SCHISTOSOMICIDES. 1
Journal of Medicinal Chemistry, 1971, Vol. 14, N o . 11 1033
this case the alkylated 6- or 7-hydroxy-.i,8-quinolinequinones were generally purified by crystn from EhO-hexane. Purification by salt formation was not necessary. The melting points and yields of the new quinolinequinone derivatives are listed In Table I and I1 along with their corresponding antimalarial activity. Pmr spectra for these new derivatives were consistent with the proposed structures.
1,2,3,4-~etrahydro-7-w-cyclohexyloctyl-6hydroxy-5.8-quino-
linequinone.-7-~ -Cyclohexyloctyl-6 -hydroxy -5,8-quiiiolinequinone (1 g) in EtOH (100 ml) was reduced (PtO,) with the Parr hydrogenator. After 4 hr the reaction mixt was filtered (Celite); the filtrate was air oxidized for several hr and then evapd in vacuo. The purple solid was repeatedly recrystd from EtOH-CHCIJ to yield purple crystals (750 mg, 747, yield): mp 158-159’; RI 1,2,3,4-Tetrahydro-7-n-tetradecyI-6-hydroxy-5,8-quinol~ne- 0.18 (EhO), 0.83 (ether-ethanol, 1 : l ) ; pmr absorptions 6.58 (t, 2 H), 7.58 (4, 4 H), and 8.0-9.0 (m, E 2 7 H). quinone.-7-n-Tetradecyl-6hydroxy-5,X-quinoli~~equinone (500 mg) in EtOIf (100 ml) was reduced (PtO,) with the Parr hydroAcknowledgments.-Appreciation is expressed to the genator at aii initial pressure of 3.1 kg/cniZ. After 6 hr, the reacU S . Army Medical Research and Development Comtion mixt was filtered (Celite); the filtrate was air oxidized for several hr and then evapd in U U C I L Oto a purple solid. Repeated mand. Their contract No. DADA 17-69-C-9067 conrecrystn from Et20-CHCl3-EtOII yielded purple crystals (400 tributed to the support of this research. This is Conmg, 79% yield): mp 136-137’; lif 0.16 (EtzO-hexane, l : l ) , 0.65 No. 924 from the Army Research Program on tribution (EhO); pmr absorptions 6.27 (m, 1 H), 6.61 (t, 2 H), 7.60 (m, Malaria. 4 H), 8.17 (t, 3 H), 8.75 (s, 1 2 4 II), and 9.12 (m, 3 H).
Schistosomicides. 1.’ Derivatives of 2-Aminomethyl-l,2,3,4-tetrahydroquinoline
c. A. R. BAXTERAND H. c. RICKARDG* Research Division, PfLzer Lld., Sandwich, Kent, England Received February 3, 1971 The dyrithesis arid structure-activity relationships of a novel series of schistosomicidal ‘L-amiriomethyl-1,2,B,4tetrahydroqriir~olinederivatives ( V ) are described. The activity pattern of these conformatiohally constrained compounds is compared with that of the mirasan series of schistosomicides (I). Thus, in mice, for I decreasing activity is i n the order It3 = halogen, CN, and NOz, whereas in V the reverse is the case, and an explanation based on lipophilicity confiiderations is proposed. The isomeric seried VI is devoid of activity whereas members of series V display marked activity in single oral doses against Schislosoma mansoni, especially 10,2-N-isopropyl:~mi~~omethyl-6-methyl-7-nitro-l,‘l,3,4-tetrahydroquinolir~e [V; It’ = IE; 11‘ = CH(CH3)2;lt3 = NOs] ; the dextro form of 10 was the more active enantiomer. 3fembers of series V show a distinct advantage over the mirasan series i n that they display activity against S . mansoni in monkeys; thus, 10 is active in a single oral dose of .i0 mg/kg. I t is metabolized i n mouse and monkey to the corresponding 6-hydroxymethyl derivative, 6-hydroxymethyl-2-~V-isopropylamiriomethyl-7-nitro-l,2,3,4-tetrahydroquinoline [XX&III; It‘ = I f ; It2 = CH(CH,),; It3 = NOZ],which has been shown to be curative i n monkeys i n single im doses of 5-73 mg/kg.
