Potential Antimalarials. XX* Mannich Base

Aust. J. Chem., 1994, 47, 1143-1154

b

Potential Antimalarials. XX* Mannich Base Derivatives of 2-[7-Chloroquinolin4-ylamino and 7-bromo(and 7-trifluoromethy1)1,5-naphthyridin-4-ylaminol-4-chloro(or 4- or 6-t-butyl or 4 or 5-fluoro)phenols and 4(or 6)-t-Butyl2- (7-trifluoromethylquinolin-4-y1amino)phenol Gordon B. BarlinYAStephen J. IrelandYA Trang M. T. N g ~ ~ e n , ~ Barbara Kotecka and Karl H. Rieckmann A Division of Neuroscience, John Curtin School of Medical Research, Australian National University, G.P.O. Box 334, Canberra, A.C.T. 2601. Army Malaria Research Unit, University of Sydney, Ingleburn, N.S.W. 2174.

Abstract

+

Syntheses are reported for some mono- and di-Mamich base derivatives of 4-chlorc-, 3or 4-fluorc-, or 2- or 4-t-butyl-substituted 2-(7'-chloroquinolin-4'-ylamino)phenols and 2-[7'bromo(and 7'-trifluoromethyl)-l',5'-naphthyridin-4'-ylamino]phenols. In tests against the FC-27 isolate of Plasmodium falcipamm, the most active compound was 2-(7'-chloroquinolin-4'-ylamino)-5-fluoro-4,bis(piperidin-l"-ylmethyl)phenol(16) with 1c5o 12.2 nM.

b

Introduction In earlier papers we have examined the syntheses and antimalarial activity of Mannich base derivatives of 2-(7-trifluoromethylquinolin-4-ylamino)phenols,1~2 2-(7-chloroquinolin-4-ylamino)phenols,3 and 2[7-bromo(and 7-trifluoromethy1)-l,5naphthyridin-4-ylamino]phenols.3We now report the syntheses and the effect on antimalarial activity of the 4-chloro, 3- or 4-fluoro, or 2- or 4-t-butyl substituents in a series of mono- and di-Mannich base derivatives of 2-(7'-chloroquinolin4'-y1amino)phenol and 2-[7'-bromo(and 7'-trifluoromethy1)-11,5'-naphthyridin-4'ylamino]phenols. Syntheses The compounds reported in this paper were prepared by Mannich reaction on the appropriate Znitrophenol, followed by reduction to the corresponding 2-aminophenol and then condensation with the relevant 4-chloro heterocycle. * Part XIX, Aust. J. Chem., 1993, 46, 1695.

Barlin, G. B., and Yan, J.-H., Aust. J. Chem., 1989, 42, 2191. Barlin, G. B., Jiravinyu, C., Butcher, G. A., Kotecka, B., and Rieckmann, K. H., Ann. Rop. Med. Parasitol., 1992, 86, 323. Barlin, G. B., Nguyen, T. M. T., Kotecka, B., and Rieckmann, K. H., Aust. J. Chem., 1992, 45, 1651. Manuscript received 10 December 1993

0004-9425/94/061143$05.00

G. B. Barlin et al.

1144

4-Chloro- and 4-fluoro-2-nitrophenol under the conditions of the Mannich reaction readily gave the mono-Mannich derivatives (1; X = C1 or F), and 4and 6-t-butyl-2-nitrophenol gave the mono-Mannich derivatives (1; X = But) and (2) respectively. However, under similar conditions, no Mannich product could be isolated from the reaction of the isomeric 5-t-butyl-2-nitrophenol, probably owing to the steric effect of the t-butyl group adjacent to positions 4 and 6. When 5-fluoro-2-nitrophenol was subjected t o the Mannich reaction with piperidine three products were isolated. These included the expected 3fluoro-6-nitro-2,4-bis(piperidin-l1-ylmethyl)phenol (3d) together with 6-nitro-3(piperidin-l1-yl)-2-(piperidin-l11-ylmethyl)phenol (4) and 6-nitro-3-(piperidin-l1yl)-2,4-bis(piperidin-l"-ylmethyl)phenol (5). We found that the fluoro substituent in 5-fluoro-2-nitrophenol was readily replaced by piperidine at 100' or by refluxing with ethanolic piperidine t o afford 2-nitro-5-(piperidin-l1y1)phenol which when subjected t o the Mannich reaction gave compound (4). Reduction of the nitro compounds was readily achieved with hydrogen over Raney nickel, and the air-sensitive amino compounds were used directly for condensation with 4,7-dichloroquinoline or 7-bromo(or 7-trifluoromethy1)-4-chloro1,5-naphthyridine to give the required compounds (6)-(11) and (14)-(16).

NR2 in formulae ( 1 H 3 ) , ( 6 H l l ) (6)

CI

(7) Br (8) CFl (9) CI (LO) CFl (11) CI (12) CI (13) CI

CH CI CI N N CI CH Bu' CH Bu' CH F CH CH2NR2 CH H

(a) (b) (c)

(dl (e)

(t) (g) (h)

(0

NMe? NEt, NPr? piperidin-I-yl 2-methylpiperidin-I- yl 3-methylpiperidin-I-yl 4-methylpiperidin-I-yl 3,s-dimethylpiperidin-I-yl pyrrolidin-I-yl

a

Potential Antimalarials. XX

Antimalarial Activities The compounds reported in this work were examined for antimalarial activity i n vitro in a preliminary screen by using the relatively inexpensive visua1415 and microscopic tests5 against the chloroquine-sensitive (FC-27) strain of Plasmodium falciparum. The results from this work are recorded in Table 1 usually as a range spanning the 1 ~ 5 0values. The most active compound (16) was further evaluated in the i n vitro assay of parasite growth against both the FC-27 and K-1 (chloroquine-resistant) isolates of P . falciparum by measurement of the uptake of [3H]hypoxanthine essentially as described by Desjardins et aL6 and as used in our earlier work.2 The results of this work are recorded in the Experimental section.

b

Examination of the data in Table 1 for the mono-Mannich base derivatives (6a-e,g-i) revealed relatively small variations in antimalarial activity, and these compounds were less active than the di-Mannich compounds (12) reported previously3. Small variations only were also observed in the activities of compounds (7a-i) and (8a-i) . The 4-chloro compound (6d) was slightly less active than the 4-fluoro analogue ( l l d ) [and the 4-t-butyl analogue (gd)], which had activity comparable t o that of the Cunsubstituted compound (13; NR2 = pyrrolidin-l-yl).3 Burckhalter et ~ 1 . ~ reported for 4-(7'-chloroquinolin-4'-ylamino)-2-diethylaminomethylphenol that the introduction of a 6-chloro substituent decreased activity from 25 t o 12 quinine equivalents. The piperidinyl compounds (7d)-(lld) all had similar activities. Significant differences in activity were observed between the isomeric pairs (9d) and (14), and (10d) and (15); those compounds (14) and (15) with the t-butyl group adjacent t o the hydroxy group were significantly less active. The activity of compound (9d) ( I C 5&100 ~ ~ nM) approached that of the di-Mannich compound3 (12; NR2 = piperidin-1-yl) (Icao 12.5-25 nM) but the 2-t-butyl compound (14) ( I C 2~ 200 ~ n ~ was ) less active. The di-Mannich base (16) [ I C ~ O 6.3-12.5 nM (visual method), 12.2 nM (hypoxanthine method) against the FC-27 isolate] with the 5-fluoro substituent was the most active of the compounds examined in this work. Against the highly Rieckmann, K. H., Lancet, 1982, i, 1333. Kotecka, B., and Rieckmann, K. H., Trop. Med. Parasitol., 1992, 43, 9. Desjardins, R. E., Canfield, C. J., Haynes, J . D., and Chulay, J. D., Antimicrob. Agents Chemother., 1979, 16, 710. Burckhalter, J . H., Tendick, F. H., Jones, E. M., Jones, P. A,, Holcomb, W. F., and Rawlins, A. L., J . A m . Chem. Soc., 1948, 70, 1363.

G. B. Barlin et al.

chloroquine-resistant (K-1) isolate of P. falcipamm its activity was only slightly diminished. The activity of compound (16) was significantly higher than that of the 4-fluoro compound ( l l d ) . The 5-fluoro substituent in compound (16) appeared slightly beneficial because compound (16) was more active than 2-(7'-chloroquinolin4'-ylamino)-4,6-bis(piperidin-l11-ylmethyl)phenol( I C 12.5-25 ~ ~ n ~ which ) ~lacked the 5-fluoro substituent, and had comparable activity3 to the 5-methyl derivative3 of the latter. The absence of any activity at 800 n~ for compound (17) clearly illustrates the significance of Mannich side chains to the antimalarial activity of derivatives of aminophenols.

