Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-06-13
2002-11-19
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S176000, C514S178000, C514S182000, C514S175000, C552S558000, C552S540000, C552S569000, C552S586000
Reexamination Certificate
active
06482813
ABSTRACT:
The present invention relates to steroid compounds substituted in position 11, the method of preparation, their application as medicine and pharmaceutical compositions containing them.
Osteoporosis is a pathology that is characterized by a quantitative and qualitative reduction of bone tissue, sufficient to lead to vertebral or peripheral fractures, occurring spontaneously or as a result of minimal trauma. Although this disorder is of multifactorial origin, in women the menopause is the predominant factor in bone loss or osteopenia.
This osteopenia is manifested by rarefaction and alteration of the architecture of the spongy bone which leads to increased fragility of the skeleton and increase in the risk of fractures. Bone loss increases considerably after the menopause owing to the decline in ovarian function and reaches 3 to 5% per year, but then slows down after the age of 65 years.
With a view to therapy, the hormone deficiency after the menopause can be compensated by hormone replacement therapy, in which oestrogen plays a major role by preserving bone mass. In the long term, however, oestrogen therapy is sometimes accompanied by undesirable effects on the genital system (endometrial hyperplasia, mammary tumours etc.), which constitutes a major drawback and limits its application.
It is therefore necessary to find compounds other than oestradiol that possess dissociated oestrogen activity, i.e. oestrogen activity in the bone tissue, yet with little or no activity of endometrial hyperplasia, nor activity of proliferation of mammary tumours.
The invention therefore relates to compounds of general formula (I):
in which:
n is an integer equal to 2 or 3,
either R
1
and R
2
, which may be identical or different, represent a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms,
or R
1
and R
2
form, together with the nitrogen atom to which they are bound, a heterocycle., mono or polycyclic, saturated or unsaturated, of 5 to 15 units, aromatic or non-aromatic, optionally containing from 1 to 3 additional heteroatoms selected from oxygen, sulphur and nitrogen, substituted or unsubstituted,
X represents a hydroxyl radical, optionally esterified, and
Y represents an alkyl radical containing from 1 to 4 carbon atoms, as well as their pharmaceutically acceptable salts of addition with acids.
Alkyl radical containing from 1 to 4 carbon atoms unsubstituted or substituted is taken to mean methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tert-butyl radicals.
when Y is substituted alkyl, it is preferably alkyl substituted with at least one halogen and preferably Y is trifluoro methyl.
When R
1
and R
2
form, together with the nitrogen atom to which they are bound, a heterocycle, this means in particular saturated mono or bicyclic 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 substituted in particular by an alkyl group containing from 1 to 4 carbon atoms on the nitrogen atom.
When X is a bydroxyl radical, optionally esterified, we mean the OCO—alc1 groups in which alc1 is an alkyl radical containing from 1 to 8 carbon atoms and preferably the groups —OCOMe and OCOEt.
By pharmaceutically acceptable salts of addition with acids, we mean salts of addition formed with inorganic or organic acids on the amine. Possible acids are hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic such as methane- or ethane-sulphonic acids, arylsulphonic acids, such as benzene- or paratoluene-sulphonic acids and arylcarboxylic acids.
The invention relates more particularly to the compounds of formula (I) as defined above in which n is equal to 2, as well as their pharmaceutically acceptable salts of addition with acids.
The invention relates more particularly to the compounds of formula (I) as defined above in which:
n is equal to 2,
either R
1
and R
2
, which may be identical or different, represent an alkyl radical containing from 1 to 4 carbon atoms,
or R
1
and R
2
form, together with the nitrogen atom to which they are bound, 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.
The invention relates quite particularly to compounds of formula (I) as well as their pharmaceutically acceptable salts of addition with acids, with the following names:
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]-oestra-1,3,5(10)-triene-3,17&bgr;-diol,
17&agr;-methyl-11-[4-[2-(diethylamino)ethoxy]phenyl]-oestra-1,3,5(10)-3,17&bgr;-diol,
17&agr;-methyl-11&bgr;-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-oestra-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]-oestra -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]oestra-1,3,5(10)-triene-3,17&bgr;-diol.
The invention also relates to a method of preparation of the compounds of general formula (I) as defined previously, 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 reducing agent of the double bond or of the triple bond, so as to obtain compounds of formula (I) in which X is a hydroxyl group And Y is an alkyl group containing from 1 to 4 carbon atoms, this compound of formula (I) being submitted if necessary to a reaction of esterification of the 17-OH, and/or to a reaction of salification.
The reaction of complete reduction can be carried out 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.
The reactions of esterification and salification a
Bouali Yamina
Nique Francois
Teutsch Jean-Georges
Van De Velde Patrick
Aventis Pharma S.A.
Bierman, Muserlian and Lucas
Qazi Sabiha
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