Several examples are known in which structural modification of a biologically active compound has yielded analogs of constrained molecular conformation without consequent loss of biological activity, and a study of such compounds has provided useful information regarding structure-activity relationships.2 1Substituted t e t r a h y d r o q ~ i n o l i r i e s(I1 ~ ~and ~ 111) and 1phenylpiperazinesj (IV), may be regarded as examples of constrained molecules which retain the schistosomicidal activity displayed by the prototype mirasan series3 (I), of which mirasan (I; R1 = R 2 = C2Hj; R3 = C1) is the parent member. As an extension of this principle, we have synthesized 2-aminomethyltetrahydroquinolines of type tT and VI which represent a new class of cyclic analogs of series I. A prime objective was the development of novel agents that would display ivorthwhile activity against schistosome infections in primates, since this is a property which is lacking in the earlier series I-IV.486 (1) A preliminary paper describing these compds has appeared: H. C. Richards and R . Foster, Nature ( L o n d o n ) , 999, 581 (1969). (2) R. 1%. Barlow, “Introduction t o Chemical Pharmacology,” 2nd ed, Wiley, New York, N . Y . , 1964. (3) H. Mauss, H. Kollinp. and R . Connert, Med. Chem.. Abhandl. Med. Chem. Forechunoaataeften Farbenfabriken Bayer. 6 , 185 (1956). (4) R . Giinnert, Bull. W .H . O.,96, 702 (1961). ( 5 ) lioechst, U. 9. Patent, 2,830,056 (1968); Chem. Abslr., 61, 32531 (1959). ( 6 ) 0. D.Standen in “Experimental Chemotherapy.” R. J. Schnitzer and F. ltawking, E d . , Vol. I , Academic Press, London, p 773 1963.
111
k
cH3xQ R3
I
H
v
CH,NRlR*
I H
CH2NRlR2
VI
Chemistry.-The following general account describes the main methods of synthesis; the particular synthesis employed for each individual compound is indicated in the appropriate table. (1) Nitro Compounds.-Three synthetic routes that have been used to prepare the key precursor XI11 are
1034 Journal of Medicinal Chemistry, 1971, Vol. 14, No. 11
GENERAL
BAXTER AND
SCHEME I REACTION SCHEMES FOR NITROCOMPOUNDS
route A RH VI1
route B
routec
RCH,
RCH, VI11
VI11
i
1
RCOzH IX
RCHO X
1
RCHzCi
XI
XI1
I
1 I
I
B
H Y
xv
xvI
J
~ ~ I C mns H
The biologically inactive 5-ni tro isomer was always the minor isomer and was frequently discarded with the crystallization mother liquors. Each isomer was identified by means of its nmr spectrum, that of XV showing 2 apparent singlets and that of XVI shouing an AB quartet in the aromatic region. Kitration of XI11 in glacial -1cOH gave the S isomw XIV, it consequence of nonprotoriation of the heterocyclic S. Route B \\.as also employed but n-as restricted to providing XV and XVI in which R1 = H since a primary amine was required" in the reductive amination step from the s1dehydel2 X, produced by SeOl oxidation of VIII. The most versatile and convenient route \viis route C in which 2,6-dimethylquinolirie (VIII) was selectively monochlorinated13 Lvith CI2 in CCl, containing SayCO1, and the chloromethyl product XI nas aminated to give X I I . In this last step, it was necessary to use a large excess of amine when this was a primary amine, in order to prevent formation of bis(quinoliny1) product. ,I number of 1-alkyl derivatives of type XVII were prepared by acylation of XIII, followed by [AH reduction and subsequent nitration in HiSO4, (route D). synthetic routes for (2) Chloro Compounds.-The preparing members of the 5- arid 7-chloro series XXI and XXII, resp, are indicated in Scheme 11. 3-ChloroSCHEME I1 GENERAL RIACTIOK SCHEMES FOR CHLORO COMPOUKDS
XVIII
VI11
i
1
CH.
