknow legem entsThe authors wish to thank Dr Jam es Stables for providing pharm acological data through the A ntiepileptic D rug D evelopm ent Program , Epilep­sy Branch, N ational Institute o f N eurological D iso­rders and Stroke N ational Institute o f H ealth, Bet- hesda, M aryland, U .S.A.R EFE R E N C E S1. Zejc A., O bniska J.: A cta Polon. Pharm 5, 529 (1984).2. O bniska J., Kulig K., Zejc A.: A cta Polon. Pharm .-D rug  Res. 55, 3,223 (1998).3. Zejc A., O bniska J., C hojnacka-W ójcik  E., Tatarczyńska E., W ilczyńska B.: Pol. J. Phar­m acol. Pharm  39, 91 (1987).4. Zejc A., O bniska J., W ilim ow ski M ., R utkow s­ka M ., W itkow ski J., Barczyńska L., K ędziers- ka-G ożdzik  L., W ojew ódzki W ., O rzechow s- ka-Juzw enko K., Pław iak T., D uś E., G ryska J., G liniak M.: Pol. J. Pharm acol. Pharm . 42, 69 (1990).5. O bniska J., Zejc A., K arolak-W ojciechow ska J.: II Farm aco 54, 423 (1999).6. K arolak-W ojciechow ska J., K wiatkow ski W ., K aczm arczyk Z., Zejc A., O bniska J.: Acta Cryst. C48, 1991 (1992).7. Kwiatkowski W ., K arolak-W ojciechowska J.: J. SAR and QSAR in Environ. Res. 1, 233 (1993).8. M iller C. A ., Long L. M.: J. Am. Chem . Soc. 73, 4895 (1951).9. Lange J., Ł apszew icz J.: Acta Polon. Pharm . 3, 289 (1978).10. Krall R. L., Penry J. K., W hite B„ G., Kupfreberg H. J., Swinyard E. A.: Epilepsia 19, 409 (1978).11. K upferberg H. J.: Epilepsia 30, (suppl. 1), 551 (1989).12. Sw inyard E. A ., B row n W. C ., G oodm an L. S.: J. Pharm acol. Exp. Ther. 106, 319 (1952).13. Sw inyard E. A.: in A nticonvulsant Drugs, Sec­tion 19, vol. 1, Pergam on Press, O xford and New Y ork 47 1972.14. D unham  M. S., M iya T. A.: J. Amer. Pharm ac. Assoc. Sei. Edit. 46, 208 (1957).Received: 7.12.2001

Synthesis and anticonvulsant properties of new 1-phenyl and l-phenylamino-3-phenylpyrrolidine-2,5-dione derivatives

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Synthesis and anticonvulsant properties of new 1-phenyl and l-phenylamino-3-phenylpyrrolidine-2,5-dione derivatives

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