Table 1. Results ( 1 ~ 5 0values) for antimalarial testing in vitm against the FC-27 isolate of P. falciparum by using the visual (and microscopic) tests described by ~ i e c k m a n n ~ ' ~ Inhibitor

Icso ( n ~ )

Inhibitor

Icso ( n ~ )

(94 (104 (114 (14) (15) (16) (17) chloroquine The microscopic test gave 1c5o > 200 nM. The microscopic test gave 1c5o within the range 50-100 nM. The microscopic test gave 1c5o 200 nM. The Experimental section gives the results of further testing by using the hypoxanthine incorporation technique with both the FC-27 and K-1 isolates. A

*

I


Experimental

b

All products were examined for the presence of impurities by thin-layer chromatography. Analytical samples were dried a t 7(r110°/0.2 mmHg for 16-24 h unless otherwise specified. Melting points were taken in Pyrex capillaries. Analyses were performed by the Australian National University Analytical Services Unit. 'H n.m.r. spectra (6 values) were recorded in CDC13 solutions a t 90 MHz and 30' on a Jeol FX9OQ Fourier-transform spectrometer unless stated otherwise. Low-resolution mass spectra were recorded on an Incos d a t a system attached to a VG-Micromass 7070 double focusing mass spectrometer by using electron ionization (e.i.) a t 70 eV (under the supervision of Dr J. K. MacLeod a t the Research School of Chemistry).

Piperidine (3.92 g, 46.1 mmol) was added t o a chilled mixture of 4-chloro-2-nitrophenol (2.0 g, 11.5 mmol), paraformaldehyde (1.38 g, 46.1 mmol) and ethanol (6.0 ml) and the reaction mixture was refluxed in an oil bath a t 97' for 17 h. After cooling, the yellow precipitate was collected, washed with methanol, and recrystallized from methanol t o give the title compound (1.52 g, 49%), m.p. 178-180' (Found: C, 53.5; H, 5.6; N, 10.2. C1~H15ClN203 requires C , 53.2; H,5.6; N, 10.3%). 'H n.m.r. 6 1.63, complex, H3',4',5'; 2.63, m, H 2',6'; 3.78, s, CH2; 7.23, d , J 3 , 5 2.5Hz, H5; 7.89, d , J 3 , 5 2.5 HZ, H3. 4-Chloro-2-nitro-6-(pyr~olidin-1 '-ylmethyl)phenol and Related Compounds

4

Pyrrolidine (3.28 g, 46.1 mmol) was added t o a chilled mixture of paraformaldehyde (1.38 g, 46.1 mmol) and 4-chloro-2-nitrophenol (2.0 g, 11. 5 mmol) in ethanol (6.0 ml) and the mixture was refluxed in an oil bath a t 97' for 22 h. The solvent was then evaporated under reduced pressure and the oily residue was subjected to column chromatography (alumina, 2% methanol in chloroform) to give a yellow solid (1.75 g, 59%). A portion of this product was recrystallized from a mixture of methanol and chloroform and gave the title compound, m.p. 214-216' (Found: C, 51.7; H, 5.2; N, 10.6. CllH13ClN203 requires C, 51.5; H, 5.1; N, 10.9%). 'H n.m.r. 6 1.92, complex, H3',4'; 2.79, m, H2',5'; 3.94, s, CH2; 6.92, br s, OH; 7 . 2 9 , d , J 3 , 5 2 . 5 H z , H5; 7 . 9 3 , d , 33.5 2 . 5 H z , H3. In a similar manner the following compounds were prepared from 4-chloro-2-nitrophenol, 4-t-butyl-2-nitrophenols and 2-t-butyl-6-nitropheno19 (cf.lO). 4-Chloro-6-(dimethylaminomethyl)-2-nitrophenol(94%), m.p. 225-227O, after recrystallization from a mixture of ethyl acetate, acetone and methanol (Found: C, 47.1; H, 4.8; N, 12.1. CgHllClN203 requires C, 46.9; H, 4.8; N, 12.2%). 'H n.m.r. 6 2.43, s, Me; 3.77, s , CH2; 5.92, br s, OH; 7.34, d , 33,s 2.5 Hz, H5; 7.93, d , 33,s 2.5 Hz, H3. 4-Chloro-6-(diethylaminornethyl)-2-nitrophenol(32%), m.p. 134-136', after column chromatography (alumina, 8% methanol in chloroform; then alumina, 4% methanol in chloroform) and recrystallization from a mixture of methanol and cyclohexane (Found: C, 51.0; H, 6.0; N, 10.6. CllH15ClN203 requires C, 51.1; H, 5.9; N, 10.8%). 'H n.m.r. 6 1.18, t , J 7 Hz, Me; 2.75, q, J 7 H z , CH2Me; 3.90, s, 6-CH2; 7.19, d , 33,s 2 . 5 HZ, H5; 7.89, d, 33,s 2 . 5 HZ, H 3. 4-Chloro-6-(dipropylaminomethy1)-B-aitrophenol (27%), m.p. 123-125', after column c h r e matography (alumina, chloroform) (Found: C, 54.6; H, 6.8; N, 9.5. C13H19ClN203 requires C, 54.4; H, 6 . 7 ; N, 9.8%). ' H n.m.r. 6 0.92, t , J 7 H z , Me; 1.65, m, CH2Me; 2.58, m, CH2CH2Me; 3.87, s, CH2; 7.20, d, 33,s 2 . 5 HZ, H5; 7.88, d, J 3 , 5 2 . 5 HZ, H3. ~-Chloro-6-(2'-methylpiperidin-l'-ylmethyl)-2-nitrophenol (42%), m.p. 105-107°, after column chromatography (alumina, 2% methanol in chloroform) (Found: C, 55.2; H, 6.4; N, 9.7. C13H17C1N203 requires C, 54.8; H, 6.0; N, 9.8%). 'H n.m.r. 6 1 . 0 6 4 . 3 5 , complex, H2',3',4',5',6', Me and 6-CHz; 7.17, d, J3,5 2 . 5 HZ, H5; 7.86, d , J3,5 2.5 HZ, H3. 4-Chloro-6-(3' -methylpiperidin-l'-ylmethyl)-2-nitrophenol(97%), m.p. 95-97', after column chromatography (alumina, chloroform) (Found: C, 54.5; H, 6.1; N, 9.5. C13H1-rClN203 Angelici, R. J., Quick, M. H., Kraus, G. A., and Plummer, D. T., Inorg. Chem., 1982, 21, 2178. Hewgill, F. R., and Middleton, B. S., J. Chem. Soc. C , 1967, 2316. lo Moore, G. G. I., and Kirby, A. R., J. Org. Chem., 1979, 44, 925.

1148

G. B. Barlin et al.

requires C, 54.8; H, 6.0; N, 9.8%). 'H n.m.r. 6 0.94, d, J 5 . 5 Hz, Me; 0.88-305, complex, H2',3',4',5',6'; 3.78, s, 6-CH2; 7.20, d , J3,s 2 . 5 H z , H5; 7.88, d, J3,5 2 . 5 H z , H3. 4-Chloro-6-(4'-methylpiperidin-l'-ylmethyl)-2-nitrophenol (71%), m.p. 171-173', after recrystallization from a mixture of methanol and chloroform (Found: C, 55.1; H, 6.3; N, 9.4. C13H17ClN203 requires C, 54.8; H, 6 . 0 ; N, 9.8%). 'H n.m.r. 6 0.99, d , J 4 . 5 Hz, Me; 1.38-3.1, complex,~~2',3',4',5',6';3.81, s, 6-CH2; 7.26, d , 53,s 2.5 HZ, H 5 ; 7.91, d , J 2 . 5 Hz, H3. 4-Chloro-6-(3', 5'-dimethylpiperidin-1 '-ylmethy1)-2-nitrophenol (53%), m.p. 160-162', after column chromatography (alumina, 2% methanol in chloroform, twice; then alumina, chloroform) (Found: C, 56.5; H, 6.6; N, 9.4. C14H19CIN203 requires C, 56.3; H, 6 . 4 ; N, 9.4%). 'H n.m.r. 6 0.90, d , J 5.5 Hz, Me; 0.86-2.98, complex, H 2',3',4',5',6'; 3.77, s, 6-CH2; 7.21, d, J3,5 2 . 5 Hz, H5; 7.88, d, J 3 , 5 2 . 5 HZ, H3. 4-t-Butyl-2-nitro-6-(piperidin-l'-ylmethyl)phenol (82%), m.p. 168-170°, after recrystallization from a mixture of methanol, chloroform and ethyl acetate (Found: C, 66.0; H, 8.3; N, 9.6. C16H21N203 requires C, 65.7; H, 8.3; N, 9.6%). 'H n.m.r. 6 1.30, br s, But; 1.60, m, H3',4',5'; 2.55, m, H2',6'; 3.77, s, 6-CHz; 7.26, d, 53,s 2 HZ, H5; 7.86, d , 53,s 2 HZ: H3; 9.89, br, OH. 6-t-Butyl-2-nitro-4-(piperidin-1'-ylmethyl)phenol (46%), m.p. 97-99', after recrystallization from a mixture of methanol, chloroform and hexane (Found: C, 65.8; H, 8.3; N, 9.6. C16H24N203 requires C, 65.7; H, 8 . 3 ; N, 9.6%). 'H n.m.r. 6 1.46, br s, But; 1.62, m, H3',4',5'; 2.39, m, H2',6'; 3.43, s, 4-CH2; 7.56, d , J3,s 2 H z ; H5; 7.96, d , J 3 , 5 ~ H z H3. ,

