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(21) Application Number: KEIP/2008/ 000844

(22) Filing Date: 29/06!2007

(30) Prioritydata: 102006030416.0 29/0612006  DE

(86) PCf datn PCf/EP07/00SS93 29/06/2007 W02008/000521 AI 03/01/2.008

(73) Owner: BAYER SCHERING PHARMA AKTJENGESELLSCHAIT of Mllllerstrasse 178, 13353 Berlin, Germany

(72) Inventor: BOHLMANN, Rolf, Kuhler Wcg 6a, 14055 Derlin,Germnny; KUHNKE, Joachim, Schulstr. 16, 14482 Potsdam,Genmmy; HOSNER, Jan , Kaskclstrassc 39, 10317 BcrlinGcrmnny; GALLUS, Norbert. Gotzstr. 25, 12099 Bcrlin,Gcrmany; MENGES, Frcdcrik,

Sonnenblumenwcg 17b, 16548 Glienicke/Norbahn,Germany; BORDEN, SteiTen, Ackerstr. 80, 13355 Dcrlin,Germany; MUHN, Hans-Peter, Markgrnfenstrnsse 61, 13465 Berlin,Gennany and

PRELLE, Katja, Laurinsteig 31, 13465 Derlin,Gcnnany

(74)    Agentlnddress ror correspondence: Kaplan & Stratton Advocates, P.O. Box401ll•OOIOO, Nairobi

(57)    Abstract:
The invention relates to novel 18-methyl-19-nor-androst-4-en-17,17• spiroether of generol formula (I}, where Z = 0, two H,

=NOR or =NNHS02R, R = H, or straight or brunched chain Cl-4 or C3-4alkyl, R4 = H, halogen, or CF3 and R6 and/or R7 nrc a- or B-positioned nnd Rei :md R7 independently "' H or stmight or branched chain Cl-4 or C3•4alkyl or a straight or branched chain C2-4 or C3-4alkylcnc or a saturated C3-5 cycloalkyl, or together form a methylene group or a double bond. The novel compounds have gestagenic and antiminernlcorticoid action 18-Methyl-19-norandrost-4-ene  17,17-spiro  ether  (18-methyl-19-nor-20-spirox-4-en-3-one),  and  pharmaceutical products  comprising  the  same

The    present   invention   relates   to   18-rnethyl-15P,16P-

methylene-19-nor-20-spirox-4-en-3-ones    [correspond    to


[15,16]estr-4-ene-17,2'-perhydrofuran]-3-ones] of the general formula I


Formula I

in  which

z is an oxygen atom, two hydrogen atoms, a group =NOR or =NNHS02R, where R is a hydrogen atom or a straight-

15    or branched-chain alkyl group having 1 to 4 or 3 to 4 carbon atoms,

R4 is a hydrogen atom, a halogen atom or a trifluoromethyl group,


R6 and/or R7 may have a or ~ configuration, and R6 and R7 are independently of one another a hydrogen atom or a straight- or branched-chain alkyl group having 1 to 4 or 3 to 4 carbon atoms or a straight- or branched-chain

25    alkenyl group having 2 to 4 or 3 to 4 carbon atoms or a saturated cycloalkyl group having 3 to 5 carbon atoms or together are a methylene group or a double bond or

R6 is a halogen atom in the a or ~ configuration and R7 is a hydrogen a tom.


Z  is  preferably  an  oxygen  atom.

In    the  case  where  Z  is  a   group  =NOR  or  =NNHS02R,   R  is

preferably  a  hydrogen  atom.

A    suitable   straight-   or   branched-chain   alkyl    group

5    having   1   to   4   or   3   to   4   carbon   atoms   is   a   methyl,
    etbyl,   n-propyl   or   an  n-butyl   group   or   an   isopropyl,
    iso-  or  tert-butyl  group.       
    In  the  case  where  R6  and/or  R7  is  a  saturated  cycloalkyl
    group,   a  suitable  one  therefor  is  a  cyclopropyl,   -butyl
10or  -pentyl  group.       
    R4  is  preferably  a   hydrogen  atom,   a   methyl  group  or  a
    chlorine  atom.       
    A   suitable   halogen   atom   R4    or   R6    is    a    fluorine,
    chlorine,  bromine  or  iodine  atom;       
15    chlorine    is   preferred   inthe   case    of    R'•R'is

preferably    a   fluorine   atom.   The   halogen   atom   R'   is

preferably  in  the  ~ position.

In    the   case   where   R6   and/or   R7     is   a   straight-   or
20    branched-chain alkyl group having 1 to 4 or 3 to 4 carbon atoms, a suitable one therefor is a methyl,

ethyl,   n-propyl   or  an  n-butyl   group,   or  an  isopropyl,

iso- or tert-butyl group. R 6 and R7 are preferably a hydrogen atom and a methyl, ethyl or propyl group or

25    together are a methylene group or a double bond. In the case of an alkenyl radical R 6 and/or R7 , this is in

particular an ethenyl radical. The preferred representative of a saturated cycloalkyl group R6 and/or R7 having 3 to 5 carbon atoms is the cyclopropyl

30    radical.

The compounds mentioned below are particularlY preferred according to the inv-ention:

35    18-methyl-15p,l6P-methylene-19-nor-20-spiroxa-4,6-dien-


18-methyl-15p,l6P-methylene-19-nor-20-spirox-4-en-3-one 18-methyl-6P, 7p, 15P, 16P-dimethylene-19-nor-20-spirox-4-en-3-one









10    3-one





15    7a-ethenyl-18-methyl-15P, 16P-methylene-19 -nor-2 0-spirox-4-en-3-one
7P-ethenyl-18-methyl-15P, 16P-methylene-19-nor-20-spirox-4-en-3-one

20    spirox-4-en-3-one

7p-cyclopropyl-18-methyl-15P, 16P-methylene-19-nor-20-spirox-4-en-3-one



25    4-chloro-18-methyl-15p,l6P-methylene-19-nor-20-spirox-


4, 18-dimethyl-6p, 7p, 15p, 16P-dimethylene-19-nor-20-spirox-4-en-3-one
4, 18-dimethyl-6a, ?a, 15p, 16P-dimethylene-19-nor-20-

