HYPOCHOLESTEREMIC 2-(2-PYRIDYL)-1,8-DIARYLALKANOLS
July 1967
565
2-(2-Pyridyl)-l,2-diarylalkanols as Hypocholesteremic Agents' J . H . BURCKHSLTER," WILLIA~U D. DIXOK, Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas
MARTINL. BLACK,^^ ROGER D. WESTLAND, LESLIE11. WERBEL,HORACE A. DEWALD, JOHN R. DICE,GERTRUDE RODNEY, A N D DOKALD H. IIAVMP Research Laboratories, Parke, Davis and Company, dnn Arbor, Jfichigan Received January 13, 1967
h series of 133 2 4 2-pyridyl)-1,2-diarylalkanols,or compounds closely related to them, were synthesized and assayed for their hypocholesteremic and estrogenic activities in rats. Many of these compounds were active in both tests, but there is no necessary correlation between the two effects. Compound 16 was selected for preclinical toxicologic study, followed by a study of its hypocholesteremic effect in man. The compound selected was remarkably nontoxic in all species studied, but it had no hypocholesteremic el'fect in the dog, the monkey, or in man.
We have been attracted by the possibility that chemical modification of one of the many known synthetic estrogens3 might lead to a hypocholesteremic agent free of the clinical stigmata associated with use of frank estrogens in the male.4 This report describes a series of compounds that approaches this goal. The series to be described conforms, for the most part, to generic structure I; the specific members of the series and their biologic properties are described in
I
Tables I-VI. The hypocholesteremic activities reported in the tables were determined by already published methods,j and refer to oral dosages in the male Holtzman rat for 7 days a t the dose level shown in parentheses. The estrogenicity figures (estrogenicity will be abbreviated as ES) refer to the number of micrograms of diethylstilbestrol that produces an estrogenic response equivalent to that produced by 1 mg of the test compound, both given orally. Each of these figures was obtained by a standard modification6 of the Allen-Doisy vaginal smear bioassay method,' by using adult ovariectomized rats of the Carworth C F S strain. The larger the ES figure the more estrogenic the compound. Compounds of type I were prepared by conversion of the appropriate benzylpyridine t o its anion with (1) (a) Presented in part before t h e Division of Medicinal Chemistry. 147th National Meeting of t h e American Chemical Society, Philadelphia, P a . , April 1964. (b) Taken in part from a Ph.D. Thesis of W. D. Dixon, T h e University of Kansas, 1960. (2) (a) Laboratory of Medicinal Chemistry, College of Pharmacy, T h e University of Michigan, Ann Arbor, Mich. 48104. (b) T o whom inquiries should be sent. (3) U. V. Solmasen, Chem. Rev., 87, 481 (1945); J. Grundy, ibid., 67, 281 (1957); J. A. Hogg and J. Korman in "Medicinal Chemistry," Vol. 2, F. F. Blicke a n d C. IM. Suter, Ed., John Wiley and Sons, Inc., New York, N. Y., 1956, p 34. (4) (a) C. Moses, "Atherosclerosis," Lea and Febiger, Philadelphia, Pa., 1963, p 128; (b) R. Pick, J. Stamler, a n d L. N. Katz in "Hormones and Atherosclerosis," G . Pincus, Ed., Academic Press Inc., New York, N. Y., 1959, p 229. ( 5 ) G. Rodney, M. L. Black, and 0. D. Bird, Biochem. Pharmacol., 14, 1336 (1965). (6) C. W. Emmens, iMethod8 Hormone Res., 2, 65 (1962). (7) E. Allen and E . A. DoiBy, J . A m . M e d . Assoc., 81, 819 (1923).
phenyllithium, and addition of the anion to an appropriate carbonyl reagent (Tables I, 11, and V). The presence of two asymmetric carbon atoms leads to the possible formation of two diastereoisomeric pairs. In many cases the two DL pairs, separated by fractional crystallization, exhibited different biological activities. Several attempts were made to resolve one of the more active DL pairs, but none was successful. Oxidation of the two DL pairs of I (R1= Rile, RP = H, RB = 4-Sille) (52, 53) with peracetic acid provided the sulfones, 61 and 62. To prepare the p-hydroxylated compounds (27, 28) the phenols were protected as the tetrahydropyranyl ethers before addition of the lithium reagent t o the carbonyl group. lllild acid hydrolysis effected cleavage of the ethers to the desired phenolic products. Alkylation of the intermediate tetrahydropyranyl ether with 2-chlorotriethylamine followed by in situ acid hydrolysis afforded the ether, 11.
