185
J . Med. Chem. 1983,26, 185-194
port, as well as the excellent technical assistance of F. Garcia, M. Charon, and P.Bucau-Varlet, in the biological assays and N. Chi-Hung and M. RautWeau in the chemical syntheses. F.W., P.T., and J.M.L. are supported by INSERM (Unit& 22 and 219). Registry No. la, 69022-46-4; lb, 65222-35-7; IC,83947-99-3; Id, 83948-00-9;le, 83948-01-0; lg, 83948-02-1; lh, 83948-03-2; lk, 83948-04-3; lm, 83948-05-4; 2b, 73323-33-8; 2i, 73323-34-9; 3a,
72237-96-8; 3b, 72238-00-7; 3c, 83948-06-5; 38, 83948-07-6; 3f, 83948-08-7; 3h, 83948-09-8; 3i, 83948-10-1; 4a, 72237-98-0; 4b, 72238-02-9; 4C, 83948-11-2; 4d, 83948-12-3; 4h, 83948-13-4;7a, 83948-154 7k, 83948-16-7; 83947-904 7b7 83948-14-5; 83947-91-5; 8b, 83948-17-8; Si, 83948-18-9; Sk, 83948-19-0; 9b, 83948-20-3; lob, 83948-21-4; lOc, 83948-22-5; lOi, 83948-23-6; 12, 72237-94-6; 13, 72238-06-3; 14, 83947-93-7; 15, 83947-92-6; 16, 83947-94-8; 17, 83947-95-9; 18, 83947-96-0; 19, 83947-97-1; 20, 83947-98-2; 21b, 72238-04-1; 22b) 72238-05-2.
Synthesis and Antileishmanial Activity of 6-Methoxy-4-methyl-N-[6-(substituted-1-piperazinyl)hexyl]-8-quinolinamines and Related Compounds1y2 Judith L. Johnson and Leslie M. Werbel* Chemistry Department, Warner-LarnbertlParke-Davis Pharmaceutical Research Division, Warner-Lambert Company, A n n Arbor, Michigan 48106. Received March 29, 1982
'""*
The 8-quinolinamine, 4-[6-[(6-methoxy-4methyl-8-quinolinyl)amino] hexyl]-1-piperazineethanol(lb), has been shown to be highly effective against Leishmania donovani infections in hamsters. In an effort to obtain a more potent, ~ that examined particularly the structural requirements less toxic &quinolinamine, a series of analogues (2) w a prepared of the terminal piperazine moiety. Of the substituted piperazines and alternative heterocycles prepared, as well as those quinoline analogues with ring insertion of a methyl group in the 2-position or an aryloxy substituent in the 5-positioq an increase in potency was achieved only with the 2-hydroxypropyl analogue (2f).
Leishmaniasis is a disease of tropical and subtropical areas caused by intracellular protozoan parasites of the genus Leishmania and is transmitted by the bite of phlebotomine flies (sandflies). It displays four general clinical forms: cutaneous, mucocutaneous, chiclero ulcer, and visceral, which are caused, respectively, by L. tropica, L. braziliensis,L. mexicana, and L. donovani. In the first 6 5 three forms the parasites invade the cutaneous tissues in 2, A = NR', S( 0),, 0 various parts of the body, causing disfiguring lesions of differing severity. In the visceral form of the disease, the phagocytic cells of the spleen, liver, and bone marrow are invaded, often resulting in death. Antimonials and the group in the 4-position has been shown to enhance activity, antibiotic Amphotericin B are used to treat the disease but and N,N-diethyl-N-(6-methoxy-4-methyl-8-quinolinyl)are often of limited efficacy and the cause of host t o ~ i c i t y ; ~ ~ ~196-hexanediamine(la) was the most