I
R=
outlined in Scheme I. Following the initially used route A, 6-methylquinoline (VII) was converted to the Reissert derivative? which on hydrolysis with HBr in AcOH gave 6-methylquinoline-2-carboxylic acids (IX). The acid chloride of IX, prepared n i t h PCls in PhNe, was treated in situ with the appropriate amine to give the corresponding amide, and subsequent reduction with LAH gave the desired quinoline amine contaminated with ring-reduced material.g Hydrogenation of the crude mixture over Raney Xi to the 1,2,3,4tetrahydroquinoline derivative XIII, followed by nitration in concd H2S04 gave the expectedlO 7 isomer XV plus a minor proportion of the 5 isomer XVI. Separation of the isomers was achieved by fractional distillation, column chromatography, or, more conveniently, by fractional crystallization of the free base or a suitable salt derivative, e . g . , hydrochloride or hydrogen maleate. ( 7 ) F. D. Pogp, W.Blount, and P. ~Melvin,J . Ora. Chem., 26, 4930 (1961). (8) J. W. Davis, ibid., 24, 1691 (1959). (9) C . E. Kaslow and W.R. Clark, i b i d . , 18, 55 (1953), suggested t h a t reduction of t h e hetero ring occurred during L.4H reduction of ethyl quinoline-2-carbox ylate, (10) M. Kulka and R. H. F. Manske, Can. J . C h e m . , 30, 720 (19521, showed t h a t nitration of 1,2,3,4-tetrahydroquinoline gave t h e 7-nitro isomer exclusively.
xx
XIX
+ I
+ I I
I
CH3&
cH3)3J I c1
I H
XXI
CHzNRIRL
CHLNR'R'
H
XXII
4-methylaniline (XVIII) underwent the DoebnerMiller reactionI4 to give a mixture of the quinaldines XIX and XX. Fractional distillation gave pure XIX but the isomer XX was difficult to purify; it was prepared betterI5 from 2,6-dimethylquinoline (VIII) by nitration, which occurs exclusively in the 5 position, followed by reduction with SnCL, diazotization of the (11) F. Zymalkowski, Arch. Pharm. (Weinheim),292, 682 (1959). (12) M. Seyhan and W. C . Fernelius, J . O r g . Chem., 2 2 , 217 (1957). (13) W . Mathes and H. SchUly, Anaew. Chem., Int. E d . E n d . , 2, 144
(1963). (14) Bayer, British Patent, 758,570 (1956); Chem. A b s t r . , 51, 180091 (1957).
(15) D. M . Bowen, R . W. Belfit, and R . A . Walser, J . d m e r . Chem. Sor., 76, 4307 (1953).
Journal of Medicinal Chemistry, 1971, Vol. 14, No. 11 1035
SCHISTOSOMICIDES. 1
k R
Compd“
T
e
R*
*e
CK > 1; > C1 > Br (cf. (19) R. Foster. 13. L. Cheetham, and E. T. Mesmer, J . Trop. M e d . H u g . , 11, 139 (1968).
(20) D. R. Bell, Bull. W . H.O., 19, 525 (1963).
BAXTER A N D RICHARDS
1036 Journal of Medicinal Chemistry, 1971, Vol. 14, N o . 11
TABLE I1
R 3
Compd
NR'W
R'
Oral activityn at 25 mg/kg (baseequiv) X 4
Salt
Formula
Mp, " C
Analyses
Method of synthesisb