A mixture of 4-fluor-2-nitrophenol (0.5 g, 3.18 mmol), paraformaldelyde (0.38 g, 12.7 mmol), piperidine (1.08 g, 12.7 mmol) and ethanol (5 .O ml) was refluxed with stirring in an oil bath at 95' for 14 h. The reaction mixture was evaporated t o dryness and the product recrystallized from ethanol to give the title compound (0.593 g, 73%), m.p. 162-164' (Found: C, 56.7; H, 6.1; N, 10.7. C12H15FN203 requires C, 56.7; H, 5.9; N, 11.0%). 'H n.rn.r. 6 1.54-1.74, complex, piperidinyl, 2.63, complex, piperidinyl; 3.81, s, 6-CHz; 7.20, dd, 53,s 3, JH,F7 . 5 Hz, H5; 7.65, dd, J 3 , 5 3, JH,F8 HZ, H3.

4

e

(A) A solution of 5-fluoro-2-nitrophenol (0.2 g, 1.17 mmol) and piperidine (0.43 g, 5.06 mmol) in ethanol (1.0 ml) was refluxed with stirring in an oil bath a t 100' overnight. The ethanol was evaporated to leave an oil which crystallized. This was extracted with hot light petroleum (b.p. 6@-80') (30 ml) which on cooling gave yellow crystals of the title compound (0.132 g, 47%), m.p. 62-64' [from light petroleum (b.p. 60-80°)] (Found, for a sample dried a t 20°/0.1 mmHg for 16 h: C, 59.6; H, 6.1; N, 12.5. CllH14N203 requires C, 59.4; H, 6.3; N, 12.6%). 'H n.m.r. 6 1.70, complex, H3',4',5'; 3.49, complex, H 2',6'; 6.29, d, J 4 , 6 2.5 HZ, H6; 6.43, dd, J 3 , 4 10, J 4 , 6 2 . 5 Hz, H4; 7.93, d , J 3 , 4 10 HZ, H3. ( B ) A mixture of 5-fluor-2-nitrophenol (0.2 g, 1 . 3 mmol) and piperidine (1.0 ml, 10 mmol) was heated in an oil bath a t 100' for 14 h. After evaporation of the piperidine under reduced pressure the residue was extracted with light petroleum (b.p. 6&80°) (40 ml) t o give a yellow crystalline solid (0.154 g, 54%) which was identical (m.p. and 'H n.m.r.) with the product isolated in (A).

A mixture of 2-nitro-5-(piperidin-l'-yl)phenol(0.05 g, 0.225 mmol), paraformaldehyde (0.084 g, 2 . 8 mmol), piperidine (0.24 g, 2 . 8 mmol) and ethanol (1.0 ml) was refluxed with stirring in an oil bath a t 95' overnight. The volatile material was then removed under reduced pressure, and the residue when examined by t.1.c. revealed only one product. It was recrystallized from light petroleum (b.p. 60-80') (10 ml) and the yellow crystals (0.040 g, 56%; m.p. 152-154') were subjected to t.1.c. (alumina, chloroform, developed twice) and again recrystallized to give the title compound, m.p. 154-155' (Found: C, 64.3; H, 8.2; N, 13.3. C17H25N303 requires C, 63.9; H, 7.9; N, 13.2%). 'H n.m.r. 6 1.5-1.75, complex, 2.6-2.85, complex, Pxpiperidinyl; 3.86, s, 2-CH2; 6.52, d, J 4 , 5 9 HZ, H4; 7.91, d, J 4 , 5 9 HZ, H5.

#


Reaction of 5-Flaoro-2-nitrophenol vrith Piperidine and Paraformaldehyde

+

+

To a cooled mixture of 5-fluoro-2-nitrophenol (2.0 g, 12.7 mmol) and paraformaldehyde (1.53 g, 50.9 mmol) in ethanol (10 ml) was added piperidine (4.34 g, 50.9 mmol) and the mixture was refluxed a t 100' for 20 h. The volatile material was then removed on a rotary evaporator to leave a n oil (6.0 g). This was subjected to column chromatography (alumina, chloroform) and the fractions which were eluted first were subjected t o t.1.c. (alumina, ethyl acetate/cyclohexane, 1: 1) and gave a t higher RF 6-nitr0-9-(~iperidin-l'-yl)-2,4-bis(piperidzn~ " - y l r n e t h ~ l ) ~ h e n (5) o l ( 0 , 4 6 g , 9%), m.p. 140-141' [from light petroleum (b.p. 60-80°)] (Found: C, 66.4; H, 9.0; N, 13.4. C23H36N403 requires C , 66.3; H, 8.7; N, 13.5%). 'H n.m.r. 6 1.45-1.75, complex, 2.35-3.15, complex, 3xpiperidinyl; 3.42, s, 2-CHz; 3.93, s, 4-CH2; 7.90, s, H5. The product a t low RF on the t.1.c. plate gave 6-nitr0-3-(piperidin-l'-~1)-2-(~i~eridinl"-ylmethyl)phenol (0.18 g, 6%) (4) [from light petroleum (b.p. 60-80°)] with 'H n.m.r. data identical with those of the product described in the previous preparation of (4) above. The fractions which were eluted later from the alumina column were subjected to t.1.c. (alumina, chloroform; and silica, methanol) and gave after recrystallization from light '-y1methyl)phenol petroleum (b.p. 60-80°), yellow crystals of 9-fluoro-6-nitro-2,4-bis(piperidin-1 (3d) (0.454 g, lo%), m.p. 157-159' (Found: C, 61.3; H, 7.8; N, 11.9. ClaHz6FN303 requires C, 61.5; H, 7.5; N, 12.0%). 'H n.m.r. 6 1.45-1.65, complex, 2.33-2.68, complex, Ixpiperidinyl; 3.42, s, 2-CHz; 3.87, s, 4-CHz; 7.94, d, JHF 7 . 5 Hz, H5.

A mixture of 4-chloro-2-nitro-6-(piperidin-l'-ylmethyl)phenol(0.6 g; 2.2 mmol), ethanolic ammonia (30 ml) and ethanol (30 ml) was shaken with Raney nickel and hydrogen until uptake ceased. The mixture was filtered through Celite and the solvent evaporated to leave the oily amine (0.45 g, 84%). 'H n.m.r. 6 1.59, m, H3',4',5'; 2.52, m, H2',6'; 3.58, s, 6-CHz; 6.37, s, H5; 6.61, s, H3. A mixture of this amine (0.213 g, 0.88 mmol) and 4,7-dichloroquinoline (0.175 g, 0.88 mmol) with ethanol (8.0 ml) and water (2.0 ml) was adjusted with concentrated hydrochloric acid to pH 4 . 7 and then refluxed a t 100' for 12 h. The solvent was evaporated under reduced pressure, and the residue was diluted with water, adjusted t o pH 9-10, and extracted with chloroform to give an oil. This product was purified by t.1.c. (alumina, chloroform) and recrystallized from a mixture of hexane and ethyl acetate t o give yellow crystals of the title compound (0.17g, 48%), m.p. 183-185' (Found: C, 62.7; H, 5.4; N, 10.3. C Z I H Z I C I Z N ~ O requires C, 62.7; H, 5 . 3 ; N, 10.4%). 'H n.m.r. 6 1.60, complex, H3",4",5"; 2.58, complex, H2",6"; 3.69, s, 6 C H 2 ; 6.73, d, 53,s 2 HZ, H5; 7.19, d, J z r , 3 ~ 5 . 5 HZ, H3'; 7.37, d, 53,s ~ H z H3; , 7.46, dd, J 5 r , y 9, J6!,y ~ H z H6'; , 7.97, d, J51,61 ~ H z H5'; , 8.05, d, J6',8'2 HZ, H8'; 8.64, d , J2r,315 . 5 HZ, H2'.

