343
Ramesh ),I. Kane j ia Division of Chemical Research Ortho Pharmaceutics 1 Corporation Raritan, New Jcrscy OR869 Received
5-16-77
AESTRACT
The synthesis of 2-hydroxy and 4-hytlroxymcstrnn(l1 by oxidation The oral of mcstranol with m-chloroperbenzoic aci cl is described. estrogcnicity and contragestational activity of these and related catechol estrogen derivatives in the rat is also prcscnted. INTRODUCTION The formation of
of
?-hydroxylated
non-17-ethynyl.ated
steroidal
laboratory
animals
derivative
has also
(EE, -la)
and its
been
the most widely
used
ccptives,
metabolic
investigations
(1).
the mctabolites subjects
for
a mct.hod of of
of
has been
structure
17r~-etllynylestratli
derivative
(mcstranol
components
of
has becn
the
subject
radioactive
-la
(3)
by I’incus
coital
(contragcstat.ional)
herein
the resu1t.s
of
as yet
not
an
separati.on for
of
1-hydroxylated
and Merrill
(t;)
antifertil.ity the biological
derivatives
S
2C -’
TD1ROXDO
proof
of
be herein In view
and nnti-
steroidal lead
contra-
in hlmxn
cstrogcnicily
could
are
as one of
Kc dcscri
agent,
and
(2b) -
(4)
01
several
of -21, and -5b.
evaluation 2d __
of
oral
uneq~livocal
reported.
and characterization
fnvorablc
as syeculatcd
and of -lb
~lowevc1-,
, PaTYE, -lb]
combination
2-hydroxymest.ranol
rcportcd.
Number 3
Since
ether
fate
in
a 4-hydroxylatcd
of
ilctivity
Vo Fume 30,
and recently
mrtabolites
cstabli.shrd
ktection
preparation
estrogen
rvcll
(2).
estrogenic
progestational
catcchol
is
as major
rcportcd
-2b and Sb is
the rcportctl
estrogens
and humans (1)
S-methyl
their
dcrilrativcs
estrogens to
wc also of 2,
a useful
\+=hich, post-
describe -3b and related
3d.
September,
19 7 7
S Efost of
Chcmi stry: -
and ‘I-hydrox),estrogcns chemical
reactions
(or
cl) stnrtjnp,
(or
c)
as the
ethers
of
step
lb
for
Ibrcl’Ciri IIJ: Z-h!-tlroxy
7,
10)
involve
for
tlic
enzymatic
(or
d),
since
Inhorious
it
ones
rccluirts
((,-:I)
multistrI1 (11,
12)
:I free
rcl)ortctl
plie~lol
such
a5 _~. la
material.
dcscrihct!
steroid31
hydroxy-3-mcthoxy OIlC
cxccpt
starting
‘I‘he method
the methotls
(6,
from
TIIROIDS
hclcw,
estrogens
to
rin.p A aromatic
or
the
other
afford +teroids
the
tl;ind,
ul i 1 i :CL! I;-nletllyl
corresponding
3- and ,I-
(711 or cl :!II~ ,313or ~1 resp.)
it!
S
such as g
(or
pcrhc,nzoic
acid
such
the method consisted
~crlcrnl)
In
d)
2-5
for
days
of
i sol a trtl I!y co1 11m1ichromntogr;lph)~
these
prop~~rti es.
wcrc
hydroxy -21~ (or
the
starting
derivative d)
the phcnolic
products
fcrri
spray.
tcmpcrnturcs
for
d)
-31) (or
(or
d)
and -21) (or
4-S hrs
[at of
recovery),
by tic,
rl) using
inl;iIJitor
1’~‘1:11’ by-pro(lucts
greatly
incl-cased
and the recovery
stnrfing
dccrcasetl.
this
one step
Ijrocedurc
starting
material
estrogens
for
Biology:
alloys
hiologicnl
in this
hydrox).lation with
coupled
the
one to prcparc
the
arc
ahilit),
low,
the
simplicity
to rec),clc
a variet!,
of
compounds
[cxljrcssed
activity
following
oral
administration
scsamc
according
procrdu~~
described
prclirnjrlnry
by their
by Ilnhn et
results
in
al.,
administration
procedure of
of
llnrcnctct!
