threshold is sometimes increased. The procedure for determining the maximum driving t'requency was as follows. The spontaneous rate was determined and a recording was made with the tissue stimulated at a frequency of 20% greater than the spontaneous frequency. This frequency was used to determine the contractile strength of the tissue by measurement of the peak height for the remainder of the study on the tissue. The driving frequency was then increased ~ I o i v l y until the tissue failed to follow the stimulator as indicated by skipped beats followed by supramaximal contractions. The determination was repeated twice and an average of the three values was used as the 1lDF. After the control readings were taken, the lowest concentration of the drug (as the hydrochloride or hydrobromide salt) to be tested was added to the bath in a small volume of buffer solution ( 0 . 1 0 4 mL). Readings were taken a t 15 min after addition of t h e compound and the second d c ~ was added to the bath without washing. The P P ~ O J reading I ~ WIS taken 15 min later and the procedure was repeated i i n t i l i h r X1I)F !vas decreased hy ab(iut 60% i~f'ccintrol. t'.;iially tour t i l six ciut;i pciints could lie obtained in a cumulative manner. 7'1iret. t i b i u e h were used for each compound tested. I he percent decrease in response (5IDF o r peak height, \vas plotted i ' s , the logarithm of the mcilar cc~ncentrationl i t ' d r u g , anti a 5traight line \vas t'itted t o the data by linear regrehsiciii. T h e log dose required tci decrease the response by 40% was determined graphically ilog ED,,,). The values from the three ti>sueh ivere averaged and standard deviations w r e then calculated lor the rep I i ca t es. I
>
( 2 ) P. H. hlorgan and I. If'. Mathison. .I. Pharm. Sci.. 65. 467 119761, (3)
P.H. 5Iorgan and I. \V.Mathison. J , Pharm. Sci,, 65. 635
(4)
S.Fujita, Arch. Int. Pharmacodyn. Ther., 220, 28 (1976).
~1.97Ci).
(5) H. R. Besch, Jr., and A. M. Watanabe, J . Pharmacol. E x p . Ther.. 202. 354 1 9 3 . ( 6 ) ( i . A. Imiger. Fed. Proc.. Fed. .Am.Soc. E x p . H i ( ~ l . 35. . 1274 11976). i 7 ) I\-. 11. Baird and H. F. Hardman. J . Pharmacol. Exp. Ther., 132: 382 11961). (8)I). Hellenbrecht, €3. Lemmer. G. LViethold. and H. Gro277. 211 liecker, S a u n j rz-Schmiedeberg's Arch. Pharmac~oi., (1973). (91 I). Hellenbrecht, K. F. Muller. and H. Grobecker. Eur. J . Pharmncoi.. 29. 22? 119741. i 101 .A. F. ('rrwther and 1,. H.Smith. ./. .bird. (~h(,/?i.. 1 I , 1009 (
i!JiiX),
1 1 1 I 'I., Kurinara.
K.O s a ~ . a and . N.Iino.
('hcjni.
. 4 h t r . . 61,
1 'Ciii4iI (1966).
( 1 2 ) H. Schultz. Pharmazie. 23. 240 (1968). I 13, XI. Rergmann and L. Zervas. C h e m . Rer.. 6.5. 1192 (1932). ( 1 4 1 7'. .Jako'hiec. Acta Poi. Pharm.. 23, 114 (1966). I l.,r ( ' . C. 1'ric.e. C;. Kabas. and I. Nakata. J . ,Wed. Chem.. 8, 650
(19651.
'r. Zincke and .J. Ruppersberg. C'hem. Rer.. 18,120 (1915).
!
16)
I
1 7 ) 11. Hiyama. I'ahicgahn Zasshi. 72. 1367 (1952). 181 I. It'. 5Iathison and R. H . Tidivell. J . .\led. ('iitJni..18, 1227
I
[IY7.51.
