Antiestrogens, process for their protection and their...

Details Antiestrogens, process for their protection and their... Antiestrogens, process for their protection and their...

2000-11-07

2003-05-06

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S724000, C514S718000, C514S727000, C514S708000, C514S709000

Reexamination Certificate

active

06559181

ABSTRACT:

SUMMARY OF THE INVENTION
This invention relates to 3,4-diphenyl-bicyclo[4.3.0]nonyl derivatives of general formula I
in which
R
1
stands for optionally substituted C
1
-C
20
alkanoyl, optionally substituted C
1
-C
20
alkyl, optionally substituted C
7
-C
20
aralkyl, optionally substituted C
7
-C
15
aroyl, a group PG
1
or a hydrogen atom,
R
2
stands for optionally substituted C
1
-C
20
alkanoyl, optionally substituted C
1
-C
20
alkyl, optionally substituted C
7
-C
20
aralkyl, optionally substituted C
7
-C
15
aroyl, a group PG
2
or a hydrogen atom,
PG
1
, PG
2
are the same or different and stand for a protective group PG,
A′—A—D—D′ stands for a —CH
2
—C(OH)—C═CH—, —CH═C—C(OH)—CH
2
—, —CH═C—C═CH—, —CH
2
—C═C—CH
2
—, —CH
2
—C(OH)—CH—CH
2
—, —CH
2
—CH—C(OH)—CH
2
—, —CH
2
—C(OH)—C(OH)—CH
2
— or
 group (hydroxy=&agr; or &bgr;; epoxy=&agr; or &bgr;),
X stands for a bond, an oxygen atom, a sulfur atom, SO or SO
2
,
E stands for a straight-chain or branched-chain alkylene, alkenylene or alkynylene group with up to 15 carbon atoms,
Y stands for halogen (F, Cl, Br, I), for a substituent R
4
, an optionally substituted aryl or heteroaryl radical, an NR
4a
R
4b
—, SO
2
NR
4a
R
4b
—, NR
4a
(CH
2
)
p
—Q—G—, NR
5
(CHR
6
—CHR
7
)—(CH
2
)
t
—Q—G—, SO
2
NR
4a
(CH
2
)
p
—Q—G, an O—G, S—G, SO—G, SO—G—, SO
2
—G group,
R
4
stands for a hydrogen atom, optionally substituted C
1
-C
20
alkyl, partially or completely fluorinated C
1
-C
20
alkyl, optionally substituted C
1
-C
20
alkanoyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C
7
-C
20
aralkyl, optionally substituted C
7
-C
15
aroyl,
Q stands for an oxygen atom, a sulfur atom, SO or SO
2
G stands for —(CH
2
)
n
—R
3
,
n stands for 0 to 10,
p stands for 1 to 10,
t stands for 0, 1 or 2
R
3
stands for hydrogen, a straight-chain or branched-chain alkyl, alkenyl or alkynyl group with up to 10 carbon atoms, a straight-chain or branched-chain, partially or completely fluorinated alkyl or alkenyl group with up to 10 carbon atoms, an optionally substituted C
4
-C
8
cycloalkyl group, an optionally substituted aryl group, an optionally substituted C
7
-C
20
aralkyl group or,
if n>0, also for a hydroxy group or a halogen atom,
R
4a
, R
4b
are the same or different in the meaning of R
4
or together stand for a C
3
-C
15
alkylene group, which can be straight-chain or branched,
R
5
means a hydrogen atom or a C
1-5
alkyl group,
R
6
and R
7
each mean a hydrogen atom, or
R
5
and R
6
together mean an alkylene group —(CH
2
)
d
— with d=2, 3, 4 or 5 and R
7
is a hydrogen atom or
R
5
and R
7
together mean an alkylene group —(CH
2
)
e
— with e=2, 3 or 4 and R
6
means a hydrogen atom,
Z stands for hydrogen, halogen, OH, N
3
, NH
2
, CO
2
H, CO
2
—(C
1
-C
20
)-alkyl, C
1
-C
20
alkoxy, —NO
2
, —CN or C
1
-C
20
acyloxy.
As used throughout this application (e.g., with respect to Y, R
4
or R
5
groups as defined above), the term heteroaryl means, e.g., a C
1
-C
10
ring which optionally contains one or more (e.g., 1-3) N, S or O atoms in place of C. Also, as used throughout (e.g., with respect to substituents E, R
3
, R
4a
or R
5
as defined above)i an alkenyene or alkynylene typically contains 1-3 unsaturated bonds.
The invention relates to the diastereomers and/or enantiomers of these derivatives and also their mixtures.
As alkyl groups R
1
, R
2
, R
3
and R
4
, straight-chain or branched-chain alkyl groups with up to 20 carbon atoms can be considered, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl and decyl.
Alkyl groups R
1
, R
2
, R
3
and R
4
can be fluorinated partially or completely or substituted by 1-10 halogen atoms, hydroxy groups, C
1
-C
4
alkoxy groups, C
6
-C
12