potent compound thus, the need for a better drug is real and ongoing. examined, exhibiting a G indexg of 4743 against L. donoAlthough a multitude of 8-quinolinamines have been vani infections in hamsters. Since an analogue with a examined for antimalarial activity, relatively little inforpiperazine side chain (lb) prepared in the course of our mation is available, and apparently only limited effort has previous investigationsproved to be quite active (G = 104) been expended toward the development of an agent for in this experimental model, we undertook the preparation Leishmaniasis from this class of compounds. of analogues with the aim of providing a more potent, less A series of 4-unsubstituted 8-quinolinamines containing toxic 8-quinolinamine structure. side chains related to that in l b had been reported to be Our primary goal was the modification of l b by variation active against L. donovani and L. tropica infections in of and substitution on the piperazine moiety as represented More recently, the presence of a methyl in structure 2. Recent efforts to develop a less toxic 8-quinolinamine for malaria therapy have revealed that the introduction (1) This investigation was supported by the U.S.Army Medic2 of a 5-phenoxy group reduced toxicity while retaining Research and Development Command Contract DAMD 17activity in murine and primate antimalarial models.1° 79-C-9122. This is contribution no. 1552 to the Army Research
cH30y$ 00
Program on Antiparasitic Drugs. preliminary report of this work has been presented; see "Abstracts of Papers", 182nd National Meeting of the American Chemical Society, New York, NY, Aug 1982, American Chemical Society, Washington, DC, 1982, Abstr MEDI 25. K. E. Kinnamon, E. A. Steck. P. S. Loiseaux. W. L. Hanson. W. L. Chapman, Ad V. B. Waits, Am. J. Trop. Med. Hyg.,271 751 (1978). E. A. Steck, Progr. Drug Res., 18, 290 (1974). L. P. Walls, British Patents 834300 (1960); 1153471 (1969). P. A. Barrett, A. G. Caldwell, and L. P. Walls, German Patent 1237 121 (1963).
(2) A
(3) (4) (5)
(6)
(7) P. A. Barrett, A. G. Caldwell, and L. P. Walls, U.S. Patent 3 142679 (1964); West German Patent 1132557 (1962). (8) P. A. Barrett, A. G. Caldwell, and L. P. Walls, J . Chem. Soc.,
2404 (1961). (9) G index = the SDW for meglumine antimoniate (standard drug) divided by the SD, for the test compound, where SD, is defined as the dose providing 90% suppression of parasitemia. (10) E. H. Chen, A. J. Saggiomo, K. Tanabe, B. L. Verma, and E. A. Nodiff, J. Med. Chem., 20, 1107 (1977).
0022-2623/83/1826-0185$01.50/0 0 1983 American Chemical Society
186 Journal of Medicinal Chemistry, 1983, Vol. 26, No. 2
Johnson, Werbel
Scheme I
'"'"* C I ICH2160H. E 1 3 N I I 5 0 'C
LiAIH4. AIC13
Procedure 0
Procedure G
u
SOCl2. C H ~ C I Z z
Procedure E
NH(CH,),OH
8
cH30*
7
1
LiAIH4, AICI,. THF/-IO
OC
Procedure C
*
E13N/
120-130
*C
Procedure F
NHICH,)~X
9a, X = C1
2
b, X = Br c,X=H
Thus, several nuclear-substituted analogues of 1 as represented by structures 3 and 4 were also included in this study.
