Indian Journal of Chemistry Vo l. 43B. January 2004, pp. 207-2 11

Note

Synthesis, eNS and chloroquin resistance reversal acti vity of benzenepropanam i nest

V L Sharma" *, Kalpana Bhandari", Girija Shankar", H K Singh h

, Pratima SrivastavaC & V C Pandey"

Di vision of Chemical Technology". Pharmacology" and Biochemistry",

Central Drug Research Institute. Lucknow-22600 I. India.

Receil'ed 3 May 2002; accepleil (rel'iseil) 17 March 2003

Several benzenepropanamines w ith a benzy l group att ached to the 3-amino function are synthesized and evaluated for their CNS and chloroquin resistant reversal activ it y.The compounds are fu lly characterized by spectral and elemental anal yses.These com­pounds are tested for their effect on gross behaviour and for ant i ­depressant. ant iconvulsant and anorex igenic acti vity. No effect is observed Oil gross behaviour where as most of them show f1uoxet­ine like untireserp ine and anorex igen ic ac ti vity . Since thi s class of compounds have been reported to modulate the ch loroquin resis­tance in P. Iaicipantlll , therefore these compounds are tested for chloroqu in resisl3nce reversal ac tiv it y ill I' ilro. Five compounds se lective ly inhibit P,faiciparl/ll/ heme oxygenase like f1uox etine.

The development of antidepressant drugs having unique and novel properties , such as reduced side ef­fec ts, enhanced c lini cal efficacy and the po te ntial for a rap id onset of acti on is a viable and rea li sti c re­search objective l as it is the major area which would remai n one of the unmet medical needs to year 2005 (ref. 2). Phenylpropy lamines class of antidepres­sants, f1uoxetine and paroxt ine (SS RI ) had been top se lling products in last many years3

-5

. It sugges ts the ir efficacy, specificity of action and acceptibility but these are not devoid of side-effec ts6 such as delayed onset of action 7

, slow e liminati onS specially in li ver9

and renal impairments 10 and suicide ideati on II. 12.

In view of above observatio ns, it was thought worthwhile to work upon benzenepropanamines (10-18) (Scheme I) with a benzyl group attached to the 3-amino function along with the req uired methyl group as in f luoxetine skeleton were prcparcd. It was hoped that this addit ional benzy l group in f1uoxetine nucleus may enhance lipophilicity lJ of the mo lecule and thu s in (urn availability in the brain.The N-demethylation of these compounds may give rise to the metabo lites which may not accumulate in the body ti ssues as in

t C.D.R.1. Communicat ion No. 6272.

case of desmethyl fl uoxetine. The phenyl ring of 3- N­benzylamine functio n was substituted with 4-methoxy and N,N-dimethylamino groups with a view to further enhance the li pophil icit/ 3

. The methoxy grou p may prov ide additio nal advantage of not being accumu­lated after demethylatio n during metabo lism. The me­tabo lite hydroxy derivative might be excreted in the form of a water-soluble g lucuronide 14. These com­pounds (10-18) were supposed to act via 5 HT­mechani sm like fluoxetine l 5

, therefore, evaluated for biological ac tivities re lated to serotonin l 6 such as anti­depressant, anorexigenic and anticonvu lsant activity.

These compounds a lso fulfill some important char­acteristics 17 of drug res istance reversal modu lators eg., lipid solubility, two planer aromatic rings and a tert iary nitrogen atom. Fluoxetine has a lso been re­ported to posses ill vitro chl oroquin res istance rever­sa l activit/ 7

.,s

. Therefore, these compou nds (10-18) may exhibit chlo roquin resistance reversal activity as well as antidepressant activity with leas t side effects. Results of various activities may he lp in unders tand­ing the structure activity re latio nship.

Chemistry The compounds (10-18) were sy nthes ized accord­

ing to Scheme I. N-Methy l benzylidines (4-6) were sy nthes ized by appropriate benzaldehyde (1-3) and methylamine.These benzylidines were reduced to co r­responding benzylmethyl am ines (7-9) by catalytic hydrogenatio n at room temperature. 3-Substituted benzylmethyl aminopropiophenones (10-12) were sy nthesized by mannich react io n of acetophenone and benzyl methy l amines (7-9). These keto compounds were reduced by sodium borohydride to correspond­ing a lcohol (13-15). The reactio ns of these alcohol (13-15) with p-chlo robenzot rifluoride in presence of sodium hydride in dimethyl acetamide gave N­methy I-N-su bsti tu ted benzy 1-3-( 4-tri lluoro methy 1)­phenoxy)benzenepropanamines (16-18). The com­POLlIlds (10-18) were converted into their hydrochlo­ride salts and characte rized by IR. 'H NMR. mass spectra and elemental analyses (Table I ).

