Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
2000-06-09
2001-05-08
Badio, Barbara P. (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
C540S470000
Reexamination Certificate
active
06229029
ABSTRACT:
This application is a 371 of PCT/EP98/03243 filed Jun. 2, 1998.
This invention relates to 11&bgr;-aryl-substituted 14,17-ethanoestratrienes of general formula I
in which
R
1
stands for a hydrogen atom, a C
1
-C
12
alkanoyl group, a benzoyl group, a straight-chain or branched-chain C
1
-C
12
alkyl group, a C
3
-C
7
cycloalkyl group or a C
4
-C
8
alkylcycloalkyl group, which all can optionally be substituted,
R
2
stands for a hydrogen atom or an optionally substituted C
1
-C
12
alkanoyl group and
R
3
stands for a grouping —(CH
2
)
n
NR
4
R
5
or —(CH
2
)
n
OCH
2
CONR
4
R
5
or —(CH
2
)
n
S(O)
m
R
6
, in which
n is 4, 5, 6 or 7,
m is 0, 1 or 2,
R
4
or R
5
, independently of one another, mean a hydrogen atom or a straight-chain or branched, optionally substituted C
1
-C
8
alkyl group, which can also be partially or completely fluorinated, or
R
4
and R
5
together mean a methylene to pentamethylene group —(CH
2
)
p
— (p=1-5), and
R
6
has the meaning of R
4
or R
5
or is an optionally substituted aryl or arylalkyl radical, whereby the alkyl radical can have up to 6 carbon atoms in it and the aryl radical alone or in the arylalkyl radical is a 5- or 6-membered monocyclic ring or a condensed 8- to 10-membered ring system, and the aryl radical can have one or more heteroatoms that are selected from among oxygen, nitrogen and sulfur.
Alkyl groups that are mentioned within the scope of this invention as R
4
and R
5
are, for example, the methyl, ethyl, n- or iso-propyl, n-, iso- or tert-butyl, pentyl, neo-pentyl, hexyl, heptyl or octyl group.
In the C
1
-C
12
alkyl group R
1
the higher homologues such as, for example, the nonyl to dodecyl group, are added.
As a C
3
-C
7
cycloalkyl group, for example, the cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl radical can be mentioned.
Typical representatives of a C
4
-C
8
alkylcycloalkyl group are the methylcyclopropyl radical, the methylcyclopentyl radical and the methylcyclohexyl radical.
A C
1
-C
12
alkanoyl radical, which can stand for R
1
and/or R
2
, is defined as the acyl radicals of the straight-chain and branched C
1
-C
12
alkanecarboxylic acids, thus, for example, the formyl, acetyl, propionyl, butyryl or isobutyl radical, as well as the higher homologues of the radicals mentioned above.
As a partially or completely fluorinated straight-chain or branched C
1
-C
8
alkyl group, for example, the trifluoromethyl group, 2,2,2-trifluoroethyl group, 4,4,4-trifluorobutyl group, 3,3,4,4,4-pentafluorobutyl group, 4,4,5,5,5-pentafluoropentyl group or the nonafluorobutyl group is to be mentioned.
The following radicals can represent aryl radical R
6
or the aryl radical within arylalkyl radical R
6
:
a monocyclic, carbocyclic radical, for example the phenyl radical;
a monocyclic, heterocyclic radical, for example the thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl radical, namely all possible isomers relative to the positions of the heteroatoms as. well as the interface site to the sulfur atom in the side chain;
a condensed, carbocyclic radical, for example the naphthyl or phenanthrenyl radical,
a condensed radical, which consists of carbocyclic and heterocyclic radicals, for example, the benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, naphtho[2,3-b]thienyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoathiinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, &bgr;-carbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl, imidazopyridyl, imidazopyrimidinyl or a condensed polyheterocyclic system, for example furo[2,3-b]pyrrole or thieno[2,3-b]furan.
As substituents to radicals R
1
, R
2
, R
4
, R
5
and R
6
, the substituents below are considered, whereby the radicals can be substituted with these substituents the same or different in one or more places:
Halogen atoms: fluorine, chlorine, bromine, iodine;
Amino, alkylamino or dialkylamino groups, in which the alkyl radical has 1 to 4 carbon atoms; especially methylamino or ethylamino, dimethylamino, diethylamino or methylethylamino;
Hydroxyl groups;
Carboxyl groups that are present in free form, esterified form or in the form of a salt; esterified with a carboxycarbonyl group, for example methoxycarbonyl or ethoxycarbonyl; as a salt for example in the form of the sodium or potassium salt;
Alkyl groups with 1 to 8 carbon atoms, such as, for example, the methyl, ethyl, n- or iso-propyl, n-, iso- or tert-butyl group, optionally substituted with one or more halogen atoms, for example with fluorine such as the trifluoromethyl group;
Oxo, cyano, nitro or formyl groups;
Acyl groups such as acetyl, propionyl, butyryl, benzoyl;
Acyloxy groups such as acetoxy, radicals of formula —O—CO—(CH
2
)
n
—COOH with n=1 to 5;
Alkoxy groups, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy;
Alkylthio groups, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio;
Carbamoyl groups;
Alkenyl groups, for example vinyl, propenyl;
Alkinyl groups, for example ethinyl, propinyl;
Aryl groups, such as phenyl, furyl, thienyl.