30    spirox-4-en-3-one

4-chloro-18-methyl-6P, 7P, 15P, 16P-dimethylene-19-nor-20-spirox-4-en-3-one


3 5    6P-fluoro-18-methyl-15P, 16P-methylene-19 -nor-2 0-spirox-


Drospirenone    (6p, 7P-15P, 16P-dimethylene-3-oxo-17-pregn-

4-ene-21,17~-carbolactone) is  a  novel  progestogen  which
is    present   for   example   in   the   oral   contraceptive

YASMIN®    and  the  product  ANGELIQ®   for   the  treatment  of

postmenopausal    symptoms   (both  SCHERING  AG) .  Because  of

its    comparatively   low   affinity   for   the   progestogen

5    receptor    and    its    comparatively    high    ovulation-

inhibitory  dose,

drospirenone is present in YASMIN® in the relatively high daily dose of 3 rng. Drospirenone is notable for

10    having, in addition to the progestational effect, an aldosterone-antagonistic (antimineralocorticoid) and antiandrogenic effect.

Both  these  properties  make  drospirenone  very  similar  in

15    its pharmacological profile to the natural progestogen progesterone which, unlike drospirenone however, has insufficient oral bioavailability.

It    is  therefore  an  object  of  the  present  invention  to

20    provide compounds which have a less dissociated profile than drospirenone in relation to their binding to the

progesterone receptor and mineralocorticoid receptor, and preferably have a stronger binding than drospirenone to the progesterone receptor. It is

25    preferably intended that the novel compounds have a more potent progestational effect than drospirenone, but have a weaker antimineralocorticoid effect than drospirenone, or one comparable to the latter.

30    This   object   is   achieved   by   the   provision   of    the

18-methy1-15~, 16~-methy1ene-19-nor-20-spirox-4-en-

3 -ones  of  the  general   formula  I   described  herein.   The
novel    compounds   are   distinguished  in  the  progesterone

receptor  binding  assay  using  cytosol  from  rabbit  uterus

homogenate    and   3H-progesterone   as   reference   substance

by    having   a   comparable   or   higher   affinity   for   the

progesterone    receptor    than    drospirenone    and    by    a

smaller    affinity   for   the   mineralocorticoid   receptor

from  rat  kidney  homogenate  (see  Tab.  1) .

Table  1:


    Example        PR  [KF]    MR  [KF]    PR  [RBA]    MR  [RBA]   
    DRSP        2.5    0.3    40        333   
    2        2.34    0.4    43        250   
    6        1.13    0.6    88        167   
    7        1. 08    0.5    93        200   
    9        4.295    42    23        2   
    12        2.355    0. 7    42        143   
    14        3.245    7.6    31        13   
    17        3.45    7.8    29        13   
    18        3.01    88    33        1   
    20        0.9    0.1    111.11        1000   
PR  [KF]:  3H-progesterone = 1;  MR  [KF]:  3H-aldosterone = 1;

PR  [REA]:  3H-progesterone  = lDD;  MR.  [RBA]:  3 H-aldosterone  = 100

The    compounds    of    the    invention    are    surprisingly

15    distinguished by strong progestational activity and are highly effective after subcutaneous administration in the pregnancy maintenance test on rats.

Procedure  for  the  pregnancy  maintenance  test  on  rats:


Removal of the corpora lutea or castration in pregnant rats induces abortion. Exogenous supply of progestins (progestogens) in combination with a suitable dose of an estrogen achieves maintenance of the pregnancy. The

25 pregnancy maintenance test on ovariectomized rats serves to determine the peripheral progestational activity of a compound.
Rats are mated during proestrus overnight. The mating is checked on the morning of the following day by inspecting a vaginal smear. The presence of sperm is

regarded    in   this   case   as   day   1   of   the   onset   of

pregnancy.    On   day   B   of   pregnancy,    the   animals   are

ovariectomized    under   ether   anesthesia.   Treatment   with

test    compound    and    exogenous    estrogen    ( es terone,

5  p.g/kg/day)   is   carried  out  subcutaneously  once  a   day

10    from day 8 to day 15 or day 21 of pregnancy. The first administration on day B is carried out 2 hours before the castration. Intact control animals receive vehicle exclusively.

15    Evaluation:

At   end   of   the   experiment    (day   15   or   day   21),    the animals   are   sacrificed   under   a   C02   atmosphere   and living    fetuses     (fetuses    with    beating    heart)     and 20    implantation  sites   (early  resorptions  and  dead  fetuses including   autolysis   and   atrophic   placentae)    in   both uterine  horns  are  counted.  On  day  22  it  is  additionally possible  to  examine  fetuses  for  malformations.   In  uteri without   fe.tuses   or   implantation   sites,   the   number   of

25    nidation sites is found by staining with 10% strength anunonium sulfide solution. The pregnancy maintenance rate is calculated as the ratio of the number of living fetuses and the total number of nidation sites (both resorbed and dead fetuses, and nidation sites).


The compounds of the invention of the general formula have very strong progestational activity with, at the same time, weak binding to the androgen receptor (dissociation) .


It has additionally been found that compounds of the invention show a potassium-retaining, natriuretic (antimineralcorticoid) effect in adrenalectomized rats.

owing    to    their   progestational    activity,    the   novel

compounds  of  the  general  formula  I  can  be  used  alone  or

in combination with estrogen in pharmaceutical products for contraception.

Because of their favorable profile of effects, the compounds of the invention are particularly sui table
for    the   treatment   of   premenstrual   symptoms   such   as

headaches,    depressive    moods,    water    retention    and



The    dosage   of    the    compounds    of    the    invention   in

contraceptive    products   is   to   be   from   0.01   to   5  mg,

preferably  0. 01  to  2  mg,  per  day.

The    daily   dose    for    the    treatment    of   premenstrual

15    symptoms  is  about  0.1  to  20  mg.

The progestational and estrogenic active ingredient components in contraceptive products are preferably administered orally together. The daily dose is

20    preferably  administered  once  a  day.

Suitable estrogens are synthetic estrogens, preferably ethinylestradiol, but also mestranol.