Pharmacology The study was carried o ut in a lbino mice (weighing

between 16-20g) of e ither sex . Each group comprises of 5 animals. All the compounds were administered in

208 INDIAN J. CHEM .• SEC B. JANUARY 2004

1-3

hCH=NCH3b.

4-6

R=H. OCH3. NMe2

r()1 + 7-9

~COCH3 c. d

uR

04 HC!~ ~ ~"CH3 ..

16-18

10-12

f. g. d

OH

13-15

a:MeNH2.b: Pd-C IH2. c: (CH20)n. PrOH. d:Conc.HCI. e: NaBH4/MeOH. f : NaH/DMAC. 9:CF3-C6H4-CI.

Scheme I

a dose of 75 Jl moll kg i.p. as aqueous solution or aqueous suspension in gum acacia. Gross behavioural f'" J 9 . I 20 . d 20 . elects , anticonvu sant , anti epressant , anorexl-

genic20 and anxiolytic activit/ J were carried out by standard methods. Saline treated controls were run concurrently. Chloroquin resistance reversal activity was assayed by inhibition of heme oxygenase at lOJlg/mL concentration22

. The results are given in Table II.

The compounds tested have no effect on gross be­haviour, however fluoxetine had shown the sign of stimulation. In antireserpine tests all the compounds except 13 showed weak to moderate activity (25-50%), whereas fluoxetine showed 100% reversal of reserpine induced ptosis and sedation. None of the compounds had any remarkable effect on reserpine

induced hypothermia like fluoxetine23. Compounds 13

and 18 exhibited significant anorexi a (>40 - 50%), like fluoxetine which caused high degree of anorexia (80%). No effect was observed in anticonvulsant ac­tivity with compounds in MES and antimetrazole tests whereas fluoxetine showed 20% activity in MES test as reported24

. In the antihypoxia test, all the com­pounds including fluoxetine showed enhancement in survival time as compared to control but it was far too less than diazepam.

Results and Discussion The results indicate that in fluoxetine skeleton, on

N-benzylation at 3-methylamino group and also on replacement of trifluoromethylphenoxy moiety by keto or hydroxy grouping at position-l the antireserpine

*Compd

10

11

12

13 H

14

IS

16 H

17

18

R

H

m.p.! b.p. (0C)

187-88

62-66

182-85

121-22

108-10

184-86

145-47

194-96

173-75

NOTES 209

Table 1- Physical data of the compounds 10-18

Yield (%) 92

63

84

82

77

57.7

77

89

69

Mass, Mol. formula

253(M+), 162, 134,120, 105,91 C 17HI9NO.HCI

283(M+), ISO, 120, 105,77 CI SH2IN02.HCI

296(M+), 164, 134, 105, 77 C 19H24N20.2HCI

255(M+), 134, 120,91 C 17H2INO.HCI

285(M+)I64, 150,121,91,77 CI SH23N02.HCI

298(M+), 254, 164, 135, 77 C19H26N20.2HCI

399(M+), 134, 121 , 91 C24H24F3NO.HCI

426(M+), 163, 121 , 90, 77 C2,H26F)N02.HCI

442(M+),166, 134, 118, 91 C26H26F3N20 2. 2HCI

I R (I!)

3035, 2902, 1678, 1589,

1450

3332, 2900, 2846, 1670. 1608, 1514

3409, 2900, 1685, 1598,

1458

3250, 3078, 2927-2806,

1458

3400-3200, 2930-2700, 1608, 1512,

1463

3338, 3030, 2928, 1608,

1478

3440, 2937-2619, 1614, 1517,1461

3440, 2937-26 13, 1614, 1515,1465

2928 , 2852, 2798 , 1614,

1520

IH NMR (8 ppm)

2.271(5, 3H, N-CH3), 2.87-2 .9(t, 2H, 3-CH2), 3.17-3.21(t, 2H, 2-CH2), 3.56(5, 2H, CH r Benzyl), 7.22-7 .30(m, 5H, ArH, Benzyl ), 7.42-7.48(m, 2H, 3' , 5' ArH), 7.53-7 .58(m, I H, 4 ', ArH), 7.92-7.95(m, 2H, 2 ' &6' ArH) (free base)

2.67-2.69(m, 2H, 2-CH2), 3.34-3.58(m, 2H, 3-CH2), 3.81(5, 6H, N-CH3&OCH3), 4.07-4.28(m, 2H, CHrBenzyl), 6.95-6.97(m, 2H, ArH adjacent to OCH3), 7.45-7 .62(m, 5H, ArH), 7.98-8 .01(d, 2H), 3.8 1(5, 2H, ArH adjacent to keto;J=9 .0Hz), 12.46(bs, I H, NH)