Acknowledgment, hi^ work \vas in p a r t by the NIGLIS Institutional National Research Service Award iIT-32-GM07099) a n d the Research Institute t i t '
!
,
19) I;. 51. Yaughan \Villiams and L. Szekeres, Rr. ,J. Pharmacol. ('hemother.. 17. 124 119611.
Pharmaceutical Sciences. Ilniversity of Mississippi,
i;,
I)a\ves, R r , J , ( ' i f c , n l o t h e r , , 9o i 1 9 4 6 ) , 1.rx.y in "hIethods in Pharmacology". \.01. 1, .A.
Antimalarials. 4. Trichloronapht halene Amino Alcohols1 Dwight A . S h a m b l e e a n d .J. S a m u e l Gillespie. .Jr.;!: D e p r ~ r ~ m o/ ~ ~( 'r/ i~o tn i i s t r > , I .nitx,r,sifJ
(11Kichrrzorici. K i c h ~ ~ ~ ~L'ireitiia nn',
2217:Y Received J u i ~ 19. , 1.978
A n improved procedure for the synthesis of naphthalene amino alcohols is described. Four new compounds were prepared and tested by Rane Laboratories for activitj. i's. P/n.,n?odiiinihwghei in mice. .Ill compounds were active. the most active being l - [ ~ i - 1 4 - c h l o r o p h e n y l I - 5 . 7 - d ~ c h l ~ ~ r c ~ - l - n a p h t h y l ] - ~ ~ - ~ d ~ - ~ ~ - b u t yhydrochloride larn~no~pr~ipan1~l i 16b). Structure- activity relationships betwren the naphthalene and quinoline isosteres are discussed.
:i-Substituted 1-naphthalenemethanols have been shown specific hvdrobromination yielded only t h e desired 2to be active against P/a.+,rnodiumberghei in mice.'" T h e (:i.j-dichloroplie~i~l)-l-bromopropane ( 5 ) in 7070 yield. In t h e alkylation s t e p t h e use of 1.5 equiv of (3-chloroactivity is approximately t h e s a m e a s t h a t of t h e better kriown l - q u i n o l i n e m e t h a i o l s . although t h e s t r u c t u r e phe1iyl)acetic acid increased t h e yield of' pure 2 - t . I activity relationships operative for t h e quinoline comchlorophenyl)-3-(3,5-dichlorophenyl)pentanoic acid (6) t o pound? do not in all cases apply t o t h e naphthalene $107~ from t h e 30-607~ range obtained with equimolar isosteres. (4 II a nt i t ie 5 . Earlier synthetic prcicedures"' were incapahle ( i t ' p t ~ Investigation t o determine the o p t i m u m conditions for ducing t h e 3-phenyl-5.7-dichloronaphthalenemethan~ils, the cyclization of 6 revealed t h a t no reaction occurred isosteric Lvith highly active 4-quinolinemethanols, hecause unless the pol3rphosphoric acid (PPA) reaction mixture was heated above 110 "C. At 185 a n d 190 "C a ]:?I mixture o f of the difficulty of ring closure meta to two chlorines. \Ye have 11mv devised a scheme which has provided a facile t h e expected tetralin 7 a n d :i-(l-chlorophen4.l)-;,.;-dichloro-1-methylnaphthalene(9) was obtained. Fiirther route to t h e c o m p o u n d s and is. with appropriate modificaticins. applicable t o t h e general s y n t h e s i s o f 1experimental evidence is required to explain this unexm e t h ~ l - : ~ - a r y l n a r ) h t h a l e n es st a. r t i n g materials for the pected result. Conversion of 7 to 9 through t h e dihydronaphthalene antimalarial naphthalenemethanols. 