U.S. patent application number 09/757678 was filed with the patent office on 2001-06-28 for new 4-halogenated steroids, their preparation process and intermediates, their use as medicaments and the pharmaceutical compositions containing them.
This patent application is currently assigned to Hoechst Marion Roussel. Invention is credited to Bouali, Yamina, Nique, Francois, Teutsch, Jean-Georges, Van De Velde, Patrick.
Application Number | 20010005756 09/757678 |
Document ID | / |
Family ID | 9505672 |
Filed Date | 2001-06-28 |
United States Patent
Application |
20010005756 |
Kind Code |
A1 |
Bouali, Yamina ; et
al. |
June 28, 2001 |
New 4-halogenated steroids, their preparation process and
intermediates, their use as medicaments and the pharmaceutical
compositions containing them
Abstract
A subject of the invention is the compounds of formula (I): 1 in
which X is a halogen atom, D represents the remainder of an
optionally substituted pentagonal or hexagonal ring and optionally
carrying an unsaturation, R.sub.1, R.sub.2, R.sub.3, R.sub.4, Y and
n are as defined in the description, their preparation process and
intermediates, their use as medicaments and the compositions
containing them.
Inventors: |
Bouali, Yamina; (Villejuif,
FR) ; Nique, Francois; (Le Perreux Sur Marne, FR)
; Teutsch, Jean-Georges; (Pantin, FR) ; Van De
Velde, Patrick; (Paris, FR) |
Correspondence
Address: |
Charles A. Muserlian
c/o Bierman, Muserlian and Lucas
600 Third Avenue
New York
NY
10016
US
|
Assignee: |
Hoechst Marion Roussel
|
Family ID: |
9505672 |
Appl. No.: |
09/757678 |
Filed: |
January 10, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09757678 |
Jan 10, 2001 |
|
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09402705 |
Nov 29, 1999 |
|
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09402705 |
Nov 29, 1999 |
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PCT/FR98/00709 |
Apr 8, 1998 |
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Current U.S.
Class: |
546/285 ;
540/107 |
Current CPC
Class: |
A61P 5/30 20180101; A61P
9/00 20180101; A61P 19/10 20180101; A61P 17/06 20180101; C07J
41/0083 20130101 |
Class at
Publication: |
546/285 ;
540/107 |
International
Class: |
C07J 043/00 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 9, 1997 |
FR |
97/04321 |
Claims
1. Compounds of general formula (I): 22in which: R.sub.1 represents
a hydrogen atom, a (CH.sub.2).sub.m--Ar--, (CO)--Ar,
(CH.sub.2).sub.m--Alk or (CO)--Alk radical, R.sub.2 represents a
radical derived from a linear or branched, saturated or unsaturated
hydrocarbon containing 1 to 6 carbon atoms D represents the
remainder of a pentagonal or hexagonal ring optionally substituted
and optionally carrying an unsaturation, X represents a halogen
atom, Y is chosen from O, S, SO, SO.sub.2 and NH, n is an integer
varying from 2 to 8, either R.sub.3 and R.sub.4, identical or
different, represent a hydrogen atom, a (CH.sub.2).sub.m--Ar,
(CH.sub.2).sub.m--Het or (CH.sub.2).sub.mAlk group, or R.sub.3 and
R.sub.4 form together with the atom of nitrogen to which they are
linked an aromatic or non-aromatic, saturated or unsaturated mono-
or polycyclic heterocycle with 3 to 15 members optionally
containing 1 to 3 additional heteroatoms chosen from oxygen,
sulphur and nitrogen, non-substituted or substituted, Ar
representing a carbocyclic aryl group containing 6 to 18 carbon
atoms, Het representing a radical derived from a saturated or
unsaturated aromatic or non-aromatic heterocycle containing 1 to 9
carbon atoms and 1 to 5 heteroatoms chosen from oxygen, nitrogen or
sulphur atoms, Alk representing a radical derived from a saturated
or unsaturated, linear, branched or cyclic, non-aromatic
hydrocarbon and containing 1 to 12 carbon atoms, the Ar, Het or Alk
radicals being able to be substituted or non-substituted, m
represents 0, 1, 2 or 3, as well as their addition salts with bases
or acids.
2. Compounds of general formula (I) as defined in claim 1, in which
D represents the remainder of a pentagonal ring of formula: 23in
which R.sub.2 retains the same meaning as in claim 1, either
R.sub.5 represents an OH, O--(CH.sub.2).sub.m--Alk, O--(CO)--Alk,
O--(CH.sub.2).sub.m1'Ar, O--(CO)--Ar, O--(CH.sub.2).sub.m--Het,
O--(CO)--Het radical and R.sub.6 represents a hydrogen atom, an
alkyl, alkenyl or alkynyl radical containing 1 to 6 carbon atoms
substituted or non substituted, m, Alk, Ar and Het being as defined
in claim 1, or R.sub.5 and R.sub.6 form together with the carbon
atom which carries them one of the following rings: 24in which Z
represents a --(CH.sub.2).sub.1-- or --CH.dbd.CH--(CH.sub.2).sub.-
1' group; 1 being an integer comprised between 1 and 4 and 1' being
an integer equal to 1 or 2, or R.sub.5 and R.sub.6 form together an
oxo group, as well as their addition salts with acids or bases.
3. Compounds of general formula (I) as defined in claim 1,
corresponding to general formula (I'): 25in which: X' represents a
chlorine or bromine atom n is comprised between 2 and 5, either
R'.sub.3 and R'.sub.4, identical or different, represent an alkyl
radical containing 1 to 6 carbon atoms or R'.sup.3 and R'.sub.4
form together with the nitrogen atom to which they are linked, a
saturated mono- or polycyclic remainder with 3 to 15 members
optionally containing an additional heteroatom chosen from oxygen,
sulphur and nitrogen, R'.sub.5 and R'.sub.6 have the same meaning
as R.sub.5 and R.sub.6, according to claim 2 as well as their
addition salts with acids and bases.
4. Compounds of general formula (I') as defined in claim 3, in
which: either R'.sub.5 represents an OH radical and R'.sub.6
represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical
containing 1 to 6 carbon atoms, substituted or non-substituted, or
R'.sub.5 and R'.sub.6 form together with the carbon atom that
carries them one of the following rings: 26or R'.sub.5 and R'.sub.6
form together an oxo group, as well as their addition salts with
acids or bases.
5. Compounds of general formula (I') as defined in claim 3 or 4, in
which: X' represents a chlorine atom n' is equal to 2, either
R'.sub.3 and R'.sub.4, identical or different, represent an alkyl
radical containing 1 to 6 carbon atoms or R'.sub.3 and R'.sub.4
form together with the nitrogen atom the following saturated
heterocycles: 27and either R'.sub.5 represents an OH radical and
R'.sub.6 represents a hydrogen atom, an alkyl, alkenyl or alkynyl
radical containing 1 to 6 carbon atoms, substituted or non
substituted, or R'.sub.5 and R'.sub.6 form together with the carbon
atom which carries them one of the following rings: 28or R'.sub.5
and R'.sub.6 form together an oxo group, as well as their addition
salts with acids or bases.
6. Compounds of formula (I) or (I') as defined in any one of claims
1 to 5, the names of which follow:
4-chloro-3-hydroxy-11.beta.-[4-[2-(diethyla-
mino)ethoxy]phenyl]-estra-1,3,5(10)-trien-17-one,
4-chloro-3-hydroxy-11.be-
ta.-[4-[2-(dimethylamino)ethoxy]phenyl]-estra-1,3,5(10)-trien-17-one,
4-chloro-3-hydroxy-11.beta.-(4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3-
,5(10)-trien-17-one,
4-chloro-3-hydroxy-11.beta.-[4-[2-(1-pyrrolidinyl)eth- oxy] 10
phenyl]-estra-1,3,5(10)-trien-17-one, 4-bromo-3-hydroxy-11.beta.-[-
4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-trien-17-one,
4-chloro-11.beta.-[4-[2-(dimethylamino)ethoxy]phenyl]-estra-1,3,5(10)-tri-
ene-3,17beta-diol,
4-chloro-11.beta.-[4-[2-(diethylamino)ethoxy]phenyl]-es-
tra-1,3,5(10)-triene-3,17beta-diol,
4-chloro-11.beta.-[4-[2-(1-piperidinyl-
)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol,
4-bromo-11.beta.-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-20
1,3,5(10)-triene-3,17beta-diol,
4-chloro-11.beta.-[4-[2-(1-pyrrolidinyl)e-
thoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol,
4-chloro-11.beta.-[4-[2-(diethylamino)ethoxy]phenyl]-19-nor-17alpha-pregn-
a-1,3,5(10)-triene-20-yne-3,17beta-diol,
4-chloro-11.beta.-[4-[3-(1-piperi-
dinyl)propoxy]phenyl]-estra-1,3,5(10)-triene-3,17beta-diol,
4-chloro-11.beta.-[4-[4-(1-piperidinyl)butoxy]phenyl]-estra-1,3,5(10)-tri-
ene-3,17bet
4-chloro-11.beta.-[4-[5-(1-piperidinyl)pentyloxy]phenyl]-estra- -30
1,3,5 (10)-triene-3,17beta-diol, gamma lactone of
(17alpha)-4-chloro-3,17beta-dihydroxy-11.beta.-(4-[2-(diethylamino)ethoxy-
]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxylic acid, gamma
lactone of
(17alpha)-4-chloro-3,17beta-dihydroxy-11.beta.-35[4-[2-(1-pyrrolindiny-
l)ethoxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxylic acid,
gamma lactone of
(17alpha)-4-chloro-3,17beta-dihydroxy-11.beta.-[4-[2-(1-piperi-
dinyl)ethoxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxylic
acid, gamma lactone of
(17alpha)-4-chloro-3,17beta-dihydroxy-11.beta.-[4-[3-(1--
piperidinyl)propoxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxylic
acid, gamma lactone of
(17alpha)-4-chloro-3,17beta-dihydroxy-11.beta.-[4--
[4-(1-piperidinyl)butoxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxy-
lic acid, gamma lactone of
(17alpha)-4-chloro-3,17beta-dihydroxy-11.beta.--
[4-[5-(1-piperidinyl)pentyloxy]phenyl]-19-nor-pregna-1,3,5
(10)-triene-21-carboxylic acid,
(17beta)-4-chloro-11.beta.-[4-[2-(diethyl-
amino)ethoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2'
(5'H)furan]-3-ol,
(17beta)-4-chloro-11.beta.-[4-[2-(1-piperidinyl)ethoxy]phenyl]-spiro[estr-
a-1,3,5(10)-triene-17,2' (5'H) furan]-3-ol,
(17beta)-4-chloro-11.beta.-[4--
[2-(1-pyrrolidinyl)ethoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2'
(5'H)furan]-3-ol,
(17beta)-4-chloro-4',5'-dihydro-11.beta.-[4-[2-(1-piper- idinyl)
ethoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2'(3'H)furan]-3-ol,
(17beta)-4-chloro-11.beta.-[4-[3-(1-piperidinyl)propoxy]phenyl]-spiro[est-
ra-1,3,5(10)-triene-17,2' (5'H)furan]-3-ol,
(17beta)-4-chloro-4',5'-dihydr- o-11.beta.-[4-[3-(1-piperidinyl)
propoxyl phenyl]-spiro[estra-1,3,5(10)-tr- iene-17,2'(3'H)
furan]-3-ol, (17beta)-4-chloro-11.beta.-[4-[4-(1-piperidin-
yl)butoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2'(5'H)furan]-3-ol,
(17beta)-4-chloro-4',5'-dihydro-113-[4-[4-(1-piperidinyl)-butoxy]phenyl]--
spiro[estra-1,3,5(10)-triene-17,2'(3'H)furan]-3-ol,
4-chloro-11.beta.-[4-[2-(diethylamino)ethoxy]phenyl]-17alpha-methyl-estra-
-1,3,5(10)-triene-3,17beta-diol,
4-chloro-17alpha-methyl-11.beta.-[4-[2-(1- -piperidinyl)ethoxy]
phenyl]-estra-1,3,5(10)-triene-3,17beta-diol.
7. Compound of formula (I) or (I') as defined in any one of claims
1 to 5, the name of which follows:
4-chloro-11.beta.-[4-[2-(diethylamino)ethoxy]p- henyl]-estra-1,3,5
(10)-triene-3,17beta-diol, as well as its addition salts with
acids.