CliHljN30~ C, Hh E Free base 133-135 H NHz c i 3 8 1 9 i y 3 0 2 .HC1 C, H I N A 246-248 HC1 N(CHs)z H C, H, N C Free base 49-51 CGHZ~IV~OZ H N(CZHB)Z C17H2&30~.2HCl C, H 4 110 dec 2HC1 N(C3H7)Z H 216-218 CijH23N302~ HCl C, H, N C H HCl N(CH3)CH(CHa)z CizHi7X~30z.HCl C, H, N iz 200-202 HC1 H NHCH3 Ci3Hi9N30z.HCI x A 244-248 HC1 H NHCZHj C, Ht A 232-235 CiaHziN30z .HCI H HC1 NHCaH, c, H A 199-203 Ci5Hz3N30z.HCl HC1 H NHCdH9 Maleate 187-189 H C ~ ~ H Z ~ P ~ ~ O Z . CC,~ H, H ~NO ~ A, B, or C NHCH(CH3)' C,H,N B Free base 63-68 H Cl;Hz3Na02 NHC(CH3)a C, H, PI; B 226 Ci3Hz3NaOz.HC1 H HC1 NHCH(CHa)CzH, 244-246 C, H, N B CijHz3K;30z.HC1 H HCl NHCHaCH(CH3)z C, H, N B 1.3HC1 192-194 H C1JIz5N302.1.5HCl NHCHzC(CH3)3 Ci,Hz8NaOz.3HCl C, H, .4 172-179 3HC1 NHCHzCHzN(C2Hj)Z H 199-201 H HC1 Ci8HziN3Oz.HCl J' F NHCHzC6Hj C14Hl~N302.CdH404 C, H , N C 172-173 H Maleate NHCaHjC C,H,N C Free base 84-86 C~~HZSN~OZ NHCeHlid H CISHZ~N~OZ C, H , N A Free base 102-104 H CsHioN" Cl;HZl??303 %, H, K A Free base 134-13#5 H C4H,NOr Ci5HZlN302 C, H , ?r' A 97-98 H Free base C,H&y NHCzHj C,Hj TsOH 172-174 Ci5H23N302.C,H803S c, H, & I) N(C2Hj)z CzH3 1.5HC1 180-183 Ci;Hz,NaOz 1.5HC1 N I) C ~ ~ H Z ~ N ~ O Z . C , HC,~ H, O ~I%S I) N(CzHj)CH(CH3)z CzH; TsOH 1do 200-202 Ci~HzjN3Oz'HC1 C, H, N I) CH3 HC1 25 N(C2Hj)z COCHa ciiHi 9x304 C,H,r\' G 191- 193 26 NHCOCH, COCH, CiiHzjN303 C, H, N H 74-77 27 N(CzHs)z 28 NCH(CH3)zCOCHa H 115-1 16 Ci6H23hT303 N I 29 NCH(CIf3)zCOCHa COCH3 110 CisHziN3Od C, H, N J 7.i-937Q; 30-75%; 95'j&; the case of inactive compounds activity xas often displayed a t higher dose levels. A, B, C, and I1 refer to appropriate routes in Scheme I ; E, by nitration of 2-aminomet~hyl-6-meth?.1-1,2,3,4-tetrahydroq~1inoline, obtained from l-benzoyl-2-cyano-l,2-dihydro-6methylquinoline (cf. ref 34). F, NaBH4 redn of Schiff base of 1 with PhCHO. G, diacetylation of 1. H, acetylation of 3. I, monoacetylation of io. J, diacetylation of 10. Cyclopropyl. d Cyclohexyl. e Piperidino. f Morpholino. 0 Pyrrolidinyl. C: calcd, 59.73; found 59.24. C : calcd, 56.05; found 56.70. 1
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
++ ++ +++ ++
++++
+++ ++ +
+++
++++ + + +
++,
+++,
++++,
+,
TABLE I11
CH3pJ-J N
R3
I
CH2NR'R'
H Oral activityQ at 25 mg/kg (base equiv) Compd
NR'R2
R'
x 4
+ + ++
Method of
Salt
MP. " C
Formula
Analyses
synthesisb
30 NHCaH9 c1 HCl 233-234 CijHzaClNz HC1 C, H, N A 31 NHCH(CH3)z C1 HC1 252-255 CiaHziClNz HC1 C, H , X c A CljHz3C1Nz HC1 C, H, N B 172-173 c1 HC1 33 N(CzH5)z CiaHziFNz .HC1 C, H, pu' C 225-228 F HC1 33 NHCH(CHa)z CisHzaFNz .2HC1 c, H, N D 2HC1 172 F 34 R(C2HS)Z Ci3Hi9FNz0 c, H, N C 91-92 F Free base 35 NHCHzCHzOH 240-241 HCl CldH2,BrNZ. HCl c1 HJ E Br 36 NHCH(CH3)z CiaHzzSz.HC1 c, H, N F 222-224 H HC1 37 NHCH(CH3)z Ci5HziN~.CaH40a c, H, N E 190 CN Maleate 38 XHCH(CH3)z 39 NHCH(CH3)z COiVHz Free base 133 Cl4H23N30 C, H, N d G 40 NHCH(CH3)z SHz 3HC1 190 dec CiaHzaN3.3HCl cJ H a Symbols as in Table 11. b A, from 7-chloro-2-formyl-6-methylquinoline. B, from 2-bromomethyl-7-chloro-6-methylquino~~ne. C, from 7-fluoro-2-formyl-6-methylquinoline. D, from 2-chloromethyl-7-fluoro-6-methylquinolir1e.E, from 10 by acylation. reduction. Sandmeyer reaction, and hydrolysis. F, precursor to 10. G, hydrolysis of 38 with 8 O q aq HzSOa. H, catalytic reduction of 10, C : calcd, .i8.10; found, 58.71. C : calcd, 68.93; found, 68.35.