hydroxylntcd
evaluation.
utc,rotropic
described
of
unrenctcd
measured
previously
Yorn.ation
of
the
to EF, (&)]was
by oral
the ),icld
of
of
out
chloride-
at cl e\;ntcd
The estrogcnicity
were carried
visualizing
(1‘1)]
sli.ght ly but
the yields
4-
in CIICl 3 or
increnscd
Although
thr
;I ferric
tlerivat-.ivc
matcrinl
CC-7
2-hytlrox)- derivative
tcq)ernture
a radical
ph)~sic:il
from SilicAR
was col!c;uctctl
t.he rcflils
wcrc
zcd by tllcir
(SO-604
was monitol~eti
d)
ether
rr-chlcrro-
products
clutjon
and the
lYhcn the rcactioll
Cl (Clip) pC1 j-11 the prcscnce 2-hpdroxylatcd
thcjr
(5-10%)
rcncti.orl
The
of
-lh
with
The major
and characteri
order
stcrojd
-.3h (or
(Z-S%).
cynnidc
In the
a S-methyl
in ;I cl~lorc~l~~~drocnrl~on solvent
as C112C12, CIIC13, or C1(CI12)2C1.
chemical
trcat.ir!l:
at room tcmpcrnturc
1. 2- 1. 5 PC,.)
(tICI’M,
345
TLIROIDS
(151
the biological
the
oil,
in rats to the
Contragestntionol
(IS). of to rats
the on
evaluntion
relatjvr
studies
test
compound 11)’ the
days
1-h
(T:lhlc
of
rcstntion.
1) indicntcd
The vc’ry low
346
S estrogcnic
oral
activity
for
the
pounds
(211, 31,, 3c nntl 3~1) that
and
showed
nntifertili
on the
hasis
.ic
expect
of
ty effect their
TDEOIDb
six
compo1lnds tc.+tcd.
cxhillited
contrnl:est:ttioJlal
at doses
cstropenicj
Of the
lobcr
four
com-
:~ctivity,
-21~
than wh:ct one mifiht
ty.
I~iologicxl Activity of Soltics Steroid:1 1 Catechol-Cstro~cris and Their- 3-blcthvl lithcrs _--..--__-._‘________..~---~~_~.-’~_-_.__._Corltrn~cst;itioll~ll Oral Estrogcnicit\ Compared to lX (la) (BS90 Confidcncc Limit) 1.0
0 . 0 07 (0.005-O.cm)
DO?c! mg/kg
Activit!’ “,* 0 i:\I0. of Animn 1s 1ml’1XII t S kit11___ Implants Resorbing---__ -.__~-
0.25 0. 10 0. OS
o/5
--_--
I/l0
100. 0
i;/ 9
IO.9
5
2/5
100. ii
_______________ ._____._~__________~___.__~__ ______.__~___~__..______~_.___-_ n Ref.
:;;
b Ref.
9
calli I lnr). “lclt in!; points were clctermined on ;I ‘I‘lio~i~:~s-lloc,vcr Uv 5;pcc tra were dctcrmincc! or 8 Car;., :1ppnrntus ai~d nrc uncorrcctctl. blodel II reccrdillg spcctrophotomcter jn ctllanol , ir spcctrn b;cre recorded 011 LI llnicam SI’lOOO i.nfrared spcctrol’hotorneter in lil!r pellet!;, NiIR spectra were obtained 011 a \‘:Irian A-00 spcctromctcr usi II! (“Xl 3 as thr solvent with tetl-;lr;lctl~ylsilanc ;IS the internal st;cm!:lrtl nncl the m;lss spectral data wcrc ohtnirlcd frolil 8 I:inni can r;C-Il:; 1015-I) couplctl with a OlOU data s),stcm. Optical rotations t:erc determined 011 a Rudolph blodcl 70 pvlnrjmcter nttncllctl to :I for 16 solutions in chloroform. TK unit, Piodcl 300 l)hotoclcctric analpcs were pcrformcd 011 Uniplatc Sj IicAR 7GF (Analtech Jnc.). SilicAR (!.lallinckrotlt Co.) was 11 .___ _-_-.-__ I-.