8. Preparation process for the compounds of general formula (I) as
defined in claim 1 or 2, characterized in that a compound of
general formula (II): 29in which D and R.sub.2 are as defined in
claim 1, R.sub.7 represents one of the following groups: 30in which
n, Y, R.sub.3 and R.sub.4 are as defined in claim 1, P is a
protective group, Hal represents a halogen, is subjected to the
action of a halogenation reagent in order to obtain the compound of
formula (III): 31which is subjected to the action of an
aromatization reagent of ring A, then to the action of a base in
order to obtain the compound of formula (IV) corresponding to
certain compounds of general formula (I): 32which compounds of
formula (II), (III) or (IV) are subjected, if desired and if
necessary, in an appropriate order, to one or more of the following
reactions: protection of the compounds in which R.sub.7 is a
--Ph--YH group, deprotection of the compounds in which R.sub.7 is a
Ph--YP group, the action of a compound of formula
Hal.sub.1--(CH.sub.2).sub.n--Hal.sub.- 2 on the compounds in which
R.sub.7 is a --Ph--YH group, Hal.sub.1 or Hal.sub.2 identical or
different representing a halogen in order to obtain compounds in
which R.sub.7 is a --Ph--Y--(CH.sub.2).sub.n--Hal.sub- .2 group,
the action of a compound of formula R.sub.3--NH--R.sub.4 on the
compounds in which R.sub.7 is a Ph--Y--(CH.sub.2).sub.n--Hal.sub.2
group, in order to obtain compounds in which R.sub.7 is a
Ph--Y--(CH.sub.2).sub.n1'NR.sub.3R.sub.4 group, the action of a
halide salt (M--Hal.sub.3) on the compounds in which R.sub.7 is a
Ph--Y--(CH.sub.2).sub.n--Hal.sub.2 group in order to obtain the
compounds in which R.sub.7 is a
--Ph--Y--(CH.sub.2).sub.n1'Hal.sub.3 group, protection of the OH
group in position 3 or 17, deprotection of the OH group in position
3 or 17, alkylation of the OH group in position 3 or 17, acylation
of the OH group in position 3 or 17, the action of a reducing agent
when D represents the remainder of a pentagonal ring as defined in
claim 2 and R.sub.5 and R.sub.6 together form an oxo group, the
action of an organometallic on the compounds of formula (IV) with D
representing the remainder of a pentagonal ring as defined in claim
2 and R.sub.5 and R.sub.6 together forming an oxo group, the action
of a lactonization agent on the compounds of formula (IV) with D
representing the remainder of a pentagonal ring as defined in claim
2 and R.sub.5 and R.sub.6 forming together an oxo group, the action
of a reducing agent of the double bond, when D represents the
remainder of a pentagonal ring as defined in claim 2 and R.sub.5
and R.sub.6 form together with the carbon that carries them, an
O--(CH.sub.2).sub.n'--CH.dbd.CH-- group, the action of a reducing
agent of the double bond, when D represents the remainder of a
pentagonal ring as defined in claim 2, and R.sub.6 is an alkenyl or
alkynyl radical containing 2 to 6 carbon atoms, halogenation in
position 4, then aromatization of ring A, of the compound of
general formula (II), aromatization of ring A of the compound of
formula (III), salification.
9. Preparation process according to claim 8, for compounds of
general formula (I') as defined in claim 3, characterized in that a
compound of general formula (II'): 33in which R'.sub.5 and R'.sub.6
are as defined in claim 3, R'.sub.7 represents: 34is subjected to
the action of a halogenation reagent in order to obtain the
compound of formula (III'): 35which is subjected to the action of
an aromatization reagent of ring A, then to the action of a base in
order to obtain the-compound of formula (IV') corresponding to
certain compounds of general formula (I'): 36which compounds of
formula (II'), (III') or (IV') are subjected, if desired and if
necessary, in an appropriate order, to one or more of the following
reactions: protection of the compounds in which R'.sub.7 is a
--Ph--OH group, deprotection of the compounds in which R'.sub.7 is
a Ph--OP group, the action of a compound of formula
Hal.sub.1--(CH.sub.2).s- ub.n--Hal.sub.2 on the compounds in which
R'.sub.7 is a --Ph--OH group, Hal.sub.1 or Hal.sub.2 identical or
different, representing a halogen in order to obtain the compounds
in which R.sub.7 is a --Ph--O--(CH.sub.2).sub.n--Hal.sub.2 group,
the action of a compound of formula R'.sub.3--NH--R'.sub.4 on the
compounds in which R'.sub.7 is a Ph--O--(CH.sub.2).sub.n--Hal.sub.2
group, in order to obtain the compounds in which R'.sub.7 is a
Ph--O--(CH.sub.2).sub.n--NR'.sub.3R'.sub- .4 group, the action of a
halide salt (M--Hal.sub.3) on compounds in which R'.sub.7 is a
Ph--O--(CH.sub.2).sub.n13 Hal.sub.2 group in order to obtain the
compounds in which R.sub.7 is a --Ph--O--(CH.sub.2).sub.n13
--Hal.sub.3 group, protection of the OH group in position 3 or 17,
deprotection of the OH group in position 3 or 17, alkylation of the
OH group in position 17, acylation of the OH group in position 17,
the action of a reducing agent when R'.sub.5 and R'.sub.6 together
form an oxo group, the action of an organometallic on the compounds
of formula (IV') with R'.sub.5 and R'.sub.6 together forming an oxo
group, the action of a lactonization agent on the compounds of
formula (IV') with R'.sub.5 and R'.sub.6 together forming an oxo
group, the action of a reducing agent of the double bond, when
R'.sub.5 and R'.sub.6 form together with the carbon which carries
them, an O--(CH.sub.2).sub.1--CH.d- bd.CH-- group, the action of a
reducing agent of the double bond, when R'.sub.6 is an alkenyl or
alkynyl radical containing 2 to 6 carbon atoms, halogenation in
position 4, then aromatization of ring A, of the compound of
formula (II'), aromatization of the compound of formula (III'),
salification.
10. As medicaments the compounds of formula (I) as defined in claim
1, as well as their addition salts with pharmaceutically acceptable
acids.
11. As medicaments the compounds of formula (I) or (I') as defined
in any one of claims 2 to 5, as well as their addition salts with
pharmaceutically acceptable acids.
12. As medicaments the compounds as defined in claim 6 or 7, as
well as their addition salts with pharmaceutically acceptable
acids.
13. The pharmaceutical compositions containing one or more of the
medicaments as defined in any one of claims 10, 11 or 12.
14. As new intermediate products, the compounds of general formula
(III), (III'), (IV) or (IV') as defined in claim 8 or 9.
Description
[0001] The present invention relates to 4-halogenated steroid
compounds, their preparation process, their use as medicaments and
the pharmaceutical compositions containing them.
[0002] Osteoporosis is a pathology which is characterized by a
quantitative and qualitative reduction in bone matter, sufficient
to lead to vertebral or peripheral fractures, in a spontaneous
fashion or on occasions due to minimal traumas. Although this
illness has many factors at its origin, it is the menopause which
in women constitutes the dominating factor in bone loss or
osteopenia.
[0003] This osteopenia manifests itself by a rarefaction and
modification of the architecture of the spongy bone, the
consequence of which is to increase the fragility of the skeleton
and the risk of fractures. Bone loss increases strongly after the
menopause due to the suppression of ovarian function and reaches 3
to 5% per year before slowing down after 65 years old.
[0004] For a therapeutic purpose, the post-menopause hormonal
deficiency can be compensated for by a hormone replacement therapy
where oestrogen plays a major role in preserving the bone mass. But
long-term oestrogenotherapy is sometimes accompanied by undesirable
effects on the genital apparatus (endometrial hyperplasia, breast
tumors . . . ), which constitutes a major drawback and limits its
use.
[0005] It is therefore convenient to find compounds other than
oestradiol having a dissociated oestrogen activity, namely an
oestrogen activity at the bone level, while having no or little
endometrial hyperplasia activity, nor breast tumor proliferation
activity.
[0006] Therefore, a subject of the invention is the compounds of
general formula (I): 2
[0007] in which:
[0008] R.sub.1 represents a hydrogen atom, a (CH.sub.2).sub.m--Ar,
(CO)--Ar, (CH.sub.2).sub.m--Alk or (CO)--Alk radical,
[0009] R.sub.2 represents a radical derived from a linear or
branched, saturated or unsaturated hydrocarbon containing 1 to 6
carbon atoms
[0010] D represents the remainder of a pentagonal or hexagonal ring
optionally substituted and optionally carrying an unsaturation,
[0011] X represents a halogen atom,
[0012] Y is chosen from O, S, SO, SO.sub.2 and NH,
[0013] n is an integer varying from 2 to 8,
[0014] either R.sub.3 and R.sub.4, identical or different,
represent a hydrogen atom, a (CH.sub.2).sub.m--Ar,
(CH.sub.2).sub.m--Het or (CH.sub.2).sub.mAlk group,
[0015] or R.sub.3 and R.sub.4 form together with the atom of
nitrogen to which they are linked an aromatic or non-aromatic,
saturated or unsaturated mono- or polycyclic heterocycle with 3 to
15 members optionally containing 1 to 3 additional heteroatoms
chosen from oxygen, sulphur and nitrogen, non-substituted or
substituted,
[0016] Ar representing a carbocyclic aryl group containing 6 to 18
carbon atoms, Het representing a radical derived from a saturated
or unsaturated aromatic or non-aromatic heterocycle containing 1 to
9 carbon atoms and 1 to 5 heteroatoms chosen from oxygen, nitrogen
or sulphur atoms, Alk representing a radical derived from a
saturated or unsaturated, linear, branched or cyclic, non-aromatic
hydrocarbon and containing 1 to 12 carbon atoms, the Ar, Het or Alk
radicals being able to be substituted or non-substituted, m
represents 0, 1, 2 or 3, as well as their addition salts with bases
or acids.
[0017] By halogen is meant: iodine, bromine, chlorine or
fluorine.
[0018] By (CH.sub.2).sub.m is meant the following values: single
bond in the case where m is equal to 0, CH.sub.2, (CH.sub.2).sub.2
and (CH.sub.2).sub.3.
[0019] By the term Ar representing the carbocyclic aryl group
containing 6 to 18 carbon atoms, is meant a derivative of an
aromatic cyclic hydrocarbon such as the phenyl, naphthyl,
phenanthrenyl radical or a derivative of a condensed, bicyclic or
tricyclic hydrocarbon containing a benzene ring such as indanyl,
indenyl, dihydronaphthyl, tetrahydronaphthyl or fluorenyl. The
junction is carried out at the level of the benzene ring.
Preferably it is phenyl.
[0020] By the term (Het) representing a radical derived from a
saturated or unsaturated, aromatic or non aromatic heterocycle
containing 1 to 9 carbon atoms and 1 to 5 heteroatoms chosen from
oxygen, nitrogen and sulphur atoms, the following are designated in
particular:
[0021] heterocyclic monocyclic radicals, for example thienyl,
furyl, pyrannyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl,
furazannyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl,
triazolyl, tetrazolyl radicals,
[0022] condensed heterocyclic rings, for example benzofuranyl,
benzothienyl, benzimidazolyl, benzothiazolyl, naphtho[2,3-b]
thienyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl,
phenoxathiinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl,
indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl,
phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,
cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, acridinyl,
phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl,
imidazopyridyl, imidazopyrimidinyl or also condensed polycyclic
systems constituted by heterocyclic moncyclics as defined above
such as for example furo[2,3-b]pyrrole or thieno[2,3-b] furan,
[0023] or saturated heterocycles such as pyrrolidine, piperidine,
morpholine.
[0024] By the term (Alk) representing a radical derived from a
saturated or unsaturated, linear, branched or cyclic non-aromatic
hydrocarbon, is designated in the case of acyclic hydrocarbons the
alkyl radicals such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, tert-butyl, n-pentyl, n-hexyl, 2-methyl pentyl,
2,3-dimethyl butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl,
3,3-dimethyl pentyl, 3-ethylpentyl, n-octyl, 2,2-dimethylhexyl,
3,3-dimethylhexyl, 3-methyl-3-ethylpentyl, nonyl,
2,4-dimethylheptyl or n-decyl, the alkenyl radicals such as vinyl,
propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl,
or the alkynyl radicals such as ethynyl, propynyl, propargyl,
butynyl or isobutynyl, and in the case of cyclic radicals, the
cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl
or cyclohexyl.
[0025] It will preferably be methyl and ethyl radicals. By CO-- Alk
is preferably meant COCH.sub.3 and COET, by CO--Ar is preferably
meant the benzoyl radical, when m is different from zero,
(CH.sub.2).sub.m--Ar will preferably be the benzyl group.
[0026] When R.sub.3 and R.sub.4 form together with the nitrogen
atom to which they are linked a heterocycle, it is in particular
mono- or bicyclic heterocycles optionally containing another
heteroatom chosen from oxygen and nitrogen such as the following
unsaturated heterocycles: pyrrolyl, imidazolyl, indolyl, pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl,
furazolinyl, pyrazolinyl, thiazolinyl, or, more particularly, the
following saturated heterocycles: 3
[0027] When the different Alk, Ar, Het groups, as well as the
remainder of a pentagonal or hexagonal ring mentioned above, are
substituted, they can in particular be substituted by the following
radicals:
[0028] halogen, namely fluorine, chlorine, bromine or iodine,
alkoxy such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy,
alkylthio such as methylthio, ethylthio, propylthio, isopropylthio,
butylthio, amino, alkylamino such as methylamino or ethylamino,
dialkylamino such as dimethylamino, diethylamino, methylethylamino,
each of these dialkylamino radicals being optionally in oxidized
form, aminoalkyl such as aminomethyl or aminoethyl,
dialkylaminoalkyl such as dimethylamino methyl or ethyl,
dialkylaminoalkyloxy such as dimethylamino ethyloxy, hydroxyl
optionally acylated, acyl such as acetyl, propionyl, butyryl,
benzoyl, free, esterified carboxy such as alkoxy carbonyl for
example methoxy carbonyl or ethoxy carbonyl, cyano,
trifluoromethyl, aryl such as phenyl, aralkyl such as benzyl,
alkyl, alkenyl or alkynyl these radicals being themselves
optionally substituted by the halogen, alkyl, alkoxy, alkylthio,
aminoalkyl or dialkylamino radicals indicated above.