8 proceeded routinely. except t h a t the aromatization of 8 Chemistry. T h e synthetic sequence to t h e 1 -methyln a p h t h a l e n e 9 is illustrated in S c h e m e I. Previously required reaction with dichlorodicyanoquinone (L)DQ) ~ v h e nchloroanil failed t o accomplish the d e h y ~ ~ r o g e n a t i o n . described procedures"' \vere followed t c i o h t a i n t h e Structure-Activity Relationships. T h e activity,' (as n a p h t h a l e n e a m i n o alccihols from 9. :3,5-Dichlorci-cimethylstyrene ( 4 ) was cihtained in excellent overall yield determined by R a n e Laboratories) of t h e trichloronaphthalene amino alcohols vs. 1'. h r , q / 2 ~ 1is p r e s e n f d i n (90% ) f'rcim t h e acid 1. H r c i u n a n d Lane's' method oi
Journal of Medicinal Chemistr?,, 1979, Vol 22, N o . 1 87
Trichloronaphthalene Amino Alcohols Scheme I
CI
-
BHs-THF
soc12
BrZ,NaOCH3
Ll
Ci
7
10
8
CHOHR
C HC
c'wQc*'
CI
11
Table I. Antimalarial Activity' of Naphthalene Amino Alcohols
-
16a, R = CH,N(C,H,)2.HCI b, R = CH,CH,N(C,H,);HCl C, R = 2-c-C,H,,N,CH3C0OH d , R = 2-CH,-c-C.H,,N.HCI
Table 11. Comparative Antimalarial Activity of Quinoline and Naphthalene Amino Alcohols
AMST, days, or no. of cures ( C ) a t dosage (mg/kg)
CHSI-':!
comad
10
20
40
80
160
320
640
16a 16b 16c 16d
7.9 2.9 0.5 3.6
9.5 12.1
10.5 3C 3C
9.8
11.8
2C 5C 4C 1C
4C 5C 3C 1C
5C 5C
1.1
1C 3C 4C 16.6
4C
6.0
' Activity vs. P. berghei in five mice, determined by
Rane Laboratories, University of Miami, as described by Osdene a n d co-workers. The mean survival time (MST) of infected controls was 6.1 days. An increase in mean survival time ( A M S T ) of mice treated with a single dose of compound administered subcutaneously 7 2 h after infection is considered evidence of antimalarial activity i f the increase is a t least 100% (6.1 days). T h e number of cures (C) is the number of mice surviving o u t of five a t 60-days postinfection. T a b l e I. In T a b l e I1 a comparison is m a d e between t h e isosteric quinoline a n d n a p h t h a l e n e amino alcohols. T h e activity, expressed as the minimum effective dose (MED), of t h e naphthalene compounds is approximately the same as t h a t of t h e quinoline derivatives. Colwell a n d coworkers6 showed t h a t increasing the distance between t h e side-chain a m i n o a n d hydroxy groups by one -CH,- increased t h e activity of antimalarial p h e n a n t h r e n e a m i n o alcohols. T h e same effect was noted with t h e naphthalene derivatives (cf. 16a,b). E x t e n d i n g t h e variation to t h e piperidyl c o m p o u n d s (cf. 16c,d) a p p e a r e d to affect t h e activity adversely. None of t h e compounds was as active as 6-chloro-tu-
[ (dibutylamino)methyl]-3-(3,4-dichlorophenyl)-1naphthalenemethanol.la
Cl
compd 16a
Z
CH N 1 6 ~ CH N
R CH:N(C,H,):.HCl CH,N(C,H,j)i.HC1 2-piperidyl acetate 2-piperidyl hydrochloride
- 10
.l o b
- 20
- 5b
Minimum effective dose, i.e., the dose which gives a AMST of a t least 6.1 days. Data furnished by Walter Reed Army Institute of Research.