prepared as the requisite intermediate by the alkylation of 5 with 6-chlorohexanol to provide 8 (procedure D), followed by chlorination with thionyl chloride (procedure E). Because of the inefficient alkylation reaction and the resultant difficult chromatographic separation, a second approach to 9 was investigated, wherein the hexanamide 6 was reduced with LiAlH4/A1C13(3:l) to afford a mixture containing approximately 9 parts of the desired 9b (64% yield) and 1part of the dehalogenated material 9c (procedure G). The mixture was utilized directly in the next reaction, and the product, 2, was separated readily from 9c by chromatography. NH[CH,),NRl R2 NH(cH,~,NR, R, Finally, several of the products, 2f, h, i, v-cc, were prepared by simply alkylating or acylating 2a with the 3 4 appropriate reagents (Scheme 11, procedures I-K). The Chemistry. Many of the 6-methoxy-4-methyl-N-[6- reaction of 9a or 9b with piperazine to obtain 2a was complicated by the simultaneous formation of the bisad(substituted-l-piperazinyl)hexyl]-8-quinolinamines and duct 2dd, and the resultant mixture was difficult to purify related compounds (2) were prepared as shown in Scheme (procedure H). We eliminated this problem by allowing I.ll In route a, acylation of 6-methoxy-ri-methyl-89 to react with phenylmethyl l-pipera~inecarboxylate~~J~ quinolinamine (5)12with 6-bromohexanoyl chloride (procedure A) afforded 6-bromo-N-(6-methoxy-4-methyl-8- (10) to afford 2u, which was hydrolyzed cleanly to 2a in a hydrobromic/acetic acid mixture (Scheme 11, procedures quinoliny1)hexanamide(6), which was allowed to react with the requisite piperazine or related heterocycle to give the L, M). We prepared 1-[2-(ethylsulfonyl)ethyl]piperazinedicorresponding substituted hexanamide 7 (procedure B; hydrobromide (17), the precursor for compound 2e by first Table I). This material was then reduced with lithium aluminum hydride/aluminum chloride (3:l) to provide 2 (Table 11, procedure C). The nuclear analogues 3 and 4 ~NANCH2CHZS0,C \ / HzcH,.E HBr (Tables I11 and IV) also were prepared in this manner. Although the above sequence was clean and provided 17 the final products in reasonably good yield, it was unacallowing 2-hydroxy-2-(ethylsulfonyl)ethyl4-methylceptable in those cases in which the terminal heterocycle benzenesulfonate16to react with the sodium salt of phecontained an acyl group that would also be reduced by the nylmethyl 1-piperazinecarboxylate (10) to provide pheLiAlH4/A.lCl3reduction. Another disadvantage when large numbers of analogues are being prepared is that two steps (13) w. 0.Fove and L. R. Fedor. J. Am. Pharm. Assoc., 48,412 are required from the common intermediate 6 to the final (1959). product 2. Therefore, a modification (route b) was emH. G. Kazmirowski, E. Carstens, and D. Lehman, East German ployed in which the products 2 were obtained by the rePatent 130658,Apr 19, 1978. action of the appropriate piperazine or related heterocycle M. W. Miller, H. L. Howes, Jr., R. V. Kasubick, and A. R. with N-(6-halohexyl)-6-methoxy-4-methyl-8-quinolinamine English, J.Med. Chem., 13, 849 (1970). Tests were performed by Dr. W. L. Hanson, University of (9a or 9b) at 120-130 OC (procedure F). Initially, N46Georgia, Athens, GA. chlorohexyl)-6-methoxy-4-methyl-8-quinolinamine (sa) was W. L. Hanson, W. L. Chapman, Jr., and K. E. Kinnamon, Int. J.Parasitol., 7,443 (1977).
qCF3
(11) Modified procedure of P. A. Barrett et al? (12) K. N. Campbell, A. H. Sommers, J. F. Kerwin, and B. K. Campbell J. Am. Chem. SOC.,68,1556 (1946).
Test results were supplied through the courtesy of Col. D. A. Davidson and Dr. E. A. Steck of the Walter Reed Army Institute of Research.
Journal of Medicinal Chemistry, 1983, Vol. 26, No.2 187
Substituted 8-Quinolinamines
m
nylmethyl 4-[2-(ethylsulfonyl)ethyl]-l-piperazinecarboxylate and then hydrolyzing this with 4890 hydrobromic acid in acetic acid. Antileishmanial Activity. Most of the side-chain analogues (2, Table V) are more potent than the reference standard and the 2-hydroxypropyl analogue ( 2 0 is more potent (G = 143) than l b (Table V). However, even the closely related 3-hydroxypropyl (2g) and the 2,3-dihydroxypropyl (2h) compounds are less active and none of the compounds is superior to la. Insertion of a methyl group at the 2-position of the quinoline ring results in a lo-fold loss of activity (3b-c, Table 111)compared with la. Although further testing at lower dose levels is required to compute G values on compounds 4a-c (Table IV), it is clear that the intent to reduce toxicity by the attachment of the 5-[3-(trifluoromethyl)phenoxy] group has not been realized. Conclusion The nature of the terminal amine function in this system is surprisingly specific with regard to antileishmanial potency. Clearly, replacement of a simple dialkyl substituent with a piperazine or more complex hetero ring system will not achieve the desired result of higher potency and lower toxicity among the 8-quinolinamines.