A mixture of 4-chloro-6-(diethylaminomethyl)-2-nitrophenol (0.61 g, 2 . 4 mmol), ethanolic ammonia (30 ml) and ethanol (30 ml) was shaken with hydrogen over Raney nickel until uptake ceased. The catalyst was filtered off on Celite and the solvent evaporated t o leave an oil ( 0 . 5 g , 93%). 'H n.m.r. 6 1.18, t , J 7 H z , Me; 2.73, q, J 7 H z , CHzMe; 3.74, s, CH2; 6.39, d , J3,5 2 HZ, H5; 6.64, d , J3,5 2 HZ, H3. This amine (0.25 g, 1 . 1 mmol) was mixed with 7-bromo-4-chloro-1,5-naphthyridine'1 (0.266 g, 1.1mmol), ethanol (8.0 ml) and water (2.0 ml) and was adjusted with hydrochloric acid to pH 2 . 5 and then refluxed a t 100' for 11.5 h. The solvent was evaporated and the residue was diluted with water, adjusted to pH 9-10, and extracted with chloroform. The product was subjected to t.1.c. (alumina, chloroform) and gave, as a yellow solid, the title compound ( 0 , 2 8 g , 59%), m.p. 132-134' (Found: C, 5 2 1 ; H, 4.6; N, 12.6. C19HzoBrClN40 requires C, 52.4; H, 4.6; N, 12.9%). 'H n.m.r. 6 1.14, t , J 7 Hz, Me; 2.71, q, CHzMe; 3.79, S, 6-CH2; 6.75, d, 33,s 2 HZ, H5; 7.24, d, J2,,3, 5 . 5 HZ, H3'; 7.45, d , 33,s ~ H z H3; , 8.44, d , J 6 r , 8 t ~ H z H8'; , 8.62, d, J2',3' 5 . 5 H z , H2'; 8.73, br s , OH(?); 8.80, d, 36',8'2 H z ,

Barlin, G. B., and Tan, W.-L., Aust. J. Chem., 1985, 38, 459.

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G. B. Barlin et al.

H6'. Mass spectrum (e.i.) m/z 438, 436, 434 (M, 1 . 9 , 8 . 8 , 6.5%), 365 (4.8), 364 (4.6), 363 (14.5), 362 (3.6), 72 (28.3), 58 (100).

4-Chloro-2-nitro-6-(pyrrolidin-l'-ylmethyl)phenol( 0 . 4 g, 1 .5 mmol) was reduced catalytically as described above for similar compounds. The amino compound was obtained as a n oil (0.25 g, 71%). 'H n.m.r. 6 1.86, br s, H3',4'; 2.68, br s, H2',5'; 3.75, s, 6-CHz; 6.41, d, J 3 , 5 2 . 5 Hz, H5; 6.63, d, J 3 , 5 2 . 5 HZ, H3. A mixture ofthis amine (0.125 g, 0.55 mmol), 4-chloro-7-trifluoromethyl-1,5-naphthyridine'z (0.128 g, 0.55 mmol), ethanol (6.0 ml) and water (2.0 ml) was adjusted with concentrated hydrochloric acid t o pH 2 . 5 and then refluxed a t 100' for 11.5 h. The solvent was evaporated, the residue was diluted with water and adjusted t o pH 9-10, and the product was extracted with chloroform. This product was purified by t.1.c. (alumina, chloroform) and recrystallized from a mixture of chloroform and light petroleum (b.p. 60-80') to give the title compound (0.14 g, 60%), m.p. 158-160' (Found: C, 56.7; H, 4.4; N, 13.1. CzoH18ClF3N40 requires C, 56.8; H, 4.3; N, 13.3%). 'H n.m.r. 6 1.88, m, H3',4'; 2.71, m, H2',5'; 3.86, s, 6-CH2; 6.79, d, J 3 , 5 2 . 5 Hz, H5; 7.30, d, J2,,,3,, 5 . 5 Hz, H3"; 7.47, d, J 3 , 5 2 . 5 Hz, H3; 7.90, br s, NH(?), 8.56, d , J6u,8" 2 HZ, H8"; 8.73, d, J2rr,3,, 5 . 5 Hz, H2"; 8.93, br s, OH(?); 8.99, s, H6".

#

Mono-Mannich Base Derivatives of 2-Amino-4-chlorophenol Catalytic reduction of the corresponding 4-chlore2-nitrophenols as described above gave the following moneMannich base derivatives of 2-amino-4-chlorophenol which were used directly without further purification. 6-Dimethylaminomethyl: 'H n.m.r. 6 2.30, s, Me; 3.53, s, CH2; 6.36, d, 53,s 2 . 5 HZ, H5; 6.61, d , J 3 , 5 2 . 5 HZ, H3. 6-Dipropylaminomethyl: 'H n.m.r. 6 0.89, t , J 7 Hz, Me; 1.62, m, J 7 Hz, CH2Me; 2.48, m, J 8 Hz, CHzCHzMe; 3.66, s, CHz; 6.36, d, J 3 , 5 2 . 5 Hz, H5; 6.60, d, 53.5 2 . 5 Hz, H3. 6-(2'-Methylpiperidin-1'-ylmethyl): 'H n.m.r. 6 1.13-4.22, complex, H 2',3',4',5',6', Me, 6-CHz; 6.36, d , 53.5 2 . 5 HZ, H5; 6.59, d , J 3 , 5 2 . 5 Hz, H3. 6-(3'-Methylpiperidin-1'-ylmethyl): 'H n.m.r. 6 0.91, d, J 5 . 5 Hz, Me; 0.85-2.85, complex, H2',3',4',5',6', 3.57, S, 6-CHz; 6.37, d , J 3 , 5 2.5 HZ, H5; 6.61: d , J3,a 2 . 5 H z , H3. 6-(4'-Methylpiperidin-1'-ylmethyl): 'H n.m.r. 6 0.96, d, J 5 Hz, Me; 1.16-3.04, complex, H2',3',4',5',6'; 3.59, s, 6-CHz; 6.37, d , J 3 , 5 2 . 5 HZ, H5; 6.61: d , J 3 , 5 2 . 5 HZ, H3. 6-(3',5'-Dimethylpiperidin-l'-ylmethyl): 'H n.m.r. 6 0.87, d, J 5 . 5 Hz, Me; 0.90-2.94, complex, H2',3',4',5',6'; 3.56, s, 6-CHz; 6.35, d, J 2 . 5 Hz, H5; 6.59, d, J 2.5 Hz, H3.

c

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Derivatives of 2-Amino-6-(pipendin-l '-ylmethyl)phenol The following compounds were prepared by catalytic reduction of the corresponding 2-nitro compounds. 4-Fluoro: 'H n.m.r. 6 1.5-1.64, complex, 2.49, complex, piperidinyl; 3.56, s, CH2; 6.08, br d , H3; 6.34, br d , H5. 4-t-Butyl: 'H n.m.r. 6 1.22, s, But; 1.55, m, H3',4',5'; 2.51, m, H2',6'; 3.59, s, 6-CHz; 6.38, s, H3; 6.68, s, H5. In a similar manner to the preparations described above, from the 2-aminophenols and 4-chloroquinolines and the 4-chloro-1,5-naphthyridinesthe following compounds have been prepared. 4-Chloro-2-(7'-chloroquinolbn-4 '-y1amino)-6-(dimethylaminomethy1)phenol(6a) (68%), m.p. 115-117', after t.1.c. (alumina, chloroform) (Found: C, 59.8; H, 4.8; N, 11.3. C18H17ClzN30 requires C, 59.7; H, 4.7; N, 11.6%). 'H n.m.r. 6 2.37, s, Me; 3.67, s, 6-CHz; 6.51, br s, OH; 6.73, d , J 3 , 5 2 . 5 Hz, H5; 7.17, d , J 3 , 5 5 . 5 Hz, H3'; 7.37, d, J 3 , 5 2 . 5 HZ, H3; 7.44, dd, .J5t,6,9, J6!,s! 2 HZ, H 6'; 7.94, d , J5,,6, 9 Hz, H 5'; 8.04, d , J6,,sr 2 Hz, H 8'; 8.63, d, J 2 ~ , 35.5 , HZ, H2'. Barlin, G. B., and Jiravinyu, C., Aust. J. Chem., 1990, 43, 1175.