[0029] Of course, the expression "substituted" indicates that one
or more identical or different substituents can be present. In the
case of (Het), the substituents can be at the level of the NH or
carbon atom.
[0030] Of course the values of R.sub.1, R.sub.2, R.sub.3 and
R.sub.4, are independent of each other.
[0031] The invention naturally extends to the salts of the
compounds of formula (I), such as for example the salts formed with
mineral or organic acids on the amine. It can then be one of the
following acids: hydrochloric, hydrobromic, nitric, sulphuric,
phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric,
succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkane
sulphonics such as methane or ethane sulphonics, arylsulphonics,
such as benzene or paratoluene sulphonics and arylcarboxylics. When
the compounds of formula (I) contain an acid function, the
invention extends to the salts of alkali metals, alkaline earth or
ammonium, optionally substituted.
[0032] A more particular subject of the invention is the compounds
of general formula (I) as defined above in which (D) represents the
remainder of a pentagonal ring of formula: 4
[0033] in which R.sub.2 retains the same meaning as previously,
either R.sub.5 represents an OH, O--(CH.sub.2).sub.m--Alk,
O--(CO)--Alk, O--(CH.sub.2).sub.m--Ar, O--(CO)--Ar,
O--(CH.sub.2).sub.m--Het, O--(CO)--Het radical and R.sub.6
represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical
containing 1 to 6 carbon atoms substituted or non substituted, m,
Alk, Ar and Het being as defined previously, or R.sub.5 and R.sub.6
form together with the carbon atom which carries them one of the
following rings: 5
[0034] in which Z represents a --(CH.sub.2).sub.1-- or
--CH.dbd.CH--(CH.sub.2).sub.1' group; 1 being an integer comprised
between 1 and 4 and 1' being an integer equal to 1 or 2,
[0035] or R.sub.5 and R.sub.6 form together an oxo group, as well
as their addition salts with acids or bases.
[0036] A quite particular subject of the invention is the compounds
of formula (I) as defined previously corresponding to general
formula (I'): 6
[0037] in which:
[0038] X' represents a chlorine or bromine atom
[0039] n' is comprised between 2 and 5,
[0040] either R'.sub.3 and R'.sub.4, identical or different,
represent an alkyl radical containing 1 to 6 carbon atoms
[0041] or R'.sub.3 and R'.sub.4 form together with the nitrogen
atom to which they are linked, a saturated mono- or polycyclic
remainder with 3 to 15 members optionally containing an additional
heteroatom chosen from oxygen, sulphur and nitrogen,
[0042] R'.sub.5 and R'.sub.6 have the same meaning as R.sub.5 and
R.sub.6, as well as their addition salts with acids and bases.
[0043] A quite particular subject of the invention is the compounds
of formula (I) as defined previously corresponding to general
formula (I') in which:
[0044] either R'.sub.5 represents an OH radical and R'.sub.6
represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical
containing 1 to 6 carbon atoms, substituted or non-substituted,
[0045] or R'.sub.5 and R'.sub.6 form together with the carbon atom
that carries them one of the following rings: 7
[0046] or R'.sub.5 and R'.sub.6 form together an oxo group, as well
as their addition salts with acids or bases.
[0047] A quite particular subject of the invention is the compounds
of formula (I) corresponding to general formula (I') as defined
previously in which:
[0048] X' represents a chlorine atom
[0049] n' is equal to 2,
[0050] either R'.sub.3 and R'.sub.4, identical or different,
represent an alkyl radical containing 1 to 6 carbon atoms
[0051] or R'.sub.3 and R'.sub.4 form together with the nitrogen
atom the following saturated heterocycles: 8
[0052] and either R'.sub.5 represents an OH radical and R'.sub.6
represents a hydrogen atom, an alkyl, alkenyl or alkynyl radical
containing 1 to 6 carbon atoms, substituted or non substituted,
[0053] or R'.sub.5 and R'.sub.6 form together with the carbon atom
which carries them one of the following rings: 9
[0054] or R'.sub.5 and R'.sub.6 form together an oxo group, as well
as their addition salts with acids or bases.
[0055] A quite particular subject of the invention is the compounds
of formula (I) as well as their addition salts with acids the names
of which follow:
[0056]
4-chloro-3-hydroxy-11.beta.-[4-[2-(diethylamino)ethoxy]phenyl]-estr-
a-1,3,5(10)-trien-17-one,
[0057]
4-chloro-3-hydroxy-11.beta.-[4-[2-(dimethylamino)ethoxy]phenyl]-est-
ra-1,3,5(10)-trien-17-one,
[0058]
4-chloro-3-hydroxy-11.beta.-[4-[2-(1-piperidinyl)ethoxy]phenyl]-est-
ra-1,3,5(10)-trien-17-one,
[0059]
4-chloro-3-hydroxy-11.beta.-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-es-
tra-1,3,5(10)-trien-17-one,
[0060]
4-bromo-3-hydroxy-11.beta.-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estr-
a-1,3,5(10)-trien-17-one,
[0061]
4-chloro-11.beta.-[4-[2-(dimethylamino)ethoxy]phenyl]-estra-1,3,5(1-
0)-triene-3,17beta-diol,
[0062]
4-chloro-11.beta.-[4-[2-(diethylamino)ethoxy]phenyl]-estra-1,3,5(10-
)-triene-3,17beta-diol,
[0063]
4-chloro-11.beta.-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(1-
0)-triene-3,17beta-diol,
[0064]
4-bromo-11.beta.-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10-
)-triene-3,17beta-diol,
[0065]
4-chloro-11.beta.-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-estra-1,3,5(-
10)-triene-3,17beta-diol,
[0066]
4-chloro-11.beta.-[4-[2-(diethylamino)ethoxy]phenyl]-19-nor-17alpha-
-pregna-1,3,5(10)-triene-20-yne-3,17beta-diol,
[0067]
4-chloro-11.beta.-[4-[3-(1-piperidinyl)propoxy]phenyl]-estra-1,3,5(-
10)-triene-3,7beta-diol,
[0068]
4-chloro-11.beta.-[4-[4-(1-piperidinyl)butoxy]phenyl]-estra-1,3,5(1-
0)-triene-3,17beta-diol,
[0069]
4-chloro-11.beta.-[4-[5-(1-piperidinyl)pentyloxy]phenyl]-estra-1,3,-
5 (10)-triene-3,17beta-diol,
[0070] gamma lactone of
(17alpha)-4-chloro-3,17beta-dihydroxy-11.beta.-[4--
[2-(diethylamino)ethoxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxyl-
ic acid,
[0071] gamma lactone of
(17alpha)-4-chloro-3,17beta-dihydroxy-11.beta.-[4--
[2-(1-pyrrolindinyl)ethoxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carbo-
xylic acid,
[0072] gamma lactone of
(17alpha)-4-chloro-3,17beta-dihydroxy-11.beta.-[4--
[2-(1-piperidinyl)ethoxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxy-
lic acid,
[0073] gamma lactone of
(17alpha)-4-chloro-3,17beta-dihydroxy-11.beta.-[4--
[3-(1-piperidinyl)propoxylphenyl]-19-nor-pregna-1,3,5(10)-triene-21-carbox-
ylic acid,
[0074] gamma lactone of
(17alpha)-4-chloro-3,17beta-dihydroxy-11.beta.-[4--
[4-(1-piperidinyl)butoxy]phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxy-
lic acid,
[0075] gamma lactone of
(17alpha)-4-chloro-3,17beta-dihydroxy-11.beta.-[4--
[5-(1-piperidinyl)pentyloxy]phenyl]-19-nor-pregna-1,3,5
(10)-triene-21-carboxylic acid,
[0076]
(17beta)-4-chloro-11.beta.-[4-[2-(diethylamino)ethoxy]phenyl]-spiro-
[estra-1,3,5(10)-triene-17,2'(5'H)furan]-3-ol,
[0077]
(17beta)-4-chloro-11-[4-[2-(1-piperidinyl)ethoxy]phenyl]-spiro[estr-
a-1,3,5(10)-triene-17,2'(5'H) furan]-3-ol,
[0078]
(17beta)-4-chloro-113-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-spiro[es-
tra-1,3,5(10)-triene-17,2'(5'H)furan]-3-ol,
[0079] (17beta)-4-chloro-4',5'-dihydro-113-[4-[2-(l-piperidinyl)
ethoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2'(3'H)furan]-3-ol,
[0080]
(17beta)-4-chloro-11.beta.-[4-t3-(1-piperidinyl)propoxy]phenyl]-spi-
ro[estra-1,3,5(10)-triene-17,2'(5'H)furan]-3-ol,
[0081]
(17beta)-4-chloro-4',5'-dihydro-11.beta.-[4-[3-(1-piperidinyl)
propoxy]phenyl]-spiro[estra-1,3,5(10)-triene-17,2'(3'H)
furan]-3-ol,
[0082]
(17beta)-4-chloro-11.beta.-[4-[4-(1-piperidinyl)butoxy]phenyl]-spir-
o[estra-1,3,5(10)-triene-17,2'(5'H)furan]-3-ol,
[0083]
(17beta)-4-chloro-4',5'-dihydro-11B-[4-[4-(1-piperidinyl)-butoxy]ph-
enyl]-spiro[estra-1,3,5(10)-triene-17,2'(3'H)furan]-3-ol,
[0084]
4-chloro-11.beta.-[4-[2-(diethylamino)ethoxy]phenyl]-17alpha-methyl-
-estra-1,3,5(10)-triene-3,17beta-diol,
[0085]
4-chloro-17alpha-methyl-11.beta.-[4-[2-(1-piperidinyl)ethoxy]
phenyl]-estra-1,3,5(10)-triene-3,17beta-diol,
[0086] Quite particularly a subject of the invention is also the
compound of formula (I) as defined above, the name of which
follows:
[0087]
4-chloro-11.beta.-[4-[2-(diethylamino)ethoxy]phenyl]-estra-1,3,5
(10)-triene-3,17beta-diol, as well as its addition salts with
acids.
[0088] A subject of the invention is also a preparation process for
the compounds of general formula (I) as defined previously,
characterized in that a compound of general formula (II): 10
[0089] in which D and R.sub.2 are as defined previously, R.sub.7
represents one of the following groups: 11
[0090] in which n, Y, R.sub.3 and R.sub.4 are as defined
previously, P is a protective group, Hal represents a halogen,
[0091] is subjected to the action of a halogenation reagent in
order to obtain the compound of formula (III): 12
[0092] which is subjected to the action of an aromatization reagent
of ring A, then to the action of a base in order to obtain the
compound of formula (IV) corresponding to certain compounds of
general formula (I): 13
[0093] which compounds of formula (II), (III) or (IV) are
subjected, if desired and if necessary, in an appropriate order, to
one or more of the following reactions:
[0094] protection of the compounds in which R.sub.7 is a --Ph--YH
group,
[0095] deprotection of the compounds in which R.sub.7 is a Ph--YP
group,
[0096] the action of a compound of formula
Hal.sub.1--(CH.sub.2).sub.n--Ha- l.sub.2 on the compounds in which
R.sub.7 is a --Ph--YH group, Hal.sub.1 or Hal.sub.2 identical or
different representing a halogen in order to obtain compounds in
which R.sub.7 is a --Ph--Y--(CH.sub.2).sub.n--Hal.sub- .2
group,
[0097] the action of a compound of formula R.sub.3--NH--R.sub.4 on
the compounds in which R.sub.7 is a Ph--Y--(CH.sub.2).sub.n--Hal2
group, in order to obtain compounds in which R.sub.7 is a
Ph--Y--(CH.sub.2).sub.n--- NR.sub.3R.sub.4 group,
[0098] the action of a halide salt (M--Hal.sub.3) on the compounds
in which R.sub.7 is a Ph--Y--(CH.sub.2).sub.n--Hal.sub.2 group in
order to obtain the compounds in which R.sub.7 is a
--Ph--Y--(CH.sub.2).sub.n--Hal- .sub.3 group,
[0099] protection of the OH group in position 3 or 17,
[0100] deprotection of the OH group in position 3 or 17,
[0101] alkylation of the OH group in position 3 or 17,
[0102] acylation of the OH group in position 3 or 17,
[0103] the action of a reducing agent when D represents the
remainder of a pentagonal ring as defined previously and R.sub.5
and R.sub.6 together form an oxo group,
[0104] the action of an organometallic on the compounds of formula
(IV) with D representing the remainder of a pentagonal ring as
defined previously and R.sub.5 and R.sub.6 together forming an oxo
group,
[0105] the action of a lactonization agent on the compounds of
formula (IV) with D representing the remainder of a pentagonal ring
as defined previously and R.sub.5 and R.sub.6 forming together an
oxo group,
[0106] the action of a reducing agent of the double bond, when D
represents the remainder of a pentagonal ring as defined previously
and R.sub.5 and R.sub.6 form together with the carbon that carries
them, an O--(CH.sub.2).sub.n'--CH.dbd.CH-- group,
[0107] the action of a reducing agent of the double bond, when D
represents the remainder of a pentagonal ring as defined
previously, and R.sub.6 is an alkenyl or alkynyl radical containing
2 to 6 carbon atoms,
[0108] halogenation in position 4, then aromatization of ring A, of
the compound of general formula (II),
[0109] aromatization of ring A of the compound of formula
(III),
[0110] salification.