-
+g
rld
++
rl
rl
Experimental Section Melting points were taken on a Thomas-Hoover capillary melting point apparatus. Satisfactory IR and NMR spectra were obtained for all compounds. Anhydrous MgSO, was used to dry solutions. Procedure A (Scheme I). 6-Bromo-N-(6-methoxy-4methyl-8-quinoliny1)hexanamide(6). To a mixture of 18.8 g (0.10 mol) of 6-methoxy-4-methyl-&quinolinamine(5)12319and 17.0 g (0.16 mol) of Na2C03in 350 mL of acetone was added dropwise a solution of 21.4 g (0.10 mol) of 6-bromohexanoyl chloride in 100 mL of acetone. The mixture was heated under reflux for 3 h and allowed to cool, and then EbN was added dropwise to the stirred mixture until the yellow color disappeared. The mixture was filtered and the filter cake was washed with acetone and then with CH2C12. The acetone filtrate and wash were concentrated to dryness, and the residue was combined with the CH2C12wash. The solution was washed with H 2 0 and with brine, dried, and concentrated to dryness to provide 38.7 g. Recrystallizationfrom EtOH afforded 31 g (85%) of the product, 6, mp 114-116 O C . Anal. (C17H21BrN202) C, H, N. 6-Bromo-N-(6-methoxy-2,4-dimethyl-8-quinolinyl) hexanamide (Table 111, 11) and 6-bromo-N-[6-methoxy-4-methyl-5-[3-(trifluoromethyl)phenoxy]-8-quinolinyl] hexanamide (Table IV, 16) were obtained similarly from 6-methoxy-2,4-dimethyl-8q u i n ~ l i n a m i n e ' and ~ ~ ~ 6-methoxy-4-methyl-5-[3-(trifluoro~ methyl)phenoxy]-8-quinolinamine.19 Procedure B (Scheme I). N-(6-Methoxy-4-methy1-8quinoliny1)-4-methyl-1-piperazinehexanamide Hydrate (1:0.2) (7a, Table I). A mixture of 5.5 g (0.015 mol) of 6bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hex~amide(6) and 1.8 g (0.018 mol) of 1-methylpiperazinein 70 mL of benzene was heated under reflux for 20 h, treated with 2 mL of Et3N, and heated for an additional 24 h. The mixture was allowed to cool and then filtered, and the filtrate was washed with HzO, dried, and concentrated to dryness in vacuo. The residue was recrystallized twice from n-hexane containing a little toluene and then dried in vacuo at 68 "C to afford 3.1 g (53%) of the title compound, mp 104-107 OC. See Tables I and I11 for compounds prepared similarly. Some were obtained as oils and are not reported in the tables but were used without further purification in the next step. Procedure C (Scheme I). 6-Methoxy-4-methyl-N-[6-(4methyl-l-piperazinyl)hexyl]-8-quinolinamine Trihydro(19) Provided by the Walter Reed Army Institute of Research. (20) F. I. Carroll, B. D. Berrang, and C. P. Linn J.Med. Chern., 23, 581 (1980).
188 Journal of Medicinal Chemistry, 1983, Vol. 26, No. 2
u 0
0, Ern
u
1?
0
h
0"
x
p:
0
i r.
3 x N
0"
n"
4
u" 0
3:
e
e,
z
Gx
jp
O
0
U
0
.