R
1
and R
2
respectively stand preferably for a hydrogen atom.
If R
1
and/or R
2
is to be an alkyl group, a methyl or ethyl group is preferred.
If R
1
and/or R
2
stands for an alkanoyl group, primarily an acetyl or propionyl group is meant. A benzoyl group is also part of the preferred representatives of these substituents.
As a cycloalkyl group for substituents R
1
and R
2
, mainly the cyclopropyl and cyclopentyl groups are to be mentioned, and as an alkycycloalkyl group, the methylcyclopropyl and methylcyclopentyl groups are to be mentioned.
Within the groupings that stand for R
3
, the substituents hydrogen, methyl, ethyl, propyl, butyl, 4,4,5,5,5-pentafluoropentyl and mainly the substituent combinations of 2 hydrogen atoms, n-butyl/methyl, —(CH
2
)
4
—, and —(CH
2
)
5
— are preferred for R
4
and R
5
.
R
6
preferably stands for an n-pentyl, 4,4,5,5,5-pentafluoropentyl or —CH
2
-2, 3- or 4-pyridine group.
In particular, R
3
stands for one of the following substituents:
—(CH
2
)
5
S(CH
2
)
4
CH
3
—(CH
2
)
5
SO(CH
2
)
4
CH
3
—(CH
2
)
5
SO
2
(CH
2
)
4
CH
3
—(CH
2
)
5
SO(CH
2
)
3
CF
2
CF
3
—(CH
2
)
5
SO
2
—CH
2
-(2-pyridyl)
—(CH
2
)
5
SO
2
—CH
2
-(3-pyridyl)
—(CH
2
)
5
SO
2
—CH
2
-(4-pyridyl)
—(CH
2
)
6
—O—CH
2
C(O)N(CH
3
)C
4
H
9
—(CH
2
)
5
SO
2
(CH
2
)
3
CF
2
CF
3
—(CH
2
)
5
SO—CH
2
-(2-pyridyl)
—(CH
2
)
5
SO—CH
2
-(3-pyridyl)
—(CH
2
)
5
SO—CH
2
-(4-pyridyl)
—(CH
2
)
5
-pyrrolidinyl
—(CH
2
)
6
S(CH
2
)
3
CF
2
CF
3
—(CH
2
)
6
SO(CH
2
)
3
CF
2
CF
3
—(CH
2
)
6
SO(CH
2
)
3
CF
2
CF
3
—(CH
2
)
6
SO
2
(CH
2
)
3
CF
2
CF
3
For the purposes of the invention, especially preferred compounds are:
14&agr;,17&agr;-Ethano-11&bgr;-{4-[5-(pyrrolidin-1-yl)pentyloxy]phenyl}-1,3,5(10)-estratriene-3,17&bgr;-diol
14&agr;,17&agr;-ethano-11&bgr;-{4-[5-(pentylthio)pentyloxy]phenyl}-1,3,5(10)-estratriene-3,17&bgr;-diol
14&agr;,17&agr;-ethano-11&bgr;-{4-[5-(pentanesulfinyl)pentyloxy]phenyl}-1,3,5(10)-estratriene-3,17&bgr;-diol
14&agr;,17&agr;-ethano-11&bgr;-{4-[5-(pentanesulfonyl)pentyloxy]-phenyl}-1,3,5(10)-estratriene-3,17&bgr;-diol
14&agr;,17&agr;-ethano-11&bgr;-{4-[5-(4,4,5,5,5-pentafluoropentylsulfinyl)pentyloxy]phenyl}-1,3,5(10)-estratriene-3,17&bgr;-diol
14&agr;,17&agr;-ethano-11&bgr;-{4-[5-(2-pyridinomethylsulfonyl)pentyloxy]phenyl}-1,3,5(10)-estratriene-3,17&bgr;-diol
14&agr;,17&agr;-ethano-11&bgr;-{4-[6-(4,4,5,5,5-pentafluoropentylthio)hexyloxy]-phenyl}-1,3,5(10)-estratriene-3,17&bgr;-diol
14&agr;,17&agr;-ethano-11&bgr;-{4-[6-(4,4,5,5,5-pentafluoropentyl)sulfinyl]hexyloxy}phenyl-1,3,5(10)-e
Bohlmann Rolf
Fritzemeier Karl Heinrich
Hegele-Hartung Christa
Knauthe Rudolf
Parzcyk Karsten
Badio Barbara P.
Millen White Zelano & Branigan
Schering Aktiengesellschaft
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