[0111] The action of a halogenation reagent such as
N-bromosuccinimide or N-chlorosuccinimide on the compounds of
formula (II) is carried out in particular in the presence of a
dipolar aprotic solvent such as dimethylformamide.
[0112] The aromatization reaction followed by the saponification
reaction (action of the base) is carried out according to standard
methods as described in the European Patent 0097572. A mixture of
acetic anhydride and acetyl bromide is preferably used as the
aromatization agent then a base such as soda in methanol as the
saponification agent.
[0113] The protection and deprotection reactions are standard
methods known to a person skilled in the art. A fairly complete
review is found in the following work: Protective groups in organic
synthesis T. W Greene, John Wiley & Sons (1981).
[0114] The protective group P preferably represents an alkyl
radical containing 1 to 4 carbon atoms, a benzyl group, an
R.sub.CR.sub.DR.sub.ESi group, in which R.sub.C, R.sub.D and
R.sub.E, identical or different, independently of each other each
represent an alkyl radical containing 1 to 4 carbon atoms or a
phenyl group. Quite particularly it is the Si(Me).sub.2CMe.sub.3 or
--Si(Ph).sub.2CMe.sub.3 groups.
[0115] As an example, the deprotection reactions of the compounds
of formula (II), (III) or (IV) with R.sub.7.dbd.Ph--OP or the
compounds of formula (IV) the 3--OH of which is protected (3-OP),
when P is a methyl radical, can be carried out by the action of
tribromoborane in dichloromethane or hydrochloric acid in pyridine,
the deprotection reactions when P is a benzyl group can be carried
out by the action of hydrogen in the presence of palladium on
carbon in ethyl acetate or by the action of trifluoroacetic acid,
the deprotection reactions when P is a tertbutyldiphenylsilyl group
can be carried out by the action of tetrabutyl ammonium fluoride in
solution in tetrahydrofuran.
[0116] When P is a tetrahydropyrannyl group, the deprotection is
carried out in the presence of an aqueous acid in an alcoholic
solvent and preferably by the action of hydrochloric acid in
methanol.
[0117] The action of a compound of formula
Hal.sub.1--(CH.sub.2).sub.n--Ha- l.sub.2 on a compound of formula
(II), (III) or (IV) in which R.sub.7.dbd.Ph--YH can be carried out,
in particular when Y.dbd.O, in the presence of a base in a solvent
such as acetone.
[0118] The action of a compound of formula R.sub.3--NH--R.sub.4 on
the compounds in which R.sub.7 is a
Ph--Y--(CH.sub.2).sub.n--Hal.sub.2 group is carried out under
standard conditions for the substitution of nucleophiles, in
particular in the presence of an aprotic solvent such as
tetrahydrofuran.
[0119] The substitution reaction of a halogen by another when in
particular R.sub.7 is a Ph--Y--(CH.sub.2).sub.n--Cl group is
preferably carried out by the action of NaI in
methyl-ethylketone.
[0120] The alkylation or acylation reactions of the OH group in
position 3 or 17 are carried out by standard methods known to a
person skilled in the art.
[0121] The reduction of 17-keto into the corresponding alcohol
(R.sub.5.dbd.OH and R.sub.6.dbd.H) is carried out according to
standard methods, in particular by the action of an alkaline
borohydride such as sodium borohydride in methanol or ethanol or by
the action of aluminium and lithium tetrahydride.
[0122] The action of an organometallic on 17-keto allows access to
the products of formula (IV) in which D represents the remainder of
a pentagonal ring as defined previously, R.sub.5 is a hydroxyl and
R.sub.6 represents an optionally substituted alkyl, alkenyl,
alkynyl radical.
[0123] The organometallic derivative of an alkyl, alkenyl or
alkynyl is chosen from the magnesium compounds of formula AlkMgHal
and the lithium compounds of formula AlkLi in which Alk represents
an alkyl, alkenyl or alkynyl group containing at most 8 carbon
atoms, Hal represents a halogen atom. In a preferred method of
implementing the process, Hal represents a chlorine, bromine or
iodine atom, preferably bromine. The reaction preferably takes
place in the presence of cerium chloride. In a preferred method for
implementing the process, Hal represents a chlorine, bromine or
iodine atom, preferably bromine.
[0124] The lactonization reaction from 17 keto is carried out
according to the method of STURTZ (ref: G. STURTZ and J-J. YAOUANC,
Synthesis, (1980), 289) in particular in the presence of alkyl
bisdimethylamidophosphate in the presence of an alkyllithium
compound such as n-butyllithium in tetrahydrofuran.
[0125] The total or partial reduction reaction when R.sub.6 is an
alkenyl or alkynyl or when R.sub.5 and R.sub.6 form together with
the carbon that carried them an O--(CH.sub.2).sub.m'--CH.dbd.CH--
group, can be carried out either in a total manner by the action of
hydrogen in the presence of a catalyst such as palladium on carbon
or a rhodium catalyst such as Wilkinson's reagent or in a partial
manner (alkynyl becomes alkenyl) by the action of a poisoned
catalyst such as palladium on barium sulphate poisoned with
pyridine or triethylamine.
[0126] The esterification and salification reactions are carried
out by current methods known to a person skilled in the art.
[0127] A more particular subject of the invention is a preparation
process for the compounds of general formula (I') as described
previously characterized in that a compound of general formula
compound (II'): 14
[0128] in which R'.sub.5 and R'.sub.6 are as defined previously,
R'.sub.7 represents: 15
[0129] is subjected to the action of a halogenation reagent in
order to obtain the compound of formula (III'): 16
[0130] which is subjected to the action of an aromatization reagent
of ring A, then to the action of a base in order to obtain the
compound of formula (IV') corresponding to certain compounds of
general formula (I'): 17
[0131] which compounds of formula (II'), (III') or (IV'), are
subjected, if desired and if necessary, in an appropriate order, to
one or more of the following reactions:
[0132] protection of the compounds in which R'.sub.7 is a --Ph--OH
group,
[0133] deprotection of the compounds in which R'.sub.7 is a Ph--OP
group,
[0134] the action of a compound of formula
Hal.sub.1--(CH.sub.2).sub.n--Ha- l.sub.2 on the compounds in which
R'.sub.7 is a --Ph--OH group, Hal.sub.1 or Hal.sub.2, identical or
different, representing a halogen in order to obtain the compounds
in which R.sub.7 is a --Ph--O--(CH.sub.2).sub.n--Hal- .sub.2
group,
[0135] the action of a compound of formula R'.sub.3--NH--R'.sub.4
on the compounds in which R'.sub.7 is a
Ph--O--(CH.sub.2)n--Hal.sub.2 group, in order to obtain the
compounds in which R'.sub.7 is a
Ph--O--(CH.sub.2)n--NR'.sub.3R'.sub.4 group,
[0136] the action of a halide salt (M--Hal.sub.3) on compounds in
which R'.sub.7 is a Ph--O--(CH.sub.2).sub.n--Hal.sub.2 group in
order to obtain the compounds in which R.sub.7 is a
--Ph--O--(CH.sub.2)n--Hal.sub.3 group,
[0137] protection of the OH group in position 3 or 17,
[0138] deprotection of the OH group in position 3 or 17,
[0139] alkylation of the OH group in position 17,
[0140] acylation of the OH group in position 17,
[0141] the action of a reducing agent when R'.sub.5 and R'.sub.6
together form an oxo group,
[0142] the action of an organometallic on the compounds of formula
(IV') with R'.sub.5 and R'.sub.6 together forming an oxo group,
[0143] the action of a lactonization agent on the compounds of
formula (IV') with R'.sub.5 and R'.sub.6 together forming an oxo
group,
[0144] the action of a reducing agent of the double bond, when
R'.sub.5 and R'.sub.6 form together with the carbon which carries
them, an O--(CH.sub.2).sub.1--CH.dbd.CH-- group,
[0145] the action of a reducing agent of the double bond, when
R'.sub.6 is an alkenyl or alkynyl radical containing 2 to 6 carbon
atoms,
[0146] halogenation in position 4, then aromatization of ring A, of
the compound of formula (II'),
[0147] aromatization of the compound of formula (III'),
[0148] salification.
[0149] The compounds of general formula (I) as well as their
addition salts with pharmaceutically acceptable acids have
oestrogen, anti-oestrogen and anti-proliferative activities.
[0150] Therefore the compounds of formula (I) can be used in the
treatment of disorders linked to hypofolliculinia, for example,
amenorrheas, dysmenorrheas, repeated abortions, premenstrual
disorders, in the treatment of certain oestrogen-dependent
pathologies such as prostatic adenomas or carcinomas, mammary
carcinomas and their metastases or in the treatment of benign
breast tumors, as an anti-uterotrophic as well as in the
replacement treatment for the menopause or the perimenopause.
[0151] Among the symptoms and consequences linked to the menopause
are more specifically meant hot flushes, sweats, vaginal atrophy
and dryness, urinary symptoms and in the long term a reduction in
bone mass and an increased risk of fractures, and the loss of the
cardiovascular protection provided by the oestrogens.
[0152] In particular, the compounds of formula (I) and their
addition salts with pharmaceutically acceptable acids or bases can
be used in the prevention or the treatment of osteoporosis.
[0153] The compounds of formula (I) and their addition salts with
pharmaceutically acceptable acids can also be used for the
prevention or the treatment of osteoporosis in man.
[0154] They can also be used for the prevention or the treatment of
secondary osteoporoses (for example cortisonal, linked with
immobilization).
[0155] The compounds of formula (I) and their addition salts with
pharmaceutically acceptable acids or bases in particular have a
dissociated oestrogenic activity.
[0156] By dissociated oestrogenic activity is meant an oestrogenic
activity at bone level while demonstrating only minimal activity at
uterine level, thus not entailing an endometrial proliferation
(much lower activity than that of oestradiol).
[0157] Furthermore, the compounds according to the invention have
the following advantages:
[0158] They have an anti-oestrogenic activity at the level of the
breast. Unlike oestradiol, they do not stimulate the growth of
human mammary tumor cells and can even inhibit their growth. The
compounds according to the invention are therefore particularly
advantageous for the treatment of the menopause in women at risk
from breast cancer (family antecedents) who are therefore excluded
from a replacement treatment using oestradiol.
[0159] They can also be used in the treatment of breast
cancers.
[0160] They lead to a lowering of the seric cholesterol level to a
level equivalent to that induced by oestradiol. Therefore, they
strengthen cardiovascular protection.
[0161] Finally, as the compounds according to the invention have no
oestrogen activity at the uterine level, they do not require to be
administered in combination with a progestomimetic compound.
[0162] A subject of the invention is thus compounds of general
formula (I) as well as their addition salts with pharmaceutically
acceptable acids or bases, as medicaments.
[0163] A more particular subject of the invention is compounds of
formula (I) and their addition salts with pharmaceutically
acceptable acids or bases as medicaments used for the prevention or
the treatment of osteoporosis.
[0164] The invention extends to the pharmaceutical compositions
containing at least one of the medicaments defined above as active
ingredient.
[0165] The compounds of formula (I) are used by digestive,
parenteral or local route, for exemple by percutaneous route. They
may be prescribed in the form of plain or coated tablets, capsules,
granules, suppositories, pessaries, injectable preparations,
ointments, creams, gels, microspheres, implants, intravaginal
rings, patches, which are prepared according to the usual
methods.
[0166] The active ingredient or ingredients can be incorporated
with-excipients usually employed in these pharmaceutical
compositions, such as talc, gum arabic, lactose, starch, magnesium
stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty
substances of animal or vegetable origin, paraffin derivatives,
glycols, various wetting, dispersing or emulsifying agents,
preservatives.
[0167] The useful dose varies as a function of the illness to be
treated and the administration route; it can vary for example from
1 to 1000 mg per day for an adult by oral route.
[0168] Patent 0057115.