25    The estrogen is administered in a daily amount which corresponds to from 0.01 to 0.04 mg of ethinyl-estradiol.

The  novel  compounds  of  the  general  formula  I   can  also 30    be    employed    in    pharmaceutical    products    for    the treatment   of  pre-,   peri-   and  post-menopausal   symptoms

and  in  products  for  hormone  replacement  therapy  (HRT) .

Estrogens  used  in  such  products   are  primarily  natural 35    estrogens,    especially   estradiol   or   its   esters,    for example  estradiol  valerate  or  else  conjugated  estrogens (CEEs  =  conjugated  equine  estrogens)  as  are  present  for

example  in  the  product  PREMARIN®.
Pharmaceutical    products   based   on   the   novel   compounds

are    formulated  in  a  manner  known  per  se  by  processing

the  active  ingredient,  where  appropriate  in  combination

with    an    estrogen,    with    the    carrier    substances,

diluents,    where  appropriate  masking  flavors  etc.   usual

in    pharmaceutical   technology,   and  converting  into   the

desired  administration  form.

Suitable    for   the  preferred  oral  administration  are   in

10    particular tablets, coated tablets, capsules, pills, suspensions or solutions.

Particularly  suitable  for  parenteral  administration  are

oily    solutions   such   as~  for   example,    solutions   in

15    sesame oil, castor oil and cottonseed oil. To increase the solubility, it is possible to add solubilizers such as, for example, benzyl benzoate or benzyl alcohol.

It is also possible to incorporate the substances of 2 0 the invention in to a trans dermal sys tern and to use it

for  transdermal  administration  thereof.

The novel compounds of the general formula I are prepared according to the invention as described below.

25    The synthetic route for the novel 19-nor-20-spiroxenones shown in scheme 1 starts for example from dienol ether 2 (Hofmeister et al. Arzneim. -Forsch.

36(1)'   781,  1986).


30    2

..    ~   H~H
RO~  ROffiM


Compound (R methyl) is then prepared by rnethenylation of the 15-acetate 2 by known methods, for example with dirnethylsulfoxonium rnethylide and sodium hydroxide (see, for example, DE-A 11 83 500, DE-A 29 22

500, EP-A 0 019 690, US-A 4,291,029; E. J. Corey and M. Chaykovsky, J. Am. Chern. Soc. 84, 867 (1962)).

Allylation    is   then   carried   out   in   position   17,   for

10 example with allylmagnesium bromide in diethyl ether to give a compound 4. Hydroboronation for example with

9-borabicyclo[3.3.l]nonane and oxidative working up for example with hydrogen peroxide results in the primary alcohol 5.

15 Introduction of a 8. 6 double bond takes place by brornination of the 3, 5-dienol ether 5 and subsequent elimination of hydrogen bromide (see, for example,

J . Fried, J . A. Edwards , Organic Reactions in Steroid Chemistry, van Nostrand Reinhold Company 1972, pp.

20    265-374).

The dienol ether bromination can take place for example in analogy to the method of J. A. Zderic, Humber to carpio, A. Bowers and Carl Djerassi in Steriods 1, 233 (1963). The elimination of hydrogen bromide takes place

25    by heating the 6-brorno compound with basic reagents such as, for example, LiBr or Li2C03 in aprotic solvents

such    as   dimethylformamide  at   temperatures   of   50-120°C

or    else  by  heating  the  6-bromo  compounds  in  a   solvent

such  as  collidine  or  lutidine,  to  give  compound  6.

Compound  6  is  then  converted  by  methenylation  of  the  8.6

double    bond   by   known   methods,    e.g.    with   dimethyl-

sulfoxonium    methylide   (see,   for   example,   DE-A   11   83

500,    DE-A  29   22   500,   EP-A  0   019   690,   US-A  4, 291,029;

E.    J .   Corey  and  M.   Chaykovsky,   J.   Am.   Chem.   Soc.   84,

8 67   ( 19 62) )   into  a  compound  7,   resulting  in  a  mixture

10    of the a and 13 isomers (compounds 3a/3b) which can be separated into the individual isomers for example by chromatography.

Introduction    of   a    substituent   R4   can   for    example
15 starting from a compound of the formula ( 6) by epoxidation of the 8.4 double bond with hydrogen

peroxide  under  alkaline  conditions  and  reaction  of  the resulting  epoxides   in  a   suitable  solvent   treated  with acids   of   the   general   formula  H-R4 ,    where  -R4   may  be  a 20    halogen    atom    or    a    pseudohalogen,    or    reacted   with catalytic     amounts     of     mineral     acid     and,      where appropriate,    the   resulting   4-bromo   compoWids   of   the general   formula   I    (where   R4    =  bromine)   reacted   with methyl        2,2-difluoro-2-(fluorosulfonyl)acetate        in

25    dimethylformamide  in  the  presence  of  copper (I}   iodide.

Introduction of a 6-methylene group can take place for example starting from a 3-amino 3,5-diene derivative by reaction with formalin in alcoholic solution to form a

3 0 6a-hydroxymethy1 group and subsequent acidic elimination of water, for example with hydrochloric acid in dioxane/water. The elimination of water can, however, also take place in such a way that initially the hydroxy group is replaced by a better leaving group

35    and is then eliminated. Examples of suitable leaving groups are the mesylate, tosylate or benzoate (see DE-A

34    02    3291,    EP-A    150    157    US-A    4,584,288;

K.  Nickisch  et  al.,  J.   Med.  Chem.   34,  2464   (l.99l.)).

A    further   possibility   for   preparing   the   6-methylene

compounds    consists   of   direct   reaction   of   the   4(5)

unsaturated    3-ketones   with   acetals   of   formaldehyde   in

the    presence   of   sodium   acetate   with,    for   example,

phosphorus    oxychloride   or  phosphorus   pentachloride   in

suitable  solvents  such  as  chloroform  (see,  for  example,

K.  Annen,    H.  Hofmeister,    H.  Laurent   and   R.  Wiechert,

Synthesis  34  (1982)).

10    The    6-rnethylene   compounds    can   be   used    to    prepare

compounds of the general fonnula I in which R6 is equal to methyl, and R6 and R7 together form an additional bond.

