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)]. -----~_.

Synthesis and biological evaluation of 2 - and 4- hydroxymestranol.

343 Ramesh ),I. Kane j ia Division of Chemical Research Ortho Pharmaceutics 1 Corporation Raritan, New Jcrscy OR869 Received 5-16-77 AESTRACT The...
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