+ ++
Journal of Medicinal Chemistry, 1971, Vol. 14, N o . 11 1037
SCHISTOSOMICIDES. I
TABLE IV
w
Compd
NRIRS
R'
MP, 'C
Salt
Formula
Method of synthesis5
Analyses
NHCH(CHa)z NO2 Maleate Ci4HziNaOz. C4H4O4 C,H N 193-194 C C N(CzH5)z NOz 2HC1 220 dec CisHzaNaOz * 2HC1 c, H A C, H, N C4HsNOb NOz Free base 175-177 CisHziNaOa D NHCH(CHa)i c1 Maleate 205-206 CiJIziClNz * C&Ot c, H, N B NH1 c1 HC1 231-232 CiiHisClNz .HC1 c, H, N 119-122 D NHCHzCHzOH C1 Free base CiaHigClNiO c, H, N a A, route A, Scheme I. B, as for 1, Table 11, but beginning with 5-chloro-6-methylquinoline. C, route C, Scheme I. D, employing 5-chloro-2-formyl-6-methylquinolinewith appropriate amine during reductive amination step, as per route B, Scheme I. b Morpholino. 41 42 43 44 45 46
TABLE V Oral sotivityo at 100 mic/kg
(Baae equiv) Analyses
Method of synthesisb
CisHz5NaOz.C1H404 CisHrsNaOz*C4H104
C, H, N C, H, N
C C
139 dec
C15HzaNaOz.HCl
c, H
B
2HC1
150-155
CisH2~NaOz.2HCl
C, H, N
D
51
TsOH
158-160
CisHisNaOa*C7HsOaS N
52
TsOH
181-183
CirHziNaOz.C7HsOaS
salt
MP, 'C
47 48
Maleate Maleate
191-192 131-132
49
HC1
50
Compd
x4
Formula
A
C, H
A
A, following route A in Scheme I, a Symbols as in Table 11; note that in Table V dose level four times that in Tables I1 and 111. but utilizing 6-ethylquinoline [R. A. Glen and J. R. Bailey, J . Amer. Chem. SOC.,68, 1840 (1946)l in the case of 51 and quinoline in the case of 52. B, as for route B in Scheme I but using 2-acetyl-6-methylquinoline (K. N. Campell, C. H. Helbing, and J. F. Kerwin, J . Amer. Chem. SOC.,63, 639 (1941)] for the reductive amination step. C, refers to route C in Scheme I, but beginning from 2,4,6trimethylquinoline [E. Roberts and E. E. Turner, J . Chem. SOC.,1837 (1927)l. D, Mannich reaction of 2,6-dimethylquinoline with HN(CzH5)z and HCHO, followed by reduction and nitration.
10, 38, 33, 31, and 36) whereas in the mirasan series I the order is reversedla &., halogen > CN > NOn. This particular difference between series I and V could well be explained in terms of lipophilicity, a property that can be correlated with a compounds partition coefficient or summation of substituent T values.21*z2I n Table I, 4 compounds have been considered, two (A and B) from the mirasan series I and the corresponding pair (C and D) from the tetrahydroquinoline series V, and ZS, the summation of T values for the substituent R and the linkage Z, has been listed with the molar EDjo. A Hansch equationz3fitting these particular values very (21) C. Hansch and T. Fujits, J . Amer. Chem. Soc., 86, 1616 (1964). (22) T . Fujita, J. Iwasa, and C. Hansch, ibid., 86, 5176 (1964). ( Z 3 ) T h e suthora thank Dr. M. 8.T u t e for this calcn; with only 4 compds
closely ( r = 0.997, s = 0.038) is log l/EDjo = 2 . 2 5 5 ~- 1.2427' - 2.843 Optimum B r
= r0 =
2.255 2 X 1.1242
=
0.91
Comparing r0 with the Z S values in Table I may explain why: (a) the C1 compound A is more active than the corresponding (insufficiently lipophilic) NO2 compound B, (b) the KOz compound D is more active than the corresponding (too lipophilic) C1 compound C, and why (c) the C1 compound A of the mirasan series the statistical significance is not high (p = 0.1 on T and T * by Student's t test) but a later correlation, using 8 compds within this series, showed both r and T S terms t o be significant a t the p = 0.01 level with co = 0.87.