Experimental Section Melting points were determined with a Thomas-Hoover capillary melting point apparatus and are uncorrected. Infrared spectra were recorded with a Beckman IR8 spectrophotometer; nuclear magnetic resonance spectra were recorded at 60 MHz with a Varian A-60 spectrometer. Molecular weights were determined from the mass spectra recorded with a Hitachi Perkin-Elmer RMU-6H spectrometer at 70 eV. All spectra were in accord with the structures assigned. &'here analyses are indicated by symbols of the elements, analytical results obtained are within 0.4% of the theoretical values. 3,5-Dichlorobenzoyl Chloride (2). :~,j-Dichlorobenzoic acid (1; Aldrich Chemical Co., Milwaukee, LVI; 50 g, 0.26 mol) was mixed with SOCl, (93.0 g, 0.78 mol) and the solution was heated under reflux for 3 h. Excess SOCI, was removed a t aspirator vacuum, and the residue was distilled under high vacuum. 2 (18.8
Trichloronaphthalene Amino Alcohols
Journal of Medicinal Chemistry, 1979, Vol. 22, No. 1 89
mp 230-238 "C; IR (KBr) 3390 (OH),2940 (CH), 1580,1495,1475, was prepared from Me2S0 (10 mL) and NaH (1.25 g, 30 mmol, 1090,1010,880, and 820 cm NMR (Me,SO-d,) d 1.35-2.35 [m, of 57% NaH-oil dispersion, which had been washed with two 8 H, (CH2),CH2NH,CH,CHOH], 2.80-3.60 (m, 3 H, CHNHCH,), 10-mL portions of Et,O to remove the oil) by heating the mixture 5.35-5.90 (m, 1 H , CHOH), 7.30-8.50 (m, 10 H, NH, OH, aroat 70 "C for 1 h and diluting with T H F (20 mL). The solution matic), 10.60-11.10 (m, 1 H , HC1); mol wt 469. Anal. (CZ3was cooled to -5 "C and a solution of trimethylsulfonium iodide Hz3C14NO) C, H, N. (TMSI; 6.1 g, 30 mmol) in Me,SO (40 mL) was added dropwise N , N - D i - n-butyl-3-[3-(4-chlorophenyl)-5,7-dichloro-lwhile stirring, maintaining the temperature at or below 0 "C during naphthyl]-3-hydroxypropionamide (15). The procedure is the addition. The milky gray mixture was poured quickly into essentially that of Colwell and co-workers.6 Lithium N,N-dia cold (5 "C) solution of 11 (6.7 g, 20 mmol) in dry T H F (500 mL). n-butylacetamide was prepared at -10 to 10 "C by adding N,After the mixture was stirred for 4 h at ambient temperature, the N-di-n-butylacetamide (4.0 g, 23 mmol, in 10 mL of T H F ) to a solvent volume was reduced to 150 mL under reduced pressure. solution of lithium di-n-butylamide [made from di-n-butylamine The mixture was poured into H 2 0 (800 mL) and extracted with (3.3 g, 25 mmol) and n-butyllithium (15 mL, 24 mmol, of 1.57 M three 150-mL portions of CHC1,. The combined extracts were in hexane) in T H F (30 mL)]. A cold (10 "C) solution of 11 (5.0 dried (NazS04)and concentrated. The residue was recrystallized g, 15 mmol) in T H F (350 mL) was added, and the mixture was from CHC1,: yield 5.5 g (79%);light yellow powder; mp 148-150 stirred for 3 h. Saturated NH,C1 solution (10 mL) was added, "C; IR (KBr) 1475, 1090, 1010, 880, 855, and 820 cm-'; NMR and the organic phase was separated and