Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2001-12-17
2002-12-31
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S169000, C514S172000, C514S177000, C540S107000, C540S108000, C552S516000, C552S517000, C552S518000
Reexamination Certificate
active
06500815
ABSTRACT:
This application is a 371 of PCT/FR00/00426 filed Feb. 21, 2000.
The present invention relates to new steroid derivatives, their preparation process and the intermediates of this process, their use as medicaments and the pharmaceutical compositions containing them.
A subject of the present invention is the compounds of general formula (I):
in which:
either X and Y form together with the carbon which carries them a C═O or C═CH
2
group,
or X represents a hydroxy, (C
1
-C
6
)-alkyloxy, (C
1
-C
6
)-alkylcarbonyloxy radical and Y is a hydrogen atom,
R
1
represents a hydroxy, (C
1
-C
6
)-alkyloxy, amino, (C
1
-C
6
)-alkylamino or (C
2
-C
12
)-dialkylamino radical,
R
2
represents a hydrogen or halogen atom,
Z represents a hydrogen atom, an NHSO
2
Ra, NHCO
2
Ra, NHCORa, NHSO
2
NHRa or NHCONHRa group,
G represents:
either an N
radical (G1 radical) in which (H) forms with the —N═C—NH— unit the remainder of a heterocycle,
or an NRbRc radical (G2 radical),
or a heterocycle (G3 radical),
or an NRb—C(═A)—NHRc radical (G4 radical) in which A is a sulphur, oxygen or NH atom,
or an NRb—SO
2
Rc radical (G5 radical),
Ra, Rb and Rc, identical or different, represent a hydrogen atom, a —(CH
2
)
m
-Alk or —(CH
2
)
m
—Ar radical,
the term Alk representing a radical derived from a linear branched or cyclic, saturated or unsaturated, non-aromatic hydrocarbon, containing from 1 to 12 carbon atoms, substituted by R
3
or non-substituted, Ar representing a carbocyclic aryl substituted by R
3
or non-substituted,
n is an integer varying from 1 to 6, m represents 0, 1, 2 or 3,
the substituent R
3
represents:
halogen, oxo, cyano, nitro, formyl, carboxy, (C
1
-C
6
)-alkyloxycarbonyl, carboxamide,
an alkyl, alkenyl, alkynyl radical or containing from 1 to 6 atoms optionally substituted by one or more halogen atoms,
a cycloalkyl radical containing from 3 to 12 carbon atoms,
an alkoxy or alkylthio radical containing from 1 to 6 carbon atoms
an amino, alkylamino radical containing from 1 to 6 atoms carbon atoms,
an amino, alkylamino containing from 1 to 6 carbon atoms dialkylamino radical containing from 2 to 12 carbon atoms optionally in oxidized form,
an aminoalkyl containing from 1 to 6 carbon atoms or dialkylaminoalkyl radical containing from 3 to 8 carbon atoms,
a dialkylaminoalkyloxy radical containing from 3 to 18 carbon atoms,
an optionally acylated hydroxy radical containing from 1 to 12 carbon atoms,
an acyl radical containing from 1 to 12 carbon atoms optionally substituted for example by a chlorine, iodine or fluorine atom,
an aryl, carbocyclic or heterocyclic, aralkyl or aryloxy radical, these radicals being themselves optionally substituted by one or more substituents mentioned above,
said compounds of formula (I) being in all their possible isomer forms, isolated or in a mixture, as well as their esters and their addition salts with pharmaceutically acceptable acids and bases.
By the term Alk or alkyl containing from 1 to 12 carbon atoms, is designated in the case of acyclic hydrocarbons 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, alkenyl radicals such as vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl, or alkynyl radicals such as ethynyl, propynyl, propargyl, butylyl or isobutynyl, and in the case of cyclic radicals, cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl radicals. Alkyl radicals containing from 1 to 6 carbon atoms and more particularly methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tertbutyl are preferably meant.