C

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+

1151

4-Chloro-2-(7'-chloroquinolin-4'-ylamino)-6-(diethylaminomethyl)phenol (6b) (68%), m.p. 149-151°, after t.1.c. (alumina, chloroform) (Found: C, 61.4; H, 5.5; N, 10.6. C20H~lC12N30 requires C, 61.5; H, 5.4; N, 10.8%). 'H n.m.r. 6 1.15, t , J 7Hz, Me; 2.68; q, J 7Hz, CH2Me; 3.80, s, 6-CH2; 6.72, d l 53,s 2.5 Hz, H5; 7.18, d , J2!,3!5 . 5 Hz, H3'; 7.36, d , 53,s 2 . 5 H z , H3; 7.44, dd, J5,,6, 9, J6t,y ~ H z H6'; , 7.95, d, J5',y ~ H z H5'; , 8.04, d , J 2 Hz, H8'; 8.63, d , J2!,3! 5 . 5 Hz, H2'. Mass spectrum (e.i.) m/z 393, 391, 389 (M, 0.5, 4.4, 6.9%), 319 (3.2), 318 (16.5), 316 (24.9), 72 (18.4), 58 (100). ~-Chloro-2-(7'-chloroquinolin-4'-ylamino)-6-(dipropylaminomethyl)phenol (6c) (go%), m.p. 137-13g0, after t.1.c. (alumina, cyclohexane/ethyl acetate, 3 : 1) and recrystallization from a mixture of chloroform and light petroleum (b.p. 60-80') (Found: C, 63.2; H, 5.9; N, 9.8. C22H25C12N30 requires C, 63.2; H, 6.0; N, 10.0%). 'H n.m.r. 6 0.92, t , J 7 Hz, Me; 1.61; m, CH2Me; 2.54, m, CH2CH2Me; 3.78, s, 6-CHz; 6.46, br s, NH(?); 6.72, d , 53,s 2 HZ, H5; 7.10, br s, OH; 7.18, d , J2t,3, 5 . 5 HZ, H3'; 7.36, d , J3,52 HZ, H3; 7.44, dd, J5',6'9, J6,,st 2 HZ, H6'; 7.95. d , J5,,y 9 HZ, H5'; 8.03, d l J6r,sr 2 HZ, H8'; 8.63, d, J2,,3t 5 . 5 HZ, H2'. 4-Chloro-2-(7'-chloroquinolin-4 '-ylamino)-6-(pyrrolidin-l" -ylmethyl)phenol (6i) (49%), m.p. 145-147', after t.1.c. (alumina, chloroform) and recrystallization from a mixture of chloroform and cyclohexane (Found: C, 61.5; H, 5.0; N, 10.5. C20H19ClzN30 requires C, 61.9; H, 4.9; N, 10.8%). 'H n.m.r. 6 1.87, m, H3",4"; 2.68, m, H2",5"; 3.83, s, 6-CH2; 6.73, d , 53,s 2 HZ, H5; 7.15, d, J2r,3, 5 . 5 H ~ H3'; , 7.35, d, 53,s 2 HZ, H3; 7.42, dd, J 5 t q 6 r 9, J6t,8, 3 H z , H6'; 7.66, br s, OH; 7.94, d, J5',6'~ H z H5'; , 8.03, d, J6r,s, 3 H z , H8'; 8.62, d , J2!,3#5 . 5 HZ, H2'. 4-Chloro-2-(7'-chloroquinolin-~-ylamino)-6-(2"-methylpiperidin-1 "-ylmethyl)phenol (6e) (47%), as an oil after t.1.c. (alumina, chloroform) (Found: C, 63.2; H, 5.7; N, 9.9. C22H23CIN30 requires C, 63.5; H, 5.6; N, 10.1%). 'H n.m.r. 6 1.17-4.31, complex, H2",3",4",5",6", Me, 6-CH2; 6.09, br s, NH; 6.72, d, 53,s 2 HZ, H5; 7.16, d, J2t,3, 5 . 5 HZ, H3'; 7.35, d , 53,s 2 HZ, H3; 7.45, dd, . J ~ J ,9,~ ,J6,,q 2 HZ, H6'; 7.97, d, J5',6'9 HZ, H5'; 8.04, d , J6t,y 2 HZ, H8'; 8.62, d, J2/,3t5.5 Hz, H2'. ~-Chloro-2-(7'-chloropuinolin-~'-ylamino)-6-(3"-methylpiperidin-l "-ylmethy1)phenol (6f) (54%), m.p. 157-15g0, after t.1.c. (alumina, cyclohexane/ethyl acetate, 3 : 1) and recrystallization from a mixture of chloroform and light petroleum (b.p. 60-80') (Found: C, 63.2; H, 5.7; N, 9.8. C22H23Cl2N30 requires C, 63.5; H, 5.6; N, 10.1%). 'H n.m.r. 6 0.94, d, J 5 . 5 Hz, 3.69, s , 6-CHz; 6.72, d, 53.5 2 HZ, H5; 6.91, Me, 0.88-2.96, complex, H2",3",4",5",6"; br s, OH(?); 7.18, d , J 2 t , 3 ' 5 . 5 H z , H3'; 7.36, d , 53,s ~ H z H3; , 7.44, dd, J5',6' 9, J6,,8, ~ H z H6'; , 7.95, d , J5,,6, ~ H z H5'; , 8.04, d , 56',8'~ H z H8'; , 8.63, d , J2!,3, 5 . 5 H z , H 2'. 4-Chloro-2-(7'-chloroquznolin-4 '-y1amino)-6- (4 "-methylpiperidin-1 "-ylmethy1)phenol (6g) (76%), m.p. 121-123', after t.1.c. (alumina, chloroform) and recrystallization from a mixture of ethyl acetate and cyclohexane (Found: C, 63.5; H, 5 . 7 ; N , 9.9. CzzHz3C12N30 requires C, 63.5; H, 5.6; N, 10.1%). 'H n.m.r. 6 0.97, d, J 4 . 5 H z , Me; 1.57-3.08, complex, H2",3",4",5",6", 3.71, s, 6-CH2; 6.41, br, OH(?); 6.72, d , 53,s 2 HZ, H5; 7.18, d, J2,,3/ 5 . 5 H z , H3'; 7.36, d, J3,5 ~ H z H3; , 7.45, dd, J 5 r , 6 1 9, J6r,8, ~ H z H6'; , 7.96, d, J5,,,y 9 HZ, H5'; 8.04, d , 56,,8t 2 HZ, H8'; 8.63, d , J2!,3, 5 . 5 HZ, H2'. 4-Chloro-2-(7'-chloroqzlinolin-4'-ylamino)-6-(3",5" -dimethylpiperidin-1 "- ylmethy1)phenol (6h) (48%), m.p. 101-103', after t.1.c. (alumina, chloroform) and recrystallization from a mixture of chloroform and light petroleum (b.p. 60-80') (Found: C, 64.5; H, 6.0; N, 9.6. C23HzsC12N30 requires C, 64.2; H, 5.9; N, 9 . 8 % ) . ' ~n.m.r. 6 0.89, d, J 5 . 5 Hz, Me; 3.71, s , 6-CH2; 6.05, br s, NH(?); 6.74, s, H 5 , 7.20, 1.54-3.00, complex, H2",3",4",5",6"; , 7.95, d , J5t,y ~ H z , d, J 2 t , 35~. 5 H z , H3'; 7.38, s , H3; 7.45, dd, J5, 6, 9, J6,,8' ~ H z H6'; H5'; 8.05, br s, H8'; 8.65, d, J2,,3, 5 , 5 H z , ~ 2 ' . 2-(7'-Bromo-1 ',5'-naphthyridin-~'-ylamino)-4-chloro-6-(dimethylaminomethyl)phen~l (7a) (91%), m.p. 174-176', after t.1.c. (alumina, 2% methanol in chloroform) (Found: C, 49.9; H, 4.2; N, 13.7. C17H16BrC1N40 requires C, 50.1; H, 4.0; N, 13.7%). 'H n.m.r. 6 2.37, s, Me; , 7.24, d , J2,,3r 5 . 5 H z , H3'; 7.47, d, 53,s 2 . 5 HZ, 3.67, S, 6-CH2; 6.76, d , J3,52 , 5 H ~ H5; H3; 8.45, d, J6,,8t 2 HZ, H8'; 8.63, d , J2,,3, 5 . 5 HZ, H 2'; 8.80, d , 36t,8!2 HZ, H 6'; 8.87, br s, NH(?); 9.32, br s, OH(?). 2-(7'-Bromo-1',5'-naphthyridin-~'-ylamino)-~-chloro-6-(dipropylaminomethyl)phen~l (7c) (98%) as a n oil after t.1.c. (alumina, cyclohexane/ethyl acetate, 3 : 1) (Found: C, 54.1;

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G. B . Barlin et al.