concentrated. The (CDCl,) 6 2.68-3.40 (m, 2 H , CH,), 4.34 (m, 1 H, CH), 7.20-8.30 residue was dissolved in C6H6(100 mL) and washed with 5 N HCl (m, 8 H, aromatic); mol wt 348. Anal. (CI8HllCl30)C, H. (20 mL) and HzO (20 mL). The solution was dried (Na,SO,) and 3 - ( 4 - C h l o r o p h e n y l ) - a - [(dibutylamino)methyl]-5,7-diconcentrated. The residue (9.0 g) was chromatographed on silica chloro-1-naphthalenemethanol Hydrochloride (16a). A gel (200 g), eluting with 5% Me,CO in C6H6. The product (6.5 solution of 12 (5.0 g, 14.3 mmol) in di-n-butylamine (40 mL) was g, 8770) was used in the next step without further purification. heated at 155 "C under N2 for 12 h and then the excess amine l-[3-(4-Chlorophenyl)-5,7-dichloro-l-naphthyl]-3-(di-n was removed at aspirator vacuum. The residue was dissolved in buty1amino)propanol Hydrochloride (16b). 15 (6.5 g, 13 mmol) a mixture of 30 mL of MeOH and 400 mL of EtPO,and anhydrous in THF (50 mL) was added dropwise to a stirred solution of borane HC1 in EkO (5 mL of saturated solution) was added. The mixture (40 mL of 1 M) in THF; the mixture was then stirred at ambient was filtered to give 16a (6.4 g, 86.7%) as a fluffy, white solid: mp temperature for 2 h and heated at reflux for 5 h. After cooling 238-241 OC; IR (KBr) 3190 (OH), 2940 (CH), 1475, 1090,1010, the mixture was treated with HCl (10 mL of 2 N). When the 880, and 820 cm NMR (Me2SO-d6)6 1.00 (m, 6 H, CH,), solvent was removed under aspirator vacuum and was replaced 1.15-2.10 (m, 8 H, CH,), 3.00-3.55 [m, 6 H , Nt(CHJ3], 6.10 (m, with MeOH (100 mL), the product-borane complex precipitated 1 H, CHOH), 7.50-8.60 (m, 8 H, aromatic), 10.80 (m, 1 H, HC1). (4.2 g, mp 140-142 "C). The base was freed by heating the Anal. (C26H31C14NO) C, H , N. complex to 150 "C under aspirator vacuum. The addition of HCl 3-(4-Chlorophenyl)-5,7-dichloro-a-( 2-pyridy1)-1 - n a p h t h a l e n e m e t h a n o l (13). To a cold (-60 "C) solution of n-buin EtzO to the residue gave 16b (3.3 g, 49%): mp 160-163 "C; tyllithium (19.0 mL, 30 mmol, of 1.57 M in hexane) in E t 2 0 (300 IR (KBr) 3250 (OH), 2950 (CH), 1460,1090,1010,880,and 820 cm NMR (CDC13) 6 0.70-1.90 [m, 14 H , (CH,CH2CH3)2], mL) 2-bromopyridine (4.9 g, 31 mmol) was added dropwise. After 2.0G2.50 (m, 2 H, CHOHCH,), 2.70-3.60 [m, 6 H. +N(CHJ3],5.15 the mixture was stirred for 30 min, a solution of 11 (3.4 g, 10 mmol) (s, 1 H, OH), 5.35-5.75 (m, 1 H, CHOH), 7.20-8.20 (m, 8 H , in dry T H F (300 mL) was added dropwise, and the resulting black aromatic), 10.70-11.15 (m, 1 H, HC1); mol wt 491. Anal. (CZ7solution was stirred at -50 "C for 2 h. After the addition of aqueous 3:2 THF-H20 (50 mL), the mixture was warmed to 20 H33CldNO) C, H , N. "C, and the organic layer was separated, dried (Na2S04),and Acknowledgment. The authors wish to thank the A. concentrated. The residue was triturated with cyclohexane (50 H. Robins Co., Inc., Richmond, VA, for the use of its mL), and the