15    For   this  purpose  it   is  possible  to  use  for  example  a

method  described  by  D.  Burn  et  al.   in  Tetrahedron  21,

1619    (1965),   in  which  isomerization  of  the  double  bond

is achieved by heating the 6-methylene compounds in ethanol with 5% palladium-carbon catalyst, which has

20    been  pretreated  either  with  hydrogen  or  by  heating  with
    a   small   amount   of   cyclohexene.   The   isomerization   can
    also   take   place   with   a   non-pretreated   catalyst   if   a
    small   amount   of   cyclohexene   is   added   to   the   reaction
25    hydrogenated   products   can   be   prevented   by   adding   an
    excess  of  sodium  acetate.
    Preparation  of    6-methyl-4, 6-dien-3-one  derivatives   is,
    however,    also    possibledirectly(seeK.Annen,

30    H. Hofmeister, H. Laurent and R. Wiechert, Lieb. Ann. 712 (1983)).

Compounds   in  which   R 6   is   an  a-methyl   function   can  be

prepared      from      the      6-methylene      compounds      by 35    hydrogenation    under    suitable    conditions.    The    best results   (selective   hydrogenation   of   the   exo-methylene function)     are    achieved    by    transfer    hydrogenation (E.  A.  Brande,   R.  P.  Linstead  and  P.  w.  D.  Mitchell,   J.

Chern.    Soc.    3578    (1954)).    Heating    the    6-methylene

derivatives  in  a  suitable  solvent  such  as,  for  example,

ethanol,    in  the  presence  of  a   hydride  donor  such  as,

for    example,   cyclohexene,   results   in  very  good  yields

of    6a-methyl    derivatives.    Small   proportions   of    61)-

5    methyl compoWld can be isomerized with acid {see, for example, D. Burn, D. N. Kirk and v. Petrow, Tetrahedron

1619   (1965)).

Targeted    preparation   of   613-alkyl   compounds   is   also

10    possible.    For    this    purpose,    the    4 (5) -unsaturated

)-ketones  are  reacted  for  example  with  ethylene  glycol,

trimethyl    orthoformate    in    dichloromethane    in    the

presence    of    catalytic    amounts    of    an    acid    (e.g.

p-toluenesulfonic    acid)    to    give    the    corresponding

15    3-ketals. The double bond in the 5(6) position isornerizes during this ketalization. Selective

epoxidation    of   this   5 (6)   double  bond   takes   place   for

example   by   using   organic   peracids,    e.g.    m-chloro-perbenzoic    acid,     in    suitable    solvents     such    as 20    dichloromethane.    As    an    alternative    to    this,     the epoxidation  can  also  take  place  with  hydrogen  peroxide in  the  presence  of,   for  example,   hexachloroacetone  or 3-ni trotrifluoroacetophenone.   The   5, 6a-epoxides   formed can     then    be     opened     axially    using     appropriate

25 alkylmagnesium halides or alkyllithium compoWlds. Sa-hydroxy-61)-alkyl compounds are obtained in this way. Cleavage of the 3-keto protective group can take place to obtain the Sa-hydroxy function by treatment Wlder mild acidic conditions (acetic acid or 4N hydrochloric

30    acid at 0°C) . Basic elimination of the Sa-hydroxy function with, for example~ dilute aqueous sodium hydroxide solution affords the 3-keto 4-ene compounds

with    a   6-alkyl   group   in   the   13   configuration.   As   an

alternative    to  this,   ketal  cleavage  under  more  drastic

35    conditions (aqueous hydrochloric acid or another strong acid) affords the corresponding 6a-alkyl compounds.

Compounds    substituted   in   position    by   an   alkyl,

alkenyl    or    cycloalkyl    group    can    be    obtained    as

described    in   the   examples   or   in   analogy   to   these

methods    using   reagents   analogous   to   those   described


5    The resulting compounds of the general formula I in which z is an oxygen atom can if desired be converted by reaction with hydroxylamine hydrochloride in the presence of a tertiary amine at temperatures between -20 and +40°C into their corresponding oximes (general

10    formula I with z meaning =NOH, where the hydroxy group may be synthetic or anti). Suitable tertiary bases are

for    example   trimethylamine,    triethylamine,    pyridine,

N,N-dimethylaminopyridine,    1, 5-diazabicyclo [4. 3. O]non-

5-ene    (DBN)    and    1,5-diazabicyc1o[5.4.0]undec-5-ene

15    {DBU},   with  preference  for  pyridine.   This  proceeds   in

analogy    to    the   description   in   WO  98/24801    for    the

preparation of corresponding 3-oxyimino derivatives of drospirenone.

20    Removal of the 3-oxo group to prepare a final product of the general formula I with Z meaning two hydrogen atoms can take place for example by the method indicated in DE-A 28 05 490 by reductive cleavage of a thioketa1 of the 3-keto compound.


The following examples serve to explain the invention in more detail :

Example  1


18-Methyl-15~, 16~-methylene-19-nor-20-spiroxa-4 1 6-dien-


a)    3-Methoxy-18-methyl-15~~16P,-methylene-estra-3 1 5-

35    dien-17-one

A   suspension   of   92.0  g   of   15a-acetoxy-3-methoxy-18-

methylestra-3,5-dien-17-one    (Hofmeister    et    al.

Arzneim.-Forsch.    36(1),    781,    1986)    in   500   m1    of

dimethyl    sulfoxide  was  added  to  a  suspension  of  254  g

-    14  -

of    trimethylsulfoxonium   iodide  in  1165  ml  of  dimethyl

sulfoxide  which  had  previously  been  stirred  with  43.5  g

of  sodium  hydroxide  at  room  temperature  under  argon  for

2  hours.  The  latter  was  stirred  at  room  temperature  for

a    further  1. 5  hours.  This  was  followed  by  stirring  into

15  1  of   ice-water/sodium  chloride,   and  the  precipitate

was  filtered  off,  washed  with  water,   and  dried  in  vacuo

at 60°C. 94.5 g of 3-methoxy-18-methy1-15~,16~-methylene-estra-3, 5-dien-3-one were obtained as crude

10    product. 134-135°C , [a]o-215.2° (ch1orofom, c = 9.9 mg/m1)

b)    3-Methoxy-18-methyl-15p,l6p-methylene-17a-{prop-2-


15    57 4 rnl of a 1M solution of allylmagnesium bromide in diethyl ether were added to a solution 7 5. 8 g of


17-one  in  920  ml  of  dichloromethane  at  0°C  and  stirred

at    0°C   under   argon   for   1   hour.   This   was   followed  by

20    dropwise addition of 290 ml of a saturated ammonium chloride solution at 0°C, stirring at 0°C for 0. 5 hours, addition to water, taking up in ethyl acetate, washing with water until neutral, drying over sodium

sulfate,    and   concentrating   in   vacuo.    86.5  g   of   3-

25    methoxy-18-methy1-15~,16~-methy1ene-17a-(prop-2-eny1)-

estra-3, 5-dien-17J3-ol were obtained as crude product. Crystals of the pure compound had a melting point of

110-112°C,   [ale=  -80.2°   (ch1orofom,  c  = 9.94  mg/m1).