[0169] The compounds of general formula (II) or (II') with 18
[0170] can also be formed from the compounds of formula (IIa):
19
[0171] or (II'a): 20
[0172] in which D, R.sub.2, R'.sub.5 and R'.sub.6 are as defined
previously and K represents a protective group of the ketone
function, which is subjected to the action of an O-alkylation
reagent of formula Hal--(CH.sub.2).sub.n--Hal then to the action of
a dehydration reagent which is equally capable of releasing the
ketone.
[0173] The compounds of formula (IIa) or (II'a) are also known
compounds and described in the following patent:
[0174] U.S. Pat. No. 5 043 332.
[0175] A subject of the invention is also, as intermediate
products, the compounds of formulae (III), (III'), (IV) and
(Iv').
[0176] The examples below illustrate the invention without however
limiting it.
[0177] Solvents described in the examples: AcOEt (ethyl acetate),
TEA (triethylamine), CH.sub.2Cl.sub.2 (dichloromethane), CHCl.sub.3
(chloroform), MeOH (methanol), NH.sub.4OH (ammonium hydroxide),
iPrOH (isopropyl alcohol).
EXAMPLE 1
4-chloro-3-hydroxy-11beta-[4-[2-(1-piperidinyl)
ethoxy]phenyl]-estra-1,3,5 (10)-trien-17-one
[0178] Stage A: 11beta-[4-(2-bromoethoxy)
phenyl]-estra-4,9-diene-3,17-dio- ne
[0179] a) O-alkylation
[0180] 8.0 g of
5.alpha.-hydroxy-11.beta.-(4-hydroxy-phenyl)-estr-9-en-3,1- 7-dione
cyclic 3-(1,2-ethanediyl acetal) is dissolved under an inert
atmosphere in 80 ml of 99% 1,2-dibromomethane, 21 ml of 50% soda,
0.800 g of tetrabutyl ammonium bromide, and agitation is carried
out under reflux for 1 hour.
[0181] b) acid hydrolysis
[0182] 93 ml of 6M hydrochloric acid is added at ambient
temperature, agitation is carried out for 45 minutes, followed by
extraction, washing, drying and evaporating under pressure reduced
until the crude product is obtained (m = 13.17 g) which is
recrystallized from a 50 ml of dichloromethane/50 ml of isopropyl
ether mixture. 5.96 9 + 7.0 g of pure expected product is obtained
(Rf CH.sub.2Cl.sub.2/ACOET 70/ 0=0.45). M.p.=208.degree. C.
[0183] IR (CHCl.sub.3)
[0184] 1735 cm .sup.-1: 17 keto; 1658 and 1609 cm.sup.-1:
conjugated ketone; 1583 and 1509: aromatic.
[0185] Stage B: 11beta-[4-(2-bromoethoxy)
phenyl]-4-chloro-estra-4,9-diene- -3,17-dione (introduction of cl
in position 4)
[0186] 1.86 g of N-chlorosuccinimide is added to a solution, under
inert atmosphere, at 60.degree. C., of 5.025 g of the product
obtained in Stage A, in 67 ml of dimethylformamide and agitation is
carried out for 10 minutes. Salt water is added, followed by
extraction, drying and evaporating under reduced pressure until the
crude product is obtained (m= 8.149 g) which is purified by
chromatography on silica eluting with a cyclohexane/ethyl acetate
mixture (60/40), 5.43 g of pure expected product is obtained (Rf
essence G/AcOEt 60/40=0.35).
[0187] IR (CHCl.sub.3)
[0188] 1736 cm.sup.-1: 17-keto; 1677 cm.sup.-1: conjugated ketone;
1609, 1582, 1550 and 1509 cm.sup.-1:C.dbd.C and aromatic.
[0189] Staqe C: 11beta-[4-(2-bromoethoxy)
phenyl]-4-chloro-3-hydroxy-estra- -1,3,5,(10)triene-17-one
[0190] a) Aromatization
[0191] 4.7 ml of acetic anhydride and 4.7 ml of acetyl bromide is
added, under an inert atmosphere, at ambient temperature to 4.7 g
of the product obtained in Stage B in 50 ml of
dichloromethane/siliporite, while cooling the reaction medium down
and agitation is carried out for 5 hours 30 minutes.
[0192] b) Saponification of the phenolic acetate
[0193] After the dichloromethane is evaporated off under under
reduced pressure and at ambient temperature, 47 ml of
tetrahydrofuran is added under an inert atmosphere while cooling
down the reaction medium, the 47 ml of methanol then 47 ml of soda
are added, agitation is carried out for 1 hour at ambient
temperature. After acidification with hydrochloric acid, extraction
is carried out followed by washing, drying and evaporating under
pressure reduced until the crude product is obtained (m=4.84 g)
which is purified by chromatography on silica eluting with a
cyclohexane/ethyl acetate mixture (70/30). 4.37 g of expected
product is obtained (Rf=essence G/ACOET 70/30=0.18).
[0194] IR (CHCl.sub.3)
[0195] 3537 cm.sup.-1: phenolic-OH; 1733 cm.sup.-1: 17-keto; 1609,
1580, 1511 and 1481 cm.sup.-1: aromatic.
[0196] Stage D: 4-chloro-3-hydroxy-11beta-[4-(2-iodoethoxy) phenyl]
-estra-1,3,5(10)trien-17-one (iodization)
[0197] 2.44 g of sodium iodide is added under an inert atmosphere,
at ambient temperature, to a solution of 4.11 g of the brominated
derivative prepared in Stage C in 80 ml of methylethyl ketone, and
agitation is carried out overnight under reflux. Water is added
followed by extraction, drying and evaporating under reduced
pressure until 4.184 g of expected crude product is obtained
(Rf=methanol/water (90/10)=0.30).
[0198] Stage E: 4-chloro-3-hydroxy-11beta-[4-[2-(1-piperidinyl)
ethoxy]phenyl]-estra-1,3,5(10)trien-17-one (substitution of the
iodine by piperidine)
[0199] 1.248 g of the iodized derivative obtained in Stage D, is
dissolved under inert atmosphere, at ambient temperature in 25 ml
of tetrahydrofuran/siliporite and 1.35 ml of piperidine is added
and the reaction medium is heated under reflux for 1 hour 30
minutes. After evaporation of the tetrahydrofuran under reduced
pressure at ambient temperature, water and ethyl acetate are added,
followed by washing, drying and evaporation under reduced pressure
until 1.185 g of the crude amino derivative is obtained which is
purified by chromatography on silica eluting with with an ethyl
acetate/triethylamine mixture 95/5. 1.039 g of expected pure
product is obtained (Rf=ethyl acetate/TEA (95/5)=0.20).
[0200] NMR CDCl.sub.3.
[0201] 0.45 ppm (s): CH.sub.3 in position 18; 2.48 ppm: cyclic
--CH.sub.2--N's, 2.71 ppm (t): CH.sub.2--N of the chain; 3.99 ppm
(t): CH.sub.2--OAr; 3.99 ppm: H.sub.11: 6.63 ppm: H.sub.2; 6.81
ppm: H.sub.1: 6.60,ppm: Ar--O; 6.91 ppm: Ar--C.
EXAMPLE 2
4-chloro-3-hydroxy-11beta-[4-[2-(1-pyrrolidinyl) ethoxy]
phenyl]-estra-1,3,5(10)-trien-17-one
[0202] The operation is carried out as in Example 1 Stage E, but
starting with 6 g of the iodized derivative obtained in Stage of
Example 1, 60 ml of tetrahydrofuran/siliporite and 4.6 ml of
pyrrolidine.
[0203] 4.2 g of expected pure product is obtained (Rf: ACOET/TEA
(80/20) =0.24).
[0204] NMR (CDCl.sub.3):
[0205] 0.45 ppm (s): CH.sub.3 in position 18; 1.78 ppm (m):
CH.sub.2 in beta position of N; 2.59 ppm (m): CH.sub.2 in alpha
position of N; 2.84 ppm (t): CH.sub.2--N of the chain; 3.98 ppm
(t): CH.sub.2--OAr; 3.98 ppm (t): H.sub.11, CH.sub.2--O of the
chain; 6.62 ppm: H.sub.2; 6.81 ppm: H.sub.1; 6.62 ppm: Ar--O; 6.91
ppm: Ar--C.
EXAMPLE 3
4-chloro-3-hydroxy-1lbeta-[4-[2-diethylamino)
ethoxy]phenyl]-estra-1,3,5(1- 0)-trien-17-one
[0206] The operation is carried out as in Example 1 Stage E, but
starting with 1.2 g of the iodized derivative obtained in Stage D
of Example 1, 25 ml of tetrahydrofuran/siliporite and 1 ml of
diethylamine.
[0207] 0.688 g of expected pure product is obtained (Rf: ACOEt/TEA
(95/5)=0.22).
[0208] NMR (CDCl.sub.3):
[0209] 0.45 ppm (s): CH.sub.3 in position 18; 1.03 ppm (t):
N--CH.sub.2--CH.sub.3; 2.60 ppm (q): N--CH.sub.2--CH.sub.3; 2.81
ppm (t): CH.sub.2--N of the chain; 3.93 ppm (t): CH.sub.2--OAr;
4.00 ppm (t): H.sub.11; 6.63 ppm: H.sub.2; 6.82 ppm: H.sub.1; 6.63
ppm: Ar--O; 6.91 ppm: Ar--C.
EXAMPLE 4
4-bromo-3-hydroxy-11beta-[4-[2-(1-piperidinyl)
ethoxy]phenyl]-estra-1,3,5(- 10)-trien-17-one
[0210] Stage A: 11beta-[4-(2-chloroethoxy)
phenyl]-estra-4,9-diene-3,1 7-dione (O-alkylation)
[0211] (7.9 ml.times.2) 1-bromo-2-chloroethane followed by 6 ml of
50% soda-and 500 mg of tetrabutylammonium bromide are added to a
suspension of 5 g of
11beta-(4-hydroxyphenyl)-estra-4,9-diene-3,17-dione in 50 ml of
acetone. The mixture is taken to reflux for 4 hours. Water is added
followed by extracting, drying and evaporating under reduced
pressure until a crude product is obtained which is purified in
ether.
[0212] 5.45 g of expected product is obtained (Rf
CH.sub.2Cl.sub.2/acetone 90/10=0.82).
[0213] NMR (CDCl.sub.3):
[0214] 0.58 3H (s): CH.sub.3 in position 18; 3.80 2H (t):
CH.sub.2Cl; 4.28 2H (t): CH.sub.2O; 4.49 1H (d): H.sub.11; 5.80 1H
(s): H.sub.4; 6.82 2H (d): 2H arom. ; 7.08 2H (d): H arom.
[0215] Stage B: 4-bromo-11beta-[4-(2-chloroethoxy)
phenyl]-estra-4,9-diene- -3,17-dione (introduction of Br in
position 4)
[0216] A solution of 2.43 g of NBromo succinimide is added under a
nitrogen atmosphere to a suspension of 5.35 g of the product of
Stage A in 70 ml of dimethylformamide. After agitation for 2 hours
at ambient temperature, 200 ml of ethyl acetate and 400 ml of water
saturated in NaCl are added followed by extraction, washing, drying
and evaporating under reduced pressure until 8 g of crude product
is obtained which is purified by chromatography eluting with a
dichloromethane/acetone mixture 98/2. 4.66 g of expected pure
product is obtained. (Rf CH.sub.2Cl.sub.2/acetone 95/5=0.92).
[0217] NMR (CDCl.sub.3):
[0218] 0.57 3H (s): CH.sub.3 in position 18; 3.25 1H (dt): H.sub.6;
3.80 2H (t): CH.sub.2Cl; 4.20 2H (t): CH.sub.2O; 4.38 1H (d, wide):
H.sub.11; 7.07 and 6.83 4H: AA'BB' H arom.
[0219] Stage C: 4-bromo-11beta-[4-(2-chloro ethoxy)
phenyl]-3-hydroxy-estra-1,3,5(10)-trien-17-one (aromatization of
ring A)
[0220] The operation is carried out as in Stage C of Example 1,
starting with 4.5 g of the product obtained in the preceding stage.
3.05 g of expected product is obtained. (Rf CH.sub.2Cl.sub.2/ACOET
90/10=0.64).
[0221] NMR (CDCl.sub.3):
[0222] 0.45 3H (s): CH.sub.3 in position 18; 3.75 2H (t):
CH.sub.2Cl; 4.12 2H (t): CH.sub.2O; 4.00 1H (t): H.sub.11; 5.48 1H
(s): OH; 6.93 and 6.64 2H: AA'BB' 4H arom; 6.85 and 6.64 2H (d):
H.sub.1 H.sub.2.
[0223] Stage D: 4-bromo-3-hydroxy-11beta-[4-(2-iodo ethoxy)
phenyl]-estra-1,3,5 (10)-trien-17-one (iodization)
[0224] The operation is carried out as in Stage D of Example 1,
starting with 1 g of the product obtained in the preceding stage.
1.14 g of expected product is obtained.
[0225] Stage E: 4-bromo-3-hydroxy-11beta-[4-[2-(1-piperidinyl)
ethoxy]phenyl]-estra-1,3,5(10)-trien-17-one (substitution of the
iodine by piperidine)
[0226] The operation is carried out as in Stage E of Example 1
starting with 1.1 g of the product obtained in the preceding stage.