aryl groups, which can be substituted by 1-3 halogen atoms, di-(C
1
-C
4
)-alkylamines and tri-(C
1
-C
4
)-alkylammonium.
A straight-chain or branched-chain, partially or completely fluorinated alkyl group is preferably the trifluoromethyl or pentafluoroethyl group.
As cycloalkyl groups R
3
, substituted and unsubstituted radicals with 4 to 8 carbon atoms are considered.
As aryl radicals R
3
and R
4
, substituted and unsubstituted carbocyclic or heterocyclic radicals, such as, e.g., phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, which can be substituted several times by halogen, OH, C
1
-C
20
alkoxy, CO
2
H, CO
2
alkyl, —NO
2
, —N
3
, —CN, C
1
-C
20
alkyl, C
1
-C
20
acyl, C
1
-C
20
acyloxy groups and defined groups are suitable. As used throughout this application, acyl can be, e.g., alkanoyl.
The alkanoyl groups that are contained in R
1
, R
2
and R
4
of general formula I are to contain 1 to 20 carbon atoms in each case, whereby formyl, acetyl, propionyl and isopropionyl groups are preferred.
The aralkyl groups in R
1
, R
2
, R
3
and R
4
can contain in the ring up to 14 C atoms, preferably 6 to 10 C atoms, and in the alkyl chain 1 to 8, preferably 1 to 4 atoms. As aralkyl radicals, for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, and pyridylpropyl are considered. The rings can be substituted in one or more places by halogen, OH, O-alkyl, CO
2
H, CO
2
alkyl, —NO
2
, —N
3
, —CN, C
1
-C
20
alkyl, C
1
-C
20
acyl, C
1
-C
20
acyloxy groups.
As aroyl radicals for R
1
, R
2
and R
4
, benzoates and benzoates that are substituted in the phenyl radical are to be preferred.
Free hydroxy groups in l can be modified functionally, for example by etherification or esterification; free hydroxy groups are preferred, however.
As ether, acyl radicals and protective group PG, the radicals that are known to one skilled in the art, such as, e.g., methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl-, tert-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl, methyl, tert-butyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, formyl, acetyl, propionyl, isopropionyl, butyryl, pivalyl, and benzoyl radicals are suitable. A survey is found in, e.g., “Protective Groups in Organic Synthesis,” Theodora W. Green, John Wiley and Sons).
As specific side chains, in which X stands for an oxygen atom, there can be mentioned
—O—(CH
2
)
5
S(CH
2
)
3
C
2
F
5
—O—(CH
2
)
5
SO(CH
2
)
3
C
2
F
5
—O—(CH
2
)
5
SO
2
(CH
2
)
3
C
2
F
5
—O—(CH
2
)
4
S(CH
2
)
3
C
2
F
5
—O—(CH
2
)
4
SO(CH
2
)
3
C
2
F
5
—O—(CH
2
)
4
SO
2
(CH
2
)
3
C
2
F
5
—O—(CH
2
)
5
—Cl
—O—(CH
2
)
4
—Cl
—O—(CH
2
)
3
—Cl
—O—(CH
2
)
2
—Cl
—O—(CH
2
)
2
—N(CH
3
)
2
—O—(CH
2
)
2
-1-Pyrrolidinyl
As side chains in which X stands for a direct bond, for example, the following are considered (DE 1 98 06 357.1)
—(CH
2
)
5
N(CH
3
)(CH
2
)
3
C
2
F
5
—(CH
2
)
5
N(CH
3
)(CH
2
)
6
C
2
F
5
—(CH
2
)
5
N(CH
3
)(CH
2
)
7
C
2
F
5
—(CH
2
)
5
N(CH
3
)(CH
2
)
8
C
2
F
5
—(CH
2
)
6
N(CH
3
)(CH
2
)
6
C
2
F
5
—(CH
2
)
6
N(CH
3
)(CH
2
)
7
C
2
F
5
—(CH
2
)
6
N(CH
3
)(CH
2
)
8
C
2
F
5
—(CH
2
)
5
N(CH
3
)(CH
2
)
2
C
4
F
9
—(CH
2
)
5
N(CH
3
)(CH
2
)
3
C
6
F
13
—(CH
2
)
5
N(CH
3
)(CH
2
)
3
C
8
F
17
—(CH
2
)
5
N(CH
3
)(CH
2
)
6
C
4
F
9
—(CH
2
)
5
N(CH
3
)(CH
2
)
6
C
6
F
13
—(CH
2
)
5
N(CH
3
)(CH
2
)
6
C
8
F
17
—(CH
2
)
5
N(CH
3
)H
—(CH
2
)
5
N(H
3
)(CH
2
)
9
H
—(CH
2
)
5
-1-Pyrrolidinyl
—(CH
2
)
5
N(CH
3
)(CH
2
)
3
OPhenyl
—(CH
2
)
5
N(CH
3
)(CH
2
)
3
OBenzyl
—(CH
2
)
5
N(CH
3
)(CH
2
)
3
O(CH
2
)
3
C
2
F
5
—(CH
2
)
9
S(CH
2
)
3
C
2
F
5
—(CH
2
)
9
SO
2
(CH
2
)
3
C
2
F
5
or
—(CH
2
)
9
SO
2
(CH
2
)
3
C
2
F
5
.
In addition, the side chains of general partial formula
(WO 98/07740)
can also be considered,
wherein
a is 4, 5 or 6,
b is 0, 1 or 2,
c is 0, 1 or 2,
R
5
is a hydrogen atom or a C
1-5
alkyl group,
R
6
and R
7
are each a hydrogen atom, or
R
5
and R
6
together are an alkylene group —(CH
2
)
d
— with d=2, 3, 4 or 5, and R
7
is a hydrogen atom or
R
5
and R
7
together are an alkylene group —(CH
2
)
e
— with e=2, 3 or 4, and R
6
i

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