1038 Journal of Medicinal Chemzstry, 1971, Vol. 14, KO.11
and the KO2 compound D of the tetrahydroquinoline series are of similar activity (optimum lipophilicity). The presence of a 6-Rk group is essential for activity (note the inactivity of the 6-de-IIe compound 52 and 6-Et compound 51) Tvhich is in harmony with the requirement3 for a X e group para to the basic side chain in series I. Recent work by Rosi, et al.,24has demonstrated that mirasan (I, R’ = R2 = E t ; R3 = C1) undergoes hydroxylation i n civo to give the active metabolite XXVI and that lucanthone (XXVIIa), from which series the mirasans were d e ~ e l o p e d ,undergoes ~,~ similar metabolismz5 to give hycanthone (XXVlIb), whish is showing promise as a schistosomicidal drug suitable for mass treatment.26 CHNh
c1 XXVI
CHZR XVII
a, R = H b, R=OH
,
BAXTER A N D I~ICHAHDS
XXX
(2) The Heterocyclic Ring.-Inclusion on the heterocyclic iY of an alkyl group such as Me (25) or Et (22, 23,and 24) produced compounds in which activity n-as retained or slightly enhanced (cf. 7 and 22) whereas Y by destruction of the basicity of the heterocyclic i acylation (26,27, and 29) resulted in a complete loss of activity. The activity of 47 and 48 s h o w that incorporation of a Me in the 4 position is “allowed” and suggests that this region of the molecule is not critical in drug-receptor interaction. However, the inactivity of the nonreduced chloroquinoline X X X I highlights the importance of the stereochemical and/or electronic nature of the hetero ring.
CHZNR1R2
A XXVIII XXXI
For certain members of series V, it has been demon(3) The Side Chain.-Table I1 illustrates the stratedZ7that a similar metabolic hydroxylation of the I i substituents on activity effect of different terminal B-Jle group occurs in mice (and other species) to give 7-NO2 series. Of the tertiary amines, 3 and 5 in the compounds of type XXVIII, several of n-hich have been n-ere the most active, and of the secondary amines preparedz8 by an oxidative fermentation techbearing a straight alkyl chain, maximum activity was nique,Z4 ? 5 , 2 9 using a strain of Aspergillus sclei otioiwiz displayed by 7. However, highest activity n a s posHuber obtained from the Centralbureau voor Schimsessed by compounds bearing an a-branched alkyl group, melcultures, Baarn, Holland ( S o . 549. 65). These hyz.e., 10, 11, and 17, which may be a reflection of their droxylated derivatives are highly schistosomicidal, a expected resistance to in vivo dealkylation to produce 1. compound of particular interest, as previously reported,’ being 6-hydroxymethyl-2-l-isopropylaminomethyl-7- The size of the terminal substituent seems t o be an important factor and possibly thwe compounds posieiinitro- l,%, 3,4-tetrahydroquinoline [XXVIII ; R1 = H ; R ing a bulky group. e . q . >14, 18, 19, 20, and 21 are inca= GPr; R3 = S O ? ] . In mice, it has been that pable of being acconimoduted in a receptor “poclcet” at p e y os, its schistosomicidal activity is similar to that of this region. -1ctivity of 7-C1 compounds (XXI) given the parent 6-I\Ie compound, 2-N-isopropylaminomethin Table 111. appeared to folloir the same pattern reyl-6-methyl-7-nitro-l,2,3,4-tetrahydroquinoline (lo), garding the effects of terminal S substitution displa) ed but by the intramuscular route its activity is very much by the 7-KO2 series (XV). superior. The most effective compound was the Y-2-TJr derivaIn series V, the effect of a Me group in the S position 10, 2-N-isopropylaminoniethyl-6-methyl-7-nitrotive, (XXX) was to lower activity markedly which was 1,2,3,4-tetrahydroquinoline [V; R1 = H ; R 2 = l-t’r, unexpected since the activity of XXIX, is reported6 t o R3 = NOz], administered ab the hydrogen maleate be superior to that of mirasan (I, R’= R 2 = Et; R3 = salt. It has been shonn?l t o be curative against 8 Cl). maiisonz infectionb in mice treated with 17 mg/kg po once daily for 3 consecutive days. or uith a single dose ( 2 4 ) 1). Rosi, T. R . Lewis, R . Lorenz, H. Freele, D. A. Berberian, and S. Archer, J . M e d . Chem., 10, 877 (1967). of 65 mg/kg; the corresponding figures obtained for a ( 2 5 ) D. Rosi, G. Peruzzotti, E. W. Dennis, D. A . Berberian, H. Freele, Puerto Rican strain of S . ina?