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Oxidation of certain of the analogs of I with peracetic acid provided the corresponding pyridine Noxides tabulated in Table 111. Several of the parent compounds were reduced to the piperidine derivatives by hydrogenation in acid over PtOz (Table IV). The reduced materials were uniformly inactive as hypocholesteremic agents. Some of the analogs of I were dehydrated to the corresponding propylenes (Table VI) by treatment with 85% phosphoric acid or other mineral acid. The olefins were generally as active or more active than the parent carbinols. Treatment of the Grignard reagent from p-chlorobenzyl chloride with phenyl 2-thienyl ketone followed by the usual work-up gave the olefin, 2-[2-(p-chloro-
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,T. H. RURCKHALTER, 11. L. BLACK, P t al.
July 1967
HYPOCHOLESTEREMIC 2-(2-PYRIDYL)-1,2-DIARYLALKANOLS
567
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dose-response curves for 16 and triparanol.
phenyl-1-phenylvinyl]thiopheiie, directly. This material did not lower serum cholesterol when administered at 25 mg/kg. a-(p-llethoxy-a-met h y l beii z y1)-a-p h e n y1-2-p yridinemethariol (111), prepared from the lithium derivative of 2-bromopyridirie and 4’-methoxy-a-methyldeoxybeiizoin, produced 36yc lowering of serum cholesterol at a dose of 25 mg/lig. a’-4-Pyridyl-4-stilbeiiol, obtained from 4-benzylpyridine and 4-hydroxybenzaldehyde, lowered serum cholesterol 16y0at a dose of 23 mg/kg. Structure-activity relationships within the series are rather erratic, but several generulizatioiis may be drawn: ring substitution of the pyridine moiety or the adjacent phenyl ring does not appear to enhance hypocholesteremic potency ; linkage of the pyridine ring at positions other than 2 abolishes the activity; similarly, reduction of the pyridine ring abolishes the activity. The data suggest other correlations, but these are too vague and uiidocumerited t o permit further comment. Compound 16 (I, R1 = CH3; R1 = H ; K3 = 3-C1) mas selected for clinical evaluation. Some of the preliminary biochemical studies leading to this choice will be presented in the following paragraphs. Compound 16, the higher melting DL pair, is soluble in water at 2.5’ at less than 1 pg/ml and unstable to aqueous base, and its hydrochloride salt is extensively hydrolyzed in water solution. Presumably the latter is due to a stronger tendency for internal hydrogen bonding than for simple salt formation. It has an ED30 7 mg/kg/day, an ES 2.9 pg of diethylstilbestrol (DES)/mg, arid an LDbo > 4 g/kg (acute, orally, or iiitraperitorieally in mice and rats). Figure 1 represents the dose-respoiise curve for 16 compared with that of a refererice drug, triparanoL8 The effects showti there are reached after 4 days of treatmelit arid indicate, by comparison of ED3, values, that 16 is two t o three times more active than triparanol. A plateau at about 677, depression of plasma cholesterol is suggested by the data. S o drug refractoriness develops upon treatment for 6 weeks. The
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:tiiiinala ooiisuiiied ;I iwrni:il diet,, ljut t,hc eflects :ire identical, rel;Ittivc t,o pair-frd coiitrols, when the diet is mildly atherogeiiicg niid trcatmciit is begun simidt :lllcnusly. Cli)mpouiid 16 does not, nffcct, the cholesterol levels s stitdicd. T h r o higiiificaiit eff cct h rcssiori i i i total c:i cholwterol :md :t ioii i i i :tdrcii:d cholc 11 :1t :L dose of 25 pit.c its effect OII adixvi:d cholesterol, 16 d o c s i i o t impair adreiinl suficiciicy ~ I IA\CTH-strcssed :in imils. The niechaiiisin c.)f nction of 16 is i i o t >.et linon-11. It (li)i+ not, affect,, in h o or z i i t:i/ro, the rate uf coiiversioii of :~cet~ute-~~C: t o cholesterol or iiitermediate sterol coiice~itrationpntte SI* in the liver, so the compound inhibitor. St'udies of the effect' of 16 on the escrc 1 of radioact,ivity after injection rail>-
t l i a t used I J Y I.. c'. Fillies, S. 13. . i n d n l s , C . V. , .I. E r p t l . .Iled.. 104, 339 (19561, h u t with 10% corn and 0.5% chcrlic arid instead of the concentrations
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