Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-10-04
2001-03-27
Qazi, Sabiha N. (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C540S107000, C514S172000, C514S176000
Reexamination Certificate
active
06207657
ABSTRACT:
The present invention relates to steroid compounds substituted in position 11, their preparation process, their use as medicaments and the pharmaceutical compounds containing them.
Osteoporosis is a pathology which is characterised 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.
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.
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.
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. The Patent Application FR 2640977 A (Jun. 29, 1990) describes steroids having an antioestrogenic and/or oestrogenic activity. These molecules differ from those of our Application in that they are substituted by an alkynyl group or are not substituted in the 17 alpha position. The publication Steroids (Lu Jin et al., Vol. 60, No. 8, August 1995, 512-518) also discloses an analogue not substituted in position 17 alpha (RU39411) which has a mixed oestrogenic/antioestrogenic activity, inhibits the growth of MCF-7 breast tumor cells and is therefore useful in treating breast cancer.
Therefore, a subject of the invention is the compounds of general formula (I):
in which:
n is an integer equal to 2 or 3,
either R
1
and R
2
identical or different represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or R
1
and R
2
form together with the nitrogen atom to which they are linked, an aromatic or non-aromatic, saturated or unsaturated, monocyclic or polycyclic heterocycle with 5 to 15 members, optionally containing 1 to 3 additional heteroatoms chosen from oxygen, sulphur and nitrogen, substituted or not substituted, X represents an optionally esterified hydroxyl radical and Y represents an alkyl radical containing 1 to 4 carbon atoms, substituted or not substituted, as well as their addition salts with pharmaceutically acceptable acids.
By alkyl radical containing from 1 to 4 carbon atoms is meant methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl radicals.
When Y represents a substituted alkyl radical, it is in particular an alkyl radical substituted by one or more halogen atoms. Preferably, Y can represent the trifluoromethyl group.
When R
1
and R
2
form together with the nitrogen atom to which they are linked a heterocycle, it is in particular mono or bicyclic saturated heterocycles optionally containing another heteroatom selected from oxygen and nitrogen, such as heterocycles selected from: pyrrolyl, imidazolyl, indolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazonyl, pyrazolinyl, thiazolinyl, and quite particularly the following saturated heterocycles:
When this heterocycle is substituted, it is in particular by an alkyl group containing 1 to 4 carbon atoms at the level of the nitrogen atom.
When X is an optionally esterified hydroxyl radical, OCO—alki groups are meant in which alki is an alkyl radical containing from 1 to 8 carbon atoms and preferably the —OCOMe or OCOEt groups.
By addition salts with pharmaceutically acceptable acids is meant addition salts formed with mineral or organic acids on the amine. These can be one of the following acids: hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, malic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkane sulphonics such as methane or ethane sulphonic, arylsulphonics, such as benzene or paratoluene sulphonic and arylcarboxylics.
A more particular subject of the invention is the compounds of formula (I) as defined above in which n is equal to 2 as well as their addition salts with pharmaceutically acceptable acids.
A more particular subject of the invention is the compounds of formula (I) as defined above in which:
n is equal to 2,
either R
1
and R
2
identical or different represent an alkyl radical containing 1 to 4 carbon atoms,
or R
1
and R
2
form together with the nitrogen atom to which they are linked, a piperidino, pyrrolidino or 2-azabicyclo(2.2.1)hept-2-yl group,
X represents a hydroxyl radical and Y represents a methyl or ethyl radical.
A particular subject of the invention is the compounds of formula (I) as well as their addition salts with pharmaceutically acceptable acids the names of which follow:
11&bgr;- [4-[2-(1-piperidinyl)ethoxy]phenyl]-19-nor-17&agr;-pregna-1,3,5(10)-triene-3,17&bgr;diol,
17&agr;-methyl-11&bgr;-[4-[2-(1-piperidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17&bgr;-diol,
17&agr;-methyl-11&bgr;-4-[2-(diethylamino)ethoxylphenyl]-estra-1,3,5(10)-3,17&bgr;-diol,
17&agr;-methyl-11&bgr;-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17&bgr;-diol,
17&agr;-methyl-11&bgr;-[4-[2-(2-aza-bicyclo(2.2.1)hept-2-yl) ethoxy]phenyl]-estra-1,3,5(10)-triene-3,17&bgr;-diol,
11&bgr;-[4-[2-(2-aza-bicyclo(2.2.1)hept-2-yl) ethoxy]phenyl]-19-nor-17&agr;-pregna-1,3,5(10)-triene-3,17&bgr;-diol,
17&agr;-(trifluoromethyl) 11&bgr;-[4-[2-(1-piperidinyl) ethoxy] phenyl] estra-1,3,5(10)-triene-3,17&bgr;-diol.
A subject of the invention is also a preparation process for compounds of general formula (I) as defined above, characterized in that a compound of general formula (II):
in which n, R
1
and R
2
are as defined previously, is submitted to the action of an organometallic compound containing from 1 to 4 carbon atoms so as to form the compounds of formula (I) in which X is a hydroxyl group and Y is an alkyl group containing from 1 to 4 carbon atoms, and this compound of formula (I) is submitted if necessary to a reaction of esterification of the 17-OH and/or to a reaction of salification.
The action of an organometallic on the 17-keto group provides access to products of formula (I) in which X is a hydroxyl group and Y is an alkyl group containing from 1 to 4 carbon atoms.
The organometallic compound derived from an alkyl radical containing from 1 to 4 carbon atoms is selected from among the magnesium compounds of formula Y—MgHal and the lithium compounds of formula Y—Li in which Y is as defined previously and Hal represents a halogen atom. Preferably the reaction takes place in the presence of cerium chloride. In a preferred manner of carrying out the method, Hal represents an atom of chlorine, bromine or iodine, preferably bromine.
To obtain compounds of formula (I) in which X is an hydroxyl radical and Ya CF
3
group, the reaction is effected by the action of CF
3
SiMe
3
on the 17-keto followed by the action of a deprotection agent such as tetrabutylammonium flouride.
The invention also relates to a method of preparation of compounds of general formula (I) as defined previously, with Y representing an alkyl radical containing from 2 to 4 carbon atoms, characterized in that a compound of general formula (III):
in which n, R
1
and R
2
are as defined previously and in which Y′ represents an alkenyl or alkynyl group containing from 2 to 4 carbon atoms, is submitted to the action of a re
Bouali Yamina
Nique Francois
Teutsch Jean-Georges
Van De Velde Patrick
Bierman, Muserlian and Lucas
Hoechst Marion Roussel
Qazi Sabiha N.
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