--
L.?u -
To a stirred solution of lb (31.0 g, 0.01 mole) in UK13 (500 ml) at RT HAS addcd a soln of KPB~(85”o, 26 g, 0.012 molt) in CilC13 After sti.rring the mixture for 5 (500 ml) over a period of 20 min. j t was washed with a IO? NazC03 solution days at room temperature, (NazS0~,) and evaporated. The crude (500 ml), 1120 (2 x 300 ml), dried product (33 g) was applied to a column of Si 1icAR CC-7 1.6 kg in benzene) and tluted with increasing proportions of LtOAc in benzene. Elution wi.th 1% EtOAc/henzene afforded unrcacted Further elution \iith 2-2.53 starting steroid lb (14.8 g, 48%). Recrystallization from EtOAc/bcnzene aff?&cd 3b (1.87 g, 5.8%). benzene gave the analyt.zal sample: n1.p. 2O4-2O70(d); nmr f; 0.58 (s, 311, 18-Cl13), 2.61 (s, 111, ;!I-II), X.:(6 (s, 311, 34!le), 6.7 (d, J=8.5 Ilz, 111, 2-11)) 6.87 (d, .J=9.5 Ilz, 111, l-11) ; 4.73, 6.2 and 6.311; uv 278 nm (20.30); [r~] 2;: + 14.1°; ir 2.81, 2.85, 3.05, “1+326. Annl. c, fl.
3-Hethoxy-19-nor-l7u-prcgna-l,3,5(10)-trien-20-yr~c-2,17-diol In another elution of the Recrystallization m . p . 171-172O; (s, 311, 3-O!le), 4.73, 6.15 and ilf32h. AllniL.
(21))
experiment carried out as described above, further column with 3% EtOAc/benzene afforded 2b in 3.7:. yield. from benzene-hexane gave the analytical sample: nmr 6 0.57 (s, 311, 18-tic), 2.60 (I;, III, 21-II), 3.S3 6.58 (s, III, 4-II), 6.90 (s, 111, I-II); ir ?.81,2.85, 3.02, 6.311; uv 285 (3930) and 288 nm (3820); [(I] ‘; + 53’; c, II.
4-Hydroxy-3-mcthoxy1,3,5(10) 3-methoxy- 1,3,5(10)-estratriene
-estratrien,~7_onc -17-one m
(3d) __Ld--_ ,,ntl ~-~Iv~~T-ox~~
Following the same procedure described above for the preparation of 3b and 2, estrone-3-methyl ether (Id, 28.4 g, 0.1 mole) gave 3d (2.98 g, m.p. 220-225’, 10%)) [lit 220-224’(8)], -.2d (0.8 g, m.p. 182-183’, 2.6%) [li.t m.p. 182-18S” (8)] and the unrenctcd starti.ng material -Id (16.7 g, 59%).
The author wishes to express his thanks to Dr. D. I!ahn and C. Allen for the biological test results. Thanks are also due to Dr. M. I,. Cotter and C. Shaw for the spectral data, to Dr. S. I.evine for valuable comments and to Mary Wcstbrook for her assistance in preparing the manuscript.
348
12.
.Jclli~~cF,
I).ll.,
1.i .
(;ell~l;c,
14.
Kishi, Y. , Arntalli, (I,) ) .I. Ghan sot. __-__L--_
().I’.,
nnd lkom, llau],t,
O., N., 04
Ii..J.. and
1:, ~_.
1x3
(1?71).
t;n~l['~'"Il, r,.) __ Stelc,id!; ___ __’
Tanino, (1972)
C-teroids, __ ____.
II.
, T'uLilyalw,
21, ..-
2o.i (lil;.?)
'I'., :IIIJ (:otO,
1‘. ,
.
15.
llnhn, 11.1:;. , Allen, 9_, ?93 (197~1) .
G. , ;IcGuirc,
.J. J,.
and l!a\,‘;in:(1,
,I .I’. , __Contracclrt _--
16.
??fter t-tic complctioll of the llrcl);!rntion cf tlii5 manuscipt, rcl>ort cd t hc s)-nthcsi c n f tllc?e C. Stul~cnraucll and R . Knuppcn nntl related conlpounds in imJ)rovctl yi clds by a rwdi t‘j cd JTroccdrlrc> [Steroids, 28, 7.3.X (1376)]. -----~_.