~soniwere 11 mg/kg for D. F. Tullar, and 9. Archer, ibid., 10,867 (1967). 3 consecutive days and 3 3 nig kg (all doses correspond (26) R. Foster and H. C. Richards, C h i n . Ther., 6 , 293 (1970). ( 2 7 ) These studies were conducted by Dr. B. Kaye and R l r . N. M . to \\eight of free base). \Voolhouse of the Department of Drug Metabolism, Research Division of Destruction of the basic nature of the terminal S Pfizer Ltd. by acylation (e.c/., 28) resulted in a complete low of (28) T h e authors t h a n k Rlr. G. F. Parker of Fermentation Development, Chemicals Division of Pfizer Ltd., for this aspect of t h e work. activity . 129) Pfiser, South African P a t e n t , 68,03636 (1968); Chem. 4 b s f r . , 71, 30369k (1969). (31) R Foster, B L Cheetham, D r King, and E T Mesmer, . i n n (30) R . Foster and B. L. Cheethrtm, manuscripts in preparation.
l’rop
W e d Parasilol 66, 59 (1971)
SCHISTOSOMICIDES. 1
Extension of the side chain by one CH2 (50) reduced activity, a result which is in harmony with the finding3 that in the mirasan series (I),the K-N distance of the basic side chain is critical and that activity is at a maximum with an ethylene linkage; inclusion of a RIe on the CH2 side chain (49) also led to a reduction in activity. Each compound listed in Tables 11-V was tested as the racemic mixture, optical isomerism arising from the presence of the asymmetric C at position 2 of the molecule. Resolution of 10, has been achieved using d-a-bromocamphor-n-sulfonic acid, and the dextro form of 10 has been shown to be the more active isomer. Thus, at single oral dosages of 36 mg/kg of the hydrogen maleate salts, the hepatic shifts recorded for d l , d , and I forms of 10 were 33,56, and 11%,resp. The isomers are likely to assume a half-chair conformation, with the side chain equatorially oriented32 although conformational changes might well occur during drug-receptor interaction. Schistosomicidal Activity in the Monkey.-At an early stage of the program we wished to establish whether the nen series displayed schistosomicidal activity in infected monkeys (which mould serve as an indication of their likely activity in man) since it is kno1vn4Jjthat members of series I-IV, despite their high activity in mice, lack convincing activity in primates. Several compounds of type V were evaluated in monkeys and it 1%as established that structure-activity patterns roughly parallelled those in mice. Compd 10, was again one of the most promising members,31complete cures being obtained with a single oral dose of 50 mg/kg (corresponding t o 7 2 mg/kg of the hydrogen maleate salt). The work of Rosi, et U Z . , ~ ~suggested that the inactivity of mirasan (I, R1 = R 2 = E t ; R 3 = C1) in the monkey is due to the inability of the host's enzymes to convert the compound into the hydroxylated metabolite, XXVI. In the case of certain compounds of type V, it has been shownz7that hydroxylation occurs in this species to give the corresponding 6-hydroxymethyl derivatives (XXVIII). The 6-hydroxymethyl derivative of 10, proved to be extremely active in the monkey, particularly im, curative doses being in the range of 5-7.5 mg/l