By aryl, is meant a carbocyclic aryl group containing from 6 to 14 carbon atoms, is meant a radical derived from an aromatic cyclic hydrocarbon such as phenyl, naphthyl, phenanthrenyl radical or a radical derived from a condensed bicyclic or tricyclic hydrocarbon comprising a benzene ring such as indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl or fluorenyl. The junction occurs at the level of the benzene ring. It is preferably phenyl. By aralkyl, benzyl is preferably meant. By aryloxy phenyloxy is preferably meant.
By heterocycle, is meant an aromatic (heteroaryl) or non-aromatic heterocycle, saturated or non-saturated, comprising 1 to 9 carbon atoms and from 1 to 5 heteroatoms chosen from oxygen, nitrogen and sulphur atoms, the following are in particular designated:
heterocyclic monocyclic radicals, for example thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazannyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl radicals,
heterocyclic condensed rings, for example benzofurannyl, benzothienyl, benzymidazolyl, benzothiazolyl, naphtho[2,3-b]thienyl, thianthrenyl, isobenzofurannyl, 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 monocyclics as defined above such as for example furo[2,3-b]pyrrole or thieno[2,3-b]furan,
or saturated heterocycles such as pyrrolidine, piperidine or morpholine.
When G is the G1 radical, G1 in particular represents one of the following heterocycles:
in which p represents an integer from 1 to 4 and preferably 2 or 3.
When G is the G2 radical, G2 can in particular be an amino, alkylamino such as —NHMe, —NHEt, dialkylamino such as —NMe
2
, —NEt
2
, —NMeEt, —NHPh, —NHCH
2
Ph or —NHCH
2
-pyrrol-2-yl group.
When G is the G4 or G5 radical, it is in particular the —NH—C(═NH)—NH
2
, —NH—CO—NHCH
2
Ph, —NHCONH
2
, —NH—CS—NH
2
, —NH—C(═NH)—NHCH
2
Ph, —NH—C(═NH)—NHCH
3
or —NHSO
2
Ph groups.
When R
1
represents alkyloxy or alkylamino it is in particular the following groups:
—OMe, —OEt, —O—(CH
2
)
2
—OH, —O—CH
2
—CH(CH)—CH
2
OH, —O—(CH
2
)
2
—NH
2
, —O—(CH
2
)
2
—NMe
2
or —OCH
2
Ph.
The optional R
3
substituents of the alkyl, aryl or heterocycle groups, as defined previously are chosen from the following radicals:
halogen: fluorine, chlorine, bromine, iodine,
alkyl, alkenyl, alkynyl containing from 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, vinyl or allenyl. These radicals being themselves optionally substituted by one or more halogen atoms, for example fluorine such as trifluoromethyl,
cycloalkyl containing from 3 to 12 carbon atoms such as cyclohexyl or adamantyl,
oxo, cyano, nitro, formyl, carboxy and carboxyalkyl containing from 1 to 6 carbon atoms, carboxamide,
alkoxy containing from 1 to 6 carbon atoms such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy,
alkylthio containing from 1 to 6 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio,
amino, alkylamino containing from 1 to 6 carbon atoms such as methylamino or ethylamino, dialkylamino containing from 2 to 12 carbon atoms such as dimethylamino, diethylamino, methylethylamino, each of these dialkylamino radicals being optionally in oxidized form,
aminoalkyl containing from 1 to 6 carbon atoms such as aminomethyl or aminoethyl,
dialkylaminoalkyl containing from 3 to 18 carbon atoms such as dimethylamino methyl or ethyl,
dialkylaminoalkyloxy containing from 3 to 18 carbon atoms such as dimethylaminoethyloxy,
optionally acylated hydroxyl containing from 1 to 12 carbon atoms, for example acetoxy,
acyl containing from 1 to 12 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, succinyl, pivaloyl benzoyl optionally substituted for example by a chlorine, iodine or fluorin
Bodary Sarah C.
Carniato Denis
Gadek Thomas R.
Gourvest Jean-Francois
Knolle Jochen
Aventis Pharma S.A.
Badio Barbara P.
Bierman, Muserlian and Lucas
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