HYPOTENSIVE LIGEXTS
Conipd
€I
R'
R:
R3
R4
cnl
16 17 18 19
€I H H 2'-Chloro analog of 1 6'-MeO analog of 1 H CHa H CHI CHs CHa H CHI H CHa CHI H CH(CH3)z H CHa CHI CHa H (CHd3CH3 H CHI CHa H CHI CHI CHCHa H H H CHI CHI CHa H H CHzCHa CH3 CHKsHs H H H H CHI H H CHGH1 CHICHB CHICHI H H H CHzCH=CH? CHa H H H CHa H H (CHd2CHa H C H ~ n r3 CHC~H, H CH?CsH0 CHg H CHJ CHa CHC6Hs CHKHa H H H CHLhHs H H H CHzCsHs
20
CHzCsH4C1-p
1
2 3e 4J 5 6 7
8 '3
101 11 12 13 14 16
CH3
CH3
H
H
H
Methoda
I 13 B
.i 0
o 0
o A .i I3
.i
.I B V I3 As 7
B B B
Crystn solvent" HCI hIerCO Hydrogen oxalate H?O Rase P(60)b HCI EtO.\c-,\I e C O H Cl MeOH-EtOAc HCI l\le?CO Hydrogen oxalate l\IeOH-EtOhc HCI MeOH-Et0 A c HCI M e 0 H-Et0.h Hydrogen oxalate EtOH-EtOAc Hydrogen oxalate lIeOH-EtO.4c H CI AleOH-EtO.ic HC1 A1 eOH-Et 0.h Oxalate AIeOH Oxalate hydrate MeOH-EtO.ic HCI X e O H-Et0.h HCI Et0.h Oxalate hemihydrate AleOH Hydrogen oxalate Et0.h hemihydrate Hydrogen oxalate AleOH-EtOhc
Form
MU. oc 122 199-200' 66 136 153-161 127 186-187 172-173 1T6-177 142-143 138-140
Formula CioHuCISO?
CI?HIGCINOG CiiHiiNOa CiiHisClNO: CiiHiaClNO CiaHaClPJO. CL6H?jS06 CI>HiUCINO?
haljses C , H. N H S ; Cd C.H N C , H, N C H.N C , H. N C, H . K
c, CI. K: H h
1.53-154
136-137 200 188-189 190-191 161
194 129
16T
Methods refer to Experimental Section. P(60) is petroleum ether (bp 60-80"). c Melting poi*it given iri ref 1 was that of crude material. d C: calcd, 47.1; found, 46.6. 0 Compound kindly prepared by Dr. B. J. IIcLoughlin. J Nmr (CDCI,) showed that this was a mixture (9: I ) of isomers but it was not possible to assign configurations. 0 See Experimental Section. H : calcd, 8.1; found, 7.4. Kmr (CIICI,) showed that this was a mixture (1l:Y) of isomers but it was not possible to assign configurations. j N: calcd, 5.3; found, 5.8. H : calcd, 7.5; found, 7.0.
TABLEI1 NITROSTYREXES S N D P - J f E T H O X U - P - P H E N Y L ~ I T R O E T H ISES
It 1
H2
Crystn solvent
EtOH EtOH JIeOH C&H EtOH
Alp,
a(:
114-113 104-10.5 61-63 SI)
114
26 CH30 c1 H MeOH 105 CioHizClNO4 C, H, N H CHaO 27b CHaO EtOH 62-63 CiiHijSOj c, H J H H 28 CeHjCHzO EtOH-HZO 67-69 CI~HI~NO, c, H J a Has C1 in the 2 position of benzene ring. Compound kindly prepared by Dr. B. J. AIcLoughlill. The intermediate 2,5-dimethoxyp-nitrostyrene was described by H. Kauffmann, Ber., 50, 635 (1917).
the evidence that it causes neither a fall in cardiac output nor a direct vasodilatation. The precise mode of action is not known. Estimates of the acute toxicity (LD50) of compound 1 in mice were made. When given orally it has an LDbo of 700-730 mg/kg and when administered intravenously i t has an LD50 of 50-55 mg/kg. The (-) isomer of 1 HC1 ( i e ., 34) was approximately twice as potent as the racemic form of 1. A t 1.5 and 0.75 mg/kg it caused a fall in blood pressure of 40 and 25%, respectively. The (+) isomer of 1 HC1 (;.e., 33) has no hypotensive effect a t similar doses. The most potent compounds in the series were those with structures very close to that of 1. Compounds in
which one or both of the methoxy groups are replaced with ethoxy groups (9, 12, and 13) and two of the three secondary amine analogs of 1 (5 and 7) had a good level of activity. Potency fell away sharply for the other compounds. Two of the six compounds in Table I V potentiated the carotid occlusion response (one only slightly) which berves to underline the doubt about the mode of action of this type of compound.
Experimental Section5 The general experimental methods A and B are representative ( 5 ) Where analyses are indicated only b y symbols of the elements, analytical results obtained for those elements were within =tO.4i.'o of theoretical values.