30    c) 17a- {3-Hydroxypropany1) -3-methoxy-18-methy1-1Sp,l6p-methylene-estra-3, 5-dien-17 p-ol

1.5  1  of  a   0.5M  solution  of  9-borabicyclo[3.3.l]nonane

in    tetrahydrofuran  were  added  to  a   solution  of   86.5  g

of    3-methoxy-18-methy1-15~,16~-methy1ene-17a-(prop-2-

35    eny1)estra-3,5-dien-17~-o1 in  1  1  of  tetrahydrofuran  at

25°C, and the mixture was stirred at 25°C under argon for 4 hours and then, at 0°C, 33.77 g of sodium hydroxide in 475 ml of water were slowly added dropwise and, after stirring at 25°C for 5 minutes, 172 ml of

-    15  -

30%    strength    hydrogen   peroxide    were    slowly    added

dropwise    and   stirred   at   25°C   for   18   hours.   This   was

followed    by   stirring   into   ice-water/sodium   chloride,

removal    of  the  precipitate  by  filtration,   washing  with

5    water  and  drying  to  dryness  in  vacuo  at  60°C.   91.5  g  of

17rt.- (3-hydroxypropanyl) -3-methoxy-18-methyl-15~, 16~­

methylene-estra-3, 5-dien-17J3-ol  were  obtained  as   crude

product.   Crystals   of   the  pure  compound  had  a   melting

point    of    152-154°C,    [rt.] 0    -155.2°    (chloroform,

10    c  =  9.76  mg/ml).

d)    17 ~-Hydroxy-l? a- ( 3 -hydroxypropanyl) -18 -methyl-

15P, 16P-m.ethylene-estra-4, 6-dien-3-one

To    a   suspension  of   91.5   g   of   l7rt.-(3-hydroxypropanyl)-

l5    3-methoxy-18-methyl-15~,16~-methylene-estra-3,5-dien-

17J3-ol    in    915    ml    of    1-methyl-2-pyrrolidone    were

successively  added,   at   0°C,   91.5  ml  of  a   10%  strength

sodium    acetate   solution   and,    at   this    temperature,

35.9  g    of    1, 3-dibromo-5, 5-dimethylhydantoin    in

20    portions, the mixture was stirred at 0°C (ice bath) for 0.5 hour, 34 g of lithium bromide and 29.9 g of lithium

carbonate were added, and the mixture was stirred at a bath temperature of 100°C for 3. 5 hours. It was then stirred into ice-water/sodium chloride, and the

25    precipitate was removed by filtration, washed with water and stirred in the moist state with 250 ml of

ethyl    acetate.    44.1  g    of    17~-hydroxy-17rt.-(3-


dien-3-one  were  obtained  as   crystals   of  melting  point

30    l32-135°C,   [rt.] 0   = -14.0°   (pyridine,   c  = 4.28  mg/ml).

e)    18-Methyl-lSP 116P-m.ethylene-19-nor-20-spiroxa-4 1 6-


720    mg   of   p-toluenesulfonyl   chloride   are   added   to   a

35    solution of 1. 07 g of 17~-hydroxy-l7rt.- (3-hydroxy-propanyl) -18-methyl-15~, 16~-methylene-estra-4, 6-dien-3-

one in 2. 5 ml of pyridine, and the mixtures is stirred at room temperature for 18 hours. It was then added to water and extracted three times with ethyl acetate, and

-    16  -

the combined organic phases were washed with 1M hydrochloric acid, water and brine until neutral, dried
over    sodium    sulfate,    concentrated    in    vacuo    and

chromatographed    on    silica    gel    with    hexane/ethyl

acetate.   630  mg  of  pure  18-methyl-15~,16~-methylene-19-

nor-20-spiroxa-4,6-dien-3-one   were   obtained.   Crystal-

lization    from   acetone/hexane   resulted   in   crystals   of

melting point 134-135°C, Wlo = -80. 6°C (chloroform, c = 10.03 mg/ml).


Example  2



15    A suspension of 9. 41 g of trimet;_hylsulfoxonium iodide in 210 ml of dimethyl sulfoxide was stirred with 1.71 g of sodium hydride (60% in oil) at room temperature

under  argon  for  2  hours  and,   after  addition  of  5. 7  g  of


20    3-one (= example 1), and stirred at room temperature for 20 hours. Working up included addition to water,

extraction three times with ethyl acetate, washing with water and brine until neutral, drying over sodium sulfate, evaporating to dryness in vacuo and

25    chromatography on silica gel with dichloromethane/-acetone. Fraction II of the chromatography afforded 438 mg of 18-methyl-6a,7a,l5~,16~-dimethylene-19-nor-

20-spirox-4-en-3-one. Crystallization from acetone

resulted in crystals of melting point 228-230°C, 30 [a] 0 = +40. 2° +/- 0. 2° (chloroform, c = 11.1 mg/ml)

Example  3

18-Methyl-6~ 1 7~ 1 15~~16~-dimethylene-19-nor-20-spirox-

35    4-en-3-one

By    the    method    of example    2, fraction I of the

chromatography    afforded    1. 2    g    of    18-methyl-

6~, 7~, 15~, 16~-dimethylene-19-nor-20-spirox-4-en-3-one.

Crystallization    from    acetone/hexane    resulted    in

-    17  -

crystals of melting point 154-155°C, [a] 0 -175.1° (chloroform, c = 9.5 mg/ml).