H, 4 . 9 ; N , 11.8. C21H24BrC1N40 requires C , 5 4 . 4 ; H , 5 . 2 ; N , 12.1%). ' H n.m.r. 6 0.91, t , J 7 H z , Me; 1 . 5 6 , m , J 7 Hz, CH2Me; 2.54, t , J 7 H z , CHzCH2Me; 3.79, s , 6-CH2; 6 . 7 6 , d , J3,5 ~ H z H, 5 ; 7 . 2 4 , d , J2/,3' 5 . 5 H z , H3'; 7 . 4 5 , d , J3,5 ~ H z H, 3 ; 8 . 4 5 , d , J6,,.3, ~ H z , H8'; 8 . 6 3 , d , J2r,3, 5 . 5 Hz, H2'; 8 . 8 1 , d , J6,,.3t 2 H Z , H6'. 2 - ( 7 ' - B m m o - l ' , 5'-naphthyridin-4 '-ylamino)-4-chloro-6-(py7m1idin-l ''-ylmethyl)phenol ( 7 i ) ( 3 3 % ) , m.p. 154-155', after t.1.c. (alumina, chloroform) and recrystallization from a mixture requires ~N~O C, o f methanol and cyclohexane (Found: C , 52.9; H , 4 . 2 ; N , 12.8. C ~ S H ~ B B ~ C 52.6; H, 4 . 2 ; N , 12.9%). ' H n.m.r. 6 1.88, m, H 3",4"; 2 . 6 9 , m, H2",5"; 3 . 8 5 , s , 6-CH2; 6 . 7 7 , d , J3,5 2 . 5 H Z , H 5 ; 7 . 2 4 , J2r,31 5 . 5 H Z , H3'; 7 . 4 6 , J3,5 2.5 H Z , H 3 ; 7 . 6 1 , br s , O H ( ? ) ; 8 . 4 5 , d , J6t,.3, 2 H Z , H8'; 8 . 6 2 , d , Jzr,3r 5.5 HZ, H 2 ' ; 8.80, d , J6t,.3, 2 H Z , H6'. 2-(7'-Bromo-l ', 5'-naphthyridin-4 '-ylamino)-~-chloro-6-(piperidin-l " - ylmethy1)phenol ( 7 d ) ( 5 5 % ) , m.p. 168-170°, after t.1.c. (alumina, chloroform) and recrystallization from a mixture o f chloroform, methanol and cyclohexane (Found: C , 5 3 9 ; H , 4 . 3 ; N , 12.3. CzoHzoBrClN40 requires C , 53.6; H, 4 . 5 ; N , 12.5%). ' H n.m.r. 6 1 . 5 9 , m, H3",4",5"; 2 . 5 9 , m , H2",6"; 3 . 6 9 , S , 6-CHz; 6.76, d , J3,5 2 H Z , H 5 ; 7 . 2 3 , J2r,3, 5 . 5 H Z , H3'; 7 . 4 5 , d , J3,5 2 HZ, H 3 ; 8 . 4 6 , d , J 6 t , 8 ~2 H z , H 8 ' ; 8 , 6 3 , d , J2',3/ 5 . 5 H z , H 2 ' ; 8 . 8 1 , d , J6t,8t 2 H z , H 6 ' ; 9.91, b r s , O H . 2-(7'-Bromo-1 ',5'-naphthyridin-4 '-ylamino)-4-chloro-6-(2"-methylpiperidin-1 "-ylmethy1)phenol ( 7 e ) (67%), m.p. 166-168', after t.1.c. (alumina, chloroform) and recrystallization f r o m a mixture o f methanol, chloroform and light petroleum (b.p. 60-80') (Found: C , 54.4; H, 5 . 1 ; N , 11.9. C z l H z z B r C 1 N 4 0 requires C , 54.6; H , 4 . 8 ; N , 12.1%). H n.m.r. 6 1.21, d , 6-CH2; 6 . 7 5 , d , 53,s 2 HZ, H 5 ; 6 . 9 1 , J 6 . 5 Hz, Me; 1.1&4.30, complex, H2",3",4",5",6", br s , O H ( ? ) ; 7 . 2 4 , d , J2',3' 5 . 5 H z , H3'; 7 . 4 4 , d , J3,5 2 H Z , H 3 ; 8 . 4 5 , d , J6r,8r 2 Hz, H 8 ' ; 8 . 6 3 , d , J2',3' 5 . 5 H Z , H 2 ' ; 8.82, d , J6,,.3t 2 HZ, H6'. 2-(7'-Bromo-l1,5'-naphthyridin-4 '-ylamino)-4-chloro-6-(3"-methyl-piperidin-l "-ylmethyl)phenol ( 7 f ) (66%), m.p. 150-152', after t.1.c. (alumina, cyclohexane/ethyl acetate, 3 : 1 ) (Found: C , 54.7; H, 4 . 5 ; N , 11.8. C z l H z z B r C l N 4 0 requires C , 5 4 . 6 ; H, 4.8; N , 12.1%). ' H n.m.r. 6 0.91, d , J 5.5 Hz, Me; 0.88-2.96, complex, H 2",3",4",5",6"; 3 . 7 1 , s , 6-CHz; 6 . 7 7 , d , 33.5 ~ H z H, 5 ; 7 . 2 4 , d , J2,,3r 5 . 5 H z , H 3 ' ; 7 . 4 7 , d , J3,5 ~ H z H, 3 ; 7 . 5 7 , br s , O H ( ? ) ; 8 . 4 7 , d , J6!,.3! 2 H Z , H 8'; 8 . 6 4 , d , J2t,3' 5 . 5 HZ, H 2'; 8 . 8 2 , d , J6,,s, 2 H Z , H 6'. -ylamino)-4-chloro-6-(4 "-methylpiperidin-1 "-ylmethyl)2-(7'- Bromo-l1,5'-naphthyridin-4' phenol ( 7 g ) ( 6 0 % ) , m.p. 172-174", after t.1.c. (alumina, chloroform) and recrystallization from a mixture o f chloroform, ethyl acetate and light petroleum ( b . p . 60-80') (Found: C , 5 4 . 3 ; H, 4 . 6 ; N , 11.9. C z l H z z B r C l N 4 0 requires C , 54.6; H , 4 . 8 ; N , 12.1%). ' H n.m.r. 6 0 . 9 6 , d , J 4 . 5 H z , Me; 1.36-3.07, complex, H 2",3",4",5",6"; 3.71, s , 6-CHz; 6 . 7 6 , d , J3,5 2 H Z , H 5 ; 7.23, d , J2t,3/ 5 . 5 H Z , H3'; 7 . 4 5 , d , J3,5 2 H Z , H 3 ; 8.45, d , J6r,.3, 2 H Z , H 8 ' ; 8.63, d , J2,,3, 5 . 5 Hz, H2'; 8.81, d , J6,,.3, 2 H Z , H6'. 2-(7'-Bromo-1 ',5'-naphthyridin-4' -ylamino)-4-chloro-6- (3",5"-dimethylpiperidin-1"- ylmethy1)phenol ( 7 h ) ( 7 2 % ) , m.p. 121-123', after t.1.c. (alumina, chloroform) (Found: C , 5 6 . 2 ; H, 5.3; N , 11.7. C22H24BrClN40 requires C , 55.5; H, 5 . 1 ; N , 11.8%). ' H n.m.r. 6 0 . 8 8 , d , 3.71, s , 6-CH2; 5 . 5 7 , br s , O H ( ? ) ; 6.77, J 6 Hz, Me; 1.53-2.99, complex, H2",3",4",5",6"; d , 53,s ~ H z H, 5 ; 7.24, d , J2r,3, 5 . 5 H z , H3'; 7 . 4 6 , d , J3,5 ~ H z H, 3 ; 8 . 4 6 , d , J6,,.3t ~ H z , H8'; 8 . 6 2 , d , J2,,3, 5 . 5 H z , H2'; 8.81, d , J6,,.3t 2 H Z , H6'. 4 - Chloro-6- (dimethylaminomethyl)-2- (7' - trifluoromethyl- 1 ',5' -naphthyridin-4 '-y1amino)phenol ( 8 a ) ( 4 1 % ) , m.p. 161-163", after t.1.c. (alumina, chloroform) and recrystallization from a mixture o f chloroform and cyclohexane (Found: C , 54.2; H, 4.3; N , 13.8. CleH16ClF3N40 requires C , 54.5; H , 4 . 1 ; N , 14.1%). ' H n.m.r. 6 2.39, s , Me; 3.69, s , 6-CHz; 6 . 7 8 , d , J3,5 2.5 H Z , H 5 ; 7 . 3 1 , d , J2',3' 5 . 5 HZ, H3'; 7 . 4 8 , d , J3,5 2 . 5 H Z , H 3 ; 8 . 5 6 , d , J6,,sr 2 H z , H 8 ' ; 8 . 7 3 , d , J2',3' 5 . 5 H z , H2'; 8 . 9 1 , br s, O H ( ? ) ; 9 . 0 0 , d , J6t,.3! 2 H Z , H6'. 4-Chloro-6-(diethylaminomethyl)-2-(7'-t-4 '-ylamino)phenol ( 8 b ) (45%), m.p. 138-13g0, after t.1.c. (alumina, cyclohexane/ethyl acetate, 3 : 1 ) and recrystallization from a mixture o f chloroform and light petroleum (b.p. 60-80') (Found: C , 56.3; H , 4.8; N , 12.9. CzoHzoC1F3N40 requires C , 56.5; H , 4 . 8 ; N , 13.2%). ' H n.m.r. 6 1.15, t , J ~ H z Me; , 2.69, q , J 7 H z , CH2Me; 3.82, s , 6-CHz; 6 . 7 9 , d , J3,5 2 H Z , H 5 ; 7 . 3 2 , d , J2!,3! 5 . 5 H z , H 3 ' ; 7 . 4 7 , d , J3,5 ~ H z H, 3 ; 8 . 5 5 , s , H 8 ' ; 8 . 7 3 , d , Jz1,3, 5 . 5 H z , H 2 ' ; 8 . 9 3 , br s , N H ( ? ) ; 9.02, d , J6t,8t 2 HZ, H6'; 9 . 9 1 , br s , O H ( ? ) . 4-Chlo~~(dipropylaminomethyl)-2(7'-trijluoromethyLl ',5'-naphthyridin-4 '-ylamino)phenol (8c) ( 4 8 % ) , m.p. 102-104°, after t.1.c. (alumina, cyclohexane/ethyl acetate, 3 : 1 ) and