HYPOCHOLESTEROLENIC &SUBSTITUTED TETRAZOLEH
Xovember 1969
The residual solid, mp 110-120", [ a l z 1 D +10.7" (c 1.0, H*O), was crystallized from MeOH uiit'il the rotation became constant. Thus 29 (6.6 g, 45%) was obtained. The free base (+)-1 (31)) (+)-1 .HC1 (33), arid (+)-1 hydrogen ( - )-t,artrat.e (35) were obtained by conventional methods. ( - )-1 Hydrogen ( - )-Tartrate (30).-The retaiiied filtrate arid the crystallizatioii mother liquors from the preparatioii of 29 were combined and evaporated. S a O H ( 2 S)aiid saturated aqueous
1001
KaC1 (100 ml) were added and the mixture \vas extracted with
Et,O (130 ml, three times). The extract yielded optically impure (-)-1 base, [ a ] * ' D -30" (c 2.2, EtOH). This (-)-1 base (13.1 g) in NeOH (60 ml) was added to a solution of ( - )-tartaric acid (10.8 g) in hIeOH (60 ml) a t room temperature. The solid which separated, mp 131-154', [ ' Y ] * ~ D-36.5' (c 1.06, HzO), was crystallized from AIeOH until the rotation became constant. Thus 30 (6.6 g, G(,';) was obtained.
Hypocholesterolemic 5- Substituted Tetrazolesl 1tOl;ALD
L.BT;CH,kN.k??, YILJIARS SPRASCIIASIS, A N D
RICHARD
h.1 ' A R T l x 4
Ifcseatcli, Division, Bristol Laboratories, Divzsion of B r i d o l - M y f r s Company, Syracuse, Al-euqYolk
13201
Received March 17, 1969
h iirimber of 5-aryloxyalkyl-, 5-arylthioalkyl-, and 5-anilinoalkyltetrazoles. along with a few other related 5-wbstituted tetrazoles, were synthesized by standard methods. A novel tetrazolylethylatioii reactioii was used tetrazole (53) aiid 5-[~-(3-~hloropheiiylthio)ethyl] tetrazole (68). In to byntheaize 5-[~-(3-chlorophenoxy)ethyl] general, the 5-arylthioalkyltetrazoles provided the be3t combination of high hypocholebterolemic activity and lnw toxicity.
It is well known that 5-substituted tetrazoles and their carboxylic acid analogs have comparable dissociation constants.2z3 I n some cases this physiochemical analogy has been reflected in similar biological act ivit ies. -$ I n connection with other studies, it was discovered that 3-aryloxymethyltetrazoles (I) were inhibitors of cholesterol biosynthesis from acetate-l-'*C z" vitro. lo l~ollow-upi~ vivo studies revealed that these compounds, although somewhat toxic, lowered normal serum cholesH
I
A~-O-CH~~N,N
1 I
E-N
I
terol levels in rats. The plant growth hormone activity of some compounds of type I has been reported by 1Ic1lanus and Herbst.: I n view of the similarity of these compounds to the known serum lipid lowering agent ethyl a-(4chIorophenoxy)isobutyrate (clofibrate) , I 1 whose active principle is the corresponding carboxylic acid, a number of compounds of general structure 11 were synthesized.
branched chain). S H 1: = H , CH3 (1) Some of these compounds have been described by R. L. Buchanan and
8. .IPartyka, . U. S.Patent 3,337,676 (1967). (2) F. R. Benson, Chem. Reo:..41. 1 (1947). ( 3 ) R. AI. Herbst, "Essays in Biochemistry," John IT-iley and Sons, Inc., New Tork. X. T..1966.. .D 141. (4) C. r a n d e Westeringh and H. Veldstra. Ree. Trav. Chim.,77, l l O i (1958). ( 5 ) .J. AI. McManux aml 11. A I . IrerIJsl, J . O r g . Chvm.. 24, 1464, (1959). (t;) J. I < . l-2lwuod. K . M. l i e h a t . nnd C.i. L. liilyour. ./. B i d . Chew., ado, W 7 3 (19651. ( 7 ) €3. Bruuwer-vau Stranleu, U. Solinger, c'. vnu de \\ edtrriugli, axid t j , V&lstra. K e f . Trau. Chim.. 77, 1 1 2 ~I 1958). (X) ( > .F. Holland and J. N. Prrrirn, J . .\lei/. C ' / Z ~ I I L10, , , 149 (1967). ( U I P. F. Juby, T. IV. IIudyma, a n d M. Broivn, ibid., 11, 111 (1968). (10) Cnpublished results. (11) .\tromid-S'8'. CPIB; .J. hl. T h o r p and TI-. S. Waring. S u t u r e , 194, 11-18 (1Y62), a n d many subsequent gapers.
The bicyclic dihydrobenzofuran and benzothiopherie derivatives 111 arid IV (compounds 86 arid 87 in Table 111) were also prepared.
Iv
I11
The object of these syrit'hetic modificatioiis was to obtain compounds which combined potent hypocholesterolemic activity with low toxicity. This paper describes the preparation and some physical properties of t'hese 5-substituted tetrazoles along with the preliminary hypocholesterolemic screening data. Chemistry.-In most cases the syntheses irivolved the preparation of the requisite nitriles (Table 11), which were then converted t o the desired tetrazoles (Table 111) by standard methods. Where carboxylic acids \yere used as starting materials, conversions to the corresponding amides (Table I ) were effected by ;iccepted methods. These amides were theri converted to nitriles (Table 11) either by vacuum distillation from l'?Ojl? or b y reaction with PoC13 arid The aryloxy- arid arylthioacetonitriles were prepared by refluxing the appropriate phenols or thiophenols with chloroacet,otiitrile in w slurry of I