2.24(5, 3H, N-CH3), 2.81-2 .88(m, 2H, 3-CH 2), 2.89(5, 6H, NCH3h, 3.13-3.20(m, 2H, 2-CH2) ' 3.46(5, 2H, CH2-Benzyl), 6.65-6.69(d, 2H, ArH adjacent to N(CH3h .1=8.6Hz), 7.12-7.16(d, 2H, ArH adj acent to CH2, J=8 .6Hz) 7.38-7 .53(m, 3H, ArH), 7.89-7.94(m. 2H, ArH adjacent to keto) (free base)

1.86-2.05(m, 2H, 2-CH2), 2.27(5, 3H, N-CH3)' 2.57-2.87(m, 2H, 3-CH2), 3.46-3.68(q, 2H, CH2-Benzyl J A=12.9Hz, J B=12.6Hz), 4.90-4.94(m, IH, I-CH), 7.21-7.38(m, IOH, ArH)

2.17-2.27(m, 2H, 2-CH2), 2.67(5, 3H, N-CH3), 3.04-3.35(m, 2H, 3-CH2), 3.81(5, 3H. OCH3), 4.04-4.27(m, 2H, CHr Benzyl), 5.0-5.02(m, IH, l-CH), 6.90-6.92(m, 2H, ArH adj acent to OCH3), 7.24-7.47(m, 7H, ArH), 11.30(bs, IH, NH)

1.81-1.91 (m, 2H. 2-CH2), 2.25(5, 3H, NCH3), 2.56-2 .87(m, 2H, 3-CH2), 2.92(5, 6H, N(CH3)2), 3.35-3 .60(q, 2H, CHrBenzyl , J A=12.63Hz, J B=12.64Hz, 4.85-4.90(m, iH , l-CH), 6.67-6.72(d, 2H, ArH adjacent to N(CH3h , Jo=8.66Hz), 7.17-7.21(d, 2H, ArH adjacent to CH2, Jo=8.76Hz)

2.45-2 .58(m, 2H, 2-CH2), 2.69(5, 3H, N-CH3), 2.92-3.33(m, 2H, 3-CH2), 4.10 -4.24 (m, 2H, CH2benzyl), 5.30-5.56 (m, IH, l -CH). 6.82-6.84 (m, 2H, ArH adj acent to 0), 7.26-7.43 (m, IOH ArH), 7.43-7.55 (m, 2H, ArH adjacent to CF3), 12.5-13.5(bs, IH , NH).

2.40-2.74(m, 5H, 2-CH2 & NCH3), 3.02-3 .39 (m, 3H, 3-CH2), 3.82(5, 3H, OCH3), 4.03-4.2 1 (q, 2H, CH2benzyJ), 5.41-5.54(m, IH, I-CH), 6.79-6.93(m, 4H, ArH adjacent to 0), 7.27-7.79 (m, 9H, ArH).

1.99-2.07(m, 2H, 2-CH2)' 2.20-2.66 (m, 2H, 3-CH2). 2.86 (s, 6H, NMe2), 3.37-3.46(m. 2H. CH2benzyl), 5.29-5.35(m. IH, -CH), 6.58-6.62(d, 2H, ArH adjacent toN), 6.84-6.88 (d. 2H, ArH adjacent to 0), 7.06-7 .11(d, 2H. ArH, adjacent to CH2), 7.22-7.30(m, 5H, ArH), 7.38-7.43(d, 2H, ArH adjacent to CF3).

*Compounds gave sati sfactory elemental analyses

210 INDIAN J. CHEM. , SEC B. JANUARY 2004

Table 11- Pharmaco logical Data of the compounds 1O-1 S at 75 ~ mol/kg.ip.

Compd" Antidepressa nt ac tivitl Anorex igenic ac ti vi ty" Anticonvul sant Antijhypoxia ac ti vit y" Reversal of reserpine Mi lk left in milk ac ti vity" Mean surviva l time.

induced ptos is consumpti on test MES test SEM (% inc rease) and sedati on 75~lmo l 1 50~l mol

+ 0 23.4± 1.21 (24.46)

++ 4 22.0± 1.05( 17.02)

+ 25 20.2±0.S6(7.44 )

40 24.0± 1.52(27.65)

+ 20 24.S± 1.93(3 1.9)

+ 0 21.4± 1.50( 13.82)

+ 12 60 21.4± I.OS( 13.32)

++ 12 60 22.4±1.2 1( 19. 14)

+ 50 20 20.6± 1.03(9.57)

Fluoxetine ++++ SO 20 SO 23 .2± 1.1 6(23.40)