solid was removed by filtration and dried: yield 2.2 g (53%). A small sample dissolved in Et20, treated with equipment and facilities to carry out this research. charcoal, and recovered gave tan crystals: mp 157-159 "C; IR Particular appreciation is expressed to Ashby F. Johnson, (KBr) 1590,1475,1090,1010,880,and 820 cm-'; NMR (CDC13) Jr., for the NMR spectra, John B. Forehand for the mass d 5.37 (m, 1 H, OH), 6.34 (s, 1 H, CHI, 6.90-8.60 (m, 1 2 H, spectra, Malcolm D. Stone for the elemental analyses, and aromatic); mol wt 413. Anal. (C2,H14C13NO)C, H, N. Dr. David A. Walsh and Dr. C. Roy Taylor for their helpful By a similar procedure 1-[3-(4-chlorophenyl)-5,7-disuggestions. The assistance of Dr. R. E. Strube, Walter chloro-l-naphthyl]-2-(2-pyridyl)ethanol (14) was prepared (1.7 Reed Army Institute of Research, is gratefully acknowlg, 40%) from 2-picoline (1.4 g, 15 mmol) and 11 (3.4 g, 10 mmol) edged. as tan crystals: mp 143-145 "C; IR (KBr) 3380 (OH), 1580, 1470, 1090,1010,880, and 820 cm-'; NMR (CDClJ 6 3.23 (d, 2 H, CH,), References and Notes 5.20 (m, 1 H , OH), 5.78 (t, 1 H, CHOH), 6.95-8.60 (m, 12 H, aromatic); mol wt 427. Anal. (C2,H16C13NO)C, H, N. (1) (a) For the previous paper see J. S. Gillespie, Jr., S. P. 3-(4-Chlorophenyl)-5,7-dichloro-a-(2-piperidyl)-lAcharya, D. A. Shamblee, and R. E. Davis, J . Med. Chem., naphthalenemethanol Acetate ( 1 6 ~ ) .A solution of 13 (2.1 g, 18, 1223 (1975); (b) taken from the M.S. Thesis of D. A. 5.1 mmol) in THF (30 mL) and glacial AcOH (30 mL) was treated Shamblee, University of Richmond, Richmond, VA, 1976. with PtO, (200 mg) and shaken under hydrogen for 3 h in a Parr (2) J. S. Gillespie, Jr., S. P. Acharya. D. A. Shamblee, and R. hydrogenation apparatus. The mixture was filtered (Celite),and E. Davis, Tetrahedron, 31, 3 (1975). the filtrate was concentrated under aspirator vacuum. When Et,O (3) J. S. Gillespie, Jr., S. P. Acharya, and D. ,4.Shamblee, J . (200 mL) was added, the product precipitated. Recrystallization Org. Chem., 40, 1838 (1975). ( 4 ) H. C. Brown and C. F. Lane. J . A m . Chem. Soc., 92, 6660 from Me2C0 gave 16c (1.8 g, 74%): mp 218-229 "C; IR (KBr) 1600, 1390, 1090, 1010, 880, and 820 cm '; NMR (Me,SO-d,) 6 (1970). 1.10-1.65 [m, 6 H, (CH,),CH,NH], 1.85 (s, 3 H, CH3COOH), ( 5 ) Results were reported to us by Walter Reed Army Institute 2.68-3.20 (m, 3 H , CH,NHCH), 5.15-5.75 (m, 4 H, CHOH, NH, of Research. The test method is described in T. S. Osdene, CH,COOH), 7.20-8.25 (m, 8 H, aromatic); mol wt 419. Anal. P. B. Russell, and L. Rane, J . Med. Chem.. 10, 431 (1967). (6) W. T. Colwell, V. Brown. P. Christie, J. Lange, C. Reece, (C&2,Cl$'JO,) C, H, N. Similarly, 1-[3-(4-chlorophenyl)-5,7-dichloro-l-naphK. Yamamoto, and D. W. Henry, J . Med. Chem., 15, 771 thyl]-2-(2-piperidyl)ethanol hydrochloride (16d) was prepared (1972). from 14 (1.6 g, 3.7 mmol): yield 0.8 g (45%); off-white crystals; (7) P. L. Creger, Org. SSnth., 50, 58-61 (1970).
';