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a

1153

recrystallization from a mixture of chloroform, methanol and light petroleum (b.p. 60-80') (Found: C , 58.2; H, 5 . 4 ; N, 12.3. C Z Z H Z ~ C I F ~ requires N ~ O C , 58.3; H, 5.4; N, 12.4%). 'H n.m.r. 6 0.92, t , J 7 H z , Me; 1.64, m, J 7 H z , CHzMe; 2.55, m, CH2CH2Me; 3.79, s, 6 C H z ; 6.77, d , J3,5 2 HZ, H5; 7.31, d, J2r,3, 5 . 5 HZ, H3'; 7.46, d , J3,5 2 HZ, H3; 8.56, S, H8'; 8.72, d , J2',3' 5 . 5 Hz, H2'; 8.90, br s, NH(?); 9.01, d, J 6 ~ , 8 2, HZ, H6'; 9.45, br s, OH(?). 4-Chloro-6-(piperidin-1 '-ylmethyl)-2-(7"-trifluoromethyl-l ",5"-naphthyridin-4"-ylamino)phenol (8d) (54%), m.p. 163-165', after t.1.c. (alumina, chloroform, twice) (Found: C, 57.9; H, 4.8; N, 12.5. C21H2oCIF3N40 requires C, 57.7; H, 4.6; N, 12.8%). 'H n.m.r. 6 1.62, m, H3',4',5'; 2.61, m, H2',6'; 3.71, s, 6-CHz; 6.37, br s, NH(?); 6.78, d, J3,5 2 HZ, H5; 7.29, d, J2,r,3,, 5 . 5 Hz, H3"; 7.46, d , J3,5 2 HZ, H3; 8.56, br s, H8"; 8.72, d , J2",3" 5 . 5 HZ, H2"; 8.93, br s, OH(?); 9.00, d , J6,,,8t, 2 HZ, H6". 4-Chlor0-6-(2~-meth~l~i~eridin-l '-ylmethyl)-2-(7"-trij?uoromethyl-l ", 5"-naphthyn'din-4 Itylamino)phenol(8e) (68%), m.p. 144-146O, after t.1.c. (alumina, chloroform) and recrystallization from a mixture of chloroform, methanol and light petroleum (b.p. 60-80°) (Found: C, 58.3; H, 5.0; N, 12.1. CzzHzzClF3N40 requires C, 58.6; H, 4.9; N, 12.4%). 'H n.m.r. 6 1.23, d , J 6 . 5 Hz, Me; 1.19-4.36, complex, H 2',3',4',5',6', 6-CHz; 6.80, d , J3,5 2 HZ, H5; 6.90, br , 8.58, br s, H8"; 8.75, d, s, NH(?); 7.33, d , J z ~ ~ ,53. 5~H, z , H3"; 7.48, d , 53,s ~ H z H3; J2,,,3,, 5 . 5 Hz, H2"; 8.95, br s , OH(?); 9.04, d, J6,t,8,t 2 HZ, H6". 4-Chloro-6-(3'-methylpiperidin-1 '-ylmethyl)-2-(7"-trij?uoromethyl-l ",5"-naphthyridin-4"y1amino)phenol (8f) (go%), m.p. 134-136O, after t.1.c. (alumina, cyclohexane/ethyl acetate, 3 : 1) (Found: C, 58.7; H, 4.9; N, 12.2. CzzHzzClF3N40 requires C, 58.6; H, 4.9; N, 12.4%). 'H n.m.r. 6 0.92, d , J 5 . 5 Hz, Me; 0.89-2.98, complex, H2',3',4',5',6'; 3.72, s, 6-CHz; 6.80, d , J3,5 2 HZ, H5; 7.31, d , J2",3"5 . 5 Hz, H3"; 7.49, d, J 3 , 5 2 HZ, H 3 ; 8.07, br s, NH(?), 8.57, br s, H 8"; 8.74, d , J2!~,3'/ 5 . 5 HZ, H 2"; 8.93, s, H 6"; 9.02, s, OH(?). 4-Chloro-6-(4'-methylpiperidin-1'-ylmethyl)-2-(7"-trij?uoromethyl-l",5"-naphthyridin-4"y1amino)phenol (8g) (77%), m.p. 173-175O, after t.1.c. (alumina, chloroform; then alumina, cyclohexane/ethyl acetate, 3 : 1) and recrystallization from a mixture of ethyl acetate and cyclohexane (Found: C, 58.3; H, 5.1; N, 12.1. CzzHzzClF3N40 requires C, 58.6; H, 4.9; N, 12.4%). 'H n.m.r. 6 0.96, d, J 4 . 5 H z , Me; 1.17-3.09, complex, H2',3',4',5',6'; 3.73, s, 6-CH2; 6.78, d , 33,s 2 Hz, H5; 7.05, br s, NH(?); 7.30, d, Jz,t ,,, 5 . 5 Hz, H3"; 7.46, d , J3,5 2 HZ, H3; 8.57, S, H8"; 8.72, d, J 2 r r , 3 r r 5 . 5 Hz, H2"; 8.92, br S, OH(?); 9.02, d , J6tt,8tt 2 HZ, H6I1. 4-Chloro-6-(.3',5'-dimethylpiperidin-1 '-ylmethyl)-%(7"-trij?uoromethyl-l",5"-naphthyridin4"-y1amino)phenol (8h) (74%), m.p. 156-157O, after t.1.c. (alumina, chloroform) (Found: C, 59.7; H, 5.5; N, 11.7. C23H24ClF3N40 requires C, 59.4; H, 5.2; N, 12.0%). 'H n.m.r. 6 0.89, d, J 5 . 5 HZ,Me; 1.56-2.99, complex, H 2',3',4',5',6'; 3.72, s, 6-CH2; 5.71, br, NH(?); 6.80, S, H5; 7.31, d, J2tr,3,, 5 . 5 H z , H3"; 7.49, S, H3; 8.57, S, H8"; 8.73, d, Jzrr,3r, 5 . 5 Hz, H2"; 9.01, s, H6"; 8.94, br, OH(?). 4-t-ButyC2-(7'-~hloro~uinolin-4 '-ylamino)-6(piperidin-l"-ylmethyl)phenol (9d) (52%), m.p. 236-238', after t.1.c. (alumina, chloroform) and recrystallization from a mixture of chloroform, methanol, ethyl acetate and hexane (Found: C, 70.6; H, 7.2; N, 9.6. CzsH3oCIN30 requires C, 70.8; H, 7.2; N, 9.9%). 'H n.m.r. 6 1.31, s , But; 1.66, m, H3",4",5"; 2.57, br m, H 2",6"; 3.74, s, 6-CH2; 6.77, d , J 3 , 5 2 HZ; H 5; 6.97, br s, NH; 7.09, d, J2",3"5.5 Hz, H3"; 7.40, d , J3,5 2 HZ, H3; 7.45, dd, Js,, 6,) 9, J6tf,8!f 2 HZ, H6"; 7.96, d, J s , , , 6 ~9, HZ, H5"; 8.02, d , J6,,,8tt 2 HZ, H8"; 8.59, d, j2tr,3,t 5 . 5 Hz, H2". 4-t-Butyl-6-(piperidin-1 "-ylmethyl)-2-(7"-trij?uoromethyl-quinolin-"-ylamino)phenol (10d) (55%), m.p. 224-226O, after t.1.c. (alumina, chloroform) and recrystallization from a mixture of hexane, ethyl acetate and methanol (Found: C , 68.0; H, 6.8; N, 8.9. C Z ~ H ~ O F ~ N ~ O requires C, 68.2; H, 6.6; N, 9.2%). 'H n.m.r. 6 1.31, s, 3xMe; 1.66, m, H3',4',5'; 2.61, m, H2',6'; 3.74, s, 6-CHz; 6.79, d, J3,5 ~ H z H, 5 ; 7.05, br s, NH; 7.18, d , J2",3"5 . 5 Hz, H3"; 7.41, d , J3,5 2 HZ, H3; 7.68, dd, Js,rI6,, 9, J6,t8" 2 HZ, H6"; 8.15, d, J5,,,6rr 9 HZ, H5"; 8.33, br s, H 8"; 8.68, d , J z , , 3,, 5 . 5 Hz, H2". 'Mass spectrum (e.i.) m/z 458 (M+1, 13%), 457 (M, 25), 373 (35), 372 (IOO),357 (20), 84 (20). '-ylamino)-4-(piperidin-l"-ylmethyl)phenol (14) (6%), m.p. 6-t-Butyl-2- (7'-~hloro~uinolin-4 216-218', after t.1.c. (alumina, chloroform) and recrystallization from a mixture of hexane and ethyl acetate (Found: C, 70.6; H, 7.2; N, 9.7. CzsH30CIN30 requires C, 70.8; H, 7.2;