"No effect on gross behaviour. hNo effec t on hypothermia, a change of < 2eC was insignifican t. (+) = 25%, (--)= no effect:" An anorex ia of < 40% was insign ifi cant , d No protecti on in antimel razole test, (-) = no protecti on. CCont ro l va lue of surviva l time IS.S ± 0.9S min: Diazepam showed the mean survival time 33.4 ± 1.2 1 min wi th an increase of 77.05%. fSe lecti vely inhibited the P . .f(dciparlllll hae moxygenase at 10 ~l g I mL concen tration.others are either inact ive or inhi bi ted the haemoxygenase.of both the host and P. Iaiciparlllll.

activity was partly retained. Among the N-benzy l groups 4-methoxy substituents were fo und to be more active (11 and 17). In these co mpounds the major side effect of f1uoxetine i.e., anorex ia was minimized . The two compounds 13 and 18 whi ch have show n significant anorex igenic acti vi ty were almost devoid of antidepressant ac ti vity. Thus it ca n be concluded that these compou nds may lead either to an antidepressant or to an anorex igenic agent.

Five compounds (10-12, 16 and 17) have se lec­tively inhibited the P. Ja lcipamlll heme oxygenase at 10 /1g/ mL concen trat ion, rest of them were ei ther inacti ve (18) or in hi bited (13-15) the heme oxygenase of both the host and P. Ja lcipartlll i. II suggested that the modi ficatio n carried out at position- I and 3 in f1uoxetine skeleton have no effect on chl oroquin res istance reversal activity except the I-hydroxy compou nds (13-15) which were not selective in inhibiting the heme oxygenase of host and parasite both. The results further confirm the

I . 17 f' d' I structura requIrements or rug res Istance reversa agents. Experimental Section

Melting points were determined in open capillaries in an electrically heated block and are uncorrected. The progress of the reacti on was monitored by TLC. IR spectra (vmax in cm-I) were recorded in KB r or neat on a rJ' lR 820 1 PC instrument. IH NMR spectra on Brucker ORX 200 MH z instrument using TMS as

internal standard (Chemi ca l shi fts in 8 ppm) and mass spectra on a l EOL lMS 0300 instrument at 70 eV . The physical data of compounds (10-18) are given in Table I.

Compounds (7-9) were prepared by known proce­dure25

.

3-[N -methyl-N -( 4-su bstituted benzyl) ]aminopro­piophenone (10-12). A mi xture of am ine (0.055 mole) and propanol (25 mL) was coo led in an ice-bath (O-SOC) for 25 min and coned HCi (0.07 mL) was added dropwise with stirring. After 30 min the mi x­ture was allowed to altai n room temperature and para­fo;-maldehyde (l/Sth of the required 0.075 mole) was added. The flask was heated at 100- 1 10°C for 30 min . Similarly other three portions of parafo rmalde­hyde were added and finall y the reac tion mi xture was heated for 2 hI' at 100- 1 10°C. Then it was al lowed to coo led to room temperature overni gh t. Concentration fo llowed by coo ling of the reacti on mixture gave the compounds (10-12) as hydrochloride sa lts.

3-[N-methyl-N-( 4-substituted benzyl)]amino-l ­phenyl-propanol (13-15). A solution of keto com­pounds (10-12, free base; 0.013 mole) in methanol (25 mL) was coo led in ice-bath for 30 min and pow­dered sodi um borohydride (0.037 mole) was added in equal port ions in I hI'. The reacti on mi xture was fur­ther stirred in ice-bath for 30 min . The reaction mi x­ture was concen trated under reduced pressure in a rotavapor and the residue was treated with water

NOTES 211

(5 mL) and ethyl acetate (30 mL). The ethyl acetate layer was separated, washed with water till neutral washings and dried (anhyd . Na2SO.j). The resultant free bases were converted into hyd rochloride salts (13-15).

N-methyl-N -( 4-su bstituted)benzyl-3-[ 4-(trifluo.'­omethyl)phenoxy]benzene-propanamines (16-18), A mi xture of sodi um hydride (0.0382 mole) and di­methylacetamide (DMAC; 15 mL) was cooled in an ice-bath for 15 min and a solution of hydroxy com­pounds (13-15; 0.024 mole; free base) in DMAC (I0mL) was added dropwise with stirring. After 15 min the reaction mi xture was allowed to attain room temperature. The flask was then placed in an oil bath and heated slowly to 80° in 90 min . The oil bath tem­perature was maintained 80-90°C for another 2 hr. The colour changed from ye ll ow to brown. This brown solution was cooled to room temperature and p-chlorobenzotrifluoride (0.0382 mole) was added in 15 min with stirring. The mixture was again heated at 100-1 IOoC for 5-6 hr. The r.m. was allowed to attain room temperature and treated with ethyl acetate and water successively. The organic layer was separated and aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layer was washed with water till neutral pH and dried (anhyd. Na2S04). The concentration of the organic layer gave free base (16-18) as oils which were transformed into respective hydrochloride salts (16-18).

Acknowledgement The authors are thankful to Mrs Tara Rawat for

technical assistance.

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