Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-05-30
2002-11-12
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S179000, C540S107000, C552S626000
Reexamination Certificate
active
06479476
ABSTRACT:
The present invention concerns 19-nor steroid compounds, substituted in position 11&bgr;, their preparation process and intermediates, their application as medicines and the pharmaceutical compositions containing them.
Osteoporosis is a pathology that is characterised by a quantitative and qualitative reduction of the bone tissue, sufficient to lead to vertebral or peripheral fractures, in a spontaneous manner or with minimum traumatism. Although this ailment is of multifactorial origin, it is the menopause that, in women, constitutes the dominating factor of bone loss or osteopenia.
This osteopenia shows itself by rarefaction and modification of the structure of spongy bone which has the consequence of accentuating skeletal fragility and the risk of fracture. The bone loss strongly accentuates after the menopause because of the suppression of ovarian function and reaches 3 to 5% per year to slow down after the age of 65 years.
In a therapeutic objective, postmenopausal hormonal deficiency can be compensated by hormone replacement therapy where oestrogen plays a major role in preserving the bone reserves. But long term oestrogen therapy is sometimes accompanied by undesirable effects on the genital organs (endometrial hyperplasia, mammary tumours), this constitutes a major drawback and limits its application.
It is thus advisable to find other compounds than oestradiol with a dissociated oestrogen activity, namely oestrogen activity at bone level, whilst having little or no endometrial hyperplasia activity, nor the activity of proliferating mammary tumours.
The invention thus has as its object the compounds of general formula (I):
in which:
R
1
represents a hydrogen atom, a (CH
2
)
m
-Ar, (CO)-Ar, (CH
2
)
m
-Alk or (CO)-Alk radical,
R
2
represents a radical derived from a saturated or unsaturated, linear or branched hydrocarbide containing from 1 to 6 carbon atoms
D represents the residue of a pentagonal or hexagonal ring optionally substituted and optionally unsaturated,
X represents a halogen or hydrogen atom, n is equal to 3, 4 or 5, either identical or different R
3
and R
4
representing a hydrogen atom, a (CH
2
)
m
-AR, (CH
2
)
m
-Het or (CH
2
)
m
-Alk group,
or R
3
and R
4
together with the nitrogen atom to which they are linked form an aromatic or non aromatic, saturated or unsaturated mono or polyclique heterocycle, with 3 to 15 bonds optionally containing from 1 to 3 additional heteroatoms chosen from amongst non substituted or substituted oxygen, sulphur and nitrogen,
Ar representing a carbocyclic aryl group containing from 6 to 18 atoms of carbon, Het representing a saturated or unsaturated aromatic or non aromatic heterocycle, comprising from 1 to 9 carbon atoms and from 1 to 5 heteroatoms chosen from amongst oxygen nitrogen or sulphur atoms, Alk representing a radical derived from a non aromatic, linear, branched or cyclique, saturated or unsaturated hydrocarbide and comprising from 1 to 12 carbon atoms, the Ar radicals Het or Alk can be substituted or non substituted, m represents 0, 1, 2 or 3, as well as their addition salts with the bases or the acids.
By halogen is meant: iodine, bromine, chlorine or fluorine.
By (CH
2
)
m
is meant the following values: single bond in the event that m is equal to 0, CH
2
, (CH
2
)
2
and (CH
2
)
3
.
By the term Ar representing the carbocyclic aryl group containing from 6 to 18 carbon atoms, is meant an aromatic cyclic hydrocarbide derivative such as the phenyl, naphtyl, phenanthrenyl radical or even a condensed bicyclic or tricyclic hydrocarbide derivative comprising a benzene ring like indanyl, indenyl, dihydronaphtyl, tetrahydronaphtyl or fluorenyl. The coupling is made at the benzene ring. It preferably concerns phenyl.
By the term (Het) representing an aromatic or non aromatic, saturated or unsaturated heterocycle, comprising from 1 to 9 carbon atoms and from 1 to 5 heteroatoms chosen from amongst oxygen, nitrogen and sulphur atoms these are notably designated:
Heterocyclic monocyclic radicals, for example thienyl, furyl, pyrannyl, pyrrolyl, imadazoyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazannyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazollinyl, triazolyl, tetrazolyl,
the heterocyclic condensed rings, for example benzofurannyl, benzothienyl, benzimidazoyl, benzothiazolyl, naphto [2,3-b] thienyl, thianthrenyl, isobenzofurannyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phtalazinyl, naphtyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl, imidazopyridyl, imidazopyrimidinyl radicals or even condensed polycyclic systems, made up of monocyclic heterocyclics like those defined above like for example furo[2,3-b]pyrrol or thieno[2,3-b]furan,
or saturated heterocycles such as pyrrolidine, piperidine and morpholine.
By the term (Alk) representing a radical derived from a saturated or unsaturated, branched or cyclic, linear, non aromatic hydrocarbide, are designated, in the case of acyclic hydrocarbides 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-dimethylpentyl, 3-ethylpentyl, n-octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl3-ethylpentyl, nonyl, 2,4-dimethylheptyl or n-decyl, radical alkenyls such as vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl, or 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.
Preferably methyl and ethyl radicals are used.
By CO-Alk is preferably meant COCH
3
and COEt, by CO-Ar is preferably meant the benzoyl radical, when m is different to zero, (CH
2
)
m
-Ar will preferably be the benzyl group.
When R
3
and R
4
together with the nitrogen atom to which they are linked form a heterocycle, they are notably mono or bicyclic heterocycles optionally containing another heteroatom chosen from amongst oxygen and nitrogen such as the following unsaturated heterocycles: pyrrolyl, imidazolyl, indolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazoyl, furazolinyl, pyrazolinyl, thiazolinyl, or more particularly, the following saturated heterocycles:
When the different Alk, Ar, Het groups as well as the residue of a pentagonal or hexagonal ring cited earlier are substituted, they could notably be so by the following radicals: 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 oxidised form, aminoalkyl such as aminoethyl or aminoethyl, dialkylaminoalkyl such as dimethylamino methyl or ethyl, dialkylaminoalkyloxy such as dimethylamino ethyloxy, optionally acylated hydroxyl, acyl such as acetyl, propionyl, butyryl, benzoyl, free carboxy, esterified like 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, amino, alkylamino or dialkylamino radicals indicated above.
Of course, the expression “substituted” indicates that one or several identical or different substitutes, can be present. As an example, when the alkyl group is a methyl radical substituted by one or several halogen atoms, it can notably be CH
2
Cl, CH
2
F, CHF
2
and CF
3
.
In the case of (Het), the substitutes can be at the level of NH or of a carbon atom.
Of course the values of R
1
, R
2
, R
3
, and R
4
Aventis Pharma S.A.
Badio Barbara P.
Bierman, Muserlian and Lucas
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