Example  4




31.2  mg  of  copper(I)   chloride  were  added  to  a  solution

of    1. 0    g    of    18-methyl-15~, 16~-methylene-19-nor-20-

10    spiroxa-4, 6-dien-3-one (= example 1) in 20 ml of tetrahydrofuran at room temperature, and the mixture was stirred for 10 minutes before being cooled to

-15°C,  having  200  mg  of  aluminium  chloride  added,  being

stirred    at   this   temperature   for   30   minutes,   having

15    3.34 rn1 of propylmagnesium bromide solution (2M in tetrahydrofuran) added dropwise, and being stirred at -15°C for one hour. Working up involved adding 3 rnl of

2M hydrochloric acid to the reaction mixture at -15°C, stirring at room temperature for 0.5 hours, adding to

20 water, extracting three times with ethyl acetate, drying over sodium sulfate, concentrating in vacuo, and chromatography on silica gel with hexane/ethyl acetate. Crystallization of fraction I resulted in 233 mg of


25    4-en-3-one   as   crystals   of   melting   point   142-143°C,

[a]    0   = -2.7°   (chloroform,  c  =  9.5  mg/ml).

Example  5

30    18-Methyl-15~,16~-methylene-7~-propyl-19-nor-20-spirox-


By    the   method   of    example   4,    fraction    II    of    the

chromatography    afforded   241   mg   of   18-methyl-15~, 16~­

methylene-7~-propyl-19-nor-20-spirox-4-en-3-one      as

35    solid of melting point 87-88°C, [a] 0 = -10.8° (chloroform, c = 10.0 mg/ml)

-    18  -

Example  6



5    By the method of example 4 with 3M methylmagnesiurn bromide in ether instead of propylmagnesium bromide, fraction I of the chromatography afforded 483 mg of


3-one  as   solid  of  melting  point  190-191 °C,   [a.] 0   =  6. so

10    (chloroform,   c  =  10.16  mg/m1).



15    3-one

By    the   method   of   example   6,    fraction   II   of   the

chromatography    afforded   201    mg    of    7~, 18-dimethyl-

15~,16~-methylene-19-nor-20-spirox-4-en-3-one  as   solid

of melting point 172-173°C, [a]o = -11.2° (chloroform, 20 c = 10.35 mg/ml).

Example  8


2 5    4-en-3 -one

By    the   method   of   example   4   with   3M   ethylmagnesiurn

bromide in ether instead of propylmagnesium bromide, fraction I of the chromatography afforded 453 mg of 7a-


30    en-3-one as solid of melting point 197-198°C, [a] 0 = -6.70 (chloroform, c = 10.42 mg/ml).


35    7~-Ethyl-18-methyl-15~,16~-methy1ene-19-nor-20-spirox-


By    the   method   of    example   8,    fraction    II    of    the

chromatography    afforded   113   mg   of   7~-ethyl-18-methyl-

15~,16~-methylene-19-nor-20-spirox-4-en-3-one  as   solid

-    19  -

of    melting  point  185-187°C,   [tl]o    -11.7°   (chloroform,

c  =  9.4  mg/m1).

Example  10



By    the   method   of    example    4,    fraction    I    of    the

chromatography    afforded    280.6    mg    of    7a-etheny1-18-

10 methyl-15~,16~-methylene-19-nor-20-spirox-4-en-3-one as solid of melting point 188-190°C, [a.Jn = -59. so

(chloroform,    c  = 9. 87  mg/ml) .

Example  11




By    the   method   of   example    4,    fraction    II    of    the

chromatography    afforded    54.4    mg    of    7~-Etheny1-18-

20    methyl-15~, 16~-methylene-19-nor-20-spirox-4-en-3-one  as

solidof    melting    point149-150°C.    [a] 0   =  -37.6°
(chloroform,    c  = 5.11    mg/ml).   

Example  12


7a-eyc1opropy1-18-methy1-15 ~, 16 ~-methy1ene-19-nor-20-


By    the   method   of    example   4,    fraction    of    the

chromatography    afforded    360    mg    of    7a-cyclopropyl-

30    18-methyl-15~,16~-methylene-19-nor-20-spirox-4-en-3-one

as solid of melting point 167-168°C. [a] 0 = -55.3° (chloroform, c = 10.14 mg/ml).

Example  13




By    the   method   of   example   4,    fraction   II    of    the

chromatography    afforded    63    mg    of    7~-cyclopropyl-

-    20  -


as solid of melting point 124-126°C. [a]o = -16.9° (chloroform, c = 10.18 mg/ml).

Example  ~4



10    a) 15a-Acetoxy-3,3-ethylenedioxy-18-methyl-19-nor-androst-5-en-17-one

40   ml   of   ethylene   glycol   and   27.5   ml   of   trimethyl

orthoformate  were  add~d to  a   solution  of  10  g   of  15a.-

acetoxy-3-methoxy-18-methyl-estra-3,5-dien-17-one    in

15    140 ml of dichloromethane and, after addition of 670 mg of para-toluenesulfonic acid, the mixture was stirred at room temperature for 1 hour. This was followed by addition of 1.85 ml of pyridine, dilution with

dichloromethane,      washing     with     saturated     sodium 20    bicarbonate   solution,    water   and   brine,    drying   over sodium  sulfate  and  concentrating  in  vacuo.   11.1    g  of crude      lSa-acetoxy-3,3-ethylenedioxy-18-methyl-19-nor-

androst-5-en-17-one  were  obtained.

25 b) 3,3-Ethylenedioxy-1B-methyl-15~,16~-methy1ene-19-nor-androst-5-en-17-one

A suspension of 28.75 g of trimethylsulfoxonium iodide in 210 ml of dimethyl sulfoxide was stirred with 4.92 g of sodium hydride ( 60% in oil) at room temperature

3 0 under argon for 2 hours and, after addition of 11.1 g of 15~-acetoxy-3,3-ethylenedioxy-18-methyl-19-nor­ androst-5-en-17-one, stirred at room temperature for 20 hours. Working up involved addition to water, extraction three times with ethyl acetate, washing with

35    water and brine until neutral, drying over sodium sulfate and concentrating to dryness in vacuo. 10.2 g of crude 3,3-ethylenedioxy-18-methyl-15~,16~-methylene-

19-nor-androst-5-en-17-one were obtained. Crystal-lization from acetone resulted in crystals of melting

-  21  -

point  221. 7°C.

c)    3,3-Ethylenedioxy-18-methyl-15~,16p-methylene-17a­


5    71   rnl    of    a    1M   allylrnagnesium   bromide   solution   in

diethyl  ether  were  added  slowly  to  a  solution  of  10.2  g

of    3,3-ethylenedioxy-18-methy1-15~,16~-methylene-19-

nor-androst-5-en-17-one  in  120  ml  of  dichlorornethane  at

ooc,    and  the  mixture  was  stirred  at  0°C  for  one  hour.