270 mg of expected pure product is obtained (Rf ACOET/TEA
90/10=0.43).
[0227] NMR (CDCl.sub.3):
[0228] 0.45 3H (s): CH.sub.3 in position 18; 2.47 4H (m): cyclic
CH.sub.2N; 2.70 2H (t): CH.sub.2--N; 3.98 2H (t): CH.sub.2--O; 3.98
1H (t wide): H.sub.11; 6.88 and 6.62 2H (d): H.sub.1 and H.sub.2;
6.90 and 6.62 4H: AA'BB' H aromatic.
EXAMPLE 5
4-chloro-11beta-[4-(3-(1-piperidinyl) propoxy]
phenyl]-estra-1,3,5(10)-tri- ene-3,17-beta-diol
[0229] Stage A: 4-chloro-11beta-[4-(phenylmethoxy)
phenyl]-estra-4,9-diene- -3,17-dione (chlorination in position
4)
[0230] 5.295 g of N-chlorosuccinimide is added at 60.degree. C.
under an inert atmosphere to a solution of 13.6 g of
11.beta.-[4-(phenylmethoxy) phenyl]-estra-4,9-diene-3,17-dione in
120 ml of dimethylformamide, agitation is carried out for 10
minutes then the reaction medium is poured into a saturated aqueous
solution of NaCl, followed by extraction, washing, drying and
evaporating under reduced pressure until the crude product is
obtained (m=19.128 g). A second trial is carried out, the crude
products are collected and purified by chromatography eluting with
an ethyl acetate-cyclohexane mixture 30/70. 23.28 g of expected
pure product is obtained. (Rf ACOET/cyclohexane 30/70=0.19).
[0231] NMR (CDCl.sub.3):
[0232] 0.58 (s): CH.sub.3 in position 18; 3.25 (dt): 1H equatorial
H.sub.6; 4.39 (dl): H.sub.11; 5.02 (s): CH.sub.2Ph; 6.89: H in
ortho position of Ph--O; 7.06: H in meta position of Ph--O; 7.29 to
7.45: aromatic H of CH.sub.2--Ph.
[0233] Stage B: 4-chloro-3-[[(2,2-dimethylethyl) (diphenyl) silyl]
oxy]11-beta-[4-(phenylmethoxy) phenyl]-estra-1,3,5(10)-trien-17-one
(aromatization/saponification/blocking of the phenol)
[0234] a) aromatization and saponification
[0235] The operation is carried out as in Stage C of Example 1
starting with the product obtained in the preceding stage. 13.5 g
of expected pure product is obtained (3--OH).
[0236] b) blocking of the phenol
[0237] 13.5 g+5.6 g of the product obtained in the preceding stage,
191 ml of dichloro methane/siliporite, 14.5 ml of terbutyl diphenyl
chlorosilane and 258 mg of 4-DMAP are dissolved under an inert
atmosphere, and agitation is carried out for 23 hours under reflux.
The reaction medium is then poured into water, extraction is
carried out followed by washing, drying and evaporating under
reduced pressure until 41.322 g of crude product is obtained in the
form of an oil which is purified by chromatography eluting with an
ethyl acetate/petroleum ether mixture 20/80 then 40/60. 1.275 g of
expected pure product is obtained. (Rf ACOET/petroleum ether
20/80=0.27).
[0238] NMR (CDCl.sub.3):
[0239] 0.42 (s): CH.sub.3 in position 18; 1.11 (s):
C(CH.sub.3).sub.3; 7.25 to 7.40-7.60 to 7.75 Si--Ph; 3.85 (t): H
.sub.11; 4.94 (s): CH.sub.2--Ph; 6.65: H in ortho position (Ph--O);
6.84: H in para position (Ph--O); 6.17 (d): H.sub.1; 6.47 (d):
H.sub.2.
[0240] Stage C: 4-chloro-3-[[(2,2-dimethylethyl) (diphenyl) silyl]
oxy]11-beta-[4-(hydroxyphenyl)-estra-1,3,5 (10)-trien-17-one
(deprotection (debenzylation))
[0241] 15.6 g of palladium hydroxide on magnesia and 40 ml of
1,4-cyclohexadiene are added, under an inert atmosphere, at ambient
temperature to a suspension of 20.82 g of the product obtained -in
the preceding stage in 420 ml of methanol, then taken to reflux for
8 hours. After filtration and evaporation under reduced pressure,
22 g of crude product is obtained which is purified by
chromatography eluting with a cyclohexane/ethyl acetate mixture
7/3. 19.4 g of expected pure product is obtained. (Rf
cyclohexane/ACOET 7/3=0.27).
[0242] NMR (CDCl.sub.3):
[0243] 0.42 (s): CH.sub.3 in position 18; 1.11 (s):
C(CH.sub.3).sub.3; 3.83 (tl): H.sub.1; 4.56 (s): OH; 6.17 (d)-6.46
(d): H.sub.1, H.sub.2; 7.25 to 7.43 (m) 6H and 7.64 (m) 4H:
SiPh.sub.2.
[0244] Staqe D: 4-chloro-3-[((2,2-dimethylethyl) (diphenyl) silyl]
oxy] 11-beta-[4-(3-iodopropoxy)
phenyl]-estra-1,3,5(10)-trien-17-one (O-alkylation)
[0245] 3.18 g of the product obtained in the preceding stage, 15 ml
of 1,3-diodopropane, 800 mg of ground soda and 300 mg of
tetrabutylammonium bromide, acidified with 2N hydrochloric acid are
mixed together for 4 hours at ambient temperature, followed by
extraction, washing, drying and evaporating under reduced pressure
until the crude product is obtained (39.8 g) which is purified by
chromatography eluting with a petroleum ether/ACOET mixture 75/25.
2.43 g of expected pure product is obtained. (Rf: petroleum
ether/AcOEt 80/20=0.3).
[0246] NMR (CDCl.sub.3):
[0247] 0.41 (s): CH.sub.3 in position 18; 1.10 (s):
C(CH.sub.3).sub.3; 3.34 (t): O--CH.sub.2--CH.sub.2--I; 3.85 (tl):
Hll; 3.91 (t): O--CH.sub.2--CH.sub.2-I; 6.16 (d)-6.46 (d): H.sub.1,
H.sub.2; 7.25 to 7.45 6H and 7.66 4H: SiPh.sub.2.
[0248] Stage E: 4-chloro-3-[[(2,2-dimethylethyl) (diphenyl) silyl]
oxy] 11-beta-[4-[3-(1-piperidinyl) propoxy]
phenyl]-estra-:1,3,5(10)-trien-17-- one (substitution of the iodine
by piperidine)
[0249] The operation is carried out as in Stage E of Example 1,
starting with the product obtained in the preceding stage. 2.07 g
of the expected pure product is obtained (Rf AcOEt/TEA
98/2=0.23).
[0250] NMR (CDCl.sub.3):
[0251] 0.42 (s):--CH.sub.3 in position 18; 1.10 (s):
C(CH.sub.3).sub.3; 2.52: cyclic CH.sub.2--N; 2.83: CH.sub.2--N of
the chain; 3.84 (tl): H.sub.11; 3.88 (t): CH.sub.2--O; 6.16
(d)-6.47 (d): H.sub.1 H.sub.2; 6.56-6.80: Ph--O; 7.25-7.40 6H and
7.65 4H: SiPh.sub.2.
[0252] Stage F: 4-chloro-llbeta-[4-[3-(1-piperidinyl) propoxy]
phenyl]-estra-1,3,5(10)-triene-3,17-beta-diol (reduction of 17-keto
and deprotection)
[0253] a) Reduction of 17-keto
[0254] 63 mg of 97% sodium borohydride is added under an inert gas
atmosphere and at ambient temperature to a solution of 600 mg of
the product obtained in the preceding stage in 4 ml of methanol and
2 ml of tetrahydrofuran, while cooling the reaction medium down in
an ice bath and agitation is carried out for 50 minutes. Ethyl
acetate is added followed by washing with salt water, drying and
evaporating under reduced pressure until 614 mg of the expected
crude product is obtained.
[0255] b) Deprotection of the phenol in position 3
[0256] 1.6 ml of a solution of tetrabutyl ammonium fluoride in
tetrahydrofuran is added under an inert gas atmosphere, at ambient
temperature to a solution of 614 mg of the product obtained
previously in 6 ml of tetrahydrofuran and agitation is carried out
for 50 minutes at ambient temperature. The reaction medium is
poured into water followed by extraction, washing, drying and
evaporating under reduced pressure until 840 mg of crude product is
obtained which is purified by chromatography eluting with a
dichloromethane/methanol/ammonium hydroxyl mixture 90/10/1. 215 g
of expected pure product is obtained.
[0257] (Rf CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 90/10/1=0.3).
[0258] NMR (CDCl.sub.3):
[0259] 0.38 (s): CH.sub.3 in position 18; 2.45 (m): CH.sub.2--N;
3.72 (t): H.sub.17; 3.86: H.sub.11, CH.sub.2--O; 6.61-6.93: Ph--O;
6.61-6.75: H.sub.1, H.sub.2.
EXAMPLE 6
4-chloro-11beta-[4-[4-(1-piperidinyl) butoxy]
phenyl]-estra-1,3,5(10)-trie- ne-3,17-beta-diol
[0260] The operation is carried out in the same manner as in
Example 5, the O-alkylation being carried out: either with
4-chloro-1-butanol, by Mitsunobu's reaction in the presence of
triphenylphosphine, diethylazodicarboxylate in tetrahydrofuran and
the chlorinated product obtained being converted into the iodized
product according to the process described in Example 1 Stage D, or
by direct action with 1,4-diiodobutane (cf Ex. 6). 189 mg of
expected pure product is obtained (Rf
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 90/10/1=0.24).
EXAMPLE 7
4-chloro-11beta-[4-[5-(1-piperidinyl) pentyloxy]
phenyl]-estra-1,3,5(10)-t- riene-3,17-beta-diol
[0261] The operation is carried out as in Example 5, the
O-alkylation is carried out with 1,5-diiodopentane. 125 mg of
expected pure product is obtained. (Rf
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 90/10/1=0.30).
EXAMPLE 8
(17beta) 4-chloro-11beta- [4-[2-(1-piperidinyl) ethoxy]
phenyl]-spiro-[estra-1,3,5(10)-triene-17,.sup.2'(5'H)
furan]3-ol
[0262] Stage A: (17beta) 4-chloro-11beta-(4-hydroxyphenyl)
spiro-[estra-4,9-diene-17,2' (5'H)-furan]-3-one (chlorination)
[0263] 4.51 g of N-chloro succinimide is added under an inert
atmosphere, at 60.degree. C. to a suspension of 10.46 g of
(17beta)-beta-(4-hydroxy
phenyl)-spiro-[estra-4,9-diene-17,2'(5'H)-furan]-3-one (WO
87/05908) in 100 ml of dimethylformamide and the reaction medium is
left to react for 10 minutes under agitation. The reaction medium
is then poured onto an ice-cooled solution of sodium chloride
followed by extracting, drying and evaporating under reduced
pressure until 20.85 g of crude product is obtained. 8.93 g of the
product obtained in a related trial carried out in an identical
manner is added and the whole is purified by chromatography eluting
with a CH.sub.2Cl.sub.2/acetone mixture 95/5, then
recrystallization from ethyl ether. 0.98 g of expected pure product
is obtained.
[0264] (Rf CH.sub.2Cl.sub.2/acetone 95/5=0.2). M.p.=258.degree.
C.
[0265] Stage B: (17beta)-4-chloro-11beta-[4-(2-bromoethoxy)
phenyl]-spiro-[estra-4,9-diene-17,2' (5'H) furan]-3-one
[0266] The operation is carried out as in Example 1 Stage A, but
starting with 1,2-dibromoethane. 5.34 g of expected pure product is
obtained. (Rf essence G/AcOEt 75/25=0.21).
[0267] Stage C: Aromatization and saponification
[0268] Stare D: Iodization
[0269] Stage E: Condensation of the piperidine
[0270] Stages C, D and E are carried out in a similar manner to
Stages C, D and E of Example 1.
[0271] 0.657 g of expected pure product is obtained (Rf AcOEt/TEA
92/8=0.21).
[0272] NMR (CDCl.sub.3):
[0273] 0.48 (s): CH.sub.3 in position 18; 2.47 (m): cyclic
CH.sub.2--N; 2.70 (t): CH.sub.2 --N chain; 3.89 (tl): H.sub.1; 3.99
(t): CH.sub.2--O chain; 4.56: CH.sub.2--O ring; 5.78: OH; 5.87:
H'.sub.3, H'.sub.4; 6.60-6.80: H.sub.1 and H.sub.2; 6.60-6.86:
Ph--O.
EXAMPLE 9
(17beta) 4-chloro-11beta-[4-[2-(diethylamino) ethoxy]
phenyl]-spiro-[estra-1,3,5(10)-triene-17,2'(5'H) furan]-3-ol
[0274] The operation is carried out as in Example 8 but with final
condensation of diethylamine on the iodine derivative. 0.512 g of
expected pure product is obtained (Rf
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 93/7/0.2=0.29).