E
m
N
E
m
6 m
42
a
rl
?
zm
w'
+
0
0, I
2
E
*W
a hl
Fr
w"
M
a*4 a" a"
cy
V
rn
u d E
Ip
c
.3
0
m
0
rl
-0
0 0
m
d
rl
hl
i
L
e,
h
$ x 0
x u" x u, i
x
i
e,
n
=:
@
0
2
i B
N
Substituted 8-Quinolinamines
Journal of Medicinal Chemistry, 1983, Vol. 26, No. 2 189
190 Journal of Medicinal Chemistry, 1983, Vol. 26, No. 2
Johnson, Werbel
I
ij
10
I m L
>
0
on I
E9
Journal of Medicinal Chemistry, 1983, Vol. 26, No. 2 191
Substituted 8-Quinolinamines
Table V. Effects of 6-Methoxy-4-methyl-N-[64 substituted-l-piperazinyl)hexyl]-8-quinolinamines and Related Compounds against Leishmania donovani Infections in Hamsters
I
NH(CHz),NR,
% suppression:
compd
208
2a 2b 2c 2d 2e 2f 2g 2h 2i 2j 2k 21 2m 2n 20 2P 2q 2r 2s
N A ~ 99.7 (4T)' Id I 99.9 T T T T T 100 T 77.8 97.5 T T I I 99.9
2t 2u 2v 2w 2x
99.5 (1T) T 98.6 (5T) T T 100 I NA NA 100 I 98.6 98.2 (5T) T T T
5
52
100 99.5 99.7 97.8 99.9 99.9 99.7 99.5 96.8 I 97.8 99.8 100 99.8 99.9 98.0 99.3 100 98.6 (5T) 99.4
Rz
L. donovani (hamster), (mg/kg)/daya 13 3.25 0.81 0.2
99.7, 99.4
99.3
64.7
99.7 99.1 96.3 100 99.7 65.8 83.5 99.4,lOO
99.6 99.4
21.1 99.8
99.98 32.6
98.5, 89.6
100
70
95.9, 49.1 98.9, 100 100, 99.8
24.4 100 99.8
18.9 96.6 97.9, 87.7
94.8, 95.9, 97.0 99.9 54.6 56.6 99.2, 99.6 93.8,lOO 89.7
Ga
26
75.7
35
25.8
57.3 1.3
19 143 38 57 6 2 5 23 Such ~ side effects are well-known and documented.7*8 Earlier pharmacological studies of buspironeg?l0led to its evaluation in schizophrenia; however, the drug exhibited only transient activity even at high d0ses.l’ Subsequent pharmacological investigation, directed at determining its mechanism of action, have demonstrated that while buspirone is without effect upon benzodiazepine binding and GABA binding or uptake, it may possess both agonist and antagonist activity at dopaminergic receptors.12-19 This profile of mixed agonist and antagonist properties may be relevant to buspirone’s mechanism of anxioselective action in which no sedation, anticonvulsant, or muscle relaxant properties are associated with the drug. In addition to in vivo studies, we have employed the receptor-binding methodology used to characterize buspirone to both investigate a number of newer buspirone *Department of Chemical Research, Mead Johnson Pharmaceutical Division, Evansville, IN 47721. 0022-2623/83/1826-0194$01,50/0
Scheme I
r-7 + “UNanalogues and t o reexamine previously described members of the series. (1) Y.-H. Wu, K. R. Smith, J. W. Rayburn, and J. W. Kissel, J.
Med. Chem., 12, 876 (1969). (2) Y.-H. Wu, J. W. Rayburn, L. E. Allen, H.C. Ferguson, and J.
W. Kissel, J. Med. Chem., 15, 477 (1972). (3) R. J. Hartmann and J. Geller, Proc. West.Pharmacol Soc., 24, 179 (1981). (4) E. C. Tompkins, A. J. Clemento, D. P. Taylor, and J. L. Perhach, Jr., Res. Commun. Psychol. Psychiatry Behau., 5, 337 (1981). ( 5 ) H. L. Goldberg and R. J. Finnerty, Am. J. Psychiatry, 136, 1184 (1979). (6) K. Rickels, J. Clin. Psychiatry, 42(11), 40 (1981). 0 1983 American Chemical Society