1154

G. B. Barlin et al.

N, 9.9). 'H n.m.r. 6 1.46, br s, But; 1.58, m, H3",4",5"; 2.36, m, H2",6"; 3.40, s, 4-CHz; 6.31, d, J2,,3t 5.5HZ, H3'; 7.07, b r s , H5; 7.18, br s, H3; 7.47, dd, J5,,6t 9, J6!,8r ~ H z , H6'; 7.80, d, J5!,6' 9 HZ, H5'; 8.02, d, J 6 r V s r 2 HZ, H8'; 8.42, d , J2,,3t 5 . 5 HZ, H2'. 6-t-Butyl-4-(piperidin-1 '-ylmethy1)-2-(7"-trifluor~rneth~l~uinolin"-y1amino)phenol (15) (13%), m.p. 212-214O, after t.1.c. (alumina, chloroform) and recrystallization from a mixture ~ N ~ O C, of hexane and ethyl acetate (Found: C, 67.8; H, 6.7; N, 9.1. C Z ~ H ~ O F requires 68.2; H, 6.6; N, 9.2%). 'H n.m.r. 6 1.50, s, But; 1.55, m, H3',4',5'; 2.35, m, H2',6'; 3.41, s, 4-CH2; 6.36, d , J211,3/15 . 5 HZ, H3"; 7.07, d , J3,5 2 HZ, H5; 7.19, d , J3,5 2 HZ, H3; 7.61, dd, .J5,,,61, 9, J6!,,8,, 2 HZ, H 6"; 7.91, d , J5r,,6,t 9 Hz, H 5"; 8.26, br S, H8"; 8.38, d , J2,,,3,, 5 . 5 HZ, H 2". 2-(7'-Chl~ro~uinolin-4 '-ylamino)-~-fluoro-6-(piperidin-l "-ylmethy1)phenol ( l l d ) (45%), m.p. 180-181°, after t.1.c. twice [silica; acetonellight petroleum (b.p. 60-80°), 1: 1 and then 1: 21 and recrystallization from cyclohexane (Found: C, 65.6; H, 5.8; N, 10.8. C2lH2lClFN30 requires C, 65.4; H, 5.5; N, 10.9). 'H n.m.r. 6 1.58, complex, 2.57, complex, piperidinyl; , 7.13, dd, J3,5 3, JH,F10 HZ, H3; 7.21, d , 3.70, s, CH2, 6.46, dd, J3,5 3, JH,F~ H z H5; J2,,3, 5.5 HZ, H3'; 7.46, dd, J 5 , 6 9, J6,8 2 HZ, H6'; 7.98, d , J5r,6, 9 HZ, H5'; 8.04, d , J6,,8t 2 HZ, H8'; 8.62, d , J2,,3, 5 . 5 HZ, H2'. 2-(7'-Chl~ro~uinolin-4 '-ylamino)-5-fluoro-~,6-bis(piperidin-l "-ylmethyl)phenol (16) (30%), m.p. 175-177O, after t.1.c. (alumina, chloroform) and recrystallization from light petroleum (b.p. 60-80°) (Found: C, 67.4; H, 7.0; N, 11.3. C27H32ClFN40 requires C, 67.1; H, 6.7; N, 11.6%). 'H n.m.r. 6 1.45-1.80, complex, 2.45, complex, piperidinyl; 3.50, s, 3.84, s, 2xCHz; 6 8 5 , br, NH; 6.95, d , J2',3'5 . 5 HZ, H3'; 7.33, d, J H ,7.5 ~ HZ)H3; 7.43, dd, J 5 r , 6 t 9, J 6 r , 8 ' ~ H z H6'; , 7.93, d , J5,,6, ~ H z H5'; , 8.01, d , J 6 t , s r ~ H z H8'; , 8.56, d , J2,,3, 5 . 5 H z , H2'. In tests of this compound against the FC-27 (chloroquine-sensitive) and K-1 (chloroquineresistant) isolates of P. falcipmrum by measurement of the uptake of [3~]hypoxanthine236 the following results were obtained: FC-27, 1c5o 12.2 nM, 1cg0 21.0 nM; K-1, 1c5o 30.2 nM, 1cg0 47.4 nM (Chloroquine: FC-27, 1c5o 1 7 . 8 nM, 1c9030.0 nM; K-1, 1c50310 nM, ~ c g o463 nM. Amodiaquine: FC-27, 1c5o 8 . 9 n u , ~ c g o1 3 . 3 nM; K-1, 1c5020.0 nM, I C ~ O24.8 n ~ ) . 2-(7' -Chloroquinolin-4'-ylamino)phenol(17) 1.5 Hydrochloride

i

b

b

c

A mixture of 4,7-dichloroquinoline (0.4 g, 2.0 mmol) and 2-aminophenol(O.218 g, 2.0 mmol) in water (2.0 ml) with 1 drop of concentrated hydrochloric acid was heated in an oil bath a t 100° for 4 h. After cooling, the solid (0.376 g) was filtered off and recrystallized from aqueous methanol containing some hydrochloric acid. The title compound had m.p. c. 175' (ref.13 states that the free base has m.p. 282O but does not give experimental details) (Found: C, 55.6; H, 3.9; N, 8.4. Cl5Hl2ClzN20.1.5HCl requires C, 55.4; H, 3 . 9 ; N, 8.6%). 'H n.m.r. (CD3SOCD3) 6 6.32, d , J 7 Hz, H 3'; 6.96-7.32, complex, H 3,4,5,6; 7.86, dd, J5,,6, 9, J6,,8, ~ H z H6'; , 8.14, d , J6t,s~ ~ H z H8'; , 8.48, d, J ~ H z H2'; , 8.80, d , J 5 r X 6 1 9 H z , H5'; 10.22, br s, 10.82, br s, NH, OH. Antimalarial Testing The compounds reported in this paper were tested for i n vitro antimalarial activity against the FC-27 (chloroquine-sensitive) isolate of P. falciparum by using the visual and microscopic '~ (16) was further tested against both the FC-27 tests described by ~ i e c k m a n n . ~Compound and K-1 isolates in i n vitro tests of the uptake of [3~]hypoxanthine.2~6

a

Acknowledgments We thank Drs D. J. Brown and M. D. Fenn for helpful discussion. One of us (T.M.T.N.) thanks this University for support as a scholar.

l3 Allais, A., Rousseau, G., Meier, J., Nomine, G., Peterfalvi, M., Deraedt, R., ChiWot, L., Benzoni, J., and Fournex, R., Chim. Ther., 1973, 8, 154.

L