[0275] NMR (CDCl.sub.3):
[0276] 0.48 (s): CH.sub.3 in position 18; 1.03 (t):
CH.sub.2--CH.sub.3; 2.60 (q): CH.sub.2--CH.sub.3; 2.81 (t):
CH.sub.2--N; 3.89 (tl): H.sub.11; 3.93 (t): CH.sub.2--O chain;
4.56: CH.sub.2--O ring (H'.sub.3); 5.87: H'.sub.3, H'.sub.4;
6.61-6.79: H.sub.1 and H.sub.2; 6.61-6.86: Ph--O.
EXAMPLE 10
(17beta) 4-chloro-11beta-[4-[2-(1-pyrrolidinyl) ethoxyl
phenyl]-spiro-[estra-1,3,5(10)-triene-17,2'(5'H) furan]-3-ol
[0277] The operation is carried out as in Example 8 but with final
condensation of the pyrrolidine on the iodine derivative. 0.628 g
of expected product is obtained.
[0278] M.p.=226-227.degree. C. (Rf CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH
93/7/0.2=0.25).
[0279] NMR (CDCl.sub.3):
[0280] 0.48 (s): CH.sub.3 in position 18; 2.59 (m): cyclic
CH.sub.2--N; 2.80 (m): CH.sub.2-N chain; 3.89 (tl): H.sub.11; 3.98
(t): CH.sub.2--O of the chain; 4.56 (m): cyclic CH.sub.2--O
(H'.sub.5); 5.87 (m): H'.sub.3, H'.sub.4; 6.60-6.78 (d): H.sub.1
and H.sub.2; 6.60-6.86 AA'BB': Ph--O.
EXAMPLE 11
(17beta) 4-chloro-11beta-[4-[3-(1-piperidinyl) propoxy]
phenyl]-spiro-estra-1,3,5(10)-triene-17,2'(5'H) furan]-3-ol
[0281] The operation is carried out as in Example 8, the
O-alkylation is carried out directly with 1,3-diiodopropane (avoids
Stage D of Example 8). 0.591 g of expected pure product is obtained
(Rf AcOEt/TEA 92/8=0.19).
[0282] NMR (CDCl.sub.3):
[0283] 0.48 (s): CH.sub.3 in position 18; 2.30 to 2.50:
CH.sub.2--N; 3.87 (m): CH.sub.2--O chain, H.sub.11; 4.56:
CH.sub.2--O ring (H'.sub.5); 5.88: H'.sub.3, H'.sub.4; 6.61-6.79:
H.sub.1 and H.sub.2; 6.61-6.86: Ph--O.
EXAMPLE 12
(17beta) 4-chloro-11beta-[4-[4-(1-piperidinyl) butoxy]
phenyl]-spiro-[estra-1,3,5(10)-triene-17,2'(5'H) furan]-3-ol
[0284] The operation is carried out as in Example 8 Stages A, B, C,
D, E, the O-alkylation is carried out with 1-bromo-4-chlorobutane.
0.494 g of pure product is obtained.
[0285] Rf AcOEt/TEA 95/5 0.22
[0286] M.p. 154.degree. C.
[0287] NMR (CDCl.sub.3):
[0288] 0.50 (s): CH.sub.3 in position 18; 2.36 (6H): CH.sub.2--N
ring, chain; 3.85 (t): CH.sub.2--O; 3.89 (t): H.sub.11; 4.57 (s):
cyclic CH.sub.2--O (H'.sub.5); 6.60 (m) (3H)-6.86 (m) (2H): Ph--O
and H.sub.2; 6.79 (d): H.sub.1.
EXAMPLE 13
4-chloro-3-hydroxy-1lbeta-[4-[2-(1-dimethyl-amino) ethoxy]
phenyl3-estra-1,3,5(10)-trien-17-one
[0289] Stage A: 4-chloro-11beta-[4-[2-(dimethylamino) ethoxy]
phenyl]-estra-4,9-diene-3,17-dione (introduction of 4-chloro)
[0290] 6 ml of sulphuryl chloride at 10% in dichloromethane is
added under an inert atmosphere, at ambient temperature to a
solution of 1.08 g of 11-[4-(2-(dimethylamino) ethoxy)
phenyl]-estra-4,9-diene-3,17-dione in 11 ml of pyridine and
agitation is carried out for 30 minutes at approximately
-36.degree. C. The reaction medium is poured into sodium
bicarbonate, followed by extraction, washing, drying and
evaporating under reduced pressure until 1.84 g of crude product is
obtained, which is purified by chromatography, eluting with an
ethyl acetate/triethylamine mixture 80/20. 616 mg of expected pure
product is obtained. (Rf AcOEt/TEA 8/2=0.35).
[0291] Stage B: 4-chloro-11beta-[4-[2-(dimethylamino) ethoxy]
phenyl]-3-hydroxy-estra-1,3,5(10)-trien-17-one (aromatization and
saponification)
[0292] The aromatization reaction, then the saponification reaction
are carried out as in Example 1, Stage C, starting with 700 mg of
the product obtained in the preceding stage. 360 mg of expected
pure product is obtained. M.p.=254.degree. C. (Rf
CH.sub.2Cl.sub.2/iPrOH/NH.sub.4OH 93/7/0.7=0.18).
[0293] NMR (CDCl.sub.3):
[0294] 0.44 (s): CH.sub.3 in position 18; 2.30 (s): NMe.sub.2; 2.67
(m): CH.sub.2--N; 3.94 (m): CH.sub.2--O; 4.00: H.sub.11; 6.62-6.91:
Ph--O; 6.62-6.81 (d): H.sub.1, H.sub.2.
[0295] The compound of Example 3 was prepared in the same
manner.
EXAMPLE 14
gamma lactone of
4-chloro-3,17beta-dihydroxy-11beta-[4-[2-(1-pyrrolidinyl) ethoxy]
phenyl]-19-nor-17alpha-pregna-1,3,5(10)-triene-21-carboxylic
acid
[0296] 6 ml of tetrahydrofuran/siliporite is added under an inert
atmosphere, at ambient temperature to 5.93 ml of n-butyllithium at
15% in hexane, then at -50.degree. C., 0.921 g of allyl
bis-dimethylamido phosphate in solution in tetrahydrofuran is added
and finally at -30.degree. C. 0.586 g of the product obtained in
Example 2 is added and the reaction medium is agitated for 1 hour
45 minutes at ambient temperature.
[0297] 8 ml of 2N hydrochloric acid and 50 ml of a saturated
solution of sodium bicarbonate are added followed by extraction,
washing, drying and evaporating under reduced pressure until 0.590
g of crude product is obtained which is purified by chromatography
eluting with an ethyl acetate/triethylamine mixture 60/40, then
recrystallization from isobutanol. 0.162 g of expected pure product
is obtained. M.p.=231.degree. C.
[0298] Rf AcOEt/TEA 60/40=0.20.
[0299] NMR (CDCl.sub.3):
[0300] 0.51 (s): CH.sub.3 in position 18; 1.79 (m): CH.sub.2 in
beta position of N ring; 2.58 (m): CH.sub.2 in alpha position of N
ring; 2.83 (t): CH.sub.2--N of the chain; 3.99 (t): CH.sub.2--OAr;
3.99 (t): H.sub.11; 6.62: H.sub.2; 6.82: H.sub.1; 6.62: ArO; 6.82:
ArC.
EXAMPLE 15
gamma lactone of
4-chloro-3,17beta-dihydroxy-11beta-[4-[2-(1-piperidinyl) ethoxy]
phenyl]-19-nor-17alpha-pregna-1,3,5(10)-triene-21-carboxylic
acid
[0301] The operation is carried out as in as in Example 14, but
starting with 1.179 g of the product of Example 1. 0.388 9 of the
expected pure product is obtained. (Rf
CH.sub.2Cl.sub.2/iPrOH/NH.sub.4OH (95/5/0.5=0.20)).
[0302] NMR (CDCl.sub.3):
[0303] 0.52 (s): CH.sub.3 in position 18; 2.50 (m): cyclic CH.sub.2
N; 2.71 (t): CH.sub.2--N of the chain; 4.00 (t): CH.sub.2--OAr;
4.00 (t masked): H.sub.11; 6.62: H.sub.2; 6.81: H.sub.1; 6.62: ArO;
6.85: ArC.
EXAMPLE 16
gamma lactone of
4-chloro-3,17beta-dihydroxy-11beta-[4-[2-(diethylamino) ethoxy]
phenyl]-19-nor-17alpha-pregna-1,3,5(10)-triene-21-carboxylic
acid
[0304] The operation is carried out as in as in Example 14, but
starting with 0.428 g of the product of Example 3. 0.195 g expected
pure product is obtained. (Rf AcOEt/TEA/Essence G
(50/30/20=0.25))
[0305] NMR (CDCl.sub.3):
[0306] 0.51 (s): CH.sub.3 in position 18; 1.03 (t):
N--CH.sub.2--CH.sub.3; 2.60 (q): N--CH.sub.2--CH.sub.3; 2.81 (t):
CH.sub.2--N of the chain; 3.94 (t): CH.sub.2--O--Ar; 3.98 (t):
H.sub.11; 6.59: H.sub.2; 6.79: H.sub.11; 6.59: ArO; 6.85: ArC.
EXAMPLE 17
gamma lactone of
(17-alpha)-4-chloro-3,17beta-dihydroxy-11beta-[4-[3-(1-pi-
peridinyl) propoxy]
phenyl]-19-nor-pregna-1,3,5(10)-triene-21-carboxylic acid
[0307] Stage A Lactonization
[0308] The operation is carried out as in Example 14, but starting
with 1.44 g of the compound of Example 5 Stage E. 2.36 g of crude
product is obtained which is used directly in the deprotection
reaction of the phenol in position 3.
[0309] Stage B: Deprotection of the phenol in position 3.
[0310] 3.8 ml of a solution of tetrabutyl ammonium fluoride in
tetrahydrofuran is added to a solution of 2.36 g of the product
obtained in the preceding stage in 24 ml of tetrahydrofuran and
agitation is carried out for 50 minutes at ambient temperature. The
reaction medium is poured into water followed by extraction, drying
and evaporating under reduced pressure until 695 mg of crude
product is obtained which is purified by chromatography eluting
with a dichloromethane/methanol mixture 93/7, then by
recrystallization. 238 mg of expected pure product is obtained.
M.p.=242.degree. C. Rf CH.sub.2Cl.sub.2/MeOH/NH4OH 93/7/0.7=
0.28.
[0311] NMR (CDCl.sub.3):
[0312] 0.51 (s): CH.sub.3 in position 18; 2.30 to 2.60:
CH.sub.2--N; 3.88: CH.sub.2--O; 3.98 (ti): H.sub.11; 6.61, 6.87:
Ar--O, Ar--C; 6.61-6.76: H.sub.1, H.sub.2.
EXAMPLE 18
gamma lactone of
4-chloro-3,17beta-dihydroxy-11beta-[4-[4-(1-piperidinyl) butoxy)
phenyl]-19-nor-17alpha-pregna-1,3,5(10)-triene-21-carboxylic
acid
[0313] The operation is carried out as in Example 17, but starting
with 1.2 g of the product of Example 6 Stage E. 310 mg of expected
pure product is obtained (Rf CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH
95/5/0.5=0.17).
[0314] NMR (CDCl.sub.3):
[0315] 0.51 (s): CH.sub.3 in position 18; 3.83 (t): CH.sub.2--O
chain; 3.99 (tl): H.sub.11; 6.61-6.85: Ar--O, Ar--C; 6.61-6.79:
H.sub.1, H.sub.2.
EXAMPLE 19
gamma lactone of
4-chloro-3,17beta-dihydroxy-11beta-[4-[5-(1-piperidinyl) pentyloxy]
phenyl]-19-nor-17alpha-pregna-1,3,5(10)-triene-21-carboxylic
acid
[0316] The operation is carried out as in Example 17, but starting
with 1.44 g of the product of Example 7 Stage E. 330 mg of expected
pure product is obtained (Rf AcOEt/TEA 90/10=0.22).
[0317] NMR (CDCl.sub.3):
[0318] 0.52 (s): CH.sub.3; 3.83 (t): CH.sub.2--O; 3.99 (t):
H.sub.11; 6.60 (m) 3H, 6.67 (d) H.sub.1, 6.85 (d) 2H: Aromatic
H.sub.1, H.sub.2.
EXAMPLE 20
4-chloro-11beta-[4-[2-(diethylamino) ethoxy] phenyl]-estra-1,3,5
(10)-triene-3,17beta-diol
[0319] 37 mg of sodium borohydride is added under an inert
atmosphere to a solution of 241 mg of the compound of Example 3, in
4 ml of methanol, agitation is carried out for 1 hour in an ice
bath, then 2 ml of hydrochloric acid is added then the reaction
medium is poured into an aqueous solution of sodium bicarbonate,
followed by extraction with ethyl acetate, washing, drying and
evaporating under reduced pressure until 245 mg of crude product is
obtained which is purified by chromatography eluting with a
dichloromethane/methanol/ammonium hydroxide mixture 90/10/1. 195 mg
of expected pure product is obtained.