10    This was followed by dropwise addition of 40 rnl of a saturated ammonium chloride solution, stirring at 0°C for 0. 5 hours, addition to water, extraction with ethyl

acetate,    washing   with   water   and  brine   until   neutral,

drying  over  sodium  sulfate  and  concentrating  to  dryness

15    in    vacuo.    Chromatography    on    silica    gel    with

hexane/ethyl    acetate   afforded   7.33   g   of   pure   3,3-



2 0    d)  3, 3 -Ethyl.enedioxy-l.7 o:- ( 3 -hydroxypropy1) -l.B -methyl.-


1.4 1 of a O.SM solution of 9-borabicyclo[3.3.1]nonane solution in tetrahydrofuran were added to a solution of

80.3  g    of    3,3-ethylenedioxy-18-methyl-15~,16~-
25    methylene-170:-(prop-2-enyl)-19-nor-androst-5-en-17~-o1

in    900  ml  of  tetrahydrofuran  at  25°C,   and  the  mixture

was  stirred  at  25°C  under  argon  for  4  hours  followed  by

slow  dropwise  addition  of  30.5  g  of  sodium  hydroxide  in

425  ml  of  water  at  0°C,  stirring  at  25°C  for  5  minutes,

30    slow dropwise addition of 155 ml of 30% strength hydrogen peroxide, and stirring at 25°C for 18 hours. This was followed by dilution with ethyl acetate, washing with water, drying over sodium sulfate and

concentrating    to   dryness   in   vacuo   at   60°C.    80.7  g

35    of  3, 3-ethy1enedioxy-17a- (3-hydroxypropy1) -18-methy1-

15~, 16~-methy1ene-19-nor-androst-5-en-17~-ol were

obtained  as  an  oil.
.    -    -    ;; - :. zz. -- :71-   


-    22  -

e)    3,3-Ethylenedioxy-18-methyl-15~,16~-methylene-19-


A    solution    of    80.7    g    of    3,3-ethylenedioxy-l?a-(3-

hydroxypropyl) -18-methyl-15~, 16~-methylene-19-nor-

5    and.rost-5-en-17~-ol  in   170   ml   of   pyridine   was   mixed

with    48  g   of  para-toluenesulfonyl  chloride  and  stirred

at 25°C for 24 hours. It was then diluted with ethyl acetate, washed with water and saturated brine until neutral, dried over sodium sulfate and concentrated to

10    dryness in vacuo at 60°C. 75.8 g of crude product were obtained. Chromatography on silica gel with hexane/ethyl acetate afforded 50.5 g of pure 3,3-


spirox-5-ene.    Crystals   of   the   pure   compound   had   a

15    melting   point   of   58-60°C,    [a} 0   = -9.3°    (chloroform,
c    = 10.59  mg/ml).

f)    18-Methyl-15~,16~-methylene-19-nor-20-spirox-4-en-


20    50 ml of aqueous sulfuric acid (8% strength) were added to a solution of 50.5 g of 3,3-ethylenedioxy-18-methyl-

15~, 16~-methylene-19-nor-20-spirox-5-ene in 500 ml of methanol, and the mixture was stirred at 25°C for 8. 5 hours. This was followed by addition to sodium

25    bicarbonate solution, extraction three times with ethyl acetate, washing with water until neutral, drying over

sodium sulfate and concentration to dryness in vacuo at 50°C. 46.2 g of crude product were obtained. Chromatography on silica gel with dichloromethane/-

30    acetone resulted in 25.8 g of pure 18-methyl-15~,16~­ methylene-19-nor-20-spirox-4-en-3-one. Crystals of the

pure compound had a melting point of 208-21ooc, [a] 0 = +4.4° (chloroform, c = 10.1 mg/ml).

35    g) 4,18-Dimethyl-15~,16~-methylene-19-nor-20-spirox-4-en-3-one

To a solution of 508 rng of potassium tert-butoxide in 20 ml of tert-butanol were added, at a bath temperature of 100°C, a solution of 1 g of 18-methyl-15~,16~-

-    23  -

methylene-19-nor-20-spirox-4-en-3-one  in  20  ml  of  tert-

butanol    and,    over   the   course   of   4   hours,    a   second

solution    of   1. 46  ml   of   iodomethane   in  50  ml   of   tert-

butanol,    and    the    mixture    was    stirred   at    a    bath

5    temperature of 100°C for another hour. It was then concentrated in vacuo to one third the volume, diluted with ethyl acetate, washed twice with water and three

times    with  saturated  brine,   dried  over  sodium  sulfate

and    concentrated   to   dryness   in  vacuo.   1.1  g   of   crude

10    product   were   obtained.   Chromatography   on   silica   gel

with    hexane/ethyl   acetate   afforded   301.2  mg   of   4,18-


as    solid    of    melting    point    155-156°C.    [a.Jn  =  +lo

(chloroform,    c  = 10.75  mg/ml).


Example  15



20    0.38  ml  of  sulfuryl  chloride  was  added  to  a  solution  of

1 g of 18-methyl-15~,16~-methylene-19-nor-20-spirox-4-en-3-one in 10 ml of pyridine at a bath temperature of 0°C, and stirring was continued for 3 hours. This was followed by addition to water, extraction three times

25    with ethyl acetate, washing with water until neutral, drying over sodium sulfate and concentration to dryness in vacuo. 1. 2 g of crude product were obtained. Chromatography on silica gel with hexane/ethyl acetate

afforded    604.8   mg   of   pure   4-chloro-18-methyl-15~,16~-

30    methylene-19-nor-20-spirox-4-en-3-one as solid of melting point 149-151°C. [a]n = +9.4° (chloroform, c = 11.06 mg/ml).