[0320] Rf CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 90/10/1=0.27.
[0321] NMR (CDCl.sub.3):
[0322] 0.32 (s): CH.sub.3; 1.03 (t): CH.sub.2CH.sub.3; 2.60 (q):
CH.sub.2CH.sub.3; 2.81 (t): CH.sub.2--N; 3.68: H17; 3.93 (t):
CH.sub.2--O; 6.62: ArO; 6.89: ArC; 6.80 (d): H.sub.1: 6.62 (d):
H.sub.2.
[0323] In a similar manner to Example 20, the following products of
formula (I') are obtained with R'.sub.550 OH and R'.sub.6H:
1 Starting product n' X' NR'.sub.3R'.sub.4 Rf s. Ex. 21 Ex. 4 2 Br
Piperidino 0.45 AcOEt/TEA 90/10 Ex. 22 Ex. 1 2 Cl Piperidino 0.13
AcOEt/TEA 95/5 Ex. 23 Ex. 2 2 Cl Piperidino 0.13
CH.sub.2Cl.sub.2/MeOH NH.sub.4OH 93/7/0.5 Ex. 24 Ex. 13 2 Cl
NMe.sub.2 0.25 CH.sub.2Cl.sub.2/iPrOH/ NH.sub.4OH 90/10/1
EXAMPLE 25
4-chloro-11beta-[4-[2-(diethylamino) ethoxy]
phenyl]-19-nor-17alpha-pregna-
-1,3,5(10)-trien-20-yne-3,17beta-diol
[0324] 4.7 ml of a 0.43 M/l solution of potassium acetylide is
added under an inert atmosphere to a solution of 250 mg of the
product of Example 3 in 3 ml of tetrahydrofuran/ siliporite,
agitation is carried out for 1 hour at ambient temperature, then 4
ml of hydrochloric acid is added. The reaction medium is poured
into a saturated aqueous solution of sodium bicarbonate followed by
extraction, washing, drying and evaporating under reduced pressure
until 260 mg of crude product is obtained which is purified by
chromatography eluting with a CH.sub.2Cl.sub.2/MeOH/NH.sub.4O- H
mixture 90/10/0.5. 215 mg of expected pure product is obtained. Rf
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 90/10/0.5=0.31.
[0325] NMR (CDCl.sub.3):
[0326] 0.43 (s): CH.sub.3 in position 18; 1.04 (t):
CH.sub.2CH.sub.3; 2.62 (q): CH.sub.2CH.sub.3; 2.64 (s):
C.ident.C--H; 2.83 (t): CH.sub.2-N; 3.95 (t): CH.sub.2--O; 4.00
(tl): H.sub.11; 6.62: Ph--O; 6.90: Ph--C; 6.82 (d): H.sub.1; 6.62
(d): H.sub.2.
EXAMPLE 26
(17beta)-4-chloro-4',5'-dihydro-1lbeta-[4-[2-(1-10 piperidinyl)
ethoxyl phenyl]-spiro-estra-1,3,5(10)-triene-17,2'
-(3'H)-furan]-3-ol
[0327] 0.041 g of 9.5% Pd/C catalyst is added to a solution of
0.411 g of the product of Example 8 in 15 ml of ethanol and 5 ml of
tetrahydrofuran and hydrogenation is carried out for 2 hours 30
minutes (vol. of H.sub.2 absorbed=17.5 cm.sup.3). After filtration
of the catalyst, evaporation is carried out under reduced pressure
until 0.42 g de crude product is obtained which is purified by
chromatography eluting with an ethyl acetate/triethylamine mixture
92/8. 0.33 g of expected pure product is obtained.
[0328] M.p.=170.degree. C. Rf AcOEt/TEA 92/8=0.21.
[0329] In a similar manner to Example 26, the following products of
formula (I') are obtained, in which R'.sub.3 and R'.sub.6 form
together with the carbon that carries them the saturated ring
2 21 Starting product n' X' NR'.sub.3R'.sub.4 Rf s. Ex. 27 Ex. 11 3
Cl Piperidino 0.19 AcOEt/TEA 92/8 Ex. 28 Ex. 12 4 Cl Piperidino
0.22 AcOEt/TEA 95/5
EXAMPLE 29
4-chloro-11.beta.-[4-[2-(diethylamino) ethoxy]
phenyl]-17alpha-methyl-estr- a-1,3,5(10)-triene-3,17beta-diol
[0330] a) Preparation of "cerium compound"
[0331] 24 ml of anhydrous THF is added to 2.42 g of
CeCl.sub.3-7H.sub.1, dried beforehand under reduced pressure at
140.degree. C. for 2 hours, then put under an inert atmosphere, the
suspension is agitated for 2 hours, cooled down to -78.degree. C.
and 4.35 ml of CH.sub.3Li in ether is added and agitation is
carried out for 30 minutes at -78.degree. C.
[0332] b) Condensation
[0333] 0.644 g of the compound prepared in Example 3 in solution in
8.5 ml of anhydrous THF is added at -78.degree. C. and the reaction
medium is maintained at this temperature for one hour. The reaction
medium is poured into 25 ml of a saturated solution of NH.sub.4Cl
followed by extraction, washing, drying and evaporating under
reduced pressure until 0.599 g of crude product is obtained which
is purified by chromatography (after having added 0.192 g of crude
product obtained during a related trial carried out in an identical
manner) eluting with a CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH
mixture (92/8/0.2), then with an AcoEt/TEA mixture (87/13). 0.402 g
of expected pure product is obtained. Rf
CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH (92/8/0.2)= 0.18
[0334] M.p.=161-163.degree. C.
[0335] NMR (CDCl.sub.3):
[0336] 0.44 (s): CH.sub.3 in position 18; 1.28 (s): CH.sub.3 in
position 17; 1.03 (t): CH.sub.2CH.sub.3; 2.61 (q):
CH.sub.2--CH.sub.3; 2.81 (t): CH.sub.2--N; 3.94 (t): CH.sub.2--O;
3.96: H.sub.11; 6.61-6.80: H.sub.1 and H.sub.2; 6.61-6.83:
Ph--O.
EXAMPLE 30
4-chloro-17alpha-methyl-11.beta.-[4-[2-(1-piperidinyl) ethoxy]
phenyl]-estra-1,3,5(10)-triene-3,17beta-diol.
[0337] The operation is carried out as in Example 28, but starting
with 2.79 g of the product obtained in Example 1.
[0338] 2.12 g of expected pure product is obtained.
[0339] Rf CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH
(93/7/0.2)=0.19
[0340] M.p.=163.degree. C.
[0341] NMR (CDCl.sub.3):
[0342] 0.44 (s): CH.sub.3 in position 18; 1.28 (s): CH.sub.3 in
position 17; 2.48 (tl) 4H: CH.sub.2N ring; 2.71 (t): CH.sub.2--N
chain; 3.99 (t): CH.sub.2--O; =4.00 masked: H.sub.11; 6.80 (d):
H.sub.1; 6.98 (d): H.sub.2; 6.60-6,88: Ph--O.
PHARMACOLOGICAL TESTS
[0343] Effect on the proliferation of mammary cells
[0344] The proliferative activity of the molecules is studied in
comparison to that of oestradiol on MCF-7 human mammary cells in
culture.
[0345] In order to reveal an agonist effect of the oestradiol
and/or the tested molecules, the cell maintenance culture (rich in
growth factors and steroids) is replaced by an impoverished medium,
amongst others free of steroids (DMEM supplemented with 5% of
steroid-free serum and without phenol red). Cells undergo this
severance twd days before the start of the test.
[0346] After 7 days culture in the presence of the products to be
studied, the cell proliferation is evaluated by determination of
the DNA. In each test, the effect of the oestradiol at 10.sup.-10 M
(cell growth in the presence of oestradiol less cell growth in the
presence of the solvent) determines the 100% agonist activity. The
activity of the molecules is evaluated in comparison to this
internal control. The molecules inducing an identical cell growth
to that observed with the solvent alone are classified as
"inactive", those inducing a lower cell growth to that observed
with the solvent are classified as "inhibitor".
3 ACTIVITY Oestradiol Agonist Example 20 Mixed* Example 22 Inactive
Example 23 Mixed Example 1 Mixed Example 30 Mixed *Mixed: slight
agonist activity at very low concentrations and an inhibitory
activity at higher concentrations. Bone impact study of a product
in the ovariectomized female rat at the age of 3 months
[0347] Compounds A, B, C, D, E are tested in order to determine
their effect on the bone mass and on the formation and resorption
activity in the model of the ovariectomized rat at the age of 3
months. The animals are treated in a preventive fashion.
4 Animals: Species rat Strain Sprague-Dawley Sex female Weight 250
g to 280 g No. of animals/group 8
[0348] Products:
[0349] 1--Product to be tested: Products of Examples 20, 22, 23, 30
and 1.
[0350] vehicle(s): corn oil, 0.5% methylcellulose
[0351] dose(s): one dose per tested product (0.3 mg/kg/d)
[0352] number of administrations: once/day; 5 days/week for 4
weeks
[0353] administration route: oral route for the products
[0354] volumes: 5 ml/kg (p.o.)
[0355] period between the last injection and sacrifice: 24
hours
[0356] number of administrations: 20.
[0357] Reference product: 17.beta. oestradiol is administered by
subcutaneous route at a dose of 0.1 mg/kg/d in solution in a
mixture of corn oil-benzyl alcohol (99:1, v/v) under a volume of
0.2 ml/kg.
Experimental protocol
[0358] Animals
[0359] The study is carried out with female rats ovariectomized at
the age of 3 months. The animals are kept in an air conditioned
room (temperature 20.degree. C..+-.2.degree. C.) and grouped by 4
into boxes. The animals receive, ad libitum, demineralized water
and compressed foods (pellets: AO4CR-10 UAR).
[0360] Surgery
[0361] The 3 month old female rats weighing approximately 250 g are
ovariectomized under anaesthesia with Imalgene 1000, at a dose of
100 mg/kg by intraperitoneal route (i.p.) and under a volume of 1
ml/kg. They also receive Nembutal (3 mg/kg i.p. under a volume of
0.3 ml/kg).
[0362] After lateral incision, cutaneous and muscular planes are
sectioned. The exeresis of each ovary is carried out after ligature
of the oviduct.
[0363] The "SHAM" control rats are anaesthetised under the same
conditions. After incision of the cutaneous and muscular planes,
each ovary is exposed then replaced in situ.
[0364] Treatment
[0365] The effects of the products are determined in a preventive
treatment. They are administered immediately after the ovariectomy.
Animals distributed into groups of 8.
[0366] Group 1: "SHAM" control rats receiving the vehicle or
vehicles
[0367] Group 2: "OVX" control rats receiving the vehicle or
vehicles.
[0368] Groups X: "OVX" rats receiving respectively defined doses of
the product or products to be tested.
[0369] Blood samples
[0370] At the end of 4 weeks (duration of the study) the animals
are decapitated by guillotine. The serums collected after
centrifugation are preserved at -20.degree. C.
[0371] A lipidic balance will be established from the serous
determinations of total cholesterol, of triglycerides and of
phospholipids on a 500 .mu.l aliquot of serum. The lowering of the
seric cholesterol level is expressed in % relative to the level
shown by the ovariectomized animals receiving only the solvent.
[0372] Orqan samples
[0373] After sacrificing the animals, the following organs are
removed:
[0374] tractus genitalis
[0375] The uteri are removed. The latter are weighed. The increase
in weight is expressed in % of the weight of the uterus of
ovariectomized animals receiving only the solvent.
[0376] at the bone level:
[0377] The bone mass (BMD or Bone mineral density) is measured by
biphotonic dual energy X-ray absorptiometry (DEXA). The
measurements are carried out on bone excized and cleaned of all
soft tissue. The BMD (Bone mineral density) is measured on the
whole bone as well as on the metaphyseal part at the level of the
proximal extremity for the left tibia. This zone is defined as
being the region which is richest in trabecular bone; and
consequently, is the most sensitive to variations in bone volume
and bone mineral density.
[0378] The results are expressed in % according to the formula: 1
Tested product BMD - OVX BMD SHAM BMD - OVX BMD .times. 100
5 Dose Route TIBIA BONE UTERUS Cholesterol mg/kg BMD % Weight % %
OVX 0 SHAM 100 Oestradiol 0.1 s.c. 105 359 -35 Ex. 20 0.3 po 69 60
-43 Ex. 20 1.0 po 74 50 -40 Ex. 22 0.3 po 63 57 -52 Ex. 23 0.3 po
67 64 -53 Ex. 23 1.0 po 71 74 -53 Ex. 1 0.3 po 57 55 -50 Ex. 1 1.0
po 64 55 -48 Ex. 30 0.3 po 52 68 -51 Ex. 30 1.0 po 71 55 -48
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