Example  16



The    method   of   example   14   with   0.5   g   of   18-methyl-

-    24  -


resulted    in    220   mg   of    4,18-dimethyl-6a,7a,l5~,16~­

dimethylene-19-nor-20-spirox-4-en-3-one    as    solid    of

melting point 190-191°C. [a] 0 = +103.3° (chloroform, c = 10.22 mg/ml).

Example  17


l0    spirox-4-en-3-one

The    method   of   example   14   with   0.66   g   of   18-methyl-


resulted    in   186.7   mg   of   4,18-dimethyl-6~,7~,15~,16~-

15 dimethylene-19-nor-20-spirox-4-en-3-one as solid of melting point 175-177°C. [a] 0 = -230.7° (chloroform, c = 10.79 mg/ml).

Example  18



The    method   of   example   15   with   0. 66   g   of   18-methyl-

25    6~,7~,15p,l6P-dimethylene-19-nor-20-spirox-4-en-3-one

resulted    in    303.4    mg    of    4-chloro-18-methyl-


as solid of melting point 152-153°C. [alo = -222.7° (chloroform, c = 10.30 mg/ml).


Example  19




The    method   of   example   15   with   534   mg   of   18-methyl-

6a, ?a, 1513, 1613-dimethylene-19-nor-20-spirox-4-en-3-one

resulted  in  128  mg  of  4-chloro-18-methyl-6a,7a,lSP,l6P-

dimethylene-19-nor-20-spirox-4-en-3-one    as    solid    of

-    25  -

melting  point  177-178°C.   [a] 0   =  +80.0°   (chloroform,  c

9. 94  mg/ml) .

Example  20



a)    3-Acetoxy-18-methyl-15p,l6P-methylene-19-nor-20-

10    spiroxa-3, 5-diene

A  suspension  of   0.25  g   of  18-methyl-15~,16~-methylene-

19-nor-20-spirox-4-en-3-one   in   2. 5   ml   of   isopropenyl

acetate    was   mixed  with   24  rng  of  para-toluenesulfonic

acid    and  stirred  at   80°C  under  argon   for  1  hour.   For

15    working   up,    0.1   ml   of   triethylamine   was   added   and

concentrated    to   dryness   in   vacuo.    0. 28  g    of   crude


spiroxa-3, 5-diene  was  obtained.

20    b) 6p-Fluoro-18-methyl-1Sp,l6P-methylene-19-nor-20-spirox-4-en-3-one

0. 2 6  g    of   1-chloromethyl-4-fluoro-1, 4-diazoniabicyclo-

[2.2.2]octane   bis(tetrafluoroborate)    was   added   to   a

solution    of    0.28  g    of    3-acetoxy-18-methyl-15~,16~-

25    methylene-19-nor-20-spiroxa-3, 5-diene in 7. 8 rnl of acetonitrile at room temperature under argon, and the mixture was stirred for 15 minutes. Working up involved addition to ethyl acetate, washing with water and

brine,    drying   over   sodium   sulfate,    concentrating   to

30    dryness in vacuo and chromatography on silica gel with hexane/ethyl acetate. Fraction I of the chromatography afforded 23 mg of 6~-fluoro-18-methyl-15~, 16~­ methylene-19-nor-20-spirox-4-en-3-one as a foam.

-  26  -


1.    18-Methy1-15P,16p-methy1ene-19-nor-20-spirox-4-en-

3-ones  of  the  general  formula  I


Formula I

in  which

z    is  an  oxygen  atom,   two  hydrogen  atoms,   a  group  =NOR

or  =NNHS02R,   where  R  is  a  hydrogen  atom  or  a  straight-

10    or branched-chain alkyl group having 1 to 4 or 3 to 4 carbon atoms,

R4 is a hydrogen atom, a halogen atom or a trifluorornethyl group,

R6 and/or  R7 may  have  a  or  ~ configuration,  and  R6 and  R7
are    independently  of  one  another  a  hydrogen  atom  or  a

straight-  or  branched-chain  alkyl  group  having  1   to  4

or  3  to  4  carbon  atoms  or  a  straight-  or  branched-chain

20    alkenyl group having 2 to 4 or 3 to 4 carbon atoms or a saturated cycloalkyl group having 3 to 5 carbon atoms
or together are a methylene group or a double bond or R6 is a halogen atom in the a or ~ configuration and R7 is a hydrogen atom.


2.    Compounds  as  claimed  in  claim  1,  specifically



18-methy1-15P, 16P-methy1ene-19-nor-20-spirox-4-en-3-one

30    18-methy1-6P, 7p, 15P, 16P-dimethy1ene-19-nor-20-spirox-4-en-3-one


-  27  -





5    4-en-3-one





10    7a-ethy1-18-methy1-15p,16P-methy1ene-19-nor-20-spirox-





15    spirox-4-en-3-one



20    7P-cyc1opropy1-18-methy1-15P, 16P-methy1ene-19-nor-20-spirox-4-en-3-one



4-ch1oro-18-methy1-15P, 16P-methy1ene-19-nor-20-spirox-

25    4-en-3-one



30    4-ch1oro-18-methy1-6P, 7P, 15P, 16P-dimethy1ene-19-nor-20-spirox-4-en-3-one


6P-fluoro-18-methy1-15P, 16P-methy1ene-19-nor-20-spirox-

3.    A  pharmaceutical  product  comprising  at   least   one
compoundasclaimedinclaim    or2anda
pharmaceutically  acceptable  carrier.   

-    28  -

4.    The  pharmaceutical  product  as   claimed  in  claim  3,

additionally  comprising  at  least  one  estrogen.

5.    The  pharmaceutical  product  as   claimed  in  claim  4

comprising  ethinylestradiol.

6.    The  pharmaceutical  product  as  claimed  in  claim  4,

comprising  a  natural  estrogen.


7.    The  pharmaceutical  product  as  claimed  in  claim  6,

comprising  estradiol.

8.    The  pharmaceutical  product  as  claimed  in  claim  6,

15    comprising  estradiol  valerate.

9. The pharmaceutical product as claimed in claim 6, comprising at least one conjugated estrogen.


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